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2005 Thermal and Photochemical Reactions of Acetylenes: I-Ortho-Effect in the Bergman Cyclization of Benzannelated Enediynes II- Photocycloaddition of Diaryl Acetylenes to Cyclic Dienes Mechanisms and Applications Tarek A. Zeidan

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THERMAL AND PHOTOCHEMICAL REACTIONS OF ACETYLENES: I-ORTHO-EFFECT IN THE BERGMAN CYCLIZATION OF BENZANNELATED ENEDIYNES II-PHOTOCYCLOADDITION OF DIARYL ACETYLENES TO CYCLIC DIENES MECHANISMS AND APPLICATIONS

By

TAREK A. ZEIDAN

A Dissertation submitted to the Department of Chemistry and Biochemistry in partial fulfillment of the requirements for the degree of Doctor of Philosophy

Degree Awarded: Fall Semester, 2005 The members of the Committee approve the Dissertation of Tarek A. Zeidan defended on September 27th 2005

Igor V. Alabugin Professor Directing Dissertation

Lloyd M. Epstein Outside Committee Member

Jack Saltiel Committee Member

Joseph B. Schlenoff Committee Member

Approved:

Naresh Dalal, Chair, Department of Chemistry and Biochemistry

The Office of Graduate Studies has verified and approved the above named committee members.

ii

To my best friend, my partner, my soul mate...... Nadine & To Ahmed and Amal

iii ACKNOWLEDGEMENTS

During my few years at Florida State University, I had the opportunity to work and interact with several professors, staff, postdocs and graduate fellows. In these few lines I will try to acknowledge them and I apologize if I forget to mention anyone. First and foremost, I would like to thank my major professor, Igor V. Alabugin, for accepting me as a graduate student in his laboratory, for his continuous support, and for giving me the opportunity to be the first doctoral student to graduate from his laboratory. Professor Alabugin taught me many lessons and equipped me with the required basics to be able to start my scientific journey. I hope I will continue to live up to his expectations. Second, I am thankful to my committee members for their encouragement and help. I would like to express my gratitude to Professor Jack Saltiel for being by my side all the time, for his help and support, for his guidance in chemistry as well as in life and especially for believing in me. I am grateful to Professor Joseph B. Schlenoff for his support and encouragement and for allowing me to use instrumentation in his laboratory and to Professor Edwin E. Hilinski for his letters of recommendation. I am eternally thankful to Dr. Serguei V. Kovalenko who taught me everything I need to know in the laboratory. I will never forget our endless discussions every Friday afternoon. I would not have been able to go this far without his guidance, support and constructive critiques. Also, I am thankful to Dr. Marriappan Manoharan for his computational studies and everyone else in the Alabugin group. I am grateful to Professor Ronald Clark for teaching me about X-ray crystallography and acquiring all X-ray data described in this dissertation and to Dr. Ion Ghiviriga from the Department of Chemistry at the University of Florida for his help in some NMR experiments. I am also thankful to Dr. T. S. R. Krishna and Dr. Xeena Pillay from Professor Saltiel’s group for their assistance in some fluorescence experiments, to Dr. Jad Jaber for his assistance in acquiring some IR spectra, to Professor Kenneth A. Goldsby for use of electrochemistry equipment, to Dr. Bert van de Burgt for use of laser equipment and acquisition of Laser Flash Excitation spectra, to Professor Gregory Dudley and his lab members for lend ing me chemicals, Professor Naresh Dalal and Ms. Saritha Mellutla for providing some chemicals and to Professor Albert E. Steigman and Dr. Paul Giunta for teaching me how to use the DSC and SDT equipments. I am extremely grateful to Dr. Umesh Goli and Hank Henricks from the

iv Biochemical Analysis and Synthesis Services laboratory (BASS Lab) for their help on HPLC, GC, MS and LC-MS and especially for their unconditional support. I am thankful to Dr. Joseph B. Vaughn and Steven E. Freitag from the NMR facility and to Dr. Tom Gedris for aquiring 19F and 13C NMR spectra. I would like to thank everyone in the administrative offices of the Department of Chemistry and Biochemistry at Florida State University, especially Ginger Martin, Cathy Flynn and Jacquelin Dulin (Jaquie). Also, I am thankful to Tia Williams, Tom Wages, Gary Poplin and Charlie Betts for computer support and Steve Leukanech from the illustration shop. I would like to thank Dr. Jean Chamoun for his support in illustration and graphics. I would not have completed this work without the support of my family (Nadine, Ahmed, Amal, Wael, Yassmine, Ola, Lama and Mohamad) and my friends (Jean and Maroun).

v TABLE OF CONTENTS

LIST OF SCHEMES ...... ix LIST OF FIGURES ...... xi LIST OF TABLES...... xiv

ABSTRACT...... xv CHAPTER I ...... 1 INTRODUCTION ...... 1 The Bergman Cycloaromatization Reaction: The Beginnings ...... 1 Enediynes as Anticancer Antibiotics Drugs: Medical Significance and Limitations...... 1 Towards More Selective Enediyne Systems...... 3 The Bergman Cycloaromatization: Computational Studies ...... 7 Setting the Paradigm: A Theoretical Background ...... 9 EXPERIMENTAL SECTION ...... 11 Synthesis of Benzannelated Enediynes...... 11 Synthetic Procedures and Spectroscopic Details ...... 12 Experimental Setup for Kinetic Studies...... 21 Kinetic Experiment for Different Concentration of Hydrogen-Atom Donor ...... 24 Experimental Setup for Differential Scanning Calorimetry Studies...... 26 RESULTS ...... 27 Differential Scanning Calorimetry Experiments ...... 27 Effective Rate Constants of Ortho-Substituted Benzannelated Enediynes...... 34 Activation Energies of Ortho-Substituted Benzannelated Enediynes ...... 37 Effect of 1,4-Cyclohexadiene Concentration on the Effective Rate Constants...... 39 DISCUSSION...... 41 Differential Scanning Calorimetry Kinetic Analysis...... 41 Ortho-Substituted Benzannelated Enediynes...... 44 Effect of Concentration of 1,4-Cyclohexadiene on Rates and Activation Energies...... 47 Dissection of the Bergman Cyclization Kinetics...... 53 Ortho-Substituted Benzannelated Enediynes: Methoxy Substituent ...... 54 CONCLUSIONS...... 63

vi CHAPTER II...... 65 INTRODUCTION ...... 65 Bergman Cyclization: The Photochemical Aspect ...... 65 En Route to Novel Photochemical Reactions: From Bergman Cycloaromatization to C1C5 Cylization...... 67 Photochemical Cycloaddition of Acetylenes to 1,4-CHD: From Hydrogen/Electron Transfer to Cycloaddition ...... 69 Photocycloaddition Reactions of Acetylenes: Literature Review ...... 71 EXPERIMENTAL SECTION ...... 78 Synthesis of Acetylenes ...... 78 Synthetic Procedures and Spectroscopic Details ...... 79 Determination of Quantum Yields...... 102 Sensitization and Quenching Studies...... 102 1H NMR Studies ...... 103 Emission and Absorption Studies ...... 103 Laser Flash Spectroscopy Studies...... 103 Electrochemistry: Cyclic Voltammetry Studies...... 104 Preparation of Homoquadricyclane-Metal Complexes...... 104 RESULTS ...... 105 Photochemistry of Pyridinyl Aryl Acetylenes ...... 105 Photochemistry of Pyrazinyl Aryl Acetylenes...... 108 Quantum Efficiency for Formation of Homoquadricyclanes ...... 112 Quantum Efficiency for Formation of Tricyclooctenes...... 116 Low Temperature Phosphorescence ...... 117 Laser Flash Spectroscopy Studies...... 120 DISCUSSION...... 123 Aryl Substituent Effect on the Photocycloaddition Reaction ...... 123 Nature of the Excited States...... 124 Competition between Triplet and Photoelectron Transfer Pathways ...... 125 Reaction Mechanisms: Formation of Homoquadricyclanes...... 127 Reaction Mechanisms: Homoquadricyclanes-Tricyclooctene Rearrangement ...... 134

vii PHOTOCYCLOADDITION REACTIONS OF DIARYL ACETYLENES WITH HETEROAROMATIC FIVE-MEMBERED RING COMPOUNDS...... 135 Reactions with Thiophene...... 135 Reactions with Furan ...... 140 HOMOQUADRICYCLANES AS NEW SUPRAMOLECULAR SCAFFOLDS...... 143 Supramolecular Chemistry: An Overview...... 143 X-Ray Crystallography Interpretation: Basic Homoquadricyclane Units ...... 144 X-Ray Crystallography Interpretation: Metal Complexes and Packing ...... 147 Substitution on the Homoquadricyclane Unit Controls Rotation of Aryl Groups...... 154 CONCLUSIONS...... 156 APPENDIX A: 1H NMR SPECTRA...... 158 Chapter I...... 158 Chapter II ...... 177 APPENDIX B: 13C NMR SPECTRA...... 234 Chapter I...... 234 Chapter II ...... 247 APPENDIX C: 19F NMR SPECTRA ...... 285 APPENDIX D: DERIVATION OF RATE CONSTANTS...... 310 APPENDIX E: X-RAY CRYSTALLOGRAPHIC ANALYSIS...... 313 APPENDIX F: UV Spectra...... 316 REFERENCES ...... 325 BIOGRAPHICAL SKETCH ...... 346

viii LIST OF SCHEMES

Scheme 1. Bergman Cycloaromatization Reaction of Enediynea ...... 1

Scheme 2. Naturally Occurring Antibiotic Enediynes...... 2

| 15- Scheme 3. Mechanism of DNA Cleavage by Calicheamicin γ1 , Neocarzinostatin Chromophore and Dynemicin A 19, 21 ...... 3

Scheme 4. Acetylenic Carbons (C1C6) Distances of Acyclic and Cyclic Enediynesa ...... 4

Scheme 5. Metal Complexation Drastically Reduces Cyclization of Enediynesa...... 5

Scheme 6. Bergman Cyclization of Enediyne Ligands Accelerated by Metal Complexationa...... 5

Scheme 7. Activation Energies for the Bergman Cyclization of Heteroaromatic Enediynes...... 6

Scheme 8. Cyclic Enediynes Based on Quinones and Hydroquinones Moieties...... 7

Scheme 9. Bergman Cyclization of Ortho-Substituted Benzannelated Enediynes...... 9

Scheme 10. Synthesis of Benzannelated Enediynes...... 11

Scheme 11. Kinetic Steps Involved in the Cycloaromatization Cascade...... 48

Scheme 12. Kinetic Model for the Bergman Cyclization of 2,3-Diethynyl-1-methoxybenzene ...... 56

Scheme 13. The First Reported Photocyclization of an Enediyne...... 65

Scheme 14. Photocyclization of Diacetylene Systems Analogous to the Bergman Cyclization ...... 66

Scheme 15. Photochemical Bergman Cyclizationa ...... 67

Scheme 16. C1C5 Photochemical Cyclization of Benzannelated Enediynes ...... 68

Scheme 17. “Simultaneous” Two Photon Absorption Process...... 69

Scheme 18. Photocycloaddition of Bis-TFP Pyrazine Enediyne 3...... 70

Scheme 19. Photochemical Cyclization of Acetylenes and Alkenes...... 72

Scheme 20. [2π+2π] Photochemical Cycloaddition of Tolane and Cyclic Dienes...... 73

Scheme 21. Photochemical Formation of Homoquadricyclanes in Reactions of Acetylenes with Dienes...... 74

Scheme 22. Photocycloaddition of Acetylenes to Aromatic Hydrocarbons ...... 75

Scheme 23. Photochemical Reactions of Acetylenes with Five-Membered Ring Heteroaromatic Hydrocarbons...... 76

Scheme 24. Photochemical Reactions of Acetylenes with Indene and Benzoheteroaromatic Systems...... 76

Scheme 25. Suggested Mechanism for Photocycloaddition of Benzothiophene to Acetylene...... 77

ix Scheme 26. Choice of Model Substrates and their Abbreviations Used in this Work...... 78

Scheme 27. Synthesis of Acetylenes 3, 5-16, 18 ...... 79

Scheme 28. Photochemical Reactions of Aryl Pyridinyl Acetylenes with 1,4-CHDa ...... 106

Scheme 29. Photochemical Reactions of Aryl Pyrazinyl Acetylenes with 1,4-CHDa ...... 109

Scheme 30. Photochemical Dimerization of Diaryl Acetylenes...... 121

Scheme 31. Photodimerization of Diaryl Acetylenes ...... 122

Scheme 32. Competing Photophysical Pathways for the Reaction of 1,4-CHD and Diaryl Acetylenesa ...... 127

Scheme 33. Most Common Reactions of Singlet 1,4-Biradicalsa ...... 128

Scheme 34. The Role of a “Phantom” 3n,π* State in Enhancing ISC in Diaryl Acetylenes...... 129

Scheme 35. Suggested Mechanism of the Homoquadricyclanes Formation in Photocycloaddition of Diaryl Acetylenes to 1,4-CHDa ...... 130

Scheme 36. Photocycloaddition of Diaryl Acetylenes to Olefins...... 131

Scheme 37. Photocycloaddition of Diaryl Acetylenes to Allyl Alcohol...... 132

Scheme 38. Retrosynthetic Analysis of the Photochemical Approach to Homoquadricyclanes Based on the Triplet Photocycloaddition of Diaryl Acetylenes and 1,4-CHD ...... 133

Scheme 39. Topological Analysis of the “Boomerang” Reaction of Vinyl-1,2-diyl with Two Double Bonds...... 133

Scheme 40. Secondary Photochemistry of Pyrazinyl Homoquadricyclanes...... 134

Scheme 41. Photocycloaddition of Diaryl Acetylenes with Thiophene...... 136

Scheme 42. Our Proposed Mechanism for Photocycloaddition of Diaryl Acetylene to Thiophene...... 139

Scheme 43. Photochemical Reactions of 2-Py-TFP Acetylenes with Furan ...... 140

Scheme 44. Proposed Mechanism for the Photochemical Reactions of Acetylenes with Furan and 1H NMR Chemical Shifts for 46, 47 and 48...... 141

Scheme 45. Photochemical Reactions of Bis-TFP Acetylenes with Furan and 1H NMR Chemical Shifts for 52 and 53...... 142

Scheme 46. Photocycloaddition of Diaryl Acetylenes to 1,5-Diemthoxy-1,4-Cyclohexadiene ...... 154

x LIST OF FIGURES

Figure 1. The energy profiles of the Bergman cyclization as measured by Roth et al. in the gas phase. ∆H is in kcal/mol...... 6

Figure 2. Comparison of the “antiaromatic region” in enediyne with the antiaromatic TS of the [2π+2π] cycloaddtion...... 8

Figure 3. Three mechanisms explaining “ortho”-effect in the Bergman cyclization: (a) steric assistance, (b) decrease in TS stabilization, and (c) extra stabilization of the TS. The energy profile for the para isomers is given by a black line, and that for the ortho isomers by a red line. Energies of πÆ σ*X-H interactions found by the NBO analysis are given in parentheses. Calculations were performed at the BS-UB3LYP/6-31G** level...... 10

Figure 4. DSC scans of neat benzannelated enediynes at a heating rate of 5, 10, 15 and 20°C/min and the activation energies (insets) for (a) 1,2-diethynylbenzene, (b) 2,3-diethynylnitrobenzene, (c) 3,4-diethynylnitrobenzene, (d) 2,3-diethynyl-1-formylbenzene, (e) 2,3-diethynyl-1-methoxybenzene and (f) 2,3-diethynyl-1- trideuteriomethoxybenzene...... 27

Figure 5. DSC scans for solutions of benzannelated enediynes in 1,4-CHD ([1,4-CHD] = 10.5 M). Heating rates are 5, 10, 15 and 20 °C/min unless noted otherwise. Arrhenius plots are shown in the inset. (a) 1,2- diethynylbenzene, (b) 2,3-diethynylnitrobenzene, (c) 3,4-diethynylnitrobenzene (1, 3, 5, 10 °C/min), (d) 2,3- diethynyl-1-formylbenzene, (e) 2,3-diethynyl-1-methoxybenzene and (f) 2,3-diethynyl-1- trideuteriomethoxybenzene...... 31

Figure 6. First-order rate constants at different temperatures determined for the disappearance of ortho-substituted enediynes: (a) 1,2-diethynylbenzene, (b) 2,3-diethynylnitrobenzene, (c) 3,4-diethynylnitrobenzene, (d) 2,3- diethynyl-1-formylbenzene, (e) 2,3-diethynyl-1-methoxybenzene, (f) 2,3-diethynyl-1- (trideuteriomethoxy)benzene and (f) 2,3-diethynyl-1-aminobenzen, and the appearance of the corresponding naphthalene products: (a’) naphthalene, (b’) 1-nitronaphthalene, (c’) 2-nitronaphthalene, (d’) 1- naphthaldehyde, (e’) 1-methoxynaphthalene, (f’) 1-(trideuteriomethoxy)naphthalene and (g’) 1- aminonaphthalene. X is defined in Eq. 2...... 34

Figure 7. Arrhenius plots for disappearance of benzannelated enediynes (solid line) and appearance of the corresponding naphthalenes (dashed lines). (a) 1,2-diethynylbenzene, (b) 2,3-diethynylnitrobenzene, (c) 3,4- diethynylnitrobenzene, (d) 2,3-diethynyl-1-formylbenzene, (e) 2,3-diethynyl-1-methoxybenzene, (f) 2,3- diethynyl-1-trideuteriomethoxybenzene and (g) 2,3-diethynyl-1-aminobenzene...... 37

Figure 8. The dependence of effective rate constant, keff, on 1,4-CHD concentration at different temperatures; (a) and (b) disappearance of ortho-NO2 and para-NO 2 enediynes, respectively and (a’) and (b’) appearance of 1- nitronaphthalenes and 2-nitronapthalene, respectively...... 39

Figure 9. Dependence of the effective rate constant on the 1,4-CHD concentration for the consumption of o-OCH3 (filled circle) and formation of 1-methoxynaphthalene (hollow circles)...... 40

Figure 10. Correlation between activation energies calculated using unrestricted MP2, broken-spin B3LYP and BLYP levels79 with 6-31G(d,p) basis set and activation energies determined using DSC method of benzannelated enediynes in 1,4-CHD bearing electron acceptor groups in the ortho position: (a) 1,4-CHD solution and (b) neat benzannelated enediynes...... 43

Figure 11. The dependence of effective rate constant, keff, from 1,4-CHD concentration at 140º C; (a) disappearance of enediynes and (b) appearance of nitronaphthalenes. Filled red circles are data for ortho-nitro enediyne and hollow red circles are data for para-nitro enediyne...... 50

xi Figure 12. First-order rate constants determined for the disappearance of ortho-CH3 (solid line) and ortho-OCD3 (Dashed line) enediynes at 170 ºC...... 56

Figure 13. Dependence of the effective rate constant on the 1,4-CHD concentration for (a) the consumption of 2,3- diethynyl-1-methoxybenzene (filled circles), 2,3-diethynyl-1-trideuteriomethoxybenzene (red crosses) and formation of 1-methoxynaphthalene (hollow circles) and (b) trends in keff at different k-1:k2 ratios predicted by Eq. 7 vs. the experimental dependence of the rate of consumption for 3.9×10-3 M 1,2-diethynylbenzene solution at 188 oC, shown in red triangles...... 58

1 Figure 14. H NMR spectra for the Bergman cyclization major products of (a) ortho-CH3 and (b) ortho-OCD 3 enediynes showing deuterium incorporation in C8 of the naphthalene ring...... 60

Figure 15. 1 H NMR spectra for products derived from trapping of radicals generated by the Bergman cyclization of ortho-OCH3 and ortho-OCD 3 enediynes...... 61

Figure 16. Structure and NMR assignments of tricyclo[3.2.1.04,6]oct-2-ene 4...... 70

Figure 17. The non-aromatic region of the 1 H NMR spectra for the homoquadricyclane product...... 106

Figure 18. ORTEP presentations of homoquadricyclanes 19 and 22...... 107

Figure 19. Changes in the 1H NMR spectra of the aromatic region during irradiation of acetylene 6; [2-Py-TFP] = 0.03 M and [1,4-CHD] = 0.13 M...... 108

Figure 20. The non-aromatic region of the 1H NMR spectra for the tricyclo[3.2.1.04,6]oct-2-ene product...... 109

Figure 21. ORTEP presentations of homoquadricyclane 27 and tricyclo[3.2.1.0.4,6]oct-2-ene 29...... 110

Figure 22. Photoreaction of acetylene 11 with 1,4-CHD followed by 1H NMR; [Pyra-Cl-TFP] = 0.04 M and [1,4- CHD] = 0.20 M...... 111

Figure 23. Time evolution of the relative amounts of acetylene 12 (green diamonds), homoquadricyclane 28 (red hollow circles) and tricyclooctene 30 (blue triangles) during photolysis at 313 nm. Slight deviations from the ideal AÆBÆC kinetics are explained by the differences in the absorbance between compounds 12 and 28 and by the quenching effect of 30...... 112

Figure 24. Limiting quantum yields for the consumption of 2-Py-TFP acetylene 6 (solid line) and formation of the corresponding tetracyclooctane product 19 (dashed line); [2-Py-TFP] = 1.0 × 10-3 M...... 114

Figure 25. Limiting quantum yields for the formation of the tetracyclooctane products from 2-Py-TFP (hollow circles) and TFP-TFP (diamonds) acetylenes; [Bis-TFP] = 1.0 × 10-3 M...... 116

Figure 26. Excitation (dotted red line) and emission (solid blue line) spectra from 10-5 M of acetylene solutions in the absence and presence of methyl iodide (dashed green line): (a) Ph-TFP 10; (b) Bis-TFP 9; (c) Pyra-TFP 12; (d) 2-Py-TFP 6; (e) Tolane 17; (f) Ph-PFB 18 in frozen methylcyclohexane glass (77 K). Both excitation and detection wavelengths are shown...... 118

Figure 27. Ball and stick representation of 1,2,3-triarylnaphthalene. The crystal used in the X-ray analysis was not suitable for achieving good structure optimization...... 122

Figure 28. Oxygen effect on conversion of acetylenes to the corresponding homoquadricyclane products; [Pyra- TFP] = 1.08 × 10-3 M, [3-Py-TFP] = 1.10 × 10-3 M and [Pyra-Cl-TFP] = 1.06 × 10-3 M...... 124

Figure 29. Quenching of the fluorescence of Bis-TFP acetylene 9 by 1,4-CHD in acetonitrile at room temperature irradiated at 285 nm; [Bis-TFP] = 2.02 × 10-4 M...... 126

xii Figure 30. Stern-Volmer plots for fluorescence quenching of Bis-TFP acetylene with 1,4-CHD in acetonitrile (diamonds) and cyclohexane (squares) and with Et3N in acetonitrile (triangles)...... 126

1 Figure 31. Photorearrangement of cyclobutene adduct 44 to 41 monitored by H NMR in CD3CN...... 138

Figure 32. Stern-Volmer plots for fluorescence quenching of Bis-TFP acetylene in acetonitrile by thiophene (triangles) and with Et3N (squares)...... 140

Figure 33. ORTEP representation of the geometry of 1,5-(4,4’-dipyridyl) homoquadricyclane 24 (L1) [di-4,4’-[7,6- tetracyclo[3.2.1.02,7.0 4,6] octyl]-pyridine] (left) and a side view showing molecular symmetry and the angle formed by the planes of the two pyridine rings (right)...... 144

