This project aimed at the development of an innovative cavitand-based modular ligand platform envisioned as a functional mimic of the natural metalloenzyme active sites. We succeeded to prepare such systems and demonstrated that they are capable of binding a wide range of first-row transition metals, including manganese, iron, cobalt, and nickel. Importantly, these new metallocavitand systems retain the dynamic behavior of classical cavitands: they can reversibly switch between folded and open conformations (Figure 1). This dynamic motion allows substrates to enter and leave the cavity efficiently, a prerequisite for catalytic turnover and a key feature shared with natural enzymes.
Using this platform, we addressed one of the long-standing challenges in inorganic chemistry: the stabilization and direct observation of high-valent metal–oxo species, known to be the key intermediates in oxidations reactions performed by natural metalloenzymes, but are typically too reactive to isolate. Within the protective cavitand environment, we succeeded in generating and fully characterizing a highly elusive Mn(IV)–oxo complex. Most notably, we obtained the first crystallographic characterization of a Mn(IV)–oxo species in an octahedral coordination environment, which prior to our has only been detected by spectroscopy. Reactivity studies revealed that this species was capable of performing the two characteristic reactions of a high-valent-oxo, namely, the hydrogen atom abstraction and the oxygen atom transfer. Crucially, the cavitand framework exerts a strong steric influence: the size and shape of substrates determine whether—and how efficiently—they can access the reactive metal center. This enzyme-like control enabled highly selective oxidation reactions, exemplified by a regioselective oxygen atom transfer to an asymmetric bisphosphine substrate with 94% selectivity (Figure 3). These findings directly validate the project’s central hypothesis that confinement within a molecular cavity can control both reactivity and selectivity of highly reactive metal-oxo intermediates. In parallel, we obtained strong evidence for the formation of an even more reactive Fe(IV)–oxo species within an analogous iron-based cavitand. Unlike the manganese system, which showed only stoichiometric reactivity, the iron system exhibited initial signs of catalytic hydroxylation of simple hydrocarbons, such as cyclopentane and cyclohexane. Although the catalytic efficiency is still modest, our ongoing efforts are focused on enhancing this reactivity through further structural modifications of the cavitand-ligand framework.
Finally, we have explored routes toward light-driven hydrocarbon oxidation by designing heterobimetallic cavitands which combine a catalytically active metal (Fe or Mn) with a photoactive Ru- or Os- based unit (Figure 4). These systems aim to harness the energy of visible light to generate reactive metal–oxo species, using a water molecule as the oxygen atom source and inexpensive oxidants, such as hydrogen peroxide. While synthetically challenging, the preparation of these complex architectures is nearing completion, paving the way for the future studies in photocatalysis.
Overall, this project has established a new and versatile metallocavitand platform for studying and controlling highly reactive metal species. Beyond the specific systems investigated, the methodology developed here provides a general strategy for stabilizing, observing, and exploiting reactive intermediates that play a central role in catalysis. The work has already led to a high-impact publication in Journal of the American Chemical Society, with several additional manuscripts in preparation, and has been communicated at several international scientific conferences in Israel and abroad.
