J. Am. Chem. Soc. 2000, 122, 4251-4252
4251
Diversity and Selection in Self-Assembled Tetrameric
Capsules
Fraser Hof, Colin Nuckolls, and Julius Rebek, Jr.*
The Skaggs Institute for Chemical Biology and
Department of Chemistry
The Scripps Research Institute,
10550 North Torrey Pines Road
La Jolla, California 92037
ReceiVed February 11, 2000
Self-assembling systems can be used to generate molecular
variance through the reversible association of a few components
into a large number of multicomponent species.1,2 The result is a
dynamic library of assemblies whose composition is thermody-
namically controlledsthe relative populations of its components
are determined by noncovalent interactions. If these assemblies
are also receptors, the library distribution will be biased toward
those members that interact most favorably with added target
molecules. Here, we report the generation of large numbers of
self-assembled molecular capsules from relatively few reversibly
associating components. This library of capsules displays spon-
taneous selection of the strongest receptors for the binding of
guest molecules.
Molecular capsules emerge when subunits displaying appropri-
ate curvature and self-complementary hydrogen bonding sites self-
assemble.3 These capsules assemble only in the presence of a
guest of suitable size and shape, empty capsules are not formed.
Compound 1 (Figure 1a) has been shown to assemble into a
tetrameric capsule that encapsulates a variety of cyclic guest
molecules.4 The assembly arises from the preferential hydrogen
bonding of the cyclic sulfamide donor and glycoluril acceptor
that results in a head-to-tail arrangement of monomers (Figure
1b,c). Substituents on the central aromatic spacer do not disrupt
the forces responsible for the assembly of the capsule but do have
effects on the size, shape and chemical surface of the cavity.5
Either attractive hydrogen-bonding interactions (R ) OH, Figure
1e)5 or repulsive steric interactions (R ) OMe, Figure 1f) result
from the proximal positioning of substituents on neighboring
subunits in the assembled state. In short, each self-assembled
capsule may show different affinities for a given guest molecule.
Figure 1. (a) Structures of compounds 1-5. Both 4 and 5 are chiral
and are each present as racemates. (b) The seam of eight hydrogen bonds
at each end of the capsule. (c) Structure of capsule 1:1:1:1.10 (d) A model10
of two neighboring subunits from the tetrameric capsule made up of
compound 1. (e) The attractive hydrogen bonding interaction due to
hydroxyl groups on the central ring (as in 2 and 4). (f) The repulsive
steric interactions due to methoxyl groups on the central ring (as in 3
and 5). Some substituents and hydrogen atoms have been omitted for
clarity.
We expected that an equilibrating system of mixed-composition
tetrameric capsules would result from the combination of subunits
1-5.6 Due to the complexity of the mixture 1H NMR is of limited
utility in analysis. Instead, electrospray mass spectrometry7
(ESMS) was used to determine the composition of the mixture
through mass coding. The peripheral alkyl groups of the mono-
mers were selected such that each of the possible tetramers has
a unique mass. Encapsulation of a charged guest species in an
organic solvent gives ionic species, their relative abundances and
energies are qualitatively reflected in the gas phase.7a
The combination of two monomers (1 and 2) can produce six
structurally different tetrameric capsules, having five different
masses. An equimolar solution of these subunits in the presence
of ethyltrimethylammonium cation (6)8 gave a nonstatistical
mixture of all five observable receptor-guest complexes in the
dynamic library as determined by ESMS. There is clearly not
one favored species in this limited dynamic library. There is,
however, a significant thermodynamic bias for the binding of the
guest 6: the measured composition of 22:32:31:13:2 (by percent-
age, from lowest to highest mass) is significantly different from
the statistically predicted 6:25:38:25:6.9 Equilibration of equimolar
amounts of 1 and 2 with methylquinuclidinium cation (7) as a
guest results in a very different profile. The mass spectrum shows
one capsule (7@1:1:1:1) in a greater than 5-fold excess over any
other combination. Capsule 7@1:1:1:1 represents 69% of the
observed tetrameric capsules, or 11x the amount predicted by
(1) Diversity achieved through the assembly of more than one type of
molecular subunit: (a) Calama, M. C.; Timmerman, P.; Reinhoudt, D. N.
