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Thioether and sulfoxide complexes of ruthenium : preliminary in vitro studies of water-soluble species Cheu, Elizabeth Lai Shuen 2000

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T H I O E T H E R A N D S U L F O X I D E C O M P L E X E S OF R U T H E N I U M ; P R E L I M I N A R Y IN VITRO S T U D I E S OF W A T E R - S O L U B L E SPECIES B y E L I Z A B E T H L A I S H U E N C H E U B . Sc., University of British Columbia, 1991 A THESIS S U B M I T T E D I N P A R T I A L F U L F I L L M E N T O F T H E R E Q U I R E M E N T S F O R T H E D E G R E E OF D O C T O R OF P H I L O S O P H Y In T H E F A C U L T Y OF G R A D U A T E S T U D I E S (Department of Chemistry) We accept this thesis as conforming to the required standard T H E U N I V E R S I T Y OF B R I T I S H C O L U M B I A January 2000 © Elizabeth La i Shuen Cheu, 2000 In presenting this thesis in partial fulfilment of the requirements for an advanced degree at the University of British Columbia, I agree that the Library shall make it freely available for reference and study. I further agree that permission for extensive copying of this thesis for scholarly purposes may be granted by the head of my department or by his or her representatives. It is understood that copying or publication of this thesis for financial gain shall not be allowed without my written permission. The University of British Columbia Vancouver, Canada Department of DE-6 (2/88) Abstract Water-soluble ruthenium chemotherapeutic agents require further investigation. One approach is to study the coordination chemistry o f a series of Ru-disulfoxide complexes, and preliminary in vitro surveys o f the effects of these complexes in C H O (Chinese hamster ovary) cells are included. Other approaches, including the metallation of some free-base porphyrins, were investigated as well. Dithioethers and disulfoxides were synthesized using the well established chemistry outlined below:^ RSH R S - + N a+ Br(CH2)nBr + 2Na+RS" *• RS(CH2)nSR + 2Na+Br" O O air/DMSO M 11 RS(CH2)r>SR • RS(CH2)nSR or H2O2 The disulfoxide and dithioethers were reacted with R u precursors to yield complexes characterized generally by a combination of elemental analyses, N M R , IR and UV-Vis ib l e spectroscopies, as well as conductivity, magnetic measurements and thermal f Ten new disulfoxides (and the corresponding new dithioethers) have been made with: (a) n = 2: R = butyl, l,2-bis(butylsulfinyl)ethane, BBSE; R = pentyl, l,2-bis(pentylsuffinyl)ethane, BPeSE; R = hexyl, 1,2-bis(hexylsulnnyl)ethane, BHSE; R = cyclohexyl, l,2-bis(cyclohexylsulfinyl)ethane, BCySE, and (b) n = 3: R = ethyl, l,3-bis(ethylsulfinyl)propane, BESP; R = propyl, l,3-bis(propylsulfinyl)propane, BPSP; R = 'propyl, 1,3-bis('propylsulfinyl)propane, B'PSP; R = butyl, l,3-bis(butylsulfmyl)propane, BBSP; R = pentyl, 1,3-bis(pentylsulfinyl)propane, BPeSP and R = phenyl, l,3-bis(phenylsulfinyl)propane, BPhSP. All alkyl groups are the normal isomer, unless otherwise indicated. i i gravimetric analyses; fifteen R u complexes were also characterized by X-ray crystallography. The Ru-sulfoxide complexes contained only S-bonded sulfoxides (except jwer-RuCl 3 (DPSO) 2 (DPSO) where O and S represent O- and S-bonded diphenylsulfoxide, respectively). The following new, mononuclear, non-water-soluble, disulfoxide complexes were synthesized and characterized: frcms-RuCl 2 (BESE) 2 ( B E S E = 1,2-bis(ethylsulfinyl)ethane), c w - R u C l 2 ( B B S E ) 2 , c /s-RuCl 2 (BPeSE) 2 , c « - R u C l 2 ( B C y S E ) 2 and c « - R u C l 2 ( B E S P ) 2 . R u C l 2 ( D M S O ) ( L ) (where L = 3,6,9,14-tetrathiabicyclo[9.2.1]tetradeca-11,13-diene), and the water-soluble [Ru(12-S-4)(DMSO)(H 2 0)][OTfJ 2 (where 12-S-4 = 1,4,7,10-tetrathiacyclododecane and O T f = CF3SO3"), were synthesized to determine how the macrocyclic ligand might affect the in vitro properties o f the Ru-sulfoxide moiety. Novel , water-soluble, dinuclear* Ru(II)-disulfoxide complexes [RuCl (BESE)(H 2 0) ] 2 ( / / -C l ) 2 , [RuCl(BPSE)(H 2 0)] 2 ( / / -Cl ) 2 ( B P S E = 1,2-bis(propylsulfinyl)ethane) and [RuCl (BBSE)(H 2 0) ] 2 ( / i -C l ) 2 were characterized, and a new type of water-soluble, dinuclear, mixed-valence Ru(II)/Ru(III)-disulfoxide complex, [RuCl(BPSP)] 2(/i-Cl)3, was characterized and its aqueous chemistry studied. Two mononuclear, dithioether complexes (/ra»s-RuCl2(BPhTE)2 and - R u C l 2 ( B C y T E ) 2 , where B P h T E = l,2-bis(phenylthio)ethane and B C y T E = 1,2-bis(cyclohexylthio)ethane), and four dinuclear, Ru(III)/Ru(III) dithioether complexes ([RuCl2(BETP)]2Cu-Cl)2, [RuCl 2 (BPTP)] 2 (>-Cl) 2 , [ R u C l 2 ( B B T P ) ] 2 ( > C l ) 2 and [RuCl 2 (BPeTP)] 2 ( / / -Cl) 2 , where B E T P = l,3-bis(ethylthio)propane, B P T P = 1,3-t The loosely used "mononuclear," "dinuclear" and "trinuclear" terms refer to the number of metal atoms within a molecule. i i i bis(propylthio)propane, B B T P = l,3-bis(butylthio)propane and B P e T P = 1,3-bis(pentylthio)propane) were also synthesized. The purpose of their synthesis was to determine whether the ligand set would retain its geometry at the R u after oxidation of the coordinated S-atom to S = 0 , but such an oxidation was not affected. A procedure involving the metallation of the water-soluble, free-base porphyrin TSPhP (the dianion of 5,10,15,20-tetrakis(4-sulfonato)phenylporphyrin), using [Ru(DMF) 6 ] [OTfJ 3 as the precursor, to give Na4[Ru(TSPhP)(CO)]-4H 20 was also shown to be effective for metallation of several non-water-soluble, free-base porphyrins with formation of Ru(CO)(Porp) species, where Porp = TPhP (the dianion of 5,10,15,20-tetraphenylporphyrin), BPhP (dianion o f 5,15-bis(phenyl)porphyrin), TrPhPyNO (dianion o f 5,10,15-triphenyl-20-(4-pyridyl-A /-oxide)porphyrin), and O E P (dianion of 2,3,7,8,12,13,17,18-octaethylporphyrin). The water-soluble [RuCl (S -S ) (H 2 0 ) ] 2 C " -C l ) 2 (S-S = B E S E , B P S E or B B S E ) , [RuCl(BPSP) ] 2 Cu-Cl) 3 and [Ru(12-S-4)(DMSO)(H 2 0 ) ] [OTf] 2 complexes were examined in vitro using Chinese hamster ovary (CHO) cells. Toxicity, cell accumulation and D N A -binding assays were used to examine the ability o f these complexes to traverse the cell membrane and bind to D N A . The biological data indicate that all five complexes are non-toxic but accumulate in C H O cells, with no difference in hypoxia. O f major interest [RuCl(BPSP)] 2 ( / / -Cl) 3 and [ R u C l ( B E S E ) ( H 2 0 ) ] 2 ( / i - C l ) 2 bind to D N A to a greater degree than cis- or 7 r a H 5 - R u C l 2 ( D M S O ) 4 , both of which are known to exhibit anti-cancer activity. The preliminary biological data strongly encourage further investigations into the use of water-soluble, dinuclear Ru-disulfoxide complexes as DNA-binding agents. iv Table of Contents Abstract i i Table of Contents v. List o f Tables xi i i . List o f Figures xvii i . List o f Abbreviations xxv. Acknowledgements xxvii i . Chapter 1 Introduction 1.1 Preamble 1. 1.2 Development of Platinum Chemotherapeutic Agents 2. 1.3 Ruthenium Chemotherapeutic Agents 5. 1.3.1 Dinuclear Ru(II)/Ru(III) Complexes 8. 1.3.2 Metallated Porphyrins 9. 1.4 Development of Ruthenium Dimethylsulfoxide Complexes 10. 1.4.1 Ru(II)-Dimethylsulfoxide Complexes: C/ \ s -RuCl 2 (DMSO) 3 (DMSO) and 7 r a m - R u C l 2 ( D M S O ) 4 10. 1.4.1.1 Chemical Behaviour of C7"s-RuCl 2 (DMSO) 3 (DMSO) and Trans-R u C l 2 ( D M S O ) 4 in Aqueous Solutions 11. 1.4.1.2 Binding of C w - R u C l 2 ( D M S O ) 3 ( D M S O ) and r ra«s-RuCl 2 (DMSO) 4 to D N A . . 13. 1.4.2 Ru(III)-Dimethylsulfoxide Complexes: trans-[ (DMSO) 2 H] + [RuCl 4 (DMSO) 2 ]"and M e r - R u C l 3 ( D M S O ) 2 ( D M S O ) 14. 1.4.3 Nitroimidazole Derivatives of R u C l 2 ( D M S O ) 4 17. 1.4.4 R u Bis-chelating Sulfoxide Complexes 19. 1.5 Goals of This Thesis 21. 1.5.1 Synthesis of the Geometrical Isomers of the Known Bis-chelating Disulfoxide Complexes of R u 21. v 1.5.2 Synthesis of Water-soluble Sulfoxide Complexes of R u 21. 1.5.3 Synthesis and Characterization of Novel Chelating Disulfoxide Complexes of R u 22. 1.5.4 Synthesis o f Chelating Dithioether Complexes o f R u 22. 1.5.5 Preliminary Biological Studies In Vitro of Sulfoxide Complexes of R u 22. 1.5.6 Metallation of Water-Soluble Porphyrins 23. 1.6 References for Chapter 1 24. Chapter 2 General Experimental and Synthesis of Ligands (Dithioethers and Disulfoxides) and Ruthenium Precursors and Sulfoxide Complexes 2.1 Chemicals and Reagents 32. 2.2 Physical Techniques and Instrumentation 32. 2.2.1 F T - N M R Instruments 32. 2.2.2 Infrared and U V - V i s Spectrophotometry, Thermal Gravimetric Analysis, Photochemistry and Conductivity and Melting Point Measurements 33. 2.2.3 Magnetic Susceptibility 34. 2.2.3.1 Calculation of x g , Magnetic Susceptibility of the Dissolved Paramagnetic Species and Magnetic Susceptibility per Gram of Sample 34. 2.2.3.2 Calculation of X M , the Molar Magnetic Susceptibility 35. 2.2.3.3 Calculation o f peff, the Effective Magnetic Moment 35. 2.2.3.4 Calculation of n, the Number of Unpaired Electrons 35. 2.2.4 Elemental Analyses, Mass Spectral Analyses and X-ray Crystallography... 36. 2.3 Synthesis o f Dithioethers 36. 2.3.1 3,7-Dithianonane 36. 2.3.2 4,8-Dithiaunadecane 37. 2.3.3 2,8-Dimethyl-3,7-dithianonane 37. 2.3.4 5,9-Dithiatridecane 38. 2.3.5 6,10-Dithiapentadecane 38. 2.3.6 l,3-Bis(phenylthio)propane 38. 2.3.7 5,8-Dithiadodecane 39. 2.3.8 6,9-Dithiatetradecane 39. vi 2.3.9 7,10-Dithiahexadecane 40. 2.3.10 l,2-Bis(phenylthio)ethane 40. 2.3.11 l,2-Bis(cyclohexylthio)ethane 40. 2.4 Oxidation o f Dithioethers to Disulfoxides 41. 2.4.1 l,3-Bis(ethylsulfinyl)propane (BESP) . 41. 2.4.2 l,3-Bis(propylsulfinyl)propane(BPSP) 42. 2.4.3 l,3-Bis(/-propylsulfinyl)propane (B'PSP) 42. 2.4.4 l,3-Bis(butylsulfinyl)propane(BBSP) 42. 2.4.5 l,3-Bis(pentylsulfinyl)propane(BPeSP) 43. 2.4.6 l,3-Bis(phenylsulfinyl)propane(BPhSP) 43. 2.4.7 l,2-Bis(ethylsulfinyl)ethane(BESE) 44. 2.4.8 l,2-Bis(propylsulfinyl)ethane (BPSE) 44. 2.4.9 l,2-Bis(butylsulfinyl)ethane(BBSE) 45. 2.4.10 1,2-Bis(pentylsulfinyl)ethane (BPeSE) 45. 2.4.11 1,2-Bis(hexylsulfinyl)ethane (BHSE) 45. 2.4.12 l,2-Bis(cyclohexylsulfinyl)ethane(BCySE) 46. 2.4.13 1,2-Bis(phenylsulfinyl)ethane (BPhSE) 46. 2.5 Synthesis of Ru(III) Precursor Complexes 47. 2.5.1 [Ru(DMF)6][OTfj3 47. 2.5.2 K 3 [ R u C l 6 ] 48. 2.6 Synthesis o f Monodentate Sulfoxide Complexes of Ruthenium 48. 2.6.1 C / s - R u C l 2 ( D M S O ) 4 48. 2.6.2 7 r a « s - R u C l 2 ( D M S 0 ) 4 49. 2.6.3 Mer-czs-[RuCl 3 (DPSO) 2 (DPSO)] 49. 2.6.4 C / 5 [ R u ( 1 2 S - 4 ) ( D M S O ) ( H 2 0 ) ] [ O T f J 2 C H 3 O H 50. 2.6.5 R u C l 2 ( D M S O ) ( L ) 50. 2.7 Synthesis of Mononuclear Ru(II) Disulfoxide Complexes 51. 2.7.1 G . v - R u C l 2 ( B E S E ) 2 51. 2.7.2 7 r a m - R u C l 2 ( B E S E ) 2 H 2 0 51. 2.7.3 r ra«5-RuCl 2 (BPSE) 2 H 2 0 52. vii 2.7.4 C / 5 - R u C l 2 ( B B S E ) 2 52. 2.7.5 C7.v-RuCl 2(BPeSE) 2 53. 2.7.6 C / '5 -RuCl 2 (BCySE) 2 53. 2.7.7 C / s - R u C l 2 ( B E S P ) 2 54. 2.8 Synthesis of Dinuclear Ru(II)/Ru(II) Disulfoxide Complexes 55. 2.8.1 [RuCl (BESE)(H 2 0) ] 2 ( / / -C l ) 2 55. 2.8.2 [RuCl(BPSE)(H 2 0)] 2 ( / / -Cl ) 2 55. 2.8.3 [RuCl(BBSE)(H 2 0 ) ] 2 C«-Cl ) 2 56. 2.9 Synthesis of a Dinuclear Ru(II)/Ru(III) Disulfoxide Complex 56. 2.9.1 [RuCl(BPSP)] 2 (/ /-CI) 3 56. 2.10 Synthesis of Mononuclear Ru(II) Dithioether Complexes 57. 2.10.1 7 r a m - R u C l 2 ( B C y T E ) 2 - 2 H 2 0 57. 2.10.2 r ra«5 -RuCl 2 (BPhTE) 2 58. 2.11 Synthesis of Dinuclear Ru(III)/Ru(III) Dithioether Complexes 59. 2.11.1 [RuCl 2 (BETP)] 2 ( /*-Cl) 2 59. 2.11.2 [RuCl 2 (BPTP)] 2 ( / i -Cl ) 2 59. 2.11.3 [RuCl 2 (BBTP ) ] 2 Cu -Cl ) 2 59. 2.11.4 [RuCl 2 (BPeTP)] 2 ( / / -Cl) 2 60. 2.12 References for Chapter 2 61. Chapter 3 Structural Properties of Sulfoxide and Thioether Complexes of Ruthenium 3.1 General Introduction 63. 3.2 Structural Properties of the S-0 Moiety in Sulfoxides 64. 3.3 Metal-Sulfoxide Bonding 65. 3.3.1 Sulfur-Bonded Metal-Sulfoxide Complexes 67. 3.3.2 Oxygen-Bonded Metal-Sulfoxide Complexes 69. 3.3.3 Bridging M e t a l - D M S O Complexes 70. 3.4 N M R and IR Spectroscopic Methods for the Determination of Sulfur- or viii Oxygen-Bonding in Metal Complexes 71. 3.4.1 'H NMR Spectroscopy 71. 3.4.2 IR Spectroscopy 72. 3.5 Disulfoxides and Their Metal Complexes 73. 3.5.1 Disulfoxide Complexes 76. 3.6 Mononuclear, Bidentate Disulfoxide Complexes of Ruthenium(II) 80. 3.6.1 Cw-RuCl2(BESE)2 and 7ra«s-RuCl2(BESE)2H20 84. 3.6.2 rrara-RuCl2(BPSE)2H20 88. 3.6.3 C/5-RuCl2(BBSE)2 89. 3.6.4 Os-RuCl2(BPeSE)2 92. 3.6.5 C/.v-RuCl2(BCySE)2 92. 3.6.6 Os-RuCi2(BESP)2 95. 3.7 Dinuclear Ru(II)/Ru(II) Chelating Disulfoxide Complexes 99. 3.7.1 Characterization of [RuCl(BESE)(H20)]2Cu-Cl)2, [RuCl(BPSE)-(H20)]2(//-C1)2 and [RuCl(BBSE)(H20)]2(//-Cl)2 100. 3.8 A Mixed-Valence Ru(II)/Ru(III) Chelating Disulfoxide Complex 105. 3.8.1 Introduction 105. 3.8.2 [RuCl(BPSP)]2(//-Cl)3 109. 3.8.3 Chemical Behaviour of [RuCl(BPSP)]2(>Cl)3 in Aqueous Solutions 116. 3.9 Dithioether Complexes of Ru 126. 3.9.1 Literature Data 127. 3.9.2 The Mononuclear Ru(II) Dithioether Complexes: Trans-RuCl2(BCyTE)2-2H20 and 7>a/75-RuCl2(BPhTE)2 129. 3.9.3 Dinuclear Ru(III)/Ru(III) Dithioether Complexes: [RuCl2(BETP)]2(//-Cl)2, [RuCl2(BPTP)]2(//-Cl)2, [RuCl2(BBTP)]2Cu-CI)2 and [RuCl2(BPeTP)]2(//-Cl)2 136. 3.10 Mer-RuCl3(DPS0)2(DPS0) 140. 3.10.1 Characterization of Mer-O'5-RuCl3(DPS0)2(DPS0) 141. 3.11 Macrocyclic Thioether, DMSO Complexes of Ruthenium 145. 3.11.1 3,6,9,14-Tetrathiabicyclo[9.2.1]tetradeca-ll,13-diene [L] 145. ix 3.11.2 RuCl 2(DMSO)(L) 146. 3.11.3 l,4,7,10-Tetrathiacyclododecane(12-S-4) 151. 3.11.4 [Ru(12-S-4)(DMSO)(H20)]fOTfJ2 151. 3.12 References for Chapter 3 155. Chapter 4 Preliminary In Vitro Examination of Water-soluble Ru Sulfoxide Complexes 4.1 Introduction 163. 4.2 Tumour Hypoxia, Radiotherapy and Progression 164. 4.3 Experimental 166. 4.3.1 Media 166. 4.3.2 Phosphate Buffer Saline Solution 167. 4.3.3 Methylene Blue Solution 167. 4.3.4 Tris-EDTA (TE) Solutions 168. 4.3.5 TNE Solutions 168. 4.3.6 TNE-Equilibrated Phenol 168. 4.3.7 Cell Preparation 168. 4.3.8 Atomic Absorption Spectroscopy 169. 4.3.9 Cell Incubation Procedures 170. 4.3.10 Cell Toxicity Assays Under Oxic and Hypoxic Conditions 171. 4.3.11 Cell Accumulation Assays 172. 4.3.12 DNA-Binding Assays 173. 4.4 In Vitro Studies of Five Ru Sulfoxides: Preliminary Results in CHO Cells... 174. 4.4.1 Toxicity of Ru Sulfoxides in CHO Cells under Oxic and Hypoxic Conditions.. 174. 4.4.2 Ruthenium Accumulation Under Oxic and Hypoxic Conditions 175. 4.4.3 DNA-binding Under Oxic and Hypoxic Conditions 178. 4.5 Conclusions 181. 4.6 References for Chapter 4 182. x Chapter 5 Metallation of Free-base Porphyrins 5.1 Introduction 184. 5.1.1 Metalloporphyrins as Hypoxic Radiosensitizers 184. 5.2 Ruthenium Porphyrins 185. 5.3 A N e w Route for the Insertion of Ruthenium into Selected Free-base Porphyrins 186. 5.4 Experimental 188. 5.4.1 Physical Techniques 188. 5.4.2 Synthesis of Precursors 188. 5.4.2.1 Na4[H 2TSPhP]-15H20 188. 5.4.2.2 [Ru(DMF) 6 ] [OTfJ 3 1 8 9 5.5 Synthesis of Ru(Porp)(CO) Complexes 189. 5.5.1 Na4[Ru(TSPhP)(CO)]-4H 20 189. 5.5.2 Ru(OEP)(CO)(THF) 190. 5.5.3 Ru(TPhP)(CO)(H 2 0) 190. 5.5.4 Ru(BPhP)(CO) 191. 5.5.5 Ru(TrPhPyNO)(CO) 191. 5.6 Results and Discussion 192. 5.6.1 Na4[Ru(TSPhP)(CO)]-4H 20 193. 5.6.2 Ru(OEP)(CO)(THF) 195. 5.6.3 Ru(TPhP)(CO)(py) 199. 5.6.4 Ru(BPhP)(CO) 201. 5.6.5 Ru(TrPhPyNO)(CO) 201. 5.7 Fluorescent Properties of Porphyrins 201. 5.7.1 Fluorescence Spectra of Selected R u Porphyrins 202. 5.8 Attempted Metallations 203. 5.9 Conclusions 206. 5.10 References for Chapter 5 207. x i Chapter 6 Conclusions and Recommendations for Future Work 6.1 General Remarks 211. 6.2 Sulfoxide and Thioether Complexes of Ruthenium 211. 6.3 Metallation of Selected Free-base Porphyrins 216. 6.4 Preliminary In Vitro Examination O f Water-soluble R u Sulfoxide Complexes .. 217. 6.5 References for Chapter 6 219. Appendices Appendix 1. Crystallographic Data A.221. Appendix 1.1 Crystallographic Data for frw?s-RuCl2(BESE)2 A.221. Appendix 1.2 Crystallographic Data for c/ \s-RuCl 2 (BBSE) 2 -EtOH A.223. Appendix 1.3 Crystallographic Data for c ;s -RuCl 2 (BCySE) 2 -EtOH- l / 3 M e O H A.227. Appendix 1.4 Crystallographic Data for c « - R u C l 2 ( B E S P ) 2 - E t O H - H 2 0 A.231. Appendix 1.5 Crystallographic Data for [RuCl (BESE) (H 2 0) ] 2 ( / / -C l ) 2 -H 2 0 A.233. Appendix 1.6 Crystallographic Data for [RuCl(BPSP)] 2 ( / / -Cl ) 3 -2H 2 0-2 .5CH 2 Cl 2 . . A.238. Appendix 1.7 Crystallographic Data for / r aws-RuCl 2 (BCyTE) 2 -2CH 2 Cl 2 A.245. Appendix 1.8 Crystallographic Data for / ra«s-RuCl 2 (BPhTE) 2 A.249. Appendix 1.9 Crystallographic Data for [RuCl 2 (BETP)] 2 ( / i -Cl ) 2 A.253. Appendix 1.10 Crystallographic Data for [RuCl 2 (BPTP) ] 2 (>Cl ) 2 A.255. Appendix 1.11 Crystallographic Data for Me7"-C /5-RuCl 3 (DPSO) 2 (DPSO) A.257. Appendix 1.12 Crystallographic Data for R u C l 2 ( D M S O ) ( L ) A.260. Appendix 1.13 Crystallographic Data for [Ru(12-S-4)(DMSO)(H 2 0)][OTfj 2 A.263. Appendix 1.14 Crystallographic Data for Ru(OEP)(CO)(THF) A.266. Appendix 1.15 Crystallographic Data for Ru(TPhP)(CO)(py) A.272. Appendix 2. Experimental for the Kinetic Studies of [RuCl(BPSP)] 2 ( / / -Cl) 3 A.276. Appendix 3. Thermal Gravimetric Analyses Plots A.277. Appendix 4. Accumulation Data o f R u in C H O Cells A.280. Appendix 5. DNA-binding Data of R u in C H O Cells A . 281. xii List of Tables Table 3.1. Selected Bond Lengths and Bond Angles for D M S O in the Gaseous and Solid States 65. Table 3.2. Selected Structural Data for Selected Transition M e t a l - D M S O Complexes.. 68. Table 3.3. The Sulfur-oxygen Stretching Frequencies of S-bonded, O-bonded and Bridging D M S O R u Complexes 73. Table 3.4. The Melting Points and vso (cm"1) for Disulfoxides 75. Table 3.5. IR Data (KBr) for v S o (cm"1) Free and v S o (cm"1) Bound, in Chelating Disulfoxide Complexes of R u 83. Table 3.6. Selected Bond Lengths (A) and Bond Angles (°) for Some trans-RuCl 2 (S -S ) 2 Complexes 85. Table 3.7. Selected Bond Lengths (A) and Bond Angles (°) for [ R u C l ( B E S E ) ( H 2 0 ) ] 2 ( / / - C l ) 2 H 2 0 , *raws-RuCl 2 (BESE) 2 and cis-R u C l 2 ( B E S E ) 2 86. Table 3.8. The Relative Configurations of the S-atoms in Chelating Disulfoxide 88. Complexes of Ru. Table 3.9. Selected Bond Lengths (A) and Bond Angles (°) o f cis-R u C l 2 ( B B S E ) 2 E t O H a n d c w - R u C l 2 ( B C y S E ) 2 E t O H - 1 / 3 M e O H 90. Table 3.10. Selected Bond Lengths (A) and Bond Angles (°) of cis-R u C l 2 ( B E S P ) 2 E t 0 H H 2 0 and c / s -RuCl 2 (BMSP) 2 98. Table 3.11. Titration data for [RuCl(BESE)(H 2 0) ] 2 ( / / -Cl ) 2 using N a O H 101. Table 3.12. Classes of Mixed-valence Complexes 106. Table 3.13. Selected Bond Lengths for the Two Asymmetric Units of [RuCl-(BPSP)] 2(//-C1) 3 115. Table 3.14. Selected Bond Angles for the Two Asymmetric Units of [RuCl(BPSP)] 2 ( / / -Cl) 3 115-Table 3.15. Titration data for [RuCl(BPSP)] 2 ( / / -Cl) 3 using N a O H 118. Table 3.16. Kinetic Data for the Hydration Reaction of [RuCl(BPSP)] 2 ( / / -Cl) 3 in H 2 0 125. xiu Table 3.17. Selected Bond Lengths (A) and Angles (°) for trans-RuCl 2 (BCyTE )2 -2CH 2 Ci2 and *ra«s-RuCl 2 (BPhTE) 2 133. Table 3.18. Selected Bond Lengths (A) and Bond Angles (°) for [RuCl2(BETP)]2Gu-Cl)2 and [RuCl 2 (BPTP)] 2 ( / / -Cl) 2 137. Table 3.19. Selected Bond Lengths (A) and Bond Angles (°) for mer-cis-[RuCl 3 (DPSO) 2 (DPSO)] and /wc/--[RuCl 3(DPSO)(DPSO)(MeOH)] 144. Table 3.20. Comparison of Selected Bond Angles (°) of L and R u C l 2 ( D M S O ) ( L ) . 149. Table 3.21. Comparison of Selected Bond Lengths (A) of L and R u C l 2 ( D M S O ) ( L ) 150. Table 3.22. Comparison of Selected Bond Angles (°) of 12-S-4 and [Ru(12-S-4) (DMSO)(H 2 0)] [OTfJ 2 152. Table 3.23. Comparison of Selected Bond Lengths (A) of 12-S-4 and [Ru(12-S-4) (DMSO)(H 2 0) ] [OTf] 2 154. Table 4.1. Water-soluble R u sulfoxide complexes studied in vitro 164. Table 4.2. Furnace parameters used in A A S for Ru, at X 265.9 nm 170. Table 5.1. Ru(Porp)(CO) species 187. Table 5.2. Selected Bond Angles and Lengths for Ru(OEP)(CO)(THF) 197. Table 5.3. Comparison of Selected Bond Lengths for Ru(TPhP)(CO)(py) 199. Table 5.4. Fluorescence wavelengths for selected Ru porphyrins 203. Table 5.5. Free-Base Porphyrins. 5,10,15,20-tetrapyridylporphyrin (TPyP), 5,10-bis(phenyl)-15,20-bis(4-pyridyl-N-oxide)porphyrin (BPhBPyNOP) , 5,10,15,20-tetramesitylporphyrin (TMP) , 5,10,15,20-tetra(pentafluorophenyl)-porphyrin (TPFPhP), 5,15-dibromo-10,20-bisphenylporphyrin (DBrBPhP), and protoporphyrin(IX)dimethylester ( P P I X D M E ) 205. Table A.1.1. Experimental Details for X-ray Crystal Structure of trans-R u C l 2 ( B E S E ) 2 A.221. Table A.1.2. Bond Angles (°) for / r a /M -RuCl 2 (BESE) 2 A.222. Table A . l 3. Bond Lengths (A) for / ra«s -RuCl 2 (BESE) 2 A.222. Table A.1 4. Atomic Coordinates for tomy-RuCl2(BESE)2 A.222. xiv Table A . l 5. Experimental Details for X-ray Crystal Structure of cis-R u C l 2 ( B B S E ) 2 E t O H A.223. Table A.1 6. Bond Angles (°) for c / s -RuCl 2 (BBSE) 2 -E tOH A.224. Table A . l 7. Bond Lengths (A) for c w - R u C l 2 ( B B S E ) 2 - E t O H A.224. Table A . l 8. Atomic Coordinates for c / s -RuCl 2 (BBSE) 2 -E tOH A.225. Table A . l 9. Hydrogen bond parameters for A - H . . . B interactions A.225. Table A . l 10. Experimental Details for X-ray Crystal Structure of cis-R u C l 2 ( B C y S E ) 2 E t O H - 1 / 3 M e O H A.227. Table A.1 11. Bond Angles (°) for c /s -RuCl 2 (BCySE) 2 -EtOH- l / 3 M e O H A.228. Table A . l 12. Bond Lengths (A) for c / s - R u C l 2 ( B C y S E ) 2 E t 0 H - l / 3 M e O H A.228. Table A . l 13. Atomic Coordinates for c«-RuCl 2 (BCySE) 2 -EtOH- l / 3 M e O H A.229. Table A . l 14. Hydrogen bond structural parameters for A - H . . . B interactions A.229. Table A.1 15. Experimental Details for X-ray Crystal Structure of cis-R u C l 2 ( B E S P ) 2 E t 0 H H 2 0 A.231. Table A . l 16. Bond Angles (°) for c / 5 - R u C l 2 ( B E S P ) 2 E t 0 H H 2 0 A.232. Table A.1 17. Bond Lengths (A) for c / s - R u C l 2 ( B E S P ) 2 E t O H - H 2 0 A.232. Table A . l 18. Atomic Coordinates for c / s - R u C l 2 ( B E S P ) 2 - E t 0 H - H 2 0 A.233. Table A . l 19. Hydrogen bond structural parameters for A - H . . . B interactions A.233. Table A . l 20. Experimental Details for X-ray Crystal Structure of [RuCl (BESE) (H 2 0) ] 2 ( / / -C l ) 2 -H 2 0 A.233. Table A . l 21. Bond Angles (°) for [RuCl (BESE) (H 2 0) ] 2 ( / / -C l ) 2 -H 2 0 A.234. Table A.1 22. Bond Lengths (A) for [RuCl(BESE)(H 2 0)] 2 Cu-Cl) 2 -H 2 0 A.235. Table A . l 23. Atomic Coordinates for [RuCl (BESE) (H 2 0) ] 2 ( / i -C l ) 2 -H 2 0 A.236. Table A . l 24. Hydrogen bond parameters for A - H . . . B interactions A.236. Table A.1 25. Experimental Details for X-ray Crystal Structure of [Ru(BPSP)Cl ] 2 ( / / -Cl ) 3 -2H 2 0-2 .5CH 2 Cl 2 A.238. Table A . l 26. Bond Angles (°) for [RuCl(BPSP)] 2 ( / / -Cl ) 3 -2H 2 0-2 .5CH 2 Cl 2 A.239. Table A . l 27. Bond Lengths (A) for [RuCl (BPSP)] 2 ( / / -Cl ) 3 -2H 2 0-2 .5CH 2 Cl 2 A.240. Table A . l 28. Atomic Coordinates for [RuCl (BPSP)] 2 ( / / -C l ) 3 -2H 2 0-2 .5CH 2 Cl 2 . . . A.241. xv Table A.1 29. Hydrogen bonds and C - H . . . C l /O interactions A.242. Table A.1 30. Experimental Details for X-ray Crystal Structure of trans-R u C l 2 ( B C y T E ) 2 - 2 C H 2 C l 2 A.245. Table A.1 31. Bond Angles (°) for / r aws-RuCl 2 (BCyTE) 2 -2CH 2 Cl 2 A.246. Table A . l 32. Bond Lengths (A) for / r aws-RuCl 2 (BCyTE) 2 -2CH 2 Cl 2 A.246. Table A . l 33. Atomic Coordinates for f raws-RuCl 2 (BCyTE) 2 -2CH 2 Cl 2 A.246. Table A . l 34. Hydrogen bond parameters for A - H . . . B interactions A.247. Table A . l 35. Experimental Details for X-ray Crystal Structure of trans-R u C l 2 ( B P h T E ) 2 A.249. Table A . l 36. Bond Angles (°) for *raws-RuCl 2(BPhTE) 2 A.250. Table A.1 37. Bond Lengths (A) for ^a«s -RuCl 2 (BPhTE) 2 A.250. Table A . l 38. Atomic Coordinates for *ra«s-RuCl 2 (BPhTE) 2 A.251. Table A.1 39. Experimental Details for X-ray Crystal Structure of [RuCl 2 (BETP)] 2 ( / / -Cl ) 2 A.253. Table A . l 40. Bond Angles (°) for [RuCl 2 (BETP)] 2 ( / / -Cl ) 2 A.254. Table A . l 41. Bond Lengths (A) for [RuCl 2 (BETP)] 2 ( / / -Cl ) 2 A.254. Table A.1 42. Atomic Coordinates for [RuCl 2 (BETP ) ] 2 Gu -Cl) 2 A.254. Table A . l 43. Experimental Details for X-ray Crystal Structure of [RuCl 2 (BPTP ) ] 2 Gu -Cl) 2 A.25 5. Table A.1 44. Bond Angles (°) for [RuCl 2 (BPTP)] 2 ( / / -Cl) 2 A.256. Table A . l 45. Bond Lengths (A) for [RuCl 2 (BPTP ) ] 2 Cu -Cl) 2 A.256. Table A . l 46. Atomic Coordinates for [RuCl 2 (BPTP)] 2 ( / / -Cl) 2 A.256. Table A . l 47. Experimental Details for X-ray Crystal Structure ofMer-Cis-R u C l 3 ( D P S O ) 2 ( D P S O ) A.257. Table A . l 48. Bond Angles (°) for Mer -C/s -RuCl 3 (DPSO) 2 (DPSO) A.258. Table A. 1 49. Bond Lengths (A) for M?r -Cw-RuCl 3 (DPSO) 2 (DPSO) A.259. Table A . l 50. Atomic Coordinates forMeA--C/5-RuCl 3(DPSO) 2(DPSO) A.260. Table A.1 51. Experimental Details for X-ray Crystal Structure of R u C l 2 ( D M S O ) ( L ) A.260. xvi Table A . l 52. Bond Angles (°) for R u C l 2 ( D M S O ) ( L ) A.261 Table A.1 53. Bond Lengths (A) for R u C l 2 ( D M S O ) ( L ) A.262 Table A.1 54. Atomic Coordinates for R u C l 2 ( D M S O ) ( L ) A.262 Table A . l 55. Experimental Details for X-ray Crystal Structure of [Ru(12-S-4) (DMSO)(H 2 0) ] [OTf j 2 A.263 Table A . l 56. Bond Angles (°) for [Ru(12-S-4)(DMSO)(H 2 0)][OTf] 2 A.264 Table A . l 57. Bond Lengths (A) for [Ru(12-S-4)(DMSO)(H 2 0)][OTfJ 2 A.264 Table A . l 58. Atomic Coordinates for [Ru(12-S-4)(DMSO)(H 2 0)][OTfJ 2 A.265 Table A . l 59. Hydrogen bonds and C-H. . . .O/F interactions A.266 Table A . l 60. Experimental Details for X-ray Crystal Structure of Ru(OEP)(CO)(THF) A.266 Table A.1 61. Bond Angles (°) for Ru(OEP)(CO)(THF) A.267 Table A . l 62. Bond Lengths (A) for Ru(OEP)(CO)(THF) A.269 Table A . l 63. Atomic Coordinates for Ru(OEP)(CO)(THF) A.270 Table A . l 64. Experimental Details for X-ray Crystal Structure of Ru(TPhP)(CO)(py) A.272 Table A . l 65. Bond Angles (°) for Ru(TPhP)(CO)(py) A.272 Table A . 1 66. Bond Lengths (A) for Ru(TPhP)(CO)(py) A.274 Table A . l 67. Atomic Coordinates for Ru(TPhP)(CO)(py) A.275 xvii List of Figures Figure 1.1. 1 = Cz's-diainininedichloroPt(II) (Cisplatin), 2 = Diammine(cyclobutane-l-l-dicarboxylato)Pt(II) (Carboplatin), 3 = Bis(acetato)amrrunedicUoro-(cyclohexylarmn ( J M 216), 4 = AmminedicMoro(2-methylpyridine)Pt(II) ( A M D 473) 4. Figure 1.2. Structures of deoxyguanosine (1) and deoxyadenosine (2) 7. Figure 1.3. Central structure of a R u porphyrin 9. Figure 1.4. Abbreviated structures of czs -RuCl 2 (DMSO) 3 (DMSO) and trans-R u C l 2 ( D M S O ) 4 , respectively. (S = S-bound D M S O and O = O-bound D M S O ) 10 Figure 1.5. Dissolution behaviour of (1) czs -RuCl 2 (DMSO) 4 and (2) trans-R u C l 2 ( D M S O ) 4 in aqueous solutions. (S = S-bound D M S O ; O = O-bound D M S O ) 12 Figure 1.6. Structures of reaction products of cis- and / r a«s -RuCl 2 (DMSO) 4 with 2-deoxyguanosine. (S = S-bound D M S O and 2'-dG = deoxyguanosine).... 14 Figure 1.7. Dissolution behaviour of (1) /wer -RuCl 3 (DMSO) 2 (DMSO) and (2) Zram-[(DMSO) 2 H] + [RuCl 4 (DMSO) 2 ]~ in aqueous solutions. (S = S-bound D M S O and O = O-bound D M S O ) 15 Figure 1.8. Abbreviated structures of /wer--RuCl 3(DMSO) 2rm and Na[zraws-RuCl 4 (DMSO)(Im)] . (S - S-bqund D M S O , O = O-bound D M S O and Im = imidazole) 16 Figure 1.9. Structures of 2-nitroimidazole (R = C H 2 C H O H C H 2 O C H 3 = misonidazole, R = C H 2 C ( 0 ) N H C H 2 C H 2 O H = etanidazole), 4-nitroimidazole (R = H) and 5-nitroimidazole (R = C H 2 C H 2 O H = metronidazole) 18 Figure 1.10. Structure of disulfoxides. ((« = 2) B M S E , R = M e ; B E S E , R = Et; B P S E , R = Pr; B B S E , R = B u ; BPeSe, R = Pe; B H S E , R = He; B C y S E , R = Cy; B P h S E , R = Ph and (n = 3) B M S P , R = M e ; B E S P , R = Pr; B P S P , R = Pr; B 'PSP, R = 'Pr; B B S P , R = B u ; BPeSP, R = Pe; BPhSP, R = Ph) 20 xviii Figure 2.1. Diagram showing the labelling of the H-atoms of 1,2-bis(cyclohexylthio)ethane 41 Figure 3.1. Structure (1) and resonance forms (2) o f a sulfoxide. 64 Figure 3.2. Structures of catena-poly^is-Ch-trans-CH^Snil^^-O.O'-meso-B P S E ) (1) and [SnCl -cw-Ph 3 ] 2 0 -0 ,0 ' - r ac - l ,2 -b i s (« -propylsulfinyl)ethylene) (2) 77 Figure 3.3. Structures containing / i -BPhSE 78 Figure 3.4. (1) R = H , (S^-bis(p-tolylsulfinyl)methane; and R = C H 3 , (SS)-2,2-bis-/>tolylsulfinylpropane. (2) (S^-l^-bis^-tolylsulfinytybenzene 79 Figure 3.5. Structures of dios ((2i?3/?)-2,3-0-isopropylidene-2,3-dihydroxy-l,4-bis(methylsulfinyl) butane monohydrate) (1), bdios ((2R3R)-2,3-0-isopropylidene-2,3,dihydroxy-1,4-bis(benzylsulfinyl) butane monohydrate (2), and ddios ((2/?3i?)-2,3-dihydroxy-l,4-bis(methylsulfinyl) butane (3)... 80 Figure 3.6 General structure for (1) c / ' s -RuCl 2 (BMSP) 2 and c / s -RuCl 2 (BESE) 2 and (2) fra«.s-RuCl 2 (BMSE) 2 and / r a«5 -RuCl 2 (BPSE) 2 ; S A S = chelating disulfoxide 82 Figure 3.7. A n O R T E P drawing of toms-RuCl2(BESE)2 with 50 % probability thermal ellipsoids shown (crystal data given in Appendix 1.1). For the data of Table 3.8, S(4) and S(3) are taken as trans to S(2) and S( l ) , respectively. 87 Figure 3.8. A n O R T E P drawing of the A configuration of cis-R u C l 2 ( B B S E ) 2 - E t O H with 50 % probability thermal ellipsoids shown; H -atoms (except for that of E tOH) are omitted for clarity 91 Figure 3.9. A n O R T E P drawing of the A configuration of cis-R u C l 2 ( B C y S E ) 2 - E t O H l / 3 M e O H with 50 % probability thermal ellipsoids shown; H-atoms are omitted for clarity (crystal data given in Appendix 1.3) 94 Figure 3.10. A n O R T E P drawing of the A configuration o f cis-R u C l 2 ( B E S P ) 2 - E t O H - H 2 0 with 50 % probability thermal ellipsoids shown; H-atoms are omitted for clarity (crystal data given in Appendix 1.4) 96 Figure 3.11. The unit cell o f c z s - R u C l 2 ( B E S P ) 2 E t 0 H H 2 0 showing the E t O H and H 2 0 solvate molecules (crystal data given in Appendix 1.4) 97 xix Figure 3.12. A n O R T E P drawing of [RuCl(BESE)(H 2 0 ) ] 2 Gu -Ci) 2 with 50 % probability thermal ellipsoids (crystal data given in Appendix 1.5) 103. Figure 3.13. Diagram of [RuCl(BESE)(H 2 0)] 2 ( / / -Cl ) 2 showing the H 2 0 solvate (crystal data given in Appendix 1.5) 104. Figure 3.14. Structures of SS-chiraphos and RR-diop 107. Figure 3.15. Structures o f a-pyridone (1), 1-methylthymine (2) and creatinine (3).. 109. Figure 3.16. Structures of [(NH3)4Pt 2(C5H4NO) 2] 2(N03)5-H 20 (1), [(NH 3) 2Pt(C6H7N 20 2) 2Pt(NH 3) 2](N03) 2-H 20(2), [Pt 2(NH 3)4(C4H7N 30) 2](N03) 2 (3), and [ ( N H 3 ) 2 P t ( C H 3 C O N H ) 2 P t ( N H 3 ) 2 ] 4 -( N O 3 ) 1 0 - 4 H 2 O (4) 1 0 9 Figure 3.17. The *H N M R (200 M H z , CDC1 3 ) spectrum showing the paramagnetic shift caused by [RuCl(BPSP)] 2 ( / / -Cl) 3 (8.8 x 10" 2 M) of the residual C H C b relative to that of the reference CHCI3. (A = residual C H C 1 3 in CDC1 3 , and B = residual CHC1 3 peak shifted by [RuCl(BPSP)] 2 ( / / -Cl) 3 ) H I . Figure 3.18. A n O R T E P drawing of one of the [RuCl(BPSP)] 2 ( / / -Cl) 3 units with 50 % probability thermal ellipsoids shown; H-atoms are omitted for clarity (crystal data given in Appendix 1.6) 113. Figure 3.19. A diagram of [RuCl(BPSP)] 2 ( / / -Cl) 3 showing short H-bonds connecting two asymmetric units via four H 2 0 molecules (the C H 2 C 1 2 atoms are not shown) (crystal data given in Appendix 1.6) 114. Figure 3.20. Proposed mechanism for the behaviour of [RuCl(BPSP)] 2 ( / / -G) 3 in aqueous solution; the two Ru(II)/Ru(III) centres are not distinguished crystallographically, and loss of the chlorides is assumed to be from the terminal positions (the propyl groups of B P S P are omitted for clarity) 117. Figure 3.21. J H N M R spectra of equilibrated [RuCl(BPSP)] 2 (>Cl) 3 in D 2 0 (after 2 h) (A) and immediate spectrum of [RuCl(BPSP)] 2 ( / / -Cl) 3 (2.02 x 10"3 M ) after addition of two or three equivalents of A g N 0 3 in D 2 0 (B) 118-xx Figure 3.22. A representative spectrum of the U V - V i s spectral changes (200-600 nm region, 1 cm cell) o f [RuCl(BPSP)3 2(//-Cl) 3 (2.96 x 10"4 M ) in an aqueous solution at 27 °C as a function of time (half life ti/2 = 120 s, for the pseudo-first order process); isosbestic points are observed at the noted wavelengths 120. Figure 3.23. Absorption spectral changes at X = 362 nm as a function of time for the reaction of [RuCl(BPSP ) ] 2 C"-Cl) 3 in H 2 0 (55.6 M ) at 27 °C 121. Figure 3.24. A representative rate-plot analyzed for a first-order dependence on [RuCl(BPSP)] 2 (/^-Cl) 3 ; At and A*, represent the absorption at 362 nm at times t and oo, respectively, at 27 °C 121-Figure 3.25. The dependence of the pseudo-first-order rate constant, k o b s , on [ H 2 0 ] at 27 °C; including the kobs values obtained from reactions run in 0.25 M aqueous NaCI and 0.1 M aqueous toluene-4-sulfonic acid (in H 2 0 / C H 3 C N solutions) 122. Figure 3.26. The dependence of the second-order rate constant k i on [RuCl(BPSP)] 2 [Cu-Cl) 3 ] in H 2 0 (22.2 M ) at 27 °C. (Ru = [RuCl(BPSP) ] 2 C"-Cl) 3 ) I 2 3 -Figure 3.27. Erying plot for the temperature dependence of the rate constant k i for the reaction of [RuCl(BPSP)] 2 ( / / -Cl) 3 (2.96 x IO"4 M ) with H 2 0 (22.2 M ) 123. Figure 3.28. A n O R T E P drawing of / ra«s-RuCl 2 (BCyTE) 2 -2CH 2 Cl 2 with 50 % probability shown; H-atoms are omitted for clarity (the C H 2 C 1 2 molecules are not shown) (crystal data are given in Appendix 1.7) 131. Figure 3.29. The unit cell o f / ra«s-RuCl 2 (BCyTE) 2 -2CH 2 Cl 2 showing the 2 C H 2 C 1 2 solvate molecules (crystal data given in Appendix 1.7) 132. Figure 3.30. Resonance structures of a phenyl ring with a thioether 134. Figure 3.31. A n O R T E P drawing of zraws-RuCl 2(BPhTE) 2 with 50 % probability thermal ellipsoids shown; H-atoms are omitted for clarity (crystal data are given in Appendix 1.8) 135. xxi Figure 3.32. A n O R T E P drawing of [RuCl 2 (BETP)] 2 ( / / -Cl ) 2 with 5 0 % probability thermal ellipsoids shown; H-atoms are omitted for clarity (crystal data are given in Appendix 1.9) 138. Figure 3.33. A n O R T E P drawing o f [RuCl 2 (BPTP)] 2 ( / / -Cl ) 2 with 5 0 % probability thermal ellipsoids shown. The H-atoms are omitted for clarity (crystal data are given in Appendix 1.10) 139. Figure 3.34. Structure of/wer-[RuCl 3 (DPSO)(DPSO)(MeOH)]; O and S are O-and S-bonded D P S O , respectively 140. Figure 3.35. A n O R T E P diagram of wer-czs-[RuCl 3 (DPSO) 2 (DPSO)] showing 50 % thermal ellipsoids; the H-atoms are omitted for clarity (crystal data are given in Appendix 1.11) 143. Figure 3.36. 3,6,9,14-Tetrathiabicyclo[9.2.1]tetradeca-ll,13-diene (L), and 1,4,7,10-tetrathiacyclododecane (12-S-4); H-atoms omitted 146. Figure 3.37. A n O R T E P diagram of R u C l 2 ( D M S O ) ( L ) showing 50 % thermal ellipsoids; the H-atoms are omitted for clarity (crystal data are given in Appendix 1.12) 148. Figure 3.38. A n O R T E P diagram of [Ru(12-S-4)(DMSO)(H 2 0)][OTf] 2 showing 50 % thermal ellipsoids; the H-atoms are omitted for clarity (crystal data are give in Appendix 1.13) 153. Figure 4.1. The absence of toxicity of [RuCl(BPSP)] 2 ( / / -Cl) 3 in C H O cells 174. Figure 4.2. Accumulation o f R u (A) and Ru-DNA-binding ( B ) in C H O cells after 2 h incubation with [Ru(12-S-4)(DMSO)(H 2 0)][OTf] 2 (1), [RuCl(BPSP)] 2 ( / / -Cl) 3 (2), [RuCl(BESE)(H 2 0)] 2 ( /z-Cl) 2 (3), [RuCl(BPSE)(H 2 0 ) ] 2 ( / / -Cl) 2 (4), [RuCl(BBSE)(H 2 0 ) ] 2 ( / / -Cl) 2 (5) 176. xxii Figure 4.3. Accumulation (A) and DNA-binding (B) with 0.5 m M R u . l = cis-R u C l 2 ( D M S O ) 4 , 2 = / ra«s-RuCl 2 (DMSO) 4 , 3 = c w - R u C l 2 ( T M S O ) 4 , 4 = * r a A M - R u C l 2 ( B M S E ) 2 , 5 = c / s -RuCl 2 (BESE) 2 , 6 = / ra«s-RuCl 2 (BPSE) 2 , 7 = c w - R u C l 2 ( B M S P ) 2 , 8 = [Ru(12-S-4)(DMSO)(H 20)][OTfJ 2 , 9 = [RuCl(BPSP ) ] 2 C"-Cl) 3 , 10 = [RuCl (BESE)(H 2 0 ) ] 2 (>Cl ) 2 , 11 = [RuCl(BPSE)(H 2 0 ) ] 2 ( / / -Cl) 2 , 12 = [RuCl(BBSE)(H 2 0 ) ] 2 ( / / -Cl) 2 179. Figure 5.1. Ru(II)(Porp)(CO) species, showing the numbering system 187. Figure 5.2. A n O R T E P diagram of Ru(OEP)(CO)(THF) showing 50 % thermal ellipsoids; the H-atoms are omitted for clarity (crystal data are given in Appendix 1.14) 196. Figure 5.3. Structures of (1) = T E M P O = 2,2,6,6-tetramethylpiperidine-l-oxyl, (2) = D A P O = trans 3,4,-diamino-2,2,6,6-tetramethyl piperidine-l-oxyl, (3) = T E M P I C O L - 2 = 4-hydroxy-4-(2-picolyl)-2,2,6,6-tetramethylpiperidine-1 -oxyl 198. Figure 5.4. A n O R T E P diagram of Ru(TPhP)(CO)(py) showing 50 % thermal ellipsoids; the H-atoms have been omitted for clarity (crystal data are given in Appendix 1.15) 200. Figure 5.5. Fluorescence spectrum of Na4[Ru(TSPhP)(CO)]4H 20. The excit-ation wavelength was 414 nm and emission was measured at 641 and 704 nm 202. Figure 6.1. Structural diagram of cw-RuCl 2(BPhSP)(l-(phenylthio)-3-(phenylsulfinyi)propane) 214. Figure 6.2. A potentially water-soluble disulfoxide 215. Figure A.1.1. Stereoview of c ; s -RuCl 2 (BBSE) 2 -E tOH A.226. Figure A.1.2. Stereoview of c*s -RuCl 2 (BCySE) 2 -E tOH- l /3MeOH A.230. Figure A.1.3. Stereoview of [RuCl(BESE)(H 2 0 ) ] 2 ( / / -Cl) 2 -H 2 0 A.237. Figure A.1.4. Stereoview o f [RuCl(BPSP)] 2 ( / / -Cl) 3 -2H 2 0 -2 .5CH 2 Cl 2 A.244. Figure A.1.5. Stereoview of / ra«s-RuCl 2 (BCyTE) 2 -2CH 2 Cl 2 A.248. Figure A. 1.6. Stereoview of / ra«s-RuCl 2 (BPhTE) 2 A.252. Figure A.1.7. Stereoview of Ru(OEP)(CO)(THF) A.271. xxiii Figure A.3.1. T G A of [RuCl(BESE)(H 2 0) ] 2 ( / / -Cl ) 2 A.277 Figure A.3.2. T G A of [RuCl(BPSP)] 2 ( / / -Cl) 3 A.278 Figure A.3.3. T G A of Na4(H2TSPhP)- 1 5 H 2 0 A.279 Figure A.3.4. T G A of Na4[Ru(TSPhP)(CO)]4H 20 A.279 Figure A.4.1. Accumulation of R u in C H O cells after a 2 h incubation with [Ru(12-S-4)(DMSO)(H 2 0)][OTfj 2 (1), [RuCl(BPSP)] 2 ( / / -Cl) 3 (2), [RuCl(BESE)(H 2 0 ) ] 2 Cu -Cl ) 2 (3), [RuCl(BPSE)(H 2 0)] 2 ( / / -Cl ) 2 (4), [RuCl (BBSE)(H 2 0) ] 2 ( / / -C l ) 2 (5) A - 2 8 0 Figure A .5.1. Ru-DNA-binding after incubation with [Ru(12-S-4 ) ( D M S 0 ) ( H 2 0 ) ] [ 0 T f J 2 (1), [RuCl(BPSP)] 2Cu-Cl) 3 (2), [RuCl (BESE)(H 2 0) ] 2 ( / / -C l ) 2 (3), [RuCl(BPSE)(H 2 0)] 2 ( / / -Cl ) 2 (4), [RuCl (BBSE) (H 2 0 ) ] 2 C" -C l ) 2 (5) A - 2 8 1 xxiv L i s t o f A b b r e v i a t i o n s A b b r e v i a t i o n M e a n i n g A A S atomic absorption spectroscopy A M P adenine monophosphate A P T attached proton test aq. * - aqueous B M S B l,4-bis(methylsulfinyl)butane B M S P l,3-bis(methylsulfinyl)propane B E SP 1,3 -bis(ethylsulfinyl)propane B P S P l,3-bis(propylsulfinyl)propane (all alkyl groups are n unless otherwise indicated) B 'P SP 1,3 -bis(z'-propylsulfinyl)propane B B S P l,3-bis(butylsulfinyl)propane BPeSP l,3-bis(pentylsulfinyl)propane BPhSP l,3-bis(phenylsulfinyl)propane B M S E 1,2-bis(methylsulfinyl)ethane B E S E 1,2-bis(ethylsulfinyl)ethane B P S E 1,2-bis(propylsulfinyl)ethane B B S E l,2-bis(butylsulfinyl)ethane B P e S E 1,2-bis(pentylsulfinyl)ethane B H S E l,2-bis(hexylsulfinyl)ethane B C y S E 1,2-bis(cyclohexylsulfinyl)ethane B P h S E 1,2-bis(phenylsulfinyl)ethane B P h T E l,2-bis(phenylthio)ethane B C y T E l,2-bis(cyclohexylthio)ethane B E T P l,3-bis(ethylthio)propane B P T P l,3-bis(propylthio)propane B B T P l,3-bis(butylthio)propane B P e T P l,3-bis(pentylthio)propane br broad ( N M R and IR) XXV B . M . Bohr magneton b. p. boiling point B P P dianion of 5,15 -bis(phenyl)porphyrin C H O Chinese hamster ovary (a cell line) C O S Y correlated spectroscopy G M P guanine monophosphate 2D 2-dimensional ( N M R ) D M S O dimethylsulfoxide coordinated via the S-atom D M S O dimethylsulfoxide coordinated via the O-atom D P S O diphenylsulfoxide E I electron impact ionization e.s.d. estimated standard deviation F A B fast atom bombardment H E P E S N-2-hydroxylethylpiperazine-N'-2-ethane sulfonic acid H E T C O R heteroatom correlation spectroscopy m. p. melting point M A L D I matrix assisted laser desorption ionization O O-bonded Q D optical density O E P dianion of 2,3,7,8,12,13,17,18-octaethylporphyrin O R T E P Oakridge Thermal Ellipsoid Program O T f triflate (CF3SO3") P B S phosphate buffered saline P E plating efficiency Porp porphyrin dianion r. t. room temperature r. p. m. revolutions per minute S S-bonded SDS sodium dodecylsulfate xxvi tris(hydroxymethyl)arrunomethane+ethylenediarm acid thermal gravimetric analysis tetramethylene sulfoxide T E + 150 m M NaCI dianion of 5,10,15,20-tetraphenylporphyrin dianion of 5,10,15,20-tetrakis(4-sulfonato)phenylporphyrin dianion of 5,10,15-triphenyl-20-(4-pyridyl-^-oxide)porphyrin molar conductivity magnetic moment xxvii Acknowledgements I would very much like to thank my supervisors Brian James and Kirsten Skov for their encouragement, guidance, patience and support over the years and for providing myself the opportunity to work with them. Many thanks to the departmental services, especially Marietta Austria, Peter Borda, Lianne Diarge, Steve Rak and the late Steve Rettig and from the B C Cancer Research Centre Hans Adomat, Jennifer Dekker, Manuel Gierth and Haibo Zhou. I would also like to thank Joanne Crocker, Lionel Harrison, Peter Wassell and Dana Zendrowski. I thank all past and present members of the James Gang. Special thanks go to Bianca Kuipers, Heather Dobson, Annie Schnyder, Krystyna Skupinska and Gay and Ipi Yuyitung for the hiking, kayaking and skiing trips and o f course, the coffee breaks. I would also like to thank Janet Gamelin, H o a L y , Matt Netherton, Dave Vocadlo, Alex Wong, James Yee, Eliza Jang, Asa Sophia t imms Maglio, Trish M a h , Debbie Sangra and Lesia Zorniak. Most importantly I must thank my father, mother, Lil l ian and R o d for all their love and support over the years. Thanks for the many "Hello, how are you today?" -Larry Weiler. I dedicate this thesis to the memory of Steve Rettig. xxviii Chapter 1 Chapter 1 Introduction 1.1 Preamble Prior studies in this laboratory on sulfoxides, particularly chiral sulfoxides, were mainly focussed on the potential of complexes of ruthenium(II) as catalysts for homogeneous hydrogenations.1 Recently, the Trieste group reported that cis- and /ra/?s-RuCl2(DMSO) 4 possess mutagenic properties, exhibit anti-cancer activity and interact with nucleobases o f D N A (see Section 1.4). Previous studies from our laboratories had utilized such complexes as precursors for the synthesis of Ru(II)-sulfoxide-nitroimidazole complexes as potential radiosensitizers (see Section 1.4.3). Cancer is a progressive disease in which malignant tissue can be distinguished from normal tissue by its property o f abnormal, uncontrolled and invasive growth. 2 Early stages o f cancer may be treated by a combination of surgery and radiotherapy, but more advanced stages require chemotherapy.2 Cancer occurs in many forms depending on the part of the body and the type of cells involved. For example, most tumours occur as a localized grouping o f cancerous cells, while in others such as leukemia, the malignant cells are widely dispersed in the blood stream.3 Chemotherapy involves directing toxic agents towards the malignant cells. Chemotherapy for lung, breast and colorectal cancers, which account for approximately 50 % of all cancer deaths in the industrialized Western world, usually results only in prolonged survival. 2 One of the major problems of chemotherapy is that chemotherapeutic agents do not exhibit selective toxicity for cancer cells over normal cells. Understanding the mechanisms of tumour biology, cellular processes involving tumour cells, and the interaction o f 1 References on page 24 Chapter 1 chemotherapeutic agents with cancer cells wil l greatly improve treatment modalities of this disease. Chemotherapeutic agents are primarily organic compounds or natural products including alkylating agents, antibiotics and alkaloids. 4 Inorganic compounds were not extensively studied as anti-cancer agents until the discovery of cisplatin (Figure 1.1).5 Since this discovery, there has been substantial interest in the development of inorganic complexes as potential anti-tumour agents but progress has been slow. 1.2 Development of Platinum Chemotherapeutic Agents Cisplatin has a proven efficacy against a wide variety of malignancies and is used in the treatment of solid tumours such as ovarian and testicular cancer, as well as head and neck, lung and cervical carcinomas.6 Breast cancer is also recognized as a potential target for cisplatin therapy.6 Furthermore, it is also used in combination chemotherapy for a variety o f other malignancies.6 Extraordinarily good results were attained in the treatment of testicular cancer.6 Moreover, in ovarian cancer, remission rates of up to 50 % have been documented.6 However, because of the compound's toxicity (e.g. nausea, ear damage, vomiting, loss of sensation in hands and kidney toxicity), 7 research has been on-going to develop analogues which are less toxic. Sherman and Lippard have reported evidence that D N A is the cellular target of Pt drugs from studies of their incubation with D N A and interaction with lysogenic strains o f E. co//',8 while Bloemink and Reedijk have presented reviews o f the mechanism o f cisplatin action and DNA-binding . 7 ' 9 The key elements of the mechanism appear to be: (1) controlled hydrolysis, transport and binding of cisplatin to D N A ; (2) a specific binding at neighbouring 2 References on page 24 Chapter 1 guanine bases, specifically at the N 7 atoms; and (3) a specific distortion of D N A , altering interactions with proteins. Whitehead and Lippard have reported on the role of structure-specific proteins that mediate cisplatin cytotoxicity. 1 0 Oldenberg and Los reviewed studies showing that cellular damage produced by cisplatin provokes a programmed response that results in the activation of some genes, the inactivation of others, major shifts in cellular metabolism, and cell cycle progression, eventually triggering apoptosis.6 They also summarize studies which show that proliferating cells are much more sensitive to the toxicity of the drug, indicating that cell-cycle associated events are involved in cisplatin cytotoxicity. 6 A second generation analogue of cisplatin, carboplatin 1 1 (Figure 1.1), offers ( reduced toxicity together with therapeutic activity similar to that of cisplatin. The complex bis(acetato)amminedichloro(cyclohexylamine)Pt(IV) ( J M 216) 1 2 is the first orally bioavailable Pt complex and is currently in Phase II clinical trials (Figure 1.1). This novel Pt(IV) complex has demonstrated promising oral activity against a variety of murine and human tumour models, and in vitro cytotoxic effects against a tumour line that exhibits intrinsic resistance to cisplatin. 1 2 This complex was designed primarily to improve quality o f life during Pt-based chemotherapy. 3 References on page 24 Chapter 1 OOCCH3 H 3 N " " C l H 3 N > t . 0 0 C ^ . H 3 N ^ ^ O O C ^ ^ ^ 1 2 3 4 Figure 1.1. 1 = C/s-diamminedichloroPt(II) (Cisplatin), 2 = Diammine(cyclobutane-l-l-dicarboxylato)Pt(II) (Carboplatin), 3 = Bis(acetato)amminedichloro-(cyclohexylamine)Pt(IV) ( J M 216), 1 2 4 = Amminedichloro(2-methylpyridine)Pt(II) ( A M D 473). 1 3 Recently, the complex amminedichloro(2-methylpyridine)Pt(II) ( A M D 473) 1 3 (Figure 1.1) has been developed as a third generation Pt complex designed to circumvent cellular resistance in vitro and enhance in vivo activity. In recognition o f an increasing awareness of the mechanisms by which tumours might become resistant to cisplatin (e.g. cytoplasmic detoxification by cellular thiols or increased D N A repair/tolerance of P t - D N A adducts) in the clinic, A M D 473 was designed primarily to prevent thiol-mediated drug resistance by sterically hindering its reaction with glutathione by introduction of steric bulk (2-methylpyridine) at the Pt centre.1 3 This complex reached Phase I clinical trials. Day and Sadler et al. have reported that iodo complexes of Pt(IV) show promise in the design of oxygen-independent photoactivated metallodrugs. 1 4 Photoactive analogues o f cisplatin, particularly />vms,c/s-[Pt(OCOCH3)2i2(15N-en)] was shown to react with guanosine 5-monophosphate upon exposure to visible light to give [Pt(5'-GMP-7Y7)2(en)] 2 +. 1 4 b Development of new generation Pt complexes has taken into consideration these characteristics: charge, lipophilicity, stability in the gastric environment, oral bioavailablity, a 4 References on page 24 Chapter 1 cis arrangement of labile ligands (this permits binding and intrastrand cross-linking o f D N A ) and a limited toxicity to the host organism. 1 5 A n exception, work by Farrell et al., has shown that certain trans and di- and tri-nuclear Pt complexes show anti-tumour activity with a mechanism of action that is different from that of cisplatin. One of these, a tri-nuclear Pt complex is in Phase I trials. 1 6 1.3 Ruthenium Chemotherapeutic Agents The potential of ruthenium complexes as anti-cancer agents has been extensively explored along with fundamental studies on their interactions with molecules of biological interest (e.g. nucleic acids). 1 7 ' 1 8 One difference between Pt-based and Ru-based anti-tumour agents is that R u complexes are usually octahedral, six-coordinate as opposed to the square-planar, four-coordinate geometry of Pt(II) complexes. The two additional coordination sites for R u complexes may allow new modes of binding to nucleic acids and, with some ligands, provide for chirality in the complexes and so in their interactions with the D N A helix. 1 9 O f note, Milkevitch et al. have reported on mixed-metal Ru(II)/Pt(II) complexes as DNA-binding . 20 agents. The sequence of events that R u complexes undergo following injection into a living body have been elucidated: 2 1 1. R u binds to transferrin and is selectively distributed to transferrin-rich receptor tissues (of note, high amounts of transferrin receptors are found on tumour cells 2 2). 2. R u exhibits a low capacity of exchange reactions but binds to molecules o f biological interest (e.g. nucleic acids). 3. R u exhibits a high D N A binding affinity. 5 References on page 24 Chapter 1 R u complexes have been studied in comparison to cisplatin in order to improve the efficacy of these metal-containing drugs by reducing toxicity and increasing potency. 1 8 Several studies show that a number of R u complexes serve as bacterial mutagens, and so indicate that some R u complexes are capable of damaging genetic material. 1 8 A s well, studies have shown that ammine complexes of both Ru(II) and Ru(III) bind to D N A in a fashion analogous to that of cisplatin. 2 3 Keppler et al. have studied the anti-tumour activities o f a series of imidazole complexes of R u including [ImH] 2 [RuImCl 5 ] , 2 4 [ ImH][RuIm 2 Cl 4 ] 2 2 ' 2 5 and other [HL][RuL 2Cl4] species (L = e.g. imidazole derivatives such as 1-butyl, pyrazole and derivatives such as 3,5-diethyl, and indazole and derivatives such as 1-methyl), with clinical trials planned for [IndH][RuInd 2 Cl 4 ]. 2 6 This compound is active against transplantable tumours and tumours induced by intrarectal application of a carcinogen and shows higher anti-tumour activity than that of [ImH][RuIm 2 Cl 4 ] . 2 7 O f note, Mestroni et al. have synthesized and characterized the R h analogue [ImH][RhIm 2Cl 4], but there was no relevant anti-tumour activity. The dominant mode of pentaammineruthenium coordination to purine nucleosides with a keto group at the 6-position is at the N 7 position on the imidazole ring (Figure 1.2(1)).18 Attachment at the N ( 7 ) o f deoxyguanosine, which is thought to be the initial point of attack of the Pt pharmaceuticals on D N A , has been shown to occur for ammineruthenium(II and III) ions. 2 9 Clarke and Stubbs have reviewed the interactions o f "metallopharmaceuticals", including R u species, with D N A . 3 0 6 References on page 24 Chapter 1 Figure 1.2. Structures of deoxyguanosine (1) and deoxyadenosine (2). Advantage can be taken of the ready availability of both the Ru(II) and Ru(III) oxidation states under physiological conditions and the general inertness of these ions toward substitution, when coordinated to N-ligands. 1 8 The chemical properties of Ru(II) vs. Ru(III) suggest that ammine Ru(III) ions should be far less active toward binding nitrogen ligands (e.g. nucleic acids) than analogous Ru(II) complexes. 1 8 Thus, a relatively inactive and ideally non-toxic Ru(III) complex might be activated toward binding to nitrogen heterocycles by in vivo reduction. 2 1 For example, a complex such as c « - R u ( H 2 0 ) 2 ( N H 3 )4 2 + readily substitutes its water molecules to bind nitrogen ligands in solution whereas analogous Ru(III) complexes are more substitution inert. 1 8 Thus a complex such as c / s -RuCkCNFkV, when introduced into an organism, might remain largely intact and so fairly innocuous until reduced to yield the "active" Ru(II) form, c/5-Ru(H 20) 2(NH3) 4 2 + which could then bind to critical cellular components and induce toxicity. 1 8 This leads to the important proposal that some Ru(III) complexes could be administered as prodrugs which should be relatively non-toxic until activated by reduction, 2 1 and indeed higher cytotoxicity and DNA-binding o f [ImrflfRuIn^CLt] and cw-piu(NH3)4Cl2]Cl were observed in human cervical cancer cells (HeLa) at low oxygen levels. 3 1 This observation is consistent with the "activation-by-reduction" hypothesis where the Ru(II) should be more prevalent inside hypoxic tumours. 3 1 7 References on page 24 Chapter 1 1.3.1 Dinuclear Ru(II)/Ru(III) Complexes The discovery of cisplatin as an effective anti-tumour agent was made after the observation that cisplatin induced filamentous growth in E. coli.5 The mechanism of cisplatin anti-tumour activity is based on cisplatin binding to D N A , modification o f the D N A template and selective inhibition of D N A replication. 6" 1 0 One indication of D N A damage or error-prone repair in bacteria is filamentous growth. Thus the testing of filamentation in bacteria provides a useful indication of possible mutagenicity or toxicity of the complex. Durig et al. extended the studies of filamentous growth of E. coli by Pt complexes to include R u and Pd complexes. 3 2 These studies showed that / a c - R u ( N H 3 ) 3 C l 3 induced an amount o f filamentous growth at concentrations comparable to that of cisplatin (6 pg/mL), while significantly higher concentrations of K 2[RuCl5(H 20)] were needed to induce the same amount of growth. The Pd complexes, however, induced only minimum filamentous growth compared to that of the R u complexes and cisplatin, and as well were toxic at relatively high concentrations. Gibson et al. studied a series of dinuclear, mixed-valence complexes o f R u of the general formula R u 2 ( N H 3 ) 6 X 5 - H 2 0 (where X = C l , Br , or I) for their ability to induce filamentation in E. coli,33 again for comparison with cisplatin data. The chloro (10" 4to 10" 5 M) and bromo ( I O 5 M ) complexes were at least as effective as cisplatin in inducing filamentation in E. coli. The bromo analogue was more effective than the chloro analogue and cisplatin, while the iodo analogue (10"3 to 10"4 M ) was the least effective in inducing filamentous growth. This effect o f filamentation is reversible on prolonged incubation and the presence of 0.43 M D M S O was effective in inhibiting filamentous 8 References on page 24 Chapter 1 growth. 