Catalyst Calls The Shots

Chemists have developed a new catalyst that accelerates oxidation of C–H bonds selectively in nonaromatic compounds such as terpenes, rather than relying on the inherent properties of the reactant molecules. The catalyst could boost the versatility with which organic compounds can be synthesized for drug discovery and other applications.

“C–H functionalization is becoming a more important synthetic methodology for drug discovery by expanding options for late-stage lead diversification,” says Pfizer researcher Mark C. Noe, who was not involved with the work. “This new methodology enables late-stage oxidative functionalization at sites that were previously inaccessible by known C–H functionalization methods.”

Several years ago, M. Christina White of the University of Illinois, Urbana-Champaign, and coworkers discovered an inexpensive iron-based catalyst with enzymelike capabilities (C&EN, Nov. 5, 2007, page 8). The catalyst, called Fe(PDP), oxidizes specific C–H bonds in aliphatic compounds with several such bonds. This type of selectivity is difficult to achieve: C–H bonds are strong and relatively unreactive, and their ubiquity in organic molecules makes them difficult for catalysts to distinguish.

A drawback of Fe(PDP) is that it has no control over the site to be oxidized—subtle property differences between reactant molecule C–H sites control site selectivity. For example, the C–H bond that is most electron-rich, less hindered sterically, or experiences the greatest strain tends to get the attention from the catalyst instead of other C–H bonds in the same substrate molecule.

By tweaking Fe(PDP)’s structure with four trifluoromethyl groups, White and coworkers have now produced a catalyst that shows substrates who’s boss (J. Am. Chem. Soc. 2013, DOI: 10.1021/ja407388y). The added groups block substrate access to the catalyst’s iron-based active site so only specific C–H bonds conforming to the catalyst’s nonnegotiable steric and electronic demands get oxidized there.

The researchers showed that Fe(CF₃-PDP) oxidizes the antimalarial drug artemisinin and other substrates at C–H bonds that were before inaccessible to chemical oxidation. The catalyst’s reactivity is modest, but White hopes to solve that issue in future work.