0469 PDF

Photochemistry
Volume 46
A Specialist Periodical Report
Photochemistry
Volume 46
Editors
Angelo Albini, University of Pavia, Italy
Stefano Protti, University of Pavia, Italy
Authors
Manabu Abe, Hiroshima University, Japan
Emilio I. Alarcon, University of Ottawa, Canada
Alessandro Aliprandi, University of Strasbourg & CNRS, France
Christophe Bour, Paris-Sud University, France
Youhei Chitose, Hiroshima University, Japan
Luisa De Cola, University of Strasbourg & CNRS, France and Karlsruhe
Institute of Technology, Germany
Brian N. DiMarco, University of Strasbourg & CNRS, France
Bo-Wen Ding, Beijing Normal University, China
Filippo Doria, University of Pavia, Italy
Pooria Farahani, KTH Royal Institute of Technology, Sweden
Antonio Francés-Monerris, University of Lorraine & CNRS, France
Angelo Giussani, University College London, UK
Andreas Herrmann, Firmenich SA, Switzerland
M. Consuelo Jiménez, Technical University of Valencia, Spain
Irene E. Kochevar, Massachusetts General Hospital and Harvard Medical
School, USA
Benjamin Lipp, University of Mainz, Germany
Ya-Jun Liu, Beijing Normal University, China
Géraldine Masson, Paris-Sud University, France
Christopher McTiernan, University of Ottawa, Canada
Miguel A. Miranda, Technical University of Valencia, Spain
Kazuhiko Mizuno, Nara Institute of Science and Technology, Japan
Antonio Monari, University of Lorraine & CNRS, France
Miriam Navarrete-Miguel, University of Valencia, Spain
Till Opatz, University of Mainz, Germany
Loı̈c Pantaine, Paris-Sud University, France
Valentina Pirota, University of Pavia, Italy
Barbara Procacci, University of York, UK
Justina Pupkaite, University of Ottawa, Canada
Carlotta Raviola, University of Pavia, Italy
Daniel Roca-Sanjuán, University of Valencia, Spain
Javier Segarra-Martı́, Imperial College London, UK
Evan M. Sherbrook, University of Wisconsin–Madison, USA
Erik J. Suuronen, University of Ottawa, Canada
Takashi Tsuno, Nihon University, Japan
Tehshik P. Yoon, University of Wisconsin–Madison, USA
Michela Zuffo, University of Pavia, Italy
ISBN: 978-1-78801-336-9
PDF ISBN: 978-1-78801-359-8
EPUB ISBN: 978-1-78801-559-2
ISSN: 0556-3860
DOI: 10.1039/9781788013598
A catalogue record for this book is available from the British Library
r The Royal Society of Chemistry 2019
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Preface
DOI: 10.1039/9781788013598-FP007
Volume 46 follows the pattern of previous titles from Volume 39 onwards,

which combines a review on the latest advancements in photochemistry
(every other year on a part of this discipline) and highlights some topics.
We thank the reviewers, who maintained their thorough work once again,
as well as the contributors of highlights. We thank Professor Elisa Fasani,
who after several years has left the editorial team.
As usual, it has been a tough job to complete all the contributions
(almost) within the planned deadlines. However, hard work as it may
have been, having the opportunity of seeing such a large wealth of
photochemical experience has been a really nice experience.
We thank the staff working on Specialist Periodical Reports (Janet,
Robin and Katie), the Royal Society of Chemistry, our colleagues of the
PhotoGreen Lab at the University of Pavia, and the young researchers in
our lab, who make photochemistry such an entertaining experience every
day. Finally, we are grateful to Dr Daria Manganaro, who supplied the
original artwork for this volume.
Angelo Albini and Stefano Protti
Photochemistry, 2019, 46, vii–vii | vii

c The Royal Society of Chemistry 2019
Author biographies
DOI: 10.1039/9781788013598-FP008
Manabu Abe was born in Sakai City, Osaka

Prefecture, Japan. He received his PhD
from the Kyoto Institute of Technology (KIT),
Professor Akira Oku, in 1995, studying
the oxidative ring-opening reaction of
cyclopropanoneacetals and its application
to organic synthesis. In 1995, he became a
faculty staff at Osaka University (HANDAI,
Prof. Masatomo Nojima’s group). From 1997
to 1998, he was an Alexander-von-Humboldt
(AvH) fellow with Professor Dr Waldemar
Adam at the Universität Würzburg in
Germany. He was also a visiting researcher
at the LMU München (Professor Dr Herbert Mayr) in 2007. He moved
to Hiroshima and became a Full Professor in Organic Chemistry at the
Department of Chemistry, Graduate School of Science, Hiroshima
University (HIRODAI) in 2007. His research focuses on reactive inter-
mediates chemistry, especially diradicals; organic photochemistry; and
unusual molecules.
Emilio I. Alarcon is a principal investigator

at the University of Ottawa Heart Institute in
Ottawa and an Assistant Professor at the
Department of Biochemistry, Microbiology,
and Immunology at University of Ottawa.
He received his PhD in Chemistry in 2009
from Pontificia Universidad Catolica de
Chile and moved to work at the University of
Ottawa under the supervision of Professor
Scaiano. Dr Alarcon’s research seeks the
development of novel biomaterials for
treating diverse organs including cornea,
skin, and heart tissue. His research has
allowed the rational integration of light-triggered photo-bonding
mechanism in the fabrication of novel regenerative platforms.
viii | Photochemistry, 2019, 46, viii–xxiii

Angelo Albini is currently Emeritus Professor
of Organic Chemistry at the University of
Pavia, Italy. A native of Milan, he completed
his studies in Chemistry at Pavia in
1972. After postdoctoral work at the Max-
Plank Institute for Radiation Chemistry in
Muelheim, Germany (1973–1974), he joined
the Faculty at Pavia in 1975 as an assistant
and then associate (since 1981) professor. He
accepted a Chair of Organic Chemistry at the
University of Torino in 1990 and then moved
again to Pavia in 1993. He has been Visiting
Professor at the Universities of Western
Ontario (Canada, 1977–78) and Odense (Denmark, 1983). He is coauthor/
editor of five books (among the others, Heterocyclic N-Oxides, CRC,
Orlando, 1990; Drugs: Photochemistry and Photostability, RSC, Cambridge,
1998; Handbook of Preparative Photochemistry, Wiley-VCH, 2009), the senior
reporter of the Specialist Periodic Reports on Photochemistry since 2008,
as well as coauthor of several reviews and research articles.
Alessandro Aliprandi received his PhD in

Chemistry from the University of Strasbourg
at the Institut de Science et d’Ingénierie
Supramoléculaires (I.S.I.S.) in 2015 under the
supervision of Prof. Luisa De Cola. His thesis
was awarded with the ‘‘Prix de these’’ de la
Fondation Université de Strasbourg in 2016.
Then he carried out postodoctoral research in
the group of Prof. Paolo Samorı̀ in the same
institute. From 2018 He is Ingénieur de Re-
cherche (CNRS) in the group of Prof. Luisa De
Cola. His research focuses on self-assembling
of (electro)-luminescent transition-metal
complexes as well as 2D materials for electronic applications.
Christophe Bour received his MSc in organic

chemistry from University of Strasbourg
where he completed his PhD in 2006 under
the supervision of Dr Jean Suffert. He then
joined the research group of Prof. Antonio
Echavarren in Tarragona (Spain) as a post-
doctoral fellow. In early 2009, he moved to
the ECPM at the University of Strasbourg
to work with Dr G. Hanquet. In September
2010, he was appointed assistant professor
at University of Paris-Sud in the group of
Prof. V. Gandon. In 2015 he received his
HDR diploma and his scientific interests
include catalysis, and new synthetic methodologies.
Photochemistry, 2019, 46, viii–xxiii | ix

Youhei Chitose received his BA in 2016 and
his MA in 2018, both from Hiroshima
University. He is a PhD candidate under the
supervision of Professor Manabu Abe at
the Graduate School of Science, Department
of Chemistry, Hiroshima University.
Luisa De Cola is, since September 2013,

Professor at the University of Strasbourg
(ISIS) and part time scientist at the INT-KIT,
Karlsruhe, Germany. She was born in
Messina, Italy, where she studied chemistry.
After a post-doc in the USA she was
appointed Assistant Professor at the
University of Bologna (1990). In 1998 she
was appointed Full Professor at the
University of Amsterdam, The Netherlands.
In 2004 she moved to the University of
Muenster, Germany. She is the recipient of
several awards, the most recent being the
IUPAC award (2011), the International Prize for Chemistry ‘‘L. Tartufari’’
and the Catalan – Sabatier prize (2015). She is a member of the German
National Academy of Sciences Leopoldina and in 2014 she was Nom-
inated ‘‘Chevalier de la Légion d’ Honneur’’ She has published more than
350 papers and filed 36 patents (H-index ¼ 67).
Brian N. DiMarco was born in Stamford,

Connecticut in 1988. He received his BS in
Biology and Chemistry at Roger Williams
University in 2010, where he began his
research career with Prof. Cliff J. Timpson.
In 2012, Brian entered Johns Hopkins
University under the guidance of Prof.
Gerald J. Meyer. Brian subsequently com-
pleted his thesis in 2017 at The University of
North Carolina – Chapel Hill, where much
of his thesis focused on electron transfer
reactions relevant to the operation of a dye-
sensitized solar cell. Brian is currently a
postdoctoral researcher in the laboratory of Prof. Luisa De Cola.
x | Photochemistry, 2019, 46, viii–xxiii

Bo-Wen Ding received her PhD degree in
physical chemistry supervised by Prof.
Ya-Jun Liu at the Beijing Normal University
(China) in 2017. Her research interests
focus on mechanic insight into the bio-
luminescence of marine organisms using
ab initio methods, QM/MM techniques,
and nonadiabatic molecular dynamics
simulations.
Filippo Doria, born on March 4, 1982,

graduated in Chemistry (magna cum laude) at
the University of Pavia, June 2006. He obtained
his PhD from the same University in 2009,
in Chemical Sciences (organic chemistry),
completing a thesis entitled ‘‘Molecular
recognition and selective alkylation of nucleic
acids by photoactivatable alkylating agents’’.
During the course of his PhD he spent nine
months as a visiting Scientist at the Biomole-
cular Structure Group, Cancer Research UK,
School of Pharmacy, University of London,
(UK) with Prof. S. Neidle, working on a project
entitled ‘‘Quadruplex nucleic acid structures and their selective recognition
by small molecules. Synthesis and chemical biology of novel quadruplex-
targeted agents’’. During his post-doc, he spent two months as exchange
visiting Scientist at the Consejo Superior de Investigaciones Cientı́ficas
(CSIC), Instituto di Parasitologia y Biomedicina, Granada, Spain. (i-LINK
0924). In 2015 he started a five years fellowship as Fixed Term Researcher
(RTDa) at the Department of Organic Chemistry, University of Pavia, PV, Italy,
working on the Synthesis and activation of molecular devices selective for
‘‘G-quadruplexes.’’ (ERC-CG615879). His current research is focused on the
synthesis and evaluation of new selective G-quadruplex fluorescent sensor.
Photochemistry, 2019, 46, viii–xxiii | xi

Pooria Farahani received his PhD degree
from Uppsala University (Sweden), in
2014, for his theoretical chemistry studies
on the chemiluminescence processes of 1,2-
dioxetane-like systems, under Prof. Roland
Lindh and Dr Marcus Lundberg’s super-
visions. In 2015, he obtained a grant from
the Fundação de Amparo à Pesquisa do
Estado de São Paulo (FAPESP) to do a
postdoctoral research at the University of
São Paulo (Brazil), within the experimental
group of Prof. Wilhelm Josef Baader, at the
Departmento de Quı́mica Fundamental,
focusing on the application of ‘‘quantum-chemical methods to ration-
alize efficient electronically excited-state formation in chemical trans-
formation’’. He is now a member of Theoretical Chemistry & Biology
Department of the KTH Royal Institute of Technology in Stockholm
(Sweden). His recent subject is to study catalytic composites for sus-
tainable synthesis which includes photochemical reactions catalysed by
metal–organic frameworks (MOFs).
Antonio Francés-Monerris graduated in

pharmacy in 2009 at the University of
València (Spain). In 2011, he received an
MSc in organic chemistry at the Poly-
technical University of València after a short
stay in a pharmaceutical company. He
received his PhD in chemistry in 2017 at the
University of València for his theoretical
studies on radiation damage to DNA/RNA
nucleobases using multiconfigurational and
DFT-based methods, a work carried out
under the supervision of Dr Daniel Roca-
Sanjuán and Prof. Manuela Merchán.
Currently, he is a post-doc researcher in the group of Dr Antonio Monari
at the University of Lorraine in Nancy (France). His main research
interests span the photoinduced phenomena in DNA/RNA nucleobase
clusters, the photosensitization of biological systems, the study of the
fluorescence and chemiluminescence phenomena and the photophysics
of iron-based metal–organic complexes.
xii | Photochemistry, 2019, 46, viii–xxiii

Angelo Giussani graduated in Chemistry in
2008 at the Universita degli Studi di Milano.
In 2011 he finalized his European MSc in
‘‘Theoretical Chemistry and Computational
Modeling’’ at the Universitat de Valencia. In
2014 he received his PhD at the Universitat
de Valencia, where he was working in the
QCEXVAL group studying aromatic chro-
mophores performing CASPT2//CASSCF cal-
culations. From 2014 until 2016, he worked
at the Universita di Bologna where he was
involved in the simulation of 2D spectra and
in the study of DNA photoreactions using a
QM/MM approach. In 2016 he moved as a Marie Curie Fellow in the
group of Dr Graham Worth, were he was performing quantum dynamics
simulations using the DD-vMCG method. His main research interest is in
the study of photophysical and photochemical phenomena performing
both ab initio and quantum dynamics computations.
Andreas Herrmann studied chemistry in

Karlsruhe (Germany) and Strasbourg
(France). In 1997, he completed his PhD at
the ETH Zürich (Switzerland) under the
guidance of Prof. François Diederich and
joined Firmenich as a research scientist.
He has been working on the development
of profragrances for 20 years. In 2016, he
received the KGF-SCS Industrial Science
Award from the Swiss Chemical Society (SCS)
and the Contact Group for Research Matters
(KGF) for his work on profragrances. He is
author or co-author of almost 70 scientific
publications and 25 patents. He has also lectured at the University of
Fribourg (Switzerland) for 10 years.
Photochemistry, 2019, 46, viii–xxiii | xiii

M. Consuelo Jiménez graduated from the
University of Valencia and obtained her PhD
from the Technical University of Valencia
(UPV) in 1997 (Organic Photochemistry),
under the supervision of Profs. Miguel A.
Miranda and Rosa Tormos. She was a
‘‘Marie Curie’’ post-doctoral fellow at Louis
Pasteur University (Strasbourg) 1999–2000
with J.-P. Sauvage (Nobel Prize in Chem-
istry 2016), working on molecular motions,
and a visiting professor at CEA (Saclay) in
2011 (femtosecond fluorescence). She is
currently Professor of Organic Chemistry at
UPV. Her main research activity is focused on organic photochemistry,
with particular interest in the study of drug–biomolecule interactions
using photophysical techniques. She has published more than 90 sci-
entific contributions in these domains.
Irene E. Kochevar is Professor of Derma-

tology, Harvard Medical School with labora-
tories in the Wellman Center for
Photomedicine of Massachusetts General
Hospital. She has applied her background in
physical organic chemistry and biochemistry
to generating an understanding of funda-
mental mechanisms by which UV radiation
and dye photosensitization generate oxida-
tive stress in cells and the responses of cells
to this stress. Dr Kochevar is a co-inventor
with Dr Robert Redmond of a light-activated
tissue repair technology based on protein
photo-crosslinking that, in studies with medical collaborators, has been
shown to have multiple applications including sealing wounded skin,
cornea, nerves, tendons as well as stiffening cornea and blood vessels.
Benjamin Lipp studied biomedicinal chem-

istry at the Johannes Gutenberg-University
in Mainz (Germany), where he joined the
group of Prof. Till Opatz for a diploma thesis
on the development of photoredox-catalysed
Minisci reactions in 2015. Currently,
Benjamin is a PhD student in the same
group. His research is focused on the
development of photoinduced electron
transfer reactions and their application to
organic synthesis.
xiv | Photochemistry, 2019, 46, viii–xxiii

Ya-Jun Liu received his PhD degree in
physical chemistry at the University of Sci-
ence and Technology of China, in 2002. After
a postdoctoral period at Uppsala University
(Sweden) with Prof. Sten Lunell and at Lund
University (Sweden) with Profs. Björn O.
Roos and Roland Lindh, he returned to
China in 2006 to Beijing Normal University
and was promoted to professor in 2012 at
the same university where he has remained
ever since. Most of his scientific work has
been devoted to the theoretical study of
photochemistry. In recent years, his research
has focused on bioluminescence and chemiluminescence.
Géraldine Masson received her PhD in 2003

from the Joseph Fourier University, (France).
She then moved to the University of
Amsterdam (Holland) as a Marie Curie
postdoctoral research fellow with Prof. Jan
van Maarseveen and Prof. Henk Hiemstra. At
the end of 2005, she was appointed ‘‘Chargé
de Recherche’’ by the CNRS in the research
group of Prof. Jieping Zhu at the Institut de
Chimie des Substances Naturelles (ICSN),
before initiating her independent career in
2011. She was promoted to Research Dir-
ector of CNRS in 2014 in the same institute.
Her contributions to the field of Organic Chemistry have been recognized
with numerous awards including the Diverchim Prize in Synthetic
Organic Chemistry from French Organic Chemistry Division (2011),
CNRS Bronze Medal (2013), Liebig Lectureship of the German Chemical
Society (2016), and Novacap Prize of the French Académie des Sciences
Award (2017). Her group’s research activities are directed toward the
development of the design and development of new catalytic methods for
the synthesis of optically active molecules displaying biologically activ-
ities. The three specific research areas focus on: (1) asymmetric organo-
catalysis; (2) photoredox-catalysis and (3) asymmetric hypervalent iodine
catalysis.
Photochemistry, 2019, 46, viii–xxiii | xv

Christopher D. McTiernan received his BSc
in Biochemistry (2008) and MSc in Chemical
Sciences (2010) from Laurentian University
before obtaining his PhD in Chemistry
(2017) from the University of Ottawa. He is
currently a postdoctoral fellow in the group
of Dr Emilio Alarcon and recipient of a
fellowship award from the University of
Ottawa Cardiac Endowment Fund. His
current research focuses on translating
his expertise in materials chemistry and
photochemistry in the development of
pro-regeneration tissue scaffolds and photo-
activated tissue adhesives.
Miguel A. Miranda is Full Professor of

Organic Chemistry at the Institute of
Chemical Technology (UPV-CSIC) of the
Technical University of Valencia. He was
post-doctoral researcher at the Universities
of Saarland and Würzburg and Associate
Professor at the University of Valencia,
before accepting his present position in
1990. His field of interest is photochemistry,
from the fundamentals to the biological,
environmental and technological appli-
cations (4500 peer-reviewed articles in the
field). He has received the Honda–Fujishima
Award of the Japanese Photochemistry Association, the Organic
Chemistry Award of the Spanish Royal Society of Chemistry, the Theodor
Förster Award of the German Chemical Society and the Bunsen Society
of Physical Chemistry, the Award for Excellence in Photobiological
Research of the European Society for Photobiology, and the Award for
Recognition to a Distinguished Career of the Spanish Royal Society of
Chemistry. He was the President of the European Society for Photo-
biology from 2009 to 2011.
xvi | Photochemistry, 2019, 46, viii–xxiii

Kazuhiko Mizuno was born in Osaka, Japan
in 1947 and obtained a PhD in 1976 at Osaka
University. He began his academic career at
Osaka Prefecture University in 1976 and was
promoted to full professor in 1996 and
retired in 2012. He became Professor
Emeritus. He is now serving as an adjunct
professor at Nara Institute of Science and
Technology. He was Secretary of the Asian
and Oceanian Photochemistry Association
(APA) (2004–2008) and President of the
Japanese Photochemistry Association (JPA)
(2008–2009). He has received the JPA Award
(1996) and Award for Distinguished Achievements to APA (2012). His
current research interests focus on microflow photochemistry.
Antonio Monari is currently a member of

the Theoretical Physics and Chemistry
Department (LPCT) of the University of
Lorraine and CNRS in Nancy, France. After
receiving his PhD in Theoretical Chemistry
from the University of Bologna, Italy in 2007
and performing a post-doctoral period in
Bologna he moved to University Paul
Sabatier in Toulouse France in 2009 before
securing a tenured associate professor pos-
ition in Nancy in 2011. His main scientific
interests are centred on the study of linear
and non-linear spectroscopies as well as
photophysical and photochemical processes in complex systems by using
hybrid QM/MM methods and non-adiabatic molecular dynamics. He
focuses his efforts on the study of the production, evolution and repair of
DNA oxidative- and photo-lesions in order to characterize fundamental
biological processes and propose alternative phototherapeutic strategies.
Miriam Navarrete-Miguel graduated in

chemistry at the University of Valencia in
2017. She is currently studying the European
Master on Theoretical Chemistry and
Computational Modelling at the Institut de
Ciència Molecular, Universitat de València
(Spain) supervised by Dr Daniel Roca-
Sanjuán. Her research project focuses on
the application of density functional theory
and multiconfigurational wavefunction
methods to DNA photochemistry and
bioluminescence.
Photochemistry, 2019, 46, viii–xxiii | xvii

Till Opatz studied chemistry in Frankfurt/M.
(Germany) and received his PhD in 2001 at
the University of Mainz (Germany) under the
supervision of Prof. Horst Kunz. After post-
doctoral research with Prof. Liskamp at
Utrecht (Netherlands), he returned to Mainz
for his habilitation on the use of imines of
normal and reversed reactivity as synthetic
building blocks. Till Opatz was appointed
Professor of Organic Chemistry at the Uni-
versity of Hamburg (Germany) in 2007. Since
2010, he is full Professor of Organic Chem-
istry at the University of Mainz and since
2013 adjunct Professor at the University of Alabama (USA). Till Opatz has
published more than 180 research articles, reviews and book chapters
and was recently selected as highly prolific author of the Journal of
Organic Chemistry. His research interests comprise natural product
synthesis and structure elucidation, carbohydrate chemistry and, more
recently, sustainable chemistry as well as preparative photochemistry.
Loı̈c Pantaine obtained his PhD (2013–2016)

in organic chemistry at the Institut Lavoisier
de Versailles (University Paris-Saclay), work-
ing on asymmetric aminocatalysis under the
supervision of Prof. Christine Greck and
Dr Vincent Coeffard. In 2017, he joined the
teams of Dr Géraldine Masson (ICSN) and Dr
Christophe Bour (UPSud) for his first post-
doctoral fellowship, during which he worked
on photoredox/gold dual catalysis. In 2018
he started his second postdoctoral fellow-
ship in the group of Prof. Gary Molander
(UPenn), working on photoredox catalysis
and photoredox/nickel dual catalysis.
xviii | Photochemistry, 2019, 46, viii–xxiii

Valentina Pirota, born on November 28,
1988, graduated in Chemistry at the
University of Pavia in 2012. She received her
PhD from the same University in 2015,
investigating the reactivity and the toxicity of
metal complexed to neuronal peptides
involved in neurodegenerative diseases. Her
PhD project was supported by the Italian
MIUR, through the PRIN. In 2015 she
received a post-doctoral fellowship in the
frame of an AIRC project at Pavia University,
studying selective recognition, covalent
modification and stabilization of DNA in
the G-quadruplex structures (G4s). In 2016 she started a second post-
doctoral project supported by ERC focused on selective compounds tar-
geting the G4s of the Long Terminal Repeat of HIV-1 to offer a novel
strategy to be used in combination with current drugs. Her current
research interest is focused on gene down-regulation, exploiting DNA and
mRNA G4s, as innovative strategy to treat neurodegenerative disease and
on metal interaction with neuronal peptides and proteins.
Barbara Procacci graduated from the

Universitàdegli Studi di Perugia in 2007. She
completed her PhD in 2012 at the University
of York under the supervision of Professor
Robin Perutz, working on photoinduced
C–F, C–H, B–H, and Si–H activation by metal
complexes focusing on mechanistic investi-
gations. She then took a position in York as a
postdoctoral research fellow to work on a
project jointly supervised by Professor
Simon Duckett and Professor Robin Perutz.
Her work is aimed at developing NMR
spectroscopy as a time-resolved technique to
monitor light-initiated organometallic reactions that happen on a fast
time scale.
Photochemistry, 2019, 46, viii–xxiii | xix

Stefano Protti (born in 1979) completed
his PhD in Pavia (2007, supervisor: Prof.
Maurizio Fagnoni) focusing on photo-
chemical arylations via phenyl cations. He
was a postdoctoral fellow at the LASIR
laboratory (Lille, France) and at the iBitTec-S
Laboratory (CEA Saclay, France). Since 2015
he has been Senior Researcher at the
University of Pavia, Italy. Stefano Protti is
currently a co-author of more than 80
research articles and reviews, 9 chapters in
multi-authored books and the book Para-
digms in Green Chemistry and Technology,
(2016, Springer IK, with Angelo Albini). The results of his research have
been presented at National and International meetings.
Justina Pupkaite received her Bachelor’s

degree (2011) and Master’s degree (2013) in
Biophysics at Vilnius University (Lithuania).
Currently, she is a doctoral candidate in a
cotutelle program between the University of
Ottawa (Canada) and Linkoping University
(Sweden). She works under the supervision
of Dr Erik Suuronen at University of Ottawa
Heart Institute, co-supervised by Drs Peter
Pahlsson and May Griffith. Her research
focuses on developing collagen-based
biomaterials for regenerative medicine
applications, with focus on cardiac repair
post myocardial infarction.
Carlotta Raviola (born in 1988) studied

chemistry at the University of Pavia where
she graduated in 2011. She received her
PhD degree from the same university in
2015 (Prof. A. Albini as the supervisor)
and spent part of this period at the Tech-
nische Universität München (Germany) in
the group of Prof. Thorsten Bach. She is
currently a post-doc at the Department of
Chemistry of the University of Pavia and
her research interests focus on the photo-
induced or photocatalytic generation of
highly reactive species (aryl cations,
(bi)radical intermediates) for synthethic applications.
xx | Photochemistry, 2019, 46, viii–xxiii

Daniel Roca-Sanjuán received his PhD
degree in 2009 for his quantum-chemistry
studies on DNA photochemistry carried out
at the Quantum Chemistry of the Excited
State (QCEXVAL) group of Profs. Manuela
Merchán and Luis Serrano-Andrés, Institut de
Ciència Molecular, Universitat de València
(Spain). In 2010, he moved to the group of
Prof. Roland Lindh at the Department of
Chemistry Ångström, Uppsala University
(Sweden), with a Marie Curie postdoctoral
grant, where he researched on the develop-
ment and application of quantum-chemical
methods with the MOLCAS program to the bioluminescence and
chemiluminescence phenomena. In 2013, he returned to the QCEXVAL
group as a postdoctoral ‘‘Juan de la Cierva’’ fellow and since 2017 he is
working as a ‘‘Ramón y Cajal’’ fellow (tenure track researcher) on com-
putational photochemistry and chemiluminescence.
Javier Segarra-Martı́ received his PhD degree

at the Instituto de Ciencia Molecular,
Univeristy of Valencia (Spain) in 2014 for
his work on photoinduced phenomena in
water clusters and DNA/RNA nucleobases
under the supervision of Prof. Merchán
and Dr Roca-Sanjuán. He then moved to the
group of Prof. Garavelli at the Dept. of
Chemistry, University of Bologna (Italy) to
work on multiscale (QM/MM) approaches
and non-linear electronic spectroscopies.
In 2016 he joined the group of Dr Rivalta at
the Dept. of Chemistry, École Normale
Supèrieure de Lyon (France), to work on DNA photo-sensitisation
monitored by employing two-dimensional electronic spectroscopy
(2DES). He is currently a Marie Curie Fellow associated to the group of
Prof. Bearpark at the Dept. of Chemistry, Imperial College London (UK),
where he studies electron dynamics in molecular systems of biological
interest.
Photochemistry, 2019, 46, viii–xxiii | xxi

Evan Sherbrook received his bachelor’s
degree in Chemistry from the University
of Vermont in 2013, studying the total
synthesis of b-carboline natural products
and structural analogues. His graduate
work with Tehshik Yoon at the University
of Wisconsin-Madison focuses on methods
for controlling absolute stereochemistry
in electron transfer and energy transfer
processes.
Erik Suuronen is a principal investigator

at the University of Ottawa Heart Institute
in Ottawa, Canada. He is also Associate
Professor in the Department of Surgery at
the University of Ottawa, with cross-
appointment to the Department of Cellular
& Molecular Medicine. He received his
Bachelor’s degree in Biology in 1996 and
his PhD in Cellular and Molecular Medicine
in 2004, both from the University of Ottawa,
followed by a post-doctoral fellowship at
the University of Ottawa Heart Institute.
His research focuses on tissue engineering
and cell-based therapeutic approaches for the treatment of cardio-
vascular disease.
Takashi Tsuno obtained his PhDs at the

University of Shizuoka under the supervision
of Prof. Dr M. Sato in 2005 and at the
University of Regensburg under the super-
vision of Prof. Dr H. Brunner in 2007.
Currently, he is a Professor at Nihon
University and has also been a contributor
to SPR Photochemistry since 2009.
xxii | Photochemistry, 2019, 46, viii–xxiii

Tehshik Yoon received his MS and PhD from
Caltech under the supervision of Erick Car-
reira and David MacMillan, respectively.
This was followed by an NIH postdoctoral
fellowship at Harvard with Eric Jacobsen. He
has served on the faculty at the University of
Wisconsin-Madison since 2005. Prof. Yoon’s
research interests largely focus on the use
of photochemistry in organic synthesis.
His research and scholarship has been rec-
ognized with several awards including
the Corporation Cottrell Scholar Award, the
Beckman Young Investigator Award, the
Amgen Young Investigator Award, an Alfred P. Sloan Research Fellow-
ship, an Eli Lilly Grantee Award, and a Friedrich Wilhelm Bessel Award
from the Humboldt Foundation.
Michela Zuffo received her BSc and MSc

degrees in Chemistry in 2012 and 2014 at
the University of Pavia (Italy). She obtained
her PhD from the same university in 2018,
with a thesis on the selective targeting of
specific G-quadruplex structures. She was
visiting researcher at the department of
Chemistry, University of Cambridge (2013),
at the Bioengineering Department, Imperial
College – London (2014), and at the IECB of
Bordeaux (2017). She is alumna of Ghislieri
College and IUSS (Pavia). Since 2018, she
holds a postdoctoral position at Institut
Curie (Paris). Her research is focussed on the synthesis and evaluation of
small molecules targeting non-natural DNA mismatches.
Photochemistry, 2019, 46, viii–xxiii | xxiii

CONTENTS
Cover
A quote from a century ago (back cover)
from W. M. Bayliss, Naturwissenschaften,
1918, 101, 295–297.
Front cover image courtesy of
Dr Daria Manganaro.
Preface vii
Angelo Albini and Stefano Protti
Author biographies viii
Part 1: Periodical Reports: Organic and

Computational aspects (2016–2017)
Introduction of the year 3

Stefano Protti and Angelo Albini
1 Introduction 3
2 The sentence of the year, 1918 4
3 Awards and medals 6
4 Reviews of the year 7
5 Highlights in volumes 37 to 46 23
References 23
Quantum chemistry of the excited state: recent trends in methods 28

developments and applications
Miriam Navarrete-Miguel, Javier Segarra-Martı́,
Antonio Francés-Monerris, Angelo Giussani, Pooria Farahani,
Bo-Wen Ding, Antonio Monari, Ya-Jun Liu and Daniel Roca-Sanjuán
1 Introduction 28
Photochemistry, 2019, 46, xxv–xxix | xxv

2 Developments of methods and theory 30
3 Conical intersections and their role in photophysics 42
and photochemistry
4 DNA/RNA spectroscopy and photochemistry 47
5 Photosensitisation of biological structures and 52
photodynamic therapy
6 Chemiexcitation 58
7 Summary and outlook 68
Acknowledgements 70
References 70
Organic aspects: photochemistry of alkenes, dienes, 78

polyenes (2016–2017)
Takashi Tsuno
1 Introduction 78
2 Photoinduced (E)–(Z) isomerization 78
3 Electrocyclization 82
4 Photoinduced addition 88
5 Photocatalysts 92
6 Photooxygenation and photooxidation 99
7 Photochemistry of polyenes 100
References 101
Photochemistry of aromatic compounds 116

Kazuhiko Mizuno
1 Introduction 116
2 Isomerization reactions 116
3 Addition and cycloaddition reactions 119
4 Substitution reactions 137
5 Intramolecular cyclization reactions 145
6 Rearrangements 154
7 Oxidation 158
References 163
Organic aspects. Oxygen-containing functions 169

M. Consuelo Jiménez and Miguel A. Miranda
1 Introduction 169
2 Norrish type I reactions 169
3 Hydrogen abstractions 171
4 Paternò–Büchi photocycloadditions 173
xxvi | Photochemistry, 2019, 46, xxv–xxix

5 Photoreactions of multichromoporic systems: dicarbonyl 175
compounds, enones, quinones and quinone methides
6 Photoeliminations: photodecarboxylations, 180
photodecarbonylations and photodenitrogenations
7 Photo-Fries and photo-Claisen rearrangements 183
8 Photocleavage of cyclic ethers 184
9 Photoremovable protecting groups 184
10 Miscellanea 186
References 188
Function containing a heteroatom different from 194

oxygen (2016–2017)
Carlotta Raviola, Stefano Protti and Angelo Albini
1 Nitrogen containing functions 194
2 Functions containing other heteroatoms 208
References 214
Part 2: Highlights
Design and synthesis of two-photon responsive chromophores

for application to uncaging reactions 221
Youhei Chitose and Manabu Abe
1 Introduction 221
2 Examples of photolabile protecting groups (PPGs) and 222
uncaging mechanism
3 Two-photon absorption and excitation 224
4 Two-photon responsive chromophores 225
5 Recent developments in TP uncaging reactions 228
6 Design and synthesis of TP responsive PPGs with stilbene core 235
7 Perspective for future TP responsive PPGs 238
References 238
Controlled release of volatile compounds using the 242

Norrish type II reaction
Andreas Herrmann
1 Introduction 242
2 Mechanism of the Norrish type II reaction 243
3 Light-induced release of volatile compounds by the 249
4 Conclusions and learnings 261
References 262
Photochemistry, 2019, 46, xxv–xxix | xxvii

Recent advances in the design of light-activated tissue repair 265
Christopher D. McTiernan, Justina Pupkaite, Irene E. Kochevar,
Erik J. Suuronen and Emilio I. Alarcon
1 Overview of light-activated tissue bonding 265
2 Sutureless tissue bonding: from laser tissue 266
welding to tissue photobonding
3 Photo tissue bonding (PTB) 269
4 Recent advances in in situ photo-polymerization 271
5 Conclusion and outlook 276
Acknowledgements 276
References 276
Photoresponsive molecular devices targeting nucleic acid 281

secondary structures
Michela Zuffo, Valentina Pirota and Filippo Doria
1 Light-up mechanisms 284
2 Fluorescent sensing of non B-DNA secondary structures 292
3 Conclusions 309
References 309
Transition metal complexes in ECL: diagnostics and 319

biosensing
A. Aliprandi, B. N. DiMarco and L. De Cola
1 Introduction to electrochemiluminescence 319
2 Ruthenium complexes 326
3 Iridium complexes 336
4 Platinum complexes 342
References 349
Photoinduced bond activation via Ru and Rh dihydrides: 352

principles and selectivity
Barbara Procacci
1 Introduction 352
2 Group 8 metal dihydrides for the reductive 353
elimination step
3 Group 9 metal dihydrides for the oxidative 359
addition step
4 Conclusions and outlook 365
Acknowledgements 366
References 366
xxviii | Photochemistry, 2019, 46, xxv–xxix

Aromatic hydrocarbons as catalysts and mediators in 370
photoinduced electron transfer reactions
Benjamin Lipp and Till Opatz
1 Introduction and theoretical background 370
2 Examples of PET reactions catalysed by aromatic 375
hydrocarbons
3 Examples of PET reactions mediated by aromatic 384
hydrocarbons
4 Conclusion and outlook 387
References 388
Photo-induced multi-component reactions 395

Loı̈c Pantaine, Christophe Bour and Géraldine Masson
1 Introduction 395
2 Direct photoactivation of reagents 399
3 Photocatalysis 408
4 Conclusions 428
References 429
Asymmetric catalysis of triplet-state photoreactions 432

Evan M. Sherbrook and Tehshik P. Yoon
1 Introduction 432
2 Arenes and aryl ketones 433
3 H-bonding xanthones, thioxanthones, and thioureas 436
4 Lewis acids 440
5 Transition metal photocatalysts 444
6 Summary and looking forward 446
References 447
Photochemistry, 2019, 46, xxv–xxix | xxix

Part 1
Periodical Reports: Organic and
Computational aspects (2016–2017)
Introduction of the year
Stefano Protti and Angelo Albini*
DOI: 10.1039/9781788013598-00003
Important advancements in photochemistry in the year 2017 are illustrated by presenting

awards, some historical perspectives and some representative examples.
1 Introduction
The present volume, no 46 in the series ‘‘Photochemistry’’ of the
Specialist Periodical Reports published by the Royal Society of Chemistry,
consists in two different parts. The first section includes a series of
reviews on the advancements in computational and organic photo-
chemistry reported in the biennium 2016–2017. The second part of the
issue consists of highlights on recent topics, with the aim to provide the
reader with a flavour of the advanced research that may be also a pleasant
reading for practitioners. In the attempt to better serve our readers,
the present introduction chapter includes, along with reviews, thematic
issues and papers published in 2017, as well as a section on awards
and prizes assigned to researchers operating in the different sectors of
photochemistry.
A presentation of the quote of the series ‘‘one hundred years ago’’
printed on the back cover has been also included herein. As hinted
below, the reviews section is devoted to the recent efforts reported in the
field of computational photochemistry and the photoreactivity of organic
compounds, including olefins, aromatics and molecules bearing differ-
ent functional groups. On the other hand, the highlights section includes
reports focused on recent advances in different research fields including
photomedicine (the design of light-activated tissue bonding and of
photoresponsive molecular devices to target nucleic acid secondary
structures, as well as of the use of electrochemiluminescent transition
metal complexes for biosensing purposes), inorganic (the photoreactivity
of metal hydrides), organic (the optimization of photoinduced multi-
component reactions, of the use of polyaromatics as photocatalysts
and the development of asymmetric catalyzed triplet-state reactions)
and applicative photochemistry (the design of two-photon responsive
chromophores for uncaging reactions, the release of volatile compounds
via the Norrish-type II reaction and the use of spectroscopy techniques
in art).
Let’s have a more personal note, before starting the volume. We would
like to remember here Professor Ugo Mazzucato. His always strong
interest in new ideas, his enthusiasm for research, his patience in lis-
tening to anybody, his optimistic and generous contribution to the
development of associations and to the growing of individuals will
PhotoGreen Lab, Department of Chemistry, University of Pavia, V.Le Taramelli 12,

27100 Pavia, Italy. E-mail: angelo.albini@unipv.it
Photochemistry, 2019, 46, 1–27 | 3

remain in the heart of anybody that had the fortune to meet him
personally.y
2 The sentence of the year, 1918

‘‘An interesting fact comes out from the curve of sensibility of the retina
compared with the energy of the light acting. At that particular frequency of
vibration corresponding with the yellow–green, the threshold of stimulus
coincides with the energy quantum of Plank for that rate of vibration. In other
words, the retina is sensitive to as small an incidence of energy as it is
possible for it to receive’’ W. M. Bayliss, Light and vision, Nature, 1918, 101,
295–297.
Some of the important steps that established the peculiar course of
photochemical processes have been portrayed in the last years through
important quotations. From the papers printed in 1918, it is appropriate,
we think, to take the chose from the photobiological field, since this
had consistently grown in those years. In a talk before the members of
the Illuminating Society on April 16, 1918 and then printed in Nature1
the authoritative specialist William M. Bayliss, a well known professor
of physiology, commented on the present situation of light and vision.
He found that the process could be divided in three phases, namely:
(1) The registration of light from outside by means of the diotropic

system of the eye;
(2) The activation and stimulation of some kind that occurred at the
nerve terminals;
y
Born in Padua in 1929, Ugo Mazzucato married Gianna Favaro, also a chemist,
and had two children: Lucia and Andrea. He received a degree in chemistry from
the University of Padua in 1955. He was lecturer in physical chemistry and
related subjects at the Universities of Padua, L’Aquila and Perugia. In Perugia, he
has been full professor of physical chemistry since 1969 and the Director of the
Chemistry Department of the Science Faculty in the 1986–1992. After his
retirement in November 2004 he continued to attend the Chemistry Department
of the University of Perugia as Emeritus Professor, following some research lines
and helping students in the thesis work. He held important positions such as
member of the Board of Governors of the University of Perugia. He worked in
chemical education as part of commissions of the Italian Chemical Society (SCI)
and of the National Research Council (CNR) for reforming the degree programs
in the scientific field. He was one of the founding members of the European
Photochemistry Association, the Italian Group of Photochemistry, the national
divisions of Physical Chemistry and Chemical Education, and the regional sec-
tion of the Italian Chemical Society. He has authored more than 220 scientific
papers on kinetics, spectroscopy, acid-base and charge-transfer equilibria,
photographic science, chemical education and, primarily, on photochemistry.
His main research interest was focused on the processes of rotation around
double bonds (cis-trans photoisomerization) and single bonds (ground-state
rotamerism) in stilbene-like compounds and their heteroanalogues and on their
bimolecular processes with energy, electron and proton donors or acceptors. His
main hobbies were stamp collection, mountain hiking and wine tasting.
4 | Photochemistry, 2019, 46, 1–27

(3) The distribution of the impulses in the brain, while in some
mysterious way this generated a conscious impression of light and
illuminated objects.
These results opened many questions. At first, what happens if the

nerve is stimulated in some other way? The answer to this question was
that, whatever is the stimulus, the sensation is always one of light (as is
the case for other senses, in each connected nerve. On the other hand,
illumination of optic nerve did not activate anything, since the nerves
per se are not responsive to light.
Some form of energy had to be operating at the level of cones and rods,
which guaranteed such a high level of sensitization arriving at a single
photon level. Cones hat to be photosensitive, because they were the only
type of cells present in the highly sensitive fovea centralis, and rods
likewise, because of the great similarity of their connections.
The only sensible conclusion was that some chemical reaction
occurred. A single photoactive pigment was then known and indicated as
‘visual purple’, although the color was rather indicated by most people as
a deep red-rose. This made interesting to measure the chemical changes
occurring in the presence of the dye. This reaction should lead to
photoproducts not disappearing at once, and a temporary bleaching of
the dye was observed. In Prof. Bayliss words, ‘‘First the curve gradually
falls, the stimulus merely disappears on the advent of darkness. There is no
indication of the stimulus of any kind produced by darkness. This is contrary
to the well-known theory of Hering, according to which the reaction of res-
toration, occurring when the light ceases, is associated with the positive
sensation of darkness. This point of view had been applied to physiological
phenomena in general, but is now practically given up. Secondly, the curve,
after it has attained its maximum, remains constant, while the illumination
lasts.
Thirdly, the reaction does not attain its full intensity suddenly, nor do the
products disappear suddenly. In other words, the sensation does not appear
at once, nor does it immediately disappear when the stimulus ceases. This
is the obvious explanation of the absence of flicker when the alteration of
light and darkness are sufficiently rapid. Further, as it would be expected
from a chemical reaction, the greater its magnitude, the longer it requires
for the products to recombine or otherwise disappear. Incidentally, the form
of the curve differs somewhat for different colours.
Fourthly, there is a short latent period between the time of incidence of
light and the electrical effect, if this is not counterbalanced by a similar
period after the illumination ceases; it would result in some deviation from
Talbot’s law’’ (that states that when the illumination of a visual field is
interrupted with sufficiently high frequency, it appears to the human eye
as continuous) ‘‘in its physiological aspect, such as has been described by
Parker and Patten. The latent period reminds us of the ‘photochemical
induction’ of Bunsen and Roscoe.’’
‘‘There is reason to believe that the maximum sensibility of the fovea is not
when it is the only part of the retina illuminated, but when there is simul-
taneously a weak illumination of the surrounding parts. This seems to be

connected with the production and migration of the visual purple. If it is so,
its importance in observations with the microscope, the polarimeter, and
other optical instruments is obvious. The explanation of positive and negative
afterimages is fairly plain – the former by the products of photochemical
change not disappearing at once, the latter by temporary exhaustion of the
visual purple. Edridge-Green has shown that the situation and shape of
the positive afterimage can be altered by jerking the head, showing at the
chemical charge is located in the liquid surrounding the rods and cones.
Hence, these structures must be affected secondarily. The negative after image
is fixed, indicting a situation in the more solid parts of the receptive
mechanism.’’
‘‘The adaptation of the retina to various degrees of illumination. . .is
probably due to a change in the position of the pseudo-equilibrium, which
results from the fact that the products of a reversible photochemical reaction
are continually recombining during the illumination itself. . . .The suggestion
that the ratio of brightness of object to which the eye turns should not exceeds
1 : 100 seems a reasonable one. The problem of ‘glare’ is also connected,
although the fact of the unpleasant and injurious effect of powerful local
stimulation of the retina has also to be taken into account. . . .However, it
requires much more investigation, and the cooperation of physiologists, the
illuminating engineers, the oculist. . . .The effect of lateral illumination brings
up the question of the function of the rods as distinct from that of the cones,
as do also vision under weak illumination and that known as ‘night-blind-
ness’. The question of the colour arose according to Ferree’s observations
where a yellow or a blue tint is more fatiguing than a white light.
. . .An equally important series of questions has been raised by Mr. Gaster,
namely the effect on school children with normal and with imperfect vision of
working in adequate light.’’
The insight and the clearsight of such article are remarkable,
particularly when considering how long has been the research to follow
these topics and the complexity of what we now call phototransduction.
3 Awards and medals

Dr Steven Lee of the University of Cambridge received the Marlow Award
2017 (that is annually given to scientists that afforded a ‘‘meritorious
contributions to physical chemistry or chemical physics’’) for ‘‘the
development of novel single-molecule super-resolution fluorescence techni-
ques’’.2 During the European Society for Photobiology 2017 Congress
(Pisa, 4–8 September 2017) Prof. Silvia E. Braslavsky, Prof. Joan E. Roberts
and Prof. Miguel A. Miranda received the European Society of Photo-
biology (ESP) Award for Excellence in Photobiological Research.3 At the
same meeting, Prof. Ilaria Testa from Stockholm was awarded with the
ESP Young Investigator Award for the contribution of her research group
to the field of bioimaging.3,4 Professor Michael Wasielewski (North-
western University) received the Physical Organic Chemistry Award of the
Royal Society of Chemistry in view of his ‘‘pioneering contributions to
understanding electron transfer reactions and their dependence on molecular
structure and spin dynamics in organic molecules’’.5 Such investigations

have been exploited in different research fields, including artificial
photosynthesis of fuel and energy production.6 Prof. Bern Kohler
(Montana State University), received the Inter-American Photochemical
Society Award in Photochemistry, for his work in ultrafast laser spec-
troscopy applied to photobiological processes.7 Prof. David G. Whitten
(University of New Mexico Center for Biomedical Engineering) received
the prestigious George S. Hammond Award for his outstanding contri-
bution to different photochemical fields, including the investigation of
energy and electron transfer reactions and the preparation and appli-
cation of self organized assemblies.8
The Honda-Fujishima Lectureship Award of The Japanese Photo-
chemistry Association (JPA) went to Prof. Fred Brouwer (Van ’t Hoff
Institute for Molecular Sciences, University of Amsterdam) for his efforts
in the field of molecular photonics, and, in particular, in the use of
organic molecules as luminescent probes.9 The European Academy of
Sciences awarded Prof. Vincenzo Balzani (University of Bologna) in
recognition for his contribution to the development of major branches of
chemistry, such as photochemistry and molecular nanotechnology.10
Professor Nicola Armaroli (CNR, Istituto per la Sintesi Organica e la
Fotoreattività – ISOF, Bologna) was the recipient of the Medal Enzo
Tiezzi, which is awarded for outstanding contributions to the field of
environmental chemistry.
Finally, Dr Davide Ravelli (University of Pavia) received the 2017
Ciamician Medal from the Italian Chemical Society as the best young
organic chemist of the year and the Vincenzo Caglioti Award (from the
National Lincean Academy) for the results obtained in the development
of photocatalysts able to promote hydrogen atom transfer reactions.11
4 Reviews of the year

4.1 Handbook and special issues
Handbooks. The volume ‘‘Photomechanical Materials, Composites, and
Systems: Wireless Transduction of Light into Work’’, (Wiley, 432 pages)
has been recently edited by T. J. White and aims to provide the reader
with an almost exhaustive overlook of the history, the current state, and
the perspectives of light-controlled systems, including photochromic
crystals and piezoelectric ceramics.12 The photophysical properties of IrIII
complexes make them as the most promising additive for the preparation
of materials for optoelectronic applications. The Volume 97 of the series
Semiconductors for Photocatalysis, prepared by Zetian Mi Lianzhou and
Wang Chennupati Jagadish is focused on the latest advances in the
preparation of efficient semiconductor (e.g. metal-oxides and -nitrides
and silicon) photocatalysts and electrodes for either water splitting
and CO2 reduction.13 The monumental 2-volume set ‘‘Iridium(III) in
Optoelectronic and Photonics Applications’’ edited by Eli Zysman-
Colman offers an exhaustive account of photoactive iridium complexes
and their wide applications.14
‘‘Phototherapy and Photodiagnostic Methods for the Practitioner’’,
written and edited by W. S. Chong, J. Y. Pan and S. T. E. Tan, represents the

first published set of practical guidelines in phototherapy for Asian skin,
based on both the many clinical experiences of the Authors at the National
Skin Centre in Singapore and the most recent scientific literature data.15
‘‘Semiconductor Quantum Dots and Rods for In Vivo Imaging and Cancer
Phototherapy’’ by M. Chu highlights the multifaceted applications of QDs
and QRs (Quantum Rods) as sentinels in lymph node mapping, in vivo
tumor target imaging as well as in photodynamic therapy.16 Elsevier
recently launched the 4th edition of the volume on Vitamin D, devoted to
the multifaceted properties and activities of such biomolecule.17
The 2016 Porter Medal James Barber recently edited, in collaboration
with Alexander V. Ruban, the volume ‘‘Photosynthesis and Bioenergetics’’, a
collection of papers from leading scientists involved in the investigation
of natural photoinduced biological processes, including the Nobel
Laureate Rudolph Marcus.18
Flow photochemistry is considered an expanding field in organic
synthesis, since in this case the mild conditions involved in photo-
chemical processes add to the ability to merge the mass transfer
enhancement of flow chemistry. A convincing approach to that field is
offered by the multi-authors handbook ‘‘Photochemical Processes in
Continuous-Flow Reactors: From Engineering Principles to Chemical
Applications’’ edited by T. Noël. The volume (that includes contributions
of, among the others, professors Yuanhai Su and Thomas Junkers) gives
an overview of technological and chemical aspects related with photo-
chemical flow processes.19 The lecture note ‘‘Essentials of Pericyclic
and Photochemical Reactions’’ written by B. Dinda represents an intro-
duction to pericyclic and photochemical processes that find application
in organic synthesis. The first section of the book focuses on electrocyclic
reactions, cycloadditions, sigmatropic rearrangements, and group
transfer reactions, while the second parts is devoted to processes
exploiting the photoreactivity of different functional groups, including
(poly)enes, carbonyls, and aromatics.20 The monograph ‘‘Naphthalene-
diimide and its Congeners: From Molecules to Materials’’ has been pub-
lished by the Royal Society of Chemistry, with the editing work of G. Dan
Pantos, and consists in ten sections focused on the application of
naphthalene- and perylene-diimides in several fields, including organic
photovoltaics and DNA binders.21
Special Issues. A celebrated quotation from ‘‘The photochemistry of the
future’’ (1912)22 of Giacomo Ciamician introduced the reader to the
theme issue of Chemical Society Reviews edited by Sebastiano Campagna
and Gary W. Brudvig23 devoted to the recent advances in artificial
photosynthesis. Among the different reviews included in the volume (that
also included contributions from the research groups of T. J. Meyer, J. J.
Conception, E. A. Gibson, R. Moré, E. Reisner and G. W Brudvig), we
would like to report the interesting digression of A. Llobet and co-workers
on the parameters that should be taken into account when designing a
robust and efficient photocatalyst.24 To the same theme was dedicated a
special issue of the Compte Rendus de Chimie assembled by Ally Aukauloo
and Harry B. Gray.25 Analogously, a theme collection of the Dalton
Transations was focused on the Role of Inorganic Materials in Renewable

Energy Applications. Most of the reviews and research papers published
therein are addressed to photocatalytic systems for the selective CO2
conversion to methane,26 improved devices/systems for water splitting,27
and water oxidation.28
A theme issue of the Chemical Society Reviews celebrating the 50th
supramolecular chemistry anniversary (guest editors: D. B. Amabilino
and P. A. Gale)29 presented, among the other contributions, a biography
of Charles Pedersen written by Reed M. Izzat30 and several reviews by,
among the others, the 2016 Nobel Prize winners, Ben L. Feringa (with
D. Leigh)31 and J. Fraser Stoddart,32 along with a report of Juyoung Yoon
et al. on recent advances in the development of crown ethers-containing
fluorescent probes.33
Another web issue of the Royal Society of Chemistry consists in
48 papers focused on the advances in the field of chemosensors.34 In
particular, the paradigms for the preparation of a fluorescent polymeric
thermometer have been discussed by the group of Inada.35 A volume of
Chemical Reviews in 2017 was devoted to the light harvesting issue (guest
editor: Gregory D. Scholes),36 and also explored the light absorption and
energy transfer mechanisms used by the antenna complexes of photo-
synthetic organisms.37 The volume discussed several aspects of this
research field, both from the computational38 and the experimental39
point of view. The development of photosynthetic biohybrid systems
(PBSs) able to merge the strengths of inorganic materials and the
selectivity of biological catalysts to generate valuable CO2-derived
chemicals by using solar light was discussed a theme issue included in
Accounts of Chemical Research.40
Tetrahedron published a special issue focused on ‘‘Dynamic Functional
Molecular Systems’’ in honour of Ben Feringa, that was awarded with the
2016 Tetrahedron Prize for Creativity in Organic Chemistry.41 The col-
lection includes 30 original papers, most of them focused on the devel-
opment of photoactivated molecular machines. In particular, Trauner
et al. described the design and the behavior of UV (360 nm) photo-
switchable azobenzenes (see for instance compound 1 in Scheme 1),
which act as antagonist for N-methyl-D-aspartate (NMDA) receptors.42
Scheme 1 Synthesis of a photoswitchable azobenzene able to act as the antagonist for

N-methyl-D-aspartate (NMDA) receptors.

In the same volume, Giuseppone et al. reported in the same issue
the multistep, gram scale synthesis of some optically pure Feringa’s
motors (2).43
A 2017 issue of Photochemical & Photobiological Sciences was devoted to

the health benefits of UV radiation exposure through vitamin D pro-
duction or non-vitamin D pathways44 and a history of phototherapy was
included therein.45 The Journal of Physical Chemistry A recently published
a volume dedicated to the memory of Klaus Schulten (1947–2016),
who focused his research on solving problems in molecular biophysics,
including the investigation of the structure and mechanisms of bio-
energetic proteins.46 A computational analysis of molecular dynamics at
microsecond scale of Photosystem II (in both monomeric and dimeric
forms) embedded in a thylakoid membrane model has been performed
by Marrink et al. in order to describe in detail the setup of the protein
complexes and the natural cofactors that characterize their mobility.47
The journal Biomedicines published a special issues entitled ‘‘Photo-
dynamic Therapy in Cancer’’ with Carmen Cantisani, Giuseppe Pellacani
and Stefano Calvieri as the guest editors.48
In March 2017 The Journal of Photochemistry and Photobiology C: Photo-
chemistry Reviews published a volume devoted to recent advances in bio-
imaging.49 Among the reports included, we’re pleased to signal the reviews
of Kim and co-workers on the synthesis of photoluminescent Quantum
Dots (QDs) and their application as optical probes in biosensing.50
A thematic issue on Polymers and Light of Macromolecular Rapid
Communications was edited by Cyrille Boyer and Garret Miyake. They
assembled 18 contributions, including communications and reviews
focused on the recent advances in photopolymerization and in the
preparation of polymeric materials.51 A report on the synthesis and sur-
face properties of stimuli-responsive polymeric nanoparticles written by
Urban and co-workers is available therein.52
To the theme ‘‘Chirality and Nanophotonics’’ the journal Advanced
Photonic Materials dedicated a selection of works selected by the editors
Ventsislav Valev, Alexander Govorov, and John Pendry.53 In the contri-
bution by Zanotti et al., the propagation of chiral light in optically
induced helical photonic waveguide arrays was explained and investi-
gated in order to demonstrate the selectivity of the system to optical
orbital angular momentum.54

Burkhard König edited a special issue of the European Journal of Organic
Chemistry.55 In it, along with a set of concise reviews,56 different scientific
contributions, including, among others, the photoredox mediated tan-
dem oxidation/nitroso-Diels–Alder cycloaddition of arylhydroxylamines
3a–d with conjugated dienes 4 described by G. Masson et al.57 for the
preparation of variously substituted 3,6-dihydro-1,2-oxazines (5a–d,
Scheme 2).
Another interesting proposal is the protocol for the photoredox cata-
lyzed cyclopropanation of electron-poor olefins, including Michael
acceptors 6a–c, described by Suero and del Hoyo (Scheme 3).58
The partner journal of EurJOC, the Asian Journal of Organic Chemistry,
also dedicated a issue on photoredox catalyzed processes, with contri-
butions of Hua Fu,59 Aiwen Lei60 and Ilhyong Ryu.61
Proceedings and research papers. A selection of research papers pre-
sented at the 9th European Meeting on Solar Chemistry & Photocatalysis:
Environmental Applications (SPEA 9) was recently included in a themed
issue of the journal Photochemical & Photobiological Sciences (guest
editors: Nicholas Keller and Sixto Malato).62 Most of the original contri-
butions included are devoted to environmental photocatalysis. The group
of Elizondo and that of Hernández-Ramı́rez proposed the modification of
TiO2 with RuII polyaza complexes for the solar induced mineralization of
the non steroidal anti-inflammatory drug Ibuprofen.63 Similarly, visible-
light absorbing Titania hollow spheres functionalised with tungstopho-
sphoric acid (see a comparison between SEM-micrographs of unmodified
and modified TiO2 hollow spheres in Fig. 1) were efficiently employed
by Orellana et al. for the photoinduced degradation of 4-chlorophenol.64
Several contributions presented at the 13th Italian Conference on
Supramolecular Chemistry (Santa Margherita di Pula (CA), June 2017)
Scheme 2
Scheme 3

Fig. 1 SEM micrographs of SiO2 (a), SiO2@TiO2 (b) and @TiO2 (c). Reproduced from
ref. 64 with permission from the European Society for Photobiology, the European
Photochemistry Association, and The Royal Society of Chemistry.
Fig. 2 Cover-art of the sister issues of Energy Technology and ChemSusChem devoted
to the applications of halide-perovskites. Left image reprinted with permission from
ref. 67, Copyright 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim. Right image
reprinted with permission from ref. 66, Copyright 2017 Wiley-VCH Verlag GmbH & Co.
KGaA, Weinheim.
have been recently collected in a special issue of Supramolecular

Chemistry (Taylor and Francis).65 The multifaceted applications of
perovskites (including the preparation of solar cells and bio-imaging)
were the topic of two issues of sister journals ChemSusChem66 and Energy
Technology,67 following the symposium on ‘‘Halide Perovskites for
Optoelectronics Applications’’, a section of the International Conference
on Materials for Advanced Technologies (ICMAT 2017) which took place
in Singapore (Fig. 2).
Several contributions presented at the XXXIII European Congress on
Molecular Spectroscopy, (2016, Szeged, Hungary) have been collected in a
special issue of the Journal of Molecular Spectroscopy.68 Among the
published papers, it should be mentioned the work of T. Sych et al. on
the synthesis and the optical properties of albumin-stabilized silver
nanodots.69

4.2 Reviews and original articles
‘‘Considering the extraordinary rate of development of photochemistry, the
decision was made to establish a journal to publish not just fundamental
studies and the latest developments in more traditional areas of pure and
applied photochemistry, but also to provide an appropriate and attractive
forum covering the newest burgeoning topics within (and around) the
discipline.’’ With such speech of intent, written by Deanne Nolan and
Greta Heydenrych, ChemPhotoChem started its activity for Wiley in
January 2017.70 The journal (that is co-owned by ChemPubSoc Europe and
has Angewandte Chemie as the sister journal) will consists in 12 issues
for year, and embraces different research fields, including environmental
photocatalysis, photoredox catalytic synthesis and photobiology. The
authors wish ChemPhotoChem luck and a considerable success story.
The ecosustainable preparation of silver nanoparticles (AgNPs) was
achieved by merging biochemistry and photochemistry. Thus, sunlight
exposure of a AgNO3 solution in the aqueous extract of Dunaliella salina
(playing the dual role of reducing and stabilizing agent) afforded the
desired NPs.71 Interestingly, the anticancer potential of such compounds
towards MCF-7 cell lines was comparable to that of well known Cisplatin,
but was not detrimental to the normal cell line. Analogously, AgNPs were
also photochemically synthesized by using Derris trifoliata leaf extract as
the reaction medium and tested as larvicidal vectors.72
Recently, inorganic perovskite quantum dots (QDs) have been
employed as optoelectronic materials in the preparation of light-
harvesting and emitting devices, but their application for photo-
catalytic purposes remains limited.73 A recent work described the use of
colloidal perovskite QDs in the photoreductive conversion of CO2
in carbon based fuels (CH4, CO). The best results were obtained with
the CsPbBr3 QDs, where CO2 was reduced with an efficiency of
20.9 mmol g cat1.74 The efficiency was improved by using the CsPbBr3
perovskite QDs/Graphene oxide composite, as schematized in Fig. 3.75
In the field of energy storage, the ‘‘meteoric rise of perovskite single-
junction solar cells’’ and ‘‘perovskite tandem solar cells’’ have been efficiently
Fig. 3 Schematic representation of a CsPbBr3 perovskite quantum dot/graphene oxide

composite in the photoreductive conversion of CO2 in carbon based fuels. Reprinted with
permission from ref. 75. Copyright 2017 American Chemical Society.

described in a progress report by Bach and co-workers, with particular
attention to the development of increasingly efficient devices.76 On the
other hand, A. Walsh focused on the advantages of preparing solar cells
based on kesterite mineral structure (such as Cu2ZnSnS4 and Cu2ZnSnSe4),
including the fact that they are composed by earth-abundant and nontoxic
elements.77 Solar cells able to operate upon indoor illumination can be
employed as electric power sources for portable electronics and devices.
Grätzel and co-workers recently described a dye-sensitized solar cell (DSSC)
obtained from the combination of sensitizers D35 (8) and XY1 (9, see
Fig. 4) with the copper complex CuII/I(tmby) (tmby ¼ 4,4 0 ,6,6 0 -tetramethyl-
2,2 0 -bipyridine) as the redox shuttle. This exhibited a open-circuit
photovoltage of 1.1 V. Notably, the developed DSSC achieved an external
quantum efficiency for photocurrent generation that exceeds 90% (when
Fig. 4 Organic dyes recently used in solar cells.

irradiated in the 400–650 nm domain, and under illumination from a
model Osram 930 warm-white fluorescent light tube, the measured power-
conversion efficiency was 28.9%.78
Despite the effectiveness of photodynamic therapy (PDT) in the treat-
ment of actinic keratoses and early skin cancers (testified by the fact that
PDT is the only FDA approved approach to control field cancerization),
the pain related with this procedure often limits a widespread PDT
application. The reported interventions on PDT-associated pain were
assessed in an impressive review paper by Zeutouni et al. in the aim of
identifying the most promising methods to manage and minimize such
side-effects.79 Great attention has been given this year to the application
of PDT in dentistry; different literature and clinical reviews have been
focused to its use as supplementary antimicrobial treatment of deep
carious lesions,80 in the disinfection of acrylic denture surfaces,81 as well
as in the non surgical cure of chronic periodontitis.82
Among the original papers, Wu et al. prepared photo-cross-linkable
semiconductor polymer dots (Pdot) doped with the photosensitizer
Chlorin e6 (Ce6) that acts as a nanoparticle platform to perform PDT. The
desired Pdots (that are in turn prepared from phototoreactive oxetane
derivatives that acted as cross-linkable groups) represent an inter-
penetrated structure that on one hand prevents Ce6 leaching out from
the polymeric matrix and on the other hand leads to an amplified gen-
eration of singlet oxygen (F ¼ 0.4 vs. 0.1 of the non Ce6 doped Pdots).83
Folic acid tetrads were used by the research group of Sortino as a
template to prepare a mesoporous silica material able to encapsulate
meso-tetrakis(4-carboxyphenyl)porphyrin (TCPP) sensitizer in its interior.
The thus prepared assembly exhibits a satisfactory singlet oxygen
photosensitization efficiency, and enhanced photo-induced mortality in
KB cancer cells when compared with the free components (Fig. 5).
The development of environment-selective photosensitizers is a
challenge in PDT. The aminated-chrysophanol 10 was found to be
Fig. 5 Idealized picture for the targeted PDT with FA (blue)/TCPP(red) assembly released
from the mesoporous silica material. Reprinted with permission from ref. 84, Copyright
2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

proton-activatable by tumor acidic microenvironment, exhibiting both
emission and reactive oxygen species generation. The presence of two ter-
tiary amines ensured an enhanced cellular uptake, while red-shifting at the
same time the wavelength of absorption and improving the phototoxicity.85
Nanocomposite particles, consisting in self-assembled porphyrin arrays

as the core surrounded by amorphous silica as the shell, have been pre-
pared by Fan and co-workers through a combined surfactant micelle
confined self assembly and silicate sol–gel process. Along with the high
yield of generated singlet oxygen, the extensive self-assembled network of
porphyrins in the core enabled efficient energy transfer and an impressive
fluorescence for cell labeling. Furthermore, the silicate shell could be
smoothly derivatized to form targeting porphyrin–silica nanocomposites
able to destroy selectively tumor cells upon irradiation.86 Photoinitiated
living processes, such as radical and cationic polymerizations, received a
great attention from both industrial and academic researchers. Fors and
co-workers resumed the impact of photoinitiated cationic polymerizations
(Fig. 6a) on polymer science and, at the same time, described the state of
the art of photocontrolled cationic polymerizations, a rather new approach,
where the control over chain growth is actuated by alternating periods of
irradiation (activation) and dark (deactivation), while the rate of poly-
merization depends on the intensity of the light. (Fig. 6b).87 In the same
Fig. 6 Schematic depiction of (a) Photoinitiated cationic polymerizations and (b) photo-
controlled cationic polymerizations. Reprinted with permission from ref. 87, Copyright
2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

paper, the authors reported a remarkable strategy for the synthesis
of different polymeric structures under identical chemical conditions.
The reaction took place with two monomers (an electron-poor and an
electron-rich olefin) in the presence of two photocatalysts (having dif-
ferent absorption spectra) able to initiate either a radical or a cationic
process. The mechanism of the polymerization and the incorporation of
the monomer can be easily tuned via the selection of the wavelength
of the light source (Fig. 7). A change in the stoichiometric ratio of the
photocatalysts resulted in a further chemical control over the polymer-
ization and allowed for the design of elaborated polymeric structures.88
Selected cases of photoinitiated polymerization taking place in ionic
liquids have been described by E. Andrzejewska. This author also
resumed most of the applications relying on this strategy, such as the
preparation of ion-conductive polymer films.89 Lange et al. reported
the gram scale single-crystal-to-single-crystal synthesis of a 2D polymer
via photochemical [2 þ 2]-cycloaddition occurring on monomer 11. As
illustrated in Fig. 8, the obtained crystals are then wet-exfoliated under
mild conditions to afford single and double layer features.90
The photorearrangement occurring in hydrazones has been exploited
in the last decade for the development of photochromic materials.
A recent feature article described minutely the state of the art of this
argument.91
The metal-free, UV-light multicomponent coupling of aryl/alkyl halides
and silyl enolates in the presence of DABCO (SO2)2 as source of sulfur
dioxide has been optimized by Wu and co-workers and exploited for the
efficient synthesis of b-keto sulfones 13a–c. The process is initiated by
the homolysis of a C-halide bond, with the consequent formation of a
carbon centered radical, and exhibits a satisfactory functional group
tolerance (Scheme 4).92
Fig. 7 Switching the polymerization mechanism and monomer selectivity by changing

the wavelength of light irradiation. Reprinted with permission with ref. 88, Copyright 2017
American Chemical Society.

Fig. 8 The single-crystal-to-single-crystal synthesis of a 2D polymer based on photo-
chemically triggered [2 þ 2]-cycloaddition. The obtained crystals are then wet-exfoliated
under mild conditions to afford single and double layer features. Reprinted with
permission from ref. 90, copyright 2017 American Chemical Society.
Scheme 4
A self-assembled (glyco)peptide inspired by elastin protein was pre-

pared by taking advantage of combining solid phase peptide synthesis
with thiol-ene chemistry. Such biomolecule could be used as biomaterial
in the field of tissue engineering and regenerative medicine.93 Single
electron transfer (SET) cyclization processes still represents a facile and
widely used approach for (macro)cycles building. The preparation of
Sansalvamide, on analogue containing two pharmacophores (cyclic
peptides and O-phthalimide moiety), has been recently described by
Jin et al. The biological activity of the obtained compound was success-
fully tested in drug-sensitive HeLa, HepG-2 and MCF-7 cell lines in the
aim of developing a novel antitumor cyclopeptide drug.94

As concerning peptido-drugs, the selective, photocatalytic decarbox-
ylative macrocyclization of oligopeptides bearing N-terminal Michael
acceptors has been presented by the research group of David MacMillan.
The developed approach allows for the preparation of cyclic peptides
ranging from 3 to 15 amino acids. The synthetic scope of the procedure
was evidenced by synthesizing the somatostatin analogue COR-005
(Scheme 5).95
Photoredox catalysis often involves metal complexes, that frequently
rely on high-priced/rare elements such as ruthenium or iridium. How-
ever, in recent years, significant efforts have been carried out to exploit
complexes containing earth-abundant redox active elements, including
the ions CrIII, FeII, CuI, ZnII, and UVI. A review by Christopher Larsen and
Oliver Wenger discussed the scope and the mechanism of the reactions
developed in this field, providing also the reader with a summary of the
electrochemical and photophysical parameters that characterize such
innovative photocatalysts.96
The rise of nucleophilic aromatic substitution (SNAr) as a versatile
synthetic method is hampered by the low reactivity of arenes. Nicewicz
optimized a radical cation accelerated SNAr reaction by using alkoxy
groups in compounds 14a–c as nucleofuges and acridinium perchlorate
15 as the visible-light absorbing photocatalyst. The method was extended
to the functionalization of guaiacol and veratrole motives that constitute
the structure of lignin as well as of polyfunctionalised heterocycles
(Scheme 6).97
Interest for processes that merge gold catalysis with photocatalytic/
photochemical processes is currently increasing. One of the most recent
Scheme 5 Photoredox macrocylization to form the bioactive cyclic peptide COR-005.

Reprinted with permission from ref. 95, Copyright 2017 Wiley-VCH Verlag GmbH & Co.
KGaA, Weinheim.

Scheme 6
Scheme 7
Scheme 8
examples is the catalytic ipsoarylative cyclization of aryl-alkynoates 17a–d

or N-arylpropiolamides with phenyl diazonium tetrafluoroborate salts
in the presence of catalytic amounts of [(4-OCH3)C6H4]3PAuCl and
Ru(bpy)3(PF6)2. This approach was found to afford arylated spirocarbo-
cycles 18a–d in moderate to good yields (Scheme 7).98 Allylarenes can also
be efficiently prepared by following the same approach.99
Similar catalytic conditions were employed in the regioselective
trifluoromethylthiosulfonylation of alkenes (mainly styrenes) 19a–c
(Scheme 8).100

Scheme 9
Scheme 10
A photocatalyst-free, visible light driven variant of the Suzuki coupling

was achieved by using arylazo sulfones as starting photoactivated sub-
strates, and afforded the desired (hetero)biaryls in discrete to good yields
(Scheme 9).101
In photoredox catalysis, a single electron transfer (SET) process is the
initial step. However, since irradiation allows for the achievement of a
series of discrete, yet fundamental, fragment-coupling steps, the viability
of excited-state organometallic is possible and the triplet sensitization
by energy transfer has long been known as a powerful activation mode.
Mac Millan et al. described the formation of the excited-state of a nickel
complex via energy transfer from a photoexcited iridium sensitizer upon
visible light irradiation. Under these conditions, aryl halides are able to
couple with carboxylic acids (an example in Scheme 10).102
Due to its promising multifaceted application, the tautomerization via
an excited state intramolecular proton transfer (ESIPT) step is probably
one of the most studied processes in photochemistry.103 The critical
review of Serdiuk and Roshal104 focused on where double intramolecular
proton transfers can occur (for example 23), as well as on the spectral
features of these compounds.
The so-called hexadehydro-Diels–Alder (HDDA) reaction, that is the

cycloisomerization of substrates containing a 1,3-butadiyne core conju-
gated to a remote alkyne (24, Scheme 11) to generate an ortho-benzyne

Scheme 11
Scheme 12
intermediate (25) was described for the first time to occur under photo-
chemical conditions by Hoye and co-workers.105 Notably, whereas the
process took place at lower temperatures than those required for the dark
reaction, the generated benzynes 25 behave in the same fashion, sug-
gesting that the intermediates obtained under either thermal or photo-
chemical conditions are of the same multiplicity.
A tutorial review on the application of time-resolved photoelectron
spectroscopy combined with quantum chemistry and dynamics calcula-
tions to deepen the electronic relaxation mechanisms of photoexcited
molecules was proposed by G. A. Worth and H. H. Fielding.106 A peculiar
advantage of this strategy is represented by the different complexity of
the examined compounds, that included simple aromatics (benzene,
aniline), a pyrrole dimer bound by a weak N–H p interaction and the
green fluorescent protein chromophore.
In the last years, a significant attention has been given to the use of
laser flash photolysis to elucidate the photochemistry of organic mol-
ecules in nanocrystalline suspensions, a in the case of the conversion of
a-azidoacetophenone 27 to imine 28 (Scheme 12).107
The same approach has been applied by Garcia Garibay and co-workers
to the investigation of the reactivity of diarylmethyl radical pairs photo-
generated from crystalline tetraarylacetones,108 as well as to the character-
ization of transient isocarbazole, playing a key role in the photochemistry of
2-azidobiphenyls.109

5 Highlights in volumes 37 to 46
Azobenzene photoisomerization, 2016, 44, 294–321
Cultural heritage, and photochemistry, 2010, 39, 256–284
Cyclodextrins, photoresponsive, 2015, 43, 226–269
Exiton fission, 2015, 43, 270–285
Flow photochemistry, 2015, 43, 173–190
Fluorescence Imaging, nanoscale, 2010, 39, 191–210
Global artificial photosynthesis, 2016, 44, 259–282
Industrial applications, of photochemistry 2009, 38, 344–368
Interfacial electronic processes, on the surface of nanostructured
semiconductors, 2008, 37, 362–392
History of photochemistry, IAPS, 2012, 41, 269–278
History of photochemistry, EPA, 2011, 40, 197–229
History of photochemistry, APA, 2011, 40, 230–244
Human skin, photoprotection of, 2011, 40, 245–273
Nitric oxide photorelease, 2012, 41, 302–318
Nucleic acids, caged, 2012, 41, 319–341
Organic solid-state luminescence, 2015, 43, 191–225
OLEDs, 2008, 37, 393–406
Photoactivatable protecting groups and carbon monoxide molecules,
2017, 45, 175–190
Photochromic, nanoparticles, 2010, 39, 211–227
Photocatalysis for depollution, 2016, 44, 346–361
Photocatalysis with Donor-Acceptor Polymers, 2017, 45, 191–220
Photolithography materials, 2009, 38, 369–387
Photo-induced water oxidation, 2011, 40, 274–294
Photoluminescence sensors, 2016, 44, 322–345
Photon–molecule coupling fields, 2010, 39, 228–255
Photo-oxygenation, 2009, 38, 307–329
Photoredox systems for building C–C bonds from carbon dioxide, 2017,
45, 165–174
Polymerization, 2014, 42, 215–232
Prebiotic atmosphere, 2012, 41, 342–359
Prebiotic photochemistry, 2009, 38, 330–343
Proton transfer, in flavonols, 2011, 40, 295–322
Reactive oxygen species, 2012, 41, 279–301
Solar energy conversion, 2016, 44, 283–293
Singlet oxygen, in biological media, 2014, 42, 233–278
Solid-state, photoreactions, 2015, 43, 286–320 and 2015, 43, 321–329
TiO2 photoredox catalysis, 2016, 44, 362–381
UV spectra, calculated, 2014, 42, 197–214
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Quantum chemistry of the excited state:
recent trends in methods developments
and applications
Miriam Navarrete-Miguel,a Javier Segarra-Martı́,b
Antonio Francés-Monerris,c Angelo Giussani,d
Pooria Farahani,e Bo-Wen Ding,f Antonio Monari,c
Ya-Jun Liu f and Daniel Roca-Sanjuán*a
DOI: 10.1039/9781788013598-00028
Advances (2016–2017) in Quantum Chemistry of the Excited State (QCEX) are presented
in this book chapter focusing firstly on developments of methodology and excited-state
reaction-path computational strategies and secondly on the applications of QCEX to
study light–matter interaction in distinct fields of biology, (nano)-technology, medicine
and the environment. We highlight in this contribution developments of static and
dynamic electron-correlation methods and methodological approaches to determine
dynamical properties, recent examples of the roles of conical intersections, novel DNA
spectroscopy and photochemistry findings, photo-sensitisation mechanisms in biological
structures and the current knowledge on chemi-excitation mechanisms that give rise to
light emission (in the chemiluminescence and bioluminescence phenomena).
1 Introduction
Quantum Chemistry of the (Electronic) Excited State (QCEX) is a field
that uses the physical principles of Quantum Mechanics and further
concepts particularly developed to efficiently model the chemical pro-
cesses derived from light–matter interaction or, in general, chemical
phenomena involving upper electronic solutions of the Schrödinger
equation. QCEX has many applications in biology, (nano)-technology,
medicine and the environment, in which the population of the excited
electronic states gives rise to chemical phenomena not allowed in
ground-state chemistry. E/Z double-bond isomerisations, [2 þ 2] cy-
cloadditions, charge transport, tautomerisations or luminescence are
examples of such rich chemistry. Here, multi-radicaloid structures,
energy degeneracies between distinct configurations of the electrons,
a
Instituto de Ciencia Molecular, Universitat de València, P.O. Box 22085,
46071 València, Spain. E-mail: Daniel.Roca@uv.es
b
Department of Chemistry, Imperial College London, London SW7 2AZ, UK
c
Université de Lorraine & CNRS, Laboratoire de Physique et Chimie Théoriques,
Boulevard des Aiguillettes, BP 70239, 54506 Vandoeuvre-lès-Nancy, France
d
Department of Chemistry, University College London, 20 Gordon Street, London
WC1H 0AJ, UK
e
Department of Theoretical Chemistry & Biology, School of Engineering sciences in
Chemistry, Biotechnology and Health (CBH), KTH Royal Institute of Technology,
SE-10691 Stockholm, Sweden
f
Key Laboratory of Theoretical and Computational Photochemistry, Ministry of
Education, College of Chemistry, Beijing Normal University, Beijing 100875, China
28 | Photochemistry, 2019, 46, 28–77

intra-molecular or inter-molecular charge transfer (CT) are common
features of the excited electronic states which allow the mentioned
chemistry.
In our previous biannual contributions to the RSC Photochemistry
Specialist Reports,1–4 we have reviewed the advances on quantum-
chemistry computational studies focusing on photo-induced chemical
processes and also on the phenomena arisen as the result of a chemical
reaction (chemiluminescence (CL), bioluminescence (BL) and dark
photochemistry). We have traditionally organised the work in two parts
firstly describing methods developments and next analysing the trends
observed in the application of QCEX. We shall continue here with such
style. For the first part, taking into account the publications in 2016 and
2017, we find convenient this time to split the section into three parts
separating static electron-correlated methods, dynamic electron-
correlated methods and methodologies or computational strategies to
obtain dynamical properties.
QCEX requires multiconfigurational approaches able to describe on
the same foot distinct configurations of the electrons around the nuclei
(or configuration state functions) which usually appear in excited states
with similar energies. The interaction of such energetically-close con-
figurations gives rise to the so-called static (also strong or long-range)
electron correlation. A representative method able to compute the static
correlation is the complete-active-space self-consistent field (CASSCF), in
which a group of chemically-relevant orbitals is chosen and all possible
electronic configurations arisen from distributing the active electrons
over those active orbitals are allowed to interact in the computational
procedure. Such strong-correlated methods provide a correct wavefunc-
tion for the excited state, however, the obtained energies are far from
accurate. Short-range interaction between electrons (dynamic correl-
ation) is still needed for an accurate energy determination. In this con-
text, a practical and general strategy in the particular case of the CASSCF
method is to use second-order perturbation theory for such purpose,
giving rise to the complete-active-space second-order perturbation theory
(CASPT2) method.
CASSCF/CASPT2 and other multiconfigurational methods allow there-
fore an accurate determination of the excited-state electronic-structure
properties, which is a big step although not enough. Excited-state chem-
istry determinations additionally require computational strategies able to
determine the accessible and relevant excited-state chemical paths.
Minimum-energy path (MEP) computations are accurate procedures
providing a static description based on energy barriers. A further step
implies determining excited-state time-dependent properties such as
lifetimes or photochemical rates, which is a complex and computationally
costly task. Nevertheless, since some years ago, advances in computer
hardware, QCEX methods and software have allowed to modestly address
such problems. Many scientists in the field are therefore spending efforts
to improve and apply such dynamical computational approaches.
Regarding applications of QCEX, adiabatic and non-adiabatic chemistry
can be distinguished. Whereas the former, similarly to the ground-state
Photochemistry, 2019, 46, 28–77 | 29

chemistry, involves only one electronic state (even though this can be
formed by many electronic configurations), the latter normally refers to
non-radiative changes between two (or more) states. In QCEX, such non-
adiabatic chemistry is associated with conical intersections (CIXs) and
singlet-triplet crossings (STCs), which are related to internal conversion
(IC) and intersystem crossing (ISC) phenomena, respectively. As can be
seen in our previous reports, CIXs and STCs are crucial in many phe-
nomena of light-matter interaction of relevance in fields such as DNA
damage, organic photovoltaics, luminescence materials or BL. We shall
include in this chapter a section dedicated to recent trends on the roles
of CIXs and STCs. The other sections shall describe advances on (i) DNA
spectroscopy and photochemistry, (ii) photosensitisation mechanisms in
biology and medicine and (iii) CL and BL.
2 Developments of methods and theory

Over the last couple of years plenty of novel advances have been made in
the field of theoretical chemistry focused on the accurate character-
isation of electronic excited states. Most theoretical developments and
implementations can be roughly separated in two markedly different
research avenues, namely those dealing with an improved description of
the so-called static (or strong) correlation and those focusing on efficient
ways to include the remaining dynamic correlation. Static correlation
manifests itself as a significant deviation of the correlated electron
density from the one given by the Hartree–Fock approximation and is
often localised in a small portion of the molecule (e.g. metals and nearby
ligands in transition metal complexes). This rationale is widely used in
CASSCF methods that represent a suitable choice of the mean-field
approximation due to its multiconfigurational character and where
only dynamic correlation is then missing.5,6 Dynamic correlation, on the
other hand, is an extensive quantity with respect to the size of the system,
and its evaluation becomes very costly for large molecules. This is mainly
due to its slow convergence with respect to the amount of molecular
orbitals included, which results in a large increase in the computational
demands for quantitative analysis even for small to medium-sized sys-
tems when using diffuse and accurate basis sets. These two different
kinds of correlation have thus attracted much attention over the last few
years and reviewing them will be the focus of the first two sub-sections. It
is worth noting, however, that widely used methodologies such as time-
dependent density functional theory (TD–DFT) have been omitted from
this review as we focus on wave function-based ab initio approaches to
correlation. The interested reader is pointed towards some recent works
that illustrate the state-of-the-art of this particular field.7–9
2.1 Methods: static (strong) correlation

A surge in the use of methods accounting for static correlation has been
witnessed over the last few years and is mainly due to a range of schemes
that has become available for solving the full configuration interaction
(FCI) problem in wave function-based multiconfigurational techniques,
30 | Photochemistry, 2019, 46, 28–77

which is the main bottleneck of CASSCF-like methods. These could
roughly be separated in a few different strategies, with those based (i) on
density matrix renormalisation group-based (DMRG)10–12 techniques, (ii)
FCI quantum Monte Carlo (FCIQMC) methods,13–15 and (iii) semi-
stochastic Heat-bath Configuration Interaction (HCI)16,17 being among
the most relevant and followed approaches. A schematic view of these
different schemes is given in Fig. 1. These different techniques are
grounded on quite diverse principles, which will be very briefly sum-
marised next, the reader being referred to the original citations given
above for a more detailed account. DMRG focuses on incorporating
locality to describe the strong correlation problem as is schematically
shown in Fig. 1a top and middle panels, where the sequence of con-
tractions of the auxiliary indices in the DMRG in its matrix product state
formalism for the wave function are shown, which induce local correl-
ation and allow for efficient evaluations of expectation values. Fig. 1a
lower panel, on the other hand, displays the matrix product form of
the states and their overlap, which allows for decomposing the overlap
itself as a series of overlaps associated with each localised site and
facilitates the computation of expectation values and the application of
the variational principle on top of such wave functions.18 DMRG-based
algorithms are the oldest and most featured, having been recently
implemented within the second-order CASSCF solver19,20 algorithm
initially devised by Werner and Knowles21 and also been extended to
restricted/complete active space state interaction (RASSI/CASSI)22,23
formulations similar to those previously introduced for standard
CASSCF/RASSCF implementations,24,25 which allow obtaining essential
magnitudes such as oscillator strengths. FCIQMC relies, on the other
hand, on finding a solution to the FCI problem through stochastic
means. The key point of FCIQMC is that instead of allocating memory
for accommodating the entire FCI vector, as is often done in standard
Fig. 1 Scheme of the different FCI solvers recently developed to tackle the static
correlation problem and featuring (a) DMRG, (b) FCIQMC and (c) HCI. Panel (a) is
reproduced from ref. 18 with permission from the American Institute of Physics, panel
(b) reproduced with permission from ref. 13, Copyright 2016 American Chemical Society
and panel (c) reproduced with permission from ref. 17, Copyright 2017 American Chemical
Society.
Photochemistry, 2019, 46, 28–77 | 31

implementations, only determinants significantly populated along the
Monte Carlo sampling (based on a hash algorithm that communicates all
walkers or particles used to this purpose, schematically represented in
Fig. 1b) are stored so that the many determinants not contributing
prominently can be excluded, allowing for much larger active spaces to be
feasible. HCI is similar to FCIQMC in that it uses the concept of removing
many of the determinants that do not significantly contribute to the wave
function, but it does so by following a different path. In this case, the
selected configuration interaction method is initially used to pick only the
important determinants in the active space (scheme given in Fig. 1c),
which is then improved by performing perturbation theory on top of
those. HCI brings in a semistochastic implementation that heavily
increases the efficiency of the Epstein–Nesbet perturbation theory treat-
ment while also improving the variational stage of the method. In this way,
HCI differs from the methods previously outlined in that it also provides
estimates of the dynamic correlation energy, neglected in CASSCF-like
methods and where dynamic correlation is often included a posteriori with
a range of different techniques that will be covered in the next section.
One weakness of these methods often mentioned in the literature is
the need to define an active space or set of orbitals in which the FCI or
similar treatment will be performed given the present inability of run-
ning such schemes over the whole molecular orbital space. The choice of
the active space is indeed important and requires certain prior know-
ledge of the system under study and of the method itself,26,27 which can
prove to be an insurmountable barrier for non-specialist users. Never-
theless, encouraging recent developments have shown different ways in
which active spaces might be automatically selected in a black-box
manner,28,29 enabling less experienced researchers to make use of
these highly correlated techniques.
Fig. 2 shows an example of such an algorithm recently devised by Stein
and Reiher29 where a systematic selection procedure is depicted for
DMRG, and where a range of initial guesses is shown to yield analogous
results thus demonstrating its robustness and thus being suitable for
applications in a black-box fashion.
Many other developments have been carried out within static correlated
methods based on the original implementations that still rely on a
Davidson-like solver for the FCI problem. Martı́nez and co-workers have
developed a graphical processing unit (GPU)-based algorithm for
CASSCF30 including its non-adiabatic coupling framework31 that exploits
the massive parallelisation offered by these state-of-the-art technologies.
They have also explored efficient approximations to CASSCF such as the
floating occupation molecular orbital-complete active space configuration
interaction (FOMO-CASCI) within GPU technologies,32,33 which comes at a
cost similar to that of TD-DFT while being able to represent states with a
sizeable multiconfigurational character. Significant advances have also
been made with respect to the more efficient treatment of the two-electron
integrals handled by these algorithms via the Cholesky decomposition,
which vastly increases the number of basis set functions and hence allows
for larger and more precise basis sets to be employed.34–36
32 | Photochemistry, 2019, 46, 28–77

Fig. 2 Automatic active space selection algorithm described by Stein and Reiher.29 Figure reproduced with permission from ref. 29, Copyright 2017 American
Chemical Society.
Photochemistry, 2019, 46, 28–77 | 33

These are but a few representative examples that display the overall
trends followed in the field, which can be summarised in the following
points: (i) alternative and more efficient FCI solvers are being pursued to
correlate more orbitals and thus extend the use of statically correlated
methods to large scale applications, (ii) methods are being introduced to
remove the potential bias of selecting the active space by providing a
robust automated active space selection algorithm transitioning these
methods to a black-box fashion, and (iii) novel technologies such as GPUs
and more sophisticated two-electron integral schemes are being adopted
to increase their computational efficiency.
2.2 Methods: dynamic correlation

Plenty of advances have been reported over the last couple of years for
including more effectively dynamic correlation. Here we will survey
recently developed techniques to include dynamic correlation on top of
statically/strongly correlated (multiconfigurational) methods. These will
be split on those based on (i) CASPT2,37 (ii) N-Electron Valence state
perturbation theory (NEVPT2),38 (iii) density functional theory (DFT) on
top of multireference wave functions and (iv) coupled-cluster based
theories.
The first type to be reviewed will be the CASPT2 method,39 which
consists on a multiconfigurational variant of second-order Møller–Plesset
perturbation theory on top of a CASSCF reference wave function.
A revived interest in the CASPT2 method has been witnessed in recent
years due to the possibility of overcoming previous limitations associated
to its elevated computational scaling. To this end, formulations of the
Pair Natural Orbital (PNO)-CASPT240 and the Frozen Natural Orbital
(FNO)-CASPT241 have been reported, providing massive speed-ups that
enable its use with larger basis sets and larger molecular systems. A novel
extrapolation scheme has also been proposed,42 whereby the Shanks
extrapolation method can be applied by combining several low-cost FNO-
CASPT2 (and potentially other similar techniques such as PNO) compu-
tations to extrapolate the exact total energy. Shiozaki and co-workers have
reported outstanding work on the derivation and implementation of
analytical fully internally contracted CASPT2 energy gradients,43,44 and
non-adiabatic couplings,45 which enable their long sought use for on-the-
fly non-adiabatic MD schemes as those that will be discussed over the
next section. The CASPT2 method has also been recently extended to
work within the Generalised Active Space (GAS) framework leading to the
GASPT2 method,46 which is a cost-effective alternative of CASPT2 where
only a few selected excitations are allowed within the active space dra-
matically reducing its cost. DMRG variants of the CASPT2 method47 and
its multistate (MS-CASPT2)48 extension have also been recently reported,
allowing the accurate determination of electronic excited states with
unprecedently large active spaces.
NEVPT2 will be reviewed next, being a very similar method to CASPT2
with the exception that it employs a two-electron Dyall Fock operator that
drastically reduces some of the known problems of CASPT2 such as
34 | Photochemistry, 2019, 46, 28–77

intruder states and the need to use further corrections for treating open-
shell systems (IPEA shift).49 Very efficient novel implementations of the
NEVPT2 method have been recently reported, featuring its explicitly
correlated (F12)50 variant and the domain based localised pair natural
orbital (DLPNO)51 among them, which enable the use of NEVPT2 for very
large systems and diffuse basis sets. Two different implementations
within a DMRG framework have also been recently reported for its par-
tially contracted form,52,53 as well as one within its strongly contracted
scheme,54 which refer to different levels of contraction used in the for-
mulation of the zeroth-order Hamiltonian employed. These advances are
particularly relevant for transition metal complexes where the double-d
shell effect55 forces the inclusion of a large amount of orbitals to the
active space in order to provide converged results. A new time-dependent
variant has also been introduced for both DMRG-based56 and Matrix
Product State (MPS)-based57 wave functions that displays lower scaling
than the strongly contracted NEVPT2 method while providing energies
analogous to those of the fully uncontracted form, which should greatly
improve the applicability of the method for large-scale applications.
Finally, two different implementations for the internally contracted
NEVPT2 have been devised within the MPS framework,58,59 displaying the
huge advances made within N electron valence perturbation theory
combined with state-of-the-art DMRG-based methodologies and being
favoured in many cases to the more popular CASPT2 method.
Another way to include dynamic correlation on top of a statically cor-
related wave function is to employ DFT, which is known to feature a very
favourable scaling and thus provide an efficient and accurate character-
isation of the remaining correlation missing combining the advantages
of wave function and DFT. To this end, many different approaches have
been recently devised and will be surveyed next. The first is the pair-DFT,
which is based on a generalisation of Kohn–Sham DFT where the electron
kinetic and classical electrostatic energies are computed from a reference
wave function and the rest of the energy is obtained from a density
functional.60 The main differences with standard Kohn–Sham DFT
approaches are the use of a multiconfigurational reference instead of a
single Slater determinant and that the density functional is in this case a
function of the total density and the on-top pair density instead of being a
function of spin-up and down densities. This method has been suc-
cessfully applied in a number of difficult cases and has been shown to
provide reliable results thus making it a promising technique in the field
of theoretical photochemistry. The next method is based on the short-
range formulation of DFT (srDFT)61 and uses the same framework pre-
viously described making use of a multiconfigurational wave function
while exploiting the advantages of DFT for adding the remaining
dynamic correlation. In this case, this is done by capitalising on the
efficient treatment of the short-range dynamical correlations provided by
a number of recent DFT developments and approximations. Another
efficient way to include correlation on top of a statically correlated wave
function, of multireference configuration interaction (MRCI) nature in
this case, is described next thorough the advances in the DFT/MRCI62,63
Photochemistry, 2019, 46, 28–77 | 35

method recently developed by Marian and co-workers. These imple-
mentations built on the original work of Grimme and Waletzke64
improves this well-established semi-empirical quantum chemistry
method by producing a redesign of the original Hamiltonian which
fixes some of its known problems such as the inability to treat bi-
chromophores due to the strong dependence of the parameters used in
the Hamiltonian for describing the different excitation classes. Marian
and co-workers provide a new parameterisation that is spin-invariant
and incorporates a lesser amount of empirical parameters compared to
the original formulation,62 which has also been recently extended to treat
open-shell systems.63 The last technique combining a multi-
configurational reference and DFT is the ensemble DFT approach.65 The
approach is based in considering an ensemble of ground and excited
states like in statistical physics, where the ensemble is characterised
by the total number of states and their respective weights, and that can
be employed in order to simulate electronic excited states in a time-
independent manner while considering a certain degree of strong
correlation.
The last group of techniques reviewed encompasses coupled cluster
and the different advances made to both its use on top of multi-
configurational wave functions as well as the recent improvements made
in single determinant formulations to treat potential energy crossing
regions. A PNO formulation has been recently presented,66 which allows
the characterisation of electronic excited states at a vastly reduced cost by
using the back-transformed PNOs within the framework of equation of
motion coupled cluster theory and its similarity transformed variant.
A derivation for equation of motion coupled cluster analytical
non-adiabatic couplings is also to be highlighted,67 as this would in
principle allow the use of these extremely accurate techniques for non-
adiabatic dynamics simulations. Despite the availability of analytical
couplings, the question still remains in whether single Slater
determinant-based methods such as these can indeed be reliable for
properly representing inherently multiconfigurational regions of the
potential energy surface (PEH) such as interstate crossings (CIXs). Koch
and co-workers report some encouraging results in this regard by pre-
senting a novel specific formulation of coupled cluster theory that cor-
rectly describes conical intersections between electronic excited states of
the same symmetry,68,69 which should in principle allow for their use in
photo-excited MD. Lastly, a DLPNO formulation of Mukherjee’s state-
specific multireference coupled cluster method has also been recently
reported,70 providing huge speed-ups for these lengthy simulations and
bridging the gap towards their routine use in real applications.
The list of recent advances outlined above is by no means exhaustive
and represents mostly the different paths taken in order to include
dynamic correlation on top of multiconfigurational reference wave
functions. These can be summarised as follows: (i) perturbation theory-
based methods (CASPT2 and NEVPT2) remain the most popular due to
their favourable scaling, (ii) DFT corrections on top of multi-
configurational wave functions appear to be increasing in popularity due
36 | Photochemistry, 2019, 46, 28–77

to being even more efficient computationally than those based on per-
turbation theory, and (iii) encouraging advances are being made on the
coupled cluster front in order to reduce its cost and make it affordable for
medium-sized systems as well as to be able to represent crossing regions
properly to enable its use in theoretical photochemistry.
2.3 Dynamics
During the years 2016 and 2017, significant developments in the field of
dynamics simulations of photophysical and photochemical processes
have been achieved. We shall focus here on achievements on quantum
dynamics, and in particular, progresses which have been made regarding
on-the-fly quantum dynamics simulations, the possibility of describing
states of different spin-multiplicity (as singlet and triplet states), a first
non-adiabatic MD method based on the exact factorisation of the
electron-nuclear wave function and a promising improvement of the
efficient multi-layer multiconfigurational time-dependent Hartree (ML-
MCTDH) approach based on an adaptively expansion of the number of
single-particle-functions during the dynamics.
On-the-fly dynamics methods are those that do not require the know-
ledge of the PEH before the dynamics can be run, but instead, as the
name suggested, the required regions of the PEHs are computed only
when needed (i.e. on-the-fly) along the dynamics, normally through the
interface with an external electronic structure theory program. On-the-fly
methods are particularly attractive, since they circumvent one of the
main bottlenecks in performing quantum dynamics that is the need of
computing beforehand the various PEHs, a task that becomes quickly
computationally prohibitive with the increase of the number of degrees
of freedom (DOFs).
Among on-the-fly dynamics simulations, the direct dynamics vari-
ational multiconfigurational method (DD-vMCG) stands out for being a
full quantum dynamics method, in which both the basis functions used
for expanding the nuclear wave function and the corresponding coeffi-
cients evolve according to a variational resolution of the nuclear time-
dependent Schrodinger equation (TDSE). DD-vMCG is consequently in
principle able to correctly describe quantum effects as tunnelling and
non-adiabatic processes. Since quantum dynamics are normally run
along diabatic states, and since electronic structure theory programs
provide instead adiabatic states, a diabatisation procedure is needed in
order to run DD-vMCG dynamics. The propagation diabatisation method
was previously presented and used in conjunction with DD-vMCG
dynamics, and in 2017, the work of Richings and Worth extended its
applicability, previously restricted to only two states, to an arbitrary
number of states.71 This diabatisation scheme is based on the propa-
gation of the adiabatic/diabatic transformation matrix K, and its rela-
tionship with the matrix of non-adiabatic couplings term (NACT) vectors,
F, which is: rK ¼ FK. The equation, strictly exact only in the limit of a
complete electronic basis set, allows to propagate the K matrix to the
subsequent point in the dynamics (R þ DR) from the knowledge of K at
Photochemistry, 2019, 46, 28–77 | 37

the initial point (R) and the integration of the F matrix along the path
from R to R þ DR. Richings and Worth used the propagation diabatisa-
tion scheme for running DD-vMCG dynamics on the butatriene cation
and on thymine, including in both cases a variable number of excited
states. The results proved the applicability of the propagation diabati-
sation scheme and showed how the number of states included in a DD-
vMCG simulation influences the outcomes of the dynamics in terms of
population transfer and wavepacket spread.
In all on-the-fly dynamics simulations a local approximation of the
PEHs based on the actual points computed on-the-fly by the electronic
structure theory program must be performed. In 2017, Richings and
Habershon presented a method called Gaussian process regression (GPR)
for an efficient construction of a global PEH from ab initio electronic
structure calculations at selected configurations (see Fig. 3).72,73
According to the GPR method, the PEH is represented by a linear com-
bination of Gaussian functions, centred at a set of M reference points in
configuration space. The weights of such an expansion are determined
imposing the equality between the approximate PEH and the computed
reference points. Initially, a fixed number of reference points are ori-
ginated by a random uniform sampling for each degree of freedom
within the limits of a predefined sampling subspace. New reference
points are then added along the dynamics, exploiting the fact that GPR
allows the evaluation of the accuracy of the approximated PEH at any
point without having to calculate the actual PEH. It is in fact possible to
compute the variance at any point, which in turn reflects the accuracy of
the PEH based on the expansion derived by the current set of reference
points, and can consequently be used in order to decide whether or not
compute and add the new geometry to the reference points. A second
strength of GPR is that it can provide an approximate PEH having a sum-
of-products form, which is the form required for MCTDH simulations,
consequently making GPR suitable for running MCTDH simulations
without the need to precompute the PEH. Richings and Habershon tested
the GPR method on the butatriene cation, and on reduced models of
malonaldehyde and salicylaldimine.
Most of the available quantum dynamics approaches are able to
account for non-adiabatic transitions only among states of the same spin-
multiplicity, with only semiclassical methods as trajectory surface
Fig. 3 Pictorical representation of the GPR introduced by Richings and Habershon.

