The emergence of verdazyl radicals as starting materials for organic synthesis is providing a unique opportunity to create a variety of distinctive heterocyclic scaffolds. These stable radicals have previously been used as spin probes, polymerization inhibitors, mediators of living radical polymerizations, and as substrates for molecular-based magnets. However, verdazyl radicals have never been employed to fulfill an organic synthetic role until recently. In an effort to pioneer the chemistry behind verdazyl radicals as novel organic substrates, our lab has been inspired to expand and explore the scope of reactions involving their synthetic utility. This thesis assesses the synthetic versatility of verdazyl radicals by constructing a library of structurally complex and diverse verdazyl-derived heterocycles in an approach called diversity-oriented synthesis. The synthetic versatility was further expanded to the preparation of a biphenyl-stacked biphenylophane, which exhibited interesting structural and conformational features as highlighted herein.

Green chemistry principles served as a guide for three industrially-relevant projects. In the first project, silylamines were applied as reversible ionic liquids for carbon dioxide capture from post-combustion flue gas streams. The effect of silylamine structure was thoroughly researched to develop a comprehensive library of silylamines and an accompanying set of structure-property relationships. The proposed solvent systems have the potential to present significant energy savings, as design has focused on their use in a non-aqueous, solvent-free environment. The second project also dealt extensively with carbon dioxide capture, as a reversible, in-situ protecting group for amines. Three strategies for the reversible protection of amines using carbon dioxide were developed and evaluated. Further, a chemoselective reaction was performed using carbon dioxide to protect a reactive amine and consequentially direct reactivity elsewhere within the same molecule. The carbon dioxide-protection technology developed has significant impact in multi-step industrial syntheses, as reversible, in-situ protection with carbon dioxide could eliminate the need for separate protection and deprotection unit operations. Lastly, a study was performed on the thermal degradation and stabilization of PVC in the presence of both plasticizers and thermal stabilizers. The study combined both model compound experiments as well as work with bulk PVC blends to gain a holistic understanding of the processes that take place during the degradation and stabilization of PVC. A bio-based plasticizer was investigated as a replacement for petroleum-based phthalate plasticizers. Additionally, two novel thermal stabilizers for PVC were presented and evaluated.

We describe an efficient synthesis of the methylene-bridged biscarbazole alkaloids bismurrayafoline-A, bismurrayafolinol and chrestifoline B–D using an Ullmann-type coupling at the benzylic position.

