Quantum mechanical investigations on the role of neutral and negatively charged enamine intermediates in organocatalyzed reactions

•M06-2X functional is suitable to model key steps of proline-catalyzed reactions.•Investigation of the proline-catalyzed aldol reaction mechanism.•Influence of water molecules on the C-C bond formation step.•Mechanism for the reaction of proline-derived enamines with benzhydrylium cations.

The proline-catalyzed aldol reaction is the seminal example of asymmetric organocatalysis. Previous theoretical and experimental studies aimed at identifying its mechanism in order to rationalize the outcome of this reaction. Here, we focus on key steps with modern first principle methods, i.e. the M06-2X hybrid exchange-correlation functional combined to the solvation density model to account for environmental effects. In particular, different pathways leading to the formation of neutral and negatively charged enamine intermediates are investigated, and their reactivity towards two electrophiles, i.e. an aldehyde and a benzhydrylium cation, are compared. Regarding the self-aldol reaction, our calculations confirm that the neutral enamine intermediate is more reactive than the negatively charged one. For the reaction with benzhydrylium cations however, the negatively charged enamine intermediate is more reactive.

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