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

Abstract

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.