Structural rules governing self-assembly emerge from new molecular capsules

Full text of DOI:10.1021/ja973341u

J. Am. Chem. Soc. 1998, 120, 819-820
819
Scheme 1
Structural Rules Governing Self-Assembly Emerge
from New Molecular Capsules
Jose´ M. Rivera,†,‡ Toma´s Mart´ın,‡ and Julius Rebek, Jr.*,‡
Department of Chemistry
Massachusetts Institute of Technology
Cambridge, Massachusetts 02139
The Skaggs Institute for Chemical Biology
The Scripps Research Institute
Scheme 2
La Jolla, California 92037
ReceiVed September 24, 1997
Structures such as 1 are self-complementary and dimerize
because hydrogen-bond donors at the ends of the molecule are
appropriately positioned for binding to the hydrogen-bond ac-
ceptors in the middle (Scheme 1). The overall dimensions of
the dimeric assembly are determined by the size of the spacers
between the glycolurils and the hinge. With spacers such as
benzene 1a or hydroquinone 1b, dimerization in organic solvents
leads to a pseudospherical capsule, the “softball” (Figure 2).1 The
present work was designed to test how much stress, in the form
of structural change, could be incorporated into the system before
its self-assembling properties broke down. We describe here two
variants using an ethylene spacer; the synthesis, assembly
properties, and encapsulation behavior of the “wiffle balls” 2 and
3 are discussed.
Scheme 3
The syntheses of 2 and 3 were performed as shown in Schemes
2 and 3 (see the Supporting Information).2, 3
Monomer 2 features five- and six-membered rings on either
end of the ethylene unit which make its spacer somewhat shorter
and more rigid than that of 1. The dimeric form, accordingly,
has a smaller volume (245 Å,3 compared with the 313 Å3 in the
“softball”).4 In compound 3, the ethylene appears as the ring
fusion between seven- and six-membered rings and the much-
reduced dimensions lead to a dimeric capsule of only 187 Å3.
The proton NMR signals of molecule 2 are sharp and well-
defined in a variety of solvents (CD2Cl2, CDCl3, C6D6, toluene-
d8), and considerable downfield shifts are observed for the NH
resonances (CD2Cl2 δ ) 7.59 ppm, CDCl3 δ ) 7.69 ppm, C6D6
δ ) 8.48 ppm, toluene-d8 δ ) 8.21 ppm). The chemical shifts
of these signals are independent of concentration and are
characteristic of an ordered, extensively hydrogen-bonded system.
The ease with which this molecule dimerizes in different solvents
suggests a higher degree of preorganization in this system
compared to that in the “softball” 1a‚1a. Nonetheless, in
p-xylene-d10 it gives a broad spectrum, suggesting dynamic effects
or the presence of higher order aggregates that form because the
solvent is a poor guest for the dimer.
Scheme 4
integrated for guests inside the capsule and those in bulk solution;
exchange is slow on the NMR time scale, though fast on the
human time scale. Data obtained from the 1H NMR spectra were
used to calculate equilibrium association constants (K′a) for
various guests.5, Direct competition experiments7, gave the
6
8
additional K′a for different guests as reported in Table 1.
Encapsulation experiments with 2 were performed in p-xylene-
d10 using the molecules of Scheme 4. Addition of these guests
results in the emergence of the sharp NMR signals of ordered,
occupied capsular forms, but the ability of these guests to induce
the capsular form at room temperature varied with their sizes,
shapes, and functionalities. Separate signals were observed and
(5) These values are derived from eq 1 and are apparent association
constants, K′a, because of the unknown resting state of 2 in the solvent
(assumed to be aggregated); g ) guest.
[2‚g‚2]
[2(aggregate)][g]
2(aggregate) + g h 2‚g‚2 K′a )
(1)
† Massachusetts Institute of Technology.
‡ The Scripps Research Institute.
(6) The assumptions are (1) the amount of dimer (unfilled or filled with
solvent) present before addition of the guest is negligible, (2) after addition
of the guest, all of the host material not assembled into the capsule is in the
aggregate state, and (3) the association of the guest with itself is negligible.