Figure 34. ORTEP representation of (a) L2 [Di-4,4’-[7,6-tetracyclo[3.2.1.02,7.0 4,6]octyl]-2,3,5,6-tetrafluoropyridine] and (b) L3 [4-[7-(2,3,5,6-tetrafluoropyridin-4-yl)-tetracyclo [3.2.1.02,7.0 4,6]oct-6-yl]-pyridine]...... 145

Figure 35. Crystal packing of Homoquadricyclanes L1, L2 and L3...... 145

Figure 36. Distances, angles and torsion angles of homoquadricyclanes L1, L2 and L3...... 147

Figure 37. Alternating layers of organic and inorganic molecules in the crystal structure of complex 1 (1:1 ratio L1:AgNO3)...... 148

Figure 38. Distances, valence and torsion angles in complex 1...... 148

Figure 39. View of the basic trimeric unit [Ag2(L1) 3(NO 3) 2 (CHCl 3 ) 2] of complex 2...... 149

Figure 40. Distances, angles and torsion angles of the basic unit in complex 2...... 150

Figure 41. “Beads on a string” packing of supramolecular rhomboids in complex 2. Different colors show three different strings forming the cavities. Hydrogens are omitted for clarity...... 150

Figure 42. TGA plots for L1 (blue line) and complexes 1 (red line), 2 (black line) and 3 (green line). Complex 2 shows a shoulder where the weight loss is 18%, corresponding to two CHCl3 molecules in complex 2...... 151

Figure 43. View of the basic unit [Cu2(L1) 2Cl 4(CHCl 3)] of complex 3...... 152

Figure 44. Distances, angles and torsion angles of the basic unit in complex 3. Chloroform molecules were omitted for clarity reasons...... 152

Figure 45. Crystal packing of supramolecular rhomboids, complex 3...... 153

Figure 46. Thicker “walls” between the inorganic layers in the 2:1 (L1/AgNO3) complex 4. Nitrate anions are disordered...... 154

Figure 47. NMR chemical shifts assignments for L4...... 155

Figure 48. 19F NMR spectrum for (a) L4 and (b) L5...... 155

xiii LIST OF TABLES

Table 1. Activation Energies and Pre-Exponential Factors (logA) Determined Computationally and from DSC Experiments.a ...... 41

-1 Table 2. Effective Rate Constants (keff, s ) for the Disappearance of Benzannelated enediynes and the Appearance of Corresponding Naphthalenes at Different Temperatures.a ...... 45

Table 3. Activation Energies, Pre-Exponential Factors (Log A) and Yields of 1-Substituted Naphthalenes.a ...... 46

ED Table 4. Effective Rate Constants for Disappearance of Nitroenediynes ( keff ) and Appearance of Napht a Nitronaphthalenes ( keff ) at 140 ºC...... 49

ED Table 5. Effective Rate Constants for Disappearance of Nitroenediynes ( keff ) and Appearance of Napht a Nitronaphthalenes ( keff )at Different Temperatues...... 51

Table 6. Activation Energies Determined from Effective Rate Constants for Consumption of NO2-enediynes (E a App) and Appearance of Nitronaphthalenes (Ea Disapp) at Different Concentration of Hydrogen-Atom Donor.a ...... 52

Table 7. Rate Constants at 140 ºC Determined using Equations 5 and 6.a ...... 53

-1 Table 8. Effective Rate Constants (keff, s ) for the Disappearance of ortho-OCH3 and ortho-OCD 3 and the Appearance of Corresponding Naphthalenes at Different Temperatures.a...... 55

a Table 9. Activation Energies, Pre-Exponential Factors (Log A) and Yields of 1-OCH3/OCD 3 Naphthalenes...... 57

Table 10. Conditions and Yields for the Photochemical Cycloaddition of Acetylenes to 1,4-Cyclohexadiene.a,b ....107

Table 11. Conditions and Yields for the Photochemical Cycloaddition of Pyrazinyl Acetylenes to 1,4- Cyclohexadiene.a,b...... 110

Table 12. Quantum Yields for the Disappearance of Acetylene and Formation of Polycyclic Photoadducts.a...... 113

Table 13. Quantum Yields for the Consumption of 2-Py-TFP 6 and Bis-TFP 9 Acetylenes and the Formation of the Tetracyclooctane Products at Different Concentration of 1,4-CHD.a ...... 115

Table 14. Quantum Yields for the Disappearance of Acetylene and Formation of Polycyclic Photoadducts in Pyrazinyl Acetylenes.a ...... 117

o Table 15. Lifetimes of Excited Species Determined by LFP, CH3CN, 25 C in Argon and Oxygen Saturated Saturated Solutions...... 121

Table 16. Reduction Potentials, Energies of Singlet and Triplet Excited States and PET Free Energies for Selected Diaryl Acetylenes...... 125

Table 17. Conditions and Yields for the Photochemical Cycloaddition of Acetylenes to Thiophene.a,b...... 136

Table 18. Selected distances (Å) and angles (deg) for homo-quadricyclanes L1, L2 and L3 and for complexes 1, 2, 3 and 4...... 146

xiv ABSTRACT

Four different sources of kinetic information were combined to study the effect of ortho substituents on the rate of Bergman cycloaromatization. All of these methods confirm that the cyclization barrier is highly sensitive to the nature of ortho-substituents. However, the measured activation energies strongly depend on the choice of experimental technique: the relative trends provided by the different methods agree with each other only in the case of acceptor substituents. Both the onset peaks and the activation energies determined by Differential Scanning Calorimetry (DSC) (either in neat enediynes or in their solutions in 10.6 M 1,4-cyclohexadiene (1,4-CHD)) strongly overestimate the reactivity of 1,2-diethynylbenzene suggesting that DSC is not a reliable indicator of enediyne reactivity. This discrepancy is likely to stem from the presence of side reactions with low activation barriers, especially important when the reaction is carried out in neat enediyne. On the other hand, kinetic measurements based on monitoring the concentrations of enediyne reactants and naphthalene products provide reliable general trends that include the parent benzannelated enediyne. These measurements confirm that both

substituents in 2,3-diethynyl-1-nitrobenzene (ortho-NO2) and 2,3-diethynyl-1-formylbenzene (ortho-CHO) substantially decrease activation energies for the Bergman cyclization supporting

our earlier computational predictions. Activation energies derived from keff, the effective rate constants, depend on the 1,4-CHD concentrations. The “true” rate constants, k1 for the

cycloaromatization step and the ratio of constants for the retro-Bergman ring opening, k-1, and

intermolecular H-atom abstraction, k2, were determined from the dependence of

cycloaromatization kinetics of ortho- and para-NO2 substituted enediynes on the concentration of 1,4-CHD. Interestingly, intramolecular hydrogen-atom (H-atom) abstraction from the ortho-

OCH3 group effectively intercepts p-benzyne intermediate in the Bergman cycloaromatization of 2,3-diethynyl-1-methoxybenzene leading to the formation of a new diradical and rendering the cyclization step essentially irreversible. Chemical and kinetic consequences of this phenomenon were investigated through the combination of computational and experimental studies. Diaryl acetylenes, in which one of the aryl groups is either a pyridine or a pyrazine, undergo efficient triplet state photocycloaddition to 1,4-cyclohexadiene with formation of 1,5-diaryl substituted tetracyclo[3.3.0.02,8.04,6]octanes (homoquadricyclanes). In the case of pyrazinyl acetylenes, the primary homoquadricyclane products undergo a secondary photochemical

xv rearangement leading to diaryl substituted tricyclo[3.2.1.04,6]oct-2-enes. Mechanistic and photophysical studies suggest that photocycloaddition proceeds through an electrophilic triplet excited state whereas the subsequent rearrangement to the tricyclooctenes proceeds through a singlet excited state. Chemical and quantum yields for the cycloaddition, in general, correlate with the electron acceptor character of aryl substituents but are attenuated by photophysical factors, such as the competition between the conversion of acetylene singlet excited state into the reactive triplet excited states (intersystem crossing: ISC) and/or to the radical-anion (photo- electron transfer from the diene to the excited acetylene: PET). Dramatically enhanced ISC between π-π* S1 state and “phantom” n,π* triplet excited state is likely to be important in directing reactivity to the triplet pathway. The role of PET can be minimized by judicious choice of reaction conditions (solvent, concentration, etc.). Furthermore, the 1,5-diaryl substituted homoquadricyclanes were used as building blocks in supramolecular scaffolds with a ca. 60o angle formed by the two aromatic rings defining a hydrophobic cavity. These structural features of pyridinyl homoquadricyclanes were applied to the design of composite organic/inorganic materials with topologies depending on the ratio of ligand to metal. Crystal structures of complexes varied from polymeric material, where the metal is shared between two homoquadricyclane molecules and alternating ligand-metal units, to supramolecular rhomboids, where crystal packing of the chain of rhomboids generates cavities which are filled with disordered solvent molecules. Substituents on the polycyclic moiety of the homoquadricyclane cause restricted rotation of the pyridine rings. This observation suggests that the flexibility of such systems can be fine-tuned to create a family of supramolecular scaffolds of controlled rigidity.

xvi CHAPTER I

INTRODUCTION

The Bergman Cycloaromatization Reaction: The Beginnings

In the early seventies, Jones and Bergman reported the thermal rearrangement of cis-3-hexene- 1,5-diyne, the simplest enediyne molecule, to an intermediate that can be intercepted by a hydrogen-atom donor to form benzene (Scheme 1).1 Extensive studies of this rearrangement led Bergman to postulate that this reaction goes through 1,4-didehydrobenzene or para-benzyne (p- benzyne) diradical. This diradical can either undergo ring opening to regenerate the starting enediyne molecule or abstract hydrogen-atom (H-atom) from available donors.1-3 It was not until a decade later that this cycloaromatization reaction became a focal point of numerous studies aimed to cure viral diseases and cancer tumors.

Scheme 1. Bergman Cycloaromatization Reaction of Enediynea

. H ∆ RH

. H Bergman Cyclization C1-C6

a ∆ is for heat and RH is the hydrogen-atom donor

Enediynes as Anticancer Antibiotics Drugs: Medical Significance and Limitations

During the second half of the 1980s, naturally occurring compounds derived from bacterial 4, 5 | 6, 7 8 9 sources, such as esperamicin A1, calicheamicin γ1 , dynemicin A and neocarzinostatins (Scheme 2) were found to induce double strand (ds) DNA cleavage. These molecules are composed of three different domains: a) the warhead which generates the active species responsible for the DNA damage; b) a delivery system which transport the molecule to the DNA; and c) the triggering device which activates the warhead. With the exception of neocarzinostatins, these families of anticancer antibiotics rely on the Bergman cycloaromatization reaction to generate the DNA-damaging species, p-benzyne. A similar cyclization reaction of the cyclic enyne-allene in the neocarzinostatin chromophore moiety,

1 known as the Myers-Saito cyclization, results in the formation of 1,5-didehydroindene (Scheme 1).10-13

Scheme 2. Naturally Occurring Antibiotic Enediynes SSSMe OH O NHCO Me H 2 O O Me Me S O CO H O O OH O N 2 OH O N O Me OMe OMe OMe O NHEt H I OMe O OH OH O Me OH O I dynemicin A calicheamicin g1 MeO OH

O O O SSSMe OMe OH H O NHCO Me Me O 2 O O Me SMe O O O O O N O O MeO O OMe O O NHiPr Me OH O NHMe OH O MeO OH O O Me OH MeO N esperamicin A1 OMe O neocarzinostatin chromophore

The mechanism of the biological activities of these substances has been studied extensively (Scheme 3).14-17 The sugar moiety of the enediyne antibiotics binds to the minor groove of the DNA where, after either a nucleophilic or a bioreductive activation, a conformational change decreases the distance between the terminal acetylenic carbon atoms in the enediyne moiety and triggers the Bergman cyclization which results in the formation of the active biradical species. Once the biradical species is formed, it abstracts hydrogen atoms from the sugar backbone of each of the DNA strands. In the presence of molecular oxygen with subsequent reduction of the resulting hydroperoxide, the two chains of DNA break.18 Because ds DNA cleavage is much more difficult to repair than single stranded (ss) DNA cleavage, the cell initiates apoptosis, the self-programmed cell death.19, 20

2 | Scheme 3. Mechanism of DNA Cleavage by Calicheamicin γ1 , Neocarzinostatin Chromophore and Dynemicin A15-19, 21

O O O NHCO Me O NHCO Me NHCO Me 2 2 2 NHCO2Me . DNA OH OH OH OH . O Sugar S S O Sugar S O Sugar S O Sugar S Cleaved DNA MeS _ Nu

O O O O O O O _ O O O O Nu O H O H OH DNA H H OH . OH Nu Nu Nu

. ArCO ArCO ArCO 2 2 2 ArCO2 Cleaved DNA O O O O Sugar Sugar Sugar Sugar

OMe OMe OMe COOH OH O NH COOH COOH O OH OH NH OH OH N O OH OMe OMe OMe _ Nu OH O OH OH OH OH OH OH OH

. OMe . OMe OMe COOH COOH OH OH NH COOH DNA OH OH NH OH OH OH NH OH OH OMe OMe Nu OMe Nu Nu

OH OH OH Cleaved DNA OH OH OH OH OH OH Unfortunately, the naturally occurring enediynes are toxic and thus much effort has been spent on the design of more selective derivatives that would combine high biological activity towards tumor cells with low toxicity towards normal cells.

Towards More Selective Enediyne Systems

Several approaches were undertaken to understand the relation between structure and activity of enediynes. Based on empirical observations, Nicolaou et al. suggested that the distance d of the acetylenic carbons (C1-C6) in enediynes is crucial for the cycloaromatization reaction to take

3 I place under physiological conditions. For example the C1-C6 distance in calicheamicin γ1 (3.35 Å) is significantly shortened after activation (3.16 Å). 21, 22, 23 Thus, embedding the enediyne moiety into a ten-membered ring drastically decreases the half-life of the enediyne (Scheme 4).24 This criterion was the subject of extensive theoretical investigations.25-27 In particular, Schreiner showed that the cyclization activation barrier depends on the ground state energy differences of the biradical products and found no linear relationship between d and the activation enthalpies of the Bergman cyclization.26, 27 He also suggested extending the threshold for spontaneous cyclization to the C1C6 distance of 3.4-2.9 Å. Despite these controversies, one can fairly state that C1C6 distance remains one of the important criteria for recognizing active enediynes.28, 29 Consequently, attempts have been made to design enediyne systems which, while sufficiently stable for isolation and handling at ambient temperatures, would be capable of cycloaromatization at physiological temperatures at rates sufficient to generate DNA damage.30- 33

Scheme 4. Acetylenic Carbons (C1C6) Distances of Acyclic and Cyclic Enediynesa H H o 200 oC 37 C t = 18 h t = 30 s 1/2 d 1/2 d HD HD

o H o H d = 4.12 A d = 3.25 A

a HD = hydrogen-atom donor

An elegant method for lowering the cyclization barrier involves complexation with transition metals. Buchwald et al. used this approach to decrease the C1-C6 distance and thus raise the energy of the reactants to achieve faster cyclization (Scheme 5).34 The authors followed the disappearance of the enediyne by 31P NMR and found that addition of palladium (II) to phosphorus enediyne accelerates the Bergman cycloaromatization reaction by a factor of more than 30,000 corresponding to a decrease in activation barrier of ca. 6 kcal/mol. Major improvements in the field of metalloenediynes have been achieved in recent years.35-38 Zaleski et al. used the Differential Scanning Calorimetry (DSC) technique to study the thermal stability of enediynes and their metal complexes as a function of the onset temperature obtained from the exothermic peak of the DSC curve. The authors showed that the reactivity of enediyne- metal complexes depends on the oxidation state of the metal. For example, the enediyne-Cu(I)

4 complex starts reacting at 203 ºC, whereas the enediyne-Cu(II) complex is substantially more reactive and reacts at 121 ºC (Scheme 6a).39 These results were rationalized in terms of copper ion geometry where Cu(II) adopts a tetragonal configuration while Cu(I) prefers a tetrahedral geometry. The latter arrangement increases the distance between the terminal acetylenic carbons, thereby decreasing reactivity. Recently, Zaleski et al. used Mg2+ salts to activate enediyne ligands and induce Bergman cyclization at room temperature (Scheme 6b).40

Scheme 5. Metal Complexation Drastically Reduces Cyclization of Enediynesa

PPh2 Ph Ph P PdCl -PdCl PPh2 d 2 d PdCl 2 2 35 oC, 42 min P PPh o o HD 2 d = 4.1 A PPh2 d = 3.3 A Ph Ph

95 oC, 19 days No reaction

Scheme 6. Bergman Cyclization of Enediyne Ligands Accelerated by Metal Complexationa

(a) +

O N N O Cu Reaction at 203 oC Cu(I) N O N N O O

2+ O S N Cu(II) O N N O Cu Reaction at 121 oC O N N O

S

(b) 2+

N N

N N o N N MgCl2 25 C, HD Mg Mg N N N N N N

a HD = hydrogen-atom donor. S = Solvent molecule

5 Roth et al. established the energy profile of the Bergman cyclization in the gas phase by studying temperature and NO concentration effects on the trapping rate of the p-benzyne 0 diradicals. While 8.5 kcal/mol difference between the enthalpy of formation (∆H f,298) for the enediyne and the diradical was found for cis-3-hexene-1,5-diyne, this difference increased to 17.8 kcal/mol for the benzannelated analogue, 1,2-diethynylbenzene (Figure 1).41, 42 These observations are in excellent agreement with the results reported by Hirama who demonstrated that the rate of Bergman cyclization does not solely depends on the cycloaromatization step, but also on the retro-Bergman and the hydrogen-atom abstraction steps.43, 44 For benzannelated enediynes, the latter steps become important in the kinetic scheme.

157.0 160.3 7.4 152.9 . 19.8 25.2 ∆H 28.5 17.8 . 138.0 . 129.5 8.5 135.1

.

Figure 1. The energy profiles of the Bergman cyclization as measured by Roth et al. in the gas phase. ∆H is in kcal/mol.

Scheme 7. Activation Energies for the Bergman Cyclization of Heteroaromatic Enediynes OMe N N N

MeO N

E = 21.5 kcal.mol-1 E = 33.6 kcal.mol-1 E = 16.1 kcal.mol-1 a a a Russell et al. determined activation energies for the disappearance of three heteroaromatic enediynes (Scheme 7).45 He concluded that addition of the second benzene ring to a pyridinyl enediyne decreases the rate of the reaction to the extent that corresponds to the activation energy increase of 12.1 kcal/mol.

6 Kinetic results for benzannelated cyclic enediyne shown in Scheme 8 were reported by Semmelhack et al.29 These authors showed that naphthodimethylhydroquinone enediyne is less reactive (t1/2 > 7 days at 120 ºC) than its naphthoquinone analogue (t1/2 > 88 hrs at 40 ºC). This discrepancy was attributed to the difference in double-bond character of the ene moiety. Kinetic studies on similar systems showed acceleration of the Bergman cyclization, in this case the oxidized species were comparable to the reduced compounds.46 These systems were applied to DNA-cleavage with the idea to use redox triggering of cycloaromatization under physiological conditions.

Scheme 8. Cyclic Enediynes Based on Quinones and Hydroquinones Moieties (a) OMe O

OMe OH O OH

o t = 88 h at 40 oC t1/2 > 7 d at 120 C 1/2

(b) OCOtBu O

OCOtBu OH O OH

t = 74 h at 110 oC t = 2.6 h at 55 oC 1/2 1/2 The Bergman Cycloaromatization: Computational Studies

In addition of its importance in medicinal chemistry, the Bergman cyclization reaction is also useful for calibrating and developing theoretical methods26, 27, 47-56 and finds further practical applications in the development of polymeric materials with valuable thermal properties,57-59 as well as in the synthesis of polycyclic compounds.60, 61 Success of the above practical applications depends on control over enediyne reactivity through either strain62-64 or electronic effects, vide infra. The seminal hypothesis rationalizing the influence of electronic factors was advanced by Koga and Morokuma65 who attributed the high activation energy of the Bergman cyclization to strong electron repulsion between the in-plane occupied acetylene π-orbitals. This notion has been

7 further confirmed by a recent Natural Bond Orbital (NBO) study66 that also found that the role of steric repulsion between the filled orbitals is accentuated by the parallel decrease in attractive two-electron interaction between the π and π* orbitals. At the “Nicolaou’s threshold” (ca. 3.2 Å), the latter interaction vanishes because the in-plane p-orbitals become parallel approaching the geometry of symmetry forbidden antiaromatic TS for thermal [2π+2π] cycloaddition (Figure 2).66 This observation provides a theoretical explanation to this empirical observation and implies that electron withdrawing substituents should promote the cyclization and that electron donors should have the opposite effect – a hypothesis that has been confirmed by several experimental studies.67-69

H H H H H H H H

Figure 2. Comparison of the “antiaromatic region” in enediyne with the antiaromatic TS of the [2π+2π] cycloaddtion.

Recent experimental findings suggest that positioning of acceptor substituents is also important. For example, Jones showed that progressive substitution of hydrogen atoms by halogens at the vinyl position decreases the reaction rate,70 and Chen found that protonation of the nitrogen atom in 3-aza-enediynes increases the cyclization barrier.71 On the other hand, a detailed computational study by Schreiner predicts that the cyclization is accelerated by σ- acceptors at the terminal acetylene atoms which are able to interact directly with the in-plane orbitals.72-74 Since the developing radical-centers are orthogonal to the out-of-plane π-system, the activation energies of thermal cycloaromatization reactions of benzannelated enediynes is not sensitive to properties of remote substituents on the aromatic ring. The reaction kinetics is controlled mainly by electronic effects involving in-plane orbitals75, 76 and is relatively insensitive to benzannelation and π-conjugative effects of substituents in the aromatic ring annealed at the vinyl part of the enediyne moiety. Although the importance of the out-of-plane interactions increases progressively after the TS,77 the low sensitivity of reaction kinetics to substituent

8 effects is one of the largest challenges to efficient control and rational design of cycloaromatization reactions. Since changes in the out-of-plane orbitals do not play an important role in the cyclization transition state (TS), benzannelation of the central double bond has little influence on the activation energy of the cyclization. However, cyclizations of benzannelated enediynes were reported to be slower and more sensitive to hydrogen donor concentration. This effect was attributed to faster retro-Bergman cyclization and slower hydrogen abstraction steps.43, 44 More recent studies showed that the reactivity of diradical species toward hydrogen abstraction is much slower than that of monoradical species.78 Furthermore, Russell et al. have shown that the rates of disappearance for a series of para-substituted benzannelated enediynes are “insensitive” to the electronic nature of the substituents.67 They concluded that the major contribution to the substituent influence is provided by field rather than resonance effect.

Setting the Paradigm: A Theoretical Background

Computational studies carried out by our group suggest that the rate of Bergman cyclization can be controlled through introduction of substituents that are spatially close to the enediyne moiety (Scheme 9).79 Depending on the substituent, three different mechanisms account for the large effect of ortho-substitution on the cycloaromatization step: (a) steric assistance80-decrease in steric destabilization in TS, (b) extra stabilization of the TS, and (c) decrease in TS stabilization.

