Agenda

The Grignard Reaction: Solving a Century-old Puzzle by Molecular Simulations
The Grignard reaction is a venerable process for the synthesis of carbon-carbon bonds discovered in 1900, which paved the
way to modern organometallic synthesis. The reaction exploits the so-called Grignard reagent RMgX (with X a halogen, and R
an organic residue), a compound characterised by strong affinity to electron-poor carbons like in carbonyl moieties. Grignardlike
reagents are daily used for organic synthesis and constitute today a critical asset for the production of a broad range of
valuable compounds. For example, 85% of the drugs manufactured by the pharmaceutical industry require the use of these
reagents at least in one step of their synthesis [1]. Despite their extensive use, the molecular structures in solution and associated
reaction mechanisms of these main group organometallic reagents are, to date, still little known or understood. This hampers the
optimisation of their performance, with detrimental effects on both the costs for their industrial use, and on the environmental
impact of related industrial processes.
Here, I will first present how by applying state-of-the-art computational modelling based on ab initio molecular dynamics and
enhanced sampling techniques, we were able to characterise the Schlenk equilibrium for model CH3MgCl, which regulates the
interconversion of the reagent into all its monomeric and dimeric isoforms [2]. I will then describe the mechanistic insights of the
Grignard reaction against model acetaldehyde substrate [3]. The winning strategy to obtain this 120-year long waited result lies
in adopting an accurate and unbiased physical description of all the species in solution, including the solvent itself. In particular,
I will show how solvent fluctuations at the first coordination shell of Mg are key for the evolution of the Schlenk equilibrium,
and how solvent dynamics is directly connected to the mechanism(s) of the Grignard reaction. Finally, I will briefly discuss how
the nature of the substrate can promote the competition of a radical-based mechanism against the most commonly understood
nucleophilic attack.
References
1. DB Collum Acc. Chem. Res. 1993, 26, 227; G Wu, M Huang, Chem. Rev. 2006, 106, 2596
2. RM Peltzer, O Eisenstein, A Nova, M Cascella J. Phys. Chem B. 2017, 121, 4226
3. RM Peltzer, J Gauss, O Eisenstein, M Cascella J. Am. Chem. Soc. 2020, 142, 2984