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The study herein described involved the detection of pyridine N-oxide reductase activity in cell-free extracts of E. coli 9723, the determination of co-factors necessary for the enzymatic process, a study of the optimum conditions for enzyme catalysis, and a general characterization of the enzyme.

This dissertation looked at the crystal structure analysis of 2-hydroxymethylpyridine-N-oxide sine this compound could provide data on both substituent effects and hydrogen bonding.

In this paper, some of the work by Talbott has been repeated and other reactions of 4-picoline and pyridine N-oxides with aromatic halogen compounds have been investigated.

This thesis describes the development of new synthetic methodologies for preparation of bioactive interesting compounds, e.g. substituted pyridines, piperidines or piparazines. Thesecompounds are synthesized from commercially available, cheap and easily prepared reagents, videlicet the reaction between Grignard reagents and heterocyclic N-oxides.  The first part of this thesis deals with an improvement for synthesis of dienal-oximes and substituted pyridines. This was accomplished by a rapid addition of Grignard reagents to pyridine N-oxides at rt. yielding a diverse set of substituted dienal-oximes. During these studies, it was observed that the obtained dienal-oxmies are prone to ring-close upon heating. By taking advantage of this, a practical synthesis of substituted pyridines was developed. In the second part, an ortho-metalation of pyridine N-oxides using Grignard reagents is discussed. The method can be used for incorporation of a range of different electrophiles, including aldehydes, ketones and halogens. Furthermore, the importance for incorporation of halogens are exemplified through a Suzuki–Miyaura coupling reaction of 2-iodo pyridine N-oxides and different boronic acids. Later it was discovered that if the reaction temperature is kept below -20 °C, the undesired ringopening can be avoided. Thus, the synthesis of 2,3-dihydropyridine N-oxide, by reacting Grignard reagents with pyridine N-oxides at -40 °C followed by sequential addition of aldehyde or ketone, was accomplished. The reaction provides complete regio- and stereoselectivity yielding trans-2,3-dihydropyridine N-oxides in good yields. These intermediate products could then be used for synthesis of either substituted piperidines, by reduction, or reacted in a Diels–Alder cycloaddtion to give the aza-bicyclo compound. In the last part of this thesis, the discovered reactivity for pyridine N-oxides, is applied on pyrazine N-oxides in effort to synthesize substituted piperazines. These substances are obtained by the reaction of Grignard reagents and pyrazine N-oxides at -78 °C followed by reduction and protection, using a one-pot procedure. The product, a protected piperazine, that easily can be orthogonally deprotected, allowing synthetic modifications at either nitrogens in a fast and step efficient manner. Finally, an enantioselective procedure using a combination of PhMgCl and (-)-sparteine is discussed, giving opportunity for a stereoselective synthesis of substituted piperazines.

The β-acyloxyalkyl radical rearrangement has been known since 1967 but its mechanism is still not fully understood, despite considerable investigation. Since the migration of a β-trifluoroacetoxy group generally proceeds more rapidly and with more varied regiochemistry than its less electronegative counterparts, this reaction was studied in the hope of understanding more about the subtleties of the mechanism of the β- acyloxyalkyl radical rearrangement. The mechanism of the catalysed rearrangement of Nalkoxy- 2(1H)-pyridinethiones was also explored because preliminary studies indicated that the transition state (TS) for this process was isoelectronic with TSs postulated for the β-acyloxyalkyl radical and other novel rearrangements. ¶ A kinetic study of the rearrangement of the 2-methyl-2-trifluoroacetoxy-1-heptyl radical in solvents of different polarity was undertaken using a radical clock method. Arrhenius equations for the rearrangement in each solvent were: hexane, log10[kr (s-1)] = 11.8±0.3 – (48.9±0.7)/ θ; benzene, log10[kr (s-1)] = 12.0±0.2 – (43.7±0.8)/ θ; and propionitrile, log10[kr (s-1)] = 11.9±0.2 – (42.0±0.3)/ θ. Rate constants at 75˚C were: hexane, kr = 2.9 × 104; benzene, kr = 2.8 × 105; and propionitrile, kr = 4.0 × 105 s-1. The equilibrium constant for the reversible rearrangement at 80°C in benzene was 15.1 <K < 52.9. ¶ A regiochemical study with oxygen-labelled radicals revealed that trifluoroacetoxy group migration occurs with 66-83% label transposition (3,2 shift). The proportion of 3,2 shift is decreased by polar solvent, high temperature and low concentration of the reducing agent. Results of labelling experiments were consistent with cooperative 1,2 and 3,2 shifts, the former having Ea 9.5 kJmol-1 higher than the latter in benzene solution. ¶ An esr study of nine β-oxygenated radicals revealed that the temperaturedependent equilibrium conformation is controlled by a balance between steric and stereoelectronic effects. The influence of the latter is increased by electron-attracting β- substituents. Barriers to C α–C β rotation in β-oxyethyl radicals are approximately the same as for the propyl radical. Consequently, there is no significant through-space interaction between the β-substituent and the unpaired electron. ¶ Experimental results were consistent with a mechanism involving a combination of polarized 1,2 and 3,2 concerted shifts. The results may also be rationalised by the intermediacy of a contact ion pair, as well as combinations of the three options. ¶ The rearrangement of N-alkoxy-2(1H)-pyridinethiones is catalysed by oxidants, Lewis acids and protic acids. Pseudo first order kinetics are observed and there are moderate solvent effects. The migration of a 1,1-dideuteroallyl group occurs almost exclusively in a 1,4 sense. Migration of an enantiomerically enriched 1-phenylethyl group proceeds with predominant retention of configuration in chloroform, but with virtual racemisation in acetonitrile. Migrating groups do not become diffusively free during the rearrangement. Substituents which stablise positive charge at C1 migrate more rapidly. The bulk of evidence indicates that a catalyst activates the pyridinethione for rearrangement by promoting aromatisation. Mass-spectrometric analysis of an isolated intermediate and kinetic results are consistent with an intermolecular mechanism.