Accurately Calculating the Stability of Molecular Crystal Polymorphs With Improved Intra- and Intermolecular Energies

Since the inception of computational chemistry, its practitioners have imagined the ability to predict the three-dimensional form of matter starting from only a two-dimensional representation of a molecule. The science of crystal structure prediction (CSP) starts by predicting rational 3-D arrangements of atoms or molecules. Then, the energy of those arrangements is calculated to determine thermodynamic stability. Complicating the energy determination step is the phenomena of polymorphism whereby a single molecule can adopt multiple solid-state arrangements. The differing physical and chemical properties of polymorphs present an opportunity and a great challenge to chemists and material scientists, and calculating the energy between polymorphs demands modeling intra- and intermolecular interactions with high accuracy.Two dispersion-corrected variants of Second-Order M{\o}ller-Plesset Perturbation Theory (MP2) will be introduced. Compared to high-level benchmark calculations, both methods accurately model both intra- and intermolecular interactions of organic molecules at reasonable computational cost. The methods presented here offer a highly accurate wavefunction alternative to density functional theory (DFT) for modeling chemical reactions, interaction energies, conformational energies, charge transfer reactions, and nuanced potential energy surfaces. Plane-wave DFT with a dispersion correction is the current state-of-the-art method for ranking molecular conformational polymorphs; however, there are many systems for which this method does not agree with experimentally determined results. Combining dispersion-corrected MP2 with periodic Hartree-Fock provides high-accuracy polymorph rankings for several systems for which DFT is found to diverge from experiment. Furthermore, the exceptional conformational energies provided by dispersion-corrected MP2 are shown to improve DFT energy rankings simply by replacing the DFT conformational energy. This monomer correction method is applicable to the conformational polymorphs of large, flexible pharmaceuticals like axitinib and galunisertib as well as the organic semiconductors rubrene and perfluororubrene

Accurately Calculating the Stability of Molecular Crystal Polymorphs With Improved Intra- and Intermolecular Energies

Since the inception of computational chemistry, its practitioners have imagined the ability to predict the three-dimensional form of matter starting from only a two-dimensional representation of a molecule. The science of crystal structure prediction (CSP) starts by predicting rational 3-D arrangements of atoms or molecules. Then, the energy of those arrangements is calculated to determine thermodynamic stability. Complicating the energy determination step is the phenomena of polymorphism whereby a single molecule can adopt multiple solid-state arrangements. The differing physical and chemical properties of polymorphs present an opportunity and a great challenge to chemists and material scientists, and calculating the energy between polymorphs demands modeling intra- and intermolecular interactions with high accuracy.Two dispersion-corrected variants of Second-Order M{\o}ller-Plesset Perturbation Theory (MP2) will be introduced. Compared to high-level benchmark calculations, both methods accurately model both intra- and intermolecular interactions of organic molecules at reasonable computational cost. The methods presented here offer a highly accurate wavefunction alternative to density functional theory (DFT) for modeling chemical reactions, interaction energies, conformational energies, charge transfer reactions, and nuanced potential energy surfaces. Plane-wave DFT with a dispersion correction is the current state-of-the-art method for ranking molecular conformational polymorphs; however, there are many systems for which this method does not agree with experimentally determined results. Combining dispersion-corrected MP2 with periodic Hartree-Fock provides high-accuracy polymorph rankings for several systems for which DFT is found to diverge from experiment. Furthermore, the exceptional conformational energies provided by dispersion-corrected MP2 are shown to improve DFT energy rankings simply by replacing the DFT conformational energy. This monomer correction method is applicable to the conformational polymorphs of large, flexible pharmaceuticals like axitinib and galunisertib as well as the organic semiconductors rubrene and perfluororubrene

Spin-component-scaled and dispersion-corrected second-order Møller-Plesset perturbation theory: A path toward chemical accuracy

Second-order Møller-Plesset perturbation theory (MP2) provides a valuable alternative to density functional theory for modeing problems in organic and biological chemistry. However, MP2 suffers from known lim- itations in the description of van der Waals 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 in- termolecular 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 interac- tions, 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

How many more polymorphs of ROY remain undiscovered.

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 polymorph structures have been reported since 2019, raising the question of how many more ROY polymorphs await future discovery. Employing crystal structure prediction and accurate energy rankings derived from conformational energy-corrected density functional theory, this study presents the first crystal energy landscape for ROY that agrees well with experiment. The lattice energies suggest that the seven most stable ROY polymorphs (and nine of the twelve lowest-energy forms) on the Z = 1 landscape have already been discovered experimentally. Discovering any new polymorphs at ambient pressure will likely require specialized crystallization techniques capable of trapping metastable forms. At pressures above 10 GPa, however, a new crystal form is predicted to become enthalpically more stable than all known polymorphs, suggesting that further high-pressure experiments on ROY may be warranted. This work highlights the value of high-accuracy crystal structure prediction for solid-form screening and demonstrates how pragmatic conformational energy corrections can overcome the limitations of conventional density functionals for conformational polymorphs

Overcoming the difficulties of predicting conformational polymorph energetics in molecular crystals via correlated wavefunction methods.

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