Dissertations / Theses on the topic 'Hydroxylation'

The electrochemical hydroxylation of aromatic substrates was investigated in some detail, with the view to develop a method, which could produce dihydroxybenzenes in acceptable yields. Of particular interest was the selectivity and yield of the 1,4-dihydroxybenzenes. Two distinctly different methods were investigated in order to achieve this goal, acyloxylation and direct electrochemical hydroxylation. Acyloxylation is the process where radical cations generated at the anode undergoes nucleophilic attack by acetate anions. The resulting aromatic acetates so produced can then be hydrolysed to the phenolic compounds. Two nucleophile systems were considered in the investigation, acetates (acetoxylation) and trifluoro-acetates (trifluoro-acetoxylation). These investigations were conducted under a variety of conditions using phenol and phenyl acetate as starting materials. From the results it was, however, concluded that the acetoxylation of these aromatic compounds occurs in unacceptable product and current yields. Trifluoro-acetoxylation on the other hand showed promise, but due to the nature and cost of the reagents it was deemed to be an impractical process. Direct electrochemical hydroxylation: in which the radical cations produced at the anode undergoes nucleophilic attack by water producing the corresponding dihydroxybenzenes. These dihydroxybenzenes are then further oxidised to the benzoquinones, which then undergo reduction at the cathode in order to produce the corresponding dihydroxybenzene. In this process phenol, 2-tert-butylphenol and 2,6-di-tert-butylphenol were investigated as substrates. The results indicated that the yield towards the 1,4-dihdroxybenzenes increased as the degree of substitution on the ring increased.

Thesis (MScEng (Process Engineering))--University of Stellenbosch, 2009.
Aromatic precursor compounds are derivatives that play an important role in biosystems and are useful in the production of fine chemicals. This work focuses on the catalytic synthesis of 2-methyl-1, 4-naphthoquinone and cresols (para- and ortho) using aqueous hydrogen peroxide as an oxidant in liquidphase oxidation of 2-methylnaphthalene and toluene over titanium-substituted zeolite TS-1 or Ti-MCM-41. Catalysts synthesised in this work were calcined at 550°C, extensively characterised using techniques such as X-ray Fluorescence for determining the catalyst chemical composition; BET for surface area, pore size and micropore volume; Powder X-ray diffraction for determining their crystallinity and phase purity and SEM was used to investigate the catalyst morphologies. The BET surface areas for Ti-MCM-41 showed a surface area of 1025 m2/g, and a 0.575 cm3/g micropore volume. However, zeolite TS-1 showed a BET surface area of 439 m2/g and a 0.174 cm3/g micropore volume. The initial experiments on 2-methylnaphthalene hydroxylation were performed using the normal batch method. After a series of batch runs, without any success as no products were generated as confirmed by GC, a second experimental tool was proposed. This technique made use of the reflux system at reaction conditions similar to that of the batch system. After performing several experimental runs and optimising the system to various reactor operating conditions and without any products formed, the thought of continuing using the reflux was put on hold. Due to this, a third procedure was brought into perspective. This process made use of PTFE lined Parr autoclave. The reactor operating conditions were changed in order to suit the specifications and requirements of the autoclave. This process yielded promising results and the formation of 2-MNQ was realised. There was a drawback when using an autoclave as only one data point was obtained, at the end of each run. Therefore, it was not possible to investigate reaction kinetics in terms of time. Addition of aqueous hydrogen peroxide (30 wt-%) solution in the feed was done in one lot at the beginning of each reaction in all oxidation reactions, to a reactor containing 2-methylnaphthalene and the catalyst in an appropriate solvent of choice (methanol, acetonitrile, 2-propanol, 1-propanol, 1-pentanol, and butanol), with sample withdrawal done over a period of 6 hours (excluding catalytic experiments done with a Parr autoclave as sampling was impossible). As expected, 2-methylnaphthalene oxidation reactions with medium pore zeolite TS-1 yielded no formation of 2-methyl-1, 4-naphthoquinone using various types of solvents, with a batch reactor, reflux system, or a Parr PTFE autoclave. This was attributed to the fact that 2-methylnaphthalene is a large compound and hinders diffusion into zeolite channels. With the use of an autoclave, Ti-MCM-41 catalysed reactions showed that the choice of a solvent and reaction temperature strongly affect 2- methylnaphthalene conversion and product selectivity. This was proven after comparing a series of different solvents (such as methanol, isopropanol, npropanol, isobutanol, n-pentanol and acetonitrile) at different temperatures. Only reactions using acetonitrile as a solvent showed 2-MNQ. Formation of 2- MNQ, indicating that acetonitrile is an appropriate choice of solvent for this system. The highest 2-methylnaphthalene conversion (92%) was achieved at 120 ˚C, with a relative product selectivity of 51.4 %. Temperature showed a major effect on 2-MN conversion as at lower reaction temperature 100˚C, the relative product selectivity (72%) seems to enhance; however, the drawback is the fact that lower 2-methylnaphthalene conversions (18%) are attained. Another important point to note is the fact that using an autoclave (with acetonitrile as a solvent), 2-methyl-1-naphthol was generated as a co-product. In conclusion, it has been shown that the hydroxylation of different aromatic compounds over zeolites conducted in this study generated interesting findings. In 2-MN hydroxylation over Ti-MCM-41 as a catalyst, only acetonitrile is an appropriate choice of solvent using an autoclave. In addition, zeolite TS-1 is not a suitable catalyst for 2-MN hydroxylation reactions. It is ideal to optimise an autoclave in order to investigate reaction kinetics and optimum selectivity. Toluene hydroxylation reactions yielded para and ortho-cresol as expected with either water or acetonitrile as a solvent. No meta-cresol was formed. The kinetic model fitted generated a good fit with water as a solvent or excess toluene, with acetonitrile as a solvent generating a reasonable fit.

Le marché mondial des enzymes industrielles, estimé à 17 milliards USD en 2025, continue à croître. La forte demande attire de plus en plus l'attention en raison des avantages de ces enzymes à efficacité élevée, faible coût et respect de l'environnement. Les biocatalyseurs sont développés en raison de la demande dans les domaines pharmaceutique, de la recherche, de la biotechnologie et du diagnostic. L'objectif de ce projet est de réaliser un système in vitro capable de catalyser une réaction d'hydroxylation aromatique. Ce projet est principalement divisé en deux parties. Après une introduction, les détails de l’établissement du système seront décrits et suivis d’une étude sur les propriétés biochimiques. Afin d’obtenir un rendement plus élevé en produits à haute valeur ajoutée, l’activité sur des substrats non naturels doit être renforcée. Une approche cristallographie-structure-mutagenèse est appliquée, basée sur la structure modèle de l'enzyme, certains résidus sont mutés en acide aminé spécifique et l'activité de ces mutants est testée sur des non-substrats. L'hydroxylation est une réaction redox, des cofacteurs sont nécessaires. Pour un système in vitro, il faut réduire les coûts de production en évitant d’utiliser des cofacteurs de forme réduite qui est à prix élevé. Un système de régénération sera introduit. Le système de régénération enzymatique actuellement utilisé dans la production industrielle reste une méthode efficace. De nouvelles méthodes telles que la régénération électrochimique, la régénération catalysée par des complexes organométalliques montrent une activité comparable au système enzymatique. Afin de faciliter le recyclage du catalyseur, un processus d’hétérogénéisation du catalyseur est appliqué. Un exemple d'immobilisation d'un complexe organométallique à base de Rh sur une Bipyridine-Périodique Mésoporeuse Organosilica (Bpy-PMO) est étudié. Ce catalyseur hétérogène montre une activité de régénération et une recyclabilité relativement intéressante
The growing global market of industrial enzymes is estimated to attain 17 billion USD in 2025. The strong demand and many advantages such as high efficiency, low cost, environmentally friendly procedures draw more attention to its use. Besides the regular utilization, specialty enzymes including biocatalysts are quickly developing due to the demand in pharmaceutics, research & biotechnology, and diagnostics. The objective of this project is to realize an in vitro system which can catalyze an aromatic hydroxylation reaction. This project is divided into two parts. After an introduction, the details of system establishment will be described, followed by a study on biochemical properties. In order to achieve a higher yield on high added value products, activity on non-natural substrates needs to be enhanced. A crystallography-structure-mutagenesis approach is applied, based on the model structure of the enzyme, chosen residues are mutated into specific amino acids and activity of these mutants is tested on non-substrates. Considering hydroxylation is a redox reaction, cofactors are needed. For an in vitro system, in order to lower production cost by avoiding using high price reduced cofactors, a regeneration system will be introduced. The enzymatic regeneration system currently used in industrial production is still considered to be an efficient method. Nevertheless, new methods such as electrochemical regeneration, organometallic complexes catalyzed regeneration show a comparable activity to the aforementioned enzymatic regeneration system. With the goal of facilitating catalyst recycling, a catalyst heterogenization process is applied. Immobilization of a Rh based organometallic complex on Bipyridine-Periodic Mesoporous Organosilica (Bpy-PMO) is investigated as an example. This heterogeneous catalyst shows relatively interesting cofactors regeneration activity and recyclability