3 3 Ion-exchange studies suggested that the chloro complex is doubly charged with three bridging chlorides, [Ru2(NH3)6Cl 3 ]Cl2H 2 0. 3 4 Hughes et al. have structurally characterized [Ru2(NH3)6Cl3][BPh4] 2 which has electronic spectra and magnetic properties identical to those of the chloride. 3 5 1.3.2 MetallatedPorphyrins Porphyrins have been reported to accumulate in tumours. 3 6 O 'Hara et al. found certain metalloporphyrins to be effective hypoxic radio sensitizers3 7 and previous work in this laboratory has involved the synthesis of water-soluble metalloporphyrins, including Ru(II) and Pt(II) species, as potential hypoxia selective agents.38 R u complexes have been shown to bind to D N A and have potential as anti-tumour agents (Section 1.3), and thus ideally, water-soluble R u porphyrins (Figure 1.3) could result in a complex that is both a hypoxic radiosensitizer as well as an anti-tumour agent. O f note, Hartmann et al. have reported on the synthesis of water-soluble R u porphyrins as potential " D N A cleavers and potential cytotoxic agents". , „ 39 Figure 1.3. Central structure of a R u porphyrin. 9 References on page 24 Chapter 1 1.4 Development of Ruthenium Dimethylsulfoxide Complexes D M S O increases the water-solubility of its complexes (thus facilitating membrane transport and penetration) and the good lability of an O-bonded D M S O , is linked to the nature of interactions with purine and pyrimidine bases.2 1 The characteristics of the D M S O ligand combined with those of R u complexes have provided a new class of possible chemotherapeutic agents. 1.4.1 Ru(II)-Dimethylsulfoxide Complexes: Cis-RuCh(DMSO) 3(DMSO) and Trans-RuCl2(DMSO)4 (see Figure 1.4). O Cl S | Cl S | S $r I ^ c i $r I i Cl Figure 1.4. Abbreviated structures of czs -RuCl 2 (DMSO) 3 (DMSO) and trans-R u C l 2 ( D M S O ) 4 , respectively. (S = S-bound D M S O and O = O-bound D M S O ) . In preliminary studies, czs -RuCl 2 (DMSO) 4 exhibited interesting biological properties, in comparison to those of cisplatin, in Ehrlich ascites carcinoma and in L1210 lymphoid leukemia. 4 0 Czs -RuCl 2 (DMSO) 4 at relatively high doses (100-800 mg/kg/day) exhibits marginal anti-tumour activity, but inhibits nucleic acid synthesis, and exerts a pattern of cell damage and mutagenicity similar to that of cisplatin at only (0.5-4 mg/kg/day). 4 0 The anti-neoplastic activity of czs -RuCl 2 (DMSO) 4 was studied using three mouse tumour models: Lewis lung carcinoma, 516 melanoma and M C a mammary carcinoma. 4 1 The complex (610 mg/kg) reduced primary tumour growth in all the tumours tested and, as well, these effects 10 References on page 24 Chapter 1 were obtained with reduced host toxicity compared to equally effective dosages o f cisplatin (0.52mg/kg). 4 1 The anti-tumour effects of cis- and / ra«s-RuCl 2 (DMSO )4 tested on mice bearing the solid tumour, Lewis lung carcinoma, were then compared to those of cisplatin. 4 2 The trans complex (76 ixmol/kg/day) exhibited a greater antimetastatic effect compared to that o f an equimolar concentration of the cis complex, particularly in the inhibition o f primary tumour growth compared to metastatic growth. 2 1 ' 4 2 The toxicity of f ra«s-RuCl 2 (DMSO )4 was 10-fold higher than that of the cis isomer. 2 1 ' 4 2 Sava et al. reported that the anti-tumour activities o f these two complexes were qualitatively comparable, with the trans isomer being more effective, by preferentially inhibiting the weight rather than the number of artificial metastases.42 A s well, both cis- and fra«s-RuCl 2 (DMSO)4 significantly prolonged the survival time of leukaemic mice, again with the effect of j ra«s-RuCl 2 (DMSO )4 (48 mg/kg) being more pronounced than that of the cis isomer (800 mg/kg). 4 3 This prolongation of survival time of the mice suggests that these complexes can control the dissemination of tumour cells to the brain by a non-cytotoxic mechanism. 4 3 1.4.1.1 Chemical Behaviour of Cis-RuCl2(DMSO)3(DMSQ) and Trans-RuCl2(DMSO)4 in Aqueous Solutions The difference in activities between cis- and 7ra»s-RuCl 2 (DMSO)4 has been attributed to the different chemical behaviours of the species in aqueous solutions. 4 4 On dissolution, the cis isomer releases the single O-bonded D M S O immediately and then slow dissociation of Cl" gives the mono-cationic species (Figure 1.5). 4 4' 4 5 The trans isomer, once 11 References on page 24 Chapter 1 dissolved in water, releases two D M S O ligands, this step being followed by the slow release of the Cl" ion (Figure 1.5). 44 O O H 2 O H 2 S - J / C l H 2 Q , S - ^ l / C l HpO^ S - ^ l ^ O H 2 | ^ C l i ^ C l Cl S ^ I ^ C l s s s (1) Cl Cl O H 2 S \ I / S H 2 0 I ^ O H 2 H 2 0 S \ I ^ O H 2 | | ^ O H 2 Cl S ^ I ^ O H 2 Cl Cl Cl (2) Figure 1.5. Dissolution behaviour of (1) czs -RuCl 2 (DMSO) 4 and (2) / ra«s-RuCl 2 (DMSO) 4 in aqueous solutions. (S = S-bound D M S O ; O = O-bound D M S O ) . Adapted from Ref. 44. With the assumption that the coordinated water molecules are labile, the cis isomer under physiological conditions immediately generates a species with a single potential coordination site, while the trans isomer generates a species with two potential sites cis to one another. The neutral species should be able to cross the cell membrane. Once inside the cell, due to the low Cl" concentration, both species should slowly lose a Cl" and generate an additional coordination site. Accordingly, a higher reactivity in aqueous solution is expected for the trans isomer, under both extra- and intracellular conditions. 4 4 The relevant equilibria are affected by the presence of free Cl", and two Cl" concentrations were tested, namely 3 m M and 150 m M , which represent conditions inside and outside the cell, respectively. In 3 m M aqueous N a C l solution the loss of Cl" is observed, whereas in a 150 m M solution this process is inhibited (see Figure 1.5).44 12 References on page 24 Chapter 1 1.4.1.2 Binding of Cis-RuCl2(DMSO)3(DMSO) and Trans-RuCh(DMSO)4 to DNA Khan and Mehmood report that reactions between c7s-RuCi2 (DMSO) 4 and adenine or cytosine lead to the isolation of Ru2(adenine) 3(DMSO) 3Cl4 or Ru 2 (cytosine )4 (DMSO) 2 Cl 4 (CH 3 OH )4 , respectively.4 6 Cauci et al. reported that cis-R u C l 2 ( D M S O ) 4 reacts in aqueous solution with double-stranded D N A to form Ru( I I ) -DNA complexes, 4 7 while a study of the interaction between rraws-RuCl 2 (DMSO) 4 and guanine by Alessio et al. indicated that the N 7 and the a-phosphate group of guanine form a chelate with the composition [Ru(n)Cl(H 20)(p]VISO)2(5'-d(GMP))] , 4 8 N M R structural characterization and molecular modeling studies by Esposito et al. show that the reaction between z r a / z s - R u C ^ D M S O ^ and d(GpG) results in formation o f a 1,2-intrastrand crosslink, 4 9 the final reaction product exhibiting structural features which are similar to those of the corresponding cisplatin complex with d(GpG). 8 Studies by Tian et al. have provided further evidence for the binding modes of czs-RuCi2(DMSO) 4 with 5 - G M P and 5 - A M P in aqueous solution under physiological conditions: 5 0 5 - G M P can coordinate to the achiral c /5-RuCl2 (DMSO) 4 to form two isomers which have opposite chirality at the R u centre, with coordination of the nucleotide being via the N 7 and a phosphate oxygen. This report also demonstrated that 5 - A M P can coordinate to czs-RuCl2(DMSO) 4 through the phosphate group, but binding through N 7 was not observed. A recent study by Davey et al. using electrospray ionization mass spectrometry and *H N M R spectroscopy examined the reactions of cis- and zraws-RuCi2(DMSO)4 with deoxynucleosides. 5 1 Both complexes react with 2'-deoxyguanosine to give identical products, two diastereomers containing a single nucleoside coordinated to Ru, and a bis(nucleoside) 13 References on page 24 Chapter 1 adduct (Figure 1.6). Coordination o f the nucleoside is via the N 7 atom o f guanine in each complex (Figure 1.2(1)). r r a « 5 - R u C l 2 ( D M S O ) 4 reacts with 2'-deoxyadenosine (Figure 1.2(2), p. 6) to give a pair of diastereomers in which the nucleosides are coordinated via the N l atom. Cw-RuCl2 (DMSO ) 4 reacts with 2'-deoxyadenosine to a lesser extent than trans-RuCl2 (DMSO ) 4 resulting in a complex mixture of products, but did include the product containing a single 2'-deoxyadenosine ligand coordinated via the N l atom. 7>a« 5-RuCl2(DMSO ) 4 reacts only to a small extent with 2'-deoxycytidine under conditions similar to those used for the other nucleosides, and does not react with thymidine. This suggests that Ru(II) complexes may react with adjacent guanine bases in D N A to form intrastrand crosslinks in a fashion analogous to that of cisplatin. 5 1 OH2 1 + OH2 1+ OH2 ^ 2 ' - d G ^ 2 ' - d G I ^ 2 ' - d G I ^OH2 I ^ 2 ' - d G Cl Cl Cl Figure 1.6. Structures of reaction products of cis- and /raw5-RuCl 2 (DMSO) 4 with 2'-deoxyguanosine. (S = S-bound D M S O and 2'-dG = deoxyguanosine). Adapted from Ref. 51. 1.4.2 Ru(III)-Dimethylsulfoxide Complexes: tr arts-[(DMSO) 2Hf[RuCl4(DMSO)2f andMer-RuCh(DMSQ)2(DMSO) Two Ru(III)-dimethylsulfoxide complexes, * r a « 5 - [ ( D M S O ) 2 H ] + [ R u C l 4 ( D M S O ) 2 ] " 5 2 and /wer-RuCl3(DMSO) 2(DMSO) 5 2 , have been synthesized and characterized, and their anti-tumour activity assessed.53 The main feature o f both complexes is the facile dissociation in aqueous solution of one of the two zra/M-S-bonded D M S O ligands (Figure 1.7).53 Preliminary 14 References on page 24 Chapter 1 results suggest that weA*-RuCl 3(DMSO)3 is as effective as cisplatin at inhibiting subcutaneous primary tumour growth and more potent than cisplatin for the prolongation of host survival time at the concentrations tested (4 mg/kg/day and 100 mg/kg/day, respectively). 5 4 The authors reported that these Ru(III) complexes preferentially concentrate in intestinal mucosa, lung epithelia and tumour tissues.5 4 s s s C K J / O - D M S C L C K I z O - p M s q C K J ^ O H 2 R L L FACT *• ^ R u ^ — ; — ^ R u ^ C l ^ I ^ C l f a s t C l ^ | ^ C l s l o w C l ^ | ^ C l S O H 2 O H 2 (1) s ^ D / C l ' - D M S O c i \ I / C l ' - c r C l \ I ^ O H 2 ^ R l L • Ru ———». Ru C l ^ | ^ C l f a s t C l ^ | ^ C l s , o w C I ^ — | ^ C l S O H 2 O H 2 (2) Figure 1.7. Dissolution behaviour of (1) /wer -RuCl 3 (DMSO) 2 (DMSO) and (2) trans-[ (DMSO) 2 H] + [RuCl 4 (DMSO )2]" in aqueous solutions. (S = S-bound D M S O and O = O-bound D M S O ) . Adapted from Ref. 53. The complex Na[/ra«s-RuCl4(DMSO) 2] is a useful precursor for synthesis of a class o f mixed DMSO-nitrogen ligand derivatives,5 5 and the effects of two such complexes, /wer-RuCl 3 (DMSO)(DMSO)Im and Na[ fran5 -RuCL,(DMSO)(Im)] (Figure 1.8), were investigated. Endpoints were primary tumour growth and survival time using three solid, mouse tumours: Lewis lung carcinoma, 516 melanoma and M C a mammary carcinoma. 5 6 15 References on page 24 Chapter 1 S C K . I / O S Figure 1.8. Abbreviated structures of mer-RuCl3(DMSO)2lm and Na[/raws-RuCl 4 (DMSO)(Im)] . (S = S-bound D M S O , O = O-bound D M S O and Im = imidazole). Adapted from Ref. 56. Na[/ra/?s-RuCl 4(DMSO)(Im)] exhibited a higher activity against the tumour lines tested, this being attributed to the water-solubility of the complex. The presence of small amounts of D M S O (used as a vehicle of administration) reduced the activity of both complexes. 5 6 Sava et al. demonstrated that Na[zra«s-RuCl 4 (DMSO)(Im)] , in combination with surgical removal o f the primary tumour, prevented new metastasis formation and inhibited the growth o f existing lung metastases in mice bearing a mammary carcinoma. 5 7 This anti-metastatic action is comparable to that of [ImH] + [RuCl 4 Im 2 ]", 2 5 b but the species exhibited lower activity than that of cisplatin on several Pt-sensitive lines. 5 8 Na[fra«5-RuCl 4 (DMSO)(Im)] also prolonged the survival time of mice bearing M C a mammary carcinoma, 5 9 while showing minimal toxicity for normal tissues such as lung and kidney epithelia, muscle and liver cells, splenocytes and bone marrow. 6 0 Although the complex exhibits no cytotoxicity in tumour cells, it does interact with nucleic acids and results in a reduction of nucleic acid activity (a reduction in polyploidy D N A ) . 6 1 A recent study of the effects of Na[/ra«5-RuCl 4 (DMSO)(Im)] on cell cycle modifications, tested in T L X 5 lymphoma cells, strongly suggests the lack of direct cytotoxic effects in the anti-metastatic action of this complex. 6 2 Bergamo et al.63 suggest that this lack of direct cytotoxicity 6 0" 6 2 may be explained by three observations. Firstly, lung metastasis 16 References on page 24 Chapter 1 formation can be reduced when no contact occurs between tumour cells and Na[trans-RuCl4(DMSO)(Im)]; secondly, a low amount of R u (10 % of the administered dose) reaches tumour cells after treatment; and thirdly, the complex exhibits rapid clearance from the blood stream. 6 3 Several Ru(III) complexes of the type Na[rra«s-RuCl4(DMSO)(L)] (L = imidazole, N-methylimidazole, isonicotinic acid, indazole, isoquinoline, oxazole, pyridine, methylpyridine and ethylpyridine) were tested in T L X 5 lymphoma and M C a carcinoma to determine the degree of cytotoxicity and antimetastatic activity; 6 4 Na[fra«s-RuCl 4 (DMSO)(Im)] was the most selective anti-metastatic compound, and in vitro cytotoxicity was present only at concentrations > 10"4 M , this being dependent upon lipophilicity. The comparison of the effects on in vitro cytotoxicity with in vivo anti-tumour and anti-metastatic action indicates that these compounds reduce metastasis formation by a mechanism independent o f that for direct tumour cell cytotoxicity. 6 4 ImH[jra/7s-RuCl 4(DMSO)(Im)], in which the cation is now IniFF was tested for anti-metastatic effects in models of solid metastasizing tumours o f the mouse, and was found to behave similarly to Na[rra/7S-RuCl 4(DMSO)(Im)], implying that the anion was responsible for all the biological actions. 6 5 J. 4.3 Nitroimidazole Derivatives of RuCh(DMSO)4 C/s-RuCl 2 (DMSO)4 has been used as a precursor for the synthesis o f Ru(II)-nitroimidazole complexes as hypoxic radiosensitizers.6 6 Many tumours contain cells which are low in oxygen content and consequently relatively resistant to radiation treatment (see Section 4.2). 6 7 To compensate the relative radioresistance of hypoxic cells, compounds which mimic the effect of oxygen, i.e. hypoxic radiosensitizers, have been studied. 6 8 RuCi2(DMS0)2(4-17 References on page 24 Chapter 1 N0 2 Im)2 was shown to be a more effective radiosensitizer and exhibited lower toxicity in Chinese hamster ovary cells (CHO) than the free 4-nitroimidazole. 6 6 This complex was also studied for clastogenic activity (chromosome damaging) and exhibited activity greater than that of c/5-RuCl 2 (DMSO) 4 and 4 - N 0 2 I m (Figure 1.9), but less than that o f cisplatin. 6 9 R u C l 2 ( D M S O ) 2 L n (L = 2-, 4- or 5-nitroimidazole and n = 1 or 2 ) 7 0 ' 7 1 (Figure 1.9) and several Ru-(substituted-4-nitroimidazole)7 2 complexes were synthesized, characterized and their radiosensitizing abilities, toxicity toward C H O cells, and DNA-binding properties examined. The Ru-(substituted-4-nitroimidazole) species were less effective sensitizers than RuCl 2 (DMSO) 2 (4 -N0 2 Im )2 and did not bind to plasmid D N A . 7 2 The complex with misonidazole (a 2-nitroimidazole) (Figure 1.9) was unstable in aqueous solution and was no better a radiosensitizer than the free nitroimidazole. 7 0 The complex with metronidazole (a 5-nitroimidazole) (Figure 1.9) was also found to dissociate in aqueous solution. 7 0 RuCl2 (DMSO)2 (NMe-4-N0 2 Im) exhibited increased sensitization and lower toxicity in C H O cells in vitro compared to those of the free imidazole. 7 1 Figure 1.9. Structures of 2-nitroimidazole (R = C H 2 C H O H C H 2 O C H 3 = misonidazole, R = C H 2 C ( 0 ) N H C H 2 C H 2 O H = etanidazole), 4-nitroimidazole (R = H) and 5-nitroimidazole (R = C H 2 C H 2 O H = metronidazole). The effects (e.g. toward sensitization, toxicity toward C H O cells and DNA-binding) of substitution of chloride by bromide, and D M S O by T M S O N. N—R N0 2 18 References on page 24 Chapter 1 ( T M S O = tetramethylenesulfoxide), as well as varying the nitroimidazole, were studied for comparison with data for R u C l 2 ( D M S O ) 2 ( 4 - N 0 2 I m ) 2 7 3 Replacement of chloride by bromide reduced the radiosensitizing ability of the 4 - N 0 2 I m complexes, whereas replacement of D M S O by T M S O did not. 7 3 The T M S O complexes did not bind to D N A and T M S O / 2 -nitroimidazole complexes were stable in aqueous media (unlike the D M S O analogues). 7 3 R u C l 2 ( T M S O ) 2 ( 4 - N 0 2 l m ) 2 and RuCl 2(TMSO) 2(etanidazole) (Figure 1.9) both exhibit promising sensitizing enhancement ratios compared to those of RuCl 2 (DMSO) 2 (4 -N02lm)2 . 7 3 These Ru-nitroimidazole complexes did not show much toxicity compared to those o f analogous Pt complexes. 7 4 1.4.4 Ru Bis-chelating Sulfoxide Complexes There is potential for using R u sulfoxide complexes as chemotherapeutic agents as can be seen from the studies on cis- and zra«s-RuCi2(DMS0)4 (Section 1.3). Our group has extended the series of sulfoxide complexes of R u to include disulfoxides o f the type R S ( 0 ) ( C H 2 ) n S ( 0 ) R (« = 2 with R = M e , Et and Pr; and n = 3 with R = M e ) . 7 5 The precursor dithioethers were synthesized in air following the procedure of Morgan and Ledbury, 7 6 and were then oxidized in air by acid-catalyzed, D M S O oxidation following the procedure reported by Hul l and Bargar. 7 7 The disulfoxides were prepared as mixtures of diastereomers (the RRJSS pair and the meso RS/SR) and repeat recrystallizations were used to isolate the diastereomers. 7 5 ' 7 7 The goals of the chelating disulfoxide studies were to reduce the number o f possible isomers in the preparation o f nitroimidazole complexes 6 6 ' 6 9" 7 3 and to extend the database for the in vitro activity of Ru-sulfoxide complexes. 7 8 19 References on page 24 Chapter 1 Four complexes, /r<ms-RuCl 2(BMSE) 2 , f ra«s-RuCl 2 (BPSE) 2 , c ; s -RuCl 2 (BESE) 2 and c /5 - R u C l 2 ( B M S P ) 2 were synthesized, characterized (including crystallographic data) and studied [ B M S E = 1,2-bis(methylsulfinyl)ethane, B E S E = l,2-bis(ethylsulfinyl)ethane, B P S E = l,2-bis(propylsulfinyl)ethane, and B M S P = l,3-bis(methylsulfinyl)propane; Figure 1.10]. 7 5 ' 7 8 Figure 1.10. Structure of disulfoxides. ((« = 2) B M S E , R = M e ; B E S E , R = Et; B P S E , R = Pr; B B S E , R = B u ; BPeSe, R = Pe; B H S E , R = He; B C y S E , R = Cy; B P h S E , R = Ph and (« = 3) B M S P , R = M e ; B E S P , R = Pr; B P S P , R = Pr; B 'PSP, R = 'Pr; B B S P , R = B u ; BPeSP, R = Pe; BPhSP, R = Ph). The chelating ligands in all four structures have opposite chiralities at the two chiral S-atoms. The trans complexes are centrosymmetric with mutually trans S-atoms having opposite configurations and are non-chiral. The two cis complexes have C2 symmetry with the pair o f mutually trans S-atoms having the same chirality. The cis complexes are chiral, but in both cases the crystal structures showed that the samples contain an equal number o f the two enantiomers. 7 5 ' 7 8 Some preliminary in vitro experiments implied that the trans complexes accumulate in cells and bind to D N A to a greater degree than the cis complexes. 7 5 ' 7 8 o o R 20 References on page 24 Chapter 1 1.5 Goals of This Thesis 1.5.1 Synthesis of the Geometrical Isomers of the Known Bis-chelating Disulfoxide Complexes of Ru A s discussed in Section 1.4.1 the complexes c /5-RuCl2 (DMSO) 4 and trans-R u C l 2 ( D M S O ) 4 exhibit different efficacies in their anti-tumour properties. Previous work (Section 1.4.4) in this laboratory involved the synthesis, characterization and in vitro studies of a series of bis-chelating disulfoxide complexes of Ru. Only one geometrical isomer (of 2 possible) was isolated, dependent upon the disulfoxide used. 7 5 ' 7 8 The initial goal o f this project was to use the precursors c /5 , -RuCl2(DMSO) 4 and zra«s-RuCl 2 (DMSO) 4 as starting materials to synthesize the other corresponding geometrical isomer of the various bis-chelating disulfoxide R u complexes (Section 1.4.4), and then to investigate the effect of the geometrical and optical isomerism and chirality on biological properties. 1.5.2 Synthesis of Water-soluble Sulfoxide Complexes ofRu The complexes c w - R u C l 2 ( D M S O ) 4 and fraws-RuCl 2 (DMSO)4 are water-soluble, which facilitates in vitro examination. O f the previously synthesized bis-chelating disulfoxides complexes of R u (Section 1.4.4), the only complex appreciably soluble in aqueous solutions was c w - R u C l 2 ( B E S E ) 2 . One further aim was to synthesize sulfoxide complexes that readily dissolved in aqueous solutions. 21 References on page 24 Chapter 1 1.5.3 Synthesis and Characterization of Novel Chelating Disulfoxide Complexes of Ru For the bis-chelating disulfoxide complexes of R u that were synthesized (Section 1.4.4) the disulfoxides used were R S ( 0 ) ( C H 2 ) „ S ( 0 ) R (n = 2 or 3 and R = M e , Et or Pr; Figure 1.10). One goal was to extend the number o f disulfoxides (e.g. R = 'Pr, B u , Pent, Hexyl, Ph and Cy, Figure 1.10), to react these disulfoxides with various R u precursor species and to characterize the resultant products, particularly the geometry of the ligand set at the R u centre. 1.5.4 Synthesis of Chelating Dithioether Complexes of Ru A further goal was to synthesize bis-chelating dithioether complexes o f R u in order to determine the geometry of the ligands at Ru , and then to oxidize the coordinated dithioethers to the corresponding disulfoxides. This was to determine whether the ligand set would retain its geometry at the R u centre after oxidation of the coordinated S-atoms to S=0. 7.5.5 Preliminary Biological Studies in Vitro of Sulfoxide Complexes of Ru Following reports on the anti-tumour and DNA-binding properties of cis-R u C l 2 ( D M S O ) 4 and fraws-RuCl 2(T)MSO) 4 (see Sections 1.4.1 and 1.4.1.2, respectively), studies had been undertaken previously in this group to increase the number of sulfoxide complexes o f R u (Section 1.4.4) and study the cytotoxicity and the DNA-binding properties of these complexes. 7 5 ' 7 8 A present goal was to extend such studies (cytotoxicity, accumulation and DNA-binding in Chinese hamster ovary (CHO) cells) to include R u complexes of novel disulfoxides. 22 References on page 24 Chapter 1 1.5.6 Metallation of Water-soluble Porphyrins Previous work in this group, initiated by Ware, 7 9 involved the insertion of R u into water-soluble porphyrins using R u precursors other than the traditional R u 3 ( C O ) i 2 . 8 0 [Ru(DMF) 6 ] [OTfJ 3 8 1 ( D M F = dimethylformamide and O T f = C F 3 S 0 3 " ) was found to be a useful precursor which enabled the metallation of several free-base porphyrins including the water-soluble Na4[H 2TSPhP]-15H 20 (TSPhP = 5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrin) which yielded Na4[Ru(TSPhP)(CO)(DMF)]solvate (solvate = 2 D M F - 2 H 2 0 or 6 H 2 0 ) . 7 9 The goal was to assess the general applicability of such metallation. 23 References on page 24 Chapter 1 1.6 References for Chapter 1 1 (a) Davies, A . R ; Einstein, F. W . B . ; Farrell, N . P.; James, B . R. ; M c M i l l a n , R. S. Inorg. Chem. 1978,17, 1965; (b) James, B . R.; McMi l l an , R. S. Can. J. Chem. 1977, 55, 3927; (c) James, B . R.; McMil lan , R. S.; Reimer, K . J. J. Mol. Catal. 1976, 1, 439. 2 Fricker, S. P. Ruthenium Compounds in Cancer Therapy, in Metal Compounds in Cancer Therapy (ed. S. Fricker), Chapman and Hall , London, 1994, p. 1. 3 Roberts, L . Cancer Today. Origins, Prevention and Treatment, National Academy Press, Washington, 1984. 4 Haiduc, I.; Silvestru, C. Coord. Chem. Rev. 1990, 99, 253. 5 Rosenberg, B . ; Van Camp, L . ; Krigas, T. Nature 1969, 205, 698. 6 Oldenberg, J.; Los , G . Cellular Mechanisms of Cisplatin Resistance, in Drug Resistance in Oncology (ed. S. D . Bernal), Marcel Dekker, N e w York , 1997, p. 331. 7 Reedijk, J. J. Chem. Soc, Chem. Commun. 1996, 801. 8 Sherman, S. E . ; Lippard, S. J. Chem. Rev. 1987, 87, 1153. 9 Bloemink, M . J.; Reedijk, J. Cisplatin and Derived Anti-cancer Drugs: Mechanism and Current Status of D N A Binding, in Metal Ions in Biological Systems (eds. A . Sigel and H . Sigel), Marcel Dekker Inc., New York, 1996, 32, p. 641. 10 Whitehead, J. P.; Lippard, S. J. Proteins that Bind to and Mediate the Biological Activity o f Platinum Anti-cancer D r u g - D N A Adducts, in Metal Ions in Biological Systems (eds. A . Sigel and H . Sigel), Marcel Dekker Inc., N e w York, 1996, 32, p. 687. 11 Heim, M . E . Platinum and Non-Platinum Complexes in Clinical Trials. Current Status and N e w Developments, in Metal Complexes in Cancer Chemotherapy (ed. B . K . Keppler), V C H , Weinheim, 1993, p. 9. 12 Giandomenico, C M . ; Abrams, M . J.; Murrer, B . A . ; Vollano, J. F . ; Rheinheimer, M . I.; Wyer, S. B . ; Bossard, G . E . ; Higgins III, J. D . Inorg. Chem. 1995, 34, 1015. 24 Chapter 1 Holford, J.; Sharp, S. Y . ; Murrer, B . A ; Abrams, M . ; Kelland L . R. Br. J. Cancer 1998, 77, 366. (a) Day, M . New Scientist 1999,162, 11; (b) Kratochwil, N . A . ; Parkinson, J. A ; Bednarski, P. J.; Sadler, P. J. Angew. Chem. Int. Ed. 1999, 38, 1460; (c) Guo, Z ; Sadler, P. J. Angew. Chem. Int. Ed. 1999, 38, 1512. Kelland, L . R. Platinum Anti-cancer Drugs, in Metal Compounds in Cancer Therapy (ed. S Flicker), Chapman and Hall , London, 1994, p. 41. (a) Farrell, N . ; Qu, Y . ; Bierbach, U . ; Valsecci, M . ; Menta, E . Structure-Activity Relationships within D i - and Trinuclear Platinum Phase-I Clinical Anti-cancer Agents, in Cisplatin Chemistry and Biochemistry of a Leading Anti-cancer Drug (ed. B . Lippert), W i l e y - V C H , Weinheim, 1999, p. 479; (b) Kasparkova, J.; Novakova, O.; Vrana, O.; Farrell, N . ; Brabec, V . Biochemistry 1999, 38, 10997; (c) Perego, P.; Caserini, C ; Gatti, L . ; Carenini, N . ; Romanelli, S.; Supino, R.; Colangelo, D . ; Viano, I.; Leone, R.; Spinelli, S.; Pezzoni, G . ; Manzotti, C ; Farrell, N . ; Zunino, F. Molecular Pharmacology 1999, 55, 528; (d) Brabec, V . ; Kasparkova, I ; Vrana, O.; Novakova, O.; Cox, J. W . ; Qu, Y . ; Farrell, N . Biochemistry 1999, 38, 6781; (e) Skov, K . A . ; Adomat, H . ; Farrell, N . ; Matthews, J. B . Anti-cancer Drug Des. 1998, 13, 207; (f) Kharatishvili, M . ; Mathieson, M . ; Farrell, N . Inorg. Chim. Acta 1997, 255, 1; (g) Zaludova, R.; Zakovksa, A . ; Kasparkova, J.; Balcarova, Z.; Kleinwachter, V . ; Vrana, Farrell, N . ; Brabec, V . Eur. J. Biochem. 1997, 246, 508; (h) Mellish, K . J.; Qu, Y . ; Scarsdale, N . ; Farrell, N . Nucleic Acids Res. 1997, 25, 1265; (i) Farrell, N . Current Status of Structure-Activity Relationships of Platinum Ant i -cancer Drugs: Activation of the Trans Geometry, in Metal Ions in Biological Systems (eds. A . Sigel and H . Sigel), Marcel Dekker Inc., N e w York , 1996, 32, p. 603; 25 Chapter 1 (j) Qu, Y . ; Farrell, N . Inorg. Chim. Acta 1996, 245, 265; (k) Kasparkova, J.; Mellish, K . I ; Qu, Y . ; Brabec, V . ; Farrell, N . Biochemistry 1996, 35, 16705; (1) Farrell, N . ; Appleton, T. G . ; Qu, Y . ; Roberts, J. D . ; Soares Fontes, A . P.; Skov, K . A ; Wu , P.; Zou, Y . Biochemistry 1995, 34, 15480; (m) Wu, P. K . ; Qu, Y ; Van Houten, B . ; Farrell, N . J. Inorg. Biochem. 1994, 54, 207; (n) Van Houten, B . ; Illenye, S.; Qu, Y ; Farrell, N . Biochemistry 1993, 32, 11794; (o) Zou, Y . ; Van Houten, B . ; Farrell, N . Biochemistry 1993, 32, 9632; (p) Landi, J.; Hacker, M . P.; Farrell, N . Inorg. Chim. Acta 1992, 202, 79; (q) Kraker, A . J.; Hoeschele, J. D . ; Elliot, W. L . ; Hollis Showalter, H . D . ; Sercel, A . D . ; Farrell, N . P. J. Med. Chem. 1992, 35, 4526; (r) Qu, Y . ; de Almeida, S. G . ; Farrell, N . Inorg. Chim. Acta 1992, 201, 123; (s) de Almeida, S. G . ; Hubbard, J. L . ; Farrell, N . Inorg. Chim. Acta 1992, 193, 149; (t) Johnson, A ; Qu, Y . ; Van Houten, B . ; Farrell, N . Nucleic Acids Res. 1992, 20, 1697; (u) Farrell, N . ; Roberts, J. D . ; Hacker, M . P. J. Inorg. Biochem. 1991, 42, 237; (v) Qu, Y . ; Farrell, N . J. Inorg. Biochem. 1990, 40, 255; (w) Hoeschele, J. D . ; Farrell, N . ; Turner, W. R.; Rithner, C. D . Inorg. Chem. 1988, 27, 4106. 17 Farrell, N . Transition Metal Complexes as Drugs and Chemotherapeutic Agents (eds. R. Ugo and B . R. James), Kluwer Academic Publishers, Dordrecht, 1989, p. 147. 18 Clarke, M . J. Oncological Implications of the Chemistry of Ruthenium, in Metal Ions in Biological Systems (ed. H . Sigel), Marcel Dekker, N e w York , 1980,11, p. 231. 19 Clarke, M . J. Ruthenium Complexes: Potential Roles in Anti-cancer Pharmaceuticals, in Metal Complexes in Cancer Chemotherapy (ed. B . K . Keppler), V C H , Weinheim, 1993, p. 129. 26 Chapter 1 Milkevitch, M . ; Storrie, H . ; Brauns, E . ; Brewer, K . J.; Shirley, B . W . Inorg. Chem. 1997, 36, 4534. Sava G . Ruthenium Compounds in Cancer Therapy, in Metal Compounds in Cancer Therapy (ed. S. Fricker), Chapman and Hall , London, 1994, p. 65. Kratz, F . ; Keppler, B . K . ; Messori, L . ; Smith, L . ; Baker, E . N . Metal-Based Drugs 1994, 1, 169 and references therein. (a) Clarke, M . J. Inorg. Chem. 1980,19, 1103. (b) Clarke, M . J.; Bitler, S.; Rennert, D . ; Buchbinder, M . ; Kelman, A . D . J. Inorg. Biochem. 1980, 2, 79. Keppler, B . K . ; Wehe, D . ; Endres, H . ; Rupp, W . Inorg. Chem. 1987, 26, 844. (a) Garzon, F . T.; Berger, M . R.; Keppler, B . K . ; Schmahl, D . Cancer Chemother. Pharmacol. 1987,19, 347; (b) Keppler, B . K . ; Rupp, W. ; Juhl, U . M . ; Endres, H . ; Niebl, R ; Balzer, W . Inorg. Chem. 1987, 26, 4366; (c) N i Dhubhghaill, O. M . ; Hagen, W. R ; Keppler, B . K . ; Lipponer, K - G . ; Sadler, P. J. J. Chem. Soc. Dalton Trans. 1994, 3305; (d) Chatlas, J.; van Eldik, R.; Keppler, B . K . Inorg. Chim. Acta 1995, 233, 59; (e) Pieper, T.; Keppler, B . K . Analusis Magazine 1998, 26, 84; (f) Keppler, B . K . NewJ. Chem. 1990,14, 389; (g) Kersten, L . ; Braunlich, H . ; Keppler, B . K . ; Gliesing, C ; Wendelin, M ; Westphal, J. J. Appl. Toxicol. 1998,18, 93. (a) Keppler, B . K . ; Lipponer, K - G . ; Stenzel, B . ; Kratz, F. N e w Tumour-Lihibiting Ruthenium Complexes, in Metal Complexes in Cancer Chemotherapy (ed. B . K . Keppler), V C H , Weinheim, 1993, p. 187. (b) Keppler, B . K . ; Henn, M . ; Juhl, U . M . ; Berger, M . R ; Niebel, R. ; Wagner, F . E . N e w Ruthenium Complexes for the Treatment of Cancer, in Progress in Clinical Biochemistry and Medicine (eds. E . Baulieu; D . T. Forman; M . Ingelman-Sundberg; L . Jaenicke; J. A . Kellen; Y . Nagai; G . F. Springer; L . Trager; L . W i l l -Shahab; J. L . Wittliff), Springer-Verlag, Berlin, 1989,10, p. 41. Lipponer, K - G . ; Vogel, E . ; Keppler, B . K . Metal-Based Drugs 1996, 3, 243. 27 Chapter 1 28 Mestroni, G ; Alessio, E . ; o Santi, A S . ; Geremia, S.; Bergamo, A ; Sava, G . ; Boccarelli, A . ; Schettino, A . ; Coluccia, M . Inorg. Chim. Acta 1998, 273, 62. 29 Clarke, M . J. The Potential o f Ruthenium in Anti-cancer Pharmaceuticals, in ACS Symposium Series (ed. A . E . Martell), American Chemical Society, Washington, 1980,140, p. 157. 30 Clarke, M . J.; Stubbs, M . Interactions of Metallopharmaceuticals with D N A , in Metal Ions in Biological Systems (eds. A . Sigel and H . Sigel), Marcel Dekker Inc., N e w York , 1996, 32, p. 727. 31 Frasca, D . ; Ciampa, J.; Emerson, J.; Umans, R. S.; Clarke, M . J. Metal-Based Drugs 1996, 3, 197. 32 Dung, J. R. ; Danneman, J.; Behnke, W . D . ; Mercer, E . E . Chem. Biol. Interact. 1976, 13, 287. 33 Gibson, J. F . ; Poole, R. K . ; Hughes, M . N . ; Rees, J. F . Arch. Microbiol. 1984, 139, 265. 34 Mercer, E . E . ; Gray, L . W . J. Am. Chem. Soc. 1972, 94, 6426. 35 Hughes, M . N . ; O'Reardon, D . ; Poole, R. K . ; Hursthouse, M . B . ; Thornton-Pett, M . Polyhedron 1987, 6, 1711. 36 (a) Kessel, D . ; Thompson, P.; Saatio, K . ; Nantwi, K . D . Photochem. Photobiol. 1987, 45, 787; (b) Fiel, R. J.; Mark, E . ; Button, T.; Gilani, S.; Musser, D . Cancer Lett. 1988, 40, 23; (c) Dougherty, T. J. Photochem. Photobiol. 1987, 45, 879; (d) Miura , M . ; Micca , P. L . ; Heinrichs, J. C ; Gabel, D . ; Fairchild, R. G . ; Slatkin, D . N . Biochem. Pharmacol. 1992, 43, 467. 37 O'Hara, J. A . ; Douple, E . B . ; Abrams, M . J.; Picker, D . J.; Giandomenico, C. M . ; Vollano, J. F. Int. J. Radial Oncol. Biol. Phys. 1989,16, 1049. 38 James, B . R.; Meng, G . G . ; Posakony, J. J.; Ravensbergen, J. A . ; Ware, C . J. ; Skov, K . A . Metal-Based Drugs 1996, 3, 85. 39 Hartmann, M . ; Robert, A . ; Duarte, V . ; Keppler, B . K . ; Meunier, B . J. Biol. Inorg. Chem. 1997,2,427. 28 Chapter 1 40 Giraldi, T.; Sava, G . ; Bertoli, G . ; Mestroni, G . ; Zassinovich, G . Cancer Res. 1977, 37, 2662. 41 Sava, G . ; Zoret, S.; Giraldi, T.; Mestroni, G . ; Zassinovich, G . Eur. J. Cancer Clin. Oncol. 1984, 20, 841. 42 Sava, G . ; Pacor, S.; Zorzet, S.; Alessio, E . ; Mestroni, G . Pharmacol. Res. 1989, 21, 617. 43 Coluccia, M . ; Sava, G . ; Loseto, F. ; Nassi, A . ; Boccarelli, A . ; Giordano, D . ; Alessio, E . ; Mestroni, G . Eur. J. Cancer 1993, 29, 1873. 44 Alessio, E . ; Mestroni, G . ; Nardin, G . ; Attia, W . M . ; Calligaris, M . ; Sava, G . ; Zorzet, S. Inorg. Chem. 1988, 27, 4099. 45 (a) Evans, L P . ; Spencer, A . ; Wilkinson, G . J. Chem. Soc. Dalton Trans. 1973, 204; (b) McMi l l an , R. S.; Mercer,' A . ; James, B . R.; Trotter, J. J. Chem. Soc. Dalton Trans. 1975, 1006. 46 Khan, B . T.; Mehmood, A . J. Inorg. Nucl. Chem. 1978, 40, 1938. 47 Cauci, S.; Alessio, E . ; Mestroni, G . ; Quadrifoglio, F. Inorg. Chim. Acta 1987,137, 19. 48 Alessio, E . ; X u , Y . ; Cauci, S.; Mestroni, G . ; Quadrifoglio, F . ; Viglino, P. ; Marzi l l i , L . G . J. Am. Chem. Soc. 1989, 111, 7068. 49 Esposito, G . ; Cauci, S.; Fogolari, F. ; Alessio, E . ; Scocchi, M . ; Quadrifoglio, F . ; Viglino, P. Biochem. 1992, 31, 7094. 50 Tian, Y - N . ; Yang, P.; L i , Q - S ; Guo, M - L . ; Zhao, M - G . Polyhedron 1997, 16, 1993. 51 Davey, J. M . ; Moerman, K . L . ; Ralph, S. F . ; Kanitz, R ; Sheil, M . M . Inorg. Chim. Acta 1998, 281, 10. 52 Jaswal, J. S.; Rettig, S. J.; James, B . R. Can. J. Chem. 1990, 68, 1808. 53 Alessio, E . ; Balducci, G . ; Calligaris, M . ; Costa, G . ; Attia, W. H . ; Mestroni, G . Inorg. Chem. 1991, 30, 609. 54 Pacor, S.; Sava, G . ; Ceschia, V . ; Bregant, F. ; Mestroni, G . ; Alessio, E . Chem. Biol. Interact. 1991, 78, 223. 29 Chapter 1 55 Alessio, E . ; Balducci, G . ; Lutman, A . ; Mestroni, G . ; Calligaris, M . ; Attia, W . M . Inorg. Chim. Acta 1993, 203, 205. 56 Sava, G . ; Pacor, S.; Mestroni, G . ; Alessio, E . Anti-Cancer Drugs 1992, 3, 25. 57 Sava, G . ; Pacor, S.; Coluccia, M . ; Mariggio, M . ; Cochietto, M . ; Alessio, E . ; Mestroni, G . Drug Invest. 1994, 8, 150. 58 Mestroni, G . The Development of Tumour-Inhibiting Ruthenium Dimethylsulfoxide Complexes, in Metal Complexes in Cancer Chemotherapy (ed. B . K . Keppler), V C H , Weinheim, 1993, p. 157. 59 Sava, G . ; Pacor, S.; Mestroni, G. ; Alessio, E . Clin. Exp. Metastasis 1992,10, 273. 60 Gagliardi, R ; Sava, G . ; Pacor, S.; Mestroni, G . ; Alessio, E . Clin. Exp. Metastasis 1994, 12, 93. 61 Sava, G . ; Capozzi, I.; Bergamo, A . ; Gagliardi, R. ; Cocchietto, M . ; Masiero, L . ; Onisto, M . ; Alessio, E . ; Mestroni, G . ; Garbisa, S. Int. J. Cancer 1996, 68, 60. 62 Capozzi, I.; Clerici, K . ; Cocchietto, M . ; Salerno, G . ; Bergamo, A . ; Sava, G . Chem. Biol. Interact. 1998,113, 51. 63 Bergamo, A . ; Cocchietto, M . ; Capozzi, I.; Mestroni, G . ; Alessio, E . ; Sava, G . Anti-Cancer Drugs 1996, 7, 697. 64 Sava, G . ; Pacor, S.; Bergamo, A . ; Cocchietto, M . ; Mestroni, G . ; Alessio, E . Chem. Biol. Interact. 1995, 95, 109. 65 Sava, G . ; Capozzi, I ; Clerici, K ; Gagliardi, G . ; Alessio, E . ; Mestroni, G . Clin. Exp. Metastasis 1998,16, 371. 66 Chan, P. K . ; Skov, K . A . ; James, B . R.; Farrell, N . P. Int. J. Radiat. Oncol. Biol. Phys. 1986, 12, 1059. 67 Thomlinson, R. H . ; Gray, L . H . Br. J. Cancer 1955, 9, 539. 68 Adams, G . E . Radiat. Res. 1992,132, 129. Chan, P. K . L . ; Skov, K . A . ; James, B . R.; Farrell, N . P. Chem. Biol. Interact. 1986, 59, 247. Chan, P. K . L . ; Skov, K . A . ; James, B . R ; Farrell, N . P. Studies on Ruthenium Nitroimidazole Complexes as Radiosensitizers, in Platinum and Other Metal 69 70 30 Chapter 1 Coordination Compounds in Cancer Chemotherapy (ed. M . Nicolini), Martinus Nijhoff Publishing, Boston, 1987, p. 638. 71 Chan, P. K . L . ; Chan, P. K . H . ; Frost, D . C ; James, B . R.; Skov, K . A . Can. J. Chem. 1988, 66, 117. 72 Chan, P. K . L . ; Skov, K . A . ; James, B . R. Int. J. Radial Biol. 1987, 52, 49. 73 Chan, P. K . L . ; James, B . R.; Frost, D . C ; Chan, P. K . H . ; H u , H - L ; Skov, K . A . Can. J. Chem. 1989, 67, 508. 74 Farrell, N . Metal Complexes as Radiosensitizers, in Progress in Clinical Biochemistry and Medicine (eds. E . Baulieu; D . T. Forman; M . Ingelman-Sundberg; L Jaenicke; J. A . Kellen; Y . Nagai; G . F . Springer; L . Trager; L . W i l l -Shahab; J. L . Wittliff), Springer-Verlag, Berlin, 1989, 10, p. 89 and references therein. 75 Yapp, D . T. T.; Rettig, S. J.; James, B . R.; Skov, K . A . Inorg. Chem. 1997, 36, 5635. 76 Morgan, S. T.; Ledbury, W . J. Chem. Soc. 1922,121, 2882. 77 Hul l , M . ; Bargar, T. W. J. Org. Chem. 1975, 40, 3152. 78 Yapp, D . T. T. Ph. D : Dissertation, University o f British Columbia, Vancouver, 1993. 79 Ware, C. J. M . Sc. Dissertation, University of British Columbia, Vancouver, 1994. 80 (a) Fleischer, E . B . ; Thorp, R.; Venerable, D. J. Chem. Soc, Chem. Commun. 1969, 475; (b) Chow, B . ; Cohen, I. Bioinorg. Chem. 1971,1, 57; (c) Eaton, G . R.; Eaton, S. S. J. Am. Chem. Soc, 1975, 97, 235. 81 Judd, R. J.; Cao, R.; Biner, M . ; Armbruster, T.; Burgi, H - B . ; Merbach, A . E . ; Ludi , A . Inorg. Chem. 1995, 34, 5080. 31 Chapter 2 Chapter 2 General Experimental and Synthesis of Ligands (Dithioethers and Disulfoxides) and Ruthenium Precursors and Sulfoxide Complexes 2.1 Chemicals and Reagents 3,6-Dithiaoctane and 4,7-dithiadecane were purchased from K & K Laboratories. Dimethylsulfoxide ( D M S O ) and 1,2-dibromoethane, were purchased from Fisher Scientific. 1,3-Dibromopropane was purchased from M C B , while ethane-, propane-, butane-, pentane-, hexane- and cyclohexyl-thiols, and 1,4,7,10-tetrathiacyclododecane and 3,6,9,14-tetrathiabicyclo[9.2.1]tetradeca-ll,13-diene were obtained from Aldrich. Benzenethiol and phenylsulfoxide were Eastman products. The chemicals were used as provided. RuCi3*3H20 was obtained on loan from Johnson-Matthey Ltd . and Colonial Metals Inc. A l l common solvents used were at least of reagent grade. Deuterated solvents used for N M R studies ( C 6 D 6 , D 2 0 , CDC1 3 , DMSO -^e and M e O D ) were purchased from M S D I S O T O P E S or I S O T E C Inc. Alumina (neutral, Brockman activity I) was purchased from Fisher chemicals. A l l samples (products and solvents) were stored in air, and all syntheses and measurements were done in air unless otherwise stated. 2.2 Physical Techniques and Instrumentation 2.2.1 FT-NMR Instruments Solution N M R spectra were obtained using a Bruker A C - 2 0 0 E (200 M H z ) , a Varian X L - 3 0 0 (300 M H z ) or Bruker WH-400 (400 M H z ) instrument operating in the 32 References on page 61 Chapter 2 Fourier Transform mode. Proton chemical shifts are given as 8 in ppm with reference to the residual solvent peak as the internal standard, relative to T M S [CerL; in C 6 D 6 8 7.15, CHCI3 in CDCI3 8 7.24, H D O in D 2 0 8 4.63, D M S O in rf6-DMSO 8 2.49 and M e O H in C D 3 O D 8 3.30, 4.78]. The ^ - N M R chemical shifts are reported as indicated by s = singlet; d = doublet; t = triplet; q = quartet; m = multiplet. 2.2.2 Infrared and UV-Vis Spectrophotometry, Thermal Gravimetric Analysis, Photochemistry and Conductivity and Melting Point Measurements Infrared spectra were obtained using an A T I Mattson Genesis Series FTJJR instrument. The samples were prepared by evenly mixing a solid compound with K B r and then compressing the resulting mixture into a pellet. Bands are reported in cm"1. UV-visible spectroscopic data were obtained using a Hewlett-Packard H P 8452A Diode-Array Spectrophotometer. Wavelength maxima, AmaX, are given in nm, and extinction coefficients are given as log e following the reported wavelengths. Thermal gravimetric measurements were obtained using a T A Instruments T G A 51 Thermogravimetric Analyzer fitted with a quartz furnace tube with a temperature range from ambient to 1200 °C. Photochemical experiments were carried out at r t . using an Ace-Hanovia 450 Watt high pressure H g vapour lamp (cat. #7825-34, Ace Glass Inc.). Conductivity measurements were obtained at r.t. at ~10"3 M concentrations using a Thomas Serfass conductivity bridge, and a cell from Yel low Springs Instrument Company. 33 References on page 61 Chapter 2 Values are given in ohm^mor'cm 2 . The value of the cell constant was determined to be 1 .016. Melting point measurements were obtained using a Fisher-Johns melting point apparatus and were uncorrected. 2.2.3 Magnetic Susceptibility Solution magnetic moments were measured at r.t. using the Evans method. 1 ' 2 A solution of the complex dissolved in M e O D / C D C U was placed in a sealed capillary tube. This was placed inside an N M R tube, with C D C I 3 as the reference, and held in place with a Teflon spacer.2 The paramagnetic shift of the residual CHC13 in CDCI3 in the capillary sample was measured and compared to that of the corresponding peak in the C D C I 3 reference. Solid-state magnetic measurements were obtained using a Johnson-Matthey magnetic susceptibility balance. 2.2.3.1 Calculation of %g, Magnetic Susceptibility of the Dissolved Paramagnetic Species and Magnetic Susceptibility per Gram of Sample % G ( 1 0 " 6 cm 3 g"1) can be calculated according to % e= X<>+ 3 A V / 4 T I V 0 C where %0= magnetic susceptibility of the pure solvent (10~ 6 cm 3 g"1), A v = paramagnetic shift (Hz), v 0 = operating frequency of the spectrometer (Hz), and c = concentration (g/mL). 2 For the solid state measurement, %s(\0"6 cm 3 g"1) can be calculated according to the equation 3 4 References on page 61 Chapter 2 Xg = C b a l ( l)(R-Ro ) /10 9 m where 1 = sample length (cm), m = sample mass (g), R = reading for tube and sample, R o = reading for the empty tube, and Cbai = balance calibration constant, 1.158. 2.2.3.2 Calculation of %M, the Molar Magnetic Susceptibility % M (10"6 cm 3 mol"1) can be calculated according to the equation X M = X g M where M = molecular weight of the paramagnetic species (g/mole). X M o f a complex consists of the summation of X M values for the central ion(s), the coordinated ligands, other species present, and the metal. Thus Xu complex - % M ( m e t a l ion) X . M (ligands) X M (other species) X M ( m e t a ' ) where X M for the ligands, solvent and metal can be determined from Pascal's constants.3 2.2.3.3 Calculation of pejf, the Effective Magnetic Moment XM(metai ion) is related to peff (B. M . ) according to the equation P e f f - 2.828(XM(metalion) -T) 1 ' 2 where T = absolute temperature (K) 2.2.3.4 Calculation of n, the Number of Unpaired Electrons For the spin-only value, p e rr is related to n and can be calculated according to the following equation 35 References on page 61 Chapter 2 p e f f = (n(n+2))1 / 2 2.2.4 Elemental Analyses, Mass Spectral Analyses and X-ray Crystallography Elemental analyses were obtained by M r . P. Borda. Mass spectral analyses were obtained in a facility headed by Dr. G . Eigendorf. Both E I and LSJJVIS (on thioglycerol and 3-nitrobenzylalcohol matrices) methods of ionization were used. X-ray crystallographic structures were obtained by the late Dr. S. J. Rettig with a Siemens S M A R T C C D diffractometer or a Rigaku A F C 6 S diffractometer (both with graphite monochromated M o -K a radiation), or a Rigaku/ADSC C C D area detector with graphite monochromated M o - K a or C u - K a radiation; and by Dr. Victor G . Young, Jr. at the University of Minnesota on a Siemens S M A R T Platform C C D area detector (graphite monochromator, M o - K a radiation). 2.3 Synthesis of Dithioethers The dithioethers, 3,6-dithiaoctane and 4,7-dithiadecane were commercially available. The other dithioethers were synthesized in air following the procedure of Morgan and Ledbury. 4 The dithioethers synthesized are new compounds unless otherwise indicated (by a superscript in the heading). The materials (except in the case of 1,2-bis(phenyl)dithiaethane) are oils and are hygroscopic in nature, and the determined elemental analyses values were not always satisfactory. 2.3.1 3,7-Dithianonane (MW = 164.32 g/mol) Ethanethiol (30 mL, 400 mmol) was added dropwise to a saturated solution (50 mL) of N a O H in M e O H cooled in a dry-ice/acetone bath. The solution was allowed to warm 36 References on page 61 Chapter 2 to r.t. and then stirred at 70 °C for 1 h. The solution was then cooled again with a dry-ice/acetone bath, and 1,3-dibromopropane (20.6 mL, 200 mmol) was added dropwise with constant stirring. The resulting mixture was then warmed to 70 °C and left for 1 h. This solution was then poured into H 2 0 (100 mL), when the oily, immiscible dithioether layer was collected. The aqueous layer was extracted three times with E t 2 0 (40 mL) portions; the organic residues were combined, the E t 2 0 was removed by rotary evaporation, and the oily product was dried over M g S 0 4 . Yield 21 g (64 %). Anal. Calcd for C 7 H i 6 S 2 : C , 51.17; H , 9.81. Found: C, 50.97; H , 9.77 %. ' H - N M R (CDC1 3 , 200 M H z ) 5 2.60 (m, 8H, CH2SCH2), 1.85 (q, 2H , C H 2 C 7 / 2 C H 2 ) , 1.25 (t, 6H, CH3). Mass spectrum [LSIMS, m/z] 164 [ M ] + , 135 [ M - C 2 H 5 f . 2.3.2 4,8-Dithiaunadecane (MW = 192.37g/mol) 4,8-Dithiaunadecane was prepared according to the procedure described in Section 2.3.1, but using propanethiol (30 mL, 330 mmol) and 1,3-dibromopropane (16.8 mL, 165 mmol). Yie ld 28 g (88 %). Anal. Calcd for C 9 H 2 0 S 2 : C, 56.19; H , 10.48. Found: C, 57.69; H , 10.77%. ^ - N M R (CDC1 3 , 200 M H z ) 8 2.60 (t, 4H , CH2CH2CH2), 2.50 (t, 4 H , C # 2 C H 2 C H 3 ) , 1.85 (q, 2H, CH 2Gr7 2 CH 2 ) , 1.60 (s, 4H , CH 2Gr7 2 CH 3 ) , 1.02 (t, 6H , CH3). Mass spectrum [LSIMS, m/z] 192 [M] + , 149 [ M - C 3 H 7 ] + . 2.3.3 2,8-Dimethyl-3,7-dithianonane (MW = 192.37 g/mol) The title dithioether was prepared according to the procedure given in Section 2.3.1, but using 2-propanethiol (40 mL, 430 mmol) and 1,3-dibromopropane (21.9 mL, 210 mmol). Yie ld 32 g (80 %). Anal. Calcd for C 9 H 2 0 S 2 : C, 56.19; H , 10.48. Found: C, 55.32; 37 References on page 61 Chapter 2 H , 10.39 %. ' H - N M R (CDC1 3 , 200 M H z ) 5 2.90 (m, 2H, (CH 3 ) 2 C#S) , 2.60 (t, 4 H , CH2CH2CH2), 1.85 (qt, 2H , C H 2 C # 2 C H 2 ) , 1.30 (d, 12H, S C H ( C ^ ) 2 ) . Mass spectrum [LSIMS, m/z] 193 [M] + . 2.3.4 5,9-Dithiatridecane (MW = 220.42 g/mol) 5.9- Dithiatridecane was prepared according to the procedure given in Section 2.3.1, but using butanethiol (40 mL, 370 mmol) and 1,3-dibromopropane (18.9 mL, 187 mmol). Yie ld 36 g (87 %). Anal. Calcd for C n H 2 4 S 2 : C, 59.94; H , 10.97. Found: C, 59.57; H , 11.10%. ' H - N M R (CDC1 3 , 200 M H z ) 6 2.60 (m, 8H, CH2SCH2), 1.85 (q, 2H , C H 2 C # 2 C H 2 ) , 1.56 (q, 4H , C / / 2 C H 2 C H 3 ) , 1.42 (s, 4H, C/72CH 3), 0.92 (t, 6H , CH3). Mass spectrum [LSIMS, m/z] 220 [ M ] + , 163 [ M - C ^ g f . 2.3.5 6,10-Dithiapentadecane (MW =248.47 g/mol) 6.10- Dithiapentadecane was prepared according to the procedure described in Section 2.3.1, but using pentanethiol (23.8 mL, 192 mmol) and 1,3-dibromopropane (9.7 mL, 96 mmol). Yie ld 21 g (88%). Anal. Calcd for C i 3 H 2 8 S 2 : C, 62.84; H , 11.36. Found: C, 60.58; H , 11.08 %. T i - N M R (CDC1 3 , 200 M H z ) 8 2.56 (m, 8H, CH2SCH2), 1.85 (q, 2 H , C H 2 C # 2 C H 2 ) , 1.56 (q, 4H , C # 2 C H 2 C H 2 C H 3 ) , 1.35 (m, 8H, C # 2 C # 2 C H 3 ) , 0.92 (t, 6H , CH3). Mass spectrum [LSIMS, m/z] 248 [ M ] + , 177 [ M - C 5 H „ ] + . 2.3.6 1,3-Bis(phenylthio)propane (MW = 260.41 g/mol)5 The dithioether was prepared according to the procedure given in Section 2.3.1, but using benzenethiol (50 mL, 487 mmol) and 1,3-dibromopropane (24.7 mL, 244 mmol). 38 References on page 61 Chapter 2 Yield 47 g (74%). Anal. Calcd for C 1 5 H 1 6 S 2 : C, 69.18; H , 6.19. Found: C, 68.28; H , 6.27 %. ' H - N M R (CDC1 3 , 200 M H z ) 5 7.55 (m, 10H, Cstfj), 2.93 (m, 4H, CH2CH2CH2 ), 2.10 (m, 2H, C H 2 C # 2 C H 2 ) . Mass spectrum [LSBVIS, m/z] 260 [ M ] + . The *H N M R data compare well with literature values.5 2.3.7 5,8-Dithiadodecane (MW'= 206.39g/mol) 5,8-Dithiadodecane was prepared according to the procedure given in Section 2.3.1, but using butanethiol (13 mL, 120 mmol) and 1,2-dibromoethane (5.3 mL, 61 mmol). Yie ld 14.5 g (58 %). Anal. Calcd for C i „ H 2 2 S 2 : C, 58.19; H , 10.74. Found: C, 58.38; H , 10.76 %. ' H - N M R (CDCI3, 200 M H z ) 8 2.73 (s, 4H, SCH2CH2S), 2.55 (t, 4H , CH2S), 1.45 (m, 8H, CH2CH2CH3), 0.90 (t, 6H, CH3). Mass spectrum [LSJJVIS, m/z] 206 [ M ] + , 149 [ M -C + H o ] * . 2.3.8 6,9-Dithiatetradecane (MW = 234.44 g/mol) The dithioether was prepared according to the procedure given in Section 2.3.1, but using pentanethiol (9.8 mL, 80 mmol) and 1,2-dibromoethane (3.4 mL, 40 mmol). Yie ld 6.1 g (65 %). Anal. Calcd for C i 2 H 2 6 S 2 : C, 61.48; H , 11.18. Found: C, 61.09; H , 10.99 %. ! H - N M R (CDCI3, 200 M H z ) 8 2.75 (s, 4H , SCH2CH2S), 2.55 (t, 4H , CH2S), 1.60 (q, 4 H , C//2CH2CH2CH3), 1.35 (m, 8H, C#2C# 2 CH 3 ) , 0.92 (t, 6H, CH3). Mass spectrum [ L S I M S , m/z] 234 [ M ] + . 39 References on page 61 Chapter 2 2.3.9 7,10-Dithiahexadecane (MW = 262.49 g/mol) 7,10-Dithiahexadecane was prepared according to the procedure given in Section 2.3.1, but using hexanethiol (40 mL, 280 mmol) and 1,2-dibromoethane (12.2 mL, 142 mmol). Yie ld 25 g (67 %). Anal. Calcd for C14H30S2: C, 64.06; H , 11.52. Found: C, 63.88; H , 11.39 %. ^ - N M R (CDCI3, 200 M H z ) 5 2.75 (s, 4H , SCH2CH2S), 2.55 (t, 4 H , CH2S), I. 55 (q, 4 H , C # 2 C H 2 C H 2 C H 2 C H 3 ) , 1.30 (m, 12H, CH2CH2CH2CH3), 0.95 (t, 6H , CH3). Mass spectrum [LSJMS, m/z] 262 [M] + . 2.3. JO J, 2-Bis(phenylthio)ethane (MW = 246.38 g/mol)5'6 l,2-Bis(phenylthio)ethane was prepared generally according to the procedure given in Section 2.3.1, but using benzenethiol (50 mL, 480 mmol) and 1,2-dibromoethane (21 mL, 240 mmol), while the aqueous layer was extracted three times with CHCI3 (40 mL) portions; the organic residues were combined and the CHCI3 was removed by rotary evaporation. The white solid obtained after removal of CHC1 3 was recrystallized using C H 2 C 1 2 (7 mL) and E t 2 0 (100 mL). Yield 39 g (65 %). Anal. Calcd for C i 4 H i 4 S 2 : C, 68.25; H , 5.73. Found: C, 68.18; H , 5.71 %. ! H - N M R (CDCI3, 200 M H z ) 8 7.15 (m, 10H, CsH5\ 3.10 (s, 4 H , CH2CH2). The X H N M R data compare well with literature values.5 2.3.11 1,2-Bis(cyclohexylthio)ethane (MW = 258.47 g/mol) The dithioether was prepared according to the procedure given in Section 2.3.1, but using cyclohexylthiol (50 mL; 400 mmol) and 1,2-dibromoethane (17.6 mL, 204 mmol). Yie ld 23.7 g (45 %). Anal. Calcd for C i 4 H 2 6 S 2 : C, 65.06; H , 10.14. Found: C, 64.91; H , 10.03 %. * H - N M R (CDCI3, 400 M H z ) 8 2.70 (s, 4H , CH&HJ, 1.95, 1.75 (m 4 H each, H 2 ) , 40 References on page 61 Chapter 2 1.58 (m, 2H, H i ) , 1.29 (m, 12H, H 3 , 4 ) . Mass spectrum [LSIMS, m/z] 258 [ M ] + . The labelled H-atoms are associated with the corresponding C-atoms as shown in Figure 2.1. C3-C2 Figure 2.1. Diagram showing the labelling of the H-atoms of l,2-bis(cyclohexylthio)ethane. 2.4 Oxidation of Dithioethers to Disulfoxides The dialkylsulfoxides were synthesized by acid-catalyzed, D M S O oxidation o f the corresponding dithioethers following the procedure reported by Hul l and Bargar. 7 The diarylsulfoxides were synthesized by H2O2 oxidation of the corresponding diarylsulfide following the procedure reported by Bennett et al.* The disulfoxides synthesized are new unless otherwise indicated (by a superscript in the heading). 2.4.1 1,3-Bis(ethylsulfinyl)propane (BESP) (MW = 196.32 g/mol) A solution consisting of 3,7-dithianonane (10 mL, 60 mmol), D M S O (9.5 mL, 120 mmol) and cone. HC1 (200 uL) was heated for 8 h at 85 °C with constant stirring. The sulfoxide precipitated as thin, white crystals when the reaction mixture was cooled to 0 °C. The crude product was collected and washed with acetone to remove excess D M S O and D M S . The filtrate was heated again for a further 4 h, and more product was obtained. The crude sulfoxide was recrystallized from E t O H (50 mL) three times. Yie ld 7.8 g (65 %). Anal. Calcd for C 7 H i 6 0 2 S 2 : C, 42.83; H , 8.21. Found: C, 43.14; H , 8.19 %. T l - N M R (CDC1 3 , 200 41 References on page 61 Chapter 2 MHz) 5 2.90 (m, 8H, CH2S(0)CH2), 2.45 (m, 2H, CH2Gr72CH2), 1.35 (t, 6H, CH3). IR v s o: 1016, 1047. M. p. °C: 127-130. 2.4.2 1,3-Bis(propylsulfmyl)propane (BPSP) (MW = 224.3 7 g/mol) BPSP was prepared according to the procedure given in Section 2.4.1, but using 4.8- dithiaunadecane (10 mL, 52 mmol), DMSO (8 mL, 100 mmol) and cone. HC1 (200 uL). Yield 8.9 g (77%). Anal. Calcd for C9H2 0O2S2: C, 48.18; H, 8.98. Found: C, 48.09; H, 9.09 %. 'H-NMR (CDCI3, 200 MHz) 5 3.00 (m, 4H, CH2CH2CH2), 2.90 (m, 4H, CH2S(0)\ 2.20 (m, 2H, CH2CrY2CH2), 1.80 (m, 4H, CH2Gr72CH3), 1.07 (t, 6H, CH3). IR v s o: 1021, 1075. M. p. °C: 140-143. 2.4.3 1,3-Bis(i-propylsulfinyl)propane (BPSP) (MW =224.37g/mol) B'PSP was prepared generally according to the procedure given in Section 2.4.1, but using 2,8-dimethyl-3,7-dithianonane (10 mL, 52 mmol), DMSO (8 mL, 100 mmol) and cone. HC1 (200 u.L). The sulfoxide precipitated as small white crystals when the reaction mixture was cooled to 0°C, after the sides of the flask were scratched and Et20 (30 mL) was added. Yield 2.3 g (20 %). Anal. Calcd for C9H20OA: C, 48.18; H, 8.98. Found: C, 48.32; H, 9.06 %. 'H-NMR (CDCI3, 200 MHz) 5 2.75 (m, 6H, C#S(0)C#2CH2C#2S(0)C#), 2.35 (m, 2H, CH2C#2CH2), 1.35 (d, 12H, (QH3)2). tRv s o: 1016. 2.4.4 l,3-Bis(butylsulfinyl)propane (BBSP) (MW = 252.42 g/mol) BBSP was prepared according to the procedure given in Section 2.4.1, but using 5.9- dithiatridecane (10 mL, 45 mmol), DMSO (7 mL, 90 mmol) and cone. HC1 (200 uL). 42 References on page 61 Chapter 2 Yield 9.9 g (87 %). Anal. Calcd for CHH24O2S2: C, 52.34; H, 9.58. Found: C, 52.36; H, 9.56%. 'H-NMR (CDCI3, 200 MHz) 8 2.80 (m, 8H, CH2S(0)CH2), 2.40 (m, 2H, CH2C/6CH2), 1.75 (q, 4H, CH 3CH 2Cft), 1.50 (s, 4H, CH3CH2), 0.95 (t, 6H, CH3). IR v s o: 1021. M. p. °C: 146-148. 2.4.5 1,3-Bis(pentylsulfinyl)propane (BPeSP) (MW = 280.47 g/mol) BPeSP was prepared according to the procedure described in Section 2.4.1, but using 6,10-dithiapentadecane (10 mL, 40 mmol), DMSO (6 mL, 80 mmol) and cone. HC1 (200 uL). Yield 3.3 g (29 %). Anal. Calcd for C13H28O2S2: C, 55.67; H, 10.06. Found: C, 55.48; H, 10.12 %. 'H-NMR (CDC13, 200 MHz) 8 2.70 (m, 8H, CH2S(0)CH2\ 2.25 (m, 2H, CH2Ci72CH2), 1.68 (q, 4H, CH3CH2CH2C#2), 128 (m, 8H, CH3CH2CH2), 0.85 (t, 6H, CH3). JRvso: 1026. M. p. °C: 125-129. 