Could you start by explaining your background in crystallography and how you began using the Rigaku Synergy-ED system?
Fraser: I began my journey into crystallography at the University of Edinburgh in 2004 as part of my Ph.D. program. My initial exposure came during an undergraduate project, where I was fascinated by the ability to determine a compound’s full 3D structure using this technique. Since then, crystallography has become central to my career. I had a brief stint as a service crystallographer in Edinburgh before joining the company as an applications scientist in 2011.
Around 2019, we observed a growing interest in electron diffraction and decided to explore its potential. In 2020, we partnered with JEOL, renowned for their excellence in electron microscopes, and launched the XtaLAB Synergy-ED in 2021. I was fortunate to be involved in the early development stages, including data collection and structure solving.
Robert: After completing my Ph.D. in physics, I was introduced to crystallography in 2013 when I joined the Max Planck Institute for the Structure and Dynamics of Matter as a postdoc. There, I focused on method development for electron diffraction and microscopy. During this period, 3D ED/MicroED—a technique that combines the strengths of traditional electron diffraction and crystallography—was rapidly gaining traction. Being part of the scientific community advancing this field and devising creative solutions to integrate methodologies from both areas was an incredible experience.
The introduction of streamlined commercial solutions for 3D ED/MicroED marked a significant milestone, making the technique accessible to a broader audience. When the opportunity to join Rigaku as a product manager for electron diffraction arose in 2022, it was the exact challenge I had been looking for.
Electron diffraction traditionally required reconfiguration of TEMs. Could you explain some of the technical challenges this posed for crystallographers not specialized in microscopy?
Robert: Technically, switching any TEM to “diffraction mode” might seem as simple as pressing a single button. However, this apparent ease is misleading. TEMs are designed with flexible imaging conditions, and steering the instrument into the precise setup required for 3D ED/MicroED can be both time-consuming and demanding. Unlike modern diffractometers, which benefit from advanced automation, TEMs still rely heavily on the specialized skills of operators for realignment throughout a measurement session.
Automation for tasks such as instrument configuration, alignment, and conducting fully unattended measurement series is generally lacking, and integration among different components of the instrument is often underdeveloped. Moreover, despite their versatility, TEMs struggle with some fundamental crystallographic requirements, such as precise goniometer control, minimal radiation dose, and background-free detection—even on high-end models.
What are some of the key features of the Rigaku Synergy-ED that differentiate it from other electron diffraction instruments?
Robert: Our focus is to create an instrument that combines intuitive operation for any crystallographer with robustness, stability, and a range of available sample environments. We achieve the former through a user experience based entirely on our acclaimed CrysAlisPro platform, which encompasses instrument control, data collection, processing, and structure solutions, even in real time.
Introduction to the XtaLAB Synergy-ED
For our beamline, we partnered with JEOL, a leading manufacturer renowned for their decades of expertise in building robust electron optics. This collaboration enabled us to harness the strengths of TEM components where they are most advantageous—such as optical adjustment of detector distance and the ability to vary illumination strength and diameter across a wide range.
We tackled the operational complexities by integrating an optical configuration designed for optimal stability, along with advanced self-alignment features and a meticulously crafted control system. Furthermore, the Synergy-ED is highly compatible with the JEOL ecosystem, offering seamless access to specialized sample environments, such as cryo-transfer, high- and low-temperature conditions, and gas cells.
How does electron diffraction complement other forms of crystallography, and what unique advantages does it offer for the study of crystalline materials?
Fraser: Single-crystal X-ray diffraction has established itself as a gold standard for structure determination over the decades since its introduction in the 1910s. The technique has advanced to a point where the required size of samples has dropped to 1 or 2 microns in their smallest dimensions, and R-factors, a measure of the agreement between the data and structural model, are now typically 3 % or less for good samples. That said, it is difficult to get good-quality data if your samples are smaller than 1 to 2 microns.