SidA from Aspergillus fumigatus is an N-hydroxylating monooxygenase that catalyzes the committed step in siderophore biosynthesis. This gene is essential for virulence making it an excellent drug target. In order to design an inhibitor against SidA a greater understanding of the mechanism and structure is needed. We have determined the crystal structure of SidA in complex with NADP+, Ornithine, and FAD at 1.9 ? resolution. The crystal structure has provided insight into substrate and coenzyme selectivity as well as residues essential for catalysis. In particular, we have chosen to study the interactions of Arg 279, shown to interact with the 2'phosphate of the adenine moiety of NADP+ as well as the adenine ring itself. The mutation of this residue to alanine makes the enzyme have little to no selectivity between coenzymes NADPH and NADH which supports the importance of the ionic interaction between Arg279 and the 2'phosphate. Additionally, the mutant enzyme is significantly more uncoupled than WT enzyme with NADPH. We see that the interactions of the guanadinyl group of Arg279 and the adenine ring are also important because KM and Kd values for the mutant enzyme are shifted well above those of wild type with coenzyme NADH. The data is further supported by studies on the reductive and oxidative half reactions. We have also explored the allosteric effect of L-arginine. We provide evidence that an enzyme/coenzyme/L-arginine complex is formed which improves coupling, oxygen reactivity, and reduction in SidA; however more work is needed to fully understand the role of L-arginine as an allosteric effector.
Master of Science in Life Sciences

Chiral a -hydroxy ketones are important structural units in many natural products, biologically active compounds and the hydroxyl group has frequently been used as a reagent directing group, such as for the selective elaboration of aldol products. In this work, enzymatic synthesis of both enantiomers of the a -hydroxy ketones (2-hydroxy indanone, 2-hydroxy tetralone) using Aspergillus niger by selective &
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-oxidation of ketones (1-indanone, 1-tetralone) was studied. The &
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-oxidation of ketones was carried out by using whole cells of Aspergillus niger in different growth media. A. niger whole cell catalyzed reactions afforded (S)-configurated 2- hydroxy-1-tetralone with %87 e.e. in DMSO at pH 5.0. In addition to this,while (S)-configurated 2-hydroxy-1-indanone with %33 e.e. in pH 8.0 (in DMSO) was synthesized, (R)-configurated-2-hyroxy-1-indanone with %32 e.e. in pH 7.0 ( in DMSO) was synthesized.

Master of Science
Department of Grain Science and Industry
Xiuzhi Susan Sun
Plant oil-based raw materials have become more attractive alternatives in polymer industry as fossil resources depletion and environmental concerns continue to arise. Camelina (camelina sativa L.) seed contains about 45% of oil and about 90% of the oil is unsaturated fatty acids such as linoleic acid, α-linolenic acid, and erucic acids. It also provides the advantages of low cost and low fertilizer demand. Functionalized oils such as epoxidized camelina oil (ECO) and di-hydroxyl camelina oil (DCO) can be used for resins, adhesives, coatings, etc. The objectives of this work were to synthesize and characterize ECO and DCO from camelina oil. The epoxidation reaction of camelina oil was completed with formic acid and hydrogen peroxide. Catalyst ratio, reaction time, and temperature effects on the epoxidation reaction were studied. The optimum epoxy content of 7.52 wt% with a conversion rate of 76.34% was obtained from camelina oil using excess hydrogen peroxide and a molar ratio of formic acid of less than 1 for 5 hours in 50 °C. Camelina oil yields higher epoxy content (7.52 wt%) than soybean oil (6.53 wt%); however, soybean oil had a higher conversion rate of 80.16% compared to camelina oil because of uniform fatty acids distribution. In this study, we found that epoxidation efficiency is significantly affected by fatty acids composition, structure, and distribution. DCO was synthesized from ECO with different reaction parameters. The ring opening of ECO was performed with water, perchloric acid, and THF as proton donor, catalyst, and solvent respectively. Hydroxyl value of DCO was measured, and the maximal hydroxyl value was 369.24 mg KOH/g. physical properties of DCO were characterized by acid value and moisture content; thermal properties of DCO were obtained using different scanning calorimeter (DSC), thermalgravimetric analysis (TGA). Amount of solvent and acid catalyst addition affected the hydroxyl value and residual acid in DCO. Heat capacity, phase transition temperatures, and thermal stability of DCO were obtained and showed higher values than ECO’s. The DCO showed higher peel adhesion when it was formulated with epoxidized soybean oils through UV curing because camelina oil allows higher epoxy content, which results in higher hydroxyl values.

L'emploi de microorganismes permet de fonctionnaliser des molecules-substrats difficilement synthetisees par voie purement chimique. Un champignon filamenteux, mucor plumbeus permet d'introduire des fonctions oxygenees, et d'obtenir en particulier des molecules hydroxylees sur des atomes de carbone non active, de facon regio- et stereo-selectives avec des rendements variables. Les produits etudies sont des di- et sesqui- terpenes, dont le squelette de base identique a subi quelques modifications. Une relation entre l'activite hydroxylante de mucor plumbeus et la structure chimique du compose se degage. Une partie de ces resultats a ete publiee: tetrahedron,1991,47,8339 et tetrahedron lett. 1992,33,7845. Plus de 25 biotransformations differentes ont fourni 40 nouveaux produits. Avec des diterpenes, mucor plumbeus conduit a des derives varies: majoritairement des produits hydroxyles sur le carbone non active c-3 en position beta (cas du sclareol), et minoritairement a des cetones, des epoxydes, voire le substrat initial inaltere ou au contraire entierement degrade. Mucor plumbeus realise aussi une hydroxylation majoritairement en position allylique sur des sesquiterpenes drimaniques, et sur des synthons possedant un groupe trimethyl-2,6,6-cyclohexene. Par exemple, le drimenol est transforme en deux derives hydroxyles, l'un majoritairement en position allylique c-6 alpha et l'autre minoritairement en position c-3, et un epoxyde

