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 formation of non-covalent complexes involving the Janus-face fluorocyclohexanes based on the all-syn-C 6 F n R 12-n motif (n = 3,5,6). When used alone, GFN methods showed moderate performance, with mean absolute deviations (MADs) from the high=level benchmarkss 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-optimized geometries significantly improved the accuracy, reducing MADs to ~0.2 and ~3.2 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, C 6 F 5 H 6 O 2 C(CH 2 ) 3 NHCOC 6 H 2 (OR) 3 , is reported (R = alkyl), calling special attention to relative stabilities of folded and extended forms and their supramolecular assembly into helical stacks.