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129
Structure and Bonding
Series Editor: D. M. P. Mingos
Editorial Board:
P. Day · X. Duan · L. H. Gade · T. J. Meyer
G. Parkin · J.-P. Sauvage
Structure and Bonding
Series Editor: D. M. P. Mingos
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123
The series Structure and Bonding publishes critical reviews on topics of research concerned with
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Preface
experimental evidence for this type of interaction. Both, solution and crystal-
lographic studies are analysed showing the potential impact that this type of
interaction could have in the design of new anion receptors.
The use of anions as templating agents is discussed by Vilar. The chapter
starts with a general overview of the area and a discussion of the applications
of anion templates in organic and coordination chemistry. The second part
of the chapter deals with examples where anions are employed as templates
in dynamic combinatorial libraries. This approach promises to provide an
efficient route for the synthesis of better and more selective anion receptors.
The last chapter by Ewen and Steinke also deals with the use of anions as
templates but in this case in the context of molecular imprinted polymers. The
first half of the chapter provides an introduction into molecularly imprinted
polymers and this is followed by a detailed discussion of examples where
anionic species have been used to imprint this class of polymeric materials.
The topics discussed in this volume provide an exciting and stimulating
overview of the most recent studies within anion recognition and templation.
Although the supramolecular chemistry of anions took a long time to develop,
it is now a mature area that provides solutions to challenging problems. There is
no doubt that its growth will continue yielding more sophisticated and efficient
receptors for the recognition of a wide range of negatively charged species.
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
2 Neutral Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
2.1 Acyclic Amide and Sulfonamide-Based Receptors . . . . . . . . . . . . . . 2
2.2 Macrocyclic Amide Receptors . . . . . . . . . . . . . . . . . . . . . . . . . 6
2.3 Urea and Thiourea-Based Receptors . . . . . . . . . . . . . . . . . . . . . . 12
5 Charged Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
5.1 Imidazolium and Pyridinium-Based Receptors . . . . . . . . . . . . . . . . 34
5.2 Guanidinium-Based Receptors . . . . . . . . . . . . . . . . . . . . . . . . . 37
5.3 Ammonium-Containing Receptors . . . . . . . . . . . . . . . . . . . . . . . 39
6 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
Abstract This review article provides a broad overview to the area of anion coordination
by synthetic organic receptors and includes examples of different functional groups used
to bind anions. The first section examines neutral anion receptors containing amide-,
sulfonamide-, urea- and thiourea-based receptors. Then aromatics such as pyrrole, car-
bazole and indole are discussed before concluding the discussion of neutral systems with
examples of hydroxy OH donors. A brief overview of charged systems is also provided.
1
Introduction
2
Neutral Receptors
2.1
Acyclic Amide and Sulfonamide-Based Receptors
Secondary amides are versatile and highly accessible hydrogen bond donors
that have been used in numerous synthetic receptors. In the biological arena,
there are many examples of proteins that employ amide NH· · ·anion interac-
tions to bind negatively charged guests [5–9]. The first example of a synthetic
amide containing receptor, published in 1986 by Pascal and co-workers, was
a crytpand-like tris-amide that was shown to interact with fluoride in DMSO-
d6 [10].
In 1993, Reinhoudt and co-workers described the synthesis and bind-
ing properties of a series of tris-amides and tris-sulfonamides based upon
the tren skeleton [11]. These receptors proved to be selective for phosphate
in acetonitrile solution and demonstrated, arguably for the first time, that
anion receptor systems need not be difficult to make but rather that sim-
ple organic compounds could function as very effective receptors. Stability
constants were calculated by conductivity experiments and showed that re-
ceptor 1f bound dihydrogenphosphate with the highest affinity (14 200 M–1 )
in acetonitrile presumably due to the preorganization of the receptor via π–π
interactions between the naphthyl groups.
Four years later, in 1997, Crabtree and co-workers reported that simple
isophthalamide receptors e.g. 2 can bind anions in organic solution [12].
These receptors, even simpler than Reinhoudt’s tren-based anion binders,
were found to bind smaller halides selectively in dichloromethane solution.
The X-ray crystal structure of the bromide complex of 2a shows the receptor
adopting the syn–syn conformation with the bromide anion coordinated to the
amide NH’s with N· · ·Br distances of 3.44 and 3.64 Å (Fig. 1). The crystal struc-
An Introduction to Anion Receptors Based on Organic Frameworks 3
ture also reveals that the bromide anion is positioned above the plane of the
central aryl ring. Solution studies revealed that receptors 2a and 2b have high
affinity for halide anions and form complexes with exclusively 1 : 1 host/guest
stoichiometry. Stability constants for 2b were determined by 1 H NMR titration
studies and found to be 6.1 × 104 M–1 for chloride, 7.1 × 103 M–1 for bromide
and 4.6 × 102 M–1 for iodide in dichloromethane-d2 .
ceptor 3 bound acetate with a stability constant of 2.1 × 103 M–1 as compared
to 1.1 × 102 M–1 found with the non-preorganized receptor 2a and acetate.
Recently J.T. Davis, Gale, Quesada and co-workers have shown that ap-
pended hydroxy groups on the central aryl ring of an isophthalamide can
pre-organize the receptor into the syn–syn conformation and again presum-
ably increase the acidity of the amide NH groups, which increases the re-
ceptor’s ability to bind chloride (Fig. 2) [14]. The preorganization occurs due
to intramolecular hydrogen bonds between the hydroxy groups and carbonyl
oxygen of the amides.
Proton NMR titration experiments in CD3 CN at 298 K revealed that re-
ceptor 4 bound chloride most strongly with a stability constant of 5230 M–1 ,
whereas a stability constant of 195 M–1 was obtained for the unfunctionalized
cleft 5. Model compound 6 contains methoxy groups in the 4- and 6-positions
and functions as a control. In this system the intramolecular hydrogen bonds
form between the amide NH groups and the methoxy oxygens and conse-
quently the compound does not interact with chloride (Fig. 2). Most interest-
ingly, it was shown that compound 4 functions as a highly efficient chloride
transport agent across EYPC lipid bilayers whilst the analogous isophtha-
lamide 5, and model compound 6 show no transport ability. Compound 4
seems to be the simplest synthetic lipid bilayer transport agent for chloride
studied so far. The origin of this ability is currently being investigated.
sociation constants for chloride and bromide were found to be much higher
than for compound 9a [17].
2.2
Macrocyclic Amide Receptors
Interestingly, the NMR data led the authors to suggest that receptor 10b
forms a 2 : 1 host/anion “sandwich” complex at low concentrations of iodide
(as evidenced by an initial up-field shift of the NH resonances until ca. 0.5
equivalents of iodide) then switching to a 1 : 1 complex at higher concentra-
tions of iodide (down-field shift of NH resonances after ca. 0.5 equivalents of
iodide) (Fig. 3). Titrations with 10a and 10b in CDCl3 /2% DMSO-d6 mixture
displayed complex binding behavior, thus titration experiments were con-
ducted in 100% DMSO-d6 at 296 K to simplify the equilibria occurring in
solution. All data for receptor 10b were fitted to a 1 : 1 binding model and
again the macrocycle was found to be oxo-anion selective with the highest
stability constants being found with dihydrogen phosphate and hydrogen sul-
fate (1.5 × 104 M–1 and 1.7 × 103 M–1 , respectively).
Fig. 3 Changes in the amide 1 H NMR proton resonance of 10b with increasing [I– ]
concentrations. Reprinted in part with permission from [18]
Stability constants were obtained for receptors 13a, 13b and 13c using anal-
ogous conditions to those employed for receptors 12a, 12b and 12c. As with
the pyridine-2,6-dicarboxamide macrocycles, the stability constants for the
isophthalamide macrocycles appear to be influenced by the size and flexi-
bility of the system with the higher constants observed in the 20-membered
receptor 13a with notable decreases in the association constants with the 22-
and 24-membered receptors 13b and 13c. The greatest decreases where ob-
served in the stability constants obtained with the carboxylate anions. In the
case of acetate the constants decreased from 3130 M–1 for 13a to 552 M–1
and 205 M–1 for 13b and 13c, respectively. In the case of benzoate a constant
of 601 M–1 was calculated for 13a decreasing to 302 M–1 and 82 M–1 for 13b
and 13c, respectively. Unexpectedly lower binding constants were obtained
for the isophthalamide macrocycles (13a–13c) compared to the pyridine-
An Introduction to Anion Receptors Based on Organic Frameworks 9
Stability constants for 14 and 15 with different anions (added as their tetra-
butylammonium salts) were obtained by 1 H NMR titrations in DMSO-d6 . In
10 G.W. Bates · P.A. Gale
both cases, a slow equilibrium was observed in the titrations with fluoride
with stability constants >105 M–1 . The expansion of the cavity from recep-
tor 14 to 15 results in a significant change in the binding and selectivity for
anions. In the smaller receptor, 14, chloride is bound much more strongly
(3000 M–1 ) as compared to 15 (180 M–1 ) whereas the receptor 15 has a much
higher affinity for hydrogen sulfate with a stability constant of 2700 M–1 as
compared to 68 M–1 for 14. These findings may be due to the size comple-
mentarity between the receptors and guests with 14 being an ideal size to
encapsulate chloride and 15 being ideal for hydrogen sulfate, as illustrated by
the crystal structures (Fig. 4).
Fig. 4 X-ray crystal structures of the chloride complex of 14 and the sulfate complex of 15
5.54 and 4.55 ± 0.23 were found by 1 H NMR and ITC respectively for 18 with
sulfate (added as Na2 SO4 ) [26].
2.3
Urea and Thiourea-Based Receptors
Ureas and thioureas possess two parallel NH hydrogen bond donor groups
and have been shown in a wide variety of receptors to function as highly ef-
ficient binding sites for “Y-shaped” anions such as carboxylates. Thioureas
are more acidic than analogous ureas and on this basis might be expected to
form stronger complexes with anions. However, other effects can often mask
or reverse this expected trend.
There have been a number of reports of anions triggering the deproto-
nation of neutral NH groups in anion receptor systems. This is often due,
in the case of fluoride, to the formation of the stable HF2 – anion driving
the deprotonation process [27–30]. Fabbrizzi and co-workers have shown
that this process can occur in urea systems containing electron-withdrawing
groups. The interactions between a number of anions and the simple 1,2-
bis(4-nitrophenyl) urea 19 were investigated. Oxo-anions were found to bind
to the receptor with a 1 : 1 host/guest stoichiometry with the strength of the
interaction depending on the partial negative charge located on each oxygen
atom of the anion [31].
receptors through the two NH protons of the thiourea group and form a 1 : 1
complex. The authors demonstrated that 20a–d act as ideal PET sensors (only
fluorescent quantum yield affected upon additions of anions) with quench-
ing of the fluorescence being observed with the addition of fluoride, acetate
and dihydrogen phosphate anions. Chloride and bromide did not induce any
changes in the fluorescence spectra.
Fluorescent titration experiments with receptors 21b and 22b were carried
out in DMSO with a variety of anions, added as the tetrabutylammonium
salts, in order to compare the stability constants of the mono- and bis-
functionalized receptors. The strongest anion binding was observed with the
bis-functionalized receptor (22b) with stability constants of 108 000, 9700
14 G.W. Bates · P.A. Gale
and 6000 M–1 calculated for fluoride, bromide and pyrophosphate, respec-
tively. For compound 21b a much lower binding constant of 4000 M–1 was
found with fluoride as compared to the strong anion complexation observed
with 22b, illustrating that there is a cooperative binding effect in operation
with the two urea groups in receptors 22a and 22b. Temperature-dependant
1 H NMR experiments in DMF-d also revealed that the anion complex stabil-
7
ity was enhanced by the formation of a hydrogen bond between the hydrogen
atom in the 9-position and both the fluoride and pyrophosphate guests in
receptors 22a and 22b.
Gale and co-workers have designed 23a, a bis-urea cleft based on o-
phenylenediamine, to selectively bind carboxylate anions [35]. The geometry
of the receptors provides a convergent cleft appropriate for the binding of
carboxylate anion through four hydrogen bonds. Stability constants of 3210,
1330 and 732 M–1 were calculated for acetate, benzoate and dihydrogen phos-
phate, respectively, after analysis of data from 1 H NMR titration experiments
conducted in DMSO-d6 /0.5% water at 298 K. The crystal structure of the ben-
zoate complex of compound 23a is shown in Fig. 5 revealing that the receptor
binds this carboxylate via four hydrogen bonds in the solid state. The sta-
bility constants for compound 23a were found to be greater than constants
Fig. 5 X-ray crystal structure of 23a with benzoate. Chem Commun, p 4696 (2005) repro-
duced by permission of The Royal Society of Chemistry
An Introduction to Anion Receptors Based on Organic Frameworks 15
obtained with N,N -diphenylurea with a 2.5-fold increase observed for 23a
with acetate compared to the diphenylurea (3210 M–1 for 23a and 1261 M–1
for diphenylurea [36]).
The same authors appended electron-withdrawing groups onto both the
central aryl ring and peripheral aryl rings of the receptor in order to increase
the acidity of the urea NH groups. Titration studies were conducted under the
same conditions as for 23a and enhanced stability constants were observed
for both receptors 23b and 23c compared to 23a [37]. In the case of acetate the
stability constant increased from 3210 M–1 for 23a, to 4020 M–1 and 8080 M–1
for 23b and 23c, respectively. In the case of dihydrogenphosphate there is
a decrease in affinity from 732 M–1 for 23a, to 666 M–1 for 23b but a large
increase to 4720 M–1 for 23c. The authors proposed that the dihydrogenphos-
phate anion interacted most strongly with the central NH groups thus with
the increased acidity of these NH groups in 23c, due to the presence of the two
chloro-groups, stronger complexation is observed.
Naphthalene and binaphthalene appended with thiourea groups (24 and
25, respectively) have been synthesized by Kondo and co-workers in order
to investigate potential cooperative binding between two thiourea groups in
25 [38]. This group found that 1 : 1 complexes were formed between 25 and
fluoride, acetate and dihydrogen phosphate anion, which was confirmed by
Job plots in acetonitrile and ESI-MS.
The anion binding abilities of 26a and 26b were evaluated by 1 H NMR
titration techniques in DMSO-d6 with CH3 COO– , F– , H2 PO4 – and H2 P2 O7 2–
(added as their tetrabutylammonium salts). Additions of fluoride to the re-
ceptor resulted in a distinctive color change attributed to deprotonation. This
process was characterized by the loss of the thiourea NH proton resonances
and the appearance of the HF2 – resonance in the 1 H NMR during the titra-
tion. Analysis of the binding isotherms of receptors 26a and 26b with acetate
revealed that the anions were strongly bound by both 26a and 26b in a 1 : 2
receptor-to-anion complex with each of the thiourea units binding to a sin-
gle acetate anion. Binding constants (log β1 and log β2 values) of 3.5 (±0.1)
and 2.4 (±0.1) were calculated for 26a and 3.5 (±0.1) and 3.0 (±0.1) for 26b
with acetate. Titrations with H2 PO4 – were fitted to a 1 : 1 binding model and
constants of 3.9 (±0.1) and 3.6 (±0.1) (log β values) were calculated for re-
ceptors 26a and 26b, respectively. Pyrophosphate was then investigated to
evaluate the binding ability of 26a and 26b with a dianion. Analysis of the
titration curves for both 26a and 26b with pyrophosphate revealed the forma-
tion of a 2 : 1 receptor-to-anion stoichiometry in which each anion terminus
is accommodated by two urea groups of a single receptor.
Extending their work on “cholapods”, A.P. Davis and co-workers have ap-
pended urea and thiourea groups from the 7 and 12 positions of the steroid
scaffold and evaluated the ability of these receptors to bind chloride and bro-
mide (added as their tetraethylammonium salts) [40].
NMR data was found to be consistent with the formation of predomin-
antly 1 : 1 complexes of the receptors and anions. Stability constants were
determined by Cram’s extraction method in water-saturated chloroform at
30 ◦ C [40]. Affinities for both chloride and bromide anions increased through
the series 27a–d, reflecting the increase in acidity of the NH groups due
to the electron-withdrawing aryl substituents and the change from urea to
thiourea in 27d. In the case of chloride the association constant for the
“unsubstituted” derivative 27a was calculated to be 1.62 × 107 M–1 , with the
An Introduction to Anion Receptors Based on Organic Frameworks 17
nitrophenyl substituted 27c the constant increased to 4.77 × 108 M–1 and the
constant increased further to 1.05 × 109 M–1 with the introduction of the
thiourea (27d). The addition of the nitrosulfonamide group in 28a–28c also
enhances the anion-binding affinities with the largest constants being ob-
served in the thiourea derivative 28c with constants of 1.03 × 1011 M–1 and
2.59 × 1010 M–1 calculated for chloride and bromide, respectively.
A further detailed study of these “cholapod” anion receptors was con-
ducted where the anion binding ability of several receptors with increas-
ing numbers of hydrogen bond donor groups was investigated [41]. It was
found that a combination of increasing numbers of hydrogen bonding groups
and increasing acidity of the NH groups via electron-withdrawing sub-
stituents had a significant effect on the anion stability constants. Receptor
29 was found to have the highest affinities for all the anions investigated
except acetate where the previously studied 28b and 28c had higher affini-
ties (2.6 × 1011 M–1 and 2.0 × 1011 M–1 , respectively) when compared to 29
(1.3 × 1011 M–1 ). These steroid-based receptors have also been studied as
transport agents for anions across vesicle and cell membranes. Electrochem-
18 G.W. Bates · P.A. Gale
ical, NMR and fluorescence techniques were employed and revealed that the
“cholapod” receptors act as mobile carriers and facilitate the transport of
chloride ions across vesicle membranes [42].
Reinhoudt and co-workers have synthesized both acyclic and cyclic recep-
tors containing multiple urea-binding sites (e.g. 30 and 31). Anion-binding
studies were conducted with these systems and a variety of putative anionic
guests (added as their tetrabutylammonium salts) using 1 H NMR titration ex-
periments in DMSO-d6 [43]. In the case of the cleft-like receptors dihydrogen
phosphate caused the largest shift in the NH group resonances of all the re-
ceptors however an association constant could not be obtained for 30a due
to the complexity of the binding processes in solution. Job plot analysis of
receptor 30b showed the formation of an exclusive 1 : 2 host/guest complex
with dihydrogen phosphate and an association constant of 5 × 107 M–2 was
calculated. The thiourea functionalized 30c cleft was also shown to bind di-
hydrogen phosphate with a 1 : 2 host/guest stoichiometry and chloride with
1 : 1 host/guest stoichiometry.
Macrocyclic receptors 31a and 31b were found to bind both dihydrogen
phosphate and chloride in exclusively 1 : 1 host/guest stoichiometries. Bind-
ing constants were calculated for 31a and 31b with dihydrogen phosphate and
chloride and revealed that dihydrogenphosphate was bound more strongly
(2.5 × 103 M–1 for 31a and 4.0 × 103 M–1 for 31b) than chloride (500 M–1 for
31a and <50 M–1 for 31b).
Gale and co-workers have combined urea and amide groups into a new
macrocyclic motif and studied the anion complexation properties of 32 [44].
Stability constants with a variety of anionic guests were elucidated by
1 H NMR titration techniques in both DMSO-d /0.5% water and DMSO-
6
d6 /5% water at 298 K. The macrocyclic receptor shows significant selectivity
for carboxylate anions over dihydrogen phosphate and chloride. Titrations
An Introduction to Anion Receptors Based on Organic Frameworks 19
for acetate (5300 M–1 ) over dihydrogen phosphate (1600 M–1 ) and chloride
(95 M–1 ) [45].
Recently, Tobe and co-workers have designed cryptand-like macrocycles
based on homobenzylic tripodal thiourea and compared their anion-binding
properties to a series of acyclic tripod-type receptors [46].
The proton resonances in the 1 H NMR spectra of cryptand-type recep-
tor 34b in various solvents were found to be very broad, possibly due to
conformational changes that are slow on the NMR timescale. Therefore, the
complexation of 34b with anionic species was evaluated by 1 H NMR titra-
tion experiments in CDCl2 CDCl2 at 373 K. Association constants of 116 M–1
and 112 M–1 were calculated for acetate and chloride, respectively, and were
found to be much lower than the tripodal receptor 35a under the same condi-
tion (3030 M–1 for acetate and 3700 M–1 for chloride). This low binding ability
of 34b was attributed to strong intramolecular hydrogen bonds between the
thiourea groups. Receptors 35a and 35c were then compared and the stability
constants (obtained from 1 H NMR titrations in DMSO-d6 at 303 K) revealed
that 35a has poor affinity towards all anionic species in DMSO solutions
whereas 35c has high affinity for dihydrogen phosphate and acetate.
An Introduction to Anion Receptors Based on Organic Frameworks 21
3
Aromatic NH Donor Containing Neutral Receptors
3.1
Pyrrole-Based Receptors
Sessler and co-workers have pioneered the use of the pyrrole NH hydrogen
bond donor group in both charged and neutral anion receptor systems [47].
In 1992 they reported the anion-binding abilities and fluoride selectivity
of sapphyrin 36a, a pentapyrrolic macrocycle [48]. Fluorescence titration
experiments carried out in methanol revealed that 1 : 1 complexes formed
between the diprotonated sapphyrin 36a and halide anions and association
constants of 2.8 × 105 , ∼102 and <102 M–1 were calculated with fluoride, chlo-
ride and bromide, respectively. Four-years later Sessler reported the effective
binding of phosphate by receptor 36b. Phosphorus NMR titration experi-
ments were carried out in methanol-d4 at ambient temperature and revealed
that compound 36b bound both phosphoric acid and phenylphosphonic acid
with affinity (1.8 × 104 and 1.3 × 104 M–1 for H3 PO4 and C6 H7 PO3 , respec-
tively) [49].
nitro groups on the peripheral phenyl rings and assessed their anion-binding
ability compared to the unfunctionalized 37a [30]. Proton NMR titrations
were carried out in DMSO-d6 /0.5% water solutions at 298 K and revealed that
the presence of the electron-withdrawing groups in receptors 37c and 37d
improved the systems affinity for anionic guests. In the case of benzoate the
association constants increased significantly from 560 M–1 (obtained for 37a
under identical conditions) to 4150 M–1 for 37c and 4200 M–1 for 37d. Upon
the addition of one equivalent fluoride to 37d the anion appears to coordinate
to the receptor. However, upon further additions of fluoride deprotonation
occurs (as indicated by the evolution of a blue color in solution due to the de-
protonated pyrrole). In the case of compound 37a fluoride was found to bind
to the receptor with a stability constant of 1245 M–1 .
