The Pebble Bed Modular Reactor (PBMR) design is one of the High Temperature Gas Cooled Reactors (HTGR) under the Generation IV initiative. These designs incorporate numerous inherent passive safety features. Graphite is an important material of construction for the reactor core and the fuel pebbles. Knowledge of the high temperature oxidative behaviour of the graphite materials utilized in such reactors is important for design and accident modelling purposes. Despite large amounts of research into the oxidation of graphite, a coherent framework for the comparison and assessment of the relative reactivity’s of graphite samples from different origins has not yet been established. This is mainly due to a lack of clarity regarding the relative contribution of different factors which influence the overall behaviour of a given sample. The objective of this work was to identify and isolate the key factors which influence the oxidation of graphite and understand their operation across the entire range of conversion. Based on this understanding a comprehensive model for the oxidation can be established. The framework of this model will allow the sensible comparison of samples from different origins, based on the relative contribution of the relevant mechanisms. The work focused purely on the kinetic factors which influence the oxidation and extreme care was taken to avoid mass transfer limitations where possible. Through a carefully established experimental methodology three key factors were found to influence the progression of oxidation in a given sample: <ul><li> First and foremost, the development of the active surface area of a given sample</li><li> Secondly, the presence of catalytic impurities</li><li> Thirdly, the influence of inhibiting impurities/li></ul> Based on these three effects, a finite element type, Monte Carlo simulation was developed. In this simulation virtually any geometry can be easily represented and the progression of the active surface area as the oxidation proceeds can be monitored. Furthermore, catalytic impurities could be easily incorporated into the simulation in a clear, consistent manner. This leads to an overall simulation which produces results that visually reflect the observed behaviour as well as accounting for the kinetic aspects of the experimentally determined conversion behaviour. This work provides a starting point for assessing samples from different origins to first determine differences in the three basic governing effects, followed by a relative assessment of their reactivity’s on a common basis. Future work should focus on refining the understanding of the mechanistic aspects of each of the individual governing effects, especially the influence of surface complexes and different reaction pathways. In addition, the work should be extended to cover a more comprehensive selection of graphite samples from different origins and a wider variety of impurity behaviours. / Thesis (PhD(Eng))--University of Pretoria, 2012. / Chemical Engineering / unrestricted

Aromatic rings are privileged structures found in a diverse range of natural and synthetic compounds, thus synthetic methods for their functionalisations are important in organic synthesis. Despite significant advancements made, especially in the field of transition metal catalysis, work still continues for the development of milder, more efficient, and more atom economical reactions. We describe here our efforts towards the development of decarboxylative/direct C(aryl)–N and C(aryl)–C bond forming reactions using aromatic carboxylic acids and unfunctionalised arenes as cheap and widely available aromatic sources. The investigations into copper-catalysed and copper/palladium-catalysed intermolecular and copper/silver/palladium-catalysed intramolecular decarboxylative amination of aromatic carboxylic acids are reported. A new approach to decarboxylation of benzoic acids is also described. The reaction uses silver (I) catalyst and peroxydisulfate salt to generate aryl radicals via oxidative decarboxylation. The applications of this approach in intra- and intermolecular decarboxylative C–H arylation, and protodecarboxylation are described. Also described is the development of silver-catalysed trifluoromethylation of simple arenes and heteroarenes. The reaction proceeds via radical trifluoromethylation using trimethyl(trifluoromethyl)silane as the trifluoromethyl radical source. This method has been applied to the trifluoromethylation of complex agrochemical molecules, proving its synthetic utility in late-stage functionalisation. Furthermore, we describe the exploitation of trifluoroacetate derivatives as cheap trifluoromethylating reagents in copper-mediated decarboxylative C–H trifluoromethylation of 2-phenylpyridine.

