SMC 009

Solvation Effects in Supramolecular Recognition
Mikhail Rekharsky and Yoshihisa Inoue

Osaka University, Suita, Japan
1 Introduction
2 Solvation and its Impact on Supramolecular
Recognition
3 Solvophobic Theory and Surface Tension
4 Binding of Neutral Versus Ionic Guest
5 Effects of HostGuestSolvent Complementarity
on Supramolecular Recognition
6 Effects of Solvation on Enthalpy- and
Entropy-Driven Complexation
7 Thermodynamic View for Global Understanding
of Molecular Recognition
8 EnthalpyEntropy Compensation as a Practical
Tool for Understanding and Analyzing Guest
Solvation and Molecular Recognition
9 Grunwald Theory on EnthalpyEntropy
Compensation
10 Conclusion
Acknowledgments
Related Articles
References
117
117
120
123
125
126
128
The solvent effect originates from diverse noncovalent

weak interactions of supramolecular host and guest with
solvent molecules, which are mutually interacting with
each other, and all these weak interactions inevitably alter
the thermodynamics of supramolecular systems. The weak
forces working in a hostguestsolvent system include the
electrostatic (ionion, iondipole, dipoledipole, dipole
induced dipole), van der Waals, hydrogen-bonding,
stacking, and other noncovalent interactions, although the
degree of contribution of each component depends on the
physicochemical properties of the particular host, guest,
and solvent employed. As a consequence of the diversity and significance of the interactions, the supramolecular
hostguest association behavior is frequently a dramatic
function of the solvent/solvation properties.
130
130
131
132
132
132
INTRODUCTION
Solvation is not simply an unavoidable passive event

but rather plays essential active roles in supramolecular chemistry. Interaction of supramolecular host and
guest with solvent, that is, host/guest solvation, critically
affects the thermodynamics of supramolecular recognition.
SOLVATION AND ITS IMPACT ON

SUPRAMOLECULAR RECOGNITION
The solvation to a neutral or charged species, including the

hydration in aqueous solution, is represented by the transfer
from gas to solution phase in the standard state, more
precisely from the hypothetical ideal gas at atmospheric
pressure (101 325 Pa) to the hypothetical ideal 1 M solution.
The standard molar Gibbs free energy, enthalpy, and
entropy changes for the above reaction are denoted by
symbols G , H , and S , respectively.
In the simplest case, a solvated guest (G) and a solvated
host (H) interact with each other to form a complex [HG]
in 1 : 1 stoichiometry in solution. The complex stability
is evaluated by the equilibrium constant or association
constant: Ka = a[HG] /aG aH , where aG , aH , and a[HG] are
the thermodynamic activities of guest, host, and complex
species, respectively. The association constant Ka is related
to the Gibbs free energy, enthalpy, and entropy changes
Supramolecular Chemistry: From Molecules to Nanomaterials, Online 2012 John Wiley & Sons, Ltd.
This article is 2012 John Wiley & Sons, Ltd.
This article was published in the Supramolecular Chemistry: From Molecules to Nanomaterials in 2012 by John Wiley & Sons, Ltd.
DOI: 10.1002/9780470661345.smc009
Concepts
(Gr , Hr , and Sr ) upon complexation by (1):
RT ln Ka = Gr = Hr TSr
(1)
It should be underscored that the thermodynamic activities of guest, host, and their complex(es) are not known
for almost all supramolecular systems described in the literature, and in reality the concentrations of guest, host,
and their complexes are directly used in the calculation
of association constant Ka . Therefore, the fundamental
thermodynamic difference between concentration (c) and
activity (a = c, where is the activity coefficient) should
always be kept in mind when supramolecular systems are
considered and discussed.
Certainly, the solvation to supramolecular host, guest,
and complex and thus the thermodynamics of supramolecular complexation are altered upon switching from one
solvent to another. Solvents used for supramolecular complexation may be divided into two very broad categories/groups: nonstructured or non-self-organized solvents
(e.g., aliphatic, aromatic, and halogenated hydrocarbons)
and structured or self-organized solvents (e.g., alcohols and
water). It is intuitive to assume that structured solvents
such as water should make profound impact on the binding behavior of supramolecular hosts and guests. However,
nonstructured solvents also should not be considered as just
inert media, and molecules of these solvents are often an
active component of supramolecular recognition process.
The hostguest association process that occurs in a nonstructured solvent is illustrated in Scheme 1. In general,
the total surface area of host and guest, which is accessible to solvent, is significantly reduced upon hostguest
complexation, limiting the number of solvent molecules
associated with the complex and consequently releasing

a number of solvent molecules back to the bulk solvent
(Scheme 1).
In the case of nonstructured solvents, the interaction
of solvent molecules in the bulk solution is rather weak
and plays only a limited role in host/guest binding. However, the extent of solvation, that is, the amount of solvating molecules, the thickness of solvation shell, and the
strength of the hostsolvent and guestsolvent interactions,
critically varies depending on the nature of the solvent
employed, as exemplified below for CDCl3 versus C6 D6 .
Kang and Rebek1 designed a supramolecular capsule
capable of reversibly binding the complementary molecules
in solution. Guest molecules of appropriate sizes, such
as 1-ferrocenecarboxylic acid and 1-adamantanecarboxylic
acid, can fill the entire inner space of the capsule, releasing the solvent molecules (CDCl3 or C6 D6 ) that originally occupy the cavity to the bulk solvent. They observed
increased guest encapsulation at higher temperatures, simply because the encapsulation is enthalpically disfavored
but entropically favored (Scheme 2). The complex obtained
was much more stable in CDCl3 than in C6 D6 , exhibiting
a >100-fold stability difference for the adamantane guest
(Scheme 2).
Kobayashi et al.2 exploited the dynamic covalent chemistry for supramolecular synthesis in the same solvent pair
(CDCl3 and C6 D6 ) as Kang and Rebek1 did to observe
very different thermodynamic behavior. As illustrated in
Scheme 3, they used the dynamic boronic ester formation
to prepare a cavitand-based capsule, which was demonstrated to have great advantages in supramolecular syntheses because the reversible covalent bond-forming/breaking
= Supramolecular host
+ n
= Guest
= Solvent molecule
Scheme 1
DOI: 10.1002/9780470661345.smc009
Solvation effects in supramolecular recognition
O
N
HN
R
HN
R
N
R = 4-n-heptylphenyl;
X = OH
HN
R
HN
N
R
N
O
O
Monomer (H1)
H1 + H1 = H2
COOH
Encapsulation
Dimeric supramolecular host (H2)
Guest (G)
Thermodynamics of encapsulation of guest (G) with supramolecular host (H2): H2 + G = [H2G]
Ka (M1)
5.6 103
2.3 10
Solvent
CDCl3
C6D6
H (kcal1 mol1)
4.1
3.2
TS (kcal1 mol1)
9.2
5.0
Scheme 2
O
(HO)2B
OH
B(OH)2
OH
R = (CH2)6CH3
(HO)2B
OH
B(OH)2
OH
and 4
"sticks"
Self-assembling of supramolecular
host from 2 "cups"
O
CH3
CH3
Guest
O
CH3
CH3
Thermodynamics of encapsulation of guest (G) with supramolecular host (H): H + G = [HG]

