Scientific Report 2008
The Skaggs Institute for Chemical Biology
Reversible Encapsulation: Molecules at Close Range
J. Rebek, Jr., D. Ajami, M. Ams, E. Barrett,
T.J. Dale, H. Dube, R.J. Hooley, J.-L. Hou, T. Iwasawa, S. Kamioka, A. Lledo
Ponsati, L. Moisan, F.P. Restorp, M. Schramm, S. Shenoy, C. Turner, H. Van Anda,
appropriate curvature and hydrogen-bonding capabilities can self-assemble into "host
container structures when suitable "guests are present. In Figure 1,
2 units of the module 1 assemble into the cylindrical capsule 1.1
in the presence of smaller molecules that fill the space inside properly. The coencapsulation
of 2 guests within a host must fulfill certain requirements: the congruence of molecular
shapes, the compatibility of lengths, the conformity with volumes, and the complementarity
of chemical surfaces. The examples shown in Figure 1 reveal that these criteria
can be met by many combinations of guests.
of the module 1 and its dimeric capsule 1.1. The capsule is shown
without peripheral alkyl groups, and the cartoon used elsewhere in this report is
shown with a large and a small guest (A), 2 identical guests (B), and a guest and
its mirror image (C).
Molecular encounters in solution last
typically a billionth of a second, and the collisions take place randomly. But molecules
in capsules can be detained for hours, and their collisions are guided by their
arrangement inside. The long contact times of coencapsulated molecules and their
fixed orientation in the space allow observation of very subtle differences. For
example, coencapsulation of isopropanol with isomers of the diol shown in Figures
2A and 2B leads to 2 different complexes. The asymmetric center near the isopropanol
is the same in both, but the distant centers are of opposite chirality or handedness.
The nuclear magnetic resonance (NMR) signals are different for the 2 complexes.
Such influences cannot be seen in bulk solution because of the rapid exchange of
partners and the free rotational motions that average the effects.
A and B, Coencapsulation amplifies magnetic effects of remote asymmetric centers.
The NMR signals for the isopropyl alcohol (top) are influenced by the nearby chiral
center (green arrow) as well as the distant center (blue arrow). C and D, Coencapsulation
of ethane (gray) and heptane (colored spheres). NMR experiments show that heptane
tumbles inside the capsule; the ethane makes contact with atoms at either end of
heptane but not with the atoms in the middle.
coencapsulation of ethane and heptane is shown in Figures 2C and 2D. NMR experiments
revealed that ethane makes contact with both ends of the heptane. This situation
is caused by the end-over-end tumbling of heptane in the capsule. It is thought
that heptane coils into a more compact shape during the tumbling motion.
The chemical reactions that take place
only slowly in bulk solution can be dramatically enhanced inside capsules. One reason
is the long contact times of the 2 coencapsulated reactants. Another reason is a
concentration effect; each molecule inside has a concentration of 4 M, even if the
concentrations outside are 1000-fold lower. A third reason is the limited motion
of the capsule itself; the capsule acts as a solvent cage already organized for
the reaction. The reaction of an isonitrile with a carboxylic acid can be accelerated
by confining both components to a capsule. The elusive initial addition product
has been directly observed by using NMR methods. The capsule not only accelerates
the reaction but also acts as a catalyst. The product is released, and the capsule
can be refilled with starting reagents (Figs. 3A and 3B).
Trapping a reactive intermediate. The coencapsulation of an acid and isonitrile
(A) positions their functional groups for an addition reaction. The intermediate
(B) is stabilized by hydrogen bonding with the nearby imides of the capsule, and
the rigid cage prevents rearrangements. This intermediate could not be observed
in free solution but has a lifetime of nearly an hour in the capsule. The cavitand
(C) features an acid catalyst that is trained on any guests inside. The confined
space influences the pathway of chemical reactions such as the cyclization shown
on the right.
also occurs with the cavitand (Fig. 3C). The inwardly directed carboxylic acid can
contact any guest that is inside the cavity. The limited space inside favors reactions
with compact transition states. The reaction of the epoxide shown is accelerated
more than 50-fold and gives exclusively the 5-membered ring, whereas the reaction
outside in bulk solution gives both 5- and 6-membered ring products.
