(N-Heterocyclic Carbene)Gold(I) Halides, Azides, Alkynyls

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SYNTHESIS AND CHARACTERIZATION OF (PHOSPHINE)- AND

(N-HETEROCYCLIC CARBENE)GOLD(I) HALIDES, AZIDES, ALKYNYLS,

TRIAZOLES, AND DENDRIMERS AND THE SYNTHESIS AND

CHARACTERIZATION OF GOLD(I) THIACROWN MACROCYCLES

THOMAS J. ROBILOTTO

Submitted in partial fulfillment of the requirements

For the degree of Doctor of Philosophy

Department of Chemistry

CASE WESTERN RESERVE UNIVERSITY

January, 2011 CASE WESTERN RESERVE UNIVERSITY

SCHOOL OF GRADUATE STUDIES

We hereby approve the thesis/dissertation of

Thomas J. Robilotto ______

candidate for the ______degreePh. D *.

(signed)______Irene Lee (chair of the committee)

______Clemens Burda

______James D. Burgess

______Horst von Recum

______Thomas G. Gray

______

(date) ______August 18, 2010

*We also certify that written approval has been obtained for any proprietary material contained therein.

This work is dedicated to the people who have helped me

along my way

Table of Contents

Page

Table of Contents i

List of Figures iv

List of Schemes x

List of Tables xii

Acknowledgements xvi

List of Abbreviations xvii

Abstract xxi

Chapter 1. General Introduction

1.1 Fundamental Gold Chemistry 1

1.2 Huisgen 1,3-Dipolar Cycloaddition Reactions and Triazole Formations 7

1.3 Thiacrown Macrocycles 10

1.4 Proposed Research 13

1.5 References 18

Chapter 2. Synthesis and Characterization of (Phosphine)- and

(N-Heterocyclic Carbene)Gold(I) Halides and Azides

2.1 Introduction 24

2.2 Results and Discussion 27

2.3 Conclusion and Final Remarks 34

2.4 Experimental 36

2.5 References 43

Chapter 3. Synthesis and Characterization of Single (Phosphine)- and

(N-Heterocyclic Carbene)Gold(I) Alkynyls and Triazoles

3.1 Introduction 48

3.2 Results and Discussion 51

3.3 Conclusion and Final Remarks 62

3.4 Experimental 64

3.5 References 71

Chapter 4. Synthesis and Characterization of (Phospine)- and (N-Heterocyclic

Carbene)Gold(I) Alkynyl and Triazole Dendrimers with 3T3 Cell Studies

4.1 Introduction 75

4.2 Results and Discussion 79

4.3 Conclusion and Final Remarks 91

4.4 Experimental 93

4.5 References 105

Chapter 5. Synthesis and Characterization of Gold(I) Thiacrown Macrocycles

5.1 Introduction 108

5.2 Results and Discussion 111

5.3 Conclusion and Final Remarks 122

5.4 Experimental 123

5.5 References 132

Chapter 6. Summary and Conclusions

6.1 Thesis Summary 135

6.2 Future Directions 142

6.3 References 143

Appendix I. X-Ray Crystallographic Data for Collected Crystal Structures 144

Appendix II. NMR Spectra of Selected Compounds 220

Bibliography 274

iii

List of Figures

1.1.1. Position of Gold in the Periodic Table of the Elements 1

1.1.2. Ratio of Relativistic to Non-Relativistic 6s Shell Radii Versus Atomic Number 4

1.1.3. Structure of Auranofin 6

1.2.1. Criteria for “Click” Chemistry Reactions 9

1.4.1. Stuctures of Gold(I) Thiacrown Ether and Gold(I) Azathiacrown Macrocycles 17

2.2.1. Crystal Structures of (Phosphine)- and 29

(N-Heterocyclic Carbene)Gold(I) Azides

3.2.1. Crystal Structures of (Triphenylphosphine)Gold(I) Triazolates 52

3.2.2. Absorption spectrum in THF of (PPh3)Au(n -pentatriazole) 54

3.2.3. Crystal structure of (PCy3)Au(4-methoxyphenyltriazole) 57

3.2.4. Crystal structure of 59

7-[(1,3-dimethyl-4,5-dichlorocarbene)Au(propargyloxy)]coumarin

4.1.1. Proposed Pathway of a Gold(I) Agent as a Thioredoxin Reductase Inhibitor 75

4.1.2. Structures of First Generation PAMAM and DAB Dendrimers 77

4.2.1. (Triazolato)gold(I) Dendrimers, End-to-End Dimensions 80

4.2.2. Light Microscopy Images of 3T3 Fibroblast Cells with 84

[(PCy3)Au(triazolate)]2-[G1]-OH

4.2.3. Fluorescence-Activated Cell Sorting Results for 85

[(PCy3)Au(triazolate)]2-[G1]-OH after 6 hours

4.2.4. Fluorescence-Activated Cell Sorting Results for 86

[(PCy3)Au(triazolate)]2-[G1]-OH after 20 hours

4.2.5. Fluorescence-Activated Cell Sorting Results for 87

(Acet)2-[G1]-OH after 6 hours

4.2.6. Fluorescence-Activated Cell Sorting Results for 88

(PCy3)Au(4-methoxyphenyltriazole) after 6 hours

4.2.7. Light Microscopy Images of 3T3 Fibroblast Cells with 89

7-[(PCy3)Au(propargyloxy)]coumarin and

7-{[(PCy3)Au(triazolate)][methoxy]}coumarin at Varying Concentrations

5.1.1. Representations of a Crown Ether, a Thiacrown Ether, 109

and a Mixed Azathiacrown Ether

5.2.1. Crystal Structure of [Au([18]aneS6)][SbF6] 112

5.2.2. Crystal Structure of [Au3([18]aneS6)2][SbF6]3 114

5.2.3. Absorbance Spectra in CH3CN of [Au{(N-(4-benzylamine)- 120

1,4,7,10,13-pentylthia-16-azacyclooctyldecane)}][SbF6]

5.2.4. Emission Spectra in CH3CN of [Au{(N-(4-benzylamine)- 121

1,4,7,10,13-pentylthia-16-azacyclooctyldecane)}][SbF6]

6.1.1. Stucture of Azathiacrown Macrocyles with an 140

Aniline or a Benzyl Amine Linker

AI-1a. ORTEP plot of [(PCy2(o-biphenyl))AuN3] 145

AI-2a. ORTEP plot of [(PCy2(2′,4′,6′-triisopropylbiphenyl))AuN3] 149

AI-3a. ORTEP plot of [(PCy3)AuN3] 154

AI-4a. ORTEP plot of [1,3-dimethyl-4,5-dichlorocarbene)AuCl] 158

AI-5a. ORTEP plot of [(1,3-dimethyl-4,5-dichlorocarbene)AuBr] 161

AI-6a. ORTEP plot of [(1,3-dimethyl-4,5-dichlorocarbene)AuN3] 164

AI-7a. ORTEP plot of [(1,3-diisopropylcarbene)AuN3] 167

AI-8a. ORTEP plot of [(PPh3)Au(n-pentatriazole)] 170

AI-9a. ORTEP plot of [(PPh3)Au(cyclohexyltriazole)] 176

AI-10a.ORTEP plot of [(PPh3)Au(3-aminophenyltriazole)] 180

AI-11a. ORTEP plot of [(PPh3)Au(4-methoxyphenyltriazole)] 188

AI-12a. ORTEP plot of [(PCy3)Au(4-methoxyphenyltriazole)] 192

AI-13a. ORTEP plot of [7-{[(1,3-dimethyl-4,5- 201

dichlorocarbene)Au(propargyloxy)][methoxy]}coumarin]

AI-14a. ORTEP plot of [Au([18]aneS6)][SbF6] 205

AI-15a. ORTEP plot of [Au3([18]aneS6)2][SbF6]3 210

1 AII-1. H NMR spectrum of [(PCy2(o-biphenyl))AuN3] 220

13 1 AII-2. C{ H} NMR spectrum of [(PCy2(o-biphenyl))AuN3] 221

31 1 AII-3. P{ H} NMR spectrum of [(PCy2(o-biphenyl))AuN3] 222

1 AII-4. H NMR spectrum of [(PCy2(2′-methylbiphenyl))AuN3] 223

13 1 AII-5. C{ H} NMR spectrum of [(PCy2(2′-methylbiphenyl))AuN3] 224

31 1 AII-6. P{ H} NMR spectrum of [(PCy2(2′-methylbiphenyl))AuN3] 225

1 AII-7. H NMR spectrum of [(PCy2(2′,4′,6′-triisopropylbiphenyl))AuN3] 226

13 1 AII-8. C{ H} NMR spectrum of [(PCy2(2′,4′,6′-triisopropylbiphenyl))AuN3] 227

31 1 AII-9. P{ H} NMR spectrum of [(PCy2(2′,4′,6′-triisopropylbiphenyl))AuN3] 228

1 AII-10. H NMR spectrum of [(PCy3)AuN3] 229

31 1 AII-11. P{ H} NMR spectrum of [(PCy3)AuN3] 230

AII-12. 1H NMR spectrum of [(1,3-dimethyl-4,5-dichlorocarbene)AuCl] 231

AII-13. 1H NMR spectrum of [(1,3-dimethyl-4,5-dichlorocarbene)AuBr] 232

1 AII-14. H NMR spectrum of [(1,3-dimethyl-4,5-dichlorocarbene)AuN3] 233

1 AII-15. H NMR spectrum of [(1,3-diisopropylcarbene)AuN3] 234

1 AII-16. H NMR spectrum of [(PPh3)Au(n-pentatriazole)] 235

31 1 AII-17. P{ H} NMR spectrum of [(PPh3)Au(n-pentatriazole)] 236

1 AII-18. H NMR spectrum of [(PPh3)Au(cyclohexyltriazole)] 237

31 1 AII-19. P{ H} NMR spectrum of [(PPh3)Au(cyclohexyltriazole)] 238

1 AII-20. H NMR spectrum of [(PPh3)Au(3-aminophenyltriazole)] 239

31 1 AII-21. P{ H} NMR spectrum of [(PPh3)Au(3-aminophenyltriazole)] 240

1 AII-22. H NMR spectrum of [(PPh3)Au(4-methoxyphenyltriazole)] 241

31 1 AII-23. P{ H} NMR spectrum of [(PPh3)Au(4-methoxyphenyltriazole)] 242

1 AII-24. H NMR spectrum of [(PCy3)Au(4-methoxyphenyltriazole)] 243

31 1 AII-25. P{ H} NMR spectrum of [(PCy3)Au(4-methoxyphenyltriazole)] 244

1 AII-26. H NMR spectrum of [7-{[(PCy3)Au(triazolate)][methoxy]}coumarin] 245

31 1 AII-27. P{ H} NMR spectrum of [7-{[(PCy3)Au(triazolate)][methoxy]}coumarin] 246

AII-28. 1H NMR spectrum of [7-{[(1,3-dimethyl-4,5- 247

dichlorocarbene)Au(triazolate)][methoxy]}coumarin]

1 AII-29. H NMR spectrum of [7-[(PCy3)Au(propargyloxy)]coumarin] 248

31 1 AII-30. P{ H} NMR spectrum of [7-[(PCy3)Au(propargyloxy)]coumarin] 249

AII-31. 1H NMR spectrum of [7-[(1,3-dimethyl-4,5- 250

dichlorocarbene)Au(propargyloxy)]coumarin]

1 AII-32. H NMR spectrum of [(PCy3)Au(triazolate)]2-[G1]-OH 251

31 1 AII-33. P{ H} NMR spectrum of [(PCy3)Au(triazolate)]2-[G1]-OH 252

1 AII-34. H NMR spectrum of [(PCy3)Au(triazolate)]4-[G2]-OH 253

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31 1 AII-35. P{ H} NMR spectrum of [(PCy3)Au(triazolate)]4-[G2]-OH 254

1 AII-36. H NMR spectrum of [(PCy3)Au(triazolate)]8-[G3]-OH 255

31 1 AII-37. P{ H} NMR spectrum of [(PCy3)Au(triazolate)]8-[G3]-OH 256

1 AII-38. H NMR spectrum of [acet]2-[G1]-7-methoxycoumarin 257

1 AII-39. H NMR spectrum of [acet]4-[G2]-7-methoxycoumarin 258

1 AII-40. H NMR spectrum of [(PCy3)Au(triazolate)]2-[G1]-7-methoxycoumarin 259

31 1 AII-41. P{ H} NMR spectrum of [(PCy3)Au(triazolate)]2-[G1]-7-methoxycoumarin 260

1 AII-42. H NMR spectrum of [(PCy3)Au(alkynyl)]2-[G1]-7-methoxycoumarin 261

31 1 AII-43. P{ H} NMR spectrum of [(PCy3)Au(alkynyl)]2-[G1]-7-methoxycoumarin 262

AII-44. 1H NMR spectrum of N-(4-nitrophenyl)-bis(2-hydroxyethyl)amine 263

AII-45. 1H NMR spectrum of N-(4-nitrophenyl)-bis(2-(tosyloxy)ethyl)amine 264

AII-46. 1H NMR spectrum of 3,6,9-trithia-1,11-undecanedithiol 265

AII-47. 1H NMR spectrum of N-(4-nitrophenyl)-1,4,7,10,13-pentylthia-16- 266

azacyclooctyldecane

AII-48. 1H NMR spectrum of N-(4-aminophenyl)-1,4,7,10,13-pentylthia-16- 267

azacyclooctyldecane

AII-49. 1H NMR spectrum of [Au{(N-(4-aminophenyl)-1,4,7,10,13-pentylthia- 268

16-azacyclooctyldecane)}][SbF6]

AII-50. 1H NMR Spectrum of N-(phenyl)-bis(2-(tosyloxy)ethyl)amine 269

AII-51. 1H NMR Spectrum of N-(phenyl)-1,4,7,10,13- 270

pentylthia-16-azacyclooctyldecane

AII-52. 1H NMR Spectrum of N-(4-formylphenyl)-1,4,7,10,13-pentylthia-16- 271

azacyclooctyldecane

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AII-53. 1H NMR Spectrum of N-(4-benzylamine)-1,4,7,10,13-pentylthia-16- 272

azacyclooctyldecane

AII-54. 1H NMR Spectrum of [Au{(N-(4-benzylamine)-1,4,7,10,13-pentylthia- 273

16-azacyclooctyldecane)}][SbF6]

List of Schemes

1.2.1. General Huisgen 1,3-Dipolar Cycloadditon 7

1.2.2. General Cu(I) Catalyzed Azide-Alkyne Cycloaddition 7

1.2.3. Synthesis of a Gold(I) Triazole from a Gold(I) Alkynyl and an Azide 8

1.3.1. General Synthesis of a Thiacrown Macrocycle 10

1.4.1. General Synthesis of a (Phosphine)Gold(I) Chloride 13

1.4.2. General Synthesis of a (N-Herterocyclic Carbene)Gold(I) Chloride 13

1.4.3. General Synthesis of a (Phosphine)- or 14

(N-Herterocyclic Carbene)Gold(I) Bromide

1.4.4. Thallium Route and Silver Route to the General Synthesis of Gold(I) Azides 15

1.4.5. General Synthesis of a Gold(I) Triazole from a Gold(I) Azide 16

and Terminal Alkyne

1.4.6. General Synthesis of a Gold(I) Alkynyl from a Gold(I) Chloride 16

and Terminal Alkyne

2.2.1. General Synthesis of Buchwald (Phosphine)Gold(I) Azides through 27

Thallium(I) Acetylacetonate

2.2.2. General Synthesis of (Phosphine)- or 28

(N-Heterocyclic Carbene)Gold(I) Azides through Silver(I) Acetate

2.2.3. Synthesis of an (N-Heterocyclic Carbene)Gold(I) Chloride 31

2.2.4. Synthesis of an (N-Heterocyclic Carbene)Gold(I) Bromide 31

3.2.1. General Synthesis of (Triphenylphosphine)Gold(I) Triazolates 51

3.2.2. General Synthesis of (Tricyclohexylphosphine)Gold(I) Triazolates 55

3.2.3. Synthesis of an (N-Heterocyclic Carbene)Gold(I) Triazolate 58

3.2.4. General Synthesis of (Phosphine)- or 58

(N-Heterocyclic Carbene)Gold(I) Alkynyls

4.2.1. Modified Synthesis of Ethynyl-Terminated Dendrimers 79

4.2.2. Synthesis of First Generation (Tricyclohexylphosphine)Gold(I) Dendrimer 80

4.2.3. Synthesis of First Generation Coumarin Tagged 82

Gold(I) Triazolate Dendrimer

4.2.4. Synthesis of First Generation Coumarin Tagged Gold(I) Alkynyl Dendrimer 83

5.1.1. General Synthesis of a Thiacrown Ether 108

5.2.1. Synthesis of [Au([18]aneS6)][SbF6] 111

5.2.2. Synthesis of [Au{(N-(4-aminophenyl)-1,4,7,10,13-pentylthia- 115

16-azacyclooctyldecane)}][SbF6]

5.2.3. Synthesis of 3,6,9-trithia-1,11-undecanedithiol 116

5.2.4. Synthesis of [Au{(N-(4-benzylamine)-1,4,7,10,13-pentylthia- 118

16-azacyclooctyldecane)}][SbF6]

6.1.1. Synthesis of (Phosphine)- and (N-Herterocyclic Carbene)Gold(I) Azides 135

6.1.2. General Synthesis of a (Phosphine)Gold(I) Triazolate 137

6.1.3. General Synthesis of a Gold(I) Alkynyl 137

List of Tables

2.2.1. Crystallographic Data for Gold(I) Azides 30

2.2.2. Crystallographic Data for 32

(1,3-Dimethyl-4,5-Dichlorocarbene)Gold(I) Products

3.2.1. Crystallographic Data for (Triphenylphosphine)Gold(I) Triazolates 53

3.2.2. Initial Starting Materials, Reaction Times, Products and 61

Isolated Yields of Gold(I) Triazolate Products

4.2.1. Reaction Times and Isolated Yields of Gold(I) Dendrimer Products 81

5.2.1. Crystallographic Data for Thiacrown Gold(I) Hexafluoroantimonates 113

AI-1a. Crystallographic data for [(PCy2(o-biphenyl))AuN3] 144

AI-1b. Data collection for [(PCy2(o-biphenyl))AuN3] 144

AI-1c. Refinement parameters of [(PCy2(o-biphenyl))AuN3] 145

AI-1d. Selected geometric parameters (Å, ) for [(PCy2(o-biphenyl))AuN3] 145

AI-2a. Crystallographic data for [(PCy2(2′,4′,6′-triisopropylbiphenyl))AuN3] 148

AI-2b. Data collection for [(PCy2(2′,4′,6′-triisopropylbiphenyl))AuN3] 148

AI-2c. Refinement parameters of [(PCy2(2′,4′,6′-triisopropylbiphenyl))AuN3] 149

AI-2d. Selected geometric parameters (Å, ) for [(PCy2(2′,4′,6′- 149

triisopropylbiphenyl))AuN3]

AI-3a. Crystallographic data for [(PCy3)AuN3] 153

AI-3b. Data collection for [(PCy3)AuN3] 153

AI-3c. Refinement parameters of [(PCy3)AuN3] 154

AI-3d. Selected geometric parameters (Å, ) for [(PCy3)AuN3] 154

AI-4a. Crystallographic data for [(1,3-dimethyl-4,5-dichlorocarbene)AuCl] 157

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AI-4b. Data collection for [(1,3-dimethyl-4,5-dichlorocarbene)AuCl] 157

AI-4c. Refinement parameters of [(1,3-dimethyl-4,5-dichlorocarbene)AuCl] 158

AI-4d. Selected geometric parameters (Å, ) for 158

[(1,3-dimethyl-4,5-dichlorocarbene)AuCl]

AI-5a. Crystallographic data for [(1,3-dimethyl-4,5-dichlorocarbene)AuBr] 160

AI-5b. Data collection for [(1,3-dimethyl-4,5-dichlorocarbene)AuBr] 160

AI-5c. Refinement parameters of [(1,3-dimethyl-4,5-dichlorocarbene)AuBr] 161

AI-5d. Selected geometric parameters (Å, ) for 161

[(1,3-dimethyl-4,5-dichlorocarbene)AuBr]

AI-6a. Crystallographic data for [(1,3-dimethyl-4,5-dichlorocarbene)AuN3] 163

AI-6b. Data collection for [(1,3-dimethyl-4,5-dichlorocarbene)AuN3] 163

AI-6c. Refinement parameters of [(1,3-dimethyl-4,5-dichlorocarbene)AuN3] 164

AI-6d. Selected geometric parameters (Å, ) for 164

[(1,3-dimethyl-4,5-dichlorocarbene)AuN3]

AI-7a. Crystallographic data for [(1,3-diisopropylcarbene)AuN3] 166

AI-7b. Data collection for [(1,3-diisopropylcarbene)AuN3] 166

AI-7c. Refinement parameters of [(1,3-diisopropylcarbene)AuN3] 167

AI-7d. Selected geometric parameters (Å, ) for [(1,3-diisopropylcarbene)AuN3] 167

AI-8a. Crystallographic data for [(PPh3)Au(n-pentatriazole)] 169

AI-8b. Data collection for [(PPh3)Au(n-pentatriazole)] 169

AI-8c. Refinement parameters of [(PPh3)Au(n-pentatriazole)] 170

AI-8d. Selected geometric parameters (Å, ) for [(PPh3)Au(n-pentatriazole)] 170

AI-9a. Crystallographic data for [(PPh3)Au(cyclohexyltriazole)] 175

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AI-9b. Data collection for [(PPh3)Au(cyclohexyltriazole)] 175

AI-9c. Refinement parameters of [(PPh3)Au(cyclohexyltriazole)] 176

AI-9d. Selected geometric parameters (Å, ) for [(PPh3)Au(cyclohexyltriazole)] 176

AI-10a. Crystallographic data for [(PPh3)Au(3-aminophenyltriazole)] 179

AI-10b. Data collection for [(PPh3)Au(3-aminophenyltriazole)] 179

AI-10c. Refinement parameters of [(PPh3)Au(3-aminophenyltriazole)] 180

AI-10d. Selected geometric parameters (Å, ) for [(PPh3)Au(3-aminophenyltriazole)] 180

AI-11a. Crystallographic data for [(PPh3)Au(4-methoxyphenyltriazole)] 187

AI-11b. Data collection for [(PPh3)Au(4-methoxyphenyltriazole)] 187

AI-11c. Refinement parameters of [(PPh3)Au(4-methoxyphenyltriazole)] 188

AI-11d. Selected geometric parameters (Å, ) for 188

[(PPh3)Au(4-methoxyphenyltriazole)]

AI-12a. Crystallographic data for [(PCy3)Au(4-methoxyphenyltriazole)] 191

AI-12b. Data collection for [(PCy3)Au(4-methoxyphenyltriazole)] 191

AI-12c. Refinement parameters of [(PCy3)Au(4-methoxyphenyltriazole)] 192

AI-12d. Selected geometric parameters (Å, ) for 192

[(PCy3)Au(4-methoxyphenyltriazole)]

AI-13a. Crystallographic data for [7-{[(1,3-dimethyl-4,5- 200

dichlorocarbene)Au(propargyloxy)][methoxy]}coumarin]

AI-13b. Data collection for [7-{[(1,3-dimethyl-4,5- 200

dichlorocarbene)Au(propargyloxy)][methoxy]}coumarin]

AI-13c. Refinement parameters of [7-{[(1,3-dimethyl-4,5- 201

dichlorocarbene)Au(propargyloxy)][methoxy]}coumarin]

xiv

AI-13d. Selected geometric parameters (Å, ) for [7-{[(1,3-dimethyl-4,5- 201

dichlorocarbene)Au(propargyloxy)][methoxy]}coumarin]

AI-14a. Crystallographic data for [Au([18]aneS6)][SbF6] 204

AI-14b. Data collection for [Au([18]aneS6)][SbF6] 204

AI-14c. Refinement parameters of [Au([18]aneS6)][SbF6] 205

AI-14d. Selected geometric parameters (Å, ) for [Au([18]aneS6)][SbF6] 205

AI-15a. Crystallographic data for [Au3([18]aneS6)2][SbF6]3 209

AI-15b. Data collection for [Au3([18]aneS6)2][SbF6]3 209

AI-15c. Refinement parameters of [Au3([18]aneS6)2][SbF6]3 210

AI-15d. Selected geometric parameters (Å, ) for [Au3([18]aneS6)2][SbF6]3 210

Acknowledgements

I will start off my acknowledgments by saying the same thing I say at the beginning of most of my group meeting presentations. “If you don’t know where to start, the best place to start is at the beginning.”

I first and foremost have to thank my family. Without their love and support I would not be where I am today. I must especially thank my parents for instilling in me the hard work ethic and values that I try my best to live by.

To my friends and colleagues at the university, you know who you are. Thanks for putting up with my terrible dry sense of humor, extreme random comments, and for eating lunch with me for five years.

My committee members, past and present, Dr. Lee, Dr. Burda, Dr. Burgess, Dr. von Recum, Dr. Kenney, and Dr. Protasiewicz. Thanks for all the knowledge and expertise that you have given me, and for the support needed to graduate.

Next, I need to thank all of the people that are and have been part of the Gray research group. There is the original crew, Jim Updegraff, Miya Peay, and Lei Gao, who have helped me more than anyone can even imagine. The new group, Ayan Maity, Nihal

Deligonul, Jim Heckler, and Amberle Browne, who are all promising chemists and I am glad I got a chance to work with them. And also David Partyka, the post-doc, who has been a great influence to me during my time here.

Finally, and most importantly, my advisor Dr. Thomas Gray. I thank you for giving me the opportunity to do important cutting-edge research and expanding my knowledge. You have my loyalty, my respect and my eternal gratitude.

xvi

List of Abbreviations a Length of unit cell axis (as in X-ray diffraction)

α Alpha angle (as in X-ray diffraction) between a and b axis

Å Angstrom acac acetylacetonate

Acet acetylene

Ar Substituted aryl group b Length of unit cell axis (as in X-ray diffraction)

β Beta angle (as in X-ray diffraction) between a and c axis t-Bu tert-Butyl

C Celsius c Length of unit cell axis (as in X-ray diffraction)

C6D6 Deuterobenzene

CDCl3 Deuterochloroform

CH2Cl2 Methylene Chloride

CH3CN Acetonitrile cm-1 Reciprocal centimeters, wavenumbers

CuAAC Copper-Catalyzed Alkynes and Azides Cycloaddition d Doublet (as in NMR spectroscopy)

Δ Heat (thermal reaction) dd Doublet of doublet (as in NMR spectroscopy)

DMEM Dulbecco's Modified Eagle Medium

DMF N,N-Dimethylformamide

xvii

DMSO Dimethyl sulfoxide

Dx Density (as in X-ray diffraction)

E Sulfur or Oxygen (in macrocycles)

ε epsilon (molar extinction coefficient in UV-Vis spectroscopy)

ESI Electrospray ionization (as in mass spectrometry)

F Structure factor (as in X-ray diffraction)

Fc Calculated structure factor (as in X-ray diffraction)

Fo Observed structure factor (as in X-ray diffraction)

FBS Fetal bovine serum

G generation g grams

γ Gamma angle (as in X-ray diffraction) between b and c axis h Hour; Miller indices (as in X-ray diffraction)

HIV Human immunodeficiency virus

H2SO4 Sulfuric acid

J Coupling constant (as in NMR spectroscopy) in Hz

K Kelvin k Miller indices (as in X-ray diffraction) l Miller indices (as in X-ray diffraction)

L Ligand; liter

Λ max lambda (wavelength of maximum adsorption in UV-Vis

spectroscopy)

M metal

xviii m multiplet (as in NMR) m Meta m/z mass-to-charge ratio (as in mass spectrometry)

MALDI-TOF Matrix assisted laser desorption ionization-time of flight (as in

mass spectrometry)

MHz Megahertz

Mo Kα Molybdenum K alpha (as in X-ray diffraction; 0.71 Å) mol Mole mmol Millimole

Mr Molecular weight (as in X-ray diffraction)

Mw Molecular weight

NHC N-heterocyclic carbene nm nanometer

NMR Nuclear Magnetic Resonance o Ortho

ORTEP Oak Ridge Thermal Ellipsiod Plot

π Bonding pi orbital

31P {1H} proton-decoupled phosphorus NMR p Para

PCy3 Tricyclohexylphosphine

PPh3 Triphenylphosphine ppm Parts per million (as in NMR)

P/S Penicillin/Streptomycin

xix

R Discrepancy index (as in X-ray diffraction)

S Goodness of fit (as in X-ray diffraction) s Singlet (as in NMR spectroscopy); strong (as in IR spectroscopy)

T Temperature

THF Tetrahydrofuran tht Tetrahydrothiophene

Ts Tosyl group

Tmin Minimum transmission (as in X-ray diffraction)

Tmax Maximum transmission ( as in X-ray diffraction)

UV-vis Ultraviolet visible (as in spectroscopy)

ω Omega (e.g, measurement angle used in X-ray diffraction)

θ Theta (e.g., Angle between the incident and the diffracted beams, as in X-

ray diffraction)

θmax Theta (e.g., maximum Bragg angle as in X-ray diffraction)

V Cell volume (as in X-ray diffraction) wR Weighted discrepancy index (as in X-ray diffraction)

X Cl, Br, or I ligand

Z Number of molecules in unit cell (as in X-ray diffraction);

nuclear charge

Synthesis and Characterization of (Phospine)- and (N-Heterocyclic Carbene)Gold(I)

Halides, Azides, Alkynyls, Triazoles, and Dendrimers and the Synthesis and

Characterization of Gold(I) Thiacrown Macrocycles

Abstract

THOMAS J. ROBILOTTO

New (phosphine)- and (N-heterocyclic carbene)gold(I) halides and azides have been synthesized and characterized as starting materials for the synthesis of gold(I) alkynyls and triazoles. For the synthesis of the gold(I) alkynyls, a one-pot synthesis of a gold(I) halide and terminal alkyne in the presence of a base forms a gold(I) alkynyl that will precipitate out of solution. For the synthesis of the gold(I) triazoles, a gold(I) azide and a terminal alkyne form a [3+2] cycloaddition adduct having a gold-carbon bond. The triazolate complex precipitates out of solution. The methods has been extended to alkyne- functionalized poly(benzyl ether) dendrimers. All of these gold(I) materials have been synthesized as part of a broad research endeavor in medicinal gold chemistry.

Three gold(I) thiacrown ether macrocycles have been synthesized. The simplest gold(I) thiacrown ether, [Au([18]aneS6)][SbF6], has been crystallographically characterized, the structure shows that the gold(I) moiety is bound to four sulfur atoms.

The synthesis for the other gold(I) monoaza-pentathia macrocycles involves a more complex procedure, with the final step being the gold(I) addition. The objective is gold(I) insertion opposite abasic lesions in duplex DNA.

xxi

Chapter 1. General Introduction

1.1 Fundamental Gold Chemistry

Gold is highly regarded and holds a special position among the metals in the periodic table, Figure 1.1.1. For at least three millennia, it has been known as the most

‗‗noble‘‘ of the metals, referring to its resistance towards most corrosive forces. It has also been dubbed ‗‗King of the Metals‖ due to its monetary value. Gold is robust; it is mechanically ductile and malleable, and has a attractive color and glittering appearance.

It is held to be an ideal construction material for objects of culture and art, for jewelry and coin currency. In more recent periods, its high electrical and thermal conductivity has made gold metal also an important material: first for the electrical and then for the electronics industry.1 Gold is not simply a homologue of the other two coinage metals in the periodic table, copper and silver, but showed entirely different oxidation states and oxidation potentials, coordination numbers and coordination geometries.2-4

Figure 1.1.1. Position of gold in the periodic table of the elements.

Gold has the atomic number 79 and it has only one stable isotope with an atomic mass 197 and a nuclear spin of S = 3/2. This nucleus is not amenable to conventional

NMR spectroscopy. However, the availability of suitable radioactive platinum isotopes will yield 197Au, which is called a ‗‗Mossbauer nucleus‘‘, and indeed recoil-free c- spectroscopy has been used very widely for the study of oxidation states, coordination numbers and geometries of gold in its compounds.1

Gold has the electronic ground state configuration[Xe][4f14][5d10]6s1. This gives rise to an abundance of gold(I) compounds with a closed-shell configuration[5d10].

Owing to the extreme oxidation potential of the metal, only very few binary chemical compounds of gold are thermodynamically stable. Fluorine, chlorine, bromine, iodine as well as for the heavy chalcogens (Se and Te) are able to form these binary compounds, but not oxygen (O) and sulfur (S). Except for alloys with the metallic elements, none of the elements in groups 13–15 (the nitrogen, carbon and boron groups) form stable binaries with gold.1

Gold(I) molecules generally form, two-coordinate species with a linear geometry of two donor atoms or ligands. The ligands can be neutral (L) or anionic (X-), thus forming species of these general types; [L—Au—X], [L—Au—L] +, or [X—Au—X]-.5

While the ready access to the higher oxidation states of gold is best rationalized by invoking relativistic contributions, the coordination number and geometry of Au3+ is not exceptional. The 5d8 electron configuration requires a square planar tetracoordinate which is confirmed by virtually all stoichiometries and structures reported to date in an already vast literature.

Cationic Au(I), Au(III), and also rarer species of Au(II) are strong Lewis acids.

They possess a high affinity to nucleophiles, and have even bound the noble gas xenon in their first coordination sphere.6,7

There are two principles that explain why gold has significant and unusual properties, and these are the lanthanide contraction and relativistic effects. For the lanthanide contraction there is a steady decrease in the size of the atoms and ions of the rare-earth elements with increasing atomic number from lanthanum (atomic number 57) through lutetium (atomic number 71). For each consecutive atom the nuclear charge is more positive by one unit, accompanied by a corresponding increase in the number of electrons present in the 4f orbitals surrounding the nucleus. The 4f electrons very imperfectly shield each other from the increased positive charge of the nucleus, so that the effective nuclear charge attracting each electron steadily increases through the lanthanoid (lanthanide) elements, resulting in successive reductions of the atomic and ionic radii. This explains the relatively small radius of the gold atom, but not why it has a maximum redox potential and electron affinity relative to the other elements with an atomic number between Z=72-83. When the velocity of a body approaches the speed of light, its mass increases, and this is the principle of relativistic effect. Taking this into account, the increase of the ionization energy and electron affinity can be explained as related to the 6s configuration.8 Figure 1.1.2 shows the calculated relativistic contraction of the 6s orbitals by increasing atomic number, with Au being at the maximum.9,10

When steric hinderance of the substituting ligands do not play into account, gold(I) centers can approach each other to form bonds with the strength similar to hydrogen bonds, 7-11 kcal/mol.11-13 These interactions are strong enough to persist in

3 solution and can direct chemical reactions.14 These interactions are termed ―aurophilic interactions‖ and typically have a Au-Au bond distance of 2.8-3.3 Å. These aurophilic interactions can lead to the formation of trimers, tetramers, and even larger three- dimensional networks. The bond strengths can vary in polymeric systems and various solids can be generated.11,12

0.98

0.96

0.94 79Au

0.92

r / r R NR 0.9

0.88

0.86

0.84

0.82 60 70 80 90 100 Z Figure 1.1.2. Ratio of relativistic to non-relativistic 6s shell radii versus atomic number.9

Many gold(I) complexes with aurophilic interactions exhibit strong luminescence.

It has been proposed that the aurophilic interactions stabilze excited states. The change in environment,15,16 such as concentration, solvents, counter-ions, solvate molecules and even physical grinding17can modify the aurophilic interactions which can alter the luminescence pattern. Aurophilic interactions can occur intermolecularly and also intramolecularly. A number of multinuclear gold(I) complexes have been formed.18

These complexes can be tetrahedral,19 square-pyramidal,20 trigonal-bipyramidal, and octahedral.21,22 As the number of gold(I) atoms increase in the molecule, the Au-X-Au

4 angles become more acute, and the gold atoms attempt to form the shortest possible bond distances with each other.18 These attractive forces are caused by a combination of relativistic effects and correlation effects.23

A tremendous and wide ranging amount of research has already been done involving gold. The interests range from catalysis,24-30 nanomaterials,31-33 cancer therapeutics34-36 to energy recovery.37-39

In terms of catalysis, Lewis acid type cationic gold(I) complexes can act as catalysts in hydroarylations,40,41 carbon-heteroatom bond forming reactions,42-44 C-C bond formation reactions,45 and hydration of alkynes.46 It has also been shown that the ligand attached to the gold(I) plays a particular role in tuning some of these catalytic reactions. Buchwald phosphines and N-heterocyclic carbenes have able to enhance ring expansions of propargylcyclopropanols,47 indene synthesis,48 and hydroamination of allenes.49,50 Gold(I) catalysis has been a valuable field of study.

Gold(I) anti-cancer and anti-tumor research has been an intense field of study for the last thirty years.35,51 These gold(I) complexes have been divided into three different classes based on their difference in targeting of the mitochondria. One of the most widely known gold(I) based drugs is known as tetraacetylthioglucose gold(I) phosphine

(auranofin), Figure 1.1.3. This drug is an orally administered anti-arthritic gold(I) therapeutic. It has been recently shown that auranofin can inhibit tumor cell growth in vitro. Mechanistic studies have shown that auranofin induces apoptosis by inhibiting the mitochondrial enzyme thioredoxin reductase, which has recently become a new target of drug development.52,53

Figure 1.1.3. Structure of auranofin.

In terms of energy recovery, because gold has two stable oxidation states, Au(I) and Au(III), it makes a good pair in an oxidation/reduction elimination cycle. This is because the oxidation states are two electrons apart. Teets and Nocera have recently reported the halogen photoreductive elimination from gold(III) centers.39 Unprecedented

- - III two-electron photoelimination of X2 (X=Cl , Br ) from a monomeric Au center from a

III Au (PR3)X3 (R=Ph,Cy), and four-electron photoelimination of X2 from bimetallic centers have been observed. Halogens can then be trapped or collected, which have the potential to be energy rich molecules.

1.2. Huisgen 1,3-Dipolar Cycloaddition Reactions and Triazole

Formations

The Huisgen 1,3-dipolar cycloadditons are exergonic fusion processes in which two unsaturated reactants unite to produce a variety of five-membered heterocycles. The

1,3-dipolar cycloaddition that occurs between an azide and a terminal or internal alkyne to give a 1,2,3-triazole products was introduced in the 1960‘s.54 This process is however not regioselective and a combination of 1,4- and 1,5-disubstituted 1,2,3-triazoles are typically produced, Scheme 1.2.1. This work was mainly conducted without catalysts at elevated temperatures in the absence of water.

Scheme 1.2.1. General Huisgen 1,3-dipolar cycloadditon.

In order to create specificity in the formation of triazoles two reactions have been developed to produce 1,4-disubstituted triazoles and 1,5-disubstituted triazoles.

