Electron Diffraction of 3D Molecular Crystals

Saha, Ambarneil; Nia, Shervin S.; Rodríguez, José A.

doi:10.1021/acs.chemrev.1c00879

Cited by 49 publications

(32 citation statements)

References 295 publications

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“…a high symmetry orientation of the crystal, see Fig. 1(a)], as outlined in more detail in Section 1.2 and also summarized by and Saha et al (2022). Later, Kolb and her colleagues (Kolb et al, 2007) determined that the best method was instead to collect electron-diffraction data off-axis (not pre-oriented) in a series of rotational steps that can then be combined to recreate the 3D information, known as automated diffraction tomography, or ADT.…”

Section: Overview Of Electron-diffraction Data-collection Methodsmentioning

confidence: 99%

Electron crystallography and dedicated electron-diffraction instrumentation

Simoncic¹,

Romeijn²,

Hovestreydt³

et al. 2023

Acta Crystallogr E Cryst Commun

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Electron diffraction (known also as ED, 3D ED or microED) is gaining momentum in science and industry. The application of electron diffraction in performing nano-crystallography on crystals smaller than 1 µm is a disruptive technology that is opening up fascinating new perspectives for a wide variety of compounds required in the fields of chemical, pharmaceutical and advanced materials research. Electron diffraction enables the characterization of solid compounds complementary to neutron, powder X-ray and single-crystal X-ray diffraction, as it has the unique capability to measure nanometre-sized crystals. The recent introduction of dedicated instrumentation to perform ED experiments is a key aspect of the continued growth and success of this technology. In addition to the ultra-high-speed hybrid-pixel detectors enabling ED data collection in continuous rotation mode, a high-precision goniometer and horizontal layout have been determined as essential features of an electron diffractometer, both of which are embodied in the Eldico ED-1. Four examples of data collected on an Eldico ED-1 are showcased to demonstrate the potential and advantages of a dedicated electron diffractometer, covering selected applications and challenges of electron diffraction: (i) multiple reciprocal lattices, (ii) absolute structure of a chiral compound, and (iii) R-values achieved by kinematic refinement comparable to X-ray data.

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Section: Overview Of Electron-diffraction Data-collection Methodsmentioning

confidence: 99%

Electron crystallography and dedicated electron-diffraction instrumentation

Simoncic¹,

Romeijn²,

Hovestreydt³

et al. 2023

Acta Crystallogr E Cryst Commun

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“…Worthy of note, in the absence of a single crystal of suitable size and quality for conventional X-ray diffraction structural analysis, other structural methods have recently become viable. These include structural powder diffraction methods [ 18 ] (well beyond their common fingerprinting use), synchrotron X-ray single-crystal analysis of tiny specimens (down to 10 μm samples [ 19 , 20 ]) and, more recently, electron diffraction methods, which have been demonstrated to provide approximate, but reliable, structural models for crystalline grains with edges as low as 50–100 nm [ 21 ]. In this respect, the much wider accessibility of powder diffractometers than that of synchrotron beamlines or ED accessories for an electron microscope makes the determination of crystal structures of moderately complex molecular compounds (e.g., drugs) a viable option, at the expenses of less accurate models [ 22 ].…”

Section: Introductionmentioning

confidence: 99%

Thermal and Structural Characterization of Two Crystalline Polymorphs of Tafamidis Free Acid

Masciocchi

Abbinante²,

Zambra

et al. 2022

Molecules

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Tafamidis, chemical formula C14H7Cl2NO3, is a drug used to delay disease progression in adults suffering from transthyretin amyloidosis, and is marketed worldwide under different tradenames as a free acid or in the form of its meglumine salt. The free acid (CAS no. 594839-88-0) is reported to crystallize as distinct (polymorphic) crystal forms, the thermal stability and structural features of which remained thus far undisclosed. In this paper, we present—by selectively isolating highly pure batches of Tafamidis Form 1 and Tafamidis Form 4—the full characterization of these solids, in terms of crystal structures (determined using state-of-the-art structural powder diffraction methods) and spectroscopic and thermal properties. Beyond conventional thermogravimetric and calorimetric analyses, variable-temperature X-ray diffraction was employed to measure the highly anisotropic response of these (poly)crystalline materials to thermal stimuli and enabled the determination of the linear and volumetric thermal expansion coefficients and of the related indicatrix. Both crystal phases are monoclinic and contain substantially flat and π-π stacked Tafamidis molecules, arranged as centrosymmetric dimers by strong O-H···O bonds; weaker C-H···N contacts give rise, in both polymorphs, to infinite ribbons, which guarantee the substantial stiffness of the crystals in the direction of their elongation. Complete knowledge of the structural models will foster the usage of full-pattern quantitative phase analyses of Tafamidis in drug and polymorphic mixtures, an important aspect in both the forensic and the industrial sectors.

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“…Since electrons have charge and mass they interact with matter more 2 strongly than X-rays, thus electron diffraction experiments can yield data sufficient for structural determination from crystals less than one-billionth the size of crystals used for SCXRD (Figure 1b). [8][9][10][11][12][13][14][15] While crystallization screens for SCXRD can be quickly triaged using an optical microscope, the formation of microand nanocrystals for microED experiments are most reliably evaluated under the high magnification of a transmission electron microscopy (TEM). [16,17] However, screening for micro-and nanocrystals utilizing a TEM can be arduous, as the deposition of a single sample on a TEM grid, followed by insertion and retraction through airlock mechanisms can take as much as one hour per sample.…”

mentioning

confidence: 99%

“…Lastly, the analysis of Periconia sp. yielded the structure of 6β-hydroxyeremophilenolide (13) and 6-methoxy-7-chloromellein (14).…”

mentioning

confidence: 99%

High-throughput identification of crystalline natural products from crude extracts enabled by microarray technology and microED

Delgadillo

Burch

Kim

et al. 2023

Preprint

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The structural determination of natural products (NPs) can be arduous due to sample heterogeneity. This often demands itera-tive purification processes and characterization of complex molecules that may only be available in miniscule quantities. Microcrystal electron diffraction (microED) has recently shown promise as a method to solve crystal structures of NPs from nanogram quantities of analyte. However, its implementation in NP discovery remains hampered by sample throughput and purity requirements akin to traditional NP-discovery workflows. In the methods described herein, we leverage the resolving power of transmission electron microscopy (TEM) and the miniaturization capabilities of DNA microarray technology to address these challenges through the establishment of an NP screening platform, array electron diffraction (ArrayED). In this workflow, an array of HPLC fractions taken from crude extracts are deposited onto TEM grids in picoliter-sized droplets. This multiplexing of analytes on TEM grids enables 1200 or more unique samples to be simultaneously inserted into a TEM equipped with an autoloader. Selected area electron diffraction analysis of these microarrayed grids allows for rapid identification of crystalline metabolites. In this study, ArrayED enabled structural characterization of 14 natural products, including four novel crystal structures and two novel polymorphs, from 20 crude extracts. Moreover, we identify several chemical species that would not be detected by standard mass spectrometry (MS) or UV/Vis and crystal forms that would not be characterized using traditional methods.

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Electron Diffraction of 3D Molecular Crystals

Cited by 49 publications

References 295 publications

Electron crystallography and dedicated electron-diffraction instrumentation

Electron crystallography and dedicated electron-diffraction instrumentation

Thermal and Structural Characterization of Two Crystalline Polymorphs of Tafamidis Free Acid

High-throughput identification of crystalline natural products from crude extracts enabled by microarray technology and microED

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