New Directions in Sustainable Open-Shell Radical C-C Bond Formations Enabled by Merging Modern Computational and Experimental Methods

University Of California Los Angeles, Los Angeles CA

Investigators

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Abstract

Project Summary/Abstract Transformations that proceed via carbon-centered radicals are amongst the most versatile and powerful reactions in the synthesis of medicinally relevant molecules and complex natural products. However, despite recent surge in the discovery of sustainable open-shell catalytic methods that enable C-C bond formations, our knowledge of the molecular-level interactions controlling the rate- and selectivity-determining steps is these transformations is rudimentary. In last grant cycle, we built a team of computational and experimental chemists that used a mechanistic-driven approach to advance the understanding of open-shell transformations and inform catalyst and reaction design. In the next five years, we will continue to combine state-of-the-art computational methods, organic synthesis, and, new to this cycle, advanced inorganic spectroscopic tools to develop predictive models of reactivity and selectivity of open-shell first-row, transition metal-catalyzed radical cross-couplings (RCCRs). As in the past, this information will be used to guide the development of highly efficient and chemo-, regio-, and stereoselective RCCRs that can be utilized in academic and industry settings for the preparation of bioactive compounds. One aspect of the proposed work involves continuing to develop sustainable methods that enable selective dicarbofunctionalization of alkenes. In particular, we will explore ligand- and ligand-free iron catalytic systems with structurally and electronically diverse alkyl radical precursors, nucleophiles, and olefin coupling partners to enable selective multicomponent carbon-carbon bond formations. High-level quantum mechanical calculations in combination with organic synthesis and in situ spectroscopic methods will be utilized to elucidate the mechanisms and, in particular, the impact of spin, oxidation state, and speciation of iron species in promoting or suppressing reaction channels that control alkyl radical formation, relay, and C-C bond formation. Another aspect of this proposed work involves continuing and expanding collaborative efforts to (i) elevate the understanding of open-shell, first row-transition metal-catalyzed radical two- and multicomponent component cross-couplings and (ii) develop predictive models of reactivity and selectivity. These reactions proceed through carbon-centered radical intermediates, open-shell organometallic species, and/or photoexicited electronic states which pose practical problems to identify and quantify the factors controlling the lifetimes, dynamics, and reactivity of these species. As in the past, through tight-knit collaborations with synthetic organic and inorganic experts, we will use high-level quantum mechanical calculations (including multireference and molecular dynamic simulations), rigorously calibrated against experimental data, to interrogate the mechanisms and to guide the development of new catalysts and reagents for currently sluggish or unselective reactions. Our long- term goal is to elevate the understanding and development of open-shell, first-row transition-metal catalyzed cross-couplings to the level of closed-shell palladium-based systems in organic synthesis.