This is where Electron diffraction comes into play. With several orders of magnitude stronger interaction with matter, electrons allow you to perform diffraction experiments with samples smaller than 1 micron. This is a double-edged sword, though, and electrons severely struggle to measure samples above this size for the same reason. The stronger interaction with matter gives rise to an effect called dynamical diffraction, that is, the sample diffracts the beam multiple times, creating a challenging mathermatical problem to solve.
Robert: First and foremost, electron diffraction offers access to a crystal size range that is quite different from X-rays, with an upper limit of 1-2 microns, extending down to nanoparticles. This allows samples that would otherwise be suited only for powder diffraction to become targets for crystallography. In this respect, X-ray and electron crystallography complement each other exceptionally well.
Other notable differences include high sensitivity to light elements, charge states, and especially absolute configuration, which can be directly determined from electron diffraction data due to the symmetry-breaking effects of dynamical diffraction. To fully exploit these advantages, specific structure refinement techniques are required, though these are becoming increasingly standard.
Could you describe the process of preparing samples for analysis with the Rigaku Synergy-ED? What challenges does this system help mitigate?
Robert: The main restriction that is lifted by the availability of electron diffraction is the need to grow crystals of sufficient size for X-ray single-crystal diffraction in the first place, which is a godsend for materials like pharmaceuticals or framework materials. Considering that the viable crystals are too small to even be seen under an optical microscope, the sample preparation, of course, differs a lot.
Typically, a tiny aliquot of nanocrystalline material is carefully deposited on a carbon-coated copper grid, a substrate commonly used in TEMs. This can be done through drop-casting in an antisolvent or by dry application of the powder. The prepared grid is then either directly loaded into the diffractometer via a vacuum airlock or cryo-preserved by plunging into liquid nitrogen. Cryo-preservation is crucial for solvated or hydrated samples to prevent decomposition inside the diffractometer’s vacuum. With a few days of experience, sample preparation usually takes no more than a few minutes.
Image Credit: Rigaku Corporation
What software does the Rigaku Synergy-ED use for data collection and analysis, and how does it enhance the user experience?
Fraser: As with all of our X-ray diffractometers, the XtaLAB Synergy-ED uses CrysAlisPro for data collection and data analysis. For structure solutions and refinement, we have a long-standing collaboration with Olexsys Ltd., which provides our AutoChem software for automatic structure solutions. All of our X-ray know-how has been adapted and applied to provide a seamless solution for the XtaLAB Synergy-ED. Consequently, X-ray crystallographers familiar with CrysAlisPro instantly feel right at home with the XtaLAB Synergy-ED and can start performing experiments almost instantly. We have also added intelligent features for use with ED, such as automatic sample centering, sample queuing, and easy-to-use data set merging tools to make the electron diffraction workflow as easy as possible.
Can you share a recent project where the Rigaku Synergy-ED was instrumental? What were the key findings?
Robert: With the number of peer-reviewed articles featuring data from Synergy-ED diffractometers approaching 40 as of July 2024, it is really hard to pick a favorite. Many of the most impactful projects are from the porous materials community, where the availability of electron diffraction enables whole new synthesis pathways that would have previously led to crystals too small for crystallographic structure elucidation.
A recent example is the realization of a spectacular framework material with zero-valent metal cluster nodes with attractive catalytic properties demonstrated by Liu et al. (Nature Communications 15, 1177). Other notable recent results include the use of electron diffraction to confirm the correct stereochemistry of an amination precursor compound in a synthetic pathway of a securamine compound and, in the process, shed light on why growing single crystals suitable for X-ray diffraction had been unsuccessful (Alexander et al., Science 383, 849-854). Lastly, a neat study where the previously unknown structure of a common antihistaminic was solved from ground tablets straight from the pharmacy, containing only small amounts of active ingredient among crystalline fillers (Karothu et al., Angew. Chem. 62, e202303761).
Looking forward, what improvements or innovations in electron diffraction technology are you most excited about?
Robert: I am particularly excited about the potential to expand the scope of electron diffraction through automation, transforming your electron diffractometer into a true high-throughput tool. The presence of virtually limitless nano-crystallites in a single sample grid, combined with data collection times of just seconds, provides a vast resource for investigating your sample.
