May 16, 2022

From Powders to Single Crystals: A Crystallographer's Toolbox for Small-Molecule Structure Determination

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Although the crystal structures of small-molecule compounds are often determined from single-crystal X-ray diffraction (scXRD), recent advances in three-dimensional electron diffraction (3DED) and crystal structure prediction (CSP) methods promise to expand the structure elucidation toolbox available to the crystallographer.

Three-dimensional electron diffraction (3DED), i.e., electron diffraction in a cryoelectron microscope (cryoEM), has been applied to the structure determination of a wide variety of molecules. Advances in detectors and sample stages for cryoEM have allowed for continuous data acquisition as a single crystal is rotated in the electron beam (approximately 140 of rotation). To combat the inherently strong dynamical scattering effects encountered in organic materials, 3DED experiments require crystals with an upper limit of 2 _m in size. Realistically, a size of 0.5 _m is ideal to reduce dynamical scattering effects. Thus, the technique is well positioned to solve the structures of many crystals that are not amenable to conventional scXRD structure determination (i.e., particles with acicular habits). Recently, Brazda et al. successfully demonstrated the use of 3DED to determine the absolute configuration of an organic molecule, further expanding on 3DED's capabilities to resolve bond connectivity in small-molecule APIs. A nice summary highlighting the application of 3DED on over 50 organic materials was recently reported by Bruhn and co-workers.


Newman, J. A.; Iuzzolino, L.; Tan, M.; Orth, P.; Bruhn, J.; Lee, A. Y. From Powders to Single Crystals: A Crystallographer's Toolbox for Small-Molecule Structure Determination. Mol Pharmaceut 2022. doi: 10.1021/acs.molpharmaceut.2c00020

Justin A. Newman, Luca Iuzzolino, Melissa Tan, Peter Orth, Jessica Bruhn, and Alfred Y. Lee
NIS Mountain Hero