Synthesis and Characterization of Metal Sonji Thesis-2015

Synthesis and characterization of metal complexes of some purine and

pyrimidine derivatives

by

Ghassan Mohamad Sonji

Thesis

Submitted in Partial Fulfillment of the Requirements for the Degree of

PhD in Chemistry

Department of Chemistry

Faculty of Science

2015



by

Ghassan Mohamad Sonji

Thesis

Submitted in Partial Fulfillment of the Requirements for the Degree of

PhD in Chemistry

Department of Chemistry

Faculty of Science

Supervised by

Prof. Shawky A. El-Shazly Professor of Physical Chemistry

Faculty of Science Beirut Arab University

Prof. Kamal H. Bouhadir Associate Professor of Organic Chemistry

Faculty of Arts and Sciences American University of Beirut

Prof. Hassan H. Hammud Professor of Inorganic & Analytical Chemistry

Faculty of Science King Faisal University

2015

iv

Abstract



Coordination compounds play critical roles in biology, biochemistry and medicine,

controlling the structure and function of many enzymes and their metabolism. They play

similarly vital roles in many industrial processes and in the development of new materials

with specifically designed properties. Thus, the synthesis and study of complexes is very

important. Moreover, complexation is very relevant in pharmacy as a means of modifying the

pharmacological, toxicological and physico-chemical properties of drugs.

This project describes the synthesis and characterization of metal complexes of purines and

pyrimidines. The synthetic techniques of ligands were based on the modification of

nucleobases by the introduction of various substituents. The purity of the newly synthesized

compounds was checked by thin layer chromatography (TLC), and their structures were

confirmed by Infrared (IR), 1H NMR and 13C NMR Spectroscopy. In order to obtain the

target compounds, the following routes were adopted:

Esterification of adenine, thymine, uracil and cytosine by ethylacrylate in the presence of a

base catalyst, the products were either hydrolyzed in acid medium to give adenine and

thymine carboxylic acids or reacted with hydrazine hydrate to yield the nucleobase-

carboxylic acid hydrazide. Adenine hydrazide was further reacted with formic acid or acetic

acid to yield N′-formyl or N′-acetylpropanehydrazide, respectively. Treatment of the

synthesized carboxylic acids with o-PDA disulfate in ethyleneglycol at 90˚C yielded good

amounts of the corresponding benzimidazole derivatives. The compounds 6-amino-1,3-

dimethyluracil and 5,6-diamino-1,3-dimethyluracil were diazotized and condensed with

aldehyde, respectively, to give the azodye and Schiff base. The ligands were reacted with

several transition metals to give various complexes which were characterized by UV-Vis and

IR spectrophotometry.

The formation constant values (Kf) of the metal complexes, estimated from the potentiometric

titration with standard NaOH at constant ionic strength, were established in ethanol-water

media and the thermodynamic parameters were discussed.

v

Because of the increased need for development of improved analytical methodology to

determine metal ions and inorganic anions for the purpose of monitoring health as well as the

quality of the water and air, an interesting point was the utilization of a cation-sensing uracil-

appended schiff base for detection and quantitation of copper, iron and silver cations in water

samples at low detection limits and with high accuracy. Finally, the photophysical

characterization of six acyclonucleosides were studied in a number of organic solvents with

diverse polarities and in aqueous solutions at different pH, and then subjected to multiple

regression analysis with more than ten different solvent parameters.

