Are Grignard Reactions in Deep Eutectic Solvents Interface-Driven?

Organolithium and organomagnesium addition reactions to ketones are important and versatile procedures used in many sectors of synthetic organic chemistry. However, due to the high reactivity of these species, the reactions are normally done under an inert atmosphere at low temperature to control their selectivity. This imposes severe limitations for scaling up. Recent work has demonstrated the possibility to carry out these procedures safely on the benchtop, in air at room temperature using deep eutectic solvents (DES) to dissolve the substrate. Surprisingly the organometallic reagent is compatible with these unconventional conditions, and instead of undergoing fast decomposition in the DES, better yields and selectivities are observed than when working under standard conditions. Earlier it was posited that the choline chloride component of the DES might chemically activate the ketone substrate making it more amenable to reaction. Here we probe this hypothesis and suggest instead that the role of the choline chloride is to reduce the solubility of the substrate, forcing it to accumulate at the air-solvent (or organic solvent/DES) interface. Computational studies for the organometallic species in a DES/ether bi-phase system, also indicate a preference to localize at the interface. These factors suggest that surface accumulation promotes the addition reaction and account for these remarkable experimental conditions.