Materials and Macromolecules Tailored for Micro and Nanoscale Organic Synthesis

Abstract High-throughput experimentation has revolutionized organic synthesis and pharmaceutical lead identification by enabling the design, execution, and analysis of previously unimaginable quantities of experiments. This paradigm shift over the past two decades has transformed the landscape of chemical research by accelerating nearly every aspect of synthesis and analysis. These advances have been realized, in part, through engineering developments such as automated liquid handlers. However, these engineering innovations have also led to certain chemical limitations. Many reagents and catalysts, despite being highly useful in conventional synthesis, are excluded from modern HT approaches because they are not compatible with automated liquid handlers used in standard HT workflows. The omission of these important compounds has resulted in significant limitations in current HT approaches. This proposal outlines efforts to address some of these gaps. Specifically, it outlines efforts to adapt heterogeneous materials and macromolecules to modern HTE approaches to better utilize their unique properties in organic synthesis. In the first goal, we aim to develop colloidal suspensions of commonly insoluble inorganic reagents, allowing them to be processed as homogenous liquid solutions. These reagents will undergo benchmarking in important cross-coupling reactions, including cross-electrophile couplings and in engineering challenges. In the second goal, we focus on the development of material and macromolecular analogs of commonly used, yet cytotoxic reagents, facilitating direct to biology synthesis and assays. Our research emphasizes macromolecular analogs of organic super bases and metal scavengers that are particularly relevant to high-throughput catalysis. Lastly, in the third goal, we plan to synthesize and evaluate easily accessible site-isolated catalysts for transformations historically constrained by bimolecular decomposition. This includes electrophilic carbon-hydrogen bond functionalization and mild fluoro-dediazotization reactions. The completion of these studies will yield innovative tools for modern synthesis and pharmaceutical development. By bridging the gap between heterogeneous reagents/catalysts and common automated reaction platforms, this research has strong potential to expand the impact of high-throughput experimentation in organic chemistry thereby accelerating the synthesis and identification of molecules important to human health.