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Biocatalytic methods of synthesis are becoming increasingly important in industry. Using enzymes as catalysts allows highly selective reactions to be performed under milder physical conditions and in a more environmentally benign fashion than most corresponding chemical catalysts. Enzymes have in general evolved to perform one type of reaction on a limited set of molecules, and hence there is often a need to alter the specificity of an enzyme to suit a desired process. Understanding the details of enzymatic catalysis at a quantum mechanical level enables the intelligent redesign of these macromolecules. For this purpose, density functional theory (DFT) has been shown to epitomise a suitable balance of accuracy and computational cost. Thus, this thesis describes the quantum chemical rationalisation of the reaction mechanism and sources of selectivity of the bacterial alcohol dehydrogenase TbSADH – an enzyme highly suited to modification for industrial processes. ADHs catalyse reversibly the interconversion of alcohols and ketones or aldehydes. Herein, the general ADH reaction mechanism was shown to be viable for this enzyme. In addition, the experimental enantiopreference of the enzyme was reproduced, and thus the reversal of selectivity seen with the slight increase in substrate size was captured. The main determinant of selectivity was found to be a fine balance of repulsive steric interactions and attractive dispersion effects between the substrate and the hydrophobic binding pockets. The ability of the modelling methodology to capture effects such as these represents further evidence of its usefulness as a complement to experimental work in designing the biocatalysts of the future. The development of protocols to allow quantum mechanical investigation of the production of large and industrially interesting axially chiral alcohols is also presented. The work described has showed that quantum chemical models of many hundreds of atoms are now within our grasp, and although they were unable to correctly describe the selectivity for the large 4-(bromomethylene)cyclohexan-1-one in TbSADH, the protocols devised can be very useful for future investigations of enzymatic catalysis.

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L-type voltage gated calcium channels are membrane bound ion channels that regulate the intracellular concentration of calcium ions as a response to changes in the membrane potential. They exist in four isoforms and recent studies have brought extra attention to the Cav1.2 isoform as it has been shown to be critical for the maturation of oligodendrocyte progenitor cells in the brain. These cells are involved in neural myelination and if they do not mature properly, it can lead to abnormal neural myelination. This is a condition that is strongly correlated with neurodegenerative diseases such as Multiple Sclerosis and has been associated with psychiatric diseases such as schizophrenia. The number of tools for studying these proteins are few, and therefore this thesis aimed to expand the toolbox by developing an analogue (FluoBar2) to an existing probe (FluoBar1). The analogous probe could resolve some of the issues currently associated with labeling using FluoBar1 as well as open up the possibility of conducting pulse-chase experiments when used with FluoBar1. The short absorption and emission wavelengths of FluoBar1 causes large amounts of autofluorescence in cellular imaging, making the images hard to interpret. In FluoBar2, the Pacific Blue fluorophore used in FluoBar1 is exchanged for 5-carboxyfluorescein, causing the absorption and emission to be redshifted which theoretically should decrease the cellular autofluoresence. The project begun with the synthesis of FluoBar1 which was isolated in a 0.19% overall yield. During this, the synthetic route towards the linker used in FluoBar1 and FluoBar2 was developed as well, increasing the yield with respect to the most expensive reagent from 41.5% to 61%. An attempt at synthesizing FluoBar2 was made and its presence was supported by 1H NMR as well as UPLC-MS, but it was not fully isolated and characterized.

