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Alkylation of adenine : a synthetic and computational study of the reaction mechanism
Dissertation (MSc (Chemistry))--University of Pretoria, 2015.
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| Format: | Thesis |
| Language: | English |
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University of Pretoria
2018
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| _version_ | 1867613726749753344 |
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| access_status_str | Open Access |
| author2 | Pilcher, Lynne A. |
| author_browse | Pilcher, Lynne A. |
| author_facet | Pilcher, Lynne A. |
| collection | Thesis |
| dc_rights_str_mv | © 2017 University of Pretoria. All rights reserved. The copyright in this work vests in the University of Pretoria. No part of this work may be reproduced or transmitted in any form or by any means, without the prior written permission of the University of Pretoria. |
| description | Dissertation (MSc (Chemistry))--University of Pretoria, 2015. |
| format | Thesis |
| id | oai:repository.up.ac.za:2263/64255 |
| institution | University of Pretoria (South Africa) |
| language | English |
| last_indexed | 2026-06-10T12:40:44.121Z |
| license_str | Other — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from UPSpace — University of Pretoria Institutional Repository |
| publishDate | 2018 |
| publishDateRange | 2018 |
| publishDateSort | 2018 |
| publisher | University of Pretoria |
| publisherStr | University of Pretoria |
| record_format | dspace |
| source_str | UPSpace — University of Pretoria Institutional Repository |
| spelling | oai:repository.up.ac.za:2263/64255 Alkylation of adenine : a synthetic and computational study of the reaction mechanism Pilcher, Lynne A. babibique@hotmail.com Cukrowski, Ignacy Buyens, Dominique Marie-Jeanne Solange SNZ mechanism N-benzyladenine IQA fragment analysis Purine deuteration UCTD Dissertation (MSc (Chemistry))--University of Pretoria, 2015. This dissertation describes the benzylation of adenine under basic conditions, the unequivocal determination of the identity of the products of this reaction, an exploration of the effect of solvent on the reaction, a thorough computational study of the reaction mechanism and an investigation into the hydrogen-deuterium exchange reaction of the N-benzyladenine products and related compounds. The preferential sites of alkylation of adenine under basic conditions in DMSO were proven to be the N9 and N3 positions. X-ray crystal structures were obtained for both compounds. Formation of the N9-benzyladenine product is the most favoured in polar aprotic solvents, such as DMSO, and as the proportion of polar protic solvents, such as water, increases, so does the formation of the N3-benzyladenine product. Characteristic 1H NMR chemical shifts of the purine ring protons and HMBC 1H-13C correlation NMR spectroscopy were useful tools to assign the 1H and 13C NMR spectra chemical shifts and confirm that the solution structures were the same as the isolated crystals. Simulating the SN2 mechanism for the N1-, N3-, N7- and N9-pathways computationally, employing DMSO as the simulated solvent, resulted in ambiguous results when considering the electronic energies of initial, TS and final products alone. However, a novel approach was developed (employing IQA-defined energy terms) to study fragment interactions along the reaction paths. It provided a full explanation of the reaction mechanism and yielded results which supported the N3/N9 positions of alkylation over the N1/N7 sites. The preference for the sites of alkylation occurs after the transition state, in which the N1/N7 reaction paths fail to proceed favourably to the end product, N1- and N7-benzyladenine, respectively. The N9-pathway dominates the N3-pathway at the product formation step, which corresponds to the N9- benzyladenine being the major product, as shown in Figure 1, and the N3-benzyladenine being the minor product from the benzylation of adenine. The faster rate of deuteration at the C8 position of N9-benzyladenine as compared to the deuteration rates at the C2 and the C8 of N3-benzyladenine, have shown support for a sp3 mediated mechanism and a carbene mediated mechanism of deuteration based on the “push” and “pull” mechanisms proposed for the C8 proton transfer of ATP in kinase enzymes. The deuteration of the C8 proton of 2,6-dichloropurine derivatives supports the existence of the carbene mediated mechanism since these compounds lack the amine moiety necessary for the sp3 mediated mechanism. These results demonstrate how experimentation and computation have led to greater insights into the reactivity of adenine and its derivatives. This strategy provides a useful platform for future research into adenine reaction mechanisms and the role adenine plays in kinase catalysis. National Research Foundation (NRF) Chemistry MSc (Chemistry) Unrestricted 2018-03-14T12:54:16Z 2018-03-14T12:54:16Z 2015 2015 Dissertation Buyens, D 2015, Alkylation of adenine : a synthetic and computational study of the reaction mechanism, MSc Dissertation, University of Pretoria, Pretoria, viewed yymmdd <http://hdl.handle.net/2263/64255> S2015 http://hdl.handle.net/2263/64255 en © 2017 University of Pretoria. All rights reserved. The copyright in this work vests in the University of Pretoria. No part of this work may be reproduced or transmitted in any form or by any means, without the prior written permission of the University of Pretoria. application/pdf University of Pretoria |
| spellingShingle | SNZ mechanism N-benzyladenine IQA fragment analysis Purine deuteration UCTD Alkylation of adenine : a synthetic and computational study of the reaction mechanism |
| title | Alkylation of adenine : a synthetic and computational study of the reaction mechanism |
| title_full | Alkylation of adenine : a synthetic and computational study of the reaction mechanism |
| title_fullStr | Alkylation of adenine : a synthetic and computational study of the reaction mechanism |
| title_full_unstemmed | Alkylation of adenine : a synthetic and computational study of the reaction mechanism |
| title_short | Alkylation of adenine : a synthetic and computational study of the reaction mechanism |
| title_sort | alkylation of adenine a synthetic and computational study of the reaction mechanism |
| topic | SNZ mechanism N-benzyladenine IQA fragment analysis Purine deuteration UCTD |
| url | http://hdl.handle.net/2263/64255 |