Apresentamos uma série de estudos, baseados em simulações de Dinâmica Molecular no vácuo e em solução, sobre o processo de complexação das supramoléculas tetraethylester p-tert-butyl calix[4]arene (CLE) e tetramethylketone p-tert-butyl calix[4]arene (CLC) com os íons Pb2+ e Cd2+ e espécies neutras. Os modelos para as moléculas de calixareno e do solvente foram baseados no campo de forças OPLS-AA. Os parâmetros para os íons foram desenvolvidos a partir de uma metodologia de ajuste de valores de modo a reproduzirem simultaneamente propriedades termodinâmicas e estruturais obtidas experimentalmente ou por cálculos de QM/MM. As simulações no estado líquido nos mostraram que o CLE aprisiona os íons de maneira mais eficiente que o CLC, formando complexos mais estáveis. A complexação do íon desencadeia um efeito alostérico em ambos os calixarenos estudados, permitindo a complexação de uma molécula de acetonitrila na cavidade hidrofóbica estabilizando o complexo. Nas simulações com o CLC observamos que a complexação da acetonitrila é necessária para manter o íon ligado à cavidade hidrofílica, evidenciando a dependência desses complexos com esse solvente em específico. Apesar de observarmos que o CLE apresenta maior afinidade com os íons Pb2+ e Cd2+ que o CLC, somente futuras simulações utilizando a água como solvente poderão confirmar a viabilidade do uso desta molécula em sistemas destinados à despoluição ambiental. / We report a series of Molecular Dynamics simulations, in vacuum and in acetonitrile solution, on the complexation process of the calixarens tetraethylester p-tert-butyl calix[4]arene (CLE) and tetramethylketone p-tert-butyl calix[4]arene (CLC) with Pb2+ and Cd2+ anions and neutral species. The solvent and calixarene molecules were modeled based on the OPLS-AA force field. The parameters for the ions were adjusted to simultaneously reproduce some structural and thermodynamic properties obtained either experimentally or from QM/MM calculations. The simulations in the liquid phase show CLE to be more efficient than CLC in trapping the studied metal ions, leading to more stable complexes. Ion complexation gives rise to an allosteric effect by which a solvent molecule is trapped in the hydrophobic cavity giving rise to further stabilization of the complex. Simulations on CLC show that formation of the calixarene-acetonitrile adduct is essential to the stabilization of the ionic complex, thus exhibiting the influence of this particular solvent in the very existence of the complex. In spite of the conclusion that CLE has higher affinity than CLC for Pb2+ and Cd2+ ions, only further studies in water solution will permit to evaluate the real potential of this molecule as an efficient scavenger of environmental heavy metal pollution.

Made available in DSpace on 2014-10-09T12:26:22Z (GMT). No. of bitstreams: 0 / Made available in DSpace on 2014-10-09T14:04:32Z (GMT). No. of bitstreams: 0 / Este trabalho apresenta um estudo sobre a síntese e caracterização de novos agentes extratores da família dos calixarenos, utilizados com a técnica de membranas líquido suportadas para recuperar íons Eu(III) e U(VI) de efluentes aquosos. Os novos agentes extratores, os n-acetatocalix[n]arenos ( n= 4, 6 e 8), foram obtidos a partir da reação de acetilação dos p-terc-butilcalix[n]arenos (n = 4, 6 e 8) com anidrido acético e caracterizados por: análise elementar de CHN, espectroscopia vibracional na região do infravermelho, espectroscopia de absorção na região do UV-Vis, ressonância magnética nuclear RMN 1H, análise termogravimétrica e testes de solubilidade. Os compostos obtidos foram usados em estudos de distribuição líquido-líquido e também na técnica de membranas líquido suportadas (MLS), utilizando suportes poliméricos de 0,45, 1,2 e 5 m. A partir dos resultados da análise de caracterização verificou-se a funcionalização dos calixarenos. Tanto os calixarenos não funcionalizados quanto os funcionalizados mostraram-se bastante efetivos para extração de íons Eu(III) e U(VI). Da análise dos resultados concluiu-se que: a eficiência de extração é dependente do pH. Para íons Eu(III) a máxima eficiência de extração foi alcançada em pH 4 e 5 e para o U(VI) em pH 7. Os solventes utilizados, tolueno e clorofórmio, mostraram-se bastante eficazes no processo de extração já que os dois tiveram eficiência de extração bastante próxima. Nos estudos de extração utilizando a técnica de membranas líquido suportadas (MLS) os resultados mostraram que a permeação dos íons Eu(III) e U(VI) é dependente do pH, da concentração dos metais e da concentração de NaNO3 na solução de alimentação, da porosidade da membrana e da concentração do HNO3 na solução de reversão. / Tese (Doutoramento) / IPEN/T / Instituto de Pesquisas Energeticas e Nucleares - IPEN-CNEN/SP

