Dynamic combinatorial chemistry: the unexpected choice of receptors by guest molecules.

Although our knowledge in the broad field of chemistry has increased enormously over the past decades, we are still unable to give precise predictions on the behavior of molecules in solution. Therefore, combinatorial approaches and high-throughput experimentation have become increasingly important by facilitating the rapid discovery of lead compounds and the optimization of processes in which trial-and-error is the dominant approach. In the mid-1990s, a fundamentally new concept in this area, dynamic combinatorial chemistry (DCC), was introduced by the groups of Sanders, Lehn, and others. Whereas traditional combinatorial libraries are based on the preparation of kinetically stable compounds and subsequent screening for their function, this new concept takes advantage of reversible bonds, covalent or noncovalent, by generating a random (virtual) library whose members are in dynamic equilibrium. The formation of the library is under thermodynamic control, which gives rise to new properties such as adaptation; that is, the library readjusts its distribution by external stimuli. Upon addition of a target molecule, the mixture of potential receptors in the library reequilibrates in favor of the best receptor(s) for the target. By using this strategy the preparation and screening of the receptor for a certain target is integrated in one step, as the receptor is chosen by the target. Libraries of receptors of variable complexity have been constructed, with the simplest comprised of a mixture of macrocycles of variable sizes based on identical building blocks (type A; Figure 1a).