Enhancing Grignard reactions via anion borrowing in deep eutectic /organic biphasic media
Year: 2026
Type: preprint
Abstract: The rational optimization of the Grignard reaction remains a considerable challenge for synthetic chemists. When assessing nucleophilic additions to unsaturated organic molecules, it has been shown that improved performance can be achieved using deep eutectic solvents (DESs). In this case, a solution of the Grignard in THF is added to the DES containing the substrate under vigorous stirring. In this study, we determine the underlying causes for this beneficial effect by combining ab initio molecular dynamics, QM/MM simulations, and enhanced sampling, using i -PrMgCl and acetophenone as reagents, THF as the organic solvent, and a 1:2 solution of choline chloride:glycerol as the DES. Our results show an increased preference for the Grignard reaction over the formation of by-products originating from a β-H transfer from the isopropyl group with the DES/THF media. This enhanced selectivity stems from the formation of chlorinated dimagnesium entities at the DES interface. While the reaction of a neutral Grignard in bulk THF kinetically favours the β-H transfer, the chlorine enrichment originating from the DES is shown to make the two reactions kinetically more equivalent, and to drastically favor the thermodynamic preference for the Grignard product, a result of increased intramolecular stabilizing interactions. This result is in line with experimental evidence of increased selectivity in the presence of various halide salts. This mechanistic interpretation paves the way for the rational improvement of Grignard reagents, allowing an even broader application of these compounds in these non-conventional solvents.
Source: ChemRxiv
Language: English
Subfield: Physical and Theoretical Chemistry
Field: Chemistry
Domain: Physical Sciences
Open Access status: green
OpenAlex ID: W7213929933