Rigorous Conformational Analysis of Pyrrolidine Enamines with Relevance to Organocatalysis

Abstract

It has been suggested that the origin of regio- and stereoselectivity in Michael additions of pyrrolidine enamines is achieved by thermodynamic rather than kinetic control through distinct conformational preferences of the enamines. We assess this proposal by elaboration of a computational protocol that warrants sufficient accuracy. The small energy differences between the conformers necessitate a high accuracy of the electronic structure method which, in addition, must allow for computationally feasible calculations of a large number of conformers. Our protocol is based on density functional theory which we validated against explicitly correlated coupled cluster theory. The results are in agreement with the available experimental data, but illustrate that conformational preferences determined for one enamine are not readily transferable to other types of enamines. We found that an appropriate conformational sampling is inevitable to arrive at meaningful conclusions. Most prominently, s-cis and strans conformers are similarly stable for aldehyde- and ketone-derived enamines. The regio- and stereoselectivity in Michael additions of pyrrolidine-derived enamines can not be explained by pronounced stability differences of the enamine isomers and conformers in general, disproving the thermodynamic-control hypothesis. The elucidation of the origin of regio- and stereoselectivity requires further theoretical investigations of the elementary steps of Michael additions.