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Calix[6]arenes disubstituted at the methylene bridges, which are stable in the cone or 1, 2, 3- alternate conformation, form pseudorotaxanes with dialkylammonium axles. The cone-wheel based pseudorotaxanes are 10-100 times more stable than those obtained with the native conformationally- mobile calix[6]arene wheel, as a consequence of their higher degree of preorganization. The threading of conformationally stable 1, 2, 3- alternate-calix[6]arenes is unprecedented in the literature. Therefore, very peculiar NMR features are here evidenced for this threading process involving the less symmetrical 1, 2, 3-alternate calix[6]arene conformation, which implies a peculiar rototranslation motion of the axle.

The development of synthetic molecular receptors that can selectively bind anions, translocate them through a lipidic bilayer membrane and release them on the other side is a very topical and emerging field of supramolecular chemistry, warranted by the biological importance of transmembrane anion transport.The first part of this thesis is devoted to the study of the transmembrane transport of chloride and of the organic ion pair propylammonium chloride with calix[6]arene receptors functionalized with three (thio)urea arms on their small rim. The transport of chloride across the lipid bilayer of liposomes was monitored by fluorescence spectroscopy using the lucigenin assay. We report the first example of calix[6]arenes able to act as mobile carrier for the transport of chloride via a Cl-/NO3- antiport. We furthermore show that our calixarene systems are able to perform the cotransport of propylammonium chloride, with the chloride bound at the level of the (thio)urea groups and the ammonium included in the calixarene cavity. To provide direct proof of cotransport, we developed a 1H NMR methodology involving a thulium- complex shift reagent with which we were able to distinguish the signals of the ammonium transported inside the liposomes from those of the external ammonium. We also highlight the role of the complexing calixarene cavity for the cotransport by comparing the calixarenes to known transporters deprived of a cavity. The transmembrane transport organic ion pairs could find applications in the transport of biologically relevant ammonium compounds such as catecholamines and amino acids. Our results are reported in the publication “Repositioning Chloride Transmembrane Transporters: Transport of Organic Ion Pairs” Grauwels, G. Valkenier, H. Davis, A. P. Jabin, I. Bartik, K. Angew. Chemie - Int. Ed. 2019, 58, 6921–6925.The second part of this thesis is devoted to the study of binding of chloride to receptors embedded in a lipid membrane, the first step of the transmembrane transport process. Both 1H and 31P NMR spectroscopy proved to be inadequate to study the binding using liposomes or micelles as model membranes. With liposomes, the NMR signals are too broad to be exploited and in the case of micelles, the competition between the lipid headgroups and chloride made it impossible to obtain a NMR signature which unambiguously characterizes chloride binding. The 35Cl NMR signal is on the other hand strongly affected by the presence of anion receptors, both in organic solvents and when incorporated lipid bilayers. We developed a methodology to evaluate the binding of chloride, based on the monitoring of the chloride linewidth during titration experiments. A linear relationship between the linewidth and the concentration of receptors is observed and the slopes can be exploited to compare the binding strengths of different structurally related receptors. We show that 35/37Cl NMR is a versatile tool which can help in the understanding and development of new transporters by providing new insights of the physicochemical understanding of the transport process., Doctorat en Sciences de l'ingénieur et technologie, info:eu-repo/semantics/nonPublished

This PhD thesis describes the design, the synthesis and the characterization of calix[6]arene-based molecular machine prototypes, and the study of their dynamic properties triggered by external stimulation. Initially, the ability of a calix[6]arene wheel to increase the rate of a nucleophilic substitution reaction on a complexed guest was demonstrated, and by virtue of these results a new supramolecularly assisted strategy for the synthesis of oriented rotaxanes was set up. Then, the properties of new hydroxy- and bis(N-phenylureido)-calix[6]arene derivatives were steered, and the effects of the structural modification of the different macrocycle’s domains were evaluated. The ability of calix[6]arenes to form oriented complexes with dialkylviologen-based axles was then exploited for the synthesis of single and double station constitutionally isomeric rotaxanes, whose ability to behave as molecular level shuttles was proved. Moreover, the design, the synthesis and the characterization of an oriented calix[6]arene-based catenane, and the study of its electrochemical and dynamic properties were developed. As last part of this thesis, the study of possible synthetic pathways towards the synthesis of oriented calix[6]arene-based dimers and containers is reported.

