Theoretical Analysis of Electronic, Vibrational Properties, and Noncovalent Interactions in Methylxanthines: Monomers to Antiparallel Dimers

Abstract

This study provides a comprehensive characterization of methylxanthines in monomeric and antiparallel dimeric configurations using DFT-D3 and SAPT0 analysis. Our results elucidate a synergistic interplay between hydrogen bonding and π–π stacking, where London dispersion accounts for over 50% of the total attractive forces. The wide HOMO–LUMO gaps (7.2–9.4 eV) obtained with M06–2X and ωB97X correlate with minimal induction contributions (Eind < 9.5%) and negligible charge transfer, confirming the noncovalent nature of the assembly. A detailed thermochemical analysis confirms the spontaneity of dimerization through calculated Gibbs free energies, revealing a strong dependence on the chosen density functional. Furthermore, color-coded NCI-RDG plots provide an unambiguous mapping of attractive and steric forces, demonstrating that while dimerization preserves monomeric reactivity, it drives a stable supramolecular assembly. These insights provide a fundamental starting point for understanding the intrinsic driving forces of methylxanthines, potentially aiding in the future rational design of methylxanthine-based cocrystals and supramolecular materials.