Investigation of the structure of selected purine derivatives in solution using NMR spectroscopy and theoretical calculations

Katarzyna Dybiec

Abstract

Within the frame of this dissertation a study of the structure of a series of purine derivatives in solutions has been conducted, using the results of quantum-mechanical calculations for quantitative interpretation of measured values of NMR parameters. In the first part of this work the literature on the chemical and physical properties of purines are reviewed, and the achievements in the research into tautomerism of purines in solutions were presented. In one of the chapters the use of NMR spectroscopy to study the structure of purines is also described. In the second part of this dissertation the test results and the description of the applied methodology are given. The work presents a method allowing the interpretation of experimental data with the use of theoretical calculations. The aim of this research was to obtain information about conformational, tautomeric and acid-base equilibriums. The results of a comparative analysis of the experimental and calculational data confirm that the use of the PCM solvation model greatly affects the agreement between theory and experiment. In addition, I have discovered that even better compliance is obtained when theoretical calculations treat the phenomenon of hydration more accurately, i.e. using the discrete hydration model in addition to PCM. Moreover, it has been confirmed that it is desirable to use large basis sets [e.g. 6- 311++G(2d,p)] at both stages of calculations, i.e. during the molecular geometry optimization and the calculation of magnetic shielding. For all test compounds 13C NMR spectra were recorded. For certain forms of oxopurines 13C NMR spectra have been obtained together with the appropriate acidity constants by the analysis of pH dependence of 13C NMR spectra recorded for aqueous solutions in the appropriate pH range. It has been found that the method based on the δ(pH, pK) fully reproduces the actual chemical shifts for neutral molecules and monoanions. Such a method is useful when the spectrum can not be registered for the species of interest in a straightforward manner. The analysis of the spectroscopic data for adenine and its methyl derivatives, based on the results of the GIAO-DFT calculations, confirmed earlier reports on the quantitative ratio of N7H and N9H adenine tautomers in DMSO solution. Previous inconsistencies in the interpretation of the spectra of adenine in DMSO were probably caused by tautomeric transformations, which at room temperature run at rates lesser than expected. The reference data for 2-oxoadenine (isoguanine) and 8-oxoadenine, which may be useful in medical diagnostics, have been gathered. The performed analysis of the experimental and calculational data for these compounds have shown that in acidified DMSO solutions isoguanine exists as monocation <137> and/or dication <1379>, while 8-oksoadenine in the neutral DMSO solution as the tautomeric form <79>. The quantum – mechanical calculations performed for N6 -formyl-9-methyladenine and the tautomer N9H of N6 -formyladenine (FA) have shown that trans-amide conformers are more energetically stable than cis conformers. Similar calculations indicate that in the case of FA the cis conformer of N7H tautomer (C3 structure), stabilized by the intramolecular hydrogen bond N7-H...O=C, represents the structure of the lowest energy. However, the analysis of the experimental data shows that the trans-type structures T2 and T1 of FA are prevailing in DMSO solution. In the case of oxopurines in aqueous solutions the populations of the most abundant tautomers for most forms of the investigated compounds have been estimated, using the elaborated NMR/DFT method. In neutral and alkaline aqueous solutions, where the oxopurines occur as neutral molecules, anions or dianions, only the oxo forms of the investigated compounds are observed. In all cases the tautomers N7H or N9H are characterized by the lowest energy values. As it concerns the tautomerism of the pyrimidine ring, the oxo-N1H forms of monoanions and neutral molecules are preferred. Analysis of the spectroscopic data and the results of the calculations has allowed the hypothesis that in strongly alkaline aqueous solutions the oxopurine monoanions can undergo another reversible reaction, besides deprotonation. It seems possible that the OH- anions can join monoanions and form non-standard dianions. In the case of xanthine the population of the unconventional dianion, C8OH-N1H-N7H, has proved to be significant (around 18%) and has had a clearly positive impact on the general fit between experimental and theoretical data.
Diploma typeDoctor of Philosophy
Author Katarzyna Dybiec (FC)
Katarzyna Dybiec,,
- Faculty of Chemistry
Title in EnglishInvestigation of the structure of selected purine derivatives in solution using NMR spectroscopy and theoretical calculations
Languagepl polski
Certifying UnitFaculty of Chemistry (FC)
Disciplinechemistry / (chemical sciences domain) / (physical sciences)
Defense Date05-02-2010
End date23-02-2010
Supervisor Adam Gryff-Keller (FC / DOC)
Adam Gryff-Keller,,
- Department Of Organic Chemistry

