Low-Coordinate Synthetic Models for Iron-Sulfur Enzymes

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Project Summary Enzymes perform amazing multielectron reductions of N2 and CO2, and for these challenging reactions they use iron-sulfur clusters. The iron-sulfur clusters in the active sites of N2-reducing (nitrogenase) and CO2-reducing (FeNi CO dehydrogenase) enzymes have unique shapes that are thought to generate binding sites on two adjacent metals. The cooperative reactivity of two metals may be the key to reducing these small molecules, but we do not yet understand how these metals work together, how they channel electrons and protons to the substrates, and how they mediate bond rearrangements under mild conditions. Direct studies on each enzyme have led to working models of the mechanism, but aspects of the protein crystal structures of intermediates are confusing and sometimes contradict inorganic chemistry principles. Moving the field forward requires new iron compounds that demonstrate what is reasonable behavior expected for these clusters. Our guiding hypothesis is that synthetic iron-sulfur "model" compounds can reveal the feasible geometries and spectroscopic signatures of cluster intermediates. Because the synthetic compounds have known structures, they enable us to correlate spectroscopic signatures with specific structural features. More importantly, they can be used to test the feasibility of mechanistic steps and pathways. The synthetic model strategy will be used for iron-sulfur and iron-sulfur-nickel compounds that contain key aspects of the active-site clusters in the nitrogenase and CO dehydrogenase enzymes. Taking advantage of our long experience in the organometallic chemistry of iron and nickel, we use innovative synthetic approaches based on bulky supporting ligands. These ligands protect active sites to enable binding of the gaseous substrates, and proton-coupled electron transfer facilitates substrate reduction without buildup of charge. In nitrogenase modeling, we will test a new mechanism where a preorganized multimetallic iron/sulfur environment enables rapid proton-coupled electron transfer to N2, rapidly converting the N2 to diazene (N2H2). Success in this aim would reveal the way that nitrogenase traps the normally unreactive N2 molecule under mild conditions, using the coupling of proton and electron movement. In CODHase modeling, we will prepare and study the first iron-sulfur clusters with three-coordinate nickel sites, which have great structural fidelity to the proposed enzyme active site. We will experimentally evaluate their redox chemistry, spectroscopy, and reactivity with CO2 and other compounds, in order to test the feasibility of mechanisms proposed in the enzyme. By studying chemistry relevant to both these iron-sulfur enzymes, we will gain generalizable knowledge about how hydrogen bonding, proton-coupled electron transfer, sulfur donors, electron migration, and multimetallic cooperativity enable biological systems to process small molecules. Further, this understanding contributes to the future ability of chemists to reduce N2 and CO2 for use in energy science.