Tornoe and Meldal introduced copper(I) into a cycloddition reaction of an organic azide and alkyne. The addition greatly improved the rate and regioselectivity of the reaction and led to the improvement of similar reactions, Scheme 1.2.2.55

Scheme. 1.2.2. General Cu(I) catalyzed azide-alkyne cycloaddition.

The reaction is known by the name copper(I) catalyzed azide-alkyne cycloaddition reaction (CuAAC). These reactions are very robust, insensitive, quantitative, and general. Modification of peptides, natural product synthesis, and a number of pharmaceuticals have used this reaction.56 CuAAC has also been used in the modification of oligonucleotides and nucleosides.57 Convenient synthesis of dendrimers have also been made using this method.58

A recently identified ruthenium(II) based catalyst (pentamethylcyclopentadienyl)- ruthenium(II) has lead to the formation of predominately 1,5-triazole isomers.59-61 The ruthenium-catalyzed reaction produces triazoles from unstrained internal alkynes. This is quite different from the CuAAC reaction which generally works with terminal organic alkynes.

In a recently discovered reaction, a variant of the Huisgen 1,3-dipolar cycloadditons, a regiospecfic 1,4-disubstituted gold(I) triazole was made. The reaction of a (phosphine)gold(I) alkynyl and trimethylsilyl azide in the presence of a protic solvent yielded gold(I) triazolates,62 Scheme 1.2.3. Due to the nature of the (phosphine)gold(I) fragment, it is isolobal with protons, and because of this (phosphine)gold(I) fragments can substitute for protons on organic molecules and can act as functional groups modifying the molecules properties.

Scheme 1.2.3. Synthesis of a gold(I) triazole from a gold(I) alkynyl and an azide.

Sharpless introduced a chemical philosophy, named ―Click Chemistry‖ in 2001.63

It describes chemistry that generates substances quickly and reliably by uniting small units together. There are a number of requirements that must be met in order to be considered to be a ―click‖ reaction, Figure 1.2.1. Very few reactions satisfy these requirements. A few are nucleophilic ring-opening reactions of strained rings, non-aldol carbonyl chemistry, and certain classes of addition to carbon-carbon multiple bonds.

Figure 1.2.1. Criteria for ―click‖ chemistry reactions.

The Huisgen 1,3-dipolar cycloadditon reaction is the acknowledged prototype of click chemistry.

1.3. Thiacrown Macrocycles

The discovery of crown ethers by Charles J. Pedersen in 1967 has led to the synthesis of numerous macrocycles and the study of their complexing abilities.64 Crown ethers, and more generally crown-like molecules of the form (-CH2-CH2-E-), where E =

S or O, have seen extensive use as bioinorganic model systems, binucleating ligands, chelators for specific metal ions, and phase-transfer catalysts. For these purposes they have several advantages. They permit control of both the coordination environment

(donor atoms) and, in principle, the stereochemistry at a metal ion. In addition, they are easily synthesized by routes that permit systematic variation of ring size as well as

65 identity and placement of heteroatoms.

Scheme 1.3.1. General synthesis of a thiacrown macrocycle.

The strategy for the template synthesis of thiacrown compounds, Scheme 1.3.1, involves a dithiol and typically a cesium dithiolate in a dilute DMF solution. The role of the cesium cation is to accelerate the cyclization of the intermediate nucleophilic thiolate chains through the creation of a coordination center. This cyclization is promoted by the

10 large radius of the cation compared with other alkali metals, by the low density of surface charge, by the high polarizability, and the poor solvation in DMF.66

A difference between oxygen-bearing and sulfur bearing crowns can be found in their conformational preferences. The oxygen crowns prefer ―endodentate‖ conformations in which the oxygens are oriented toward the center or inside of the macrocyclic cavity. The resulting region of negative electrostatic potential that lines the inside of the cavity creates an ideal receptacle for a small cation. Oxygen-bearing crowns are said to be ―pre-organized‖ for cation binding. This preference for endodentate conformations requires an underlying preference for gauche dihedral angles about C-C bonds and trans angles about C-O bonds.67

Thiacrowns prefer an ―exodentate‖ structure in which the sulfur atoms are pointing away from the cavity interior, creating a lining of hydrogen atoms. This difference with oxygen-bearing crowns is due to the longer carbon-electron donor atom distances; 1.8 Å C-S vs. 1.4 Å C-O. In order for thiacrowns to bond with a metal cation, it is necessary first to distort the crown macrocycle to permit multiple metal-sulfur bonds, a step which bears an energetic cost.68,69 Rather than pay this penalty, thiacrowns can encompass a cation by forming bridged and sandwich complexes.70-73

Macrocyclic thiacrown ethers have been a subject of interest during the past three decades. Because of the softness of sulfur, these molecules are especially appropriate for complexation with heavy-metal ions such as Hg2+, Ag+, Cd2+, and Pb2+.74

Hg(II) complexation by a thiacrown was described in 1998 by Baumann and co- workers. They reported the synthesis and Hg(II) extraction studies of a pentathiacrown that was attached as a pendant group to a polystyrene polymer. The polythioether

11 macrocycle was shown to be highly effective in extracting Hg(II) ions in acidic aqueous

(pH = 3.60) environments. The removal of Hg(II) by this thiacrown-based system was found to be 99% or higher, showing how efficient the ligand can be in the removal of the heavy metal ion.75

1.4 Proposed Research

Describe here are the research projects for the synthesis of gold(I) halides and azides, synthesis of gold(I) triazoles, synthesis and cell studies of gold(I)-based dendrimers, and the synthesis of gold(I) thiacrown and azathiacrown macrocycles.

A. Synthesis of Gold(I) Halides and Azides76,77

The most common method by which (phosphine)gold(I) chlorides are synthesized is by the reaction of (tht)AuCl and a phosphine in an approximate 1:1 ratio in a non- halogenated solvent. A representative reaction for this synthesis is seen in Scheme 1.4.1.

Scheme 1.4.1. General synthesis of a (phosphine)gold(I) chloride.

The synthesis of (carbene)gold(I) chlorides is generally though the initial synthesis of a free carbene from an imidazolium chloride precursor followed by reaction of the free carbene with silver(I) oxide under reflux to obtain a (carbene)silver(I) chloride. After the formation of the (carbene)silver(I) chloride complex it is then reacted with (tht)AuCl to make the (carbene)gold(I) chloride. Scheme 1.4.2 depicts a general synthesis of (carbene)gold(I) chlorides.

Scheme 1.4.2. General synthesis of a (N-heterocyclic carbene)gold(I) chloride. 13

To form both the (phosphine)- and (carbene)gold(I) bromides the synthesis that is used is to take the corresponding (phosphine)- or (carbene)gold(I) chloride and react it in a biphasic solution of chloroform and water (1:1) with an excess of potassium bromide.

The reaction must be stirred vigoriously for the ion exchange to occur. The synthesis of a gold(I) bromide can be seen in Scheme 1.4.3.

Scheme 1.4.3. General synthesis of a (phosphine)- or (N-Heterocyclic carbene)gold(I) bromide.

The synthesis of the (phosphine)- or (carbene)gold(I) azides can occur through two different routes. The initial synthesis involves reacting the gold(I) chloride with thallium(I) acetylacetonate. Thallium chloride precipitates out of solution yielding a

(phosphine)gold(I) acac intermediate. This intermediate is then reacted in situ with trimethylsilyl azide in the presence of a protic solvent to yield the (phosphine)gold(I) azide.78 The second route, which is the routinely used route, involves reacting the

(carbene)- or (phosphine)gold(I) chloride with silver(I) acetate. The silver(I) chloride precipitates out of solution yielding a (carbene)- or (phosphine)gold(I) acetate complex.

These gold acetate complexes can be isolated, however they are normally reacted in situ with trimethylsilyl azide to yield the (carbene)- or (phosphine)gold(I) azide. The general

14 reactions for both the thallium (I) acetylacetonate and the silver(I) acetate can be seen in

Scheme 1.4.4.

Scheme 1.4.4. Thallium route and silver route to the general synthesis of (N-Heterocyclic carbene)- or (phosphine)gold(I) azides.

Commercially available phosphines and imidazolium salts are used. All new gold(I) compounds were fully characterized by multinuclear NMR (31P{1H}, 1H, and

13C{1H} when necessary), elemental analysis, infrared spectroscopy, and X-ray crystallography when defraction quality single crystals are available.

B. Synthesis of Single (Phosphine)- and (N-Heterocyclic Carbene)Gold(I) Alkynyls and

Triazoles62

(Phosphine)- or (N-heterocyclic carbene)gold(I) azides are reacted with terminal alkynes to produce linear coordinate gold(I)-containing products through a [3+2] cycloaddition. These reactions are done under mild conditions that create a stable carbon- gold bond that is hydrolytically stable, Scheme 1.4.5. This metal-mediated reaction is analogous to 1,3-dipolar cycloadditions with exception to the formation of a C-Au bond.

Scheme 1.4.5. General synthesis of a gold(I) triazole from a gold(I) azide and terminal alkyne.

In addition, a number of new (phosphine)- or (N-heterocyclic carbene)gold(I) alkynyls were synthesized for comparison to their triazolate counterparts. They were prepared in a reaction of a gold(I) halide with an alkynyl anion deprotonated by base,

Scheme 1.4.6.

Scheme 1.4.6. General synthesis of a gold(I) alkynyl from a gold(I) chloride and terminal alkyne.

C. Synthesis of (Phosphine)Gold(I) Dendrimers58,62 with 3T3 Cell Studies

Gold(I) triazolates dendrimers were synthesized through a [3+2] cycloaddition by reacting a gold(I) azide with a multiple terminal alkyne molecule. The gold(I) alkynyl dendrimers were synthesized though a reaction of a gold(I) chloride with terminal alkynes deprotonated by sodium tert-butoxide. With each increase in the generation, there is an exponential increase of number of gold moieties attached. Bound gold atoms is 2n, where n is the cardinal number corresponding to the dendrimer‘s generation (e.g., the fourth-generation dendrimer has 24 = 16 gold(I) centers). The organic alkyne scaffold will be prepared by a procedure designed by Hawker and coworkers.58

D. Synthesis of Gold(I) Thiacrown Macrocycles

Thiacrown macrocycles encapsulate transition metals. Synthesis of a gold(I) thiacrown ether, and two azathiacrown macrocycles with functional linkers will be peformed. These reactions are to be done under dilute conditions in DMF to form the azathiacrown ethers, and then in methylene chloride and [(tht)2Au](SbF6) to form the gold adducts. The objective of these compounds is gold(I) insertion opposite abasic lesions in duplex DNA. Figure 1.4.1. shows the target molecules.

Figure 1.4.1. Stucture of gold(I) thiacrown ether (left) and azathiacrown macrocycles (middle, right).

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Chapter 2. Synthesis and Characterization of (Phosphine)- and (N-

Heterocyclic Carbene)Gold(I) Halides and Azides

2.1 Introduction

The dialkylbiarylphosphines of Buchwald and collaborators are among the most impressive organo-group 15 ligands to have emerged in the past decade.1 They promote or enable a number of interesting transformations, many palladium-catalyzed,2-6 including the Suzuki-Miyaura coupling,7-11 carbon-hydrogen bond functionalizations,

Sonogashira couplings of aryl chlorides,12 Negishi coupling of hindered biaryls,13 aromatic ether synthesis by coupling of aryl halides with alcohols,14,15 and amidations and aminations of aryl sulfonates, aryl halides, and heteroaryl halides.16 These phosphine ligands are believed to stabilize critical intermediates in metal-mediated catalytic cycles.2

N-heterocyclic carbenes are a novel class of electron-donating ligands that form strong metal-ligand bonds and have become general ligands in organometallic and coordination chemistry.17 Similarity between the N-heterocyclic carbenes and phosphines in terms of their metal coordination chemistry has been proposed.18 N-heterocyclic carbenes, however, are easy to change by varying the N- or C functionalization in the corresponding imidazolium and carbene precursors.19-23 They not only bind to many transition metals, in low or high oxidation states,24-27 but also to main group elements.28

The metal complexes with N-heterocyclic carbenes as ligands were first synthesized by Wanzlick and Öfele and co-workers29,30 and later extended by Lappert and co-workers.31-33 It was not until the isolation of free and stable N-heterocyclic carbenes

24 by Arduengo34 in 1991 that the chemistry of metal–NHCs came back to life. Since then, information about their fundamental chemical and physical properties has been ascertained. 35-39 N-heterocyclic carbenes have found tremendous application in the field of catalysis; for example, C-H activation, C-C, C-H, C-O, and C-N bond formation, and many more.43,44 They are a promising area of study for Au(I) complex formation.

(Phosphine)- and (N-heterocyclic carbene)gold(I) species have been intensely studied. These cations are isolable with proton,45 and they bind terminally to aromatic carbons much like hydrogen and halogens. Unlike protons, they act as soft Lewis acids, and their Lewis acidity is modulated by the relativistic contraction of the 6s orbital,46-48 which contributes to the two-coordinate linear geometry bonding.49 Synthesis of the relativistic (phosphine)- and (N-heterocyclic carbene)Au+ fragments has obtained recognition in organometallics.50-52 The heavy atom effect of gold and its perturbation in spin-orbit coupling causes interesting properties in both the ground and excited states.53-56

Attaching a (phosphine)- and (N-heterocyclic carbene)Au+ fragment to the outside of an polycyclic aromatic organic skeleton leads to efficient intersystem crossing, triplet-state emission that is not observed for the free ligand.50,57 The synthesis of (phosphine)- and

(N-heterocyclic carbene)Au containing molecules, namely halides and azides is the primary focus of this research. These materials are designed for the purpose of attaching

(ligand)Au+ fragments to organic skeletons or for [3+2] cycloaddition reactions.57,58

The copper-catalyzed Huisgen cycloaddition of azides and terminal alkynes has gained much attention for its unarguable utility. This reaction is one prototype of what

Kohl, Finn, and Sharpless59 term click chemistry. Cycloaddition reactions of metal azide complexes, or of metal alkynyls with organic azides, have attracted less study.60,61

Numerous metal azide complexes are known, and the azide ligand can bind terminally or in any of several bridging geometries.62

(Phosphine)gold(I) azides undergo (1,3)-dipolar cycloaddition reactions with nitriles, isonitriles, and carbon disulfide to yield tetrazolato and thiotetrazolato complexes, respectively.60,63,64 It has been shown that (triphenylphosphine)gold(I) azide reacts with terminal alkynes to yield the C-bound tautomer of the corresponding gold(I) triazolate.65 Similar chemistry has been described here for the same reaction with the use of N-hertrocyclic carbenes as a surrogate for phosphines. Such cycloaddition reactions hold promise as one means of metalating terminal alkynes.

Reported here are synthetic and structural studies of (phosphine)- and (N- heterocyclic carbene)gold(I) azide, chloride and bromide complexes. Accordingly, we have sought to develop new gold(I) azide complexes for reaction with alkynes and other dipolarophiles. We describe two reaction protocols that realize (phosphine)- or (N- heterocyclic carbene)Au azide complexes in moderate to high yields. There is also described protocol for the synthesis of (N-heterocyclic carbene)gold(I) chlorides and bromides. Syntheses and spectroscopic characterization are discussed for eight new compounds, six of which are azide complexes. The new compounds are expected to be useful synthons for reaction chemistry that produces gold(I) alkynyls and triazolates.

2.2 Results and Discussion

There are two protocol that produce (phosphine)- or (N-heterocyclic carbene)gold(I) azides. In the first, which was used exclusively with bulky phosphine ligands, a solution of a (phosphine)gold(I) chloride in toluene reacts with thallium(I) acetylacetonate in slight excess. Thallium(I) chloride precipitates and a

(phosphine)gold(I)-acac product is produced. This species is reacted in situ with trimethylsilyl azide and a small amount of methanol. The methanol is needed as a proton source for this reaction. Reaction with the trimethylsilyl azide yields the

(phosphine)gold(I) azide complexes, Scheme 2.2.1. This procedure was used to make the

[(PCy2(o-biphenyl))AuN3] 1, [(PCy2(2′-methylbiphenyl))AuN3] 2, and [(PCy2(2′,4′,6′- triisopropylbiphenyl))AuN3] 3, in 87%, 82%, and 77% yields respectively.

Scheme 2.2.1. General synthesis of Buchwald (phosphine)gold(I) azides through thallium(I) acetylacetonate.

The second synthesis of (phophine)- or (N-heterocyclic carbene)gold(I) azides proceeds through a gold(I) acetate intermediate. A solution of a (phosphine)- or (N-

27 heterocyclic carbene)gold(I) chloride in benzene is reacted with silver(I) acetate in slight excess. The reaction is run for ~16-24 hours in the absence of light. Silver(I) chloride precipitates, yielding a gold(I) acetate complex that is not isolated and then reacts with an excess of trimethylsilyl azide. The solvent is removed yielding the (phosphine)- or (N- heterocyclic carbene)gold(I) azide complex, Scheme 2.2.2. [(PCy3)AuN3] 4, [(1,3- dimethyl-4,5-dichlorocarbene)AuN3] 7, and [(1,3-diisopropylcarbene)AuN3] 8, were synthesized by this method in 85%, 92%, and 82% yield respectively.

Scheme 2.2.2. General synthesis of (phosphine)- or (N-heterocyclic carbene)gold(I) azides through silver(I) acetate.

The characterization of all of the (phosphine)gold(I) azides can be easily ascertained by multinuclear NMR, in particular 31P{1H}. All complexes have a upfield shift in the 31P{1H} chemical shift compared to the initial (phosphine)gold(I) chloride precursors.

Diffraction quality crystals for all complexes except for [(PCy2(2′- methylbiphenyl))AuN3] were obtained by vapor diffusion of pentane into saturated solutions in tetrahydrofuran. Figure 2.2.1 depicts the compounds 1, 4, 7 and 8, the remaining structures can be found in Appendix I.

Figure 2.2.1. Crystal structures (100 K) of compounds 1 (top left), 4 (top right), 7 (bottom left), and 8 (bottom right). 50% probability ellipsoids are shown. Hydrogen atoms are omitted for clarity.

Each of the new phosphine or N-heterocyclic carbene complexes possesses a near-linear coordination with the terminal phosphine or carbene carbon and a nitrogen from the azide moiety. The C-Au-N or P-Au-N bond angles range from 173.08(3) for 3 to 178.6(3) for 8. Due to the bulk and steric hinderance of the PCy2(2′,4′,6′- triisopropylbiphenyl) ligand, the angle has slightly deviated from its near linearity compared to the remaining complexes.

Table 2.2.1. Crystallographic Data for Gold(I) Azides, 1, 3, 4, and 8.

1 3 4 8 formula C24H31AuN3P C33H49AuN3P C18H33AuN3P C9H16AuN5 fw 589.45 715.69 519.41 391.23 cryst syst Triclinic Monoclinic Monoclinic Orthorhombic space group P-1 C2/c P2(1)/c Pnma a, Å 10.2546(4) 18.161(3) 9.4837(10) 9.1386(7) b, Å 10.8364(4) 17.165(3) 14.6205(15) 6.9823(5) c, Å 11.6070(4) 22.038(4) 14.3846(15) 18.7475(14) α, deg 62.768(2) 90 90 90 β, deg 82.646(2) 101.120(2) 103.3770(10) 90 Γ, deg 75.921(2) 90 90.00 90 cell volume, 1112.19(7) 6741(2) 1940.4(3) 1196.25(15) Å3 Z 2 8 4 4 Dcalcd, Mg 1.760 1.410 1.778 1.700 m-3 T, K 100(2) 100(2) 100(2) 170(2) μ, mm-1 6.701 4.436 7.668 12.276 F(000) 580 2896 1024 736 Cryst size, 0.29 x 0.15 x 0.33 x 0.24 x 0.46 x 0.34 x 0.16 x 0.08 x mm 0.15 0.08 0.24 0.05 θmin, θmax, 2.65, 35.31 2.00, 27.03 2.35, 28.28 2.17, 26.71 deg no. of reflns 20534 36453 22034 12809 collected no. of indep 5040 7313 4442 1391 reflns no. of 262 349 208 88 refined params goodness- 1.070 1.053 0.998 1.440 of-fit on F2 a final R 0.0154 0.0230 0.0148 0.0314 indicesb [I > 2σ(I)] R1 wR2 0.0174 0.0276 0.0161 0.0333 R indices 0.0357 0.0559 0.0391 0.0606 (all data) R1 wR2 0.0376 0.0572 0.0398 0.0611 a 2 2 2 1/2 b GOF = [Σw(Fo -Fc ) /(n-p)] ; n = number of reflections, p = number of parameters refined. R1 = Σ( ||Fo| 2 2 2 4 1/2 - |Fc|| )/Σ|Fo|; wR2 = [Σw(Fo -Fc ) /ΣwFo ] .

The nitrogen-gold bond lengths range from 2.033(7) Å for 8 to 2.095(2) Å for complex 4.

The phosphorus-gold bond lengths for 1, 3, and 4 are 2.2346(6) Å, 2.2279(7) Å, and

2.2442(6) Å, respectively. The carbon-gold bond lengths for 7 and 8 are 1.962(6) Å and

1.973(8) Å respectively. Table 2.2.1 shows a list of parameters for compounds 1, 3, 4, and 8.

The synthesis of [(1,3-dimethyl-4,5-dichlorocarbene)AuN3] requires the corresponding gold(I) chloride precursor, Scheme 2.2.3. The imidazolium iodide salt is refluxed in chloroform with silver(I) oxide. An (N-heterocyclic carbene)silver(I) iodide complex forms. This species is reacted with (tht)AuCl in a fast reaction to form the N- heterocyclic carbene gold(I) chloride 5 in high yield.

Scheme 2.2.3. Synthesis of an (N-heterocyclic carbene)gold(I) chloride.

In order to obtain the N-heterocyclic carbene gold(I) bromide complex, the chloride complex is reacted in a biphasic solution of methylene chloride or chloroform and water with an excess of potassium bromide, Scheme 2.2.4. The reaction must be stirred vigorously so mixture of the two layers occurs. This affords the carbene gold(I) bromide complex 6 in an excellent yield of 89%.

Scheme 2.2.4. Synthesis of an (N-heterocyclic carbene)gold(I) bromide.

Table 2.2.2. Crystallographic Data for (1,3-dimethyl-4,5-dichlorocarbene)gold(I) products 5-7.

5 6 7 formula C H AuN Cl C H AuN Cl Br C H AuN Cl 5 6 2 3 5 6 2 2 5 6 5 2 fw 397.43 441.89 404.01 cryst syst Tetragonal Tetragonal Orthorhombic space group I-42d I-42d Pnma a, Å 15.9232(6) 16.1627(8) 16.7352(16) b, Å 15.9232(6) 16.1627(8) 6.3794(6) c, Å 7.3430(4) 7.4366(5) 8.8122(9) α, deg 90 90 90 β, deg 90 90 90 Γ, deg 90 90 90 cell volume, 1861.81(14) 1942.68(19) 940.80(16) Å3 Z 8 8 4 Dcalcd, Mg 2.836 3.022 2.852 m-3 T, K 170(2) 170(2) 170(2) -1 μ, mm 16.601 19.749 16.163 F(000) 1440 1584 736 Cryst size, 0.17 x 0.09 x 0.15 x 0.05 x 0.15 x 0.08 x mm 0.07 0.05 0.08 θmin, θmax, 2.56, 27.98 2.52, 27.87 2.43, 26.69 deg no. of reflns 11060 11604 9985 collected no. of indep 1128 1169 1097 reflns no. of 53 53 81 refined params goodness- 1.261 1.079 1.067 of-fit on F2 a final R 0.0143 0.0144 0.0204 b indices [I > 2σ(I)] R1 wR2 0.0147 0.0154 0.0224 R indices 0.0391 0.0339 0.0513 (all data) R1 wR2 0.0392 0.0340 0.0520 a 2 2 2 1/2 b GOF = [Σw(Fo -Fc ) /(n-p)] ; n = number of reflections, p = number of parameters refined. R1 = Σ( ||Fo| 2 2 2 4 1/2 - |Fc|| )/Σ|Fo|; wR2 = [Σw(Fo -Fc ) /ΣwFo ] .

Diffraction quality crystals for the N-heterocyclic carbene gold(I) chloride and bromide complexes were obtained by vapor diffusion of pentane into saturated solutions in THF. There structures can be found in Appendix A.

In comparison, the (1,3-dimethyl-4,5-dichlorocarbene)gold(I) complexes 5-7 all possesses a near linear coordination with the carbene carbon and a nitrogen from the azide moiety. The C-Au-N bond angles are 180 for 5, 180 for 6, and 175.6(2) for 7.

Only the azide complex has a slightly deviation from its near linearity compared to the remaining complexes. The carbon-gold bond lengths are 1.977(5) Å for 5, 1.990(5) Å for

6, and 1.962(6) Å for complex 7. The halide- or nitrogen-gold bond lengths are

2.2923(13) Å for 5, 2.4050(5)Å for 6, and 2.019(6) Å for complex 7.

2.3 Conclusion and Final Remarks

Six new (phosphine)- and (N-heterocyclic carbene)gold(I) azides, one new (N- heterocyclic carbene)gold(I) chloride and one new (N-heterocyclic carbene)gold(I) bromide were synthesized. The bulky (phosphine)gold(I) azides were synthesized through a thallium(I) acetylacetonate method, while the (N-heterocyclic carbene)- and

(tricyclohexylphosphine)gold(I) azides were using a silver(I) acetate method. The (N- heterocyclic)carbene gold(I) chloride was synthesized by initial reaction with an imidizolium salt with silver(I) oxide and then by (tht)AuCl. The (N-heterocyclic carbene)gold(I) bromide was synthesized by a metathesis reaction of potassium bromide with the (N-heterocyclic carbene)gold(I) chloride. These compounds are air stable, and all are white or off-white color in the solid state. Their solutions take on no color change when dissolved in organic solvents.

All products were characterized by 1H NMR, and all of the phosphine containing products were also characterized by 31P{1H} NMR. Compared to the 31P{1H} of the phosphine gold(I) starting materials all products experienced a upfield shift.

Seven of these of these compounds were identified crystallographically, with the lone exception being [(PCy2(2′-methylbiphenyl))AuN3]. Diffraction quality crystals were grown from saturated solutions of tetrahydrofuran with the diffusion of pentane. All compounds conformed to a near linear two-coordinate system. The most bulky of the products, [(PCy2(2′,4′,6′-triisopropylbiphenyl))AuN3] deviated the most from linearity with having a P-Au-N of 173.08(3) .

In the future, more (phosphine)- and (N-heterocyclic carbene)gold(I) azides and halides will be pursued. They will be used for cyclometallation reactions and gold(I)

34 fragment attachment onto organic scaffold periphery. The phosphines and N-heterocyclic carbenes used will be intended to modulate the lipophilicity and the hydrophilicity of the gold(I) appended molecules. Absorbance and emission studies are also to be pursued, specifically for the smaller (N-heterocyclic carbene)gold(I) products. These compounds are more likely to have Au-Au interactions and unique photophysical properties.

2.4 Experimental

Unless otherwise stated, all reactions were carried out under a dry, inert atmosphere of argon using standard Schlenk techniques for the handling of air or moisture sensitive materials.

2.4.1. Reagents

(tht)AuCl was synthesized based on modified procedures from the literature.

2.4.2. Instrumentation

NMR spectra (1H, 31P{1H}, and 13C{1H}) were recorded on a Varian AS-400 spectrometer operating at 399.7, 161.8, and 100.5 MHz respectively. For 1H NMR spectra, chemical shifts were determined relative to the solvent residual peaks. For

31 1 P{ H} NMR spectra, chemicals shifts were determined relative to external 85% H3PO4 aqueous solution. Unless otherwise stated, NMR spectra were recorded in C6D6 or

CDCl3. NMR spectra of the gold(I) complexes can be found in Appendix II.

Single-crystal diffraction studies were done on a Bruker AXS SMART APEX II

CCD diffractometer using monochromatic Mo Kα radiation with the omega scan technique.

Measurements were made at 100 K; samples were mounted on a mitogen tip using Paratone-

N, then flash-frozen under a stream of nitrogen gas. The unit cells were determined using

SMART and SAINT+. Data collection for all crystals was conducted at 100 K (-173.5 °C).

All structures were solved by direct methods and refined by full matrix least squares against

2 F with all reflections using SHELXTL. Refinement of extinction coefficients was found to

36 be insignificant. All non-hydrogen atoms were refined anisotropically. All hydrogen atoms were placed in standard calculated positions and all hydrogen atoms were refined with an isotropic displacement parameter 1.2 times that of the adjacent carbon.

Microanalyses (C, H, and N) were performed by Robertson Microlit Laboratories,

Inc. (Madison, N.J.).

Mass spectrometry was performed at the Ohio State University (Columbus, OH) or the University of Cincinnati (Cincinnati, OH) Mass Spectrometry facilities.

2.4.3. Synthesis of Gold(I) Complexes

[(PCy2(o-biphenyl))AuN3] (1)

In 20 mL toluene was suspended [(PCy2(o-biphenyl))AuCl] (151 mg, 0.256 mmol) and to this suspension was added thallium(I) acetylacetonate (97 mg, 0.319 mmol). The resultant suspension was stirred under nitrogen for 24 h. The suspension was then filtered though celite yielding a clear filtrate. To the filtrate was added 70 μL (0.525 mmol) of trimethylsilyl azide and 4 mL of methanol which upon addition formed a white precipitate. The suspension was then stirred for 16 h. The suspension was filtered through celite resulting in a clear filtrate, which was then rotovaped to near dryness and then triturated with pentane. This resulted in the formation of a white crystalline precipitate.

The white solid was then collected and washed with pentane (3 × 50 mL) and then

1 vacuum dried. Yield: 133 mg (87%). H NMR (C6D6): δ 7.66 (td, J = 7.2 Hz, 1.6 Hz, 1H,

2′-biphenyl), 7.52 (t, J = 7.6 Hz, 2H, 2′-biphenyl), 7.13 (dd, J = 8.0 Hz, 1.2 Hz, 2H, 2′-

31 1 biphenyl), 6.95-7.08 (m, 4H, 2′-biphenyl), 0.71–1.72 (m, 22H, C6H11) ppm. P{ H}

13 1 NMR (C6D6): δ 37.84 ppm. C{ H} NMR (C6D6): δ 132.36-132.57 (m), 130.38 (d, J =

2.1 Hz), 129.41 (s), 127.39 (d, J = 6.4 Hz), 127.14 (d, J = 7.8 Hz), 36.23 (d, J = 33.6 Hz),

30.73 (s), 29.12 (s), 26.58 (s), 26.44 (d, J = 5.1 Hz), 26.26 (s), 25.34 (s) ppm. IR (KBr):

-1 2054.65 (νas N=N=N, vs), 1286.25 (νs N=N=N, w) cm . Anal. Calcd for C24H31AuN3P: C,

48.90; H, 5.30; N, 7.13. Found: C, 49.17; H, 5.53; N, 6.78.

[(PCy2(2′-methylbiphenyl))AuN3] (2)

In 8 mL toluene was suspended [(PCy2(2′-methylbiphenyl))AuCl] (87 mg, 0.146 mmol), and to this suspension was added thallium(I) acetylacetonate (63 mg, 0.208 mmol). The resultant suspension was stirred under nitrogen for 48 h. The suspension was then filtered though celite yielding a clear filtrate. To the filtrate was added 40 μL (0.300 mmol) of trimethylsilyl azide and 2 mL of methanol, which upon addition formed a white precipitate. The suspension was then stirred for 16 h. The suspension was filtered through celite resulting in a clear filtrate, which was then evaporated to near dryness and then triturated with pentane. This resulted in the formation of a white crystalline precipitate.

The white solid was then collected and washed with pentane (3 × 50 mL) and then

1 vacuum dried. Yield: 73 mg (82%). H NMR (C6D6): δ 7.62-7.71 (m, 2H, 2′- methylbiphenyl), 7.31 (td, J = 7.2 Hz, 1.6 Hz, 1H, 2′-methylbiphenyl), 6.94-7.22 (m, 4H,

2′-methylbiphenyl), 6.87-6.92 (m, 1H, 2′-methylbiphenyl), 1.98 (s, 1H, CH3), 0.68–1.82

31 1 13 1 (m, 22H, C6H11) ppm. P{ H} NMR (C6D6): δ 35.11 ppm. C{ H} NMR (C6D6): 149.70

(d, J = 13.0 Hz), 140.59 (d, J = 5.2 Hz), 135.77 (s), 132.45 (d, J = 7.6 Hz), 132.23 (d, J =

3.8 Hz), 131.28 (s), 130.83 (d, J = 2.3 Hz), 129.92 (J = 7.6 Hz), 128.53 (s), 127.11 (d, J =

7.7 Hz), 125.89 (s), 125.38 (s), 124.88 (s), 37.67 (d, J = 32.8 Hz), 34.84 (d, J = 35.1 Hz),

30.74 (d, J = 2.3 Hz), 30.54 (d, J = 5.4 Hz), 29.56 (s), 28.71 (d, J = 2.3 Hz), 26.90 (s),

26.75 (d, J = 6.9 Hz), 26.38 (s), 26.24 (s), 25.69 (d, J = 15.3 Hz), 20.99 (s) ppm. IR

-1 (KBr): 2057.64 (νas N=N=N, vs), 1288.24 (νs N=N=N, w) cm . Anal. Calcd for C25H33AuN3P:

C, 49.76; H, 5.51; N, 6.96. Found: C, 49.79; H, 5.33; N, 6.68.

[(PCy2(2′,4′,6′-triisopropylbiphenyl))AuN3] (3)

In 8 mL toluene was suspended [(PCy2(2′,4′,6′-triisopropylbiphenyl))AuCl] (51 mg,

0.072 mmol) and to this suspension was added thallium(I) acetylacetonate (36 mg, 0.117 mmol). The resultant suspension was stirred under nitrogen for 48 h. The suspension was then filtered though celite yielding a clear filtrate. To the filtrate was added 30 μL (0.230 mmol) of trimethylsilyl azide and 2 mL of methanol which upon addition formed a white precipitate. The suspension was then stirred for 16 h. The suspension was filtered through celite resulting in a clear filtrate, which was then evaporated to near dryness and triturated with pentane. This resulted in the formation of a white crystalline precipitate.

The white solid was then collected and washed with pentane (3 × 50 mL) and then

1 vacuum dried. Yield: 40 mg (77%). H NMR (C6D6): δ 7.51 (s, 2H, 2′,4′,6′- triisopropylbiphenyl), 7.14–7.18 (m, 1H, 2′,4′,6′-triisopropylbiphenyl), 6.94–7.05 (m, 3H,

2′,4′,6′- triisopropylbiphenyl), 3.32 (sep, J = 6.8 Hz, 1H, CH(CH3)2), 2.38 (sep, J = 6.8

Hz, 2H, CH(CH3)2), 1.61 (d, J = 6.8 Hz, 6H, CH(CH3)2), 1.50 (d, J = 6.8 Hz, 6H,

CH(CH3)2), 1.04 (d, J = 6.4 Hz, 6H, CH(CH3)2), 0.79–1.80 (m, 22H, C6H11) ppm.

31 1 13 1 P{ H} NMR (C6D6): δ 34.11 ppm. C{ H} NMR (C6D6): δ 150.78 (s), 147.86 (d, J =

14.5 Hz), 146.01 (s), 135.56 (d, J = 6.1 Hz), 133.72, (d, J = 7.6 Hz), 131.94 (d, J = 3.1

Hz), 130.32 (d, J = 2.3 Hz), 128.44 (s), 127.03 (d, J = 6.8 Hz), 121.88 (s), 37.04 (s),

36.70 (s), 34.88 (s), 31.38 (s), 31.05 (d, J = 2.3 Hz), 29.94 (s), 26.97 (d, J = 13.7 Hz),

26.59 (d, J = 30.0 Hz), 25.91 (s), 25.64 (s), 24.24 (s), 22.97 (s) ppm. IR (KBr): 2056.32

-1 (νas N=N=N, vs), 1265.31 (νs N=N=N, w) cm . Anal. Calcd for C33H49AuN3P: C, 55.38; H,

6.90; N, 5.87. Found: C, 55.60; H, 7.14; N, 5.61.

[(PCy3)AuN3] (4)

In 10 mL benzene was dissolved (PCy3)Au(OAc) (62 mg, 0.116 mmol), and to this solution was added by syringe ~3 equiv (0.05 mL, 3.80 mmol) of trimethylsilyl azide. There was no visible change. The solution was stirred for 16 h, the solvent was removed by rotary evaporation, and the solid triturated with pentane and collected. Yield:

1 31 1 51 mg (85 %). H NMR (C6D6): δ 0.74-1.56 (m, 33H) ppm. P{ H} NMR (C6D6): δ

13 1 51.01 ppm. C{ H} NMR (C6D6): δ 32.97 (d, J = 30.5 Hz), 30.66 (s), 26.96 (d, J = 12.2

-1 Hz), 25.86 (s) ppm. IR (KBr): 2049.45 (νas N=N=N, vs), 1283.65 (νs N=N=N, w) cm . Anal.

Calcd. for C18H33AuN3: C, 41.62; H, 6.40; N, 8.09. Found: C, 41.46; H, 6.44; N, 7.87.

[(1,3-dimethyl-4,5-dichlorocarbene)AuCl] (5)

In 10 mL tetrahydrofuran was dissolved (1,3-dimethyl-4,5-dichlorocarbene)AgI

(102 mg, 0.255 mmol), and to this solution was added 85.0 mg (0.265 mmol) of

(THT)AuCl. A white precipitate quickly formed. The solution was stirred for 16 h, the solvent was filtered through a plug of celite and then removed by rotary evaporation. A

40 white solid remained that was washed with pentane (3 × 50 mL) and then vacuum dried.

1 Yield: 94 mg (93 %). H NMR (CDCl3): δ 3.83 (s, 6H) ppm. Anal. Calcd. for

C5H6AuN2Cl3: C, 15.11; H, 1.52; N, 7.05. Found: C, 15.49; H, 1.53; N, 7.15.

[(1,3-dimethyl-4,5-dichlorocarbene)AuBr] (6)

In 30 mL dichloromethane was dissolved (1,3-dimethyl-4,5- dichlorocarbene)AuCl (65 mg, 0.164 mmol), and to this solution was added a 25 mL aqueous solution of KBr (195 mg, 1.64 mmol). The biphasic mixture was stirred 4 h, and the organic layer was collected. The aqueous layer was washed once with dichloromethane (10 mL), and the organic layers were combined, washed with water (2 ×

10 mL), dried with MgSO4, and filtered. The filtrate was stripped of solvent via rotary evaporation to yield a white solid. The white solid remained was washed with pentane

1 (3 × 50 mL) then vacuum dried and collected. Yield: 64 mg (89 %). H NMR (CDCl3): δ

3.84 (s, 6H) ppm.

