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

Area of Science:

• Computational Chemistry
• Physical Chemistry
• Molecular Modeling

Background:

• Accurate prediction of molecular conformations and their energy differences is crucial for understanding chemical processes.
• Hydrogen-bond-dependent conformational switches are important model systems for benchmarking computational methods.
• Existing computational methods often face challenges in achieving quantitative accuracy for flexible organic molecules.

Purpose of the Study:

• To establish an experimental dataset (SWITCH10) of equilibrium constants for hydrogen-bond-dependent conformational switches.
• To benchmark the performance of various computational methods, including Hartree-Fock (HF) theory and several density functionals, against experimental Gibbs energy differences.
• To identify factors contributing to errors in computed thermochemistry for flexible systems.

Main Methods:

• Compilation of the SWITCH10 experimental dataset.
• Application of Hartree-Fock (HF) theory.
• Evaluation of density functionals: B3LYP, B3LYP-D3, CAM-B3LYP, ωB97X-D, and M06-2X.
• Analysis of structural optimization errors and thermal contributions (quasi-rigid rotor harmonic oscillator).

Main Results:

• All tested computational methods exhibited average errors (0.4-1.7 kcal·mol⁻¹) larger than HF theory for predicting Gibbs energy differences.
• B3LYP demonstrated superior performance compared to implicitly and explicitly dispersion-corrected functionals, with a 1 kcal·mol⁻¹ lower average error.
• Unsystematic errors in optimized molecular structures significantly impacted computational accuracy.
• Quasi-rigid rotor harmonic oscillator thermal contributions were essential for improving computed Gibbs energy differences.

Conclusions:

• Achieving quantitative accuracy in computing solution-phase thermochemistry for flexible systems remains a significant challenge.
• The study cautions against assuming error cancellation when comparing conformers or stereoisomers using computational methods.
• Hartree-Fock theory provided surprisingly competitive results compared to more advanced density functional approximations for this dataset.