Pseudomonas Aeruginosa est un pathogène opportuniste qui adapte son comportement aux molécules présentes dans son milieu. Il augmente en virulence lorsqu’il détecte des peptides natriurétiques dans son environnement. L’isatine est une molécule qui bloque cet effet. Pour mieux comprendre sur quel récepteur l’isatine agit, la conception d’un biocapteur a été menée. Un biocapteur est un outil alliant un bioélément, réagissant spécifiquement avec une cible biologique, et un support physique permettant la transduction du signal pour le rendre mesurable. Les travaux de thèse suivants décrivent la préparation d’un transducteur polymérique, le copolymère d’oléfines cycliques (COC), par greffage de sels de diazonium en surface. La modification de l’isatine par couplage pallado-catalysé compose la partie principale des travaux de synthèse organique effectués. Les méthodes de couplages peptidiques en surface et techniques d’accroche des isatines modifiées sur les surfaces des transducteurs (or ou COC) sont également décrites dans ce manuscrit. Pour finir, l’évaluation des effets biologiques des isatines modifiées et des biocapteurs conçus a été effectuée sur Pseudomonas Aeruginosa et sur d’autres bactéries. / Pseudomonas Aeruginosa is an opportunistic pathogen which can adapt its behavior to the present molecules in its surrounding. It increases in virulence when it detects natriuretics peptides in its environment. Isatin is a molecule which can block this effect. To determine on which receptor isatin acts on, the conception of a biosensor have been conducted. A biosensor is a tool combining a bioelement, reacting specifically with a biological target, and a physical support allowing the transduction of the signal to make it measurable. The following thesis describes the preparation of a polymeric transducer, the cyclic olefin copolymer (COC), by diazonium salts surface grafting. Isatin modification by palladium-catalysed coupling reaction represents the major part of the organic synthesis carried out. Surface peptide coupling methods and techniques to link the modified isatins to the surfaces of transducers (gold or COC) are also described in this dissertation. To finish, biological effects of the modified isatins and designed biosensors have been evaluated on Pseudomonas Aeruginosa and others bacteria.

Yes / The first example of an intramolecular hydroarylation of 1,6-en-α-chloro-enamides was achieved by a palladium-catalysed ligand-free reductive Heck cycloisomerisation with no competing Heck-cyclised by-product.

The discovery and mechanistic investigation of a new class of photochemical reactions of benzophenones and related compounds is documented in this Thesis. Their photobehaviour in aqueous solvent media varied dramatically from their well-known behaviour in organic solvents and suggests unique and unprecedented mechanistic pathways. The aqueous photoredox chemistry of various substituted benzophenones was initially explored. Particular attention was paid to 3-(hydroxymethyl)benzophenone (47), which upon photolysis in acidic aqueous media undergoes an intramolecular photoredox reaction to produce 3-formylbenzhydrol (61). Extensive investigation into the mechanistic behaviour of 3-(hydroxymethyl)benzophenone (47) produced evidence of a unique solvent-mediated, acid catalysed photoreaction. A mechanism has been proposed for the intramolecular photoredox reaction that proceeds via the protonated triplet state. This protonated triplet state subsequently promotes the deprotonation of the benzylic carbon before rearranging to form the redox product. The modification of the benzylic carbon with an alkyl group or with a phenyl group resulted in only slight changes in the photobehaviour. In both cases intramolecular photoredox reactions were observed although significantly more oligomeric side products were observed in some cases. To more fully elucidate the photobehaviour and to test the generality of the photoredox reaction, a variety of structurally related hydroxyalkyl aromatic carbonyls were synthesized and studied. Alternative chromophores were explored using xanthone and fluorenone derivatives. Both types of derivative compounds underwent an intramolecular photoredox reaction, supporting the assertion that the intramolecular photoredox reaction could be considered a general feature of aromatic carbonyls under aqueous conditions. However, significant differences in photoreactivity were also observed. It was found that 2-(hydroxymethyl)xanthone (53) exhibited sufficient photoactivity that the intramolecular photoredox reaction was observable even under neutral conditions whereas 2-(hydroxymethyl)fluorenone (54) was nearly photoinert. The last topic focuses on the extension of the electronic transmission from the carbonyl functional group to the benzylic alcohol by insertion of an additional phenyl group. The addition of the phenyl group also provided a bichromophoric molecule, rather than the monochromophoric substrates studied to this point. The substituent’s position played an important role in the photobehaviour, in that both of the meta- and ortho- substituted compounds underwent intramolecular photoredox reaction, while the para- substituted compound primarily exhibited photobehaviour indicative of hydrogen abstraction.