Solvent
CDCl3
C6D6
Ka (M1)
53
6.1 104
H (kcal mol1)
2.7
18.6
TS (kcal mol1)
0.3
11.6
Scheme 3
DOI: 10.1002/9780470661345.smc009
Concepts
process is controlled by thermodynamics. In contrast to

the case of Kang and Rebek,1 the supramolecular recognition in the Kobayashis system was found to be exclusively enthalpy-driven (Scheme 3) in both CDCl3 and
C6 D6 . Furthermore, the recognition ability was much
C D
CDCl
more effective in C6 D6 than in CDCl3 (Ka 6 6 /Ka 3 =
1150), which was the opposite to the results of Kang
and Rebek.1 The comparison of the hostguest combination of Kang and Rebek1 (Scheme 2) with that of
Kobayashi et al.2 (Scheme 3) presents a nice illustration of
an extremely strong dependence of the recognition thermodynamics on the physicochemical properties as well
as the solvation behavior of both host and guest. This
comparison also provides a clear experimental support
for the claim that the noncovalent interactions of guest
and host with nonstructured solvents can make profound
impacts on the thermodynamic behavior of supramolecular
recognition.
The hostguest association process, incorporating structured solvent molecules (with water as the best example),
is illustrated in Scheme 4. It is widely recognized36 that
water is a unique solvent capable of playing active roles
in supramolecular and biological recognition processes; the
detailed information and discussion on this topic may be
found in a recent review.7
One of the recent examples to underscore the unique
water properties is the endohedral clusterization of water
molecules into a molecular ice within a hydrophobic selfassembled cage.8 It was known earlier that the hydrogenbond network of water can spontaneously grow not only on
the surface of hydrophobic solute, affording stable hydrate
+ n
= Supramolecular host
= Guest
= Solvent molecule
Scheme 4
complexes such as methane hydrate, but also within the

hydrophobic interior of supramolecular hosts.9 However,
the Fujitas case8 is special, since 10 water molecules are
self-organized in a Td -symmetrical diamond-like (H2 O)10
cluster that can be considered as a supramolecular guest
(Figure 1) composed of noncovalently bounded solvent
molecules. They suggested that the molecular recognition
by this cage is entropy-driven, and the guest binding is
compensated by the melting of the diamond-like cluster
to free water molecules.
SOLVOPHOBIC THEORY AND

SURFACE TENSION
According to the solvophobic theory originally proposed

in Sinanoglus pioneering papers,10 the free energy change
of complex formation is regarded as a linear function of
3.06
O6
3.09
O3
O1
O4
*O4
*O5
O2
*O3
O5
*O6
(b)
(a)
Figure 1 (a) X-ray crystal structure of self-assembled cage with oxygen atoms (water molecules) around the cage. (b) ORTEP
O1 O3 =
drawing (50% probability ellipsoids) of 10 oxygen atoms (diamond-like cluster) with the cage. Interatomic distances (A):
2.87, O2 O5 = 2.78, O3 O4 = 2.93, O3 O6 = 2.72, O4 O5 = 2.85, O5 O6 = 2.92. (Reproduced from Ref. 8 American Chemical
Society, 2005.)
DOI: 10.1002/9780470661345.smc009

(b)
(a)
H
H
Figure 2 Configurations of liquid water molecules near

hydrophobic cavities in molecular dynamics simulations. The
blue and white particles represent the oxygen (O) and hydrogen
(H) atoms, respectively, of the water molecules. The dashed lines
indicate hydrogen bonds. The space-filling size of the hydrophobic (red) particles in (a) is similar to the methane molecule. The
hydrophobic cluster in (b) contains 135 methane-like particles that
are hexagonally close-packed to form a roughly spherical unit of
radius larger than 1 nm. (Reproduced from Ref. 8 American
Chemical Society, 2005.)
the solvents surface tension ( ). Computer simulations by

Chandler6 allow us to visualize Sinanoglus idea applied
to bulk water, where one could imagine a sort of cavity
or solvent cage that exists around the hydrophobic part
of a guest in bulk water (Figure 2) but would entirely
disappear upon penetration of the hydrophobic part into
appropriate supramolecular host. It is important to underscore that the thermodynamic properties of the cavity
or solvent cage depend on the size of the solute. Small
hydrophobic molecules, such as methane, form the cavity by excluding bulk water molecules from a spherical
volume <0.5 nm across (Figure 2a). This volume is small
enough to accommodate a solute molecule without breaking

the original hydrogen-bonding patterns of bulk water. Thus,
water molecules can adopt such orientations that allow
the hydrogen-bonding network to go around the solute
(Figure 2a). However, large solutes gave a different result
in simulation, where the solute surface expands to an area
larger than 1 nm2 with decreasing curvature (Figure 2b).
The large surface area with a low curvature makes it unbearable for adjacent water molecules to maintain the original hydrogen-bonding network of bulk water, where most
molecules participate typically in four hydrogen bonds.
Most supramolecular hostguest combinations have solvent accessible areas much larger than that of single
methane molecule (Figure 2a), and therefore the cavities
originated from host/guest solvation are accompanied by an
interface similar to that of liquid and vapor, as suggested
by the solvophobic theory. If so, the thermodynamic cost
to solvate to a spherical host or guest of radius R is equal
to G 4 R 2 + (4/3) R 3p, where is liquidvapor
surface tension, and p is pressure, both at the given temperature. When the host/guest dimensions do not exceed few
nanometers, the second term (4/3) R 3p is negligible relative to the first term 4 R 2 , and then we can simplify the
above equation to G 4R 2 . The solvophobic theory was successful in explaining many recognition events
in supramolecular chemistry.11, 12
One of the most convenient supramolecular systems
for investigating the hydrophobic effect is cyclodextrin
(CD) (Scheme 5). - to -CDs, cyclic oligosaccharides
composed of six to eight glucopyranose units, are truncated cone-shaped macrocyclic molecules with a hollow,
tapered cavity (Scheme 5). As a result of the -1,4 linkage
of each glucopyranose unit, all the hydrophilic 2-, 3-,
and 6-hydroxyl groups are located at the exterior of the
OH
4
HO
5
3
n =7
OH
b-CD
a-, b-, g -Cyclodextrin; a -, b -, g- CD (n = 6 8)

