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In chapter 1, we describe development of a mild and efficient method for SNAr iodination of 6-chloropurine 2'-deoxynucleosides and nucleosides. Our studies demonstrate that 6-iodopurine nucleosides are excellent substrates for certain transition metal-catalyzed cross-coupling reactions. In chapter 2, we describe synthesis of protected 6-fluoro, 6-chloro, 6-bromo and 6-sulfonylpurine nucleosides. Comparisons among 6-fluoro-, 6-chloro-, 6-bromo, 6-iodo and 6-sulfonylpurine nucleosides for SNAr reactions with various N, O and S nucleophiles were investigated. Our results demonstrate that the 6-fluoropurine nucleoside is the best substrate for SNAr reactions among the four 6-halopurine nucleosides with oxygen, sulfur and aliphatic amine nucleophiles, and also with an aromatic amine plus TFA as a catalyst. However, the 6-iodopurine nucleoside is the best substrate for the aromatic amine without acid. With oxygen and sulfur nucleophiles, the 6-sulfonylpurine nucleoside reacted even faster than the 6-fluoropurine nucleoside. In chapters 3 and 4, nickel- and palladium-based systems with imidazolium-carbene ligands can catalyze efficient Suzuki cross-couplings of arylboronic acids and 6-[(imidazol-1-yl)-, (1,2,4-trizaol-4-yl), fluoro, alkylsulfanyl and alkylsulfonyl]purine 2'-deoxynucleosides and nucleosides to give the corresponding 6-arylpurine products.

Students studying organic chemistry often have difficulty applying prior knowledge from general chemistry in their thinking about organic reaction mechanisms. In the United States, electrophilic aromatic substitution (EAS) mechanisms can be taught towards the end in a second-semester course of organic chemistry, providing students with almost two-semesters' worth of experience with organic chemistry reactions before solving problems on synthesis of substituted aromatic compounds.<div>Little research has been done on how, or if, instructors consider their students' prior knowledge or understanding of these concepts in EAS in their teaching activities. The purpose of this study was to describe how students reason through EAS synthesis problems and to identify concepts or gaps in understanding that inhibit students from successfully solving these types of problems. Participants were interviewed using a think-aloud protocol in which they were asked to describe the reactants and mechanisms necessary to synthesize di- and tri-substituted benzenes using EAS. The interviews were transcribed and analyzed using a qualitative inquiry approach and the data interpreted in terms of the ACS Examinations Institute's Anchoring Concepts Content Maps for general and organic chemistry.</div><div>The findings from this study indicated that while students correctly applied their knowledge of substituent effects to solve these types of problems, they relied on rote-memorization of these effects, resulting in inflexibility when applying them to novel situations. Additionally, students exhibited gaps in understanding of fundamental concepts in resonance theory and Lewis structures, differentiating and utilizing Friedel-Crafts reactions, and recognizing when to use oxidation/reduction reactions in their syntheses.</div><div>Another component of this study focused on instructors of organic chemistry from a range of institutions in the United States. The purpose of this study was to describe how organic chemistry instructors perceived their students' reasoning about these types of problems, and to describe the characteristics of each instructors' topic-specific pedagogical content knowledge (TS-PCK) and the three general knowledge domains (GKDs) instructors draw upon to inform their TS-PCK. These knowledge domains are knowledge of students, subject matter knowledge, and pedagogical knowledge. These participants were remotely-interviewed using a think-aloud protocol in which they were asked to describe their classroom practices and teaching strategies when teaching EAS, and to describe how they would synthesize the same aromatic compounds as their students (a selection of which were interviewed in the previous study). Participants were asked to consider how their students would approach the syntheses and to specify what parts of the syntheses their students would find challenging, and why. The interviews were transcribed and analyzed using a qualitative inquiry approach. </div><div>The findings from this study indicated that the instructors were aware of their students' tendencies to use rote-memorization without understanding in the course, but there was still a mis-alignment between how instructors' perceived their students' reasoning through EAS synthesis problems and the reasoning the students actually used. The instructors believed that their students would only rely on the directing effects of substituents in their reasoning, but the students demonstrated they were aware of the activating and deactivating effects too. Additionally, instructors believed their students would not be hindered by an understanding of resonance or Lewis structures in their syntheses.</div><div>Finally, there are some recommendations for addressing the students' propensity for rote-memorization by providing a visual way to represent directing and activating/deactivating effects of substituents using electrostatic potential maps. There are also suggestions for further building on this work. <br><div><br></div></div>