Afin de corriger la suractivation de la voie de signalisation Raf/MEK/ERK observée dans 30 % des cancers,nous avons choisi d’inhiber la kinase Raf-1. Les inhibiteurs potentiels de Raf-1 ont été conçus avec un cyclecentral original 4-azaindolique. Pour apporter de la diversité fonctionnelle au niveau des sommets C-2 et C-5lors de la synthèse, nous avons optimisé deux méthodes à partir du synthon 5-méthoxy-4-azaindole-Nphénylsulfonyle.La première est une réaction de lithiation du sommet C-2 suivie de la condensation dedifférents électrophiles et la deuxième est la C-arylation ou N-arylation du sommet C-5 à partir du dérivétriflate en 5 via des réactions de couplage pallado-catalysées de type Suzuki et Buchwald, respectivement.Ces deux méthodes ont permis d’aboutir à 2 séries de composés : une première série fonctionnalisée enposition N-1 et C-5 du noyau 4-azaindole et une deuxième série substituée en position C-5 et C-2.Pour tester les nouveaux inhibiteurs synthétisés et un inhibiteur naturel appelé PEBP, nous avons mis aupoint des tests d’activité in vitro sur l’ensemble de la cascade Raf/MEK/ERK et sur chacune des 3 kinases.Les tests ont été développés avec 2 méthodes de TR-FRET, Lance UltraTM et LanthascreenTM, et ont étévalidés avec des inhibiteurs commerciaux et comparés par rapport à la méthode radioactive PFBA.Au total, 30 produits finaux ont été évalués in vitro sur la kinase Raf-1. Grâce aux plateformes duCancéropôle GO, les produits ont aussi été testés sur 6 lignées de cellules cancéreuses et sur les kinasesdu cycle cellulaire DYRK1A, GSK3 et CDK5. Plusieurs molécules ont montré une activité antitumoraleencourageante de l’ordre du μM et un composé a été identifié comme inhibiteur de Raf-1 avec une valeurd’IC50 de 9,8 μM et une cytotoxicité sélective vis-à-vis des cellules du foie Huh7 (IC50 = 3 μM). / Considering the implication of the Raf/MEK/ERK pathway deregulation in 30 % of human cancers, wedecided to synthesize potential Raf-1 inhibitors. They were synthesized using the original 4-azaindole as thecentral core. To introduce various types of substituents in C-2 and C-5, we developed two methodologiesfrom the building block N-benzenesulfonyl-5-methoxy-4-azaindole. The first one is the C-2 lithiation followedby the addition of various electrophiles. The second methodology is the C-5 C-arylation or the N-arylationusing palladium-catalysed cross-couplings from the C-5 triflate derivative through Suzuki or Buchwald crosscoupling reactions, respectively. The two methodologies ended up to the synthesis of two series ofcompounds. The first one is functionalized in N-1 and C-5 of the 4-azaindole core. The second one issubstituated in C-2 and C-5.In order to test the newly synthesized inhibitors as well as the natural inhibitor PEBP, we have developedseveral tests to measure in vitro the effect of inhibitors on the activity of the complete cascade Raf/MEK/ERKand also on the activities of each individual kinase. The assays were developed by using 2 TR-FRETmethods, Lance UltraTM and LanthascreenTM, and were validated with commercially available inhibitors andcompare to the radioactive PFBA method.Finally, 30 compounds were evaluated through in vitro Raf-1 assays. By using the facilities offered by theCanceropôle GO platforms, the compounds were also tested on six different tumor cell lines and on thekinases DYRK1A, GSK3 and CDK5. Several compounds displayed encouraging antitumoral activity and onecompound was identified as a Raf-1 inhibitor with an IC50 value of 9.8 μM and a selective cytotoxicity activitytowards liver tumor cells Huh7 (IC50 = 3 μM).

Des composés de type 3-arylpyrroles appelés pyakols ont montré une activité antimitotique sur des cellules tumorales murines, avec en particulier un effet sur les microtubules. Ce type d’activité biologique présentant un intérêt important en cancérologie, le travail présenté dans ce manuscrit est consacré à l’étude de ces hétérocycles. La première partie a pour objectif de développer une stratégie de synthèse permettant d’accéder efficacement au composé chef de file (pyakol I), basée sur la cyclisation d’intermédiaires α-amino-ynols catalysée par des complexes d’or. L’évaluation de l’activité biologique du pyakol I sur le cycle cellulaire et le cytosquelette de diverses lignées tumorales humaines a été réalisée. Les premiers résultats ont révélé une action originale du pyakol I sur le cytosquelette, provoquant une désorganisation du réseau de microtubules et un défaut de positionnement du fuseau mitotique. La séquence réactionnelle a ensuite été validée en l’appliquant pour la réalisation de modulations autour du motif 3-arylpyrrole ainsi que pour l’obtention de molécules marquées. La deuxième partie concerne un travail de méthodologie basée sur la réaction de cyclisation à l’or pour la synthèse de nouveaux pyrroles trifluorométhylés polysubstitués. La stratégie utilisant le trifluoroacétaldéhyde comme substrat de départ permet d’accéder à divers 3-trifluorométhylpyrroles avec de bons rendements, dans des conditions douces. / A family of 3-arylpyrroles named pyakols have shown antimitotic properties on murine cell lines, displaying in particular an effect on microtubules. Given the interest of these properties in cancerology, this work is focused on these heterocycles. The objective of the first part was to develop a synthetic strategy based on the gold-catalysed cyclisation of α-amino-ynols intermediates in order to access the lead (Pyakol I). Then, the evaluation of the biological activity of this molecule on the cell cycle and on the cytoskeleton of various human tumoral cell lines was carried out. The first results revealed an original effect on the organization of the microtubules network and the positioning of the mitotic spindle. The developed strategy was then validated by modulating the 3-arylpyrrole moiety on diverse positions, and used for the synthesis of labelled derivatives. The second part of this manuscript focused on the development of a methodology to synthesize new polysubstituted 3-trifluoromethylpyrroles, based on the gold-catalyzed cyclisation reaction. Using trifluoroacetaldehyde as building-block, various trifluoromethylated pyrroles were obtained in mild conditions with good yields.

