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This dissertation describes a set of experiments loosely unified under the general theme of 3D electron crystallography.Chapter 1 provides a comprehensive overview of the scientific literature in the field, with particular emphasis on experiments aimed at using electron diffraction to elucidate the atomic structure of three-dimensional molecular crystals. Chapter 2 focuses on the development of a publicly accessible web server, FAES (Factors of Atomic Electron Scattering, https://srv.mbi.ucla.edu/faes), containing a database of electron scattering factors parameterized into Gaussian approximations compatible with widely used least-squares refinement programs. These include all neutral and ionic species tabulated in the International Tables for Crystallography, as well as fractionally charged scattering factors calculated by computing linearly weighted sums of adjacent integral neighbors. FAES provides numerical fitting coefficients, statistical goodness-of-fit values, and elastic and estimated inelastic cross-sections at a range of accelerating voltages relevant to transmission electron microscopy. Chapter 3 details rigorous studies involving the mapping of electron beam-induced radiolytic damage in molecular crystals using 4D scanning transmission electron microscopy (4D-STEM), conducted on a variety of organic and organometallic species spanning a wide gamut of chemical space. By acquiring a series of consecutive 4D-STEM scans on the same crystal, we explicitly visualize the spatial evolution of coherently diffracting zones (CDZs) as a function of accumulating electron fluence, providing a detailed, time-resolved map of the internal lattice reorientation induced by radiolysis. These experiments also unveil the resolution-dependent propagation of tides of amorphization from impact craters created by asymmetric, localized delivery of incident electrons. Chapter 4 relates the development of the 4D-STEM method nanobeam electron diffraction tomography into a technique capable of overcoming obstacles that thwart structural elucidation by conventional microcrystal electron diffraction (microED). 4D-STEM's unique ability to pinpoint a specific nanoscale volume for data analysis enables pixel-by-pixel spatial exclusion of unwanted signal from disordered or Bragg-silent regions, empowering us to simply pick and choose whichever CDZs generate the highest-quality diffraction patterns. These experiments represent the first 4D-STEM structures phased ab initio by direct methods.

Structural elucidation of small macromolecules such as peptides has recently been facilitated by a growing number of technological advances to existing crystallographic methods. The emergence of electron micro-diffraction (MicroED) of protein nanocrystals under cryogenic conditions has enabled the interrogation of crystalline peptide assemblies only hundreds of nanometers thick. Collection of atomic or near-atomic resolution data by these methods has permitted the ab initio determination of structures of various amyloid-forming peptides, including segments derived from prions and ice-nucleating proteins. This chapter focuses on the process of ab initio structural determination from nano-scale peptide assemblies and other similar molecules.

Advances in radical-based catalytic reactions have created a demand for understanding their mechanistic underpinnings. Here, we present the isolation, structural elucidation, and theoretical analysis of a catalytically relevant charge-transfer species formed between the azidyl radical and (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO). The unusual bond angles and pancake bonding between these two fragments highlight the weak bonding interactions present in this complex. This X-ray structure validates computational predictions as well as mechanistic proposals of TEMPO-mediated radical azidation reactions.