Submitted by BRUNA BERGAMIN null (brubergamin@iq.unesp.br) on 2017-07-10T23:16:27Z No. of bitstreams: 1 Dissertação final 1.pdf: 3270750 bytes, checksum: 7a706d3e4baa0dc96bb2561c2d8ab723 (MD5) / Approved for entry into archive by LUIZA DE MENEZES ROMANETTO (luizamenezes@reitoria.unesp.br) on 2017-07-13T19:11:23Z (GMT) No. of bitstreams: 1 bergamin_b_me_araiq.pdf: 3270750 bytes, checksum: 7a706d3e4baa0dc96bb2561c2d8ab723 (MD5) / Made available in DSpace on 2017-07-13T19:11:23Z (GMT). No. of bitstreams: 1 bergamin_b_me_araiq.pdf: 3270750 bytes, checksum: 7a706d3e4baa0dc96bb2561c2d8ab723 (MD5) Previous issue date: 2017-06-06 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / O desenvolvimento de métodos analíticos cada vez mais seletivos e sensíveis é de grande importância para uma melhor qualidade na determinação de espécies químicas, aumentando assim a confiabilidade dos resultados obtidos. Com isso, o emprego e otimização das etapas de separação/concentração se faz necessário. O emprego de polímeros molecularmente impressos (do inglês - “Molecularly Imprinted Polymers” - MIP) tem demonstrado ser uma eficiente ferramenta analítica com grande potencialidade para minimizar as limitações das técnicas de separação/concentração tradicionalmente empregadas. No caso deste trabalho, o template utilizado será o valerato de estradiol, principalmente pela sua importância inerente na reposição hormonal feminina e por se tratar de um disruptor endócrino (hormônio) lançado ao meio ambiente sem nenhum controle. Assim a síntese do polímero para identificação do valerato de estradiol foi realizada por diferentes rotas (bulk e precipitação) através de duas vias de polimerização (termopolimerização e fotopolimerização) variando o monômero funcional (MAA, acrilonitrila, 2-vinil-piridina e 1-vinilimidazol). O MIP e NIP foram colocados, um de cada vez, em sistema soxhlet contendo metanol/ácido acético na proporção 70/30 a 60º C, para remoção da molécula impressa, através de cinco lavagens sucessivas em períodos de 24 h. Essas águas de lavagem foram analisadas utilizando espectrofotometria UV/Vis. Posteriormente com os parâmetros otimizados o polímero que apresentou melhor resultado foi modificado com nanopartículas magnéticas (core@shell), sendo assim sintetizado MIP magnético (MMIP) para valerato de estradiol, usando ácido metacrílico (MF) e TRIM (ME); aumentando o reconhecimento do MIP e, além de, facilitar a separação do material da solução pela aplicação de um campo magnético externo. Todos os materiais sintetizados foram amplamente caracterizados, física e físico-quimicamente. O material sintetizado apresentou um excelente magnetismo (2,0 emu g-1 ), uma alta porcentagem de retenção (superior a 80%) e um Qmáx acima de 24 mg g-1 , indicando que é promissor para adsorção de valerato de estradiol. / The development of selective and sensitive analytical methods has significant importance for an improvement at determination of chemical species; increasing the reliability of the results obtained. So, the use and optimization of separation and concentration steps is necessary. The use of Molecularly Imprinted Polymers (MIP) has been shown to be an efficient analytical tool with great potential to minimize the limitations of separation/concentration techniques traditionally employed. In the case of this study, the template used will be estradiol valerate, once of its inherent importance in female hormone replacement and because it is an endocrine disruptor (hormone) released into the environment without any control. Thus, the synthesis of the polymer for the identification of estradiol valerate was performed by different routes (bulk and precipitation) through two polymerization techniques (thermopolymerization and photopolymerization) by varying the functional monomer (MAA, acrylonitrile, 2-vinyl pyridine and 1- vinylimidazole). MIP and NIP were placed in a soxhlet system containing 70/30 methanol/acetic acid at 60 ° C for removal of the imprinted molecule through five successive washes in 24 h periods. These wash waters were analyzed using UV/Vis spectrophotometry. Subsequently, with the optimized parameters, the polymer that presented the best result was modified with magnetic nanoparticles (core@shell); being synthesized magnetic MIP (MMIP) for estradiol valerate, increasing the recognition of the MIP and, furthermore, facilitating the separation of the material from the solution by the application of an external magnetic field. It was used methacrylic acid as functional monomer, TRIM as structural monomer and all the synthesized materials were widely characterized, physically and physico-chemically. The synthesized material showed excellent magnetism (2.0 emu g-1 ), an elevate percentage retention (higher than 80%) and a Qmax above 24 mg g-1 , indicating that MMIP is a promising material for adsorption of estradiol valerate. / CAPES: 33476991814

The synthetic studies include the synthesis of the cyclic siloxydiyne, 3,3,5,5,8,8,10,10-octamethyl-4,9-dioxa-3,5,8,10-tetrasilacyclodeca-1,6- diyne [VI] and its novel iron carbonyl complex. In the preparation of [VI] by HBr promoted condensation of bis (methoxydimethylsilyl) acetylene, a minor product, a cyclic trimer was always formed along with the major product [VI]. No evidence of an equilibrium between the trimerization product and the dimerization product was found. Compound [VI] can react with iron carbonyl reagents to produce a novel binuclear iron complex of trimethylenemethane [VII] in very low yield either in a thermal or photo-reaction. The key step proposed by us in the formation of [VII] is a I,2-silyl shift in a complexed bis (silyl) acetylene to form a vinylidene intermediate. Experiments aimed at isolating this intermediate were not successful.

