Perspective

pubs.acs.org/crystal

Is Organic Fluorine Really Not Polarizable?

Deepak Chopra*
Department of Chemistry, Indian Institute of Science Education and Research Bhopal, Bhopal 462023, India
ABSTRACT: The covalent chemistry of the main group element fluorine is well understood. In
contrast, its noncovalent chemistry, which forms the pillar of the paradigm of supramolecular
chemistry, is still in its infancy. The latter involves a complete understanding of the different
interactions (both intermolecular and intramolecular) involving donor and acceptor atoms. This
perspective highlights the recent developments in the understanding of noncovalent interactions
in relation to organic fluorine (partially fluorinated compounds) and the versatility and
importance of such interactions to the scientific community.

INTRODUCTION TO THE CF BOND

Organic compounds are abundant in nature. In addition to the
presence of the conventional CC (single, double, and triple
bonds), CO, CN, and other C-heteroatom bonds can also
be present. However, there are only a dozen natural organic
fluorine compounds known. In addition, the important
functional groups that form building blocks in organic
molecules comprises strong donors, namely, O/NH, activated
CH (depends on the hybridization of the carbon atom, being
most acidic for sp carbon) and strong acceptors, namely, C
O/N. The chemical nature of these atoms plays a decisive role
in molecular recognition events, particularly in the formation of
O/NHO/N strong H-bonds.1 In addition to these, weak
acceptors exist, namely, -rich systems involved in the
formation of O/N/CH and interactions which
contribute to crystal formation.2 In recent years, the
phenomenon of molecular association, involving the presence
of the CF bond (termed organic fluorine) in organic
molecules (partially fluorinated) has assumed extreme significance. It has been envisaged that CF bonds are the
strongest among all the bonds because of the strong orbital
overlap between the F 2s and 2p (referred to as organic
fluorine) with corresponding orbitals of other second period
elements.3 The changes in conformational and electronic
features (stereoelectronic effects) associated with substitution
of a CH by a CF bond in organic molecules, with
concomitant changes in chemical reactivity, is of interest, and
this feature is neatly summarized in a tutorial review.3
Furthermore, this aspect also has its implications in the field
of organocatalysis.4 This feature is extremely important in the
context of practical application of fluorine-containing compounds because 20% of drugs and 30% of agrochemicals on the
market contain organic fluorine.5 Recent reviews6 in this area of
research summarize a comprehensive list of the relevant
fluorinated compounds with potential applications in pharamaceutics and the agrochemical industry. The area of
fluoroorganic chemistry is an emerging field, and the last two
decades has witnessed immense growth in this area of research,
2011 American Chemical Society

both from a synthetic perspective (namely, in the development

of reagents and catalysts; selectfluors (1-chloromethyl-4-fluoro1,4-diazoniabicyclo[2.2.2]octane bis-(tetrafluoroborate)) and
NFSI (N-fluorobenzenesulfonimide).7 Furthermore in medical
applications, the direct impact of fluoro-organic compounds in
the field of molecular imaging (namely, 18F PET and MRI),
biomaterials, and pharmaceutics has already been realized. All
these features and related applications are highlighted in detail
in the book titled Fluorine and Health edited by Tressaud and
Haufe.8 In addition, the importance of modern fluoroorganic
chemistry is comprehensively reviewed in a number of excellent
textbooks which bring out the significance of these classes of
compounds.9 From pure electronegativity considerations, it is
known that fluorine withdraws the electron density in any bond
toward itself and is thus highly polarized. On the contrary, the
resonance effect observed in C(aromatic)F bonds, wherein
the lone pair of electrons in p-orbital has a weak interaction
with the benzene nucleus, enhances the stability of such bonds.
This feature introduces an electropositive character on
fluorine.10 To illustrate the back-bonding or -donation from
F to C to form CF, Kraka and Kremer have characterized
these bonds using the theory of adiabatic internal vibrational
modes (AIVM) and evaluated the bond lengths, stretching
force constant, and bond order for fluorine-containing
molecules. The value of the bond order for fluorobenzene
was observed to be 1.18 indicating back bonding.11

SUPRAMOLECULAR CHEMISTRY IN
ORGANOFLUORINE COMPOUNDS: PAST AND
PRESENT
(a). An Overview of NHF, OHF, and CHF
Intra- and Intermolecular Interactions: Inputs from
Theoretical and Experimental Studies. The role of fluorine
as a structure-directing element is well established in organoReceived: November 14, 2011
Revised: December 17, 2011
Published: December 19, 2011
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metallic systems.12 Extending the realm of bonding in fluorine,

