Cooperativity in multiply H-bonded complexes

Article abstract of DOI:10.1039/b908010d

The free energy of complexation of supramolecular complexes containing phenol-carbamate H-bonds is an additive function of the number of H-bonds, with a constant increment of 6 kJ mol^-1 per interaction in carbon tetrachloride.

Full text of DOI:10.1039/b908010d

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Cooperativity in multiply H-bonded complexesw
Christopher A. Hunter,* Ndidi Ihekwaba, Maria Cristina Misuraca,
Maria Dolores Segarra-Maset and Simon M. Turega
Received (in Cambridge, UK) 21st April 2009, Accepted 20th May 2009
First published as an Advance Article on the web 2nd June 2009
DOI: 10.1039/b908010d
The free energy of complexation of supramolecular complexes
containing phenol–carbamate H-bonds is an additive function of
the number of H-bonds, with a constant increment of 6 kJ molÀ1
per interaction in carbon tetrachloride.
(Fig. 2). The one, two and three H-bond scaffolds are all based
on a methane core, and a porphyrin core was used as the basis
for the four H-bond system. Compounds 1b, 2b and 3b were
prepared from the commercially available phenols, 1a, 2a and
3a (Fig. 2). The porphyrin tetraphenol 4a was prepared using
literature procedures,4 and this was converted to 4b in the
same way.
Multiple intermolecular interactions between two molecules
lead to cooperative stabilisation of the resulting non-covalent
complex.1 The magnitude of this stabilisation depends on the
number of interactions, the properties of the functional
groups, the solvent and the overall supramolecular architecture.
Although it is possible to make reasonably accurate predictions
of the stability of complexes that feature a single functional
group interaction, extension to more complex systems with
multiple interactions remains a challenge.2 There are two key
issues that must be addressed in order to achieve this:
how transferrable are the thermodynamic contributions of
individual functional group interactions from one system to
another? And what are the thermodynamic contributions
associated with geometric complementarity and conforma-
tional flexibility of the covalent scaffolds that display the
interaction sites? We have previously found that free energy
and enthalpy contributions of metal–ligand coordination
bonds are additive in porphyrin assemblies held together by
multiple interactions.3 In this paper, we extend these studies to
more weakly bound H-bonded complexes. We address the
issue of transferrability by studying the properties of one type
of H-bond in a variety of supramolecular contexts.
Fig. 1 shows the structures of the complexes that can be
formed between complementary pairs of compounds. Binding
studies were carried out in carbon tetrachloride, because it is a
very non-competitive solvent (a = 1.4, b = 0.6),2 so that even
the complex with only one H-bond is sufficiently stable for
1
accurate measurement of the association constant. H NMR
dilution experiments on the carbamates showed no evidence of
self-association in carbon tetrachloride. The phenols are
relatively insoluble, and for 3a and 4a, it is not possible to
obtain 1H NMR spectra in carbon tetrachloride on a timescale
suitable for NMR titrations. However, mM solutions of 3a or
4a could be obtained in the presence of an excess of the
complementary carbamate, 3b or 4b, respectively. The phenols
are fully bound in the resulting solution, and 1 : 1 association
constants were measured by dilution of the mixtures. Phenols
1a and 2a were sufficiently soluble in carbon tetrachloride to
be used as hosts in conventional titration experiments with the
complementary carbamate, 1b or 2b, respectively, as the guest.
The dilution and titration data fit well to a 1 : 1 binding
isotherm in all cases. For 1aÁ1b, 2aÁ2b and 3aÁ3b, +2 ppm
1
limiting complexation-induced changes in H NMR chemical
To minimise the thermodynamic contributions associated
with different supramolecular architectures, we designed a set
of related self-complementary covalent scaffolds containing
one, two, three and four sites for functionalisation with
H-bonding groups (Fig. 1). Phenol was chosen as the H-bond
donor and carbamate as the H-bond acceptor, because these
functional groups have relatively high H-bond parameters
(a = 3.8, b = 8.3) and so form stable complexes in non-polar
solvents.2 These functional groups do not self-associate to any
significant extent, because phenol is a very weak H-bond
acceptor and carbamate only has CH donors, and this greatly
simplifies the experimental characterisation of systems with
multiple interaction sites. In addition, the carbamates can be
readily prepared from the corresponding phenols, so that
complementary oligomeric scaffolds are synthetically accessible
shift were determined for the signals due to the phenol OH
protons, indicative of H-bond interactions (the phenol OH
Department of Chemistry, University of Sheffield, Sheffield,
UK S3 7HF. E-mail: c.hunter@shef.ac.uk;
Fax: +44 (0)114 2229346; Tel: +44 (0)114 2229476
w Electronic supplementary information (ESI) available: Spectro-
scopic characterisation of new compounds and NMR titration data.
See DOI: 10.1039/b908010d
Fig. 1 H-bonded complexes containing one to four H-bonds. Some
bonds in the porphyrins (4a and 4b) are omitted for clarity.
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Fig. 3 The statistically corrected free energy of complexation À(DGN +
RT ln N) versus the number of intramolecular H-bonds (N À 1) for the
complexes in Fig. 1. The best fit straight line is shown (r2 = 0.99).
