(626f) Investigating the Impact of Water on the Energetics and Kinetics of a Reductive Amination Reaction – a Computational and Experimental Approach

Reductive amination reactions constitute up to 14% of the total reactions used for drug synthesis in pharmaceutical industry [1]; in particular, the reductive amination of carbonyl compounds is a highly useful, robust, and broadly employed transformation for the synthesis of further functionalised amines and has become an important work tool of pharmaceutical industry. [2] A key emerging consideration within pharmaceutical research is the use of better candidate solvents in these reactions as replacements for those that are less sustainable, pose adverse health and safety issues or demonstrate a detrimental environment impact. Therefore, studying the detailed mechanism, energetics and kinetics of imine formation and sequential reductive amination reactions is central to improving our understanding of the critical role that these reactions hold in pharmaceutical processes. The mechanism of such reactions follows a two-step approach in which an imine is formed via a carbinolamine intermediate (step 1) and the subsequent elimination of a water molecule (step 2). Previous computational studies have suggested the catalytic effect of water molecules on reaction energetics and kinetics. [3-5] In this study, we investigate the impact of water molecules on the energetics and kinetics of the reaction between benzaldehyde and 4-trifluoromethyl aniline, using quantum-mechanical and molecular-mechanical methods. Our efforts are focused on studying the microsolvation process in the gas and liquid phase, incorporating a varied number of water molecules around the reagents of the reaction. We demonstrate that addition of water molecules monotonically reduces the energy barrier of both reaction steps and accelerates the reaction kinetics, suggesting solvent effect importance on the energy and kinetic properties of the selected reaction. We additionally perform different water-content kinetic experiments, through ¹⁹F-NMR and ¹H-NMR spectroscopy, which strongly support our computational findings regarding the trend in barrier heights and reaction kinetics.

References

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2. McGonagle F. et al., Green Chem. 2013, 15, 1159.
3. Williams, I. H. Am. Chem. Soc. 1987, 109, 6299.
4. Hall and Smith, Phys. Chem. A 1998, 102, 4930
5. Louie M. K. et al., Phys. Chem. A 2016, 120, 1358