Outer-Sphere Tuning of Synthetic Iron-Sulfur Clusters by Molecular Cage Assemblies

Iron-sulfur clusters are ubiquitous and versatile metallocofactors capable of catalyzing challenging multielectron, multiproton-driven reactions that are essential to life on Earth. Exquisite catalytic efficiency and selectivity are enabled for a remarkable breadth of reactions by changes to the cluster core configuration together with primary and outer coordination sphere effects. The latter represents a powerful means of tuning cofactor structure and function, including by hydrogen bonding effects, electric field effects, hydrophobic effects, and cooperative substrate activation and delivery. Decades of intensive research on synthetic iron-sulfur cofactor models has led to an improved understanding of structure and function, but modelling the specific impact of the outer coordination sphere remains exceptionally challenging owing to difficulties in synthetically manipulating its structure. Herein, we introduce a molecular host-guest approach for the selective and systematic tuning of the outer coordination sphere of synthetic iron-sulfur cofactor models. Thus, cofactors [Fe4S4(SR)4]2– [1R]2– in which R = Ph ([1Ph]2–), -CH2CH2OH ([1OH]2–, or tBu ([1tBu]2–) are readily encapsulated inside self-assembled, tetrahedral [M4L6]8+ molecular cages functionalized with electron-deficient naphthalenediimide (NDI) panels and M2+ corner nodes (M = Ni, Fe, Zn). Robust cofactor encapsulation is conclusively established by 1H and DOSY NMR spectroscopy, ESI mass spectrometry, and electronic absorption, nuclear absorption, and vibrational spectroscopies. The impact of cage encapsulation on the electronic structure of the cofactors is interrogated using 57Fe Mössbauer and Fe 2p and S 2p X-ray photoelectron spectroscopy coupled with infrared and UV-vis spectroscopy, demonstrating a substantial increase in the electropositive character at Fe and attendant increase in covalency on encapsulation. These effects are attributed to hydrogen bonding, noncovalent interactions, and non-specific hydrophobic interactions between the NDI panels and thiolate substituents, which result in net electron density withdrawal from the Fe centers. Differences in the magnitude of these effects, where [1Ph]2– > [1OH]2– ≥ [1tBu]2–, are proposed to result from the extent of host-guest binding interactions, which is influenced by the type of interaction and relative sizes of the host cavity and guest. These studies establish molecular cages as a powerful means of tuning cofactor electronic structure via outer-sphere noncovalent effects, and shed light on the impact of the hydrophobic cage environment on the electronic and bonding character of the cluster core.