An official website of the United States government
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.
more »
« less
The interplay of intra- and intermolecular errors in modeling conformational polymorphs
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.
more »
« less
- Award ID(s):
- 1955554
- PAR ID:
- 10364032
- Publisher / Repository:
- American Institute of Physics
- Date Published:
- Journal Name:
- The Journal of Chemical Physics
- Volume:
- 156
- Issue:
- 10
- ISSN:
- 0021-9606
- Page Range / eLocation ID:
- Article No. 104112
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
-
Molecular crystal structure prediction is increasingly being applied to study the solid form landscapes of larger, more flexible pharmaceutical molecules. Despite many successes in crystal structure prediction, van der Waals-inclusive density functional theory (DFT) methods exhibit serious failures predicting the polymorph stabilities for a number of systems exhibiting conformational polymorphism, where changes in intramolecular conformation lead to different intermolecular crystal packings. Here, the stabilities of the conformational polymorphs of o -acetamidobenzamide, ROY, and oxalyl dihydrazide are examined in detail. DFT functionals that have previously been very successful in crystal structure prediction perform poorly in all three systems, due primarily to the poor intramolecular conformational energies, but also due to the intermolecular description in oxalyl dihydrazide. In all three cases, a fragment-based dispersion-corrected second-order Møller–Plesset perturbation theory (MP2D) treatment of the crystals overcomes these difficulties and predicts conformational polymorph stabilities in good agreement with experiment. These results highlight the need for methods which go beyond current-generation DFT functionals to make crystal polymorph stability predictions truly reliable.more » « less
-
Second-order Møller–Plesset perturbation theory (MP2) provides a valuable alternative to density functional theory for modeling problems in organic and biological chemistry. However, MP2 suffers from known limitations in the description of van der Waals (London) dispersion interactions and reaction thermochemistry. Here, a spin-component-scaled, dispersion-corrected MP2 model (SCS-MP2D) is proposed that addresses these weaknesses. The dispersion correction, which is based on Grimme's D3 formalism, replaces the uncoupled Hartree–Fock dispersion inherent in MP2 with a more robust coupled Kohn–Sham treatment. The spin-component scaling of the residual MP2 correlation energy then reduces the remaining errors in the model. This two-part correction strategy solves the problem found in earlier spin-component-scaled MP2 models where completely different spin-scaling parameters were needed for describing reaction energies versus intermolecular interactions. Results on 18 benchmark data sets and two challenging potential energy curves demonstrate that SCS-MP2D considerably improves upon the accuracy of MP2 for intermolecular interactions, conformational energies, and reaction energies. Its accuracy and computational cost are competitive with state-of-the-art density functionals such as DSD-BLYP-D3(BJ), revDSD-PBEP86-D3(BJ), ωB97X-V, and ωB97M-V for systems with ∼100 atoms.more » « less
-
Symmetry-adapted perturbation theory (SAPT) directly computes intermolecular interaction energy in terms of electrostatics, exchange-repulsion, induction/polarization, and London dispersion components. In SAPT based on Hartree–Fock (“SAPT0”) or based on density functional theory, the most time-consuming step is the computation of the dispersion terms. Previous work has explored the replacement of these expensive dispersion terms with simple damped asymptotic models. We recently examined [Schriber et al. J. Chem. Phys. 154, 234107 (2021)] the accuracy of SAPT0 when replacing its dispersion term with Grimme’s popular -D3 correction, reducing the computational cost scaling from O(N5) to O(N3). That work optimized damping function parameters for SAPT0-D3/jun-cc-pVDZ using estimates of the coupled-cluster complete basis set limit [CCSD(T)/CBS] on a 8299 dimer dataset. Here, we explore the accuracy of SAPT0-D3 with additional basis sets, along with an analogous model using -D4. Damping parameters are rather insensitive to basis sets, and the resulting SAPT0-D models are more accurate on average for total interaction energies than SAPT0. Our results are surprising in several respects: (1) improvement of -D4 over -D3 is negligible for these systems, even charged systems where -D4 should, in principle, be more accurate; (2) addition of Axilrod–Teller–Muto terms for three-body dispersion does not improve error statistics for this test set; and (3) SAPT0-D is even more accurate on average for total interaction energies than the much more computationally costly density functional theory based SAPT [SAPT(DFT)] in an aug-cc-pVDZ basis. However, SAPT0 and SAPT0-D3/D4 interaction energies benefit from significant error cancellation between exchange and dispersion terms.more » « less
-
Molecular crystal engineering seeks to tune the material properties by controlling the crystal packing. However, the range of achievable properties is constrained by the limited energy range of polymorphs which can be crystallized. Here, computational modeling highlights that a solid-state crystal-to-crystal chemical reaction in 9- tert -butyl anthracene ester (9TBAE) nanorods [Al-Kaysi et al. , J. Am. Chem. Soc. , 2006, 128 , 15938] imparts “synthetic memory” into the crystal structure that allows reproducible formation of a highly metastable, yet long-lived polymorph. Specifically, whereas the vast majority of known polymorphs exhibit lattice energy differences below 10 kJ mol −1 , the conformational polymorph formed via solid state reaction chemistry lies 14 kJ mol −1 higher in energy than the form grown from solution, according to calculations that combine a dispersion-corrected second-order Møller–Plesset perturbation theory (MP2D) treatment of the monomer and photodimer with a density functional theory treatment (B86bPBE-XDM) of the intermolecular interactions in the crystal. Moreover, the solid-state reaction environment traps a highly unstable intramolecular photodimer conformation which defies the conventional wisdom surrounding conformational polymorphs. These observations suggest that solid-state reaction chemistry represents an under-appreciated strategy for producing polymorphs that would likely be unobtainable otherwise.more » « less