[(1,3-dimethyl-4,5-dichlorocarbene)AuN3] (7)

In 15 mL benzene was added (1,3-dimethyl-4,5-dichlorocarbene)AuCl (155 mg,

0.390 mmol), and to this was solution was added silver acetate (66.8 mg, 0.400 mmol), with formation of a gray precipitate. The solution was stirred for 16 hours in the absence of light. The solution was filter twice through celite to remove the precipitate and the solution was collected. To the filtrate 0.05 mL (3.80 mmol) trimethylsilyl azide was

41 added by syringe. There was no visible change. The solution was stirred for 16 h, the solvent removed by rotary evaporation, and the solid triturated with pentane and

1 collected. Yield: 144 mg (92 %). H NMR (CDCl3): δ 3.82 (s, 6H) ppm. IR (KBr):

-1 2052.31 (νas N=N=N, vs), 1285.95 (νs N=N=N, w) cm . Anal. Calcd. for C5H6AuN5Cl2: C,

14.86; H, 1.50; N, 17.33. Found: C, 14.63; H, 1.53; N, 17.01.

[(1,3-diisopropylcarbene)AuN3] (8)

In 15 mL benzene was added (1,3-diisopropylcarbene)AuCl (99 mg, 0.258 mmol), and to this was solution was added silver acetate (45 mg, 0.270 mmol). A gray precipitate quickly fell out of solution. The solution was stirred for 16 hours in the absence of light. The solution was filter twice through celite to remove the precipitate and the solution was collected. To the filtered solution 0.05 mL (3.80 mmol) of trimethylsilyl azide was added by syringe. There was no visible change. The solution was stirred for 16 h, the solvent removed by rotary evaporation, and the solid triturated with pentane and

1 collected. Yield: 83 mg (82 %). H NMR (CDCl3): δ 6.97 (s, 2H, HC=CH), 4.97 (sept, J

= 6.8 Hz, 2H, CH(CH3)2), 1.46 (d, J = 6.8 Hz, 12H, CH(CH3)2) ppm. IR (KBr): 2051.19

-1 (νas N=N=N, vs), 1285.32 (νs N=N=N, w) cm . Anal. Calcd. For C9H16AuN5: C, 27.63; H,

4.12; N, 17.90. Found: C, 27.54; H, 3.98; N, 17.65.

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Chapter 3. Synthesis and Characterization of Single (Phosphine)- and

(N-Heterocyclic Carbene)Gold(I) Triazoles and Alkynyls

3.1 Introduction

The synthesis of gold organometallics has received a considerable amount of attention. Certain gold materials have already shown their versatility in gold-catalyzed reactions, such as C-C bond formation,1-3 selective redox reactions,4-6 and nucleophilic additions.7 Gold chemistry has also been investigated because of its strong relativistic effects.8-10 As a result of this effect s-shell electrons become strongly bound and their orbitals constrict, while simultaneously the d-shell electrons become less effectively bound. Relativistic effects lead to gold being more resistant to oxidation, and also allows gold to achieve more accessible higher oxidation states, at least compared with silver.11

The formation of a gold(I)-carbon bond is a recurring step in catalytic reactions.12-

14 The (phosphine)gold(I) fragment is isolobal with a proton, and can substitute for terminal hydrogens on organic molecules. Gold(I) can act as a functional group modifying molecular properties.15,16 N-heterocyclic carbenes are also effective neutral ligands for gold(I) cations.17 The oxidation state of Au+ is typically associated with two- linear coordinate complexes.10,18

The Huisgen cycloaddition is a 1,3-dipolar cycloaddition that occurs between an azide and a terminal or internal alkyne to give a 1,2,3-triazole products.19 The uncatalyzed reaction is not regioselective, and a combination of 1,4- and 1,5-disubstituted

1,2,3-triazoles results. In a variant of Huisgen cycloaddition there is a copper(I)-catalyzed

48 synthesis that takes terminal alkynes and organic azides to forms regioselective 1,4- disubstituted 1,2,3-triazoles, in the terms of Sharpless click chemistry.20-26 While the copper(I) catalyzed variant gives rise to a triazole from a terminal alkyne and an azide, formally it is not a 1,3-dipolar cycloaddition and thus should not be termed a Huisgen cycloaddition. This reaction is better termed the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC).

Gold(I) alkynyls of the type LAuC≡CR (L = phosphine or N-heterocyclic carbene) are among the oldest organometallic compounds.27,28 They are commonly prepared in a reaction of a gold(I) halide with an alkyne deprotonated by base,29,30 or by proton interchange of a gold acetylacetonate complex with a terminal alkyne.31,32 The

LAuC≡CR compounds possess a linear bonding coordination that runs through the triple bonded carbons to Au which conforms to the two-coordinate linear bonding geometry so prevalent for gold(I). Current research in gold(I) alkynyls typically concern their luminescence properties. Their emission is either from an intra- or intermolecular interaction between two or more gold(I) centers,33-35 or from the triplet excited-state manifold of the alkynyl promoted by the heavy atom effect of gold.36

Coumarins are a naturally occurring class of compounds that were first isolated in bean plants in the early 1800’s, with many other varieties being isolated from a wide range of plant sources.37 The structure of coumarins, or benzo-α-pyrones, consists of fused benzene and pyrone rings, with a carbonyl group at the 2-position of the pyrone ring. Coumarins have biological applications such as anti-bacterials, anti-carcinogenics and analgesics,38 but most notably they serve as anti-inflammatory drugs, anti-oxidants, and inhibiters of HIV protease.39 For these reasons, the synthesis of coumarins has

49 intrigued chemists, and many synthetic strategies have been developed.40-42 Their photophysical properties also make coumarins particularly useful in light-based applications, such as fluorescent tags and laser dyes.43

In this account, we will show that (phosphine)- or (N-herterocyclic carbene)gold(I) azides will reaction with terminal alkynes to produce linear coordinate gold(I)-containing products through a [3+2] cycloaddition. These reactions are done under mild conditions that create a carbon-gold bond that is hydrolytically stable. This metal-mediated reaction is analogous to 1,3-dipolar cycloadditions with exception to the formation of a C-Au bond. In addition, a number of new (phosphine)- or (N- herterocyclic carbene)gold(I) alkynyls have been synthesized for comparison to their triazolate counterparts. The synthesis of their gold(I) products holds strong value for future organogold starting materials through gold(I) azides precursors.

3.2 Results and Discussion

Reaction of suspensioned (triphenylphosphine)gold(I) azide in toluene with 1- heptyne affords the (PPh3)Au(n-pentatriazole)complex 1. The product formed a precipitate upon reaction that was washed repeatedly with toluene and recovered at a

61% isolated yield. In analogous reactions, the terminal alkynes cyclohexylacetylene, 3- aminophenylacetylene, and 1-ethynyl-4-methoxybenzene were used to form triazolate complexes 2-4 in isolated yields of 67%, 54%, and 59% respectively, Scheme 3.2.1. For solubility reasons the products 2-4 were repeatedly washed with benzene instead of toluene. The reactions all occurred at ambient temperatures for the duration of 72 hours to afford clean triazolate products.

Scheme 3.2.1. General synthesis of (triphenylphosphine)gold(I) triazolates.

(Phosphine)gold(I) triazolates were characterized 31P{1H} and 1H. The 31P{1H} of

(triphenylphosphine)gold(I) azide is found at ~31.1 ppm. During the course of the reaction there is a steady decline of the starting material peak and a growth of a peak at

~44-45 ppm for all triazole products seen in the 31P{1H} NMR.

In addition to simple 31P{1H} NMR characterization, all products have a distinct

N-H resonance that occurs at ~14 ppm in the 1H NMR spectra. This also supports the

[3+2] cycloaddition rearrangement and the formation of an Au-C bond.

Diffraction quality crystals for 1, 3, and 4 were obtained by vapor diffusion of pentane into saturated solutions in THF. Diffraction quality crystals of 2 were obtained by slow evaporation from a saturated solution of ethyl acetate. Figure 3.2.1 depicts the structures 1 and 4, the structures of 2 and 3 can be found in Appendix I.

Figure 3.2.1. Crystal structures (100 K) of compounds 1 (left) and 4 (right). 50% probability ellipsoids are shown. Hydrogen atoms are omitted for clarity.

Table 3.2.1. Crystallographic Data for (Triphenylphosphine)Gold(I) Triazolates 1, 3, 4, and 8.

1 2 3 4 formula C25H27AuN3P C26H27AuN3P C26H22AuN4P C27H23AuN3OP fw 597.43 609.44 618.41 633.42 cryst syst Monoclinic Tetragonal Triclinic Tetragonal space group P21 P43 P-1 P43 a, Å 12.7141(3) 12.8742(2) 13.4001(14) 13.9165(5) b, Å 12.5924(3) 12.8742(2) 15.0853(15) 13.9165(5) c, Å 14.5253(3) 14.6812(3) 20.853(2) 12.8078(7) α, deg 90 90 70.2910(10) 90 β, deg 97.4650(10) 90 86.9520(10) 90 Γ, deg 90 90 66.5160(10) 90 cell volume, 2305.81(9) 2433.34(7) 3623.5(6) 2480.47(19) Å3 Z 4 4 6 4 Dcalcd, Mg 1.721 1.664 1.700 1.696 m-3 T, K 100(2) 100(2) 100(2) 298(2) μ, mm-1 6.466 6.129 6.176 6.019 F(000) 1168 1192 1800 1232 Cryst size, 0.55 0.12 0.17 0.07 0.14 x 0.06 x 0.30 x 0.16 x mm 0.08 0.07 0.06 0.08 θmin, θmax, 1.62, 29.61 2.10, 20.90 1.57, 27.50 2.07, 27.49 deg no. of reflns 53261 34557 42136 21833 collected no. of indep 12797 2340 16364 5506 reflns no. of 543 268 865 299 refined params goodness- 0.982 1.089 0.891 0.987 of-fit on F2 a final R 0.0160 0.0250 0.0657 0.0252 indicesb [I > 2σ(I)] R1 wR2 0.0337 0.0521 0.1503 0.0453 R indices 0.0174 0.0322 0.1150 0.0367 (all data) R1 wR2 0.0341 0.0553 0.1691 0.0484 a 2 2 2 1/2 b GOF = [Σw(Fo -Fc ) /(n-p)] ; n = number of reflections, p = number of parameters refined. R1 = Σ( ||Fo| 2 2 2 4 1/2 - |Fc|| )/Σ|Fo|; wR2 = [Σw(Fo -Fc ) /ΣwFo ] .

Each of the triazolate complexes synthesized possesses a near-linear coordination with the terminal triphenylphosphine and a carbon from the triazolate structure. The C-

Au-P bond angles for 1-4 are 175.00(7)°, 177.4(3)°, 175.9(3)°, and 175.20(12)°, respectively. The carbon-gold bond lengths for 1-4 are 2.026(10) Å, 2.018(10) Å,

2.033(11) Å, and 2.025(4) Å, respectively. The phosphorus-gold bond lengths for 1-4 are

2.2837(6) Å, 2.273(3) Å, 2.279(3) Å, and 2.2798(12) Å, respectively. Table 3.2.1 displaces crystallographic parameters for products 1-4.

417 nm Conc. = 0.00226 M in THF

-1

cm -1

10 MolarM Absorptivity

0 400 500 600 700

Wavelength (nm)

Figure 3.2.2. Absorption spectrum in THF of (PPh3)Au(n -pentatriazole), 1.

A preliminary absorption spectrum was taken of the (PPh3)Au(n-pentatriazole) complex, Figure 3.2.2. The absorbance was taken in dry tetrahydrofuran and the complex

54 showed a single weak absorbance peak at 417 nm. The (PPh3)Au(n-pentatriazole) complex also shows no emission peaks in the same solvent and concentration.

Scheme 3.2.2. General synthesis of (tricyclohexylphosphine)gold(I) triazolates.

The synthesis of the (tricyclohexylphosphine)gold(I) triazolate complexes followed the same procedure as for the synthesis of the (triphenylphospine)gold(I) triazolate complexes except for isolation of the products. With the change from a phenyl phosphine ligand to a cyclic alkyl phosphine ligand the solubility of the resulting products increased dramatically. This lead to the difficultly of isolation of pure product material. In general, a solution of (tricyclohexylphosphine)gold(I) azide in toluene with

1-ethynyl-4-methoxybenzene affords the (PCy3)Au(-methoxyphenyltriazole) complex 5,

Scheme 3.2.2, left. The product however did not form a precipitate upon complex reaction. In order to obtain the product the solution must be cooled to -78°C. A white precipitate forms and the remaining toluene is removed by decanting. The product is subsequently washed with cold benzene to afford clean triazolate product that is both air- and water-stable in 52% yield. The synthesis of the 7-

{[(PCy3)Au(triazolate)][methoxy]}coumarin 6, Scheme 3.2.2, right, is analogues to the

(PPh3)Au(triazolate) complex, however it is still a more soluble product in comparison and is isolated in 91% yield.

The characterization of all of the tricyclohexylphosphine triazoles can be easily ascertained by multinuclear NMR, in particular 31P{1H} and 1H. The resonance of the initial starting material of (tricyclohexylphosphine)gold(I) azide is found at ~51.0 ppm.

During the course of the reaction there is a steady decline of the starting material peak and a growth of a peak at ~57-60 ppm for all tricyclohexylphosphine triazole products seen in the 31P{1H} NMR.

In terms of a distinct N-H resonance that occurs for the tricyclohexylphosphine triazoles complexes, the [(PCy3)Au(-methoxyphenyltriazole)]complex has a peak 13.91

1 ppm in the H NMR spectra. The [7-{[(PCy3)Au(triazolate)][methoxy]}coumarin] however has a N-H peak at 11.51 ppm, which is noticeably more upfield compared to all other triazolate complexes. This still however supports the [3+2] cycloaddition rearrangement and the formation of an Au-C bond.

Diffraction quality crystals for 5 were obtained by vapor diffusion of pentane into saturated solutions in tetrahydrofuran. This triazolate complex possesses a near linear coordination with the terminal tricyclohexylphosphine and a carbon from the triazolate structure. The C-Au-P bond angles for 5 is 177.98(8)º, and the carbon-gold bond length is

2.047(3) Å. The phosphorus-gold bond length for 5 is 2.2928(7) Å. There are no apparent

Au-Au interactions seen in the packing structure of this complex. Figure 3.2.3 depicts the structure of compound 5.

Figure 3.2.3. Crystal structure (100 K) of compound 5. 50% probability ellipsoids are shown. Hydrogen atoms are omitted for clarity.

In expanding the range of different gold(I) triazolates, an N-heterocyclic carbene was proposed as an ancillary ligand to be use instead of a phosphine. The (N- heterocyclic carbene)gold(I) azide used in this synthesis was (1,3-dimethyl-4,5- dichlorocarbene)AuN3. The synthesis for the the N-heterocyclic carbene triazolate complexes followed the same procedure as for the synthesis of (phospine)gold(I) triazolate complexes. A solution of (1,3-dimethyl-4,5-dichlorocarbene)AuN3 in toluene with 7-(propargyloxy)coumarin affords the 7-{[(1,3-dimethyl-4,5- dichlorocarbene)Au(triazolate)][methoxy]}coumarin complex, 7, Scheme 3.2.3. The product readily precipitated out of solution and was washed with benzene to afford a clean product in 91% yield. Unlike the tricyclohexylphosphine triazolate complexes, this

N-heterocyclic carbene triazolate complex is less soluble in organic solvents, and readily decomposed when dissolved in chlorinated solvents. The product is however stable to air and water over an extended period. Table 3.2.3 displays initial starting materials, reaction times, products and isolated yields of all triazolate products.

Scheme 3.2.3. Synthesis of (N-Heterocyclic carbene)gold(I) triazolate, 7.

The distinct N-H resonance that occurs for [7-{[(1,3-dimethyl-4,5- dichlorocarbene)Au(triazolate)][methoxy]}coumarin] appears at 14.05 ppm in the 1H

NMR spectra. This complex does not contain phosphorus so no identification can occur through 31P{1H} NMR. Crystals however were grown from DMSO/THF and diethyl ether combinations as well as DMF and diethyl ether. Crystal quality however was not satisfactory for X-ray diffraction analysis, but the samples passed elemental analysis.

Scheme 3.2.4. General synthesis of (phosphine)- or (N-heterocyclic carbene)gold(I) alkynyls.

For comparison to the number of gold(I) triazolates synthesized, a pair of gold(I) alkynyls were synthesized. For both alkynyls the alkyne used in this synthesis was 7-

(propargyloxy)coumarin, and for the ancillary ligand gold(I) chloride starting material either tricyclohexylphoshine or (1,3-dimethyl-4,5-dichlorocarbene) was used. In the general synthesis a 1:1 ratio of the alkynyl and gold(I) chloride was dissolved in 2-

58 propanol. An excess of sodium tert-butoxide base was used for deprotonation of the alkyne, Scheme 3.2.4. The reaction was then allowed to stir for 48 hours and the product formed upon precipitation. The [7-[(PCy3)Au(propargyloxy)]coumarin] 8, and 7-[(1,3- dimethyl-4,5-dichlorocarbene)Au(propargyloxy)]coumarin] 9, were synthesized in 72% and 85% yield respectively.

The characterization of tricyclohexylphosphine alkynyl can be easily ascertained by 31P{1H}. The resonance of the initial starting material of

(tricyclohexylphosphine)gold(I) chloride is found at ~53.1 ppm. During the course of the reaction there is a steady decline of the starting material peak and a growth of a peak at

55.95 ppm for the alkynyl product seen in the 31P{1H} NMR.

Figure 3.2. 4. Crystal structure (100 K) of compound 9. 50% probability ellipsoids are shown. Hydrogen atoms are omitted for clarity.

Authentication of the 7-[(1,3-dimethyl-4,5-dichlorocarbene)

Au(propargyloxy)]coumarin] was done through x-ray crystallography. X-ray defraction quality crystals were grown in a saturated tetrahydrofuran solution layered with pentane.

This alkynyl complex possesses a near linear coordination with the terminal alynynl and a carbon from the carbene structure, Figure 3.2.4. The Ccarbene-Au-Calkynyl bond angles for

9 is 177.3(2) º, and the carboncarbene-gold bond length is 2.013(5) Å. The carbonalkynyl - gold bond lengths for 9 is 1.982(5) Å. This complex shows that the carbene lies in the same plane as the coumarin functionality, and the packing of this molecules shows that there are -stacking interactions occurring.

Table 3.2.2. Initial starting materials, reaction times, products and isolated yields of gold(I) triazolate products.

3.3 Conclusion and Final Remarks

Seven new (phosphine)- and (N-heterocyclic carbene)gold(I) triazolates and two new (phosphine)- and (N-heterocyclic carbene)gold(I) alkynyls were synthesized. All gold(I) triazolates were synthesized through a [3+2] cycloaddition by reacting a gold(I) azide with a terminal alkyne. All reactions were done under mild conditions that create a stable carbon-gold bond that is hydrolytically meta-stable. The gold(I) alkynyls were synthesized though a reaction of a gold(I) chloride with an alkynyl anion deprotonated by sodium tert-butoxide. All compounds synthesized are air stable, and all are white or off-white color in the solid state except for the coumarin containing species, these compounds were light yellow. All compounds are stable in organic solvent except for the

(1,3-dimethyl-4,5-dichlorocarbene)gold(I) products. These compounds quickly decompose upon expose to chlorinated solvents.

Six of these of these compounds were identified crystallographically, with five compounds being gold(I) triazoles and one being a gold(I) alkynyl. Defraction quality crystals were grown from saturated solutions of tetrahydrofuran with the diffusion of pentane or from slow evaporation of ethyl acetate. All compounds conformed to a near linear two-coordinate geometry.

In the future, more phosphine and N-heterocyclic carbene gold(I) triazoles and alkynyls will be pursued. They will be primarily used for in vitro cellular studies to

62 demonstate the effects of gold containing molecular on living systems. More hydrophilic and lipophilic phosphines and N-heterocyclic carbenes will be use so the compounds will be able to pass cellular membranes. Absorbance and emission studies are also to be pursued, specifically with gold(I) products containing coumarin functionalities. These compounds have the possibility to be luminescent markers in cellular studies.

3.4 Experimental

Unless otherwise stated, all reactions were carried out under a dry, inert atmosphere of argon using standard Schlenk techniques for the handling of air or moisture sensitive materials.

3.4.1. Reagents

Unless otherwise specified, commercially available reagents were used as received without further purification. Solvents were passed through on Mbraun solvent purification system before use. The (phosphine)- or (N-heterocyclic carbene)gold(I) azides used to synthesize triazolate complexes were prepared according to the modified literature procedure.44,45 The (phosphine)gold(I) chloride used was prepared according to a modified literature procedure.46 The (N-heterocyclic carbene)gold(I) chloride synthesis was taken from the procedure of Section 2.4.3 of this work.

3.4.2. Instrumentation

NMR spectra (1H and 31P{1H}) were recorded on a Varian AS-400 spectrometer operating at 399.7 and 161.8 MHz respectively. For 1H NMR spectra, chemical shifts were determined relative to the solvent residual peaks. For 31P{1H} NMR spectra, chemicals shifts were determined relative to external 85% H3PO4 aqueous solution.

Unless otherwise stated, NMR spectra were recorded in DMSO-d6 or CDCl3. NMR spectra of the as-synthesized molecules can be found in Appendix II.

Single-crystal diffraction studies were done on a Bruker AXS SMART APEX II

CCD diffractometer using monochromatic Mo Kα radiation with the omega scan technique. Measurements were made at 100 K; samples were mounted on a mitogen tip using Paratone-N, then flash-frozen under a stream of nitrogen gas. The unit cells were

64 determined using SMART and SAINT+. Data collection for all crystals was conducted at

100 K (-173.5 °C). All structures were solved by direct methods and refined by full matrix least squares against F2 with all reflections using SHELXTL. Refinement of extinction coefficients was found to be insignificant. All non-hydrogen atoms were refined anisotropically. All hydrogen atoms were placed in standard calculated positions and all hydrogen atoms were refined with an isotropic displacement parameter 1.2 times that of the adjacent carbon.

UV spectra were measured on a Cary 500 spectrophotometer in HPLC grade solvents. Fluorescence measurements were made on a Cary Eclipse spectrophotometer at room temperature; samples were deaerated approximately fifteen minutes prior to taking the measurement.

Microanalyses (C, H, and N) were performed by Robertson Microlit Laboratories,

Inc. (Madison, N.J.).

Mass spectrometry was performed at the Ohio State University (Columbus, OH) or the University of Cincinnati (Cincinnati, OH) Mass Spectrometry facilities.

3.4.3. Synthesis of Gold(I) Triazolate and Alkynyl Complexes

[(PPh3)Au(n-pentatriazole)] (1)

In 20 mL of toluene was suspended [(PPh3)Au(N3)] (122 mg, 0.24 mmol), and to this was added 1-heptyne (100 µl, 0.76 mmol). The resultant suspension was stirred under argon for 72 h. The toluene from the resultant suspension was removed yielding a white solid. The product was the washed with toluene and then n-pentane and then

1 vacuum dried. Yield: 88 mg (61%). H NMR (DMSO-d6): δ 13.92 (s br, 1H, NH), 7.54-

7.67 (m, 15H, CH), δ 2.68 (t, J = 7.6 Hz, 2H, CH2), δ 1.70 (quint, J = 7.2, 2H, CH2), δ

31 1 1.21-1.31 (m, 4H, CH2), δ 0.75 (t, J = 6.8, 3H, CH3) ppm. P{ H} NMR (DMSO-d6): δ

44.97 ppm. Anal. Calcd for C25H27AuN3P: C, 50.26; H, 4.56; N, 7.03. Found: C, 49.99;

H, 4.52, N, 7.02.

[(PPh3)Au(cyclohexyltriazole)] (2)

In 10 mL of toluene was suspended [(PPh3)Au(N3)] (67 mg, 0.13 mmol), and to this was added cyclohexylacetylene (50 µl, 0.38 mmol). The suspension was stirred under argon for 72 h. The resultant suspension was dried under vacuo and yielded a white product. The product was the washed with benzene and then n-pentane and then vacuum

1 dried. Yield: 54 mg (67%). H NMR (DMSO-d6): δ 13.91 (s br, 1H, NH), 7.52-7.64 (m,

31 1 15H, CH), 2.79 (t, J = 11.6, 1H, CH), 1.05-1.98 (m, 10H, CH2) ppm. P{ H} NMR

(DMSO-d6): δ 45.02 ppm. Anal. Calcd for C26H27AuN3P: C, 51.24; H, 4.47; N, 6.89.

Found: C, 50.94; H, 4.48, N, 6.74.

[(PPh3)Au(3-aminophenyltriazole)] (3)

In 10 mL of toluene was suspended [(PPh3)Au(N3)] (74 mg, 0.14 mmol), and to this was added 3-aminophenylacetylene (80 µl, 0.71 mmol). The suspension was stirred under argon for 72 h. The resultant suspension was dried under vacuo and yielded a light orange product. The product was the washed with benzene and then n-pentane and then

1 vacuum dried. Yield: 49 mg (54%). H NMR (DMSO-d6): δ 14.22 (s br, 1H, NH), 7.57-

7.66 (m, 15H, CH), 7.43 (d, J = 7.6, 2H, CH), 7.39 (s, 1H, CH), 6.97 (t, J = 7.6, 1H, CH),

31 1 6.45 (d, J = 8.0, 1H, CH), 5.02 (s br, 2H, NH2) ppm. P{ H} NMR (DMSO-d6): δ 44.52 ppm. Anal. Calcd for C26H22AuN4P: C, 50.50; H, 3.59; N, 9.06. Found: C, 49.40; H, 3.69,

N, 8.70.

[(PPh3)Au(4-methoxyphenyltriazole)] (4)

In 10 mL of toluene was suspended [(PPh3)Au(N3)] (64 mg, 0.13 mmol), and to this was added 1-ethynyl-4-methoxybenzene (50 µl, 0.21 mmol). The suspension was stirred under argon for 72 h. The resultant suspension was dried under vacuo and yielded a white product. The product was the washed with benzene and then n-pentane and then

1 vacuum dried. Yield: 48 mg (59%). H NMR (DMSO-d6): 14.27 (s br, 1H, NH), 8.10 (d,

J = 8.4, 2H, CH), 7.56-7.64 (m, 15H, CH), 6.91 (d, J = 8.4, 2H, CH), 3.78 (s, 3H, CH3)

31 1 ppm. P{ H} NMR (DMSO-d6): δ 44.67 ppm. Anal. Calcd for C27H23AuN3OP: C, 51.20;

H, 3.66; N, 6.63. Found: C, 51.44; H, 3.92, N, 6.41.

[(PCy3)Au(4-methoxyphenyltriazole)] (5)

In 5 mL of toluene was dissolved [(PCy3)Au(N3)] (125 mg, 0.241 mmol), and to this was added 1-ethynyl-4-methoxybenzene (120 µl, 0.50 mmol). The solution was stirred under argon for 72 h. The resultant solution was cooled to near freezing in an acetone/dry ice bath. Upon cooling a white solid precipitated out of solution. The product was collected by decanting the solution while at a low temperature. The white solid was washed repeatedly n-pentane, vacuum dried and collected. Yield: 82 mg (52%). 1H NMR

(DMSO-d6): 14.04 (s br, 1H, NH), 8.07 (d, J = 8.8 Hz, 2H, CH), 6.88 (d, J = 8.8 Hz, 2H,

31 CH), 3.75 (s, 3H, CH3), 2.45-1.12 (m, 33H, cyclohexyl) ppm. P NMR (DMSO-d6): δ

59.99 ppm. Anal. Calcd for C27H41AuN3OP: C, 49.77; H, 6.34; N, 6.45. Found: C, 49.73;

H, 6.15, N, 6.17.

[7-{[(PCy3)Au(triazolate)][methoxy]}coumarin] (6)

In 20 mL of toluene was dissolved [(PCy3)Au(N3)] (156 mg, 0.300 mmol), and to this was added 7-(propargyloxy)coumarin (30.0 mg, 0.150 mmol). The solution was stirred under argon for 48 h. A pale yellow precipitate formed, which was collected and washed 3 times with 10 mL portions of benzene and then with pentane. The remaining light yellow solid was collected and then vacuumed dried. Yield: 71 mg (66%). 1H NMR

(CDCl3): 11.51 (s br, 1H, NH), 7.62 (d, J = 9.2 Hz, 1H, CH), 7.34 (d, J = 8.4 Hz, 1H,

CH), 7.04-7.96 (m, 2H, CH), 6.22 (d, J = 9.6 Hz, 1H, CH), 5.31 (s, 2H, Ar-OCH2-tri),

31 1 2.30-0.85 (m, 33H, cyclohexyl) ppm. P{ H} NMR (CDCl3): δ 57.95 ppm. Anal. Calcd for C30H41AuN3O3P: C, 50.07; H, 5.74; N, 5.84. Found: C, 49.89; H, 5.54, N, 5.56.

[7-{[(1,3-dimethyl-4,5-dichlorocarbene)Au(triazolate)][methoxy]}coumarin] (7)

In 20 mL of toluene was dissolved [(1,3-dimethyl-4,5-dichlorocarbene)AuN3] (80 mg, 0.198 mmol), and to this was added 7-(propargyloxy)coumarin (20.0 mg, 0.100 mmol). The solution was stirred under argon for 48 h. A pale white precipitate formed, which was collected and washed 3 times with 10 mL portions of benzene and then with pentane. The off-white solid was collected and then vacuumed dried. Yield: 54 mg

1 (91%). H NMR (DMSO-d6): 14.05 (s br, 1H, NH), 7.93 (d, J = 9.6 Hz, 1H, CH), 7.56 (d,

J = 8.8 Hz, 1H, CH), 7.25 (s, 1H, CH), 6.97 (dd, J = 2.4, 8.4 Hz, 1H, CH), 6.22 (d, J =

9.6 Hz, 1H, CH), 5.23 (s, 2H, Ar-OCH2-tri), 3.78 (s, 6H, CH3) ppm. Anal. Calcd for

C17H14AuCl2N5O3: C, 33.79; H, 2.34; N, 11.59. Found: C, 33.55; H, 2.47, N, 11.37.

[7-[(PCy3)Au(propargyloxy)]coumarin] (8)

In 10 mL of 2-propanol was dissolved [(PCy3)AuCl] (55 mg, 0.105 mmol), and 7-

(propargyloxy)coumarin (20.0 mg, 0.100 mmol). To the solution was added sodium tert- butoxide (57 mg, 0.593 mmol). The solution was stirred under argon for 48 h and a yellow precipitate evolved. The yellow precipitate was collected by filtration and washed repeated with cold 2-propanol and then with pentane. The yellow-brownish solid was

1 then collected and dried by vacuum. Yield: 49 mg (72%). H NMR (CDCl3): 7.62 (d, J =

9.6 Hz, 1H, CH), 7.34 (d, J = 8.4 Hz, 1H, CH), 6.82-6.91 (m, 3H, CH), 6.63 (d, J = 2.4,

2H, CH), 6.59 (t, J = 2.4 Hz, 1H, CH), 6.23 (d, J = 9.2 Hz, 1H, CH), 5.03 (s, 2H, OCH2),

31 1 4.74 (s, 2H, OCH2), 1.22-2.08 (m, 33H, cyclohexyl) ppm. P{ H} NMR (CDCl3): δ

55.94 ppm. Anal. Calcd for C30H40AuPO3: C, 53.26; H, 5.95. Found: C, 53.11; H, 6.31.

[7-[(1,3-dimethyl-4,5-dichlorocarbene)Au(propargyloxy)]coumarin] (9)

In 10 mL of 2-propanol was dissolved [(1,3-dimethyl-4,5-dichlorocarbene)AuCl]

(43 mg, 0.108 mmol), and 7-(propargyloxy)coumarin (20.0 mg, 0.100 mmol). To the solution was added sodium tert-butoxide (53 mg, 0.551 mmol). The solution was stirred under argon for 48 h and a light yellow precipitate evolved. The yellow precipitate was collected by filtration and washed repeated with cold 2-propanol and then with pentane.

The light yellow solid was then collected and dried by vacuum. Yield: 48 mg (85%). 1H

NMR (CDCl3): 7.61 (d, J = 9.6 Hz, 1H, CH), 7.33 (d, J = 8.8 Hz, 1H, CH), 7.05 (d, J =

2.4 Hz, 1H, CH), 6.92 (dd, J = 2.4, 8.4 Hz, 1H, CH), 6.22 (d, J = 9.6 Hz, 1H, CH), 4.90

(s, 2H, Ar-OCH2-tri), 3.79 (s, 6H, CH3) ppm. Anal. Calcd for C17H13AuCl2N2O3: C,

36.39; H, 2.33; N, 4.99. Found: C, 35.67; H, 2.33, N, 4.78.

3.5 References

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Chapter 4. Synthesis and Characterization of (Phospine)Gold(I)

Triazole and Alkynyl Dendrimers with 3T3 Cell Studies

4.1 Introduction

Gold is perhaps the most biologically friendly heavy transition element. This perception derives partly from its history, now decades-long, in rheumatoid arthritis treatment.1 In recent years, the focus of medicinal gold(I) chemistry has shifted toward cancer therapy in response to observations that gold(I) anti-arthritics possess anti- inflammatory and immunosuppressive activity.2 The orally bioavailable prodrug auranofin [(triethylphosphine)gold(I) peracetylthioglucose] is toxic to P388 leukemia and

B16 melanoma cell lines.3 Results from Berners-Price, Filipovska, and co-workers find cationic, bis(diphosphine) gold(I) cations to be membrane-permeable, and indeed, to trigger apoptosis in human breast-cancer cell lines.4-6

Figure 4.1.1. Proposed pathway of a gold(I) agent as a thioredoxin reductase inhibitor.

A central role in the apoptotic process is played by mitochondria, which act by releasing several factors leading to cell death.7 This apoptotic function is added to those already known for mitochondria such as energy production, ion homeostasis control and the production of hydrogen peroxide. The level of the latter is modulated by two systems, present both in the cytosol and in mitochondria which depend on glutathione, glutathione reductase and peroxidase8 and thioredoxin, thioredoxin reductase and peroxidase.9 Both glutathione peroxidase and thioredoxin reductase are endowed with a selenol group at their active site. The mechanism for the apoptosis cascade biological activity is drawing scrutiny in terms of reactivity with metal complexes. One hypothesis that enjoys substantial experimental support is that gold(I) inhibits the mitochondrial form of the enzyme thioredoxin reductase, Figure 4.1.1. The single SeCys residue of this enzyme, which lies near the protein’s C-terminus, is held to bind gold in a favorable soft-soft match.10 The inhibited (gold-bound) reductase then fails to reduce thioredoxin, and thereby triggers mitochondrial membrane permeability. Apoptosis ensues. Malignant tissues up-regulate thioredoxin reductase, and this enzyme is emerging as a chemotherapeutic target. The anticancer propensities of gold(I) compounds continue to attract clinical attention, and the medicinal prospects of gold chemistry are far from exhausted.

Dendrimers are branched polymers having precisely controllable architectures and uniform composition. One consequence of their symmetrical and layered structure is the large number of functional groups at the chain ends/periphery.11-17 In repeated studies, the nature of these chain ends has been shown to dictate the chemical and physical properties of dendritic macromolecules.18-23 This novel characteristic of dendritic macromolecules,

76 when compared to traditional linear polymers, is perhaps best represented by the poly(amido amine) PAMAM dendrimers of Tomalia,24 or the ((poly-(propylene imine))

25,26 DAB dendrimers from DSM/Meijer, Figure 4.1.2.

Figure 4.1.2. Structures of first generation PAMAM(left) and DAB(right) dendrimers.

The use of dendrimers as targetable drug carriers now represents a mature field of study.27 Dendrimers exploit the enhanced permeability and retention of tumors, where the ramshackle vasculature of cancerous tissue traps macromolecules. Polymeric drugs, or polymer-immobilized prodrugs, linger inside tumors and acquire a longer residence time.

Selectivity results for malignant over healthy tissues.

Reported here are synthetic and structural studies of (phosphine)gold(I) triazole and alkynyl dendrimers. In addition, 3T3 cellular studies including light microscopy and fluorescence-activated cell sorting (FACS) are discussed. We will show that

(phosphine)gold(I) azides will reaction with terminal alkynes to produce linear coordinate gold(I)-containing products through a [3+2] cycloaddition in a number dendrimer generations that possess terminally alkyne moieties. These reactions are done under mild conditions that create a stable carbon-gold bond. Syntheses and spectroscopic characterization are discussed for eight new compounds, five of which are

77 gold(I)triazolate denrimers, and one which is an gold(I)alkynyl dendrimer. The new compounds are intended as gold delivery vehicles for biological settings that have small diameters and precisely controllable metal-ion loadings.

4.2 Results and Discussion

The reaction of Cy3PAuN3 (Cy = cyclohexyl) with the ethynyl-terminated dendrimers synthesized by Hawker and co-workers,28 Scheme 4.2.1, yields dendrimers bearing C-bound (phosphine)gold(I) triazolates. Four generations of dendrimer have been metalated this way, and the number of bound gold atoms is 2n, where n is the cardinal number corresponding to the dendrimer’s generation (e.g., the fourth-generation dendrimer has 24 = 16 gold(I) centers). Figure 4.2.1 depicts line-drawings of the first few dendrimer generations. End-to-end diameters, estimated from molecular mechanics minimization, range from 2 nm for the first-generation dendrimer to 4 nm for the fourth.

Scheme 4.2.1. Modified synthesis of ethynyl-terminated dendrimers adapted from ref 28.

These sizes fall below the ≤ 5.5-nm limit encountered for kidney clearance of

nanocrystals.29 Thus the new dendrimers are potentially compatible with renal

elimination.

Figure 4.2.1. (Triazolato)gold(I) dendrimers. End-to-end dimensions are estimated from molecular mechanics minimizations.

Reaction of a solution of excess (tricyclohexylphosphine)gold(I) azide in toluene

with the first generation dendrimer (G1) affords the [(PCy3)Au(triazolate)]2-[G-1]-OH

complex 1, Scheme 4.2.2. The product formed a precipitate upon reaction that was

subsequently washed repeatedly with benzene and recovered at an 88% isolated yield.

Scheme 4.2.2. Synthesis of (tricyclohexylphosphine)gold(I) dendrimer, 1.

In attempts of triazolate formation with higher generations of dendrimer with the same procedure incomplete reaction was taking place. The product precipitation would occur before all terminal alkynes could form triazoles. In order to have complete product formation tetrahydrofuran was used instead of toluene. The more polar aprotic solvent was able to allow complete product formation for the higher generations of triazolate dendrimers 2-4 using a similar procedure as in the synthesis of 1. All triazolate dendrimer reactions occurred at 50 C, and with the increase in generation there had to be a proportional increase in reaction time for the reaction to run to completion. Table 4.2.1 shows reaction times and yields of products 1-4.

Table 4.2.1. Reaction times and isolated yields of gold(I) dendrimer products, 1-4.

