Les macrolactones sont des squelettes structuraux importants dans de nombreuses sphères de l’industrie chimique, en particulier dans les marchés pharmaceutiques et cosmétiques. Toutefois, la stratégie traditionnelle pour la préparation de macrolactones demeure incommode en requérant notamment l’ajout (super)stœchiométrique d’agents activateurs. Conséquemment, des quantités stœchiométriques de sous-produits sont générées; ils sont souvent toxiques, dommageables pour l’environnement et nécessitent des méthodes de purification fastidieuses afin de les éliminer. La présente thèse décrit le développement d’une macrolactonisation efficace catalysée au hafnium directement à partir de précurseurs portant un acide carboxylique et un alcool primaire, ne générant que de l’eau comme sous-produit et ne nécessitant pas de techniques d’addition lente et/ou azéotropique. Le protocole a également été adapté à la synthèse directe de macrodiolides à partir de mélanges équimolaires de diols et de diacides carboxyliques et à la synthèse de dimères tête-à-queue de seco acides. Des muscs macrocycliques ainsi que des macrolactones pertinentes à la chimie médicinale ont pu être synthétisés avec l’approche développée. Un protocole pour l’estérification directe catalysée au hafnium entre des acides carboxyliques et des alcools primaires a aussi été développé. Différentes méthodes pour la macrolactonisation catalytique directe entre des alcools secondaires et des acides carboxyliques ont été étudiées. En outre, la stratégie de séparation de phase en macrocyclisation en débit continu a été appliquée lors de la synthèse totale formelle de la macrolactone ivorenolide A. Les étapes-clés de la synthèse incluent une macrocyclisation par le couplage d’alcynes de Glaser-Hay et une réaction de métathèse d’alcènes Z-sélective. / Macrolactones are important structural motifs in numerous chemical industries particularly in the pharmaceutical and cosmetic markets. However, the traditional strategy for the preparation of macrolactones remains cumbersome, often requiring stoichiometric or excess amounts of activating reagents. Consequently, stoichiometric quantities of by-products are generated. They are often toxic, environmentally damaging, and/or require tedious purification methods to remove them. The following thesis describes the development of an efficient hafnium-catalyzed direct macrolactonization between carboxylic acid and primary alcohol functionalities, generating only water as a by-product and without the need for slow addition or azeotropic techniques. The protocol was also adapted for the direct synthesis of macrodiolides from equimolar mixtures of diols and dicarboxylic acids and for the selective head-to-tail dimerization of seco-acids. Macrocyclic musks and macrolactones relevant to medicinal chemistry were synthesized using the developed approach. A hafnium-catalyzed esterification protocol between carboxylic acids and primary alcohols was also developed. Different methods for the direct catalytic macrolactonization from secondary alcohols and carboxylic acids were studied. Furthermore, the phase separation strategy for macrocyclization in continuous flow was applied in the formal total synthesis of the macrolactone ivorenolide A. The key steps of the synthesis include the Glaser-Hay alkyne coupling macrocyclization and a Z-selective olefin metathesis reaction.

Palladium complexes have the ability to catalyse cross-coupling of two organic moieties through the formation of transient metal-carbon bonds, thus bringing them closer to each other to facilitate the formation of a new bond. Palladium-catalysed coupling reactions are one of the most important carbon-carbon forming reactions available to organic chemists and many of these reactions rely on the reactivity of aryl-palladium complexes. The investigation of new aryl-palladium precursors is thus of great interest, especially as more sustainable and economic methods can be developed. This thesis describes the use of carboxylic acids and sodium arylsulfinates as such new arylating agents. Protocols for microwave-assisted palladium(II)-catalysed decarboxylative synthesis of electron-rich styrenes and 1,1-diarylethenes were developed. However, these transformations had very limited substrate scopes which prompted the investigation of sodium arylsulfinates as alternative arylating agents. These substrates were employed in the microwave-assisted palladium(II)-catalysed desulfitative addition to nitriles, and the substrate scope was demonstrated by combining a wide array of sodium arylsulfinates and nitriles to yield the corresponding aryl ketones. The application of the desulfitative reaction in a continuous flow setup was demonstrated, and aluminium oxide was identified as safe alternative to borosilicate glass as a reactor material. The mechanisms of the decarboxylative and desulfitative transformations were investigated by density functional theory (DFT) calculations. The desulfitative reaction was also investigated by direct electrospray ionization mass spectrometry (ESI-MS), providing further mechanistic insight. Finally, a protocol for the safe and convenient synthesis of a wide range of sodium arylsulfinates was developed.

