Simulations unveil Grignard reactions’ complex mechanism

Abstract

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. Textbook 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—modeling solvents more accurately using molecular dynamics—the two realized they might be able to make Eisenstein’s dream reality. They were right. They