New Insights on Choline Chloride Role in Synthesis: The Case of Direct Amidation

The synthesis of amides is one ofthe most exploited reactionsin pharmaceutical chemistry. It usually requires stoichiometric activators,thus representing an impactful reaction regarding sustainability.For this reason, the development of ecofriendly methods for amidationhas 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 carboxylicacids. This work aims to use ChCl as a promoter for the direct amidationof carboxylic acids. Various microwave (MW)-assisted amidation testswere carried out with primary, secondary, benzyl, and aromatic amines.It has been verified that the reaction benefits from the specificMW effect. This is a thermal effect in which the nature of the reagentsand the mechanism of the reaction allows effective accumulation ofthe MW. The energy is then relaxed with kinetics compatible with theactivation of the reaction. The reaction mechanism was investigatedby FT-IR analysis and DFT calculations, thus revealing a new rolefor ChCl in the stabilization of the reaction intermediates and thecoordination of the two reagents. This work made it possible to rewritethe role of ChCl, not only as a component of reaction solvents butalso as a coreactant able to determine the mechanistic path of thereaction. Choline chloride activated the directamidation by coordinatingboth acid and amine in a four-center transition state.

Automated summary

The synthesis of amides, a commonly used reaction in pharmaceutical chemistry, usually requires stoichiometric activators and impacts sustainability. Developing eco-friendly methods for amidation has become a challenge. This study explores the use of non-toxic biological molecule choline chloride (ChCl) as a promoter for direct amidation of carboxylic acids. Microwave-assisted amidation tests reveal that the reaction benefits from specific microwave effects, which accumulate energy and activate the reaction. FT-IR analysis and DFT calculations shed light on the reaction mechanism and uncover a new role for ChCl in stabilizing intermediates and coordinating reagents.