An integrated hardware-software platform for three-dimensional electron diffraction (3D ED) has been developed using the JUNGFRAU 1M charge-integrating hybrid pixel detector. The system combines the FPGA-based Jungfraujoch backend with the JFGui graphical interface, providing centralized control of the detector, electron microscope, and data-processing software. This workflow enables synchronized data acquisition, live visualization, and instantaneous post-processing with established programs of crystallography, XDS, DIALS, and SHELX. Applications to l-histidine and PTCDI- C8 crystals are presented including charge-density evaluation employing the recently developed iSFAC (ionic Scattering FACtors) model. The workflow supports continuous rotation measurements at speeds up to 10 ◦ s−1, enabling higher-throughput measurements. Comparative measurement at 100 kV and 200 kV beam energies revealed the trade-off between real-space contrast and diffraction resolution. These developments establish a complete and efficient practical workflow of 3D ED coupled with instrumental evaluation, providing a robust route toward quantitative electron crystallography.

AbstractC−H‐Funktionalisierung rein aliphatischer Substrate ist eine herausfordernde Aufgabe, da das Fehlen von dirigierenden Gruppen Versuche zur Steuerung der Regioselektivität meist vereitelt. Dies gilt insbesondere für Difunktionalisierungsreaktionen, bei denen die Kontrolle der relativen Stereochemie eine zusätzliche Hürde darstellt. Die Baddeley‐Reaktion an Decalinen ist, trotz Einschränkungen hinsichtlich Ausbeute und Vielseitigkeit, von besonderem Interesse, da sie eine der wenigen bekannten Transformationen ist, die in der aliphatischen C−H‐Funktionalisierung Regio‐ und Stereokontrolle ermöglichen. Hier berichten wir über eine regio‐ und diastereoselektive Methode zur Difunktionalisierung von Decalin, die Zugang zu einem neuen, bisher nicht beschriebenen Regioisomer in synthetisch nützlichen Ausbeuten ermöglicht. Diese Methode wurde erfolgreich auf eine Reihe anderer Alkansubstrate angewandt, was eine unkomplizierte Synthese von Ketoalkoholen aus den einfachsten Alkanbausteinen ermöglicht.

Atomic partial charges, integral to understanding molecular structure, interactions and reactivity, remain an ambiguous concept lacking a precise quantum-mechanical definition1,2. The accurate determination of atomic partial charges has far-reaching implications in fields such as chemical synthesis, applied materials science and theoretical chemistry, to name a few3. They play essential parts in molecular dynamics simulations, which can act as a computational microscope for chemical processes4. Until now, no general experimental method has quantified the partial charges of individual atoms in a chemical compound. Here we introduce an experimental method that assigns partial charges based on crystal structure determination through electron diffraction, applicable to any crystalline compound. Seamlessly integrated into standard electron crystallography workflows, this approach requires no specialized software or advanced expertise. Furthermore, it is not limited to specific classes of compounds. The versatility of this method is demonstrated by its application to a wide array of compounds, including the antibiotic ciprofloxacin, the amino acids histidine and tyrosine, and the inorganic zeolite ZSM-5. We refer to this new concept as ionic scattering factors modelling. It fosters a more comprehensive and precise understanding of molecular structures, providing opportunities for applications across numerous fields in the chemical and materials sciences.

The alluaudite-type compound Na3.4Co1.3(MoO4)3 has been successfully synthesized by a solid-state process route. It crystallizes in the monoclinic system (C2/c), cell parameters (Å,°): a = 12.582(5) Å, b = 13.449(8) Å, c = 7.119(7) Å, β = 112.02(4)°, V = 1116.8(14) Å3, and Z = 4. Its crystal structure consists of octahedral [MO6] (M = Co, Na) and tetrahedral [MoO4] that share corners and/or edges to build the 3D framework. The sample was also characterized by X-ray powder diffraction, which confirmed crystal data, and infrared (FT-IR) and Raman spectroscopies. Its morphology was analyzed using scanning electron microscopy (SEM). The vibrational study confirms the existence of the MoO_4^2- functional groups. The title compound was determined to be paramagnetic. In addition, the compound was characterized by cyclic voltammetry (CV), and its electrochemical performance and impedance were analyzed by electrochemical impedance spectroscopy (EIS). The electrochemical reaction mechanism and the limiting factors of Na3.4Co1.3(MoO4)3 as electrode material in Na-ion batteries at room temperature were also discussed. The prepared electrocatalyst showed modest hydrogen evolution reaction (HER) performance with an overpotential of 309 mV required to afford a current density of 10 mA cm−2.

