Unveiling Electric Field-Driven Stereocontrol in Hurd-Claisen Rearrangements

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.