Striking Impact of Solvent Polarity on the Strength of Hydrogen‐Bonded Complexes: A Nexus Between Theory and Experiment

Abstract The binding free energy of hydrogen‐bonded complexes is generally inversely proportional to the solvent dielectric constant. This occurs because the solvent‐accessible surface area of the complex is always smaller than that of the individual subsystems, leading to a reduction in solvation energy. The present study explores the potential for stabilizing hydrogen‐bonded complexes in a solvent with higher polarity. Contrary to the established understanding, we have demonstrated that the hydrogen‐bonded complex (CH 3 CH 2 COOH⋅⋅⋅2,4,6‐trimethylpyridine) can be better stabilized in a solvent with higher polarity. In this case, a significant charge transfer between the subsystems results in an increased dipole moment of the complex, leading to its stabilization in a more polar solvent. The expected inverse relationship between binding free energy and solvent dielectric constant is observed when the charge transfer between the subsystems is low. Thus, the magnitude of the charge transfer between subsystems is possibly the key factor in determining the stabilization or destabilization of H‐bonded complexes in different solvents. Here, we present a comprehensive study that combines experimental and theoretical approaches, including nuclear magnetic resonance (NMR), infrared (IR) spectroscopies and quantum chemical calculations to validate the findings.