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Syntheses and Structural Studies of Metal Complexes of Sulfa Drugs

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SYNTHESES AND STRUCTURAL STUDIES OF METAL COMPLEXES OF SULFA DRUGS A thesis submitted to the Cardiff University By G. M. Golzar Hossain in candidature of the degree of Doctor of Philosophy August 2005 Department of Chemistry Cardiff University UMI Number: U584873 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. Dissertation Publishing UMI U584873 Published by ProQuest LLC 2013. Copyright in the Dissertation held by the Author. Microform Edition © ProQuest LLC. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 DECLARATION This work has not previously been accepted in substance for any degree and is not being concurrently submitted in candidature for any degree. Signed (Candidate) Date: O 3 / ^ 6 STATEMENT 1 This thesis is the result of my own investigations, except where otherwise stated. Other sources are acknowledged by in the appended bibliography. Signed (Candidate) Date: STATEMENT 2 I hereby give consent for my thesis, if accepted, to be available for photocopying and for inter-library loan, and for the title and summary to be made available to outside organisations. Signed (Candidate) Date: / 3 / o 3 / II <tm ^d ic a te < d t o JAfroza andJAsif III ACKNOWLEDGEMENTS This work would not have been completed without the encouragement and patience of my supervisors Professor Peter G. Edwards and Dr. Angelo J. Amoroso, to whom, I will always be grateful. I am also grateful to Dr. K. M. A. Malik for collecting crystal data and valuable advice. I want to express my gratitude to Dr. Ian A. Fallis and Dr. S. Aldridge for their helpful discussion. Many thanks go to Dr. Murphy and Dr. Farley for EPR data and discussion. Thanks go to all the technical staffs- Rob Jenkins, Alan, Robin, Ricky, Sham, John Bowly and Gary for helping me to work smoothly. Special thanks go to everyone in the Department of Chemistry, Cardiff University, specially Caroline, Ozra, Steve, Graham, Dave, Miles, Claire, Rob, Willium, Deborah, Lisa, Amal, Chris, Andrea and Mark for making the work enjoyable. Finally, I would like thank my wife Afroza and lovely son Asif for their support and inspiration throughout the research works. IV ABSTRACT This thesis presents the results of the synthesis of metal complexes of sulfa drugs (sulfadiazine, sulfamerazine, sulfamethazine, sulfathiazole and sulfadimethoxine) with secondary ligands, which were subjected to X-ray crystallographic studies. The aim of this work was to synthesise metal complexes of sulfa drugs with secondary nitrogen donor ligands e.g. ammonia, pyridine (py), ethylenediamine (en), diethylenetriamine (dien), 2,2'- bipyridine, 1,10-phenanthroline, 4,4'-dimethyl-2,2'-bipyridine, A(A^(3-aminopropyl)-bis- (ethylenediamine) (apen) and oxygen donor ligands such as, water and dimethylformamide (DMF) and to investigate the different modes of coordination of the sulfa drugs molecules to the metal ions in the presence of nitrogen/oxygen donor ligands. Chapter 1, details an introduction into the fundamental concepts, procedures and equipment involved in data collection, solution and refinement of single crystal structures. In Chapter 2, a review of the literature on the metal complexes of sulfa drugs along with the main aims of this work is presented. In Chapter 3, the general experimental procedure and synthetic methods have been described for the metal complexes of sulfa drugs whose results and discussion are described in chapter 4. In chapter 4, the crystal structure of sulfadiazine, a new polymorph of sulfamerazine and the syntheses of the metal complexes of sulfadiazine, sulfamerazine and sulfamethazine, their analytical and spectral data along with the X-ray structure determination of the complexes are presented. The complexes studied in this chapter are: A) Cobalt complex {[Co(smz)2(H20)].DMF}„ (3); B) Nickel complexes [Ni(en)3(sdz)2].H20 (4) and [Ni(smr)2(py)2].4py (5); C) copper complexes [Cu(en) 2 (sdz) 2 ] (6), [Cu(dien) 2 (sdz) 2 ] (7), [Cu(en)2(H20)2][smr)2] (8), [Cu(en)2(H20)2][smr)2].H20 (9), [Cu2(smr)4].2DMF (10), [Cu2(smr)4] .2DMSO (11), [Cu(smz)2(apen)].3H2O.CH3OH (12) and {[Cu(smz)2.NH3].2H20}„ (13); D) Zinc complexes [Zn(smz) 2 (NH 3 )2 ] (14) and [Zn(smz)2(py)2].2py (15), E) Cadmium complexes [Cd(dien) 2 (sdz) 2 ].DMF (16), V [Cd(dien)(smr)2].H20 (17), [Cd(sdz)2(bpy)] (18), [Cd(sdz)2(phen)] (19), [Cd(sdz)2(dmbpy)].2DMF (20), [Cd(smr)2(phen)] (21), {[Cd(smz)2(H20)].DMF}„ (22), {[Cd(smz)2(H20)].2H20}„ (23) and [Cd(smz)2(en)].2DMF (24); and F) Mercury complexes [Hg(sdz)2(DMF)2] (25), [Hg(smr)2] (26) [Hg(smr)2(bpy)] (27) and [Hg(smz)2(DMF)2] (28). The