An Introduction to Anion Receptors Based on Organic Frameworks 23
Sessler, Gale and co-workers have further developed receptors based on the
2,5-diamidopyrrole skeleton by appending 2-aminopyrrole groups (e.g. com-
pound 39) thus increasing the number of hydrogen-bonding groups, which
was hoped would increase the selectivity for oxo-anions compared to the pre-
viously studied 37a and 37b [52].
Proton NMR titration experiments were conducted in DMSO-d6 /0.5% wa-
ter at 298 K to investigate the solution phase anion complexation properties
of 39 compared to 37a. The stability constants revealed that 39 showed en-
24 G.W. Bates · P.A. Gale
Recently Katayev, Sessler and co-workers have further developed the hy-
brid macrocycle systems by replacing the pyridine-2,6-dicarboxamide moi-
eties used in receptors 43 and 44 with bipyrrole and dipyrromethane subunits
26 G.W. Bates · P.A. Gale
tional hydrogen bond donor groups. For example, Lee, Sessler and co-
workers have recently reported the synthesis of isophthalamide strapped
calix[4]pyrroles [65]. The authors studied the effect of varying the length of
the strap on the anion complexation properties of the macrocycle and isother-
mal titration calorimetry was employed to investigate the anion-binding
abilities of receptors 48a–c (in CH3 CN at 30 ◦ C). Receptors 48a–c were found
to have high binding affinities toward halide anions however they failed to
show an appreciable size-dependence selectivity based on the increase of
strap length. This is illustrated in the case of chloride (the most strongly
bound anion) where association constants of 3.89 × 106 M–1 , 3.35 × 106 M–1
and 3.24 × 106 M–1 were calculated for 48a, 48b and 48c, respectively.
of anions with higher affinities. 51a was found to have selectivity for fluo-
ride with a constant of approximately 20 000 M–1 estimated from competitive
binding studies in the presence of 51b. This selectivity is presumably due to
good size complementarity between 51b and the fluoride anion.
3.2
Carbazole and Indole-Based Receptors
compound 54c bound benzoate most strongly (log Ka = 5.9) followed by phos-
phate (log Ka = 5.3) then fluoride (log Ka = 5.0) and chloride (log Ka = 4.9),
a trend observed in both 54a and 54b.
Recently, indole-based receptors have attracted increasing attention.
Sessler and co-workers have described the use of indole subunits for an-
ion recognition within diindolylquinoxalines receptors (55a and 55b) [73].
Stability constants were determined by UV-Vis spectroscopic titrations in
dichloromethane at 22 ◦ C and showed that both receptors have apprecia-
ble selectivity for dihydrogenphosphate with constants of 6800 M–1 and
20 000 M–1 calculated for compounds 55a and 55b, respectively. Receptor 55b
was found to be highly colored and upon the addition of dihydrogenphos-
phate a visible change in color was observed.
Jeong and co-workers have extended the research into biindolyl scaffolds
as a building block for anion receptors by synthesizing new macrocyclic sys-
tems 58 and 59 [75]. Both compounds 58 and 59 were found to strongly
bind various anions (stability constants determined by UV-Vis spectroscopy
titrations in CH3 CN at 295 K). In the case of the halide anions a size comple-
mentarity was observed for both macrocycles where the smaller fluoride and
chloride anions were found to bind more strongly to 58 and 59 than the larger
bromide and iodide anions.
Recently, Gale and co-workers have synthesized simple clefts with indole
subunits appended to isophthalamide and pyridine-2,6-dicarboxamide spac-
ers and described their anion-binding properties [76].
Proton NMR titrations in DMSO-d6 /0.5 water at 298 K were conducted to
elucidate stability constants for a number of anions, added as their terabuty-
lammonium salts. Fluoride affects the largest change on the proton reson-
ance however an association constant was only calculated for 60a (>104 M–1 )
therefore titrations were repeated in more competitive media (DMSO-d6 /5%
water). Both receptors showed selectivity for fluoride however 60a bound
with a 1 : 1 binding stoichiometry (1360 M–1 ) whereas the data for 60b could
only be fitted to a 1 : 2 receptor/anion model (K1 = 940 M–1 and K2 = 21 M–1 ).
The crystal structures of 60a with chloride and fluoride are shown in Figs. 8
and 9 respectively.
32 G.W. Bates · P.A. Gale
4
Hydroxy (OH) Donors in Neutral Receptors
In 2003, D.K. Smith showed that simple aromatic hydroxides can complex
chloride anions. Smith compared stability constants (obtained from NMR
competition experiments in CD3 CN) of phenol, 61, resorcinol, 62 and cat-
echol, 63, with chloride (added as its tetrabutylammonium salt) and found
that 63 bound chloride with greater affinity than 61 and 62 (1015 M–1 for 63
against 125 M–1 for 61 and 145 for 62) [77].
An Introduction to Anion Receptors Based on Organic Frameworks 33
Row, Maitra and co-workers have linked two steroid subunits to synthe-
size macrocycle 66. The fluoride-binding properties of compound 66 were
then investigated by a 1 H NMR titration experiment in CDCl3 at 22 ◦ C, which
found that the receptor bound fluoride with a 1 : 2 receptor/anion stoichi-
ometry (a result confirmed by Job plot analysis) and stability constants of
K1 = 1.8 (±0.1) ×103 M–1 and K2 = 2.5 (±0.35) ×102 M–1 were found [79].
5
Charged Receptors
The incorporation of charged groups into receptors designed for anion recog-
nition allows for the receptors to bind the anion with both electrostatic in-
teraction and additional interactions dependent on the group and receptor
34 G.W. Bates · P.A. Gale
design. In the case of imidazolium groups, the cation can stabilize the anion
complex with additional CH· · ·A– type hydrogen bonds.
5.1
Imidazolium and Pyridinium-Based Receptors
Kang and Kim have synthesized the fluorescent anion receptor compound
67 where two methylene bridged bis-imidazolium subunits are attached to
a naphthalene backbone through the 1- and 8-position [80].
showed that compound 71c selectively binds acetate over the spherical halide
anions due to mixtures of conformers being adopted in solution through
anthracene-anthracene mutual interactions. Further evidence of the confor-
mational behavior of compound 71c and its selectivity for acetate over other
anions was provided by UV spectroscopy and fluorescence studies.
Shinoda and co-workers have reported the one-step synthesis and anion
binding properties of macrocycle 72. Proton NMR titration experiments (in
D2 O) were used to determine the binding properties of 72 for tricarboxylate
anions and revealed that the tricarboxylate 72b was bound with the highest
affinity (log Ka = 5.1) [86].
5.2
Guanidinium-Based Receptors
the tetrafluoroborate anion a binding constant of 414 000 M–1 was calculated
compared to a binding of 38 000 M–1 with chloride.
For several years Schmuck has investigated the binding affinities of guani-
dinium salts appended to hydrogen bonding pyrrole-containing motifs and
has shown how carboxylate anion binding is enhanced by the hybrid re-
ceptors. In 1999 Schmuck reported the binding ability of 74a with various
carboxylate anions in highly competitive media [88]. Proton NMR titration
in DMSO-d6 /40% H2 O at 25 ◦ C revealed that 74a formed stronger complexes
with acetate and Ac-L-Phe anions with binding constants of 2790 M–1 and
1700 M–1 , respectively.
Schmuck then investigated a series of guanidinium-appended pyrrole re-
ceptors and found that 74b bound Ac-l-Ala-O– more strongly than 74a
(1610 M–1 and 770 M–1 , respectively) [89]. The binding ability of 74b was
then assessed with a range of carboxylate anions by 1 H NMR titrations in
DMSO-d6 /40% H2 O at 25 ◦ C and showed that compound 74b formed stronger
complexes with the anions than 74a. High affinities were observed for 2-
pyrrole-COO– and acetate (5275 M–1 and 3380 M–1 ). A notable result was
that compound 74b displayed enantioselectivity in the case of Ac-Ala-O– an-
ions where a higher affinity was observed for the l-enantiomer over the
d-enantiomer (1610 M–1 vs. 930 M–1 ).
ion more strongly than the acyclic system. The constants obtained for the
macrocycles 77a–c revealed a size dependence on the binding of nitrate with
the largest macrocycle 77c giving rise to the highest association constant of
73.7 × 103 M–1 , an order of magnitude greater than the smallest macrocycle
77a (7.26 × 103 M–1 ).
5.3
Ammonium-Containing Receptors
The work of Park and Simmons [92] has inspired many efforts into the re-
search of ammonium- and polyammonium-based anion receptors and are
the subject of numerous reviews [93, 94] Here we will only look at recep-
tors containing quaternary ammonium centers. These groups bind anions via
electrostatic interactions only.
An early pioneer in the area of ammonium-based anion receptors,
Schmidtchen synthesized the quaternary ammonium-based macrocyclic re-
ceptors 78a–c in 1977 [95].
40 G.W. Bates · P.A. Gale
6
Conclusions
The examples discussed in this review provide a broad overview of the variety
of synthetic organic receptors used for binding and sensing of anionic species.
As the understanding of the processes and factors that influence the effect-
ive binding of anions improves there is an increasing impetus to apply this
knowledge to solve real-world problems. Areas that are likely to benefit from
this knowledge are in the transport of anions, in separation processes and in
biological systems leading towards new treatments for disease and cancer.
Acknowledgements We would like to thank the EPSRC/Crystal Faraday for a project stu-
dentship (GWB).
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DOI 10.1007/430_2007_073
© Springer-Verlag Berlin Heidelberg
Published online: 19 January 2008
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
1.1 Metal Complexes in Anion Sensing . . . . . . . . . . . . . . . . . . . . . . 46
1.2 Basis of Anion Sensing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
5 Conclusion/Outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
Abstract Metal complexes play an important role in anion receptor chemistry. In the
majority of examples metal centres are used as optical and/or electrochemical re-
porter groups in anion-sensing applications. Metal centres can also act as Lewis acidic
anion-binding sites in their own right, and/or as structural components allowing the
self-assembly of anion-binding domains. This review describes the development of metal-
based receptors with regard to their anion-sensing properties, and is therefore divided
into sections on electrochemical and optical anion sensing. Within these sections cover-
age has been given to the diverse range of metals and anion-binding groups that have
been studied. Emphasis has been placed on recently described novel supramolecular,
nanoscale and surface confined anion receptor systems that give added functionality. The
last section describes metal-based anion receptors without reporter groups.
46 S.R. Bayly · P.D. Beer
1
Introduction
1.1
Metal Complexes in Anion Sensing
1.2
Basis of Anion Sensing
2
Redox-Active Transition Metal-Based Receptors
for Electrochemical Anion Sensing
2.1
Theory of Electrochemical Sensing
2.2
Metallocene Redox Anion Sensors
HSO4 – leads to protonation of the amine group of the receptor. The result-
ing complex is cationic and this has a very high affinity for the residual SO4 2–
anion. Electrostatic interactions are particularly important in redox anion
sensing, and even very simple anion-binding motifs such as the ammonium
cation provide an increased redox response. This has been demonstrated
by Moutet and co-workers using 9 [13]. This molecule is able to sense di-
hydrogenphosphate and ATP2– in a range of solvents, displaying a shift of
470 mV in CH2 Cl2 with dihydrogenphosphate, solely due to a strong ion-
pairing interaction.
In receptor molecules that contain multiple metal centres and anion bind-
ing groups the redox sensing properties are dictated by the precise spatial
arrangement of these groups. In receptors where the pendant reporter groups
are in close proximity to each other an increased redox response to anion
binding is often observed. For example, the cyclotriveratrylene amides 15 and
16 include closely spaced multiple amide anion-binding groups with pen-
dant ferrocene reporter units [18]. In CH2 Cl2 or acetonitrile solution cathodic
shifts of up to 260 mV were observed in the presence dihydrogenphosphate or
ATP2– . On oxidation 15 and 16 gain a triple positive charge. The magnitude of
the redox shift can be attributed to the increased electrostatic affinity of this
multiply charged oxidised species for a single anion compared to monoferro-
cenyl receptors which are monopositive on oxidation.
Receptor 17 has a similar topology—it comprises four cobaltocenium
amide groups attached to a porphyrin backbone as the cis-α,α,α,α-atrop-
isomer [19]. Proton NMR titrations in CD3 CN showed chloride and bro-
mide to be bound in 1 : 1 stoichiometry with stability constants of 860
and 820 M–1 , respectively, whereas nitrate exhibited weaker binding with
K = 190 M–1 . Electrochemical studies displayed cathodic shifts in the cobal-
tocene/cobaltocenium redox couple of 35–75 mV on addition of chloride or
hydrogensulfate, and 225 mV for dihydrogenphosphate in acetonitrile solu-
52 S.R. Bayly · P.D. Beer
tion. Smaller shifts were seen in the porphyrin oxidation wave. The overall
selectivity trend was Cl– > Br– NO3 – .
The anion recognition properties of cobaltocenium calix[4]arene recep-
tors 18–20 were found to be dependent on the structure of the upper-rim of
the calix[4]arene [20]. In 1 H NMR studies in DMSO-d6 solution 18 shows
a greater affinity for acetate than for dihydrogenphosphate whereas its iso-
mer 19 displays the opposite trend. In 20 there is only a single cobaltocenium
group which bridges the upper rim of the calix[4]arene. This receptor displays
a significantly greater affinity for the above anions despite possessing only
a single positive charge. For example, the cobaltocene/cobaltocenium redox
couple of 20 was found to undergo a cathodic shift of 155 mV in the presence
of acetate. It is proposed that the surprising strength of the interaction is due
to the topology of the anion-binding cavity, in which the arrangement of the
two amide hydrogen bond donors is complementary to bidentate anions such
as carboxylates. The same selectivity is seen in the ferrocene-1,1 -bisamide
analogues 21–23 [21]. Results of 1 H NMR studies in CD3 CN show that these
receptors also preferentially bind carboxylate anions (acetate and benzoate)
over dihydrogenphosphate and chloride.
Other carboxylate selective redox sensors based on ferrocene include neu-
tral molecule 24, which utilises hydrogen bonding to bind mono and dicar-
Metal-Based Anion Receptor Systems 53
2.3
Mixed Metal Metallocene-Lewis Acid Anion Receptors
2.4
Transition Metal Polypyridyl Anion Receptors
2.5
Transition Metal Dithiocarbamates as Receptors for Redox Anion Sensing
2.6
Dendrimers as Redox Anion Sensors
sulfate > chloride > nitrate. Evidence of a “dendritic effect” was observed
in the redox response of the consecutive dendrimer generations in the
presence of dihydrogenphosphate or hydrogensulfate. As the number of
amido-ferrocene units is increased, the magnitude of the cathodic shift in
62 S.R. Bayly · P.D. Beer
2.7
Surface Confined Redox Anion-Sensing Systems
Fig. 1 Self-assembly of anion templated rotaxane SAM (RC = redox centre). From [46],
reproduced by permission of The Royal Society of Chemistry
68 S.R. Bayly · P.D. Beer
(40±5 mV), but gives no significant response to the oxoanions tested. This
suggests that chloride binding inside the interlocked cavity of the surface
confined rotaxane results in a conformation where the macrocycle’s pendant
ferrocene group is in proximity to the complexed halide anion, whereas the
oxoanions are too large to penetrate the rotaxane binding pocket. Preliminary
electrochemical competition experiments in acetonitrile solutions revealed
that these rotaxane SAMs are capable of selectively detecting chloride in the
presence of 100-fold excess amounts of dihydrogenphosphate and exhibit an
appreciably greater detection sensitivity than that shown by the free macro-
cycle. The superior electrochemical response of rotaxane SAMs to chloride
over dihydrogenphosphate mirrors the high degree of chloride anion selectiv-
ity of previous rotaxanes prepared via chloride anion templation.
3
Optical Anion Sensors
3.1
Theory of Optical Anion Sensing
Optical reporter groups signal anion binding through a change in their elec-
tronic absorption or emission spectra. The precise nature of the response in
the UV/vis absorption spectrum will largely depend on the energy differences
between the molecular orbitals of the receptor before and after anion bind-
ing. For changes of any magnitude to be observed the anion-binding site must
be strongly coupled to the metal centre. In the case of metal-based transitions
such as d-d transitions this typically requires the anion to bind directly to the
metal centre. In the case of MLCT or LMCT transitions it is advantageous if
the anion-binding site is π-conjugated to the ligand involved. Luminescence
spectroscopy can be a more sensitive technique for probing anion binding
to metal-based receptors. In addition to altering the energy of the emission
maxima, anion binding often causes significant changes in their intensity.
The intrinsic luminescence of a particular reporter group can be “switched
off” if the anion : receptor complex provides a more efficient pathway for
non-radiative energy loss. Similarly, in systems where the luminophore is
quenched by a nearby functional group, anion binding can “switch on” the
luminescent emission by blocking this non-radiative decay process.
3.2
Metallocene Optical Anion Sensors
The common reporter groups cobaltocenium and ferrocene have not fre-
quently been used in optical anion sensing, since these chromophores are
generally insensitive to anion binding. However, metallocene-based receptors
Metal-Based Anion Receptor Systems 69
Luminescence sensing of anions has also been achieved using ferrocene re-
ceptors. Example 72 uses amide groups for anion binding in conjunction with
naphthalene groups to provide the fluorescence signal [50]. Addition of fluo-
ride to a DMSO solution of 72 led to a 3-fold enhancement (at 5 equivalents)
of the intramolecular naphthalene-naphthalene excimer emission at 492 nm.
Dihydrogenphosphate also generated a significant response, causing a 2-fold
enhancement at 5 equivalents. In electrochemical studies in DMF electrolyte
solution fluoride generated a 120 mV cathodic shift in the redox potential.
The receptor 73, based on an azaferrocenophane structure bearing two
urea groups as linkers between the redox active (ferrocene) and fluorescent
(naphthalene) signalling subunits, also shows both fluorescent and electro-
chemical sensing of fluoride [51]. On addition of excess fluoride it displays
an enhancement factor of 13 in the naphthalene emission bands at 362 and
380 nm in DMF solution and a cathodic shift of the ferrocene/ferrocenium
couple of 190 mV in DMSO electrolyte solution.
72 S.R. Bayly · P.D. Beer
3.3
Ruthenium(II) Polypyridyl Complexes as Optical Anion Sensors
The spectroscopic and redox properties of {RuII (bpy)3 } have allowed this
metal complex to be used for combined optical and electrochemical sensing
of anions without the need for additional chromophores or luminophores.
The luminescent emission of {RuII (bpy)3 } is also very useful for signalling
anion binding. In the emission spectra of 37–40 both a blue shift (of up to
16 nm for 40) and an increase in intensity of the λmax of the MLCT emis-
sion band was observed on addition of dihydrogenphosphate. It has been
proposed that the conformational flexibility of the receptors is decreased by
complexation of the anion guest thus reducing the rate of non-radiative decay
through vibrational and rotational relaxation. Similarly, macrocyclic com-
plexes 41–44 and 77–79 were also found to sense chloride by luminescence
enhancement.
In other examples anion binding can cause quenching of the {RuII (bpy)3 }
MLCT emission. In aqueous solution polyaza receptors 80-82 bind phosphate
and ATP anions, producing up to a 15% reduction in the emission intensity of
λmax at 605 nm [16]. Similarly, 76 shows up to a 40% reduction in the intensity
of the luminescent emission at 630 nm in the presence of dihydrogenphos-
phate in DMSO solution.
The RuII bipyridylcalix[4]diquinone receptor 83 selectively binds and
senses acetate anions (from 1 H NMR titrations in DMSO-d6 solution
K = 9990 M–1 ) [54]. This receptor is only weakly luminescent because the
{RuII (bpy)3 } MLCT emission is partially quenched by oxidative electron
transfer to the electron-poor calix[4]diquinone. Addition of acetate to ace-
tonitrile solutions of 83 resulted in a five-fold increase in luminescence
intensity (60% for chloride) concomitant with a slight blue shift of the emis-
sion maximum. Anion binding causes this increase in emission intensity
by interrupting the electron transfer pathway from the {RuII (bpy)3 } to the
calix[4]diquinone, thus reducing its quenching effect.
A similar effect is seen in macrocycle 36 which incorporates the
{RuII (bpy)3 } moiety with a bridging cobaltocenium unit [29]. In acetoni-
74 S.R. Bayly · P.D. Beer
trile solution the quantum yield of the {RuII (bpy)3 } emission of this complex
is relatively low. However, in the presence of chloride a 100% increase in
emission intensity is observed.
Complexes 45 and 46 are capable of selectively sensing fluoride in ace-
tonitrile solution both by UV-vis and luminescence spectroscopy [33]. This
anion causes a dramatic reduction in the intensity of the MLCT absorption in
the 350–450 nm range with a new absorption appearing in the 500–650 nm
range ascribed to a ligand-based CT process. The emission spectra of the
complexes (exciting at 465 nm) show no significant peaks, indicating that the
characteristic Ru-centred luminescence is quenched by the dinitrophenylhy-
drazone group. Upon addition of fluoride a strong peak at 625 nm develops,
with quantum yields for the 45 : F– and 46 : F– adducts of 8.0 × 10–5 and
4.0 × 10–4 , respectively. Again it is apparent that anion binding interrupts the
non-radiative decay pathway.
3.4
Optical Anion Sensing Using Reporter Groups
Based on Other Transition-Metal Complexes
Zn(II) porphyrins are another class of complex which can operate both as
UV/vis and luminescent sensors for anions. Example 86 is a picket-fence por-
phyrin with four imidazolium anion-binding groups [57]. In DMSO solution
this receptor undergoes slight (5 nm) bathochromic shifts in the Q-bands of
the absorption spectrum on addition of anions—indicative of the anion bind-
ing directly to the Zn centre. Using UV/vis titrations in DMSO solution 86 was
found to be selective for hydrogensulfate over chloride and dihydrogenphos-
phate. In water : DMSO (5 : 95) solution the receptor was found to be selective
for sulfate and hydrogensulfate over ATP2– and dihydrogenphosphate. Under
similar conditions the Q bands in the luminescence emission spectrum of 86
(λex = 424 nm) are also bathochromically shifted with a concomitant decrease
in intensity.
