Enhancing Grignard reactions via anion borrowing in deep eutectic /organic biphasic media
4 affiliations
- 1Department of Chemistry and Hylleraas Centre for Quantum Molecular Sciences, University of Oslo, PO Box 1033 Blindern, Oslo, Norway, 0315
- 2Department of Chemistry, Biochemistry, and Pharmaceutical Sciences, University of Bern, Freiestrasse 3, Bern, Switzerland, 3012
- 3ICGM
- 4ENSCM
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.
Related
- Enhancing acetaminophen solubility and stability using an aqueous betaine chloride–acetic acid natural deep eutectic solvent: experimental and mechanistic insights
- Copper-Catalyzed Defluorinative Coupling of gem-Difluoroallenes with Grignard Reagents
- Aggregation-Driven Self-Inhibition of Grignard Reagents: Insights from DFT and Microkinetic Modeling
- Origin of Reagent-Dependent Diastereoselectivity in Grignard Additions to a TADDOL-Derived α-Ketiminophosphonate
- Borrowing the fold, building the site: non-catalytic protein scaffolds in the age of computational metalloenzyme design
BibTeX
@misc{bortoli2026enhancing,
title = {{Enhancing Grignard reactions via anion borrowing in deep eutectic /organic biphasic media}},
author = {Marco Bortoli and Eva Hevia and Odile Eisenstein and Michele Cascella},
howpublished = {ChemRxiv},
year = {2026},
month = sep,
doi = {10.26434/chemrxiv.15005835/v3},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15005835/v3},
note = {CC BY},
}
RIS
TY - UNPB
TI - Enhancing Grignard reactions via anion borrowing in deep eutectic /organic biphasic media
AU - Marco Bortoli
AU - Eva Hevia
AU - Odile Eisenstein
AU - Michele Cascella
PY - 2026
DA - 2026/09/21
PB - ChemRxiv
DO - 10.26434/chemrxiv.15005835/v3
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15005835/v3
AB - 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.
ER -