O objetivo deste trabalho é explorar a síntese e funcionalização de 1,2,3- triazóis empregando o uso de reações do tipo \"Click-chemistry\", que é uma abordagem para a síntese de diversos compostos com base em reações de formação de ligação carbono-heteroátomo, onde a reação é estereoespecífica, altamente eficiente e geralmente com elevados rendimentos e em alguns casos ausência de subprodutos. O composto 1,2,3-triazol, sendo o material de partida para a continuidade do projeto foi preparado a partir do álcool propargílico (4) em presença de uma azida orgânica (1) e utilizando cobre(I) como agente promotor. Após a obtenção de uma série de compostos 1,2,3-triazólicos (2), procedeu-se a etapa de tosilação da hidroxila e posterior cicloadição multicomponente de um novo 1,2,3-triazol formando compostos bis-triazólicos. Os bis-triazóis (5) obtidos foram testados frente a cepas fúngicas, responsáveis por dermatites, com resultados satisfatórios. Ainda essas estruturas poderão ser empregados como blocos construtores para a síntese de estruturas mais complexas. / The aim of this work has been exploring the synthesis and functionalization of 1,2,3-triazoles employing the use of \"click-chemistry\" concept, which is defined as an approach for synthesis of various compounds based on reactions of carbon-heteroatom bond formation, which the reaction is stereospecific, high-efficiently, commonly gives high yields and in some cases no by-products are formed. The compound 1,2,3-triazole, which is the main starting material for the next steps was prepared from propargyl alcohol (4) in the presence of an organic azide (1) and copper(I) as a reaction promoter. Subsequently with a series of 1,2,3-triazole (2n) prepared we proceeded to the next step which is the substitution of hydroxyl for a tosyl group and after that a multicomponent cycloaddition of a new 1,2,3-triazole compound forming bis-triazoles. Bis-triazoles (5) were tested against fungal strains, responsible for dermatitis, with delighted results, furhtermore this class of strutures can be used as building blocks to improve efficiency in some other more complex structure.

Le polyéthylène (PE) est omniprésent dans notre vie de tous les jours et ce principalement car il présente des propriétés thermiques et mécaniques qu’on ne retrouve pas d’autres polymères. Cependant, sa très faible réactivité chimique fait qu’il est difficile de l’incorporer dans des architectures macromoléculaires plus complexes qui pourraient profiter de ses propriétés uniques. La modification de polymères fonctionnels en extrémité de chaîne par des réactions de couplage efficaces est un outil très utilisé pour la conception d’architectures macromoléculaires. Parmi les différentes réactions envisageables, la réaction de cyclo-addition 1,3 dipolaire de Huisgen entre un azoture et un alcyne est très utilisée dans le domaine de la science des polymères pour lier des polymères entre eux. Une autre méthode performante est le couplage par une réaction d’addition de type hétéro Diels-Alder (HDA) entre un diène et un dithioformate. L’objectif de ce travail de thèse est dans un premier temps d’identifier un système de polymérisation catalytique de l’éthylène qui permette de synthétiser du polyéthylène de masse molaire variable et comportant à une extrémité une fonction réactive. Puis cette extrémité réactive est mise à profit dans des réactions de couplage efficaces comme celles mentionnées plus haut pour la synthèse d’architectures macromoléculaires incorporant des segments de PE / Polyethylene (PE) is a polymer of great importance in our everyday life due to its unique thermal and mechanical properties. However, it suffers from lack of reactivity that prevents to introduce it into more complexed architectures the final properties of which would benefit from these unique features. The modification of end-functionalized polymers through orthogonal and efficient coupling reactions is a powerful and widely used tool for the design of various macromolecular architectures. In today’s polymer science the copper catalyzed azide-alkyne cycloaddition (CuAAC) is the most frequently used « click » reaction. Another efficient coupling method is the hetero Diels-Alder (HDA) reaction between a diene end-functionalized polymer and the electron deficient dithioester end-group of a polymer synthesized by reversible addition fragmentation chain transfer (RAFT) polymerization. Our first aim was to fin and optimize the best ethylene catalytic polymerization system that would allow to produce PE with different molar masses and end functional groups. In a second step, we tried to introduce polyethylene segments in macromolecular architectures by taking advantage of the best attributes of the aforementioned coupling reactions

