Accurate Enthalpies of Formation for Bioactive Compounds from High-Level Ab Initio Calculations with Detailed...

Our recently developed approach based on the local coupled-cluster with single, double, and perturbative triple excitation [LCCSD(T)] model gives very efficient means to compute the ideal-gas enthalpies of formation. The expanded uncertainty (95% confidence) of the method is about 3 kJ·mol^-1 for medium-sized compounds, comparable to typical experimental measurements. Larger compounds of interest often exhibit many conformations that can significantly differ in intramolecular interactions. Although the present capabilities allow processing even a few hundred distinct conformer structures for a given compound, many systems of interest exhibit numbers well in excess of 1000. In this study, we investigate how to reduce the number of expensive LCCSD(T) calculations for large conformer ensembles while controlling the error of the approximation. The best strategy found was to correct the results of the lower-level, surrogate model (density functional theory, DFT) in a systematic manner. It was also found that the error in the conformational contribution introduced by a surrogate model is mainly driven by a systematic (bias) rather than a random component of the DFT energy deviation from the LCCSD(T) target. This distinction is usually overlooked in DFT benchmarking studies. As a result of this work, the enthalpies of formation for 20 cannabinoid and cannabinoid-related compounds were obtained. Comprehensive uncertainty analysis suggests that the expanded uncertainties of the obtained values are below 4 kJ·mol^-1.