Disentangling Cooperative Electron Correlation and Primary Coordination Sphere Effects in [4Fe-4S]+ Structural Isomerism and π-Acid Activation

Iron-sulfur (Fe-S) clusters are ubiquitous cofactors known to perform critical biological functions like multi-electron transfer and redox catalysis within complex enzymatic frameworks, making them promising targets for the rational design of modular, bio-inspired catalysts. Advancements have been made towards establishing structure-function-activity relationships through synthesis and structural characterization of biomimetic Fe-S clusters. However, their conformational plasticity and multi-configurational character pose significant challenges in capturing the underlying electronic structure. The treatment of both strong and dynamic correlation effects are integral in bridging the gap between electronic and physical structure to rationalize metallocluster reactivity. Here, we employ a computationally tractable, multi-reference methodology that captures both strong and dynamic correlation effects to simulate a series of chemically and electronically diverse, site-differentiated [4Fe-4S]+ clusters, elucidating the effects of cooperative electron correlation and primary coordination sphere modification on electronic structure, geometric isomerism, and chemical reactivity.