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 <b>int1</b> was found to be the real active intermediate for the formation of benzaldehyde <b>pro1</b> from acetophenone <b>sub1</b>. <b>sub1</b> transforms into <b>int1</b> 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. <b>int1</b> further generates <b>pro1</b> 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 <b>int3</b> is less kinetically favorable overall, but <b>int3</b> can generate <b>pro1</b> faster than <b>int1</b> does via a dehydrogenation mechanism. These mechanistic discoveries are consistent with the previously reported KIE effect, deuterium-labeling experiment, different reactivity of <b>sub1</b>, <b>int1</b> and <b>int3</b>, 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.