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

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.