Synthetic molecular receptors find applications in the selective extraction, transport and detection of neutral or charged species and the study of these systems is an important facet of supramolecular chemistry. In this thesis, we focused our attention on a specific family of molecular receptors called calix[6]arenes. These receptors possess a hydrophobic cavity formed by 6 aromatic rings that can accommodate small organic molecules. They can furthermore be easily functionalized and give rise to for example ditopic receptors or sensing systems. We worked with two families of calix[6]arenes but also looked at the complexation properties of some related compounds: a homooxacalix[3]arene and a resorcin[4]arene derivatives. The first part of this thesis is devoted to the study of the complexation properties of a fluorescent calix[6]tris-pyrenylurea. The binding of anions, ion pairs, ion triads and phospholipids was monitored by 1H Nuclear Magnetic Resonance (NMR) and Emission Spectroscopy. Our results showed that the receptor exhibits a remarkable selectivity for the sulfate anion in DMSO for which a binding constant of the order of 103 M-1 was found. In chloroform the affinity for sulfate is of the order of 105 M-1 and the selective recognition of ammonium-TBASO4 triads was observed (TBA = tetra-n-butylammonium; ammonium = PrNH3+, HexNH3+ or DodNH3+). This work has been reported in the paper “Fluorescent Chemosensors for Anions and Contact Ion Pairs with a Cavity-Based Selectivity” Emilio Brunetti, Jean-François Picron, Karolina Flidrova, Gilles Bruylants, Kristin Bartik and Ivan Jabin J. Org. Chem. 2014, 79, 6179–6188. We also showed that calix[6]tris-pyrenylurea displays a remarkable selectivity in chloroform for phospholipids bearing a phosphatidylcholine head (PCs) over those bearing a phosphoethanolamine head (PEs). We were able to show that this fluorescent receptor is able to extract PCs from a water solution enabling their quantification. This work has been reported in the paper “A Selective Calix[6]arene-based Fluorescent Chemosensor for Phosphatidylcholine Type Lipids” Emilio Brunetti, Steven Moerkerke, Johan Wouters, Kristin Bartik and Ivan Jabin Org. Biomol. Chem. 2016. Accepted Manuscript. DOI: 10.1039/C6OB01880G.The second part of this thesis is devoted to the evaluation of the binding properties of different receptors incorporated into dodecylphosphocholine (DPC) micelles. This strategy was used to make the hydrophobic molecular receptors “water-compatible” without having to undertake synthetic modifications. Our results showed that a calix[6]azacryptand-based receptor can be incorporated into DPC micelles, either as a zinc complex or as a polyammonium at low pH. We observed that the zinc complex incorporated in the micelles is able to bind small and long linear primary amines in its cavity and we were able to highlight that complexation is driven by the hydrophobic effect. This work has been reported in the paper “Primary Amine Recognition in Water by a Calix[6]aza-cryptand Incorporated in Dodecylphosphocholine Micelles” Emilio Brunetti, Alex Inthasot, Flore Keymeulen, Olivia Reinaud, Ivan Jabin and Kristin Bartik Org. Biomol. Chem. 2015, 13, 2931-2938.We also validated the micellar incorporation strategy with a homooxacalix[3]tris-acid and with a resorcin[4]arene zinc complex bearing four methyl-imidazole moieties. Once incorporated into DPC micelles, we showed that the two receptors can bind small organic guests: the homooxacalix[3]arene derivative can bind tert-butylammonium or adamantylammonium, albeit with low affinity and the resorcin[4]arene-based zinc complex can bind acetate and acetylacetone.The final part of this thesis is devoted to the work undertaken in order to try and elucidate the guest exchange mechanism of calix[6]arene-zinc complexes where the zinc is tri-coordinated to the calixarene-based ligand and coordinates a guest molecule inside the calixarene cavity. The hypothesis that we put forward is that when the zinc is only tri-coordinated to the calixarene ligand, the guest exchange mechanism involves a zinc penta-coordinated intermediate where the zinc atom is simultaneous coordinated to an endo-complexed guest (inside the cavity) and an exo-complexed molecule (outside the cavity). 1D EXchange SpectroscopY experiments (EXSY) were undertaken with two calix[6]arene-zinc complexes where the zinc is tri-coordinated to the calixarene ligand and with a calix[6]arene-zinc complex where the zinc is tetra-coordinated to the calixarene ligand. The exchange of different guests (ethanol, dimethylformamide and acetonitrile) was monitored in deuterated dichloromethane. We observed that in all cases water accelerates guest exchange but that the guest residence times are highly dependent on the acidity of the metal center and on the nature of the guest buried inside the cavity., Doctorat en Sciences de l'ingénieur et technologie, info:eu-repo/semantics/nonPublished

This Ph.D. thesis describes the synthesis, characterization and study of calix[6]arene derivatives as pivotal components for the construction of molecular machine prototypes. Initially, the ability of a calix[6]arene wheel to supramolecularly assist and increase the rate of a nucleophilic substitution reaction was exploited for the synthesis of two constitutionally isomeric oriented rotaxanes. Then, the synthesis and characterization of several hetero-functionalised calix[6]arene derivatives and the possibility to obtain molecular muscle prototypes was reported. The ability of calix[6]arenes to form oriented pseudorotaxane towards dialkyl viologen axles was then exploited for the synthesis of two calixarene-based [2]catenanes. As last part of this thesis, studies on the electrochemical response of the threading-dethreading process of calix[6]arene-based pseudorotaxanes and rotaxanes supported on glassy carbon electrodes are reported.

