Orientador: Claudio Francisco Tormena / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Química / Made available in DSpace on 2018-08-26T02:29:08Z (GMT). No. of bitstreams: 1 Favaro_DenizeCristina_D.pdf: 6372818 bytes, checksum: c89cc5eb491bd0129e563fc2dd200aac (MD5) Previous issue date: 2014 / Resumo: A tese "Estudo dos mecanismos de transmissão dos acoplamentos escalares via ligações e/ou via nuvem eletrônica próxima no espaço e estudos de difusão (DOSY) de 19F" é composta de 5 capítulos. O primeiro capítulo é uma visão geral sobre Ressonância Magnética Nuclear (RMN), sequências de pulso para determinação experimental das constantes de acoplamento, mecanismos envolvidos na transmissão desse importante parâmetro de RMN e Teoria dos Orbitais Naturais de Ligação (NBO). No segundo capítulo há uma introdução sobre acoplamentos transmitidos "espacialmente" (TS). Posteriormente, os valores de nJFN, cujo n4, são correlacionados com distância (dFN) e densidade eletrônica ao longo do caminho do acoplamento. No terceiro capítulo os mecanismos de transmissão da constante de acoplamento JFH em 2-F-benzaldeído foram investigados. A motivação para este estudo foi a observação do maior valor dessa constante em meio polar. Os resultados teóricos mostraram que a forma sinperiplanar é a mais estável, porém a porcentagem da forma antiperiplanar aumenta em solvente polar. Além disso, os resultados teóricos suportam um JFH maior para a forma anti. Esses resultados corroboram com o dado experimental acima mencionado. Seguindo a apresentação dos resultados, o capítulo 4 versa sobre o uso de constante de acoplamento vicinal (3JCH) para a determinação da estereoquímica de duplas ligações. Primeiro apresentamos a metodologia sel-HSQMBC-TOCSY utilizada para determinação do acoplamento 3JCH. Posteriormente apresentamos uma racionalização para os valores observados para derivados de quinolina e pirrolizidinonas, mostrando a importância da ocupância dos orbitais e da % de caráter s dos carbonos envolvidos para a transmissão desse acoplamento. Por fim, no capítulo 5 são apresentados os resultados para os experimentos de DOSY (Diffusion Ordered SpectroscopY). Neste capítulo apresentamos a sequência Oneshot-19F{1H} uma modificação da sequência original Oneshot-1H para detecção de 19F com desacoplamento de 1H / Abstract: The thesis "Study of the mechanisms of transmission of the scalar couplings through bond and/or through the electronic cloud close in space and studies of diffusion (DOSY) of 19F" is composed by 5 chapters. The first chapter is an overview of Nuclear Magnetic Resonance (NMR), pulse sequences to determine experimentally scalar spin-spin coupling constants (SSCC), mechanisms involved in the transmission of SSCC and Natural Bond Orbital analysis (NBO). The second chapter introduced the through space coupling constant (TS) transmission pathway. In addition, it was proposed a correlation among the values of nJFN, with n?4, the distance (dFN) and the electronic density along the coupling pathway. In the third chapter the mechanisms involved in the transmission of the JFH coupling constant in 2-F-benzaldehyde were investigated. The experimental observation of a higher coupling constant in polar solvent compared to the nonpolar one was our motivation to evaluate in details this coupling constant. It is important to highlight that was not possible to determine experimentally this coupling constant in nonpolar solvent because the value is smaller than spectral resolution. From theoretical calculation it was observed that the syn periplanar is the most stable conformer, however the population of the antiperiplanar conformer increases in polar solvent. Besides, the theoretical results support higher JFH value for the antiperiplanar conformer in comparison to syn periplanar. These results are in agreement with the experimental. Following the discussion, chapter 4 is related to the application of vicinal coupling constant (3JCH) for relatively stereochemical determination. The experimental 3JCH coupling was measured using sel-HSQMBC-TOCSY pulse sequence. In addition, it was done a rationalization of the couplings observed for quinolines and pirrozilidinones derivatives, suggesting that the % s character of the carbons and occupancy of the orbitals involved in the coupling pathway describes the experimental behavior. Finally, chapter 5 introduces the use of DOSY (Diffusion Ordered SpectroscopY). For this purpose, It was designed a pulse sequence dubbed Oneshot-19F{1H} ¿ consisting in a modification of the original Oneshot-1H to allow radiofrequency changes between 1H and 19F channels and a 1H decoupling during 19F acquisition / Doutorado / Quimica Organica / Doutora em Ciências