Reproduced with permission from ref. 72, Copyright 2017 American Chemical Society.
38 | Photochemistry, 2019, 46, 28–77

hopping (TSH) offering the possibility of describing ISC processes. So,
despite the recognised importance in many photoinduced processes of
the interplay between singlet and triplet states, spin–orbit couplings
(SOCs) and the resulting ISC processes were not included in most
dynamics simulations. Things have improved since 2016, the year in
which two independent publications presented an extension of the ab
initio Multiple Spawning (AIMS) method able to describe the interaction
between states of different spin-multiplicity.74,75 In both works, the
Hamiltonian appearing in the AIMS equation of motion for the wave
function amplitudes now includes a SOC part, added to the usual spin-
free electronic Hamiltonian and the nuclear kinetic operator. In such a
way the off-diagonal elements of the Hamiltonian between two spin-
diabatic electronic states having different spin multiplicity are equal to
the corresponding SOC. The latter can be computed along the dynamics
using the first-order saddle-point approximation, which is here particu-
larly justified by the smooth change that the SOC describes with respect
to the nuclear position. In line with AIMS philosophy, when an ISC
process from state I to J is considered to be likely, the phenomenon is
described by creating (spawning) new Gaussian functions on the PEH of
state J. The likelihood of an ISC process is evaluated computing an ef-
fective coupling parameter, which is proportional to the ratio between
the corresponding SOC and electronic energy gap. If the effective coup-
ling parameter is larger than a predefined threshold, and the resulting
new spawned basis functions will have an overlap with the parent basis
functions larger than a certain value, then ISC is supposed to happen and
the spawning process on the J PEH is indeed undertaken. In both papers
the new approach has been tested using a Breit–Pauli Hamiltonian in
order to account for the SOC. In the first of these two papers,74 resulting
from the work of Martinez and co-workers, the new approach, called
generalised AIMS (GAIMS, see Fig. 4), has been tested on a model system
and for simulating the non-adiabatic dynamics of thioformaldehyde. For
the model system GAIMS reproduces the exact results within a maximum
Fig. 4 Pictorical representation of all possible coupling between trajectory basis func-
tions included in the GAIMS method. Reprinted from ref. 74 with permission of AIP
Publishing.
Photochemistry, 2019, 46, 28–77 | 39

deviation of 7%. In the characterisation of thioformaldehyde, GAIMS
describes a small but sizable population of the T2 pp* state in a 200 fs time
window after S1 np* excitation. In the second of these two papers,75
resulting from the work of Varganov and co-workers, the approach was
tested studying the ISC process between the excited 3B1 and ground 1A1
states of GeH2 and comparing the results with values calculated using
statistical non-adiabatic transition state theory. From the comparison a
shorter 3B1 lifetime is predicted based on the improved version of AIMS,
which is ascribed by the authors to the ability of the implemented method
to account for ISC processes at any point along the intersection seam.
While Martinez and co-workers used in their tests an interface between
AIMS and Molpro in order to compute the needed SOCs, Varganov and
co-workers created an interface between AIMS and GAMESS.
In 2016 the exact factorisation of the electron-nuclear wave function
has been employed for deriving a trajectory-based dynamics method and
in 2017 the so derived approach was used for the first time for simulating
the photoexcited dynamics of a molecular system.76,77 In the exact
factorisation the solution of the TDSE is written as a single product of
a time-dependent nuclear function and a time-dependent electronic
function, which leads to a decomposition of the original TDSE in coupled
equations for the nuclei and the electrons. The nuclear equation is a
standard nuclear TDSE, but evolving on a ‘‘time-dependent’’ PEH (TD-
PEH) and including a time-dependent vector potential, which can be seen
as the time-dependent analogous of the non-adiabatic coupling vectors.
In the electronic equation, the presence of a so-called ‘‘electron-nuclear
coupling operator’’ couples the evolution of the electrons with the
nuclear degrees of freedom. Min, Agostini, and co-workers, formulated a
coupled-trajectory mixed quantum-classical (CT-MQC) scheme able to
solve the two equations.76,77 The approach is based on three main
approximations. First, the classical limit of the nuclear equation is
derived, and the corresponding Newton equation is instead treated.
Second, the time-dependent electronic function is expanded, accordingly
to a Born–Huang-like expansion, in the basis of electronic adiabatic
states. Third, the term that determines explicit dependence in the
electron-nuclear coupling operator on the nuclear wave function is
approximated employing information obtained from the trajectories. The
resulting CT-MQC equations simply require quantities that can be
obtained by standard electronic structure packages, consequently al-
lowing the on-the-fly implementation of the method. In order to test the
CT-MQC performances, and in particular its intrinsic ability to correctly
account for decoherence effects (which is a well-recognised pitfall of TSH
methods), the method has been employed for simulating the photo-
chemistry of oxirane in gas phase, comparing the results with simu-
lations obtained using fewest-switches surface hopping (FSSH) and a
corrected version of this algorithm (corr-FSSH) that accounts for quan-
tum decoherence in a phenomenological manner. The results show the
ability of CT-MQC to correctly describe quantum decoherence without
the need for empirical corrections, as in corr-FSSH, and to have with
respect to the latter method a better convergence with the number of
40 | Photochemistry, 2019, 46, 28–77

trajectories. Further work on the use of the exact factorisation for
dynamics simulations performed by Curchod and Agostini analysed the
topological features of the TD-PEH and of the time-dependent vector
potential.78 From their study it emerged that both the TD-PEH and the
time-dependent vector potential behave at all times as smooth function
of the nuclear coordinates, even in the region of CIX. This latter fact is
very promising, since it shows that the EF formalism greatly simplifies
the description of non-adiabatic processes, even in the presence of CIXs,
which in the adiabatic representation lead to the well-known singularity
of the non-adiabatic coupling vectors.
In the ML-MCTDH method, the key idea of MCTDH (i.e. an efficient
expansion of the N dimensional nuclear wave function in a sum-of-
products of functions, called single-particle functions (SPFs), with
reduced dimensionality) is in turn re-used in order to expand the SPFs.
The resulting SPFs can again go through a time-dependent multi-
configuration expansion, and the procedure can be repeated for each new
set of SPFs, creating various ‘‘layers’’ in the original expansion, from
which the name ‘‘multi-layer’’ MCTDH arises. As in MCTDH, the last
expansion will be on the basis of one-dimensional time-independent
functions, called primitives. In each layer of MCTDH expansion, SPFs
having a certain dimensionality, are expanded in terms of basis functions
(either new SPFs or primitives) having a reduced dimensionality. For
example, in a three-layer ML-MCTDH approach, the original wave func-
tion is described by a first MCTDH expansion (first layer), each of the
so-resulting SPFs is in turn expanded accordingly to a new MCTDH
expansion (second layer), and finally, the SPFs generated by the second
MCTDH expansion are expanded in the basis of the time-independent
primitives (third layer). The method is known to be very efficient and
able to treat systems of hundreds to thousands of degrees of freedom.
For example, in 2017, ML-MCTDH has been used for running dynamics
in a high-dimensional model of the LH2 antenna complex of purple
bacteria.79 Before starting ML-MCTDH dynamics, a specific multi-layer
structure must be chosen, answering the following three questions.
How many times the SPFs are expanded accordingly to a new MCTDH
expansion? How many SPFs are used in each expansion (which in turn
determines the number of configurations in each expansion)? How to
combine the degrees of freedom (which in turn determines the reduction
in dimensionality undertaken in each layer)? These decisions are key for
the efficiency of the method, and are normally taken on the bases of
prior experience and a ‘‘trial and error’’ approach. In 2017, Mendive-
Tapia and Gatti proposed a more systematic way for both selecting the
number of SPFs and combining the DOFs, implemented in the so-called
ML-spawning algorithm.80 The central idea behind their implementation
is to start with a reduced number of SPFs, and then automatically
increases their number during the dynamics in a ‘‘on-the-fly’’ fashion,
using as a criteria the value of the lowest natural orbital population. The
natural orbital population of each SPF is in fact related to the importance
of the corresponding SPF for the wave function. Normally, in a con-
sidered converged dynamics, the value of the lowest natural orbital
Photochemistry, 2019, 46, 28–77 | 41

population should not be greater than 103. In the ML-spawning
approach when the value of the lowest natural orbital population is
above a predefined threshold, more SPFs are created (spawned) into the
dynamics. The method consequently follows the philosophy of adding
new resources (in this case SPFs) when the dynamics requires them,
consequently saving the effort of starting with too many resources (SPFs)
than needed, which is particularly true at the beginning of a dynamics
where a wave-packet is normally quite localised and fewer SPFs are
enough. Regarding the way of combining DOFs, the authors suggested
that DOFs in a ML-spawning simulation have grown (i.e. rate at which the
associated SPFs are increased) in a similar fashion, should be grouped
together. This idea, although successful for the tested cases, implies that
test dynamics must be run in order to identify the most efficient way of
combining DOFs. The ML-spawning method was tested running simu-
lations on the non-adiabatic dynamics of pyrazine from the S2 excited
state and on the quantum dissipative dynamics in a spin boson bath,
showing for both cases a significant computational saving using the ML-
spawning approach with respect to normal ML-MCTDH implementation.
Apart from the above reported contributions on quantum dynamics,
which provided just a selection by no means meant to be exhaustive,
various significant contributions have been presented for semiclassical
dynamics. Here we just mention the publication of two thorough reviews
on the famous surface hopping method, one presented by Subotnik
et al.,81 and the second one published by Wang, Akimov, and Prezhdo.82
3 Conical intersections and their role in photophysics

and photochemistry
CIXs are quantum-chemical entities that arise from the Born–
Oppenheimer approximation of the Schrödinger equation as regions of
crossing between at least two PEHs. In case of involving singlet electronic
states, they are simply called CIXs, while for crossings between singlet
and triplet spin-free states, the term STC is commonly used. As men-
tioned in the Introduction, they represent the non-adiabatic processes IC
and ISC, respectively, and are related to ultrafast excited-state chemistry,
in the first case, and spin multiplicity changes, in the second case. In
order to properly describe these PEH crossings, special quantum-
chemistry methods are needed able to describe at the same time at
least two electronic configurations (representing each one of the elec-
tronic states which cross). For example, the E/Z photo-isomerisation of
ethylene is characterised by a CIX that is reached by elongating the
double bond, twisting it and pyramidalising one of the carbon atoms. At
such crossing structure, two electronic configurations (diradical and
zwitterionic) become energetically close to each other. Methods using
only one configuration (single-reference methods) cannot deal with the
multiconfigurational nature of these crossing regions, with multi-
reference methods being the most appropriate to provide an accurate
description. One of the most general and practical methods is CASPT2,
which has a good accuracy in photo-chemistry and excited-state
42 | Photochemistry, 2019, 46, 28–77

chemistry for small and medium-size molecules. Such usefulness is evi-
dent in the bibliography analysis done in this work (it is the most used
method in CIX studies; see Fig. 5a). Other methodological strategies are
also already available which were developed to allow approximate solu-
tions in the CIX region. They are motivated by the fact that CASPT2
computations are relatively slower as compared to other types of methods
such as TD-DFT and become prohibitive for practical applications in
large-size molecular systems or semi-classical dynamics studies with a
large ensemble of trajectories. It is however not always possible due to the
intrinsic multiconfigurational nature of the CIX. Regarding computa-
tional strategies, it is worth noting in Fig. 5b that a significant percentage
of articles have addressed the determination of time-dependent prop-
erties by using either a quantum or semiclassical approaches. Whereas in
the former, a quantum description is provided for both electrons and
nuclei, in the latter, nuclei positions and velocities are obtained by
integrating Newton’s equations and using electrons gradient computed
with quantum methods. As can be seen in Fig. 5, non-adiabatic chemistry
or CIXs have been mainly studied in organic p-conjugated molecules
(Fig. 5c, CQC) with relevant implications for the design of new materials
in nanotechnology or to understand the mechanisms present in nature
derived from light–matter interaction (Fig. 5d). Note also the large per-
centage of studies focused on improvements of methodology to more
accurately treat CIX or to decipher new conceptual or mechanistic aspects
of the PEH crossings (Fig. 5e). Finally, it is interesting to see that there is
a significant number of studies in which CIX characterisations are car-
ried out together with experimental measurements.
In this work, in order to illustrate the relevance of CIXs and the synergy
of joint experimental-theoretical research approaches, we shall review a
Fig. 5 Statistics calculated on the basis of CIX studies published in 2016 and 2017.
Distinct concepts are analysed: the method used to PEHs at or around the crossing region
(a), the computational strategy to obtain the excited-state chemistry (energy profiles or
semiclassical/quantum dynamics) (b), the chemical nature of the studied molecules (c),
the main fields of application (d) and the type of work (e) (201 articles considered).83
Photochemistry, 2019, 46, 28–77 | 43

few works carried out by some of the authors of the present chapter
mainly during the period 2016–2017 and focusing on the characterisation
of the CIXs and their link to observable data in the experiments. In
particular, we shall focus firstly on the CIXs which are reached upon an
excited-state double-bond E/Z isomerisation84–86 and secondly, those
which imply twisting of bonds in composites of borane clusters and
organic rings.87–90 As we shall see, CIXs are useful depending on the case
for the design of molecular rotors, organic photovoltaics and better
luminescent materials.
In 2016, we performed a joint experimental and theoretical study on
the photochemical properties of indan-1-ylidene malononitrile (IM) and
fluoren-9-ylidene malononitrile (FM).85 They are molecules containing
fulvene, which is an interesting chemical structure in the fields of
molecular rotors and optoelectronics due to its synthetic versatility,
commercial availability and ease of purification for electro-optic studies.
Low band-gap materials can be formed when FM is attached to tetra-
thiafulvene. The experimental study produced ground-state absorption
spectra of IM and FM with band maxima at B350 nm and very short
excited-state decay lifetimes in the ps scale for IM and in the order of
100 ps for FM. Systematic computations were performed for the IM, FM
and their basic chemical unit, the 1,1-dicyanoethylene (DCE) using the
CASPT2 method and computational strategies for determining the
photochemical decay paths. The main excited-state properties obtained
for these systems were the following:
– Loss of p-bonding character. The low-lying excited states mainly imply

excitations from orbitals with p-bonding character of the non-cyclic
double bond to others with p*-anti-bonding nature. Excited states in
IM and FM have CT nature from the cyano moiety to the rings.
– Elongation, twisting and pyramidalisation. The minimum energy path
in DCE is characterised by the elongation and torsion of the non-cyclic
double bond and the pyramidalisation of the carbon atom close to the
cyano groups. Such distortions bring the ground and excited-state PEHs
energetically close (CIX). As for ethylene, the electronic configuration that
represents the two states which cross have diradical and zwitterionic
nature.
– Stabilisation of charge separation upon increasing p-conjugation. The
positive charge density in the rings is more stabilised in FM than in IM.
This effect is lower at the CIX. Thus, whereas in DCE the CIX energy is
clearly lower than the energy of the excited states at the Franck-Condon
(FC) region, the relative energy decreases in IM and the CIX becomes
much less accessible in FM.
The joint experimental and theoretical study85 allows to interpret the

experimental observations. Thus, the lower accessibility to the CIX upon
excitation to the lowest-lying excited states found for FM as compared to
the findings obtained for IM, which can be associated to the higher
experimental decay lifetime of the former. Based on the outcomes,
one would suggest DCE/IM excited-state properties for the design of
44 | Photochemistry, 2019, 46, 28–77

molecular rotors (accessible E/Z isomerisation CIX), whereas those of FM
or larger p-conjugated systems (with less-accessible CIX) would be more
important for generating optoelectronic materials in which charge sep-
aration is an important target.
The elongated-twisted-pyramidalised CIX was also determined in a
previous study on indoline, which is the donor moiety of the dye in dye-
sensitised solar cells (DSSCs).84 In such study, which was already
reviewed in our previous contribution,4 the non-radiative decay path via
the ethylene-like CIX was associated to the loss of efficiency of the solar
cells based on the indoline-dye. We also suggested avoiding flexible
double bonds to improve the efficiency. In the same context of E/Z photo-
isomerisations, we have recently finished another study in collaboration
with the experimental group of J. Gierschner in which we have proposed
an interpretation for the distinct luminescence properties of dicyano-
substituted p-conjugated materials.86 Two groups of molecules were
considered depending on the relative a and b position of the cyano
groups in the non-cyclic double bonds with respect to the central ring of
the distyrylbenzene skeleton (a- and b-DCS series, respectively). In
chloroform solution, a-DCS molecules were found to have much lower
experimental fluorescence quantum yields than b-DCS systems. Mean-
while, in highly viscous/solid solutions and in crystalline state, all
quantum yields are clearly increasing. A rough approximation of the non-
radiative photochemical path by performing TD-DFT and CASSCF com-
putations on representative molecules of the a- and b-DCS series showed
that whereas the CIX point appears at similar energies for both type of
molecules, the vertical absorption energy is higher for a-DCS than for
b-DCS and the energy barrier to reach the CIX point is estimated to be
higher for the latter compounds. This implies that in chloroform solution
the non-radiative decay path is much less probable in b-DCS than in
a-DCS, which directly relates to the higher fluorescence quantum yield of
the former. A second interpretation of the experimental data that was
provided on the basis of the theoretical results was that the higher yields
observed in solid solution and crystalline state (which was called solid-
state luminescence enhancement) can be related to the large geometrical
distortion that is needed to reach the CIX point. Such distortion is largely
hindered when the molecules are packed in the solid state, thus
favouring the radiative (fluorescence) decay path.
The link between the restricted accessibility to CIX and the lumi-
nescence enhancement is also illustrated in a series of studies performed
on borane clusters and composites between borane clusters and organic
molecules.87–90 As it is commonly known, boron hydrides form clusters
such as closo, nido or arachno. Meanwhile, they combine to give rise to
macrostructures such as the syn-B18H22 and anti-B18H22 molecules. In
2012, a joint study lead by the theoreticians J. M. Oliva and L. Serrano-
Andrés and the experimentalist M. Londesborough explained why the
anti-isomer is fluorescent and not syn-B18H22.87 Such explanation was
provided based on CASPT2 and photochemical path computations,
which showed that the route on the excited state from the FC region to
the CIX is barrierless in the syn isomer and has a well-defined minimum
Photochemistry, 2019, 46, 28–77 | 45

in the anti-B18H22 molecule. In a subsequent study, the theoretical work
predicted that –SH substituents at the 4 and 4 0 positions of the anti-
isomer would give rise to phosphorescence, which was non-significant in
the parent molecule.88 In fact, while triplet population can be only
reached in anti-B18H22 at the CIX region, which requires to surmount a
relatively high energy barrier, the lowest-lying singlet and triplet states
are energetically degenerated along the photochemical decay path of 4,4 0 -
(SH2)-anti-B18H22 on the singlet manifold. Therefore, radiative decays
from both singlet and triplet states were predicted from the theoretical
predictions, which were confirmed by performing the pertinent experi-
ments. In the period 2016–2017, some of the authors of the present book
chapter have extended the analyses of borane photochemistry to
inorganic–organic composites, particularly, the B18H20-(NC5H5)2 mol-
ecule, which has pyridine (Py) substituents at the 6 0 and 9 0 positions of
the anti-B18H20 system.89 Experiments show that there is a blue shift of
the emission band maximum when measurements are carried out in
solution with less polar solvents. The blue shifting continues when
measuring spectrum in the crystal and especially at low temperatures.
Meanwhile, the lowest and highest fluorescence quantum yields were
obtained in solution with high-polar solvents and in the crystal at low
temperature, respectively. Theoretical analyses of the rotation of the
pyridine rings show small effects on the ground and excited states energy
profiles. Further photochemical analyses indicated that there are two
types of excited-state minima, one in which the two organic rings are co-
planar and other minima in which they are twisted. According to the
CASPT2 results, the former has larger vertical emission energies than the
latter. Therefore, the coplanar geometry was associated with the emissive
states in the experimental conditions in which blue shifting was
observed. Indeed, twisted structures are hindered in solid state. Twisted
structures have also larger dipole moments and accordingly they are
expected to be more stabilised in polar solvents. This is in agreement
with the band maxima observed in such conditions, which appears red
shifted as compared to the other spectra (in solution with less polar
solvents or in the crystalline state). Interestingly, the CIX related to the
non-radiative decay path in these systems was determined to have a
distorted geometry, which implies a rotation and flapping motion of the
two pyridine rings. To reach such crossing point, the boron–boron con-
nectivity holding the B(6) atom to the reminder of the boron cluster must
be broken. The CIX was found to be energetically above the position of
the coplanar and twisted minima and slightly above the position of the
bright states at the FC region in the computations in vacuo, which are
expected to be a good approximation for the experimental conditions in
solution with solvents of low polarity. The high dipole moment obtained
for the CIX structure indicates that the non-radiative path should be
expected to be more accessible in solution with polar solvents and
therefore it was associated to the decrease of the fluorescence quantum
yield measured in the experiments in such conditions. Finally, the fur-
ther increase of the yield in the solid state and especially at low tem-
perature was ascribed to the restricted access to the highly distorted
46 | Photochemistry, 2019, 46, 28–77

structure of the CIX. This is similar to the previous findings for the DCS
compounds86 and points to the crucial role of the CIX to interpret the
well-known phenomena of solid-state enhanced luminescence (also
known in the literature with the less concrete statements J-aggregation,
aggregation-induced emission or aggregation-induced enhanced
emission).
Recently, we have also characterised and interpreted the spectroscopic
properties of other inorganic–organic composites which are formed
when mixing anti-B18H20 and pyridine, B18H20-8 0 -Py and B16H18-3 0 ,8 0 -
Py2.90 Both molecules have accessible CIXs on the excited state and
accordingly they are not fluorescent. Computations on the former show a
STC region along the decay path on the singlet manifold, which could be
related to the fact that this system possesses measurable phosphor-
escence quantum yield of 0.01.
4 DNA/RNA spectroscopy and photochemistry

Understanding nucleic acids’ excited states represents a crucial task for
modern science since it enhances our comprehension of life evolution
and functioning. Processes of utmost relevance, such as the natural
selection of the DNA/RNA current chemical structures and the formation
of photolesions that may induce serious diseases like skin cancer, have a
molecular basis that may be elucidated using the adequate computa-
tional tools. However, the inherent difficulties coming from the correct
description of the electronic states and their dynamics, the assessment of
the influence of the environment and the multi-chromophoric character
of DNA/RNA systems, challenge state-of-the-art theoretical method-
ologies. The development of novel theoretical approaches and the grad-
ual increase in computational power over time allows a tackling of these
major issues subsequently yielding remarkable advances in the field of
DNA/RNA spectroscopy and photochemistry.
The present section covers some of the achievements related to the
field reported in 2016 and 2017. It is divided in two subsections. The first
one concerns the advances in the comprehension of DNA/RNA spectro-
scopic features, mainly vertical absorptions and the study of electronic
excited-state wave functions, and the second one is devoted to the
photochemical pathways that drive the excited-state decay. Photo-
chemical channels of photostability, damage and repair involving p-
stacked DNA/RNA nucleobases will be emphasised as hot topics of
research.
4.1 DNA/RNA light absorption

UV light absorption enables populating the excited states of DNA/RNA
systems and takes place in nucleobases given its p-conjugated nature.
The correct determination of the electronic-state energies and the relative
positions of the bright (or optically active) states is fundamental because
it determines the initially accessed electronic state upon light absorption
and allows direct comparison between theoretical and experimental data.
Photochemistry, 2019, 46, 28–77 | 47

Single nucleobases and related structures. Recent efforts have been
dedicated to assess the specific impact of the environment in the excited
states calculation of DNA/RNA monomeric nucleobases. The absorption
spectrum of DNA/RNA nucleobases can be simulated sampling the FC
region to obtain a set of nuclear coordinates, which are later on used to
compute the vertical absorptions on top of each geometry.91 Pola et al.92
have used a Wigner distribution (quantum harmonic oscillator) on the
FC regions of the four DNA nucleobases to assess the impact of the first
solvation shell, explicitly included in the system. The authors show non-
negligible solvent effects, demonstrating the well-known destabilisation
on the n,p* states due to the explicit hydrogen bonding of water.
Another usual approach to include environmental effects is the so-
called quantum mechanics/molecular mechanics (QM/MM) hybrid
approach, in which the chromophore(s) is(are) described with accurate
quantum mechanics (QM) methods whereas the environment is treated
as point charges surrounding the QM part. Within this approach, the FC
region can be sampled by means of MD or QM/MM MD simulations.
Martı́nez-Fernández et al.93 have recently validated this methodology
to correctly capture the blue shift in the absorption spectrum of
5-methylcytidine due to solvent effects. The authors have employed three
different solvation approaches and have contrasted the theoretical results
with experimental recordings. Nørby et al.94 have reported averaged
embedding parameters for nucleobases inserted in DNA double strands,
with the aim to save computational time without a significant accuracy
loss when making use of the polarizable embedding model to compute
DNA optical properties. The proposed approach was illustrated with
2-aminopurine, a common DNA probe, as a model compound. The
authors showed that treating the bulk water around the DNA double
strand as a continuum has slight impact in the UV spectra as compared
to reference values.
Nucleobase clusters. The comprehension of the spectroscopic prop-
erties of nucleobase monomers constitutes a first necessary step towards
understanding DNA/RNA photochemistry. Nucleic acids are however
polymeric chains of chromophores and therefore absorption studies
must be expanded to nucleobase multimers in order to describe add-
itional phenomena such as delocalised excitons and charge/energy
transport taking place all over the double strands.95 Nevertheless, the
complexity for describing the absorption properties of nucleobase clus-
ters, interacting either via Watson–Crick (WC) base pairing and/or p–
stacking interactions, increases with the number of atoms considered,
requiring larger computational efforts. Nogueira et al.96 have performed a
QM/MM study of a solvated polyadenine (dA)20 double strand deter-
mining the excited states of eight p-stacked adenine nucleobases making
use of a TD-DFT method to describe the electronic states. The quantita-
tive analysis of the delocalisation extent of the excited-state wave func-
tions, shown in Fig. 6, revealed that light absorption takes place mainly
over two adjacent nucleobases (47.9%), whereas excitations localised over
monomers (22.7%) and trimers (22.8%) also contribute to the spectral
intensity. Another important conclusion of the work is that the observed
48 | Photochemistry, 2019, 46, 28–77

Fig. 6 Decomposition of the lowest-energy band of the UV absorption spectrum of
(dA)20 computed using the QM/MM approach and the TD-DFT method on top of 100
different geometries. DL stands for delocalisation length, followed by the number of
stacked adenine molecules. Reproduced from ref. 96 with permission from the Royal
Society of Chemistry.
hypochromism in DNA can be mainly explained by long-range interaction

between nucleobases, and not by delocalisation or charge-transfer
phenomena. The remarkable delocalisation over the stacked adenine
moieties was also reported by other computational studies using
coupled-cluster methods.97,98 In particular, Sun et al.98 used ab initio
results to parameterise DFT functionals to describe the excited states of a
series of DNA tetramers, including alternating and non-alternating AT
and GC oligomers. Results also showed vertical delocalisations between
p-stacked nucleobases not only for AT but also for GC dimers. By using a
different approach, Saha and Quiney99 applied the effective fragment
potential method100 to represent the solvent effects in model AT dimers,
showing that hydration enhances delocalisation in p-stacked AT clusters
whereas showing much less delocalisation in the WC arrangement. The
authors interpret this phenomenon in light of the number of hydrogen
bonding with the solvent available for each model system.
4.2 DNA/RNA decay pathways

The natural photostability of nucleic acids, survivors in a world flooded
by UV radiation, has been ascribed to the intrinsic ultrafast decays dis-
played by natural nucleobases.101 From a theoretical standpoint, this fact
has been often explained due to the barrierless decay of the p,p* bright
state towards the CI with the ground state in an ultrafast (sub-ps)
manner.95,102 Even though this phenomenon is fairly well understood,
there are still some open questions without a satisfactory answer, such
as the excited-state mechanism of non-canonical nucleobases or the
deactivation routes responsible for the long-lived (several to dozens of ps)
excited-state components recorded experimentally in double-stranded
DNA/RNA.95
Decay pathways of nucleobase monomers and related structures. The
advent of new developments as those previously outlined in Section 2 has
paved the way for the use of more correlated methods in the character-
isation of the photoinduced phenomena triggered in DNA/RNA nucleo-
bases and nucleosides upon UV-light irradiation. Recent studies have
Photochemistry, 2019, 46, 28–77 | 49

Fig. 7 Evolution of the different lowest-lying electronic excited states for water-solvated
deoxy-thymidine. Panel a displays the ultrafast decay channels, based on 1pp* and 1pHs*
excitations, whereas panel b shows the longer-lived channels featuring optically dark
1
nOp* state and two different triplet (3nOp*/3pp*) states. Panel a reproduced from ref. 104,
Copyright 2017 American Chemical Society. Panel b reproduced from ref. 105 with
permission from the PCCP Owner Societies.
shown the intrinsic differences obtained by mapping the different PEHs

of nucleobases103 and nucleosides,104,105 at the CASSCF and CASPT2 le-
vels of theory, illustrating how dynamic correlation is key to faithfully
depict photoinduced phenomena in these species (see Fig. 7 for the
particular example of deoxy-thymidine). Despite displaying similar PEHs
as those reported at the CASSCF level,106 MS-CASPT2 results highlight the
role of dynamic correlation in enhancing the ring puckering motion
along the main reaction coordinate as shown by the characterised 1pHp*
twisted minimum (see Fig. 7a) not featured at CASSCF. Moreover,
dynamic correlation also plays a key role in stabilising the 1pHs* state,
which under solvation offers an alternative competitive decay channel
through a ring-opening CIX with the ground state. Fig. 7b shows the dark
states (1/3nOp* and 3pp*), which display a lesser dependence to dynamic
correlation and thus resemble more those previously obtained at the
CASSCF level.107 The PEHs and associated spectroscopic signals have
been shown to be in agreement with the available experimental evidence,
not just for canonical nucleobases but also for epigenetic modifications
such as 5-methyl-cytosine,108 which display an increased lifetime with
respect to its canonical form.
Decay pathways of nucleobase clusters. The presence of additional
nucleobases in photoexcited DNA/RNA oligonucleotides opens alternative
decay routes to the monomeric decays localised in a single nucleobase, due
to p–stacking interactions and the WC hydrogen bonding occurring in
DNA/RNA double strands. Whereas the former interactions are usually
ascribed to long excited-state lifetimes109–113 and the formation of photo-
lesions such as cyclobutane-pyridine dimers (CPDs) or 6-4 photoproduct
(64-PP) the inter-strand hydrogen bonding drives photoresponses at the
picosecond scale, as shown by recent experimental measurements.114–116
The disentanglement of the excited-state components measured at
very different timescales117 represents a challenge for the scientific
50 | Photochemistry, 2019, 46, 28–77

community and needs the use of theoretical methodologies to resolve
the riddle. Using TD-DFT in combination with continuum models, it has
been recently suggested that the nanosecond fluorescence experimentally
registered corresponds to the presence of high-energy long-lived mixed
(HELM) states.118,119 These states constitute mixtures of intra-strand
Frenkel excitons and CT excitations over alternated AT and GC DNA
oligomers. It is proposed that the long-lived fluorescence indeed
correspond to the exciplex emission from the excited-state minima of the
HELM states. Recently, the decay rate for the electron transfer process
from the intra-strand CT state to the ground state in GC stacked dimers
has been studied using theoretical methods.120
One of the most common photolesions in DNA is the occurrence of
excited-state cycloadditions, which covalently bond the p-stacked nu-
cleobases leading to CPD and 64-PP structures that can induce muta-
genesis. Rauer et al.121 have studied the photodimerisation of p-stacked
thymine dimers by means of surface-hopping MD using the CASSCF
method. In this study, the photoreaction took place in the singlet mani-
fold even though ISC processes with triplet states were allowed to occur.
The authors reported that the photo-cycloaddition is mediated by a
doubly excited state delocalised over two thymine moieties, placed above
the bright state at the FC region. It was suggested that the system needs
to overcome an energy barrier in order to populate the reactive state. In
a different work, Mendieta-Moreno et al.122 conducted QM/MM non-
adiabatic simulations to study the same photoprocess. The authors
reported the presence of energy barriers attributable to the motion
restrictions imposed by the WC hydrogen bonding and the sugar-
phosphate backbone. Given the significance of the CPD lesions, even
though they are formed in low yield, cells need to repair the photodamage
in order to preserve the correct biological function of nucleic acids.
Photolyases constitute a family of bacterial enzymes that are able to repair
the damage by absorbing blue light. Notwithstanding the relevance of
these processes, the molecular basis of the reparation is not completely
understood yet. Lee et al.123 have applied QM/MM methodologies to study
the photorepair processes, reporting a variety of competing charge-
transfer states that could explain the high repair yield of the enzyme.
Photodimerisations involving other nucleobases have also been
recently studied. The adenine-adenine photoreaction mechanism was
tackled by Banyasz et al.124 The authors explained the base-sequence
dependence of the experimental quantum yield of the photolesion in
terms of molecular–orbital interactions between the two adenine nu-
cleobases. Another study on the adenine–thymine dimerisation also
revealed the remarkable influence of the relative syn/anti orientation
between the two nucleobases influencing the reactivity of the photo-
cycloaddition.125
Another kind of photolesions consists in the formation of a single C–C
bond between two adjacent pyrimidine nucleobases, leading to the so-
called 64-PP. Recently, the photoprocess taking place between two
stacked thymine molecules was studied by Giussani et al.126 employing
the QM/MM approach, describing the QM part with the CASPT2//CASSCF
Photochemistry, 2019, 46, 28–77 | 51

protocol.127 The authors found a reactive path along the PEH of a charge-
transfer state from the 5-end to the 3-end thymine. From a pro-reactive
initial structure, the CT state can decay towards a CIX with the ground
state, from which the system, after surmounting an energy barrier on the
ground-state PEH, can lead to the formation of an oxetane ring, the
known intermediate for 64-PP production.
Regarding the photochemical decay channels involving the hydrogen
bonding between opposed nucleobases, i.e. WC base pairs, recent efforts
have been devoted to understand the electron-driven proton transfer
processes in presence of additional p-stacked nucleobases.128 It has been
recently shown that not only inter-strand CT states can initiate the pro-
cess but also intra-strand CT states.129 Martı́nez-Fernández et al.130 have
studied the PEHs associated to these types of mechanisms in alternate
GCGC and ATAT tetramers, reporting a barrierless profile for the former
and the presence of a significant barrier for the latter, in agreement with
the available experimental evidences.
Despite recent advances, more sophisticated and better-resolved
spectroscopic methods are sought in order to unequivocally assign the
different deactivation channels populated in DNA upon UV-exposure.
One recent development in that front comes from two-dimensional
electronic spectroscopy (2DES), where an enhanced spatial and tem-
poral resolution is obtained with respect to the widely used standard
pump–probe set-ups and that has the potential to separate monomeric
contributions to those due to excimer/exciplex formation in oligomeric
systems. Moreover, this technique is in principle also able to disentangle
specific conformations in solvated dimeric and multimeric systems,
elucidating the concrete conformations favouring specific chan-
nels.131–133 The field is still in its infancy and plenty of work has been
dedicated theoretically to the accurate description of the seldom studied
high-lying excited state manifold, which characterise the different tran-
sitions recorded in these complex experiments.134–136
5 Photosensitisation of biological structures and

photodynamic therapy
With the notable exception of important chromophores such as retinal
embedded in rhodopsin or photosynthetic systems, whose biological
significance is obvious, most of the biological polymeric structures,
nucleic acids, proteins, and lipid membrane do not absorb visible light,
and are instead sensible to ultraviolet UVA and more often UVB and UVC
light. This feature can be easily understood in terms of the necessity to
protect their integrity in the biological environment, as absorption of
light may trigger unwanted photochemical reaction leading to the
destruction or modification of the biological structure and hence
ultimately to the cell death or to mutation. Actually, given the amount of
UVC and UVB light reaching the Earth being filtered by the ozone layer
one can recognise a protective strategy of biological organisms to limit
the unwanted effects of exposure to the sun as already mentioned in
Section 4.2. Direct damage produced by direct exposure, especially in the
52 | Photochemistry, 2019, 46, 28–77

case of nucleic acids, cannot be neglected, being related to skin cancer
(cf. Section 4.2). Here, we want to consider the indirect effects produced
by relative small chromophores interacting covalently, or most often non-
covalently, with biological systems and able to absorb light in the UVA or
visible region of the spectrum to subsequently trigger photochemical and
photophysical phenomena resulting in the production of damages in the
biological structure. The latter is the process known as photosensitisa-
tion and from a photophysical and photochemical point of view one can
recognise different types of mechanisms. The most common processes
involved in sensitisation are related to ISC, i.e. the sensitizers are sup-
posed to populate their triplet manifold with a reasonable efficiency, the
triplet states may then evolve to induce electron- or energy-transfer, in a
sort of direct mechanisms, or may lead to the production of singlet
oxygen (1O2) that will subsequently produce oxidative lesions to the
biological systems. However, we will show in the following that such a
characterisation is certainly too simplistic and indeed, several different
and competitive pathways, including or not triplet population, should be
taken into account to provide a comprehensive picture of the phenomena
into play.
Photosensitizers can be of different nature, but in general are consti-
tuted of p-conjugated aromatic moieties, and where the presence of
relatively heavy atoms, such as sulphur, may increase the ISC effi-
ciency.137 As an example we remind that polyunsaturated hydrocarbons,
produced by fuel combustion and present in the air as a source of
pollution may also act as sensitizers, urging to the development of a
protective strategy and to the comprehension of the combined pollution
plus UV exposome.138
Despite the possible harmful effects related to photosensitisation, the
former general process is nowadays gaining a very important popularity
as the base of the so-called photodynamic, or light assisted therapeutic
strategy.139 The latter are indeed based on the combination of drug
administration and exposition to light in order to treat resistant lesions
such as surgically untreatable cancers. It is noteworthy that the previous
strategy has also been used in antimicrobial and antiviral therapy, as well
as in food industry for water and food processing. In many instances,
photodynamic therapy requires the use of photosensitizers able to pro-
duce 1O2. Furthermore, in order to allow for the non-invasive treatment
of deep lesions, sensitizers absorbing in the red or infrared regions of the
solar spectrum are strongly envisaged to reach the therapeutic window
(650–1350 nm) in which human, and in general biological, tissues are
transparent.
From those two examples it appears evident how sensitisation may be
considered both as a fundamental process necessary to be understood to
rationalise the insurgence of harmful diseases and as an opportunity to
develop novel therapeutic strategies and drugs. Hence, it is not sur-
prising that a considerable amount of theoretical work has been devoted
to such problems in the past two years. From a computational point of
view the task is extremely challenging requiring a very well balanced
description of different spatial and temporal scales. Indeed, a fully
Photochemistry, 2019, 46, 28–77 | 53

description of the photophysical and photochemical pathways experi-
enced by the different chromophores should be accompanied by a good
sampling of the conformational space defining the interaction with the
biological system and, at the same time, the specific effects and the
influence of the environment should be properly taken into account.
One of the most paradigmatic photosensitisation processes is certainly
DNA photosensitisation and benzophenone as a model system has been
the subject of a large number of studies140 elucidating its binding
modes141 and their main photophysical pathways, i.e. triplet–triplet
energy transfer to thymine.142 However, the interest of benzophenone
relies in the fact that its interaction with DNA may open the way to a
number of competitive pathways. In particular and due to the increased
basicity in the n–p* excited states, benzophenone can act by hydrogen
abstraction either from nucleobases or from the backbone sugar of DNA,
hence possibly leading to harmful lesions including strand breaks. It has
been shown143 that the possible hydrogen-abstraction pathways strongly
depend on the interaction modes. Indeed, when benzophenone is
interacting in the DNA minor groove, i.e. in the most stable conform-
ation,144 only the backbone sugar hydrogen can be accessed by the car-
bonyl oxygen. On the contrary, in the case of the double insertion mode,
the backbone is not accessible and instead the hydrogen from the nu-
cleobase should be considered as potentially reactive. The free energy
profile and the transition state (TS) of the two reactions, i.e. H-abstraction
from sugar or from the nucleobase, by the T1 state of benzophenone have
been obtained at DFT and wave-function based levels of theory. Results
obtained on the isolated model system have unequivocally pointed to-
wards relatively low activation energy of the order of 9–10 kcal mol1, in
the same order of some enzymatic reactions. While those results are
coherent with the observation that benzophenone may be used as a
photocatalyst, these do not explain why the aforementioned pathways
and the related photoproduct are observed only marginally. To resolve
such an apparent contradiction it is necessary to turn towards the
description of the conformational space spanned by benzophenone
interacting with DNA as provided by classical MD trajectory. Indeed, if
one considers the distribution of the distance between benzophenone
carbonyl oxygen and the DNA reactive hydrogens one finds, coherently
between minor groove binding and double insertion, that the probability
is peaked at around 5–6 Å and only a very marginal population (less than
10%) is found between distances of 2.0–2.5 Å, i.e. only a very minor
fraction of benzophenone molecules will be at potentially reactive dis-
tances with the DNA components, and hence the energy transfer
deactivation channel will be favoured compared to the photochemical
hydrogen-abstraction. Hence, in a certain sense this mechanism can be
regarded as a sort of self-protection strategy, in which the molecular
environment of the macromolecules hampers the reactants encounter
and hence strongly diminishes the outcome of the reaction despite the
presence of a generally low activation barrier. Apart from its biological
significance, this study also provides a clear evidence of the complex
interplay and equilibrium between photophysical, electronic and
54 | Photochemistry, 2019, 46, 28–77

structural effects that should be taken into account in the study of the
photosensitisation of biological structures.
The effects of the molecular environment in tuning and in some
instance driving the available photophysical channels when interacting
with DNA is also exemplified in the case of two dyes, nile red and nile
blue, widely used in biological applications and proposed as sensitizers
acting by photoinduced electron transfer to guanines. The optical and
photophysical properties of the two isolated and solvated dyes have been
fully analysed underlying their absorption in the visible part of the
spectrum and characterizing the different excited states.145 More
importantly, the reproduction of the absorption and emission spectra
has allowed from the one hand to underline the importance of dynamic
and vibrational effects in shifting the absorption wavelengths with
respect to the one obtained from the ground state equilibrium geometry
and on the other hand to validate TD-DFT level of theory against high
level CASPT2 results. Furthermore, the reproduction of the absorption
spectrum from snapshots obtained from quantum-based Wigner distri-
bution or from classical MD, has also provided an alternative way to
refine force field parameters. Subsequently,146 and by using classical MD
the interaction modes of the two dyes with self-complementary DNA
double strand constituted of guanine and cytosine bases has allowed to
pinpoint two stable modes of interaction for both dyes, namely inter-
calation and minor groove binding. Snapshots issued from the MD tra-
jectories have then been used as starting points to analyse at hybrid QM/
MM level the behaviour of the different excited states. In particular, we
have considered local excited states as compared to the states in which
the electron is transferred to orbitals localised on the guanine. In the case
of the nile red chromophore, it appears that the CT state involving
guanine is always higher in energy compared to the local states, whatever
the interaction mode considered; hence electron-transfer sensitisation
should be excluded for such system. On the other hand, and quite sur-
prisingly, it appears that in the case of nile blue, while intercalation mode
always provides energetically inaccessible CT states, in minor binding
mode a state inversion operates and the population of the charge-transfer
state becomes possible, hence sensitisation should be considered as
possible. This occurrence can be rationalised taking into account the fact
that in minor groove binding nile blue will be residing close to the
negatively charged DNA backbone, hence stabilizing a CT state leaving a
hole, i.e. positive charge, on the chromophore. On the other hand, in
intercalation the charge separation process will take place in the hydro-
phobic DNA core, hence destabilizing the CT state. Remarkably enough
the effects of nile blue on DNA have been confirmed by experimental
results and have also recently led to the latter being officially declared
as a potentially genotoxic compound by the European Commission
Agencies.147
As evidenced in the case of benzophenone, in addition to the more
studied sensitisation phenomena based on electron- or energy-transfer
and 1O2 activation, an important consideration has been devoted to the
study of alternative photochemical pathways possibly leading to harmful
Photochemistry, 2019, 46, 28–77 | 55

photoproduct and therefore to biological structure disruption. As an
example, high level molecular modelling has allowed to pinpoint the
molecular basis of the induced photo-toxicity of two widely used non-
steroidal anti-inflammatory drugs, ketoprofen and ibuprofen.148 Once
again, the combination of TD-DFT and CASSCF/CASPT2 strategy has al-
lowed unravelling an easy accessible pathway resulting in the case of both
drug to homolytic dissociation. Hence, the two drugs upon excitation in
the UVA region evolve to the production of two highly reactive radical
species in the vicinity of the biological structures. Actually, the photo-
dissociation pathway is characterised by very small activation barrier and
can be easily accessible upon excitation. In the case of ibuprofen,
photodissociation is the only accessible relaxation channel, while in the
case of ketoprofen, an analogous of benzophenone, the former is in
competition with ISC. However, one should consider that upon triplet
population the activation of 1O2 can be triggered contributing to the
increase of phototoxicity and oxidative stress. In addition, while classical
molecular mechanics (MM) has pointed to the existence of metastable
interaction modes with DNA, basically minor groove binding; by using
cellular biology assays it has been proved that the combination of
exposure to UVA light and to both drugs results in an increase of cell
mortality. Given that ibuprofen is used in topic creams to be applied on
the skin, its phototoxicity should be taken into account and sun exposure
avoided in the case of topic usage.
Going from the domain of phototoxicity to the one of phototherapy,
efforts have been devoted to take into account two main crucial factors:
shifting the absorption maxima to the red portion of the spectrum to
cover the therapeutic window, and avoid the activation of singlet oxygen
to allow the efficient treatment of solid tumours that produce hypoxic
conditions. One efficient way of inducing absorption red-shift is also
related to the use of non-linear two-photon absorption (TPA). Indeed, the
advantage of TPA is twofold, it allows dividing by two the excitation
energy required by the chromophore, hence doubling the absorption
wavelength. Furthermore, TPA requires the simultaneous absorption of
two photons and its efficiency depends on the square of the light source.
Thus, it is significant only at the laser focal point allowing for a much
better spatial resolution especially suitable for the treatment of cerebral
lesions. The mechanism of action of a TPA active photodrug, bmec, able
to significantly decrease viability of cancer cell lines has been fully
characterised at molecular level.149 In particular, thanks to QM/MM
calculations it has been proved that bmec has an important TPA cross-
section reaching hundreds of GM, while it may also interact persistently
with DNA strands in both intercalation and minor groove modes as
underlined by classical MD simulations. The interaction with DNA does
not alter the TPA cross-section and hence the efficiency of the drug
activation. Finally, the mechanism of action inducing phototoxicity has
been elucidating on both the solvated and DNA interacting bmec and
related to the spontaneous production of solvated electrons by the first
singlet excited state (S1). Indeed, the energy level of the radical cation
plus the solvated electron has been consistently found to be lower than
56 | Photochemistry, 2019, 46, 28–77

that of the S1 state. The interaction with DNA does not modify this feature
allowing for the opening of this photochemical channel both for minor
groove binding and intercalation. Both the solvated electron and the
radical cation can further interact with DNA components inducing either
base lesions or strand breaks.
In addition to the effects of DNA non-covalent sensitizers, increasing
attention has been devoted to the photoinduced effects produced by
modified nucleobases, either artificial or derived from DNA lesions.150,151
Resolving the remarkable differences in the spectroscopic features
between the canonical nucleobases and their thionated analogues, as
well as the elucidation of the excited-state decay molecular mechanisms
of the latter, have received an important piece of computational
effort.152–154 Substitution of oxygen by sulphur, a heavier element,
increases the SOC and therefore increases the efficiency of ISC processes.
Thus, the relative positions of STC along the excited-state PEHs play a key
role. It has been recently proven that the excitation energies of thiobases
are significantly smaller than that of the natural nucleobases, whereas
the S0/S1 CIXs are placed at almost the same level.155 The excited-state
gets consequently trapped in minima suppressing the intrinsic photo-
stability of natural DNA nucleobases.
Finally, and in addition to the DNA sensitisation, computational
studies in the period 2016–2017 have been devoted to the elucidation of
the sensitisation mechanism acting against biological lipid membranes.
In particular, it has been shown156 that the photosensitizer methylene
blue is able to interact with a lipid bilayer taken as a model of a biological
membrane. Methylene blue mechanism of action being related to an
efficient ISC followed by the production of singlet oxygen it is used to
generate photo-induced oxidative stress affecting the lipid unsaturations.
By classical MD, also using biased methods such as potential of mean
force (PMF), it has been shown that methylene blue cannot spon-
taneously penetrate inside the lipid bilayer, the process requiring to
bypass a free energy barrier of around 30 kcal mol1. Further QM/MM
CASPT2 calculations on selected MD snapshots have shown that the
penetration in the membrane actually decreases the ISC probability, and
hence singlet oxygen yield, because it reduces the overlap between singlet
and triplet energy levels. Therefore, one should suppose that methylene
blue would activate molecular oxygen in the vicinity of the membrane
polar heads and the reactive oxygen species would have to diffuse to the
centre of the layer to reach the unsaturation. On the contrary, and using a
similar protocol combining MD simulations with QM/MM modelling, it
has been shown that the naturally occurring hypericin drug157 is able to
spontaneously penetrate in the hydrophobic core of lipid bilayers, hence
its density nicely overlaps with the one of the lipid double bond. Fur-
thermore, the photophysical key parameters such us singlet triplet gap
and SOCs are less affected by the presence of the membrane environ-
ment. As a consequence, hypericin ISC probability should remain high,
moreover, since its position overlaps almost perfectly with the one of the
lipid unsaturation, it could produce singlet oxygen in close proximity to
its target increasing thereby the phototoxicity.
Photochemistry, 2019, 46, 28–77 | 57

6 Chemiexcitation
Excited-state chemistry arisen from a chemical reaction by a chemiexci-
tation process has been also the focus of a number of computational
works in 2016–2017. We shall firstly describe in this section those works
mainly studying the mechanistic aspects of the chemiexcitation which
gives rise to light emission (CL) and next the studies with important
relevance for the CL phenomena taking place in living organisms (BL).
For further reading on the topic, we highlight here a recent extensive
work establishing the current knowledge on the molecular basis of the
chemi- and bio-luminescence phenomena.158
6.1 Chemiluminescence mechanisms

In the CL phenomena, a thermally activated reactant generates a highly-
unstable intermediate that undergoes a non-adiabatic transition to an
electronically excited-state product. The subsequent transition back from
excited- to ground-state product is accompanied by a release of energy in
form of cold light. The simplest discovered models for CL transforma-
tions consist in unimolecular decomposition of 1,2-dioxetanes and 1,2-
dioxetanones. The mechanism of these four-membered ring peroxides
cleavages has been extensively studied in the last decade by both
experimental and theoretical means. On the basis of these studies,159–161
it is known that the unimolecular decomposition of 1,2-dioxetane and
1,2-dioxetanone occurs via a stepwise biradical mechanism. The two-step
biradical decomposition implies that once the O–O bond is cleaved, the
system enters a biradical region where four singlet and four triplet states
are degenerated. After that, the C–C bond rupture begins, leading to
dissociation of the molecule into two separated fragments. As we briefly
described in the previous contribution to the Photochemistry Specialist
Periodical Reports of the Royal Society of Chemistry,4 a very interesting
aspect of this proposed mechanism is the presence of a so-called
‘‘entropic trapping’’ region, in which the molecule can split the popu-
lation among the degenerated manifolds. The entropic trapping region
has been shown to play a pivotal role on the dissociation. It basically,
regulates the outcome by delaying the ground-state decomposition and
giving time to the system to get access to the excited states, e.g., S1 and T1.
Based on several experimental studies, the unimolecular decomposition
of 1,2-dioxetane and 1,2-dioxetanone has been shown to lead to the for-
mation of triplet excited carbonyl products with the yield of up to 30%.
However, the formation of singlet excited state is quite inefficient and
can barely reach 1%. Previous theoretical studies on 1,2-dioxetane159,160
and 1,2-dioxetanone162 are in good agreement with this observation. For
instance, the computed MS-CASPT2 activation energy for the decom-
position of 1,2-dioxetane is of 22 kcal mol1. In 1,2-dioxetanone, the
larger triplet population was explained by Francés-Monerris et al. by
means of CASPT2//CASSCF computations.162 The authors found that two
triplet excited states, namely T1 and T2, are accessible along the peroxide
decomposition path, whereas only one singlet excited state (S1) is avail-
able. However, these studies did not clarify how the entropic trapping
58 | Photochemistry, 2019, 46, 28–77

region determines the efficiency of the CL, as well as what its role is in
regulating the outcome, or what the lifetime in the biradical region is.
In the period of 2016–2017, substantial efforts have been invested to
address these fundamental questions in understanding CL phenom-
enon. Among the whole list, we would like to begin our journey by
reviewing some of them wherein simulations of the actual dynamics of
the molecular system are reported.
In early 2017, Vacher et al.163 revisited the biradical O–O rupture
mechanism of the parent 1,2-dioxetane to provide some accurate pre-
dictions from molecular basis of the reaction process. By initiating the
trajectories at the rate-limiting TS, corresponding to the O–O cleavage,
with Wigner distribution, and giving 1 kcal mol1 of kinetic energy, the
authors propagated the ‘‘on-the-fly’’ dynamics through the biradical
region. The authors used a time-step of 10 au (or 0.24 fs). Moreover, the
hopping between the close-lying surfaces along the MEP was allowed
throughout the simulations, which was missing in the former report by
Farahani et al.160 This indicates transitions among any of the four lowest-
lying singlet states. The PEHs were probed at the CASSCF level of theory
with state-averaging over the four singlet states. On one hand, the results
of the ground-state dynamics simulations support a so-called ‘‘frus-
tration’’ before dissociations, postponing the decomposition reaction.
They also found a relation between the O–C–C–O dihedral angle and the
time spent in the entropic trap. The half lifetime of the biradical region
has been reported to be t1/2 ¼ 58 fs. This is indeed shorter than the pre-
vious theoretical study in which ground-state dynamics of 1,2-dioxetane
was examined (613 fs).160 However, the difference was justified by dif-
ferent initial conditions used in both articles. On the other hand, the
results on singlet excited-state dynamics have shown that the longer a
trajectory stays in the excited state, the longer it takes to dissociate.
Therefore, the singlet excited state even further postpones the dissoci-
ation. However, no decomposition was observed along the singlet excited
state, supporting the extremely low singlet emission yield (0.0003%)
which had been reported by experimentalists. The half lifetime of the
biradical region is hence increased to t1/2 ¼ 77 fs. It is noteworthy to
mention that the ISCs between the singlet and triplet states are neglected
in this contribution and thus further dynamics simulations taking into
account the triplet states are required to complement the statements and
give an insight into the CL decomposition of 1,2-dioxetane.
Later in 2017, Vacher et al.164 performed another theoretical study on
substituted 1,2-dioxetanes with various CL quantum yields, which was
initially studied experimentally by Baader et al.,165 explaining how the
entropic trap determines the efficiency of the CL process. The authors
here could successfully rationalise why the excitation yield increases with
the degree of methylation wherein four hydrogen atoms of parent 1,2-
dioxetane were replaced by methyl groups. This methyl substitution
enhances the CL yield from 0.3% (parent 1,2-dioxetane) to 35% (tetra-
methyl-1,2-dioxetane), see Fig. 8. In this contribution, the authors
applied the same approach as for the previous study on parent 1,2-
dioxetane. The results show that the substitution would increase the time
Photochemistry, 2019, 46, 28–77 | 59

60 | Photochemistry, 2019, 46, 28–77
Fig. 8 Biradical mechanism has been proposed for the decomposition process of dioxetanes.
spent in the ‘‘trap’’ due to the increase in the number of degrees
of freedom which would subsequently increase the population of the
excited-state product. Nevertheless, the heavier substituents, simply
through their larger mass, slow down the torsional motion around the
O–C–C–O dihedral angle which can trap the system for longer time and
hence postpones the dissociation. Normally, a dihedral angle of 551 is
required to escape the entropic trapping region, thus, longer time to
reach large dihedral angle equals to slower dissociation. These results are
consequently supported by fitting the calculated dissociation half life-
time to the experimental data.
After 1,2-dioxetane, the simplest model for CL and BL transformations
is the unimolecular decomposition of 1,2-dioxetanone. To address if
there are distinct reaction pathways for the ground and excited state
formation in unimolecular four-membered ring peroxide decomposition
that possess different activation energies, Farahani et al.166 reported a
combined theoretical and experimental mechanistic study on the un-
imolecular decomposition of spiro-adamantyl-1,2-dioxetanone as a
prototype. This system was chosen as a model since it is relatively stable
and therefore, can be purified by low-temperature recrystallisation. Based
on the intensity measurements at different temperatures, the activation
energy of the CL is not the same as the activation energy for the
decomposition reaction. This indicates the occurrence of two different
pathways for the formation of ground and singlet excited state products.
To better understand this difference, multiconfigurational approaches
with dynamical corrections have been applied to study the unimolecular
decomposition. The decomposition mechanism has been shown to be a
two-step biradical pathway in which the stationary points are reported to
be optimised at the partial CASPT2 level of theory using constrained
numerical gradients and composite gradients167 in conjunction with
ANO-L-VDZP basis set. The obtained results confirm the presence of a
common TS in the rate-limiting step for ground- and excited-state
product formation. However, the TS corresponding to C–C rupture (not-
rate-limiting) is shown to possess different energies for ground and
singlet excited states (see Fig. 9). It is noteworthy to mention that the
theoretical activation energy for the rate-limiting step is overestimated as
compared to the experiment. The authors however, justified their results
by the deviation involved in the CASPT2 excitation energies using the
IPEA correction which was reported in a benchmark study by Zobel
et al.168 Nonetheless, they claim that the qualitative aspects of the reac-
tion mechanism is in agreement with the experimental findings.
In exploring the prototypes in CL reactions, the next generation is 1,2-
dioxetanedione. Here, the catalysed decomposition (bimolecular
decomposition) is proven to occur with very efficient formation of elec-
tronically excited state. This is quite different compared to 1,2-dioxetane
and 1,2-dioxetanone decompositions for which the reported quantum
yields are shown to be low. To rationalise this difference, Farahani and
Baader reported a qualitative and quantitative study on the electronically
excited formation of unimolecular decomposition on 1,2-dioxetanedione
hoping that it could be applied in the study of bimolecular
Photochemistry, 2019, 46, 28–77 | 61

Fig. 9 Schematic representation of the PEH for the unimolecular decomposition of
spiro-adamantyl-1,2-dioxetanone.
Fig. 10 The 2D-PEH of unimolecular decomposition of 1,2-dioxetanedione.
decomposition of this intermediate.169 By performing MS-CASPT2

geometry optimisations of the stationary points along the PEH as well
as MEP searches, the authors analysed mechanistic aspects of the chemi-
excitation process. Interestingly, the findings confirm a concerted
mechanism for the ground-state dissociation which is contrary to the
reported process in 1,2-dioxetane and 1,2-dioxetanone, see Fig. 10. The
62 | Photochemistry, 2019, 46, 28–77

concerted mechanism is a single-step reaction process in which both C–C
and O–O ruptures occur simultaneously by overcoming only one TS of
30 kcal mol1. At this TS, the crossings take place which can lead to
formation of the excited states. After that, the system enters an extended
biradical-like region from which singlet and triplet low-lying manifolds
are degenerated. To produce CL, a second TS corresponding to C–C
cleavage must be surmounted in the lowest-lying singlet and triplet
excited manifolds (37 and 29 kcal mol1 for singlet and triplet manifolds,
respectively). Since the activation energy for this second TS is higher in
singlet excited state and populating the triplet manifold requires high
amount of SOC, there should not be any formation of singlet excited
states and/or very low formation of triplet state in the unimolecular
decomposition. These findings consequently, support why there is no
clear-cut experimental evidence on a direct CL emission from this un-
imolecular decomposition process.
So far, we have only reviewed the studies on unimolecular decom-
position of simple models of CL transformation. However, it has been
shown that oxidizable fluorescent dyes based on p-conjugated aromatic
rings, so-called activators, can promote the decomposition of 1,2-
dioxetanones. So that the more the activator is oxidizable, the higher
intensity the light emission will have. In 2017, Augusto et al.170 studied
the interactions between unsubstituted 1,2-dioxetane and 1,2-dioxe-
tanone with model activators (naphthalene and anthracene). The
CASPT2//SA-CASSCF potential energy curves along the O–O dissociation
show an excited state of CT nature related to the electron-density pro-
motion from the activator to the s* antibonding orbital of the O–O bond.
The energy gap between the ground ss* and the intermolecular CT
excited state ps* is smaller for the 1,2-dioxetanone complex as compared
to the 1,2-dioxetane parent peroxide. This finding supports why acti-
vators do not activate the catalysed decomposition of 1,2-dioxetanes and
why the efficiency of this process is quite low for 1,2-dioxetanone. The
mechanism proposed for the catalysed CL corresponds to two non-
adiabatic steps, firstly from the ground ss* state to the excited ps*
state of CT nature and secondly from the latter to the emissive excited pp*
state of the activator (see Fig. 11).
6.2 Chemiluminescence in biology: bioluminescence

BL has been an attractive subject in scientific research for decades due to
its broad applications in biotechnology and biomedical fields, such as
gene expression, medical imaging and drug screening. In 2016 and 2017,
theoretical studies on BL are concentrated on these issues concerning the
BL mechanism, the chemical structure or protonated species of light
emitter, and the factors modulating the colour and intensity of light
emission.171–185 The following paragraphs briefly summarise some
impressive contributions to firefly,171,172 firefly squid,177 bacteria,178 and
dinoflagellate BL.180,181
Firefly bioluminescence. Among the luminescent organisms, firefly,
the paradigmatic BL system, has received the most attention in these
Photochemistry, 2019, 46, 28–77 | 63

Fig. 11 CASPT2//SA-CASSCF PEH for the dissociation of a CT complex formed between
parent 1,2-dioxetane and anthracene. Reproduced from ref. 170 with permission from the
PCCP Owner Societies.
two years.171–176 These contributions mainly focused on the spectra

character and the factors affecting firefly BL. Although the absorption or
emission energy of firefly luciferin (LH2 shown in Fig. 12) or its oxidative
product (oxyluciferin, oxLH2) have been calculated to be compared to the
absorption or emission spectra maximum in experiments, the calculated
vibronic spectrum was absent. For the first time, the vibrationally
resolved absorption and fluorescent spectra of firefly luciferin were
simulated using DFT and convoluted by a Gaussian function with dis-
placement, distortion, and Duschinsky effects in the framework of the
Frank–Condon approximation.171 The firefly luciferin-luciferase system
has been applied in in vivo imaging, hence investigating the factors
affecting light colour and intensity is important. A recent theoretical
study employed ONIOM approach to investigate the variation of the
barrier heights for the decomposition of the high-energy intermediate of
LH2 (firefly dioxetanone, DO) and its two analogues in the local electro-
static field (LEF) produced by firefly luciferase.172 The two modified lu-
ciferins (BoLH2 and BtLH2) that obviously differ in bioluminescent
intensities are shown in Fig. 12. BoLH2 and BtLH2 are modified from LH2
via replacing benzothiazole ring by benzoxazole and benzothiophene
64 | Photochemistry, 2019, 46, 28–77

Fig. 12 Molecular structures of firefly luciferin and its two analogues (BoLH2, BtLH2:
replacing the benzothiazole ring in LH2 with benzoxazole and benzothiophene, respect-
ively), oxyluciferin (oxLH2) and their corresponding dioxetanones.
ring, respectively. Those calculated results indicated that positive LEF

created by luciferase along the long-axis direction (the x direction, see
Fig. 12) could lower the activation energy and serves as an electrostatic
catalyst for DO thermolysis.
Firefly Squid Bioluminescence. Firefly squid luciferin has a universal
core structure, imidazopyrazinone (ImPy, the blue skeleton in Fig. 13),
which is common in the luciferins of about eight phyla of luminescent
organisms. But this bioluminescent mechanism remains largely
unknown, especially for the two key steps: the addition of molecular
oxygen to luciferin and the formation of light emitter. In 2017, the
detailed mechanism of the two key steps was investigated for the first
time by QM calculation with non-adiabatic MD simulation.177 By ana-
lyzing the energetics, electronic structures, and CT process, the calcu-
lated results indicated that (see Fig. 13): (1) the oxygenation reaction of
luciferin is initiated by a single electron transfer (SET) from the luciferin
to molecular oxygen, which occurs at the C2 position of the ImPy ring in
the luciferin. The high-energy dioxetanone intermediate is formed via a
nucleophilic addition reaction followed by biradical annihilation and an
Photochemistry, 2019, 46, 28–77 | 65

Fig. 13 The detailed process for the oxygenation of luciferin and the formation of light
emitter.
ISC in the vicinity of the singlet/triplet surface intersection. (2) The light
emitter is produced from the anionic dioxetanone intermediate via the
gradually reversible charge-transfer-induced luminescence (GRCTIL)
mechanism with a high quantum yield FS ¼ 43%.
Bacteria Bioluminescence. Luminous bacteria emit continuous glow
and have been widely used in BL imaging fields, especially as a sensitive
and convenient tool for monitoring environmental toxin. But the light
emitter of bacteria BL is still a debatable point. An intermediate called 4a-
hydroxy-5-hydro flavin mononucleotide (HFOH, see Fig. 14) and the final
products (flavin mononucleotide, FMN) are assumed as candidates
responsible for bacteria BL, because they have similar molecular struc-
tures and fluorescence wavelengths. It is worth noting that the similar
HFOH and FMN perform opposite fluorescence behaviours in solution
and in luciferase. FMN emmits fluorescence in solution but exhibits
fluorescence quenching in the bacterial luciferase. What is the exact
chemical form of bacterial bioluminophore and why FMN fluorescence
quenching occurs in the bacterial luciferase? In 2016, the above problems
were solved via high-level QM method, the combined QM and MM
method QM/MM, and MD simulation.178 The calculated results revealed
that: (1) the S1-state HFOH is the bacterial bioluminophore; (2) FMN
fluorescence quenching results from the electron transfer from the
quencher (the tyrosine residue 110 in the bacterial luciferase) to FMN
with the aid of protein fluctuation.
Dinoflagellate Bioluminescence.180,181 Dinoflagellates BL are featured
in two aspects: they are the major component of sparkling lights in
coastal water; the sparkling luminescence results from fluid shear stress.
This luminescence reaction is a luciferin–luciferase one in which the
dinoflagellate luciferin is oxidised to the oxyluciferin with the light
emission. (see Fig. 15) Generally, the oxyluciferin is the chemical source
of light emitter for the luciferin–luciferase systems, such as firefly,
Cypridina. But dinoflagellate oxyluciferin is not fluorescent. It is not clear
what is the light emitter of dinoflagellate BL and what is the chemical
66 | Photochemistry, 2019, 46, 28–77

Photochemistry, 2019, 46, 28–77 | 67
Fig. 14 Molecular structures of HFOH and FMN, and the fluorescence quenching process of FMN.
Fig. 15 The general process of dinoflagellate BL.
process of light emission. In 2016, dinoflagellate BL was theoretically

studied by TD-DFT method for the first time. In this study, the excited-
state E/Z-isomer luciferin or its analogue rather than oxyluciferin is
assumed as the bioluminophore and a Dexter energy transfer mechanism
for light emission is proposed.180 The excited-state oxyluciferin produced
from the oxidation of luciferin acts an energy provider transferring
energy to another ground-state luciferin or its analogue that emits
radiative transition. The subsequent theoretical study investigated four
chemical forms of intermediate in the luciferase catalytic cycle and
suggested that the gem-diol(ate) intermediate shown as Fig. 16 is the
bioluminophore and E/Z-isomer luciferin proceeds via chemically initi-
ated electron-exchange luminescence (CIEEL)/twisted intramolecular
charge transfer (TICT) to produce the bioluminophore.181
7 Summary and outlook

In 2016 and 2017, Quantum Chemistry of the Excited State has continued
its rapid growth observed during the last decades within the group of
powerful tools to address photochemical and chemiluminescent studies.
Method developments carried out in the period reviewed in the present
book chapter point towards an even brighter future for QCEX. Thus, we
observe relevant advances achieved which overcome the known limi-
tations of the multiconfigurational quantum-chemistry methods related
to the amount of strongly correlated electrons or reduce the computa-
tional cost needed to obtain the remaining electron correlation (dynamic
correlation). We focus in this review on developments carried out in the
DMRG, FCIQMC and semi-stochastic HCI methods to provide correct
wave functions for determining the static electron correlation, and for-
mulations which largely decrease the cost of computing the short-range
or dynamical correlation such as the pair natural orbital or frozen natural
orbital within the CASPT2 method. Advances are also observed in the
computational strategies for obtaining a dynamical description of
excited-state phenomena including lifetimes and population distribution
in non-adiabatic processes. We highlight in this work improvements
within the quantum dynamics methodologies.
68 | Photochemistry, 2019, 46, 28–77

Photochemistry, 2019, 46, 28–77 | 69
Fig. 16 Proposed mechanism of dinoflagellate luciferase catalytic cycle involving CIEEL for E-isomer luciferin and TICT for Z-isomer of luciferin.
Applications of QCEX methodologies and computational strategies
show a progressive trend towards computations on larger-size molecules
and systems with a more extended p-conjugation. Illustrative examples
are given in the present book chapter in the fields of luminescent
materials, molecular rotors, organic optoelectronics, DNA photostability,
damage and repair, photosensitisation of biological structures, CL and
BL. For instance, works on DNA nucleobases begin to focus more on
the competition between distinct excited-state processes in clusters of
bases and less on intrinsic properties of the isolated bases which were
exhaustively analysed in previous studies. CIXs and STCs remain as
relevant targets of many QCEX works and shall remain in future studies.
The reason is that such quantum-chemistry entities are crucial to correctly
interpret many observable properties measured in spectroscopic, photo-
chemistry and CL experiments. The present book chapter also shows
synergic combinations of QM methods with MM static and dynamic
approaches to properly deal with the environmental effects. We also
observe that analysis of inter-molecular processes are becoming more
common in some fields (DNA photochemistry and photosensitisation)
and new in others (CL). In chemiluminescence, we find the first attempt
to analyse the inter-molecular catalysed CL mechanism by using multi-
configurational quantum chemistry (CASPT2/CASSCF). Accurate deter-
minations of excited-state inter-molecular phenomena are however still a
challenge for protocols which are based on a highly-accurate determin-
ation of CASPT2 energies on top of CASSCF optimised structures or for
semiclassical dynamics studies based on CASSCF gradients. This is due
to the fact that CASSCF is not considering dispersion interactions.
Approximate TD-DFT structures or computationally-demanding CASPT2
gradients can be used here, although this is not possible in all cases. In
this context, DMRG, FCIQMC, HCI or new and practical corrections of the
popular CASSCF method shall be of great relevance.
Acknowledgements
J.S.-M. acknowledges support from the European Commission through
the Marie Curie actions (FP8-MSCA-IF, grant no 747662). D.R.-S. is
thankful to the Spanish MINECO/FEDER for financial support through
project CTQ2017-87054-C2-2-P and the Ramón y Cajal fellowship with
Ref. RYC-2015-19234. A.F.-M. and A.M. are grateful to the French ANR
and the Université de Lorraine for their support.
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Photochemistry, 2019, 46, 28–77 | 77

Organic aspects: photochemistry of
alkenes, dienes, polyenes (2016–2017)
Takashi Tsuno
DOI: 10.1039/9781788013598-00078
This review deals with the photochemistry of alkenes, dienes, polyenes, and related
compounds through a choice of the literature published during the period January 2016 –
December 2017. This chapter also covers the nanotechnology and supramolecular
chemistry utilizing isomerization/electrocyclization/cycloaddition reactions of the title
compounds.
1 Introduction
The winners of the Nobel prize in chemistry 2016 were Prof. J.-P. Sauvage,
Prof. Sir J. F. Stoddart and Prof. B. L. Feringa for the design and synthesis
of molecular machines.1–7 Their achievements will be addressed in many
parts of this chapter. Especially, the molecular motors, developed by
Prof. Feringa and his group, will play a key-role for molecular machines
and nanomachines in the future.8
The number of reports regarding addition reactions and functionali-
zation of alkenes and dienes using visible-light photocatalysts9–19 has
increased remarkably in recent years. As visible-light sources have been
used mainly cheap LED lamps, fluorescent lamps or the sun instead of
traditional Hg or Xe lamps. The LED-flow-reactors including photo-
catalysts have been also developed toward greener synthesis.20–28
In addition, the progress of artificial intelligence (AI)29,30 and internet
of things (IoT)31–33 in chemistry and science will be revolutionized during
a few decades. What will chemists and scientists do at that time?
This review deals with the photochemistry of the title compounds
and also covers recent advances in nanotechnology, supramolecular
chemistry, and visible-light photocatalysts utilizing isomerization/
electrocyclization/cycloaddition reactions of the title compounds.
2 Photoinduced (E)–(Z) isomerization

2.1 (E)–(Z) Isomerization
The photoinduced (E)–(Z) isomerization mechanism and dynamics of
stilbene and its derivatives are of great interest as a key-step in photo-
chemistry. Many researchers reported theoretical and spectroscopic
studies of the photoinduced (E)–(Z) isomerization mechanism and
dynamics of stilbene and its derivatives.34–40
Department of Applied Molecular Chemistry, College of Industrial Technology,

Nihon University, Narashino, Chiba 275-8575, Japan.
E-mail: tsuno.takashi@nihon-u.ac.jp
78 | Photochemistry, 2019, 46, 78–115

A combination of the Christiansen filter and the photoinduced (E)–(Z)
isomerization of stilbene could be used as a phototunable color filter.41
The nanoparticles of the organoboron-bearing stilbene (1) with PS-PEG-
COOH were used as a long-term cell tracker with a high fluorescence
quantum yield, photostability and low cytotoxicity.42 Photochemistry
and photophysics of stilbene-cored dendrimers and their derivatives have
been reported by Arai et al.43–46 The photoinduced (E)–(Z) isomerization
of stilbene absorbed onto graphene under the exposure to the solar light
rendered the energy storage of 0.49 eV.47 Millimeter-size 2D single crystals
of (2) were employed as a photo-switchable organic field-effect tran-
sistors.48 The (E)-form of (3) under UV-irradiation by the higher absorp-
tion ability as compared to the (Z)-isomer enriched the (Z)-isomer.49
The p-cyanostyrylpyridine moiety of the Re complex (4) showed photo-
switchable (E)–(Z) isomerization.50 Functionalization of gold particles
with supramolecular hosts allowed their plasmon-based photocatalytic
activity for (Z)–(E) isomerization of (Z)-4-dimethylaminostilbene to
be enhanced.51 ()-Riboflavin acted as a photocatalyst for (Z)-(E)
isomerization of 3-phenyl-substituted (Z)-2-alkenenitriles.52
2.2 Stiff-stilbene and molecular motors

In 2009, Boulatov et al. reported the photoswitch of a stiff-stilbene
bearing a trans-dialkylcyclobutene ring (5).53 Stauch and Dreuw
re-investigated the mechanism of the photoswitch using judgement of
energy distribution analysis. The analysis suggested that the mechanical
Photochemistry, 2019, 46, 78–115 | 79

efficiency of stiff-stilbene and the mechanochemical susceptibility of
cyclobutene were much too low to explain the experimentally observed
enhancement of the bond dissociation upon the (Z)–(E) photo-
isomerization of stiff-stilbene.54,55 Boulatov et al. made a quick response
to their paper.56 The photoswitch of stiff-stilbene with chiral binaphthyl
moieties (6) showed good reversibility under alternative UV irradiation.57
The (Z)-form (7) bearing an urea moiety acted as an anion receptor
for anions such as OAc and H2PO4. The (E)–(Z) isomerization of (7)
showed a photoswitching system for their anion receptors.58 The (P,Z)-
and (M,Z)-forms (8) acted as chiral receptors for the recognition of the
binol phosphate anion (9).59 The stiff-stilbene (10) bearing alkyl chains
on urea substituents exhibited reversible gel–sol photoswitching in
aromatic hydrocarbon solvents.60 The photoisomerization of the stiff-
stilbenes (11)61 and (12)62 as guest molecules with pillar[5]arene as a host
molecule could be controlled by host–guest interactions. Feringa et al.
isolated separately enantiopure stiff-stilbenes (13) in their (R,R,Z)-
and (S,S,Z)-forms through supramolecular complex formation with
N-benzylcinchonidinium chloride.63 A transfer of chirality from the
molecular motor of the chiral dicarboxylic acid (14) to a dynamic helical
polymer was found.64 The bis[3.3.3]propellane (15) underwent (E)–(Z)
isomerization under UV irradiation in benzene to give an equilibrium
mixture of (E) : (Z) ¼ 55 : 45, but under UV irradiation in the presence of
I2 and propylene oxide, the oxidative photoinduced electrocyclization
of the (Z)-isomer took place to afford the compound (16).65
The motions of the molecular motors extremely fascinate scien-

tists.8,66–69 Computational studies of the molecular motors were
reported.70–72 The compound (17) is well-known as the basic molecular
motor. The rotation mechanism has been investigated well, but some
excited dynamics including the dark state, are still not opened. The dark
state has been discussed by using spectroscopic and computational
methods.73–76 The rotation speed of (18) coordinated three metal (Zn, Pd
and Pt) dichloride were investigated. The rotation speed could be con-
trolled by the metal species.77 The key-step of the molecular motor (19) in
50 different solvents and solvent mixture was discussed.78 Chiral (2S,3S)-
(20) and (21) were prepared using (S)-1-naphthylethanol and their
photochemical and subsequent thermal isomerization was examined.79
Statistical analysis suggested that the solvent parameters govern the iso-
merization process of the molecular motors. The molecular motor (22)
translated light-driven unidirectional rotary motion to controlled move-
ment of a connected biaryl rotor.80 Fluorine-substituted molecular motors
including (23) were developed. Due to the fluorine atom the activation
80 | Photochemistry, 2019, 46, 78–115

barrier for the thermal helix inversion was higher than the barrier for
backward thermal (E)–(Z) isomerization.81 The SH group of the light-
driven molecular motor (24) picked up an acetyl group from one side of
the lower stator, and the acetyl group was transferred to the amino group
after the photoinduced (E)–(Z) isomerization (24)-(25)-(26)-(27).82
HS
AcS
O CH2NH2
AcO O CH2NH2
HO
(24) (25)
hν
SH SAc
O CH2NHAc O
HO HO CH2NH2
(27) (26)
Photochemistry, 2019, 46, 78–115 | 81