Fig. 2 Synthesis and structures of the compounds used in this study.
H-bonds, and the third term is the statistical factor. Thus
plotting the statistically corrected free energy of complexation
(DGN + RT ln N) versus the number of intramolecular
H-bonds (N À 1) should give a straight line with a slope of
ÀRT ln(K0EMN), the free energy contribution of an intra-
molecular H-bond, which is concentration-independent, and
an intercept of ÀRT ln(K0), the free energy contribution of an
intermolecular H-bond, which is concentration-dependent.
Fig. 3 shows that a plot of (DGN + RT ln N) versus (N À 1)
does indeed give a straight line, which is consistent with
eqn (2), if K0 and EMN are constants for all of the complexes
and independent of N. In other words, these experiments
indicate that the cooperativity associated with the formation
of intramolecular H-bonds does not depend on the overall
stability of the complex or on the degree of conformational
restriction imposed by the formation of a (poly)macrocyclic
architecture. The functional groups involved in H-bonding,
phenol and phenyl carbamate, are attached to their central
scaffold (methane or porphyrin) by a single rotatable bond in
all cases, and so statistical or entropic factors associated with
changes in rotameric states are unlikely to vary significantly
from one system to another. The observed value of EMN
includes these contributions, but this factor appears to be
similar for each intramolecular interaction in the complexes
studied here. The best fit straight line in Fig. 3 has a slope of
6 kJ molÀ1, which is the contribution of each intramolecular
H-bond to the overall stability of the complex. The intercept
is 7 kJ molÀ1, which allows determination of the values of
K0 = 17 MÀ1 and EMN = 0.5 M.
(i) 4-Nitrophenyl chloroformate, (ii) bis(2-ethylhexyl)amine.
signal was not resolved in the spectrum of the 4aÁ4b complex).
The association constants in Table 1 show that the stabilities
of the complexes increase with the number of H-bonds (N):
addition of each H-bond increases the association constant by
an order of magnitude.
A more detailed analysis of the cooperativity in these
systems requires consideration of their symmetry, because
there is a statistical factor (N) that biases the equilibrium in
favour of multiply H-bonded complexes.5 In systems that
make more than one intermolecular interaction, effective
molarity is usually used to quantify the degree of cooperativity
associated with the intramolecular contacts.6 Effective
molarity is the ratio of the equilibrium constants for intra-
molecular and the corresponding intermolecular interactions.
In the complexes described here, it is difficult to separate
individual effective molarities for each of the intramolecular
contacts.7 Thus we estimate the average effective molarity for
all of the intramolecular interactions in a complex that makes
N H-bonds, EMN, using eqn (1)
KN = NK0NEMNNÀ1 = NK0(K0EMN)NÀ1
(1)
where K0 is the microscopic association constant for the
formation a single H-bond (in principle, equal to K1).
Eqn (1) can be used to express the free energy of complexation,
DGN, as a function of N (eqn (2)).
DGN = ÀRT ln K0 À (N À 1) RT ln(K0EMN) À RT ln N (2)
The complexes described here span a range of stability of
more than three orders of magnitude, due to cooperativity in
the multiply H-bonded systems. By attaching increasing
numbers of identical H-bonding groups to rigid scaffolds, it
is possible to quantify the thermodynamic contribution of
individual H-bond interactions to the overall stability of the
complexes. A phenol–carbamate H-bond increases the stability
of a complex by 6 kJ molÀ1 in carbon tetrachloride. This
contribution is the same for all of the systems studied and is
independent of the overall stability of the complex or number
of interactions. This suggests that it is possible to understand
the thermodynamic properties of multiply H-bonded complexes
based on free energy increments associated with the individual
H-bonds using a simple additive approach.2,3,8 The H-bonding
sites in these complexes have been deliberately selected to be
The first term in eqn (2) represents the free energy contribution
of the first intermolecular H-bond, the second term is the free
energy contribution of the subsequent N À 1 intramolecular
Table 1 Association constants measured using 1H NMR titrations
and dilutions in carbon tetrachloride at 298 K
Complex
N
KN/MÀ1
Errora (%)
1aÁ1b
2aÁ2b
3aÁ3b
4aÁ4b
1
2
3
4
18
260
7200
50 000
20
10
60
40
a
The values of KN are the average of at least three experiments and
errors are quoted at the 95% confidence limit.
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remote in order to minimise secondary electrostatic inter-
actions, but in systems where the H-bonding sites are
very close in space, there may be additional free energy
contributions due to secondary interactions.
2 C. A. Hunter, Angew. Chem., Int. Ed., 2004, 43, 5310–17725;
E. Chekmeneva, C. A. Hunter, M. J. Packer and S. M. Turega,
J. Am. Chem. Soc., 2008, 130, 17718–17725.
3 A. Camara-Campos, C. A. Hunter and S. Tomas, Proc. Natl. Acad.
Sci. U. S. A., 2006, 103, 3034–3038.
4 A. Wiehe, Y. M. Shaker, J. C. Brandt, S. Mebs, S. M. Stefan and
M. O. Senge, Tetrahedron, 2005, 51, 5535–5564.
We thank the EPSRC for funding.
5 G. Ercolani, J. Am. Chem. Soc., 2003, 125, 16097–16103;
G. Ercolani, C. Piguet, M. Borkovec and J. Hamacek, J. Phys.
Chem. B, 2007, 111, 12195–12203.
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3966 | Chem. Commun., 2009, 3964–3966