Scheme 9. Bergman Cyclization of Ortho-Substituted Benzannelated Enediynes

Repulsion or Attraction X X . X H

Heat H-donor . H X = H, F, Cl, CH , CN, CF , OH, NO , CHO, OCH , NH , NH + 3 3 2 3 2 3

The NO2, CF3, Syn-CHO, and OMe groups are predicted to decrease the activation energy for Bergman cyclization by destabilizing the reactant through steric repulsion between the ortho- substituent and the in-plane acetylenic π-orbitals (Figure 3a). This interaction becomes less significant in the TS in which the acetylene moiety is bent away from the ortho functional group.

9 On the other hand, the CH3, NH2, and syn-OH moieties are predicted to have minor decelerating effect on the cyclization step. These substituents stabilize the reactant by the attractive “hydrogen bond-like” interaction between the acetylenic π-orbitals and the ortho- substituent moiety. This interaction results in bending of the acetylene group toward the ortho- substituent (outward) and thus an increase in the distance between the terminal acetylenic carbons (Figure 3b). In the TS, this stabilizing interaction diminishes due to inward bending of the acetylene moiety, away from the ortho-substituent group.

(a) 35 TS 2.8 O N E 30 2 kcal mol-1 Repulsion 25 O + O N 20 27.9

15 30.9

10 2. P 0 6.6 5 R 5.8 10.4 0

(c) (b) 35 Attractive interaction TS 35 H +N TS Y E 30 3 2NH H 0.8 z kcal mol-1 E 30 X 6.8 kcal mol-1 25 25 20 20 32.3 15 15 28.4 P P 31.5 10 0. 30.3 10 2.5 8 X=C, Y=Z=H (E=0.8 kcal/mol) X=O, Y=Z=lone pair (E=2.7 kcal/mol) 5 5 11.5 9.2 12.4 3:X=N, Y=H, Z=lone pair (E=1.3 kcal/mol) R 11.6 R 0 0 3H+: X=N, Y=Z=H (E=5.2 kcal/mol) 1.6 5.0 -5 -5

Figure 3. Three mechanisms explaining “ortho”-effect in the Bergman cyclization: (a) steric assistance, (b) decrease in TS stabilization, and (c) extra stabilization of the TS. The energy profile for the para isomers is given by a black line, and that for the ortho isomers by a red line. Energies of πÆσ*X-H interactions found by the NBO analysis are given in parentheses. Calculations were performed at the BS-UB3LYP/6-31G** level.

+ In the case of a positively charged functional group, NH3 , the strength of hydrogen bonding is increased, thus providing stabilization of the reactants. However, the transition state acquires extra stabilization and the activation barrier is markedly decreased. This is a result of strong through space electron transfer from the adjacent in-plane π-bond to the ammonium group, which decreases population of this π-bond, thus alleviating repulsion between the filled in-plane orbitals in the transition state (Figure 3c).

10 In this part, we test our computational predictions with experimental studies designed to determine whether ortho substituents are capable of decreasing the activation energy of the Bergman cyclization.

EXPERIMENTAL SECTION

Synthesis of Benzannelated Enediynes

The requisite enediyne molecules were synthesized according to standard literature procedures outlined in Scheme 10.

Scheme 10. Synthesis of Benzannelated Enediynes

OMe OH OH OMe OMe I I a b c d

I NO NO2 2 78% 50% 54% 67% ortho-OCH3

I Br c d c d

O2N I O2N Br O N 70 % 2 78% 35% para-NO 70% 1,2-Diethynylbenzene 2

O

NO NO2 NH2 NH CF 2 2 NH 3 NO2 Br Br d d c e c

Br Br 68 % 75% 59% 80 % 85% ortho-NO2 ortho-NH2

CHO CHO CHO CHO OH f OTf g d

OH OTf 40% 98 % 42% ortho-CHO

Reagents and conditions: (a) 1. NaOH, Hg(OAc)2 and 2. KI, I2 (b) 1. KOH/MeOH 2. MeI. 3. SnCl2 3. NaNO2, HCl, KI (c) 1. Pd(PPh3)2Cl2, (i-Pr)2NH, Cu(I), HCCSiMe3 and 2. NaOH, MeOH (d) PhCl, 1,4-cyclohexadiene (e) 1. SnCl2 2. (CF CO) O (f) Tf O, Pyridine, CH Cl (g) 1. Pd(PPh ) Cl , K CO , THF , HCCSiMe 2. MeOH, K CO 3 2 2 2 2 3 2 2 2 3 (Dry) 3 2 3

11 The aromatic dihalides or ditriflates81 were coupled with trimethylsilyl (TMS) acetylene under Sonogashira conditions.82-84 Treatment of the TMS protected enediynes with a base afforded ortho-substituted benzannelated enediynes in good yields. Bergman cyclizations of enediynes on a preparative scale were performed in Pyrex glass tubes containing a solution of the enediyne (0.10 M) and 1,4-cyclohexadiene (10.0 M) in chlorobenzene.

Synthetic Procedures and Spectroscopic Details

Materials. 3-Nitrophenol was purchased from Aldrich. 1,2-Dibromobenzene was purchased from Acros Fisher Scientific and used as received. Trimethylsilylacetylene was purchased from Petra Research Inc. 1,4-Cyclohexadiene was purchased from Fisher Scientific and distilled before use. Chlorobenzene (certified grade) was purchased from Fisher Scientific and used as received. Capillaries (300 mm length, 1.5-1.8 mm outer diameter, 0.2 mm wall) used in kinetic studies were purchased from Freidrick and Dimmock Inc. 85 79 1,2-Diethynylbenzene and 2,3-diethynyl-1-methoxybenzene (ortho-CHO3) were prepared according to literature procedures.

Physical Measurements. HPLC purifications were performed on a Beckman-Coulter HPLC system (125 gradient pump, 166 variable UV detector, equipped with a 508 Beckman autosampler) using a normal phase prep-column (SupelcosilTM LC-SI, 250 mm, 21.2 mm, 5 m) unless stated otherwise. Differential scanning calorimetry (DSC) measurements were recorded on a DSC Q-1000 TA Instruments. 1H and 13C NMR spectra were recorded on a 7 Tesla Varian Mercury 300 NMR spectrometer. UV spectra were recorded on a Shimadzu UV-2100 spectrophotometer. Infrared (IR) spectra were recorded on a NICOLET AVATAR 360 FT-IR spectrometer. High resolution mass spectra (HRMS) were recorded with a JEOL Model JMS 600H spectrometer using PFK (perfluorokerosene) as the internal standard. Flash chromatography was performed using ISCO, Inc. Combi Flash Companion system 1.2.11 and HPLC grade solvents. Melting points were determined using a Thomas Hoover melting point apparatus.

12 General Procedure for Sonogashira Coupling. A suspension of aryl dihalide or ditriflate

(5.8 mmol), PdCl2(PPh3)2 (0.29 mmol), Cu(I) iodide (0.29 mmol) in 40 mL of (i-Pr)2NH was degassed three times with freeze/pump/thaw technique in a flame dried screw-cap Ace pressure tube. Trimethylsilyl (TMS) acetylene (14.5 mmol) was added using a syringe. The tube was capped and the mixture was heated to the corresponding temperature in an oil bath. The reaction was monitored by TLC. After total consumption of the aryl halide, the reaction mixture was filtered through celite and washed with methylene chloride (3 × 30 mL). The organic layer was washed with a saturated solution of ammonium chloride (2 × 30 mL), water (2 × 30 mL) and dried over anhydrous Na2SO4. Solvent was removed in vacuo. The reaction mixture was purified by flash chromatography on silica gel.

General Procedure for TMS Deprotection: 1N NaOH (5 mL) was added to a methanol solution (50 mL) of enediyne (3.2 mmol). The mixture was stirred at room temperature for 15 min. The progress of the reaction was monitored by TLC. After total transformation of the TMS acetylenes, the solvent was removed in vacuo. Aqueous HCl (1 N, 10 mL) was added to the crude mixture. The acidic mixture was extracted by dichloromethane (3 × 20 mL). The organic layer was washed with water (2 × 30 mL) and dried over anhydrous Na2SO4. Solvent was removed in vacuo. The reaction mixture was purified by flash chromatography on silica gel.

General Procedure for Preparative Scale of Bergman Cyclizations: Enediyne (0.5 mmol) was dissolved in anhydrous chlorobenzene (9 mL). 1,4-Cyclohexadiene (50 mmol) was added and the mixture was placed in a Pyrex glass tube equipped with a joint. The tube was attached through the joint to a vacuum line and the mixture was degassed three times by the freeze/pump/thaw technique. The tube was sealed under argon, placed in an oil bath and heated to the corresponding temperature. After cooling down, chlorobenzene was distilled under vacuo and the products were isolated and purified by chromatography.

2,3-Diethynylnitrobenzene (ortho-NO2 enediyne) Synthesis of 2,3-Bis(trimethylsilylethynyl)nitrobenzene. The title compound was prepared by Sonogashira coupling of 2,3-dibromonitrobenzene (2.2 g, 7.8 mmol) with

trimethylsilylacetylene (1.92 g, 19.6 mmol) in 60 mL (i-Pr)2NH at 95º C for 24 hours. The

13 reaction mixture was purified by flash chromatography on silica gel (hexanes) to afford 1.85 g 1 (72%) of the desired product as brown solid; m.p. 67-68 ºC; H NMR (300 MHz, CDCl3) į 7.86 (d, 1H, J = 7.5 Hz), 7.68 (dd, 1H, J = 8.1 Hz), 7.36 (dd, 1H, J = 8.1, 7.5 Hz), 0.28 (s, 9H), 0.27 13 (s, 9H); C NMR (75.5 MHz, CDCl3) į 150.9, 136.2, 128.8, 127.7, 123.7, 120.0, 108.6, 101.4,

101.1, 97.0, -0.5, -0.7; UV/Vis (CH3CN): λmax(lgε) = 328 nm (4.28), 264 (4.20), 250 (4.48), 214 (4.49); IR (neat) 2962, 2900, 2164, 1532, 1353, 1248, 846, 761 cm-1; HRMS (EI+) calculated for

C16H21NO2Si2 315.11109, found 315.11104. Synthesis of 2,3-Diethynylnitrobenzene. The title compound was prepared by TMS deprotection procedure of 2,3-bis(trimethylsilylethynyl)nitrobenzene (1.01 g, 3.21 mmol) with 1N NaOH (5 mL) in 50 mL MeOH at room temperature for 15 min. The reaction mixture was purified by flash chromatography on silica gel (hexanes) to afford 0.49 g (90%) of the desired 1 product as a white solid; m.p. 84 ºC, H NMR (300 MHz, CDCl3) į 7.9 (d, 1H, J = 8.1 Hz), 7.7 13 (d, 1H, J = 8.1 Hz), 7.4 (dd, 1H, J = 8.1), 3.8 (s, 1H), 3.4 (s, 1H); C NMR (75.5 MHz, CDCl3)

į 151.0, 136.6, 128.5, 128.4, 124.2, 119.6, 89.7, 83.7, 79.9, 76.2; UV/Vis (CH3CN): λmax(lgε) = 330 nm (2.98), 282 (3.85), 261 (4.07), 228 (4.05); IR (neat) 3276, 2105, 1517, 1352, 741 cm-1;

HRMS (EI+) calculated for C10H5O2N 171.03203, found 171.03211.

3,4-Diethynylnitrobenzene (para-NO2 enediyne) Synthesis of 3,4-Bis(trimethylsilylethynyl)nitrobenzene. The title compound was prepared by Sonogashira coupling of 3,4-dibromonitrobenzene (3.1 g, 9.8 mmol) with trimethylsilylacetylene (2.41 g, 246 mmol) in 60 mL (i-Pr)2NH at 110º C for 24 hours. The reaction mixture was purified by flash chromatography on silica gel (hexanes) to afford 2.78 g (80%) of the desired product as an off-white solid; m.p. 118-121 ºC; 1H NMR (300 MHz, 13 CDCl3) į 8.3 (d, 1H, J = 2.4 Hz), 8.0 (dd, 1H, J = 9.0, 2.7 Hz), 0.29 (s, 18H); C NMR (75.5

MHz, CDCl3) į 146.9, 133.2, 132.1, 127.4, 127.3, 122.8, 105.1, 102.0, 101.6, 101.1, 0.03, -0.01;

UV/Vis (CH3CN): λmax(lgε) = 307 nm (4.17), 261 (4.34), 229 (4.27), 220 (4.28); IR (neat) 3280, -1 3106, 2110, 1573, 1522, 1354, 909, 661 cm ; HRMS (EI+) calculated for C16H21NO2Si2 315.11109, found 315.11016. Synthesis of 3,4-Diethynylnitrobenzene. The title compound was prepared by TMS deprotection procedure of 3,4-bis(trimethylsilylethynyl)nitrobenzene (1.50 g, 4.76 mmol) with 1N NaOH (10 mL) in 150 mL MeOH at room temperature for 15 min. The reaction mixture was

14 purified by flash chromatography on silica gel (hexanes) to afford 0.59 g (72%) of the desired 1 product as a white solid; m.p. 92 ºC, H NMR (300 MHz, CDCl3) į 8.3 (d, 1H, J = 2.4 Hz), 8.1 (dd, 1H, J = 8.4, 2.4 Hz), 7.6 (d, 1H, J = 9.0), 3.6 (s, 1H), 3.5 (s, 1H); 13C NMR (75.5 MHz,

CDCl3) į 147.3, 133.7, 131.4, 127.6, 126.8, 123.4, 86.6, 84.1, 80.4, 79.9; UV/Vis (CH3CN):

λmax(lgε) = 289 nm (413), 238 (4.26), 218 (4.30); IR (neat) 2960, 2899, 2145, 1523, 1346, 1248, -1 847 cm ; HRMS (EI+) calculated for C10H5O2N 171.03203, found 171.03107.

2,3-Diethynylbenzaldehyde (ortho-CHO enediyne) Synthesis of 3-formyl-phenyl-1,2-bis(trifluoromethanesulfonate). 2,3-Dihydroxy-

benzaldehyde ( 0.50 g, 3.62 mmol) and pyridine (1.5 mL, 18.1 mmol) were dissolved in CH2Cl2 (25 mL). The mixture was cooled to 0 ºC under Argon and trifluoromethanesulfonic anhydride (1.4 mL, 8.0 mmol) was added dropwise. The reaction was slowly warmed to room temperature and stirred for 6 hrs. The mixture was diluted with CH2Cl2, washed with water and dried over

Na2SO4. The solvent was removed under vacuo. The reaction mixture was purified by chromatography on silica gel (9:1 hexanes:ethyl acetate) to afford 1.82 g (98%) of the desired 1 product as a white solid; m.p. 38 ºC, H NMR (300 MHz, CDCl3) į 10.2 (s, 1H), 8.0 (dd, 1H, J = 7.5, 1.5 Hz), 7.8 (dd, 1H, J = 8.1, 1.2 Hz), 7.7 (dd, 1H, J = 8.1, 7.8 Hz); 13C NMR (75.5 MHz,

CDCl3) į 185.0, 141.1, 140.2, 131.0, 130.2, 129.8, 128.5, 118.3 (q, J = 321.2 Hz), 118.2 (q, J =

321.8 Hz); UV/Vis (CH3CN): λmax(lgε) = 280 nm (3.18), 238 (3.85), 203 (4.54); IR (neat) 3401, 3094, 2888, 2758, 1709, 1432, 1223, 1210, 1129, 958, 873 cm-1; HRMS (EI+) calculated for

C9H4O7F6S2 401.93025, found 401.92998. Synthesis of 2,3-Bis(trimethylsilylethynyl)-1-formylbenzene. The title compound was prepared by Sonogashira coupling of 3-formyl-phenyl-1,2-bis(trifluoromethanesulfonate) (0.70

g, 1.74 mmol) with trimethylsilylacetylene (0.41 g, 4.18 mmol) in 20 mL Et3N at 110º C for 8 hours. The reaction mixture was purified by flash chromatography on silica gel (99:1 hexanes:ethyl acetate) to afford 0.10 g (20%) of the desired product; 1H NMR (300 MHz,

CDCl3) į 10.5 (s, 1H), 7.8 (d, 1H, J = 7.5 Hz), 7.7 (d, 1H, J = 7.5 Hz), 7.3 (dd, 1H, J = 8.1, 7.2 13 Hz), 0.28 (s, 9H), 0.27 (s, 9H); C NMR (75.5 MHz, CDCl3) į 191.4, 137.2, 136.2, 128.8,

127.9, 127.4, 126.4, 106.9, 101.7, 100.1, 97.9, -0.4, -0.5; UV/Vis (CH3CN): λmax(lgε) = 322 nm (3.07), 284 (3.79), 253 (4.31); IR (neat) 2956, 2846, 2361, 2336, 1699, 1559, 1250, 844 cm-1;

HRMS (EI+) calculated for C17H22OSi2 298.12093, found 298.12017.

15 Synthesis of 2,3-Diethynyl-1-formylbenzene. The title compound was prepared by TMS deprotection procedure of 2,3-bis(trimethylsilylethynyl)-1-formylbenzene (0.50 g, 1.68 mmol) with 1N NaOH (2 mL) in 30 mL MeOH at room temperature for 15 min. The reaction mixture was purified by flash chromatography on silica gel (hexanes) to afford 0.13 g (50%) of the 1 desired product as white solid; m.p. 113-114 ºC, H NMR (300 MHz, CDCl3) į 10.6 (s, 1H), 7.9 (dd, 1H, J = 7.8, 1.2 Hz), 7.7 (dd, 1H, J = 8.1, 1.2 Hz), 7.4 (dd, 1H, J = 8.1, 7.5), 3.7 (s, 1H), 3.4 13 (s, 1H); C NMR (75.5 MHz, CDCl3) į 190.9, 137.5, 136.7, 128.5, 127.9, 127.1, 126.9, 88.5,

82.5, 80.4, 77.0; UV/Vis (CH3CN): λmax(lgε) = 319 nm (3.00), 262 (4.03), 242 (4.54); IR (neat) -1 3261, 2853, 2102, 1694, 1437, 1244, 794, 637 cm ; HRMS (EI+) calculated for C11H6O 154.04187, found 154.04208.

2,3-Diethynyl-1-trideuteriomethoxybenzene (o-OCD3 enediyne) Synthesis of 2-Iodo-1-trideuteriomethoxy-3-nitrobenzene. KOH pellets (0.11 g, 1.96 mmol) were added to a solution of 2-iodo-3-nitrophenol (0.50 g, 1.89 mmol) in MeOH (10 mL) and stirred for 20 hrs. The red precipitate of 2-iodo-3-nitro potassium phenolate (0.50 g, 1.65 mmol)

was filtered, dissolved in dry acetonitrile and placed in an Ace pressure tube. CD3I was added and the reaction was heated to 80 ºC for 30 min. After the reaction mixture turned yellow, the

solvent was evaporated under vacuo. The residue was dissolved in CH2Cl2, washed with H2O (2

× 20 mL) and dried over Na2SO4. The solvent was removed under vacuo. Recrystallization from hexanes afforded 0.45 g (85%) of the desired product as yellow crystals; m.p. 93-95 ºC, 1H NMR

(300 MHz, CDCl3) į 7.4 (dd, 1H, J =8.4, 7.8 Hz), 7.3 (dd, 1H, J = 8.4, 1.2 Hz), 6.9 (dd, 1H, J = 13 8.1, 1.2 Hz); C NMR (75.5 MHz, CDCl3) į 159.7, 155.7, 130.0, 119.8, 113.4, 79.9; UV/Vis

(CH3CN): λmax(lgε) = 317 nm (3.81), 272 (3.46), 222 (4.13); IR (neat) 3074, 1522, 1448, 1348, -1 1285, 1098 cm ; HRMS (EI+) calculated for C7H3D3NO3I 281.95810, found 281.95872.

Synthesis of 2-Iodo-3-deuteriomethoxy-phenylamine. SnCl2 (2.5 g, 12.9 mmol) was added to 2-iodo-1-trideuteriomethoxy-3-nitrobenzene (0.73 g, 2.59 mmol) to 5 mL of EtOH. The reaction was stirred at room temperature for 32 hrs. The solvent was evaporated under vacuo and

the residue was rendered alkaline by adding NaOH (1N). The mixture was extracted with CH2Cl2

(3 × 10 mL) and the organic mixture was washed with H2O (2 × 10 mL) and dried over Na2SO4. The solvent was removed under vacuo. The reaction mixture was purified by chromatography on silica gel (hexanes) to afford 0.49 g (75%) of the desired product as a yellow solid; m.p. 42 ºC,

16 1 H NMR (300 MHz, CDCl3) į 7.08 (d, 1H, J = 8.1, 7.8 Hz), 6.39 (dd, 1H, J = 8.1, 1.2 Hz), 6.20 13 (dd, 1H, J = 8.1, 1.2 Hz), 4.25 (bs, 2H); C NMR (75.5 MHz, CDCl3) į 185.8, 148.4, 129.6,

107.8, 100.4, 75.8, 55.4 (septet, J = 21.7 Hz); UV/Vis (CH3CN): λmax(lgε) = 293 nm (3.36), 238 (3.93), 214 (4.54); IR (neat) 3348, 1608, 1454, 1266, 1101, 761 cm-1; HRMS (EI+) calculated for

C7H5D3NOI 251.98392, found 251.98476. Synthesis of 2,3-Diiodo-1-trideuteriomethoxybenzene. Dropwise addition of solution of sodium nitrite (0.21 g, 3.06 mmol) in 6 mL of water to solution of 2-iodo-3-deuteriomethoxy- phenylamine (0.70 g, 2.78 mmol) in 11 mL HCl prepared from 5 mL concentrated HCl and 6 mL

H2O solution at 5 ºC was carried out over 30 min. After the mixture was stirred for 20 min more

at 5 ºC, a solution of potassium iodide (3.1 g, 19.2 mmol) in H2O (4 mL) was added dropwise.

The solution was then heated at 80 ºC for 2 hrs, cooled and extracted with CH2Cl2 (3 × 10 mL).

