Thermoanalytical Evidence of Metastable Molecular Defects in Form I of Benzamide

Butterhof, Christian; Martin, Thomas; Ectors, Philipp; Zahn, Dirk; Niemietz, Paul; Senker, Jürgen; Näther, Christian; Breu, Josef

doi:10.1021/cg3009706

Cited by 22 publications

(27 citation statements)

References 23 publications

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“…For example, the PXRD pattern of rank 2 contains the two peaks (2θ approximately 20°and 21°, λ = 1.54 Å) previously used to distinguish forms I and III. 6 Form II is not observed anywhere in the CSP results as is the case for previous CSP studies. 8 Validation by geometry optimization of the original Pba2 structure in the DFT-D potential results in a heavy distortion of 0.88 Å RMSCD, which is well above the threshold of 0.35 Å, thus strongly indicating a problem with the Pba2 structure.…”

Section: Resultssupporting

confidence: 57%

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: Resultssupporting

confidence: 57%

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

Johansson

Streek

2016

Crystal Growth & Design

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“…The CSD contains 12 crystal structures of benzamide including atomic coordinates: BZAMID (Penfold & White, 1959), BZAMID01 (Blake & Small, 1972), BZAMID02 and BZAMID03 (Gao et al, 1991), BZAMID04 (Ruble & Galvao, 1995), BZAMID05 (Kobayashi et al, 2003), BZAMID06 (Blagden et al, 2005), BZAMID07 and BZAMID08 (Thun et al, 2009), BZAMID11 (Fronczek, 2014), BZAMID12 (Butterhof et al, 2012), and BZAMID13 (Johansson & van de The molecular structure of benzamide, with the atomic numbering used in this article.…”

Section: Packing Similarity Of Crystal Structures Of Benzamidementioning

confidence: 99%

CrystalCMP: an easy-to-use tool for fast comparison of molecular packing

et al. 2016

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A new approach is introduced for the comparison of molecular packing and the identification of identical crystal structure motifs. It has been tested on data sets for the solid forms of benzamide, cabergoline and trospium. In this approach, the packing similarity is calculated using a simple formula involving the distances between molecular centres and the relative orientations of molecular entities inside a finite molecular cluster. The approach is independent of the atomic labelling, the unit‐cell parameters, the space group setting and the number of molecules in the asymmetric part of the unit cell. Owing to its low sensitivity to volume changes, this approach allows the comparison of various solid forms (such as polymorphs, hydrates, solvates, co‐crystals or salts) of identical or similar molecular compounds. The method is also suitable for identifying similar results from direct space methods, which are often used in powder diffraction.

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“…8 Further studies were therefore carried out to address three problems: (1) Is it possible to obtain a reliable supply of the less common form 1o? (2) Can the solid state forms 1o and 1t be interconverted? (3) Do the different configurations interconvert 45 readily in solution, as would be expected?…”

Section: Differential Scanning Calorimetrymentioning

confidence: 99%

Two polymorphs of 4-hydroxypiperidine with different NH configurations

et al. 2015

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54-Hydroxypiperidine 1 exists in two crystal forms, tetragonal 1t, space group P 4 2 1 c and orthorhombic 1o, space group Fdd2, both with one molecule in the asymmetric unit. The latter form was obtained only rarely and in small quantities. In form 1t, the NH hydrogen is axial, whereas in 1o it is equatorial; the OH group is equatorial in both structures. The packing of both forms involves one hydrogen bond N-HLO and one O-HLN. In solution, NMR spectra indicate the presence of separate axial and equatorial forms (with respect to the OH group) below ca. -53°C; however, not even at -104°C, the lowest temperature reached, could any freezing out of the inversion at 10 nitrogen be observed, implying that the energy barrier for this process is (as expected) small.. We were unable to convert 1t, which appears to be the more stable form over the whole temperature range up to the melting point, to 1o by heating or via melting and recooling (or by any other method), perhaps because the hydrogen-bonding pattern is resistant to change. The crystalline forms 1t and 1o, despite being polymorphs of 1 with different NH configurations, should not be described as "configurational polymorphs" because of the facile interconversion in solution.

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Thermoanalytical Evidence of Metastable Molecular Defects in Form I of Benzamide

Cited by 22 publications

References 23 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

CrystalCMP: an easy-to-use tool for fast comparison of molecular packing

Two polymorphs of 4-hydroxypiperidine with different NH configurations

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