Project Summary/Abstract: For decades, transition metal catalysis has been integral to reaction discovery, method development, and large-scale synthesis in pharmaceutical research. The primary metal used to date is palladium. However, palladium is toxic (requiring rigorous removal prior to biological studies), expensive (with volatile pricing), and unsustainable (low earth abundant and deriving primarily from Russian mines). As such, there is great interest in replacing palladium with base metals, (iron, cobalt, nickel, and copper), which can have similar reactivity to palladium, while also opening up novel mechanistic manifolds and transformations. However, an ongoing challenge plaguing research in base metal catalysis is the lack of access to stable precursors (termed “pre-catalysts") to the reactive catalytic species [Mn], which are typically FeI, Co0/I, Ni0/I, or CuI complexes. Limited prior research has focused on developing stable base metal pre-catalysts for accessing [Mn]. However, these approaches have been specialized to each metal, often hard to synthesize, targeted to a single application, and often activated under heating or introduction of substrate. This forces researchers to develop synthetic methods around these reaction conditions. The overall objective of my project is to address these limitations by developing a general, stable, and easy to access pre-catalyst platform for all of the target active species (Mn = FeI, Co0/1,Ni0/I, or CuI). I hypothesize that complexes in the Mn+2 oxidation state bound to readily available and tunable LXX pincer ligands will serve as modular and versatile pre- catalysts. Activation will be triggered by the addition of an external reagent, an alkyne, promoting reductive annulation of the pincer ligand to general an inert organic byproduct along with the active metal catalyst [Mn]. In Aim 1a, I will develop a general synthetic route that offers efficient access to seven different [Mn+2] pre- catalysts. Importantly, preliminary studies from our lab show the feasibility of synthesizing the nickel analogues (Mn = NiIII or NiII) under mild conditions. In Aim 1b, I will study the reactivity of these pre-catalysts with alkynes to trigger generation of [Mn]. I hypothesize that alkynes will undergo reductive annulation with the LXX pincer ligand to release inert N-substituted 1(2H)-isoquinolinone species along with [Mn]. After this key reactivity is established, in Aim 2 I will benchmark these pre-catalysts in the well-studied Suzuki-Miyaura cross coupling reaction. My complexes will be compared to known pre-catalysts in terms of their performance: rates, turnover numbers, yields, and stability. Finally, in Aim 3 I will investigate the ability of these pre-catalysts to perform C– C and C–heteroatom bond-forming reactions unique to each of the metal species. Overall, the proposed research will demonstrate the ability of these pre-catalysts to facilitate catalytic reaction discovery and optimization using a ...