A mechanistic study reveals the roles of the ligand and substrate in the Pd-catalyzed C–H bond hydroxylation of a carboxylic acid with molecular oxygen

Abstract

The mechanism of the Pd(II)-catalyzed, pyridine–pyridone ligand-enabled hydroxylation of the C(sp²)–H bond in pyridine-4-carboxylic acid with molecular oxygen has been studied. The elemental steps include C–H bond activation, substrate-assisted O₂ oxidative addition, dimeric Pd species formation, O–O bond cleavage, and C–O reductive elimination, among which the reductive elimination is the rate-determining step. The ligand plays important roles in both facilitating C–H bond activation and facilitating proton-shuttling in O₂ activation and O–O cleavage steps. Our study reveals that the binding of the substrate's pyridine motif to Pd from the axial direction in the O₂ activation process is critical: without axial ligand binding or with weakly donating ligand binding, the O₂ activation is impractical. Thus, the substrate has a self-promoting effect on the oxidative addition with the O₂ oxidant. The O–O cleavage occurs from an unconventional dimeric cationic Pd species with a moderate reaction barrier. The final C–O bond formation takes place via reductive elimination from the Pd(IV) center. This work would shed light on further development of transition-metal catalyzed C–H bond oxidation reactions with green and practical oxidants, such as O₂.