Aerobic oxidation reactions have been the focus of considerable attention, but their use in mainstream organic chemistry has been constrained by limitations in their synthetic scope and by practical factors, such as the use of pure O2 as the oxidant or complex catalyst synthesis. Here, we report a new (bpy)CuI/TEMPO catalyst system that enables efficient and selective aerobic oxidation of a broad range of primary alcohols, including allylic, benzylic and aliphatic derivatives, to the corresponding aldehydes using readily available reagents, at room temperature with ambient air as the oxidant. The catalyst system is compatible with a wide range of functional groups and the high selectivity for 1° alcohols enables selective oxidation of diols that lack protecting groups.

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)CuI/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 CuI and TEMPO–H are oxidized by O2 via a binuclear Cu2O2 intermediate and (2) “substrate oxidation” mediated by CuII and the nitroxyl radical of TEMPO via a CuII-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 O2 is turnover limiting with benzylic alcohols, while numerous steps contribute to the turnover rate in the oxidation of aliphatic alcohols.

Combinations of homogeneous Cu salts and TEMPO have emerged as practical and efficient catalysts for the aerobic oxidation of alcohols. Several closely related catalyst systems have been reported, which differ in the identity of the solvent, the presence of 2,2′-bipyridine as a ligand, the identity of basic additives, and the oxidation state of the Cu source. These changes have a significant influence on the reaction rates, yields, and substrate scope. In this report, we probe the mechanistic basis for differences among four different Cu/TEMPO catalyst systems and elucidate the features that contribute to efficient oxidation of aliphatic alcohols.

This protocol describes a practical laboratory-scale method for aerobic oxidation of primary alcohols to aldehydes, using a chemoselective CuI/TEMPO catalyst system. The catalyst is prepared in situ from commercially available reagents, and the reactions are performed in a common organic solvent (acetonitrile) with ambient air as the oxidant. Three different reaction conditions and three procedures for the isolation and purification of the aldehyde product are presented. The oxidations of eight different alcohols, described here, include representative examples of each reaction condition and purification method. Reaction times vary from 20 min to 24 h, depending on the alcohol, while the purification methods each take about 2 h. The total time necessary for the complete protocol ranges from 3 – 26 h.

A scalable, continuous-flow process has been developed to implement a homogeneous Cu I /TEMPO catalyst system for aerobic oxidation of primary alcohols to aldehydes. This catalyst system is compatible with a wide range of alcohols bearing diverse functional groups. A dilute oxygen source (9% O 2 in N 2 ) is used to avoid flammable oxygen/organic mixtures. Residence times in the heated reaction zone can be as low as 5 min with activated (e.g., benzylic) alcohols. The method has been demonstrated with nine different alcohols, including one up to 100 g scale. This flow-based catalytic method exhibits significant advantages for aerobic oxidation of alcohols, including substantially shorter residence times and broader substrate scope relative to a Pd-catalyzed method that we reported recently.