Molecular Cages as Encapsulants for the Stabilization of Reactive Iron-Sulfur Cofactor Models

Iron-sulfur clusters are desirable targets for bioinspired synthesis due to their versatility in promoting a range of catalytic reactions (N2 reduction to NH3, CO2 reduction to hydrocarbons, and selective C–H functionalizations) and ability to serve as model systems for the systematic interrogation of structure and mechanism. However, a challenge in replicating the activity of clusters remains their instability outside of the protein scaffold. Previous efforts to mitigate this challenge include incorporation into polymeric and aerogel networks and artificial metalloenzymes or installation of bulky, strong-field ligands, but none of these retain both the native weak-field primary ligand sphere and capacity for molecular-level tuning of the cofactor and second coordination sphere. Herein, we present a new strategy for stabilizing weak-field synthetic clusters and conferring second coordination sphere functionality via encapsulation inside molecular cages. Thus, clusters [Fe4S4(SR)4]2– ([1a-c]2–: R = Ph, CH2CH2OH, tBu) are encapsulated inside tetrahedral naphthalene diimide (NDI)-functionalized cages [M4L6]8+ (M = Fe, Ni, Zn) via a robust and generalizable electrostatic binding strategy. 1H and DOSY NMR, ESI-MS, and 57Fe Mössbauer studies confirm immediate and quantitative binding and suggest the cluster electronic structure is minimally perturbed by the cage. At the same time, the cage’s redox-switching ability is demonstrated in CV and 57Fe Mössbauer studies demonstrating that NDI reduction renders the encapsulated cofactors [1a-b]2– significantly more reducing, consistent with their effective charge donation to the cofactor via pi-pi stacking and H-bonding interactions. Importantly, cofactor reactivity is maintained as demonstrated in diphenylacetylene reduction trials, showing that the encapsulated clusters are not only structural but also functional cofactor models. Combined, these results demonstrate that molecular cages can function as protein-like encapsulants to site isolate, tune, and deliver substrate to functional weak-field models of bioinorganic cofactors, and support the use of molecular host-guest complexes as functional enzyme mimics for both catalytic and structure-function studies.