News and Publications
The Skaggs Institute for Chemical Biology
Scientific Report 1999-2000
Molecules Inside Molecules
J. Rebek, Jr., M. Brody, R. Castellano, Y.-L. Cho, S. Craig, G. Haberhauer,
T. Haino, F. Hof, P. Iovine, S. Körner, U. Lücking, S. Mecozzi, C.
Nemes, C. Nuckolls, A. Rafai Far, A. Renslo, J. Rivera-Ortiz, D. Rudkevich, S.
Saito, L. Sébo, L. Somogyi, S. Starnes, N. Svenstrup, F. Tucci, P. Wash
Chiral Microenvironments For Molecular Recognition
Chirality is defined as the lack of mirror-image symmetry. Any object that
is chiral exists as a pair of mirror-image isomers, or enantiomers, that are
not superimposible on each other. Nucleic acids, carbohydrates, proteins, and
most drugs are chiral and are present as only a single enantiomer. The
chemical reactions that fuel life are carried out when chiral macromolecules
(enzymes) recognize and bind smaller chiral molecules (substrates) within pockets
or cavities. We have undertaken studies of chiral assembly and recognition to
better understand how biological molecules recognize and discriminate between
pairs of enantiomers.
We synthesized a chiral molecule that is curved and has self-complementary
hydrogen-bonding sites. When 4 copies of the molecule come together, they self-organize
in a head-to-tail manner to form a molecular capsule that encloses a pseudospherical
cavity. The result is a capsule that is itself chiral. The self-assembled capsule
binds small molecules of appropriate size and shape within its cavity. The relatively
weak forces that the individual molecules can exert on their surroundings are
amplified through the assembly process. The capsule can discriminate between
mirror-image isomers of guest molecules and successfully mimics the ability of
biological macromolecules to recognize and bind single enantiomers of chiral
molecules (Fig. 1).
Much of our research has been concerned with designing, synthesizing, and
characterizing molecules that self-assemble into molecular capsules. In the course
of our investigations, we created heterodimers, versions of these molecules that
form capsules composed of 2 different pieces. We continue to develop new types
of heterodimeric capsules so that we can move closer to realizing one of our
ultimate goals: incorporating the capsules into informational polymers reminiscent
Calixarenes provide a bowl-shaped molecular scaffold that is easily changed
on the rim by substituting parts with hydrogen-bonding functionality. We showed
several years ago that aryl urea-derived calixarenes form dimers through a directional,
hydrogen-bonding seam at the capsule equator (Fig. 2). By synthesizing and analyzing
a host of different calixarenes that differed in their urea substituents, we
discovered that amino acid-derived ureas with ß-branched side chains, such
as isoleucine and valine, exclusively heterodimerize with aryl-derived ureas.
The point chirality, or the handedness, of the amino acids in these assemblies
is smoothly transferred to the hydrogen-bonding seam, giving rise to a chiral
capsule with only a single direction to its head-to-tail arrangement of ureas.
These chiral capsules act as hosts that can discriminate between mirror-image
forms of guests in solution. The compounds described here illustrate the consequences,
both chemical and stereochemical, of a well-positioned, yet remote, chiral center
on molecular assembly.
Nanoscale Self-Folding Cavities
One of the ultimate goals of molecular recognition is to construct molecular
hosts that completely surround their guests. A "scaggs" molecule (semicapsule
allowing giant guest seizure) is the most recent development in this field. The
new structure (Fig. 3) consists of 2 deepened, bowl-shaped molecules connected
by an extended aromatic spacer. The structure is among the largest of synthetic
unimolecular hosts, with cavity dimensions of approximately 23 x 10 Å and
an internal volume of approximately 800 Å3. In addition to covalent
bonding, intramolecular hydrogen bonding holds the internal cavity in place.
These hydrogen bonds also control the reversible seizing and release of the guest
and make access to the cavity easy under mild conditions.
