The reactivity of perfluoroarenes and hetarenes towards SNAr reactions was studied as part of a synthetic programme to form an assembly of novel heterocyclic aromatic compounds for material and pharmaceutical applications. In chapter 1 the chemistry of perfluoroarenes is reviewed together with the use of conjugated compounds in organo-electronic applications. In chapter 2 the successful replacement of the remaining fluorine atoms in 6,12-difluorobenzo[1,2-b:4,5-b']bis[b]benzothiophene through SNAr reaction with long chain alkoxy and alkylthio nucleophiles is reported. An X-ray crystallographic investigation into their solid state packing was undertaken which would provide useful information for organoelectronic applications. Reactions with nitrogen and carbon based nucleophiles were also studied but met with little success. In chapter 3, alternative methods for the reductive cyclization of aryl and 2-bromoaryl perfluoroethers and sulfides to replace the currently used lithium-bromine exchange were explored, namely the use of radical cyclizations, palladium, magnesium, copper and Rieke metals. Some success was found using magnesium as a reagent although yields were low. Attempts to effect cyclisation reactions by ortho-lithiation and Ullmann coupling reaction with fluoroarenes is also reported. In chapter 4 attempts to generate alternative ring fusion in annulation reactions to form fused benzothiophenes by a dianion strategy are described. Development of methods to synthesise helicene or curved polycyclic structures from dibenzothiophene precursors is reported. In chapter 5 the synthesis of nitrogen containing fluorinated compounds with potential bioactivity is described. A series of novel amino substituted fluoroaromatics were successfully synthesised by adding different nitrogen based nucleophiles to pentafluoropyridine. Smiles rearrangement of a tetrafluoropyridyl sulphonamide was found to occur. A number of fluoropyridyl aniline derivatives were successfully synthesised some of which were submitted for biological screening. Substitution reactions of bis-nucleophiles bearing two heteroatom groups to form fused six membered rings were also studied. A Smiles rearrangement was identified in the reaction with an aminobenzenethiolate and confirmed by X-ray crystallography. Experimental procedures are given in chapter 6 as well as characterisation and crystallographic data of molecules synthesised during the research.

Fluorinated organic compounds play important roles in our society, as these products range from life-saving pharmaceuticals and agrochemicals, to fluoropolymers with extremely high thermal and chemical stability. Although elemental fluorine (F2) is the most reactive element, some fluoro-organic compounds are chemically inert. As such, controlled reactivity of fluorine or highly-fluorinated organic fragments is a considerable, yet important challenge for synthetic chemists. Fluoro-organometallic chemistry has been studied for decades, as researchers attempt to maximize the potential of metal mediated/catalyzed processes for the synthesis of fluorinated organic molecules. Within this framework, metal fluorocarbene complexes are particularly interesting because of their highly tunable reactivity, and are proposed for use in important metathesis/polymerization reactions of perfluorinated alkenes. While considerable work is still needed to make these proposed reactions a reality, this thesis outlines contributions from our research group. We showed that cobalt fluorocarbene complexes CpCo(=CFRF)(PPh2Me) (RF = F, CF3) undergo [2+2] cycloaddition reactions with tetrafluoroethylene (TFE) and phenylacetylene to form perfluorometallacyclobutane and partially fluorinated metallacyclobutene products, respectively. For both reactions, computational studies reveal a stepwise ring-closing mechanism, which proceeds through a singlet 1,4-diradical intermediate. Next, the formation of CpCo(=CF2)(L) complexes is achieved via the direct addition of difluorocarbene, generated in situ, to a cobalt(I) precursor. Subsequent addition of CF2 to cobalt fluorocarbene complexes results in [2+1] cycloaddition and formation of perfluorinated alkene complexes. The [2+1] addition is highly favored as the cobalt fluorocarbenes readily react with electrophilic CF2. A series of experiments provide evidence for the stepwise nature of fluoroalkene complex formation. From Co(I) fluorocarbene complexes, the focus shifts to preparing metal fluorocarbenes with electrophilic-type reactivity. The synthesis of bis(perfluoroalkyl) complexes serve as precursors for preparation of perfluoroalkyl cobalt(III) fluorocarbenes, which undergo migratory insertion reactions of the fluorocarbene into the perfluoroalkyl ligand. Using a similar synthetic approach, nickel(II) and palladium(II) difluorocarbene complexes are prepared from their corresponding trifluoromethyl precursors. The synthesis, characterization and reactivity of cobalt(III) fluoride complexes is also described, including the catalytic fluorination of acyl chlorides, demonstrating the first example of a cobalt(III) catalyzed fluorination reaction. The effects of the various ancillary ligands on these cobalt catalysts are investigated using high-throughput experimentation technology, and the scope of the reaction is expanded to include the synthesis of a variety of acyl fluoride compounds. Finally, the results and learnings from this work will be summarized and highlighted. The future directions and novel research which could result from the continuation of these projects is discussed, with an emphasis placed on the areas believed to have the highest potential impact.

