Lyle Isaacs

CUCURBIT[N]URIL MOLECULAR CONTAINERS

Introduction. Molecular containers compounds bind to, sequester, and thereby modify the properties of compounds bound within their interiors. Currently, the most well-known and widely used class of molecular container compounds is the cyclodextrins (Figure 1). Cyclodextrins are cyclic oligosaccharides that come in three useful sizes (α-, β-, and γ-cyclodextrin; volumes = 174, 262, 427 Å3). Cyclodextrins function as molecular containers that bind to hydrophobic substances in aqueous solution. Cyclodextrins are used in a wide range of practical applications including the formulation of hydrophobic drug species in water, as an immobilized component of chiral chromatographic stationary phases, as an additive to mask unpleasant odors in foods, and even as the active ingredient in the household product Febreze where it releases perfume and sequesters malodorant molecules. The use of cyclodextrins for these applications are particularly noteworthy given their modest binding constants (Ka up to 104 M-1), rapid guest release rates (on the order of seconds), and difficulties in performing their selective functionalization. Despite these limitations, cyclodextrins, cyclodextrin derivatives, and value added cyclodextrin products currently constitute a > $1 billion / year industry.

We, and others, have been investigating a relatively new class of molecular container compounds known as cucurbit[n]urils (Figure 1).2 Cucurbit[n]urils (CB[n], n = 5, 6, 7, 8, 10) are macrocyclic methylene bridged glycoluril oligomers comprising n glycoluril rings. These currently known CB[n] compounds have cavity volumes (82, 164, 279, 479, and 870 Å3) that span and exceed those available with the cyclodextrins. In addition to the range of sizes available, CB[n] complexes are typically quite strong (Ka up to 1012 M-1), show very high selectivities based on small structural changes, and some exhibit dissociation kinetics that are remarkably slow (koff ≈ 10-9 s-1).3,4 CB[n]•guest pairs are also very highly responsive to environmental stimuli (e.g. pH, photochemical, electrochemical, or chemical) which makes them extraordinarily well suited for the preparation of molecular machines. In these regards, CB[n]•guest complexes behave more like protein-ligand pairs than typical synthetic host-guest systems.

Known Applications of CB[n] Compounds. Because of their outstanding recognition
properties, CB[n] molecular containers have been used in a variety of applications including:
drug delivery, waste water purification, fluorophore stabilization, scent release and odor control,
transmembrane ion- and molecular transport, and gene transfection.

Isaacs Group Applications of CB[n] Compounds. Our research group has expertise in the
synthesis of new CB[n] compounds and pursues new applications of the obtained molecular
containers. For example, within CB[10] – a container with a 1000 Å3 cavity and no parallel in
the cyclodextrins – we have created molecular switches that respond to small organic molecules,
entrapped catalysts for oxidation of alkanes, and created fluorescent sensors for certain organic
bases. We are using multi-cavity nor-seco-CB[n] to develop methods for “non-covalent
dimerization” in water, in the preparation of stimuli responsive polymers, and for chiral
recognition of drug molecules. Other applications of interest include affinity column
purification, non-covalent immobilization on solid supports, and as a component of enzyme
assays.