The mechanistic details on enamine formation between
dimethylamine and
propanal are unraveled using the ab initio and density functional theory methods. The addition of secondary
amine to the electrophile and simultaneous
proton transfer results in a carbinolamine intermediate, which subsequently undergoes
dehydration to form enamine. The direct addition of
amine as well as the
dehydration of the resulting carbinolamine intermediate is predicted to possess fairly high activation barrier implying that a unimolecular process is unlikely to be responsible for enamine formation. Different models are therefore proposed which could explain the relative ease of enamine formation under neat condition as well as under the influence of
methanol as the co-catalyst. The explicit inclusion of either the
reagent or the co-catalyst is considered in the transition states as
stabilizing agents. The participation of the
reagent or the co-catalyst as a monofunctional ancillary species is found to stabilize the transition states relative to the unassisted or the direct addition/
dehydration pathways. The reduction in enthalpy of activation is found to be much more dramatic when two co-catalysts participate in an active bifunctional mode in the rate-determining
dehydration step. The transition structures exhibited characteristic features of a relay
proton transfer mechanism. The free energy of activation associated with the two
methanol-assisted pathway is found to be 16.7 kcal/mol lower than that of the unassisted pathway. The results are found to be in concurrence with the available reports on the rate acceleration by co-catalysts in the Michael reaction between enamine and
methyl vinyl ketone under neat conditions.