A biomimetic strategy for the monofunctionalization of a calix[6]arene core is described. It is based on host-guest chemistry (mimicking the Michaelis-Menten adduct in enzymes) and allows the finely tuned pre-organization of the substrate (an alkyne) with respect to the reactant (three azido groups introduced at the calixarene large rim). It is shown that the thermal Huisgen reaction implemented in this work proceeds under very mild conditions with total regioselectivity of the cycloaddition process. The scope of the reaction was explored and the results suggest that such a supramolecular strategy is quite versatile and could be applied to the selective functionalization of other cavitands bearing different recognition patterns. A detailed structural, thermodynamic, and kinetic study is also reported, highlighting interesting biomimetic features: The importance of the host-guest adduct strength, the high sensitivity of the reaction to the pre-organization of the reactive partners (alkyne vs. azide), and a significant impact of the embedment on the transition state. The self-coordination of the monofunctionalized products was also studied and an "endo/exo" switch of the internal side-chain could be triggered by adding competitive ligands.

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.

The Huisgen thermal reaction between an organic azide and an acetylene was employed for the selective monofunctionalization of a X6 -azacryptand ligand bearing a tren coordinating unit [X6 stands for calix[6]arene and tren for tris(2-aminoethyl)amine]. Supramolecular assistance, originating from the formation of a host-guest inclusion complex between the reactants, greatly accelerates the reaction while self-inhibition affords a remarkable selectivity. The new ligand possesses a single amino-leg appended at the large rim of the calixarene core and the corresponding Zn(2+) complex was characterized both in solution and in the solid state. The coordination of Zn(2+) not only involves the tren cap but also the introverted amino-leg, which locks the metal ion in the cavity. Compared with the parent ligand deprived of the amino-leg, the affinity of the new monofunctionalized X6 tren ligand 6 for Zn(2+) is found to have a 10-fold increase in DMSO, which is a very competitive solvent, and with an enhancement of at least three orders of magnitude in CDCl3 /CD3 OD (1:1, v/v). In strong contrast with the fast binding kinetics, decoordination of Zn(2+) as well as transmetallation appeared to be very slow processes. The monofunctionalized X6 tren ligand 6 fully protects the metal ion from the external medium thanks to the combination of a cavity and a closed coordination sphere, leading to greater thermodynamic and kinetic stabilities.