Mechanism of Copper(I)/TEMPO-Catalyzed Aerobic Alcohol Oxidation

Homogeneous Cu/TEMPO catalyst systems (TEMPO = 2,2,6,6-tetramethylpiperidine-N-oxyl) have emerged as some of the most versatile and practical catalysts for aerobic alcohol oxidation. Recently, we disclosed a (bpy)Cu-I/TEMPO/NMI catalyst system (NMI = N-methylimidazole) that exhibits fast rates and high selectivities, even with unactivated aliphatic alcohols. Here, we present a mechanistic investigation of this catalyst system, in which we compare the reactivity of benzylic and aliphatic alcohols. This work includes analysis of catalytic rates by gas-uptake and in situ IR kinetic methods and characterization of the catalyst speciation during the reaction by EPR and UV-visible spectroscopic methods. The data support a two-stage catalytic mechanism consisting of (1) "catalyst oxidation" in which Cu-I and TEMPO-H are oxidized by O-2 via a binuclear Cu2O2 intermediate and (2) "substrate oxidation" mediated by Cu-II and the nitroxyl radical of TEMPO via a Cu-II-alkoxide intermediate. Catalytic rate laws, kinetic isotope effects, and spectroscopic data show that reactions of benzylic and aliphatic alcohols have different turnover-limiting steps. Catalyst oxidation by O-2 is turnover limiting with benzylic alcohols, while numerous steps contribute to the turnover rate in the oxidation of aliphatic alcohols.