How many more polymorphs of ROY remain undiscovered

Beran, Gregory J. O.; Sugden, Isaac J.; Greenwell, Chandler; Bowskill, David H.; Pantelides, Constantinos C.; Adjiman, Claire S.

doi:10.1039/d1sc06074k

Cited by 64 publications

(98 citation statements)

References 106 publications

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“…Four new ROY polymorphs have been reported since 2019 through the joint efforts between experiment and computation [115][116][117][118]. It is expected that more ROY polymorphs await future discovery according to the improved energy ranking method by Beran et al [119].…”

Section: High Zʹ Crystalsmentioning

confidence: 99%

Organic crystal structure prediction and its application to materials design

Zhu

Hattori²

2022

Journal of Materials Research

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In recent years, substantial progress has been made in the modeling of organic solids. Computer simulation has been increasingly shaping the area of new organic materials by design. It is possible to discover new organic crystals by computational structure prediction, based on the combination of powerful exploratory algorithms and accurate energy modeling. In this review, we begin with several key early concepts in describing crystal packing, and then introduce the recent state-of-the-art computational techniques for organic crystal structure prediction. Perspectives on the remaining technical challenges, functional materials screening and software development are also discussed in the end. It is reasonable to expect that, in the near future, accurate predictive computational modeling can be accomplished within a time frame that is appreciably shorter than that needed for the laboratory synthesis and characterization. Graphical abstract

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Section: High Zʹ Crystalsmentioning

confidence: 99%

Organic crystal structure prediction and its application to materials design

Zhu

Hattori²

2022

Journal of Materials Research

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“…31,32 Delocalization error can artificially stabilize structures with more extended π conjugation, for example. 33,34 In molecular crystal conformational polymorphs, this behavior can spuriously stabilize selected conformations, as occurs for the prolific polymorph former ROY (so-named for its red, orange, and yellow crystals), [35][36][37][38] ortho-acetamidobenzamide, 37 molecule X 14,37 from the third blind test of crystal structure prediction, 3 the pharmaceuticals axitinib and galunisertib, 37 and rubrene derivatives. 39 Delocalization error has also been blamed for the spurious proton transfer in a set of acid-base co-crystals 40 and poor lattice energies for halogen-bonded crystals.…”

Section: Introductionmentioning

confidence: 99%

“…It can be applied to entire crystal energy landscapes readily. 37,38 These recent studies raise a number of questions. How widespread are large conformational energy errors in conformational polymorphs when using conventional density functionals?…”

Section: Introductionmentioning

confidence: 99%

The interplay of intra- and intermolecular errors in modeling conformational polymorphs

Beran

Wright

Greenwell

et al. 2022

The Journal of Chemical Physics

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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 twenty 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 (DFT) 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. Density functionals such as B86bPBE-XDM, PBE-D4, PBE-MBD, PBE0-D4, and PBE0-MBD are found to exhibit sizable 1-body and 2-body errors versus 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. Models like SCS-MP2D, and, to a lesser extent, ωB97M-V exhibit smaller errors and rely less on error cancellation. Implications for crystal structure prediction of flexible compounds are discussed. Finally, the 1-body and 2-body DLPNO-CCSD(T) energies taken from these conformational polymorphs establish the CP1b and CP2b benchmark data sets which 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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“…Tailor-made force fields (TMFFs) represented an initial breakthrough in the field, allowing sufficiently accurate calculations of the energy minima associated with crystal packings. 8 , 9 Currently, TMFFs and first-principles energy ranking approaches with dispersion-inclusive hybrid functionals 10 , 11 and many-body dispersion interactions 12 , 13 are the most successful methods for yielding reliable and accurate lattice energies. 14 , 15 More recently, molecular dynamics and enhanced molecular dynamics have also been rigorously utilized to probe free energy stabilities and to eliminate labile structures.…”

Section: Introductionmentioning

confidence: 99%

Efficient Crystal Structure Prediction for Structurally Related Molecules with Accurate and Transferable Tailor-Made Force Fields

Mattei

Hong

Dietrich³

et al. 2022

J. Chem. Theory Comput.

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Crystal structure prediction (CSP) is generally used to complement experimental solid form screening and applied to individual molecules in drug development. The fast development of algorithms and computing resources offers the opportunity to use CSP earlier and for a broader range of applications in the drug design cycle. This study presents a novel paradigm of CSP specifically designed for structurally related molecules, referred to as Quick-CSP. The approach prioritizes more accurate physics through robust and transferable tailor-made force fields (TMFFs), such that significant efficiency gains are achieved through the reduction of expensive ab initio calculations. The accuracy of the TMFF is increased by the introduction of electrostatic multipoles, and the fragment-based force field parameterization scheme is demonstrated to be transferable for a family of chemically related molecules. The protocol is benchmarked with structurally related compounds from the Bromodomain and Extraterminal (BET) domain inhibitors series. A new convergence criterion is introduced that aims at performing only as many ab initio optimizations of crystal structures as required to locate the bottom of the crystal energy landscape within a user-defined accuracy. The overall approach provides significant cost savings ranging from three- to eight-fold less than the full-CSP workflow. The reported advancements expand the scope and utility of the underlying CSP building blocks as well as their novel reassembly to other applications earlier in the drug design cycle to guide molecule design and selection.

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How many more polymorphs of ROY remain undiscovered

Abstract: With 12 crystal forms, 5-methyl-2-[(2-nitrophenyl) amino]-3-thiophenecabonitrile (a.k.a. ROY) holds the current record for the largest number of fully characterized organic crystal polymorphs. Four of these polymorphs were discovered or characterized since 2019,...

Cited by 64 publications

References 106 publications

Organic crystal structure prediction and its application to materials design

Organic crystal structure prediction and its application to materials design

The interplay of intra- and intermolecular errors in modeling conformational polymorphs

Efficient Crystal Structure Prediction for Structurally Related Molecules with Accurate and Transferable Tailor-Made Force Fields

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