Les performances des piles à combustible à échange de protons (PEMFC) sont fortement influencées par la conductivité protonique de l'électrolyte solide. Les polymères à base d'azole sont parmi les matériaux les plus prometteurs pour améliorer l'efficacité de ces systèmes. Une étude théorique de réaction du transfert de protons (PT) en dimères protonée du imidazole, 1,2,3-triazole et tétrazole a été effectuée. Le protocole DFT mis au point a été appliqué sur des systèmes plus complexes. Les résultats obtenus à partir de l'étude réalisée sur le poly(4-vinyl-imidazole) (P4VI) suggèrent que le mécanisme de conduction communément admis (Grotthuss) pourrait être entravé dans ce système en raison de l'effet de la matrice polymérique. Cette étude, réalisée par le biais d'une approche combinée théorie du fonctionnelle de la densité (DFT) / simulations de Dynamique Moléculaire (MD), a permis de proposer un mécanisme alternatif de conduction. Une étude supplémentaire réalisée sur des modèles avec du acide phosphorique (H3PO4) a révélé que faibles concentrations de H3PO4 pourrait permettre le mécanisme de Grotthuss malgré la matrice polymérique. Le rôle crucial joué par la matrice polymérique sur la conductivité a été ensuite confirmée par l'étude menée sur un second polymère : la position d'attache du imidazole peut fortement affecter le mécanisme de conduction. En bref, les simulations obtenus montrent comment la matrice polymérique jouent un rôle crucial dans le mécanisme de la conductivité. La présente recherche représente une première tentative pour une étude plus systématique de la relation entre la connectivité de la matrice polymère et l'efficacité du transport de charge

This thesis describes an investigation of the molecular mechanism underlying solar conversion processes that occur in Type I photosynthetic reaction centers, in which P700 plays a central role. Static Fourier transform infrared (FTIR) difference spectroscopy (DS) was used to probe the electronic and structural organization of P700 and P700+. In combination with isotope labeling and site directed mutagenesis we have investigated how protein interactions such as histidine ligation and hydrogen bonding modulate this organization. Comparison of (P700+-P700) FTIR difference spectra (DS) obtained using wild type and mutant PS I led us to suggest that the 131 keto carbonyl group of PA is essentially free from hydrogen bonding in the ground state. Upon cation formation, this hydrogen bonding becomes stronger, probably because of a cation induced reorientation of the hydroxyl group of a nearby threonine residue. We also tentatively suggested that a difference band at 1639(-)/1660(+) cm-1 in (P700+-P700) FTIR DS might be due to a C=C mode of the imidazole side chain of the ligating histidine residues. Most of this thesis is geared towards investigating the validity of this interpretation. (P700+-P700) FTIR DS obtained using mutant PS I particles in which hydrogen bonding to P700 is altered can be reconciled within the context of our new interpretation. (P700+-P700) FTIR DS obtained using uniformly 2H, 15N, and 13C labeled PS I particles also support our new interpretation, and indicate that the difference band at 1639(-)/ 1660(+) cm-1 cannot be associated with a strongly hydrogen bonded keto carbonyl group of PA. To investigate if the imidazole side-chain of ligating histidine residues could contribute to bands in (P700+-P700) FTIR DS vibrational mode frequencies and intensities for several protonation forms of 4-methylimidazole were calculated. The calculations suggest that the 1639(-)/1660(+) cm-1 band in (P700+-P700) FTIR DS may not be due to a C=C mode of the imidazole side chain of the ligating histidine residues. Thus we have produced data that suggests neither of the proposed interpretations alone can adequately explain the origin of the 1639(-)/1660(+) cm-1 difference band in (P700+-P700) FTIR DS. The origin of the 1639(-)/1660(+) cm-1 difference band in (P700+-P700) FTIR DS is therefore still an open question.

