Understanding Mechanisms of Organic Reactions and Processes through Imaging

University Of California-Irvine, Irvine CA

Investigators

Abstract

Project Summary A mechanistic understanding of reactivity has enabled the development of nearly all modern synthetic organic chemistry, which has in turn revolutionized the discovery and production of therapeutics to treat human diseases. Yet, traditional ensemble analytical tools for investigating mechanisms, like NMR spectroscopy and mass spectrometry, measure primarily the major components in mixtures and provide averaged and non-spatially resolved information, thus missing key reaction intermediates and distributions of behaviors. Approach: Here, focusing on two challenging systems—aqueous–surfactant emulsions for sustainable organic chemistry in water and the synthesis of organometallic reagents and catalytic intermediates directly from metal powders—we now develop fluorescence lifetime imaging microscopy (FLIM) methods. These methods overcome the limitations of prior analytical techniques and, we propose, lead to exciting insights into previously poorly understood classes of organic reactions and processes. Innovation: The experiments described here are the first FLIM studies of any synthetic organic chemistry reactions or processes under preparative conditions. We innovate by using this spatially resolved fluorescence lifetime data to characterize reaction intermediates, assign fates of catalysts, understand reaction mechanisms, and create predictive reaction models. Significance: Information gained from these FLIM studies provides guiding principles for surfactant selection and medium recycling in sustainable aqueous–organic systems, efficient methods for accessing organometallic reagents, and tactics for lowering temperatures, ligand quantities, and/or catalyst amounts in carbon–carbon bond-forming cross-coupling reactions. We focus our efforts on understanding and developing areas of high significance: organozinc, organocopper, and organopalladium reagent and/or catalytic intermediate syntheses, as well as Negishi, Suzuki, and Heck cross-coupling reactions, with applications in the synthesis of drug-like molecules. Beyond uncovering guiding principles, we plan to develop next-generation chemical imaging agents and strategies, including autofluorescence methods that function in the absence of exogenous imaging agents. Instead, these methods will harness the inherent fluorescence lifetime and emission signatures of native reaction components. Once developed, these imaging tools will be primed for use by our laboratory and others for the broader study of mechanisms and processes in synthetic organic chemistry. Expertise in our diverse team uniquely encompasses fluorescence microscopy, FLIM, organic synthesis methods development, transition-metal chemistry, catalysis, surface characterization, and mechanistic studies—exactly the angles needed for the success of this ambitious, multidisciplinary proposal, as demonstrated by robust preliminary results and an impactful publication record. Together, these studies have a positive impact because they lead to efficient, sustainable routes for the construction of carbon–carbon bonds and organometallic reagents and catalysts, thus facilitating the next generation of therapeutic agents used to treat human diseases.