Bromoarenes are important aromatic building blocks that are commonly used to synthesize various functional compounds in pharmaceutical, agrochemical and related industries.1,2 This great demand for bromoarenes makes their preparation a widely studied area of synthetic organic chemistry. However, further understanding of the reactivity and regiochemistry of aromatic functionalization reactions is still necessary, as much about the secondary substitution and solvent effects remain unknown. Resonance Theory is a widely used theoretical model to predict the regiospecifity and reactivity of the bromination of various aromatic compounds.3 The reactivity and regiospecificity of many substituted aromatic compounds is well explained using resonance theory.4 However, kinetic understanding of the p-bromination of halosubstituted aromatic compounds has not been investigated to the best of our knowledge.5,6In this thesis, the reactivity and regiospecifity of the p-bromination of activated secondary substituted aromatic compounds as well as media effects on the process will be discussed. Synthesizing bromoarenes has been accomplished using many different experimental setups.7-11 N-bromosuccinimide is the most highly utilized electrophilic aromatic brominating agent. Many of the NBS- based aromatic bromination reactions have been reported using strong acids, strong bases, halogenated solvents, nonpolar solvents and polar solvents alike.12 The bromination reactions reported herein were performed using two different solvents, acetonitrile and acetone, to investigate the effects of solvent polarity on p-bromination. Although acetonitrile is one of the most commonly used solvents in the p-bromination of aromatic compounds, acetone has not been investigated.

Chirality is a key principle in organic chemistry. All chiral compounds are non-superimposable mirror images of each other and therefore lack an improper axis of rotation (Sn). These mirror images often have identical properties in an achiral environment, however when two chiral molecules interact, they produce different shapes and properties. Nature, to this extent takes advantage of this aspect through unique formation of shape defined biological macromolecules that are tailored to carry out various life processes. This level of shape control is only made possible because of natural chiral monomers such as amino acids or glycosides that make up such macromolecules. Under new methods such as Chirality Assisted Synthesis (CAS), shape and size-controlled polymers and macromolecules can be realized through the use of chiral monomers to make well defined macromolecules. Because chirality dictates shape, and shape defines function in reference to macromolecules, controlling the chirality of monomers, while concurrently dictating shape and size can lead to the potential of biomimetic methodologies and cage like structures. Accessing shape defined monomers can be difficult especially when in reference to chiral compounds. The unique structure of enantiopure tribenzotriquinacenes show promise in the formation of well-defined cage like structures through utilization of CAS methodology. Synthesis of functionalized tribenzotriquinacenes along with development of an enantioselective electrophilic aromatic nitration method was attempted. Further exploration into the effectiveness of through-space enantioselective nitrations found a dependence on solvent temperature, and the auxiliary that is used. Synthetic difficulties, results, modifications and processes toward a generalized method are presented herein. In addition, controlling the size of polymers has always been a difficult synthetic challenge. Overall selectivity toward one product over another is determined via a variety of chemical properties. However, the formation of sequence and size defined polymers are a prominent aspect of natural polymers. The size selective synthesis, of unique ABAB sequenced polymers was attempted using an iterative exponential growth method. The ability to scale up these processes and create monodisperse oligoethers is also presented and described herein.