It should be noted that 86 also functions as an electrochemical anion
sensor, where the Zn(II) porphyrin-based oxidation potential is sensitive to
76 S.R. Bayly · P.D. Beer
4.03 and 3.14, respectively. This selectivity trend is ascribed to the combined
effect of the basicity and geometry of the guest anions [59].
Complexes of rhenium(I)tricarbonylchloride with pyridyl ligands are lu-
minophores and hence in anion sensing have principally been used as re-
porter groups. For instance calix[4]diquinone receptor 90 selectively binds
and senses acetate in DMSO solution [54] (from 1 H NMR titrations K =
1790 M–1 in DMSO-d6 solution). The receptor exhibits relatively weak lumi-
nescence because calix[4]diquinone is an electron acceptor, quenching the
Re(I) bipyridyl emission by oxidative electron transfer. Addition of anions to
DMSO solutions of 90 resulted in a significant increase in luminescence inten-
sity. It is clear that the presence of the anion in the binding pocket between
the {ReI (bpy)} moiety and the quencher interrupts the oxidative electron-
transfer process.
The mixed Re(I)/Pd(II) molecular square 91 has been found to sense
perchlorate in acetone (giving K = 900 M–1 ) by enhancement of the Re(I) lu-
minescent emission [60]. In this case luminescence quenching by oxidative
transfer to the Pd(II) ion is inhibited by the bound anion. The Pd(II) ion
also plays a role as a structural element and charge carrier. Squares 92–96
are very similar, but incorporate a bis-phosphinylferrocene supporting lig-
and [61]. Again the normally strong luminescence of the Re(I) component is
partially quenched by the bimetallic corners. Binding studies of the squares
with different inorganic anions were carried out by luminescence titrations
in acetone solution. Of the anions investigated, only hexafluorophosphate and
tetrafluoroborate induced significant changes in luminescence. As these an-
ions were added an initial decrease in emission intensity was followed by
an increase to a plateau. This is taken to indicate the presence of two com-
peting quenching pathways which are inhibited to different extents by anion
binding.
Lees and co-workers have investigated Re(I) bipyridyl anion hosts based
on aryl bisamide skeletons 97–99 [62]. Measurement of anion-induced lumi-
nescence quenching in CH2 Cl2 showed 97 to have strong binding affinities for
halides, acetate and cyanide, weaker affinity for dihydrogenphosphate, and
even less affinity for nitrate and perchlorate. The iso- and terephthalamide re-
ceptors 98 and 99 possess smaller stability constants for all the anions tested.
It is proposed that the anion-sensing efficiency of 98 is due to intramolecular
hydrogen-bonding of the amido NH proton to the pyridyl nitrogen holding
the receptor in a “cleft” conformation.
A metal-templated approach has been used by Thomas and co-workers to
produce the Re(I) metallomacrocycle 100 [63]. In acetonitrile solution this
receptor displayed luminescence enhancement on addition of anions. Stabil-
ity constants for the 1 : 1 adducts with BF4 – (1575 M–1 ), SO4 2– (7135 M–1 )
and BPh4 – (2895 M–1 ) were determined. Since SO4 2– is of similar size to
BF4 – the comparatively high affinity of this anion for 100 is thought to be
due to its additional charge. The slightly higher stability of the 100 : BPh4 –
78 S.R. Bayly · P.D. Beer
3.5
Transition Metals as Anion-Binding Groups and/or Structural Components
Complexes of the late transition metals are well studied in anion sensing,
much of the work has been pioneered by Fabbrizzi and co-workers. As well
as providing an optical signalling function the Lewis acid metal ion can act
as a binding site for the anion. In addition the metal ion often forms an or-
ganisational unit designed to create a receptor of a specific shape. In order to
harness the metal-anion interaction for anion sensing the binding properties
of the metal must be modulated by an ancillary ligand. In this way one or two
vacant coordination sites can be made available for anion binding, and other
elements appended to allow signalling or modified selectivity.
In complexes with simple tripodal amines such as 102 and 103 zinc(II)
forms five-coordinate metal complexes of trigonal bipyramidal geometry,
leaving one of the axial coordination sites of the metal available for an-
ion binding. The Zn(II) complex of 102 was found to undergo quench-
ing (by photoinduced electron transfer) of the anthracene fluorescent
emission in the presence of aromatic carboxylate anions such as 4-N,N-
dimethylaminebenzoate in ethanol solution [65]. Complete quenching was
observed at the 1 : 1 anion to receptor ratio (log K = 5.45). Likewise the Zn(II)
complex of 103 was found to form 1 : 1 adducts with carboxylate anions in
methanol solution, with log K values ranging from 4 to 5 [66]. Only aromatic
carboxylates induced quenching of the ligand luminescence.
80 S.R. Bayly · P.D. Beer
for the anion:receptor complexes were calculated for fluoride (4160 M–1 ),
chloride (3230 M–1 ), bromide (2500 M–1 ), acetate (4760 M–1 ), and phosphate
(4000 M–1 ). Decomplexation of the chelated Zn(II) ion from 104 by the weakly
coordinating anions was ruled out as the sensing mechanism. It is proposed
that the quenching of the ligand luminescence by electron transfer to the
Zn(II) centre is inhibited by anion coordination.
Fabbrizzi and co-workers have demonstrated the use of bis-copper(II)
cryptates to sense ambidentate anions [68]. On titrating molecule 105 with
NaN3 in aqueous solution the colour changed from pale blue to bright green
and an anion-metal LMCT absorption appeared at 400 nm. X-ray diffraction
studies have shown that the azide anion is held colinear with the two Cu(II)
centres, coordinated through the two terminal sp2 hybridised nitrogen atoms.
Stability constants for 105 with a variety of anions in aqueous solution were
calculated and the selectivity of this anion sensor for the azide anion was
found to be determined by the bite distance between the two copper atoms.
Cryptate 106, in which the aryl spacer of 107 is replaced with a furanyl
unit, acts as a colourimetric sensor for anions. UV/vis titrations in aqueous
solution gave log K values for the 1 : 1 halide/receptor adducts of 3.98 for chlo-
ride, 3.01 for bromide and 2.39 for iodide. X-ray diffraction studies confirm
that bromide is held between the two copper atoms. Under the same con-
ditions 106 also interacts strongly with azide (log K = 4.7) and thiocyanate
(log K = 4.28) anions. This receptor is interesting because of its lack of se-
lectivity compared to 105. The complex appears to be able to expand and
contract its bite-length in order to accommodate anions of various dimen-
sions.
The use of this class of receptors in practical applications is limited by
the small changes in UV-vis absorption which indicate anion binding. To
overcome this problem of sensitivity a chemosensing ensemble approach has
been applied. The fluorescent indicator coumarine 343 carries a carboxylate
group which allows it to be bound by 105 in a 1 : 1 complex (log K = 4.8) with
complete quenching of the luminescent emission [69]. Titration of a solution
containing 0.2 mM 105 and 0.1 µM coumarine 343 with hydrogencarbonate,
azide or cyanate anions resulted in complete recovery of the indicator lu-
minescence. Anions with a lower affinity for the receptor were unable to
displace the coumarine 343 and produced only a slight luminescence en-
hancement. The usefulness of this chemosensing ensemble was demonstrated
by the quantitative determination of carbonate in mineral water. Using the
same principle Han and Kim have recently reported a chemosensing ensem-
ble made up of the dizinc complex 107 and pyrocatechol violet which is
selective for phosphate [70].
Anslyn and co-workers have developed a series of tripodal Cu(II) com-
plexes 108 and 109 in which the metal ion and three cationic organic groups
form a tetrahedral cavity designed to host phosphate [71]. Receptor 108 is
built from the tris(2-ethylamino)amine skeleton with appended benzylamine
82 S.R. Bayly · P.D. Beer
groups. UV/vis anion titrations were carried out in aqueous solution at pH 7.4
where it can be assumed the terminal amines are all protonated. Hydrogen-
phosphate and its congener hydrogenarsenate were found to bind strongly
in a 1 : 1 anion/host ratio, both with a log K value of 4.40. Perrhenate was
bound an order of magnitude less strongly and the affinity for chloride was
too small to measure. Model complex 110, which has no ammonium groups,
gave a log K value of 2.95 with hydrogenphosphate, indicating that the Cu(II)-
anion interaction contributes significantly to anion binding. Receptor 109 fol-
lows the same design principle, this time incorporating guanidinium binding
units with a tris-[(2-pyridyl)methyl]amine skeleton. log K values for hydro-
genphosphate and hydrogenarsenate were found to be 4.18 and 4.23, respec-
tively. Other anions, including perrhenate had no significant affinity for 109.
It is apparent that the guanidinium groups are responsible for the improved
selectivity of this receptor for phosphate. In a separate study the driving force
for hydrogenphosphate binding was found to be entropic for receptor 108, but
enthalpic for receptor 109 [72]. Partnered with the colourimetric indicator
5-(and 6)-carboxyfluorescein receptor 109 provides an effective chemosens-
ing ensemble for the determination of inorganic phosphate in serum and
saliva [73].
Zinc has been used as a binding site for the detection of pyrophosphate
in aqueous solution by fluorescence. Complex 111 couples two tridentate Zn
centres to a fluorescent naphthalenediimide core. In HEPES buffer the ap-
pearance of a new emission band at 490 nm was observed on addition of
pyrophosphate, attributed to naphthalenediimide excimer formation. This
did not occur with other anions including halides, acetate and ADP. It is pro-
posed that 111 binds pyrophosphate in a 2 + 2 complex, which brings two
naphthalenediimides in close enough proximity to give the excimer emis-
sion [74].
The recent tripodal Cu(II) complex 112 has intriguing optical anion-
sensing properties [75]. This receptor has a cavity with two distinct anion-
binding sites—the vacant site on the Lewis acidic Cu(II) centre, and the
three favourably arranged nitrophenylurea fragments. On titration with up
Metal-Based Anion Receptor Systems 83
Fig. 2 X-ray crystal structure of bromide encapsulated in the Fe : 117 complex. Repro-
duced with permission from [79]. © Wiley-VCH Verlag GmbH & Co. KGaA
86 S.R. Bayly · P.D. Beer
3.6
Optical Anions Sensing by Lanthanide(III) Complexes
Other groups have subsequently reported anion receptors that work on the
same principle. For instance an Eu(III) complex of the bis-bipyridinephenyl-
phosphine oxide ligand 119 made by Ziessel and co-workers is able to sense
anions by luminescence enhancement in acetonitrile with stability constants
which follow the trend fluoride > acetate > chloride > nitrate [82]. Tsukube
and co-workers have investigated the properties of the Eu(III) and Tb(III)
complexes of the chiral ligand 120 [83]. Anion binding was assessed by profil-
ing luminescence enhancement in acetonitrile and it was found that the dif-
ferent metal centres provided different selectivities. The emission at 548 nm
88 S.R. Bayly · P.D. Beer
of the Tb(III) complex was increased by 5.5 times in the presence of 3 equiva-
lents of chloride compared to 2.2 for nitrate and 1.1 for acetate. Conversely the
emission at 618 nm of the Eu(III) complex was increased 8.3 times by 3 equiv-
alents of nitrate, 2.5 times for chloride and 1.0 times for acetate. Stability
constants were not reported.
The same group most recently reported the use of neutral lanthanide(III)
tris-diketonates of type 121 for the determination of chloride [84]. The
response in luminescence of the Eu(III) complex for chloride in acetoni-
trile solution was large enough to be seen by the naked eye. Incorpora-
tion of the complexes in PVC membrane electrodes allowed measurement
of potentiometric selectivity coefficients. These showed the Eu(III) complex
to be the more selective for chloride than the Pr(III), Dy(III) or Yb(III)
analogues.
Gunnlaugsson and co-workers have developed an anion sensor based on
a ternary europium complex [85]. In 122 the naphthalene β-diketonato ligand
acts as a sensitising group for Eu(III) emission. Displacement of this antenna
group from 122 by competitor anionic species would therefore be expected
to decrease the intensity of this emission. In aqueous solution at pH 7.4 it
was found that iodide and dihydrogenphosphate reduced the intensity of the
emission at 616 nm by 20–40%. More pronounced changes, which could be
seen with the naked eye, were observed with highly competitive anions such
as tartarate and fluoride.
Gunnlaugsson and co-workers have also studied di-europium(III) com-
plex 123, which incorporates two different macrocyclic ligands for Eu(III) in
addition to a covalently bound antenna group [86]. Upon titrating 123 with
acetate, aspartate and succinate at pH 6.5, each of the Eu(III) emission bands
was quenched by up to 50% for acetate and aspartate. Malonate, however, pro-
duced a nearly two-fold enhancement in the emission intensity. It is thought
that this particular anion is able to displace coordinated water molecules from
both the Eu(III) centres thereby reducing the rate of non-radiative energy
transfer.
3.7
Surface Confined Systems for Optical Anion Sensing
Table 1 Association constant (log K) data of 124 and 124 modified nanoparticles in DMSO
solution determined at 293 K, errors ±0.1
4
Metal-Based Anion Receptors Without Reporter Groups
solution [90]. Stability constants were determined with Ka = 551, 133, 51, and
49 M–1 , respectively.
Cr(CO)3 is an effective electron-withdrawing group [91]. The coordination
of this organometallic unit to the arene substituents of the isophthalamide in
128 increases the acidity of the NH protons and hence their affinity for an-
ions. 1 H NMR titrations in CD3 CN solution provided stability constants of the
same order of magnitude as those for the non-metallated receptor in the far
less competitive solvent CD2 Cl2 .
Loeb, Gale and co-workers have used Pt(II) as a structural template for the
self-assembly of a series of anion receptors. Receptors 129–132 were found
to bind a variety of anions in DMSO-d6 solution [92, 93]. Even the simple
tetrapyridine receptor 129 has an affinity for anions due to its electrostatic
charge. The addition of pyrrole hydrogen-bond donors increases the stabil-
ity of the receptor : anion complexes by more than five-fold in 130, but in 131
Metal-Based Anion Receptor Systems 91
they are poorly orientated for anion coordination and the stability constants
are only marginally higher than in 129. Receptor 132 which uses urea groups
as hydrogen-bond donors binds anions with 1 : 2 receptor : anion stoichiom-
etry, with stability constants an order of magnitude higher than 131.
5
Conclusion/Outlook
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94 S.R. Bayly · P.D. Beer
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
6 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
Abstract Phosphate derivatives are ubiquitous in living organisms playing several import-
ant roles. Therefore, the development of sophisticated artificial phosphate receptors and
chemosensors that can work in aqueous conditions is currently an area of great inter-
est. There is a need to develop new methodologies for detection, separation or transport
of biologically relevant phosphate derivatives. In the past two decades, many artificial
chemosensors have been reported; these can be broadly classified into (1) chemosensors
utilizing electrostatic interactions and hydrogen bonds and (2) chemosensors utilizing co-
ordination chemistry. The development of these receptors is often inspired by the design
of substrate-binding centers in natural enzymes such as protein kinases, phosphatases
and phospholipases. More recently, the targets of such chemosensors have been broad-
ened to include the recognition of phosphorylated protein surfaces. Here we review the
recent progress in the development of molecular receptors and chemosensors that can
selectively detect phosphate derivatives in aqueous media.
96 S.-i. Tamaru · I. Hamachi
Abbreviations
ADP adenosine 5 -diphosphate
AMP adenosine 5 -monophosphate
ATP adenosine 5 -triphosphate
AXP adenosine nucleotide
cAMP adenosine 3 ,5 -cyclic monophosphate
CD circular dichroism
CTP cytosine 5 -triphosphate
CoA coenzyme A
5-CF 5-carboxylfluorescein
diMeP dimethyl phosphate
GTP guanosine 5 -triphosphate
IP3 d-myoinositol 1,4,5-triphosphate
MAPK mitogen-activated protein kinase
MeP methyl phosphate
MLCT metal-ligand charge transfer
NPP 4-nitrophenyl phosphate
PDGFR-β platelet-derived grows factor receptor-β
PET photo-induced electron transfer
PhP phenyl phosphate
PPi pyrophosphate
PV pyrocatechol violet
p-Tyr O-phospho-L-tyrosine
UDP-Gal uridine 5 -diphospho-α-d-galactose
Zn-Dpa zinc(II)-dipicolylamine
1
Introduction
tives utilizing artificial small molecular receptors that can work in aqueous
media.
2
Phosphate Recognition by Electrostatic Interactions and Hydrogen Bonds
2.1
Cyclic/Acyclic Polyamine Type Artificial Chemosensors
The Czarnik group then prepared compound 2, which has two polyamine
chains at the 1- and 8-positions of anthracene, as a fluorescence chemosen-
sor toward pyrophosphate (PPi) [14]. To effectively bind both phosphates
of PPi simultaneously, the polyamine chains were geometrically preorga-
nized. The dissociation constant (Kd ) for the 2-PPi complex was found to be
2.9 µM, whereas that for 2-phosphate was 6.3 mM. In particular, chemosen-
sor 2 displayed a 2200-fold pyrophosphate/phosphate discrimination at pH 7
(Scheme 2). Such high ion selectivity allows a real-time assay of pyrophos-
phate hydrolysis catalyzed by inorganic phosphatase.
Since macrocyclic polyamines have a much greater charge density within
the molecular skeletons in the multi-protonated state as compared to the lin-
ear polyamines, they should have an entropic advantage for the complexation
of phosphates. On the basis of this advantage of macrocyclic polyamines over
the corresponding acyclic polyamines, Kimura et al. reported that a macro-
cyclic hexaamine 3 showed stronger affinity to AMP, ADP and ATP at pH 8.0
(logKs = 3.2, 5.6 and 6.4, respectively) than those for corresponding spermine
complexes (mentioned above) [15].
Lehn and his co-workers reported that the oxygen-containing macrocyclic
polyamine 4 is a good receptor of nucleotides such as ATP and ADP [16, 17].
Due to the formation of multiple ionic interactions, 4 strongly bound ATP, es-
pecially under very acidic conditions (logKs = 4.8 at pH 7.6, 11.0 at pH 4.0).
Interestingly, they found that compounds 4 and 5 were capable of catalyzing
the hydrolysis of ATP to ADP (Scheme 3). In the complex of 4-ATP, a nitrogen
atom attacked the terminal phosphate to yield ADP and thus phosphorylated
4. The phosphorylated 4 was immediately hydrolyzed to regenerate the ori-
ginal 4 in the catalytic process. Compound 5, in which a fluorogenic acridine
ring was introduced to the polyamine ring, showed greater selectivity be-
tween ATP and ADP than the parent compound 4. Compound 5 bound such
nucleotides using two distinct forces, electrostatic interactions between the
macrocyclic polycationic moiety and the polyphosphate and π-π stacking
interactions between the acridine ring and nucleic base. The latter inter-
actions induced the fluorescence change of the acridine moiety of 5 upon
complexation.
Scheme 3 Schematic representation of the catalytic cycle for ATP hydrolysis by the chemo-
sensor 5 following the nucleophilic pathway
Phosphate Recognition Utilizing Artificial Small Molecular Receptors 101
2.2
Artificial Chemosensors Containing Other Cationic Groups
ing off the guanidium groups by the split-and-pool method yielded a small
library of potential candidates for chemosensors. Several “hit” molecules
were selected and picked up by the fluorescence assay with ATP derivative
(N-methylanthraniloyl-ATP: MANT-ATP). Among them, chemosensor 17 con-
taining Ser-Tyr-Ser sequences, was finally discovered as an ATP selective
chemosensor. The binding constant of 17 for ATP was found to be 3.4 × 103 M–1 ,
approximately 10 times greater than that of the reference compound 18.
Alternatively, Rebek et al. rationally designed and synthesized a water-
soluble nucleotide receptor 19 that is comprised of a carbazole backbone,
a cyclic guanidinium cation, and two Kemp’s triacidic imides [33]. Compound
19 bound cyclic AMP (cAMP) to form a 1 : 1 complex (logKs = 2.8) in aqueous
media by cooperatively accumulated interactions, specifically electrostatic in-
teraction between its guanidinium cation and the anionic phosphate diester,
π-π stacking interaction between its carbazole backbone and adenine ring,
and hydrogen bonding interactions (Fig. 1).
Fig. 1 Structure of 19 and the predicted lowest energy conformation of the complex
between 19 and cAMP
Fig. 2 Structure of 20 and the energy-minimized structure of the complex formed be-
tween chemosensor 20 and AMP
3
Phosphate Anion Recognition Utilizing Coordination Chemistry
affinity toward various metal ions, however, the metal complexation with such
binding sites competes with the desired phosphate capturing under physio-
logical conditions. Therefore, the utilization of the polyamine type phosphate
receptors in biological applications may be seriously restricted. In addition,
the moderate binding affinity of polyamines toward phosphates under bi-
ological conditions is another drawback. On the other hand, coordination
chemistry provided by metal complexes is often employed to bind a phos-
phate unit of substrates in the enzyme active site [35, 36]. This gives one
an important clue for the design of phosphate-binding motifs that show the
stronger affinity in aqueous media.
3.1
Zn-cyclen Type Artificial Chemosensors
3.2
Zn-Dpa Type Artificial Chemosensors
displaced with phosphate anion at the binding site so as to cause the remark-
able color change of the solution from blue to yellow (Scheme 5).
Excimers, excited dimers of two planar fluorophores, often display sig-
nificantly red-shifted fluorescence relative to the corresponding monomer.
Hence, suitable molecules that can form excimers resulting from complexa-
tion with the target phosphate would become unique chemosensors that show
drastic fluorescence change during phosphate recognition. A chemosensor 30
attaching two Zn-Dpa units to both ends of naphtalenediimide formed a 2 : 2
complex with pyrophosphate resulting in an excimer formation (logKapp =
4.1 × 105 M–1 ), whereas the addition of other anions including AXP did not
show any meaningful fluorescence change [49]. This sensor can selectively
detect pyrophosphate in the presence of ATP or inorganic phosphate by the
characteristic red-shifted emission. In addition to the four Zn binding sites
for pyrophosphate, the favorable π-π interaction of the two flat aromatic
3.3
Ratiometric Detection of Phosphate Derivatives
(Fig. 4) [51]. In the resting state, these sensors are in equilibrium between
mono- and binuclear Zn complexes. In this state the sensors predominantly
exist as mononuclear Zn complexes, with binuclear Zn complexes as the
minor species, as illustrated in Scheme 8. The binding of anionic nucleo-
Fig. 4 Change in the fluorescence emission of 32 (a) and 33 (b) induced by ATP addition
Phosphate Recognition Utilizing Artificial Small Molecular Receptors 111
complexes was approximately 10–5 M. This chemosensor was utilized for the
real-time monitoring of the activity of a phosphodiesterase which cleaves
an undetectable cyclic nucleotide (e.g. cAMP) to produce the corresponding
detectable nucleotide (e.g. AMP).