The molecular motors with the larger volume substituents such as
poly(phenylethnylene) groups exhibited the highest photochemical cross
sections.83 The sequential occupation of the molecular motor rotation on
a quartz surface during a UV and heat-induced cycle was imaged in real-
time using defocused wide-field imaging technique.84 A novel uni-
directional light-driven molecular motor suitable for a host–guest surface
inclusion complex with tris(o-phenylene)cyclo-triphosphazene was pre-
pared. This system could provide a versatile way to 2D surface confine-
ment by precise molecular driven.85 The molecular motor (28) with an
extended aromatic core allowed the photoinduced isomerization with
visible light up to 490 nm.86 The photoinduced (E)–(Z) isomerization of
(29) exhibited dynamic control of the catalytic activity of the Michael
addition of 2-cyclopentenone with 3-phenylpropanal.87 The amphiphilic
molecular motor (30) underwent responsive aggregation in water by
alternate UV and thermal isomerization steps.88 Molecular motors have
been applied to some molecular machines. The molecular motors (31)
and (32) could act as an engine of a nanocar89 or cell membrane
opener.90 Some new molecular switches via the photoinduced (E)–(Z)
isomerization were also developed.91–96 The compound (33) bearing
an amino group showed weakly photoactivity in the absence of acids,
while protonation increased the quantum yields for the isomerization.91
3 Electrocyclization
3.1 Helicenes
Martinetti et al. reported a review on the catalytic uses of chiral phos-
phorus compounds characterized by a helical scaffold as the key ste-
reogenic element of their structures.97 Iodine and ethylene oxide are
generally used as oxidants for dihydrophenanthrenes, which are derived
from the photoinduced electrocyclization of (Z)-stilbene. Matsushima
et al. developed the air-driven KI-mediated oxidative photoinduced
electrocyclization of stilbene derivatives as a novel method.98 The fused
p-system aromatics have characteristic physical properties. They can be
readily prepared by the oxidative photoinduced electrocyclization of
diarylethenes. Several diphenanthrylethene derivatives were prepared
and their oxidative photoinduced electrocyclization led to fused p-system
82 | Photochemistry, 2019, 46, 78–115

aromatics with seven benzene rings.99 The triene (34) underwent
oxidative photoinduced electrocyclization to give a three-bladed propel-
ler-shaped triple [5]helicene.100 The oxidative photoinduced electro-
cyclization of the corannulene-phenylethene (35) afforded extended
corannulene drivatives.101 The oxidative photoinduced electrocyclization
of the compound (36) afforded dibenz[a,h]anthracene in 77% yield.
Scholl reaction of dibenz[a,h]anthracene with AlCl3 at room temperature
gave liquid-crystalline benzo[ghi]perylene diimde.102 The racemic
hexahelicene with a nitrile group was prepared by the oxidative photo-
induced electrocyclization of (37) in the presence of I2 in THF. The (P)-
and (M)-enantiomers were isolated separately by HPLC on a chiral
stationary phase.103 Sequentially performed Wittig reactions and the
oxidative photoinduced electrocyclization by continuous flow reactors
was developed by Okamoto et al. Various phenacene derivatives have
been readily prepared by the flow reactor method.104 Phenanthrene
derivatives, obtained by the oxidative photoinduced electrocyclization of
stilbenes, were studied for anticancer properties against human colon
and epithelial cancer cell lines. The compound (38) showed potency with
good IC50 values.105 The oxidative photoinduced electrocyclization of the
biphenyl based tetraenes (39) and (41) led to no-planar oligoarylene
macrocycles (40) and (42) in moderate yields.106 Heterohelicenes
have been expected to have potential applications.97,107,108 Novel het-
erohelicene derivatives were prepared by the oxidative photoinduced
electrocyclization of heterodiarylethenes.109–122
3.2 Dithienylethene and derivatives

The photochromism of dithienylethene and its derivatives leads to
extremely fascinating photoswitches, optical memories, and actuators in
molecular devices and nanotechnology.123–129 Many researchers reported
on the photochromic mechanism of dithienylethene derivatives by
DFT and/or spectroscopic techniques.130–142 Although the centre part of
Photochemistry, 2019, 46, 78–115 | 83

photochromic dithienylethenes is generally a perfluorocyclopentene ring
or cyclopentene ring, photochromism of dithienylethenes and diaryl-
ethenes with a new centre part have been recently investigated.143–161
Shirinian et al. prepared novel photochromic dithienylethenes and
diarylethenes which possessed a cyclohexene ring, cycloalkenone ring,
and furan-2(5H)-one ring as the centre part and reported their photo-
chromism.143–147 An increase in ring size of cycloalkenones showed
a hypsochromic shift of the absorption maximum of the closed form. The
intramolecular hydrogen bond of (43) increased the quantum yield of the
photocyclization.143 Hollow crystals of the diarylethene (44) with a per-
fluorocyclohexene ring as the centre part showed photosilent phenomena
by UV irradiation, i.e., the crystal was bending at the UV-irradiated
part.148,149 Such photosilent phenomena of the diarylethenes show a
trend in single-crystal-to-single-crystal phase transitions.162–165 The ring-
close isomer of the dithienyl p-benzoquinone (45) could be utilized for
the visible-light-driven oxidation reaction.150 The acenaphthylene (46)
bearing two thienyl groups did not show photochromism. However (46)
readily underwent a tandem addition of a nucleophile and an electrophile
to afford (47). The resulting (47) showed photochromic behaviour.151
The formyl-substituted dithienylethene (48) acted as a light-active

sensitive probe for primary and secondary amines.166 Multi-addressing
photoswitches of the diarylethene derivatives by metal ions [Mg(II),167
Ca(II),167 Al(III),168–178 Cr(III),178 Fe(III),178–180 Cu(II),181–189
175–177,190–200 197,198,201–203 187 204
Zn(II), Cd(II), Sn(II), and Hg(II) ], anions
[F,186,192,199,205 I,206 CN174,206], pH control,168–170,207–216 amino acid
84 | Photochemistry, 2019, 46, 78–115

[cysteine],180,205 and PhSH217 have been developed. Especially Pu and
his group made contributions to this area and also prepared many
novel diarylethene derivatives.218–229 Of course, other groups have also
prepared new diarylethenes and examined their photochromism.230–238
Photoresponsible switches of diarylethenes bearing organometallic

moieties239–248 or coordinated metals249–258 including MOFs123–126,259–261
have been widely studied. The carbene ruthenium complexes (49) and
(50) acted as a photoswitchable olefin metathesis catalysts. (Z,Z)-1,4-
Cyclooctadiene was polymerized by metathesis with the open form of
(49), while diethyl diallylmalonate underwent metathesis with the closed
form of (50) to afford the ring-closed form.239 The bimetallic complex (51)
showed high cytotoxic potential for various cell lines, but did not undergo
photoinduced electrocyclization by UV irradiation.248
The dithienylethene derivatives coordinated iron,249,250 manganese,251
or lanthanide ions252 are expected to be magneto-optical molecular
devices. For example, the dithienylethene (52), containing bis-
(pyrazolylpyridyl) ligand parts, reacted with Fe(ClO4)2 to yield the
supramolecular helicate [Fe2(52)3](ClO4)4 as orange crystals.
The helicate [Fe2(52)3](ClO4)4 showed spin crossover in the solid state
and in the solution.250 The dithienylethene (53) reacted with CuX2
(X ¼ OAc or NO3) in pyridine to afford two different one-dimensional
polymers, [Cu(53)(py)3]2py and [Cu(53)(py)3]2H2O 0.5Et2O, whose su-
pramolecular organization significantly differed in the crystal lattice.
[Cu(53)(py)3]2py showed reversible solid state photochromism, whereas
this process was hampered for [Cu(53)(py)3]2H2O 0.5Et2O.256
The reaction of the close-form of (54) with [Pd(NCMe)4]2BF4 yielded a
rhombicuboctahedral sphere (6.4 nm) of [Pd24(close-54)48]. The rhombi-
cuboctahedral sphere [Pd24(close-54)48] upon 617 nm irradiation imme-
diately afforded a tentative sphere [Pd24(open-54)48]. The tentative sphere
slowly underwent decomposition to give an equilibrium mixture of
assemblies of [Pd3(open-54)6] and [Pd4(open-54)8].257 The dithienylethene
(55) reacted with Zn(II) to yield a bistable MOF. The pore size of the MOF
Photochemistry, 2019, 46, 78–115 | 85

could be changed by photoswitching without structural damage of the
framework.258
The photoswitching of dithienylethenes on solid surfaces or metal

nanoparticles has been widely applied as optoelectronic devices.262–276 A
bifunctional organic thin-film transistor with the dithienylethene (56)
resulted in a flexible non-volatile optical memory device with over 256
distinct current levels.262 The photoswitching of dithienylethenes
exhibited superwater-repellency.277,278 A double roughness structure
with the dithienylethene (57) microcrystalline surface was reversibly
controlled by UV and visible irradiation and the photoswitching showed a
water-droplet-bouncing phenomenon. This result supported the origin of
self-cleaning on a lotus leaf.278
Photoswitches of the dithienylethenes have been widely investigated in
life sciences and supramolecular chemistry.279–304 Several dithieny-
lethenes, bearing a tetraphenylethylene moiety, were prepared and
showed photoswitchable aggregation-induced emissions.279–281 A supra-
molecular assembly was constructed with the [Ru(bpy)3]21 complex
bearing two crown ethers as the host moieties and the dithienylethene
bonding two dialkylammomiun ions as the guest moieties, which could
switch on/off the luminescence of [Ru(bpy)3]21 by a high Förster reson-
ance energy transfer efficiency (FRET) and photoisomerization of the
dithienylethene.284 Such FRTE studies using photoswitchable dithieny-
lethenes were also reported.285,286,297,305 Dithienylethene-bonded
permethyl-b-cyclodextrins/porphyrins285 or borondipyrromethene287
could be applied to control singlet oxygen generation in aqueous
solution. This controllable technique has potential for photodynamic
therapy. Ulrich’s group designed a photodynamic therapy using the
photoswitching of the dithienylethene (58). Second generation photo-
switchable peptidomimetics exhibited the practical possibility of
86 | Photochemistry, 2019, 46, 78–115

cytotoxicity by photoregulation in vitro. The open-form (58) had about
8.0-fold higher cytotoxicity than the close-form.293 The close-form of the
dithiazolylethene (59) with 436 nm irradiation showed a good cytotoxicity
for Madin-Darby canine kidney cells, while the open-form with 436 nm
irradiation or the close-form with 546 nm irradiation was not lethal.
The dithiazolylethene (59) intercalated between DNA base pairs. The
open-form (59) was released from DNA, but the photocytotoxicity
was characterized by a large charge transfer in the DNA to the close-form
direction.294 The photoswitching of dithienylethenes was applied for
bioimaging of liposomes,290,291 mitochondria,292 or cells.295–297 The
PEGylated perylenemonoimide-dithienylethene (60) could be observed
under super-resolution fluorescent microscopy with an optical resolution
of 30 nm for liposomes.290 The similar photochrom (61), bearing
hydrophilic and mitochondria-targeted polymers, acted as super-
resolution MitoTrakers with sub-30 nm spatial resolution.292 Upon UV
irradiation, the dithienylethene (62) incorporated in human serum
albumin underwent enantioselective cycloaddition to give the close-form
in over 99ee%.296 The photochromism of the dithienylethene, bearing
peptide chains, was investigated for the flexibility and rigidity of the
structure of lipid membranes. The open- and close-forms could influence
the conformation of the adjacent residues when incorporated into the
backbone of a linear peptide.299 König et al. reported that the photo-
chromism of dithienylethenes and fulgimides was controllable by his-
tone deacetylase inhibitors.302 Fatigue-resistance photoswitches of
dithienylethenes, bearing deazaadenosine303 or natural deoxy-
adenosine,304 were developed.
Many photoswitches of diarylethenes bearing polymer chains or of
diarylethenes in polymers were synthesized and their photochromic
properties were reported.306–318 Polymer micelles including 9,10-
diphenylanthracene as a fluorescence resonance energy transfer donor
and (63) as an acceptor photoswitch showed that the color of the emitted
fluorescence was continuously changed from blue to yellow by photo-
isomerization of (63).306 Dithienylethene/ionic liquid/cellulose paper was
developed, which exhibited vivid coloration/decoloration upon UV/visible
irradiation.307 The photochromic diarylethene (64) underwent retro-
Diels–Alder reaction at 130 1C, but not the close-form. Such differences
are expected to be applicable to stimuli-regulatable polymer recycling
and polymer mechanochemistry.308 The reaction of dithienylethene
(65) with amino-functionalized polysilane chains led to photochromic
rubbery materials with viscoelasticity. The rubbery materials had
reversible self-healing properties by UV/visible irradiation.316 A
dithienylethene-graphene composite film acted as photoswitchable
micro-supercapacitor.318
The photochromic properties of diarylethenes in single crystals
or in the solid state were widely investi-
gated.128,148,162–164,203,205,220,221,223,225,226,233,319–323 The photochromic
behavior of (66) in the crystal under application of shear stress was
reported. The application of shear stress allowed the non-photochromic
crystal (66) to undergo photochromism.319 Because the photocyclization
Photochemistry, 2019, 46, 78–115 | 87

of (67) upon UV irradiation generated a large strain in the rigid crystalline
phase, the crystal underwent photoinduced explosive fragmentation
accompanied by a color change from colorless to blue.320
4 Photoinduced addition
Photochemical [2 þ 2] cycloaddition is a very useful organic synthetic
tool. In 2016, Chemical Reviews focused on photochemical [2 þ 2]
cycloaddition by publishing several reviews.9,324,325 The photochemical
[2 þ 2] cycloaddition was applied to the synthesis of natural products
such as solanoeclepin A,326 aplydactone,327 8-epi-isoaplydactone,328
phenalinolactone,329 and xylopiana A.330 Mykhailiuk et al. developed a
multigram two-step approach to substituted 3-azabicyclo[3.2.0]heptane
derivatives from benzaldehyde, allylamine, and cinnamic acid as starting
materials. This method is expected to be applicable to drug synthesis.331
In addition, using incandescent floodlights, a gram-scale synthesis
for photochemical [2 þ 2] cycloaddition of (E)-cinnamic acid was
developed.332
Styrylpyrenes in the context of a DNA duplex upon visible irradiation

underwent photochemical [2 þ 2] cycloaddition to yield the cross-linked
duplex. This duplex was converted into the uncross-linked single strands
88 | Photochemistry, 2019, 46, 78–115

by UV-irradiation.333 DNA three-way junctions, bearing 4-methoxy-
benzophenone and 4-methylbenzophenone as C-nucleosides at the hydro-
phobic binding pocket, acted as aptamers and chiral photoDNAzymes.
Upon 369 nm LED irradiation, 4-(3-butenoxy)quinolinone underwent
regioselective and enantioselective intramolecular [2 þ 2] cycloaddition.334
Cyanostilbene liquid crystals (68) and (69) in their mesophases provided
two different routes for polarization light-driven modulation. The stilbene
(68) underwent photoinduced (E)–(Z) isomerization, while slow
intermolecular [2 þ 2] cycloaddition of (69) was found. The resulting [2 þ 2]
cycloadducts readily underwent retrocycloaddition above 240 1C.335
N N
R N
N N
(72) R = 3-pyridyl
(75) R = 4-pyridyl
(78) R = C6H4F-o N
N
N N
N N (73) (74)
N
N
(79) H
R1
N
N N
N R2
H Cl-
(80) (76) R1 = COOH, R2 = H
(77) R1 = H, R2 = COOH
N N
HN CH2
N
O
2
N
(81) (82)
R1 MeO
N
N N Et X-
COOEt MeO N
N
R2 N
Se
(83) R1 = Me, R2 = H (85) (86) X = I, I3, or TsO
(84) R1 = H, R2 = Me
O
N
F MeOOC COOCH2CH2Br
NH
MeOOC COOMe
N O N
H
(87) (88) (89)
Photochemical [2 þ 2] cycloaddition of supramolecular complexes of

(18-crown-6)styryl dyes with alkylammonium chains336,337 and of
(15-crown-5)styryl dyes with the Ba21 ion338 was reported. The styryl dye
(70) underwent photochemical [2 þ 2] cycloaddition in the crystal and in
aqueous solution in the presence of cucurbit[8]uril to give a syn-head-to-
tail adduct. The topochemistry of the photochemical [2 þ 2] cycloaddition
of the host–guest complex of the styryl dye (70) with cucurbit[8]urils
Photochemistry, 2019, 46, 78–115 | 89

was investigated by fluorescence upconversion techniques.339 The bis-
(styrylbenzoquinoline) (71) upon UV irradiation resulted in stereospecific
intramolecular [2 þ 2] cycloaddition to yield the rctt-cycloadduct.122
Photochemical [2 þ 2] cycloaddition of diarylethenes in the solid state
including MOFs128,129 and hydrogen-bonded organic frameworks (HOF)
is a high-performance tools for green-sustainable chemistry and for
crystal engineering.324 Unsymmetrical dipyridylethene (72) reacted with
AgNO3 and 1,4-naphthalenedicarboxylic acid (1,4-H2ndc) to give a one-
dimensional zigzag coordination polymer, {[Ag(1,4-ndc)(72)2] 2H2O}n,
while the reaction with Zn(NO3)2 led to a diamond framework,
{[Zn(1,4-ndc)(72)]2 H2O}n. The head-to-head and head-to-tail cyclobu-
tanes (73) and (74) were obtained from the solid state photocycloaddition
of {[Ag(1,4-ndc)(72)2] 2H2O}n and {[Zn(1,4-ndc)(72)]2 H2O}n, respect-
ively.340 Three dimension photoresponsible porous magnetic material,
{[Co3(75)3 4H2O][Cr(CN)6 2(75) 2EtOH 2H2O]}, was prepared by the
reaction of (75), Co(NO3)2 and K3[Cr(CN)6] in a mixture of EtOH/H2O. The
guest (75) in the 3D material allowed photoinduced postsynthetic
modification of the pore surface via [2 þ 2] cycloaddition. The resulting
3D MOF including [2 þ 2] cycloadducts introduced enhanced CO2
selectively over that of N2.341 Solid state photochemical [2 þ 2] cycload-
dition of [{Zn(75)2 3H2O}2(75)]4NO3 3(75) 14H2O was also reported.342
The reaction of the pyridinium chloride (76) with Zn(NO3)2 in DMF
afforded a 2D MOF with rare clockwise and anti-clockwise spiral nano-
tubular channels arranged alternately in the structure. The photo-
chemical [2 þ 2] cycloaddition of the 2D MOF could be triggered to
undergo structural transformation from 2D to 3D. This structural
transformation could be applicable to separate ethanol and water.343 UV
irradiation of the complex, [CdCl2(77)] 3.5H2O, in the solid state induced
[2 þ 2] cycloaddition in 100% yield. The cycloadduct underwent iso-
merization into the unusual rcct-isomer by recrystallization.344 Crystals of
the complex, [Zn(NCS)2(78)2] DMF were photosilent, i.e., the complex
underwent photochemical [2 þ 2] cycloaddition, whose crystals were
popping under UV irradiation.345 Coordination polymers of (79)–(81)
were prepared and their photochemical [2 þ 2] cycloadditions were
investigated.346,347 Crystallization of the complex, [Zn{H(82)}Cl3], led to
large-size hollow hexagonal tubular crystals. A stereoselective photo-
chemical [2 þ 2] cycloaddition of [Zn{H(82)}Cl3] was found, whereas its
methyl blue-coated crystals did not respond to UV irradiation.348
McGillivray et al. reported template effects for the photochemical
[2 þ 2] cycloaddition of metal complexes and hydrogen bond-based
templates of (83) and (84). The hydrogen bond-based templates of (83)
or (84) with resorcinol derivatives were photostable, whereas the Ag
complexes underwent stereoselective photochemical [2 þ 2] cycloaddi-
tion.349 The hydrogen bond-based templates of (75) with sulfuric acid350
or 1,2,4,5-tetrabromobenzene351 also underwent photochemical [2 þ 2]
cycloaddition. In addition, the hydrogen bond-based templates of (75)
with sulfuric acid had a 2D-hydrogen bonded network, transformed into
a 3D HOF by heating at 50 1C.350 The hydrogen-bonded cocrystals of the
diene (85) with 5-methoxyresorsinol led to the intermolecular [2 þ 2]
90 | Photochemistry, 2019, 46, 78–115

cycloadduct upon 313.5 nm irradiation, whereas irradiation without
an optical filter afforded the cyclooctadiene dimer.352 The styryl-
benzoselenazoles (86) with iodide, triiodine, or the tosylate anion were
prepared. Their crystal packing was favorable for photochemical [2 þ 2]
cycloaddition.353 5-Fluorouracil (87) is well-known as the anticancer
drug. An 1 : 1 mixture of (87) and bis(2,2-pyridylethene) (88) in methanol
gave colorless plate-like cocrystals. The cocrystals upon UV irradiation
underwent quantitative photochemical [2 þ 2] cross-cycloaddition.354
Unsymmetrical p-quinodimethane (89) underwent topochemical [6 þ 6]
photocycloaddition via single-crystal-to-single-crystal to yield a bridge-
substituted [2.2]paracyclophane.355 2D polymer crystals of (90) having a
biphenyl core were prepared by crystallization of a saturated solution in
methanol/acetonitrile. The 2D polymer upon LED irradiation underwent
topochemical [2 þ 2] cycloaddition to give the 2D polymer.356
But
O
But
But
O N
But N
(91)
3BF4-
But
O
But (90)
The aggregation state of supramolecular assemblies constructed with

calixarene incorporating stilbene moieties could be tuned by heating and
photochemical [2 þ 2] cycloaddition.357 The molecular assemblies con-
sisted of different layers of redox-active Ru or Os complexes with redox-
inactive spacers, (91) and PdCl2. The photochemical [2 þ 2] cycloaddition
of the spacer (91) in the assemblies increased chemical and electron
permeability.358
R
Mes MeO N O
COOH
Br Br N
MeO N Me
N O
HO O O
R X- (94) R = Bu
Br (95) R = CH2CONH(CH2)3Si(OEt)MCM-41
(91) R = Me, X = ClO4- (93)
(92) R = Ph, X = BF4- I I
R
O
O O O-
N
R R I I
O S
Cl COO-
NH 2Na+
O (96) (97) R = C C
Cl Cl
N N Cl
S
(98)
Photochemistry, 2019, 46, 78–115 | 91

5 Photocatalysts
5.1 Metal-free photocatalysts
Recently, functionalization of alkenes, dienes, and polyenes using
visible-light redox photocatalysts aroused much attention in organic
chemistry. Some reviews regarding this area were published.9–19 This
method can employ greener light sources as LED lamps, fluorescent
lamps or the sunlight instead of Hg or Xe lamps. In addition, from the
back ground of green and sustainable chemistry, metal-free photoreac-
tions using organic photocatalysts (91)–(103)359–386 have advantages.
9-Mesityl-10-methylacridinium perchlorate (91) which is known as the
Fukuzumi catalyst, acted as a good visible-light photocatalyst for
hydration (Path I),359 alkylation (Path II),360 decarboxylative Giese-type
reaction (Path III),361 oxo-acyloxylation (Path IV),362 trifluoromethylation
(Path V),363 and oxidative [4 þ 2] cycloaddition (Path VI).364 Upon blue
LED irradiation, p-methoxystyrene in the presence of (92) as a photo-
catalyst and PhSSPh as a hydrogen transfer catalyst underwent inter-
molecular [4 þ 2] cycloaddition to give tetrahydronaphthalene in 77%
yield (Path VII).365 Eosin Y (93) is also a green light photoredoxcatalyst
for cross-coupling of diazonium salts (Path VIII),366 sulfonylation (Path
IX),367 oxosulfonylation (Path X),368 decarboxylative alkylation (Path
XI),369 and trifluoromethylation (Path XII).370,371 Intramolecular [2 þ 2]
cycloaddition of nitrogen- or sulfur-containing dienes mediated by flavin
(94) and visible light irradiation was reported (Path XIII).372 In addition,
flavin (95) immobilized on mesoporous silica was developed as a het-
erogeneous visible light photocatalyst for intramolecular [2 þ 2] cy-
cloaddition of dienes (Path XIV).373 The thiothanthone (96) having a
chiral building block acted as an enantioselective visible-light photo-
catalyst for the intermolecular [2 þ 2] cycloaddition of electron-deficient
alkenes with 2(1H)-quinolones. Solar irradiation of 1-penten-3-one with
2(1H)-quinolones led to a cyclobutane in 86%ee yield (Path XV).374 The
cross-linked poly(benzothiodiazole) network (97) was prepared by
Sonogashira–Hagihara cross-coupling, which was a good homogeneous
visible-light photocatalysts for regioselective and stereoselective [2 þ 2]
92 | Photochemistry, 2019, 46, 78–115

cycloaddition of styrene derivatives (Path XVI).375 Rose Bengal (98)
also acted as a visible-light photocatalysts for the intermolecular [2 þ 2]
cycloaddition of 3-ylideneoxindoles (Path XVII).376
Fluoroalkylations using visible-light metal-free photocatalysts

have been developed (Paths V, XII, XVIII–XXI). A Hantzsch ester (99)
was employed by the photoreductive hydrofluoroacetamidation for
alkenes with 2-bromo-2,2-difluoro-N-phenylacetamide (Path XVIII).377
Blue LED irradiation of styrene derivatives in the presence of
an S-(difluoromethyl)sulfonium reagent and perylene (100) as a
photocatalyst in acetonitrile afforded N-(3,3-difluoro-1-phenylpropyl)-
acetamide in good yields (Path XIX).378 Trifluoroalkylated alkenes
(Path XX) and trifluoromethylated iodoalkanes (Path XXI) were
selectively prepared by controlling the reaction conditions of the Niel
red (101) visible-light photocatalyst.379 The cyanamide-functionalized
carbon–nitride (102) was a good visible-light heterogeneous
photocatalyst for sulfonylation of alkenes with sulfinate salts
(Path XXII).380
Benzophenone and its derivatives were used as photocatalysts for
substitution of vinyl sulfones (Path XXIII)381 and for addition of alkenes
(Paths XXV–XXVII).382–385
Photochemistry, 2019, 46, 78–115 | 93

Non-acidic C(sp3)–H bonds of cycloalkanes or heterocycloalkenes in
dichloromethane were readily abstracted by 2-chloroanthraquinone (103)
upon 365 nm irradiation to give radical species. The resulting radical
species reacted with 1,1-bis(phenylsulfonyl)ethene with alkanes to give
adducts.386
94 | Photochemistry, 2019, 46, 78–115

N-Halosaccharins (104) acted effectively in the visible-light promoted
intermolecular haloamination and haloetherification of alkenes.387
5.2 Visible-light metal photocatalysts

Photoreactions of alkenes using visible-light metal photocatalysts are
recently making remarkable progress.9–19 It is well known that the Ir
and Ru complexes, Ir[dF(CF3)ppy]2(dtbbpy)PF6, Ir(ppy)2(dtbbpy)PF6,
[Ir(ppy)2(bpy)]PF6, fac-Ir(ppy)3, and [Ru(bpy)3]2X are typical visible-
light metal photocatalysts. In addition, other useful visible-light
metal photocatalysts have been developed. Radical conjugated add-
ition of electron deficient alkenes and alkylidenemalonates, upon
blue LED irradiation in the presence of a catalytic amount of
Ir[dF(CF3)ppy]2(dtbbpy)PF6, led to the adducts in good yields (Paths
XXVIII388 and XXIX389). The conjugated addition of a-amino radicals to
2-pyridylstyrenes was achieved by the combination of Brønsted acid
and visible-light metal photocatalyst, Ir[dF(CF3)ppy]2(dtbbpy)PF6 (Path
XXX).390 Fluoroalkyl substituents have attracted increasing attention
due to the specific effects of the fluorine atoms on physical and bio-
logical properties. Many fluoro-substituted chemicals were prepared by
visible-light metal photocatalytic reaction of alkenes (Paths XXXI–
XLIX)391–409 with several fluoroalkyl sources under optimal conditions.
Although decarboxylative difluoroacetylation of cinnamic acid with
ICF2COOEt was achieved by merging a photocatalyst, Ru(bpy)3Cl2 and a
copper catalyst, [Cu(NCMe)4]PF6 (Path XLVI).406 The platinum(II) com-
plex (105) acted as a good visible-light photocatalyst for the di-
fluoroacetylation (Path XLVII).407 Upon blue LED irradiation, a mixture
of a-trifluoromethylalkenes with a-keto acids in the presence of
Ir[dF(CF3)ppy]2(dtbbpy)PF6 as the photocatalyst and LiOH as a base in
DMSO afforded gem-difluoroalkenes in good yields (Path XLVIII).408
When N-Boc-substituted a-amino acids were used as the decarbox-
ylative reagents instead of the a-keto acids, 1,1-difluorohomoallyic
amines were obtained.408 a-Trifluoromethylalkenes also underwent
visible-light induced [3 þ 3] annulation with tertiary amines using
Ir(dmppy)2(dtbbpy)PF6 to yield 3-fluorotetrahydropyridine (Path
XLIX).409
Photochemistry, 2019, 46, 78–115 | 95

N-Phenyl-substituted amino acids underwent visible-light photo-
catalyzed decarboxylative addition with 2-cyclohexenone (Path L).410
Tetrabutylammonium decatungstate acted as a photocatalyst for the
decarboxylative addition of electron-deficient alkenes with arylacetic
acids, but the irradiation source was a UV-lamp (Path LI).411 Styrene
underwent visible-light photocatalyzed hydroacylation with benzoic acid
by blue LED irradiation in the presence of tris(trimethylsilyl)silane (Path
LII).412 Visible-light metal photocatalytic dual functionalization of
alkenes were reported.413,414 Dual functionalization took place in a
mixture of methyl acrylate and t-butyldimethyl((1-phenylvinyl)oxysilane)
as electron-deficient and electron-rich partners and benzoic acid as
the acyl radical precursor in the presence of the fac-Ir(ppy)3 photocatalyst
to yield methyl 1,1-dibenzoylacetate in 94% yield (Path LIII).413
White LED irradiation of a mixture of styrene and 2,2,2-trichloroethoxy
96 | Photochemistry, 2019, 46, 78–115

p-cyanobenzoyloxycarbamate in the presence of fac-Ir(ppy)3 in acetoni-
trile afforded the diamidation product in 67% yield (Path LIV).414 The
hydroamination of unactivated alkenes with secondary alkyl amines was
developed (Path LV). Several visible-light Ir photocatalysts were examined
and a combination of Ir[dF(Me)ppy]2(dtbbpy)PF6 as the photocatalyst
and 10 mol% 2,4,5-triisopropylbenzenethiol gave the best result.415
As shown in reaction Paths XXXIX,399 XL,400 XLIX,409 LVI–LXIV,416–424

many heterocyclic compounds were prepared by intermolecular cycload-
dition or intramolecular cyclization using visible-light photocatalysts. The
dual Au and photoredox-catalyzed difunctionalization mechanism was
Photochemistry, 2019, 46, 78–115 | 97

investigated by DFT calculation (Path LXIV). The calculation suggested that
the favored Au catalytic cycle was the sequence of radical addition, single
electron transfer, coordination, cyclization and reductive elimination.424
Methyl N-phthalimidoyl oxalate generated the methoxycarbonyl radical
by visible-light photocatalyst, Ru(bpy)32PF6 and (99). The methoxycarbonyl
radical readily trapped with electron-deficient alkenes to give adducts
(Path LXV).425 Upon blue LED irradiation, 1-methylstyrene in the presence
of fac-Ir(ppy)3 underwent hydroxysulfonylation with p-nitrobenzenesulfo-
nylchloride (Path LXVI),426 while oxidative sulfonylation of alkenes using
the Ir(ppy)2(dtbbpy)PF6 photocatalyst was found (Path LXVII).427
A synergistic combination of the gold catalyst, PriAuCl, and the pho-

tocatalyst, Ru(bpy)3Cl2, achieved that both the CF3S group and the PhSO2
group were regioselectively introduced into alkenes (Path LXVIII).428 A
combination of the selenium catalyst, (PhSe)2, and the photocatalyst
(106) under air resulted in oxidative allyic esterification of alkenes (Path
LXIX).429 Visible-light mediated photocatalytic reactions using palladium
catalysts were also reported (Paths LXX430 and LXXI431).
Novel visible-light photocatalyzed cyclopropanations were reported
(Paths LXXII432 and LXXIII433). In Path LXXII, the formation of the
iodomethyl radical carbenoid ICH2 in the photoredox-catalyzed cycle
was suggested.432 Cr(Ph2Phen)33BF4 was a better visible-light photo-
catalyst for the diazo-based cyclopropanation of electron-rich alkenes
than the ruthenium complexes, Ru(bpy)32PF6 and Ru(bpz)32PF6.433
98 | Photochemistry, 2019, 46, 78–115

The visible-light photocatalyzed hydrocarboxylation of alkenes with CO2
was achieved by the combined use of [Rh{P(C6H4CF3-p)3}2Cl]2 and
Ru(bpy)32PF6 (Path LXXIV).434 The UV light/3,6-Ph2xanthen-9-one/
Cu(IPr)2Cl system was used for the carboxylation of cyclohexene at the
3-position with CO2 (Path LXXV).435 Green LED irradiation of N-
phenylmaleimide with N,N-dimethylaniline in the presence of the visible-
light photocatalyst, Cu(dap)2Cl led to a tetrahydroquinoline in 77% yield
(Path LXXVI).436 Co(dmg)2(py)Pri acted as a visible-light photocatalyst for
the regioselective coupling reaction of alkenes with an epoxy group (Path
LXXVII).437 A combination of Co(dmg)2(py)Cl and (91) upon blue LED
irradiation allowed the photocatalytic anti-Markovnikov oxidation of
b-alkyl-substituted styrenes with water (Path LXXVIII).438 The visible-light
photocatalyzed hydrophosphination of alkenes with diphenylphosphine
using [CpFe(CO)2]2 was developed. Although the hydrophoshination of
styrene afforded the adduct in a low yield, styrenes with methyl, tri-
fluoromethyl, or methoxy groups as the substituents on the phenyl ring
gave the adducts in excellent yields (Path LXXIX).439
The regioselective intramolecular [2 þ 2] cycloaddition of cinnamates
to cyclobutanes was achieved by using Ir[dF(CF3)ppy2]2(dtbbpy)PF2 as the
visible-light photocatalyst (Path LXXX).440 Yoon et al. reported the visible-
light photocatalyzed intermolecular [2 þ 2] cycloadditions of alkenes
(Path LXXXI)441 and of alkenes with butadienes (Path LXXXII).442 When
the photocatalyst, chiral ligand and Lewis acid Ru(bpy)32PF6, (S,S)-
ButPyBox and Sc(OTf)3 were used, excellent enantiomeric excess values
were obtained. The intermolecular [2 þ 2] cycloaddition of 3-
ylideneoxindols in Path XVII also took place using Ru(bpy)321 as the
photocatalyst. A computational study was published.443 Yoon et al.
developed the Ru(bpz)32B(ArF)4 photocatalyzed Diels–Alder reaction of
alkenes with dienes (Path LXXXIII).444 Substituted styrenes in the pres-
ence of heterogeneous TiO2 photocatalysts upon 395 nm irradiation
under oxygen atmosphere afforded aryltetralones via intermolecular
[2 þ 2] cycloaddition, ring expansion and oxygenation (Path LXXXIV).445
Blue LED irradiation of estragol with Pd-decorated TiO2 nanoparticles as
a visible-light photocatalyst led to isomerization to anethole in 93%
yield.446 A combination of TiO2 as visible-light heterogeneous photo-
catalyst and the Togni I reagent as a hypervalent iodine(III) co-initiator
resulted in the addition reaction of unactivated alkenes with
BrCH(COOEt)2, C4F9I, CHCl3 or CCl4.447
6 Photooxygenation and photooxidation

Singlet oxygen which is readily produced by photosensitization, is well
known as a very useful oxidant for alkenes, dienes, and polyenes. Hence,
the microflow reactors connected with low energy LED lamps have been
widely applied in this area. Reviews regrading oxygenation and oxidation
of alkenes including LED-microflow-reactors were published.27,448,449
The 1 : 2 complex of meso-tetraphenylporphyrin and 2,3-dichloro-5,6-
dicyano-1,4-benzoquinone acted as a visible-light photooxygenative
catalyst of alkenes.450 Griesbeck et al. reported a synthetic approach to
Photochemistry, 2019, 46, 78–115 | 99

mono- and bicyclic perortho-esters with a central 1,2,4-trioxane ring
using the singlet oxygen ene-reaction of allylic alcohols.451 In addition,
his group discussed the ene-reaction mechanism of allylic alcohols with
singlet oxygen by DFT calculation.452 Novel nitrogen-containing en-
doperoxides were prepared by the [4 þ 2] cycloaddition of dienes with
singlet oxygen.453 A vortex reactor for continuous flow thermal and
photochemical reactions was developed. The vortex reactor prepared ar-
temisinin (109) in 50% yield by optimal conditions from the starting
material dihydroaltemisinic acid (110).454
Several aerobic epoxidations of alkenes using heterogeneous455–459 and

homogeneous460 photocatalysts have been reported. Though oxygen is
usually used as an oxygen source in the epoxidation, novel photocatalytic
epoxidations of alkenes with water as the oxygen source were
developed.461–463 Synergetic photocatalytic systems constructed with
Ru(bpy)3Cl2, [Co(NH3)5Cl]Cl2 and [(bTAML)FeOH2]NEt4 enabled the
epoxidation of alkenes with water to yield epoxides in good yields.461 The
manganese(V) complex, [Mn(N)(CN)4]2PPh4, was also applicable to the
epoxidation of alkenes.462 In addition, when the chiral manganese
complex, [(R,R-BQCN)Mn(OTf)2] was employed as the epoxidation cata-
lyst, asymmetric epoxidation was found.463
7 Photochemistry of polyenes
The effect of different conformations and substitutions on the photo-
induced (E)–(Z) isomerization of a retinal protonated Schiff base model
(111) was investigated by nonadiabatic molecular dynamics simulations.
The simulations indicated that the effect on bond selectivity, the direc-
tionality of the isomerization, the excited-state lifetime, and the product
distribution of (111) was derived from the ensemble of trajectories.464
The triene (112) which is a donor-acceptor Stenhouse adduct, as a new
class photoswitch underwent the photoinduced (E)–(Z) isomerization,
followed by the thermal 4p-electrocyclization to afford (113).
The identification of the role of the intermediate during the formation

(113) revealed a key step in the photoswitching mechanism.465 Fensterbank
100 | Photochemistry, 2019, 46, 78–115

et al. prepared the polyenes (114) and (115) and tried the synthesis of
ladderanes by photoinduced multiple intramolecular [2 þ 2] cycloaddition.
The polyene (114) upon 300 nm irradiation led to two stereoisomeric
cyclobutane derivatives, sym- and dis-(116) in 45% and 25% yields,
respectively. Under similar conditions, the polyene (115) afforded a mixture
of sym- and dis-(117) and the macrocycle (118). The macrocycle (118) was
derived from multiple Cope rearrangements of dis-(117).466
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Photochemistry, 2019, 46, 78–115 | 115

Photochemistry of aromatic compounds
Kazuhiko Mizuno
DOI: 10.1039/9781788013598-00116
This chapter deals with the photochemical reactions of aromatic compounds including
photoisomerization, photoaddition and cycloaddition, photosubstitution, intramolecular
photocyclization, photorearrangement, photo-reduction and oxidation, and related
photoreactions.
1 Introduction
The photochemistry of aromatic compounds is classified into the similar
categories adopted in the previous reviews in the series.1–3 The photo-
isomerization of arylalkenes, photorearrangement, and photo-reduction
and oxidation reactions have less appeared in the period (2016–2017).
The photochromic properties including E–Z photoisomerization of
azobenzenes and intramolecular photocyclization and cycloreversion of
1,2-di(hetero)arylethenes both in solution and in solid and crystalline
states are interesting subjects, but this chapter does not deal with them.
Under mild visible-light irradiation conditions, a variety of photo-
chemical transformation using organic dyes and metal complexes such
as Ru(bpy)321 and Ir(ppy)3 was reported in view of green sustainable
chemistry.4–6 In addition, convenient methods using flow microreactors
have been developed for synthetic organic photochemical reactions.7,8
Synthetic organic transformation using photochemistry was also covered
in Chemical Reviews as a special issue including historical photoinduced
reactions.5–7,9–15
2 Isomerization reactions
Photoisomerization of E-9,9 0 -bitriptindanylidene (E-1), a sterically
crowded stilbene bearing E-oriented triptindane moieties, generated
the corresponding Z-stilbene (Z-1) in a photostationary mixture (55 : 45).
Photocyclodehydrogenation of (Z-1) in benzene solution afforded
1,2,9,10-tetrahydrocyclopenta[hi]acephenanthrylene (2) merged with two
triptindane units in 85% yield16 (Scheme 1).
Feringa demonstrated a visible-light driven molecular motor bearing
dibenzofluorenyl moiety. Irradiation of ((R)-3) (420 nm light) was isom-
erized to its isomer17 (Scheme 2).
Bell reported the photoisomerization of 2,2,2-triphenylethylidene-
fluorene derivatives (4) as moleculer rotors. Quantum yields for photo-
isomerization varied significantly with substitutents (f ¼ 0.26 for 2-nitro
Nara Institute of Science and Technology (NAIST) 8916-5 Takayama, Ikoma,

Nara 630-0192, Japan. E-mail: kmizuno@ms.naist.jp
116 | Photochemistry, 2019, 46, 116–168

hν
hν
(E-1) (Z-1)
hν
(2)
Scheme 1
Meax Meeq
hν
((P)-(R)-3) ((M)-(R)-3)
Scheme 2
Ph Ph
Ph Ph
Ph Ph
hν
X X
(E-4) (Z-4)
tBu,
4a; X = H, 4b; X = 4c; X = NO2, 4d; X = CN, 4e; X = I
Scheme 3
(4c), f ¼ 0.39 for 2-cyano (4d), f ¼ 0.50 for 2-iodo (4e)). 2-Nitro deriveative
(4c) is photochemically robust and has a large quantum yield for
photoisomerization in the near-UV, which is useful for drive rotor
moiety18 (Scheme 3).
The amino-substituted fulvene (5) became aromatic in the photoactive
excited state (6). It was found to increase the rotary quantum yields of the
photoisomerization for light-driven rotary moleculer motors19 (Scheme 4).
Upon visible-light irradiation, photoisomerization of E- and Z-stilbene
was sensitized by W(CO)4L complexes (L ¼ 2-(1H-imidazol-2-yl)pyridine
Photochemistry, 2019, 46, 116–168 | 117

-
hν
+
N N
(5) (6)
Scheme 4
CO
CO OC N
OC N
W
W
OC N NH
OC N NH CO
CO
7 8
Scheme 5
200 fs
Tws
266 nm
HTf
MeO N
VR
~13.4 ps N
Z-9
E-9
OMe
Scheme 6
(7) and 2-(2 0 -pyridyl)benzimidazole (8)), which exhibited enhanced

phosphorescence from the metal-to-ligand charge transfer (MLCT)
excited state with the quantum yield in the order of 103, almost two
orders of magnitude higher than those reported for W(CO)4(diimine)
complexes. The latter complex (8) also sensitized the photoisomerization
of a-methylstilbene, a-phenylcinnamonitrile, and cinnamyl alcohol20
(Scheme 5). Ultrafast E–Z photoisomerization of N-(2-methox-
ybenzylidene)aniline (9) around C–N double bond was observed and
twisted intermediate states were elucidated21 (Scheme 6).
Irradiation with 420 nm visible light of the E,Z-configuration (E,Z-10) of
bis-hemithioindigo afforded the planar Z,Z-isomer (Z,Z-10) in a highly
selective manner. The E,Z-isomer, which has helical conformation, rec-
ognized electron-poor aromatic guest (11) to give a charge-transfer (CT)
complex (12), which thermally generated the stable Z,Z-isomer (Z,Z-10)22
(Scheme 7).
Photoisomerization of aromatic thiol giving thione and thiyl radical
was discussed using time-resolved X-ray absorption spectroscopy.23
118 | Photochemistry, 2019, 46, 116–168

NMe2 O
C5H11
Me2N
S S
C5H11 Me2N
hν (420 nm) (Z,Z)-10
NMe2
Δ
Δ
hν (420 nm)
O NC CN
C5H11
S S O2N NO2
O (11) iE,Z-10 - 11Åj
CT complex
C5H11 Me2N NMe2
12
NMe2
Me2N
(E,Z-)10
Scheme 7
3 Addition and cycloaddition reactions

Yang and Cong synthesized oligoparaphenylene-derived nanohoop (16)
using photodimerization-cycloreversion of anthracene (15),24 which was
prepared from diborylanthracene (13) and/or its photocyclodimer (14)
(Scheme 8).
The photodimerization and cycloreversion of bis-anthracene cyclo-
phane (18) was discussed from the effect of pressure on the reaction rate
by Plotnikov and Martinez. Their model predicts that the barrier
reduction is linear in the low-pressure regime (up to 2 GPa), but has a
nonlinear at higher pressure.25 (Scheme 9).
Upon irradiation at 300 nm, the fluorinated azacyclophane (19)
afforded the photodimer (20) of benzene core, which was thermally
isomerized to syn-o,o 0 -dibenzene isomer (21). The syn-isomer was pho-
tochemically cyclized to the cage diene isomer (20)26 (Scheme 10).
Maeda and Mizuno reported the disasterselective photocycloaddition
of (l )-menthyl 2-naphthalenecarboxylate (22) with 3-furanmethanol (23)
to afford caged products (24), (25) (d.e. ¼ 48%, 40% respectively). In
photoreactions of di-8-phenyl-(l)-menthyl 2,3-naphthalenedicarboxylate
with (23), maximum 67% d.e. was obtained27 (Scheme 11).
The photoreaction of 1-cyano-4-hydroxymethylnaphthalene (26) with
ethyl vinyl ether (27a) afforded [2 þ 2] cycloadducts (28) and (29) at room
temperature in a highly endo-selective manner (89 : 11) via inter-
molecular hydrogen bonding. However, in the photoreaction with 2-
hydroxyethyl vinyl ether (27b), lower stereoselectivity (56 : 44) was
Photochemistry, 2019, 46, 116–168 | 119

Scheme 8
hν
hν
17 18
Scheme 9
observed at room temperature, but at 40 1C highly endo-selective [2 þ 2]

photocycloaddition occurred in an 81 : 19 ratio28 (Scheme 12).
The hexadehydro Diels–Alder cycloisomerization to produce reactive
benzyne derivative (31) afforded polycyclic benzene derivative (32) upon
photo-irradiation of tetrayne compound (30). The photoreaction pro-
ceeded at much lower temperature (including even at 70 1C) than the
thermal reaction29 (Scheme 13).
120 | Photochemistry, 2019, 46, 116–168

F F
NR NR
F F F
Δ F
F F hν F F F
RN NR F
F F F hν
F F F
F (300 nm)
F F
RN RN F
F F 21
19 20 R = COtBu
Scheme 10
O
CH2OH
O + O
hν
22 23
O OH
O OH
O + O
O O
25
24
Scheme 11
OH OH OH
R
hν O
+ +
R
O
R
CN 27 CN CN O
a; R = H b; R = OH 28 29
26 endo exo
>8 <2
Scheme 12
Irradiation of o-divinylbenzenes (33) bearing a,b-unsaturated carbonyl

group resulted in a pericyclic reaction to generate cyclic o-quinodi-
methane intermediates (34), which efficiently afforded oxatricyclic com-
pounds (35) in good yields by intramolecular oxa-[4 þ 2] cycloaddition30
(Scheme 14).
Air- and moisture-stable ruthenium naphthalene complexes (36) in
the presence of endiyne (37) underwent photochemical dissociation of
the naphthalene ligand and replaced to the endiyne, which caused
photo-Bergman cycloaromatization. Similarly, the same ruthenium
naphthalene complexes (36) triggered dienyne (39) cyclization under
photochemical conditions31 (Scheme 15).
Intramolecular [3 þ 2] photocycloaddition of cycloalkene-linked
1-cyanonaphthalenes (41) at 2-position efficiently afforded pentacyclic
compounds (42) and (43) as linear-type triquinanes in a stereoselective
Photochemistry, 2019, 46, 116–168 | 121

MeO
hν OMe
E (254 or 300 nm)
E Pyrex, CDCl3
E
30 MeO E = CO2Me E O
32
OMe OMe OMe
E E E
E OMe + +
E E
-
O O X-
benzyne Me H/D Me
31
Scheme 13
O R1 R1
O
R1 hν R3
R3 R3 O
R2 R2
33 34 35
R1 = H, Me, MeO R2 = CO2Me, CO2Et, CN etc. R3 = Me, Et, tBu, Ph
Scheme 14
Me
Me
Me 37 +
Me Ru
R R
hν RT
1,4-CHD acetone-d6 R1 R
R
+ 1,4-CHD; 1,4-cyclohexadiene
Ru 38
R R
R1 R
R
39 +
Ru
36 R R
hν, RT R
R = Me R1 = CF3 R
R
40
Scheme 15
122 | Photochemistry, 2019, 46, 116–168

manner32 (Scheme 16). Spiro compound (45), which was isomerized to
(46), was obtained via intramolecular photocyclization of 1-cyano-4-
(4-alkenyl)naphthalene (44). On the other hands, angular-type triquinane
derivatives (48) were selectively produced in the [3 þ 2] photocycloaddi-
tion of 1-cyanonaphthalenes (47) linked cycloalkenyl groups at 4-position
in good yields33 (Scheme 17).
Intramolecular photocycloaddition of arylcyclopropanes to 1-
cyanonaphthalene derivatives (49) and (52) afforded [3 þ 2] and [3 þ 4]
cycloadducts (50), (51), (53), and (54) depending on the position of sub-
stituents34 (Scheme 18). Similarly, [3 þ 2] photocycloadducts (56) from
9-cyanophenanthrenes tethered to arylcyclopropanes (55) were obtained
accompanying dihydroisochroman derivatives (57)35 (Scheme 19).
Intramolecular 10,10a-[2 þ 2] photocycloaddition of phenanthrenes
(58) with linked styrene afforded unusual 8-membered ring products (61)
by ring-opening of strained [2 þ 2] cycloadducts (60)36 (Scheme 20).
n = 1-4
NC
n
NC CN
hν (> 280 nm)
41
CH3CN
CN CN
NC H NC H
CN CN
H + H
H H
H H n H H n
42 43
Scheme 16
NC NC NC
hν
> 280 nm
dry CH3CN aq. CH3CN
O O
44 46 O
45
NC CN
hν
> 280 nm
CH3CN
H
n H
NC n
47 CN
NC NC H 48
n = 1,2
Scheme 17
Photochemistry, 2019, 46, 116–168 | 123

Ar
O
CN NC NC
O hν +
O
49 Ar Ar
50 51
Ar = Ph, p-MeOC6H4, p-MeC6H4 head-to-head head-to-tail
CN
CN NC
Ar Ar
hν
+
O O 54
Ar O 53
52
Ar = Ph, p-MeOC6H4, p-MeC6H4
Scheme 18
R1
CN
55
O
Ar
R2 hν
> 280 nm
R1 R1
CN Ar CN Ar
+
O
H
R2 O
R2
57
56
Scheme 19
Although C-9 C-10 [2 þ 2] cycloadducts (59), which underwent cyclor-

eversion under longer irradiation, were initially produced, prolonged
irradiation selectively afforded (61). Product distributions were
dependent on electron-donating and accepting substituents. In the case
of R1 ¼ R4 ¼ CN, R2 ¼ H, R3 ¼ OMe, (61) was exclusively produced from
the initial stage in a highly selective manner.
Aminobenzocyclobutenes (62) were conveniently synthesized by [2 þ 2]
cycloaddition of arynes with ketenes followed by reductive amination.
The distonic radical cations of (62) upon photooxidation by an excited
iridium complex underwent the annulation with arylalkynes (63) to give a
variety of naphthalenes (64)37 (Scheme 21).
Copper ([Cu(dap)2]1)-catalyzed visible-light irradiation of maleinimides
(65) with N,N-dimethylanilines (66) and N-aryltetrahydroisoquinolines (68)
124 | Photochemistry, 2019, 46, 116–168

R2 R4
R1
O
hν
benzene
R3 58
R2
R2 R4 R1
R1
O
+
R3
R3 O
59
60 R4
R1 = H, CN R2 = H, CN
R3 = H, OMe R4 = H, CN, OMe
R2 R1
R3
61 R4
Scheme 20
H Ar [Ir(ppy)2(dtbbpy)][PF6] Ar
N
+ (2 mol%), K2HPO4 R
R toluene
CF3
visible light
62 63 64
ppy; 2-phenylpyridine
R = MeO, (MeO)2, BnO dtbbpy; di-tbu-2,2’-bipyridine
Ar = Ph, p-BrC6H4, p-MeOC6H4, p-nBuC6H4 etc.
Scheme 21
in the presence of Brønsted acid such as trifluoroacetic acid (TFA) afforded

tetrahydroquinolines (67) and octahydroisoquinolino[2,1-a]pyrrolo[3,4-
c]quinolines (69) in good yields38 (Scheme 22).
Strained and macrocyclic [k](1,7)naphthalenophanes (m ¼ 1, 2, 4, 12;
n ¼ 0, 1, 2; k ¼ 11, 12, 14, 16, 18, 22, 24) (71) were synthesized in moderate
to good yields by using the photo-dehydro-Diels–Alder reaction of (70)39
(Scheme 23).
A suspension of several solid photoactive trans-cinnamic acid deriva-
tives (72) and (73) in cyclohexane exclusively afforded [2 þ 2] homo-
cycloadducts (74) and (75) with total regio- and stereo-selectivities,
and no cross-adducts were obtained40 (Scheme 24). Similarly p-, m-, o-
hydroxycinnamic acid (76), (77), and (78) gave only homo-cycloadducts
(79), (80), and (81), respectively.40
Photochemistry, 2019, 46, 116–168 | 125

O N
N 5% [Cu(dap)2]Cl
+ H
N 2.0 equiv TFA
R1 R2
O R2 green LED O H
DMF, RT, air N
O
R1 = Ph, Bn, C6F5 R2 = H, Br, i Pr R1
65 67
66
O 5% [Cu(dap)2]Cl
+ N H N
N 2.0 equiv TFA
Ph H
O green LED
65 R DMF, RT, air O R
68 H
N
R = H, F, OMe Ph O
R3 69
R3
N N R3 = p-OMeC6H4
Cu
N [Cu(dap)2]+
N
R3
R3
Scheme 22
O
O
O
n hν n O
O O
CH2Cl2
m O O
O n O O n
m
70
m = 2, 3, 4, 6, 10 12 O 71
n = 0, 1, 2
k = m + 2n + 8 = 11, 12, 14, 16, 18, 22, 24
Scheme 23
Visible-light induced intermolecular [2 þ 2] photodimerization of

chalcones (82) and cinnnamic acid derivatives in the presence of fac-
tris(2-phenylpyridinato-C2,N) iridium (Ir(ppy)3) efficiently occurred
to give cyclobutanes (83) in a highly regio- and diastereo-selective
manner. In a similar manner, Ir-complex-sensitized photoreaction of
(82) and related a,b-unsaturated aryl compounds (84) with 1,1-diphe-
nylethene (85) afforded [2 þ 2] cycloadducts (86) in high yields41
(Scheme 25).
Yamada reported the [2 þ 2] photocyclodimerization of (E)-4-(2-(2-
naphthyl)vinyl)pyridine (87) and (E)-4-(2-(1-naphthyl)vinyl)pyridine (88) in
acidic solution (HCl) via cation–p interaction in a highly stereoselective
manner accompanying Z-isomers (93). Anti-head-to-tail cyclodimer (89) was
126 | Photochemistry, 2019, 46, 116–168

hν
Me 365 nm
Me Me cyclohexane
CO2H CO2H suspennsion

stirring
48 h
72 73
p-Tol CO2H 4,3 Me2C6H3 CO2H
HO2C p-Tol HO2C

3,4-Me2C6H3
74 75
HO OH
4-HOC6H4 CO2H 3-HOC6H4 CO2H
CO2H
CO2H
76 77 HO2C HO2C
4-HOC6H4 3-HOC6H4
365 nm
cyclohexane
OH 79 80
suspennsion
CO2H stirring 2-HOC6H4
48 h CO2H
78 81
HO2C
2-HOC6H4
Scheme 24
O O
O hν, 1 mol % Ir(ppy)3 Ar‘ Ar’
2
Ar Ar’ 83
1,4-dioxane, Ar, RT, 24h
Ar Ar
82 anti-head-to-head
Ar, Ar’ = Ph, o-, p-MeC6H4, o-, p-FC6H4, o-, p-ClC6H4 etc.
O
O Ph hν, 1 mol % Ir(ppy)3 Ph
+ Ph
Ar R
Ph ClCH2CH2Cl, Ar, RT
Ph
84 Ph
85
86
R = Ph, OMe, OBn, OH, NH2 etc.
Scheme 25
selectively obtained. This photoreaction proceeded upon visible and/or UV

light irradiation42 (Scheme 26).
Visible-light induced photocatalytic [4 þ 2] benzannulation in the
presence of Ir(ppy)3 and tBuONO as a diazotizing agent afforded poly-
cyclic aromatic compounds such as phenanthrenes (95) in moderate to
high yields43 (Scheme 27).
An efficient radical addition/elimination reaction occurred in the
diarylketone-sensitized photoreaction of alkenyl and alkynyl sulfones (96)
Photochemistry, 2019, 46, 116–168 | 127

N N
87 88
hν(> 300 nm)

HCl (3 equiv)
MeOH
Py Np Py Py Py Py Py Np
+ + + +
Np Py N Np
Np Py Np Np Np Np
89 90 91 92 93
Scheme 26
R1 R1
R3 blue LEDs (7 W)
fac-Ir(ppy)3 R3
NH2 t
BuONO
+
R4
R4
R2 R2
94
95
R1 = H, p-F, p-Me, p-CO2Me R3 = H, Ph, CO2Et
R2 = H, m-Cl, p-Cl, p-tBu R4 = CO2Et, Ph, p-F-C6H4, p-Cl-C6H4,
p-MeO-C6H4, o-CF3-C6H4, p-tBu-C6H4
Scheme 27
4,4’-Cl2Ph2CO (20 mol%)

SO2Ph
Ph + Ph
O 36 W CFL O
96 97
E : Z = 94 : 6
O O
4,4’-Cl2Ph2CO (20 mol%)
Ph SO2Ph + Ph
NHCH3 36 W CFL N
H
98 99
Scheme 28
and (98) in the presence of ethers or amides in high yields. The process is
based on the catalytic formation of a-alkoxy/a-amidyl radicals via homo-
lytic activation of the C(sp3)–H bond of ethers/amides with a catalytic
amount of diarylketones in the presence of fluorescent light44 (Scheme 28).
Unsymmetrical 2,3-diaryl substituted indoles (102) were synthesized
from arylsulfonyl chlorides (100) and o-azidoarylalkynes (101) in the
presence of Na2HPO4 under transition-metal free, visible-light irradi-
ation45 (Scheme 29).
128 | Photochemistry, 2019, 46, 116–168

R
Ar
SO2Cl 1,4-CHD
Eosin Y, MeCN
R + Ar
N3 Na2HPO4 N 102
visible light H
100 101
R = F, Cl, Me, MeO etc. Ar = Ph, p-FC6H4, p-MeOC6H4 etc.
Scheme 29
Br
Eosin Y CO2H CBr3
CoI2
R + CBr4 R + R
DMSO
visible light
103 104 105
R = H, o-, m-, p-Me, p-F, p-Cl, p-Br, p-MeO etc.
Scheme 30
5 mol% CuCl O O
+ Ar
Ar
N NH2 CH3CN, RT, 10 h N N
63 N - CO N Ar
O2 blue LEDs H H
O 108
106
107
Ar = Ph, p-tBuC6H4, p-MeOC6H4, 4-FC6H4, 1-naphthyl, 2-naphthyl etc.
Scheme 31
Photoredox and cobalt-catalyzed carboxylation of styrenes (103) with

CBr4 afforded the a,b-unsaturated carboxylic acids (104) via radical
addition and Kornblum (DMSO) oxidation accompanied by addition
products (105). DMSO serves as the oxidant, oxygen source and solvent
under the photocatalytic conditions46 (Scheme 30).
Visible-light irradiation of 2-aminopyridine (106) with terminal ar-
ylalkynes (63) in the presence of copper(I)-catalysis afforded aerobic oxi-
dative C–N coupling products (108). At room temperature, C–C triple
bond cleavage occurred with the elimination of carbon monoxide to give
(108)47 (Scheme 31).
Visible-light irradiation of aryl halides (109) with arylalkynes (63) in the
presence of rhodamine 6G (Rh-6G) and N,N-diisopropylethylamine
(DIPEA) gave pyrrolo[1,2-a]quinolines (110) and ullazines in moderate to
good yields48 (Scheme 32).
Furo[3,2-c]coumarines (112) using visible-light promoted photoredox
neutral coupling of 3-bromo-4-hydroxycoumarines (111) with arylalkynes
(63) were synthesized in the presence of Ir(ppy)2(dtbbpy)PF6 and NaHCO3
in DMSO49 (Scheme 33).
Photochemistry, 2019, 46, 116–168 | 129

R1 R1
Br Rh-6G
+
N N
DIPEA, DMSO
LED 455 nm
R 63 R
109 110
R1 = H, CF3, COCH3 R = H, Me, MeO, F, Cl
Scheme 32
Ar
OH O
Br Ir(ppy)2(dtbbpy), NaHCO3
R + DMSO, 13 W white LEDs R
O O Ar
O O
111 63
112
R = H, OMe, Br, Cl
Ar = H, p-MeC6H4, o-, m-, p-MeOC6H4, p-tBuC6H4 etc.
Scheme 33
H
N+ Me Me
N N
Broensted acid +
113 pseudo
R iminium ion R
114
R = H, o-, m-, p-Me, o-, m-, p-F etc. Me
N N
Broensted acid (10 mol%) Ph
IrIII photocatalyst
Blue LEDs strip
PhMe, 25 oC, 14 h 115
R
Scheme 34
The conjugated addition of a-amino radicals to arylalkenylpyridines

(113) occurred to give (115) in the presence of Brønsted acid and visible-
light photoredox catalysis Ir[dF(CF3)ppy]2(dtbbpy)PF6 via pseudo imi-
nium cation intermediates (114)50 (Scheme 34).
Axially chiral 3,4-bisbenzylidene succinate amide esters (116) and (118)
photocyclized to give a formal skeleton of ()-podophyllotoxins (117) and
(119) by using continuous flow photochemical reactor51 (Scheme 35).
Visible-light irradiation of styrenes (103) with difluoromethyl-
triphenylphosphonim bromide (120) as difluoromethylating reagent and
alcohols/water as the nucleophiles afforded difluoromethyl-containing
alcohols and ethers (121) in moderate to excellent yields52 (Scheme 36).
130 | Photochemistry, 2019, 46, 116–168

O CH3
N
R O CH3 CH3
N R
CH3 hν
Ph
O
Ph O
O
R O R 117
116 R = 3,4,5-trimethoxy
R2 O
N
R2
O
R1 N
hν R1
R2 O
O
R1 O
O 119
R2
118
R1 = methoxy R2 = methyl
R1
Scheme 35
Nu
visible light
CF2H
Ar + [Ph3PCF2H]+Br-
photocat, NuH Ar
103
120 Nu = OH, OR’ 121
Ar = Ph, p-MeOC6H4, p-ClC6H4, p-PhC6H4 etc.
Scheme 36
O HO R’
hν (350 nm)
R’ TI(Oi Pr)4, BF3•Et2O O
O X
R 123
122
X = CH2, OCH2, CH2CH2 X R = H, o-, m-, p-Me, 2,4,6-Me3
R’ = H, Me, Ph
Scheme 37
Griesbeck et al. reported the hydroxyalkylation of aromatic aldehydes

and ketones (122) with cyclic ethers giving (123) in the presence of a
mixture of Ti(OiPr)4 and BF3 Et2O53 (Scheme 37).
Upon metal-free visible-light irradiation, hydroxyazidation of a-
methylstyrene (124) efficiently occurred to give (126) via (125) in the
presence of trimethylsilyl azide (TMSN3), oxygen, and 9-mesityl-10-
methylacridinium perchlorate (Acr1Mes ClO4) as a photocatalyst54
(Scheme 38).
Photochemistry, 2019, 46, 116–168 | 131

Acr+Mes ClO4- (3 mol%)
N3 N3
toluene (0.05 M)
O OR OH
TMSN3
O2 balloon, 4 Ä MS
124 rt, 12 h, 8 W blue LEDs R = TMS, H
125 126
Scheme 38
Me Ru(bpy)3Cl2
O HE, additive Me
O O O
+ solvent, rt, Ar
S Ph
O O N 40 W CFL
O
O 129
127 98
H H
EtO2C CO2Et
HE : Hantzsch ester 128
Me N Me
H
Scheme 39
NH2
HO CN
O
CHO
CN visible light (22 W)
+ +
O2 N CN O O RT O NO2
O
130
131 132
Scheme 40
Internal alkynes (129) from 1-(2-(phenylsulfonyl)ethynyl)benzene (98)

with N-phthalimidoyl oxalate (127) were efficiently synthesized by using
visible-light in the presence of Ru(bpy)3Cl2 and Hantzsch ester (128)55
(Scheme 39).
Highly functionalized dihydropyrano[2,3-c]chromenes (132) using
visible-light irradiation of p-nitrobenzaldehyde (130), malononitrile, and
4-hydroxycoumarine (131) via a multicomponent-tandem strategy were
efficiently synthesized under solvent and catalyst free mild conditions56
(Scheme 40).
Visible-light irradiation of N-aryl glycines (133) with diazo compounds
in the presence of rose bengal afforded N-arylaziridines (135) via de-
carboxylative cyclization (aza-Darzens reaction)57 (Scheme 41).
A visible-light induced regio- and stereo-selective addition of alkyl
bromide (136) to arylacetylenes (63) gave alkenyl bromides (137) in
high efficiency under ambient and metal-free reaction conditions58
(Scheme 42).
The photoredox-induced intra- and inter-molecular radical [4 þ 2]
annulations of indole derivatives (138) and (142) in the presence of
132 | Photochemistry, 2019, 46, 116–168

-
visible light N
H H +
N CO2H Rose Bengal -H Ar
Ar N+
O2 Ar N2 + CO2R
133 N2
H
134 H CO2R
Ar = Ph, o-, m-, p-MeC6H4, p-F-, p-Cl-, p-Br-C6H4 etc. 3-exo-tet
R = Et, i Pr, nBu, tBu etc. cyclization
Ar
N
CO2R
135
Scheme 41
Ar
O NC CN photocatalyst O NC CN Br
Br (5 mol %)
N + Ar H H
N
Ph
light source
Ph
O 63 solvent. 48 h O
136 137
Ar = Ph, p-F-, p-Cl-, p-Me-, p-MeO-, p-NO2-C6H4 etc.
Scheme 42
Scheme 43
Ru(bpy)321 or Ir(ppy)2(dtbbpy)1 complex as photocatalyst (PC*) afforded

tricyclic tetrahydropyridoindoles (139, 140, 143, and 144) via 3-indolyl
radicals59 (Scheme 43).
Dual gold/photoredox-catalyzed C(sp)–H arylation of terminal arylal-
kynes (63) using aryl diazonium salts (145) afforded functionalized
arylalkynes (146) under mild, redox-neutral conditions60 (Scheme 44).
Photochemistry, 2019, 46, 116–168 | 133

AuI complex (10 mol%)
N2+BF4-
Ru(bpy)3 (2.5 mol%)
+
R DMF (0.1 M) R
R’
’R 23 W CFL, rt. 2h
63 145 146
Au complex ; (p-MeOC6H4)3PAuCl
R = H, p-CN, m-, p-CF3 etc. R’ = H, p-CN, p-CO2Et etc.
Scheme 44
O
N Ir(ppy)3, Li2CO3 N
S Br + R O
Ar R DMSO, hν
O O
147 148
149 CH2SO2Ar
Ar = Ph, p-MeC6H4, p-NO2C6H4, p-MeOC6H4
R = Ph, p-NO2C6H4, p-MeOC6H4
Scheme 45
visible light F F
O O
S CO2Me fac-Ir(ppy)3 (3.5 mol%) CO2Me
+
F 151
R NMP, N2, rt, 20 h R
103 F F
150 t
R = H, p- Bu
O O visible light
CO2Me fac-Ir(ppy)3 (3.5 mol%) F F
S
+
F
150 NMP, N2, rt, 20 h CO2Me
F F 153
152
Scheme 46
Visible-light induced radical (phenylsulfonyl)methylation reaction of

N-arylacrylamides (148) using bromomethyl phenyl sulfone derivatives
(147) in the presence of Ir(ppy)3 and Li2CO3 occurred to give cyclized
(arylsulfonyl)methylated compounds (149) under a mild and efficient
processs61 (Scheme 45).
The visible-light-induced reaction of FO2SCF2CO2Me (Chen’s Reagent)
(150) with styrenes (103), indene (152), unactivated alkenes, and hetero-
arenes using fac-Ir(ppy)3 afforded a variety of carbomethoxydi-
fluoromethylated products such as (151) and (153) in good to excellent
yields62 (Scheme 46).
Han et al. found the regio- and stereo-selective photoredox-catalyzed
chlorotrifluoromethylation of internal arylalkynes (154) to give functio-
nalized alkenes (156) in the presence of CF3SO2Cl (155) under mild
conditions using visible light63 (Scheme 47).
Photoinduced tandem cyclization of 3-iodoflavones (157) with electron-
rich five-membered heteroarenes in acetonitrile without any additives
134 | Photochemistry, 2019, 46, 116–168

O blue LED CF3
Ir(ppy)3(2 mol%)
R1 R2 + Cl S CF3 Ar R
O THF, Ar, 30 oC
154 155 Cl 156
R1 = MeO, CN, CO2Me, TfO, NHAc, NHTs etc

R2 = Me, n-Bu, t-Bu, cyclopentyl, cyclohexyl, CO2Et etc.
Scheme 47
OMe
OMe
Me
O
O N hν, Ar
+
MeCN
I
158 O N
O 157 Me
OMe
O
hν, Ar
MeCN
O N
159 Me
Scheme 48
O Ru(dtbbpy)3Cl2•6H2O
O Alkyl NiCl2, Salen, base
Ar Alkyl O Ar
O white LED
63 160 161 Alkyl
Ar = Ph, m-, p-MeC6H4, p-FC6H4, p-ClC6H4 etc.
Alkyl = C5H11, C7H15, C11H23, etc.
Scheme 49
such as transition metals, ligands, and oxidants, afforded (159) via (158)
under mild conditions64 (Scheme 48).
A photo- and nickel co-catalyzed hydroalkylation of terminal arylalkynes
(63) by alkyl diacyl peroxides (160) occurred to give Z-preferred alkenes
(161) in moderate to good yields under visible-light irradiation con-
ditions65 (Scheme 49).
Polysubstituted furans from a-chloro-alkyl ketones (162) and styrenes
(103) via domino radical addition/oxidation sequence were efficiently
synthesized to give 2,3,5-trisubstituted furans (163) under visible-light
irradiation conditions using photocatalyst fac-Ir(ppy)3, oxidant K2S2O8
and base Cs2CO366 (Scheme 50).
An intermolecular radical-radical cross-coupling reaction of secondary
and tertiary amines (164) with diaryl ketones (165) and aldehydes
occurred to give 1,2-amino alcohols (166) using visible light photoredox
Photochemistry, 2019, 46, 116–168 | 135

R
O
visible light
+ fac-Ir(ppy)3, DMSO
O
Cl Na2S2O8, Cs2CO3, rt
103 163 R
162
Scheme 50
H Ar Ar
N CO2Et O H
fac-Ir(ppy)3 (2 mol%) N
+ OH
Ar Ar DMAP, LiBF4, RT
Me 164 Me CO2Et
3 W blue LEDs
165 166
Ar = Ph, p-MeO-C6H4, p-F-C6H4
Scheme 51
O R1
H Br
N hν, Ir(ppy)3 (2 mol%)
R2 + Ph N
N R1 N
Na2CO3, CH3CN, rt
167 168
R2
169
R1 = Ph, o-, m-, p-MeC6H4, p-MeOC6H4, p-FC6H4, p-ClC6H4, p-BrC6H4, etc.
R2 = Ph, m-, p-MeC6H4, p-MeOC6H4, p-FC6H4, p-BrC6H4, Me, tBu
Scheme 52
Ir(ppy)2(bpy)+
(10 mol%) O O
Me
O O Fe(OTf)2
R N O
N Ar (2 equiv)
+ R N O
CH2Cl2
170 10 oC, 18 h 172
171
Ar = 3,5-di-tBuC6H3 visible light NMeAr
R = Pr, PhCH2CH2 etc.
Scheme 53
catalyst fac-Ir(ppy)3 in moderate to good yields under mild conditions67

(Scheme 51).
1,3,5-Trisubstituted pyrazoles (169) under visible-light irradiation
conditions using Ir(ppy)3 were synthesized via radical addition of hy-
drazones (167) by a-bromo ketones (168)68 (Scheme 52).
Miyake et al. reported visible light mediated a-arylation of a,b-
unsaturated imides (171) via aminium radicals from diarylalkylamines
(170) to produce (172) using a photoredox catalyst69 (Scheme 53).
Aromatic amides (175) via radical arylation of tert-butyl isonitrile (174)
using arylazo sulfones (173) in aqueous acetonitrile were prepared under
metal-free visible-light irradiation conditions70 (Scheme 54).
136 | Photochemistry, 2019, 46, 116–168

SO2CH3 O
LEDs
N N + R-NC C R
Ar CH3CN/H2O 9/1 Ar N
174 H
173 175
R = tBu, cyclohexyl
Ar = p-COCH3, m-, p-NO2, m-, p-CN etc.
Scheme 54
4 Substitution reactions
The visible light catalyzed photosubstitution of aryl diazonium salts (145)
have been investigated by several groups. Upon blue LED irradiation, aryl
methyl sulfoxides (176) were efficiently synthesized using (141) and DMSO
in the presence of Ru(bpy)3Cl2 as a photosensitizer under mild conditions.
Diaryl sulfides (178) were efficiently obtained via organocatalytic visible-
light-mediated process from aryl thiols (177) with (145) in the presence of
eosin Y under air. Diaryl disulfides (179) were efficiently produced via
visible-light-promoted coupling of (145) and CS271–73 (Scheme 55).
Direct photoarylation of heteroarenes such as furan, thiophene, and
N-methylpyrrole and coumarines with (145) smoothly occurred in the
presence of porphyrins as photosensitizers. One-electron transfer from
excited porphyrin to (145) causes the formation of aryl radical as a key
intermediate74 (Scheme 56). Similar C–H arylation of heteroarenes with
(145) using TiO2 was efficiently achieved by use of continuous flow
microreactor.75
The cross-coupling of nitroalkenes (181) with (145) under transition-
metal-free conditions efficiently afforded trans-stilbene derivatives (182)
under visible light irradiation. This photoreaction proceeded via a radical
pathway, with (181) serving as the radical acceptor76 (Scheme 57).
Protti and Fagnoni reported the formation of aryl-carbon bonds via
photogenerated phenyl cations. A variety of arylated products including
biaryls, allylarenes, and 2-arylacetals were smoothly synthesized using
flow system under metal-free mild conditions.77 UV irradiation of aryl
chloride (183) and (186) in the presence of inert arenes (185), (189), and
(190) caused C–C coupling to give biaryls as a facile, efficient, and
catalyst-free method78 (Scheme 58). The aryl radical via homolytic
cleavage of C–Cl bond is a key intermediate for the formation of biaryls
(185, 189, and 190). 5-Phenylpirimidine (192) from 5-bromopyrimidine
(191) in the presence of benzene was obtained under UVA irradiation
conditions79 (Scheme 59). A variety of hetero-biaryl derivatives were
synthesized under mild conditions.
Rossi et al. reported the mechanistic insight of a photoinduced base-
promoted homolytic aromatic substitution (photo-BHAS). Dimsyl anion,
from a strong base such as KOtBu and DMSO, is responsible for inducing
the initiation by a photo-BHAS process on alkyl halide. 1-Phenyl-
adamantane (194) via photo-BHAS in the presence of KOtBu and DMSO
was efficiently obtained from 1-iodoadamantane (193) and benzene
(187)80 (Scheme 60). They also found the direct arylation of benzene to
afford 194 using KOtBu and DMSO at room temperature in the absence of
Photochemistry, 2019, 46, 116–168 | 137

O
O
N2+BF4- [Ru(bpy)3]Cl2 (2 mol%) S
+ S Me
R oC R
Me Me blue light, N2, 25
145 176
R = H, 4-MeO, 3,4-diMeO, 4-Me, 3,4-diMe, 4-isopropyl, 4-nitro, 4-Cl, 4-F etc.
SH
N2+BF4- Green LEDs S
+
R
cat., Air, 23 oC
OMe
145 177 178
N2+BF4- R
Ru(bpy)3 (PF6)2 (1 mol%) S
R + CS2
R S
visible light, DMSO, rt
145
179
Scheme 55
N2+BF4
hν
+ O
O Porphyrin
R or TiO2 R
145
180
R = p-F, p-Cl, p-Br, p-NO2, m-CF3
Scheme 56
N2BF4
NO2
Eosin-Y (5 mol%) R1
+
181 DMF, rt
R1 LED (530 nm) 182
145
R1 = H, o-, p-Me, o-, m-, p-OMe, o-, m-, p-Cl, p-NEt2,1-naphthyl etc.
Scheme 57
any additive. The same methodology was applied to the photoarylation of

alkenes to give 196 and 197 using only KOtBu and/or 18-crown-6-ether
without any solvent.
The visible-light-mediated C–C and C–O cross-coupling of electron-rich
phenols (198) and arenes (199) were reported by using [Ru(bpz)3](PF6)2]
as photosensitizer and ammonium persulfate as terminal oxidant81
(Scheme 61).
138 | Photochemistry, 2019, 46, 116–168

MeO OMe
hν
+
+ C6H5OMe
flow reactor
MeCN–H2O (5 : 1)
Cl 184
185
183
D D D D
hν
Cl + + D D D +
254 nm
D D D D
186 187 189 190
188 70% yield
KH /KD = 0.92
Scheme 58
Br Ar
UVA, K2CO3 (1.1 equiv)
+ ArH
N N MeCN, rt, 24 h N N
ArH: C6H6, C6H5Cl
191 192
Scheme 59
KOtBu, hν
I + Ph
DMSO
187 95% 194
193
Ph R1
R1 Ph X Ar
t
ArH 197
KO Bu, hν
KOtBu, hν
18-crown-6
DMSO
ether
R R R
196 ArH = benzene,
30-87% 195 X = I, Br, Cl thiophene 44-97%
R1 = H, Me, Ph R = Me, OMe, CN
CO2Et, CF3, Ph, etc.
Scheme 60
Irradiation of primary alkyl bis-catecholato silicates (203) with aryl and

heteroaryl bromides 204 in the presence of photoredox and nickel cata-
lysis afforded aryl- and heteroaryl-alkyl cross coupling products (205,
Scheme 62).82
Photochemistry, 2019, 46, 116–168 | 139

OMe
OH OMe
+
MeO OMe
198 199 Ru(bpz)3(PF6)2
(NH4)2S2O8
blue LEDs OMe
23 oC MeO
OMe
OMe OMe
OH OMe OMe
+ O O
202
OMe +
OMe
200 OMe
MeO OMe
201 OMe MeO OMe
Scheme 61
R [Ir] (2 mol%)
R
Ni(COD)2 (3 mol%)
+ + dtbbpy (3 mol%)
O K
AcO O -
Si [18-C-6] DMF, Blue LEDs OAc
O 24 h, rt
O Br
203
204 205
R = p-CH3CO, m-CH3CO, Me3Si, F, Cl, Br, Me etc.
Scheme 62
CN R
N UV-bulb N
O + or sunlight
R 207 210
OH phenanthrene
206 NC EWG R EWG
208 211
209
R = PhCH2-, Me2CHNHBoc, etc. EWG = CN, CO2Me

O
Scheme 63
Opatz et al. reported the transition-metal-free decarboxylative photo-

redox coupling of carboxylic acids 206 with aromatic and heteroaromatic
nitriles (207, 208) in the presence of phenanthrene (209). This C–C bond
formation upon inexpensive UV sources or sunlight proceeded through a
free radical mechanism83 (Scheme 63).
140 | Photochemistry, 2019, 46, 116–168

Irradiation of 2-methylquinoline (212) with hydrogen donors (213) in
the presence of tetrabutylammonium decatungstate photocatalysis
(TBADT) afforded cross-dehydrogenative coupling products (214) under
mild conditions84 (Scheme 64).
Cross-coupling reaction of 4-iodobiphenyl (215) with 4-benzyl-1,4-
dihydropyridine derivative (216) was promoted by a combination of nickel
and photoredox catalysts85 (Scheme 65). In the absence of NaOAc or 4,4 0 -
di-tert-butyl-2,2 0 -bipyridyl (dtbbpy), the yield of (217) was decreased.
Balaraman reported the metal-free radical trifluoromethylation of
b-nitroalkenes (181) with CF3SO2Cl (218) as a CF3-source using visible-
light photoredox catalysis86 (Scheme 66).
A large scale perfluoroalkylation of arenes and heteroarenes
using pyridine N-oxide derivatives was achieved under visible-light
irradiation conditions. Irradiation of 1,3,5-trimethylbenzene (184) in
the presence of trifluoroacetic anhydride as inexpensive CF3 source and
4-phenylpyridine N-oxide efficiently afforded 1-trifluoromethyl-2,4,6-tri-
methylbenzene (220) and 1,3-bis(trifluoromethyl)-2,4,6-trimethylbenzene
(221)87 (Scheme 67).
Photoinduced aromatic trifluoromethylation of unactivated arenes (222)
and heteroarenes was achieved under a simple, metal- and oxidant-free
TBADT (4 mol%) R
K2S2O8 (4.0 mmol)
+ R-H Solarbox (500 W/m2, 40 oC)
N MeCN/CH2Cl2 5:1 (20 mL) N
(212) (213) (214)
O O
R-H = TBADT ; (Bu4N)4[W10O32]
n O
n = 1, 2, 3
Scheme 64
fac-[Ir(ppy)3] (1 mol%)
Ph NiCl2 (10 mol%)
Ph dtbbpy (15 mol%)
EtO2C CO2Et Ph
+ NaOAc (1.5 equiv)
DMI, 25 oC,40 h
I N Ph
H visible light
(215) (216) DMI; 1,3-dimethyl-2-imidazolidinone (217)
Scheme 65
Eosin-Y (5 mol%) CF3

NO2
K2HPO4
+ CF3SO2Cl
MeCN MeO 219
MeO 218
visible light
181
Scheme 66
Photochemistry, 2019, 46, 116–168 | 141

Me
Ru(bpy)3Cl2 (1 mol %) Me Me
TFAA, N-oxide CF3 F3C CF3
+
13.2 W blue LEDs
Me Me Me Me Me Me
MeCN, 35 oC
184 220 221
TFAA: (CF3CO)2O
N-oxide ; 4-phenylpyridine N-oxide
Scheme 67
CF3
+ NaSO2CF3 hν, Ar
R R
acetone
222 223 224
R = H, 4-t-Bu ,2,4,6-(MeO)3, 2,4,6-Me3 etc.
Scheme 68
R NaH
+ [Ph3P-CF2H]+Br- R
HS hν (365 nm) HF2CS
177 225
226
R = 4-Me, 2-Me, 4-t-Bu, 4-CO2Me, 4-NH2, 4-OH etc.
Scheme 69
O Ir(ppy)3
H O H
S Br N Li2CO3 S N
+ CO2Et CO2Et
O DMSO, hν O
227
147 228
Scheme 70
conditions. CF3 radicals from NaSO2CF3 (223) were generated in the

photoexcited aliphatic ketones such as acetone and diacetyl as low cost
radical initiators88 (Scheme 68).
Studer reported the radical difluoromethylation of arylthiols (177) with
(difluoromethyl)triphenylphosphonium bromide (225) through radical
pathway under mild reaction conditions. This difluoromethylation che-
moselectively occurred via a SRN1 mechanism89 (Scheme 69).
Visible-light-promoted (phenylsulfonyl)methylation of electron-rich
heteroarenes (227) and N-arylacrylamides in the presence of Li2CO3 was
developed using Ir(ppy)3 as a photocatalyst under mild reaction con-
ditions90 (Scheme 70).
Both sulfoxidation and sulfenylation of diphenyl iodonium with
common sulfurating reagents such as RSSO3Na (R ¼ alkyl, aryl) (229) were
achieved via a facile variation of the atmosphere under photocatalyzed
conditions91 (Scheme 71).
A simple and efficient method for the synthesis of a-arylthioethers
(233) via a visible-light-induced direct thiolation with diaryl disulfides
142 | Photochemistry, 2019, 46, 116–168

BF4-
I+
O- hν, Eosin Y Ph S
Ph hν, Eosin Y
S+ + Ph nPent
Ph nPent air N2
NaO3S2+-nPent 231
230 Sulfidation
Sulfoxidation
229
Scheme 71
R O acridine red (2.0 mol%)

S TBHP (4 equiv), 4A MS S O
S
R + R
3 W green LED
rt, 12 h
TBHP; tert-butylhydroperoxide
232 233
R = H, m-,p-Me, p-MeO-, p-CN-, o-, m-, p-F- etc.
Scheme 72
O
Br P OR
Rh-6G
OR
P(OR’)3, DMSO, DIPEA,25 oC
R R
204 455 nm Blue LED
234
R = H, m-, p-MeO, o-, p-CN, p-CF3 etc.
R’ = Me, Et
DIPEA : (i Pr)2EtN Rh-6G
COOEt
N O N•HCl
H
Scheme 73
(232) was developed usind acridine red as a photosensitizer under mild

conditions92 (Scheme 72).
König et al. reported visible-light photo-Arbuzov reaction of aryl
bromides (204) with trialkyl phosphites giving aryl phosphonates
(234) under mild reaction conditions. Rhodamine 6G (Rh-6G) is used
as the photocatalyst, generating aryl radicals under blue light93
(Scheme 73).
Benzene (187), naphthalene (236) and several polycyclic aromatic
hydrocarbons underwent metal-free photochemical (hydro)silylation and
transfer-hydrogenations at mild conditions, with the highest yield for
naphthalene (photosilylation; 21%)94 (Scheme 74). The waterborne hy-
perbranched polyurethane/CD nanocomposite (CD@WPU) in the pres-
ence of H2O2 catalyzed para-selective hydroxylation of substituted
benzene derivatives (239) under UV light95 (Scheme 75).
Photochemistry, 2019, 46, 116–168 | 143

hν
(254 nm) +
+ Et3SiH + polymers
24 h
SiEt3 SiEt3 SiEt3
187 235
SiEt3
hν
SiEt3
(254 nm)
+
236
237 238
Scheme 74
R R
CD@WPU
H2O2
HO
UV light
239 240
R = CO2H, NO2, CHO, CH3, CN
Scheme 75
4CzIPN (2 mol%)
NiCl2 dme (10 mol%)
Br
pyridine (2 equiv) SR1
R1SH +
N
NC CN
R2 MeCN/DMF (23:1)(0.05 M)
R2
tr = 30 min (433 μL/min) N N
241 242
rt, Blue LED 243 N
flow microreactor
R1 = p-ClC6H4CH2, p-MeOC6H4CH2 etc.
R2 = Ph, p-MeOC6H4, p-MeC6H4, p-BrC6H4 etc. 244
Scheme 76
O O
R hν R
+ CO2
CH3 R = Ph, CH3 CH2CO2H
245 246
Scheme 77
The cross-coupling of thiols (241) and bromoarylalkynes (242) was

promoted by a soluble organic carbazole-based photocatalyst (244) using
continuous flow techniques96 (Scheme 76).
Mechanism of the photochemical carboxylation of o-alkylphenyl
ketones (245) with carbon dioxide giving the corresponding carboxylic
acid (246) was theoretically studied. This photoreaction occurs on the S0
surface, rather than on the excited T1 state97 (Scheme 77).
144 | Photochemistry, 2019, 46, 116–168

5 Intramolecular cyclization reactions
A variety of phenanthrenes (248) substituted with phenylethynyl and
trimethylsilylethynyl groups were synthesized by use of Mallory photo-
cyclization using (247) and their photophysical properties were investi-
gated. Introducing ethynyl groups into the phenanthrene skeleton
caused an increase in the fluorescence quantum yields compared to
phenanthrene. The quantum yields and rates of fluorescence were
dependent on the substituting position(s) and the terminating group for
the C–C triple bond98 (Scheme 78).
Okamoto et al. prepared many phenacenes possessing chrysene (252),
picene, and fulminene frameworks using a continuous-flow microreactor
without isolation of the intermediary diarylethenes (251). They also
synthesized [9]phenacenes (254) and applied to field-effect transistors
(FETs)99,100 (Scheme 79).
Tetracarboxy-functionalized [8]-, [10]-, [12]-, [14]-phenacenes (255) and
(257) including esters and imides were synthesized by Durola et al.101,102
(Scheme 80). The imide derivatives were significantly stronger electron
acceptor than the corresponding esters.
Stuparu et al. developed the synthesis of the coannulene nucleus (260)
and (262) by using Mallory-like photocyclization of (259) and (261)103,104
(Scheme 81).
Three-bladed propeller-shaped triple [5]helicene (264) was synthesized
by use of eliminative and oxidative photocyclization of (263) in moderate
hν
O2, I2
R R
247 248
R = Ph, trimethylsilyl 1-, 3-substituted phenanthrenes
1,6-, 1,8-, 2,7-, 3,6-, 9,10-disubstituted
phenanthrenes
Scheme 78
PPh3X
CHO
hν, I2, air
KOH
+
CH2Cl2/ H2O
flow photolysis
249 250
251 252
hν, I2
bromobenzene
130-140 oC
253 254
Scheme 79
Photochemistry, 2019, 46, 116–168 | 145

EtO2C CO2Et EtO2C CO2Et
hν, I2, O2
ethyl acetate
EtO2C CO2Et EtO2C CO2Et
255 256
HxO2C CO2Hx HxO2C CO2Hx
hν, I2, O2
ethyl acetate
HxO2C CO2Hx HxO2C CO2Hx
Hx : hexyl
257 258
Scheme 80
R1
R1 R2 R2
hν, I2,
R3 propylene oxide
toluene R3
259 260
R1 = H, Me R2 = H, CF3 R3 = H, Me, F, CN, MeO, NMe2 etc.
hν, I2,
propylene oxide
toluene
261 262
Scheme 81
R hν
R
R = H, OMe
263 264
Scheme 82
yields105 (Scheme 82). Diastereoisomers, PPM and PMM, were isolated by

chromatographic purifications, which were converted to the thermo-
dynamically more stable PPP and MMM isomers.
146 | Photochemistry, 2019, 46, 116–168

O O Ar1
S Ar
N Ar F 267 F
hν 268
S F
Ar1CHO F
265 LHMDS 266

F
F
269 270
271
F
Scheme 83
R R
X
X
hν
solvent
X X
R
272 273 R
Cl
hν
solvent
Cl
274 275
Cl Cl
C12H25
C12H25 277
Cl Cl hν
C12H25
solvent
276
C12H25
Scheme 84
Several fluorinated polycyclic aromatic hydrocarbons (267)–(271) via

Julia-Kocienski olefination from (265) and oxidative photocyclization of
(266) were synthesized in a regiospecific manner106 (Scheme 83).
Morin et al. prepared nanographenes (273), (275), and (277) by photo-
chemical cyclodehydrochlorination of (272), (274), and (276)107 (Scheme 84).
Photochemistry, 2019, 46, 116–168 | 147

Hayashi et al. synthesized tetra- and octa-fluorinated bianthracene
derivatives (280) for investigating the effect of electronegative fluorine
substitution on their structure and physical property108 (Scheme 85).
A triisopropylsilylethynyl(TIPS)-substituted octafluoro compound (280)
exhibited strong fluorescence at 657 nm with high fluorescence quantum
yield (F ¼ 0.84).
Alabugin et al. reported the synthesis of fused helicene (286) using
alkynyl precursors (281) under mild conditions109 (Scheme 86).
Rapenne and Kawai reported dual photocleavage for 1,2-diarylethene
isomers (287) and (288) based phototrigger depending on polarity of
solvents110 (Scheme 87). In polar solvents, methanol was selectively
eliminated to afford (289), but elimination of acetic acid occurred in
apolar solvents to give (290).
Phenanthridines (292) were obtained through visible light induced
isocyanides (291) insertion promoted the combination of an amide and a
TIPS
O O
F F F F F
F
F hν F F F
F F
F F F F F F
F F F F
F F
O O
(278) (279) (280) TIPS
Scheme 85
ICI
DCM (286) - HI
(283)
(281) - 78 oC
hν
I
benzene H
I I
(285)
(284)
(282)
Scheme 86
148 | Photochemistry, 2019, 46, 116–168