Exciting developments are unfolding in the realm of chemical crystallography, especially with the profound impact of electron diffraction and the remarkable progress it has witnessed in recent years.

C-H functionalization of purely aliphatic substrates is a challenging endeavor, as the absence of directing groups generally thwarts attempts at regiocontrol. This is particularly true for difunctionalization reactions, where the control of relative stereochemistry poses an additional obstacle. The Baddeley reaction of decalins, despite suffering from strong limitations with regard to yield and generality, stands as one of only few known transformations capable of regio- and stereocontrol in aliphatic C-H functionalization. Herein, we report a regio- and diastereoselective method for the double functionalization of decalins enabling access to a novel, unreported regioisomer in synthetically useful yields. This method was also successfully applied to a range of other alkane substrates, enabling a straightforward synthesis of keto alcohols from the simplest alkane building blocks.

Detoxification of heme in Plasmodium depends on its crystallization into hemozoin. This pathway is a major target of antimalarial drugs. The crystalline structure of hemozoin was established by X-ray powder diffraction using a synthetic analog, β-hematin. Here, we apply emerging methods of in situ cryo-electron tomography and 3D electron diffraction to obtain a definitive structure of hemozoin directly from ruptured parasite cells. Biogenic hemozoin crystals take a striking polar morphology. Like β-hematin, the unit cell contains a heme dimer, which may form four distinct stereoisomers: two centrosymmetric and two chiral enantiomers. Diffraction analysis, supported by density functional theory analysis, reveals a selective mixture in the hemozoin lattice of one centrosymmetric and one chiral dimer. Absolute configuration has been determined by morphological analysis and confirmed by a novel method of exit-wave reconstruction from a focal series. Atomic disorder appears on specific facets asymmetrically, and the polar morphology can be understood in light of water binding. Structural modeling of the heme detoxification protein suggests a function as a chiral agent to bias the dimer formation in favor of rapid growth of a single crystalline phase. The refined structure of hemozoin should serve as a guide to new drug development.

Cobalt complexes with multiproton- and multielectron-responsive ligands are of interest for challenging catalytic transformations. The chemical and redox noninnocence of pentane-2,4-dione bis(S-methylisothiosemicarbazone) (PBIT) in a series of cobalt complexes has been studied by a range of methods, including spectroscopy [UV-vis, NMR, electron paramagnetic resonance (EPR), X-ray absorption spectroscopy (XAS)], cyclic voltammetry, X-ray diffraction, and density functional theory (DFT) calculations. Two complexes [Co-III(H2LSMe)I]I and [Co-III(L-SMe)I-2] were found to act as precatalysts in a Wacker-type oxidation of olefins using phenylsilane, the role of which was elucidated through isotopic labeling. Insights into the mechanism of the catalytic transformation as well as the substrate scope of this selective reaction are described, and the essential role of phenylsilane and the noninnocence of PBIT are disclosed. Among the several relevant species characterized was an unprecedented Co(III) complex with a dianionic diradical PBIT ligand ([Co-III(L-SMe center dot center dot)I]).

Developments in direct electron detector technology have enabled many advances in topics related to electron microscopy, particularly in the field of structural biology [1].Especially important when addressing beam-sensitive samples, the detector's sensitivity and frame rate are decisive to assure sufficient experimental flexibility and reliable results with Transmission Electron Microscopy (TEM) imaging techniques.Recently, approaches based on Electron Diffraction (ED) have been gaining popularity in structural characterization of both organic [2] and inorganic materials [3].These techniques lower the sample preparation requirements and offer significant advantages on electron dose management.Given the typically uneven intensity distribution on diffraction patterns, extended dynamic range became a must-have requirement for direct electron detectors alongside high sensitivity and high frame rate [4].The impact the direct electron detectors have on ED characterization is evident as it opens new possibilities in structural studies on complex and beam-sensitive systems [5].Prominent examples of such subjects are supramolecular structures, which are beamsensitive due to their high solvent content.This contribution addresses the use of hybrid-pixel detector technology [6] in the characterization of beam-sensitive functional materials with complex crystal structures.It presents the diffraction tomography experiment design, as well as the results of the structural characterization of (a) guest molecules in zeolites sample, (b) a supramolecular cage, and (c) a bioinorganic compound.The sensitivity of hybrid-pixel detectors enables data collection with extremely low total dose and dose rate -below the lower limit that can be read out on a state-of-the-art TEM -and allows viable ED data even at room temperature.

