Stéphane Le Gac

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.

Calix[6]tris(thio)ureas: heteroditopic receptors for the cooperative binding of organic ion pairs.

The straightforward syntheses of C3v symmetrical calix[6]trisureas and -thiourea have been achieved. NMR studies have shown that these flexible compounds possess a major cone conformation. While these neutral hosts can strongly bind anions such as AcO(-) or HSO4(-) through induced fit processes, they can also behave as unique heteroditopic receptors for organic ion pairs with a remarkable positive cooperativity in the complexation process, the anion acting as an allosteric effector.

An allosteric heteroditopic receptor for neutral guests and contact ion pairs with a remarkable selectivity for ammonium fluoride salts.

Two novel calix[6]cryptamides bearing a tren-based cap have been synthesized and their host-guest properties have been investigated by (1)H and (19)F NMR spectroscopy. One of them behaves as a remarkable heteroditopic receptor toward either polar neutral guests, anions or contact ion pairs. It has been shown that only F(-) can be encapsulated into the tris-amido cap of this host. Moreover, the fluoride anion acts as an allosteric activator by favoring the inclusion of ammonium ions into the calixarene cavity. The ammonium fluoride salts are bound as contact ion pairs and, remarkably, the calix[6]cryptamide host is reluctant to other ammonium salts. To our knowledge, such an highly cooperative and selective process toward contact ammonium fluoride salts is unique in the literature. Allosteric regulation of all the host-guest systems can also be achieved through protonation of the aza-cap. Indeed, guest release can be triggered by addition of various acids. In comparison to related calixarene-based receptors, all these unique properties are due to the smallness and the higher preorganization of the binding site provided by the convergent hydrogen bond donor groups of the tris-amido cap.

Second generation of calix[6]aza-Cryptands: synthesis of heteroditopic receptors for organic ion pairs.

The efficient syntheses of calix[6]azacryptands decorated with anion-binding groups on the narrow rim have been achieved from an 1,3,5-tris-protected calix[6]hexa-amine. These heteroditopic receptors can bind ammonium ions or organic ion pair salts with a positive cooperativity. In regard to their functionalization at the 1,3,5-phenolic positions, these compounds constitute the first examples of a second generation of C3 v symmetrical calix[6]azacryptands.

Formation of a Dinuclear Mercury(II) Complex with a Regular Bis‐Strapped Porphyrin Following a Tunable Cooperative Process

The richness of metalloporphyrin chemistry is an important source of innovative features which justifies active investigation of their coordination properties towards post-transition elements. Mercury(II) complexation by porphyrins was first motivated by the observation of its catalytic effect on the complexation of other elements (Cu, Zn), and regained attention in view of the sensing of toxicological organomercury(II) compounds. Although first studies appeared in the 1970s, the coordination of mercury by porphyrins is still largely misunderstood. Solution studies, mostly performed with “naked” porphyrins, revealed various Hg–porphyrin stoichiometries, such as 1:1, 2:1, 2:2, and 3:2, on the basis of spectroscopic investigations. Equilibria between the different species are often solvent-, concentration-, and pHdependent, and there are no definite elements in the literature for a possible correlation between an XRD-based coordination mode and the corresponding species observed in solution. Such analysis is crucial for a better understanding of the complexation processes and could also provide elements for the rational design of mercury-based porphyrinoid objects. To the best of our knowledge, XRD structures of mercury–porphyrin complexes are very scarce. Five of the six reported examples involve an N-modified macrocycle, 7] a single report being related to a regular porphyrin. In this mononuclear complex, the mercury atom is four-coordinate to the four nitrogen atoms of the porphyrin, and is sitting 0.60 above the 24-atom mean plane with an average covalent mercury to nitrogen bond length of 2.20 . In this context, the design of new porphyrin ligands with purposely introduced coordinating groups deserves particular attention. We recently reported a centrosymmetrical homodinuclear complex of lead(II) with the L ditopic ligand 1 (Scheme 1). We reasoned that, in the case of mercury(II), such a bis-strapped chelate with hanging COOH groups could provide a means to obtain discrete species, rather than sandwich assemblies, and better control of the nuclearity. Herein, we describe the first solid-state structure of a dinuclear mercury(II) complex with a regular porphyrin, and report on the evidence for a tunable cooperative process for its formation. Mercury insertion was performed at room temperature in pyridine with a 3 equivalent excess of mercury acetate (Scheme 1). The reaction was monitored by UV/Vis spectroscopy and a final pattern showing three absorption bands at l = 448, 550, and 576 nm was obtained after 15 min. After solvent evaporation, the green solid was taken up in neutralized CH2Cl2, and excess mercury salt was removed by filtration on celite. The mercury complex was isolated upon precipitation with pentane (82 % yield). Elemental analysis indicated a 1:2 1/Hg stoichiometry, which is in agreement with the formation of dinuclear bis(mercury) complex 1·Hg2. [9]