Biologically active peptides are important for many physiological functions in the human body and therefore serve as interesting starting points in drug discovery processes. In this work the neuropeptide substance P 1–7 (SP1–7, H-Arg-Pro-Lys-Pro-Gln-Gln-Phe-OH), which has been demonstrated to reduce neuropathic pain and attenuate opioid withdrawal symptoms in animal models, has been addressed in a medicinal chemistry program with the overall aim of transforming this bioactive peptide into more drug-like compounds. Specific binding sites for this neuropeptide have been detected in the brain and the spinal cord. Interestingly, the smaller neuropeptide endomorphin-2 (EM-2, H-Tyr-Pro-Phe-Phe-NH2) also interacts with these binding sites, although 10-fold less efficient. In this work the structure–activity relationship of SP1–7 and EM-2, regarding their affinity to the SP1–7 binding site was elucidated using alanine scans, truncation, and terminal modifications. The C-terminal part of both peptides, and especially the C-terminal phenylalanine, was crucial for binding affinity. Moreover, the C-terminal functional group should preferably be a primary amide. The truncation studies finally resulted in the remarkable discovery of H-Phe-Phe-NH2 as an equally good binder as the heptapeptide SP1–7. This dipeptide amide served as a lead compound for further studies. In order to improve the drug-like properties and to find a plausible bioactive conformation, a set of rigidified and methylated dipeptides of different stereochemistry, and analogs with reduced peptide character, were synthesized and evaluated regarding binding, metabolic stability and absorption. Small SP1–7 analogs with retained affinity and substantially improved permeability and metabolic stability were identified. Beside peptide chemistry the synthetic work included the development of a fast and convenient microwave-assisted protocol for direct arylation of imidazoles. Furthermore, microwave-assisted aminocarbonylation using Mo(CO)6 as a solid carbon monoxide source was investigated in the synthesis of MAP amides and for coupling of imidazoles with amino acids. In a future perspective the present findings, together with the fact that some of the SP1–7 analogs discovered herein have been shown to reproduce the biological effects of SP1-7 in animal studies related to neuropathic pain and opioid dependence, can ultimately have an impact on drug discovery in these two areas.

Este trabalho tem como objetivo a síntese e a determinação de propriedades micelares de líquidos iônicos tensoativos (LITs) catiônicos. Dentre as características importantes desses compostos destacamos: alta deslocalização da carga e caráter ácido no hidrogênio H2 do anel heterocíclico e a grande flexibilidade estrutural, estas são relevantes para as propriedades de soluções desses tensoativos, e, consequentemente, para suas aplicações. A influência da variação estrutural nas suas propriedades é importante para modular as propriedades micelares e, por consequência suas aplicações. A síntese de LITs foi realizada por aquecimento convencional e irradiação por micro-ondas, o último método foi o mais eficiente. Inicialmente, estudamos a influência do comprimento da cadeia carbônica (fator importante para a energia de formação de micelas), de cloretos de 1-alquil-3-metilimidazólio, tendo a cadeia n-alquílica 10 a 16 átomos de carbonos. Em seguida, comparamos as propriedades dos LITs acima mencionados com as de tensoativos convencionais, cloretos de 1-alquilpiridínio e cloretos 1-alcanoil-amidoetil benzildimetilamônio. Por fim, estudamos a influência do volume da cabeça-polar, utilizando cloretos de 1-alquil-3-hexadecilimidazólio, tendo a cadeia alquílica secundária 1 a 5 átomos de carbono. As propriedades micelares foram investigadas por tensão