4
Recognition of Phosphorylated Protein Surfaces
Table 1 Summary of the apparent binding constants (Kapp , M–1 ) of 35 and 36 to phos-
phate species by fluorescence change
NaH2 PO4 b 4.2 × 105 2.9 × 105 ATP c > 107 4.0 × 105
PhP b 2.1 × 105 5.1 × 104 ADP c > 107 1.6 × 105
p-Tyr b 3.1 × 105 6.1 × 105 AMP c 2.3 × 105 9.1 × 103
MeP b 1.1 × 105 7.9 × 103 cAMP c –d –d
DiMeP b –d –d
a PhP = phenyl phosphate, p-Tyr = O-phospho-L-tyrosine, MeP = methyl phosphate,
diMeP = dimethyl phosphate, ATP = adenosine 5 -triphosphate, ADP = adenosine 5 -di-
phosphate, AMP = adenosine 5 -monophosphate, cAMP = adenosine 3 ,5 -cyclic mono-
phosphate.
b Measurement conditions: 10 mM HEPES, pH 7.2, 20 ◦ C.
c 50 mM HEPES, 50 mM NaCl, pH 7.2, 20 ◦ C.
d Since the fluorescence change was scarcely observed, the association constant cannot be
obtained.
114 S.-i. Tamaru · I. Hamachi
species among various anions, and can distinguish phosphate and phosphate
monoesters from phosphate diesters.
Determination of the binding ability of the chemosensors 35, 36 to phos-
phorylated peptides was conducted as a model study of phosphorylated pro-
tein surface recognition. Similar to phosphate sensing, the fluorescence inten-
sity of 35 increased upon addition of a phosphorylated peptide in aqueous
solution. In the titration study with peptide-a (EEEI-pY-EEFD), a consensus
sequence phosphorylated by a protein kinase v-Src, the fluorescence of 35
was enhanced, with the intensity finally reaching a 2.5 fold increase relative
to that in the absence of the peptide. In contrast, the corresponding non-
phosphorylated peptide-g (EEEI-Y-EEFD) did not cause any emission change,
showing that the chemosensor can distinguish a phosphorylated peptide
from a non-phosphorylated one. Interestingly, the affinity of the chemosen-
sors depended on the number of negative charges located on the phospho-
rylated peptide. Among the tested peptides, both chemosensors showed the
strongest binding affinity (Kapp of 106 –107 M–1 ) for peptide-a, which has a
larger negative charge (– 8) (Table 2).
The significant emission enhancement of these chemosensors and the high
selectivity towards phosphorylated peptides enabled the detection of phos-
phorylated peptides by naked inspection of the emission change. This is
illustrated in the photograph shown in Fig. 5. Such fluorescence intensifica-
tion of the chemosensors is clearly ascribed to the phosphate-assisted binding
of the second Zn cation. A schematic illustration of the sensing mechanism
toward the phosphorylated peptide is depicted in Scheme 11. In the absence
of a phosphorylated peptide, the second Dpa site of the chemosensor is
Table 2 Amino acid sequences of peptides containing optimal consensus sequences phos-
phorylated by different protein kinases and apparent binding constants (Kapp , M–1 ) of 35
and 36 to the peptides as determined by fluorescence change
partially free from the Zn-complexation, so that the PET quenching by the
benzylic amine of Dpa lessened the fluorescence intensity of anthracene. In
the presence of phosphorylated peptide, on the other hand, the binding of
the second Zn cation to the free Dpa site was facilitated, and as a result the
PET quenching was canceled so as to recover the fluorescence intensity. The
careful thermodynamic study of this molecular recognition using isothermal
titration calorimetry (ITC) undoubtedly demonstrated that the binding was
an endothermic and entropy-driven event in the aqueous buffer solution.
These chemosensors were applied to two biological assays. Firstly, the real-
time fluorescence monitoring of phosphatase-catalyzed dephosphorylation
reactions was demonstrated. A phosphopeptide DADE-pY-LIPNNG (a frag-
ment (988–998) of EGFR) was dephosphorylated by phosphatase PTP1B
to yield the non-phosphorylated peptide (Fig. 6) [54]. The pre-binding of
the substrate peptide with 35 enhanced the fluorescence intensity of the
chemosensor. After the addition of PTP1B, the fluorescence declined in a
time-dependent manner during the progress of enzymatic dephosphoryla-
tion of the peptide. This method is much simpler than the conventional
one using a radio-active phosphorylated peptide as the enzyme substrate.
Secondly, the selective staining of phosphoprotein in SDS-PAGE was car-
ried out [55]. The chemosensor 36 was shown to work well as a fluorescent
staining reagent in the conventional gel electrophoresis of the protein mix-
tures. As shown in Fig. 7, only two distinct bands were fluorescently observed
under a UV trans-illuminator, those corresponding to phospho-ovalbumin
(MW = 45.0 kDa) and phospho-α-casein (MW = 23.6 kDa). In contrast, very
slight or no emission was observed in other bands corresponding to the
Fig. 7 Selective phosphoprotein detection in SDS-PAGE using 36. Each lane includes
two phosphoproteins (ovalbumin (45.0 kDa) and α-casein (24.0 kDa)), and four non-
phosphorylated proteins (β-galactosidase) (MW = 116.0 kDa), bovine serum albumin
(MW = 66.2 kDa), avidin (MW = 18.0 kDa), and lysozyme (MW = 14.4 kDa). Lane 1: CBB
staining of the six proteins. Lane 2, 3: Detection of the phosphoproteins with UV transil-
luminator after staining with 36. The amount of each protein in lane 2 and lane 3 is 5.0
and 2.5 µg, respectively
ated by circular dichroism (CD) spectral studies (Fig. 8), in which the α-helix
content of the peptide was measured upon addition of the chemosensors.
Sensors 37, 38 induced the α-helix formation of peptides having two phos-
phoserine residues (pS-5,16, – 9,16, and – 12.16), whereas they did not affect
the secondary structure of the mono-phosphorylated peptide (pS-16). The
complexation process was also monitored by changes in the emission inten-
sity. The fluorescence titration of 38 with pS-9,16 gave the affinity constant
(Kapp = 2.0 × 106 M–1 ), the value of which is over 40-fold higher than that
of 38 with the mono-phosphorylated pS-16 peptide (Kapp = 4.8 × 104 M–1 ).
This indicated that 38 can discriminate the number of phosphorylation sites
Phosphate Recognition Utilizing Artificial Small Molecular Receptors 119
of peptides. More recently, it was found that similar binuclear type artificial
receptors could strongly bind phosphorylated CTD peptide by tight two-
point interactions between Zn-Dpa sites and phosphates on the peptide. Such
a complexation disrupted phosphoprotein/protein interactions in a phospho-
rylated CTD peptide and the Pin1 WW domain, a phosphoprotein-binding
domain [57]. The strategy based on a small molecular disruptor that directly
interacts with phosphoprotein is unique and should be promising in develop-
ing a designer inhibitor for phosphoprotein-protein interaction.
5
High Throughput Sensing System for Phosphate Derivatives
Using Semi-wet Sensor Arrays
5.1
Molecular Recognition of Chemosensors in a Supramolecular Hydrogel
5.2
Use of Hydrophobic Micro-domains of Supramolecular Hydrogel Fibers
for Discrimination of Phosphate Derivatives
Fig. 11 Photo images of the sensing patterns of semi-wet molecular recognition (MR)
chips of the hydrogel of GalNAc-suc-glu(O-metyl-cyc-hexyl)2 containing (a) 36 (40 µM),
(b) 42 (60 µM)
6
Summary
Fig. 12 a Construction of the hybrid biosensor and fluorescence sensing for the doubly
phosphorylated peptide. b Structure of the chemosensor unit on the hybrid biosensor.
c Amino acid sequences of the WW domain and its mutant
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Struct Bond (2008) 129: 127–174
DOI 10.1007/430_2007_070
© Springer-Verlag Berlin Heidelberg
Published online: 6 November 2007
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172
Abstract Hydrogen bonds and charge–charge interactions have been widely used (either
alone or in combination) in the design of efficient and selective synthetic receptors for
anions. Intuitively, the interaction between anions and π-aromatic systems is associated
with a repulsive force. Consequently, for many years, anion-π interactions have been
completely neglected as favorable non-covalent interactions for the construction of ef-
ficient anion receptors. Recently, however, theoretical studies indicate the existence of
an attractive interaction between anions and certain type of π-acidic aromatic systems.
These theoretical studies together with the observation of supramolecular complexes
in the solid state in which anions are included in deep aromatic cavities have encour-
aged an in depth study of the anion-π interaction. Nowadays, the anion-π interaction
is considered by several researchers a potential non-covalent interaction for the design
of anion receptors. This chapter will provide an overview of recent theoretical investiga-
tions, performed since 2002, on anion binding involving six-membered aromatic rings.
A series of experimental studies, carried out since 2004, also evidencing the existence of
a possible attractive interactions betweens anions and six-membered aromatic moieties
of host-guest systems in the solid state and in solution is also discussed.
Abbreviations
HB Hydrogen bond
RHF Restricted Hartree-Fock
128 P. Ballester
1
Introduction
1 q
V(r) = (1)
4πξ0 r
1 2dq
V(r, θ) = cos θ (2)
4πξ0 r2
The main virtue of the ion–dipole compared to the ion–ion interaction, from
the viewpoint of host–guest chemistry, is its directionality (i.e., the energy of
the interaction of an ion and the dipole depends on their mutual orientation
defined by the θ angle). This translates into a fundamental property to achieve
selective recognition of anions using hydrogen-bonding receptors, that is, the
topology of the targeted anion should be considered when deciding the place-
ment of the hydrogen bond donors in the receptor’s structure. Other virtues
of hydrogen bonding in the design of abiotic receptors for anions derive from
its electroneutrality, from its capacity to form simultaneously several bonding
interactions with the anion and from the rich chemistry available to incorpo-
rate this functionality into the molecular scaffold.
Scheme 1 Preparation of the diazabicycloalkanes and ion pairing in acidic aqueous media
130 P. Ballester
1The researchers working in the area of anion recognition having an inorganic chemistry back-
ground usually refer to the field as anion coordination chemistry
Anions and π-Aromatic Systems. Do They Interact Attractively? 131
tive interactions between negative charges and aryl rings towards the same
end has remained dormant in the literature since they were first noticed by
Scheneider in 1993 [9].
Recently, the studies into the anion-π interaction have intensified and
gained interest among the scientific community. This is due, on the one
hand, to the publication in 2002 of several papers dedicated to exploring the
physical nature of the interaction of anions with aromatic compounds using
electronic structure methods and, on the other hand, to the observation since
2004 of supramolecular complexes in the solid state in which anions are in-
cluded in deep aromatic cavities. Furthermore, the recently noticed fact that
the orientation of negatively charged groups [10] and lone pairs [11] above
the plane of an aromatic is a frequently occurring structural motif in biopoly-
mers has added additional interest to the subject.
At first sight, a stabilizing effect for the interaction between a pair of
electrons or a negative charge and the face of a π system seems to be coun-
terintuitive. Not surprisingly, simple modelling studies indicated a repulsive
interaction between anions and a benzene ring. It is now clear that non-
covalent interaction between aromatics and positively charged cations, the
cation-π interaction, are prominent in a wide variety of systems and should
be considered as an important and general binding force [12]. The cation-
π interactions are expected simply from electrostatic arguments. In fact,
a simple electrostatic model based on the visual inspection of electrostatic
potential surface of the aromatic ring has been used to rationalize the major
binding trends of the cation-π interaction. In line with the principles outlined
above for the preparation of anion receptors through the inversion of the
electronic character of suitable Lewis-basic centers (amine to ammonium),
a possible explanation for the observed geometry that points lone pairs or
places negative charges into the face of the π system has to do with an inver-
sion of the electronic character of the aromatic ring [13].
Theoretical investigations have clearly established the existence of bind-
ing interactions between a negatively charged species and an electron-poor
π system. The theoretical results have encouraged the experimental obser-
Fig. 1 Inversion of the electronic character of Lewis-basic centers: a the lone pair of
an amine is a good binding site for a cation while the protonated ammonium group is
complementary to anions; b the π-system of an electronically rich aromatic compound
establishes attractive interactions with cations (cation-π interaction) the introduction
of electro-withdrawing substituents produces the depletion of electronic density of the
π-system giving rise to attractive interaction with anions
132 P. Ballester
2
Theoretical Investigations of the Interaction of Anions (Halides)
with π Aromatic Systems
Since 2002 several groups have studied in detail the interaction of anions
with electron deficient aromatic rings using theoretical methods. These stud-
ies can be considered to derive from earlier fundamental work carried out
by Dougherty [14], Besnard [15] and Alkorta [16] on the interaction between
hexafluorobenzene and the heteroatom in molecules such as H2 O, HCN and
HF wherein the negative end of the dipole is directed toward the π-system
and aligned with the C6 axis of the ring.
In particular, Alkorta et al. [16] studied the interaction of C6 F6 with
HF using both MP2 and hybrid DFT methods (B3LYP) with 6-31-G∗∗ and
6-311++G∗∗ basis sets. The authors considered that these methods are more
accurate for weak complexes than methods without electron correlation.
A shortening effect in the calculated distance value between the interacting
atom and the centroid of the aromatic ring is clearly observed by the inclusion
of electron correlation (MP2 and B3LYP methods). Thus, for the minimum
structure of the C6 F6 · · ·FH complex the computed distance is 3.076 Å when
using the RHF method and the 6-31G∗∗ basis set and 2.858 Å and 2.814 Å,
respectively, when the B3LYP/6-31G∗∗ and MP2/6-31G∗∗ methodologies are
applied. The use of a more extended basis set B3LYP/6-311++G∗∗ produces
a larger elongation of the same distance to 3.127 Å while the calculated bind-
ing energy at this level of theory and basis set for the C6 F6 · · ·FH complex is
2 Complexes in which the anion is one component of an aromatic ring sandwich complex are out-
side of the scope of this chapter. Likewise, examples for the interaction of anions with five and seven
membered aromatic rings will not be presented
Anions and π-Aromatic Systems. Do They Interact Attractively? 133
Fig. 2 Schematic representation of the geometry of the complexes of water, HCN, and HF
with C6 H6
∆EBSSE = 1.23 kcal mol–13 . The interaction energy of the C6 F6 · · ·FH complex
is similar to the one observed in the formation of weak hydrogen bonds.
Several years later, in 2002, Mascal et al. [17], Alkorta et al. [18] and
Frontera, Deyà et al. [19] reported almost simultaneously the theoretical
demonstration of the existence of an attractive interaction between a formally
charged negative species and the π-system of an aromatic ring.
Mascal et al. [17] performed ab initio orbital calculations at the MP2
level of theory with the 6-31+G∗ basis set, including counterpoise correc-
tions for the basis set superposition error (BSSE), for the interaction of
both 1,3,5-triazine and trifluoro-1,3,5-triazine with chloride and fluoride. The
molecular electrostatic potential (MEP)4 maps of 1,3,5-triazine and trifluoro-
1,3,5-triazine clearly indicate an area of positive density concentrated on the
C3 rotational axis passing through the center of the hexagonal ring and being
perpendicular to the plane of the aromatic ring, similar to that observed for
C6 H6 on the C6 rotational axis.
Optimization from geometries that place the chloride near the area of
positive density found on the C3 rotational axis of 1,3,5-triazine demon-
3 BSSE stands for Basis Set Superposition Error and the interaction energies are corrected for this
inherent error
4 The MEP maps have been used for long time as a tool to identify both nucleophilic and elec-
trophilic regions in a molecule
134 P. Ballester
strated the existence of an attractive interaction between the chloride and the
π-system. The optimized structure obtained for the chloride-1,3,5-triazine
complex positioned the chloride anion exactly on the C3 rotational axis of the
1,3,5-triazine (Φ = 90) and at a distance of 3.2 Å of the aryl centroid. The fact
that the structure of the complex was a minimum was confirmed by calculat-
ing the corresponding frequencies (no negative vibrational frequencies were
found). The MP2/6-31+G∗ energy calculated for the geometry of the chloride-
aryl-centroid complex optimized using the same level of theory and basis set
was ∆EBSSE –1
0 K =– 4.8 kcal mol .
Mascal et al. [17] also located another geometry for the complexation of
the chloride and bromide anion with 1,3,5-triazine. This geometry is also
a minimum and involves a C – H· · ·Cl– hydrogen bond. The formed hydro-
gen bond shows good geometrical characteristics, having a C· · ·Cl– distance
of 3.4 Å and a C – H· · ·Cl– angle of 180◦ . The calculated MP2/6-31+G∗ en-
ergy of this interaction geometry optimized at the same level of theory and
basis set was ∆EBSSE –1 –1
0 K =– 7.4 kcal mol , that is 2.6 kcal mol more stable than
chloride-aryl centroid complex discussed above. The authors clearly state that
although the participation of ions in gas phase chemistry yields interaction
energies which seem to be exaggerated when compared to solution values,
the reported energies of these interactions may still be relevant in the inte-
rior of a receptor. The authors used the trifluoro-1,3,5-triazine as a model
to evaluate the extent to which further electron withdrawal in the triazine
Fig. 4 Side and top views of the minimized structures at the MP2/6-31+G∗ level of a the
triazine chloride aryl centroid complex and b the triazine chloride hydrogen-bonding
complex. The triazine and the chloride are shown in a scaled ball-and-stick representation
Anions and π-Aromatic Systems. Do They Interact Attractively? 135
Fig. 5 Side view and top view of the “attack” structure for the fluoride 1,3,5-triazine
complex
high energy and close interaction distance computed for the Cl– -trifluoro-
1,3,5-triazine complex is comparable to those of the potassium cation-π com-
plexes of benzene calculated at the same level of theory [20, 21]5 .
The corresponding fluoride-aryl centroid complexes with 1,3,5-triazine
and trifluoro-1,3,5-triazine are characterized by the presence of one negative
vibrational frequency and represent a shallow inflection point on a surface
connecting to a second geometry, the so-called “attack” structure which is
a real minimum structure. This structure was suggestive of a reactant com-
plex with the nucleophilic fluoride anion “attacking” one of the carbon atoms
with close to the Bürgi-Dunitz trajectory [22, 23]. The considerable stabiliza-
tion energy of the “attack” structure (∆EBSSE –1
0 K =– 18 kcal mol , r = 1.5 Å and
◦
θ = 106.6 ) together with the distance values for the C· · ·F interaction and the
lengthening of the adjacent C – N bonds points to a strong σ -complex.
5 Na+ · · ·C6 H6 interaction E0 = –15.0 kcal mol–1 , r=2.84 Å. K+ · · ·C6 H6 interaction E0 =–18.3 kcal mol–1
136 P. Ballester
The calculated energies for these interactions fall off sharply with increas-
ing polarity of the medium. The simple comparison of uncorrected MP2
single point energies of chloride-aryl centroid complex with triazine, using
Tomasi’s Polarized Continuum solvent Model (PCM), gas phase (–8.5), hep-
tane (–0.4), chloroform (2.1), ethanol (2.8), and finally water (3.2 kcal mol–1 )
suggest that the practical manifestation of these forces will be most likely in
the context of anion containment.
Alkorta et al. [18] studied the complexes formed by a variety of anions
with perfluoro derivatives of benzene, naphthalene, tiophene and furan using
DFT (B3LYP/6-31++G∗∗ ) and MP2 (MP2/6-31++G∗ and MP2/6-311++G∗∗ )
ab initio methods.
The minimum structures of hexafluorobenzene with chloride and bromide
show the anion interacting with the π-system with an anion-aryl centroid
geometry. In both cases, a C6v symmetry was assumed during the optimiza-
tion procedure. However, the C6 H6 · · ·F– complex structure that locates the
anion on the C6 symmetry axis and on top of the aromatic ring (r = 2.5 Å)
shows two degenerate imaginary frequencies. In this case, the minimum
structure corresponds to an “attack” geometry similarly to the interaction of
fluoride with 1,3,5-triazine discussed above.
The calculated interaction energy values for the anion-aryl centroid geom-
etry range between –18.7 and –12.19 kcal mol–1 , which is comparable, as
mentioned above, to the interaction energy of some benzene-cation com-
plexes [20, 21].
The centroid-to-anion distance varies from 2.554 to 3.230 Å (see Table 1).
The effects of the complexation of the anion to the C6 F6 molecule are short-
ening of the C – C bonds (0.004 Å) and a lengthening of the C – F bonds
(0.006 Å). On complexation, the fluorine atoms move slightly towards the
anion and the plane formed by the carbon atoms is about 0.02 Å further
away from the anion than that formed by the fluorine atoms. The hexafluoro-
benzene molecule adopts a “cup” conformation.
Non-covalent interactions have been characterized using Bader’s theory of
“Atoms In Molecules” (AIM) [24] which has been used successfully to under-
Fig. 7 Schematic representation of the location of a bond (red), a ring (blue) and the cage
critical point (black) originated from the interaction of hexafluorobenzene with fluoride
stand conventional [25] hydrogen bonds and cation-π interactions [26]. The
AIM analysis of the electron density of these complexes (C6 F6 · · ·X– , X = F, Cl,
Br) carried out by Alkorta et al. [18] indicated the formation of six degenerate
bond critical points (bcp) between the anion and each of the carbon atoms of
the C6 F6 molecule in a similar way to what was observed for the C6 F6 · · ·X – Y
neutral complexes [16] and the C6 F6 · · ·Na+ complex [20]. In addition, six-
ring critical points (rcp) and one cage critical point (ccp) are generated. The
rcp connect the anion with the middle of the C – C bond. The ccp is located
over the hexafluorobenzene molecules along the C6 axis, connecting the an-
ion with the center of the ring. The quantitative values for ρ and ∇ 2 ρ at the
cps give a hint on the character and strength of the interaction. The values of
electron density of the new bcp and its corresponding rcp are almost the same
values. The positive and small value of the Laplacian of the bcps indicates
a depletion of the electron density, as is common in closed shell interactions
like those found in hydrogen bonds, ionic and cation-π interactions.