La structure de l’acide kojique et sa réactivité permet d’effectuer des transformations conduisant à la synthèse de composés polycycliques différents et structurellement très diversifiés. Ces hétérocycles sont obtenus en plusieurs étapes en s’appuyant sur des réactions typiques telles que des cycloadditions [5+2], Diels-Alder, [5+2]/[4+2] tandem, des réactions à 3 composantes ou encore l’utilisation de lithiens. L’utilisation d’appareillages spécifique tels que un réacteur micro-ondes et un synthétiseur en flux continue permettent l’obtention des molécules ciblées d’une façon plus spécifique et efficace. Les chimiothèques de molécules obtenues peuvent dès lors être testé pour une éventuelle activité biologique envers diverses structures. / The structure of kojic acid and its reactivity give the opportunity to make tranformations leading to the synthesis of different polycyclic compounds and structurally diversified. These heterocycles are obtained in several steps by typical reactions like [5+2] cycloaddtions, Diels-Alder reactions, tandem [5+2]/[4+2] cycloadditions, 3 compounds reactions or the use of lithiens. The use of specific equipments like microwave equipment and continuous-flow equipment give the opportunnity to obtain target molecules. Compounds libraries will be test for a biological activity.

Le monoxyde d'azote est exclusivement synthétisé chez les mammifères par une famille d’hémoprotéines, les NO-Synthases. Le cœur de l’activité des NO-Synthases est l’activation de l’oxygène c'est-à-dire l’activation de l’intermédiaire réactionnel FeIIO2. Cette étape est contrôlée par la réactivité intrinsèque du fer, par les transferts de proton et les transferts d’électron. Elle doit être parfaitement maîtrisée car elle contrôle le chemin catalytique emprunté et la nature du produit final. Comprendre l’étape d’activation de l’oxygène est essentiel à la compréhension du rôle biologique et/ou pathologique de la NO-Synthase de mammifère. Cette question s'étend aux NO-Synthases bactériennes pour lesquelles on ne connait ni le mécanisme moléculaire ni la fonction biologique. Ce manuscrit propose une analyse approfondie de l’étape d’activation de l’oxygène de la NO-Synthase. Dans un premier temps, nous avons étudié l’influence de l’environnement proximal sur la réactivité intrinsèque du fer et l’activation de l’oxygène. Nous avons généré des protéines mutées qui modifient les propriétés électroniques de la liaison proximale de l’hème. Ces protéines mutées ont été caractérisées par différentes spectroscopies (résonance paramagnétique électronique, Raman de résonance). Dans un second temps nous avons directement étudié le complexe FeIIO2, en présence d’analogues de substrat, grâce à des analyses de cinétique rapide en flux continu et en flux arrêté (stopped-flow). Dans un troisième temps, le rôle du cofacteur tetrahydrobioptérine dans le transfert de proton et d’électron a été étudié par une méthode de piégeage à des temps très courts : le freeze-quench. L'ensemble de nos résultats montrent que l’activation de l’oxygène est régulée par les propriétés électro-donneuses du ligand proximal et par le réseau de liaisons H distal. Nous mettons en évidence des différences dans le rôle redox du cofacteur tetrahydrobioptérine entre la NO-Synthase de mammifère et la NO-Synthase bactérienne. La difficulté majeure pour comprendre l’étape d’activation de l’oxygène de la NO-Synthase réside dans la complexité et la rapidité de la réaction catalytique. Dans ce contexte, nous avons cherché à adapter une méthodologie qui a prouvé son efficacité dans le cas des cytochromes P450 : la cryo-réduction couplée à des sauts en température. / Nitric oxide is exclusively synthesized by NO-Synthases in mammals. The heart of the NO-synthase activity is oxygen activation, which corresponds to the activation of the FeIIO2 intermediate. This step depends on the heme electronic properties and on the electron and proton transfers. Oxygen activation has to be well mastered to control exactly the nature of the end-product. Understanding the oxygen activation step is necessary to better understand the biological/pathological role of the mammalian NO-Synthases. Furthermore, bacterial NO-Synthases function and oxygen activation mechanism are unknown. This PhD work proposes a deep analysis of the oxygen activation step in NO-Synthases. First, proximal environment has been studied with mutated proteins. These mutations impact the electronic properties of the heme proximal bond. Spectroscopic analyses of these mutants have been done by electron paramagnetic resonance and resonance Raman. Then, we have studied the FeIIO2 intermediate with substrate analogs which has necessitated continuous flow and stopped-flow analyses. Finally, the role of the tetrahydrobiopterin cofactor in the electron and proton transfer has been studied and clarified thanks to a very fast trapping method : the freeze-quench. Our results show that the oxygen activation step is elaborately controlled by the proximal bond electron donation and the distal H bond network. At the same time we show some differences between mammalian and bacterial NO-Synthases concerning the redox role of the tetrahydrobiopterin cofactor. The major obstacle to understand the oxygen activation step resides in the complexity of the active site chemistry and the rate of catalytic reactions. For this reason, we propose to adapt an already successful protocol to trap some intermediates in the cytochromes P450 mechanism : cryo-reduction coupled with temperature jumps.