superficial, condutividade, calorimetria, espalhamento de luz e ressonância magnética nuclear. Os resultados mostraram que ligações de hidrogênio (devido ao H2 ácido do anel imidazólio) e as interações hidrofóbicas são relevantes para a formação de micelas e que o aumento do volume da cabeça-polar favorece a micelização e a formação de agregados pré-micelares / The objective of this work is the synthesis and determination of the micelar properties of cationic surface-active ionic liquids (SAILs). Among the important characteristics of these compounds are: high charge delocalization and acid character of hydrogen H2 of the heterocyclic ring and large structural flexibility, the latter is relevant to solution properties of these surfactants, hence to their applications. Synthesis of SAILs was carried out by conventional heating or by microwave irradiation, the later method was more efficient. Initially, we studied the influence of the chain length of the alkyl group (an important factor for the energy of micelle formation) of 1-alkyl-3-methylimidazolium chlorides, n-alkyl group having 10 to 16 carbon atoms. Then, we compared the properties of the above mentioned SAILs with conventional surfactants, 1-alkylpyridinium chlorides and 1-alkanoyl-amidoethyl benzyldimethylammonium chlorides. Finally, we studied the influence of the head-group volume, by studying 1-alkyl-3-hexadecylimidazolium chlorides, with secondary n-alkyl group having 1 to 5 carbon atoms. The micelar properties were investigated by surface tension, conductivity, calorimetry, light scattering and nuclear magnetic resonance. Our results have shown that hydrogen bonding (due to the acidic H2 of the imidazolium ring) and hydrophobic interactions are relevant to micelle formation; increasing the head-group volume favors micellization and the formation of pre-micellar aggregates

Gegenstand dieser Arbeit ist die Synthese und Charakterisierung von Bis-1,3-azol-Derivaten insbesondere im Hinblick auf ihre potentielle Einsatzfähigkeit als chemisches Sensormaterial. Nach bereits bekannten Methoden gelang es, zehn neue Bisoxazol-Derivate sowie zehn neue Dicarbonsäurediester herzustellen. Weiterhin wurden 13 neue Bisimidazol- und vier neue Lophin-Derivate synthetisiert. Die erhaltenen Röntgeneinkristallstrukturanalysen zeigen, dass vor allem lineare Bisimidazol- und Bisoxazol-Derivate gute Eigenschaften als Clathratbildner aufweisen. Die Bisoxazol-Derivate mit Pyridin als Spacerelement eignen sich vorwiegend zur Komplexierung von Nickel(II)-, Kupfer(II)- und Kobalt(II)-ionen. Aus den fluoreszenzspektroskopischen Untersuchungen geht hervor, dass verschiedene Analytdämpfe unterschiedliche Auswirkungen auf die Festkörperfluoreszenz ausüben. Somit erscheint der Einsatz von Derivaten dieser Verbindungsklasse in chemischen Fluoreszenzsensoren erfolgversprechend.

Une large série d’imidazo[4,5-b]porphyrines a été synthétisée par condensation acido catalysée du 2,3-dioxo-5,10,15,20-tétraarylchlorines avec des aldéhydes aromatiques. Les propriétés stériques et électroniques des substituants méso-aryle sur le macrocycle tétrapyrrolique ont une influence importante sur le rendement en produit qui peut varier de 18% à 90%. L'analyse par diffraction des rayons X de la structure cristalline du 5,10,15,20-tétramésityl-2-(4-pyridyl)-1H-imidazo[4,5-b]porphyrinate de zinc(II) a montré qu'à l'état solide ce complexe forme des polymères de coordination. Ensuite, différentes méthodes de greffage des imidazoporphyrines sur la surface de TiO2 et ZrO2 mésoporeux ont été étudiées pour évaluer l'intérêt de ces matériaux hybrides en catalyse. La photo-oxydation en milieu homogène des sulfures en sulfoxydes par l'oxygène de l'air en présence de 5,10,15,20-tétramésityl-2-(4-diéthoxyphosphorylphényl)-1H-imidazo[4,5-b]porphyrinate d'indium(III) a été mis en œuvre. Il a été ainsi montré