Dynamic Combinatorial Chemistry

What is the best way to create synthetic receptors or hosts that are capable of recognizing guests? Such molecular recognition systems might be useful for sensing, for catalysis or for scrubbing unwanted residues from a factory effluent stream. The recognition of a guest by a host is more complicated than it sounds, in part because each component is extensively solvated; indeed complex formation between solvent and solute is necessary for solution to take place. The formation of a host-guest complex then requires an unpredictable degree of desolvation by each component. Computer modelling is developing very rapidly, but is not yet able to predict reliably where the balance lies between these various intermolecular interactions.

The conventional synthetic chemist's approach is to design a potential receptor, make it if they can, study its properties, and then refine the design to improve its performance. The problem with this approach is that successful design is often identified only after the event: one designs and makes many different structures, and then discovers by experiment which, if any, was the right design. We have an excellent record of success using the design strategy, and indeed we still pursue it, but we have also developed an entirely new approach, inspired by the example of evolution and selection in biology, i.e. to generate chemically or biologically a range of different structures and then to select the most effective. This new approach is dynamic combinatorial chemistry (DCC).

The key feature of DCC is the dynamic combinatorial library (DCL) in which each library member is assembled from building blocks that are connected through reversible bonds. As a result of this reversibility, all library members are interconverting to give a distribution that is under thermodynamic control. Thus addition of a guest molecule, or template, that can selectively bind to one receptor in the library will serve to increase the concentration of that host at the expense of others in the DCL. The successful host is then isolated and identified. In addition to discovering new receptors and catalysts, this approach may also teach us much about the fundamentals of molecular recognition and supramolecular chemistry.

Figure 1. A small dynamic combinatorial library of macrocycles and its free energy landscape, showing the effect of adding a template that strongly and selectively binds to one of the equilibrating species.

Of the many different reversible chemical reactions that have been explored for DCC we generally focus on just three: metalloporphyrin-ligand coordination, hydrazone exchange, thioester exchange and disulfide exchange (the latter in collaboration with Dr. Sijbren Otto). Alkene metathesis is an additional possible reaction for the future.