A new polymorph (IV) of benzamide: Structural characterization and mechanism of the I↔IV phase transition

Benoit, David M.; Ectors, Philipp; Duchstein, Patrick; Breu, Josef; Zahn, Dirk

doi:10.1016/j.cplett.2011.08.071

Cited by 10 publications

(17 citation statements)

References 19 publications

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“…3 A correction to the Pba2 structure has previously been suggested by Ectors et al to account for the poor DFT-D energy. 12 In their study, the authors rotated the amide group by 180°(which in terms of electron density is equivalent to exchanging the N and the O atom, which is not uncommon in crystal structures determined from PXRD data; see, e.g., ref 7) and geometry optimized the structure without symmetry imposed. We repeated this experiment and arrived at a new structure in space group Pna2 1 but with an energy 1.76 kcal/ mol above rank 1, which is significantly above the two alternatives shown in Figure 4.…”

Section: Resultsmentioning

confidence: 99%

Revision of the Crystal Structure of the First Molecular Polymorph in History

Johansson

Streek

2016

Crystal Growth & Design

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Despite being the earliest reported case of polymorphism in a molecular crystal, the unstable form II of benzamide has thus far evaded thorough structural characterization because collection of experimental data at atomic resolution has proven extremely challenging. Using a highly validated computational crystal structure prediction (CSP) method based on dispersion-corrected density functional theory, we correctly predict the stable form I with the lowest energy among all sampled structures and its polytypic form III with slightly higher energy. From Rietveld refinement of selected CSP models against synchrotron X-ray powder diffraction data of the historical polymorph, we are able to identify a subtle weakness in the available experimental data and arrive at a revised structure of form II. The revised crystal structure is the first benzamide structure to form catemers rather than dimers and possesses the rare space-group symmetry Fdd2 with two molecules in the asymmetric unit, which is necessary to support the new hydrogen bonding network. This rare space group is only found in the CSP by a complete structural search in all 230 space groups with one or two molecules in the asymmetric unit.

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Section: Resultsmentioning

confidence: 99%

Revision of the Crystal Structure of the First Molecular Polymorph in History

Johansson

Streek

2016

Crystal Growth & Design

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“…10,11 Yet, another polymorph has been suggested by crystal structure prediction (CSP) but not found experimentally. 12 The characterization of the metastable benzamide polymorphs is complicated further by the formation of bi-or triphasic mixtures, requiring extensive optimization of crystallization protocols to minimize secondary nucleation of Form I. 11,13,14 Computational studies suggested an alternative structure for Form II, attributing the previous structure solution to insufficient data owing to the preferred orientations of needle-like crystals and the associated weak intensity of hkl reflections with l ≠ 0.…”

Section: ■ Introductionmentioning

confidence: 99%

“…The single crystal structure of the stable (rhombic) Form I was not solved until 1959 and was assigned as monoclinic . Nearly 50 years later, the transient Form II was prepared in situ as a mixture with I , and a structure was extracted from powder X-ray diffraction (PXRD) data. , A third metastable polymorph (Form III ), revealing a polytypic relationship to Form I , was characterized shortly afterward. , Yet, another polymorph has been suggested by crystal structure prediction (CSP) but not found experimentally . The characterization of the metastable benzamide polymorphs is complicated further by the formation of bi- or triphasic mixtures, requiring extensive optimization of crystallization protocols to minimize secondary nucleation of Form I . ,, Computational studies suggested an alternative structure for Form II , attributing the previous structure solution to insufficient data owing to the preferred orientations of needle-like crystals and the associated weak intensity of hkl reflections with l ≠ 0 .…”

Section: Introductionmentioning

confidence: 99%

Disorderly Conduct of Benzamide IV: Crystallographic and Computational Analysis of High Entropy Polymorphs of Small Molecules

Fellah

Shtukenberg

Chan

et al. 2020

Crystal Growth & Design

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Benzamide, a simple derivative of benzoic acid and a common intermediate of pharmaceutical compounds, was reported to form two polymorphs in 1832, but the single crystal structure of the more stable form was not solved until 1959. Nearly 50 years later, the second form was characterized by powder diffraction, followed shortly thereafter by characterization of a third form, a polytype of the most thermodynamically stable Form I. These two new forms, Forms II and III, are metastable. Herein, we describe a fourth polymorph, Form IV, discovered by melt crystallization concurrently with its crystallization under confinement at small length scales (<10 nm), where it is stable indefinitely. Form III exists under confinement in larger pores, and melting point data for different pore sizes corroborate the existence of Form IV below 10 nm. Form IV is highly disordered, precluding indexing of powder diffraction data other than hk0 reflections. Nonetheless, a combination of powder X-ray diffraction and computational crystal structure prediction reveals that Form IV contains a 2D motif resembling that of Form II, but with long-range order in the third dimension masked by ubiquitous stacking faults. This approach relies on distilling a large number of candidate structures to a few possible disorder models based on benzamide tetrads that organize in 2D parquet-like tiles, with organization along the third dimension, that can be modeled with various stacking fault configurations having distinct intermolecular interactions and translations in the dimension orthogonal to the tiling planes. These observations reveal a bewildering crystallographic complexity for such a simple molecule. Nonetheless, the approach described herein demonstrates that challenging structures that may be abandoned prematurely because of poor crystallinity, twinning, or disorder can be solved.

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“…While structure identification from experiments is still most common, rapid progress in theory has paved the way for suggesting structures and ranking them in terms of energy and/or enthalpy. [2][3][4][5][6][7] Moreover, molecular dynamics simulations, if combined with accurate force-fields may provide insights into polymorphic transformations [8][9][10] and into crystal nucleation. 11 While characterization of such process dynamics in most cases needs to rely on force-field models to avoid outrageous computational costs, for well-chosen structural motifs we may rationalize the underlying interactions using more accurate quantum calculations.…”

Section: Introductionmentioning

confidence: 99%

Analysis of the molecular interactions governing the polymorphism of benzamide – a guide to syntheses?

Ectors

Zahn

2013

Phys. Chem. Chem. Phys.

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Dispersion-corrected density functional calculations are used to rationalize the subtle differences in the molecular interactions in benzamide crystals. The potential energy of the different polymorph structures is dominated by the interplay between intermolecular attraction and molecular torsion/deformation to accommodate favourable molecular packing. Using suitable proxies arranged in pseudo-crystalline setups we discriminate the contribution of hydrogen bonding, π-π interactions and intra-molecular interactions to the lattice energies of the most relevant (P1 and P3) benzamide polymorphs. Strikingly, these commonly anticipated binding/packing concepts cannot account for the observed ranking of benzamide structures, thus hinting at the importance of the interactions between the benzene rings and the polar amide groups. Moreover, individual structural motifs that account for the competition between the two crystal structure types are elaborated. On the basis of such in-depth understanding of molecular interactions - in terms of both structure and chemistry - we suggest nucleation scenarios as guides to a more controlled synthesis of the stable P1 form or to direct nucleation in favour of the P3 polymorph.

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A new polymorph (IV) of benzamide: Structural characterization and mechanism of the I↔IV phase transition

Cited by 10 publications

References 19 publications

Revision of the Crystal Structure of the First Molecular Polymorph in History

Revision of the Crystal Structure of the First Molecular Polymorph in History

Disorderly Conduct of Benzamide IV: Crystallographic and Computational Analysis of High Entropy Polymorphs of Small Molecules

Analysis of the molecular interactions governing the polymorphism of benzamide – a guide to syntheses?

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