This thesis focuses on the development of carbohydrate coupling chemistry on nanomaterials and their biological activity studies. It is divided into two parts: In part one, two carbohydrate immobilization approaches, based on perfluorophenyl azide (PFPA)-functionalized silica nanoparticles (SNPs), are presented, where the binding affinity of the glyconanoparticles was evaluated through carbohydrate-lectin interaction. In the first approach, PFPAfunctionalized SNPs were treated with propargylated glycosides and functionalized under copper-catalyzed azide-alkyne cycloaddition (CuAAC) conditions to give glyconanoparticles. For the second approach, a metal-free coupling chemistry based on perfluorophenyl azide-aldehyde-amine cycloaddition (AAAC) was developed for carbohydrate immobilization on PFPA-functionalized SNPs using glycosyl amine and phenylacetaldehyde. Subsequently, a quantitative fluorine nuclear magnetic resonance (19F qNMR) technique was developed to determine the carbohydrate density on the glyconanoparticles. The addition of an internal standard allowed the accurate determination of carbohydrate density, which was then used to calculate the apparent dissociation constant (Kd ) of the glyconanoparticles with lectin by a ligand competition assay. The developed approaches proved general and versatile, and the carbohydrate-presenting nanoplatforms showed high binding specificity in lectin binding. In part two, microwave irradiation was used to functionalize carbon nanomaterials with PFPA followed by carbohydrate conjugation. The microwave-assisted method proved efficient for a number of carbon nanomaterials including carbon nanotubes (CNTs), graphene and fullerene. The carbohydrates on the glyconanomaterials retained their binding patterns towards cognate lectins. / <p>QC 20150907</p>

La préparation de polymères à base d’acides biliaires, molécules biologiques, a attiré l'attention des chercheurs en raison des applications potentielles dans les domaines biomédicaux et pharmaceutiques. L’objectif de ce travail est de synthétiser de nouveaux biopolymères dont la chaîne principale est constituée d’unités d’acides biliaires. La polymérisation par étapes a été adoptée dans ce projet afin de préparer les deux principales classes de polymères utilisés en fibres textiles: les polyamides et les polyesters. Des monomères hétéro-fonctionnels à base d’acides biliaires ont été synthétisés et utilisés afin de surmonter le déséquilibre stoechiométrique lors de la polymérisation par étapes. Le dérivé de l’acide lithocholique modifié par une fonction amine et un groupement carboxylique protégé a été polymérisé en masse à températures élevées. Les polyamides obtenus sont très peu solubles dans les solvants organiques. Des polyamides et des polyesters solubles en milieu organique ont pu être obtenus dans des conditions modérées en utilisant l’acide cholique modifié par des groupements azide et alcyne. La polymérisation a été réalisée par cycloaddition azoture-alcyne catalysée par l'intermédiaire du cuivre(Ι) avec deux systèmes catalytiques différents, le bromure de cuivre(I) et le sulfate de cuivre(II). Seul le bromure de cuivre(Ι) s’est avéré être un catalyseur efficace pour le système, permettant la préparation des polymères avec un degré de polymérisation égale à 50 et une distribution monomodale de masse moléculaire (PDI ˂ 1.7). Les polymères synthétisés à base d'acide cholique sont thermiquement stables (307 °C ≤ Td ≤ 372 °C) avec des températures de transition vitreuse élevées (137 °C ≤ Tg ≤ 167 °C) et modules de Young au-dessus de 280 MPa, dépendamment de la nature chimique du lien. / Bile acids have drawn attention in the synthesis of polymers for biomedical and pharmaceutical applications due to their natural origin. The objective of this work is to synthesize main-chain bile acid-based polymers. The step-growth polymerization was used to prepare two important classes of polymers used in textile fibers, polyamides and polyesters. Heterofunctional bile acid-based monomers were synthesized and used in order to overcome stoichiometric imbalances during step-growth polymerization. The lithocholic acid derivative bearing amine and protected carboxylic functional groups was polymerized in bulk at high temperatures, yielding polyamides that were poorly soluble in common organic solvents. Soluble triazole-linked polyamides and polyesters were obtained when the cholic acid derivative bearing azide and alkyne functional groups was polymerized under mild conditions via copper(Ι)-catalyzed azide-alkyne cycloaddition. Two different catalytic systems, copper(Ι) bromide and copper(ΙΙ) sulfate, were tested. Only copper(Ι) bromide proved to be an effective catalyst for the system, allowing the synthesis of the polymers with a degree of polymerization of ca. 50 and an unimodal molecular weight distribution(PDI ˂ 1.7). The main-chain cholic acid-based polymers are thermally stable (307 °C ≤ Td ≤ 372 °C) with high glass transition temperatures (137 °C ≤ Tg ≤ 167 °C) and Young’s moduli in excess of 280 MPa, depending on the chemical structure of the linker.

