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Abstract The inclusion of benzoic acid (BA) in β -CD in distinct water-solvent systems poses a challenge for theoretical methodologies. The experimental data indicate a decrease in stabilization with increasing organic solvent content relative to water. In this work, the multi-equilibrium (QC/ME) and quantum computational/molecular dynamics (QC/MD) approaches, both using the GFN2-xTB semiempirical quantum computational method, were applied to investigate the formation of BA@ β -CD inclusion complex in water, ethanol, and DMSO, as well as across solvent mixtures. According to the QC/ME data from the investigation of 1512 supramolecular systems, a preferred inclusion mode is one in which the –COOH group of the benzoic acid points toward the tail portion of the CD cavity (Form A). The QC/MD analysis identified this spatial arrangement as the most stable; however, a configuration in which the carboxyl group is oriented toward the wider rim of β -CD (Form B) is also predicted, consistent with experimental findings. MD simulations of β -CD inclusion complexes in explicit solvent indicate that these species are stable only in pure water. In contrast, in pure organic solvents and in solvent mixtures, even at low organic solvent fractions consistent with experimental conditions, the complexes exhibit very low stability and are primarily governed by competition between the guest molecule and solvent molecules for occupancy of the β -CD cavity.
Rezende et al. (Mon,) studied this question.