Abstract

In this work, we extend Molecular Density Functional Theory (MDFT) to investigate the effect of high pressure on solvation and chemical reactivity. As a representative case study, we consider a Diels–Alder reaction in model nonpolar and polar CH₂Cl₂ solvents. MDFT enables the efficient calculation of solvation free energies for molecular structures along the reaction pathway over a broad pressure range. By combining these solvation contributions with electronic Density Functional Theory (eDFT) calculations that provide gas-phase energetic differences between reactants, transition states, intermediates, and products, we construct full reaction free energy profiles from ambient pressure up to 1.5 GPa. Particular attention is devoted to the solvent dielectric response and its influence on reaction kinetics. The model reproduces the experimental dielectric constant at moderate pressures (0–0.2 GPa) and predicts its significant increase in the GPa regime. Our results are consistent with experimental observations, showing that high pressure promotes the reaction and induces a trans/cis diastereoselectivity in the product distribution. The analysis highlights the central role of electrostatic interactions in driving these effects. Moreover, the activation volume—a key quantity characterizing pressure-dependent reactivity—is obtained directly from the computed free energy profiles. The calculated values are in good agreement with typical experimental measurements. Overall, this work demonstrates that coupling MDFT with electronic DFT provides an efficient and predictive framework to investigate pressure effects on chemical reactions in solution.