2.4.6 l,3-Bis(phenylsulftnyl)propane (BPhSP) (MW = 292.41 g/mol) l,3-Bis(phenylthio)propane (10 g, 38 mmol) was added to 200 mL of glacial acetic acid, and the solution was cooled to 0 °C. 9 mL of 30 % H 2 0 2 (76 mmol) was added dropwise at 0 °C. The resulting solution, after being stirred for 24 h at r.t., was then extracted three times with C H C I 3 (50 mL portions). The CHC13 was neutralized with a saturated NaHC03 solution. This CHC13 layer was then washed with H 20 and then dried over MgS04. The MgS0 4 was removed and the CHCI3 was removed by rotary evaporation before the product was collected as a white solid. The crude product was recrystallized with a minimal of CH2C12 (7 mL) and Et 20 (50 mL). Yield 2.1 g (19 %). Anal. Calcd for C 1 5 H 1 6 0 2 S 2 : C, 61.61; H, 5.51. Found: C, 61.42; H, 5.42 %. 'H-NMR (CDC13, 200 MHz) 8 7.50 (m, 10H, 43 References on page 61 Chapter 2 CeHs), 2.90 (m, 2H, C H 2 C / / 2 C H 2 ) , 2.15 (m, 4H, Ci / 2 CH 2 C#2). IR v s o : 1021, 1040, 1084. M . p. °C: 137-140. Of note, an attempt to oxidize l,3-bis(phenylthio)propane using air/DMSO oxidation led to an oily product, which by TLC, J H N M R spectroscopy and Vso data appeared to be the disulfoxide. However, reaction of this oil with RuCi3-3H 20, using the procedure described in Section 2.7.4, led to the isolation of red crystals which were submitted for X-ray analysis. The structural diagram (see Chapter 6) shows one coordinated disulfoxide and one 'half-oxidized' dithioether. 2.4.7 1,2-Bis(ethylsulflnyl)ethane (BESE) (MW = 182.29g/mol)910 B E S E was prepared according to the procedure given in Section 2.4.1, but using 3.6- dithiaoctane (10 mL, 66 mmol) in DMSO (11 mL, 150 mmol) and cone. HC1 (200 uL). Yield 7.8 g (65 %). J H - N M R (D 20, 200 MHz) 8 3.30 (m, 4H, CH&H3), 2.92 (m, 4H, CH3C//2), 1.23 (t, 6H, CH3). M. p. °C: 148-149. The ! H N M R data compare well with reported values.9'10 2.4.8 l,2-Bis(propylsulfinyl)ethane (BPSE) (MW'= 210.34g/mol)9'10 BPSE was prepared according to the procedure given in Section 2.4.1, but using 4.7- dithiadecane (10 mL, 56 mmol) in DMSO (8.7 mL, 110 mmol) and cone. HC1 (200 uL). Yield 8.2 g (70%). *H-NMR (CDC13, 200 MHz) 8 3.20, 3.00 (m, 2H each, S(0)C//;C/^S(0)), 2.77 (m, 4H, CftS(O)), 1.92 (m, 4H, CH 3 C# 2 ) , 1.10 (t, 6H, CH3). M . p. °C: 162-164. The X H N M R data compare well with reported values.9'10 44 References on page 61 Chapter 2 2.4.9 1, 2-Bis(butylsulflnyl)ethane (BBSE) (MW = 238.34 g/mol) B B S E was prepared according to the procedure described in Section 2.4.1, but using 5,8-dithiadodecane (10 mL, 48 mmol) in DMSO (8 mL, 97 mmol) and cone. HC1 (200 uL). Yield 2.3 g (20 %). Anal. Calcd for C 1 0 H 2 2 O 2 S2: C, 50.37; H , 9.30. Found: C, 50.29; H , 9.43 %. ^ - N M R (CDC13, 200 MHz) 5 3.20, 3.00 (m, 2H each, S ( 0)Gr7 2Gr7 2 S ( 0 ) ) , 2.75 (m, 4H, C # 2 S ( 0 ) ) , 1.72 (m, 4H, CH 3 CH 2 C# 2 ) , 1.45 (m, 4H, CH 3 C# 2 ) , 0.95 (t, 6H, CH3). I R v s o : 1014. M . p. °C: 172-173. 2.4.10 1,2-Bis(pentylsulfmyl)ethane (BPeSE) (MW = 266.39 g/mol) BPeSE was prepared according to the procedure given in Section 2.4.1, but using 6.9- dithiatetradecane (10 mL, 40 mmol) in DMSO (7 mL, 80 mmol) and cone. HC1 (200 uJL). Yield 3.9 g (34%). Anal. Calcd for C i 2 H 2 6 0 2 S 2 : C, 54.09; H , 9.83. Found: C, 54.11; H , 10.10 %. ^ - N M R (CDC13, 200 MHz) 5 3.20, 3.10 (m, 2H each, S(0)CH2CH2S(0)\ 2.80 (m, 4H, C / / 2 S ( 0 ) ) , 1.80 (m, 4H, CH 3 CH 2 CH 2 C#,) , 1.40 (m, 8H, CH3CH2CH2), 0.93 (t, 6H, CH3). I R v s o : 1014, 1073, 1100. M . p. °C: 134-135. 2.4.11 1,2-Bis(hexylsulfinyl)ethane (BHSE) (MW= 294.44g/mol) BHSE was prepared according to the procedure given in Section 2.4.1, but using 7.10- dithiahexadecane (10 mL, 38 mmol) in DMSO (6 mL, 76 mmol) and cone. HC1 (200 uL). Yield 6.2 g (55 %). Anal. Calcd for Ci4H 3 0O 2S 2 : C, 57.09; H , 10.27. Found: C, 57.00; H , 10.19%. ! H - N M R (CDC13, 200 MHz) 5 3.20, 3.10 (m, 2H each, S(0)CH2CH2S(0)\ 45 References on page 61 Chapter 2 2.80 (m, 4H, Cf tS (O) ) , 1.80 (m, 8H, C ^ C H z C H z C f t C / ^ ) , 1.40 (m, 8H, CH3CH2CH2), 0.93 (t, 6H , CH3). IR v s o : 1016, 1114. M . p. °C: 176.5-177.5. 2.4.12 1,2-Bis(cyclohexylsulfinyl)ethane (BCySE) (MW = 290.47 g/mol) B C y S E was prepared according to the procedure given in Section 2.4.1, but using l,2-bis(cyclohexylthio)ethane (10 mL, 40 mmol) in D M S O (6 mL, 77 mmol) and cone. HC1 (200 uL) . Yie ld 9.1 g (80%). Anal. Calcd for C14H26O2S2: C, 57.89; H , 9.02. Found: C, 58.13; H , 9.13 %. X H - N M R (CDC1 3 , 400 M H z ) 5 3.60 (m, 4H, CH2CH2), 2.56, 2.15 (m, 2 H each, H 2 ) , 1.69 (m, 2H, HO, 1.35 (m, 12H, H 3 , 4 ) . IR v s o : 1018. M . p. °C: 172-174. (See Section 2.3.11 for the labelling of the H-atoms). 2.4.13 1,2-Bis(phenylsulfinyl)ethane (BPhSE) (MW = 278.38g/mol)6 B P h S E was prepared according to the procedure given in Section 2.4.6, but using l,2-bis(phenylthio)ethane (10 g, 40 mmol) and 9 mL of 30 % H 2 0 2 (80 mmol). Yie ld 7.4 g (65 %). Anal. Calcd for C i 4 H i 4 0 2 S 2 : C, 60.40; H , 5.07. Found: C, 60.52; H , 5.06 %. *H-N M R (CDCI3, 200 M H z ) 5 7.45 (m, 10H, C(Ji5), 3.35, 2.70 (m, 2 H each, CH2CH2). IR v s o : 1035, 1089. M . p. °C: 165-170. The spectroscopic data compare well with the literature data.6 46 References onpage 61 Chapter 2 2.5 Synthesis of Ru(ni) Precursor Complexes The precursors listed below were synthesized according to literature reports. 2.5.1 [Ru(DMF)6][OTfJ3 (MW = 986.85 g/mol)'1 The [Ru(DMF) 6 ][OTf |3 was synthesized by a modified literature procedure by Judd et al.11 A solution of R u C l 3 - 3 H 2 0 (2.00 g, 10 mmol) in D M F (120 mL) with Sn granules (7.0 g, 59 mmol) was vigorously stirred at r.t. under N 2 . The suspension turned from dark-brown, through red-brown, green, to blue. Pb(OTf) 2 (6.50 g, 13 mmol) was then added. The mixture was stirred at 50 °C for 2 h, during which time the colour changed to deep brown-red. The mixture was then filtered to remove unreacted Sn and was concentrated on a rotary evaporator to 20 mL. C H 2 C 1 2 (300 mL) was added, and the resulting suspension was then stirred in air at r.t. overnight. The mixture was filtered through Celite and the P b C l 2 was collected and discarded. C H 2 C 1 2 was then removed. To the residue at r.t. was added 1,2-C 2 H4C1 2 (40 mL), after which the solution was cooled to 4 °C to give a yellow precipitate. This was collected, redissolved in C H 2 C 1 2 , and the solution filtered. The filtrate was evaporated to dryness, 5 m L of «-pentanol were added and the resulting yellow precipitate was collected, washed with E t 2 0 (50 mL), and dried in vacuo. The product was stored in the absence of light. Yield 2.3 g (31 %). Anal. Calcd for C z i ^ N e d s S s F p R u : C, 25.56; H , 4.29; N , 8.52. Found: C, 25.43; H , 4.30; N , 8.54 %. 47 References on page 61 Chapter 2 2.5.2 K3[RuCl6] (MW = 431.08 g/mol)12 R u C l 3 - 3 H 2 0 (1.00 g., 4 mmol) was dissolved in 50 m L of M e O H . The solution was refluxed under H 2 , when the yellow-brown solution began to turn green after about 5 h. A t this stage, KC1 (0.90 g, 12 mmol) was added and the mixture refluxed in air. The KC1 slowly dissolved with concomitant formation of a brown precipitate; this was filtered off from the colourless supernatant and washed with M e O H . The crude product was recrystallized from 12M HC1, washed with M e O H and vacuum-dried. Yield 1.1 g (67 %). U V - V i s (12 M HC1) 348 (3.45), 312 (3.33), 228 (4.38). The U V - V i s data compare well with the literature data. 1 2 2.6 Synthesis of Monodentate Sulfoxide Complexes of Ruthenium 2.6.1 Cis-RuCl2(DMSO)4 (MW = 484.50 g/mol)13 R u C l 3 - 3 H 2 0 (2.00 g, 7.6 mmol) was dissolved in D M S O (8 mL, 110 mmol), and the reaction mixture was refluxed for 20 min. The complex precipitated as a fine, yellow, crystalline powder when the reaction mixture was cooled to r.t. Acetone (30 mL) was added and more complex precipitated. The yellow precipitate was collected in air and dried in vacuo at 70 °C. Yie ld 3.1 g (85 %). ' H - N M R (CDC1 3 , 200 M H z ) 5 3.55, 3.52, 3.46, 3.45 ( D M S O ) , 2.75 ( D M S O ) , 2.62 (free D M S O ) . The X H N M R data and yield compare well with the literature data. 1 3 48 References on page 61 Chapter 2 2.6.2 Trans-RuCl2(DMSO)4 (MW = 484.50 g/mol)14 C w - R u C l 2 ( D M S O ) 4 (2.5 g, 5.2 mmol) was dissolved in D M S O (40 mL, 560 mmol), and this resulting solution was transferred to a glass photolysis tube (450 W H g lamp, see Appendix 2, Figure A.2.1) outfitted with a water-cooled condenser and a septum that allowed for a constant flow of A r through the solution. The solution was photolysed for 4 h after which a yellow/orange microcrystalline solid formed from the solution. The solid was collected in air and dried at 70 °C in vacuo. Yield 1.8 g (72 %). ' H - N M R ( D 2 0 , 200 M H z ) 8 3.30 (s, D M S O ) , 2.63 (free D M S O ) . The spectroscopic data agree well with those previously reported. 1 5 2.6.3 Mer-cis-[RuCh(DPSO)2(DPSO)] (MW = 814.24 g/mol) Cone. HC1 (250 p.L) was added to a solution of R u C l 3 - 3 H 2 0 (250 mg, 1 mmol) in E t O H (15 mL), and the mixture was heated at 85 °C for 5 h until the solution turned green. D P SO (1.4 g, 7 mmol) was added and the mixture was refluxed for a further 6 h. The volume o f the resulting dark-orange solution was then reduced until the reaction solution became oily. Ether was added and the resulting orange solution was set aside for 5-7 days at r.t. Crystals suitable for X-ray analysis formed on the side of the flask and were collected by filtration. Yie ld 360 mg (46 %). ' H - N M R (CDC1 3 , 200 M H z ) 5 8.80 (broad peak), 7.70 and 7.45 (free DPSO) . Anal. Calcd for C 3 6 H 3 0 C l 3 O 3 R u S 3 : C, 53.10; H , 3.71; S, 11.81. Found: C, 53.02; H , 3.72; S, 11.77 %. U V - V i s (CH 2 C1 2 ) 448 (3.14), 388 (3.39), 240 (4.46). IR v s o : 922, 1063, 1129. u, e f f (Evans) = 2.3 + 0 . 1 B . M . During this thesis work, the Trieste group reported on the synthesis and structural characterization of this same D P S O complex. 1 6 49 References on page 61 Chapter 2 2.6.4 Cis-[Ru(12-S-4)(DMSO)(H20)][OTf]2-CH3OH(MW = 767.84g/mol) C/ '5 -RuCl 2 (DMSO) 4 (100 mg, 0.2 mmol) was added to 1,4,7,10-tetrathiacyclododecane (50 mg, 0.2 mmol) dissolved in C H C I 3 (25 mL) to give a yellow solution that was then refluxed for 3 h. The reaction solution was then cooled to r.t. when A g O T f (104 mg, 0.4 mmol) dissolved in acetone (10 mL) was added dropwise. The A g C l was filtered off through Celite, and to the filtrate was added C H C I 3 (5 mL). Yel low crystals suitable for X-ray analysis formed upon slow evaporation of the CHCI3. Yie ld 66 mg (45 %). Anal. Calcd for C i 2 H 2 4 F 6 0 8 R u S r C H 3 O H : C, 20.33; H , 3.67. Found: C, 20.55; H , 3.49 %. ^ - N M R (MeOD, 400 M H z ) shows a multiplet centred at 8 3.1. IR v s o : 1027, 1082, 1158. U V - V i s (H 20) 398 (3.19), 350 (3.05), 264 (4.01), 236 (3.99). A M (H 20) 139. 2.6.5 RuCl2(DMSO)(L) (MW = 512.44g/mol) C / s - R u C l 2 ( D M S O ) 4 (50 mg, 0.1 mmol) was added to a solution of 3,6,9,14-tetrathiabicyclo[9.2.1]tetradeca-ll,13-diene (27 mg, 0.1 mmol) dissolved in C H C 1 3 (20 mL) to give a yellow solution that was then refluxed for 3 h. The resulting red solution was cooled to r.t. and then evaporated to dryness. Hexanes (20 mL) was added to give an orange/red precipitate that was then dissolved in D M S O (1 mL). Crystals suitable for X-ray analysis were formed by vapour diffusion of E t 2 0 into the D M S O solution. Yie ld 22 mg (42 %). Anal. Calcd for C i 2 H 2 „ C l 2 O R u S 5 : C, 28.12; H , 3.93. Found: C, 28.46; H , 4.22 %. ^ - N M R ( D M S O d6, 400 M H z ) 8 7.1 (m, 2H, CH=CH) and a complex pattern between 2.7-4.5 ( C H 2 protons of the macrocycle and methyls of D M S O ) . IR v s o : 1015, 1083, 1105. U V - V i s ( D M S O ) 416 (2.47), 272 (3.91). 50 References on page 61 Chapter 2 2.7 Synthesis of Mononuclear Ru(DI) Disulfoxide Complexes 2.7.1 Cis-RuCl2(BESE)2 (MW = 536.57 g/mol) To a solution of K 3 [ R u C l 6 ] (250 mg, 0.6 mmol) in H 2 0 (15 mL) was added a solution of B E S E (210 mg, 1.2 mmol) in M e O H (5 mL), and the mixture was heated to 50 °C for 5 h. The colour changed from light brown to yellow, and a yellow precipitate formed. Yie ld 112 mg (36 %). Anal Calcd for Ci2H28Cl204RuS4:C, 26.86; H , 5.26. Found: C, 26.72; H , 5.22 %. ' H - N M R (D 2 0, 200 M H z ) 8 3.95-2.95 (m, 16H, CH2S(0)CH2), 1.45, 1.30 (t, 6 H each, CH3). IR v S o: 1092, 1122. The spectroscopic data agree well with those previously reported. 9 ' 1 0 Other methods using RuCl 3 -3H 2 0 and / ra t t£-RuCl 2 (DMSO) 4 as precursors for the attempted synthesis of / ra«s-RuCl 2 (BESE) 2 led to the isolation of c / s -RuCl 2 (BESE) 2 . Unsuccessful attempts were made to utilize photolysis (see Section 2.6.2) to effect the isomerization of c /5 , -RuCl 2 (BESE) 2 to / ra«s-RuCl 2 (BESE) 2 , following a report by Alessio et al. in which the cis to trans isomerization of c / s -RuCl 2 (DMSO) 4 to f ra«s-RuCl 2 (DMSO )4 was achieved using photolysis. 1 4 2.7.2 Trans-RuCl2(BESE)rH20 (MW = 554.56g/mol) To a solution of [RuCl(BESE)(H 2 0 ) ] 2 (^-Cl ) 2 (25 mg, 0.035 mmol; see Section 2.8.1) in H 2 0 (10 mL) was added B E S E (12.2 mg, 0.07 mmol), and the resulting yellow solution was refluxed for 4 h before being reduced in volume; the product formed as a crystalline powder. Crystals suitable for X-ray analysis were formed by slow evaporation of an aqueous solution of the complex. Yield 12 mg (33 %). Anal. Calcd for 51 References on page 61 Chapter 2 Ci 2H 2 8Cl 204RuS4-H 20: C, 25.98; H , 5.45. Found: C, 26.10; H , 5.18 %. ' H - N M R (D 2 0, 200 M H z ) 8 3.70 (m, 16H, CH2S(0)CH2), 1.45 (m, 12H, CH3). IR v s o : 1093, 1119. U V - V i s (H 2 0 )374 (2.78), 310(3.19). 2.7.3 Trans-RuCl2(BPSE)2H20(MW = 610.48g/mol) To a solution of czs -RuCl 2 (DMSO) 4 (172 mg, 0.36 mmol) in M e O H (10 mL) was added a solution of B P S E (150 mg, 0.70 mmol) in M e O H (5 mL). This yellow solution was refluxed for 3 h when a yellow precipitate formed. Yield 99 mg (47 %). Anal. Calcd for C i 6 H 3 6 C l 2 0 4 R u S 4 - H 2 0 : C, 31.47; H , 6.27. Found: C, 31.62; H , 5.92%. ! H - N M R (CDC1 3 , 200 M H z ) 8 3.75, 3.35 (m, 8 H each, CH2S(0)CH2), 2.30, 2.85 (m, 4 H each, CU3CH2), 1.10 (t, 12H, CHi). IR vso: 1094. The spectroscopic data agree well with those previously reported. 9 ' 1 0 Other methods using RuCl 3 -3H 2 0 and K 3 [RuCle] as precursors for the attempted synthesis of cz's-RuCl 2 (BPSE) 2 led to the isolation of fra«5,-RuCl2(BPSE)2. Again, attempts were made to utilize photolysis to effect the isomerization of f ra«s-RuCl 2 (BPSE) 2 to cis-R u C l 2 ( B P S E ) 2 (see Section 2.6.2), but these were unsuccessful. 2.7.4 Cis-RuCl2(BBSE)2 (MW = 648.78 g/mol) Cone. HC1 (IOOJIL) was added to a solution of R u C l 3 - 3 H 2 0 (100 mg, 0.4 mmol) in E t O H (30 mL), and the mixture was refluxed for 5 h. B B S E (182 mg, 0.8 mmol) was added and the mixture was refluxed for a further 6 h. The resulting yellow solution was then reduced in volume until a fine yellow precipitate formed, and this was collected. Yie ld 52 mg (21 %). Anal. Calcd for C20H44Cl2O4RuS4: C, 37.03; H , 6.83. Found: C, 36.95; H , 6.80 %. 52 References on page 61 Chapter 2 Crystals o f an E t O H solvate suitable for X-ray analysis were formed by slow evaporation of an E t O H / C H 2 C l 2 solution of the complex. ^ - N M R (CDC1 3 , 200 M H z ) 6 3.60 (m, 16H, CH2S(0)CH2), 1.55 (m, 16H, CH3CH2CH2\ 0.98 (m, 12H, CH3). rRv S 0: 1081, 1126. U V -Vis (CH 2 C1 2 ) 236 (4.38). 2.7.5 Cis-RuCl2(BPeSE)2 (MW = 704.87 g/mol) The procedure used was as given in Section 2.7.4, but using B P e S E (204 mg, 0.8 mmol). The yellow product was purified by column chromatography using neutral alumina with 5 % E t O H / C H 2 C l 2 . Crystals, obtained by slow evaporation of an E t O H / C H 2 C l 2 solution of the complex, were subjected to X-ray analysis but excessive thermal motion due to the long pentyl groups prevented an accurate determination of the structure; however, c/'s-geometry was established. Yie ld 24 mg (9 %). Anal. Calcd for C 24H 5 2Cl 204RuS 4: C, 40.89; H , 7.43. Found: C , 41.01; H , 7.58 %. ^ - N M R (CDC1 3 , 200 M H z ) 8 3.70 (m, 16H, CH2S(0)CH2\ 2.30, 1.85 (m, 4 H each, CH2CH2S(0)), 1.45 (m, 16H, CH3CH2CH2), 0.90 (m, 12H, CH3). IR v s o: 1081, 1128. U V - V i s (CH 2 C1 2 ) 240 (4.17). 2.7.6 Cis-RuCl2(BCySE)2 (MW = 752.92 g/mol) The procedure used was given in Section 2.7.4, but B C y S E (222 mg, 0.8 mmol) was used. A n orange-yellow precipitate formed and was collected. Yie ld 86 mg (30 %). Anal. Calcd for C 2 8H 5 2Cl 204RuS 4: C, 44.67; H , 6.96. Found: C, 44.34; H , 7.04 %. Crystals suitable for X-ray analysis were formed by slow evaporation of the reaction solution, and were found to contain one E t O H and 1/3 M e O H solvates per molecule. The ' H - N M R spectrum of the title complex is a complicated pattern of overlapping multiplets in the 8 1.0-4.4 region. 53 References on page 61 Chapter 2 Attempts to assign the spectrum using 1 3 C , H E T C O R , A T P and *H decoupling experiments were unsuccessful. IR v s o : 1046, 1100. U V - V i s (CH 2 C1 2 ) 428 (2.81), 338 (3.01). 2.7.7 Cis-RuCl2(BESP)2 (MW = 564.60 g/mol) The procedure used was described in Section 2.7.4, but B E S P (150 mg, 0.8 mmol) was used, and the resulting yellow solution was evaporated to near dryness. The complex was purified by column chromatography as described in Section 2.7.5. Yie ld 77 mg (36 %). Anal. Calcd for Ci4H 3 2 Cl 2 04RuS 4 : C, 29.78; H , 5.71. Found: C, 29.57; H , 5.80 %. Crystals (containing one E t O H and one H 2 0 solvate molecules) suitable for X-ray analysis were formed by vapour diffusion of E t O H into a C H 2 C 1 2 solution of the complex. ^ - N M R (CDC1 3 , 200 M H z ) 8 3.45 (m, 16H, CH2S(0)CH2), 2.75, 2.10 (m, 2 H each, C H 2 C # 2 C H 2 ) , 1.45 (m, 12H, CH3). IR v s o : 1042, 1088. U V - V i s (CH 2 C1 2 ) 348 (2.62), 262 (4.04), 246 (4.01). Reactions of BPhSE , B H S E , B 'PSP, B B S P , BPeSP, BPhSP and B M S B with R u C l 3 - 3 H 2 0 , utilizing the procedure in Section 2.7.4, led to yellow, uncharacterized products which by column chromatography yielded several bands or, in the case of B M S B , the isolated product was insoluble in common solvents. Elemental analyses for the products obtained from the major chromatography bands and the insoluble products were variable from repeat reactions. 54 References on page 61 Chapter 2 2.8 Synthesis of Dinuclear Ru(II)/Ru(II) Disulfoxide Complexes 2.8.1 [RuCl(BESE)(H20)]2(p-Cl)2(MW'= 744.59 g/mol) The procedure used was as given in Section 2.7.4, but using B E S E (70 mg, 0.4 mmol). A yellow precipitate was formed, and was collected. Yie ld 87 mg (60 %). Anal. Calcd for C 6 Hi6Cl 2 03RuS 2 : C, 19.35; H , 4.33; S, 17.22. Found: C, 19.63; H , 4.38; S, 17.44 %. ! H - N M R (D 2 0, 200 M H z ) 5 3.60 (m, 16H, CH2S(0)CH2\ 1.50 (m, 12H, CH3). U V - V i s (H 20) 424 (2.63), 326 3.16), 278 (3.42), 238 (3.47). IR v s o : 1042, 1071, 1118. Crystals suitable for X-ray analysis were formed by slow evaporation of H 2 0 solution of the complex and were found to contain one H 2 0 solvate per molecule. T G A (crystals): Calcd loss of 3H 2 0: 7.1 % and 2 B E S E : 51.5 %. Found: 6.8 % (from ~ 20°C to ~ 220°C) and 4 6 . 0 % (from ~ 220°C to ~ 370°C), respectively (Appendix 4, Figure A.4.1). A M (H 2 0, increasing to a maximum, steady value at > 20 min) 358. Initial attempts to synthesize imidazole complexes using [RuCl(BESE)(H 2 0) ] 2 ( / / -C l ) 2 as a precursor, with 2-nitroimidazole, 2-methyl-5-nitroimidzole and imidazole led to the isolation of water-soluble, red complexes that could not be purified by column chromatography and did not analyze well for C or H content. These reactions wil l be discussed in more detail in Chapter 6. 2.8.2 [RuCl(BPSE)(H20)]2(p-Cl)2(MW = 800.61 g/mol) The procedure used was as given in Section 2.7.4, but using B P S E (84 mg, 0.4 mmol). The yellow precipitate was collected. Yield 70 mg (46 %). Anal. Calcd for 55 References on page 61 Chapter 2 C 8 H 2 o C l 2 0 3 R u S 2 : C, 24.00; H , 5.03. Found: C, 23.64; H , 4.82 %. * H - N M R (D 2 0, 400 M H z ) 5 3.70 (m, 16H, CH2S(0)CH2), 2.00 (m, 8H, C # 2 C H 3 ) , 1.05 (m, 12H, CH3). IR v s o : 1048, 1083 and 1119. U V - V i s (H 20) 268 (4.60). A M (H 2 0, increasing to a maximum, steady value at > 30 min) 282. 2.8.3 [RuClfBBSE) (H20)]2(p-Cl)2 (MW = 856.75 g/mol) The procedure used was as given in Section 2.7.4, but using B B S E (95 mg, 0.4 mmol). The yield of the yellow precipitate was 100 mg (61 %). Anal. Calcd for C i o H 2 4 C l 2 0 3 R u S 2 : C, 28.04; H , 5.43. Found: C, 28.51; H , 5.43 %. ' H - N M R (D 2 0, 400 M H z ) 8 3.65 (m, 16H, CH2S(0)CH2), 2.00 (m, 8H, G r 7 2 C H 2 C H 3 ) , 1.49 (m, 8H, CH2CH3), 0.95 (m, 12H, CH3). IR v s o : 1046, 1098 and 1116. U V - V i s (H 20) 424 (2.92), 268 (4.39). A M (H 2 0, increasing to a maximum, steady value at > 30 min) 497. 2.9 Synthesis of a Dinuclear Ru(Il)/Ru(m) Disulfoxide Complex 2.9.1 [RuCl(BPSP)]2(p-Cl)3 (MW = 828.16 g/mol) The procedure used was as described in Section 2.7.4, but with use of B P S P (172 mg, 0.8 mmol). The final orange solution was evaporated to near dryness, C H 2 C 1 2 (5 mL) was added, and crystals suitable for X-ray analysis were formed by slow evaporation o f the solution. Elemental analysis was performed on a crystal sample that was crushed and dried in vacuo at 70 °C overnight. Yield 24 mg (15 %). Anal. Calcd for C i g r L w C l s O t o S * C, 26.11; H , 4.87. Found: C, 26.05; H , 5.09%. T i - N M R (CDC1 3 , 200 M H z ) 8 2.18 (broad peak), 1.10 (broad peak). ' H - N M R (D 2 0, 200 M H z ) 8 3.95 (m, 4H, S(0)C# 2 CH 2 C# 2 S(0)) , 3.40 56 References on page 61 Chapter 2 (m, 4 H , CH2S(0)\ 2.62 (m, 2H, C H 2 C / ^ C H 2 ) , 1.90 (m, 4H, C H 2 C # 2 C H 3 ) , 1.10 (m, 6H, CH3). IR v s o : 1053, 1084. U V - V i s (immediately upon dissolution in C H 3 C N ) 424 (2.52), 324 (2.94), 286 (3.32). U V - V i s (after 20 min in H 2 0) 450 (3.78), 318 (4.42), 282 (4.78). N o conductivity was observed in C H 3 C N . A M (CHC1 3 , time independent) 2. A M (H 2 0, increasing to a maximum, steady value at > 20 min) 234. The colour of the solutions used for U V - V i s and conductivity did not change over the period of the experiments. The crystal structure revealed the presence of 2 H 2 0 and 2.5 C H 2 C 1 2 . T G A (crystals; complex formulated as-2 H 2 0 or-2 H 20-2.5 C H 2 C 1 2 ; the two formulations are used as the C H 2 C 1 2 solvates are readily lost at ambient conditions): Calcd loss of 2H 2 0: 4.2 or 3.3 % and for loss of 2BPSP: 54.2 %. Found: 6.1 % (from ~ 20°C to ~ 200°C) and 51.9 % (from ~ 200°C to ~ 300°C), respectively (Appendix 4, Figure A.4.2). pefr (Evans) = 1.7 ± 0.1 B . M . 2.10 Synthesis of Mononuclear Ru(ll) Dithioether Complexes 2.10.1 Trans-RuCl2(BCyTE)2-2H20(MW= 724.59 g/mol) Cone. HC1 (lOOpL) was added to a solution of RuCl 3 -3H 2 0 (100 mg, 0.4 mmol) in E t O H (30 mL), and the mixture was refluxed for 5 h. l,2-Bis(cyclohexylthio)ethane ( B C y T E , . 198 mg,. 0.8 mmol) was added and the mixture was refluxed for a further 6 h. The resulting red precipitate was collected by filtration and dried in vacuo. Elemental analysis was performed on the isolated precipitate. Yield 223 mg (81 %). Anal. Calcd for C 2 8 H 5 2 Cl 2 S4Ru -2H 2 0: C, 46.39; H , 7.78. Found: C, 46.82; H , 7.43 %. Crystals suitable for X-ray analysis were grown by recrystallization of the complex from D M F / C H 2 C 1 2 (500 uL/2 mL) and were found to contain 2 C H 2 C 1 2 solvates per molecule. The ^ - N M R spectrum of 57 References on page 61 Chapter 2 the title complex is a complicated pattern of broad peaks in the range of 5 1.20-3.35. Attempts to assign the *H N M R spectrum using 1 3 C , 2 D - C O S Y and *H decoupling experiments were unsuccessful. The broad nature of the proton signals presumably results from the rotation of each of the cyclohexyl rings. U V - V i s (CH 2 C1 2 ) 438 (3.55), 400 (3.53), 280 (3.74), 236 (4.31). 2.10.2 Trans-RuCh(BPhTE)2 (MW = 664.75g/mol)'7 The synthesis of the red complex was as described above in Section 2.10.1, but using l,2-bis(phenylthio)ethane (BPhTE, 188 mg, 0.8 mmol). The product was then dissolved in minimum C H 2 C 1 2 and was purified by column chromatography using neutral alumina with C H 2 C 1 2 as eluant. The C H 2 C 1 2 was removed by rotary evaporation. Yie ld 184 mg (73 %). Anal. Calcd for C 2 8 H 2 8 C l 2 R u S 4 : C, 50.59; H , 4.24. Found: C, 50.82; H , 4.11 %. Crystals suitable for X-ray analysis were formed by slow evaporation of a D M F solution of the complex. X H - N M R (CDC1 3 , 400 M H z ) 5 7.65 (br s, 8H, o-CeHs), 7.28 (br s, 4 H , p-CeH5\ 7.12 (br s, 8H, m - C A ) , 3.07 (br s, 8H, CH2CH2). U V - V i s (CH 2 C1 2 ) 410 (3.50), 298 (4.55), 268 (4.54). A preliminary experiment to attempt oxidation of the coordinated B P h S E by in situ generation of dimethyldioxirane was unsuccessful as no Vso was detected in the crude reaction product, and no colour change of the reaction solution was observed (the details wi l l be discussed in Chapter 6). 58 References on page 61 Chapter 2 2.11 Synthesis of Dinuclear Ru(III)/Ru(ni) Dithioether Complexes 2.11.1 [RuCl2(BETP)]2(p-Cl)2(MW= 743.50 g/mol) Cone. HC1 (500uL) was added to a solution of RuCl 3 -3H 2 0 (500 mg, 2 mmol) in E t O H (30 mL), and the mixture was refluxed for 5 h. 3,7-Dithianonane ( B E T P , (1,3-bis(ethylthio)propane), 600 mg, 4 mmol) was added and the mixture was refluxed for a further 6 h. The volume of the resulting dark-brown solution was reduced until the solution became oily. Acetone (25 mL) was added and a purple-brown precipitate formed. Crystals suitable for X-ray analysis were formed by slow evaporation of a solution of the complex in CH2CI2. Yie ld 178 mg (24 %). Anal. Calcd for C 7 H i 6 C l 3 R u S 2 : C, 22.62; H , 4.34. Found: C, 22.38; H , 4.30 %. U V - V i s (CH2CI2) 454 (3.42), 376 (3.49), 268 (4.53). u, e f f (Gouy) = 3.8 ± 0.1 B ; M . 2.11.2 [RuCl2(BPTP)]2(p-Cl)2 (MW = 799.61 g/mol) The procedure used for the production of X-ray quality crystals was as described in Section 2.11.1, but using RuCl 3 -3H 2 0 (100 mg, 0.4 mmol) and 4,8-dithiaunadecane (BPTP, (l,3-bis(propylthio)propane), 147 mg, 0.8 mmol) and only 15 m L of acetone was added. Yie ld 83 mg (52 %). Anal. Calcd for C 9 H 2 0 C l 3 R u S 2 : C, 27.04; H , 5.04. Found: C, 27.51; H , 5.08 % U V - V i s (CH 2 C1 2 ) 448 (2.62), 374 (2.61), 252 (3.44). u. e f f (Gouy) = 3.0 ± 0.1 B. M . 2.11.3 [RuCl2(BBTP)]2(p-Cl)2 (MW = 855.72 g/mol) The procedure used was identical to that described in Section 2.11.1, but using R u C l 3 - 3 H 2 0 (100 mg, 0.4 mmol) and 5,9-dithiatridecane ( B B T P , (l,3-bis(butylthio)propane), 59 References on page 61 Chapter 2 160 mg, 0.8 mmol), and only 15 mL of acetone was added. Yield 43 mg (25 %). Anal. Calcd for CnH24Cl3RuS2: C, 30.88; H, 5.65. Found: C, 30.70; H, 5.52 %. UV-Vis (CH2C12) 454 (3.51), 376 (3.57), 268 (4.68). p e f f (Gouy) = 3.2 ± 0.1 B. M . 2.11.4 [RuCl2(BPeTP)]2(p-Cl)2 (MW = 911.82 g/mol) The method described above for the other Ru(III)/Ru(III) complexes was used with RuCl 3 -3H 2 0 (100 mg, 0.4 mmol), 6,10-dithiapentadecane (BPeTP, (1,3-bis(pentylthio)propane), 190 mg, 0.8 mmol) and a final addition of acetone (15 mL). Yield 100 mg (55 %). Anal. Calcd for C i 3 H 2 8 Cl 3 RuS 2 : C, 34.25; H, 6.19. Found: C, 34.34; H , 6.25 %. UV-Vis (CH2C12) 434 (3.41), 396 (3.45), 266 (4.86), 216 (4.83). peff (Gouy) = 3.4 ±0 .1 B. M . 60 References on page 61 Chapter 2.12 References for Chapter 2 1 Evans, D F . J. Chem. Soc. 1959, 2003. 2 Sur, S. K . J. Mag. Resort. 1989, 82, 169. 3 (a) Carlin, R. L . Magnetochemistry Springer-Verlag, Berlin, 1986, p. 3; (b) Selwood, P. W . Magnetochemistry (2nd ed), Interscience Publishers, Inc., N e w York, 1956, p. 78; (c) C R C Handbook of Chemistry and Physics (66th ed.), (eds. R. C. Weast, M . J. Astle and W. H . Beyer), C R C Press, Inc., Boca Raton, 1985-1986, p. E-121. 4 Morgan, S. T.; Ledbury, W . J. Chem. Soc. 1922,121, 2882. 5 Hartley, F. R ; Murray, S. G . ; Levason, W. ; Soutter, H . E . ; McAuliffe, C. A . Inorg. Chim. Acta 1979, 35, 265. 6 Cattalini, L . ; Michelon, G . ; Marangoni, G . ; Pelizzi, G. J. Chem. Soc. Dalton Trans. 1979, 96. 7 Hul l , M . ; Bargar, T. W . J. Org. Chem. 1975, 40, 3152. 8 (a) Bel l , E . V . ; Bennett, G . M . J. Chem. Soc. 1927, 1798; (b) Bennett, G . M . ; Statham, F. S. J. Chem. Soc. 1931, 1684. 9 Yapp, D . T. T. Ph. D . Dissertation, University of British Columbia, Vancouver, B . C , 1993. 10 Yapp, D . T. T.; Rettig, S. J.; James, B . R ; Skov, K . A . Inorg. Chem. 1997, 36, 5635. 11 Judd, R. J.; Cao, R ; Biner, M . ; Armbruster, T.; Burgi, H - B . ; Merbach, A . E . ; Ludi , A . Inorg. Chem. 1995, 34, 5080. 12 James, B . R ; McMil lan , R. S. Inorg. Nucl. Chem. Lett, 1975,11, 837. 13 (a) Evans, I. P.; Spencer, A . ; Wilkinson, G. J. Chem. Soc. Dalton Trans. 1973, 204; (b) McMi l l an , R. S.; Mercer, A . ; James, B . R ; Trotter, J. J. Chem. Soc. Dalton Trans. 1975, 1006. 14 Alessio, E . ; Mestroni, G ; Nardin, G. ; Attia, W . M . ; Calligaris, M . ; Sava, G . ; Zorzet, S. Inorg. Chem. 1988, 27, 4099. 61 Chapter 2 15 (a) Jaswal, J.; Rettig, S. I ; James, B. R. Can. J. Chem. 1990, 68, 1808; (b) Alessio, E.; Balducci, G.; Lutman, A. ; Mestroni, G.; Calligaris, M . ; Attia, W. M . Inorg. Chim. Acta 1992, 203, 205. 16 Calligaris, M . ; Faleschini, P.; Todone, F.; Alessio, E.; Geremia, S. J. Chem. Soc. Dalton Trans. 1995, 1653. 17 Chatt, J.; Leigh, G. J.; Storace, A. P. J. Chem. Soc. (A) 1971, 1380. 62 Chapter 3 Chapter 3 Structural Properties of Sulfoxide and Thioether Complexes of Ruthenium 3.1 General Introduction Early work by Cotton and Francis in sulfoxide chemistry was initiated partly by trade literature, commercial availability, favourable solvent properties of D M S O , and the resemblance of sulfoxides to phosphine oxides as the latter were used as extracting agents.1 Davies' interest in the coordination chemistry of sulfoxides originated mainly because of the excellent solvation properties of D M S O . 2 D M S O (b. p. 189 °C) is a convenient solvent in laboratory and industrial use because of its resistance to hydrolysis and thermal decomposition. Reactions involving alkylation, cyclization, condensation and ether formation are more selective and provide higher yields when using D M S O as the solvent.3 The coordination chemistry of sulfoxides has been studied since the early 1960s (and sulfoxides are capable of acting as Lewis bases), when sulfoxides were recognized as being potential ambidentate ligands, coordinating to specific metals via either oxygen or sulfur.2 The sulfur-oxygen bond in sulfoxides is very polar making sulfoxides good acceptors for hydrogen bonding. 4 Transition-metal complexes of sulfoxides are useful as reactive intermediates in preparative coordination chemistry and homogeneous catalysis.5 The bioinorganic chemistry of R u sulfoxide complexes as chemotherapeutic agents has also been investigated (Chapter 1). 63 References on page 155 Chapter 3 3.2 Structural Properties of the S-O Moiety in Sulfoxides Sulfoxides Ri-S(0)-R 2 have an S-atom in an oxidation state (4) intermediate to that found in sulfides R i - S - R 2 (2) and sulfones Ri-S(0) 2-R 2 (6), while the geometry about the S-atom is distorted trigonal pyramid with the S-atom sp 3 hybridized (Figure 3.1(1)). 0 R \ + - R ^ . . .. R ^ - + II / S O: - / S = 0 - / S = 0 S : R R R / ^ I II III (1) (2) Figure 3.1. Structure (1) and resonance forms (2) of a sulfoxide. The sulfoxide moiety is non-fluctional around room temperature, allowing for the isolation of chiral sulfoxides,6 while their racemization is possible by thermal treatment or by photochemical methods.7 The bond angles within free D M S O (Table 3.1) illustrate the trigonal pyramid geometry of the molecule, with the average C-S-0 (107 °) and C-S-C (98 °) angles deviating from 109 ° because of the lone electron pair on the S-atom and the double bond character present in the sulfur-oxygen bond. 8 The C-S-C bond angle is invariably smaller than the O-S-C bond angles in metal-sulfoxide complexes regardless of the type of side-groups, this being attributed to the repulsion between the bulkier sulfur-oxygen bonding double pair, the S lone-pair and the S-C bonding pair electrons. 1 4 The sulfur-oxygen bond length is in the range 1.47 to 1.531 A (Table 3.1), 9" 1 1 while a bond length of 1.51 A (estimated from S - N bond lengths) is considered consistent with a bond order o f - 2.0. 1 2 64 References on page 155 Chapter 3 A valence-bond description can be used to illustrate the bonding nature of sulfoxides. The sulfoxide structure is considered to be a hybrid of three resonance forms with form II the normal representation (Figure 3.1(2)).2 X-ray emission spectroscopic studies on sulfoxides indicate that the sulfur-oxygen bond is polarized with the S-atom having net positive charge. 1 3 Calligaris and Carugo stated that the average value of the S-0 bond length, 1.492 A (c / the estimated bond length o f 1.51 A 1 2 ) , is consistent with double bond character in the S-0 bond and is shorter than the 1.66 A expected for a single bond. 1 4 Table 3.1. Selected Bond Lengths and Bond Angles for D M S O in the Gaseous and Solid States. Bond Lengths (A) Bond Angles (°) State S-0 C-S C-S-C C - S - 0 Ref. Gaseous 1.47" 1.82° 100(5) 107(5) 10 Solid at 5°C f l 1.531 1.775-1.821 97.4 106.7-106.8 9 Solid at -60°C 1.471(8) 1.801(96)- 97.86(54) 107.04(57)- 11 1.812(14) 107.43(56) a E.s.d. not given. 3.3 Metal-Sulfoxide Bonding Sulfoxides are ambidentate and can coordinate either through the S- or O-atom. Initial observations suggested that D M S O coordinated to "harder" metals via oxygen and to "softer" metals via the sulfur.1 5 However, the "hardness" or "softness" of a metal ion can be 65 References on page 155 ^ Chapter 3 affected by the nature of the coordinated ligands, and steric effects can force O-bonding even in softer metal ions. 1 4 In addition, the introduction of highly electronegative substituents with ancillary ligands lowers the electron charge density on the metal, this also favouring O-bonding. 1 4 In mixed-ligand complexes the preferred coordinating atom of sulfoxides is determined in part by the ability of other ligands at the metal centre to compete for electron density. 1 6 The presence of strong 7i-electron acceptors withdraws electron density from the metal, and causes "softer" metals to become "harder". This reduction in electron density at the metal may be accompanied by a change in coordination of the ligand from a "soft" to a "hard" donor atom to optimize orbital overlap. 1 6 The "hardness" or "softness" of a metal is a qualitative indication of the degree of diffuseness and size of its atomic orbitals, the more diffuse and the larger the orbital, the "softer" the metal i s . 1 5 Metal-ligand orbital overlap with "hard" acids is more favourable with the less diffuse (i.e. "hard") donor orbitals o f oxygen, while "soft" acids have better orbital overlap with the more diffuse donor orbitals of sulfur. 2 ' 1 5 Steric constraints may cause coordination of sulfoxides through the O-atom to "softer" metals in some metal-sulfoxide systems, as coordination through the O-atom is less sterically demanding than through the sulfur. 1 7 ' 2 5 For example, electronic and steric factors have been used to rationalize the existence of the following two complexes in which sulfoxide coordinates to "softer" metals via oxygen; cis- [ P d ( D M S O ) 2 ( D M S O ) 2 ] 2 + and P d ( P h 2 P ( C H 2 ) 2 P P h 2 ) 2 ( D M S O ) 2 + . 1 7 1 8 Valence bond rationalizations utilizing the different resonance forms of the free sulfoxides are satisfactory in explaining much of the structural data determined for metal-66 References on page 155 Chapter 3 D M S O complexes (e.g. Table 3.2), while steric constraints also play roles in determining whether sulfoxides coordinate through the S- or O-atom. Rationalizations of this type also encompass the initial empirical observation that coordination of sulfoxides occurred in "softer" metals via sulfur, and via oxygen in "harder" metals. 1 4 A value o f 1.531 A for the sulfur-oxygen bond length for non-coordinated D M S O was obtained after correction for thermal motion whereas most of the sulfur-oxygen bond lengths reported for metal complexes refer to uncorrected values. 1 4 For comparison of sulfur-oxygen bond lengths, Calligaris and Carugo have used the average value of 1.492(1) A for a wide range o f non-coordinated sulfoxides (excluding low temperature and gas phase values, and data for H-bonded sulfoxides). 1 4 The sulfur-oxygen bond length of 1.492(1) A wil l be used for further comparisons. 3.3.1 Sulfur-Bonded Metal-Sulfoxide Complexes According to the hard-soft-acid-base theory, in soft metal-ion complexes, diffuse orbitals of acceptor atoms interact favourably with diffuse orbitals on the S-atoms, thus favouring S-bonding. 1 5 However, certain soft metal ions ( A g + , C d 2 + and H g 2 + ) exhibit O-bonding even in the absence o f sterically hindering or TC acceptor ligands, suggesting that a particular electronic structure is necessary that favours S-bonding over O-bonding, probably involving TC back-bonding from the metal orbitals to the S-atom orbitals , 1 4 Davies suggests that for Ru(I I ) -DMSO complexes, the Ru-S bond has a partial double bond character because of the drt-drc back donation from the metal to the sulfur.2 Selected structural data for some metal-DMSO complexes are listed in Table 3.2 and show that the geometries o f the sulfoxide 67 References on page 155 Chapter 3 Table 3 .2. Selected Structural Data for Selected Transition Me ta l -DMSO Complexes. Complex S -0 Bond (A) C - S - 0 Angle (°) Ref. * ra«s-FeCl 2 (DMSO) 4 + 1.541(6) 103.5(4)-103.7(4) 19,20 *ra«s-CuCl 2 (DMSO) 2 1.531(4) 103.9(3)-104.7(3) 21 c / s -P t 2 (DMSO) 2 1.454(9)-1.469(6) 107.6(5)-110.3(5) 22 c / s -RuCl 2 (DMSO) 3 (DMSO) 1.557(4);° 1.483(5), 1.485(5)* 101.6(3)-104.2(3):° 106.0(4)-107.7(4)* 23 /we/--Rh(py) 2Cl 3(DMSO) 1.48(1) 108.0(8)-110.6(8) 24 /Me / - -RuCl 3 (DMSO) 2 (DMSO) 1.545(4);" 1.474(4). 102.4(2), 102.7(3);° 25 1.484(4)* 107.5(2)-109.3(2)* [Ru2Cu-Cl)Cu-H)Cu-DMSO)Cl2(DMSO)4]- 1.442(5)- d 26 2 C H 2 C 1 2 1.486(4);* 1.532(4)c [Ru 2 Cl(DMSO) 5 ] ( / / -Cl ) 3 1.467(3)-1.479(3) 105.7(2)-107.2(2) 27 [Ru 20u-Cl)C"-DMSO)Cl 3(DMSO) 3(CO) 2] 1.455(7)-1.480(5); 1.508(5)e d 28 [ R u ( 0 2 C C H 3 ) 4 ( D M S O ) 2 ] [PF 6 ] 2 1.517(5), 1.523 (6) 105.5(5)-108.0(4) 29 c/'5-[CrCl(en) 2(DMSO)]ZnCl 4 e 1.537(5) 101.6(4)-103.9(3) 30 CIJ-[OSC1 2(DMSO) 41 1.467(4)-1.483(3) 105.3(2)-107.1(2) 31 " O-bonded. * S-bonded. c Bridging. d Data not given. e en = ethylenediamine. remain essentially unchanged from that of the free ligand. However, effects of coordination are most evident in the sulfur-oxygen bond length (in D M S O ) as this is lengthened to 1.517(5)-1.557(4) A (see Tables 3.1 and 3.2). Valence bond arguments imply that donation from resonance form III could account for S-bonding (Figure 3.1(2)), but structural data on the coordinated sulfoxides ' indicate that the S-atom upon coordination becomes more positive than in the free ligand (it I i I has been shown that an increase in the degree of oxidation of sulfur, accompanied by an 68 References on page 155 Chapter 3 increase in effective positive charge, leads to a displacement of the K absorption edge in the X-ray spectrum towards higher energies). 1 3 d Donation from form II, however, leaves a positive charge on the S-atom and is more consistent with X-ray spectral data, 1 3 with the sulfur-oxygen bond order closer to two than three.2 The sulfur-oxygen bond environment is directly affected by coordination through the S-atom, as an sp 3 orbital of sulfur is directly involved in the sulfur-metal bond. Donation of electron density from oxygen to sulfur through pTC-dTC overlap compensates for the depletion of electron density at the sulfur. The coordination of the sulfoxide, via the S-atom, to the metal results in an increase in the sulfur-oxygen bond order, and a decrease in the sulfur-oxygen bond length, for example, as in the S-bonded complexes listed in Table 3.2. 2 3.3.2 Oxygen-Bonded Metal-Sulfoxide Complexes Generally, O-bonding is observed in metal complexes having "hard" metal ions and/or strong TC accepting ancillary ligands, or in order to avoid a trans arrangement o f S-bonded sulfoxides (in softer metals). 1 4 The structural data for O-bonded D M S O ligands within the complexes listed in Table 3.2 indicate that the geometry of the sulfoxide changes little upon coordination. The average C - S - 0 bond angle (103 °) is slightly smaller than that of ~ 1 0 7 0 found in free D M S O (Table 3.1), which indicates that the ligand retains its "trigonal pyramid" geometry upon coordination to a metal centre. The sulfur-oxygen bond lengths in O-bonded sulfoxide complexes (1.517(5)-1.557(4) A , Table 3.2) are longer than that found in free D M S O (1.492(1) A). Davies had concluded earlier that the sulfur-oxygen bond length changes little on such coordination. 2 69 References on page 155 Chapter 3 Calligaris and Carugo suggest that a hybrid of resonance forms I and II predominates, with structure I accounting for coordination of sulfoxides through the O-atom (Figure 3.1(2)). 1 4 Transfer of electron density from the negative oxygen to the metal is not expected to affect the positive charge on the sulfur.2 The O-atom within the S + -0" resonance form can be considered to be sp 2 hybridized; then overlap of one oxygen sp 2 orbital with the sp 3 hybridized S-atom results in a single sulfur-oxygen o-bond, leaving the two sp 2 lone pairs on the oxygen for coordination to the metal. 2 ' 5 The interaction between the remaining lone-pair p-orbital of the O-atom and the vacant d-orbitals of the S-atom (pTt-dTt) is not affected directly by the coordination environment of the oxygen. Coordination to a weak Lewis acid should have a small effect on the TC overlap, while coordination to a strong Lewis acid should decrease the overlap and result in a decrease in the S-0 bond order. Experimental data support this reasoning with S-0 bond lengths for O-bonded D M S O in Ru , Fe, Cu, and Cr complexes in the range 1.517(5)-1.557 A (Table 3.2) which are longer than the bond length in free D M S O (1.492(1) A ) . 3.3.3 Bridging DMSO Metal Complexes The structural data for bridging D M S O ligand complexes (Table 3.2) indicate again that the sulfoxide geometry does not change much upon coordination. Bridging S-0 bond lengths are 1.532(4) A 2 6 and 1.508(5) A 2 8 (Table 3.2) and are longer compared to the bond length of free D M S O 1.492(1) A . O f note, the bridged S-0 bond lengths are intermediate between those of S- and O-bound Ru(II)-sulfoxide complexes. 2 8 70 References on page 155 Chapter 3 3.4 NMR and IR Spectroscopic Methods for the Determination of Sulfur- or Oxygen-Bonding in Metal Complexes The presence of sulfur- and/or oxygen-bonded sulfoxides in metal-sulfoxide complexes can often be detected using two standard spectroscopic methods. 3.4. J 'H NMR Spectroscopy ! H N M R shifts of the a-protons of free sulfoxide change upon coordination o f the sulfoxide and can indicate the presence of either S- or O-bonding, the peaks generally shifting dowrifield. The magnitude of the shift depends upon the coordination mode, with larger effects being observed upon coordination via the S-atom than the O-atom. Free D M S O in C D C U has a single resonance at 5 2.62 for the equivalent methyl groups. 3 2 In cis-R u C l 2 ( D M S O ) 3 ( D M S O ) , the methyl resonance of the O-bonded D M S O is shifted dowrifield to 5 2.75, while the methyl resonances of the S-bonded D M S O are shifted further and fall in the range 8 3.00-3.52. 3 2 Generally, O-bonding of sulfoxides results in small chemical shifts of the a-protons (< 8 0.5 ) while larger shifts 8 ~ 1 are seen for coordination through the S-atom, and this trend is observed for the B- and y-protons although the extent of these effects decreases as the protons become further removed from the S-atom.2 Using the bonding model shown in Figure 3.1(2), coordination of the sulfoxide via the O-atom occurs through the sp 2 orbitals of oxygen, and hence the electron density in the carbon-sulfur bond, which involves sp 3 orbitals from the S-atom, is affected only to a small degree. The a-protons are consequently only deshielded to a small degree, which is reflected in the small downfield shift observed in the *H N M R spectrum. In contrast, coordination 71 References on page J55 Chapter 3 through the sulfur involves the sp3 orbitals of the S-atom, which results in direct withdrawal of electron density from the C-S bond and a greater deshielding effect. The inequivalence of diastereomeric a - C H 2 protons of a coordinated sulfoxide such as diethylsulfoxide 3 3 is observed in the *H N M R spectrum as a complicated pattern of peaks. This pattern is only observed for S-bonded sulfoxides and not for O-bonded sulfoxides. 3 3 The *H signal observed for the oc-protons of O-bonded diethylsulfoxide is simpler than that observed for the a-protons of S-bonded diethylsulfoxide.3 4 However, in the case of coordinated T M S O , a greater inequivalence is observed for the 0- than the a - C H 2 protons in the *H N M R spectrum. 3 5 3.4.2 IR Spectroscopy Upon coordination of sulfoxide, a greater shift is observed in v S o , the sulfur-oxygen IR stretching frequency, in O-bonded than in S-bonded sulfoxides; a shift to a higher v s o is observed for S-bonded sulfoxides, and a lower v s p for O-bonded. These changes are useful indications of the bonding mode. Examples of complexes with S- and/or O-bonded sulfoxides (with their respective v S o assignments) are tabulated in Table 3.3. Coordination via the S-atom results in both a shorter sulfur-oxygen bond and higher v S o due to donation of electron density from the O-atom to compensate for the withdrawal of electron density from the S-atom by the metal (Figure 3.1(2)). In the case of O-bonded sulfoxides, donation o f electron density occurs through one sp 2 orbital of the oxygen (Figure 3.1(2)), and this results in changes in the sulfur-oxygen bond and v S o- A bridging sulfoxide, with coordination via both S- and O-atoms, 2 6 ' 2 8 has the characteristics of both S- and O-bonding; v S o o f ^u-DMSO shows 7 2 References on page 155 Chapter 3 a coordination shift of 45 cm"1 (Table 3.3), reflecting relatively minor changes in the sulfur-oxygen bond, consistent with structural data (see Section 3.3.3). Table 3.3. The Sulfur-oxygen Stretching Frequencies of S-bonded, O-bonded and Bridging D M S O R u Complexes."'* Complex vso (cm"1) Ref. S-bonded O-bonded Bridging c / s - R u C l 2 ( D M S O ) 3 ( D M S O ) c 1115 960 32 c / s -RuBr 2 (DMSO) 3 (DMSO) 1111.5 924 36 / r a«s -RuCl 2 (DMSO) 4 1086 36,37 * r a « s - R u B r 2 ( D M S O ) / 1082 38 m e r - R u C l 3 ( D M S O ) 2 ( D M S O ) 1127,1107 912 25 [ R u 2 ( 0 2 C C H 3 ) 4 ( D M S O ) 2 ] ( P F 6 ) 1006 29 [Ru 2 ( / / -Cl)Gu-DMSO)(DMSO) 3 C l 3 (CO) 2 ] 1141,1107 1010 28 a In K B r , unless stated otherwise. * v s o free D M S O , 1055 cm"1 in Nujol (ref. 34). c NaCI, Nujol or hexachlorobutadiene mulls. d Nujol mulls between CsBr windows. 3.5 Disulfoxides and Their Metal Complexes In this thesis work, several disulfoxides were synthesized by oxidation o f the corresponding dithioethers by the methods of Hul l and Bargar 3 9 and Bennett et al.,40 and were characterized by elemental analysis, melting point, and IR and *H N M R spectroscopies (Section 2.4 and Table 3.4). O f note, a comprehensive review by Madesclaire includes several methods for oxidizing sulfides to the corresponding sulfoxides, 4 1 and recently Rakivumar et 73 References on page 155 Chapter 3 al. reported a selective conversion of sulfides to sulfoxides using 30 % H2O2 in C F 3 C H ( O H ) C F 3 . 4 2 The disulfoxides used in this thesis work were synthesized as mixtures o f diastereomers (the RR/SS pair, and the meso RS/SR) but use of several recrystallizations yielded one diastereomer (Section 2.4). 3 9 As reported, repeat recrystallizations can be used to separate the diastereomers, 4 3 ' 4 4 while separation of the enantiomeric forms o f 1,2-bis(phenylsulfinyl)ethane has been achieved by column chromatography on lactose. 4 5 ' 4 6 Zipp and Madan stated that "previous studies have indicated that the sole product obtained from the D M S O oxidation is the higher melting isomer, now identified as the racemic mixture of the RR and SS forms"; 4 7 however, X-ray crystal structural analyses of R S ( 0 ) ( C H 2 ) 2 S ( 0 ) R ; R = methyl ( B M S E ) , 4 3 propyl (BPSE) and phenyl (BPhSE) 4 4 suggest that generally the higher melting isomer is that of the meso form (vs. the rac form) (Table 3.4). 4 8 Attempts, during this thesis work, to crystallize the disulfoxides to obtain X-ray structural analyses were not successful; attempts included variation of solvent combinations and temperatures, and sublimation methods. For example, some "crystals" of B P S P were found not to be single crystals and were apparently characteristic of "soft thread"; attempts by Calligaris to crystallize B P S P have also been unsuccessful.4 9 Svinning et al. have reported that crystals of the B form (the lower melting isomer) of rac-BMSE were "clusters o f interpenetrating needles that were easily shattered or deformed". 4 3 74 References on page 155 Chapter 3 Table 3.4. The Melting Points and vSo (cm"1) for Disulfoxides.0 Compound M. p. (°C) Ref. vso (cm"1) (KBr) BMSE(itf) 158-162* and 165-166e; 163-164;c 169-170;c 50; 40a; 39; 43 1018 (ref. 39)e 174-175d BMSEfrac) 117-119* and 118-12(/; 128-130;c 132-133rf 50; 40a; 43 1018 (ref. 39)e BESE 142-145;s 149-149.5;e 148-149; 150* 47; 39; tw; 40b 1019 (ref. 39); 1015 (tw) BPSE 161-162.5;' 162-164 39; tw 1012 (ref. 39); 1010 (tw) BBSE 172-173 tw 1014 BPeSE 134-135 tw 1014,1073,1100 BCySE 172-174 tw 1018 BHSE 176.5-177.5 tw 1016,1114 BPhSE(itf) 166-167* 48; 44 1033 (ref. 44) BPhSE(SS) 120-122/122-123* 48; 44 1037 (ref. 44) BPhSE 165-170 tw 1035,1089 BMSP 117-118' 39 1050 BESP 127-130 tw 1016,1047 BPSP 140-143 tw 1021,1075 BBSP 146-148 tw 1021 BPeSP 125-129 tw 1026 BPhSP 137-140 tw 1021,1040,1084 " tw, this work. The superscripts h' d and s'' indicate the recrystallization solvents that were used in each case. 6 EtOH/ethyl acetate. eEtOH. d Acetone/ethyl acetate. e The value 1018 cm"1 is assumed to be quoted for a crude product (m. p. 125-164 ° C). ^Recrystallized from the mother liquor using ethyl acetate and toluene. 8 Benzene. h Ethyl acetate. ' Benzene/hexane 3:2. J Chloroform and petroleum ether. k CHCb/light petroleum and ethanol. 'THF. 75 References on page 155 Chapter 3 3.5. J Disulfoxide Complexes For the higher melting diastereomer of meso-BMSE (see Section 3.5), the range o f the sulfur-oxygen bond lengths was 1.501(2)-1.515(2) A . 4 3 Madan et al. synthesized a series of complexes with formulations [M(L)3](C104)2 ( M = M n 2 + , Fe 2 + , C o 2 + , N i 2 + , C u 2 + , Z n 2 + and Cd 2 + ) , M(L)C1 2 ( M = P t 2 + and Pd 2 + ) (L = 2,5-dithiahexane 2,5-dioxide, i.e. B M S E ) , and [ML n ] (C10 4 ) 2 (« = 3, M = M n 2 + , C o 2 + , N i 2 + and Z n 2 + ; n = 2, M = C u 2 + ; and L = B M S P , B M S B (l,4-bis(methylsulfinyl)butane) and B E S E ) , as characterized by elemental analyses, IR and magnetic measurements.4 7'5 1 IR spectroscopy suggested that the disulfoxides were generally O-bonded, except for the P t 2 + and P d 2 + complexes. Previous work in this laboratory by Yapp et al. led to the isolation o f the cis complexes R u C l 2 ( B M S P ) 2 and R u C l 2 ( B E S E ) 2 , and the trans complexes R u C l 2 ( B M S E ) 2 and R u C l 2 ( B P S E ) 2 , shown by X-ray crystallography to contain solely S-bonded disulfoxide. 5 2 ' 5 3 The sulfur-oxygen bond length of coordinated B M S E had shortened to an average of 1.47 A (Table 3.6, seep. 85). 76 References on page 155 Chapter 3 Cl P h - S r i I > O •Ph Ph Pr Pr ? H 3 ' Pr \ - 4 C H 2 — S S - C H 2 f -S —Pr n O ' S n — P h (1) (2) Figure 3.2. Structures of ca/e«a-poly[c/5-Cl2-^ra«5-(CH 3 )2Sn(IV)](//-0,0 '-/Me5o-BPSE) (1) and [SnCl-c /5-Ph 3 ] 2 ( / / -0,0 ' -rac-l ,2-bis(«-propylsulnnyl)ethylene) (2). De Azevedo Jr. et al. have structurally characterized c z s - P t C ^ B P S E ) with S-bonded disulfoxide, and a sulfur-oxygen bond length of 1.45(2)-1.46(1) A , 5 4 while Carvalho et al. have structurally characterized catena-^oly[cis-Cl2-trans-(CH3)2Sn](ju-0,0,-meso-BPSE) with a sulfur-oxygen bond length of 1.520(3) A (Figure 3.2(1)); the increase in S-0 bond length is consistent with O-bonded sulfoxides (Section 3.3.2) compared to the shorter S-0 bond lengths observed for S-bonded sulfoxides (Section 3.3.1). 5 5 Filgueiras et al. have structurally characterized the complex [SnCl-cz'5-Ph 3] 2(//-C>,0'-rac-l,2-bis(»-propylsulfinyl)ethylene) with a sulfur-oxygen bond length of 1.488(6) A (Figure 3.2(2)).56 Musgrave and Kent synthesized a series of complexes with formulations [M(L) 3](C10 4)2 ( M = C o 2 + , N i 2 + and C u 2 + ; L = O-bonded meso- and rac-bis(phenylsulfinyl)methane (BPhSM), and meso- and rac-l,2-bis(phenylsulfinyl)ethane (BPhSE)) and M(L)C1 2 ( M = Pt 2 + ; L = S-bonded meso- and rac-BPhSE) as characterized by elemental analyses, IR spectroscopy, while the ligands were characterized by N M R 77 References on page 155 Chapter 3 spectroscopy. The authors assigned (perhaps incorrectly) the a - B P h S M (m. p. 196 °C) as the racemic mixture and /3-BPhSM (m. p. 104 °C) as the meso compound by N M R spectroscopy. They incorrectly quoted a report by Taddei 4 5 and, therefore, incorrectly assigned the a -BPhSE (higher melting isomer) and yS-BPhSE (lower melting isomer) as the racemic mixture and meso isomer, respectively.5 7 Taddei's findings45 were later confirmed by Cattalini et al.u by X-ray structural analyses for meso- and rac-(BPhSE). The range o f the sulfur-oxygen bond lengths determined for B P h S E (RS and SS) is 1.487(2)-1.494(6) A, 4 4 and in the S-bound complexes cis-PtCl2(meso-Bl?hSE) and czs-PtCl^rac-BPhSE) these were shortened to 1.461(8)-1.470(8) A and 1.40(2)-1.46(1) A, respectively. 4 4 In the complex [SnClPh3]2(/wes,0-BPhSE), in which B P h S E acts as a bridge between the two tin centres, the sulfur-oxygen bond length is 1.525(4) A (Figure 3.3(1)). 4 8 Within [PtCl 2(PEt 3)] 2(//-S, S-meso-BPhSE) , where B P h S E bridges two Pt centres via the S-atoms, the sulfur-oxygen bond length is 1.475(9) A (Figure 3.3(2)). 5 8 Figure 3.3. Structures containing / i -BPhSE. A corresponding distance of 1.46 A has been reported for the S-bound complex c/5-PtCl 2(rac-c/5-l,2-bis(phenylsulfinyl)ethylene). 