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<p>Solvolysis reactions of a range of tertiary substrates in largely aqueous solvents were studied in such respects as β-deuterium kinetic isotope effects, linear free energy relationships and stereochemistry.</p><p>Solvolysis of the fluorene derivatives 9-methyl–9-(2´-X-2´-propyl)fluorene (<b>1-X,</b> X = Cl, Br, OOCCF₃) involves a very short-lived carbocation intermediate. The fraction of alkene is increased by addition of general bases, which can be expressed by a Brφnsted parameter β = 0.07. The kinetic deuterium isotope effects vary with solvent composition in a way which is not consistent with a common carbocation intermediate which has time to choose between dehydronation and addition of a solvent water molecule. </p><p>In the absence of bases, the reaction of 4-chloro-4-(4´-nitrophenyl)pentan-2-one (<b>2-Cl</b>) proceeds through a short-lived carbocation intermediate yielding 4-(4´-nitrophenyl)-2-oxopent-4-ene (<b>2-</b><b>t</b>-ne)as the main elimination product. Addition of acetate ion and other weak bases results in the base-promoted E2 (or E1cb) reaction to give (<i>E</i>)-4-(4´-nitrophenyl)-2-oxopent-3-ene (<b>2-</b><b>E</b>-ne) and (<i>Z</i>)-4-(4´-nitrophenyl)-2-oxopent-3-ene(<b>2-</b><b>Z</b>-ne). There is no evidence for a water-promoted E2 (or E1cb) reaction.</p><p>The stereochemistry studies of elimination from (<i>R,S</i> and <i>S,R</i>)-[1-(3´-fluoro)phenyl-2-methyl]cyclopentyl-<i>p-</i>nitrobenzoate (<b>3-PNB</b>) and its (<i>R</i>,<i>R</i> and <i>S,S</i>)isomer <b>3´-PNB</b> and (<i>R,S</i> and <i>S,R</i>)-[1´-(3´´-fluoro)phenyl-2´-methylcyclopentyl]-2,2,2-trifluoroacetate(<b>3-OOCCF</b><b>3</b>) exclude the concerted pericyclic elimination mechanism for formation of the alkene 1-(3´-fluoro)phenyl-2-methylcyclopentene(<b>3-</b><b>m</b>-ne). The effects of added thiocyanate ion and halide ions on the solvolysis reaction are discussed.</p><p>Mass spectrometry analysis showed complete incorporation of the labeled oxygen from solvent water into the product 2-hydroxy-2-phenyl-3-butene (<b>4-OH</b>), confirming that it is the tertiary carbon-oxygen bond that is broken in the acid-catalyzed solvolysis of 2-methoxy-2-phenyl-3-butene (<b>4-OMe</b>). The mechanism for the dominant formation of the less stable <b>4-OH</b> is discussed.</p>

<p>The Ru(arene)[(1<i>S</i>, 3<i>R</i>, 4<i>R</i>)-3-(Hydroxymethyl)-2-azabicyclo[2.2.1]heptane catalyst was optimized as ligand in the asymmetric transfer hydrogenation of ketones and resulted in increased activity and enantioselectivity of the catalyst. Dioxolane substitution at the rear end of the amino alcohol ligand and introduction of a (<i>R</i>)-methyl substituent yielded a catalyst that reduced acetophenone in 96% enantiomeric excess in 90 minutes with a substrate to catalyst molar ratio of 5000. A diversity of substituted aromatic ketones was reduced with excellent rate and enantioselectivity. Based on experimental and computational results, a study of the origin of the enantioselectivity was conducted. A combination of electrostatic, steric, dispersion forces and solvation effects was suggested to be the cause of the stereo discrimination. A set of amino sulfides built upon the 2-azabicyclo and the cyclohexane structures were prepared and tested as ligands in the enantioselective transfer hydrogenation of acetophenone with [IrCl(COD)]₂ as metal precursor. With this type of catalysts, the reaction rates were good but the enantioselectivity unsatisfactory with 70% as the highest obtained enantiomeric excess. The first enantioselective reduction of aromatic 2<i>H</i>-azirines was accomplished by using the asymmetric transfer hydrogenation protocol. Aromatic azirines were reduced to yield chiral aziridines with up to 72% enantiomeric excess and good yields. The enantioselectivity and reactivity of the reaction were strongly influenced by substituents on the aromatic and aliphatic moiety of the substrate.</p>