vi

Table of Contents

Chapter One: INTRODUCTION..………………………………………………………… 1

1.1 Metal Complexes and Applications………………………………………….. 2

1.2 Purine and Pyrimidine Metal Complexes:History/Importance………………. 2

1.3 Purines and Pyrimidines as Heterocyclic Compounds.…………………...…. 3

1.4 Role of Nucleic bases in DNA and RNA…………………………………….. 4

1.5 Pyrimidines ………………………………………………………………... 6

1.5.1 Biological Importance of Pyrimidines……………………………………... 6

1.5.2 The Structure of Pyrimidine ……………………………………………….. 7

1.5.3 The pKa of Pyrimidine …………………………………………………... 8

1.5.4 Reactivity of Pyrimidine ...………………………………………………… 8

1.5.5 General Methods for the Synthesis of Pyrimidine…………………………. 8

1.5.6 Tautomerism and pKa Values of Pyrimidine Nucleic Bases.……………… 12

1.6 Purines……………………………………………………………………….. 14

1.6.1 Biological Importance of Purines………………………………………….. 14

1.6.2 The Structure of Purine…………………………………………………….. 15

1.6.3 The pKa of Purine………………………………………………………….. 16

1.6.4 Reactivity of Purine………………………………………………………... 16

1.6.5 General Methods for the Synthesis of Purine……………………………… 16

1.6.6 Tautomerism and pKa values of Purines…………………………………... 18

1.7 Transition metal purine/pyrimidine complexes……………………………… 20

1.7.1 Synthesis…………………………………………………………………… 20

1.7.2 Binding modes……………………………………………………………... 21

vii

1.7.3 Structural features of Purine/Pyrimidine metal complexes…………….…... 24

1.7.4 Applications of Purine and pyrimidine complexes………………………… 25

Chapter Two: SYNTHESIS OF PURINE AND PYRIMIDINE METAL COMPLEXES LITERATURE REVIEW……………………………………………………………….… 26

2.1 Biological activity of purine derivative……….……....................................... 27

2.2 Biological activity of pyrimidine derivatives….…........................................... 27

2.3 Purine and pyrimidine metal complexes……….................................….……. 28

Chapter Three: EXPERIMENTAL PROCEDURE………………………………….……. 47

3.1 General Information…………………………………………………….……. 48

3.1.1 Reagents and Solvents……………………………………………………... 48

3.1.2 Thin Layer Chromatography……………………………………………….. 48

3.1.3 Melting point measurement ...……………………………………………... 48

3.1.4 pH measurement…………………………………………………………… 48

3.1.5 Spectroscopic Techniques………………………………………………….. 48

3.2 Preparation of Purine and Pyrimidine Ligands………………..…………………. 49

3.3 Preparation of Purine and Pyrimidine Metal Complexes…………………….. 57

3.3.1 General method for synthesis of [AA] metal complexes…………………... 57

3.3.2 General method for synthesis of [AE] metal complexes…………………... 58

3.3.3 Methods for synthesis of AH metal complexes……………………………. 59

3.3.4 Methods for synthesis of [AF] metal complexes…………………………... 60

3.3.5 General Method for synthesis of CoCl2 and ZnSO4-[CE] metal complexes. 61

3.3.6 Method for synthesis of CuCl2-[TE] metal complexes…………………….. 61

3.3.7 Method for synthesis of PdBr2 complex with the Schiff base formed between 5,6-diamino-1,3-dimethyluracil hydrate and 5-methyl-thiophenecarboxaldehyde…………......................……………………………….. 62