COOH
b -CD
= 1 : 1 inclusion complex
Scheme 5
DOI: 10.1002/9780470661345.smc009
Concepts
C5H11NH3+
H
H O
O
H
H
Direct correlation between size of "solvent cavity" and complex stability
N+
H
O
H
H H O
H
H
O H
C5H11NH3+
H O
H
O
H
H
O H
H
HO
O
H
O H
O H
H
O H
H
H O
O H
H
H
H
H O
H
O
H
O
H
O H
H O
O
H
H
O H
H
O H
O H
H
HO
H
O
O H
H
H
H
O H
H
H
O
H
H H O
H
O
H
H
H O
O H
H
H
O H
H O
H
O H
H
H
O
H
O
H
O H
O
H
O
H
O H
H
O
H
O
H
H O
O H
H
O H
O H
H
H
H
H
H
H O
H
O
H
O
H
O H
HO
O H
H
H O
H
H
H O
H
H
H
O H
O
H
O H
H
O
H
N+
H
O HO
H
O H
O H
H
HO
H
H O
H
H
H
O H
H
O
H H O
H
H H O
O
H
O
H
H
O
H H
OH
O
H
O H
O H
H
O H
O H
H
O H
H
H
H
O
H
H
O H
O
H
O H
H
H
O H
H
H
O
O HO
H
H
H
O
H
O H
H O
O H
H
H O
H
O
O H
H
H
O
H H O
H
O
O H
O
H
H
H
H
OH
O
H
O
H
H O
O
H
O H
O H
H
H
O
H
O
H
H
O H
O
H
O H
H
H
O H
O H
H O
H
H
O
O HO
H
H
H
OH
H
HO
H
O
O H
H
O
H H
O
H
O
H
O H
O H
H
O H
H
O
H
H
O
O H H
H O
H
O
H H
H
O
H
O H
H O
H
O
O H
Aliphatic ammonium guest
H
O H O
Imaginated solvent cavity

around aliphatic chain
N+
Hydration shell around

ammonium cation
H H O
O H
H
O
H
H
H
O H
O
H H
O
H
H
O
H
O
H
H H O
N+
H O
H
O
H O
H
OH
H
H
H
H O
H
O
OH
H
H
O
H
O
H
H
O
O H
C7H15NH3+
H H O
O
H
H
O
H H O
H
O H
O H
O
H
C7H15NH3+
H
O H
O H
H
H
O
H
O H
O H
H
H
H O
HO
H
H O
H
H
H
H
OH
O HO
H
H
H O
O H
O
H
H O
H
O
OH
H
H OH
H
OH
O H
H
H O
H
O
O
H
C6H13NH3+
N+
H
O HO
C6H13NH3+
H
H O
N+
O
H
H
H
O H
O
H H
H H O
O H
H
O
H
H
O
H
H
H
OH
O H O
H
H
H
H O
H
OH
H
O H
O
H
- CD macrocyclic host in aqueous solution
Scheme 6
DOI: 10.1002/9780470661345.smc009
O
H
H
O

hydrophobic cavity (Scheme 5).13 In aqueous solution, the
cavity is occupied by several water molecules, which
are excluded from the cavity upon inclusion of a guest.
The most common binding mode of native and modified CDs with various guests involves the penetration
of the more hydrophobic (nonpolar) part of a guest
molecule into the CD cavity, while the more hydrophilic,
often charged, part of the guest stays just outside the
primary or secondary rim of the cavity. This binding mode makes native and modified CDs a very convenient model for investigating the hydrophobic effect
and for verifying the predictions of the solvophobic
theory.
According to the solvophobic theory, the large round
solvent cavity surrounding the hydrophobic adamantyl
moiety should disappear upon inclusion by an appropriate host. Harrison and Eftink14 investigated the inclusion
thermodynamics of adamantanecarboxylate with -CD
(Scheme 5) as a model system for examining the hydrophobic effect. Indeed, a linear correlation of G with was
observed for the 1 : 1 complexation of adamantanecarboxylate with -CD and also for the complexation of several
other guests with CDs.15
According to the solvophobic theory, when the guests
hydrophobic moiety and therefore the solvent cavity
surface increase, the stability of its complex with an
appropriate host capable to comfortably accommodate the
increased moiety should be enhanced. This prediction of
the solvophobic theory is in nice agreement with the
experimental results obtained for the inclusion of homologous aliphatic guests with -CD (Scheme 6). The diameter of simple alkyl chains matches well with the inner
diameter of -CD cavity, which is occupied by several
water molecules in aqueous solution in the absence of
guest (Scheme 6). Upon inclusion of an aliphatic guest
with -CD, not only the water molecules residing in the
CD cavity but also those water molecules that are located
around the penetrating alkyl chain are returned to the
bulk solution. The complex stability (G ) increases
proportionally with increasing alkyl chain length up to
a certain limit, indicating that the G increment per
methylene is kept constant,11 as anticipated from the
solvophobic theory. Certainly, the solvophobic theory is not faultless in explaining a wide variety of
supramolecular recognition phenomena. For instance, the
higher complex stabilities in D2 O than in H2 O are better explained by the appreciably higher surface tension of
D2 O.16
According to the solvophobic theory, the solvent cavity
surface surrounding a hydrophobic moiety (Scheme 6) is
similar to the watervapor interface and thus the configurational rearrangement of water molecules at the interface
does not propagate deep into the bulk water. In contrast,
the hydration shell around a positively or negatively

charged group, schematically illustrated by green sphere in
Scheme 6, can reach several water molecules in the nearest
proximity of the ion, as discovered recently by Tielrooij
et al.17 by using femtosecond infrared spectroscopy.1820
Consequently, it is anticipated that the solvation effect
upon supramolecular recognition behavior may significantly
differ between neutral hydrophobic organic and charged
hydrophilic metal ionic guests.
BINDING OF NEUTRAL VERSUS

