Nitroxyl Surprise: A Simple Amine Additive Revealed as Copper’s Co-Catalyst in the Aerobic Oxidation of Alcohols

In the search for new catalytic activity, chemists rely on working hypotheses and their intuition. All new transformations involve a combination of design and fortuitous discovery, whether they are discovered in a highthroughput platform, or by more traditional flask-by-flask experimentation. Particular additives or ligands are typically chosen based on a mechanistic hypothesis. The beauty of true discovery occurs when careful experimentalists, in fully developing and analyzing their reactions, are surprised to find that the added reagent facilitates catalysis by an unexpected pathway. Such happenstances exemplify the best of the scientific method, as the scientist must remain impartial, breaking allegiance with the original working hypothesis and generates new ones. The highlighted paper provides a new example of serendipitous discovery that may guide development of related oxidation reactions and inform bioinorganic chemistry. While developing environmentally friendly copper-catalyzed oxidation reactions, it was determined that the diamine originally added as a ligand for copper actually acts as a co-catalyst upon oxidation in situ to a nitroxyl radical (Scheme 1). Furthermore, this mechanism provides an example of a catalyst performing two roles: the copper complex must first oxidize the diamine to the nitroxyl radical, and then it must catalyze the oxidation of the alcohol to the carbonyl. Oxidation reactions are among the most prevalent transformations in chemical synthesis, used by both biological systems and synthetic chemists. Enzymatic oxidases, such as galactose oxidase, use molecular oxygen as the terminal oxidant for alcohol oxidation, whereas most common synthetic methods require toxic and/or atom-inefficient stoichiometric oxidants. Development of sustainable catalytic oxidation reactions that employ molecular oxygen and nonprecious transition metals has been an active field of study. To address this challenge, a number of copper-catalyzed oxidations have been developed. Most of these transformations require the use of a redox active co-catalyst that lowers the kinetic barrier for hydrogen-atom transfer from a copper alkoxide species. The mechanisms of these transformations often mirror those of enzymatic oxidations, as the co-catalyst serves a similar function to cofactors present in the active site. In 2015 Lumb and Arndtsen reported an efficient oxidation of alcohols that did not require a redoxactive co-catalyst (Scheme 1). Stahl, Lumb, and Arndtsen have now collaborated to provide an in-depth mechanistic investigation of this reaction, discovering the mechanistic parallels to enzymatic activity are more pronounced than expected.