Computational Revision of the Mechanism of the Thorpe Reaction

The Thorpe reaction is described as a self-condensation of nitriles in the presence of a basic catalyst producing an imine which tautomerizes spontaneously into a β-enaminonitrile. This reaction is studied because of its wide applications in the synthesis of cyclic, aromatic, and open-chain nitrogen derivatives. However, its reaction mechanism has not yet been studied with modern methods allowing the development of the experimental synthesis through a more economical, efficient and safety route. We performed theoretical calculations within the Density Functional Theory (DFT) framework at the ωB97XD/def2-svpd level to explore different mechanistic proposals when propionitrile is used as reagent and sodium ethoxide (EtONa) as catalyst. Furthermore, the influence of different solvents, such as ethanol (EtOH), tetrahydrofuran (THF), 1,2-dimethoxyethane (DME) and propionitrile (EtCN), was assessed. Finally, we also evaluated the effect of fluorine group (-F), compared to the methyl group (-CH₃), substituted in the α position of acetonitrile (MeCN). Our theoretical findings show that THF and DME are the best solvents to perform the reaction. Also, a fluorine group, as an electron withdrawing group, in the α position decreases both the activation energy and the Gibbs free energy of the reaction. This is in agreement with different experimental reports on the Thorpe reaction.