No description available.

No description available.

Globalization and the increasing time to market have led to ever-higher requirements on the production systems. More than often the short-term thinking and the chase for profit lead to cheap quick fixes. The manufacturing industry changes slowly while the market is changing rapidly, which requires long-term planning for capacity increase but at the same time the ability to rapidly respond to changes. The most crucial factors determining the ability to efficiently produce and deliver a product to market is the utilized production system and a well stated manufacturing strategy. The choice of a certain production system depends on company conditions and requirements as well as the market demands. The current production systems performance and ability to handle different production volumes and divergence must be considered and evaluated from an economical perspective. During this thesis work the benefits and disadvantages with batch flow and one-piece flow have been examined. Generally one-piece flow had been considered the most efficient regarding performance and economical aspects. Meanwhile, batch flow had some benefits associated to it regarding high level of flexibility to handle several different product variants and better possibilities to govern the material flow compared to one-piece flow. There has also been examined which are the most crucial factors affecting the choice between one-piece flow and batch flow. It emerged during the thesis work that the most crucial factor affecting the choice of production system was the Manufacturing Strategy. It can be considered as the ground for every decision regarding the production system and future investments. It determines where the company currently stands, where they want to be in the future and which steps they need to take to get there. The economical factor is as least as important because all decisions include more or less costly investments. At the same time the chosen production system must be as efficient as possible and generate money for the company. Based on these two main factors other interesting factors have been presented. These factors may not affect the choice as much, but are to be considered as important in this context The most crucial factors found to affect the choice of a production system were; Manufacturing Strategy, Economical factors, Production planning and control, Flexibility and capacity, Production volume, variants and trends. The research work has been conducted over a twenty-week period, during which data collection has been performed via Multiple Case Studies at four companies manufacturing similar components within the light and heavy automotive industry. Additional data collection has been performed through a literature review by examining relevant material for the research questions. This have led to a collected knowledge base regarding benefits and disadvantages with each production system along with underlying reasons for deciding on one of them. Based on the collected material from the Case Studies and the theoretical findings, a Mind map visualizing the crucial factors affecting the choice of a production system is presented. This can be utilized by the companies in order for structured evaluation of their current production system and for planning for future changes within production. / Globaliseringen och den ökande pressen på företag att producera och få ut produkter på marknaden på kortast möjliga tid har lett till att det ställs allt högre krav på produktionssystemen. Allför ofta leder kortsiktigt tänkande och jakten på vinster till att företag väljer enkla och billiga snabblösningar. Tillverkningsindustrin förändras långsamt medans marknaden ändras fort, vilket kräver att företagen kan planera för långsiktiga kapacitetsökningar och ändå ha beredskap för att snabbt kunna anpassa sig till förändringar. Det som till allra största del avgör hur effektivt man kan producera och leverera en produkt till marknaden är vilket produktionssystem ett företag använder samt en välformulerad tillverkningsstrategi. Vilket produktionssystem man väljer är beroende av vilka förutsättningar och krav ett företag har lika mycket som av marknadskraven. Man måste ta hänsyn till det nuvarande produktionssystemets prestanda och möjlighet att hantera ändrade produktionsvolymer och variantflora och utvärdera detta ur en ekonomisk synvinkel. Under detta examensarbete har för- och nackdelar med batchflöde och enstycksflöde undersökts och utvärderats. Generellt sätt har enstycksflöde konstaterats vara mest effektivt rent ekonomiskt och prestandamässigt. Däremot, har batchflöde tilldelats fördelar som hög flexibilitet att hantera olika produktvarianter och bättre möjligheter att styra materialflödet jämfört med enstycksflöde. Det har även undersökts vilka som är de mest avgörande faktorerna som styr valet av enstycksflöde eller batchflöde. Under arbetets gång framkom det att den mest avgörande faktorn som påverkar valet av produktionssystem var företagets Produktionsstrategi. Den kan anses vara grunden för alla beslut rörande produktionssystemet och framtida satsningar. Där visar man var företaget befinner sig idag samt var man vill vara i framtiden och vilka beslut man måste ta för att ta sig dit. Den ekonomiska faktorn är minst lika viktig, då alla beslut i slutändan handlar om mer eller mindre kostsamma investeringar. Samtidigt måste det valda produktionssystemet vara så effektivt som möjligt och generera pengar till företaget. Med utgångspunkt från dessa två huvudfaktorer har andra intressanta faktorer tagits fram, som inte påverkar valet av produktionssystem i lika hög grad, men som ändå kan anses vara viktiga i sammanhanget. Forskningsarbetet har bedrivits under 20 veckors tid, där datainsamling har utförts via fallstudier på fyra företag som tillverkar liknande komponenter inom fordonsindustrin. Vidare datainsamling har gjorts genom en litteraturstudie där relevant material för forskningsfrågorna har undersökts. Detta har lett till en samlad kunskapsbas gällande för- och nackdelar med de respektive produktionssystemen samt bakomliggande orsaker till att välja något av dessa produktionssystem. Utifrån det samlade materialet från fallstudierna samt de teoretiska rönen har sedan en tankekarta tagits fram, som visualiserar de avgörande faktorerna som påverkar valet av ett produktionssystem. Denna tankekarta kan företag använda sig av för att på ett strukturerat sätt utvärdera nuvarande produktionssystemet samt planera för framtida förändringar inom produktionen.

