Jean-Noël Rebilly

Calixarenes and resorcinarenes as scaffolds for supramolecular metallo-enzyme mimicry

Metallo-enzymes are natural catalysts carrying out highly selective and demanding reactions under mild conditions, using readily available metal ions (iron, copper, zinc, etc.). Understanding the factors explaining these performances is thus of fundamental and applicative interest. Classical model complexes displaying significant limitations in reactivity led to the development of supramolecular systems associating a reactive complex to a molecular cavity receptor, in order to not only mimic the first coordination sphere of the metal, but also the supramolecular enzymatic environment (access channel and binding pocket) responsible for their remarkable kinetics and selectivities. Calixarenes and resorcinarenes are particularly suited to this goal due to their wide range of sizes and flexibility. This review illustrates several specific aspects of enzymatic systems that were successfully mimicked with such supramolecular model systems. This toolbox of supramolecular effects could be used for future developments of bioinorganic supramolecular catalysts.

Supramolecular Control of Hetero-multinuclear Polytopic Binding of Metal Ions (ZnII, CuI) at a Single Calix[6]arene-Based Scaffold

A Calix[6]arene scaffold was functionalized to provide a tridentate binding site at the small rim and three bidentate chelate sites at the large rim of the cone to generate a heteropolytopic ligand. Its complexation to one equivalent of Zn(II) at the small rim yields a funnel complex displaying both host-guest properties and preorganization of the three chelate groups at the large rim. These two aspects allowed the full control of the binding events to regioselectively form dinuclear Zn(II) and heteropolynuclear Zn(II)/Cu(I) complexes. The heteropolynuclear systems all rely on the host-guest relationship thanks to the induced-fit behavior of the calix cavity. With the short guest MeCN, the large rim is preorganized into a trigonal tris-triazole core and accommodates a single Cu(I) ion. A long guest breaks this spatial arrangement, and three Cu(I) ions can then be bound at the tris-bidentate triazole-dimethylamine site at the large rim. In a noncoordinating solvent however, the tetranuclear complex is submitted to scrambling and the addition of exogenous π-acceptor ligands is required to control the binding of Cu(I) in a well-defined environment. Hindrance selectivity was then induced by the accessibility at the small rim site. Indeed, while CO can stabilize Cu(I) at both coordination sites, PPh(3) cannot fit into the cavity and forces Cu(I) to relocate at the large rim. The resulting well-defined symmetrical tetranuclear complex thus arises from the quite remarkable selective supramolecular assembly of nine partners (1 Zn(II), 3 Cu(I), 1 calixarene, 1 guest alkylamine, 3 PPh(3)).

Guest-Triggered ZnII Translocation and Supramolecular Nuclearity Control in Calix[6]arene-Based Complexes

Two new polytopic ligands based on a calix[6]arene scaffold were synthesized. The truncated cone-shaped calixarene was functionalized at its small rim by a tris-imidazole site, aimed at generating a tetrahedral Zn(II) complex, where a fourth labile site inside the cavity is accessible through the funnel provided by its large rim. Tridentate aza ligands (either two or three) were then grafted at this large rim (the entrance of the cavity). Zn(II) coordination studies, monitored by (1)H NMR spectroscopy, showed unprecedented behavior in this family of heteropolytopic ligands. Indeed, it gives access to complexes of various nuclearities in acetonitrile, where zinc binding is under the supramolecular control of the guest. It is first shown that, in the absence of a good guest donor (a primary amine), Zn(II) binding is favored at the large rim where two tridentate nitrogenous groups can form an octahedral complex. The addition of a long guest such as heptylamine induces the quantitative translocation of the Zn(II) ion from the large rim octahedral (O(h)) site to the small rim tetrahedral (T(d)) site provided by the trisimidazole core and the guest ligand. With 2 equiv of Zn(II), well-defined dinuclear complexes were obtained and isolated, with one Zn(II) ion bound at each rim. Interestingly, it is shown that the binding mode at the large rim is under the supramolecular control of the guest bound at the small rim (with short guests, the O(h) environment is obtained at the large rim, whereas long guests disrupt this core through an induced-fit process); the partially included and dangling alkyl chain opens the large rim (entrance of the cavity) and pushes apart the tridentate moieties. As a result, a guest-induced switch of Zn(II) binding mode occurs and frees one of the tridentate groups from coordination, allowing further extension of the complex nuclearity.

Selective Fluorimetric Detection of Primary Alkylamines by a Calix[6]arene Funnel Complex

The association of host-guest and coordination chemistry was used to develop a fluorescent molecular sensor. A calix[6]arene bearing three imidazole arms at the small rim and three quinoline fluorophores at the large rim was synthesized and characterized. A two-step coordination sequence was observed upon addition of ZnII . The first ZnII center binds the tris-imidazole small rim site, leading only to a small perturbation of the fluorescence. In contrast, a large bathochromic shift is observed upon binding of the second ZnII center at the large rim as a result of the direct interaction of ZnII with the quinoline fluorophores. The system acts as a selective receptor for primary amines. Host-guest adduct formation could be identified by a shift and enhancement of the fluorescence emission that is dependent on the length and shape of the primary amine. This system constitutes a fluorescent reporter with a selective response among primary amines.

Mimicking the Regulation Step of Fe-Monooxygenases: Allosteric Modulation of FeIV-Oxo Formation by Guest Binding in a Dinuclear ZnII–FeII Calix[6]arene-Based Funnel Complex

A heteroditopic ligand associated with a calix[6]arene scaffold bearing a tris(imidazole) coordinating site at its small rim and an amine/pyridine ligand at its large rim has been prepared, and its regioselective coordination to ZnII at the small rim and FeII in the amine/pyridine ligand has been achieved. The heterodinuclear complex obtained displays an overall cone conformation capped by the tris(imidazole)ZnII moiety and bears a non-heme FeII complex at its base. Each of the metal centers exhibits one labile position, allowing the coordination inside the cavity of a guest alkylamine at ZnII and the generation of reaction intermediates (FeIII (OOH) and FeIV O) at the large rim. A dependence between the chain length of the encapsulated alkylamine and the distribution of FeIII (OOH) intermediates and FeIII (OMe) is observed. In addition, it is shown that the generation of the FeIV O intermediate is enhanced by addition of the alkylamine guest. Hence, this supramolecular system gathers the three levels of reactivity control encountered in oxidoreductases: i) control of the FeII redox properties through its first coordination sphere, allowing us to generate high valent reactive species; ii) control of guest binding through a hydrophobic funnel that drives its alkyl chain next to the reactive iron complex, thus mimicking the binding pocket of natural systems; iii) guest-modulated reactivity of the FeII center towards oxidants.