Density functional study of the l-proline-catalyzed α-aminoxylation of aldehydes reaction: The reaction mechanism and selectivity

The reaction mechanism of the l-proline-catalyzed α-aminoxylation reaction between aldehyde and nitrosobenzene has been investigated using density functional theory (DFT) calculation. Our calculation results reveal following conclusions [1]. The first step that corresponds to the formation of C–O bond, is the stereocontrolling and rate-determining step [2]. Among four reaction channels, the syn-attack reaction channel is more favorable than that of the anti one, and the TS-ss channel dominates among the four channels for this reaction in the step of C–O bond formation [3]. The intermolecular hydrogen bond between the acidic hydrogen of l-proline and the N atom of the nitrosobenzene in an early stage of the process catalyzes very effectively the C–O bond formation by a large stabilization of the negative charge that is developing at the O atom along the electrophilic attack [4]. The effect of solvent decreases the activation energy, and also, the calculated energy barriers are decrease with the enhancement of dielectric constants for C–O bond formation step. These results are in good agreement with experiment, and allow us to explain the origin of the catalysis and stereoselectivity for l-proline-catalyzed α-aminoxylation of aldehyde reaction. The addition of H₂O to substituted imine proline, intermolecular proton-transfer steps, and the l-proline elimination process were also studied in this paper.