M.Sc. / The contamination of water by toxic compounds is one of the most serious environmental problems today. These toxic compounds mostly originate from industrial effluents, agriculture runoff, natural sources (e.g. heavy metals in water from rocks and soil erosion) and human waste. The contamination, which is both “organic” and “inorganic” has an impact on the environment and human health. The demand for water and the pressure to re-use this valuable resource has increased the need for improved techniques and materials to remove pollutants from water. The Nanomaterials Science research group at the University of Johannesburg has focused on developing synthetic polymers that can be employed in water treatment and pollutant monitoring. Recently, cyclodextrins (CD) and carbon nanotubes (CNTs) have been included in polymers for this application. For example, CD-co-hexamethylene-/toluene-diisocyanate polyurethanes and CNT-modified equivalents have been developed and have been successfully applied in removing organic contaminants from water to very low levels.1 Calixarenes are synthetic analogues of cyclodextrins that can be exploited via chemical modification to express a range of properties. In the present study, calixarenes, thiacalixarenes and carbon nanotube-based polymeric materials incorporating these molecules have been synthesised, characterised and tested for removing both organic pollutants (such as p-nitrophenol) and inorganic pollutants (Cd2+, Pb2+) from water. Lead(II) and Cadmium(II) are a threat in South Africa because of their toxicity, and while p-nitrophenol is much less of a problem it represents a useful model organic pollutant. The absorption capacity of the polymers towards heavy metals and organic contaminants was tested by mixing the polymer with synthetic water containing known concentration of the contaminants at about 10 mg/L. Atomic absorption spectrometry (AAS) and ultraviolet-visible spectrometry (UV-vis) were used to determine the levels of heavy metals and organic contaminants, respectively. The target pollutants (Cd2+, 1 see KL Salipira MTech dissertation, University of Johannesburg 2008 Pb2+ and p-nitrophenol) were all successfully removed from water by the various polymers, however the degree of removal and loading capacities of the polymers differed. This information gives some insight into what functional components are needed for making successful adsorbents. It was observed, for example, that ptert- butylcalix[8]arene/hexamethylene diisocyanate (C8A/HMDI) had a higher adsorption capacity towards p-nitrophenol and Pb2+ than towards Cd2+, and also a higher capacity than the corresponding calix[4]arene polymers with smaller calixarene cavities.

Les travaux de thèse ont porté sur l'étude de la complexation de métaux lourds par des molécules supramoléculaires qui offrent un moyen facile de détection de ces polluants qui présentent un caractère de toxicité élevé (mercure, plomb, cadmium…..) et sont des polluants des eaux courants. Le durcissement des réglementations concernant les seuils admissibles de polluants nécessite la mise au point de moyens de détection sensibles et de mise en œuvre facile associée à un coût réduit. L’étude est basée sur une famille de calixarènes modifiés par un groupe azoïque qui permet une détection visuelle directe de la présence de métaux lourds par un changement de couleur. Une première étape a porté sur la caractérisation des changements de propriétés optiques (couleur: absorption optique, mais aussi fluorescence) induite par l'ajout des cations métalliques à une solution des calixarènes qui a permis de valider la pertinence du protocole expérimental. Une deuxième étape a porté sur la réalisation des couches minces de calixarènes sur un support pour la réalisation de capteurs optiques. La possibilité de détection en phase dense a pu être démontrée. La détection par fluorescence des sondes calixarènes s'est avérée particulièrement intéressante pour le développement de capteurs chimiques parce que d'une part le signal est bien isolé et d'autres part en raison de la grande sensibilité de cette réponse. La troisième étape a porté sur la réalisation et l'optimisation d’un capteur chimique à réponse optique. Deux types de récepteurs calixarènes aptes à détecter des polluants, révélés par un changement de couleur caractéristique lors d’une simple immersion dans une eau à analyser, ont ainsi pu être sélectionnés / The thesis focused on the study of the complexation of heavy metals by supramolecular that provide an easy way of detecting these pollutants of a high toxicity (mercury, lead, cadmium ...). The tightening of regulations on allowable levels of pollutants requires the development of sensitive detection means and easy implementation associated with a reduced cost. The study is based on a family of calixarenes modified with an azo group which allows direct visual detection of the presence of heavy metals by a color change. The first phase focused on the characterization of changes in optical properties (color: optical absorption, but also fluorescence) induced by the addition of metal cations to a solution of calixarenes which validate the relevance of the experimental protocol. A second stage involved the realization of thin film on a support of calixarenes for producing optical sensors. The possibility of detecting dense phase has been demonstrated. Fluorescence detection probes calixarenes was particularly interesting for the development of chemical sensors because on the one hand the signal is isolated and on the other hand due to the high sensitivity of this response. The third stage involved the implementation and optimization of a chemical sensor optical response. Two types of receptors calixarenes able to detect pollutants, revealed by a characteristic color change in a simple immersion in a water sample, were able to be selected