A series of latonduine derivatives, namely 11-nitro-indolo[2,3-d]benzazepine-7-(1-amino-hydantoin) (B), triazole-fused indolo[2,3-d]benzazepine-based Schiff bases HL1 and HL2 and metal complexes [M(p-cymene)(HL1)Cl]Cl, where M = Ru (1), Os (2), and [Cu(HL2)Cl2] (3) were synthesized and characterized by spectroscopic techniques (UV–vis, 1H, 13C, 15N–1H HSQC NMR) and ESI mass spectrometry. The molecular structures of B and HL1 were confirmed by single-crystal X-ray diffraction, while that of 3 by electron diffraction of nanometer size crystalline sample. Molecular docking calculations of species B in the binding pocket of PIM-1 enzyme revealed that the 1-amino-hydantoin moiety is not involved in any hydrogen-bonding interactions, even though a good accommodation of the host molecule in the ATP binding pocket of the enzyme was found. The antiproliferative activity of organic compounds B, HL1 and HL2, as well as complexes 1–3 was investigated in lung adenocarcinoma A549, colon adenocarcinoma LS-174 and triple-negative breast adenocarcinoma MDA-MB-231 cells and normal human lung fibroblast cells MRC-5 by MTT assays; then, the results are discussed.

Unveiling the coke formation in zeolites is an essential prerequisite for tackling the deactivation of these catalysts in the transformations of hydrocarbons. Herein, we present the direct mapping of coke in the micropores of ZSM-5 catalysts used in methanol-to-hydrocarbons conversion by single-crystal electron diffraction analysis. The latter technique revealed a polycyclic aromatic structure along the straight channel, wherein the high-quality data permit refinement of its occupancy to about 40 %. These findings were exploited to analyze the evolution of micropore coke during the reaction. Herein, coke-associated signals, which correlate with the activity loss, indicate that the nucleation of coke commences in the intersections of sinusoidal and straight channels, while the formation of coke in the straight pores occurs in the late stages of deactivation. The findings uncover an attractive method for analyzing coke deposition in the micropore domain.

Crystal structure of natural product argyrin D was determined from electron diffraction data.

Electron diffraction enables structure determination of organic small molecules using crystals that are too small for conventional X-ray crystallography. However, because of uncertainties in the experimental parameters, notably the detector distance, the unit-cell parameters and the geometry of the structural models are typically less accurate and precise compared with results obtained by X-ray diffraction. Here, an iterative procedure to optimize the unit-cell parameters obtained from electron diffraction using idealized restraints is proposed. The cell optimization routine has been implemented as part of the structure refinement, and a gradual improvement in lattice parameters and data quality is demonstrated. It is shown that cell optimization, optionally combined with geometrical corrections for any apparent detector distortions, benefits refinement of electron diffraction data in small-molecule crystallography and leads to more accurate structural models.

Detoxification of heme in Plasmodium depends on its crystallization into hemozoin. This pathway is a major target of antimalarial drugs. X-ray powder diffraction has established that the unit cell contains a cyclic hematin dimer, yet the pro-chiral nature of heme supports formation of four distinct stereoisomers, two centrosymmetric and two chiral enantiomers. Here we apply emerging methods of in situ cryo-electron tomography and diffraction to obtain a definitive structure of biogenic hemozoin. Individual crystals take a striking polar morphology. Diffraction analysis, supported by density functional theory, indicates a compositional mixture of one centrosymmetric and one chiral dimer, whose absolute configuration has been determined on the basis of crystal morphology and interaction with the aqueous medium. Structural modeling of the heme detoxification protein suggests a mechanism for dimer selection. The refined structure of hemozoin should serve as a guide to new drug development.

In the past few years, many exciting papers reported results based on crystal structure determination by electron diffraction. The aim of this review is to provide general and practical information to structural chemists interested in stepping into this emerging field. We discuss technical characteristics of electron microscopes for research units that would like to acquire their own instrumentation, as well as those practical aspects that appear different between X-ray and electron crystallography. We also include a discussion about applications where electron crystallography provides information that is different, and possibly complementary, with respect to what is available from X-ray crystallography.

The emerging field of 3D electron diffraction (3D ED) opens new opportunities for structure determination from sub-micrometre-sized crystals. Although the foundations of this technology emerged earlier, the past decade has seen developments in cryo-electron microscopy and (X-ray) crystallography that particularly enable the widespread use of 3D ED. This Perspective describes to chemists and chemical crystallographers just how similar electron and X-ray diffraction are and discusses their complementary aspects. We wish to establish 3D ED in the broader chemistry community, such that electron crystallography becomes a common part of the analytical chemistry toolkit. With a suitable instrument at their disposal, every skilled crystallographer can quickly learn to perform structure determinations using 3D ED.

Electron diffraction data for the MOF Vie-1 and for Oseltamivir. Associated with the manuscript "Iterative cell optimization in refinement of small molecule electron diffraction data." in submission process.