Na parte inicial deste trabalho faz-se estudo monográfico sobre o íon azoteto e sua estrutura. Também nesta parte encontram-se reunidas referências sobre o íon uranilo em meio aquoso e os possíveis produtos de hidrólise, propostos na literatura, bem como, em presença de azoteto. Algumas considerações sobre a formação de complexos mistos polinucleares são também apresentadas. Sendo o ácido azotídrico um eletrólito fraco, as mudanças de pH nos tampões N-3/HN3 podem ser acompanhadas após a introdução de íons U2O2+5, potenciometricamente, com eletrodo de vidro. No intuito de obtenção de medidas mais precisas, determinou-se a resposta Nernstiana do eletrodo utilizado. O tratamento de dados aplicado à obtenção das constantes de formação, em meio azoteto, através do numero médio de ligantes e do grau de complexação, a diferentes concentrações de ligante, força iônica 2,00 M e temperatura de (25,0 ± 0,l) ºC, permitiu a avaliação de três constantes de equilíbrio: &#946;1 = 2,136 x 104 (M-1), &#946;2 = 6,090 x 105 (M-2), &#946;3 = 1,421 x 108 (M-3). Tais constantes de formação, nas condições estudadas, bem como o crescimento da estabilidade especialmente do primeiro complexo, sugerem a existência dos seguintes equilíbrios: (Ver arquivo PDF). É proposto um método alternativo , para a determinação de acidez livre das soluções padrões de câtions de metais hidrolisáveis, por medidas de pH condicional, à força iônica constante, por adição de padrão ácido. Correção de pH para respostas não Nernstianas do eletrodo de vidro recomenda o processo para resultados analíticos mais precisos. Estudos espectrofotométricos em meio aquoso complementam os estudos de hidrólise para o íon uranilo. Estudos das características espectrais dos sistemas U(VI), Fe(III) e Cu(II) em meio azotídrico, sugerem apresentação de um método analítico, para a determinação simultânea destes íons, baseado nas altas absortividades molares dos complexos formados: (Ver arquivo PDF). Em decorrência do estudo de interferentes, após extenso estudo sobre a oxidação e estabilidade dos sistemas cobalto (II) e níquel(II), em meio azotídrico, baseado nas trocas espectrais de cobalto(II) à cobalto(III), é apresentado um método alternativo para a detecção de traços de cobalto em diferentes sais de níquel (perclorato, nitrato, sulfato e cloreto), após estudo monográfico apresentando os clássicos para tal finalidade. Em meio 2,9 M de &#8204;N-3&#8204; e 0,10 M &#8204;HN3&#8204; pela ação de 10 mM de H2O2 à 365 - 353 nm marcantes diferenças espectrais devidas à oxidação de íons de cobalto recomendam o método da adição de padrão para limites entre 0,59 - 1,7 mg de Co(II) com interferências de níquel(II) em concentrações superiores à 250 mg . Medidas potenciométricas permitiram uma estimativa da constante global de formação da espécie &#8204;Co(N3)6&#8204;3- por oxidação anódica de íons de cobalto(II) em meio não complexante, a baixas temperaturas e pela ação de oxidante químico, PbO2, em meio complexante, como sendo da ordem de 1016 (M-6) em força iônica 2,00 M (NaClO4) à (25,0 ± 0,1) °C. / The study starts with a monographic study about the azide ion and its structure. In this part we can also meet bibliographic references about the uranyl ion, in aqueous medium, and its possible hydrolysis products is proposed in the literature. Some considerations of the mixed polinuclear complex formation are also presented. Being hydrazoic acida weak electrolyte, the change of pH in N-3/HN3 buffers can be followed after introduction of U2O2+5 ions, potentiometrically, with glass electrode. In order to obtain accurate measurements the Nernstian response of this electrode was determined. Data