que le complexe supporté par le TiO2 pouvait être recyclé plusieurs fois malgré un lessivage partiel (1%) du catalyseur en solution. Puis, le 5,10,15,20-tétramésityl-2-(4-diéthoxyphosphorylphényl)-1H-imidazo[4,5-b]porphyrinate de manganèse(III) supportée par TiO2 a été utilisé comme catalyseur pour l'oxydation de sulfures en sulfoxydes par l'oxygène moléculaire en présence d'isobutyraldéhyde. Une large série de sulfoxydes a été préparée avec des rendements élevés (> 89%). Le catalyseur a été recyclé 7 fois sans perte de son efficacité et de sa sélectivité. Dans les conditions mises en jeu le lessivage du catalyseur en solution n'a pas été observé. / A broad series of functionalized imidazo[4,5-b]porphyrins was synthesized by the acid-catalyzed condensation of 2,3-dioxo-5,10,15,20-tetraarylchlorins with aromatic aldehydes. Both steric and electronic features of meso-aryl substituents influence on the product yield ranging from 18% to 90%.Single-crystal X-ray diffraction analysis of the structure of zinc(II) 5,10,15,20-tetramesityl-2-(4-pyridyl)-1H-imidazo[4,5-b]porphyrinate showed that this compound forms 1D coordination chains in the solid state.The post-synthetic modifications of imidazo[4,5-b]porphyrins were investigated by performing the Suzuki-Miyaura coupling reaction, preparing water-soluble imidazoporphyrins and linear/angular bis(imidazo)porphyrins.Several methods of grafting of imidazoporphyrins on the surface of mesoporous TiO2 and ZrO2 were investigated to prepare hybrid materials for catalysis.Then, it was demonstrated that indium(III) 5,10,15,20-tetramesityl-2-(4-diethoxyphospho-rylphenyl)-1H-imidazo[4,5-b]porphyrinate catalyzes the photooxidation of sulfides to sulfoxides by oxygen from air. This complex grafted on TiO2 surface was efficient as a reusable catalyst in spite of partial (1%) leaching of imidazoporphyrin in solution. TiO2-supported manganese(III) 5,10,15,20-tetramesityl-2-(4-diethoxyphosphoryl-phenyl)-1H-imidazo[4,5-b]porphyrinate was employed for catalytic oxidation of a broad range of sulfides by pure oxygen in the presence of isobutyraldehyde. All sulfoxides were obtained in high yields (>89%). The catalyst was reused in 7 consecutive cycles without loss of its efficiency and selectivity. Leaching of the catalyst was not observed under studied conditions.

The naturally occurring dipeptide carnosine (-alanyl-L-histidine) specifically attenuates tumor growth. Here, we ask whether other small imidazole-containing compounds also affect the viability of tumor cells without affecting non-malignant cells and whether the formation of histamine is involved. Patient-derived fibroblasts and glioblastoma cells were treated with carnosine, L-alanyl-L-histidine (LA-LH), -alanyl-L-alanine, L-histidine, histamine, imidazole, -alanine, and L-alanine. Cell viability was assessed by cell-based assays and microscopy. The intracellular release of L-histidine and formation of histamine was investigated by high-performance liquid chromatography coupled to mass spectrometry. Carnosine and LA-LH inhibited tumor cell growth with minor effects on fibroblasts, and L-histidine, histamine, and imidazole affected viability in both cell types. Compounds without the imidazole moiety did not diminish viability. In the presence of LA-LH but not in the presence of carnosine, a significant rise in intracellular amounts of histidine was detected in all cells. The formation of histamine was not detectable in the presence of carnosine, LA-LH, or histidine. In conclusion, the imidazole moiety of carnosine contributes to its anti-neoplastic effect, which is also seen in the presence of histidine and LA-LH. Despite the fact that histamine has a strong effect on cell viability, the formation of histamine is not responsible for the effects on the cell viability of carnosine, LA-LH, and histidine.