Table 2 Corrected interaction energy at the MP2/6-31++G∗ level (kcal mol–1 ) and electro-
static, polarization and van der Waals contribution (kcal mol–1 ) to the interaction energy
calculated using GMIPp method
Table 3 Interaction energies with (∆EBSSE , ∆EBSSE 0K kcal mol–1 ) and without (∆E,
kcal mol–1 ) the basis set superposition error (BSSE) and zero-point vibrational energy
correction (ZPE, 0 K) and equilibrium distances (r/Å) at HF/6-31G++G∗∗ and MP2/6-
31++G∗∗ (italics) levels of theory and selected electron-density topological properties for
the complexes of hexafluorobenzene with anions from reference [19]
Table 4 Contribution to the total interaction energy (kcal mol) calculated with MIPp for
hexafluorobenzene interacting with F– at several distances (Å) from the center of the ring
Fig. 8 Schematic representation (top and side view) of the positive molecular quadrupole
moment of C6 F6 as cylinders with positive charges on the ends and negative charges in
the center
static (Eele ), polarization (Epol ), van der Waals (Evdw ), and total interacting
energies were calculated when a fluorine ion approaches the hexafluoroben-
zene molecule perpendicular to the center of the aromatic ring. The obtained
results point out the importance of the polarization component, which is
similar to the electrostatic term in the 2.0 to 3.0 Å range, the equilibrium dis-
tance for the fluoride aryl centroid complex is 2.6 Å. The authors mention the
importance of the quadrupole moment for understanding intermolecular in-
teractions of aromatic system but they do not elaborate on this issue in this
work.
To date, most of the work reported on anion-π interactions using theor-
etical methods is between anions and electron deficient aromatics rings, i.e.,
hexaflurorobenzene, 1,3,5-trinitrobenzene, and 1,3,5-triazine. The electron-
deficient aromatic rings are also called π-acidic aromatic rings and are char-
acterized by having a permanent positive quadrupole moment value Qzz . The
value of the quadrupole moment is a measure of the distribution of charge
within a molecule, relative to a particular axis. In six-membered aromatic
rings, the Qzz quadrupole measures the distribution of charge relative to the
C6 rotational axis passing through the center of the hexagonal ring and be-
ing perpendicular to the plane of the aromatic ring. When the ring presents
a high degree of symmetry, one may relate the distribution of charge with re-
spect to the axis perpendicular to the aromatic plain to that along the main
rotational axis and gain a quick characterization of the charge distribution in
the molecule [30]. The SI value of the electric quadrupole moment of hex-
afluorobenzene is 31.7 × 10–40 C m2 (Qzz =+ 9.5 B); 1 B (Buckingham)6 . The
schematic representation of such a molecule as two like positive charges,
through which the main rotational axis (C6 ), passes, separated by the oppo-
site, balancing negative charges lying perpendicular to the main rotational
axis gives a clear picture of its molecular positive quadrupole value.
Topologically, the quadrupoles can be considered equivalent to d orbitals, as
dipoles are to p orbital [12]. In particular, the Qzz quadrupole of six-membered
6Debye suggested in the 1960s that the quantity 1 unit of charge distributed over 1 Å2 be termed
the Buckingham
Anions and π-Aromatic Systems. Do They Interact Attractively? 141
Fig. 9 Plot of the regressions between the quadrupole moments and molecular polariz-
abilities to: a the electrostatic contribution, b polarization contribution and c van der
Waals contribution of the total interaction energy calculated with MIPp for the com-
pounds interacting with chloride at the minimum. d Plot of the regression between the
quadrupole moments to the interaction energy at the MP2/6-31++G∗∗ level of theory for
the compounds interacting with chloride at the minimum. From reference [31]
Anions and π-Aromatic Systems. Do They Interact Attractively? 143
ical studies although sometimes the major component of the binding energy
could be “non-electrostatic”. It is worth to note that across a series of aromat-
ics compound having quadrupole moment values from Qzz = 8.23 to 0.57 B
the “non-electrostatic” component of the interaction energy (Epol + EvdW )
makes a contribution of –3 to –7 kcal mol–1 . The binding energy of the anion-
π interaction decreases slightly with the increase of the ionic radius of the
anions which is also consistent with an electrostatic model.
Kim et al. [32] also studied the nature of the anion-π interactions using
the symmetry-adapted perturbation theory (SAPT) [33] to obtain a physi-
cal interpretation of the interaction energy. In this method, the interaction
energy is expressed as a sum of perturbative corrections in which each
correction results from a different physical effect. The different intermole-
cular terms obtained from this method can be summarized in electrostatic,
exchange-repulsion, induction, and dispersion contribution. The authors
show that for different halogen complexes with several π systems the elec-
trostatic term follows the same trend as the total interaction energy. This
tendency can be explained by taking in consideration the fact that both dis-
persion and induction energies can be ascribed, to a large extent, to the
interaction of the molecular orbitals of the anion and the π system. The at-
tractive dispersion and induction energies increase as the diffuse electron
cloud of the anion interacts with the substrate. The repulsive exchange inter-
action also depends on the molecular orbitals overlap. This has the effect of
establishing a balance between dispersion-induction and exchange-repulsion
energies resulting in a good correlation between the electrostatic energy and
the total interaction energy. One of the main conclusions of Kim’s work is
that the total interaction energies calculated for the anion-π complexes are
comparable to those obtained for the cation-π complexes. This is a funda-
mental statement also mentioned in other theoretical studies, if one wants
to hypothesise on the strength and importance of the anion-π interaction
in solution. It has been possible to estimate an energy value in the range of
–2 to –0.5 kcal mol–1 for a single cation-π interaction using supramolecular
model systems [34–36] and protein engineering studies [37]. As complement
to these experimental studies, other experimental gas-phase measurements
and high-level theoretical studies have been used to assign a binding energy
of approximately –10 kcal mol–1 for the interaction of tetramethylammonium
with benzene in the absence of solvent [12].
Frontera and Deyà [38] warn that although it is true that the interac-
tion energies of benzene with cations and hexafluorobenzene with anions
are similar, it is not possible to generalize that the interaction energies cal-
culated for the anion-π complexes are comparable to those obtained for the
cation-π complexes. These authors also indicate that the same is applicable to
Kim’s conclusion stating that the largest contribution in anion-π complexes
are electrostatic and induction, because as we have seen before, these con-
tributions sharply depend of the Qzz and α|| values of the aromatic system.
144 P. Ballester
Molecules with negligible Qzz values are expected to interact favorably with
either anions or cations, and the strength of the interaction would be com-
parable, especially if the ionic van der Waals radii of the charged species are
similar. Other conclusions from the work by Frontera and Deyà [38] com-
paring different aspects of the cation-π and anion-π interactions are: a) the
contribution of dispersion and correlation terms to the total interaction en-
ergy are small, but they are more important in anion-π complexes, b) the
density at the cage critical point generated upon complexation of the ion
is a useful parameter for measuring the strength of the interaction, even
when comparing anion-π to cation-π complexes, and c) a gain in aromatic-
ity of the ring is observed, based on the nucleus-independent chemical shift
(NICS) [39] criterion at the center of the ring, upon complexation of the an-
ion, and the contrary is observed for the cation. Many authors agree that the
contribution from the dispersion energy is more important in the anion-π
complexes than in the cation-π interaction. The induction energy emerges
from the interaction of the occupied p orbital of the halide anion and the
LUMO of the π-system. The inductive type of the MO interaction can also
be correlated to the extent of charge transfer from the anion to the π sys-
tem. In fact, several experimental studies have established a charge-transfer
character to anion-π complexes (see below). The degree of charge transfer
in several anion-π complexes has been evaluated using different quantum
chemical approaches. The computed charge transfer reported in the work of
Frontera and Deyà from the anion (F– ) to the π-system is in the range of 0.1 to
0.2|e| and 0.005 to 0.14|e| in Kim’s study. The results based on AIM method-
ology indicate that the charge transfer is almost negligible for all complexes
studied.
Complex ∆E ∆EBSSE r
Fig. 10 Schematic geometries of the anion-π complexes studied by Frontera and Deyà [38]
The additivity of the anion-π interactions has also been explored by Fron-
tera and Deyà using high-level ab initio calculations [38]. They optimized
chloride and bromide complexes with one, two, and three aromatic units,
such as trifluoro-1,3,5-triazine (TFZ) and 1,3,5-triazine (TAZ) – and analyzed
the interaction using the AIM theory and studied the charge transfer using
several methods for deriving atomic charges. The results revealed additivities
in the binding energies and complex geometries that are almost insensitive
Table 6 Computed binding energies (∆E, kcal mol–1 ) for TFZ complexes with chloride
simulating two solvents and in the gas phase at the MP2(full)/6-31++G∗∗ /RI-MP2(full)/
6-31++G∗∗ level of theory
Fig. 12 CAChe optimized structure of the chloride complex based on the receptor
proposed by Frontera and Deyà [38]. The receptor binds the anion via four anion-π
interactions
Fig. 13 Molecular structures of the anion receptors proposed by Mascal [13]. The anion is
bound by a combination of three ion-pair reinforced hydrogen-bonding and two anion-π
interactions
Anions and π-Aromatic Systems. Do They Interact Attractively? 147
Table 7 Interaction energies (kcal mol–1 ) for the complexes of the triazine cages (TAZ)
and its analogues cyanuric acid (CNA) and boroxine (BOX) with fluoride and chloride
ion
a a
Complex ∆EBSSE ∆EF–Cl b ∆EBSSE
H2 O ∆EF–Cl(H2 O) b
The binding properties of the halide complexes (F– , Cl– ) were evaluated
in the gas phase and solution. Energies were also determined using the
conductor-like polarisable continuum model for water, with the molecular
cavity specified by the United Atom Topological Model applied on radii op-
timized for the PBE0/6-31g(d) level of theory. The complexation of fluoride
with the three receptors is calculated to be more energetically favorable than
chloride by >40 kcal mol–1 in the gas phase and >13 kcal mol–1 in water. It is
worth noting that the complexation energies calculated for F– ion are about
three times the experimental enthalpy of F– hydration. The author indicates
that the raw comparison of these values is of limited predictive significance
in regard to the potential of these receptors to extract F– from water, given
the absence of activation and entropy values, as well as, the assumptions in-
herent to nonexplicit, polarized continuum models of water. The comparison
of relative energetics of complexation, however, clearly indicates a preference
for fluoride binding over chloride, from the gas phase to water, in all three
receptors (see Table 7).
The principal interaction force in these complexes is the ion-pair rein-
forced hydrogen bond of the ammonium groups with the anions. It may be
supposed that the intrinsic stronger ammonium· · ·F– interaction could actu-
ally form the basis for the difference in binding energy. The isolation of the
relative binding contributions (ion-pair reinforced hydrogen bond and anion-
π interactions) was achieved by modelling the association of three NH4 + ions
in a trigonal plane around a chloride and fluoride ions. The obtained results
are shown in Table 8.
The high differences in binding energies calculated for the cage complexes
and the modelled NH4 + trigonal systems are clearly due to the fact that the
three ammonium groups are enforced in close proximity in the free recep-
tor. The point to note is that although the stabilization of three NH· · ·F–
bonds in the trigonal (NH4 + )3 · · ·F– complex is about 11 kcal mol–1 greater
than the corresponding (NH4 + )3 · · ·Cl– complex, in the triazine and cyanuric
acid cage complexes there is still >10 kcal mol–1 “additional” stability in the
fluoride complexes in aqueous solution. This observation suggests that the
discrimination has to do with a better fit of the anion at least in these two
a a
Aggregate ∆EBSSE ∆EF–Cl b ∆EBSSE
H2 O ∆EF–Cl(H2 O)
Table 9 Interaction energies (kcal mol–1 ) and noncovalent bonded distances for selected
complexes of 1,3,5-triazine (TAZ) and boroxine (BOX) with chloride and fluoride anions
a
Complex ∆E a ∆EBSSE ∆EF–Cl b rc
Table 10 Calculated interaction energies (kcal mol–1 ) of the investigated tweezer-ion com-
plexes
Fig. 15 Schematic representations of the geometries for Cl– complexes with TCBm
the aromatics substituents. The work concludes indicating that even electron
rich, negative Qzz aromatics should be considered experimentally tenable for
anion-π interactions. We believe that this statement should be taken with
serious caution.
Johnson, Hay et al. [45] have refined the nature of the interactions be-
tween electron deficient arenes and halide anions. In particular, they have
performed calculations at the MP2/aug-cc-pVDZ level of theory of 1 : 1 com-
plex formed between 1,2,4,5-tetracyanobenzene (TCB) and F– , Cl– , Br– an-
ions. Four geometries were evaluated for each halide. The well-known anion-
aryl centroid (A) (termed non-covalent anion-π complex in this study), two
charge transfer (CT) complexes in which the halide is positioned above
a C – H bond (B) or above a C – CN bond (C), and a C – H hydrogen bond
complex (D) similar to the one already discussed by Mascal in his seminal
study of the interaction of triazine with halide anions [17]. The theoretical
analysis of TCB halide complexes revealed the first example in which non-
covalent anion-aryl centroid complexes are not stable for Cl– and Br– . These
halides do interact with the π system, but the interaction involves CT, char-
acterized by a high second-order stabilization energy ∆E(2) . The resulting
optimized geometries of the CT complexes locate the anion over the periph-
ery ring rather than over the center of the ring.
Since as we have presented above prior computational studies on Cl– and
–
Br have focused almost exclusively on the anion-aryl centroid complex, there
has been no investigation to determine the existence of such CT complexes
for other arenes. Consequently, the authors expand the electronic structure
calculations to halide complexes with triazine, hexafluorobenzene and 1,3,5-
152 P. Ballester
Fig. 16 Calculated EPS at the HF-6-31G level for TCB. The range of energy values is
–39 (red) to +39 (blue) kcal mol–1
tricyanobenzene. The results with F– and triazine are fully consistent with
earlier work [17]. Although the anion-aryl centroid and hydrogen-bonding
geometries have been previously identified as minima for Cl– and Br– [17],
none of the previous studies report the existence of an “attack” geometry
for either Cl– or Br– only for F– . Two geometries were located for hexafluo-
robenzene, the anion-aryl centroid which is not a stable point for F– and the
“attack” geometry that is the global minimum for F– but was not located as
a stable point for Cl– or Br– . These results are in complete agreement with
prior theoretical studies [18, 19]. Results obtained for 1,3,5-tricyanobenzene
are similar to those obtained for TCB. The anion-aryl centroid geometry is
only stable for Br– . The CT complex that locates the anion above a C – H bond
is the global minimum for the three halides. The hydrogen bond geometry is
also a stable structure for all the halides. All anion-aryl centroid complexes
have a low extend of charge transfer. Alternate geometries do have a high
extend of charge transfer. It is worth noting that for the interaction of F–
with triazine in the “attack” geometry, the computed values for the param-
eters used to gauge the extent of charge transfer, indicate the formation of
a strong σ bond. In conclusion, triazine, TCB and 1,3,5-tricyanobenzene form
stable off-center CT complexes with Cl– and Br– . Except for the CT complex
of Br– with triazine, the CT complexes are more stable than the anion-aryl
centroid complexes. The differences in energies, however, are very small
(<1 kcal mol–1 ), indicating a relative flat potential surface for positioning the
halide above the arene plane. In fact, the EPS of TCB shows a widespread
distribution of positive electrostatic potential values all over the π-system.
3
Experimental Evidence of the Anion-π Interaction
3.1
Solution and Related Crystallographic Studies
To the best of our knowledge, the first report suggesting the experimen-
tal existence of attractive interactions between anionic negative charges and
π-electron aromatic systems was published by Schneider et al. in 1993 [9].
The 1 H NMR measurement of the association constant between a simple
Anions and π-Aromatic Systems. Do They Interact Attractively? 153
Fig. 17 Schematic representation of the complex formed with the cleft-like para-sulfonato
receptor and diphenylamine placing the ionic part above the aromatic guest center
Fig. 19 Mulliken dependence of the energy of the low-energy absorption band (νCT ) in
the TCP/Hal– complexes and the oxidation potential of the anion
Anions and π-Aromatic Systems. Do They Interact Attractively? 155
are 3.45 Å (Cl– · · · C), 3.55 Å (Br– · · · C), and 3.65 Å (I– · · · C)
b The average of the distances to the two or three neighbouring acceptors is given
stant values calculated for the complexes formed in acetonitrile with TCP and
Br– as different tetraalkylammonium salts are in the range of 7–9 M–1 . Fur-
thermore, a job plot indicates a 1 : 1 stoichiometry for the TCP/Br– complex
formed in solution. A clear correlation between the energy of the low-energy
band and the oxidation potential of the anion was also observed and used to
establish a charge-transfer character for the complexes.
Furthermore, the study of the interaction of Br– with the series of neu-
tral organic π-acceptor reveals that the increase of acceptor strength of the
aromatic (characterized by a positive shift of the reduction potential) is ac-
companied by a bathochromic shift of the new absorption band (from 355 to
465 nm). This observation further confirms the charge-transfer (CT) charac-
ter of these complexes.
The isolation and X-ray characterization of single crystals containing the
halide salt and the aromatic compound allows the identification in the solid-
state of the non-covalent anion-π complexes. The anion is located in the space
Fig. 20 Local packing of the solid-state structures of the Br– complexes with TCP. Left:
Bromide used as tetraethylammonium salt. Right: Bromide used as tetrabutylammonium
salt. Only molecules that are in short contact (< sum of vdw radii) with respect to the Br–
atom are shown. In the case of the [(TCP)3(Br– )2 ](Et4 N+ )2 complex, the two different Br–
ions located within the asymmetric unit are represented
156 P. Ballester
close to the electron deficient aromatic ring explaining the observed elec-
tronic (charge-transfer) transitions. The bromide ion lies approximately 3 Å
over the periphery of the aromatic ring. The observed complex geometry dif-
fers from those derived from quantum-mechanical calculations that usually
show the anion placed along an axis perpendicular to the aromatic ring and
passing through its centroid. The existence of multiple halide-π interactions
becomes evident either directly in the asymmetric unit or after the packing
of the lattice. The complex stoichiometries that can be derived from the X-ray
molecular formula of the asymmetric unit i.e., [(TCP)3 (Br– )2 ](Et4 N+ )2 (1.5 :
1), [(TCP)4 Br– ]Pr4 N+ (4 : 1) and [(TCP)I– ]Bu4 N+ (1 : 1), [(TCP)2 I– ]Et4 N+
(2 : 1), as well as, the number of contacts established between the anion and
the aromatic rings seems to be controlled not only by the anion itself but by
the size of its countercation, which should influence the three-dimensional
solid structure.
Johnson, Hay et al. [45] have used 1,2,4,5-tetracyanobenzene (TCB) to
gain further structural information of the anion-π interaction. TCP, 18-
crown-6 and alkali halide were dissolved in acetonitrile (KBr) or 9 : 1
dichloromethane:acetonitrile (KI, NaI) mixture. The purpose of the crown
ether is to enhance the solubility of the salt. It is important to note that the
solution of the crown ether and TCB is colorless, however, the addition of the
halide salt produces a color change consistent with the formation of CT com-
plexes and in complete agreement with Kochi’s previous observation using
TCP instead. Slow evaporation at room temperature yielded single crystals
suitable for X-ray analysis. Despite packing differences, the local environment
about each halide is remarkably similar in all crystals. As shown in Fig. 21,
four TCB molecules surround the anion at interaction distances. Three dif-
ferent orientations can be distinguished for the anion: above the arene plane
nearest to a C atom bearing a CN group (a and b), above the arene plane near-
est to a C atom bearing a H atom (c), and nearly within the plane of the arene,
forming a C – H hydrogen bond (d). This latter orientation was not observed
in the study of Kochi. In conclusion, Kochi’s and Johnson’s results clearly
Fig. 21 Local packing of four TCB molecules around the anion. The closest contact to each
arene is indicated by a dotted black line
Anions and π-Aromatic Systems. Do They Interact Attractively? 157
show that the anions are not located over the center of the arene (anion-aryl
centroid geometry) in the solid state structures of these complexes. As dis-
cussed above, theoretical studies indicate that TCB and 1,3,5-tricyanobenzene
are capable of forming stable off-center CT complexes with Cl– and Br– .
In 2003, Hoffmann et al. [49] introduced an uncharged host for the selec-
tive binding of Cl– as the tetrabutylammonium salt in CDCl3 : DMSO 95 : 5
– /K – = 105). This host features a triazine-trione platform with three short
(KCl Br
arms that are conformationally preorganized through the introduction of
methyl groups. The three arms are equipped with p-nitrophenylsulfonamide
groups capable of hydrogen-bonding to the anion. In this study, they also used
an analogous receptor with slightly longer side chains in order to evaluate
how the relative position of the anionic host with respect to the triazine-trione
platform (anion-π interaction) could affect the stability of the complex.
The binding parameters of both hosts with chloride were determined
using isothermal titration calorimetry. The microcalorimetry experiments re-
Fig. 22 Molecular structures of the receptors based on the triazine-trione platform hav-
ing three arms of different length terminated with p-nitrosulfonamide hydrogen-bonding
groups
Table 12 Thermodynamic binding parameters determined using ITC for the complexation
of tetrabutylammonium chloride by the tris-sulfonamides in CHCl3 at 298 K
vealed that the host with the longer arms binds chloride slightly stronger that
the one with the shorter arms (∆∆G ≈ 0.4 kcal mol–1 ).
