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

Abstract

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_x/oxoammonium and Cu/nitroxyl catalysts, (b) high-potential quinones and amine oxidase biomimetic quinones, and (c) Pd aerobic oxidation catalysts with or without NO_x 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.

Figure 1.

Different classes of aerobic oxidation methods, including (A) radical chain autoxidation, highlighted by the Mid-Century Co-Mn-Br cocatalyzed oxidation of p-xylene to terephthalic acid, (B) monooxygenase reactions that feature reductive activation of O₂ to achieve oxygen-atom transfer to organic molecules, exemplified by cytochrome P450 enzymes, and (C) oxidase reactions that couple O₂ reduction and substrate oxidation redox half-reactions.

Figure 2.

Comparison of redox half-reactions and their overpotentials (η) for (A) an H₂/O₂ fuel cell with Pt-based electrocatalysts for the oxygen reduction and hydrogen oxidation reactions (ORR and HOR, respectively) and (B) homogeneous catalytic aerobic oxidation reactions that proceed via an oxidase-type mechanism.

Figure 3.

(A) Half-reactions related to oxygen reduction, (B) half-reactions of common oxidants used in organic oxidation reactions, and (C) common organic oxidation reactions as redox half-reactions, all presented with their reduction potentials vs SHE. The difference between the red and blue redox potentials reflects the driving force available for the organic oxidation reactions with the different oxidants (see ref. for additional details and discussion, including derivation of the organic redox potentials).

Figure 4.

Comparison of (A) NO_x/oxoammonium-catalyzed aerobic oxidation of organic molecules and (B) Cu/TEMPO-catalyzed alcohol oxidation reactions. Cu/TEMPO features a mechanism in which Cu^II and TEMPO serve as cooperative one-electron oxidants, avoiding formation of the high-potential oxoammonium species. This mechanistic difference results in a lower overpotential for substrate oxidation (η_sub) and rationalizes the high chemoselectivity for alcohol oxidation in the presence of other oxidatively sensitive functional groups.

Figure 5.

Comparison of (A) DDQ/NO_x-catalyzed oxidation of organic molecules and (B) [Ru(phd)₃]²⁺/Co(salophen)-catalyzed aerobic dehydrogenation of amines (including 1°, 2°, and 3° amines). DDQ is a much stronger oxidant (high η_sub) than [Ru(phd)₃]²⁺ and shows a broader scope of reactivity, while [Ru(phd)₃]²⁺ has a lower η_sub and mediates highly chemoselective dehydrogenation of amines and tolerates diverse oxidatively sensitive functional groups.

Figure 6.

Comparison of aerobic (A) Pd/NO_x-catalyzed acetoxylation of benzene and (B) Pd-catalyzed biaryl coupling. Both pathways share a common L_nPd^II(OAc)(Ph) intermediate, but the low η_ORR NO_x cocatalyst supports oxidation of Pd^II to Pd^IV (lower left inset) to enable C─O reductive elimination. In the absence of NO_x, the O₂ is kinetically inert toward Pd^II (the O₂/HO₂^• redox potential is too low; lower right inset) and, therefore, transmetalation between two L_nPd^II(OAc)(Ph) species affords a L_nPd(Ph)₂ species (not shown) that undergoes C─C reductive elimination to yield biphenyl.

Figure 7.

Energy diagrams highlighting the use of a sacrificial reductant (Sac─H), such as an aldehyde, to promote 2 e⁻ reduction of O₂ to generate a peroxide or other strong oxidant, capable of promoting challenging oxidation reactions, such as C─H oxidation or alkene epoxidation. The precise values of the high-potential oxidants and organic oxidation reactions can vary.

Figure 8.

(A) Ni-catalyzed Mukaiyama epoxidation of alkenes, and the proposed mechanism, highlighting in situ generation of an acylperoxyl species as a high-potential oxidant capable of promoting oxygen-atom transfer. (B) Catalyst-free Mukaiyama epoxidation of alkenes, showing the peracid-mediated epoxidation pathway.

Figure 9.

Pd^II/IV–mediated aerobic intramolecular C─N bond formation enabled by dioxane autoxidation and in situ peroxide formation.

Figure 10.

High-potential acyl hydroperoxides may be generated via autoxidation of acetaldehyde as a means to generate iodine(III) reagents with O₂.