IONIC GUEST
Upon supramolecular complexation, neutral hydrophobic

organic compounds and hydrophilic metal cations usually
show entirely different, often opposite, solvent polarity
dependencies. Such contrasting behavior is very generally
observed when one compares the solvophobically versus
electrostatically driven complexation; for detailed discussion, see, for example, the study by Mizutani et al.21 This
difference in solvation property is exploited as a conventional tool for creating a vast variety of supramolecular architectures and devices, including rotaxane-based
molecular shuttles and other so-called molecular
machines.2224
Scheme 7 illustrates an example of the opposite solvent polarity dependencies observed upon complexation
of nonpolar hydrophobic pyrene versus highly hydrophilic
potassium cation. The solvent effect on the binding behavior of neutral nonpolar pyrene with a 3D-cyclophane host
was examined in various solvents (Scheme 7a). Using
this hostguest system, we can make a valuable comparison, since it was revealed that in all the solvents
employed (Scheme 7a) the complex has the same structure and geometry and the large cyclophane cavity is
freely accessible to all solvents, assuring complete solvation.25 The complex stabilities determined for pyrene in
these solvents are nicely correlated with the surface tension of the solvent used, as anticipated from the solvophobic theory. Thus, the affinity for pyrene is highest
in water and lowest in nonpolar solvents such as benzene and carbon disulfide. The logarithm of the obtained
association constant (log K) is nicely correlated with
the solvent polarity parameter ET (30).26 Analogous good
affinitypolarity relationship was found for several other
systems, including the aromatic interactions in metal trisbipyridine complexes.27 These observations are consistent
with the solvophobic nature of aromatic interactions, which
are strengthened in polar solvents that lack the ability
to properly solvate to the nonpolar surfaces of aromatic ring.
DOI: 10.1002/9780470661345.smc009
Concepts
Guest
Solvent
E T(30)
log K
kJ mol1
Host
O
C2H5N
O
N
NC2H5
O
O
N
C2H5N
Water
6.8
264
Methanol
4.6
232
Ethanol
4.4
217
Acetone
3.1
177
Dimethyl sulfoxide
2.8
188
N,N-Dimethylformamide
2.2
183
Dichloromethane
2.1
173
Tetrahydrofuran
1.9
156
Chloroform
1.6
164
Benzene
1.1
144
Carbon disulfide
1.0
136
O
(a)
K+
Guest
Physical properties
Solvent
Host
O
(b)
Surface
tension
/ N m1
Dipole
moment
/D
log K
O
O
Relative
permeability
Water
Dimethylsulfoxide
Benzyl alcohol
N,N-Dimethylformamide
Acetonitrile
Acetone
Methanol
Ethanol
78.4
46.7
13.1
36.7
37.5
20.7
32.7
24.6
0.072
0.043
0.040
0.035
0.028
0.023
0.022
0.022
1.8
3.9
1.7
3.9
3.4
2.7
2.9
1.7
2.0
3.7
4.1
4.3
5.7
6.0
6.2
6.1
Scheme 7
In contrast, the affinity of hydrophilic potassium cation to

simple 18-crown-6 becomes larger by changing the solvent
from water to organic solvents (Scheme 7b).28 Thus, the log
K value is almost proportional to the surface tension ( ) of
the solvent used. The affinity shows similar dependence on
some other solvent parameters, such as relative permeability
and dipole moment.29, 30
Cyclophano-crown ether host (Scheme 8),31 possessing
cyclic polyether and cyclophane moieties in a single
molecule and ability to simultaneously bind a potassium
cation and 6-methoxy-2-naphthonitrile in a watermethanol
mixture, is of particular interest, since the contrasting
solvent effects can be examined in the same host. Indeed,
neutral 6-methoxy-2-naphthonitrile guest forms a 160-fold
more stable complex with the cyclophane moiety in more
hydrophilic 60 : 40 watermethanol solvent than in pure
methanol. In contrast, the affinity toward potassium ion is
enhanced by a factor of 120 in pure methanol rather than
in 60 : 40 watermethanol.
CN
Guests
and
K+
O
Host
CH3
O
CH3
Et +
N
Et
CH3
O
O
O
O
O
O
CH3
Methanol content
(% vol) in water
40
60
80
100
log K
6-Methoxy-2naphthonitrile
K+
3.6
2.6
2.1
1.4
1.1
1.9
2.0
3.2
Scheme 8
DOI: 10.1002/9780470661345.smc009
EFFECTS OF
HOSTGUESTSOLVENT
COMPLEMENTARITY ON
SUPRAMOLECULAR RECOGNITION
It is almost spontaneous to anticipate that inappropriate

molecular size/shape and/or chemical functionality of a
guest prevent it from fully enjoying the most comfortable
association with a designated host. However, a large amount
of the experimental data available for CD complexation
reactions allow us to discuss the roles of hostguest complementarity in supramolecular recognition in further detail.
One of the intriguing issues encountered frequently in guest
inclusion by native CDs is that only the specific part of the
guest penetrating into the CD cavity contributes to the overall complexation thermodynamics. Indeed, the introduction
of a methyl group to the less-polar penetrating part of a
guest consistently enhances the binding constant by a factor
of 24, while the methylation of a charged group (such as
ammonium) that stays outside the cavity when complexed
(Schemes 5 and 6) scarcely affects the complexation thermodynamics.11 Furthermore, the chemical nature, structure,
and even sign of the charged group do not play any significant thermodynamic roles upon complexation with native
CDs, as far as the hydrophobic part of the guest is kept the
same.11 This is obviously nonclassical, unusual, thermodynamic behavior in view of the ordinary solutesolvent
interactions or the conventional solute transfer from water
to nonpolar media.
Another major difference between the conventional

solute transfer and the supramolecular association is the
critical influence of the shape of the guest molecule in
the latter case. This is clearly demonstrated upon complexation of -CD with 2- and 3-phenylbutyric acids. The
apparently trivial change in methyl position leads to a profound difference in complexation thermodynamics. Despite
virtually the same hydrophobicity (judged from the distribution ratio between water and nonpolar organic solvent),
the affinity of 3-phenylbutyric acid toward -CD (K =
402430 M1 ) is more than four times larger than that
of 2-phenylbutyric acid (K = 9495 M1 ).32, 33 This significant difference arises from the greater steric hindrance
encountered by the latter guest upon complexation. The crucial steric effect upon guest binding is commonly found in
the complexation of ortho-substituted phenyl guests, which
always exhibit much lower complexation affinities toward
-CD than their para analogues, due to the steric hindrance
caused by the ortho-substituent.32, 33 This is a good example
of the critical role of steric factors played in CD complexation and supramolecular association in general, highlighting
the intrinsic difference between the inclusion complexation
by CD and the classical hydrophobic processes (e.g., the
transfer from water to nonpolar organic media).
In this context, it is intriguing to investigate the effects of
the size and shape of solvent molecule on supramolecular
association. For instance, the cyclophane host with functionalized tethers, illustrated in Scheme 9, can bind a small
guest such as imidazole in ethers and chlorinated hydrocarbons.34 However, the binding constant for imidazole varies
Host: 3D cyclophane
NO2
O2N
O
Solvent:
chlorinated hydrocarbons
Ka (M1)
CH2Cl2
240
CHCl3
490
CH3CCl3
CHCl2CHCl2
8161
128 000
H
H
N
H
H
N
H
N
N
Guest: imidazole
NO2
O 2N
N
Solvent:
aliphatic ethers
Tetrahydrofurane (THF)
2-CH3-THF
1,4-Dioxane
Tetrahydropyran
2,2-(CH3)2-THF
2,5-(CH3)2-THF
2,2,5,5-(CH3)4-THF
Ka (M1)
29
77
87
104
156
185
1067
Scheme 9
DOI: 10.1002/9780470661345.smc009
10
Concepts
dramatically by twothree orders of magnitude from 29