Made available in DSpace on 2014-12-17T14:09:19Z (GMT). No. of bitstreams: 1 JonatasALJ_TESE.pdf: 9049452 bytes, checksum: dd9b668c8bc7791108be8a6bbc44e152 (MD5) Previous issue date: 2014-04-28 / A self-flotator vibrational prototype electromechanical drive for treatment of oil and water emulsion or like emulsion is presented and evaluated. Oil production and refining to obtain derivatives is carried out under arrangements technically referred to as on-shore and off-shore, ie, on the continent and in the sea. In Brazil 80 % of the petroleum production is taken at sea and area of deployment and it cost scale are worrisome. It is associated, oily water production on a large scale, carrier 95% of the potential pollutant of activity whose final destination is the environment medium, terrestrial or maritime. Although diversified set of techniques and water treatment systems are in use or research, we propose an innovative system that operates in a sustainable way without chemical additives, for the good of the ecosystem. Labyrinth adsor-bent is used in metal spirals, and laboratory scale flow. Equipment and process patents are claimed. Treatments were performed at different flow rates and bands often monitored with control systems, some built, other bought for this purpose. Measurements of the levels of oil and grease (OGC) of efluents treaty remained within the range of legal framework under test conditions. Adsorbents were weighed before and after treatment for obtaining oil impregna-tion, the performance goal of vibratory action and treatment as a whole. Treatment technolo-gies in course are referenced, to compare performance, qualitatively and quantitatively. The vibration energy consumption is faced with and without conventional flotation and self-flotation. There are good prospects for the proposed, especially in reducing the residence time, by capillary action system. The impregnation dimensionless parameter was created and confronted with consecrated dimensionless parameters, on the vibrational version, such as Weber number and Froude number in quadratic form, referred to as vibrational criticality. Re-sults suggest limits to the vibration intensity / Um prot?tipo vibr?til autoflotador de acionamento eletromec?nico para tratamento de ?gua de produ??o de petr?leo e emuls?o cong?nere ? apresentado e avaliado. A produ??o de petr?leo para refinamento e obten??o de derivados ? realizada sob modalidades tecnicamente referidas como on-shore e off-shore, isto ?, no continente e no mar. No Brasil 80% da produ??o petrol?-fera ? feita no mar e ?rea de implanta??o e escala de custo s?o preocupantes. Associa-se ?gua oleosa de produ??o, efluente abundante em larga escala, carreadora de 95% do potencial polu-idor da atividade cujo destino final ? o meio ambiente mar?timo ou terrestre. Embora diversi-ficado conjunto de t?cnicas e sistemas de tratamento d ?gua encontram-se em uso ou pesqui-sa, prop?e-se um sistema inovador que opera de forma sustent?vel sem aditivos qu?micos, pa-ra o bem do ecossistema. Utilizou-se labirinto adsorvente, em espirais met?licos, e escala la-boratorial de fluxo. Patentes de equipamento e processo s?o reivindicadas. Realizaram-se tra-tamentos em vaz?es e faixas de frequ?ncia distintas, monitoradas com sistemas de controle, uns constru?dos, outros aquistados para tal. Medi??es do teor de ?leo e graxa (TOG) do eflu-ente tratado mantiveram-se dentro do intervalo de enquadramento legal nas condi??es de en-saio. Pesaram-se os adsorventes antes e ap?s o tratamento para obten??o da impregna??o de ?leo, meta de desempenho da a??o vibrat?ria e tratamento como um todo. Tecnologias atuais de tratamento s?o referenciadas para compara??o de desempenho, qualitativa e quantitativa-mente. Confrontou-se consumo energ?tico operando-se em vibra??o, com e sem flota??o con-vencional, e com autoflota??o. Vislumbram-se boas perspectivas de rendimento do sistema proposto, sobretudo, na redu??o do tempo de resid?ncia por a??o de capilaridade. Criou-se o par?metro adimensional de impregna??o e se lhe confrontou com consagrados par?metros a-dimensionais, na vers?o vibracional, como n?mero de Weber e n?mero de Froud quadr?tico, referido como criticalidade vibr?til. Resultados sugerem limites ? intensidade vibrat?ria