Angew. Chem., Int. Ed. 2000, 39, 755. (b) Klekota, B.; Miller, B. L.
Tetrahedron 1999, 55, 11687. (c) Huc, I.; Krische, M. J.; Funeriu, D. P.; Lehn,
J.-M. Eur. J. Inorg. Chem. 1999, 1415. (d) Hioki, H.; Still, W. C. J. Org.
Chem. 1998, 63, 904. (e) Rivera, J. M.; Mart´ın, T.; Rebek, J., Jr. J. Am. Chem.
Soc. 1998, 120, 819. (f) Castellano, R. K.; Kim, B. H.; Rebek, J., Jr. J. Am.
Chem. Soc. 1997, 119, 12671. (g) Klekota, B.; Hammond, M. H.; Miller, B.
L. Tetrahedron Lett. 1997, 38, 8639. (h) Huc, I.; Lehn, J.-M. Proc. Nat. Acad.
Sci. U.S.A. 1997, 94, 2106. Diversity achieved by the association of a single
molecule into different assembled states: (i) Hiraoka, S.; Fujita, M. J. Am.
Chem. Soc. 1999, 121, 10239. (j) Lee, S. B.; Hwang, S.; Chung, D. S.; Yun,
H.; Hong, J.-I. Tetrahedron Lett. 1998, 39, 873. (k) Hasenknopf, B.; Lehn,
J.-M.; Boumediene, N.; Dupont-Gervain, A.; Dorsselaer, A. V.; Kneisel, B.;
Fenske, D. J. Am. Chem. Soc. 1997, 119, 10956. (l) Brady, P. A.; Sanders, J.
K. M. J. Chem. Soc., Perkin Trans. 1 1997, 3237. For reviews and
discussions: (m) Lehn, J.-M. Chem. Eur. J. 1999, 5, 2455. (n) Klekota, B.;
Miller, B. L. Trends Biotech. 1999, 17, 205. (o) Ganesan, A. Angew. Chem.,
Int. Ed. 1998, 37, 2828.
(2) Guest templation of receptors: (a) Eliseev, A. V.; Nelen. M. I. J. Am.
Chem. Soc. 1997, 119, 1147. (b) Scherer, M.; Caulder, D. L.; Johnson, D.
W.; Raymond, K. N. Angew. Chem., Int. Ed. 1999, 38, 1588. (c) Fujita, M.;
Nagao, S.; Ogura, K. J. Am. Chem. Soc. 1995, 117, 1649. (d) Ibukoro, F.;
Kusukawa, T.; Fujita, M. J. Am. Chem. Soc. 1998, 120, 8561.
(3) (a) Conn, M. M.; Rebek, J., Jr. Chem. ReV. 1997, 97, 1647. (b) Rebek,
J., Jr. Acc. Chem. Res. 1999, 32, 278.
(4) Mart´ın, T.; Obst, U.; Rebek, J., Jr. Science, 1998, 281, 1842.
(5) Nuckolls, C.; Hof, F.; Mart´ın, T.; Rebek, J., Jr. J. Am. Chem. Soc. 1999,
121, 10281.
(6) Compounds 2, 3, and 5 were synthesized by routes analogous to those
previously published for compounds 14 and 4.5
(7) For the use of ESMS to study the parent tetrameric capsule, see (a)
Schalley, C. A.; Mart´ın, T.; Obst, U.; Rebek, J., Jr. J. Am. Chem. Soc. 1999,
121, 2133. (b) For application to other self-assembled systems, see: Schalley,
C. A. Int. J. Mass. Spec. 2000, 194, 11 and references therein.
(8) All cationic guests were added as the tetrafluoroborate salts.
(9) It is impossible to measure the distribution of capsules formed in the
absence of a guest’s thermodynamic bias, due to the inability of the capsules
to form without a guest. Thus, comparison to the mixture predicted by statistics
is the only means of examining the thermodynamic bias imparted by the guests.
10.1021/ja0005136 CCC: $19.00 © 2000 American Chemical Society
Published on Web 04/14/2000