M1 in THF to 1067 M1 in (CH3 )4 -THF and from 240
M1 in CH2 Cl2 to 128 000 M1 in CHCl2 CHCl2 , critically
depending on the size of the solvent used. Some of the
solvent molecules are larger in size than the guest and the
relatively small binding site of the host is hardly accessible
for the large solvent molecules, which facilitates the guests
access to the interacting site. Consequently, the association
constant increases gradually with increasing size of solvent
molecule in both solvent series of THFs and chloroalkanes.
Probably, the largest sized CHCl2 CHCl2 molecules cannot
penetrate into the host interior, thus giving the largest affinity of 128 000 M1 in the absence of competitors for the
binding site.
When the guest and host interact with the solvent,
the guest binding is expected to become weaker. In the
above case, both imidazole and cyclophane (Scheme 9)
can more strongly interact with THFs, than chloroalkanes,
through hydrogen-bond formation. Hence, the hostguest
association is always much stronger in chloroalkanes than
in THFs of comparable sizes.
EFFECTS OF SOLVATION ON
ENTHALPY- AND ENTROPY-DRIVEN
COMPLEXATION
The greatest affinity that can be achieved by synthetic low

molecular-weight hostguest systems is one of the hot topics in supramolecular chemistry. It has widely been debated
in the literature whether a small receptor can reach the
extraordinary affinities routinely attained by proteinligand
systems or there is something special for proteins that cannot be achieved by small host molecules.35 In this regard,
the avidinbiotin complex is a clear inspiration, as it is
one of the tightest binding biomolecular system, achieving
an extraordinarily high affinity of up to 1015 M1 through
noncovalent interactions.36 The crystal structure of streptavidinbiotin complex provides some clues on how to
achieve such an ultrahigh stability.37 A rigid hydrophobic
box composed predominantly of several heavy aromatic
amino acid residues, that is, Trp, Phe, and Tyr, is formed
around the binding site (Figure 3a). This structure of the
binding site allows robust van der Waals contacts inside the
hydrophobic box and also provides the structural frame
for a multiple hydrogen-bonding network with nearby polar
residues, that is, Tyr, Thr, Ser, and Asn. This highly sophisticated architecture leads to a large negative (favorable)
enthalpy change (H ), which is assignable to the synergetic multiple noncovalent interactions.36 At the same
time, a large negative (unfavorable) entropy change (S )
is anticipated as a consequence of the severe conformational
restriction of the biotin molecule upon complexation with

streptavidin. This effect is, however, cancelled by a large
positive entropy of desolvation, eventually making the overall entropy of complexation nearly zero.36
Recently, by employing a similar synergetic multiple
noncovalent approach and a purely synthetic low molecularweight hostguest system, Rekharsky et al.38 succeeded
in obtaining an equally ultrahigh affinity of 1015 M1 .
Cucurbit[7]uril (CB[7]), which possesses a solid barrelshaped skeleton with a hydrophobic interior and seven
highly polarized carbonyls at each portal (Scheme 10), was
chosen as the host, since CB[7] was known to tightly
bind size/shape-matched aliphatic and aromatic guests.3942
Appropriately sized spherical guest with positively charged
ammonium ions at the opposite ends can establish not only
strong van der Waals hostguest contacts but also develop
electrostatic interactions with negatively charged carbonyl
oxygens of CB[7] at both portals (Scheme 10). Thus, 1,1 bis(trimethylammoniomethyl)ferrocene guest (Scheme 10)
was rationally designed and synthesized as a monovalent
guest fully complementary to CB[7] host that possesses a
round hydrophobic cavity and electrically negative portals.
The tilting of the ferrocene moiety allows the optimized
positioning of the two trimethylammonium groups near
the carbonyl rims to maximize the electrostatic interactions, while keeping the ferrocene at the center, as shown
in Figure 3(b). The extremely large affinity of CB[7] to
1,1 -bis(trimethylammoniomethyl)ferrocene is due to the
large enthalpic gain (Hr = 21.5 kcal mol1 ), originating from the tight fit of the ferrocene core to the rigid CB
cavity, critically assisted by the entropic gain arising from
the dehydration of the CB portals and ammonium ions upon
complexation with little entropic penalty from the loss of
conformational freedoms.
Although purely synthetic systems with larger association constants have been reported,43 the CB[7]-ferrocene
pair (Scheme 10) is unique because it does not rely on
polyvalency. Instead, it achieves the extreme affinity by
overcoming the compensatory enthalpyentropy relationship generally observed in supramolecular complexation,
as exemplified for CDs in Figure 4. The unusually low
entropic cost is traced back to the extensive host desolvation
and also to the rigidity of both host and guest.
As discussed above, the extraordinary high affinity of
avidinbiotin complex originates exclusively from the
large favorable enthalpic gain obtained without paying any
entropic cost to the overall free energy. However, such
proteinligand complexes that are stabilized exclusively
by the entropy term can also exhibit very high affinities.
For instance, HIV-1 protease forms a very stable complex with its strong inhibitor Indinavir with a very high
affinity exceeding 109 M1 .44, 45 The Indinavir binding site
is located between the two subunits of the protease as
DOI: 10.1002/9780470661345.smc009
Guest: biotin
11
Host: streptavidin protein
O
NH
HN
H
H
Phe 130
S
Tyr 43
Trp 92 Trp 75
COOH
Trp 79
(a)
Host: cucurbit[7]uril
Guest:
(CH3)3N+CH2
Fe
CH2N+(CH3)3
(b)
Figure 3 Exclusively enthalpy-driven complexes: (a) biotinstreptavidin complex as one of the tightest binding biomolecular systems,
achieving an extraordinarily high affinity of 1015 M1 through noncovalent interactions (created by the PyMol software based on PDB
entry 2izf ); (b) CB[7] complex with 1,1 -bis(trimethylammoniomethyl)ferrocene as the tightest man-made supramolecular complex that
also achieves an extraordinarily high affinity of 1015 M1 through noncovalent interactions.
shown in Figure 5(a). In contrast to biotinstreptavidin

complex (Figure 3a), almost all heavy and rigid amino
acid residues, that is, Trp, Phe, and Tyr, are located far
from the binding site, making the bound ligand flexible
and adjustable. Consequently, the main driven force for the
proteaseIndinavir complexation is expected to be a large
positive entropic gain arising from the host/guest desolvation. Indeed, the results of calorimetric titration experiments revealed that the complex formation is associated
with a positive (unfavorable) enthalpy change (Hr =
2.1 kcal mol1 ), rendering the entropic term as the sole

favorable driving force.44, 45
Similarly to proteinligand complexation,7 many supramolecular recognition events are entropically favored46
as a result of the profound desolvation from host and
guest. Extensive host/guest desolvation may occur not
only upon classical hydrophobic event, for example,
inclusion of the hydrophobic part of a guest into the
hydrophobic cavity of a host, but also as a result of
charge-neutralizing ion pairing. For instance, the 2 : 1
DOI: 10.1002/9780470661345.smc009
12
Concepts
Host
OO
O
N
N
N
NN N
N
N
NN
N N
OO O
O O O
N
N
N
N
N
N
O
Guest
N NN
N N
N NN
N N
OO
CH2N+(CH3)3
Fe
(CH3)3N+CH2
Scheme 10
TS kJ1 mol1
50
0
Cyclodextrin + Guest
50
100
120
80
40
40
H kJ1 mol1
Figure 4 CB[7] complex with 1,1 -bis (trimethylammoniomethyl)ferrocene achieves its ultrahigh affinity by overcoming the
compensatory enthalpyentropy relationship commonly observed
in supramolecular complexation, as exemplified for cyclodextrins.
hostguest complexation of triguanidinium macrocycles

