The application of quantum-based NMR methods for the structural elucidation of natural and unnatural products has grown significantly. However, accurately calculating the conformational landscape of flexible molecules with intricate intramolecular hydrogen bonding (IHB) networks continues to be a major challenge. Previous studies have shown that to solve biased systems with strong IHB interactions, it is necessary to calculate the Boltzmann contributions using Gibbs free energies computed with at least a triple-ξ basis set and the SMD solvation model. In this work, we thoroughly studied the effect of entropic contributions (through Gibbs free energy calculations) on the performance of DP4+, a chemoinformatics tool designed for in silico structural elucidation.
The goal is to advance the development of computational methodologies that accurately describe systems with IHB, improving the prediction of molecular properties for these systems while contributing to sustainability. By utilizing these methodologies, the traditionally negative impact of experimental chemistry is reduced, minimizing the use of reagents, solvents, and energy, while promoting the exploration of new molecules and materials with lower environmental and economic costs.