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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, S. Xiao

Molecular Encapsulation

Molecules with 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.
Fig. 1. Formula 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).

Remote Influences

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.


Fig. 2. 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.

The 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.

Reactivity

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).
Fig. 3. 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.

Catalysis 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.


Fig. 4. 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 pressure inside.

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.

Publications

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.

 

Julius Rebek, Jr., Ph.D.
Director and Professor



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