with trianionic citrate in aqueous media46 is an exclusively
entropy-driven process due to the large desolvation upon
ion pairing (Figure 5b). The authors concluded46 that
controlling supramolecular complexation by entropy effects
may be a more general strategy than the conventional
enthalpy considerations, especially in ion-pairing-driven
molecular recognition.
More detailed information about the differences and
similarities of solvation effect on molecular recognition in
supramolecular hostguest systems versus proteinligand
interactions can be found in recent reviews.4749
parameters for the relevant (supra)molecular systems of

interest. For a wide variety of chemical and biological
molecular recognition systems, the thermodynamic quantities have already been compiled, analyzed, and discussed
in order to extract insights into the mechanistic profiles
of molecular recognition. However, most of the foregoing discussion and conclusions, though certainly selfconsistent within the particular and closely related systems,
unfortunately seem ad hoc or tentative and are not always
applicable to other molecular recognition systems composed of different categories of hostguest combinations. Probably, a most general thermodynamic approach
to globally understand the molecular recognition phenomena is the comprehensive analysis of the compensatory enthalpyentropy relationship observed in many
supramolecular systems.
The enthalpyentropy compensation has long been a hot
topic in chemical literature, because in principle no explicit
relationship between the enthalpy change and the entropy
change can be derived from the fundamental thermodynamics. Nevertheless, the compensatory enthalpyentropy
relationship has frequently been observed in both activation
and thermodynamic quantities determined for a vast variety
of rates and equilibria.
The linear H S relationship observed experimentally leads to empirical equation (2), where the proportional coefficient has the dimension of temperature.
From (2) and the differential form of the GibbsHelmholtz
equation (3), we obtain (4).
H = S
Gr = H T S
Gr = (1 T /)H
THERMODYNAMIC VIEW FOR

GLOBAL UNDERSTANDING OF
MOLECULAR RECOGNITION
In quantitatively discussing the molecular recognition phenomena in various solvents from the supramolecular point
of view, it is indispensable to determine the thermodynamic
(2)
(3)
(4)
Equation (4) clearly indicates that, at the critical point,

so-called isokinetic or isoequilibrium temperature (), the
rate or equilibrium constant is totally independent of the
enthalpic change caused by any alterations in substituent,
solvent, and so on. It is interesting that such phenomena
have been abundantly observed for a wide variety of rates
and equilibria.
DOI: 10.1002/9780470661345.smc009
Host: 2 subunits of HIV-1 protease
Guest: indinavir
N
O
Phe96
OH
13
NH
O
Trp6
Phe96
Trp6
Tyr59
Tyr59
Trp42
Trp42
Phe53
Phe53
(a)
Host: 2 triguanidinium macrocycles
Guest: citric anion (-3)
NH
NH
NH
NH
NH
NH
NH
NH
O
O
NH
O
O
HO
O
NH
NH
NH
NH
NH
NH
NH
NH
NH
(b)
Figure 5 Exclusively entropy-driven complexes: (a) the strong biological complex of inhibitor Indinavir with two subunits of HIV-1
protease (created by the PyMol software based on PDB entry 2r5p); (b) the supramolecular complex of citrate anion (-3) with two
triguanidinium macrocycles through ion pairing.
DOI: 10.1002/9780470661345.smc009
14
Concepts
ENTHALPYENTROPY
COMPENSATION AS A PRACTICAL
TOOL FOR UNDERSTANDING AND
ANALYZING GUEST SOLVATION AND
MOLECULAR RECOGNITION
From the compensatory enthalpyentropy relationship

observed experimentally, the TS value can be linearly correlated with the H value to give (5). When
integrated, (6) and the subsequent combination with (3)
affords (7).
TS = H
TS = H +
Gr
(5)
T S0
(6)
= (1 )H
(7)
Thus, the slope () of the TS -versus-H plot (6)

indicates to what extent the enthalpic gain (H ), which
is induced by any alteration in host, guest, and/or solvent,
is canceled by the accompanying entropic loss (S ). In
other words, only a fraction (1 ) of the enthalpic gain
can contribute to the enhancement of complex stability. On
the other hand, the intercept (TS0 ) represents the inherent
complex stability (Gr ) obtained at H = 0, where the
complex is stabilized even in the absence of enthalpic
gain as long as the TS0 term is positive. From the
comparative analyses of the thermodynamic data for three
types of cation-binding ionophores with different topologies
and rigidities (i.e., glyme, crown ether, and cryptand),50
the slope () and intercept (TS0 ) of the regression line
were related to the degree of conformational change and

the extent of desolvation upon complexation, respectively.
Using and TS0 as quantitative measures for the changes
in conformation and desolvation of both host and guest, the
diverse chemical and biological supramolecular systems can
be analyzed consistently, despite the quite different weak
interactions involved in each supramolecular system.50
The slopes () and the intercepts (TS0 ) obtained for
a variety of supramolecular systems are listed in Table 1.
It is obvious that the conformational changes and desolvation are much larger for the association reactions involving
enzymes, antibodies, and DNA/RNA than for simple synthetic hosts, such as crown ether. In accordance with that,
the slope and the intercept TS0 are larger for the biological systems than for the synthetic systems. It should be
emphasized that even closely related systems, such as CDs
of different sizes (Figure 6), can be consistently analyzed
in terms of the slope and intercept TS0 as measures of
the conformational changes and desolvation, respectively.
Indeed, the slope and intercept TS0 increase from CD to -CD and then to -CD in accordance with the
increased conformational changes and extent of desolvation
upon guest inclusion.
GRUNWALD THEORY ON
ENTHALPYENTROPY
COMPENSATION
The general concept and methodology developed by Grunwald et al.51 provide us with a reliable tool for analyzing the complexation thermodynamic parameters and, in
Table 1 Slope () and intercept (TS ) of H TS plots for supramolecular interactions
of natural and synthetic hosts with a variety of ionic, molecular and biomolecular guests in
homogeneous and heterogeneous solutions.
Host
Guest
Solvent
Glyme
Crown ether
Crown ether (solvent extraction)
Crown ether (sandwich complex)
Long glyme
Cryptand
Ionophore antibiotic
Lariat ether
Bis(crown ether)
Cyclodextrin
Quinone-receptor porphyrin
Metalloporphyrin
Cyclophane/calixarene
Enzyme
Antibody
DNA/RNA
Ion
Ion
Ion
Ion
Ion
Ion
Ion
Ion
Ion
Organic molecule
Quinone
Pyridine
Organic molecule
Coenzyme/substrate/inhibitor
Antigen
DNA/RNA/intercalator
Aqueous
Aqueous
Binary
Aqueous
Aqueous
Aqueous
Aqueous
Aqueous
Aqueous
Aqueous
Organic
Organic
Aqueous
Aqueous
Aqueous
Aqueous
0.89
0.77
0.73
0.93
1.03
0.42
0.93
0.89
1.03
0.93
0.60
0.61
0.78
1.11
0.88
1.03
TS0
2.0
2.9
2.6
3.2
4.2
4.0
5.4
4.3
4.6
3.3
0.0
1.6
3.4
7.0
8.7
8.5
DOI: 10.1002/9780470661345.smc009