The triazolate dendrimers products were characterized by multinuclear NMR and infrared spectroscopy. The resonance of the initial starting material of

(tricyclohexylphosphine)gold(I) azide is found at ~51.0 ppm. During the course of the reaction there is a steady decline of the starting material peak and a growth of a peak at

~59 ppm for all tricyclohexylphosphine triazole dendrimers seen in the 31P{1H} NMR.

Mass spectra and elemental analysis indicate that all terminal alkynyl groups in the organic precursors are transformed into (triazolato)gold(I) moieties. Vibrational

signatures corresponding to terminal alkynes or azide complexes are absent in the

products’ infrared spectra. The organogold dendrimers are colorless, and the absorption

spectra are featureless in the near-UV and visible regions.

The first generation triazolate Au-dendrimer has been prepared with a

fluorescent coumarin attached in a two-step procedure from readily prepared starting

material. The design requires a brominated linker coming from the dendrimer scaffold,

and a pendant hydroxyl group from the fluorescent marker. The hydroxyl group must be

deprotonated by a base, in this case potassium carbonate, for the conjugation to proceed

to completion, Scheme 4.2.3. The second step is analogous to the synthesis of the first

generation gold dendimer without the fluorescent marker. The final product of the

synthesis produces [(PCy3)Au(triazolate)]2-[G1]-7-methoxycoumarin 6, in 74% isolated

yield.

Scheme 4.2.3. Synthesis of coumarin tagged gold(I) triazolate dendrimer, 7.

For comparison, the first generation alkynyl Au-dendrimer has been prepared

with the fluorescent 7-hydroxycoumarin attached in a two-step procedure from readily

prepared starting material. The initial step is identical to synthesize the (acet)2-[G1]-7-

82 methoxycoumarin as in the two-step synthesis of the triazolate dendrimer. For the second step, a solution of (tricyclohexylphosphine)gold(I) chloride and (acet)2-[G1]-7- methoxycoumarin in 2-propanol is stirred for 48 hours with an excess of sodium tert- butoxide, Scheme 4.2.4. The product precipitates out of solution as a light yellow powder. This material must be washed with cold 2-propanol to obtain

[(PCy3)Au(alkynyl)]2-[G1]-7-methoxycoumarin, in 64% isolated yield.

Scheme 4.2.4. Synthesis of coumarin tagged gold(I) alkynyl dendrimer, 8.

3T3 mouse fibroblast cells were obtained from the American Type Culture

Collection and stored in a medium of DMEM, 10% FBS, and 1% P/S solution (D8 medium) and incubated at 37°C and 5% CO2. Initially to determine if gold(I) dendrimers had any cytotoxic effects on cells an exploratory experiment on 3T3 cells were performed. Using ~100,000 cells in 1 mL of D8 medium per experiment a series of

[(PCy3)Au(triazolate)]2-[G1]-OH solutions, 230 μM, 100 μM, and 50 μM in 50% DMSO, as well as a 50% DMSO control were prepared and the cells were treated with 100 μL individually and incubated at 37°C and 5% CO2 for 20 hours. Light microscopy images were taken of each experimental well, Figure 4.2.2.

a 10x b 10x c 10x d 10x

Viable Cells

Figure 4.2.2. Light microscopy images of 3T3 fibroblast cells with [(PCy3)Au(triazolate)]2-[G1]- OH , 1. a) 20.9 μM b) 9.09 μM c) 4.55 μM d) 4.5% DMSO. (Final concentrations given, not initially prepared concentrations.)

The results of the experiment show that for all concentrations from 4.55-20.9 μM that the cytotoxicity is greater than 95%. As seen in the light microscopy images, Figure

4.2.2.d, a living viable cell is seen as an elongated globules attach to the culture plate. In comparison, the dead cells have lost their cellular structure and have detached from the culture plate and appear as small spheres. The DMSO for these experiments were initially at a 4.5% final concentration, which experimentally show little effect in terms of cytotoxicity and the cells still appear viable for the control.

With cytotoxicity established for the first generation of gold(I) dendrimers, experiments were performed to measure the extent of apoptosis, if any. Apoptosis can be characterized by the loss of plasma membrane asymmetry and attachment, condensation of the cytoplasm and nucleus, and internucleosomal cleavage of DNA. In apoptotic cells, the membrane phospholipid phosphatidylserine (PS) is translocated from the inner to the outer leaflet of the plasma membrane, thereby exposing PS to the external cellular environment. Using annexin V-Phycoerythrin (PE), which is a 35-36 kDa Ca2+ dependent phospholipid-binding protein that has a high affinity for phospholipid phosphatidylserine and is conjugated to Phycoerythrin as a fluorochrome for fluorocent identification, was used to determine apoptotic activity.30-35

In two sets of experiments done in triplicate, [(PCy3)Au(triazolate)]2-[G1]-OH, dendrimer solutions at 110, 55, 11, and 1.0 μM in 20% DMSO, giving final concentrations of solutions of 10, 5.0, 1.0, and 0.1 in 1.8% DMSO were added to

~100,000 cells in 1 mL of D8 medium and incubated at 37°C and 5% CO2 for 6 hour for the first experiment and for 20 hours for the second. Upon workup of each experimental well, fluorescent-activated cell sorting (FACS) analysis was performed to determine amounts of apoptotic activity.

Figure 4.2.3. Fluorescence-activated cell sorting results for 1, after 6 hours.

Treatment of the 3T3 cells after 6 hours shows that apoptosis occurs, with particularly positive results with the 10.0 μM [(PCy3)Au(triazolate)]2-[G-1]-OH dendrimer solution,

Figure 4.2.3. With increasing concentration from 0.1 to 10 μM of gold(I) dendrimer solutions there is a discernible increase of apoptosis as seen in for both experiments.

Treatment of the 3T3 cells after 20 hours with the same sample concentration shows a very similar pattern, but for the 10.0 μM experiment there is a distinct increase in the relative amount of apoptosis, Figure 4.2.4.

Figure 4.2.4. Fluorescence-activated cell sorting results for 1, after 20 hours.

The initial results for the [(PCy3)Au(triazolate)]2-[G1]-OH dendrimer were extremely promising. However, to ensure that that apoptotic effects that the 3T3 cells were undergoing were due to the gold(I) containing species a set of control experiments were performed. The first set was a 6 hour experiment with the 3T3 cells exposed to

(acet)2-[G1]-OH, G1, the alkynyl starting material used to synthesis the first generation gold(I) dendrimer. The second control was a 6 hour experiment with the 3T3 cells exposed to [(PCy3)Au(4-methoxyphenyltriazole)]. The purpose of this experiment was to

determine of a single gold moiety had the same effect as the first generation gold(I)

dendendrimer with two gold(I) moieties.

Results for the (acet)2-[G-1]-OH control experiments were done under the same

conditions as the experiment with the [(PCy3)Au(triazolate)]2-[G-1]-OH dendrimer.

(Acet)2-[G1]-OH solutions at 110, 55, 11, and 1.0 μM in 20% DMSO, giving final

concentrations of solutions of 10, 5.0, 1.0, and 0.1 in 1.8% DMSO were added to

~100,000 cells in 1 mL of D8 medium and incubated at 37°C and 5% CO2 for 6 hour.

Fluorescent-activated cell sorting (FACS) analysis was performed to determine amounts

of apoptotic activity. The 3T3 cells were not affected by the non-aurated alkynyl

dendrimer at all concentrations exposed, Figure 4.2.5. This is supporting evidence that

the gold(I) containing functionality is the species that causes apoptotic activity.

Figure 4.2.5. Fluorescence-activated cell sorting results for (acet)2-[G1]-OH, G1, after 6 hours.

Figure 4.2.6. Fluorescence-activated cell sorting results for (PCy3)Au(4-methoxyphenyltriazole), after 6 hours.

Results for the [(PCy3)Au(4-methoxyphenyltriazole)] control experiments were

done under the same conditions as the experiment with the [(PCy3)Au(triazolate)]2-[G1]-

OH dendrimer. [(PCy3)Au(4-methoxyphenyltriazole)] solutions at 110, 55, 11, and 1.0

μM in 20% DMSO, giving final concentrations of solutions of 10, 5.0, 1.0, and 0.1 in

1.8% DMSO were added to ~100,000 cells in 1 mL of D8 medium and incubated at 37°C

and 5% CO2 for 6 hour. The FACS analysis of this set of experiments shows a striking

similarity to the experiments of the [(PCy3)Au(triazolate)]2-[G1]-OH dendrimer

solutions, Figure 4.2.6. The [(PCy3)Au(4-methoxyphenyltriazole)] apoptotic active is

slightly better than the Au-dendrimer at concentrations of 0.1-5.0 μM. However the Au-

dendrimer has a slightly better apoptotic active at 10 μM. The main reasoning why the

[(PCy3)Au(4-methoxyphenyltriazole)] solutions has a comparable effect on the 3T3 cells

is that the compound far more soluble in aqueous solutions than the

[(PCy3)Au(triazolate)]2-[G1]-OH dendrimer. Solubility and the ability to pass through

cellular members to be able to disrupt the thioredoxin enzyme is of great importance for

these molecules to induce apoptosis.

10x 10x 10x

Figure 4.2.7. Light microscopy images of 3T3 fibroblast cells with 7- [(PCy 3)Au(propargyloxy)]coumarin (top row) and 7-{[(PCy3)Au(triazolate)][methoxy]}coumarin (bottom row) at 0.1, 1.0, and 10 M concentrations in 1.8% DMSO.

A pair of experiments was done to determine which type of gold(I) contain

molecule has the better apoptotic activity, gold(I)-triazolate or gold(I)-alkynyl. The two

complexes used in this experiment were [7-[(PCy3)Au(propargyloxy)]coumarin] and [7-

{[(PCy3)Au(triazolate)][methoxy]}coumarin]. The addition of the coumarin functional

group also meant that these coumpounds could be used for fluorescent microscopy

experiments. Solutions of both [7-[(PCy3)Au(propargyloxy)]coumarin] and [7-

{[(PCy3)Au(triazolate)][methoxy]}coumarin] were prepared at 110, 11, and 1.1 μM in

20% DMSO, giving final concentrations of solutions of 10, 1.0, and 0.1 in 1.8% DMSO were added to ~100,000 cells in 1 mL of D8 medium and incubated at 37°C and 5% CO2 for 6 hour. Light microscopy images were taken of each set of cells containing the solutions, Figure 4.2.7. The figure shows that for the gold(I)-alkynyl there is very little cytotoxicity for the concentrations at 0.1 and 1.0 μM. It is not until the 10 μM concentration that about ~75% of the 3T3 cells have died. As compared to the gold(I)- triazolate, the cytotoxicity for the concentrations at 0.1 μM is very low, but for 1.0 and 10

μM they are at ~75% and <99%, respectively. The evidence indicates that gold(I)- triazolate complexes are more cytotoxic than gold(I)-alkynyl complexes.

4.3 Conclusion and Final Remarks

Five new (tricyclohexylphosphine)gold(I) triazolates and one new

(tricyclohexylphosphine)gold(I) alkynyl dendrimer were synthesized. All gold(I) triazolates were synthesized through a [3+2] cycloaddition by reacting a gold(I) azide will with a terminal alkyne dendrimer. All reactions were done under mild conditions that create a stable carbon-gold bond that is hydrolytically stable. The gold(I) alkynyls were synthesized through a reaction of a gold(I) chloride with an alkynyl anion deprotonated by sodium tert-butoxide. All compounds synthesized are air stable, and all are white or off-white color in the solid state except for the coumarin containing species, these compounds were light yellow. All compounds are stable in organic solvents.

With each increase in the generation, there is an exponential increase of number of gold moieties attached. Bound gold atoms is 2n, where n is the cardinal number corresponding to the dendrimer’s generation (e.g., the fourth-generation dendrimer has 24

= 16 gold(I) centers). The first generations of dendrimers were very soluble in all organic solvents. The solubility however decreased as the generation, or amount of gold attached, went up. Compound 4, was so inherently insoluble that it would not dissolve in any solvents.

3T3 cell studies were performed using light microscopy and fluorescence- activated cell sorting. The results show that there is cytotoxic effects on 3T3 cells by both

(phosphine)gold(I) triazoles and (phosphine)gold(I) alkynyls under micromolar exposure.

Through light microscopy it was shown that (phosphine)gold(I) triazoles are more potent molecules than (phosphine)gold(I) alkynyls in terms of cytotoxicity. With fluorescence- activated cell sorting, it was shown that compound 1 and (PCy3)Au(4- methoxyphenyltriazole) cause apoptosis to 3T3 cells with concentrations of 1.0-10 M.

In the future, more (phosphine)- and (N-heterocyclic carbene)gold(I) triazoles and alkynyls dendrimers will be pursued. They will be primarily used for in vitro and in vivo cellular studies to demonstate the effects of gold containing molecular on living systems.

More hydrophilic and lipophilic phosphines and N-heterocyclic carbenes will be used so the compounds will be more soluble and be able to pass though cellular membranes.

Absorbance and emission studies are also to be pursued, specifically with gold(I) products containing coumarin functionalities. These compounds have the potential to be anti-cancer and anti-tumor gold containing drugs.

4.4 Experimental

Unless otherwise stated, all reactions were carried out under a dry, inert atmosphere of argon using standard Schlenk techniques for the handling of air or moisture sensitive materials. All cell studies were performs under an ultra-clean and sterilized vacuum hood.

4.4.1. Reagents

Unless otherwise specified, commercially available reagents were used as received without further purification. Solvents were passed through on Mbraun solvent purification system before use. The (tricyclohexylphosphine)gold(I) azide used to synthesize triazolate complexes were prepared according to the modified literature procedure.36 The (phosphine)gold(I) chloride used was prepared according to a modified literature procedure.37

3T3 mouse fibroblast cells were obtained from the American Type Culture

Collection and stored a medium of DMEM, 10% FBS, and 1% P/S solution (D8 medium) and incubated at 37°C and 5% CO2. All solution and medium materials were obtained from Thermo Scientific. The Annexin V-PE apoptosis detection kit was obtained from

BD Biosciences.

4.4.2. Instrumentation

Unless otherwise stated, NMR spectra were recorded in CDCl3. NMR spectra of the as- synthesized compounds can be found in Appendix II.

Microanalyses (C, H, and N) were performed by Robertson Microlit Laboratories,

Inc. (Madison, N.J.).

Mass spectrometry was performed at the Ohio State University (Columbus, OH) or the University of Cincinnati (Cincinnati, OH) Mass Spectrometry facilities.

Fluorescent-activated cell sorting (FACS) analysis was performed on a Becton

Dickinson FACSCalibur machine with excitation wavelength at 488 nm. Analysis was performed using a 564-601 nm and a 670LP (long pass) filter.

Microscopy images were obtained from a Nikon Eclipse TE300 microscope using a Q Imaging Retiga-SRV Fast 1394 camera and Image-Pro 6.2 software.

3.4.3. Synthesis of Gold(I) Triazolate and Alkynyl Dendrimer Complexes

[(PCy3)Au(triazolate)]2-[G1]-OH (1)

In 4 mL of toluene was stirred (Acet)2-[G-1]-OH (0.0090 g, 0.041 mmol) and

(PCy3)AuN3 (0.065 g, 0.11 mmol). The solution was degassed under argon for 30 minutes and allowed to stir for 72 hours at 50°C. The solution produced a white precipitate after 72 hours. The resultant suspension was allowed to cool to room temperature and the precipitate was allowed to settle. The toluene was pipetted off. The white precipitate was washed toluene (3 × 20 mL) and then with n-pentane (3 × 20 mL).

The precipitate was collected and vacuum dried. Yield: 44 mg (88%). 1H NMR (DMSO- d6): δ 14.01 (s br, 2H, NH), 6.51-6.93 (m, 3H, o,p-Ar), 4.97 (s, 4H, OCH2-triazole), 4.38

31 1 (s, 2H, CH2OH), 0.98-2.21 (m, 66H, cyclohexyl) ppm. P{ H} NMR (DMSO-d6): δ

59.52 ppm. IR (KBr): 3211 (νs NH, m, br), 2927 (νas -CH2-, s), 2850 (νs -CH2-, s), 1594

-1 (νtriazole ring stretch, s), 1447 (νtriazole ring stretch, s), 1346 (νtriazole ring stretch, m) cm . Electrospray mass spectrum: Calcd for C49H78N6O3Au2P2: 1255.06. Found: 1255.3. Anal. Calcd for

C49H78N6O3Au2P2: C, 46.89; H, 6.26; N, 6.70. Found: C, 46.68; H, 5.98; N, 6.44.

[(PCy3)Au(triazolate)]4-[G2]-OH (2)

In 6 mL of tetrahydrofuran was stirred (Acet)4-[G-2]-OH (0.020 g, 0.038 mmol) and (PCy3)AuN3 (0.11 g, 0.20 mmol). The solution was degassed under argon for 30 minutes and allowed to stir for 96 hours at 50°C. The solution was allowed to cool to room, was filtered, and vacuumed to ~0.5 mL of solution remaining. 20 mL of toluene was added and a white suspension fell out of the remaining solution. The white precipitate was washed toluene (3 × 20 mL) and then with n-pentane (3 × 20 mL). The white precipitate was collected and vacuum dried. Yield: 88 mg (89%). 1H NMR

(DMSO-d6): δ 14.02 (s br, 4H, NH), 6.41-6.63 (m, 9H, o,p-Ar), 4.99 (s, 8H, OCH2- triazole), 4.91 (s, 4H, Ar-OCH2-Ar), 4.41 (s, 2H, CH2OH), 0.98-2.17 (m, 132H,

31 1 cyclohexyl) ppm. P{ H} NMR (DMSO-d6): δ 59.49 ppm. IR (KBr): 3145(νs NH, m, br),

2925 (νas -CH2-, s), 2850 (νs -CH2-, s), 1594 (νtriazole ring stretch, s), 144 6(νtriazole ring stretch, s),

-1 1344 (νtriazole ring stretch, m) cm . MALDI mass spectrum: Calcd for C105H160N12O7Au4P4:

2614.23. Found: 2614.17. Anal. Calcd for C105H160N12O7Au4P4: C, 48.24; H, 6.17; N,

6.43. Found: C, 48.27; H, 5.89; N, 6.13.

[(PCy3)Au(triazolate)]8-[G3]-OH (3)

In 6 mL of tetrahydrofuran was stirred (Acet)8-[G-3]-OH (0.021 g, 0.018 mmol) and (PCy3)AuN3 (0.12 g, 0.23 mmol). The solution was degassed under argon for 30 minutes and allowed to stir for 120 hours at 50°C. The solution was allowed to cool to room, was filtered, and vacuumed to ~0.5 mL of solution remaining. 30 mL of toluene was added and a white suspension fell out of the remaining solution. The white precipitate was washed toluene (3 × 30 mL) and then with n-pentane (3 × 30 mL). The white precipitate was then collected and vacuum dried. Yield: 85 mg (89%). 1H NMR

(DMSO-d6): δ 14.02 (s br, 8H, NH), 6.43-6.63 (m, 21H, o,p-Ar) , 4.80-5.06 (m, 28H,

OCH2-triazole, Ar-OCH2-Ar), 4.4 (s, 2H, CH2OH), 0.97-2.19 (m, 264H, cyclohexyl)

31 1 ppm. P{ H} NMR (DMSO-d6): δ 59.47 ppm. IR (KBr): 3146 (νs NH, m, br), 2926 (νas -

CH2-, s), 2850 (νs -CH2-, s), 1594 (νtriazole ring stretch, s), 1446 (νtriazole ring stretch, s), 1343 (νtriazole

-1 ring stretch, m) cm . MALDI mass spectrum: Calcd for C217H324N24O15Au8P8: 5332.57

Found: 5329.37. Anal. Calcd for C217H324N24O15Au8P8: C, 48.88; H, 6.12; N, 6.30.

Found: C, 48.62; H, 6.00; N, 6.53.

[(PCy3)Au(triazolate)]16-[G4]-OH (4)

In 6 mL of tetrahydrofuran was stirred (Acet)16-[G-4]-OH (0.084 g, 0.034 mmol) and (PCy3)AuN3 (0.571 g, 1.10 mmol). The solution was degassed under argon for 30 minutes and allowed to stir for 120 hours at 50°C. A white precipitate formed upon completion. The suspension was allowed to cool to room and vacuumed to ~0.5 mL of solution remaining. The white precipitate was washed toluene (3 × 30 mL) and then with n-pentane (3 × 30 mL). The white precipitate was then collected and vacuum dried.

Yield: 33 mg (90%). The material was insoluble in all solvents tested and no NMR or

96 mass spectra data was obtained for this reason. IR (KBr): 3141 (νs NH, m, br), 2925 (νas -

CH2-, s), 2849 (νs -CH2-, s), 1594 (νtriazole ring stretch, s), 1446 (νtriazole ring stretch, s), 1342 (νtriazole

-1 ring stretch, m) cm . Anal. Calcd for C441H652N48O31Au16P16: C, 49.18; H, 6.10; N, 6.24.

Found: C, 45.17; H, 5.60; N, 6.18.

[acet]2-[G1]-7-methoxycoumarin (5)

In 50 mL of dry acetone was stirred (Acet)2-[G-1]-Br (2.031 g, 7.28 mmol), 7- hydroxycoumarin (1.201 g, 7.41 mmol), and potassium carbonate (1.009 g , 7.24 mmol).

The solution was heated to reflux under argon for 48 h. The solution turned light yellow upon completion. The excess potassium carbonate was removed by filtration yielding a light yellow filtrate. The filtrate was rotoevaporated to yield a crude yellow oil, which was dissolved in chloroform. An extraction was performed and the organic layer was collected and dried to a pale yellow solid. The solid was washed with diethyl ether,

1 collected and vacuumed dried. Yield: 1.889 g (72%). H NMR (CDCl3): δ 7.62 (d, J = 9.6

Hz, 1H, CH), 7.36 (d, J = 8.8 Hz, 1H, CH), 6.89 (dd, J = 2.4, 8.4 Hz, 1H, CH), 6.84 (d, J

= 2.4 Hz, 1H, CH), 6.67 (d, J = 2.4 Hz, 2H, o-Ar), 6.58 (t, J = 2.4 Hz, H, p-Ar), 5.08 (2,

2H, OCH2), 4.68 (d, J = 2.4 Hz, 4H, OCH2), 2.53 (t, J = 2.4 Hz, 2H, CCH) ppm.

[acet]4-[G2]-7-methoxycoumarin (6)

In 50 mL of dry acetone was stirred (Acet)4-[G-2]-Br (1.252 g, 2.09 mmol), 7- hydroxycoumarin (0.352 g, 2.17 mmol), and potassium carbonate (0.501 g , 3.62 mmol).

The solution was heated to reflux under argon for 72 h. The solution turned light yellow upon completion. The excess potassium carbonate was removed by filtration, yielding a light yellow filtrate. The filtrate was rotoevaporated to yield a crude yellow oil. The oil was dissolved in a minimum amount of methanol and by slow evaporation yielded pale yellow crystals. The crystals were collected, washed with ether and vacuumed dried.

1 Yield: 0.432 g (30%). H NMR (CDCl3): δ 7.64 (d, J = 9.2 Hz, 1H, CH), 7.37 (d, J = 8.4

Hz, 1H, CH), 6.80-6.95 (m, 2H, CH), 6.52-6.69 (m, 9H, o,p-Ar), 6.25 (d, J = 9.6 Hz, 1H,

CH), 5.06 (2, 2H, OCH2), 4.99 (s, 4H, OCH2), 4.67 (d, J = 2.4 Hz, 8H, OCH2), 2.52 (t, J

= 2.4 Hz, 4H, CCH) ppm.

(PCy3)Au(triazolate)]2-[G1]-7-methoxycoumarin (7)

In 15 mL of toluene was stirred (Acet)2-[G-1]-7-methoxycoumarin (0.025 g,

0.069 mmol) and (PCy3)AuN3 (0.208 g, 0.11 mmol). The solution was degassed under argon for 30 minutes and allowed to stir for 48 hours at 50°C. The solution produced a off-white precipitate after 48 hours. The toluene was pipetted off. The white precipitate was washed three times with toluene (20 mL), and three times with n-pentane (20 mL).

The precipitate was collected and vacuum dried. Yield: 71 mg (74%). 1H NMR (DMSO- d6): δ 14.03 (s br, 2H, NH), 7.97 (d, J = 9.6 Hz, 1H, CH), 7.61 (d, J = 8.4 Hz, 1H, CH),

6.91-7.08 (m, 2H, CH), 6.51-6.70 (m, 3H, o,p-Ar), 6.28 (d, J = 9.4 Hz, 1H, CH), 4.90-

31 1 5.13 (m, 6H, OCH2), 0.90-2.19 (m, 66H, cyclohexyl) ppm. P{ H} NMR (DMSO-d6): δ

59.48 ppm. Anal. Calcd for C58H82N6O5Au2P2: C, 49.79; H, 5.91; N, 6.01. Found: C,

49.16; H, 5.72; N, 5.40.

[(PCy3)Au(alkynyl)]2-[G1]-7-methoxycoumarin (8)

In 15 mL of 2-propanol was dissolved [(PCy3)AuCl] (56 mg, 0.109 mmol), and

[acet]2-[G1]-7-methoxycoumarin (18.0 mg, 0.050 mmol). To the solution was added sodium tert-butoxide (61 mg, 0.635 mmol). The solution was stirred under argon for 48 h and a yellow precipitate evolved. The yellow precipitate was collected by filtration and washed repeated with cold 2-propanol and then with pentane. The yellow-brownish solid

1 was then collected and dried by vacuum. Yield: 42 mg (64%). H NMR (CDCl3): 7.62 (d,

J = 9.6 Hz, 1H, CH), 7.34 (d, J = 8.0 Hz, 1H, CH), 6.80-7.91 (m, 2H, CH), 6.63 (d, J =

2.0 Hz, 2H, o-Ar), 6.59 (t, J = 2.4 Hz, 1H, p-Ar), 6.23 (d, J = 9.6 Hz, 1H, CH), 5.03 (s,

2H, OCH2), 4.72 (d, J = 1.6 Hz, 4H, OCH2) 1.13-2.08 (m, 66H, cyclohexyl) ppm.

31 1 P{ H} NMR (CDCl3): δ 56.50 ppm. Anal. Calcd for C58H80O5Au2P2: C, 53.05; H, 6.14.

Found: C, 53.33; H, 6.41.

Fluorescent-activated cell sorting analysis of 3T3 mouse fibroblast cells with varying concentrations of [(PCy3)Au(triazolate)]2-[G-1]-OH after 6 hours.

Into a 6 well culture plate was added 1.0 ml of D8 medium containing ~100,000

3T3 cells and allowed to stand for 1 hour for the cells to attach to the plate. To individual wells was added 100 μL of a [(PCy3)Au(triazolate)]2-[G-1]-OH dendrimer solution at

110, 55, 11, and 1.0 μM in 20% DMSO, giving final concentrations of solutions of 10,

5.0, 1.0, and 0.1 in 1.8% DMSO respectively. The cell culture plate was then incubated at

37°C and 5% CO2 concentration for 6 hours. The cell plate medium was collected into a

3 mL test tube and then the well was washed with 1 mL of 1x PBS buffer solution and that was collected and added to the 3 mL test tube. 100 μL of 0.25% trypsin solution was added to the plate well. The well was then incubated at 37°C and 5% CO2 concentration for 5 minutes. To the well was added 1 mL of D8 medium, stirred and then collected into the 3 mL test tube. The 3 mL test tube was centrifuged at 1060 rpm to obtain a cell pellet.

The medium was then removed via vacuum, and the cell pellet was washed with 1 mL of

1x PBS buffer solution. The 3 mL test tube was then centrifuged to obtain a cell pellet and this washing process was repeated. The cells were resuspended in 200 μL of 1x annexin V binding buffer and 100 μL of this solution was transferred to a 3 mL culture tube. 5.0 μL of Annexin V-PE and 5.0 μL of 7-amino-actinomycin stain was added and the suspension and was gently mixed and incubated at room temperature in the dark for

15 minutes. 500 μL of 1x annexin V binding buffer was added and the culture tube and was gently mixing and fluorescent-activated cell sorting analysis was performed.

Fluorescent-activated cell sorting analysis of 3T3 mouse fibroblast cells with varying concentrations of [(PCy3)Au(triazolate)]2-[G-1]-OH after 20 hours.

Into a 6 well culture plate was added 1.0 ml of D8 medium containing ~100,000

3T3 cells and allowed to stand for 1 hour for the cells to attach to the plate. To individual wells was added 100 μL of a [(PCy3)Au(triazolate)]2-[G-1]-OH dendrimer solution at

110, 55, 11, and 1.0 μM in 20% DMSO, giving final concentrations of solutions of 10,

5.0, 1.0, and 0.1 in 1.8% DMSO respectively. The cell culture plate was then incubated at

37°C and 5% CO2 concentration for 20 hours. The cell plate medium was collected into a

100

The medium was then removed via vacuum, and the cell pellet was washed with 1 mL of

1x PBS buffer solution. The 3 mL test tube was then centrifuged to obtain a cell pellet and this washing process was repeated. The cells were resuspended in 200 μL of 1x annexin V binding buffer and 100 μL of this solution was transferred to a 3 mL culture tube. 5.0 μL of annexin V-PE and 5.0 μl of 7-amino-actinomycin stain was added and the suspension and was gently mixed and incubated at room temperature in the dark for 15 minutes. 500 μL of 1x annexin V binding buffer was added and the culture tube and was gently mixing and fluorescent-activated cell sorting analysis was performed.

Fluorescent-activated cell sorting analysis of 3T3 mouse fibroblast cells with varying concentrations of [(acet)]2-[G-1]-OH after 6 hours.

Into a 6 well culture plate was added 1.0 ml of D8 medium containing ~100,000

3T3 cells and allowed to stand for 1 hour for the cells to attach to the plate. To individual wells was added 100 μL of a [(acet)]2-[G-1]-OH dendrimer solution at 110, 55, 11, and

1.0 μM in 20% DMSO, giving final concentrations of solutions of 10, 5.0, 1.0, and 0.1 in

1.8% DMSO respectively. The cell culture plate was then incubated at 37°C and 5% CO2 concentration for 6 hours. The cell plate medium was collected into a 3 mL test tube and

101 then the well was washed with 1 mL of 1x PBS buffer solution and that was collected and added to the 3 mL test tube. 100 μL of 0.25% trypsin solution was added to the plate well. The well was then incubated at 37°C and 5% CO2 concentration for 5 minutes. To the well was added 1 mL of D8 medium, stirred and then collected into the 3 mL test tube. The 3 mL test tube was centrifuged at 1060 rpm to obtain a cell pellet. The medium was then removed via vacuum, and the cell pellet was washed with 1 mL of 1x PBS buffer solution. The 3 mL test tube was then centrifuged to obtain a cell pellet and this washing process was repeated. The cells were resuspended in 200 μL of 1x annexin V binding buffer and 100 μL of this solution was transferred to a 3 mL culture tube. 5.0 μL of Annexin V-PE and 5.0 μL of 7-amino-actinomycin stain was added and the suspension and was gently mixed and incubated at room temperature in the dark for 15 minutes. 500

μL of 1x annexin V binding buffer was added and the culture tube and was gently mixing and fluorescent-activated cell sorting analysis was performed.

Fluorescent-activated cell sorting analysis of 3T3 mouse fibroblast cells with varying concentrations of (PCy3)Au(4-methoxyphenyltriazole) after 6 hours.

Into a 6 well culture plate was added 1.0 ml of D8 medium containing ~100,000

3T3 cells and allowed to stand for 1 hour for the cells to attach to the plate. To individual wells was added 100 μL of a (PCy3)Au(4-methoxyphenyltriazole) solution at 110, 55,

11, and 1.0 μM in 20% DMSO, giving final concentrations of solutions of 10, 5.0, 1.0, and 0.1 in 1.8% DMSO respectively. The cell culture plate was then incubated at 37°C and 5% CO2 concentration for 6 hours. The cell plate medium was collected into a 3 mL

102 test tube and then the well was washed with 1 mL of 1x PBS buffer solution and that was collected and added to the 3 mL test tube. 100 μL of 0.25% trypsin solution was added to the plate well. The well was then incubated at 37°C and 5% CO2 concentration for 5 minutes. To the well was added 1 mL of D8 medium, stirred and then collected into the 3 mL test tube. The 3 mL test tube was centrifuged at 1060 rpm to obtain a cell pellet. The medium was then removed via vacuum, and the cell pellet was washed with 1 mL of 1x

PBS buffer solution. The 3 mL test tube was then centrifuged to obtain a cell pellet and this washing process was repeated. The cells were resuspended in 200 μL of 1x annexin

V binding buffer and 100 μL of this solution was transferred to a 3 mL culture tube. 5.0

μL of Annexin V-PE and 5.0 μL of 7-amino-actinomycin stain was added and the suspension and was gently mixed and incubated at room temperature in the dark for 15 minutes. 500 μL of 1x annexin V binding buffer was added and the culture tube and was gently mixing and fluorescent-activated cell sorting analysis was performed.

Fluorescent-activated cell sorting analysis of 3T3 mouse fibroblast cells with a (+)- camptothecin solution.

An intial solution of 1.0 mM (+)-camptothecin in DMSO was prepared. To a well cell culture plate was added 1 ml of D8 medium containing ~100,000 3T3 cells and allowed to stand for 1 hour for the cells to attach to the plate. To the well was added 5 μL of the 1.0 mM (+)-camptothecin solution giving a final concentration of 5 μM. The cell culture plate was incubated at 37°C and 5% CO2 concentration for 6 hours. The cell plate medium was collected into a 3 mL test tube and then the well was washed with 1 mL of

103

1x PBS buffer solution and that was collected and added to the 3 mL test tube. 100 μL of

0.25% trypsin solution was added to the plate well. The well was then incubated at 37°C and 5% CO2 concentration for 5 minutes. To the well was added 1 mL of DMEM medium, stirred and then collected into the 3 mL test tube. The 3 mL test tube was centrifuged at 1060 rpm to obtain a cell pellet. The medium was then removed via vacuum, and the cell pellet was washed with 1 mL of 1x PBS buffer solution. The 3 mL test tube was then centrifuged to obtain a cell pellet and this washing process was repeated. The cells were resuspended in 200 μL of 1x annexin V binding buffer and 100

μL of this solution was transferred to a 3 mL culture tube. 5.0 μL of annexin V-PE and

5.0 μL of 7-amino-actinomycin stain was added and the suspension and was gently mixed and incubated at room temperature in the dark for 15 minutes. 500 μL of 1x annexin V binding buffer was added and the culture tube and was gently mixing and fluorescent- activated cell sorting analysis was performed.

104

4.5 References

(1) Shaw, C. F., III In Gold: Progress in Chemistry, Biotechnology, and Technology;

Schmidbauer, H., Ed.; Wiley: New York, 1999, pp 259-308.

(2) Ho, S. Y.; Tiekink, E. R. T. In Metallotherapeutic Drugs & Metal-based

Diagnostic Agents: The Use of Metals in Medicine; Gielen, M.; Tiekink, E. R. T., Eds.;

Wiley: New York, 2005; pp 507-528.

(3) Mirabelli, C. K.; Johnson, R. K.; Hill, D. T.; Faucette, L. F.; Girard, G. R.; Kuo,

G. Y.; Sung, C. M.; Crooke, S. T. J. Med. Chem. 1986, 29, 218-223.

(4) Barnard, P. J.; Berners-Price, S. J. Coord. Chem. Rev. 2007, 251, 1889-14.

(5) Hickey, J. L.; Ruhayel, R. A.; Barnard, P. J.; Baker, M. V.; Berners-Price, S. J.;

Filipovska, A. J. Am. Chem. Soc. 2008, 130, 12570-12571.

(6) Rackham, O.; Nichols, S. J.; Leedman, P. J.; Berners-Price, S. J.; Filipovska, A.

Biochem. Pharmacol. 2007, 74, 992-1002.

(7) Green, D. R.; Reed, J. C. Science 1998, 281, 1309-1312.

(8) Schirmer, R. H.; Krauth-Siegel, R. L.; Schulz, G. E. 1989. In Glutathione.

Chemical, Biochemical, and Medical Aspects. Part A; Dolphin, D.; Avramovich, O.;

Poulson, R. Eds.; John Wiley and Sons: New York, 1989; pp. 553-596.

(9) Arner, E. S. J.; Holmgren, A. Eur. J. Biochem. 2000, 267, 6102-6109.

(10) Rigobello, M. P.; Folda, A.; Baldoin, M. C.; Scutari, G.; Bindoli, A. Free Radical.

Res. 2005, 39, 687-695.

(11) Bosman, A. W.; Janssen, H. M.; Meijer, E. W. Chem. Rev. 1999, 99, 1665-1688.

(12) Grayson, S. M.; Frechet, J. M. Chem. Rev. 2001, 101, 3819-3868.

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(13) Frechet, J. M. J. J. Polym. Sci. Pol. Chem. 2003, 41, 3713-3725.

(14) Hecht, S. J. Polym. Sci. Pol. Chem. 2003, 41, 1047-1058.

(15) Tomalia, D. A.; Naylor, A. M.; Goddard, W. A. Angew. Chem. Int. Ed. 1990, 29,

138-175.

(16) Gudipati, C. S.; Greenlief, C. M.; Johnson, J. A.; Prayongpan, P.; Wooley, K. L. J

Polym. Sci. Pol. Chem. 2004, 42, 6193-6208.

(17) Percec, V.; Barboiu, B.; Grigoras, C.; Bera, T. K. J. Am. Chem. Soc. 2003, 125,

6503-6516.

(18) Zimmerman, S. C.; Zharov, I.; Wendland, M. S.; Rakow, N. A.; Suslick, K. S. J.

Am.Chem. Soc. 2003, 125, 13504-13518.

(19) Kimata, S.; Jiang, D. L.; Aida, T. J. Polym. Sci. Pol. Chem. 2003, 41, 3524-3530.

(20) Dahan, A.; Portnoy, M. Macromolecules 2003, 36, 1034-1038.

(21) Harth, E. M.; Hecht, S.; Helms, B.; Malmstrom, E. E.; Frechet, J. M. J.; Hawker,

C. J. J. Am. Chem. Soc. 2002, 124, 3926-3938.

(22) Pochan, D. J.; Pakstis, L.; Huang, E.; Hawker, C. J.; Vestberg, R.; Pople, J.

Macromolecules 2002, 35, 9239-9242.

(23) Mackay, M. E.; Hong, Y.; Jeong, M.; Hong, S.; Russell, T. P.; Hawker, C. J.;

Vestberg, R.; Douglas, J. F. Langmuir 2002, 18, 1877-1882.

(24) Kobayashi, H.; Kawamoto, S.; Star, R. A.; Waldmann, T. A.; Tagaya, Y.;

Brechbiel, M. W. Cancer Res. 2003, 63, 271-276.

(25) Jansen, J. F.; de Brabander-van den Berg, E. M.; Meijer, E. W. Science 1994, 266,

1226-1229.

