Mechanistic study of intramolecular aldol reactions of dialdehydes

Transition states associated with the C-C bond-formation step in proline-catalyzed intramolecular aldol reactions of 1,7-dialdehydes were studied using density functional theory methods (DFT), at the B3LYP/6-31G(d,p) level. A polarizable continuum model (PCM) was used to describe solvent effects. Two reactive channels, corresponding to the anhydrous system or to the explicit inclusion of water have been analysed. Computational data allow us to rationalize the intramolecular aldol reaction experimental outcome, validating the proposed enamine-based mechanism, as well as to suggest the importance of water in the control of the reaction stereoselectivity.