En raison de leur résistance aux agents chimiothérapeutiques, les transporteurs ABC de phénotype MDR ont attiré l'attention de la communauté scientifique. Notre projet vise à trouver des conditions dans lesquelles les transporteurs ABC restent fonctionnels en solution pour aboutir à la cristallisation de ces protéines dans une conformation active. Dans ce but, nous avons conçu et développé une nouvelle classe de détergents, à base de calix[4]arène, qui stabilisent ces protéines. Afin de résoudre la structure 3D à résolution atomique du transporteur ABC bactérien "BmrA", responsable de la résistance aux antibiotiques, nous avons utilisé une approche classique utilisant des détergents commerciaux en parallèle à nos détergents innovants. En présence de la Foscholine 12, nous avons obtenu des cristaux diffractant jusqu’à 5 Å de résolution. Cependant, les données de diffraction n’étaient pas suffisantes pour déterminer la structure tridimensionnelle complète de la protéine, seuls les domaines transmembranaires ont été résolus. D'autre part, nous avons atteint l'objectif de l'extraction, la purification et la stabilisation de ce transporteur à l'aide des détergents à base de calix [4] arène. Nous avons également montré que ces détergents promeuvent et améliorent la cinétique de cristallisation de BmrA, une étape que nous sommes en train d’optimiser, pour obtenir des cristaux de meilleure résolution, pour résoudre la structure 3D de BmrA qui sera utilisé pour concevoir des inhibiteurs adaptés / Due to their preponderance in the resistance to chemotherapies, the MDR ABC transporters have drawn the attention of the scientific community. Our project aimed at finding conditions in which ABC transporters are active in solution to lead the crystallization of these proteins in an active conformation. In this purpose, we conceived and developed a new class of detergents, based on calix[4]arene ring, that stabilize these proteins. In order to solve the 3D-structure to atomic resolution of bacterial ABC transporter “BmrA” responsible for antibiotic resistance, we used a classical approach with commercial detergents in addition to the innovative ones. We have crystallized the protein in presence of Foscholine 12 with a diffraction resolution up to 5 Å. The data was incomplete; solving partially the structure of the transmembrane domains. On the other hand, we have reached the objective of extraction, purification and stabilization of this transporter by using calix[4]arene-based detergents. We have also shown that these detergents promote and enhance the kinetics of crystallization of BmrA, a step that we are improving, to get crystals of better resolution, for resolving the BmrA 3D-structure which will be used to design adapted inhibitors

