New Insights on Choline Chloride Role in Synthesis: The Case of Direct Amidation
Salvatore Mario Romano, Antonio Rescifina, Giuseppina De Luca, Mónica Nardi, Manuela Oliverio, Antonio Procopio
Abstract
The synthesis of amides is one of the most exploited reactions in pharmaceutical chemistry. It usually requires stoichiometric activators, thus representing an impactful reaction regarding sustainability. For this reason, the development of ecofriendly methods for amidation has become a challenge in organic chemistry. Choline chloride (ChCl) is a nontoxic biological molecule that can form eutectic mixtures (deep eutectic solvents, DES) with proton donors, including carboxylic acids. This work aims to use ChCl as a promoter for the direct amidation of carboxylic acids. Various microwave (MW)-assisted amidation tests were carried out with primary, secondary, benzyl, and aromatic amines. It has been verified that the reaction benefits from the specific MW effect. This is a thermal effect in which the nature of the reagents and the mechanism of the reaction allows effective accumulation of the MW. The energy is then relaxed with kinetics compatible with the activation of the reaction. The reaction mechanism was investigated by FT-IR analysis and DFT calculations, thus revealing a new role for ChCl in the stabilization of the reaction intermediates and the coordination of the two reagents. This work made it possible to rewrite the role of ChCl, not only as a component of reaction solvents but also as a coreactant able to determine the mechanistic path of the reaction.