Les réactions de couplage croisé ont révolutionné la chimie organique. Par exemple, dans le domaine de la chimie médicinale, les réactions de couplage sont de puissants outils pour générer rapidement et facilement une librairie de composés. Depuis la découverte des premières réactions de couplage croisé catalysé par des complexes de palladium, ce métal reste le plus utilisé. Cependant, d’autres métaux tels que le cuivre, le nickel, le cobalt ou le fer sont apparus comme de bonnes alternatives aux complexes de palladium, chers et toxiques.D’autre part, en chimie médicinale, les hétérocycles sont des motifs essentiels puisqu’ils sont présents dans un grand nombre de médicaments. Le développement de nouvelles méthodes permettant de former des molécules incorporant des motifs hétérocycliques tels que des azétidines, des pyrrolidines ou des oxétanes, est un réel défi pour un chimiste organicien. Les halogénures d’alkyle sont généralement des substrats difficiles à utiliser en couplage croisé car l’addition oxydante du métal y est difficile. Des réactions parasites peuvent également avoir lieu telles que des réactions de -H élimination ou de déshalogénation. Cependant, les sels de cobalt et de fer se sont révélés être des catalyseurs efficaces pour réaliser des réactions de couplage sur des halogénures d’alkyle. Au cours de cette thèse, deux systèmes catalytiques à base de sels de cobalt ou de fer ont été développés pour réaliser des réactions de couplage croisé entre des halogénures d’alkyle hétérocycliques et des réactifs de Grignard. Une étude mécanistique des réactions de couplage croisé catalysé par des sels de cobalt a également été réalisée. / Cross-coupling reactions, as Prof. K. C. Nicolaou said “have changed the way we think about synthesis”. Indeed, cross-coupling reactions are powerful tools to access easily and rapidly to a library of compounds in the context of medicinal chemistry. Palladium-catalysed cross-coupling rules the field and was recognized by the Nobel Prize in 2010 but, since its discovery, others metals have appeared as good alternatives to the expensive and toxic palladium salts such as copper, nickel, cobalt and iron salts. In medicinal chemistry, heterocycles are essential moieties since they are found in a great number of drugs on the market. It is always a challenge for organic chemists to develop new methods to produce motifs with interesting pharmacological properties such as substituted azetidines, pyrrolidines and oxetanes. sp3 Halides are challenging substrates for cross-coupling because the oxidative addition of the metal in the C-X bond is difficult and because side reactions can take place like -hydride elimination or dehydrohalogenation. Nevertheless, cobalt and iron are suitable catalysts to perform cross-coupling reactions on sp3 halides. Herein, we would like to report two catalytic systems allowing the cross-coupling between heterocyclic alkyl halides and Grignard reagents using cobalt and iron salts. A mechanistic study on cobalt-catalysed cross-coupling reaction between halides and Grignard reagents will be also presented.

Yes / The synthesis of cyclic amphiphilic graft copolymers with a hydrophobic polycarbonate backbone and hydrophilic poly(N-acryloylmorpholine) (PNAM) side arms via a combination of ring-opening polymerization (ROP), cyclization via copper-catalyzed azide–alkyne cycloaddition (CuAAC), and reversible addition–fragmentation chain transfer (RAFT) polymerization is reported. The ability of these cyclic graft copolymers to form unimolecular micelles in water is explored using a combination of light scattering, small-angle X-ray scattering (SAXS), and cryogenic transmission electron microscopy (cryoTEM) analyses, where particle size was found to increase with increasing PNAM arm length. Further analysis revealed differences in the solution conformations, loading capabilities, and morphologies of the cyclic graft copolymers in comparison to equivalent linear graft copolymer unimolecular micelle analogues. Furthermore, the cyclic and linear graft copolymers were found to exhibit significantly different cloud point temperatures. This study highlights how subtle changes in polymer architecture (linear graft copolymer versus cyclic graft copolymer) can dramatically influence a polymer’s nanostructure and its properties. / Royal Society (Great Britain), Engineering and Physical Sciences Research Council (EPSRC), European Research Council (ERC)

