Unveiling Electric Field-Driven Stereocontrol in Hurd–Claisen Rearrangements

High Resolution Image Download MS PowerPoint Slide Herein, we present a comprehensive computational study of the Hurd–Claisen rearrangement in both ester- and nitrile-containing substrates under oriented and nonoriented external electric fields (EEFs). Using high-level DFT calculations, we systematically mapped how EEFs perturb dipole–field interactions and transition-state geometries across a wide range of aryl and alkyl substituents. Fields aligned along the traditional reaction axis impart only modest differential stabilization (0.5–1.0 kcal·mol –1 ), insufficient to reverse E / Z ratios except in nearly degenerate cases, whereas molecular-axis alignment boosts this difference to over 2 kcal·mol –1, reliably inverting selectivity by maximizing dipole overlap. To bridge theory and experiment, we have applied the gold–thiolate anchoring in our model, harnessing substrate polarization to amplify transition-state stabilization from roughly 5 kcal·mol –1 in the free system to over 20 kcal·mol –1 at higher field strengths. We further show, via isotropic field ensembles weighted by Boltzmann and von Mises–Fisher statistics, that even nonoriented fields can impose a stereochemical bias of at most 2.5 kcal·mol –1 through dipole torque. These findings establish dipole orientation as a quantitative predictor of EEF-mediated stereocontrol and provide concrete blueprints for deploying “invisible catalysts” in flow reactors, surface-confined assemblies, and microreactor platforms for reagent-free, on-demand synthesis of stereochemically defined molecules.