Olivia Reinaud

Biomimetic and self-assembled calix[6]arene-based receptors for neutral molecules

The selective recognition of substrates or cofactors is a key feature of biological processes. It involves coordination bonds, hydrogen bonding, charge/charge and charge/dipole interactions. In this Perspective, we describe how the calix[6]arene core can be functionalized and shaped to act as a biomimetic molecular receptor. The strategy relies on the selective introduction of three amino arms on alternate phenolic positions. Upon metal ion binding or self-assembly via multiple ion-pairing and H-bonding, these amino arms are projected towards each other, thus closing the calixarene small rim. The resulting cone-shaped receptors act as molecular funnels displaying high affinities for a variety of neutral guests. Their hosting properties can be finely tuned by changing the small or the large rim or by allosteric effects. Induced-fit processes are also often observed as the cavity can expand for large guests or shrink for small ones. Hence, the different families of calix[6]arene-based receptors presented here highlight the importance of having a flexible and polarized hydrophobic structure to accommodate the guest.

Calixarene‐Based Copper(I) Complexes as Models for Monocopper Sites in Enzymes

A cavity that acts as a molecular funnel is formed from calix[6]arene 1 and [CuI (NCCH3 )4 ]PF6 [Eq. (a)]. An exchange of the well-protected acetonitrile ligand for other nitriles RCN is only possible with small R groups. The protection of the copper ions precludes oxidative dimerization; thus, the complexes mimic the mononuclear site of copper enzymes.

Dioxygen activation at a mononuclear Cu(I) center embedded in the calix[6]arene-tren core.

The reaction of a cuprous center coordinated to a calix[6]arene-based aza-cryptand with dioxygen has been studied. In this system, Cu(I) is bound to a tren unit that caps the calixarene core at the level of the small rim. As a result, although protected from the reaction medium by the macrocycle, the metal center presents a labile site accessible to small guest ligands. Indeed, in the presence of O2, it reacts in a very fast and irreversible redox process, leading, ultimately, to Cu(II) species. In the coordinating solvent MeCN, a one electron exchange occurs, yielding the corresponding [CalixtrenCu-MeCN](2+) complex with concomitant release of superoxide in the reaction medium. In a noncoordinating solvent such as CH2Cl2, the dioxygen reaction leads to oxygen insertions into the ligand itself. Both reactions are proposed to proceed through the formation of a superoxide-Cu(II) intermediate that is unstable in the Calixtren environment due to second sphere effects. The transiently formed superoxide ligand either undergoes fast substitution for a guest ligand (in MeCN) or intramolecular redox evolutions toward oxygenation of Calixtren. Interestingly, the latter process was shown to occur twice on the same ligand, thus demonstrating a possible catalytic activation of O2 at a single cuprous center. Altogether, this study illustrates the oxidizing power of a [CuO2](+) adduct and substantiates a mechanism by which copper mono-oxygenases such as DbetaH and PHM activate O2 at the Cu(M) center to produce such an intermediate capable of C-H breaking before the electron input provided by the noncoupled Cu(H) center.

Electrochemically Triggered Double Translocation of Two Different Metal Ions with a Ditopic Calix(6)arene Ligand

A ditopic ligand based on a calix[6]arene with three imidazoles (Im) appended at the small rim and three triazoles (Tria) at the large one is able to form selectively two stable heterodinuclear complexes with Zn(II)(Im)/Cu(I)(Tria) and Cu(II)(Im)/Zn(II)(Tria). In the Cu(I) case, the zinc cation is preferentially coordinated at the Im site while the copper is bound at the Tria site. The situation is the opposite when Cu(II) is used. The position of the two cations within the complex can be electrochemically switched via the oxidation-reduction of the copper cation between oxidation states +I and +II. The presence of the zinc cation is crucial (i) to control the bistability of the system by an allosteric structuring role and (ii) to promote the metal switch since the monocopper complex exhibits reversible behavior with Cu located at the imidazole site in both oxidation states. This represents the first example of a double translocation of two different metal cations.

Biomimetic Copper(I)–CO Complexes: A Structural and Dynamic Study of a Calix[6]arene-Based Supramolecular System

Four novel calix[6]arene-based cuprous complexes are described. They present a biomimetic tris(imidazole) coordination core associated with a hydrophobic cavity that wraps the apical binding site. Each differs from the other by the methyl or ethyl substituents present on the phenoxyl groups (OR1) and on the imidazole arms (NR2) of the calix[6]arene structure. In solution, stable CO complexes were obtained. We have investigated their geometrical and dynamic properties with respect to the steric demand. IR and NMR studies revealed that, in solution, these complexes adopted two distinct conformations. The preferred conformation was dictated only by the size of the OR1 group. When R1 was an ethyl group, the complex preferentially adopted a flattened C3-symmetrical structure. The corresponding helical enantiomers were in conformational equilibrium, which, however, was slow on the 1H NMR time scale at -80 degrees C. When R1 was a methyl group, the low-temperature NMR spectra revealed the partial inclusion of one tBu group. The complex wobbled between three dissymmetric but equivalent conformations. Hence, small differences in the steric demand of the calixarenes skeleton changed the geometry and dynamics of the system. Indeed, this supramolecular control was promoted by the strong conformational coupling between the metal center and the host structure. Interestingly, this was not only the result of a covalent preorganization, but also stemmed from weak interactions within the hydrophobic pocket. The vibrational spectra of the bound CO were revealed to be a sensitive gauge of this supramolecular behavior, similar to copper proteins in which allosteric effects are common.

