Catalytically Generated Amidyl Radicals for Site-Selective Intermolecular C-H Functionalization

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Project Summary The selective activation and functionalization of C–H bonds is one of the most important and challenging chemical transformations. The ability to activate any targeted C–H bond in a given molecule would immensely expand the scope of synthetically accessible chemical transformations and would be a powerful method of late- stage functionalization of complex molecules such pharmaceuticals, natural products, and commodity chemicals. Furthermore, carrying out these reactions using abundant, non-toxic catalysts and renewable energy sources (e.g., solar energy) is critical for the development of sustainable chemical processes. Achieving selectivity in C– H activation is often difficult due to the presence of numerous C–H bonds of similar strength in a given molecule. Even more challenging is discriminately functionalizing strong C–H bonds in proximity to weaker C–H bonds. Selectivity for C–H activation is often dictated by properties of the substrate, and in such cases, reactivity may be limited to the weakest or most acidic C–H bond. However, catalyst-control of selectivity, wherein the structure of the H-atom abstractor dictates selectivity, offers a powerful method of predictably introducing chemical diversity from hydrocarbon feedstocks. Amidyl radicals are potent H-atom abstractors (BDE(N–H) > 100 kcal mol-1) that are capable of cleaving strong C–H bonds, but their applications in intermolecular C–H activation reactions often rely on pre-functionalized amidyl sources, rendering them stoichiometric reagents. The direct activation of amide N–H bonds to generate amidyl radicals would provide catalytic access to these reactive intermediates and would dramatically improve their utility in C–H functionalization reactions. This proposed research strategy aims to develop new electro- and photocatalytic methods for direct N–H bond activation via proton-coupled electron transfer to generate amidyl radicals for selective C–H activation. By exploiting these modes of N–H bond activation in sterically shielded amide catalysts, the steric pressures imposed the amidyl radicals can dictate site-selectivity. A combination of electrochemical kinetics and photophysical studies, including time-resolved transient absorption spectroscopy and photocrystallography, will be employed to delineate the key structural and electronic features that govern selectivity. Overall, these studies will expand our ability to perform catalytic, site-selective C–H functionalization reactivity using sustainable energy sources.