40
10
b
a
8
6
TS kJ1 mol1
TS kJ1 mol1
20
0
20
40
4
2
0
2
60
80
100
15
4
4
80
60
40
20
20
H kJ1 mol1
10
H kJ1 mol1
8
particular, for predicting the existence or nonexistence of

meaningful enthalpyentropy compensation in a particular set of limited thermodynamic data. The idea is based
on the separation of overall complexation thermodynamic
parameters into two terms: nominal and environmental. The
nominal part (Gnom , Hnom , and Snom ) is associated
with the complexation of a solvated host with a solvated
guest to form a solvated hostguest complex, while the
environmental part (Genv , Henv , and Senv ) is associated with water molecules involved in solvation/desolvation
processes upon complexation. It was shown that Genv is
equal to zero in dilute solution and thus only Henv and
Senv terms are subject to distinct enthalpyentropy compensation.52
Recently, the experimental confirmation of the Grunwald
theory was achieved by comparing the quality of differential
enthalpyentropy compensation plots for the exchange
equilibrium between (R)- and (S)-enantiomers of chiral
guests in -CDs cavity (8),32 and the exchange equilibrium
between native -CD and 6-ammonio-6-deoxy--CD (am-CD) for chiral and achiral guests (9) 33 :
(8)
TS kJ1 mol1
Figure 6 The H TS compensation plots for complexation

of -, -, and -cyclodextrins with a variety of neutral and
charged guests in aqueous solutions.
[-CDR] + S = [-CDS] + R
(a)
4
2
0
2
4
6
(b)
0
H
2
kJ1
mol1
Figure 7 Differential H TS compensation plots for the

exchange of (a) guest between (R)- and (S)-enantiomers (8) and
of (b) host between native -cyclodextrin and 6-amino-6-deoxy-cyclodextrin (9) in aqueous solutions.
relationships are a direct experimental confirmation of

the Grunwalds prediction that Genv is equal to zero
in dilute solution and thus only Henv and Senv are
subject to the enthalpyentropy compensation. It is obvious
indeed that a larger contribution from the nominal part
(Gnom , Hnom , and Snom ), associated with the particular
complex structure, is expected for the host exchange
from -CD to am--CD than for the enantiomeric guest
exchange in the same -CD cavity.
[-CDG] + am--CD = [am--CDG] + -CD

(9)
Differential thermodynamic parameters calculated for the
hypothetical exchange equilibria, that is, (8) and (9), were
used to build the compensation plot shown in Figure 7(a)
and (b), respectively. Interestingly, in spite of the same
accuracy level and encompassing range of the original
data, the two compensation plots show strikingly different
scattering levels. These compensatory enthalpyentropy
10
CONCLUSION
Solvation to the guest, host, and resulting complex plays

a crucial role in supramolecular chemistry, where several
weak interactions work together. Importantly, the seemingly complicated solvation/desolvation behavior as well
as the conformational changes upon supramolecular interaction can be rationally and globally understood first by
DOI: 10.1002/9780470661345.smc009
16
Concepts
determining the thermodynamic parameters for a wide

variety of chemical and biological supramolecular systems,
and then by analyzing the compensatory enthalpyentropy
relationship widespread in supramolecular recognition phenomena with the aid of the Grunwald theory.
20. J. L. Skinner, Science, 2010, 328, 985.

21. T. Mizutani, K. Wada, and S. Kitagawa, J. Org. Chem.,
2000, 65, 6097.
22. W. R. Browne and B. L. Feringa, Nat. Nanotech., 2006, 1,
25.
23. R. Ballardini, V. Balzani, A. Credi, et al., Acc. Chem. Res.,
2001, 34, 445.
ACKNOWLEDGMENTS
24. V. Balzani, A. Credi, F. M. Raymo, and J. F. Stoddart,

Angew. Chem., Int. Ed., 2000, 39, 3348.
This work was supported in part by Japan Society for the

Promotion of Science (No. 21245011).
25. D. B. Smithrud and F. Diederich, J. Am. Chem. Soc., 1990,

112, 339.
26. C. Reichardt, Solvents and Solvent Effects in Organic Chemistry, 2nd edn, VCH, Weinheim, 1998.
RELATED ARTICLES
27. G. A. Breault, C. A. Hunter, and P. C. Mayers, J. Am.

Chem. Soc., 1998, 120, 3402.
The Thermodynamics of Molecular Recognition
28. R. M. Izatt, K. Pawlak, J. S. Bradshaw, and R. L. Bruening,

