Aggregation-Driven Self-Inhibition of Grignard Reagents: Insights from DFT and Microkinetic Modeling

A mechanistic DFT study with explicit Et2O microsolvation and microkinetic modeling unveils how organomagnesium reagents (nBuMgX, X = Cl, Br, nBu) undergo structural reorganization during nitrile additions, generating aggregates that hamper reactivity. Starting from halide-bridged dimers (Et2O)·nBuMg(µ-X)2MgnBu·(Et2O), nitrile addition proceeds via a bimetallic 6-centered transition state (∆G‡ ∼ 19 kcal mol−1) and yields imido-bridged products stabilized by more than 30 kcal mol−1. For mixed reagents (X = Cl, Br), post-nucleophilic addition Schlenk equilibria lead to di-imido dimers (Et2O)·XMg(µ-[N])2MgX·(Et2O) along with the initial reactive dimer. In contrast, starting from the homoleptic nBu2Mg, post-nucleophilic addition equilibria deliver a Mg-based tetramer Mg4(µ-[N])4nBu4 that scavenges nucleophilic groups. Engaging the remaining Mg–alkyl bonds in such a tetramer requires overcoming an overall energy barrier of 27 kcal mol−1, thus limiting conversion. Microkinetic simulations, based on computed free energy profiles and experimental initial conditions, quantitatively reproduce the experimental 50% conversion plateau and 4:1 product:side product ratio, establishing aggregation-driven inhibition as the origin of incomplete reactivity. These findings provide rational guidelines for optimizing Grignard transformations through reagent selection, additive strategies and solvation engineering, with applications for polyolefin upgrading and pharmaceutical synthesis.