Involvement of multiple oxidation pathways in regiodivergent Cu-directed C-H oxidation reactions

In this research article, we analyze the regioselectivity of Cu-directed C-H oxidations of substrate-ligands derived from alkyl aryl ketone substrates and bidentate directing groups. The oxidation of the substrate-ligands was carried out under 4 different reaction conditions (1. Cu I /H 2 O 2 ; 2. Cu I /O 2 ; 3. Cu II /OH - /H 2 O 2 ; and 4. Cu II /OH - /O 2 ) that led to marked changes in the regioselectivity of the Cu-promoted oxidation. Our mechanistic analysis suggests that 3 reaction pathways are operative, the first one involving the formation of mononuclear Cu/O 2 derived from H 2 O 2 (peroxygenase-like reactivity), the second one suggesting the formation of Cu 2 O 2 derived from O 2 (monooxygenase-like reactivity), and the third one induced by the deprotonation of cupric substrate-ligand species that generates cuprous-radical reaction intermediates (oxidase-like chemistry). Our research findings shed light on the reaction mechanisms by which Cu-dependent metalloenzymes carry out C-H hydroxylation reactions in nature, as well as provide strategies to perform regioselective oxidative transformations that can be used in organic synthesis.