The Skaggs Institute
for Chemical Biology

Molecular Assembly and Encapsulation

J. Rebek, Jr., D. Ajami, E. Barrett, S. Biros, S. Butterfield, A. Carella, T.J. Dale, C. Haas, F. Hauke, R.J. Hooley, T. Iwasawa, E. Mann, E. Menozzi, L. Moisan, A. Myles, H. Onagi, L. Palmer, B. Purse, D. Rechavi-Robinson, R. Salvio, M. Schramm, H. Van Anda, A. Volonterio, F. Zelder

We have been using molecule-within-molecule complexes to determine the rules of self-assembly in solution. In these systems, molecular guests are completely surrounded by assembled molecules of a synthetic host. The synthetic host molecules feature a curvature and a self-complementary array of hydrogen-bond donors and acceptors, and a maximum number of hydrogen bonds can be formed when a closed shell of the receptor is assembled. Even so, the complexes self-assemble when, and only when, the spaces inside the capsules are appropriately filled; for typical assemblies in solution, a little more than half the space should be occupied by guests.

An example is the self-assembly of 6 pyrogallol molecules into a spherical capsule with a cavity of 1200 ų. The assembly takes place in many hydrocarbons, and molecules such as octadecane (C₁₈) can be found inside. The molecule folds to fit within the space, and each methylene can be observed via nuclear magnetic resonance spectroscopy as a separate signal. These methylenes have never previously been resolved, and their observation underscores the advantages of encapsulation for detailed studies of molecular shape.

A related capsular structure is shown in Figure 1.

Fig. 1. Encapsulation of 6 glutaric acid guests within the resorcinarene hexamer. Eight water molecules complete the seam of hydrogen bonds that hold the capsule together.

Again, 6 molecules of the resorcinarene provide the curvature, but the continuous seam of the hydrogen bonds that hold the capsule together requires 8 water molecules in addition. The overall effect is that of a capsule that is a cube: 6 resorcinarene sides and 8 water corners. In wet benzene, for example, 8 molecules of the benzene are also found inside as guests. In total, 22 molecules come together to an ordered assembly. The instructions are provided by the curvature of the modules, the requirements of the hydrogen bonds, and the appropriate filling of space.

When two or more molecules are encapsulated, intermolecular phenomena are revealed that cannot be observed by any other methods. These phenomena lead to questions such as, What is it like inside a capsule? Can catalysis occur inside? Can the space be made chiral? Are intermolecular interactions amplified when 2 different molecules are inside? These questions represent our ongoing pursuits.

Coencapsulation of structurally related molecules such as isomers can provide information about the weak intermolecular forces at work between the molecules. These forces can be evaluated at the subkilocalorie level by using simple nuclear magnetic resonance techniques. We have studied a series of carboxylic acids that go into a cylindrical capsule 2 at a time, and we determined whether the capsule prefers 2 identical molecules or a molecule and its mirror image. Unexpectedly, we found that there is a preference, but it is not yet predictable. The 2 asymmetric centers involved are more than 6 Å apart, yet they sense each other through the carboxylic acid hydrogen-bonded dimer (Fig. 2).

Fig. 2. Two molecules of an asymmetric carboxylic acid are guests in a cylindrical capsule. Two identical guests, rather than mirror-image guests, are preferentially encapsulated.

Computational methods indicate that in some instances hydrogen bonding to the capsule itself brings the asymmetric centers closer to each other. Just how the space inside the capsule is filled seems to determine the intermolecular forces that operate at such close range.

Fluorescence resonance energy transfer takes place through space, but, in general, the donor and acceptor dyes are held together, either by covalent bonds or through temporary hydrogen bonds. We have prepared a donor and acceptor pair in which the components are held together by mechanical bonding (Fig. 3). The result is highly efficient fluorescence resonance energy transfer because very strong covalent bonds must be broken in order for the 2 dyes to move apart.

Fig. 3. A, Schematic representation of the rotaxane showing that a macrocycle was mechanically interlocked by a dumbbell composed of an axle with a hydrogen-bonding site terminated by the bulky end group. Interlocked components were tagged by the donor (D) and acceptor (A). B, Chemical structure of the [2]rotaxane 1.

Publications

Ceide, S.C., Trembleau, L., Haberhauer, G., Somogyi, L., Lu, X., Bartfai, T., Rebek, J., Jr. Synthesis of galmic: a nonpeptide galanin receptor agonist. Proc. Natl. Acad. Sci. U. S. A. 101:16727, 2004.

Hauke, F., Myles, A.J., Rebek, J., Jr. Lower rim mono-functionalization of resorcinarenes. Chem. Commun. (Camb.) 4164, 2005, Issue 33.

Onagi, H., Rebek, J., Jr. Fluorescence resonance energy transfer across a mechanical bond of a rotaxane. Chem. Commun. (Camb.) 4604, 2005, Issue 36.

Palmer, L.C., Rebek, J., Jr. Hydrocarbon binding inside a hexameric pyrogallol[4]arene capsule. Org. Lett. 7:787, 2005.

Palmer, L.C., Shivanyuk, A., Yamanaka, M., Rebek, J., Jr. Resorcinarene assemblies as synthetic receptors. Chem. Commun. (Camb.) 857, 2005, Issue 7.

Palmer, L.C., Zaho, Y.-L., Houk, K.N., Rebek, J., Jr. Diastereoselection of chiral acids in a cylindrical capsule. Chem. Commun. (Camb.) 3667, 2005, Issue 29.

Yamanaka, M., Amaya, T., Rebek, J., Jr. Dynamics of supramolecular capsule. J. Syn. Org. Chem. Jpn. 62:1218, 2004.