Computational Exploration of Remote Directing Groups and Their Effects on Creating Grignard Reagents

Abstract

The commonly employed Grignard reaction involves carbon-carbon bond formation between a Grignard reagent, a magnesium halide bound to a carbon, and an electron-accepting substrate. Formation of alkyl Grignard reagents is often difficult and hence expensive for late stage intermediates. Creating inexpensive exchange agents that can place a magnesium halide on those intermediates while accepting a halide from the intermediate are highly desirable. Electron-rich groups potentially facilitate this exchange by directing the magnesium to the exchange position and stabilizing it. We explored aryl groups tethered by alkyl chains of varying lengths as remote directing groups. Using the B3LYP/CC-PVTZ level of theory in GAMESS on the Hopper Cluster, the exchange energies for various designs were calculated. Tether length mattered for the directing group, with shorter chains favored. Several aromatics yielded favorable exchange capacities. While these results are encouraging, a more complete exploration of the dependence of exchange capacity on tether length and electronic effects in the aromatic system are still required.