Computational investigation on the mechanism and the stereoselectivity of Morita-Baylis-Hillman reaction and the effect of the bifunctional catalyst N-methylprolinol

The mechanism of the Morita-Baylis-Hillman (MBH) reaction between formaldehyde and methyl vinyl ketone (MVK) catalyzed by N-methylprolinol was investigated using density functional theory (DFT) method. The overall reaction includes two steps: C-C bond formation and hydrogen migration. In the presence of water, the hydrogen migration occurs via a six-membered ring transition state and the corresponding energy barrier decreases dramatically, and therefore the RDS is the C-C bond formation step. The calculations indicate that the C-C bond formation step controls the stereochemistry of the reaction. In this step, the hydrogen bonding induces the direction of the attack of enamine to aldehyde from the -OH group side of N-methylprolinol. The energy-favored transition states are mainly stabilized by hydrogen bonding, while the chirality of the products is affected by the hydrogen bonding and the steric hindrance. The calculations correctly reproduce the major product in (R)-configuration, which is consistent with the experimental observation.