N-Heterocyclic Carbene Silver(I) Complexes from Xanthines And
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N-HETEROCYCLIC CARBENE SILVER(I) COMPLEXES FROM XANTHINES AND THEIR ANTIMICROBIAL APPLICATIONS A Dissertation Presented to The Graduate Faculty of the University of Akron In Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy Aysegul Kascatan Nebioglu May, 2007 N-HETEROCYCLIC CARBENE SILVER(I) COMPLEXES FROM XANTHINES AND THEIR ANTIMICROBIAL APPLICATIONS Aysegul Kascatan Nebioglu Dissertation Approved: Accepted: _______________________________ _______________________________ Advisor Department Chair Dr. Wiley J. Youngs Dr. Kim C. Calvo ______________________________ _______________________________ Co-Advisor Dean of the College Dr. Claire A. Tessier Dr. Ronald F. Levant ______________________________ _______________________________ Committee Member Dean of the Graduate School Dr. Michael Taschner Dr. George R. Newkome ______________________________ _______________________________ Committee Member Date Dr. Christopher J. Ziegler ______________________________ Committee Member Dr. Amy Milsted ii ABSTRACT This dissertation discusses a newly growing area of the synthesis from xanthine ligands of new silver(I) N- heterocyclic carbene (NHC) complexes and their potential antimicrobial use in cystic fibrosis lung infections. In chapter I, the ligand properties of NHCs and the synthetic methods for the formation of silver(I) NHC complexes are outlined. An overview of silver antimicrobials and previously synthesized silver(I) NHC complexes from pyridine linked and tripodal imidazolium salts for the topical applications is discussed. Furthermore, a brief summary of cystic fibrosis is given. Chapter II presents the introductory studies to explore the NHC silver(I) chemistry of caffeine. Formation and characterization of mono and dinuclear bis(NHC) silver(I) complexes from different methylated caffeine salts are given. Chapter III focuses on the formation of an NHC-silver(I) acetate complex from the iodide salt of methylated caffeine. This complex demonstrates a promising antimicrobial activity against numerous resistant respiratory pathogens including members of the Burkholderia cepacia complex which causes a high rate of mortality in patients with cystic fibrosis. Synthesis of NHC silver(I) complexes from theophylline derivatives is given in chapter IV. The antimicrobial activity of these complexes against the same pathogens used in chapter III is presented. In chapter V, the use of a bis(NHC) silver(I) complex from methylated caffeine as a carbene transfer agent is demonstrated and formation of a Rh(I) NHC iii complex is outlined. Furthermore, the synthesis and characterization of Pt(II) and Pd(II) NHC complexes of methylated caffeine are presented. iv DEDICATION To my beloved husband, Ahmet, for his exceptional support and love. v ACKNOWLEDGEMENTS I would like to express my sincere gratitude to my advisor, Professor Wiley J. Youngs, for his guidance, encouragement and generous support. His kind and understanding approach made me motivated throughout my graduate study. I would also like to extend my thanks to my co-advisor Professor. Claire A. Tessier for her invaluable contributions, knowledge and encouragement. I would like to thank Professor. Carolyn L. Cannon and her coworkers in Washington University, Division of Allergy and Pulmonary Medicine for the in vitro and in vivo antimicrobial studies. I extend my thanks to Professor Amy Milsted and Professor Daniel Ely for letting me use their facilities in Biology department. I also would like to thank Professor Seth D. Crosby for the microarray gene expression analysis. I would also like to extend my thanks to my committee members for their contributions. My appreciation is to National Science Foundation, National Cancer Institute and National Institute of Allergy and Infectious Diseases for their financial support. I would also to thank Dr. Jered C. Garrison, Dr. Matthew Panzner, Dr. Semih Durmus and Doug Medvetz for the characterization of my crystals. I thank to Khadijah Hindi for the toxicity studies and Dr. Abdulkareem Melaiye for teaching me antimicrobial tests. I would also like to thank all of the other Youngs group members: vi Dr. Carol Quezada, Samittichai Seeyangnok, Tammy Siciliano, Paul Custer and Brian Wright for their support and friendship. I appreciate all of the faculty and staff in the Chemistry department for their assistance. I would like to thank my parents; ùengül and Adem with all my heart. They always made me feel their love and support. I was their little girl at all times. I would also like to express my gratefulness and appreciation to my elder sister Dilek, and her husband Mehmet Ali for their extraordinary support and encouragement. Finally, I would like to express my