treatment was applied to obtain the hydrolysis formation constants , in azide medium, through the average ligand number and complexity function, at several ligand concentrations, ionic strenght 2.00 M and temperature of (25.0 ± 0.l) ºC. The following constants are avaliable: &#946;1 = 2,136 x 104 (M-1), &#946;2 = 6,090 x 105 (M-2), &#946;3 = 1,421 x 108 (M-3). Referred to the equilibria (3) - (5): (See file PDF). It has been proposed an alternative method for the determination of free strong acid in standard solutions of hydrolysable cations, can be achieved by measurements of the conditional pH, at constant ionic strenght, with standard acid addition. Corrections of the measured pH for non Nernstian response of the glass electrode is a recomended procedure for more accurate analytical results. Spectrophotometric studies, in aqueous medium, are completing the hydrolysis studies of uranyl ion. Spectral studies of the U(VI), Cu(II) and Fe(III) systems, in azide medium, to render possible a new analytical method, for simultaneous determination of these ions, based in high molar absortivities of the complex formed (See file PDF). Running allway of the foreign ins study, after the great study about the oxidation and stability of cobalt(II) and nickel(II) systems, in azide medium, based in spectral changes of cobalt(II) to cobalt(III), it has been formed an alternative method for determination of traces of cobalt in different nickel salts (perchlorate, nitrate, sulphate, and chloride). A monographic study, giving the different methods of the literature, has been completed. In 2.9 M &#8204;N-3&#8204; and 0.10 M &#8204;HN3&#8204; by the action of 10 mM of H2O2 at 365 - 353 nm a marked spectral differences arosen from oxidation of cobalt(II). A standard addition method leved to determination of 0.59 - 1.7 mg Co of nickel interferes when in concentrations higher than 250 mg, i.e., higher than 0.010 M. Potentiometric measurements lead to an estimation of overall formation constant of &#8204;Co(N3)6&#8204;3- specie by anodic oxidation of cobalt(II) ions, in non complexing medium, at low temperatures and by chemical oxidant action, PbO2, in complexing medium, as being 1016 (M-6) order in ionic strenght 2.00 M (NaClO4) at (25.0 ± 0.1) ºC.

A solução de cobalto(lI) em meio de perclorato de sódio apresenta uma onda polarográfica de redução próxima a -1,4 V em relação ao ECS a 25°C. A adição do ligante azoteto, N3-, causa a antecipação desta onda catódica para a região mais positiva de potencial. A máxima antecipação - de 320 mV - é atingida pela adição de 0,600 M do ligante. A antecipação da onda por ocasião da adição de azoteto, é explicada pela capacidade deste Iigante se adsorver sobre a superfície do mercúrio, formando uma ponte entre o eletrodo e o cátion metálico, facilitando a transferência de elétrons. A diminuição de sobretensão verificada com a adição do ligante reflete a queda da energia de ativação necessária para que ocorra a transferência de elétrons e como o azoteto é o responsável por este fenômeno, ele pode ser chamado de ligante catalítico. Critérios de caracterização para processos de eletrodo mostraram que a adição do ligante diminui o grau de irreversibilidade do processo de redução do cobalto(lI) - na técnica de pulso - em relação ao meio de perclorato. Em concentrações de azoteto inferiores a 0,600 M ocorre a antecipação gradativa da onda de redução do cobalto(lI) com um desdobramento em duas ondas com potenciais de meia-onda próximos a -1,1 V e -1,4 V, respectivamente. Da análise das curvas de distribuição das espécies complexas em equilíbrio concluiu-se ser a onda em -1,1 V correspondente à redução