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Conformational polymorphs of organic molecular crystals represent a challenging test for quantum chemistry because they require careful balancing of the intra- and intermolecular interactions. This study examines 54 molecular conformations from 20 sets of conformational polymorphs, along with the relative lattice energies and 173 dimer interactions taken from six of the polymorph sets. These systems are studied with a variety of van der Waals-inclusive density functionals theory models; dispersion-corrected spin-component-scaled second-order Møller–Plesset perturbation theory (SCS-MP2D); and domain local pair natural orbital coupled cluster singles, doubles, and perturbative triples [DLPNO-CCSD(T)]. We investigate how delocalization error in conventional density functionals impacts monomer conformational energies, systematic errors in the intermolecular interactions, and the nature of error cancellation that occurs in the overall crystal. The density functionals B86bPBE-XDM, PBE-D4, PBE-MBD, PBE0-D4, and PBE0-MBD are found to exhibit sizable one-body and two-body errors vs DLPNO-CCSD(T) benchmarks, and the level of success in predicting the relative polymorph energies relies heavily on error cancellation between different types of intermolecular interactions or between intra- and intermolecular interactions. The SCS-MP2D and, to a lesser extent, ωB97M-V models exhibit smaller errors and rely less on error cancellation. Implications for crystal structure prediction of flexible compounds are discussed. Finally, the one-body and two-body DLPNO-CCSD(T) energies taken from these conformational polymorphs establish the CP1b and CP2b benchmark datasets that could be useful for testing quantum chemistry models in challenging real-world systems with complex interplay between intra- and intermolecular interactions, a number of which are significantly impacted by delocalization error.
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This content will become publicly available on December 1, 2025
Contrasting conformational behaviors of molecules XXXI and XXXII in the seventh blind test of crystal structure prediction
Accurate modeling of conformational energies is key to the crystal structure prediction of conformational polymorphs. Focusing on molecules XXXI and XXXII from the seventh blind test of crystal structure prediction, this study employs various electronic structure methods up to the level of domain-local pair natural orbital coupled cluster singles and doubles with perturbative triples [DLPNO-CCSD(T1)] to benchmark the conformational energies and to assess their impact on the crystal energy landscapes. Molecule XXXI proves to be a relatively straightforward case, with the conformational energies from generalized gradient approximation (GGA) functional B86bPBE-XDM changing only modestly when using more advanced density functionals such as PBE0-D4, ωB97M-V, and revDSD-PBEP86-D4, dispersion-corrected second-order Møller–Plesset perturbation theory (SCS-MP2D), or DLPNO-CCSD(T1). In contrast, the conformational energies of molecule XXXII prove difficult to determine reliably, and variations in the computed conformational energies appreciably impact the crystal energy landscape. Even high-level methods such as revDSD-PBEP86-D4 and SCS-MP2D exhibit significant disagreements with the DLPNO-CCSD(T1) benchmarks for molecule XXXII, highlighting the difficulty of predicting conformational energies for complex, drug-like molecules. The best-converged predicted crystal energy landscape obtained here for molecule XXXII disagrees significantly with what has been inferred about the solid-form landscape experimentally. The identified limitations of the calculations are probably insufficient to account for the discrepancies between theory and experiment on molecule XXXII, and further investigation of the experimental solid-form landscape would be valuable. Finally, assessment of several semi-empirical methods findsr2SCAN-3c to be the most promising, with conformational energy accuracy intermediate between the GGA and hybrid functionals and a low computational cost.
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- Award ID(s):
- 1955554
- PAR ID:
- 10521748
- Publisher / Repository:
- International Union of Crystallography
- Date Published:
- Journal Name:
- Acta Crystallographica Section B Structural Science, Crystal Engineering and Materials
- Volume:
- 80
- Issue:
- 6
- ISSN:
- 2052-5206
- Page Range / eLocation ID:
- 606 to 619
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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