Deuteration is the replacement of a hydrogen atom by deuterium atom in a molecule. The replacement begins at the most acidic hydrogen in the molecule. In ATP, the deshielded hydrogen is C8-H which is the first replaced during deuteration. During ATP deuteration some of the ATP is hydrolysed to ADP concurrently. Using kinetic analysis, it was confirmed that the ATP hydrolysis that occurs is 1st order in ATP concentration, while the hydrogen replacement is 2nd order. The ATP and its C8 deuterated analogue were tested against three enzymes shikimate kinase (SK), acetate kinase (AK) and glutamine synthetase (GS) to determine if a kinetic isotope effect (KIE) exists in these systems. With AK and GS, the KIED increased as the KIEH decreased, while with SK the KIED decreased as the KIEH increased as the concentration of the ATP or deuterated analogue increased. Deuteration of imidazole and purine compounds reduced the specific activity of AK or SK at low concentrations in an enzyme-catalysed reaction. From a library of imidazole-containing compounds that inhibited SK, three compounds were selected and their IC50 values were determined on the SK-catalysed reaction. These compounds show a differential potency and efficiency between their protonated and deuterated analogues when compared in a 1:1 mixture. Synthesized purines incorporating three different substituents at N-9 were tested against AK or SK for their ability to lower the specific activity of the enzymes used / Physics / M. Sc. (Physics)

Ce travail est centré sur la synthèse de complexes du rhodium contenant un ligand azoté et leur mise en œuvre dans la réaction catalytique de carbonylation du méthanol en acide acétique. Dans une première partie, nous nous intéressons à la préparation de complexes neutres de formule générale [RhI2(CO)(L)] (L = amines, imidazoles et pyrazoles) et à quelques homologues chlorés. Ces complexes plans carrés manifestent une réactivité directement liée à l’encombrement stérique du ligand azoté L dans la réaction d’addition oxydante de l’iodomethane suivie de la cis-migration du groupement méthyle pour former l’espèce acétyle. Dans une deuxième partie, les complexes précédents ont été engagés dans des essais catalytiques de carbonylation du méthanol dans les conditions du procédé industriel. Comme il s’est avéré que les complexes neutres se transforment en espèce [RhI2(CO)2]- pour laquelle les contre-cations associés sont constitués du ligand azoté protoné ou methylé, nous avons effectué la préparation et la caractérisation des complexes [HNR3][RhI2(CO)2] ou [MeNR3][RhI2(CO)2]. Par IR, RMN et électrochimie, nous nous sommes intéressés aux phénomènes d’appariement d’ions et nous montrons qu’il s’agit dans le meilleur des cas d’interactions hydrogènes. Celles-ci influent la vitesse de la réaction oxydante de CH3I. Dans la dernière partie, nous avons complété une étude, précédemment initiée au laboratoire, sur le mécanisme, qui dans la dernière étape du cycle catalytique permet de passer de l’espèce acétyle [RhI3(COCH3)(CO)2]- à l’espèce active [RhI2(CO)2]- avec production de l’iodure d’acyle. A l’inverse du concept admis d’élimination réductrice de CH3COI suivie de son hydrolyse immédiate en CH3COOH et HI, nous montrons, avec l’appui de calculs théoriques (DFT) qu’en fait un ligand I- est substitué par un ligand acetate pour conduire à l’espèce [RhI2(OAc)(COCH3)(CO)2]-. L’élimination réductrice produit alors l’anhydride acétique qui est hydrolysé en CH3COOH régénérant [RhI2(CO)2]-. Un tel mécanisme opère en présence d’ions acetate dans les milieux faiblement hydratés visés par l’industriel. / This study focuses on the synthesis and reactivity of rhodium complexes bearing N- containing ligands or counter-cations for the [Rh]-catalyzed methanol carbonylation reaction to produce acetic acid under the industrial Celanese Acid Optimization (AO) process conditions. In a first part, full synthesis and characterization of neutral Rh(I) square planar cis- [RhX(CO)2(L)] (X = Cl or I) complexes have been described, for which L is an N-ligand belonging to the amine, imidazole or pyrazole family. For the [RhI(CO)2(L)] complexes, variable-temperature 13C{1H} NMR spectroscopy has put in evidence a