do azoteto-complexo de cobalto(ll) (presente já no seio da solução ou formado na superfície do eletrodo) e a onda em -1,4 V relacionada ao aquo-íon de cobalto(II). Especificamente na concentração de azoteto 0,160 M a onda na região de -1,1 V na polarografia de pulso diferencial apresentou um desdobramento bem nítido. Tal fato foi interpretado como transferência de elétrons por etapa ou, em outras palavras, entrada de elétrons com velocidades diferentes, possibilitando a existência de cobalto no estado monovalente ainda que por um lapso de tempo curto. Medições coulométricas a potencial controlado foram feitas em dois potenciais da onda do azoteto-complexo: (1) potencial em que ocorreu o desdobramento e (2) potencial limite. Em (1) o número de elétrons obtido foi menor que 2, a solução turvou-se devido à elevação do pH e a análise de toque na solução final detectou a presença do cátion amônio. Em (2) o número de elétrons obtido foi 2, a solução permaneceu límpida, e a análise de toque não determinou a presença de amônio. Os fatos observados em (1) reforçaram a hipótese da formação do intermediário de cobalto(l) que seria reoxidado a cobalto(lI) pelo HN3 produzindo NH4+ e N2. No caso (2), por sua vez, a redução possivelmente leva à formação de cobalto metálico, que não interage com o HN3. Outras evidências da formação de cobalto(l) obtidas foram: a) o número de elétrons fracionado e maior que 3 quando aumentou-se a concentração de HN3 no caso (1); b) a elevação significativa apenas da corrente associada ao primeiro pico (supostamente atribuído ao Co(l)) com a elevação da concentração de HN3 em solução; c) a quebra em duas retas, nas curvas de polarização, cujos coeficientes angulares foram maiores na presença de 0,160 M de azoteto e, finalmente d) a relação Ic/la, próxima de 1 quando o Ei no PPR foi fixado no potencial do desdobramento, e bem maior que 1, com Ei fixado no limite. / The electroreduction of Co(ll) in perchloric media gives origin to a polarographic wave about -1.4 V VS. SCE at 25°C. With the addition of the azide ligand, N3-, that wave shifts towards more positive potentials. The higher value of the potential shift, 320 mV, is recorded for the concentration 0,600 M of ligand. The shift can be explained by the adsorption of the azide ion on mercury electrodes, bridging the electrode and the metal ion, and promoting, then, the electron transfer more easily. With intermediary ligand concentrations the reduction wave of the cobalt ion breaks in two curves having walf-wave potentials around -1.1 and -1.4 V. Taking into account the distribution curve of the complexes species in equilibrium, it is concluded that the first wave corresponds to the azide complex of cobalt(lI) (already present in the solution or formed on the electrode surface), and the second one is related to the Co(lI) aquo íon. The wave correspondent to the reduction of azide complex, in the differential pulse polarography, too shows a splitting in two curves. This behavior dependents of the ligand concentration can be interpreted in terms of a stepwise charge transfer reaction, with the possible production of a labil Co(l) intermediate. Coulometric experiments performed at the potential where the breaks occurs, confirmed the supposition of the presence of Co(l) species, which could be oxidized to Co(ll) by HN3 yielding NH4+ and N2. Two linear regions exhibited by polarization curves in the solution 0,160 M azide and the Ic/la current ratio equal to 1, obtained by reverse pulse polarography with the initial potential coinciding with the potential at which break occurs, gave further evidences of the possible formation of Co(l) species.