(26) Froehling, P. J. Polym. Sci. Pol. Chem. 2004, 42, 3110-3115.

106

(27) Gillies, E. R.; Frechet, J. M. J. Drug Discov.Today 2005, 10, 35-43.

(28) Malkoch, M.; Schleicher, K.; Drockenmuller, E.; Hawker, C. J.; Russell, T. P.;

Wu, P.; Fokin, V. V. Macromolecules 2005, 38, 3663-3678.

(29) Choi, H. S.; Liu, W.; Misra, P.; Tanaka, E.; Zimmer, J. P.; Ipe, B. I.; Bawendi, M.

G.; Frangioni, J. V. Nat. Biotech. 2007, 25, 1165-1170.

(30) Andree, H. A.; Reutelingsperger, C. P.; Hauptmann, R.; Hemker, H. C.; Hermens,

W. T.; Willems, G. M. J. Biol. Chem. 1990, 265, 4923-4928.

(31) Casciola-Rosen, L.; Rosen, A.; Petri, M.; Schlissel, M. Proc. Natl. Acad. Sci. USA

1996, 93, 1624-1629.

(32) Homburg, C. H. E.; Dehaas, M.; Vondemborne, A. E. G. K.; Verhoeven, A. J.;

Reutelingsperger, C. P. M.; Roos, D. Blood 1995, 85, 532-540.

(33) Koopman, G.; Reutelingsperger, C. P. M.; Kuijten, G. A. M.; Keehnen, R. M. J.;

Pals, S. T.; Vanoers, M. H. J. Blood 1994, 84, 1415-1420.

(34) van Engeland, M.; Ramaekers, F. C. S.; Schutte, B.; Reutelingsperger, C. P. M.

Cytometry 1996, 24, 131-139.

(35) Vermes, I.; Haanen, C.; Steffensnakken, H.; Reutelingsperger, C. J. Immunol.

Meth. 1995, 184, 39-51.

(36) Partyka, D. V.; Robilotto, T. J.; Zeller, M.; Hunter, A. D.; Gray, T. G. Proc. Natl.

Acad. Sci. USA 2008, 105, 14293-14297.

(37) Partyka, D. V.; Robilotto, T. J.; Zeller, M.; Hunter, A. D.; Gray, T. G.

Organometallics 2008, 27, 28-32.

107

Chapter 5. Synthesis and Characterization of Gold(I) Thiacrown Macrocycles

5.1 Introduction

The discovery of crown ethers by C. J. Pedersen in 1967 has led to the synthesis of numerous macrocycles and the study of their complexing abilities.1 Many macrocycles have been synthesised due to their close resemblance to biological systems. The ability of oxygen donor crown ethers to coordinate specifically to cations has been used extensively to bind and isolate alkali and alkaline earth metal ions from solution.2 Macrocyclic thiacrown ethers have been a subject of interest during the past three decades as well.3-6 Because of the softness of sulfur, these molecules are especially appropriate for complexation with heavy-metal ions such as Hg2+, Ag+, Cd2+, and Pb2+.7 In addition to this, polythiaethers have found applications in coordination chemistry,8-13 kinetic studies of electron transfer in Cu (I/II) systems,14 the delivery of radioisotopes, 15 and metal ion recognition and absorption.16-20 The most popular method for the preparation of polythiaethers is the reaction of dithiols employing the cesium dithiolate methodology developed by Kellog, Scheme 5.1.1.21

Scheme 5.1.1. General synthesis of a thiacrown ether.

108

The major difference between oxygen-bearing and sulfur bearing crown can be found in their conformational preferences. The former prefer “endodentate” conformations in which the oxygens are oriented toward the center of the macrocycle cavity. The resulting region of negative electrostatic potential that lines the inside of the cavity creates an ideal receptacle for a cation.

Thiacrowns prefer “exodentate” structures in which the sulfur atoms are pointing away from the cavity interior, creating a lining of hydrogen atoms. In order for thiacrowns to bond with a metal cation, it is necessary to first distort the crown macrocycle to permit multiple metal-sulfur bonds, a step which bears an energetic cost.22,23 Unlike oxygen-bearing crowns, which tend to preferentially bind main group metal cations, thiacrowns prefer transition metal cations.24 The presence of sulfur donors as part of a macrocyclic ligand has been shown to stabilize low valent metal complexes as well as to have a marked influence on the coordination geometry at the metal center.25-28

Figure 5.1.1. Representations of a crown ether (left), thiacrown ether (middle), and a mixed azathiacrown ether (right).

Macrocycles containing nitrogen and/or sulfur donor atoms are of interest as they exhibit high affinities towards heavy transition metal ions, and their selectivity is readily tunable by altering the composition of the donor-atom set and ring size. Mixed N,O,S-donor crowns, therefore, form an interesting class of compounds, which have found use as selective extractants for soft metal cations,29,30 and as models for the active sites of some enzymes.31 Such ligands

109 have proven to be valuable in the selective extraction of transition-metal ions after immobilization of these ligands onto organic polymeric resins, where the selectivity can be tuned by variation of the macrocyclic ligand.32,33 Furthermore, N-substituted mixed-donor crown ethers may find application as redox chemosensors34,35 or as hosts for the simultaneous binding of anions and cations.36,37 Figure 5.1.1 shows a general representation of a crown ether, thiacrown ether, and a mixed azathiacrown ether.

Reported here are synthetic and structural studies of a gold(I) thiacrown ether, and two gold(I) azathiacrown ethers with functional linkers. These reactions are done under dilute conditions in DMF it form the azathiacrown ethers, and then in methylene chloride and

[(tht)2Au](SbF6) to form the gold adducts. The objective of these compounds is gold(I) insertion opposite abasic lesions in duplex DNA. Potential applications also include imaging with non- ionizing (radiofrequency) radiation.

110

5.2 Results and Discussion

To determine is a gold(I) moiety could be captured and held by a thiacrown macrocycle with a functional group an initial experiment was done with simple cyclic thiacrown ethers. In a solution of [18]aneS6 in methylene chloride was add an excess of a [(tht)2Au][SbF6]. The tetrahydrothiophene (tht) ligands were easily displaced by the sulfurs on the [18]aneS6 molecule within 4 hours of reaction to produce [Au([18]aneS6)][SbF6], 1, scheme 5.2.1. The solution was layered with diethyl ether to produce defraction quality crystals and an isolated yield of 78%. In a subsequent reaction involving the smaller thiacrown ethers [12]aneS4, under the same conditions did not yield a solid upon layered with diethyl ether. This indicated that there needs to be a certain size that a macrocycle needs to be to be able to encapsulate a gold(I) moiety.

Scheme 5.2.1. Synthesis of [Au([18]aneS6)][SbF6], 1.

X-ray defraction quality crystals were grown from a saturated methylene chloride solution with the diffusion of diethyl ether. Figure 5.2.1 depicts the structure of the desired compound. Its crystal structure shows gold bound to S2 and S5 with S-Au bond lengths of

2.321(2) Å and 2.307(2) Å. Weaker interactions occur with S1 and S3 to close two five- membered chelate rings and these S-Au interactions are both 2.889(2) Å. Sulfurs S4 and S6 are

- non-ligating. There is a single SbF6 counter ion in the crystal lattice which gives that the

111 encapsulated gold has kept its +1 charge. This structure concludes that a minimum of four sulfurs are needed to be about to encapsulate a gold(I) moiety.

Figure 5.2.1. Crystal structure (100 K) of compound 1. 50% probability ellipsoids are shown. Hydrogen atoms are omitted for clarity.

A related tri-gold(I) cation thiacrown crystallized separately from the same mother liquor, and this is of the structure of [Au3([18]aneS6)2][SbF6]3, 2, Figure 5.2.2. If an excess amount of

[(tht)2Au][SbF6] is used in reaction, a small amount of this complex is created. The X-ray crystal structure shows gold interacting with four sulfurs of the thiacrown macrocycles. In this structure, three gold(I) moieties bind two [18]aneS6 molecules. One possible reason behind this is that there is a total of twelve sulfurs among the two [18]aneS6 which would be able to accommodate threee gold(I) moieties. The Au-S bond lengths that occur in this molecule range from 2.3270(16) Å to

2.3474(17) Å. The S-Au interactions that occur range from 2.8174(18) Å to 2.9419(17) Å. This molecule also possess Au-Au interactions due to the gold atoms be 3.0368(5) Å and 3.0867(5) Å apart, and with a linear bond angle of 180 . Table 5.2.1 displaces crystallographic parameters for products 1-2.

112

Table 5.2.1. Crystallographic data for thiacrown gold(I) hexafluoroantimonates 1 and 2.

1 2 formula C13H26AuCl2F6S6Sb C25H50Au3Cl2F18S12Sb3 fw 878.31 2104.42 cryst syst Monoclinic Triclinic space group P2(1)/c P-1 a, Å 5.2007(4) 11.6724(15) b, Å 17.2256(14) 11.7190(15) c, Å 28.170(2) 20.219(3) α, deg 90 86.160(2) β, deg 90.722(2) 88.086(2) Γ, deg 90 73.294(2) cell volume, 2523.4(4) 2642.7(6) Å3 Z 4 2 -3 Dcalcd, Mg m 2.312 2.645 T, K 100 (2) μ, mm-1 7.631 10.470 F(000) 1672 1956 Cryst size, mm 0.55 x 0.09 x 0.05 0.17 x 0.14 x 0.10

θmin, θmax, deg 2.47, 30.53 2.635, 30.525 no. of reflns 18825 27736 collected no. of indep 6095 13080

reflns no. of refined 317 700

params goodness-of- 1.171 1.140

fit on F2 a final R 0.0602 0.0405 indicesb [I > 2σ(I)] R1 wR2 0.1046 0.0876 R indices (all 0.0845 0.0442 data) R1 wR2 0.1112 0.0895 a 2 2 2 1/2 b GOF = [Σw(Fo -Fc ) /(n-p)] ; n = number of reflections, p = number of parameters refined. R1 = Σ( ||Fo| - |Fc|| 2 2 2 4 1/2 )/Σ|Fo|; wR2 = [Σw(Fo -Fc ) /ΣwFo ] .

113

Figure 5.2.2. Crystal structure (100 K) of compound 2. 50% probability ellipsoids are shown. Hydrogen atoms are omitted for clarity.

A synthesis was developed for a thiacrown macrocycle that contained an amine functional group, Scheme 5.2.2. A neat mixture of bis-2-hydroxyethylamine and 4- fluoronitrobenzene in a 2 to 1 ratio was stirred at 90 °C under an inert atmosphere for 16 hours, which resulted in a viscous yellow oil. When the reaction mixture cooled, calcium hydroxide dissolved in methanol was added and stirred. Silica gel column was necessary to obtain the final product, N-(4-nitrophenyl)-bis(2-hydroxyethyl)amine, 3, which collect in 89% isolated yield and is a brilliant yellow solid.

N-(4-nitrophenyl)-bis(2-hydroxyethyl)amine can be reacted with p-toluenesulfonyl chloride and an excess of base to produce the N-(4-nitrophenyl)-bis(2-(tosyloxy)ethyl)amine product, 4. A base is needed to deprotonate the hydroxyl groups coming of the amine arms of the starting material. The tosyl functional group is an excellent leaving group for the sequent conjugation of the thiol chain. Purification of the product through methanol recrytallization is necessary to afford pure product. Identification is readily seen in 1H NMR the addition of new peaks in the aromatic region with the addition of the tosyl groups.

114

Scheme 5.2.2. Synthesis of [Au{(N-(4-aminophenyl)-1,4,7,10,13-pentylthia-16-

azacyclooctyldecane)}][SbF6], 8.

In order to synthesis a thiacrown macrocyle there is a need to first synthesis a straight chain dithiol. Initially a procedure by Wolf and coworkers38 was used to prepare the 3,6,9-trithia-

1,11-undecanedithiol needed for the completion of the proposed thiacrown macrocycles, however this is hazardous. A more benign route was devised in order to produce the same dithiol chain, Scheme 5.2.3. Potassium hydroxide made into a slurry in THF (15 mL) was used to deprotonate (HOCH2CH2)2S. The reaction mixture was stirred vigorously and then cooled to 0

°C. The solution was reacted with p-toluenesulfonyl chloride to form a ditosyl compound which was not collected. The species was filtered to remove the excess potassium hydroxide and the filtrate was added dropwise into a THF solution of potassium carbonate and 1,2-dithiolethane.

Addition of the ditosyl compound dropwise is essential so that there is less of a chance for self conjugation or super-macromolecule thiol chain conjugation. Upon completion of the reaction through additional heating the solution must be acidified with concentrated HCl and extracted

115 with methylene chloride to obtain the product. Recrystallization in hot chloroform is needed to obtain the 3,6,9-trithia-1,11-undecanedithiol, 5, as a white crystalline solid. The synthesis of this dithiol chain should be done with extreme caution for the intermediates are still potentially harmful.

Scheme 5.2.3. Synthesis of 3,6,9-trithia-1,11-undecanedithiol, 5.

A solution 3,6,9-trithia-1,11-undecanedithiol in DMF is added extremely slowed by addition funnel into a very dilute solution of N-(4-nitrophenyl)-bis(2-(tosyloxy)ethyl)amine in

DMF to afford the N-(4-nitrophenyl)-1,4,7,10,13-pentylthia-16-azacyclooctyldecane product, 6.

The ditosylate solution must be dilute and the addition of the dithiol must be slow in order to limit the amount of super-macromolecule byproduct formation. Upon addition and heating of the solution the DMF must be removed and the product must be obtained by silica gel chromatography. Using a chloroform-methanol mix, the product is the first fraction off the column. Additional large macrocycle byproducts where also elude of the column, but were not characterized.

A reduction of the nitro group was needed to transform the NO2-macrocycle into a NH2- macrocycle. A reaction of zinc metal in acetic acid with N-(4-nitrophenyl)-1,4,7,10,13-

116 pentylthia-16-azacyclooctyldecane yields the desired reduced product N-(4-aminophenyl)-

1,4,7,10,13-pentylthia-16-azacyclooctyldecane, 7. Through mass spectroscopy analysis it was determined that Zn2+ ions were found encapsulated by the thiacrown macrocycle. In order to remove the zinc ion, the product needed to be treated with a mixture of sulfuric acid and trifluoroacetic acid. The concentration of sulfuric acid and trifluoroacetic acid needed to be in a strict 1:3 ratio or product decomposition would occur. Extraction in methylene chloride and trituration with ether afforded the product in the form of a red viscous oil obtained in 73% yield.

A solution of N-(4-aminophenyl)-1,4,7,10,13-pentylthia-16-azacyclooctyldecane in methylene chloride was added to a solution of [(tht)2Au]SbF6 in methylene chloride and was allowed to react for 16 hours in the absence of light. Upon removal of the solvent and trituration with diethyl ether, the final product of [Au{(N-(4-aminophenyl)-1,4,7,10,13-pentylthia-16- azacyclooctyldecane)}][SbF6], 8, was recovered in 27% isolated yield. Mass spectrometry analysis identified the desired product. In addition, 1H NMR shows an extreme broadening in the protons associated with the thiol-chain. This is indicative of the addition of the gold(I) moiety into the thiacrown.

A second synthetic procedure was devised for a thiacrown macrocyle that contained a amine functionality want a methylene spacer, Scheme 5.2.4. With the initial synthesis of azathiacrown macrocycle 8, there arose possible conflict with bioconjugation. The amine, when attached directly to a phenyl ring is fairly deactivated and unreactive. An amine with a spacer does not have these problems and is more capable to undergo bioconjugation reactions with a carboxylic acid.

117

Scheme 5.2.4. Synthesis of [Au{(N-(4-benzylamine)-1,4,7,10,13-pentylthia-16- azacyclooctyldecane)}][SbF6], 12.

N-phenyl-diethanolamine reacts with p-toluenesulfonyl chloride in methylene chloride and an slight excess of base to product the N-phenyl-bis(2-(tosyloxy)ethyl)amine product, 9. An extraction removes the excess base and starting material. A base deprotonates the hydroxyl groups coming off amine arms of the starting material. The tosyl functional group is an excellent leaving group for the sequent conjugation of the thiol chain. Purification through methanol recrytallization is necessary to afford pure product in 67% yield. Identification is readily seen in

1H NMR the addition of new peaks in the aromatic region with the addition of the tosyl groups.

A solution 3,6,9-trithia-1,11-undecanedithiol in DMF is added extremely slowly by addition funnel into a very dilute solution of N-phenyl-bis(2-(tosyloxy)ethyl)amine in DMF to afford the N-(phenyl)-1,4,7,10,13-pentylthia-16-azacyclooctyldecane product, 10. Just like with the initial 8 macrocyle, the ditosylate solution must be dilute and the addition of the dithiol must be slow in order to limit the amount of super-macromolecule byproduct formation. Upon

118 addition and heating of the solution the DMF must be removed. The crude product was purified by recrystallization in a mixture of benzene and ethanol to obtain the desired product as an off- white solid in a 56% isolated yield.

N-(phenyl)-1,4,7,10,13-pentylthia-16-azacyclooctyldecane reacts with DMF in the presence POCl3 to add a formyl group at the para position. The product must be chilled on ice and neutralized with sodium acetate. In order to obtain pure product, silca gel column chromatography is necessary. The yield is modest at only 38% for N-(4-formylphenyl)-

1,4,7,10,13-pentylthia-16-azacyclooctyldecane, 11. Identification is readily seen in 1H NMR with the addition of a new formyl peak in the high aromatic region.

Reductive N-alkyation is the method used to transform the formyl group into a primary amine. N-(4-formylphenyl)-1,4,7,10,13-pentylthia-16-azacyclooctyldecane is reacted with 4- butylcarbamate and triethylsilane in chloroform to form a Boc-protected amine macrocycle.

Reaction with trifruoroacetic acid cleaves the Boc-group resulting in the N-(4-benzylamine)-

1,4,7,10,13-pentylthia-16-azacyclooctyldecane product, 12. An extraction is necessary to obtain the final product as an orange oil in 60% yield.

A solution of N-(4-benzylamine)-1,4,7,10,13-pentylthia-16-azacyclooctyldecane in methylene chloride was added to a solution of [(tht)2Au]SbF6 in methylene chloride and was allowed to react for 16 hours in the absence of light. Upon removal of the solvent and trituration with diethyl ether, the final product of [Au{(N-(4-benzylamine)-1,4,7,10,13-pentylthia-16- azacyclooctyldecane)}][SbF6], 13, was recovered as an orange solid in 27% isolated yield. Mass spectrometry analysis identified the desired product. In addition, 1H NMR shows an extreme broadening in the protons associated with the thiol-chain, and a down field shift of the methylene spacer protons. This is indicative of the addition of the gold(I) moiety into the thiacrown.

119

An absorbance spectra was taken of the [Au{(N-(4-benzylamine)-1,4,7,10,13-pentylthia-

16-azacyclooctyldecane)}][SbF6] complex, Figure 5.2.3. The absorbance was taken in dry acetonitrile and the spectra shows a strong absorbance peak at 272 nm with a second absorbance at 399 nm with a trailing shoulder into the red region. An emission spectra was also taken,

Figure 5.2.4, showing that there is a strong emission at 352 nm with a secondary emission at 580 nm when excited at 271 nm. The emission band exhibited by the spectra at 352 nm is indicative of Au-Au metal interactions.

16000 272 nm

14000 -5

Conc. = 4.41 x 10 M

) -1

12000 399 nm

cm -1

10000

8000

6000

4000 Molar(M Absorptivity

470 nm 2000

0 300 400 500 600

Wavelength (nm)

Figure 5.2.3. Absorbance spectra in CH3CN of [Au{(N-(4-benzylamine)-1,4,7,10,13-pentylthia-16- azacyclooctyldecane)}][SbF6], 13.

120

200 Excitation = 271 nm 352 nm 180 -5 Conc. = 2.21 x 10 M

160

140

120

100 2nd Harmonic

80 Intensity (a.u.) Intensity

566 nm 60

300 400 500 600 700 800 Wavelength (nm)

Figure 5.2.4. Emission spectra in CH3CN of [Au{(N-(4-benzylamine)-1,4,7,10,13-pentylthia-16- azacyclooctyldecane)}][SbF6], 13. Excitation wavelength is 271 nm.

121

5.3 Conclusion and Final Remarks

One new gold(I) thiacrown ether, and two new gold(I) azathiacrown macrocycles were synthesized. In addition, a three-gold(I) encapsulated dithiacrown ether was also identified. All gold(I) products were synthesized through a final step of adding [(tht)2Au][SbF6] to a macrocycle and undergoing a ligand exchange. The gold(I) azathiacrown macrocycles were designed to have a bioconjugation linker so that they have the ability to react with DNA lesions.

One species contains an amine functionality attached to a phenyl ring while the other is a benzyl amine functionality. All compounds are stable in organic solvent and are stable in air for days.

Two of these compounds were identified crystallographically, [Au([18]aneS6)][SbF6] and

[Au2([18]aneS6)2][SbF6]3. These crystal structures show that the gold(I) moieties need four sulfurs to be able to coordinate to the macrocycle. Two sulfurs form actual Au-S bonds, while the other two sulfurs form loose Au-S interactions. Previous experiments also showed that there is a certain pore size needed to encapsulate a gold(I) moiety. A [12]aneS4 is too small a thiacrown to encapsulate gold(I), but [18]aneS6 is easily able to accomplish it.

In the future, more azathiacrown macrocycles will be pursued. The objective of these compounds is gold(I) insertion opposite abasic lesions in duplex DNA. They will be primarily used for in vitro cellular studies to demonstate the effects of gold containing molecule on living systems. Absorbance and emission studies are also to be pursued.

122

5.4 Experimental

Unless otherwise stated, all reactions were carried out under a dry, inert atmosphere of argon using standard Schlenk techniques for the handling of air or moisture sensitive materials.

1. Reagents

2. Instrumentation

1H and NMR spectra was recorded on a Varian AS-400 spectrometer operating at 161.8

MHz. For 1H NMR spectra, chemical shifts were determined relative to the solvent residual peaks. Unless otherwise stated, NMR spectra were recorded in CDCl3. NMR spectra of the as- synthesized compounds can be found in Appendix II.

Single-crystal diffraction studies were done on a Bruker AXS SMART APEX II CCD diffractometer using monochromatic Mo Kα radiation with the omega scan technique.

Measurements were made at 100 K; samples were mounted on a mitogen tip using Paratone-N, then flash-frozen under a stream of nitrogen gas. The unit cells were determined using SMART and SAINT+. Data collection for all crystals was conducted at 100 K (-173.5 °C). All structures were solved by direct methods and refined by full matrix least squares against F2 with all reflections using SHELXTL. Refinement of extinction coefficients was found to be insignificant.

All non-hydrogen atoms were refined anisotropically. All hydrogen atoms were placed in

123 standard calculated positions and all hydrogen atoms were refined with an isotropic displacement parameter 1.2 times that of the adjacent carbon.

UV spectra were measured on a Cary 500 spectrophotometer in HPLC grade solvents.

Fluorescence measurements were made on a Cary Eclipse spectrophotometer at room temperature; samples were deaerated approximately fifteen minutes prior to taking the measurement.

Microanalyses (C, H, and N) were performed by Robertson Microlit Laboratories, Inc.

(Madison, N.J.).

Mass spectrometry was performed at the Ohio State University (Columbus, OH) or the

University of Cincinnati (Cincinnati, OH) Mass Spectrometry facilities.

[Au([18]aneS6)][SbF6] (1)

In an inert atmosphere 3 mL of methylene chloride dissolved [18]aneS6 (19 mg, 0.053 mmol), and to this was added a 2 mL solution of [(tht)2Au][SbF6] (38 mg, 0.062 mmol) in methylene chloride. The solution was stirred in the absence of light for 4 h. The solution was transferred into a scintillation vial which was layered with diethyl ether. After 24 h this produced diffraction quality crystals which were collected and dried. Yield: 33 mg (78%).

N-(4-nitrophenyl)-bis(2-hydroxyethyl)amine (3)

A mixture of bis-2-hydroxyethylamine (4.15 mL, 31.2 mmol) and 4-fluoronitrobenzene

(2.00 mL, 14.2 mmol) was stirred at 90 °C under an inert atmosphere for 16 h. When the reaction mixture cooled, calcium hydroxide (2.5 g, 33.7 mmol) in methanol (10 mL) was added and stirred for 1 hour. The suspension was loaded directly onto a silica gel column and eluted with a

124 chloroform-methanol solution (9:1). Upon evaporation of the solvents, the product was obtained

1 as a yellow solid. Yield: 2.87 g (89.4%). H NMR (CDCl3): δ 2.75 (s br, CH2OH, 2H), 3.73 (t, J

= 5.6 Hz, NCH2CH2, 4H), 3.94 (t, J = 4.0 Hz, NCH2CH2, 4H), 6.66 (d, J = 9.2 Hz, Ar-H, 2H),

8.11 (d, J = 9.2 Hz, Ar-H, 2H) ppm.

N-(4-nitrophenyl)-bis(2-(tosyloxy)ethyl)amine (4)

A solution of p-toluenesulfonyl chloride (5.34 g, 28.0 mmol) in THF (20 mL) was added dropwise with stirring to a solution of 3 (2.85 g, 12.6 mmol) in THF (20 mL) and NaOH (1.51 g,

37.8 mmol) in water (20 mL). The mixture was stirred vigorously in an ice water bath for 6 h.

Brine (20 mL) was added to the reaction mixture, and the organic layer was then isolated in a separatory funnel. Treatment of the organic layer with MgSO4 and removal of the solvent by a rotary evaporator yielded the crude material that was further purified by recrystallization from methanol to give the desired product as a yellow crystalline solid. Yield: 4.20 g (62.4%). 1H

NMR (CDCl3): δ 2.40 (s , Ar-CH3, 6H), 3.68 (t, J = 5.6 Hz, NCH2CH2, 4H), 4.15 (t, J = 6.0 Hz,

NCH2CH2, 4H), 6.41 (d, J = 9.2 Hz, Ar-H, 2H), 7.25 (d, J = 8.4 Hz, Ar-H, 4H), 7.67 (d, J = 8.8

Hz, Ar-H, 4H), 8.11 (d, J = 9.2 Hz, Ar-H, 2H) ppm.

3,6,9-trithia-1,11-undecanedithiol (5)

A slurry of pulverized KOH (3.96 g, 70.6 mmol) in THF (15 mL) was added to a solution of (HOCH2CH2)2S (2 mL, 19.3 mmol) in THF (10 mL). The reaction mixture was stirred vigorously at room temperature for 1 h and then cooled to 0 °C. A solution of p-toluenesulfonyl

125 chloride (7.63 g, 40.0 mmol) in THF (25 mL) was added dropwise to the chilled mixture over the course of 1 h. The reaction mixture was stirred vigorously at 0 °C for 24 h and filtered. The filtrate was added dropwise to a 3-neck flask containing potassium carbonate (16.32 g, 0.118 mol), 1,2-dithiolethane (9.72 mL, 0.116 mol), and dry THF (20 mL). The solution was heated to reflux under argon for 48 hours. The resulting suspension was acidified with concentrated HCl

(to pH 2) and extracted with CH2Cl2 (2 × 40 mL). A white precipitate persisted in the CH2Cl2 layer, which was removed by filtration. The filtrate was concentrated in vacuo to a yellow oil.

The oil was then dissolved in chloroform, heated to form a saturated solution and placed in an ice bath. A microcrystalline yellow solid precipitated out of the solution, which were filtered and

1 vacuumed to dryness. Yield: 2.49 g (47.0%). H NMR (CDCl3): δ 1.74 (t , J = 8.0 Hz, SH, 2H),

2.69-2.82 (m, CH2S, 16H) ppm.

N-(4-nitrophenyl)-1,4,7,10,13-pentylthia-16-azacyclooctyldecane (6)

A solution of ditosylate 4 (6.86 g, 12.8 mmol) and 3,6,9-trithia-1,11-undecanedithiol 5

(3.35 g, 12.2 mmol) in DMF (125 mL) was added dropwise over 8 h to a mixture of DMF (450 mL) and Cs2CO3 (8.34 g, 25.6 mmol) at 60 °C. After the addition was complete, the mixture was stirred for an additional 48 h at 60 °C. Distillation of the DMF under reduced pressure yielded a crude solid that was partitioned between chloroform and water. The organic layer was collected, and the solvent removed via a rotary evaporation to yield a brown oil. The crude product was purified on a silica gel column eluted with chloroform to elude an initial undesired fraction and then with (19:1) chloroform to methanol to obtain the desired product. The solvent was removed via a rotary evaporation to yield a yellowish orange oil. Yield 1.25 g (22.1%): 1H NMR

126

(CDCl3): δ 2.75-2.89 (m, CH2S, 20H), 3.71 (t, J = 7.2 Hz, NCH2CH2, 4H), 6.61 (d, J = 9.6 Hz,

Ar-H, 2H), 8.12 (d, J = 9.2 Hz, Ar-H, 2H) ppm.

N-(4-aminophenyl)-1,4,7,10,13-pentylthia-16-azacyclooctyldecane (7)

A suspension of macrocycle 6 (0.30 g, 0.646 mmol) and zinc dust (0.49 g, 7.49 mmol) in acetic acid (25 mL) and THF (3 mL) was stirred for 16 hours. The suspension was filtered through celite resulting in a reddish brown filtrate. The filtrate was evacuated to dryness giving a red oil. The oil was then dissolved in 1:3 solution of sulfuric acid (5.0 mL) and trifluoroacetic acid (15.0 mL) and allowed to stir for 1 hour. The solution was partitioned with 75 mL of dichloromethane and 15 mL of distilled water and stirred for 3 hours. The organic layer was extracted and evaporated to dryness resulting in a red oil. The oil was triturated with diethyl ether which made the oil a red solid. The solid was then collected and evacuated to dryness.

Upon drying the solid turned back into a viscous red oil. Yield: 0.19 g (72.9%).1H NMR

(CDCl3): δ 2.75-2.89 (m, CH2S, 20H), 3.43 (t, J = 7.6 Hz, NCH2CH2S, 4H), 6.63-6.66 (m, Ar-H,

4H) ppm. MS (ESI): m/z 435.1 (MH+).

[Au{(N-(4-aminophenyl)-1,4,7,10,13-pentylthia-16-azacyclooctyldecane)}][SbF6] (8)

To a solution of (tht)AuCl (0.067 g, 0.209 mmol) in methylene chloride (15 mL) was added 18 μL (0.204 mmol) tetrahydrothiophene and 0.090 g (0.262 mmol) of AgSbF6. The solution was stirred for 16 hours in the absence of light. A white precipitate formed and the solution was filtered through celite to yield a colorless filtrate. To the filtrate was added a 5 mL

127 solution of 7 (.091 g, 0.225 mmol) in methylene chloride. The red solution was stirred under argon for 16 hours in the absence of light. The solvent was removed by evaporation yielding a reddish black oil. The oil was triturated with diethyl ether to yield a reddish black solid which

1 was collected and vacuumed to dryness. Yield: 49.3 mg (27.2%). H NMR (DMSO-d6): δ 2.50-

3.80 (m, C H2CH2S, 24H), 6.67 (d, J = 9.6 Hz, Ar-H, 2H), 7.98 (d, J = 9.6 Hz, Ar-H, 2H) ppm.

+ - MS (ESI): m/z 631.0632 (MH -[SbF6 ]).

N-(phenyl)-bis(2-(tosyloxy)ethyl)amine (9)

A solution of p-toluenesulfonyl chloride (7.92 g, 41.5 mmol) in methylene chloride (25 mL) was added dropwise with stirring to a solution of N-phenyl-diethanolamine (3.02 g, 16.7 mmol) in methylene chloride (20 mL) and triethylamine (7.0 mL, 50.0 mmol). The mixture was stirred vigorously in an ice water bath for 6 h. Water (20 mL) was added to the reaction mixture, and the organic layer was then isolated in a separatory funnel. Treatment of the organic layer with MgSO4 and removal of the solvent by a rotary evaporator yielded the crude material that was further purified by recrystallization from methanol to give the desired product as a white

1 crystalline solid. Yield: 5.46 (67.2%). H NMR (CDCl3): δ 2.42 (s , Ar-CH3, 6H), 3.54 (t, J = 6.0

Hz, NCH2CH2, 4H), 4.08 (t, J = 6.0 Hz, NCH2CH2, 4H), 6.42 (d, J = 8.8 Hz, Ar-H, 2H), 6.70 (t,

J = 9.6 Hz, Ar-H, 1H), 7.12 (d, J = 8.0 Hz, Ar-H, 2H), 7.26 (d, J = 9.2 Hz, Ar-H, 2H), 7.70 (d, J

= 6.4 Hz, Ar-H, 2H) ppm.

128

N-(phenyl)-1,4,7,10,13-pentylthia-16-azacyclooctyldecane (10)

A solution of ditosylate 9 (3.01 g, 6.15 mmol) and 3,6,9-trithia-1,11-undecanedithiol, 5

(1.69 g, 6.16 mmol) in DMF (125 mL) was added dropwise over 8 h with stirring to a mixture of

DMF (450 mL) and Cs2CO3 (5.25 g, 16.1 mmol) at 60 °C. After the addition was complete, the mixture was stirred for an additional 48 h at 60 °C. Distillation of the DMF under reduced pressure yielded a crude tan solid that was partitioned between chloroform and water. The organic layer was collected, and the solvent removed via a rotary evaporation to yield a tan solid.

The crude product was purified by recrystallization in a mixture of benzene and ethanol (1:1) to

1 obtain the desired product as an off-white solid. Yield: 1.46 g (56.4%). H NMR (CDCl3): δ

2.75-2.85 (m, CH2CH2S, 20H), 3.60 (t, J = 7.2 Hz, NCH2CH2, 4H), 6.67 (d, J = 8.8 Hz, Ar-H,

2H), 6.73 (t, J = 9.6 Hz, Ar-H, 1H), 7.24 (t, J = 8.0 Hz, Ar-H, 2H) ppm. MS (ESI): m/z 420.1139

(MH+).

N-(4-formylphenyl)-1,4,7,10,13-pentylthia-16-azacyclooctyldecane (11)

To a solution of macrocycle 10 (0.319 g, .760 mmol) in DMF (25 mL) degassed with argon was added 0.15 mL (1.6 mmol) of POCl3 dropwise. The solution was stirred for 1 hour at 0°C, then at room temperature for 16 hours. The solution was poured onto 50 g of ice and then neutralized with an excess of sodium acetate. The water was partitioned with CH2Cl2 and the organic layer was extracted off and dried to a light yellow solid. The solid was redissolved in CH2Cl2 and silica chromatography was performed using CH2Cl2 as the elutant. A light yellow band was collected as the first fraction off the column which was the desired product. The fraction was then

1 vacuumed to dryness yielding a yellow solid. Yield: 0.13 g (38.2%). H NMR (CDCl3): 2.75-

129

2.88 (m, CH2CH2S, 20H), 3.71 (t, J = 7.2 Hz, NCH2CH2, 4H), 6.70 (d, J = 8.8 Hz, Ar-H, 2H),

6.75 (d, J = 9.2 Hz, Ar-H, 1H), 9.76 (s, OCH, 1H) ppm.

N-(4-benzylamine)-1,4,7,10,13-pentylthia-16-azacyclooctyldecane (12)

To a solution of macrocycle 11 (0.083 g, 1.9 mmol) in chloroform (10 mL) was added

0.065 g (0.55 mmol) 4-butylcarbamate, 89 μL ( 0.56 mmol) triethylsilane, and 0.03 mL (0.40 mmol) trifluoroacetic acid and stirred for 16 hours. The solvent was removed via a rotary evaporation to yield a yellow oil. The oil was washed with a saturated NaHCO3 solution, and then was a saturated brine solution. The washes were decanted off and the oil that remained was vacuumed to dryness. Trifluoroacetic acid (10 mL) was added to the oil and stirred for 1 hour.

The solvent was then removed by vacuum, and the oil was the dissolved in methylene chloride and then partitioned with water. Na2CO3 was added to the water layer to make it basic. The organic fraction was collected and vacuumed to drieness yielding an orange oil. Yield: 50 mg

1 (60.5%). H NMR (CDCl3): 2.75-2.87 (m, CH2CH2S, 20H), 3.59 (t, J = 7.6 Hz, NCH2CH2, 4H),

3.76 (s, CH2NH2, 2H), 6.64 (d, J = 8.4 Hz, Ar-H, 2H), 7.19 (d, J = 8.8 Hz, Ar-H, 2H) ppm. MS

(ESI): m/z 448.8 (MH+).

[Au{(N-(4-benzylamine)-1,4,7,10,13-pentylthia-16-azacyclooctyldecane)}][SbF6] (13)

To a solution of (tht)AuCl (0.039 g, 0.12 mmol) in methylene chloride (10 mL) was added 12 μL (0.14 mmol) tetrahydrothiophene and 0.047 g (0.14 mmol) of AgSbF6. The solution was stirred for 3 hours in the absence of light. A white precipitate formed, and the solution was filtered through celite to yield a colorless filtrate. To the filtrate was added a 5 mL solution of 12

130

(.050 g, 0.11 mmol) in methylene chloride. The red solution was stirred under argon for 16 hours in the absence of light. The solvent was removed by rotary evaporation yielding an orange solid.

The solid was washed with diethyl ether to yield an orange solid which was collected and

1 vacuumed to dryness. Yield: 26.9 mg (27.4%). H NMR (CD3CN): δ 2.70-3.14 (m, C H2CH2S,

20H), 3.59 (t, NCH2CH2S, 4H), 3.74 (s, CH2NH2, 2H), 6.86 (d, Ar-H, 2H), 7.24 (d, Ar-H, 2H)

+ - ppm. MS (ESI): m/z 645.7 (MH -[SbF6 ]).

131

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134

Chapter 6. Thesis Summary and Future Directions

6.1. Thesis Summary

6.1.1. (Phosphine)- and (N-Herterocyclic Carbene)Gold(I) Azides and Halides

Synthesis and formation of (phosphine)- and (N-herterocyclic carbene)gold(I) azides and halides were described. There are two general reactions used in the synthesis of gold(I) azides, they are shown in Scheme 6.1.1.1,2

Scheme 6.1.1. Synthesis of phosphine- and (N-herterocyclic carbene)gold(I) azides.

The synthesis of the bulky Buchwald-type (phosphine)gold(I) azides were synthesized through a thallium(I) acetylacetonate method, while the (N-heterocyclic carbene)- and (tricyclohexylphosphine)gold(I) azides were though a silver(I) acetate method. Attempts made at making the carbene gold(I) azides through the thallium(I) acetylacetonate method never yielded complete product formation. Four new

(phosphine)- and two new (N-heterocyclic carbene)gold(I) azides were synthesized

135 through these methods. These products are important reactant materials for [3+2] cycloaddtion reactions involving terminal alkynes.

