Outer‐Sphere Tuning of Synthetic Iron–Sulfur Clusters Within Nanoscale Cage Frameworks

ABSTRACT As atomic‐scale archetypes for multi‐electron transfer, iron–sulfur clusters are compelling candidates for the design of redox‐active, catalytic nanomaterials; yet, translating their enzymatic proficiency into robust synthetic platforms remains a challenge. A key bottleneck lies in replicating the outer‐sphere environment, which modulates the cluster's electronic landscape, provides site‐isolation, and facilitates catalytic pathways via programmable noncovalent interactions. Herein, we demonstrate a host‐guest strategy for systematically tuning iron–sulfur cofactor models within tetrahedral [M ₄ L ₆ ] ⁸⁺ cages (M = Ni, Fe, Zn). Successful encapsulation of [Fe ₄ S ₄ (SR) ₄ ] ²⁻ (R = Ph, ─CH ₂ CH ₂ OH) was confirmed by 1D/2D NMR spectroscopy and ESI mass spectrometry, while titration studies confirmed association constants ( K _a ) > 10 ⁷ m ⁻¹ . Spectroscopic characterization by ⁵⁷ Fe Mössbauer, X‐ray photoelectron, IR, and UV–vis spectroscopy reveals significant shifts in Fe─S bond covalency and electron density that converge toward those of the native, protein‐bound cofactors. Control studies with [Fe ₄ S ₄ (S ^t Bu) ₄ ] ²⁻ , which associates with the host primarily through outer‐sphere ion pairing, demonstrate that while the electrostatic field generated by the framework's corner vertices is a primary driver of these electronic perturbations, internal confinement effects such as π–π stacking and hydrogen bonding provide important secondary modulations. This work establishes a foundation for utilizing cage‐stabilized cofactors in the development of sophisticated, energy‐efficient catalytic systems.