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Scientific Report 2004


The Skaggs Institute for Chemical Biology




Encapsulation Complexes


J. Rebek, Jr., T. Amaya, S. Biros, T.J. Dale, A. Gissot, S. Gu, F. Hauke, A. Myles, H. Onagi, L. Palmer, B. Purse, D. Rachavi-Robinson, S. Richeter, A. Scarso, A. Shivanyuk, L. Trembleau, E. Ullrich, M. Yamanaka, F. Zelder

Encapsulation complexes offer snapshots of molecules isolated in space and in time. In these complexes, a reversibly assembled host surrounds 1, 2, or 3 molecular guests on timescales that last for milliseconds to hours. The typical lifetime of the encapsulation complex is about 1 second at room temperature in the liquid phase, a lifetime convenient for nuclear magnetic resonance studies. The nuclear magnetic resonance spectra provide information on the magnetic and asymmetric environments inside the capsule and on the detailed interactions or contortions of the guests held there. We have used the cylindrical capsule shown in Figure 1 as our host for these studies.

This capsule can accommodate 3 small molecules at a time, and because of its shape, it offers 2 environments, 1 at the ends of the capsule and 1 in the center. The molecular guests cannot squeeze past each other while within the capsule, and if 2 different guests are involved, then isomeric possibilities exist. For example, we recently characterized all of the isomers available from pairwise selections of isopropyl chloride, dichloromethane, and chloroform. Two of the isomers are shown in Figure 1. If these systems could be created at will, maintained on a longer timescale, and retrieved, then truly nanoscale data storage would be possible.

Fig. 1. Top, Schematic drawing of the synthetic receptor, the energy-minimized dimeric capsule, and the oval used to indicate a capsule. Bottom, The 2 different arrangements in space (isomeric constellations) of encapsulated chloroform and isopropylchloride.

At the other extreme, when a single large hydrocarbon guest is offered to the capsule, the guest must coil up into a helical shape in order to be accommodated. Figure 2 shows the extended and coiled shapes of tetradecane inside a cross section of the capsule. Mere addition of a single carbon on the guest prevents encapsulation, because even tight coiling cannot accommodate the length of the hydrocarbon. When 2 guests are desired, care must be taken to arrange for a specific complex: 2 different guests are coencapsulated when the combination of the 2 guests, but not either guest alone, makes a good fit for the capsule. This property allows the observation and evaluation of interactions of solutes and solvents of a single molecular pair at a time.

Fig. 2. Top, Extended conformation of tetradecane (C14H30), space-filling model and cross section of the cavity showing C-H/p contacts, and helical conformation that brings Ci and Ci+4 close together. Bottom, The 2 modes of interaction (social isomerism) shown by carbon tetrachloride and p-ethyltoluene in the capsule.

We evaluated a panel of 15 common solvents and measured the equilibrium preferences for one end of a coencapsulated guest or another (Fig. 2). The intermolecular forces involved are in the subkilocalorie range but are easily measured by using nuclear magnetic resonance. These measurements have never been made under these conditions. We have studied the pairwise interaction of molecules known as social isomerism and have evaluated the effect of solvents on keto enol equilibria inside the capsule.

If a chiral molecule is placed inside the capsule, a chiral space is left for a second molecule (Fig. 3), very much the way placing a glove in a box creates a chiral space around the glove.

Fig. 3. Top, A chiral object (hand) in an achiral container leaves a chiral space. The methyl groups of isopropyl chloride are diastereotopic in the coencapsulation complex with styrene oxide. Bottom, The methyl groups of an encapsulated guest respond to asymmetric centers outside the capsule.

The space is sterically and magnetically asymmetric in the capsule, and enantioselection inside has been observed. We have now separated the steric and magnetic components by placing asymmetric elements outside the capsule. The space inside is achiral, yet we see the effects of asymmetric centers outside on the guests held within. This separation of asymmetric senses is unprecedented.

We have also examined a much more complex assembly, which, ironically, is very easy to make. The resorcinarene shown in Figure 4 assembles in wet organic solvents into beautiful hexameric structures reminiscent of a cube. A total of 1 resorcinol is on each side of the cube, and 1 water molecule appears at each of the 8 corners of the cube. The resting state in benzene for example, contains 8 benzene guests, but these can be easily displaced by large tetra alkylammonium salts. We have been able to determine the kinetic and thermodynamic parameters involved in complexation; these allowed us to propose the mechanism shown in Figure 4 of how guests get in and out of this capsule. Dissociation of 1 face of the cube gives a new space large enough for tetra alkylammonium guests to squeeze through. These systems provide modern models for the behavior of molecules within the confines of active sites of enzymes or within large viral capsids.

Fig. 4. Top, Resorcinarenes and the crystal structure of the hexamer assembly in a ball-and-stick representation. Bottom, Proposed mechanism for guest exchange.

Publications

Amaya, T., Rebek, J., Jr. Steric and magnetic asymmetry distinguished by encapsulation. J. Am. Chem. Soc. 126:6216, 2004.

Scarso, A., Rebek, J., Jr. Single molecule solvation and its effects on tautomeric equilibria in a self-assembled capsule. J. Am. Chem. Soc. 126:8956, 2004.

Scarso, A., Shivanyuk, A., Rebek, J., Jr. Individual solvent/solute interactions through social isomerism. J. Am. Chem. Soc. 125:13981, 2003.

Scarso, A., Trembleau, L., Rebek, J., Jr. Encapsulation induces helical folding of alkanes. Angew. Chem. Int. Ed. 42:5499, 2003.

Scarso, A., Trembleau, L., Rebek, J., Jr. Helical folding of alkanes in a self-assembled, cylindrical capsule. J. Am. Chem. Soc. 126:13512, 2004.

Shivanyuk, A., Friese, J.C., Rebek, J., Jr. Anion dependent molecular recognition of cations. Tetrahedron 59:7067, 2003.

Yamanaka, M., Rebek, J., Jr. Constellational diastereomers in encapsulation complexes. Chem. Commun. (Camb.) 7:1690, 2004.

Yamanaka, M., Shivanyuk, A., Rebek, J., Jr. Kinetics and thermodynamics of hexameric capsule formation. J. Am. Chem. Soc. 126:2939, 2004.

Yamanaka, M., Shivanyuk, A., Rebek, J., Jr. Stereochemistry in self-assembled encapsulation complexes: constellational isomerism. Proc. Natl. Acad. Sci. U. S. A. 101:2669, 2004.

 


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

Rebek Web Site