Ph Ph
UV
S N polar S N
AcO
AcO solvent
S MeOH OMe S Ph
Ph
UV S N
289 287 S N
MeO apolar MeO
solvent
S
OAc S
AcOH
290
288
Scheme 87
R2 R2
rt, white LED

R1 R1
photocatalyst N
NC N
C
CF3-BHA
291 292 O
CF3-BHA = O-(4-CF3-benzoyl)-hydroxylamine
R1 = H, 5-Cl, 4-Me, 4-MeO etc. R2 = H, 4-Ph, 4-tBu etc.
Scheme 88
R2
R2
NO2 visible light, N2
R1 NO R1 N
Eosin Y, i Pr2NEt
R3 NO2
R3
293 294
R1 = H, F, Me, MeO R2 = H, F, Me, MeO, R3 = H, Me
Scheme 89
photoredox system under mild and eco-friendly reaction conditions111

(Scheme 88).
Metal-free photoredox catalyzed cyclizetion of O-(2,4-dinitrophenyl)ox-
imes (293) in the presence of eosin Y and iPr2NEt efficiently afforded
phenanthridines (294) in moderate to good yields112 (Scheme 89).
Xia et al. found the tunable synthetic route to phenanthrenes (296) and
(297) from 3-aryl-N-(arylsulfonyl)propionamides (295) including aryl
migration, C–C coupling, 1,3-hydrogen shift, desulfonylation and elim-
ination process113 (Scheme 90).
Dihydropyrazole-fused benzosultams (299) and (300) under visible-light
irradiation in the presence of co-catalyst (303) and electron accepting
additives such as 1,3-dinitrobenzene (301) and tetracyanobenzoquinone
(302) were prepared via N-radical 5-exo cyclization/addition/aromatization
cascade of b,g-unsaturated hydrazines (298)114 (Scheme 91).
Photochemistry, 2019, 46, 116–168 | 149

R1 R1
R1 O O O
S hν, morpholine
O N + R3 N
toluene S
295 R3 O
R2 O
296
R2 297 R2
R1 = H, Me, OMe, F, Cl, Br, Ph, t-Bu, CN etc.
R2 = H, Me, OMe
R3 = Me, Bn, allyl, propagyl etc.
Scheme 90
Ts PC (2 mol%)
Additives O O
HN K2CO3 (1.5 equiv) O S O S
N
3 W blue LEDs, Ar N N + N N
Ph CH3CN, rt, 24 h
Ph Ph
298 300
299
Additives: H
O O O
Cl
N
O2N NO2 NC CN N
Co
N N
NC CN Py
O O
O
301 302 H
303
Scheme 91
O
Ru(bpy)3Cl2
R + H2N NH2 N
R
TsOH, CH3CN
82 oC, 23 W CFL, 48 h 306
304 305
R = o-, p-Me, o-, p-F, o-, p-Cl, o-, p-Br, p-MeO, etc.
Scheme 92
Arylpyridines (306) and arylquinolines via visible-light induced aerobic

C–N bond activation using Ru(bpy)321 were efficiently synthesized in the
presence of acetophenones (304) and easily available 1,3-diaminopropane
(305)115 (Scheme 92).
Indole derivatives (308) were obtained via photoinduced nitrene C–H
insertion from arylazide compounds (307)116 (Scheme 93).
Yoshmi et al. found the one-step synthesis of spiro dihy-
droisoquinolinone derivatives (311) from alicyclic amino acids (309) bearing
N-(2-phenyl)benzoyl groups via photoinduced electron transfer–promoted
decarboxylation using (209) and p-dicyanobenzene (p-DCB)117 (Scheme 94).
150 | Photochemistry, 2019, 46, 116–168

R
hν (365 nm) R
MeCN N
N3
H
307 308
R = t-BuOOC-CH(OH)-, (EtOOC)2CH, PhthN-
Scheme 93
CO2H •
N hν N
O (209)-p-DCB N
O
- CO2 O
ipso-position
309 p-DCB : p-dicyanobenzene 311
310
Scheme 94
CO2H O
hν (> 350 nm), TiO2 O
CH3CN, H2O, O2 + CO2, H2O

HO2C
312 313
CO2H
hν
CO2H
CO2H CO2H
(E)-314 (Z)-314
hν (> 350 nm), TiO2
+ CO2, H2O
CH3CN, H2O, O2 O O
315
Scheme 95
Upon TiO2-catalyzed UV irradiation, aromatic lactones (313) and (315)

from diphenic acid (312) and (E)-2-(2-carboxyvinyl)benzoic acid (E-314)
were obtained with high selectivity via decarboxylation118 (Scheme 95).
A highly regionselective [2 þ 2 þ 2] cyclization of two arylalkynes (63)
with nitriles using pyrilium salts (T(p-Cl)PPT) as photoredox catalysts
was reported under visible-light irradiation giving 2,3,6-trisubstituted
pyridine derivatives (316)119 (Scheme 96). Visible-light induced and
oxygen-promoted oxidative cyclization from aromatic enamines (317)
intramolecularly afforded quinoline derivatives (318) in good to moder-
ate yields120 (Scheme 97). Similar compounds (321) were obtained in the
intermolecular photocycloaddition of (319) with dimethyl acetylene di-
carboxylate (320).
Photochemistry, 2019, 46, 116–168 | 151

Ar’
T(p-Cl)PPT (30 mol%) Ar

2 N
+
blue LED, rt, 12 h Ar‘ O+ Ar’
Ar Me Me N Ar
BF4-
63 316 Ar’ = p-ClC6H4
Ar’ = Ph, p-MeC6H4, p-FC6H4 etc.
T(p-Cl)PPT
Scheme 96
O OEt 5% Mes-Acr-Me*
N Ph
Ph 20% CuCl2
NH 20% Phen CO2Et
R1 TBHP (3.0 equiv) O
R2
O2 (1 atm), DMF (3 mL)
R2 blue LED, r.t.
317 318
R1 = H, 4-F, 4-Cl, 4-CF3 etc.
R2 = H, 2-F, 3-F, 4-F, 4-Cl, etc.
NH2 CO2Me N CO2Me

5% Ru(bpy)3Cl2
R1 + R1
CO2Me
20% CuCl
O
R2 CO2Me O2 (1 atm), r.t. R2
blue LED, DMF (3 mL)
319 320 321
R1 = H, 4-Me, 4-Cl, etc.
R2 = H, 4-Me 4-MeO, 4-Cl, 4-NO2, etc.
Scheme 97
O CO2H
CO2H CO2H
254 nm, 25 oC
O + O +
N3 EtOH, NaOAc N NH NH2
R R
R H R
322 323 324 325
H2O
CO2H CO2H CO2H

•
R N
R N R N
Scheme 98
Irradiation of 2-azidobenzoic acids (322) in the presence of NaOAc in

ethanol selectively gave 2,1-benzisooxazole-3(1H)-ones (323) via for-
mation of nitrene121 (Scheme 98). Here, in some cases, small amounts of
2-oxo-3-carboxy-3H-azepine (324) and (325) were produced.
152 | Photochemistry, 2019, 46, 116–168

O
N
N fac-Ir(ppy)3 O
+ BrCH2R2
C Na2CO3, DMSO
R1
visible light N
N R2
R1 = H, Et, tBu, MeO, PhO etc.
326 R1 327
R2 = CN, CO2Et, COPh
hν
N
N 6-exo-dig
O
O
C
N
R2 R2
N
R1 R1
iminyl radical
Scheme 99
R3
R2
N2+BF4- 1,4-CHD
R1 + hν, MeCN
R1 R2
N3 R3 Eosin Y N
K2HPO4 H
328 145
329
R1 = H, 4-F, 4-Cl, 4-MeO etc.
R2 = Ph, 4-MeOC6H4, 4-FC6H4, tBu etc.
R3 = H, F, Cl, CN, Me, MeO etc.
Scheme 100
CO2Et
CO2Et
[Ir(ppy)2(dtb-bpy)]PF6
Br Ph
N DIPEA, MeCN N
Ph
visible light
CO2Me
CO2Me
331
330
Scheme 101
Phenanthridine derivatives (327) from N-arylacrylamide (326) using

cyano group as a bridge under photoredox catalysis were synthesized via
radical addition/insertion/cyclization cascade reaction in moderate to
Transition-metal-free and visible-light-mediated photocyclization of o-
azidoarylalkynes (328) with diazonium salts (145) giving 2,3-disubstituted
indoles (329) was reported123 (Scheme 100).
Photochemistry, 2019, 46, 116–168 | 153

TEEDA (1.5 equiv)
+ Rf -I CFL (25 W)
THF, Ar, 30 oC, 36 h
NC TEEDA ; Et2NCH2CH2NEt2 N Rf
332 333 334
Scheme 102
R R R
NH2 DMSO
NH + NH2
X t-BuOK, hν
+ X-
335 R = H, CN X = Cl, Br
336
337
Scheme 103
2,3-Disubstituted indolines (331) utilizing visible-light photoredox

catalysis were obtained through tandem cyclization of vinyl radicals in
Perfluoroalkylation of phenanthridines (334), alkenes, alkynes, and
electron-rich arenes and hetero arenes using isonitrile (332) and per-
fluoroalkyl iodides (333) was reported by Chen et al. under compact
fluorescent lamp (CFL), low-intensity UV lamp, or sunlight irradiation125
(Scheme 102).
Irradiation of 2 0 -halo-[1,1 0 -biphenyl]-2-amines (335) in basic medium
caused N-arylation reaction. In general, biphenylamines with electron
donating groups such as Me and OMe gave cyclized and reduced prod-
ucts (336) and (337). On the other hand, biphenylamines containing
electron withdrawing groups such as CN, CO2Et, and CF3 afforded only
the corresponding carbazoles (336)126 (Scheme 103).
6 Rearrangements
Lvov and Shirinyan reviewed a new type of diarylethene photoreactions.
Photorearrangement of diarylethenes (338) or (341) via cascade processs
of photocyclization/[1,n]-H shift/cycloreversion under inert atmosphere
occurred to give benzofurans and benzothiophenes (340) or naphthalene
derivatives (344). The quantum yields of the photorearrangement are
rather high (0.34–0.49) although the processs includes multi-steps127,128
(Scheme 104). Photodeprotection of 2-nitrobenzyl esters (345) efficiently
released the acid (347) with the formation of the corresponding 2-
nitrosoketones (346), which underwent a photorearrangement to afford
bicyclic oxazoles (348) via 1,2-shift of alkyl group (R ¼ iPr). However,
methyl group rearranged slowly and phenyl group did not rearrange to
give the corresponding bicyclic isoxazolones. In the case of tBu group,
154 | Photochemistry, 2019, 46, 116–168

R
UV UV
X X
O2 anaerobic
X H2C
R conditions R
339 338 CH2Cl2 340
X = O, S R = alkyl, halogen Yield 52-96%
O O
O ortho-substituent O
UV
H R N
N
R O Ph Vis / Δ Me O Ph
Me
341 342
φ = 0.34-0.49 yield 74-92% (meta/para-R)
UV 31-59% (ortho-R)
O O
O [1,n]-H shift / O
cycloreversion
H N NH
Me Ph
R O Ph R
Me O
343 344
Scheme 104
R O R O
MeO hν MeO HO
O O
+
Br MeO Br
MeO NO2 NO 347
345 346
R = Me, i Pr. tBu, Ph
hν
R O
MeO
O
MeO N
348 R = i Pr, tBu
Scheme 105
many products including bicyclic isoxazolones (348) were produced129

(Scheme 105). Bonesi et al. reported the formation of 2,2-dimethylchro-
man-4-ones (350) via photo-Fries rearrangement of aryl 3-methyl-2-
butenoate esters (349) followed by thermal 6p-electrocyclic reactions
and/or thermal (intramolecular oxa-Michael addition) cyclization of the
ortho-regioisomers. They also found the regioselective photo-Fries
Photochemistry, 2019, 46, 116–168 | 155

rearrangement of acetoanilides (354) under the aqueous micellar green
environment. The photoreaction involves homolytic cleavage of a C–N
bond to yield a singlet radical pair130,131 (Scheme 106).
Maeda reported photo-Fries rearrangement of 1-pyrenyl benzoate
derivatives (358) in benzene to give 1-hydroxy-2-pyrenyl aryl ketones (359)
along with 1-pyrenol (360)132 (Scheme 107). The exceptionally down field
1
H NMR chemical shift of OH proton in the photoproducts (359) indicates
OH OH
O hν O OH
+ + +
O Solvent R R
R
Ar, 25 oC O O R
O
349 350 351 352
R = H, CH3, OPh, Cl, NO2
353
O
HN R’ NH2
NH2 O NH2
hν R’ + +
Solvent
R R
25 oC R O R
’R
354 355 356 357
R = H, Me, MeO, PhO, Cl, CN, COCH3, NO2 etc.
Surfactants
Cationic Surfactants
Br-
Cl-
N+ N+
Anionic Surfactant
O O-
S Na+
O O
Non-ionic Surfactants
O OH
O O
O OH 8-9
22
Scheme 106
R O
O R OH OH
hν (> 280 nm)

O
+
360
358 359
R = Ph, p-NO2C6H4, p-CF3C6H4, p-ClC6H4, p-MeC6H4, p-MeOC6H4 etc.
Scheme 107
156 | Photochemistry, 2019, 46, 116–168

Scheme 108
the existence of intramolecular hydrogen bonding. However, 1-pyrenyl

aliphatic esters did not rearrange to give the corresponding ketones.
Oxidative [1,2]-Brook rearrangement of (361) via hypervalent silicon
intermediates (364) induced by photoredox-catalyzed one-electron
transfer afforded alkylation and arylation products (363). The formation
of reactive radical species (362) have been postulated133 (Scheme 108).
Irradiation of ethyl 3-azido-4,6-difluorobenzoate (365) in the presence
of oxygen gave ethyl 5,7-difluoro-4-azaspiro[2.4]-hepta-1,4,6-triene-1-
carboxylate (370) via seven-membered keteneimine intermediate (367).
The structure of spiro compound was assigned by NMR spectroscopy134
(Scheme 109).
Irradiation of vinyl tosylates (371) in the presence of photoinitiator
such as eosin B afforded the rearranged products b-ketosulfones (372) via
a sulfinyl radical135 (Scheme 110).
Photolysis of 1-cyclopentylidene- and 1-cyclobutylidene-1a,9b-dihydro-
1H-cyclopropa[l]phenanthrenes (373) produced the strained cyclohexyne
and cyclopentyne (375) respectively via the putative cycloalkylidene-
carbenes (374). These cycloalkynes (375) were intercepted as Diels–Alder
adducts (377) and (379)136 (Scheme 111).
Irradiation of a-chlorinated propiophenones (381) gave 2-arylpropanoic
acids (382) as rearranged products accompanied by unexpected benzoic
acids (383). The formation of benzoic acids as byproducts could be
explained by the oxygenation of a-chlorinated propiophenones via their
triplet states137 (Scheme 112).
Photochemistry, 2019, 46, 116–168 | 157

N3
F hν, O2 N
F
CO2Et
CO2Et TFE-d3 F
F TFE ; CF3CH2OH
365 370
- N2 hν
N F +
+
N
F
CO2Et F
F CO2Et
366 369
hν
F N F N
hν
F CO2Et F
CO2Et
367 368
Scheme 109
OTs
O
photoinitiator (1 mol%)
5 W white LED Ts
solvent, 12 h, rt. 372
F3C F3C
371
Scheme 110
7 Oxidation
Irradiation of ethyl 2-(anthracen-9-yl)acetates (384) with a household
fluorescent light bulb in the presence of oxygen and a photosensitizer
such as methylene blue or tetraphenylporphyrin afforded endoperoxide
intermediates (385) in the absence of base. The peroxide was converted to
anthrone derivatives (386) and anthraquinones (387) by use of base such
as K2CO3 at the elevated temperature. Anthrones (386) thermally con-
verted to anthraquinones (387) at 90 1C in the presence of K2CO3 in good
to high yields138 (Scheme 113).
Upon irradiation in the presence of oxygen, the endoperoxides (389) of
bis(triisopropylsilyl)ethynyl)bistetracene and bis(2-(n-octyldiisopropylsi-
lyl)ethynyl)bistetracene (388) were formed in an extremely slow rate.
From computational results, it was explained not on the ring with least
aromaticity, but on the ring with smallest distortion energy. Substituted
bistetracenes displayed the increased stability toward oxidation com-
pared to pentacene and rubrene139 (Scheme 114).
Zhu reported the visible-light induced conversion of styrenes (101) to
ketones (391) by use of phenylhydrazines (390), which generated phenyl
158 | Photochemistry, 2019, 46, 116–168

n
hν
- phenanthrene n n
n = 1,2 374 375

373
Ph
O Ph O
376 Ph
n
Ph
377
O
Ph
Ph
Ph Ph
- CO
n n
Ph Ph Ph
Ph Ph
Ph
O
380
Ph 379
Ph
378
Scheme 111
O CH3
CH3 hν CO2H
Cl CO2H +
aq. acetone Cl Cl
Cl
381 382 383
O T* • O•
O O O
CH3 CH3 CH3
hν O2
Cl Cl Cl
Cl aq. acetone Cl Cl
381
O O O
O• OH
O H• O hν OH
Cl Cl Cl
H•
383
Scheme 112
and substituted phenyl radicals, in the presence of methylene blue (MB1)

under metal-free conditions. This photoxidation included broad sub-
strate scope, readily available reagents and amenability to gram-scale
synthesis140 (Scheme 115).
Visible light irradiation of methyl aromatics (392) in the presence of
Acr1Mes ClO4 and oxygen in methanol afforded the corresponding
methyl esters (393) under mild catalytic conditions141 (Scheme 116).
Photochemistry, 2019, 46, 116–168 | 159

CO2Et
methylene blue (5.0 mol%)
K2CO3 (1.0 equiv)
R1 R2
t
AmylOH, O2 (1 atm)
384 30 W CFL, 90 oC, 48 h
CO2Et
HO CO2Et O
R1 O O R2 + R1 R 2 + R1 R2
O O 387
385 386
K2CO3 (1 equiv)
R1, R2 = Me, MeO, tBu, F, Cl, SiMe3 etc. tAmylOH
90 oC, 1.5 h
Scheme 113
O
O
R R
hν/O2
CDCl3
R
R
R=
388
389
R= Si , Si C8H17
Scheme 114
MB+ {2 mol%) O
NHNH2 DABCO (1 equiv)
+ R2
air, 7 W blue LEDs, rt
R1 R2 MeCN R1
(390) (101) (391)
R1 = H, p-Me, o-Me, p-Cl, p-MeO, p-Br, p-F, p-CH=CH2 etc.

R2 = H, p-Cl, o-Cl, p-F, p-MeO, p-CF3 etc.
Scheme 115
Meyer et al. reported the photoxidation of aromatic hydrocarbons by a

phosphate-bearing flavin mononucleotide (FMN) photocatalyst on high
surface area metal-oxide films142 (Scheme 117).
Photocatalytic oxygenation of thioanisole (394) and styrene (103) in
the presence of trinuclear Ru complexes (396) and Co complex
([CoCl(NH3)5]Cl2) as visible-light sensitizers afforded phenyl methyl
160 | Photochemistry, 2019, 46, 116–168

Acr+-Mes ClO4- (7 mol%) O
Me
HCl (0.2 equiv)
R OMe
R
MeOH (3 mL), O2
blue LEDs, 30 h
(392) (393)
R = 2-Me, 3-Me, 4-Me, 4-Ph, 4-tBu, 4-MeO, 3,5-Me2
Scheme 116
hν ISC
1 3
FMN FMN* FMN*
440 nm
-
2e /2H+
3
FMN* + PhCH2OH FMNH2 + PhCHO
O2
FMNH2 FMN + H2O2
Scheme 117
O
S S
hν (435 nm)
Ru3 complexes
395
394 O
[CoCl(NH3)5]Cl2
H2O H
103 396
N
N
N N N
Ru Ru R
N N N
N
N N
N
N N
R
Ru
R = CH3, H, Br N N
N
397
Scheme 118
sulfoxide (395) and benzaldehyde (396)143 (Scheme 118). The catalytic

activity of 5,5 0 -dibromo-2,2 0 -bipyrimidine ligand was much higher than
that of 5,5 0 dimethyl derivative and nonsubstituted one.
The photoxidation of ortho-substituted aromatic azides (398) gave
nitrile oxide derivatives (400) and (403). In the case of (398b), (400b)
and (403b) were intramolecularly cyclized to (401b) and (404b)144
(Scheme 119).
Inter- and intra-molecular oxidative photocycloaddition of styrene de-
rivateives (103) and (406) afforded 1-tetralones (405) and (407) in the
presence of molecular oxygen and TiO2145 (Scheme 120).
Photochemistry, 2019, 46, 116–168 | 161

Upon visible-light irradiation, a-chloro or a-alkoky ketones (408) were
synthesized by use of aryl diazonium salts (145), which produced aryl
radicals, in the presence of NaCl and ROH with aryl alkyne (63) under
mild oxygen atmosphere146 (Scheme 121).
Scheme 119
Scheme 120
NuX (2.2 equiv) Nu

N2+BF4- Ar
Eosin Y (3 mol%)
R1 + Ar
blue LED, O2 R1
O
145 63 408
R1 = 4-MeO, 2-, 3-, 4-NO2, 4-CN, 4-Ph etc.
Ar = Ph, 4-ClC6H4, 4-BrC6H4, 4-CNC6H4, 4-PhC6H4 etc.
NuX : NaCl, MeOH, iPr
Scheme 121
162 | Photochemistry, 2019, 46, 116–168

Ru(bpy)3Cl2, copper
CH2NH2 Blue LED, DMSO, O CN
2
R R
409 410
R = H, Me, MeO, F, CF3 etc.
Scheme 122
The oxidative transformation of amines (409) to nitriles (410) in the

presence of photoredox and copper catalysis such as Ru(bpy)3Cl26H2O
and CuBr was achieved upon visible-light irradiation147 (Scheme 122).
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168 | Photochemistry, 2019, 46, 116–168

Organic aspects. Oxygen-containing
functions
M. Consuelo Jiménez* and Miguel A. Miranda*
DOI: 10.1039/9781788013598-00169
In this chapter, most of the reported work deals with photochemistry of the carbonyl
group; however, the photoreactions of other oxygen-containing functions are included as
well. The coverage period is 2016–2017, and as a general rule, only original research
articles reporting new experimental results are discussed; reviews or purely theoretical
calculations are not quoted.
1 Introduction
As in the previous volumes of these periodical reports, the chapter is
mainly organised according to reaction types (e.g., Norrish I/II, Paternò-
Büchi, photo-Fries/photo-Claisen, etc.). After each heading, the basic
photochemical results are presented first, and then more specific aspects
are mentioned (synthetic applications, stereoselectivity, biological,
technological or environmental applications, etc.). This is followed
by photoreactions in microheterogeneous systems, in solid matrixes or in
the crystalline state. When available, mechanistic studies based on
time-resolved spectroscopies, including ultrafast detection, are included.
Only photoreactions where the oxygen containing compounds are the
light absorbing species are considered, so the fast-growing field of
visible-light reactions using different types of photocatalysts is beyond
the scope of the present chapter.
2 Norrish type I reactions

Fundamental aspects of the reaction in structurally simple carbonyl
compounds still deserve some attention. Thus, photolysis of cyclohex-
anone in the vapour phase has been performed using 311 nm UV light.
The main primary photoproducts, detected by FTIR spectroscopy, are
5-hexenal and butylketene. The obtained results agree with theoretical
calculations at DFT/B3LYP/6-311þþG** level.1 Likewise, a theoretical
study on the photochemistry of Irgacure 907 (1) has been performed by
DFT methodologies. The photocleavage reaction orginates from a np*
triplet excited state, generating two radical species, as expected for a
typical type-I photoinitiator.2
Several synthetic applications of the Norrish type I reaction have been
reported. They include the diastereoselective synthesis of (Z)-3-(alkoxy-
methylene)isobenzofuran-1-ones by photolysis of benzamides (2),3 the
total synthesis of protoilludanes involving photocleavage of the bicyclic
Departamento de Quı́mica/Instituto de Tecnologı́a Quı́mica UPV-CSIC,

Universitat Politècnica de València, Camino de Vera s/n, 46022 Valencia,
Spain. E-mail: mcjimene@qim.upv.es; mmiranda@qim.upv.es
Photochemistry, 2019, 46, 169–193 | 169

ketone (3) with intramolecular 1,3-acyl migration to indenone 44 and the
synthesis of 12,12 0 -azo-13,13 0 -diepi-ritterazine N using Norrish type I
cleavage of polycyclic ketone (5) as key step.5
Photocleavage of appropriate ketone precursors has been used as a tool
to generate site-specific radicals in nucleic acids. For instance, photolysis
of ketone (6) leads to formation of 2 0 -deoxyadenosin-N6-yl radical with
release of acetone.
The formation of such an intermediate is followed by laser flash pho-

tolysis, as the growth of a transient with lmaxE340 nm within ca. 5 ms.6
The independent generation of 5,6-dihydropyrimidin-5-yl radicals in
organic solvents has been achieved by Norrish type I cleavage of the
lipophilic tert-butyl ketone precursors (7). The formation of the purported
intermediates has been confirmed by trapping with a nitroxide-derived
profluorescent probe. Further evidence has been furnished by nano-
second laser flash photolysis through detection of long-lived transients,
with absorption maxima in the range 350–420 nm, depending on the
substitution. The experimental results are supported by multi-
configurational ab initio CASPT2//CASSCF methodology.7 Following a
similar approach, Norrish type I photocleavage of the benzyl substituted
nucleotide (8) leads to generation of a C2 0 -uridine radical and sub-
sequently produces strand breaks via cleavage of the b-phosphate. This is
relevant in connection with RNA strand scission by the hydroxyl radical,
particularly under anaerobic conditions.8
The Norrish type I reaction appears to be involved in the
photodegradation of polymers, such as polyvinyl acetate,9 lignin10 and
poly(3-hydroxybutyrate-co-3-hydroxyhexanoate).11 This is accompanied by
changes in colour, morphology, crystallinity index, fluorescence intensity,
etc. The photodegradation process has been followed by UV–Vis, FTIR-ATR,
FT-Raman or SEM measurements. Addition of UV absorbers such as p-
hydroxybenzophenone or 5-benzoyl-2-hydroxy-4-methoxybenzenesulphonic
acid may result in an enhanced photostability.9 The Norrish type I
photofragmentation is involved not only in polymer photodegradation,
170 | Photochemistry, 2019, 46, 169–193

but also in photopolymerisation. Thus, covalent attachement of TEMSI2-
BAPO (9) onto silica particles leads to inmobilised photoactive moieties that
promote photocuring of thyol-ene systems. The reaction kinetics is followed
by FT-IR, photo-DSC and thermogravimetric analysis.12
Manipulation of the excited state behaviour of selected guests is

achieved within two new cavitands derived from octa acid in aqueous
medium. The presence of a benzoate anion at the top periphery is
associated with a triplet sensitiser behaviour of the host. Interestingly,
the Norrish type I cleavage of 1-phenyl-3-(p-tolyl)propan-2-one whitin the
confined space of the cavitands leads exclusively to cage products.13
3 Hydrogen abstractions
3.1 Norrish type II and related intramolecular hydrogen abstractions
Visible light irradiation of pyreneacyl sulphides (10) gives rise to intra-
molecular g-hydrogen abstraction by the ketone group, followed by
b-cleavage of the intermediate 1,4-biradical. This Norrish type II elimin-
ation yields thioaldehydes that can be trapped by nucleophiles or
dienophiles, providing a versatile ligation platform.14
Intramolecular hydrogen abstraction occurring in o-alkylsustituted
phenyl ketones leads to photoenols (o-quinodimethanes), which are
trapped by electrophiles. Using the Togni reagent, trifluoromethylation at
the o-benzylic position is observed,15 whereas in the presence of enones
and chiral amino acid esters as catalysts, asymmetric Michael addition
occurs,16 to give saturated ketones (11). Likewise, the photoenolisation
of o-methylbenzophenones leads to the corresponding hydroxy-o-
quinodimethanes, which serve as nucleophiles in an intermolecular
aldol desymmetrisation of achiral 2-fluoro-substituted cyclopentane-1,3-
diketones.17 In the case of o-alkylbenzoylphosphonates, the electron
withdrawing nature of the phosphonate substituent facilitates ring
closure of the o-quinodimethane intermediate and results in formation
of strained benzocyclobutenols (12).18
The intramolecular hydrogen abstraction by carbonyl compounds can
also be used with synthetic purposes. For example, irradiation of diketone
(13) at ca. 405 nm leads to Norrish–Yang cyclisation. This transformation
is used as a key step in the total synthesis of zaragozic acid C (14).19 When
the hydrogen atom is abstracted from remote positions, larger rings are
Photochemistry, 2019, 46, 169–193 | 171

formed in a Yang-like reaction. Thus, cyclopropyl ketones (15) undergo a
stereospecific photocyclisation to afford dihydrobenzopyranols.20
Intramolecular hydrogen abstraction has found application in the field
of polymers. In this context, photoactive benzoxazines containing a
carbonyl chromophore and a hydrogen donating site, such as (16), are
effective in the photomodification of polybutadiene under 300–350 nm
light. The resulting benzoxazine-functionalised polybutadienes undergo
thermally activated curing without any catalyst.21 Related dyes (17) con-
taining N,N-dialkylamino and ketone groups are efficient one-component
visible light photoinitiators for the polymerisation of methyl methacry-
late. The process can be followed by absorption and emission spectra,
combined with ESR and CV analysis.22
The Norrish–Yang photocyclisation of ketones (18)–(20) has been
investigated in the solid state and monitored by single crystal XRD
experiments. The external stimuli, such as pressure, temperature,
radiation energy as well as the crystal parameters, have different degrees
of influence on the course of the reaction.23–26
Suspensions of nanocrystals are appropriate media for transient

absortion spectroscopic studies. In this context, laser flash photolysis of
crystalline a-(o-tolyl)acetophenone and a-(o-tolyl)-p-methylacetophenone
shows rate limiting d-hydrogen atom transfer in the triplet excited state
(2.7107 s1 and 1.5106 s1, respectively) leading to very short-lived
biradicals that do not accumulate. The markedly slower rate for the
p-methylsubstituted derivative is assigned to an increased contribution of
the p,p* excited state.27 Likewise, laser flash photolysis has been employed
to monitor the photoenolisation of ketoester (21). Intramolecular benzylic
hydrogen abstraction leads to a 1,4 biradical (lmaxB340 nm) that evolves
to the Z- and E- photoenols, after intersystem crossing. Steady-state
photolysis of (21) under anaerobic conditions does not give any product,
whereas in the presence of oxygen peroxide (22) is obtained.28
Steady-state irradiation of a-cholesterol conjugated with (R)- or (S)-
suprofen results in intramolecular hydrogen abstraction from the allylic
C7 position, to give biradicals that collapse to coupling products such as
(23). The conjugate of (R)-suprofen reacts significantly faster, indicating a
stereodifferentiation in the photobehaviour.29
172 | Photochemistry, 2019, 46, 169–193

3.2 Intermolecular hydrogen abstraction reactions
The rate of formal hydrogen abstraction can be markedly increased by
proton-coupled electron transfer. As an example, the triplet excited state of
o-benzoylbenzoic acid is quenched by toluene with kQ ¼ 8.0105 M1 s1,
whereas in the absence of the intramolecular Lewis acid, the reaction does
not occur.30
Solar photolysis of amphiphilic 2-oxoalkanoic acids in aqueous
media, under environmentally relevant conditions, leads to oligomeric
amphiphiles, arising from intermolecular hydrogen abstraction and
subsequent radical coupling processes. These photoproducts are multi-
tailed lipids, which exhibit interesting properties, including spontaneous
self-assembly into aggregates. In addition, monomeric products result
from Norrish type II to generate pyruvic acid.31 Glyoxilic acid, another
2-oxoalkanoic acid, undergoes a-cleavage or participates in hydrogen
abstraction, generating reactive species under solar irradiation;
UV–Visible and fluorescence spectroscopies reveal that the photo-
products undergo dark thermal aging.32
The triplet excited state of benzophenone abstracts hydrogen atoms from

positions 3 and/or 7 of sodium cholate, giving radical pairs which eventually
end up with formation of the oxo analogues of the bile salts
with concomitant reduction of the benzophenone chromophore. This
radical-mediated dehydrogenation is reminiscent of the enzymic action of
hydroxysteroid dehydrogenases.33 A related hydrogen abstraction by
photoexcited benzophenone from DNA substructures (thymine nucleobase
and backbone sugar) has been analysed by means of theoretical calculations,
using high level multiconfigurational perturbation and density functional
theory. In DNA, simulations have made use of molecular dynamics
and hybrid quantum mechanics methods. A strong dependence of
the H-abstraction with the interaction mode is evidenced.34
Solvent effects, especially intermolecular hydrogen bonding, on the
structure and behaviour of the triplet excited state of xanthone have been
investigated by a combination of time-resolved resonance Raman and
UV–Vis transient absorption spectroscopies, together with time-
dependent DFT calculations. As a result of these studies, it is proposed
that the different hydrogen bonding modes operating in the two lowest
triplet states of xanthone lead to a lower contribution of the np* triplet
state, being thus responsible for the reduced photoreactivity of this
ketone towards hydrogen abstraction in protic solvents.35,36
4 Paternò–Büchi photocycloadditions
Among the fundamental aspects of this reaction, it has been recently
found that a complementary strategy based on pp* excited alkenes
Photochemistry, 2019, 46, 169–193 | 173

(rather than np* excited carbonyls) is effective in the formation of
oxetanes. In the case of enamides (24), this is achieved by changing the R
substituent from phenyl to methyl or hydrogen. In both cases, oxetanes
(25) are obtained.37 The Paternò–Büchi photoreaction efficiency has been
remarkably improved in a flow microreactor (under slug flow conditions)
in water. The method has been optimised for the photocycloaddtion
between ethyl benzoylformate and 2,3-dimethyl-2-butene.38 Flow photo-
chemistry has been employed to scale-up the photoreaction between enol
ether (26) and benzaldehyde, yielding oxetane (27) in multigram
amounts. The latter has been used as synthetic precursor of the cytotoxic
lactone (þ)-goniofufurone.39
The oxetane core of oxetin and epi-oxetin (28) has been constructed by
Paternò–Buchi photoreaction between a N-formyl enamine and a glyox-
ilate ester. Further steps, including final resolution protocols, afford the
enantiomerically pure compounds on gram scale.40
The known directing effect of hydroxyl groups on the regiochemistry of

the Paternò–Büchi reaction has been extended to 5-oxazoylmethanol
derivatives (29). When aromatic aldehydes are used, an unsual endo
stereoselectivity is observed.41 The photoreaction between benzaldehydes
and 2,3-dihydrofuran has been achieved inside the cavities of NaY zeolite,
with enhanced stereoselectivity.42 In both cases, the stereoselectivity is
explained by the interaction between HSOMO and LSOMO in the
biradical intermediates.
Coupling of the Paternò–Büchi reaction with tamdem mass
spectrometry has been exploited for localisation of the C–C double bonds
in a variety of lipids, including unsaturated fatty acids,43 cholesteryl
esters44 and glycerophospholypids.45–47 This approach is based on the
production of characteristic fragment ions, which are diagnostic for CQC
location and isomer quantitation and has revealed itself as a useful tool
in uncovering structural diversity of lipids due to unsaturation.
Steady-state irradiation of thymine derivatives (30) in the presence
of benzophenone results in the formation of the two regioisomeric
oxetanes with a new C–O bond between C5 or C6 of the pyrimidine
and the carbonyl oxygen. The observed photoreactivity is markedly
higher for the methyl than for the t-butyl derivative, due to steric
hindrance. By contrast, direct irradiation in the absence of sensitiser
gives rise to a Norrish–Yang photoreaction (30, R ¼ C(CH3)3) or to
cyclobutane dimers (30, R ¼ CH3). The mechanistic insights obtained
by laser flash photolysis are in accordance with the observed
photoreactivity.48
174 | Photochemistry, 2019, 46, 169–193

5 Photoreactions of multichromoporic systems:
dicarbonyl compounds, enones, quinones and quinone
methides
5.1 Dicarbonyl compounds
The photophysical and photochemical properties of 1,3-diketones have
been examined by means of theoretical calculations. These relatively
simple systems may undergo a variety of processes, including excited
state proton transfer or charge transfer, keto-enol tautomerization, Z–E
isomerization, rotation about single bonds and a-cleavage.49,50 In the
case of avobenzone, widely used as UV-filter in sunscreens, torsion
around the C2–C3 bond of photoexcited chelated enol leads to internal
conversion to the ground state and formation of the E-rotamer. The
solvent dependent photolability is connected with the relative order of
the lowest triplet pp* and np* states of the keto tautomer.50
Oxidative photocyclisation of 1,3-diketones (31) affords the highly
functionalised polycyclic products (32) via 6p electrocyclisation of the
enol form, without addition of transition metals or any other oxidant.51
Spiropyran derivatives (33) are synthesised by one-pot three-component
visible light irradiation of indantrione, active methylene compounds and
1,3-diketones.52 Although the reaction mechanism is unclear, cyanoole-
fin intermediates (34) have been isolated.
Diketone (35) is a two photon dye, wich displays favourable photo-

physical properties and a remarkable polarity sensitivity, based on the
keto-enol tautomerism. In addition, it also possesses red-light emission,
sufficient photostability, and low pH sensitivity. Hence, this dye has been
used for living cells imaging to visualize the small changes of intracel-
lular polarity in apoptotic cells.53
Several p-expanded a,b-unsaturated 1,3-diketones, for instance (36),
with excellent solubility in most organic solvents, exhibit very broad
absorption spectra and negligible fluorescence. Interestingly, these dyes
Photochemistry, 2019, 46, 169–193 | 175

have two-photon absorption cross-sections at polymerisation wavelengths
that make them suitable photoinitiators with broad fabrication windows.54
The keto-enol tautomerisation of 2-alkyl-1,3-diketones (37) in solution
has been investigated by means of steady-state and laser flash photolysis.
The diketo tautomers are photoconverted into the keto-enol forms
mainly through the triplet excited state. The enols can be considered as
temporal UVA sunscreens, as the back reaction occurs thermally within a
few days.55
5.2 Enones
Blue-light irradiation of o-aminoaryl substituted a,b-unsaturated ketones
such as (38) results in double bond isomerisation; subsequent thermal
cyclodehydration affords the corresponding quinolines in good yields.56
Photochemical electrocyclisation of aryl b-halovinyl ketones (39) leds to
tetrahydrofluorenones and related structures. The method has been
applied to the synthesis of natural products containing the tetrahydro-
fluorenone moiety.57 In a related reaction, photocyclisation of acrylani-
lides has been achieved using a microfluidic flow photoreactor, to obtain
tetrahydroquinolines. This approach has been used for the synthesis
of ()-t-vabicaserin (40).58 The UVA induced oxa-6p electrocyclisation of
dienone systems has been used to achieve a biomimetic synthesis of
briareolate ester B (41) from briareolate ester L (42). The process is
reversed by UVC irradiation, which allows establishing a photochromic
switch.59 Photorearrangement of chromones such as (43) to diarylketones
(44) also involves a 6p electrocyclisation, which is followed by hydrogen
shift and final ring opening with rearomatisation.60
Sensitised irradiation of the tricyclic b,g-enones (45) follows a oxa di-p-

methane rearrangement, to give triquinanes (46) along with 1,3-acyl shift,
affording cyclobutanones (47). Direct irradiation leads only to the latter
products.61
176 | Photochemistry, 2019, 46, 169–193

Site-selective photochemical fluorination of steroidal enones can be
achieved at allylic and homoallylic positions through a reaction pathway
that includes intramolecular hydrogen abstraction, radical fluorination
and restoration of the enone. This has been applied to the synthesis of
complex molecules, such as the triterpenoid saponin derivative (48).62
Intramolecular [2 þ 2] photocycloaddition of enones (49) to afford
tricyclic products (50) occurs from the excited triplet state with a
remarkable regioselectivity, favouring straight- over cross cycloaddition A
susbstitution-dependent atropselectivity is also observed.63
Direct irradiation of aryloxycyclohexenones (51) at 366 nm leads to
racemic tetrahydrodibenzofuranones (52) in moderate to good yields.
In the presence of a chiral copper–bisoxazoline complex or upon
photosensitisation by thioxantone, significant enantioselectivities are
observed.64 Stereoselective photosantonin rearrangement of cross-
conjugated cyclohexadienone (53) affords the corresponding cyclo-
pentenone (54). This transformation constitutes the key step in a scalable
synthesis of ()-thapsigargin.65 A related photorearrangement leads from
dienone (55) to valuable intermediates in the synthesis of cubebane-,
spiroaxane-, and guaiane-type sesquiterpenes.66
Furyl substituted enones (56) udergo photoisomerisation to unsatur-
ated aldehydes (57). The reaction mechanism has not been proven,
although a carbene is proposed as intermediate. The nitro-substituted
photoproduct shows polarity-dependent fluorescent properties and has
potential application in optical data storage.67
Solar simulated photolysis of dienogest (58), an oral contraceptive

containing a dienone moiety, gives rise to complex mixtures in aqueous
media at different pH values. The major process is a reversible photo-
hydration that increases its environmental persistence. In addition,
several minor photoproducts are obtained with enhanced strogenic
properties. This information is important regarding environmental risk
assessment of this synthetic drug.68
Photochemistry, 2019, 46, 169–193 | 177

Solid-state irradiation of 2-allyl, 2,4-dimethoxy and 5-bromo-2-methoxy
substituted cis-cinnamic acid results in the head-to-head cyclobutane di-
mers as the almost exclusive products. This process competes with geo-
metric isomerisation as a minor reaction pathway. By contrast, the
corresponding trans-cinnamic acids give rise to the head-to-tail dimers,
except in the case of an unreactive bromo derivative.69 The [2 þ 2] photo-
dimerization of 2,6-difluorocinnamic acid in the crystal state has been
investigated at different pressures. The main observation is that the rate of
the reaction increases with increasing pressure due to the decrease in the
volume of free space columns and the decrease in the distance between the
reactive carbon atoms in adjacent monomer molecules.70 Topochemical
photocycloaddition of tetrasubstituted p-quinodimethane (59) affords the
[2.2]paracyclophane (60) via a single crystal-to-single crystal [6 þ 6] photo-
cycloaddition. In solution, under aerobic conditions, a peroxide resulting
from formal oxygen trapping of a biradical intermediate is obtained.71
While irradiation of achiral enone carboxamides (61, R1QH) results in 6p
electrocyclisation to 3,4-dihydroquinolin-2-ones (62), o-phenyl-substitued
enone carboxamides (61, R1 ¼ t-Bu) undergo intramolecular hydrogen
abstraction, leading to spiro-b-lactams (63). This dual reactivity and
selectivity pattern is supported by photophysical measurements (including
detection of the triplet excited states and zwitterionic intermediates by
transient absorption spectroscopy) and theoretical calculations.72
5.3 Quinones
Photoinduced intramolecular hydrogen abstraction in naphthoquinones
(64) leads to 1,4-biradical intermediates, which ultimately afford naphthols
(65). This can be regarded as an intramolecular redox reaction.73
Photolysis of (þ)-komaroviquinone (66) gives rise to ()-cyclo-
coulterone (67) and komarovispirone (68). Both natural products contain
the methylendioxy group, whose photolytic formation provides an
evidence for the possible involvement of a non enzymatic route in the
biogenesis of this unit.74
Photochemical migration of a phenyl group in 1-phenoxy anthraqui-

none conjugates with tetraethylene glycol (69) gives rise to isomeric
compounds (70). This photochromic transformation has a strong
178 | Photochemistry, 2019, 46, 169–193

influence on the complexation with sodium or calcium cations, so (69)
and (70) can be regarded as photocontrolled ionophores.75
Photoreduction of the 3,6-di-tert-butyl-o-benzoquinone (71), in the
presence of N,N-dimethylanilines, leads to the corresponding hydro-
quinones both in the acrylate monomer and in poly(quinone methacry-
late) or on the surface of polymer matrix pores. The kinetics of the
reaction depends on the electron-donating ability of the amine and on
the monomeric or polymeric nature of the quinone.76 The donor/acceptor
nature of the solvent has a significant influence on the photoreduction
kinetics of 3,6-di-tert-butyl-1,2-benzoquinone in the presence of N,N-
dimethylanilines.77 Quinone photoredox chemistry appears to be
involved in the daytime/nighttime conversion of NO2 into HONO on soils.
This is supported by experiments performed on mineral surfaces coated
with juglone as a model quinone.78
Theoretical calculations are in agreement with experimental results
obtained for antrhaquinone (72) in neutral aqueous solution by means
of transient UV–Vis absorption and time-resolved resonance Raman
spectroscopy in the nanosecond timescale, which indicate that proton-
coupled electron transfer is the initial step for the intramolecular
photoredox process leading to (73).79 The nature of the solvent and the
substitution pattern have a marked influence on the properties, relative
energies and chemical reactivities of the np* and pp* triplet excited states
within a family of related compounds.80
Proton coupled electron transfer has been investigated by means of
CIDNP in the photoreaction between 2,6-disubstituted benzoquinones
and DABCO as a model system of the primay electron transfer during
photosynthesis.81
5.4 Quinone methides
Conjugated quinone methides (74) are obtained from appropriate

precursors (75) upon UV–Vis light activation. Laser flash photolysis
allows detection of 74, along with the triplet excited states of (75). The
reactivity of (75) towards photohydration and trapping by thiols has been
studied to evaluate the capability of these compounds to act as alkylating
agents and singlet oxygen sensitisers.82
Photochemistry, 2019, 46, 169–193 | 179

Visible light irradiation of anthrols (76) affords the corresponding
quinone methides (77). These intermediates have been detected by LFP,
and their reactivity towards nucleophiles investigated in connection
with the light enchanced antiproliferative effect of 76 on human cancer
cell lines.83,84
Quinone methide precursors have been prepared from tyrosine and
used as building blocks in the synthesis of peptides, which can be
modified afterwards by photoactivation. In this context quinone
methides from dipeptides have been detected by laser flash photolysis
(lmaxE400 nm, t ¼ 100 ms-20 ms) and their reactivity with nucleophiles
has been studied in connection with their possible applications in
organic synthesis, materials science, biology and medicine.85
Photoexcitation of the binol derivative (78) in aqueous solution affords
the corresponding quinone methide (79). Fluorescence quenching of
the precursor by water suggests the involvement of an excited state
intramolecular proton transfer. Femtosecond and nanosecond transient
absorption spectra prove that water molecules participate in the process
and in the subsequent release of the leaving group to afford the quinone
methide.86
6 Photoeliminations: photodecarboxylations,
photodecarbonylations and photodenitrogenations
Photolysis of phthaloyl peroxide at l ¼ 266 nm in acetonitrile at
room temperature gives rise to decarboxylation, affording o-benzyne.
A minor product is ketene (80). Trapping of o-benzyne with methyl
1-methylpyrrole-2-carboxylate leads to the Diels–Alder cycloadduct (81).87
Photodecarboxylation of cyclic carbonate esters occurs with formation
of 1,3-biradical intermediates, which ultimately yield oxiranes and
several other radical-derived products. By contrast, photolysis of the
corresponding cyclic sulphite esters follows ionic pathways that afford
products resulting form nucleophilic trapping by the solvent, without
generation of oxiranes.88
Solar photolysis of aqueous pyruvic acid under aerobic conditions
produces acetyl and ketyl radicals, which react further to afford 2,3-
dimethyltartaric acid, 2-(1-carboxy-1-hydroxyethoxy)-2-methyl-3-oxobutanoic
acid, and 2-hydroxy-2-((3-oxobutan-2-yl)oxy)propanoic acid. The results from
kinetic isotope effect studies are in agreement with an initial proton coupled
electron transfer.89
The acyl radicals generated upon photodecarboxylation of

a-oxocarboxylic acids react with phenyl propiolates to give coumarins (82).
The reaction is catalysed by hypervalent iodine reagents through formation
180 | Photochemistry, 2019, 46, 169–193

of esters, which are the actual light absorbing species.90 The reaction also
works with acrylamides, but in this case five-membered ring products such
as (83) are formed.91 Likewise, when the substrates are vinylcyclobutanols,
decarboxylative acylation is concomitant with ring expansion, and 1,4-
dicarbonyl compounds (84) are obtained.92
Photodecarboxylative addition of phenylacetates to N-(bromoalkyl)-
phthalimides gives hydroxyphthalimidines, which are readily converted
into isoindolinones (85).93
Phthalimide activated adamantane carboxylic acids such as (86)
undergo photodecarboxylation. In the case of the b-substituted analogues
(87, 88), this process is acompanied by cyclisation, to afford complex
product mixtures.94 By contrast, phthalimidoadamantane-tyrosine
conjugates do not exhibit the usual photodecarboxylation reactivity,
which is attributed to quenching of the excited phthalimide by intra-
molecular electron transfer from the tyrosine moiety.95 Selected photo-
decarboxylations involving intra- or inter-molecular activation by
phthalimides have been successfully achieved in a meso-scale continuous-
flow photoreactor, with improved efficiency and productivity.96 Not only
phthalimides, but also maleimides connected to C-terminal cysteines (89)
mediate photodecarboxylation, releasing the corresponding vinylamino
derivatives.97
The photoreactivity of ketoprofen is enhanced upon complexation with
b-cyclodextrin. This is attributed to conformational changes of the drug
in the inclusion complex, associated with variations in the dihedral angle
between the two aromatic rings and with a reduced mobility of the car-
bonyl group.98 The photobehaviour of a ketoprofen/ibuprofen dyad (90)
has been investigated by femtosecond transient absorption spectroscopy.
Decarboxylation takes place from the triplet state in the picosecond
timescale (time constant ca. 550 ps), to give a carbanionic species with
lmax ¼ 610 nm.99
The photoreactivity of fenofibric acid is characterised by decarboxyla-
tion from the triplet excited state. This process has been investigated
in the presence of human serum albumin by steady-state irradiation,
fluorescence, and laser flash photolysis. Covalent photobinding to the
protein is detected, resulting in the covalent attachement to he Tyr-476
residue.100
Photochemistry, 2019, 46, 169–193 | 181

Steady-state and time-resolved photolytic studies have shown that
cyclopropenones (91) release the corresponding alkynes upon photo-
decarbonylation within 5 nanoseconds. These photoproducts are used
for click chemistry in [3 þ 2] or [4 þ 2] cycloaddition reactions with benzyl
azide and 1,2,4,5-tetrazines, respectively.101
Two- or three-photo excitation of cyclopropenones (92) with femto-
second near-IR pulses leads to photodecarbonylation with formation of
the corresponding dibenzocyclooctynes. The latter are traped by azides,
affording the corresponding triazoles. This process enables high
resolution 3D photoclick derivatisation of hydrogels and tissues.102
Photolysis of carbonyl diisocyanate OC(NCO)2 with an ArF laser
(lexc ¼ 193 nm) in solid argon matrixes at 16 K leads to photo-
decarbonylation, yielding a novel carbonyl nitrene OCNC(O)N. Subsequent
visible light ((lexc4395 nm) irradiation results in a Curtius-rearrangement
affording OCNNCO.103
Aqueous nanocrystaline suspensions of tetraarylacetones in the pres-
ence of submicellar CTAB undergo an eficcient photodecarbonylation
reaction, giving rise to intermediate diarylmethyl radical pairs within the
laser pulse duration (8 ns). The transient absorption spectra under these
conditions exhibit maxima at lmax ¼ 330–360 nm, according to expect-
ations from measurements in homogeneous solutions. The triplet radical
pair has a relatively long lifetime, in the range of 40–90 ms, depending on
the substitution pattern.104
Gas-phase photolysis of 5-diazo Meldrum’s acid (93) yields three pho-
toproducts within less than 1 ps: a carbene formed after denitrogenation,
a ketene resulting from Wolf rearrangement and a second carbene
involving both denitrogenation and decarbonylation. This has been
explained by theoretical calculations at the MS-CASPT2//CASSCF level.105
Enantioselective Sharpless dihydroxylation of a,b-unsaturated diazoke-
tones, followed by Wolff photorearrangement have been used as key
steps in the synthesis of enantiopure 4,5-disubstituted 2-furanones.106
Whereas direct irradiation of diazoketones (94) leads mainly to the Wolf
rearrangement products, benzophenone photosensitisation in the pres-
ence of hydrogen-donating solvents (RH) gives rise to hydrazones (95),
without elimination of nitrogen.107
Photolysis of 3-azido-2,2-dimethyl-1,3-diphenylpropan-1-one in the
solid state leads to isobutyrophenone and benzonitrile. Laser flash
photolysis of nanocrystals allows detection of the triplet excited
azidoketone at lmax ca. 475 nm. The triplet energy, calculated by time-
dependent density functional theory, is 79 kcal mol1, which is sufficient
for cleavage of the Cb-Cg bond.108
182 | Photochemistry, 2019, 46, 169–193

7 Photo-Fries and photo-Claisen rearrangements
Multiconfigurational theoretical calculations on the photo-Fries
rearrangement of phenyl acetate have proposed a three state model for
the reaction: an aromatic 1pp*, generated immediately after light
absorption, a pre-dissociative 1np*, where the energy is transferred to the
dissociative region and a 1ps*, where bond cleavage occurs. The con-
version of 1pp* to 1np* involves pyramidalisation of the carbonyl carbon,
while transformation of 1np* to 1ps* occurs through stretching of the CO
group.109 It is generally assumed that the photo-Fries rearrangement of
aryl esters takes place from the singlet excited state of the aryloxy chro-
mophore. Interestingly, in the case of 1-pyrenyl benzoates, the reaction
takes place from the singlet excited state of the benzoyl chromophore,
because the energy of the pyrenyl singlet is insufficient to cleave the
CO–O bond. Accordingly, 1-pyrenyl alkanoates do not undergo the
photorearrangement.110
The known formation of 2,2-dimethylchroman-4-ones during the
photo-Fries rearrangement of aryl 3-methyl-2-butenoate esters in non-
protic solvents has been attributed to excited state intramolecular
proton transfer in the primary acylphenols, followed by thermal
cyclisation.111
The photo-Fries rearrangement continues to attract attention in the
field of polymer curing and stability. Photogeneration of radical pairs
in the photo-Fries rearrangement triggers polymerisation of 4,4 0 -
dimethacryloyloxy biphenyl and 3,3 0 -dimethacryloyloxy biphenyl in
liquid crystals.112 Likewise, photo-Fries rearrangement of the aryl ester
groups and photoinitiated crosslinking of methacryloyl moieties are
observed under UV irradiation of polyhydroxystyrene with azofragments
containing free methacrylic double bonds.113 Chemical structure chan-
ges during aging of poly(acrylonitrile-butadiene-styrene)/polycarbonate
(ABS/PC) blend under UV irradiation have been investigated by FTIR
analysis. Due to photo-Fries rearrangement of the PC component, the
ABS/PC blends display enhanced photostability.114 Photodecomposition
of block copolymers synthesised from polyurethane and poly(methyl
methacrylate) occurs both by photo-Fries rearrangement of the urethane
linkages and photodeprotection of end-functionalised o-nitro benzyl
groups.115
Photo-Fries rearrangement of aryl acetamides has been investigated in
micellar (ionic and non-ionic) media. Control of the primary radical pair
mobility in these microheterogeneous systems results in a remarkable
photoproduct selectivity, with enhanced yields of the o-rearranged
products.116
Photolysis of 1,4-bis(phenylsulphonyloxy)benzene produces S–O
cleavage, with generation of a phenylsulphonyl/phenylsulphonyloxy-
phenoxy radical pair. Further steps end with formation of photo-Fries
rearrangement products, together with a large amount of acidic
species.117 Likewise, N-arylsulphonimides have been found to be efficient
nonionic photoacid generators. This is because, in addition to the
photo-Fries products, photolysis of the sulphonimides releases sulphinic
Photochemistry, 2019, 46, 169–193 | 183

and sulphonic acids under anaerobic or aerobic conditions,
respectively.118
Irradiation of coumarin-caged 4-hydroxy tamoxifen (96) does not only

lead to uncaging, but also to a significant amount of the photo-Claisen
rearrangement product (97). The use of an extended, self-immolative
linker, allows circumventing this undesired side reaction.119
8 Photocleavage of cyclic ethers

Direct photolysis of styrene oxide yields phenylacetaldehyde, toluene and
bibenzyl as primary photoproducts. Styrene glycol carbonate gives rise to
a similar mixture of photoproducts. This is consistent with initial
cleavage of the benzylic C–O bond, to give a singlet 1,3-biradical; this
intermediate affords directly the aldehyde or, after intersystem crossing
to the triplet biradical, the other two photoproducts.120
Epoxide (98) is successfully reduced upon irradiation with white light
in the presence of sodium carbonate, sodium hydrosulphite and a
pyridinium salt to give alcohol (99). This is a key step in the synthesis of
juglocombins A and B.121
9 Photoremovable protecting groups

Coumarin-caged ceramide analogues (100), useful for cell studies, pho-
torelease the parent ceramides upon direct exposure to 350 nm UV
light.122 The dicyano derivatives (101) are appropriate photocages for
carboxylic acids and amines, which can be released upon irradiation with
green light.123 This principle has been applied to the photocontrolled
delivery of cyclic RGD peptides.124 Related photoremovable protecting
groups containing a coumarin chromophore with extended p conjugation
display suitable two-photon absorption properties in the near-IR region.
Thus, benzoates (102) are efficiently uncaged by two-photon irradiation
above 700 nm, with optimal wavelength depending on the substitution
pattern.125
Quinone trimethyl locks, such as (103), are appropriate long-
wavelength photoremovable protecting groups for alcohols and amines.
184 | Photochemistry, 2019, 46, 169–193

Intramolecular photoreduction using visible light generates reactive
phenols, whose fast lactonisation to (104) is accompanied by uncaging in
quantitative yields.126 Product analysis, kinetic isotope effects, stereo-
chemical labeling, radical clock and transient absorption studies support
an electron transfer mechanism.127
Thiochromone S,S-dioxides are efficient photolabile protecting groups

for phosphates, amino acids and sulphonic acids. The uncaging of (105)
proceeds straightforward, with formation of a condensed furan derivative
(106) along with the released substrates.128
Carboxylic acids, including amino acids, can be photoreleased from the
corresponding bimane caged compounds (107) by means of visible light.
Both single and dual release can be achieved from the same bimane unit.129
Photolysis of o-nitrobenzyl esters (108) releases the deprotected carb-
oxylic acids along with the corresponding o-nitrosoketones. Substitution
at the a position by a bulky alkyl group increases the rate of the reaction.
Further photorearrangement of the nitrosoketones affords bicyclic ox-
azoles (109).130 Thiocarbamates (110), which contain a photoremovable
protecting group of the same family, undergo a photoactivated release of
carbonyl sulphide, which is readily hydrolysed to hydrogen sulphide by
carbonic anhydrase.131 A photocleavable o-nitrobenzyl-caged antitumour
prodrug of 5-fluorouracil has been reported (111). It shows a decreased
toxicity, but retains the antitumor activity against cancer cells after
exposure to UV radiation.132 An alternative approach for the photo-
controlled release of 5-fluorouracil makes use of a pyrene substituted
oligonucleotide trimer (112). The process is triggered by electron injec-
tion from the excited pyrene unit.133
Coumarin fused oxazoles (113) have been employed as photocages for
carboxylic acids, using butanoic acid as model compound.134 Likewise,
fused coumarin esters (114) have been reported to photorelease 5-
aminolevulinic acid, which is an established prodrug in photodynamic
therapy.135
Photochemistry, 2019, 46, 169–193 | 185

Sunscreen-based photocages are not only useful for the photo-
controlled release of bioactive compounds, but also to prevent photo-
degradation. The concept has been proven linking avobenzone, a widely
used UVA filter, to the photosensitive nonsteroidal anti-inflammatory
drug ketoprofen (115).136
Photoremovable protecting groups based on bis-acetyl carbazole (116)
are appropriate systems for the dual release of carboxylic acids, alcohols,
thiols, and amines in a sequential mode. These systems are appropriate
for drug delivery, cellular uptake and biocompatibility, as shown by
in vitro studies.137
The concept of photoremovable protecting groups has also found
application in the field of polymers. Thus, attachement of the photo-
cleavable o-nitrobenzyl moiety to polymeric micelles based on amphiphilic
polyaspartamides loaded with paclitaxel provides a photo-responsive sys-
tem for the controlled release of this anticancer drug.138 Epoxy monomers
containing photolabile o-nitrobenzyl esters are cured via photoinduced
cationic ring opening. The resulting crosslinked networks are photo-
degraded upon excitation of the nitrobenzyl chromophore, which allows
obtaining patterned films for applications in photolithography.139 Poly-
(carbonate)s with pendent o-nitrobenzyl esters self-assemble in aqueous
solution to spherical micelles. Upon controlled exposure to UV light,
cleavage of the photolabile group leaads to disassembling of the micelles.
This assembling/disassembling strategy provides a potential entry to
smart polycarbonates nanocarriers for controlled drug release.140
Random methacrylic copolymers based on photocleavable 6-bromo-7-
hydroxycoumarinyl esters and N,N-dimethylaminoethyl methacrylate
(117) undergo photochemical deprotection leading to film dissolution.
The process can be trigerred by exposure to either UV or near-IR light,
due to the substantial two-photon cross section of the photolabile
chromophore.141
10 Miscellanea
Irradiation of a-bromo carbonyl compounds in the presence of alkynes
in aqueous media yields b,g-alkynoates (118), which can be readily con-
verted into the corresponding allenoates.142
186 | Photochemistry, 2019, 46, 169–193

Irradiation of (119) in toluene leads mainly to the tricyclic
butyrolactone (120), together with a minor regioisomer. Control experi-
ments indicate that ring contraction with release of the amine fragment
is a UV–Vis photochemical process, which is independent from the
UV-driven 6p electrocyclisation.143 Photocyclisation of a related chiral
1,2-bisbenzylidene succinate amide ester (121) in methanol is the key
step in the synthesis of ()-podophyllotoxin. The reaction can be
performed in a multigram scale, using a flow photoreactor.144
Photochemical splitting of the b-lactam ring in the antihyperlipidemic
drug ezetimibe (122) follows a formal retro- Staudinger reaction, giving a
highly reactive ketene intermediate that is intramolecularly trapped by
the benzylic alcohol, to give lactone (123). When complexed to human
serum albumin, the ketene is trapped by the neighbouring Lys414 and
Lys525 residues, leading to covalent amide adducts.
Docking and molecular dynamics simulation studies explain the

selectivity of (122) for these amino acid residues and the covalent
modification mechanism.145
Oxime ester derivatives are typical photoinitiating systems in photo-
polymerisation. In the case of (124) and (125), photocleavage of the N–O
bond leads to radicals capable of triggering polymerisation of methyl
methacrylate. The highest efficiency is observed at lexc ca. 400 nm, even if
the molar absorption coefficient of the photoinitiators is higher at
shorter wavelengths.146
Three ketones containing benzoyl and phenylthiylmethyl groups (126)–
(128) have been studied by laser flash photolysis in acetonitrile. Whereas
(127) and (128) show exclusively the transient absorption spectra of their
triplet states, (126) gives rise to the phenylthiyl radical, indicative of C–S
Photochemistry, 2019, 46, 169–193 | 187

bond breaking. Xanthone photosensitisation leads to similar results in
the case of (126) and (127); by contrast, under these conditions (128) gives
rise to the phenylthiyl radical. The latter result is explained by the
involvement of an upper triplet state in the photosensitisation of (128) by
xanthone.147
The photobehaviour of m-substituted benzophenones (129) and (130)
in acidic aqueous medium has been examined by time-resolved spec-
troscopy and density functional theory calculations. The hydroxymethyl
derivative (129) undergoes an intramolecular photoredox reaction, to give
(131). Converserly, the only process observed for (130) is excited-state
deprotonation to the benzylic carbanion.148
Through-bond triplet exciplex formation in donor–acceptor systems
linked through a rigid bile acid scaffold has been demonstrated in (132)
and (133) using laser flash photolysis, upon population of the triplet
acceptors (naphthalene, or biphenyl) by through-bond triplet–triplet
energy transfer from a benzophenone donor.149
Femtosecond stimulated Raman spectroscopy has been used to study
the hydrogen bonding dynamics of a photoexcited coumarin (134) in
ethanolic solution. Following 400 nm excitation, cleavage of the hydrogen
bond is observed in the singlet photoexcited fluorophore with less
than 140 fs time constant. The subsequent dynamics are attributed to
solvation of the nascent free (134), hydrogen bond reformation and
radiative emission from the relaxed excited state (13 ps, 37 ps and more
than 1ns decay time constants, respectively). These studies on hydrogen
bond making and breaking dynamics are important because this type
of interactions play a key role in numerous chemical reactions and
biological processes.150
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Photochemistry, 2019, 46, 169–193 | 193

Function containing a heteroatom
different from oxygen (2016–2017)
Carlotta Raviola, Stefano Protti* and Angelo Albini
DOI: 10.1039/9781788013598-00194
The main photochemical processes involving chromophores containing nitrogen, boron,

silicon, germanium, phosphorous, sulfur and halogen atoms reported in the 2016–2017
period have been briefly described herein. It should be noticed that the reactions
occurring by means of photocatalysts/photosensitizers able to activate such chromo-
phores have not been considered throughout the account but have been mentioned at
the end of each paragraph.
1 Nitrogen containing functions

As in the previous volume (44, 2016), the reaction of nitrogen containing
molecules have been described starting from those bearing a single
bonded C–N function, and then multiple bond. Then, molecules with
more nitrogen atoms have been reviewed in decreasing oxidation
level order.
1.1 C–N, a single nitrogen atom

1.1.1 Nitro derivatives. Dong et al. recently investigated the degrad-
ation kinetics of nitro-based pharmaceuticals, namely ranitidine
(1, RNTD, Fig. 1) and nizatidine (2, NZTD) and the potential generation
of halonitromethanes during the photolysis. A pH-dependent reactivity
was found, since the neutral species of RNTD and NZTD resulted more
reactive than the corresponding anionic forms. Nitrite (and nitrate
from it) anion was released upon irradiation, via either homolytic or
heterolytic C–N bond cleavage. Notably, both drugs (almost at acid and
neutral pH) were found to be photochemical precursors of halonitro-
methanes with quantum yield values of 0.056 and 0.047, respectively
(pH 7.0). Cleavage of C–S bond has been also observed in both
molecules.1
Starting from early experiments of Giacomo Ciamician,2 the photo-
chemistry of ortho-nitrobenzaldehyde (3) has been investigated in details
all along the history of photochemistry. This mechanism of the
rearrangement of 3 to 2-nitrosobenzoic acid 5 in aqueous solution has
been recently studied in detail by Fröbel and Gilch by means of femto-
second IR and Raman spectroscopy. This technique was exploited to
confirm the formation of the ketene intermediate 4 (Scheme 1).3
Such investigative approach has been also applied to the study of the
photoinduced enolization of ortho-nitrotoluene.3
PhotoGreen Lab, Department of Chemistry, University of Pavia, V.Le Taramelli 12,

27100 Pavia, Italy. E-mail: stefano.protti@unipv.it
194 | Photochemistry, 2019, 46, 194–217

Fig. 1 Ranitidine (1, RNTD) and nizatidine (2, NZTD).
Scheme 1
Fig. 2 Proposed Branching Relaxation Mechanism for 1,6-DNP Leading to the Formation
of a Nitropyrenoxy Radical (NO2PyO ) or to Intersystem Crossing to the Triplet (T1) State
on an Ultrafast Time Scale in Acetonitrile. Reprinted with permission from ref. 4. Copyright
2016 American Chemical Society.
The nitropolycyclic aromatic pollutant 1,6-dinitropyrene (1,6-DNP) can

be photochemically (300–500 nm) degradated to 1-hydroxy-6-nitropyrene
and 1,6-pyrenedione. The photoreactivity of this compound was investi-
gated by Brister et al., who highlighted the presence of an energy barrier
in the excited singlet manifold, that favors intersystem crossing to
(unproductive) triplet at the expenses of photodissociation and sub-
sequent nitropyrenoxy radical NO2PyO formation (Fig. 2).4
In these two years, nitroarenes have been used with success to visible
light driven photoredox catalyzed processes.5 In a peculiar case,
palladium–loaded silicon (Pd/Si) catalyst was employed in the dual role of
photocatalyst (in order to generate hydrogen from formic acid) and
catalyst (to promote reduction of nitroaromatics to the corresponding
anilines).6
1.1.2 Hydroxylamines, amines and ammonium salts. Hydroxyla-

mine (NH2OH) is considered a simple model molecule for investigating
Photochemistry, 2019, 46, 194–217 | 195

the NH and OH bond interactions. Recently, attention has been
focused on the direct photolysis of such compound (in aqueous solu-
tion) as described in eqn (1):
3NH2OH þ hn-NH3 þ 3H2O þ N2 (1)
A computational analysis carried out on different small

hydroxylamine–water clusters (NH2OH(H2O)n, n ¼ 1–4) evidenced the fact
that the primary process in NH2OH was O–H bond homolysis. On the
other hand, complexation with water impressively affect the photo-
dissociation pathways of NH2OH, via Excited State Proton Transfer
(ESPT) to a water molecule and dissociation of one of the free O–H bond
in the cluster.7
Despite the renewed interest for the photochemistry of organic groups,
only little attention has been given to the behavior of amines under
irradiation. The 3-(N,N-diethylamino)benzyl (DEABn) group has been
proposed by Wang et al. for the release of differently substituted amines
7. The process takes place via direct photolysis of the benzylic C–N bond
in the corresponding ammonium salts 6. A marked solvent dependence
in the efficiency of the release process was found. Primary and secondary
amines were efficiently generated in methanol, whereas tertiary amines
required the use of MeCN/water mixture as solvent in order to minimize
side reactions (some examples in Scheme 2).8
Asad et al. investigated by means of time resolved spectroscopy the
photoreactivity of tertiary amines linked to the 8-cyano-7-hydroxyquinolinyl
(CyHQ) photoremovable protecting group (PPG), with the aim of
developing photoactivated caged compounds. Notably, the photoactivation
of anticancer drugs tamoxifen (Compound 8 in Fig. 3) and 4-hydro-
xytamoxifen was achieved through both one- and two-photon excitation of
CyHQ protected anilines.9
Analogously, the use dicyanocoumarinylmethyl- (DEAdcCM), and
dicyanocoumarinylethyl (DEAdcCE)-based photoprotecting groups were
exploited for the release of carboxylic acids and primary amines upon
irradiation with visible light.10 As concerning the use of amine in
photochemical synthesis, great attention has been given to their
activation under photoredox catalyzed conditions.11
Apart from this approach, an intriguing case has been reported by
Chen and Coworkers, that reported a light induced (UV or sunlight)
Scheme 2
196 | Photochemistry, 2019, 46, 194–217

Fig. 3 Photoactive Tamoxifen.
(a)
(b)
Scheme 3
radical perfluoroalkylation protocol by exploiting the halogen bond

between a perfluoroalkyl iodide and N,N,N 0 ,N 0 -tetraethylethylenediamine
(TEEDA, some examples in Scheme 3a).12 In a similar way, the solar or
visible-light assisted amidation of carboxylic acids 11 was developed by
having recourse to the formation of an electron donor–acceptor complex
between an amine and CCl4 used as the promoter (some representative
example in Scheme 3b).13
The Single Electron Transfer (SET) addition of N-trimethylsilylmethyl
substituted a-aminonitriles onto fullerene C60 was exploited by Mariano
et al. for the preparation of fulleropyrrolidine nitriles.14 The irradiation of
2 0 -halo-[1,1 0 -biphenyl]-2-amines in basic medium was reported to afford
exclusively carbazoles via SRN1 mechanism from substrates bearing EWG
Photochemistry, 2019, 46, 194–217 | 197

groups such as CN or COOR. In contrast, photolysis of 1,1 0 ,-biphenyl-2-
amines having electron-donating substituents (CH3, OCH3) as well as
unsubstituted 1,1-biphenyl-2-amine afforded a mixture of carbazole and
dehalogenated amine.15
1.1.3 Amides and imides. The photochemistry of a set of substi-

tuted N-arylsulfonimides 13 was investigated by Torti et al. by means of
both steady-state and time resolved spectroscopy analysis. Importantly,
it was found that the homolytic cleavage of the S–N bond takes place
exclusively from the singlet state to afford, in a competitive fashion,
N-arylsulfonamides 14 and the corresponding photo-Fries rearrange-
ment product 15 in a ratio that strictly depends on the nature of the
aromatic substituents and on the reaction conditions. Furthermore,
sulfinic and sulfonic acids were released in the absence and in the
presence of oxygen, respectively (Scheme 4). Notably, in oxygen satur-
ated solution, 13 generated up to 2 equivalents of strong sulfonic acid
for mole of substrate, highlighting the potentialities of such com-
pounds as non ionic PhotoAcid Generators (PAGs),16a that have been
used as initiators for the polymerization of epoxy-based materials.16b
N,N 0 -diaryloxalyl amides (16, smoothly obtained via a three component
process) were recently employed as substrates for the one-pot, two-steps
photochemical preparation of complex alkaloid structures 17. In this way,
bioactive products such as those bearing the imidazolidine-4,5-dione
core, can be obtained in only 2 to 4 simple synthetic steps. (Scheme 5).17
Scheme 4
Scheme 5
198 | Photochemistry, 2019, 46, 194–217

Fig. 4 Double hydrazone prepared by Gordillo et al.18 Reproduced with permission from
ref. 18, Copyright 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
Fig. 5 Photoactive precursors of iminyl and perfluoroalkyl radicals.
1.1.4 Hydrazones, imines, oximes and iminium ions. Gordillo et al.

described the synthesis of a double hydrazone (18, Fig. 4) that under-
went photoinduced E/Z isomerization through the CQN double bonds
and pointed out the potentialities of the structure for developing
molecular machines.18
Very recently, the adoption of imine and iminium catalytic approaches
in enantioselective photochemical reactions has been reviewed by Bach
and coworkers.19 Imines were mainly used as radical acceptors20 as well
as electron donor21 in photoredox catalysis. On the other hand, oxime 19
and iminium triflate salts 20 (Fig. 5) were described as source of iminyl22
and perfluoroalyl radicals,23 respectively, under photoredox catalytic
conditions.
Taking inspiration from the behavior of 11-cis-retinal, the group of
Melchiorre recently exploited the oxidant properties of photoexcited
iminium ions to promote the enantioselective catalytic b-alkylation of
enal 20 upon visible and solar light irradiation. The iminium ion is in situ
generated by the intermediacy of chiral amine 21 as the organocatalyst
(Scheme 6).24
An investigation of the wavelength-dependent photochemistry of
oxime esters 23, 24 (Fig. 6), typically employed in photoinduced poly-
merization, pointed out that the highest conversion of such compounds
was achieved at 405 nm, where the molar extinction coefficients of the
two photoinitiators are low (eo50 M1 cm1).25
A set of pyridine and p-nitrophenyl oxime esters was synthesized and
characterized, with the aim of developing a new class of photoactive
derivatives able to cleave or bind DNA upon irradiation. Some of the
compounds examined was found to photocleave DNA at 365 nm at a
concentration of 500 mM (some of the most promising compounds are
illustrated in Fig. 7).26
Photochemistry, 2019, 46, 194–217 | 199

Scheme 6
Fig. 6 Oxime esters as photoinitiators.
Fig. 7 p-Nitrophenyl oxime esters tested in ref. 26. Reproduced from ref. 26 under a CC
BY 4.0 Licence (https://creativecommons.org/licenses/by/4.0/).
Oxime ethers 27 were employed with success in the three-component,

(photo)catalyst-free preparation of a wide range of sulfonated 3,4-
dihydro-2H-pyrroles 29 that involves a N-radical-initiated cyclization as
the key step (Scheme 7).27
Finally, preparation of cyclohexanone oxime, a key intermediate in the
preparation of Nylon-6 was recently optimized by using tert-butyl nitrite
and UV-emitting LED diode.28
1.1.5 Nitriles. 2,5-Disubstituted tetrazoles are long-time know precur-

sors of nitrile imines. Cristiano et al. investigated in details the photo-
chemical behavior of 1- and 2-methyl-substituted 5-aminotetrazoles when
they are isolated in an argon matrix (15 K) by means of IR spectroscopy.
200 | Photochemistry, 2019, 46, 194–217

Scheme 7
Fig. 8 Photochemistry of 1- and 2 Methyl-5-aminotetrazoles. Reprinted with permission

from ref 29. Copyright 2016 American Chemical Society.
The matrix system was irradiated with a narrow band UV excitation

at different wavelengths in order to selectively induce photochemical
transformations of different species. Whereas both isomers afforded a
common diazirine intermediate (see Fig. 8) which in turn underwent
subsequent photoconversion to 1-amino-3-methylcarbodiimide, an
amino cyanamide species is exclusively generated from the 1-methyl iso-
mer. In contrast a nitrile imine is obtained from photolysis (at 222 nm)
of 2-methylaminotetrazole. This behavior pointed out the chance that
only 2H -tetrazoles can have a direct access to nitrile imines, while obser-
vation of the amino cyanamide (that is peculiar of 1 H derivatives)
represents a novel reaction pathway in the photochemistry of tetrazoles.29
The gas-phase photosynthesis of methylcyanobutadiyne, a compound
significantly present in the interstellar medium, was studied starting
from different acetylenes. Interestingly, formation of the examined
compound was observed by irradiation at 193 nm of a mixture of
1-propyne and dicyanoacetylene, with a suggested radical mechanism.30
1.2 Two nitrogen atoms

1.2.1 Azobenzenes. As predictable, the investigation of the mechan-
ism of the photochemical isomerization of azobenzenes is still a sig-
nificant research issue. One of the challenge in this field is the precise
calculation of the molar absorption coefficients (e) of both E and Z iso-
mers, but in most case, the absorption spectra of the isomers reported
in literature resulted mutually contaminated by significant amounts of
Photochemistry, 2019, 46, 194–217 | 201

the other isomer. Wirtz et al. obtained recently the spectrum of cis-
azobenzene by means of three different approaches, the Thulstrup,
Eggers and Michl (TEM) method, NMR analysis and thermal isomeriza-
tion. In this way, the value of e cis at different wavelength was calcu-
lated within the limits of error (e.g. 1402 23 M1 cm1 at 436 nm).31
Ramamurthy and Raj recently reported an elegant work focused on the
role of the supramolecular steric effects and free volume on photo-
chemical processes. To this aim, they investigated the isomerization of
a set of neutral alkylsubstituted azobenzenes as well as of their corres-
ponding radical ions (in turn obtained via electron transfer with gold
nanoparticles) included within an octa acid capsule.32 The photoisome-
rization occurring in protonated trans-azobenzene and trans-4-amino-
azobenzene was recently studied in the gas phase by having recourse to
a tandem ion mobility spectrometer and electronic structure calcula-
tions. Both cations underwent isomerization across their S1’S0 bands,
with peaks located at 435 and 525 nm.33 The photochemical transfor-
mation taking place in 2,2 0 -dihydroxyazobenzene, 2,2 0 -azotoluene and
azobenzene (AB) was investigated in argon and xenon matrices by
means of infrared spectroscopy and theoretical calculations.34 Again,
the ultrafast dynamics of bisazobenzenes 30 (Fig. 9) isomerization, was
investigated by Wachtveitl and coworkers, in order to develop photo-
switchable multiazobenzene nanostructures.35
The introduction of photoresponsible azoarenes is traditionally
exploited in the preparation of photoswitchable systems.36 Precision
polymers containing (cis/trans)-azo-(substituted)benzenes as defects
within a polyalkylene chain were prepared via ADMET followed by
hydrogenation. Such macromolecules are designed to present an azo-
benzene moiety after exactly 18 methylene units. The synthesized polymers
are thus able to photochemically switch cis/trans configuration, and
change the geometrical constraint exerted on the alkyl chain during crys-
tallization.37 Two molecular receptors 31a,b containing an azobenzene
moiety functionalized with urea hydrogen-bonding groups and D-carbo-
hydrates as chiral selectors were developed to achieve control over the
chiral recognition of a-amino acid-derived carboxylates. Such receptors
exhibits two photo- and thermally interconvertible planar E-1 and
concaved Z-1 conformations, with different affinities, selectivities and
binding modes, that have been exploited for the use of the molecules as
sensors for chiral biomolecules binding carboxylic acid groups (Fig. 10).38
Fig. 9 Bisazobenzenes 30 tested in ref. 35. Reproduced from ref. 35 with permission
from the PCCP Owner Societies.
202 | Photochemistry, 2019, 46, 194–217

Fig. 10 Schematic representation of molecular receptors. 31a and b which were developed
to achieve control over the chiral recognition of a-amino acid-derived carboxylates.
Adapted with permission from ref. 38. Copyright 2016 American Chemical Society.
Fig. 11 Azobenzene-containing ammonium amphiphile (32) and Ionic liquids (33).
Photoswitchable reverse micelles (RMs) were prepared by the group

of Klàn by means of azobenzene-containing ammonium amphiphile
32 (Fig. 11).39 Ionic liquids containing a photoswitchable azobenzene
moiety (see for instance compound 33) were prepared and their
photochemical behavior investigated. Interestingly, such compounds
undergo a reversible solid-to-liquid phase transition induced by both
photo- and thermal-stimulation.40
A photoresponsive Zn-MOF (metal–organic framework) consisting of
diarylethene and azobenzene photochromic moieties was reported by
Luo et al., and its photochemical behavior used to modulate the
adsorption selectivity of the MOF material.41 Azobenzene structures were
also exploited in the preparation of short-interfering RNAs (siRNAs),
which structure and (as consequence) activity can be modulated via light
stimulation.42 Interestingly, as illustrated in Scheme 8, photoresponsive
siRNAzos can be inactivated and reactivated upon irradiation with UV
and visible light, respectively. A water-soluble adhesive photoswitch
based on azobenzene chemistry able to binds selectively to a target
enzyme in order to tune photochemically its enzymatic activity was
recently described.43
1.2.2 Azo sulfones. Molecules belonging to the class of arylazo sul-
fones were recently investigated by Protti and Coworkers as a new class
of photoactivated molecules. Such compounds (34) have been smoothly
Photochemistry, 2019, 46, 194–217 | 203

Scheme 8 Reproduced with permission from ref. 42. Copyright 2017 Wiley-VCH Verlag
GmbH & Co. KGaA, Weinheim.
prepared by a two steps procedure from colorless and easily available

anilines via diazotization and treatment of the obtained diazonium
salts with sodium methansulfinate (Scheme 9a). The obtained arylazo
sulfones were colored, bench-stable and a series of experimental analy-
sis pointed out their wavelength selective photoreactivity (Scheme 9b).
Indeed, visible-light irradiation of 34 populates the 1np* state, thus
homolysis of the S–N bond occurs to give, after loss of a nitrogen mol-
ecule, an aryl (Ar )/methanesulfonyl (CH3SO2 ) radical pair. In contrast,
irradiation with UV-light (e.g. 366 nm) induces an excitation to the 1pp*
state, and the following intersystem crossing (ISC) to the triplet 3pp*
favors the heterolytic cleavage of the S–N bond and generates, again
after nitrogen loss, a triplet phenyl cation (3Ar1).44 Obviously, upon
solar exposition both species are generated. Such derivatives have been
exploited to generate selectively highly reactive intermediates under
photocatalyst-free and tunable conditions. The N2–SO2CH3 structural
motif able to imparts both color and photoreactivity has been dubbed
as dyedauxiliary group and a wide range of arylazo sulfones has been
employed in the development of arylation protocols for the prepar-
ation, under metal-free conditions, of allylarenes,45 aromatic amides46
and (hetero)biaryls.44 Furthermore, the same substrates have been
involved in the visible-light promoted, gold catalyzed Suzuki
coupling.47
1.2.3 Diazonium salts. The interest in photochemistry for arenedia-

zonium salts is mainly limited to their use as aryl radical precursors in
photoredox catalyzed processes.48 In the last two years, significant
204 | Photochemistry, 2019, 46, 194–217

Scheme 9
Scheme 10
attention has been given to the developed of a dual photoredox/gold

protocols for different cross coupling processes, including the Suzuki
reaction between a boronic acid and a diazonium salts.49 In this
field, however, Hashmi and coworker reported that such coupling
could occur under photocatalyst-free conditions, in the presence of tris-
(4-trifluoromethyl) phosphine gold(I) chloride as the catalyst50 (some
examples in Scheme 10). The intermediacy of a visible light absorbing
complex between the arenediazonium salt and the gold complex was
pointed out as the key step in the reaction.
The same research group also optimized a photocatalyst free, visible
light driven, gold(I) catalyzed 1,2-difunctionalization of alkynes by
arenediazonium salts, to form the corresponding a-arylketones.51
Photochemistry, 2019, 46, 194–217 | 205

1.3 Functions containing three nitrogen atoms
1.3.1 Azides. Vicinal 1,2-bromine azides can be synthesized via
photoinduced addition of bromine azide (BrN3) onto alkenes. However,
the reaction if performed under batch conditions, presents several
drawbacks since BrN3 is a highly toxic and explosive reagent. For this
aim, Cantillo et al. developed a continuous flow protocol were the
compound is generated in situ from NaBr and NaN3 in aqueous
solution under oxidative conditions and extracted by an organic phase
containing the alkenes 36 (Scheme 11) that was then irradiated. After
work-up with Na2S2O3 the desired difunctionalized products 37 were
obtained in satisfactory yields.52
Acyl azides were prepared in good to excellent yields via visible light
induced azidation of aldehydic C–H in the presence of carbon tetra-
bromide and sodium azide. Notably, the strategy was also applied to the
one-pot synthesis of carbamoyl azides 40a–c from aldehydes 38a–c
(Scheme 12), via C–H azidation followed by thermal Curtius rearrenge-
ment of the resulting acyl azides 39a–c.53
Organic azides have been extensively used as reactants in photoredox
catalysis in the last two years.54 On the other hand, the photoreactivity of
aromatic azides is still a subject of research in organic chemistry.
Sydnes et al. recently reported that the photolysis of ethyl 3-azido-4,6-
difluorobenzoate (41, Scheme 13) at room temperature in the presence of
oxygen afforded regioselectively the corresponding ethyl 5,7-difluoro-4-
azaspiro[2.4]-hepta-1,4,6-triene-1-carboxylate 45, via the suggested inter-
mediacy of a ketenimine (43, in turn obtained from the corresponding
nitrene 42) that then underwent a photoinduced electrocyclization to
bicycle 44 followed by a rearrangement. The reaction mechanism and the
structure of the final product were clarified by means of multinuclear
solution NMR spectroscopic techniques supported by DFT calculations.55
Scheme 11 Adapted from ref. 52 with permission of The Royal Society of Chemistry.
206 | Photochemistry, 2019, 46, 194–217

Scheme 12
Scheme 13
Scheme 14
Recently, the aqueous nanocrystalline suspensions has emerged as

efficient media to investigate the reaction mechanism in solid state by
means of spectroscopy techniques. Recently, Garcia-Garibay and co-
workers described the photolysis of 2-azidobiphenyls (46, Scheme 14),
that affords, in nanocrystalline suspension, the corresponding carbazoles
always in quantitative yields. Apart from the synthetic interest for the
reaction, Laser Flash Photolysis analyses of the reaction pathways
revealed the initial formation of a singlet nitrene (47) followed by cycli-
zation to the corresponding isocarbazole 48.56
The photochemistry of p-bromophenylsulfonyl azide (BsN3), p-
tolylsulfonyl azide (TsN3) and methylsulfonyl azide (MsN3) in halogenated
solvents (dichloromethane and tetrachloromethane) was investigated by a
combined femtosecond time-resolved infrared spectroscopy/computational
Photochemistry, 2019, 46, 194–217 | 207

Fig. 12 Pseudo Curtius intermediate observed in ref. 57. Reproduced from ref. 52 with
permission from the PCCP Owner Societies.
Scheme 15
Scheme 16
approach. The nature and the kinetic of intermediates including singlet

and triplet nitrenes as well as the formation of speudo Curtius photo-
produts 50 (Fig. 12) has been characterized.57
The photoreactivity of monofluorinated 2-azido-1-methylbenzimidazoles
51 was exploited to prepare labeling agents. Indeed, UV irradiation of 4-, 5-,
or 7-fluoro-2-azidoimidazole, in the presence of N-protected aminoacids
52a–c afforded regioselectively the monofluorinated 2-amino-6-
acyloxybenzimidazoles 53a-c (Scheme 15). Other nucleophile additives,
including halide anions and carboxylic acids were also employed with
satisfactory results.58
As concerning other synthetic used of aromatic azides, the photolysis
of 2-azidobenzoic acids under basic conditions was exploited for the
preparation of 2,1-benzisoxazole-3(1H)-ones.59 Analogously, quinazoli-
nones were obtained upon visible-light exposition of the corresponding
a-azidyl benzamides in the presence of N-Bromosuccinimide (NBS).60
Polycyclic heterocycles were obtained from arylazides also under con-
tinuous flow conditions. Collins and coworkers reported the synthesis of
substituted carbazoles by following a protocols that is tolerant to a wide
range of UV sensitive functional groups (some examples in Scheme 16).61
2 Functions containing other heteroatoms

2.1 Boron
The photochemical properties of B,N-centered heterocycles (56a–c) have
been deeply investigated. These compounds upon irradiation at 300 nm
208 | Photochemistry, 2019, 46, 194–217

Scheme 17
Fig. 13 Absorption and fluorescence spectra of 57a–c in THF. Adapted with permission
from ref. 62. Copyright 2016 American Chemical Society.
undergo photoelimination affording heterocycles fused B,N-naphtalenes

(57a–c) which exhibit yellow/green or blue fluorescent. In some case this
transformation can occur also under thermal conditions (Scheme 17 and
Fig. 13).62
The same study have been performed on compounds having two B,N-
heterocycles units connected by an aromatic linker. Experimental and
computational data demonstrated that while diboron B,N-heterocycles
which share the central linker are unstable or poorly reactive under
irradiation, those which don’t share the central linker undergo photo-
elimination efficiently.63
2.2 Phosphorous
The photolysis of Carbon-Phosphorous bond was studied in details in the
case of free radical iniziator (2,4,6-trimethylbenzoyl)diphenyl phosphine
oxide (TMDPO) in dichloromethane at room temperature combining
femptosecond UV pump and mild infrared probe spectroscopy.64 The first
singlet excited state S1 undergoes intersystem crossing to triplet ground
state T1 with a time constant of 135 ps. At this stage a cleavage of C–P bond
takes place with a time constant of 15 ps affording trimethylbenzoyl
Photochemistry, 2019, 46, 194–217 | 209

Fig. 14 Photochemistry of (2,4,6-trimethylbenzoyl)diphenyl phosphine oxide (TMDPO)
in liquid dichloromethane. Reprinted with permission from ref. 64. Copyright 2017
radical and diphenylbenzoyl radical which were identified throught their

characteristic infrared absorption in the carbonyl and phosphoryl spectral
regions (Fig. 14).
On the basis of this photoreactivity TMDPO have been employed as
iniziator in the reaction with disulfides, diselenides, ditellurides, di-
phosphines for the synthesis of the corresponding phosphinates (58a–c,
Scheme 18) and esters (59b–d).65
The formation of C–P bond was mainly obtained by having recourse to
photoredox catalysis.66 However, the metal-free and catalyst-free re-
gioselective phosphonation of quinolines has been recently reported.
This target can be achieved by simple irradiation of the heterocyclic
substrate in presence of diphenylphosphine oxide, pyridinium salt 62 as
oxidant and NaHCO3 as base.67 The excited state of the reagent acts as
photosensitizer promoting the N–O bond cleavage in pyridinium salt
throught a SET reduction affording 2-methylpyridine and ethoxy radical
(Scheme 19). The latter undergoes hydrogen abstraction from diphenyl-
phosphine oxide to yield phosphinoyl radical 61 which reacts with 60.
The so formed radical 63 undergoes a second SET with 60 1 or products
radical cation (63 1) affording cation 631 which after deprotonation
gives the desidered product 63. The scope of the reaction is large and
both electron-donating and electron-withdrawing group are tolerated
onto the aromatic ring. The process was also extended to coumarin
derivatives. In this case a mixture of mono and biphosphonated products
was obtained, but monosubstitution was achieved throught a one-pot
process involving phosphonation and elimination.67
2.3 Sulfur
Recently fluorinations have received much attention due to the import-
ance of fluorine containing molecules in pharmacological field. On this
210 | Photochemistry, 2019, 46, 194–217

Scheme 18
Scheme 19
topic, Studer and coworkers have reported a photo-induced metal-free

difluoromethylation of (hetero)aryl thiols using readly accesible
(difluormethyl)triphenylphosphonium bromide as fluorinating agent.
Photochemistry, 2019, 46, 194–217 | 211

Scheme 20
Fig. 15 Photoinduced homolysis of S–H bond of 4-methylthiol at 267 nm. Adapted with
permission from ref. 70. Copyright 2017. American Chemical Society.
The reaction tolerates different functional group on the (hetero)aromatic

ring (OH, NH2, amide, ester) and procedes throught a SRN1 mechanism.
Noteworthy the iniziation step which involved the formation of di-
fluoromethyl radical occurs also in the dark, although less efficiently.68
(Scheme 20)
An alternative approach for the synthesis of new Sulfur-(Heteroatom)
Carbon bonds is represented by visible light photocatalysis.69
The importance of the thiol moiety in processes with biological rele-
vance has prompted to develop new methods to track sulphur species
(e.g. thiyl radicals, thiolate). Recently time resolved X-rays absorption
spectroscopy at sulfur K-edge revealed very efficient for this purpose.
Indeed its high spectral sensitivity to different oxidation states and
chemical arounds of sulfur atoms allows to study chemical reactions
involving sulfur functional groups. For example this technique was able
to detect the formation of thiyl radical and two thione isomers obtained
via photoinduced homolysis of the S–H bond of 4-methylthiol (Fig. 15).70
The photoinduced homolytic cleavage of sulfur–carbon bond has been
reported to occur in thymidine phosphorilated aryl sulfides (66a,b).
The so formed thymidine phosphate triester radical (67a,b) undergoes
heterolysis affording thymidine radical cation (68a,b) which is supposed
to be an important intermediate in DNA electron transfer with A–T rich
substrates (Scheme 21).71
2.4 Halogen
Chen and co-workers have developed a mild protocol for perfluoroalk-
ylation reactions irradiating unsaturated substrate and perfluoroalkyl
212 | Photochemistry, 2019, 46, 194–217

Scheme 21
Scheme 22
iodide (RFI) in presence of amine as additive and THF as solvent.