(7) The competition experiments were performed using a solution of 2 in
p-xylene-d10 with 1 equiv of a guest (2‚g‚2) and addition of 1 equiv of another
guest (g′).
(1) (a) Meissner, R. S.; Rebek, Jr., J.; de Mendoza, J. Science 1995, 270,
1485-1488. (b) Kang, J.; Rebek, Jr., J. Nature 1996, 382, 239. (c) Conn, M.
M.; Rebek, Jr., J. Chem. ReV. 1997, 97, 1647.
(2) Rudkevich, D. M.; Rebek, J., Jr. Angew. Chem., Int. Ed. Engl. 1997,
36, 846.
(3) The compounds 2 and 3 were obtained together with their corresponding
geometrical isomers (2s, 2w, 3s, 3w), which were separated by chromato-
graphic methods. Tokunaga, Y.; Rudkevich, D. M.; Rebek, J., Jr. Angew.
Chem., Int. Ed. Engl. 1997, 36, 2656-2659.
K′′a
K′a
[2‚g′‚2][g]
[2‚g‚2][g′]
2‚g‚2 + g′ h 2‚g′‚2 + g K )
)
(4) Results obtained from the GRASP program. Nicholls, A.; Sharp, K.
A.; Honig, B. Proteins 1991, 11, 281.
S0002-7863(97)03341-6 CCC: $15.00 © 1998 American Chemical Society
Published on Web 01/16/1998

820 J. Am. Chem. Soc., Vol. 120, No. 4, 1998
Communications to the Editor
Table 1. Inclusion of Guest Species in the Cavity of the Dimer
2‚2
packing
coefficient
-∆G°
guest
K′a (M-1
)
(kcal mol-1
)
15
16
17
18
19
20
21
22
0.43
0.45
0.47
0.60
0.61
0.63
0.68
0.71
1.7 × 102 b
1.8 × 103 b
5.0 × 102 b
3.8 × 103 b
5.2 × 105 b
5.2 × 105 b
9.1 × 102 a
1.3 × 102 a
3.00
4.38
3.63
4.83
7.72
7.72
3.98
2.85
Figure 2. Schematic representation of the capsular dimers and the
intermolecular glycoluril carbonyl distances (O-Od), and spacer length
(S1).11
a Calculated by encapsulation experiment. b Calculated by competi-
tion experiment.7,8
ment showed that the complex is stable up to 330 K. From 350
to 380 K, it was basically a single species. This complex can be
dissociated by adding chloroform-d. After addition of 14%
chloroform-d, the aggregate breaks up to give a simplified
spectrum with the NH and CH2 signals broadened.
Dilution of a solution of 3 in chloroform-d with benzene-d6
caused the NH and the CH2 signals to move downfield, which
might indicate a conformational change induced by whatever
nucleation process is underway. A parallel dilution experiment
using 3w showed an upfield shift for the NH signal; however,
the CH2 signals remained constant.
The similarities between 2 and 3 suggested that a hybrid
structure could be formed. This heterodimer would neces-
sarily have a cavity shape and size (210 Å3) which is inter-
mediate between the parent homodimers. A one-to-one mixture
of 2 and 3 was prepared and analyzed in different solvents
(CD2Cl2, CDCl3, C6D6, toluene-d8, p-xylene-d10). Only in benzene-
d6 was the heterodimer observed: the spectrum showed the signals
corresponding to 2‚2 and two new sets of signals with the one-
to-one intensity corresponding to the heterodimer 2‚3 (Figure
1d).10
Why does 3 form a heterodimer but not a homodimer?
Molecular modeling studies11 show that in the homodimer 3‚3
the intermolecular O-Od distance between glycoluril carbonyls
is quite short (3.1 Å) and some repulsion between the two oxygens
can be expected (Figure 2). This distance in the hetereodimer
2‚3 is increased to 3.5 Å while that in the homodimer 2‚2 is large
enough (3.7 Å) that repulsion between oxygens is negligible.
Accordingly, there are subtle, often unpredictable, effects that can
dramatically change the assembly information contained within
similar systems.
