A theoretical study of the nornicotine-catalyzed Mannich reaction in wet solvents and water

Nornicotine can catalyze the intermolecular Mannich reaction in wet solvents and water to enable a green version of this versatile C-C bond forming reaction. M06-2X/6-31++G(d,p) calculations combined with a polarizable continuum model are used to explore the possibilities of nornicotine catalysis. The bottleneck of the uncatalysed Mannich reaction is the formation of an enol from a ketone, while that of the catalysed Mannich reaction is the formation of an enamine from a ketone and nornicotine. The calculated barriers for the enamine formation are significantly lower than those for the enol formation and an overall speed-up of the Mannich reaction is predicted. The detailed analysis of four possible reaction paths suggests that nornicotine has a mild stereoinductive effect on the Mannich reaction favoring the S-Mannich product. The analysis further shows that water molecules play an active role in the reaction and indicates that wet solvents are actually needed for nornicotine catalysis.