Calix[6]arene Tris-carboxylic Acid Derivatives: X-ray and NMR Characterization of their Remarkable Host-guest Properties Toward Ammonium Ions

The ability of calix[6]arene tris-carboxylic acid derivatives to include ammonium guests has been investigated both in solution and in the solid state. NMR studies and crystallographic data showed that the highly flexible calix[6]arene structures can be shaped in a well defined cone conformation thanks to the formation of an ion-paired cap between the carboxylate groups of the calixarene and their ammonium counter-ions. The resulting supramolecular edifices exhibit remarkable host-guest properties toward ammonium ions even in polar and protic solvents. The recognition process has been rationalized in the solid state by the combination of hydrogen bonding, electrostatic and CH–π interactions, and a remarkable C 3-complementarity between the well-organized binding carboxylates of the host and the ammonium guest. Very interestingly, the endo-cavity complexation of large polycyclic ammonium ions as well as bioactive ammonium ions has been clearly demonstrated through NMR spectroscopy. Finally, the tuning of the nature of the ammonium ions involved in the supramolecular cap led to highly responsive molecular receptors.

Highly diastereoselective cyclopropanation of α-methylstyrene catalysed by a C2-symmetrical chiral iron porphyrin complex.

A new chiral iron porphyrin-based catalyst performed α-methylstyrene stereoselective cyclopropanation with excellent yields (up to 99%), enantio- and diastereoselectivities (ee(trans) up to 87%, trans/cis ratios up to 99 : 1) and outstanding TON and TOF values (up to 20,000 and 120,000 h(-1) respectively).

Translocation-coupled transmetalation at the origin of a dinuclear lead porphyrin complex: implication of a hanging-atop coordination mode

Translocation of a lead cation from the N-core of a porphyrin to a hanging carboxylate group is coupled to a transmetalation process with a second lead cation, leading to a dinuclear species. A novel hanging-atop coordination mode is responsible for the dynamic and stereocontrolled binding of lead to the porphyrin core.

Acid–Base‐Controlled Stereoselective Metalation of Overhanging Carboxylic Acid Porphyrins: Consequences for the Formation of Heterobimetallic Complexes

Overhanging carboxylic acid porphyrins have revealed promising ditopic ligands offering a new entry in the field of supramolecular coordination chemistry of porphyrinoids. Notably, the adjunction of a so-called hanging-atop (HAT) Pb(II) cation to regular Pb(II) porphyrin complexes allowed a stereoselective incorporation of the N-core bound cation, and an allosterically controlled Newtons cradle-like motion of the two Pb(II) ions also emerged from such bimetallic complexes. In this contribution, we have extended this work to other ligands and metal ions, aiming at understanding the parameters that control the HAT Pb(II) coordination. The nature of the N-core bound metal ion (Zn(II), Cd(II)), the influence of the deprotonation state of the overhanging COOH group and the presence of a neutral ligand on the opposite side (exogenous or intramolecular), have been examined through (1)H NMR spectroscopic experiments with the help of radiocrystallographic structures and DFT calculations. Single and bis-strap ligands have been considered. They all incorporate a COOH group hung over the N-core on one side. For the bis-strap ligands, either an ester or an amide group has been introduced on the other side. In the presence of a base, the mononuclear Zn(II) or Cd(II) complexes incorporate the carbonyl of the overhanging carboxylate as apical ligand, decreasing its availability for the binding of a HAT Pb(II). An allosteric effector (e.g., 4-dimethylaminopyridine (DMAP), in the case of a single-strap ligand) or an intramolecular ligand (e.g., an amide group), strong enough to compete with the carbonyl of the hung COO(-), is required to switch the N-core bound cation to the opposite side with concomitant release of the COO(-), thereby allowing HAT Pb(II) complexation. In the absence of a base, Zn(II) or Cd(II) binds preferentially the carbonyl of the intramolecular ester or amide groups in apical position rather than that of the COOH. This better preorganization, with the overhanging COOH fully available, is responsible for a stronger binding of the HAT Pb(II). Thus, either allosteric or acid-base control is achieved through stereoselective metalation of Zn(II) or Cd(II). In the latter case, according to the deprotonation state of the COOH group, the best electron-donating ligand is located on one or the other side of the porphyrin (COO(-)>CONHR>COOR>COOH): the lower affinity of COOH for Zn(II) and Cd(II), the higher for a HAT Pb(II). These insights provide new opportunities for the elaboration of innovative bimetallic molecular switches.

Unprecedented incorporation of α-emitter radioisotope 213Bi into porphyrin chelates with reference to a daughter isotope mediated assistance mechanism

For the first time, α-emitter radioisotope (213)Bi has been incorporated into porphyrin chelates, with rates matching with the short period of the radionuclide. An in situ transmetalation mechanism involving the daughter isotope (209)Pb is expected to boost the (213)Bi radiolabeling process.