L'activation de l'oxygene moleculaire par les metaux de transition est fondamentale pour de nombreuses oxydations biologiques dans lesquelles interviennent des systemes enzymatiques qui peuvent etre modelises. Celui du cytochrome p-450 est imite par un catalyseur chimique a base de fer: le systeme d'udenfriend (fer ferreux-edta-oxygene). Ce systeme biomimetique permet d'oxyder selectivement des composes aromatiques et, dans cette etude, le catalyseur est regenere par reduction electrochimique. Les objectifs de ce travail sont, d'une part, l'amelioration du systeme electrochimique et, d'autre part, une meilleure comprehension des mecanismes des reactions d'hydroxylation des composes aromatiques en phase liquide. L'etude electrochimique du catalyseur a montre qu'il s'oxydait rapidement et que ses proprietes etaient modifiees en fonction de la nature de l'electrode. Lors de l'hydroxylation du phenol, premier substrat modele choisi, on a mis en evidence que la cathode (tresse de carbone) ameliorait l'activite du systeme catalytique. Cependant, ce type de cathode n'est pas stable ce qui nous a conduit a utiliser plutot une cathode en mousse de nickel. D'autre part, le fait que la cathode ne soit pas separee de l'anode entraine des reactions secondaires que nous avons significativement diminuees en utilisant une cellule a compartiments separes. L'hydroxylation du toluene (second substrat modele) a ete etudiee en utilisant comme solvant un melange ch#3cn, h#2o, acoh de composition variable. On a montre que la selectivite (l'hydroxylation du noyau aromatique par rapport a l'oxydation du groupement methyle) dependait de la composition et de la polarite du solvant ainsi que l'acidite du milieu. Enfin cette etude nous a permis de proposer parmi toutes les especes actives susceptibles d'etre mises en jeu (les especes feroxo, ferryl et fer-dihydroxo) un schema reactionnel faisant intervenir l'espece ferryl

There is an increasing commercial interest in finding alternative ways to produce phenol that overcome the disadvantages of the current cumene process used to synthesize phenol. The drivers for the change are both economic and environmental. A direct oxidation route for producing phenol from benzene is based on using N2O as an oxidizing agent in the gas phase in the presence of modified Fe-ZSM5 zeolite. One of the main objectives was to examine the effect of different Si/Al ratios, temperatures and iron content on the selective conversion of benzene to phenol with a desire to achieve high selectivity and minimise catalyst deactivation. Also one of the research objectives was to identify the active sites in the catalyst and design the catalyst which is able to delay coke formation. The methodology was to incorporate iron directly at extra-framework positions via liquid ion-exchange. In this project, a series of selective Fe-ZSM5 catalysts with different Si/Al ratios have been prepared and evaluated for selective formation of phenol. The catalyst samples were characterized (by Atomic Absorption Spectroscopy (AAS), Malvern mastersizer and Nitrogen adsorption using N2 at 77 K via Micromeritics to determine the elemental composition, average particle size, BET surface area and pore size distribution) and their catalytic activities compared. A quantitative comparison between the number of active sites using isopropylamine decomposition method shows that active sites increase as the Si/Al ratio increased and also as the iron content increased. (Continues...).

Il s'agit des premiers modeles chimiques de la dopamine beta hydroxylase, une enzyme impliquee dans la biosynthese des catecholamines. Ainsi in vivo, cette enzyme oxyde de facon enantioselective la dopamine en noradrenaline. Ces modeles sont constitues de complexes mononucleaires du cuivre afin de mimer le site acitf de l'enzyme et de mettre en evidence les differentes especes actives impliquees dans le mecanisme d'hydroxylation de la dopamine par la proteine. Grace a ces modeles et en presence d'oxygene ou d'iodosylbenzene, nous avons realise un ensemble d'hydroxylations de noyaux pyridine ou de chaines aliphatiques en alpha de carbonyle de fonction amide ou en alpha de noyau pyridine. De plus l'un de nos complexes s'est avere etre un modele de peroxydase et a permis de mettre en evidence le cuivre au degre d'oxydation (+3). De maniere generale, au cours de ces travaux, nous avons realise l'activation du dioxygene et ainsi, nos complexes se sont averes etre de veritables modeles de monooxygenases

L'activation des alcanes (projet actane) et leur fonctionnalisation selective sont des defis actuels que le chimiste organicien essaie de relever. Dans ce domaine, l'adamantane est une cible de choix de par sa symetrie, la stabilite de sa structure et le potentiel d'applications que lui confere sa lipophilie. Apres une mise au point bibliographique sur la chimie de l'adamantane et l'activation des alcanes, nous decrivons dans ce memoire de nouvelles methodes de fonctionnalisation de l'adamantane en milieu acide de lewis ou de bronsted (et non en milieu superacide). La chloration de l'adamantane par transfert d'halogene a partir de tbucl en presence de alcl#3 conduit au meilleur rendement et a la meilleure selectivite jamais observes en 1-chloroadamantane. La preparation de l'acide 1-adamantanecarboxylique peut se faire par echange de la fonction acide avec l'acide pivalique ou en presence des formiates d'alkyles. Ce sont deux nouvelles reactions de fonctionnalisation. Le traitement de l'adamantane en milieu acide sulfurique conduit suivant les conditions de reaction, a une hydroxylation ou a une alkylation. L'analyse des resultats experimentaux et l'apport de la chimie theorique nous permettent de discuter le mecanisme de transfert intermoleculaire d'hydrure implique dans ces reactions

This thesis describes the application of a number of whole cell systems to the hydroxylation of organic compounds and thus the production of high value synthetic intermediates. Such transformations are currently very difficult, or impossible to achieve using purely synthetic techniques. Biocatalysis on the other hand, offers the potential to achieve this process in a mild, regio- and stereoselective manner. A range of compounds comprised of a carbo- or heterocycle attached via a linker to an aromatic group have been prepared. These compounds were screened as potential substrates with a number of whole cell systems thought to contain cytochromes P-450. Subsequent biotransformation, product isolation and characterisation are described. Investigation of the biohydroxylation of a series of N-carboxybenzylalkylpiperidines by Beauveria bassiana ATCC 7159 and study of the factors important to the selectivity of hydroxylation by the organism is illustrated. Research into the biohydroxylation capabilities of two members of the Rhodococcus genus has also been carried out. Rhodococcus sp. NCIMB 9784 and Rhodococcus rhodochrous NCIMB 9703 were found to be suitable biocatalysts for the hydroxylation of non-natural substrates. Subsequent exploration of the regio- and enantioselectivity of this hydroxylation process is discussed.

La synthese et la substitution regioselective d'aryldiethoxymethylsilanes fonctionnels ont ete etudiees. D'une part, les modeles silicies aromatiques ont ete obtenus de facon originale par scission du 1,2-dimethyltetraethoxydisilane par des halogenoarenes, la reaction etant catalysee par un complexe du palladium. La mise au point a necessite une etude prealable du choix des differents parametres. D'autre part, l'hydroxylation regioselective des precurseurs arylsilanes, par l'eau oxygenee ou par le peroxyde de bis(trimethylsilyle), a ete realisee, conduisant a l'obtention de phenols fonctionnels. La preparation d'une cible, le 3-fluoro-4-(1'-methyl)heptyloxyphenol, constituant l'etape cle de l'elaboration de nouveaux cristaux liquides, a ete conduite a son terme