5 9 P h f \ APh SnPh 3 CI SnPh3CI (1) PtCI 2 PEt 3 o = II P h ^ S - C H 2 C H 2 — S Ph II 1 0 * PtCI 2 PEt 3 (2) 78 References on page 155 Chapter 3 Khiar et al. have synthesized Fe(III) complexes containing O-bound (SS)-b\s(p-tolylsulfinyl)methane and (5'5)-2,2-bis(p-tolylsulfinyl)propane ligands, respectively (Figure 3.4(1)), although no characterization data were presented.6 0 Figure 3.4. (1) R = H , (S^-bis(p-tolylsulfinyl)methane; and R = C H 3 , (SS)-2,2-bis-p-tolylsulfinylpropane. (2) (^-l^-bisf^-tolylsulfinyObenzene. Tokunoh et al. synthesized (i^i^-l^-bis^-tolylsulfiny^benzene ( B T S B , Figure 3.4(2)), and the corresponding [Rh(BTSB)(cod)](C10 4), f ra«s-RuCl 2 (BTSB) 2 and cis-P d C l 2 ( B T S B ) complexes, containing S-bound sulfoxide. The Pd(II) complex was characterized by X-ray crystallography; the crystal structure is centrosymmetric thus implying the presence of both enantiomers.61 The sulfur-oxygen bond lengths of the Pd(II) complex are 1.461(12) A compared to that of 1.481(1) A for the free disulfoxide. The authors suggest that the relatively small change in the S-0 bond length (complexed vs. free B T S B ) was because the electron deficiency of the S-atom may be compensated for by Tt-back donation from the aryl groups o f B T S B rather than by the O-atom. 6 1 Previous work in this laboratory has included the synthesis and characterization o f chiral sulfoxides, for example, i?-methyl p-tolyl sulfoxide (MPTSO) , and chiral disulfoxides, for example, dios, bdios.and ddios (see Figure 3.5),. and their R h (O-bonded) 6 2 and R u (mainly p-tol (1) (2) 79 References on page J55 Chapter 3 S-bonded) complexes which were studied as catalysts for asymmetric hydrogenation of prochiral olefins. 6 3 P-o-H i ^ C H 2 S O C H 3 o-H i ^ C H 2 S O C H 2 P h M X Me H XH2SOCH3 o-H H O . i > C H 2 S O C H 3 H C H 2 S O C H 2 P h H O A H C H 2 S O C H 3 (1) (2) (3) Figure 3.5. Structures of dios ((2i?3/?)-2,3-0-isopropylidene-2,3-dihydroxy-l,4-bis(methylsulfinyl) butane monohydrate) (1), bdios ((2i?3i?)-2,3-0-isopropylidene-2,3,dihydroxy-l,4-bis(benzylsulfinyl) butane monohydrate (2), and ddios ((2R3R)-2,3-dihydroxy-l,4-bis(methylsulfinyl) butane (3). Adapted from ref. 63b. Various methods have been utilized to maximize the optical purities o f chiral sulfoxides, including electrochemical asymmetric oxidation of unsymmetric sulfides to the corresponding chiral sulfoxides using poly(amino-acid)-coated electrodes, 6 4 and chloroperoxidase catalyzed oxidations in /-butyl alcohol/water mixtures. 6 5 O f note, a review by Al l in includes thirty-seven references for the synthesis of chiral sulfoxides via nucleophilic displacement at the S-atom. 6 6 3.6 Mononuclear, Bidentate Disulfoxide Complexes of Ruthenium(H) • i • Previous workers in this laboratory have used c7's-RuCl 2 (DMSO)4 and cis-R u C l 2 (TMSO) 4 as precursors for the synthesis of RuCl2(sulfoxide)2(nitroimidazole)2 complexes, but their configurations were not easily resolved because of the number of possible isomers that could be formed. 6 7 The range of sulfoxides was then extended to include disulfoxides in order to reduce the number of possible isomers formed in these exchange 80 References on page 155 Chapter 3 reactions, and the four complexes cw-RuCi2(BMSP)2, c / 5 - R u C l 2 ( B E S E ) 2 , trans-R u C i 2 ( B M S E ) 2 and / ra«5 -RuCl 2 (BPSE)2 were synthesized (via "Ru-blue" solutions, Section 3.8.1, p. 104) and structurally characterized. 5 2 ' 5 3 One of the first goals for this thesis work was to extend the range o f the R u disulfoxide complexes to include the geometrical isomers o f the previously characterized complexes, especially as the trans Ru-disulfoxide complexes exhibited greater in vitro biological activity than the cis complexes. 5 2 A logical step to attempt to synthesize such isomers was to use the precursors cis- and Zra«5-RuCl2(DMSO) 4 in sulfoxide-exchange reactions to give c w - R u C l 2 ( B M S E ) 2 and c«-RuCl 2 (BPSE) 2 , and / r a « 5 - R u C l 2 ( B E S E ) 2 and zra«s-RuCi2(BMSP)2, respectively, and then study their in vitro biological activity. However, a reaction of czs -RuCl 2 (DMSO) 4 with B P S E gave *raws-RuCl 2(BPSE)2 (Section 2.7.3), and reactions of / r a«s -RuCl 2 (DMSO) 4 and K 3 [ R u C l 6 ] with B E S E both gave czs -RuCl 2 (BESE) 2 (Section 2.7.1) as characterized by X H N M R spectroscopy. During this thesis work, the Trieste group published a molecular mechanics investigation of the stereochemistry of Ru-bis-chelating disulfoxide complexes, 6 8 and concluded that / ra«s-RuCl 2 (BMSE) 2 , c / s -RuCl 2 (BESE) 2 and / ra«s -RuCl 2 (BPSE) 2 corresponded to the lowest strain diastereomers (Figure 3.6). The minimum energy structure found a c/'s-isomer (Figure 3.6(1)) for the diastereomer containing meso-BESE ligands (i.e. c /5 -RuCl 2 (BESE) 2 ) and this required trans S-atoms with the same R or S chirality. 6 8 81 References on page 155 Chapter 3 Cl Cl C l I—S— I / S — 1 I ^ S — 1 Cl (la) (lb) (2) Figure 3.6 General structure for (la) c / s -RuCl 2 (BMSP) 2 and (lb) c / s -RuCl 2 (BESE) 2 and (2) / r a«s -RuCl 2 (BMSE) 2 and *raws-RuCl 2(BPSE) 2; S A S = chelating disulfoxide. The lowest energy form of /raws-systems (2) is with mutually trans S-atoms of opposite chirality. Analogous stereomers have been observed in the crystal structures of both trans-R u C l 2 ( B M S E ) 2 and zra«s-RuCl 2 (BPSE) 2 , where again only S-bonding was found. 5 3 ' 6 8 During the course of the present work, the water-soluble complex [RuCl(BESE)(H 2 0) ] 2 ( / / -Cl ) 2 was synthesized and structurally characterized, and its reaction with two equivalents of B E S E gave the complex f ra /M-RuCl 2 (BESE) 2 . The mononuclear, bis-chelating R u disulfoxide complexes isolated during this present work have the general formula c/s-RuCl 2(disulfoxide) 2 (with the exception of the complex fra«s-RuCl 2 (BESE) 2 ) , and they all contain only S-bonded disulfoxides as indicated by Vso data (Table 3.5, p. 83) and confirmed by X-ray crystallography in all but one case (cis-RuCl 2 (BPeSE) 2 ) . N o conductivity was observed for any of these complexes in chlorinated solvents. A s well, a Ru(II)/Ru(III), mixed-valence complex [RuCl(BPSP)] 2 (/ /-Cl)3 and a series of Ru(II)/Ru(II) chelating disulfoxide complexes (with [RuCl (BESE)(H 2 0) ] 2 ( / / -C l ) 2 structurally characterized) were isolated during the present work (Sections 3.7 and 3.8). Again, all these complexes contain only S-bonded sulfoxides. 82 References on page 155 Chapter 3 Of note, the in situ reduction of both the RuCl 3-3H 20 "green solutions" and the Ru(III) precursor [RuCU]3" to the Ru(II) product was possibly due to the disulfoxide acting as a reductant, which is correspondingly oxidized to the sulfone; this might account for the relatively low isolated yield (~ 25 %), as only a 2:1 sulfoxide:Ru ratio was used. Higher yields might result by using increased sulfoxide concentration. Evidence for this redox process will be discussed in Section 3.9, p. 126. Table 3.5. IR Data (KBr) for Vso(cm_1) Free and vsoCcm"1) Bound, in Chelating Disulfoxide Complexes of Ru. Complex IR Vso (cm"1) free IR Vso (cm"1) bound #*w,s-RuCl2(BMSE)2 a 1018 (ref. 39) 1109° czs-RuCl 2(BESE) 2 f l 1019 (ref. 39); 1015 1128;° 1092, 1122 /ra«s-RuCl 2 (BESE) 2 H 2 0 6 1019 (ref. 39); 1015 1093, 1119 fra«s-RuCi 2(BPSE) 2 f l 1012 (ref. 39); 1010 1128;° 1094c c/5-RuCl 2(BBSE) 2 f e 1014 1081, 1126 c/5-RuCl 2(BPeSE) 2 1014, 1073, 1100 1081, 1128 c7s-RuCl 2(BCySE) 2 6 1018 1046, 1100 c/5-RuCl 2(BMSP) 2 f l 1050 1085" c/\s-RuCl2(BESP)2 f c 1016, 1047 1042, 1088 [RuCl(BESE)(H 20)] 2(//-Cl) 2 6 1019 1042, 1071, 1118 [RuCl(BPSE),(H20)]2(//-Cl)2 1012 1048, 1083, 1119 [RuCl(BBSE)(H 20)] 2(//-Cl) 2 1014 1046, 1098, 1116 [RuCl(BPSP)] 2(//-Cl) 3 6 1021, 1075 1053, 1084 " Indicates data taken from refs. 52 and 53 for the 4 complexes, all of which were characterized by X-ray analysis; otherwise data represent this thesis work. b Complexes characterized by X-ray analysis. 0 Formulated with one H 2 0. 83 References on page 155 Chapter 3 3.6. 1 Cis-RuCl2(BESE)2 and Trans-RuCl2(BESE)2 H20 The reaction of B E S E with K 3 [ R u C l 6 ] gave the yellow cis complex in 36 % yield. The *H N M R spectrum in CDC1 3 corresponds well to that reported, 5 2 ' 5 3 with two distinctive triplets at 8 1.45 and 1.30 of equal integration for the methyls. Attempts to photolyze cis-R u C l 2 ( B E S E ) 2 to the trans isomer, following a report on photo-induced isomerization of cis-to fra«s-RuCi2(DMSO)4, 3 6 were unsuccessful (Section 2.7.1). The reaction of [RuCl(BESE)(H 2 0)] 2 ( / i -Cl)2 with 2 equivalents of B E S E gave the trans complex in 33 % yield. The ! H N M R spectrum ( D 2 0 ) of the free ligand consists o f multiplets at 8 3.30 (CH2CH2), 2.92 (CH 3 Gr7 2 ) , and a triplet at 1.23 (CH3), which in this complex are shifted downfield to a coalesced peak at 8 3.70 (for the C H 2 protons) and a multiplet at 8 1.45 (CH 3 ) , respectively; the ! H solution spectrum ( D 2 0 ) , which does not change over 3 weeks, shows equivalent methyl groups (cf. data for the cis complex), consistent with the trans geometry determined crystallographically. Crystals of a non-solvated species were grown by slow evaporation of an H2O solution of the complex. This complex crystallizes in a centrosymmetric space group with the Ru-atom on a centre of symmetry, and is thus achiral; the O R T E P diagram is shown in Figure 3.7. The structural data are similar to those of /ra«s-RuCl 2 (BMSE)2 and fra«5-RuCl2(BPSE)2 (Table 3.6). The key bond lengths and angles are essentially the same as those for the other Ru(II) bis-chelating disulfoxide complexes. The molecule has a slightly distorted octahedral geometry at the R u with trans angles of 180 .0 0 and cis angles that range from 85.42(3)-90.88(3) 0 (Table 3.7). The sulfur-oxygen bond lengths for c /5 -RuCl 2 (BESE) 2 , z ra«s-RuCl 2 (BESE) 2 and 84 References on page 155 Chapter 3 [RuCl(BESE)(H 20)]2(//-Cl)2 average about 1.48 A and show that there is not much of a change in the sulfur-oxygen bond distance in the three complexes (see Table 3.7). Table 3.6. Selected Bond Lengths (A) and Bond Angles (°) for Some />"aw5-RuCl2(S-S)2 Complexes." Bond or Angle *ratts-RuCl2(BMSE)2 rratts-RuCl2(BPSE)2 Ru-Cl 2.402(2), 2.405(2) 2.4077(8) Ru-S 2.305(2)-2.319(2) 2.300(4), 2.319(3) S-0 1.453(6)-1.495(7) 1.44(1), 1.47(1) C-S 1.717(7)-1.855(7) 1.74(1)-1.911(6) Ru-S-0 118.4(3)-120.4(3) 118.1(5),120.6(5) O-S-C 103.9(3)-110.8(4) 99.5(6)-l14.8(6) C-S-C 98.1(3)-106.3(3) 89.3(6), 112.1(6) S-C-C 6 107.1(4)-112-5(4) 108.3(3)-109.0(4) S-C-C c 109(1)-116.2(9) Ru-S-C f e 102.7((3)-105.6(3) 100.4(2)-106.5(2) Ru-S-C c 113.9(2)-!15.7(3) 114.5(6)-117.8(4) " Data taken from refs. 52 and 53. 6 Bonds involving backbone carbons. c The C-atom of an alkyl substituent. 85 References on page J55 Chapter 3 Table 3.7. Selected Bond Lengths (A) and Bond Angles (°) for [RuCl(BESE)(H 20)] 2(//-C1) 2 H 2 0, fra«s-RuCl 2(BESE) 2 and cw-RuCl 2(BESE) 2. Bond or Angle [RuCl(BESE)(H20)]2(//- 7ra«s-RuCl 2(BESE) 2 Cis-C1) 2 H 2 0 RuCl 2 (BESE) 2f l Ru-Cl 6 2.4098(10);e 2.4636(10/ Ru-Cf 2.4006(10/ 2.4018(7) 2.4217(8)-2.4486(8/ Ru-S 2.1985(10);c 2.1958(10/ 2.3212(9), 2.3288(7) 2.2712(8)-2.273 8(8);c 2.2973(8)-2.3076(8/ Ru-0 2.140(3/ S-0 1.475(3), 1.496(2) 1.479(2)-1.480(2) 1.470(2)-1.479(2) C-S 1.803(4)-1.805(4) 1.797(3)-1.809(3) 1.796(3)-1.814(3) cis angles 82.11(3)-95.11(4) 85.42(3)-90.88(3) 87.19(3)-92.08(3) trans angles 171.77(4)-178.01(8) 180.0 176.92(3)-178.54(3) Ru-Cl-Ru 96.83(3), 97.89(3) C-S-C 99.3(2)-102.9(2) 99.1(2)-101.3(2) 100.0(1)-102.8(1) O-S-C 104.9(2)-107.4(2) 106.6(1)-108.1(2) 106.3(1)-109.3(1) Ru-S-0 118.52(13)-119.24(13) 119.31(9)-119.44(9) 116.28(8)-120.43(8) S-C-C* 106.3(3)-108.6(3) 106.8(2)-110.9(2) 106.5(2)-111.0(2) S-C-CA 111.6(3)-114.1(4) 111.1(2)-112.2(2) 111.3(2)-112.0(2) Ru-S-C g 105.56(12)-107.43(13) 103.5(1)-104.9(1) 103.0(1)-104.8(1) Ru-S-CA 115.47 115.7(1)-116.6(1) 113.4(1)-117.3(1) a Data taken from refs. 52 and 53. b Bridging. c Trans to Cl. d Trans to S. e Terminal. f Trans to O. g Backbone. h End substituents. 86 References on page 155 Chapter 3 Figure 3.7. An ORTEP drawing of *ra«s-RuCl2(BESE)2 with 50 % probability thermal ellipsoids shown (crystal data given in Appendix 1.1). For the data of Table 3.8, S(4) and S(3) are taken as trans to S(2) and S(l), respectively. 87 References on page 155 Chapter 3 Table 3.8. The Relative Configurations of the S-atoms in Chelating Disulfoxide Complexes of R u in Refs. 52 and 53 and those depicted in Figures 3.7-3.10, 3.12 and 3.18. Complex S( l ) S(2) S(3) S(4) / r a « s - R u C l 2 ( B M S E ) / R S S R c / s - R u C l 2 ( B E S E ) / ' 6 R e sd R e Sd *raws-RuCl 2 (BESE) 2 6 S R R s *ra«s -RuCl 2 (BPSE) 2 f l i S R R s c / 5 - R u C l 2 ( B B S E ) 2 E t O H 6 R c Rd S c Rd c / 5 - R u C l 2 ( B C y S E ) 2 E t O H l / 3 M e O H * R c Sd Rc sd c / s - R u C l 2 ( B M S P ) 2 a ' 6 R c sd R c sd c / 5 - R u C l 2 ( B E S P ) 2 E t O H H 2 0 6 S c Rd S c Rd [RuCl(BESE)(H 2 0 ) ] 2 Cu -Cl) 2 H 2 O h Sc R e [RuCl (BPSP) ] 2 ( | / -C l ) 3 -2H 2 0-2 .5CH 2 Cl 2 6 sc Rc R c sc a Data taken from refs. 52 and 53; otherwise data are from this thesis work. * Unit cell contains both enantiomers. c Trans to C l . d Trans to S. e Trans to O. 3.6.2 Trans-RuCl2(BPSE)2 -H20 I The reaction of B P S E with cz 's-RuCl 2 (DMSO) 4 gave the yellow title complex in i 47 % yield. The ' H N M R spectrum in CDC1 3 compare well with data reported in the i I literature for the structurally characterized trans complex with one signal at 5 1.10 assigned to j the methyls. 5 2 ' 5 3 Attempts to photolyze f ra77S -RuCl 2 (BPSE) 2 to the cis isomer (refer to Section 3.6.1) were not successful as monitored by ! H N M R spectroscopy. 88 References on page 155 Chapter 3 3.6.3 Cis-RuCl2(BBSE)2 The title compound was synthesized from R u C l 3 - 3 H 2 0 and precipitated in an analytically pure form with 21 % yield. *H N M R data are consistent with S-bonded sulfoxides with the cis geometry shown crystallographically. The *H N M R spectrum of the free ligand in CDC1 3 consists o f multiplets at 8 3.20 and 3.00 (S(0)CH2CH2S(0), 2.75 (CH2S(0)), 1.72 (CH3CH2C/6), 1.45 (CH3C//2), and a triplet at 8 0.95 (CH3), all o f which in the complex are shifted downfield (multiplets) to 8 3.60 (CH2S(0)CH2), 1.55 (CH3CH2CH2) and 0.98 (CH3); no free disulfoxide was observed. The crystal structure (Figure 3.8) is comparable to that of cz ' s -RuCl 2 (BESE) 2 5 2 ' 5 3 in having slightly distorted octahedral geometry at the R u centre with trans angles that range from 173.01(3) to 177.46(3) °, and cis angles that range from 85.79(3) to 96.22(3) 0 (Table 3.9). Selected bond lengths and bond angles are tabulated in Table 3.9 and are comparable to those of c z s - R u C l 2 ( B C y S E ) 2 E t O H - l / 3 M e O H , czs -RuCl 2 (BESE) 2 (Table 3.7), and czs-RuCl 2 (BESP) 2 and - R u C l 2 ( B M S P ) 2 (Table 3.10); the key bond lengths and angles are basically similar in all these cis complexes. Within c z s - R u C l 2 ( B B S E ) 2 E t O H three S-atoms have the relative R configuration and one S-atom has the S configuration (Table 3.8); this is the only complex with S( l ) and S(2) showing the same relative configuration. The synthesis of this complex could be plausible by starting with a mixture of the meso and rac ligands but the sharp melting point (Table 3.4) implies only one diastereomer o f the ligand was present. This complex is chiral, with approximate C 2 symmetry, but the crystal structure is centrosymmetric and contains an equal number of the two enantiomers. Figure 3.8 depicts the A isomer in which the trans S-atoms (S(2) and S(4)) both have the R configuration. The unit cell contains the E t O H molecule H-bonded to both an O-atom and a Cl-atom of the 89 References on page 155 Chapter 3 complex. The H-O, and the H-Cl distances are 2.12 and 2.71 A, respectively, which are 0.58 and 0.19 A shorter than the sum of the van der Waals radii of an O- and an H-atom (2.70 A), and a Cl - and an H-atom (2.90 A), respectively.70 The interactions appear to be strong. Table 3.9. Selected Bond Lengths (A) and Bond Angles (°) of czs-RuCl 2(BBSE) 2EtOH and cz5-RuCl2(BCySE)2EtOH-1/3 MeOH. Bond or Angle cw-RuCl 2 (BBSE) 2 EtOH cis-RuCl 2 (BCySE) 2 EtOHl /3 MeOH Ru-Cl 2.4159(8), 2.4288(7)° 2.4201(13), 2.4344(13)° Ru-S 2.32892(9), 2.3035(9);° 2.2674(7), 2.3364(13), 2.3484(13);° 2 2.2906(8)* .2719(13), 2.2988(13)* S-0 1.477(2), 1.482(2);° 1.468(2), 1.444(4), 1.464(4);° 1.469 1.480(2)* (3), 1.470(3)* C-S 1.794(3)-1.838(4) 1.782(5)-1.842(5) cis angles 85.79(3)-96.22(3) 86.27(5)-96.50(5) trans angles 173.01(3)-177.46(3) 176.38(5)-178.01(5) Ru-S-0 116.88(9)-118.59(8) 117.5(2)-119.8(2) O-S-C 105.91(13)-109.23(15) 106.5(2)-107.9(2) C-S-C 101.28(4)-102.8(2) 100.0(2)-104.5(2) S-C-C e 106.3(2)-112.2(2) 106.7(4)-109.6(3) S-C-Cd 111.5(2)-113.2(2) 106.3(3)-113.4(4) Ru-S-C c 102.72(12)-105.92(10) 101.5(2)-104.3(2) Ru-S-C° 113.85(10)-! 19.29(10) 116.0(2)-118.2(2) J ° Trans to S. * Trans to Cl. c Bonds involving backbone carbons. d The C-atom of an alkyl ! substituent. 90 References on page 155 Chapter 3 Figure 3.8. A n O R T E P drawing of the A configuration of c / s -RuCl 2 (BBSE) 2 -E tOH with 50 % probability thermal ellipsoids shown; H-atoms (except for that of E t O H ) are omitted for clarity (crystal data given in Appendix 1.2). 91 References on page 155 Chapter 3 3.6.4 Cis-RuCl2(BPeSE)2 The title compound was synthesized from RuCl 3 -3H 2 0 , purified using column chromatography, and obtained in only 9 % yield; v S o data (Table 3.5) imply S-bonded sulfoxides. The *H N M R spectrum (CDCI3) of the free ligand consists of multiplets at 8 3.20 and 3.10 (S(0)C#2Cr72S(0)), 2.80 (C/72S(0)), 1.80 ( C H 3 C H 2 C H 2 G r 7 2 ) , 1.40 (CH 3 Cr7 2 Cr7 2 ) , and a triplet at 0.93 (CH3\ these being shifted to 8 3.70 (CH2S(0)CH2), 2.30 and 1.85 (C# 2C# 2S(0)), 1.45 (CH3CH2CH2) and 0.90 (CH3) (all multiplets), respectively, in the coordinated ligand, and no free disulfoxide was observed. The signal for the methyls was observed as one multiplet (presumably 2 overlapping triplets), compared to the two triplet signals observed for c / 5 - R u C l 2 ( B E S E ) 2 (Section 2.7.1). Crystals were obtained by slow evaporation of an E t O H / C H 2 C l 2 solution of the complex and were subjected to X-ray analysis, but excessive thermal motion exhibited by the long pentyl side chains prevented an accurate determination of the structure; however, cis geometry was established.6 9 3.6.5 Cis-RuCl2(BCySE)2 The reaction of RuCl 3 -3H 2 0 and B C y S E gave the title complex in 30 % yield, with no purification steps being required. The *H N M R spectrum of the free ligand consists of peaks at 8 3.60 (CH2CH2), 2.56, 2.15 (H 2 ) , 1.69 (Hi ) , 1.35 (H 3 , 4 ) (see Figure 2.1, in Section 2.3.11, for the proton labelling), while the lH spectrum of the title complex is a complicated pattern of overlapping multiplets between 8 1.0-4.4 (see Section 2.7.6, Chapter 2). The complicated spectrum is due to the inequivalence of the cyclohexyl rings oriented in the cis geometry. Crystals of the complex with one E t O H and one third M e O H solvate molecules 92 References on page J55 Chapter 3 were grown by slow evaporation of the preparative reaction solution. This complex is chiral, has approximate C 2 symmetry with the pair of mutually trans S-atoms (S(2) and S(4)) having the same chirality. The complex crystallizes in a centrosymmetric space group which contains equal numbers of the two enantiomers. A n O R T E P diagram shown in Figure 3.9 depicts the A isomer in which the trans S-atoms both have the S configuration. The molecule has a slightly distorted octahedral geometry at the R u with trans angles ranging from 176.38(5) to 178.01(5) ° and cis angles from 86.27(5) to 96.50(5) 0 (Table 3.9). Selected bond lengths and bond angles (Table 3.9) are comparable to those of c z s - R u C l 2 ( B B S E ) 2 E t O H (Table 3.9) and cz '5-RuCl 2 (BESE) 2 (Table 3.7). The key bond lengths and angles are again similar to those found in the other cis Ru(II) bis-chelating disulfoxide complexes. Each disulfoxide has opposite chiralities at the two chiral S-atoms (Table 3.8). The unit cell o f cis-R u C l 2 ( B C y S E ) 2 - E t O H - 1 / 3 M e O H contains a M e O H molecule on a three-fold axis and one poorly resolved E t O H molecule in a general position. The thermal motion of the cyclohexyl rings was generally large, even at the low temperature used in the structural determination (crystal data are given in Appendix 1.3). 93 References on page J55 Chapter 3 C(26) Figure 3.9. A n O R T E P drawing of the A configuration o f cis-R u C l 2 ( B C y S E ) 2 - E t O H - l / 3 M e O H with 5 0 % probability thermal ellipsoids shown; H-atoms are omitted for clarity (crystal data given in Appendix 1.3). 94 References on page 155 Chapter 3 3.6.6 Cis-RuCl2(BESP)2 The reaction of B E S P with RuCl 3 -3H 2 0 gave a yellow product in 36 % yield after purification by column chromatography. The J H N M R spectrum in CDCI3 o f the free ligand consists o f multiplets at 5 2.90 (Ci72S(0)Cr72), 2.45 (CH 2 Gr7 2 CH 2 ) and a triplet at 1.35 (CH3), which in the complex are shifted downfield to 8 3.45, 2.75, 2.10 and 1.45 (multiplets), respectively (the multiplet at 8 2.45 splits into the two multiplets at 8 2.75 and 2.10). The J H N M R data are consistent with the structurally determined cis configuration. N o free disulfoxide was observed in C D C U solution in the J H N M R spectrum. The crystal structure o f the c « - R u C l 2 ( B E S P ) 2 E t O H - H 2 0 (Figure 3.10) is similar to that of c / s - R u C l 2 ( B M S P ) 2 . 5 2 , 5 3 Selected bond lengths and angles are tabulated in Table 3.10 and are given together with those of c /5 -RuCl 2 (BMSP) 2 . The key bond lengths and angles are basically similar to those found in the other cis Ru(II) bis-chelating disulfoxide complexes. The molecule has a slightly distorted octahedral geometry at R u with trans angles that range from 171.64(4) to 176.35(4) 0 and cis angles that range from 84.96(3) to 97.57(4) °. The complex crystallizes in a centrosymmetric space group and contains an equal number of the two enantiomers. Figure 3.10 depicts the A isomer in which the trans S-atoms (S(2) and S(4)) both have the R configuration. The unit cell contains a water molecule H-bonded to an O-atom of the sulfur-oxygen moiety of the disulfoxide ligand and to the E t O H solvate (Figure 3.11). The average H -0 distance is 1.89 A , which is 0.81 A shorter than the sum of the van der Waals radii of an H - and an O-atom (2.70 A ) , suggesting a strong interaction between the water molecule, the complex and the E t O H solvate. 7 0 95 References on page 155 Chapter 3 Figure 3.10. A n O R T E P drawing of the A configuration of cw-RuCl 2 (BESP) 2 -E tOH-H 2 0 with 50 % probability thermal ellipsoids shown; H-atoms are omitted for clarity (crystal data given in Appendix 1.4). 9 6 References on page J55 Chapter 3 Figure 3.11. The unit cell of c/£-RuCl 2(BESP) 2-EtOH-H 20 showing the EtOH and H 2 0 solvate molecules (crystal data given in Appendix 1.4). 97 References on page 155 Chapter 3 Table 3.10. Selected Bond Lengths (A) and Bond Angles (°) of cis-RuCl 2(BESP) 2-EtOH-H 20 and czs-RuCl 2(BMSP) 2. Bond or Angle cz5-RuCl 2(BESP) 2-EtOHH 20 c/s-RuCl 2(BMSP) 2 f l Ru-Cl 2.4167(8), 2.4310(10)* 2.4354(7), 2.4395(7)* Ru-S 2.3311(10), 2.3528(10);* 2.2766(8), 2.3518(7), 2.3569(7);* 2.2905(10)c 2.2682(6), 2.2710(6)c S-0 1.489(2), 1.490(3);* 1.479(2), 1.481(3)c 1.473(2), 1.480(2);* 1.476(2), 1.480(2)c C-S 1.791(4)-1.820(3) 1.773(3)-1.801(3) cis angles 84.96(3)-97.57(4) 83.42(2)-97.55(2) trans angles 171.64(4)-176.35(4) 174.21(2)-178.42(2) Ru-S-0 113.38(10)-117.94(11) 113.91(8)-116.51(9) C-S-0 106.3(2)-107.8(2) 104.9(1)-107.1(1) C-S-C 98.4(2)-102.5(2) 98.9(2)-100.6(l) S-C-C d 112.2(3)-l16.5(3) 114.4(2)-115.6(2) S-C-C* 111.9(3)-112.8(3) C-C-C 111.7(3)-117.1(3) 113.1(3), 113.4(2) Ru-S-C r f 109.03(13)-115.79(13) 115.3(1)-115.80(9) Ru-S-C e 112.45(14)-!15.12(12) 111.2(1)-113.6(1) a Data taken from refs. 52 and 53. * Trans to S. 0 Trans to Cl. d Bonds involving backbone carbons. e The C-atom of an alkyl substituent. I 98 References on page 155 Chapter 3 3.7 Dinuclear Ru(II)/Ru(II) Chelating Disulfoxide Complexes Previous work in this laboratory involved the synthesis of czs-RuCl2 (BESE) 2 , 5 2 ' 5 3 while one initial goal of this thesis was to synthesize the corresponding trans isomer by utilizing fra«s-RuCi2(DMSO)4 as a precursor or photolysis of cz's-RuCl 2(BESE)2. These attempts, however, led to the isolation of cz's-RuCl 2 (BESE) 2 (Section 3.6.1). During the course of this work, Geremia et al. reported the topological analysis o f bis-chelate disulfoxide metal complexes and the results of molecular mechanical calculations on R u C l 2 ( B M S E ) 2 . They implied that czs-RuCl 2(BESE)2 w a s t n e l ° w e s t strain energy diastereomer of a series of possible isomeric forms, 6 8 thus suggesting that attempts to synthesize the corresponding trans isomer would likely lead to the isolation of cis-RuCl2(BESE)2, at least as the thermodynamic product. The reported procedure for the synthesis of cz '5-RuCl2(BESE) 2 involved the reaction of two equivalents of B E S E with one equivalent of RuCi3-3H 2 0. 5 2 ' 5 3 However, in the present studies, on reduction of the amount of ligand to one equivalent, the interesting water-soluble, dinuclear complex [RuCl(BESE)(H 20)j2(//-Cl)2 was obtained. Then the reaction o f one equivalent of [RuCl(BESE)(H20 ) ] 2 ( / / -Cl) 2 with two equivalents of B E S E led to the isolation of zraws-RuCl2(BESE) 2 as shown by *H N M R spectroscopy and X-ray crystallographic analysis (Section 3.6.1). 99 References on page 155 Chapter 3 3.7.1 Characterization of [RuCl(BESE)(H20)]2(p-Cl)2, [RuCl(BPSE)(H20)]2(p-Cl)2 and [RuCl(BBSE)(H20)]2(p-Cl)2 Reaction of one equivalent of B E S E , B P S E and B B S E with R u C l 3 - 3 H 2 0 resulted in the isolation of [RuCl(BESE)(H 2 0)] 2 ( / / -Cl) 2 , [RuCl(BPSE)(H 2 0 ) ] 2 ( / / -Cl) 2 and [RuCl(BBSE)(H 2 0 ) ] 2 ( / / -Cl) 2 in 60, 46 and 61 % yield, respectively. The v s o data are consistent with S-bonded sulfoxides (Section 3.4.2, Table 3.5), later confirmed for [RuCl(BESE)(H 2 0 ) ] 2 ( / / -Cl) 2 by X-ray crystallography. The solution lH N M R spectra o f all three complexes in D 2 0 generally reveal small downfield shifts from the resonances of the free ligand protons, again consistent with S-bonding (Section 3.4.1). The values o f "equilibrium" conductivity for these complexes in water (~ 10"4 M , A M 358, 282 and 497, respectively) correspond to those of a 2:1-3:1, 2:1 and 3:1 electrolyte, respectively, when these conductivity values are compared to the equivalent conductances of salts. 7 1 A titration of [RuCl(BESE)(H 2 0 ) ] 2 ( / i -Cl) 2 with N a O H in water showed that two equivalents of a standardized N a O H solution were required to titrate 1 equivalent of [RuCl(BESE)(H 2 0 ) ] 2 ( / / -Cl) 2 (see Table 3.11), suggesting the loss of 2 equivalents of V? from [RuCl(BESE)(H 2 0 ) ] 2 ( / / -Cl) 2 . O f note, the measured equivalent conductance o f 10"3 M HC1 was ~ 430 (literature data at 25 °C give ~ 420 7 2 ) and this value was reduced to ~ 350 upon addition of 10"3 M cz's-RuCl 2 (BESE) 2 (the molar conductance of an equilibrated 10' 3 M aqueous solution of c / 5 - R u C l 2 ( B E S E ) 2 is ~ 33.9 5 3). The conductivity data are thus consistent with the loss of 2 equivalents of HT and 2 equivalents of Cl" per [RuCl(BESE)(H 2 0 ) ] 2 ( / / -Cl ) 2 (see p. 101). 100 References on page 155 Chapter 3 Table 3.11. Titration data for [RuCl(BESE)(H 2 0)] 2 ( / / -Cl ) 2 using N a O H . [NaOH] (mM) Volume used (mL, mmol) [RuCl(BESE)(H 2 0) ] 2 ( / / -Cl ) 2 (mg, mmol) 5.80 ( ± 0 . 0 9 ) 1.96 (±0 .15 ) , 1.13 ( ± 0 . 0 8 ) x 10"2 4.22 (± 0.05), 5.67 (± 0.06) x IO"3 *H N M R data on [RuCl (BESE) (H 2 0) ] 2 (>Cl ) 2 in aqueous solution suggest that this complex loses 2 Cl" per complex. The equilibrium ! H N M R spectrum of the complex in D 2 0 (under air) does not change upon addition of up to three equivalents o f A g N 0 3 . Upon addition of two equivalents of A g N 0 3 , added dropwise, to a solution o f [RuCl(BESE)(H 2 0)] 2 ( > w-Cl) 2 in D 2 0 , a precipitate formed immediately, but the resulting *H N M R spectrum of the solution (i.e. the solution obtained from the filtered heterogeneous mixture) was the same as that of the equilibrium spectrum of [RuCl (BESE)(H 2 0) ] 2 ( / / -C l ) 2 in D 2 0 . One more equivalent of A g N 0 3 was added dropwise to the filtrate. N o further precipitate was observed, and the resulting *H N M R was identical to that of the equilibrium ! H N M R of [RuCl(BESE)(H 2 0)] 2 ( / / -Cl ) 2 . These water-soluble, complexes were tested in vitro for cytotoxicity, accumulation and DNA-binding properties in Chinese hamster ovary cells with the results presented in Chapter 4. Crystals of the B E S E complex containing one H 2 0 solvate molecule were grown by slow evaporation of a saturated aqueous solution of [RuCl(BESE)(H 2 0)] 2 ( / / -Cl ) 2 . The structure is shown in Figure 3.12, and selected bond lengths and angles, together with those o f cis- and frvms-RuCl2(BESE)2, are given in Table 3.7. 101 References on page 755 Chapter 3 The complex crystallizes in a centrosymmetric space group with a centre o f symmetry and is thus achiral. The asymmetric unit consists of two independent half-molecules and a water molecule (Figure 3.13). The H(33)-0(4) and H(34)-C1(2) distances are 1.81 and 2.28 A , respectively, which are 0.89 and 0.62 A less than the sum of the van der Waals radii of an H - and an O-atom (2.70 A ) , and that of an H-atom and a Cl-atom (2.90 A ) , respectively, an indication of strong H-bond interactions between the H 2 0 and the complex. The complex has Ru-Cl -Ru bridging angles of 96.83(3) and 97.89(3) °. Thus the R u atoms are further apart than expected for an ideal cofacial bioctahedron (for which M - X t e n „ i n a i = M-Xbridgin g , X -M - X angles = 90 ° and the M - X ^ ^ - M angles = 70.53 0 (given by cos 0/2 = (2/3) 1 / 2 ) 7 3 ; M = metal and X = ligand) 7 4 and no Ru-Ru interaction was detected out to 3.90 A ; there is no metal-metal bond. The usual range found for a Ru-Ru bond is ~ 2.28-3.04 A as exemplified by: 2.281 A for Ru 2 (02CC 3 H7)4Cl, 7 5 2.540 A for [Ru 2 ( / / -H) 3 (PMe 3 ) 6 ] [BF 4 ] , 7 6 2.728 A for [ R u C « - O O C C H 2 C H 2 C H 3 ) ( C O ) 2 ( P ( ' B u ) 3 ) 3 ] 2 , 7 7 2.743 A for [Ru 2 (Et 2 dtc) 5 ][BF 4 ] (Et 2dtc = N , N -diethyldithiocarbamato, S 2 CNEt 2 " ) , 7 8 2.80 A for [Ru(H) 2 Cl(Ptol 3 ) 2 ] 2 (Ptol 3 = p-tris(tolylphosphine), 7 9 2.811 A R u 2 H 4 ( P M e 3 ) 6 , 7 6 and 2.827-3.034 A for R u 6 C ( C O ) i 7 . 8 0 The cis angles at the R u range from 82.11(3)° to 95 .11(4)° and the trans angles range from 171.77(4)° to 178.01(8) °. The B P S E and B B S E complexes presumably have the corresponding dinuclear, dichloro-bridged structures. 102 References on page J55 Chapter 3 Figure 3.12. A n O R T E P drawing of [RuCl(BESE)(H 2 0)] 2 ( / / -Cl ) 2 with 50 % probability thermal ellipsoids (crystal data given in Appendix 1.5). 103 References on page J55 Chapter 3 H 2 9 Figure 3.13. Diagram of [RuCl(BESE)(H20)]2C"-Cl)2 showing the H 20 solvate (crystal data given in Appendix 1.5). 104 References on page 155 Chapter 3 3.8 A Mixed-Valence Ru(ll)/Ru(lll) Chelating Disulfoxide Complex Previous synthetic reactions using 2 equivalents of disulfoxide and RuCi3-3H 20 gave mononuclear Ru(II) bis-disulfoxide complexes (Section 3.6). However, reaction o f 2 equivalents of B P S P with RuCi3*3H20 led to the isolation of the first known type of a mixed-valence Ru(II)/Ru(III), chelating disulfoxide complex, [RuCl(BPSP)] 2C"-Cl)3, which contains three bridging chlorides. O f major interest, the species was readily soluble in water. This complex was tested in vitro for cytotoxicity, accumulation and DNA-binding properties in Chinese hamster ovary cells with the results presented in Chapter 4. 3.8. J Introduction Diruthenium complexes form the largest group of any mixed-valence systems,8 1 and R u has been the transition metal of choice to study electron transfer or exchange reactions because it is relatively inexpensive and forms stable Ru(II) and Ru(III) coordination complexes. 8 1 Allen and Hush have described the physical properties of mixed-valence compounds, 8 2 which contain an element in two different oxidation states and often exhibit unusually intense colouration unrelated to the colours of either of the individual metal ions. Homonuclear intervalence transfer absorption is a result of light absorption causing the transfer of an electron from a lower to a higher oxidation state of the same element, 8 2 the probability being smaller the larger the internuclear distance. These electron transfer absorptions may occur in the U V , visible or near-IR regions. 8 2 Mixed-valence complexes have been classified into three types (Table 3.12). 8 1" 8 5 105 References on page 155 Chapter 3 Table 3.12. Classes of Mixed-valence Complexes." Class I Class II Class III metal ions in ligand fields of very different symmetry and/or strength (i.e. tetrahedral vs. octahedral) metal ions in ligand fields of nearly identical symmetry III-A: metal ions indistinguishable but grouped into polynuclear clusters III-B: metal ions indistinguishable no mixed-valence transitions in the visible region one or more mixed-valence transitions in the visible region or near IR III-A: one or more mixed-valence transitions in the visible region III-B: absorption edge in the IR, opaque with metallic reflectivity in the visible region no coupling between metal ions (completely valence trapped) weak coupling between metal ions (valence trapped) strong coupling between metal ions (delocalized valency) exhibits properties observable only for isolated mononuclear M and M + complexes ( M = metal centre, M ' = one electron oxidation product) exhibits slightly perturbed M and h/L characteristics, and may also manifest properties not associated with isolated units properties of the ( M - M ) + unit are discerned " Based on data in refs. 81-85. Examples of R u mixed-valence complexes include R u red, [(NH3)5Ru-0-Ru(NH3)4-0 - R u ( N H 3 ) 5 ] 6 + , 8 6 " R u blues", 8 7" 9 1 and the now classic Creutz-Taube ion, [(NH 3 ) 5 Ru-(//-pyr)-Ru(NH3)s]5 + (pyr = N ^ N ) 8 1 ' 8 5 ' 9 2 . "Ru blue" solutions, well known as synthetic precursors to ! many Ru(II) and Ru(III) complexes, 8 8 appear to contain several species. Mercer and Dumas have identified three of these as being dinuclear Ru(II)/Ru(III) species of the type • Ru2Cl3+n(2"")+, where n = 0, 1 or 2 . 8 7 Rose and Wilkinson isolated green salts from the blue i j solutions and have proposed that such solutions may contain the anion R u C l 3 " and the cluster [RU4CI12] 4", 8 9 while Bino and Cotton later structurally characterized a green, mixed-valent 106 References on page 155 Chapter 3 complex [R113CI12]4" containing a linear arrangement of Ru(III)-Ru(Ii)-Ru(Hi).90 Bottomley and Tong suggested that the species responsible for one "Ru blue" solution was the mixed-valence dimer [Ru 2(NH3)6Cl 4(H 20)]Cl, formed either by reduction of chloroammine-complexes of Ru(III) or by reaction of ammine complexes of Ru(II) with acids.91 Gibson et al. reported that mixed-valence chloroammine complexes of Ru, like cisplatin, induced filamentation in E. coli (Section 1.3.1).93 [Ru2(NH3)6Cl3](BPh4)294 has been structurally characterized as a trichloro-bridged bioctahedral dimer, with a Ru-Ru distance of 2.753 A and an average Ru-Cl-Ru angle of 70.2 °; the related complex [(NH3)3RuBr3Ru(NH3)3](ZnBr4)95 has a Ru-Ru distance of 2.852 A and an average Ru-Br-Ru angle of 68.5 °. Other characterized trichloro-bridged Ru(II)/Ru(III) complexes include R u 2 C l 5 ( P " B u 3 ) 4 7 4 and the series [RuCl(P-P)]2(//-Cl)3 (P-P = chiraphos, diop or PPh 2(CH 2) nPPh 2 , n = 3 or 4; Figure 3.14)96. A Ru-Ru distance of 3.25 A (i.e. no Ru-Ru bond) and an average Ru-Cl-Ru angle of 83.4° were determined for [RuCl(chiraphos)]2(/i-Cl)3.96 Thorburn et al. stated that the X-ray data do not distinguish between a weakly interacting system and a completely delocalized system, but did suggest that [RuCl(chiraphos)]2Cw-Cl)3 would be best formulated as a valence-delocalized, class III A system (Table 3.12).96 H 4^-.CH 2PPh2 H Figure 3.14. Structures of SS-chiraphos and RR-dioip. 107 References on page 155 Chapter 3 Yapp in this laboratory reported the mixed-valence sulfoxide complexes Ru 2 Cl 5 (Et2SO)4, Ru 2Cl5(Pr 2SO)5 and R u 2 C l 5 ( B u 2 S O ) 5 . 5 2 Based on IR and *H N M R <s spectroscopies, Ru 2 Cls(Et 2 SO)4 was proposed to be a trichloro-bridged dimer with all terminal S-bonded sulfoxides arranged symmetrically around the R u centres, whereas Ru 2 Cls(Pr 2 SO)5 and Ru 2 Cls(Bu 2 SO )5 were tentatively assigned with four S- and one O-bonded sulfoxides to be dichloro-bridged (e.g. Cl(Pr 2SO) 3Ru(II)C«-Cl) 2Ru(III)Cl 2(Pr 2SO) 2). 5 2 O f interest, mixed-valent Pt complexes, the so-called "Pt blues", have been studied as a potentially useful class of anti-cancer drugs. These complexes, which may be obtained by reaction of cisplatin 9 7 with pyrimidine bases, 9 9 ' 1 0 0 are characterized by high solubility in aqueous solutions, low toxicity, minimal kidney toxicity and high anti-tumour activity as compared to cisplatin. 9 8 Insights into Pt blue chemistry were the structural determinations and detailed characterizations of the dimeric cz's-diammineplatinum a-pyridone blue (average oxidation state 2.25) and cz5-diammineplatinum(II)methylthymine (see Figures 3.15 and 3.16 for the structures of a-pyridone and methylthymine, and [QSM3)4Pt 2 (C5£i4NO) 2 ] 2 (N0 3 )5-H 2 0 9 9 and [(NH3)2Pt(C6H 7N 20 2) 2Pt(NH3)2](N03) 2-H 20, 1 0 0 respectively). Related Pt(II) creatinine blues (see Figures 3.15 and 3.16) 1 0 1 and a mixed-valence octanuclear Pt blue complex (average oxidation state 2.25) with bridging acetamido or 2-fluoroacetamido ligands (see Figure 3.16) 1 0 2 are also known. 108 References on page 755 Chapter 3 HN •K o T o NH u - N ' ^ N H o (1) (2) (3) Figure 3.15. Structures of a-pyridone (1), 1-methylthymine ( 2 ) and creatinine (3). 5+ 2 / V N H 3 H 3 N. H 3 N N N H 3 H 3 N X N H , W 5 H 3 N ' r l - N H 3 2+ (1) (2) (3) H3N NH3 WV N H , 1 V/ f / n ' r ^ N H 9 N H 3 \ / N H 3 110+ H 3 N N H — ^ (4) Figure 3.16. Structures of [(NH3)4Pt2(C5H4NO)2]2(N03)5H20 (1), [(NH3)2Pt(C6H7N202)2Pt(NH3)2](N03)2-H20 ( 2 ) , [Pt2(NH3)4(C4H7N30)2](N03)2 (3), and [(NH3)2Pt(CH3CONH)2Pt(NH3)2]4(N03)io-4H20 (4) adapted from refs. 9 9 - 1 0 2 . 3.8.2 [RuCl(BPSP)]2(p-Cl)3 Reaction of RuCl3-3H20 with two equivalents of BPSP in EtOH led to the isolation in 1 5 % yield of the unexpected dinuclear, mixed-valence complex [RuCl(BPSP)]2(//-Cl)3 1 0 9 References on page 155 Chapter 3 containing three bridging chloride ligands. A possible explanation for the low yield could be that some of the "green solution" containing Ru(II) (formed from RuCl 3 -3H 2 0 with concomitant oxidation of EtOH to acetaldehyde) was oxidized in situ to Ru(III) with reduction of disulfoxide to dithioether; a distinctive thioether odour was detected during the workup of the reaction solution (see Section 3.9, p. 126 for discussion of this redox chemistry). Vso data for the title complex indicated S-bonded sulfoxides (see Section 3.4.2, Table 3.5) and this was later confirmed by X-ray crystallography (Figure 3.18). The ' H N M R spectrum in CDC1 3 of the free ligand consists of multiplets at 8 3.00 (C# 2 CH 2 C/Y 2 ), 2.90 (C# 2 CH 2 CH 3 ) , 2.20 (CH 2 C#2CH 2 ) , 1.70 (C# 2CH 3) and a triplet at 1.07 (CH3), while for the complex (an equilibrated solution in D 20) these appear more downfield (with the exception of the methyl multiplet at 0.90) as broad signals at 8 3.72, 3.20, 2.44, 1.72 and 0.90, respectively (see Figure 3.21, p. 118); the *H spectrum in CDC1 3 consists of two broad peaks at 8 2.18 and 1.10. These data suggest that the Ru(II)/Ru(III) centres are delocalized, as broad resonances were observed in the *H N M R spectrum. No transitions were observed in the near-IR region (800-2000 nm). The complex exhibited no conductivity in CHC1 3, but in H 2 0 the molar conductivity (per mole of dimer) increased to a steady value of 234 after 20 min, the value corresponding to that of a 2:1 electrolyte (based on the equivalent conductance of salts (see Section 3.7.1); however, evidence suggests the solution contains 2 FF and 2 Cl" produced from each mole of dimer (Section 3.8.3), although the equivalent conductance of 10"3 M HC1 at 25 °C is ~ 420 7 2 and is much greater than that observed for [RuCl(BPSP)] 2(//-Cl) 3 (but see p. 100 that shows that the conductivity of the HC1 solution is decreased considerably in the presence of a 'neutral' Ru disulfoxide complex). The solution peff value, determined by a 110 References on page 155 Chapter 3 modified Evans' method (see Figure 3.17, and Section 2.2.3), was 1.7 + 0.1 B . M . consistent with one unpaired electron per molecule. A B i— i—i—r - -i—i—i—r— i—i—t— 4 0 p p m Figure 3.17. The *H N M R (200 M H z , CDC1 3 ) spectrum showing the paramagnetic shift caused by [RuCl(BPSP)] 2 ( / / -Cl) 3 (8.8 x 10" 2 M) of the residual CHC1 3 relative to that of the reference CHC1 3 . (A = residual CHC1 3 in CDC1 3 , and B = residual CHC1 3 peak shifted by [RuCl(BPSP)] 2 ( / /-Cl) 3 ) . A n X-ray diffraction study of a single crystal of [RuCl(BPSP)] 2 ( / / -Cl) 3 , obtained from a saturated solution of C H 2 C 1 2 , showed the dinuclear, triply chloro-bridged geometry (Figures 3.18 and 3.19). The complex crystallizes in an acentric space group containing a glide plane and thus enantiomers are present in the crystal structure. Figure 3.18 depicts one of the enantiomers. Selected bond lengths and bond angles for the observed two asymmetric units are given in Tables 3.13 and 3.14, respectively; crystallographically the two Ru-atoms are indistinguishable, consistent with the description as a delocalized Ru(II)/Ru(III) system. I l l References on page 155 Chapter 3 The bond lengths are in fact comparable to those found in [RuCl(BESE)(H 2 0)]2Ca -Cl) 2 where, for example, R u - C l is 2.4636(10) A (bridging, trans to S) and Ru-S is 2.1985(10) A. The coordination geometry about each R u is irregular octahedral with cis angles that range from 79.21(5)-97.46(6)° and trans angles that range from 168.66(6)-174.70(6) ° (Table 3.14). The bridging chloride C l ( l ) trans to terminal chlorides has a shorter R u - C l distance (2.3877(14)-2.4081(15) A) compared to those of the bridging chloro ligands trans to sulfur (2.444(2)-2.4882(15) A) (Table 3.13). This results from a weaker trans influence o f the chloro ligands and produces a wider Ru-Cl ( l ) -Ru angle (84.69(5) and 85.01(5) °) compared to the other two Ru-Cl -Ru (81.25(5)-82.61(5) °). The range of the bridging angles and the Ru-Ru distance (3.2300(6) and 3.2321(6) A) are outside those observed for a Ru-Ru bonded system (Section 3.7.1). The crystallographic and X H N M R spectral data taken together suggest that [RuCl(BPSP)] 2 ( / / -Cl) 3 is best formulated as a valence-delocalized class III system. 112 References on page J55 Chapter 3 Figure 3.18. An ORTEP drawing of one of the [RuCl(BPSP)]2C"-Cl)3 units with 50 % probability thermal ellipsoids shown; H-atoms are omitted for clarity (crystal data given in Appendix 1.6). 113 References on page 155 Chapter 3 Figure 3.19. A diagram of [RuCl(BPSP)] 2 ( / / -Cl) 3 showing short H-bonds connecting two asymmetric units via four H 2 0 molecules (the C H 2 C 1 2 atoms are not shown) (crystal data given in Appendix 1.6). 114 References on page 755 Chapter 3 Table 3.13. Selected Bond Lengths for the Two Asymmetric Units of [RuCl(BPSP)] 2 ( / / -Cl) 3 . Bond Length (A) R u - C l " 2.3877(14)-2.4081(15); 62.444(2)-2.4882(15) c Ru-Cl*" 2.377(2)-2.3903(15) Ru-S 2.204(2)-2.2093(15) S-0 1.474(5)-1.501(4) C-S 1.776(6)-1.809(6) ° Bridging. b Trans to C l . ° Trans to S. d Terminal. Table 3.14. Selected Bond Angles for the Two Asymmetric Units of [RuCl(BPSP)] 2 ( / / -Cl) 3 . Bond angle Angle (°) Bond angle Angle (°) cis angles 79.21(5)-97.46(6) Ru-S-0 117.1(2)-119.7(2) trans angles 168.66(6)-174.70(6) S-C-C° 109.5(4)-112.8(5) Ru-Cl -Ru 81.25(5)-82.61(5)c S-C-C f e 110.7(4)-117.6(5) 84.69(5) and 85.01(5)° C - S - C 100.3(3)-102.3(3) Ru-S-C° 110.6(2)-112.7(2) o-s-c 104.2(3)-107.0(3) R u - S - C 6 111.3(2)-115.8(2) " Backbone. 6 End substituents. c Trans to sulfur. d Trans to chloride. Crystals of the complex were found to contain 2 H 2 0 and 2.5 C H 2 C 1 2 solvate molecules per molecule. The range of the H -0 distances (H-atoms of the water molecules and the O-atoms of the sulfoxides) is 1.61-1.76 A, which is 0.94-1.09 A shorter than the sum 115 References on page 155 Chapter 3 of the van der Waals radii o f an H - and an O-atom (2.70 A) (Figure 3.19). 7 0 This suggests a strong interaction between the solvate water molecules and the two asymmetric units. The range of the H - C l distances (H-atoms of the sulfoxides and the Cl-atoms o f CH2CI2) is 2.77-2.93 A (not illustrated), the average being shorter than the sum of the van der Waals radii o f an H - and a Cl-atom (2.90 A), 7 0 thus implying relatively weak interactions between the CH2C1 2 solvates and the complex. The chiralities at the S-atoms on each of the B P S P ligands are R and S, respectively (Table 3.8). O f interest, during the preparation of this thesis, Geremia et al. reported a structure consisting of parallel layers of [Cu(BPSP)2(C104)]„"+ cations intercalated by «[C104]~ anions with the O-atoms of B P S P acting as a bridge linking the Gu atoms. 1 0 3 3.8.3 Chemical Behaviour of [RuCl(BPSP)]2(u-Cl)3 in Aqueous Solutions In view of the potential biological interest of the water-soluble Ru(II)/Ru(III) complex [RuCl(BPSP)]2(^-Cl)3, its chemical behaviour in aqueous solutions was studied. The proposed mechanism for the chemical behaviour in aqueous solution is summarized in Figure 3.20, with supporting data being given subsequently (the experimental details are given in Appendix 2). 116 References on page 155 Chapter 3 Figure 3.20. Proposed mechanism for the behaviour of [RuCl(BPSP)] 2 ( / / -Cl)3 in aqueous solution; the two Ru(II)/Ru(III) centres are not distinguished crystallographically, and loss o f the chlorides is assumed to be from the terminal positions (the propyl groups of B P S P are omitted for clarity). The equilibrium ' H N M R spectrum of the complex in D 2 0 (under air) does not change upon addition of up to three equivalents of AgNC"3. Upon addition of two equivalents o f A g N 0 3 , added dropwise, to a solution of [RuCl(BPSP)] 2 (/ /-Cl)3 in D 2 0 , a precipitate formed immediately, but the resulting ' H N M R spectrum of the heterogeneous mixture was the same as that of the equilibrium spectrum of [RuCl(BPSP)] 2 ( / /-Cl)3 in D 2 0 (Figure 3.21), suggesting that the two terminal chlorides dissociate in D 2 0 . The D 2 0 solution containing the A g C l precipitate was then filtered and one more equivalent of AgNC»3 was added dropwise to 117 References on page 155 Chapter 3 the filtrate. N o further precipitate was observed, and the resulting *H N M R (Figure 3.21B) was identical to that in Figure 3.21 A . ppm ppm Figure 3.21. *H N M R spectra of equilibrated [ R u C l ( B P S P ) ] 2 O C l ) 3 in D 2 0 (after 2 h) (A) and immediate spectrum of [RuCl(BPSP)] 2 ( / /-Cl) 3 (2.02 x 10"3 M ) after addition of two or three equivalents of A g N 0 3 in D 2 0 ( B ) . A titration of [RuCl(BPSP)] 2 ( / / -Cl) 3 with N a O H in water showed that two equivalents of a standardized N a O H solution were required to titrate 1 equivalent of [RuCl(BPSP)] 2 ( / / -Cl) 3 (see Table 3.15), suggesting the loss of 2 equivalents of H " from [RuCl(BPSP)] 2 ( / / -Cl) 3 . Table 3.15. Titration data for [RuCl(BPSP)] 2 ( / /-Cl) 3 using N a O H . [NaOH] (mM) Volume used (mL, mmol) [RuCl(BPSP)] 2 ( / / -Cl) 3 (mg, mmole) 2.23 (± 0.09) 3.32 (±0 .13 ) , 7.5 (+0.3)x IO"3 3.10 (±0 .05 ) , 3.74 (± 0.06) x 10"3 118 References on page J55 Chapter 3 ' H N M R studies and p H measurements in H 2 0 are consistent with the loss of two FT and two Cl" ions on dissolution of [RuCl(BPSP)] 2 (/z-Cl) 3 in H 2 0 while conductivity measurements are somewhat inconclusive (p. 110). [RuCl(BPSP)] 2 ( / / -Cl) 3 is yellow-orange in solution; in C H 3 C N no conductivity was observed and the spectrum was time invariant, with absorption maxima at 286, 324 and 424 nm, while dissolution in H 2 0 leads to a final product (> 20 min) with absorption maxima at 282, 318 and 450 nm, the colour then remaining yellow-orange and invariant with time. A n example o f the spectral changes observed for [RuCl(BPSP)] 2 ( / / -Cl) 3 in aqueous solution is shown in Figure 3.22 (the initial spectrum was recorded 30 s after dissolution of the sample). The aqueous solution system was well-behaved in that isosbestic points at X 268, 336 and 396 nm were observed as the U V - V i s spectrum changed with time (Figure 3.22). Absorbance changes were then monitored as a function of time at X = 362 nm (Figure 3.23). A n example o f a pseudo-first-order rate plot is shown in Figure 3.24 and the pseudo-first-order rate-constants, kobs, obtained were found to be directly dependent on the concentration o f H 2 0 from 22.2-55.6 M (in mixtures of H 2 0 / C H 3 C N , Table 3.16, Figure 3.25). For reactions run in 0.25 M aqueous N a C l , 0.1 M aqueous toluene-4-sulfonic acid, and under N 2 , the measured kobs values were 5.34 x 10"3, 5.22 x 10"3 s"1 and 5.33 x 10"3 respectively (Table 3.16 and Figure 3.25); the data reveal an independence of the reaction on added [CT], [FT] and show that the solutions are not air-sensitive. 119 References on page 155 Chapter 3 2.97 0.00 ' — | i i i i | i — i — r — i — j — i — i i i | 200 300 400 500 600 wavelength (nm) Figure 3.22. A representative spectrum of the U V - V i s spectral changes (200-600 nm region, 1 cm cell) o f [RuCl(BPSP)] 2 (^-Cl) 3 (2.96 x 10"4 M ) in an aqueous solution at 27 °C as a function of time (half life Un = 120 s, for the pseudo-first order process, see Figure 3.24); isosbestic points are observed at the noted wavelengths. 120 References on page 155 Chapter 3 Figure 3.23. Absorption spectral changes at X - 362 nm as a function of time for the reaction of [RuCl(BPSP)] 2 (>Cl ) 3 in H 2 0 (55.6 M ) at 27 °C. Figure 3.24. A representative rate-plot analyzed for a first-order dependence on [RuCl(BPSP)] 2 ( / i -Cl) 3 ; A and A „ represent the absorption at 362 nm at times t and oo, respectively, at 27 °C. 121 References on page 155 Chapter 3 0 10 20 30 40 50 60 LHPl(M) Figure 3.25. The dependence of the pseudo-first-order rate constant, kobs, on [ H 2 0 ] at 27 °C; including the ko b s values obtained from reactions run in 0.25 M aqueous N a C l and 0.1 M aqueous toluene-4-sulfonic acid (in H 2 0 / C H 3 C N solutions, see Table 3.16). A s the reaction rate is independent of added chloride and added protons, the rate-law for the stepwise process outlined in Figure 3.20 (p. 117) becomes simply k i [ A ] [ H 2 0 ] : the independence on [Cl"] implies k-i is negligible, while the independence on [FT] implies that K i and K 2 are sufficiently large that variation of the [FT] during any single kinetic run does not change the concentration of any kinetically significant species, in this case C and D. O f note, [Cl"] and [FT] production should also be governed kinetically by k i . Under pseudo first-order conditions, with excess H 2 0 , the rate = kobs[A] where kobs = k i [ H 2 0 ] ; the second-order rate-constant k i was determined from Figure 3.25 to be 9.82 x 10"5 M " 1 s'1 at 27 °C, and was essentially independent of the concentration of [RuCl(BPSP)] 2 ( / / -Cl) 3 from (1.48-14.8) x 10"4 M (Figure 3.26). 122 References on page 155 Chapter 3 1.40 -i 1.20 -' CO 1.00 -0.80 -T O *H 0.60 -H 0.40 -0.20 -0.00 -10 12 14 16 [Ru] x 10 ( M ) Figure 3.26. The dependence of the second-order rate constant ki on [RuCl(BPSP)]2[C"-Cl)3] in H 2 0 (22.2 M ) at 27 °C. (Ru = [RuCl(BPSP)] 2 (/ /-Cl) 3 ) . -14 -i -14.4 --14.8 -fc: -15.2 -£ -15.6 --16 --16.4 -0.0032 0.00325 0.0033 0.00335 0.0034 0.00345 0.0035 1/T (K ) Figure 3.27. Erying plot for the temperature dependence of the rate constant ki for the reaction of [RuCl(BPSP)] 2 ( / / -Cl) 3 (2.96 x IO - 4 M ) with H 2 0 (22.2 M ) . 123 References on page J55 Chapter 3 The temperature dependence data for k i were obtained at a single concentration of [RuCl(BPSP)] 2 ( / / -Cl) 3 , 2.96 x IO"4 M , with 22.2 M H 2 0 in acetonitrile (3:2 V / V ) . A n Erying plot (Figure 3.27) of the data from 15-35 °C (Table 3.16) gave a straight line from which the activation parameters A I T ' = 65 ± 7 k j mol"1 and A S " =-105 ± 21 J mol^K" 1 were determined. These data, taken together with the second-order rate-law, are consistent with an associative process for the k i step. O f note, Alessio et al. have studied the chemical behaviour of ~Na[trans-R u C l 4 ( D M S O ) 2 and w e r - R u C l 3 ( D M S O ) 2 ( D M S O ) in aqueous solution (Section 1.4.2).25 These two complexes turned greenish grey in a few hours at 25 °C and the authors attributed this, and a noted p H drop of the solutions, to the formation of polymeric Ru(III) species probably with hydroxo or ju-oxo bridges. 2 5 ' 1 0 4 Chloride concentrations up to 0.3 M did not significantly influence the rates of these processes in solution, but a strong acid dependence was observed down to p H < 3. 2 5 A t this stage, such polymer formation from the mixed-valence Ru(II)/Ru(III) system seem unlikely. Attempts to isolate the product from an aqueous solution were unsuccessful; only an oily residue was obtained. 124 References on page 155 Chapter 3 Table 3.16. Kinetic Data for the Hydration Reaction of [RuCl(BPSP)]2(//-Cl)3 in H 2 0 . ° [[RuCl(BPSP)]2(//-Cl)3] (M) [ H 2 0 ] ( M ) T(°C) kobs (s"1) k i ( M Y1 ) 2.96 x IO"4 55.6 27 5.82 x 10"3 1.05 x lO"4 2.96 x If/ 4 44.4 27 4.54 x 10"3 1.02 x IO- 4 2.96 x 10"4 33.3 27 3.46 x IO -3 1.04 x IO- 4 2.96 x IO"4 2.8 27 2.94 x 10'4 1.05 x 10"4 2.96 x IO"4 22.2 27 2.30 x IO"3 1.04 x 10"4 2.96 x IO"4 22.2 35 4.78 x IO -3 2.15 x IO- 4 2.96 x IO"4 22.2 27 2.22 x 10 "3 1.00 x 10"4 2.96 x IO"4 22.2 20 1.37 x 10"3 6.17x IO"5 2.96 x IO"4 22.2 15 7.20 x IO - 4 3.24 x IO- 5 5.92 x 10"4 22.2 27 2.75 x IO"3 1.24 x IO- 4 1.48 x IO"4 22.2 27 2.51 x lO" 3 1.13 x lO"4 1.48 x IO - 3 22.2 27 2.62 x lO" 3 1.18 x IO- 4 2.96 x IO"4 55.6 27 5.34-5.62 x 0.96-1.01 x [0.05-0.25M Cl'] IO"3 , IO"4 2.96 x lO" 4 55.6 [0 .1MH 4 ] 27 ' 5.22 x IO"3 9.39 x IO'5 2.96 x 10"4 55.6 (under N 2 ) 27 5.33 x IO"3 9.59 x IO"5 a In mixtures of H 2 0 / C H 3 C N . i 125 References on page 155 Chapter 3 \ 3.9 Dithioether Complexes of Ru Previous workers in this laboratory have isolated RuX 3(thioether)3 complexes (thioether = D M S or T M S ; X = C l or Br) from reactions of RuCl 3 -3H 2 0 with acidified D M S O or T M S O . 3 5 3 ' 3 7 The reported synthetic procedures for these complexes were similar to those which gave the anionic complexes ' ' with protonated D M S O and T M S O as associated cations, ^a /75 - [ (DMSO) 2 H] + [RuCl 4 (DMSO )2] " and / ra«s- [ (TMSO)H] + [RuCl 4 (TMSO) 2 ]" , respectively, except that a higher reaction temperature was used (130-140 vs. 70-80 °C); formation of the thioether was attributed to redox processes involving Ru(III) and the sulfoxide. 3 5 3 ' 3 7 Commercially available RuCl 3 -3H 2 0 analyzes well for such a composition, but actually consists of a mixture of Ru(III) and Ru(IV) species of which the latter is thought to be a hydroxo species. 1 0 6 ' 1 0 7 O f note, Lipponer et al. have recently described three methods of purifying RuCl 3 -3H 2 0 to yield solutions of pure Ru(III). 