This dissertation is concerned with the understanding of physico-chemical properties of energetic materials (EMs). Recently, a substantial amount of work has been directed towards calculations of equations of state and structural changes upon compression of existing EMs, as well as elucidating the underlying chemistry of initiation in detonating EMs. This work contributes to this effort by 1) predicting equations of state and thermo-physical properties of EMs, 2) predicting new phases of novel EMs, and 3) examining the initial stages of chemistry that result in detonation in EMs. The motivation for the first thrust, is to provide thermodynamic properties as input parameters for mesoscale modeling. Such properties are urgently sought for a wide range of temperatures and pressures, and are often difficult or even impossible to obtain from experiment. However, thermo-physical properties are obtained by calculating structural properties and vibration spectra using density function theory and employing the quasi-harmonic approximation. The second thrust is directed towards the prediction and investigation of novel polymorphs of known azide compounds to identify precursor materials for synthesis of polymeric nitrogen EMs. Structural searches are used to identify new polymorphs, while theoretical Raman spectra for these polymorphs are calculated to aid experimentalists in identifying the appearance of these azide compounds under high pressure. The final thrust is concerned with elucidating the initial chemical events that lead to detonation through hypervelocity collision simulations using first-principles molecular dynamics. The chemical mechanisms of initiation are determined from the atomic trajectory data, while heats of reaction are calculated to quantify energy trends of chemical transformations.

Two classes of C5 azido-modified pyrimidine nucleosides were synthesized and explored as radiosensitizers. The 5-azidomethyl-2'-deoxyuridine (AmdU) was prepared from thymidine and converted to its cytosine counterpart (AmdC). The 5-(1-azidovinyl) modified 2'-deoxyuridine (AvdU) and 2'-deoxycytidine (AvdC) were prepared employing regioselective Ag-catalyzed hydroazidation of 5-ethynyl pyrimidine substrates with TMSN3. AmdU and AmdC were converted to 5'-triphosphates AmdUTP and AmdCTP, and incorporated into DNA-fragments via polymerase-catalyzed reaction during DNA replication and base excision repair. Radiation-mediated prehydrated electrons formed in homogeneous aqueous glassy (7.5 M LiCl) systems in the absence of oxygen at 77 K led to site-specific formation of π-type aminyl radicals (RNH•) from AmdU, AmdC, AvdU, and AvdC. The ESR spectral studies and DFT calculations showed RNH• undergo facile conversion to thermodynamically more stable σ-type iminyl radicals, R=N•. For AmdU, conversion of RNH• to R=N• was bimolecular involving α-azidoalkyl radical as intermediate; however, for AvdU, RNH• tautomerized to R=N•. Our work provides the first evidence for the formation of RNH• attached to C5 position of azidopyrimidine nucleoside and its facile conversion to R=N• under reductive environment. These aminyl and iminyl radicals can generate DNA damage via oxidative pathways. The azido-nucleosides were successfully applied as radiosensitizers in EMT6 cancer cells in both hypoxic and normoxic conditions. To explore the generation and reactivity of 2'‑deoxyguanosin-N2-yl radical (dG(N2-H)•) postulated to generate from guanine moiety towards •OH, 2-azido-2'-deoxyinosine (2-N3dI) was prepared by conversion of 2-amino group in protected dG into 2-azido via diazotization with tert-butyl nitrite followed by displacement with azide and deprotection. The investigation of dG(N2-H)• generated from 2-N3dI and its subsequent reactions using ESR will be discussed. Cycloaddition between 5-ethynylpyrimidine or 8-ethynylpurine nucleosides and TMSN3 in the presence of Ag2CO3, CuI, or CuSO4/sodium ascorbate provided N-unsubstituted 1,2,3-triazol-4-yl analogues of the parental DNA bases (i.e. 5-TrzdU, 5‑TrzdC, 8-TrzdA, and 8-TrzdG). These novel triazolyl nucleosides showed excellent fluorescent properties: 8-TrzdA exhibits the highest quantum yield (ΦF) of 44% while 8‑TrzdG had ΦF of 9%. The 5-TrzdU and 5-TrzdC showed a large Stokes shift of ~110 nm. The application of these fluorescent nucleosides to cell imaging and DNA modifications will also be discussed.