One new (N-heterocyclic carbene)gold(I) chloride and one new (N-heterocyclic carbene)gold(I) bromide were synthesized. Gold(I) halide precursors are necessary for the synthesis of gold(I) azides. They also hold value in the synthesis of Au-C bond formation reactions from base-promoted transmetallations with boronic esters or boronic acids.3

These products were characterized by 1H NMR, and all of the phosphine containing products were also characterized by 31P{1H} NMR. Compared to the 31P{1H} of the phosphine gold(I) starting materials all products experienced a downfield shift. In addition to this seven of these of these compounds were identified crystallographically.

Defraction quality crystals were grown from saturated solutions of tetrahydrofuran with the diffusion of pentane. All compounds conformed to a near linear two-coordinate system.

136

6.1.1. (Phosphine)- and (N-Herterocyclic Carbene)gold(I) Triazolates and Alkynyls

(Phosphine)- and (N-herterocyclic carbene)gold(I) triazolates and alkynyls were synthesized as potential to be anti-cancer and anti-tumor gold containing drugs. All gold(I) triazolates were synthesized through a [3+2] cycloaddition by reacting a gold(I) azide with a terminal alkyne. Scheme 6.1.2 depicts the general synthesis of the formation of a (phosphine)gold(I) triazolate.4

Scheme 6.1.2. General synthesis of a (phosphine)gold(I) triazolate.

Mono-aurated triazolates were initially synthesized to determine reaction conditions and limitations. Seven new (phosphine)- and (N-heterocyclic carbene)gold(I) triazolates were synthesized through this process. All products were characterized by 1H

NMR, and all of the phosphine containing products were also characterized by 31P{1H}

NMR. Compared to the 31P{1H} of the phosphine gold(I) starting materials all products experienced a downfield shift. all products have a distinct N-H resonance that occurs at

~14 ppm in the 1H NMR spectra. This also supports the [3+2] cycloaddition rearrangement and the formation of an Au-C bond.

Scheme 6.1.3. General synthesis of a gold(I) alkynyl.

137

Gold(I) alkynyls were synthesized though a reaction of a gold(I) chloride with an alkynyl anion deprotonated by sodium tert-butoxide,5 Scheme 6.1.3. The pursuit to these compounds were to be a comparison to the gold(I) triazolate complexes. Two new mono- aurated (phosphine)- and (N-heterocyclic carbene)gold(I) alkynyls were synthesized and characterized.

The success of the synthesis of mono-aurated triazoles and alkynyls encouraged the development and synthesis of gold(I) triazolate and alkynyl dendrimers. In an identical synthesis from the mono-gold(I) triazolates, four generations of

(tricyclohexylphosphine)gold(I) triazolate dendrimers have been synthesized. With each increase in the generation, there is an exponential increase of number of gold moieties attached. Bound gold atoms is 2n, where n is the cardinal number corresponding to the dendrimer’s generation. One generation of (tricyclohexylphosphine)gold(I) alkynyl was also prepared for comparison.

3T3 cell studies were performed using light microscopy and fluorescence- activated cell sorting. The results show that there is cytotoxic effects on 3T3 cells by both

(phosphine)gold(I) triazoles and (phosphine)gold(I) alkynyls under micromolar exposure.

Through light microscopy it was shown that (phosphine)gold(I) triazoles are more potent molecules than (phosphine)gold(I) alkynyls in terms of cytotoxicity. With fluorescence- activated cell sorting, it was shown that the first generation gold(I) dendrimer causes apoptosis to 3T3 cells with concentrations of 1.0-10 M.

138

The first generation of (tricyclohexylphosphine)gold(I)triazole and gold(I) alkynyl were synthesized with a methoxycoumarin attached. The coumarin is intended to be a fluorescent tag to be able to identify the accumulation points of the gold(I) molecules in cells. The difficult with this compound and higher generations of gold(I) dendrimers is solubility. In vitro cell studies of second and high generation of dendrimers have yielded studies of very little cytotoxic activity. This is due partly because for these molecules, the more gold moieties attached the less soluble the molecule becomes.

139

6.1.1. Gold(I) Thiacrown Macrocycles

The objective for the synthesis of gold(I) thiacrown macrocycles is for gold(I)

insertion opposite abasic lesions in duplex DNA. Initial studies used a [12]aneS4 and

[18]aneS6 thiacrown ether to see if there were any gold interactions. Gold(I)

encapsulation only occurred with the [18]aneS6 thiacrown, and the results were

characterized by X-ray crystallography.

Two synthesis stratagies were developed in order to create thiacrown

macrocycles, or to be more precise azathiacrown macrocycles, to encapsulate a gold(I)

moiety and be able to conjugate the complex to a lesion in DNA. For this purpose the

azathiacrown macrocycles needed to have a bioconjugation linker, and the two choosen

were an aniline and a benzylamine, as shown in Figure 6.1.1.

Figure 6.1.1. Stucture of azathiacrown macrocyles with aniline (left) and benzyl amine (right) linkers.

These complexes were formed by reaction of a ditosylated species with a thiol

chain in an extremely dilute solution of DMF.6 The solution must be dilute or supra-

140 macromolecules will form. The final step for product formation is adding

[(tht)2Au][SbF6] to a macrocycle and having it undergoing a ligand exchange.

The gold(I) containing benzylamine azathiacrown macrocycle exhibits an strong absorbance at 272 nm and at 399 nm. This compound also features an emission 352 nm and a secondary emission at 566 nm. The initial emission is due to Au-Au bonding interactions. These compounds also have the potential to be imaging agents used for non- ionizing radiation.

141

6.2. Future Directions

The future design of (phosphine)- or (N-heterocyclic carbene)gold(I) azides will be centered around the ancillary ligand. There is a need to create new base starting materials that will help enhance membrane permeability, hydrophilicity, and general solubility. (N-heterocyclic carbene)gold(I) azides with different functionalities from the amines is the best target to accomplish these purposes.

There are two areas of interest in the future of gold(I) triazolate and alkynyl dendrimers. The first is in the synthesis of higher generations of dendrimers that are more soluble, especially in aqueous solutions. This correlates with the synthesis of a new type of gold(I) azide. The other interest is the attachment of different fluorescent tags onto the dendrimer. The need for detection to where these gold(I) based drug is needed to determine the cause of why these molecules cause cytotoxic activity.

The synthesis of gold(I) azathiacrown macrocyles will continue to be explored.

The two complexes are still in need to be tested to determine if they can conjugate onto a carboxylic acid of a DNA lesion, and also to see it they can intercalate into DNA itself.

Absorbance and emission still need to be explored with these macrocycles. These macrocycles have the propensity to encapsulate a number of transition metals. Other studies involving Ag+ and Pt2+ will also be tried of Au+ is not the ideal metal for this macrocycle and DNA conjugation.

142

6.3. References

(1) Partyka, D. V.; Robilotto, T. J.; Updegraff, J. B.; Zeller, M.; Hunter, A. D.; Gray,

T. G. Organometallics 2009, 28, 795-801.

(2) Partyka, D. V.; Robilotto, T. J.; Zeller, M.; Hunter, A. D.; Gray, T. G. Proc. Natl.

Acad. Sci. USA 2008, 105, 14293-14297.

(3) Partyka, D. V.; Zeller, M.; Hunter, A. D.; Gray, T. G. Angew. Chem. Int. Ed.

Engl. 2006, 45, 8188-8191.

(4) Partyka, D. V.; Updegraff, J. B.; Zeller, M.; Hunter, A. D.; Gray, T. G.

Organometallics 2007, 26, 183-186.

(5) Gao, L.; Partyka, D. V.; Updegraff, J. B.; Deligonul, N.; Gray, T. G. Eur. J.

Inorg. Chem. 2009, 2711-2719.

(6) Buter, J.; Kellogg, R. M.; Vanbolhuis, F. J. Chem. Soc. Chem. Comm. 1990, 282-

284.

143

Appendix I. Crystallographic Data of Synthesized New Compounds

1. X-Ray Crystal Data for [(PCy2(o-biphenyl))AuN3]

Table AI-1a. Crystal data for ju090706 Table AI-1b. Data collection C24H31AuN3P Bruker SMART CCD area-detector

Mr = 589.45 diffractometer

Triclinic, P-1 ω scans a = 10.2546(4) Å Absorption correction: multi-scan b = 10.8364(4) Å Tmin = 0.2467, Tmax = 0.4330 c = 11.6070(4) Å 20534 measured reflections

α = 62.768(2) º 5040 independent reflections

β = 82.646(2) º 4778 reflections with I > 2σ(I)

γ = 75.921(2) º R int = 0.0233

V = 1112.19(7) Å3 θ max = 27.50º

Z = 2 h = -13 → 13

Dx = 1.760 Mg m-3 k = -14 → 14

Mo Kα radiation l = -15 → 15

Cell parameters from 9326 reflections

θ = 2.65±35.31º

μ = 6.701 mm-1

T = 100 (2) K irregular, colorless

0.29 x 0.15 x 0.15 mm

144

Table AI-1c. Refinement Figure AI-1a. ORTEP plot of title compound. Ellipsoids are at the 50% probability level. Hydrogen atoms omitted.

Refinement on F2

R[F2 > 2σ(F2)] = 0.0154 wR(F2) = 0.0357

S = 1.070

5040 reflections

262 parameters P1 Au1 H-atom parameters constrained N1

2 2 2 w = 1/[σ (Fo ) + (0.0135P + 1.3854P]

2 2 where P = (Fo + 2Fc )/3

(Δ/σ)max = 0.090

Δρmax = 1.278 e×Å-3

-3 Δρmin = -0.829 e×Å

Table AI-1d Selected geometric parameters (Å, º). Au1-N1 2.070(2) N1-Au1-P1 177.99(6)

Au1-P1 2.2346(6) C1-P1-C13 107.05(10)

P1-C1 1.832(2) C1-P1-C19 105.26(10)

P1-C13 1.836(2) C13-P1-C19 107.12(10)

P1-C19 1.849(2) C1-P1-Au1 114.65(7)

145

C13-C18 1.533(3) C13-P1-Au1 112.02(8)

C13-C14 1.536(3) C19-P1-Au1 110.26(8)

N1-N2 1.141(3) C18-C13-C14 110.69(19)

C1-C2 1.402(3) C18-C13-P1 108.85(15)

C1-C6 1.410(3) C14-C13-P1 111.42(15)

C7-C12 1.394(3) N2-N1-Au1 120.17(18)

C7-C8 1.400(3) C2-C1-C6 119.1(2)

C7-C6 1.499(3) C2-C1-P1 117.90(16)

C6-C5 1.398(3) C6-C1-P1 123.00(17)

C2-C3 1.390(3) C12-C7-C8 118.9(2)

C3-C4 1.390(3) C12-C7-C6 121.9(2)

C12-C11 1.393(3) C8-C7-C6 119.2(2)

C14-C15 1.534(3) C5-C6-C1 118.7(2)

C15-C16 1.525(4) C5-C6-C7 115.7(2)

C11-C10 1.383(4) C1-C6-C7 125.5(2)

C10-C9 1.385(4) C3-C2-C1 121.2(2)

C8-C9 1.389(4) C2-C3-C4 119.8(2)

C5-C4 1.390(4) C11-C12-C7 120.7(2)

C18-C17 1.528(3) C15-C14-C13 110.84(19)

C20-C21 1.535(3) C16-C15-C14 111.1(2)

C20-C19 1.537(3) C10-C11-C12 119.8(2)

C19-C24 1.540(3) C11-C10-C9 120.0(2)

C24-C23 1.528(3) C9-C8-C7 120.1(2)

146

N2-N3 1.191(4) C4-C5-C6 121.7(2)

C21-C22 1.520(4) C10-C9-C8 120.5(2)

C22-C23 1.517(4) C17-C18-C13 111.5(2)

C21-C20-C19 110.78(19)

C20-C19-C24 111.12(19)

C20-C19-P1 115.58(15)

C24-C19-P1 109.15(15)

C23-C24-C19 112.2(2)

N1-N2-N3 175.9(3)

C22-C21-C20 110.9(2)

C23-C22-C21 111.1(2)

C22-C23-C24 111.6(2)

C15-C16-C17 110.2(2)

C16-C17-C18 110.8(2)

147

2. X-Ray Crystal Data for [(PCy2(2′,4′,6′-triisopropylbiphenyl))AuN3]

Table AI-2a. Crystal data for mc031108 Table AI-2b. Data collection C33H49AuN3P Bruker SMART CCD area-detector

Mr = 715.69 diffractometer

Monoclinic, C2/c ω scans a = 18.161(3) Å Absorption correction: multi-scan b = 17.165(3) Å Tmin = 0.3159, Tmax = 0.7035 c = 22.038(4) Å 36453 measured reflections

α = 90 º 7313 independent reflections

β = 101.120(2) º 6377 reflections with I > 2σ(I)

γ = 90 º R int = 0.0457

V = 6741(2) Å3 θ max = 27.04º

Z = 8 h = -23 → 23

Dx = 1.410 Mg m-3 k = -21 → 21

Mo Kα radiation l = -27 → 28

Cell parameters from 9203 reflections

θ = 2.00±27.03º

μ = 4.436 mm-1

T = 100 (2) K

Irregular, colorless

0.33 x 0.24 x 0.08 mm

148

Table AI-2c. Refinement Figure AI-2a. ORTEP plot of title compound. Ellipsoids are at the 50% probability level. Hydrogen atoms omitted.

Refinement on F2

R[F2 > 2σ(F2)] = 0.0230 wR(F2) = 0.0559

S = 1.053 N1 7313 reflections P1 Au1

349 parameters

H-atom parameters constrained

2 2 2 w = 1/[σ (Fo ) + (0.0291P) + 0.0000P] where P = (F 2 + 2Fc2)/3 o (Δ/σ)max = 0.097

Δρmax = 1.078 e×Å-3

-3 Δρmin = -1.277 e×Å

Table AI-2d Selected geometric parameters (Å, º). Au1-N1 2.057(2) N1-Au1-P1 173.08(6)

Au1-P1 2.2279(7) C13-P1-C1 103.99(11)

P1-C13 1. 831(2) C13-P1-C7 103.65(11)

P1-C1 1.836(2) C1-P1-C7 108.59(11)

P1-C7 1.838(2) C13-P1-Au1 117.79(8)

C17-C16 1.381(3) C1-P1-Au1 109.92(8)

C17-C18 1.392(3) C7-P1-Au1 112.23(8)

149

C18-C13 1.411(3) C16-C17-C18 122.1(2)

C18-C19 1.498(3) C17-C18-C13 118.2(2)

C7-C8 1.527(3) C17-C18-C19 117.8(2)

C7-C12 1.534(3) C13-C18-C19 124.0(2)

C6-C5 1.519(4) C8-C7-C12 110.80(19)

C6-C1 1.530(3) C8-C7-P1 112.86(17)

C2-C3 1.519(3) C12-C7-P1 114.51(17)

C2-C1 1.525(3) C5-C6-C1 110.2(2)

C5-C4 1.515(4) C3-C2-C1 111.00(19)

C13-C14 1.390(3) C4-C5-C6 111.6(2)

C3-C4 1.522(3) C14-C13-C18 118.9(2)

C10-C11 1.515(4) C14-C13-P1 118.43(17)

C10-C9 1.514(4) C18-C13-P1 122.64(18)

C8-C9 1.518(4) C2-C3-C4 111.9(2)

C11-C12 1.517(4) C11-C10-C9 111.4(2)

C14-C15 1.380(3) C9-C8-C7 111.1(2)

C16-C15 1.386(3) C5-C4-C3 111.9(2)

C19-C24 1.400(3) C2-C1-C6 109.9(2)

C19-C20 1.416(4) C2-C1-P1 109.58(15)

C21-C22 1.386(4) C6-C1-P1 112.19(17)

C21-C20 1.385(4) C10-C11-C12 111.4(2)

C22-C23 1.388(3) C15-C14-C13 122.1(2)

C22-C28 1.509(3) C17-C16-C15 119.7(2)

150

C20-C25 1.510(3) C11-C12-C7 111.3(2)

C24-C23 1.383(3) C14-C15-C16 119.1(2)

C24-C31 1.515(3) C10-C9-C8 111.5(2)

C25-C27 1.524(4) C24-C19-C20 119.5(2)

C25-C26 1.531(3) C24-C19-C18 120.8(2)

C31-C33 1.512(3) C20-C19-C18 119.7(2)

C31-C32 1.522(3) C22-C21-C20 122.2(2)

N1-N2 1.171(3) C21-C22-C23 118.0(2)

N2-N3 1.156(3) C21-C22-C28 121.7(2)

C28-C30 1.518(4) C23-C22-C28 120.2(2)

C28-C29 1.529(3) C21-C20-C19 118.8(2)

C21-C20-C25 119.6(2)

C19-C20-C25 121.6(2)

C23-C24-C19 119.4(2)

C23-C24-C31 119.0(2)

C19-C24-C31 121.7(2)

C24-C23-C22 122.0(2)

C20-C25-C27 112.9(2)

C20-C25-C26 109.9(2)

C27-C25-C26 110.7(2)

C24-C31-C33 112.4(2)

C24-C31-C32 110.48(19)

C33-C31-C32 110.2(2)

151

N2-N1-Au1 124.3(2)

N3-N2-N1 175.0(3)

C22-C28-C30 112.3(2)

C22-C28-C29 110.6(2)

C30-C28-C29 111.1(2)

152

3. X-Ray Crystal Data for [(PCy3)AuN3]

Table AI-3a. Crystal data for TomsGold Table AI-3b. Data collection C18H33AuN3P Bruker SMART CCD area-detector

Mr = 519.41 diffractometer

Monoclinic, P2(1)/c ω scans a = 9.4837(10) Å Absorption correction: multi-scan b = 14.6205(15) Å Tmin = 0.0771, Tmax = 0.1589 c = 14.3846(15) Å 22034 measured reflections

α = 90 º 4442 independent reflections

β = 103.3770(10) º 4209 reflections with I > 2σ(I)

γ = 90.00 º R int = 0.0811

V = 1940.4(3) Å3 θ max = 27.50º

Z = 4 h = -12 → 12

Dx = 1.778 Mg m-3 k = -18 → 18

Mo Kα radiation l = -18 → 18

Cell parameters from 8962 reflections

θ = 2.35±28.28º

μ = 7.668 mm-1

T = 100 (2) K needle, colorless

0.46 x 0.34 x 0.24 mm

153

Table AI-3c. Refinement Figure AI-3a. ORTEP plot of title compound. Ellipsoids are at the 50% probability level. Hydrogen atoms omitted.

Refinement on F2

R[F2 > 2σ(F2)] = 0.0148 wR(F2) = 0.0391

S = 0.998

4442 reflections

208 parameters

H-atom parameters constrained

2 2 2 w = 1/[σ (Fo ) + (0.0228P) + 2.3276P]

2 2 where P = (Fo + 2Fc )/3

(Δ/σ)max = 0.080

Δρmax = 1.286 e×Å-3

Δρmin = -0.713 e×Å-3

Table AI-3d Selected geometric parameters (Å, º). Au1-N1 2.095(2) N1-Au1-P1 177.78(6)

Au1-P1 2.2442(6) C13-P1-C7 106.71(9)

P1-C13 1.842(2) C13-P1-C1 108.16(9)

P1-C7 1.843(2) C7-P1-C1 106.79(10)

P1-C1 1.850(2) C13-P1-Au1 113.28(7)

N1-N2 1.066(4) C7-P1-Au1 110.68(7)

N2-N3 1.207(4) C1-P1-Au1 110.92(7)

154

C13-C18 1.536(3) N2-N1-Au1 121.38(18)

C13-C14 1.537(3) N1-N2-N3 174.8(3)

C1-C2 1.537(3) C18-C13-C14 110.30(18)

C1-C6 1.541(3) C18-C13-P1 110.55(15)

C7-C8 1.536(3) C14-C13-P1 111.17(14)

C7-C12 1.542(3) C2-C1-C6 109.87(17)

C8-C9 1.530(3) C2-C1-P1 114.43(14)

C3-C2 1.526(3) C6-C1-P1 112.21(14)

C3-C4 1.531(3) C8-C7-C12 110.66(17)

C18-C17 1.532(3) C8-C7-P1 114.56(14)

C17-C16 1.525(4) C12-C7-P1 111.66(14)

C12-C11 1.531(3) C9-C8-C7 110.39(17)

C15-C16 1.521(3) C2-C3-C4 111.18(18)

C15-C14 1.533(3) C17-C18-C13 111.46(18)

C5-C4 1.528(3) C16-C17-C18 111.3(2)

C5-C6 1.533(3) C11-C12-C7 110.42(18)

C11-C10 1.524(3) C3-C2-C1 110.86(18)

C9-C10 1.524(3) C16-C15-C14 110.82(19)

C15-C14-C13 110.69(18)

C4-C5-C6 111.53(18)

C10-C11-C12 112.01(19)

C10-C9-C8 111.35(18)

C15-C16-C17 110.2(2)

155

C9-C10-C11 110.54(18)

C3-C4-C5 110.89(19)

C5-C6-C1 110.98(18)

156

4. X-Ray Crystal Data for [(1,3-dimethyl-4,5-dichlorocarbene)AuCl]

Table AI-4a. Crystal data for nd021710 Table AI-4b. Data collection C5H6AuN2Cl3 Bruker SMART CCD area-detector

Mr = 397.43 diffractometer

Tetragonal, I-42d ω scans a = 15.9232(6) Å Absorption correction: multi-scan b = 15.9232(6) Å Tmin = 0.1704, Tmax = 0.3938 c = 7.3430(4) Å 11060 measured reflections

α = 90 º 1128 independent reflections

β = 90 º 1107 reflections with I > 2σ(I)

γ = 90 º R int = 0.0265

V = 1861.81(14) Å3 θ max = 28.03º

Z = 8 h = -20 → 20

Dx = 2.836 Mg m-3 k = -20 → 20

Mo Kα radiation l = -9 → 9

Cell parameters from 8629 reflections

θ = 2.56±27.98º

μ = 16.601 mm-1

T = 170 (2) K irregular, colorless

0.17 x 0.09 x 0.07 mm

157

Table AI-4c. Refinement Figure AI-4a. ORTEP plot of title compound. Ellipsoids are at the 50% probability level. Hydrogen atoms omitted.

Refinement on F2

R[F2 > 2σ(F2)] = 0.0143 wR(F2) = 0.0391

S = 1.261

1128 reflections

53 parameters

H-atom parameters constrained

2 2 2 w = 1/[σ (Fo ) + (0.0159P) + 0.0000P]

2 2 where P = (Fo + 2Fc )/3

(Δ/σ)max = 0.203

Δρmax = 0.429 e×Å-3

-3 Δρmin = -1.340 e×Å

Table AI-4d Selected geometric parameters (Å, º). Au1-C1 1.977(5) C1-Au1-Cl2 180.0

Au1-Cl2 2.2923(13) N1-C1-N1 105.6(5)

C1-N1 1.349(5) N1-C1-Au1 127.2(2)

N1-C2 1.382(6) C1-N1-C2 110.2(4)

N1-C3 1.460(6) C1-N1-C3 125.3(4)

C2-C2 1.341(9) C2-N1-C3 124.5(4)

158

C2-Cl1 1.694(4) C2-C2-N1 107.0(2)

C2-C2-Cl1 129.67(16)

N1-C2-Cl1 123.3(3)

159

5. X-Ray Crystal Data for [(1,3-dimethyl-4,5-dichlorocarbene)AuBr]

Table AI-5a. Crystal data for nd031910 Table AI-5b. Data collection C5H6AuN2Cl2Br Bruker SMART CCD area-detector

Mr = 441.89 diffractometer

Tetragonal, I-42d ω scans a = 16.1627(8) Å Absorption correction: multi-scan b = 16.1627(8) Å Tmin = 0.1544, Tmax = 0.4702 c = 7.4366(5) Å 11604 measured reflections

α = 90 º 1169 independent reflections

β = 90 º 1129 reflections with I > 2σ(I)

γ = 90 º R int = 0.0337

V = 1942.68(19)Å3 θ max = 27.99º

Z = 8 h = -21 → 21

Dx = 3.022 Mg m-3 k = -21 → 21

Mo Kα radiation l = -9 → 9

Cell parameters from 1584 reflections

θ = 2.52±27.87º

μ = 19.749 mm-1

T = 170 (2) K irregular, colorless

0.15 x 0.05 x 0.05 mm

160

Table AI-5c. Refinement Figure AI-5a. ORTEP plot of title compound. Ellipsoids are at the 50% probability level. Hydrogen atoms omitted. Refinement on F2

R[F2 > 2σ(F2)] = 0.0144 Cl1 Cl1A wR(F2) = 0.0339

S = 1.079

1169 reflections

53 parameters C1 H-atom parameters constrained

2 2 2 w = 1/[σ (Fo ) + (0.0141P) + 0.0000P] Au1

2 2 where P = (Fo + 2Fc )/3

(Δ/σ)max = 0.145 Br1 Δρmax = 0.642 e×Å-3

-3 Δρmin = -0.885 e×Å

Table AI-5d Selected geometric parameters (Å, º). Au1-C1 1.990(5) C1-Au1-Br1 180.000(1)

Au1-Br1 2.4050(5) N1-C1-N1 106.7(4)

C1-N1 1.344(4) N1-C1-Au1 126.7(2)

C2-N1 1.463(5) C1-N1-C3 109.6(3)

N1-C3 1.380(5) C1-N1-C2 125.4(3)

C3-C3 1.347(8) C3-N1-C2 124.9(3)

161

C3-Cl1 1.697(4) C3-C3-N1 107.1(2)

C3-C3-Cl1 129.29(14)

N1-C3-Cl1 123.6(3)

162

6. X-Ray Crystal Data for [(1,3-dimethyl-4,5-dichlorocarbene)AuN3]

Table AI-6a. Crystal data for nd030310 Table AI-6b. Data collection C5H6AuN5Cl2 Bruker SMART CCD area-detector

Mr = 404.01 diffractometer

Orthorhombic, Pnma ω scans a = 16.7352(16) Å Absorption correction: multi-scan b = 6.3794(6) Å Tmin = 0.1954, Tmax = 0.3769 c = 8.8122(9) Å 9985 measured reflections

α = 90 º 1097 independent reflections

β =90 º 1029 reflections with I > 2σ(I)

γ = 90 º R int = 0.0273

V = 940.80(16) Å3 θ max = 26.87º

Z = 4 h = -21 → 21

Dx = 2.852 Mg m-3 k = -8 → 8

Mo Kα radiation l = -11 → 11

Cell parameters from 5128 reflections

θ = 2.43±26.69º

μ = 16.163 mm-1

T = 170 (2) K irregular, colorless

0.15 x 0.08 x 0.08 mm

163

Table AI-6c. Refinement Figure AI-6a. ORTEP plot of title compound. Ellipsoids are at the 50% probability level. Hydrogen atoms omitted.

Refinement on F2

R[F2 > 2σ(F2)] = 0.0204 wR(F2) = 0.0513

S = 1.067

1097 reflections

81 parameters

H-atom parameters constrained

2 2 2 w = 1/[σ (Fo ) + (0.0328P) + 1.3236P]

2 2 where P = (Fo + 2Fc )/3

(Δ/σ)max = 0.289

Δρmax = 0.637 e×Å-3

-3 Δρmin = -1.695 e×Å

Table AI-6d Selected geometric parameters (Å, º). Au1-C1 1.962(6) C1-Au1-N1 175.6(2)

Au1-N1 2.019(6) N5-C1-N4 104.7(5)

C1-N5 1.346(7) N5-C1-Au1 128.8(4)

C1-N4 1.363(7) N4-C1-Au1 126.5(4)

C2-C3 1.329(7) C-C2-N4 106.9(5)

C2-N4 1.370(7) C3-C2-Cl1 130.5(5)

C2-Cl1 1.691(5) N4-C2-Cl1 122.6(4)

164

N4-C4 1.453(7) C2-N4-C1 110.0(5)

N2-N3 1.155(7) C2-N4-C4 124.6(5)

N2-N1 1.179(7) C1-N4-C4 125.4(5)

N5-C3 1.360(7) N3-N2-N1 174.6(6)

N5-C5 1.461(7) N2-N1-Au1 123.8(5)

Cl2-C3 1.699(6) C1-N5-C3 110.5(5)

C1-N5-C5 123.2(5)

C3-N5-C5 126.3(5)

C2-C3-N5 107.9(5)

C2-C3-Cl2 129.2(5)

N5-C3-Cl2 123.0(4)

165

7. X-Ray Crystal Data for [(1,3-diisopropylcarbene)AuN3]

Table AI-7a. Crystal data for nd062310 Table AI-7b. Data collection C9H16AuN5 Bruker SMART CCD area-detector

Mr = 391.23 diffractometer

Orthorhombic, Pnma ω scans a = 9.1386(7) Å Absorption correction: multi-scan b = 6.9823(5) Å Tmin = 0.2504, Tmax = 0.5961 c = 18.7475(14) Å 12809 measured reflections

α = 90 º 1391 independent reflections

β = 90 º 1326 reflections with I > 2σ(I)

γ = 90 º R int = 0.0260

V = 1196.25(15) Å3 θ max = 26.85º

Z = 4 h = -11 → 11

Dx = 1.700 Mg m-3 k = -8 → 8

Mo Kα radiation l = -23 → 23

Cell parameters from 6312 reflections

θ = 2.17±26.71º

μ = 12.276 mm-1

T = 170 (2) K

Irregular chunk, colorless

0.16 x 0.08 x 0.05 mm

166

Table AI-7c. Refinement Figure AI-7a. ORTEP plot of title compound. Ellipsoids are at the 50% probability level. Hydrogen atoms omitted.

Refinement on F2

R[F2 > 2σ(F2)] = 0.0314 wR(F2) = 0.0606

S = 1.440

1391 reflections C1 88 parameters

H-atom parameters constrained Au1

2 2 2 w = 1/[σ (Fo ) + (0.0000P) + 8.3672P]

2 2 N3 where P = (Fo + 2Fc )/3

(Δ/σ)max = 0.153 Δρmax = 1.548 e×Å-3

-3 Δρmin = -2.077 e×Å

Table AI-7d Selected geometric parameters (Å, º). Au1-C1 1.973(8) C1-Au1-N3 178.6(3)

Au1-N3 2.033(7) N1-C1-N2 105.3(7)

C1-N1 1.309(11) N1-C1-Au1 127.1(6)

C1-N2 1.344(10) N2-C1-Au1 127.7(6)

C2-C3 1.342(13) C3-C2-N1 105.2(8)

C2-N1 1.380(11) C2-C3-N2 107.1(8)

C3-N2 1.379(11) C1-N1-C2 112.4(7)

167

N1-C5 1.484(11) C1-N1-C5 126.1(8)

N2-C8 1.468(11) C2-N1-C5 121.5(8)

N3-N4 1.198(11) C1-N2-C3 110.1(7)

N4-N5 1.144(11) C1-N2-C8 124.5(7)

C8-C9 1.499(9) C3-N2-C8 125.4(8)

C8-C9 1.499(9) N4-N3-Au1 121.5(6)

C5-C7 1.511(9) N5-N4-N3 174.6(10)

C5-C7 1.511(9) N2-C8-C9 110.3(5)

N2-C8-C9 110.3(5)

C9-C8-C9 114.9(9)

N1-C5-C7 110.9(5)

C7-C5-C7 113.8(8)

168

8. X-Ray Crystal Data for [(PPh3)Au(n-pentatriazole)]

Table AI-8a. Crystal data for ju082306 Table AI-8b. Data collection C25H27AuN3P Bruker SMART CCD area-detector

Mr = 597.43 diffractometer

Monoclinic, P2(1) ω scans a = 12.7141(3) Å Absorption correction: multi-scan b = 12.5924(3) Å Tmin = 0.1189, Tmax = 0.5945 c = 14.5253(3) Å 53261 measured reflections

α = 90 º 12797 independent reflections

β = 97.4650(10) º 12371 reflections with I > 2σ(I)

γ = 90 º R int = 0.0272

V = 2305.81(9) Å3 θ max = 29.61º

Z = 4 h = -17 → 17

Dx = 1.721Mg m-3 k = -16 → 17

Mo Kα radiation l = -20 → 20

Cell parameters from 9646 reflections

θ = 2.29±29.59º

μ = 6.466 mm-1

T = 100 (2) K needle, colorless

0.55 x 0.12 x 0.08 mm

169

Table AI-8c. Refinement Figure AI-8a. ORTEP plot of title compound. Ellipsoids are at the 50% probability level. Hydrogen atoms omitted.

Refinement on F2

R[F2 > 2σ(F2)] = 0.0160 wR(F2) = 0.0337

S = 0.982

12797 reflections

543 parameters

H-atom parameters constrained

2 2 2 w = 1/[σ (Fo ) + (0.0000P) + 0.0000P]

2 2 where P = (Fo + 2Fc )/3

(Δ/σ)max = 0.085

Δρmax = 1.585 e×Å-3

-3 Δρmin = -0.511 e×Å

Table AI-8d Selected geometric parameters (Å, º). Au1-C2 2.037(2) C2 Au1 P1 178.85(7)

Au1-P1 2.2913(6) C3 Au2 P2 171.15(7)

Au2-C3 2.014(2) C10 P2 C7 107.09(11)

Au2-P2 2.2761(6) C10 P2 C6 105.39(11)

P2-C10 1.814(2) C7 P2 C6 104.97(12)

P2-C7 1.815(3) C10 P2 Au2 116.02(8)

P2-C6 1.821(3) C7 P2 Au2 115.11(8)

170

P1-C14 1.817(2) C6 P2 Au2 107.27(8)

P1-C19 1.818(2) C14 P1 C19 105.16(11)

P1-C1 1.820(3) C14 P1 C1 104.07(12)

C1-C30 1.392(4) C19 P1 C1 105.70(11)

C1-C15 1.399(4) C14 P1 Au1 115.89(8)

C2-N1 1.354(3) C19 P1 Au1 112.66(8)

C2-C27 1.390(3) C1 P1 Au1 112.43(8)

N2-N3 1.324(3) C30 C1 C15 118.3(2)

N2-N1 1.339(3) C30 C1 P1 122.42(19)

N3-C27 1.365(3) C15 C1 P1 119.3(2)

N4-N5 1.344(3) N1 C2 C27 102.0(2)

N4-C3 1.345(3) N1 C2 Au1 122.27(17)

C5-C4 1.494(3) C27 C2 Au1 135.64(19)

C5-C32 1.513(4) N3 N2 N1 105.55(19)

C4-N6 1.356(3) N2 N3 C27 109.2(2)

C4-C3 1.403(3) N2 N1 C2 114.02(19)

C8-C9 1.387(4) N5 N4 C3 112.7(2)

C8-C7 1.394(4) C4 C5 C32 113.9(2)

C9-C35 1.396(4) N6 C4 C3 109.3(2)

C7-C36 1.402(4) N6 C4 C5 121.5(2)

C6-C12 1.394(4) C3 C4 C5 129.1(2)

C6-C37 1.400(4) N4 C3 C4 102.3(2)

N6-N5 1.313(3) N4 C3 Au2 127.62(18)

171

C13-C21 1.383(4) C4 C3 Au2 129.77(18)

C13-C10 1.398(3) C9 C8 C7 120.4(3)

C10-C11 1.399(3) C8 C9 C35 119.9(3)

C11-C50 1.385(4) C8 C7 C36 119.1(2)

C12-C40 1.393(4) C8 C7 P2 123.4(2)

C17-C31 1.373(4) C36 C7 P2 117.42(19)

C17-C16 1.388(4) C12 C6 C37 119.1(2)

C20-C29 1.383(4) C12 C6 P2 122.1(2)

C20-C19 1.395(4) C37 C6 P2 118.72(19)

C14-C23 1.391(3) N5 N6 C4 108.5(2)

C14-C26 1.398(3) N6 N5 N4 107.2(2)

C19-C18 1.397(3) C21 C13 C10 120.0(2)

C15-C16 1.380(4) C13 C10 C11 119.2(2)

C18-C47 1.397(3) C13 C10 P2 119.05(19)

C28-C27 1.499(4) C11 C10 P2 121.70(19)

C28-C41 1.534(3) C50 C11 C10 120.1(2)

C31-C30 1.384(4) C40 C12 C6 120.1(3)

C23-C24 1.400(4) C31 C17 C16 119.7(2)

C26-C45 1.394(4) C29 C20 C19 120.0(2)

C25-C24 1.371(4) C23 C14 C26 119.7(2)

C25-C45 1.383(4) C23 C14 P1 118.91(19)

C29-C46 1.388(4) C26 C14 P1 121.19(19)

C22-C21 1.383(4) C20 C19 C18 119.6(2)

172

C22-C50 1.386(4) C20 C19 P1 117.56(19)

C39-C40 1.382(4) C18 C19 P1 122.79(19)

C39-C38 1.388(4) C16 C15 C1 120.8(2)

C44-C43 1.524(4) C47 C18 C19 119.5(2)

C43-C42 1.527(4) C15 C16 C17 120.0(2)

C34-C33 1.519(4) C27 C28 C41 113.7(2)

C34-C48 1.529(4) C17 C31 C30 120.6(2)

C46-C47 1.382(4) C14 C23 C24 119.6(2)

C41-C42 1.522(4) C45 C26 C14 120.0(2)

C37-C38 1.381(4) C24 C25 C45 120.8(3)

C33-C32 1.530(4) N3 C27 C2 109.2(2)

C36-C49 1.390(4) N3 C27 C28 120.3(2)

C35-C49 1.379(4) C2 C27 C28 130.5(2)

C31 C30 C1 120.5(2)

C20 C29 C46 120.7(3)

C21 C22 C50 119.9(2)

C25 C24 C23 120.2(3)

C13 C21 C22 120.5(2)

C40 C39 C38 120.3(3)

C44 C43 C42 113.5(2)

C33 C34 C48 112.1(3)

C47 C46 C29 119.6(2)

C42 C41 C28 112.7(2)

173

C38 C37 C6 120.5(3)

C41 C42 C43 113.9(2)

C34 C33 C32 114.6(2)

C46 C47 C18 120.6(2)

C49 C36 C7 120.2(3)

C25 C45 C26 119.7(3)

C37 C38 C39 120.0(3)

C39 C40 C12 120.1(3)

C5 C32 C33 112.2(2)

C49 C35 C9 120.2(3)

C35 C49 C36 120.2(3)

C11 C50 C22 120.2(3)

174

9. X-Ray Crystal Data for [(PPh3)Au(cyclohexyltriazole)]

Table AI-9a. Crystal data for ju082406 Table AI-9b. Data collection C26H27AuN3P Bruker SMART CCD area-detector

Mr = 609.44 diffractometer

Tetragonal, P4(3) ω scans a = 12.8742(2) Å Absorption correction: multi-scan b = 12.8742(2) Å Tmin = 0.4784, Tmax = 0.7082 c = 14.6812(3) Å 34557 measured reflections

α = 90 º 2582 independent reflections

β = 90 º 2340 reflections with I > 2σ(I)

γ = 90 º R int = 0.0556

V = 2433.34(7) Å3 θ max = 20.90º

Z = 4 h = -12 → 12

Dx = 1.664 Mg m-3 k = -12 → 12

Mo Kα radiation l = -14 → 14

Cell parameters from 9321 reflections

θ = 2.10±20.90º

μ = 6.129 mm-1

T = 100 (2) K thin plate, colorless

0.17 x 0.07 x 0.07 mm

175

Table AI-9c. Refinement Figure AI-9a. ORTEP plot of title compound. Ellipsoids are at the 50% probability level. Hydrogen atoms omitted. Refinement on F2

R[F2 > 2σ(F2)] = 0.0250 wR(F2) = 0.0521

S = 1.089

2582 reflections

268 parameters

H-atom parameters constrained

2 2 2 w = 1/[σ (Fo ) + (0.0199P) + 5.3199P]

2 2 where P = (Fo + 2Fc )/3

(Δ/σ)max = 0.071

Δρmax = 0.563 e×Å-3

-3 Δρmin = -0.364 e×Å

Table AI-9d Selected geometric parameters (Å, º). C24-C25 1.3900 C25-C24-C17 120.0

C24-C17 1.3900 C25-C24-P1 118.3(6)

C24-P1 1.817(7) C17-C24-P1 121.7(6)

C25-C26 1.3900 C26-C25-C24 120.0

C26-C27 1.3900 C25-C26-C27 120.0

C27-C28 1.3900 C26-C27-C28 120.0

C28-C17 1.3900 C17-C28-C27 120.0

176

Au1-C9 2.018(10) C28-C17-C24 120.0

Au1-P1 2.273(3) C9-Au1-P1 177.4(3)

P1-C22 1.799(12) C22-P1-C1 105.9(5)

P1-C1 1.805(10) C22-P1-C24 107.3(5)

C2-C1 1.375(12) C1-P1-C24 104.5(4)

C2-C3 1.384(13) C22-P1-Au1 113.3(4)

C1-C6 1.400(13) C1-P1-Au1 114.9(3)

C6-C5 1.367(15) C24-P1-Au1 110.4(3)

C8-C29 1.361(19) C1-C2-C3 120.2(9)

C8-C22 1.386(15) C2-C1-C6 118.2(9)

C9-N1 1.339(11) C2-C1-P1 119.1(7)

C9-C10 1.386(13) C6-C1-P1 122.7(8)

C5-C4 1.350(14) C5-C6-C1 119.4(10)

C3-C4 1.359(14) C29-C8-C22 118.6(14)

C10-N3 1.384(12) N1-C9-C10 103.2(9)

C10-C11 1.511(16) N1-C9-Au1 122.9(7)

C21-C11 1.480(17) C10-C9-Au1 133.6(8)

C21-C18 1.560(17) C4-C5-C6 122.2(10)

C11-C13 1.438(16) C4-C3-C2 121.0(9)

C13-C19 1.52(2) C5-C4-C3 118.8(10)

C16-C15 1.35(2) N3-C10-C9 110.8(9)

C16-C29 1.38(3) N3-C10-C11 119.9(9)

C15-C23 1.401(18) C9-C10-C11 129.3(10)

177

N3-N2 1.308(10) C11-C21-C18 113.7(11)

N2-N1 1.362(9) C13-C11-C21 116.0(14)

C18-C20 1.49(2) C13-C11-C10 114.4(12)

C19-C20 1.48(2) C21-C11-C10 111.7(11)

C23-C22 1.393(16) C11-C13-C19 113.8(15)

C15-C16-C29 119.7(16)

C16-C15-C23 117.8(17)

N2-N3-C10 105.4(8)

N3-N2-N1 109.7(7)

C9-N1-N2 110.8(8)

C20-C18-C21 109.6(14)

C20-C19-C13 112.4(16)

C19-C20-C18 116.1(15)

C22-C23-C15 122.4(13)

C8-C22-C23 118.2(11)

C8-C22-P1 122.9(10)

C23-C22-P1 118.9(9)

C8-C29-C16 123.0(17)

178

10. X-Ray Crystal Data for [(PPh3)Au(3-aminophenyltriazole)]

Table AI-10a. Crystal data for ju112806 Table AI-10b. Data collection C26H22AuN4P Bruker SMART CCD area-detector

Mr = 618.41 diffractometer

Triclinic, P-1 ω scans a = 13.4001(14) Å Absorption correction: multi-scan b = 15.0853(15) Å Tmin = 0.4784, Tmax = 0.7082 c = 20.853(2) Å 42136 measured reflections

α = 70.2910(10) º 16364 independent reflections

β = 86.9520(10) º 9693 reflections with I > 2σ(I)

γ = 66.5160(10) º R int = 0.0811

V = 3623.5(6) Å3 θ max = 27.50º

Z = 6 h = -17 → 17

Dx = 1.700 Mg m-3 k = -19 → 19

Mo Kα radiation l = -27 → 27

Cell parameters from 8629 reflections

θ = 1.57±27.50º

μ = 6.176 mm-1

T = 100 (2) K needle, colorless

0.14 x 0.06 x 0.06 mm

179

Table AI-10c. Refinement Figure AI-10a. ORTEP plot of title compound. Ellipsoids are at the 50% probability level. Hydrogen atoms omitted.