1 0 8 The exact mechanistic steps leading to the reduction of the sulfoxide are not known, but there is some evidence to indicate that the following reactions may play a role: 2Ru(III) + D M S O + H 2 0 -> 2Ru(II) + DMS (0) 2 + 2lT 2Ru(II) + R 2 S O + 2lT — 2Ru(III) + R 2 S + H 2 0 The reduction of Ru(III) to Ru(II) with accompanying oxidation of D M S O to the sulfone was initially suggested by Ledlie et al.,109 and the Trieste group subsequently detected the presence of dimethyl sulfone (in a stoichiometric amount) in the reduction of /wer-RuCl 3 (DMSO) 3 (in D M S O under Ar) to fr*a«5-RuCl2(DMSO)4.25 Evidence for the second equilibrium (R = Bu) was reported by Ledlie et al. and under highly acidic conditions the reaction is likely pushed to 126 References on page 155 Chapter 3 the right-hand side generating the Ru(IIi)-thioether.109 The ligand sets on Ru during this process, however, remain undefined, and more studies are required before the mechanistic steps in this new route to thioether complexes are more fully understood. 3.9.1 Literature Data As discussed in Section 3.6, reactions of disulfoxides with Ru precursors gave mainly RuCl2(disulfoxide)2 complexes of a preferred cis- or zraws-geometry regardless of the nature of the precursor. The goal of synthesizing RuCl2(dithioether)2 complexes was to determine the cis- or zraws-geometry, and then oxidize the coordinated dithioethers to the disulfoxides to determine if the geometry was retained. Chatt et al. reported that RuCl 3 -3H 2 0 reacted with mono-(S), di-(SS), or tri-organic sulfides (SSS) to give complexes with the formulations mer-\KuChSi\, [{RuCl3(SS)..5}„] and *ra«s-[RuX2(SS)2] (X = Cl or Br), or [RuCl3(SSS)], respectively.110 The authors state that in the series of [{RuCl 3 (RSCH2CH 2 SR)i . 5 },] complexes (R = Me, Et, Pr or Ph); 'these complexes are at least dinuclear although they are too insoluble for molecular weight determination' and it is 'likely that one sulfide molecule is chelating and one bridging'. 1 1 0 The authors also reported the isolation of RuCl2(RSCH 2 CH 2 SR)2 species (R = Ph) during attempts to isolate Ru(III) complexes and suggested that RSCH2CH2SR (R = Ph) is more strongly reducing than the thioethers with R = Me, Et or Pr; trans geometry was suggested based on IR data. 1 1 0 127 References on page 155 Chapter 3 Within related complexes, Lucas et al. have reported on the Pt or Pd complexes M X r B B T E ( M = Pd and X = C l or I, and M = Pt and X = C l with B B T E = 1,2-bis(benzylthio)ethane).1 1 1 Hartley et al. have reported on the Pd or Pt complexes cz 's-[MLX 2 ] and [ M L 2 ] ( C 1 0 4 ) 2 ( X = C l , B r or I; L = (a) RS(CH 2 )„SR, R = M e or Ph, and n = 2 or 3; (b) c/5 -RSCH=CHSR, R = M e , Ph or o -C 6 H4 (SR ' ) 2 ( R = M e or Ph). With L = PhS(CH 2 )„SPh, n = 6 or 8, polymeric [PdLX 2]„ species were obtained, while with n = 12 zra«s-PdLX 2 ( X = C l or Br) and trans-P\LC\2 were formed. 1 1 2 The complexes [ M ( M e S C H 2 S M e ) X 2 ] ( M = P d or Pt; X = C l , B r or I), [Rh(PhSCH 2 SPh) 3 Cl 3 ] , [ I r (PhSCH 2 SPh) 3 Cl 3 ] and R u ( P h S C H 2 S P h ) 2 C l 3 E t O H have also been reported. 1 1 3 None of the above was characterized structurally. Song et al. have structurally characterized the complex Rh 2Cl 2(CO) 2(bis(ethylthio)methane) 2 1 1 4 and Shao et al. have reported the use o f R S C H 2 C H 2 S R (R = » - C 3 H 7 , /7 -C 5 Hn, « - C 8 H n and Ph) as reagents used in the extraction of A g . 1 1 5 This thesis work reveals that reactions of B P h T E and B C y T E with R u C l 3 - 3 H 2 0 gave mononuclear Zraw5-Ru(II) complexes (Section 3.9.2), whereas the longer chain dithioethers 3,7-dithianonane, 4,8-dithiaunadecane, 5,9-dithiatridecane, and 6,10-dithiapentadecane gave the dinuclear Ru 2(III) complexes [RuCl 2(BETP)] 2(yU-Cl) 2, [RuCl 2 (BPTP)] 2 ( / / -Cl) 2 , [RuCl 2 (BBTP)] 2 ( / / -Cl ) 2 and [RuCl 2 (BPeTP)] 2 ( / / -Cl) 2 (Section 3.9.3), respectively. 128 References on page 155 Chapter 3 Schenk et al. have reported that Ru-thioether complexes can be directly converted with dimethyldioxirane to the corresponding sulfoxide complexes; for example, [RuCp(chiraphos)(SR/R')]PF 6 gave [RuCp(chiraphos)(SOR/R')]PF 6 (Cp = cyclopentadienyl; R/R ' = Me/Ph, Me/'Pr, M e / B z , E t /Bz or M e / C y ) , 1 1 6 and this led to the idea of such an alternative oxidation route to different geometrical isomers of the known disulfoxide R u complexes. However, an initial attempt to oxidize Jraws-RuCl 2 (BPhTE) 2 using dimethyldioxirane was unsuccessful; no v S o was detected in an isolated crude product (Section 2.10.2). O f note, Schenk et al. noted that "conversions of the thioether to the sulfoxide drop sharply when both substituents at sulfur are sterically more demanding" (e.g. SR/R' = Et /Bz) and "using a large excess of dimethyldioxirane in this case leads to increased decomposition". 1 1 6 3.9.2 The Mononuclear Ru(II) Dithioether Complexes: Trans-RuCl2(BCyTE)2-2H20 and Trans-RuCl2(BPhTE)2 Reaction of R u C l 3 - 3 H 2 0 with B C y T E gave the complex zra /w-RuCl 2 (BCyTE) 2 . Its ! H N M R spectrum in C D C I 3 is a complicated pattern of broad peaks between 8 1.20-3.35 that could not be assigned by using 1 3 C , 2 D - C O S Y and *H N M R decoupling experiments; the broad signals presumably result from the rotation of the cyclohexyl rings. A n O R T E P of the complex is shown in Figure 3.28, and the unit cell showing 2 C H 2 C 1 2 solvate molecules is shown in Figure 3.29. Selected bond lengths and angles are given in Table 3.17. N o significant H-bonding interactions are evident with the solvate molecules. The R u - C l bond length in the centrosymmetric structure is 2.4262(6) A , while the R u - C l bond lengths (trans to 129 References on page 155 Chapter 3 S) for the disulfoxide complex czs-RuCl 2 (BCySE) 2 are 2.4201(13) and 2.4344(13) A , indicating that the trans influence of the sulfoxide moiety is similar to that of Cl". The Ru-S bond lengths of 2.3629(9) and 2.3646(9) A for the dithioether complex and are longer than those for czs-RuCl 2 (BCySE) 2 (2.3364(13) and 2.3484(13) A) . The isolation of zra«s-RuCl 2 (BCyTE) 2 implies that the suggestion by Chatt et al. that P h S C H 2 C H 2 S P h is a more strongly reducing thioether is not valid in a general sense (Section 3.9.1). 130 References on page 155 Chapter 3 Figure 3.28. A n O R T E P drawing of /raws-RuCl 2(BCyTE)2-2CH 2Cl2 with 50 % probability shown; H-atoms are omitted for clarity (the CH2CI2 molecules are not shown) (crystal data are given in Appendix 1.7). 131 References on page 155 Chapter 3 Figure 3.29. The unit cell of Jram-RuCl 2(BCyTE) 2-2CH 2Cl 2 showing the 2 CH 2 C1 2 solvate molecules (crystal data given in Appendix 1.7). 132 References on page 155 Chapter 3 Table 3.17. Selected Bond Lengths (A) and Angles (°) for zra/M-RuCl2(BCyTE)2-2CH2Cl2 and /ratf£-RuCl2(BPhTE)2. Bond or angle fraw5-RuCl2(BCyTE)r2CH2Cl2 rra«£-RuCl 2(BPhTE) 2 Ru-Cl 2.4262(6) 2.4244(8), 2.4266(8) Ru-S 2.3629(6), 2.3646(7) 2.3424(7), 2.3594(8) C-S 1.813(3)-1.840(3) 1.815(4)-1.83 6(4),° 1.777(3)-1.799(3f cis angles 84.14(2)-95.86(2) 83.65(3)-98.09(3) trans angles 180.0 167.66(3)-178.13(4) C-S-C 97.89(11), 104.30(11) 98.52(15)-102.22(15) S - C - C 110.4(2), 112.3(2) 106.8(2)-108.9(2) S-C-C c 105.5(2)-l 12.6(2) 118.2(3)-124.3(3) Ru-S-C 101.76(9), 104.13(9) 102.61(11)-104.14(10) Ru-S-C c 110.98(9), 117.26(9) 117.01(10)-120.96(11) " Backbone C-atoms. b Phenyl rings. c End substituents. Reaction of RuCl 3 -3H 2 0 and BPhTE gave the complex fraH5 -RuCl 2 (BPhTE) 2 (confirming the geometry of the complex previously suggested by Chatt et al., Section 3.9.1). i The *H N M R spectrum in CDC1 3 of the free ligand consists of a singlet at 8 3.10 assigned to the C H 2 C H 2 backbone and a multiplet centred at 8 7.15 due to the phenyl protons; the *H signals for the aromatic protons of the coordinated dithioether are split into three signals at 8 ! 7.65, 7.28 and 7.12 assigned to the o-,p- and zw-protons, respectively. The assignments are based on the resonance structures of the phenyl ring with a thioether (Figure 3.30). These 133 References on page 155 Chapter 3 resonance structures show that the S-atom removes electron density from the o- and p-positions and results in downfield shifts of these signals, while the protons at the m- positions are not affected directly. Figure 3.30. Resonance structures of a phenyl ring with a thioether. The structure of the complex is shown in Figure 3.31, and selected bond lengths and angles are given in Table 3.17. The R u - C l bond lengths are 2.4244(8) and 2.4266(8) A for this bis-chelating dithioether complex (Table 3.17). N o conductivity was observed for these /raHs-bis(dithioether) complexes in C H 2 C 1 2 solution. R R + 134 References on page 155 Chapter 3 Figure 3.31. An ORTEP drawing of /ra«5-RuCl 2(BPhTE) 2 with 50 % probability thermal ellipsoids shown; H-atoms are omitted for clarity (crystal data are given in Appendix 1.8). 135 References on page 155 Chapter 3 3.9.3 Dinuclear Ru(III)/Ru(III) Dithioether Complexes: [RuCl2(BETP)]2(p-Cl)2, [RuCl2(BPTP)]2(p-Cl)2, [RuCl2(BBTP)]2(p-Cl)2 and [RuCl2(BPeTP)]2(p-Cl)2 Reactions of 3,7-dithianonane, 4,8-dithiaunadecane, 5,9-dithiatridecane, and 6,10-dithiapentadecane with R u C l 3 - 3 H 2 0 gave the dark purple-brown, dinuclear Ru 2(III) complexes [RuCl 2 (BETP)] 2 ( / / -Cl) 2 , [RuCl 2 (BPTP)] 2 Cu-Cl) 2 , [RuCl 2 (BBTP)] 2 ( / / -Cl ) 2 and [RuCl 2 (BPeTP)] 2 ( / / -Cl) 2 , respectively, while crystals of [RuCl 2 (BETP)] 2 ( / / -Ci ) 2 and [RuCl 2 (BPTP)] 2 ( / / -Cl) 2 suitable for X-ray analysis were obtained by slow evaporation of a solution of the respective complex in C H 2 C 1 2 . Both complexes (Figures 3.32 and 3.33) have two bridging Cl-atoms, each Ru(III) centre also having two terminal Cl-atoms. The R u - C l bond lengths for the terminal Cl-atoms for [RuCl 2 (BETP)] 2 Gu-Cl) 2 and [RuCl 2 (BPTP) ] 2 ( / i -C l ) 2 are 2.3258(7) A and 2.3213(9) A (trans to Cl) and 2.3501(8) A and 2.3579(10) A (trans to S), respectively, (Table 3.18), suggesting a small trans influence of S (vs. Cl) . The R u - C l bond lengths for the bridging Cl-atoms are 2.3915(7) A and 2.4617(7) A for [RuCl 2 (BETP)] 2 ( / / -Cl ) 2 , and 2.3833(9) A and 2.4605(9) A for [RuCl 2 (BPTP)] 2 ( / / -Cl) 2 . The two Ru-S bond lengths are 2.3201(8) and 2.3677(8) A for [RuCl 2 (BETP)] 2 ( / / -Cl ) 2 , and 2.3311(10) and 2.3564(11) A for [RuCl 2 (BPTP)] 2 Cu-Cl) 2 . [RuCl 2 (BETP)] 2 ( / / -Cl ) 2 and [RuCl 2 (BPTP)] 2 Cu-Cl ) 2 have bridging angles of 95.86(3) 0 and 97.02(3) °, respectively, and there are no Ru-Ru bonds (usually considered in the range 2.28-3.034 A , see Section 3.7.1). Elemental analyses of [RuCl 2 (BBTP)] 2 ( / / -Cl ) 2 and [RuCl 2 (BPeTP)] 2 ( / / -Cl) 2 show a formulation consistent with the structurally characterized dinuclear, dichloro-bridged Ru 2(III) species described above. The solid-state magnetic susceptibilities of [RuCl 2 (BETP)] 2 ( / / -Cl ) 2 , 136 References on page 155 Chapter 3 [RuCl 2(BPTP)] 2(//-Cl) 2, [RuCl 2(BBTP)] 2(//-Cl) 2 and [RuCl 2(BPeTP)] 2(//-Cl) 2 were p e f f = 3.8, 3.1, 3.2 and 3.4 ± 0.1 B. M . , respectively, showing in 1 unpaired electron/Ru(III) center in each case, and are consistent with no interaction between the metal centres. No conductivity was observed for these dimeric Ru(III)/Ru(III) complexes in CH 2 C1 2 solution. The complexes are insoluble in water. Table 3.18. Selected Bond Lengths (A) and Bond Angles (°) for [RuCl 2(BETP)] 2(//-Cl) 2 and [RuCl 2(BPTP)] 2(//-Cl) 2. Bond or Angle [RuCl 2(BETP)] 2(//-Cl) 2 [RuCl2(BPTP)]2Gu-Cl)2 Ru-Cf 2.3258(7),* 2.3501(8)c 2.3213(9),* 2.3579(10)' Ru-C^ 2.3915(7), 2.4617(7) 2.3833(9), 2.4605(9) Ru-S 2.3201(8), 2.3677(8) 2.3311(10), 2.3564(11) C-S 1.808(3)-1.823(3) 1.806(4)-1.821(4) cis angles 84.14(3)-96.74(3) 82.98(3)-97.50(3) trans angles 172.05(3)-175.81(3) 173.32(4)-175.93(4) C-S-C 99.78(15), 100.54(15) 99.0(2), 100.6(2) S-C-C 6 112.9(2), 117.3(2) 112.0(3), 117.5(3) S-C-C / 110.7(2), 112.5(3) 111.3(3), 112.8(3) Ru-S-C e 110.16(11), 111.62(11) 110.27(14), 112.80(14) Ru-S-C 7 107.85(11), 110.65(10) 109.73(13), 110.74(13) Ru-Cl-Ru 95.86(3) 97.02(3) a Terminal Cl. * Trans to Cl. 0 Trans to S. d Bridging Cl. 6 Backbone C-atoms. ^End substituents. 137 References on page 155 Chapter 3 Figure 3.32. An ORTEP drawing of [RuCl 2(BETP)] 2(//-Cl) 2 with 50 % probability thermal ellipsoids shown; H-atoms are omitted for clarity (crystal data are given in Appendix 1.9). 138 References on page 155 Chapter 3 Figure 3.33. A n O R T E P drawing of [RuCl 2 (BPTP)] 2 ( / i -Cl) 2 with 50 % probability thermal ellipsoids shown. The H-atoms are omitted for clarity (crystal data are given in Appendix 1.10). 139 References on page 155 Chapter 3 3.10 A f e r - R u C l 3 ( D P S O ) 2 ( D P S O ) According to literature data, /weA--[MCl3(sulfoxide-S)2(sulfoxide-0)] ( M = Ru(III) or Rh(III)) have been isolated with the sulfoxides = D M S O , T M S O , Me(Ph)SO and "Pr2SO. 1 0 5 , 1 1 7 Previous work in this group has included the synthesis and structural characterization of two complexes with Ph 2 SO (DPSO): mer-[RhCl 3 (DPSO)(DPSO)( 'PrOH)] 1 1 7 and /wer-[RuCl 3 (DPSO)(DPSO)(MeOH)] 5 2 (see Figure 3.34). Figure 3.34. Structure of wer-[RuCl 3 (DPSO)(DPSO)(MeOH)]; O and S are O- and S-bonded D P S O , respectively. These results perhaps suggest that coordination of three D P S O ligands may be prevented sterically as the electronic properties of the S-0 moiety of D P S O have been considered to be "similar to those of the other sulfoxides". 1 1 8 The crystal structure o f D P S O 1 1 9 reveals approximate pyramidal geometry at each S-atom with a sulfur-oxygen bond length o f 1.47 A indicating some double bond character in this bond. The coordination of a third D P S O is not, in fact, restricted as shown here by reaction of excess D P S O with R u C l 3 - 3 H 2 0 to generate mer-RuCl 3(DPSO) 2(TJPSO); the Trieste group independently synthesized and characterized this complex during the course of this present thesis work . 1 1 8 O Cl | MeOH S 140 References on page 155 Chapter 3 3.10.1 Characterization ofMer-Cis-RuCh(DPSQ)2(DPSP) A s noted above, the title complex was synthesized by reacting excess D P S O with RuCi3-3H20, and crystals were obtained following the addition of ether to a reduced-in-volume reaction solution. Strong IR vso bands were observed in the solid state at 922 cm"1 attributed to O-bonded D P S O , and at 1063 and 1129 cm"1 attributed to S-bonded D P S O (the Trieste group report v s o (DPSO) at 919 cm"1 and (DPSO) at 1128 cm" 1 ) . 1 1 8 J H N M R spectral data (Section 2.6.3) consisted of a broad peak centred at 8 8.80, and sharp peaks that correspond to those of free D P S O . Very similar lH N M R data have been observed for mer-[RuCl 3 (DPSO)(DPSO)(MeOH)] . 5 2 The solution magnetic susceptibility of the complex u. e f f = 2.33 B . M . corresponds to one unpaired electron. The X-ray analysis revealed the presence of two O-bonded and one S-bonded D P S O ligands in a /wer-geometry (Figure 3.35); the S-bonded sulfoxide is trans to an O-bonded one. This is the first example of a R u complex showing more O- than S-bonded sulfoxides (cf. mer-trans-[RuCh(DMSO)2(DMSO)])25m Table 3.19 summarizes geometrical data for the complex, and the related mer-[RuCl 3 (DPSO)(DPSO)(MeOH)] 5 2 . The R u - C l bond distance trans to oxygen is 2.305(1) A which is shorter than the mutually trans Cl-atoms, 2.338(1) and 2.324(1) A; in mer-[RuCl 3 (DPSO)(DPSO)(MeOH)] (Figure 3.34) the R u - C l bond distance trans to the O-atom of M e O H is 2.301(1) A and the mutually trans R u - C l bonds are 2.3165(9) and 2.339(1) A. 5 2 These data suggest that D P S O and M e O H (trans to Cl) have a similar trans influence, which is somewhat less than that of C l . A s expected, the Ru(III)-Cl bond lengths are shorter than those found in Ru(II)/Cl/sulfoxide complexes (typically 2.39-2.45 A , Section 3.6), because o f 141 References on page 155 Chapter 3 the electrostatic effect of the greater charge on Ru(III). 1 2 0 In both D P S O complexes, the R u -O distance trans to S is 0.02 to 0.03 A longer than the R u - 0 bond trans to C l , because of the greater trans influence of S vs. C l . The Ru-S bond lengths (trans to an O-atom) in the tris-and bis(DPSO) complexes are 2.251(1) and 2.2391(9) A, respectively. These Ru-S bonds are shorter than those found for example, in /ra«5-[(TMSO)H] + [RuCl 4 (TMSO)2]" (2.3219(8) A). 1 0 5 A similar situation is found within Ru(II) /DMSO systems where the shorter Ru-S bonds are those in which the S-atoms are trans to O (e.g. 2.248 A in c/s-RuCl2(DMSO) 4) while those trans to C l or S are longer (e.g. 2.277 A in c / s -RuCl 2 (DMSO) 4 and 2.353 A in / r a«5 - R u C l 2 ( D M S O ) 4 . 2 3 ' 3 6 ' 3 7 The sulfur-oxygen bond lengths of the O-bonded D P S O are 1.524(3) (trans to Cl) and 1.544(3) A (trans to S) in the tris D P S O complex, slightly longer than that found in /wer-[RuCl 3 (DPSO)(DPSO)(MeOH)] 1.529(2) A (trans to S ) 5 2 . The sulfur-oxygen bond distance in the S-bonded D P S O is 1.472(3) A , the same as that o f free D P S O ; 1 1 9 however, the sulfur-oxygen bond length found for the S-bonded D P S O in mer-[RuCl 3 (DPSO)(DPSO)(MeOH)] is just longer at 1.486(2) A, 5 2 and the increase was considered to be due to the interaction between the oxygen of the S-bonded D P S O and the hydroxyl proton of the bound M e O H . 5 2 142 References on page 155 Chapter 3 Figure 3.35. A n O R T E P diagram of mer-c/s-[RuCl 3 (DPSO) 2 (DPSO)] showing 50 % thermal ellipsoids; the H-atoms are omitted for clarity (crystal data are given in Appendix 1.11). 143 References on page 155 Chapter 3 Table 3.19. Selected Bond Lengths (A) and Bond Angles (°) for mer-cis-[RuCl 3(DPSO) 2(DPSO)] and wer-[RuCl3(DPSO)(DPSO)(MeOH)]. wer-C7S-[RuCl3(DPSO_)2(DPSO)] mer-[RuCl 3(DPSO)(DPSO) (MeOH)](ref. 52) Bond or Angle this work Ref. 118 Ru-Cl 2.338(1), 2.324(1);" 2.307(2), 2.337(2);" 2.3165(9), 2.339(1);" 2.305(1)* 2.307(2)* 2.301(1)* Ru-S 2.251(1)* 2.251(2)* 2.2391(9)* Ru-0 2.090(3)," 2.111(3)c 2.091(6),"2.114(5)c 2.094(3)," 2.122(2)c S-0 1.524(3),° 1.472(3),* 1.522(6)," 1.486(2),* 1.529(2)c 1.544(3)c 1.463(7),* 1.546(6)c Cl-Ru-Cl 172.63(5) 172.54(9) 172.03(4) trans Cl-Ru-0 173.70(9) 174.0(2) 175.02(8) trans S-Ru-0 trans 173.65(9) 173.5(2) 171.84(7) Cl-Ru-0 cis 86.82(9)-89.57(9) 86.3(1)-89.7(1) 85.93(9)-86.82(9) Cl-Ru-Cl cis 93.02(4)-93.22(5) 93.17(8)-93.19(8) 92.11(4)-94.84(4) Cl-Ru-S cis 91.18(5)-98.86(4) 91.19(7)-98.88(8) 90.31(3)-99.06(4) O-Ru-S cis 87.42(9) 87.1(2) 85.61(8) O-Ru-0 cis 86.5(1) 86.6(2) 86.8(1) "7hmstoCl . 6 Trans to O. c Trans to S. 144 References on page 155 Chapter 3 3.11 Macrocyclic Thioether, DMSO Complexes of Ruthenium Interest in the coordination chemistry of macrocyclic thioethers has stemmed from the observation that these can bind to a range of transition metal ions to form stable complexes. 1 2 1 In this present work, the goal was to synthesize and characterize Ru/sulfoxide/macrocyclic thioether complexes and study how the macrocycle might affect the in vitro properties of the R u sulfoxide moiety, particularly the cytotoxicity, accumulation and DNA-binding properties with respect to Chinese hamster ovary cells (Chapter 4). 3.11.1 3,6,9,14-Tetrathiabicyclo[9.2.1Jtetradeca-11,13-diene [L] This structurally characterized macrocyclic thioether l igand 1 2 2 (Figure 3.36) was used as purchased from Aldrich; the structure shows the thiophene moiety to be placed 60 ° relative to the plane of the three S-atoms of the macrocycle, all the S-atoms lying in exocyclic positions with respect to the macrocyclic cavity. Inclusion of the thiophene sub-unit imposes limitations on the possible orientations of the S-atom electron pairs and on the size and shape o f the cavity. Several metal complexes of this macrocyclic thioether are known, for example, with Cu(I ) , 1 2 3 C u (II) 1 2 3 and Pd(II) . 1 2 4 145 References on page 155 Chapter 3 Figure 3.36. 3,6,9,14-Tetrathiabicyclo[9.2.1]tetradeca-ll,13-diene (L), and 1,4,7,10-tetrathiacyclododecane (12-S-4); H-atoms omitted. Adapted from refs. 122 and 125, respectively. 3.11.2 RuCh(DMSO)(L) A Ru(II) complex containing ligand L , RuCi2(DMSO)(L), was synthesized by sulfoxide displacement from c/s-RuCl2(DMSO) 4 and structurally characterized (Figure 3.37, Tables 3.20 and 3.21). Three S-atoms of the ligand coordinate in a ^ arc-arrangement. Two five-membered rings are formed, one involving the S-atom of the thiophene and S(2) of the macrocycle, and the other involving the S(2)- and S(3)-atoms. One eight-membered ring is formed between the S-atom of the thiophene, the R u and S(3)-atom of the macrocycle. The S-bound D M S O is trans to S(3) of the macrocycle, Cl(2) is trans to S(2), and C l ( l ) is trans to the thiophene S. The complex has slightly distorted octahedral geometry at the Ru(II) centre with trans angles ranging from 171.63(8)-175.80(9) °, and cis angles ranging from 82.27(8)-100.25(8) 0 (Table 3.20). The Ru-S bond lengths (macrocycle) are 2.320(2) and 2.300(2) A trans to C l , and 2.375(2) A trans to S (Table 3.21). The eight-membered chelate ring of S(l)-Ru-S(3) spans an angle of 100.25(8) °, and the five-membered chelate rings span angles of 85.64(9) and 88.42(7) 0 The sulfur-oxygen bond length is 1.479(8) A , and the R u - S ( D M S O ) bond (trans 146 References on page 155 Chapter 3 to S) is 2.290(2) A. The two R u - C l bond lengths are 2.400(2) and 2.430(2) A. The crystallographic data show that the macrocycle changes remarkably little upon coordination. The solid state IR spectrum of the complex exhibits a strong v S o at 1083 cm"1 o f the S-bonded D M S O (free D M S O v s o 1055 cm"1). The *H N M R spectrum ( D M S O - ^ ) exhibits a multiplet centred at 5 7.1 assigned to the olefinic protons, and a complex pattern centred between 8 2.7-4.5 presumably because of the overlap of the resonances of the H-atoms of the macrocycle with those of the S-bound D M S O . 147 References on page 155 Chapter 3 Figure 3.37. An ORTEP diagram of RuCl 2(DMSO)(L) showing 50 % thermal ellipsoids; the H-atoms are omitted for clarity (crystal data are given in Appendix 1.12). 148 References on page J55 Chapter 3 Table 3.20. Comparison of Selected Bond Angles (°) of L and RuCl 2(DMSO)(L). Bond angle L(ref. 122) RuCl 2(DMSO)(L) C(l)-S(l)-C(8) 91.7(3) 92.3(5) C(2)-S(2)-C(3) 101.7(3) 97.3(5) C(4)-S(3)-C(5) 101.2(3) 101.9(4) C(6)-S(4)-C(7) 102.4(3) 100.7(4) S(l)-C(l)-C(10) 109.8(4) 111.0(7) S(l)-C(l)-C(2) 120.6(5) 115.4(7) C(10)-C(l)-C(2) 129.5(5) 133.0(9) C(l)-C(10)-C(9) 115.2(5) 112.8(9) C(10)-C(9)-C(8) 111.6(5) 115.2(10) S(l)-C(8)-C(9) 111.6(4) 108.1(8) S(l)-C(8)-C(7) 119.2(4) 122.4(7) C(9)-C(8)-C(7) 128.8(5) 129.4(9) S(2)-C(2)-C(l) 115.3(5) 110.3(7) S(2)-C(3)-C(4) 112.2(4) 109.6(6) S(3)-C(4)-C(3) 111.8(4) 111.7(6) S(3)-C(5)-C(6) 114.2(5) 106.6(6) S(4)-C(6)-C(5) 114.7(5) 113.9(6) S(4)-C(7)-C(8) 112.8(4) 114.2(7) cis angles 82.27(8)-100.25(8) trans angles 171.63(8)-175.80(9) S(l)-Ru-S(3) 100.25(8) S(2)-Ru-S(3) 88.42(7) S(l)-Ru-S(2) 85.64(9) 149 References on page 155 Chapter 3 Table 3.21. Comparison of Selected Bond Lengths (A) of L and RuCl 2(DMSO)(L). Bond L (ref. 122) RuCl 2(DMSO)(L) S(l)-C(l) 1.737(5) 1.764(9) S(l)-C(8) 1.721(5) 1.749(5) S(2)-C(2) 1.805(8) 1.82(1) S(2)-C(3) 1.816(7) 1.846(10) S(3)-C(4) 1.814(6) 1.822(9) S(3)-C(5) 1.800(7) 1.808(9) S(4)-C(6) 1.800(8) 1.784(10) S(4)-C(7) 1.840(8) 1.81(1) C(l)-C(10) 1.344(9) 1.32(1) C(l)-C(2) 1.485(8) 1.48(1) C(10)-C(9) 1.406(9) 1.44(2) C(9)-C(8) 1.363(8) 1.36(1) C(8)-C(7) 1.505(8) 1.50(1) C(3)-C(4) 1.529(9) 1.49(1) C(5)-C(6) 1.53(1) 1.57(1) Ru-Cl(l) 2.400(2) Ru-Cl(2) 2.430(2) Ru-S(l) 2.320(2) Ru-S(2) 2.300(2) Ru-S(3) 2.375(2) Ru-S(5) 2.290(2) S-0 1.479(8) 150 References on page 155 Chapter 3 3.11.3 1,4,7,10-Tetrathiacyclododecane (12-S-4) This macrocyclic thioether l igand 1 2 5 ' 1 2 6 (Figure 3.36) was used as purchased from Aldrich. In the solid state, 12-S-4 adopts a square conformation with the S-atoms at the corners, giving a structure with the terminal S-atoms forming two "bracket" units, and all eight C-S bonds assume mutually gauche placements in order to minimize S - S repulsions by incorporating an exo formation where the S-atoms point out of the macrocyclic r i n g . 1 2 5 ' 1 2 7 These observations explain the tendency for tetrathia-macrocycles to bind to metal ions in an exo manner. 1 2 5 Complexes with Ni ( I I ) , 1 2 6 Cu(I) , 1 2 8 Cu(II) 1 2 8 and Pt(II) 1 2 9 are known. 3.11.4 [Ru(12-S-4)(DMSO)(H20)][OTf]2 The Ru(II) complex of 12-S-4 was synthesized by sulfoxide displacement from cis-R u C l 2 ( D M S O ) 4 , followed by Cl" abstraction by utilization of AgOTf. The six-coordinate complex has a slightly distorted octahedral geometry (Figure 3.38, Tables 3.22 and 3.23) with trans angles that range from 166.83(2)-178.17(5) 0 and cis angles that range from 84.29(2)-100.72(2)° (Table 3.22). The Ru-S(macrocycle) bond lengths range from 2.2903(6)-2.3907(6) A. The S-bound D M S O ligand is trans to S(2) and has a Ru-S bond length of 2.3011(6)A; the sulfur-oxygen bond length is 1.494(2)A. The Ru-0 bond length is 2.193(2) A which is comparable to others found within Ru(II)-aqua complexes (e.g. values for [RuCl(BESE)(H 2 0)] 2 (//-Cl) 2 (Table 3.7), RuCl2(PPh3)(P-N)(H20)-2C6H6,130 RuCl 2(PPh3)(P-N)(H 20)1.5C6H6, 1 3 0 and RuCl 2(P(p-tolyl)3)(P-N)(H 20) 1 3 0 ( P - N = [o-(N,N-dimethylamino)phenyl]diphenylphosphine) are 2.140(3), 2.238(3), 2.187(2) and 2.252(4) A, respectively). The coordinated H 2 0 is H-bonded to the O-atoms of the two triflate anions. 151 References on page 155 Chapter 3 The average H . . . . 0 distance is 1.905 A is 0.795 A shorter than the sum of the van der Waals radii o f an H - and an O-atom (2.70 A) 7 0 and indicates a strong interaction between the bound H 2 0 molecule and the two triflate anions. Tables 3.22 and 3.23compare selected bond angles and bond lengths, respectively, of free 12-S-4 with those of the complex [Ru(12-S-4) (DMSO)(H 2 0)] [OTf] 2 . The crystallographic data show that the macrocycle does not change much upon coordination. A strong v S o band was observed in the solid state IR spectrum of the complex at 1082 cm"1 attributed to the S-bonded D M S O . The J H N M R spectrum (MeOD) shows a complex pattern for the protons of the complex centred at 8 3.1 presumably because o f the presence of the diastereomeric H-atoms of the macrocycle and the methyl groups o f the S-bound D M S O . This complex was tested in vitro for cytotoxicity, accumulation and D N A -binding properties in Chinese hamster ovary cells with the results presented in Chapter 4. Table 3.22. Comparison of Selected Bond Angles (°) of 12-S-4 and [Ru(12-S-4)(DMSO)(H 2 0)] [OTfJ 2 . Bond angle 12-S-4 (ref. 125) [Ru( 12-S-4)(DMSO)(H 2 0)] [OTf] 2 C(8) -S( l ) -C( l ) 101.3(2) 101.5(1) C(3)-S(2)-C(2) 102.2(3) 106.1(1) C(4)-S(3)-C(5) 100.7(3) 100.6(1) C(7)-S(4)-C(6) 100.8(2) 106.4(1) cis angles 84.29(2)-100.72(2) trans angles 166.83(2)-178.17(5) 152 References on page 155 Chapter 3 Figure 3.38. A n O R T E P diagram of [Ru(12-S-4)(DMSO)(H 2 0)][OTf] 2 showing 50 % thermal ellipsoids; the H-atoms are omitted for clarity (crystal data are give in Appendix 1.13). 153 References on page 155 Chapter 3 Table 3.23. Comparison of Selected Bond Lengths (A) of 12-S-4 and [Ru(12-S-4)(DMSO)(H 20)] [OTf]2. Bond 12-S-4 (ref. 125) [Ru( 12-S-4)(DMSO)(H20)] [OTf]2 S(l)-C(l) 1.826(5) 1.864(3) S(l)-C(8) 1.806(5) 1.860(3) S(2)-C(3) 1.801(6) 1.823(3) S(2)-C(2) 1.808(6) 1.822(3) S(3)-C(4) 1.815(6) 1.872(3) S(3)-C(5) 1.820(5) 1.851(3) S(4)-C(6) 1.825(5) 1.836(3) S(4)-C(7) 1.817(5) 1.837(3) C(7)-C(8) 1.505(8) 1.528(4) C(l)-C(2) 1.528(8) 1.525(4) C(3)-C(4) 1.504(8) 1.526(4) C(5)-C(6) 1.508(8) 1.533(4) Ru-S(l) 2.3852(6) Ru-S(2) 2.3708(6) Ru-S(3) 2.3907(6) Ru-S(4) 2.2903(6) Ru-S(5) 2.3011(6) Ru-0 2.193(2) S-0 1.494(2) 154 References on page 155 Chapter 3 3.12 References for Chapter 3 1 Cotton, F. A . ; Francis, R. J. Am. Chem. Soc. 1960, 82, 2986. 2 Davies, J. A . Adv. Inorg. Chem. Radiochem. 1981, 24,115. 3 Sze, K . H . ; Brion, C. E . ; Tronc, M . ; Bodeur, S.; Hitchcock, A . P. Chem. Phys. 1988, 121, 279. 4 Kagan, H . B . ; Ronan, B . Rev. Heteroatom. Chem. 1992, 7, 92. 5 Reynolds, W. L . Prog. Inorg. Chem. 1970,12, 1. 6 Rayner, D . R.; Miller, E . G . ; Bickart, P.; Gordon, A . J.; Mis low, K . J. Am. Chem. Soc. 1966, 88, 3138. 7 Jacobus, J.; Mislow, K . J. Am. Chem. Soc. 1967, 89, 5228. 8 Bhandary, K . K . ; Manohar, H . ; Venkatesan, K . Indian J. Pure Appl. Phys. 1976, 14, 111. 9 Thomas, R.; Shoemaker, C. B . ; Eriks, K . Acta Cryst. 1966, 21, 12. 10 Bastiansen, O.; Viervoll, H . Acta Chem. Scand. 1948, 2, 702. 11 Viswamitra, M . A . ; Kannan, K . K . Nature 1966, 209, 1016. 12 Bennett, M . J.; Cotton, F. A ; Weaver, D . L . ; Williams, R. J.; Watson, W . H . Acta Cryst. 1967, 23, 788. 13 (a) Coulson, C. A . ; Zauli, C. Mol. Phys. 1963, 6, 525; (b) Sato, T.; Takahashi, Y . ; Yabe, K . Bull. Chem. Soc. Jap. 1967, 40, 298; (c) Takahashi, Y . ; Yabe, K . ; Sato, T. Bull. Chem. Soc. Jap. 1970, 42, 2707; (d) Nikolaev, A . V . ; Torgov, V . G . ; Andrievskii, V . N . ; Gal'tsova, E . A . ; Gilbert, E . N . ; Kotiyarovskii, I. L . ; Mazalov, L . N . ; Mikhailov, V . A . ; Cheremisina, I. M . Russ. J. Inorg. Chem. 1970, 75, 685 and references therein. 14 Calligaris, M . ; Carugo, O. Coord. Chem. Rev. 1996, 753, 83. 15 (a) Pearson, R. G. . J. Am. Chem. Soc. 1963, 85, 3533; (b) Pearson, R. G. J. Chem. Educ. 1987, 64, 561; (c) Pearson, R. G. Coord. Chem. Rev. 1990,100, 403; (d) Pearson, R. G. Chemical Hardness - A n Historical Introduction, in Structure and Bonding (ed. K . D . Sen), Springer-Verlag, Berlin, 1993, 80, p. 1. 155 Chapter 3 16 Burmeister, J. L . , Basolo, F. Inorganic Linkage Isomerism of the Thiocyanate Ion, in Hard and Soft Acids and Bases (ed. R. G. Pearson), Dowden, Hutchinson and Ross Inc., Stroudsburg, Pennsylvania, 1973, p. 300. 17 Davies, J. A . Hartley, F. R ; Murray, S. G . J. Chem. Soc. Dalton Trans. 1979, 1705. 18 Wayland, B . B . ; Schramm, R. F. Inorg. Chem. 1969, 8, 971. 19 Bennett, M . J.; Cotton, F. A . ; Weaver, D . L . Nature 1966, 212, 286. 20 Bennett, M . J.; Cotton, F. A . ; Weaver, D . L . Acta Cryst. 1967, 23, 581. 21 Willet, R. D . ; Chang, K . Inorg. Chim. Acta 1970, 4, 447. 22 Melanson, R ; Rochon, F. D . Can. J. Chem. 1975, 53, 2371. 23 Mercer, A . ; Trotter, J. J. Chem. Soc. Dalton Trans. 1975, 2480. 24 Colamarino, P.; Orioli, P. J. Chem. Soc. Dalton Trans. 1976, 845. 25 Alessio, E . ; Balducci, G . ; Calligaris, M . ; Costa, G . ; Attia, W . M . ; Mestroni, G . Inorg. Chem. 1991, 30, 609. 26 Tanase, T.; Aiko , T.; Yamamoto, Y . J. Chem. Soc. Dalton Trans. 1996, 2341. 27 (a) Calligaris, M . ; Faleschini, P.; Alessio, E . Acta Cryst. 1993, C49, 663; (b) Ghosh, P.; Pramanik, A . Acta Cryst. 1995, C51, 824. 28 Geremia, S.; Mestroni, S.; Calligaris, M . ; Alessio, E . J. Chem. Soc. Dalton Trans. 1998, 2447. 29 Drysdale, K . D . ; Beck, E . J.; Cameron, T. S.; Robertson, K . N . ; Aquino, M . A . S. Inorg. Chim. Acta 1997, 256, 243. 30 House, D . A . ; Steel, P. J. Inorg. Chim. Acta 1998, 269, 229. 31 McDonagh, A . M . ; Humphrey, M . G. ; Hockless, D . C. R. Aust. J. Chem. 1998, 57, 807. 32 (a) Evans, I. P.; Spencer, A . , Wi lk inson / . Chem. Soc. Dalton Trans. 1973, 204; (b) McMi l l an , R. S.; Mercer, A . ; James, B . R.; Trotter, J. J. Chem. Soc. Dalton Trans. 1975, 1006. 33 Kitching, W. ; Moore, C. J.; Doddrell, D . Aust. J. Chem. 1969, 22, 1149. 34 Kitching, W. ; Moore, C. J.; Doddrell, D . Inorg. Chem. 1970, 9, 541. 156 Chapter 3 35 (a) Yapp, D . T. T.; Jaswal, J. S.; Rettig, S. J.; James, B . R.; Skov, K . A . Inorg. Chim. Acta 1990,177, 199; (b) Jaswal, J. S.; Yapp, D . T. T.; Rettig, S. J.; James, B . R.; Skov, K . A . J. Chem. Soc, Chem. Commun. 1992, 1528. 36 Alessio, E . ; Mestroni, G . ; Nardin, G . ; Attia, W. M . ; Calligaris, M . ; Sava, G . ; Zorzet, S. Inorg. Chem. 1988, 27, 4099. 37 Jaswal, J. S.; Rettig, S. J.; James, B . R. Can. J. Chem. 1990, 68, 1808. 38 Oliver, J. D . ; Riley, D . P. Inorg. Chem. 1984, 23, 156. 39 Hul l , M . ; Bargar, T. W. J. Org. Chem. 1975, 40, 3152. 40 (a) Bel l , E . V . ; Bennett, G. M . J. Chem. Soc. 1927, 1798; (b) Bennett, G . M . ; Statham, F. S. J. Chem. Soc. 1931, 1684. 41 Madesclaire, M . Tetrahedron 1986, 42, 5459. 42 Ravikumar, K . S.; Begue J-P.; Bonnet-Delpon, D . Tetrahedron Lett. 1998, 39, 3141. 43 Svinning, T.; M o , F.; Bruun, T. Acta Cryst. 1976, B32, 759. 44 Cattalini, L . ; Michelon, G . ; Marangoni, G. ; Pelizzi, G . J. Chem. Soc. Dalton Trans. 1979, 96. 45 Taddei, F. Boll. Sci. Fac. Chim. Ind. Bologna 1968, 26, 107. 46 Personal communication from S. Colonna. 47 Zipp, A . P.; Madan, S. K . Inorg. Chim. Acta 1977, 22, 49, and references therein. 48 Zhu, F. C ; Shao, P. X . ; Yao, X . K . Wang, R. J.; Wang, H . G . Inorg. Chim. Acta 1990,171, 85. 49 Calligaris, M . Personal communication to B . R. James. 50 Nieuwenhuyse, H . ; Louw, R. J. Chem. Soc, Perkins 11973, 839. 51 Madan, S. K . ; Hul l , C. M . ; Herman, L . J. Inorg. Chem. 1968, 7, 491. 52 Yapp, D . T. T. Ph. D . Dissertation, University of British Columbia, Vancouver, 1993. 53 Yapp, D . T. T.; Rettig, S. J.; James, B . R.; Skov, K . A . Inorg. Chem. 1997, 36, 5635. 157 Chapter 3 54 De Azevedo Jr., W. F.; Mascarenhas, Y . P.; De Sousa, G . F. ; Filgueiras, C. A . L . Acta Cryst. 1995, C51, 619. 55 Carvalho, C. C ; Francisco, R. H . P.; Gambardella, M . T. do P.; de Sousa, G . F. ; Filgueiras, C. A . L . Acta Cryst. 1996, C52, 1627. 56 Filgueiras, C. A . L . ; Holland, P. R.; Johnson, B . F. G . ; Raithby, P. R. Acta Cryst. 1982, B38, 2684. 57 Musgrave, T. R.; Kent, G. D . J. Coord. Chem. 1972, 2, 23. 58 Francisco, R. H . P.; Gambardella, M . T. P.; Rodrigues, A . M . G . D . ; de Souza, G . F. ; Filgueiras, C. A . L . Acta Cryst. 1995, C51, 604. 59 Filgueiras, C. A . L . ; Holland, P. R.; Johnson, B . F. G . ; Raithby, P. R. Acta Cryst. 1982, B38, 954. 60 Khiar, N . ; Fernandez, I.; Alcudia, F. Tetrahedron Lett. 1993, 34, 123. 61 Tokunoh, R.; Sodeoka, ML; Aoe, K . ; Shibasaki, M . Tetrahedron Lett. 1995, 36, 8035. 62 James, B . R.; Morris, R. H . ; Reimer, K . J. Can. J. Chem. 1977, 55, 2353. 63 (a) McMil lan , R. S. Ph. D . Dissertation, University of British Columbia, Vancouver, 1976; (b) James, B . R ; McMil lan , R. S. Can. J. Chem. 1977, 55, 3927; (c) James, B . R ; McMil lan , R. S.; Morris, R. H . ; Wang, D . K . W . Ruthenium and Rhodium Hydrides Containing Chiral Phosphine or Chiral Sulfoxide Ligands, and Catalytic Asymmetric Hydrogenation in Advances in Chemistry Series, No. 167 Transition Metal Hydrides (ed. R. Bau), American Chemical Society, Washington, 1978, p. 122. 64 Komori , T.; Nonaka, T. J. Am. Chem. Soc. 1984,106, 2656. 65 van Deurzen, M . P. J.; Remkes, I. J.; van Rantwijk, F. ; Sheldon, R. A . J. Mol. Cat. A: Chemical 1997, 117, 329. 66 Al l in , S. M . Organosulfur Chem. 1998, 2, 41. 67 (a) Chan, P. K . L . ; Chan, P. K . H . ; Frost, D . C ; James, B . R ; Skov, K . A . Can. J. Chem. 1988, 66, 117; 158 Chapter 3 (b) Chan, P. K . L . ; James, B . R.; Frost, D . C ; Chan, P. K . H . ; Hu , H - L . ; Skov, K . A . Can. J. Chem. 1989, 67, 508; 68 Geremia, S.; Vicentini, L . ; Calligaris, M . Inorg. Chem. 1998, 37, 4094. 69 Rettig, S. J. Private communication. 70 Huheey, J. E . Inorganic Chemistry (3rd ed.), Harper & Row, N e w York , 1983, p. 269. 71 (a) Huheey, J. E . Inorganic Chemistry (3rd ed.), Harper & Row, N e w York , 1983, p. 362; (b) Geary, W . J. Coord. Chem. Rev. 1971, 7, 110. 72 Glasstone, S. Textbook of Physical Chemistry (2nd ed.), MacMil lan and Co. Limited, London, 1951, p. 892. 73 Chioccola, G . ; Daly, J. J. J. Chem. Soc. (A) 1968, 1981. 74 Cotton, F. A ; Ucko, D . A . Inorg. Chim. Acta 1972, 5, 161. 75 (a) Bennett, M . J.; Caulton, K . G. ; Cotton, F. A . Inorg. Chem. 1969, 8, 1; (b) Cotton, F. A . Chem. Soc. Rev. 1975, 4, 27. 76 Jones, R. A . ; Wilkinson, G . ; Colquohoun, I. J.; McFarlane, W. ; Galas, A . M . R.; Hursthouse, M . B . J. Chem. Soc. Dalton Trans. 1980, 2480. 77 Schumann, H . ; Opitz, J.; Pichardt, J. J. Organomet. Chem. 1977,128, 253. 78 Mattson, B . M . ; Heiman, J. R.; Pignolet, L . H . Inorg. Chem. 1976, 75, 564. 79 Dekleva T. W. ; Thorburn, I. S.; James, B . R., Inorg. Chim. Acta 1985,100, 49. 80 Sirigu, A . ; Bianchi, M . ; Benedetti, E . J. Chem. Soc, Chem. Commun. (D) 1969, 596. 81 Crutchley, R. J. Adv. Inorg. Chem. 1994, 41, 273. 82 Allen, G . C ; Hush, N . S. Prog. Inorg. Chem. 1967, 8, 357. 83 Robin, M . B . ; Day, P. Adv. Inorg. Chem. Radiochem. 1967,10, 247. 84 Shriver, D . E . ; Atkins, P. W. ; Langford, C. H . Inorganic Chemistry, W . H . Freeman and Company, New York, 1990, p. 461. 85 Creutz, C. Prog. Inorg. Chem. 1983, 30, 1. 86 Clausen III, C. A ; Prados, R. A . ; Good, M . L . Inorg. Nucl. Chem. Lett. 1971, 7, 485. 159 Chapter 3 87 Mercer, E . E . ; Dumas, P. E . Inorg. Chem. 1971,10, 2755. 88 (a) Gilbert, J. D . ; Rose, D . , Wilkinson, G. J. Chem. Soc. (A) 1970, 2765; (b) Seddon, E . A . ; Seddon, K . R. The Chemistry of Ruthenium, Elsevier, Amsterdam, 1984, p. 310. 89 Rose, D . ; Wilkinson, G. J. Chem. Soc. (A) 1970, 1791. 90 Bino, A . ; Cotton, F. A . J. Am. Chem. Soc. 1980,102, 608. 91 Bottomley, F. ; Tong, S. B . Can. J. Chem. 1971, 49, 3739. 92 Creutz, C ; Taube, H . J. Am. Chem. Soc. 1969, 91, 3988. 93 Gibson, J. F. ; Poole, R. K . ; Hughes, M . N . ; Rees, J. F. Arch. Microbiol. 1984,139, 265. 94 Hughes, M . N . ; O'Reardon, D . ; Poole, R. K . ; Hursthouse, M . B . ; Thornton-Pett, M . Polyhedron 1987, 6, 1711. 95 Beattie, J. K . ; Del Favero, P.; Hambley, T. W. ; Hush, N . S. Inorg. Chem. 1988, 27, 2000. 96 Thorburn, I. S.; Rettig, S. J.; James, B . R. Inorg. Chem. 1986, 25, 234. 97 Rosenberg, B . ; Van Camp, L . ; Krigas, T. Nature 1969, 205, 698. 98 Rosenberg, B . Cancer Chemother. Rep. 1975, 59, 589. 99 Barton, J. K . ; Szalda, D . J.; Rabinowitz, H . N . ; Waszczak, J. V . ; Lippard, S. J. J. Am. Chem. Soc. 1979,101, 1434. 100 Lock, C. J. L . ; Persie, H . J.; Rosenberg, B . ; Turner, G . J. Am. Chem. Soc. 1978, 100, 3371. 101 Geraldes, C. F. G. C ; Aragon-Salgado, M . ; Martin-Gil , J. Polyhedron, 1991, 10, 799. 102 Matsumoto, K . ; Sakai, K . ; Nishio, K . ; Tokisue, Y . ; Ito, R.; Nishide, T.; Shichi, Y . J. Am. Chem. Soc. 1992,114, 8110. 103 Geremia, S.; Calligaris, M . ; Mestroni, S. Inorg. Chim. Acta 1999, 292, 144. 104 Taqui Khan, M . M . ; Ramachandraiah, G. ; Prakash Rao, A . Inorg. Chem. 1986, 25, 665. 105 Alessio, E . ; Milani, B . ; Mestroni, G. ; Calligaris, M . ; Faleschini, P.; Attia, W . M . Inorg. Chim. Acta 1990, 777, 255. 160 Chapter 3 106 Halpern, I ; James, B . R. Can. J. Chem. 1966, 44, 495. 107 Hui , B . C ; James, B . R. Can. J. Chem. 1974, 52, 348. 108 Lipponer, K - G . ; Vogel, E . ; Keppler, B . K . Metal-Based Drugs 1996, 3, 243. 109 Ledlie, M . A . ; Allum, K . G . ; Howell, I. V . ; Pitkethley, C. R. J. Chem. Soc. Perkin I 1976, 1734. 110 Chatt, J.; Leigh, G. J.; Storace, A . P. J. Chem. Soc. (A) 1971, 1380. 111 Lucas, C. R.; L iu , S.; Newlands, M . J.; Gabe, E . J. Can. J. Chem. 1990, 68, 1357. 112 Hartley, F . R.; Murray, S. G . ; Levason, W. ; Soutter, H . E . ; McAuliffe, C . A . Inorg. Chim. Acta 1979, 35, 265. 113 Murray, S. G . ; Levason, W. ; Tuttlebee, H . E . Inorg. Chim. Acta 1981, 51, 185. 114 Song, H . ; Haltiwanger, R. C ; Rakowski-DuBois, M . Organometallics 1987, 6, 2021. 115 Shao, P.; Yao, X . ; Wang, H . ; Wang, W. ; L i u , B . ; L i , M . ; Luo , L . ; X u , D . Gaodeng Xuexiao Huaxue Xuebao 1991, 12, 143 (from Chem. Abstr. 1998, 115, 190904). 116 Schenk, W . A ; Frisch, J.; Durr, M . ; Burzlaff, N . ; Stalke, D . ; Fleischer, R.; Adam, W. ; Prechtl, F. ; Smerz, A . K . Inorg. Chem. 1997, 36, 2372. 117 James, B . R.; Morris, R. H . Can. J. Chem. 1980, 58, 399. 118 Calligaris, M . ; Faleschini, P.; Todone, F. ; Alessio, E . ; Geremia, S. J. Chem. Soc. Dalton Trans. 1995, 1653. 119 Abrahams, S. C. Acta Cryst. 1957, 10, 417. 120 Stynes, H . C ; Ibers, J. A . Inorg. Chem. 1971,10, 2304. 121 (a) DeSimone, R. E . ; Glick, M . D . Inorg. Chem. 1978, 17, 3574; (b) Schroder, M . PureAppl. Chem. 1988, 60, 517. 122 Lucas, C. R.; Shuang, L . ; Newlands, M . J.; Charland, J-P.; Gabe, E . J. Can. J. Chem. 1988, 66, 1506. 123 (a) Lucas, C. R.; L iu , S.; Newlands, M . J.; Charland, J-P.; Gabe, E . J. Can. J. Chem. 1989, 67, 639; (b) Lucas, C. R.; L i u , S.; Thompson, L . K . Inorg. Chem. 1990, 29, 85; (c) Lucas, R. C ; Shuang, L . ; Newlands, M . J.; Charland, J-P.; Gabe, E . J. Can. J. Chem. 1988, 66, 1506. 161 Chapter 3 124 L i u , S.; Lucas, C. R ; Newlands, M . J.; Charland, J-P. Inorg. Chem. 1990, 29, 4380. 125 W o l f Jr., R. E . ; Hartman, J. R.; Storey, J. M . E . ; Foxman, B . M . ; Cooper, S. R. J. Am. Chem. Soc. 1987, 109, 4328. 126 (a) Rosen, W. ; Busch, D . H . J. Am. Chem. Soc. 1969, 91, 4694; (b) Rosen, W. ; Busch, D . H . Inorg. Chem. 1970, 9, 262. 127 Robinson, G . H . ; Sangokoya, S. A . J. Am. Chem. Soc. 1988, 110, 1494. 128 Gorewit, B . V . ; Musker, W. K . J. Coord. Chem. 1976, 5, 67. 129 Blake, A . J.; Holder, A . J.; Reid, G. ; Schroder, M . J. Chem. Soc. Dalton Trans. 1994, 627. 130 M a , E . S. F. Ph. D . Dissertation, University of British Columbia, Vancouver, 1999. 162 Chapter 4 Chapter 4 Preliminary In Vitro Examination of Water-soluble Ru Sulfoxide Complexes 4.1 Introduction A s outlined in Chapter 1, preliminary investigation into the in vitro activity of water-soluble ruthenium bis-chelating sulfoxide complexes was suggested by reports of the anti-tumour activity of cis- and / r a w s - R u C l ^ D M S O ^ , 1 and other R u - D M S O complexes. 2 ' 3 These reports show that Ru-sulfoxide complexes exhibit anti-leukaemic,4 anti-metastatic5 and anti-neoplastic6 activity without appreciable toxicities to the murine host. In addition, the complex Na[rraws-RuCl 4(DMSO)(Im)] exhibits no cytotoxicity in tumour cells; however, it does reduce lung metastasis formation to less than 10 % of that seen in controls. 7 Studies o f reactions between cis- and *>"<ms-RuCl2(DMSO)4 and D N A have shown that these complexes accumulate in cells 8 and bind to bases,9 nucleosides, 1 0 , 1 1 and nucleotides. 1 2" 1 4 Durig et al.15 and Gibson et al.16 have studied the ability of R u complexes to induce filamentous growth in E. coli, which is an indication of possible D N A damage, suggesting interaction between the complex and D N A (Section 1.3.1). Previous work in this laboratory has suggested that trans-RuCl 2 (disulfoxide) 2 8 ' 1 7 complexes accumulate in cells and bind to D N A to a greater degree than c/5-RuCl 2(disulfoxide) 2 complexes (chelating disulfoxide = B M S E , B E S E , B P S E and B M S P , see Chapter 1). The ability of these complexes to traverse the cell membrane and to bind to D N A are two important considerations, as D N A is considered to be a main target for anti-tumour activity. For example, Na[/ ra«s-RuCl 4 (DMSO)(Im)] interacts with nucleic acids which results in a reduction of nucleic acid activity (Chapter l ) . 7 Complexes which accumulate in the cell and bind to D N A may also exhibit toxicity which is relevant. 163 References on page 182 Chapter 4 The toxicities, accumulation and DNA-binding characteristics in Chinese hamster ovary (CHO) cells (under oxic and hypoxic conditions) of selected Ru-sulfoxides are presented in this chapter. The five complexes, discussed in Chapter 3 and listed in Table 4.1 were selected for in vitro studies because of solubility in aqueous solutions. Table 4.1. Water-soluble R u sulfoxide complexes studied in vitro." Complex Cone. (mM) 6 [Ru( 12-S-4)(DMSO)(H 20)] [OTf] 2 [RuCl(BPSP)] 2 ( / / -Cl) 3 [RuCl(BESE)(H 2 0 ) ] 2 ( / / -Cl) 2 [RuCl(BPSE)(H 2 0 ) ] 2 ( / / -Cl) 2 [RuCl(BBSE)(H 20)] 2Cu-Cl) 2 1.5, 3.0 and 5.0 0.1,0.5, 1.2 and 1.4 0.1, 0.5, 0.64 and 1.4 0.25 and 0.42 0.16, 0.5 and 0.89 " See Chapter 3, Sections 3.7, 3.8 and 3.11.4 for formulations of the complexes. 6 Concentrations of the complex used in buffered aqueous solutions, chosen in relation to the amount of complex available for repeat experiments (at least two experiments, same concentrations) and in a range for possible toxicity. 4.2 Tumour Hypoxia, Radiotherapy and Progression One characteristic of many solid tumour masses is a poor blood supply which results in inadequate levels of both oxygen and nutrients in regions of the tumour. 1 8 The degree of hypoxia within tumours varies according to the proximity of blood vessels in a rapidly growing tumour in which development of vasculature does not keep up with cell proliferation and where rapid replication of cancer cells deplete 02.1 9'2 0 I f the cells are too far from the capillaries for effective delivery of nutrients and oxygen and for elimination for 164 References on page 182 Chapter 4 wastes, necrotic regions can result. Hypoxia can also be the result of periodic suspension of blood flow because of irregularities and occlusions in the tumour vasculature and the high interstitial pressure of tumours with poorly developed lymphatic systems. 1 9 a ' b Normal or malignant tissue that is poorly supplied with oxygen at the time of conventional radiotherapy (e.g. ionizing radiation such as X-rays) is much less damaged by a given dose of radiation than the same well-oxygenated tissue. Thus hypoxic mammalian tissue may only be one-half to one-third as sensitive to radiation compared to well-oxygenated tissue. 2 1 Radiotherapy may remove the oxygenated areas of a tumour while the hypoxic areas, being radioresistant and not having received as much radiation damage, become reoxygenated, and recommence growth and regenerate the tumour. 1 9 Hypoxia also has an effect on malignant progression and the responsiveness to therapy of advanced cervical tumours. 2 2 Hockel et al. have studied the effect of hypoxia on metastasis and survival probabilities of patients. Those with hypoxic tumours exhibited relatively inferior survival probability compared with those with non-hypoxic cervical cancers. The authors suggest that tumour oxygenation acts as a prognostic indicator of malignant progression in terms of tumour metastasis (as well as radioresistance) in advanced cervical cancers. 2 2 165 References on page 182 Chapter 4 Radiotherapy is effective against localized neoplasms but is not effective toward a widely disseminated disease (e.g. leukemia), mainly because a curative dose will cause too much damage to the surrounding healthy tissue.19 There are certain clinical situations in which the use of radiotherapy is limited by a radioresistant neoplasm or by a tumour that has invaded radiosensitive normal tissue. Again, a curative dose of radiation may cause excessive damage to normal tissue. Hypoxic cells of solid neoplasms may be unresponsive to conventional chemotherapy.19 The proliferation patterns of hypoxic tumour cells probably differ from those of the oxic cells, in that many hypoxic cells are non-cycling or are cycling with prolonged and abnormal cell cycle times. Such cells would have reduced sensitivities to cycle-active chemotherapeutic agents.19 As well, hypoxic cells are found in regions of vascular deficiency and may not be exposed to the chemotherapeutic agents which are mainly distributed through the vascular system. 4.3 Experimental All media, buffer solutions and drug solutions were sterilized by filtration through a 0.22 pm filter (Nalgene) before cell suspensions were added. All flasks and humidifiers were sterilized in a BBMC Century 21 Laboratory Sterilizer. 4.3.1 Media An alpha-modification of Eagle's minimum essential medium (Gibco) was used in all procedures involving the maintenance or incubation of CHO cells. Three different forms of the medium were used, a-/-, a+/- and a+/+ depending on the requirements of the procedure. 166 References on page 182 Chapter 4 To make a-/- medium, one packet of a-medium powder and 10,000 units of penicillin/streptomycin antibiotic (Gibco) were added to 10 L of doubly distilled water and the solution was stirred for 2 h at r.t. and pH adjusted to 7.3. Preparation of a+/+ medium involved the addition of fetal bovine serum (Gibco) to a final concentration of 10 % and NaHC03 (20 g/10 L) was added to the solution before filtration; then the pH was adjusted to 7.3 with 4 M aq. NaOH. Preparation of ct+/- medium involved the addition of 10 % (v/v) of fetal bovine serum to a-/- medium buffered with 10 mM HEPES. Al l media were stored at 4°C. 4.3.2 Phosphate Buffer Saline Solution To prepare the phosphate buffer saline solution (PBS), NaCl (160 g), KC1 (4 g), N a 2 H P 0 4 (23 g) and K H 2 P 0 4 (4 g) were dissolved in distilled water (20 L); the solution was stored at r.t. and cooled to 4 °C before use. 4.3.3 Methylene Blue Solution Methylene blue (2 g, Sigma) was dissolved in H 2 0 (1 L) and the solution allowed to stand for 1 h prior to filtration. This solution was used for fixing and staining colonies after incubation to assess colony forming ability. The methylene blue solution was filtered after use in toxicity experiments and re-used several times before being discarded. 167 References on page 182 Chapter 4 4.3.4 Tris-EDTA (TE) Solutions Stock solutions of T E (0.5 M Tris-HCl , Sigma and 50 m M E D T A , Sigma) were prepared, and the p H of the solutions adjusted to 8.0 with 4 M N a O H . The stock solutions were then diluted to the final concentration of 10 u M Tris-HCl and 1 u M E D T A . 4.3.5 TNE Solutions T N E . was prepared from stock solutions and had a final composition o f 10 m M Tr i s -HCl (Sigma), 150 m M NaCI and 10 m M E D T A (Sigma), with the final p H o f the solution being adjusted to 8.0. 4.3.6 TNE-Equilibrated Phenol Pure phenol (250 mL, 99 %, Aldrich) was liquefied by heating in a water-bath (60 °C) and saturated with an equal volume of 0.5 M Tr is -HCl (250 mL, p H 8.00, Sigma), the two phases then being allowed to separate. The aqueous layer was discarded and the process repeated with fresh Tr i s -HCl solutions until the p H of the aqueous layer was about 7.0. The final wash consisted of equal volumes of T N E and phenol. The TNE-equilibrated phenol was then transferred into 50 mL polypropylene tubes and stored at -20 °C in darkness. The frozen stock was thawed to r.t. just prior to use in the DNA-extraction experiments. 4.3.7 Cell Preparation The cells used for in vitro experiments were obtained from a Chinese hamster ovary (CHO) cell line, chosen for its rapid growth cycle and high plating efficiency. The cells (1.3 x 10 5 cells/mL) were routinely grown in a+/+ medium (-60 mL) (Section 4.3.1), and the cell 168 References on page 182 Chapter 4 suspensions were maintained in spinner culture flasks at 37 °C in an Associated Biomedic Systems "Incu-cover" incubator under an atmosphere of 95 % air/5 % C 0 2 (Canadian Liquid A i r Co. Ltd.). Spinner flasks were diluted twice a week, and 1 x 10 s cells were plated in T-75 flasks (Falcon) once a week as backups in the event that the spinner culture was contaminated. The cell cultures were diluted daily to a cell count of about 1 x 10 s cells/mL to maintain an exponential growth phase cell population (doubling time was about 13-14 h); higher cell suspensions were prepared i f a larger number of cells was required the following day. The cell suspension (cells/mL) was determined using a Coulter Cell Counter from Coulter Electronics Inc., Hialeah, Florida. 4.3.8 A tomic A bsorption Spectroscopy A Varian "SpectrAA 300" atomic absorption spectrometer, controlled by a Compaq Deskpro 386s computer, was used to analyze for the R u atoms. A R u hollow cathode lamp, X 265.9 nm (Varian), was used as the source. The samples were dried, ashed and atomized in graphite tube furnaces (Varian). Corrections for background absorption were done using a technique, developed by Varian, based on the Zeeman effect. Calibration of the spectrometer was completed by using R u standards (Sigma). A reslope was performed after every fifth sample to ensure that buildup on the pyrolytic graphite surface did not cause significant variations in the calibration. The furnace parameters used in the drying, ashing, and atomization stages of the analysis are tabulated below in Table 4.2. 169 References on page 182 Chapter 4 T a b l e 4.2. Furnace parameters used in AAS for Ru, at X 265.9 nm. Step No. Temp. (°C) Time (s) Gas Flow Gas Type Read Command 1 90 20.0 3.0 Ar No 2 100 5.0 3.0 Ar No 3 120 15.0 3.0 Ar No 4 500 15.0 3.0 Ar No 5 1100 5.0 3.0 Ar No 6 1100 10.0 3.0 Ar No 7 1100 0.5 0.0 Ar No 8 2800 0.9 0.0 Ar Yes 9 2800 2.0 0.0 Ar Yes 10 2800 2.0 3.0 Ar No 4.3.9 Cell Incubation Procedures The required number of cells was harvested from the culture solution using a I centrifuge (Sorvall RC-3, 600 rpm, 80 g at 4 °C for 7 min, where g = gravity = relative centrifugal factor = 28.38(R)(N/1000)2, R = 23.11 cm and N = rpm). The cells were then resuspended in a+l- medium and added to solutions of the complexes previously made up in I the same media. The incubation conditions and sampling frequencies were varied depending on the experiment being performed. The cells were incubated with solutions of the complexes (10 mL) at a cell suspension of about 3.0 - 3.7 x 105 cells/mL in standard Erlenmeyer flasks 170 References on page 182 Chapter 4 fitted with a modified rubber stopper to introduce a flow of gas (through a syringe needle) and made for easy sampling (through a stoppered glass tube). The solutions were maintained at 37 °C in a Labline Instruments "Orbit Shaker Bath" which is a modified water-bath designed to rotate the flasks continuously but gently. For assessment under hypoxic conditions, N 2 was passed over the flasks for 1 h before introduction of the cells into the flasks, which contained solutions of the complexes, and this was maintained during the experiment (oxygen-free N 2 (Linde Specialty Gas, Union Carbide)). For aerobic experiments, air (filtered through a cotton plug) was passed over the suspensions and this prevented build up of C 0 2 due to cellular respiration. Both gases were humidified in a glass bubbler filled with sterile water maintained at 37 °C. 4.3.10 Cell Toxicity Assays Under Oxic and Hypoxic Conditions The toxicities of the complexes in C H O cells under air and under N 2 were measured by comparing the plating efficiency of cells as a function of concentration (2 h) with those incubated in control solutions. C H O cell suspensions (approximately 3.5 x 10 5cells/mL in a+/-) with the appropriate complex were incubated for a period of 2 h at 37 °C. Thereafter, samples (1 mL) were taken from each flask, diluted immediately in fresh a-/- media (10 mL, 0 °C), and pelleted. The supernatant was decanted and the cells resuspended in fresh a-/-medium (10 mL, 0 °C). A n aliquot (2 mL) of this cell suspension was then diluted in P B S (10 mL, 0 °C), and the cell suspension determined using the Coulter Counter. Aliquots of this cell solution (typically 10, 100, and 1000 u.L) were then plated onto Petri dishes (Falcon), prepared previously by filling with a+/+ medium (5 mL) and left to 171 References on page 182 Chapter 4 equilibrate in a tray incubator (National Inc.) maintained at 37 °C with a 95 % air/5 % CO2 gas flow. The dishes were then incubated in the tray incubator for 7 days for the cells to form colonies. The a+/+ medium was then discarded, and the colonies stained with methylene blue solution for ~7 min; the stain was then decanted, and the dishes rinsed with cold water. The number of colonies per dish was counted, and the plating efficiency (PE = number of colonies/number of cells plated) was calculated. 