Synthesis and Complexation of Functionalized Mixed Thia‐Aza‐Macrocyclic
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© 2009 WILHELM S. MALASI ALL RIGHTS RESERVED SYNTHESIS AND COMPLEXATION OF FUNCTIONALIZED MIXED THIA‐AZA‐MACROCYCLIC AND MEDIUM SIZED LIGANDS A Dissertation Presented to The Graduate Faculty of the University of Akron In Partial Fulfillment of the Requirement for the Degree Doctor of Philosophy Wilhelm Malasi May 2009 SYNTHESIS AND COMPLEXATION OF FUNCTIONALIZED MIXED THIA‐AZA‐MACROCYCLIC AND MEDIUM SIZED LIGANDS Wilhelm Malasi Dissertation Approved: Accepted: _________________________ _________________________ Advisor Department Chair Dr. Michael J. Taschner Dr. Kim C. Calvo _________________________ _________________________ Committee Member Dean of the College Dr. David Modarelli Dr. Chand Midha _________________________ _________________________ Committee Member Dean of the Graduate School Dr. Jun Hu Dr. George R. Newkome _________________________ _________________________ Committee Member Date Dr. Wiley J. Youngs _________________________ Committee Member Dr. Amy Milsted ii ABSTRACT Six ligands of mixed thia-aza donor atoms 40, 90, 100, 107, 110 and 112 have been synthesized and characterized. The metal complexes of Copper 114, Rhodium 116, and Nickel 115 with 1,8-dithia-4,11-diazacyclotetradecane 40 have been made and crystal structures grown in appropriate solvents to give good crystals suitable for X-ray crystallographic analysis. Other molecules whose crystals have been made and analyzed by X-ray crystallography are the secondary amine 82, tosylated double ligand tertiary amine 91, the seven member ring ester 100 and the perchlorate salt of the double nine member ligand tertiary amine 110. All these crystals have their analysis data in Appendix D. The seventh ligand 113 has been adapted, and complexed with rhodium and its crystal structure 117 has been analyzed. The curative activity of the rhodium complex 116 was tested against ovarian cancer cells Nutu-19 at 1.54 mM concentrations. The results showed that the cells became detached with extreme morphological changes and extreme internal vesicle formation causing the cells to die. Ovarian normal cells, tested at the same concentration, showed that the cells remain attached, with no morphological changes and only slightly vesicle formation. Table 4 in Chapter II shows 87% of the cancer cells died while only 30% of the normal ovarian cells died. If the toxicity of this complex can be further controlled and minimized, it may be very useful in the treatment of cancer in the future. iii The ligand 40 was functionalized through carboxylic acid derivatives to give rise to the new ligand 90. Also ligand 107 was functionalized in the same way to give the new ligand 110, while the liands 82 and 107 were successfully joined by a butane chain to form a new ligand 112. In an attempt to synthesize the carbon bridged functionalized fourteen membered ring, ligand 99, the functionalized seven membered ring molecule 100 was isolated instead. iv DEDICATION To my mother Delfina and memory of my father Simon Lucas who passed away July 22, 2008. Those who sow in tears shall reap rejoicing (Ps 126:5) v ACKNOWLEDGEMENTS Heartfelt appreciations to my mentor Dr. Michael J. Taschner for his commitment, fraternal assistance, constant guidance and encouragement the whole period of my course. Special thanks to my colleagues Zin Min from Dr. Tessier’s research group for her encouragement and computer data handling, Dr. Wiley Young’s group for X-ray crystallography, Dr. Wedsmiotes’s group for mass spectrometry, Jacob Weingart in Dr. Jun Hu’s group for Infrared (IR) spectra and the staff members Dr. Joe Massey, Dr. Venkat Dudipala and Simon Stakleff for NMR instruments operations and technicalities. Also, the chemistry department secretaries Nancy Homa and Jean Garcia for their constant availability to assist and direction. The chemstore provider and instructor Lisa Zickefoose for promptness and efficiency. I acknowledge my research group members and friends Swaranjali Bhide, Wenchao Qu, Tara Scheiber and Aaron Lineberry for cooperation and providing a viable environment to work smoothly. Special recognition to all my committee members and professors who made my course work, subsequent studies and research possible, and brought my dream to reality. Remarkable acknowledgement to my superiors for offering me the opportunity for studies, my family, relatives and friends at home (Tanzania) for their sacrifices and patience, especially my mother for understanding. vi TABLE OF CONTENTS Page LIST OF TABLES............................................................................................................. ix LIST OF FIGURES .............................................................................................................x