Mechanistic investigation suggested the presence of a halogen-bond
interaction between RFI and amine and THF promote the photo-
reactivty of perfluoroalkyl iodide under low-intensity UV irradiation. This
protocol allowed to prepare perfluoroalkylated alkenes, alkynes and
(hetero)aromatics in modest to good yields. Noteworthy this method can
be used for selective perfluoroalkylation of oligopeptides 69 at the C2
position of triptophan residue (Scheme 22).12
Melchiorre and co-workes have reported that electron-poor organic
halides and chiral enamines can form photoactive electron donor–
acceptor complex which play a key role in the visble light driven stereo-
selective a-alkylation of aldehydes.72 Few examples of photocatalytic and
photoredox catalytic reactions involving halogenated compounds are
reported in literature.73
Photochemistry, 2019, 46, 194–217 | 213

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Photochemistry, 2019, 46, 194–217 | 217

Part 2
Highlights
Design and synthesis of two-photon
responsive chromophores for application
to uncaging reactions
Youhei Chitosea and Manabu Abe*a,b
DOI: 10.1039/9781788013598-00221
Light-responsive materials provide unique and useful techniques for investigating life
phenomena. In this chapter, recent developments on design, synthesis, and application
of new two-photon (TP)-responsive chromophores are summarized: (1) photo-labile pro-
tecting group; (2) molecular design of TP-responsive chromophores; and (3) examples of
TP-responsive caged compounds.
1 Introduction
Light-responsive molecules and materials provide unique techniques for
investigating life phenomena. For example, the method using ‘‘fluor-
escent probes’’ frequently utilized for visualizing bioactive substances is
a standard method in physiological studies.1 The process of ‘‘caging &
uncaging’’ is another powerful tool for investigating the bioactivity of a
specified substance (Fig. 1), which was established by Kaplan, Engel and
their coworkers in the late 1970s.2 The spatiotemporal release of bioac-
tive substances using the photolysis of caged compounds in living tissues
allows us to perform the real-time study of biological dynamics.
The inactivation of bioactive compounds by masking their functional
groups using photo-labile protecting groups (PPGs)3–8 produces caged
compounds, which is the ‘‘caging’’ process. Upon irradiation, PPGs
are removed, reproducing the bioactivity. This unmasking process of
inactivated substances is called the ‘‘uncaging’’ process, by which a local
rise in the concentration of bioactive compounds on the micro to milli-
second time scale becomes possible.9 That is why caged compounds have
been utilized as useful reagents to capture short biological responses of
living tissues.
Since the photo-triggered technique emerged, a large number of
uncaging reactions of bioactive compounds have been attempted using
one-photon (OP) excitation with UV–vis region light. However, UV–vis
irradiation may cause cellular toxicity and light scattering in living
tissues. The physiological applications of caged compounds include
developing new chromophores with two-photon (TP) absorption10
character in the near infrared (NIR) region of light, 650–1050 nm,
because three-dimensionally controlled release of bioactive compounds
a
Department of Chemistry, Graduate School of Science, Hiroshima University,
1-3-1 Kagamiyama, Higashi-Hiroshima, Hiroshima 739-8526, Japan.
E-mail: mabe@hiroshima-u.ac.jp
b
Hiroshima University Research Center for Photo-Drug-Delivery Systems
(HiU-P-DDS), 1-3-1 Kagamiyama, Higashi-Hiroshima, Hiroshima 739-8526, Japan
Photochemistry, 2019, 46, 219–241 | 221

Fig. 1 The process of ‘‘caging & uncaging’’ for physiological study.
is possible deep within living tissue using TP excitation with NIR light. In
this review, typical examples of PPGs and their uncaging mechanisms are
first introduced, and then, recent developments of caged compounds11
with TP-responsive character are shown.
2 Examples of photolabile protecting groups (PPGs) and

uncaging mechanism
The development of new PPGs has been progressing for the last three
decades to improve the uncaging efficiency, light-absorption property,
thermal stability, and water solubility for physiological study. In this
section, beginning from the most used o-nitrobenzyl (oNB)12–14 PPGs such
as o-nitrophenylethyl (oNPE),15–19 nitroindoline (NI),20–26 p-hydroxy-
phenacyl (pHP),27–32 coumarin-4-yl,33,34 and quinoline35–38 types will be
introduced, which are categorized according to the uncaging mechanism:
(1) intramolecular rearrangement type and (2) photo-SN1 type of uncaging
reactions.
2.1 Intramolecular rearrangement type

o-Nitrobenzyl (oNB) and o-nitrophenylethyl (oNPE) PPGs are the most
studied PPGs for protecting carboxylic acids, amides, and other func-
tional groups (Fig. 2a). Since Shlaeger and Hoffmann started caging and
uncaging studies in the 1970s,2 the oNB type of PPG is the most
frequently used for physiological studies. The uncaging mechanism of
NB-based caged compounds is shown in Fig. 2. After photo-induced
intramolecular H-abstraction at the benzylic carbon, the leaving group X
is thermally released via the aci-nitro intermediate. To avoid possible
thermal hydrolysis at the benzylic position of oNB esters, the oNPE type
of PPG was developed. In 1976, Amit and co-workers succeeded in the
preparation of 7-nitroindoline type PPG and reported that free carboxylic
222 | Photochemistry, 2019, 46, 219–241

Fig. 2 (a) o-Nitrobenzyl (oNB) and o-nitrophenylethyl (oNPE) PPGs; (b) coumarin-4yl
methyl PPG.
acids were obtained by UV irradiation of thermally and hydrolytically

stable C–N bonds.19
2.2 Photo-SN1 type

Givens and co-workers first applied coumarin-4yl-based caged com-
pounds to the release of diethyl phosphate in 1984 (Fig. 2b).30 Higher
thermal stability, large molar extinction coefficient in the visible region of
light, and relatively high quantum yield of uncaging reactions are the
advantages while using PPG. In general, the photo-induced release of the
leaving group in coumarin-4yl caged compounds is proposed to occur via
the singlet excited state. After SN1-type of bond cleavage, a nucleophile
such as water traps the intermediary ion pair to release the corres-
ponding bioactive compounds.
2.3 Other types of PPGs developed for UV–vis region

Other examples of PPGs are summarized in Fig. 3. In 1996, Givens and co-
workers discovered the use of the p-hydroxyphenacyl (pHP) group,24
which is thermally stable, highly water soluble, and efficiently under-
goes the uncaging reaction under physiological conditions. In 2002,
Fedoryak and co-workers reported quinoline type PPG using an 8-bromo-
7-hydroxy quinoline (BHQ) based structure.32 Quinoline derivatives have
also been used in the photo-SN1 uncaging reaction. A new thiochromone
Photochemistry, 2019, 46, 219–241 | 223

Fig. 3 Photo-SN1-type of PPGs.
based PPG was developed by Kakiuchi and co-workers in 2008.39 The

caged compounds release acids via intramolecular rearrangement.
For visible-light induced uncaging reactions, many types of PPGs such
as BODIPY,40–42 bimane,43 coumarin (DEDCC),44,45 and carbazole (CBZ)46
derivatives possessing fluorescent characters were developed. Bimane
and CBZ derivatives realized the dual uncaging of carboxylic acids with
two uncaging parts.
3 Two-photon absorption and excitation

As mentioned in the introduction, the 3D-controlled release of bioactive
substances in the deeper parts of living tissues is becoming important for
state-of-the-art research studies in biology. To achieve such activation
processes, TP excitation of chromophores using bio-permeable NIR-light
is needed. In this section, the fundamental knowledge of TP absorption
and their use for uncaging reactions are described. The one-photon (OP)
excitation energy of near IR light (650–1050 nm ¼ 1.9–1.2 eV) is not en-
ough for bond cleavage (necessary for the uncaging reaction). Physicist
Göppert-Mayer first theoretically proposed two-photon absorption in the
1930s47 and it was experimentally observed in 1961.48 If the molecules
absorb two-photons (TP) to generate the same exited state as OP exci-
tation, less harmful low-energy NIR light can be used for molecular
excitation. Another advantage of TP excitation processes is that mol-
ecules at the focal point can be excited by TP excitation, because unlike
linear light-intensity (I) vs. excitation-probability (P) relationship of the
OP absorption in which one photon electronically excites one molecule,
224 | Photochemistry, 2019, 46, 219–241

Fig. 4 Two-photon (TP) excitation versus one-photon (OP) excitation process.
in the nonlinear TP process the excitation probability is proportional to

the square of the intensity (Fig. 4). The ground state (S0) molecule can
absorb two photons to generate the corresponding electronically excited
state. The half energy (hn 0 ¼ 1/2hn) of the corresponding OP excitation
(E ¼ hn) is used for TP excitation to the final state (S1 and S2 for non-
symmetric and centrosymmetric compounds, respectively).
Although a light source with high intensity (typically from a femtose-
cond laser) is required,49 TP excitation is restricted to the focal point of a
lens where light intensity is optically the strongest. These factors allow:
(1) less harmful excitation light to the cellular tissues, (2) higher three-
dimensional spatial resolution, (3) deeper penetration in living cells, and
(4) lower light scattering during TP excitation (Fig. 4)50 The TP uncaging
efficiency du (¼s2ju) can be evaluated using the TPA cross-section (s2)
and uncaging quantum yield (ju). The unit of GM (1050 cm4s per pho-
ton) is in honor of Göeppert-Mayer. A similar equation to qualify OP
uncaging efficiency has been developed: du ¼ eju (e: molar coefficient).
TPA cross-section is described by s2, which corresponds to the molar
coefficient in the OP case.
4 Two-photon responsive chromophores

4.1 p-conjugation
The most common structure of p-conjugated molecule, benzene, pos-
sesses no TP absorption character (B0 GM). Similarly, Weitz et al.
reported in 1964 that naphthalene, which has two condensed benzene
rings, has a small TP absorption character (0.9 GM at 530 nm).51 In the
Photochemistry, 2019, 46, 219–241 | 225

Fig. 5 TP characters of simple p-conjugated molecules.
case of the stilbene molecule, in which two benzenes are linked via
a double bond, significant improvement in TP absorption cross-
section (12 GM at 514 nm)52 was reported. The TP-responsive character
in spite of the relatively small p-conjugated structure prompted us to
design new higher TP responsive chromophores with the stilbene core
(Fig. 5).
4.2 Multi-polar system combining p-conjugation and substituents

Increasing the intramolecular charge transfer character by tuning the
molecular structure by introducing an electron-donating or electron-
withdrawing group enhances the TP cross-section. Dipolar, quad-
rupolar, and octupolar systems are typical examples of increase in the TP
cross-sections of chromophores. This section describes the basic con-
cepts of the TP-induced excited state on the model of chromophores.
4.2.1 Dipolar topology. The dipolar system is generally constructed

by introducing an electron-donating (D) and an electron-withdrawing
(A) group to the end of the chromophore. Theoretically, this TPA cross-
section s2 value is proportional to the product of the squared transition
dipole moment (m) of the chromophore and the squared difference
between the excited and ground state dipole moments (eqn 1). In the
non-centrosymmetric chromophore, electron transition results from
the electron donor to the acceptor moiety, leading to high transition
dipole moment, and thus, high TPA cross-section. Fig. 6 shows an
example of a push-pull substituted stilbene derivative, which exhibits
larger s2 value than that of the parent stilbene due to strong dipolar
character.53 Since the first electronic transition is the charge-transfer
process (HOMO-LUMO) that corresponds to the S0–S1 transition, the
TP absorption maxima are nearly double the wavelengths of the OP
absorption maxima.
m2gi m2if
s2 C (1)
ðEgi =hvÞ1G
s2: TPA cross-section

mgi: transition dipole moment from g-i
mif : transition dipole moment from i-f
G: half-width at half-maximumof the 2PA band
226 | Photochemistry, 2019, 46, 219–241

Fig. 6 TP excitation in a dipolar system.
Fig. 7 TP excitation in a quadrupolar system.
4.2.2 Quadrupolar system. Quadrupolar polarization arises in cen-

trosymmetric structures such as electronically push–push and pull–pull
structures. For example, Fig. 7 shows centrosymmetric analogues based
on the D–p–D stilbene structure. The s2 value of the above is almost
ten times higher (110 GM at 620 nm)54 than that of unsubstituted
E-stilbene (12 GM at 514 nm). The excited states can be considered
using the three states model. The lower one with rigid fluorenyl struc-
ture shows further increase in s2 value through its extended
p-conjugation system (1300 GM at 740 nm).55 In this quadrupolar sys-
tem, the lower and higher excited states are OP and TP allowed, respect-
ively. In many cases, the TP absorption maxima are shorter than twice
the wavelengths of OP absorption maxima.56
4.2.3 Octupolar system. As a different model of multi-polarity, the

trimetric chromophore in Fig. 8 has an octupolar character, composed
of three dipolar branches (D(p–A)3). This molecule also shows sizable
TPA cross-section of about 450 GM at 740 nm.57,58 The excited states
derived from three zwitterionic structures are separated into the high-
est excited state and two degenerate excited states. The two degenerate
states are OP allowed, but with slight TP transition. The highest excited
Photochemistry, 2019, 46, 219–241 | 227

Fig. 8 TP excitation in the octupolar system.
Fig. 9 TP excitation in a diradical system.
state can be reached by TP excitation despite vanishing transition

dipolar moment. The S0–S3 transition is TP allowed in the octupolar
system.53
4.2.4 Diradical character. Nakano and co-workers theoretically

found large two-photon absorption character induced by third-order
nonlinear optical properties in open-shell singlet molecules with diradi-
cal characters. Kamada and Nakatsuji et al. experimentally showed that
Kekulé molecules with phenalenyl-ring possess high two-photon
absorption cross-sections with diradical characters (Fig. 9).59
5 Recent developments in TP uncaging reactions

Discoveries of efficient structural modifications using classic PPGs and
their potential TP activation have contributed to developments in TP
uncaging reactions. In this part, we focus on TP uncaging reports since
2015. Examples of TP-induced uncaging reaction before 2015 are sum-
marized in recent review articles.60–63
5.1 TP responsive PPGs based on classical PPG structure

5.1.1 Cooperative dyads for TP uncaging (o-nitrobenzyl type).
Blanchard-Desce and co-workers selected 4,5-dimethoxy-2-nitrobenzyl
228 | Photochemistry, 2019, 46, 219–241

Fig. 10 TP-uncaging using cooperative dyads.
PPG64 combined with a rigid fluorene core via phosphorus-based clip

for the NIR uncaging unit (Fig. 10).65
The FRET system from the fluorene-cored chromophore promoted the
TP-induced uncaging of acetic acid. Symmetric breaking in the TPA
process was obtained due to its inherent asymmetric structure. Despite
the quadrupolar character based on donor–donor (R ¼ NR2, X ¼ OR) and
acceptor–acceptor (R ¼ SO2CF3) substituted chromophores, all molecules
showed TPA bands (720–800 nm) at twice the wavelength of OPA bands
because TP excitation to the lowest excited state was allowed. The donor–
donor substituted derivative showed the largest TP uncaging efficiency of
du ¼ 0.25 GM (s2 ¼ 310 GM) at 800 nm.
5.1.2 Caged calcium with bis-styrylthiophene backbone (o-nitroben-

zyl type). Calcium ion (Ca21), the second messenger in biology, plays
important roles in the neurotransmission process. Since Ca21 itself can-
not covalently bond to organic chromophores, ethylene glycol tetraacetic
acid (EGTA) is selected as calcium chelator introduced to o-NB type PPG
to realize selective Ca21 binding to the chromophore. Upon photolysis,
the EGTA chelator releases Ca21. The chelator is photolyzed to iminodia-
cetic acid, which has a lower affinity for Ca21. The first TP effective
caged calcium was nitrodibenzofuran-EGTA (NDBF-EGTA) developed by
Ellis-Davies and co-workers in 2006.66 A new symmetric Ca21 caging che-
lator bearing two EGTA units based on the bis-styrylthiophene (BIST)
backbone was recently developed.67 The BIST chromophore provided a
sizable TPA cross-section of 350 GM at 775 nm and the chelator showed
high affinity for Ca21 (Kd 84 nM at pH 7.2, 50 nM at pH 7.35, and
19 nM at pH 7.5). Fast Ca21 release (in o0.2 ms) from BIST-2EGTA was
observed using 2P excitation at 810 nm (Fig. 11).
5.1.3 4-Methoxy-7-indolinyl caged auxins (nitroindoline type). The

plant hormone auxin plays a crucial role in plant growth and develop-
ment. However, the development of caged auxin is limited due to its
instability in higher plant metabolic activities. Hayashi and co-workers
Photochemistry, 2019, 46, 219–241 | 229

Fig. 11 Caged calcium with bis-styrylthiophene (BIST) backbone.
Fig. 12 Caged auxins.
used 2 0 ,5 0 -dimethoxyphenyl-2-nitrobenzyl (DMPNB)-caged auxins to per-

form an artificial gradient of auxin. In 2015, this group developed higher
thermally stable caged auxins and 4-methoxy-7-nitroindolinyl (MNI)-
caged auxins (Fig. 12).68 Light-induced uncaging of indole-3-acetic acid
was demonstrated using an OP laser system. In plant cell experiments,
MNI-caged auxins were more stable than esterase-resistant DMPNB-
caged auxins at high concentrations. Additionally, the photoproducts of
MNI-caged auxins showed non-toxicity to plant cells. These results show
that MNI-caged auxins will be applicable for TP-induced uncaging.
5.1.4 TP uncaging of diethyl phosphate (DEP) and ATP (p-hydroxy-
phenacyl type). Two-photon activation of the pHP group was demon-
strated by Houk, Givens, and Elles for the first time in 2016.69 pHP
diethyl phosphate (DEP) and pHP (adenosine triphosphate) ATP includ-
ing the parent p-hydroxyacetophenone chromophore were examined to
obtain the TPA spectrum (Fig. 13). TP broadband signal (410 GM) was
observed and it was confirmed that both OP and TP absorption were
assigned to the S3 (1pp*) excited state, following the previously known
uncaging mechanism. Monitoring the progress of TP-induced uncaging
of DEP and ATP opened the possibility for two-photon activation of the
pHP protecting group in the range 500–620 nm. The deprotonation of
the hydroxy group of pHP under mildly basic condition extended the
excitation range to longer wavelength. The conjugate bases have red-
shifted absorption near 330 nm that are both one- and two-photon
active. This also indicates the possibility of two-photon excitation in
the range 550–720 nm.
5.1.5 Cloaked caged compounds (coumarin-4yl group). Ellis-Davies
and co-workers developed DEAC450-GABA in 2013 for a highly
230 | Photochemistry, 2019, 46, 219–241

Fig. 13 TP uncaging of diethyl phosphate (DEP) and ATP using p-hydroxyphenacyl type
caged compound.
Fig. 14 A cloaked caged GABA (G5-DEAC450-GABA).
TP-active caged neurotransmitter.70 However, it is concerning that most

caged transmitters are severe antagonists of ionotropic gamma-
aminobutyric acid (GABA) receptors. To overcome this problem, new
‘‘cloaked’’ caged GABA (G5-DEAC450-GABA) bearing fifth generation
(G5) 2,2-bis(methylol)propionic acid dendrimer-conjugated molecules
were invented (Fig. 14).71 Embedding DEAC450-GABA within G5 dendri-
mers reduced antagonism to a very low level. The ‘‘cloaked’’ caged
compound enabled a promising technology for highly TP responsive
uncaging and essentially inert caged GABA towards its target ionotropic
receptors, for the first time.
5.1.6 Three-dimensional control of DNA hybridization by orthog-

onal two-color two-photon uncaging (coumarin-4yl group and o-nitro-
benzyl type). Heckel and co-workers developed 3D control of DNA
hybridization by introducing two types of TP responsive PPG ([7-diethyl-
aminocoumarin-4-yl] methyl and p-dialkylaminonitrobiphenyl group)
into DNA strands.72 The fluorescence-based assay demonstrated TP
uncaging reactions of DNA-1 and DNA-2 based on double-strand dis-
placement in a hydrogel and in neurons. Selective uncaging of DNA-1
Photochemistry, 2019, 46, 219–241 | 231

and DNA-2 was possible by changing the irradiation wavelength
(Fig. 15). 3D control will enable us to investigate more complex
scenarios.
5.1.7 Two-photon photocleavable linker for triggering light-induced

DNA strand breaks in oligonucleotides (coumarin-4yl type). Heckel and
co-workers also developed a TP-induced cleavable linker based on the
7-diethylaminocoumarin structure, which acted as a strand break in
oligonucleotides (Fig. 15).73 To demonstrate TP activity in the strand
displacement assay, a coumarin-linker modified oligonucleotide in
hydrogel was used for TP uncaging using irradiation at 780 nm
(Fig. 16). A new class of DNA decoy (CRDD) modified by the same cou-
marin based photo-trigger was invented for the photochemical regula-
tion of gene expression.
5.1.8 Effect of position isomery on photorelease properties of

aminoquinoline-derived photolabile protecting groups (quinoline type).
To enhance the TPA ability of DMAQ PPG, the substituent effects of
the carboxyl electron-withdrawing group on TP uncaging reaction were
examined by Dalko and co-workers.74 Introducing the substituent at
the C5 position of parent 5-H-8-DMAQ acetate was found to be most
efficient for fragmentation. A variety of groups (5-CO2H-8-DMAQ, 5-
acryl-8-DMAQ, and 5-Ph-8-DMAQ) were introduced to the C5 position.
5-CO2H-8-DMAQ showed roughly six times less TP efficiency (0.11 GM)
at 730 nm than the parent 5-H-DMAQ acetate (0.67 GM). However, the
Fig. 15 Orthogonal two-color two-photon uncaging.
Fig. 16 Light-induced DNA strand breaks in oligonucleotides.
232 | Photochemistry, 2019, 46, 219–241

du value increase followed 5-CO2H-8-DMAQ (0.11 GM)o5-Acryl-8-DMAQ
(0.25 GM)o5-Ph-8-DMAQ (2.0 GM). These results show that tuning of
dipolar character by introducing electron-withdrawing group on the
parent 8-DMAQ platform can promote internal charge transfer (ICT)
and increase the TPA value (Fig. 17).
5.1.9 Photochemical activation of tertiary amines for applications

in studying cell physiology (quinoline type). Several types of tertiary
amines were caged using 8-cyano-7-hydroxyquinolinyl (CyHQ) PPG to
examine photo-activation for biological use (Fig. 18).75 Phillips, Du,
Dore, and co-workers demonstrated the fast release of tertiary amines
(Fu ¼ 0.1–0.5, du ¼ 0.23–0.38 GM) under both OP and TP photolysis con-
ditions (pH ¼ 7.2). The photo-activation of bioactive tamoxifen and
4-hydroxytamoxifen, which are used to temporally regulate gene expres-
sion in Cre-recombinase and CRISPR-Cas9 systems, was achieved by
OP and TP excitation. However, CyHQ protected anilines underwent
photoaza-Claisen rearrangement instead of releasing amines.
Stern–Volmer quenching experiments and ground-state and time-
resolved spectroscopy support the photolysis reaction mechanism that
proceeds via a singlet excited state. This photolysis rate is 70 times
Fig. 17 Photorelease properties of aminoquinoline derivative.
Fig. 18 8-cyano-7-hydroxyquinolinyl (CyHQ) PPG.
Photochemistry, 2019, 46, 219–241 | 233

faster than that of the related BHQ protected acetate, which releases
carboxylates from a triplet excited state with time constant of B5 ns.75
5.1.10 Quinoline-derived two-photon sensitive quadrupolar and

octupolar Probes (quinoline type). Dalko and coworkers synthesized
TP-sensitive quadrupolar and octupolar probes derived from the 8-
dimethylaminoquinoline (8-DMAQ) structure (Fig. 19).76 As quadrupo-
lar probes, donor–neutral–donor (D–N–D) based photolabile quinoline
groups bearing fluorene as central chromophore were selected. Two
probes D–N–D (C5) and D–N–D (C6) designed from fluorene coupled at
C5 and C6-branched 8-DMAQ chromophores exhibited large du values
(2.3 GM (C5) and 1.3 GM (C6)) measured using 1.05 ps pulses with
730 nm irradiation.76
Three probes bearing third-order rotational symmetry were chosen for
the octupolar system (Fig. 20).77 The photochemical study on the effect of
C6, C7, and C8 isomers on TP photolysis was presented. The C6 and C7
isomers mainly resulted in intramolecular cyclization to produce carba-
zole derivatives instead of releasing acid. TP uncaging of the C8 isomer
was observed using 730 nm irradiation with du value 0.67 GM.
5.2 Other types of TP responsive PPGs

5.2.1 Uncaging of GABA and Tryptophan using TP-induced electron-
transfer reactions (4-pyridylmethyl type). Anderson and co-workers
developed a new approach for designing TP responsive PPG based on
Fig. 19 Quinoline-derived two-photon-sensitive quadrupolar probes.
Fig. 20 Quinoline-derived two-photon-sensitive octupolar probes.
234 | Photochemistry, 2019, 46, 219–241

Fig. 21 Uncaging using TP-induced electron-transfer reactions.
photoinduced intramolecular electron transfer from an electron-

donating fluorene chromophore to the electron-accepting pyridinium
unit (Fig. 21).78 Caged g-amino butyric acid (GABA) and caged
L-tryptophan released neurotransmitters with irradiation at 700 nm and
720 nm, respectively. The photochemical release of GABA was clean
(chemical yield of 495%) and the uncaging quantum yield was
determined to be 1% (Fu ¼ 0.01). Caged GABA exhibited high TPA
cross-section value (s2 ¼ 1100 GM at 700 nm) and high TP uncaging
efficiency (du ¼ 10 3 GM).
5.2.2 Cascade photo-uncaging of diazeniumdiolate (o-nitrobenzyl

type and 7-hydroxy-(coumarin-3-yl)methyl type). Diazeniumdiolates
(NONOates) are attractive nitric oxide (NO) donors that can release two
moles of NO under physiological conditions. Caged NONOates are
considerably useful for therapeutic purposes. However, several caged
NONOates cause undesirable uncaging pathways to form carcinogenic
photoproducts instead of releasing NONOates. Mandal, Singh, and co-
workers designed a TP triggerable cascade photocage (ONB-COU-DEA-
NONOate) that protected NONOate without having direct linkage to
PPG and avoided undesirable pathways. Successful uncaging upon OP
and TP irradiation was demonstrated. ONB-COU-DEA-NONOate has
shown potential anticancer activity (Fig. 22).79
6 Design and synthesis of TP responsive PPGs with

stilbene core
To investigate the role of neurotransmitters such as glutamic acid and
calcium ion, we started to design and synthesize new TP responsive caged
neurotransmitters. In particular, a caged compound should possess high
water-solubility, uncaging efficiency, and TP-absorption in the NIR region
for biological application. For example, our target molecules head for s2
value of at least 100 GM in the NIR region and uncaging quantum yield
over 0.05. The extension of p-conjugation enhances TP absorption and
increases hydrophobicity. Considering the balance of TP property and
hydrophilicity, we focus on designing an inherently high TP absorbable
Photochemistry, 2019, 46, 219–241 | 235

Fig. 22 Cascade photo-uncaging of nitric oxide donors.
Fig. 23 Inherent character of trans–cis isomerization of stilbene derivatives.
Fig. 24 Stilbene-based new TP-responsive chromophore.
chromophore in spite of small structure. First, as mentioned in part 4,

trans-stilbene was selected for the basic backbone. However, trans-
stilbene derivatives show cis/trans isomerization via excited states, which
affects the photo-reactivity of the caged compound (Fig. 23).
To avoid this undesired phenomenon, we initially decided to use a
cyclic structure such as 7,8-dihydronaphthalene combined with o-
nitrobenzyl PPG, which also behaved as a strong electron–acceptor. First,
the newly designed parent chromophore 6-(4-nitrophenyl)-7,8-dihydro-
naphthalen-2-amine was computed to predict the TPA spectrum at the
TD-B3LYP/6-31G(d) theory level (Fig. 24).80 A relatively high s2 value of
B150 GM at B810 nm was predicted due to its strong dipolar character.
Based on this result, we began to prepare caged glutamate, which con-
sisted of three units (photolabile protecting group unit, rigid stilbene
core, and amino groups). Water-soluble groups such as carboxylic group
and polyethylene glycol group were introduced to the amino group.
236 | Photochemistry, 2019, 46, 219–241

TP induced release of glutamate was observed and the uncaging quan-
tum yield was unfortunately low (Fu ¼ B0.01).
In 2006, Ellis-Davies and co-workers reported efficient TP-induced
calcium ion uncaging using a 3-nitrodibenzofuran (NDBF) derivative for
the first time.63 Considering its low TP uncaging efficiency (du ¼ B0.6 GM
at 720 nm), we decided to design a second TP responsive chromophore
based on the 2-(4-nitropheyl)benzofuran (NPBF) structure (Fig. 24). As
expected, the computational result of the NPBF chromophore showed
sizable s2 value of 150 GM at 700 nm, which was higher than that of the
NDBF chromophore (75 GM at 600 nm). The caged benzoate (NPBF-BA)
exhibited high du value of 5.0 GM at 740 nm.81 NPBF-EGTA showed a
much higher du value of 20.7 GM at 740 nm.82 Finally, our NPBF chro-
mophore enabled biological application for calcium ion uncaging
(Fig. 25).
Very recently, Heckel and coworkers developed a modified NDBF
chromophore, that is DMA-NDBF core, for a high TP-responsive chro-
mophore for TP-uncaging reaction (Fig. 26).83
Recently, we developed TP responsive coumarin derivatives with rigid
stilbene structure.84,85 The flexibility of the coumarin core allowed
investigation of substituent effects such as donor–p–acceptor and donor–
p–donor type. The NCO (donor–p–acceptor) and ACA (donor–p–donor)
chromophores were designed as dipolar and quadrupolar systems,
respectively. The NCO chromophore with dipolar character was com-
puted to possess a sizable s2 of 150 GM at 700 nm. A computational value
that was more than four times higher was found (700 GM at 650 nm) in
Fig. 25 A new high TP-responsive chromophore, PBF.
Fig. 26 DMA-NDBF.
Photochemistry, 2019, 46, 219–241 | 237

Fig. 27 New TP-responsive chromophore of NPBF and its use for TP-uncaging.
ACA core due to its quadrupolar character. TP photolysis of caged

benzoates NCO-BA and ACA-BA resulted in relatively high du of 3.4 GM at
710 nm and B16 GM at 650 nm irradiation, respectively (Fig. 27).
7 Perspective for future TP responsive PPGs

New design and synthesis of PPGs is ongoing in laboratories, which
contribute to the sustainable development of our society. Recent devel-
opments in TP responsive PPGs have been remarkable. TP activation in
the NIR region renders possibilities for physiological investigation in the
deeper areas of living tissue. Elucidation of biological processes using
photo-triggers is convenient because of the spatiotemporal control of
release of bioactive substances. The principles and strategies described
in this review and new techniques for efficient molecular design will
contribute to future developments of TP responsive PPGs. The photo-
triggers bearing high uncaging efficiency, water-solubility, and TPA
property will open the door to the next generation of photo-chemistry and
reveal unknown biological dynamics.
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Photochemistry, 2019, 46, 219–241 | 241

Controlled release of volatile compounds
using the Norrish type II reaction
Andreas Herrmann
DOI: 10.1039/9781788013598-00242
The Norrish type II photofragmentation of 1-phenylalkan-1-ones (phenyl alkyl ketones) or

2-oxoacetates (a-ketoesters) is useful to control the release of volatile compounds from
surfaces exposed to daylight. The reaction proceeds in the UV-A region of the solar
spectrum and tolerates the presence of oxygen and water. Suitably designed photocages
allow the generation of alkenes, aldehydes, ketones, esters or lactones. Mechanistic
aspects are discussed in view of using the corresponding light-responsive profragrances
or properfumes as delivery systems in practical applications.
1 Introduction
Following an increasing demand by the general public for sustainable
and environmentally friendly processes, research activities in life sci-
ences have been directed towards the use of natural and biocompatible
reagents for molecular transformations of all kinds.1–4 Photochemical
systems using natural daylight as the energy source have attracted par-
ticular interest, not only for the preparation of chemicals,5–7 but also as a
trigger for the controlled release of various bioactive materials.8–15
Volatile signalling compounds, such as fragrances, pheromones or
plant growth hormones, represent a particular class of compounds for
triggered release applications. Because these molecules have to efficiently
evaporate from a surface and travel through the air by diffusion to reach
their target, they are characterised by high vapour pressures (volatilities),
which limit their duration of action. To slow the evaporation of these
volatile molecules and prolong their perception, researchers have
developed less volatile precursors with a selectively cleavable covalent
bond to generate the volatiles in situ.15,16 Because the surfaces from
which volatile compounds evaporate are typically exposed to natural
daylight, light-responsive precursors (so-called photocages) are particu-
larly suitable for their release.12–16
Natural daylight as a controlled release reagent has several advantages.
It is ubiquitously available and the ultraviolet (UV) region of terrestrial
sunlight provides a sufficient amount of energy for the formation,
isomerisation and cleavage of covalent bonds. Because the ozone layer of
the atmosphere efficiently filters wavelengths below about 300 nm,17
photoreactions that are expected to proceed under ambient daylight
conditions have to take place in the UV-A region (typically between 320
and 400 nm). Furthermore, the intensity of outdoor sunlight is subject to
seasonal, daily or even hourly fluctuations,17–19 which has a direct impact
on the efficiency of daylight-dependent processes.
Firmenich SA, Division Recherche et Développement, Route des Jeunes 1, B. P. 239,

CH-1211 Genève 8, Switzerland. E-mail: andreas.herrmann@firmenich.com
242 | Photochemistry, 2019, 46, 242–264

O O
β hν
+
α < 320 nm
Scheme 1 Photochemical decomposition of 2-hexanone (methyl butyl ketone)

described by Norrish and Appleyard.20
To occur in an everyday environment, photochemical reactions have to

work under natural daylight conditions and, furthermore, they must
tolerate the presence of oxygen and water.12 One reaction fulfilling these
requirements is the Norrish type II photofragmentation, which was first
described in the 1930s for the photo-induced fragmentation of alkyl
ketones.20,21 Photoirradiation of 2-hexanone (methyl butyl ketone)
resulted almost quantitatively in the cleavage of the C(a)–C(b) bond to
form acetone and propylene (Scheme 1). The originally reported reaction
occurred at wavelengths below 320 nm, and therefore does not usually
take place under ambient daylight. However, 1-phenylalkan-1-ones
(phenyl alkyl ketones) or alkyl and phenyl 2-oxoacetates (a-ketoesters)
and their derivatives fragment at higher wavelengths in the UV-A region
and are thus readily cleavable upon exposure to natural daylight. Fur-
thermore, they tolerate broad structural variability around the ketone
function, provided that there is at least one abstractable hydrogen atom
in the g-position to the carbonyl group. Depending on the substitution
pattern of these structures, Norrish type II fragmentation can generate
acetophenone derivatives together with alkenes (including exo- and en-
docyclic structures), aldehydes and ketones, or esters and lactones
(Scheme 2), all of which can be volatile compounds with various bio-
logical functions. Most of the delivery systems described so far use the
Norrish type II reaction for the controlled release of fragrances from so-
called profragrances or properfumesy.12–16
Interestingly, despite many similarities between the two reactions, the
mechanistic aspects of the Norrish type II reaction of phenyl alkyl
ketones and a-ketoesters have rarely been directly compared.12,13 In the
following sections, I discuss the general mechanism of the Norrish type II
photofragmentation of phenyl alkyl ketones and a-ketoesters in view of
using this reaction to develop light-responsive precursors for the con-
trolled release of structurally different volatile compounds in practical
applications.
2 Mechanism of the Norrish type II reaction

2.1 General aspects
The mechanism of the Norrish type II reaction of phenyl alkyl ketones
(X ¼ CHR and Y ¼ CHR)22–27 and a-ketoesters (X ¼ CO and Y ¼ O)28–34 as
outlined in Scheme 3 has been studied in some detail in the scientific
y
A fragrance is a single perfumery raw material, and a perfume is a mixture of
fragrances. In analogy, the term ‘‘profragrance’’ should be used if one single
fragrance molecule is generated, and the term ‘‘properfume’’ if several fra-
grances are released from the same precursor simultaneously or in several steps.
Photochemistry, 2019, 46, 242–264 | 243

(a)
R1 R2
O
R3
R'
acetophenones alkenes
(e) (b)
R1 R2 R1 R2 R1 R2
O O O
O Y
X OH
R' R' R'
O aldehydes
variable
benzaldehydes ketones substitution acetophenones aldehydes
(d) R2 (c)
R1 O R1 R2
O O
O O
R' R'
esters aldehydes
acetophenones lactones acetophenones ketones
Scheme 2 Norrish type II-induced generation of acetophenone derivatives and alkenes,

aldehydes, ketones, esters or lactones from phenyl alkyl ketones as a result of different
substitution patterns at X and Y. Formally, the hatched bond between X and Y is cleaved in
the photoreaction and a double bond (dotted line) is formed.
literature. The reaction typically proceeds from the excited n,p* singlet
state of the carbonyl group (A) via efficient intersystem crossing (ISC) to
the corresponding n,p* triplet state (B), followed by g-hydrogen abstrac-
tion (1,5-hydrogen shift) to form a 1,4-biradical (C). The biradical can
either regenerate the starting carbonyl compound or, upon cleavage of
the X–Y covalent bond, form an enol (D) and an alkene (E, if Y ¼ C) or a
carbonyl compound (E, if Y ¼ O) as fragmentation products. Depending
on the structure of X, the enol can then tautomerise to the corresponding
carbonyl derivative (F) as the final product (Scheme 3). To some extent,
d-hydrogen abstraction to yield an intermediate 1,5-biradical can be
observed as a side reaction, for example if conformational constraints
hinder the preferred g-hydrogen abstraction.35
2.2 Substituent effects

While aliphatic ketones undergo the reaction from both excited n,p* singlet
and triplet states of the carbonyl group, phenyl alkyl ketones with ISC yields
that are close to unity react mainly from their lowest excited n,p* triplet
state.23–26 The formation of cyclobutanols (G) as the most important side
products of the photofragmentation (Yang photocyclisation) confirmed
that the reaction passed through the intermediate 1,4-biradical C.36,37
In phenyl alkyl ketones, the lowest excited n,p* and p,p* triplet states
lie relatively close together, with the former being by far more reactive
than the latter.38–44 Electron-withdrawing substituents on the phenyl ring
244 | Photochemistry, 2019, 46, 242–264

O
R1 R1 R1 R1
1O* H R2 H R2 O R2 HOO R2
hν O γ OH O
Y α Y Y Y
X X β X X
R' R' R' R'
A K J
ISC O2
R1 R1 R1
3 H R2 γ-H ab- R2 O R2
O* OH
straction O2 HO O
Y Y Y
X X X
R' R' R'
Photochemistry, 2019, 46, 242–264 | 245
B C L
- O2
R2
R1
O OH OH
HO R1 R2 O R1
Y
X X + Y
X O + X +
R' R' R' Y R' R2
G F D E M N O
Scheme 3 General mechanism for the Norrish type II photofragmentation of phenyl alkyl ketones (X ¼ CHR, Y ¼ CHR or Y ¼ O) and a-ketoesters (X ¼ CO, Y ¼ O).
(R 0 ¼ F or CF3) have been shown to enhance the photochemical reactivity
of the compounds, while electron-donating substituents (R 0 ¼ CH3 or
OCH3) decrease it.40,44 In many cases, the desired photoreaction also
occurred for compounds with the lowest p,p* triplet states if the upper
n,p* triplet states were close in energy and thus partly populated.40 Only a
few substituents (e.g. R 0 ¼ SCH3, Ph, OH or NH2) with very low-lying p,p*
triplet states entirely prevent the Norrish type II reaction.39–42 Some dif-
ferences in reactivity were also observed when the same ring substituents
were placed in the ortho-, meta- or para-position.39–43
Photofragmentation of alkyl a-ketoesters can occur from both excited
n,p* singlet and excited n,p* triplet states,31 while their phenyl analogues
mainly react in a triplet deactivation pathway.30 If abstractable
g-hydrogen atoms are present in the alkyl group of the a-ketoesters, a
certain amount of alkyl chain fragmentation has been observed in
addition to the desired ester chain reaction.31,34,45,46 In these cases,
a-ketoesters with shorter alkyl chains are typically formed, which can
then further react in a second Norrish type II process by g-hydrogen
abstraction at the ester side chain (Scheme 4).34 Because both alkyl and
phenyl a-ketoesters fragment upon irradiation in the UV-A region, broad
structural variability is tolerated on this side of the carbonyl group. In all
cases, the efficiency of the photoreaction depended on the solvent in
which the irradiations were carried out.
Substituent effects at the alkyl chain of phenyl alkyl ketones or at the
ester chain of a-ketoesters can influence the strength of the g-hydrogen
bond to be cleaved and the lifetime of the 1,4-biradical through electronic
and geometric effects.24,30,34,47,48 As geometric requirements, the dis-
tance of the carbonyl group with respect to the g-hydrogen to be
abstracted and their spatial orientation have to be favourable.34,48
Furthermore, arrangements that stabilise the intermediate radical or
that weaken the g-hydrogen bond have a positive impact on the reactivity
of the system. These arrangements are mainly influenced by the choice of
substituents at C(g).49,50
Once the 1,4-biradical has been formed, there a several possibilities for
further reaction (Scheme 3). Reverse hydrogen transfer regenerates the
starting material, Yang cyclisation yields cyclobutanols (G) and frag-
mentation gives rise to the desired Norrish type II products (D–F). The
choice of the substituents at C(a) and C(b) and their stereochemistry
influence the ratio of the triplet 1,4-biradiacal to partition between
Norrish type II fragmentation and Yang cyclisation.51–53
Ra H Rb
O
+ CO +
H R b R a
H H R b hν O
O O H
γ γ
Ra hν ester
+ O O chain
alkyl reaction
O chain O Ra H Rb
reaction hν O
+ CO2 +
O2 OH O
Scheme 4 Alkyl or ester chain fragmentation in aliphatic a-ketoesters by abstraction of

different g-hydrogen atoms at either side of the reactive carbonyl group.
246 | Photochemistry, 2019, 46, 242–264

Overall, the structures tolerate substitution at various positions,
especially at the alkyl chain of phenyl alkyl ketones or at the ester chain of
a-ketoesters, thus allowing the generation of a broad variety of struc-
turally different compounds by Norrish type II photofragmentation.
Nevertheless, substituent effects impact on the ratio of the different
products formed in the reaction and therefore have to be carefully chosen
in order to favour the desired Norrish type II fragmentation over other
side reactions.
2.3 Presence of water

Humidity is ubiquitously present in our everyday life. Therefore, to be
useful as a delivery system under ambient conditions, the Norrish type II
reaction should efficiently proceed in a polar environment or (at least)
tolerate the presence of water. The polarity of the solvent has an impact
on the relative energies of n,p* and p,p* excited states, with p,p* triplets
being stabilised in highly dielectric and hydrogen-bonding media,54,55
and on the solvation of the intermediate biradical.56 Polar solvents
considerably enhance the quantum yields of photofragmentation, and
the solvation of the intermediate biradical has a larger impact on the
photoreaction than do solvent interactions with the excited state.56 The
photoirradiation of phenyl alkyl ketones in water showed that the Norrish
type II reaction (to form compounds E and F) and Yang cyclisation (to
give two isomers of G) are the predominant pathways of photoreaction,
with quantum yields close to unity.57
The reaction of alkyl or phenyl a-ketoesters in polar solvents or in water
has been studied to a much lesser extent than that of phenyl alkyl
ketones. Photoirradiation in alcohols resulted in the formation of
2-hydroxyester H by reaction of the solvent alcohol with Norrish type II
reaction product D (Scheme 3, with X ¼ CO) and of dimer I by dimer-
isation and intermolecular hydrogen abstraction of biradical C from
the solvent alcohol (Scheme 5).58–61 The formation of H is due to the
particular structure of the a-ketoesters, for which compound D (X ¼ CO,
Scheme 3) represents an unstable hydroxy ketene that further reacts by
R1 R1
H R2 R2
O OH OH
R1 R2
O O
+
R' R' R' O O
O O
C D E
ROH ROH
O R1 OH
R' OH
OR
O R2
R'
2 O
O R
R' OH H
O R1
I
Scheme 5 Formation of side products H and I in the Norrish type II photofragmentation

of a-ketoesters according to Scheme 3 (with X ¼ CO and Y ¼ O) in alcoholic solution.
Photochemistry, 2019, 46, 242–264 | 247

elimination of CO to form compound F (X ¼ H) in apolar solvents or to
form compound H in polar solvents. An equivalent to H cannot be
formed from the irradiation of phenyl alkyl ketones. Nevertheless, the
formation of 2-hydroxyesters H implies the formation of one equivalent
of E, which could still be a volatile carbonyl compound to be released.
Compound I (together with other side products that are not shown) has
also been formed in aprotic solution as a result of intermolecular
hydrogen abstraction.32
2.4 Presence of oxygen

Molecular oxygen is known to quench excited singlet or triplet states.62 Its
presence under ambient everyday conditions might thus have an import-
ant impact on the outcome of the Norrish type II photoreaction. Indeed,
oxygen has been reported to quench the triplet state of phenyl alkyl
ketones,63,64 as well as to interact with the 1,4-biradical accompanied by
the consumption of oxygen.64–67 Its interaction with the 1,4-biradical C
resulted in about 25% quenching in the formation of hydroperoxides (J),
e.g. via 1,6-biradical K, and in about 75% quenching in the generation of
cyclobutanols (G) together with alkenes (E) and acetophenones (F) as the
expected Norrish type II fragmentation products (Scheme 3).64 The yields
of cyclisation and fragmentation products have even been reported to
increase in the presence of oxygen,66,67 which would be an advantage for
practical applications, which are necessarily carried out in a non-degassed
environment. Oxygen trapping of biradical C has been suggested to afford
cyclic intermediate L65 which, upon regeneration of oxygen, yields frag-
mentation products E and F. If no oxygen is eliminated from L, a carboxylic
acid (M), an alkene (N) and a carbonyl compound (O) are obtained.68 The
corresponding hydroperoxide J and the cyclic intermediate L have also
been proposed for the reaction of a-ketoesters (X ¼ CO, Y ¼ O) in the
presence of oxygen to account for the formation of benzoic acid derivatives
(M), CO2 (N) and a carbonyl compound (O).33,69 Notably, in the case of
a-ketoesters, fragmentation products E (with Y ¼ O) and O are identical,
whereas in the case of phenyl alkyl ketones (Y ¼ CHR), two different
structures are obtained for E and O.
Environmental conditions such as ambient humidity or the presence of
oxygen influence the Norrish type II reaction of phenyl alkyl ketones and
a-ketoesters, but they do not inhibit the desired photofragmentation. The
reaction should allow for an efficient light-induced generation of target
compounds D–F and M–O, if the formation of side products G, I and J can
be minimised (Schemes 3 and 5). In the following sections, I discuss this
aspect in further detail in the example of practical applications.z
z
Note that most of the practical applications for using the Norrish type II reaction
for the controlled release of volatile compounds were originally described in the
patent literature. However, because most aspects that are relevant for the present
discussion have also been reported in journal articles at a later date, the present
report gives priority to the work published in the scientific literature.
248 | Photochemistry, 2019, 46, 242–264

3 Light-induced release of volatile compounds by the
3.1 Release of acetophenones and alkenes from phenyl alkyl ketones
The most straightforward approach to using Norrish type II photo-
fragmentation for the light-induced release of volatile compounds is
the generation of acetophenones and alkenes, which should be obtained
as a 1 : 1 mixture from structures depicted in Scheme 2a. Several
acetophenone derivatives, such as acetophenone itself, as well as
4-methylacetophenone or 4-methoxyacetophenone, are used as per-
fuming ingredients with pungent sweet and floral odours.70,71 Fragrance
alkenes, such as b-pinene (dry-woody, resinous piney odour), limonene
(sweet citrus smell) or d-damascone (fruity blackcurrant note), can be
generated from photocages 1–4,72,73 and 2-phenylethyl (ethereal rosy and
sweet odour) or decyl vinyl ether (citrusy-waxy, floral smell) and allyl
3-cyclohexylpropionate (sweet-fruity pineapple note) can be released from
properfumes 5–7 (Fig. 1)y.68
The choice of the acetophenone and alkene to be released in the
photoreaction determines the final structure of the precursor. Variable
substitutions at the alkyl part of the ketone have shown that alkenes with
both exo- (()-1) and endocyclic double bonds (2) can be generated.
Irradiation of ()-1 in methanol resulted in an almost complete cleavage
of the photocage to yield acetophenone and b-pinene with an exocyclic
double bond.72 In the case of precursor 2, two chemically different
g-hydrogen atoms can be abstracted to form endocyclic double bonds,
giving rise either to limonene (double bond between C(1) and C(6)) or to
Fig. 1 Properfumes 1–7 studied for the controlled release of acetophenones and differ-
ent alkenes (as indicated) from phenyl alkyl ketones.68,72,73 The wavy line indicates the
C–C bond to be cleaved; the dotted line indicates the position of the alkene double bond
to be formed.
y
The perception of odours can vary from one individual to another. The odour
descriptors used here are those reported in the literature (ref. 70 and 71).
Photochemistry, 2019, 46, 242–264 | 249

iso-limonene (double bond between C(1) and C(2)). Irradiation of 2a
resulted in the exclusive formation of iso-limonene (26%); no limonene
was obtained under these conditions.73 This observation has been
rationalised by preferred hydrogen abstraction at C(2), which allows it to
pass through an energetically favourable, chair-like, six-membered tran-
sition state. Limonene (15%) can be released from precursor 3a by
photochemically generating the iso-propenyl double bond of the mol-
ecule, rather than the endocyclic double bond. In addition to the desired
fragrances, Yang cyclisation products (ca. 45%) were obtained as major
reaction products from the irradiation of 2a and 3a.73 Replacing the para-
hydrogen atom of the phenyl group in 2a and 3a by a methoxy group
slowed the photoreaction (as in 2b) or even fully prevented the formation
of limonene (in the case of 3b).73
The influence of phenyl group substituents on the efficiency of
fragrance release has also been studied in the example of precursors
()-4a–e, which are expected to form propiophenones together with
an enone (d-damascone) as a mixture of cis–trans isomers.72 Again,
g-hydrogen atom abstraction is possible from two different positions,
which results in two structurally different cyclobutanols (()-8 and ()-9,
Scheme 6) upon cyclisation of the intermediate biradical. Obtaining cy-
clobutanols is not necessarily a problem because they are not very volatile
and should not contribute to the odour of the system. Irradiation of an
undegassed solution of ()-4a in methanol afforded the desired fra-
grance and about 30% of the two cyclobutanols, the major component
being the one resulting from hydrogen abstraction from the methyl
group (8). Formation of the fragrance compound with a terminal double
bond was not observed. Substituting the para-hydrogen atom of the
phenyl group with a methyl group (()-4b) gave similar results. However,
one methoxy group in the para-position (()-4c) or two methoxy groups
in the meta- and para-positions (()-4d) suppressed the formation of
cyclobutanol, but increased the time required for full conversion, thus
indicating an increasing p,p* character of the excited triplet states in
()-4c and ()-4d compared with that in ()-4a and ()-4b. Finally,
linking the two methoxy substituents together as a 3,4-dioxolane
group (()-4e) completely stopped the Norrish type II photoreaction.72
These findings suggest that optimum photocages for the controlled
light-induced release of fragrances via the Norrish type II process
have low-lying triplet states directing the g-hydrogen atom transfer to
the desired position, combined with a slow transfer, because in the
presence of oxygen, most triplets are quenched before the transfer takes
place.72
Xenon arc lamps are commonly used in reproducible simulation of
natural daylight irradiance under laboratory conditions, because their
emission spectrum between 200 and 1000 nm correlates reasonably well
to that of outdoor sunlight.74 Irradiation of properfumes 5–7 in different
solvents with a xenon lamp or outdoor sunlight of comparable intensity
released the target alkenes in equivalent yields.68
Detailed analysis of the product distribution obtained after irradiation
of properfumes 5a–c and 6a–c with a xenon lamp in undegassed
250 | Photochemistry, 2019, 46, 242–264

HO O O
R''
HO
R''
R' γ
O O
R'
(±)-8 (±)-9
hν γ hν
Photochemistry, 2019, 46, 242–264 | 251
O O O O
(±)-4a
+ +
not observed δ-damascone
Scheme 6 Norrish type II fragmentation and Yang cyclisation products formed upon photoirradiation of photocage ()-4a in undegassed methanol.72
acetonitrile afforded acetophenones (30–50%) and vinyl ethers (30–50%)
as the major fragmentation products, together with alkyl formates
(5–10%) and alcohols (5–10%) as additional volatile side products
(Scheme 7).68 The formation of all four fragmentation products (with
comparable product distribution ratios) has been observed independ-
ently of the substitution at the phenyl ring, and after irradiation in to-
luene, acetonitrile or iso-propanol. While the formation of alkyl formates
can be rationalised by the rearrangement of cyclic intermediate L, as
outlined in Scheme 3, the occurrence of the alcohols could not be
explained from the general mechanism, but might arise from hydrolysis
of the formates. Both alkyl formates and alcohols are used in per-
fumery,70 and their formation as side products in the Norrish type II
reaction of 5 and 6 is therefore not a general problem for practical
applications. Again, substituting the para-hydrogen atom of the phenyl
moiety of the precursors with 4-methyl or 4-tert-butyl groups (not shown)
resulted in similar product distributions, while the presence of the
4-methoxy group in 5c and 6c slowed the desired photoreaction, giving
rise to lower amounts of fragmentation products.68
Repetitive preparative gas chromatography of an irradiated solution of
precursor 6a led to the identification of cyclobutanol ()-10 and ester 11
as the most important non-fragmented reaction products (Scheme 7).68
Although this has not rigorously been proven, the structural similarity of
11 to hydroperoxide J or intermediates K or L suggests that it might arise
from either one of these species. To my surprise, no reaction products
arising from intermediate L have been reported in the studies with
photocages 1–4. This might be because the authors have not specifically
been looking for them or because the corresponding biradical C is
sterically hindered and less easily intercepted by molecular oxygen to
form species L. In the latter case, the consecutive reaction products
would be formed to a much lesser extent or even not at all.
Headspace analysis is a convenient method to quantitatively assess
the evaporation of volatile compounds from various surfaces with a
minimum effort required in sample preparation.75 This technique has
been used to investigate the impact of environmental light intensity on
the photoreaction in the example of properfume 7, which was exposed
to variable outdoor sunlight for a day in a film of an all-purpose cleaner
formulation (Fig. 2).12,13 On an unclouded day, the light intensity
increases in the morning to reach a maximum around noon and then
decreases again during the afternoon. The presence or absence of
clouds further changes the apparent light intensity to which a sample is
exposed,19 and therefore should also influence the rate of the photo-
reaction. The results of the headspace measurements depicted in Fig. 2,
showed that short-term clouding, which was observed during
the sampling of the second data point, did not significantly influence
the amount of fragrance release. However, longer periods of clouding,
such as occurred in the early afternoon during the sampling of data
points 5 and 6, resulted in a decrease in fragrance release, with the
recorded headspace concentrations correlating to the drop in light
intensity.12,13
252 | Photochemistry, 2019, 46, 242–264

Fragmentation products
O O
hν
O O O HO
R xenon lamp + O
R + R + R
R' R'
5a-c: R = C6H5
acetophenone vinyl ether alkyl formate alcohol
6a-c: R = C8H17
Non-fragmentation products
Photochemistry, 2019, 46, 242–264 | 253
R
O hν O O
O O R
O xenon lamp HO
R +
6a: R = C8H17 (±)-10: R = C8H17 11: R = C8H17
Scheme 7 Products obtained after photolysis of properfumes 5 and 6 in undegassed acetonitrile (R 0 as defined in Fig. 1).68
600 10
500
8
400
6
c x 100 / ng L-1
I x 104 / lux
300 light intensity
4
200 amount of
acetophenone
2
100
amount of
allyl 3-cyclohexylpropanoate
0 0
0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0
t/h
Fig. 2 Dynamic headspace concentrations of acetophenone and allyl 3-cyclohexyl-

propionate released from properfume 7 in a film of an all-purpose cleaner after exposure
to clouded and unclouded natural outdoor sunlight. Reprinted from ref. 12 with permis-
sion from the Royal Society of Chemistry.
3.2 Release of acetophenones and aldehydes or ketones from phenyl

alkyl ketones
Aldehydes and ketones can be released from phenyl alkyl ketones in a
Norrish type II photoreaction if the double bond generated in the process
is not formed between two carbon atoms (as in the case for the structures
depicted in Fig. 1), but between a carbon atom and an oxygen atom.
Examples for general structures that can form aldehydes and/or ketones
upon photolysis are shown in Scheme 2b and c. Again, the carbonyl
compounds are obtained together with acetophenones, and substitution
at both sides of the photolabile carbonyl group influences the outcome of
the reaction.
Aromatic aldols ()-12–()-14 obtained by condensation of propio-
phenone with a fragrance aldehyde or ketone allowed the light-induced
generation of melonal (oily-green, vegetable-like smell), octanal (powerful
harsh-fatty odour) or a-ionone (sweet-floral violet note) (Fig. 3).72
Photoirradiation with a solar simulator in solution generated the
desired carbonyl compounds as a result of the Norrish type II fragmen-
tation, together with cyclobutanols from Yang cyclisation.72 The number
of abstractable g-hydrogen atoms in photocages ()-12–()-14 increased
from one (CH-group in 12) to three (CH3-group in 14), which suggests
differences in reactivity for the three compounds. A strong solvent
dependence for the fragmentation versus cyclisation ratio was found for
the photolysis of ()-12, which formed a higher amount of cyclobutanol
in aprotic solution than did analogues ()-13 and ()-14, the latter of
which mainly generated the desired fragmentation products.72
Phenacyl ethers, such as ()-15 and ()-16 (Fig. 3), have been prepared
from a primary or secondary alcohol (derived from the fragrance alde-
hyde or ketone to be released) by reaction with bromoacetonitrile and
consecutive addition of a phenylmagnesium halide to give ()-15, or by
transacetalisation with a dialkoxyacetophenone to afford ()-16.14 If both
254 | Photochemistry, 2019, 46, 242–264

Fig. 3 Aldol photocages ()-12–()-1472 and phenacyl ethers ()-15 and ()-1614 stud-
ied for the photolytical generation of acetophenones and different carbonyl compounds
(as indicated) from phenyl alkyl ketones. The wavy line indicates the C–C bond to be
cleaved; the dotted line indicates the position of the carbonyl double bond to be formed.
the carbonyl compound and the acetophenone derivative are fragrances,

the perceived odour of the delivery system will depend on the ratio in
which the two components are released. While photolysis of properfume
()-15 is expected to release the fragrance aldehyde Lilials (with a mild-
flowery lily of the valley odour) and the acetophenone derivative in a ratio
of 1 : 1, precursor ()-16 should generate the two compounds in a ratio of
2 : 1. Depending on the preferred final composition of the two com-
pounds, either ()-15 or ()-16 might thus be chosen as the properfume
for a given application.
Photolysis of a solution of phenacyl ether ()-15 in acetonitrile showed
that Norrish type II fragmentation and Yang cyclisation took place to a
similar extent,14 while irradiation of ()-16 resulted in the release of only
low amounts of the desired fragrances (ca. 15% of Lilials and ca. 5% of
acetophenone). Furthermore, the formation of precursor ()-15 as an
expected reaction intermediate was not observed. These results indicated
the presence of other side reactions, which have not been further
investigated. Application studies showed that despite the low amounts
of Lilials released from properfume ()-16, the delivery system still
provided a sufficient long-lasting fragrance effect when compared with
the free fragrance reference.14
3.3 Release of acetophenones and esters or lactones from phenyl alkyl

ketones
Replacing one of the alkyl groups of phenacyl ethers (Scheme 2c) with an
alkoxy group gives access to phenacyl acetals capable of releasing carb-
oxylic esters (Scheme 2d). Furthermore, if both substituents R1 and R2 at
the acetal moiety are linked together with an alkyl chain to form a cyclic
structure, lactones can be generated.14
Phenacyl acetals ()-17–()-20 (Fig. 4) have been prepared to release
Tonalides (with a musky odour) or methyl naphthyl ketone (having an
orange blossom smell) as fragrance acetophenones, together with hexyl
acetate (with a sweet and fruity odour) as a perfume ester (17, 18) and
g-undecalactone (having a sweet, fruity peach-like smell) as a perfume
Photochemistry, 2019, 46, 242–264 | 255

Fig. 4 Phenacyl acetals ()-17–()-20 prepared for the controlled release of acetophe-
nones and different esters or lactones (as indicated).76 The wavy line indicates the C–C
bond to be cleaved; the dotted line indicates the position of the ester double bond to be
formed.
lactone (19, 20).76 Photoirradiation of the properfumes in ethanol

released the different fragrances as expected. Depending on the structure
of the phenyl and alkyl substituents, half-life times of about 15 min up to
1 h were recorded for the photolysis of ()-17 and ()-18, and a few
minutes to about half an hour for ()-19 and ()-20, respectively.76 As
outlined in the mechanistic discussion earlier, both parts of the molecule
have an influence on the rates of light-induced fragrance release, with an
increasing chromophore at the phenyl group decreasing the rate of
photolysis and with lactones being more efficiently released than esters.
Spraying ethanol solutions of the properfumes onto cotton sheets and
exposing them to the light of a tanning lamp released perceivable
amounts of the fragrances, as shown by an olfactive panel evaluation,
thus demonstrating the applicability of the systems as fragrance delivery
systems.76
3.4 Release of aldehydes or ketones from a-ketoesters

Upon photolysis in the UV-A region, 2-oxoacetates (a-ketoesters,
Scheme 2e) release aldehydes and ketones by photofragmentation of the
ester side chain. a-Ketoesters are readily prepared from primary or sec-
ondary alcohols derived from the corresponding fragrance aldehyde or
ketone to be released. In contrast to phenyl alkyl ketones, which require
the presence of an aromatic ring next to the carbonyl group to efficiently
respond to wavelengths in the UV-A region, a-ketoesters tolerate a much
broader structural variability at the photolabile carbonyl group.
Fig. 5 shows some typical examples of a-ketoesters that have been
investigated for the release of volatile aldehydes and ketones by Norrish
type II photooxidation.34,77–80 Both aryl (21–()-23) and alkyl a-ketoesters
(()-24–()-26) have been prepared, releasing different fragrances such
as 2-phenylacetaldehyde (with a pungent-green floral and sweet odour)
(21), (Z)-3-hexenal (a deep-green leafy note) (22) and ()-3,7-dimethyl-6-
octenal (citronellal, a fresh, green-citrusy fragrance) (()-23–()-26).
Photoirradiation of citronellal-releasing profragrances ()-23–()-26 in
solution revealed additional aspects to be considered for the optimisa-
tion of the delivery system for practical applications. First, all compounds
256 | Photochemistry, 2019, 46, 242–264

Fig. 5 Aryl (21–()-23) and alkyl (()-24–()-26) a-ketoesters investigated for the light-
induced release of different aldehydes and ketones (as indicated).34,77,79 The wavy line
indicates the C–O bond to be formally cleaved; the dotted line indicates the position of
the carbonyl double bond to be formed.
generated the desired fragrance aldehyde by Norrish type II fragmen-

tation of the ester chain. However, a series of interesting additional side
products have been identified that result from specific particularities of
their individual structural features (Scheme 8).
Photoirradiation of aryl a-ketoester ()-23 in degassed or undegassed
solution, for example, afforded oxetane ()-27 by the intramolecular
Paternò–Büchi reaction81 of the citronellyl double bond with the carbonyl
group of the ketoester.34,78,79 Oxetane formation has generally been
observed for aryl a-ketoesters with isobutylene side chains of different
lengths; in the case of 22, bearing no isobutylene group in its ester side
chain, cyclol ()-28 was isolated instead.79 The formation of ()-27 and
()-28 arises from charge transfer between the ketoester carbonyl group
in its triplet state and the alkene function in the side chain. The resulting
exciplex can form different biradicals, which then react further to the
oxetane or the cyclol.79 Of two possible regioisomers, only ()-27 was
formed, thus indicating that oxetane formation does not exclusively
depend on the most stable radical that can be formed, but also on sterical
constraints, as confirmed by density-functional calculation of the energies
of the different possible biradicals in their singlet and triplet states.34,79
Oxetane formation was not observed in the photoreaction of alkyl
a-ketoesters ()-24–()-26 under similar irradiation conditions.34 Epox-
idation of the double bond in the citronellyl moiety was the most
important side reaction for these compounds in undegassed solution.
Epoxidation of olefins in the presence of a-ketoacids or esters has pre-
viously been reported, and the epoxide formation has been rationalised
as a photochemical a-cleavage generating an acylperoxy radical, which
then transfers an oxygen atom to the alkene.82 The identification of
epoxidised precursors ()-29–()-31 indicated that the citronellyl double
bond reacts (at least in part) before the desired Norrish type II reaction
(Scheme 8). Furthermore, formation of small amounts of 5-(3,3-dimethyl-
oxiran-2-yl)-3-methylpentanal (epoxy-citronellal) has been observed.
This might arise from the Norrish type II reaction of ()-29–()-31 or by
direct epoxidation of citronellal under the given reaction conditions. Tra-
ces of the epoxidised precursor and small amounts of epoxy-citronellal
have also been identified as side products in the irradiation of aryl
Photochemistry, 2019, 46, 242–264 | 257

Aryl α-ketoesters
258 | Photochemistry, 2019, 46, 242–264
Paternò-
HO O Büchi hν
Ph Ph (±)-23
O ester
O O O chain
(±)-28 (from 22) (±)-27 reaction
Alkyl α-ketoesters epoxi-

hν dation hν
(±)-29 (±)-24
ester ester
chain chain
reaction alkyl alkyl reaction
O
hν chain hν chain
reaction reaction
epoxi-
O hν dation hν citronellal
O (±)-30 (±)-25
ester ester
chain chain
epoxy-citronellal reaction reaction
epoxi-
hν dation hν
(±)-31 (±)-26
ester ester
chain chain
reaction reaction
O O O
O O O
O O O
O O O
(±)-29 (±)-30 (±)-31
Scheme 8 Products identified from the photoirradiation of citronellal-releasing a-ketoester profragrances ()-23–()-26 in solution.34,79
a-ketoester ()-23.34 Nevertheless, the desired Norrish type II reaction to
generate citronellal is the main reaction pathway, yielding 50–70% of the
desired aldehyde, around 1% of the epoxidised precursor and 8–10%
of epoxy-citronellal.34 The final product distribution is concentration
dependent, with increasing profragrance concentrations affording higher
amounts of epoxy-citronellal.
As outlined earlier (Scheme 4), alkyl a-ketoesters with abstractable
g-hydrogen atoms in the alkyl side chain, such as ()-25, also undergo
alkyl chain fragmentation. In this case, a-ketoester ()-24 with a shorter
alkyl chain is obtained, which can then further react by ester chain
fragmentation to form the desired Norrish type II products (Scheme 8).34
The desired fragmentation of the ester chain can be favoured by making
g-hydrogen abstraction from the alkyl part of the a-ketoesters sterically
impossible, e.g. by choosing a cyclopentyl or cyclohexyl residue, as in
profragrance ()-26.
The desired long-lastingness of the fragrance perception of profra-
grances, such as ()-26, in different applications of functional perfumery
has been demonstrated by dynamic headspace analysis.80 The amount of
the unmodified reference fragrance decreases continuously over time,
while that released from the profragrance remains more or less constant
during the measurement.
During storage in aqueous product formulations over prolonged peri-
ods, a-ketoesters partially hydrolyse, which limits their applicability in
some consumer products. To stabilise the precursors against premature
hydrolysis during product storage and to maintain the performance of
the light-induced delivery systems in application, we have investigated
polymer-based delivery systems of a-ketoesters. To achieve this goal,
we have addressed two complementary approaches, namely the
(co-)polymerisation of a suitable a-ketoester monomer into latex nano-
particles and the encapsulation of the profragrances into core-shell
microcapsules.83 The two concepts are outlined in Scheme 9 in the
example of profragrance 21.
Grignard reaction of 4-bromostyrene with dialkyloxalate affords
polymerisable 2-oxo-2-(4-vinylphenyl)acetates, such as 32. Radical co-
polymerisation with methyl methacrylate in the presence of small
amounts of a cross-linker yielded dispersions of latex particles with an
average diameter varying between 200 and 1200 nm.83 Alternatively, 21
has been encapsulated from an oil-in-water emulsion by interfacial
polymerisation into aminoplast83 or polyurea84 microcapsules, with
capsule sizes typically ranging between 10 and 25 mm. On the one hand,
the rather hydrophobic environment within the polymeric systems has
been shown to protect the a-ketoester moiety against hydrolysis. On the
other hand, the delivery systems still efficiently released the desired
fragrance aldehyde when exposed to light.83,84 The polymeric environ-
ment thus does not prevent the Norrish type II photoreaction, and the
targeted fragrance has been released even at low light intensities. Fur-
thermore, the latex particles and microcapsules performed even better
than just the profragrance.83 However, this might be due to specific
Photochemistry, 2019, 46, 242–264 | 259

260 | Photochemistry, 2019, 46, 242–264
Scheme 9 Stabilisation of a-ketoester profragrances against hydrolysis in application by (co-) polymerisation into latex nanoparticles and encapsulation into core–
shell microcapsules.83,84
conditions of the application, such as a different amount of deposition of
the various delivery systems on the target surface.
Studies with a-ketoester-containing polyurea microcapsules revealed
that the photoreaction taking place under UV-A light is sufficiently fast
that the gas (CO and/or CO2) formed as a side product in Norrish type II
fragmentation (see Scheme 4) generated overpressure inside the cap-
sules, which extended or cleaved the capsule wall and resulted in a burst
release of the capsule content (Scheme 9).84 This observation consider-
ably increases the potential of the present delivery system, because it not
only allows the light-induced controlled release of aldehydes or ketones
from the profragrance, but it also allows the release of any active com-
pound that has been co-encapsulated with the ketoester.
4 Conclusions and learnings

We have seen that the Norrish type II photofragmentation is a robust
process that readily occurs under everyday conditions in our environ-
ment. The reaction proceeds in the UV-A region of the sunlight spectrum.
Its speed directly depends on the apparent intensity of the UV-A light and
is influenced by fluctuations, such as seasonal changes, variable daylight
intensities and the presence or absence of clouds. The reaction performs
in an aqueous environment and in the presence of oxygen, both of which
have an impact on the mechanism of the photodegradations, but do not
prevent the potential practical use of the system. Although light-induced
delivery systems based on the Norrish type II reaction have mainly been
described for the controlled release of fragrances, they can theoretically
be used to form any kind of bioactive material, such as pheromones,
plant growth hormones, agrochemicals and many others, as long as these
materials are generated on a surface from a suitable precursor that is
exposed to ambient daylight.
Both phenyl alkyl ketones and a-ketoesters work well, and their
structures can be varied to a large extent to enable the release of different
types of compounds, such as acetophenones and aldehyde or carboxylic
acid derivatives on the one hand, and alkenes, aldehydes, ketones, esters
or lactones on the other hand. Structural variations at either side of the
molecule have an important impact on the desired photoreaction, in
particular if additional side products are formed. Understanding the
mechanism of the photoreaction under environmental conditions is
therefore an important aspect for the design of efficient delivery systems.
The formation of side products is not necessarily a problem, e.g. if they
are fragrance molecules themselves or if they are non-volatile and thus
have no inherent smell. In some cases, the formation of particular side
products might have to be avoided, which then requires modification of
the precursor structure. Considerable effort has been made to optimise
photocages for an efficient controlled release and to understand the
structural and environmental impacts on the Norrish type II process by
identifying and quantifying side products in order to favour or disfavour
their formation.
Photochemistry, 2019, 46, 242–264 | 261

Nevertheless, the successful development of delivery systems for
practical applications with a commercial purpose implies consideration
of specific additional restrictions. These restrictions, which might still
cause the failure of the delivery system in practice, have not been dis-
cussed in much detail here. In particular, the rates at which the com-
pounds need to be released and their absolute concentrations vary from
one application to another. This implies that a system that performs in
one application does not automatically work in another, and that indi-
vidual adaptations are usually required. Furthermore, biodegradability,
bioaccumulation, toxicological and economic considerations (which have
in part been addressed in a previous report)15 are decisive parameters for
the successful development of delivery systems for practical use. Despite
the knowledge acquired so far, it is not possible to easily predict whether
a given structure will work in application or not. As is usually the case in
science, it will be the experiment that determines the success or failure of
a given technology on its way to the marketplace.
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264 | Photochemistry, 2019, 46, 242–264

Recent advances in the design of
light-activated tissue repair
Christopher D. McTiernan,a Justina Pupkaite,a
Irene E. Kochevar,b Erik J. Suuronena and
Emilio I. Alarcon*a,c
DOI: 10.1039/9781788013598-00265
Fundamental concepts, key mechanisms, and future challenges in light-activated tissue

repair techniques including photo-tissue bonding, laser tissue welding, and in situ photo-
polymerization are reviewed in this chapter. We aim to present a fresh perspective on the
fundamental concepts of the photochemistry involved that will allow further advancement
in the development ofsafe technologies and efficient clinical translation.
1 Overview of light-activated tissue bonding

Light-initiated in vivo tissue bonding has the potential to address needs in
many medical treatments. This chapter will discuss three distinct
approaches to the use of photocrosslinking in medical applications: Laser
Tissue Welding (LTW),1 Photochemical Tissue Bonding (PTB),2 and in situ
photo-polymerization (PHP). While all of these techniques involve the
use of light to generate cross-links in vivo, LTW and PTB are considered
to be tissue adhesive technologies, whereas the more general photo-
polymerization terminology can be used to describe light-mediated
methods for the generation of matrices and scaffolds which can both
support and promote endogenous tissue regeneration (see Fig. 1).
LTW involves the use of high energy lasers, and in some cases dye
molecules, to aid in laser light absorption to raise local temperatures and
denature extracellular matrix (ECM) proteins to create a weld. This differs
from PTB, in which the end result is the creation of covalent crosslinks
between the proteins at or near the tissue surface. Typically, visible light
absorbing molecules have been utilized for this technique, with Rose
Bengal,3–6 and Riboflavin5,7,8 being the more popular choices. While the
precise mechanism by which PTB forms these crosslinks is still up for
debate, it is commonly accepted that these linkages are formed through
reactions with singlet oxygen or other reactive oxygen species that are
generated upon the sensitization of the excited chromophore.9 One of the
main advantages PTB has over LTW is that the heat damage caused to
surrounding tissues is alleviated by replacing the photo-thermal reaction
with photochemical ones.
a
Division of Cardiac Surgery, University of Ottawa Heart Institute, 40 Ruskin Street,
Ottawa, Ontario K1Y 4W7, Canada. E-mail: Ealarcon@ottawaheart.ca
b
Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard
Medical School, 40 Blossom Street, Boston, Massachusetts 02114, USA
c
Department of Biochemistry, Microbiology, and Immunology, University of Ottawa,
Canada
Photochemistry, 2019, 46, 265–280 | 265

Fig. 1 Schematic representation for the three-main light-activated processes used for
in situ tissue repair: laser tissue welding (LTW), photobonding tissue (PTB), and photo-
polymerization (PHP). The main operative mechanisms for each strategy are also shown.
While PHP is not an adhesive technique it has found an important role

in tissue repair and regeneration through its ability to produce polymeric
biomimetic matrices. Owing to its unique spatial and temporal control
plus the ability to adopt complex shapes, its minimally invasive in situ
implantation, ease of application, ability to entrap a variety of molecules,
drugs, or cells, and finally the ability to store the various components
of the mixture under ideal conditions until they are ready to be mixed
and applied; PHP is a powerful tool in biomaterial design and
implementation.
2 Sutureless tissue bonding: from laser tissue welding to

tissue photobonding
The concept of using light as a replacement for stitches was first pro-
posed in the late 1970s, when Jain and Gorisch reported employing a
laser to close incisions made in blood vessels of rats.10 The advantages of
this procedure include the quick creation of a water tight seal, and the
ability to close very small incisions easily. Additionally, this procedure
has an absence of foreign materials, such as sutures or staples, which is
important in reducing inflammation and potential scarring. However,
this type of laser tissue welding is a thermal process, wherein light
absorption by tissue components results in heating. In this process,
the extracellular matrix (ECM) components undergo thermal changes,
followed by cooling and interlinking of the altered collagen fibers, which
leads to bonding of the molecules on the opposing edges of the wound or
incision.11,12
An improvement to the laser tissue welding procedure was the intro-
duction of a soldering agent, which may be a protein,13 dye,14 or a dye-
protein solution.15 Akin to the soldering of metals; the dye-protein solder
is applied to the wound and laser light is used to locally heat and seal the
solder to the edges of the wound. This method provides a few advantages,
266 | Photochemistry, 2019, 46, 265–280

compared to classical laser welding. Firstly, it lowers the risk of thermal
tissue damage as the dye molecules preferentially absorb light, resulting
in local heating of the solder solution. Secondly, the superior absorption
property of the solder allows lower laser irradiation dose, thus reducing
the time of exposure and/or laser power required. Thirdly, using a dye
solution with known absorption parameters and thermal properties
makes it easier to estimate laser dose requirements for reproducible
results. In addition, the protein creates a solder that can fill the gap
between and around the edges of the wound and provide additional
bonds, thus increasing the strength of the bonded tissue. The downside
of the laser soldering method is the requirement to introduce a foreign
material, which may create an unexpected reaction or toxicity, although
published reports indicate that the dye and protein solutions commonly
used in this procedure are safe.
A number of dye-protein solders have been reported. The initial report
by Oz et al. described the use of fibrinogen mixed with indocyanine green
(ICG) dye (lex ¼ 805 nm) in a rabbit model of vascular anastomosis.15
Over a period of 90 days,the dye-protein solder did not induce any
apparent foreign body response and the fibrinogen was infiltrated by
cells and almost completely degraded. Albumin and ICG solutions
have also became a popular solder choice to weld cartilage,16 blood
vessels,17–19 and urinary tract.20 A few other dyes, such as methylene blue
(lex ¼ 670 nm) and Janus Green (lex ¼ 665 nm) have also been used in
combination with albumin to perform vascular anastomosis,21 and
corneal incision repair,22 respectively.
The bonding caused by thermal denaturation processes and sub-
sequent interlinking of ECM proteins does not reliably produce covalent
crosslinks although they may sometimes form.23,24 Introducing covalent
bonds would arguably result in stronger tissue bonding. One of the first
reports of photochemical laser welding (nowadays also termed PTB25)
was made by Judy et al., in the early 90s.26 In this case, laser-excited dye
molecules interact with oxygen creating reactive oxygen species and
radicals, which in turn interact with the proteins in the ECM resulting in
covalent crosslinks bonding the edges of the wound. Thermal denatur-
ation of ECM components is not required. This allows for use of a lower
laser irradiation dose, protecting tissues from thermal damage. PTB
can even be achieved using light-emitting diode (LED) illumination,27
which admittedly requires longer exposure times but reduces cost and
can be done with simple LED equipment. However, while PTB eliminates
the concern of thermal tissue damage, it introduces additional con-
siderations regarding potential damage caused by excess reactive oxygen
species and radicals produced by light-activated sensitizers.
A few photoactive molecules have been reported as PTB agents. Judy
et al. introduced a 1,8-naphthalimide dye (lex ¼ 420 nm), which they used
to bond two sheets of ex vivo porcine dura mater,26 as well as ex vivo
human cartilage.28 The bonded tissues demonstrated superior shear
strength compared to thermal laser welding. Preclinical large animal
studies were also carried out. A sheep model was used to demonstrate
photochemical bonding of meniscal tears and articular cartilage defects.
Photochemistry, 2019, 46, 265–280 | 267

No adverse effects were observed within 6 months post-operation, and
histology showed cell recruitment and ECM deposition. Additionally,
the animals that received the photochemical bonding operation showed
no limping and were exercising similarly to healthy controls within 2–3
weeks post-operation.29 However, there does not appear to be any
published data of clinical studies using this dye.
The use of the xanthene dye rose Bengal (lexcE532 nm RB) excited by
green light (532 nm) as a tissue photobonding agent was first used to seal
incisions in cornea.5 Since then this approach has been used to seal
wounds in vivo in several tissues including skin,30 cornea,31 and vocal
cords.32 In addition, PTB using RB and green light has been demon-
strated in vivo in small and large animals to reattach severed nerves,33
blood vessels,4 and tendons.34 Other in vivo studies have shown that PTB
can be used to seal wounds by bonding a biological membrane over
wounds in cornea6 and bowel.35 A 30-patient clinical study clearly
demonstrated that RB/green light PTB sealed skin wounds effectively
and with substantially reduced scarring and greater patient satisfaction.36
The major concern regarding RB is that it demonstrates high cyto-
toxicity in vitro.37,38 However, this effect does not appear to be present
in vivo under conditions used for PTB and RB use in the clinic as a
diagnostic tool in ophthalmology was approved long before its intro-
duction as a tissue bonding agent.39 Different in vitro and in vivo cell
responses were investigated by Yao et al.,38 who found that in vivo PTB
requires much higher irradiance compared to all prior studies investi-
gating RB cytotoxicity in vitro. Higher irradiance results in singlet oxygen
depletion reducing the consequent cell death. Additionally, cells grown
in a monolayer in vitro are affected by the lack of surrounding 3D matrix.
One of the downsides of using RB or a different photosensitizer solu-
tion of low viscosity is that the edges of the wound or incision need to be
pressed together closely so that the ECM proteins on opposite sides are in
contact in order for them to be close enough to form covalent bonds. This
is not often possible as most wounds are not precise surgical incisions.
As such, the next logical step is to introduce a filler, akin to the protein
solutions used in laser tissue soldering, except in this case the high
viscosity polymer solution needs the ability to form covalent crosslinks
via a sensitizer-mediated light activated mechanism. A few different
approaches have been proposed. One of the earliest attempts was pub-
lished in the 90s shortly after the introduction of the concept of PTB: the
Ernest group used fibrinogen and riboflavin (lexE445 nm) to repair
corneal incisions.40 They also showed that photochemical bonding
resulted in higher eye burst pressure than the laser soldering method.7
Our group has proposed the use of methacrylated collagen and RB
solution as a light-activated agent and demonstrated its use on a mouse
skin incision model.27 Elvin et al. created a tyrosine-rich protein photo-
bonding agent crosslinked with [RuII(bpy)3] (lexE450 nm). They used
fibronectin41 and modified gelatin.42 Although the use of a ruthenium
catalyst raises toxicity concerns, in vitro studies demonstrated no sig-
nificant toxicity on murine fibroblast cells and human chondrocytes,
when [RuII(bpy)3] concentrations necessary for cross linking of gelatin
268 | Photochemistry, 2019, 46, 265–280

sealant was used. Additionally, in vivo studies using sheep lung as well
as rabbit and canine colon models demonstrated air- and water-tight
sealing of incisions and no adverse effects were observed for the duration
of the studies (2 weeks and 7 days, respectively).43 Another alternative
to solve the low viscosity problem was proposed by Lauto et al., who
introduced a photoactive chitosan sealant in the form of a thin sheet,
doped with ICG.44 After applying the sheet in such a way that it overlaps
with the tissue on both sides of the incision, the sheet is irradiated to
form a tight seal. This method was used to perform light-activated repair
of sciatic nerves45 and intestines.46 A variation of the chitosan film doped
with RB was also used with success in vivo for nerve anastomosis in a rat
model and showed superior healing compared to sutures during the
observation period of 12 weeks.47
Despite many promising preclinical animal studies demonstrating
efficient photoactivated wound closure and no immediate adverse effects,
only a few laser welding/soldering and PTB methods have been investi-
gated in terms of long-term in vivo effects. Even fewer have progressed to
clinical application. In two of the earliest trials, albumin and ICG solu-
tions were used in clinical studies for urinary tract reconstruction and
hypospadias repair.20,48 In these trials, patients were followed for up to 9
months and 12 months, respectively. No complications were observed in
the first trial which was a small first-in-human study, while the second
study showed that laser soldering surgery decreased the complication
rate by 2-fold compared to traditional surgery, in addition to decreasing
surgery time. More recently, PTB using RB solution was used to close skin
wounds.36 No phototoxicity was observed and there was only minimal
inflammation. After 6 months, photobonded tissue showed less scarring
than traditionally sutured wounds.
3 Photo tissue bonding (PTB)

Rose Bengal (RB), a member of the halogenated fluorescein family, whose
properties have been exhaustively investigated in aqueous solution,49,50
and also clinically used for assessing ocular surfaces,51 is among the
most archetypical dyes used in PTB. Typically in rose Bengal-PTB, an
aqueous solution of the dye is applied directly to the tissues to be bound,
they are then placed in contact and irradiated with green light for a few
minutes. A major advantage of RB-PTB, and of PTB in general, is the
minimal scarring and fibrosis when compared to traditional suturing
reported for wound sealing of skin, cornea, tendon, blood vessels, and
even nerves.4–6,35,36,52,53 Using rose Bengal for PTB reactions also results
in reduced inflammation of tissues, which has been coined as ‘‘photo-
chemical tissue passivation.’’54 Rose Bengal-PTB has also been used for
increasing the strength and stiffness of tissues allowing them to tolerate
shape changes as in the case of certain cornea diseases and arteriovenous
fistulas.55–58
As hinted above, Rose Bengal is commonly used as a photosensitiser
for singlet oxygen (1O2) generation for chemical transformations.59 Some
studies have suggested that the observed phenomenon is due to this
Photochemistry, 2019, 46, 265–280 | 269

reactive oxygen species reacting with histidine residues to form protein–
protein crosslinks.60 The ultimate goal of PTB is rapid wound closure,
which directly involves proteins of the extracellular matrix (ECM) and
radicals generated upon dye excitation, like singlet oxygen. Thus,
photophysical models aimed at understanding the behaviour of dyes
must consider alterations in dye photochemistry upon its interaction
with proteins. In the case of RB, we, and others, have demonstrated that
this dye readily binds to a variety of proteins such as albumin, collagen,
hemo-proteins, lactoferrin, lysozyme, and transferrin.9,61–65 For PTB,
binding of RB to type I collagen is most relevant as it is the most abun-
dant protein in connective tissues such as skin, a typical target of PTB.9,62
Using a short peptide sequence that mimics type I collagen, we recently
demonstrated that the binding of RB to collagen leads to changes in the
dye’s photophysical properties.9,62 Such changes were found to be linked
to ground state interactions between the dye and the protein structure,
with terminal amino groups of lysine and hydroxyproline residues
involved in 1 : 1 binding of RB.9,62 Furthermore, multi-cooperative bind-
ing of RB to the protein was observed. In contrast to the multi-occupation
of RB found in other proteins such as human serum albumin,61,63 the
binding observed for collagen was unique as it involved dye aggregation
promoted by the first dye molecule bound to the protein followed by p–p
stacking for the subsequently bounded dyes. This particular type of dye
association has important implications on the photophysical properties
of the photosensitizer (see Table 1).
Although the photo-behaviour of a given dye within a complex bio-
logical matrix will vary depending on the photophysical properties of the
dye; some lessons can be learned from our recently reported study on RB
incorporated within a 3D collagen matrix. Table 1 contains selected
photophysical and photochemical properties of the dye when incorpor-
ated within a 3D type I collagen matrix (bottom row). Firstly, changes in
the absorption spectra of the dye account for modifications in the elec-
tronic configuration of the dye upon collagen binding. For the case of RB-
3D-collagen there was a red shift of E7 nm in the absorption maximum
Table 1 Selected photophysical properties for rose Bengal measured in aqueous

solutions or in the presence of proteins like human serum albumin and type I collagen.
Data compiled using a collagen matrix containing rose Bengal is also included. Original
data taken from ref. 9 and 61–63.
lnma jF jT tT (ms) jD tD (ms)

