Room temperature structures of solvated organic molecules enabled by liquid cell electron diffraction

Electron diffraction (MicroED/3DED) facilitates atomic structure determination from nano- or microcrystals, allowing structural analysis of dry crystalline powders or mixtures. However, radiation damage and instrument vacuum limit the interrogation of molecular crystals in solution at room temperature. We now present a strategy for room-temperature MicroED of organic molecular microcrystals suspended in solvent, using simple liquid cells: grid sandwiches comprised of two continuous carbon grids pressed and held together by the surface tension of a thin liquid layer. While room-temperature, hydrated microcrystals are particularly prone to electron beam radiation damage, we find that fast, low dose data collection schemes, direct electron detectors, and pseudo-serial multi-crystal data collection can minimize damage of crystals in liquid cells and facilitate ab initio structures. This tactic enables study of molecular conformations and crystalline phases only accessible in a room-temperature solvated state, which may be of particular relevance for research and pharmaceutical samples.