Refinement on F2

R[F2 > 2σ(F2)] = 0.0657 wR(F2) = 0.1503

S = 0.891

16364 reflections

865 parameters

H-atom parameters constrained

2 2 2 w = 1/[σ (Fo ) + (0.0964P) + 0.0000P]

2 2 where P = (Fo + 2Fc )/3

(Δ/σ)max = 0.276

Δρmax = 7.455 e×Å-3

-3 Δρmin = -1.966 e×Å

Table AI-10d Selected geometric parameters (Å, º). Au(1)-C(1) 2.019(11) C(73)-P(3)-Au(3) 113.7(4)

Au(1)-P(1) 2.270(3) N(11)-N(10)-N(9) 106.3(8)

Au(2)-C(27) 2.032(10) N(3)-N(2)-N(1) 104.1(8)

Au(2)-P(2) 2.289(3) N(7)-N(6)-N(5) 104.9(8)

Au(3)-C(53) 2.049(10) C(53)-N(9)-N(10) 112.1(9)

Au(3)-P(3) 2.278(3) N(10)-N(11)-C(54) 107.6(9)

P(2)-C(35) 1.795(11) N(2)-N(3)-C(2) 111.5(9)

180

P(2)-C(47) 1.817(12) N(6)-N(5)-C(27) 113.3(9)

P(2)-C(41) 1.823(12) N(2)-N(1)-C(1) 114.2(9)

P(1)-C(9) 1.796(11) N(6)-N(7)-C(28) 110.1(9)

P(1)-C(21) 1.811(12) N(1)-C(1)-C(2) 101.8(9)

P(1)-C(15) 1.822(12) N(1)-C(1)-Au(1) 119.4(8)

P(3)-C(61) 1.810(13) C(2)-C(1)-Au(1) 138.4(8)

P(3)-C(67) 1.811(12) C(26)-C(21)-C(22) 118.1(11)

P(3)-C(73) 1.816(13) C(26)-C(21)-P(1) 119.1(9)

N(10)-N(11) 1.337(13) C(22)-C(21)-P(1) 122.6(9)

N(10)-N(9) 1.362(11) C(11)-C(10)-C(9) 120.5(11)

N(2)-N(3) 1.312(12) C(14)-C(9)-C(10) 118.6(11)

N(2)-N(1) 1.351(12) C(14)-C(9)-P(1) 121.2(9)

N(6)-N(7) 1.323(12) C(10)-C(9)-P(1) 120.0(8)

N(6)-N(5) 1.350(12) C(20)-C(15)-C(16) 119.2(11)

N(9)-C(53) 1.344(14) C(20)-C(15)-P(1) 123.3(9)

N(11)-C(54) 1.376(13) C(16)-C(15)-P(1) 117.3(8)

N(3)-C(2) 1.360(13) C(18)-C(19)-C(20) 119.0(11)

N(5)-C(27) 1.358(14) C(15)-C(20)-C(19) 120.6(11)

N(1)-C(1) 1.365(14) N(4)-C(7)-C(6) 121.9(11)

N(4)-C(7) 1.380(15) N(4)-C(7)-C(8) 121.3(11)

N(7)-C(28) 1.342(14) C(6)-C(7)-C(8) 116.5(11)

N(8)-C(33) 1.373(16) C(17)-C(18)-C(19) 121.5(10)

C(1)-C(2) 1.392(15) C(18)-C(17)-C(16) 119.0(11)

181

C(21)-C(26) 1.372(17) C(15)-C(16)-C(17) 120.7(11)

C(21)-C(22) 1.416(15) C(3)-C(8)-C(7) 123.3(10)

C(10)-C(11) 1.379(17) C(23)-C(22)-C(21) 120.8(11)

C(10)-C(9) 1.405(15) C(24)-C(23)-C(22) 120.5(11)

C(9)-C(14) 1.390(15) C(8)-C(3)-C(4) 118.0(11)

C(15)-C(20) 1.381(15) C(8)-C(3)-C(2) 121.5(10)

C(15)-C(16) 1.382(16) C(4)-C(3)-C(2) 120.5(11)

C(19)-C(18) 1.385(17) C(12)-C(11)-C(10) 120.0(12)

C(19)-C(20) 1.389(15) N(3)-C(2)-C(1) 108.3(9)

C(7)-C(6) 1.408(16) N(3)-C(2)-C(3) 122.6(9)

C(7)-C(8) 1.409(16) C(1)-C(2)-C(3) 129.0(10)

C(18)-C(17) 1.362(16) C(11)-C(12)-C(13) 121.2(12)

C(17)-C(16) 1.397(15) C(6)-C(5)-C(4) 122.7(11)

C(8)-C(3) 1.393(16) C(13)-C(14)-C(9) 120.9(12)

C(22)-C(23) 1.399(16) C(14)-C(13)-C(12) 118.7(12)

C(23)-C(24) 1.376(18) C(5)-C(6)-C(7) 121.0(11)

C(3)-C(4) 1.402(16) C(3)-C(4)-C(5) 118.5(12)

C(3)-C(2) 1.452(15) N(5)-C(27)-C(28) 102.1(9)

C(11)-C(12) 1.355(18) N(5)-C(27)-Au(2) 121.5(7)

C(12)-C(13) 1.405(18) C(28)-C(27)-Au(2) 136.2(8)

C(5)-C(6) 1.339(17) C(30)-C(29)-C(34) 120.1(11)

C(5)-C(4) 1.409(16) C(30)-C(29)-C(28) 122.5(10)

C(14)-C(13) 1.384(17) C(34)-C(29)-C(28) 117.3(10)

182

C(27)-C(28) 1.384(14) C(48)-C(47)-C(52) 118.0(11)

C(29)-C(30) 1.345(15) C(48)-C(47)-P(2) 125.0(10)

C(29)-C(34) 1.398(15) C(52)-C(47)-P(2) 116.8(9)

C(29)-C(28) 1.495(15) C(40)-C(35)-C(36) 116.3(10)

C(47)-C(48) 1.379(16) C(40)-C(35)-P(2) 125.7(9)

C(47)-C(52) 1.415(17) C(36)-C(35)-P(2) 117.9(9)

C(35)-C(40) 1.392(16) C(46)-C(45)-C(44) 119.1(13)

C(35)-C(36) 1.422(15) C(37)-C(36)-C(35) 120.5(11)

C(45)-C(46) 1.358(17) C(29)-C(30)-C(31) 119.5(11)

C(45)-C(44) 1.382(18) C(46)-C(41)-C(42) 118.4(12)

C(36)-C(37) 1.407(15) C(46)-C(41)-P(2) 123.9(10)

C(30)-C(31) 1.400(15) C(42)-C(41)-P(2) 117.6(9)

C(41)-C(46) 1.364(16) N(8)-C(33)-C(34) 121.6(12)

C(41)-C(42) 1.385(17) N(8)-C(33)-C(32) 122.0(12)

C(33)-C(34) 1.418(16) C(34)-C(33)-C(32) 116.4(10)

C(33)-C(32) 1.423(18) C(31)-C(32)-C(33) 119.8(11)

C(32)-C(31) 1.370(18) C(39)-C(40)-C(35) 122.8(12)

C(40)-C(39) 1.374(16) N(7)-C(28)-C(27) 109.5(10)

C(37)-C(38) 1.359(18) N(7)-C(28)-C(29) 119.6(10)

C(39)-C(38) 1.376(19) C(27)-C(28)-C(29) 130.8(10)

C(25)-C(26) 1.385(18) C(38)-C(37)-C(36) 119.8(12)

C(25)-C(24) 1.426(18) C(45)-C(46)-C(41) 122.5(13)

C(49)-C(50) 1.368(17) C(40)-C(39)-C(38) 119.5(12)

183

C(49)-C(48) 1.386(17) C(32)-C(31)-C(30) 122.2(12)

C(43)-C(44) 1.339(18) C(26)-C(25)-C(24) 119.7(12)

C(43)-C(42) 1.416(18) C(37)-C(38)-C(39) 121.0(12)

C(53)-C(54) 1.363(14) C(50)-C(49)-C(48) 118.0(12)

C(61)-C(62) 1.392(17) C(29)-C(34)-C(33) 121.9(11)

C(61)-C(66) 1.416(17) C(44)-C(43)-C(42) 119.9(14)

C(66)-C(65) 1.363(18) C(21)-C(26)-C(25) 122.0(12)

C(67)-C(68) 1.355(16) C(43)-C(44)-C(45) 120.8(12)

C(67)-C(72) 1.404(17) C(41)-C(42)-C(43) 119.4(13)

C(54)-C(55) 1.449(16) C(47)-C(48)-C(49) 121.8(12)

C(59)-C(60) 1.338(18) N(9)-C(53)-C(54) 104.1(9)

C(59)-C(58) 1.39(2) N(9)-C(53)-Au(3) 122.7(8)

C(62)-C(63) 1.412(17) C(54)-C(53)-Au(3) 133.3(9)

C(56)-C(57) 1.399(17) C(62)-C(61)-C(66) 118.5(12)

C(56)-C(55) 1.411(16) C(62)-C(61)-P(3) 117.4(9)

C(69)-C(70) 1.33(2) C(66)-C(61)-P(3) 124.1(10)

C(69)-C(68) 1.382(17) C(65)-C(66)-C(61) 121.2(13)

C(65)-C(64) 1.36(2) C(68)-C(67)-C(72) 118.6(12)

C(57)-C(58) 1.37(2) C(68)-C(67)-P(3) 123.6(10)

C(57)-N(12) 1.411(17) C(72)-C(67)-P(3) 117.4(9)

C(55)-C(60) 1.430(16) C(53)-C(54)-N(11) 109.9(10)

C(71)-C(70) 1.38(2) C(53)-C(54)-C(55) 129.3(10)

C(71)-C(72) 1.389(18) N(11)-C(54)-C(55) 120.2(10)

184

C(64)-C(63) 1.387(17) C(60)-C(59)-C(58) 120.3(13)

C(52)-C(51) 1.374(17) C(61)-C(62)-C(63) 118.5(11)

C(51)-C(50) 1.373(19) C(57)-C(56)-C(55) 120.4(12)

C(73)-C(74) 1.389(17) C(70)-C(69)-C(68) 120.6(13)

C(73)-C(78) 1.406(18) C(66)-C(65)-C(64) 120.9(14)

C(74)-C(75) 1.389(19) C(58)-C(57)-C(56) 120.3(13)

C(78)-C(77) 1.381(17) C(58)-C(57)-N(12) 122.0(13)

C(77)-C(76) 1.433(19) C(56)-C(57)-N(12) 117.7(13)

C(76)-C(75) 1.37(2) C(56)-C(55)-C(60) 116.6(12)

C(56)-C(55)-C(54) 120.6(10)

C(1)-Au(1)-P(1) 177.5(3) C(60)-C(55)-C(54) 122.8(11)

C(27)-Au(2)-P(2) 172.9(3) C(70)-C(71)-C(72) 120.4(13)

C(53)-Au(3)-P(3) 177.2(3) C(69)-C(70)-C(71) 119.5(13)

C(35)-P(2)-C(47) 103.0(6) C(71)-C(72)-C(67) 118.9(12)

C(35)-P(2)-C(41) 107.9(5) C(65)-C(64)-C(63) 119.3(14)

C(47)-P(2)-C(41) 104.0(5) C(59)-C(60)-C(55) 122.1(13)

C(35)-P(2)-Au(2) 111.2(4) C(57)-C(58)-C(59) 120.2(14)

C(47)-P(2)-Au(2) 118.9(4) C(64)-C(63)-C(62) 121.0(13)

C(41)-P(2)-Au(2) 111.0(4) C(67)-C(68)-C(69) 121.3(13)

C(9)-P(1)-C(21) 109.0(5) C(51)-C(52)-C(47) 120.5(12)

C(9)-P(1)-C(15) 105.5(5) C(23)-C(24)-C(25) 118.9(12)

C(21)-P(1)-C(15) 104.4(5) C(50)-C(51)-C(52) 118.7(12)

C(9)-P(1)-Au(1) 115.4(4) C(49)-C(50)-C(51) 122.7(13)

185

C(21)-P(1)-Au(1) 112.5(4) C(74)-C(73)-C(78) 120.5(12)

C(15)-P(1)-Au(1) 109.2(4) C(74)-C(73)-P(3) 122.3(11)

C(61)-P(3)-C(67) 104.5(6) C(75)-C(74)-C(73) 119.7(15)

C(61)-P(3)-C(73) 104.3(6) C(77)-C(78)-C(73) 121.5(12)

C(67)-P(3)-C(73) 106.5(6) C(78)-C(77)-C(76) 116.0(13)

C(61)-P(3)-Au(3) 116.7(4) C(75)-C(76)-C(77) 123.2(13)

C(67)-P(3)-Au(3) 110.3(4) C(76)-C(75)-C(74) 119.1(14)

186

11. X-Ray Crystal Data for [(PPh3)Au(4-methoxyphenyltriazole)]

Table AI-11a. Crystal data for JU10907 Table AI-11b. Data collection C27H23AuN3OP Bruker SMART CCD area-detector

Mr = 633.42 diffractometer

Tetragonal, P4(3) ω scans a = 13.9165(5) Å Absorption correction: multi-scan b = 13.9165(5) Å Tmin = 0.2654, Tmax = 0.6445 c = 12.8078(7) Å 21833 measured reflections

α = 90 º 5506 independent reflections

β =90 º 4625 reflections with I > 2σ(I)

γ =90 º R int = 0.0375

V = 2480.47(19) Å3 θ max = 27.49º

Z = 4 h = -18 → 18

Dx = 1.696 Mg m-3 k = -18 → 17

Mo Kα radiation l = -15 → 16

Cell parameters from 5367 reflections

θ = 2.16±27.85º

μ = 6.019 mm-1

T = 298(2) K irregular, clear

0.30 x 0.16 x 0.08 mm

187

Table AI-11c. Refinement Figure AI-11a. ORTEP plot of title compound. Ellipsoids are at the 50% probability level. Hydrogen atoms omitted.

Refinement on F2

R[F2 > 2σ(F2)] = 0.0252 wR(F2) = 0.0484

S = 0.986

5506 reflections

299 parameters

H-atom parameters constrained

2 2 2 w = 1/[σ (Fo ) + (0.0097P) + 0.0000P]

2 2 where P = (Fo + 2Fc )/3

(Δ/σ)max = 0.062

-3 Δρmax = 0.555 e×Å

-3 Δρmin = -0.302 e×Å

Table AI-11d Selected geometric parameters (Å, º). Au(1)-C(1) 2.025(4) C(1)-Au(1)-P(1) 175.20(12)

Au(1)-P(1) 2.2798(12) C(22)-P(1)-C(10) 106.0(3)

P(1)-C(22) 1.803(5) C(22)-P(1)-C(16) 105.8(2)

P(1)-C(10) 1.814(5) C(10)-P(1)-C(16) 105.1(2)

P(1)-C(16) 1.819(5) C(22)-P(1)-Au(1) 114.82(18)

C(1)-N(1) 1.346(5) C(10)-P(1)-Au(1) 110.32(18)

C(1)-C(2) 1.391(6) C(16)-P(1)-Au(1) 113.99(15)

188

C(2)-N(3) 1.361(5) N(1)-C(1)-C(2) 101.9(4)

C(2)-C(3) 1.467(6) N(1)-C(1)-Au(1) 124.6(3)

N(2)-N(3) 1.325(5) C(2)-C(1)-Au(1) 133.4(3)

N(2)-N(1) 1.336(5) N(3)-C(2)-C(1) 109.7(4)

C(3)-C(8) 1.373(7) N(3)-C(2)-C(3) 121.2(4)

C(3)-C(4) 1.399(7) C(1)-C(2)-C(3) 129.0(4)

C(4)-C(5) 1.369(7) N(3)-N(2)-N(1) 106.2(4)

C(7)-C(6) 1.357(8) N(2)-N(1)-C(1) 113.9(4)

C(7)-C(8) 1.397(8) N(2)-N(3)-C(2) 108.3(3)

C(11)-C(10) 1.388(8) C(8)-C(3)-C(4) 115.8(5)

C(11)-C(12) 1.390(10) C(8)-C(3)-C(2) 123.4(4)

C(12)-C(13) 1.323(12) C(4)-C(3)-C(2) 120.8(4)

C(10)-C(15) 1.370(7) C(5)-C(4)-C(3) 122.0(5)

C(15)-C(14) 1.399(9) C(6)-C(7)-C(8) 119.6(6)

C(16)-C(21) 1.359(8) C(3)-C(8)-C(7) 121.8(5)

C(16)-C(17) 1.375(6) C(10)-C(11)-C(12) 120.0(7)

C(17)-C(18) 1.370(8) C(13)-C(12)-C(11) 120.1(9)

C(23)-C(22) 1.375(8) C(15)-C(10)-C(11) 118.2(6)

C(23)-C(24) 1.380(8) C(15)-C(10)-P(1) 123.2(5)

C(22)-C(27) 1.348(9) C(11)-C(10)-P(1) 118.6(4)

C(5)-C(6) 1.342(8) C(10)-C(15)-C(14) 120.3(7)

C(6)-O(1) 1.381(7) C(21)-C(16)-C(17) 117.0(6)

O(1)-C(9) 1.306(9) C(21)-C(16)-P(1) 123.1(4)

189

C(13)-C(14) 1.342(11) C(17)-C(16)-P(1) 119.9(4)

C(19)-C(20) 1.329(9) C(18)-C(17)-C(16) 120.2(6)

(19)-C(18) 1.336(8) C(22)-C(23)-C(24) 119.8(7)

C(20)-C(21) 1.382(9) C(27)-C(22)-C(23) 118.5(5)

C(24)-C(25) 1.362(12) C(27)-C(22)-P(1) 117.9(5)

C(25)-C(26) 1.320(12) C(23)-C(22)-P(1) 123.5(5)

C(27)-C(26) 1.410(10) C(6)-C(5)-C(4) 120.5(6)

C(5)-C(6)-C(7) 120.3(5)

C(5)-C(6)-O(1) 115.2(5)

C(7)-C(6)-O(1) 124.6(6)

C(9)-O(1)-C(6) 121.1(6)

C(12)-C(13)-C(14) 122.0(8)

C(13)-C(14)-C(15) 119.4(8)

C(20)-C(19)-C(18) 118.4(6)

C(19)-C(20)-C(21) 121.4(7)

C(19)-C(18)-C(17) 122.1(6)

C(16)-C(21)-C(20) 120.9(6)

C(25)-C(24)-C(23) 121.0(8)

C(26)-C(25)-C(24) 119.6(8)

C(22)-C(27)-C(26) 120.8(7)

C(25)-C(26)-C(27) 120.3(9)

190

12. X-Ray Crystal Data for [(PCy3)Au(4-methoxyphenyltriazole)]

Table AI-12a. Crystal data for nd030509 Table AI-12b. Data collection C27H41AuN3PO Bruker SMART CCD area-detector

Mr = 651.56 diffractometer

Monoclinic, P2(1)/c ω scans a = 13.0682(16) Å Absorption correction: multi-scan b = 28.854(3) Å Tmin = 0.2124, Tmax = 0.4983 c = 21.952(3) Å 98406 measured reflections

α = 90 º 19391 independent reflections

β = 102.4510(10) º 16924 reflections with I > 2σ(I)

γ = 90 º R int = 0.0314

V = 8082.8(17) Å3 θ max = 28.12º

Z = 12 h = -16 → 17

Dx = 1.606 Mg m-3 k = -37 → 37

Mo Kα radiation l = -28 → 29

Cell parameters from 9894 reflections

θ = 2.20±28.04º

μ = 5.543 mm-1

T = 100 (2) K

Irregular, colorless

0.41 x 0.18 x 0.15 mm

191

Table AI-12c. Refinement Figure AI-12a. ORTEP plot of title compound. Ellipsoids are at the 50% probability level. Hydrogen atoms omitted.

Refinement on F2

R[F2 > 2σ(F2)] = 0.0221 wR(F2) = 0.0529

S = 1.058

19391 reflections

895 parameters

H-atom parameters constrained

2 2 2 w = 1/[σ (Fo ) + (0.0323P) + 7.0977P] where P = (F 2 + 2Fc2)/3 o (Δ/σ)max = 0.140

Δρmax = 2.150 e×Å-3

-3 Δρmin = -0.851 e×Å

Table AI-12d Selected geometric parameters (Å, º). Au1-C1 2.047(3) C1-Au1-P4 177.98(8)

Au1-P4 2.2928(7) C55-Au2-P5 178.24(8)

Au2-C55 2.030(3) C28-Au3-P6 177.81(8)

Au2-P5 2.2883(8) C16-P4-C10 105.56(13)

Au3-C28 2.023(3) C16-P4-C22 105.64(13)

Au3-P6 2.2775(8) C10-P4-C22 108.63(13)

P4-C16 1.840(3) C16-P4-Au1 109.88(9)

192

P4-C10 1.843(3) C10-P4-Au1 111.69(9)

P4-C22 1.850(3) C22-P4-Au1 114.87(9)

P5-C76 1.837(3) C76-P5-C64 106.63(14)

P5-C64 1.844(3) C76-P5-C70 107.03(14)

P5-C70 1.853(3) C64-P5-C70 109.11(13)

P6-C49 1.838(3) C76-P5-Au2 112.91(10)

P6-C37 1.836(3) C64-P5-Au2 109.85(10)

P6-C43 1.848(3) C70-P5-Au2 111.12(10)

N3-N2 1.308(4) C49-P6-C37 105.70(14)

N3-C2 1.372(4) C49-P6-C43 112.72(14)

N2-N1 1.343(3) C37-P6-C43 106.30(14)

N1-C1 1.355(4) C49-P6-Au3 110.53(10)

C1-C2 1.391(4) C37-P6-Au3 112.05(10)

C22-C23 1.530(4) C43-P6-Au3 109.45(10)

C22-C27 1.545(4) N2-N3-C2 108.4(2)

C16-C21 1.536(4) N3-N2-N1 106.6(2)

C16-C17 1.538(4) N2-N1-C1 113.7(2)

N9-N8 1.338(3) N1-C1-C2 101.4(2)

N9-C28 1.358(4) N1-C1-Au1 121.1(2)

N7-N8 1.331(3) C2-C1-Au1 137.4(2)

N7-C29 1.361(4) C23-C22-C27 110.6(2)

C28-C29 1.390(4) C23-C22-P4 113.08(19)

C76-C81 1.532(4) C27-C22-P4 114.81(19)

193

C76-C77 1.540(4) C21-C16-C17 110.2(2)

N4-N5 1.319(3) C21-C16-P4 110.25(19)

N4-C56 1.367(4) C17-C16-P4 116.3(2)

N5-N6 1.338(3) N8-N9-C28 113.8(2)

N6-C55 1.360(4) N8-N7-C29 109.0(2)

C62-C61 1.388(4) N9-N8-N 105.7(2)

C62-C57 1.399(4) N9-C28-C29 102.0(2)

C61-C60 1.384(4) N9-C28-Au3 123.5(2)

C70-C71 1.541(4) C29-C28-Au3 134.4(2)

C70-C75 1.542(4) C81-C76-C77 110.2(3)

C57-C58 1.393(4) C81-C76-P5 115.8(2)

C57-C56 1.476(4) C77-C76-P5 111.2(2)

C74-C75 1.525(4) N5-N4-C56 108.9(2)

C74-C73 1.528(4) N4-N5-N6 106.1(2)

C56-C55 1.386(4) N5-N6-C55 113.7(2)

O2-C60 1.383(4) C61-C62-C57 120.8(3)

O2-C63 1.421(4) C60-C61-C62 120.1(3)

C59-C58 1.388(4) C71-C70-C75 110.9(2)

C59-C60 1.384(4) C71-C70-P5 116.0(2)

C64-C65 1.538(4) C75-C70-P5 109.57(19)

C64-C69 1.541(4) C58-C57-C62 117.9(3)

C81-C80 1.528(5) C58-C57-C56 120.9(3)

C27-C26 1.528(4) C62-C57-C56 121.2(3)

194

C23-C24 1.533(4) C75-C74-C73 111.4(2)

C3-C4 1.382(4) N4-C56-C55 109.5(3)

C3-C8 1.400(4) N4-C56-C57 120.6(3)

C3-C2 1.471(4) C55-C56-C57 129.9(3)

C21-C20 1.535(4) C74-C75-C70 111.8(2)

C65-C66 1.535(4) C60-O2-C63 116.3(2)

C8-C7 1.377(4) C58-C59-C60 119.6(3)

C17-C18 1.533(4) C61-C60-O2 116.5(3)

C15-C10 1.526(4) C61-C60-C59 120.0(3)

C15-C14 1.531(4) O2-C60-C59 123.5(3)

C10-C11 1.543(4) C65-C64-C69 109.8(3)

C11-C12 1.529(4) C65-C64-P5 110.0(2)

C26-C25 1.529(4) C69-C64-P5 110.3(2)

C29-C30 1.475(4) C80-C81-C76 111.0(3)

C30-C35 1.394(4) N6-C55-C56 101.8(2)

C30-C31 1.390(4) N6-C55-Au2 123.8(2)

C35-C34 1.375(4) C56-C55-Au2 134.2(2)

C12-C13 1.524(5) C26-C27-C22 110.3(2)

C38-C39 1.524(5) C22-C23-C24 110.1(2)

C38-C37 1.546(4) C4-C3-C8 117.5(3)

C43-C48 1.524(4) C4-C3-C2 121.2(3)

C43-C44 1.529(5) C8-C3-C2 121.2(3)

C37-C42 1.538(4) C16-C21-C20 111.1(2)

195

C77-C78 1.533(4) C66-C65-C64 112.1(3)

C71-C72 1.535(4) N3-C2-C1 109.9(3)

C73-C72 1.528(4) N3-C2-C3 121.5(3)

C54-C53 1.531(4) C1-C2-C3 128.6(3)

C54-C49 1.538(4) C7-C8-C3 120.9(3)

C49-C50 1.530(4) C18-C17-C16 109.9(2)

C69-C68 1.530(4) C10-C15-C14 111.6(3)

C50-C51 1.531(4) C15-C10-C11 109.9(2)

O1-C33 1.376(4) C15-C10-P4 111.2(2)

O1-C36 1.421(4) C11-C10-P4 110.72(19)

C33-C34 1.382(5) C12-C11-C10 111.5(2)

C33-C32 1.384(5) C27-C26-C25 111.1(3)

C32-C31 1.399(4) N7-C29-C28 109.5(3)

C18-C19 1.523(5) N7-C29-C30 120.7(3)

C20-C19 1.527(4) C28-C29-C30 129.7(3)

C6-O3 1.370(4) C35-C30-C31 117.5(3)

C6-C5 1.379(4) C35-C30-C29 121.8(3)

C6-C7 1.389(4) C31-C30-C29 120.7(3)

C53-C52 1.522(5) C34-C35-C30 121.3(3)

C24-C25 1.529(4) C11-C12-C13 110.8(3)

C5-C4 1.391(4) C39-C38-C37 112.1(3)

C42-C41 1.520(5) C48-C43-C44 111.2(3)

C39-C40 1.527(5) C48-C43-P6 117.6(2)

196

C52-C51 1.524(5) C44-C43-P6 112.1(2)

C40-C41 1.515(5) C42-C37-C38 108.8(3)

C48-C47 1.532(5) C42-C37-P6 111.0(2)

C13-C14 1.518(5) C38-C37-P6 110.5(2)

C45-C46 1.524(6) C78-C77-C76 110.9(3)

C45-C44 1.535(5) C72-C71-C70 110.6(2)

C47-C46 1.518(6) C72-C73-C74 110.0(3)

C79-C80 1.520(5) C50-C49-C54 110.1(3)

C68-C67 1.522(5) C50-C49-P6 117.2(2)

O3-C9 1.414(4) C54-C49-P6 113.7(2)

C68-C69-C64 112.2(3)

C49-C50-C51 110.0(3)

C33-O1-C36 117.4(3)

O1-C33-C34 115.9(3)

O1-C33-C32 124.2(3)

C34-C33-C32 119.9(3)

C33-C32-C31 119.0(3)

C19-C18-C17 110.5(3)

C19-C20-C21 110.9(2)

C18-C19-C20 111.4(3)

C77-C78-C79 111.0(3)

C67-C66-C65 111.3(3)

C35-C34-C33 120.5(3)

197

O3-C6-C5 124.1(3)

O3-C6-C7 115.6(3)

C5-C6-C7 120.2(3)

C52-C53-C54 111.0(3)

C8-C7-C6 120.2(3)

C25-C24-C23 111.0(2)

C6-C5-C4 118.7(3)

C3-C4-C5 122.4(3)

C41-C42-C37 111.0(3)

C38-C39-C40 111.5(3)

C53-C52-C51 111.4(3)

C41-C40-C39 111.2(3)

C40-C41-C42 111.3(3)

C43-C48-C47 110.9(3)

C14-C13-C12 110.9(3)

C13-C14-C15 111.7(3)

C46-C45-C44 110.6(3)

C43-C44-C45 110.7(3)

C46-C47-C48 111.4(3)

C50-C51-C52 112.1(3)

C80-C79-C78 111.8(3)

C79-C80-C81 111.1(3)

C30-C31-C32 121.7(3)

198

C67-C68-C69 111.8(3)

C68-C67-C66 111.2(3)

C24-C25-C26 110.4(2)

C73-C72-C71 110.6(2)

C59-C58-C57 121.6(3)

C6-O3-C9 117.3(3)

C47-C46-C45 110.1(3)

199

13. X-Ray Crystal Data for [7-{[(1,3-dimethyl-4,5- dichlorocarbene)Au(propargyloxy)][methoxy]}coumarin]

Table AI-13a. Crystal data for nd022410 Table AI-13b. Data collection C20H16AuCl2N2O3 Bruker SMART CCD area-detector

Mr = 600.21 diffractometer

Monoclinic, P2(1)/c ω scans a = 18.6675(15) Å Absorption correction: multi-scan b = 7.1299(6) Å Tmin = 0.2935, Tmax = 0.7647 c = 15.0132(12) Å 23164 measured reflections

α = 90 º 4713 independent reflections

β = 92.5000(10) º 3652 reflections with I > 2σ(I)

γ = 90 º R int = 0.0491

V = 1996.3(3) Å3 θ max = 27.92º

Z = 4 h = -24 → 24

Dx = 1.997 Mg m-3 k = -9 → 9

Mo Kα radiation l = -19 → 19

Cell parameters from 5286 reflections

θ = 2.72±23.65º

μ = 7.661 mm-1

T = 170 (2) K

Irregular, brown

0.21 x 0.09 x 0.04 mm

200

Table AI-13c. Refinement Figure AI-13a. ORTEP plot of title compound. Ellipsoids are at the 50% probability level. Hydrogen atoms omitted.

Refinement on F2

R[F2 > 2σ(F2)] = 0.0277 wR(F2) = 0.0621

S = 1.069

16364 reflections

865 parameters

H-atom parameters constrained

2 2 2 w = 1/[σ (Fo ) + (0.0408P) + 0.0000P]

2 2 where P = (Fo + 2Fc )/3

(Δ/σ)max = 0.153

Δρmax = 1.498 e×Å-3

-3 Δρmin = -0.716 e×Å

Table AI-13d Selected geometric parameters (Å, º). Au1-C6 1.982(5) C6-Au1-C1 177.3(2)

Au1-C1 2.013(5) C1-N1-C2 110.7(4)

Cl1-C2 1.698(5) C1-N1-C4 124.7(4)

Cl2-C3 1.698(5) C2-N1-C4 124.6(4)

N1-C1 1.346(6) C1-N2-C3 110.5(4)

N1-C2 1.375(6) C1-N2-C5 124.6(5)

N1-C4 1.462(6) C3-N2-C5 125.0(5)

201

N2-C1 1.358(6) C9-O1-C8 117.4(4)

N2-C3 1.371(6) O1-C9-C17 123.7(4)

N2-C5 1.474(7) O1-C9-C10 114.8(4)

O1-C9 1.361(6) C17-C9-C10 121.5(5)

O1-C8 1.431(6) C7-C6-Au1 174.4(5)

C9-C17 1.390(7) N1-C1-N2 104.9(4)

C9-C10 1.390(7) N1-C1-Au1 127.1(4)

C6-C7 1.186(7) N2-C1-Au1 127.9(4)

C16-O2 1.378(6) O2-C16-C12 120.8(5)

C16-C12 1.383(7) O2-C16-C17 116.3(5)

C16-C17 1.388(7) C12-C16-C17 122.8(5)

C12-C11 1.395(7) C16-C12-C11 117.9(5)

C12-C13 1.439(7) C16-C12-C13 118.1(5)

C10-C11 1.376(7) C11-C12-C13 123.9(5)

C3-C2 1.341(7) C11-C10-C9 119.3(5)

C7-C8 1.471(7) C2-C3-N2 107.0(5)

C13-C14 1.323(8) C2-C3-Cl2 130.1(4)

C14-C15 1.435(9) N2-C3-Cl2 122.9(4)

C15-O3 1.194(7) C10-C11-C12 121.1(5)

C15-O2 1.382(7) C6-C7-C8 176.8(5)

C19-C20 1.339(10) C3-C2-N1 107.0(4)

C19-C18 1.364(12) C3-C2-Cl1 129.6(4)

C18-C20 1.356(11) N1-C2-Cl1 123.4(4)

202

C20-C18 1.356(11) O1-C8-C7 108.9(4)

C16-C17-C9 117.4(5)

C14-C13-C12 120.0(6)

C13-C14-C15 122.5(5)

O3-C15-O2 117.0(6)

O3-C15-C14 126.4(6)

O2-C15-C14 116.6(5)

C16-O2-C15 121.8(5)

C20-C19-C18 120.0(7)

C20-C18-C19 119.0(7)

C19-C20-C18 121.0(8)

203

14. X-Ray Crystal Data for [Au([18]aneS6)][SbF6]

Table AI-14a. Crystal data for Table AI-14b. Data collection 07mz142m C13H26AuCl2F6S6Sb Bruker SMART CCD area-detector

Mr = 878.31 diffractometer

Monoclinic, P2(1)/c ω scans a = 5.2007(4) Å Absorption correction: multi-scan b = 17.2256(14) Å Tmin = 0.433, Tmax = 0.683 c = 28.170(2) Å 18825 measured reflections

α = 90 º 6095 independent reflections

β = 90.722(2) º 4713 reflections with I > 2σ(I)

γ = 90 º R int = 0.0687

V = 2523.4(4) Å3 θ max = 28.28º

Z = 4 h = -6 → 6

Dx = 2.312 Mg m-3 k = -18 → 22

Mo Kα radiation l = -37 → 37

Cell parameters from 5793 reflections

θ = 2.47±30.53º

μ = 7.631 mm-1

T = 100 (2) K needle, colorless

0.55 x 0.09 x 0.05 mm

204

Table AI-14c. Refinement Figure AI-14a. ORTEP plot of title compound. Ellipsoids are at the 50% - probability level. SbF6 counter ion omitted for clarity. Hydrogen atoms omitted.

