Stereochemical Inversion of a Cyano-Stabilized Grignard Reagent: Remarkable Effects of the Ethereal Solvent Structure and Concentration

Abstract

Chiral organometallic reagents are useful in asymmetric synthesis, and configurational stability of these species is critical to success. In this study we followed the epimerization of a chiral Grignard reagent, prepared by Mg/Br exchange of bromonitrile <i>trans</i>-<b>2b</b>. This compound underwent highly retentive Mg/Br exchange in Et₂O; less retention was observed in 2-MeTHF and THF. Epimerization rate constants <i>k</i>_tc were determined at 195 K by measuring the diastereomer ratio of deuteration product <i>d</i>₁-<b>3b</b> as a function of the delay time before quench. Studies were also performed at varying concentrations of Et₂O in toluene. Remarkable dynamic range in <i>k</i>_tc was seen: relative to reaction at 0.12 M Et₂O in toluene, epimerization was 26-, 800-, and 1300-fold faster in Et₂O, 2-MeTHF, and THF, respectively. Thus, the identity and concentration of an ethereal solvent can dramatically affect configurational stability. Reaction stoichiometry experiments suggested that, in Et₂O, the Grignard reagent derived from <i>trans</i>-<b>2b</b> exists as an <i>i</i>-PrMgCl heterodimer; the invariance of <i>k</i>_tc over a 20-fold range in [Mg]_total ruled out mandatory deaggregation (or aggregation) on the epimerization path. Analysis of the dependency of <i>k</i>_tc on [Et₂O] and temperature in Et₂O/toluene solution at 195, 212, and 231 K indicated fast incremental solvation before rate-limiting ion-pair separation and provided an estimate of the entropic cost of capturing a solvent ligand (−13 ± 3 eu). Calculations at the MP2/6-31G*­(PCM)//B3LYP/6-31G* level provide support for these conclusions and map out a possible “ionogenic conducted tour” pathway for epimerization