A unique characteristic of NMR is that, unlike other spectroscopic techniques, it separates the excitation of signals from their detection. By manipulating the type of signal excitation used, the chemical information content of a spectrum can be controlled. This versatility has made NMR a powerful and flexible weapon in the analytical arsenal of chemists, not only for the determination of structural, chemical, dynamic, and physical properties of molecules, but also for the analysis of mixtures, since NMR has the ability to study these intact without the need for physical separation. Chapter 1 contains an introduction to the theoretical NMR background necessary for this thesis. Chapter 2, 3 and 6 detail the development of new methods that suppress 13C satellites not only in conventional 1D 1H and 19F spectra, but also in 1H DOSY spectra, and can facilitate the analysis of minor components in high dynamic range mixtures (i.e. those with a wide range of concentrations). Chapter 4 introduces a new experiment which suppresses low-level artefacts in pure shift NMR, and gives clean pure shift spectra that can be used for the detection of minor components in the presence of strong signals. Chapter 5 and 7 illustrate how 19F NMR can be exploited for the acquisition of simplified proton spectra associated with a given 19F chemical shift, or for the virtual separation of mixture components using broadband 19F DOSY. Chapter 8 summarises the conclusions extracted from the research introduced in the main body of this thesis, and gives suggestions for future developments. Chapters 2, 3, 4, 5, and 7 contain published research articles and their Supporting Information and are presented without modification. Chapter 6 is presented as a manuscript intended for publication.

Les ARN constituent des cibles thérapeutiques extrêmement intéressantes bien qu'encore assez peu exploitées. En effet, les obstacles pour la conception de ligands spécifiques de ces cibles non traditionnelles, polyanioniques et très flexibles, sont encore loin d'être levés. Les aminoglycosides, utilisés depuis longtemps pour leurs propriétés antibiotiques, sont souvent décrits comme des " ligands universels " d'ARN. Leur structure constitue donc une architecture favorable pour l'élaboration de nouveaux ligands spécifiques des ARN.Le but de cette thèse a été de développer une méthode systémique originale combinant chimie organique et microbiologie pour synthétiser de nouvelles molécules de structure analogue aux aminoglycosides, se fixant de façon spécifique sur des cibles ARN. Ce travail repose sur la compréhension récente des voies de biosynthèse des aminoglycosides permettant leur ingénierie rationnelle selon une stratégie de mutasynthèse. Cette approche expérimentale s'appuie sur la conception de mimes de métabolites naturels pouvant être transformés par des bactéries génétiquement modifiées. Le développement de méthodologies novatrices en ingénierie métabolique, synthèse organique et chimie analytique nous a permis de concevoir des analogues d'aminoglycosides fluorés qui se sont avérées être d'excellentes sondes dans l'étude des ARN par RMN du fluor.

The aim of this Master Thesis is to synthesize and study new macrocyclic ligands containing fluorine atoms for use as potencial contrast agents in 19 F magnetic resonance imaging. New ligands were designed as analogues of ligands used in contrast agents already utilized in clinical practice - macrocyclic ligand for complexation of trivalent lanthanide ions based on DOTA skeleton and series of macrocyclic ligands for complexation of divalent nickel ion based on cyclam skeleton. All designed ligands were synthesized a characterized. The complexes [LnIII (dotptfe )]− were tested in vitro and in vivo to study 19 F NMR relaxation times enhancements.

