Synthesis of C3v-Symmetrical 1,3,5-Tris-Protected Calix[6]arene-Based Molecular Platforms.

Few synthetic methodologies that yield tris-functionalized C3v-symmetrical calix[6]arenes have been reported. In this work, three allyl protecting groups are selectively placed in 1,3,5 alternate positions of three pristine calix[6]arenes, each differing by their substituent on the large rim, resulting in three new C3v-symmetrical molecular platforms. Removal of the protecting allylic groups gives access to sophisticated calix[6]arenes that can be further modified. The potential of these new C3v-symmetrical molecular platforms is notably exemplified through the development of a new family of calix[6]arene-based N ligands.

Selective Metal-ion Complexation of a Biomimetic Calix[6]arene Funnel Cavity Functionalized with Phenol or Quinone.

In the biomimetic context, many studies have evidenced the importance of the 1st and 2nd coordination sphere of a metal ion for controlling its properties. Here, we propose to evaluate a yet poorly explored aspect, which is the nature of the cavity that surrounds the metal labile site. Three calix[6]arene-based aza-ligands are compared, that differ only by the nature of cavity walls, anisole, phenol or quinone (LOMe , LOH and LQ ). Monitoring ligand exchange of their ZnII complexes evidenced important differences in the metal ion relative affinities for nitriles, halides or carboxylates. It also showed a possible sharp kinetic control on both, metal ion binding and ligand exchange. Hence, this study supports the observations reported on biological systems, highlighting that the substitution of an amino-acid residue of the enzyme active site, at remote distance of the metal ion, can have strong impacts on metal ion lability, substrate/product exchange or selectivity.

A Promising Approach for Controlling the Second Coordination Sphere of Biomimetic Metal Complexes: Encapsulation in a Dynamic Hydrogen-Bonded Capsule.

The design of biomimetic models of metalloenzymes needs to take into account many factors and is therefore a challenging task. We propose in this work an original strategy to control the second coordination sphere of a metal centre and its distal environment. A biomimetic complex, reproducing the first coordination sphere, is encapsulated in a self-assembled hydrogen-bonded capsule. The cationic complex is co-encapsulated with its counter-anion or with solvent molecules. The capsule is dynamic, allowing a fast in/out exchange of the co-encapsulated species. It also provides both a hydrogen-bonding site in the second coordination sphere and a source of proton as it can be deprotonated in the presence of the complex, providing a globally neutral host-guest assembly. This simple and broad scope strategy is unprecedented in biomimetic studies. The approach appears to be a very promising method for the stabilisation of reactive species and for the study of their reactivity.

Dual Electroactivity in a Covalent Organic Network with Mechanically Interlocked Pillar[5]arenes.

The synthesis and characterization of a polyrotaxanated covalent organic network (CON) based on the association between the viologen and pillar[5]arene (P[5]OH) units are reported. The mechanical bond allows for the irreversible insertion of n-type redox centers (P[5]OH macrocycles) within a pristine structure based on p-type viologen redox centers. Both redox units are active on a narrow potential range and, in water, the presence of P[5]OH greatly increases the electroactivity of the material.

Remote electrochemical modulation of pKa in a rotaxane by co-conformational allostery.

Allosteric control, one of Nature's most effective ways to regulate functions in biomolecular machinery, involves the transfer of information between distant sites. The mechanistic details of such a transfer are still an object of intensive investigation and debate, and the idea that intramolecular communication could be enabled by dynamic processes is gaining attention as a complement to traditional explanations. Mechanically interlocked molecules, owing to the particular kind of connection between their components and the resulting dynamic behavior, are attractive systems to investigate allosteric mechanisms and exploit them to develop functionalities with artificial species. We show that the pKa of an ammonium site located on the axle component of a [2]rotaxane can be reversibly modulated by changing the affinity of a remote recognition site for the interlocked crown ether ring through electrochemical stimulation. The use of a reversible ternary redox switch enables us to set the pKa to three different values, encompassing more than seven units. Our results demonstrate that in the axle the two sites do not communicate, and that in the rotaxane the transfer of information between them is made possible by the shuttling of the ring, that is, by a dynamic intramolecular process. The investigated coupling of electron- and proton-transfer reactions is reminiscent of the operation of the protein complex I of the respiratory chain.

Photoinduced Electron Transfer Involving a Naphthalimide Chromophore in Switchable and Flexible [2]Rotaxanes.

The interlocking of ring and axle molecular components in rotaxanes provides a way to combine chromophoric, electron-donor and electron-acceptor moieties in the same molecular entity, in order to reproduce the features of photosynthetic reaction centers. To this aim, the photoinduced electron transfer processes involving a 1,8-naphthalimide chromophore, embedded in several rotaxane-based dyads, were investigated by steady-state and time-resolved absorption and luminescence spectroscopic experiments in the 300 fs-10 ns time window. Different rotaxanes built around the dialkylammonium/ dibenzo[24]crown-8 ether supramolecular motif were designed and synthesized to decipher the relevance of key structural factors, such as the chemical deactivation of the ammonium-crown ether recognition, the presence of a secondary site for the ring along the axle, and the covalent functionalization of the macrocycle with a phenothiazine electron donor. Indeed, the conformational freedom of these compounds gives rise to a rich dynamic behavior induced by light and may provide opportunities for investigating and understanding phenomena that take place in complex (bio)molecular architectures.

