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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
Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Bioorganic Chemistry.
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis concerns the study of reaction mechanisms by means of kinetic isotope effects (KIEs). Studies of the nucleophilic bimolecular substitution (SN2) 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 SN2 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 SN2 reactions between cyanide ions and para-substituted benzyl chlorides were found to have reactant-like transition states, of which the Cα-Cl bond was most influenced by the para-substitution. Theoretical calculations indicated that the chlorine KIEs could be used as probes of the substituent effect on the Cα-Cl bond if bond fission was not too advanced in the transition state. Furthermore, the nucleophile carbon 11C/14C KIEs were determined for the reactions between cyanide ions and various ethyl substrates in dimethyl sulphoxide.

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.

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.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2006. , p. 93
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 265
Keywords [en]
Organic chemistry, nucleophilic bimolecular substitution/SN2, kinetic isotope effects, precision conductometry, monoamine oxidase B/MAO B, reaction mechanism, carbon 11C/14C kinetic isotope effect, ion pairing/triple-ion formation, para-substituted benzyl chlorides, tetrabytylammonium cyanide
Keywords [sv]
Organisk kemi
Identifiers
URN: urn:nbn:se:uu:diva-7441ISBN: 978-91-554-6776-8 (print)OAI: oai:DiVA.org:uu-7441DiVA, id: diva2:169546
Public defence
2007-01-27, B22, BMC, Husargatan 3, Uppsala, 09:15
Opponent
Supervisors
Available from: 2007-01-05 Created: 2007-01-05Bibliographically approved
List of papers
1. The Effect of Solvent on the Structure of the Transition State for the SN2 Reaction between Cyanide Ion and Ethyl Chloride in DMSO and THF Probed with Six Different Kinetic Isotope Effects
Open this publication in new window or tab >>The Effect of Solvent on the Structure of the Transition State for the SN2 Reaction between Cyanide Ion and Ethyl Chloride in DMSO and THF Probed with Six Different Kinetic Isotope Effects
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2006 In: Journal of Organic Chemistry, ISSN 0022-3263, Vol. 71, no 13, p. 4742-4747Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-95360 (URN)
Available from: 2007-01-05 Created: 2007-01-05Bibliographically approved
2. A New Insight into Using Chlorine Leaving Group and Nucleophile Carbon Kinetic Isotope Effects To Determine Substituent Effects on the Structure of SN2 Transition States
Open this publication in new window or tab >>A New Insight into Using Chlorine Leaving Group and Nucleophile Carbon Kinetic Isotope Effects To Determine Substituent Effects on the Structure of SN2 Transition States
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2007 (English)In: Journal of Physical Chemistry A, ISSN 1089-5639, E-ISSN 1520-5215, Vol. 111, no 33, p. 8110-8120Article in journal (Refereed) Published
Abstract [en]

Chlorine leaving group k(35)/k(37), nucleophile carbon k(11)/k(14), and secondary alpha-deuterium [(k(H)/k(D))(alpha)] kinetic isotope effects (KIEs) have been measured for the S(N)2 reactions between para-substituted benzyl chlorides and tetrabutylammonium cyanide in tetrahydrofuran at 20 degrees C to determine whether these isotope effects can be used to determine the substituent effect on the structure of the transition state. The secondary alpha-deuterium KIEs indicate that the transition states for these reactions are unsymmetric. The theoretical calculations at the B3LYP/aug-cc-pVDZ level of theory support this conclusion; i.e., they suggest that the transition states for these reactions are unsymmetric with a long NC-C-alpha and reasonably short C-alpha-Cl bonds. The chlorine isotope effects suggest that these KIEs can be used to determine the substituent effects on transition state structure with the KIE decreasing when a more electron-withdrawing para-substituent is present. This conclusion is supported by theoretical calculations. The nucleophile carbon k(11)/k(14) KIEs for these reactions, however, do not change significantly with substituent and, therefore, do not appear to be useful for determining how the NC-C-alpha transition-state bond changes with substituent. The theoretical calculations indicate that the NC-C-alpha bond also shortens as a more electron-withdrawing substituent is placed on the benzene ring of the substrate but that the changes in the NC-C-alpha transition-state bond with substituent are very small and may not be measurable. The results also show that using leaving group and nucleophile carbon KIEs to determine the substituent effect on transition-state structure is more complicated than previously thought. The implication of using both chlorine leaving group and nucleophile carbon KIEs to determine the substituent effect on transition-state structure is discussed.

National Category
Chemical Sciences
Identifiers
urn:nbn:se:uu:diva-95361 (URN)10.1021/jp0729765 (DOI)000248758800010 ()
Available from: 2007-01-05 Created: 2007-01-05 Last updated: 2017-12-14Bibliographically approved
3. The Nucleophile Carbon 11C/14C Kinetic Isotope Effect for the Reactions between Cyanide Ions and Ethyl Substrates in DMSO
Open this publication in new window or tab >>The Nucleophile Carbon 11C/14C Kinetic Isotope Effect for the Reactions between Cyanide Ions and Ethyl Substrates in DMSO
Manuscript (Other academic)
Identifiers
urn:nbn:se:uu:diva-95362 (URN)
Available from: 2007-01-05 Created: 2007-01-05 Last updated: 2010-01-13Bibliographically approved
4. Solvent Effects on Ion Pairing of Tetrabutylammonium Cyanide. A Conductometric Study
Open this publication in new window or tab >>Solvent Effects on Ion Pairing of Tetrabutylammonium Cyanide. A Conductometric Study
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Article in journal (Refereed) Submitted
Identifiers
urn:nbn:se:uu:diva-95363 (URN)
Available from: 2007-01-05 Created: 2007-01-05Bibliographically approved
5. Nitrogen Kinetic Isotope Effects as Probes of the Mechanism of Monoamine Oxidase B
Open this publication in new window or tab >>Nitrogen Kinetic Isotope Effects as Probes of the Mechanism of Monoamine Oxidase B
Manuscript (Other academic)
Identifiers
urn:nbn:se:uu:diva-95364 (URN)
Available from: 2007-01-05 Created: 2007-01-05 Last updated: 2010-01-13Bibliographically approved

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