The combined extracts were washed with 5% aqueous sodium bisulfite and dried over Na2SO4. The solvent was removed under vacuo. The reaction mixture was purified by chromatography on silica gel (hexanes) to afford 0.71 g (70%) of the desired product as a white solid; m.p. 71-72 ºC, 1 H NMR (300 MHz, CDCl3) į 7.5 (d, 1H, J = 8.1, 1.5 Hz), 7.0 (dd, 1H, J = 8.1, 8.1 Hz), 6.7 (d, 13 1H, J = 7.2 Hz); C NMR (75.5 MHz, CDCl3) į 159.8, 131.7, 130.5, 109.7, 109.4, 100.4;

UV/Vis (CH3CN): λmax(lgε) = 291 nm (3.36), 283 (3.43), 217 (4.40); IR (neat) 3054, 2255, 2228, -1 2068, 1558, 1335, 1267, 1102, 989, 764 cm ; HRMS (EI+) calculated for C7H3D3OI2 362.86970, found 362.86909. Synthesis of 2,3-Bis(trimethylsilylethynyl)-1-trideuteriomethoxybenzene. The title compound was prepared by Sonogashira coupling of 2,3-Diiodo-1-trideuteriomethoxybenzene

(3.1 g, 9.8 mmol) with trimethylsilylacetylene (2.41 g, 246 mmol) in 60 mL (i-Pr)2NH at 100º C for 3 hours. The reaction mixture was purified by flash chromatography on silica gel (hexanes) to afford 1.40 g (80%) of the desired product as yellow needles; m.p. 65 ºC, 1H NMR (300 MHz,

CDCl3) į 7.12 (dd, 1H, J = 8.1, 7.8 Hz), 7.04 (d, 1H, J = 7.8 Hz), 6.74 (d, 1H, J = 8.2 Hz), 0.27 13 (s, 9H), 0.25 (s, 9H); C NMR (75.5 MHz, CDCl3) į 160.2, 128.9, 127.7, 124.5, 114.9 110.6,

103.1, 102.8, 99.2, 89.1, 55.5 (septet, J = 22.3 Hz), -0.2, -0.3; UV/Vis (CH3CN): λmax(lgε) = 328 nm (3.14), 315 (3.10), 283 (3.98), 243 (4.44); IR (neat) 2960, 2156, 1562, 1460, 1249, 1110, -1 844, 760 cm ; HRMS (EI+) calculated for C17H21D3OSi2 303.15541, found 303.15549. Synthesis of 2,3-Diethynyl-1-trideuteriomethoxybenzene. The title compound was prepared by TMS deprotection procedure of 2,3-Bis(trimethylsilylethynyl)-1-trideuteriomethoxybenzene

17 (1.10 g, 3.63 mmol) with 1N NaOH (10 mL) in 150 mL MeOH at room temperature for 15 min. The reaction mixture was purified by flash chromatography on silica gel (hexanes) to afford 0.50 1 g (86%) of the desired product as a white solid; m.p. 52 ºC, H NMR (300 MHz, CDCl3) į 7.2 (dd, 1H, J = 8.1, 7.8 Hz), 7.1 (d, 1H, J = 7.5 Hz), 6.8 (dd, 1H, J = 9.3), 3.6 (s, 1H), 3.3 (s, 1H); 13 C NMR (75.5 MHz, CDCl3) į 160.6, 129.4, 126.5, 124.6, 113.9, 110.9, 85.4, 81.6, 81.2, 78.0,

55 (septet, J = 22.3 Hz); UV/Vis (CH3CN): λmax(lgε) = 321 nm (3.61), 267 (3.99), 258 (3.94), 254 (3.93), 235 (4.57); IR (neat) 3280, 2230, 2073, 1565, 1458, 1294, 1104, 789, 633 cm-1;

HRMS (EI+) calculated for C11H5D3O 159.07635, found 159.07608.

2,3-Diethynyl-1-aminobenzene (ortho-NH2 enediyne) 2,3-Dibromo-N-(trifluoroacetyl)-1-aminobenzene. 2,3-Dibromoaniline (0.57 g, 2.27 mmol) was dissolved in dried THF (20 mL). Trifluoroacetic anhydride (0.63 mL, 4.54 mmol) was added dropwise to the solution at 0 ºC within 15 min. The solution was further stirred for 40 min at room temperature. The reaction mixture was evaporated to dryness and the resulting residue was stirred with 1.2 L of H2O (twice). The product was extracted from the aqueous solution with ether (3 × 30 mL) and dried over Na2SO4. The solvent was removed under vacuo to afford 0.78 g 1 (99%) of the desired product as off-white crystals; m.p. 72-74 ºC, H NMR (300 MHz, CDCl3) į 8.6 (bs, 1H), 8.1 (d, 1H, J = 8.1 Hz), 7.4 (d, 1H, J = 7.8 Hz), 7.2 (dd, 1H, J = 8.1 Hz); 13C NMR

(75.5 MHz, CDCl3) į 154.7 (q, J = 37.8 Hz), 134.8, 130.7, 129.0, 125.4, 120.5, 117.3, 116.8 (q,

J = 318.4 Hz); UV/Vis (CH3CN): λmax(lgε) = 317 nm (3.81), 272 (3.46), 222 (4.13); IR (neat) -1 3304, 1709, 1578, 1537, 1163 cm ; HRMS (EI+) calculated for C8H4NOF3Br2 344.86120, found 344.86073. 2,3-Bis(trimethylsilylethynyl)-N-(trifluoroacetyl)-1-aminobenzene. The title compound was prepared by Sonogashira coupling of 2,3-dibromo-N-(trifluoroacetyl)-1-aminobenzene (0.65

g, 1.87 mmol) with trimethylsilylacetylene (0.44 g, 4.50 mmol) in 20 mL (i-Pr)2NH at 110º C for 10 hours. The reaction mixture was purified by flash chromatography on silica gel (100:1 hexanes:ethyl acetate) to afford 0.61 g (85%) of the desired product as yellow crystals; m.p. 86- 1 88 ºC, H NMR (300 MHz, CDCl3) į 8.9 (bs, 1H), 8.3 (m, 1H), 7.2 (m, 2H), 0.3 (s, 9H), 0.2 (s, 13 9H); C NMR (75.5 MHz, CDCl3) į 154.3 (m), 136.8, 129.1, 128.7, 125.8, 118.8, 115.8, 108.4,

101.9, 99.7, 97.0, -0.5, -0.7; UV/Vis (CH3CN): λmax(lgε) = 328 nm (3.34), 296 (3.32), 283 (4.19),

18 273 (4.26) 243 (4.65); IR (neat) 3365, 2963, 2155, 1744, 1467, 1252, 1156, 845 cm-1; HRMS

(EI+) calculated for C18H22NOF3Si2 381.11921, found 381.11833. 2,3-Diethynyl-1-aminobenzene. The title compound was prepared by TMS deprotection procedure of 2,3-Bis(trimethylsilylethynyl)-N-(trifluoroacetyl)-1-aminobenzene (1.10 g, 2.89 mmol) with 1N NaOH (20 mL) in 100 mL EtOH at room temperature for 1 hour. The reaction mixture was purified by flash chromatography on silica gel (95:1 hexanes:ethyl acetate) to afford 1 0.35 g (86%) of the desired product as brownish oil; H NMR (300 MHz, CDCl3) į 7.1 (dd, 1H, J = 8.1, 7.8 Hz), 6.9 (d, 1H, J = 8.1 Hz), 6.7 (d, 1H, J = 8.1 Hz), 4.3 (bs, 2H), 3.6 (s, 1H), 3.3 (s, 13 1H); C NMR (75.5 MHz, CDCl3) į 148.6, 129.2, 125.0, 122.2, 114.5, 108.9, 86.1, 82.2, 80.0,

78.7; UV/Vis (CH3CN): λmax(lgε) = 342 nm (3.81), 244 (4.54), 233 (4.60), 213 (4.29); IR (neat) -1 3476, 3381, 3282, 2099, 1609, 1464, 1293, 789, 619 cm ; HRMS (EI+) calculated for C10H7N 141.05785, found 141.05794.

Preparative Scale of Bergman Cyclizations of 2,3-Diethynyl-1-methoxybenzene and 2,3- Diethynyl-1-trideuteriomethoxybenzene. 2,3-Diethynyl-1-methoxybenzene or 2,3-diethynyl-1- trideuteriomethoxybenzene (75 mg, 0.48 mmol) was dissolved in anhydrous chlorobenzene (9 mL). 1,4-Cyclohexadiene (4.5 mL, 48 mmol) was added and the mixture was placed in a Pyrex glass tube equipped with a joint. The tube was attached through the joint to a vacuum line and the mixture was degassed three times by the freeze/pump/thaw technique. The tube was sealed under argon, placed in an oil bath and heated to the corresponding temperature. After cooling down, chlorobenzene was distilled under vacuo and the products were isolated and purified by HPLC using hexanes HPLC grade as solvent with 4 mL/min flow rate, 265 nm detection wavelength and 500 µl loop. Proton chemical shifts of 1-methoxynaphthalene were calculated using Gassian98 (B3LYP 6- 31G**) and are given below (experimental 1H NMR shifts are given in parentheses):

4.0 (4.0) H 3.8 H 8.5 (8.3) H O H H H 6.6 (6.8) 7.5 (7.4-7.5)

H H 7.4 (7.4-7.5) 7.5 (7.4-7.5) H H 7.7 (7.8) 7.3 (7.4-7.5)

19 1 1-Methoxynaphthalene: (38 mg, 48%) H NMR (500 MHz, CDCl3) į 8.3 (d, 1H, J = 8.8 Hz),

OMe 7.8 (d, 1H, J = 7.3 Hz), 7.4-7.5 (m, 4H), 6.8 (d, 1H, J = 7.3 Hz), 4.0 (s, 3H);

HRMS (EI+) calculated for C10H7N 141.05785, found 141.05794.

1 1-(Cyclohexa-2,5-dienylmethyloxy)-naphthalene: (3.4 mg, 3%) H NMR (500 MHz, CDCl3) į 8.3 (d, 1H, J = 6.9 Hz), 7.8 (d, 1H, J = 7.8 Hz), 7.4-7.5 (m, 4H), 6.8 (d, 1H, J O = 7.3 Hz), 5.9 (m, 4H), 4.1 (d, 2H, J = 6.5 Hz), 3.4 (dd, 1H, J = 7.7, 7.3 Hz),

2.8 (d, 2H, J = 7.6 Hz); HRMS (EI+) calculated for C17H16O 236.12012, found 236.11950.

1-Cyclohexa-2,5-dienyl-8-methoxynaphthalene: (1.1 mg, 2%) 1H NMR (500

OMe MHz, CDCl3) į 7.6 (d, 1H, J = 7.8 Hz), 7.4-7.5 (m, 4H), 6.8 (d, 1H, J = 7.3 Hz), 5.9 (dm, 2H, J = 10.2 Hz), 5.8 (dm, 2H, J = 10.2 Hz), 5.6 (m, 1H), 3.9 (s, 3H), 2.8

(m, 2H); HRMS (EI+) calculated for C17H16O 236.12012, found 236.11977.

1-Trideuteriomethoxynaphthalene and 1-dideuteriomethoxy-8-deuterionaphthalene: (39 1 mg, 51%) H NMR (500 MHz, CDCl3) 8.3 (d, 0.8H, J = 7.5 Hz), CD2H į OCD3 OD 7.8 (d, 1H, J = 7.0 Hz), 7.4-7.5 (m, 4H), 6.8 (d, 1H, J = 7.0 Hz), + 4.0 (m, 0.2H); HRMS (EI+) calculated for C11H7D3O 161.09176, 4:1 found 161.09200.

1-Cyclohexa-2,5-dienyltrideuteriomethoxynaphthalene: (2.2 mg, 2%) 1H NMR (500 MHz,

D D CDCl3) į 8.2 (d, 0.65H, J = 7.8 Hz), 7.7 (d, 0.65H, J = 7.8 Hz), 7.4-7.5 (m, 4H), O D 6.8 (d, 1H, J = 7.3), 5.9 (m, 4H), 4.7 (m, 1H), 2.8 (m, 2H); HRMS (EI+)

calculated for C17H13D3O 239.13895, found 239.13828.

1-Cyclohexa-2,5-dienyl-8-trideuteriomethoxynaphthalene: (2.2 mg, 2%) 1H CD 3 O NMR (500 MHz, CDCl3) į 7.6 (d, 1H, J = 7.8 Hz), 7.4-7.5 (m, 4H), 6.8 (d, 1H, J = 7.3 Hz), 5.9 (dm, 2H, J = 10.2 Hz), 5.8 (dm, 2H, J = 10.2 Hz), 5.6 (m, 1H),

20 2.8 (m, 2H); HRMS (EI+) calculated for C17H13D3O 239.13895, found 239.13781.

Experimental Setup for Kinetic Studies

Kinetic data were obtained by analytical GC on a Varian Model LP-3800 Gas Chromatograph (column: DB-5MS J&W Scientific, 30 m Length, 0.25 mm ID, 0.25 µm Film) or analytical TM HPLC (columns: normal phase column Supelcosil LC-SI, 250 mm × 21.2 mm, 5 µm or C18 reverse phase column Beckman, 250 mm × 21.2 mm, 5 µm) on a Beckman-Coulter HPLC system with 125 gradient pump equipped with a 508 Beckman auto sampler and 166 variable UV detector. 1,2,3,4-Tetraphenylnaphthalene or anthracene were used as the internal standard. Chlorobenzene was used as solvent in all experiments. 1,4-Cyclohexadiene was distilled before use.

General Procedure. A 10 mL volumetric flask was charged with the enediyne, 1,2,3,4- tetraphenylnaphthalene as an internal standard and 1,4-cyclohexadiene. The volumetric flask was filled to the mark with chlorobenzene. For each temperature, fifteen capillary melting-point tubes were filled with 75 µL of this solution. The capillary tubes were frozen with liquid nitrogen, degassed under high vacuum, and sealed with only enough space for liquid expansion to eliminate “dead volume”. The capillary tubes were placed in a preheated oil bath and removed at different time intervals. The reaction was monitored for 2-3 half-lives. Kinetic experiments were performed at four different temperatures.

Kinetic Studies of 1,2-Diethynylbenzene. A 10 mL volumetric flask was charged with 1,2- diethynylbenzene (7.1 mg), 1,2,3,4-tetraphenylnaphthalene (5.3 mg), and 1,4-cyclohexadiene (0.4 mL, 100 mole excess). The solution was analyzed with GC and HPLC to determine the initial concentration of enediynes (5.6 × 10-3 M). Kinetic experiments were performed at 150, 160, 170 and 180 ºC. The GC time program had the following parameters: Initial temperature = 70 ºC for 5 min, 20 ºC/min until 220 C and hold for 5 min, then 30 ºC/min until 250 ºC and hold for 20 min. Retention times were: tED = 5.5 min, tNapth = 7.0 min and tstd = 28.5 min. The following conditions were used for kinetic analysis using HPLC: A:B 9.5:0.5 solvent system (A:

21 hexanes; B: hexanes/Ethyl acetate 100/1), 1 mL/min flow rate, 250 nm detector wavelength.

Retention times were: tstd = 7.7 min and tED = 23.6 min.

Kinetic Studies of 2,3-Diethynylnitrobenzene (ortho-NO2). A 10 mL volumetric flask was charged with 2,3-diethynylnitrobenzene (3.8 mg), 1,2,3,4-tetraphenylnaphthalene (7.8 mg), and 1,4-cyclohexadiene (0.22 M, 100 mole excess). The solution was mixed and analyzed with HPLC to determine the initial concentration of enediynes (2.2 × 10-3 M). Kinetic experiments were performed at 140, 148, 156 and 164 ºC. The following conditions were used for kinetic analysis using HPLC: A:B 9:1 solvent system (A: hexanes; B: hexanes/Ethyl acetate 30/1), 1

mL/min flow rate, 265 nm detector wavelength. Retention times were: tstd = 6.9 min, tNapth =

11.3, tED = 21.5 min. Kinetic Studies of 2,3-Diethynyl-1-formylbenzene (ortho-CHO). A 10 mL volumetric flask was charged with 2,3-diethynyl-1-formylbenzene (3.7 mg), 1,2,3,4-tetraphenylnaphthalene (5.3 mg), and 1,4-cyclohexadiene (0.24 M, 100 mole excess). The solution was mixed and analyzed with GC and HPLC to determine the initial concentration of enediynes (2.4 × 10-3 M). Kinetic experiments were performed at 140, 150, 160, 170 and 180 ºC. The GC time program had the following parameters: Initial temperature = 70 ºC for 5 min, 20 ºC/min until 220 ºC and hold for

5 min, then 50 ºC/min until 320 ºC and hold for 1 min. Retention times were: tED = 4.7 min, tNapth

= 5.2 min and tstd = 8.9 min. The following conditions were used for kinetic analysis using HPLC: A:B 8:2 solvent system (A: hexanes; B: hexanes/Ethyl acetate 100/1), 1 mL/min flow

rate, 265 nm detector wavelength. Retention times were: tstd = 8.5 min, tNapth = 30.8, and tED = 33.8 min.

Kinetic Studies of 2,3-Diethynyl-1-aminobenzene (ortho-NH2). A 10 mL volumetric flask was charged with 2,3-diethynyl-1-aminobenzene (5.1 mg), 1,2,3,4-tetraphenylnaphthalene (5.3 mg), and 1,4-cyclohexadiene (0.36 M, 100 mole excess). The solution was mixed and analyzed with GC and HPLC to determine the initial concentration of enediynes (3.6 × 10-3 M). Kinetic experiments were performed at 160, 170, 180 and 190 ºC. The GC time program had the following parameters: Initial temperature = 70 ºC for 3 min, 50 ºC/min until 280 ºC and hold for

1 min, then 20 ºC/min until 320 ºC and hold for 1 min. Retention times were: tED = 4.9 min, tNapth

= 5.3 min and tstd = 9.1 min.

Kinetic Studies of 2,3-Diethynyl-1-methoxybenzene (ortho-OCH3) /trideuteriomethoxy-

benzene (ortho-OCD3). A 10 mL volumetric flask was charged with 2,3-diethynyl-1-

22 methoxybenzene (5.2 mg), 1,2,3,4-tetraphenylnaphthalene (5.6 mg), and 1,4-cyclohexadiene (0.33 M, 100 mole excess). The solution was mixed and analyzed with GC and HPLC to determine the initial enediyne concentration (3.33 × 10-3 M). Kinetic experiments were performed at 150, 160, 170 and 180 ºC. The GC time program had the following parameters: Initial temperature = 70 ºC for 5 min, 20 ºC/min until 220 ºC and hold for 5 min, then 30 ºC/min

until 250 ºC and hold for 20 min. Retention times were: tED = 8.8 min, tNapth = 9.4 min and tstd = 28.5 min. The following conditions were used for kinetic analysis using HPLC: A:B 8.5:1.5 solvent system (A: hexanes; B: hexanes/Ethyl acetate 120/1), 1 mL/min flow rate, 265 nm

detector wavelength. Retention times were: tstd = 13.0 min and tED = 41.5 min.

Kinetic Studies of 3,4-Diethynylnitrobenzene (para-NO2). A 10 mL volumetric flask was charged with 3,4-diethynylnitrobenzene (6.5 mg), anthracene (10.5 mg), and 1,4-cyclohexadiene (0.38 M, 100 mole excess). The solution was mixed and analyzed with HPLC to determine the initial enediyne concentration (3.80 × 10-3 M). Kinetic experiments were performed at 140, 150, 160 and 170 ºC. The following conditions were used for kinetic analysis using HPLC (reverse phase): A:B 3:7 solvent system (A: water; B: acetonitrile), 1 mL/min flow rate, 315 nm detector

wavelength. Retention times were: tED = 5.8 min, tNapth = 6.6 min and tstd = 15.1 min.

Kinetic Analysis using GC. For every enediyne a calibration curve was constructed and used to determine the response of enediynes, naphthalene products and the internal standard at different ratios using the GC. All curves showed linear responses to decrease in the concentrations of enediynes and increase in the concentrations of naphthalene products, under constant concentration of standard. Samples were injected into the GC using an autosampler with a corresponding time program. The areas of the peaks corresponding to enediynes and naphthalene products were normalized against the areas of the internal standard. Concentrations of the enediynes and naphthalenes were determined from the linear calibration plots. Concentrations of enediynes were plotted versus time, and the resulting curve was fitted to a single exponential decay rate equation using Oakdale Engineering DataFit program

− eff tk [SM ] = [SM ]0 e 1

where [SM]0 is the initial concentration of enediyne, [SM] is the concentration of enediyne at

time t and keff is the effective rate concentration of the reaction.

23 For the formation of products, concentration values used in rate constant determinations were corrected to the yield of the product and fitted to the following equation

⎛ P][ ⎞ ⎜ inf ⎟ 2 ln()X = ln⎜ ⎟ = eff tk ⎝ P][ inf − P][ ⎠ where [P] and [P]inf are concentrations of the corresponding naphthalene product at time t and infinity time, respectively, and keff is the effective rate constant for the appearance of the Bergman product. Activation energies were determined from Arrhenius plots (lnk vs 1/T). Kinetic Analysis using HPLC. For every enediyne a calibration curve was constructed and used to determine the response of enediynes, naphthalene products and the internal standard at different ratios using the HPLC. All curves showed linear responses to decrease in the concentrations of enediynes and increase in the concentrations of naphthalene products, under constant concentration of standard. The reaction mixtures were diluted with hexane before being injected into the HPLC column. The areas of the starting material or products were normalized against the areas of the internal standard. Concentrations of the enediynes or naphthalenes were determined from a linear calibration plot. Rate constants were determined according to procedures described above for GC analysis.

Kinetic Experiment for Different Concentration of Hydrogen-Atom Donor

General Procedure. A 10 mL volumetric flask was charged with enediyne and 1,2,3,4- tetraphenylnaphthalene. The volumetric flask was filled to the mark with chlorobenzene. Five master solutions were prepared by taking 1 mL from the initial stock solution and diluted to 5 mL in a volumetric flask after adding the desired volume of 1,4-cyclohexadiene. The solutions were mixed and analyzed with HPLC and GC to determine the enediynes initial concentration. For each concentration of 1,4-cyclohexadiene, fifteen capillary melting-point tubes were filled with 75 µL of the master solution. The capillary tubes were frozen by liquid nitrogen, degassed under high vacuum, and sealed with only enough space for liquid expansion. The capillary tubes were placed in an oil bath heated at the desired temperature and monitored for 2-3 half-lives.

Kinetic Studies of 1,2-Diethynylbenzene. A 10 mL volumetric flask was charged with 1,2- diethynylbenzene (25.0 mg, 19.8 × 10-3 M) and 1,2,3,4-tetraphenylnaphthalene (25.0 mg). Five

24 master solutions (3.96 × 10-3 M each) were prepared with different concentration of 1,4- cyclohexadiene, [1,4-CHD] = 0.04, 0.10, 0.20, 0.40, 0.60 and 0.80 M. The enediynes initial concentration for every stock solution was determined by GC and HPLC as 3.9 × 10-3 M. Kinetic experiments were performed at 188 ºC. The GC time program had the following parameters: Initial temperature = 70 ºC for 5 min, 20 ºC/min until 220 C and hold for 5 min, then 30 ºC/min until 250 ºC and hold for 20 min. Retention times were: tED = 5.5 min, tNapth = 7.0 min and tstd = 28.5 min. For kinetic analysis using HPLC the following conditions were used: A:B 9.5:0.5 solvent system (A: hexanes; B: hexanes/ethyl acetate 100/1), 1 mL/min flow rate, 250 nm

detector wavelength. Retention times were: tstd = 7.7 min and tED = 23.6 min. Kinetic Studies of 2,3-Diethynylnitrobenzene. A 10 mL volumetric flask was charged with 2,3-diethynylnitrobenzene (25.0 mg, 14.6 × 10-3 M) and 1,2,3,4-tetraphenylnaphthalene (25.0 mg). Five master solutions (2.9 × 10-3 M each) were prepared with different concentration of 1,4- cyclohexadiene, [1,4-CHD] = 0.03, 0.07, 0.15, 0.29, 0.44 and 0.58 M. The enediynes initial concentration for every stock solution was determined by GC and HPLC as 2.7 × 10-3 M. Kinetic experiments were performed at 140, 148, 156 and 164 ºC. The following conditions were employed for kinetic analysis by HPLC: A:B 9:1 solvent system (A: hexanes; B: hexanes/ethyl acetate 30/1), 1 mL/min flow rate, 265 nm detector wavelength. Retention times were: tstd = 6.9 min, tNapth = 11.3, tED = 21.5 min. Kinetic Studies of 3,4-Diethynylnitrobenzene. A 10 mL volumetric flask was charged with 3,4-diethynylnitrobenzene (30.0 mg, 17.5 × 10-3 M) and anthracene (60.0 mg). Six master solutions (3.5 × 10-3 M each) were prepared with different concentration of 1,4-cyclohexadiene, [1,4-CHD] = 0.03, 0.07, 0.15, 0.29, 0.44, 0.58 and 0.87 M. The enediynes initial concentration for every stock solution was determined by GC and HPLC as 3.8 × 10-3 M. Kinetic experiments were performed at 140, 150, 160 and 170 ºC. The following conditions were used for kinetic analysis using HPLC (reverse phase): A:B 3:7 solvent system (A: water; B: acetonitrile), 1 mL/min flow rate, 315 nm detector wavelength. Retention times were: tED = 5.8 min, tNapth = 6.6 min and tstd = 15.1 min. Kinetic Studies of 2,3-Diethynyl-1-methoxybenzene. A 10 mL volumetric flask was charged with 2,3-diethynyl-1-methoxybenzene (1) (12.5 mg, 8.1 × 10-3 M) and 1,2,3,4- tetraphenylnaphthalene (25.0 mg). Five master solutions (1.6 × 10-3 M each) were prepared with different concentration of 1,4-cyclohexadiene, [1,4-CHD] = 0.00, 0.02, 0.04, 0.08, 0.16, 0.24,

25 0.32 and 0.40 M. The enediynes initial concentration for every stock solution was determined by GC as 1.4 × 10-3 M. Kinetic experiments were performed at 170 ºC. The GC time program had the following parameters: Initial temperature = 70 ºC for 5 min, 20 ºC/min until 220 ºC and hold for 5 min, then 30 ºC/min until 250 ºC and hold for 20 min. Retention times were: tED = 8.8 min, tNapth = 9.4 min and tstd = 28.5 min.

