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Letters to the editor

C–H functionalization

Thanks for the C&EN article on selective C–H functionalization (March 8, 2021, page 28). Continuing questions about the best ways to discriminate between bonds of the same type and functionalize a strong bond in the presence of a weaker one have been key challenges “at the heart of C–H activation chemistry.” Since understanding the past can inspire the future, this letter notes advances not discussed in your article and looks to exciting future challenges.

Before 2007, it was recognized that you could distinguish C–H bonds of different bond types: for example, radical reagents prefer weaker 3° aliphatic bonds over stronger 2° or 1° bonds (as in the Fenton reaction). And organometallic reagents prefer less sterically hindered 1° bonds over more hindered 3° bonds (as in the Shilov reaction).

But it was believed that the differences in C–H bonds of the same bond type (for example, 2°) were not large enough to distinguish between them usefully. It was thought that an enzyme, an elaborate catalyst mimicking an enzyme, or a substrate directing group was required to discriminate between these bonds.

In 2007, my group reported a simple catalyst, Fe(PDP), and used it to first delineate a series of selectivity rules that showed aliphatic C–H bonds can be discriminated in preparatively meaningful ways on the basis of differences in their electronic, steric, and stereoelectronic environments. And in 2010 we showed this for the most ubiquitous bonds in small molecules, 2° (methylene) C–H bonds. In 2013, we reported Fe(CF₃PDP), a catalyst that reads the rules differently and can predictably alter the site selectivities obtained with Fe(PDP). Using these catalysts, you can functionalize very strong bonds (like methylenes) in the presence of much weaker bonds (like 3° and benzylic) and specific methylenes in the presence of many others because discrimination is based on elements beyond their bond strengths alone.

Today a paradigm shift has happened in the community’s thinking on this topic. Many catalysts and reagents have been discovered whose site selectivity may be understood and predicted according to these selectivity rules. These findings point to exciting future directions, such as discovering general classes of catalysts that selectively target C–H bonds predictably according to their local chemical environments and that oxidize strong C–H bonds in the presence of oxidatively labile functionality. Addressing such challenges will further enable late-stage C–H functionalization to streamline synthesis and diversification of small molecules for discovery.

M. Christina White
Urbana, Illinois