Selective C-H Functionalization

The selective functionalization of unactivated C–H bonds is a long-standing challenge in synthetic chemistry. Recent developments in the catalytic activation of strong C–H bonds generally involve reactive heteroatom-centered radicals. Published in JACS, Carla Morton, Ludovic Troian-Gautier, and Erik Alexanian, from the Alexanian Group, along with Rob Knowles and collaborators at Princeton University describe a new strategy for C(sp3)–H alkylation that circumvents such reactive species by utilizing multisite-proton-coupled electron transfer, multisite-PCET, to directly activate a C–H bond.

Multisite-PCET involves the concerted transfer of a proton and an electron to two distinct acceptor molecules. Traditionally, this requires pre-equilibrium H-bonding of the substrate with the proton acceptor, reducing the molecularity of the abstraction and limiting the substrates to polar functional groups such as amides and alcohols.

Detailed mechanistic studies indicate that this C–H alkylation is catalyzed by a non-covalent complex formed between an iridium(III) photocatalyst, electron acceptor, and a phosphate base, proton acceptor. The association of the acceptor molecules similarly reduces the molecularity of the abstraction without the requirement for H-bonding of the substrate, and thus allows for the activation of non-polar C–H bonds. The reported C–H alkylation proceeds efficiently with diverse hydrocarbon substrates and represents a new elementary step for C­–H cleavage.