LIST OF SCHEMES......................................................................................................... xii CHAPTER I. INTRODUCTION......................................................................................................1 1.1 Synthesis and Study of Supramolecular Properties .......................................1 1.2 Metal Complexes of the Macrocyclic Ligands..............................................9 1.3 Other [14] Member Ring Macrocylic Molecules ........................................18 1.4 Medium Cyclic Molecules Synthesized ......................................................20 II. RESULTS AND DISCUSSIONS ............................................................................25 2.1 Synthesis, Complexation and Characterization of the Ligands ...................25 2.2 The Macrocyclic Ligands Synthesized in This Work..................................26 III. SUMMARY .............................................................................................................51 IV. EXPERIMENTAL ...................................................................................................53 4.1 General Procedure........................................................................................53 4.2 Synthesis ......................................................................................................55 4.3 Complexing the Synthesized Ligands..........................................................79 REFERENCES ..................................................................................................................82 vii APPENDICES ...................................................................................................................90 APPENDIX A. 1H AND 13C NMR SPECTRA OF THE COMPOUNDS....................91 APPENDIX B. IR SPECTRA OF THE MOLECULES AND THE LIGANDS ........122 APPENDIX C. MASS SPECTRA OF SELECTED PRODUCTS .............................133 APPENDIX D. X-RAY CRYSTAL STRUCTURES AND DATA ANALYSIS OF THE PRODUCTS........................................................................136 viii LIST OF TABLES Table Page 1. Enthalpies and Entropies of Cu(II) Complexation with 29-37...................................6 2. Summary of Some Specific Rate Constants for Aquocopper(II) Ions Reacting with Various Protonated Amino/thia Ethers2 Quadridentate and Quinquedentate Macrocycles.....................................................................................9 3. Selected Crystallography Data for 40, 114, 116 and 115.........................................37 4. Activity of Rhodium Complex on Ovarian Cancer..................................................39 ix LIST OF FIGURES Figure Page 1. Plastocyanin6 and Rusticyanin8 as examples of blue copper protein in nature ..........3 2. A variety of ligands with mixed donor atom..............................................................4 3. Various size all tetra-aza ligands used to complex copper (II) to study enthalpies and entropies of complex formation..........................................................................5 4. Various macrocyclic ligands studied by Westerby et al.............................................8 5. Demonstrating electron transfer in Cu(II/I) redox, D1-4 represent donor atoms.......11 6. Electron transfer and geometry changes of Cu(II/I)/Fe (II/III) complexes ..............11 7. Complexes of nickel and the ligand .........................................................................12 8. Arca et al.119 synthesized ligands 121-123 and Taylor et al.120 synthesized 124,125 .....................................................................................................................14 9. The model of ligands functionalized at the bridging carbons ..................................15 10. Ball and stick X-ray structures developed from available data for rhodium complexed with [14]aneN2S2 and [14]aneNS3 .........................................................18 11. Nine member rings reported in literature .................................................................20 12. Two copper atoms complexed with [9]aneNS2 in a bridging manner......................21 13. Copper atom sandwiched between two [9]aneNS2 ligands......................................22 14. Nickel complexed with [9]aneNS2 ...........................................................................23 15. A crystal structure of rhodium complexed with a nine member ring ligand............24 16. Crystal structures of the tosylated amine 82.............................................................29 17. The crystal structure of the ligand 40 .......................................................................31 x 18. Crystal structure 114 of copper complexed with ligand 40.....................................32 19. Crystal