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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.

The three isomers of dichlorobenzene (DCB) exhibit marked differences in hepatotoxicity following intraperitoneal (ip) administration in male F-344 rats. Plasma GPT activity, measured 24 hours post exposure, was elevated to approximately 4080 units/ml following a 1.8 mmol/kg dose of o-DCB. Conversely, n-DCB produced only a moderate elevation (306 units/ml) following a 4.5 mmol/kg dose, while p-DCB produced no elevation in GPT activity at this dose (24 units/ml). Ultra-structurally, o- and m-DCB induced elevations in GPT activity were associated with a centrilobular pattern of hepatic necrosis. The role of cytochrome P-450 mediated bioactivation in DCB-induced hepatotoxicity was demonstrated by elevated GPT activities following an otherwise nontoxic 0.9 mmol/kg dose of either o- or m-DCB in phenobarbital pretreated animals (16770 and 21540 units/ml, respectively). The paraisomer of DCB showed no induction of toxicity with phenobarbital pretreatment. Hepatic glutathione (GSH) concentrations were reduced 0.5, 3 and 5 hours after a 1.8 mmol/kg dose of either o- or m-DCB, a dose which produces hepatotoxicity only for o-DCB. Pretreatment of animals with phorone depleted hepatic GSH to 15% of control levels within two hours; subsequent ip administration of either o- or m-DCB (1.8 mmol/kg) produced approximately equivalent elevations in GPT activity for both isomers (5749 ± 648 and 4732 ± 857 units/ml, respectively). In vitro incubations of o- and m-DCB with GSH and rat liver cytosolic fraction, suggested that GSH may bind m-DCB without prior bioactivation, thereby reducing the hepatotoxicity of this isomer relative to the more toxic ortho isomer. The interactive hepatotoxicity of the dichlorobenzenes with carbon tetrachloride (CCl₄) was also investigated. Concomitant ip injection of CCl₄ (1.0 mmol/kg) and o-DCB (2.7 mmol/kg) produced a marked inhibition of o-DCB hepatotoxicity, as measured by GPT activity (approximately 200 units/ml vs. 7450 units/ml for o-DCB alone). The mechanism of this inhibition of o-DCB hepatotoxicity was shown to be a reduction in the cytochrome P-450 mediated bioactivation of o-DCB, by CCl₄. A similar inhibition of o-DCB hepatotoxicity was seen following administration of CCl₄ as a pretreatment, via the drinking water. Concomitant ip administration of CCl₄ with either m- or p-DCB also produced a reduction in the metabolism of the dichlorobenzene.

The use of alkali and alkaline earth metals as reducing agents in liquid ammonia solvent for aromatic and conjugated systems has been investigated by chemists at least since the early 1900's, e.g., Lebau and Picon (1). By subsequent additions of a proton source, the system yielded the first successful partial reduction of a monobenzenoid system, as reported by Wooster and Godfrey (2), in 1937. As a result of that success a patent was issued to Wooster for the process (3). Little additional work was reported until Birch and his co-workers picked up the investigation in the early 1940's. It was through his vigorous study and development of this reduction system that Birch's name came to be associated with reductions of organic compounds by alkali metals in liquid ammonia, hence, the Birch reduction. In this thesis the Birch reduction of cinnamic acid is investigated.

Interstellar chemistry has been a growing field over the last several decades. There is particular interest on the nature and reactivity of interstellar molecules; most notably that of polycyclic aromatic hydrocarbons (PAHs). My thesis focused on the kinetics of unimolecular dissociation of small PAH and PAH-like molecules under interstellar conditions. PAHs (naphthalene (NAP), anthracene (ANT) and pyrene (PYR)), some dihydro- equivalents (1,2-dihydronapthalene (DHN) and 9,10-dihydrophenanthrene (DHP)) and a few other small aromatic organic molecules (indene (IND), ethynylbenzene (EB), propynylbenzene (PB) and benzocyclobutene (BCB)) were studied using imaging photo-electron photo-ion coincidence spectroscopy (iPEPICO) and electron impact mass spectrometry (MS); both mass analyzed ion kinetic energy spectrometry (MIKES) and collision induced dissociation (CID). Experiments were performed at different ionization energies to produce breakdown diagrams for the various fragments. These diagrams are then fit using RRKM theory to determine the zero Kelvin activation energy (E0) and the entropy of activation (Δ‡S); these results are then compared and discussed. All these molecules were compared in order to try and find any overlying trends which could be applied to their role in the interstellar medium (ISM). It was determined that H loss was the dominant fragmentation channel, as it was the only dissociation channel common to the majority of molecules studied. It was also seen that organic fragment loss (C2H2, CH3 and C4H2) was only observed in smaller molecules which indicates that PAHs are not likely a source of these molecules. The small fragment molecules gave insight into the stability of closed ring structures, such as PAHs, through the comparison of the dissociation of closed and open structures. The dihydro-PAHs, selected as a probe to investigate the proposed catalytic role of PAHs in the formation of molecular hydrogen, yielded very interesting results. It was seen that these molecules would readily undergo isomerisation prior to dissociation. This added an unexpected level of difficulty to the calculations but quickly demonstrated how the presence of additional hydrogen atoms could greatly disrupt the dissociations, as it was not the simple process of removing them as it was originally believed. The overall trend observed was that it is the structure, not the size, which has the dominating effect on the dissociation. Ions of similar structure behaved similarly, regardless of a change in mass; isomers, however, had radically different behaviours which can only be attributed to their differing molecular conformations. This observation could aid in the understanding of larger PAHs, those which are believed to exist in the ISM, and what role they may play in the chemistry of the universe.

