Role of water in the reaction mechanism and endo/exo selectivity of 1,3-dipolar cycloadditions elucidated via quantum chemistry and machine learning.

The asymmetric 1,3-dipolar cycloadditions of azomethine ylides with activated olefins are one of the most important and versatile methods for the synthesis of enantioenriched pyrroline and pyrrolidine derivatives. Despite both theoretical and practical importance, the roles of water molecules in reactivity and endo/exo selectivity remain unclear. To explore how water accelerates the reaction rates and improves the endo/exo selectivity of the cycloadditions of 1,3-dipole phthalazinium-2-dicyanomethanide (1) and two dipolarophiles, an ab initio-quality neural network potential that overcomes the computational bottleneck of explicitly considering water molecules has been used. We demonstrate that not only the nature of both the dipolarophile and the 1,3-dipole used but also the solvent medium can perturb or even alter the reaction mechanism. An extreme case has been found for the 1,3-dipole 1 + methyl vinyl ketone reaction in which the reaction mechanism changes from a concerted to a stepwise fashion in going from MeCN to H2O as a solvent, forming a zwitterionic intermediate that is a very shallow minimum on the energy surface. Thus, high stereocontrol can still be expected despite the stepwise nature of the mechanism. Results indicate that water can induce a global polarization along the reaction coordinate and highlight the role of microsolvation effects and bulk-phase effects in reproducing the experimentally observed aqueous acceleration and enhanced endo/exo selectivity.