Small-molecule crystallography is routinely done with X-rays, but who says electrons cannot be used for the same purpose? Last week small-molecule electron crystallography made big waves when two research groups almost simultaneously reported the rapid structure determination of chemical compounds using a transmission electron microscope.
Why are chemists so excited?
X-ray crystallography is a mature technology. The bottleneck for structure determination lies in the sample itself: the first few steps, required to obtain a suitable 3D crystal before data collection can start, are hard to control. A suitable crystal is well-ordered and large enough to be analyzed by X-rays. Obtaining such a single crystal is not trivial and largely depends on the complexity of the compound(s) to be crystallized.
The excitement about the recent reports comes from the fact that much smaller crystallites, such as those that make up most powders, are amenable to a very similar crystallographic analysis. In Micro Electron Diffraction (MicroED), electrons are diffracted by crystallites of sub-micron sizes, usually 100 to 500 nm.
MicroED can be done in transmission electron microscopes, which are in common use in laboratories. This offers several advantages. Hundreds of crystals can be deposited and screened on one 3 mm disk used as support (the “grid”), and this screening process can be automated to some extent. Once a good crystal is found, data collection takes only a few seconds when using shutter-less direct electron detection by hybrid pixel detectors (Grüne et al. 2018). If throughput is not an issue, the use of standard CCDs can provide good results within less than 15 minutes per compound, as illustrated in a preprint shared by the Gonen group (Jones et al., 2018) who have been advocating the use of MicroED of protein nano-crystals since 2013 (Shi et al., 2013).
MicroED will become increasingly useful for structural chemistry and structure-based drug design. It is likely to fill the gap between traditional X-ray crystallography and powder X-ray diffraction and make sure structure determination faster and easier. We embrace the enthusiasm surrounding the two recent reports and congratulate our collaborator Dr. Tim Grüne and his colleagues for their publication in Angewandte Chemie.
Detail of the crystal structure of a Methylene-Blue derivative in the presence of BF4, solved with electron crystallography. The data quality shows the disorder in a BF4 counterion and the difference map reduced upon modelling of two conformations. From Angew. Chem. Int. Ed. 10.1002/anie.201811318