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 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.
Highlights
Estimates indicate that about half of organic molecules exhibit polymorphism in the solid state,[1] and these changes in crystal packing can profoundly alter physical properties such as color, stability, solubility, and carrier mobility
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
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
Summary
Estimates indicate that about half of organic molecules exhibit polymorphism in the solid state,[1] and these changes in crystal packing can profoundly alter physical properties such as color, stability, solubility, and carrier mobility. These experimental structures lie as high as rank 144 (Y19) on that landscape.[26] In the initial new Z0 1⁄4 1 landscape generated here (Fig. 2a) that will be discussed in detail below, the Y19 polymorph rises further to rank 172. Structure prediction and applies our conformational energy correction approach to investigate the landscape containing all experimentally-known polymorphs of ROY and hundreds of additional candidate structures This effort results in the rst ROY crystal energy landscape that is highly consistent with experiment. One currently unknown candidate structure is predicted to become thermodynamically more stable than all existing ROY polymorphs at around 10 GPa of pressure, suggesting that high pressure experiments might discover a new polymorph
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