Small Crystals, Big Insights: How Electron Diffraction is Transforming Materials, Life Science, and Chemistry Research

Webinar summary

This webinar is an introduction to a series about how electron diffraction is transforming materials, life science, and chemistry research.

Electron diffraction (ED), also known as microED, is rapidly emerging as a critical tool for structural analysis in cases where conventional X-ray crystallography is limited by sample size or crystal quality. While single crystal X-ray diffraction remains the gold standard for determining atomic arrangements in crystalline materials, it requires crystals typically at least one micron in size with sufficient order to yield high-quality diffraction patterns. Many compounds, however, especially those encountered in early-stage drug development, advanced materials, or complex mixtures, do not crystallize readily into such forms.

Electron diffraction overcomes this barrier by leveraging the much stronger interaction between electrons and matter. Electrons are scattered by the coulombic potential surrounding atomic nuclei rather than by electron density alone, which allows high-resolution diffraction data to be collected from nanocrystals orders of magnitude smaller than those suitable for X-ray diffraction. This dramatically expands the range of analyzable samples, enabling single-crystal-like structural determination from sub-micron powders, precipitates, or trace quantities.

This capability is transforming workflows across pharmaceutical development, materials science, and chemistry. In particular, it provides a robust method for characterizing polymorphs, distinguishing salts from co-crystals, identifying solvent or guest molecule inclusion, and assessing disorder in mechanically treated or poorly crystalline samples. Electron diffraction also facilitates high-throughput polymorph screening, as automated software can acquire data from numerous grains on a single transmission electron microscope (TEM) grid without manual intervention.

Recent advances in instrumentation are further broadening access. Dedicated electron diffractometers now feature optimized hardware and user interfaces designed for crystallographers rather than microscopy specialists. This shift is making electron diffraction a more approachable and routine part of the structural analysis toolkit, with the potential to complement, and in some cases replace, traditional crystallographic methods when sample conditions are unfavorable.

In essence, electron diffraction is not just a workaround for poor crystals—it is becoming an essential method in its own right, offering structural researchers a way to extract atomic-level detail from materials that would otherwise remain structurally elusive.

Key questions answered in the webinar

What is a crystal structure and why is it important in scientific research?

A crystal structure provides a clear, unambiguous picture of how molecules are arranged in a solid, periodic pattern. It allows for the precise location and identification of every atom within a molecule, revealing its molecular connectivity. This is crucial for confirming the identity of a compound, determining the absolute configuration of chiral molecules, distinguishing between salts and co-crystals, and identifying guest molecules within host structures (like drug candidates in protein active sites or molecules in the pores of Metal-Organic Frameworks - MOFs). Furthermore, the way molecules pack together in the crystal (crystal packing) reveals information about hydration or solvation and helps identify different polymorphs (different crystal forms of the same compound). Crystal structure analysis is considered the ultimate method for gaining these structural insights, often providing answers that are difficult or impossible to obtain through other techniques like NMR or FTIR, especially when dealing with complex mixtures or subtle structural differences.

How does traditional X-ray crystallography work?

X-ray crystallography involves directing an X-ray beam onto a single crystal. As the beam passes through the crystal, it is diffracted by the electron density around the atoms, producing a pattern of discrete reflections. A 2D detector records the location and intensity of these reflections. This data is then processed using mathematical techniques like Fourier transforms to generate an electron density map. The peaks in this map correspond to the positions of atoms, allowing researchers to build a molecular model and determine the crystal structure. While effective for many samples, X-ray crystallography typically requires crystals with dimensions of at least one micron.

What are the limitations of X-ray crystallography, and when is electron diffraction needed?

X-ray crystallography faces limitations when dealing with samples that do not form crystals large enough (at least one micron) or of sufficient quality to produce a strong diffraction pattern. Factors like the tightness of molecular packing, the size and shape of the molecule, the presence of solvent, and the presence of voids can all affect crystal quality and diffraction intensity. When crystals are too small or too imperfect for X-ray diffraction, or when dealing with a precipitate that only forms tiny crystalline grains, electron diffraction becomes a necessary alternative.

How does electron diffraction (microED) overcome the limitations of X-ray crystallography?

Electron diffraction utilizes an electron beam instead of an X-ray beam. Electrons interact much more strongly with crystalline matter (by several orders of magnitude) because they are diffracted by the coulombic potential around the atomic nuclei, whereas X-rays are diffracted by electron density. This stronger interaction allows electron diffraction to be performed on much smaller crystals, specifically sub-micron particles. This means that researchers can obtain single-crystal-like structural information from crystalline powders or precipitates that might be too small or poor quality for X-ray analysis. This capability is particularly beneficial for compounds that are difficult to crystallize, are only available in low quantities, or naturally form nanocrystals.

What are the key advantages of using electron diffraction for structural analysis?

The two primary advantages of electron diffraction are its ability to analyze extremely small crystals (sub-micron to nanoscale) and the minimal amount of sample required. Because it can work with tiny crystalline particles, electron diffraction enables single crystal crystallography on crystalline powders or precipitates, even when traditional crystallization methods fail to produce larger crystals. The amount of sample needed is often so small that it's mainly required for visual observation during sample preparation, not for the diffraction analysis itself.

Can electron diffraction be used for high-throughput screening of polymorphs?

Yes, electron diffraction is well-suited for high-throughput screening of polymorphs. Since a typical TEM grid used for electron diffraction can hold a multitude of tiny crystalline grains from a powder sample, automated software can be used to sequentially locate and collect diffraction data from many different particles without user intervention. This allows researchers to efficiently analyze and characterize the different polymorphs present in a single powder sample.

What types of samples and research areas benefit significantly from electron diffraction?

Electron diffraction is transforming research across various fields, including materials science, life sciences, and chemistry. It is particularly useful for:

• Characterizing compounds that are difficult to crystallize or available in limited quantities.
• Analyzing inorganic and intermetallic compounds that form nanocrystals and exist in multiple phases or stoichiometries.
• Solving structures of Metal-Organic Frameworks (MOFs), especially when they are difficult to crystallize or need to be studied in solvated or empty states.
• Drug discovery and pharmaceutical research, including characterizing initial solid forms, mapping out polymorph populations, and studying disorder in milled crystals.
• Battery materials research, where materials are often poorly crystalline and involve the study of ion ordering and structural changes during charge/discharge cycles.
• Analyzing samples that require cryo conditions, such as those containing water or labile solvent molecules within the crystal lattice, which are stabilized by freezing.

Is specialized expertise in electron microscopy required to use electron diffraction in a lab setting?

While electron microscopy itself is a complex field, dedicated electron diffractometers are being designed with hardware and software specifically tuned for diffraction experiments and for use by crystallographers rather than electron microscopists. This approach aims to make electron diffraction accessible as an analytical tool available in home laboratories, reducing the need for extensive prior background in electron microscopy techniques.