Topical treatment containing undeclared corticosteroids and illegal topical treatment with corticosteroid content have been seen on the Swedish market. In creams and ointments corticosteroids in the category of glucocorticosteroids are used to reduce inflammatory reactions and itchiness in the skin. If the inflammation is due to bacterial infection or fungus, complementary treatment is necessary. Side effects of corticosteroids are skin reactions and if used in excess suppression of the adrenal gland function. Therefore the Swedish Medical Products Agency has published related warnings to make the public aware. There are many similar structures of corticosteroids where the anti-inflammatory effect is depending on substitutions on the corticosteroid molecular skeleton. In legal creams and ointments they can be found at concentrations of 0.025 ‑ 1.0 %, where corticosteroids with fluorine substitutions usually are found at concentrations up to 0.1 % due to increased potency. At the Medical Products Agency 19F-NMR and 1H-NMR have been used to detect and quantify corticosteroid content in creams and ointments. Nuclear Magnetic Resonance, NMR, is an analytical technique which is quite sensitive and can have a relative short experimental time. The low concentration of corticosteroids makes the signals detected in NMR small and in 1H‑NMR the signals are often overlapped by signals from the matrix. With 1H‑NMR characteristic signals could be detected in a less crowded spectral window between 5.96 ‑ 6.40 ppm where overlapping signals from the matrix often are absent. Since fluorine is less common in molecules, the option of using 19F‑NMR increases the possibility of finding fluorine-containing corticosteroids in creams and ointments. The corticosteroid signals in 19F‑NMR are detected at -165 ppm and -187 ppm, depending on where fluorine is located on the structure. Quantifying with 1H-NMR and 19F-NMR gave similar result with an accuracy of 98‑116 % and 89-106 % respectively, and RSD values between 2‑35 %, depending on the kind and amount of corticosteroid. Relations between the structure and some signals in 1H‑NMR were found, making it easier to determine the basic structure of unknown corticosteroids in creams and ointments. Screening experiments were performed on creams and ointments with known concentration corticosteroid in order to find minimum NS for analyzing products which might contain corticosteroids. In order to detect a corticosteroid concentration of 0.05 % 19F‑NMR needed 64 NS with an experimental time of 2 min and 1H-NMR needed 160 NS with an experimental time of 17 min. Concentrations of 0.025 % could for some corticosteroids be detected with these parameters. The possibility of spiking samples in order to discriminate between corticosteroids was also investigated. The corticosteroids available at the MPA could be discriminated from each other with at least one of the methods 1H‑NMR or 19F-NMR, and in most cases with both. A market research was done in order to search for counterfeits and salespersons in different health food stores were asked to recommend the best product to treat eczema or psoriasis. Nine recommended products were bought where one was found illegally containing a corticosteroid. In previous experiments at the MPA there had been occurrences of a split signal in 19F-NMR when analyzing creams. The split 19F‑NMR signal was shown to be related both to the presence of water and structural effects of the corticosteroid

Die vorliegende Arbeit befasst sich mit mechanistischen Untersuchungen der fluorolytischen Sol-Gel-Synthese von nano-Magnesiumfluorid, sowie verschiedenen Abwandlungen der bekannten Synthese zur gezielten Veränderung der Eigenschaften der erhaltenen Materialien. Es werden die drei im folgenden beschriebenen Themenbereiche behandelt: Der Verlauf der Fluorolyse von Magnesiummethoxid mit methanolischer HFLösung wird mit der 19F-NMR-Spektroskopie über sechs Monate untersucht. Es wird gezeigt, dass MgF2-Nanopartikel, Agglomerate von gestörten MgF2-Partikeln und nicht umgesetzte, adsorbierte HF-Spezies in den Solen nachweisbar sind. Erstmalig werden MAS-NMR-Experimente an Solen beschrieben. Zusätzlich wird die schrittweise Fluorolyse von MgCl2 mittels NMR-Spektroskopie und XRD untersucht. Es werden drei verschiedene Synthesewege vorgestellt, mit denen eine Veränderung von Partikel- oder Kristallitgrößen erreicht wird. Eine sequentielle Synthese ermöglicht die Vergrößerung der Agglomerate im Sol. Das Erhitzen eines Sols zum Sieden unter Rückflusskühlung führt zu einem geringfügigen Anwachsen der Kristallitgröße. Durch Solvothermal-Synthesen wird eine signifikante Vergrößerung der Kristallite erzielt. Der Einfluss verschiedener Reaktionsparameter wird untersucht. Der Einfluss von MgF2 auf die Kristallisation von amorphem TiO2 wird untersucht. Es wird gezeigt, dass die Sol-Gel-Synthese von TiO2 in Gegenwart eines MgF2-Sols (min. 5 mol%) zur Kristallisation von Rutil-TiO2 bei vergleichsweise niedrigen Temperaturen führt. Verschiedene alternative Synthesen werden vorgestellt, durch die bei vergleichbaren Bedingungen nur Anatas-TiO2 erhalten werden kann. Ein möglicher Mechanismus der Strukturinduktion wird vorgeschlagen. / The present Ph.D. thesis deals with mechanistic investigations of the fluorolytic sol-gel synthesis of nano magnesium fluoride. Furthermore, variations of the well known synthesis are introduced. The aim of these variations is to tailor the properties of the synthesized materials. The thesis covers three main chapters briefly introduced below: The course of the fluorolysis of magnesium methoxide with methanolic HF-solution will be monitored for six months using 19F NMR spectroscopy. The existence of MgF2 nanoparticles and agglomerates of disturbed MgF2 particles will be proven. It is demonstrated that hydrogen fluoride does not react immediately after the addition of HF-solution. For the first time MAS-NMR experiments of sols will be conducted. Furthermore, stepwise fluorolysis of magnesium chloride will be followed by NMR spectroscopy and X-ray diffraction. In this case no intermediates will be detected. Three different synthetic approaches capable of tailoring the crystallite and particle sizes will be presented. Using a sequential synthesis leads to increased size of the agglomerates in the sols. It will be demonstrated that heating and refluxing of a sol increases the crystallite size slightly. Solvothermal synthesis will be the last method leading to significant increase in crystallite sizes. Several synthetic parameters will be varied to identify their influence on the received crystallites. The influence of nano MgF2 on the crystallisation of amorphous TiO2 is investigated. It will be shown, that the sol-gel synthesis of TiO2 in the presence of a MgF2 sol leads to the crystallisation of the rutile polymorph of TiO2. The temperature treatment for that is comparatively low and just 5 mol% MgF2 are necessary. Furthermore, a different alternative synthesis will be introduced, that gives the anatase polymorph at the same conditions. Eventually a possible mechanism for the structural induction is proposed.

