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, alpha-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-alpha-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 alpha,alpha-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 H-2 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.