There are, however, more important differences in the binding processes
of the hosts to the tetrabutylammonium chloride. Although both complex-
ation processes of chloride by the hosts are entropically favored, due to the
release upon binding of ordered solvent molecules from the surface of the
chloride and the host to the bulk, the entropic change (– T∆S) for the host
with longer arms is far less negative. This result may be the consequence of
a higher reduction in the rotational entropy of the host with the long arms on
complex formation. In terms of enthalpy, the binding of chloride by the host
with short arms is clearly less exothermic. In order to explain the observed
result, the authors speculate about the relationship between complex geom-
etry and enthalpy. The more flexible host could adopt a conformation that is
more optimal for coordination of chloride giving rise to higher exothermic-
ity. Furthermore, they conclude that from the measured enthalpy values of
complexation a potential electrostatic attraction of chloride by the triazine-
trione platform in the receptor with the short arms, an anion-π interaction,
can be discarded. We believe that the thermodynamic parameters measured
for the chloride complexation with these systems are highly contaminated
with solvent effects. If the number of solvent molecules released to the bulk
on complexation is different for each host, then the comparison of the data is
completely inappropriate. In terms of free energy of binding, the experimen-
tal results indicate that both chloride complexes formed with the two triden-
tate p-nitrophenylsulfonamide hosts have approximately the same binding
energy and the potential electrostatic attraction of chloride by the triazine-
trione (cyanuric) platform is not reflected.
In 2005, Frontera, Saczewski, Deyà et al. [50] performed a combined
crystallographic and computational study of the anion-π interactions with
Fig. 23 Minimized structures (Maestro, MMFFF) of the chloride complexes formed with
the tridentate p-nitrophenylsulfonamide having long and short arms. The distance of the
chloride atoms to the centroid of the cyanuric acid ring is shown in each case
Anions and π-Aromatic Systems. Do They Interact Attractively? 159
Fig. 24 Synthesis of the halide salts of the 2-ethyleneamine derivatives of thio- and dithio-
cyanuric acid
cyanuric acids [50]. These authors interpreted the experimental results pre-
viously obtained by Hoffmann et al. making use of MIPp calculations. The
MIPp value for the interaction of cyanuric acid with a chloride anion placed
2.5 Å apart from the ring centroid is almost the same to that computed at
a distance of 3.5 Å (≈–16 kcal mol–1 ). Consequently, a likely explanation for
the similarity of free energies of complexation measured experimentally with
long or short arms tridentate p-nitrophenylsulfonamide hosts is that the ef-
fect of the cyanuric platform on the anion binding is similar and does not
allow to differentiate one with respect to the other.
To obtain experimental evidences of the ability of cyanuric acid to interact
favorable with anions, Frontera, Saczewski, Deyà et al. [50] synthesized
several derivatives of thiocyanuric and dithiocyanuric acid with a flexible
2-ethyleneamine arm attached to the s-triazine ring. The one-step synthesis
of these compounds requires a 1–4 h reflux in aqueous 12% HX (X = Cl, Br,
Fig. 25 Top view and side view of the local packing of the chloride in the crystal structure
of the hydrochloride salt of the 2-ethyleneamine thiocyanuric acid derivative
160 P. Ballester
Fig. 26 Top view and side view of the local packing of the chloride in the crystal structure
of the hydrochloride salt of the 2-ethyleneamine dithiocyanuric acid derivative
Fig. 27 Top view and side view of the local packing of the bromide in the crystal structure
of the hydrochloride salt of the 2-ethyleneamine dithiocyanuric acid derivative
Fig. 28 Top view and side view of the local packing of the iodide in the crystal structure
of the hydrochloride salt of the 2-ethyleneamine dithiocyanuric acid derivative
The X-ray crystal structures of all the hydrohalide salts except the hydro-
bromide of the thiocyanuric acid derivative revealed the existence of anion-π
interactions. The organic cation, which has several hydrogen-bond donor and
acceptor functionalities, displays an electrostatic interaction between the N
atom of the ammonium moiety and an anion (X– ) located nearly above the
center of the electron-deficient ring. The packing of the lattice reveals that the
anion (X– ) placed on top of the aromatic rings also interacts electrostatically
with at least one ammonium group of an adjacent cyanuric acid derivative.
Additionally, one of the NH groups of the s-triazine ring of another adjacent
organic cation binds the anion (X– ) through a hydrogen-bond interaction.
Finally, two other molecules of the organic cation are also surrounding the
anion. One of them has the 2-ethyleneamine arm positioned at short contact
of the anion (distance < sum of vdW radii).
The distance between the ring centroid and the chloride anion is 0.1 Å
longer in the dithione than in the monothione derivative. In conclusion, the
X-ray structures of the halide salts of mono- and dithiocyanuric acid deriva-
tives having an ethylenenammonium arm attached to one of the nitrogen
atoms of the s-triazine do show the existence of anion-π accompanied by salt-
bridge and hydrogen-bonding interactions as a robust structural motif of the
solid-state packing.
In an attempt to probe the efficacy of the non-covalent anion-π interac-
tion, Johnson et al. [51] have prepared two sulfonamide-derived receptors
(A and B in Fig. 29). The design of the receptor is based on a convergent
two-point recognition motif utilizing both a hydrogen bond and an aromatic
ring that can be involved in the formation of anion-π interactions. The pre-
pared receptors differ in the electronic properties of one of the rings of the
biphenylamino moiety due to the substitution with five fluorine atoms. The
quadrupole moment of such an aromatic ring should be highly positive while
the simple phenyl should have a negative quadrupole moment.
Receptor B has a pentafluoro substituted aromatic ring that is electron-
deficient and more appropriate to engage in an attractive anion-π interaction.
Fig. 29 Molecular structures of the receptors used by Johnson et al. to evaluate the anion-
π interaction in solution
162 P. Ballester
Table 13 Ka (M–1 ) for the sulfonamide receptors with Cl– , Br– and I–
Cl– <1 30 ± 3
Br– <1 20 ± 2
I– <1 34 ± 6
The stability constants of the complex formed with receptor B and a series
of anions (Cl– , Br– , I– ) were evaluated in CDCl3 using NMR titration tech-
niques. Receptor B binds all the screened halides with a measurable but mod-
est association constant. The association constants measured were 20 M–1 for
Fig. 31 X-ray crystal structure of the complex formed between the pentafluorophenyl
receptor B and tetra-n-butylammonium bromide. The sulfonamide receptor and the or-
ganic cation are shown in stick representation while the bromide is represented with van
der Waals surface
Anions and π-Aromatic Systems. Do They Interact Attractively? 163
Br– , 30 M–1 for Cl– and 34 M–1 for I– . On the other hand, the association
constant for receptor A lacking the electron-deficient aromatic ring required
for the anion-π interaction, were too small to be determined using the same
titration methodology. The enhanced affinity exhibited by receptor B over re-
ceptor A with the array of halides is attributed to the existence of anion-π
interaction in the anion complex.
The experiments presented by Johnson et al. support further studies on
the possible use of the anion-π interaction as an emerging no covalent inter-
action of the selective targeting of anions in solution. The difference in the
reported stability constants (∆∆G) can be used to estimate a value for the
anion-π interaction in the range of approximately –2 kcal mol–1 . This value
almost doubles the value estimated for the cation-π interaction using pro-
tein engineering [37] (–2.75 kcal mol–1 for a cavity lined by three π-systems
– 2.75/3 = 0.9 kcal mol–1 ) and supramolecular chemical model systems [35]
(–2.4 kcal mol–1 for a receptor with four π-systems – 2.4/4 = 0.6 kcal mol–1 ).
Probably, the anion-π interaction is over-evaluated when using the chem-
ical model based on sulfonamides. Johnson et al. performed the 1 H NMR
titrations experiments in CHCl3 , and the literature indicates that tetraalky-
lammonium salts form tight ion pairs with small anions, i.e., Cl– in CHCl3
solutions [34, 52]. Consequently, the sulfonamide receptors bind the tight
ion-pair and the observed enhancement of the association constants for the
pentafluorophenyl receptors could be partially caused due to the existence of
electrostatic interactions between the fluorine atoms and the tetraalkylam-
monium salt. The X-ray crystal structure of the pentafluorophenyl receptor
and tetra-n-butylammonium bromide, in which the ion-pairing in the solid
state is held responsible to force the sulfonamide NH away from the preferred
conformation, shows close contacts between the fluorine atoms and the or-
ganic cation (Fig. 21).
3.2
Further Crystallographic Evidence of Anion-π Interactions
Fig. 32 Left: molecular structure of the ligand (L). Right: side view and top view of the
copper(II) chloride complex, few solvent molecules, some hydrogen and chloride atoms
are omitted for clarity. The atoms Cl(8) and Cl(5) are shown in CPK representation. Spe-
cial emphasis is placed on the location of these two atoms in relation to the triazine ring
of the cationic moiety of the complex [L2 (CuCl)3]3+
Fig. 33 Side view and top view of a fragment of the crystal structure of the Cl– complex
reported by Meyer. The six hydrogen-bonding interactions with the aryl C – H groups of
the Cu(II) coordinated pyridine rings are indicated. C – H· · ·Cl– angles ≥150◦ and C to
Cl– distances range from 3.9 to 4.3 Å
Anions and π-Aromatic Systems. Do They Interact Attractively? 165
Fig. 34 Left: Molecular structure of azadendritz. Right: side views and top view of
the crystal structure of the Cu(II) complex of azadendritz reported by Gamez, Reedijk
et al. [54]. Solvent molecules and hydrogen atoms are omitted for clarity. The structure
shows the four pentacoordinate Cu(II) ions coordinated two apical chloride atoms (scaled
ball-and-stick representation) and two encapsulated chloride anions (CPK representa-
tion)
The authors state that a “Cl– · · ·triazine complex due to electrostatic anion-
π interaction is present in the complex”. Johnson, Hay et al. [45] have recently
noticed that the role of the C – H groups of deficient arenes as potent hydro-
gen bonds should not be overlooked, in fact the structure of Meyer nicely
illustrates this observation. The Cl(8) anion positioned above the center of
the melamine is interacting with the C – H groups of the Cu(II)-coordinated
pyridines. The hydrogen bonds formed may play a dominant role in deter-
mining the position of the anion within this cavity.
Almost at the same time, Gamez, Reedijk et al. [54] described the first co-
ordination compound of the ligand azadendritz. The supramolecular Cu(II)
complex shows intramolecular π–π interactions between two 1,3,5-triazine
rings.
Similar to the structure reported by Meyer, four pyridine-N groups and
an apical chloride constitute a square pyramidal coordination of each metal
center. In this case, however, the chloride atoms are not located on top
of the 1,3,5-triazine rings, which are perfectly stacked, instead the anion
is nestled against four aromatic pyridyl residues. In Meyer’s structure, this
same position was occupied by Cl atoms of Cl2 CH2 molecules. Each en-
capsulated chloride is in close contact with the four pyridine rings with
centroid· · ·Cl– distances ranging from 3.5 to 3.7 Å. It has to be noted that
in both examples the electron-poor character of the pyridine moieties is
probably enhanced by their coordination to the Cu(II) metals. In addition
to the π interaction with the pyridine rings the authors noted that the
chloride ions are in close proximity to the triazine rings, suggesting the
existence of some additional electrostatic interactions with the electron de-
ficient triazine moiety. The angles of the Cl– · · ·centroid axis to the plane
of the different pyridine rings ranges from 74◦ to 82◦ . This result en-
couraged the authors to investigate further the anion · · · triazine interaction
166 P. Ballester
using other triazine-based ligands and anions [55, 56]. Thus, the reaction
of Zn(NO3 ) · 6H2 O or Cu(NO3 ) · 3H2 O with the ligand dipicatriz in acetoni-
trile afforded mono- or trinuclear coordination complexes depending on the
metal-to-ligand ratio used during the crystallization process [56]. In par-
ticular, the trinuclear Zn(II) complex shows anion-π interactions between
two nitrate anions coordinated to two different zinc atoms and the same tri-
azine ring, one in each face of the aromatic ring. On the other hand, the
corresponding trinuclear Cu(II) complex exhibits an even more remarkable
double anion-π interaction between the triazine ring and two nitrate anions.
In this case, the two nitrate anions are now uncoordinated. One of the ni-
trates interacts via a somewhat longer distances, which is most likely due
to the fact that the triazine is already involved in a nitrate-centroid contact.
These examples constitute one of the first reports on anion-π-anion inter-
action. It is also worth noting that the observed spatial arrangement of the
nitrate anion with respect to the triazine ring is distinct to the one pro-
posed by Kim et al. [32] based on theoretical calculations. Gamez, Reedijk
et al. [56] performed ab initio calculations demonstrating that the interaction
energies calculated for this peculiar positioning of the nitrate is compara-
ble to the energy of the binding geometry proposed by Kim et al. in his
theoretical studies of the interaction of triazine with nitrate [32]. In the
model proposed by Kim et al., the anion is parallel to the triazine ring and
the oxygen atoms are located on top of the electropositive carbon atoms
of the ring.
Related to the previous example Gamez, Reedijk et al. [55] also found
crystallographic evidences of another geometry for the nitrate-π interac-
tion in the tetranuclear complex [Cu4 (dpatta)(NO3 )4 ](NO3 )4 obtained under
hydrothermal conditions from the reaction of copper(II) nitrate and the
ligand dpatta [55]. Each two triazine units are perfectly π–π stacked but
staggered with a centroid-to-centroid distance of 3.45 Å. Both triazine rings
Fig. 35 Left: Molecular structure of dipicatriz. Right: side views of the crystal structures
of the Zn(II) and the Cu(II) trinuclear complexes of dipicatriz. The structures show the
three coordinate Zn(II) and Cu(II) ions in scaled ball-and-stick representation and the
distances between the centroids of the triazine ring and the closest oxygen atoms of the
interacting nitrate anions
Anions and π-Aromatic Systems. Do They Interact Attractively? 167
Fig. 37 Molecular structure of the ligands bptz and bppn. Middle: portion of the pack-
ing diagram of [Ag2 (bptz)3 ][SbF6 ]2 depicting the anion and cation arrangement. Right:
portion of the grid-type structure of [Ag2 (bppn)4 ][PF6 ]4 depicting π–π and anion-π
interactions
Anions and π-Aromatic Systems. Do They Interact Attractively? 169
vey of the CSD has been carried out by several authors [10, 19, 45]. It is
clear that the result of a search of the CSD will be highly dependent on
the search criteria used to store a hit. Johnson, Hay et al. [45] carried
out a search for halide anions located within 4.0 Å of the centroid of six-
membered ring π systems yielded 600 examples. In most cases, however,
the π-system was either positively charged or bonded directly to a posi-
tively charged atom. If only charge-neutral π systems are considered, a much
smaller set of 19 different structures is retrieved. Within these structures,
30 halide arene complexes were found. They performed an analysis of sev-
eral distances of the complexes, i.e., distance anion-to-centroid, distance
anion-to-plane, etc., concluding that 84% of the anions in the data set are
closer to the ring carbons than to the centroid. Thus, the available struc-
tural data of the CSD indicates that the CT-binding motif of a halide in-
teracting with a π systems is more prevalent that the anion-aryl centroid
motif. The authors explained that the incongruence of their results with
prior analysis of the CSD—which reported evidences of a marked prefer-
ence of charge-neutral atoms bearing lone pairs to position themselves over
the center of pentafluoroarenes [19] and trinitrobenzene derivatives [61]—is
due to the use of a misleading search criterion. Finally, based on the sta-
tistical analysis of the hits obtained for a search criteria, which is that the
electronegative atoms must be 4 Å of the pentafluorophenyl centroid, they
established a complete absence of any preferred location over the π sys-
tem. The use of solid-state structures to analyze the geometric parameters
of weak intermolecular forces such as anion-π interactions, has a general
drawback, that is, other intermolecular interactions that are stronger, i.e.,
charge–charge interactions may determine the final crystal packing arrange-
ment. Consequently, the geometry observed in the crystal for the weak inter-
action could be not the preferred one but the one resulting of the balance of
intermolecular forces that controls the packing of the lattice. Probably, this
is one of the causes that produces the complete absence of a preferred loca-
tion of the anion over the π system of perfluorobenzenes. However, several
searches carried out in the CSD do show that many of the geometries the-
oretically calculated for the interaction of anions with π systems are in fact
present in the solid state. Consequently, this type of non-covalent interaction
is worth to be seriously investigated by the practitioners of supramolecular
chemistry.
A recent account by Matile et al. [62] can be considered as the first ex-
perimental example of the use of anion-π interactions for the design of
a synthetic anion channel. Matile and co-workers report the design, syn-
thesis, and evaluation of π-acidic, shape-persistent oligo-(p-phenylene)-N,N-
naphthalenediimide (O-NDI) rods that can transport anions across lipid
bilayer membranes with a rare selectivity Cl– > F– > Br– > I– and a sub-
stantial anomalous mole fraction effect. DFT calculations revealed a global
quadrupole moment Qzz =+ 19.4 B for a model NDI. By comparison with
170 P. Ballester
Fig. 38 a The concept of the anion-π slide in lipid bilayer; b MEP for model NDI; red:
electron-rich, blue: electron-poor
rigid p-oligophenyl rods, the authors deduced that the alignment of three
NDI acceptors separated by phenyl spacers would afford rods with the ap-
propriate length for hydrophobic matching with common lipid bilayer mem-
branes. The results obtained in this study are in agreement with opera-
tional dynamic anion-π interactions and the existence of multiple anion-π
sites for transmembrane anion hopping, that is, anion-π slide as shown in
Fig. 38. A final caveat of the authors indicates that further studies are ne-
cessary to corroborate insights on the novel and complex system introduced
in the study.
4
Summary and Outlook
The last paragraph of a chapter like this one asks the writer to predict
if the non-covalent interaction of anions with π-system will be as import-
ant and useful as the nowadays well-established cation-π interaction. We are
cautious in answering this question affirmatively, but we have to confess that
we are currently working in the construction of synthetic receptors for an-
ions that do incorporate electron deficient π-aromatic systems. We hope that
our designs will be valuable for the experimental evaluation of the anion-
π interaction in solution and we will report shortly our findings. Once the
strength of the anion-π interaction in solution is determined, it will be easier
to evaluate its possible use in the construction of selective receptors for an-
ions making use of the directionality properties that we have discussed in the
chapter.
Acknowledgements I want to thank Dr. Antonio Frontera, Dr. David Quiñonero, and Prof.
Pere M. Deyà from the University of the Balearic Islands for sharing with me his interest
and results of their studies on the anion-π interaction. As a consequence, my group is now
involved in trying to quantify experimentally the strength of this new, counterintuitive and
rather unnoticed non-covalent interaction, and I find myself writing a book chapter on the
topic. Generous financial support from MEC (CTQ2005-08989-C01-02/BQU and CSD2006-
0003), ICIQ Foundation, ICREA Foundation and Generalitat de Catalunya (2005SGR00108)
is gratefully acknowledged.
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Struct Bond (2008) 129: 175–206
DOI 10.1007/430_2008_083
© Springer-Verlag Berlin Heidelberg
Published online: 12 March 2008
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205
1
Introduction
2
Templating Effects in Chemistry
3
Recent Examples of Anion-Templated Processes
3.1
Macrocycles
Böhmer has recently shown that the presence of chloride can dictate the
size of macrocyclic poly-urea systems. The reaction between diamine 1 and
diisocyanate 2 yield the macrocyclic species 3 and 4 in a 5:1 ratio (see
Scheme 1) [24].
When this reaction was repeated in the presence of two equivalents of
tetrabutylammonium chloride, the formation of the larger macrocycle 4 was
favoured over the trimeric species 3. In fact, the ratio reverted to 1:5 in
favour of the larger macrocycle. Crystals of macrocycle 4 were obtained from
the crude of the first reaction when grown in the presence of tetrabutyl-
ammonium chloride. The structure (Fig. 1) revealed an interesting host-guest
complex in which two chlorides are bound by the macrocycle (which explains
the need of two equivalents of chloride to favour the formation of the hexam-
eric compound).
Alfonso and Luis have recently reported an example of anion-templated
synthesis of a pseudopeptidic macrocycle. The reaction between diamine 5
and dialdehyde 6 was carried out (see Scheme 2) [25]. 1 H NMR spectroscopy
showed a complex patter of signals together with protons associated with
aldehyde and methoxyamine suggesting the presence of a range of different
macrocyclic and acyclic products. Addition of different anions to the reaction
mixture had little effect to the distribution of products shown by 1 H NMR
spectroscopy. However, when the reaction was repeated in the presence tereph-
thalate, the almost quantitative formation of a single product as revealed by
1 H NMR spectroscopy was observed. This intermediate product has been
Fig. 1 X-ray crystal structure of macrocycle 4 highlighting the two chloride anions (solid
spheres) bound to the macrocycle
180 R. Vilar
It is worth noting that this process could in principle lead to dynamic com-
binatorial libraries of products since the type of bond that brings together
the different components in the reaction is a reversible one (namely imine
formation). In fact, the initial mixture of products observed by the authors
has been postulated to be a mixture of different-sized macrocycles and linear
species (from which one of them is amplified upon addition of terephthalate).
More detailed studies would be needed to determine whether this system in-
deed leads to the formation of a DCL of receptors (see Sect. 4 for examples of
anion-directed DCLs).
A widely used approach to the synthesis of large macrocycles and cages (see
Sect. 3.2) is by self-assembly of metal centres and polydentate ligands. Careful
choice of the geometry around the metal and the number and relative position
of the coordinating groups on the bridging ligands can generate large 2D and
3D assemblies from a one-pot reaction. Often, the addition of a template to the
reaction mixture provides a more efficient path for the formation of one spe-
cific assembly. Some recent examples of anion-templated metallo-macrocycles
and -cages are discussed in this and the following sections.
Lippert has shown that the assembly between platinum(II) centres and
purine bases can be controlled by specific anions. In analogy to the hydrogen-
bonded tetrads that guanine bases can form, this group synthesised a metallo-
square in which the purine bases are interconnected by coordination to plat-
inum(II) centres rather than hydrogen bonding interactions (see Fig. 2) [26].
Anion Templates in Synthesis and Dynamic Combinatorial Libraries 181
Fig. 2 Schematic representation of: a guanine quartet with a cationic guest and b metallo-
square 9 based on platinum(II) and methylpurine with an anionic guest
When the same reaction was carried out in methanol the macrocyclic species
[Cu4 (pprd)4 (C2 H4 )4 ](PF6 )4 (11) was formed instead. The crystal structure of
this metallo-assembly revealed a bowl-shaped structure with the PF6 – anion
positioned at its centre (see Fig. 3).
