An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

The effect of pressure on the α and β polymorphs of a derivative of Blatter's radical, 3-phenyl-1-(pyrid-2-yl)-1,4-dihydrobenzo[e][1,2,4]triazin-4-yl, has been investigated using single-crystal X-ray diffraction to maximum pressures of 5.76 and 7.42 GPa, respectively. The most compressible crystallographic direction in both structures lies parallel to π-stacking interactions, which semiempirical Pixel calculations indicate are also the strongest interactions present. The mechanism of compression in perpendicular directions is determined by void distributions. Discontinuities in the vibrational frequencies observed in Raman spectra measured between ambient pressure and ∼5.5 GPa show that both polymorphs undergo phase transitions, the α phase at 0.8 GPa and the β phase at 2.1 GPa. The structural signatures of the transitions, which signal the onset of compression of initially more rigid intermolecular contacts, were identified from the trends in the occupied and unoccupied volumes of the unit cell with pressure and in the case of the β phase by deviations from an ideal model of compression defined by Birch-Murnaghan equations of state.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

The crystal structure of Blatter's radical (1,3-diphenyl-1,4-dihydrobenzo[e][1,2,4]triazin-4-yl) has been investigated between ambient pressure and 6.07 GPa. The sample remains in a compressed form of the ambient-pressure phase up to 5.34 GPa, the largest direction of strain being parallel to the direction of π-stacking interactions. The bulk modulus is 7.4 (6) GPa, with a pressure derivative equal to 9.33 (11). As pressure increases, the phenyl groups attached to the N1 and C3 positions of the triazinyl moieties of neighbouring pairs of molecules approach each other, causing the former to begin to rotate between 3.42 to 5.34 GPa. The onset of this phenyl rotation may be interpreted as a second-order phase transition which introduces a new mode for accommodating pressure. It is premonitory to a first-order isosymmetric phase transition which occurs on increasing pressure from 5.34 to 5.54 GPa. Although the phase transition is driven by volume minimization, rather than relief of unfavourable contacts, it is accompanied by a sharp jump in the orientation of the rotation angle of the phenyl group. DFT calculations suggest that the adoption of a more planar conformation by the triazinyl moiety at the phase transition can be attributed to relief of intramolecular H...H contacts at the transition. Although no dimerization of the radicals occurs, the π-stacking interactions are compressed by 0.341 (3) Å between ambient pressure and 6.07 GPa.

In materials, chemistry, and medicine, small molecules can form different crystal structures of the same compound, called polymorphs. [1]Determining the specific atomic structure of a complex molecule and the many polymorphs is challenging, often requiring X-ray synchrotron or neutron facilities. [2]Understanding how these polymorphs behave in a variety of conditions is crucial to their potential applications.In this work, we aim to combine 3D electron diffraction methods [3] with a novel nanofluidic microchip system [4] and establish a foundational platform to solve new crystal structures of molecular organic crystals and their polymorphs in-situ.

Polymorphism occurs when a material crystallizes into more than one distinct solid forms, which is commonly observed in organic chemistry.Polymorphs of small organic molecules differ in solubility, bioavailability and processing characteristics, affecting their properties and performances in applications such as opto-electronics, energy storage and pharmaceuticals [1].Recent developments in 3D electron diffraction (3D ED) [2-5], also known as Micro-crystal electron diffraction (MicroED) [6,7], allowed rapid, atomic resolution structure determination of small organic molecules from nanoand micron-sized crystals.With our recent results, we show that 3D ED/MicroED is a powerful method for studying polymorphism of small organic molecules.The method can be used for 1) rapid structure determination of small organic molecules from small crystals [5,8], 2) structural determination of complex and disordered crystal structures, 3) studying polymorph evolution of small organic molecules by in situ crystallization [9], and 4) investigating the growth mechanism of small organic molecules by capturing the earliest stages of the crystallization.In order to further increase the throughput of polymorph analysis and phase identification, our group has developed serial electron diffraction (SerialED), where single diffraction patterns are collected from thousands of individual micro-crystals.By automated data collection enabled by software development, up to 3500 crystals can be studied per hour.SerialED, along with 3D ED/MicroED, will greatly accelerate polymorphic discovery and provide new possibilities to study reaction mixtures, dynamical processes and other applications where rapid structural analyses of materials are required.

Following the in-situ development of glycine polymorphs from an aqueous solution via 3D electron diffraction, revealing three polymorphs crystallizing at differing timepoints according to stability. Beta glycine forms after 3 minutes, followed by alpha glycine after only one minute more. Gamma glycine forms after prolonged standing. The same methodology was applied to carbamazepine which, alongside the expected dihydrate form, shows four forms after 30 seconds of crystallization. When the time is reduced to 20 seconds, dark, liquid-like, droplets appear to agglomerate together and form the dihydrate. This suggests the dihydrate forms via the non-classical nucleation similar to liquid-liquid phase separation. High pressure X-ray crystallography is a well-established technique for studying polymorphism and was used to probe the nature of t he dimer interactions within isostructural organic ‘Blatter’ radicals. One of which showed a pseudo 2 nd order phase transition. This transition is driven by flexibility on the phenyl ring which rotates and allows the benzotriazine moiety to flatten and become more planar. Implementation of 3DED/MicroED technique on TEM in Edinburgh for routine structure solution, previously only used for imaging has also been successfully accomplished. Broadhurst, Lightowler, Nudelman, ., Zou, & Parsons, S. “Polymorph evolution during crystal growth studied by 3D electron diffraction” (2020), 7(1),

Butyl substituents enhance solution processing, but undermine the short Pt⋯Pt contacts that enable metallisation under pressure.

Time-resolved carbamazepine crystallization from wet ethanol has been monitored using a combination of cryoTEM and 3D electron diffraction. Carbamazepine is shown to crystallize exclusively as a dihydrate after 180 s. When the timescale was reduced to 30 s, three further polymorphs could be identified. At 20 s, the development of early stage carbamazepine dihydrate was observed through phase separation. This work reveals two possible crystallization pathways present in this active pharmaceutical ingredient.

3D electron diffraction (3DED) has been used to follow polymorph evolution in the crystallization of glycine from aqueous solution. The three polymorphs of glycine which exist under ambient conditions follow the stability order β < α < γ. The least stable β polymorph forms within the first 3 min, but this begins to yield the α-form after only 1 min more. Both structures could be determined from continuous rotation electron diffraction data collected in less than 20 s on crystals of thickness ∼100 nm. Even though the γ-form is thermodynamically the most stable polymorph, kinetics favour the α-form, which dominates after prolonged standing. In the same sample, some β and one crystallite of the γ polymorph were also observed.