La mesure d’interaction entre une molécule candidate et sa cible biologique est d’un intérêt majeur dans la recherche de nouveaux composés thérapeutiques. A l’heure actuelle, le marquage radioactif est la méthode de référence pour ce type d’étude pharmacologique, permettant une détection spécifique et extrêmement sensible de la molécule d’intérêt dans des matrices biologiques complexes. Cependant l’utilisation de la radioactivité présente de nombreux inconvénients, principalement en termes de sécurité pour les utilisateurs et problématiques environnementales induites par le stockage de déchets radioactifs. Au regard de ces limitations, des technologies alternatives ont été développées principalement basées sur une détection de fluorescence. Toutefois, l’incorporation de groupements encombrants tels que les fluorophores peut potentiellement perturber les propriétés physico-chimiques de la molécule et ainsi altérer son affinité envers le récepteur, ce qui limite l’application de ce type de stratégie pour les ligands de faible poids moléculaire. Dans ce contexte, nous souhaitons développer une méthodologie alternative pour quantifier les interactions récepteur-ligands. La spectrométrie de masse présente de remarquables capacités en termes de sensibilité et de spécificité d’analyse. Parmi les technologies existantes, l’ICP-MS est une technique extrêmement sensible permettant la quantification absolue d’hétéroéléments indépendamment de la matrice dans laquelle se trouve l’échantillon. Cette technique associée à un marquage approprié de la molécule d’intérêt a donc été évaluée. Le sélénium a été sélectionné comme un bon compromis entre la réponse obtenue en ICP-MS et la possibilité d’introduire ce marqueur au sein de la molécule d’intérêt selon des protocoles de chimie conventionnelle, sans perturbation de l’affinité pour le récepteur. La preuve de concept a été illustrée sur le récepteur à la vasopressine V1A impliquant des ligands de nature peptidique. Différentes stratégies ont été appliquées pour la conception de ligands marqués au sélénium basées sur la substitution d’acides aminés par leurs analogues séléniés (ex : remplacement de la cystéine (Cys) par la sélénocystéine (Sec) et de la proline (Pro) par la sélénazolidine (Sez)) ainsi que la dérivatisation en position N-terminale du peptide avec une petite molécule organique. La méthodologie analytique par ICP-MS a été développée de manière à obtenir une mesure du sélénium à la fois sensible et fiable. La forte proportion de sels inorganiques contenus dans la matrice pharmacologique a nécessité le recours à une séparation chromatographique et à une cellule de collision en amont de la détection par ICP-MS. Le protocole pharmacologique a également été adapté aux exigences analytiques. Ces modifications ont notamment porté sur la récupération de l’échantillon pour procéder à son injection ainsi que sur la quantité de cellules utilisées. La robustesse des expériences pharmacologiques ainsi conçues a été évaluée par la mesure de la constante d’affinité (Ki) de ligands caractéristiques du récepteur V1A présentant des affinités élevées et faibles pour ce dernier. Les résultats obtenus ont présenté une très bonne corrélation avec les valeurs de référence indiquées dans la littérature, permettant ainsi de valider la preuve de concept de cette méthodologie et de proposer une alternative viable au marquage radioactif. / Measuring interactions between a drug candidate and its specific target constitutes a parameter of upmost importance in drug discovery process. Because of its robustness and very high sensitivity, radio-isotopic labeling represents up to now the reference method for these pharmacological studies. However, the use of radioactivity confers several constraints about security, health hazards and environmental issues involved by radioactive waste storage. Regarding such limitations, non-radioactive technologies have been developed principally based on fluorescence detection. But the cost of such assay as well as the fact that incorporation of a bulky fluorescent block can affect the affinity for small ligand limit their use. In this context, we aim to develop a new methodology to quantify receptor-ligands interactions. Mass spectrometry (MS) presents very interesting features in terms of detection sensitivity and specificity, making this technique a challenging analytical tool to replace radioactivity and fluorescence measurements commonly used in pharmacology. Among all MS technologies, the capacity of inductively coupled plasma-mass spectrometry (ICP-MS) to provide metallic and hetero elements absolute quantification, whatever the nature of the sample medium, prompted us to investigate this technique in combination with an appropriate labeling of the molecule of interest. Selenium was selected as a good compromise between ICP-MS response and chemical tagging ability through the creation of covalent bonds using conventional organic sulfur chemistry without disturbance of the affinity toward targeted receptor. Proof of concept was illustrated on the vasopressin receptor (V1A), a GPCR involved in vasoconstriction and emotional behavior and implying peptide as native ligand. Different strategies were applied to design selenium labeled peptides relying in either conventional amino acid substitution by corresponding selenium containing residue into peptide sequence such as cysteine (Cys) replacement by selenocysteine (Sec) as well as proline (Pro) by selenazolidine (Sez), or N-terminal peptide derivatization with a selenium containing small organic entity. ICP-MS analytical methodology was carefully investigated to provide sensitive and reliable selenium signal measurement. High inorganic salts contents of pharmacological buffer along with polyatomic interferences from plasma interfering selenium detection necessitate chromatographic separation and collision reaction cell equipment before ICP-MS detection. The pharmacological protocol was also adapted to the analytical requirements, in particular quantity of cells and sample handling. Robustness of the designed competitive binding assay was evaluated through the affinity constant (Ki) measurement of several known V1A-R ligands exhibiting either high or poor affinity for the receptor. Experimental values were strongly correlated to literature data, enabling to validate the proof of concept of such methodology and to propose a suitable alternative to radioactive labeling.

