Performance of semiempirical DFT methods for the supramolecular assembly of Janus-face cyclohexanes

A series of GFN-xTB methods were benchmarked against high-level DFT and <i>ab initio</i> thermodynamic data for a set of conformational equilibria and driving forces for the formation of non-covalent complexes involving the Janus-face fluorocyclohexanes based on the all-<i>syn</i>-C₆F_<i>n</i>R_12-<i>n</i> motif (<i>n</i> = 3, 5, 6). When used alone, GFN methods showed moderate performance, with mean absolute errors (MAEs) from the high-level benchmarks of approximately 2.5 kcal mol^-1 for conformational equilibria and ∼5.0 kcal mol^-1 for molecular complexes. However, applying DFT-level single-point energy corrections on GFN-optimised geometries significantly improved the accuracy, reducing MAEs to ∼0.2 and ∼1.0 kcal mol^-1 for the same systems. This hybrid approach achieves DFT-D3-level accuracy while maintaining a low computational cost, offering up to a 50-fold reduction in computational time. As such, it provides a new cost-efficient and accurate tool for the computational modeling of Janus-face systems. An illustrative application to a flexible system, C₆F₅H₆O₂C(CH₂)₃NHCOC₆H₂(OR)₃, is reported (R = alkyl), highlighting the relative stabilities of folded and extended forms and their supramolecular assembly into helical stacks.