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

Abstract

A series of GFN-xTB methods were benchmarked against high-level DFT and ab initio 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-syn-C₆F_nR_12−n motif (n = 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.