Riassunto Questo lavoro di tesi di Dottorato descrive uno studio per lo sviluppo di devices in grado di rispondere a stimoli esterni basati su sistemi pseudorotaxanici e rotaxanici a base calix[6]arenica. Inizialmente sono stati investigati i parametri the guidano l’orientazione e la direzione del processo di infilamento di assi asimmetrici nella ruota calix[6]arenica attraverso studi di tipo cinetico e termodinamico. Inseguito i risultati ottenuti sono stati trasferiti per promuovere un transito unidirezionale di un asse viologeno attraverso la cavità calixarenica. L’asimmetria del recettore calix[6]arenico è stata poi sfruttata per modificare le proprietà chimiche di un legante terpiridinico in sistemi pseudorotaxanici e rotaxanici. Come ultima parte di questa tesi viene riportata la sintesi e lo studio di nuovi recettori anfifilici a base calix[6]arenica in grado di generare strutture 3D in soluzione acquosa. Abstract This Ph.D. thesis describes a study on the development of stimuli-responsive devices based on calix[6]arene-based rotaxanes and pseudorotaxanes. Initially the parameters responsible for the orientation and direction of asymmetric axles threading into the calix[6]arene wheel were investigated through kinetic and thermodynamic studies. Then the results were transferred to achieve the unidirectional transit of a viologen axle through the wheel cavity. The asymmetry of the calix[6]arene receptor has been then exploited to modify the chemical properties of a terpyridinic ligand in a pseudorotaxane and rotaxane system. As last part of this thesis the syntheses and studies of new amphiphilic calix[6]arene receptors, able to form 3D self-assembled structure in water are reported.

Solvent polymeric membrane electrodes incorporating p-t-butyl hexaethyl ester and hexaethyl ester calix[6 ]arene as neutral carriers have been constructed for use in caesium selective electrodes. The potentiometric sensing electrodes including 2-nitrophenyloctyl ether as solvent mediator exhibit near-Nernstian behaviour in the range 1x10 M to 1x10 M CsCl. The pattern of selectivity encountered for a range of common interferents is not modified by the inclusion of potassium tetrakis(p-ch!orophenyl)borate as ion-exchanger in the case of the hexaethyl ester although some improvement in sensitivity is obtained in the case of the hexaethyl ester. The hexaethyl ester is superior with respect to rubidium and potassium selectivities, with the coefficients being of the order of 3x10 and 2.7x10 respectively. Both electrodes are relatively stable and responses are essentially complete within seconds. Different types of sodium electrodes have also been constructed using twomeric calixarene ionophores, namely methyl p-t-butylcalix[4]aryl acetate and the methyl tetraketone derivative of p-t-butylcalix[4]arene. The selectivity of both electrodes is similar although discrimination against ammonium ions is improved by a factor of ten in the case of the methyl tetraketone based electrode. The selectivities against lithium, potassium and hydrogen ions are improved in comparison to other commercially available ionophores. Response times, stability, reproducibility and life time characteristics agree well with the requirements made of these devices for clinical applications. On the assessment of a large number of blood plasma samples, the methyl ester tetrameric based electrode exhibits excellent correlation when compared to two hospital based auto-analysers and to flame photometry. The residual standard deviation is typically within 1 to 3 mmol/1 and highly influenced by the dipping method employed for the determination. Optimisation of the selective membrane in the case of methyl tetraketone based electrodes also give excellent results for the analysis of sodium in plasma samples, although in this case correlation with the above mentioned reference methods is higher and the residual standard deviation is lower. The incorporation of the methyl ester calix[4]arene electrode in a flow injection system has proven advantageous in improving both precision and accuracy in comparison to the dipping technique. Solid-state monomeric and polymeric calixarene based electrodes have been constructed and found to exhibit promising features to varying degrees. Thus, platinum coated electrodes based on the methyl tetraketone calix[4]arene gave similar performance to the conventional sort in terms of Nernstian response, selectivity and response time, although the electrodes are less stable. Another chemically modified tetrameric calixarene (monomer VI) has been found to be responsive to potassium ions. Copolymerisation of two monomeric calixarenes with methyl methacrylate carried out have led to non-responsive electrodes while other polymers exhibited sub-Nernstian slopes to sodium and caesium. Amperometric studies have been also carried out to assess the voltammetric behaviour of pipemidic acid. The drug has been investigated by linear sweep, differential pulse and square wave voltammetry at a hanging mercury drop electrode. Two reduction processes were observed in Britton-Robinson buffer in acidic solutions, whereas only one or two processes were observed in alkaline solutions, depending on the pH of the b u ffer employed. Adsorptive effects have been used to accumulate the drug onto the electrode and linear calibration graphs were obtained in the range 2.5x10 to 1x10" M. A simple procedure of extraction has been employed for the determination of pipemidic acid in urine samples.