Ce travail porte sur la synthèse et la caractérisation de fluorures à base d’alcalins, d’alcalinoterreuxet de terres rares et sur la réactivité de ces composés vis-à-vis de ReF6 pour lapurification de UF6. L’étude traite dans un premier temps de la synthèse de fluorures tels queKMgF3, MgF2 et CaF2 en couplant une voie solvothermale assistée par micro-ondes et uneétape de fluoration à partir de fluor élémentaire (F2). Les techniques de caractérisationutilisées mettent notamment en avant le caractère basique au sens de Lewis de ces composéset la possibilité de contrôler leur surface spécifique et leur taux d’oxygène, à l’origine dessites basiques, via la température de fluoration (F2) en phase gaz. Dans un second temps, lasolution solide Ce1-xZrxF4 à base de Ce4+ et Zr4+ a été obtenue par fluoration directe d’oxydesmixtes à partir de fluor élémentaire dilué. L’étude par DRX et RMN du 19F montre laprésence d’une solution solide pour des compositions voisines de x=0,5. Enfin, la réactivité deReF6 et UF6 sur KMgF3, MgF2 et CaF2 montre que KMgF3 est un très bon candidat pour lapurification de UF6 vis-à-vis de ReF6, qui dépend à la fois de paramètres intrinsèques auxfluorures divisés (surface spécifique, taux d’oxygène, basicité, cations mis en jeu…) maisaussi du procédé de purification (température, temps de contact). / This work deals with the synthesis and characterization of alkali, alkali-earth and rare earthbased fluorides and the reactivity of the latter with ReF6 for UF6 purification. In a first part,we focused our attention on the synthesis of KMgF3, MgF2 and CaF2 high surface area metalfluorides coupling both microwave assisted solvothermal process and a fluorination step withelemental fluorine (F2). The higher the surface area, the higher the oxygen rate. Thesenanofluorides exhibit Lewis basic character. In a second part, several compositions of theCe1-xZrxF4 solid solution were synthesized by direct fluorination of mixed oxides usingelemental fluorine (F2). XRD an 19F NMR characterizations show the occurence of a newsolid solution for compositions close to x=0.5. Finally, the reactivity between ReF6/UF6 andKMgF3, MgF2 and CaF2 leads to conclude that KMgF3 is the best candidate for thepurification of UF6. This study indicates that the purification depends on several parameters :intrinsic parameters of the divided fluorides (surface area, oxygen rate, basicity, cations…)and parameters directly related to the process (temperature, contact time).

