American Chemical Society
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Conformational and Nonconformational Polymorphism in 4′-Hydroxyvalerophenone: A Structure–Energetics–Dynamics Perspective

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journal contribution
posted on 2020-03-09, 20:13 authored by Ricardo G. Simões, Cátia S. D. Lopes, M. Fátima M. Piedade, Carlos E. S. Bernardes, Hermínio P. Diogo, Manuel E. Minas da Piedade
Compounds based on the HOC6H4C­(O)­R (R = H, alkyl, OH, etc.) framework have provided excellent models to investigate the complex interplay of structural and energetic effects behind polymorphism and crystallization as a whole. In this work, the polymorphic behavior of 4′-hydroxyvalerophenone (HVP, R = C4H9) was experimentally and theoretically explored from a holistic structural–energetics–dynamics perspective. The molecular and crystal structures of two new forms (II and III) were determined by single crystal X-ray diffraction. They share with the previously known form I, and with analogous systems (R = H, CH3) that do not contain a flexible R group, an infinite C11(8) chain sustained by “head-to-tail” OH···OC hydrogen bonds as the main one-dimensional (1D) packing motif. The molecular organization within the chain (“herringbone” type in form I and planar in forms II and III) and the relative orientation of the CO and OH groups (Z in form I and E in forms II and III) are, however, different. These differences are reflected by the thermodynamic and kinetic relationships between the three polymorphs. Differential scanning calorimetry and microscopy experiments revealed that (i) the structurally very similar III/II pair is enantiotropically related by a fast and reversible phase transition at 247.5 ± 0.4 K. (ii) In contrast, the form II → form I transition is severely hindered, and, although form II is monotropic relative to form I, it can be observed to melt upon heating, or stored for days at ambient pressure and temperature without signs of transformation to form I, unless subjected to a perturbation (e.g., scratching, grinding). These findings are consistent with microscopy and molecular dynamics (MD) simulation results, suggesting that the III → II transition occurs by a concerted displacement of the molecules in the crystal lattice, while the II → I process is compatible with a diffusive nucleation and growth mechanism. It was also found that, despite being metastable, form II preferentially crystallizes from the melt in accordance with Ostwald’s rule of stages. MD simulations indicated that this observation is most likely originated by the fact that the structure of liquid HVP is much closer to form II than to form I. Finally, a thermodynamic analysis suggested that the relative stability of the three HVP polymorphs, at 298 K, ranked in terms of Gibbs energy (I > II > III) does not follow the corresponding lattice enthalpy trend (I > III > II). This stresses the importance of accounting for entropy contributions when discussing polymorph stability.