to understand noncovalent interactions, it was proposed that
fluorine cannot participate in the formation of H-bonds, due to
the low polarization associated with the tightly held lone pairs
(three in number). But it does so ...in exceptional molecular
and crystal environments.13 It has been observed that in case
of HF, the crystal structure contains zig-zag chains of these
molecules stabilized via (HFHF) H-bonds [14].
Furthermore, in the case of KHF2 it was found that the proton
in the HF2 ion is symmetrically positioned between both the
fluorine atoms and forms very strong hydrogen bonds with the
fluorine atom. The obvious question that then arose was are
similar bonding features observed in organic compounds
containing organic fluorine. Initial investigations by Dunitz
and co-workers mention that organic fluorine does not
participate in the formation of intermolecular hydrogen
bonds as the donor CH is weak and so is the acceptor C
F.13 The participation of the fluorine atom in the formation of
hydrogen bonds has been considered to be a subject of debate.
In comparison to the other heavier halogens, namely, chlorine,
bromine, and iodine, which are relatively less electronegative
and have polarizable electron density, fluorine lacks these
properties. These features form the basis of the debate
regarding the involvement of organic fluorine in the formation
of intra- and intermolecular interactions. An important
breakthrough was achieved when Boese and Desiraju
determined the crystal structures of fluorobenzenes which are
liquids at room temperature wherein CHF intermolecular
interactions were observed.15 A molecular-pair analysis of the
CHF interactions in fluorobenzenes by Dunitz proposed
that CHF interactions have approximately the same
structure-directing ability and influence on the intermolecular
energy as the corresponding CHH interactions in
benzene.16 But a recent investigation again by Boese and
Desiraju on the crystal structure of 1,2,3,5-tetrafluorobenzene
unequivocally established that weak CHFC intermolecular H-bonds were indeed realistic and responsible for
supramolecular recognition.17 The paradigm of these weak
H-bonds was even studied in chemically modified ribonucleic
acids.18 Of further significance was the feature that these were
highly directional interactions that contributed toward the
stability of the crystal packing. The importance of such weak
CHF interactions being weak, cooperative and flexible in
nature has been realized in the absence of strong H-bonds in
isoquinolines,19ad keto-tetrahydroindoles,19e fluorine-rich cyclotriphosphazene hydrazones,19f and all-syn-isomer of 1,2,3,4tetrafluorocyclohexane.19g In the presence of strong H-bond
donors, a detailed investigation of CHF interactions
involving ordered and disordered fluorine has been performed
in fluorinated benzanilides,20a N-(2-chloropyridin-4-yl)-Nphenylureas,20b optically active halogenated beta-hydroxysulphoxides,20c tetrahydropyrimidines,20d,e and cocrystals.20f The
significant attributes of these interactions have been probed via
polymorphism in organic solids21 and via in situ cryocrystallography in molecular liquids (amines,22a halogenated trifluoroacetophenones,22b fluorobenzonitriles,22c and phenylacetylenes.22d,e) A detailed in-depth analysis of the structural features
in a series of crystal structures belonging to the aspirin family of
molecules containing methoxy, fluoro, and trifluoromethyl
groups brings out the significant involvement of weak CHF
intermolecular interactions which contribute to crystal
packing.23 Furthermore, a detailed topological analysis of the
experimental electron density features in fluorine containing

solids proves that CHF is a weak H-bond.24 Additional

evidence from a neutron diffraction study on but-2-yne-1,4-diyl
bis(2,3,4,5,6-pentafluorophenylcarbonate), at 90 K, characterizes that a short C(sp3)HF contact of distance 2.162(8)
in the crystal is responsible for the observed cisoid
conformation.25
In the past two decades, significant inputs by various
researchers have contributed toward the understanding of intraand intermolecular interactions involving organic fluorine,
utilizing experimental, theoretical, spectroscopic, and database
studies. The relevant literature is contained in a recent
highlight.26 Of further significance are the detailed investigations of CHF interactions in organic solids, containing
organic fluorine, which are in the crystal structures of tricyclic
DielsAlder adducts derived from diarylfulvenes and Narylimides,27a N-phthalimide protected (E)- and (Z)-4-amino2-butenyl 5-substituted pyrimidine derivatives,27b di- and
trifluorolactates,27c N-phenylmaleimides and corresponding
phthalimides27d wherein the solid state organization of the
molecules is dictated by these weak interactions acting in
conjunction with other related weak intermolecular interactions, namely, FF, CF, and aromatic interactions. The
nature of these related fluorine-based interactions is discussed
in the later sections of this article. Furthermore, extremely short
CHF hydrogen bonds have been observed in the solid-state
structures of 2-fluoro-2-phenylcyclopropane derivatives, and a
comparison made with the nonfluorinated analogues reveals
that such close contacts are not solely due to crystal forces but
are caused by weak XHFC hydrogen bridges.28 The
existence of CHF weak intramolecular contacts have found
relevance with regard to potential applications in the design of
catalyst for applications in olefin polymerization reactions.29
The nature of weak and short CHF3CC(sp3) intramolecular interactions, due to restricted rotation around the
F3CC(sp3) bond, has also been exploited in both solution and
the solid state in O-alkyl-9-dehydro-9-trifluoromethyl-9-epiquinidine. 30 In an overall perspective, these intra- and
intermolecular interactions are of extreme significance and
find applications in development of materials,31a electronic and
optoelectronic devices,31b design of peptides,31c protein
engineering,31d medicinal chemistry,31e and organometallic
chemistry.31f
To complement the experimental determinations, detailed
theoretical investigations have been performed to bring out the
nature of such weak interactions. A systematic theoretical study
was performed by Hyla-Kryspin, wherein it was proposed that
the nature and strength of these interactions depend on the
subtle balance between the Lewis acidity of the hydrogen donor
and the Lewis basicity of the acceptor.32a In recent times, a
detailed theoretical study using the IMPT method and aug-ccpVTZ basis set by Novoa in chemical systems containing
organic fluorine proves that CHF interaction is indeed a Hbond, the stabilization being approximately 0.43 kcal/mol.32b A
combined MP2 and QCISD(T) study on the evaluation of the
theoretical interactions energies of weak OHFC, C
HO, and CHF hydrogen bridges brings out the structural
features associated with blue-shifted/red-shifted H-bonds which
in turn depends on the nature of the donor (strong/weak) and
the acceptor (strong/weak).33 The energetics associated with
CHF weak intermolecular contacts in molecular pairs in
diazafluorene crystals were obtained from quantum-chemical
calculations at the DFT/PBE/3z level.34 Ab initio molecular
dynamics (MD) simulations has been used to investigate the
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electronic and vibrational properties of blue-shifted H-bonded

