Development of quantum methods for invisible catalysts: external electric fields and solvation effects in Hurd–Claisen rearrangements

Abstract

This work presents the development of computational protocols to investigate the catalytic effects of oriented external electric fields and solvation on the Hurd-Claisen rearrangement. The study integrates density functional theory calculations with sequential Quantum Mechanics / Molecular Mechanics simulations, incorporating the average electrostatic configuration approximation of the solvent together with the free energy gradient approximation. These computational protocols allow for accurate modeling of solvent interactions and fieldinduced perturbations, providing insights into reaction kinetics and stereoselectivity. A key innovation of this research is the Python module MoleKing, developed to automate computational workflows, including molecular geometry manipulation, rotation, and alignment with electric fields. Written in C++, MoleKing streamlines the preparation of quantum chemical calculations by automatically reorienting molecules along the reaction or molecular axes, facilitating the efficient application of electric fields. Furthermore, the module handles input/output file processing for software such as Gaussian and PSI4, significantly reducing manual intervention and computational errors. The developed methodology was applied to a series of Hurd-Claisen rearrangements with different substituents, given the well-known sensitivity of this reaction to electrostatic interactions, systematically evaluating the influence of oriented external electric fields along the reaction and molecular axes. Solvation effects were modeled using ethyl vinyl ether within the Quantum Mechanics / Molecular Mechanics Sequential framework, revealing the interaction between the solvent and external fields in modulating dipole moments and transition state geometries. Computational simulations demonstrate that external fields can significantly alter stereoselectivity by selectively stabilizing specific transition states, while solvation introduces non-negligible polarization effects that influence activation barriers. These findings highlight the potential of invisible catalysis as a precise tool for stereochemical control.