The Effect of Microsolvation on the Mechanism, Kinetics and Energetics of a Reductive Amination Reaction

The reductive amination of carbonyl compounds is widely employed to synthesize functionalized amines in solution. The presence of water is known to impact the reaction rate but the underlying phenomena are poorly understood. Here, we combine nuclear magnetic resonance spectroscopy and quantum mechanical (QM) calculations to elucidate the effect of microsolvation on the mechanism, kinetics and energetics of the reaction between benzaldehyde and 4-(trifluoromethyl)-aniline in tetrahydrofuran. Kinetic data with varying water content indicate an autocatalytic effect. We explain this process by including two water molecules in QM calculations, demonstrating the transition-state stabilization that results from hydrogen bond formation. Through an extensive investigation of different QM methods, we find a “high-low” computational scheme with the G2MP2 method and SMD solvation model yields good quantitative agreement with experimental evidence, providing a theoretical approach to accelerate the development of other reductive amination reactions.