Multi-Site Proton-Coupled Electron Transfer Enables Iodanyl Radical Catalysis

The utility of hypervalent iodine reagents in synthesis is often ascribed to the selective two-electron redox events that interconvert I(I), I(III), and I(V) species during oxidative substrate functionalization. We recently reported that 1,2-diiodoveratrole (4a) is an efficient catalyst for intramolecular oxidative C–H/N–H coupling and proposed that N–H activation was accomplished by an iodanyl radical (i.e., an I(I)/I(II) catalytic cycle) without generation of the corresponding I(III) derivative. Transient iodanyl radicals have been proposed during reductive activation of I(III) reagents but the role of I(II) intermediates in substrate activation is unknown. Here, we report a combined experimental and computational investigation of N–H activation and C¬–N coupling mechanism promoted by iodanyl radicals. The assembled data indicate that anodically generated iodanyl radicals directly promote C–H/N–H coupling through a multi-site proton-coupled electron transfer (MS-PCET) mechanism in which the iodanyl radical serves as an electron acceptor and a carboxylate additive serves as a proton acceptor. Based on these mechanistic insights, two second-generation catalysts — 1-iodo-4-methoxy-2-(trifluoromethyl)benzene (4c) and 6,7-diiodo-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (4d) — were developed. These catalysts display tailored redox properties that significantly expand the scope of both inter- and intramolecular metal-free electrocatalytic C–N bond-forming chemistry. Together, these results demonstrate that 1) iodanyl radicals can engage directly in substrate activation without the intermediacy of closed-shell hypervalent iodine species and 2) systematic variation of the redox properties of iodanyl radical intermediates enables rational catalyst optimization. The realization of open-shell hypervalent iodine mechanisms provides complementary synthetic opportunities with respect to classical two-electron hypervalent iodine strategies and enables development of new catalyst design concepts for metal-free electrocatalysis.