The title chroman is useful in synthesis and as a water-soluble analog of γ-tocopherol, a member of the vitamin E family. This new synthesis of γ-trolox proceeds via selective aromatic demethylation of Trolox, the more easily available 2,5,7,8-tetramethyl homolog compound. This route is shorter than the previous synthesis, avoids the use of cyanide and methoxybutadiene, and requires no chromatography.

Four casein-derived peptides fractions of varying hydrophobicity were obtained from á-chymotryptic digest of acid casein using hydrophobic interaction chromatography, termed fractions one through four (abbreviated, F1, F2, F3, and F4). Four standard methods involving alkoxyl, peroxyl, 2, 2-diphenyl-1-picrylhydrazl (DPPH), and 2, 2'-azino-bis (3-ethylbenzothiazoline-6-sulphonic acid) ABTS•+ radicals, were used to measure antioxidative properties. While significantly superior efficacy was exhibited by F2 for all tests except against DPPH, no correlation between antioxidant efficacy and surface hydrophobicity was found. By using capillary electrophoresis and high performance liquid chromatography, the detection of aromatic chromophores by ultraviolet at 280 nm in the fractions revealed that F2 contained the highest concentration of aromatic amino acids and a unique peptide. Result from circular dichroism exhibited remaining residual structure in F2 compared with undigested casein. The F2 possesses a high potential to be used in food industry as a natural source of antioxidant with pronounced antioxidant capacity.

The objective of this thesis was to investigate firefighters’ exposures to carcinogens and mutagens. This thesis aimed to (1) characterize firefighters’ exposures during emergency fire suppression, (2) examine the use of silicone wristbands as passive samplers to assess firefighters’ exposures, and (3) assess the ability of post-fire decontamination protocols to reduce firefighters’ exposures. Chapter 1 provides a general introduction and background information on the concepts covered in this thesis. In Chapter 2, I examined air and surface contamination with polycyclic aromatic hydrocarbons (PAHs) and metals, both at fire stations and following emergency fire suppression activities. I also investigated the ability of current laundering methods to remove surficial PAHs and metals from firefighters’ personal protective equipment. In Chapter 3, I assessed the ability of silicone wristband passive samplers to measure firefighters’ exposures to PAHs during live fire training. In Chapter 4, I assessed the ability of three post-fire dermal decontamination methods to remove surface contamination and reduce internal dose. In Chapter 5, conclusions and implications for each chapter are summarized. Future directions for the field are described. The overall conclusions for this thesis were: i. firefighters experience significant occupational exposures to carcinogens during emergency fire suppression and live fire training; ii. the ability of silicone wristbands to properly sample PAHs is altered in a fire environment and correction factors must be determined to improve their utility for exposure assessment; iii. current post-fire dermal decontamination methods, which are intended to reduce firefighters’ exposures, do not reduce their internal dose of PAHs.

M. S.

There are a number of inherent problems associated with the analysis of polycyclic aromatic compounds (PAC) in airborne particulate matter. The compounds of interest constitute a very small fraction of the total sample, but consist of hundreds of different components. Therefore, analytical techniques with very high resolving power are required. To try to address these problems, methods have been developed and improved to isolate, and subsequently profile, and identify the PAC present in typical airborne particulate samples. Since no single chromatographic technique can provide the desired resolution, a multi-stage clean-up scheme was required prior to analysis. Two methods were investigated in this study. Both methods used a Soxhlet extraction followed by fractionation using an adsorption chromatography step (silica or alumina) and Sephadex LH-20 to isolate the PAC fraction from the other organic constituents. Another problem associated with the analysis of PAC in airborne particulate matter was because of the method of sample collection. It was believed that there were changes in the chemical composition of the particulate and hence the PAC, during sample collection using a Hi-Vol sampler. Artifacts were being formed by reaction of gaseous pollutants with the particulate collected on the filter. An experiment was established to show that the addition of a denuder bundle to a Hi-Vol sampler could reduce this artifact formation during sampling by removing the reactive gases prior to the surface of the filter. The value of the denuder bundle was evaluated by comparison of the PAC from the denuder Hi-Vol with a standard Hi-Vol. Normal-phase HPLC coupled with mass spectrometry was shown to be a good method to compare the PAC in these samples. Some differences between standard and denuder Hi-Vol samples were observed in laboratory experiments, while the results from field sampling were inconclusive. The use of a parallel column gas chromatography-mass spectrometry (GC-MS) (also called third order chromatography) technique was investigated to determine its viability for the identification of the diverse range of PAC present in environmental samples. The PAC . in the NBS urban dust sample (SRM 1649) was analyzed to evaluate the method. To aid in data processing, a semi-automated peak detection routine has been developed. This routine used programs to aid in the data processing by simplifying peak detection and allow calculation of the retention indices of the components. Using the information supplied by the retention indices and the mass spectra, a data base was developed that was applied to a typical airborne particulate sample. / Thesis / Doctor of Philosophy (PhD)