Theoretical mechanistic investigation of zinc(II) catalyzed oxidative amidation of benzyl alcohols with amines

Density functional theory (DFT) calculations have been performed to investigate the mechanism of Zn(II)-catalyzed oxidative amidation of benzylic alcohol with amines. A two-step oxidation mechanism is proposed where oxidation of benzyl alcohol to benzaldehyde is the first step. In the 2nd step, hemiaminal generated from the aldehyde is converted to amide through oxidation. Inner sphere, out sphere and intermediate sphere mechanisms for the oxidation of benzyl alcohol to benzaldehyde, are investigated. The inner sphere mechanism is kinetically more demanding (Ea = 30.59 kcal mol−1), and not believed to contribute to the progress of the reaction under the experimental conditions (at 40 °C). The activation barrier associated with outer sphere mechanism is 24.4 kcal mol−1, which can be easily surpassed under the reaction conditions. Therefore, the more plausible mechanism is outer sphere mechanism. The oxidation of hemiaminal to amide is also kinetically highly favorable with Ea = 7.88 kcal mol−1 (outer sphere mechanism). The intermediate sphere mechanism involving transfer of hydrogen to tert-butyl hydrogen peroxide (TBHP) has activation barrier of 25.98 kcal mol−1, and therefore cannot be excluded safely. The preference of zinc (II) for outer sphere mechanism is quite contrary to the other later transition metals (Ru, Ir, Pd) catalysis for the similar reaction where inner sphere mechanism is the predominant one.

The first theoretical study of zinc catalyzed oxidative amidation of alcohols with amines reveals that the plausible mechanism is outer sphere mechanism, and this is remarkably different than the operating mechanism in similar reaction catalyzed by other late transition metals.Figure optionsDownload as PowerPoint slide