Are Grignard Reactions in Deep Eutectic Solvents Interface-Driven?

Organolithium and organomagnesium addition reactions to ketones are important and versatile processes used in synthetic organic chemistry. However, due to the high reactivity of these species, the reactions are usually done under an inert atmosphere at low temperature. 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 organic substrate. Surprisingly the organometallic reagent, added in an organic solution, is compatible with these unconventional conditions, and instead of undergoing fast decomposition by 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 with experiments; liquid diffraction, neutron reflectometry, NMR and interfacial tension measurements for acetophenone in DES and with all-atom molecular dynamics simulations. We show instead that the role of the choline chloride is to reduce the solubility of the ketone, forcing it to accumulate at the air-solvent (or organic solvent/DES) interface. Molecular dynamics simulations for isopropyl magnesium chloride in the same DES/tetrahydrofuran bi-phase system also indicate a preference to localize at the interface. These results suggest that surface accumulation promotes the addition reaction and account for these remarkable experimental conditions. Accumulation of the organic non-protic substrate at the interface could also protect the organometallic species from rapid decomposition by the protons of the DES.