Optimizing the Synthetic Potential of O₂: Implications of Overpotential in Homogeneous Aerobic Oxidation Catalysis

Molecular oxygen is the quintessential oxidant for organic chemical synthesis, but many challenges continue to limit its utility and breadth of applications. Extensive historical research has focused on overcoming kinetic challenges presented by the ground-state triplet electronic structure of O₂ and the various reactivity and selectivity challenges associated with reactive oxygen species derived from O₂ reduction. This Perspective will analyze thermodynamic principles underlying catalytic aerobic oxidation reactions, borrowing concepts from the study of the oxygen reduction reaction (ORR) in fuel cells. This analysis is especially important for "oxidase"-type liquid-phase catalytic aerobic oxidation reactions, which proceed by a mechanism that couples two sequential redox half-reactions: (1) substrate oxidation and (2) oxygen reduction, typically affording H₂O₂ or H₂O. The catalysts for these reactions feature redox potentials that lie between the potentials associated with the substrate oxidation and oxygen reduction reactions, and changes in the catalyst potential lead to variations in effective overpotentials for the two half reactions. Catalysts that operate at low ORR overpotential retain a more thermodynamic driving force for the substrate oxidation step, enabling O₂ to be used in more challenging oxidations. While catalysts that operate at high ORR overpotential have less driving force available for substrate oxidation, they often exhibit different or improved chemoselectivity relative to the high-potential catalysts. The concepts are elaborated in a series of case studies to highlight their implications for chemical synthesis. Examples include comparisons of (a) NO/oxoammonium and Cu/nitroxyl catalysts, (b) high-potential quinones and amine oxidase biomimetic quinones, and (c) Pd aerobic oxidation catalysts with or without NO cocatalysts. In addition, we show how the reductive activation of O₂ provides a means to access potentials not accessible with conventional oxidase-type mechanisms. Overall, this analysis highlights the central role of catalyst overpotential in guiding the development of aerobic oxidation reactions.