gratitude to my lovely husband Ahmet. You were always there for me in every step of the way with your love and support. Thank you being the way you are. You complete me. vii TABLE OF CONTENTS Page LIST OF TABLES .........................................................................................................xi LIST OF FIGURES...................................................................................................... xii LIST OF SCHEMES ....................................................................................................xiv LIST OF ABBREVIATIONS AND ACRONYMS……………………………………..xv CHAPTER I. INTRODUCTION.....................................................................................................1 1.1 N-Heterocyclic Carbenes (NHCs) and Silver(I) Complexes ..............................1 1.2 The Use of Silver Compounds as Antimicrobials ..............................................6 1.3 Current Literature on the Antimicrobial Properties of Silver NHC Complexes ...........................................................................................................10 1.4 Cystic Fibrosis................................................................................................19 II. SYNTHESIS AND STRUCTURAL CHARACTERIZATION OF BIS(N-HETEROCYCLIC CARBENE) COMPLEXES OF SILVER(I) FROM CAFFEINE..............................................................................................................22 2.1 Introduction....................................................................................................22 2.2 Results and Discussion ...................................................................................23 2.3 Conclusions....................................................................................................31 2.4 Experimental ..................................................................................................31 III. SYNTHESIS FROM CAFFEINE OF A MIXED N- HETEROCYCLIC CARBENE-SILVER ACETATE COMPLEX ACTIVE AGAINST RESISTANT RESPIRATORY PATHOGENS........................................................37 viii 3.1 Introduction....................................................................................................37 3.2 Results and Discussion ...................................................................................39 3.3 Conclusion .....................................................................................................53 3.4 Experimental ..................................................................................................54 IV. SYNTHESIS OF N- HETEROCYCLIC CARBENE SILVER ACETATE COMPLEXES FROM THEOPHYLLINE DERIVATIVES AND ANTIMICROBIAL ACTIVITY AGAINST RESISTANT RESPIRATORY PATHOGENS.........................................................................................................63 4.1 Introduction....................................................................................................63 4.2 Results and Discussion ...................................................................................66 4.3 Conclusions....................................................................................................77 4.4 Experimental ..................................................................................................78 V. SYNTHESIS AND CHARACTERIZATION OF N-HETEROCYCLIC CARBENE RHODIUM(I), PLATINUM(II) AND PALLADIUM(II) COMPLEXES FROM CAFFEINE ..........................................................................87 5.1 Introduction....................................................................................................87 5.2 Results and Discussion ...................................................................................88 5.3 Conclusions....................................................................................................95 5.4 Experimental ..................................................................................................96 VI CONCLUSION .....................................................................................................100 REFERENCES......................................................................................................103 APPENDICES.................................................................................................................114 APPENDIX A: SUPPLEMENTARY MATERIAL FOR THE X-RAY CRYSTAL STRUCTURE OF C9H13F6N4O2P (CHAPTER II-1b).................................115 APPENDIX B: SUPPLEMENTARY MATERIAL FOR THE X-RAY CRYSTAL STRUCTURE OF C18H24N8O4Ag, C7H8, PF6 (CHAPTER II-2b)...............121 ix APPENDIX C: SUPPLEMENTARY MATERIAL FOR THE X-RAY CRYSTAL STRUCTURE OF C18H24Ag2N10O10 (CHAPTER II-2d) ............................130 APPENDIX D: SUPPLEMENTARY MATERIAL FOR THE X-RAY CRYSTAL STRUCTURE OF C9H13N4O2I,