Kinetic Studies of 2,3-Diethynyl(OCD3)anisole in the absence of 1,4-CHD. A 10 mL -3 volumetric flask was charged with 2,3-diethynyl(OCD3)anisole (7.8 mg, 8.1 × 10 M) and 1,2,3,4-tetraphenylnaphthalene (7.2 mg). The volumetric flask was filled to the mark with chlorobenzene. The solution was mixed and analyzed with HPLC to determine their initial enediynes concentration (5.3 × 10-3 M). The capillary tubes were placed in an oil bath heated at 170 ºC. The GC time program had the following parameters: Initial temperature = 70 ºC for 5 min, 20 ºC/min until 220 ºC and hold for 5 min, then 30 ºC/min until 250 ºC and hold for 20 min.

Retention times were: tED = 8.8 min and tstd = 28.5 min.

Experimental Setup for Differential Scanning Calorimetry Studies

TA Instruments DSC Q-1000 calorimeter was used for DSC scans. Temperature and enthalpy calibrations were performed using indium standard. The heat capacity was calibrated using a 25 mg sapphire standard. About 8-10 mg of enediyne was used for each experiment. For neat samples, enediynes were sealed in aluminum hermetic pans. The samples were equilibrated in the purge gas (argon) for about 15 min prior to each run. For solution samples, stock solutions of enediynes (5.0 mg) in 1,4-CHD (0.5 mL) were prepared and 50 µL of the stock solutions were sealed in high volume aluminum pans with O-rings in a glove-box under argon. Conventional DSC was used to determine the reaction kinetics using ASTM E-698 thermal stability protocol.86 This protocol is used to determine Arrhenius activation energies and pre- exponential factors.

26 RESULTS

Differential Scanning Calorimetry Experiments

Differential scanning calorimetry (DSC) is a useful technique for studying the chemical transformation of a system which state is dependent on temperature and chemical conversion. Both parameters can be monitored using DSC. Conventional DSC was used to determine the reaction kinetics, Arrhenius activation energies and pre-exponential factors, using the ASTM E- 698 thermal stability protocol.59 Two sets of DSC experiments were performed. In the first set, neat enediynes were sealed in hermetic pans and heated at different heating rates. Then according to the ASTM E-698 protocol, log(β) was plotted versus 1000/RT, where β in K/min is the heating rate and T is the peak maximum in Kelvin. Four different heating rates (5, 10, 15 and 20 K/min) were used and the resulting plot gave a linear correlation. The activation energy and pre-exponential factor can be determined from the slope. Figure 4 shows DSC scans for benzannelated enediynes at different heating rates and the activation energy plots.

(a) 40 168.81°C 0.006

) β 0.005 30 ( 164.46°C

0.004 ×R ×Log 19 . 1 y = -22.11x + 0.06 20 0.003 157.46°C R2 = 0.9995

0.002 0.00224 0.00228 0.00232 0.00236 0.0024 146.99°C 10 1/T Heat Flow (W/g) Flow Heat

0

-10

-20 -100 -50 0 50 100 150 200 250 300 Exo Up Temperature (°C) Universal V3.4C TA Instruments

Figure 4. DSC scans of neat benzannelated enediynes at a heating rate of 5, 10, 15 and 20°C/min and the activation energies (insets) for (a) 1,2-diethynylbenzene, (b) 2,3-diethynylnitrobenzene, (c) 3,4-diethynylnitrobenzene, (d) 2,3-diethynyl-1-formylbenzene, (e) 2,3-diethynyl-1- methoxybenzene and (f) 2,3-diethynyl-1-trideuteriomethoxybenzene.

27 (b) 40 0.006 ) NO β 2 0.005 30

0.004 1.19×R ×Log(

157.35°C 0.003 y = -23.63x + 0.06 2 20 R = 0.9987

0.002 152.41°C 0.00228 0.00238 0.00248 1/T 10 146.95°C 137.57°C Heat Flow (W/g) Flow Heat

0

-10

-20 0 50 100 150 200 250 300 Exo Up Temperature (°C) Universal V3.4C TA Instruments

(c) 10 0.006

) β ( 0.005

×R ×Log ×R 0.004 223.05°C 19 . 5 1 y = -26.33x + 0.06 2 216.79°C 0.003 R = 0.9979 210.47°C 0.002 0.002 0.00204 0.00208 0.00212 198.87°C 1/T 0 Heat Flow (W/g) Flow Heat

-5

O2N

-10 0 50 100 150 200 250 300 Exo Up Temperature (°C) Universal V3.4C TA Instruments

Figure 4. Continues

28 (d) 40 0.006

) y = -24.80x + 0.06 β CHO 0.005 R2 = 0.9988 30 154.77°C 0.004 1.19×R ×Log( 1.19×R

0.003 20 150.43°C 0.002 144.81°C 0.00232 0.00236 0.0024 0.00244 0.00248 1/T 10 136.22°C Heat Flow (W/g) Flow Heat

0

-10

-20 0 50 100 150 200 250 300 Exo Up Temperature (°C) Universal V3.4C TA Instruments

(e) 40 0.006 ) OMe β 0.005 30 0.004

1.19×R ×Log( 1.19×R y = -22.50x + 0.06 R2 = 0.9997 0.003 20 158.82°C 0.002 154.36°C 0.00228 0.00232 0.00236 0.00240 0.00244 1/T 10 147.88°C 137.47°C Heat Flow (W/g) Flow Heat

0

-10

-20 0 50 100 150 200 250 300 Exo Up Temperature (°C) Universal V3.4C TA Instruments

Figure 4. Continues

29 (f) 40 0.006 ) β OCD3 0.005 30 0.004 1.19×R ×Log( y = -22.49x + 0.06 0.003 R2 = 0.9992 20 157.96°C 0.002 153.07°C 0.0023 0.0023 0.0024 0.0024 0.0024 0.0025 1/T 10 146.85°C 137.36°C Heat Flow (W/g)

0

-10

-20 0 50 100 150 200 250 300 Exo Up Temperature (°C) Universal V3.4C TA Instruments

Figure 4. Continues

All DSC plots exhibit an initial endothermic peak due to melting followed by an exothermic peak which corresponds to a chemical reaction taking place in the hermetic pan. Higher heating rates result in sharpening of the exothermic peak and shifting its peak maximum to higher temperatures. Interestingly, all enediynes react only after they melt. In the case of para-NO2 and ortho-CHO enediynes the reaction starts immediately after melting. In the second set of experiments, 10.5 M stock solutions of enediynes in 1,4-CHD were prepared and 50 µl of each solution was sealed in high volume pans under argon in a glove box. DSC scans were run under conditions similar to those described for the neat enediynes. Figure 3 depicts DSC scans of the enediynes in 1,4-CHD solution. For all enediynes, the DSC scans initially showed a decrease in the heat flow. This decrease is followed by an exothermic peak attributed to the chemical reaction, in this case the Bergman cyclization. After the DSC runs, TLC analysis of each sample showed that the corresponding naphthalene is the major reaction product.

30 (a) 0.5 0.006 ) β 0.005

0.004 1.19×R ×Log( 1.19×R y = -23.852x + 0.053 0.003 2 0.0 R = 0.9886

0.002 0.00196 0.002 0.00204 0.00208 0.00212 1/T 229.52°C 225.88°C Heat Flow (W/g) Flow Heat 218.54°C -0.5 206.18°C

-1.0 0 50 100 150 200 250 Exo Up Temperature (°C) Universal V3.4C TA Instruments

(b) 0.5 0.006 ) NO β 2 0.005

0.004 1.19×R ×Log( 1.19×R

0.003 y = -22.614x + 0.0541 0.0 R2 = 0.9972

0.002 0.00212 0.00216 0.0022 0.00224 0.00228 1/T

194.50°C

Heat Flow (W/g) Flow Heat 190.09°C -0.5 182.52°C 170.31°C

-1.0 0 50 100 150 200 250 Exo Up Temperature (°C) Universal V3.4C TA Instruments

Figure 5. DSC scans for solutions of benzannelated enediynes in 1,4-CHD ([1,4-CHD] = 10.5 M). Heating rates are 5, 10, 15 and 20 °C/min unless noted otherwise. Arrhenius plots are shown in the inset. (a) 1,2-diethynylbenzene, (b) 2,3-diethynylnitrobenzene, (c) 3,4- diethynylnitrobenzene (1, 3, 5, 10 °C/min), (d) 2,3-diethynyl-1-formylbenzene, (e) 2,3- diethynyl-1-methoxybenzene and (f) 2,3-diethynyl-1-trideuteriomethoxybenzene.

31 (c) 0.1 0.005 ) β 0.004 y = -26.43x + 0.0561 R2 = 0.9964 0.003 0.0

0.002 1.19×R ×Log( O2N 0.001

-0.1 0 0.00196 0.002 0.00204 0.00208 0.00212 0.00216 1/T

-0.2 Heat Flow (W/g) Flow Heat 236.74°C 233.63°C 228.69°C 213.11°C -0.3

-0.4 0 50 100 150 200 250 Exo Up Temperature (°C) Universal V3.4C TA Instruments

(d) 0.5 0.006 ) CHO β 0.005

0.004

1.19×R ×Log( 1.19×R y = -23.689x + 0.0558 0.003 R2 = 0.9961 0.0

0.002 0.00208 0.00212 0.00216 0.0022 0.00224 1/T 198.82°C 196.17°C

Heat Flow (W/g) Heat Flow 188.42°C -0.5 176.79°C

-1.0 0 50 100 150 200 250 Exo Up Temperature (°C) Universal V3.4C TA Instrument

Figure 5. Continues

32 (e) 0.5 0.006

) 0.005 OMe β

0.004

1.19×R ×Log( 1.19×R y = -23.802x + 0.0532 0.003 R2 = 0.9968 0.0

0.002 0.00196 0.002 0.00204 0.00208 0.00212 1/T

226.05°C 222.74°C Heat Flow (W/g) Flow Heat 214.22°C -0.5 201.90°C

-1.0 0 50 100 150 200 250 Exo Up Universal V3.4C TA Instruments Temperature (°C)

(f) 0.5 0.006

OCD ) 3 β 0.005

0.004

1.19×R ×Log( 1.19×R y = -24.846x + 0.0555 0.003 R2 = 0.9994 0.0

0.002 0.002 0.00204 0.00208 0.00212 1/T 225.77°C 222.15°C

Heat Flow (W/g) Flow Heat 215.57°C -0.5 202.86°C

-1.0 0 50 100 150 200 250 Exo Up Temperature (°C) Universal V3.4C TA Instruments

Figure 5. Continues

As in the first set of DSC experiments, higher heating rates result in sharpening of the exothermic peaks and shifting the peak maxima to higher temperatures. Due to the low reactivity of the para-NO2 enediyne, higher temperatures were required for completing the exothermic peak. Because the maximum temperature in which high volume pans are operated is 250 ºC,

33 lower heating rates were used for para-NO2 benzannelated enediyne in order to alleviate this problem and reach the peak maximum of the exotherm.

Effective Rate Constants of Ortho-Substituted Benzannelated Enediynes

Apparent or effective rate constants, keff, for the Bergman cyclization of ortho-substituted enediynes were determined under pseudofirst order conditions when the concentration of hydrogen-atom donor, 1,4-CHD, is 100 times larger than the concentration of enediynes. We used two different chromatography techniques (GC and HPLC). Consumption of enediyne showed single exponential decay behavior. Concentrations of enediyne determined at different time interval were fitted to Eq. 1 (Figure 6).

(a) (a') o 7.0E-03 o 1.6 o T=180 C T=180 C T=170 C y = 0.006e-7.83E -04x y = 7.3 1E-04 x + 0 .01 y = 4.2 6E-04x - 0.02 1.4 2 6.0E-03 R2 = 0.998 R 2 = 0 .9 8 1 R = 0.999 1.2 T=160 oC 5.0E-03 o T=170 C y = 2.21E-04x + 0.00 -4.50E -04x [SM], M y = 0.005e 1 2 ) R = 0.998 4.0E-03 R2 = 0.998 X 0.8 Ln( T=160 oC 3.0E-03 y = 0.006e-2.27E-04x 0.6 2 R = 0 .9 9 8 o 2.0E-03 T=150 oC T=150 C 0.4 y = 0.005e-1.02E-04x y = 9.38E-05x - 0.008 2 2 R = 0 .9 9 2 1. 0 E- 0 3 R = 0.994 0.2 0.0E+00 0 0 5000 10000 15000 20000 25000 0 2000 4000 6000 8000 Time, s Time, s

Figure 6. First-order rate constants at different temperatures determined for the disappearance of ortho-substituted enediynes: (a) 1,2-diethynylbenzene, (b) 2,3-diethynylnitrobenzene, (c) 3,4- diethynylnitrobenzene, (d) 2,3-diethynyl-1-formylbenzene, (e) 2,3-diethynyl-1-methoxybenzene, (f) 2,3-diethynyl-1-(trideuteriomethoxy)benzene and (f) 2,3-diethynyl-1-aminobenzen, and the appearance of the corresponding naphthalene products: (a’) naphthalene, (b’) 1-nitronaphthalene, (c’) 2-nitronaphthalene, (d’) 1-naphthaldehyde, (e’) 1-methoxynaphthalene, (f’) 1- (trideuteriomethoxy)naphthalene and (g’) 1-aminonaphthalene. X is defined in Eq. 2.

34 (b) (b') o o 2.5E-03 T=164 oC NO2 4.5 T=164 C T=156 C y = 0.002e-2.42E-03x y = 2.20E-03x + 0.05 y = 9.07E-04x + 0.02 4 2 2 R 2 = 1.0 0 R = 0.999 R = 0.999 2.0E-03 o 3.5 T=156 C T=148 oC y = 0.002e-1.54E-03x 3 ) y = 1.53 E-0 3x + 0.00 5

1.5E- 0 3 2 X 2 [SM], M R = 0 .9 9 9 R = 0.998 o 2.5

T=148 C Ln( -5.74E-04x y = 0.002e 2 1.0 E- 0 3 R 2 = 1.0 0 T=140 oC 1. 5 y = 0.002e-9.43E -04x T=140 oC 1 5.0E-04 R2 = 0.999 y = 5.48E-04x - 0.003 2 0.5 R = 1.0 0

0.0E+00 0 0 1000 2000 3000 4000 0 1000 2000 3000 4000 Time, s Time, s

(c) (c') T=170 oC 4.0E-03 T=170 oC 2 y = 9.64E-04x + 0.03 y = 0.0038e-1.06E-03x R2 = 0 .9 9 9 O2N 3.5E-03 2 R = 0 .9 9 9 o T=160 oC 1.6 T=160 C -5.86E-04x y = 4.99E-04x + 0.04 o 3.0E-03 y = 0.0038e T=150 C 2 2 ) R = 0.999 y = 2.67E-04x + 0.06 R = 0 .9 9 9 X 2.5E-03 2 o 1.2 R = 0 .9 9 9

T=150 C Ln( -3.01E-04x [SM], M [SM], 2.0E-03 y = 0.0038e R 2 = 0.999 0.8 1. 5E - 0 3 o T=140 oC T=140 C 1.0 E- 0 3 -1.48E-04x y = 1.26E-04x + 0.03 y = 0.0038e 0.4 2 2 R = 0.999 5.0 E-0 4 R = 0.999

0.0E+00 0 0 2000 4000 6000 8000 0 2000 4000 6000 8000

Time, s Time, s

(d') o (d) 8 T=180 C 2.5E-03 CHO o y = 4.0 3E-03x - 0.4 T=180 C T=160 oC 7 R2 = 0 .9 3 6 y = 0.0028e-3.36E-03x y = 1.05E-03x + 0.04 2 2 2.0E-03 R = 0 .9 9 6 T=170 oC T=170 oC R = 0.998 6 o -2.02E-03x y = 2.06E-03x - 0.06 T=150 C y = 0 .00 25e ) R 2 = 0.999 X 5 R 2 = 0 .9 78 y = 6.6 5E-04x - 0 .15 [SM], M 1.5E- 0 3 R2 = 0.995 Ln( T=160 oC T=150 oC 4 y = 0.0025e-1.12E-03x y = 0.0024e-5.96E-04x 1. 0 E - 0 3 R 2 = 1.0 0 3 R 2 = 0 .9 9 8 T=140 oC 2 T=140 oC y = 3.48E-04x - 0.03 5.0E-04 2 y = 0.0024e-3.15E-04x R = 0 .9 9 9 1 R2 = 1.0 0

0.0E+00 0 0 2000 4000 6000 8000 10000 12000 0 2000 4000 6000 8000 10000 12000

Time, s Time, s

Figure 6. Continues

35 (e') o (e) o T=180 C T=180 C o 4.0E-03 1. 6 y = 1.11E- 0 3 x - 0 .0 0 8 T=170 C y = 0.003e-1.17E-03x OMe R2 = 0 .9 9 8 y = 5.72E-04 x + 0 .04 2 R = 0.998 1. 4 R2 = 0.985

3.0E-03 1. 2 T=170 oC ) X [SM], M [SM], y = 0.003e-6.31E-04x 1 2 o R = 0 .9 9 7 Ln( T=160 C 2.0E-03 0.8 o y = 2.71E-04x + 0.04 T=160 C 2 -3.03E-04x R = 0 .9 9 6 y = 0.003e 0.6 R 2 = 0 .9 9 3 T=150 oC 1. 0 E - 0 3 T=150 oC 0.4 y = 1.60E-04x + 0.01 y = 0.003e-1.58E-04x R 2 = 0.997 0.2 R 2 = 0.995

0.0E+00 0 0 5000 10000 15000 20000 0 2000 4000 6000 8000 Time, s Time, s

(f) o 3.0E-03 o T=180 C T=180 C OCD3 (f') 1 y = 8.07E-04x - 0.02 y = 0.002e-7.85E-04x 2 2 R = 0.999 R = 0.998 T=170 oC 0.8 y = 3.65E-04x + 0.02 o T=170 C R2 = 0 .9 9 2

[SM], M [SM], 2.0E-03 y = 0.002e-4.45E-04x R 2 = 0.997 ) 0.6 X T=160 oC Ln( o y = 0.002e-2.45E-04x T=160 C 0.4 2 y = 2.20E-04x + 0.01 1. 0 E - 0 3 R = 0.994 R2 = 0.998 T=150 oC T=150 oC 0.2 y = 1.13E-0 4x + 0.00 5 y = 0.002e-1.16E-04x R2 = 0.998 R2 = 0 .9 9 6 0.0E+00 0 0 5000 10000 15000 20000 0 2000 4000 6000

Time, s Time, s

(g) (g') 3.5E-03 NH 2.5 o T=190 oC 2 T=190 C -3.99E-04x y = 3.55E-04x + 0.014 y = 0.003e 2 3.0E-03 2 R = 0.999 R = 0 .9 9 9 2 2.5E-03 o o T=180 C ) T=180 C -2.29E-04x X 1.5 [SM], M 2.0E-03 o y = 0.003e T=170 C y = 2.29E-04x + 0.004

2 Ln( 2 R = 0.998 y = 0.003e-1.27E-04x R = 0.999 1. 5 E - 0 3 2 R = 0.999 1 T=170 oC 1.0 E- 0 3 T=160 oC y = 1.11E-04x + 0.014 -6.61E-05x 2 y = 0.003e 0.5 T=160 oC R = 0 .9 9 9 5.0 E-04 2 R = 0 .9 9 9 y = 6.59E-05x - 0.002 R2 = 1.0 0 0.0E+00 0 0 10000 20000 30000 40000 0 10000 20000 30000 40000 Time, s Time, s

Figure 6. Continues

36 Similarly, concentrations of the naphthalene product were monitored and the slopes of Eq. 2 provide the effective rate constants for the formation of the products (Figure 6). Eq. 2 normalizes the formation of the product to the observed reaction yield. Since an additional adjustable parameter (P∞) has to be used in Eq. 2, these activation energies are less accurate. Effective rate constants were measured at different temperatures. When the temperature is increased by 10 ºC, the effective rate constant for the consumption of enediynes roughly doubles.

Activation Energies of Ortho-Substituted Benzannelated Enediynes

Effective rate constants at different temperatures enabled us to determine the activation energies from the Arrhenius plots shown in Figure 7. Arrhenius plots determined from effective rates of the disappearance of benzannelated enediynes and those determined from effective rates of the appearance of naphthalene products are identical within experimental error.

1000/RT, kcal/mol (b) 1000/RT, kcal/mol (a) 1. 14 1. 16 1. 18 1. 2 1. 2 2 1. 2 4 1.1 1.12 1.14 1.16 1.18 1.2 -5 -5

-6 Consumptio n of 1,2-Diethynylbenzene y = -25.90x + 21.69 ) Consumptio n of 2 ,3-Diethynylnitro benzene eff

k -6 ) R2 = 0 .9 9 6 y = -21.54x + 18.8 eff

ln( 2 k -7 R = 0.9999 NO2 ln( -8 -7 Formation of Naphthalene y = -2 5.9 8 x + 2 1.72 Formation of 1-Nitronaphthalene -9 R 2 = 0.993 y = -2 1.0 4 x + 18 .16 R2 = 0.996 -8 -10

Figure 7. Arrhenius plots for disappearance of benzannelated enediynes (solid line) and appearance of the corresponding naphthalenes (dashed lines). (a) 1,2-diethynylbenzene, (b) 2,3- diethynylnitrobenzene, (c) 3,4-diethynylnitrobenzene, (d) 2,3-diethynyl-1-formylbenzene, (e) 2,3-diethynyl-1-methoxybenzene, (f) 2,3-diethynyl-1-trideuteriomethoxybenzene and (g) 2,3- diethynyl-1-aminobenzene.