For extremely radiation-sensitive or poorly diffracting specimens, automated serial collection can often lead to successful structure solutions by merging datasets with very weak individual signals. More significantly, mixtures containing dozens of compounds or polymorphs—where traditional powder diffraction signals are too congested for quantitative analysis—can be effectively managed through automated measurements. By automatically assigning each grain to a specific crystal type, you can map out entire grid regions at the level of single crystallites. This process is coupled with automated structure solution pipelines for one-crystal or merged datasets, all requiring minimal user interaction.
With the introduction of a dedicated diffractometer like the Synergy-ED, how has the experiment time been reduced, and what does this mean for throughput in crystallographic studies?
Fraser: The XtaLAB Synergy-ED can collect data in just a few minutes or even seconds. While rapid data collection has been possible with X-rays, the crucial advantage here is that it applies to sample sizes much smaller than those feasible with X-ray techniques. Electron diffraction is the go-to method when X-rays are not an option.
Instead of spending time growing crystals large enough for X-ray experiments or conducting multiple experiments to gather structural evidence, the XtaLAB Synergy-ED provides a direct route to obtaining 3D structures. This capability significantly accelerates R&D across various fields, from pharmaceutical drug development to battery innovation. Thus, the XtaLAB Synergy-ED not only enhances crystallographic throughput but also streamlines the entire R&D process.
Image Credit: Rigaku Corporation
Since the launch of the XtaLAB Synergy-ED, what has been the feedback from the crystallography community? Are there any success stories that particularly stand out?
Robert: Feedback from the crystallography community has been unanimously positive. We did encounter some initial skepticism regarding electron diffraction, based on a long-standing concern that dynamical diffraction will lead to poor-quality structures and also that it is simply too complicated for everyday use.
However, it has become evident from numerous groundbreaking studies over the past decade that modern data collection schemes, as implemented in the Synergy-ED, effectively mitigate dynamical diffraction to a level where it becomes manageable or even advantageous—for instance, in determining absolute structure. We believe that dedicated solutions like the Synergy-ED have streamlined the process, removing much of the complexity typically associated with electron diffraction. Indeed, during demonstrations and training sessions, we observe that crystallographers with no prior experience in electron-based techniques can become proficient with the instrument within a day.
About the Speakers
Robert Bücker
Dr. Robert Bücker obtained a PhD degree in experimental quantum physics from the Vienna University of Technology. In 2013, he joined the department of Prof. Dwayne Miller at the Max Planck Institute for the Structure and Dynamics of Matter in Hamburg and the University of Toronto, where he worked on developing novel techniques to visualize the atomic structure and dynamics of beam-sensitive biological specimens using electron diffraction and microscopy. In 2020, he worked within a shared project between the Technion Israel Institute of Technology (Group of Prof. Meytal Landau) and the Leibniz Institute of Virology (Group of Prof. Kay Grünewald), studying aggregation dynamics and polymorphism of functional amyloid fibrils using cryo-electron microscopy. Returning to diffractive methods, in 2022 he joined Rigaku as product manager for electron diffraction, steering the development of the XtaLAB Synergy-ED, Rigaku’s fully integrated solution for three-dimensional microcrystal electron diffraction (3D ED/MicroED).
Fraser White
Fraser began his career as a crystallographer at the University of Edinburgh in 2004. Following completion of his PhD, he stayed at Edinburgh, accepting the position of staff crystallographer tasked with running the departmental X-ray crystallography service. During this time Fraser solved and refined over 1000 structures for a variety of different sample chemistries and gained broad experience in solving crystallographic problems. After several years in this role, Fraser first joined Agilent technologies in 2011 as an applications scientist based in Oxfordshire and remained with the company through the acquisition of Agilent’s single crystal business by Rigaku in 2015. Now in the role of product marketing manager for Rigaku Oxford Diffraction, Fraser is involved in the scientific aspects of single-crystal product marketing.
This information has been sourced, reviewed and adapted from materials provided by Rigaku Corporation.
For more information on this source, please visit Rigaku Corporation.
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