Room Temperature Structures of Solvated Organic Molecules Enabled by Liquid Cell Electron Diffraction

Electron diffraction (MicroED/3DED) enables atomic structure determination from nano- or microcrystals, including dry crystalline powders or mixtures. However, radiation damage and instrument vacuum can 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 solution, using simple liquid cells: grid sandwiches comprised of two continuous carbon grids that when pressed retain a thin liquid layer between them. In this setting, we find that some room-temperature, hydrated microcrystals are particularly prone to electron beam radiation damage, requiring fast, low dose data collection schemes, direct electron detectors, and multi-crystal data collection. These approaches minimize damage of crystals in liquid cells and facilitate ab initio structures at sub-Ångstrom resolution. This tactic enables study of molecular conformations and crystalline phases that may only be accessible in a room-temperature solvated state.