CF3H(HF)n (1 n 3) complexes to establish cooperativity
among the various interactions.35 A related Fourier transform
infrared spectroscopy (FTIR) study in cryosolution combined
with ab initio approaches have been used to characterize the
nonlinear structures having relatively short CHF blueshifted H-bonds in F 2 ClCHFCD 3 and Cl 2 FCHFCD 3
complexes.36 The effect of the change in the hybridization of
the carbon atom connected to the fluorine acceptor, with
associated change in the strength of the CHF hydrogen
bond, has been studied using a combination of ab initio
calculations along with atoms in molecules (AIM) theory.37
The importance of cooperativity among the weak intermolecular H-bonds has been addressed recently in an excellent
perspective.38 In addition to these weak interactions, the
significance of NHF hydrogen bonding has also been
realized in foldamers, aromatic amides, and hydrazides,39ac and
in the pairing free energies of fluorinated bases compared with
nonfluorinated analogues are greater by 0.51.0 kcal/mol.39d
The intramolecular NHX (X = -Cl, Br, I) H-bonding in
heavier halogens has also been studied crystallographically and
spectroscopically via 1H NMR.39e
(b). Insights into CFFC, XF (X = Cl, Br, I), CX:
(lp) and anion Contacts in the Context of Crystal
Packing. In addition to CHFC interactions, another
important associated interaction is the CFFC contact and
this has also been in focus for a long time. Fluorine being highly
electronegative should electrostatically repel another fluorine
atom. But difluorine does exist, although it is a weak bond and
hence reactive. The importance of CFFC contacts has
been realized in 5-fluorouracil wherein a new form was
obtained after being predicted computationally.40a In another
investigation of polymorphism performed on 1-(4-fluorophenyl)-3,6,6-trimethyl-2-phenyl-1,5,6,7-tetrahydro-4H-indol-4-one,
an anti-implantation agent, it was observed that dimorphs were
obtained under different conditions of crystal growth, occurring
morphologically as plates (monoclinic, non-centrosymmetric)
and blocks (tetragonal, centrosymmetric), respectively.40b It is
noteworthy that there was a short CFFC contact (Type I
across 2-fold axis), not occurring across the center of symmetry,
in the tetragonal form, but the given intermolecular contact was
absent in the monoclinic plate form. Extending the concept of
halogenhalogen interactions beyond organic fluorine, a
detailed investigation of XF (X = -F, -Cl, -Br, -I), namely,
homohalogen and heterohalogen interactions in substituted
benzanilides, have been performed, and this study brings out
the significance of their interactions in crystal packing.41 It was
concluded that fluorine prefers Type-I contact, and the heavier
halogens prefer Type-II contacts (Figure 1). The presence of
fluorine synthons in fluorinated aza-distyrlbenzenes42 bring out
the relevance of FF contacts in crystal packing. The
competition existing among different weak interactions,
involving halogens, particularly of the XX type has been
investigated in benzils.43
The CClClC, CFFC, and CClFC intermolecular contacts have also been studied topologically (both
experimentally and theoretically) using the multipolar atom
model, and these are essentially closed-shell interactions.44 The
repulsive interaction that exists between two fluorine atoms in a
crystal can be altered by a modification of the chemical
environment in the molecule (addition of electron withdrawing
groups such as nitro, cyano, trifluoromethyl, sulfonyl). This
facilitates a resonance effect to dominate in opposition to the

Figure 1. Diagram illustrating Type-I and Type-II contacts involving

halogens.

direction of CF dipole moment. This results in anisotropic

distribution of the electron density around the fluorine atom,
and this feature has been investigated using electron density
studies performed on fluorine-containing organic compounds.44a This introduces a positive electrostatic potential (termed
sigma-hole), and this electronic feature has been investigated
using ab initio calculations.45a This anisotropy can dictate FF
intermolecular bonding to prevail in organic molecules in the
solid state. Hence similar to CHF, these bonding
interactions are also directional, and this stems from the
existence of the sigma hole. The electronic features associated
with the existence of the sigma hole have been studied
theoretically, by Politzer et al.45bd Latest investigations by
Metrangalo and co-workers from crystallographic database and
computational studies46a,b also point to the existence of the
sigma hole in molecules, particularly in the context of halogen
bonding, to be discussed later.
In recent years, a new molecular recognition motif, namely,
the lone-pair interaction, has been considered extremely
important in the context of supramolecular recognition.47 This
lone pair can come from a fluorine atom and interact with any
electrophilic center. The importance of CFCO interactions has been recognized by Diederich48a to investigate
fluorophobicity in the active thrombin site by incorporation of
fluorine atoms on the inhibitor ligands. The coinage of the
word orthogonal interactions is a geometrical necessity if the
lone pair (nucleophile) has to approach a relatively electrondeficient site, and the importance of these interactions are
summarized in an excellent review by Diederich.48b The lone
pair can also be contributed by a negatively charged ion which
can interact electrostatically with an electron-deficient aromatic
ring. The anion interaction so constituted embodies a key
structural element that has been lately deemed to be important
in supramolecular chemistry49a,b with implications for drug
discovery and biomolecular design.49c These interactions have
also been observed experimentally in crystallographic determinations. It has been observed that the nature of anion
interactions in crystals of fluorobenzyl ammonium bromide
salts can be attractive or repulsive, and this depends on the
degree of fluorination at the aromatic centers.50
A series of theoretical investigations by Frontera et al. into
this structural motif along with inputs from crystallographic
database studies depict the stabilizing role these motifs have in
the solid state. The directionality associated with this
interaction is also performed using RI-MP2/aug-cc-pVDZ
level of theory.51
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(c). Halogen Bonding (XO/N; X = -F, -Cl, -Br, -I). In