37

1000/RT, kcal/mol 1000/RT, kcal/mol

(c) 1. 12 1.14 1.16 1.18 1. 2 1.2 2 1. 2 4 (d) 1.1 1.15 1.2 1.25 -5 -4

Formation of 1-Naphthaldehyde -6 Consumption of 3,4-Diethynylnitrob enzene -5 y = -22.37x + 19.28 y = -23.89x + 20.32 2

) R = 0.993 2 CHO )

eff R = 0.9996 k eff

-7 k -6 ln( ln( O N 2 -8 -7

Formation of 2-Nitronaphthalene -9 y = -24.4 6x + 20.8 6 -8 Consumptio n of 2,3-Diethynyl-1-fo rmylbenzene R2 = 0 .9 9 9 y = -22.14x + 18.94 2 -10 -9 R = 0.9996

1000/RT, kcal/mol 1000/RT, kcal/mol (e) 1.1 1.12 1.14 1.16 1.18 1.2 (f) 1.1 1.12 1.14 1.16 1.18 1.2 -5 -5

Consumptio n of 2,3-Diethynyl-1-methoxybenzene Consumption of 2,3-Diethynyl-1-trideuterio methoxybenzene y = -25.6 4x + 21.76 -6 -6 y = -24.12x + 19.69 2 R = 0.999 R2 = 0 .9 9 8 ) OMe eff )

k OCD eff 3 -7 k ln( -7 ln( -8 -8 Fo martion of 1-Methoxynaphthalene -9 y = -24.92x + 20.86 R2 = 0.993 -9 Formation of 1-Trid euterio methoxynaphthalene y = -2 4 .3 6 x + 19 .8 9 2 -10 R = 0.991 -10

1000/RT, kcal/mol

(g) 1.0 8 1.1 1.12 1.14 1.16 1.18 -6

Consumption of 2,3-Diethynyl-1-amino benzene -7 y = -2 3.71x + 17.96

) 2 eff R = 0.9997 NH k 2 ln( -8

-9 Formatio n of 1-Aminonaphthalene y = -23.00x + 17.11 2 -10 R = 0.993

Figure 7. Continues

38 Effect of 1,4-Cyclohexadiene Concentration on the Effective Rate Constants

We also studied the effect of concentration of hydrogen-atom donor, 1,4-CHD, on the effective rate constants for the disappearance of enediynes and the appearance of the corresponding

naphthalenes. 2,3-Diethynylnitrobenzene (ortho-NO2) and 3,4-diethynylnitrobenzene (para-

NO2) were chosen as model compounds.

(a) (a')

4.E-03 4.E-03 ortho-NO ortho-NO2 2

0 T = 162 C 0

-1 3.E-03 -1 3.E-03 T = 162 C , s , s eff eff k k

2.E-03 T = 156 0C 2.E-03 T = 156 0C

T = 148 0C T = 148 0C 1. E - 0 3 1. E - 0 3 T = 140 0C T = 140 0C

0.E+00 0.E+00 0 0.2 0.4 0.6 0.8 0 0.2 0.4 0.6 0.8

[1,4-CHD], M [1,4-CHD], M (b) (b')

1. 6 E - 0 3 1. 6 E - 0 3 para-NO para-NO2 2 T = 170 0C T = 170 0C 1. 2 E - 0 3 1. 2 E - 0 3

-1 -1 , s , s eff eff k k 8.0E-04 T = 160 0C 8.0E-04 T = 160 0C

4.0E-04 T = 150 0C 4.0E-04 T = 150 0C

T = 140 0C T = 140 0C

0.0E+00 0.0E+00 00.20.40.60.8 1 00.20.40.60.8 1

[1,4-CHD], M [1,4-CHD], M

Figure 8. The dependence of effective rate constant, keff, on 1,4-CHD concentration at different temperatures; (a) and (b) disappearance of ortho-NO2 and para-NO2 enediynes, respectively and (a’) and (b’) appearance of 1-nitronaphthalenes and 2-nitronapthalene, respectively.

In both cases, effective rate constants for the consumption of enediynes and the formation of nitronaphthalene showed dependence on the concentrations of hydrogen-atom donor. Plots of the effective rate constants versus the 1,4-CHD concentration are shown in Figure 8. At low

39 concentrations of 1,4-CHD, the effective rate constants for the consumption of enediynes are highly dependent on the concentration of 1,4-CHD. However, this dependence is less pronounced at higher concentrations of the hydrogen-atom donor where the plot finally approaches a plateau. Similar behavior is observed for the effective rate constants for the formation of nitronaphthalene. Clearly, reactivity of the ortho-enediyne is more sensitive to the concentration of 1,4-CHD. While 0.3 M of 1,4-CHD (∼ 100 fold excess) is sufficient to reach the

plateau for para-NO2 enediyne, 0.6 M of 1,4-CHD (∼ 300 fold excess) is barely sufficient for the ortho isomer. Similar studies were performed for the reaction of 2,3-diethynyl-1-methoxybenzene (ortho-

OCH3). Interestingly, effective rates for the consumption of ortho-OCH3 are independent of the concentration of the hydrogen-atom donor (Figure 9). On the other hand, the dependence of effective rate constants for the appearance of 1-methoxynaphthalene is similar to that shown for the nitro substituted enediynes. These observations will be discussed in detail in the following sections.

8.0E-04

-1 6.0E-04 , s eff k

4.0E-04

2.0E-04 00.10.20.30.4 [1,4-CHD], M

Figure 9. Dependence of the effective rate constant on the 1,4-CHD concentration for the consumption of o-OCH3 (filled circle) and formation of 1-methoxynaphthalene (hollow circles).

40 DISCUSSION

Differential Scanning Calorimetry Kinetic Analysis

Differential Scanning Calorimetry (DSC) is a powerful technique for obtaining qualitative and quantitative information about the effect of temperature on materials.59, 87, 88 Although the DSC method allows quick acquisition of kinetic information, it is also the crudest approach due to restrictions imposed on the calculations and to assumptions, such as the order of the reaction, used for determining Arrhenius parameters. Nevertheless, DSC experiments described in literature provided suitable comparison of reactivity among the enediynes. ASTM E-698-99 procedure is a standard test method for determining first-order Arrhenius constants. This technique requires several nonisothermal experiments with different heating rates.86 It is based on plotting the maxima of peak exotherms at various heating rates and refining the activation energy value according to the ASTM protocol. Arrhenius activation energies determined from these measurements are compared with computationally predicted Bergman cyclization barriers in Table 1.

Table 1. Activation Energies and Pre-Exponential Factors (logA) Determined Computationally and from DSC Experiments.a

Activation Energies, kcal/mol Pre-Exponential Factor, Log[A (s-1)] X BLYP (B3LYP)b Neat ED In 1,4-CHD Neat ED In 1,4-CHD H 24.5 (31.3) 21.7 ± 0.3 23.1 ± 0.1 10.8 ± 0.3 10.0 ± 0.1

ortho-NO2 20.9 (27.9) 23.2 ± 0.1 22.0 ± 0.6 11.9 ± 0.1 10.3 ± 0.6

para-NO2 24.1(30.9) 25.8 ± 0.3 25.9 ± 0.3 12.6 ± 0.2 10.8 ± 0.3

ortho-CHO (syn) 20.6 (27.7) 24.4 ± 0.2 23.2 ± 0.3 12.6 ± 0.2 10.8 ± 0.3 ortho-CHO (anti) 22.1 (29.2)

ortho-OCH3 24.7 (31.4) 23.2 ± 0.2 22.1 ± 0.5 10.1 ± 0.2 11.3 ± 0.5

ortho-OCD3 24.8 (31.3) 24.3 ± 0.2 22.1 ± 0.7 10.6 ± 0.2 11.3 ± 0.7 a Errors are standard deviations of the Arrhenius fits with 90% confidence limits. b 6-31G** basis set.

41 DSC plots in Figure 4 show that, for similar heating rates, the onset temperaturesi for 1,2- diethynylbenzene are ca. 9-20 ºC higher than for ortho-NO2 and ortho-CHO substituted

benzannelated enediynes and 60 ºC lower than that for para-NO2 enediyne. This is in sharp contrast with the earlier findings of Russell at al,67 who compared rate constants for the consumption of 1,2-diethynylbenzene and 3,4-diethynyl-1-nitrobenzene (para-NO2) and found that the latter reacts ca. 2.5 time faster than the former. 1,2-Diethynylbenzene exhibits the largest exotherm (the y-axis in Figure 4a) among all benzannelated enediynes in this study. Under identical conditions (amount of material and heating rate) the exothermic peak for 1,2-diethynylbenzene reaches 40 g/W while the second largest exotherm (for ortho-CHO enediyne) only reaches 30 g/W. Furthermore, the sharp peak in the DSC of the unsubstituted enediyne indicates that the process is autocatalytic and suggests that the major reaction taking place in neat 1,2-diethynylbenzene is radical addition of the p- benzyne to the triple bonds of the enediyne rather than combination of p-benzyne diradicals. This mechanism has been implicated as the major path in enediyne polymerization.89, 90 In contrast, ortho and para-NO2 showed a 2.6-3.9 kcal/mol difference in activation barriers determined by DSC. These results are in excellent agreement with the predicted activation barriers (3.2

kcal/mol difference). In addition, ortho-OCH3 and ortho-OCD3 enediynes showed deviation from the expected values and we will discuss these cases in a separate section, vide infrra. These observations along with the unresolved question about the role of crystal constraints on reactivity suggest that the trends in the peak maxima of DSC temperatures of pure enediynes cannot be used as an accurate measure of relative reactivity. In order to answer the question about the effect of crystalline state, we performed DSC analysis in pure 1,4-CHD. In this case, DSC response shows endothermic behavior at the 25-60 ºC due to partial evaporation of 1,4-CHD. At high temperatures, enxothermic peak starts to form indicating that a thermal transformation is taking place. Similar to the neat enediyne DSC

experiments, 1,2-diethynylbenzene showed a smaller activation barrier than para-NO2, although the effect is less pronounced. Again, this anomaly is incompatible with the experimental results

i Onsets of the exothermic peaks for enediynes at different heating rates (5, 10, 15 and 20 ºC) are: 1,2- diethynylbenzene (132, 142, 149 and 151 ºC), ortho-NO2 (114, 123, 133 and 129 ºC), para-NO2 (193, 203, 210 and 217 ºC), ortho-CHO (127, 137, 142 and 147 ºC)

42 of Grissom85 and Russell67 and with the computationally predicted trends. This discrepancy is likely to stem from the presence of side reactions with low activation barriers, especially important when the reaction is conducted in neat enediyne. Unfortunately, the cumulative heat evolution does not provide individual information about evolution of chemical species involved in specific processes which may co compete with the Bergman cyclization. Chain radical cyclizations involving addition of p-benzyne or other radical intermediates to the acetylene moieties are the most likely candidates for such processes.91

In this set of experiments, ortho-NO2 enediynes reacted at the lowest temperatures. DSC activation energies for three enediynes with acceptor substituents are in excellent agreement with barriers determined computationally. Figure 10 suggests that BLYP values are closer to the experimental DSC data than B3LYP. However, the difference is small and B3LYP is at least as good as BLYP (or better) in predicting relative trends in reactivity of this family of substituted enediynes. Interestingly, MP2 results in Figure 10b show the closest correspondence ot the experiment with correlation slope approaching 1. Again, the case of X=H is an outlier. One can attribute this difference to enediynes and their lesser propensity to participate in radical chain processes.92

(a) (b)

27 27

-1 B3LYP -1 B3LYP p -NO2 BLYP y = 1.31x - 14.86 p -NO2 y = 0.86x - 0.89 26 26 BLYP 2 p -NO2 y = 0.80x + 6.55 2 R = 0.9801 R = 0.9989 p -NO2 y = 1.23x - 3.86 R 2 = 0.9902 MP2 MP2 R 2 = 0.9944 25 y = 1.38x - 8.7 2 25 y = 0.92x + 2.69 2 R 2 = 0.934 o -CHO R = 0.9927 o -CHO 24 24 o -CHO o -CHO H o -CHO o -NO 23 H 23 2 o -CHO o -NO2 from Methods, DSC kcal.mol from Methods, DSC kcal.mol a 2 a H

E 22 o -NO E 22 H o -NO2

21 21 20 22 24 26 28 30 32 20 22 24 26 28 30 32

E Calculated, kcal.mol-1 E Calculated, kcal.mol-1 a a

Figure 10. Correlation between activation energies calculated using unrestricted MP2, broken- spin B3LYP and BLYP levels79 with 6-31G(d,p) basis set and activation energies determined using DSC method of benzannelated enediynes in 1,4-CHD bearing electron acceptor groups in the ortho position: (a) 1,4-CHD solution and (b) neat benzannelated enediynes.

43 In general, the above results suggest that DSC is a useful but not universally reliable method for kinetic studies on the Bergman cyclization. Only in the cases of kinetically simple and chemically efficient processes within a family of related compounds are such comparisons justifiable. Thus, we carried out a more thorough kinetic study based on monitoring of the concentrations of reactants and products during the cycloaromatization process.

Ortho-Substituted Benzannelated Enediynes

In this section, we will discuss the effect of ortho substituents on rate and activation barriers of the Bergman cyclization. The parent benzannelated enediynes, 1,2-diethynylbenzene, was included to evaluate our kinetic experimental setup and to compare our results to those previously published.85 Table 2 depicts effective rate constants values from Figure 4 for benzannelated enediynes bearing electron accepting substituents. Effective rate constants for the consumption of enediynes and formation of the naphthalene products are almost equal. This implies that the rate limiting step is the same for the disappearance of enediynes and the appearance of naphthalene products. However, it is not the case for ortho-CHO where at some temperatures the effective rate constants for the appearance of product become slightly larger than the rates of enediyne disappearance, which would be physically impossible if it were not within error margins.

Table 2 indicates that ortho-NO2 enediyne is the most reactive enediyne. For example, at 140

ºC, the effective rate constant for disappearance of ortho-NO2 enediynes is ca. four times higher than para-NO2 and two times than that of ortho-CHO. Similar comparison can be made for the effective rate constant for formation of naphthalene products. Although, we do not have data for 1,2-diethynylbenzene at the same temperature one can clearly conclude that the nitro group placed in close proximity to the acetylene moiety increases the enediyne reactivity and renders the Bergman cyclization to proceed faster. Furthermore, the para-NO2 enediyne is also more reactive than the parent benzannelated enediyne, in good agreement with Russell and coworkers earlier findings.67 Arrhenius kinetic parameters can be determined from the effective rate constants presented above at different temperatures. At least four temperatures were used for each compound. Activation energies were derived from Arrhenius plots of the effective rate constants determined by monitoring the disappearance of enediynes and the appearance of the corresponding naphthalenes. These data are presented in Table 3.

44 -1 Table 2. Effective Rate Constants (keff, s ) for the Disappearance of Benzannelated enediynes and the Appearance of Corresponding Naphthalenes at Different Temperatures.a

ED 4 Napht 4 Temperature, ºC keff × 10 keff × 10 1,2-Diethynylbenzeneb 180 ± 0.2 7.83 ± 0.36 7.31 ± 0.45 170 ± 0.2 4.50 ± 0.15 4.26 ± 0.04 160 ± 0.1 2.27 ± 0.06 2.21 ± 0.04 150 ± 0.1 1.02 ± 0.10 0.94 ± 0.03 c 2,3-Diethynyl-1-nitrobenzene (ortho-NO2) 164 ± 0.1 24.95 ± 0.31 21.96 ± 0.29 156 ± 0.1 16.02 ± 0.34 15.30 ± 0.26 148 ± 0.1 9.88 ± 0.26 9.07 ± 0.11 140 ± 0.1 5.82 ± 0.06 5.48 ± 0.01 d 3,4-Diethynyl-1-nitrobenzene (para-NO2) 170 ± 0.2 10.58 ± 0.21 9.64 ± 0.12 160 ± 0.1 5.89 ± 0.11 4.99 ± 0.05 150 ± 0.1 3.01 ± 0.05 2.67 ± 0.03 140 ± 0.1 1.49 ± 0.02 1.26 ± 0.01 2,3-Diethynyl-1-formylbenzene (ortho-CHO) e 180 ± 0.2 33.64 ± 1.99 40.25 ± 3.71 170 ± 0.2 20.15 ± 0.34 20.64 ± 1.08 160 ± 0.1 11.26 ± 0.31 10.51 ± 0.19 150 ± 0.1 5.96 ± 0.22 6.65 ± 0.17 140 ± 0.1 3.15 ± 0.04 3.48 ± 0.03 f 2,3-Diethynyl-1-aminobenzene (ortho-NH2) 190 ± 0.2 3.94 ± 0.05 3.55 ± 0.03 180 ± 0.2 2.28 ± 0.07 2.29 ± 0.02 170 ± 0.2 1.26 ± 0.02 1.11 ± 0.01 160 ± 0.2 0.66 ± 0.01 1.66 ± 0.01 a Errors are standard deviations of the Arrhenius fits with 90% confidence limits. b Initial [ED] = 5.6 × 10-3 M; Initial [1,4-CHD] = 0.6 M. c Initial [ED] = 2.2 × 10-3 M; Initial [1,4-CHD] = 0.2 M. d Initial [ED] = 3.8 × 10-3 M; Initial [1,4-CHD] = 0.4 M. e Initial [ED] = 2.4 × 10-3 M; Initial [1,4-CHD] = 0.5 M. f Initial [ED] = 3.6 × 10-3 M; Initial [1,4-CHD] = 0.4 M.

45 Unlike the DSC data, the results are consistent with the theoretically predicted trends. Computational data showed a 3.6 kcal/mol decrease in activation energy when nitro group is

placed in proximity to the acetylene (ortho-NO2). Activation energies determined experimentally agree with this prediction and show a 4-5 kcal/mol difference. The difference between

experimental and theoretical values is within the error margin. Similarly, para-NO2 enediyne was predicted to have ca. 3 kcal/mol lower in activation energy for the Bergman cyclization than

ortho-NO2 enediyne which is nicely reflected in the experimentally determined activation

barrier. Comparison of para- and ortho-NO2 enediynes clearly confirms that it is not the presence of acceptor substituents per se but their position which is of the primary importance. Similarly, activation energies for ortho-CHO enediyne are within experimental error in good agreement with the computational predictions. However, the rate constants are less accurate in this case because the data are more scattered due to the presence of side reactions and low yield of the Bergman product.

Table 3. Activation Energies, Pre-Exponential Factors (Log A) and Yields of 1-Substituted Naphthalenes.a

Activation Energies, kcal/mol Pre-Exponential Factor, Log[A (s-1)] BLYP ED Naphthalene ED Naphthalene X Yields % (B3LYP)b Consumption Formation Consumption Formation H 24.5 (31.3) 25.9 ± 1.1 26.0 ± 1.7 9.4 ± 0.6 7.8 ± 0.8 35

ortho-NO2 20.9 (27.9) 21.5 ± 0.1 21.0 ± 0.9 8.2 ± 0.1 7.9 ± 0.5 75

para-NO2 24.1(30.9) 23.9 ± 0.3 24.5 ± 0.4 8.8 ± 0.2 9.0 ± 0.2 70

ortho-CHO (syn) 20.6 (27.7) 22.1 ± 0.4 22.4 ± 1.0 7.9 ± 0.5 8.4 ± 0.5 48 ortho-CHO (anti) 22.1 (29.2)

ortho -NH2 25.6 (31.3) 23.7 ± 0.3 23.0 ± 1.4 7.8 ± 0.1 7.4 ± 0.7 61 a Errors are standard deviations of the Arrhenius fits with 90% confidence limits; ED = Enediynes. b 6-31G** basis set.

As any other benzannelated enediyne described in this work, ortho-NH2 enediynes follow a pseudofirst order exponential behavior (Eq.1) for consumption of enediynes and the formation of 1-aminonaphthalene (Eq. 2). As depicted in Figure 6g and Table 2, the correlations for ortho-

NH2 enediynes are excellent. Amino substituent in the ortho position of benzannelated enediynes slows down the rate of the reaction significantly, ca. 10 times decrease in effective rate constants

46 in ortho-NH2 enediyne compared to para-NO2 enediyne. However, the activation energies determined from the effective rate constants for the consumption of enediyne and the formation of 1-aminonaphthalene do not agree very well with the predicted values. These discrepancies can be rationalized in terms of limitations of Density Functional Theory (DFT) used to perform these calculations in description of non-bonding interactions, such as hydrogen bonding.93-95 Table 3 also includes yields for the formation of the corresponding naphthalene products.

Nitro enediynes form the naphthalene product in the highest yields (75% yield for ortho-NO2 and

70% yield for para-NO2). This observation indicates that the Bergman cycloaromatization reaction is the major thermal pathway. On the other hand, 1,2-diethynylbenzene and ortho-CHO enediynes form the naphthalene products in relatively low yield suggesting that these enediynes undergo different reaction paths not necessarily leading to the Bergman product. These results rendered 1,2-diethynylbenzene an unreliable reference for studying the ortho-effect in Bergman cyclization.

As a result, the 3,4-diethynylnitrobenzene (para-NO2 enediyne) which reacts cleanly forming 2-nitronaphthalene in high yield is much better suited to be the reference point than 1,2- diethynylbenzene. Also, the presence of the para-NO2 moiety at the para position approximates the electronic effect of the ortho nitro group on the out-of-plane π-system. The following section is devoted to a more detailed kinetic analysis including the concentration effect of hydrogen- atom donor on the effective rate constants.

Effect of Concentration of 1,4-Cyclohexadiene on Rates and Activation Energies

Since the discovery of the natural occurring enediynes and their DNA damaging activity, considerable effort has been made to tune their reactivity. The focus was on the cycloaromatization step in studying the kinetics of the reaction despite the fact that other steps are needed to form the final product. The earlier observation that the rate of cycloaromatization of benzannelated enediynes is sensitive to the concentration of the hydrogen-atom donor indicate that other steps in the reaction cascade, including hydrogen-atom abstraction, contribute to the overall rate constant or the effective rate constants, keff. The most significant steps are the retro-Bergman cyclization step (B→A, Scheme 11) which is much faster in benzannelated enediynes than in their non-benzannelated analogues,43, 44, 67 and the first hydrogen-atom abstraction step which is decelerated by the loss of Through Bond (TB)

47 interaction between the two radical centers.96 It has been suggested that polymeric by-products contribute to lower mass balance of cyclized product and we refer to this and other by-products as D, (Scheme 11).92, 97

Scheme 11. Kinetic Steps Involved in the Cycloaromatization Cascade

. k 1 k2 NO NO 2 NO2 2 k 1,4-CHD -1 . A B C

k3

D (by-products) If one assumes that the major path for consumption of nitro enediynes and formation of nitro naphthalenes is the one depicted in Scheme 11, and that formation of by-products is independent on the presence of hydrogen donor, the effective rate constant for the consumption of A and the formation of C and D can be described by equations 3, 4 and 5, respectively.ii

kk [HD]+ kk A 21 31 3 keff = k2[HD]+()k−1 +k3

kk [HD] C 21 4 keff = k2[HD]+()k−1 +k3

kk D 31 5 keff = k2[HD]+()k−1 + k3

Effective rate constants determined from monitoring the disappearance of enediynes include rates for the cycloaromatization step, retro-Bergman ring opening step, hydrogen-atom abstraction steps in addition to other steps that do not lead to the naphthalene product. On the other hand, effective rate constants determined from the appearance of naphthalene products comprise only the steps leading to the Bergman product.

ii Full derivations of kinetic equations are included in Appendix D

48 In the case when the hydrogen abstraction step is much more important than the step leading to

the by-products D at high concentration of 1,4-CHD, (k2[HD] >> k3), one can reduce equations 3 and 4 to Eq. 6. The latter can be rearranged to Eq. 7:

kk [HD ] 21 6 k eff = k 2 [HD ] + k −1

1 k 1 = −1 + 7 keff kk 21 [HD ] k1

As indicated in Eq. 3 and 4, the effective rate constants for the consumption of enediynes and the formation of naphthalene products depend on the concentration of hydrogen-atom donor (Table 4 and Figure 11).