Electrophilic aromatic substitution (EAS) and directed ortho-metalation (DoM) involve the direct substitution of an arene hydrogen. A major drawback involving EAS is the necessity for harsh forcing conditions for the reaction to proceed. Catalysts such as Lewis acids FeBr3 and AICI3 for the introduction of halogens and acyl groups, respectively, are each highly toxic and corrosive. Textbook preparations of aryl iodides classicaly involved the use of iodine and nitric acid. This approach affords only modest yields and does not provide regiospecific substitution of most substituted aromatics because most contain ortho/para directors which afford mixtures of isomers. The novelty of our procedure for the synthesis of the iodinated aromatics is twofold in that regiospecific para-iodination is observed and hydrocarbon media are utilized. Hydrocarbon media are less hazardous and greener than media used for halogenations reported in literature. This procedure always yields derivatives regiospecifically substituted para to an electron donating substituent. Moreover, this method eliminates the need to use hazardous oxidative catalysts. DoM is a reaction regiospecifically substitute an arene hydrogen at the ortho position. The media used in DoM reactions are less hazardous than those required for a variety of EAS reactions. The only problem for this reaction is use of extremely strong bases, alkyllithium reagents, which are known to be air and water sensitive. However, the DoM reaction does eliminate the need to separate ortho/para isomer mixtures so that only a single product is generated. The metalation yields predominantly products regiospecifically substituted ortho-to the direcing metalating group (DMG). With our deficiency catalysis concept and subsequent purificaion methods, relatively pure ortho-lithiated intermediates have been prepared. The study of catalysts/promoters on the derivatization of these intermediates is anticipated to be extremely insightful. For this study, we have shown that highly selective, efficient ortho-lithiation can be achieved by deficiency catalysis utilizing n-BuLi as the only strong metalating base.

The electronegativity of thiolate ligation in the hemeprotein nitric oxide synthase (NOS) proteins has been identified as an influence on autoinhibition in this enzyme. The mutation of a conserved tryptophan residue, which hydrogen bonds to the coordinating thiolate ligand and therefore influences its electronegativity, to either phenylalanine or tyrosine has had various effects including heme loss and dimer disruption in the inducible isoforms, while hyperactivity occurs in the neuronal isoforms. I have performed the analogous mutations in W180 of eNOSoxy, the endothelial isoform. UV/visible and resonance Raman spectroscopy have demonstrated that the mutants experienced increased basicity of the thiolate due to loss of the hydrogen bond between the mutated residue in the absence of the cofactor (6R)5,6,7,8-tetrahydrobiopterin (H4B). The mutants also displayed relative rates of NO2- production that were comparable to the nNOSoxy mutants, which is consistent with the nNOSoxy results. The presence of H4B alters porphyrin planarity, which enabled hydrogen bonding to occur in W180Y, thus restoring thiolate basicity to that of wild-type eNOSoxy. Reduced overall activities by the proteins suggest that H4B stabilizes the heme. The analogous W56 mutants of saNOS, a NOS oxygenase domain-like protein from Staphylococcus aureus (saNOS), have been previously characterized using resonance Raman spectroscopy. These mutants also exhibit increased thiolate electronegativity over wild-type. As the homodimers had already been investigated, saNOS was an ideal system in which to explore heterodimers. Heterodimers were generated through the co-expression of one wild-type and one mutated subunit, enabling the examination of each subunit individually through resonance Raman spectroscopy. The subunits of the resulting proteins were shown to have heme environments that resembled those of their corresponding homodimers. The activity of saNOS did not vary significantly for the various W56 mutants, suggesting that saNOS catalysis may be unaffected by thiolate electronegativity. / Thesis (Master, Chemistry) -- Queen's University, 2008-09-04 11:37:38.688