L’objet de cette étude est d’utiliser la technique des micelles inverses pour synthétiser des nanoparticules à transition de spin, de taille et de forme contrôlées afin d’en permettre l’utilisation en électronique moléculaire. Dans la première partie, nous avons déterminé les paramètres de synthèse influençant la taille et la forme des particules d’un complexe à transition de spin à fort potentiel d’application. Dans un deuxième temps, nous avons utilisé ces paramètres sur trois autres complexes afin de comprendre la relation entre les paramètres de la synthèse et la morphologie des particules. Les nanoparticules ainsi synthétisées constituent la base d’une discussion sur l’existence d’un lien entre la taille/forme des particules et les propriétés de transition de spin. Enfin, la dernière partie de ce travail est consacrée à l’utilisation de ces matériaux en électronique moléculaire, et l’observation des propriétés de photoconductivité et photovoltaïque à l’échelle des nanoparticules. / The aim of this project is to use the reverse micelles technique to synthesize spin crossover (SCO) nanoparticles with controlled size and shape in order to use them in molecular electronic applications. In the first part, we have determined the synthesis parameters that influence the particles size and shape of an attractive spin crossover complex, due to his potential application. In a second time, we used the determined parameters on three other SCO complexes to generalize the relationship between the synthesis parameters and the particles morphology. All the as-prepared nanoparticles are the basis of a discussion about the existence of a link between the size and/or shape of the particles and the SCO properties. The last part of this work is dedicated to the utilization of this materials in molecular electronic, and the observation of photovoltaic and photoconductive properties at the nanoparticles scale.

L'objectif de cette thèse est d'appliquer la réaction de cycloaddition-1,3-dipolaire catalysée par le Cu(I) entre un alcyne et un azoture (CuAAC) pour la synthèse de nouveaux polymères utilisables pour le stockage d'énergies alternatives. Dans une première partie, la polyaddition par CuAAC de type AA+BB a été étudiée à partir de plusieurs monomères difonctionnels afin d'obtenir des poly(1,2,3-triazole)s à structures norbornadiènes. Grâce à un réarrangement structural régi par une irradiation photochimique, le norbornadiène au sein du polytriazole est transformé en quadricyclane qui est une molécule capable de stocker l'énergie solaire. Dans une deuxième partie des polymères linéaires à motif 1,2,3-triazole ont été obtenus à partir de monomères hétérofonctionnels α-azoture-ω-alcyne. La modification chimique post-polymérisation de ces poly(1,2,3-triazole)s (quaternisation du noyau 1,2,3-triazole suivie d'un échange anionique) a permis d'obtenir de nouveaux poly(liquide ionique)s à base 1,2,3-triazolium (TPILs). Différents TPILs ont été obtenus et leurs propriétés de conductivité ionique ont été étudiées par spectroscopie diélectrique. Enfin, la synthèse d'un poly(1,2,3- triazolium) photoréticulable a permis, lors d'un processus de photolithographie, de servir en tant que résine photosensible à tonalité négative ce qui a conduit pour la première fois à la structuration d'électrolytes solides à l'échelle du micron / The present work aims at elaborating new polymers by copper (I)-catalyzed azide-alkyne cycloaddition (CuAAC) step growth polymerization suited for the storage of alternative energies. In a first part, the AA+BB CuAAC polyaddition has been investigated using several difunctional monomers to prepare norbornadiene-containing poly(1,2,3-triazole)s. The norbornadiene units present in the main chain of these polymers are isomerized after UVirradiation into quadricyclane units able to store solar energy. In a second part, other linear poly(1,2,3-triazole)s were prepared from α-azide-ω-alkyne heterofunctional monomers. The post-polymerization chemical modification of these poly(1,2,3-triazole)s (quaternization of the 1,2,3-triazole units followed by anion metathesis reaction) resulted in new 1,2,3-triazolium-based poly(ionic liquid)s (TPILs). Various TPILs were obtained and their ionic conductivity properties were studied by dielectric spectroscopy. Finally, a UV-crosslinkable poly(1,2,3-triazolium) was synthesized and was used as a negative tone photoresist for lithography thus affording the efficient patterning of solid electrolytes

The procedure of Takimoto, Denault, and Hotta was followed in order to prepare 4-amino-3-hydrazino-5-methyl-s-triazole hydrochloride (II) and its precursor, triamino-guanidine hydrochloride (I).

