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Isotopes as Mechanism Spies : Nucleophilic Bimolecular Substitution and Monoamine Oxidase B Catalysed Amine Oxidation Probed with Heavy Atom Kinetic Isotope Effects

<p>This thesis concerns the study of reaction mechanisms by means of kinetic isotope effects (KIEs). Studies of the nucleophilic bimolecular substitution (S<sub>N</sub>2) reaction had the dual purpose of improving our fundamental understanding of molecular reactivity and assessing the ability of kinetic isotope effects to serve as mechanistic tools. The transition state of the S<sub>N</sub>2 reaction between a cyanide ion and ethyl chloride in tetrahydrofuran was found to be reactant like and only slightly tighter than has been found previously for the same reaction in dimethyl sulphoxide. One conclusion was that the transition-state structure in this reaction was predicted fairly well by the theoretical calculations, even without solvent modelling. The S<sub>N</sub>2 reactions between cyanide ions and <i>para</i>-substituted benzyl chlorides were found to have reactant-like transition states, of which the C<sub>α</sub>-Cl bond was most influenced by the <i>para</i>-substitution. Theoretical calculations indicated that the chlorine KIEs could be used as probes of the substituent effect on the C<sub>α</sub>-Cl bond if bond fission was not too advanced in the transition state. Furthermore, the nucleophile carbon <sup>11</sup>C/<sup>14</sup>C KIEs were determined for the reactions between cyanide ions and various ethyl substrates in dimethyl sulphoxide.</p><p>Precision conductometry was employed to estimate the aggregation status of tetrabutylammonium cyanide in tetrahydrofuran and in dimethyl sulphoxide, which is of interest as tetrabutylammonium cyanide is frequently used as the nucleophilic reagent in mechanistic investigations and synthetic reactions. The tendency for ion-pair formation was found to be very slight, significant, and very strong in dimethyl sulphoxide, water, and tetrahydrofuran, respectively. </p><p>The nitrogen kinetic isotope effect on monoamine oxidase B catalysed deamination of benzylamine was determined in an attempt to obtain conclusive evidence regarding the mechanism of the oxidation. Monoamine oxidase is an important drug target in connection with the treatment of, for example, depression and Parkinson’s disease, and knowledge on how the enzyme effects catalysis would facilitate the design of highly selective and efficient inhibitors.</p>

Identiferoai:union.ndltd.org:UPSALLA/oai:DiVA.org:uu-7441
Date January 2006
CreatorsMacMillar, Susanna
PublisherUppsala University, Department of Bioorganic Chemistry, Uppsala : Acta Universitatis Upsaliensis
Source SetsDiVA Archive at Upsalla University
LanguageEnglish
Detected LanguageEnglish
TypeDoctoral thesis, comprehensive summary, text
RelationDigital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, 1651-6214 ; 265

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