Phase and Pressure in Capsules
What "phase do molecules experience
inside a capsule? When a single or only a few molecules are involved, it is inappropriate
to refer to solids, liquids, or gases, yet my colleagues and I have found that molecules
in these different phases occupy different fractions of the space inside. The packing
coefficients are about 70% for solids, 55% for liquids, and around 40% for gas molecules
inside the capsules.
Even if only a single or a few molecules
of the gas are present, the pressure inside a capsule can be calculated. When 1.1
is dissolved in cyclopropane-saturated solvent, 3 cyclopropane guests can be detected
inside the capsule. The space inside can be calculated by using modeling software;
the volume of 1.1 in Figure 4 is 425 Å3. At 1 atm, a molecule
of an ideal gas has a space of approximately 37,000 Å3, nearly
90 times the space in the capsule 1.1. Accordingly, 3 ideal gas molecules
at ambient temperature in the capsule are at a pressure of approximately 270 atm,
yet the system is at equilibrium at room temperature with cyclopropane in solvent
at ambient pressure.
Left, The shape of the space inside the capsule. The tapered ends can accommodate
only the narrowest of functional groups. Right, A total of 3 cyclopropane gas molecules
occupy the capsule; the calculated pressure is several hundred atmospheres, but
attraction between the surfaces of the gas and the capsule lowers the energy and
The pressures are, of course, unrealistic
because these systems are not ideal gases; the gases take up space and their collisions
with the walls are not elastic. The capsule has 16 aromatic panels, and attractions
exist between the gas guest and the aromatic inner surface of the host. This binding
of carbon-hydrogen bonds to π
surfaces lowers the potential energy and the pressure.
Barrett, E., Dale, T.J., Rebek, J.,
Jr. Stability, dynamics, and
selectivity in the assembly of hydrogen-bonded hexameric capsules. J. Am. Chem.
Soc. 130:2344, 2008.
Barrett, E.S., Dale, T.J., Rebek,
J., Jr. Synthesis and assembly
of monofunctionalized pyrogallolarene capsules monitored by fluorescence resonance
energy transfer. Chem. Commun. (Camb.) Issue 41:4224, 2008.
Hooley, R.J., Iwasawa, T., Rebek,
J., Jr. Detection of reactive
tetrahedral intermediates in a deep cavitand with an introverted functionality.
J. Am. Chem. Soc. 129:15330, 2007.
Hooley, R.J., Restorp, P., Iwasawa,
T., Rebek, J., Jr . Cavitands
with introverted functionality stabilize tetrahedral intermediates. J. Am. Chem.
Soc. 129:15639, 2008.
Hou, J.-L., Ajami, D., Rebek, J.,
Jr. Reaction of carboxylic
acids and isonitriles in small spaces. J. Am. Chem. Soc., in press.
Mann, E., Rebek, J., Jr. Deepened
chiral cavitands. Tetrahedron, in press.
Purse, B.W., Butterfield, S.M., Ballester,
P., Shivanyuk, A., Rebek, J., Jr.
Interaction energies and dynamics of acid-base pairs isolated in cavitands. J. Org.
Chem., in press.
Schramm, M.P., Rebek, J., Jr. Effects
of remote chiral centers on encapsulated molecules. New J. Chem. 32:794, 2008.
Schramm, M.P., Restorp, P., Zelder,
F., Rebek, J., Jr. Influence
of remote asymmetric centers in reversible encapsulation complexes. J. Am. Chem.
Soc. 130:2450, 2008.
Shenoy, S.R., Pinacho Crisostomo,
F.R., Iwasawa, T., Rebek, J., Jr. Organocatalysis
in a synthetic receptor with an inwardly directed carboxylic acid. J. Am. Chem.
Soc. 130:5658, 2008.