Cette étude concerne l'optimisation, la conception et la caractérisation de microréacteurs, de type multicanaux, appliqués à l'électrosynthèse organique de composés fluorés à intérêt médical tels que le 2-Fluoro- 2-Deoxy-D-Glucose (18FDG). Les microsystèmes ont connu un développement important ces dernières années dans le domaine de la chimie fine où la volonté est de développer des outils toujours plus compétitifs. Les microréacteurs appliqués à la synthèse offrent l’avantage d’un rapport surface sur volume de la zone réactionnelle élevé (> 100 cm-1), ce qui améliore nettement les transferts de masse et d’énergie et permet de traiter de très faibles quantités dans des conditions plus sûres et plus respectueuses de l’environnement. L’élément de base du microréacteur est souvent constitué d’un simple microcanal qu’il est nécessaire de dupliquer pour fournir le débit de production adapté à une application donnée. Ainsi, un microréacteur sera souvent composé d’une série de microcanaux disposés en parallèle et connectant un canal distributeur et un canal collecteur. Cette configuration peut entraîner une faible uniformité de la distribution de l’écoulement dans les différents microcanaux de réaction et il est particulièrement important d’optimiser la géométrie du microréacteur complet pour tendre vers une distribution uniforme des temps de séjour (DTS). Dans le cas de la synthèse électrochimique, les microcanaux sont directement gravés dans deux électrodes placées en vis-à-vis et séparées par une membrane échangeuse d’ions. Une optimisation préliminaire de la DTS au sein d’une électrode composée de microcanaux parallèles de section rectangulaire est réalisée. L’arrivée et la sortie du fluide s’effectue par l’intermédiaire de deux canaux distributeur et collecteur de section également rectangulaire, mais non constante. L’optimisation vise à déterminer une évolution linéaire optimale de la largeur de ces canaux distributeur et collecteur. Un modèle analytique basé sur des hypothèses simplificatrices permet de calculer les différentes pertes de charge ainsi que les débits dans chaque microcanal, dans le cas d’un écoulement laminaire de liquide. Les résultats obtenus sont ensuite confirmés par des simulations numériques 3-D, plus précises. Un modèle hybride combinant les simulations numériques pour les canaux distributeur et collecteur et le modèle analytique pour les microcanaux parallèles est également développé. Il permet d’augmenter la finesse du maillage dans les zones sensibles de l’écoulement, sans nécessité d’accroître les ressources informatiques (mémoire et temps de simulation). Les résultats obtenus montrent un très bon accord entre les simulations numériques 3-D, le modèle hybride et le modèle analytique. Sur un exemple de 10 microcanaux parallèles, il est montré que dans le cas de la géométrie initiale, pour laquelle les canaux collecteur et distributeur sont de section constante, des écarts de l’ordre de 50 % existent entre les débits traversant les microcanaux latéraux et centraux. Après optimisation, cet écart est réduit à moins de 0,1 %. Le modèle analytique est ensuite étendu au cas d’écoulements gazeux en prenant en compte les effets non linéaires et antagonistes de la raréfaction et de la compressibilité de l’écoulement. La raréfaction est ici caractérisée par un nombre de Knudsen compris entre 0 et 0,1 et se traduit pas des sauts de vitesse à la paroi ; les écoulements dans ce régime modérément raréfié sont alors correctement modélisés par les équations compressibles de Navier Stokes associées à des conditions de glissement du second ordre en Knudsen, en prenant en compte la géométrie tridimensionnelle des microcanaux de réaction et des canaux collecteur et distributeur. / This study focuses on the optimisation, design and characterization of microreactors, of multichannel type, applied to the organic electrosyntheses of fluorinated compounds of medical interest such as the 2-Fluoro-2-Deoxy-D-Glucose (18FDG). Microsystems have known an important development these last years in the field of fine chemicals where