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.
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Solid state photodimerization of 9- tert -butyl anthracene ester produces an exceptionally metastable polymorph according to first-principles calculations
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.
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- Award ID(s):
- 1665212
- NSF-PAR ID:
- 10098713
- Date Published:
- Journal Name:
- CrystEngComm
- Volume:
- 21
- Issue:
- 4
- ISSN:
- 1466-8033
- Page Range / eLocation ID:
- 758 to 764
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1039/C8CE01985A