Le travail suivant est consacré d'une part à l'emploi du calix[4]arène comme une plate-forme organisatrice de principes actifs pour la conception de nouvelles prodrogues. Ce concept a été développé avec des substances antibactériennes ou antivirales, choisies comme modèles. Les conjugués calixarène - anti-infectieux ainsi synthétisés sont amphiphiles et insolubles dans l'eau. Leur comportement interfacial a été étudié via l'interface eau-air, mime d'une interface hydrophile-hydrophobe physiologique, à l'aide de la technique des films monomoléculaires de Langmuir. Nos résultats indiquent que ces prodrogues étalées à l'interface eau-air peuvent libérer leurs principes actifs dans la sous-phase. La méthodologie développée pour ces études de réactivité interfaciale pourrait à l'avenir être appliquée à d'autres prodrogues à base de calix[4]arène. Un second projet a concerné le trifluoroacétate de tétra-p-(guanidinoéthyl)-calix[4]arène (CX1). Ce composé présente des propriétés antibactériennes à large spectre, couplées à une faible toxicité cellulaire. Nos travaux ont visé à mieux comprendre son mode d'action, lié à une perturbation des parois bactériennes, par une approche physico-chimique. La technique de Langmuir a donc été employée afin d'étudier les interactions entre le CX1 et des films monomoléculaires de phospholipides étalés à l'interface eau-air, utilisés comme modèles de membrane bactérienne. Nos résultats nous ont permis de proposer un mode d'organisation des membranes bactériennes sous l'influence du CX1. Nous avons ainsi apporté des précisions sur son mécanisme d'action qui pourraient être utiles dans le développement de nouveaux calixarènes antibactériens / This work begins with utilization of the calix[4]arene macrocycle as organizing platform of anti-infectious molecules shaped as prodrug. The concept has been explored using antibacterial (nalidixic acid) and antiviral (aciclovir, ganciclovir) molecules, chosen as models. The calixarene - anti-infectious conjugates synthesized have amphiphilic structure and are insoluble in aqueous media. Their interfacial behavior was studied via the air-water interface, considered as mimic of biological hydrophilic-hydrophobic interfaces, using Langmuir monolayers technique. Our results indicate that calixarene-based prodrugs spread at the air-water interface are able to release anti-infectious molecules into the subphase. The original methodology employed for interfacial reactivity studies could be applied to further calixarene-based prodrugs. A second project concerns the trifluoroacetate salt of tetra-p-(guanidinoethyl)-calix[4]arene (CX1). CX1 is antibacterial, active against various Gram-positive and Gram-negative bacteria, with low eukaryotic cell toxicity. The aim of our work was to get more insight in the mechanism of action of CX1, involving bacterial wall disruption, by a physico-chemical approach. The Langmuir monolayers technique was employed in order to study interactions between CX1 and phospholipid monolayers spread at the air-water interface, used as models of bacterial membranes. Our results led us to propose a particular reorganization mode of bacterial membranes upon interactions with CX1. This proposal gives more understanding in the mechanism of biological activity of CX1, and could be helpful in developing new antibacterial calixarene derivatives

This thesis covers combination of two independent works accomplished throughout the study. One part research is about the unexpected cyclization of Dipyridyl-glycoluril, and the other part is about synthesis of precursor calix[4]arene derivatives. In an attempted synthesis of peripherally pyridine substituted cucurbituril, an unexpected cyclized product was obtained. A careful NMR analysis followed by mass spectrometry and preliminary crystallographic analyses, helped us in resolving the structure. The structure has two quaternized pyridine functionalities and a groove suitable as a potential receptor site. In addition, just like the parent glycoluril structure, two remaining urea-derived nitrogens can be alkylated by alkyl halides. Thus, we believe this high yielding reaction may become an entry point to a new class of anion receptors. In the second work, certain important calix[4]arene derivatives were synthesized. They are the building blocks of important potential molecular, anion and cation sensing, and enzyme mimics. For these precursor molecules, functionalizations both on lower and upper rim have been studied. A careful study on NMR data has been performed and detailed investigation on the NMR data was discussed herein. Applying further one or two step procedures produces important target molecules having potential as sensors or artificial enzymes.

[Truncated abstract] The scientific endeavours described within this thesis attempt to create novel solutions to current scientific, commercial and industrial downfalls, and contribute to the advancement of technologies in these areas. This has been achieved through the application of theoretical and experimental principles, entrenched in the domains of chemistry and physics, which have been harnessed to assist in the transformation from nanoscience to nanotechnology. These solutions range from unique supramolecular systems capable of selective-diameter enrichment of single-walled carbon nanotubes (SWCNTs), to the fabrication of low-cost, potentially remote deployable carbon nanotube-based gas and vapour sensors, and expand right through to the development of water-soluble fluoroionophoric sensors and manipulations of a molecular form of carbon in constructing all-carbon nano-architectures. For the advancement and successful integration of carbon nanotubes (CNTs) into commercial processes, the advent of scalable separation protocols based on their electronic properties is required. SWCNTs have been successfully solubilised using water-soluble p-phosphonated calix[n]arenes (n = 4, 6, 8) and 'extended arm' upper rim functionalised (benzyl, phenyl) p-sulfonated calix[8]arenes. Selective SWCNT diameter solubilisation has been demonstrated and subsequent preferential enrichment of SWCNTs with semiconducting or metallic electronic properties has been achieved. In addition, semiconducting nanotube-enriched supernatants (liquid) have been utilised to fabricate on/off field effect transistors (FET). These water-soluble supramolecular systems can be incorporated into post-growth purification protocols, with direct implications in areas such as carbon nano-electronics and device fabrication. In the current global environment there is a heightened level of public and governmental disquiet due to the reality of impending terrorist attacks. This is compounded by the inherent ease of manufacture and effectiveness of specific chemical warfare agents (CWAs) used in small-scale terrorist operations. ... Additional all-carbon structures are described with the formation of rings of helical SWCNT bundles through post-growth SWCNT modifications, and a variety of fibrous all-carbon structures, most notably novel square-geometry carbon nano-fibres (CNFs), through catalytic-chemical vapour deposition (C-CVD) synthesis strategies. The current requirement for entirely water-soluble fluorescent sensors is routinely documented in the literature. The autofluorescence properties of p-phenyl-sulfonated calix[8]arene are characterised and this water-soluble cavitand is surveyed as a metal cation sensor candidate. This particular system was found to exhibit a change in fluorescence response when exposed to divalent metal cations, and interactions with [UO2]2+, Pb2+, Co2+, and Cu2+ ions are discussed in detail. The system is characterised through a variety of analytical techniques to yield sensor calibration data, degradation characteristics, pH sensitivity and suitability as a 'small molecule' drug-carrier.