Click chemistry is a very powerful chemical strategy that overcome carbon-carbon bond with carbon-heteroatom bond by joining small units with heteroatom links (C-X-C) using spring-loaded reactants. The Cu(I)-catalyzed Huisgen 1,3-dipolar cycloaddition is a major example based on the click chemistry philosophy. This method was used for the last 10 years to join different functional groups, carbohydrates, aminoacids, polymers to calix[4]arene and resorcin[4]arene cavitands by a stable 1,2,3-triazole linkages. Herein I describe our interest in this type of click chemistry reaction in the synthesis of dimeric capsules resorcin[4]arene via four 1,2,3-triazole linkages. Two different resorcin[4]arene derivatives were synthesized in which four azide and four alkyne functional groups were attached on the upper rim of two different resorcin[4]arenes. The dimerization reaction was quite challenging due to steric factors. Each resorcin[4]arene derivative was then studied individually via click chemistry and all click reaction results were excellent and the products were isolated in good yields. These results enhanced the synthesis of the dimeric resorcin[4]arene.

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

As cumarinas são compostos com potente atividade biológica. Foi explorada sua funcionalização, iniciando pela sua bromação, gerando o composto 3-bromocumarina, utilizado como material de partida para as reações de acoplamento do tipo Suzuki-Miyaura, que são uma das reações mais empregadas para a formação de ligação carbono-carbono, a qual utiliza paládio como catalisador e ácidos e ésteres borônicos como nucleófilo. Esses ácidos e ésteres borônicos possuem desvantagens, por isso foram substituídos pelos sais de organotrifluoroboratos de potássio, que são mais nucleofílicos, estáveis à umidade e à luz e não são higroscópicos. Assim, foi associada a catacterística reativa da cumarina para gerar derivados cumarínicos. Foram utilizados sais de ariltrifluoroboratos de potássio na primeira etapa e alquiniltrifluoroboratos de potássio na segunda etapa. Após o término destas duas etapas, foi utilizado o acoplamento de Sonogashira para a geração de um segundo material de partida, o 3-etiniltrimetilsililcumarínico, para poder sintetizar os 1,2,3-triazolilcumarínicos através da 1,3-dipolar cicloadição de Huisgen. Os 1,2,3-triazóis também possuem vasta atividade biológica, sendo de grande interesse sua preparação. / The coumarins are compounds with great biologic activity, for this reason in this dissertation we explored the functionalization beginning with bromination, generating the compound 3-bromocoumarin, used as starting material for the Suzuki-Miyaura cross-coupling reactions.The Suzuki-Miyaura cross-coupling reactions is one of the most employed protocol for carbon-carbon bond formation that use palladium as catalyst, boronic acid and ester as nucleophiles. But this boronic acid and ester have drawback and were substituted for potassium organotrifluoroborate salts that are more nucleophilic, moisture and light stable and are not hygroscopic. In this context, we associated the coumarin reactivity characteristic with the methodology mentioned above for create coumarin derivatives. We used potassium aryltrifluoroborate salts in the first step and potassium alkynyltrifluoroborate salts for the second step. After finished both steps mentioned before, we used the Sonogashira coupling to create the second starting material, the 3-((trimethylsilyl)ethynyl)-2H-chromen-2-one, so we could synthesize the 1,2,3-triazolyl coumarins through Huisgen 1,3-dipolar cycloaddtion. The 1,2,3-triazole also have a huge biologic activity, that represent a large interest for your preparation.

Na primeira parte deste trabalho apresentamos uma forma eficiente para sintetizar quinze novos compostos α-amino-1,3-dicarbonílicos através da reação multicomponente de Ugi. Para estas sínteses foi utilizado o microrreator de fluxo contínuo, um aparelho que possibilita uma excelente transferência de calor, de massa e alta relação superfície / volume. Algumas das vantagens em se utilizar um microrreator de fluxo contínuo na síntese são: redução do tempo de reação, aumento de rendimento, seletividade das reações e menor geração de resíduos. Foi possível assim estudar as reações químicas em condições inéditas, variando parâmetros como: temperatura, pressão, tempo de residência e relação estequiométrica. Um comparativo de rendimento da síntese de quatro moléculas foi realizado e pôde-se notar a eficiência do equipamento utilizado, pois os rendimentos obtidos foram superiores quando as mesmas moléculas foram sintetizadas através da reação one-pot. Um scale-up da reação de Ugi também foi realizado e apresentou um resultado satisfatório. Na segunda parte alguns destes compostos foram utilizados como intermediários na formação de uma ligação amídica e também aplicamos a metodologia relacionada à cicloadição catalisada por cobre entre alquinos e azidas na síntese de cinco novos compostos 1,2,3-triazóis. Este foi o primeiro trabalho realizado no Laboratório de Compostos Heterocíclicos da Faculdade de Ciências Farmacêuticas utilizando o microrreator de fluxo contínuo e este equipamento atendeu as necessidades deste trabalho com efetividade. / The first part of this work we present an efficient way to synthesize fifteen new α-amino-1,3-dicarbonyl compounds through the multicomponent Ugi reaction. For these syntheses was used the continuous flow micro-reactor, an equipment that allows an excellent transfer of heat, mass and high surface / volume ratio. Some of the advantages of using a continuous flow micro-reactor in the synthesis are: reduction of reaction time, increase of yield, selectivity of reactions and less generation of residues. It was possible to study the chemical reactions under new conditions, varying parameters such as: temperature, pressure, residence time and stoichiometric ratio. A yield comparison of the synthesis of four molecules was carried out and it was possible to note the efficiency of the equipment used, because the obtained yields were superior when the same molecules were synthesized through the one-pot reaction. A scale-up of the Ugi reaction was also performed and presented a satisfactory result. In the second part some of these compounds were used as intermediates in the formation of an amide bond and we also apply the methodology related to the copper catalyzed cycloaddition between alkynes and azides in the synthesis of five new 1,2,3-triazoles compounds. It was the first work performed in the Laboratory of Heterocyclic Compounds of the Faculty of Pharmaceutical Sciences using the continuous flow micro-reactor and this equipment met the needs of this work with effectiveness.