L'oxazolidine trifluorométhylée (trans-Fox) dérivée du (R)-phénylglycinol a été préparée sous forme diastéréoisomériquement pure par résolution dynamique induite par la cristallisation d'un mélange d'oxazolidines cis et trans.La trans-Fox a été utilisée avec succès comme auxiliaire chiral pour des réactions d'hydroxylation par l'oxygène moléculaire et de fluoration électrophile d'énolates d'amide ainsi qu'en réarrangement sigmatropique [2,3] d'amines allyliques. Après clivage, des composés énantiomériquement purs d'une grande importance synthétique sont obtenus.Une voie d'accès à des pyrrolydines trifluorométhylées chirales a été mise au point à partir de la trans-Fox. La trans 2-phenyl-5-trifluoromethylpyrrolidine a été utilisée comme auxiliaire chiral pour des réactions d'alkylation asymétriques
The trifluoromethylated oxazolidine (trans-Fox) derived from (R)-phenylglycinol was prepared as a single diastereoisomer by a cristallisation induced dynamic resolution of a mixture of cis and trans oxazolidines.The trans-Fox was used with success as a chiral auxiliary for hydroxylation by oxygen and electrophilic fluorination of amide enolates reactions and [2,3] sigmatropic rearrangements of allylic amines. After deprotection, very synthetically useful enantiomerically pure compounds were obtained.An acces to chiral trifluoromethylated pyrrolidines was developped starting from trans-Fox. The trans 2-phenyl-5-trifluoromethylpyrrolidine was used as a chiral auxiliary for asymmetric alkylation reactions

Thesis (MScEng (Process Engineering))--University of Stellenbosch, 2010.
ENGLISH ABSTRACT: Partially oxygenated aromatic compounds, e.g. quinones, hydroquinones and cresols, play a vital role in the fine chemical industry and were initially prepared by stoichiometric oxidation processes that produce toxic products that are hazardous towards the environment. As a result, it was important to investigate environmentally friendly processes for the hydroxylation of aromatic compounds. This resulted in newer methods using Ti-substituted microporous zeolites as catalysts with hydrogen peroxide as oxidant in the presence of a solvent. However, the methods were found to be ineffective for large, bulky substrates due to the small pore structure. This led to using Ti-mesoporous materials as catalysts but suffered from two drawbacks; the hydrophilic nature and low hydrothermal stability of the catalyst structure. Ti-microporous and Ti-mesoporous materials acting as catalysts for the oxidation of bulky substrates achieved environmentally friendly processes but obtained low conversions and quinone yields. Therefore, the challenge has been to develop a process that is environmentally friendly, achieves high conversions, where the catalyst acts truly heterogeneous and obtains high quinone yields for the hydroxylation of bulky substrates. Recently, micropores/mesopores catalysts incorporating advantages of both micropores and mesopores materials were synthesised and seemed promising for the hydroxylation of bulky substrates. This study focuses on synthesising and evaluating the feasibility of various Ti-substituted catalysts for improving the hydroxylation of the bulky substrate, 2-methylnaphthalene (2MN) with hydrogen peroxide as oxidant in the presence of a solvent, acetonitrile. The oxidation of 2MN produces 2-methyl-1,4-naphthoquinone (2MNQ). 2MNQ is also known as menadione or Vitamin K3 and acts as a blood coagulating agent. The catalysts synthesised for this study were mesoporous catalysts, Ti- MCM-41 and Ti-MMM-2 and microporous/mesoporous catalysts, Ti-MMM-2(P123) and a highly ordered mesoporous material. The main objective of this study was to design an efficient process that is environmentally friendly and achieves high 2MN conversions and 2MNQ yields. This was achieved by evaluating the various catalysts synthesised, reaction conditions, testing if the catalyst was truly heterogeneous and identifying the products formed from the process. The designed process was proved to be environmentally friendly because the system did not produce products that were harmful towards the environment. The products identified in this study were 2MNQ, 2-methyl-1-naphthol, 2-naphthaldehyde, 3-ethoxy-4-methoxybenzaldehyde and menadione epoxide. An investigation was conducted to determine which catalyst synthesised favoured this process by quantifying the effect reaction conditions have on the various catalysts. The reaction conditions were defined in terms of the hydrogen peroxide volume, catalyst amount, solvent volume, substrate amount, reaction time and reaction temperature. The desired catalyst for this study obtained the highest 2MN conversions in comparison with the other catalysts and favoured the formation of 2MNQ. The catalyst achieving the highest conversions and favouring 2MNQ in most cases for this investigation was the highly ordered mesoporous material. Improving operating conditions to obtain high 2MNQ yields for the oxidation of 2MN to 2MNQ over the highly ordered mesoporous material was determined by varying the reaction conditions with the one factor at a time approach and a factorial design. The one factor at a time approach showed that best 2MNQ yields were obtained at 1 g substrate when investigating a change in substrate amount between 0.5 g and 2 g. Best 2MNQ yields were obtained at 10 ml solvent when investigating a change of solvent volume between 5 ml and 20 ml. The 2MNQ yield increased with increasing the catalyst amount (50 mg to 200 mg), hydrogen peroxide volume (1 ml to 6 ml) and increasing the reaction times (2 hour to 6 hours) at reaction temperatures, 120°C and 150°C. The yield decreased with increasing the reaction time (2 hours to 6 hours) at reaction temperature, 180°C. A preliminary 2 level factorial design was prepared to observe if there were any important interactions affecting the 2MNQ yield. The results from the factorial design indicated that the hydrogen peroxide volume had the most influence on the 2MNQ yield followed by the reaction time-reaction temperature interaction and reaction temperature. From the factorial design, the yield increased by increasing the hydrogen peroxide volume and reaction temperature whilst decreasing the reaction temperature-reaction time interaction. The highest 2MNQ yields and 2MN conversions obtained for the hydroxylation of 2MN to 2MNQ over the highly ordered mesoporous material in this study were in the ranges 48-50 % and 97-99 %, respectively. This study indicates that the process system, reaction conditions and catalyst type have an impact on the products formed, 2MN conversion, 2MNQ selectivity and 2MNQ yield. The highly ordered mesoporous material was found to be truly heterogeneous because no leaching occurred and the catalyst could be recycled without losing its catalytic activity and selectivity for at least two catalyst cycles. It can be concluded that the highly ordered mesoporous material is therefore a promising catalyst for the selective oxidation of bulky substrates with aqueous H2O2 because it produces an environmentally friendly process, achieves high conversions, obtains high quinone yields and the catalyst truly acts heterogeneous.
AFRIKAANSE OPSOMMING: Gedeeltelik geoksideerde aromatiese verbindings (bv. kinone, hidrokinone en kresole) speel ‘n belangrike rol in die fynchemiebedryf. Hierdie verbindings is aanvanklik voorberei deur stoïchiometriese oksidasie prosesse wat gifstowwe nadelig vir die omgewing veroorsaak. Daarom is dit belangrik om omgewingsvriendelike prosesse vir die hidroksilering van aromatiese verbindings te ondersoek. Hierdie ondersoeke het gelei tot nuwe metodes wat Ti-vervangde mikroporeuse seoliete as katalisator met waterstofperoksied as oksideermiddel in die teenwoordigheid van ʼn oplosmiddel benut. Dit is egter gevind dat hierdie metodes oneffektief is vir groot, lywige substrate weens die fyn poriestruktuur van die katalisator. Dit lei tot die gebruik van Ti-mesoporeuse materiale as katalisators, maar toon twee tekortkominge, naamlik die hidrofiliese aard en lae hidrotermiese stabiliteit van die katalisatorstruktuur. Ti-mikroporeuse en Ti-mesoporeuse materiale benut as katalisators vir die oksidasie van lywige substrate lewer omgewingsvriendelike prosesse, maar vermag lae omsetting en kinoonopbrengs. ʼn Uitdaging is dus om ʼn omgewingsvriendelike proses te ontwikkel met hoë omsetting, waar die katalisator werklik heterogeen optree en hoë kinoonopbrengs lewer vir die hidroksilering van lywige substrate. Katalisators vir die hidroksilering van lywige substrate wat die voordele van beide mikroporieë/mesoporieë ten toon stel is onlangs gesintetiseer, met belowende resultate. Hierdie studie is ingestel op die sintetisering en evaluering van uitvoerbaarheid van verskeie Tivervangde katalisators vir die optimering van die hidroksilering van die lywige substraat, 2- metielnaftaleen (2MN), met waterstofperoksied as oksideermiddel met asetonitriel as oplosmiddel. Die oksidering van 2MN produseer 2-metiel-1,4-naftokinoon (2MNK), ook bekend as vitamien K3, ʼn bloedstollingsmiddel. Die katalisators vervaardig vir hierdie studie was die mesoporeuse katalisators, Ti-MCM-41 en Ti-MMM-2, en die mikroporeuse/mesoporeuse katalisor Ti-MMM-2(P123), sowel as ʼn hoogs geordende mesoporeuse materiaal. Die hoofdoel van hierdie studie was om ʼn doeltreffende, omgewingsvriendelike proses met hoë 2MN omsetting en 2MNK opbrengs te ontwerp. Voorgenoemde is vermag deur verskeie gesintetiseerde katalisators en reaksiekondisies te evalueer, om te toets of katalisators werklik heterogeen is, en om die prosesprodukte te identifiseer. Die ontwerpte proses kan beskou word as omgewingsvriendelik, aangesien die stelsel geen produkte lewer wat skade aan die natuur kan veroorsaak nie. 2MNK, 2-metiel-1-naftol, 2-naftaldehied, 3- etoksi-4-metoksibensaldehied en menadioonepoksied is in hierdie studie geïdentifiseer as prosesprodukte. Om te bepaal watter gesintetiseerde katalisators hierdie proses begunstig, is ʼn ondersoek geloods om die effek van reaksiekondisies op die verskeie katalisators te kwantifiseer. Die reaksiekondisies is omskryf in terme van waterstofperoksiedkonsentrasie, katalisatorhoeveelheid, oplosmiddelvolume, substraathoeveelheid, reaksietyd en reaksietemperatuur. Die gewenste katalistor vir hierdie proses was die katalisator wat die hoogste 2MN omsetting lewer en die vorming van 2MNK bevorder. Die hoogs geordende mesoporeuse materiaal was in hierdie ondersoek die katalisator met die hoogste omsetting wat ook 2MNK-vorming bevorder het in die meeste gevalle. Om die beste bedryfstoestande vir hoë 2MNK opbrengs vanaf die oksidering van 2MN oor hoogs geordende mesoporeuse materiaal te bepaal, is die reaksiekondisies verander deur met een faktor op ʼn slag te verander, sowel as faktorverandering volgens ʼn faktoriaalontwerp. Die een-faktor-op-‘nslag benadering het getoon dat die 2MNK opbrengs ʼn maksimum bereik waar die substraathoeveelheid tussen 0.5 g en 2 g wissel, met die oplosmiddelvolume tussen 5 ml en 20 ml. Die opbrengs het ietwat verbeter met ʼn groter hoeveelheid katalisatorhoeveelheid (van 50 mg na 200 mg), terwyl die opbrengs drasties verbeter het waar die waterstofperoksiedvolume van 3 ml tot 6 ml verhoog is. Die opbrengs het ook verbeter met ʼn styging in reaksietemperatuur (van 120°C tot 180°C) met reaksietydintervalle van 1 tot 6 ure. Die opbrengs het egter gedaal by 180°C waar reaksietye langer as 2 ure. Volgens die resultate van die een-faktor-op-‘n-slag benadering blyk dit dat reaksietemperatuur, waterstofperoksiedvolume, katalisatorhoeveelheid en reaksietyd faktore is wat verhoogde 2MNK opbrengs bevorder. Hierdie reaksiekondisies is geselekteer vir die faktoriaalontwerp. ʼn Voorlopige 2- vlak faktoriaalontwerp is voorberei om te bepaal of daar enige belangrike interaksies is wat die 2MNK opbrengs beïnvloed. Die resultate van die faktoriaalontwerp het aangetoon dat waterstofperoksiedvolume die grootste invloed op 2MNK opbrengs het, gevolg deur die interaksie van reaksietyd en reaksietemperatuur, en dan reaksietemperatuur. Die faktoriaalontwerp resultate toon verder dat opbrengs verhoog met toenemende waterstofperoksiedvolume en reaksietemperatuur, terwyl die opbrengs verlaag soos wat die reaksietyd-reaksietemperatuur interaksie toeneem. Hierdie studie het hoogste 2MNK opbrengs van 48-50% en 2MN omsetting van 97-99% vir die hidroksilering van 2MN na 2MNK oor hoogs geordende mesoporeuse materiale behaal. Hierdie studie bevestig bevindinge van die literatuur dat die prosesstelsel, reaksiekondisies en katalisatortipe ʼn groot impak het op prosesprodukte, 2MN omsetting, 2MNK selektiwiteit en 2MNK opbrengs. In hierdie navorsingstudie is bevind dat hoë 2MN omsetting en 2MNK opbrengs behaal word by hoë reaksietemperature met kort reaksietye en hoë waterstofperoksiedvolumes. Dit is gevind dat die hoogs geordende mesoporeuse materiaal werklik heterogeen is, aangesien geen loging plaasgevind het nie, en aangesien die katalisator hergebruik kon word sonder verlies aan katalisatoraktiwiteit en –selektiwiteit, vir ten minste twee katalisatorsiklusse. ʼn Gevolgtrekking kan gemaak word dat die hoogs geordende mesoporeuse materiaal ʼn belowende katalisator vir die selektiewe oksidering van lywige substrate met waterige H2O2 is, aangesien dit ʼn omgewingsvriendelike proses lewer met hoë omsetting, hoë kinoonopbrengs en katalisatorgedrag wat waarlik heterogeen is.

