The Skaggs Institute
for Chemical Biology

Scientific Report 2006

Alkyl Groups in Small Spaces

J. Rebek, Jr., D. Ajami, E. Barrett, S. Biros, S. Butterfield, A. Carella, T.J. Dale, N. Gombosuren, C. Haas, F. Hauke, R.J. Hooley, T. Iwasawa, E. Mann, E. Menozzi, L. Moisan, A. Myles, S. Odermatt, L. Palmer, R. Salvio, M. Schramm, H. Van Anda, A. Volonterio

Molecular recognition between small molecules and biological macromolecules such as enzymes and receptors is often of the lock-and-key sort; that is, the biological molecule has a well-defined cavity and the small molecule fits the cavity with a congruent shape. A different type of recognition involves induced fit. In this type, the receptor molecule can assume a number of shapes, and one shape is selected on the basis of the best fit to a more or less rigid small molecule. We have now encountered a third type of recognition in which the macromolecule receptor is rigid, but the small molecule is flexible and adopts the size, shape, and chemical surface for the best fit. We have studied this type of recognition with the self-assembled capsule shown in Figure 1. The capsule completely surrounds alkanes as shown. Decane for example, fits in a fully extended conformation, but tetradecane must coil into a helix in order to fill the space properly. Longer alkanes such as pentadecane cannot fit at all.

Fig. 1. Two views of encapsulated alkanes. Tetradecane coils into a helical conformation (left), whereas decane (right) is accommodated in its fully extended, anti conformation; Peripheral alkyl groups and some capsule “walls” have been removed for viewing clarity in this and other figures.

We have discovered that certain additional molecules can act as spacers for this capsule by providing a surface rich in hydrogen-bond donors and acceptors. These spacers can be inserted between the 2 halves of a capsule similar to the way leaves can be inserted to expand tables. Molecules such as tetradecane relax to an extended conformation in the expanded capsule and alkanes as long as 21 carbons can be accommodated. We have shown that the coiled tetradecane acts as a compressed spring. The spacers can be removed to recreate the original capsule with the compressed coil tetradecane inside. This compression and relaxation can be controlled by acid-base chemistry. The coiled alkane in the capsule acts as a spring-loaded molecular machine.

The shape of the capsule involves a space with tapered ends, and we have explored what groups can fit into these tapered ends. The narrowest of functional groups in organic chemistry is a terminal acetylene, and we found that the acetylene pentadecyne is accommodated, even though it is 15 carbons long. The acetylenic carbon-hydrogen bond can fit into the tapered ends of the capsule, whereas a methyl group cannot. Figure 2 shows the capsule with another acetylene in the tapered end.

Fig. 2. An acetylene (left) can be encapsulated (right) when the terminal carbon-hydrogen bond is positioned in the tapered end of the capsule. The butyl group assumes a twisted shape at the other end of the capsule.

The compression of alkanes can also be observed in open-ended vessels known as cavitands. We studied a series of straight-chain alkanes in which the alkyl groups are forced into the limited space, as shown in Figure 3 for octane.

Fig. 3. A water-soluble cavitand (left) can bind alkanes. Octane coils into a helical conformation inside (right). This shape reduces surface areas exposed to water and properly fills the cavitand’s space.

We are developing an optical sensor for the detection of highly toxic nerve gases. We adapted one of our previously prepared molecules to contain a fluorescent group for an output signal and optimized the group to react with the electrophilic nerve gases. Photo-induced electron transfer is used to control the sensor’s output: the fluorescence is quenched until the sensor reacts with one of these chemical weapon mimics that enable the fluorescence to be emitted. When a thin film of the sensor was exposed to the vapor of a nerve gas mimic, a brightly fluorescent circle was formed where the reaction had occurred (Figure 4, top right). The surrounding area acts as a control, because it was not exposed to the vapor.

Fig. 4. Sensor reaction with a nerve gas mimic. Top left, Before the reaction, the electrons on the nitrogen atom quench the fluorescence. Top right, The circle indicates the area exposed to nerve gas mimic for 5 seconds.

Publications

Ajami, D., Iwasawa, T., Rebek, J., Jr. Experimental and computational probes of the space in a self-assembled capsule. Proc. Natl. Acad. Sci. U. S. A. 103:8934, 2006.

Ajami, D., Rebek, J., Jr. Coiled molecules in spring loaded devices. J. Am. Chem. Soc. 128:15038, 2006.

Ajami, D., Rebek, J., Jr. Expanded capsules with reversibly added spacers. J. Am. Chem. Soc. 128:5314, 2006.

Dale, T.J., Rebek, J., Jr. Fluorescent sensors for organophosphorus nerve agent mimetics. J. Am. Chem. Soc. 128:4500, 2006.

Davis, C.N., Mann, E., Behrens, M.M., Gaidarova, S., Rebek, M., Rebek, J., Jr., Bartfai, T. MyD88-dependent and -independent signaling by IL-1 in neurons probed by bifunctional Toll/IL-1 receptor domain/BB-loop mimetics. Proc. Natl. Acad. Sci. U. S. A. 103:2953, 2006.

Iwasawa, T., Ajami, D., Rebek, J., Jr. Experimental and computational probes of a self-assembled capsule. Org. Lett. 8:2925, 2006.

Iwasawa, T., Mann, E., Rebek, J., Jr. A reversible reaction inside a self-assembled capsule. J. Am. Chem. Soc. 128:9308, 2006.

Purse, B., Rebek, J., Jr. Self-filling cavitands: packing alkyl chains into small spaces. Proc. Natl. Acad. Sci. U. S. A. 103:2530, 2006.

Scarso, A., Rebek, J., Jr. Chiral spaces in supramolecular assemblies. In: Supramolecular Chirality. Crego-Calama, M., Reinhoudt, D.N. (Eds.). Springer, New York, 2006, p. 1. Topics in Current Chemistry; Vol. 265.

Schramm, M.P., Rebek, J., Jr. Moving targets: recognition of alkyl groups. Chem. Eur. J. 12:5924, 2006.