Triazoles have been widely used as amide bond isosteres in chemical biology as linkers and to enhance proteolytic stability. The use of triazoles has grown exponentially since the discovery of the copper (I) catalysed alkyne azide cycloaddition reaction in 2002 as the reaction is solvent and functional group tolerant, and usually high yielding. The reaction is also orthogonal to reactions used in nature, meaning it has become a powerful coupling tool. In post-translational modification (PTM), proteins are modified by covalent attachment of functional groups to amino acid side chains. These PTM processes are generally thought to be dynamic and highly regulated by cell machinery, controlling protein function in response to stimuli. The ability to control function post protein synthesis allows organisms to have a smaller genome, which is advantageous as it reduces the energy required for DNA replication and repair. Research into the function of PTMs has been limited by the difficulty in generating recombinant proteins that bear a single PTM in a specific location. Although many elegant methods have been proposed that solve this problem, to date cysteine alkylation is one of the most successful techniques. For lysine PTMs, thia-lysine II (sLys) derivatives have been shown to be excellent mimics of lysine, where the only perturbation between the native lysine-containing analogue is the switch of a CH2 for S in the side chain. Biotin is a well-known PTM in biotin dependent carboxylases, where biotin is involved in CO2 transfer. Recently biotinylation has also been shown to be a PTM on many other proteins, however the role of biotinylation is not well understood. Biotin triazole III has been shown to be a good mimic of the biotin amide bond and retains excellent affinity to Avidin (Av). In Chapter 1 the effects of modification to the valeryl side chain, and orientation of the biotin triazole bond affect affinity to Av using ITC are investigated. Compounds III, V and VI are shown to have a KD < 120 pM, but further information on the binding affinity of these compounds could not be assessed by ITC. Biotin triazoles III-VI were also shown to be resistant to hydrolysis in serum, unlike the native biotin amide bond, which is hydrolysed by the enzyme biotinidase (BTD). Generation of amide sLys derivatives has been shown to be synthetically challenging. In Chapter 2, the synthesis and applications of chloromethyl-triazole biotin as a sulfhydryl selective alkylation reagent are investigated. The electron withdrawing nature of the triazole was proposed to give a ‘pseudo-benzylic’ halide α to the triazole, thus increasing reactivity. The controlled alkylation of peptides and proteins has shown that chloromethyl-triazole biotin shows enhanced reactivity over many commercial alkylation reagents and also gives good selectivity for cysteine. Alkylation of histone H4K12C gave the singly alkylated product, accompanied by low amounts of double alkylation. Biotinylation was confirmed by Western blot with anti-biotin. Due to the wide range of readily available functional azides, it was envisaged that halomethyltriazoles could be incorporated into other PTM mimics. In Chapter 3, efforts to expand the range of PTMs accessible using halomethyl-triazoles and further enhance the reactivity of chloromethyl triazoles by preparation of bromo- and iodomethyl triazoles are detailed. Synthesis of reagents to mimic malonylation, succinylation and GlcNAcylation PTMs is described and the reactivity of these halomethyl-triazole reagents is assessed. An alternate approach to the development of PTM mimics through cysteine propargylation and subsequent CuAAC coupling is also described in chapter 3. In conclusion, a series of new reagents have been developed to mimic protein PTMs through alkylation of cysteine. The reagents, which include biotin, GlcNAc, succinyl and malonyl mimics, are based on a halomethyl-triazole scaffold and have been successfully reacted with cysteine containing peptides and proteins.