L'hydroxylation du phenol par le peroxyde d'hydrogene en phase liquide est catalysee par des solides acides. En presence d'une acidite forte, les resultats cinetiques sont en accord avec une substitution electrophile aromatique. Par contre, lorsque la force des sites acides est faible, la reaction de substitution electrophile est lente, mais suivie d'une autocatalyse. Lorsque la force acide du catalyseur est tres faible, une periode d'induction, pouvant atteindre plusieurs heures, est observee. L'addition en debut de reaction d'un des produits: pyrocatechol, hydroquinone ou quinone, permet de supprimer cette periode d'induction. L'ajout d'autres agents de transfert d'electron produit le meme effet. Ainsi, la reaction autocatalytique fait intervenir un mecanisme d'oxydo-reduction sans qu'il s'agisse necessairement d'une reaction de fenton

N-hydroxylating monooxygenases (NMOs) are Class B flavin-dependent monooxygenases found only in fungi and bacteria. These enzymes catalyze the hydroxylation of nucleophilic primary amines, such as those found in histamine, L-ornithine, L-lysine, and small aliphatic diamines. The hydroxamate moiety produced by this reaction is key for the production of siderophores, small chelating compounds that allow survival in iron limiting conditions. NMOs involved in siderophore biosynthesis have been shown to be essential for pathogenesis in organisms such as Aspergillus fumigatus, Pseudomonas aeruginosa, and Mycobacterium tuberculosis. Therefore, NMOs are considered novel drug targets for the treatment associated with these diseases. Herein we present the characterization of TheA, an NMO from Thermocrispum agreste. The enzyme mechanism was studied using steady state kinetic measurements, thermostability, and stopped flow spectrophotometry assays. Using these techniques, the catalytic rates, substrate binding affinities, thermal stability, and coenzyme specificities were determined. Additionally, NADPH analogues were produced to use as tools to study FAD reduction in NMOs. An unspecific reduction reaction of NADP+ using NaB2H4 yielded [6-2H]-NADPH, [2-2H]-NADPH, and [4-2H]-NADPH. Compound identity was confirmed by mass spectrometry and unidimensional proton nuclear magnetic resonance (NMR). Results presented in this thesis lay the foundation for future studies of NMOs using NADPH analogues. In conjunction, these results will improve the general knowledge and understanding of flavoenzymes, ornithine monooxygenases, and their associated mechanisms.
Master of Science in Life Sciences

