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1. How many more polymorphs of ROY remain undiscovered

   https://doi.org/10.1039/d1sc06074k  

   Beran, Gregory J.; Sugden, Isaac J.; Greenwell, Chandler; Bowskill, David H.; Pantelides, Constantinos C.; Adjiman, Claire S. (February 2022, Chemical Science)

   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. 

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

   https://doi.org/10.1039/C9SC05689K  

   Greenwell, Chandler; McKinley, Jessica L.; Zhang, Peiyu; Zeng, Qun; Sun, Guangxu; Li, Bochen; Wen, Shuhao; Beran, Gregory J. (February 2020, Chemical Science)

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

   https://doi.org/10.1063/5.0088027  

   Beran, Gregory J. O.; Wright, Sarah E.; Greenwell, Chandler; Cruz-Cabeza, Aurora J. (March 2022, The Journal of Chemical Physics)

   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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4. Two-bond ¹³ C– ¹³ C spin-coupling constants in saccharides: dependencies on exocyclic hydroxyl group conformation

   https://doi.org/10.1039/d1cp03320d  

   Lin, Jieye; Meredith, Reagan J.; Oliver, Allen G.; Carmichael, Ian; Serianni, Anthony S. (October 2021, Physical Chemistry Chemical Physics)

   Seven doubly 13 C-labeled isotopomers of methyl β- d -glucopyranoside, methyl β- d -xylopyranoside, methyl β- d -galactopyranoside, methyl β- d -galactopyranosyl-(1→4)-β- d -glucopyranoside and methyl β- d -galactopyranosyl-(1→4)-β- d -xylopyranoside were prepared, crystallized, and studied by single-crystal X-ray crystallography and solid-state 13 C NMR spectroscopy to determine experimentally the dependence of 2 J C1,C3 values in aldopyranosyl rings on the C1–C2–O2–H torsion angle, θ 2 , involving the C2 carbon of the C1–C2–C3 coupling pathway. Using X-ray crystal structures to determine θ 2 in crystalline samples and by selecting compounds that exhibit a relatively wide range of θ 2 values in the crystalline state, 2 J C1,C3 values measured in crystalline samples were plotted against θ 2 and the resulting plot compared to that obtained from density functional theory (DFT) calculations. For θ 2 values ranging from ∼90° to ∼240°, very good agreement was observed between the experimental and theoretical plots, providing strong validation of DFT-calculated spin-coupling dependencies on exocyclic C–O bond conformation involving the central carbon of geminal C–C–C coupling pathways. These findings provide new experimental evidence supporting the use of 2 J CCC values as non-conventional spin-coupling constraints in MA′AT conformational modeling of saccharides in solution, and the use of NMR spin-couplings not involving coupled hydroxyl hydrogens as indirect probes of C–O bond conformation. Solvomorphism was observed in crystalline βGal-(1→4)-βGlcOCH 3 wherein the previously-reported methanol solvate form was found to spontaneously convert to a monohydrate upon air-drying, leading to small but discernible conformational changes in, and a new crystalline form of, this disaccharide. 

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5. Myriad Mapping of nanoscale minerals reveals calcium carbonate hemihydrate in forming nacre and coral biominerals

   https://doi.org/10.1038/s41467-024-46117-x  

   Schmidt, Connor A.; Tambutté, Eric; Venn, Alexander A.; Zou, Zhaoyong; Castillo Alvarez, Cristina; Devriendt, Laurent S.; Bechtel, Hans A.; Stifler, Cayla A.; Anglemyer, Samantha; Breit, Carolyn P.; et al (February 2024, Nature Communications)

   Abstract Calcium carbonate (CaCO₃) is abundant on Earth, is a major component of marine biominerals and thus of sedimentary and metamorphic rocks and it plays a major role in the global carbon cycle by storing atmospheric CO₂into solid biominerals. Six crystalline polymorphs of CaCO₃are known—3 anhydrous: calcite, aragonite, vaterite, and 3 hydrated: ikaite (CaCO₃·6H₂O), monohydrocalcite (CaCO₃·1H₂O, MHC), and calcium carbonate hemihydrate (CaCO₃·½H₂O, CCHH). CCHH was recently discovered and characterized, but exclusively as a synthetic material, not as a naturally occurring mineral. Here, analyzing 200 million spectra with Myriad Mapping (MM) of nanoscale mineral phases, we find CCHH and MHC, along with amorphous precursors, on freshly deposited coral skeleton and nacre surfaces, but not on sea urchin spines. Thus, biomineralization pathways are more complex and diverse than previously understood, opening new questions on isotopes and climate. Crystalline precursors are more accessible than amorphous ones to other spectroscopies and diffraction, in natural and bio-inspired materials. 

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