SolVent Effects in Aromatic Stacking Interactions
Table 1. Summary of Binding Data (T ) 298 K)
J. Am. Chem. Soc., Vol. 123, No. 31, 2001 7561
Ka (M-1
)
Ka (M-1
)
Ka (M-1
)
-∆G° (kcal/mol)
(donor-acceptor)
ET(30)
solvent
CDCl3
acetone-d6
DMSO-d6
CD3CN
CD3OD
3:1 CD3OD/D2O
1:1 CD3OD/D2O
1:3 CD3OD/D2O
D2O
(donor-donor)a
(acceptor-acceptor)a
(donor-acceptor)b
(kcal/mol)c
1
2
3
4
5
6
7
8
9
(1)d
(1)d
2 ( <0.5e
8 ( <0.5
3 ( <0.5
11 ( <0.5
30 ( <0.5
63 ( 2
254 ( 41
952 ( 64
2045 ( 63
0.4
1.2
0.7
1.4
2.0
2.5
3.3
4.1
4.5
39.1
42.2
45
45.6
55.5
57
58.9
60.8
63
1 ( <0.5
1 ( <0.5
2 ( <0.5
3 ( <0.5
8 ( <0.5
15 ( <0.5
28 ( 2
1 ( 1
1 ( 1
1 ( <0.5
1 ( <0.5
2 ( <0.5
10 ( 2
20 ( 4
101 ( 28
245 ( 101
a Self-association constants calculated using HOSTEST dimerization model (Option 2).8 b Association constants calculated using HOSTEST 1:1
and 2:1 binding models (Option 3), including self-association of solutes. c ET(30) values are of nondeuterated solvents. These values should be a
good approximation for deuterated solvents based on comparisons of deuterated vs nondeuterated solvents found in ref 10a. The ET(30) values for
CD3OD/D2O mixtures were calculated from a linear curve-fit of ET(30) vs CH3OHH2O mixtures.9 d Small effects of concentration of chemical
shift were observed, but HOSTEST could not calculate a binding constant from dilution data. e The CDCl3 titration data could only be fit to a
binding model that excluded self-association of the solutes.
these complementary electrostatic surfaces could provide a
significant driving force for face-to-face stacking and thus
aedamer folding. However, the flat surfaces of aromatic
molecules are traditionally considered hydrophobic.4 As a result,
aedamer conformation could also be the result of desolvation,
also known as the hydrophobic effect, in which the hydrophobic
surface area of the aedamer structure exposed to polar solvent
is minimized upon aromatic stacking.4,5 Note that Moore et al.
have concluded that solvophobic interactions dictate the con-
formation of the phenylacetylene foldamers.3
Trends observed in the association constants between 1 and
2 in solvents of varying polarity can be used to distinguish
between these two possibilities. If complexation is due primarily
to electrostatic interactions, donor-acceptor interactions will
decrease with increasing solvent polarity as more polar solvents
are assumed better able to disrupt electrostatic attraction.
However, if complexation is the result of a hydrophobic effect,
association constants will increase with increasing solvent
polarity. Note that biphasic behavior is also a possibility and
would indicate that both interactions are important, but con-
tribute differently in different solvents. Mayers et al. observed
such a biphasic behavior within metal tris-bipyridine com-
plexes,6 indicating strong intramolecular aromatic interactions
within these complexes in both nonpolar and polar solvents.
Donor monomer 1 was found to be completely soluble in a
variety of organic solvents (CHCl3, acetone, DMSO, CH3CN,
and CH3OH) and water. Acceptor monomer 2 was found to be
completely soluble in all these solvents except for acetone,
CH3CN, and CH3OH, which required the addition of up to 10%
(v/v) DMSO to give homogeneous solutions.
1H NMR Dilution Studies. Ideally, a 1:1 complex would be
the only type of association event occurring in solution
throughout the 1H NMR binding studies. However, in practice,
additional binding events must be considered with stacking of
aromatic species. Of particular importance in this study is
contributing equilibria resulting from the self-association of
monomers 1 and 2 as well as the formation of donor-acceptor
complexes beyond 1:1.
Prior to any binding analyses of monomers 1 and 2, 1H NMR
dilution studies were carried out with both monomers in each
of the nine solvents or solvent mixtures to quantify the
propensity of these compounds to self-associate (see Table 1).