Of particular importance, the molecule accommodates guests of nanoscale dimensions
(up to 18 Å). The direct observation of encapsulated species and their
orientation within the cavity and the determination of the stoichiometry of the
complexes can be accomplished by using nuclear magnetic resonance spectroscopy.
The most immediate applications of scaggs molecules are as sensors for chemical
analysis and as delivery vehicles. They can also be used as reaction vessels;
the internal space can accommodate more than a single guest, and the constant
flow of guests into and products out of the cavity is visible. The synthesis
of water-soluble scaggs versions for molecular recognition in aqueous solution
is under way.
A unique and useful feature of our molecular hosts is that guests enter and
leave in convenient lengths of time. For example, it takes approximately 1 hour
for a single guest to displace another guest from the "softball" (Fig. 4). We
established that guest exchange occurs in 2 steps. First, solvent molecules rinse
out the resident guest, leaving a capsule filled temporarily with the less desirable
solvent. The solvent is then rapidly displaced, either by one of the original
guest molecules or by one of the preferred, incoming guests.
The host remains intact during the exchange but is not static. The ring of
atoms in the box in Figure 4A acts as a hinge, and windows are constantly opening
and closing in the softball casing. When 2 windows open at once, solvent and
guest molecules have enough room to sluice through the exposed interior (Fig.
At no point is the host completely empty: one molecule enters as another
molecule exits. The guests and solvent, therefore, must pass simultaneously through
passageways of a size comparable to the size of the molecules themselves. Here,
as in the capsule interior, molecular recognition plays a role; guests move in
and out at rates that depend on their size, shape, and functionality. The windows
and the interior are selective for different attributes, and we have observed
relatively poor guests that outrace their preferred counterparts for the capsule
interior. Our understanding of these processes has contributed to new uses for
encapsulation complexes, including molecular imprinting and the kinetic control
of reactions in solution. Brody, M.S., Schalley, C.A., Rudkevich, D.M., Rebek,
J., Jr. Synthesis and characterization of an intramolecularly self-assembled
capsule. Angew. Chem. Int. Ed. 38:1640, 1999.
Castellano, R.K., Nuckolls, C., Rebek, J., Jr. Transfer of chiral
information through molecular assembly. J. Am. Chem. Soc. 121:11156, 1999.
Lützen, A., Renslo, A.R., Schalley, C.A., O'Leary, B.M., Rebek, J.,
Jr. Encapsulation of ion-molecule complexes: Second-sphere supramolecular
chemistry. J. Am. Chem. Soc. 121:7455, 1999.
Ma, S., Rudkevich, D.M., Rebek, J., Jr. Supramolecular isomerism in
caviplexes. Angew. Chem. Int. Ed. 38:2600, 1999.
Nuckolls, C., Hof, F., Martin, T., Rebek, J., Jr. Chiral microenvironments
in self-assembled capsules. J. Am. Chem. Soc. 121:10281, 1999.
Renslo, A.R., Rudkevich, D.M., Rebek, J., Jr. Self-complementary cavitands.
J. Am. Chem. Soc. 121:7459, 1999.
Renslo, A.R., Tucci, F.C., Rudkevich, D.M., Rebek, J., Jr. Synthesis
and assembly of self-complementary cavitands. J. Am. Chem. Soc., in press.
Rudkevich, D.M., Rebek, J., Jr. Deepening cavitands. Eur. J. Org.
Chem. 9:1991, 1999.
Santamaria, J., Martin, T., Hilmersson, G., Craig, S.L., Rebek, J., Jr. Guest
exchange in an encapsulation complex: A supramolecular substitution reaction.
Proc. Natl. Acad. Sci. U. S. A. 96:8344, 1999.
Tucci, F.C., Renslo, A., Rudkevich, D.M., Rebek, J., Jr. Nanoscale
container structures and their host-guest properties. Angew. Chem. Int. Ed. 39:1076,