Elucidating the mechanisms of copper-catalyzed aerobic transformations: From oxidative coupling of boronic acids and nucleophiles to copper/tempo-catalyzed alcohol oxidation

The selective oxidation of organic molecules is a key challenge in the transformation of simple hydrocarbons to functionalized products. Copper catalysts are effective for the aerobic oxidations of organic substrates, including carbon-heteroatom bond-forming reactions and selective alcohol oxidations. Rigorous mechanistic understanding of these catalysts have more recently begun to guide reaction development of new classes of reactivity.;The copper(II)-catalyzed oxidative coupling of boronic acids and heteroatom nucleophiles, the Chan-Evans-Lam reaction, is an alternative to non-oxidative cross-coupling technologies. Kinetic and spectroscopic (UV-visible, EPR, NMR) analysis of the reaction of 4-tolylboronic acid with methanol provides insight on the catalyst resting state(s) and steps preceding transmetalation (Chapter 2). The Chan-Lam reaction has an unpredictable substrate scope, and our results (Chapter 3) begin to rationalize the factors that govern the nucleophile reactivity, highlighting the inhibitory role of coordinating nucleophiles. Acidic nucleophiles form coupling products without interacting with the catalyst resting state. These results are in contrast to cross-coupling strategies, which are accelerated by coordination of donating nucleophiles.;Homogeneous Cu/TEMPO catalysts have emerged as versatile and practical systems for aerobic alcohol oxidation. Our group has developed a CuI/TEMPO catalyst that oxidizes 1° aliphatic and benzylic alcohols with ambient air. Spectroscopic and kinetic measurements outline a two-stage mechanism that explains observed reactivity and directs further catalyst development (Chapter 4). CuI and TEMPO-H aerobic oxidation to make CuII and TEMPO, and substrate oxidation involving reaction of a CuII-alkoxide and TEMPO to make aldehyde, and reduced catalyst. Computational investigation (Chapter 5) of the substrate oxidation suggests TEMPO coordination to form a transient intermediate followed by facile hydride transfer.