Aqueous solutions 549 0.018 0.90 40 5.0 0.75 66 3.0b
Human serum albuminc 563 0.12 E0.45 130 10 0.33 68 5.0d
Type I collagenc 559 nd nd nd nd nd
Type I 3D-collagen matrix 556 E0.004 e
E3.0 e
E10
a
Absorption maximum in nm. nd ¼ not detectable.
b
Measured in deuterium oxide.
c
Measured at occupation numbers of 1.0 (1 dye per protein).
d
Long-lived component for 1270 nm emission.
e
Quantum yields calculation was not possible due to scattering interferences derived from
the nature of the sample.
270 | Photochemistry, 2019, 46, 265–280

alongside a 4.5 times decrease in fluorescence quantum yield. Mean-
while, the triplet lifetime of the dye was shortened upon incorporation
within the 3D matrix by E13 times, and the singlet oxygen lifetime was
measured as E6 times shorter than for what is measured in fluid solu-
tions (see Table 1). These changes are attributable to fast quenching
mechanisms taking place in the RB-collagen, most likely due to the for-
mation of intra-protein aggregates, which are known to reduce the triplet
lifetime. Reduction in the singlet oxygen lifetime can be linked directly to
how the intrinsic 3D nature of the matrix affects the oxygen mobility.
Additionally, the interactions between RB and the 3D collagen matrix
result in a considerable reduction in the rate of photodegradation for the
incorporated dye. While one could blindly extrapolate the solution based
findings to in vivo tissue settings,4–6,34–36,52,53,55 the findings using the 3D
collagen structure reveal the relevance of considering the interaction
between RB and collagen as a key factor in dictating the photophysical
and photochemical performance of the dye. However, when making such
assumptions it is also important to take into consideration that the
reactivity of singlet oxygen in solution and tissue may be markedly dif-
ferent as the rigidity of the protein chains, oxygen depletion within the
tissue, and radical migration within the protein backbone could have an
effect on this diffusion controlled process.
4 Recent advances in in situ photo-polymerization

Recently, there has been a push to develop techniques and materials
which are amenable to the in situ photo-polymerization of biomaterials
and biomimetic matrices. In general, photo-polymerization is a light-
mediated technique that uses light to both initiate and propagate a
polymerization reaction to give rise to either linear, branched, or cross-
linked polymer structures. Light-mediated polymerizations have found a
role in a variety of areas, such as in photolithographic resists in opto-
electronics,66 non-linear fibre optic communications and data storage,67
coating and painting industries,68 as well as in three-dimensional litho-
graphy;69 however, its use in the production of biomimetic matrices has
somewhat lagged behind. This is not to say there has not been much
research in the use of light as a tool to polymerize/cross-link materials
in situ, the problem is that much of the developed technologies have not
yet made their way to the clinical setting. In the next few sections, we will
discuss some of the key features that make light an interesting and useful
tool in the development of biomimetic matrices.
There are many reasons photo-polymerization has found a place in the
production of polymeric biomimetic matrices. Some of these ideal
qualities relate to the spatial and temporal control of the process, the
ability to easily generate complex shapes, and the ability to perform the
polymerization in situ. These properties allow for matrix production and
implantation using minimally invasive techniques, with ease of appli-
cation, the ability to entrap a variety of molecules, drugs, or cells, and the
ability to store the various components of the mixture under ideal con-
ditions until they are ready to be mixed and employed. It is for these
Photochemistry, 2019, 46, 265–280 | 271

reasons that one will find photo-polymerized materials being used in
areas such as tissue engineering,70 cell encapsulation and drug
delivery,71 as well as restorative biomaterials such as dental fillings.72
4.1 Components of photopolymer systems

Typically, photopolymerization technologies comprise a polymerizable
monomer, a photoinitiator, and an appropriate light source. These 3 key
components can be mixed alongside other cross-linkers, bioactive mol-
ecules, cells, and a variety of supplements to give rise to matrices that are
best suited for its particular function and placement within the body.
4.1.1 Light source. A variety of different light sources have been
employed in the photopolymerization of matrices for tissue engin-
eering. While historically UV, halogen, and plasma arc lamps, as well
as femto-second pulsed lasers have been the light source of choice,
light emitting diodes (LEDs) are quickly gaining popularity as they are
a relatively cheap and widely available in a variety of colours meaning
it is easier to match the absorption spectrum of the chromophore/
photoinitiator with the emission spectrum of the light source.73 The
emission spectrum of the LED light sources also tends to be quite nar-
row, and as such, through the use of simple filters one can easily
ensure that only the photoinitiator is being excited, thereby decreasing
the likelihood of side reactions and photodegradation of other com-
ponents of the matrices. While both UV and visible wavelengths of
light can be employed in the in situ photopolymerization, it is import-
ant to realize that the high energy UV photons do not have the ability
to penetrate tissues to any significant depth and can actually result in
tissue damage. Visible light photons are typically safer for these types
of applications, and as one approaches the Red/Near-IR region of the
spectrum the photons tend to have more penetrating power as there
are typically less interfering absorbers in this region.74
4.1.2 Photoinitiator/chromophore. The photoinitiator or chromo-
phore in these systems is the molecule which is responsible for absorbing
the incident light and generating the reactive intermediates that will initi-
ate the polymerization reaction. A variety of different molecules have been
employed as photoinitiators for in situ polymerizations; Table 2 lists some
of these photoinitiators along with a brief description of the components
of the employed system as well as target tissue/organ of the resulting
biomimetic matrix. While for the most part these photoinitiators are
UV absorbers, there has been a recent push to develop systems which
absorb in the visible light spectrum.75,76 Typically, these systems will
employ tertiary amines as sacrificial electron donors.77 Due to the fact
that there are so many different types of photoinitiatior systems, it can be
beneficial to classify these systems according to (i) the type of polymeriza-
tion they bring about (e.g. free radical,76 anionic,78 cationic79), (ii) the
number of components required to initiate polymerization (e.g. one-, two-,
n-component system), and (iii) the mechanism of initiation.80
Photoinitiation of the polymerization can take place either directly
through excitation of the photoinitiator, or indirectly through excitation
272 | Photochemistry, 2019, 46, 265–280

Table 2 Summary of studies employing in situ photopolymerization to generate scaffolds/biomimetic matrices.
Photoinitiator Light Monomer Additive Target tissue/model References

s
Irgacure 184 UV light Methyl methacrylate Dermis 95
Eosin Y Visible light PEG-tetra-acrylate/PEG-tetra- N-vinylpyrrolidone (NVP) Bone 96
acrylamide/PEG-tetra-allylether/
PEG-tetra-methacrylate and DTT or
bis-cysteine containing peptides
Monomer UV light p-Azide benzoic acid and lactobionic — Dermis 97
acid modified chitosan
2,2-Dimethoxy-2-phenyl- UV light PEG diacrylate and acrylate modified 1-vinyl-2-pyrrolidinone Multiple tissues 88
acetophenone (DMPA) RGD peptide
2,2-Dimethoxy-2-phenyl- UV light Acrylate and lactic acid modified N-vinylpyrrolidone (NVP) Rat cecum abrasion model 98
acetophenone (DMPA) hydroxy PEG and rabbit uterine horn
ischemia model
2,2-Dimethoxy-2-phenyl- UV light Lactic acid modified di(ethylene NaCl crystals Cranial defect 93
acetophenone (DMPA) glycol)
Camphorquinone Visible light Acrylate functionalized bovine Type I Triethanolamine Transdermal – 94
Photochemistry, 2019, 46, 265–280 | 273
Collagen Mandibular Joint

1-Hydroxycyclohexyl phenyl UV light Poly(ethylene oxide)-dimethacrylate — Dermis – Athymic mice 99
ketone and poly(ethylene oxide)
2,2-Dimethoxy-2-phenyl- UV light Methacrylated sebacic acid and — Bone – Sprague Dawley 100
acetophenone (DMPA) poly(carboxyphenoxy hexane) Rat
Eosin Y Visible light PEG core with flanking lactic acid N-vinylpyrrolidone (NVP) Vasculature – Sprague 101
oligomer and terminal tetra- and Triethanolamine Dawley Rat
acrylate functionalities
2,2-Dimethoxy-2-phenyl- UV or Visible Dimethacrylated anhydride — Bone – Sprague Dawley 102
acetophenone (DMPA) or Light monomers (Sebacic acid, 1,3-bis- Rat
Camphorquinone or Ethyl-4- (p-carboxyphenoxy)propane,
N,N-dimethylaminobenzoate 1,6-bis(p-carboxyphenoxy)hexane
2,2-Dimethoxy-2-phenyl- UV light PEG core with flanking lactic acid N-vinylpyrrolidone (NVP) Vasculature – Sprague 103
acetophenone (DMPA) oligomer and terminal tetra- Dawley Rat
acrylate functionalities
of a photosensitizer that works in conjunction with another molecule(s)
that can act as initiator and bring about the required initiating species. In
the direct photoinitiation technique the initiating species is derived upon
excitation of the photoinitiator. In some instances, this process can be
catalytic in nature (that is the photoinitiator is not consumed during the
initiation process and is turned over through some type of catalytic cycle).
While under catalytic conditions the required loading of photoinitiator is
significantly reduced. In some instances where the initiator is consumed
(i.e. Norrish type cleavage),73 a chain reaction/propagation can occur that
increases the efficiency of the process; thus equimolar amounts of pho-
toinitiator are not always required. In the indirect initiation mechanism,
the light absorbing molecule, typically referred to as the photosensitizer,
is excited by an appropriate wavelength of light. This generates an excited
state (singlet or triplet – depending on the employed photosensitizer),
whereby the excited chromophore will likely either undergo energy
transfer or react with an appropriately selected initiator molecule to
generate a reactive intermediate which can initiate the polymerization
reaction.81 Typical excited state processes which lead to the generation of
reactive intermediates include: (i) redox reactions/electron transfers, (ii)
hydrogen abstraction, and (iii) photocleavage.81 All of these processes
give rise to free radicals which happen to be the most common type of
initiation employed in these in situ polymerizations.
Finally, in selecting an appropriate photoinitiator/photosensitizer for
the employed system there are a few things that must be taken into
consideration. (i) Typically, the photosensitizer should have a high
extinction coefficient for the wavelength of light employed; however, one
should ensure that the light is capable of penetrating the entire depth of
the material. If the light is absorbed only at the interface, the polymer-
ization process may not be homogeneous. To get around this one could
either decrease the loading of photosensitizer or excite the molecule in
the tail region of its absorption spectrum. (ii) The photosensitizer should
have a high initiation efficiency and have high rates of initiation
(Efficiency ¼ # photons absorbed/# of events initiated), and (iii) lastly, the
photosensitizer and its photoproducts should be biocompatible (i.e. not
toxic locally or systemically), as they will likely become entrapped within
the matrix and be in close proximity to cells and other tissues.
4.1.3 Monomers. There is currently a wide variety of commercially

available and designer molecules which can or have been utilized as
monomers in photo-polymerizations for the generation of biomimetic
matrices. Typically, these monomers will have one or more photo-
polymerizable units, as well as other functionalities that allow for post
polymerization modifications such as cross-linking or the addition of
marker molecules and other bioactive components. While the initial
examples/studies typically employed methacrylated or acrylated deriva-
tives as monomers, recently other polymerizable functionalities and
bio-inspired monomers have been employed (see Table 2).
It is through the addition of functionalities and biomolecules that one
can modify and introduce specific properties into the resulting matrix
274 | Photochemistry, 2019, 46, 265–280

such as degradability/non-degradability,82 cell and protein adhesive-
ness,83,84 as well as mechanical properties such as strength, flexibility,
and viscosity.85 Of these properties, degradability and cell adhesiveness
are quite important for materials intended to mimic biological tissue and
deliver both cells and other factors to target areas. Regarding degrad-
ability, the type of chemical bonds created during the polymerization will
largely dictate the degradability and as such the rate of degradability and
release of cells or other molecules included in these matrices. For the
most part, degradability will arise from crosslinks formed between lateral
side chains of the monomer as these are typically enzymatically
degradable functionalities such as esters, and amides. While there have
been photopolymerizable monomers designed to be enzymatically
degraded,86 the commonly employed acryclic and methacrylic monomers
tend to give rise to polymeric structures with hydrocarbon based back-
bones which are not enzymatically degradable. As such, one must also
look at controlling other properties such as the molecular weight and
hydrophobicity of the resulting polymeric network as both of these
properties can drastically influence the rate of degradation.87 Cell
adhesion on photopolymerized matrices can also be difficult to attain.
Typically, photo-crosslinked hydrogels are composed of swollen and
insoluble hydrophilic polymeric networks. While this is great for the
encapsulation and viability of cells capable of growing in suspension, it
can be quite difficult for such types of materials to support adherent cell
types, which are quite important in various applications. As such there
has been a push to increase the adhesiveness of the materials through
the modification of monomers with a variety of amino acid sequences
such as an Arg-Gly-Asp (RGD), or other peptides and proteins known to
be involved in cell adhesion.88–90
4.1.4 In situ applications. For the most part, in situ photopolymeri-

zations involve free radical mechanisms. Many of these polymerizations
involve the classical steps of initiation, propagation, and termination.
Recently, there has been a push to improve these types of light-
mediated processes through the introduction of ‘‘living’’ or controlled
free radical processes; however there are not many examples of these
processes being used to generate biomimetic scaffolds in situ.91
In general, there are two different types of photo-polymerization, which
are classified as (i) bulk and (ii) interfacial.92 As its name suggests, in
bulk polymerizations all of the components are first mixed and then the
resulting mixture is polymerized via irradiation with an appropriate
wavelength of light. In the interfacial technique, the photosensitizer/
initiator is first adsorbed onto the target surface and then the rest of the
mixture is added and irradiated to form a thin polymeric network at the
interface.
When performing these types of polymerizations in situ the resulting
shape of the polymeric network will be the same as the cavity in which
the material is placed or injected. Additionally, it has been demonstrated
that one can introduce porosity into the network through the addition
of salts and other molecules which can be washed out post
Photochemistry, 2019, 46, 265–280 | 275

polymerization.93 One of the main advantages of photo-polymerization in
the context of biomaterials is that the technique may in some cases serve
as an alternative to otherwise invasive surgeries. By exploiting the tem-
poral and spatial control of the process, one can encapsulate and deliver
cells and other biologically active molecules to the site of interest using
laparoscopic instruments and needles, while initiating the polymer-
ization process via irradiation directly through the needle or depending
on the employed photosensitizer directly through the tissue in a sub-
cutaneous fashion.94
5 Conclusion and outlook

The advancements in understanding polymerization mechanisms and the
development of novel biocompatible matrices and incorporation of less
expensive irradiation sources like LEDs have enormously impacted the
field of photo-activated matrices for wound closure and tissue repair.
However, some fundamental questions remain to be answered including
the underlying mechanism for in vivo PTB. Novel approaches in PTB and
PHP should also incorporate the use of biomimetic matrices whose
composition and mechanical properties can be fine-tuned for application
in different tissues. In addition, the development of novel composite
materials for PTB as well as for PHP that are able to modulate inflam-
matory responses and reduce tissue remodelling will provide powerful
tools for reconstructive and plastic surgery. Undoubtedly, there is much
left to learn; however, identifying key clinical needs are pivotal for focus-
sing our efforts to develop novel and improved clinically translatable
technologies.
Acknowledgements
This work was made possible thanks to funding from the Natural Sciences
and Engineering Research Council (E.I.A.) and the Canadian Institutes
of Health Research (E.I.A. & E.J.S.). C.D.M. was supported by a University
of Ottawa Cardiac Endowment Fund postdoctoral fellowship award.
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280 | Photochemistry, 2019, 46, 265–280

Photoresponsive molecular devices
targeting nucleic acid secondary
structures
Michela Zuffo,y Valentina Pirota and Filippo Doria*
DOI: 10.1039/9781788013598-00281
Non B-DNA structures are non-canonical nucleic acid conformations adopted by single
strands fulfilling specific sequence requirements. Numerous experimental evidences
support their roles as regulators of biological processes, involving genetic information
transfer. However, direct visualization of the folding and unfolding of such structures in
live cells still remains elusive, as well as a detailed understanding of their mechanisms of
action and functions. Fluorescent light-up probes are excellent tools to address these
pending questions. This review aims at classifying the multitude of dyes available to date in
terms of operating mechanism (conformational restriction, TICT, aggregation related
phenomena, conjugation, etc.) and targeted structures. The most promising results are
presented for each conformational class, contextually highlighting the main criticalities
and the remaining gaps.
In its resting state, DNA occurs in the renowned double helix B-form,
wound around histones in nucleosome arrays and then packaged in a
dense complex, called chromatin. However, in order to be accessible to
enzymes and thus allow genetic information transfer, DNA must be
unwound. The resulting single-stranded regions may thus fold into
alternative secondary structures modelled by unusual nucleobases
interactions (e.g. Hoogsteen hydrogen bonds).1 Adoption of a peculiar
one depends on several factors, such as oligonucleotide sequence,
hydration state, super-helical stress, molecular crowding and interaction
with ions, protein partners and exogenous ligands. To date, more than
ten alternative DNA conformations, collectively called non-B DNA, have
been studied and characterized. Besides alternative double helix con-
formations, such as A, S and Z-DNA, these include bulges, hairpins,
parallel-stranded helices, triplexes, quadruplexes and i-motif structures
(Fig. 1).2–6 Some of these were also observed in RNA transcripts.
Research on such extensive polymorphism shed light on its active
roles in directing biological processes (Fig. 2).7 Experimental data
suggest that these alternative structures represent hotspots for muta-
tions, such as deletions or expansions, as well as interacting with pro-
teins involved in replication, gene expression and recombination. In
more detail, they are believed to act as roadblocks to proteins pro-
cessing single-stranded DNA templates during such transactions.6,8,9
Department of Chemistry, University of Pavia, V.le Taramelli 10, 27100 Pavia, Italy.
E-mail: filippo.doria@unipv.it
y
Present address: CNRS UMR9187, INSERM U1196, Institut Curie -Centre de
Recherche, Rue Henri Bequerel, 91400, Orsay, France; E-mail: michela.zuffo@
curie.fr
Photochemistry, 2019, 46, 281–318 | 281

Fig. 1 Schematic representation of non-B DNA structures. (1) G-quadruplex; (2) I-Motif;
(3) A-Motif; (4) Three-way junction; (5) Holliday junction; (6) Triplex; (7) Hairpin; (8) Z-DNA;
(9) S-DNA; (10) Bulge; (11) Mismatch.
Fig. 2 Schematic representation of the main biological roles of (1) G-quadruplex;22–24

(2) I-Motif;25–27 (3) A-Motif;28,29 (4) Three-way junction;30–32 (5) Triplex;33–35 (6) Holliday
junction;36–38 (7) Bulge;39–42 (8) Hairpin;43–45 (9) Mismatch;46,47 (10) S-DNA;48,49
(11) Z-DNA.50–52
Accordingly, RNA secondary structures seem to affect transcription with

analogous mechanisms. Despite these interferences with genetic
information transfer are generally recognized, debate is still ongoing on
282 | Photochemistry, 2019, 46, 281–318

their nature, either as native regulatory mechanisms or aberrant toxic
elements.10,11
Occurrence in vivo of many of these non-canonical DNA structures has
been proven in the recent past. In other cases, evidences are still indirect,
based on biochemical and molecular genetics data. In both cases,
extensive mechanistic models of their action are still missing and should
be the target of future research.
Moreover, many of these structures have been linked to various
diseases, such as cancer and genetic disorders. Demonstration and
detailing of such correlations would pave the way to develop treatments
based on DNA secondary structures targeting.12,13 Direct visualization of
non-canonical DNA structures with fluorescent probes is accepted as a
valuable approach to address these questions. In fact, it allows to directly
monitor folding and unfolding events in a time- and space-controlled
manner. Sensitivity compares favourably to other detection methods,
such as colorimetric and electrochemical ones. Moreover, it is a fast
and easily applicable technique, with the necessary equipment (e.g.
fluorometers, plate readers, confocal microscopes) being available to
most users.14
Certainly, this method requires probes with a high degree of speci-
ficity, to target peculiar secondary structures. Excellent sensitivity and
high affinity for the structures in question are also necessary. Even if
fluorescent monoclonal antibodies15–18 fulfil most of these requirements,
they display several limitations in terms of handling and costs. Moreover,
artefacts arising from chromatin fixation cannot be excluded when
targeting transient DNA conformations. A complementary approach is
represented by small molecules.19–21 In fact, if properly designed they can
penetrate the cellular membrane without the need to permeabilize it with
exogenous agents. For this reason, they allow to monitor the cell cycle in
real time. This is particularly relevant when trying to elucidate transient
secondary structure roles during cell life. Certainly, selectivity, affinity
and sensitivity vary depending on the probe, but outstanding results have
already been achieved.
In this review, we describe the considerable number of fluorescent
probes designed to selectively bind the different nucleic acid second-
ary structures, focussing on the most efficacious. Regardless of their
target, fluorescent sensors can be divided in three categories, light-up
probes, light-off probes and fluorescent tags, depending on how the
binding event affects their emission. Light-up probes display a more
or less marked fluorescence enhancement when interacting with the
analyte. On the contrary, light-off probes have their fluorescence
quenched. Finally, fluorescent tags do not undergo any modification
in terms of emission intensity. Among these three groups, light-up
probes are the most sensitive, as they are only slightly affected by
background fluorescence. For this reason, herein we will focus on
light-up probes. In particular, we will discuss the most common
light-up mechanisms and then present specific examples of their
applications in the targeting of various secondary nucleic acid
structures.
Photochemistry, 2019, 46, 281–318 | 283

1 Light-up mechanisms
1.1 Light-up via conformational restriction
Compounds working according to this mechanism are non-emissive in
the unbound state, due to their conformational freedom. In fact, free
rotation or vibration of the two moieties around a single bond produces a
thermal deactivation of the excited species. Moreover, twisting of one of
the molecule sections outside the plane relieves steric hindrance at the
expense of p-system conjugation. Once the probe binds to the analyte, it
is forced to adopt a planar, conjugated conformation, resulting in a
marked light-up (Fig. 3). A good exemplification of this mechanism is
constituted by cyanine dyes.53,54 These consist in two hetero-aryl moieties
conjugated through a methine or polymethine bridge (Fig. 4).
Fig. 3 Exemplification of the conformational restriction mechanism for the cyanine dye
thiazole orange.
Fig. 4 Structures of some representative cyanine dyes.
284 | Photochemistry, 2019, 46, 281–318

Nature of the aromatic moieties and length of the bridge define the
absorption and emission wavelength, as well as the dye quantum yield.
Although being particularly promiscuous in DNA binding, light-up inten-
sity is generally affected by the nature of the interacting structure.
A selection of cyanine dyes of increasing complexity is shown in Fig. 4.55–58
Other dye families belonging to this class are constituted by carba-
zole,59–64 benzimidazole65–67 and alkynil68 derivatives. As cyanines, they
tend to bind multiple secondary structures, rather than being specific.
For this reason, benzimidazole derivative Hoechst 33258 is widely used as
a nuclear stainer. Interestingly, though, carbazoles display different
emission wavelengths and fluorescence lifetimes, depending on the
peculiar analyte. The alkynyl Ant-PIm (Fig. 5) is one of the few selective
G4 sensors engineered to afford NIR emission, achieved by two-photon
excitation. Additional advantages of this probe are its excellent photo-
stability and biocompatibility.
Additionally, various natural alkaloids belonging to the family of iso-
quinoline (IQAs, Fig. 6) fit into this class of sensors. Many different IQAs,
e.g. chelerythrine (CHE),69 berberine (BER),70 epiberberine (EPI)71 and
palmitine (PAL)72 display interesting bioactivities, ascribable to their
binding to DNA secondary structures. Despite exhibiting similar scaf-
folds, the substitution patterns on the different family members seem to
govern their selectivity for different secondary structures.
Fig. 5 Structures of selected carbazole derivatives, benzimidazole dye Hoechst 33258

and poly-cationic ANT-PIm probe.
Photochemistry, 2019, 46, 281–318 | 285

Fig. 6 Scaffold of IQAs. All IQAs contain A, C, and D aromatic rings. For Sanguinarine
(SAN), chelerythrine (CHE), and nitidine (NIT), the unsaturated ring B is involved. Palmatine
(PAL), berberine (BER) and epiberberine (EPI), contain the saturated ring E instead.
Fig. 7 Examples of ‘‘turn-on’’ fluorescent sensors designed according to the TICT

mechanism.
The conformational restriction mechanism can be further enriched by

the twisted intramolecular charge transfer (TICT) phenomenon (Fig. 7).73
This occurs when two or more p-systems containing electron donor and
acceptor groups are connected through single bonds. Fast intramolecular
electron transfer between the two groups occurs in polar environments
(e.g. physiological medium) and is followed by twisting of one or more
aromatic units outside the plane. As in the previous cases, the twisted
structure has a large number of relaxation pathways available, resulting
in fluorescence quenching. Planarization occurring upon DNA inter-
action is responsible once again for fluorescence light-up, as it impedes
the charge transfer process. Examples of probes working by a TICT
mechanism are triphenylmethane (TPM),74–76 thioflavin,77,78 indol,79
bodipy,80 diarylaminoanthracene81 and julolidine82,83 derivatives.
In some cases, the planarization of the sensor’s structure that occurs
upon DNA binding allows the conjugation of several aromatic moieties,
which yield the actual fluorophore structure. DAOTA84 is one of the most
studied probes lighting up via this mechanism.
286 | Photochemistry, 2019, 46, 281–318

1.2 Aggregation-related processes
Many organic probes tend to aggregate in aqueous solution, due to their
hydrophobic aromatic scaffolds. Although the propensity to form such
supramolecular assemblies depends on the specific structure, it always
increases with the dye concentration. The process has a remarkable
influence on the compounds spectroscopic properties. Most probes
undergo an emission quenching, frequently referred to as ‘‘aggregation-
caused quenching’’ (ACQ). However, a number of probes behave in the
opposite manner, undergoing the so called aggregation-induced emis-
sion (AIE).85 While being non-emissive in dilute solution, such dyes start
to fluoresce upon aggregate formation. Rationalization of such phe-
nomenon has relied on various hypotheses, including the restriction of
intramolecular motion (RIM),86,87 excimer formation,88 J-aggregates,89–91
inhibition of TICT process,92,93 and excited state intramolecular proton
transfer (ESIPT).94,95
In general, the spectroscopic outcome strongly depends on the aggre-
gate geometry. Briefly, the nature of the aggregate depends on the relative
alignment of the transition dipole moments of the adjacent molecules.
Monomers can interact with each other adopting a face-to-face (H-
aggregates) or head-to-tail (J-aggregates) arrangement (Fig. 8). The for-
mation of such aggregates has important consequences on the energies
of the excited states, strongly affecting the dyes’ absorption and emission
behaviour. In most cases, the H-aggregates are non-emitting compared to
the monomer. In contrast, J-aggregates display a marked fluorescence, at
a wavelength peculiar to the new structure. As the interactions that
govern aggregates formation can also trigger the interaction with the
Fig. 8 Cartoon representing the aggregation process of H- and J-Aggregates.
Photochemistry, 2019, 46, 281–318 | 287

DNA analyte, many groups have exploited these mechanisms for sec-
ondary structures sensing. In the case of H-aggregates, emission is
quenched in the absence of the analyte. Then, interaction with DNA
induces the disaggregation, restoring the monomer emission. In the case
of J-aggregates, aggregation and thus emission light-up are selectively
triggered by DNA binding.
Examples of J-aggregates exploited in this sense are TPE (tetra-
phenylethene),96–98 cyanines91,99–102 and silole85 derivatives.
TPE belong to the category of ionic AIE sensors (Fig. 9), with non-
conjugated and conjugated linkages between the ionic moieties and
central hydrophobic core. Their emission turns on upon DNA binding,
according to the RIM mechanism.
J-aggregates of cationic cyanine dyes can be formed by complexation
with a variety of biomacromolecules,103 including DNA (Fig. 10).
Dye design implementation can serve to achieve the target specificity
necessary for practical applications.
A few examples of ACQ J-aggregates able to switch on their fluorescence
upon binding were also reported (Fig. 11).104,105 They are mostly DNA
groove binders, although some modified cyanine derivatives display good
selectivity for non B-DNA structures.
Certainly, reports on H-aggregates for sensing scopes are more
numerous. Some examples are constituted by dicyano vinilene squar-
aines,106,107 core extended naphthalene diimmides108,109 and perylene
bisimides110,111 (Fig. 12).
Fig. 9 TPE derivatives working via J-aggregates formation.
288 | Photochemistry, 2019, 46, 281–318

Fig. 10 Cyanine e Pseudo Isocyanine derivatives.
Photochemistry, 2019, 46, 281–318 | 289
Fig. 11 Structure of MTC and DMSB derivatives.

Fig. 12 Probes used for G4 sensing working via H-aggregates formation.
1.3 Dimeric and multimeric sensors

This third family of sensors includes multiple dyes, with different
mechanisms of action. The feature common to all the group components
is the partitioning in two or more moieties with peculiar and distinct
functions. One is the real DNA ligand, the other mediates the sensing
event, either behaving as a proper fluorophore or acting as a harvesting
antenna. Although conjugation is commonly utilized to build permanent
tags, the uniqueness of this third approach resides in the new role
attributed to it. In fact, the two moieties are able to interact with each
other when in close proximity, as in a conjugate. This induces remarkable
changes in the spectroscopic properties of the two components, in the
absence of the analyte. In most cases, the respective emission of one or
both moieties is switched off due to the interaction, via mechanisms
such as D–A ground state interaction, eT, ET and contact quenching.
Upon interaction with DNA, the two moieties split up, behaving as free
monomers. The resulting change in fluorescence is used to signal the
binding event (Fig. 13).
This is the case of naphthalene diimide (NDI) based dyads reported by
Freccero’s group,112,113 in which one NDI works as G4 ligand and either a
coumarin or another NDI work respectively as a harvesting antenna and
a proper fluorescent reporter.
Using the same light up mechanism, a multimeric polyethylenimine–
pyrene composite,114 a Hoechst-naphthalimide dyad115 and a quinoline-
naphthalimide dyad116 are able to selectively recognize other DNA
secondary structures.
Analogously, twice-as-smart G4 ligands reported by Monchaud and co-
workers117,118 are constituted by a central aromatic core attached to four
guanines. Interaction with a G4 contributes to restore the core fluo-
rescence, which is quenched by the free guanines in the unbound state.
1.4 Metal complex sensors

Metal complexes are widely exploited for DNA binding and sensing.119,120
Examples are numerous and involve an increasing number of transition
metals and lanthanides. Applicability to DNA sensing relies on the
intense metal-to-ligand charge transfer (MLCT) bands that are often
290 | Photochemistry, 2019, 46, 281–318

Photochemistry, 2019, 46, 281–318 | 291
Fig. 13 (A) Structure and schematic representation of the proposed mechanism of action for NI-quinoline and NDI–NDI dyads; (B) Structure and proposed
functioning mechanism of the NDI-coumarin dyad.
observed for complexes of such metals. In fact, these are normally cou-
pled to intense luminescence in the visible region. Electronic transitions
of this type are particularly sensitive to the surrounding environment.
Complexation to the DNA secondary structures induces significant
changes in this sense, as the ligand passes from a hydrophilic environ-
ment to a highly hydrophobic one. As a result, the emission behaviour is
affected as well and can thus be exploited for sensing.
1.5 Integrated probes

A critical issue encountered when designing DNA probes and with
sensing in general is that the analyte secondary structure could be
modified when the interaction takes place. In the worst-case scenario,
the probe could even induce the folding of the structure of interest. As a
consequence, a certain stream of research has been focussed on pro-
ducing internal probes by modification of the nucleobases composing
the sequence. Folding of the structure affects the probe spectroscopic
behaviour and thus enables to discriminate between the adopted con-
formations. For example, Luedtke’s group produced probes of this sort
for both G-quadruplexes and i-motifs.121–123 Besides being useful for
in vitro investigation, production of nucleobases that are recognized and
incorporated by polymerase enzymes could be a valuable mean to observe
sequences folding in live cells.
1.6 Miscellaneous probes

Despite the usefulness of the presented classification, this is not fully
comprehensive. In fact, multiple probes cannot be assigned to any of the
discussed categories, either because they present an extremely peculiar
mechanism of action or because the details were not deeply investigated.
Compounds of this kind will be discussed in more detail in the specific
subsections.
2 Fluorescent sensing of non B-DNA secondary

structures
2.1 G-quadruplex
In recent years, G-quadruplexes (G4s) certainly had the lion share of
attention among the non B-DNA secondary structures. G4s are consti-
tuted by stacks of two or more guanine quartets, cyclically connected
through Hoogsteen hydrogen bonds. Additional stabilization is provided
by alkali metal cations – chiefly K1 and Na1 – positioned in the internal
channel.124,125 Robust, although not conclusive, empirical proofs suggest
their implication in a number of DNA and RNA transactions, such as
telomeres maintenance, transcription, translation, alternative splicing
etc.126 Impairment of G4 stability via small molecules is regarded as an
effective way to gain control over such processes, and the related
pathological states.127,128 Therefore, the last decades have seen a gold-
rush to G4 ligands.129 However, G4s significance extends beyond
292 | Photochemistry, 2019, 46, 281–318

biological investigation. In fact, they found diverse applications e.g. as
DNAzymes, aptamers, logic gate components, etc.
Due to this widespread interest, numerous red-NIR absorbing and
emitting sensors are now available, displaying excellent turn-on effects
and selectivity.21,130 A considerable number works via the conversion
from a quenched, conformationally-free state into a fluorescent, rigid one
upon binding (mono- and polymethine dyes,56,131,132 triphenylmethane
probes,133,134 thioflavine T,135–138 etc.). The most remarkable results were
recently provided by Chen et al., with the probe QUMA-1 (Fig. 14).139
Stacking onto the RNA G4 external tetrads is responsible for the rotation
restriction around the methine bridge, connecting the N-methylated
quinoline and coumarin moieties. This results in a 60-fold increase of the
emission at 660 nm (Kd ¼ 0.57 mM for TERRA G4), which was used to
track RNA G4 folding in live cells cytoplasm. Notably, this is the first
report of time-resolved visualization of such structures.
Aggregation was also extensively explored for G4 sensing. In this
regard, most probes rely on the shift of the fluorescent monomer –
quenched aggregate equilibrium towards the monomeric species, by
Fig. 14 G-quadruplex light-up probes working via conformational locking or aggre-

gation related phenomena.
Photochemistry, 2019, 46, 281–318 | 293

complexation to the G4 structure. This is the case of Red-NIR (near
infrared) emitting distyrilpyridinium dyes (BCVP),140 core-extended
naphthalene diimides (cex-NDIs)141,142 and squaraines (Fig. 14).143,144
Both BCVP and cex-NDIs interact not only with G4s but also with
dsDNA. Interestingly, though, the binding produces a moderate light-up
with G4s and a quenching with dsDNA. cex-NDIs were further optimized
to implement a topologically-selective response, obtaining a light-up
exclusively with anti-parallel and hybrid G4s.142 Squaraine SQgI was
even more effective in this sense, since the sharp selectivity for parallel
G4 structures was coupled with high fluorescence quantum yield and
sensitivity.143 On the contrary, a few G4 probes function through an
aggregation induced emission (AIE) mechanism, forming a fluorescent
J-aggregate upon binding (Fig. 14). This was achieved, for example, with
the silole scaffold.145 Blue emission (l ¼ 470 nm) of the resulting
complex was successfully employed to monitor G4 survival during
enzymatic degradation. Tetraphenylethene salt (TTAPE) behaved simi-
larly. In fact, interaction with the G4 resulted in an intense
concentration-dependent light-up (l ¼ 492 nm).146 The probe was also
incorporated in an oligonucleotide conjugate.147 Hybridization of four
independent constructs with the flanking regions of a tetramolecular
G4 induced the spatially controlled aggregation of the dyes and the
related AIE phenomenon.
Transition metal complexes were also exploited as G4 sensors, due to
the effect of binding on their luminescence. Numerous metal centres
have been examined in this respect, including Ru(II), Ir(III),148 Pt(II)149 and
Zn(II).150 One notable example is that of [Ru(bpy)2(dppz)]21. Starting from
its tight interaction with dsDNA, the affinity was redirected towards G4s
through some stratagems, such as the insertion of more extended aro-
matic ligands151,152 or polyarginine chains.153 For example, Liao et al.
reported [Ru(bpy)2(bqdppz)]21, in which the dipyridophenazine ligand is
fused to a benzo[j]quinoxaline polycycle.151 The remarkable enhance-
ment of the CT emission band (l ¼ 600 nm) is 45-fold more intense with
the telomeric G4 sequence 5 0 -d[AG3(T2AG3)3]-3 0 (250-fold) with respect
to dsDNA.
Finally, the rational design of fluorophore-ligands dimeric sensors has
found wide application in the G4 field (Fig. 15). We recently reported two
NDI-based dimer types, one containing two optically complementary
NDIs154 and the other a tetra-substituted NDI conjugated to a cou-
marin.155,156 In the first case, the emission of the displaced tetra-
substituted NDI was restored upon binding of the tri-substituted one.
In the second case, the coumarin behaved as an antenna, transferring the
harvested light to the bound NDI (l ¼ 666 nm). Moreover, Monchaud and
co-workers reported the so-called twice-as-smart G4 ligands (TASQ).117
Conjugation of four guanines to a central polycycle quenches the fluo-
rescence of the core by eT. When Gs assemble in a synthetic quartet,
recognizing the G4, lowering of their HOMO restores the polycycle
emission. Notably, a multi-photon mechanism can be used to excite the
probe via ET from the G4 structure to the emitting core,157 with inter-
esting applications in RNA G4s sensing in live cells.158
294 | Photochemistry, 2019, 46, 281–318

Photochemistry, 2019, 46, 281–318 | 295
Fig. 15 Transition metal and dimeric light-up probes for G4 structures.

Fig. 16 G4 probes working via uncommon sensing methods.
Aside from this categorization, a handful of uncommon sensing

methods were described (Fig. 16). Ladame and co-workers reported the
fluorogenic assembly of a cyanine dye, templated by the G4 structure.159
In more detail, its non-emitting components were conjugated to peptide
nucleic acid (PNA) sequences, complementary to the nucleobases
adjacent to the G4 structure. The close proximity and the correct
orientation provided by the G4 shifted the equilibrium towards the
fluorescent product. Moreover, Luedtke’s group introduced fluorescent
8-substituted guanine analogues (e.g. 2PyG) in G4 forming
sequences.121,122 These work as internal folding reporters due to the
variation of ET efficiency from G to 2PyG in the different conformations.
Finally, Vilar and co-workers reported DAOTA-M2.160 Despite displaying
only a small fluorescent enhancement and poor G4 selectivity, its fluo-
rescence had significantly longer lifetimes upon G4 binding than with
double and single stranded DNA. Notably, fluorescence lifetime imaging
(FLIM) revealed that this feature is maintained in live osteosarcoma
cells, providing a conceptually new method for the tracking of G4
folding.
2.2 i-Motif
As well as G-rich strands, the complementary C-rich strands can adopt
their own secondary structure, called i-motif.161,162 This is constituted
by stacks of hemiprotonated C : C þ base pairs. These form two
parallel-stranded intercalated duplexes, which run anti-parallel to each
other. Since protonation of each base pair is required for optimal
hydrogen bonding, i-motifs are generally stable at slightly acidic pH
(4.2–5.2). For long time, this was regarded as a major obstacle to
in vivo folding. Therefore, biological investigation on i-motifs advanced
at a much slower pace than that on G4s, despite 40% of genes, and
notably oncogene promoters and telomeres, contain putative i-motif
sequences. However, recent advances demonstrated that stability
of i-motifs also depends on factors other than pH, such as length of C
stretches and loops, as well as environmental conditions. Such find-
ings renewed the interest in their cellular occurrence. To date, a
number of i-motif putative sequences have been identified and char-
acterized163 and their cellular folding has been proven by means of
fluorescent antibodies.164
For these reasons, research on i-motif sensing with small molecules
was mostly directed towards the construction of label-free DNA switches
and nanomachines,165 instead of focussing on their biological
296 | Photochemistry, 2019, 46, 281–318

Fig. 17 i-Motif fluorescent probes.
occurrence. This is the case of crystal violet (CV)166 and berberine

(BBR),167 both working via a conformational restriction mechanism
(Fig. 17). Ma et al. reported the application of the former in a ‘‘OR’’ logic
gate, based on simultaneous or alternate fluorescent sensing of i-motif
and G4 folding upon H1 or K1 stimuli. Similarly, fluorescence
enhancement of the latter (l ¼ 530 nm) upon telomeric i-motif binding
was used to construct ‘‘INHIBIT’’, ‘‘AND’’ and OR’’ logic gates by Xu et al.
These applications do not require highly selective sensors (e.g. CV and
BBR are not i-motif specific binders). Nonetheless specificity would be
desirable for biological investigation. Unfortunately, the first probes
reported for this scope suffered from similar limitations, due to the
difficulties in the selective targeting of such a narrow structure. This is
the case for several TICT probes (Fig. 17). For example, ThT lights-up
upon binding to the i-motif sequence formed in the retinoblastoma
(Rb) gene,168 but, at the same time, yields similar outcomes with the
RET proto-oncogene hairpin and G4 structures.135,168 Similarly, pro-
miscuous binding and light-up (151-fold, l ¼ 630 nm) was reported
for Quinaldine Red.169 Analogous selectivity issues were observed for
metal complexes as well. This is the case of the Ir(III) based complex
reported by Lu et al., whose luminescence increased upon i-motif and
G4 binding (lMLCTE590 nm).170 However, the complex found useful
application in indirect TdT (terminal deoxynucleotidyl transferase)
activity tracking, through the sensing of the i-motif structure synthesized
by the enzyme.
The only sensor reported to date showing meaningful sensing
selectivity for i-motif structures is Neutral Red (NR, Fig. 17).171 The
sensing mechanism relies on NR protonation in the pH range relevant
for telomeric i-motif folding. This triggers both the fluorescence light-
up and the binding. In turn, the emission is further enhanced by the
interaction with the C : C þ base pair. Although the calculated associ-
ation constants are similar for telomeric i-motif and G4, the emission
light-up is reported to be peculiar to the i-motif structure, providing a
useful sensing tool.
Photochemistry, 2019, 46, 281–318 | 297

Finally, many groups reported modified i-motif forming oligonu-
cleotides, yielding a fluorescent emission upon folding. Among
these, Mata et al. presented a fluorescent cytosine analogue, resulting
from the fusion of N,N-dimethylaniline to the nucleobase core
(DMAC, lmax ¼ 548 nm upon protonation and folding).123 Despite
its fluorescence is greatly reduced upon folding, ET from C to DMAC
is efficient only in the folded i-motif structure. This effect was exploited
to gain insights on the unexpected kinetic barriers in i-motif
unfolding.
2.3 A-motif
Poly(A) sequences can adopt two distinct conformations depending on
the pH.172 Above pH 7, poly(A) single strands form a right-handed helix.
When lowering the pH, protonation of adenine N1 induces the assembly
of two strands into a parallel right-handed duplex. Tightness of the
packaging depends on protonation extent. The structure is held together
by reverse hydrogen bonds and is further stabilized by electrostatic
attraction between the protonated bases and the phosphate backbone.
Interest in such structures mainly arises from their putative occurrence
in mRNA tails, which contain sequences of up to 200 A bases in
eukaryotes.173 Assembly of two different tails into a poly(A) duplex might
be a way to control polyadenylation extent.174 More in general, A-motifs
might control poly(A) binding proteins synthesis and the production of
alternative protein forms.175
Despite the relevance of such motifs, reports on light-up probes for
their investigation are quite limited. Attention was mostly focussed on
isoquinoline alkaloids (berberine, sanguinarine, palmatine, coralyne,
Fig. 18).
Emission of all these structures is centred between 525 and 570 nm
and is turned on upon interaction with the NA structure. Among these,
berberine, sanguinarine and palmatine preferentially interact with the
single stranded poly(A) helix in an intercalative fashion.176–178 On the
Fig. 18 A-motif light-up probes.
298 | Photochemistry, 2019, 46, 281–318

contrary, coralyne induces the self-assembly of an anti-parallel duplex.179
The light-up mechanism was not investigated in detail. However, based
on their extended aromatic structure, with some saturated C–C bonds,
either an aggregate-monomer equilibrium or the presence of a TICT state
can be hypothesized. Safranin T, a phenazine dye, was also reported to
undergo a moderate light-up upon binding of the single stranded poly(A)
helix (l ¼ 580 nm), with affinity constants comparable to isoquinoline
alkaloids.180
2.4 Three-way junctions

Three-way junctions (TWJ) are non-canonical NA structures consisting of
three duplex branches converging in a single central point.181 TWJ
forming sequences are composed of three inverted repeats, able to pair
with each other. The three resulting arms are disposed around a central
cavity, with a C3 axis. TWJ putative sequences exist in both DNA and RNA,
playing definite biological roles. In more detail, TWJs are intermediates
of DNA replication and are associated with triplet repeat expansions in
several genetic diseases.182 In RNA, TWJs are involved in translation and
splicing.183
Compared to other NA secondary structures, interest in the develop-
ment of TWJ ligands is more recent. These currently include only three
classes of small molecules, all fitting in the TWJ central cavity: metallo-
supramolecular helicates,184 tryptycenes185 and macrocyclic aza-
cryptands.186 As a consequence, research on suitable fluorescent probes
is only at an early stage. Yang et al. recently reported a cationic calix[3]-
carbazole as the first selective TWJ sensor (Fig. 19).187 After an initial
quenching, a bright light-up was observed at 389 nm, resulting from the
1 : 1 complex formation (Ka ¼ 4.33104 M1). This new emission was
assigned to the ‘‘trap II’’ excimer formed by the overlap of the carbazole
moieties. This particular orientation was obtained through the restriction
of the moieties rotation when locked in the TWJ cavity.
Fig. 19 TWJ light-up probe.
Photochemistry, 2019, 46, 281–318 | 299

2.5 Holliday junctions
Holliday junctions (HJ) are constituted by four duplex branches con-
verging towards a central cavity.188 Such four-way junctions can adopt
two possible conformations: anti-parallel stacked-X and open planar.
Occurrence of such structures was initially postulated by R. Holliday, as
transient conformations adopted by DNA during homologous recom-
bination (HR),189 and was later confirmed by electron-microscopy.190
Their stabilization by small molecules is regarded as a mean to stall HR,
by blocking resolvases activity, and induce related DNA damage. How-
ever, only a handful of compounds were reported for the task. These
include acridine dimers,191 hexa-peptides,192 porphyrins193 and a num-
ber of cleaving complexes, such as methidiumpropyl-EDTA-FeII.194
Unfortunately, no fluorescent probe has been reported yet.
2.6 Triplex
Triplex-forming oligonucleotides (TFOs) are supramolecular structures in
which a third strand of nucleic acid binds to a double helix, through
Hoogsteen or reverse Hoogsteen hydrogen bonds. The prerequisite for
the existence of this structure is the presence of polypurine-
polypyrimidine repeats in the DNA duplex target.195
There are three classes of triplex DNA that differ in NA sequence and in
phosphate backbone orientation of the oligopurine strand with respect to
the duplex: TC, GT and GA triplexes.196 In TC triplexes the third strand
presents the same orientation as the duplex (from 5 0 to 3 0 orientation)
forming TA*T or CG*C triplets through Hoogsteen hydrogen bonds. In
GT triplexes the third strand can be either anti-parallel or parallel to the
purinic strand of the duplex, interacting through reverse Hoogsteen and
Hoogsteen bonds respectively and forming CG*G or TA*T triplets.
Finally, in GA triplexes the third strand has an anti-parallel orientation
with respect to the bound duplex and forms reverse Hoogsteen CG*G and
TA*A triplets.196
Each of these structures is thermodynamically stable under physio-
logical conditions.197 Nevertheless, high levels of multivalent cations,
such as Mn21, Ni21, Mg21,198 or polyamines are necessary to compensate
the unfavourable charge repulsion between the three negatively charged
backbones.
As much as other non B-DNA secondary structures, TFOs have been
identified as bioactive structures involved in the regulation of gene
expression,199–201 in DNA damage202 and repair,203–205 and even in pro-
gression of some diseases.206 Therefore, their detection has been of
fundamental interest over the last 15 years.
Fan et al.207 synthesised a highly selective triplex fluorescent sensor
based on the conjugation of a 4-aminonaphthalimide unit, already used
as a biomolecular sensor, and a 2-(2-naphthyl)quinoline moiety, inas-
much recognized as potent TA*T triplex intercalator.208 Fluorescent
enhancement is selectively observed with TFOs at pH higher than 6.5.
The sensor exhibits a two-fold difference in fluorescence response upon
binding with the triplex in comparison with duplex and ssDNA.
300 | Photochemistry, 2019, 46, 281–318

Weisz et al.209 studied 11-phenyl-substituted indolo[3,2-b]quinoline
derivatives (Fig. 20), that exhibited significant in vitro anticancer activity
thanks to the high binding affinity to TFOs. Fluorescence emission
spectra of these compounds showed 20-fold fluorescence enhancement
upon TFOs binding with respect to ss-DNA.
Recent in vitro studies demonstrated that also the renowned dye
Thiazole Orange has a higher affinity for TFOs structures than for duplex
DNA.210 Nevertheless, comparable affinity for G4 structures impedes
biological applications in TFOs sensing.211
Although these small molecules are easily modifiable by synthetic
means, they all exhibit at least a moderate binding to other DNA struc-
tures. Finding a selective and sensitive ligand exclusively interacting with
triplex structures is instead crucial for the development of viable ana-
lytical and therapeutic tools. The first breakthrough in this sense were
provided by Shao et al.212 They identified Fisetin (FIS, Fig. 21) as a high
performance and selective sensor for TFOs, screening a family of 18
flavonoids. FIS interacts with triplexes in an end-stacking mode with a
binding constant of about 3.6106 M1 and provides considerable sta-
bilization (DTm ¼ 14 1C). The interaction activates FIS green emission via
an ESIPT mechanism. Interestingly, FIS is highly selective for the triplex
structure over other secondary structures (e.g. ds-, ssNA, hairpins and
DNA/RNA G4s). Moreover, this selectivity is maintained in a wide pH
range and does not depend on molecularity (intra- and intermolecular),
sequence and length of the TFOs.
In a more recent work, the same group proposed the natural product
chelerythrine (CHE, Fig. 21) as a triplex specific binder, inducer and
sensor, screening a variety of natural isoquinoline alkaloids.213 CHE is
able to bind TA*T triplets with a fluorescence response 20- and 54-fold
higher than those observed with dsDNA and G4s, respectively. The pro-
posed binding stoichiometry is 2 : 1 (CHE:triplex), regardless of TFO type,
loop sequence and stem length. Binding constants are between 5 and
6.4106 M1, depending on the specific triplex.
Another interesting approach to the development of novel triplex-
based sensors was proposed by Zhao et al.214 They exploited the triplex
DNA structures to create a multi-functional platform based on a fluo-
rescence ‘‘turn off-on’’ mechanism, designed to discriminate cisplatin
from transplatin compounds.
The ZnCdSe quantum dots fluorescence is quenched by the interaction
with cisplatin anti-cancer drugs through electron transfer. The presence
of DNA restores this emission, by interaction with the metal complex.
Triplex DNA binding efficiency exceeds that of ss-DNA and duplex of
about 20% and 10%, respectively. This is due to its larger aromatic sur-
face and to the presence of more negative charges able to attract
positively-charged hydrolysates of cisplatin.
2.7 Hairpin
Hairpin structures, or stem-loops, are intramolecular structures. In par-
ticular, they occur when two regions of the same filament form a double
Photochemistry, 2019, 46, 281–318 | 301

302 | Photochemistry, 2019, 46, 281–318
Fig. 20 Triplex-selective fluorescent sensors.
Fig. 21 Fisetin and Chelerythrine structures.

helix ending in a loop, with unpaired or non-Watson–Crick-paired
nucleotides. Generally, they can arise in ssDNA or, more commonly, in
RNA regions containing complementary sequences running in opposite
directions.215
Hairpins play an essential role in the regulation of gene expression,
in replication initiation and in transcription.215 Moreover, they can guide
RNA folding, protect mRNA from degradation, act as a substrate for
enzymatic reactions and as a binding site for a large number of RNA
binding proteins.216 An interesting attempt to recognize and sense this
particular secondary structure was done by Hong et al., who developed a
sandwich-type DNA biosensor.217
Despite the recognized necessity to develop highly specific fluorescent
sensors for the labelling of hairpin structures, such tools are completely
missing to date. More than considering them as analytes, most research
groups have devoted their efforts to exploit hairpins as fluorescently
labelled probes.218,219 For example, they have found fruitful application
as probes attached to gold nanoparticles,220 in the fluorescent imaging
and detection of miRNA221,222 in vitro and in live cells,223 and in metal ion
detection inside cells.224
2.8 Z-DNA
Z-DNA is a DNA duplex conformation with left-handed helicity.225 This
imposes relevant structural differences with respect to B-DNA. In fact, the
phosphate backbone has a zig–zag shape, with negatively charged groups
lying closer to each other than in B-DNA (8 Å vs. 11.7 Å). Moreover, the
distinction between the major and minor grooves is lost, in favour of a
single deep one. Nucleobases are located farther from the central axis
than in B-DNA and are oriented perpendicularly to the backbone. Finally,
glycosidic bonds are forced to adopt an alternate anti-syn orientation.
Therefore, the Z-DNA conformation is observed mostly in sequences with
alternating purines and pyrimidines (e.g. d(GC)n, occurring every 3000
bp),226 under specific circumstances. For example, high ionic strength
favours B-to-Z DNA transition, since it relieves phosphate–phosphate
repulsion.225 Interestingly, a number of evidences (e.g. specific binding
proteins) demonstrate Z-DNA occurrence in vivo, with negative super-
coiling apparently triggering the transition from B-DNA.227 Proposed
biological roles concern regulation of gene expression.50
Selective sensing of Z-DNA with respect to B-DNA is quite demanding
and reports of specific ligands are limited. Attention was mostly focussed
on porphyrins, not as fluorescent sensors, but as chiroptical probes
(Fig. 22).228 However, slight modifications of their emission were
observed upon complexation. Moreover, metal ions inserted in the cen-
tral cavity (Zn21, Ni21) take up guanine N7 in their coordination sphere
upon interaction with DNA. For these reasons, implementation of the
scaffolds for Z-DNA fluorescent sensing could be envisaged.
Fluorophores insertion into the sequence was proposed as a mean to
monitor B-to-Z helix transition in vitro (Fig. 22). For example, Okamoto
et al. reported a DNA sequence containing adjacent pyrene ethynyl-G and
Photochemistry, 2019, 46, 281–318 | 303

Fig. 22 Z-DNA fluorescent reporters.
304 | Photochemistry, 2019, 46, 281–318
pyrene propargyl-C.229 Shifting of the conformation from B- to Z-DNA
forced the two pyrene moieties in the correct orientation to form an
excimer. As a result, a marked red-shift (from 440 to 507 nm) in
absorption and the related fluorescence were observed. Insertion of a
single pyrene ethynyl-A or U at the oligonucleotide terminus yielded
similar results.230 In fact, the monomer fluorescence lights-up upon
transition to the Z-DNA conformation and subsequent suppression of
p-stacking with the helix nucleobases.
2.9 S-DNA
Slipped-strand DNA (S-DNA) are sequence-specific non-Watson–Crick
DNA structures, displaying remarkable stability at physiological salt
concentrations. These are involved in dynamic mutations associated with
a large number of genetic diseases.231,232 These occur when the com-
plementary strands comprehend at least two copies of identical repeats.
Unpairing of one repeat and subsequent bulging out of one of the single
strands forces the remaining strand to pair with the second repeat, thus
producing a misalignment. Therefore, S-DNA motifs could cause errors
during DNA replication, repair, recombination or transcription.233,234
Structural DNA changes occurring during overstretching235 seem to
play a key role in many genomic processes. Therefore, identification of
the conditions leading to S-DNA formation is a fundamental step to
understand their implication in mechanical DNA stress. Their cellular
occurrence is supported by the existence of proteins able to bind them in
a structure-specific mode.232 Despite these promising experimental data
and the biological significance of the structure, no specific fluorescent
light-up probe is available yet.
However, Peterman et al.231 recently demonstrated by indirect means
the formation of S-DNA when the dsDNA is overstretched in high ionic
strength conditions. In particular, they guessed S-DNA formation due to
the lack of binding to the target DNA by fluorescently labelled replication
protein A (RPA), a ssDNA binding protein,236 and the switch off of Syntox
fluorescence, a dsDNA probe.237 The same method had previously been
applied using YOYO, as dsDNA-specific dye, and Alexa-555-labeled
human mitochondrial single-stranded DNA-binding proteins
(mtSSB).236 This possible structural transition was additionally supported
in the work of Zhang et al. with a complementary technique, single-
molecule calorimetry, in the aforementioned overstretching DNA
conditions.238
2.10 DNA bulges

Bulged structures are interruptions in double-helical DNA caused by the
absence on one strand of the nucleotides complementary to the opposite
strand tract. This induces a tight junction in the duplex.239 As other non-
canonical NA structures, bulges seem to be involved in a large number of
biological processes, for example as intermediates in RNA splicing,240
regulatory protein binders,241 mediators of frameshift and intercalator-
induced mutagenesis242 and of imperfect homologous recombination.243
Photochemistry, 2019, 46, 281–318 | 305

Fig. 23 Neocarzinostatin and b-aminoglucose chromophores structures.
Fig. 24 a- and b-aminofucosylated structures.
Although the involvement in such processes is linked to some relevant

diseases, such as HIV-1241 and neurodegenerative pathologies,244 rather
few endeavours have been made to identify fluorescent small molecules
able to recognize bulge structures. Starting from the observation that the
neocarzinostatin chromophore (NCSi-gb, Fig. 23) was capable of binding
bulged DNA with good selectivity over the duplex form,245 Goldberg
et al.240 synthetized a new thermodynamically stable analogue. This
consisted in a spiro-alcohol conjugated to b-aminoglucose (Fig. 23).
Its ability to adopt of the right wedge-shape is the key to its good affinity
for bulges. Association constants with two-base bulges were in the sub-
micromolar range. Unfortunately, the interaction only produced a
fluorescence quenching.
Subsequently, Jones et al. synthetized two a-aminofucosylated dia-
stereomeric adducts (Fig. 24) that selectively bind two-base bulges with
affinity constants of E80 nM.246 In this case, a fluorescence quenching
occurred for bulges located next to a GC base pair. Conversely, an
increase in fluorescence intensity was observed with AT base pairs close
the bulge. In any case, results demonstrated a remarkable selectivity for
two-base bulge structures against duplex DNA. The difference in dis-
sociation constants was more than two orders magnitude. Interestingly,
the probe was even able to discriminate against one-base and three-base
bulge, displaying Kd values one order magnitude lower than for two-base
bulges.
306 | Photochemistry, 2019, 46, 281–318

Two years later, recognizing the key role of stereochemistry, the same
group synthetized b analogues of the structures,247 lowering the dis-
sociation constant value for two-base bulges to 200 nM. No discernible
binding was observed to duplex DNA and unbulged hairpins.
2.11 Mismatches and apurinic/apyrimidinic sites

Mismatched base pairs statistically occur in cells every 106–108 nucleo-
bases.248 Endogenous causes for their generation include replication
errors, HR related events and spontaneous nucleobases deamination.249,250
Moreover, exogenous agents (reactive species, alkylating molecules,
UV light, etc.) also have a role in their production.251 Structure and stability
of the mismatch depend on the nature of the bases involved, with G being
the most promiscuous one and C the least adaptable one. Apurinic/
apyrimidinic sites (AP sites, or abasic sites) production is closely related
to mismatch repair, and in particular to the base excision mechanism.252
Intervening glycosilases flip out the incorrect base and cleave it in the first
step, to then let other enzymes repair the lesion. Alternatively, AP sites
can be produced spontaneously. Targeting of these structures by small
molecules has been widely explored for medical purposes, as recently
reviewed by Granzhan et al.253 In fact, deficiency of repair enzymes is
associated with carcinogenesis.254 In addition, mismatches accumulation
in trinucleotides subject to expansion can be used to tackle the related
pathologies (e.g. fragile X syndrome).255 Moreover, mismatches targeting
and signalling has relevant in vitro applications, e.g. in single nucleotide
polymorphism (SNP) typing.256
Some light-up probes have already been reported, targeting either
proper mismatches or AP sites. Concerning mismatches sensing,
Zeglis et al. reported a dimer constituted by Oregon Green 514 fluor-
ophore and [Rh(phen)(bpy)(chrysi)]31 metalloinsertor (Fig. 25).257
Electrostatic interaction brings the two moieties in close proximity in
the unbound state. In such conformation, the fluorophore emission is
quenched by eT. Selective insertion of the Rh ligand into the mismatch
cavity separates the two moieties, partially restoring Oregon Green 514
emission (E8-fold enhancement). Interestingly, the dimer is able to
sense most mismatches, except for particularly stable ones. Mismatches
sensing was also achieved through modified nucleotides, mostly for SNP
typing (Fig. 25). This is the case of 8-aza-2 0 -deoxyguanosine.258 Con-
version to the fluorescent anion is favoured for the unpaired nucleotide
(F ¼ 0.55, pKa ¼ 8.8) and the resulting emission can be used to monitor
the formation of mismatches with complementary strands. Similarly,
fluorescent pyrrolo-dC click adducts (F ¼ 0.32) were incorporated in
single strand probes.259 Such emission was maintained only in the
absence of Watson–Crick base pairing, with the signal intensity being
inversely dependent on the mismatch stability.
Multiple probes for AP sites were designed, adapting the well-
established 2-amino-1,8-naphthyridine scaffold of ATMND. For
example, Wang et al. reported an ATMND-DBD dimer (Fig. 26), which
signals the ligand binding to the AP site through the light-up of DBD
Photochemistry, 2019, 46, 281–318 | 307

Fig. 25 Mismatched DNA fluorescent probes.
Fig. 26 AP sites fluorescent probes.
emission (l ¼ 585 nm, LOD ¼ 1.4–32 nM depending on the AP site).260

Affinity for dsDNA with C or T opposite to the AP site is comparable
(KaE106 M1). Instead, association constants are two orders of magni-
tude lower for G and A, suggesting a role of the cavity size in determining
the affinity. ATMND-TO (l ¼ 530 nm) and DMP-BO (l ¼ 483 nm) dimers
combined use was reported for apurinic and apyrimidinic sites dis-
crimination, due to their affinities for AP site facing C/T and G,
respectively.261 Fluorescent AP site recognition relying on hydrogen
bonding was also achieved with 3,5-diamino-6-chloro-2-pyrazine carbo-
nitrile (DCPC, Fig. 26).262 Weak emission of DCPC is significantly
308 | Photochemistry, 2019, 46, 281–318

enhanced (l ¼ 412 nm, 35-fold) upon binding of AP sites facing a T,
although the sensitivity depends on the flanking nucleobases identity.
Finally, FIS signals AP sites facing C or T nucleobases through an ESIPT
(excited state intramolecular proton transfer) mechanism.263 The intra-
molecular process occurs exclusively inside a hydrophobic pocket, such
as that of an AP site, preventing proton transfer from the solvent. For-
mation of the active tautomer in the excited state (lE550 nm) produces
the fluorescent sensing. Since the compound is selective for AP sites
facing T and C bases, recognition likely happens via intercalation in the
size-matching cavity or by partial hydrogen bonding to the involved
nucleobases.
3 Conclusions
Mounting evidence suggest that DNA is far from being a passive mol-
ecule, simply undergoing enzymes action during genetic information
transfer. Non-B DNA structures and their RNA counterparts seem to play
active roles in regulating these processes, in a complex interplay of
enzymes controlling their folding and unfolding. Deeper understanding
of their biological roles and of their occurrence at specific stages of cell
cycles is the focus of current research. The use of fluorescent probes, and
in particular light-up ones, holds great potential in this investigation, due
to the advantages in terms of costs, rapidity and sensitivity. Certainly,
considerable advances have been made in the last decades in terms of
specificity and affinity of the available fluorophores, culminating in cel-
lular visualization of some of the structures (e.g. G4, triplex and i-motifs).
However, the effort devoted to the search of suitable and selective dyes
and the subsequent results vary greatly depending on the NA conform-
ation, with some of them still lacking a proper detection system. Filling
these gaps should be the aim of the future research, contextually to
exploiting the available probes for deeper biological investigation of the
structures already addressed.
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318 | Photochemistry, 2019, 46, 281–318

Transition metal complexes in ECL:
diagnostics and biosensing
A. Aliprandi,a B. N. DiMarcoa and L. De Cola*a,b
DOI: 10.1039/9781788013598-00319
This chapter addresses the main principles, challenges and achievements in ECL using
metal complexes. Selected applications in diagnostics and biosensing are described.
1 Introduction to electrochemiluminescence
Luminescent molecular excited-states can be generated through several
different processes that include light absorption (photoluminescence),
mechanical action (mechanoluminescence), chemical reaction
(chemiluminescence) or by charge injection across the electrodes (elec-
troluminescence). Electrochemiluminescence, or electrogenerated
chemiluminescence (ECL), is a process that uses an applied electrical
bias to generate reactive species at an electrode surface that undergo
subsequent electron-transfer reactions to generate luminescent species.
This technique can be considered as the combination of electrolumin-
escence (EL) and chemiluminescence (CL), since the electrical bias is
used to generate the reactive species in situ, which then react to form
the luminescent species, in contrast to the direct generation of the
luminescence species through electrochemical reduction/oxidation or a
spontaneous chemical reaction. The ability to electrochemically generate
the reactive species provides several advantages over chemiluminescence
such as excellent stability, simplicity, and great spatial and temporal
control. Additionally, this technique retains the extremely high signal-
to-noise ratio typical of conventional CL measurements, due to the
elimination of the background noise from the excitation source used
in traditional photoluminescent measurements, thus making it an
extremely powerful analytical technique.1 In general, there are two main
categories of ECL reactions that are classified based on the specific
mechanism for the electrochemical generation of the excited state.
Annihilation ECL (Fig. 1a) takes place between the oxidized and the
reduced forms of the luminophore, where the two oxidation states are
generated sequentially by applications of alternating oxidative and
reductive bases at the working electrode. In contrast, co-reactant ECL
(Fig. 1b) involves the use of a secondary reagent that converts to a reactive
and potent sacrificial electron donor/acceptor upon oxidation/reduction
a
Institut de Science et d’Ingénierie Supramoléculaires (ISIS), University of
Strasbourg & CNRS, 8 Rue Gaspard Monge, 67000 Strasbourg, France.
E-mail: decola@unistra.fr
b
Institute of Nanotechnology (INT) and Karlsruhe Nano Micro Facility, Karlsruhe
Institute of Technology (KIT), Hermann-von-Helmholtz-Platz 1, 76344 Eggenstein-
Leopoldshafen, Germany
Photochemistry, 2019, 46, 319–351 | 319

Fig. 1 (a) Schematic representation of annihilation ECL of a generic luminophore A.
(b) Schematic representation for co-reactant ECL where A is a generic luminophore and B
a sacrificial agent.
and subsequently reacts with the luminophore during a single potential

step or can.
When a sacrificial agent is used as co-reactant there are two possible
scenario: (i) the luminophore can be electrochemically oxidized at the
anode in the presence of a strong reducing agent such as C2O42 or amines
such as tripropylamine (TPA), oxidative-reduction ECL; (ii) the lumino-
phore can be electrochemically reduced at the cathode in the presence of a
strong oxidant such as S2O82, reductive-oxidation ECL. The decomposition
pathways of the co-reactants are often complicated, and can involve highly
reactive radicals species2 that make it difficult to identified the mechanism
with certainty. Understanding the processes occurring during the
generation of the ECL (i.e. electron transfer reactions, products formation,
and charges recombination) is important for improving the efficiency of
the process. To this end, mechanisms for the most common co-reactants
have been confirmed in the last decade through EPR investigation.3
The first observation of electrochemically generated light dates back a
century,4 while the first discussion of possible analytical applications
occurred more than a decade later.5 However, it was not until the middle
of the 1960s6–10 that the modern field of ECL was definitively born. The
studies at the time focused primarily on organics luminophores and low
ECL yields were generally observed. In 1973 Tokel and Bard11 published
their seminal work that demonstrated efficient ECL from the transition
metal complex [Ru(bpy)3]Cl2 (bpy ¼ 2,2 0 -bipyridine) through the annihi-
lation mechanism. Since then, ruthenium polypyridyl complexes have
320 | Photochemistry, 2019, 46, 319–351

become the dominant luminophores over the past 40 years, having been
extensively studied. Although the photoluminescent quantum yields
(PLQY) of such compounds are relatively low, even under anaerobic
conditions12 (PLQY ¼ 6.3%), the highly favourable electrochemical prop-
erties, both in terms of electrochemical stability and oxidation potentials,
results in an intense emission suitable for practical ECL applications. It is
indeed the superior detection limits of an analyte (down to picomolar
levels) of emission-based techniques, combined with the simplicity of the
experimental setup, that makes ECL extremely important and an area of
increasing interest. At the time of writing, there are nearly 5000 references
focused on ECL listed on Web of Science (see Fig. 2).
Improvements in the electrochemical understanding of the mech-
anism involved in ECL has opened new frontiers for the exploration of
additional transition metal complexes as well as the use of modified
electrodes, and the development of systems based on organic and
aqueous solutions. More recently, novel approaches employing nano-
material and supramolecular chemistry have also been reported. Fur-
thermore, the development of ECL has been boosted by the parallel
growth of OLED technologies that are based on electroluminescence.
Indeed, these two phenomena share many distinct similarities. One
particular example is the role of the spin statistics during the formation
of the exciton, which in the context of OLEDs led to the use of triplet
emitters and on the stability of the luminescent excited states. The
realization that phosphorescent emitters also outperform fluorescent
dyes13 for ECL applications resulted in numerous reports of OLED
phosphorescent emitters being used as ECL luminophores. This is
Fig. 2 The number of published journal papers per year on electrochemiluminescence as

of 13 March 2018. Source: Web of Science.
Photochemistry, 2019, 46, 319–351 | 321

particularly true for the highly emissive and color tunable Ir(III) com-
plexes, which have been in the focus for ECL applications over the past
decade. The growth of these two fields lead many researchers to start
investigating the role of the chemical design on the photophysical and
electrochemical properties of Ru(II), Ir(III), and other metal complexes.
Many attempts are reported to correlate the spectroscopic behaviour with
the ECL performances to develop guidelines for the design of efficient
ECL systems, however the complexity of the ECL processes often prevent
a full understand and prediction of the systems. Some general charac-
teristics of efficient ECL emitters are described in the next section.
1.1 Characteristics of ECL emitters

Many parameters must be considered for the design of ECL system which
consider both optical and electrochemical properties. The luminophore
must be highly emissive since the ECL efficiency is inherently limited by
the PLQY.14 As anticipated, spin statistics plays an important role in ECL
since the lowest excited singlet (S1) and triplet (T1) state of a lumino-
phore formed by non-radiative process, such as ion annihilation (ECL, EL
or CL), are considered to be in a 1 : 3 ratio.15 However, for most
fluorescent molecules radiative decay between the triple state T1 and the
ground state is not possible due to spin conservation in the induced-
dipole energy-transfer process, and thus the maximum ECL efficiency is
expected to be 25% for the majority of the fluorescent materials with
intrinsic PLQY of 100%. In order to overcome this limitation both singlet
and triplet states must contribute to luminescence. An efficient solution
to this problem is the use of phosphorescent transition metal complexes,
where the presence of the heavy metal reduces the phosphorescence
lifetime through increased spin–orbit coupling which mixes the singlet
and triplet characters of the excited-state. The heavy metal also increases
the efficiency of intersystem crossing from the first singlet excited state to
the triplet excited state manifold.13,16 Another strategy is to minimize the
energy gap between the singlet and triplet excited states (DEST) through
molecular design, thus promoting a highly efficient spin up-conversion
process from the non-radiative triplet states to radiative singlet states
while maintaining high radiative decay constants.17,18 This process,
known as thermally activated delayed fluorescence (TADF), requires a
combination of a small DEST (o100 meV) and a fast radiative decay rate
4106 s1, to overcome competitive non-radiative decay pathways.
Because these two properties conflict with each other, the overlap of the
highest occupied molecular orbital and the lowest unoccupied molecular
orbital need to be carefully balanced while maintaining a rigid structure
in order to minimize the geometrical changes between the ground state
and the singlet excited state that result in non-radiative decay. Though
TADF molecules can be considered an attractive alternative to phos-
phorescent molecules based on rare-earth metals, such as Ir and Pt,
factors including stability, electrochemical activity and biocompatibility
limit their applicability for use in bioanalytical assays.
The electrochemical properties of a compound and the stability of
the reduced or oxidized species, are of paramount importance for
322 | Photochemistry, 2019, 46, 319–351

determining ECL applications. Photophysical properties are often less
important, since it is very hard to rationalize the emission properties and
in particular the correlation between the observed PLQY and ECL
intensity.19 Indeed, the overall ECL performance depends on how effi-
ciently the excited state is formed during the ECL reaction. As an
example, the ECL reaction efficiencies for [Ru(bpy)3]21 has been reported
to be near unity under certain conditions.11 This high efficiency is due to
a number of factors that include a high degree of electrochemical
reversibility that ensures the rapid generation of a stable Ru(III) species
capable of undergoing subsequent electron transfer reactions, and a
favourable oxidation potential (Eox ¼ þ1.2 V vs. NHE) that is potent en-
ough to provide sufficient driving force for desired reactions, but low
enough as to not give rise to parasitic side reactions. This high efficiency
has also important implications in terms of electron transfer theory since
such quantitative yield can only be obtain if the emitting state is popu-
lated directly and not through an energy transfer reaction. The reaction is
also thermodynamically favoured while reactions that lead to the direct
formation of the ground state product are kinetically inhibited.
These observations can be explained through Marcus theory. The
deactivation reaction which leads to two ground state Ru(II) species is
highly exergonic, while the desired reaction leading to and excite Ru(II)*
species, annihilation reaction, is less so. Given the similar reorganization
energies for both reactions, they will likely falls within the Marcus
inverted region, where increasing driving force leads to a decrease in the
electron transfer rate. In all cases, the deactivation reaction with for-
mation of only ground state species will be more exergonic and therefore
slower in rate when compared to the desired annihilation reaction.
However, this may be an oversimplification as it does not take electron
spin configurations into consideration.
Due to the 100% efficiency in the generation of the excited states, the
photophysical and electrochemical properties of [Ru(bpy)3]21 have been
used as model for developing novel ECL emitters and, in particular, those
based on the Ir(ppy)314 (ppy ¼ 2-phenylpyridine) which is known to pos-
sess a PLQY of 100%20 thus making it extremely appealing as ECL
emitter. The extremely high PLQY of iridium(III) complexes has motivated
scientist to systematically investigate the effects of the ligand design on
the electrochemical and photophysical properties, and consequently
their effects on the ECL efficiency.21,22
Besides the choice of the emitter, the development of efficient co-
reactants for ECL is central to the advancement of the field. For example,
the discovery of the co-reactant tripropylamine (TPA) was especially
important since it allowed efficient ECL not only in aqueous media, but
also at physiological pH (B7.4), thus enabling bioanalytical applications.2
For obtaining efficient ECL using TPA the oxidation potential of
the emitter should be positive enough for an efficient generation of TPA1
(E0TPA/TPA 1¼ þ 0.9 V vs. SCE23) while the potential of the TPA should be
more negative than the reduction potential of the emitter (E0TPA ¼ 1.7 V
vs. SCE23).24,25 As a result the best performing ECL emitters have similar
emission energy of the [Ru(bpy)3]21 with luminescence in the red region
Photochemistry, 2019, 46, 319–351 | 323

(l¼600 40 nm). Consequently, tuning the emission colour while
keeping high ECL yield is still an important challenge since it would
allow novel applications such as multiplexed detection, but new co-
reactants are needed to fulfil the different redox properties.
Solubility in aqueous media and resistance to oxygen quenching
impose new challenges in emitter design beyond the electrochemical and
photophysical properties. Charged species, such as the Ru(II)-polypyridyl
complexes, possess an intrinsic water solubility, especially if a halogen
anion is used as counterion, while neutral complexes require specific
ligand design to achieve sufficient solubility to translate efficient ECL
system from organic solvent to aqueous media. Often these strategies rely
in the introduction of polar groups in the ligand architecture or in the
engineering of the coordination sphere such that the complex is charged
rather than neutral. However, substitution of the coordinated ligands
often has a profound impact on the photophysical and electrochemical
properties of the emitter. Another interesting approach is the encapsu-
lation of the hydrophobic luminophore inside water dispersible struc-
tures, such as nanoparticles, which offer both water solubility and
protection against oxygen quenching. The combination of nanostruc-
tures with ECL luminophore is probably the most recent trend in the
field, since the scaffold may possess intrinsic conductive or semi-
conductive properties that can be used to enhance the ECL intensity.
Furthermore, it is generally possible to further functionalize the nano-
material with groups suitable for bioconjugation such that the hybrid
system can be used for detection of proteins (e.g. immunoassays) or DNA
(e.g. DNA hybridisation assays).
1.2 Diagnostics and biosensing

Commercial ECL analytical platforms rely on molecular architectures for
the recognition of specific analytes. Typically, the surface of the electrode
is modified with an agent that binds to the analyte with high specificity in
order to keep it close to the electrode itself. Upon immobilization of the
component, a second agent capable of binding to it and bearing the ECL-
active label is added, to give a ‘‘sandwich’’ structure. In this way, the
presence of the ECL label indicates the presence of the analyte and the
total intensity of the ECL signal can be correlated to the concentration of
the latter.26–28 A general strategy utilized by Roche Diagnostics takes
advantage of microparticles immobilization on a Pt electrode to perform
highly sensitive immunoassays able to detect more than 150 analytes
with subpicomolar sensitivity. The assay consists in the incubation of a
patient sample with two antibodies (or oligonucleotide sequences) of
which one is labelled with ruthenium as ECL emitter and the second is
labelled with biotin, both are highly specific to binding site on a target
antigen (or the matching oligonucleotide). The two antibodies form a
sandwich complex with the antigen (Fig. 3, stage 1). Next paramagnetic
microbeads coated with streptavidin are introduced in the solution,
the streptavidin forms a strong complex with biotin (Fig. 3, stage 2). Then
the completed immunoassay sandwich complex is transferred to the
324 | Photochemistry, 2019, 46, 319–351

Photochemistry, 2019, 46, 319–351 | 325
Fig. 3 Simplified view of all the steps for an ECL immunoassay, based on the capture, immobilization and detection of the analyte.
measuring cell where a magnet pushes the microbeads against the
electrode. The cell is then washed with a solution containing the co-
reactant (TPA) in order to both separate the bounded immunoassay
complex from the free remaining particles and enable the ECL reaction
(Fig. 3, stage 3). Voltage is then applied to trigger the ECL reaction. The
emitted light is then detected by a photomultiplier and it is directly
proportional to the concentration of the analyte (Fig. 3, stage 4).
2 Ruthenium complexes
The complex Ru(bpy)321 has been of paramount importance in the field
of ECL since the first report by Tokel and Bard in 1972.11 As mentioned in
the introduction, a bright luminescence was observed from a simple
acetonitrile solution containing Ru(bpy)321 after the application of an
alternate oxidative and reductive electrochemical potential. Though this
was not the first report of ECL, the observation of ECL from a metal
complex opened many possibilities for expansion of the field. The au-
thors asserted that the luminescence resulted from an electron transfer
reaction between the reduced and the oxidized forms of Ru(bpy)321 that
generated the luminescent excited state. Since these early observations,
Ru(bpy)321 and its derivatives have become the most important lumi-
nophores used for ECL analysis, as evidenced by its frequency of use in
academic study and the fact that it is currently used in all commercially
available ECL immunoassay devices and in more than 150 assays. The
remarkable electrochemical and photophysical properties of Ru(bpy)321
have been well recognized in other fields, but of particular attraction to
ECL are its superior electrochemical properties, low toxicity29 and is good
solubility in a wide range of solvents, including buffer aqueous solutions.
The low toxicity and water solubility also make it ideal for biological
applications. An additional draw of Ru(bpy)321 is the high efficiency of
the ECL reaction, which is often consider to be quantitative in annihi-
lation mode.30 As mentioned in the introduction, a major drawback of
these luminophores are the low intrinsic PLQYs, which do not exceed
0.05 in oxygen free solutions and ultimately sets an upper limit to the
luminescence achieved through ECL. Additionally, the luminescence
profile is difficult to tune due to the limited ligand-field splitting of the
octahedral Ru(II) centre. This often limits its use for ECL lighting appli-
cations, though it has not greatly impacted its applicability for biological
assays, where the wavelength of emission is less relevant. It is worth
noting that several organic and transition metal based luminophores
have recently begun to rival the classic Ru(II) based systems, though it
may still be few years until Ru(II) systems are replaced.21,31
In addition to the numerous applications of Ru(bpy)321, these mol-
ecules have served as model systems for understanding the mechanisms
governing both annihilation and co-reactant ECL. Such information is
vital for creating the next generation of luminophores, co-reactants and
assays built around ECL.32 A review of fundamental studies are beyond
the scope of this chapter, and an interested reader is directed towards
several high-quality reviews which discuss the fundamentals of
326 | Photochemistry, 2019, 46, 319–351

ECL.30,31,33 Instead, this section will focus on recent advancements in
ECL based biological assay which employ Ru(bpy)321 as the primary lu-
minophore. Commonly, Ru(bpy)321 forms a bioconjugate with an anti-
body, single-strand DNA or other biologically relevant molecule that can
bind with an analyte of interest. Several recent trends have been focused
on the amplification of the signal from Ru(bpy)321 by encapsulation of
multiple emissive cores within a nanoparticle or polymer matrix, which
can then be attached to the biological tag with the goal of increasing the
luminescence. Encapsulation of multiple luminophores can also impart
additional benefits, such as increase solubility in aqueous media and
reduced quenching by oxygen.34
A recent example of this strategy has been published by Paolucci et al.35
and focused on the encapsulation of Ru(bpy)321 within silica nano-
particles. The SiNPs were prepared through standard synthetic methods
in the presence of a Ru(II) species that possessed a trietheoxysilane
functional group, Fig. 4, allowing the luminescent tag to be covalently
Fig. 4 (A) Structure of Ru(II) luminophore and its assembly into a silica nanoparticle.
(B) Change of ECL mechanism observed as the concentration of Ru(II) inside the
nanoparticle increases. Adapted with permission from ref. 35, Copyright 2016 American
Chemical Society.
Photochemistry, 2019, 46, 319–351 | 327

linked to the SiNP and thus eliminated the possibility of the dye leaching
from the system after preparation. By varying the concentration of the
Ru(II) complex during NP synthesis, the doping level can be tuned
between 0.05–0.8% wt/wt. The dye-doped nanoparticles (DDNPs) pos-
sessed a hard B10 nm core and a hydrodynamic radius of B25 nm due to
the presences of a PEG shell, which was included to increase the water
solubility of the NPs. Interestingly, the DDNPs zeta-potential was found
to be Ru(II) loading dependent, with an increase from 10 to 0.9 mV
being observed from the lowest to highest doping concentrations. This
was likely due to the inclusion of the cation Ru(II) species within the NP.
This change in zeta potential was not observed to impact the dis-
persability of the nanoparticles. As expected, encapsulation of the Ru(II)
reduced the quenching of the sensitizers by dioxygen, as evidenced by the
excited state lifetime and emission quantum yields measurements. ECL
studies of the lowest doping concentrations found a strong intensity
emission which associated well with the oxidation of the 2-(dibutylami-
no)ethanol co-reactant, in addition to a weak emission signal found in
the potential range for Ru(III/II) chemistry. In general, the ECL intensity
increased with increases Ru(II) doping, though the intensity increase was
not linear with concentration and eventually plateaued at the highest
concentrations. This is likely due to self-quenching reactions that intro-
duces an additional non-radiative decay pathway. Interestingly, increas-
ing in Ru(II) doping also saw a decrease in intensity in over the potential
range for co-reactant oxidation, though an increase in intensity was seen
over the potential range associated with Ru(II) oxidation. The change was
attributed to a decrease in a favorable attractive interaction between
cationic products of co-reactant oxidation and the negative zeta potential
of the NP as higher Ru(II) loading. The increase in intensity over the
Ru(III/II) potential was thought to be due to direct co-reactant oxidation by
Ru(III). Since the Ru species are imbedded within the NP, this likely
occurs through an electron self-exchange reaction between the Ru within
the NP. This report demonstrates that one cannot assume a linear rela-
tionship between luminophore loading and intensity and more complex
parameters must be considered in ECL. Nevertheless, the increased
luminesce intensity of these nano-particle systems contributes to the
development of biological assays, where an increase in the tag luminesce
can increase the sensitive of the device.
Polymer systems can also be used to encapsulate multiple Ru(II) spe-
cies. Similar to the silica NPs, these species provide protection from
quenching by dioxygen, and can be modified to improve solubility or to
impart target specificity. A recent example by Ju et al. generated a mul-
tinuclear polymer tag through a simple flash injection technique.36 The
authors flash injected a THF solution containing the hydrophobic salt
[Ru(bpy)3][B(C6F5)4]2 and a precursor for the formation of nano polymer
dots (Pdots) into water under sonication. The rapid injection saw the
formation of Pdots spheres which encapsulated Ru(bpy)321. The weight
percentage of the Ru(II) within the Pdots could be varied by altering the
Ru(II) concentration in the THF solution, and this was used to investigate
the influence of loading on the ECL properties. The Ru(II) species were
328 | Photochemistry, 2019, 46, 319–351

confirmed to be encapsulated inside the spherical polymer matrix pri-
marily through TEM-EDX. The Pdots themselves have previously been
shown to be emissive and ECL active.37 Interestingly the strong spectral
overlap between the Pdot emission and the Ru(II) absorption allows a
Förster energy transfer that was observed between the polymer shell and
the encapsulated Ru(II). This energy transfer pathway increased the ECL
luminescence for the hybrid Ru-Pdot, which out-performed on Au elec-
trodes functionalized with Pdot or for the unencapsulated Ru(II). Con-
centration dependent studies proved the highest ECL performance
arising from a 2 : 1 ratio of Ru(II) to polymer, with a decrease in ECL
observed at higher concentrations. As a result, the 2 : 1 material was used
to develop an assay for the detection of mutant strands of DNA through
the functionalization of the Ru-Pdots with complimentary strands of the
mutant DNA. These assays demonstrated that the Ru-Pdots could provide
superior detection limit when compared to the non-encapsulated RNA,
achieving a limit of detection of 0.8 fM. This value was significantly lower
than all current analytical methods, including those of nanoparticle-
enhanced plasmon resonance imaging (1 pM) and of the magnetic beads-
ECL systems often used in commercial apparatuses (10 fM). Such an
achievement corroborated the potential of polymer encapsulation of
luminophore for biological assays.
ECL signals can also been boosted by the addition of secondary
structures into the device. An interesting example has been published by
Guo et al. that focused on the generation of an ultrasensitive ECL assay
using Ru(bpy)321 functionalized SiO2 NPs in conjunction with AuNPs for
the detection of carcinoembryonic antigen (CEA).38 Surface enhanced
ECL (SEECL) had previously been observed by Lakowicz and co-workers,
who employed a gold film coated glass substrate to enhances the ECL
efficiency of Ru(bpy)321.39,40 This effect is similar to SERS, though in this
example the presence of a Au surface enhances the ECL efficiency of
Ru(bpy)321. In order to detect the presence of CEA, the authors functio-
nalized a polished gold electrode with two different CEA specific apta-
mers. Samples containing a known concentration of CEA were
introduced, which bound to the aptamers on the gold surface. The
introduction of a single layer of Ru–SiO2NPs that was functionalized with
a CEA specific aptamer, allowed the tag to bind the target strand. When
CEA is present in the analyte and bound at the interface, ECL was
observed using TPA as the co-reactant. The signal from this initial setup
was then enhanced using two different techniques. The first was based
on the use of an assembly of multiple layers of the Ru–SiO2 that provided
an increase in the concentration of emissive species, while the second
was to incorporate aptamer functionalized gold nanoparticles into the
assembled structure. The multiple Ru–SiO2 provided more emissive cores
to the centre, while the Au was expected to enhance the emission from
each Ru–SiO2 though the aforementioned SEECL effect. The author
demonstrated that both of these techniques improved the signal compared
to the one for the Ru–SiO2 layer, though the best performance was observed
with combination of these two factors and reported a 30 increase in
intensity over the initial setup. When arranged in this configuration, the
Photochemistry, 2019, 46, 319–351 | 329

assay achieved a limit of detection for 1.52106 ng mL1, several orders of
magnitudes lower than prior literature reports. Such an appreciable
increase in sensitive merits further investigation on the use of AuNP for
SEECL in other biologically relevant assays.
Another recent trend in the quantification of an ECL signal has been
based on a ratiometric approach, where two signals are compared rather
than taking the absolute value from a single emitter. This has the added
benefit of eliminating background emission from the co-reactant, oxygen,
etc. Ru(bpy)321 and its derivatives find themselves perfectly amenable to
this technique. Systems used for ratiometric ECL can be relatively simple,
as demonstrated by Peng et al.41 The system described the ratio of the
emission from a Ru(II) and Os(II) polypyridyl dyad complex, where the two
emissive cores were tethered together with an alkyl chain. The two species
have significantly different emission profiles that allows them to be easily
distinguished. Os(II) polypyridyl complexes are also known to efficiently
quench the emission of Ru(II) polypyridyl complexes through energy
transfer. The authors were able to determine the concentration of a co-
reactant present in the electrolyte by rationing the emission for between
Ru(II) and Os(II). Such a simple system could be used to detect the presence
of naturally occurring co-reactants, such as NADH.
An additional example of ratiometric ECL was described by Chen et al.,
which took advantage of the strong spectral overlap between the emis-
sion profile of gold doped carbon nitride nanosheets (Au–g–C3N4) and
the absorption profile of Ru(bpy)321 to develop a FRET based device for
microRNA detection.42 Au–g–C3N4 itself was previously shown to be ECL
active and provided a signal when no microRNA was present. In
this report, a glassy carbon, GC, electrode was first functionalized with
Au–g–C3N4, which allowed for a thiol terminated hairpin molecular
beacon probe to be bound to the gold, Fig. 5. A microRNA chain of
interest was then introduced that could interact and open this beacon
probe, forming a linear hybrid DNA/RNA duplex. Duplex selective
nuclease (DSN) was then used to cleave the duplex species, leaving a
shortened DNA chain bound to the Au–g–C3N4 nanosheet. Finally, a
Ru(bpy)321 moiety functionalized with a DNA strand, that was compli-
mentary to the shortened surface bound DNA, was introduced to com-
plement with the surface hairpin beacon probes that were previously
opened by the target RNA. This entire process ensures that only hairpin
probe beacon probes which interacted with the target RNA strand would
be available for binding to the DNA functionalized Ru(bpy)321 and thus
cuts down on background noise. Ultimately, an increase in the concen-
tration of the target microRNA results in an increase in the Ru(bpy)321
concentration at the interface. ECL measurements found that an increase
in the concentration of the Ru(bpy)321 resulted in a decrease in the
Au–g–C3N4 emission (460 nm) concomitant with an increase in the
emission from the Ru(bpy)321 (630 nm). The changes in the emission
intensities is caused by the contribution to the normal ECL process, from
Ru(bpy)321, of the energy transfer between the Au–g–C3N4 to the
Ru(bpy)321. The ratio between the two signals allowed for the deter-
mination of Ru(bpy)321 present at the interface, and therefore the
330 | Photochemistry, 2019, 46, 319–351