No description available.

La chimie supramoléculaire est un domaine qui porte sur l’étude des interactions<p>faibles entre molécules. Ces interactions sont très répandues dans les systèmes naturels et de<p>nombreux récepteurs moléculaires synthétiques ont été développés, soit pour un apport<p>théorique à la compréhension de ces processus de reconnaissance, soit pour d’éventuelles<p>applications en biologie ou en chimie analytique par exemple.<p>Les calix[6]arènes sont des composés intéressants pour la reconnaissance moléculaire.<p>Ils possèdent une cavité idéale pour l’inclusion de petites molécules et peuvent être modifiés<p>par l’ajout de divers motifs de reconnaissance. Le premier calix[6]crypturée préalablement<p>étudié au sein du Laboratoire de Chimie Organique est un récepteur dont la cavité aromatique<p>est juxtaposée à un motif de reconnaissance pour anions. Ce dernier est composé d’un<p>chapeau à base de tren (tris(2-aminoéthyl)amine) portant trois groupes urée. Ce récepteur<p>possède notamment une forte sélectivité pour le chlorure et une forte affinité pour les paires<p>d’ions organiques de type chlorure d’ammonium, dans un solvant apolaire (CDCl3).<p>Cependant, ces propriétés de reconnaissance sont beaucoup plus limitées dans un solvant<p>protique (CD3OD), ce qui restreint les éventuelles applications. L’objectif de ces travaux a été<p>de synthétiser de nouveaux dérivés avec une modification autour du site tris-urée pour<p>renforcer les propriétés de reconnaissance, notamment en milieu protique.<p>La première stratégie a consisté à agrandir le chapeau cryptant reliant les trois groupes<p>urée. Trois modes différents de complexation d’ammonium intra-cavitaire ont été mis en<p>évidence dans un solvant apolaire, dont deux sont remarquables. Avec un anion peu<p>coordinant (le picrate), le récepteur protoné inclut l’ammonium selon un processus<p>allostérique pour donner un complexe dicationique. Avec la protonation du récepteur et un<p>anion dichargé (SO4<p>2-), l’inclusion de l’ammonium constitue un complexe cascade, stable en<p>milieu protique.<p>La deuxième stratégie a consisté à supprimer les groupes méthyle du petit col<p>calixarénique via une réaction de déméthylation sélective pour obtenir le calix[6]crypturée<p>1,3,5-trishydroxyle. Dans un solvant apolaire, ce récepteur a montré une plus forte sélectivité<p>pour la complexation de paires d’ions par rapport à la complexation d’anions, permettant par<p>exemple de complexer le chlorhydrate de O,O-diméthyldopamine.<p>La troisième stratégie a été de synthétiser le calix[6]cryptothiourée, un récepteur dont<p>le chapeau comporte trois groupes thiourée. Cette modification structurale a fortement<p>renforcé la complexation d’anions mais n’a pas favorisé la complexation de paires d’ions dans<p>un solvant protique.<p>Enfin, la complexation de zwittérions a été testée sur l’ensemble de ces récepteurs et le<p>calix[6]cryptothiourée s’est avéré être un remarquable complexant de la B-alanine bétaïne.<p>Dans un mélange protique (CD3OD/CDCl3 1:1) la constante d’association est élevée (K ≈ 104<p>M-1) et supérieure d’au moins trois ordres de grandeur par rapport aux autres zwittérions<p>testés. C’est à notre connaissance un des rares récepteurs de bétaïnes et le premier à être<p>sélectif pour la B-alanine bétaïne. Enfin, le biomimétisme du mode de reconnaissance a été<p>montré par comparaison avec une protéine transporteur de bétaïne (Corynebacterium<p>glutamicum). / Doctorat en sciences, Spécialisation chimie / info:eu-repo/semantics/nonPublished