UC Irvine

Chapter 1. This chapter introduces both the importance of generating organometallic reagents through oxidative addition to metal powders, and the prior analytical limitations that created difficulties studying the mechanisms of their synthesis through these routes. My thesis research developed fluorescence microscopy as a tool to overcome these prior difficulties, with a focus on the reaction of organohalides with zinc metal to form organozinc complexes. Fluorescence microscopy methods for the observation of organozinc intermediates under reaction conditions, originally developed by Dr. Chao Feng and Dr. Kristof Jess in our laboratory, have now been expanded, harnessed, and further developed to provide insight into four systems: 1) An origin of batch-to-batch variation in organoindium synthesis, 2) Solvent effects in organozinc synthesis, 3) Salt effects in Rieke zinc systems, 4) Effect of TMSCl pretreatment on commercial zinc powder, and 5) Environment heterogeneity of commercial zinc powder during oxidative addition. To enable insight into the mechanisms of activators with zinc metal, imaging experiments were taken into a new direction—fluorescence lifetime imaging microscopy (FLIM)—which had not previously been used to study oxidative addition of organohalides to metal surfaces. Together, the findings in this dissertation could lead to targeted improvement of the synthesis of organozinc reagents and to the activation of currently unreactive metals beyond zinc.Chapter 2. Yields of organoindium reagents synthesized from indium metal were previously reported to be highly dependent on metal batch and supplier due to the presence or absence of anticaking agent. Here, single-particle fluorescence microscopy established that magnesium oxide, an additive in some batches nominally for anticaking, is able to accomplish physisorption of small-molecule organics, and Aldrich-brand indium (which does not have a magnesium oxide coating) contains no detectable physisorption of organic molecules. An inert and relatively nonpolar boron dipyrromethene fluorophore with a hydrocarbon tail provided a sensitive probe for this surface physisorption. Further documented was the incomplete commercial bottle labeling regarding the presence and composition of this anticaking agent, both within our laboratory and previously in the literature, which may complicate reproducibility between laboratories. Adapted with permission from Jess, K.; Hanada, E. M.; Peacock, H.; Blum, S. A. Origins of Batch-to-Batch Variation: Organoindium Reagents from Indium Metal. Organometallics, 2020, 39, 2575–2579. Chapter 3. Solvent effects are often difficult to understand in cases where reaction intermediates, and thus their differential behaviour in different solvents, are not directly observable by traditional ensemble analytical techniques. Herein, the sensitivity of single-particle fluorescence microscopy uniquely enables direct observation of organozinc intermediates and solvent effects on their build-up and persistence. When combined with NMR spectroscopy, these imaging data pinpoint the previously elusive mechanistic origin of solvent effects in the synthesis of widely used organozinc reagents. These findings characterize the acceleration of oxidative addition of the starting organoiodide to the surface of zinc metal in DMSO relative to THF, but once formed, surface intermediates display similar persistence in either solvent. The current studies are the first demonstration of a highly sensitive, single-particle fluorescence microscopy technique to pinpoint otherwise elusive solvent effects in synthetic chemistry. Copyright 2020 Wiley. Used with permission from Hanada, E. M.+; Jess, K.+; Blum, S. A. Mechanism of an Elusive Solvent Effect in Organozinc Reagent Synthesis. Chem. Eur. J. 2020, 26, 15094–15098. Chapter 4. Contrary to prevailing thought, the salt content of the supernatants is found to dictate reactivity differences of different preparation methods of Rieke zinc toward oxidative addition of organohalides. This conclusion is established through combined single-particle microscopy and ensemble spectroscopy experiments, coupled with careful removal or keeping of the supernatants during Rieke zinc preparations. Fluorescence microscopy experiments with single-Rieke-zinc-particle resolution determined the microscale surface reactivity of the Rieke zinc in the absence of supernatant, thus pinpointing its inherent reactivity independent of convoluting supernatant composition. In parallel experiments, SEM, EDS, XPS, and ICP-MS characterized zinc metal chemical composition at the bulk and single-particle levels. 1H NMR spectroscopy kinetics characterized bench-scale Rieke zinc reactivity in the presence and absence of different supernatants and exogenous salt additives. Together, these experiments show that the differences in reactivity from sodium-reduced vs. lithium-reduced Rieke zinc arise from the residual salts in the supernatant rather than the differing salt compositions of the solids. This supernatant salt also determines the structure of the ultimate organozinc product, generating either the diorganozinc or monoorganozinc halide complex. That different organozinc complexes formed upon direct insertion to different preparations of Rieke zinc was not previously reported, despite Rieke zinc’s widespread use. These findings impact organozinc-reagent and nanomaterial synthesis by showing that, unexpectedly, desired Rieke zinc reactivity can be achieved through simple addition of soluble salts to solutions that were used to prepare the metals—a substantially easier synthetic manipulation than solid composition and morphology control. Reprinted with permission from Hanada, E. M.; Tagawa, T. K. S.; Kawada, M.; Blum, S. A. J. Am. Chem. Soc. 2022, 144, 12081–12091. Copyright 2022 American Chemical Society. Chapter 5. Trimethylsilyl chloride (TMSCl) is commonly used to “activate” metal(0) powders toward oxidative addition of organohalides, but knowledge of its mechanism remains limited by the inability to characterize chemical intermediates under reaction conditions. Here, fluorescence lifetime imaging microscopy (FLIM) overcomes these prior limitations and shows that TMSCl aids in solubilization of the organozinc intermediate from zinc(0) metal after oxidative addition, a previously unknown mechanistic role. This mechanistic role is in contrast to previously known roles for TMSCl before the oxidative addition step. To achieve this understanding, FLIM, a tool traditionally used in biology, is developed to characterize intermediates during a chemical reaction—thus revealing mechanistic steps that are unobservable without fluorescence lifetime data. These findings impact organometallic reagent synthesis and catalysis by providing a previously uncharacterized mechanistic role for a widely used activating agent, an understanding of which is suitable for revising activation models and for developing strategies to activate currently unreactive metals. Adapted with permission from Hanada, E. M.; McShea, P. J.; Blum, S. A. Angew. Chem. Int. Ed. 2023, e202307787. Copyright 2023 Wiley. Chapter 6. Zinc metal powder commonly requires activation for consistent and reliable use as a reductant for organohalides in the formation of organozinc reagents, and for associated avoidance of batch-to-batch variability. Here, fluorescence lifetime imaging microscopy (FLIM) reveals and provides a method to quantify the heterogeneity of environments on the surface of different zinc particles. Different activation methods (i.e., none/stirring/TMSCl) produced different surface environments and different degrees of heterogeneity. Without the fluorescence lifetime information available through FLIM, the heterogeneity of the different chemical environments is undetectable.