Refinement on F2

R[F2 > 2σ(F2)] = 0.0602 wR(F2) = 0.1046

S = 1.171

6095 reflections

317 parameters

H-atom parameters constrained

2 2 2 w = 1/[σ (Fo ) + (0.0249P) + 8.1661P]

2 2 where P = (Fo + 2Fc )/3

(Δ/σ)max = 0.228

Δρmax = 2.037 e×Å-3

Δρmin = -1.121 e×Å-3

Table AI-14d Selected geometric parameters (Å, º). Au1-S5 2.307(2) S5-Au1-S2 164.38(8)

Au1-S2 2.321(2) S5-Au1-S3 106.29(7)

Au1-S3 2.889(2) S2-Au1-S3 84.10(7)

Au1-S1 2.889(2) S5-Au1-S1 107.05(7)

C1-C2 1.530(11) S2-Au1-S1 84.01(7)

C1-S1 1.804(9) S3-Au1-S1 90.61(6)

205

C2-S2 1.799(8) C2-C1-S1 116.1(6)

C3-C4 1.529(11) C1-C2-S2 118.6(6)

C3-S2 1.809(9) C4-C3-S2 117.8(6)

C4-S3 1.814(9) C3-C4-S3 116.9(6)

C5-C6 1.516(13) C6-C5-S3 111.3(6)

C5-S3 1.815(9) C5-C6-S4 116.9(7)

C6-S4 1.800(10) C8-C7-S4 110.0(6)

C7-C8 1.525(12) C7-C8-S5 112.1(6)

C7-S4 1.814(8) C10-C9-S5 111.9(6)

C8-S5 1.823(9) C9-C10-S6 111.8(6)

C9-C10 1.506(12) C12-C11-S6 116.4(6)

C9-S5 1.820(9) C11-C12-S1 110.9(6)

C10-S6 1.796(8) F3-Sb1-F2 91.0(8)

C11-C12 1.508(14) F3-Sb1-F6 89.7(7)

C11-S6 1.807(10) F2-Sb1-F6 89.7(6)

C12-S1 1.808(8) F3-Sb1-F1 90.7(7)

Sb1-F3 1.835(19) F2-Sb1-F1 90.1(6)

Sb1-F2 1.863(13) F6-Sb1-F1 179.5(5)

Sb1-F6 1.868(12) F3-Sb1-F5 179.6(8)

Sb1-F1 1.870(13) F2-Sb1-F5 89.4(6)

Sb1-F5 1.872(10) F6-Sb1- F5 90.1(5)

Sb1-F4 1.877(11) F1-Sb1-F5 89.5(5)

C13-Cl1 1.77(2) F3-Sb1-F4 90.0(8)

206

C13-Cl2 1.780(19) F2-Sb1-F4 179.0(6)

Sb2-F11 1.85(4) F6-Sb1-F4 90.3(5)

Sb2-F10 1.858(13) F1-Sb1-F4 89.9(5)

Sb2-F12 1.862(12) F5-Sb1-F4 89.6(5)

Sb2-F9 1.866(10) Cl1-C13-Cl2 111.7(16)

Sb2-F7 1.872(11) F11-Sb2-F10 89.4(10)

Sb2-F8 1.882(10) F11-Sb2-F12 89.5(13)

F7-F12 1.484(13) F10-Sb2-F12 90.4(6)

F12-F7 1.484(13) F11-Sb2-F9 178.9(11)

C14-Cl3 1.76(2) F10-Sb2-F9 89.5(5)

C14-Cl4 1.78(2) F12-Sb2-F9 90.9(5)

F11-Sb2-F7 90.3(13)

F10-Sb2-F7 90.0(6)

F12-Sb2-F7 179.6(5)

F9-Sb2-F7 89.3(5)

F11-Sb2-F8 92.3(10)

F10-Sb2-F8 178.2(6)

F12-Sb2-F8 90.1(5)

F9-Sb2-F8 88.8(5)

F7-Sb2-F8 89.5(5)

F12-F7-Sb2 169.7(9)

F7-F12-Sb2 169.9(9)

Cl3-C14-Cl4 111.5(14)

207

C1-S1-C12 99.4(4)

C1-S1-Au1 95.0(3)

C12-S1-Au1 102.9(3)

C2-S2-C3 106.6(4)

C2-S2-Au1 106.8(3)

C3-S2-Au1 107.8(3)

C4-S3-C5 99.8(4)

C4-S3-Au1 94.5(3)

C5-S3-Au1 101.4(3)

C6-S4-C7 100.6(4)

C9-S5-C8 98.2(4)

C9-S5-Au1 107.2(3)

C8-S5-Au1 107.4(3)

C10-S6-C11 101.1(4)

208

15. X-Ray Crystal Data for [Au3([18]aneS6)2][SbF6]3

Table AI-15a. Crystal data for Table AI-15b. Data collection 07mz143m C25H50Au3Cl2F18S12Sb3 Bruker SMART CCD area-detector

Mr = 2104.42 diffractometer

Triclinic, P-1 ω scans a = 11.6724(15) Å Absorption correction: multi-scan b = 11.7190(15) Å Tmin = 0.223, Tmax = 0.351 c = 20.219(3) Å 27736 measured reflections

α = 86.160(2) º 13080 independent reflections

β = 88.086(2) º 12139 reflections with I > 2σ(I)

γ = 73.294(2) º R int = 0.0349

V = 2642.7(6) Å3 θ max = 28.28º

Z = 2 h = -15 → 15

Dx = 2.645 Mg m-3 k = -15 → 15

Mo Kα radiation l = -26 → 26

Cell parameters from 7286 reflections

θ = 2.635±30.525º

μ = 10.470 mm-1

T = 100 (2) K block, colorless

0.17 x 0.14 x 0.10 mm

209

Table AI-15c. Refinement Figure AI-15a. ORTEP plot of title compound. Ellipsoids are at the 50% probability level. Counter ions omitted for clarity. Hydrogen atoms omitted.

Refinement on F2

R[F2 > 2σ(F2)] = 0.0405 wR(F2) = 0.0876

S = 1.140

13080 reflections

700 parameters

H-atom parameters constrained

2 2 2 w = 1/[σ (Fo ) + (0.0148P) + 18.5853P]

2 2 where P = (Fo + 2Fc )/3

(Δ/σ)max = 0.193

Δρmax = 1.775 e×Å-3

Δρmin = -1.743 e×Å-3

Table AI-15d Selected geometric parameters (Å, º). Au1-S5 2.3270(16) S5-Au1-S5 180.00(4)

Au1-S5 2.3270(16) S5-Au1-Au2 93.42(4)

Au1-Au2 3.0368(5) S5-Au1-Au2 86.58(4)

Au1-Au2 3.0368(4) S5-Au1-Au2 86.58(4)

Au2-S1 2.3325(17) S5-Au1-Au2 93.42(4)

Au2-S4 2.3474(17) Au2-Au1-Au2 180.0

210

Au2-S3 2.8301(16) S1-Au2-S4 159.58(6)

Au2-S2 2.9419(17) S1-Au2-S3 114.17(6)

Au3-S11 2.3238(16) S4-Au2-S3 84.49(5)

Au3-S11 2.3238(16) S1-Au2-S2 82.57(6)

Au3-Au4 3.0867(5) S4-Au2-S2 111.60(6)

Au3-Au4 3.0867(5) S3-Au2-S2 74.93(5)

Au4-S7 2.3303(18) S1-Au2-Au1 79.41(4)

Au4-S10 2.3409(19) S4-Au2-Au1 91.88(4)

Au4-S9 2.8174(18) S3-Au2-Au1 93.10(3)

Au4-S8 2.844(2) S2-Au2-Au1 151.95(4)

C1-C2 1.518(13) S11-Au3-S11 180.0

C1-S1 1.800(8) S11-Au3-Au4 86.15(4)

C2-S2 1.818(9) S11-Au3-Au4 93.85(4)

C3-C4 1.508(9) S11-Au3-Au4 93.85(4)

C3-S2 1.812(7) S11-Au3-Au4 86.15(4)

C4-S3 1.819(7) Au4-Au3-Au4 180.0

C5-C6 1.517(10) S7-Au4-S10 164.70(8)

C5-S3 1.805(7) S7-Au4-S9 110.33(7)

C6-S4 1.816(7) S10-Au4-S9 84.53(8)

C7-C8 1.507(9) S7-Au4-S8 84.28(7)

C7-S4 1.825(6) S10-Au4-S8 103.34(8)

C8-S5 1.818(7) S9-Au4-S8 76.50(6)

C9-C10 1.517(10) S7-Au4-Au3 85.90(5)

211

C9-S5 1.818(8) S10-Au4-Au3 89.64(4)

C10-S6 1.794(8) S9-Au4-Au3 93.77(4)

C11-C12 1.533(13) S8-Au4-Au3 162.76(6)

C11-S6 1.876(9) C2-C1-S1 117.1(8)

C12-S1 1.808(10) C1-C2-S2 115.7(6)

C11B-C12B 1.515(15) C4-C3-S2 109.8(5)

C11B-S6 1.779(11) C3-C4-S3 111.2(5)

C12B-S1 1.881(12) C6-C5-S3 115.8(4)

C13-C14 1.508(13) C5-C6-S4 115.7(5)

C13-S7 1.818(8) C8-C7-S4 114.8(5)

C14-S8 1.805(10) C7-C8-S5 117.9(5)

C15A-C16A 1.513(14) C10-C9-S5 111.0(6)

C15A-S8 1.810(12) C9-C10-S6 115.6(5)

C16A-S9 1.844(11) C12-C11-S6 113.0(8)

C15B-C16B 1.538(15) C11-C12-S1 106.8(7)

C15B-S8 1.913(11) C12B-C11B-S6 108.0(10)

C16B-S9 1.850(12) C11B-C12B-S1 116.1(11)

C17-C18 1.545(15) C14-C13-S7 116.7(6)

C17-S9 1.787(10) C13-C14-S8 117.1(6)

C18-S10 1.792(10) C16A-C15A-S8 113.1(10)

C19-C20 1.520(12) C15A-C16A-S9 117.6(10)

C19-S10 1.828(8) C16B-C15B-S8 106.9(10)

C20-S11 1.819(8) C15B-C16B-S9 107.9(10)

212

C21-C22 1.510(14) C18-C17-S9 115.3(6)

C21-S11 1.825(8) C17-C18-S10 116.1(6)

C22-S12 1.818(9) C20-C19-S10 113.4(7)

C23-C24 1.453(14) C19-C20-S11 117.7(5)

C23-S12 1.828(11) C22-C21-S11 110.9(6)

C24-S7 1.811(8) C21-C22-S12 115.4(6)

C25-Cl1 1.750(10) C24-C23-S12 116.2(8)

C25-Cl2 1.767(10) C23-C24-S7 111.7(6)

C25B-Cl1B 1.753(17) Cl1-C25-Cl2 109.7(7)

C25B-Cl2B 1.758(16) Cl1B-C25B-Cl2B 109.1(15)

Sb1A-F15A 1.762(10) C1-S1-C12 97.6(5)

Sb1A-F18A 1.852(11) C1-S1-C12B 107.8(7)

Sb1A-F14A 1.862(11) C1-S1-Au2 106.5(3)

Sb1A-F13A 1.89(2) C12-S1-Au2 117.4(4)

Sb1A-F17A 1.929(12) C12B-S1-Au2 101.7(5)

Sb1A-F16A 1.938(10) C3-S2-C2 102.3(5)

Sb1B-F14B 1.794(13) C3-S2-Au2 98.8(2)

Sb1B-F13B 1.84(2) C2-S2-Au2 94.6(3)

Sb1B-F15B 1.844(10) C5-S3-C4 100.8(3)

Sb1B-F18B 1.874(11) C5-S3-Au2 95.4(2)

Sb1B-F17B 1.893(12) C4-S3-Au2 102.7(2)

Sb1B-F16B 1.963(11) C6-S4-C7 98.4(3)

Sb2B-F3B 1.85(3) C6-S4-Au2 102.2(2)

213

Sb2B-F5B 1.855(13) C7-S4-Au2 111.0(2)

Sb2B-F6B 1.857(9) C8-S5-C9 101.1(3)

Sb2B-F2B 1.868(10) C8-S5-Au1 108.1(2)

Sb2B-F1B 1.869(14) C9-S5-Au1 110.1(3)

Sb2B-F4B 1.884(10) C11B-S6-C10 118.1(6)

Sb2A-F2A 1.859(10) C10-S6-C11 93.4(5)

Sb2A-F5A 1.860(16) C24-S7-C13 100.8(4)

Sb2A-F6A 1.865(10) C24-S7-Au4 110.5(4)

Sb2A-F1A 1.866(14) C13-S7-Au4 104.9(3)

Sb2A-F4A 1.881(10) C14-S8-C15A 122.5(7)

Sb2A-F3A 1.92(6) C14-S8-C15B 90.9(5)

Sb3A-F8A 1.823(10) C14-S8-Au4 95.6(3)

Sb3A-F7A 1.837(10) C15A-S8-Au4 105.4(5)

Sb3A-F11A 1.839(12) C15B-S8-Au4 97.8(4)

Sb3A-F10A 1.848(9) C17-S9-C16A 111.6(6)

Sb3A-F12A 1.863(11) C17-S9-C16B 92.0(6)

Sb3A-F9A 1.867(9) C17-S9-Au4 95.9(3)

Sb3B-F11B 1.806(12) C16A-S9-Au4 102.7(5)

Sb3B-F10B 1.842(8) C16B-S9-Au4 103.7(6)

Sb3B-F9B 1.849(9) C18-S10-C19 100.3(4)

Sb3B-F12B 1.850(12) C18-S10-Au4 100.8(3)

Sb3B-F8B 1.857(9) C19-S10-Au4 112.7(2)

Sb3B-F7B 1.864(10) C20-S11-C21 101.3(4)

214

C20-S11-Au3 107.3(3)

C21-S11-Au3 109.1(3)

C22-S12-C23 96.9(5)

F15A-Sb1A-F18A 94.5(6)

F15A-Sb1A-F14A 96.8(6)

F18A-Sb1A-F14A 92.3(6)

F15A-Sb1A-F13A 90.8(8)

F18A-Sb1A-F13A 173.5(9)

F14A-Sb1A-F13A 90.6(7)

F15A-Sb1A-F17A 176.4(7)

F18A-Sb1A-F17A 85.9(6)

F14A-Sb1A-F17A 86.7(6)

F13A-Sb1A-F17A 88.5(8)

F15A-Sb1A-F16A 92.2(6)

F18A-Sb1A-F16A 88.9(5)

F14A-Sb1A-F16A 170.8(6)

F13A-Sb1A-F16A 87.2(6)

F17A-Sb1A-F16A 84.2(6)

F14B-Sb1B-F13B 93.7(6)

F14B-Sb1B-F15B 99.5(9)

F13B-Sb1B-F15B 93.3(7)

F14B-Sb1B-F18B 88.3(6)

F13B-Sb1B-F18B 174.1(8)

215

F15B-Sb1B-F18B 91.9(5)

F14B-Sb1B-F17B 85.4(9)

F13B-Sb1B-F17B 88.9(8)

F15B-Sb1B-F17B 174.4(8)

F18B-Sb1B-F17B 85.7(5)

F14B-Sb1B-F16B 171.5(9)

F13B-Sb1B-F16B 88.5(6)

F15B-Sb1B-F16B 88.5(8)

F18B-Sb1B-F16B 88.7(5)

F17B-Sb1B-F16B 86.5(8)

F3B-Sb2B-F5B 174(2)

F3B-Sb2B-F6B 95.5(18)

F5B-Sb2B-F6B 90.2(6)

F3B-Sb2B-F2B 92.5(16)

F5B-Sb2B-F2B 89.8(6)

F6B-Sb2B-F2B 92.4(6)

F3B-Sb2B-F1B 82.8(18)

F5B-Sb2B-F1B 91.6(7)

F6B-Sb2B-F1B 178.0(5)

F2B-Sb2B-F1B 86.6(7)

F3B-Sb2B-F4B 86.6(16)

F5B-Sb2B-F4B 91.0(6)

F6B-Sb2B-F4B 89.0(6)

216

F2B-Sb2B-F4B 178.4(5)

F1B-Sb2B-F4B 92.0(7)

F2A-Sb2A-F5A 89.2(7)

F2A-Sb2A-F6A 92.4(6)

F5A-Sb2A-F6A 91.2(7)

F2A-Sb2A-F1A 93.6(7)

F5A-Sb2A-F1A 86.1(7)

F6A-Sb2A-F1A 173.3(7)

F2A-Sb2A-F4A 179.1(7)

F5A-Sb2A-F4A 90.4(7)

F6A-Sb2A-F4A 86.7(6)

F1A-Sb2A-F4A 87.2(7)

F2A-Sb2A-F3A 87(2)

F5A-Sb2A-F3A 174(2)

F6A-Sb2A-F3A 84(2)

F1A-Sb2A-F3A 99(2)

F4A-Sb2A-F3A 94(2)

F8A-Sb3A-F7A 90.3(5)

F8A-Sb3A-F11A 104.6(13)

F7A-Sb3A-F11A 90.7(6)

F8A-Sb3A-F10A 166.4(12)

F7A-Sb3A-F10A 89.8(6)

F11A-Sb3- F10A 89.0(6)

217

F8A-Sb3A-F12A 77.9(12)

F7A-Sb3A-F12A 89.7(6)

F11A-Sb3- F12A 177.5(8)

F10A-Sb3A-F12A 88.5(6)

F8A-Sb3A-F9A 90.6(5)

F7A-Sb3A-F9A 178.6(7)

F11A-Sb3A-F9A 90.1(5)

F10A-Sb3A-F9A 89.1(4)

F12A-Sb3A-F9A 89.5(5)

F11B-Sb3B-F10B 100.3(9)

F11B-Sb3B-F9B 81.7(9)

F10B-Sb3B-F9B 88.7(5)

F11B-Sb3B-F12B 172.9(12)

F10B-Sb3B-F12B 86.2(9)

F9B-Sb3B-F12B 95.9(9)

F11B-Sb3B-F8B 88.8(9)

F10B-Sb3B-F8B 170.9(7)

F9B-Sb3B-F8B 92.2(5)

F12B-Sb3B-F8B 84.7(9)

F11B-Sb3B-F7B 87.9(11)

F10B-Sb3B-F7B 91.8(7)

F9B-Sb3B-F7B 169.6(9)

F12B-Sb3B-F7B 94.6(11)

218

F8B-Sb3B-F7B 89.0(7)

219

Appendix II. NMR Spectra of Synthesized New Compounds

ObserveH1, 399.7467632 MHz Pulse 45.0 degrees Relax. Delay 1.000 sec INOVA Ambient Temperature Solvent: C6D6 Sequence:Pulse s2pul

400

1 Figure AII-1. H NMR Spectrum of [(PCy2(o-biphenyl))AuN3]

220

Power 40 dB Decoupled H1, 399.7467632 MHz Oberserved C13, 100.5163715 MHz Pulse 45.0 degrees Relax. Delay 1.000 sec INOVA Ambient Temperature Solvent: C6D6 Sequence:Pulse s2pul

400

13 1 Figure AII-2. C{ H} NMR Spectrum of [(PCy2(o-biphenyl))AuN3]

221

Decouple H1, 399.7467632 Observe 31, P 161.8190104 MHz Pulse 35.0 degrees Relax. Delay 1.500 sec INOVA Ambient Temperature Solvent: C6D6 Sequence:Pulse s2pul

400

MHz

37.84 ppm

31 1 Figure AII-3. P{ H} NMR Spectrum of [(PCy2(o-biphenyl))AuN3]

222

ObserveH1, 399.7467632 MHz Pulse 45.0 degrees Relax. Delay 1.000 sec INOVA Ambient Temperature Solvent: C6D6 Sequence:Pulse s2pul

400

1 Figure AII-4. H NMR Spectrum of [(PCy2(2′-methylbiphenyl))AuN3]

223

Power 40 dB Decoupled Oberserved C13, 100.5163715 MHz Pulse 45.0 degrees Relax. Delay 1.000 sec INOVA Ambient Temperature Solvent: C6D6 Sequence:Pulse s2pul

400

H1, 399.7467632 MHz

13 1 Figure AII-5. C{ H} NMR Spectrum of [(PCy2(2′-methylbiphenyl))AuN3]

224

Decouple H1, 399.7467632 MHz Observe 31, P 161.8190104 MHz Pulse Relax. Delay 1.500 sec INOVA Ambient Temperature Solvent: C6D6 Sequence:Pulse s2pul

35.0 degrees

400

35.11 ppm

31 1 Figure AII-6. P{ H} NMR Spectrum of [(PCy2(2′-methylbiphenyl))AuN3]

225

ObserveH1, 399.7467632 MHz Pulse 45.0 degrees Relax. Delay 1.000 sec INOVA Ambient Temperature Solvent: C6D6 Sequence:Pulse s2pul

400

1 Figure AII-7. H NMR Spectrum of [(PCy2(2′,4′,6′-triisopropylbiphenyl))AuN3]

226

Power 40 dB Decoupled H1, 399.7467632 MHz Oberserved C13, 100.5163715 MHz Pulse 45.0 degrees Relax. Delay 1.000 sec INOVA Ambient Temperature Solvent: C6D6 Sequence:Pulse s2pul

400

13 1 Figure AII-8. C{ H} NMR Spectrum of [(PCy2(2′,4′,6′-triisopropylbiphenyl))AuN3]

227

Decouple H1, 399.7467632 MHz Observe 31, P 161.8190104 MHz Pulse 35.0 degrees Relax. Delay 1.500 sec INOVA Ambient Temperature Solvent: C6D6 Sequence:Pulse s2pul

400

34.11 ppm

31 1 Figure AII-9. P{ H} NMR Spectrum of [(PCy2(2′,4′,6′-triisopropylbiphenyl))AuN3]

228

ObserveH1, 399.7467632 MHz Pulse 45.0 degrees Relax. Delay 1.000 sec INOVA Ambient Temperature Solvent: C6D6 Sequence:Pulse s2pul

400

1 Figure AII-10. H NMR Spectrum of [(PCy3)AuN3]

229

Decouple H1, 399.7467632 MHz Observe 31, P 161.8190104 MHz Pulse 35.0 degrees Relax. Delay 1.500 sec INOVA Ambient Temperature Solvent: C6D6 Sequence:Pulse s2pul

400

51.01

ppm

31 1 Figure AII-11. P{ H} NMR Spectrum of [(PCy3)AuN3]

230

ObserveH1, 399.7467632 MHz Pulse 45.0 degrees Relax. Delay 1.000 sec INOVA Ambient Temperature Solvent: CDCl3 Sequence:Pulse s2pul

400

Figure AII-12. 1H NMR Spectrum of [(1,3-dimethyl-4,5-dichlorocarbene)AuCl]

231

ObserveH1, 399.7467632 MHz Pulse 45.0 degrees Relax. Delay 1.000 sec INOVA Ambient Temperature Solvent: CDCl3 Sequence:Pulse s2pul

400

Figure AII-13. 1H NMR Spectrum of [(1,3-dimethyl-4,5-dichlorocarbene)AuBr]

232

ObserveH1, 399.7467632 MHz Pulse 45.0 degrees Relax. Delay 1.000 sec INOVA Ambient Temperature Solvent: CDCl3 Sequence:Pulse s2pul

400

1 Figure AII-14. H NMR Spectrum of [(1,3-dimethyl-4,5-dichlorocarbene)AuN3]

233

ObserveH1, 399.7467632 MHz Pulse 45.0 degrees Relax. Delay 1.000 sec INOVA Ambient Temperature Solvent: CDCl3 Sequence:Pulse s2pul

400

1 Figure AII-15. H NMR Spectrum of [(1,3-diisopropylcarbene)AuN3]

234

ObserveH1, 399.7467632 MHz Pulse 45.0 degrees Relax. Delay 1.000 sec INOVA Ambient Temperature Solvent: DMSO Sequence:Pulse s2pul

400

1 Figure AII-16. H NMR Spectrum of [(PPh3)Au(n-pentatriazole)]

235

Decouple H1, 399.7467632 MHz Observe 31, P 161.8190104 MHz Pulse 35.0 degrees Relax. Delay 1.500 sec INOVA Ambient Temperature Solvent: DMSO Sequence:Pulse s2pul

400

44.97

ppm

31 1 Figure AII-17. P{ H} NMR Spectrum of [(PPh3)Au(n-pentatriazole)]

236

ObserveH1, 399.7467632 MHz Pulse 45.0 degrees Relax. Delay 1.000 sec INOVA Ambient Temperature Solvent: DMSO Sequence:Pulse s2pul

400

1 Figure AII-18. H NMR Spectrum of [(PPh3)Au(cyclohexyltriazole)]

237

Decouple H1, 399.7467632 MHz Observe 31, P 161.8190104 MHz Pulse 35.0 degrees Relax. Delay 1.500 sec INOVA Ambient Temperature Solvent: DMSO Sequence:Pulse s2pul

400

5.02

ppm

31 1 Figure AII-19. P{ H} NMR Spectrum of [(PPh3)Au(cyclohexyltriazole)]

238

ObserveH1, 399.7467632 MHz Pulse 45.0 degrees Relax. Delay 1.000 sec INOVA Ambient Temperature Solvent: DMSO Sequence:Pulse s2pul

400

1 Figure AII-20. H NMR Spectrum of [(PPh3)Au(3-aminophenyltriazole)]

239

Decouple H1, 399.7467632 MHz Observe 31, P 161.8190104 Pulse 35.0 degrees Relax. Delay 1.500 sec INOVA Ambient Temperature Solvent: DMSO Sequence:Pulse s2pul

400

MHz

44.

ppm

31 1 Figure AII-21. P{ H} NMR Spectrum of [(PPh3)Au(3-aminophenyltriazole)]

240

ObserveH1, 399.7467632 MHz Pulse 45.0 Relax. Delay 1.000 sec INOVA Ambient Temperature Solvent: DMSO Sequence:Pulse s2pul

400

degrees

1 Figure AII-22. H NMR Spectrum of [(PPh3)Au(4-methoxyphenyltriazole)]

241

Decouple H1, 399.7467632 MHz Observe 31, P 161.8190104 MHz Pulse 35.0 degrees Relax. Delay 1.500 sec INOVA Ambient Temperature Solvent: DMSO Sequence:Pulse s2pul

400

44.

ppm

31 1 Figure AII-23. P{ H} NMR Spectrum of [(PPh3)Au(4-methoxyphenyltriazole)]

242

ObserveH1, 399.7467632 MHz Pulse 45.0 degrees Relax. Delay 1.000 sec INOVA Ambient Temperature Solvent: DMSO Sequence:Pulse s2pul

400

1 Figure AII-24. H NMR Spectrum of [(PCy3)Au(4-methoxyphenyltriazole)]

243

Decouple H1, 399.7467632 MHz Observe 31, P 161.8190104 MHz Pulse 35.0 degrees Relax. Delay 1.500 sec INOVA Ambient Solvent: DMSO Sequence:Pulse s2pul

400

Temperature

59.99

ppm

31 1 Figure AII-25. P{ H} NMR Spectrum of [(PCy3)Au(4-methoxyphenyltriazole)]

244

ObserveH1, 399.7467632 MHz Pulse 45.0 degrees Relax. Delay 1.000 sec INOVA Ambient Temperature Solvent: CDCl3 Pulse

Sequence: s2pul

400

1 Figure AII-26. H NMR Spectrum of [7-{[(PCy3)Au(triazolate)][methoxy]}coumarin]

245

Decouple H1, 399.7467632 MHz Observe 31, P 161.8190104 MHz Pulse 35.0 degrees Relax. Delay 1.500 sec INOVA Ambient Temperature Solvent: CDCl3 Sequence:Pulse s2pul

400

57.95

ppm

Figure AII-27. 31P{1H} NMR Spectrum of [7-

{[(PCy3)Au(triazolate)][methoxy]}coumarin]

246

ObserveH1, 399.7467632 MHz Pulse 45.0 degrees Relax. Delay 1.000 sec INOVA Ambient Temperature Solvent: DMSO Sequence:Pulse s2pul

400

Figure AII-28. 1H NMR Spectrum of [7-{[(1,3-dimethyl-4,5- dichlorocarbene)Au(triazolate)][methoxy]}coumarin]

247

ObserveH1, 399.7467632 MHz Pulse 45.0 degrees Relax. Delay 1.000 sec INOVA Ambient Temperature Solvent: CDCl3 Sequence:Pulse s2pul

400

1 Figure AII-29. H NMR Spectrum of [7-[(PCy3)Au(propargyloxy)]coumarin]

248

Decouple H1, 399.7467632 MHz Observe 31, P Pulse 35.0 degrees Relax. Delay 1.500 sec INOVA Ambient Temperature Solvent: CDCl3 Sequence:Pulse s2pul

400

161.8190104 MHz

55.94

ppm

31 1 Figure AII-30. P{ H} NMR Spectrum of [7-[(PCy3)Au(propargyloxy)]coumarin]

249

ObserveH1, 399.7467632 MHz Pulse 45.0 degrees Relax. Delay 1.000 sec INOVA Ambient Temperature Solvent: CDCl3 Sequence:Pulse s2pul

400

Figure AII-31. 1H NMR Spectrum of [7-[(1,3-dimethyl-4,5- dichlorocarbene)Au(propargyloxy)]coumarin]

250

ObserveH1, 399.7467632 MHz Pulse 45.0 degrees Relax. Delay 1.000 sec INOVA Ambient Temperature Solvent: DMSO Sequence:Pulse s2pul

400

1 Figure AII-32. H NMR Spectrum of [(PCy3)Au(triazolate)]2-[G1]-OH

251

Decouple H1, 399.7467632 MHz Observe 31, P 161.8190104 MHz Pulse 35.0 degrees Relax. Delay 1.500 sec INOVA Ambient Temperature Solvent: DMSO Sequence:Pulse s2pul

400

59.52

ppm

31 1 Figure AII-33. P{ H} NMR Spectrum of [(PCy3)Au(triazolate)]2-[G1]-OH

252

ObserveH1, 399.7467632 MHz Pulse 45.0 degrees Relax. Delay 1.000 sec INOVA Ambient Temperature Solvent: Sequence:Pulse s2pul

400

DMSO

1 Figure AII-34. H NMR Spectrum of [(PCy3)Au(triazolate)]4-[G2]-OH

253

Decouple H1, 399.7467632 MHz Observe 31, P 161.8190104 MHz Pulse 35.0 degrees Relax. Delay 1.500 sec INOVA Ambient Temperature Solvent: DMSO Sequence:Pulse s2pul

400

59.49

ppm

31 1 Figure AII-35. P{ H} NMR Spectrum of [(PCy3)Au(triazolate)]4-[G2]-OH

254

ObserveH1, 399.7467632 MHz Pulse 45.0 degrees Relax. Delay 1.000 sec INOVA Ambient Temperature Solvent: DMSO Sequence:Pulse s2pul

400

1 Figure AII-36. H NMR Spectrum of [(PCy3)Au(triazolate)]8-[G3]-OH

255

Decouple H1, 399.7467632 MHz Observe 31, P 161.8190104 MHz Pulse 35.0 degrees Relax. Delay 1.500 sec INOVA Ambient Temperature Solvent: DMSO Sequence:Pulse s2pul

400

59.47

ppm

31 1 Figure AII-37. P{ H} NMR Spectrum of [(PCy3)Au(triazolate)]8-[G3]-OH

256

ObserveH1, 399.7467632 MHz Pulse 45.0 degrees Relax. Delay 1.000 sec INOVA Ambient Temperature Solvent: CDCl3 Sequence:Pulse s2pul

400

1 Figure AII-38. H NMR Spectrum of [acet]2-[G1]-7-methoxycoumarin

257

ObserveH1, 399.7467632 MHz Pulse 45.0 degrees Relax. Delay 1.000 sec INOVA Ambient Temperature Solvent: CDCl3 Sequence:Pulse s2pul

400

1 Figure AII-39. H NMR Spectrum of [acet]4-[G2]-7-methoxycoumarin

258

ObserveH1, 399.7467632 MHz Pulse 45.0 degrees Relax. Delay 1.000 sec INOVA Ambient Temperature Solvent: DMSO Sequence:Pulse s2pul

400

1 Figure AII-40. H NMR Spectrum of [(PCy3)Au(triazolate)]2-[G1]-7-methoxycoumarin

259

Decouple H1, 399.7467632 MHz Observe 31, P 161.8190104 MHz Pulse 35.0 degrees Relax. Delay 1.500 sec INOVA Ambient Temperature Solvent: DMSO Sequence:Pulse s2pul

400

59.48

ppm

31 1 Figure AII-41. P{ H} NMR Spectrum of [(PCy3)Au(triazolate)]2-[G1]-7- methoxycoumarin

260

ObserveH1, Pulse 45.0 degrees Relax. Delay 1.000 sec INOVA Ambient Temperature Solvent: CDCl3 Sequence:Pulse s2pul

400

399.7467632 MHz

1 Figure AII-42. H NMR Spectrum of [(PCy3)Au(alkynyl)]2-[G1]-7-methoxycoumarin

261

Decouple H1, 399.7467632 MHz Observe 31, P 161.8190104 MHz Pulse 35.0 Relax. Delay 1.500 sec INOVA Ambient Temperature Solvent: CDCl3 Sequence:Pulse s2pul

400

degrees

56.50

ppm

31 1 Figure AII-43. P{ H} NMR Spectrum of [(PCy3)Au(alkynyl)]2-[G1]-7- methoxycoumarin

262

Decouple H1, 399.7467632 MHz Observe 31, P 161.8190104 MHz Pulse 35.0 degrees Relax. Delay 1.500 sec INOVA Ambient Temperature Solvent: CDCl3 Sequence:Pulse s2pul

400

Figure AII-44. 1H NMR Spectrum of N-(4-nitrophenyl)-bis(2-hydroxyethyl)amine

263

Decouple H1, 399.7467632 MHz Observe 31, P 161.8190104 MHz Pulse 35.0 degrees Relax. Delay 1.500 sec INOVA Ambient Temperature Solvent: CDCl3 Sequence:Pulse s2pul

400

Figure AII-45. 1H NMR Spectrum of N-(4-nitrophenyl)-bis(2-(tosyloxy)ethyl)amine

264

Decouple H1, 399.7467632 MHz Observe 31, P 161.8190104 MHz Pulse 35.0 degrees Relax. Delay 1.500 sec INOVA Ambient Temperature Solvent: CDCl3 Sequence:Pulse s2pul

400

Figure AII-46. 1H NMR Spectrum of 3,6,9-trithia-1,11-undecanedithiol

265

Decouple H1, 399.7467632 MHz Observe 31, P 161.8190104 MHz Pulse 35.0 degrees Relax. Delay 1.500 sec INOVA Ambient Temperature Solvent: CDCl3 Sequence:Pulse s2pul

400

Figure AII-47. 1H NMR Spectrum of N-(4-nitrophenyl)-1,4,7,10,13-pentylthia-16- azacyclooctyldecane

266

Decouple H1, 399.7467632 MHz Observe P Pulse 35.0 degrees Relax. Delay 1.500 sec INOVA Ambient Temperature Solvent: DMSO Sequence:Pulse s2pul

400

31, 161.8190104 MHz

Figure AII-48. 1H NMR Spectrum of N-(4-aminophenyl)-1,4,7,10,13-pentylthia-16- azacyclooctyldecane

267

Decouple H1, 399.7467632 MHz Observe 31, P 161.8190104 MHz Pulse 35.0 degrees Relax. Delay 1.500 sec INOVA Ambient Temperature Solvent: CDCl3 Sequence:Pulse s2pul

400

Figure AII-49. 1H NMR Spectrum of [Au{(N-(4-aminophenyl)-1,4,7,10,13-pentylthia-

16-azacyclooctyldecane)}][SbF6]

268

Decouple H1, 399.7467632 MHz Observe 31, P 161.8190104 MHz Pulse 35.0 degrees Relax. Delay 1.500 sec INOVA Ambient Temperature Solvent: CDCl3 Sequence:Pulse s2pul

400

Figure AII-50. 1H NMR Spectrum of N-(phenyl)-bis(2-(tosyloxy)ethyl)amine

269

Decouple H1, 399.7467632 MHz Observe 31, P 161.8190104 MHz Pulse 35.0 degrees Relax. Delay 1.500 sec INOVA Ambient Temperature Solvent: CDCl3 Sequence:Pulse s2pul

400

Figure AII-51. 1H NMR Spectrum of N-(phenyl)-1,4,7,10,13-pentylthia-16- azacyclooctyldecane

270

Decouple H1, Observe 31, P 161.8190104 MHz Pulse 35.0 degrees Relax. Delay 1.500 sec INOVA Ambient Temperature Solvent: CDCl3 Sequence:Pulse s2pul

400

399.7467632 MHz

Figure AII-52. 1H NMR Spectrum of N-(4-formylphenyl)-1,4,7,10,13-pentylthia-16- azacyclooctyldecane

271

Decouple H1, 399.7467632 MHz Observe 31, P 161.8190104 MHz Pulse Relax. Delay 1.500 sec INOVA Ambient Temperature Solvent: CDCl3 Sequence:Pulse s2pul

35.0 degrees

400

Figure AII-53. 1H NMR Spectrum of N-(4-benzylamine)-1,4,7,10,13-pentylthia-16- azacyclooctyldecane

272

Decouple H1, 399.7467632 MHz Observe 31, P 161.8190104 MHz Pulse 35.0 degrees Relax. Delay 1.500 sec INOVA Ambient Temperature Solvent: CD3CN Sequence:Pulse s2pul

400

Figure AII-54. 1H NMR Spectrum of [Au{(N-(4-benzylamine)-1,4,7,10,13-pentylthia-

16-azacyclooctyldecane)}][SbF6]

273

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