the aim is to develop increasingly competitive tools. The microreactors applied to synthesis offer a reaction zone with high surface to volume ratio (> 100 cm-1), which significantly improves mass and energy transfers and allows treating small quantities in safer conditions and a better respect of environment. The basic element of the microreactor is often composed of a single microchannel, which is necessary to duplicate in order to provide the suitable production rate for a given application. Thus, a microreactor is often composed of a series of microchannels arranged in parallel and connecting a distributing channel to a collecting one. This configuration can result in poor uniformity of flow distribution among the reaction microchannels and it is particularly important to optimize the geometry of the microreactor in order to obtain a uniform residence time distribution (RTD). In the case of electrochemical synthesis, microchannels are directly etched into two electrodes facing each other and separated by an ion exchange membrane. A preliminary optimisation of the RTD in an electrode composed of parallel microchannels with rectangular cross-section is performed. The fluid inlet and outlet are connected to a distributing and a collecting channel with non constant rectangular cross-section. The aim of the optimisation is to determine an optimal linear evolution of the width of the distributing and collecting channels. An analytical model based on simplifying assumptions allows calculating the various pressure drops and the flowrate in each microchannel, in the case of a laminar liquid flow. The obtained results are then confirmed by more accurate 3-D numerical simulations. A hybrid model combining numerical simulations for the distributing and collecting channels and the analytical model for the parallel microchannels is also developed. This model allows a more refined mesh in the sensitive areas of the flow, without requiring additional numerical effort (memory and simulation time). The results show a good agreement between the 3-D numerical simulations, the hybrid model and the analytical model. On an example of 10 parallel microchannels, it is shown that in the case of the initial geometry (with a constant cross-section of collecting and distributing channels), the flowrate difference through the lateral and the central microchannels is in the order of 50%. After optimization, this difference is reduced to less than 0.1%. The analytical model is then extended to the case of gas flows, taking into account nonlinear and antagonist effects of rarefaction and compressibility. Rarefaction is characterized by the value of the Knudsen number which remains lower than 0.1; the flow in this moderately rarefied regime is accurately modelled by the compressible Navier-Stokes equations associated with second-order slip boundary conditions, taking into account the three-dimensional geometry of the reaction microchannels and of the collecting and distributing channels.

No description available.

We describe an efficient synthesis of the methylene-bridged biscarbazole alkaloids bismurrayafoline-A, bismurrayafolinol and chrestifoline B–D using an Ullmann-type coupling at the benzylic position.

<p>  </p> <p>Aromatic C-N bond formation is critical for synthetic chemistry in pharmaceutical, agrochemical, and natural product synthesis. Due to the prevalence of this bond class, many synthetic routes have been developed over time to meet the demand. The most recent and robust C-N bond formation reaction is the palladium catalyzed Buchwald-Hartwig amination. Considering the importance of the Buchwald-Hartwig amination, a high-throughput experimentation (HTE) campaign was devised to create a library in which chemists can refer to optimal reaction conditions and ligand/catalyst choice based on the nature of their substrates to be coupled. This study showed trends for the appropriate choice of ligand and catalyst, along with what bases, temperatures, stoichiometries, and solvents are appropriate for the selected substrate combination at hand. </p>