Loline alkaloids (LA) are secondary metabolites produced by Epichloandamp;euml; (anamorph, Neotyphodium) grass endophytes. They are toxic and deterrent to a broad range of herbivorous insects but not to livestock. This protective bioactivity has spurred considerable research into the LA biosynthetic pathway. LOL, the gene cluster containing nine genes, is required for LA biosynthesis. The regulation of LOL genes during LA production in culture and in symbio is of interest. In this study, coordinate regulation between LOL gene expression and LA production level was investigated in both MM culture and symbiota. Results showed that expression of LOL genes in N. uncinatum MM culture were tightly correlated with each other (p andamp;lt; 0.0005), and all presented a significant temporal quadratic pattern during LA production. Gene expression started before LA were detectable, and increased while LA accumulated. The highest gene expression level was reached before the highest amounts of LA were detected, and gene expression level declined to a very low level after amounts of LA plateaued. Observations suggested that the hierarchical clusters based on the correlation coefficient could help to predict the roles of LOL genes in the LA pathway. In symbiota, coordinate coregulation of LOL gene expression with LA was found in E. festucae-meadow fescue inflorescences and stromata, whereby lower LOL gene expression corresponded with the lower LA level in stromata. In N. uncinatum (or N. siegelii)-meadow fescue vegetative tissues, dramatically higher LA levels were found in younger leaf tissue than in older leaf tissue, yet no evidence was found to relate this difference to LOL gene expression differences. Instead, substrate availability may regulate the LA level. In particular, asparagine was more than 10-fold higher in young leaf tissue than in old tissue, although proline was significantly lower in young tissue. Therefore, different regulatory mechanisms underlie LOL gene expression and LA production in different circumstances. The GUS activity of Pro-lolC2-GUS and Pro-lolA2-GUS in Neotyphodium species was almost undetectable in culture, though the activity could be detected in symbiota. The mRNA of GUS did not exhibit the same pattern as lolC2 or lolA2 in culture during LA production time course. A Pro-lolC2-cre transgene was expressed in complex medium, in which lolC2 mRNA was not detectable. These results suggest that proper regulation of LOL genes in culture or symbiota is dependent on the LOL cluster.

Le développement d'une nouvelle voie de synthèse de poly(éther cétone cétone),polymères thermostables, a été étudiée pour des matériaux composites à matrice thermoplastique obtenus par le procédé de moulage par injection de résine RTM. Pour cela,nous nous sommes orientés vers une polymérisation par couplage réactif entre des monomères difonctionnels et des agents de couplage. Neuf monomères X-EKKE-X avec différentes extrémités réactives ont été synthétisés par acylation de Friedel-Crafts ou substitution nucléophile aromatique puis caractérisés structurellement et thermiquement.Des essais de couplage à partir de monomères à extrémités COOH sur des bisoxazoline sont permis la synthèse en masse de quatre polymères, semi-cristallins ou amorphes, de faibles masses molaires. A travers l'étude du comportement thermique de molécules modèles, une fragilité thermique à partir de 250°C a été mise en évidence pour ces polymères et attribuée au pont ester-amide entre deux unités EKKE. / A new synthetic route to poly(ether ketone ketone), thermostable and semi-crystalline polymers, has been studied towards composite materials with a thermoplastic matrix obtained by a resin transfer molding process (RTM). This original synthesis was conducted by coupling reactions between difunctionals monomers and coupling agents. Nine X-EKKE-X monomers with different reactive extremities have been synthesized by Friedel-Crafts acylation or nucleophilic aromatic substitution. Thermal and structural properties were thoroughly investigated. Four polymers with semi-crystalline or amorphous morphologies and low molecular weights were obtained by coupling reactions between monomers with COOH functional extremities and bisoxazolines. Through the study of the thermal behavior of models molecules, a thermal fragility was highlighted for these polymers from 250°C and assigned to the amide-ester bridge between two EKKE units.

The pentafluorosulfanyl (SF5) group displays remarkable and unique properties, including large dipole moment, high electronegativity, high thermal and chemical stability, as well as high lipophilicity. However, only a few synthetic methods for the preparation of aromatic pentafluorosulfanyl building blocks have been developed to date. This work aims at improving availability and accessibility of aryl sulfurpentafluoride building blocks. In the first part of the work, the synthesis of aryl sulfurpentafluorides by the direct fluorination of diaryl disulfides with elemental fluorine is described. Nowadays, this synthetic strategy is used by industry on a multi-kilogram scale. However, the scope of the reaction is only limited to 3- and 4- nitro-1-(pentafluorosulfanyl)benzenes. In this work, the synthesis of various para-, meta- and ortho-substituted-(pentafluorosulfanyl)benzenes following the same approach was carried out. In the second part, the derivatization of aryl sulfurpentafluoride building blocks was investigated. Direct fluorination of 3-nitro-1-(pentafluorosulfanyl)benzene afforded 3-fluoro-5-nitro-1- (pentafluorosulfanyl)benzene. The titled compound was derivatized by two different processes: nucleophilic aromatic substitution (SNAr) of fluorine and vicarious nucleophilic substitution of...