Chem. Rev., 1995, 95, 2529.
29. Y. Marcus, Chem. Rev., 2009, 109, 1346.
REFERENCES
1. J. Kang and J. Rebek Jr, Nature, 1996, 382, 239.
2. N. Nishimura, K. Yoza, and K. Kobayashi, J. Am. Chem.
Soc., 2009, 132, 777.
3. D. Eisenberg and W. Kauzmann, The Structure and Properties of Water, Oxford University Press, New York, 1969.
4. F. H. Stillinger, Science, 1980, 209, 451.
5. R. Ludwig, Angew. Chem. Int. Ed., 2001, 40, 1808.
6. D. Chandler, Nature, 2005, 437, 640.
7. P. Ball, Chem. Rev., 2008, 108, 74.
8. M. Yoshizawa, T. Kusukawa, M. Kawano, et al., J. Am.
Chem. Soc., 2005, 127, 2798.
9. K. Koga, G. T. Gao, H. Tanaka, and X. C. Zeng, Nature,
2001, 412, 802.
10. O. Sinanoglu, in Solvent Effects on Molecular Associations
in Molecular Associations in Biology, ed. B. Pullman, Academic Press, New York, 1968, 427.
11. M. V. Rekharsky and Y. Inoue, Chem. Rev., 1998, 98, 1875.
12. F. Diederich, Cyclophanes; Royal Society of Chemistry:
Cambridge, 1991.
13. J. Szejtli and T. Osa, eds., Comprehensive Supramolecular
Chemistry (Cyclodextrins), Vol. 3, Pergamon: Oxford, 1996.
14. J. C. Harrison and M. R. Eftink, Biopolymers, 1982, 21,
1153.
30. Y. Marcus, Ion Solvation, John Wiley & Sons, Ltd, Chichester, 1985.
31. F. Diederich, M. R. Hester, and M. A. Uyeki, Angew. Chem.
Int. Ed., 1988, 100, 1775.
32. M. V. Rekharsky and Y. Inoue, J. Am. Chem. Soc., 2000,
122, 4418.
124, 813.
34. K. T. Chapman and W. C. Still, J. Am. Chem. Soc., 1989,
111, 3075.
35. K. N. Houk, A. G. Leach, S. P. Kim, and X. Y. Zhang,
Angew. Chem., Int. Ed., 2003, 42, 4872.
36. N. M. Green, Biochem. J., 1963, 89, 585.
37. O. Livnah, E. A. Bayer, M. Wilchek, and J. L. Sussman
Proc. Natl. Acad. Sci. U.S.A., 1993, 90, 5076.
38. M. V. Rekharsky, T. Mori, C. Yang, et al., Proc. Natl. Acad.
Sci. U.S.A., 2007, 52, 20737.
39. J. W. Lee, S. Samal, N. Selvapalam, et al., Acc. Chem. Res.,
2003, 36, 621.
40. J. Lagona, P. Mukhopadhyay, S. Chakrabarti, and L. Isaacs
Angew. Chem. Int. Ed., 2005, 44, 4844.
41. W. S. Jeon, K. Moon, S. H. Park, et al., J. Am. Chem. Soc.,
2005, 127, 12984.
42. S. Liu, C. Ruspic, P. Mukhopadhyay, et al., J. Am. Chem.
Soc., 2005, 127, 15959.
15. A. Orstan and J. B. A. Ross, J. Phys. Chem., 1987, 91, 2739.
43. D. H. Williams, E. Stephens, D. P. OBrien, and M. Zhou,

Angew. Chem. Int. Ed., 2004, 43, 6596.

124, 12361.
44. H. Ohtaka, S. Muzammil, A. Schon, et al., Int. J. Biochem.

Cell Biol., 2004, 36, 1787.
17. K. J. Tielrooij, N. Garcia-Araez, M. Bonn, and H. J. Bakker,

Science, 2010, 328, 1006.
45. I. Luque and E. Freire, Proteins, 2002, 49, 181.
18. M. Ji, M. Odelius, and K. J. Gaffney, Science, 2010, 328,

1003.
19. D. Laage and J. T. Hynes, Science, 2006, 311, 832.
46. M. Rekharsky, Y. Inoue, S. Tobey, et al., J. Am. Chem. Soc.,

2002, 124, 14959.
47. E. A. Meyer, R. K. Castellano, and F. Diederich, Angew.
Chem. Int. Ed., 2003, 42, 1210.
DOI: 10.1002/9780470661345.smc009
17
48. R. Paulini, K. Muller, and F. Diederich, Angew. Chem. Int.

Ed., 2005, 44, 1788.
G. W. Gokel, ed., JAI Press, Greenwich, CT, 1997, Vol. 4,

pp. 5596.
49. A. K. H. Hirsch, F. R. Fischer, and F. Diederich, Angew.

Chem. Int. Ed., 2007, 46, 338.
51. E. Grunwald and C. Steel, J. Am. Chem. Soc., 1995, 117,

5687.
50. Y. Inoue and T. Wada, Molecular recognition in chemistry and biology as viewed from enthalpy-entropy compensation effect, in Advances in Supramolecular Chemistry,
52. E. Grunwald, Thermodynamics of Molecular Species, WileyInterscience, New York, 1996.
DOI: 10.1002/9780470661345.smc009

SMC 009

Transféré par

Informations du document

Titre original

Copyright

Formats disponibles

Partager ce document

Partager ou intégrer le document

Options de partage

Avez-vous trouvé ce document utile ?

Ce contenu est-il inapproprié ?

Droits d'auteur :

Formats disponibles

SMC 009

Transféré par

Droits d'auteur :

Formats disponibles

Solvation Effects in Supramolecular Recognition

Mikhail Rekharsky and Yoshihisa Inoue

The solvent effect originates from diverse noncovalent

Solvation is not simply an unavoidable passive event

SOLVATION AND ITS IMPACT ON

The solvation to a neutral or charged species, including the

(Gr , Hr , and Sr ) upon complexation by (1):

RT ln Ka = Gr = Hr TSr

associated with the complex and consequently releasing

Solvation effects in supramolecular recognition

Dimeric supramolecular host (H2)

Thermodynamics of encapsulation of guest (G) with supramolecular host (H2): H2 + G = [H2G]

Thermodynamics of encapsulation of guest (G) with supramolecular host (H): H + G = [HG]

process is controlled by thermodynamics. In contrast to

complexes such as methane hydrate, but also within the

SOLVOPHOBIC THEORY AND

According to the solvophobic theory originally proposed

Solvation effects in supramolecular recognition

Figure 2 Configurations of liquid water molecules near

the solvents surface tension ( ). Computer simulations by

enough to accommodate a solute molecule without breaking

a-, b-, g -Cyclodextrin; a -, b -, g- CD (n = 6 8)

Direct correlation between size of "solvent cavity" and complex stability

Aliphatic ammonium guest

Imaginated solvent cavity

Hydration shell around

- CD macrocyclic host in aqueous solution

Solvation effects in supramolecular recognition

the hydration shell around a positively or negatively

BINDING OF NEUTRAL VERSUS

Upon supramolecular complexation, neutral hydrophobic

In contrast, the affinity of hydrophilic potassium cation to

Solvation effects in supramolecular recognition

It is almost spontaneous to anticipate that inappropriate

Another major difference between the conventional

dramatically by twothree orders of magnitude from 29

The greatest affinity that can be achieved by synthetic low

restriction of the biotin molecule upon complexation with

Solvation effects in supramolecular recognition

Host: streptavidin protein

shown in Figure 5(a). In contrast to biotinstreptavidin

2.1 kcal mol1 ), rendering the entropic term as the sole

hostguest complexation of triguanidinium macrocycles

parameters for the relevant (supra)molecular systems of

Gr = H T S

THERMODYNAMIC VIEW FOR

Equation (4) clearly indicates that, at the critical point,

Solvation effects in supramolecular recognition

Host: 2 subunits of HIV-1 protease

Host: 2 triguanidinium macrocycles

Guest: citric anion (-3)

From the compensatory enthalpyentropy relationship

Thus, the slope () of the TS -versus-H plot (6)

were related to the degree of conformational change and

Solvation effects in supramolecular recognition

particular, for predicting the existence or nonexistence of

Figure 6 The H TS compensation plots for complexation

Figure 7 Differential H TS compensation plots for the

relationships are a direct experimental confirmation of

[-CDG] + am--CD = [am--CDG] + -CD

Solvation to the guest, host, and resulting complex plays

determining the thermodynamic parameters for a wide

20. J. L. Skinner, Science, 2010, 328, 985.