Selective EPR Detection of Primary Amines in Water with a Calix[6]azacryptand-Based Copper(II) Funnel Complex.

A water-soluble calix[6]arene-based azacryptand was synthesized. The corresponding tren [tris(2-aminoethyl)amine] cap grafted at the small rim coordinates strongly a copper(II) ion over a wide range of pH. The host-guest properties of the complex were explored by EPR spectroscopy. Due to second coordination sphere effects and the hydrophobic effect ascribed to the calixarene cavity, this funnel complex selectively binds neutral molecules (alcohols, nitriles, amines) versus anions in water near physiological pH. Among the coordinating guests, hydrophobic primary amines are preferentially recognized thanks to the combined effect of the better metal-ligand interaction and hydrogen bonding to the oxygen atoms present at the small rim. Hence, this Cu(II) calix[6]arene-based funnel complex behaves as a sensitive and selective EPR probe for primary amines, including biologically important molecules such as tyramine and tryptamine, in water, over a large pH window.

Thermodynamic Insights on a Bistable Acid-Base Switchable Molecular Shuttle with Strongly Shifted Co-conformational Equilibria.

Bistable [2]rotaxanes in which the affinities of the two stations can be reversed form the basis of molecular shuttles. Gaining quantitative information on such rotaxanes in which the ring distribution between the two stations is largely nonsymmetric has proven to be very challenging. Herein, we report on two independent experimental methodologies, based on luminescence lifetime measurements and acid-base titrations, to determine the relative populations of the two co-conformations of a [2]rotaxane. The assays yield convergent results and are sensitive enough to measure an equilibrium constant (K≈4000) out of reach for NMR spectroscopy. We also estimate the ring distribution constant in the switched (deprotonated) state (K'<10-4 ), and report the highest positional efficiency for stimuli-induced shuttling to date (>99.92 %). Finally, our results show that the pKa of the pH-responsive station depends on the ring affinity of the pH-insensitive station, an observation that paves the way for the design of new artificial allosteric systems.

Kinetic and Thermodynamic Stabilization of Metal Complexes by Introverted Coordination in a Calix[6]azacryptand.

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.

Biomimetic cavity-based metal complexes.

The design of biomimetic complexes for the modeling of metallo-enzyme active sites is a fruitful strategy for obtaining fundamental information and a better understanding of the molecular mechanisms at work in Nature's chemistry. The classical strategy for modeling metallo-sites relies on the synthesis of metal complexes with polydentate ligands that mimic the coordination environment encountered in the natural systems. However, it is well recognized that metal ion embedment in the proteic cavity has key roles not only in the recognition events but also in generating transient species and directing their reactivity. Hence, this review focuses on an important aspect common to enzymes, which is the presence of a pocket surrounding the metal ion reactive sites. Through selected examples, the following points are stressed: (i) the design of biomimetic cavity-based complexes, (ii) their corresponding host-guest chemistry, with a special focus on problems related to orientation and exchange mechanisms of the ligand within the host, (iii) cavity effects on the metal ion binding properties, including 1st, 2nd, and 3rd coordination spheres and hydrophobic effects and finally (iv) the impact these factors have on the reactivity of embedded metal ions. Important perspectives lie in the use of this knowledge for the development of selective and sensitive probes, new reactions, and green and efficient catalysts with bio-inspired systems.

Supramolecular assistance for the selective demethylation of calixarene-based receptors.

The selective demethylation of methoxy groups of several multifunctionalized 1,3,5-trimethoxycalix[6]arene-based receptors has been achieved. It is shown in this study that the best reagent is trimethylsilyl iodide (TMSI) and that the conformation adopted by the calixarene core is crucial for both the selectivity and the efficiency of the process. A key feature appears to be the "in" or "out" orientation of the methoxy substituents relative to the macrocyclic cavity. If projected inward, the reaction is slow and not selective. If projected outward, the reaction is fast and selective. A strategy that consists of exploiting the host-guest properties of the receptors to change their conformation and to permit their selective demethylation has been developed. Four cases of such a supramolecular assistance are reported, demonstrating the efficiency of the strategy. Such an allosteric control is highly reminiscent of biological processes allowing selective transformation of multifunctional molecules.

Supramolecular assistance for the selective monofunctionalization of a calix[6]arene tris-carboxylic acid-based receptor.

