Simulations unveil Grignard reactions’ complex mechanism

Organic chemistry students and bench chemists alike rely on the Grignard reaction, a relatively simple way to make carbon-carbon bonds. But even though the reaction was first described 120 years ago, chemists have only now uncovered the details of its complex mechanism (J. Am. Chem. Soc. 2020, DOI: 10.1021/jacs.9b11829)

In a Grignard reaction, a carbon-bonded magnesium halide adds to a carbonyl group to form an alcohol. Textbooks explanations describe the reaction’s mechanism as a nucleophilic addition, or mention a possible radical mechanism. Odile Eisenstein of the University of Oslo and the University of Montpellier has dreamed of fleshing out the reaction in more detail with a computational simulation since she was a PhD student in the 1970s. When she and Oslo colleague Michele Cascella started talking about Cascella’s work—more accurately modeling solvents using molecular dynamics—the two realized they might be able to make Eisenstein’s dream reality.

They were right. They simulated the reactions of CH₃MgCl with acetaldehyde and fluorenone in tetrahydrofuran, revealing a complicated mechanistic landscape involving competing nucleophilic and radical pathways that differ in energy by just 1 kcal—too small for their simulations to differentiate. But because they were able to simulate more solvent molecules than previous groups, Eisenstein and Cascella uncovered a critical role for THF. Although magnesium typically only accepts four ligands, they found THF can add as a fifth, changing the metal’s electronic symmetry and helping bonds break and form.

The research shows that whichever pathway the reaction takes, it’s not just the reactant and substrate that matter: “The number and movements of attached solvent molecules play a supporting role in the mechanism,” says Grignard-reaction expert Robert E. Mulvey of the University of Strathclyde.

Eisenstein and Cascella say they want to model every variation of the reaction they can. Different reagents and additives can guide Grignard reactions in desired directions, and the researchers think their approach could show new ways to improve the time-tested reaction.