Internal reviewers Przemysław Szczeciński (FC / DOC)
Przemysław Szczeciński,,
- Department Of Organic Chemistry
External reviewers Krystyna Kamieńska-Trela
Krystyna Kamieńska-Trela,,
-
Pages173
Keywords in Englishxxx
Abstract in EnglishWithin the frame of this dissertation a study of the structure of a series of purine derivatives in solutions has been conducted, using the results of quantum-mechanical calculations for quantitative interpretation of measured values of NMR parameters. In the first part of this work the literature on the chemical and physical properties of purines are reviewed, and the achievements in the research into tautomerism of purines in solutions were presented. In one of the chapters the use of NMR spectroscopy to study the structure of purines is also described. In the second part of this dissertation the test results and the description of the applied methodology are given. The work presents a method allowing the interpretation of experimental data with the use of theoretical calculations. The aim of this research was to obtain information about conformational, tautomeric and acid-base equilibriums. The results of a comparative analysis of the experimental and calculational data confirm that the use of the PCM solvation model greatly affects the agreement between theory and experiment. In addition, I have discovered that even better compliance is obtained when theoretical calculations treat the phenomenon of hydration more accurately, i.e. using the discrete hydration model in addition to PCM. Moreover, it has been confirmed that it is desirable to use large basis sets [e.g. 6- 311++G(2d,p)] at both stages of calculations, i.e. during the molecular geometry optimization and the calculation of magnetic shielding. For all test compounds 13C NMR spectra were recorded. For certain forms of oxopurines 13C NMR spectra have been obtained together with the appropriate acidity constants by the analysis of pH dependence of 13C NMR spectra recorded for aqueous solutions in the appropriate pH range. It has been found that the method based on the δ(pH, pK) fully reproduces the actual chemical shifts for neutral molecules and monoanions. Such a method is useful when the spectrum can not be registered for the species of interest in a straightforward manner. The analysis of the spectroscopic data for adenine and its methyl derivatives, based on the results of the GIAO-DFT calculations, confirmed earlier reports on the quantitative ratio of N7H and N9H adenine tautomers in DMSO solution. Previous inconsistencies in the interpretation of the spectra of adenine in DMSO were probably caused by tautomeric transformations, which at room temperature run at rates lesser than expected. The reference data for 2-oxoadenine (isoguanine) and 8-oxoadenine, which may be useful in medical diagnostics, have been gathered. The performed analysis of the experimental and calculational data for these compounds have shown that in acidified DMSO solutions isoguanine exists as monocation <137> and/or dication <1379>, while 8-oksoadenine in the neutral DMSO solution as the tautomeric form <79>. The quantum – mechanical calculations performed for N6 -formyl-9-methyladenine and the tautomer N9H of N6 -formyladenine (FA) have shown that trans-amide conformers are more energetically stable than cis conformers. Similar calculations indicate that in the case of FA the cis conformer of N7H tautomer (C3 structure), stabilized by the intramolecular hydrogen bond N7-H...O=C, represents the structure of the lowest energy. However, the analysis of the experimental data shows that the trans-type structures T2 and T1 of FA are prevailing in DMSO solution. In the case of oxopurines in aqueous solutions the populations of the most abundant tautomers for most forms of the investigated compounds have been estimated, using the elaborated NMR/DFT method. In neutral and alkaline aqueous solutions, where the oxopurines occur as neutral molecules, anions or dianions, only the oxo forms of the investigated compounds are observed. In all cases the tautomers N7H or N9H are characterized by the lowest energy values. As it concerns the tautomerism of the pyrimidine ring, the oxo-N1H forms of monoanions and neutral molecules are preferred. Analysis of the spectroscopic data and the results of the calculations has allowed the hypothesis that in strongly alkaline aqueous solutions the oxopurine monoanions can undergo another reversible reaction, besides deprotonation. It seems possible that the OH- anions can join monoanions and form non-standard dianions. In the case of xanthine the population of the unconventional dianion, C8OH-N1H-N7H, has proved to be significant (around 18%) and has had a clearly positive impact on the general fit between experimental and theoretical data.
Thesis file
Dybiec.pdf 3.79 MB

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