fluxional behavior for the different sized L ligands involved. The rate of this fluxional process reveals to be related to both electronic and steric contributions brought by L to the Rh center. These parameters (mainly steric), supported by single-crystal X-ray analyses in the solid state, also influence significantly the kinetics of the methyl iodide oxidative addition reaction followed by rapid CO migratory insertion, the overall being the rate determining step of the [Rh]-catalyzed methanol carbonylation cycle. In absence of CO, this reaction gives rise to the corresponding neutral Rh(III) acetyl complex, which immediately dimerizes to afford [Rh(μ- I)I(COMe)(CO)(L)]2 complex, for which several X-ray crystal structures have been obtained and studied. In addition, the surprising C-H activation in the case of a tBu-pyrazole ligand giving rise to a cyclometalated Rh dimer is reported. In a second part, the reactivity of the latter neutral Rh(I) [RhI(CO)2(L)] complexes as potential precursors has been investigated by batch experiments for the methanol carbonylation reaction. Mechanistic understanding via VT-HP-NMR experiments enabled to detect mainly anionic Rh(I) [RL][RhI2(CO)2] (R = H or CH3 according to the working conditions) complexes formed by decoordination followed by quaternization of the L ligand. Despite this result, the pyrazole family ligands showed better stability under the harsh process conditions. Thus, it cannot be ruled out that equilibrium between neutral and anionic species co-exist in the reaction medium at high temperatures and that [RL]I salt dissociation occurs, restoring the L ligand into the Rh coordination sphere. At this stage we focused on the anionic Rh(I) complex and prepared a series of [XNR3][RhI2(CO)2] (X = H or CH3) species, which have been fully characterized. Infrared, NMR, conductivity experiments and DFT model calculations together put in evidence ion interactions according to the nature of the ammonium counter-cation. Protonated cations significantly impact on the kinetics of the methyl iodide oxidative addition presumably due to H-interactions with the Rh square plane. The final part deals with the mechanism of the reductive elimination reaction, the last step of the [Rh]-catalyzed methanol carbonylation cycle, which from complex [RhI3(COCH3)(CO)2]-, regenerates [RhI2(CO)2]-. In contrast to the classically admitted mechanism of reductive elimination of CH3COI followed by subsequent hydrolysis to form AcOH and HI, we demonstrate from experimental DFT calculation that substitution of an iodo ligand by an acetate ion occurs to give rise to the [RhI2(OAc)(COCH3)(CO)2]- species. Thus, reductive elimination regenerates [RhI2(CO)2]- and produces acetic anhydride, which after hydrolysis affords two molecules of acetic acid. Such a mechanism operates under process conditions at low water content with a significant amount of acetate ions.

A fusion protein composed of antibody fragments and β-lactamase was earlier created by Kojima et al. (2011), with antigen specificities against a bone disease marker and a pesticide. The enzyme was circularly permutated and fused to the variable heavy and light chain antibody fragments, thereby ensuring inactivity until binding of the target antigen triggered enzyme activation. Upon activation, the β-lactamase produced a colorimetric signal, which indicated antigen presence. In this work, a similar strategy was used to create two novel fusion proteins composed of circularly permuted β-lactamase and superfolder green fluorescent protein with anti-benzo[a]pyrene variable antibody fragments. The fusion proteins were designed and expressed in E. coli for the development of a single-step visual immunoassay. It was hypothesized that the cp reporter proteins would be activated once the binding of B[a]P to the variable antibody fragments occurred, and this interaction was expected to produce a detectable colorimetric or fluorescent signal. Although positive results were obtained in one instance, substantial supportive evidence in favour of the hypothesis could not be obtained. / SENTINEL Bioactive Paper Network, Natural Sciences and Engineering Research Council of Canada (NSERC), Canada Research Chairs Program.