Mechanism of Cu-Catalyzed Aerobic C(CO)–CH3 Bond Cleavage: A Combined Computational and Experimental Study
journal contributionposted on 24.12.2018, 00:00 by Yuan-Ye Jiang, Guoqing Li, Daoshan Yang, Zhaoshun Zhang, Ling Zhu, Xia Fan, Siwei Bi
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 Cα–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.