The selective functionalization of macrocyclic receptors remains extremely challenging because it generally requires the transformation of one and only one functional group among several identical groups. Recently, some of us described that the host-guest properties of a calix[6]arene-based Zn complex could be exploited for its selective monofunctionalization. Herein, we report on the extension of this synthetic strategy to a calix[6]arene-based receptor displaying a different recognition pattern with its guest. More precisely, a calix[6]arene tris-carboxylic acid-based receptor bearing three azido groups at the large rim was selectively monofunctionalized through an intramolecular thermal Huisgen reaction with a hexynNH3(+) ion accommodated into the cavity. This work shows that the monofunctionalization methodology can also be performed efficiently with host-guest systems involving ionic/H-bonding interactions, and it is thus not limited only to the use of metal-ligand interactions. In other words, this supramolecular methodology can be used as a general tool for the selective functionalization of molecular receptors.

A versatile strategy for appending a single functional group to a multifunctional host through host-guest covalent-capture.

Mono-functionalization of a molecular host is a key step for the development of various efficient systems ranging from supramolecular fluorescent probes to supramolecular catalysts. The presence of several identical reactive groups on the host makes its selective mono-functionalization a challenge. We propose a general two-step strategy to achieve this, based on the receptor properties of the host. A guest bearing two orthogonal functions is first reacted with the host presenting itself a reactive function that is complementary to one of those of the guest. As a result, the host is selectively mono-functionalized by the covalent capture of the guest, which inhibits further reaction of the host. The second function that was present on the guest and which is now covalently linked to the host can be activated in the second step for the grafting of various objects. As a proof of concept, the strategy is described on a calix[6]arene scaffold presenting three identical reactive units. Using Huisgen thermal azide-alkyne cycloaddition for the host-guest covalent-capture step, three examples of post-functionalization are described, allowing cavities bearing a single redox tag, fluorescent probe or polydentate ligand through esterification, Schiff base formation or nucleophilic substitution to be obtained.

An induced-fit process through mechanical pivoting of aromatic walls in host-guest chemistry of calix[6]arene aza-cryptands.

The per-ipso-nitration of a TMPA-capped calix[6]arene has been achieved. The substitution of the six bulky tBu substituents for nitro groups has a strong impact on the behavior of the ligand during guest recognition. The complexation of the aza cap (by H(+) or Cu(+)) associated with the encapsulation of a guest triggers an induced-fit process leading to the loss of the cone conformation of the host in favor of alternate conformations. Such a "pivoting" response of one or two walls of the calixarene core induces a large mechanical motion of the corresponding aromatic units. This stands in strong contrast with the "breathing" phenomena previously identified with other calix[6]arene-based complexes that expand or shrink the size of their cone as a function of the guest. Because of the covalently attached rigid TMPA cap, three arene units of this new calixarene host have a restricted mobility, which forces it to respond in a different manner to a supramolecular stress.

Guest covalent capture by a host: a biomimetic strategy for the selective functionalization of a cavity.

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.

Electrochemically driven cup-and-ball CuI and CuII complexes.

The conformation of copper "funnel" complexes that contains a coordinating appended arm can be electrochemically switched between endo, which corresponds to the self-coordination of the arm through the cavity, and exo positions. This process, which is reminiscent of a cup-and-ball device, is activated by an exogenous ligand for complexes that contain a hydroxy-terminated arm. The exchange is electrochemically triggered and is operated in either Cu(I) or Cu(II) redox states, depending on the exogenous ligand, that is, CO or n-butylamine, respectively.

Guest-triggered Zn(II) 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.

Novel pyrene-calix[4]arene derivatives as highly sensitive sensors for nucleotides, DNA and RNA.

Covalent functionalization of a calix[4]arene with one or two pyrene arms at one rim and two imidazoles at the opposite rim of the macrocyclic basket, yields fluorescent conjugates characterized by intramolecular pyrene-calixarene exciplex emission of a mono-pyrene conjugate, whereas the bis-pyrene derivative exhibits pyrene excimer fluorescence. The pyrene emission in these novel compounds is shown to be sensitive to non-covalent interactions with both mono- and polynucleotides. Pyrene-calixarene conjugates, acting as host molecules, strongly interact with nucleotides, as monitored by moderate emission quenching, reaching 0.1 µM affinities, comparable to some of the most effective supramolecular sensors for nucleotides. These compounds are efficiently inserted into ds-DNA/RNA grooves, with a high, 0.1-1 µM affinity, not influencing significantly any of the ds-polynucleotide native properties, whereby complete emission quenching allows the detection of DNA at nM concentration.

Ipso-Nitration of calix[6]azacryptands: intriguing effect of the small rim capping pattern on the large rim substitution selectivity.

The ipso-nitration of calix[6]arene-based molecular receptors is a important synthetic pathway for the elaboration of more sophisticated systems. This reaction has been studied for a variety of capped calixarenes, and a general trend for the regioselective nitration of three aromatic units out of six in moderate to high yield has been observed. This selectivity is, in part, attributed to the electronic connection between the protonated cap at the small rim and the reactive sites at the large rim. In addition, this work highlights the fact that subtle conformational properties can drastically influence the outcome of this reaction.

Supramolecular control of hetero-multinuclear polytopic binding of metal ions (Zn(II), Cu(I)) 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)).