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 [M4L6]8+ cages (M = Ni, Fe, Zn). Successful encapsulation of [Fe4S4(SR)4]2- (R = Ph, ─CH2CH2OH) was confirmed by 1D/2D NMR spectroscopy and ESI mass spectrometry, while titration studies confirmed association constants (Ka) > 107 m-1. Spectroscopic characterization by 57Fe 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 [Fe4S4(StBu)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.