Figure 1. 1H NMR spectra at 600 MHz of (a) 3 (2.3 mM) in DMSO-d6
solvent. The signal at 3.3 ppm is H2O. (b) 3 (5.4 mM) in benzene-d6. (c)
2‚2 (3.8 mM) in benzene-d6. (d) Equimolar mixture of 2 and 3 (3.8 mM)
in benzene-d6.
From the table and the calculated values of the packing factor,9
it appears that guests that occupy between 0.60 and 0.63 showed
particular affinity for the cavity of 2‚2; the presence of the
functional groups in the guests enhances their affinity. Compare,
for example, adamantane (18) with 2-adamantanone (19): they
are approximately equal in size and shape but their K′a are very
different, probably due to attractive interactions of the carbonyl
of the guest with the hydrogen bonds that line the cavity of the
host.
In contrast to 2, the smaller 3 was not easily characterized,
and some difficulties were encountered in distinguishing 3 from
3w (3s has doubled NMR signal patterns since its two ends are
different). Neither shows the characteristic downfield shifts of
the NH signals associated with dimerization, and dilution experi-
ments using 3, 3w, or 3s in chloroform-d and dichloromethane-
d2 showed that their NH signals were all concentration dependent.
Thus, none of the isomers gave capsules in these solvents; rather
they existed as largely monomeric species. In solvents such as
benzene-d6 and toluene-d8 only one of the isomers (3 or 3w) was
soluble, and the 1H NMR spectra exhibited unprecedented
complexity (Figure 1a,b). The isomer 3 (identified ultimately
by the heterodimerization experiments described below) forms
In summary, the structural diversity available with congeners
of the softball provides useful information for the further
development of capsules and self-assembly in general. The use
of two different spacers in the subunit can lead to dimers with
dissymmetric caVities and we will report on these in the sequel.
Acknowledgment. We thank the Skaggs Research Foundation and
the National Institutes of Health for support. We also thank Dr. Tomas
Szabo for advice on the synthesis of protected glycolurils. Administracio´n
de Fomento Econo´mico of Puerto Rico provided fellowship support to
J.M.R. The Ministerio de Educacio´n y Cultura of Spain provided
fellowship support to T.M.
1
an ordered aggregate of yet unknown structure. The H COSY
Supporting Information Available: Procedures and spectral data for
all compounds (33 pages). See any current masthead page for ordering
and Internet access instructions.
spectrum in toluene-d8 reveals 8 different NH resonances, the
lowest at 10.3 ppm, and 16 different methylene resonances:
therefore, the complex is at least a dimer. Dilution experiments
in benzene-d6 and toluene-d8 showed concentration-independent
behavior from 12.2 to 1.8 mM. A variable-temperature experi-
JA973341U
(10) (a) Koh, K.; Araki, K.; Shinkai, S. Tetrahedron Lett. 1994, 35, 8255.
(b) Valde´s, C.; Spitz, U. P.; Toledo, L. M.; Kubik, S. W.; Rebek, J., Jr. J.
Am. Chem. Soc. 1995, 117, 12733. (c) Mogck, O.; Bo¨hmer, V.; Vogt, W.
Tetrahedron 1996, 52, 8489.
(11) Molecular modeling was performed using MACROMODEL 5.5
(MM2* force field). These distances were obtained from the energy-minimized
structures of the corresponding dimers. Mohamadi, F.; Richards, N. G.; Guida,
W. C.; Liskamp, R.; Lipton, M.; Caufield, C.; Chang, G.; Hendrickson, T.;
Still, W. C. J. Comput. Chem. 1990, 11, 440.
(8) All of these spectra are in p-xylene-d10 solution. Some signals of the
guest inside are impossible to observe because they coincide with the p-xylene-
d10 or n-heptyl signals. When 21 and 22 were used as guests, it was possible
to observe clearly the guest outside and inside of the dimer, the signals of
which were easily integrated. The reliable K′a for 21 was then used to calculate
constants for the rest of the guests 15-20 by competition experiments.
(9) Garel, L.; Dutasta, J.; Collet, A. Angew. Chem., Int. Ed. Engl. 1993,
32, 1169.