Mechanism of Cu-Catalyzed Aerobic C(CO)–CH₃ Bond Cleavage: A Combined Computational and Experimental Study

Cu-catalyzed aerobic C­(CO)–CH₃ activation of (hetero)­aryl methyl ketones provides a rare tool for aldehyde formation from ketones through oxidative processes. To elucidate the detailed reaction mechanism, a combined computational and experimental study was performed. Computational study indicates a dinuclear Cu-catalyzed spin-crossover-involved mechanism explains the aldehyde formation. Meanwhile, α-mono­(hydroxy)­acetophenone int1 was found to be the real active intermediate for the formation of benzaldehyde pro1 from acetophenone sub1. sub1 transforms into int1 via oxygen activation and rate-determining C_α–H activation. The resulting dinuclear Cu complex regenerates the active Cu­(I) complex through spin-crossover-involved disproportionation and retro oxygen activation. int1 further generates pro1 via oxygen activation, O–H activation, iodide atom transfer, 1,2-H shift, ligand rotation, spin crossover, and nucleophilic substitution. By comparison, the previously proposed reaction route involving α,α-bis­(hydroxy)­acetophenone int3 is less kinetically favorable overall, but int3 can generate pro1 faster than int1 does via a dehydrogenation mechanism. These mechanistic discoveries are consistent with the previously reported KIE effect, deuterium-labeling experiment, different reactivity of sub1, int1 and int3, and detection of H₂ and CO₂. Furthermore, computational study unexpectedly revealed the competitive generation of aromatic acids in the C­(CO)–CH₃ activation process for especially electron-rich substrates. This reaction route is supported by the experimental study, which confirmed the aromatic acid formation in Cu-catalyzed aerobic C­(CO)–CH₃ cleavage of ketones and excluded the in situ oxidation of aldehyde products to aromatic acid products.