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This thesis describes the chemistry developed during a study of novel transition metalcatalysed reactions for the synthesis of carboxylic acid derivatives. Chapter 2 describes a novel protocol for the synthesis of primary amides from alcohols in one-pot where a metal complex mediates two fundamentally different catalytic processes. An iridium catalyst has been shown to be effective for the selective rearrangement of aldoximes into primary amides. In addition, an iridium-catalysed oxidation of activated alcohols via hydrogen transfer has been developed using an alkene as formal oxidant. These reactions have been combined in a sequential process affording good yields for a range of benzylic alcohols. An improved system for the rearrangement of aldoximes into amides using a new ruthenium catalyst is described in Chapter 3. Through a systematic program of optimisation excellent selectivity was achieved for a wide range of substrates at markedly reduced catalyst loading. Chapter 4 describes the development of a ruthenium-catalysed elimination reaction for the conversion of oxime ethers into nitriles. The application of this reaction to tandem and sequential reactions has been explored, albeit with limited success. Also, a method for the ruthenium-catalysed oxidation of alcohols using an electron-deficient alkene as hydrogen acceptor is described, and its application to a tandem oxidation process with a nitrogen nucleophile demonstrated. As an extension of the concept presented in Chapter 4, tandem oxidation processes with oxygen nucleophiles are the subject of Chapter 5. This strategy has been used for the oxidation of primary alcohols to their corresponding methyl esters in one-pot, with good yields obtained for a range of substrates. The use of water as a nucleophile in such a process has also been examined.

Organophosphates (OP) interacting with acetylcholinesterase (AChE) carry limited therapeutic benefits and are effective biodegradable insecticides when used judiciously. However, certain volatile OP’s have been used insidiously in terrorism. Current drugs that reactivate AChE and are used to combat the inhibitory effects of OP’s are oximes, but the mechanism by which these oximes act in the gorge of the enzyme is not well-understood. General base catalysis dictates that the oximate anion acts as a nucleophile against the organophosphate esters, which is consistent with in-solution pH dependent oximolysis reactions. I employed pH dependent oxime-induced reactivations of OP-AChE and looked at kinetic isotope effects for reactivation in order to deconstruct the mechanism in which these oximes nucleophilic attack within the enzyme. My studies found that oxime-induced reactivation optimizes at pH ~7.5, contradictory to general base catalysis. Solvent isotope effects exhibited a reduction in reactivation rates, with different magnitudes of depression for different oximes and respective oxime concentrations. Therefore, the existence of a hydrogen bonding network that contributed to the formation of the oximate anion is proposed. In addition, I studied fluoride-induced reactivation of OP-AChE, which is predicted to operate differently than oximes. These findings showed that fluoride-induced reactivation was enhanced by low pH and higher ionic strength environments.

Pyrethroids are the only class of insecticides approved by the World Health Organization (WHO) for use in insecticide treated nets (ITNs), the first line of malaria vector control. Widespread resistance development to pyrethroids undermines current control efforts, and hence an urgent need for alternative chemistries. I report the evaluation of pharmacological differences between insect and vertebrate acetylcholinesterase (AChE) as well as selectivity and toxicity testing of new carbamate insecticides on Anopheles gambiae, the African malaria mosquito. AChE gorge pharmacology data revealed differences between insect and vertebrate AChE that can be exploited in the design of a bivalent insecticide. Toxicokinetic analysis showed that metabolic detoxication and cuticular penetration affect toxicity of carbamates in a manner dependent on the chemical structure. Structure activity relationships of side-chain branched N-methylcarbamates emphasized the importance of structural complementarity of ligands to the AChE catalytic active site and the substrate, acetylcholine. Monovalent pyrazoles and acetophenone oxime carbamates were toxic to both susceptible and carbamate-resistant mosquitoes carrying a G119S mutation within the catalytic site. A bivalent phthalimide-pyrazole carbamate and sulfenylated phenyl N-methyl carbamates were highly toxic when topically applied onto insect but less toxic by treated filter paper assays. In vitro evaluation of a molecular mosquito-selectivity model using AChE peripheral site ligands confirmed that selectivity of PRC 472 was due to presence of I70 in mosquito, which is Y70 in human AChE. The findings presented here are important steps in the on-going search of a mosquito-selective and resistance mitigating carbamate insecticide for control of malaria mosquitoes.

Ni(II) complexes containing amidates and thiolates have been shown to react with O2 via irreversible ligand oxidation. We have constructed a series of Ni(II) complexes based on a tripodal amine bis(oxime) ligand framework. These complexes display oxygen reactivity upon deprotonation of the oximes without requiring irreversible ligand oxidation. This project investigated the reaction involving one of the complexes in the library, [Ni(TRISOXH 3 )(NO 3 )(H 2 O)](NO 3 )· (H 2 O), where TRISOXH 3 = (tris(1-propan-2-onyl oxime)amine). It was discovered that the reaction of this complex with molecular oxygen is contingent upon the presence of a source of hydrogen atoms. This two-hydrogen atom donor acts as a substrate. Several primary alcohols, including the relatively inert methanol, and amines were catalytically oxidized by this reaction. Spectroscopic analysis using a variety of techniques has demonstrated that reversible oxidation occurs on the oximate nitrogen to form an iminoxyl radical. Many of the other complexes in the series were also investigated to examine their electronic structure, their electrochemical properties, and their ability to oxidize methanol.

The purpose of this research was to develop a single sludge multi-environment anoxic/aerobic biological treatment scheme that could achieve oxime degradation and nitrification in the same treatment process. Aerobic and anoxic batch experiments were initially performed to determine degrees of nitrification inhibition caused by three oximes, acetaldehyde oxime (AAO), aldicarb oxime (ADO), and methyl ethyl ketoxime (MEKO), and to investigate the fate of these oximes under anoxic, denitrifying conditions. Results from aerobic batch studies showed that MEKO was the only oxime which caused significant nitrification inhibition at concentrations expected in the industrial client's waste streams. Nitrification rates were reduced by 31% at MEKO concentrations as low as 2 mg/L and were almost completely inhibited above 9 mg/L. Results from anoxic batch studies demonstrated that MEKO was biologically degraded under nitrate limiting conditions, although the microorganism( s) responsible were not explicitly identified. Similar degradation trends were seen for AAO, but at significantly lower rates. ADO, however, appeared to be stable under all anoxic conditions examined. Results from batch studies were utilized to determine operational conditions for a single sludge multi-environment anoxic/anaerobic/aerobic sequencing batch reactor supplied with a synthetic organic wastewater containing up to 40 mgIL MEKO and 56 mgIL AAO. The system was able to achieve complete oxime degradation and nitrification when operated on a one day cycle with a twelve hour anoxic/anaerobic reaction phase and a nitrate:carbon ratio below 0.15 mg N0₃-N/mg TOC.