DFT study on the mechanism of amides to aldehydes using Cp 2Zr(H)Cl

Density functional theory (DFT) calculations at the B3LYP/6-31G(d,p) (LANL2DZ for Zr) level of theory were performed to elucidate the reaction mechanism for the reduction of amides to aldehydes using Cp 2Zr(H)Cl as a reducer. In particular, a detailed study was done that involved a proposed iminium cation species in the reaction mechanism. Our calculations suggest the first step of the reaction is the insertion of the C=O moiety into Zr-H through an "inside" mode of action that leads to the formation of a Zr-O intermediate that has been observed in previously reported experiments. Under anhydrous conditions, the cleavage of the O-C bond of the Zr-O intermediate results in the formation of an iminium cation, but this process is both kinetically and thermodynamically unfavorable. Nevertheless, under hydrous conditions, the cleavage of the O-C bond of the Zr-O intermediate leads to the formation of a highly active iminium cation intermediate, and this process occurs with the assistance of water hydrogen bonding. This step is also the rate-determining step, and the activation energy was determined to be 19.8 kcal/mol. Subsequently a water molecule attacks the iminium cation to produce an amine intermediate. Finally, the water-catalyzed elimination reaction occurs to yield the aldehyde product. Water hydrogen bonding plays an important role in assisting the cleavage of the O-C and the C-N bonds during the reaction. The above reaction mechanism indicates that the sources of the aldehyde-group oxygen and the hydrogen in the aldehyde product are H 2O and Cp 2Zr(H)Cl, respectively, which is consistent with the experimental observations of Georg and co-workers. © 2009 American Chemical Society.link_to_subscribed_fulltex