addition to the already existing arsenal of intermolecular
interactions, another predominantly electrostatic interaction
that came into view was halogen bonding52 wherein a heavier
halogen containing polarizable electron density electrostatically
interacts with a more electronegative atom, namely, oxygen and
nitrogen. This bonding has been explored in detail via both
computational and experimental approaches for complexes of
DMAP with di- and tri-iodofluorobenzenes, which exhibit a
very short NI bond in the crystal, the distance being less than
3.00 .53
To investigate the geometric and energetic features of
halogen bonded complexes between aromatic moieties and to
study substituent effects in both rings (halogen bond donor and
acceptor molecules) high level ab initio studies (RI-MP2/augcc-pVDZ) have been performed, along with QTAIM
approaches and molecular modeling studies in chloroform
and water.54a A deeper theoretical evaluation of the sigma
bonding of complexes of NF3 with ambidentate electron donor
and acceptor molecules, namely, HF, HCl, HNC, HCN, has
been performed wherein either nitrogen or fluorine in NF3 can
function as donors.54b In a very recent study, compounds
containing either pyridyl or N,N-dimethylanilino groups as
electron-donor moieties and a p-iodo-tetrafluorophenyl ring as
an electron-acceptor group have been synthesized and short
halogen bonding NI have been observed. These compounds
exhibit high polarizabilities in solution, and these observations
are supported by molecular modeling calculations at the DFT
PBE0/6-311++G** and TDDFT SAOP/TZP level.54c Recently, a combined experimental and database studies of threecentered halogen bonds with bifurcated acceptors present in
molecular crystals, cocrystals, and salts have been studied with
organic iodine as the donor atom and N, O, S, F, Cl, Br, or I
atom as acceptors. It was concluded that three-centered
halogen bonds are rare compared to hydrogen bonds.54d
Furthermore, symmetrical [NXN]+ halogen bonds have
been observed in solution, and the iodous halogen bond has
this symmetry in both solution and the solid state, whereas in
the bromous isomer, there is asymmetry in the solid state.54e
These interactions have also been investigated in the gas phase
by molecular beam scattering experiments and ab initio charge
displacement calculations.54f Molecular Dynamics (MD)
simulations have also been performed to investigate the sigma
hole bonding and account for the strong anisotropy around the
covalently bonded halogen atom by introduction of an extra
point of charge in the classical force field calculations.54g The
results obtained by this method compared well with both the
crystallographic investigations and QM/MM calculations.54h,i
Electrostatic potentials for the halogen bonding ligands are also
generated in order to study the relationship between halogen
bond strengths and halogen -hole size (and charge). It is
found that the strength and character of the proteinligand
halogen bonds investigated here are strongly dependent on
geometric factors and -hole characteristics.54j Recently, a
parallelism between halogen bonds and hydrogen bonds has
been explored in proteinligand complexes.54k These have also
been observed in liquid crystals.55 The structure and properties
(energy, electronic, and thermodynamic properties) of
complexes of pyridine with XY [X, Y = halogen] have been
investigated at the MP2/aug-cc-pVDZ level to characterize the
nature of halogen bonding. It is observed that charge transfer
from the pyridine nitrogen to the antibonding XY orbital is
responsible for the stability of the -bonded complex.56

Today, a vast body of literature is available that highlights the

relevance of halogen bonding particularly in the context of
heavier halogens. It is now of extreme significance to consider
the fact that the lightest halogen fluorine can participate in
halogen bonding. At the first instance the mention of an FO
contact seems unrealistic as both being electronegative repel
each other. However, we know that O2F2 is stable and exists as
a solid although the OF bond is a 3-center-2-electron (3c-2e)
bond.57 To substantiate further, the first systematic study
employing ab initio intermolecular perturbation theory and
crystallographic database studies on understanding of the
nature of interactions between halogens with O/N/S indicates
that anisotropic electron distribution around the halogen atom
leading to lowering of the repulsive wall and increase in
electrostatic attraction is responsible for stability.58 It was
concluded: If the carbon-bound halogen atom is in a
sufficiently electron-withdrawing environment, then a strong
attractive overall interaction will exist.58 The point of
consideration here is that when the halogen is fluorine and
when the above-mentioned concept is realized in a molecule of
interest then attractive FO contacts will exist. The presence of
a sigma hole on the fluorine atom substantiates this
observation.4446 Subsequent topological characterization of
this electronic feature in organofluorine compounds containing
strong electron withdrawing groups will be the focus of
futuristic studies in the area of crystal engineering.