Fig. 3 X-ray crystal structures of a the tetra-copper assembly [Cu4 (pprd)4 (C2 H4 )4 ](PF6 )4
(11) and b the tri-copper assembly {[Cu3(pprd)3 (C2 H4 )3 ](ClO4 )3 }3 (12)
3.2
Cages and Capsules
bly of eight units of amidinothiourea (H-atu, see Scheme 5) and six nickel(II)
centres to yield [Ni6 (atu)8 ⊂Cl]Cl3 (13). The resulting assembly showed to
contain a completely encapsulated chloride interacting via hydrogen bonding
and weak metal-anion interactions with the cage.
Fig. 4 X-ray crystal structure of mixed-metal cage [Ni4 Pt2 (atu)8⊂Cl]Cl3 showing the en-
capsulated chloride anion
X = BF4 – , ClO4 – ; see Figs. 5 and 6) was dependant on the presence of specific
anions [32]. Detailed investigations (by NMR spectroscopy) of the assem-
bly process in solution demonstrated that the tetrahedral BF4 – and ClO4 –
anions indeed act as templating agents for the formation of these metallo-
assemblies [33].
More recently, Ward has explored the effect that the length of bidentate
pyrazolyl-based ligands has on the formation of the metallo-cages [34]. When
Fig. 6 X-ray crystal structure of [Co4 (L1 )6 ⊂(ClO4 )](ClO4)7 highlighting the encapsulated
tetrahedral anion (in space-fill representation)
L3 was used as ligand, the expected [Co4 (L3 )6 ⊂X](X)7 (X = BF4 – , ClO4 – ,
PF6 – , I– ) cages were formed, but in this case the anion did not seem to play
a determinant role in defining the geometry of the final assembly. As indi-
cated by the authors, the resulting cage is sufficiently large to leave gaps in the
centre of the faces through which the encapsulated anion can easily exchange
with the external anions.
186 R. Vilar
Fig. 7 X-ray crystal structure of [Co2(L4 )4 (MeCN)2 ⊂(BF4 )](BF4 )3 showing the encapsu-
lated anion and its interactions with the metal centres
3.3
Interlocked Species
Fig. 11 X-ray crystal structure of rotaxane 20 showing the chloride anion bound to the
interlocked species
Fig. 12 X-ray crystal structure of catenane 23 showing the chloride anion bound to the
interlocked species
Anion Templates in Synthesis and Dynamic Combinatorial Libraries 191
4
Anions as Templates in Dynamic Combinatorial Chemistry
that the assembly of iron(II) salts and a tris-bipy ligand (L5 ) is a dynamic
process that can yield a range of different metal helicates. Which assembly
is formed, is highly dependent on the nature of the counter-anions present
in solution. With FeCl2 , the pentanuclear circular helicate [Fe5 (L5 )5 Cl]9+ (24)
was formed in high yields (see Scheme 9), while a mixture of the penta-
and hexa-nuclear helicates were obtained in the presence of bromide (and
only the hexa-nuclear helicate [Fe6 (L5 )6 (SO4 )]10+ (25) was formed with sul-
fate). Further studies by the same authors demonstrated that in the reaction
with FeCl2 (and also in the analogous one with NiCl2 ) a linear helicate is
formed first (i.e., the kinetic product) which progressively converts into the
thermodynamic circular helicate product [Fe5 (L5 )5 Cl]9+ [46] Structural char-
acterization of 25 confirmed the assembly to be a circular double helix with
a chloride ion located in the central cavity.
Although this anion-directed system was one of the first examples of DCCs
reported in the literature, there are in fact very few known systems to date
where negatively charged species are used to amplify the formation of a spe-
cific assembly from a dynamic combinatorial library. Such examples will be
reviewed in Sects. 4.1 and 4.2.
4.1
Using Metal–Ligand Coordination Bonds
Dunbar has elegantly demonstrated the use of anionic templates for the syn-
theses of a range of nickel(II) and zinc(II) metalla-cyclophanes using 3,6-
bis(2-pyridyl)-1,2,4,5-tetrazine (bptz) as bridging ligand (see Scheme 10) [47,
48]. Anions such as BF4 – and ClO4 – induce the formation of the tetra-metallic
square assemblies [{M4 (bptz)4 (CH3 CN)8 }X](X)7 , (M = ZnII , NiII ; X = BF4 – ,
ClO4 – ), while the larger octahedral anion SbF6 – templates the formation
of the molecular pentagon [{Ni5 (bptz)5 (CH3 CN)10 }SbF6 ](SbF6 )9 . The X-ray
crystal structures of these species (see Figs. 13 and 14) have shown that in
both the squares and pentagon one anion is encapsulated at the centre of the
corresponding metalla-cyclophane (displaying anion-π interactions between
the O and F atoms of the anions and the tetrazine rings of bptz).
Further studies by the same authors showed that the molecular pentagon
can be easily converted into the corresponding molecular square in the pres-
ence of excess BF4 – and ClO4 – . The conversion of the molecular pentagon to
the square is also observed upon addition of iodide (which due to its large size
and polarizability it can adopt the directionality of a tetrahedral anion).
In contrast to the above, the conversion of the nickel square to the corres-
ponding pentagon upon addition of excess SbF6 – is not readily observed (only
partial conversion takes place). This apparent higher stability of the molecu-
lar square in comparison to the molecular pentagon has been attributed to
more strain in the pentagon. This is supported by the X-ray crystal structure
of the metallo-pentagon in which the btpz ligands are considerably bent.
Anion Templates in Synthesis and Dynamic Combinatorial Libraries 193
Fig. 13 X-ray crystal structure of metallo-square [{Ni4 (bptz)4 (CH3 CN)8 }BF4 ](BF4 )7
Fig. 14 X-ray crystal structure of metallo-square [{Ni5 (bptz)5 (CH3 CN)10 }SbF6 ](SbF6 )9
In this study it was shown that the nature of the resulting metallo-
assemblies was highly dependant on the conditions employed. For example,
the reaction between L6 and [Pd(en)(NO3 )2 ] in DMSO was found to yield two
macrocycles (26 and 27) in roughly 60:40 proportions when the concentra-
tion of the ligand was 5 mM. By reducing the concentration of the ligand to
1 mM, the equilibrium was shifted to the simpler [2+2] assembly 26 which
was present in nearly 90%.
Increasing the concentration of ligand to 20 mM or above, yielded yet an-
other product, metallo-assembly 28 which at 500 mM concentration of ligand
was practically the only product observed by 1 H NMR spectroscopy.
In the same paper, the reactions between these two ligands and “naked”
palladium(II) cations were also discussed. Interestingly, the structure and nu-
clearity of the resulting assemblies was shown to depend on the counteranion
of the palladium salt used. Thus, the reaction between Pd(NO3 )2 and ligand
Anion Templates in Synthesis and Dynamic Combinatorial Libraries 195
196 R. Vilar
L6 yielded mainly the tetrahedral assembly 29 (see Fig. 15). An analogous as-
sembly was obtained in the presence of BF4 – . However, when the reaction
was carried out in the presence of triflate a double-walled triangle (30) was
obtained as the major product (Scheme 11).
When carrying out a similar reaction with ligand L7 (which is longer than
L6 )the structures of the resulting metallo-assemblies were again found to be
anion-dependant. In this case, dynamic equilibrium between the two assem-
blies 31 and 32 was observed. With nitrate as the counter-anion, a roughly 1:1
mixture of the two assemblies was observed; however, with triflate the main
Anion Templates in Synthesis and Dynamic Combinatorial Libraries 197
Fig. 16 X-ray crystal structure of assembly 34 showing the triflate anion at the centre of
the bowl-type assembly
Anion Templates in Synthesis and Dynamic Combinatorial Libraries 199
Although the solid-state structures obtained for these systems indicate the
formation of the [2+2] assembly, 1 H NMR studies showed that more than one
species co-existed in solution. As indicated above, in principle a 1:1 mixture
of the bis-pyridyl ligands and cis-[Pd(dppp)]2+ centres could yield macrocy-
cles of different sizes or a range of different acyclic products. Several 1 H NMR
spectroscopic and ESI-mass spectrometric studies were carried out (using
[Pd(dppp)(OTf)2 ] and L8 ) to establish the behaviour of the system in solu-
tion. These studies suggested that there is an equilibrium between two species
which have been assigned to the [2+2] and a [3+3] metallo-assemblies (see
Scheme 14).
Scheme 14 Reaction scheme showing the equilibrium between the [2+2] and [3+3]
metallo-macrocycles
Scheme 15 Reaction scheme showing the different possible complexes that can be formed
by mixing Co(NO3 )2 with L10 and bipy
[Co(L10 )3 ]2+ (80%), [Co(bipy)(L10 )2 ]2+ (100%), [Co(bipy)2 (L10 )]2+ (91%)
and [Co(bipy)3 ]2+ (11%). Furthermore, 1 H NMR spectroscopy indicated that
for each of the complexes – except for [Co(bipy)3 ]2+ which gave an enan-
tiomeric pair – the corresponding ∆- and Λ-diastereomers were present.
The equilibrium of the above mixture was shown to change upon add-
ition of CF3 COOH. Addition of the acid led to protonation of the amines
groups on L8 inducing diasteroselectivity and, as a consequence, some of the
complexes initially present in the mixture disappeared. Interestingly, when
DCl rather than CF3 COOH was added to the reaction mixture, only the two
homoleptic complexes {Cl2 ⊂∆-[Co(L10 H2 )3 ]6+ } and [Co(bipy)3 ]2+ could be
detected suggesting that chloride acts as a template amplifying the formation
of these species. These observations have been rationalised on the grounds
that coulombic repulsion between the protonated amines is minimized by the
presence of chloride.
A similar approach to the one discussed above has been recently reported
by Rice [52, 53]. In these investigations it was shown that nitrate can mod-
ify the distribution of products in a mixture of cobalt(II) and two different
N,N chelating ligands. First, the reaction between Co(ClO4 )2 and ligand L11
was studied showing that a triple helicate with formula [Co2 (L11 )3 ](ClO4 )4
Scheme 16 Reaction scheme showing the different possible complexes that can be formed
by mixing Co(ClO4)2 with L11 and L12
Anion Templates in Synthesis and Dynamic Combinatorial Libraries 201
formed (see Scheme 16). The ligands around the cobalt(II) centres generate
“pockets” of the right size to bind perchlorate anions via hydrogen bonding
(see Fig. 17).
Fig. 17 X-ray crystal structure of the triple helicate [Co2 (L11 )3 ](ClO4 )4 showing the per-
chlorate anions bound to the “pockets” formed by the three ligands
The authors then studied the possibility of anion exchange in this complex.
Thus, upon addition of two equivalents of [Bu4 N][NO3 ] to [Co2 (L11 )3 ](ClO4 )4
a new host-guest complex with formula [Co2 (L11 )3 ](ClO4 )2 (NO3 )2 was ob-
tained. The X-ray crystal structure of this mixed-anion helicate showed that
the perchlorates initially bound to the binding pockets of the helicate, had
been replaced by nitrates.
Having established the basic host-guest chemistry between the helicate
and the two anions, the authors then investigated the reaction between
[Co(ClO4 )2 ]·6H2 O, L11 and L12 (see Scheme 16 for the chemical structure of
the ligands) in a 2 to 1.5 to 1.5 ratio. This reaction resulted in the forma-
tion of four complexes: [Co2 (L11 )3 ]4+ , [Co2 (L11 )2 (L12 )]4+ , [Co2 (L11 ) (L12 )2 ]4+
and [Co2 (L12 )3 ]4+ , with a 1:3:3:1 statistical distribution. This was confirmed
by both 1 H NMR spectroscopy and ES mass spectrometry. Interestingly,
upon addition of KNO3 to this mixture a dramatic change in product dis-
tribution was observed. The two homoleptic complexes [Co2 (L11 )3 ]4+ and
[Co2 (L12 )3 ]4+ were found to be the main components of the mixture (with
only 5% of the heteroleptic compounds being present). This behaviour has
been attributed to the strong binding of nitrate (which acts as a template) to
the anion-binding pockets present in [Co2 (L11 )3 ]4+ .
4.2
Using Reversible Covalent Bonds
5
Conclusions and Outlook
References
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DOI 10.1007/430_2008_084
© Springer-Verlag Berlin Heidelberg
Published online: 25 April 2008
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208
1.1 Context . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 244
Abstract Molecularly imprinted polymers (MIPs) are a class of solid-phase artificial re-
ceptors that are prepared using templates during the polymer network forming step; these
are subsequently removed to generate the selective receptor sites. The ease of synthesis,
the possibility of nanomolar binding constants and high levels of molecular discrimina-
tion, as well as environmental stability and ability to be reused, have led to a dramatic
boost in research interest in MIPs. One particularly promising area of study is the use
of anionic templates in the synthesis of MIPs and the targeting of substrates that carry
biologically important anionic functionalities. Benefiting from concurrent developments
in supramolecular receptor design and synthesis, it has become clear that MIPs for anion
recognition will impact biological screening, diagnosis, point-of-care devices (including
online sensing) and read-out.
Abbreviations
FIP Functional group imprinted polymer
ISFET Ion-sensitive field effect transistor
208 S.L. Ewen · J.H.G. Steinke
1
Introduction
1.1
Context
charge distribution in anions, is one reason for the recent surge in interest in
preparing MIPs for anion recognition. Another reason is the impact of pro-
teomics and the challenges and opportunities that accompany it with regard
to sensing and detection of charged species (simple anions as well as carboxy-
late, phosphate and sulfate derivatives) in the interrogation and analysis of
complex biological systems. A third reason relates to advances in the ability of
chemists to apply supramolecular and self-assembly approaches to the design
of complex structures and materials, from which MIP synthesis has already
begun to benefit.
2
Molecularly Imprinted Polymers
2.1
The Concept
takes place once template and binding sites have self-assembled, typically
in solution, and crosslinking molecules have been added which produce
a crosslinked polymer network once polymerisation has been initiated, in
most instances thermally or photochemically although electrochemical or re-
dox initiation has also been demonstrated successfully. The template is then
removed from the polymer, most commonly through liquid extraction, leav-
ing behind a polymer matrix made up of supramolecular receptor sites which
have been formed throughout the polymer network as a result of the pre-
organisation of the binding site/template complex [15]. These receptor sites
are often referred to as molecularly imprinted cavities as a polymer matrix
has formed around the template, becoming part of the receptor structure.
The complementarity of shape and electron density distribution transferred
into the polymer matrix has obvious analogies with the substrate recognition
sites of enzymes or antibodies where the spatial organisation of the func-
tional groups of amino acid side chains define catalytic sites and substrate
selectivity [12]. As the ability of conformational adaptation to the substrate
is a key feature of enzyme recognition and catalysis, so is a certain level
of conformational freedom in a MIP [16]. Regarding the molecular recogni-
tion mechanism operational in MIPs, a number of recent studies illustrate
the decade-old controversy between the imprint mechanism (cavity gener-
ated by template) and the association mechanism (trapped templates act as
binding/nucleation sites) [17, 18].
2.2
Inspiration, Incorporation and Assimilation
2.3
A Brief “Developmental” History
Polyakov et al. were the first to report the effect of generating selectivity in
a polymer matrix through addition of a template molecule (for a more de-
tailed account see [14]). In 1931 they prepared silica particles from sodium
silicate and (NH4 )2 CO3 in water, adding benzene, toluene or xylene in the
process. After prolonged drying and exhaustive extraction with hot water, the
polymer showed higher capacity for the additive (template) than for struc-
turally related compounds. A contemporary debate ensued about the origin
of antibody selectivity in the immune system with contributions from Breinl
and Haurowitz [41], Mudd [42] and Linus Pauling [43]. The latter favoured
the view that antibodies are generated in the presence of an intruding anti-
gen which would determine the antibody conformation (as he attempted to
demonstrate in 1942 [14]). Similar work to that of Polyakov was reported in
1949 by Dickey, this time using alkyl orange dyes as the templates. The im-
printed silica gel showed pronounced selectivity for the template, which was
present throughout the silica network-forming step [44]. Curti et al. showed
the first examples of enantioselectivity with both mandelic acid and camphor
sulfonic acid (also in silica) and their application as stationary phases for
chromatography (Fig. 2) [45, 46].
A particularly imaginative example was contributed by Patrikeev et al. in
1960, in which they resorted to bacteria as templates. Curiously the imprinted
212 S.L. Ewen · J.H.G. Steinke
Fig. 2 A selection of important anionic template molecules and their corresponding bind-
ing sites reflecting the development of MIPs
Molecularly Imprinted Polymers Using Anions as Templates 213
silica promoted certain bacterial growth over that of control samples im-
printed with other varieties [47]. In a related study either the levo or dextro
form of the same bacillus (Bacillus cereus var. mycoides) was incorporated
into a silica gel matrix showing discrimination for L- and D-linanool vapour
respectively [48]. The same group provided perhaps the earliest example of
a catalytic MIP templating amino acid condensation reactions, though rates
were enhanced modestly by a factor of two and experimental details are
scarce [49]. Two decades later, in 1972, Wulff et al. [50] and Klotz et al. were
independently pioneering the use of organic polymers as tailor-made recep-
tors. Wulff et al. were the first to harness the versatility of radical vinyl chem-
istry as polymerisation methodology and exemplified the covalent imprinting
approach (Fig. 2), whereas Klotz and coworkers harnessed the benefits of
ring-opening polymerisation combined with reversible disulfide crosslinking
employing non-covalent interactions [51]. In the following years Wulff et al.
elaborated the covalent approach with the addition of non-covalent (predom-
inantly electrostatic) interactions [52, 53]. A method to imprint on a surface
(“surface imprinting”) was first developed by Sagiv et al. in 1979 using sil-
ica particles as surfaces with polymerisable siloxane as surface modifiers [54].
This methodology is transferable to other surfaces as long as the template
absorbs onto the chosen surface [55]. The work in the group of Mosbach
in 1981 revolutionised molecular imprinting through the non-covalent ap-
proach [56] (Fig. 2). The impact derived from the much simpler synthetic
route for making MIPs. Rather than having to prepare templates connected
to polymerisable binding sites via reversible covalent bonds, non-covalent in-
teractions allow the self-assembly of template and binding sites in solution,
affording a pre-polymerisation complex prior to vinyl monomer network for-
mation. In further development, Mosbach et al. demonstrated that MIPs with
high selectivity could be obtained even without the necessity to invoke cova-
lent or ionic bonds [57]. With time, more and more groups have taken up the
non-covalent approach and today it is the most widely used methodology to
prepare MIPs [14].
However, comparative studies of covalent and non-covalent imprinting are
rare, and even those reported lack the confidence in which optimised condi-
tions have been employed for both approaches, so that clear conclusions from
which to select the better approach could not be drawn [58, 59].
Although the notion of combining the advantages of covalent bonds during
the imprinting step with those of non-covalent interactions for rebinding was
present in earlier work by Wulff et al. [50, 52, 60, 61], the first example of using
exclusively covalent interactions for the imprinting step and noncovalent ones
for rebinding was executed by Sellergren and Andersson in 1990 [62]. Poly-
merisable groups were linked by ester bonds, though the target molecule,
p-aminophenylalanine ethyl ester, was necessarily different to the template.
This changed completely in 1994, when Whitcombe et al. significantly refined
the semi-covalent approach, outlining a concept based on a small covalent
214 S.L. Ewen · J.H.G. Steinke
fragment as space holder (“sacrificial spacer approach”) [63]. With this strat-
egy, template and a binding site are covalently linked with a cleavable spacer
which is designed to reveal complementary functional groups upon removal,
closely following the geometry of the covalent juncture for improved com-
plementarity [64]. The semi-covalent approach is an attempt to synergise the
advantages of the covalent methodology (strict control of functional group
location, more uniform distribution) with that of the non-covalent one (re-
duced kinetic restriction upon rebinding).
As a “natural” coalescence of the covalent and the original non-covalent
approach, a stoichiometric non-covalent approach was developed [65]. If the
non-covalent interactions are strong enough to produce association constants
of at least 103 M–1 (or preferably higher) the equilibrium will lie well on the
side of the template-functional monomer complex. On the way to stoichio-
metric non-covalent interactions (discussed in detail in Sect. 3) a representa-
tive example of carboxylic acid templates and various N-base binding sites is
found in Kempe et al. (1993) [66]. Polymerisable amidines were first used for
stoichiometric imprinting of a transition-state analogue (TSA) by Wulff et al.
in 1997 (Fig. 2) [67]. Other noteworthy developments were valine-derived
binding sites for dipeptide imprinting by Yano et al. in the same year [68]
and bidentate dioxoborolanyl recognition sites for carboxylates exploited by
Lübke et al. in 2000 [69]. In 1994 Sellergren was already successful in comple-
menting the standard MAA binding site monomer with pentamidine, offering
association constants close to those typically considered to be required for
stoichiometric imprinting strategies (Fig. 2) [70].
With time and improved synthetic protocols, larger templates (fullerenes,
dendrimers, nanoparticles, colloids, micelles, lipid bilayers, self-assembled
block copolymers, oligonucleotides, DNA and proteins) have been im-
printed [14] and the choice of matrices has expanded to liquid crystal
polysiloxanes, carbon networks, zeolites, layered aluminophosphates and
colloidal crystals, though organic polymer networks remain the dominant
imprint casting medium [14].
Further important developments related to templates emerged in the mid-
and late 1990’s. In 1999, Sreenivasan et al. demonstrated that it is possible
to imprint with two different template molecules simultaneously [71]. A year
later, Rachkov and Minoura introduced the epitope imprinting methodology
in which a structurally unique 3-amino acid fragment of a peptide chain was
shown to be a sufficient template to produce MIPs that are selective for the
entire nonapeptide [72]. Another year later, Sellergren et al. used a template
analogue rather than the target molecule itself for generating MIPs [73], fur-
ther suggesting that complex molecules can be imprinted successfully on the
basis of a molecular information-rich substructure or derivative. Also, ma-
nipulation of the binding site chemistry has widened the opportunities for
MIP applications. Useful synthetic post-polymerisation transformations were
elaborated on disulfide templates by Mukawa et al. in 2002, as their reduction
Molecularly Imprinted Polymers Using Anions as Templates 215
2.4
Scope and Limitations
Discussions about the current and general scope and limitations associated
with MIPs are ongoing. For a while, a good number of publications were of
two minds in their assessment of the potential of MIPs, where small advances
in performance were hailed as stepping stones to rival, if not excel, anti-
body and enzyme methods. This was followed by a healthy sobering period.