ED Table 4. Effective Rate Constants for Disappearance of Nitroenediynes ( keff ) and Appearance Napht a of Nitronaphthalenes ( keff ) at 140 ºC.

b c o- NO2 Enediynes p-NO2 Enediynes

ED 4 Napht 4 ED 4 Napht 4 [1,4-CHD], M keff × 10 keff × 10 keff × 10 keff × 10

0.73 - - 1.85 ± 0.02 1.64 ± 0.01 0.58 6.98 ± 0.07 6.63 ± 0.06 1.68 ± 0.03 1.57 ± 0.01 0.44 6.44 ± 0.10 6.44 ± 0.03 1.60 ± 0.03 1.53 ± 0.01 0.29 5.74 ± 0.06 5.48 ± 0.01 1.48 ± 0.02 1.46 ± 0.01 0.15 4.31 ± 0.02 4.28 ± 0.02 1.22 ± 0.02 1.15 ± 0.01 0.07 3.06 ± 0.02 2.66 ± 0.01 0.99 ± 0.02 0.92 ± 0.02 0.03 2.23 ± 0.02 1.06 ± 0.02 0.73 ± 0.01 0.63 ± 0.01

a -1 b -3 Pseudofirst order effective rate constants (keff)are in s . Initial concentration of enediynes = 2.7 × 10 M. c Initial concentration of enediynes = 3.8 × 10-3 M.

The dependence of effective rate constant on 1,4-CHD concentration can be divided into two regions. First, at low concentrations of 1,4-CHD (0.03, 0.07 and 0.15 M) the rate depends strongly on the availability of hydrogen-atom donor. This is followed by the second region at [1,4-CHD] ≥ 0.29 M where the increase in the CHD concentration has little impact on the effective rate constants. This indicates that at infinite concentration of hydrogen-atom donor the rate constant for enediyne consumption will reach a plateau and asymptotically approach the

limit of the maximum rate (Figure 8). As a result, the effective rate constant, keff, will be equal to

49 the rate of the Bergman cyclization step, k1, consistent with Eq. 7. A similar behavior is observed for effective rate constants for the formation of nitronaphthalene product.

(a) (b)

9.E-04 9.E-04

8.E-04 8.E-04

-1 7.E-04 ortho -1 7.E-0 4 ortho , s , s

eff eff 6.E-04 k 6.E-04 k 5.E-04 5.E-0 4

4.E-04 4.E-04

3.E-04 3.E-04 para para 2.E-04 2.E-04

1. E - 0 4 1. E - 0 4

0.E+00 0.E+00 0 0 .2 0 .4 0 .6 0 .8 0 0.2 0.4 0.6 0.8 [1,4-CHD], M [1,4-CHD], M

Figure 11. The dependence of effective rate constant, keff, from 1,4-CHD concentration at 140º C; (a) disappearance of enediynes and (b) appearance of nitronaphthalenes. Filled red circles are data for ortho-nitro enediyne and hollow red circles are data for para-nitro enediyne.

We compared our experimental data with theoretical predictions using Eq. 6 and found that the

ratio of experimental rate constants for retro-Bergman reaction and hydrogen-atom abstraction, k- -4 -1 -4 -1 1/k2, is ca. 8 M (k1 = 8.3 × 10 s ) and 15 M (k1 = 1.8 × 10 s ) for ortho and para-NO2 enediynes, respectively (Figure 11). These results suggest that, in the case of ortho-NO2, at 0.12- 0.14 M of 1,4-CHD concentration the rate of hydrogen abstraction reaches that of retro-Bergman ring opening and thus half of the diradical is converted back to the starting enediyne while the other half is trapped by 1,4-CHD. On the other hand, para-NO2 enediyne requires only 0.06-0.07 M 1,4-CHD to render the rates of retro-Bergman reaction and hydrogen abstraction equal. This difference may be attributed to the steric effect of the ortho-nitro group which blocks the approach of 1,4-CHD from one side of the p-benzyne (syn to the nitro substituent). The other factor may be the difference in the rate of retro-Bergman processes for the two p-benzynes. A similar interpretation can be observed for experiments performed at different temperatures. Table 5 depicts effective rate constants for consumption of nitro enediynes and formation of nitronaphthalene products when the concentration of 1,4-CHD and temperatures are varied.

50 ED Table 5. Effective Rate Constants for Disappearance of Nitroenediynes ( keff ) and Appearance Napht a of Nitronaphthalenes ( keff )at Different Temperatues.

b c o- NO2 Enediynes p-NO2 Enediynes

ED 4 Napht 4 ED 4 Napht 4 [1,4-CHD], M keff × 10 keff × 10 keff × 10 keff × 10 T = 148 ºC T = 150 ºC 0.73 - - 3.70 ± 0.11 3.67 ± 0.09 0.58 11.53 ± 0.35 11.50 ± 0.10 3.49 ± 0.04 3.12 ± 0.02 0.44 10.69 ± 0.14 11.13 ± 0.08 3.26 ± 0.07 3.08 ± 0.03 0.29 9.43 ± 0.26 9.07 ± 0.11 3.01 ± 0.05 2.81 ± 0.03 0.15 7.00 ± 0.03 6.99 ± 0.05 2.40 ± 0.04 2.37 ± 0.03 0.07 5.09 ± 0.09 5.03 ± 0.05 1.92 ± 0.03 1.47 ± 0.02 0.03 3.59 ± 0.02 3.30 ± 0.03 1.36 ± 0.01 1.29 ± 0.02 T = 156 ºC T = 160 ºC 0.73 - - 7.56 ± 0.14 6.73 ± 0.05 0.58 20.14 ± 0.13 20.13 ± 0.24 7.09 ± 0.15 6.15 ± 0.08 0.44 17.43 ± 0.23 17.20 ± 0.22 6.37 ± 0.01 6.20 ± 0.07 0.29 15.37 ± 0.34 15.30 ± 0.26 5.86 ± 0.11 5.68 ± 0.05 0.15 11.01 ± 0.10 11.04 ± 0.12 4.59 ± 0.08 4.51 ± 0.03 0.07 7.21 ± 0.12 6.17 ± 0.09 3.58 ± 0.06 3.59 ± 0.04 0.03 5.31 ± 0.07 5.90 ± 0.14 2.66 ± 0.04 2.59 ± 0.07 T = 164 ºC T = 170 ºC 0.73 - - 14.05 ± 0.17 13.24 ± 0.18 0.58 32.50 ± 0.25 32.94 ± 0.43 13.11 ± 0.20 12.59 ± 0.08 0.44 27.46 ± 0.19 27.41 ± 0.17 11.84 ± 0.21 10.33 ± 0.10 0.29 24.19 ± 0.31 21.96 ± 0.29 10.57 ± 0.21 9.35 ± 0.13 0.15 17.01 ± 0.12 15.85 ± 0.15 8.05 ± 0.16 8.02 ± 0.05 0.07 11.75 ± 0.04 11.84 ± 0.13 6.08 ± 0.12 5.80 ± 0.03 0.03 8.10 ± 0.04 7.84 ± 0.08 4.47 ± 0.05 3.74 ± 0.10

a -1 b -3 Pseudofirst order effective rate constants (keff)are in s . Initial concentration of enediynes = 2.7 × 10 M. c Initial concentration of enediynes = 3.8 × 10-3 M.

51 Effective rate constants at different temperatures allowed us to determine Arrhenius activation energies at different concentration of 1,4-CHD. The measured effective activation barriers are given in Table 6. Increase in concentration of 1,4-CHD raises the activation energies for both nitro enediynes but the ortho-isomer is more sensitive. For instance, the difference between activation energies determined at high concentration of 1,4-CHD and at low concentration of

1,4-CHD is 4.1 and 2.6 kcal/mol for the ortho and para-NO2 substitution, respectively.

Table 6. Activation Energies Determined from Effective Rate Constants for Consumption of NO2-enediynes (Ea App) and Appearance of Nitronaphthalenes (Ea Disapp) at Different Concentration of Hydrogen-Atom Donor.a

b c o- NO2 Enediynes p-NO2 Enediynes

[1,4-CHD], M Ea App Ea Disapp Ea App Ea Disapp 0.73 - - 24.8 ± 0.3 24.9 ± 0.8 0.58 23.2 ± 0.5 24.0 ± 0.3 25.0 ± 0.4 25.2 ± 0.6 0.44 21.7 ± 0.1 22.8 ± 1.3 24.0 ± 0.8 23.4 ± 0.9 0.29 21.5 ± 0.1 21.0 ± 0.9 23.9 ± 0.3 22.8 ± 0.9 0.15 20.5 ± 0.1 19.6 ± 0.7 22.9 ± 0.4 23.5 ± 0.5 0.07 19.6 ± 0.9 20.9 ± 2.8 22.1 ± 0.5 22.9 ± 2.3 0.03 19.1 ± 0.4 19.8 ± 2.0 22.2 ± 0.6 23.2 ± 4.8 a Activation Energies in kcal/mol. b Initial concentration of enediynes = 2.7 × 10-3 M. c Initial concentration of enediynes = 3.8 × 10-3 M.

Standard deviation for activation energies for consumption of enediynes is good with less than ±1 kcal/mol error. On the other hand, effective rate constants for formation of naphthalene products are more scattered especially at low concentration of 1,4-CHD. Consequently, activation energies for the appearance of nitronaphthalenes at 0.07 and 0.03 M concentration of 1,4-CHD have error bars of ± 2.0-4.8 kcal/mol. These results are consistent with the change in the main reaction pathway from Bergman cyclization to polymerization and formation of by- product D. At low concentration of 1,4-CHD, effective rate constant in Eq. 3 transforms to Eq. 7 which is based mainly on rate constants of the path leading to the formation of by-product D. Table 6 indicates that the reaction pathway for formation of by-product D has activation energies equal or less than 19.1 and 22.1 kcal/mol for ortho-NO2 and para-NO2 enediynes, respectively. Since these values are lower than the activation barriers for the Bergman cyclization, the side

52 reaction are not likely to include p-benzyne. Instead, chain polymerization is a reasonable possibility. In the following section, we will determine rate constants for the Bergman cycloaromatization step and the “true” activation energies for the Bergman cycloaromatization reaction.

Dissection of the Bergman Cyclization Kinetics

The data presented in the previous section point to a real problem in comparing data for different compounds based on effective rate constants, keff, thus the need for a better approach. Eq. 7 allows one to determine the “true” rate constant for the Bergman cycloaromatization reaction, k1, which is the intercept of the plot of the effective rate constants, keff, versus 1,4-CHD concentration. Furthermore, this analysis provides a general method to dissect kinetic contribution from the individual steps to the overall kinetics of the reaction cascade (k1, k-1, k2 etc.). An important feature of this scheme is the possibility to elucidate rate constants of individual steps by studying the concentration effect of the hydrogen-atom donor on the overall rate constant, keff. From multicomponent fitting of the data, both k1 and the k-1/k2 ratio can be determined from Equations 6 and 7 (in the last case, the constants can be also obtained graphically). Table 7 shows the single step rate constants for the two nitro enediynes.

Table 7. Rate Constants at 140 ºC Determined using Equations 5 and 6.a

o-NO2 p-NO2 Disappearance of Appearance of Disappearance of Appearance of

Enediyne Naphthalene Enediyne Naphthalene Equation 6 4 -1 b k1 × 10 , s 8.52 ± 1.33 7.97 ± 2.22 1.88 ± 1.11 1.79 ± 1.00 2 b k-1/k2 × 10 , M 13.78 ± 2.12 13.63 ± 2.40 6.15 ± 1.56 7.25 ± 2.01 R2 0.997 0.984 0.951 0.990 Equation 7 4 -1 k1 × 10 , s 8.26 ± 0.23 8.27 ± 0.49 1.87 ± 0.07 1.76 ± 0.04 2 k-1/k2 × 10 , M 12.58 ± 0.02 15.11 ± 0.10 6.82 ± 0.06 6.86 ± 0.41 R2 0.997 0.991 0.974 0.989 a Data for [1,4-CHD] = 0.03 M was not included in the fit, unless otherwise noted. b Data for [1,4-CHD] = 0.03 M was included.

53 First, these results indicates that under conditions where concentration of 1,4-CHD is 0.58 M

the effective rate constants reaches the maximum rate constant for the consumption of ortho-NO2 enediyne. On the other hand, effective rate constant determined at 0.73 M concentration of 1,4- CHD is the asymptotic value of Figure 8. Second, the results suggest that only at 0.12-0.14 M concentration of 1,4-CHD the rates of hydrogen abstraction in ortho-NO2 reaches that of the retro-Bergman opening and thus half of the p-benzyne intermediate is intercepted before reverting to the starting material. Such trapping is more efficient in the case of para-NO2 substrate where such 50/50 threshold is achieved at 3-4 fold smaller concentration of the hydrogen-donor. These observations are in excellent agreement with the results determined earlier using theoretical comparison, vide supra, and thus leads to similar conclusions. Arrhenius activation energies determined from rate constants of the Bergman cyclization step

for the consumption of ortho- and para-NO2 enediynes are 23.7 ± 1.1 and 25.4 ± 0.2 kcal/mol, whereas, activation energies determined from formation of nitronaphthalene products are 23.4 ±

3.2 and 24.3 ± 1.2 kcal/mol for ortho- and para-NO2, respectively. These values are in excellent agreement with activation energies determined from effective rate constants at high concentration of 1,4-CHD. Although these values should be more accurate than all of the previous results, it is harder to achieve the same precision in the respective correlations and, thus, the uncertainty in the measurements increases. Nevertheless, the difference in the activation

energy between ortho-NO2 and para-NO2 enediynes unequivocally supports the earlier computational prediction of ortho effect in the Bergman cyclization.

Ortho-Substituted Benzannelated Enediynes: Methoxy Substituent

The ortho-methoxy benzannelated enediyne, 2,3-diethynyl-1-methoxybenzene (ortho-OCH3), is an interesting case. The methoxy group in methanol is known to be a good hydrogen-atom donor. Abstraction of a hydrogen atom from the methyl group in methanol rather than from the OH group of the methanol molecule can be used to differentiate between radical and proton transfer mechanisms.98 Because the Bergman cyclization forms a diradical as an intermediate, one would expect the methoxy group adjacent to the radical center to act as a hydrogen donor, especially when the abstraction takes place through a favorable six-membered transition state.

54 -1 Table 8. Effective Rate Constants (keff, s ) for the Disappearance of ortho-OCH3 and ortho- a OCD3 and the Appearance of Corresponding Naphthalenes at Different Temperatures.

ED 4 Napht 4 Temperature, ºC keff × 10 keff × 10

b 2,3-Diethynyl-1-methoxybenzene (ortho-OCH3) 180 ± 0.2 11.7 ± 0.09 11.1 ± 0.18 170 ± 0.2 6.31 ± 0.39 (6.17 ± 0.39)c 5.72 ± 0.27 160 ± 0.1 3.03 ± 0.17 2.71 ± 0.06 150 ± 0.1 1.58 ± 0.08 1.60 ± 0.03 d 2,3-Diethynyl-1-(trideuteriomethoxy)benzene (ortho-CD3) 180 ± 0.2 7.85 ± 0.20 8.07 ± 0.11 170 ± 0.2 4.45 ± 0.14 (2.50 ± 0.14)c 3.65 ± 0.13 160 ± 0.1 2.45 ± 0.09 2.20 ± 0.05 150 ± 0.1 1.16 ± 0.04 1.13 ± 0.02 a Errors are standard deviations of the Arrhenius fits with 90% confidence limits. b Initial [ED] = 3.3 × 10-3 M; Initial [1,4-CHD] = 0.3 M. c Values in parentheses are determined in absence of 1,4-CHD. d Initial [ED] = 2.5 × 10-3 M; Initial [1,4-CHD] = 0.3 M.

Effective rate constants determined for ortho-CH3 enediyne are larger than those for ortho-

OCD3 enediyne. This suggests that the substituent on the benzene ring affects the reaction kinetics. From the effective rate constant presented in Table 8 we can estimate the isotope effect

as kH/kD = 1.4 at 170 ºC, however, the effective rate constants used to calculate this value include rate constants for all steps involved in the reaction process. So we determined the effective rate constant for the consumption of the enediynes in the absence of 1,4-CHD (Table 8 value in parentheses) which results in an isotope effect of kH/kD = 2.5 at 170 ºC (Figure 12). Although, this value indicates a primary isotope effect, one can not exclude the interference of other reactions taking place before the intramolecular reaction.

55 2.5E-03

2.0E-03

[SM], M [SM], 1.5E - 0 3 y = 2.35E-03e-2.50E-04x R 2 = 9.91E-01 1.0 E - 0 3

5.0E-0 4 y = 2.10E-03e-6.17E-04x R 2 = 9.98E-01

0.0E+00 0 1000 2000 3000 4000 5000 6000

Time, s

Figure 12. First-order rate constants determined for the disappearance of ortho-CH3 (solid line) and ortho-OCD3 (Dashed line) enediynes at 170 ºC.

If our proposed mechanism, where the methoxy group acts as an intramolecular hydrogen- atom donor and competes with the intermolecular hydrogen-atom donor, 1,4-CHD, is correct then the sequence of steps involved in the Bergman cycloaromatization cascade can be illustrated in Scheme 12.

Scheme 12. Kinetic Model for the Bergman Cyclization of 2,3-Diethynyl-1-methoxybenzene k k H(D) k = 1 3 k [HD] << k . H(D) eff 2 3 k-1 + k3 O H(D)

k OR OR 3 OR' H(D) . . C k1 k 1,4-CHD -1 . 1,4-CHD A B 1,4-CHD D H k2 R = CH , CD R' = CH3, CD2H 3 3 Monoradical k [HD] k2[HD]+k3 2 k = k k = k k3 << k2[HD] eff 1 k [HD]+(k + k ) eff 1 k [HD]+k 2 -1 3 2 -1 Since the cyclization of benzannelated enediynes is significantly endothermic, the barrier for 44 the retro-Bergman ring opening of p-benzyne is small (k-1 is large). As a result, the rate of cyclization of benzannelated enediynes depends on the hydrogen-atom donor concentration43, 99 and, thus, the prior steps in the cycloaromatization cascade contribute to the overall kinetic

56 expression. In the absence of intramolecular hydrogen-atom abstraction and other side reactions, the rate of disappearance for the enediyne reactant can be described by the Equation 8

k [HD] 2 8 k eff = k1 k 2 [HD]+ k −1 where rate constants are defined in Scheme 12 and HD stands for hydrogen-atom donor. However, when the OMe group is capable of serving as hydrogen atom donor, it intercepts the p- benzyne radical. As a result, the effective rate for the disappearance of OMe enediyne increases and becomes less dependent on the “external” hydrogen-atom donor concentration. In the

extreme case, when k3 is much faster than the rate of intermolecular hydrogen-atom abstraction

(k2[HD]<

kk 31 9 k eff = k −1 + k 3

is independent on the concentration of hydrogen-atom donor.

Table 9 shows Arrhenius parameters determined for ortho-OCH3 and ortho-OCD3 enediynes. Within experimental error, activation energies for the consumption of enediynes and formation of 1-methoxynaphthalenes are in a good agreement with the predicted value.

Table 9. Activation Energies, Pre-Exponential Factors (Log A) and Yields of 1-OCH3/OCD3 Naphthalenes.a

Activation Energies, kcal/mol Pre-Exponential Factor, Log[A (s-1)] BLYP ED Naphthalene ED Naphthalene X Yields % (B3LYP)b Consumption Formation Consumption Formation

ortho-OCH3 24.7 (31.4) 25.5 ± 0.6 24.9 ± 1.4 9.4 ± 0.3 9.0 ± 0.7 65

ortho-OCD3 24.8 (31.3) 24.2 ± 0.8 24.4 ± 1.6 8.6 ± 0.4 8.6 ± 0.8 62 a Errors are standard deviations of the Arrhenius fits with 90% confidence limits. b 6-31G** basis set.

A direct prediction from the above model is that keff should be influenced by relative values of 43 k2 and k-1 as shown before by kinetic studies of Kaneko et al. If k-1 (the rate of the retro- Bergman opening) is significantly faster in comparison with intermolecular hydrogen-atom abstraction by the p-benzyne diradical (k2[HD]), the effective rate for the enediyne disappearance will depend on the concentration of the hydrogen-atom donor. The second prediction is that if the intramolecular hydrogen-atom abstraction is important, effective rate for the disappearance of

57 ortho-OCH3 enediyne should increase and become less dependent on the “external” hydrogen- atom donor concentration. We compared reaction rates and activation energies for the 2,3-diethynyl-1-methoxybenzene and its OCD3 analog by: a) Differential Scanning Calorimetry (DSC) of neat samples and solutions in 1,4-CHD and b) kinetic analysis under the pseudofirst order conditions. For both enediynes the activation energies for the disappearance of reactants and for the formation of corresponding naphthalene products are the same within experimental error. However, the DSC barrier determined in 1,4-CHD is higher for the deuterated enediyne (Table 1) and consumption

of ortho-OCH3 proceeds on average 1.4 faster than that of ortho-OCD3 at this concentration of 1,4-CHD, vide supra. This observation supports our proposed mechanism and reflects the deuterium isotope effect on intramolecular hydrogen-atom abstraction step displayed indirectly as described in Eq. 9.

(a) (b) 2.5E-03 k2/k-1 = 100

k2/k-1 = 25 6.0E-04 2.0E-03

-1 k /k = 5 -1 2 -1 , s , s

eff experimental eff k k 1. 5 E - 0 3

k2/k-1 = 2 4.0E-04 1. 0 E - 0 3

5.0E-04

2.0E-04 0.0E+00 0 0 .1 0.2 0.3 0.4 0 0.2 0 .4 0.6 0.8 [1,4-CHD], M [1,4-CHD], M

Figure 13. Dependence of the effective rate constant on the 1,4-CHD concentration for (a) the consumption of 2,3-diethynyl-1-methoxybenzene (filled circles), 2,3-diethynyl-1- trideuteriomethoxybenzene (red crosses) and formation of 1-methoxynaphthalene (hollow circles) and (b) trends in keff at different k-1:k2 ratios predicted by Eq. 7 vs. the experimental dependence of the rate of consumption for 3.9×10-3 M 1,2-diethynylbenzene solution at 188 oC, shown in red triangles.