CONCLUSIONS
In conclusion, it is to be realized that the realm of chemical
bonding present in organic molecules containing fluorine is not
weak. Fluorine is special as in the presence of activated
hydrogen bond donors it forms H-bonds, can donate a lone
pair to electrophilic center, and hence has both donor and
acceptor characteristics. It is of extreme importance that all
these forces albeit weak can cooperatively play a pivotal role in
formation of crystalline molecular solids. Their contribution in
addition to the already present arsenal of relatively stronger Hbonds is indeed noteworthy. It is of interest to investigate these
noncovalent forces as a function of the hybridization of the
carbon atom to which fluorine is connected in organic
compounds. A detailed working knowledge of the geometrical
features, along with the associated energetics of such noncovalent forces (also subsequent changes due to functional
group modifications), can benefit the molecular, crystal, and
protein engineering community in the future.

AUTHOR INFORMATION

Corresponding Author

*E-mail: dchopra@iiserbhopal.ac.in. Fax: (+) 91-07554092392. Web: http://home.iiserbhopal.ac.in/dchopra/.

ACKNOWLEDGMENTS
D.C. thanks IISER Bhopal for facilities and DST, India, for
research funding under the fast track scheme.

DEDICATION
Dedicated to the 60th birthday of Prof T.N. Guru Row
REFERENCES

(1) (a) Jeffrey, G. A. An Introduction to Hydrogen Bonding; Oxford

University Press Inc: New York, 1997. (b) Guru Row, T. N. Coord.
544

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Crystal Growth & Design

Perspective

Chem. Rev. 1999, 183, 81100. (c) Khan, M.; Enkelmann, V.;
Brunklaus, G. Cryst. Growth Des. 2009, 9, 23542362.
(2) (a) Desiraju, G. Angew. Chem., Int. Ed. 2011, 50, 5259
andreferences therein. (b) Nishio, M.; Umezawa, Y.; Honda, K.;
Tsuboyama, S.; Suezawa, H. CrystEngComm 2009, 11, 17571788 and
referencestherein.
(3) (a) OHagan, D. Chem. Soc. Rev. 2008, 37, 308319. (b) Smart,
B. E. J. Fluorine Chem. 2001, 109, 311.
(4) Zimmer, L. E.; Sparr, C.; Gilmour, R. Angew. Chem., Int. Ed. 2011,
50, 1186011871.
(5) Roesky, H. Nat. Chem. 2011, 2, 240.
(6) (a) Muller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881
1886. (b) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem.
Soc. Rev. 2008, 37, 320330. (c) Hagmann, W. K. J. Med. Chem. 2008,
51, 43594369. (d) Kirk, K. L. Org. Proc. Res. Dev. 2008, 12, 305321.
(e) Jeschke, P. Pest Manag. Sci. 2010, 66, 1027. (f) OHagan, D. J.
Fluorine Chem. 2010, 131, 1071 1081.
(7) Justik, M. W. Annu. Rep. Prog. Chem., Sect. A 2011, 107, 125134.
(8) Tressaud, A.; Haufe, G. Fluorine and Health: Molecular Imaging,
Biomedical Materials and Pharmaceuticals; Elsevier: Amsterdam, 2008.
(9) (a) Kirsch, P. Modern Fluoroorganic Chemistry, Synthesis, Reactivity
and Applications; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim,
2004. (b) Uneyama, K. Organofluorine Chemistry; Blackwell Publishing:
Oxford, 2006. (c) Ojima, I. Fluorine in Medicinal Chemistry & Chemical
Biology; Wiley-Blackwell: Chichester, 2009.
(10) (a) Ernet, T.; Maulitz, A. H.; Wurthwein, E. -U.; Haufe, G. J.
Chem. Soc. Perkin Trans. 1 2001, 19291938. (b) Chambers, R. D.;
Vaughan, J. F. S. Top. Curr. Chem. 1997, 192, 138. (c) Reinke, D.;
Baumgartel, H.; Cvitaks, T.; Klasinc, L.; Gusten, H. Ber. Bunsen-Ges.
Phys. Chem. 1974, 78, 1145. (d) Heaton, M. M.; El-Talbi, M. R. J.
Chem. Phys. 1986, 85, 71987210.
(11) Kraka, E.; Cremer, D. ChemPhysChem 2009, 10, 686698.
(12) Roesky, H. W.; Haiduc, I. J. Chem. Soc., Dalton Trans. 1999,
22492264.
(13) (a) Dunitz, J. D.; Taylor, R. Chem.Eur. J. 1997, 3, 8998.
(b) Dunitz, J. D. ChemBioChem 2004, 5, 614621.
(14) Atoji, M.; Lipscomb, W. N. Acta Crystallogr. 1954, 7, 173175.
(15) Thalladi, V. R.; Weiss, H.-C.; Blaser, D.; Boese, R.; Nangia, A.;
Desiraju, G. R. J. Am. Chem. Soc. 1998, 120, 87028710.
(16) Dunitz, J. D.; Schweizer, W. B. Chem.Eur. J. 2006, 12, 6804
6816.
(17) Thakur, T. S.; Kirchner, M. T.; Blaser, D.; Boese, R.; Desiraju,
G. R. CrystEngComm 2010, 12, 20792085.
(18) Parsch, J.; Engels, J. W. J. Am. Chem. Soc. 2002, 124, 5564
5672.
(19) (a) Choudhury, A. R.; Urs, U. K.; Nagarajan, K.; Guru Row, T.
N. J. Mol. Struct. 2002, 605, 7177. (b) Choudhury, A. R.; Nagarajan,
K.; Guru Row, T. N. Cryst. Eng. 2003, 6, 145152. (c) Choudhury, A.
R.; Guru Row, T. N. CrystEngComm 2006, 8, 265274.
(d) Choudhury, A. R.; Guru Row, T. N. Cryst. Growth. Des. 2004, 4,
4752. (e) Chopra, D.; Nagarajan, K.; Guru Row, T. N. J. Mol. Struct.
2008, 888, 7083. (f) Chandrasekhar, V.; Thilagar, P.; Krishnan, V.;
Bickley, J. F.; Steiner, A. Cryst. Growth Des. 2007, 7, 668675.
(g) Durie, A. J.; Slawin, A. M. Z.; Lebl, T.; Kirsch, P.; OHagan, D.
Chem. Commun. 2011, 47, 82658267.
(20) (a) Chopra, D.; Guru Row, T. N. CrystEngComm 2008, 10, 54
67. (b) Abad, A.; Agullo, C.; Cunat, A. C.; Vilanova, C.; Ramrez de
Arellano, M. C. Cryst. Growth Des. 2006, 6, 4657. (c) Asensio, G.;
Medio-Simon, M.; Aleman, P.; Ramrez de Arellano, C. Cryst. Growth
Des. 2006, 6, 27692778. (d) Nayak, S. K.; Venugopala, K. N.;
Chopra, D.; Vasu.; Guru Row, T. N. CrystEngComm 2010, 12, 1205
1216. (e) Nayak, S. K.; Venugopala, K. N.; Chopra, D.; Guru Row, T.
N. CrystEngComm 2011, 13, 591605. (f) Sunil, S. L.; Nayak, S. K.;
Hathwar, V. R.; Chopra, D.; Guru Row, T. N. Role of Fluorine in
Weak Interactions in Co-crystals. In Pharmaceutical Salts and
Cocrystals; Wouters, J., Quere, L., Eds.; RSC, London, U.K., 2012;
Chapter 3.
(21) (a) Lee, H. Y.; Olasz, A.; Pink, M.; Park, H.; Lee, D. Chem.
Commun. 2011, 47, 481483. (b) Coste, S.; Schneider, J. -M.; Petit,