L'etude electrochimique de differentes proteines contenant du fer montre que l'activite biologique de ces molecules peut etre modulee au moyen d'une electrode. Le premier exemple concerne la peroxydase de raifort. Il est possible de preparer electrochimiquement les differents composes intermediaires rencontres aussi bien dans le cycle catalytique classique de cette enzyme que dans le cycle ou elle montre une activite d'oxydase (compose iii). Le second exemple est relatif a la ferritine, la proteine de stockage du fer dans l'organisme. Dans ce cas, le transfert electronique direct est impossible et la reduction du fer ii du noyau de la proteine necessite une mediation, par une flavine par exemple. La spectroelectrochimie en couche mince est utilisee pour comprendre le role du mediateur. Le modele cinetique propose exclut la limitation par la diffusion du mediateur dans les pores et montre que la complexite de la cinetique est due a la presence du cristal dans une cavite de volume fini et au couplage des phenomenes de transport de matiere et de reaction chimique entre le mediateur et le fer iii cristallise

Pour élucider les rôles physiologiques des hydroxylases d’acides gras P450-dépendantes de plantes, de nouveaux P450s ont été clonés et caractérisés au laboratoire. La sous-famille CYP709C a été isolée chez le blé lors du clonage systématique des P450s métabolisant les xénobiotiques. L’étude biochimique de l’isoforme CYP709C1 a permis de montrer qu’elle hydroxyle les acides gras sur les positions sub-terminales (-1 et -2). Sa forte induction lors de traitements chimiques suggère un rôle potentiel dans la défense ou dans la détoxication de xénobiotiques. CYP94C1 est un P450 d’Arabidopsis induit par le méthyle jasmonate. Son étude biochimique a montré qu’il s’agissait d’une -hydroxylase d’acides gras pouvant catalyser une suite de réactions d’oxydation menant au carboxyle. Cette caractéristique suggère un rôle potentiel de CYP94C1 dans la formation de la cutine d’Arabidopsis ou encore dans le catabolisme des acides gras via la voie de béta-oxydation
In order to understand the physiological functions of plant P450-dependent fatty acid hydroxylases, new P450 enzymes were cloned and characterized in the laboratory. In an attempt to clone all cytochromes P450 from wheat involved in xenobiotic metabolism, the CYP709C subfamily has been isolated. Biochemical study demonstrated that the isoform CYP709C1 hydroxylates fatty acids in subterminal positions (-1 and -2). CYP709C1 is strongly induced by chemical treatments indicating a potential role in defense or in xenobiotic detoxification. CYP94C1 is a P450 of Arabidopsis induced by methyl jasmonate. The enzyme corresponds to a fatty acid -hydroxylase according to biochemical study. Furthermore, it has the capability to oxidize the -hydroxyl group successively to the respective aldehyde and carboxylic groups. This property suggest a possible role for CYP94C1 in Arabidopsis cutin biosynthesis or in fatty acid catabolism via the beta-oxidation pathway

La dopamine beta-hydroxylase (dbh), monooxygenase a cuivre, intervient dans la biosynthese des catecholamines en hydroxylant de maniere stereospecifique la dopamine en noradrenaline. Klinman et al. Ont recemment propose un mecanisme ou l'etape cinetiquement limitante est la rupture homolytique de la liaison c-h benzylique du substrat par une espece cuivre-oxygene hautement reactive. Nous avons etudie le mecanisme d'activation de l'oxygene et d'hydroxylation benzylique par modelisation chimique. La stereochimie du transfert d'atome d'oxygene par les especes cuivre-oxygene a ete etudiee via une modelisation du site actif par des ligands a substrat endogene. Pour cette etude, des complexes de cuivre (ii) et cuivre (i) sont prepares et exposes a differents systemes oxydants. Dans tous les cas, le transfert d'atome d'oxygene au ligand est regio- et stereoselectif. D'une part, l'utilisation de complexes marques au deuterium, a montre que le transfert d'oxygene s'effectue avec retention de configuration. Les importants effets isotopiques cinetiques, determines par spectroscopie rmn #1#3c, suggerent l'intervention de deux especes cuivre-oxygene reactives differentes selon le systeme oxydant utilise. D'autre part, nous avons mis en evidence les effets de substituants et l'influence de la geometrie sur l'hydroxylation du ligand. De nouveaux complexes derives de ligand de type alkylpy2 qui, par reaction avec le dioxygene, conduisent a l'hydroxylation d'un liaison c-h aliphatique du ligand et peuvent etre consideres comme des modeles fonctionnels de monooxygenases a cuivre. Sur la base de ces resultats nous avons pu proposer un mecanisme d'hydroxylation pour nos modeles fonctionnels de dh et de monooxygenases.

La fonctionnalisation tardive de molécules (Late stage functionalization – LSF) offre l’opportunité d’explorer l’espace chimique plus efficacement, en particulier en considérant les liaisons C-H aromatiques comme des points potentiels de diversification pour générer de nouveaux analogues directement en une seule étape au lieu de faire une synthèse totale dite de novo. La fonctionnalisation directe de composés élaborés peut en particulier se faire en utilisant la technologie superacide comme démontré par les nombreux travaux du professeur Jacquesy. L’un des meilleurs exemples de cette stratégie est certainement la transformation directe de la vinorelbine (Navelbine®) par fluoration en conditions superacides pour conduire à son analogue difluoré (Vinflunine), commercialisé par les laboratoires Pierre Fabre comme agent anticancéreux Javlor®. C’est dans ce contexte que ce travail de thèse a porté sur le développement de nouvelles méthodes de fonctionnalisation directe de composés aromatiques azotés.Il s’agissait effectivement de développer de nouveaux outils de synthèse en conditions superacides afin :1. d’hydroxyler directement des composés aromatiques par voie électrophile;2. d’halogéner des composés aromatiques azotés allant d’anilines simples à des composés élaborés naturels ou de synthèse;3. d’appliquer ces méthodes à la synthèse de molécules marquées par des isotopes stables
Late-stage functionalization can now be considered as a synthetic tool of choice to create molecular diversity, especially in a medicinal chemistry context. For example, aromatic C-H bonds can be regarded as functional groups and points of potential diversification to generate new analogs of a lead structure without resorting to de novo synthesis.The direct functionalization of elaborated compounds can also be done using superacid chemistry as demonstrated by the previous work of professor Jacquesy. One of the best examples of this strategy is certainly the direct transformation of vinorelbine (Navelbine®) by fluorination in superacid conditions to lead to its difluorinated analogue (Vinflunine), marketed by Pierre Fabre laboratories as an anticancer agent Javlor®.In this context, these studies focused on the development of new methods for the direct functionalization of aromatic nitrogen containing compounds.In particular, this work aimed at developing new synthetic tools in superacid for:1. the direct hydroxylation of aromatic compounds;2. the halogenation of aromatic nitrogen compounds from simple anilines to naturally occurring or synthetic compounds;3. the synthesis of labelled compounds with stable isotopes