No description available.

Las ciudades altamente congestionadas requieren de una óptima gestión de la movilidad urbana. Muchas de estas ciudades se caracterizan porque su infraestructura vial no va acorde con su demanda vehicular, como es el caso de la ciudad de Lima. Por consiguiente, se debe priorizar el desarrollo de la infraestructura vial, ya que existen por ejemplo intersecciones amplias que presentan gran cantidad de puntos de conflicto. En efecto, reducen la capacidad operacional y el nivel de servicio de la intersección. Esta investigación tiene como objetivo reducir los puntos de conflicto y el tiempo de cruce en intersecciones amplias tipo cruz, en base a la Metodología de Flujo Continuo (CFI, por sus siglas en inglés) con delineadores elevados (bolardos compuestos) y detectores (sensores) a fin de mejorar la capacidad y seguridad operacional de la intersección. El objeto de estudio de la presente investigación se encuentra en una zona comercial ubicada entre la Avenida República de Venezuela con la Avenida Aurelio García y García, Lima. Los movimientos vehiculares de giro a la izquierda son los que afectan el rendimiento de las intersecciones señalizadas. Por tanto, se recolectaron 3219 vehículos en total, de los cuales 561 vehículos giraron a la izquierda demostrando así la alta densidad de este tipo de maniobras. La efectividad del diseño propuesto se valida empleando una microsimulación en el software Vissim. Los resultados obtenidos muestran los puntos de conflictos tipo cruz se redujeron a 8 puntos con el modelo propuesto frente al estado actual, el cual posee 58 puntos de conflictos tipo cruz. Por otro lado, el tiempo promedio de cruce de los vehículos disminuyó en 4.20 y 9.79 segundos en la fase 1, debido al rediseño de la geometría de la intersección. En efecto, la capacidad operacional aumentó en 33.85%, ya que el aforo vehicular con el nuevo ciclo semafórico de 150 segundos es de 431vehículos con respecto a los 322 vehículos que se tenía con el modelo anterior. Finalmente, los riesgos de colisiones posteriores y laterales se reducen mediante el uso de delineadores elevados en un 83%. / Highly congested cities require optimal management of urban mobility. Many of these cities are characterized because their road infrastructure does not match their vehicular demand, as is the case in the city of Lima. Therefore, the development of road infrastructure should be prioritized, since there are, for example, wide intersections that present a large number of conflict points. In effect, they reduce the operational capacity and service level of the intersection. This research aims to reduce conflict points and crossing time at wide cross-type intersections, based on the Continuous Flow Methodology (CFI) with elevated eyeliners (composite bollards) and detectors (sensors) in order to improve the capacity and safety of the intersection. The object of study of the present investigation is in a commercial area located between avenue Republica de Venezuela with avenue Aurelio Garcia y Garcia, Lima. The left-turn vehicular movements are those that affect the performance of the signposted intersections. Therefore, 3219 vehicles were collected in total, of which 561 vehicles turned left demonstrating the high density of this type of maneuver. The effectiveness of the proposed design is validated using microsimulation in the Vissim software. The results obtained show the points of cross-type conflicts were reduced to 8 points with the proposed model compared to the current state, which has 58 points of cross-type conflicts. On the other hand, the average crossing time of the vehicles decreased by 4.20 and 9.79 seconds in phase 1, due to the redesign of the intersection geometry. In fact, the operational capacity increased by 33.85%, since the vehicle capacity with the new traffic light cycle of 150 seconds is 431 vehicles with respect to the 322 vehicles that had the previous model. Finally, the risks of posterior and lateral collisions are reduced by the use of elevated eyeliners by 83%. / Tesis