A Mononuclear Scenario for the Copper‐Catalyzed Monooxygenation of Phenolic Substrates

Whereas a dinuclear pathway applies to the monooxygenation of phenols by the type 3 copper enzyme tyrosinase, a mononuclear pathway has been identified for the same reaction in corresponding small-molecule systems. DFT calculations of five copper model complexes reveal that the latter mechanism is energetically feasible, identifying all intermediates, and transition states. The mechanism closely resembles the biosynthesis of the topaquinone (TPQ) cofactor in the enzyme amine oxidase (AO), though the latter process is not catalytic. Additionally, it is shown that the hydroxo-quinone complex formed after the hydroxylation step further converts into a copper-geminal diolate species, which is confirmed by MS/MS experiments using isotope labeling with ¹⁸O₂.