Ce travail de thèse a pour but de suivre le comportement du liant ionomère après vieillissement en condition réelle d'utilisation de la pile. Dans un premier temps, diverses techniques de caractérisation en phase solide ont été utilisées afin d'étudier le ionomère présent dans les électrodes. La majeure partie de ces techniques se sont avérées insatisfaisantes pour le suivi du vieillissement du ionomère. Seule l'analyse par diffraction rayon X (DRX) a mis en avant un changement d'organisation structurale du ionomère dans les électrodes. Par la suite, nous avons choisi de caractériser le ionomère en solution après extraction par l'eau. Préalablement, un protocole de quantification en 2 à 3 étapes, dans lequel intervient une quantification via le rapport signal-sur-bruit (S/N), a été mis en place afin de quantifier le Nafion® et autres petites molécules fluorés. L'extraction Soxhlet a ensuite été réalisée sur les électrodes permettant de révéler la présence d'un produit de dégradation hydrosoluble après fonctionnement en pile, à la fois en cathode et en anode. Enfin, la macération des électrodes dans le diméthylacétamide (DMAc) a permis d'extraire le polymère Nafion® ainsi que deux acides : l'acide trifluoroacétique (TFA) et l'acide triflique (TFI). En conclusion, la corrélation de l'ensemble des observations nous a permis de proposer un mécanisme de dégradation du liant ionomère présent dans les électrodes. / The purpose of this study was to follow the behavior of ionomer binder after fuel cell operation. First, a series of techniques were used to investigate to characterize ionomer in electrode at solid state. Most of them were inefficient to study ionomer degradation. Only X-Ray Diffraction (XRD) pointed out a structural change of the binder in electrodes. Second, it has been decided to characterize ionomer in liquid state after water extraction. But first of all, a quantitative 19F NMR protocol composed of two to three steps, with a first step using a quantification through signal-to-noise ratio (S/N), was establish in order to quantify Nafion® and degradation products. Soxhlet extraction performed on electrodes allowed to detect a degradation product water-soluble. Finally, extraction with organic solvent (Dimethylacetamide) allowed to extract Nafion® and two acid: trifluoroacetic acid (TFA) and triflic acid (TFI) from electrodes. In conclusion, correlation between observation and literature allowed us to propose a degradation mechanism of ionomer in electrodes.

La synthèse de matériaux zéolithiques est régie par de nombreux paramètres, en particulier la nature de l'hétéroélément associé au silicium et celle de l'agent organique structurant. Ainsi, l'introduction de germanium dans les milieux réactionnels ainsi que l'utilisation de structurants dérivés d'imidazole, les cations 1-éthyl-3-méthylimidazolium et 1-butyl-3-méthylimidazolium, ont permis la découverte de deux nouveaux solides microporeux nommés respectivement IM-16 et IM-20 et présentant des topologies de charpente inédites (respectivement UOS et UWY). De plus, un troisième germanosilicate poreux nommé IM-17 a été obtenu en présence du cation décaméthonium. Chacun de ces trois matériaux possède un système tridimensionnel de canaux avec des ouvertures de 8 et 10 atomes T (IM-16) ou de 10 et 12 atomes T (IM-17 et IM-20), ainsi que des unités de construction composites d4r au sein de leur charpente. Enfin, une partie importante du travail a été consacrée à l'élaboration de molécules structurantes originales (dérivés du décahydro-dicyclopenta[b,d]pyrrole) puis de leur emploi en synthèse hydrothermale. Ces essais ont permis d'obtenir divers matériaux déjà connus, parmi lesquels les zéolithes IM-12 (UTL), ITQ-7 (ISV), ITQ-17 (BEC) et ITQ-21. / The synthesis of zeolitic materials is ruled by numerous parameters, particularly the nature of the heteroelement associated with silicon and of the organic structure-directing agent (SDA). The introduction of germanium into the synthesis gels and the use of imidazole-derived SDAs, the cations 1-ethyl-3-methylimidazolium and 1-butyl-3-methylimidazolium, allowed us to discover two new microporous solids named IM-16 and IM-20 and exhibiting novel framework structures (respectively UOS and UWY). Furthermore, a third porous germanosilicate named IM-17 was obtained in the presence of the decamethonium cation. Each of these materials possesses a three-dimensional channel system with 8- and 10-ring pores (IM-16) or 10- and 12-ring pores (IM-17 and IM-20), as well as double-4-ring (d4r) composite building units in their framework. Finally, an important part of this work was dedicated to the elaboration of original SDAs (decahydro-dicyclopenta[b,d]pyrrole derivatives) and their use in hydrothermal synthesis. This led to the synthesis of several known zeolites such as IM-12 (UTL), ITQ-7 (ISV), ITQ-17 (BEC) and ITQ-21.

Cyclam (1,4,8,11-tetraazacyclotetradecane) derivatives are widely used for various purposes. In a medicine they are applied as ligands for radiometals applied as diagnostic or therapeutic agents against tumours, hypoxic brain tissues etc. In this thesis a new method for asymmetric cyclam derivati- ves preparation was developed. New cyclam derivatives with trifluoroethyl groups were prepared too. Paramagnetic metal complexes with these fluori- nated ligands can be used as contrast agents for 19 F-MRI. Keywords: Cyclam; Non-symmetric protection; Contrast agents; Trifluoroethylamines; Paramagnetic relaxation; 19 F-MRI.