The aromatic signals of monomers 1 and 2 were monitored as
a function of concentration and quantitative analysis of the data
was accomplished using the HOSTEST program developed by
Wilcox and Glagovich.7 Self-association of monomer 1 was very
weak (<2 M-1) in the majority of solvents, although dimer-
ization was more significant in 1:3 CD3OD/D2O and D2O (10
( 2 and 20 ( 4 M-1, respectively). The dimerization constants
for acceptor monomer 2 were significantly larger and increased
with increasing polarity of the solvent. In D2O, self-association
Results
Synthesis. Monomers 1 and 2 were synthesized utilizing a
of acceptor monomer 2 was found to be 245 ( 101 M-1
.
previously reported procedure (see the Supporting Information).2c
1H NMR Binding Studies. Since acceptor 2 has a greater
tendency to self-associate than donor 1, binding analyses were
carried out in which the concentration of 2 was held constant
at 0.4 mM in the presence of increasing concentrations of 1.
The Scatchard plots of the binding data were noticeably curved.
Deranleau showed that a curved Scatchard plot is consistent
with multiple equilibria (i.e. 1:1 + 2:1 complexes).8 Thus, a
model that accounted for multiple equilibria (1:1 and 2:1
binding) as well as self-association of the monomers was used
(4) For leading references, see: (a) Privalov, P. L.; Gill, S. J. Pure Appl.
Chem. 1989, 61, 1097. (b) Silverstein, K. A. T.; Haymet, A. D. J.; Dill, K.
A. J. Am. Chem. Soc. 1998, 120, 3166. (c) Muller, N. Acc. Chem. Res.
1990, 23, 23. (d) Besseling, N. A. M.; Lyklema, J. J. Phys. Chem. B 1997,
101, 7604. (e) Baldwin, R. L. Proc. Natl. Acad. Sci. U.S.A. 1986, 83, 8069.
(f) Kronberg, B.; Costas, M.; Silveston, R. J. Dispersion Sci. Technol. 1994,
15, 333. (g) Blokzijl, W.; Engberts, J. B. F. N. Angew. Chem., Int. Ed.
Engl. 1993, 32, 1545. (h) Makhatadze, G. I.; Privalov, P. L. J. Mol. Biol.
1990, 213, 375. (i) Tanford, C. The hydrophobic effect: formation of
micelles and biological membranes, 2nd ed.; John Wiley & Sons: New
York, Chichester, Brisbane, Toronto, 1980. (j) Marmur, A. J. Am. Chem.
Soc. 2000, 122, 2120. (k) Ben-Naim, A. Hydrophobic interactions; Plenum
Press: New York, London, 1980. (l) Shinoda, K. J. Phys. Chem. 1977, 81,
1300. (m) Cramer, R. D., III J. Am. Chem. Soc. 1977, 99, 5408. (n)
Makhatadze, G. I.; Privalov, P. L. J. Mol. Biol. 1993, 232, 639, 660. (o)
Kauzmann, W. In AdVances in protein chemistry; Anfinsen, C. B., Jr.,
Anson, M. L., Bailey, K., Edsall, J. T., Eds.; Academic Press: New York,
London, 1959; Vol. 6, pp 1-63.
1
to analyze the H NMR binding data using the HOSTEST
program. Chemical shift data obtained from aedamer and
aedamer-related compounds 2c,9 are in good agreement with the
chemical shifts calculated from this binding model.
(6) Breault, G. A.; Hunter, C. A.; Mayers, P. C. J. Am. Chem. Soc. 1998,
120, 3402.
(7) Wilcox, C. S.; Glagovich, N. M. HOSTEST, v5.1; Department of
Chemistry, University of Pittsburgh: Pittsburgh, PA, 1994.
(8) Deranleau, D. A. J. Am. Chem. Soc. 1969, 91, 4050.
(9) Hamilton, D. G.; Davies, J. E.; Prodi, L.; Sanders, J. K. M. Chem.
Eur. J. 1998, 4, 608.
(5) For studies of solvophobic effects in aromatic-aromatic interactions,
see: (a) Gardner, R. S.; McKay, S. L.; Gellman, S. H. Org. Lett. 2000, 2,
2335. (b) Gardner, R. S.; Christianson, L. A.; Gellman, S. H. J. Am. Chem.
Soc. 1997, 119, 5041. (c) Newcomb, L. F.; Haque, T. S.; Gellman, S. H. J.
Am. Chem. Soc. 1995, 117, 6509. (d) Newcomb, L. F.; Gellman, S. H. J.
Am. Chem. Soc. 1994, 116, 4993.