4.3.11 Cell Accumulation Assays The remaining 9 mL cell solution from the cell toxicity studies (2 h, 37 °C, Section 4.3.10) were pelleted by centrifugation and the supernatant discarded (2 h). The cells were then washed twice with P B S (10 mL, 0 °C) to remove unbound complex, and then resuspended in P B S (7.5 mL, 0 °C). At this point the samples were vortexed and then separated into three portions into polypropylene tubes: a 3 m L fraction was used for cell accumulation, 4 m L for the DNA-binding assay (Section 4.3.12) and the remaining 0.5 m L to determine the population of cells (200 u.L of the cell suspension being added to 20 m L of PBS) . The cells for the accumulation assay were pelleted, the supernatant decanted, and the cell pellet air-dried overnight at 37 °C. Concentrated H N 0 3 (50 (iL) was then added to the cell pellet, and the acid mixture vortexed vigorously and left at 37 °C overnight to enhance digestion of the cell pellet. T E buffer (250 \\L, p H 8.0) was then added to the digested cell solutions, and the mixtures analyzed for R u content using atomic absorption. The analytical 172 References on page 182 Chapter 4 results were first calculated as ng Ru/mL and then expressed as ng (Ru)/10 6 cells (using the cell counts). 4.3.12 DNA-Binding Assays The 4 mL sample obtained from the toxicity assay (Section 4.3.10) was pelleted, the supernatant decanted, and 1 mL of a solution made up of 10 m L T N E , 0.2 m L RNase ( lOmg/mL, Sigma), 0.2 m L 1 0 % S . D . S (sodium dodecyl sulfate, Sigma) and 0.2 m L Proteinase K (10 mg/mL, Sigma) was then added while the pellet was vortexed. The samples were stored at 37 °C overnight to ensure the cells were fully digested. The following day, each sample was sonicated for ~ 8 s and then extracted with washes ( 2 x 1 mL) of T N E -equilibrated phenol. The samples were centrifuged (5 min at 1000 rpm, 200 g) to ensure that the separation between the aqueous and organic layer was well defined. The samples were then washed (2 x 1 mL) with CHCI3 containing 4 % /so-amyl alcohol. The D N A was precipitated by adding 99.5 % E t O H (2 mL), vortexing and cooling the solution to -20 °C for at least 2 h. The precipitated D N A was pelleted by centrifugation (30 min at 3000 rpm, 2300 g, 4 °C), the supernatant decanted and the pelleted D N A air-dried. The dried D N A was then re-hydrated in 200 u L of T E and analyzed for R u content using atomic absorption; the amount of R u bound was normalized to the amount of D N A present which was determined by measuring the optical density (OD) of the re-hydrated D N A solutions using a dilution of 20 u L with 980 u L T E at 260 nm. The analytical results were first calculated as ng (Ru)/mL and then expressed as ng (Ru)/mg ( D N A ) . 173 References on page 182 Chapter 4 4.4 In Vitro Studies of Five Ru Sulfoxides (Table 4.1): Preliminary Results in CHO Cells 4.4.1 Toxicity of Ru Sulfoxides in CHO Cells under Oxic and Hypoxic Conditions A study was undertaken to determine whether the presence of oxygen might affect the toxicity of the R u sulfoxide complexes. The toxicity of the complexes in C H O cells was measured as P E , after an incubation time of 2 h in the solutions of the complexes (Section 4.3.10). The toxicity is expressed in terms of the P E as a function of concentration. None of the complexes listed in Table 4.1 exhibited significant toxicity in C H O cells, after an incubation time of 2 h at the concentrations tested under oxic or hypoxic conditions (see Figure 4.1 for an example). 0.01 0.5 1 Concentration (mM) 1.5 Figure 4.1. The absence of toxicity of [RuCl(BPSP)] 2 ( / i -Cl) 3 in C H O cells. Similar results were obtained by Yapp et al. in that no significant toxicity was observed for R u sulfoxide complexes of the type cis- and /raH£-RuCl2(sulfoxide)4 and 174 References on page 182 Chapter 4 RuCl 2(disulfoxide) 2 (sulfoxide = D M S O and T M S O , 1.0 m M ; disulfoxide = B M S E (1.0 mM) , B E S E (0.5 mM) , B P S E (0.5 mM) and B M S P (1.0 mM)) toward C H O cells in vitro2'17 4.4.2 Ruthenium Accumulation Under Oxic and Hypoxic Conditions Simultaneously, the effect of oxic or hypoxic conditions on the accumulation of the R u sulfoxide complexes was examined. The results indicate the gross amount of R u present (up to 2 h) in the whole cell (expressed at ng (Ru)/10 6 cells), and are presented as a plot of ng(Ru)/10 6 cells vs. concentration (mM) (Figure 4.2(A); the accumulation (of Ru) plots of the individual complexes are presented in Appendix 4). The errors were calculated using the average of repeat experiments (a minimum of 2) performed (e.g. control ± 20 %). The results indicate that R u does accumulate in C H O cells but there is no difference for these complexes between accumulation under oxic or hypoxic conditions. Yapp et al. observed linear profiles for the accumulation of selected Ru-sulfoxide complexes in C H O cells for periods up to 6 h , 8 ' 1 7 implying that the accumulation had not yet reached equilibrium or that the complex was being bound irreversibly to some cellular component. The accumulation of R u (ng (Ru)/10 6 cells) was estimated for 0.5 m M concentration for each of the complexes studied and was compared to those of the R u -sulfoxides previously studied by Yapp et a/ . 8 ' 1 7 For a comparison, these values were estimated assuming a linear response for accumulation over the concentration range up to 1.0 m M to facilitate this preliminary comparison (Figure 4.3(A)). 175 References on page 182 Chapter 4 0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 Concentration (mM) Figure 4.2. Accumulation of R u (A) and Ru-DNA-binding (B) in C H O cells after 2 h incubation with [Ru(12-S-4)(DMSO)(H 2 0)][OTf] 2 (1), [RuCl(BPSP)] 2 ( / / -Cl) 3 (2), [RuCl(BESE)(H 2 0 ) ] 2 (>-Cl) 2 (3), [RuCl(BPSE)(H 2 0 ) ] 2 ( / / -Cl) 2 (4), [RuCl(BBSE)(H 2 0)] 2 (//-C l ) 2 (5). 176 References on page 182 Chapter 4 Comparison of accumulation of R u in C H O cells shows that the mononuclear R u bis-disulfoxide complexes 8 ' 1 7 generally accumulate to a lesser degree relative to the corresponding dinuclear R u sulfoxides (9-12), with the exception of fr-a«s-RuCl2(BPSE)2 (6) which exhibits a higher accumulation than [RuCl(BPSE)(H 2 0)] 2 ( / / -Cl ) 2 (11). [Ru(12-S-4) (DMSO)(H 2 0)] [OTfJ 2 (8), [RuCl(BPSP)] 2 (^-Cl) 3 (9) and [RuCl(BPSE)(H 2 0) ] 2 ( / / -Cl ) 2 (11) accumulate in C H O cells to a similar extent under both oxic and hypoxic conditions. [RuCl (BESE)(H 2 0) ] 2 ( / / -Cl ) 2 (10) also accumulates in C H O cells to a similar extent under both oxic and hypoxic conditions; however, relatively less than that of 8, 9, 11 or 12. [RuCl (BBSE)(H 2 0) ] 2 ( / / -C l ) 2 (12) exhibits the greatest degree of accumulation under hypoxic conditions. Although (10) exhibits only moderate cellular accumulation, however, it is -10 times greater than the accumulation of the corresponding mononuclear complex, cis-R u C l 2 ( B E S E ) 2 (5). 177 References on page 182 Chapter 4 4.4.3 DNA-binding Under Oxic and Hypoxic Conditions The extent of Ru binding to DNA, and the possible enhancement in hypoxic conditions, were examined. The results are presented as the gross amount of Ru bound to the extracted D N A (expressed at ng (Ru)/mg (DNA)) vs. concentration (mM) (Figure 4.2(B); the Ru-DNA-binding plots of the individual complexes are presented in Appendix 5). Again, the errors were calculated using the average of repeat experiments (a minimum of 2) performed (e.g. control ± 20 %). Ru appears to bind to D N A without significant difference between DNA-binding under oxic or hypoxic conditions. The DNA-binding of Ru studied for complexes [RuCl(BPSP)]2(//-Cl)3 and [RuCl(BPSE)(H 2O)] 20u-Cl) 2 decreased at high concentrations possibly because of incomplete extraction of the D N A using the protocol described in Section 4.3.12. As with the cell accumulation, the binding of Ru to D N A (ng (Ru)/mg DNA) was estimated for 0.5 mM concentration (see Section 4.4.2) for a period of 2 h for each of the complexes studied. The findings are compared to complexes 1-7 of Yapp et a/.8' 1 7 (Figure 4.3(B) (studied only under oxic conditions after an incubation period of 4 h). Figure 4.3(B) shows that the complexes 9-12 from this present study exhibit greater binding of Ru to D N A than the previously studied Ru-sulfoxide complexes.8'17 178 References on page 182 Chapter 4 180 160 140 120 H 40 20 • Oxic • Hypoxic ~i— r JLHl 16 - i 14 -12 -NA) 10 -e OJD -I 8 -I 6 -cs 4 -2 -o -• Oxic • Hypoxic 6 7 8 Com plex B 10 n n . n 6 7 8 Com plex 10 11 12 Figure 4.3. Accumulation (A) and DNA-binding (B) with 0.5 m M of R u complex. 1 = cis-R u C l 2 ( D M S O ) 4 , 2 = / ra«s-RuCl 2 (DMSO) 4 , 3 = czs-RuCl 2 (TMSO) 4 , 4 = trans-R u C l 2 ( B M S E ) 2 , 5 = czs-RuCl 2 (BESE) 2 , 6 = Zra«s-RuCl 2(BPSE) 2 , 7 = c / s -RuCl 2 (BMSP) 2 , 8 = [Ru(12-S-4)(DMSO)(H 2 0)][OTfJ 2 , 9 - [RuCl(BPSP)] 2 ( / /-Cl) 3 , 10 = [ R u C l ( B E S E ) ( H 2 0 ) ] 2 C a -C l ) 2 , 11 = [RuCl (BPSE)(H 2 0) ] 2 C"-Cl ) 2 , 12 = [RuCl(BBSE)(H 2 0)] 2 ( / / -Cl ) 2 . (Data for 1-7 taken from refs. 8 and 17; for 1-7 (B) a 4 h incubation period was used and a 2 h incubation period was used for 8-12 (B)). 179 References on page 182 Chapter 4 Although [Ru(12-S-4)(DMSO)(H 2 0)][OTf] 2 (8) and [RuCl(BPSP ) ] 2 C"-Cl) 3 (9) show similar whole cell accumulation at 0.5 m M (Section 4.4.2), DNA-binding of 8 is much less than that of 9. It is interesting to note that greater uptake is not necessarily reflected in greater DNA-binding. This suggests that 8 accumulates elsewhere in the cell while 9 shows some binding to D N A . While [RuCl(BESE)(H 2 0 ) ] 2 (^ -Cl ) 2 (10) exhibits somewhat less accumulation than 9 (Section 4.4.2), the DNA-binding of the two complexes is similar with 10 binding somewhat to a greater extent than 9 at 0.5 m M . Complex 10 exhibits greater accumulation than c/ ' s -RuCl 2 (BESE) 2 (5) in the whole cell by a factor of -10 (Section 4.4.2) and the D N A -binding of 10 is -100 times greater than for 5 (under oxic conditions). The DNA-binding of 10 is the highest (hypoxic conditions) of all the complexes studied. While [RuCl(BPSE)(H 2 0 ) ] 2 ( / / -Cl) 2 (11) exhibited moderate accumulation and [RuCl(BBSE)(H 2 0 ) ] 2 Cu -Cl) 2 (12) exhibited the highest accumulation (Section 4.4.2), the DNA-binding of these two complexes is relatively small. The data suggest that these complexes accumulate in the cell, but not by extensive binding to D N A . O f note, 11 exhibits DNA-binding that is -10 times greater than that of the corresponding mononuclear complex, frYms-RuCl2(BPSE)2 (6), yet the latter exhibits greater accumulation (Section 4.4.2). This suggests that 6 accumulates in the whole cell but exhibits less D N A binding. 180 References on page 182 Chapter 4 4.5 Conclusions The biological assays present a preliminary survey of the biological activity of these five complexes. The complexes do enter C H O cells, bind to D N A , but are non-toxic at the concentrations tested. Furthermore, no hypoxic selectivity was observed in C H O cells with respect to the toxicity, cell accumulation and DNA-binding assays. A high degree of D N A -binding (e.g. with [RuCl(BPSP) ] 2 0-Cl) 3 and [RuCl (BESE) (H 2 0) ] 2 (>Cl ) 2 ) does not necessarily depend on an equally high degree of accumulation in whole cells. While there are insufficient data to rationalize the in vitro behaviour of the complexes, the results do suggest future studies. Yapp et a / . 8 , 1 7 have shown previously that trans R u bis-chelating disulfoxide and D M S O complexes exhibit more accumulation and DNA-binding than cis complexes. The new data show that the dinuclear R u sulfoxides generally accumulate to a greater degree than the trans complexes (with the exception of /ra/ is-RuCl 2 (BPSE) 2 ) and cis- or trans-RuCl 2 (DMSO)4, both of which have shown anti-tumour effects and binding to D N A without appreciable toxicity to the murine host (Chapter 1). The new complexes bind to D N A up to 270 times more than the complexes studied by Yapp et a/. , 8 ' 1 7 and - 1 6 and - 23 times more than cis- and fra«s-RuCl 2(DMSO)4, respectively. The in vitro results suggest that these water-soluble, R u sulfoxide complexes, which are non-toxic toward C H O cells but yet show binding to D N A , may possess anti-tumour activity similar to that o f complexes studied by Sava et al.,1 Alessio et al.,2 and Mestroni 3 . 181 References on page 182 Chapter 4 4.6 References for Chapter 4 1 Sava, G . Ruthenium Compounds in Cancer Therapy, in Metal Compounds in Cancer Therapy (ed. S Flicker), Chapman and Hall , London, 1994, p. 80. 2 Alessio, E . ; Balducci, G. ; Calligaris, M . ; Costa, G . ; Attia, W . H . ; Mestroni, G . Inorg. Chem. 1991, 30, 609. 3 Mestroni, G. The Development of Tumour-Inhibiting Ruthenium Dimethylsulfoxide Complexes, in Metal Complexes in Cancer Chemotherapy (ed. B . K . Keppler), V C H , Weinheim, 1993, p. 157. 4 Coluccia, M . ; Sava, G . ; Loseto, F. ; Nassi, A ; Boccarelli, A . ; Giordano, D . ; Alessio, E . ; Mestroni, G . Eur. J. Cancer 1993, 29, 1873. 5 (a) Sava, G . ; Pacor, S.; Mestroni, G . ; Alessio, E . Clin. Exp. Metastasis 1992, 10, 273; (b) Gagliardi, R.; Sava, G . ; Pacor, S.; Mestroni, G . ; Alessio, E . Clin. Exp. Metastasis 1994, 12, 93; (c) Sava, G . ; Capozzi, I.; Clerici, K . ; Gagliardi, G . ; Alessio, E . ; Mestroni, G . Clin. Exp. Metastasis 1998,16, 371. 6 (a) Sava, G . ; Zoret, S.; Giraldi, T.; Mestroni, G. ; Zassinovich, G . Eur. J. Cancer Clin. Oncol. 1984, 20, 841; (b) Pacor, S.; Sava, G . ; Ceschia, V . ; Bregant, F. ; Mestroni, G . ; Alessio, E . Chem. Biol. Interactions 1991, 78, 223. 7 Sava, G . ; Capozzi, I.; Bergamo, A ; Gagliardi, R.; Cocchietto, M . ; Masiero, L . ; Onisto, M . ; Alessio, E . ; Mestroni, G. ; Garbisa, S. Int. J. Cancer 1996, 68, 60. 8 Yapp, D . T. T. Ph. D . Dissertation, University of British Columbia, Vancouver, 1993. 9 Khan, B . T.; Mehmood, A . J. Inorg. Nucl. Chem. 1978, 40, 1938. 10 Alessio, E . ; X u , Y . ; Cauci, S.; Mestroni, G. ; Quadrifoglio, F. ; Viglino, P.; Marzi l l i , L . G . J. Am. Chem. Soc. 1989, 111, 7068. 11 Davey, J. M . ; Moerman, K . L . ; Ralph, S. F.; Kanitz, R.; Sheil, M . M . Inorg. Chim. Acta 1998, 281, 10. 12 Sherman, S. E . ; Lippard, S. J. Chem. Rev. 1987, 87, 1153. 182 Chapter 4 13 Esposito, G . ; Cauci, S.; Fogolari, F.; Alessio, E . ; Scocchi, M . ; Quadrifoglio, F . ; Viglino, P. Biochem. 1992, 31, 7094. 14 Tian, Y - N . ; Yang, P.; L i , Q-S.; Guo, M - L . ; Zhao, M - G . Polyhedron 1997,16, 1993. 15 Durig, J. R.; Danneman, J.; Behnke, W. D . ; Mercer, E . E . Chem. Biol. Interact. 1976, 13, 287. 16 Gibson, J. F. ; Poole, R. K . ; Hughes, M . N . ; Rees, J. F. Arch. Microbiol. 1984, 139, 265. 17 Yapp, D . T. T.; Rettig, S. J.; James, B . R ; Skov, K . A . Inorg. Chem. 1997, 36, 5635. 18 (a) Vaupel, P.; Fortmeyer, H . P.; Runkel, S.; Kallinowski, F. Cancer Res. 1987, 47, 3496; (b) Vaupel, P.; Kallinowski, F. ; Okunieff, P. Cancer Res. 1989, 49, 6449. 19 (a) Denny, W. A . ; Wilson, W. R. J. Med. Chem. 1986, 29, 879; (b) Chaplin, D . J. Int. J. Radiat. Oncol. Biol. Phys. 1992, 22, 685; (c) Brown, J. M . ; Giaccia, A . J. Int. J. Radiat. Biol. 1994, 65, 95. 20 Kennedy, K . A . ; Teicher, B . A . ; Rockwell, S.; Sartoelli, A . C. Biochem. Pharmacol. 1980, 29, 1. 21 Gray, L . H . ; Conger, A . D . ; Ebert, M . ; Hornsey, S.; Scott, O. C. A . Br. J. Radiol. 1953, 26, 638. 22 Hockel, M . ; Schlenger, K . ; Aral, B . ; Mitze, M . ; Schaffer, U . ; Vaupel, P. Cancer Res. 1996, 56, 4509. 183 Chapter 5 Chapter 5 Metallation of Free-base Porphyrins 5.1 Introduction Water-soluble porphyrins have potential to interact with biological systems and can be involved, for example, in double-stranded cleavage of D N A , photochemical oxidations, photodynamic therapy, and photoinduced intramolecular electron- and energy transfer.1 The radiosensitizing properties of metalloporphyrins2'3 and the anti-tumour activity of certain ruthenium complexes (see Sections 1.3 and 1.4 and ref. 4) have been reported. Porphyrins have been shown to accumulate at tumours,5 and ruthenium(II) complexes have been shown to bind to D N A (see Sections 1.3 and 1.4). Combining the accumulating properties of porphyrins at a tumour and the binding properties of a ruthenium(II) centre to D N A provides an approach to Ru(porphyrin) systems that offer potential for both radiosensitizing and chemotherapeutic activity (see Section 1.3.2). 5.1.1 Metalloporphyrins as Hypoxic Radiosensitizers Water-soluble porphyrins have been reported to accumulate at tumour tissue5 (although this remains controversial), and compounds containing methylpyridinium, sulfonato or carboxylato substituents, and their metal complexes, have been reported to be moderate radiosensitizers.2 Synthetic, water-soluble porphyrins and their metalloporphyrin derivatives with Co(III), Cu(II), Ru(II) and Pt(II) have been synthesized and evaluated as hypoxic agents, especially as cytotoxins and radiosensitizers.3 O f the porphyrins studied, the Co(III) complexes exhibited some selective toxicity and radiosensitizing activity toward C H O cells. 3 184 References on page 207 Chapter 5 Ru(II) porphyrins were included in the study3 as complexes o f R u have been recognized for their anti-tumour activity. 6 ' 7 5.2 Ruthenium Porphyrins Fleischer et al. synthesized the first R u porphyrin in 1969 (reported as [Ru(TPhP)Cl(CO)] t ) by bubbling C O through an E t O H solution of R u C k - 3 H 2 0 for 3 h, then adding a glacial acetic acid solution of H 2 T P h P and refluxing the solution for 21 h; 8 however, in 1971 Chow and Cohen reformulated the material correctly as Ru(TPhP)(CO), after a synthesis using either Ru3(CO) i 2 or [RuCl 2 (CO) 3 ] 2 as the precursor with H 2 T P h P in refluxing acetic acid or propionic acid under N 2 for 24 h . 9 Synthetic methods for the insertion of R u into porphyrins remain largely based on modifications of the original procedures.8"10 These all produce stable Ru(II) carbonyl species, which are formed by the interaction of the free base porphyrin, H 2 (Porp), with the ruthenium precursors Ru3(CO)u or RuCl3-3H20, either in the presence or absence o f a C O atmosphere. The thermolysis of Ru3(CO) i 2 in the presence of H 2 (Porp) remains the most common method of synthesis.1 1 Massoudipour and Pandey have synthesized Ru(TPhP)(CO)(EtOH) utilizing R u C V 3 H 2 0 as the metallation agent by refluxing a solution of 50:50 % vol . ethyl glycol/formaldehyde under N 2 until the colour of the solution changed to pale yellow. This solution was reduced in volume and added dropwise to a solution of H 2 T P h P over a period of 1 h., with the reaction complete in 30 h . 1 2 t TPP and TSPP are normally used as the standard abbreviations for the dianion of 5,10,15,20-tetraphenylporphyrin and -tetrakis(4-sulfonato)phenylporphyrin, respectively, although a more consistent abbreviation for them would be TPhP and TSPhP, as used here. 185 References on page 207 Chapter 5 The only published route to Ru(IT) water-soluble porphyrins, e.g. the synthesis of [Ru(II)(TSPhP)(CO)] 4" requires refluxing a D M F solution o f the free-base, water-soluble porphyrin [H 2 (TSPhP)] 4 " and Ru3(CO)i2 under A r for a period of 1-3 weeks, 1 3 and by adding 2,4,6-collidine, the reaction time was reduced to 24 h . 1 4 In addition to the long reaction times, the preparation of the Ru3(CO)i2 precursor requires the stirring of a solution o f R u C U under a steady stream of C O for several hours. 1 5 5.3 A New Route for the Insertion of Ruthenium into Selected Free-base Porphyrins Work from this group has led to a new, more convenient route to ruthenium(II) water-soluble porphyrin complexes. 3 ' 1 6 The reaction time is decreased from 1-3 weeks (see above) to just 24 h and the method does not require an atmosphere of C O at any stage of the preparation, in which the Ru(III) precursor [Ru(III)(DMF) 6][OTf]3 1 7 is used. The refluxing o f this precursor in D M F in the presence of the free-base, water-soluble porphyrin yields, for example, Na4[Ru(II)(TSPhP)(CO)]-4H 20. The process involves in situ reduction o f [ R u ( D M F ) 6 ] 3 + , but the nature of this reduction remains unclear. 1 6 The following non-water-soluble Ru(II)(CO)porphyrin complexes were then synthesized, using [Ru(III)(DMF)6][OTf] 3 , in this current thesis work: Ru(II)(TPhP)(CO), Ru(II)(BPhP)(CO), Ru(II)(TrPhPyNO)(CO) and Ru(II)(OEP)(CO) (BPhP = dianion of 5,15-bis(phenyl)porphyrin, TrPhPyNO = dianion o f 5,10,15-triphenyl-20-(4-pyridyl-A /-oxide)porphyrin, and O E P = dianion of 2,3,7,8,12,13,17,18-octaethylporphyrin) (Figure 5.1 and Table 5.1). 186 References on page 207 Chapter 5 Figure 5.1. Ru(II)(Porp)(CO) species, showing the numbering system. Table 5.1. Ru(Porp)(CO) species. Porp Substituent Positions (TSPhP)4 - (TPhP) (BPhP) (TrPhPyNO) (OEP) 5- -o H 10- -o H -o H 15- H 20- H H 2,3,7,8,12,13,17,18- H H H H C H 3 C H 2 187 References on page 207 Chapter 5 5.4 Experimental The free-base porphyrin Na 4 [H 2 TSPhP] -15H 2 0 was prepared according to a literature procedure. 1 8 H 2 ( O E P ) and H 2 (TPhP) were kindly donated by Dr. C. Alexander; H 2 (BPhP) , H 2 (TrPhPyNO), H 2 (TPyP) , H 2 ( B P h B P y N O P ) , H 2 ( D B r B P h P ) and H 2 ( P P I X D M E ) were kindly donated by Dr. J. Posakony; and H 2 ( T M P ) and H 2 (TPFPhP) were kindly donated by Dr. S. Cheng (see Table 5.5 on p. 205 for porphyrin abbreviations). Water was distilled and deionized before use. Silica gel (grade 60, 230-400 mesh) was purchased from B D H . Cone. H 2 S 0 4 was purchased from Fisher. A l l other chemicals and reagents used are described in Chapter 2, Section 2.1. 5.4.1 Physical Techniques The general spectroscopic methods and instrumentation used are described in Chapter 2, Section 2.2. In addition M A L D I - T O F was also used as a method of mass spectral analysis. Fluorescence spectroscopic data were obtained using an S L M Aminco 8100 Spectrofluorometer; wavelength maxima, Amax, are given in nm. 5.4.2 Synthesis of Precursors 5.4.2.1 Na4[H2TSPhP]- 15H20 (MW = 1292.88 g/mol) Na 4 [H 2 TSPhP] -15H 2 0 , the free-base porphyrin was synthesized from H 2 T P h P and cone. H 2 S 0 4 according to the procedure reported by Meng et a/ . 1 8 The purity of the product was determined by U V - V i s and lH N M R spectroscopies and T G A . The spectroscopic data are in good agreement with those previously reported. 1 8 ^ - N M R ( D M S 0 - c 4 200 M H z ) 8 188 References on page 207 Chapter 5 8.85 (s, 8H, pyrrole H), 8.20 (d, 8H, m-C^SOi), 8.03 (d, 8H, o-C67^S0 3"), -3.00 (s, 2 H , N/7). U V - V i s ( H 2 0 ) 636 (3.24), 578 (3.79), 550 (3.78), 516 (3.90), 414 (5.03). T G A : Calcd loss of 1 5 H 2 0 : 20.9. Found: 19.6 % (from ~ 25 to ~ 155°C) ( T G A plot is given in Appendix 4, Figure A.4.3). 5.4.2.2 [Ru(DMF)6][OTf]3 The synthesis of [Ru(DMF)6][OTfJ3 was described in Chapter 2, Section 2.5.1. 5.5 Synthesis of Ru(Porp)(CO) Complexes 5.5.7 Na4[Ru(TSPhP)(CO)]-4H20 (MW= 1221.95 g/mol) Na4[H 2(TSPhP)]-15H 20 (210 mg, 0.205 mmol) was dissolved in D M F (80 mL) and the solution heated to 50 °C under N 2 . [Ru(DMF) 6 ] [OTf] 3 (614 mg, 0.622 mmol) was then added and the dark purple solution was heated to reflux under N 2 , in the absence of light for 24 h. The resulting dark red solution was concentrated to a minimal volume by rotary evaporation. The product was purified as a purple-red band by column chromatography using silica gel and M e O H as the eluant. The solvent was removed by rotary evaporation, and the purple product was collected and dried in vacuo for 1 week. Yield: 133 mg (53 %). Anal. Calcd for • C u H s z W n S ^ a ^ : C, 44.23; H , 2.64; N , 4.58; S, 10.49. Found: C, 44.36; H , 2.70; N , 4.55; S, 10.68%. ' H - N M R (MeOD-d, , 200 M H z ) 5 8.65, 8.60 (s, 4 H each, pyrrole H), 8.25 (m, 16H, m-C^SOi and o-C^SOi). IR v c o : 1923, v 0 H : 3460. U V - V i s ( H 2 0 ) 528 (4.21), 410 (5.43). T G A : Calcd loss of 4 H 2 0 : 5.9%. Found: 5.1 % (from - 3 7 to - 60°C) ( T G A plot is given in Appendix 4, Figure A.4.4). The ' H - N M R , v c o , and U V - V i s 189 References on page 207 Chapter 5 spectroscopic data are consistent with those previously reported for the Ru(II)(TSPhP)(CO) 4" moie ty . 1 3 ' 1 4 ' 1 6 , 1 9 Attempts to analyze this product by mass spectroscopic methods (EI and LSEVIS) did not show the parent peak or any other peaks related to the title compound. 5.5.2 Ru(OEP)(CO)(THF) (MW= 733.96g/mol) The procedure used was as given in Section 5.5.1, but using H 2 ( O E P ) (60 mg, 0.11 mmol), [Ru(DMF) 6 ] [OTf] 3 (312 mg, 0.316 mmol) and D M F (30 mL), with the reaction time being reduced to 6 h. The product was purified by column chromatography using neutral alumina with C H 2 C 1 2 as eluant for unreacted H 2 (OEP) , and with 10 % T H F / M e O H as eluant for the product. Red crystals suitable for X-ray analysis were obtained from slow evaporation of a saturated solution of the complex in 10 % THF/toluene. Yield: 45 mg (56 %). Anal. Calcd for C 4 i H 5 2 N 4 0 2 R u : C, 67.09; H , 7.14; N , 7.63. Found: C, 66.51; H , 7.17; N , 8.40%. X H - N M R of a sample left under vacuo for 24 h (CDC1 3 , 200 M H z ) 6 9.90 (s, 4 H , meso-H), 4.03 (q, 16H, G?7 2 CH 3 ) , 1.90 (t, 24H, C H 2 C # 3 ) . IR v c o : 1925. U V - V i s ( D M F ) 548 (4.76), 518 (4.49), 396 (5.63). Mass spectrum [LSEVIS, m/z] 662 [M-(THF) ] + and 634 [M-(THF) -(CO)] + . The • H - N M R , V C O , and U V - V i s spectroscopic data are consistent with those previously reported for the Ru(II)(OEP)(CO) moiety. 1 0 ' 2 0" 2 2 5.5.3 Ru(TPhP)(CO)(H20) (MW= 759.78g/mol) The procedure used was as given in Section 5.5.1, but using H 2 (TPhP) (25 mg, 0.042 mmol), [Ru(DMF) 6 ] [OTf] 3 (125 mg, 0.126 mmol) and D M F (30 mL). Benzene was used as eluant for unreacted H 2 (TPhP) , and 5 % THF/benzene was used as eluant for the product. Yie ld: 18 mg (51 %). Anal. Calcd for C 4 5 H 2 8 N 4 O R u H 2 0 : C, 71.14; H , 3.98; N , 190 References on page 207 Chapter 5 7.37. Found: C, 70.65; H , 4.31; N , 7.10%. ' H - N M R (CDC1 3 , 200 M H z ) 5 8.60 (s, 8H, B-pyrrole-//), 8.18 and 8.02 (m, 8H, o-CeH5), 7.65 (m, 12H, m-C(JI5 and p-CaH5). ER v c o : 1946, v O H : 3412. U V - V i s ( D M F ) 532 (4.72), 412 (5.60). Mass spectrum [LSIMS, m/z] 742 [ M - ( H 2 0 ) ] + and 714 [M-(H 2 0) - (CO)] + . The *H N M R , v c o , and U V - V i s data are consistent with those previously reported for a complex containing the Ru(II)(TPhP)(CO) moiety. 9 ' 2 3" 2 6 Red crystals of the complex Ru(TPhP)(CO)(py) containing a coordinated pyridine suitable for X-ray analysis were obtained by slow evaporation of a saturated solution o f the aquo complex in 5 % pyridine/benzene. 5.5.4 Ru(BPhP)(CO) The procedure used was as given in Section 5.5.1, but using H 2 (BPhP) (4.67 mg, 0.01 mmol), [Ru(DMF) 6 ] [OTf] 3 (30 mg, 0.03 mmol) and D M F (3 mL). C H 2 C 1 2 was used as eluant for unreacted H 2 (BPhP) , and 2 % T H F / C H 2 C 1 2 was used as eluant for the product. Yie ld < 2 mg (not determined). ! H - N M R (CDC1 3 , 200 M H z ) 5 10.00 (s, 2H , meso-H), 9.13, 8.85 (s, 4 H each, B-pyrrole-#), 8.25 and 8.02 (m, 2 H each, o-CaHs), 7.95 (m, 6H, m-CeHs and p-CsHs). IR v c o : 1930. U V - V i s (CH 2 C1 2 ) 520, 402. Mass spectrum [LSIMS, m/z] 590 [ M ] + , 562 [M-(CO)] + . 5.5.5 Ru(TrPhPyNO)fCO) The procedure used was as given in Section 5.5.1, but using H 2 (TrPhPyNO) (6.4 mg, 0.01 mmol), [Ru(DMF) 6 ] [OTf] 3 (30 mg, 0.03 mmol) and D M F (3 mL). C H C 1 3 was used as eluant for unreacted H 2 (TrPhPyNO) and 2 % pyridine/CHCl 3 was used as eluant for the 191 References on page 207 Chapter 5 product. Yie ld < 2 mg (not determined). IR v c o : 1935, v N O : 1251. U V - V i s (CH 2 C1 2 ) 532, 414. Mass spectrum [LSIMS, m/z] 743 [M-(0)] + , 715 [M-(0 ) - (CO)] + . 5.6 Results and Discussion Previous work has shown that metallation failed to occur using a 3:1 molar ratio of [Ru(DMF) 6][OTf]3 and H 2 (TSPhP) 4 " in D M F under 1 atm of H 2 . 1 6 The present work demonstrates that an inert atmosphere and neat D M F are both necessary in order for metallation to occur. O f note, attempts to metallate the free-base porphyrins using D M S O , or D M S O / D M F as the solvent, under N 2 or air did not result in the insertion of Ru. The metallation reaction involves an in situ reduction of Ru(III) to Ru(II). The mechanism of this reduction is unclear; 1 6 however, C O has been proposed to be the reductant which derives from the decarbonylation of D M F . Such decarbonylation of D M F by R u -porphyrins to generate carbonyl derivatives has been reported, 2 7 and the mechanisms of reactions in which C O acts as a reductant are well established.2 8 Baird et al, from this laboratory, have reported the synthesis of [Ru(L)e][OTf] 2 complexes (L = an imidazole) utilizing [Ru(DMF) 6 ] [OTf] 3 as the precursor. 2 9 These reactions carried out in M e O H involve ligand exchange of the D M F ligands of [Ru(DMF) 5 ][OTf]3 with imidazole as well as the in situ reduction of Ru(III) to Ru(II). The authors suggest that M e O H and/or imidazoles may be acting as the reducing agent; both these reagents can act as reductants. 3 0 ' 3 1 192 References on page 207 Chapter 5 5.6.1 Na4[Ru(TSPhP)(CO)] 4H20 Pawlik et al. reported the first water-soluble Ru(II) porphyrin as Na4[Ru(TSPhP)(CO)] formed by reaction of R u 3 ( C O ) 1 2 with Na4(TSPhP)12H 20 in refluxing D M F under A r for a period of 1-3 weeks. However, the authors noted that the sodium salt is contaminated by other sodium salts, but addition of a saturated solution of C a C l 2 gave Ca 2 [Ru(TSPhP)(CO)]12H 2 0 , 1 3 while Yong-Wu and Xing-Min reported the isolation of Na4[Ru(TSPhP)(CO)]12H 20 from the reaction of Ru 3 (CO ) i 2 and the sodium salt quoted as Na4(TSPhP)-9H 20. 1 9 Recently, Hartmann et al. reported the characterization o f Na4[Ru(TSPhP)(CO)(EtOH)]. 1 4 Ware in this laboratory reported the isolation o f the complex Na4[Ru(TSPhP)(CO)(DMF)]-solvate 1 6 (solvate = 2 D M F - 2 H 2 0 or 6H 2 0) by the method described in Section 5.5.1. During the present work, Na4[Ru(TSPhP)(CO)]-4H 20 was isolated from the reaction between Na 4 [H 2 TSPhP]-15H 2 0 and [Ru(DMF) 6 ][OTfJ 3 (Section 5.5.1). The complex was formulated with four solvate H 2 0 molecules as elemental and thermal gravimetric analyses provide support for this formulation. The calculated elemental analyses agree well with the determined analyses, while thermal gravimetric analyses of the complex (Section 5.5.1) showed a weight loss corresponding to 3.5 H 2 0 molecules from the formulated Na4[Ru(TSPhP)(CO)]-4H 20. O f note, Buchler et al. reported the use of gel electrophoresis as an efficient method for the separation and analysis of several free-base and metallated water-soluble porphyrins, and the authors report that "results of elemental analyses are not definitive because the substances are strongly hygroscopic". 3 2 The v C o stretch for the C O ligand was observed at 1923 cm"1 (KBr) which compares with the reported values of 1925 193 References on page 207 Chapter 5 cm' 1 for Ru(TSPhP) (CO)12H 2 0 (medium not given), 1 9 1940 cm' 1 for Ca 2 [Ru(TSPhP)(CO)]12H 2 0 (medium not given), 1 3 2042 and 1936 cm"1 for Na4[Ru(TSPhP)(CO)(EtOH)] ( K B r ) , 1 4 2035, 1959 and 1924 cnf 1 for Na4[Ru(TSPhP)(CO)(DMF)]-2DMF-2H 2 0 ( K B r ) 1 6 and 2027, 1971 and 1929 c r n 1 for Na4[Ru(TSPhP)(CO)(DMF)]-6H 2 0 ( K B r ) . 1 6 Ware noted that "the solid state IR spectrum of Na4[Ru(TSPhP)(CO)(DMF)]-solvate (solvate = 6 H 2 0 or 2DMF-2H 2 0) shows three v c o stretches which could indicate the presence of more than one mono-CO complex (e.g. with H 2 0 as the axial ligand), a trace of some R u - C O impurity or solid state effects".1 6 Hartmann et al. tested a series of water-soluble R u porphyrins ([Ru(II)(TMPyP)(CO)(CH 3 OH)](OAc)4, Na4[Ru(II)(TSPhP)(CO)(EtOH)] and [Ru(II)(p-COOH-PP)(CO)(MeOH)] (TMPyP = dianion of /weso-tetrakis(4-N-methylpyridinium)porphyrin and /7 -COOH-PP = dianion of /weso-tetrakis(4-carboxylphenyl)porphyrin)) and their M n and Fe analogues for possible in vivo anti-tumour activity using mice bearing P388 leukemia cells, and these results were compared to those for cisplatin. 1 4 O f the complexes studied, only Na4[Ru(TSPhP)(CO)(EtOH)] exhibited "borderline" anti-tumour activity (0.047 mmol/kg) compared to that of cisplatin (0.013 mmol/kg). 1 4 Previous biological results, in this laboratory, reported by Ware 1 6 indicate that Na4[Ru(TSPhP)(CO)(DMF)] does not accumulate in C H O cells as well as, for example, f ra ra-RuCl 2 (BPSE) 2 (up to 8.81 x 10' 6 ng(Ru)/cell at 50-200 u M after 1 h 1 6 vs. 175 x IO"6 ng(Ru)/cell at 500 u M for 4 h). 3 3 Na 4 [Ru(TSPhP)(CO)(DMF)] was shown to be non-toxic toward C H O cells in air at the concentrations tested (50-200 p M ) which parallels other reports from this laboratory showing that various Co, Cu and Pt porphyrin complexes are also 194 References on page 207 Chapter 5 non-toxic to oxic cells. 3 ' 3 4 The complex Na4[Ru(TSPhP)(DMSO) 2 ] , derived from Na4[Ru(TSPhP)(CO)(DMF)], was found to show no radiosensitizing ability toward C H O cells under oxic or hypoxic conditions, and indeed seemed to be weakly radioprotecting. 3 ' 1 6 5.6.2 Ru(OEP)(CO)(THF) The reaction of H 2 ( O E P ) with [Ru(DMF) 6 ][OTfJ 3 led to the isolation of the title complex (Section 5.5.2), which has been made previously via the R u 3 ( C O ) l 2 precursor; 1 0 vco observed at 1925 cm"1 (KBr) compares with the reported values of 1950 cm"1 for Ru(OEP)(CO)(THF) (medium not given), 1 0 1952 cm"1 for Ru(OEP)(CO)(PPh 3 ) (medium not given), 2 0 3 1917 cm"1 for Ru(OEP)(CO) (in 0.1 M [ n Bu 4 N][PF 6 ] in C H 2 C 1 2 ) , 2 1 and 1945 and 1928 cm"1 for Ru(OEP)(CO)(MeOH) ( K B r ) . 2 2 Crystals of Ru(OEP)(CO)(THF) (Section 5.5.2) were grown by slow evaporation of a 10 % THF/toluene solution of the complex. It was not possible to obtain good elemental analysis or definitive N M R data for the complex because the T H F was removed during attempts to remove associated solvent by pumping. Eaton and Eaton have reported X H N M R multiplets at 5-1.23 and -0.45 peaks for bound T H F inRu(OEP) (CO) (THF) . 1 0 Structural data (Figure 5.2 and Table 5.2) show that the molecule has a slightly distorted octahedral geometry at the R u with trans angles that range from 172.66(12) to 177.23(12) °, cis N - R u - N angles from 89.53(10)-89.97(10) °, cis C - R u - N angles from 89.92(13)-97.41(13) °, and cis O - R u - N angles from 85.31(10)-87.35(10) ° The complex possesses a linear binding mode for the C O ligand with a Ru-C -0 angle of 176.6(3)°, a R u - C bond length of 1.805(4) A and a C -0 bond length of 1.144(4) A. The Ru-0(2) distance is 2.241(3) A which is somewhat longer than those reported (2.019(3) A (av.) for the Ru-0 195 References on page 207 Chapter 5 bond in Ru(TPhP)(OEt)(EtOH)-2EtOH, 2 2 and 2.21(2) A for Ru(TPhP)(CO)(EtOH) 2 5 ) and suggests a weak ligation of T H F in the solid state. C ( 2 8 ) Figure 5.2. A n O R T E P diagram of Ru(OEP)(CO)(THF) showing 50 % thermal ellipsoids; the H-atoms are omitted for clarity (crystal data are given in Appendix 1.14). 196 References on page 207 Chapter 5 Table 5.2. Selected Bond Angles and Lengths for Ru(OEP)(CO)(THF). Bond Distance (A) Bond angles Angle (°) R u - C 1.805(4) trans angles 172.66(12)-177.23(12) Ru-N(porp) 2.052(2)-2.059(2) cw-N-Ru-N 89.53(10)-89.97(10) Ru-O 2.241(3) c/s-C-Ru-N 89.92(13)-97.41(13) C - O 1.144(4) c/5-O-Ru-N 85.31(10)-87.35(10) R u - C - 0 176.6(3) Seyler et al. have reported on the reaction of T E M P O (Figure 5.3) with Ru(OEP) (CH 3 ) to give Ru(OEP)(CO)(TEMPO) , the first reported transformation of a C H 3 to a C O within a metal complex. 3 5 The C O ligand is linearly bound with a R u - C - 0 angle o f 178.6 °, a Ru-C bond distance of 1.798(5) A and a C - 0 bond distance of 1.150(5) A. The reported R u - 0 distance of 2.348(3) A is larger than those noted above and suggests a weak ligation of the T E M P O ligand. The *H N M R solution spectrum of Ru(OEP) (CO) (TEMPO) revealed no evidence for T E M P O ligation with the Ru(OEP)(CO) moiety in solution. 3 5 Other Ru(OEP) complexes characterized by X-ray crystallography include Ru(OEP)(R 2 S)2 (R2 = n-decylmethyl and Ph 2 ) , 3 6 [Ru(OEP)(R 2 S) 2 ][BF 4 ] (R 2 = H-decylmethyl), 3 7 and Ru(OEP)(CO)(py) . 3 8 Funatsu et al. have reported the structure of the 'diporphyrin species' Ru(OEP)(CO)(H 2 PyP 3 P) (H 2 PyP 3 P = 5-pyridyl-10,15,20-triphenylporphyrin), in which the carbonyl ligand is again linearly coordinated to R u with the R u - C - 0 angle of 179.7(6) °, a R u -C bond distance of 1.801 A and a C - 0 bond distance of 1.165(7) A. 3 9 197 References on page 207 Chapter 5 [Of interest, T E M P O has been utilized previously in this group to study bond homolysis within Ru(IV)-diaryl/dialkyl porphyrin complexes. 4 0 Hanada et al. have reported the structure and magnetic properties of a bis(nitroxide)diruthenium (II,III) cation within the mixed cation complex [Ru2(02CCMe3)4(TEMPO)2][Ru2(02CCMe3)4(H20)2](BF4)2.41 (1) (2) (3) Figure 5.3. Structures of (1) = T E M P O = 2,2,6,6-tetramethylpiperidine-l-oxyl, 3 5 (2) = D A P O = trans 3,4,-diamino-2,2,6,6-tetramethyl piperidine-l-oxyl, 4 2 (3) = T E M P I C O L - 2 = 4-hydroxy-4-(2-picolyl)-2,2,6,6-tetramethylpiperidine-1 -oxyl . 4 3 More generally, derivatives of T E M P O and associated metal complexes have been studied as novel classes of antioxidants and anticancer agents. Sen' et al. have reported the synthesis and anti-tumour activity of the Pt(II) complexes P t ( D A P O ) X 2 (see Figure 5.3). 4 2 The toxicity of the Pt complexes was dependent on the nature of X , and in terms of L D 5 0 varied between 11 mg/kg ( X = N03) and 400 mg/kg ( X 2 = 1,1-cyclobutanedicarboxylate) compared to that of cisplatin, 12 mg/kg. The complex with X = C l (at 4.75 mg/kg) appeared to more efficient than cisplatin (1.88 mg/kg) in suppressing tumour growth (evaluated as an inhibition of growth of tumour diameter) against subcutaneously transplanted adenocarcinoma 755 in mice. Metodiewa et al. have reported studies of T E M P I C O L - 2 (see Figure 5.3) as an anticancer agent, in which administration of the nitroxide to rats bearing 3 day-old Yoshida Sarcoma led to growth inhibition. 4 3] 198 References on page 207 Chapter 5 5.6.3 Ru(TPhP)(CO)(py) The title complex was synthesized 'inadvertently' by reaction of [ R u ( D M F ) 6 ] 3 + and H 2 (TPhP) , followed by crystallization from a pyridine/benzene solution (Section 5.5.3). Structural determination revealed that the molecule was identical to that reported by Little and Ibers in 1973. 3 8 The v C o value compares with those reported in the literature: 1945 cm"1 for Ru(TPhP)(CO) in K B r 9 or NaCI 2 3 , 1945 cm"1 for Ru(TPhP)(CO)(imidazole) in C H C 1 3 , 2 4 1934 and 1939 cm"1 for Ru(TPhP)(CO) and Ru(TPhP)(CO)(py), respectively in tetrachloroethane2 5 and 1922 cm"1 for Ru(TPhP)(CO) in D M S O 2 6 . (Table 5.3 shows a comparison o f selected bond lengths for the two determined structures of Ru(TPhP)(CO)(py)). Table 5.3. Comparison of Selected Bond Lengths for Ru(TPhP)(CO)(py) (Figure 5.4). Bond This Work Ref. 38 R u - C 1.837(3) A 1.838(9) A Ru-N(porp) 2.057(2)-2.062(2) A 2.055(6)-2.058(5) A Ru-N(py) 2.207(2)A 2.193(4) A C-0 1.151(3)A 1.141(10) A 199 References on page 207 Chapter 5 Figure 5.4. An ORTEP diagram of Ru(TPhP)(CO)(py) showing 50 % thermal ellipsoids; the H-atoms have been omitted for clarity (crystal data are given in Appendix 1.15). 200 References on page 207 Chapter 5 5.6.4 Ru(BPhP)(CO) The title complex was synthesized by reaction of [ R u ( D M F ) 6 ] 3 + and H 2 (BPhP) (Section 5.5.4), and has been partially characterized: V c o is observed at 1930 cm"1, the mass spectrum shows peaks for Ru(BPhP)(CO) and Ru(BPhP), and the *H N M R data are consistent with the formulation. 5.6.5 Ru(TrPhPyNO)(CO) The title complex ( v c o 1935, V N O 1251 cm"1) was synthesized by reaction o f [ R u ( D M F ) 6 ] 3 + and H 2 (TrPhPyNO) (Section 5.5.5). The mass spectrum shows peaks for Ru(TrPhPyN)(CO) and Ru(TrPhPyN); the oxidopyridyl groups were deoxygenated using the ionization techniques (EI, L S I M S and M A L D I - T O F ) and no molecular ion peak was observed. O f note, the free-base porphyrins, 5,15-bis(l-oxido-4-pyridyl)-10-20-diphenylporphyrin and 5,10-bis(l-oxido-4-pyridyl)-15-20-diphenylporphyrin, were deoxygenated under conditions of E I or LSEVIS, but were analyzed by M A L D I - T O F mass spectrometry which led to less deoxygenation of these porphyrin-N-oxides. 4 4 5.7 Fluorescent Properties of Porphyrins The accumulation of non-metallated (free-base) porphyrins in cells has been previously studied using fluorescence microscopy, 5 3 ' 4 5 including the water-soluble sodium salt of 5-(l-oxido-4-pyridyl)-10, 15, 20-tris(4-sulfonatophenyl) porphyrin. 4 4 Fluorescence from porphyrin chromophores localized in cells was observed when the cells were irradiated with 201 References on page 207 Chapter 5 U V light (330-380 nm, with emission measured at > 420 nm) and in the green region (510-560 nm, with emission measured at > 590 nm). 4 4 5.7.1 Fluorescence Spectra of Selected Ru Porphyrins A qualitative measure of fluorescence was determined for some Ru(Porp)(CO) species. The excitation wavelengths chosen are the absorbance maxima in the U V - V i s spectrum. Fluorescence was observed from the porphyrin chromophores when the samples were irradiated with U V light (300-380 nm, with emission measured at > 570 nm) and with visible light in the violet region (389-421 nm, with emission measured at > 429 nm). The fluorescence data are summarized in Table 5.4. The fluorescence spectrum o f Na4[Ru(TSPhP)(CO)]-4H 20 is shown in Figure 5.5 as an example. 60001 a A i 6 4 1 nm •I— i—,—,—i—•—|—•—|—.—i—'—i—•—i—•—i—•—i—•—r— 300 350 400 450 500 550 BOO 650 700 750 600 wavelength Figure 5.5. Fluorescence spectrum of Na 4 [Ru(TSPhP)(CO)]-4H 2 0. The excitation wavelength was 414 nm and emission was measured at 641 and 704 nm. 202 References on page 207 Chapter 5 Table 5.4. Fluorescence wavelengths for selected R u porphyrins. Porphyrin Excitation (k) nm Emission (k) nm Na4[Ru(TSPhP)(CO)]-4H 2O f l 414 641 and 704 Ru(OEP)(CO)(THF) f c 389 429 Ru(BPhP)(CO) c 315 570 and 633 406 698 Ru(TrPhPyNO)(CO) c 421 650 " D M S O / H 2 0 . 6 THF/toluene/acetone. e CH 2Cl 2/acetone. 5.8 Attempted Metallations A s described in Section 5.6 the metallation, using [Ru(DMF) 6 ] [OTf] 3 , o f selected porphyrins has proven to be quite useful and convenient. Several attempts to metallate other porphyrins were unsuccessful. These reactions were monitored by: (a) T L C for the disappearance of H 2 (Porp), (b) U V - V i s spectroscopy by shifts in the spectra, and (c) by IR for the appearance of Vco- Porphyrins that were not metallated using the [ R u ( D M F ) 6 ] 3 + precursor are shown in Table 5.5 (for the numbering scheme of the free-base porphyrins refer to Figure 5.1, p. 187). Ware reported that the metallation of H 2 (TPyP) with [Ru(DMF) 6 ] [OTf] 3 led to the isolation of an insoluble, red product "Ru(TPyP)" that is likely of a polymeric nature. 1 6 Shi and Anson exposed graphite electrodes coated with Co(TPyP) to solutions o f fac-[ R u ( N H 3 ) 3 ( O H 2 ) 3 ] 2 + and postulated the formation of a polymeric substance containing bridging R u atoms linked to Co(TPyP) via the nitrogen of the pyridyl group. 4 6 During this 203 References on page 207 Chapter 5 present work, the reaction of H 2 (TPyP) and [Ru(DMF) 6 ][OTf]3 (following the methodology described in Section 5.5) resulted in the isolation of an insoluble microcrystalline purple compound that did not analyze well for either "Ru(TPyP)(CO)" or a polymeric "Ru(TPyP)" material. Alessio et al. have reported the design of a "pentamer of vertically linked porphyrins" (MTPyP)[Ru(TPhP)(CO)] 4 ( M = 2H+ or Zn 2 + ) formed by treating (MTPyP) with [Ru(TPhP)(CO)(EtOH)]. 4 7 O f note, the "pentamer" (H 2 TPyP)[Ru(TPhP)(CO)] 4 was considerably more soluble than H 2 (TPyP) in CHCI3. The authors have also observed that (ZnTPyP)[Ru(TPhP)(CO)] 4 can interact with the O-atom of D M S O (both free and S-bonded to a metal centre) to form adducts containing the "rare bridging D M S O " . 4 7 Funatsu et al. have synthesized a series of cyclic R u porphyrin tetramers including [Ru(TrPhPyP)(CO)] 4 , 4 8 which represent a class of molecules capable of supramolecular self-assembly. More generally, porphyrin oligomers have assisted in elucidation of important electronic and photochemical consequences for bacteriochlorophyll molecules in photosynthetic reaction centres.4 9 For example, Stibrany et al. have reported on a structural and spectroscopic comparison between Zn(II) porphyrin dimers and bacterial photosynthetic reaction centres in bacteriochlorophyll molecules, 4 9 3 while Kobuke and Miyaji reported the synthesis of porphyrin dimers and oligomers as models of photosynthetic reaction centres, 4 9 0 and Nagata et al. reported the synthesis and spectroscopic properties of trimeric and pentameric porphyrin arrays as models toward the development of synthetic catalysts for photosynthetic charge 49c separation. 204 References on page 207 Chapter 5 Table 5.5. Free-Base Porphyrins. 5,10,15,20-tetrapyridylporphyrin (TPyP), 5,10-bis(phenyl)-15,20-bis(4-pyridyl-7V-oxide)porphyrin (BPhBPyNOP), 5,10,15,20-tetramesitylporphyrin (TMP), 5,10,15,20-tetra(pentafluorophenyl)porphyrin (TPFPhP), 5,15-dibromo-10,20-bisphenylporphyrin(DBrBPhP), and protoporphyrin(IX)dimethylester (PPIXDME). Porp Substituent Positions (TPyP) (BPhBPyNOP) (TMP) (TPFPhP) (DBrBPhP) (PPIXDME) 5- Br H 10- > H 15- -O Br H 20- H 2,7,12,18- H H H H H C H 3 3,8- H H H H H CH 2 =CH 13,17- H H H H H D M E " a D M E = C H 3 C O O C H 2 C H 2 . 205 References on page 207 Chapter 5 5.9 Conclusions Ware in this laboratory has shown that [Ru(ffi)(DMF) 6][OTf|3 is an effective precursor for the metallation of the water-soluble porphyrin, H 2 (TSPhP) 4 " . 1 6 The present work has shown that this metallation method is not limited to the water-soluble porphyrin H 2 (TSPhP) 4 " but applies also to several non-water-soluble porphyrins to give Ru(II)(Porp)(CO) complexes. This method is both convenient and efficient, in that an atmosphere of C O is not required and the reaction times are reduced from 1-3 weeks (using Ru 3 (CO ) i 2 as precursor) to a period of 3-24 h. The in situ reduction of the Ru(III) to Ru(II) in this metallation process may involve C O (derived from the D M F ) as the reductant (Section 5.6). As well, metallation does not occur in air, implying that Ru(III) is first reduced to Ru(II) and then inserted into the porphyrin to yield Ru(II)(Porp)(CO). Further work is required to determine the mechanism of this metallation process involving the in situ reduction of Ru(III) to Ru(II). 206 References on page 207 Chapter 5 5.10 References for Chapter 5 1 Markel, G . ; Reiss, M . ; Kreitmeier, P.; Ndth, H . Angew. Chem. Int. Ed. Engl. 1995, 34, 2230 and references therein. 2 O'Hara, J. A . ; Douple, E . B . ; Abrams, M . J.; Picker, D . J.; Giandomenico, C. M . ; Vollano, J. F. Int. J. Radiat. Oncol. Biol. Phys. 1989, 16, 1049. 3 James, B . R.; Meng, G. G. ; Posakony, J. J.; Ravensbergen, J. A . ; Ware, C. J.; Skov, K . A . Metal-Based Drugs 1996, 5, 85. 4 Jaswal, J. S.; Yapp, D . T. T.; Rettig, S. J.; James, B . R ; Skov, K . ; A . J. Chem. Soc, Chem. Commun. 1992, 1528 and references therein. 5 (a) Kessel, D . ; Thompson, P.; Saatio, K . ; Nantwi, K . D . Photochem. Photobiol. 1987, 45, 787; (b) Fiel, R. J.; Mark, E . ; Button, T.; Gilani, S.; Musser, D . Cancer Lett. 1988, 40, 23; (c) Dougherty, T. J. Photochem. Photobiol. 1987, 45, 879; (d) Miura, M . ; Micca, P. L . ; Heinrichs, J. C ; Gabel, D . ; Fairchild, R. G . ; Slatkin, D . N . Biochem. Pharmacol. 1992, 43, 467. 6 Farrell, N . P. Transition Metal Complexes as Drugs and Chemotherapeutic Agents, Kluwer Academic Publishers, Dordecht, 1989. 7 Sava G . Ruthenium Compounds in Cancer Therapy, in Metal Compounds in Cancer Therapy (ed. S Fricker), Chapman and Hall , London, 1994, p. 65. 8 Fleischer, E . B . ; Thorp, R ; Venerable, D . J. Chem. Soc, Chem. Commun. 1969, 475. 9 Chow, B . ; Cohen, I. Bioinorg. Chem. 1971,1, 57. 10 Eaton, G . R ; Eaton, S. S. J. Am. Chem. Soc. 1975, 97, 235. 11 Mlodnicka, T.; James, B . R. Oxidations Catalyzed by Ruthenium Porphyrins, in Metalloporphyrins Catalyzed Oxidations (eds. F. Montanari and L . Casella), Kluwer Academic Publishers, Dordrecht, 1994, 77, p. 121. 12 Massoudipour, M . ; Pandey, K . K . Inorg. Chim. Acta 1989, 760, 115. 13 Pawlik, M . ; Hoq, M . F.; Shepherd, R. E . J. Chem. Soc, Chem. Commun. 1983, 1467. 207 Chapter 5 14 Hartmann, M . ; Robert, A . ; Duarte, V . ; Keppler, B . K . ; Meunier, B . J. Biol. Inorg. Chem. 1997, 2, 427. 15 Dawes, J. L . ; Holmes, J. D . Inorg. Nucl. Chem. Lett. 1971, 7, 847. 16 Ware, C. J. M . Sc. Dissertation, University of British Columbia, Vancouver, 1994. 17 Judd, R. J.; Cao, R.; Biner, M . ; Armbruster, T.; Biirgi , H - B . ; Merbach, A . E . ; Ludi , A . Inorg. Chem. 1995, 34, 5080. 18 Meng, G . G . ; James, B . R.; Skov, K . A . ; Korbelik, M . Can. J. Chem. 1994, 72, 2447. 19 Yong-Wu, L . ; Xing-Min , A . Acta Chim. Sin. 1986, 44, 964. 20 (a) Barley, M . ; Becker, G. ; Domazetis, G . ; Dolphin, D . ; James, B . R. Can. J. Chem. 1983, 61, 2389; (b) Antipas, A . ; Buchler, J. W. ; Gouterman, M . ; Smith, P. D . J. Am. Chem. Soc. 1978, 100, 3015. 21 Brown, G . M . ; Hopf* F. R.; Ferguson, J. A . ; Meyer, T. J.; Whitten, D . G . J. Am. Chem. Soc. 1973, 95, 5939. 22 Collman, J. P.; Barnes, C. E . ; Brothers, P. J.; Collins, T. J.; Ozawa, T.; Gallucci, J. C ; Ibers, J. A . J. Am. Chem. Soc. 1984,106, 5151. 23 Tsutsui, M . ; Ostfeld, D . ; Francis, J. N . ; Hoffman, L . M . J. Coord. Chem. 1971, 1, 115. 24 Tsutsui, M . ; Ostfeld, D . ; Hoffman, L . M . J. Am. Chem. Soc. 1971, 93, 1820. 25 Bonnet, J. J.; Eaton, S. S.; Eaton, G. R.; Holm, R. H . ; Ibers, J. A . J. Am. Chem. Soc. 1973, 95, 2141. 26 Rillema, D . P.; Nagle, J. K . ; Barringer Jr., L . F. ; Meyer, T. J. J. Am. Chem. Soc. 1981, 103, 56. 27 Belani, R. M . ; James, B . R.; Dolphin, D . ; Rettig, S. J. Can. J. Chem. 1988, 66, 2072. 28 Sheldon, R. Chemicals from Synthesis Gas, Reidel Publishing Co. , Dordrecht, 1983, p. 33. 29 Baird, I. R.; Rettig, S. J.; James, B . R.; Skov, K . A . Can. J. Chem. 1998, 76, 1379. 30 Hallman, P. S.; Stephenson, T. A . ; Wilkinson, G. Inorg. Synth. 1970, 12, 237. 31 (a) Collman, J. P.; Gagne, R. R.; Halbert, T. R.; Marchon, J - C ; Reed, C. A . J. Am. Chem. Soc, 1973, 95, 7868; 208 Chapter 5 (b) Chin, D - H . ; Balch, A . L . ; L a Mar, G. N . J. Am. Chem. Soc. 1980,102, 1446; (c) Anderson, C ; Beauchamp, A . L . Inorg. Chem. 1995, 34, 6065. 32 Buchler, J. W. ; Kunzel, F. M . ; Mayer, U . ; Nawra, M . Fresenius J. Anal. Chem. 1994, 348, 371. 33 (a) Yapp, D . T. T. Ph. D . Dissertation, University of British Columbia, Vancouver, 1993; (b) Yapp, D . T. T.; Rettig, S. J.; James, B . R.; Skov, K . A . Inorg. Chem. 1997, 36, 5635. 34 (a) Meng, G . G. Ph.D. Dissertation, University of British Columbia, Vancouver, 1993; (b) Ravensbergen, J. A . M . M . Sc. Dissertation, University of British Columbia, Vancouver, 1993. 35 Seyler, J. W. ; Fanwick, P. E . ; Leidner, C. R. Inorg. Chem. 1992, 31, 3699. 36 James, B . R.; Pacheco, A . ; Rettig, S. J.; Ibers, J. A Inorg. Chem. 1988, 27, 2414. 37 Pacheco, A ; James, B . R.; Rettig, S. J. Inorg. Chem. 1995. 34, 3477. 38 Little, R. G . ; Ibers, J. A . J. Am. Chem. Soc. 1973, 95, 8583. 39 Funatsu, K . ; Kimura, A ; Imamura, T.; Ichimura, A . ; Sasaki, Y . Inorg. Chem. 1997, 36, 1625. 40 Ke , M . ; Rettig, S. J.; James, B . R ; Dolphin, D . J. Chem. Soc, Chem. Commun. 1987, 1110. 41 Hanada, M . ; Sayama, Y . ; Mikuriya, M . ; Nukada, R ; Hiromitsu, I.; Kasuga, K . Bull. Chem. Soc. Jpn. 1995, 68, 1647. 42 Sen', V . D . ; Golubev, V . A . ; Volkova, L . M . ; Konovalova, N . P. J. Inorg. Biochem. 1996, 64, 69. 43 Metodiewa, D . ; Skolimowski, J.; Kochman, A . ; Gwozdsinski, K . ; Glebeska, J. Anticancer Res. 1998,18, 369. 44 (a) Posakony, J. J. Ph.D. Dissertation, University of British Columbia, Vancouver, 1998, p. 94; (b) Posakony, J. J.; Pratt, R C ; Rettig, S. J.; James, B . R ; Skov, K . A . Can. J. Chem. 1999, 77, 182. 209 Chapter 5 45 (a) Berg, K . ; Western, A . ; Bommer, J. C ; Moan, J. Photochem. Photobiol. 1990, 52, 481; (b) Woodburn, K . W. ; Vardaxis, N . I ; Hi l l , J. S.; Kaye, A . H . ; Phillips, D . R. Photochem. Photobiol. 1991, 54, 725; (c) Berg, K . ; Madslien, K . ; Bommer, J. C ; Oftebro, R.; Winkelman, J. W. ; Moan, J. Photochem. Photobiol. 1991, 53, 203; (d) Karagianis, G . ; H i l l , J. S.; Stylli, S. S.; Kaye, A . H . ; Varadaxis, N . J.; Reiss, J. A ; Phillips, D . R. Br. J. Cancer 1996, 73, 514. 46 Shi, C ; Anson, F. C. Inorg. Chim. Acta 1994, 225, 215. 47 Alessio, E . ; Macchi, M . ; Heath, S.; Marzil l i , L . G. J. Chem. Soc, Chem. Commun. 1996, 1411. 48 Funatsu, K . ; Imamura, T.; Ichimura, A ; Sasaki, Y . Inorg. Chem. 1998, 37, 1798. 49 (a) Stibrany, R. T.; Vasudevan, J.; Knapp, S.; Potenza, J. A ; Emge, T.; Schugar, H . I. J. Am. Chem. Soc. 1996, 118, 3980; (b) Kokube, Y ; Miyaji, H . J. Am. Chem. Soc. 1994, 116, 4111; (c) Nagata, T.; Osuka, A ; Maruyama, K . J. Am. Chem. Soc. 1990,112, 3054. 210 Chapter 6 Chapter 6 Conclusions and Recommendations for Future Work 6.1 General Remarks This chapter highlights the most significant results obtained from the projects described, specifically the characterizations of water-soluble, dinuclear, Ru-disulfoxide complexes. Suggestions for future investigations are made. Less successful experiments are also considered, including suggestions on how syntheses might be improved. Finally, some comments are made regarding the potential use of water-soluble R u complexes as chemotherapeutic agents. 