M.-N.; Coquerel, G. Cryst. Growth Des. 2004, 4, 12371244. (c) Kato,

T.; Okamoto, I.; Masu, H.; Katagiri, K.; Tominaga, M.; Yamaguchi, K.;
Kagechika, H.; Azumaya, I. Cryst. Growth. Des. 2008, 8, 38713877.
(d) Chopra, D.; Guru Row, T. N. Cryst. Growth Des. 2005, 5, 1679
1681. (e) Chopra, D.; Guru Row, T. N. Cryst. Growth Des. 2006, 6,
12671270. (d) Chopra, D.; Guru Row, T. N. Cryst. Growth Des.
2008, 8, 848853.
(22) (a) Chopra, D.; Thiruvenkatam, V.; Guru Row, T. N. Cryst.
Growth Des. 2006, 6, 843845. (b) Chopra, D.; Thiruvenkatam, V.;
Manjunath, S. G.; Guru Row, T. N. Cryst. Growth Des. 2007, 7, 868
874. (c) Vasylyeva, V.; Merz, K. Cryst. Growth Des. 2010, 10, 4250
4255. (d) Thakur, T. S.; Sathishkumar, R.; Dikundwar, A. G.; Guru
Row, T. N.; Desiraju, G. R. Cryst. Growth. Des. 2010, 10, 42464249.
(e) Dikundwar, A. G.; Sathishkumar, R.; Guru Row, T. N.; Desiraju, G.
R. Cryst. Growth. Des. 2011, 11, 39543963.
(23) Hursthouse, M. B.; Montis, R.; Tizzard, G. J. CrystEngComm
2011, 13, 33903401.
(24) Chopra, D.; Cameron, T. S.; Ferrara, J. D.; Guru Row, T. N. J.
Phys. Chem. A 2006, 110, 1046510477.
(25) Dikundwar, A. G.; Venkateswarlu, C.; Piltz, R. O.;
Chandrasekaran, S.; Guru Row, T. N. CrystEngComm 2011, 13,
15311538.
(26) Chopra, D.; Guru Row, T. N. CrystEngComm 2011, 13, 2175
2186.
(27) (a) Schwarzer, A.; Bombicz, P.; Weber, E. J. Fluorine Chem.
2010, 131, 345356. (b) Cetina, M.; Nagl, A.; Kristafor, V.; Benci, K.;
Mintas, M. Cryst. Growth Des. 2008, 8, 29752981. (c) Takahashi, S.;
Jukurogi, T.; Katagiri, T.; Uneyama, K. CrystEngComm 2006, 8, 320
326. (d) Schwarzer, A.; Weber, E. Cryst. Growth. Des. 2008, 8, 2862
74.
(28) Frohlich, R.; Rosen, T. C.; J. Meyer, O . G.; Rissanen, K.; Haufe,
G. J. Mol. Struct. 2006, 787, 5062.
(29) (a) Kui, S. C. F.; Zhu, N.; Chan, M. C. W. Angew. Chem., Int. Ed.
2003, 42, 16281632. (b) Chan, M. C. W.; Kui, S. C. F.; Cole, J. M.;
McIntyre, G. J.; Matsui, S.; Zhu, N.; Tam, K.-H. Chem.Eur. J. 2006,
12, 26072619. (c) Chan, M. C. Chem. Asian J. 2008, 3, 1827.
(30) Surya Prakash, G. K.; Wang, F.; Rahm, M.; Shen, J.; Ni, C.;
Haiges, R.; Olah, G. A. Angew. Chem., Int. Ed. 2011, 50, 1176111764,
DOI: .
(31) (a) Berger, R.; Resnati, G.; Metrangolo, P.; Weber, E.; Hulliger,
J. Chem. Soc. Rev. 2011, 40, 34963508 and references therein.
(b) Babudri, F.; Farinolo, G. M.; Naso, F.; Ragni, R. Chem. Commun.
2007, 10031022. (c) Zheng, H.; Comeforo, K.; Gao, J. J. Am. Chem.
Soc. 2009, 131, 1819. (d) Jackel, C.; Koksch, B. Eur. J. Org. Chem.
2005, 44834503. (e) Campbell, N. H.; Smith, D. L.; Reszka, A. P.;
Neidle, S.; O'Hagan, D. Org. Biomol. Chem. 2011, 9, 13281331.
(f) Hughes, R. P. J. Fluorine Chem. 2010, 131, 10591070.
(32) (a) Hyla-Kryspin, I.; Haufe, G.; Grimme, S. Chem.Eur. J.
2004, 10, 34113422. (b) OOria, E. D.; Novoa, J. J. CrystEngComm
2008, 10, 423436.
(33) Hyla-Kryspin, I.; Haufe, G.; Grimme, S. Chem. Phys. 2008, 346,
224236.
(34) Rybalova, T. V.; Bagryanskaya, I. Y. J. Struct. Chem. 2009, 50,
741753.
(35) Rodziewicz, P.; Rutkowski, K. S.; Melikova, S. M.; Koll, A.
Chem. Phys. 2009, 361, 129136.
(36) Rutkowski, K. S.; Herrebout, W. A.; Melikova, S. M.; van der
Veken, B. J.; Koll, A. Chem. Phys. 2008, 354, 7179.
(37) Checinska, L.; Grabowski, S. J. Chem. Phys. 2006, 327, 202208.
(38) Melandri, S. Phys. Chem. Chem. Phys. 2011, 13, 1390113911.
(39) (a) Li, C.; Ren, S.-F.; Hou, J.-L.; Yi, H. P.; Zhu, S.-Z.; Jiang, X.K.; Li, Z.-T. Angew. Chem., Int. Ed. Engl. 2005, 44, 57255729. (b) Li,
C.; Zhu, Y.-Y.; Yi, H.-P.; Li, C.-Z.; Jiang, X.-K.; Li, Z.-T.; Yu, Y.-H.
Chem.Eur. J. 2007, 13, 99909998. (c) Zhu, Y.-Y.; Wu, J.; Li, C.;
Zhu, J.; Hou, J.-L.; Li, C.-Z.; Jiang, X.-K.; Li, Z.-T. Cryst. Growth Des.
2007, 7, 149096. (d) Koller, A. N.; Bozilovic, J.; Engels, J. W.;
Gohlke, H. Nucleic Acids Res. 2010, 38, 31333146. (e) Zhu, Y.-Y.; Yi,
H.-P.; Li, C.; Jiang, X.-K.; Li, Z.-T. Cryst. Growth Des. 2008, 8, 1294
1300.
545

