Mechanistic insights into radical formation and functionalization in copper/ N -fluorobenzenesulfonimide radical-relay reactions.

Copper-catalysed radical-relay reactions that employ N -fluorobenzenesulfonimide (NFSI) as the oxidant have emerged as highly effective methods for C(sp 3 )-H functionalization. Herein, computational studies are paired with experimental data to investigate a series of key mechanistic features of these reactions, with a focus on issues related to site-selectivity, enantioselectivity, and C-H substrate scope. (1) The full reaction energetics of enantioselective benzylic C-H cyanation are probed, and an adduct between Cu and the N -sulfonimidyl radical (˙NSI) is implicated as the species that promotes hydrogen-atom transfer (HAT) from the C-H substrate. (2) Benzylic versus 3° C-H site-selectivity is compared with different HAT reagents: Cu/˙NSI, ˙O t Bu, and Cl˙, and the data provide insights into the high selectivity for benzylic C-H bonds in Cu/NFSI-catalyzed C-H functionalization reactions. (3) The energetics of three radical functionalization pathways are compared, including radical-polar crossover (RPC) to generate a carbocation intermediate, reductive elimination from a formal Cu III organometallic complex, and radical addition to a Cu-bound ligand. The preferred mechanism is shown to depend on the ligands bound to copper. (4) Finally, the energetics of three different pathways that convert benzylic C-H bonds into benzylic cations are compared, including HAT/ET (ET = electron transfer), relevant to the RPC mechanism with Cu/NFSI; hydride transfer, involved in reactions with high-potential quinones; and sequential ET/PT/ET (PT = proton transfer), involved in catalytic photoredox reactions. Collectively, the results provide mechanistic insights that establish a foundation for further advances in radical-relay C-H functionalization reactions.