GFN2-xTB study of the inclusion of thymol and carvacrol in β-cyclodextrin

Thymol and carvacrol belong to the class of terpenoids that usually contribute to the flavor, color, and development of plants, and their complexation with CD has been recently reported. Due to their structural similarities, including such guests in CD poses a challenging task to theoretical methodologies. With the present contribution, we applied the recently developed GFN2-xTB multi-equilibrium approach to study the inclusion of those guests into β-CD. The inclusion of 1-adamantane carboxylic acid in β-CD was also investigated for comparison. The study was conducted with a progressive increase in the number of systems in steps, comprising 792, 1,188, and 1,584 systems. Therefore, for the three guest/host pairs studied, complete optimization in vacuum and water with the ALPB continuum method was applied to 10,692 systems at the GFN2-xTB level of theory. Furthermore, single-point calculations at the B97-3c/def2-TZVPP level of theory were carried out using the SMD solvation model. As a result, beyond determining the experimental trend, we addressed that the additional degree of freedom represented by the gamma Euler parameter decreased the errors related to the estimated adjusted binding constants. On the other hand, the use of the B97-3c/def2-TZVPP in conjunction with the set of systems selected by GFN2-xTB (ALPB) must be further investigated since the experimental trend was obtained only with a basis in the difference in electronic energies.

Graphical Abstract