The ¹H and ¹⁹F nuclear magnetic resonance (n.m.r.) spectra of a series of hexopyranosyl and pentopyranosyl fluorides were examined in some detail. The ¹H n.m.r. analyses (first order) enabled the gross molecular conformations to be determined and at the same time provided an opportunity to check the anomeric assignments previously made through application of other techniques. The¹⁹F n.m.r. parameters were then considered and several steric dependencies were observed. The ¹⁹F chemical shifts are controlled, in part, by the spatial orientation of the fluorine, but also, by the orientation of remote acetate groups or other substituents. Rules were subsequently developed for predicting the ¹⁹F chemical shifts for axial fluorines attached to C₁ of a pyranose carbohydrate. These rules were used to predict the ¹⁹F chemical shifts of the remaining "rare" giycopyranosyl fluorides. It was also noted that the ¹⁹F-¹H couplings resemble the ¹H-¹H couplings in that J(trans) > J(gauche). Moreover these ¹⁹F-¹H couplings are several times larger than the corresponding ¹H-¹H couplings and are also more sensitive to their precise steric environment. This study led to the observation that the β-D-anomers of the pentopyranosyl fluorides exist in the alternate chair form (¹C₄), which allows the fluorine atom to adopt an axial orientation. Subsequent to these initial n.m.r. investigations, a new reaction sequence was developed for the addition of "XF" to alkenes, Whereas this reaction sequence (AgF and X₂) results only in trans addition to cyclohexene (courtesy of D.L. Jones); it results in both cis and trans additions to cyclic vinyl ethers, although the trans adduct(s) always predominate: a possible reaction mechanism is discussed. This reaction sequence (X = I, Br,CI) was first applied successfully to D-glucal triacetate and then extended to other α,β-unsaturated cyclic ethers. The reaction products to D-glucal triacetate were for the most part crystalline. These 2-deoxy-2-halo-D-hexo-pyranosyl fluorides proved to be excellent models for extending previously observed electronegative dependencies. Moreover, when related to the 2-deoxy-D-glycopyranosyl fluorides, these compounds revealed that the orientation of remote substituents must play an important role in - determining ¹⁹F chemical shifts. Finally, a brief introduction is given to the utilization of both the "selective irradiation" and the "spin-tickling" methods for determining the relative signs of proton-proton coupling constants of carbohydrate derivatives. For most saturated carbohydrates the vicinal ¹H-¹H couplings have been found to be positive and the geminal couplings are negative in sign. For unsaturated derivatives both vicinal and geminal couplings are positive. The signs of the couplings of an episulphide derivative are the same as those of the saturated carbohydrates, whereas, the signs for an epoxide resemble those of unsaturated carbohydrates. These findings arc in accord with previous experimental and theoretical results. It has been demonstrated that the signs of long-range ( ⁴J) couplings of saturated derivatives exhibit a regular stereospecificity: those between two equatorially oriented protons (⁴ J, ₑ,ₑ) being positive and those between an axial and an equatorial proton (⁴Jₑ,ₐ ) being negative in sign. These findings are contrasted with the previous theoretical predictions and their potential as an adjunct to stereochemical studies is discussed. For unsaturated carbohydrate derivatives the long-range couplings are all negative in sign. The "selective irradiation" and "spin-tickling" homonuclear magnetic double resonance (n.m.d.r.) techniques have been used to determine the relative signs of the vicinal and geminal ¹⁹F- ¹H couplings of a series of glycopyranosyl fluorides. In all cases these two couplings have the same relative signs. Heteronuclear decoupling experiments on 2-bromo-2-deoxy-α-D-mannopyranosyl fluoride triacetate showed that for this derivative the vicinal coupling between H₁ and H₂ and the geminal coupling between H₁ and F₁ have the same relative signs. On this basis an absolute positive sign was assigned to both vicinal and geminal ¹⁹F- ¹H couplings. / Science, Faculty of / Chemistry, Department of / Graduate

Kinetic equation parameters for the curing reaction of a commercial glass fiber reinforced high performance epoxy prepreg composed of the tetrafunctional epoxy tetraglycidyl 4,4-diaminodiphenyl methane (TGDDM), the tetrafunctional amine curing agent 4,4'-diaminodiphenylsulfone (DDS) and an ionic initiator/accelerator, are determined by various thermal analysis techniques and the results compared. The reaction is monitored by heat generated determined by differential scanning calorimetry (DSC) and by high speed DSC when the reaction rate is high. The changes in physical properties indicating increasing conversion are followed by shifts in glass transition temperature determined by DSC, temperature-modulated DSC (TMDSC), step scan DSC and high speed DSC, thermomechanical (TMA) and dynamic mechanical (DMA) analysis and thermally stimulated depolarization (TSD). Changes in viscosity, also indicative of degree of conversion, are monitored by DMA. Thermal stability as a function of degree of cure is monitored by thermogravimetric analysis (TGA). The parameters of the general kinetic equations, including activation energy and rate constant, are explained and used to compare results of various techniques. The utilities of the kinetic descriptions are demonstrated in the construction of a useful time-temperature-transformation (TTT) diagram and a continuous heating transformation (CHT) diagram for rapid determination of processing parameters in the processing of prepregs. Shrinkage due to both resin consolidation and fiber rearrangement is measured as the linear expansion of the piston on a quartz dilatometry cell using TMA. The shrinkage of prepregs was determined to depend on the curing temperature, pressure applied and the fiber orientation. Chemical modification of an epoxy was done by mixing a fluorinated aromatic amine (aniline) with a standard aliphatic amine as a curing agent for a commercial Diglycidylether of Bisphenol-A (DGEBA) epoxy. The resulting cured network was tested for wear resistance using tribological techniques. Of the six anilines, 3-fluoroaniline and 4-fluoroaniline were determined to have lower wear than the unmodified epoxy, while the others showed much higher wear rates.