dx.doi.org/10.1021/cg201498u | Cryst. Growth Des. 2012, 12, 541546

Crystal Growth & Design

Perspective

(40) (a) Hulme, A. T.; Price, S. L.; Tocher, D. A. J. Am. Chem. Soc.
2005, 127, 11161117. (b) Chopra, D.; Nagarajan, K.; Guru Row, T.
N. Cryst. Growth Des. 2005, 5, 10351039.
(41) Nayak, S. K.; Reddy, M. K.; Guru Row, T. N.; Chopra, D. Cryst.
Growth Des. 2011, 11, 15781596.
(42) Collas, A.; Borger, R. D.; Amanova, T.; Blockhuys, F.
CrystEngComm 2011, 13, 702710.
(43) Felsmann, M.; Eissmann, F.; Schwarzer, A.; Weber, E. Cryst.
Growth Des. 2011, 11, 982989.
(44) (a) Hathwar, V. R.; Guru Row, T. N. Cryst. Growth. Des. 2011,
11, 13381346. (b) Hathwar, V. R.; Guru Row, T. N. J. Phys. Chem. A.
2010, 114, 1343413441. (c) Hathwar, V. R.; Thakur, T. S.; Dubey,
R.; Pavan, M. S.; Guru Row, T. N.; Desiraju, G. R. J. Phys. Chem. A.
2011, 115, 1285212863.
(45) (a) Murray, J. S.; Lane, P.; Clark, T.; Politzer, P. J. Mol. Model.
2007, 13, 10331038. (b) Politzer, P.; Murray, J. S.; Concha, M. C. J.
Mol. Model. 2008, 14, 659665. (c) Murray, J. S.; Lane, P.; Politzer, P.
J. Mol. Model. 2009, 15, 723729. (d) Murray, J. S.; Lane, P.; Clark,
T.; Riley, K. E.; Politzer, P. J. Mol. Model. 2011, DOI: 10.1007/s00894011-1089-1.
(46) (a) Metrangolo, P.; Murray, J. S.; Pilati, T.; Politzer, P.; Resnati,
G.; Terraneo, G. CrystEngComm 2011, 13, 65936596. (b) Metrangolo, P.; Murray, J. S.; Pilati, T.; Politzer, P.; Resnati, G.; Terraneo, G.
Cryst. Growth Des. 2011, 11, 42384246.
(47) (a) Mooibroek, T. J.; Gamez, P.; Reedijk, J. CrystEngComm
2008, 10, 15011515. (b) Robertazzi, A.; Krull, F.; Knapp, E. W.;
Gamez, P. CrystEngComm 2011, 13, 32933300. (c) Choudhury, S.
R.; Dey, B.; Das, S.; Gamez, P.; Robertazzi, A.; Chan, K. T.; Lee, H.
M.; Mukhopadhyay, S. J. Phys. Chem. A 2009, 113, 16231627.
(d) Granifo, J.; Toledo, D.; Garland, M. T.; Baggio, R. J. Fluorine
Chem. 2010, 131, 510516.
(48) (a) Olsen, J. A.; Banner, D. W.; Seiler, P.; Obst-Sander, U.;
DArcy, A.; Stihle, M.; Muller, K.; Diederich, F. Angew Chem. Int. Ed.
2003, 42, 25072511. (b) Paulini, R.; Muller, K.; Diederich, F. Angew.
Chem., Int. Ed. 2005, 44, 17881805.
(49) (a) Estarellas, C.; Frontera, A.; QuiC onero, D.; Deya, P. M.
Chem.Asian J. 2011, 6, 23162318. (b) Das, A.; Choudhury, S. R.;
Estarellas, C.; Dey, B.; Frontera, A.; Hemming, J.; Helliwell, M.;
Gamez, P.; Mukhopadhyay, S. CrystEngComm 2011, 13, 45194527.
(c) Lu, Y.; Wang, Y.; Zhu, W. Phys. Chem. Chem. Phys. 2010, 12,