6.2 Sulfoxide and Thioether Complexes of Ruthenium The initial focus of this work was to synthesize geometrical isomers of the cis and trans forms of some existing R u bis-chelating, disulfoxide complexes (Chapter 1 ) . However, because of the unsuccessful early attempts of utilizing various R u precursors (Chapter 2 ) , it was decided to extend the series of disulfoxides (Chapter 2 ) , and to synthesize their corresponding R u complexes. The successful reactions are discussed in Chapter 3 . Reactions of 2 equivalents of disulfoxide with RuCi3-3H 2 0 generally give the mononuclear c/'s-RuCl 2(disulfoxide) 2 complexes, which contain solely S-bonded sulfoxides as indicated by IR data and established by X-ray crystallography for c / s - R u C l 2 ( B B S E ) 2 E t O H , cis-R u C l 2 ( B C y S E ) 2 E t O H l / 3 M e O H and c / s - R u C l 2 ( B E S P ) 2 E t O H H 2 0 . With the exception of c / 5 - R u C l 2 ( B B S E ) 2 E t O H , which contains one RR and one meso form of B B S E , the coordinated disulfoxides are all the meso diastereomers. O f major interest are the water-2 1 1 References on page 219 Chapter 6 soluble, dinuclear, disulfoxide complex [RuCl(BPSP)] 2 ( / / -Cl) 3 , which represents a new type of mixed-valence species, and a series of [RuCl(disulfoxide)(H20)]2(//-Cl)2 complexes (disulfoxide = B E S E , B P S E or B B S E ) . The aqueous solution chemistry o f [RuCl(BPSP)] 2 ( / / -Cl )3 was studied and the data suggest the formation of a dihydroxy species. However, attempts to isolate this complex were unsuccessful, possibly due to its hygroscopic nature. Such aqueous solution chemistry needs further study. Reaction of the dinuclear complex [RuCl(BESE)(H 2 0 ) ] 2 ( / / -Cl ) 2 with 2 equivalents o f B E S E gave the mononuclear / ra«5 -RuCl 2 (BESE) 2 containing again just S-bonded sulfoxides. The cis isomer was described by the Trieste group as the lowest energy diastereomer (Chapter 3, p. 99), 1 implying that the cis isomer would likely be isolated in attempts to synthesize the trans form, and early attempts to synthesize the trans complex via the /ra»s-RuCl 2 (DMSO)4 precursor or and photolyzing c / s -RuCl 2 (BESE) 2 yielded only the cis isomer. It is not clear why f raws-RuCl^BESE^ is isolated by utilizing the dinuclear complex as precursor. The generality of this method to synthesize the unknown geometrical isomers c / s -RuCl 2 (BPSE) 2 and frvms-RuCl2(BBSE)2 from [RuCl (BPSE)(H 2 0 ) ] 2 ( / / -C l ) 2 and [RuCl (BBSE)(H 2 0 ) ] 2 ( / / -C l ) 2 , respectively, should be examined. Reactions of BPhSE, B H S E , B 'PSP, B B S P , BPeSP, BPhSP and B M S B with RuCl3-3H20, utilizing procedures described in Chapter 2, led to yellow, uncharacterized products which by column chromatography yielded several bands or, in the case of B M S B , a product insoluble in common solvents. Elemental analyses for the products obtained from the major chromatography bands and the insoluble products were variable from repeat 212 References on page 219 Chapter 6 reactions. Further investigations into the reactions of the disulfoxides containing (CH2)2 and ( C H 2 ) 3 backbones with R u precursors should be pursued. A n attempt to oxidize l,3-bis(phenylthio)propane using a i r /DMSO oxidation led to an oily product, which by T L C , *H N M R spectroscopy and vso data appeared to be the disulfoxide. Reaction of this oil and RuCl3-3H20, again utilizing the procedure described in Chapter 2, led to the isolation of red crystals which were submitted for X-ray analysis. The structural diagram shows one coordinated disulfoxide and one 'half-oxidized' dithioether. Large thermal motion prevented an accurate determination of the structure; however, cis geometry was established (Figure 6.1). The coordination chemistry of 'half-oxidized' dithioether R u complexes is intriguing. The oxidation of dithioethers using only one-half o f the required oxidizing agent should be examined. Thus a novel series of mixed thioether/sulfoxide R u complexes could presumably be synthesized and characterized. 213 References on page 219 Chapter 6 214 References on page 219 Chapter 6 Most o f the disulfoxides synthesized in this work are water-soluble; however, the mononuclear, bis-chelating disulfoxide R u complexes are all non-water-soluble. Synthesis o f disulfoxide ligands incorporating moieties that would render the complexes water-soluble (for example, that shown in Figure 6.2) would seem a worthwhile endeavour. r M e 3 N M ^ > — S — - — S - ^ ^ ^ N + M e 3 r Figure 6.2. A potentially water-soluble disulfoxide. The disulfoxides in this work were synthesized as mixtures o f diastereomers (Chapter 3), thus preventing the determination of the absolute configurations of the S-atoms. Stereospecific syntheses of disulfoxides should be undertaken (Chapter 3, Section 3.5.1), and subsequent reactions with R u precursors investigated. Such syntheses should result in isolation of complexes with known stereochemistry as opposed to mixtures of diastereomers. Reactions of dithioethers with RuCi3-3H 20 resulted in isolation of the mononuclear Ru(II) species / ra«s-RuCl 2 (BCyTE) 2 and - R u C l 2 ( B P h T E ) 2 and the dinuclear Ru(III) complexes [RuCl 2 (BETP)] 2 ( / / -Cl ) 2 , [RuCl 2 (BPTP)] 2 ( / / -Cl) 2 , [RuCl 2 (BBTP)] 2 ( / / -Cl )2 and [RuCl 2 (BPeTP)] 2 ( / / -Cl) 2 . The redox chemistry of these requires study, as complexes of both Ru(II) and Ru(III) were isolated using dialkyldithioethers. Chatt et al.2 suggested that diphenyldithioether may be a stronger reductant than dialkyldithioethers in reactions with RuCi3-3H 20, as it gives / r a«5 -RuCl 2 (BPhTE) 2 ; however, the isolation of trans-R u C l 2 ( B C y T E ) 2 implies that such a conclusion is not valid in a general sense. The redox chemistry of the disulfoxide and dithioether systems is o f interest and needs study, particularly for the dinuclear Ru(II)/Ru(II) and Ru(II)/Ru(III) disulfoxides, and 215 References on page 219 Chapter 6 the Ru(III)/Ru(III) dithioethers. It should be possible to isolate entire ranges of Ru(II)/Ru(II), Ru(II)/Ru(III) and Ru(III)/Ru(III) complexes for each disulfoxide and dithioether. One possible route to Ru(III)/Ru(IH) disulfoxides is via oxidation of coordinated dithioethers (for example, [RuCl 2 (BPTP ) ] 2 Cu -Cl) 2 to give [RuCl(BPSP) ] 2 Gu-Cl) 3 or [RuCl 2 (BPSP)] 2 ( / / -Cl) 2 ) . Oxidation of Ru(II)-thioethers to Ru(II)-sulfoxides has been reported by Schenk et al.3 Initial attempts to oxidize fra«5-RuCl2(BPhTE)2 using in situ dimethyldioxirane were unsuccessful in that no v S o band was detected in the isolated product (Chapter 3); perhaps the bulky substituents at the sulfur prevent its oxidation. This oxidation should be attempted using complexes with thioethers containing less bulky substituents. 6.3 Metallation of Selected Free-base Porphyrins [Ru( in)(DMF) 6 ][OTf ]3 is an effective precursor for the metallation o f the water-soluble porphyrin, H 2 ( T S P h P ) 4 " 4 The present work has shown that this metallation method is not limited to the water-soluble porphyrin H 2 (TSPhP) 4 " but applies also to several non-water-soluble porphyrins to give Ru(II)(Porp)(CO) complexes. Earlier work from this laboratory has shown that Na4[Ru(TSPhP)(DMSO) 2] has no radiosensitization activity in C H O cells and that Na4[Ru(TSPhP)(CO)(DMF)] is non-toxic and does not accumulate in C H O cells. 4 ' 5 The radiosensitizing capability of R u porphyrins may be improved in principle by the attachment of a nitroimidazole group either to R u or to the porphyrin ring. 6 Photochemical studies with nitroimidazoles, misonidazole and metronidazole (see Chapter 1, Section 1.4.3), using photo sensitizers such as hematoporphyrin, uroporphyrin, (H 2 TSPhP) 4 " and its Z n complex, and mono-Z-aspartyl chlorin e6, have given evidence for Type I photoprocesses,7 these yielding the radical cation 216 References on page 219 Chapter 6 of the photosensitizer and radical anion of metronidazole.8 The accumulation properties of R u porphyrins in C H O cells may be improved by the attachment of cationic groups to the porphyrin ring, as James et al. have shown enhanced accumulation profiles for cationic porphyrins. 5 ' 9 H 2 T M P y P (TMPyP = dianion of /wes0-tetrakis(4-N-methylpyridinium)porphyrin) has been shown to interact with D N A , and a M n derivative activated by a water-soluble oxygen-atom donor (potassium monopersulfate, KHSO5) has been shown to be an efficient DNA-cleaving system. 1 0 During this present thesis work, the anticancer properties of T E M P O derivatives have been reported. 1 1 The reported isolation of Ru(OEP) (CO)(TEMPO) encourages a study to coordinate T E M P O (or a related nitroxide derivative) to a cationic, R u porphyrin. 6.4 Preliminary In Vitro Examination Of Water-soluble Ru Sulfoxide Complexes A preliminary survey of the biological activity of five complexes was presented in Chapter 4 . The 5 selected complexes do accumulate in C H O cells, bind to D N A , but are non-toxic at the concentrations tested. Furthermore, no hypoxic selectivity was observed in C H O cells with respect to toxicity, cell accumulation and DNA-binding. A relatively high degree of DNA-binding occurs with these water-soluble complexes, particularly [RuCl(BPSP)] 2 ( / / -Cl) 3 and [RuCl (BESE) (H 2 0 ) ] 2 ( / / -C l ) 2 . The DNA-binding assays imply that Ru-disulfoxide-DNA adducts are formed, and thus more extensive in vitro studies should be undertaken to understand the nature o f these interactions. In vivo assays should also be undertaken to determine whether these complexes resemble the R u - D M S O complexes in murine experiments. 217 References on page 219 Chapter 6 Some metal complexes have potential as "carriers" to target radio sensitizers to D N A . 1 2 The non-toxic, cell accumulating and DNA-binding properties of these complexes might be retained with the addition of a nitroimidazole ligand that would act as the 12 radiosensitizer (see Chapter 1, Section 1.4.3). For example, Chan et al. have shown that the radiosensitizing activities of selected 2- and 4-nitroimidazoles are improved upon coordination using c/'s-RuCl2(DMSO)41 3 and cis-RuCl2(TMSO)4 1 4 as precursors. The geometric formulations of some resulting RuCl2(sulfoxide)2(L)2 complexes (sulfoxide = D M S O or T M S O , and L = a nitroimidazole) were not definitely resolved because no crystal structures were determined, and there are several possible isomers within such complexes. The advantage of using chelating disulfoxide ligands would be to reduce the number of possible isomers in the preparation o f nitroimidazole complexes. Preliminary attempts to synthesize (in a i r /H 2 0) such complexes using [RuCl(BESE)(H 20)]2(//-Cl)2, as a precursor, with 2-nitroimidazole, 2-methyl-5-nitroimidzole and imidazole led to water-soluble, red complexes that could not be purified by column chromatography and did not analyze well for C or H content. O f note, Yapp previously isolated red mixtures, from reactions of RuCl2(disulfoxide)2 and nitroimidazoles, that could not be purified. 1 2" Follow-up of this chemistry might prove useful for targeting applications. 218 References on page 219 Chapter 6 6.5 References for Chapter 6 1 Geremia, S.; Vicentini, L . ; Calligaris, M . Inorg. Chem. 1998, 37, 4094. 2 Chatt, J.; Leigh, G. J.; Storace, A . P. J. Chem. Soc. (A) 1971, 1380. 3 Schenk, W . A . ; Frisch, J.; Diirr, M . ; Burzlaff, N . ; Stalke, D . ; Fleischer, R. ; Adam, W. ; Prechtl, F. ; Smerz, A . K . Inorg. Chem. 1997, 36, 2372. 4 Ware, C. J. M . Sc. Dissertation, University of British Columbia, Vancouver, 1994. 5 James, B . R.; Meng, G . G . ; Posakony, J. J.; Ravensbergen, J. A . ; Ware, C. J.; Skov, K . A Metal-Based Drugs 1996, 3, 85. 6 (a) Posakony, J. J. Ph.D. Dissertation, University of British Columbia, Vancouver, 1998, p. 94; (b) Posakony, J. J.; Pratt, R. C ; Rettig, S. J.; James, B . R.; Skov, K . A . Can. J. Chem. 1999, 77, 182. 7 (a) Oschner, M . Photochem. Photobiol. B: Biol. 1997, 39, 1; (b) Dolphin, D . Can. J. Chem. 1994, 72, 1005. 8 (a) Bazin, M . ; Patterson, L . K . ; Ronfard-Haret, J. C ; Santus, R. Photochem. Photobiol. 1988, 48, 177; (b) Bazin, M . ; Santus, R. Photochem. Photobiol. 1986, 43, 235. 9 Meng, G . G . Ph.D. Dissertation, University of British Columbia, Vancouver, 1993. 10 (a) Pitie, M . ; Bernadou, J.; Meunier, B . Am. Chem. Soc. 1995, 117, 2935 and references therein; (b) Bigey, P.; Pratviel, G . ; Meunier, B . Chem. Soc, Chem. Commun. 1995, 181. 11 (a) Sen', V . D . ; Golubev, V . A . ; Volkova, L . M . ; Konovalova, N . P. J. Inorg. Biochem. 1996, 64, 69; (b) Metodiewa, D . ; Skolimowski, J.; Kochman, A . ; Gwozdsinski, K . ; Glebeska, J. Anticancer Res. 1998,18, 369. 12 (a) Yapp, D . T. T. Ph. D . Dissertation, University of British Columbia, Vancouver, 1993; 219 Chapter 6 (b) Yapp, D . T. T.; Rettig, S. J.; James, B . R ; Skov, K . A . Inorg. Chem. 1997, 36, 5635. 13 (a) Chan, P. K . L . ; Skov, K . A . ; James, B . R. Int. J. Radiat. Biol. 1987, 52, 49; (b) Chan, P. K . L . ; Chan, P. K . H . ; Frost, D . C ; James, B . R ; Skov, K . A . Can. J. Chem. 1988, 66, 117. 14 Chan, P. K . L . ; James, B . R ; Frost, D . C ; Chan, P. K . H . ; Hu , H - L . ; Skov, K . A . Can. J. Chem. 1989, 67, 508. 220 I. Appendix Appendix 1. Crystallographic Data Appendix 1.1 Crystallographic Data for fraHs-RuCl^BESE^ Table A . l 1. Experimental Details for X-ray Crystal Structure of *raws-RuCl2(BESE)2 A. Crystal Data Empirical Formula C12H28CI2O4RUS4 Formula Weight 536.57 Crystal Colour, Habit yellow, plate Crystal Dimensions 0.05 x 0.25 x 0.35 mm Crystal System monoclinic Lattice Type Primitive Lattice Parameters a= 10.309(2) A b = 7.6799(9) A c = 12.9465(7) A P= 104.721(1)° V = 991.4(2) A 3 Space Group P2i/n (# 14) Z Value 2 1.797 g/cm3 Fooo 548.00 //(MoKa) 14.94 cm"1 B. Intensity Measurements Diffractometer Rigaku/ADSC CCD Radiation MoKa (k = 0.71069^) graphite monochromated Detector Aperature 94 mm x 94 mm Data Images 460 exposures at 90.0 seconds </> oscillation Range (x = -90) 0.0 - 190.0 0 co oscillation Range (% = -90) -22.0 -18.0 0 Detector Position 39.18(1) mm Detector Swing Angle -10° 60° Scan Width -0.30 0 1Qmax 67.0° No. of Reflections Measured Total: 9574 Unique: 2344 (R,„, = 0.024) Corrections Lorentz-polarization Absorption/scaling (trans, factors: 0.7927 - 0.9986) C. Structure Solution and Refinement Structure Solution Direct Methods (SIR92) Refinement Full-matrix least-squares Function Minimized E c o ( | F o 2 | - | F c 2 | ) 2 Least Squares Weights co = lta2(Fo2) p-factor 0.0100 Anomalous Dispersion All non-hydrogen atoms No. Observations (I>0.00a(I)) 2344 No. Variables 162 Reflection/Parameter Ratio 14.47 Residuals (on F 2 , all data): R; Rw 0.063; 0.075 A.221 I. Appendix Goodness of Fit Indicator 2.57 No. Observations (I>3a(I)) 1928 Residuals (on F, I>3a(I)): Rl ; Rlw 0.033; 0.037 Max Shift/Error in Final Cycle 0.0006 Maximum peak in Final Diff. Map 0.38 e'/A3 Minimum peak in Final Diff. Map -0.84 elA3 Table A . l 2. Bond Angles (°) for / ra«s-RuCl 2 (BESE) 2 atom atom atom angle atom atom atom angle Cl(l) Ru(l) Cl(l) 180.00 Ru(l) S(l) C(l) 104.9(1) Cl(l) Ru(l) S(l) 89.12(3) Ru(D S(l) C(3) 116.6(1) Cl(l) Ru(l) S(D 90.88(3) 0(1) S(D C(l) 107.6(1) Cl(l) Ru(D S(2) 92.27(3) 0(1) S(l) C(3) 107.1(2) Cl(l) Ru(l) S(2) 87.73(3) C(l) S(l) C(3) 99.1(2) Cl(l) Ru(l) S(l) 90.88(3) Ru(l) S(2) 0(2) 119.44(9) Cl(l) Ru(l) S(D 89.12(3) Ru(l) S(2) C(2) 103.5(1) Cl(l) Ru(l) S(2) 87.73(3) Ru(D S(2) C(5) 115.7(1) Cl(l) Ru(l) S(2) 92.27(3) 0(2) S(2) C(2) 106.6(1) S(l) Ru(l) S(l) 180.00 0(2) S(2) C(5) 108.1(2) S(D Ru(l) S(2) 85.42(3) C(2) S(2) C(5) 101.3(2) S(D Ru(l) S(2) 94.58(3) S(D C(l) C(2) 110.9(2) S(D Ru(D S(2) 94.58(3) S(2) C(2) C(l) 106.8(2) S(D Ru(l) S(2) 85.42(3) S(D C(3) C(4) 111.1(2) S(2) Ru(l) S(2) 180.00 S(2) C(5) C(6) 112.2(2) Ru(l) S(D O(l) 119.31(9) Angles are in degrees. Estimated standard deviations in the least significant figure are given in parentheses. Table A . l 3. Bond Lengths (A) for *ra«s-RuCl 2(BESE) 2 atom atom distance atom atom distance Ru(l) Cl(l) 2.4018(7) S(D C(3) 1.802(3) Ru(l) Cl(l) 2.4018(7) S(2) 0(2) 1.480(2) Ru(l) S(D 2.3288(7) S(2) C(2) 1.809(3) Ru(l) S(l) 2.3288(7) S(2) C(5) 1.797(3) Ru(l) S(2) 2.3212(9) C(l) C(2) 1.512(5) Ru(l) S(2) 2.3212(9) C(3) C(4) 1.518(5) S(l) 0(1) 1.479(2) C(5) C(6) 1.518(5) S(l) C(l) 1.804(3) Distances are in angstroms. Estimated standard deviations in the least significant figure are given in p'arentheses. Table A . l 4. Atomic Coordinates for *ra/ is-RuCl 2 (BESE) 2 atom Ru(l) Cl(l) S(f) S(2) 0(1) 0(2) C(l) C(2) C(3) C(4) 0.50000 0.55954(8) 0.49825(8) 0.72217(8) 0.4587(2) 0.8297(2) 0.6684(3) 0.7293(3) 0.4137(3) 0.2626(4) 0.50000 0.78088(9) 0.39123(9) 0.40991(9) 0.5070(3) 0.5363(3) 0.3216(4) 0.2437(4) 0.1865(4) 0.2098(5) 0.50000 0.57951(6) 0.66755(6) 0.54113(6) 0.7456(2) 0.5870(2) 0.7255(3) 0.6414(3) 0.6700(3) 0.6371(3) A.222 I. Appendix C(5) 0.7718(3) 0.2886(4) 0.4388(3) C(6) 0.9153(4) 0.2238(5) 0.4752(3) Appendix 1.2 Crystallographic Data for c/5-RuCl 2(BBSE) 2-EtOH Table A.1 5. Experimental Details for X-ray Crystal Structure of c/s-RuCl 2(BBSE) 2-EtOH A. Crystal Data Empirical Formula C 2 2H5oCl 20 5RuS4 Formula Weight 694.85 Crystal Colour, Habit yellow, prism Crystal Dimensions 0.50x0.35 x 0.20 mm Crystal System orthorhombic Lattice Type Primitive Lattice Parameters a= 16.1309(3) A b = 15.7775(7) A c = 24.9852(4) A V= 6358.9(5) A 3 Space Group Pbca (# 61) Z Value 8 Dca/c 1.452 g/cm3 Fooo 2912.00 /i(MoKa) 9.52 cm"1 B. Intensity Measurements Diffractometer Rigaku/ADSC CCD Radiation MoKa (X = 0.71069^) graphite monochromated Detector Aperature 94 mm x 94 mm Data Images 769 exposures of 25.0 seconds ^oscillation Range (% = -90) 0.0 - 190.2 ° co.oscillation Range (% = -90) -23 .0 -17 .8° Detector Position 39.21(2) mm Detector Swing Angle -10° 2$mor 60.1° No. of Reflections Measured Total: 58797 Unique: 8641 (R,„, = 0.036) Corrections Lorentz-polarization Absorption/scaling (trans, factors: 0.6880 - 1.0000) C. Structure Solution and Refinement Structure Solution Patterson Methods (DIRDIF92 PATTY) Refinement Full-matrix least-squares Function Minimized Sco(|Fo 2 | - |Fc 2 | ) 2 Least Squares Weights co = \la\Fo2) p-factor 0.0000 Anomalous Dispersion All non-hydrogen atoms No. Observations 8641 No. Variables 2317 Reflection/Parameter Ratio 27.26 Residuals (on F 2 , all data): R; Rw 0.067; 0.062 Goodness of Fit Indicator 1.75 No. Observations (I>3a(I)) 4889 A.223 Appendix Residuals (on F, I>3a(I)): R; Rw 0.040; 0.028 Max Shift/Error in Final Cycle 0.008 Maximum peak in Final Diff. Map 1.62 el A3 (near Ru) Minimum peak in Final Diff. Map -2.30 e'/A3 (near Ru) Table A . l 6. Bond Angles (°) for c/s-RuCl 2(BBSE) 2EtOH atom atom atom angle atom atom atom angle Cl(l) Ru(D Cl(2) 86.16(3) Cl(l) Ru(D S(l) 173.01(3) Cl(l) Ru(D S(2) 90.21(3) Cl(l) Ru(D S(3) 89.94(3) Cl(l) Ru(D S(4) 89.11(3) Cl(2) Ru(D S(l) 87.71(3) Cl(2) Ru(l) S(2) 88.99(3) Cl(2) Ru(l) S(3) 176.04(3) Cl(2) Ru(D S(4) 93.41(3) S(l) Ru(D S(2) 86.32(3) S(D Ru(D S(3) 96.22(3) S(l) Ru(l) S(4) 94.62(3) S(2) Ru(D S(3) 91.76(3) S(2) Ru(D S(4) 177.46(3) S(3) Ru(D S(4) 85.79(3) Ru(D S(D O(l) 116.88(9) Ru(l) S(D C(l) 104.36(11) Ru(l) S(l) C(3) 119.29(10) 0(1) S(D C(l) 107.40(13) 0(1) S(D C(3) 105.91(13) C(l) S(l) C(3) 101.28(14) Ru(l) S(2) 0(2) 117.32(9) Ru(l) S(2) C(2) 103.74(11) Ru(l) S(2) C(7) 115.81(12) 0(2) S(2) C(2) 108.17(13) 0(2) S(2) C(7) 107.82(15) C(2) S(2) C(7) 102.59(14) Ru(l) S(3) 0(3) 118.59(8) Ru(l) S(3) C(H) 105.92(10) Ru(l) S(3) C(13) 123.85(10) 0(3) S(3) C(ll) 107.06(15) 0(3) S(3) C(13) 108.12(14) C(ll) S(3) C(13) 101.69(15) Ru(l) S(4) 0(4) 118.37(10) Ru(l) S(4) C(12) 102.72(12) Ru(D S(4) C(17) 114.25(12) 0(4) S(4) C(12) 107.84(14) 0(4) S(4) C(17) 109.23(15) C(12) S(4) C(17) 102.8(2) S(D C(l) C(2) 110.0(2) S(2) C(2) C(l) 107.5(2) S(D C(3) C(4) 111.6(2) C(3) C(4) C(5) 112.4(3) C(4) C(5) C(6) 112.1(3) S(2) C(7) C(8) 111.5(2) C(7) C(8) C(9) 113.3(3) C(8) C(9) C(10) 113.0(4) S(3) C(ll) C(12) 112.2(3) S(4) C(12) C(H) 106.3(2) S(3) C(13) C(14) 113.2(2) C(13) C(14) C(15) 111.3(3) C(14) C(15) C(16) 117.7(5) C(14) C(15) C(16a) 125.2(6) S(4) C(17) C(18) 113.5(2) C(17) C(18) C(19) 111.0(3) C(18) C(19) C(20) 113.5(3) 0(5) C(21) C(22) 108.4(4) Angles are in degrees. Estimated standard deviations in the least significant figure are given in parentheses. Table A . l 7. Bond Lengths (A) for c«-RuCl 2(BBSE) 2EtOH atom atom distance Ru(l) Cl(l) 2.4159(8) Ru(l) Cl(2) 2.4288(7) Ru(l) S(l) 2.2906(8) Ru(D S(2) 2.3035(9) Ru(D S(3) 2.2674(7) Ru(D S(4) 2.2892(9) S(D 0(1) 1.480(2) S(l) C(l) 1.802(3) S(l) C(3) 1.804(3) S(2) 0(2) 1.482(2) S(2) C(2) 1.797(3) S(2) C(7) 1.791(3) atom atom distance 0(5) C(21) 1.402(4) C(l) C(2) 1.503(4) C(3) C(4) 1.516(4) C(4) C(5) 1.521(4) C(5) C(6) 1.522(5) C(7) C(8) 1.515(5) C(8) C(9) 1.504(5) C(9) C(10) 1.514(5) C(H) C(12) 1.501(5) C(13) C(14) 1.521(4) C(14) C(15) 1.511(5) C(15) C(16a) 1.35(1) A.224 I. Appendix S(3) 0(3) 1.468(2) C(15) C(16) 1.341(8) S(3) C(ll) 1.838(4) C(16a) C(16) 1.71(1) S(3) C(13) 1.794(3) C(17) C(18) 1.521(4) S(4) 0(4) 1.477(2) C(18) C(19) 1.503(4) S(4) C(12) 1.820(3) C(19) C(20) 1.511(5) S(4) C(17) 1.793(3) C(21) C(22) 1.420(6) Distances are in angstroms. Estimated standard deviations in the least significant figure are given in parentheses. Table A.1 8. Atomic Coordinates for c/s-RuCl 2(BBSE) 2-EtOH atom X y z atom X y z S(l) 0.51156(5) 0.15392(4) 0.43542(3) C(7) 0.6035(2) 0.1196(2) 0.60824(14) S(2) 0.55568(5) 0.18151(5) 0.55669(3) C(8) 0.5624(2) 0.1341(2) 0.6619(2) S(3) 0.60476(5) 0.33631(4) 0.47490(4) C(9) 0.6048(3) 0.0887(2) 0.7073(2) S(4) 0.70447(5) 0.21496(5) 0.40146(4) C(10) 0.5726(3) 0.1149(3) 0.7617(2) O(l) 0.51180(12) 0.06875(11) 0.41064(9) C(ll) 0.6678(2) 0.3771(2) 0.41934(14) 0(2) 0.52370(14) 0.26026(12) 0.58154(9) C(12) 0.7425(2) 0.3229(2) 0.40877(14) 0(3) 0.51937(13) 0.36492(11) 0.46570(10) C(13) 0.6458(2) 0.3944(2) 0.53062(14) 0(4) 0.66035(13) 0.20936(13) 0.34979(9) C(14) 0.6193(2) 0.4869(2) 0.5312(2) 0(5) 0.6514(2) -0.02427(14) 0.36083(10) C(15) 0.6423(4) 0.5293(2) 0.5833(2) C(l) 0.4335(2) 0.1536(2) 0.48702(13) C(16a) 0.7059(7) 0.5060(6) 0.6154(5) C(2) 0.4686(2) 0.1172(2) 0.53776(13) C(16) 0.6014(5) 0.5053(4) 0.6276(3) C(3) 0.4653(2) 0.2239(2) 0.38669(13) C(17) 0.7982(2) 0.1541(2) 0.39778(14) C(4) 0.3857(2) 0.1873(2) 0.36417(13) C(18) 0.8506(2) 0.1741(2) 0.34878(15) C(5) 0.3452(2) 0.2459(2) 0.32350(15) C(19) 0.9172(2) 0.1085(2) 0.3410(2) C(6) 0.2636(3) 0.2104(3) 0.3027(2) C(20) 0.9698(3) 0.1236(2) 0.2919(2) C(21) 0.6377(3) 0.0040(2) 0.3084(2) /' C(22) 0.6884(4) -0.0444(5) 0.2733(2) Table A.1 9. Hydrogen bond parameters for A - H . .B interactions. A' '' H B A....B A-H H....B A-H....B P(5) H(45) 0(1) 2.963(3) 0.90 2.12 155.7 0(5) H(45) Cl(2) 3.301(3) 0.90 2.71 124.1 C(12) H(26) 0(5) 3.189(4) 0.98 2.50 127.5 C(21) H(47) 0(4) 3.421(4) 0.98 2.55 148.5 A.225 I. Appendix Figure A . l . l . Stereoview of c/s-RuCl 2(BBSE) 2-EtOH. A.226 I. Appendix Appendix 1.3 Crystallographic Data for c«-RuCl 2 (BCySE) 2 -EtOH- l / 3 M e O H Table A . l 10. Experimental Details for X-ray Crystal Structure of cis-R u C l 2 ( B C y S E ) 2 - E t O H - l / 3 M e O H A. Crystal Data Empirical Formula C30.333H59.333CI2O5.333RUS4 Formula Weight 809.68 Crystal Colour, Habit yellow, hexagonal prism Crystal Dimensions 0.15 x 0.50x0.50 mm Crystal System trigonal Lattice Type Primitive Lattice Parameters a =23.2038(7) A c= 12.1481(2) A V = 5664.4(2) A 3 Space Group P 3 (# 147) Z Value 6 1.424 g/cm3 Fooo 2556.00 «(MoKa) 8.14 cm 1 B. Intensity Measurements Diffractometer Rigaku/ADSC CCD Radiation MoKa (k = 0.71069 A) graphite monochromated Detector Aperature 94 mm x 94 mm Data Images 768 exposures of 12.0 seconds $ oscillation Range (x = -90) 0.0 - 189.9° co oscillation Range (x = -90) -23 .0 -17 .8° Detector Position 39.23(3) mm Detector Swing Angle -10.0° 2 0max 60.1° No. of Reflections Measured Total: 51678 Unique: 10114 (R,„, = 0.050) Corrections Lorentz-polarization Absorption/scaling (trans, factors: 0.7224 - 1.0000) C. Structure Solution and Refinement Structure Solution Patterson Methods (DIRDIF92 PATTY) Refinement Full-matrix least-squares Function Minimized S c o ( | F o 2 | - | F c 2 | ) 2 Least Squares Weights co = \lo\F02) p-factor 0.0000 Anomalous Dispersion All non-hydrogen atoms No. Observations 10114 No. Variables 370 Reflection/Parameter Ratio 27.34 Residuals (on F 2 , all data): R; Rw 0.096; 0.090 Goodness of Fit Indicator 1.11 No. Observations (I>3a(I)) 3492 Residuals (on F, I>3a(I)): R; Rw 0.045; 0.041 Max Shift/Error in Final Cycle 0.0007 Maximum peak in Final Diff. Map 2.08 e'/A3 (at origin) 1" ' . A.227 I. Appendix Minimum peak in Final Diff. Map -1.64 e'/A3 Table A.1 11. Bond Angles (°) for c/s-RuCl2(BCySE)2-EtOH-l/3MeOH atom atom atom angle atom atom atom angle Cl(l) Ru(D Cl(2) 88.25(4) S(2) C(2) C(l) 106.7(4) Cl(l) Ru(l) S(l) 178.01(5) S(l) C(3) C(4) 113.4(4) Cl(l) Ru(l) S(2) 92.03(5) S(D C(3) C(8) 109.0(3) Cl(l) Ru(D S(3) 92.96(5) C(4) C(3) C(8) 109.9(4) Cl(l) Ru(D S(4) 87.61(5) C(3) C(4) C(5) 108.5(5) Cl(2) Ru(l) S(D 90.08(5) C(4) C(5) C(6) 110.1(5) Cl(2) Ru(l) S(2) 86.27(5) C(5) C(6) C(7) 109.4(5) Cl(2) Ru(l) S(3) 176.38(5) C(6) C(7) C(8) 111.7(5) Cl(2) Ru(l) S(4) 96.50(5) C(3) C(8) C(7) 112.0(5) Sd) Ru(l) S(2) 86.78(5) S(2) C(9) C(10) 106.3(3) S(D Ru(D S(3) 88.65(5) S(2) C(9) C(14) 112.3(4) S(l) Ru(l) S(4) 93.65(5) C(10) C(9) C(14) 111.7(4) S(2) Ru(D S(3) 90.28(5) C(9) C(10) C(ll) 109.9(4) S(2) Ru(D S(4) 177.19(5) C(10) C(ll) C(12) 112.7(6) S(3) Ru(l) S(4) 86.96(5) C(ll) C(12) C(13) 110.4(5) Ru(l) S(D 0(1) 119.2(1) C(12) C(13) C(14) 113.3(5) Ru(l) S(D C(l) 102.8(2) C(9) C(14) C(13) 110.5(5) Ru(l) S(l) C(3) . 118.2(2) S(3) C(15) C(16) 109.6(3) 0(1) S(l) C(l) 107.8(2) S(4) C(16) C(15) 108.8(4) O(l) S(D C(3) 106.5(2) S(3) C(17) C(18) 112.0(4) C(l) S(D C(3) 100.0(2) S(3) C(17) C(22) 108.4(4) Ru(l) S(2) 0(2) 118.2(2) C(18) C(17) C(22) 108.5(5) Ru(D S(2) C(2) 101.5(2) C(17) C(18) C(19) 110.1(6) Ru(l) S(2) C(9) 116.0(2) C(18) C(19) C(20) 107.3(7) 0(2) S(2) C(2) 107.6(3) C(19) C(20) C(21) 107.7(7) 0(2) S(2) C(9) 107.6(2) C(20) C(21) C(22) 106.2(7) C(2) S(2) C(9) 104.5(2) C(17) C(22) C(21) 107.1(5) Ru(D S(3) 0(3) 117.5(2) S(4) C(23) C(24) 108.7(4) Ru(D S(3) C(15) 104.3(2) S(4) C(23) C(28) 112.1(4) Ru(l) S(3) C(17) 117.8(2) C(24) C(23) C(28) 111.5(5) 0(3) S(3) C(15) 106.8(2) C(23) C(24) C(25) 109.6(6) 0(3) S(3) C(17) 106.7(2) C(24) C(25) C(26) 109.5(6) C(15) S(3) C(17) 102.1(2) C(25) C(26) C(27) 110.5(6) Ru(D S(4) 0(4) 119.8(2) C(26) C(27) C(28) 110.6(7) Ru(D S(4) C(16) 102.6(2) C(23) C(28) C(27) 110.5(5) Ru(D S(4) C(23) 116.4(2) 0(5) C(29) C(30) 124(2) 0(4) S(4) C(16) 106.5(2) 0(4) S(4) C(23) 107.9(2) C(16) S(4) C(23) 101.3(3) S(l) C(l) C(2) 109.5(3) Angles are in degrees. Estimated standard deviations in the least significant figure are given in parentheses. Table A.l 12. Bond Lengths (A) for c/5-RuCl2(BCySE)2-EtOH-l/3MeOH atom atom distance atom atom distance Ru(l) Cl(l) 2.420(1) C(5) C(6) 1.555(8) Ru(l) Cl(2) 2.434(1) C(6) C(7) 1.506(8) Ru(l) S(l) 2.299(1) C(7) C(8) 1.532(7) Ru(l) S(2) 2.336(1) C(9) C(10) 1.547(6) Ru(D S(3) 2.272(1) C(9) C(14) 1.530(7) A.228 I. Appendix R u ( l ) S(4) 2.348(1) C(10) C ( l l ) 1.528(7) SO) 0(1) 1.470(3) C ( l l ) C(12) 1.503(8) S ( l ) C ( l ) 1.815(5) C(12) C(13) 1.486(8) S ( l ) C(3) 1.835(5) C(13) C(14) 1.526(7) S(2) 0 (2 ) 1.444(4) C(15) C(16) 1.494(7) S(2) C(2) 1.782(5) C(17) C(18) 1.497(7) S(2) C(9) 1.842(5) C(17) C(22) 1.530(7) S(3) 0 (3 ) 1.470(3) C(18) C(19) 1.585(8) S(3) C(15) 1.814(5) C(19) C(20) 1.55(1) S(3) C(17) 1.837(5) C(20) C(21) 1.454(9) S(4) 0(4 ) 1.464(4) C(21) C(22) 1.662(9) S(4) C(16) 1.821(5) C(23) C(24) 1.523(7) S(4) C(23) 1.812(5) C(23) C(28) 1.496(7) 0 (5 ) C(29) 1.39(2) C(24) C(25) 1.569(9) 0 (6 ) C(31) 1.57(2) C(25) C(26) 1.527(9) C ( l ) C(2) 1.508(7) C(26) C(27) 1.496(9) C(3) C(4) 1.497(7) C(27) C(28) 1.560(9) C(3) C(8) 1.531(6) C(29) C(30) 1.24(2) C(4) C(5) 1.549(7) Distances are i n angstroms. Estimated standard deviations i n the least significant f igure are given i n parentheses. Table A.1 13. Atomic Coordinates for czs-RuCl 2(BCySE) 2EtOH-l/3MeOH atom X y z atom x y z R u ( l ) 0.23894(2) 0.40975(2) 0.49281(3) C(10) 0.3571(3) 0.4190(3) 0.7646(4) C l ( l ) 0.21241(7) 0.31625(6) 0.61228(10) C ( l l ) 0.4029(3) 0.3959(4) 0.8134(5) Cl(2) 0.31782(6) 0.38685(6) 0.39821(9) C(12) 0.4741(4) 0.4511(4) 0.8205(5) S ( l ) 0.26788(6) 0.49927(6) 0.37892(10) C(13) 0.4987(3) 0.4810(3) 0.7102(6) S(2) 0.32838(6) 0.48219(6) 0.60370(10) C(14) 0.4564(3) 0.5066(3) 0.6565(5) S(3) 0.17089(6) 0.43702(7) 0.58553(11) C(15) 0.0964(2) 0.4035(3) 0.5014(4) S(4) 0.14555(7) 0.33764(7) 0.38722(11) C(16) 0.0771(2) 0.3346(3) 0.4654(4) 0 (1 ) 0.2173(2) 0.5169(2) 0.3487(3) C(17) 0.1375(3) 0.3963(3) 0.7186(4) 0 (2 ) 0.3151(2) 0.5122(2) 0.6972(4) C(18) 0.1914(3) 0.4139(3) 0.8019(6) 0 (3 ) 0.1940(2) 0.5081(2) 0.6011(3) C(19) 0.1603(4) 0.3771(5) 0.9147(5) 0 (4 ) 0.1390(2) 0.3560(2) 0.2745(3) C(20) 0.1134(5) 0.4019(5) 0.9561(6) 0 (5 ) -0.0396(9) 0.1081(9) 0.0229(12) C(21) 0.0582(4) 0.3786(5) 0.8790(6) 0 (6 ) 0.3333 0.6667 -0.3194(14) C(22) 0.0903(4) 0.4192(4) 0.7620(5) C ( l ) 0.3323(3) 0.5682(2) 0.4568(4) C(23) 0.1229(3) 0.2507(3) 0.3868(4) C(2) 0.3778(3) 0.5470(2) 0.5090(4) C(24) 0.1713(3) 0.2424(3) 0.3130(6) C(3) 0.3140(2) 0.5057(2) 0.2525(4) C(25) 0.1537(4) 0.1677(4) 0.3138(7) C(4) 0.2770(3) 0.4482(3) 0.1758(4) C(26) 0.0818(4) 0.1235(3) 0.2762(6) G(5) 0.3223(4) 0.4576(3) 0.0757(5) C(27) 0.0352(4) 0.1322(4) 0.3504(7) C(6) 0.3385(4) 0.5223(3) 0.0125(5) C(28) 0.0523(3) 0.2063(3) 0.3517(6) C(7) 0.3724(3) 0.5810(3) 0.0893(5) C(29) 0.0655(10) 0.1469(12) 0.0605(15) C(8) 0.3313(3) 0.5708(3) 0.1938(4) C(30) -0.0334(7) 0.2087(8) 0.0633(10) C(9) 0.3836(2) 0.4513(3) 0.6507(4) C(31) 0.3333 0.6667 -0.190(2) Table A . l 14. Hydrogen bond structural parameters for A - H . . .B interactions. A H B A . . . . B A - H H.. . .B A - H . . . . B 0 (5 ) H(58) 0 (5 ) 3.12(2) 0.95 2.23 156.6 A .229 I. Appendix Figure A.1.2. Stereoview of cw-RuCl2(BCySE)2-EtOH-l/3MeOH. A.230 I. Appendix Appendix 1.4 Crystallographic Data for c/s-RuCl2(BESP)2-EtOH-H20 Table A . l 15. Experimental Details for X-ray Crystal Structure of cis-RuCl 2(BESP) 2EtOHH 20 A. Crystal Data Empirical Formula Ci 6H40CI2RUS4 Formula Weight 628.70 Crystal Colour, Habit yellow, plate Crystal Dimensions 0.05x0.20x0.35 mm Crystal System monoclinic Lattice Type Primitive Lattice Parameters a= 10.1443(7) A b = 21.287(3) A c= 11.9548(4) A P = 98.8216(9)0 V = 2551.0(3) A 3 Space Group P2,/a (# 14) Z Value 4 D c f l/C 1.637 g/cm3 Fooo 1304.00 MMoKa) 11.80 cm"1 B. Intensity Measurements Diffractometer Rigaku/ADSC CCD Radiation MoKoc (A, = 0.71069 A) graphite monochromated Detector Aperature 94 mm x 94 mm Data Images 462 exposures of 70.0 seconds 0 oscillation Range (% = "9 0) 0.0 -190.0 0 ro oscillation Range (% = -90) -23 .0 -18 .0° Detector Position 39.21(3) mm Detector Swing Angle -10° 60.1° No. of Reflections Measured Total: 21407 Unique: 6125 (R,„, = 0.037) Corrections Lorentz-polarization Absorption/scaling (trans, factors: 0.7749 - 1.0000) C. Structure Solution and Refinement Structure Solution Patterson Methods (DIRDIF92 PATTY) Refinement Full-matrix least-squares Function Minimized Eco( |Fo 2 | - |Fc 2 | ) 2 Least Squares Weights co = l/a2(Fo2) p-factor 0.0000 Anomalous Dispersion All non-hydrogen atoms No. Observations 6125 No. Variables 262 Reflection/Parameter Ratio 23.38 Residuals (on F 2 , all data): R; Rw 0.072; 0.065 Goodness of Fit Indicator 1.77 No. Observations (I>3a(I)) 4104 Residuals (on F, I>3a(I)): R; Rw 0.038; 0.031 A.231 I. Appendix Max Shift/Error in Final Cycle 0.002 Maximum peak in Final Diff. Map 1.56 e'lA3 Minimum peak in Final Diff. Map -1.46 elA3 Table A . l 16. Bond Angles (°) for cz5-RuCl 2(BESP)2-EtOH-H 20 atom atom atom angle atom atom atom angle Cl(l) Ru(l) Cl(2) 89.53(3) 0(2) S(2) C(6) 107.7(2) Cl(l) Ru(D S(D 176.35(4) C(3) S(2) C(6) 100.9(2) Cl(l) Ru(D S(2) 91.89(3) Ru(l) S(3) 0(3) 116.3(1) Cl(l) Ru(D S(3) 86.89(3) Ru(l) S(3) C(8) 112.7(1) Cl(l) Ru(l) S(4) 88.90(3) Ru(l) S(3) C(ll) 113.8(1) Cl(2) Ru(D SU) 92.94(3) 0(3) S(3) C(8) 107.3(2) Cl(2) Ru(l) S(2) 86.72(4) 0(3) S(3) C(ll) 106.7(2) Cl(2) Ru(D S(3) 175.56(3) C(8) S(3) C(ll) 98.4(2) Cl(2) Ru(D S(4) 84.96(3) Ru(D S(4) 0(4) 113.4(1) S(D Ru(l) S(2) 90.94(3) Ru(l) S(4) C(10) 115.8(1) S(l) Ru(l) S(3) 90.76(3) Ru(D S(4) C(13) 112.2(1) S(D Ru(D S(4) 88.63(3) 0(4) S(4) C(10) 107.2(2) S(2) Ru(l) S(3) 90.78(4) 0(4) S(4) C(13) 107.8(2) S(2) Ru(D S(4) 171.64(4) C(10) S(4) C(13) 99.4(2) S(3) Ru(l) S(4) 97.57(4) S(l) C(l) C(2) 116.5(3) Ru(l) S(D 0(1) 115.8(1) C(l) C(2) C(3) 117.1(3) Ru(l) S(D C(l) 109.5(1) S(2) C(3) C(2) 112.9(3) Ru(l) S(D C(4) 115.1(1) S(D C(4) C(5) 111.9(3) O(l) S(D C(l) 106.3(2) S(2) C(6) C(7) 112.8(3) 0(1) S(D C(4) 106.4(2) S(3) C(8) C(9) 112.4(2) C(l) S(D C(4) 102.5(2) C(8) C(9) C(10) 111.7(3) Ru(D S(2) 0(2) 117.9(1) S(4) C(10) C(9) 113.3(3) Ru(l) S(2) C(3) 109.0(1) S(3) C(ll) C(12) 112.2(3) Ru(l) S(2) C(6) 112.5(1) S(4) C(13) C(14) 112.7(3) 0(2) S(2) C(3) 107.4(2) 0(5) C(15) C(16) 111.8(5) Angles are in degrees. Estimated standard deviations in the least significant figure are given in parentheses. Table A.1 17. Bond Lengths (A) for c/s-RuCl 2(BESP) 2EtOHH 20 atom atom distance atom atom distance Ru(D Cl(l) 2.4167(8) S(3) C(ll) 1.820(3) Ru(l) Cl(2) 2.431(1) S(4) 0(4) 1.489(2) Ru(D S(D 2.2766(8) S(4) C(10) 1.806(4) Ru(l) S(2) 2.331(1) S(4) C(13) 1.792(4) Ru(l) S(3) 2.291(1) 0(5) C(15) 1.376(7) Ru(D S(4) 2.353(1) C(l) C(2) 1.547(5) S(l) 0(1) 1.481(3) C(2) C(3) 1.536(5) S(l) C(l) 1.799(4) C(4) C(5) 1.529(5) S(D C(4) 1.791(4) C(6) C(7) 1.500(5) S(2) 0(2) 1.490(3) C(8) C(9) 1.524(5) S(2) C(3) 1.789(4) C(9) C(10) 1.513(5) S(2) C(6) 1.808(4) C(H) C(12) 1.484(6) S(3) 0(3) 1.479(2) C(13) C(14) 1.527(5) S(3) C(8) 1.802(4) C(15) C(16) 1.533(9) i Distances are in angstroms. Estimated standard deviations in the least significant figure are given in ! parentheses. A.232 I. Appendix Table A . l 18. Atomic Coordinates for c / s -RuCl 2 (BESP) 2 -E tOH-H 2 0 atom X y z Ru(D 0.71815(2) 0.402560(14) 0.29850(3) Cl(l) 0.95155(7) 0.38026(4) 0.36032(8) Cl(2) 0.69663(8) 0.43432(5) 0.49019(8) S(l) 0.49722(8) 0.41752(4) 0.23460(8) S(2) 0.76308(8) 0.50771(4) 0.26506(8) S(3) 0.75461(8) 0.37600(5) 0.12011(8) S(4) 0.66649(8) 0.30141(4) 0.35820(8) O(l) 0.4294(2) 0.36644(12) 0.1637(2) 0(2) 0.7842(2) 0.52583(12) 0.1487(2) 0(3) 0.6513(2) 0.39595(12) 0.0257(2) 0(4) 0.5257(2) 0.29492(12) 0.3781(2) 0(5) 0.6262(4) 0.7273(3) 0.1793(4) C(l) 0.4757(3) 0.4876(2) 0.1497(4) C(2) 0.5028(3) 0.5507(2) 0.2133(4) C(3) 0.6301(3) 0.5551(2) 0.3009(3) C(4) 0.3968(3) 0.4333(2) 0.3422(3) C(5) 0.2504(3) 0.4437(2) 0.2923(4) C(6) 0.9023(3) 0.5377(2) 0.3631(4) C(7) 0.9526(3) 0.5995(2) 0.3264(3) C(8) 0.7799(3) 0.2929(2) 0.1044(4) C(9) 0.6688(3) 0.2538(2) 0.1422(4) C(10) 0.6991(3) 0.2376(2) 0.2667(3) C(H) 0.9138(3) 0.4035(2) 0.0863(3) C(12) 0.9155(4) 0.4056(3) -0.0375(4) C(13) 0.7726(3) 0.2781(2) 0.4853(3) C(14) 0.7393(4) 0.2127(2) 0.5254(4) C(15) 0.4890(7) 0.7293(3) 0.1638(6) C(16) 0.4339(5) 0.7166(3) 0.2741(6) Table A . 1 19. Hydrogen bond structural parameters for A - H . . .B interactions. A H B A....B A-H H....B A-H....B C(16) H(36) 0(5) 3.374(7) 0.98 2.47 152.9 0(5) H(38) 0(6) 2.755(6) 0.95 1.83 165.2 0(6) H(39) 0(2) 2.814(4) 0.95 1.95 150.3 0(6) H(40) 0(1) 2.752(4) 0.95 1.83 165.2 Appendix 1.5 Crystallographic Data for [RuCl (BESE)(H 2 0) ] 2 ( / / -C l ) 2 -H 2 0 t,. z -Table A . l 20. Experimental Details for X-ray Crystal Structure of [RuCl(BESE)(H 2 0) ] 2 ( / / -C l j 2 - H 2 0 I A: Crystal Data Empirical Formula C] 2H34CI4O7RU2S4 Formula Weight 762.59 Crystal Colour, Habit orange, prism Crystal Dimensions 0.25x0.20x0.10 mm Crystal System triclinic Lattice Type Primitive Lattice Parameters a= 10.2101(6) A A.233 I. Appendix b = 10.8016(10) A c= 13.391(2) A a = 93.968(3)0 P = 97.099(2)0 y= 117.5490(9)° V= 1285.9(2) A 3 Space Group PI (#2) Z Value 2 D c a / C 1.969 g/cm3 Fooo 764.00 #(MoKoc) 19.45 cm-1 B. Intensity Measurements Diffractometer Rigaku/ADSC CCD Radiation MoKa (X = 0.71069.4") graphite monochromated Detector Aperature 94 mm x 94 mm Data Images 462 exposures of 16.0 seconds <j> oscillation Range (% = -90) 0 .0 -190 .0° co oscillation Range (x = -90) -23 .0 -18 .0° Detector Position 38.845(7) mm Detector Swing Angle -10.0° 61.1° No. of Reflections Measured Total: 11840 Unique: 5905 (R,nI = 0.035) Corrections Lorentz-polarization Absorption/scaling (trans, factors: 0.8181 - 1.0000) C. Structure Solution and Refinement Structure Solution Direct Methods (SIR97) Refinement Full-matrix least-squares Function Minimized Zco(Fo2-Fc2)2 Least Squares Weights co = l/a2(Fo) p-factor 0.0000 Anomalous Dispersion All non-hydrogen atoms No. Observations 5905 No. Variables 262 Reflection/Parameter Ratio 22.54 Residuals (on F 2 , all data): R; Rw 0.056; 0.064 Goodness of Fit Indicator 1.10 No. Observations (I>3a(I)) 4055 Residuals (on F, I>3a(I)): R; Rw 0.029; 0.031 Max Shift/Error in Final Cycle 0.0016 Maximum peak in Final Diff. Map 1.33 e7i3(1.8 A from 0(7)) Minimum peak in Final Diff. Map -1.33 elA3 Table A . l 21. Bond Angles (°) for [RuCl(BESE)(H 20)]2(/i-Cl) 2-H 20 atom atom atom angle atom atom atom angle Cl(l) Ru(l) Cl(l) 82.11(3) Ru(l) S(l) 0(1) 118.5(1) Cl(l) Ru(l) Cl(2) 171.77(4) Ru(l) S(l) C(l) 105.6(1) Cl(l) Ru(D S(D 92.56(4) Ru(l) S(l) C(3) 114.3(1) ci(i) Ru(l) S(2) 93.31(4) 0(1) S(D C(l) 106.8(2) A.234 I. Appendix Cl(l) Ru(l) 0(3) 86.53(8) 0(1) S(D C(3) 107.4(2) Cl(l) Ru(l) Cl(2) 91.93(3) C(l) S(D C(3) 102.9(2) Cl(l) Ru(l) S(l) 174.31(4) Ru(l) S(2) 0(2) 119.2(1) Cl(l) Ru(D S(2) 95.11(3) Ru(D S(2) C(2) 107.4(1) Cl(l) Ru(l) 0(3) 86.83(8) Ru(l) S(2) C(5) 116.7(1) Cl(2) Ru(D S(l) 93.17(4) 0(2) S(2) C(2) 107.2(2) Cl(2) Ru(D S(2) 92.87(4) 0(2) S(2) C(5) 104.9(2) Cl(2) Ru(l) 0(3) 87.48(8) C(2) S(2) C(5) 99.3(2) S(D Ru(D S(2) 87.15(4) Ru(2) S(3) 0(4) 117.3(1) S(l) Ru(D 0(3) 90.88(8) Ru(2) S(3) C(7) 105.3(2) S(2) Ru(l) 0(3) 178.01(8) Ru(2) S(3) C(9) 115.5(2) Cl(3) Ru(2) Cl(3) 83.17(3) 0(4) S(3) C(7) 106.6(2) Cl(3) Ru(2) Cl(4) 171.20(4) 0(4) S(3) C(9) 107.2(2) Cl(3) Ru(2) S(3) 92.98(4) C(7) S(3) C(9) 103.7(2) Cl(3) Ru(2) S(4) 94.74(4) Ru(2) S(4) 0(5) 120.8(1) Cl(3) Ru(2) 0(6) 87.33(7) Ru(2) S(4) C(8) 106.7(2) Cl(3) Ru(2) Cl(4) 92.49(3) Ru(2) S(4) C(ll) 116.4(2) Cl(3) Ru(2) S(3) 176.04(3) 0(5) S(4) C(8) 106.8(2) Cl(3) Ru(2) S(4) 94.09(4) 0(5) S(4) C(H) 104.7(2) Cl(3) Ru(2) 0(6) 86.26(8) C(8) S(4) C(ll) 98.8(2) Cl(4) Ru(2) S(3) 91.21(4) S(D C(l) C(2) 106.3(3) Cl(4) Ru(2) S(4) 93.19(4) S(2) C(2) C(l) 108.6(3) Cl(4) Ru(2) 0(6) 84.74(7) S(l) C(3) C(4) 111.6(3) S(3) Ru(2) S(4) 87.10(4) S(2) C(5) C(6) 110.9(3) S(3) Ru(2) 0(6) 92.68(8) S(3) C(7) C(8) 106.1(3) S(4) Ru(2) 0(6) 177.92(8) S(4) C(8) C(7) 109.3(3) Ru(l) Cl(l) Ru(l) 97.89(3) S(3) C(9) C(10) 114.1(4) Ru(2) Cl(3) Ru(2) 96.83(3) S(4) C(H) C(12) 111.6(3) Angles are in degrees. Estimated standard deviations in the least significant figure are given in parentheses. Table A . l 22 . Bond Lengths (A) for [RuCl(BESE)(H 20)] 2(//-Cl) 2-H 20 atom atom distance atom atom distance Ru(l) Cl(l) 2.410(1) S(2) 0(2) 1.496(2) Ru(l) Cl(l) 2.464(1) S(2) C(2) 1.805(4) Ru(l) Cl(2) 2.401(1) S(2) C(5) 1.805(4) Ru(D S(l) 2.199(1) S(3) 0(4) 1.482(3) Ru(D S(2) 2.196(1) S(3) C(7) 1.800(5) Ru(l) 0(3) 2.140(3) S(3) C(9) 1.776(5) Ru(2) Cl(3) 2.426(1) S(4) 0(5) 1.483(3) Ru(2) Cl(3) 2.468(1) S(4) C(8) 1.813(4) Ru(2) Cl(4) 2.3748(9) S(4) C(ll) 1.807(4) Ru(2) S(3) 2.198(1) C(l) C(2) 1.531(5) Ru(2) S(4) 2.193(1) C(3) C(4) 1.518(6) Ru(2) 0(6) 2.155(3) C(5) C(6) 1.514(6) S(l) 0(1) 1.475(3) C(7) C(8) 1.505(7) S(D C(l) 1.803(5) C(9) C(10) 1.512(6) S(D C(3) 1.803(4) C(ll) C(12) 1.519(7) ! Distances are in angstroms. Estimated standard deviations in the least significant figure are given in j parentheses. i < ' A.235 I. Appendix Table A.1 23. Atomic Coordinates for [RuCi(BESE)(H 20)] 2(//-Ci) 2-H 20 atom X y z Ru(l) 0.05846(3) 0.86283(4) 0.49128(2) Ru(2) 0.36391(3) 0.32199(4) 0.01720(2) Cl(l) 0.11786(10) 1.08352(11) 0.42905(7) Cl(2) 0.00001(10) 0.65984(11) 0.57629(8) Cl(3) 0.63194(10) 0.47823(11) 0.06388(7) Cl(4) 0.10770(10) 0.17152(12) -0.05468(8) S(D 0.22818(10) 0.83737(11) 0.41901(8) S(2) -0.10391(10) 0.73688(11) 0.35331(7) S(3) 0.37718(10) 0.15122(12) 0.09048(8) S(4) 0.31050(11) 0.38575(12) 0.15921(8) O(l) 0.3270(3) 0.9524(3) 0.3673(2) 0(2) -0.1954(3) 0.7945(3) 0.2980(2) 0(3) 0.2228(3) 0.9857(3) 0.6232(2) 0(4) 0.5277(3) 0.1770(4) 0.1391(3) 0(5) 0.4005(3) 0.5318(3) 0.2135(2) 0(6) 0.4079(3) 0.2538(3) -0.1240(2) 0(7) 0.7793(4) 0.1666(4) 0.2242(3) C(l) 0.1245(4) 0.6835(5) 0.3239(3) C(2) -0.0018(4) 0.7019(5) 0.2643(3) C(3) 0.3461(4) 0.7893(5) 0.5009(3) C(4) 0.4531(5) 0.7634(5) 0.4443(4) C(5) -0.2370(4) 0.5578(5) 0.3635(3) C(6) -0.3482(4) 0.5549(5) 0.4295(3) C(7) 0.2677(4) 0.1252(5) 0.1901(3) C(8) 0.3206(5) 0.2694(5) 0.2476(3) C(9) 0.2894(5) -0.0166(5) 0.0138(4) C(10) 0.2983(6) -0.1321(6) 0.0672(4) C(ll) 0.1177(5) 0.3463(6) 0.1570(4) C(12) 0.0762(6) 0.4368(6) 0.0919(4) Table A . l 24. Hydrogen bond parameters for A-H.. .B interactions. A H B A....B A-H H....B A-H....B 0(7) H(33) 0(4) 2.733(4) 0.92 1.81 179.6 0(7) H(34) Cl(2) 3.105(4) 0.89 2.28 152.8 A.236 I. Appendix Figure A.1.3. Stereoview of [RuCl(BESE)(H 2 0)] 2 (/ /-Cl) 2 -H 2 0. A . 2 3 7 I. Appendix Appendix 1.6 Crystallographic Data for [RuCl(BPSP)]2C"-Cl) 3-2H 20-2.5CH 2Cl 2 Table A . l 25. Experimental Details for X-ray Crystal Structure of [RUC1(BPSP ) ] 2 ( /J-C1 ) 3 -2H 2 0 -2 .5CH 2 C1 2 A. Crystal Data Empirical Formula C20.50H49O10O6PvU2S4 Formula Weight 1076.52 Crystal Colour, Habit orange, plate Crystal Dimensions 0.10x0.20x0.40 mm Crystal System monoclinic Lattice Type Primitive Lattice Parameters a= 10.5354(4) A b= 15.8739(11) A c = 24.6983(4) A P = 96.6438(6) 0 V = 4102.8(3) A 3 Space Group Pn (# 7) Z Value 4 D^ a/c 1.743 g/cm3 Fooo 2168.00 ^(MoKa) 16.22 cm"1 B. Intensity Measurements Diffractometer Rigaku/ADSC CCD Radiation MoKa (k = 0.71069.4°) graphite monochromated Detector Aperature 94 mm x 94 mm Data Images 766 exposures of 70.0 seconds ^ oscillation Range (% = -90) -22.0 -17.9 0 co oscillation Range (% = -90) 0.0 -190.2 0 Detector Position 39.18(1) mm Detector Swing Angle -10° 2dmax 60.1° No. of Reflections Measured Total: 37619 Unique: 10572 (R,„, = 0.045) Corrections Lorentz-polarization Absorption/scaling (trans, factors: 0.7434 - 1.0016) C. Structure Solution and Refinement Structure Solution Patterson Methods (DIRDIF92 PATTY) Refinement Full-matrix least-squares Function Minimized E C O ( | F O 2 | - | F C 2 | ) 2 Least Squares Weights CO = l/a2(Fo2) = [a2(Fo2) + p\Fo2)\l p-factor 0.0000 Anomalous Dispersion All non-hydrogen atoms No. Observations (Including Friedel pairs) 16879 No. Variables 785 Reflection/Parameter Ratio 21.50 Residuals (on F 2 , all data): R; Rw 0.077; 0.088 Goodness of Fit Indicator 1.75 No. Observations (I>3a(I)) 13319 Residuals (on F, I>3CT(I)): Rl ; Rlw 0.040; 0.042 Max Shift/Error in Final Cycle 0.02 A.238 I. Appendix Maximum peak in Final Diff. Map 1.65 elA3 (nearRu) Minimum peak in Final Diff. Map -2.96 eTi 3 (near Ru) Table A . l 26. Bond Angles (°) for [RuCl(BPSP)] 2(>Cl)3-2H 20-2.5CH 2Cl 2 atom atom atom angle atom atom atom angle Cl(l) Ru(D Cl(2) 81.46(5) Cl(5) Ru(2) S(4) 91.93(6) Cl(l) Ru(l) Cl(3) 82.63(5) S(3) Ru(2) S(4) 88.48(6) Cl(l) Ru(l) Cl(4) 170.87(5) Cl(6) Ru(3) Cl(7) 82.65(5) Cl(l) Ru(l) S(D 92.33(5) Cl(6) Ru(3) Cl(8) 80.76(5) Cl(l) Ru(l) S(2) 94.19(6) Cl(6) Ru(3) Cl(9) 168.66(6) Cl(2) Ru(D Cl(3) 79.33(5) Cl(6) Ru(3) S(5) 97.29(5) Cl(2) Ru(D Cl(4) 91.09(5) Cl(6) Ru(3) S(6) 92.47(5) Cl(2) Ru(D S(D 172.11(6) Cl(7) Ru(3) Cl(8) 79.74(5) Cl(2) Ru(l) S(2) 95.78(6) Cl(7) Ru(3) Cl(9) 87.63(6) Cl(3) Ru(D Cl(4) 90.83(5) Cl(7) Ru(3) S(5) 174.70(6) Cl(3) Ru(D S(l) 95.11(6) Cl(7) Ru(3) S(6) 96.05(6) Cl(3) Ru(l) S(2) 174.50(6) Cl(8) Ru(3) Cl(9) 91.80(5) Cl(4) Ru(l) S(l) 94.61(5) Cl(8) Ru(3) S(5) 95.00(6) Cl(4) Ru(D S(2) 91.80(6) Cl(8) Ru(3) S(6) 172.40(6) S(D Ru(l) S(2) 89.49(6) Cl(9) Ru(3) S(5) 91.86(6) Cl(l) Ru(2) Cl(2) 81.70(5) Cl(9) Ru(3) S(6) 94.36(6) Cl(l) Ru(2) Cl(3) 82.46(5) S(5) Ru(3) S(6) 89.25(6) Cl(l) Ru(2) Cl(5) 169.83(6) Cl(6) Ru(4) Cl(7) 82.08(5) Cl(l) Ru(2) S(3) 94.70(5) Cl(6) Ru(4) Cl(8) 80.66(5) Cl(l) Ru(2) S(4) 92.71(6) Cl(6) Ru(4) Cl(10) 170.20(5) Cl(2) Ru(2) Cl(3) 79.21(5) Cl(6) Ru(4) S(7) 92.63(5) Cl(2) Ru(2) Cl(5) 88.73(6) Cl(6) Ru(4) S(8) 96.27(6) Cl(2) Ru(2) S(3) 173.16(5) Cl(7) Ru(4) Cl(8) 79.79(5) Cl(2) Ru(2) S(4) 97.46(6) Cl(7) Ru(4) Cl(10) 90.10(5) Cl(3) Ru(2) Cl(5) 92.42(5) Cl(7) Ru(4) S(7) 173.01(6) Cl(3) Ru(2) S(3) 94.59(6) Cl(7) Ru(4) S(8) 93.86(6) Cl(3) Ru(2) S(4) 174.46(6) Cl(8) Ru(4) Cl(10) 92.19(6) Cl(5) Ru(2) S(3) 94.47(6) Cl(8) Ru(4) S(7) 94.89(6) Cl(8) Ru(4) S(8) 173.25(6) Ru(3) S(6) C(25) 113.9(2) Cl(10) Ru(4) S(7) 94.66(6) 0(6) S(6) C(21) 104.3(3) Cl(10) Ru(4) S(8) 90.12(6) 0(6) S(6) C(25) 106.2(3) S(7) Ru(4) S(8) 91.24(6) C(21) S(6) C(25) 102.0(3) Ru(l) Cl(l) Ru(2) 85.01(5) Ru(4) S(7) 0(7) 117.4(2) Ru(l) Cl(2) Ru(2) 81.26(5) Ru(4) S(7) C(28) 112.4(2) Ru(l) Cl(3) Ru(2) 81.45(5) Ru(4) S(7) C(31) 115.8(2) Ru(3) Cl(6) Ru(4) 84.69(5) 0(7) S(7) C(28) 104.5(3) Ru(3) Cl(7) Ru(4) 82.61(5) 0(7) S(7) C(31) 104.3(3) Ru(3) Cl(8) Ru(4) 81.25(5) C(28) S(7) C(31) 100.5(3) Cl(17a Cl(17) C(40) 73.1(8) Ru(4) S(8) 0(8) 118.4(2) Cl(17) Cl(17a C(40) 70.8(8) Ru(4) S(8) C(30) 112.7(2) Cl(18) Cl(18a C(40) 86(1) Ru(4) S(8) C(34) 111.4(2) Cl(18a Cl(18) C(40) 47.5(7) 0(8) S(8) C(30) 105.7(3) Cl(19) Cl(19a Cl(20) 129.5(7) 0(8) S(8) C(34) 107.0(3) Cl(19) Cl(19a C(41) 81.4(7) C(30) S(8) C(34) 99.9(3) Cl(20) Cl(19a C(41) 53.1(4) S(l) C(l) C(2) 109.5(4) Cl(19a Cl(19) C(41) 64.6(6) C(l) C(2) C(3) 115.0(5) Cl(20) Cl(20a C(41) 50.0(4) S(2) C(3) C(2) 111.3(4) A.239 I. Appendix Cl(19a Cl(20) Cl(20a 85.7(4) S(D C(4) C(5) 117.6(5) Cl(19a Cl(20) C(41) 50.7(4) C(4) C(5) C(6) 110.2(7) Cl(20a Cl(20) C(41) 58.8(4) S(2) C(7) C(8) 113.9(5) Ru(D S(D 0(1) 117.1(2) C(7) C(8) C(9) 112.9(6) Ru(l) S(l) C(l) 112.3(2) S(3) C(10) C(ll) 109.8(4) Ru(D S(D C(4) 115.3(2) C(10) C(ll) C(12) 116.2(5) O(l) S(l) C(l) 105.1(3) S(4) C(12) C(ll) 109.8(4) 0(1) S(l) C(4) 104.5(3) S(3) C(13) C(14) 117.0(5) C(l) S(D C(4) 100.9(3) C(13) C(14) C(15) 109.0(6) Ru(D S(2) 0(2) 118.6(2) S(4) C(16) C(17) 111.6(4) Ru(D S(2) C(3) 111.9(2) C(16) C(17) C(18) 112.0(5) Ru(D S(2) C(7) 112.7(2) S(5) C(19) C(20) 112.8(5) 0(2) S(2) C(3) 104.2(3) C(19) C(20) C(21) 115.1(6) 0(2) S(2) C(7) 106.7(3) S(6) C(21) C(20) 110.2(4) C(3) S(2) C(7) 101.0(3) S(5) C(22) C(23) 115.8(5) Ru(2) S(3) 0(3) 118.1(2) C(22) C(23) C(24) 111.8(6) Ru(2) S(3) C(10) 110.6(2) S(6) C(25) C(26) 110.7(4) Ru(2) S(3) C(13) 114.3(2) C(25) C(26) C(27) 109.7(5) 0(3) S(3) C(10) 106.1(3) S(7) C(28) C(29) 110.5(4) 0(3) S(3) C(13) 104.7(3) C(28) C(29) C(30) 115.1(5) C(10) S(3) C(13) 101.4(3) S(8) C(30) C(29) 111.7(4) Ru(2) S(4) 0(4) 117.9(2) S(7) C(31) C(32) 116.3(5) Ru(2) S(4) C(12) 111.5(2) C(31) C(32) C(33) 110.5(7) Ru(2) S(4) C(16) 113.0(2) S(8) C(34) C(35) 114.3(5) 0(4) S(4) C(12) 104.4(3) C(34) C(35) C(36) 110.3(6) 0(4) S(4) C(16) 106.3(3) Cl(ll) C(37) Cl(12) 111.9(4) C(12) S(4) C(16) 102.3(3) Cl(13) C(38) Cl(14) 114.0(5) Ru(3) S(5) 0(5) 119.7(2) Cl(15) C(39) Cl(16) 112.9(6) Ru(3) S(5) C(19) 112.0(2) Cl(17) C(40) Cl(17a 36.1(4) Ru(3) S(5) C(22) 111.3(2) Cl(17) C(40) Cl(18a 141(1) 0(5) S(5) C(19) 105.6(3) Cl(17) C(40) Cl(18) 110.3(8) 0(5) S(5) C(22) 105.8(3) Cl(17a C(40) Cl(18a 149(1) C(19) S(5) C(22) 100.3(3) Cl(17a C(40) Cl(18) 101.7(9) Ru(3) S(6) 0(6) 117.1(2) Cl(18a C(40) Cl(18) 46.9(8) Ru(3) S(6) C(21) 111.8(2) Cl(19a C(41) Cl(19) 34.0(4) Cl(19a C(41) Cl(20a 105.9(5) Cl(19a C(41) Cl(20) 76.2(6) Cl(19) C(41) Cl(20a 103.9(6) Cl(19) C(41) Cl(20) 107.6(6) Gl(20a C(41) Cl(20) 71.2(5) Angles are in degrees. Estimated standard deviations in the least significant figure are given in parentheses. i Table A . l 27. Bond Lengths (A) for [RuCl(BPSP)]2C«-Cl)3-2H20-2.5CH2Cl2 atom atom distance atom atom distance atom atom distance Ru(D Cl(l) 2.393(2) Cl(13) C(38) 1.74(1) C(2) C(3) 1.528(9) Ru(D Cl(2) 2.483(1) Cl(14) C(38) 1.733(9) C(4) C(5) 1.50(1) Ru(D Cl(3) 2.469(2) Cl(15) C(39) 1.74(1) C(5) C(6) 1.51(1) Ru(l) Cl(4) 2.383(2) Cl(16) C(39) 1.67(1) C(7) C(8) 1.51(1) Ru(l) S(D 2.209(2) Cl(17) Cl(17a 1.10(1) C(8) C(9) 1.50(1) Ru(l) S(2) 2.206(2) Cl(17) C(40) 1.76(1) C(10) C(ll) 1.54(1) Ru(2) Cl(l) 2.388(1) Cl(17a C(40) 1.78(2) C(ll) C(12) 1.515(9) Ru(2) Cl(2) 2.477(2) Cl(18a Cl(18) 1.27(1) C(13) C(14) 1.523(9) A.240 I. Appendix Ru(2) Cl(3) 2.482(2) Cl(18a C(40) 1.28(2) C(14) C(15) 1.52(1) Ru(2) Cl(5) 2.390(2) Cl(18) C(40) 1.73(1) C(16) C(17) 1.513(9) Ru(2) S(3) 2.209(2) Cl(19a Cl(19) 1.027(9) Ru(2) S(4) 2.208(2) Cl(19a Cl(20) 2.08(1) Ru(3) Cl(6) 2.390(1) Cl(19a C(41) 1.66(1) Ru(3) Cl(7) 2.444(2) Cl(19) C(41) 1.81(1) Ru(3) Cl(8) 2.488(2) Cl(20a Cl(20) 2.12(1) Ru(3) Cl(9) 2.388(2) Cl(20a C(41) 1.92(1) Ru(3) S(5) 2.205(2) Cl(20) C(41) 1.71(1) Ru(3) S(6) 2.207(2) S(D 0(1) 1.490(4) Ru(4) Cl(6) 2.408(2) S(D C(l) 1.800(6) Ru(4) Cl(7) 2.453(1) S(l) C(4) 1.789(7) Ru(4) Cl(8) 2.476(2) S(2) 0(2) 1.491(4) Ru(4) Cl(10) 2.377(2) S(2) C(3) 1.805(6) Ru(4) S(7) 2.200(2) S(2) C(7) 1.801(6) Ru(4) S(8) 2.224(2) S(3) 0(3) 1.487(4) Cl(ll) C(37) 1.750(8) S(3) C(10) 1.805(6) Cl(12) C(37) 1.750(8) S(3) C(13) 1.796(7) S(4) 0(4) 1.490(4) C(17) C(18) 1.50(1) S(4) C(12) 1.800(6) C(19) C(20) 1.523(9) S(4) C(16) 1.788(7) C(20) C(21) 1.52(1) S(5) 0(5) 1.501(4) C(22) C(23) 1.512(9) S(5) C(19) 1.809(6) C(23) C(24) 1.50(1) S(5) C(22) 1.804(7) C(25) C(26) 1.538(9) S(6) 0(6) 1.497(4) C(26) C(27) 1.52(1) S(6) C(21) 1.796(6) C(28) C(29) 1.51(1) S(6) C(25) 1.800(7) C(29) C(30) 1.536(9) S(7) 0(7) 1.489(4) C(31) C(32) 1.52(1) S(7) C(28) 1.802(6) C(32) C(33) 1.50(1) S(7) C(31) 1.804(7) C(34) C(35) 1.52(1) S(8) 0(8) 1.474(5) C(35) C(36) 1.52(1) S(8) C(30) 1.776(6) S(8) C(34) 1.799(6) C(l) C(2) 1.514(9) C(l) C(2) 1.514(9) Distances are in angstroms. Estimated standard deviations in the least significant figure are given in parentheses. fable A.1 28. Atomic Coordinates for [RuCl(BPSP)] 2C"-Cl)3-2H 20-2.5CH 2Cl 2 atom X V z B(eq) Ru(D 0.4973 0.93066(2) 0.5020 1.076(8) Ru(2) 0.74647(4) 0.82149(2) 0.54648(2) 1.153(8) Ru(3) 0.17353(4) 0.47576(2) 0.33053(2) 1.145(8) Ru(4) 0.41381(4) 0.36548(2) 0.38406(2) 1.181(8) Cl(l) 0.55025(10) 0.78507(7) 0.49337(5) 1.25(2) Cl(2) 0.72494(10) 0.94752(7) 0.48699(5) 1.45(2) Cl(3) 0.60312(10) 0.91018(7) 0.59562(5) 1.47(2) Cl(4) 0.47834(11) 1.07804(7) 0.51770(5) 1.85(3) Cl(5) 0.93411(11) 0.88287(8) 0.59434(6) 2.04(3) Cl(6) 0.36512(10) 0.51354(7) 0.38674(5) 1.23(2) Gl(7) 0.18397(10) 0.35297(7) 0.39055(5) 1.49(3) Gl(8) 0.32840(10) 0.38690(7) 0.28737(5) 1.44(2) Cl(9) -0.00404(11) 0.41011(8) 0.27806(6) 2.15(3) Cl(10) 0.42739(11) 0.21724(7) 0.37227(5) 1.96(3) Cl(ll) -0.0818(2) 0.11076(14) 0.32572(10) 7.15(6) A.241 I. Appendix Cl(12) -0.0025(2) 0.17855(11) 0.43332(8) 4.65(4) Cl(13) 0.3373(2) 0.67487(13) 0.60869(9) 5.17(5) Cl(14) 0.2849(2) 0.50223(13) 0.63999(10) 6.01(5) Cl(15) 0.0901(2) 0.3810(2) 0.72513(13) 9.16(8) Cl(16) 0.1325(3) 0.2071(2) 0.74737(15) 10.87(10) Cl(17) 0.4759(4) 0.1605(2) 0.6984(2) 8.25(10) Cl(17a) 0.5662(8) 0.1685(6) 0.6809(4) 6.7(2) Cl(18a) 0.6236(9) 0.0469(7) 0.7704(4) 8.6(2) Cl(18) 0.6810(2) 0.1163(2) 0.77944(11) 5.46(7) Cl(19a) 0.8820(6) 1.1805(3) 0.5723(2) 7.71(15) Cl(19) 0.9512(6) 1.1387(4) 0.5636(3) 8.5(2) Cl(20a) 0.8782(6) 1.0826(3) 0.6691(2) 8.92(15) Cl(20) 0.7500(5) 1.1710(3) 0.6285(2) 9.4(2) S(l) 0.30356(10) 0.90033(7) 0.52220(5) 1.39(3) S(2) 0.41971(11) 0.94440(7) 0.41561(5) 1.32(2) S(3) 0.74339(10) 0.71334(7) 0.60260(5) 1.37(2) S(4) 0.86066(10) 0.74423(7) 0.49566(5) 1.48(3) S(5) 0.17477(10) 0.57985(8) 0.27151(5) 1.46(3) S(6) 0.05391(10) 0.55325(8) 0.37881(5) 1.47(3) S(7) 0.61382(11) 0.38943(8) 0.37129(6) 1.65(3) S(8) 0.46771(11) 0.35031(7) 0.47326(6) 1.61(3) O(l) 0.2485(3) 0.8177(2) 0.50290(15) 1.94(8) 0(2) 0.3782(3) 0.8672(2) 0.38402(15) 2.11(8) 0(3) 0.6705(3) 0.6370(2) 0.58276(13) 1.69(7) 0(4) 0.7986(3) 0.6691(2) 0.46781(14) 1.92(8) 0(5) 0.2549(3) 0.6565(2) 0.28605(14) 1.99(8) 0(6) 0.1141(3) 0.6303(2) 0.40575(14) 2.02(8) 0(7) 0.6689(3) 0.4728(2) 0.3889(2) 2.13(8) 0(8) 0.4938(3) 0.4266(2) 0.50666(15) 2.33(8) 0(9) 0.3088(3) 0.6592(3) 0.4794(2) 5.30(12) 0(10) 0.4163(4) 0.7102(3) 0.3682(2) 7.8(2) 0(11) 0.5130(3) 0.5906(2) 0.49572(14) 2.25(8) 0(12) 0.6173(3) 0.6387(2) 0.38562(14) 2.01(8) C(l) 0.1872(4) 0.9775(3) 0.4960(2) 1.90(10) C(2) 0.1708(4) 0.9745(3) 0.4343(2) 2.12(10) Table A . l 29. Hydrogen bonds and C-H....C1/0 interactions. A H B A....B A-H H....B A-H....B 0(9): H(l) 0(1) 2.676(7) 0.95 1.73 170.8 0(9) H(2) 0(6) 2.620(6) 0.95 1.68 170.4 O(10) H(3) 0(2) 2.563(7) 0.95 1.61 179.0 O(10) H(4) 0(5) 2.633(7) 0.95 1.68 179.4 0(11) H(5) 0(3) 2.663(6) 0.95. 