viii

Chapter Four: RESULTS AND DISCUSSION………………………………...…………. 64

4.1Synthesis Motivation of Acyclonucleosides………………………………........…… 65

4.2 N-Alkyation of Nucleobases……...............………………………………………… 69

4.2.1 Aza-Michael Reactions…………………………………………………………… 70

4.3 Synthesis of Ligands…………………………………………………………........... 71

4.3.1 Synthesis of N-substituted nucleobase derivatives……………………………..…. 71

4.3.2 Synthesis of Uracil-Azo dye by diazotization………………………………….…. 75

4.3.3 Synthesis of the Uracil Schiff Base Ligand……………………………...……..…. 77

4.3.4 Synthesis of Nucleobase-Benzimidazole derivatives………………...……............ 78

4.4 Characterization of Ligands ...…………………………………………………….... 80

4.4.1 IR Spectroscopy………………………………………………………….……….. 80

4.4.2 NMR Spectroscopy……………………………………………………………….. 81

4.5 IR Spectra of Synthesized Metal Complexes……………………………………….. 83

4.5.1 Adenine ester [AE] metal complexes……………………………………………... 84

4.5.2 Adenine acid [AA] metal complexes……………………………………………… 84

4.5.3 Adenine hydrazide[AH] metal complexes…………………………………........... 85

4.5.4 Adenineformylhydrazide[AF] metal complexes………………………………….. 85

4.5.5 Schiff base [DDUTS] metal complexes……………………………………........... 85

4.6 Solubilities of the prepared Complexes in Different Solvents……………………… 86

Chapter Five: POTENTIOMETRIC DISSOCIATION CONSTANTS OF 3-(ADENINE-9-YL)-PROPIONIC AND 3-(THYMINE-1-YL)-PROPIONIC ACIDS AND THEIR METAL COMPLEXES IN ETHANOL-WATER MEDIA………………………………. 88

5.1 Introduction…………………………………………………………………………. 89

5.2 Different Methods for pKa Determination ……..........................……………….….. 90

ix

5.2.1 Potentiometric titration…………………………………………………... 90

5.2.2 Spectrophotometric methods…………………………………………….. 90

5.2.3. NMR titration…………………………………………………………… 91

5.2.4 Liquid chromatography (LC).…………………………………………… 91

5.2.5 Capillary electrophoresis (CE)………….……………………………….. 92

5.3 Importance of Stability Constants….……………………………………… 93

5.4 Factors affecting the Stability of Metal Complexes….……………………. 93

5.5 Potentiometric studies conducted on complexation of Adenine and Thymine……………………………………………………....…………...

93

5.6 Experimental part………………………………………………………….. 94

5.6.1 Materials and methods…………………………………………………... 94

5.6.2 Calibration of the glass electrode………………………………………... 94

5.7 Determination of acid dissociation constants of Ligands…………………. 95

5.8 Complex formation studies………………………………………………... 99

5.9 Thermodynamic parameters……………………………………………….. 104

5.10 Conclusion………………………………………………………………... 106

Chapter Six: THIOPHENE ALDEHYDE-DIAMINOURACIL SCHIFF BASE: A NOVEL FLUORESCENT PROBE FOR DETECTION AND QUANTITATION OF CUPRIC, SILVER AND FERRIC IONS IN SOLUTION……………………….

107

6.1 Introduction…………………………………………………….………….. 108

6.1.1 Fluorescence Sensors……………………………………………………. 108

6.2 Experimental Procedure…………………………………………………… 111

6.2.1 Preparation of metal ions standard solutions……………………………. 111

6.2.2 Fluorescence titration of DDUTS with different metal ions…….………. 112

x

6.3 Results and Discussion…………………………………………………… 112

6.3.1 Stern-Volmer analysis for response of DDUTS in ethanol to Fe3+, Ag+ and Cu2+ Ions……………………………………………..……….…….. 115

6.3.2 Selective recognition of Ag+, Cu2+ and Fe3+……………..….…….……. 117

6.3.3 Comparison of DDUTS with common chemosensors……………….…. 119

6.3.4 Method validation in quantitative assay of Cu2+, Ag+ and Fe3+……....... 120

6.4 Determination of Binding Stoichiometry and the Association Constants Ka of Cu2+, Ag+, Fe3+ binding to chemosensor……………...................... 123

6.5 Study on Reversibility and mechanism for the binding of DDUTS with Cu2+, Ag+ and Fe3+………...………………………………………........... 125

6.6 Effect of standing time on complexation…………………………….…… 126

6.7 Preliminary Analytical Application……………………………….……… 126

6.8 Conclusion………………………………………….…………………….. 126

Chapter Seven: SOLVENT EFFECT STUDIES ON THE ABSORPTION AND EMISSION SPECTRA OF ADENINE, THYMINE AND URACIL DERIVATIVES. 128

7.1 Introduction………………………………………………………….……. 129

7.2 Experimental Procedure…………………………………………….…….. 131

7.2.1 Materials and methods………………………………………………….. 131

7.3 Results and Discussion…………………………………………………… 131

7.3.1 UV absorption and fluorescence study of the purine and pyrimidine derivatives (I–VI) ………………………………………………………... 133

7.3.2 Methods of calculations and results……………………………............. 147

7.4 Conclusion……………………….....…………………………….............. 163

191

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