Over the last ten years a much more realistic assessment of the potential of
216 S.L. Ewen · J.H.G. Steinke
Limitations of MIPs:
• There are some common limitations associated with MIPs regardless of
the chosen template, binding site, solvent, etc.:
– Binding sites are heterogeneous (polyclonal rather than monoclonal
as in enzymes and monoclonal antibodies) as a consequence of the
statistical nature of the polymer network forming process, leading to
undesirable band broadening in chromatographic separations and to
a distribution of different activities of catalytic sites [89].
– Similarly not all template molecules may be accessible within the poly-
mer matrix, or will require very long extraction times leading to prob-
lems of template leaching especially when employing MIPs for trace
analysis [35].
– Diffusion to and from the recognition sites within the MIP matrix is
typically slow, depending on the solid-phase format and phase struc-
ture. High pore volume and interconnectivity can reduce the diffusion
problem but generating such a hierarchical pore structure may not
be compatible with the requirement of forming a strongly associated
template complex. Thin film, surface imprinting and membrane ap-
proaches are alternative means of addressing diffusion problems but
are in many cases accompanied by lower selectivity due to interface
effects or changes in the crosslinking stoichiometry, leading to a reduc-
tion of the molecular fidelity of the imprint [14].
– For applications such as enantiopolishing or chiral separations, MIPs
are said to offer low capacity. This is true when comparing MIPs with
sorbents that rely on an interaction with a surface or a surface modi-
fied with a chiral selector (e.g. Pirkle phases). On the other hand, MIPs
are at least competitive if one compares their atom economy with that
of enzymes or antibodies adding up the molar mass of crosslinker and
receptor sites per template (between ∼5–100 kDa depending on syn-
thesis recipe) [14].
– Dealing with polar and particularly water soluble template molecules
and recognition in aqueous milieu have been major issues for MIPs
for many years. Progress across the field however indicates that generic
strategies are available to overcome this limitation [34].
• Major issues regarding deficits in technology for anion MIPs will be dis-
cussed in more detail in Sects. 3.1–3.4.
2.5
Formats
terial, once polymerisation has taken place the molecular structure is fixed
and cannot be reconfigured. The most common formats encountered for
MIPs are:
• Irregular particles
– The most popular format prepared by grinding the bulk-polymerised
MIP into smaller particles. For chromatographic applications this is
usually followed by sizing through sieving [90].
• Monoliths
– Upon crosslinking, the polymerisation mixture retains the shape of the
reaction vessel. Separating the inner wall of the reaction vessel from
the polymer reveals a single piece of MIP, a monolith. The monoliths
could be used for MIP applications that have been shown to be use-
ful as a direct means of packing chromatographic columns (HPLC,
CEC) [90, 91]. If the monolith is exposed to large variations in sol-
vent polarity without space constraints it will slowly disintegrate into
smaller particles due to the high density of crosslinks in connection
with a glass transition temperature (Tg ) that is usually well above room
temperature.
• Beads
– This third format is particularly useful to pack chromatography columns
and generally to manipulate MIPs in automated processes [90]. As it re-
quires a two- or multi-phase solvent system during polymerisation to
impart the spherical shape, until recently it has proven quite challeng-
ing to obtain narrow disperse bead sizes with high yield at the desired
size. Protocols are now available that offer generic solutions for beading
a wide range of MIP formulations [92]. Beads are particularly desir-
able for catalytic MIP applications as selectivity improves (compared to
monolith synthesis) and catalytic activity increases due to faster mass
transfer [93].
• Films
– Especially for sensing (UV-Vis, luminescence, QCM), film formats, i.e.
surfaces coated with a MIP layer, are attractive as a simple means of
device fabrication. This does not differ greatly from the monolith for-
mat, and film thicknesses can be controlled through an appropriately
shaped substrate or through spin coating. The changes in solvent con-
centration caused by evaporation of solvent and precipitation of the
MIP during the film forming processes will alter the stoichiometry of
the template/binding site complex set in the starting solution [94].
• Membranes
– Free standing films of MIPs have been prepared in various ways.
Mechanical robustness has been imparted through lower crosslink
Molecularly Imprinted Polymers Using Anions as Templates 219
2.6
Design Criteria
parameter space involved when synthesising MIPs has prompted the use of
parallel synthesis combined with statistical data analysis to more rapidly ana-
lyse data sets and identify trends. These activities will mature and, with time,
will have wider impact on our ability to design MIPs for any given template
molecule with tunable thermodynamic and kinetic performance parameters.
Although there are always exceptions, the following design criteria have been
selected as being useful and reliable guides that help one arrive at a reason-
able starting point for developing a new MIP:
• Polymerisation temperature
– Lower temperatures improve selectivity and capacity. The exothermic
nature of radical vinyl polymerisation compounded by the gelling of
the imprint mixture is likely to cause higher internal temperatures than
those used to control the environment externally.
• Binding site design
– Statistical copolymerisation kinetics with the crosslinker lessens the
heterogeneity of receptor sites.
– Too much conformational freedom between binding site and polymer
backbone reduces selectivity.
– Strong, ideally close to stoichiometric ratios of binding interactions
improve the quality of the imprint.
– Faster equilibration kinetics increase performance in chromatography-
based application.
• Crosslinker
– There is an optimum level of crosslinking with typical values to be
around 70–95 mol %. Conformational flexibility of the crosslinker has
to be balanced with the overall level of crosslinks. The chemical na-
ture of the crosslinker determines the useful solvent range for a MIP.
The size of the crosslinker ideally matches the dimensions of the tem-
plate, to avoid conformational frustrations within the polymer matrix
as a result of a structural misfit, which can lead to a loss in capacity
and/or selectivity.
• Solvent
– The best choice is a solvent that maximises template binding site in-
teractions while producing a highly porous MIP matrix to minimise
diffusion limitations.
• Template
– Imprinted cavities can be viewed as multi-point receptor sites plus
the added shape of the cavity as an additional recognition feature.
A template offering many points for binding and where stoichiomet-
ric binding sites for the exhibited functional groups exist offers the
best conditions for high selectivity. On the other hand, large templates
Molecularly Imprinted Polymers Using Anions as Templates 221
3
Molecular Imprinting Using Anionic Templates
Table 1 Examples of molecules that have been used as templates for molecular imprinting
Naproxen [164–166]
(S)-Propranolol [167]
L-Menthol [27]
Bisphenol A [174]
224 S.L. Ewen · J.H.G. Steinke
3.1
Anionic Phosphate Derivatives
Fig. 3 Schematic representation of cAMP inside MIP, showing possible binding interac-
tions
The catalytic performance of the MIP and appropriate controls were in-
vestigated with the hydrolysis of diphenylcarbonate. Reaction kinetics, fol-
lowed by HPLC analysis of aliquots, were calculated as pseudo first-order
rate constants. Rather encouragingly, the imprinted polymer showed typical
Michaelis-Menten kinetics, in line with natural enzymes. The catalytic activ-
ity of the MIP (expressed as kcat /kuncat , the ratio of turnover number of the
catalysed reaction to turnover number in the absence of catalyst) was calcu-
lated to be 6900. This is markedly higher than has been reported for catalytic
antibodies for carbonate hydrolysis (kcat /kuncat = 810), clearly demonstrating
the great potential of MIPs for use as artificial enzymes.
All of the imprinted polymers discussed above involve phosphory-
lated/phosphonylated organic molecules, where the recognition process relies
equally upon binding to, and accommodation of, both the organic backbone
and the anionic functional group of the template. In fact, we are aware of only
one report of a MIP designed to target inorganic phosphate, H2 PO4 – . In this
one example, Kugimiya et al. present a series of MIPs prepared using thiourea-
derived functional monomers [114]. The thiourea group is known to be a good
host for anions, particularly for the phosphate anion, to which the N – H moi-
eties bind through a set of coplanar H-bonds. The authors’ initial experiments
indicated that 1-allyl-2-thiourea is particularly suitable for use in aqueous
media: this was in direct contrast to a related functional monomer, N-methyl-
N -(4-vinylphenyl)-thiourea, which showed almost no binding ability under
the conditions studied. Such results were explained by the greater hydrophilic-
ity of 1-allyl-2-thiourea. Thus a polymer was imprinted with phenylphosphonic
acid as the template molecule, using EGDMA as the crosslinker, acetonitrile as
the porogen and four equivalents (to template molecule) of 1-allyl-2-thiourea
as the functional monomer. Incidentally, Kugimiya et al. omit explaination as
to why a phosphonic acid template molecule was chosen for a MIP designed for
NaH2 PO4 recognition. Presumably they had anticipated that the difference in
geometry between these two functional groups would be negligible.
To evaluate the ability of the MIP to selectively bind NaH2 PO4 , MIP and
NIP particles were stirred in distilled water with a mixture of various anions
(NaH2 PO4 , KNO3 , NaCl, Na2 SO4 , CH3 COONa). After 1 h, the supernatant
was removed and analysed by ion chromatography. Under these conditions,
both the MIP and the NIP preferentially bound phosphate over the other an-
ions measured, and the MIP bound 58% more template than the NIP, thus
demonstrating a clear imprinting effect and selectivity for the target anion.
Unfortunately, due to the insufficient level of information provided, it is diffi-
cult to fully appreciate the data. For example, while the amount of each anion
bound is presented as % binding activity, it is unclear how this relates to the
estimated number of available binding sites. Furthermore, it was belatedly
discovered that CH3 COO– could not actually be detected via ion chromatog-
raphy, and the influence of this potentially-competitive anion was therefore
not determined.
232 S.L. Ewen · J.H.G. Steinke
3.2
Carboxylates
Smith [130], exploits internal Lewis acid coordination between the boron and
the carbonyl oxygen, which serves to polarise the amide, thereby increasing
affinity for the oxyanion. Imprinting was carried out by allowing stoichiomet-
ric amounts of the monomers and the tetrabutylammonium salt of ampicillin
to complex in DMSO over 24 h, prior to incorporation into a highly crosslinked
polymer. Subsequent extraction with acetonitrile afforded a 92% recovery of
the template. The resulting MIP showed good potential, performing well in
aqueous media with optimal binding at pH 8 (where the carboxylate is present
as the anion) and with selectivity over structural analogues.
Zhang et al. reported the design and four-step synthesis of a novel
guanidinium-functionalised monomer which was built upon a vinylan-
thracene scaffold to effect fluorescence [116]. NMR titration experiments
in deuteriomethanol indicated the formation of a 1 : 1 complex with ac-
etate, with estimated association constants of the order of 105 M–1 . Although
synthesis of this particular monomer does demand more expertise than
monomers typically used for imprinting – with somewhat uninspiring re-
coveries reported by the authors – it nonetheless appears to be a promising
candidate for stoichiometric non-covalent imprinting with carboxylates.
Hall et al. are amongst the most prolific authors in the field of car-
boxylate imprinting. Making use of expertise in the field of supramolecular
234 S.L. Ewen · J.H.G. Steinke
Fig. 10 Schematic representation of ampicillin inside MIP, showing possible binding in-
teractions
chemistry, viz. Hamilton et al. [131, 132], they have developed a series of
novel monotopic and ditopic functional monomers based upon a urea core
(Fig. 11) [112, 133]. These synthetically accessible host species can usually be
prepared in a one-step procedure, either from 1-isopropenyl-4-isopropyl-2-
isocyanate and the corresponding amine or by reaction of 4-vinylaniline with
the corresponding isocyanate. Ureas bind to oxyanions via donation of two
H-bonds, and it was shown that varying the substitution of the monomers
– and hence modifying the acidity of the urea core – can result in quite
dramatic changes in affinity for the model substrate, tetrabutylammonium
benzoate. For example, NMR titration experiments in DMSO-d6 afforded an
association constant of 1322 ± 48 M–1 for 4 where R1 = R2 = H, while the
corresponding value for 4 where R1 = R2 = CF3 was 8820 ± 1600 M–1 . The
authors have explored a number of potential applications for these urea-based
monomers. These include a class-selective MIP for β-lactam antibiotics, for
which it was hypothesised that the mono-urea functionalised binding site
directly targets the β-lactam carboxylate moiety while providing sufficient
Molecularly Imprinted Polymers Using Anions as Templates 235
Fig. 11 Functional monomers based upon urea core, designed by Hall et al.
Fig. 12 Functional monomers based upon a urea core, designed by Schmitzer and Gomy
ing complete hydrolysis, aqueous ammonia was used to remove the template,
affording a sol–gel film with imprinted recognition sites. It was suggested
that rebinding of the template molecule occurs via a combination of covalent
bonding, H-bonding, metal coordination, and hydrophobic interactions with
Ti–O moieties. Such molecularly imprinted films are particularly suited to use
as transducer elements in chemosensor devices.
This method was demonstrated to afford molecularly imprinted TiO2
films selective for azobenzene carboxylic acids [136, 139], chloroaromatic
acids [138], chiral carboxylic acids including amino acid derivatives [140, 141]
and anthracenecarboxylic acids [139]. The methodology was also adapted
for use with water-soluble di- and tri-peptides [142]. In this latter case, even
though NaOH solution was used as an alternative to aqueous ammonia, com-
plete template removal proved impracticable, with 30–40% of the template
trapped in the film: nonetheless, the TiO2 films were said to show repro-
ducible binding for guest molecules. More recently, TiO2 films were also used
for imprinting thiolate- and phosphonate-functionalised templates [143].
The inherent simplicity of metal oxide sol–gel films, in particular the
lack of requirement for carefully chosen functional monomers, makes this
approach an attractive alternative to the use of highly crosslinked organic
polymers. The technique is optimised for – indeed, necessitates – an anionic
functional group on the template, and results in imprinted films with a no-
table degree of regioselectivity, structural selectivity and enantioselectivity.
To date no studies have been published demonstrating the degree of selectiv-
ity between substrates with differing anionic functional groups.
Finally, we wish to mention an interesting and somewhat more unusual
example of molecular imprinting, albeit it is debatable as to whether this
particular application should rightly be included within a discussion on
anionic templates. D’Souza et al. copolymerised 6-methacrylamidohexanoic
acid and divinylbenzene in the presence of calcite (calcium carbonate poly-
morph) crystals and, after exhaustive removal of the template, showed that
the imprinted polymer promoted nucleation of calcite from an aqueous su-
persaturated calcium carbonate solution [144, 145]. Using several methods of
analysis, it was demonstrated that no template remained in the MIP after the
wash steps; subsequent crystal-formation was therefore attributed to hetero-
geneous nucleation as opposed to seeding by residual crystals. Regarding the
functional monomer used, though the authors do not explicitly state their
reasoning behind choosing 6-methacrylamidohexanoic acid, they report that
the use of other functional monomers (acrylic or methacrylic acids) in place
of 6-methacrylamidohexanoic acid afforded MIPs with inferior nucleating
abilities. It was suggested that the presence of the flexible spacer allowed the
acidic head group of the monomer to more easily match the spacing of ions
on the surface of the crystal. More recently, Egan et al. applied this same
methodology to imprinting with calcium oxalate crystals, using the resulting
MIP to model nucleation of renal calculi from artificial and real urine [146].
238 S.L. Ewen · J.H.G. Steinke
3.3
Anionic Sulfate Derivatives
tial hazard with constructing such hosts: there is often a fine balance between
obtaining high affinity binding interactions while still retaining the selectivity
afforded by the act of imprinting.
The recent work of Albano et al. illustrates a particularly innovative ap-
plication of molecular imprinting [148]. In the presence of sodium dodecyl
sulfate (SDS), a thin layer of polypyrrole was electrodeposited onto the sur-
face of a quartz crystal. Removal of the SDS by washing with water afforded
a molecularly imprinted sensor element which could be used to monitor lev-
els of pollutant surfactants in river water. Thus, the piezoelectric quartz sensor
was contained within a flow cell so that the MIP-coated side of the crystal re-
mained in contact with analyte solution while the electrodes of the sensor were
connected to an oscillator circuit. A significant drop in the quartz crystal os-
cillation frequency occurred when the sensor was in contact with SDS. This is
consistent with an increase in mass on the surface of the sensor, suggesting that
SDS molecules had bound to the layer of imprinted polypyrrole. A reference
polypyrrole-coated sensor, prepared in parallel to the MIP-sensor but in the
absence of SDS, showed only a minimal response to the target analyte.
The influence of pH on sensor performance was investigated: MIP-coated
sensors exhibiting the highest response and sensitivity were those buffered
at pH 9 during the polymerisation step; likewise, an alkaline measurement
solution (pH 8) was found to afford the best results. It is evident that the
anionic form of SDS, rather than the free acid, is required for optimal bind-
ing to the pyrrole moieties. With regard to selectivity, the sensor was also
applied to solutions of both sodium dodecanoate (structurally identical to
SDS except bearing a carboxylate group in place of the sulfate ester) and
sodium dodecylbenzenesulfonate. While the sensor showed low sensitivity to
the carboxylate-functionalised analyte, a response equal to that afforded by
SDS was attained with the benzenesulfonate analogue. Nonetheless, the degree
to which molecular recognition by the MIP was governed by ionic strength, as
opposed to a definite molecular imprinting effect, is as yet unclear.
Recently, Sineriz et al. reported the first example of a MIP imprinted with
a sulfated sugar [149]. Sulfated sugars, such as heparan sulfate and chon-
droitin sulfate, are a class of highly abundant biological molecules with im-
portant intercellular roles. Their activities are directly related to patterns and
degree of sulfation. Understanding their biological functions therefore neces-
sitates structure elucidation, yet antibodies developed for this purpose have
generally been found to be insufficiently selective.
In an initial study, various amine-functionalised monomers (Fig. 14) were
incorporated into polymers templated around glucose-6-O-sulfate. Relative
binding strengths of the resulting MIPs were determined by equilibration
with glucose-6-O-sulfate solution followed by HPLC analysis of the super-
natant. In DMSO, it was found that the MIP made using quaternary amine-
functionalised monomer 7 exhibited high affinity towards the analyte but no
selectivity (the MIP and corresponding NIP performing equally). In contrast,
240 S.L. Ewen · J.H.G. Steinke
the MIP made using a primary amine (8) was observed to bind up to 80% of
a given concentration of glucose-6-O-sulfate in DMSO, while the correspond-
ing NIP showed negligible binding. Consistent with the aforementioned work
of Simon and Spivak [109], it was apparent that the directional nature of H-
bonds from the primary amine, coupled with the inherent pre-organisation
of the imprinted binding site, were crucial for selectivity. Further experi-
ments showed that the MIP prepared using the primary amine-functionalised
monomer preferentially bound glucose-6-O-sulfate over other sulfated sac-
charides (galactose-6-sulfate, glucose-3-sulfate and N-acetyl-glucosamine-6-
sulfate). The degree of selectivity over other anionic functional groups was
not investigated.
3.4
Other Anions
While relatively few MIPs have been made to recognise the oxyanionic
functional groups phosphate/phosphonate, carboxylate and sulfate/sulfonate,
MIPs designed to target inorganic anions are even more scarce. The following
paragraphs list examples of this mode of imprinting.
Fujiwara and co-workers attempted to surface imprint pyridine-bearing
microspheres using tetravalent ferrocyanide anions as the template [150]. Ad-
sorption studies indicated that, while the imprinted microspheres did show
greater affinity for the template anion in comparison to non-imprinted mi-
crospheres, they lacked selectivity and bound all other polyvalent anions
tested. This suggests that, although the pyridine groups were apparently pre-
organised by the imprinting process, negligible selectivity for the target an-
ions may be due to the absence of imprinted cavities on the surface of the
microspheres.
In 1988, Dong et al. reported a chloride-ion selective electrode, prepared
via electropolymerisation of pyrrole in the presence of LiCl [151]. The resul-
tant polymer film was observed to give a Nernstian response to chloride, with
a limit of detection of 3.5 × 10–5 M (said to be comparable to that of most
other contemporary chloride-selective electrodes). Later, the same methodol-
ogy was adapted to produce a chloride-selective microsensor, used to detect
chloride in serum [152]. Both the ion-selective electrode and the microsensor
Molecularly Imprinted Polymers Using Anions as Templates 241
showed poor selectivity for chloride over other anions. For example, poten-
tial selectivity coefficients of the electrode were of the order 10–1 for other
halides, IO4 – and ClO4 – , and >1 for NO3 – , HCOO– [151]. It was postulated
that selectivity was related to ionic radius.
A rare example of electropolymerisation employed for the formation of
an anion selective crosslinked polymer matrix was introduced by Kamata
et al. [153, 154]. Reductive coupling between trifunctional p-cyanopyridinium
crosslinkers (Fig. 15) in water containing the required counteranion led to
stable polymer networks which showed thermodynamic and kinetic anion
selectivity. A size exclusion effect was observed whereby only the imprint
halogen (and any smaller halogen anion) was electrochemically recognised.
Diffusion of the counterion was reduced in the case of the same template an-
ion MIP, but increased with the size of the templating anion. Experiments
clearly demonstrating anion selectivity have yet to be carried out.
In the mid-1990s, the molecular imprinting principle was adopted for the
preparation of a nitrate-selective electrode [155]. Ion-selective electrodes,
i.e. sensors which convert the activity of a specific ion into an electrical
potential, have widespread application in biochemical and biophysical an-
alysis; however, their major limitation is poor selectivity leading to interfer-
ence from other ions. Hutchins and Bachas electropolymerised pyrrole onto
a glass-carbon electrode in the presence of an aqueous solution of NaNO3 .
The polymer-coated electrode was demonstrated to detect aqueous nitrate,
giving a near-Nernstian response, with response times ranging from 24 to
<6 s. Recognition appeared to be based on size-exclusion phenomena. There-
fore, while the polymer was able to discriminate over traditional interferents
whose radii is larger than that of NO3 – , such as ClO4 – and I– , the much
smaller SCN– still effected a response. It was hypothesised that the hydropho-
bicity of the polypyrrole films induced the superimposition of a Hofmeister-
type selectivity (i.e. based upon lipophilicity) upon the nitrate imprinting
selectivity. Thus lipophilic anions not large enough to be sterically hindered
242 S.L. Ewen · J.H.G. Steinke
from the film, such as thiocyanate, still interfered with nitrate recognition.
Much more recently, this technology has been translated into the production
of nanolitre-scale electrochemical cells [156].
3.5
Concluding Comments
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Molecularly Imprinted Polymers Using Anions as Templates 245