1.72 175.7 0(11) H(6) 0(8) 2.628(6) 0.95 1.68 175.5 0(12) H(7) 0(4) 2.665(6) 0.95 1.73 166.1 0(12) H(8) 0(7) 2.688(6) 0.95 1.76 166.5 0(9) H(l) Cl(l) 3.222(5) 0.95 2.90 101.5 0(11) H(5) Cl(l) 3.113(4) 0.95 2.90 94.1 0(12) H(8) Cl(6) 3.320(4) 0.95 2.95 104.7 C(6) H(19) Cl(17) 3.578(12) 0.98 2.86 132.1 C(7) H(22) Cl(10) 3.592(6) 0.98 2.81 137.2 C(18) H(47) Cl(16) 3.750(9) 0.98 2.92 143.1 C(19) H(49) Cl(17) 3.733(8) 0.98 2.90 144.0 A.242 7. Appendix C(19) H(49) Cl(17a) 3.847(14) 0.98 2.93 156.8 C(23) H(58) Cl(20) 3.647(9) 0.98 2.91 132.4 C(29) H(71) Cl(19a) 3.682(9) 0.98 2.85 143.1 C(36) H(88) Cl(17) 3.543(9) 0.98 2.77 135.7 C(37) H(90) Cl(7) 3.254(8) 0.98 2.75 112.8 C(38) H(92) Cl(9) 3.650(10) 0.98 2.74 154.8 C(40) H(96) Cl(20a) 3.59(2) 0.98 2.82 136.8 C(40) H(96) Cl(20) 3.47(2) 0.98 2.85 122.7 C(41) H(97) Cl(2) 3.546(9) 0.98 2.73 140.9 C(41) H(98) Cl(5) 3.555(10) 0.98 2.85 129.7 C(41) H(98a) Cl(5) 3.555(10) 0.98 2.76 138.3 C(41) H(98a) Cl(2) 3.546(9) 0.98 2.80 133.7 A.243 I. Appendix Figure A.1.4. Stereoview of [RuCl(BPSP)]2C"-Cl)3-2H20-2.5CH2Cl2. A.244 I. Appendix Appendix 1.7 Crystallographic Data for /ra«5-RuCl2(BCyTE)2-2CH2Cl2 Table A.1 30. Experimental Details for X-ray Crystal Structure oftrans-RuCl2(BCyTE)2-2CH2Cl2 A. Crystal Data Empirical Formula C30H56O6RUS4 Formula Weight 858.80 Crystal Colour, Habit orange, irregular Crystal Dimensions 0.45 x 0.35 x 0.25 mm Crystal System triclinic Lattice Type Primitive Lattice Parameters a =7.5953(10) A b = 10.638(2) A c= 12.5100(13) A <x= 103.349° (3 = 96.6436(13)0 y = 96.3757(14)° V = 966.9(2) A 3 Space Group PI (#2) Z Value 1 Dca/c 1.475 g/cm3 Fooo 446.00 //(MoKa) 10.56 cm"1 B. Intensity Measurements Diffractometer CCD Radiation MoKa (A, = 0.71069 A) graphite monochromated Detector Aperature 94 mm x 94 mm Data Images 462 exposures @ 16.0 seconds ^oscillation Range (% = 0) 0.0 -190.0 0 co oscillation Range (% = -90) -23.0 -18.0 0 Detector Position 39.24 mm Detector Swing Angle -10.00 ° 60.0° No. of Reflections Measured Total: 8775 Unique: 4348 (R,„, = 0.033) Corrections Lorentz-polarization Absorption/scaling (trans, factors: 0.8770 - 1.0000) i C. Structure Solution and Refinement Structure Solution Patterson Methods (DIRDIF92 PATTY) Refinement Full-matrix least-squares Function Minimized I C O ( | F O 2 | - | F C 2 | ) 2 Least Squares Weights co = \la\Fo) = [a2c(Fo) + p2/4(Fo)Y p-factor 0.0000 Anomalous Dispersion All non-hydrogen atoms No. Observations 4348 No. Variables 187 Reflection/Parameter Ratio 23.25 Residuals (on F 2 , all data): R; Rw 0.055; 0.061 Goodness of Fit Indicator 1.52 Max Shift/Error in Final Cycle 0.00 A.245 I. Appendix Maximum peak in Final Diff. Map 0.84 elA3 Minimum peak in Final Diff. Map -0.95 e/A3 Table A.1 31. Bond Angles (°) for >rara-RuCl 2 (BCyTE) 2 -2CH 2 Cl 2 atom atom atom angle atom atom atom angle Cl(l) Ru(D Cl(l) 180.00 C(2) S(2) C(9) 97.9(1) Cl(l) Ru(D S(D 95.86(2) S(l) C(l) C(2) 112.3(2) Cl(l) Ru(l) S(D 84.14(2) S(2) C(2) C(l) 110.4(2) Cl(l) Ru(D S(2) 92.42(2) S(l) C(3) C(4) 112.6(2) Cl(l) Ru(D S(2) 87.58(2) S(l) C(3) C(8) 105.5(2) Cl(l) Ru(l) S(D 84.14(2) C(4) C(3) C(8) 111.4(2) Cl(l) Ru(D S(l) 95.86(2) C(3) C(4) C(5) 109.1(2) Cl(l) Ru(D S(2) 87.58(2) C(4) C(5) C(6) 111.6(2) Cl(l) Ru(l) S(2) 92.42(2) C(5) C(6) C(7) 111.6(3) S(D Ru(D S(l) 180.00 C(6) C(7) C(8) 110.6(3) S(D Ru(l) S(2) 87.22(2) C(3) C(8) C(7) 110.7(2) S(D Ru(l) S(2) 92.78(2) S(2) C(9) C(10) 111.3(2) S(D Ru(D S(2) 92.78(2) S(2) C(9) C(14) 109.3(2) S(D Ru(D S(2) 87.22(2) C(10) C(9) C(14) 111.2(2) S(2) Ru(D S(2) 180.00 C(9) C(10) C(ll) 110.6(2) Ru(D S(D C(l) 101.76(9) C(10) C(ll) C(12) 111.1(3) Ru(D S(D C(3) 110.98(9) C(ll) C(12) C(13) 110.7(3) C(l) S(l) C(3) 104.3(1) C(12) C(13) C(14) 112.0(2) Ru(l) S(2) C(2) 104.13(9) C(9) C(14) C(13) 109.6(2) Ru(l) S(2) C(9) 117.26(9) Cl(2) C(15) Cl(3) 112.8(2) Angles are in degrees. Estimated standard deviations in the least significant figure are given in parentheses. Table A . l 32. Bond Lengths (A) for *rans-RuCl 2 (BCyTE) 2 -2CH 2 Cl 2 atom atom distance atom atom distance Ru(l) Cl(l) 2.4262(6) C(3) C(4) 1.526(4) Ru(D Cl(l) 2.4262(6) C(3) C(8) 1.525(4) Ru(l) S(D 2.3629(6) C(4) C(5) 1.536(4) Ru(l) S(D 2.3629(6) C(5) C(6) 1.513(4) Ru(l) S(2) 2.3646(7) C(6) C(7) 1.531(4) Ru(l) S(2) 2.3646(7) C(7) C(8) 1.527(4) Cl(2) C(15) 1.740(4) C(9) C(10) 1.507(4) Cl(3) C(15) 1.718(4) C(9) C(14) 1.529(4) S(l) C(l) 1.813(3) C(10) C(ll) 1.536(4) S(l) C(3) 1.840(3) C(ll) C(12) 1.522(4) S(2) C(2) 1.830(3) C(12) C(13) 1.500(4) S(2) C(9) 1.837(3) C(13) C(14) 1.547(4) C(l) C(2) 1.515(4) Distances are in angstroms. Estimated standard deviations in the least significant figure are given in parentheses. Table A.1 33. Atomic Coordinates for / r aws-RuCl 2 (BCyTE) 2 -2CH 2 Cl 2 atom X y z atom x y z Ru(D Cl(l) Cl(2) Gl(3) S(D 0.5000 0.30784(9) 0.2417(2) 0.2281(2) 0.55040(9) 0.5000 0.56458(7) 0.48924(12) 0.74202(12) 0.30267(6) 0.5000 0.35930(5) -0.04824(8) 0.09370(10) 0.38305(5) C(6) C(7) C(8) C(9) C(10) 0.2008(5) 0.1198(4) 0.2364(4) 0.7353(4) 0.6625(4) 0.1089(3) 0.1981(3) 0.2226(3) 0.7213(3) 0.8376(3) 0.0454(2) 0.1355(2) 0.2482(2) 0.3690(2) 0.4327(2) A.246 I. Appendix S(2) 0.76224(9) 0.60009(7) 0.45092(5) C(ll) 0.6425(5) 0.9383(3) 0.3633(3) C(l) 0.7835(4) 0.3399(3) 0.3675(2) C(12) 0.8200(5) 0.9807(3) 0.3276(3) C(2) 0.8248(4) 0.4721(3) 0.3429(2) C(13) 0.8939(5) 0.8647(3) 0.2656(3) C(3) 0.4282(4) 0.2775(3) 0.2422(2) C(14) 0.9151(4) 0.7621(3) 0.3341(2) C(4) 0.5096(4) 0.1859(3) 0.1547(2) C(15) 0.2760(7) 0.5865(4) 0.0869(3) C(5) 0.3921(4) 0.1628(3) 0.0415(2) Table A.1 34. Hydrogen bond parameters for A-H.. .B interactions. A H B A...B A-H H....B A-H....B C(2) H(3) Cl(2) 3.785(3) 0.98 2.91 148.7 A.247 Appendix Figure A.1.5. Stereoview of/raw5-RuCl 2(BCyTE) 2-2CH 2Cl2. A.248 I. Appendix Appendix 1.8 Crystallographic Data for fraws-RuCl2(BPhTE)2 Table A . l 35. Experimental Details for X-ray Crystal Structure of rra«s-RuCl 2(BPhTE) 2 A. Crystal Data Empirical Formula Formula Weight Crystal Colour, Habit Crystal Dimensions Crystal System Lattice Type Lattice Parameters Space Group Z Value F o o o C28H28CI2R.US4 664.75 orange-red, plate 0.05 x 0.25 x 0.25 mm triclinic Primitive a = 10.264(2) A b = 10.866(2) A c = 12.9980(14) A a = 93.802(5)° P = 108.4136(13) y = 92.490(2) 0 V = 1875.9(3) A 3 PI (#2) 2 1.612 g/cm3 676.00 10.90 cm'1 B. Intensity Measurements Diffractometer Rigaku/ADSC CCD Radiation MoKa (X = 0.71069^) graphite monochromated Detector Aperature 94 mm x 94 mm Data Images 462 exposures of 30.0 seconds ^oscillation Range (x = -90) 0 .0 -190 .0° co oscillation Range (x = -90) -23 .0 -18 .0° Detector Position 39.23(1) mm Detector Swing Angle -10.0° 60.1° No. of Reflections Measured Total: 12689 Unique: 6147 (R,„, = 0.036) Corrections Lorentz-polarization Absorption/scaling (trans, factors: 0.7088 - 1.0000) ' C.' Structure Solution and Refinement Structure Solution Patterson Methods (DIRDIF92 PATTY) Refinement Full-matrix least-squares Function Minimized S C D ( | F O 2 | - | F C 2 | ) 2 Least Squares Weights co = \la\Fo2) p-factor 0.0000 Anomalous Dispersion All non-hydrogen atoms No. Observations 6147 No. Variables 316 Reflection/Parameter Ratio 19.45 Residuals (on F 2 , all data): R; Rw 0.055; 0.052 Goodness of Fit Indicator 1.35 No. Observations (I>3a(I)) 4088 Residuals (on F, I>3a(I)): R; Rw 0.031; 0.025 A.249 I. Appendix Max Shift/Error in Final Cycle 0.0007 Maximum peak in Final Diff. Map 1.05 e/i3(nearRu) Minimum peak in Final Diff. Map -1.45 e/A3 Table A.1 36. Bond Angles (°) for fraws-RuCl2(BPhTE)2 atom atom atom angle atom atom atom angle Cl(l) Ru(D Cl(2) 178.13(4) C(3) C(4) C(5) 119.7(3) Cl(l) Ru(D S(D 84.14(3) C(4) C(5) C(6) 120.4(3) Cl(l) Ru(l) S(2) 95.08(3) C(5) C(6) C(7) 119.9(4) Cl(l) Ru(l) S(3) 83.65(3) C(6) C(7) C(8) 119.5(4) Cl(l) Ru(l) S(4) 96.90(3) C(3) C(8) C(7) 121.3(3) Cl(2) Ru(l) S(l) 94.09(3) S(2) C(9) C(10) 116.6(2) Cl(2) Ru(D S(2) 84.18(3) S(2) C(9) C(14) 124.3(3) Cl(2) Ru(D S(3) 98.09(3) C(10) C(9) C(14) 119.1(3) Cl(2) Ru(l) S(4) 83.92(3) C(9) C(10) C(ll) 120.1(3) S(D Ru(l) S(2) 86.03(3) C(10) C(ll) C(12) 119.9(4) S(l) Ru(D S(3) 167.66(3) C(ll) C(12) C(13) 120.6(4) S(D Ru(D S(4) 97.97(3) C(12) C(13) C(14) 120.2(3) S(2) Ru(l) S(3) 93.26(3) C(9) C(14) C(13) 120.0(3) S(2) Ru(l) S(4) 167.69(3) S(3) C(15) C(16) 107.2(2) S(3) Ru(D S(4) 85.29(3) S(4) C(16) C(15) 108.4(2) Ru(D S(l) C(l) 102.6(1) S(3) C(17) C(18) 123.3(3) Ru(D S(D C(3) 121.9(1) S(3) C(17) C(22) 115.6(2) C(l) S(l) C(3) 98.5(1) C(18) C(17) C(22) 121.1(3) Ru(l) S(2) C(2) 103.59(9) C(17) C(18) C(19) 118.8(3) Ru(D S(2) C(9) 117.0(1) C(18) C(19) C(20) 120.7(3) C(2) S(2) C(9) 102.2(2) C(19) C(20) C(21) 119.8(3) Ru(l) S(3) C(15) 103.6(1) C(20) C(21) C(22) 120.5(3) Ru(D S(3) C(17) 119.2(1) C(17) C(22) C(21) 119.1(3) C(15) S(3) C(17) 100.3(1) S(4) C(23) C(24) 122.1(2) Ru(D S(4) C(16) 104.1(1) S(4) C(23) C(28) 116.5(3) Ru(l) S(4) C(23) 121.0(1) C(24) C(23) C(28) 121.2(3) C(16) S(4) C(23) 99.7(1) C(23) C(24) C(25) 119.9(3) S(D C(l) C(2) 108.9(2) C(24) C(25) C(26) 119.2(3) S(2) C(2) C(l) 106.8(2) C(25) C(26) C(27) 120.0(3) S(l) C(3) C(4) 122.6(3) C(26) C(27) C(28) 121.4(3) S(l) C(3) C(8) 118.2(3) C(23) C(28) C(27) 118.3(3) C(4) C(3) C(8) 119.1(3) Angles are in degrees. Estimated standard deviations in the least significant figure are given in parentheses. Table A . l 37. Bond Lengths (A) for *ra«s-RuCl2(BPhTE)2 atom atom distance atom atom distance Ru(l) Cl(l) 2.4266(8) C(7) C(8) 1.372(5) Ru(D Cl(2) 2.4244(8) C(9) C(10) 1.393(4) Ru(l) S(l) 2.3557(9) C(9) C(14) 1.387(4) Ru(l) S(2) 2.3424(7) C(10) C(ll) 1.378(5) Ru(D S(3) 2.3440(9) C(ll) C(12) 1.368(5) Ru(l) S(4) 2.3594(8) C(12) C(13) 1.370(5) S(D C(l) 1.844(3) C(13) C(14) 1.377(5) S(l) C(3) 1.788(3) C(15) C(16) 1.508(4) S(2) C(2) 1.815(4) C(17) C(18) 1.378(4) S(2) C(9) 1.777(3) C(17) C(22) 1.388(5) S(3) C(15) 1.835(3) C(18) C(19) 1.397(4) A.250 I. Appendix S(3) C(17) 1.799(3) C(19) C(20) 1.383(5) S(4) C(16) 1.836(4) C(20) C(21) 1.373(5) S(4) C(23) 1.793(3) C(21) C(22) 1.394(5) C(l) C(2) 1.514(5) C(23) C(24) 1.373(4) C(3) C(4) 1.389(4) C(23) C(28) 1.403(4) C(3) C(8) 1.384(5) C(24) C(25) • 1.401(4) C(4) C(5) 1.390(5) C(25) C(26) 1.397(4) C(5) C(6) 1.377(6) C(26) C(27) 1.378(5) C(6) C(7) 1.389(5) C(27) C(28) 1.383(4) Distances are in angstroms. Estimated standard deviations in the least significant figure are given in parentheses. Table A . l 38. Atomic Coordinates for *ra«s-RuCl2(BPhTE)2 atom X y z Ru(D 0.17633(3) 0.42116(3) 0.28037(2) Cl(l) 0.38363(8) 0.30901(7) 0.32390(6) Cl(2) -0.03416(8) 0.52838(7) 0.23181(6) S(D 0.07126(8) 0.23633(7) 0.17658(6) S(2) 0.19651(8) 0.48748(8) 0.11791(6) S(3) 0.32480(8) 0.58400(7) 0.38769(6) S(4) 0.12045(8) 0.38616(8) 0.43917(6) C(l) 0.0429(4) 0.2765(3) 0.0359(2) C(2) 0.1717(4) 0.3453(3) 0.0304(2) C(3) -0.1013(3) 0.1836(3) 0.1629(3) C(4) -0.1778(3) 0.2414(3) 0.2209(3) C(5) -0.3100(4) 0.1933(4) 0.2090(3) C(6) -0.3647(4) 0.0880(4) 0.1413(3) C(7) -0.2873(4) 0.0289(4) 0.0850(3) C(8) -0.1579(4) 0.0778(3) 0.0954(3) C(9) 0.3620(3) 0.5466(3) 0.1210(2) C(10) 0.3748(4) 0.6709(3) 0.1030(3) C(ll) 0.5022(4) 0.7266(4) 0.1141(3) C(12) 0.6159(4) 0.6591(4) 0.1405(3) C(13) 0.6040(4) 0.5356(4) 0.1538(3) C(14) 0.4780(4) 0.4791(3) 0.1454(3) C(15) 0.2620(4) 0.6101(3) 0.5042(3) C(16) 0.2481(4) 0.4861(3) 0.5468(2) C(17) 0.3147(3) 0.7359(3) 0.3397(3) C(18) 0.1957(3) 0.7774(3) 0.2714(3) C(19) 0.2001(4) 0.8954(3) 0.2356(3) C(20) 0.3217(4) 0.9691(3) 0.2673(3) C(21) 0.4387(4) 0.9272(4) 0.3369(3) C(22) 0.4371(4) 0.8095(3) 0.3732(3) C(23) 0.1473(3) 0.2409(3) 0.4979(2) C(24) 0.1873(3) 0.1413(3) 0.4474(2) C(25) 0.1977(4) 0.0274(3) 0.4929(3) C(26) 0.1665(4) 0.0170(4) 0.5892(3) C(27) 0.1252(4) 0.1177(4) 0.6380(3) C(28) 0.1138(4) 0.2306(3) 0.5937(3) ij i • A.251 I. Appendix Figure A.1.6. Stereoview of fra«s-RuCl2(BPhTE)2. A.252 I. Appendix Appendix 1.9 Crystallographic Data for [RuCl 2(BETP)] 2(//-Cl) 2 Table A . l 39. Experimental Details for X-ray Crystal Structure of [RuCl 2(BETP)] 2(//-Cl) 2 A. Crystal Data Empirical Formula Formula Weight Crystal Colour, Habit Crystal Dimensions Crystal System Lattice Type Lattice Parameters Space Group Z Value Dcaic Fooo ^(MoKa) Ci 4H32CI6RU2S4 743.50 orange, block 0.30x0.40x0.45 mm monoclinic Primitive a = 9.4203(13) A b = 7.8644(13) A c= 17.2910(5) A P = 98.8128(7) 0 V = 1265.3(2) A 3 P2,/n (# 14) 2 1.951 g/cm3 740.00 21.58 cm"1 B. Intensity Measurements Diffractometer Rigaku/ADSC CCD Radiation MoKa (k = 0.71069 ^ f) graphite monochromated Detector Aperature 94 mm x 94 mm Data Images 462 exposures of 40.0 seconds tj> oscillation Range (x = -90) 0 .0 -190 .0° co oscillation Range (x = -90) -23.0 -18.0 0 Detector Position 39.22(1) mm Detector Swing Angle -10° 16max 63.6° 60.1° No. of Reflections Measured Total: 10528 Unique: 3419 (Rint = 0.024) Corrections Lorentz-polarization Absorption/scaling (trans, factors: 0.7434 - 1.0018) C. Structure Solution and Refinement Structure Solution Patterson Methods (DIRDIF92 PATTY) Refinement Full-matrix least-squares Function Minimized Sco(|Fo 2 | - |Fc 2 | ) 2 Least Squares Weights co = l/a2(Fo2) = [a2(Fo2) + p2Fo2]A p-factor 0.0200 Anomalous Dispersion All non-hydrogen atoms No. Observations 3419 No. Variables 118 Reflection/Parameter Ratio 28.97 Residuals (on F 2 , all data): R; Rw 0.060; 0.076 Goodness of Fit Indicator 1.90 No. Observations (I>3a(I)) 2650 Residuals (on F, I>3a(I)): Rl ; Rlw 0.034; 0.036 Max Shift/Error in Final Cycle 0.001 A.253 I. Appendix Maximum peak in Final Diff. Map 1.15 e7i3(nearRu) Minimum peak in Final Diff. Map -1.50 e7i3(nearRu) Table A . l 40. Bond Angles (°) for [RuCl 2 (BETP)] 2 ( / / -Cl) 2 atom atom atom angle atom atom atom angle Cl(l) Ru(l) Cl(l)* 84.14(3) Cl(l) Ru(l) Cl(2) 173.59(3) Cl(l) Ru(l) Cl(3) 90.35(3) Cl(l) Ru(D S(D 85.46(3) Cl(l) Ru(D S(2) 96.74(3) Cl(l)* Ru(D Cl(2) 91.62(3) Cl(l)* Ru(D Cl(3) 86.95(3) Cl(l)* Ru(l) S(l) 92.49(3) Cl(l)* Ru(D S(2) 172.05(3) Cl(2) Ru(D Cl(3) 94.22(3) Cl(2) Ru(l) S(D 89.94(3) Cl(2) Ru(l) S(2) 88.13(3) Cl(3) Ru(D S(D 175.81(3) Cl(3) Ru(l) S(2) 85.14(3) S(l) Ru(l) S(2) 95.45(3) Ru(l) Cl(l) Ru(l)* 95.86(3) Ru(D S(D C(l) 110.16(11) Ru(l) S(l) C(4) 107.85(11) C(l) S(l) C(4) 99.78(15) Ru(l) S(2) C(3) 111.62(11) Ru(D S(2) C(6) 110.65(10) C(3) S(2) C(6) 100.54(15) S(l) C(l) C(2) 112.9(2) C(l) C(2) C(3) 113.6(3) S(2) C(3) C(2) 117.3(2) S(l) C(4) C(5) 112.5(3) S(2) C(6) C(7) 110.7(2) Angles are in degrees. Estimated standard deviations in the least significant figure are given in parentheses. Table A . l 41. Bond Lengths ( A ) for [RuCl 2 (BETP)] 2 ( / / -Cl) 2 atom atom distance atom atom distance Ru(D Cl(l) 2.3915(7) S(D C(4) 1.823(3) Ru(l) Cl(l) 2.4617(7) S(2) C(3) 1.808(3) Ru(l) Cl(2) 2.3258(7) S(2) C(6) 1.813(3) Ru(D Cl(3) 2.3501(8) C(l) C(2) 1.523(5) Ru(D S(D 2.3677(8) C(2) C(3) 1.521(5) Ru(D S(2) 2.3201(8) C(4) C(5) 1.511(5) S(D C(l) 1.815(3) C(6) C(7) 1.521(5) Distances are in angstroms. Estimated standard deviations in the least significant figure are given in parentheses. Table A.1 42. Atomic Coordinates for [ R u C l 2 ( B E T P ) ] 2 ( > C i ) 2 atom X y z Ru(l) 0.01544(2) 0.07158(3) 0.402663(12) Cl(l) -0.11601(7) 0.15130(10) 0.50486(4) Cl(2) 0.16600(8) -0.00636(10) 0.31390(4) Cl(3) -0.16463(8) -0.12495(10) 0.35461(4) S(l) 0.18705(8) 0.27429(10) 0.45849(4) S(2) -0.10155(8) 0.25303(10) 0.30786(4) C(l) 0.2389(4) 0.4103(4) 0.3827(2) C(2) 0.1131(4) 0.5094(4) 0.3385(2) C(3) 0.0208(3) 0.4055(4) 0.2757(2) C(4) 0.3563(3) 0.1630(5) 0.4888(2) C(5) 0.4615(4) 0.2672(5) 0.5443(2) C(6) -0.2217(3) 0.3943(4) 0.3497(2) C(7) -0.3655(3) 0.3083(5) 0.3524(2) A.254 I. Appendix Appendix 1.10 Crystallographic Data for [RuCl 2(BPTP)] 2C"-Cl) 2 Table A.1 43. Experimental Details for X-ray Crystal Structure of [RuCl 2(BPTP)] 2Ct/-Cl) 2 A. Crystal Data Empirical Formula C20H44CI10RU2S4 Formula Weight 969.48 Crystal Colour, Habit red, platelet Crystal Dimensions 0.40 x 0.20 x 0.03 mm Crystal System monoclinic Lattice Type Primitive Lattice Parameters a= 11.803(2) A b = 7.4111(6) A c = 21.7417(8) A P = 99.4766(10) A V= 1875.9(3) A 3 Space Group P2j/n (# 14) Z Value 2 D c a / C 1.716 g/cm3 Fooo 972.00 #(MoKa) 17.52 cm"1 B. Intensity Measurements Diffractometer Rigaku/ADSC CCD Radiation MoKa (X = 0.71069 A) graphite monochromated Detector Aperature 94 mm x 94 mm Data Images 462 exposures of 50.0 seconds <f> oscillation Range (x = -90) 0.0 -190.0 0 co oscillation Range (x = -90) -23.0 -18 .0 ° Detector Position 39.180(7) mm Detector Swing Angle -10° 60.1° No. of Reflections Measured Total: 17721 Unique: 4854 (R,Bt = 0.037) Corrections Lorentz-polarization Absorption/scaling (trans, factors: 0.6735 - 1.0000) C.' Structure Solution and Refinement Structure Solution Direct Methods (SIR92) Refinement Full-matrix least-squares Function Minimized Ico( |Fo 2 | - |Fc 2 | ) 2 Least Squares Weights co = 1/CT2(FO2) p-factor 0.0000 Anomalous Dispersion All non-hydrogen atoms No. Observations 4854 No. Variables 163 Reflection/Parameter Ratio 29.78 Residuals (on F 2 , all data): R; Rw 0.077; 0.070 Goodness of Fit Indicator 1.52 No. Observations (I>3a(I)) 2896 A.255 I. Appendix Residuals (on F, I>3a(I)): R; Rw 0.037; 0.029 Max Shift/Error in Final Cycle 0.0007 Maximum peak in Final Diff. Map 2.35 e/A3 (nearRu) Minimum peak in Final Diff. Map -3.98 e/A3 (nearRu) Table A . l 44. Bond Angles (°) for [RuCl 2(BPTP)]2Gu-Cl) 2 atom atom atom angle atom atom atom angle Cl(l) Ru(l) Cl(l)* 82.98(3) Cl(l) Ru(D Cl(2) 174.10(4) Cl(l) Ru(D C(3) 90.06(3) Cl(l) Ru(l) S(D 85.89(3) Cl(l) Ru(l) S(2) 97.50(3) Cl(l)* Ru(D Cl(2) 92.56(3) Cl(l)* Ru(l) Cl(3) 88.83(3) Cl(l)* Ru(l) S(D 91.07(3) Cl(l)* Ru(l) S(2) 173.32(4) Cl(2) Ru(D Cl(3) 93.72(4) Cl(2) Ru(l) S(l) 90.36(4) Cl(2) Ru(l) S(2) 87.39(3) Cl(3) Ru(l) S(D 175.93(4) Cl(3) Ru(l) S(2) 84.51(4) S(l) Ru(l) S(2) 95.62(4) Ru(l) Cl(l) Ru(l)* 97.02(3) Ru(l) S(l) C(l) 110.27(14) Ru(l) S(l) Cl(4) 110.74(13) C(l) S(D C(4) 99.0(2) Ru(D S(2) C(3) 112.80(14) Ru(D S(2) C(7) 109.73(13) C(3) S(2) C(7) 100.6(2) S(l) C(l) C(2) 112.0(3) C(l) C(2) C(3) 114.1(3) S(2) C(3) C(2) 117.5(3) S(D C(4) C(5) 112.8(3) C(4) C(5) C(6) 112.3(4) S(2) C(7) C(8) 111.3(3) C(7) C(8) C(9) 114.0(4) Cl(4) C(10) Cl(5) 112.0(3) Angles are in degrees. Estimated standard deviations in the least significant figure are given in parentheses. Table A . l 45. Bond Lengths (A) for [RuCl 2 (BPTP)] 2 ( / / -Cl) 2 atom atom distance atom atom distance Ru(D Cl(l) 2.3833(9) S(D C(4) 1.814(4) Ru(D Cl(l) 2.4605(9) S(2) C(3) 1.806(4) Ru(l) Cl(2) 2.3213(9) S(2) C(7) 1.821(4) Ru(l) Cl(3) 2.358(1) C(l) C(2) 1.515(5) Ru(D S(D 2.356(1) C(2) C(3) 1.531(6) Ru(l) S(2) 2.331(1) C(4) C(5) 1.511(6) Cl(4) C(10) 1.746(6) C(5) C(6) 1.509(6) Cl(5) C(10) 1.782(6) C(7) C(8) 1.527(6) S(l) C(l) 1.813(4) C(8) C(9) 1.500(6) Distances are in angstroms. Estimated standard deviations in the least significant figure are given in parentheses. Table A.1 46. Atomic Coordinates for [RuCl 2 (BPTP)] 2 ( / / -Cl) 2 atom x V z Ru(l) 0.44366(3) 0.43216(4) 0.420673(14) Cl(l) 0.46196(8) 0.30652(11) 0.52274(4) Cl(2) 0.44475(9) 0.56642(12) 0.32431(4) Cl(3) 0.26444(8) 0.55676(12) 0.43201(4) Cl(4) 0.15729(15) 0.3947(2) 0.21330(7) Cl(5) 0.14123(14) 0.7728(2) 0.24937(7) S(D 0.62293(9) 0.29734(12) 0.41622(4) S(2) 0.33402(9) 0.20132(12) 0.36777(4) C(l) 0.6184(4) 0.1775(5) 0.3432(2) C(2) 0.5319(4) 0.0247(5) 0.3364(2) C(3) 0.4080(4) 0.0842(5) 0.3133(2) C(4) 0.7292(4) 0.4670(5) 0.4063(2) A.256 I. Appendix C(5) 0.8507(4) 0.3956(6) 0.4195(2) C(6) 0.9385(5) 0.5396(7) 0.4135(3) C(7) 0.3168(4) 0.0193(4) 0.4217(2) C(8) 0.2161(4) 0.0554(5) 0.4560(2) C(9) 0.1007(4) 0.0433(7) 0.4153(2) C(10) 0.1353(5) 0.5429(9) 0.2726(2) Appendix 1.11 Crystallographic Data for M?r -C/s -RuCl 3 (DPSO) 2 (DPSO) Table A . l 47. Experimental Details for X-ray Crystal Structure of Mer-Cis-RuCl 3 (DPSO) 2 (DPSO) A. Crystal Data Empirical Formula C36H30CI3O3RUS3 Formula Weight 814.24 Crystal Colour, Habit orange, plate Crystal Dimensions 0.15x0.35x0.40 mm Crystal System triclinic Lattice Type Primitive No. of Reflections Used for Unit Cell 25 (22.6-28.4 °) Determinations (20 range) Omega Scan Peak Width at Half-height 0.37° Lattice Parameters a= 13.097(2) A b= 15.701(2) A c= 10.312(1) A a = 106.765(9)0 P = 102.02(1)0 y= 103.14(1)° V = 1890.2(5) A 3 Space Group PI (#2) Z Value 2 D c a / C 1.431 g/cm3 Fooo 826 «(MoKa) 8.25 cm"1 B. Intensity Measurements Diffractometer Rigaku AFC6S Radiation MoKoc (A, = 0.71069 A) graphite monochromated Take-off Angle 6.0° Detector Aperature 6.0 mm horizontal 6.0 mm vertical Crystal to Detector Distance 285 mm Temperature 21.0 °C Scan Type co-20 Scan Rate 16° /min (in co) (up to 9 scans) Scan Width (1.21 + 0.35 tan 0)0 60° No. of Reflections Measured Total: 11483 - • Unique: 11033 (R,„, = 0.044) Corrections Lorentz-polarization Absorption (trans, factors: 0.906 - 1.000) A.257 I. Appendix C. Structure Solution and Refinement Structure Solution Patterson Methods (DIRDIF92 PATTY) Refinement Full-matrix least-squares Function Minimized S C O ( | F O | - | F C | ) 2 Least Squares Weights co = l/a2(Fo) = [a20(Fo) + p2/4FoY p-factor 0.0000 Anomalous Dispersion All non-hydrogen atoms No. Observations (I>3CT(I)) 5914 No. Variables 451 Reflection/Parameter Ratio 13.11 Residuals: R; Rw 0.040; 0.045 Goodness of Fit Indicator 2.01 Max Shift/Error in Final Cycle 0.01 Maximum peak in Final Diff. Map 0.73 e/A3 Minimum peak in Final Diff. Map -0.50 e/A3 Table A . l 48. Bond Angles (°) forMer-Czs-RuCl 3(DPSO) 2(DPSO) atom atom atom angle atom atom atom angle Cl(l) Ru(D Cl(2) 172.63(5) S(l) C(7) C(12) 120.1(4) Cl(l) Ru(D S(3) 91.18(5) C(7) C(8) C(9) 118.1(5) Cl(l) Ru(l) 0(2) 86.82(9) C(9) C(10) C(ll) 121.1(6) Cl(2) Ru(l) S(3) 91.73(5) C(7) C(12) C(H) 118.4(5) Cl(2) Ru(l) 0(2) 89.57(9) S(2) C(13) C(18) 120.4(4) Cl(3) Ru(l) O(l) 173.70(9) C(13) C(14) C(15) 118.9(5) S(3) Ru(l) 0(1) 87.42(9) C(15) C(16) C(17) 120.5(5) 0(1) Ru(D 0(2) 86.5(1) C(13) C(18) C(17) 119.8(5) 0(1) S(l) C(la) 112.0(5) S(2) C(19) C(24) 120.9(4) C(l) S(D C(7) 97.9(4) C(19) C(20) C(21) 119.4(5) 0(2) S(2) C(13) 103.0(2) C(21) C(22) C(23) 121.0(5) C(13) S(2) C(19) 101.4(2) C(19) C(24) C(23) 118.8(5) Ru(l) S(3) C(25) 117.1(2) S(3) C(25) C(30) 123.4(4) 0(3) S(3) C(25) 106.0(2) C(25) C(26) C(27) 118.8(5) C(25) S(3) C(31) 99.0(2) C(27) C(28) C(29) 119.7(5) Ru(D 0(2) S(2) 120.0(2) C(25) C(30) C(29) 119.2(5) S(D C(l) C(6) 123.9(9) S(3) C(31) C(36) 122.0(4) S(D C(la) C(2) 123.6(10) C(31) C(32) C(33) 118.6(5) C(2) C(la) C(6a) 112(1) C(33) C(34) C(35) 119.5(5) C(la) C(2) C(3) 132.3(9) C(31) C(36) C(35) 118.1(5) C(2) C(3) C(4a) 108.9(9) C(8) C(7) C(12) 120.9(5) C(3) C(4a) C(5a) 124(1) C(8) C(9) C(10) 121.2(6) C(4a) C(5a) C(6a) 120(1) C(10) C(ll) C(12) 120.4(6) C(la) C(6a) C(5a) 118(1) S(2) C(13) C(14) 118.2(4) Cl(l) Ru(l) Cl(3) 93.22(5) C(14) C(13) C(18) 121.0(5) Cl(l) Ru(l) 0(1) 87.14(9) C(14) C(15) C(16) 120.1(5) Cl(2) Ru(l) Cl(3) 93.02(4) C(16) C(17) C(18) 119.7(5) Cl(2) Ru(l) 0(1) 86.23(9) S(2) C(19) C(20) 117.3(4) Cl(3) Ru(l) S(3) 98.86(4) C(20) C(19) C(24) 121.6(5) Cl(3) Ru(l) 0(2) 87.28(9) C(20) C(21) C(22) 119.9(5) S(3) Ru(l) 0(2) 173.65(9) C(22) C(23) C(24) 119.3(6) 0(1) S(l) C(l) 94.9(4) S(3) C(30) C(29) 119.2(5) 0(1) S(D C(7) 105.2(2) C(26) C(25) C(30) 121.1(4) C(la) S(l) C(7) 107.1(5) C(26) C(27) C(28) 121.3(5) 0(2), S(2) C(19) 103.5(2) C(28) C(29) C(30) 119.8(5) A.258 I. Appendix Ru(D S(3) 0(3) 113.0(1) S(3) C(31) C(32) 116.5(4) Ru(D S(3) C(31) 114.5(2) C(32) C(31) C(36) 121.5(5) 0(3) S(3) C(31) 105.8(2) C(32) C(33) C(34) 120.9(6) Ru(l) O(l) S(D 119.8(2) C(34) C(35) C(36) 121.4(5) S(l) C(l) C(2) 115.9(8) C(2) C(l) C(6) 119(1) S(D C(la) C(6a) 123(1) C(l) C(2) C(3) 123.1(3) C(2) C(3) C(4) 123.0(9) C(3) C(4) C(5) 115(1) C(4) C(5) C(6) 119(1) C(l) C(6) C(5) 116(1) S(l) C(7) C(8) 118.9(4) Angles are in degrees. Estimated standard deviations in the least significant figure are given in parentheses. Table A . l 49. Bond Lengths ( A ) forMe/--C75-RuCl3(DPSO)2(DPSO) atom atom distance atom atom distance Ru(D Cl(l) 2.338(1) C(8) C(9) 1.359(8) Ru(l) Cl(2) 2.324(1) C(9) C(10) 1.335(8) Ru(l) Cl(3) 2.305(3) C(10) C(H) 1.335(9) Ru(D S(3) 2.251(1) C(ll) C(12) 1.375(8) Ru(D 0(1) 2.090(3) C(13) C(14) 1.379(6) Ru(D 0(2) 2.111(3) C(13) C(18) 1.385(6) S(D O(l) 1.524(3) C(14) C(15) 1.365(7) S(D C(l) 1.93(1) C(15) C(16) 1.397(8) S(D C(la) 1.65(1) C(16) C(17) 1.365(8) S(l) C(7) 1.790(5) C(17) C(18) 1.368(7) S(2) C(13) 1.788(5) C(19) C(20) 1.377(6) S(2) C(19) 1.780(5) C(19) C(24) 1.373(7) S(3) 0(3) 1.472(3) C(20) C(21) 1.370(7) S(3) C(25) 1.798(4) C(21) C(22) 1.359(8) S(3) C(31) 1.806(5) C(22) C(23) 1.394(8) C(l) C(2) 1.18(1) C(23) C(24) 1.379(7) C(l) C(6a) 1.85(2) C(25) C(26) 1.385(6) C(l) C(6) 1.38(1) C(25) C(30) 1.371(6) S(4) C(10) 1.806(4) C(26) C(27) 1.362(7) C(la) C(2) 1.38(2) C(27) C(28) 1.371(7) C(la) C(6a) 1.35(2) C(28) C(29) 1.382(7) C(2) C(3) 1.347(5) C(29) C(30) 1.385(6) C(3) C(4) 1.30(1) C(31) C(32) 1.381(6) C(3) C(4a) 1.34(2) C(31) C(36) 1.384(6) C(4) C(5) 1.38(2) C(32) C(33) 1.371(7) C(4a) C(5a) 1.36(2) C(33) C(34) 1.370(8) C(5) C(6) 1.41(1) C(34) C(35) 1.374(8) C(5a) C(6a) 1.40(2) C(35) C(36) 1.369(7) C(7) C(8) 1.379(7) C(7) C(12) 1.366(7) Distances are in angstroms. Estimated standard deviations in the least significant figure are given in parentheses. i "; ; . A.259 I. Appendix Table A . l 50. Atomic Coordinates forMer-C/5 -RuCl 3 (DPSO) 2 (DPSO) atom X V z atom X y z Ru(l) 0.11952(3) 0.35548(3) 0.21549(4) C(17) -0.4144(4) 0.2955(4) 0.1702(7) Cl(l) 0.0664(1) 0.23915(9) -0.0082(1) C(18) -0.3131(4) 0.3151(4) 0.2618(6) Cl(2) 0.17137(10) 0.45567(8) 0.4495(1) C(19) -0.1110(4) 0.2882(3) 0.4516(5) Cl(3) 0.02953(9) 0.44822(9) 0.1329(1) C(20) -0.0696(4) 0.3426(4) 0.5932(5) S(l) 0.1149(1) 0.16519(10) 0.2600(2) C(21) -0.0755(5) 0.3011(5) 0.6927(6) S(2) -0.08971(10) 0.34429(8) 0.3277(1) C(22) -0.1225(5) 0.2073(5) 0.6510(7) S(3) 0.28516(9) 0.41504(8) 0.1919(1) C(23) -0.1653(5) 0.1520(4) 0.5078(7) 0(1) 0.1854(2) 0.2652(2) 0.2955(3) C(24) -0.1588(5) 0.1933(4) 0.4073(6) 0(2) 0.0299(2) 0.2870(2) 0.2400(3) C(25) 0.2887(4) 0.4226(3) 0.0221(5) 0(3) 0.3627(2) 0.3644(2) 0.2261(3) C(26) 0.3753(4) 0.4013(4) -0.0232(6) C(l) 0.1724(9) 0.1609(8) 0.446(1) C(27) 0.38675) 0.4101(5) -0.1474(6) C(la) 0.110(1) 0.1398910) 0.403(2) C(28) 0.3156(5) 0.4408(4) -0.2264(5) C(2) 0.1455(7) 0.2059(5) 0.5378(8) C(29) 0.2288(4) -0.4612(4) -0.1815(5) C(3) 0.1635(7) 0..1989(6) 0.6673(8) C(30) 0.2153(4) 0.4520(4) -0.0559(5) C(4) 0.234(1) 0.1611(10) 0.715(1) C(31) 0.3535(4) 0.5363((3) 0.3011(5) C(4a) 0.114(1) 0.111(1) 0.654(2) C(32) 0.4592(4) 0.5573(4) 0.3854(5) C(5) 0.284(1) 0.1181(10) 0.617(2) C(33) 0.5149(4) 0.6486(5) 0.4692(6) C(5a) 0.061(1) 0.039(1) 0.585(2) C(34) 0.4674(5) 0.7178(4) 0.4686(6) C(6) 0.2501(10) 0.1178(9) 0.477(1) C(35) 0.3620(5) 0.6952(4) 0.3841(6) C(6a) 0.057(1) 0.0544(9) 0.400(1) C(36) 0.3031(4) 0.6047(4) 0.3006(6) C(7) 0.1833(4) 0.0929(3) 0.1670(5) C(8) 0.1306(5) -0.0017(4) 0.1015(7) C(9) 0.1826(6) -0.0550(4) 0.0279(7) C(10) 0.2815(6) -0.0171(5) 0.0181(8) C(ll) 0.3322(6) 0.0748(5) 0.0790(9) C(12) 0.2839(5) 0.1322(4) 0.1554(7) C(13) -0.2235(4) 0.3068(3) 0.2094(5) C(14) -0.2380(4) 0.2797(4) 0.0659(6) C(15) -0.3398(6) 0.2580(4) -0.0250(6) C(16) -0.4284(5) 0.2667(5) 0.0278(7) Appendix 1.12 Crystallographic Data for R u C l 2 ( D M S O ) ( L ) Table A.1 51. Experimental Details for X-ray Crystal Structure of R u C l 2 ( D M S O ) ( L ) Empirical Formula C12H2oCl2ORuS5 Formula Weight 512.57 Crystal Colour, Habit red, prism Crystal Dimensions 0.12x0.15x0.35 mm Crystal System tetragonal Lattice Type Primitive No. of Reflections Used for Unit Cell 25 (56.1-64.1°) Determinations (2 Grange) Omega Scan Peak Width at Half-height 0.42° Lattice Parameters a = 20.784(2) A c = 9.284(2) A V = 4010(1) A 3 Space Group P42ic(# 114) Z Value 8 A.260 I. Appendix 1.698 g/cm3 Fooo 2064.00 wfCuKa) 136.13 cm"1 B. Intensity Measurements Diffractometer Rigaku AFC6S Radiation CuKcx (k = 1.54178 A) graphite monochromated Take-off Angle 6.0° Detector Aperature 6.0 mm horizontal 6.0 mm vertical Crystal to Detector Distance 285 mm Voltage, Current 0 kV, 0 mA Temperature 21.0 °C Scan Type ©-2 6> Scan Rate 8.0 7min (in co) (up to 9 scans) Scan Width (0.89 + 0.20 tan 0)° 26max 154.7° No. of Reflections Measured Total: 4647 Unique: 2428 (Rint = 0.063) Corrections Lorentz-polarization Absorption (trans, factors: 0.5012 - 1.0000) C. Structure Solution and Refinement Structure Solution Direct Methods (SIR92) Refinement Full-matrix least-squares Function Minimized Sco(|Fo|-|Fc|) 2 Least Squares Weights co = 1/G\FO) = [a2c(Fo) + p^Fo2]"1 p-factor 0.0000 Anomalous Dispersion All non-hydrogen atoms No. Observations (I>3.00a(I)) 1951 No. Variables 190 Reflection/Parameter Ratio 10.27 Residuals: R; Rw 0.033; 0.037 Goodness of Fit Indicator 0.81 Max Shift/Error in Final Cycle 0.00 Maximum peak in Final Diff. Map 0.58 e/A3 Minimum peak in Final Diff. Map -0.48 e/A3 Table A . l 52. Bond Angles (°) for RuCl 2(DMSO)(L) atom atom atom angle atom atom atom angle Cl(l) Ru(l) Cl(2) 90.39(9) Cl(2) Ru(l) S(l) 97.64(8) Cl(l) Ru(l) S(2) 86.46(9) Cl(2) Ru(D S(3) 88.41(8) Cl(l) Ru(l) S(5) 91.43(9) S(l) Ru(l) S(2) 85.64(9) Cl(2) Ru(D S(2) 175.80(9) S(D Ru(l) S(5) 86.14(8) ei(2) Ru(l) S(5) 90.53(9) S(2) Ru(D S(5) 92.31(9) S(l) Ru(l) S(3) 100.25(8) Ru(l) S(l) C(l) 106.5(3) S(2) Ru(l) S(3) 88.42(7) C(l) S(l) C(8) 92.3(5) S(3) Ru(D S(5) 173.61(9) Ru(l) S(2) C(3) 102.7(3) Ru(l) S(D C(8) 132.9(3) Ru(l) S(3) C(4) 100.9(3) Ru(D S(2) C(2) 106.4(3) C(4) S(3) C(5) 101.9(4) C(2) S(2) C(3) 97.3(5) Ru(D S(5) 0(1) 116.3(3) A.261 I. Appendix Ru(l) S(3) C(5) 112.0(3) Ru(l) S(5) C(12) 114.5(4) C(6) S(4) C(7) 100.7(4) 0(1) S(5) C(12) 105.8(5) Ru(l) S(5) C(ll) 113.0(4) S(l) C(l) C(2) 115.4(7) 0(1) S(5) C(ll) 104.5(7) C(2) C(l) C(10) 133.0(9) C(ll) S(5) C(12) 101.2(8) S(2) C(3) C(4) 109.6(6) S(D C(l) C(10) 111.0(7) S(3) C(5) C(6) 106.6(6) S(2) C(2) C(l) 110.3(7) S(4) C(7) C(8) 114.2(7) S(3) C(4) C(3) 111.7(6) S(l) C(8) C(9) 108.1(8) S(4) C(6) C(5) 113.9(6) C(8) C(9) C(10) 115.2(10) S(D C(8) C(7) 122.4(7) C(7) C(8) C(9) 129.4(9) C(l) C(10) C(9) 112.8(9) Cl(l) Ru(l) S(l) 171.63(8) Cl(l) Ru(D S(3) 82.27(8) Angles are in degrees. Estimated standard deviations in the least significant figure are given in parentheses. Table A . l 53. Bond Lengths (A) for RuCl 2(DMSO)(L) atom atom distance atom atom distance Ru(l) Cl(l) 2.400(2) Ru(l) S(5) 2.290(2) Ru(l) S(l) 2.320(2) S(D C(8) 1.749(9) Ru(l) S(3) 2.375(2) S(2) C(3) 1.846(10) S(l) C(l) 1.764(9) S(3) C(5) 1.808(9) S(2) C(2) 1.82(1) S(4) C(7) 1.81(1) S(3) C(4) 1.822(9) S(5) C(H) 1.75(1) S(4) C(6) 1.784(10) C(l) C(2) 1.48(1) S(5) 0(1) 1.479(8) C(3) C(4) 1.49(1) S(5) C(12) 1.79(1) C(7) C(8) 1.50(1) C(l) C(10) 1.32(1) C(9) C(10) 1.44(2) C(5) C(6) 1.57(1) C(8) C(9) 1.36(1) Ru(D Cl(2) 2.430(2) Ru(D S(2) 2.300(2) Distances are in angstroms. Estimated standard deviations in the least significant figure are given in parentheses. fable A.1 54. Atomic Coordinates for RuCl 2(DMSO)(L) atom X y z atom X y z Ru(D 0.49905(3) 0.21941(2) 0.32258(6) C(5) 0.3540(4) 0.1718(4) 0.168(1) Cl(l) 0.5282(1) 0.1497(1) 0.5180(3) C(6) 0.3148(4) 0.2298(5) 0.232(1) Cl(2) 0.4351(1) 0.2850(1) 0.4853(3) C(7) 0.3589(5) 0.3345(5) 0.077(1) S(l) 0.48339(9) 0.2801(1) 0.1157(2) C(8) 0.4150(5) 0.2991(4) 0.0147(10) S(2) 0.55666(10) 0.1508(1) 0.1771(3) C(9) 0.4247(6) 0.2784(6) -0.123(1) S(3) 0.41066(10) 0.14742(9) 0.3052(2) C(10) 0.4820(5) 0.2407(5) -0.1447(10) S(4) 0.2876(1) 0.2858(1) 0.0999(3) C(ll) 0.5677(6) 0.3652(5) 0.375(2) S(5) 0.5870(1) 0.2833(1) 0.3631(3) C(12) 0.6255(6) 0.2703(7) 0.533(1) 0(1) 0.6387(4) 0.2803(4) 0.2538(8) C(l) 0.5175(4) 0.2359(5) -0.027(1) C(2) 0.5732(5) 0.1950(5) 0.012(1) C(3) 0.4936(5) 0.0975(4) 0.104(1) C(4) 0.4490(4) 0.0780(4) 0.222(1) A.262 Appendix Appendix 1.13 Crystallographic Data for [Ru( 12-S-4)(DMSO)(H20)][OTf]2 Table A . l 55. Experimental Details for X-ray Crystal Structure of [Ru(12-S-4)(DMSO)(H 20)][OTf] 2 A. Crystal Data Empirical Formula C, 2H 2 4F 60 8RuS7 Formula Weight 735.80 Crystal Colour, Habit yellow, plate Crystal Dimensions 0.04x0.18x0.35 mm Crystal System monoclinic Lattice Type Primitive No. of Reflections Used for Unit Cell 5461 (3.0-76.6 °) Determinations (2 0 range) a= 11.6308(2) A b = 12.2220(2) A c = 18.0054(1) A (3 = 91.736(1)° V= 2558.32(5) A 3 Lattice Parameters Space Group P2,/n(#14) Z Value 4 1.910 g/cm3 Fooo 1480.00 12.64 cm"1 uOMoKoO B. Intensity Measurements Diffractometer Siemens SMART CCD Radiation MoKa (k = 0.71073 A) graphite monochromated Take-off Angle 2.8° Detector Aperature 35 mm circle Crystal to Detector Distance 2.964 mm Voltage, Current 50 kV, 40 mA Temperature -80.0 °C Scan Type CO Sec/frame 10 ScanWidth -0.30 ° 2 0max 67.0° No. of Reflections Measured Total: 27813 Unique: 9942 (R,„, = 0.055) Corrections Lorentz-polarization Absorption (trans, factors: 0.661 - 0.814) C. Structure Solution and Refinement Structure Solution Direct Methods Refinement Full-matrix least-squares Function Minimized zZa(\Fo\-\Fc\)2 Least Squares Weights © = l/a2(Fo2) = [ c T ^ o 2 ) ] " 1 p-factor 0.0000 Anomalous Dispersion All non-hydrogen atoms No. Observations 9942 No. Variables 403 Reflection/Parameter Ratio 24.67 Residuals (based on F2): R; Rw 0.064; 0.073 A.263 I. Appendix No. Observations (I>3cr(I)) 6560 Residuals (on F, I>3a(I)): Rl ; Rlw 0.042; 0.034 Goodness of Fit Indicator 1.44 Max Shift/Error in Final Cycle 0.005 Maximum peak in Final Diff. Map 2.04 e/A3 Minimum peak in Final Diff. Map -1.93 e/A3 Table A . 1 56. Bond Angles (°) for [Ru(12-S-4)(DMSO)(H 2 0)][OTf] 2 atom atom atom angle atom atom atom angle S(D Ru(l) S(2) 84.29(2) Ru(D S(2) C(3) 99.36(9) S(D Ru(l) S(4) 87.46(2) Ru(l) S(3) C(4) 103.87(8) S(l) Ru(D 0(1) 94.28(5) C(4) S(3) C(5) 100.6(1) S(2) Ru(D S(4) 91.98(2) Ru(l) S(4) C(7) 102.56(9) S(2) Ru(D 0(1) 87.62(5) Ru(l) S(5) 0(2) 113.97(7) S(3) Ru(l) S(5) 100.72(2) Ru(l) S(5) C(10) 114.18(9) S(4) RuO) S(5) 87.18(2) 0(2) S(5) C(10) 106.7(1) S(5) Ru(l) 0(1) 93.36(5) 0(3) S(6) 0(4) 114.4(1) Ru(D SO) C(8) 101.23(8) 0(3) S(6) C(H) 103.3(1) Ru(l) S(2) C(2) 98.96(9) 0(4) S(6) C(ll) 102.7(1) C(2) S(2) C(3) 106.2(1) 0(6) S(7) 0(7) 114.5(1) Ru(l) S(3) C(5) 101.31(8) 0(6) S(7) C(12) 102.9(1) Ru(D S(4) C(6) 102.59(9) 0(7) S(7) C(12) 103.3(1) C(6) S(4) C(7) 106.4(1) SO) CO) C(2) 113.5(2) Ru(l) S(5) C(9) 113.77(10) S(2) C(3) C(4) 106.6(2) 0(2) S(5) C(9) 107.8(1) S(3) C(4) C(3) 112.4(2) C(9) S(5) C(10) 99.3(1) S(4) C(6) C(5) 105.7(2) 0(3) S(6) 0(5) 113.3(1) SO) C(8) C(7) 113.9(2) 0(4) S(6) 0(5) 116.8(1) S(6) C(ll) F(2) 111.8(2) 0(5) S(6) C(ll) 102.2(1) F(D C(ll) F(2) 107.7(3) 0(6) S(7) 0(8) 115.5(1) F(2) C(ll) F(3) 107.4(3) 0(7) S(7) 0(8) 114.4(1) S(7) C(12) F(5) 110.4(2) 0(8) S(7) C(12) 103.9(1) F(4) C(12) F(5) 107.9(3) S(2) C(2) C(l) 107.7(2) F(5) C(12) F(6) 107.0(3) S(l) Ru(l) S(3) 116.83(2) S(3) C(5) C(6) 113.6(2) S(l) Ru(D S(5) 91.10(2) S(4) C(7) C(8) 105.7(2) S(2) Ru(l) S(3) 83.80(2) S(6) C(H) F(l) 110.8(2) S(2) Ru(l) S(5) 175.35(2) S(6) C(ll) F(3) 111.1(2) S(3) Ru(l) S(4) 87.35(2) F(l) C(ll) F(3) 107.9(2) S(3) Ru(l) 0(1) 90.83(5) S(7) C(12) F(4) 112.4(2) S(4) Ru(l) 0(1) 178.17(5) S(7) C(12) F(6) 111.2(2) Ru(l) SO) CO) 103.60(8) F(4) C(12) F(6) 107.8(3) CO) SO) C(8) 101.5(1) Angles are in degrees. Estimated standard deviations in the least significant figure are given in parentheses. Table A . l 57. Bond Lengths (A) for [Ru(12-S-4)(DMSO)(H 2 0)][OTfJ 2 atom atom distance atom atom distance Ru(l) SO) 2.3852(6) Ru(D S(2) 2.3708(6 RuO) S(3) 2.3907(6) RuO) S(4) 2.2903(6) Ru(l) S(5) 2.3011(6) Ru(l) 0(1) 2.193(2) SO) CO) 1.864(3) SO) C(8) 1.860(3) S(2) C(2) 1.822(3) S(2) C(3) 1.823(3) S(3) C(4) 1.872(3) S(3) C(5) 1.851(3) i A.264 I. Appendix S(4) C(6) 1.836(3) S(4) C(7) 1.837(3) S(5) 0(2) 1.494(2) S(5) C(9) 1.794(3) S(5) C(10) 1.798(3) S(6) 0(3) 1.461(2) S(6) 0(4) 1.445(2) S(6) 0(5) 1.444(2) S(6) C(ll) 1.837(3) S(7) 0(6) 1.442(2) S(7) 0(7) 1.463(2) S(7) 0(8) 1.442(2) S(7) C(12) 1.829(3) F(l) C(H) 1.341(4) F(2) C(H) 1.339(3) F(3) C(ll) 1.335(4) F(4) C(12) 1.331(4) F(5) C(12) 1.347(3) F(6) C(12) 1.344(4) C(l) C(2) 1.525(4) C(3) C(4) 1.526(4) C(5) C(6) 1.533(4) C(7) C(8) 1.528(4) Distances are in angstroms. Estimated standard deviations in the least significant figure are given in parentheses. Table A . l 58. Atomic Coordinates for [Ru(12-S-4)(DMSO)(H20)][OTf]2 atom X y Z Ru(l) 0.55767(2) 0.14052(2) 0.27009(1) S(l) 0.74761(5) 0.20227(5) 0.30121(3) S(2) 0.61800(5) -0.02319(5) 0.33019(4) S(3) 0.38734(5) 0.03806(5) 0.24033(3) S(4) 0.62666(5) 0.08322(5) 0.15882(3) S(5) 0.51429(5) 0.30424(5) 0.21269(3) S(6) 0.16915(6) 0.16505(6) 0.37392(4) S(7) 0.69027(5) 0.33126(6) 0.50386(3) F(l) 0.0652(2) 0.1233(2) 0.4986(1) F(2) 0.0796(2) 0.2961(2) 0.4738(1) F(3) 0.2286(2) 0.2062(2) 0.5133(1) F(4) 0.6086(2)) 0.5146(2) 0.5591(1) F(5) 0.6536(2) 0.3909(2) 0.64105(9) F(6) 0.4987(2) 0.3739(2) 0.5724(1) O(l) 0.4868(2) 0.1919(2) 0.37607(10) 0(2) 0.6159(1) 0.3609(1) 0.18159(10) 0(3) 0.2570(1) 0.2455(2) 0.3561(1) 0(4) 0.2113(2) 0.0542(2) 0.3809(1) 0(5) 0.0623(2) 0.1804(2) 0.3323(1) 0(6) 0.6857(2) 0.2205(2) 0.5312(1) 0(7) 0.6251(2) 0.3498(2) 0.43423(9) 0(8) 0.8023(2) 0.3819(2) 0.5072(1) C(l) 0.7993(2) 0.1031(2) 0.3734(1) C(2) 0.7030(2) 0.0361(2) 0.4067(2) C(3) 0.4819(2) -0.0648(2) 0.3691(2) C(4) 0.3982(2) -0.0835(2) 0.3034(2) C(5) 0.4252(2) -0.0251(1) 0.1509(1) C(6) 0.5540(2) -0.0488(2) 0.1447(2) C(7) 0.7778(2) 0.0519(2) 0.1827(2) C(8) 0.8271(2) 0.1555(2) 0.2189(2) C(9) 0.4062(2) 0.2933(2) 0.1398(2) C(10) 0.4449(2) 0.4018(2) 0.2712(2) C(ll) 0.1338(3) 0.1997(2) 0.4699(2) C(12) 0.6087(3) 0.4074(2) 0.5721(2) A.265 I. Appendix Table A . l 59. Hydrogen bonds and C-H. . . .O/F interactions. A H B A....B A-H H B A-H....B 0(1) H(l) 0(3) 2.765(3) 0.84(4) 1.96(4) 178(4) 0(1) H(2) 0(7) 2.703(3) 0.85(3) 1.85(4) 173(3) C(l) H(3) 0(2) 3.283(3) 0.91(2) 2.53(3) 140(2) C(2) H(5) 0(6) 3.189(4) 0.93(3) 2.46(3) 135(2) C(2) H(6) F(3) 3.378(3) 0.92(3) 2.50(3) 161(2) C(3) H(7) 0(1) 3.141(4) 0.91(2) 2.55(3) 124(2) C(4) H(10) 0(4) 3.112(4) 0.95(3) 2.49(3) 122(2) C(5) H(ll) 0(8) 3.401(3) 0.95(3) 2.46(3) 169(2) C(6) H(14) 0(8) 3.357(3) 0.93(3) 2.46(3) 161(2) C(8) H(17) 0(5) 3.378(3) 0.94(3) 2.51(3) 154(2) C(10) H(23) 0(3) 3.311(3) 0.96(3) 2.40(3) 158(2) Appendix 1.14 Crystallographic Data for Ru(OEP)(CO)(THF) Table A . l 60. Experimental Details for X-ray Crystal Structure of Ru(OEP)(CO)(THF) A. Crystal Data Empirical Formula C41H52N4O2RU Formula Weight 733.96 Crystal Colour, Habit red, irregular Crystal Dimensions 0.30x0.15 x 0.08 mm Crystal System monoclinic Lattice Type Primitive Lattice Parameters a = 10.4420(8) A b = 32.418(2) A c= 10.7811(2) A (3 = 99.5847(7) 0 V = 3598.6(3) A 3 Space Group P2,/c (# 14) Z Value 4 1.355 g/cm3 Fooo 1544.00 «(MoKa) 4.77 cm"1 B. Intensity Measurements Diffractometer Rigaku/ADSC CCD Radiation MoKa (k = 0.71069 A) graphite monochromated Detector Aperature 94 mm x 94 mm Data Images 768 exposures of 30.0 seconds ^oscillation Range (x = -90) 0.0 -189.9 0 co oscillation Range (% = -90) -23.0 -17.8 0 Detector Position 39.218(8) mm Detector Swing Angle -10.0° 2 0max 60.1° No. of Reflections Measured Total: 33364 Corrections Unique: 9166 (R,„, = 0.057) Lorentz-polarization Absorption/scaling 1 i : (trans, factors: 0.8404 - 1.0000) i • ' I ; ; A.266 i i I. Appendix C. Structure Solution and Refinement Structure Solution Patterson Methods (DIRDIF92 PATTY) Refinement Full-matrix least-squares Function Minimized I C O ( | F O 2 | - | F C 2 | ) 2 Least Squares Weights co = l/a2(Fo2) p-factor 0.0000 Anomalous Dispersion All non-hydrogen atoms No. Observations 9166 No. Variables . 505 Reflection/Parameter Ratio 18.15 Residuals (on F 2 , all data): R; Rw 0.096; 0.077 Goodness of Fit Indicator 1.21 No. Observations (I>3cr(I)) 4171 Residuals (on F, I>3a(I)): R; Rw 0.044; 0.034 Max Shift/Error in Final Cycle 0.01 Maximum peak in Final Diff. Map 3.07 e'/A3 (1.37 A from Ru) Minimum peak in Final Diff. Map -2.21 e/A3 Table A . l 61. Bond Angles (°) for Ru(OEP)(CO)(THF) atom atom atom angle atom atom atom angle 0(2) Ru(D N(l) 87.0(1) C(16) N(4) C(19) 106.6(3) 0(2) Ru(l) N(2) 85.3(1) N(l) C(l) C(2) 110.2(3) 0(2) Ru(l) N(3) 87.0(1) N(l) C(l) C(20) 124.1(3) 0(2) Ru(l) N(4) 87.4(1) C(2) C(l) C(20) 125.6(3) 0(2) Ru(D C(37) 177.2(1) C(l) C(2) C(3) 106.6(3) N(l) Ru(l) N(2) 89.89(9) C(l) C(2) C(21) 125.2(3) N(l) Ru(D N(3) 174.0(1) C(3) C(2) C(21) 128.2(3) N(l) Ru(l) N(4) 90.0(1) C(2) C(3) C(4) 107.6(3) N(l) Ru(l) C(37) 92.5(1) C(2) C(3) C(23) 128.4(3) N(2) Ru(D N(3) 89.5(1) C(4) C(3) C(23) 124.0(3) N(2) Ru(D N(4) 172.7(1) N(l) C(4) C(3) 108.7(3) N(2) Ru(D C(37) 97.4(1) N(l) C(4) C(5) 124.6(3) N(3) Ru(l) N(4) 89.8(1) C(3) C(4) C(5) 126.7(3) N(3) Ru(l) C(37) 93.5(1) C(4) C(5) C(6) 127.8(3) N(4) Ru(l) C(37) 89.9(1) N(2) C(6) C(5) 124.8(3) Ru(l) 0(2) C(38) 123.1(3) N(2) C(6) C(7) 109.9(3) Ru(l) 0(2) C(41) 127.1(3) C(5) C(6) C(7) 125.3(3) C(38) 0(2) C(41) 109.0(4) C(6) C(7) C(8) 106.6(3) Ru(l) N(l) C(l) 126.7(2) C(6) C(7) C(25) 125.3(3) Ru(l) N(l) C(4) 126.3(2) C(8) C(7) C(25) 128.1(3) C(l) N(l) C(4) 106.9(3) C(7) C(8) C(9) 106.8(3) Ru(l) N(2) C(6) 126.5(2) C(7) C(8) C(27) 127.7(3) Ru(D N(2) C(9) 126.3(2) C(9) C(8) C(27) 125.4(3) C(6) N(2) C(9) 107.2(3) N(2) C(9) C(8) 109.5(3) Ru(D N(3) C(H) 126.6(2) N(2) C(9) C(10) 124.8(3) Ru(l) N(3) C(14) 125.6(2) C(8) C(9) C(10) 125.7(3) C(ll) N(3) C(14) 107.7(3) C(9) C(10) C(ll) 127.7(3) Ru(D N(4) C(16) 126.6(2) N(3) C(ll) C(10) 124.6(3) Ru(D N(4) C(19) 126.7(2) N(3) C(ll) C(12a) 106.3(5) N(3) C(H) C(12) 110.4(4) C(13) C(13a) C(14) 81(1) C(10) C(ll) C(12a) 124.3(5) C(13) C(13a) C(31) 60(1) C(10) C(ll) C(12) 124.5(4) C(13) C(13a) C(31a) 97(1) C(12a) C(ll) C(12) 30.4(4) C(14) C(13a) C(31) 113.6(8) A.267 I. Appendix C(ll) C(12a) C(12) 76(1) C(14) C(13a) C(31a) 127.1(9) C(ll) C(12a) C(13) 99.2(7) C(31) C(13a) C(31a) 37.1(6) C(ll) C(12a) C(13a) 106.6(9) N(3) C(14) C(13) 108.2(4) C(ll) C(12a) C(29a) 124.6(9) N(3) C(14) C(13a) 107.7(5) C(ll) C(12a) C(29) 109.2(8) N(3) C(14) C(15) 125.0(3) C(12) C(12a) C(13) 63(1) C(13) C(14) C(13a) 30.5(4) C(12) C(12a) C(13a) 95(2) C(13) C(14) C(15) 126.1(4) C(12) C(12a) C(29a) 90(1) C(13a) C(14) C(15) 123.1(6) C(12) C(12a) C(29) 56(1) C(14) C(15) C(16) 127.5(3) C(13) C(12a) C(13a) 31.1(5) N(4) C(16) C(15) 125.2(3) C(13) C(12a) C(29a) 122.1(9) N(4) C(16) C(17) 110.4(3) C(13) C(12a) C(29) 101.2(8) C(15) C(16) C(17) 124.4(3) C(13a) C(12a) C(29a) 128(1) C(16) C(17) C(18) 106.6(3) C(13a) C(12a) C(29) 124(1) C(16) C(17) C(33) 125.1(3) C(29a) C(12a) C(29) 34.1(6) C(18) C(17) C(33) 128.2(3) C(ll) C(12) C(12a) 73(1) C(17) C(18) C(19) 106.9(3) C(ll) C(12) C(13) 105.7(6) C(17) C(18) C(35a) 127.4(5) C(ll) C(12) C(13a) 93.6(6) C(17) C(18) C(35) 125.2(5) C(ll) C(12) C(29a) 111.8(6) C(19) C(18) C(35a) 120.2(5) C(ll) C(12) C(29) 125.8(7) C(19) C(18) C(35) 126.9(5) C(12a) C(12) C(13) 86(1) C(35a) C(18) C(35) 30.1(5) C(12a) C(12) C(13a) 57(1) N(4) C(19) C(18) 109.4(3) C(12a) C(12) C(29a) 63(1) N(4) C(19) C(20) 124.1(3) C(12a) C(12) C(29) 98(1) C(18) C(19) C(20) 126.4(3) C(13) C(12) C(13a) 29.0(4) C(l) C(20) C(19) 128.0(3) C(13) C(12) C(29a) 119.7(7) C(2) C(21) C(22) 112.3(4) C(13) C(12) C(29) 127.3(8) C(3) C(23) C(24) 115.1(4) C(13a) C(12) C(29a) 102.5(7) C(7) C(25) C(26) 112.5(3) C(13a) C(12) C(29) 126.5(8) C(8) C(27) C(28) 113.4(3) C(29a) C(12) C(29) 34.5(5) C(12a) C(29a) C(12) 26.7(5) C(12a) C(13) C(12) 30.9(5) C(12a) C(29a) C(29) 84(1) C(12a) C(13) C(13a) 63(1) C(12a) C(29a) C(30) 158(2) C(12a) C(13) C(14) 95.3(6) C(12a) C(29a) C(30a) 104(1) C(12a) C(13) C(31) 124.4(7) C(12) C(29a) C(29) 57.0(9) C(12) C(13) C(13a) 94(1) C(12) C(29a) C(30) 169(2) C(12) C(13) C(14) 106.8(6) C(12) C(29a) C(30a) 77.8(9) C(12) C(13) C(31) 129.2(8) C(29) C(29a) C(30) 116(2) C(13a) C(13) C(14) 68(1) C(29) C(29a) C(30a) 22.3(9) C(13a) C(13) C(31) 92(1) C(30) C(29a) C(30a) 97(1) C(14) C(13) C(31) 122.2(7) C(12a) C(29) C(12) 26.3(4) C(12a) C(13a) C(12) 28.8(5) C(12a) C(29) C(29a) 62(1) C(12a) C(13a) C(13) 86(1) C(12a) C(29) C(30) 90.3(7) C(12a) C(13a) C(14) 107.3(9) C(12a) C(29) C(30a) 160(2) C(12a) C(13a) C(31) 119.6(9) C(12) C(29) C(29a) 88(1) C(12a) C(13a) C(31a) 125(1) C(12) C(29) C(30) 116.6(7) C(12) C(13a) C(13) 57(1) C(12) C(29) C(30a) 142(2) C(12) C(13a) C(14) 98.8(7) C(29a) C(29) C(30) 28.6(9) C(12) C(13a) C(31) 101.1(8) C(29a) C(29) C(30a) 123(3) C(12) C(13a) C(31a) 124.5(9) C(30) C(29) C(30a) 98(2) C(29a) C(30) C(29) 35(1) C(31) C(32a) C(32) 69(2) C(29a) C(30) C(30a) 55(1) C(31a) C(32a) C(32) 26.6(6) C(29) C(30) C(30a) 21.9(4) C(17) C(33) C(34) 112.3(3) C(29a) C(30a) C(29) 34(2) C(18) C(35a) C(35) 61(1) A.268 I. Appendix C(29a) C(30a) C(30) 27.5(5) C(18) C(35a) C(36) 160(2) C(29) C(30a) C(30) 60(2) C(18) C(35a) C(36a) 93(1) C(13) C(31) C(13a) 27.6(4) C(35) C(35a) C(36) 137(3) C(13) C(31) C(31a) 93(1) C(35) C(35a) C(36a) 35(1) C(13) C(31) C(32) 117.2(9) C(36) C(35a) C(36a) 107(2) C(13) C(31) C(32a) 153(2) C(18) C(35) C(35a) 89(1) C(13a) C(31) C(31a) 66(1) C(18) C(35) C(36) 109.6(7) C(13a) C(31) C(32) 89.7(8) C(18) C(35) C(36a) 147(1) C(13a) C(31) C(32a) 168(2) C(35a) C(35) C(36) 21(1) C(31a) C(31) C(32) 25(1) C(35a) C(35) C(36a) 113(2) C(31a) C(31) C(32a) 111(3) C(36) C(35) C(36a) 96(1) C(32) C(31) C(32a) 86(2) C(35a) C(36) C(35) 22(1) C(13a) C(31a) C(31) 77(1) C(35a) C(36a) C(35) 32(1) C(13a) C(31a) C(32) 157(2) Ru(l) C(37) 0(1) 176.6(3) C(13a) C(31a) C(32a) 103(1) 0(2) C(38) C(39) 108.7(4) C(31) C(31a) C(32) 119(3) C(38) C(39) C(40) 104.6(4) C(31) C(31a) C(32a) 26.9(9) C(39) C(40) C(41) 103.7(4) C(32) C(31a) C(32a) 92(2) 0(2) C(41) C(40) 112.0(5) C(31) C(32) C(31a) 37(2) C(31) C(32) C(32a) 25.3(4) C(31a) C(32) C(32a) 62(2) C(31) C(32a) C(31a) 42(2) Angles are in degrees. Estimated standard deviations in the least significant figure are given in parentheses. Table A . l 62. Bond Lengths (A) for Ru(OEP)(CO)(THF) atom atom distance atom atom distance Ru(D 0(2) 2.241(3) C(3) C(23) 1.524(5) Ru(l) N(l) 2.052(2) C(4) C(5) 1.387(4) Ru(D N(2) 2.059(2) C(5) C(6) 1.392(4) Ru(D N(3) 2.056(2) C(6) C(7) 1.454(4) Ru(l) N(4) 2.054(3) C(7) C(8) 1.362(4) Ru(l) C(37) 1.805(4) C(7) C(25) 1.512(4) 0(1) C(37) 1.144(4) C(8) C(9) 1.452(4) 0(2) C(38) 1.413(5) C(8) C(27) 1.510(4) 0(2) C(41) 1.306(6) C(9) C(10) 1.388(4) N(l) C(l) 1.364(4) C(10) C(H) 1.382(5) N(l) C(4) 1.374(4) C(ll) C(12a) 1.49(1) N(2) C(6) 1.360(3) C(H) C(12) 1.507(9) N(2) C(9) 1.371(3) C(12a) C(12) 0.78(1) N(3) C(H) 1.370(4) C(12a) C(13) 1.52(1) N(3) C(14) 1.376(4) C(12a) C(13a) 1.36(2) N(4) C(16) 1.354(4) C(12a) C(29a) 1.56(2) N(4) C(19) 1.361(4) C(12a) C(29) 1.75(1) C(l) C(2) 1.443(4) C(12) C(13) 1.37(1) C(l) C(20) 1.393(5) C(12) C(13a) 1.62(1) C(2) C(3) 1.348(5) C(12) C(29a) 1.75(2) C(2) C(21) 1.493(5) C(12) C(29) 1.46(1) C(3) C(4) 1.455(4) C(13) C(13a) 0.79(1) C(13) C(14) 1.535(8) C(29a) C(30a) 1.47(2) C(13) C(31) 1.48(1) C(29) C(30) 1.54(1) C(13a) C(14) 1.44(1) C(29) C(30a) 0.67(1) C(13a) C(31) 1.70(1) C(30) C(30a) 1.76(2) C(13a) C(31a) 1.59(2) C(31) C(31a) 1.05(2) I '- •• - A.269 I. Appendix C(14) C(15) 1.391(5) C(31) C(32) 1.56(2) C(15) C(16) 1.376(4) C(31) C(32a) 0.71(1) C(16) C(17) 1.441(4) C(31a) C(32) 0.75(1) C(17) C(18) 1.342(4) C(31a) C(32a) 1.47(2) C(17) C(33) 1.510(4) C(32) C(32a) 1.67(2) C(18) C(19) 1.451(5) C(33) C(34) 1.526(5) C(18) C(35a) 1.70(2) C(35a) C(35) 0.85(1) C(18) C(35) 1.483(9) C(35a) C(36) 0.79(1) C(19) C(20) 1.405(5) C(35a) C(36a) 1.49(2) C(21) C(22) 1.504(7) C(35) C(36) 1.53(1) C(23) C(24) 1.494(6) C(35) C(36a) 0.93(1) C(25) C(26) 1.519(5) C(38) C(39) 1.504(6) C(27) C(28) 1.510(5) C(39) C(40) 1.466(7) C(29a) C(29) 0.99(1) C(40) C(41) 1.498(7) C(29a) C(30) 0.82(1) Distances are in angstroms. Estimated standard deviations in the least significant figure are given in parentheses. Table A . l 63. Atomic Coordinates for Ru(OEP)(CO)(THF) atom X y z atom X y z Ru(D 0.56609(3) 0.373289(8) 0.26066(3) C(33) 0.1207(3) 0.38011(12) 0.4961(4) O(l) 0.3995(2) 0.37021(8) 0.0117(2) C(34) 0.1720(4) 0.3655(2) 0.6297(4) 0(2) 0.6812(2) 0.37786(9) 0.4552(2) C(35a) 0.1566(13) 0.4763(5) 0.3869(13) N(l) 0.6195(3) 0.43320(7) 0.2352(3) C(35) 0.2017(9) 0.4719(3) 0.4592(8) N(2) 0.7369(2) 0.35312(7) 0.2095(3) C(36) 0.0976(8) 0.4906(3) 0.3582(10) N(3) 0.5239(3) 0.31366(8) 0.3047(3) C(36a) 0.2160(11) 0.4953(4) 0.5085(11) N(4) 0.4086(2) 0.39373(8) 0.3348(3) C(37) 0.4671(3) 0.37092(10) 0.1067(4) C(l) 0.5511(4) 0.46782(9) 0.2544(4) C(38) 0.7628(5) 0.3459(2) 0.5117(5) C(2) 0.6162(4) 0.50401(10) 0.2180(4) C(39) 0.8182(4) 0.3585(2) 0.6441(5) C(3) 0.7260(4) 0.49074(10) 0.1805(4) C(40) 0.7680(8) 0.4003(2) 0.6567(5) C(4) 0.7287(4) 0.44597(10) 0.1906(4) C(41) 0.6694(8) 0.40574(15) 0.5400(6) C(5) 0.8258(3) 0.41992(9) 0.1636(3) C(25) 1.0600(3) 0.36703(10) 0.1057(3) C(6) 0.8309(3) 0.37710(10) 0.1731(3) C(26) 1.0404(3) 0.37301(12) -0.0360(4) C(7) 0.9389(3) 0.35150(9) 0.1502(3) C(27) 0.9858(3) 0.27338(10) 0.1633(4) C(8) 0.9058(3) 0.31178(9) 0.1714(3) C(28) 0.9548(4) 0.25166(10) 0.0381(4) C(9) 0.7782(3) 0.31302(9) 0.2081(3) C(29a) 0.6058(12) 0.2013(4) 0.3739(13) C(10) 0.7092(3) 0.27911(10) 0.2399(4) C(29) 0.5561(10) 0.1982(2) 0.2878(11) C(H) 0.5918(4) 0.27897(10) 0.2831(4) C(30) 0.6565(7) 0.1826(2) 0.3987(8) C(12a) 0.5495(12) 0.2460(3) 0.3630(11) C(30a) 0.5370(13) 0.1801(3) 0.2624(15) C(12) 0.5121(8) 0.2409(3) 0.2954(7) C(31) 0.3079(7) 0.2304(3) 0.3958(12) C(13) 0.4039(7) 0.2543(2) 0.3395(7) C(31a) 0.3569(14) 0.2351(4) 0.4884(15) C(13a) 0.4427(11) 0.2606(3) 0.4060(10) C(32) 0.3215(10) 0.2309(3) 0.5418(10) C(14) 0.4167(4) 0.30131(11) 0.3540(4) C(32a) 0.2451(12) 0.2216(4) 0.3958(15) C(15) 0.3253(3) 0.32777(11) 0.3911(4) C(16) 0.3225(3) 0.37014(11) 0.3838(3) C(17) 0.2277(3) 0.39571(11) 0.4298(3) C(18) 0.2585(4) 0.43493(11) 0.4078(4) C(19) 0.3723(4) 0.43364(11) 0.3469(4) C(20) 0.4375(4) 0.46771(11) 0.3063(5) C(21) 0.5673(5) 0.54719(11) 0.2215(6) C(22) 0.4545(5) 0.55555(12) 0.1184(6) C(23) 0.8313(4) 0.51621(11) 0.1342(5) C(24) 0.8188(4) 0.51964(13) -0.0054(5) A.270 I. Appendix Figure A.1.7. Stereoview of Ru(OEP)(CO)(THF). A . 2 7 1 I. Appendix Appendix 1.15 Crystallographic Data for Ru(TPhP)(CO)(py). Table A . l 64. Experimental Details for X-ray Crystal Structure of Ru(TPhP)(CO)(py) A. Crystal Data Empirical Formula CsosofttsNjORu Formula Weight 959.09 Crystal Colour, Habit red, plate Crystal Dimensions 0.50x0.45x0.12 mm Crystal System triclinic Lattice Parameters a = 10.6294(3) A b= 11.6314(3) A c = 19.6878(5) A a = 96.460(1) ° P = 99.5847(7) ° y = 9 3 . 8 1 5 ( l ) ° V= 2409.81(11) A 3 Space Group PI Z Value 2 D c a ; c 1.322 Mg/m3 Fooo 990 absorption coefficient 0.373 mm"1 B. Data Collection Diffractometer Siemens SMART Platform CCD Wavelength 0.71073 A Temperature 173(2)K 6 range for data collection 1.77 to 25.01 ° Index ranges -10</?<12, -11<A:<13, -21</<23 Reflections Collected 11799 Independent Reflections 7993 (Rw = 0.0223) C. Solution and Refinement System used SHELXTL-V5.0 Solution Direct Methods Refinement method Full-matrix least-squares on F 2 Weighting Scheme co = l/a2(Fo2)+(AP)2(BP), where P = (Fo2+2Fc2)/3, A = 0.0291, and B= 1.9388 Absorption correction SADABS (Sheldrick, 1996) Max. and min. transmission 0.96 and 0.83 Data/restraints/parameters 7993/13/646 Final R indices [I>2a(I)] Rl = 0.0369, wR2 = 0.0814 R indices (all data) Rl = 0.0478, wR2 = 0.0868 Goodness of Fit on F 2 1.017 Largest diff. peak and hole 0.345 and -0.391 eA3 Table A.1 65. Bond Angles (°) for Ru(TPhP)(CO)(py) atoms angle atoms angle C(45)-Ru(l)-N(4) 91.53(10) C(ll)-C(10)-C(27) 118.0(2) C(45)-Ru(l)-N(l) 92.91(10) N(3)-C(ll)-C(10) 125.9(2) N(4)-Ru(l)-N(l) 89.81(8) N(3)-C(ll)-C(12) 108.8(2) C(45)-Ru(l)-N(3) 90.06(10) C(10)-C(ll)-C(12) 125.3(2) N(4)-Ru(l)-N(3) 90.14(8) C(13)-C(12)-C(ll) 107.2(2) A.272 N(l)-Ru(l)-N(3) C(45)-Ru(l)-N(2) N(4)-Ru(l)-N(2) N(l)-Ru(l)-N(2) N(3)-Ru(l)-N(2) C(45)-Ru(l)-N(5) N(4)-Ru(l)-N(5) N(l)-Ru(l)-N(5) N(3)-Ru(l)-N(5) N(2)-Ru(l)-N(5) C(l)-N(l)-C(4) C(l)-N(l)-Ru(l) C(4)-N(l)-Ru(l) N(l)-C(l)-C(20) N(l)-C(l)-C(2) C(20)-C(l)-C(2) C(9)-N(2)-C(6) C(9)-N(2)-Ru(l) C(6)-N(2)-Ru(l) C(3)-C(2)-C(l) C(14)-N(3)-C(ll) C(14)-N(3)-Ru(l) C(ll)-N(3)-Ru(l) C(2)-C(3)-C(4) C(16)-N(4)-C(19) C(16)-N(4)-Ru(l) C(19)-N(4)-Ru(l) N(l)-C(4)-C(5) N(l)-C(4)-C(3) C(5)-C(4)-C(3) C(46)-N(5)-C(50) C(46)-N(5)-Ru(l) C(50)-N(5)-Ru(l) C(6)-C(5)-C(4) C(6)-C(5)-C(21) C(4)-C(5)-C(21) N(2)-C(6)-C(5) N(2)-C(6)-C(7) C(5)-C(6)-C(7) C(8)-C(7)-C(6) C(7)-C(8)-C(9) N(2)-C(9)-C(10) N(2)-C(9)-C(8) C(10)-C(9)-C(8) C(9)-C(10)-C(ll) C(42)-C(41)-C(40) C(43)-C(42)-C(41) C(42)-C(43)-C(44) C(39)-C(44)-C(43) 0(1)-C(45)-Ru(l) N(5)-C(46)-C(47) C(48)-C(47)-C(46) C(49)-C(48)-C(47) C(48)-C(49)-C(50) 177.03(8) 93.37(10) 175.09(8) 89.80(8) 90.00(8) 178.27(10) 87.91(8) 88.73(8) 88.30(8) 87.19(8) 107.3(2) 126.4(2) 126.3(2) 126.0(2) 108.9(2) 125.2(2) 107.3(2) 126.1(2) 126.6(2) 107.7(2) 107.5(2) 126.2(2) 126.2(2) 107.3(3) 107.2(2) 126.2(2) 126.6(2) 125.7(2) 108.9(2) 125.3(3) 117.0(3) 121.9(2) 121.1(2) 125.9(3) 117.2(2) 116.9(2) 125.5(2) 108.9(2) 125.6(3) 107.4(2) 107.3(2) 126.4(2) 109.0(2) 124.6(2) 125.3(2) 120.7(4) 118.7(3) 120.8(3) 121.7(3) 177.8(2) 122.9(3) 118.5(3) 120.1(3) 118.7(3) C(12)-C(13)-C(14) N(3)-C(14)-C(15) N(3)-C(14)-C(13) C(15)-C(14)-C(13) C(16)-C(15)-C(14) C(16)-C(15)-C(33) C(14)-C(15)-C(33) N(4)-C(16)-C(15) N(4)-C(16)-C(17) C(15)-C(16)-C(17) C(18)-C(17)-C(16) C(17)-C(18)-C(19) N(4)-C(19)-C(20) N(4)-C(19)-C(18) C(20)-C(19)-C(18) C(19)-C(20)-C(l) C(19)-C(20)-C(39) C(l)-C(20)-C(39) C(22)-C(21)-C(26) C(22)-C(21)-C(5) C(26)-C(21)-C(5) C(21)-C(22)-C(23) C(24)-C(23)-C(22) C(25)-C(24)-C(23) C(24)-C(25)-C(26) C(21)-C(26)-C(25) C(28)-C(27)-C(32) C(28)-C(27)-C(10) C(32)-C(27)-C(10) C(27)-C(28)-C(29) C(30)-C(29)-C(28) C(31)-C(30)-C(29) C(30)-C(31)-C(32) C(31)-C(32)-C(27) C(38)-C(33)-C(34) C(38)-C(33)-C(15) C(34)-C(33)-C(15) C(33)-C(34)-C(35) C(36)-C(35)-C(34) C(37)-C(36)-C(35) C(36)-C(37)-C(38) C(33)-C(38)-C(37) C(40)-C(39)-C(44) C(40)-C(39)-C(20) C(44)-C(39)-C(20) C(57)-C(52)-C(51) C(53)-C(52)-C(51) C(52)-C(53)-C(54) C(55)-C(54)-C(53) C(54)-C(55)-C(56) C(57)-C(56)-C(55) C(52)-C(57)-C(56) C(60)-C(59)-C(58) C(59)-C(60)-C(61) A.273 I. Appendix N(5)-C(50)-C(49) 122.8(3) C(39)-C(40)-C(41) 121.0(3) C(57)-C(52)-C(53) 118.3(3) Table A.1 66. Bond Lengths (A) for Ru(TPhP)(CO)(py) atom distance atom distance Ru(l)-C(45) 1.837(3) C(ll)-C(12) 1.449(4) Ru(l)-N(4) 2.057(2) C(12)-C(13) 1.351(4) Ru(l)-N(l) 2.057(2) C(13)-C(14) 1.447(4) Ru(l)-N(3) 2.062(2) C(14)-C(15) 1.404(4) Ru(l)-N(2) 2.062(2) C(15)-C(16) 1.401(4) Ru(l)-N(5) 2.207(2) C(15)-C(33) 1.504(4) N(l)-C(l) 1.377(3) C(16)-C(17) 1.448(4) N(l)-C(4) 1.379(3) C(17)-C(18) 1.346(4) C(l)-C(20) 1.403(4) C(18)-C(19) 1.446(4) C(l)-C(2) 1.444(4) C(19)-C(20) 1.401(4) 0(1)-C(45) 1.151(3) C(20)-C(39) 1.497(4) N(2)-C(9) 1.374(3) C(21)-C(22) 1.382(4) N(2)-C(6) 1.377(3) C(21)-C(26) 1.386(4) C(2)-C(3) 1.350(4) C(22)-C(23) 1.403(5) N(3)-C(14) 1.377(3) C(23)-C(24) 1.371(6) N(3)-C(ll) 1.381(3) C(24)-C(25) 1.362(7) C(3)-C(4) 1.447(4) C(25)-C(26) 1.387(5) N(4)-C(16) 1.378(3) C(27)-C(28) 1.380(4) N(4)-C(19) 1.378(3) C(27)-C(32) 1.388(4) C(4)-C(5) 1.402(4) C(28)-C(29) 1.390(4) N(5)-C(46) 1.343(4) C(29)-C(30) 1.377(4) N(5)-C(50) 1.349(4) C(30)-C(31) 1.369(4) C(5)-C(6) 1.403(4) C(31)-C(32) 1.381(4) C(5)-C(21) 1.505(4) C(33)-C(38) 1.360(4) C(6)-C(7) 1.445(4) C(33)-C(34) 1.367(4) C(7)-C(8) 1.352(4) C(34)-C(35) 1.389(5) C(8)-C(9) 1.447(4) C(35)-C(36) 1.358(5) C(9)-C(10) 1.404(4) C(36)-C(37) 1.347(5) C(10)-C(ll) 1.406(4) C(37)-C(38) 1.397(5) G(10)-C(27) 1.505(4) C(39)-C(40) 1.370(4) C(39)-C(44) 1.374(4) C(56)-C(57) 1.379(5) C(40)-C(41) 1.395(5) C(58)-C(59) 1.576(8) G(41)-C(42) 1.367(5) C(59)-C(60) 1.366(6) C(42)-C(43) 1.350(5) C(60)-C(61) 1.396(6) C(43)-C(44) 1.386(5) C(46)-C(47) 1.379(4) C(47)-C(48) 1.365(5) C(48)-C(49) 1.360(5) C(49)-C(50) 1.377(4) C(51)-C(52) 1.515(5) C(52)-C(57) 1.382(5) C(52)-C(53) 1.379(5) C(53)-C(54) 1.395(5) C(54)-C(55) 1.374(5) C(55)-C(56) 1.378(5) A.274 I. Appendix Table A . l 67. Atomic Coordinates for Ru(TPhP)(CO)(py) atom X y z atom X y z Ru(l) 1156(1) 1742(1) 7607(1) C(25) -4819(4) 3675(5) 6583(2) N(l) 340(2) 2210(2) 6721(1) C(26) -3763(3) 3110(4) 6758(2) C(l) 779(3) 2010(2) 6074(1) C(27) 223(2) 2353(2) 10067(1) 0(1) -244(2) -595(2) 7448(1) C(28) 570(3) 3383(3) 10472(2) N(2) -219(2) 2529(2) 8159(1) C(29) 272(4) 3555(3) 11154(2) C(2) -88(3) 2440(2) 5593(1) C(30) -384(3) 2683(3) 11438(2) N(3) 2025(2) 1355(2) 8503(1) C(31) -752(3) 1665(3) 11039(2) C(3) -1032(3) 2891(2) 5948(1) C(32) -460(3) 1496(3) 10360(1) N(4) 2611(2) 1093(2) 7064(1) C(33) 5066(3) -115(2) 8188(1) C(4) -772(3) 2746(2) 6661(1) C(34) 6193(3) 532(3) 8301(2) N(5) 2256(2) 3437(2) 7755(1) C(35) 7309(3) 26(4) 8442(2) C(5) -1503(2) 3139(2) 7203(1) C(36) 7300(3) -1138(3) 8463(2) C(6) -1238(2) 3040(2) 7898(1) C(37) 6196(4) -1787(3) 8352(2) C(7) -1993(3) 3452(2) 8454(1) C(38) 5073(3) -1279(3) 8214(2) C(8) -1426(3) 3188(2) 9040(1) C(39) 2193(3) 1362(2) 5166(1) C(9) -308(3) 2605(2) 8857(1) C(40) 2831(4) 2252(3) 4896(2) C(10) 524(2) 2174(2) 9324(1) C(41) 3073(4) 2166(4) 4203(2) C(ll) 1602(2) 1589(2) 9154(1) C(42) 2665(3) 1194(3) 3773(2) C(12) 2466(3) 1150(2) 9636(1) C(43) 2047(4) 308(3) 4035(2) C(13) 3384(3) 667(2) 9274(1) C(44) 1810(4) 388(3) 4725(2) C(14) 3118(2) 792(2) 8560(1) C(45) 275(3) 314(2) 7503(1) C(15) 3872(2) 441(2) 8018(1) C(46) 1847(3) 4370(2) 7492(2) C(16) 3630(2) 582(2) 7327(1) C(47) 2486(3) 5451(3) 7607(2) C(17) 4418(3) 217(2) 6774(1) C(48) 3582(4) 5577(3) 8006(2) C(18) 3872(3) 505(2) 6193(1) C(49) 4039(3) 4643(3) 8265(2) C(19) 2730(3) 1053(2) 6368(1) C(50) 3362(3) 3585(3) 8129(2) C(20) 1889(3) 1479(2) 5905(1) C(51) 3477(4) 5765(4) 5147(2) C(21) -2663(3) 3741(3) 7023(1) C(52) 2449(3) 6210(3) 5593(2) C(22) -2643(4) 4938(3) 7111(2) C(53) 1357(3) 5539(3) 5669(2) C(23) -3717(5) 5496(4) 6928(2) C(54) 404(4) 5981(3) 6063(2) C(24) -4793(4) 4854(5) 6664(2) C(55) 543(4) 7100(3) 6380(2) C(56) 1638(4) 7771(3) 6311(2) C(59) 5456(4) 3896(3) 10059(2) C(57) 2580(4) 7329(3) 5923(2) C(60) 4192(4) 4049(3) 10029(2) C(59') 5456(4) 3896(3) 10059(2) C(61) 3735(4) 5134(4) 9975(3) C(58) 5990(7) 2703(7) 10189(5) A.275 I. Appendix Appendix 2. Experimental for the Kinetic Studies of [RuCl(BPSP)]2(/J-Cl)3. The chemical behaviour of [RuCl(BPSP)] 2 ( / /-Cl) 3 in aqueous solution was monitored spectrophotometrically in a thermostated Hewlett-Packard H P 8452A Diode Array instrument using quartz cells of path length 1.0 cm fitted with a plastic cap. The cell was thermostated at temperatures in the range of 15-35 °C and [RuCl(BPSP)] 2 ( / / -Q) 3 was added to H 2 0 (10 mL) or H 2 0 / C H 3 C N (10 mL). The sample was shaken to ensure complete mixing prior to monitoring absorbance changes at a fixed wavelength. The concentration of [RuCl(BPSP)] 2 ( / / -Cl) 3 ranged from (0.15-1.5) x 10"3 M and that of H 2 0 from (0-55.6) M ; thus pseudo-first-order conditions were maintained. L o g (absorbance difference) vs. time plots gave linear plots for at least 2.5 to 3 half-lives, from which the pseudo-first-order rate constants, kobs, were determined. A.276 Appendix Appendix 3. Thermal Gravimetric Analyses Plots ;ure A.3.1. TGA of [RuCl (BESE) (H 2 0 ) ] 2 ( / ^Cl ) 2 H 2 0. A.277 Appendix 204^  « » 1 r — i 1 — i 1 r—•—Tjr: »—r* 0 100 200 300 400 500 600 700 Temperature (°C) Figure A.3.2. T G A of [RuCl(BPSP)]2(//-Cl)3-2H20-2.5CH2Cl2. A.278 I. Appendix 0 100 200 300 400 500 600 Temperature (° C) Figure A.3.3. T G A of Na 4(H 2TSPhP)15H 20 (12.7460 mg). 30 40 50 60 70 80 90 100 Temperature (° C) Figure A.3.4. T G A of Na4[Ru(TSPhP)(CO)]-4H20 (9.9060 mg). A . 2 7 9 I. Appendix Appendix 4. Accumulation Data of Ru in CHO Cells 0.00 0.20 0.40 0.60 0.80 1.00 Concentration (mM) Figure A.4.1. Accumulation of R u in C H O cells after a 2 h incubation with [Ru(12-S-4)(DMSO)(H 2 0)][OTfJ 2 (1), [RuCl(BPSP)]2Cu-Cl)3 (2), [RuCl(BESE)(H 2 0) ] 2 ( / / -C l ) 2 (3), [RuCl(BPSE)(H 2 0)] 2 ( / / -Cl ) 2 (4), [R U C1(BBSE)(H 2 0)] 2 ( / / -C1) 2 (5). A.280 Appendix Appendix 5. DNA-binding Data of Ru in C H O Cells 1 2 3 4 Concentration (mM) 0.5 1 Concentration (mM) 0.5 1 Concentration (mM) 1.5 1.5 Concentration (mM) 0.2 0.4 0.6 0.8 Concentration (mM) Figure A.5.1. Ru-DNA-binding after incubation with [Ru(12-S-4)(DMSJD)(H20)][OTf]2 (1), [RuCl(BPSP)]2Gu-Cl)3 (2), [RuCl(BESE)(H20)] 2(//-Cl) 2 (3), [RuCl(BPSE)(H20)] 2(/i-Cl) 2 (4), [RuCl(BBSE)(H20)]2Cu-Cl)2 (5) (CHO cells, 2 h). A . 2 8 1 

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