A arilação seletiva de compostos orgânicos confere-lhes propriedades com amplas aplicações: em compostos de atividade biológica, inibidora da protease do vírus HIV-1, e de interesse como agroquímicos ou na engenharia de materiais. Em razão disso, novos métodos e reagentes tem sido desenvolvidos com essa finalidade. Sabe-se que a N-arilação de várias aminas, catalisadas por paládio, com haletos de arila e triflatos é tida como ferramenta importante a disposição do químico sintético. Do mesmo modo, publicou-se que a N-arilação de certos -amino ácidos por haletos de arila, procede-se facilmente quando catalisada por CuI. Alternativamente, a literatura cita outros métodos eficientes usando ácidos borônicos, compostos arilbismuto e compostos organochumbo. Neste trabalho foi estudada a arilação seletiva de ânions ambidentados pelo sal de iodo polivalente cloreto de difenil iodônio, em diferentes condições de reação, visando a otimização da síntese: 1) reação térmica (agitação magnética), sem catalisador, e em diferentes solventes, ou mistura de solventes; 2) reação sonoquímica, sem catalisador e em diferentes soluções; 3) reação térmica e sonoquímica na presença de catalisador CuCl (10%). Sacarinato de sódio, acesulfame de potássio, e ftalimida potássica foram escolhidos como ânions ambidentados derivados de sulfoimidas e imidas a serem arilados. No caso de N-fenil sacarina a quemiosseletividade e o melhor rendimento são observados com acetonitrila/água (1:1, v/v), sob refluxo para formação do par iônico intermediário (ou o iodano correspondente), seguido por fusão térmica na ausência de solvente. O acesulfame potássico, por sua vez, forneceu seletivamente produtos de N- ou O-fenilação, de acordo com as seguintes condições estabelecidas: 1) produto de fenilação por via térmica ou sonoquímica em etanol; 2) produto de O-fenilação, por via térmica ou sonoquímica em acetonitrila. A ftalimida potássica, na ausência de catalisador, é arilada em baixos rendimentos. A melhor condição de síntese é encontrada com acetonitrila e CuCl (10%), sendo 92% o rendimento por via sonoquímica e 78% por via térmica. A seletividade verificada foi analisada em termos das interações dos ânions ambidentados e dos solventes em questão. / The arylation of organic compounds gives place to a wide number of applications: concerning to their biological properties as HIV-1, protease inhibitor, as well as synthetic intermediates in pharmaceuticals, agrochemical and polymer chemistry. New methodologies and reagents have been developed as consequence of this. It is already known that N-arylation of several amines, catalyzed by palladium, with aryl halides and trifflates is a valuable tool to various reported organic synthesis. In the same way, it has been published that the N-arylation of certain -amino acids by aryl halides, proceeds smoothly when catalized by CuI. Alternatively, the literature reports other efficient methods using boranic acids, arylbismuth and organolead compounds. In the present work, it was studied the selective arylation of ambident anions by hypervalent iodine salts (chloride of diphenyl iodonium), in a different set of conditions, seeking the synthesis optimizations: 1) thermal reactions (silent mode, magnetic stirring), without catalyst, and, in different solvents or mixture of then; 2) sonochemical reactions, without catalyst, and in a different solvent composition; 3) thermal and sonochemical reactions carried out in the presence of (10%) CuCl as the catalyst. Sodium saccharinate, acessulfame K and potassium phthalimide were chosen as the ambident anions (derived from sulfonimides and imide functional groups) to be studied. In the N-phenyl saccharin case the chemioselectivity was achieved along the best yields when water/acetonitrila (1:1, v/v) solvent was employed in the step to form the ion pair (or the 3-iodane, intermediate), followed by the thermal fusion in the absence of solvent. The acessulfame K, for its turn, supplied selectively products of N- and O-arylation under the following established conditions: 1) N-phenylation in etanol through thermal and sonochemical approach; 2) O-phenylation product, in acetonitrila, by thermal and sonochemical method. Finally, arylation of potassium phthalimide with diaryliodonium is sluggish and gives low yields without catalyst. The best protocol to this synthesis was found with the solvent acetonitrile and (10%) CuCl catalyst addition, being 92% the yield of sonochemical reaction and 78% of the thermal one. The selectivity achieving was analyzed in accord with the solution interaction between the ambident anion and the solvent molecules.