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

Abstract

We have compiled an experimental dataset (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 dataset 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.

Design and Optimization of Catalysts Based on Mechanistic Insights Derived from Quantum Chemical Reaction Modeling

“…Many organometallic catalysts such as Schrock’s catalyst in N 2 activation have bulky and flexible ligands which are essential and should not be truncated. The orientations of these ligand centers should be modeled properly through careful conformational search, which is nontrivial. − This is particularly important in theozyme based reaction modeling.…”

Accuracy of DLPNO-CCSD(T): Effect of Basis Set and System Size

“…This strategy significantly reduces the cost of these calculations comparable to density functional theory (DFT) methods. This approximation has enabled the first CCSD­(T) calculation of a protein containing 644 atoms and has since been widely used in the calculation of large supramolecular complexes, model systems of enzymatic reactions, iron-porphyrin complexes, functionalized fullerene cations, conformational energies, − formation enthalpy of medium-sized organic compounds, and dissociation energies of Lewis adducts . In addition, several groups have also implemented DLPNO-CCSD­(T) within the framework of composite methods or basis set extrapolation schemes. − …”

An experimental and computational study of new spiro-barbituric acid pyrazoline scaffolds: restricted rotationvs.annular tautomerism

“…Spectral data of some synthesized derivatives revealed many additional peaks, which motivated us to rationalize them. Afterwards, we used the theoretical calculation at the B3LYP/ 6-311++G(d,p) level of theory 19 with implicit PCM solvation corresponding to DMSO to explore all possibilities associated with the restricted rotation and tautomerism. Considering two positions for tautomerism (Scheme 2), we used thermodynamic and kinetic calculations to find the kinetic barrier and the equilibrium constant for 4a and 4e derivatives.…”