Electrografting of calix[4]arenediazonium salts to form versatile robust platforms for spatially controlled surface functionalization

An essential issue in the development of materials presenting an accurately functionalized surface is to achieve control of layer structuring. Whereas the very popular method based on the spontaneous adsorption of alkanethiols on metal faces stability problems, the reductive electrografting of aryldiazonium salts yielding stable interface, struggles with the control of the formation and organization of monolayers. Here we report a general strategy for patterning surfaces using aryldiazonium surface chemistry. Calix[4]tetra-diazonium cations generated in situ from the corresponding tetra-anilines were electrografted on gold and carbon substrates. The well-preorganized macrocyclic structure of the calix[4]arene molecules allows the formation of densely packed monolayers. Through adequate decoration of the small rim of the calixarenes, functional molecules can then be introduced on the immobilized calixarene subunits, paving the way for an accurate spatial control of the chemical composition of a surface at molecular level.

Mimicking the protein access channel to a metal center: effect of a funnel complex on dissociative versus associative copper redox chemistry.

The control of metal-ligand exchange in a confined environment is of primary importance for understanding thermodynamics and kinetics of the electron transfer process governing the reactivity of enzymes. This study reveals an unprecedented change of the Cu(II)/Cu(I) binding and redox properties through a subtle control of the access to the labile site by a protein channel mimic. The cavity effect was estimated from cyclic voltammetry investigations by comparison of two complexes displaying the same coordination sphere (tmpa) and differing by the presence or absence of a calix[6]arene cone surrounding the metal labile site L. Effects on thermodynamics are illustrated by important shifts of E(1/2) toward higher values for the calix complexes. This is ascribable to the protection of the labile site of the open-shell system from the polar medium. Such a cavity control also generates specific stabilizations. This is exemplified by an impressively exalted affinity of the calixarene system for MeCN, and by the detection of a kinetic intermediate, a noncoordinated DMF guest molecule floating inside the cone. Kinetically, a unique dissymmetry between the Cu(I) and Cu(II) ligand exchange capacity is highlighted. At the CV time scale, the guest interconversion is only feasible after reduction of Cu(II) to Cu(I). Such a redox-switch mechanism results from the blocking of the associative process at the Cu(II) state, imposed by the calixarene funnel. All of this suggests that the embedment of a reactive redox metal ion in a funnel-like cavity can play a crucial role in catalysis, particularly for metallo-enzymes associating electron transfer and ligand exchange.

Drastic effects of the second coordination sphere on neutral vs. anionic guest binding to a biomimetic Cu(II) center embedded in a calix[6]aza-cryptand

A calix[6]arene capped by a tmpa unit provides Cu(ii) funnel complexes that, for the first time, accept not only neutral guest ligands but also anionic ones such as a hydroxide, which is due to a small conformational change in the calixarene cone.

Oxidative metabolism of linoleic acid by human leukocytes

Upon incubation with human leukocytes, [1-14C] linoleic acid is almost exclusively transformed into 13-hydroxy-9Z, 11E-octadecadienoic acid (13-HODE) if the linoleic acid concentration is lower than 50 microM. Identification of 13-HODE was done by GLC-MS at the level of its methyl ester, trimethylsilyl ether and by comparison with authentic 13-HODE in two different HPLC systems. Analysis of the products by chiral phase HPLC shows that 13(S)-hydroxy-9Z, 11E-octadecadienoic acid is by far the major metabolite formed by human leukocytes. Comparison of reactions performed with intact or lyzed cells suggests that the formation of 13(S)-HODE by human leukocytes occurs in two steps, a dioxygenation catalyzed by a 15-lipoxygenase and a reduction of intermediate 13-HPODE by a glutathione-dependent peroxidase.

Calix[6]arene-BasedN3-Donors − A Versatile Supramolecular System with Tunable Electronic and Steric Properties − Study on the Formation of Tetrahedral Dicationic Zinc Complexes in a Biomimetic Environment

Novel tridentate N-ligands containing tertiary amines, pyrazoles, or benzimidazole groups were synthesized from tBu-calix[6]arene. Together with the previously described pyridine and imidazole-based ligands, they form a large family of biomimetic ligands (X6Me3N3) with different electronic and steric properties. Their capacity at stabilizing a tetrahedral Zn dicationic center in acetonitrile was investigated. Tertiary amines were too basic and sterically hindered, leading to precipitation of Zn(OH)2. The resulting protonated ligand was, in one case, structurally characterized by X-ray analysis. Ligands with pyrazole, benzimidazole and imidazole donors, all formed a stable Zn complex under stoichiometric conditions in acetonitrile. An 1H NMR spectroscopic study together with X-ray crystallography showed that the metal ion is coordinated to the three nitrogen arms with MeCN as a fourth ligand included in the calixarene conic pocket. These complexes provide new but rare examples of stable dicationic tetrahedral Zn species. The calixarene functionalized by three pyridine groups, on the other hand, did not appear to be a good ligand, which stands in contrast with its remarkable ability at stabilizing copper(I). Finally, these funnel complexes are chiral due to their helical shape. In solution, both enantiomers are in equilibrium. However, sterically hindered N-donors increased the enantiomerization barrier above 16 kcal/mol.