Photochemistry, 2019, 46, 319–351 | 331
Fig. 5 MicroRNA determination using a combination of gold doped carbon nitride nanosheets (Au-g-C3N4) and Ru(bpy)32 þ used as ECL detection unit.
Reprinted with permission from ref. 42, Copyright 2015 American Chemical Society.
evaluation of the concentration of RNA applied in the previous step.
Calibration testing using target RNA concentrations that varied between
1.0 fM and 1.0 nM found a highly linear trend (Correlation
coefficient ¼ 0.9914) between the log of the concentration and log of the
ratio of the two signals. Linear regression analysis determined a limit of
detection 0.5 fM, based on a S/N ratio of 3, which outperformed all
previous reports for ECL based microRNA analyses. The high sensitivity
results from the ratiometric approach to this analysis, and highlights the
benefits of such an analysis.
Another trend in ECL analyses is the use of potential dependent ECL,
which often used multiple luminophores with different turn-on poten-
tials to impart both wavelength and voltage dependence to the electro-
chemically generated emission.43 Multiple emission ECL was originally
demonstrated as a proof-of-concept by Richter and coworkers using a
combination of Ru(bpy)321 and Ir(ppy)3 (ppy ¼ 2-phenyl pyridine).44
However, applications of this technique did not appear for many years,
though several notable reports have been recently published. One
example is a recent study by Xu et al. that combined the two ECL lumi-
nophores, Ru(bpy)321 and Ir(ppy)3, within a bipolar electrode based
device.45 In this example, the two luminophores were dissolved within a
chamber containing an acetonitrile electrolyte. It was previously shown
that increasing in the applied potential results in the ECL profile tran-
sition from red, to yellow, to green as the emission transition from pri-
marily Ir(ppy)3 in character to Ru(bpy)321. Though such mixed emissive
properties have been previously reported,43,44 the authors took advantage
of this interesting observation to designed a bipolar electrode setup,
where the anodic and cathodic chambers were separated by a small gap
that could be bridged by a resistor. The anodic chamber was filled with
an acetonitrile electrolyte containing the two luminophores and the TPA
co-reactant, while the cathodic chamber was filled with an aqueous
solution containing a buffered salt solution. Using a resistor to bridge the
chambers, a 5.5V external bias was applied across the two sample
chambers. ECL was observed from the chamber containing the lumino-
phores, with the color of emission being controlled by the resistor size
used to bridge the two chambers. This was due to the relationship
between the resistor and the cell potential, which increased with increas-
ing resistance. As the cell voltage increased, the colors changed from green
to red. This experiment provided as a proof of concept for the design of an
analytical tool for the facile detection of the clinical biomarker prostate-
specific antigen (PSA). Subsequent experiments did not use a resistor, but
instead functionalized the gap with an anti-PSA antibody. The device was
realized using a microfluidic design that allowed multiple reagents to flow
over the gap in order to introduce different analytes and reagents to the
interface, Fig. 6. A solution containing a known concentration of PSA was
first flowed through the gap, followed by a second solution containing a
second gold-labelled PSA antibody that created a sandwich complex with
PSA. A silver reagent was then introduced, which reacted with the gold
labelled antibody, creating a conductive pathway between the two sample
chambers. An increase in the amount of PSA present in the analyte
332 | Photochemistry, 2019, 46, 319–351

Photochemistry, 2019, 46, 319–351 | 333
Fig. 6 Colorimetric bipolar electrode ECL device for the detection of PSA employing two ECL active complexes. Adapted with permission from ref. 45, Copyright
solution controls how much silver reagent will be deposited between the
two chambers and there for controls the resistance, which ultimately
controls the ECL color. As a final proof of concept, the authors obtained
a series of PSA samples from hospital patients that had the concentration
PSA previously determined through standard clinical techniques.
Remarkably, the design of the device triggered the transition green to
yellow at PSA concentrations which corresponds to a cut-off value for
possible prostate cancer (4.0 ng mL1), while a transition from yellow to
red was observed at higher concentrations (10.0 ng mL1) where a prostate
biopsy is highly recommended. The entire sample process required
approximately 35 minutes, demonstrating that this device could be used as
a fast assay for determining prostate cancer risk.
Self-enhancement ECL, where the co-reactant and the luminophore are
combined within a single molecule or system, have received increased
attention over the past few years. This likely due to the improved
performance and longevity of the system when compared to traditional
co-reaction methods, where the luminophore and co-reactant are present
separately, and to the intrinsic toxicity and volatility of some of the co-
reactants. In a recent example by Yuan et al., the authors prepared the
complex Ru(bpy)2(mcbpy)21-TAPA, Fig. 6, which contained amine func-
tional groups that could be used as the ECL coreactant.46 The authors
developed a highly sensitive assay for the detection of N-acetyl-B-D-
glucosamidnidase (NAG), which can be used for the detection of diabetic
nephropathy. Upon solvent evaporation, the complex forms a rod-shaped
structure, with an average length of 260 30 nm and a width of
100 20 nm. These rods were found to have excellent electrochemical
properties, and produced efficient ECL. A mechanism for ECL was pro-
posed in this article, which involved the formation of a radical on the
TAPA moiety after oxidation that undergoes an intramolecular electron
transfer to the bound Ru(III) species to form the excited state Ru(II)*. In an
effort to improve the conductivity of these rods, Pt nanoparticles (PtNPs)
were also incorporated. The Pt functionalized rods showed an increase in
electroconductivity, as evidenced with electrochemical experiments using
the well know Fe(CN)63/2 redox couple as the redox shuttle. To form the
ECL label, a bioconjugate between the Pt nanoparticles functionalized
Ru(bpy)2(mcbpy)21-TAPA rods was made with bovine serum albumin
(BSA). The final assembly was then generated after the introduction of the
targeting antibody. A polished Au electrode was also functionalized with
the detection antibody. The target of interest, here NAG, was incubated on
this surface. After washing, the Ru(II) labelled antibody was introduced to
create the commonly used sandwich structure for ECL analysis, Fig. 7.
After optimization of the experiment conditions, including incubation
time, a linear trend was observed between the concentration of NAG pre-
sent during incubation and the ECL signal obtained. Based on these val-
ues, a limit of detection for NAG of 0.17 pg mL1 was achieved, which
outperformed the previous best detection limit (50 pg mL1) by over two
orders of magnitude. The authors also demonstrated that different inter-
fering agents had little influence of the ECL performance, showing good
specificity for the target of interest.
334 | Photochemistry, 2019, 46, 319–351

Fig. 7 Schematic representation of an assay for the detection NAG using a self-
enhancing Ru(II) luminophore. Reprinted with permission from ref. 46, Copyright 2016
Fig. 8 Self-enhanced ECL from a Ru(II)-NCND hybrid system. Reprinted with permission
from ref. 47, Copyright 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
Our group recently reported a self-enhanced ECL system obtained by

combining Ru(bpy)321 with amine functionalized carbon nano-dots
(NCNDs), where the NCNDs were capable of acting as the co-reactant
in the ECL experiment.47 The combination of these two species in an
aqueous PBS buffer afforded efficient ECL, that was 4 times as intense as
the signal obtained in the absence of the NCND, upon the application of
an oxidative bias. The use of NCND as co-reactant afforded superior
stability over multiple electrochemical cycles when compared to TPA,
likely due to the abundance of amino-group present on each carbon dot
(Fig. 8). Further enhancement of the ECL signal was observed after
methylation of the amines, consistent with previous literature reports. In
a final effort to increase the intensity of ECL, the Ru(II) complex was
covalently linked to the NCND through the formation of an amide link-
age. This hybrid structure yielded a two-fold increase in ECL efficiency
when compared to the free Ru(II)/co-reactant system. Additionally, no
evidence of quenching of the Ru(II) emission by the NCND was observed,
Photochemistry, 2019, 46, 319–351 | 335

as evidenced by the similar emission quantum yields between the full
assembly and the free Ru(bpy)321. This self-enhancement effect, in
addition to the use of a novel, more stable co-reactant represents a sig-
nificant improvement over the classic TPA system.
A final area of interest has been the development of low-cost, point-
of-care devices which rely on ECL. The majority of these technologies
currently rely on Ru(bpy)321 and its derivatives. Simple devices have been
generated by Hogan et al. based on now ubiquitous smart phones com-
bined with cheap and printable paper based electrodes.48 These clever
examples utilize the phone’s camera as the detector, and use the phones
headphone-jack as a potential source. A simple tone is played through
the headphone-jack, which generates an oscillating potential wide en-
ough to generate ECL from Ru(bpy)321 in the presence of a coreactant.
Later versions have also utilized the mini-USB port of the phone to pro-
vide a more consistent voltage.49 These innovative technologies open
opportunities to perform ECL based diagnostic tests in areas that do not
have access to more advanced testing equipment.
Despite the first ECL reports occurring more than 40 years ago,
Ru(bpy)321 remains the dominating luminophore in ECL. This is clearly
evidenced by the abundance of studies which continue to use Ru(bpy)321.
This emitter has been of paramount importance to the development of
this field, and will likely continue to be studied for many years to come.
3 Iridium complexes
Ir(III) complexes have attracted considerable attention as novel lumino-
phores for ECL applications over the past decade.21,50 A major promise of
Ir(III) complexes comes from the fact they often possess significantly
higher PLQYs and longer luminescence lifetimes than the prototypical
Ru(II) complexes. Though this does not necessarily translate to a higher
ECL performance, as evidenced by numerous reports, the higher PLQY
translates to a higher upper limit for ECL quantum yields relative to Ru(II)
polypyridyl complexes. An additional feature of Ir(III) based emitters is the
ease in which the emission energies can be tuned across the visible
spectrum with simple modifications of the coordinated ligands. This is in
contrasts to Ru(bpy)321 and its derivatives which generally emit in the red
region, around 630 nm. For the iridium complexes it has been shown that
ligand substitution can be used to shift the electrogenerated emission
from the blue to the red or NIR, a property already utilized for light
emitting devices, including ECL based lighting applications.51 The use of
Ir(III) complexes for ECL applications in aqueous solutions is relatively
recent, despite several earlier reports investigating ECL in different
conditions from several systems.50 Indeed most of the initial studies
utilized electrochemical potentials which were not sufficient to oxidize or
reduce the complex to generate ECL through an annihilation mech-
anism. The first modern reports of Ir(III) based ECL appeared only in the
early 2000s by several groups.21,44,50 In these cases the ECL was generated
through the previously discussed annihilation mode, where the emissive
species is produced through an electron transfer reaction between an
336 | Photochemistry, 2019, 46, 319–351

oxidized and a reduced form of the luminophore. Co-reactant ECL for
iridium complexes took an additional few years to be realized, likely due
to the use of co-reactants optimized for Ru(II) chemistry, which often has
different electrochemical properties than Ir(III) based systems. In early
attempts the Ir(III) complexes were less potent oxidizers when compare to
their Ru counterparts, which meant that the driving force for co-reactant
oxidation was often insufficient to drive the electron transfer reaction.
A major breakthrough in Ir(III) based ECL came from the group of Lee
in a publication released in 2005.52 The report investigated the ECL
performance of a series of cyclometalated Ir(III) species in acetonitrile
solutions. Most impressive were the complexes Ir(pq)2(acac) and
(pq)2Ir(tmd) (pq ¼ 2-phenylquinoline anion, acac ¼ acetylacetonate and
tmd ¼ 2,2 0 ,6,6 0 -tetramethylhepta-3,5-dione anion), which were found to
significantly outperform the classic Ru(bpy)321 system using a TPA co-
reactant, by factors of 77 and 44 respectively. This study highlighted the
promise that Ir(III) held in increasing the luminescent output of various
ECL applications, even though the investigation were based in an organic
solvent and the translation to water was not fast. For ECL based bio-
assays, an increase in luminophore luminescence means lower detection
limits, as fewer probes would be need to generate a measurable amount
of light. Unfortunately, more than 10 years after this report, Ru(bpy)321
remains the main luminophores for ECL applications, most likely due to
the poor water solubility of these often neutral species, which limits their
applications for biological assay. This has not stopped innovative scien-
tists from developing new ligand systems to increase solubility, incorp-
orating Ir(III) species into more advance materials or designing new ECL
assay that can take full advantage of the luminescence properties of Ir(III)
compounds. This section will focus on several recent examples of Ir(III)
based luminophores that highlight the progress being made in creating
new ECL based biological assays.
As mentioned, poor water solubility and low emission quantum yields
in aereated aqueous solution often plagues Ir(III) from being used in
biological applications. In an effort to ameliorate this problem, De Cola
et al. recently reported intense ECL emission from a series of neutral Ir(III)
complexes utilizing phenylpyridine-based ligands in water, Fig. 9.53 In
order to achieve ECL in aqueous solutions, this series of compounds was
first dissolved into a very small amount of DMSO before being added to
the commercially available ECL aqueous buffer ProCell, that contains the
TPA co-reactants and a number of different surfactants. Typical con-
centrations of the complexes in the ProCell buffer were on the order of
mM. The photophysical properties of these compound were quantified in
both acetonitrile and ProCell solutions. The photoluminescence peaks
for these complexes dissolved in acetonitrile was found to vary between
583–648 nm. A slight blue-shift was observed upon solvation within the
ProCell solution, with values ranging between 578–645 nm. Excited-state
lifetimes in acetonitrile under inert atmosphere were found to be
between 1.69–1.99 us, while the PLQY were found to be vary between
0.27–0.70. The PLQY in the ProCell buffer in the presence of oxygen were
found to be lower, ranging between 0.11–0.20, but the quenching was not
Photochemistry, 2019, 46, 319–351 | 337

Fig. 9 Ir(III) complexes investigated in ECL by De Cola et al. Reproduced with permission
from ref. 53, Copyright 2016 American Chemical Society.
so efficient as expected. Such behaviour was rationalized by the presence

of surfactants within the ProCell solution, which could form protective
micelles around the emissive compounds, shielding them from dioxygen.
This was further supported by the observed blue shift in the photo-
luminescence relative to acetonitrile that was attributed to hydrophobic
interactions within the micelles. The electrochemical properties of this
family of compounds was quantified in air free acetonitrile in order to
assess the compatibility with the TPA co-reactant. The oxidation poten-
tials for all the complexes fell within a narrow range of 1.07–0.93 V vs.
SCE. The oxidation was thought to be metal-aryl centre and therefore
more profoundly influenced by substitution on the aryl ligand. This was
evidenced by complex and 3–5, which showed nearly identical oxidation
potentials, while complex 2 showed a significant shift to lower potential.
Reduction potentials for all the complexes were nearly identical, while 5
was shifted to less reductive potentials due to the increase conjugation
on the ring. The ECL activities of each Ir(III) compound was evaluated in
the ProCell buffer using Ru(bpy)321 as reference. A positive potential was
applied and interestingly complexes 5 was able to outperform the
Ru(bpy)321 standard. The emission for this compound was found to be
3.72 times higher that of Ru(bpy)321 under the same conditions. This
338 | Photochemistry, 2019, 46, 319–351

study highlights the promise that Ir(III) complexes have in replacing
traditional Ru(II) based luminophore while demonstrating the amount of
work still needed until these compounds can effectively replace the
emitter on the market.
Often reports simple take biological assays which work well using a
Ru(II) based chromophore, and introduce an Ir(III) complex to greatly
improve the sensitive. Zhang et al. recently developed the cationic species
[Ir(bt)2(dmphen)]1 (bt ¼ 2-phenylbenzothiazole, dmphen ¼ 5,6-dimethyl-
1,10-phenanthroline).54 The compound displayed an intense yellow-
green luminescence that possess maxima at 522 and 561 nm, with a
high PLQY (0.92). Reversible oxidative and reductive electrochemistry
was observed for this compound, with reversible waves being observed at
þ1.51 and 1.29 V vs. SCE, respectively. ECL experiments confirmed the
intense yellow-green emission during annihilation mode. Remarkably,
the compound displayed 12 times higher ECL efficiency over the proto-
typical Ru(bpy)321 luminophore in a non-aqueous medium, in annihi-
lation mode. Efficient ECL was also observed in aqueous-media while
using TPA as a co-reactant and interestingly the Ir(III) luminophore was
found to be capable of intercalating within double-stranded DNA.
Intercalation greatly improves the PLQY and the ECL efficiency for this
compound. This effect is well known for several Ru(II) emitters, and has
been used previously for studying DNA. The observation was central to
the development of an ECL assay for the detection of m-RNA122, a
potential biomarker for different liver diseases. A self-assembled layer of
short thiolate dss-DNA on a gold electrode surface was exposed to
the m-RNA analyte present in an aqueous buffer, Fig. 10. The m-RNA then
hybridized with the surface bound DNA, forming a hybrid DNA/RNA
double-helix. The DNA was specifically selected as to not fully conjugate
with the RNA, leaving additional RNA nucleotides available for sub-
sequent interactions. A second auxiliary probe double-helix was then
introduced, which bound with the RNA nucleotides which were not yet
bound to the surface anchored DNA, creating a so called ‘‘supersandwich
Fig. 10 Schematic representation of a biological assay that utilized a Ir(III) luminophore

capable of intercalating within double stranded DNA/RNA for the detection of microRNA.
Reprinted with permission from ref. 54, Copyright 2017 Wiley-VCH Verlag GmbH & Co.
KGaA, Weinheim.
Photochemistry, 2019, 46, 319–351 | 339

double-stranded helix’’. Finally, the Ir(III) species was introduced, able to
intercalate in the groves of the double helix strand. This assembled
structure generated efficient ECL through the co-reactant mechanism in
an aqueous buffer. A much lower ECL signal was detected in the absence
of the RNA, which represented a control for the experiment. The intro-
duction of the second auxiliary probe double-helix was justified on the
basis of the approximate two-fold increase in intensity when compared to
the system based solely on the original DNA/RNA system. A linear rela-
tionship was observed between the concentration of the analyte RNA
strand and the ECL intensity, confirming this technique as a feasible
analytical tool. Moreover, a limit of detection of 1.31014 M
for m-RNA122 was achieved. This compared extremely well to other
similar assays.
In another report, Wang et al. developed a series of Ir(III) complexes
bearing pendant carboxylic acid functional groups capable of forming
covalent bonds to antibodies used in biological assays, Fig. 11.55 An
analogous Ru(II) was also prepared which acted as a control to compare
against the Ir(III) labels. The photophysical properties of these complexes
were quantified in acetonitrile solution. The emission wavelength peaks
varied between 508–707 nm, dependent on the nature of the non-
carboxylic acid bearing ligand, while the PLQY for the Ir(III) complexes
varied between 0.13–0.28 in nitrogen saturated acetonitrile. The nature of
this emissive state was further investigated through DFT studies. In
general, the excited-state was assigned to a HOMO to LUMO transition,
with the observed charge distribution allowing the assignment of a
mixture of metal-to-ligand and ligand-to-ligand charge transfer to the
transition. Due to its importance to ECL, the authors then investigated
the electrochemical properties of each compound, and found that most
compound possessed a reversible oxidation between 0.78–1.26 V vs.
Fc1/0, and irreversible reduction behaviour between 1.39 and 1.66 V.
ECL measurement were then performed for each compound using TPA as
a co-reactant. The ECL intensity were compared against Ru(bpy)321 under
the same experimental conditions. All Ir(III) based luminophores were
Fig. 11 Series of Ir(III) complexes for bioconjugation prepared by Wang et al. Reproduced
from ref. 55 with permission from The Royal Society of Chemistry.
340 | Photochemistry, 2019, 46, 319–351

found to outperform the standard, with the greatest increase arising from
Complex 10 at nearly 10 the intensity of Ru(bpy)321. In order to cal-
culate the absolutely ECL quantum efficiencies, ECL signals were
obtained from each label in annihilation mode using a previously
reported method for determine the yields. Remarkable, label 3 reached a
quantum yield of 0.85, nearly 18 times higher than the standard
Ru(bpy)321. The authors selected this label for subsequent experiments
for the development of a probe using the model protein bovine serum
albumin. For this experiment, the carboxylic acid was transformed into
a N-hydroxysuccinimide (NHS) ester, and the transformed molecule was
added to a PBS buffer containing BSA, which then formed the active
label. The same procedure was followed for the preparation of the Ru
based dye, as to provide a standard for the Ir(III). Bicinchoninic acid
protein assay was used to quantify the amount of BSA present, and the
absorbance of the label was used to quantify the amount of metal com-
plex presence. The Ir(III) based label gave a more intense signal (1.9 times)
under the same label concentration relative to Ru(II). Though no assays
were performed in this report, such an observation suggest that Ir(III)
could improve the sensitive of many assay and improve the detection
limit for the quantification of proteins.
A recent example of biological ECL assays using Ir(III) emitters for the
detection of specific cell-surface carbohydrates was presented by Zhang
et al.56 These carbohydrates are important for many cellular processes,
including cell adhesion, differentiation and detection of different
pathological processes. Abnormal expression of surface carbohydrates
are also associated with many diseases such as cancer and Alzheimer. In
this report, the authors combined previously prepared Ir(III) lumino-
phores with mesoporous silica nanoparticles and Au nanoparticles
to prepare a composite material (Au/Ir-MSN) as a novel ECL signaling
probe. The composite functioned by encapsulating the Ir complex,
[Ir(ppy)2(dcbpy)]1 (dcbpy ¼ 4,4 0 -dicarboxy-2,2 0 -bipyirinde) within the
pores of the MSN, and then sealing the pores with the AuNPs. The system
was based on the binding between concanavalin A (Con A) and mannose.
Con A was attached to both a GC electrode previously functionalized with
a modified graphene layer and to the AuNP used to seal the pores of the
MSNs. Test cells were first introduced to the functionalized GC electrode,
where the cells adhered to the electrode if they expressed the target
carbohydrates. After washing away the unbound cells, the Au/Ir-MSN was
introduced creating a sandwich-type system consisting of the GC elec-
trode, target cell, and the Au/Ir-MSN, Fig. 12. The presence of a TPA co-
reactant in the external electrolyte led efficient ECL from the cells present
at the interface, allowing for the quantification of cells expressing the
target carbohydrate. No ECL was observed in the absence of Au/Ir-MSN,
demonstrating that the hybrid system was the source of the emission.
Additionally, the absence of a target cell shows no significant ECL, de-
mostrating that this system was effective for the detection of cells
expressing the target carbohydrate. The performance Au/Ir-MSN was
compared against a similar structured probe utilizing Ru(bpy)321 instead
of the Ir(III) luminophore. The authors claimed a 24-fold increase in the
Photochemistry, 2019, 46, 319–351 | 341

Fig. 12 Assay for the detection of specific surface carbohydrates based on a Au/Ir-MSN
probe. Reprinted with permission from ref. 56, Copyright 2014 WILEY-VCH Verlag GmbH
& Co. KGaA, Weinheim.
ECL emission of free Ir-MSN when compared to Ru-MSN before incu-

bation with the cells, while a 20-fold increase was observed for the full Ir
assembly after incubation with 1.0105 cell mL1 when compared to
signal observed from the Ru system under analogous conditions. A linear
relationship between cell concentration and signal was observed from
the Ir system, and a lower limit of detection of 100 cells mL1 was
determined through a linear regression, similar to several other techni-
ques for surface carbohydrate detection. Specificity towards a specific
carbohydrate was demonstrated by a lack of ECL signal when the system
was incubated with cells that did not express the target carbohydrate.
The above summarized studies highlight the progress being made in
developing Ir(III) luminophores for biological assay. Arguable, Ir(III) rep-
resent the most promising alternative to Ru(bpy)321, and novel devel-
opments will lead to more performant systems for biomedical assays.
Though solubility, non specific binding and long term stability remain a
problem, ligand modification and incorporation into hybrid systems can
solve the problems. Nevertheless, considerable work remains before the
full potential of Ir(III) complexes can be realized.
4 Platinum complexes
The first example of ECL from platinum complexes date back 1984
by Vogler et al.57 who showed ECL through annihilation method from
Tetrakis(diphosphonato)diplatinate(II). Interestingly, such complexes are
characterized by a dual emission at room temperature in solution: a weak
fluorescence (lmax ¼ 407 nm) of the singlet 1A2u state, and an intense
phosphorescence (lmax ¼ 517 nm) of the triplet 3A2u state. However when
ECL experiment were performed by alternating current electrolysis with
variable frequency using TBABF4 as supporting electrolyte in dry acet-
onitrile only a marked green luminescence was observed at the electrode,
which was visible even by eye. Such a result suggested that the
342 | Photochemistry, 2019, 46, 319–351

recombination of the oxidized and reduced species furnishes sufficient
energy to generate one of the two states: the lowest luminescent excited
state, the triplet 3A2u while the highest energy one cannot be populated or
immediately decay to the triplet state. A few years later, another example
of ECL of luminescent platinum(II) complex was reported by Balzani
et al.58 in 1986 using the cyclometalated Pt(Thpy)2 where Thpy is 2-(2-
thienyl)-2-pyridine. This compound is characterized by photo-
luminescence in fluid solution at room temperature in dimethylforma-
mide at lmax ¼ 580 nm, while its electrochemistry is characterized by two
one-electron reversible reduction processes (Epc ¼ 1.80 and 2.11 V vs.
SCE) and one irreversible oxidation (EpaEþ0.82V vs. SCE). Also in that
case ECL was observed trough annihilation method by alternating current
electrolysis experiments stepping the potential between 1.80 and
þ0.85 V. Interesting they also investigated the effect of a co-reactant in the
system. In particular, in presence of S2O82 ECL was generated upon
continuous reduction at 1.80 V. Also in that case the ECL spectrum was
consistent with the photoluminescence spectrum, indicating that the
chemical reactions that follow the electrochemical processes lead to the
same metal-to-ligand charge-transfer excited state that is generated by
light excitation.
Pt(II) porphyrins showing ECL have been reported at the beginning
of 2000 by Kulmala et al.59 who showed that cathodic pulse polarisation
of oxide-covered aluminium electrodes can generate electro-
chemiluminescence (ECL) from platinum(II) coproporphyrin (PtCP) and its
bovine serum albumin (BSA) conjugate. This allows the detection of this
molecule below nanomolar concentrations while the relatively long lumi-
nescence lifetime allows discrimination from the background ECL signal
using time resolved measurements, further increasing the sensitivity of the
system. Furthermore the detection of PtCP-BSA clearly indicated the
potential use of platinum porphyrins as labels in ECL-based bioassays.
Another example was reported few years later by Richter et al.60 that showed
ECL of platinum (II) octaethyl-porphyrin (PtOEP) in organic solvents. In this
case ECL was generated by co-reactant method using TPA and the efficiency
of the process was evaluated versus Ru(bpy)3 and found to be 18%.
An important step towards the design of new ECL emitters based on
platinum(II) complexes has been made by Hogan et al.61 that reported a
series of platinum(II) Schiff base complexes in which the electronic
density can be directed selectively toward the LUMO or HOMO by ligand
design. As anticipated in the introduction, the possibility of tuning
independently the HOMO and LUMO of a luminophore is extremely
important in ECL since it allows the modulation of the emission colour
without altering the oxidation (HOMO not altered) or reduction (LUMO
not altered) potential of the complex thus enabling multiplexed detec-
tion. In the Schiff base compounds reported by Hogan (see Fig. 13) the
modulation of the electronic density was obtained by varying the number
and position of the methoxy substituents on the phenoxy ring. The effects
of the change in the electronic properties were then correlated with their
photophysical, electrochemical and electrochemiluminescent (ECL)
properties.
Photochemistry, 2019, 46, 319–351 | 343

Fig. 13 Schiff base Pt(II) complexes 12–18 reported by Hogan. Reproduced with permis-
sion from ref. 61, Copyright 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Table 1 Properties of the Schiff base Pt(II) complexes 12–18 reported by Hogan.61
Electrochemical potential are reported against ferrocene (Fc) which was 0.35 versus
Ag/AgCl. ECL intensities are calculated against the standard [Ru(bpy)3]21. Reproduced with
permission from ref. 61, Copyright 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
lem Fem
Complex [nm] [%] labs [nm] Eox [V] Ered [V] ECLann ECLTPA
12 620 3.8 534, 498, 463, 381, 362, 0.73 1.98 489.6 0.1
321, 252
13 587 1.6 496, 401, 381, 361, 254 0.45 2.11 229.0 0.2
14 590 5.6 505, 475, 441, 381, 365, 0.63 2.05 73.5 1.0
315, 254
15 615 4.9 526, 505, 461, 407, 384, 0.68 1.97 0.6 2.0
334, 254
16 647 3.5 538, 516, 468, 395, 373, 0.35 1.80 0.6 49.5
351, 263
17 698 4.8 575, 545, 498, 387, 366, 0.46 1.75 1.0 35.6
322, 263
18 739 0.6 581, 548, 508, 396, 370, 0.53 1.83 3.9 1.9
335, 254
[Ru(bpy)3]21 620 2.7 450, 270 100 100
When an electron-donating and ortho/para directing such as OMe is

placed at positions R3 and/or R5 it can destabilise the imine-localised
LUMO whilst having virtually no impact on the HOMO. Contrarily, if the
electron-donating group is placed at positions R6 or R4 which are ortho/
para positions respect to the Pt-O the HOMO is destabilised without
impacting the energy of the LUMO. This resulted in a clear trend in the
photophysical properties across the series, with the MLCT absorbance
bands progressively shifting from 496 to 581 nm and the emission
maxima shifting from 587 to 739 nm going from complex 13 to complex
18 (see Table 1).
In particular in the complexes 13, 14 and 15 which contain the methoxy
group at positions ortho and/or para to the imine group (R6 and R4) the
emission energy increases according to the following pattern: orthoopara
oortho and para. This is consistent with a LUMO residing substantially
on the imine moiety, which is progressively destabilised on going from 15
to 14 to 13. The same trend has been observed for the electrochemical
reduction potentials: the more electron density is located on the imine
344 | Photochemistry, 2019, 46, 319–351

moieties (LUMO) the higher is the reduction potential which moves from
1.97 to 2.11 V. A similar argument applies to complexes 16, 17 and 18,
which are substituted at positions R3 and R5, ortho and/or para to the
metal bonded oxygen. In this case the reduction potential is almost
unchanged while the complexes display the lowest emission energy thus
indicating that HOMO level must have been increased. Unfortunately, the
quasi-reversible nature of the electron transfer processes complicates the
interpretation of the anodic part of the cyclic voltammetry thus obscuring
the correlation between the oxidation potential and the molecular
design. The selective modulation of the electron density has been further
confirmed by DFT calculation showing that is also possible to employ
other substituents such as methyl, NH2 or CN group, the latter having an
effect equal but opposite to OMe.
The annihilation ECL was observed for all the complexes and the
mechanism proposed the generation of the oxidized and reduced species
(eqn 1 and 2) followed by two electron transfer reaction (eqn 3 and 4) the
latest resulting in the formation of the excited state.
[PtIISal]-[PtIVSal]21 þ 2e (1)
[PtIISal] þ e-[PtIISal] (2)
[PtIVSal]21 þ [PtIISal]-[PtIIISal]1 þ [PtIISal] (3)
[PtIIISal]1 þ [PtIISal]-[PtIISal]* þ [PtIISal] (4)

Indeed the driving force in the annihilation reactions, calculated from
the electrochemical potential (Eox Ered) are sufficiently exergonic to
form the excited state for all the complex of at least 0.27 eV. However the
most intense ECL emitters under annihilation conditions are complex 12,
13 and 14 that possess also the most negative reduction potentials even
exceeding the Ru(bpy)3 benchmark in the same conditions. Also co-
reactant ECL was observed for all complexes using TPA as sacrificial
agent at the potential corresponding to the oxidation of the platinum
complex. The mechanism proposed in that case is similar to the one
generally reported for Ru(bpy)3 in which the TPA is oxidized at the same
potential of the metal followed by electron transfer from the oxidized TPA
to the oxidized metal complex resulting in the generation of the excited
state. The only difference is that most likely there are two consecutive
reduction steps.
[PtIISal]-[PtIVSal]21 þ 2e (5)
TPA-TPA 1-TPA þ H (6)
[PtIVSal]21 þ TPA -[PtIIISal]1 (7)
[PtIIISal]1 þ TPA -[PtIISal]* (8)

Contrarily to the annihilation ECL, the most intense ECL emitter under
such conditions were complex 16 and 17 that were the worst performing
Photochemistry, 2019, 46, 319–351 | 345

in the annihilation ECL. Interestingly both complexes possess the least
negative reduction potentials (1.80 and 1.75 V respectively) thus less
negative then the TPA (B2.1 V vs. Fc) which is a fundamental require-
ment as pointed out in the introduction. Also the fact that they possess
the lowest oxidation potentials while being still high enough to oxidize
TPA can have an important impact on the ECL efficiency since it assure a
fast generation of the oxidized species and probably less parasitic
reactions.
Due to their square planar geometry, Pt(II) complexes generally display
a high tendency to stack resulting into the formation of supramolecular
structures. This self-assembly process is often accompanied by a dra-
matic change in the electronic properties which is due to the establish-
ment of Pt Pt metallophilic interaction. Such peculiar property has
attracted particular attention in the last decade since such complexes can
be weakly emissive in the molecularly dissolved state and become
extremely emissive in the aggregate form with PLQY up to 90%.62 Fur-
thermore the control of the degree of metallophilic interactions can be
used to tune the emission spectra over almost the entire visible spec-
trum63,64 thus making them extremely appealing for light emitting
application such OLED. Even if the change of the photophysical prop-
erties due to the establishment of Pt Pt metallophilic interactions was
already reported by in 197465 it was only last year that an example of
ECL system based on aggregated species has been reported.66 The
amphiphilic complexes reported by De Cola et al. contain an hydrophobic
terdentate ligand (see Fig. 14) and an hydrophilic ancillary 4-amino
pyridine substituted with one (complex 19) or two triethylene glycol
chains (complex 20).
Interestingly when 19 or 20 are dissolved in dichloromethane (DCM)
solution at room temperature they display the same photophysical fea-
tures, in particular they are characterized by intense absorption bands in
the UV region, mainly attributed to the intraligand (1IL) and metal-
perturbed interligand charge transfer (1ILCT) states and low energy
transitions up to 420 nm assigned to a metal-to-ligand charge transfer
transitions (MLCT). Also upon photoexcitation, in organic solvents, they
exhibit the same structured blue luminescence with low emission
quantum yield (PLQY ¼ 1%), assigned mainly to the ligand-centered tri-
plet excited state (3LC) typical of the monomeric form (molecularly dis-
solved state), Fig. 14. For both complexes ECL experiments performed in
such solvent using TPA as co-reactant gave rise to negligible light emis-
sion. The main difference between the two complexes relies indeed in
their different tendency to self-assemble in aqueous media; while 19 is
not water soluble 20 readily dissolves forming stable clear suspension of
spherical nanoaggregates of 22 nm of diameters. Such particles showed a
strong yellow–orange emission centred at 600 nm with PLQY up to 72%
which is due to the establishment of Pt Pt metallophilic interactions.
Furthermore, it was found that, conversely to the molecularly dissolved
state, the aggregates are extremely ECL active. Indeed, ECL experiments
in aqueous media with TPA as co-reactant, have shown an ECL efficiency
20% higher than Ru(bpy)321 while employing Na2C2O4 as co-reactant
346 | Photochemistry, 2019, 46, 319–351

Photochemistry, 2019, 46, 319–351 | 347
Fig. 14 Structures of the complex 19 and 20 reported by De Cola et al. and their photophysical and ECL properties.
instead of TPA increased the ECL intensity dramatically, exceeding the
standard Ru(bpy)321 by a factor of 14.
The Pt Pt metallophilic interactions does not only change the pho-
tophysical properties of the emitter but also its electrochemical behav-
iour since it destabilizes the HOMO, resulting in a lower oxidation
potential of the species. Indeed, in the monomeric form, the oxidation of
the Pt(II) falls above the electrochemical window of the solvent thus it
could not be detected while, in the aggregated form, an irreversible oxi-
dation peak at þ1.33 V vs. Ag/AgCl was observed and ascribed to the
oxidation of Pt21 to Pt41.
The presence of two hydrophilic chains allows the solubilisation of the
complex in aqueous media but also keep the particle size relatively small.
Complex 19, which features a single PEG chain, required instead a pre-
solubilization in organic solvent (i.e. dioxane) followed by flash injection
in distilled water to form the orange emitting suspension which consist
of 130 nm particles that tends to increase their size over time.67 It is likely
the large size of the aggregates as well as the stability of the dispersion
that causes the failure of the ECL experiment for such complex since it
can limit the diffusion of the species to the electrode surface.
Even if ECL could not be performed in solution using complex 19, a
further evidence that the establishment of Pt Pt metallophilic inter-
actions is responsible of the electrochemical generation of light was
obtained in the solid state. Profiting of the mechanochromic properties
of the complexes,68 compound 19 in the blue emitting form was phys-
ically transfer on carbon screen-printed electrodes (SPEs) and oxidize in
presence of the co-reactant resulting in a very weak emission. Then it was
mechanical stress with a gentle grinding to convert the blue emitting
form into to orange bright emissive one resulting into a 20 times higher
intensity than that before grinding.
Even though the mechanism of the electrochemical light generation in
such kind of system has not been explored yet, the formation of supra-
molecular systems involving metallophilic interactions opens the route
for the design of new efficient ECL emitters that can be applied for bio-
sensing and immunoassays.
In conclusion only few examples of ECL based on luminescent plat-
inum complexes has been reported so far. Probably one of the biggest
limitation is the irreversible character of the oxidation of the Pt(II) to Pt(IV)
which result in a change of the coordination geometry from square pla-
nar to octahedral. Due to such change of the coordination geometry, the
chemical or electrochemical formation of the Pt(IV) should be followed by
an insertion of two or more ligands in the coordination sphere which can
come from the co-reactant, the solvent or from some electrogenerated
species as well. The resulting complex can possess different stability and
(opto)electronic properties and its reduction back to the square planar
Pt(II) complex in the excited state should also be preceded by the expul-
sion of the two ligands in excess which can be different from the ones
captured during the oxidation step. In order to amplify the ECL signal the
emitter should be able to undergo many oxidation/reduction cycles being
the co-reactant the only specie consumed since it is this process that
348 | Photochemistry, 2019, 46, 319–351

results in the amplification of the signal. Indeed many challenges have
still to be addressed from the mastering of the metallophilic interactions
through supramolecular approaches to the understanding of the mech-
anism involved in the ECL and the design of new ligands which takes into
account the geometry switch between Pt(II) and Pt(IV).
In conclusions only noble metals have been so far employed for ECL
and to the best of our knowledge no examples employing cheap and
abundant metals have been developed for bioassays.
There is plenty of room for other systems and the advancement in
ligand design, corroborated by calculations and spectroscopic measure-
ments can definitely lead to exciting new systems.
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Photochemistry, 2019, 46, 319–351 | 351

Photoinduced bond activation via Ru and
Rh dihydrides: principles and selectivity
Barbara Procacci
DOI: 10.1039/9781788013598-00352
This account reports on the fundamental principles of photoinduced bond activation

through reductive elimination and oxidative addition reactions at group 8 and group 9
metal dihydrides. A recap of the seminal studies on the two elementary steps is presented.
In addition, new developments employing laser pump-NMR probe methods are described
with relevant examples. Kinetic and thermodynamic selectivities on C–H, C–C, C–F, B–H
and Si–H bond activations are discussed.
1 Introduction
Over the years, a massive effort by the organometallic community has been
directed into gaining a better understanding of the activation and func-
tionalisation of strong bonds (C–H, C–F, Si–H and B–H) by homogeneous
metal complexes. Several comprehensive reviews have covered this
topic.1–13 The understanding of selective bond cleavage, although of sig-
nificance, is often neglected in the investigation of catalytic processes. For
instance, very good borylation9,14 and hydrosilylation catalysts8 selectively
cleave the B–H and Si–H bond, without altering other functional groups in
the molecule. Selectivity becomes most important when the products of a
reaction may also react with the catalyst and is critical in scenarios where
the catalyst can react with the product in preference to the starting
material.15 Oxidation of alkanes to alcohols (e.g. methane to methanol)16
faces this issue; the latter will readily oxidize to yield aldehydes or ketones.
The photochemistry of metal dihydride complexes has proved a
powerful tool to generate unsaturated reactive intermediates which can
activate strong bonds in various molecules. Although many catalytic cy-
cles are thermally driven the possibility to use photochemistry has helped
a great deal in understanding the fundamental principles of catalysis
through the detection of unstable products via irradiation at low tem-
perature17,18 and the use of time-resolved methods19,20 to determine
reaction kinetics. We have recently produced a wide-ranging review on
this topic covering very early metal dihydride photochemistry through to
the latest discoveries, including a systematic survey of photochemical
reactions of metal hydrides by group, and the analysis of the theory on
metal dihydride photochemistry. The techniques for studying photo-
chemical mechanisms were also surveyed.21
Group 8 (Fe,14,22–27 Ru,28–31 Os32–34) and group 9 (Rh,35–45 Ir46–53) metal
dihydrides have been found to possess the best qualities for use as
homogeneous catalysts for the oxidative addition of very strong bonds via
Centre for Hyperpolarisation in Magnetic Resonance, Department of Chemistry,

York Science Park, University of York, York YO10 5NY, UK.
E-mail: barbara.procacci@york.ac.uk
352 | Photochemistry, 2019, 46, 352–369

Scheme 1 Reaction scheme showing the H2 reductive elimination step (dashed circle) to
the formation of the unsaturated fragment (intersection point), the oxidative addition step
(solid circle) with the cleavage of the EX bond follow to generate a saturated product.
photogeneration of the unsaturated intermediates; their reactivity has

been explored over the years and these results contributed to a better
understanding of bond-breaking and bond-making.
In examining photoreaction as a tool to activate a strong bond, one of
the preferred routes is via the formation of a vacant site on the metal centre
by photoreductive elimination of a ligand with subsequent oxidative
addition of the substrate (Scheme 1) creating two new metal bonds. This
report will be concerned with this class of reactions providing a summary
of the seminal studies for the reductive elimination step, as exemplified via
group 8 metal dihydrides. The same approach will be adopted for the
oxidative addition step using group 9 metal dihydrides. In addition,
thermodynamic and kinetic selectivity on the activation of C–H bond
will be discussed with a focus on the latest discoveries on competition
reactions between C–H and the hetero bonds, C–C, C–F, B–H and Si–H.
The process will be analysed as two stand-alone reactions (Scheme 1):
(1) The photochemical reductive elimination which yields the reactive

intermediate.
(2) The thermal oxidative addition of the EX bond that forms the product.
2 Group 8 metal dihydrides for the reductive

elimination step
One of the main pathways to access a reactive intermediate is by the
reductive elimination of a photolabile ligand. This causes a decrease
in oxidation state at the metal centre (usually by two), and the generation
of an unsaturated 16e complex.54,55 Group 8 mutually cis-dihydrides
are among the best photoactive species to yield reactive intermediates;
studies of their reactivity via steady state photochemistry but particularly
via time resolved methods have helped to unveil the nature of photo-
chemical processes involved. Many reports have reviewed these early
experiments21,56 and therefore only a brief summary of the key findings is
provided here. A highlight of recent results obtained on group 8 dihy-
drides in the development of a new pump–probe method which involves
nuclear magnetic resonance (NMR) as a probing step follows.
2.1 Seminal studies

Reductive elimination of H2 from group 8 metal dihydride complexes is a
well-understood photoprocess. The reductive elimination was established
Photochemistry, 2019, 46, 352–369 | 353

to be concerted and to compete successfully with loss of other ligands
such as CO or phosphines.57–59 Fe(CO)4H2 was among the first metal
complexes for which H2 reductive elimination was observed by matrix
photochemistry; the microscopic reverse oxidative addition of H2, was
also reported to take place in matrices at longer wavelengths.60 An
extensive theoretical description of the reductive elimination mechanism
for the tetracarbonyldihydridoiron complex supported the experimental
observation for H2 reductive elimination as the preferred photochemical
pathway.61,62
Mass spectrometry was used to look at H/D cross over experiments in
the photolysis of Ru(dmpe)2H2 and Ru(dppe)2H2; only a very minor
amount of HD was detected in these experiments and therefore H2
reductive elimination was postulated as the main photochemical
process.63 Since then, other techniques such as matrix photo-
chemistry,55,56,64–68 time resolved UV–Vis absorption29–31,34,66,69–72 and
more recently time resolved-IR57,73 have allowed detection of the tran-
sients, establishing prompt cleavage of the M–H bond (ca. 16 ps
for [Ru(dmpe)2])70 with concomitant formation of molecular hydrogen.
H2 readdition to the transient species [Ru(dmpe)2] was measured to
take place almost at the diffusion limit ((6.8 0.3)109 M1 s1).66
Experiments to prove homolytic cleavage of the M–H bond were
unconvincing63 while measurement in the presence of a D2 atmosphere
corroborated the concerted nature of H2 reductive elimination.31
2.2 Trends
A variety of group 8 dihydride complexes (M-carbonyl, M-phosphine, or
mixed-ligand compounds) consistently showed the same photochemical
mechanism in which H2 is photoejected within timescale of the laser
flash (typically nanosecond). The rates reported for the oxidative addition
of the quencher varied depending on the electronic and the steric
properties of the ligands around the metal centre. As an example, a trend
in the k2 values (Fig. 1, top) for a series of Ru(H)2 complexes with different
bidentate phosphine ligands (Fig. 1, bottom) in the presence of H2 and
HBpin is analysed; second order rate constants k2 are larger for com-
plexes with less bulky phosphines, (e.g. dmpe, depe). The fragment
[Ru(dppe)2] shows 10 times greater reactivity towards HBpin than to-
wards the BPE analogue.31
The transient [Ru(DuPHOS)2] is almost 100 times slower to react with
HBpin than the [Ru(dppe)2] transient. The difference in reactivity can be
explained by the use of phoshines Me-BPE and Me-DuPHOS where the
methyl substituent on the phosholane ring causes steric congestion and
limits the access for the ligands to the unsaturated Ru centre. The
reduction in reactivity towards HBpin observed on going from
[Ru(dmpe)2] to [Ru(dppe)2] spans a factor of 1500 and it is probably due
to the sum of a steric effect played by the bulkier dppe phosphine and the
smaller electron donation from the ligand to the Ru centre. The same
trend is observed for reactions with H2. [Ru(dppe)2] is again less reactive
than [Ru(depe)2] and [Ru(dmpe)2] and the rate constants for complexes
354 | Photochemistry, 2019, 46, 352–369

Fig. 1 Top: Plot of log10 k2 versus the different Ru(PP)2H2 complexes in the presence of
HBpin (dense lines) and H2 (sparse lines) where k is the second order rate constant for
substrate oxidative addition. Bottom: Structures of the various PP bidentate phosphines
used. Relevant ref. 30, 31, 66. iPr-BPE ref. 74.
[Ru(BPE)2] and [Ru(DuPHOS)2] are even smaller than those observed for
[Ru(dppe)2]. However, since H2 is a small ligand, the steric effects of the
methyl groups on the phospholane ring are less significant than in
reactions with HBpin. For the reaction with HBpin a reduction in rate
constant by a factor of 80 is observed when going from [Ru(dppe)2] to
[Ru(DuPHOS)2], while for the reaction with H2 a reduction in rate con-
stants of just a factor of 4 is observed when going from [Ru(dppe)2] to
[Ru(DuPHOS)2]. A huge effect on the rate constants is observed with the
[Ru(iPr-BPE)2] fragment in which the rate constant for reaction with H2 is
massively reduced and no reactivity is observed in the presence of
HBpin.74 The geometry of the transient formed by reductive elimination
of H2 is found to greatly influence the reactivity towards the same mol-
ecule.75 The reaction of [Ru(dmpe)2] with H2 in solution was measured to
be 7500 times faster than the same reaction for the [Fe(dmpe)2] transient,
these findings were rationalised on the basis of a butterfly C2v geometry
Photochemistry, 2019, 46, 352–369 | 355

for the Fe complex and a square planar D2d geometry for the Ru
analogue.75
2.3 Laser pump-NMR probe & para-H2: revisiting old insights

The degenerate reaction of ruthenium dihydrides in the presence of an
H2 atmosphere was particularly suitable to the development of our laser
pump-NMR probe method.76 The use of hyperpolarisation (deviation
of nuclear magnetisation from the standard Boltzmann distribution
through the selective population of energy levels, Fig. 2, top) afforded by
the para-isomer of H277,78 yielded an exceptional increase in the sensi-
tivity of NMR spectroscopy allowing measurements to be done with
a single NMR scan on optically dilute samples (nanomoles of product).
Briefly, para-H2 is one of the two nuclear spin isomers of H2, it is a
nuclear spin singlet state. This singlet state has no net angular
momentum. As such, it is disconnected from the other nuclear spin
isomer (triplet states) and therefore it possesses a much longer lifetime
than the common triplet states.79,80 However, the absence of a net
angular momentum also makes it NMR silent. In order to unlock the
signal intensity benefits of the hyperpolarisation the symmetry of the
singlet state needs to be broken; this can be achieved by oxidative add-
ition to a metal centre to generate a metal dihydride where the two
hydrides will be either chemically or magnetically inequivalent.81
The degenerate product formed by para-H2 addition is now in a
hyperpolarised state (Fig. 2, bottom), the 1H NMR spectrum will show
characteristic antiphase signals (Fig. 2, top) greatly enhanced in com-
parison to a standard NMR spectrum.
In the pump–probe experiments a single laser shot photoinitiates the
reaction and a single NMR pulse detects the outcome; a well-controlled
delay t, between the two steps is what resolves the method in time
(Scheme 2); this delay can be as short as few ms.76 The observation of
hyperpolarised hydride signals for a series of RuH2 complexes has been
Fig. 2 Top: State population for a para-H2-derived reaction product containing nuclei I1
and I2, under hyperpolarised conditions with the resultant antiphase NMR peaks illustrated.
Reprinted with permission from ref. 76, Copyright 2014 American Chemical Society.
Bottom: General reaction for the photochemical reactivity of a metal dihydride toward
para-H2. Blue denotes hyperpolarized 1H nuclei originating from para-H2 oxidative add-
ition. Reproduced from ref. 82 with permission from The Royal Society of Chemistry.
356 | Photochemistry, 2019, 46, 352–369

Scheme 2 NMR pump–probe sequence used in the laser pump-NMR probe experi-
ments. Reprinted with permission from ref. 76, Copyright 2014 American Chemical
Society.
Fig. 3 Metal complexes that undergo concerted reductive elimination of H2 investigated

by the laser pump-NMR probe method.
reported by the use of this new approach (Fig. 3).76,81 The method has
also been applied successfully to a Vaska Ir dihydride system and the
kinetics of H2 oxidative addition to the unsaturated fragment determined
(Fig. 4, left).82 In all of the systems shown in Fig. 3, a concerted reductive
elimination and readdition of H2 was decisively confirmed by the laser
pump-NMR probe method; these results found agreement with those
previously reported by different time resolved techniques.
Interestingly, the development of this novel technique has not just
contributed to the understanding of the elementary photochemical steps
but has also allowed the observation of magnetic phenomena in the form
of signal oscillations (zero quantum coherences, ZQ). ZQ coherences are
not directly observable in NMR. The synchronous initiation step (laser
pulse) in this method allows these phenomena to be chemically created
and detected; the frequency at which ZQ coherences oscillates is dictated
by the difference in chemical shift (Dn) of the chemically inequivalent
hydrides derived by para-H2 addition or by the P–H coupling network
| JPHtrans JPHcis| in the case of chemical equivalence but magnetic non-
equivalence of the para-H2 derived hydrides.76,81 The importance of ZQ
coherences has been recently reviewed.83
The reactivity of Ru(H)2(CO)(PPh3)3 has been reinvestigated by photo-
chemistry inside an NMR spectrometer in conjunction with para-H2
induced polarisation.57 In addition, nanosecond time resolved-IR spec-
troscopy was employed to provide parallel information on shorter time-
scales. Two competing photochemical pathways were determined to take
place with approximately the same quantum yield at 355 nm:
H2 reductive elimination as previously reported,73 and PPh3 loss. The
hyperpolarised hydride peak confirmed the concerted H2 photoejection;
Photochemistry, 2019, 46, 352–369 | 357

358 | Photochemistry, 2019, 46, 352–369
Fig. 4 Left: Hydride signal integral values of Ir(PPh3)2(CO)H2 versus t (time) taken from a series of 1H{31P} NMR spectra that were recorded under 3.31 bar of para-
H2 pressure. Coloured squares/circles are the experimental points while the lines show the best fit to the points yielding kobs for para-H2 oxidative addition.
Reproduced from ref. 82 with permission from The Royal Society of Chemistry. Right: Integral of the hyperpolarized hydride signal of Ru(ddpe)2H2 in a series of 1H
laser pump-NMR probe experiments acquired with increasing delay t, demonstrating the impact of ZQ coherence evolution. Blue squares: experimental points. Red
line: fit to a decaying sine-wave of frequency 84 0.1 Hz. Reprinted with permission from ref. 76, Copyright 2014 American Chemical Society.
H2, pyridine and triphenylarsine substitution products, all of which were
characterised by NMR supported PPh3 loss. TRIR allowed detection of the
transients [Ru(CO)(PPh3)3] and [Ru(H)2(CO)(PPh3)2] generated via both
the photochemical pathways.57
3 Group 9 metal dihydrides for the oxidative

addition step
The reactive intermediate formed by reductive elimination of H2 will
undergo a chemical transformation to restore the 18e configuration.
Oxidative addition is one route to restore the initial oxidation state at the
metal centre through the cleavage of a strong bond and the formation of
two new M–X and M–E bonds (Scheme 1, step 2).
For many years the organometallic community has focused on C–H
bond activation of hydrocarbons; this process has proved to be a chal-
lenge due to the strength and apolar nature of the C–H bond. Never-
theless, substantial discoveries have been made since the initial
studies.84 Similarly, the understanding of Si–H and B–H bond cleavage
along with the control of site selectivity has been fundamental to achieve
C–H bond functionalisation.9
Fluorine also forms a very strong bond with carbon resulting in
inertness of perfluorinated compounds against chemical attack and as a
consequence they have proved very good solvents in many organometallic
reactions.85 However, selective C–F activation was found to be feasible
when certain metal complexes were employed.2,86,87
Photogenerated Rh and Ir fragments have proved excellent in lowering
the energy barriers for the activation of strong bonds and the study of
their reactivity has provided a better understanding of the thermo-
dynamics and kinetics properties that govern bond activation. A brief
summary of the seminal studies on C–H activation will be given here with
a focus on the most recent findings in intramolecular and intermolecular
selectivity between the activation of C–H bonds and the ‘‘hetero bonds’’
(Si–H, B–H, C–F and C–C).
3.1 Seminal studies

Cp*Ir(H)2(PMe3) was one of the first photochemical C–H activator of
alkanes to be reported.46 The extraordinary reactivity of the unsaturated
metal fragment [Cp*Ir(PMe3)] formed by photochemical H2 elimination
made it impossible to find a suitable inert solvent. Solution photo-
chemistry in C6H6, C6H12, and (CH3)4C all resulted in the formation of
the respective hydrido alkyl/aryl–Ir complexes.46 Liquid xenon was
employed as a medium to investigate oxidative addition reactions at
B195 K; activation of CH4 and secondary C–H bonds of cyclic alkanes was
observed under this conditions.88 C–H bond cleavage in alcohols was
obtained with isopropyl alcohol and tert-butyl alcohol; whereas methanol
and ethanol underwent O–H bond cleavage.88 The selectivity for the
activation of primary C–H bonds over secondary ones was determined via
competition experiments;47 the kinetic isotope effect was used to estab-
lish the preference for intermolecular C–H activation of the reactants
Photochemistry, 2019, 46, 352–369 | 359

over intramolecular C–H activation of the bonds of the ligands on the
metal complex; intramolecular C–H activation of the phosphine phenyl
C–H bond was observed in the photochemical reaction of
Cp*Ir(H)2(PPh3) to yield a metallacycle. The rates at which the inter-
mediate [Cp*Ir(PMe3)] reacts with different types of C–H bonds were
established relative to cyclohexane (1.0) to be: benzene (4.0), cyclo-
propane (2.65), cyclopentane (1.6), neopentane (1.14), cyclodecane (0.23),
and cyclooctane (0.09). The C–H activation process was determined to
take place via a concerted three centres oxidative addition mechanism.47
Similar reactivity was observed when Cp* was replaced with Cp89 and
indole51 ligands, the substitution of the phosphine by CO did not alter
the reactivity of the metal fragment.50,90
The analogous rhodium complex Cp*Rh(H)2(PMe3) was also reported
to activate C–H bonds via photoinduced H2 elimination with a wide
variety of substrates spanning from C–H activation of arenes to many
different alkanes.40 Similar to the iridium analogue, selectivity for pri-
mary over secondary C–H bonds in alkanes was observed; intramolecular
kinetic selectivity for the aryl C–H bonds of toluene over the aliphatic
C–H bond was also determined.35
Mechanistically, evidence for a Z2-alkane intermediate was established
via isotope investigations; this route would allow for activation of sec-
ondary C–H bonds but isomerization to the preferred primary alkyl com-
plex delivered the final product.38 Activation of aromatic C–H bonds was
postulated to go through the formation of a p-coordinated-arene species
instead of direct C–H cleavage as a consequence of a high kinetic selectivity
for the activation of aryl bonds (benzene/cyclopentane ¼ 5.4/1).91
A detailed energy diagram was constructed from a series of photo-
chemical competition reactions of the [Cp*Rh(PMe3)] fragment in the
concomitant presence of C6H6 and C3H8 at low temperature (Fig. 5);
the strength of the Rh–C bond of the product formed via the oxidative
addition process was established as an overwhelming thermodynamic
driving force for the product distribution (a slight kinetic preference of
4 : 1 for C6H6 over C3H8 was determined). If the bond strength of the
reactants played a key role, more facile formation of the propyl–hydride
rhodium complex would have been preferred to the formation of the
aryl complex. The C–H bond of propane is weaker than the one of
benzene but the Rh–C bond formed in the phenyl C–H activation is
16–17 kcal mol1 stronger than the Rh–C bond formed via activation of
the propane C–H bond (similarly, the activation of weaker secondary C–H
bonds of alkanes over primary ones would have been preferred).
As a result of these studies a general trend in the M–C bond strength
was established for different types of C–H bonds: M–PhcM–vinylc
M–CH3cM–CH2RcM–CHR2cM–CR3cM–CH2Ph.40
3.2 C–H and the hetero-bonds: the selectivity issue

C–H versus C–CN bond activation was the subject of a recent study that
looked at the photochemical reaction of Cp*Rh(H)2(PMe3) in neat
CH3CN.42
360 | Photochemistry, 2019, 46, 352–369

Fig. 5 Diagram showing the difference in free energy of activation for competition
experiments of benzene vs propane. Adapted with permission from ref. 40, Copyright
The C–H activated compound Cp*Rh(PMe3)(CH2CN)H was formed

with kinetic preference, conversion to the C–C activated species
Cp*Rh(PMe3)(CH3)(CN) was obtained upon heating the reaction mixture
establishing the latter as thermodynamic product. The same distribution
of products was observed when the complex was photolysed in neat
benzonitrile.42
The reactivity of three novel rhodium–dihydride complexes of the type
Tp 0 Rh(L)(H)2 (L ¼ PMe3, PMe2Ph, CNCH2CMe3) was investigated photo-
chemically and all of the complexes were found to photogenerate a
transient capable of inserting into C–H bonds of arenes, thermolysis in
C6D6 up to 400 K showed no reactivity.41 Intramolecular C–H activation to
form a rhodacycle was observed only in the case of the Tp 0 Rh(PMe2Ph)(H)2
complex and C–C bond cleavage of biphenylene was reported for the PMe3
complex.
In a striking investigation, Tp 0 Rh(PMe3)(H)2 was photochemically
initiated and the fragment used to look at intramolecular competition
reactions between C–H and C–F bonds in a variety of fluoroaromatics.
Selectivity for the activation of the C–H bond over the C–F bond was
observed but notably the C–H bond cleaved was the one with the greater
number of fluorines ortho to it. The origin of the selectivity was once
more explained by the strength of the Rh–C bond formed which showed
linear correlation to the C–H bond dissociation energy (Fig. 6a); a slope of
2.15 was extrapolated.43 This value closely matched the DFT-calculated
slope of 2.05 (Fig. 6b) as well as the slope determined for a series of
Tp 0 Rh(CNneopentyl)(ArF)H of 2.14.92
Reaction of the same compound in neat CH3CN yielded the C–H
activated product with kinetic preference. Near quantitative conversion
Photochemistry, 2019, 46, 352–369 | 361

Fig. 6 Plot of relative Rh–ArF bond strength vs. calculated C–H bond strength
(kcal mol1); Experimental result (a) and DFT calculated result (b). Reproduced from
ref. 43 with permission from The Royal Society of Chemistry.
to the C–CN activated species (thermodynamic product) was achieved

upon heating a solution of the Tp 0 Rh(PMe3)(CH2CN)H to 373 1K for five
days.44 Similar reactivity was observed for the PPhMe2 analogue except
for the detection of a small amount of the intramolecular C–H activation
product. The photochemical reaction in the presence of succinonitrile,
designed to look at preferential activation of secondary C–H bonds over
terminal C–CN bonds proved uninformative; a thermal route for looking
at these studies employing the Tp 0 Rh(PMe3)(Ph)H as a precursor was
preferred.44
The complex Tp 0 Rh(PMe3)(H)2 was also the subject of a more recent
study that looked at intramolecular and intermolecular selectivity
between C–H and Si–H, B–H and C–F bonds (Fig. 7).45 The reaction in
neat silanes yielded rhodium silyl hydride compounds as major
products; total selectivity for activation of the Si–H bond to form
Tp 0 Rh(PMe3)(SiEt2H)H was determined in neat Et2SiH2, no evidence for
C–H activation on the ethyl groups was established. Reaction with PhSiH3
produced the rhodium silyl hydride Tp 0 Rh(PMe3)(SiPhH2)H as the major
product with 20% of byproducts formed via orto- meta- and para-phenyl
C–H activation. The same metal fragment was employed in the reaction
with pinacolborane HBpin, and the main product was the rhodium boryl
hydride Tp 0 Rh(PMe3)(Bpin)H, with no activation of the C–H bonds on the
pinacol moiety observed. DFT calculations supported the experimental
results; a thermodynamic preference for intramolecular B–H over C–H
activation and for Si–H over C–H activation was computed. Most sur-
prisingly, the intermediate was found capable of activating C–F bonds of
pentafluoropyridine. The C–F activated products were fully characterised
and assigned as two rotamers of the same complex resulting from
selective activation of the C–F bond ortho to the nitrogen; activation of
the C–F bonds in meta and para positions were not observed. The
photochemical reaction in the presence of neat 2,3,5,6-tetra-
fluoropyridine was undertaken to explore intramolecular competition
between C–H and C–F activation. At 30% NMR conversion, a ratio of 4 : 1
was observed in favour of C–H activation. This was a surprising result as
362 | Photochemistry, 2019, 46, 352–369

Fig. 7 Photochemical reactivity of Tp 0 Rh(PMe3)H2 in the presence of the hetero bonds.
Adapted with permission from ref. 45, Copyright 2014 American Chemical Society.
the detection of the C–F activated product contradicted previous studies

where total selectivity for the cleavage of the C–H bond in the presence
of fluoroarenes was reported.43,92 Irradiation of Tp 0 Rh(PMe3)H2 in neat
C6F6 did not yield any metal fluoride product nor did it provide any
evidence for perfluoroarene Z2-coordination. As a consequence, hexa-
fluorobenzene was identified as an inert solvent and used for inter-
molecular competition reactions. A strong intramolecular selectivity
towards the activation of the hetero-bonds versus alkyls C–H bonds
within the same molecule was established; less prominent was the
selectivity in the presence of aromatic C–H bonds.
Monochromatic photolysis (355 nm) inside the NMR probe was used
to generate the [Tp 0 Rh(PMe3)] fragment to investigate intermolecular
competition reactions between the hetero-bonds and the C–H bond
of benzene which was employed as standard (Fig. 8). The results were
added to a previous set of competition reactions run for different types
of C–H bonds93 and are shown in Table 1. Kinetic selectivity followed
the order Si–H (PhSiH3)4C–H(C6H6)4B–H (HBpin)cC–F (C5NF5); these
reactions together with those previously reported span a factor of 37 in
rates. The possible mechanisms that give rise to the selectivities
were analysed by the authors. For comparison, CpRh(PPh3)(C2H4)
showed no significant selectivity between H–Bpin, H–C6F5, and
Photochemistry, 2019, 46, 352–369 | 363

364 | Photochemistry, 2019, 46, 352–369
Fig. 8 Product distribution of photochemical competition reactions of Tp 0 Rh(PMe3)(H)2 with the substrates and C6H6 as competing ligand (a) HBpin/C6H6, (b)
PhSiH3/C6H6, (c) C5NF5/C6H6. Reprinted with permission from ref. 45, Copyright 2014 American Chemical Society.
Table 1 Intermolecular selectivity derived from photochemical competition reactions.
Adapted with permission from ref. 45, Copyright 2014 American Chemical Society.
Substrate Si–H (PhSiH3) CH2F2 C6H6 HCCPh Pentane CH4

krel 2.3 1.6 1 0.47 0.41 0.39
Substrate B–H (HBpin) CH3CF3 (CH3)2CO C–F (C5NF5) c-C5H10 CH3CF3
krel 0.36 0.20 0.16 0.07 0.063 0.20
H–SiMe2Et substrates,94 whereas the trend for [Ru(DuPHOS)2] was

established as H–SiH2Ph4H–Bpin4H–C6F5 by laser flash photolysis.31
The full set of photochemical reactions discussed earlier was paralleled
using the thermal precursor Tp 0 Rh(PMe3)(CH3)H; interestingly the same
product distribution was observed but the mechanism proved to be
substantially different. A dissociative mechanism was experimentally
established for the photochemical reactions while a bimolecular pathway
(associative mechanism) was found to be operative in the thermal
chemistry.
3 Conclusions and outlook

The study of the photoactivity of group 8 dihydrides towards H2 reductive
elimination has provided extensive knowledge on the nature of this
photoprocess. Particularly, the use of specialist techniques (time resolved
spectroscopy, matrix isolation and computational methods) has allowed
determination of structures and reactivity of the intermediate towards
different substrates. The role played by the so called ‘‘spectator ligands’’
has proved highly influential in determining the type of chemistry that
will take place at the unsaturated metal fragment. Substantial differences
in the rates for the oxidative addition of substrates have been reported
for a class of ‘‘apparently’’ similar RuH2 complexes with bidentate
phosphines.
The recent development of our laser pump-NMR probe method in
conjunction with para-H2 induced hyperpolarisation has offered the
possibility of creating metal hydrides in a selected nuclear spin state by
incorporation of para-H2. The concerted nature of H2 elimination was
confirmed by these experiments but most importantly, the possibility of
recording diagnostic NMR spectra at the same time as quantifying rates
of reaction allowed identification of the products unambiguously. This
differs from conventional laser flash photolysis where a broad UV/vis
absorption of the reaction intermediate or an average spectrum of the
intermediates is obtained. It is important to mention that the detection
limit of NMR spectroscopy is enhanced into a similar range to time-
resolved UV/vis absorption methods by this new approach. The potential
of this method can be expanded to a broader range of hydrogenation
processes; moreover reactions with a number of molecules that can be
prepared in a singlet state (N2, fumarate, stilbene) offer scope for
investigation.95
Fundamental physical organometallic studies, designed to unveil the
mechanism and driving forces of catalytic cycles, have been and will
Photochemistry, 2019, 46, 352–369 | 365

continue to be of vital importance to the optimisation and the applic-
ability of these processes on a large scale. The understanding of kinetic
and thermodynamic selectivity has come a long way since the advent of
strong bond activation via metal complexes, especially for C–H bond
cleavage which has had a major impact on synthetic chemistry. Such
detailed mechanistic investigations often do not receive significant
interest. However, the recent experiments on the reactivity of the
[Tp 0 Rh(PMe3)] fragment towards hetero bonds demonstrated how a
much wider variety of bonds than had been previously realised can be
activated by this system. While this fragment was well established as C–H
bond activator, it showed almost total photochemical intramolecular
selectivity for the activation of Si–H and B–H bonds expanding on the
scope of this system. Similarly, activation of the Si–H bond over aromatic
C–H bonds was favoured in intermolecular competition reactions.
Acknowledgements
BP is very thankful to Professor Robin Perutz for all the knowledge on
metal hydrides photochemistry he has bestowed to her over many years.
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Photochemistry, 2019, 46, 352–369 | 369

Aromatic hydrocarbons as catalysts and
mediators in photoinduced electron
transfer reactions
Benjamin Lipp and Till Opatz*
DOI: 10.1039/9781788013598-00370
Aromatic hydrocarbons are frequently used as catalysts and mediators in photoinduced

electron transfer reactions. For more than forty years, significant developments in this field
have helped to expand the general understanding of free radical chemistry and to pave the
way for today’s era of visible light photoredox catalysis. This article reviews these devel-
opments and the impact they have had alongside modern applications of aromatic
hydrocarbons in photoinduced electron transfer chemistry. The theoretical background as
well as future prospects of such reactions are explained with a focus on organic synthesis.
1 Introduction and theoretical background

Beginning with the publication of several landmark papers by the groups
of MacMillan,1 Yoon2 and Stephenson3 in 2008 and 2009, visible light
photoredox catalysis has emerged as one of the most vital research areas
within the field of preparative organic chemistry.4 The roots of this
technique however date back more than four decades and the first
applications of photoredox catalysis to organic synthesis were already
reported in the 1970s.5–9 This decade has also been marked by seminal
works concerning the utilisation of aromatic hydrocarbons (AHs) as
catalysts for synthetically useful photoinduced electron transfer (PET)
reactions.10–12 Further exploration of this field has ever since led to a
deeper understanding of free radical chemistry which has also contrib-
uted to the recent revitalization of visible light photoredox catalysis.13–17
Although they are less in the focus of current interest than polypyridyl
complexes of ruthenium or iridium18 and organic dyes,19 AHs continue to
be employed for the most challenging light-induced redox transforma-
tions.20–22 The aim of this chapter is to review the past, present and
potential future of AHs as catalysts and mediators (vide infra) in PET
reactions. The theoretical background as well as the impact of these
transformations will be highlighted, followed by improvements needed
to ensure that AHs continue to find broad application in the era of visible
light photoredox catalysis. This review is limited in scope and it will only
cover AHs devoid of any heteroatoms. Furthermore, only findings with
applicability to organic synthesis will be treated.
1.1 The basics of direct, catalysed and mediated PET reactions

Fundamental processes associated with uncatalysed (direct) PET are
depicted in Scheme 1a.23 For a more detailed description, the reader is
Institute of Organic Chemistry, University of Mainz, Duesbergweg 10-14,

D-55128 Mainz, Germany. E-mail: opatz@uni-mainz.de
370 | Photochemistry, 2019, 46, 370–394

(a) (b)
(c)
Scheme 1 Fundamental processes and catalytic cycles associated with (a) direct PET,
(b) catalysed PET, commonly referred to as photosensitisation or photoredox catalysis,
and (c) redox mediated versions of these two. D ¼ electron donor, A ¼ electron acceptor,
cat. ¼ catalyst, RM ¼ redox mediator, BET ¼ back electron transfer.
directed to excellent reviews by Kavarnos and Turro.13,23 The absorption

of a photon results in either the donor (D) or the acceptor (A) reaching the
first excited singlet state S1*, which might eventually convert into the
lowest excited triplet state T1*. These electronically excited species can
then either return to the ground state by radiative or nonradiative decay
pathways or engage in bimolecular reactions such as PET if they
encounter a suitable reaction partner within their lifetime. Regardless of
whether the donor or the acceptor has been excited, electron exchange
results in the same pair of radical ions (A and D 1, as contact ion
pair ¼ CIP, or solvent-separated ion pair ¼ SSIP). These radical ions can
then diffuse apart (free, solvated ions) and undergo various transforma-
tions affording new product/s. They can however also undergo back
electron transfer (BET) leading to the ground state species. BET is a
severe limitation for PET processes and the main reason for their typi-
cally low quantum yields.14,23,24 To facilitate the separation of the ion
pairs, PET reactions are usually performed in polar solvents and some-
times in the presence of added salts.23,25,26
As depicted in Scheme 1b, PET processes can also be accelerated or
even enabled by catalysts which have traditionally been referred to as
photosensitisers (probably the most accurate name in the case of
AHs).4,14,27 Nowadays, this expression is closely linked to energy transfer
processes and the term ‘‘photoredox catalyst’’ has become common,
especially for visible light absorbing complexes or dyes.4,19,27 Although it
was pointed out by Mizuno and co-workers that there is a difference
between photocatalysts and photosensitisers or photoredox catalysts, we
will refer to all of these species simply as catalysts throughout this
Photochemistry, 2019, 46, 370–394 | 371

review.27 Upon absorption of a photon, the catalyst reaches an excited
state (S1* or T1*). It is then converted back to the electronic ground state
by two successive electron transfer reactions, the first one being called
oxidative or reductive quenching. Substrates of the reaction mixture or
sacrificial acceptors/donors engage in both redox steps. In many cases,
the acceptor or donor of the second electron transfer is a reaction
intermediate derived from trapping the radical ion produced during the
quenching process or a fragment of the latter. Thus, net-redox neutral
transformations can be performed in a one-pot fashion.18 The most
obvious reason for the addition of a catalyst would be that the substrates
themselves do not absorb light of the provided wavelength (in particular
visible light).4 This is often not the case for AHs which are frequently not
used to enable but rather to enhance UV-driven PET reactions. Their
beneficial effect may then be a result of their longer excited state lifetimes
or the more efficient use of the provided UV-light due to the AHs
absorbing light of longer wavelengths.19,28,29 They can also suppress BET.
For an oxidative quenching cycle, this is the case if the oxidised form of
the catalyst has a higher oxidation potential than the electron donor.25
Assuming that BET is operating in the so-called Marcus-inverted region
where increasing exergonicity results in a lower rate constant,30 BET from
the ion pair (Cat 1/A ) should be slower than from the original ion pair
(D 1/A ).14,24,31
As shown in Scheme 1c, PET reactions can also benefit from the
addition of a redox mediator (RM), regardless of whether a catalyst is
used or not.14,16 An RM does not enhance PET by absorbing light and
then triggering SET, but rather serves as an electron shuttle undergoing
two consecutive redox reactions with both the excited species (donor/
acceptor/catalyst) and the ground state acceptor/donor.32 Such RMs are
also referred to as co-sensitisers or electron relays.14,33 An RM might
enhance PET reactions suffering from endergonic and inefficient
quenching of the excited species by the ground state acceptor/
donor.16,34,35 If endergonic quenching is intercepted by an RM (i.e. a
better quencher), SET between the resulting radical ions of the RM and
the ground state acceptor/donor is then of course endergonic.35 This
electron transfer is however favoured, given that the RM’s radical ions
have a longer lifetime than the excited species.16,35,36 RMs may also
enhance PET reactions operating through an exergonic quenching pro-
cess which is hindered for other reasons such as electrostatic repulsion.37
However, in most PET processes of synthetic interest, quenching of the
excited species by the acceptor/donor is exergonic and efficient. In these
cases, an RM can still enhance the overall reaction by means of its long-
lived radical ions favouring substrate oxidation/reduction16,38,39 and by
impeding BET. Therefore, the RM needs to be significantly more oxi-
dising or reducing than the original acceptor or donor.24,40 This leads to
increased exergonicity for BET, which, due to the location within the
Marcus-inverted region, is then slowed down.24,30,41
1.1.1 Photophysical and electrochemical properties of selected aro-

matic hydrocarbons. This section deals with photophysical and
372 | Photochemistry, 2019, 46, 370–394

electrochemical properties of selected AHs and the question why some
of them have outcompeted others as catalysts and mediators in PET
reactions. Table 1 summarises relevant properties of selected AHs.
They are often used in combination with certain aromatic nitriles,
which are therefore also included in the table. Excited state redox
potentials have been calculated using eqn (1) (excited state oxidation
potentials) or (2) (excited state reduction potentials), whereat E*00 is
the zero–zero excitation energy for the singlet or triplet state (conver-
sion factor of 1 eV V1 on a per molar basis).19,42,43
E1/2(D 1/D*) ¼ E1/2(D 1/D) E*00 (1)
E1/2(A*/A ) ¼ E(1/2)(A/A ) þ E*00 (2)

Increased p-conjugation of the aromatic system results in a decreased
energy gap between HOMO and LUMO, lower excitation energies, longer
excitation wavelengths and reduced excited state redox potentials.44 This
effect is less pronounced for angular systems than for linear ones.44
In polar solvents such as acetonitrile (in which Coulombic interactions
can be neglected), the thermodynamic feasibility of a PET process can be
approximated solely on the basis of the involved excited and ground state
redox potentials.13,19,42 Accordingly, oxidative quenching of a catalyst by
a substrate is thermodynamically feasible when the excited state oxi-
dation potential of the catalyst is more negative than the ground state
reduction potential of the substrate. Similarly, reductive quenching of a
catalyst by a substrate is thermodynamically favourable when the excited
state reduction potential of the catalyst is more positive than the ground
state oxidation potential of the substrate. Thus, a catalyst for challenging
transformations will have a large excited state oxidation or (negative)
reduction potential. In this respect, the excited singlet state is obviously
better suited than the triplet state, although the latter has a much longer
lifetime. Consequently, an ideal AH will have a long-lived S1*-state and
display a high fluorescence quantum yield.13,19 For the second electron
transfer (Scheme 1b) to be useful, the potential catalyst should also have
a large ground state oxidation or reduction potential as this will increase
the scope of substrates which can be employed in redox reactions.
Importantly, this will also lead to increased exergonicity for BET, which is
then slowed down.14,24,31 The catalyst should of course be the main light-
absorbing species within the reaction mixture and thus, absorb light of
longer wavelength than the substrates.13 In addition, the ideal AH-
catalyst will be chemically inert under the reaction conditions, inexpen-
sive, readily available and as harmless as possible. Phenanthrene (4) has
become the most frequently used AH for oxidatively quenched reactions
(vide infra). Except for its relatively low fluorescence quantum yield, it
fulfils all the requirements mentioned above. Reductive quenching cycles
are generally less common with AHs as catalysts and in these cases
pyrene (6), perylene (7) and p-terphenyl (9) have proven useful (vide infra).
Furthermore, aromatic nitriles such as 9,10-DCA (12) are versatile cata-
lysts for reductively quenched reactions and they are frequently used in
combination with AHs as RMs.16 In contrast to a catalyst, the mediator
Photochemistry, 2019, 46, 370–394 | 373

374 | Photochemistry, 2019, 46, 370–394
Table 1 Photophysical and electrochemical properties of selected aromatic hydrocarbons and aromatic nitriles.a
S1 T1
Number Compound E00 (eV) lS00
1
(nm) ts (ns) jfl jISC E00 (eV) ts (ms)
45 45 46 47 47
1 Naphthalene 3.98 312 105 0.21 0.71 2.6448 180049
2 Anthracene 3.3050 37550 5.851 0.2752 0.6653 1.8450 330049
3 Tetracene 2.6350 47150 6.4 (np)54 0.1655 0.6655 1.27 (np)56 400 (np)57
4 Phenanthrene 3.5758 34758 60.759 0.1347 0.8047 2.6660 91061
5 Chrysene 3.4450 36050 42.662 0.1747 0.8247 2.4860 710 (np)63
6 Pyrene 3.3264 37364 19065 0.7247 0.2747 2.0964 1100066
7 Perylene 2.8366 43966 6.051 0.9452 0.0167 1.5666 500066
8 Biphenyl 4.0568 30668 16.0 (np)62 0.15 (np)69 0.84 (np)70 2.8471 130 (np)63
9 p-Terphenyl 3.99 (np)62 310 (np)62 0.95 (np)62 0.77 (np)69 0.11 (np)63 2.5372 450 (np)63
10 1,4-DCB 4.2773 29073 9.774 n. a. n. a. 3.0675 n. a.
11 1,4-DCN 3.69 (np)76 336 (np)76 10.174 n. a. 0.1977 2.4074 4077
12 9,10-DCA 2.9078 42878 15.178 0.8779 0.008519 1.81 (np)80 100 (np)81
Number 1 2 3 4 5 6 7 8 9 10 11 12
E1/2(R 1/R) þ1.54b,82 þ1.09b,82 þ0.77b,82 þ1.50b,82 þ1.35b,82 þ1.16b,82 þ0.85b,82 þ1.95b,83 þ1.80b,84 n. a. n. a. n. a.
E1/2(R 1/1[R]*) 2.44 2.21 1.86 2.07 2.09 2.16 1.98 2.10 2.19 n. a. n. a. n. a.
E1/2(R 1/3[R]*) 1.10 0.75 0.50 1.16 1.13 0.93 0.71 0.89 0.73 n. a. n. a. n. a.
E1/2(R/R ) 2.49c,28 1.95c,28 1.58c,85 2.44c,85 2.25c,85 2.09c,85 1.67c,85 2.55c,28 2.63c,86 1.64b,87 1.27b,88 0.91b,88
E1/2(1[R]*/R ) þ1.49 þ1.35 þ1.05 þ1.13 þ1.19 þ1.23 þ1.16 þ1.50 þ1.36 þ2.63 þ2.42 þ1.99
E1/2(3[R]*/R ) þ0.15 0.11 0.31 þ0.22 þ0.23 0.00 0.11 þ0.29 0.10 þ1.42 þ1.13 þ0.90
a
Unless indicated in brackets (np ¼ non-polar), all photophysical values were obtained in polar solvents. All redox potentials are given in V versus the saturated calomel
electrode (SCE). Excited state redox potentials were calculated as described in the text.
b
Measured in MeCN.
c
Measured in DMF. DCB ¼ dicyanobenzene, DCN ¼ dicyanonaphthalene, DCA ¼ dicyanoanthracene, n. a. ¼ not available. For definitions and an extensive compilation
of the listed photophysical quantities see Steven L. Murovs Handbook of Photochemistry, see ref. 28.
ideally does not absorb light of the wavelength range used to drive the
reaction.38 Unless the quenching process which is to be intercepted is
endergonic,35 the RM should be more oxidising than the ground state
acceptor or more reducing than the ground state donor.24 As explained
above, this will lead to reduced BET.24,30,41 Thus, for 9,10-DCA (12) as well
as for other highly oxidising catalysts, biphenyl (8) has been established
as a suitable RM (vide infra).
2 Examples of PET reactions catalysed by aromatic

hydrocarbons
In this section, synthetically useful PET reactions catalysed by AHs as well
as the impact they have had on visible light photoredox catalysis will be
surveyed. The transformations are categorised according to their catalytic
cycles (Scheme 1b). Reactions occurring through oxidative quenching
cycles will be covered first, followed by those involving reductive
quenching.
2.1 Reactions involving oxidative quenching of aromatic

hydrocarbons
In 1977, the groups of Pac,10 Tazuke11 and Yamamoto12 independently
reported that the photoinduced dimerization of electron-rich alkenes
such as indene6 (13), N-vinylcarbazole5 and styrene derivatives89,90 15
could be catalysed by AHs like phenanthrene (4) or perylene (7). To the
best of our knowledge, these are the first reports of synthetically useful
PET reactions using AHs as catalysts. Exemplary results are summarised
in Scheme 2 (compounds 14, 17, 21).10,12,91
Scheme 2 Photoinduced dimerization of exemplary electron-rich alkenes 13, 16 and

addition of water or alcohols catalysed by AHs using aromatic nitriles as RMs.10,12,91
Phen ¼ phenanthrene (4).
Photochemistry, 2019, 46, 370–394 | 375

Detailed mechanistic investigations, mainly by Pac et al.,91 provided
evidence for oxidative quenching of the AH’s excited singlet state by the
aromatic nitrile (1,2-, 1,3- or 1,4-DCB) acting as an RM (see also:
Scheme 1c).12 Electron transfer from the alkene to the AH’s radical cation
regenerates the catalyst and affords the radical cation of the olefin.11,12,91
The latter is attacked by another alkene molecule, which results in a
dimeric (distonic) radical cation. Reduction by the aromatic nitrile’s
radical anion completes the catalytic cycle and is followed by ring clos-
ure.6,91 When performed in non-polar solvents such as benzene, the
aromatic nitrile’s radical anion can add to the olefin’s radical cation in a
formal [4 þ 2]-cycloaddition (not shown in Scheme 2).92 This allows for
the synthesis of isoquinolines from 1,1-diphenylethylene derivatives and
1,4-DCB (10).92 In the presence of water and alcohols, these nucleophiles
add to the alkene’s radical cation to form the anti-Markovnikov products
15, 18, 22 upon reduction and subsequent protonation.89,91 Unlike 1,1-
diphenylethylene (16a), a-methylstyrene (16b) mainly affords product 23
resulting from the addition of the alcohol to the dimeric radical cation.12
Similar transformations using different alkenes and nucleophiles have
been reported.93,94 Dienes95,96 and polyenes97 give rise to complex cycli-
sation products. Exemplarily, Scheme 3 highlights a stereoselective tan-
dem cyclisation of 1,1-diphenyl-1,n-alkadienes 24 reported by Hirano and
Niwa et al. in 1998.98
If an alkene is oxidised in the presence of a nucleophile and the
addition of the latter to the olefin’s radical cation is not followed by
reduction and protonation, the photo-NOCAS (nucleophile-olefin com-
bination aromatic substitution) reaction might occur (Scheme 4).14 The
intermediate radicals are then trapped by the radical anions of the aro-
matic nitriles, followed by elimination of cyanide. This is usually the case
if the oxidised alkenes are not aryl substituted.14 Exemplary reactions
presented by Arnold et al. in 1984 are highlighted in Scheme 4.29 Inter-
estingly, alkene radical cations are quite acidic and if no nucleophile is
present in reasonable concentration to trap them, they might instead be
deprotonated to form allylic radicals which subsequently engage in ipso-
substitutions.29,99 Similar transformations have been reported using
amines100 or malononitrile101–103 as nucleophiles and furan deriva-
tives10,91 instead of electron-rich alkenes as the coupling partners.
It is noteworthy that alkene oxidations can also be achieved in the
absence of the AHs, either via direct PET (ipso-substitutions such as those
in Scheme 4) or with the DCBs operating as catalysts themselves (trans-
formations similar to those in Schemes 2 and 3).89–91,97 Such PET reac-
tions are however far less efficient14,29,91,97,104 and require the use of
higher-energy UV-irradiation.11,12 This is due to the reasons outlaid in
Section 1. If the added AH is the main light-absorbing species, it will act
as catalyst being oxidatively quenched by the DCBs.29,91,104 Photoinduced
anti-Markovnikov additions to alkenes (Scheme 2) have recently been
revitalized using strongly oxidising visible light photoredox catalysts such
as acridinium salts.105–114 Visible light-induced [2 þ 2] cycloadditions
(see Scheme 2) of olefins have also been reported.115,116 In contrast,
the ipso-substitution of aromatic nitriles by radicals derived from
376 | Photochemistry, 2019, 46, 370–394

Photochemistry, 2019, 46, 370–394 | 377
Scheme 3 Stereoselective tandem cyclisation of 1,1-diphenyl-1,n-alkadienes 24.98

378 | Photochemistry, 2019, 46, 370–394
Scheme 4 Exemplary photo-NOCAS reaction and simple ipso-substitution of DCBs 10, 20 or 26 with 2,3-dimethyl-2-butene (27) catalysed by phenanthrene (4).29
alkenes (Scheme 4) is highly challenging regarding the redox potentials
(E1/2(10/10 ) ¼ 1.64 V87 and E1/2(27 1/27) ¼ þ1.62 V104, both in MeCN
vs SCE) and cannot be achieved with the common visible light absorbing
catalysts.18,19 This reaction has thus not played a significant role in the
recent renaissance of photoredox catalysis.4 Oxidation potentials of sev-
eral alkenes can be taken from ref. 117. They are usually very high and in
cases where electron transfer to the AH’s radical cation would be ther-
modynamically unfavourable, the formation of a p-complex between
these two species has been suggested.10,91,104
The photoinduced ipso-substitution of aromatic nitriles by oxidatively
generated alkyl radicals (for the proposed mechanism see Scheme 4) is a
general transformation of great synthetic utility.118,119 Scheme 5 high-
lights two exemplary transformations reported by Mizuno, Otsuji, Yosh-
imi, Hatanaka and their co-workers using group 14 organometallic
compounds (a) or carboxylates (b) as radical precursors.120,121
While 1,4- (10) and 1,2-DCB (26) are suited for such reactions, 1,3-DCB
(20) affords only very low yields (see also Scheme 4). The radical anion of
20 might not be stable (long-lived) enough for the radical coupling to
occur efficiently.122 Indeed, the reason such ipso-substitution reactions
mainly afford the cross-coupling products probably is the persistent
radical effect.123 A significant factor governing the regioselectivity of
radical combinations is spin density. In the radical anions of 10 and 26,
the highest spin density is found at the nitrile-substituted carbons, where
the attack of alkyl radicals can be followed by fast rearomatisation
through elimination of cyanide.122 This is not the case for the radical
anions of 20 possessing the largest spin density in 4- and 6-position.122
Alkylation of these positions is usually observed when 1,3-DCB (20) is
employed, albeit in low yields.121 Such products are formed via oxidative
(a)
(b)
Scheme 5 Phenanthrene-catalysed ipso-substitution of dicyanobenzenes 10, 20 or 26

by radicals generated from (a) group 14 organometallic compounds and (b)
carboxylates.120,121
Photochemistry, 2019, 46, 370–394 | 379

(a)
(b)
Scheme 6 Phenanthrene-catalysed (a) ipso-substitution of aromatic nitriles 33 with

carboxylic acids and activated alcohols as radical precursors and (b) C(sp3)–C(sp3)-s-
bond metathesis using 1-benzyl tetrahydroisoquinoline derivatives 35.132,133 aFrom
carboxylic acids. bFrom oxalate half-esters.
rearomatisation (Minisci reaction).124,125 The works highlighted in

Scheme 5 have likely been a source of inspiration for the recent discovery
of a multitude of visible light driven ipso-substitutions of aromatic
nitriles using precious iridium-based catalysts.126–131 Also inspired by the
work of Yoshimi,121 the Opatz group has presented some additions to the
portfolio of phenanthrene-catalysed ipso-substitution reactions
(Scheme 6).132,133 In these works, the scope of aromatic nitriles 33 (cya-
nobenzenes, -pyridines, -pyrimidine and -isoquinoline) and radical pre-
cursors (carboxylic acids, alcohols activated as their oxalate half-esters
and 1-benzyl tetrahydroisoquinolines 35) was significantly extended. The
use of very weak UV lamps or even sunlight as the sole energy source is
also noteworthy.
When similar transformations are performed in the presence of a more
effective radical trap such as electron-deficient olefins 39, the alkyl rad-
icals do not combine with the radical anions of the nitriles but prefer-
entially attack the Michael acceptors in a photoinduced Giese reaction
(Scheme 7).17,134,135 In the resulting radical adducts, the unpaired elec-
tron is located next to the electron-withdrawing group (EWG) rendering
380 | Photochemistry, 2019, 46, 370–394

Scheme 7 Phenanthrene-catalysed Giese reaction with amino acids 38 as radical
precursors.136
Scheme 8 Phenanthrene-catalysed Giese reaction with allylic silanes 42 as radical

precursors.145
these radicals electrophilic and preventing polymerisation. Instead, they

are reduced to carbanions, followed by protonation to yield saturated
products such as 40.17 Throughout the past decade, the group of Yoshimi
has put remarkable effort into the exploration of such reactions using
carboxylic acids,136–141 esters,142 and arylboronic or alkenylboronic
acids143 as radical precursors. Their findings cannot be covered in detail
here and have recently been reviewed.17 Scheme 7 summarises some of
their early results (2009).136
Alternatively, group 14 organometallic compounds144–149 such as 42 or
cyclopropanone acetals150,151 have been used as radical precursors. These
species often afford stabilized allylic or benzylic radicals. The latter cannot
be trapped efficiently by olefins, unless they are highly electron-deficient
(easily reducible).37 In these cases, product formation likely involves
combination of the stabilised radicals with the radical anions 41 gen-
erated by reduction of the olefins 41, followed by protonation of the
resulting carbanions (Scheme 8).145 A multitude of such reactions have
been reported.144,145,148,149,152 Exemplary results presented by Mizuno and
Otsuji et al. in 1988 are summarised in Scheme 8.145
If such easily reducible olefins are not conjugated with an aromatic
moiety, alkylation occurs in a-position to the EWGs.145 Photoinduced
Giese-type reactions catalysed by AHs have certainly had an impact on the
Photochemistry, 2019, 46, 370–394 | 381

revitalisation of visible light photoredox catalysis and there are mean-
while numerous reports of related transformations.153–157
As explained previously, reactions using aromatic nitriles either as RMs
(Schemes 2, 3, 7) or as substrates (Schemes 4–6) can often also be per-
formed in the absence of AHs, albeit with lower efficiency (see Section 1).
This means that reaction times are prolonged,29,91,122 side reactions
such as the polymerisation of olefins are enhanced,91,140 yields are
lower29,91,121,158 and stronger lamps121 as well as light of shorter wave-
lengths12,92,98,150 might be required. In reactions affording product
mixtures, the addition of AHs can alter the product distribution.95,101 It is
difficult to give a quantitative estimate of the reaction enhancement.
Even in a single reaction such as the photo-NOCAS process (Scheme 4),
some substrates benefit much more from the addition of an AH than
others104 and temperature effects have been reported as well.100 It is also
difficult to estimate the quantity of an AH required to achieve optimal
enhancement and it is obvious that this will depend on the specific
reaction. There are only very few optimisation studies concerning the AH-
loading.132,133,143 As expected, an inverse correlation to the required
irradiation time has been found.140,143 However, a reduction of the
catalyst loading cannot always be compensated by prolonged irradiation
as side reactions might behave differently.140 In practice, the AH has
sometimes been used in catalytic amounts (r10 mol%),10,100,140,150 but in
the majority of reports, stoichiometric quantities have been
employed.17,92,98,121,136 Most AHs are inexpensive, readily available and
can usually be recovered in very high yields (480%) so that their use is
not an economic factor.10,29,91,92,98,132,136,137,148,159
2.1.1 Reactions involving reductive quenching of aromatic hydrocar-

bons. Although long considered,160 electron transfer has only been
experimentally proven a mechanism for fluorescence quenching when
the radical anions of perylene (7) were detected upon irradiation of this
AH in the presence of N,N-dialkylanilines about sixty years ago.161–164
However, PET reactions operating through reductive quenching cycles
have found only few applications to organic synthesis until very
recently.11,20,21,165–167 Thus, such transformations did not have signifi-
cant impact on the revitalisation of visible light photoredox catalysis.4,19
In 2016 and 2017, the group of Sudo reported perylene-catalysed
reductive couplings of aromatic aldehydes and ketones 44 or imines 46
in the presence of N,N-diisopropylethylamine (DIPEA) as sacrificial
reductive quencher (Scheme 9).166,167 These reactions afford a variety of
1,2-diols 45 and 1,2-diamines 47.
Except for its S1*-state being relatively short-lived, perylene (7) offers
advantageous photophysical properties, namely a high fluorescence
quantum yield and absorption of visible light.168 For very challenging
transformations, its radical anion might however not be a sufficiently
strong reductant (see Table 1). In these cases, other AHs such as pyrene
(6) are better suited. The necessity of using UV-light for pyrene-excitation
can be circumvented by taking advantage of energy transfer from the
visible light absorbing [Ru(bpy)3]21-complex,169 which is one of the most
382 | Photochemistry, 2019, 46, 370–394

(a)
(b)
Scheme 9 Perylene-catalysed reductive coupling of (a) aromatic aldehydes or ketones

44 and (b) imines 46. aIsolated after acylation of hydroxy groups. bRatio D/L:meso.166,167
Scheme 10 Subsequent energy and electron transfer for the visible light-induced
coupling of aryl halides and triflates with electron-rich aromatics using a [Ru(bpy)3]21-
complex and pyrene (6) as catalysts.22
frequently used photoredox catalysts, readily available and significantly

less expensive than its Ir-based counterparts.4,18
In 2017, König et al. used this strategy for the photoreduction of
electron-deficient aryl chlorides, bromides and triflates 48 (Scheme 10).22
Reduction potentials of some aryl halides can be taken from ref. 28 and
117. Trapping of the resulting aryl radicals by electron-rich aromatics 49
affords the cross coupling products 50.22
Photochemistry, 2019, 46, 370–394 | 383

Energy transfer from the 3MLCT1-state of [Ru(bpy)3]21 to pyrene (6) is
much faster than reductive quenching of the excited Ru-complex by
DIPEA and gives rise to the T1*-state of 6.22 The subsequent mechanistic
steps are not fully elucidated yet. Reductive quenching of pyrene’s T1*-
state by DIPEA was proposed, but should be significantly endergonic.170
Instead, Ceroni, Balzani and co-workers suggested that triplet–triplet-
annihilation (TTA) might afford S1*-pyrene, which would then be quen-
ched by the amine resulting in the radical anion of 6.170 This species is a
sufficiently strong reductant to transfer an electron to electron-deficient
aryl halides or triflates 48, which, upon mesolytic cleavage, gives rise to
aryl radicals. These are then trapped by the electron-rich aromatics, fol-
lowed by oxidative rearomatisation.22 The radical anions of 6 might
however also be formed via reductive quenching of pyrene’s T1*-state by
the reduced Ru-complex (produced either during the rearomatisation or
via quenching by DIPEA).171 A more detailed discussion of the underlying
mechanism is included in ref. 22, 170 and 171.
For even more challenging transformations, p-terphenyl (9) has proven
useful (see Table 1). Recently, the group of Jamison exemplified the
enormous utility of this AH as catalyst for the photoreduction of carbon
dioxide (E1/2(CO2/CO2 ¼ 2.21 V vs. SCE in DMF)172 in continuous
flow.20 The resulting CO2-radical anions have been used for the synthesis
of a-amino acids 52 from tertiary amines 51 and for the b-selective hy-
drocarboxylation of styrenes 53 (Scheme 11).20,21 The utilisation of a
continuous flow reactor (Beeler’s photoreactor)173 was crucial to achieve
high yields as the applied segmented flow allows for a better gas-liquid
mixing.174 These works were preceded by studies concerning the photo-
reduction of carbon dioxide86,175–183 and water184–188 by oligo- or poly(p-
phenylene)s, albeit (with few exceptions)165,184,189–191 not with a focus on
organic synthesis.
This section has sought to give an overview over synthetically useful PET
reactions using AHs as catalysts. Due to the limited length of this chapter,
the survey has of course not been exhaustive, but rather intended to
showcase general findings and the most recent developments.
3 Examples of PET reactions mediated by aromatic

hydrocarbons
In electrochemical transformations, AHs are commonly employed to
mediate cathodic reductions via their radical anions.192,193 This is a
fundamental difference to PET reactions, which AHs mediate by reductive
quenching of the catalyst, followed by substrate oxidation via their radical
cations (see Scheme 1c). Since the use of RMs in PET processes has
recently been covered as part of an excellent review by Yoon et al.,16 this
section will only provide a short survey of akin transformations. Different
modes of action by which RMs enhance PET processes have been
explained in Section 1. Here, we will try to highlight situations in which
one or the other of these mechanistic modes is especially important.
As early as 1975, the group of Farid and Evans reported the 9-
cyanoanthracene-catalysed dimerization of phenyl vinyl ether.34
384 | Photochemistry, 2019, 46, 370–394

(a)
(b)
Scheme 11 p-Terphenyl-catalysed (a) synthesis of a-amino acids 52 from tertiary amines

51 and (b) hydrocarboxylation of styrenes 53, both via photoreduction of carbon dioxide in
continuous flow.20,21 PMP ¼ 1,2,2,6,6-pentamethylpiperidine (54).
Quenching of the catalyst by the olefin is endergonic and extremely slow.