Halogenases are enzymes with the ability to regioselectively and stereoselectively form carbon-halogen bonds, transferring a halogen onto various carbon scaffolds forming organohalogens. These organohalogens have many biological properties, for example, antibacterial, antifungal, anti-inflammatory, anti-proliferative, anti-fouling, anti-feedant, cytotoxic, ichthyotoxic and insecticidal activity. Additionally, the halogen is highly important for biological activity and consequently pharmaceutical and agrochemical industries are interested in environmentally sustainable and economically viable methods to selectively halogenate various organic scaffolds used during organic synthesis. One such method is to use nonheme iron halogenases, which are structurally and biochemically similar to nonheme iron hydroxylases. Common to both groups is the reactive intermediate, the iron(IV)-oxo, which abstracts a hydrogen atom from a substrate. Post hydrogen atom abstraction the catalytic cycle bifurcates, producing either hydroxylated or halogenated products. Of current debate are the factors separating halogenation and hydroxylation and in this thesis we have investigated the mechanisms of the nonheme iron halogenase (HctB) and hydroxylase (P4H) using a combination of density functional theory (DFT) and quantum mechanics/molecular mechanics (QM/MM) to gain further insight into the bifurcation factors. The QM/MM and DFT studies on the hectochlorin biosynthesis enzyme HctB revealed that substrate binding and positioning are key for optimal substrate halogenation. Additionally, key residues (Glu223) were found to influence the charge density on the chloride ligand pushing the mechanism toward halogenation. Furthermore, the influence of substrate binding and positioning was explored further in a QM/MM and MD study on the nonheme iron hydroxylase, P4H, which hydroxylates proline residues to produce 4-hydroxyproline. The QM/MM and MD study identified that mutations to either Trp243 or Tyr140 disrupted both long and short-range interactions resulting in alterations to the enzymes regioselectivity and stereoselectivity. This study also revealed that Arg161 and Glu127 formed key interactions with the substrate, which became the focus of the next study on P4H. Together these two studies on P4H, highlighted the importance of substrate positioning and selective hydrogen bonding between the protein and substrate for correct product outcome. Additionally, we were able to explore several mutations to Trp243, Tyr140, Arg161 and Glu127, identifying mutations which resulted in changes to the enzyme’s regioselectivity and stereoselectivity. Finally, in this thesis we also investigated the ability of a nonheme iron halogenase to transfer groups other than a halogen, such as nitrate and azide, using the biomimetic system , [FeIV(O)(TPA)X]+, TPA = tris(2-pyridylmethy1)amine whereby X = Cl, NO2, N3. The reaction of TPA with ethyl benzene revealed that the product distributions vary with the nature of the equatorial ligand at the metal centre. The results of this study also predict the effect of other substituents potentially opening up the application of halogenases to transferring groups other than halogens. Altogether, the studies in this thesis have looked at the different factors influencing substrate halogenation from various perspectives and have revealed the fascinating biochemistry of these enzyme’s and models to perform regioselective and stereoselective reactions with potential future industrial application.

Cette these est consacree a l'etude des systemes d'oxydation par les couples hydroperoxyde d'alkyle/composes du bore dans les domaines de l'hydroxylation des hydrocarbures aromatiques et de l'epoxydation des alcenes non-fonctionnalisees. Ces systemes peuvent etre mis en uvre soit en synthetisant le perborate desire puis en utilisant celui-ci comme oxydation stchiometrique, soit en formant le perborate in situ en presence de substrat a oxyder. Dans la premiere partie consacree a la synthese de perborates, nous avons montre que si les triperborates sont des especes stables et isolables, les monoperborates tartriques se decomposent tres rapidement, meme a temperature ambiante. Il est cependant possible de les stabiliser en presence d'une base de lewis mais pas de facon suffisante pour etre capable de les isoler et de les purifier. Dans la deuxieme partie, nous avons utilise les perborates prepares in situ pour etudier la reaction d'hydroxylation des hydrocarbures aromatiques et l'epoxydation asymetrique des olefines. L'etude de la reactivite des perborates vis-a-vis de divers noyaux aromatiques et de l'hydroxylation d'hydrocarbures monodeuteres nous ont permis d'ecarter diverses possibilites mecanistiques et de proposer un mecanisme d'addition-rearrangement ionique pour la reaction d'hydroxylation. De plus, divers borates et quelques aluminates chiraux associes a des hydroperoxydes d'alkyle ont ete testes dans la reaction d'epoxydation asymetrique. Les meilleurs resultats ont ete obtenus avec les borates tartriques (e. E. Jusqu'a 51%), pour certaines olefines reactives, le systeme peut fonctionner avec une quantite catalytique de bore (20 mol%)

Metal and oxide interactions are of broad scientific and technological interest in areas such as heterogeneous catalysis, microelectronics, composite materials, and corrosion. In the real world, such interactions are often complicated by the presence of interfacial impurities and/or high electric fields that may change the thermodynamic and kinetic behaviors of the metal/oxide interfaces. This research includes: (1) the surface hydroxylation effects on the aluminum oxide interactions with copper adlayers, and (2) effects of high electric fields on the interface of thin aluminum oxide films and Ni3Al substrate. X-ray photoelectron spectroscopy (XPS) studies and first principles calculations have been carried out to compare copper adsorption on heavily hydroxylated a- Al2O3(0001) with dehydroxylated surfaces produced by Argon ion sputtering followed by annealing in oxygen. For a heavily hydroxylated surface with OH coverage of 0.47 monolayer (ML), sputter deposition of copper at 300 K results in a maximum Cu(I) coverage of ~0.35 ML, in agreement with theoretical predictions. Maximum Cu(I) coverage at 300 K decreases with decreasing surface hydroxylation. Exposure of a partially dehydroxylated a-Al2O3(0001) surface to either air or 2 Torr water vapor results in recovery of surface hydroxylation, which in turn increases the maximum Cu(I) coverage. The ability of surface hydroxyl groups to enhance copper binding suggests a reason for contradictory experimental results reported in the literature for copper wetting of aluminum oxide. Scanning tunneling microscopy (STM) was used to study the high electric field effects on thermally grown ultrathin Al2O3 and the interface of Al2O3 and Ni3Al substrate. Under STM induced high electric fields, dielectric breakdown of thin Al2O3 occurs at 12.3 } 1.0 MV/cm. At lower electric fields, small voids that are 2-8 A deep are initiated at the oxide/metal interface and grow wider and deeper into the metal substrate, which eventually leads to either physical collapse or dielectric breakdown of the oxide film on top.

Abstract Type XII minicollagen chain association was studied using baculovirus-directed insect cell expression. Since insect cells contain low endogenous prolyl 4-hydroxylase activity, the mechanism of the effect of prolyl hydroxylation on trimer formation in this collagen could be studied directly by adding recombinant baculoviruses directing the synthesis of prolyl 4-hydroxylase. Prolyl 4-hydroxylase was shown to be involved in the trimeric assembly process of type XII collagen through its α subunit, and thus through its hydroxylase activity. The transmembrane protein type XIII collagen was also characterized by means of insect cell expression, for which purpose new antibodies against its non-collagenous domains NC2 and NC4 were generated, together with a pan-collagen antibody against collagenous sequences. Type XIII collagen α chains were found to form disulphide-bonded homotrimers, and this was enhanced by prolyl 4-hydroxylation. Analysis of the disulphide-bonding pattern of the eight cysteine residues of the α1(XIII) chains revealed that some of the cysteines in the NC1 domain, and possibly the cysteines at the junction of the COL1 and NC2 domains, are interchain-linked, while the cysteines in the NC4 domain are intrachain-linked. The three collagenous domains of type XIII collagen were shown to be in triple-helical conformation and have different thermal stabilities, i.e. 38±C for the COL1 domain, 49±C for COL2 and 40±C for COL3. Furthermore, it was shown that type XIII collagen is oriented in the plasma membrane of insect cells so that its non-collagenous N-terminus is intracellular and its mostly collagenous C-terminus is extracellular. Type XIII collagen was also found to be cleaved into the insect cell culture medium by a furin-like protease. The expression of various type XIII collagen deletion variants suggested that chain recognition and the association of type XIII collagen α chains into trimers occur in the N-terminal portion of this molecule. An internal in-frame deletion of residues 63-83 immediately adjacent to the transmembrane domain indicated that this short ectodomain sequence is necessary for the formation of disulphide-bonded trimers. Since a sequence homologous with these deleted residues was also found at the same plasmamembrane-adjacent location in other collagenous transmembrane proteins, this points to common features in their chain association.