45434551.
(50) Giese, M.; Albrecht, M.; Bannwarth, C.; Raabe, G.; Valkonen,
A.; Rissanen, K. Chem. Commun. 2011, 47, 85428544.
(51) (a) Lucas, X.; Quinonero, D.; Frontera, A.; Deya, P. M. J. Phys.
Chem. A 2009, 113, 1036710375. (b) Estarellas, C.; Bauza, A.;
Frontera, A.; Quinonero, D.; Deya, P. M. Phys. Chem. Chem. Phys.
2011, 13, 56965702. (c) Estarellas, C.; Frontera, A.; Quinonero, D.;
Deya, P. M. J. Phys. Chem. A 2011, 115, 78497857.
(52) (a) Metrangalo, P.; Resnati, G. Science 2008, 321, 918919.
(b) Parisini, E.; Metrangolo, P.; Pilati, T.; Resnati, G.; Terraneo, G.
Chem. Soc. Rev. 2011, 40, 22672278. (c) Ojala, W. H.; Lystad, K. M.;
Deal, T. L.; Engebretson, J. E.; Spude, J. M.; Balidemaj, B.; Ojala, C. R.
Cryst. Growth. Des. 2009, 9, 964970.
(53) Roper, L. C.; Preasang, C.; Kozhevnikov, V. N.; Whitwood, A.
C.; Karadakov, P. B.; Bruce, D. W. Cryst. Growth. Des. 2010, 10, 3710
3720.
(54) (a) Bauza, A.; Quinonero, D.; Frontera, A.; Deya, P. M. Phys.
Chem. Chem. Phys. 2011, 13, 2037120379. (b) Blanco, F.; Alkorta, I.;
Rozas, I.; Solimannejad, M.; Elguero, J. Phys. Chem. Chem. Phys. 2011,
13, 674683. (c) Cariati, E.; Cavallo, G.; Forni, A.; Leem, G.;
Metrangolo, P.; Pilati, T.; Paolo Resnati, G.; Righetto, S.; Terraneo,
G.; Tordin, E. Cryst. Growth. Des. 2011, 11, 56425648. (d) Cincic,
D.; Friscic, T.; Jones, W. CrystEngComm 2011, 13, 32243231.
(e) Carlsson, A.-C. C.; Grafenstein, J.; Laurila, J. L.; Bergquist, J.;
Erdelyi, M. Chem. Commun. 2011, DOI: 10.1039/c1cc15839b.
(f) Cappelletti, D.; Candori, P.; Pirani, F.; Belpassi, L.; Tarantelli, F.
Cryst. Growth Des. 2011, 11, 42794283. (g) Ibrahim, M. A. A. J.
Comput. Chem. 2011, 32, 25642574. (h) Rendine, S.; Pieraccini, S.;
Forni, A.; Sironi, M. Phys. Chem. Chem. Phys. 2011, 13, 1950819516.

(i) Ibrahim, M. A. A. J. Chem. Inf. Model. 2011, 51, 25492559.

(j) Riley, K. E.; Hobza, P. Cryst. Growth Des. 2011, 11, 42724278.
(k) Voth, A. R.; Khuu, P.; Oishi, K.; Ho, P. S. Nat. Chem. 2009, 1, 74
79.
(55) Metrangolo, P.; Prasang, C.; Resnati, G.; Liantonio, R.;
Whitwood, A. C.; Bruce, D. W. Chem. Commun. 2006, 32903292.
(56) Wang, Z.; Zheng, B.; Yu, X.; Li, X.; Yi, P. J. Chem. Phys. 2010,
132, 164104164105.
(57) Jackson, R. H. J. Chem. Soc. 1962, 4585.
(58) Lommerse, J. P. M.; Stone, A. J.; Taylor, R.; Allen, F. H. J. Am.
Chem. Soc. 1996, 118, 31083116.

546

dx.doi.org/10.1021/cg201498u | Cryst. Growth Des. 2012, 12, 541546