The chemistry of fluorolkyl hypervalent iodine reagents has witnessed a great boast in recent years. These compounds are highly attractive as drug candidates, advanced materials and agrochemicals as described in detail in the Introduction. Despite this fact, applications of these reagents in biological studies are rather rare and under developed. The goal of this thesis is therefore the development of mild and metal-free methods in order to fill this gap. Two ways of application of fluoroalkyl hypervalent iodine reagents in labeling of biologically relevant compounds was explored. First, the applicability of previously reported parent Togni CF3 and their analogous tetrafluoroethyl reagents in radical fluoroalkylation of electron-rich substrates such as indole and pyrrole derivatives using sodium ascorbate as reductant was described. This afforded trifluoromethyl or 1,1,2,2-tetrafluoroethyl containing products in moderate to high yields. Next, same reagents were applied for labeling of several peptides and proteins bearing aromatic amino acids in their structure. This way, peptides and proteins containing electron-rich aromatics such as Trp, Phe, Tyr and His were reacted with fluoroalkyl groups with high selectivity toward Trp. In the second part of the work, a different approach of radical...

Grâce à des propriétés physico-chimiques particulières, le fluor prend de plus en plus d’importance dans la chimie médicinale et plus particulièrement dans les peptidomimétiques. Dans ce mémoire, deux classes de peptidomimétiques fluorées ont été étudiées.Dans la première partie, de nouveaux groupements N-Rf ; les hydrazines difluoro ou trifluorométhylées et les 1,2,3 triazoles N-difluorométhylés ont été préparés et des études de leurs propriétés structurales ont montré l’intérêt de l’incorporation du fluor sur la conformation des pseudopeptides via des interactions NH-F.Dans la seconde partie, de nouveaux peptidomimétiques comportant des groupements cyclopropanes trifluorométhylés ont été conçus et synthétisés en tant qu’inhibiteurs potentiels du protéasome 26S (un macro-complexe protéique impliqué dans la dégradation de nombreuses protéines intracellulaires et qui a fait ses preuves en tant que cible pour le traitement de cancers). / Through special physico-chemical properties, fluorine is becoming increasingly important in medicinal chemistry and particularly in peptidomimetics. In this paper, two classes of fluorinated peptidomimetics were studied.In the first part, new N-Rf moieties; difluoro or trifluoromethylated hydrazines and N-difluoromethyl 1,2,3 triazoles were prepared and the study of their structural properties have shown the benefit of the incorporation of fluorine on the conformation of the peptidomimetics via NH-F interactions.In the second part, new trifluoromethylated cyclopropanes containing peptidomimetics were designed and synthesized as potential inhibitors of the 26S proteasome, a macro-complex protein involved in the degradation of many intracellular proteins and which has been recognized as a target for cancer treatment.

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The subject of whether fluorine (F) is detrimental to human health has been controversial for many years. Much of the discussion focusses on the known benefits and known detriments to dental care and problems that fluorine causes in bone structure at high doses. It is therefore desirable to have the means to monitor fluorine concentrations in the human body as a means to directly assess exposure. A monitoring tool could be applied in studies of human health and perhaps answer some of the questions regarding levels at which fluorine has protective effects and negative health consequences. This thesis presents work in the further development of a low risk non-invasive method for the monitoring of fluorine in human bone. The work was based on the technique of neutron activation analysis (NAA). Fluorine accumulates in bone as a long term storage site following exposure. In this thesis, the McMaster Tandem accelerator was used to produce neutrons through the 7Li(p,n)7Be reaction, measuring F levels in the human hand bone using IVNAA. The gamma rays emitted through the 19F(n,γ )20F reaction are measured using nine NaI(Tl) detectors with 4π geometry. Four published papers are presented in this thesis. The main outcome of the first publication was the development of a new phantom. This was needed to reduce the aluminum contamination. The main outcome of the second publication was a series of improvements to the method for the in vivo measurement of bone fluorine using NAA of the new phantoms. In the third publication the best hand position and neutron flux map in the irradiation cavity were determined through both Monte Carlo simulation (FLUKA) and experimental methods. Finally, the fourth publication describes the utility of the improved technique in a pilot study of environmentally exposed people. The overall conclusion from this thesis work is that a low risk monitoring tool, based on an NAA technique, has been developed which is capable of monitoring fluorine in urban Canadians. The technique can now be applied in studies of human health. / Thesis / Doctor of Philosophy (PhD)

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