This thesis describes the use of 2H-azirines, three-membered unsaturatednitrogen-containing heterocycles, as reactive intermediates ina number of Lewis acid promoted alkylations and Diels-Alderreactions providing synthetically useful aziridines. In order to carry out this investigation a new generalprocedure for the ring closure of vinyl azides, forming theresultant 3-substituted-2H-azirines, was developed applying low boiling solventsin closed reaction vessels at elevated temperatures. The addition of organolithium reagents in the presence ofcommercially available chiral ligands, to the 3-(2-naphthyl)-2H-azirine was studied, which gave the correspondingaziridines. Several Lewis acids were shown to catalyze the normalelectron-demand Diels-Alder reaction between 3-alkyl-,3-aromatic-, and 3-ester-substituted 2H-azirines and various dienes. These reactions gave theexpected cycloadducts in moderate yields. Using a chiral auxiliary high diastereoselectivity wasobtained in the addition of alkyl radicals to a8-phenylmenthyl-substituted 2H-azirine-3-carboxylate. The alkyl radicals weregenerated from the corresponding trialkyl borane and molecularoxygen. Hydroborations and transmetallations were used toprepare these trialkylboranes. Catalytic amounts of CuClincreased the diastereoselectivity in the radical additionreactions. Attempts were made to explain how the coordination of aLewis acid to the azirine nitrogen atom affects thereactivity/stability of the azirine. DFT calculations and NMRexperiments involving Lewis acid-azirine complexes wereperformed. Keywords:Enantioselective, diastereoselective, vinylazide, 2H-azirines, aziridines, Lewis acid, chiral ligand,chiral auxiliary, organolithiums, Diels-Alder reaction, alkylradicals, triethylborane.

A tetrazole is a 5-membered ring containing 4 nitrogens and 1 carbon. Due to its energetic potential and structural similarity to carboxylic acids, this ring system has a wide number of applications. In this thesis, a new and safe sustainable process to produce tetrazoles was designed that acheived high yields under mild conditions. Also, a technique was developed to form a trityl-protected tetrazole in situ. The rest of this work involved the exploitation of the energetic potential of tetrazoles. This moiety was successfully applied in polymers, ionic liquids, foams, and gels. The overall results from these experiments illustrate the fact that tetrazoles have the potential to serve as a stable alternative to the troublesome azido group common in many energetic materials. Due to these applications, the tetrazole moiety is a very important entity.

<p>This thesis describes the use of 2<i>H</i>-azirines, three-membered unsaturatednitrogen-containing heterocycles, as reactive intermediates ina number of Lewis acid promoted alkylations and Diels-Alderreactions providing synthetically useful aziridines.</p><p>In order to carry out this investigation a new generalprocedure for the ring closure of vinyl azides, forming theresultant 3-substituted-2<i>H</i>-azirines, was developed applying low boiling solventsin closed reaction vessels at elevated temperatures.</p><p>The addition of organolithium reagents in the presence ofcommercially available chiral ligands, to the 3-(2-naphthyl)-2<i>H</i>-azirine was studied, which gave the correspondingaziridines.</p><p>Several Lewis acids were shown to catalyze the normalelectron-demand Diels-Alder reaction between 3-alkyl-,3-aromatic-, and 3-ester-substituted 2<i>H</i>-azirines and various dienes. These reactions gave theexpected cycloadducts in moderate yields.</p><p>Using a chiral auxiliary high diastereoselectivity wasobtained in the addition of alkyl radicals to a8-phenylmenthyl-substituted 2<i>H</i>-azirine-3-carboxylate. The alkyl radicals weregenerated from the corresponding trialkyl borane and molecularoxygen. Hydroborations and transmetallations were used toprepare these trialkylboranes. Catalytic amounts of CuClincreased the diastereoselectivity in the radical additionreactions.</p><p>Attempts were made to explain how the coordination of aLewis acid to the azirine nitrogen atom affects thereactivity/stability of the azirine. DFT calculations and NMRexperiments involving Lewis acid-azirine complexes wereperformed.</p><p><b>Keywords:</b>Enantioselective, diastereoselective, vinylazide, 2<i>H</i>-azirines, aziridines, Lewis acid, chiral ligand,chiral auxiliary, organolithiums, Diels-Alder reaction, alkylradicals, triethylborane.</p>

No description available.