structural results for the complexes are discussed and compared with other related complexes. In this context, the different types of coordination geometries, important parameters within the coordination sphere, the various modes of coordination of the sulfa drugs in the anionic form, dimeric polymeric complexes, the role of hydrogen bonds in the formation of the “cation-anion pair” and the packing diagram have been discussed. In Chapter 5, we have described the syntheses and characterisation of the complexes of sulfathiazole, their analytical and spectral data along with the X-ray structure determination of these complexes are presented. The complexes studied are: [(H 2 stz)2 ][N 0 3 ].H 2 0 (29), [C0 CI4 ][(H2 stz)2 ].CH 3 COOH (30) and [Cu(en)2(H20)2][stz)2].2H20 (31). In all the complexes the sulfathiazole molecules act as ionic species. The structural results for the complexes are discussed and compared with other related complexes. In this context, the role of hydrogen bonds in the formation of the “cation-anion pair” and the packing diagram has been discussed. Chapter 6 describes the structure of sulfadimethoxine and synthesis and characterisation of a zinc complex of sulfadimethoxine [Zn(sdm)2(NH3)2].2H20 (33) by analytical and spectral data along with the X-ray structure determination. The structural results of the complex are discussed and compared with other related complexes. The packing diagram of the complex with the hydrogen bonds is discussed in this chapter. VI ABBREVIATIONS A angstrom (1 A = 10"10 cm) X wavelength V cell volume a, b , c cell axes a, J3, y cell angles d interplanar spacing Fhki structure factor fj scattering factor hkl general indices (°) degree centigrade (Celcius) cm centimeter cm-1 wave number g grams ml milliliter mmol millimolar tsd triple sulfa drugs Hsdz sulfadiazine Hsmr sulfamerazine Hsmz sulfamethazine Hstz sulfathiazole Hsdm sulfadimethoxine py pyridine DMF dimethylformamide DMSO dimethylsulfoxide en ethylenediamine bpy 2,2'-bipyridine phen 1,10-phenanthroline dmbpy 4,4'-dimethyl-2,2'-bipyridine dien diethylenetriamine apen NJSF (3 -aminopropy l)-bi s(ethy lenediamine) IR infrared EPR Electron Paramagnetic Resonance c. w. continuous wave NMR nuclear magnetic resonance s singlet d doublet t triplet PABA p-aminobenzoic acid UTI urinary tract infection VIII CONTENTS TITLE I DECLARATION II DEDICATED TO III ACKNOWLEDGEMENT IV ABSTRACT V ABBREVIATIONS VII CHAPTER 1 - X-RAY CRYSTALLOGRAPHY 1 1.1 Historical background 1 1.2 Bragg’s equation 3 1.3 Reciprocal lattice 4 1.4 Crystal Lattice 6 1.4.1 Crystal Systems 8 1.4.2 Unit cell 8 1.4.2 Miller Indices 9 1.5 Systematic absences 10 1.6 Symmetry Elements 10 1.6.1 Point Symmetry 10 1.6.2 Translational Symmetry 10 1.6.3 Space groups 11 1.7 Structure determination 12 1.7.1 Atomic Scattering Factor 12 1.7.2 Structure F actor 12 1.7.3 Thermal motion 14 1.7.4 The Lorentz Factor, Polarisation Factor and Absorption Corrections 15 1.7.5 Thermal Ellipsoid 16 IX 1.7.6 Electron Density 16 1.7.7 Phase problem 17 1.7.8 Solutions to the phase problem 18 1.7.8.1 Direct Methods 18 1.7.8.2 Patterson Synthesis 19 1.7.9 Structure Refinement 21 1.8 Experimental Section 22 1.8.1 Data collection using a CCD area detector 23 1.8.2 The programs used for structure solution, refinement and structural drawing 25 References 26 CHAPTER 2 - INTRODUCTION 27 2.1 History 28 2.2 Pharmacology 29 2.3 Mechanism of Action 30 2.4 Pharmacokinetics 31 2.5 Clinical Uses 31 2.6 Adverse reactions 31 2.7 Previous work on triple sulfa drugs (TSD) 32 2.7.1 Sulfadiazine 33 2.7.2 Sulfamerazine 38 2.7.3 Sulfamethazine 39 2.8 Aim of the work 41 References 46 CHAPTER 3 - EXPERIMENTAL 48 3.1 Chemical and their purifications 48 3.2 Physical measurements 48 3.2.1 Elemental analysis 48 3.2.2 IR Studies 48 3.2.3 Electron Paramagnetic Resonance 48 3.2.4 'H and l3C NMR spectra 49 3.2.5 X-ray crystallography 49 3.3 Synthetic Procedure 49 X 3.4 Syntheses of the complexes 50 3.4.1 Preparation of the crystal of sulfadiazine (1) 50 3.4.2 Preparation of the crystal of sulfamerazine (2) 50 3.4.3 Preparation of the complex {[Co(smz)2(H20)].DMF}„ (3) 51 3.4.4 Preparation of the complex [Ni(en)3(sdz)2].H20 (4) 51 3.4.5 Preparation of the complex [Ni(smr)2(py)2].4py (5) 51 3.4.6 Preparation of the complex [Cu(en) 2 (sdz) 2 ] (6) 52 3.4.7 Preparation of the complex [Cu(dien)(sdz) 2 ] (7) 52 3.4.8 Preparation of the complex [Cu(en)2(H20)2][(smr)2] (8) 52 3.4.9 Preparation of the complex [Cu(en)2(H20)2][(smr)2].H20 (9) 53 3.4.10 Preparation of the complex [Cu 2 (smr)4 ].DMF (10) 53 3.4.11 Preparation of the complex [Cu 2 (smr)4 ].DMSO (11) 53 3.4.12 Preparation of the complex [Cu(smz) 2 (apen)].
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