Notre travail traite de l' utilisation actuelle des neuroleptiques retard : - de l' aspect pharmacologique, - de leurs indications, posologies et effets secondaires, - surtout, nous nous intéressons à leurs résultats : en fonction des médications associées, du mode de prise en charge, de la réinsertion sociale et professionnelle des sujets traités. Cette étude repose sur des statistiques à propos de cinquante six patients d' un service sectorisé, sous traitement depuis au moins cinq ans.

Recemment, des chercheurs ont reussi a synthetiser une zeolithe de type mfi ne contenant que du silicium et du titane dans son reseau qu'ils ont appele titanosilicalite-1 (ts-1). Dans ce memoire, nous avons etudie les conditions de synthese visant l'incorporation du titane en nombre et en site particulierement celles concernant la purete de l'agent structurant et les conditions d'hydrolyse. Nous avons utilise les methodes physiques propres a mieux definir la coordination du titane et par la-meme sa nature reticulaire ou extra-reticulaire. Ces memes methodes ont permis de cerner ses proprietes physico-chimiques notamment acidobasiques et redox et de degager des criteres fiables permettant de distinguer diverses especes de titane susceptibles d'etre presentes lors de la synthese ou generees lors de l'activation de la ts-1. Nous avons etudie ensuite les proprietes catalytiques de la ts-1 en hydroxylation du phenol par l'eau oxygenee et mis en evidence l'influence de divers facteurs sur son activite et sa selectivite. Un mecanisme reactionnel a ete propose. Les resultats ont montre que c'est le titane incorpore au reseau qui est le responsable de l'activite catalytique. Nous avons donc tente d'augmenter la teneur en titane incorpore tout en evitant la precipitation du tio#2, qui meme a faible concentration, decomposerait l'eau oxygenee. Cependant au-dela d'une teneur limite, quelle que soit la methode de synthese, le titane cesse de s'incorporer en site t pour precipiter sous forme d'oxyde

L'objectif principal de ce travail est la synthese, par la methode sol-gel, de zeolithes a structure mfi refermant du vanadium dans le reseau (vanadosilicalite) et leur caracterisation par differentes techniques physico-chimiques (uv-vis. , rmn#5#1v ram, rpe, ir et drx). Le choix de precurseurs de vanadium et de silicium du type alcoxyde semble necessaire pour la synthese de la vanadosilicalite, mais il faut eviter l'hydrolyse trop rapide de l'un de ces precurseurs. Le solide cristallise a partir de l'ethoxyde de silicium et de l'ethoxyde ou du methoxyde de vanadium presente une faible quantite d'ions vanadyles disperses sur la surface de la zeolithe. Il en est de meme pour celui resultant de l'hydrolyse simultanee de l'ethoxyde de silicium et du compose vcl#2(oc#2h#5)#2. C#2h#5oh. La preparation du gel a partir d'un alcoxyde de vanadium monomerique (isopropoxyde ou tertiobutoxyde) s'avere plus appropriee, mais des ions vanadyles et des especes condensees type polyoxovanadate sont egalement formees. Les solides prepares a partir de l'ethoxyde de silicium partiellement hydrolyse et du tertiobutoxyde de vanadium presentent exclusivement des especes vanadium en site t. Au vanadium en position tetraedrique correspond une bande de transfert de charge vers 240 nm (uv), une raie rmn #5#1v ram situee vers -530 ppm/vocl#3. En revanche la spectrometrie ir et la diffraction de rayons x ne permettent pas de discuter de l'insertion du vanadium dans la charpente zeolithique. Les especes vanadyles des solides synthetises a partir de l'alcoxyde vcl#2(oc#2h#5)#2. C#2h#5oh sont faiblement liees a la structure zeolithique. Elles ne sont actives en hydroxylation du phenol qu'apres leur elution dans la solution reactionnelle. Les solides ayant des especes du type polyoxovanadate sont faiblement actifs en hydroxylation du phenol et inactifs en oxydation de l'ethanol. D'autre part, les especes localisees en site t zeolithique sont actives en hydroxylation du phenol et en oxydation de l'ethanol, surtout en presence d'especes vanadyles bien dispersees et fortement greffees sur la surface zeolithique

Les CYP4F sont impliquées dans l'oxydation de messagers cellulaires importants comme le LTB4 et les prostaglandines. Le LTB4, agent pro-inflammatoire, tout comme les dérivés époxydés des acides gras insaturés de la famille C18 sont générés suite à un stress biotique et associés à plusieurs maladies inflammatoires. Cette étude décrit le métabolisme des acides époxystéarique, coronarique, vernolique (C18) et des dérivés monoépoxydés de l'acide arachidonique. Les microsomes hépatiques humains métabolisent les C18 avec un Km compris entre 27,6 et 175 æM. La formation du dérivé w-hydroxylé des acides gras époxydés en C18 est inhibée par le LTB4, un substrat des CYP4F2 et 4F3, mais n'est pas affectée par l'acide laurique, un substrat du CYP4A11. Parmi les CYP450 recombinants, les CYP4F2 et 4F3B sont les meilleurs catalyseurs de l'w-hydroxylation des C18-époxydés. Les CYP4F2 et 4F3 w-hydroxylent majoritairement le 8,9-EET, alors que les microsomes hépatiques humains catalysent préférentiellement le 11,12-EET suivi du 8,9-EET. Les diols des C18-époxydés et des EETs sont également w-hydroxylés par les microsomes hépatiques, ainsi que par les CYP4F2 et 4F3
CYP4F are involved in the oxidation of important cellular mediators such as LTB4 and prostaglandins. The proinflammatory agent LTB4 as well as epoxide derived from unsaturated fatty acids of the C18 family were generated under biotic stresses and are associated with several inflammatory deseases. Here we report the metabolism of epoxystearic, coronaric, vernolic acids and of monoepoxides from arachidonic acid (EETs). Hepatic microsomes from human converted the three C18-epoxides to 18-hydroxy C18-epoxides with Km ranging from 27. 6 to 175 æM. The microsomal 18-hydroxy C18-epoxides formation was completely inhibited by LTB4, a substrate of CYP4F2 and 4F3, but was unaffected by lauric acid, a substrate of CYP4A11. Among P450s recombinant, CYP4F2 and 4F3B catalyze mainly the w-hydroxylation of C18-epoxides. CYP4F2 and CYP4F3 exhibit preference for w-hydroxylation of 8,9-EET whereas human liver microsomes prefer 11,12-EET followed by 8,9-EET. Conjugated diols from both C18-epoxydes and EETs were also w-hydroxylated by liver microsomes and by CYP4F2 and CYP4F3