Hydrogen-Bond-Dependent Conformational Switching: A Computational Challenge from Experimental Thermochemistry

We have compiled an experimental data set (SWITCH10) of equilibrium constants for a series of hydrogen-bond-dependent conformational switches. These organic molecules possess common functionalities and are representative in terms of size and composition of systems routinely studied computationally. They exist as two well-defined conformations which serve as a useful tool to benchmark computational estimates of experimental Gibbs energy differences. We examine the performance of HF theory and a variety of density functionals (B3LYP, B3LYP-D3, CAM-B3LYP, ωB97X-D, M06-2X) against these experimental benchmarks. Surprisingly, despite a strong similarity between the two switch conformations, the average errors (0.4–1.7 kcal·mol–1) obtained across the data set for all methods are larger than obtained with HF calculations. B3LYP was found to outperform implicitly and explicitly dispersion-corrected functionals, with an average error smaller by 1 kcal·mol–1. Unsystematic errors in the optimized structures were found to contribute to the relatively poor performance obtained, while quasi-rigid rotor harmonic oscillator thermal contributions are important in improving the accuracy of computed Gibbs energy differences. These results emphasize the challenge of quantitative accuracy in computing solution-phase thermochemistry for flexible systems and caution against the often used (but unstated) assumption of favorable error cancellation in comparing conformers or stereoisomers