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 multielectron transfer and redox catalysis within complex enzymatic frameworks, making them promising targets for the rational design of modular, bioinspired catalysts and materials. Advancements have been made toward establishing structure-function-activity relationships through synthesis and structural characterization of biomimetic Fe-S clusters. However, their conformational plasticity and multiconfigurational character pose significant challenges in capturing the underlying electronic structure. The treatment of both strong and dynamic correlation effects is integral in bridging the gap between electronic and physical structure to rationalize metallocluster reactivity. Here, we employ a computationally tractable, multireference 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 electron and spin (de)localization, geometric isomerism, and chemical reactivity.