Phenols, hydroquinones, quinones and related compounds are common intermediates and products of various biochemical and chemical synthetic pathways. These compounds can be generated via enzymatic aerobic oxidation of organic precursors in biochemical systems; however, analogous chemical methods for aerobic oxidation remain challenging. The quinone motif is an important structure in many natural products and therapeutics. For example, the natural product mitomycin C is a prominent example of a family of quinone-containing therapeutics that exhibit potent anti-cancer properties. Quinones also play an important role as redox mediators in many biochemical processes. Plastoquinone is an example that facilitates electron-transfer processes associated with the oxidation of water to molecular oxygen in Photosystem II, and topaquinone catalyzes the oxidation of primary amines to aldehydes in copper amine oxidases. Hydroquinones and quinones can be generated selectively by aerobic oxidation of phenol precursors in Nature by the copper-containing enzyme tyrosinase; however, selective oxidation of phenols by chemical catalysts is rare. Oxygenase reactivity produces hydroquinones and quinones from phenols, while oxidase reactivity generates biphenols from phenols. Most non-enzymatic reaction conditions produce a mixture of these products. Elucidation of mechanistic principles that enable selective functionalization of phenols could have important impact. Recent synthetic advances suggest that Cu-catalyzed aerobic oxidation of phenols can switch between oxygenase and oxidase reactivity, and these systems provide ideal models for probing the mechanistic basis for the change in selectivity. The proposed research will interrogate the mechanism of phenol and naphthol oxidation reactions that appear to involve cooperative redox catalysis between Cu and quinone centers that resembles copper amine oxidases. The mechanistic approach will involve the determination of the catalytic reaction mechanisms of Cu oxidase and Cu oxygenase reactions of phenolic substrates. Several plausible catalytic intermediates will be prepared (e.g., CuII/semiquinone species) and these species will be tested for chemical and kinetic competence under the catalytic reaction conditions. A variety of spectroscopic techniques (e.g., UV-visible spectroscopy, electron paramagnetic resonance spectroscopy) will be used to identify the catalyst resting state species. The identity of the resting state, together with kinetic rate law data should enable identification of the turnover-limiting step, and the collective insights should illuminate the origin of oxygenase vs. oxidase reactivity. Ultimately, it is anticipated that the results of this work will allow for mechanisticaly guided design of new catalytic reactions.

Public Health Relevance

The need for efficient and environmentally-responsible routes for the synthesis of pharmaceuticals is of paramount importance in today's healthcare system, since they are frequently used in the treatment, prevention and curing of illnesses and diseases. The proposed study investigates biomimetic oxidation reactions that produce diverse biologically- and pharmaceutically-relevant structural motifs using O2, an environmentally-benign oxidant, and copper, an abundant and non-toxic metal, as a catalyst.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Predoctoral Individual National Research Service Award (F31)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Barski, Oleg
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Wisconsin Madison
Schools of Arts and Sciences
United States
Zip Code
Jaworski, Jonathan N; McCann, Scott D; Guzei, Ilia A et al. (2017) Detection of Palladium(I) in Aerobic Oxidation Catalysis. Angew Chem Int Ed Engl 56:3605-3610
McCann, Scott D; Lumb, Jean-Philip; Arndtsen, Bruce A et al. (2017) Second-Order Biomimicry: In Situ Oxidative Self-Processing Converts Copper(I)/Diamine Precursor into a Highly Active Aerobic Oxidation Catalyst. ACS Cent Sci 3:314-321
Zhang, Wen; Wang, Fei; McCann, Scott D et al. (2016) Enantioselective cyanation of benzylic C-H bonds via copper-catalyzed radical relay. Science 353:1014-1018