The addition of AHs, which quench the catalyst more efficiently,
increased the quantum yield tremendously, albeit electron transfer from
the alkene to the oxidised AH was endergonic.34 However, the radical
cations of AHs have much longer lifetimes than the excited catalyst,
which is beneficial for the alkene oxidation.36 One should also consider
the formation of a p-complex between the AH’s radical cation and the
olefin as stated previously.10,91,104
In 2013, Nicewicz and co-workers reported a related dimerization of
styrene derivatives such as 56 using pyrylium salt 57 as visible light-
absorbing catalyst alongside naphthalene (1) or anthracene (2) as RM
(Scheme 12a).33
Photochemistry, 2019, 46, 370–394 | 385

(a)
(b)
Scheme 12 (a) Dimerization of (E)-asarone (56) and (b) anti-Markovnikov addition of

water to polyene 59 with subsequent radical cascade cyclisation, both via PET reactions
mediated by AHs.33,194 PMP ¼ p-methoxyphenyl.
They applied this method to the synthesis of the lignan natural product
magnosalin (58).33 In this study, the RM was adjusted to the respective
styrene whose oxidation potential it should outperform only marginally.
In this fashion, the RM does not trigger oxidative degradation of the
cyclobutane products and prevents the stronger-oxidising catalyst from
doing so.33 As explained in the previous section, alkene oxidations give
rise to the anti-Markovnikov addition products when performed in the
presence of nucleophiles and such transformations, both in inter195- and
intramolecular fashion,196,197 can be mediated by AHs. These reactions
have had significant impact on the recent revitalisation of photoredox
catalysis.198 If polyenes are employed, the neutral radicals derived
from addition of a nucleophile to the initial radical cation can
induce cyclisation.38,39,95,194,199–203 As an example, Scheme 12b
highlights a biphenyl-mediated cascade cyclisation of the (E,E,E)-
geranylgeranylmethyl dioxinone 59 reported by the group of Demuth in
1999.194 In this case, addition of water to the radical cation is followed by
four trans ring fusions creating eight stereogenic centres in a single step.
The S1*-state of 60 is quenched at comparable rates by both, polyenes like
59 and biphenyl (8).38 In such reactions, the beneficial effect of the AH is
mostly attributed to its long-lived radical cations increasing the rate of
substrate oxidation.16,38,39
Redox-mediated Giese reactions have been studied intensively.204–206
Over decades, the groups of Albini and Fagnoni at the University of Pavia
have contributed significantly to a deeper understanding of such trans-
formations.37,146,152,207,208 Scheme 13 highlights the tetra-n-butylammo-
nium decatungstate (TBADT, 64)-catalysed benzylation of easily reducible
386 | Photochemistry, 2019, 46, 370–394

Scheme 13 Benzylation of electron-deficient olefins (63) using arylacetic acids (62) as
radical precursors, TBADT (64) as catalyst and biphenyl (8) as RM.37
olefins209 63 with arylacetic acids 62 as radical precursors reported by

Ravelli and Fagnoni et al. in 2016.37
Upon excitation, TBADT (64) rapidly converts to an unknown catalyti-
cally active species,210,211 the oxidation potential of which is estimated to
be far superior to those of carboxylates.37 Nevertheless, reductive
quenching of the negatively charged tungstate catalyst by carboxylates is
inefficient, due to electrostatic repulsion. The addition of biphenyl (8) as
RM, which can overcome this repulsion, was found to be crucial to
achieve high yields.37 Given that biphenyl’s oxidation potential is sig-
nificantly larger than that of carboxylates, but still smaller than that of
the catalyst, this transformation is also a good example for impeding BET
by increasing its exergonicity.24,30,37,41 Biphenyl (8) has also proven a
useful RM for the 9,10-DCA (12)-catalysed photooxygenation of cyclo-
propanes35,212–214 and epoxides,35,215–217 the photo-NOCAS reaction14 as
well as for oxidative rearrangements.218–221 In most PET reactions
mediated by AHs, high loadings of the latter are required (see above) as
the RM competes with the substrates for reductive quenching of the
catalyst.
4 Conclusion and outlook

Ever since the synthetic utility of PET reactions catalysed or mediated by
AHs has been exemplified in seminal publications in the 1970s, signifi-
cant developments in this field have greatly expanded the general
understanding of free radical chemistry. This has unarguably been a
contributing factor to the recent resurgence of visible light photoredox
catalysis. AHs offer distinct advantages such as low costs, good avail-
ability and very high recovery rates. Their ground and excited state redox
potentials are superior to those of common photoredox catalysts (see
Table 1), which renders them especially useful for challenging
transformations.18,19
However, AHs such as phenanthrene (4) and p-terphenyl (9) are used
less commonly as catalysts than polypyridyl complexes of ruthenium or
iridium and organic dyes.4,19 This is likely due to the fact that most AHs
Photochemistry, 2019, 46, 370–394 | 387

do not absorb visible light. In contrast, they are often utilised in com-
bination with classical mercury lamps, which is not appealing to the
broader photoredox community. Thus, future research on AHs as cata-
lysts for PET reactions should include screening for alternative light
sources as the use of high-power UV-lamps may likely be avoided in many
cases. The Opatz lab has for example recently shown that some
phenanthrene-catalysed transformations can be efficiently driven by a
25 W UV/vis CFL bulb with no reduction of yield when compared to a
400 W Hg lamp.132,133 This laboratory and the group of Yoshimi have also
recently reported that such reactions can be initiated by sunlight,
whereat reaction times are greatly reduced when employing a micro-
capillary flow reactor.132,133,141,222 The recent reports on perylene (7) as
low-priced and powerful visible light absorbing catalyst for PET reactions
are also promising and may inspire future applications.166–168 Further-
more, the concept of utilising visible light absorbing sensitisers for
energy transfer to AHs, which may then display their powerful redox
chemistry, holds significant potential.22 AHs are valuable RMs for PET
reactions and their application in this regard is likely to continue.33,37
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394 | Photochemistry, 2019, 46, 370–394

Photo-induced multi-component
reactions
Loı̈c Pantaine,a,b Christophe Boura and Géraldine Masson*b
DOI: 10.1039/9781788013598-00395
The recent advances in the field of photochemical, photocatalyzed and photoredox

catalyzed Multi-Component Reactions (MCRs) are resumed in this highlight chapter.
1 Introduction
Over the past decades, one of the main concerns in the field of organic
chemistry and synthesis has been reducing, recycling or even eliminating
the waste it creates. This trend has in recent years known a surge in
popularity, due to ever greater economic strain and growing environ-
mental awareness. A reaction’s yield and selectivity are no longer the only
criteria that determine its success: it must also have a limited financial
and environmental impact.
Several methods have been developed throughout the years to reach
such goals. One is for example the use of Multi-Component Reactions,
or MCRs, which are defined as 3 or more compounds reacting together
in a multistep one pot sequence to afford a product possessing most or
all the atoms of the reagents involved.1–3 They allow for the generation
of complex compounds from simple material through the formation of
numerous new bonds in a single process. Such reactions reduce a multi-
step sequence’s time and cost (both to the environment and the
experimenter) by eliminating any need for isolation and purification of
the intermediates. It can also allow for better yields and new reactivities,
should any of these intermediates be unstable, since they are consumed
quickly after they are formed, limiting their potential degradation.
MCRs can either be a linear reaction sequence, in which each reagent
is added to the product one after the other, or a convergent sequence,
in which several intermediates can be formed from different starting
material and only then react together to form the final product
(Scheme 1).
On the other hand, photoinduced reactions, defined as any reaction in
which light (visible or UV) activates the reaction in some way, have been
substantially developed because of their considerable advantages, most
notable of all is the obvious fact that light is a renewable and cheap
a
Institut de Chimie Moléculaire et des Matériaux d’Orsay, CNRS UMR 8182,
Université Paris-Sud, Université Paris-Saclay, bâtiment 420, 91405 Orsay Cedex,
France
b
Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Université Paris-
Sud, Université Paris-Saclay, 1, avenue de la Terrasse, 91198 Gif-sur-Yvette Cedex,
France. E-mail: Geraldine.MASSON@cnrs.fr
Photochemistry, 2019, 46, 395–431 | 395

Scheme 1 General Scheme for a multi-component reaction.
energy source.4–8 If considering sunlight itself, rather than artificial light,

it can also be said that it is non-polluting, free, unexhaustible and
accessible to all. Photoinduced reactions can be divided into two main
categories: photoactivation of the starting material and photocatalysis
(which can be divided in the use of photoredox catalyst and
photosensitisors).
Photoactivation needs nothing else but light to directly activate
the reaction. However, it requires at least one of the reagents to be
light-sensitive, which is a rare trait in most chemical compounds.
This is particularly true regarding visible light, so photoactivation
often requires the use of stronger UV light to allow the reaction to
happen.
Photopromotion solves this issue by introducing a relay substance
between light and reagents. These relay compounds can absorb light and
allow chemical transformations by electron or energy transfer to the
reagents. If this promoter can be brought back to its ground state in the
reaction, through the reactive pathway or the introduction of a sacrificial
species, then they can be refered to as photocatalysts. Catalysis in general
is a well-known means to develop greener alternatives to synthetic
pathways: the use of another molecule, separate from the starting
material, can accelerate reaction rates or even enable new reactivity and
selectivity. The regeneration of the relay species means it can be intro-
duced in sub-stoichiometric amounts and even be recycled, limiting its
cost and environmental impact. As a sub-group of the field of catalysis,
photocatalysis shares all of these advantages, while also providing the
benefits of light activation.
396 | Photochemistry, 2019, 46, 395–431

The definitions of photocatalysts and photosensitizers are very similar
and can be interchangeable in most situations; however for the sake of
clarity, we will be using those terms in separate cases:
– The use of a photocatalyst, or photoredox catalyst, will be defined as

the use of a species that, after passing into an excited state through light
activation, undergoes single electron transfers (SET) with the reagents to
enable the reaction (Scheme 2). The photocatalytic cycle can go through 2
different pathways: after reaching the photoinduced excited state, the
photocatalyst can either return to its ground state by reductive or oxidative
quenching. In the reductive quenching, as the name indicates, the excited
photocatalyst is reduced by a SET. This intermediate reduced species then
undergoes a second SET to be oxidated back to its initial state. The oxi-
dative quenching goes through the same double SET process, but swaps
over oxidation and reduction. Whether the photocatalyst will go through
one or the other depends on the reaction conditions, the compounds
present in the solution and the nature (particularly its redox potential) of
the photocatalyst itself. Depending on the reaction, the reagents (and
subsequent intermediates) can be responsible for either or both of the
SET steps. In the case of the former, a sacrificial oxidant/reductant species
must be added to close the photocatalytic cycle. In any case, the catalytic
cycle is redox neutral, i.e. it will gain as many electrons as it loses.
The word photosensitizer will in this chapter be a shortcut to refer to

non-electron transferring photocatalysts: in these cases, such species are
also activated by light to an excited state, but transfer only energy to
activate the reagents. We must stress that this is not the strict definition
of a photosensitisor, but merely a means for us to clearly differentiate
them from photoredox catalysts. Photoinduced reactions can therefore
go through three distinct reactive pathways (Scheme 3): either direct
photoactivation of at least one of the starting material or the use of an
intermemdiate species that absorbs light and retransmits it to the
reagents through electron or energy transfer.
In most cases, a photoinduced MCR begins by direct or indirect
photoactivation of one of the reagents which will produce a radical
species that will then go on to react with an unsaturated reagent, most
Scheme 2 General Scheme for the photoredox catalytic cycle
Photochemistry, 2019, 46, 395–431 | 397

Scheme 3 General Scheme for a photoinduced reaction.
Scheme 4 Photoactivated mechanistic pathways.
often an olefin, to form an intermediate radical (Scheme 4). This radical

reaction chain can go on for several steps depending on the nature and
number of reagents involved, however its conclusion can be through 2
main pathways: either another radical species will add onto the inter-
mediate, therefore closing the cycle with a radical–radical mechanism, or
alternatively the intermediate can be oxidized/reduced to the cationic/
anionic species and then react with a nucleophile/electrophile to end the
reaction. This second option is called radical–polar crossover (Scheme 4).
While any number of species can play the role of oxidant or reductant, in
the case of photoredox catalysis, this is most often used to regenerate the
photoredox catalyst to its ground state and close the photocatalytic cycle.
A less common option is for the newly reactive intermediate to directly
terminate either on itself or by reacting with a second activated species
thereby modifying the initial reagent.
Both radical–radical and radical–polar crossover routes have been
explored to develop new photoinduced MCR, either involving insertion
processes or light induced substrate modifications that will further react
with other reagents.
398 | Photochemistry, 2019, 46, 395–431

The development of photoinduced MCRs allows for a vast array of
possible reactivities to be explored as well as combining the benefits of
both photochemistry and MCRs, making for a significant synthetic
means to achieve great complexity from simple starting material in an
efficient and cost-effective manner in time, money and environmental
impact. While such reactions have been given a substantial amount of
attention,9 there is still much to develop within this field.
This chapter will focus on the achievements and advances concerning
photoinduced MCRs up to the end of 2017.
2 Direct photoactivation of reagents

Reactions based on the direct activation of substrates via light irradi-
ation, are the simplest and most straightforward of the photoinduced
reactions, since they do not require any intermediate between the energy
source (light) and the reagents. Therefore, they have been developed and
reported for over a century.11 Multicomponent photochemical reactions
however are far more recent, only starting around the end of the 20th
century. These reactions can be divided into different subgroups
depending on the type of photoactivated reagent and photoinduced
reactivity they generate.
2.1 Photoactivated organometallic compounds as radical initiators

Among the earliest examples of direct photo activation MCRs is the olefin
dialkylation performed by the group of Otsuji in 1988 (Scheme 5).12 This
reaction uses electron-deficient alkenes, organoiodo compounds and
allylic stannates, the latter being used as both reagent and radical initi-
ator. Though the reaction can be initiated by AIBN in refluxing con-
ditions, Otsuji and co-workers have shown that UV light can also initiate
the reaction at room temperature, even affording, in some cases,
better yields. The light activates the stannate compound, forming the
Scheme 5 Organo-stannates and -plumbates as photoactivated radical precursors.12–14
Photochemistry, 2019, 46, 395–431 | 399

Bu3Sn radical that breaks the C–I bond, forming the alkyl radical that
adds to the alkene. The new resulting radical then adds to the allyl-
stannate, forming the desired product and enabling the radical propa-
gation by releasing another Bu3Sn radical. A similar reaction sequence,
replacing organostannates with organoplumbates, was also reported in
1992 by Toru and co-workers, starting from a,b-unsaturated ketones
and derivatives, as electron-poor alkenes (Scheme 5).13 In 1993, Keck
and Kordik presented another light activated vicinal dialkylation, with
dimethoxy-(phenylthio)-methane instead of organoiodo compounds
(Scheme 5).14 In this case, the stannate species used as initiator is dif-
ferent from the allylic stannate used as reagent.
2.2 Photoactivated selenides and sulphides as radical initiators

Non-metallic photosensitive compounds have also been used as light
activated radical sources. In particular, the S–S and Se–Se bonds can be
cleaved by UV light irradiation, forming the corresponding thio- and
seleno-radicals that then react with alkenes or alkynes (Scheme 5). The
new radical formed then reacts again with a second thio or seleno radical,
which ends the radical chain. When both disulfide and diselenide are
introduced, the differences in their reactivity leads to the multi-
component formation of functionalized compounds carrying both
vicinal C–S and C–Se bonds.15 When in the presence of an alkyne and an
alkene (or isocyanate), an extra radical step is added: as before, the
radical PhSe adds to the alkyne, generating a new radical. However, this
radical adds preferentially to the alkene, before the radical chain is ended
by addition of a second diselenide radical.16,17 This radical chain can be
even more expanded when the alkene is added in excess or when two
different alkenes are introduced, leading to an intramolecular radical
cyclization before the chain-ending PhSe second addition occurs.18
Furthermore, organoselenides have also shown to be UV-light sensi-
tive, promoting multi-component olefin difunctionalization (Scheme 6):
in 1996, Sonoda and co-workers developed a photoinduced alkylative
carbonylation from alkenes, carbon monoxide and organoselenides.19
The mechanistic pathway is similar than the one previously described:
UV light irradiation induces the rupture of the C–Se bond, forming a
radical which in turn adds to an alkene. The resulting alkyl radical is
trapped by CO, forming the carbonyl radical species, and finally the
radical chain reaction is closed by addition of the phenylselenenyl rad-
ical, formed by the initial photoinduced C–Se bond breaking.
2.3 Photoactivated functionalized arenes as cationic initiators

Alkene difunctionalization can also be initiated by the photoactivation of
specific alkenes or aromatic compounds. Photochemical Nucleophile-
Olefin Combination, Aromatic Substitution reactions, or photo-NOCAS,
have been thoroughly developed throughout the past decades, most
notably by Arnold and co-workers, and is still being improved upon today
(Scheme 7).20,21 As the name implies, this reaction is initiated by
photoactivation of both a 1,4-di or 1,2,4,5-tetra-cyano aromatic
400 | Photochemistry, 2019, 46, 395–431

Scheme 6 Selenides as photoactivated radical precursors.15–19
Scheme 7 General Scheme for a photo-NOCAS reaction.
compound and an alkene, which undergo an electron transfer forming 2

radical species: an aromatic anionic radical and an aliphatic cationic
radical. In the presence of a nucleophile (historically methanol, used as
co-solvent with acetonitrile), the latter undergoes addition upon the ali-
phatic electrophilic radical, generating a new radical intermediate that
reacts with the aromatic radical through a radical pair combination.
Photochemistry, 2019, 46, 395–431 | 401

Scheme 8 An alternative to the photo-NOCAS.
The final product is then obtained by rearomatisation via the elimination

of one of the cyano groups. It is important to note that, while not
necessary to the reaction process, the addition of a photosensitisor, often
phenanthrene or biphenyl, can help accelerate the reaction by reducing
electron back transfer from the aromatic ring to the alkene. Advances
regarding this particular reaction have enabled to broaden the scope by
modifying certain reagents. Concerning nucleophiles, other alcohols,
ammonia and (primary) amines, fluoride anions, cyanides, or more
recently, malonates, 1,3-diketones and ketoesters, have been used. Vari-
ations upon the alkenes have also been tried out, such as allenes or
dienes.
An alternative to this method was reported by Fagnoni and co-workers:
the photoactivation of the aromatic species leads to the cleavage of a
leaving group and the formation of an aromatic cation, upon which an
enol ether can be added, producing a oxonium intermediate that
undergoes addition from a nucleophilic alcohol species (Scheme 8).10
This case appears similar to the photoNOCAS previously described,
however the mechanistic pathway is notably different, involving a
photogenerated triplet phenyl cation and enabling the use of aromatic
species other than di or tetra-cyanophenyls. Indeed, a number of
electron-donating functional groups and electron-withdrawing leaving
groups were found to be compatible with these reaction conditions.
2.4 Photoactivated alkylhalides as radical initiators

In 1997, Sonoda and co-workers developed a new photoinduced radical
carboxylation, starting from secondary or tertiary alkyl iodides, alcohols
and carbone monoxide gas, in the presence of a base (Scheme 9, left).22 In
this new reactive pathway, UV light activates the iodoalkyl, forming the
corresponding alkyl radical that then reacts with CO to form the aldehyde
radical. This intermediate reacts with the iodoalkyl to produce the cor-
responding acyl iodide and the radical alkyl, allowing for the propagation
of the radical reaction. Esterification of the acyl iodide by the alcohol in
the presence of a base affords the final product. The mechanistic pathway
402 | Photochemistry, 2019, 46, 395–431

Scheme 9 Photoinduced radical carboxylation using CO gas.22,23
is made up of equilibriums that are not in favour of the product, there-

fore the base is crucial in the last step to deprotonate the product and
pull the reaction forward. The reaction is even more unfavourable to the
formation of primary alkyl radicals and the reaction requires longer
reaction times.
Many different versions of this reaction have since then been
developed, with the most notable modification being the addition of a
Pd(0) complex to increase yields and lower reaction times, by facilitating
the formation of the radical from the alkyliodide (Scheme 9, right).23–29
In those cases, the mechanism is altered accordingly: while it is generally
accepted that the Pd(0) improves the first step through a SET with the
alkyliodide, forming the corresponding radical and Pd(I)I, which later
complexes to the radical carbonyl and is regenerated as Pd(0) by substi-
tution of the iodide by the alcohol, followed by reductive elimination.
Other variations include extending the initial scope to primary alkylio-
dides (easily accessible in the presence of the Pd catalyst) and aryliodides,
as well as replacing the alcohol by an amine to lead to the corresponding
amide.23,24,30,31 It is also possible to obtain the corresponding primary
alcohol by replacing the nucleophilic species (alcohol or amine) by a
reductant. The radical carbonyl will in this case yield the aldehyde and
then be reduced to the alcohol.32 Alternatively, adding an alkene to the
reaction mix allows for an extra radical step to be included, as in this case
the alkyl radical will first add to the alkene (Scheme 10).25,31,33
The new radical intermediate will then add to CO and pursue the
previously described mechanism. Among the most recent developments,
the group of Ryu has replaced the alcohol by a boronic ester,27 alkene,28
or alkyne,34 yielding the corresponding ketones through photoactivated
Suzuki, Heck or Sonogashira type cross-couplings as completary alter-
natives to their thermal counterparts that favour aryl-halides or allyl-
halides (Scheme 10). It is important to note the main limitation to this
type of synthetic method is not so much its scope but rather its technical
requirements: indeed, this method uses both photochemistry and high
pressure, meaning the reactor must have an autoclave with a quartz
window allowing the light to shine through while maintaining
Photochemistry, 2019, 46, 395–431 | 403

works of Gosh, Singh and co-workers recently developed an alternative to
the synthesis of new polycyclic chromene derivatives, in which the
chromene core is itself generated in situ (Scheme 12).39 The sequence
starts with a similar condensation/cyclization as seen reported by Ghosh,
but using hydrazines rather than hydroxylamines. The Knoevenagel
condensation/cyclization sequence from malononitrile and 2-hydroxy-
benzaldehyde provides the iminochromene core. Once both heterocycles
are formed in situ, they can undergo light-activated radical addition,
leading to the final product.
Other groups have elaborated multi-component convergent sequences
in which light is used only to activate and form a single one of the two
products generated in situ, which then react together to give the desired
final product. This is the case for the work performed by Sun and co-
workers: 1,2-dihydrofurane (or variations thereupon) is generated from
THF by light activated radical transformation (Scheme 13).40 Once gen-
erated, the dihydrofurane undergoes a nucleophilic addition on an in situ
formed iminium species from the aldehyde. A second intramolecular
addition between the thiourea and the previously generated oxonium
form the end heterocyclic product. Another such example was reported
by Pusch and Opatz: again, only one branch of the convergent
Scheme 13 Single photoactivated step in convergent MCRs.40,41
406 | Photochemistry, 2019, 46, 395–431

multi-component reaction is light activated, while the other is simply the
condensation of the cyanoamine onto the aldehyde (Scheme 13).41
The light induced branch of the sequence is a photoisomerisation of
the initial isoxazol into azirine. In the presence of a base, the cyanoimine
formed in situ is deprotonated and adds to the azirine. This step is fol-
lowed by an addition of the azirine anion onto the imine, elimination of
the cyano group, deprotonation and opening of the azirine ring.
Recently, a new photoinduced 3-component reaction was developed by
Basso and co-workers, starting from a diazoketone, a carboxylic acid and
an isocyanide in batch or flow conditions (Scheme 14).42–44 The UV light
irradiation activates the diazoketone that undergoes a Wolff rearrange-
ment into a reactive ketene. This ketene reacts with the carboxylic
acid and isocyanide through a passerini type reaction to provide
acyloxyacrylamides, a useful synthon in organic synthesis.
In 2017 the Xiao group has reported a photoinduced reaction
starting from 1-aminostyrene, a radical source and a sulphur ylide
(Scheme 15).45 The reaction goes through a radical addition on the
aminostyrene’s double bond, forming a stabilized radical that is oxidized
to the cationic species, then deprotonated to form the azaquinone me-
thides. These intermediates are further submitted to a [4 þ 1] cycload-
dition with the sulphur ylides, followed by rearomatizaion, yielding the
final indol derivatives. When the radical precursor is an iodoalkyl, a
photoredox catalyst is required for the reaction to take place, and will
therefore be addressed in the second part of this chapter. However, when
the radical precursor is the Umemoto reagent, leading to a CF3 radical,
the photoredox cycle is not necessary. Instead, the radical initiation is
produced by the formation of a colored Electron–Donor–Acceptor (EDA)
complex between the aminostyrene and the Umemoto reagent. Moreover,
the oxidation to the cationic species is not undertaken by the photo-
catalyst but by a second Umemoto reagent molecule, affording not only
the cation intermediate but also another CF3 radical, allowing for radical
chain propagation of the reaction. It is relevant to note that strictly
speaking this is a 2 step one pot reaction in which light activation is only
used in the first step. If the photoactivation step were considered on its
own, it would not be a MCR, however as it is part of a one-pot reaction
sequence, it can be included as relevant to this chapter.
Scheme 14 Photoactivation of diazoketones into reactive ketenes.
Photochemistry, 2019, 46, 395–431 | 407

Scheme 15 Photochemical indole synthesis.
3 Photocatalysis
While direct photoactivation of starting material remains the most eco-
nomic photoreactive pathway, both financially and environmentally, it
relies on the innate ability of certain specific compounds to absorb light.
Unfortunately, they are the exceptions, not the norm, as photosensitive
compounds remain scarce, particularly when switching from UV to vis-
ible light. To broaden the scope of available reaction and starting
materials, it is necessary to introduce an intermediate. This energy relay
or promoter will absorb light and go into an activated state. From there it
can return to its ground state by transmitting either electrons (photo-
redox catalyst) or energy (photosensitizer) to the reagents, starting off a
reaction that would not have been possible by direct light activation.
3.1 Photoredox catalysis

Photoredox catalysis is a fairly new concept that has known an explosive
popularity since its discovery a decade ago.5,6 This concept has grown
exponentially during the last decade and is still developing, producing
new families of products through novel reactive pathways.46,47 While
many different reactions and reactivities have been either discovered or
improved upon through this concept, one key reaction stands out as the
main MCR developed with this method: olefin difunctionalization.48 It
can be divided into the two main reaction subgroups described in the
introduction: radical–radical reactions (two radical species will be added
onto the alkene) or radical–polar cross over reactions (a radical species
and a nuclephile/electrophile will be added onto the alkene). One crucial
aspect of photocatalysis is ensuring the quenching of the catalyst and its
return to the ground state to ensure turnover. This can be achieved either
from the reaction intermediates or from compatible additional sacrificial
reagents (such as amines, thiols and O2).
3.1.1 Olefin difunctionalization
3.1.1.1 Radical–radical olefin difunctionalization. Most radical–radical
photoredox olefin difunctionalisation reported in the literature are
408 | Photochemistry, 2019, 46, 395–431

actually hydroalkylations: after the first alkyl radical species adds to the
alkene, a hydrogen atom transfer (HAT) occurs between a H donor and
the newly generated radical intermediate. This means the third reagent
of these multi-component reactions is simply a hydrogen source, pla-
cing it at the limit of what can be conceived as an MCR, as the defin-
ition states that all or most of the atoms of the reagents should be
included in the final product for them to be part of the component
count. Nevertheless, while debatable, these reactions are recognised as
MCR and have their place in this chapter.
Among these photoredox hydroalkylations of alkenes, most of those
are used to add tri- or di-fluorinated methyl groups, from various CF3 or
CF2 radical precursors. For instance, the group of Nicewicz developed in
2013 a photoredox hydrotrifluoromethylation of alkenes using sodium
trifluoromethanesulfinate (Langlois’ reagent) as the radical precursor
and TFE as the hydrogen atom source (Scheme 16).49 While both TFE and
thiol are required for the reaction to give good yields, they do concede
other mechanistic pathways, such as the direct HAT between the inter-
mediate radical and the thiol, bypassing the TFE, cannot be dismissed.
A similar reaction was reported by Rueping and co-workers in 2016, in
which they either used a diarylketone (under UV light) or an iridium
complex (under visible light) as photocatalyst (Scheme 17).50 Furthermore
they adapted their method to flow chemistry to obtain similar or better
yields in a fraction of the time (30 min instead of 6 h). Other like-minded
reactions include the separate works of the groups of Qing51 and of
Gouverneur,52 who respectively used CF2Br2 or the Umemoto reagent as
fluorinated radical precursors, THF or methanol as H donors respectively,
and an eosin Y or a ruthenium complex as photocatalyst (Scheme 17). It is
Scheme 16 Hydrotrifluoromethylation of alkenes through radical addition/HAT
Photochemistry, 2019, 46, 395–431 | 409

Scheme 17 Tri/difluoromethylation & HAT reaction sequences.50–53
noteworthy to mention that the work of Gouverneur and co-workers was

expanded to alkynes as well. Using relatively similar conditions , Qing’s
group went on to use another difluoroalkyl radical in 2015 to access RCF2H
moieties (Scheme 17).53 In all these cases, the species providing the
hydrogen atom (HFIP, MeOH or THF) is consequently turned into a radical
species that undergoes oxidation with the photoredox catalyst, enabling it
to return to its ground state and close the photocatalytic cycle.
Non-fluorinated radicals have also been used in photoredox hydro-
alkylation of alkenes: the group of Gagné used glycosyl halides as radical
precursors to add onto alkenes, with Hantsch esters as a H source
(Scheme 18).54 The additional amine is used as a sacrificial reductant
to return the photocatalyst to its ground state and close the photo-
catalytic cycle. This method inspired the Overman group, who
used similar conditions in a late stage step of the total synthesis towards
()-Aplyviolene.55 In this case, the radical precursor is no longer a simple
alkylhalide but a (N-acyloxy)phthalimide that undergoes decarboxylative
reduction to provide the corresponding alkyl radical.
Another family of photocatalyst was developed by the Ryu group: tet-
rabutylammonium decatungstate TBADT (Scheme 19).56 Mechanistic
studies have shown that TBADT is both the photocatalyst, initiating the
formation of the alkyl radical, as well as an H radical trap and donor later
in the reaction pathway, therefore eliminating the need for an extra H
source and ensuring catalyst regeneration. In that case, the hydroal-
kyaltion is no longer a MCR (the first radical and the final HAT come
410 | Photochemistry, 2019, 46, 395–431

Scheme 18 Radical addition/HAT reactions and application in total synthesis.54,55
Scheme 19 Radical–radical olefin difunctionalization towards ketone synthesis.
from the same starting material). However, in the presence of a CO

atmosphere, the alkyl radical first adds to the CO, before the new radical
intermediate adds to the alkene, forming the corresponding ketones as
3-component photoredox reactions. The same group used this synthetic
method on electron-deficient azo compounds instead of alkenes, yielding
the corresponding hydrazides (Scheme 19).57 While obviously not an
olefin difunctionalisation, the paralleles between the two reactions called
for it to be mentioned here.
Photochemistry, 2019, 46, 395–431 | 411

A few other photoredox MCR radical–radical reactions have been
reported that do not go through a HAT as a final mechanistic step.
Indeed, following the previous works in the field and adding further
diversity to the potentially accessible products, the group of Xiao
developed an azotrifluoromethylation of alkenes from Langlois’ reagent
by replacing the HAT step by the radical addition of a diazonium salt
(Scheme 20).58 While most photoredox reactions take a substantial
number of hours to reach completion, this particular reaction only takes
40 min.
In 2015, Guo and co-workers reported the use of F3CCH2I as a radical
precursor, forming the F3CCH2 radical, that adds to the alkene
(Scheme 21).59 From there, the reaction depends on the presence or
absence of dioxygene: if no oxygene is present (N2 atm), then the inter-
mediate radical will dimerize, forming the final product through an ABB
MCR type reaction. However, if dioxygene (and water) is present, then the
corresponding alcohol is formed. Mechanistic studies using 18O in both
the water and oxygene show that the alcohol actually comes from the
oxygene, not the water. This weighs in favour of a purely radical pathway,
rather than an oxidation/nucleophilic addition final step. In both
cases, Hunig’s base is used as sacrificial reductant to ensure catalyst
regeneration.
The same year, another group also described a similar radical–radical
photoredox MCR with O2 as a reagent (Scheme 22).60 Diazonium salts is
also used here, but as a radical precursor towards aryl radicals, not to-
wards azo compounds as seen reported by Xiao et al.,58 obtaining the
corresponding ketones rather than the alcohols as previously described
by Guo et al.59 The photoactivated catalyst is oxidized in the presence of
diazonium salt, generating the aryl radical which adds to the styrene
Scheme 20 Azotrifluoromethylation of alkenes from diazonium salts.58
Scheme 21 Hydroxyalkylation of alkenes with O2
412 | Photochemistry, 2019, 46, 395–431

Scheme 22 Carbonylalkylation of alkenes with O2.
Scheme 23 Xanthates in photoredox radical–radical alkene difuntionalization.
derivative. The newly formed benzyl radical reacts with dioxygene to give
a peroxy radical that turns into an alkoxy radical. A final SET yields the
desired product and closes the photocatalytic cycle. In this case, the
reaction shuts down completely if the styrene derivative carries an EDG
on the aryl moiety, which the authors attribute to the increased ease of
radical quenching of the benzyl radical intermediate in the presence of
dioxygen via hydrogen abstraction. Another like-minded work produced
the corresponding hydroperoxyls from similar reagents, rather than the
alcohol or ketone, in the presence of a photosensitisor, which will be
discussed later on (see Section 3.2).
O2 was also used by Yadav and Yadav for the formation of 1,3-ox-
athiolane-2-thiones (Scheme 23).61 In this work, xanthates are formed
in situ from methanol and CS2, before being converted to their radical
equivalents by eosin Y as photocatalyst. This radical adds to the styrenes
and, while the rest of the mechanism is not precisely described in this
work, we can follow the assumption that the new radical in turn reacts
with oxygene to give the peroxide, which is reduced (possibly by the
photoredox catalytic cycle) to the alcohol. The reaction ends with the
addition of the alcohol on the xanthate and elimination of the methanol,
affording the heterocyclic final product.
Photochemistry, 2019, 46, 395–431 | 413

Scheme 24 Double carbon–carbon bond formation through photoredox radical–
radical olefin difunctionalization.
Finally, a 3-component photoredox radical reaction was reported in

2017 starting from a carboxylic acid, an electron deficient alkene and a
TMS protected enol (Scheme 24).62 In the presence of Dimethyl dicarbo-
nate DMDC, the carboxylic acid is transformed into the anhydride, which
is reduced by the photocatalyst to the acyl radical. The acyl radical then
adds onto the alkene, forming a new radical intermediate which in turn
adds to the protected enol. This final radical undergoes oxidation/
deprotection to afford the final product. While involving a cationic inter-
mediate, the ligation of the 3 reagents together goes through a radical–
radical pathway warranting its place among the radical–radical MCRs.
3.1.1.2 Olefin defunctionalisation, radical–polar crossover. Compared

to the radical–radical photoredox MCRs, this synthetic pathway is
much more common regarding olefin difunctionalization and have
become the most reported photoredox MCR. They can be divided by
sub-type, mostly depending on the nucleophilic species used: oxyalkyla-
tion (or -arylation), aminoalkylation, haloalkylation, double alkylation,
oxyamination, and so on. Among these sub-types, the most common is
oxyalkylation/oxyarylation, in which the intermediate cation is trapped
by water or an alcohol used as co-solvent.
In that aspect, Akita and co-workers developed in 2012 a photoredox
oxytrifluoromehtylation of alkenes using Umemoto reagent as CF3 radical
precursor and water/alcohols as nucleophiles (Scheme 25).63 The mech-
anism starts with the Umemoto reagent being reduced by an oxidative
quenching of the activated photocatalyst. The CF3 radical then adds to
the alkene. The corresponding new radical is oxidated to the cation by the
oxidated form of the photocatalyst. This brings the photocatalyst back to
its former ground state and closes the photocatalytic cycle. As for the
cation, it undergoes nucleophilic addition by either water or various
alcohols, forming the final product. While radical precursors and nu-
cleophiles will vary significantly in the examples to come, this mech-
anistic pathway can be generalized to all or most of the radical–cation
414 | Photochemistry, 2019, 46, 395–431

Scheme 25 Photoredox hydroxytrifluoromethylation of alkenes.63
polar crossovers of alkene difunctionalization reactions mentioned in

this part. Furthermore, one might have noticed the similarities between
Akita’s reaction conditions and those reported a year later by
Gouverneur52 (Scheme 17) but the first case reaction goes through a
radical–cation polar crossover, while the second reaction involves a
radical–radical difunctionalization. This is a testimony of the delicate
balance between the two possible pathways, which may come into com-
petition: whether the reaction pathway preferentially goes one way (for-
mation of the cation and nucleophilic addition of the methanol) or
another (HAT between the radical and the methanol) depends mostly on
the photoredox potential of the catalyst and the stability of the inter-
mediate radical. Both these key elements should be carefully looked into
when developing a new methodology of that type.
Akita’s group was also performed the same reaction but with Togni’s
reagent and in DMSO, rather than the aprotic solvent/water (or alcohol)
mix (Scheme 26).64 In that case, they could access a-trifluoro-
methylketones instead of the corresponding alcohols, without the use of
a further oxidant. Indeed, the DMSO adds to the intermediate cation, just
as the alcohol does, and then goes through a Kornblum type oxidation via
a second photocatalytic cycle, yielding the ketone.
Other groups have since then reported similar MCR photoredox oxy-
alkylation reactions (Scheme 26), through the diversification of the rad-
ical precursor, such as alkylbromides65 and N-(acyloxy)phthalimides66
(generating alkyl radicals), or difluoromethylsulfoximines (generating a
difluoromethyl radical).67 The group of Zhou even used cyclobutanone
oximes as radical precursors, that undergo radical photoredox N–O and
C–C bond cleavage to yield the linear radical.68 Recently a collaboration
Photochemistry, 2019, 46, 395–431 | 415

Scheme 26 Photoredox oxyalkylation of alkenes.64–69
between the Masson and Magnier groups has developed a new type of
radical precursor : Fluorinated Sulfilimino Iminiums,69 which have been
used as a source of diverse fluorinated radicals such as CF3, CF2Br, CFCl2
or C4F9. The reaction has also shown good results beyond the use of aryl
bearing alkenes.
Alternatively, the team of Masson directed the general method in
another direction with the use of enecarbarmates rather than alkenes,
with either organohalides70 or the Togni reagent as radical precursors
(Scheme 27).71
The Masson group also used this type of reactivity to form functiona-
lized Phtalans from 2-Vinylbenzaldehyde, through a slightly modified
mechanistic pathway (Scheme 28).72 In this particular case, the nucleo-
philic species (TMSCN or TMSN3) does not close the reaction pathway,
but starts it, by adding onto the aldehyde moiety, forming the azido- or
cyano-alcoholate. This in situ generated species still possesses an alkene,
which reacts with the CF3 radical formed during the photocatalyst’s
oxidative quenching by Umemoto’s reagent. As usual for this type of
416 | Photochemistry, 2019, 46, 395–431

Scheme 27 Photoredox oxyalkylation of enecarbamates.70,71
Scheme 28 Photoredox synthesis of phthalans and isoindolines.
Scheme 29 Photoredox oxyarylation of alkenes.73,74
reaction, the new radical is oxidated to the cation (closing the photo-
catalytic cycle) and is trapped by a (this time intramolecular) nucleophilic
addition of the alcoholate, forming the corresponding cyano- or azido-
phthalans. This reaction has also been extended to the formation of
isoindolines by replacing the vinylbenzaldehydes by their imine equiva-
lents through an aminotrifluoromethylation reaction.
Oxyarylations have also been developed (Scheme 29), following similar
reaction conditions and mechanistic pathways, using various aryl radical
precursors, such as hypervalent iodine73 or diazonium salts.74 When
using the latter, a mix of water and DMF as solvent afforded
Photochemistry, 2019, 46, 395–431 | 417

the O-addition of DMF (rather than an alcohol) onto the in situ generated
cation, leading to formyloxyarylations through a photo Meerwein add-
ition. In the work of Greaney and colleagues, the addition of Zn(OAc)2
was shown to improve yields when methanol was used as nucleophilic
species, but was not essential to the reaction.
In the very last days of 2017, the group of Yu published the oxy-
difluoroalkylation of allylamines with a RCF2 radical precursor and CO2
gas (Scheme 30). In the presence of DABCO, the amine reacts with CO2 to
form the carbamates.75 The alkene chain carried by the newly formed
carbamate undergoes the usual photoredox radical addition and oxi-
dation to the cation. An intramolecular nucleophilic addition between
the cation and the carbamate forms the final product. In this case
however, the first SET of the reaction is not the first SET of the photo-
catalytic cycle, therefore DABCO is required to initiate the reductive
quenching that will later be performed by the intermediate radical species.
It is essential we address here a main limitation of the radical–polar
crossover method: as an observant reader may have already realized,
most of these reactions are limited to the use of styrene derivatives,
which help stabilize the radical intermediate long enough for the oxi-
dation into a cation to occur without radical side-reactions. Very few
examples are shown using alkenes that do not possess at least one aro-
matic substituent. An alternative previously described here is the use of
enamines/enamides by the Masson group. Another approach diverging
from styrene was reported by Glorius and co-workers in 2014
(Scheme 31).76 In their work, both reagents and final products are similar
to those seen in the previously described photoredox oxyarylation, how-
ever the mechanistic pathway is very different : rather than a purely
photoredox catalytic cycle, they employ a dual gold/photoredox catalytic
cycle. In this case, the cationic gold species coordinates to the alkene,
allowing for the nucleophilic addition of the alcohol. The gold I complex
then undergoes two single electron transfers (SET) with the photoredox
Scheme 30 CO2 in photoredox alkene difunctionalization.
418 | Photochemistry, 2019, 46, 395–431

Scheme 31 Merging gold and photoredox catalysis.76
catalytic cycle, affording the gold(III) complex. Au(III) being an unstable

species, it undergoes a reductive elimination, regenerating the Au(I)
species and affording the desired product. This method allows for a wide
range of non aromatic alkenes to be used and represents a comple-
mentary method to the one described above.
As with the example seen above (Scheme 28),72 most groups have
developed the amino counterparts of the oxy-alkylations and -arylations
described above (Scheme 25–30), by replacing the nucleophile from water
or alcohol to an amine. The mechanism follows the same pathway as the
previous reactions. In this way, the year after publishing their oxytri-
fluoromethylation, Akita and co-workers reported the corresponding
aminotrifluoromethylation, with very similar reaction conditions, save
for the solvent (Scheme 32).77 Here the solvent is no longer a DCM/
alcohol mix but a RCN/water mix, forming the a-CF3-amides through a
Ritter-type amination. Similar reactions were developed, by switching to a
nitrogen-containing nucleophile, by the groups of Masson,71,78 Greany73
and König.79
Besides from these two main subgroups, various other radical–polar
crossover photoredox MCRs involving olefin difunctionalization have been
reported. The Masson group has developed numerous alkene or enamides
trifluoromethylations in the presence of nucleophiles other than alcohols
and amines, such as cyanide71 and halide salts80 or electron-rich (het-
ero)aromatic compounds (Scheme 33).81 In 2017, Magnier and co-workers
extended this synthetic pathway to sulfoarylations through the use of N-
trifluoromethylthiosaccharin as an SCF3 radical precursor, with electron-
rich aromatic species as nucleophiles once more (Scheme 33).82
Lastly, a few photoredox MCR olefin difunctionalization have also al-
lowed for the formation of two carbon–heteroatom bonds to be formed.
While a first example was vaguely reported by Griesbeck and co-workers
in 2010,83 double-heteroatomic olefin functionalization is still very rare,
with only two recent examples to date (Scheme 34). The Greaney group
used a Togni-like radical precursor, upon which the CF3 has been
exchanged for an azide, to achieve a photoredox oxyazidation with an
unusual copper based photoredox catalyst, rather than the classic
Photochemistry, 2019, 46, 395–431 | 419

Scheme 32 Photoredox amino-alkylation and -arylation.71,77–79
iridium or ruthenium ones.84 Following the usual synthetic pathway, this

has allowed for the formation of a C–N bond (by radical addition of the
N3 on the alkene) and a C–O bond (by the nucleophilic addition of an
alcohol on the cation formed by oxidation of the intermediate radical).
The same year, Akita and co-workers reported an aminohydroxylation by
using aminopyridinium salts as precursors for an electrophilic amine
radical and water as the nucleophile.85 While this method works for non-
aromatic bearing alkenes, the styrene derivatives still give far better
yields.
All these alkene difunctionalizations described above go through an
oxidative quenching of the photoexcited catalyst, with the photocatalytic
cycle being closed by the reduction of the PC1 species through oxidation
of the intermediate radical into a cation. The reductive quenching
mechanism is far less common and, to the best of our knowledge, has
only one example as an MCR: a hydroalkoxy-methylation developed by
the group of Akita in 2013.86 Here the radical initiator is an alkoxymethyl
420 | Photochemistry, 2019, 46, 395–431

Scheme 33 Radical–polar crossover photoredox alkene difunctionalization other than
amino- or oxy-alkylation or -arylation.71,80–82
Scheme 34 Photoredox double carbon–heteroatom vicinal bond formation.84,85
trifluoroborate, which is oxidated by reductive quenching of the photo-

catalyst. The alkoxymethyl radical then adds onto the alkene, forming a
new radical that is reduced to the anion, closing the photocatalytic cycle.
This anionic species is then hydrated, yielding the final product
(Scheme 35).
3.1.2 Other photoredox reactions. Reactions involving a photoredox

process between 2 reagents to create a new species that further reacts
with a third reagent have been developed beyond olefin difunctionaliza-
tion in numerous different directions. Such reactions include the for-
mation of a-amino amides from tertiary amines and isocyanides,
developed in batch or flow, with various organo, metallic or organomet-
allic photocatalysts (Scheme 36),87–89 as well as the double substitution
Photochemistry, 2019, 46, 395–431 | 421

Scheme 35 Hydroalkylation through a photoredox reductive quenching pathway.
Scheme 36 Photoredox synthesis of a-amino amides.
of fluorobromoesters towards symmetrical or unsymmetrical diarylated

esters,90 through a multiphotocatalytic reactive pathway (Scheme 37). It
is important to note that the authors of the latter do concede that,
while the first steps are definitely the radical cleavage of the C–Br bond
and subsequent radical addition onto the aromatic species, the rest of
the reactive sequence is up for debate.
Besides from those reactions, photoredox MCR reactions leading to
hetero- and/or poly-cycles have received a substantial amount of attention.
Starting from 2-aminostyrene, the group of Xiao developed a new
photoredox access to functionalized indoles (Scheme 38), with a synthetic
pathway that starts off very similar to the radical–polar crossover seen
previously (Scheme 15).45 However, when the intermediate cation is
formed, after the radical addition, the typical nucleophilic addition does
422 | Photochemistry, 2019, 46, 395–431

Photochemistry, 2019, 46, 395–431 | 423
Scheme 37 Photoredox synthesis of symmetrical or unsymmetrical diarylated esters.

Scheme 38 Photoredox synthesis of indoles.
not occur. Instead, the amine is deprotonated, leading to a conjugated

imine. This imine is then used in a [4 þ 1] cycloaddition that affords the
desired compound. This particular reaction was already described in a
previous chapter when the Umemoto is used as radical precursor, as in
that case there is no need for a photocatalyst and therefore the reaction is
considered simply photochemical.
The same group also developed the photoredox generation of aryl
esters from diazonium salts, methanol and CO gas (Scheme 39).91
This alkoxycarbonylation has a mechanism similar to the photo-
chemical reactions involving CO, previously described (Schemes 9–10),
however the original radical is here generated by oxidative quenching of
excited fluorescein. This aryl radical adds to CO, forming the carbonyl
radical which is oxidized, returning fluorescein to its ground state in the
process, following the classic mechanistic pathway seen in radical–polar
cross overs. The final step is the nucleophilic addition of methanol upon
this intermediate, to yield the desired product. Using specifically func-
tionalized diazonium salts leads to the formation of a benzofuran core.
Alternatively, Jacobi von Wangelin and co-workers developed a photo-
catalyzed chlorosulfonylation, based around a SO insertion, rather than a
CO insertion, onto diazonium salts (Scheme 39). These salts can poten-
tially be generated in situ from the corresponding amines and can lead to
an efficient one-pot photo-MCR synthesis of Saccharin.92
Several other MCR photoredox reactions were used to achieve various
heterocyclic and/or polycyclic compounds.46 In 2016, König and co-
workers developed an ABB MCR photocatalytic reaction to access pyri-
dine scaffolds (Scheme 40).93 The reactive imine is formed by oxidation of
benzylamine (by reductive quenching of the excited eosin), followed by
nucleophilic addition of a second equivalent of benzylamine and elim-
ination of ammonia. The Imine undergoes a double nucleophilic add-
ition of enol, assited by a second photoredox catalytic cycle, and the
ammonia closes the ring by double condensation upon the ketone moi-
eties. Elimination of a benzylamine molecule allows for aromatisation of
424 | Photochemistry, 2019, 46, 395–431

Scheme 39 Photoredox carboxylation.91,92
Scheme 40 Photoredox synthesis of pyridines.
the heterocycle to pyridine. Here Oxygen is essential in the process as it

enables catalytic turnover by bringing the PC back to its ground state.
A double photoredox catalytic cycle with eosin was also used by Singh and
co-workers to generate organoazides in situ for a click chemistry [3 þ 2]
cycloaddition.94
Photochemistry, 2019, 46, 395–431 | 425

426 | Photochemistry, 2019, 46, 395–431
Scheme 41 Final step photoredox reaction amidst a cascade MCR.95,96

In these previous cases, the photoredox cycle was an integral part of
the heterocyclic synthesis. However, there exist some examples in which
the photoredox step is only used at the end of a cascade reaction
sequence (Scheme 41). In the work of Ananthakrishnan and Gazi,
the photoredox step is simply used after a Hantzsch reaction to
aromatize the product to the corresponding pyridine.95 In the MCR
reported by Lin and Yang, most of the reaction is acid catalyzed, with
only the last intramolecular cyclization/aromatisation step being
photocatalyzed.96
3.2 Use of a photosensitizer

In this last part, we shall address MCR catalysed by an energy transfer,
rather than an electron transfer, through the use of a photosensitizer.
Compared to photoactivated or photoredox catalyzed reactions, examples
of such reactions are rare, and MCR versions are even less developped. In
these cases, the photosensitizer is excited by light (visible or UV) and the
excited state photosensitizer then undergoes intersystem crossing to
reach a triplet state. It is this state that allows for the transfer of energy
towards another compound. In the cases we present, the energy-receiving
compound is oxygen, with reaches a singlet state upon which it becomes
very reactive (Scheme 42). While it does appear very similar to oxygene

being reduced to O2 - via a SET mechanism in a photoredox catalytic
cycle, it should be considered as separate reactivity in which the oxygene
is only activated to an excited state (with no electron transfer happening)
before reacting with the other reagents.
In 2009, Che and co-workers developed a one-pot MCR combining the
photooxidation of secondary amines to the corresponding imines by
photogenerated singlet oxgen, with an Ugi-type reaction (Scheme 43).97 A
similar photoinduced MCR was developed by Azarifar and co-workers in
2017 in which an alcohol, rather than an amine, was oxidized to the
corresponding aldehyde by singlet oxygene, itself produced by a light-
activated MOF species (Scheme 43).98 The aldehydes were then submitted
to a Passerini type reaction. Building on previously described radical–
radical oxyarylations, the group of Leow developed a similar reaction to
the separate works of Guo59 and Cai60 (Schemes 21 and 22), but starting
from a hydrazine in the presence of Remazol Brilliant Blue R (RBBR) as
photosensitizer (Scheme 43). Unlike the works of Cai and Guo, this
reaction leads to the hydroperoxyl, not the corresponding alcohol or
ketone. Finally in 2015, the group of Greck reported the use of BODIPY as
Scheme 42 General Scheme for the photooxygenation reaction.
Photochemistry, 2019, 46, 395–431 | 427

Scheme 43 Use of a photosensitizer to form reactive singlet oxygen.97–100
photosensitizers in a MCR reaction (Scheme 43):99 under light irradi-

ation, the BODIPY would produce singlet oxygene which would react with
naphthol, generating naphthoquinones by photooxygenation. The in situ
generated naphthoquinones would then undergo an asymmetric ami-
nocatalysed reaction sequence, leading to polycyclic 3D chiral archi-
tectures from a multi-catalytic MCR. In these last 2 cases, it is interesting
to note that oxygen is part of the compound count for the MCR as it is
integrated into the final product.
4 Conclusions
Photoinduced multi-component reactions have shown a broad scope of
reactivity. Whether via direct reagent photoactivation or photocatalysis,
they have known a recent surge in popularity which should continue as
both the fields of MCRs and photochemistry continue to be developed
-separately or concomitantly-, helping the field of organic synthesis to
build ever more cost-efficient and environmentally benign means to
reach ever more complex architectures.
428 | Photochemistry, 2019, 46, 395–431

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Photochemistry, 2019, 46, 395–431 | 431

Asymmetric catalysis of triplet-state
photoreactions
Evan M. Sherbrook and Tehshik P. Yoon*
DOI: 10.1039/9781788013598-00432
For many decades, stereocontrol in triplet-state photoreactions was widely regarded

an elusive goal. Catalytic strategies to influence the reactivity of transient electronically
excited intermediates remains a significant challenge, but many distinctive molecular
scaffolds are uniquely available through excited-state chemistry . This Chapter summar-
izes studies ranging from the first asymmetric photoisomerizations to recent develop-
ments in highly enantioselective photocycloaddition reactions.
1 Introduction
The stereochemistry of organic molecules is crucial to their function and
to their chemical and biological properties. Thus, the controlled con-
struction of complex chiral molecules ranks among the most important
challenges facing contemporary synthetic organic chemistry.1 Asym-
metric catalysis has become as an essential tool for the enantioselective
preparation of a variety of molecular scaffolds including drugs and new
drug targets, functional organic materials, and chemical feedstocks. One
important frontier for continued research in this area is the development
of new, highly enantioselective catalytic strategies that are applicable to a
broader range of reaction types and product structures.
Photochemical reactions constitute a large and diverse class of syn-
thetically useful transformations for which stereocontrol has long proven
to be challenging.2 Photochemical activation frequently results in the
generation of highly energetic intermediates that react in distinctive ways
and provide access to structural patterns that are otherwise difficult to
access. However, these highly reactive intermediates are also generally
quite short-lived, which can challenge the ability of exogenous chiral
catalysts to intercept them and modulate their reactivity. Indeed, robust
strategies for the design of highly enantioselective catalytic photoreac-
tions have only become available within the last decade.
The majority of these successful enantioselective photoreactions,
however, can be classified as secondary photoreactions: they are reactions
of photogenerated reactive intermediates such as radicals or radical ions
in their ground-state electronic configurations.3 The reactions that are
accessible using photoredox catalysis belong to this class, and the recent
renewal of interest in these reactions4 has motivated much of the devel-
opment in enantioselective photocatalysis. Stereocontrol in primary pho-
toreactions, in which the key bond-forming steps occur from electronically
excited-state intermediates, has proven to be a more challenging
objective. This discrepancy has practical implications. While photoredox
Department of Chemistry, University of Wisconsin–Madison, 1101 University

Avenue, Madison, Wisconsin, 53726, USA. E-mail: tyoon@chem.wisc.edu
432 | Photochemistry, 2019, 46, 432–448

catalysis offers a particularly convenient means to access the reactivity of
open-shelled odd-electron intermediates, there exist numerous classical
non-photochemical methods for the initiation of radical reactions.5 The
chemistry of electronically excited organic molecules, on the other hand,
is uniquely accessible using photochemical activation and cannot be
recapitulated through alternate means.
Much of the early research in enantioselective excited-state reactions
involved chiral analogues of well-studied organic photosensitizers. These
studies, however, generally resulted in low enantioselectivities, a feature
that was attributed to weak, poorly-defined associations with the excited-
state intermediates. More successful subsequent studies have shown that
preassociation between the substrate and chiral catalyst prior to the
excitation process can confer higher levels of selectivity in these reac-
tions. This Chapter will focus both upon early exploratory investigations,
which helped to establish an understanding of how to best control
excited-state reactivity, as well as more recent developments, which have
made use of these insights to develop highly enantioselective excited-
state photoreactions.
The broadest class of enantioselective photoreactions are those that
utilize enantiopure photocatalysts to transfer stereochemical information
to prochiral or racemic substrate molecules. Sections 2 and 3 address
these types of reactions using purely organic photosensitizers, while
Sections 4 and 5 cover the use of Lewis acids and transition metal-
centered photocatalysts. Overall, this Chapter summarizes asymmetric
photochemical transformations enabled by substoichiometric small-
molecule catalysts. Photoreactions involving superstoichiometric chiral
environments, complex supramolecular catalyst scaffolds (e.g. enzymes
and zeolites), chiral auxiliaries, and circularly polarized light have not
been included. For surveys of these areas, we direct the reader to several
important reviews published in recent years.2a,6
2 Arenes and aryl ketones

The first enantioselective catalytic excited-state photoreaction, reported
in 1965 by Hammond and Cole, was the desymmetrization of trans-1,2-
diphenylcyclopropane (DPC) (rac-1, Scheme 1) using the modified chiral
naphthalene sensitizer 3.7 The process itself is a relatively simple geo-
metrical photoisomerization; 1 was recovered from the reaction in 7% ee,
along with meso cyclopropane 2. Although the magnitude of the en-
antioselectivity in this experiment is low by modern standards, the
insight that chiral sensitizers could perturb the stereochemical course of
a photoreaction was profound.
The original report proposed a mechanism involving triplet energy
transfer; however, it was later determined that the reaction occurs
through a singlet manifold.8 Indeed, this latter discovery is consistent
with a general trend observed using chiral modified arene photo-
sensitizers, which often form singlet-state exciplexes with their substrates.
In contrast to arenes, ketones often undergo efficient intersystem
crossing (ISC) and thus have a greater propensity to participate in
Photochemistry, 2019, 46, 432–448 | 433

Scheme 1 Geometrical photoisomerization of diphenylcyclopropane by arene and
ketone sensitizers.
Scheme 2 Photochemical rearrangement of oxapinone 7 by naphthyl carbonyls.
catalyst-to-substrate triplet energy transfer processes. The desymme-

trization of racemic DPC using indanone 4 was reported by Ouannès
in 1980. This example was the first asymmetric photoreaction known
to occur via a triplet manifold.9 Ouannès proposed that the low-energy
triplet of trans-DPC (ca. 53 kcal mol1) would easily be sensitized by
a high triplet energy aryl ketone.10 This experiment produced en-
antiomerically enriched 1 in 3% ee. Other aromatic ketones were
reported to be less successful: tetralones 5 and 6 afford lower selectivity.
Sato reported the first asymmetric triplet-state photorearrangement in
1980.11 The sensitization of oxepinone rac-7 (Scheme 2) was explored
using several naphthyl carbonyls such as 10–12 at a variety of catalyst
loadings (0.5 to 2.0 equiv). This effects a 1,5-phenyl shift to 8, followed
by a di-p-methane rearrangement to give oxabicyclo[4.1.0]heptanone 9 as
the product. When the reactions were halted at 50% conversion, both the
starting oxepinone 7 and the product 9 were found to be optically active.
The enrichment of both starting material and product suggest that the
stereochemistry-determining step is the initial sensitization itself.
434 | Photochemistry, 2019, 46, 432–448

Contemporaneous with these studies, Demuth and Schaffner investi-
gated the oxa-di-p-methane rearrangement of bicyclo[2.2.2]octenone rac-
14 (Scheme 3) to tricyclo[3.3.0.0]octenone 15 using 16 as a sensitizer.12
Quantitative evaluation of optical rotation showed that the product was
formed in 4.5% ee at room temperature and 10% ee at 78 1C. This
provided an excellent demonstration of the potential utility of sensitized
excited-state reactions, as the product generated through energy transfer
(15) is different from the product of direct irradiation (13), which arises
from a 1,3-acyl shift.
The asymmetric photoextrusion occurring in trans-3,5-diphenylpyr-
azoline (DPY) (rac-17, Scheme 4) to give 1 and 2 (meso) was reported by
Rau and Horman in 1981.13 ()-Rotenone (18) and (þ)-testosterone (19)
were studied as chiral photosensitizers and gave 1 in 4% ee and 1% ee,
respectively. While DPY can react to afford racemic 1 upon direct pho-
tolysis,14 it also has a low triplet energy (55 kcal mol1).15 Both 18 and 19
possess triplet energies near 70 kcal mol1, which makes them competent
photosensitizers for this reaction. Irradiation was thus conducted at
wavelengths above 350 nm where the absorbance of DPY is minimal but
where 18 and 19 absorb strongly, in an effort to prevent direct absorption
and maximize the photosensitized process. An intramolecular variant of
this reaction was also explored in which the pyrazoline is covalently
tethered to the ketone, but levels of enantioenrichment were low.16
The first asymmetric [2þ2] photocycloaddition to be accomplished
through a triplet manifold was published over 20 years later by Krische,17
Scheme 3 Reaction outcomes for rac-14 under direct irradiation and triplet energy transfer.
Scheme 4 Desymmetrization of diphenylpyrazoline 17 to diphenylcyclopropanes by

rotenone and testosterone.
Photochemistry, 2019, 46, 432–448 | 435

Scheme 5 Intramolecular [2þ2] photocycloaddition of quinolone 20 using a chiral
H-bonding bisamide.
who studied the reaction of quinolone 20 in the presence of

benzophenone-modified bisamide 22 (Scheme 5) as a chiral, hydrogen-
bonding host. When this mixture was irradiated at 70 1C, cyclobutane
21 was produced in good yield and in 19%, 20%, and 22% ee with 25, 50,
and 100 mol% of the catalyst, respectively. This catalyst design differed
from previous efforts because the hydrogen-bonding scaffold results in a
significant ground-state preassociation between the substrate and the
photosensitizer. This both maximizes the probability that the reactive
excited-state intermediate is generated within a well-defined chiral
environment defined by the hydrogen-bonding sensitizer and extends the
lifetime of the substrate–catalyst interaction. Although the enantios-
electivities observed in these experiments remained relatively modest by
modern standards, the improvement over previous approaches shifted
the focus of research in this field towards other catalysts capable of
similar ground-state interactions.
3 H-bonding xanthones, thioxanthones, and thioureas

The first true photocatalysts capable of producing synthetically relevant
enantioselectivities in triplet-state asymmetric photoreactions were
developed by Bach and coworkers. In previous work, Bach had demon-
strated that Kemp’s triacid-derived hydrogen-bonding host structures
bearing benzoxazole units (23, Fig. 1) could be used as super-
stoichiometric chiral hosts to control a number of photocycloadditions
and photocyclization reactions.18
The benzoxazole moiety in this design serves as a steric shield that
blocks one of the prochiral p faces of bound quinolone substrates. By
replacing the benzoxazole with benzophenone (24), Bach was later able
to design a photocatalytically active hydrogen-bonding scaffold. This
compound was shown to be a highly enantioselective photocatalyst
at sub-stoichiometric loadings for a spirocyclization reaction of a photo-
generated a-aminoradical.19
The first excited-state photoreaction using this strategy involved a
modified catalyst (25a) featuring a photoactive xanthone moiety. This
photosensitizer has the benefit of both a red-shifted absorption profile
436 | Photochemistry, 2019, 46, 432–448

Fig. 1 A series of chiral H-bonding photocatalysts.
Scheme 6 Intramolecular [2þ2] photocycloadditions of quinolone 20 by a chiral

H-bonding xanthone.
(40 nm) compared to benzophenone, and a higher triplet energy (74 vs.
69 kcal mol1). This catalyst was used to sensitize the intramolecular
cycloaddition of quinolone 20 (Scheme 6). Both regioisomers ent-21a and
26 were produced in 91% ee (3.3 : 1 r.r.) at a catalyst loading of 10 mol%
and a reaction temperature of 25 1C.20
Subsequent studies of the scope of this reaction21,22 revealed that
high enantioselectivities could be obtained for various modified sub-
strates provided that the [2þ2] cycloaddition proceeds at a fast rate. Bach
suggested that compounds that underwent cycloaddition more slowly
(e.g., 21b) gave poorer ee’s because the rate of dissociation from the chiral
photocatalyst could become competitive, enabling some proportion of the
product to be formed in an achiral environment. This catalyst can also be
used to carry out intermolecular [2þ2] cycloadditions (Scheme 7) between
pyridone 27 and acetylenedicarboxylates to give cyclobutene products
28a–f with good enantioselectivities.23 Catalyst loadings were reduced to
only 2.5–5.0 mol% and reactions were performed at 65 1C using a tri-
fluorotoluene/hexafluoro-m-xylene (HFX) solvent mixture.
Photochemistry, 2019, 46, 432–448 | 437

Scheme 7 Intermolecular [2þ2] photocycloaddition of pyridones and
acetylenedicarboxylates.
Thioxanthone catalyst 25b is structurally analogous to xanthone 25a

but exhibits a longer-wavelength absorption spectrum.24 As such, this
thioxanthone catalyst is capable of mediating reactions using visible
light, rather than UV. Initially, Bach demonstrated that this catalyst
enables several quinolones to undergo cycloaddition with 400–700 nm
light. Selectivities were found to be consistently high using 10 mol% of
the catalyst at 25 1C. For example, using 25b, cycloadduct 21d was
generated in 86% yield and 91% ee, improving on the reaction outcome
observed with 25a. This was attributed to the fact that the longer wave-
length irradiation minimizes the formation of product by direct irradi-
ation of the quinolone, which in turn minimizes the rate of formation of
racemic cycloadduct.
This improved thioxanthone catalyst also enables the highly en-
antioselective intermolecular cycloaddition of quinolone 29 (Scheme 8)
with ethyl vinyl ketone to give cyclobutane 30a as a single diastereomer in
high yields and ee (25 1C, 419 nm light, 10 mol% catalyst).25 A variety of
other alkenes, including benzyl acrylate, methyl vinyl ketone, acrolein,
and similar variants offer good results, although a large excess of the
acceptor alkene is required for optimal results.
In 2014, concurrent with much of Bach’s work on chiral xanthones
and thioxanthones, Sibi and Siviguru reported an intramolecular [2þ2]
photocycloaddition of 4-alkenyl coumarins using chiral binaphthyl
thiourea 33a as a photocatalyst (Scheme 9).26 Irradiation of coumarin 31
in the presence of this thiourea catalyst using 350 nm light at 78 1C gave
438 | Photochemistry, 2019, 46, 432–448

Scheme 8 Intermolecular [2þ2] photocycloaddition of quinolones and electron poor
olefins by a chiral H-bonding thioxanthone.
Scheme 9 Intramolecular [2þ2] photocycloadditions of coumarin 31 by naphthyl

thioureas.
32a in 84% yield and 74% ee in only 30 min. Iterative structural opti-
mizations of the catalyst led to the identification of 33b, which afforded
quantitative yield of the product in 96% ee with only 10 mol% catalyst
loading. From a design perspective, this thiourea catalyst is similar to
Bach’s xanthone catalysts in that it couples a hydrogen-bonding domain
to a p-conjugated chromophore.
Mechanistically, however, the mode of catalysis in the Sivaguru system
appears distinct. First, energy transfer was determined to not be ener-
getically feasible because fluorescence spectroscopy revealed that
both the lowest singlet and triplet excited states were insufficiently
energetic to sensitize coumarin 31. Instead, Sivaguru and Sibi proposed
the formation of an absorption complex. UV/vis spectroscopic analysis
revealed that the catalyst-substrate complex exhibited a distinct
Photochemistry, 2019, 46, 432–448 | 439

bathochromic shift compared to the catalyst or substrate species in
isolation. Thus, a chiral substrate–catalyst complex was proposed to
absorb long-wavelength light preferentially over the free substrate.
Moreover, these investigators observed a nonlinear Stern-Volmer
response to the concentration of coumarin substrate, which is indica-
tive of both static and dynamic quenching mechanisms occurring
competitively. As a result, a concentration-dependent mechanism was
proposed. At low substrate concentration (high concentrations of
thiourea), the higher optical density of the biaryl catalyst results in its
selective photoexcitation; product formation was proposed to proceed the
formation of an exciplex. At high substrate concentration, on the other
hand, the pre-associated absorption complex is selectively photoexcited,
similarly leading to product. A variety of structurally diverse chiral
thiourea scaffolds were also investigated as catalysts for the same intra-
molecular coumarin cycloaddition.27 Interestingly, while none of these
catalysts gave enantioselectivities comparable to 33a or 33b, the precise
mechanism of photochemical activation varied as a function of catalyst
structure.
4 Lewis acids
The ability of Lewis acids to modulate excited-state photocycloadditions
has been known for some time. The most thorough studies of this
phenomenon were conducted by Lewis in the 1980s.28 Although the [2þ2]
photocycloaddition of coumarin can be achieved through direct exci-
tation, this process is inefficient because the singlet excited state of
coumarin relaxes rapidly to the ground state, decreasing its propensity
to undergo intermolecular cycloaddition reactions. Coordination of the
coumarin to a Lewis acid significantly increases the lifetime of the
excited state. Thus, intermolecular cycloadditions between coumarins
and alkenes are considerably faster in the presence of Lewis acids such as
BF3 and EtAlCl2.29 Similar effects on the rate of cinnamate photo-
cycloadditions have been documented as well.30
This effect was successfully exploited in enantioselective photocatalysis
by Bach.31,32 Chiral oxazaborolidine catalyst 34a (50 mol%, Fig. 2) is an
effective asymmetric catalyst for the cycloaddition of 4-alkenyl coumarin
31 to afford cyclobutane ent-32a in 84% yield and 82% ee. In addition,
this catalyst allows for alteration of the alkene tether (Fig. 3) while
maintaining high yields and good selectivities. While the uncatalyzed
reaction proceeds through a singlet excited-state manifold, Bach
proposed that the catalysed reaction proceeds through a triplet-state
biradical intermediate. Consistent with this hypothesis, coumarins
featuring isomeric (E) and (Z) alkene-containing substituents undergo
stereoconvergent cycloaddition, suggesting a stepwise triplet-state
mechanism. Bach also observed that the UV–vis absorption spectra of
this class of coumarin compounds undergoes a bathochromic shift in the
presence of Lewis acids. An important feature of this successful strategy,
therefore, is selective irradiation at the red-shifted tail of the coumarin
absorption with a monochromatic light (l ¼ 366 nm), which maximizes
440 | Photochemistry, 2019, 46, 432–448

Fig. 2 A series of chiral oxazaborolidine-AlBr3 Lewis acids.
Fig. 3 Representative scope of intramolecular [2þ2] coumarin photocycloadditions using

chiral Lewis acid 34a.
the photoexcitation of the Lewis acid-bound substrate and minimizes

direct photoexcitation of unbound coumarin.
This Lewis acid-mediated strategy has enabled asymmetric photo-
cycloaddition reactions to be applied to a much broader range of
enone substrates.33 Bach has developed conditions for the highly en-
antioselective [2þ2] cycloaddition of dihydropyridone 35 (Scheme 10) to
afford 36a in 84% yield and 88% ee, again using catalyst 34a. The mode
of catalysis for this substrate features a subtle but important mechanistic
difference.
Unlike coumarin photocycloadditions, there is no change in the
reactive spin state of photoexcited 35 in the presence of a Lewis
acid catalyst; both the free and Lewis-acid-bound pyridine undergo
cycloaddition through the triplet state when irradiated at 366 nm.
Indeed, the intrinsic rate of cycloaddition is somewhat depressed upon
coordination of 35 to a Lewis acid. However, in addition to a significant
50 nm bathochromatic shift of the p,p* transition feature, the UV–vis
spectrum of the Lewis acid-pyridone complex exhibits a marked increase
in molar absorptivity. Thus the high selectivity appears largely to be a
consequence of the higher extinction coefficient of the Lewis acid-bound
substrate compared to the achiral free pyridone, which provides an
alternative means to minimize the participation of racemic background
cycloaddition.34
Subsequent investigations by Bach have continued to extend the scope
of this strategy towards simpler enone substrates. Catalyst 34b has been
applied in the intramolecular photocycloaddition of b-alkoxysubstituted
Photochemistry, 2019, 46, 432–448 | 441

Scheme 10 Intramolecular [2þ2] photocycloaddition of pyridones.
cycloalkenones.35 Very recently, oxazaborolidine 34c was identified as

an optimal catalyst for the intermolecular cycloadditions of simple
cycloalkenones such as 37 (Scheme 11) with an impressive variety of
alkenes to give 38a–h.36
This is an important contribution because many of the classic
applications of photocycloadditions to the synthesis of natural products
have involved such simple cycloalkenone substrates.37 Bach’s strategy
thus appears to provide a strategy to render these syntheses en-
antioselective. Although the alkene coupling partner must be used in
significant excess, the structural variety of olefins that participate in this
reaction is impressive and distinctive to this approach.
Although nearly all methodologies in asymmetric triplet state photo-
chemistry employ chiral enantiopure photocatalysts, several dual catalyst
strategies for highly enantioselective photoredox reactions have been
developed.38 The approach is appealing because it allows for independ-
ent optimization of the chiral stereocontrolling co-catalyst without
altering the robust photophysical and photoelectrochemical properties of
an achiral or racemic photoredox catalyst.39 Until recently, however, this
strategy had not been applied to transformations involving excited-state
photochemistry.
In 2016, Yoon reported a dual catalytic approach to asymmetric
intermolecular [2þ2] photocycloadditions between 2 0 -hydroxychalcone
39 (Scheme 12) and dienes to give 40a in 84% yield, 93% ee, and 3:1 d.r.40
This result constitutes a rare example of a highly enantioselective
photocycloaddition reaction involving an acyclic enone. In this trans-
formation, Ru(bpy)3(PF6)2 acts as a photosensitizer and a (pybox)Sc(OTf)3
Lewis acid co-catalyst (41) serves as the chiral controller. The distinctive
mechanistic feature of this process is a Lewis acid-mediated lowering of
the triplet energy (ET) of the substrate. This renders triplet energy transfer
442 | Photochemistry, 2019, 46, 432–448

Scheme 11 Intermolecular [2þ2] photocycloaddition of cyclohexenones and aliphatic
alkenes.
Scheme 12 Intermolecular [2þ2] photocycloadditions of 2 0 -hydroxychalcones and

dienes to using a chiral Lewis acid complex.
Photochemistry, 2019, 46, 432–448 | 443

Scheme 13 Expansion of intermolecular [2þ2] photocycloadditions with chalcones to
include syrenes and vinyl sulfides.
from Ru*(bpy)321 to the substrate feasible only when bound to the

chiral Lewis acid catalyst, making the free substrate unreactive and thus
minimizing racemic background photocycloaddition. To support this
hypothesis, Yoon utilized a combination of computational and spectro-
scopic studies to show that the ET of 41 decreases from from 54 kcal/mol
to 33 kcal mol1 upon coordination to the Lewis acid. Thus sensitization
by Ru(bpy)321, which has an ET of 47 kcal mol1, is indeed thermo-
dynamically feasible only to the Lewis acid-bound complex.
The reaction demonstrates both modest functional group tolerance
and works well with several other dienes (40b–f). Other alkenes such as
styrenes and vinyl sulfides could also function as acceptor alkenes to give
diaryl cyclobutane products such as 40g–i (Scheme 13)41 This method
was applied to a concise synthesis of norlignin cyclobutane 42.
5 Transition metal photocatalysts

Almost all chiral photocatalysts investigated for organic transformations
have relied on the tetrahedral chirality of chiral organic sensitizers or
cocatalysts. Alternate approaches exploiting the helical chirality of octa-
hedral transition metal complexes have recently been reported. Meggers
has played a pioneering role in designing chiral-at-metal octahedral
Lewis acidic catalysts capable of controlling the stereochemistry of a
variety of photoredox reactions with exceptional enantiocontrol (e.g., 43a,
Fig. 4).42 Very recently, Meggers demonstrated that this class of catalysts
can also control excited state photoreactions through the formation of
direct absorption complexes.43 Chiral-at-rhodium complex 43b binds to
imidazoyl enone 44 to form a new species that features a distinct new
absorption feature that is red-shifted compared to the UV–vis spectra of
either the enone or Rh catalyst alone (Scheme 14).
444 | Photochemistry, 2019, 46, 432–448

Fig. 4 Chiral-at-metal iridium and rhodium photocatalysts.
Scheme 14 Intermolecular [2þ2] photocycloadditions of imidazoyl, pyridyl, and Pyrazoyl

enones with alkenes.
When this complex is excited with visible light, it undergoes a facile

intermolecular [2þ2] photocycloaddition with electron rich alkenes to
afford a diverse array of vinylcyclobutanes 45a–g in excellent yield and ee
using quite low catalyst loadings (2–4 mol%). Interestingly, the reaction
was found to be feasible without a catalyst, albeit at a substantially slower
rate. The origin of the extremely high selectivities is attributable to a
nearly 170-fold increase in molar extinction coefficient for the complex
as compared to the substrate, effectively outcompeting any direct back-
ground cycloaddition.
Yoon recently designed a chiral-at-iridium catalyst 48 (Scheme 15) that
employs outer-sphere hydrogen-bonding interactions via a functionalized
pyrazole ligand rather than substrate-metal interactions.44 Using this
catalyst, quinolone 46 undergoes highly enantioselective intramolecular
Photochemistry, 2019, 46, 432–448 | 445

Scheme 15 Intramolecular [2þ2] photocycloadditions of quinolones with an H-bonding
chiral-at-metal iridium photocatalyst.
[2þ2] cycloaddition to afford 47 in 98% yield and 91% ee using visible

light and only 1 mol% of catalyst at 78 1C. The mode of interaction
between the quinolone substrate and the pryazole ligand is unique;
Yoon proposed that the primary hydrogen-bonding interaction occurs
between the Brønsted acidic N–H moiety of the pyrazole and the quino-
lone carbonyl, and that a weak, secondary H–bonding interaction
from the quinolone N–H to the pyrazole p-surface orients the substrate
relative to the chiral Ir stereocenter and facilitates rapid triplet energy
transfer. Consistent with this model, coumarin and N-methylquinoline
undergo rapid but essentially unselective cycloaddition upon sensitiza-
tion with 48.
6 Summary and looking forward

Over the past decade, the development of multiple highly en-
antioselective excited-state photoreactions has demonstrated conclu-
sively that stereocontrol in this class of transformations is indeed feasible
using small-molecule chiral catalysts. A key feature common to all of
these successful catalytic asymmetric photoreactions has been the use
of ground-state preassociations between the substrate and the chiral
controller that facilitate the photoactivation step. Many of the most
successful chiral catalyst structures reported to date for these appli-
cations are the same well-understood privileged catalysts that have been
broadly applied to other non-photochemical transformations. Thus, the
field of asymmetric photochemistry is poised for a period of significant
growth as synthetic chemists learn to apply these principles to a broader
range of excited-state photoreactions. The reactivity of these photo-
generated intermediates afford structurally unique products that have
previously been difficult to access in enantiomerically enriched form,
and these efforts to develop stereoselective photochemistry into a robust
446 | Photochemistry, 2019, 46, 432–448

contemporary synthetic tool is an exciting prospect for modern organic
chemistry.
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Photochemistry

r The Royal Society of Chemistry 2019

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The Royal Society of Chemistry is a charity, registered in England and

For further information see our web site at www.rsc.org

Printed in the United Kingdom by CPI Group (UK) Ltd, Croydon,

Volume 46 follows the pattern of previous titles from Volume 39 onwards,

Angelo Albini and Stefano Protti

Photochemistry, 2019, 46, vii–vii | vii

Manabu Abe was born in Sakai City, Osaka

Emilio I. Alarcon is a principal investigator

viii | Photochemistry, 2019, 46, viii–xxiii

Alessandro Aliprandi received his PhD in

Christophe Bour received his MSc in organic

Photochemistry, 2019, 46, viii–xxiii | ix

Luisa De Cola is, since September 2013,

Brian N. DiMarco was born in Stamford,

x | Photochemistry, 2019, 46, viii–xxiii

Filippo Doria, born on March 4, 1982,

Photochemistry, 2019, 46, viii–xxiii | xi

Antonio Francés-Monerris graduated in

xii | Photochemistry, 2019, 46, viii–xxiii

Andreas Herrmann studied chemistry in

Photochemistry, 2019, 46, viii–xxiii | xiii

Irene E. Kochevar is Professor of Derma-

Benjamin Lipp studied biomedicinal chem-

xiv | Photochemistry, 2019, 46, viii–xxiii

Géraldine Masson received her PhD in 2003

Photochemistry, 2019, 46, viii–xxiii | xv

Miguel A. Miranda is Full Professor of

xvi | Photochemistry, 2019, 46, viii–xxiii

Antonio Monari is currently a member of

Miriam Navarrete-Miguel graduated in

Photochemistry, 2019, 46, viii–xxiii | xvii

Loı̈c Pantaine obtained his PhD (2013–2016)

xviii | Photochemistry, 2019, 46, viii–xxiii

Barbara Procacci graduated from the

Photochemistry, 2019, 46, viii–xxiii | xix

Justina Pupkaite received her Bachelor’s

Carlotta Raviola (born in 1988) studied

xx | Photochemistry, 2019, 46, viii–xxiii

Javier Segarra-Martı́ received his PhD degree

Photochemistry, 2019, 46, viii–xxiii | xxi

Erik Suuronen is a principal investigator

Takashi Tsuno obtained his PhDs at the

xxii | Photochemistry, 2019, 46, viii–xxiii

Michela Zuﬀo received her BSc and MSc

Photochemistry, 2019, 46, viii–xxiii | xxiii

Author biographies viii

Part 1: Periodical Reports: Organic and

Introduction of the year 3

Quantum chemistry of the excited state: recent trends in methods 28

Photochemistry, 2019, 46, xxv–xxix | xxv

Organic aspects: photochemistry of alkenes, dienes, 78

Photochemistry of aromatic compounds 116

Organic aspects. Oxygen-containing functions 169

xxvi | Photochemistry, 2019, 46, xxv–xxix

Function containing a heteroatom diﬀerent from 194

Design and synthesis of two-photon responsive chromophores

Controlled release of volatile compounds using the 242

Photochemistry, 2019, 46, xxv–xxix | xxvii

Photoresponsive molecular devices targeting nucleic acid 281

Transition metal complexes in ECL: diagnostics and 319