The key evidence for the intramolecular p-benzyne interception is provided by the response of experimental reaction rates to variations in the hydrogen-atom concentration. The experimentally measured trend in Figure 13a clearly follows Eq 8 where the consumption of ortho-OCH3 is independent of the concentration of the external hydrogen donor, 1,4-CHD. As a result, the

58 Bergman cyclization in this case can be considered as irreversible reaction, with the p-benzyne intermediate being funneled down the reaction path and the retro-Bergman step effectively shut- off. In contrast, the rate of consumption of 1,2-diethynylbenzene depends on 1,4-CHD concentration. Comparison of the experimental curve with theoretical predictions at different

k2:k-1 ratios based on Eq. 8 suggests that the ratio of experimental rate constants for hydrogen- atom abstraction and retro-Bergman reaction is ca. 5 M-1 (Figure 13b). Consequently, 1,2- diethynylbenzene requires 0.2 M 1,4-CHD concentration to reach the state when the rates of retro-Bergman ring opening and hydrogen-atom abstraction are equal. This result is readily explained by the large endothermicity of the reaction.79 Further experimental evidence for the intramolecular H-atom transfer includes: a) D- incorporation at the C8 of the naphthalene ring with the concomitant H-incorporation at the

OCD3 group (Figure 14) and b) formation of the product of OCD2 radical trapping by reaction at the C3 of cyclohexa-2,4-dien-1-yl radical (Figure 15). The extent of D-incorporation provides an insight into the relative rates of intramolecular and intermolecular H-atom abstraction. At the 0.33 M (100-fold excess) concentration of 1,4-

cyclohexadiene (1,4-CHD), about 20% of D is transferred, indicating the k2[HD]/k3 ratio of 4:1, integration in Figure 14b. Although direct determination of the extent of D-incorporation at lower concentration of 1,4-CHD is complicated by low yields of naphthalene products under these conditions, this data suggests the dominance of the intermolecular hydrogen-atom transfer (>96%) at equal concentrations (0.0033 M) of the enediyne and the hydogen-atom donor when

k2[HD]/k3 ratio reaches 0.04:1. Most interestingly, these observations suggest that the D-effect

on k3 is significant and intramolecular interception becomes less competitive. Indeed, the rate of

disappearance of CD3-labeled enediyne becomes sensitive to [1,4-CHD]-concentration (Table 8 values in parentheses).

59 (a)

OMe

(b)

CD2H OCD3 OD

+

4:1

0.8

0.2

1 Figure 14. H NMR spectra for the Bergman cyclization major products of (a) ortho-CH3 and (b) ortho-OCD3 enediynes showing deuterium incorporation in C8 of the naphthalene ring.

60 Finally, both the intramolecular hydrogen abstraction and the relatively long lifetime of the intermediate α-aryloxy radical are further supported by formation of the product of the

cyclohexadienyl radical recombination with OCH2 moiety derived from the methoxy group. Although, yield for these products are low (1-2%), their 1H NMR spectra (Figure 15) support the proposed structures. Furthermore, Electron Impact Mass Spectrometry (EI-MS) showed the presence of the compound with m/z = M++82 Da, where M is the molecular weight of ortho enediyne. However, the major m/z peak was M++80 Da which refers to two Da units loss. This radical ion is mostly generated through the loss of 2H atoms from the 1,4-cyclohexadienyl substituent in the parent compound at the gas phase to form the more stable phenyl ring adduct.

(a)

O

Figure 15. 1H NMR spectra for products derived from trapping of radicals generated by the Bergman cyclization of ortho-OCH3 and ortho-OCD3 enediynes.

61 (b) D D O D

(c)

OMe

Figure 15. Continues

62

(d)

OCD3

Figure 15. Continues

CONCLUSIONS

Kinetic investigations on the Bergman cyclozaromatization reaction for a family of substituted benzannelated enediynes confirm our theoretical predictions that placing a substituent in close proximity to the acetylenic moiety (ortho-position) of enediynes alters the activation barrier of the cyclization. This hypothesis was confirmed with various experimental approaches. Activation energies determined from differential scanning calorimetry for enediynes with substituents in the ortho position showed good agreement with the predicted values, though this technique should be restricted to qualitative assessments of reactivity. A more thorough kinetic analysis based on monitoring the disappearance of enediynes and the appearance of the corresponding naphthalene products provided effective rate constants for the consumption of reactants and the formation of products. Under the pseudofirst order conditions,

the ortho-NO2 enediynes is six times more reactive than its para-NO2 analogue. The ortho-CHO substituent substantially accelerates the reaction as well, on the other hand, ortho-NH2

63 significantly retard the reaction. These observations are in agreement with our theoretical predictions.

In the case of ortho- and para-NO2 enediynes, effective rate constants were determined under different concentrations of hydrogen-atom donor, 1,4-CHD. We found that rates for disappearance of nitro enediynes and the appearance of nitronaphthalenes are strongly dependent on the presence of 1,4-CHD. At low initial concentrations of the hydrogen-atom donor, rate constants increased dramatically with increasing 1,4-CHD concentration. However, at higher initial concentration of hydrogen-atom donor, the rate of the reaction reaches a plateau where change in concentration of 1,4-CHD does not affect the observed rate constant. Rate constants at different concentrations of 1,4-CHD and different temperatures enabled us to determined the “true” activation barrier for the Bergman cyclization step from the reaction mechanism. We conclude that at high concentration of hydrogen-atom donor, the Bergman cyloaromatization step is the rate-limiting step; however, at low concentration of 1,4-CHD other reaction steps, such as retro-Bergman reaction and hydrogen-atom abstraction steps, or reaction pathways, such as polymerization, become significantly important in the reaction mechanism.

In the case of ortho-OCH3 enediyne, we found that the methoxy substituent intercepts the p- benzyne diradical through intramolecular hydrogen-atom abstraction. This observation was

supported by deuterium isotope effect, kH/kD = 2.5, and by product analysis of the thermal

reaction of ortho-OCD3 enediyne which shows that significant amount of the naphthalene product contained deuterium incorporated carbon 8 of the naphthalene ring. The intramolecular hydrogen abstraction step renders cyclization effectively irreversible and provides a route to diradicals with new topologies which are likely to be longer living than p-benzyne. An important conclusion from this work is that studies of Bergman cyclization kinetics by monitoring of the disappearance of enediynes instead of the product formation are based on a approximation that may lead to inaccurate description of the reaction kinetics. For instance, despite its common use, the parent benzannelated enediyne is a poor reference point for comparison due to the low (30%) yield of the Bergman cyclization product. Moreover, conclusions drawn from kinetic analysis that rely on monitoring only the consumption of enediynes are questionable due to the risk of incorporating kinetics for reaction pathways that do not include the Bergman cyclization reaction during experimental measurements.

64 CHAPTER II

INTRODUCTION

In this chapter, we present studies conducted on a family of diaryl acetylenes that undergoes photochemical cycloaddition to 1,4-cyclohexadiene (1,4-CHD) to yield diaryl polycyclic hydrocarbons. An investigation of unexpected results has led to the discovery of a novel reaction. Mechanistic and photophysical studies provide insight into the mechanism of these reactions. In addition, we found that the polycyclic products are interesting supramolecular building blocks.

Bergman Cyclization: The Photochemical Aspect

Photochemically initiated cyclization of enediynes has been known since 1968, even before the discovery of its thermal counterpart.1 Cambell and Eglinton irradiated a benzene solution of 1,2-diiodoethynylbenzene and isolated, in addition to 1,2-diphenylethynylbenzene as the major product (40% yield), substituted naphthalene products, which were suggested to form from 1,4- dehydronaphthalene as an intermediate (Scheme 13).100

Scheme 13. The First Reported Photocyclization of an Enediyne

I Ph Ph hν + + benzene Ph Ph I Ph 40%

In the early 70s, Zimmerman and Pincock reported a photochemical cyclization of a nonconjugated diacetylene, 3,3-dimethyl-1,5-diphenyl-1,4-pentadiyne (Scheme 14).101 Although this reaction does not involve an enediyne moiety, the proposed mechanism is similar to that of the Bergman cyclization where a cyclopentadienyl ring is formed in the presence of hydrogen atom donors. This cyclization was suggested to go through a biradical intermediate. More recently, Matzger et al. reported the photochemical cyclization of the sulfide analogue and proposed a similar mechanism (Scheme 14).102

65 Scheme 14. Photocyclization of Diacetylene Systems Analogous to the Bergman Cyclization

. hν RH X X X .

X = C(CH3)2, 15 %. Zimmerman et al. JACS 1973, 95, 3246. X = S, 16 %. Matzger et al. Org. Lett. 2003, 5, 2195. Photochemical activation of enediynes has attracted attention since it has been shown that dynemicin A causes ds-DNA cleavage under irradiation.103 Kagan and coworkors were the first to investigate the possibility of utilizing an enediyne moiety in phototherapy.104 They found that, although, 1,6-diphenyl-3-hexene-1,5-diyne only undergoes cis-trans isomerization, it still exhibited photochemically induced DNA-cleaving activity (Scheme 15). Incorporation of the ene moiety of enediyne into an arene ring prevents isomerization reaction of the parent enediynes (Scheme 15b and c). In 1994, Turro et al. reported photochemical Bergman cyclization of 1,2-di(pent-1-ynyl)benzene to 1,2-dipropylnaphthalene in isopropanol as the hydrogen-atom donor (Scheme 15).105 Later, they reported the photocycloaromatization reaction of 1,2-diethynylphenylbenzene to 2,3-diphenylnaphthalene (75% conversion) in isopropanol.106 In addition, photoreduction of one of the triple bonds by the solvent was observed. The extent of photoreduction of the acetylene moiety is dependent on the substituents at the triple bonds. The authors showed that photoreduction products are formed from the excited triplet state of enediynes; however, the results were not conclusive on the question of whether the cyclization resulted from a singlet or triplet excited enediyne. They suggested the 1,4- dehydronaphthalene biradical species as the most likely intermediate.106 Matzger et al. recently reported the same reaction to proceed in only 1% yield.107 Funk et al. studied the photochemical cycloaromatization of a series of arene fused enediynes with different sizes (Scheme 15) and investigated their DNA-cleaving properties.108 The first photochemical Bergman cyclization of non-benzannelated enediynes was reported in 1999 by Hirama and coworkers.109 They studied a family of 1,2-diethynylcyclopentene derivatives and found acceptable yields only when a methyl group is attached to the terminal acetylene the yield was acceptable (Scheme 15d). Furthermore, irradiation of a strained ten- membered cyclic enediyne at 254 nm led to the formation of the tetrahydronaphthalene as the

66 major product, in addition to appreciable amount of 1,2-diethynylcyclohexene (6% in hexane and 24 % in acetonitrile) formed by retro-Bergman ring opening (Scheme 15e). Later, it was reported that incorporating the double bond of enediyne into a six membered ring maximized yield for the Bergman product (Scheme 15f).110 Recently, Zaleski used metal-ligand charge transfer to trigger the Bergman cyclization in metalloenediynes and investigated their ability to cleave DNA.111, 112

Scheme 15. Photochemical Bergman Cyclizationa H R R . R R RH hν hν (a) Kagan et al. Phochem. Photobiol. 1993, 21, 135 R R . R = Phenyl H R R

R . H Turro et al. R R JACS 1998, 120, 1835 hν RH (b) R = Propyl (40%) Phenyl (75%) . R R R H Matzger et al. JACS 2005, 127, 9968 R = Phenyl (1%) H . hν RH (c) Funk et al. JACS 1996, 118, 3291 . (100%) H

H R . R R hν RH TBSO (d) TBSO TBSO R . R Hirama et al. R H Angew. Chem., Int. Ed. Engl. 1999, 38, 1267 H . R = H (3%) Me (71%) RH hν + (e) . 29% H 6%

R . H hν R CH RH R Jones et al. (f) 2 2CH CH

n n 2 JACS 2000, 122, 9872 n R = Phenyl . R R n = 2-6 (0-21%) R H a hν is UV-irradiation and RH is hydrogen-atom donor

En Route to Novel Photochemical Reactions: From Bergman Cycloaromatization to C1C5 Cylization

As stated earlier, Koga and Morokuma ascribed the low reactivity of enediynes to the strong repulsion between in-plane π-orbitals of acetylenes, vide supra.65 The in-plane orbitals are

67 directly involved in the Bergman cyclization process because they are responsible for the formation of the new σ-bond and the two radical centers in p-benzyne. Consequently, attachment of strong electron acceptor substituents at the terminal acetylenic moiety is expected to decrease the repulsion between the in-plane orbitals and thus facilitate the reaction. Driven by this hypothesis, our group prepared a new family of benzannelated enediynes bearing the electron accepting substituent tetrafluoropyridyl (TFP) on the acetylenic termini. Unlike the photochemical Berman cyclization in which the biradical intermediate abstracts two hydrogen-atoms, these benzannelated enediynes cyclize upon irradiation to the corresponding indenes, C1C5 cyclization (Scheme 16). This photochemical reaction takes place in polar solvents (CH3CN) and in the presence of 1,4-cyclohexadiene (1,4-CHD) which plays a dual role as hydrogen and electron donor.113 In the first step, 1,4-CHD reduces the enediyne by electron donation to the singlet excited state of the enediyne diverting reactivity towards the C1C5 cyclization. Our computational studies revealed that although one-electron reduction of benzannelated enediyne destabilizes the resulting radical anion due to loss of aromaticity at the transition state, crossing of in-plane and out-of-plane molecular orbitals at the TS restores aromaticity.114 In the following steps, 1,4-CHD provides four hydrogens (in the form of protons or hydrogen atoms) which are incorporated into the final product.

Scheme 16. C1C5 Photochemical Cyclization of Benzannelated Enediynes

F F F N N F F F H H F F F F hν, CH CN F 3 N F

N H H F F F 1 F 2, 22% Currently, our group is developing and investigating novel DNA photocleaving agents. Our recent progress indicates that benzannelated enediynes, capable of undergoing the C1C5 cyclization, cause non-random double-strand DNA breaks.115

68 Photochemical Cycloaddition of Acetylenes to 1,4-CHD: From Hydrogen/Electron Transfer to Cycloaddition

The two-photon activation of antitumor drugs is a promising direction for the phototherapy of cancer.116 In simple terms, a molecule is irradiated with high intensity light resulting in simultaneous absorption of two photons mediated by a “virtual state”, a state with no classical analog.117 The combined energy of the two photons leads to a stable excited state of the molecule (Scheme 17). This method provides extremely mild conditions for drug activation by delivering high intensity photons of very low energy (700-800 nm) through the therapeutic window of tissues. In addition, quadratic dependence of the two photon absorption cross-section on light intensity confines the affected part to the focal point of the laser, thus assuring excellent three- dimensional spatial control on the location of the treated tissue and minimal photodamage to healthy tissue.

Scheme 17. “Simultaneous” Two Photon Absorption Process one-photon absorption two-photon absorption 350 nm 700 nm excited state

virtual state

ground state Analysis of molecular orbitals suggested that the symmetry of excited states of heteroaromatic benzannelated enediynes, for instance 1,2-diethynylpyrazine, may be favorable for a two-photon absorption transition. 2,3-Bis(tetrafluoropyridinylethynyl)pyrazine 3 was prepared by Sonogashira coupling of 2,3-dichloropyrazine with trimethylsilyl acetylene followed by fluorine mediated nucleophilic substitution of trimethylsilyl group with pentafluoropyridine. Irradiation of 3 with 1,4-CHD in acetonitrile at 313 nmiii results in neither the Bergman cyclization nor the C1C5 cyclization. In this case, one of the triple bonds reacts with 1,4-CHD to form diaryl substituted tricyclo[3.2.1.04,6]oct-2-ene as the major product in the moderate yield of 35% (Scheme 18).

iii Solution of 0.001M K2CrO4 was used as a filter; maximum transmission at 313 nm wavelength.

69 Scheme 18. Photocycloaddition of Bis-TFP Pyrazine Enediyne 3 F F N F F N F F N F N F hν, CH3CN F F N N F F

N N F F 3 F 4, 35% F The structure was elucidated from the H1-C13 one-bond and long-range couplings revealed by the ghmqc and ghmbc spectra. The assignments of the 1H, 13C and 19F NMR chemical shifts in compound 4 are given in Figure 16.iv

-92.2 F N -139.9 142.41 F2.02 22.27 1.81 F 21.42 26.39 138.94 134.23 1.23 F N 128.04 2.90 8.16 30.65 153.68 141.07 6.69 134.23 133.71 8.33 141.22 F N 101.22 112.60 75.01 F

140.26 N F 143.51 -136.7 F -89.6

Figure 16. Structure and NMR assignments of tricyclo[3.2.1.04,6]oct-2-ene 4

Since only one of the acetylene moieties was involved in the photocycloaddition, we investigated the reactivity of diaryl substituted monoacetylenes. Discussion of our experimental studies will be preceded by on overview of literature examples of photochemical reactions of acetylenes and dienes.

iv The structure was determined in collaboration with Dr. Ion Ghiviriga from the Chemistry Department at University of Florida, Gainesville.

70 Photocycloaddition Reactions of Acetylenes: Literature Review

Recently, the photochemistry of acetylenes received much attention from the point of view of organic synthesis, reaction mechanisms and biological activity.104, 118-120 Still, despite continuing effort, alkynes are not able to match the wealth of photochemistry reported for alkenes, dienes and polyenes. Most photochemical reactions of alkynes concentrate on mono- or disubstituted acetylenes in which the substituents are either alkyl, aryl or alkoxycarbonyl. This is probably due to the greater tendency of compounds containing carbon-carbon triple bond to undergo photopolymerization rather than any other reaction upon irradiation.121-125 Nonetheless, there is a wide variety of reactions that involve the excited state of alkynes and some of these reactions have promissing synthetic application or potential. The most studied area in acetylene photochemistry is photocycloaddition to carbon-carbon double bonds and to aromatic compounds. For instance, excited diphenylacetylene (tolane) adds to alkenes in a [2π+2π] fashion to form cyclobutene products (Scheme 19a).126 In some cases, when the cyclobutene adduct absorbs light, electrocyclic ring opening yields the 1,3-diene (Scheme 19b).127 In the case of sterically accessible alkenes such as ethylene, two molecules of the alkene add to the acetylene to form the fused dicyclobutane adduct, bicyclo[2.2.0]hexane (Scheme 19c).128 Interestingly, a minor product of this reaction is 1,2-dicyclopropylethane adduct (6%) which was suggested to be formed through a cyclopropylcarbene-ethylene insertion mechanism. Likewise, acetylenes add to maleic anhydride to form a mixture of cyclobutene and the dicyclopropyl adducts (Scheme 19d).129 It has been suggested that cycloaddition reactions which lead to the cyclopropyl products involve the triplet excited state of alkynes.130 The proposed mechanism is reasonable in light of the non-concerted nature of the cycloaddition and the formation of three isomers of the dicyclopropylhexane product (Scheme 19d). Triplet sensitizers, such as benzophenone, enhance the yield of the photochemical cycloaddition of acetylene to alkenes, thus supporting the suggested triplet excited state mechanism.

71 Scheme 19. Photochemical Cyclization of Acetylenes and Alkenes Ph O Serve et al. hν (a) Ph Ph + JOC 1970, 35, 1237 O Ph 82%

Ph Ph Arnold et al. hν hν J. Heterocyl. Chem. 1971, 8, 1097 (b)* Ph CO2Me + CO2Me MeO2C

CO2Me Owsley et al. hν MeO2C (c) + JACS 1971, 93, 782 MeO C CO Me + 2C2H4 2 2 o -80 C MeO2C CO2Me C H hν 6% 2 4 distillation

C2H4 . . .. CO2Me CO Me MeO CCOMe 2 MeO2CCO2Me 2 2

57%

O O O O R R Hartman et al. hν (d) R H + O O + O O Chem.Ber. Recueil 1971, 104, 2864 Ph2CO R = Propyl, t-Bu O O O O 48-86% 3 isomers 0-55%

* No Yield was reported

When acetylenes react with dienes, [2π+2π] cycloaddition competes with dicyclopropanation. The nature of the major product depends on both the acetylene and the diene. For example, the parent diaryl acetylene, tolane, reacts with 1,4-CHD only when irradiated with high energy 254 nm light to give the cyclobutene [2π+2π] adduct (Scheme 20a).131 When the two double bonds of the diene are separated by a more flexible linker (e.g., in 1,5-cyclooctadiene), the initially formed [2π+2π] adduct reacts with the second double bond of the diene, forming a polycyclic product (Scheme 20b).132 Similarly, phenylacetylene adds to one of the double bonds in norbornadiene to form the corresponding cyclobutene adduct. Under further irradiation, another phenylacetylene molecule adds to the cyclobutene double bond of the adduct followed by electrocyclic ring

72 opening and a retro-Diels-Alder process forming tetraphenylbenzene and cyclopentadiene as the major products (Scheme 20c).133

Scheme 20. [2π+2π] Photochemical Cycloaddition of Tolane and Cyclic Dienes Ph hν Kaup et al. (a) Ph Ph + Chem. Ber. Recueil 1978, 111, 3608 Ph 59%

Ph Ph Kuboto et al. hν (b) Ph Ph + JOC 1973, 38, 1762

72% Ph Ph Ph (c) Ph Ph + hν hν Ph Tolane Ph Ph Kuboto et al. J. Chem. Soc., Chem. Comm. 1971, 360

Ph Ph Ph Ph + Ph Ph Ph Ph 40% Upon irradiation, acetylene molecules bearing a carbonyl or a carboxyl substituents add to 1,4- cyclohexadiene molecules and form homoquadricyclane products (Scheme 21).134-137 Only few of acetylenes undergo this reaction in rather low isolated yields. The structure of the tetracyclic products was derived exclusively from spectroscopic analysis (1D NMR and nOe experiments) without crystallographic evidence to confirm these assignments. Literature data suggests that the competition between the [2π+2π] and homoquadricyclane pathways is sensitive to the structure of the reagents. For example, although photocycloaddition of several acetylenes to a carboxyl substituted cyclohexadiene also leads to homoquadricyclanes,138, 139 the reaction of diphenylacetylene proceeds mainly through the [2π+2π] pathway (Scheme 21c). Even though the factors controlling the competition between the two pathways remain unknown, the regiochemistry of [2π+2π] cycloadditions suggests that they are likely to proceed through an

73 excited state of the diene where the excitation is concentrated at the double bond conjugated with the carbonyl groups.

Scheme 21. Photochemical Formation of Homoquadricyclanes in Reactions of Acetylenes with Dienes

HO C Takahashi et al. (a) + hν 2 HO2C CO2H Tetrahedron Lett 1968, 30, 3387 HO C 2 13%

Fujita et al. hν (b) Ph R + R Nippon Kagaku Kayshi 1975, 1024 Ph

R = COMe, CO2Me 25-35%

R O R R' R' O O Askani et al. hν (c) R R' + O O + O Chem. Ber. 1991, 124, 2307 O O ABO 0-55%

R, R' (A:B) = H (49:1), Me (23:2), SiMe3 (0:1), Ph (1:4) CH OCH (11:14), CO CH (1:0), CH OH(1:1) 2 3 2 3 2 Furthermore, alkynes undergo cycloaddition upon irradiation in the presence of benzene or naphthalene derivatives. Reaction of acetylenes with benzene yielded cyclooctatetraene as the major product as a result of electrocyclic ring-opening of the initially formed cyclobutene adduct (Scheme 22a).140-143 When electron deficient aromatic compounds such as hexafluorobenzene are irradiated with tert-butylphenyl acetylene, the [2π+2π] cycloaddition adduct can be isolated in good yield (Scheme 22b).144 Sasse et al. reported photocycloaddition of acetylenes to naphthalene derivatives.145 In these reactions, naphthalene is excited and undergoes double [2π+2π] photocycloaddition with acetylene (Scheme 22c). In addition, aromatic compounds can react with acetylenes through a meta-cycloaddition mechanism to form polycyclic hydrocarbons (Scheme 22d).146-149

74 Scheme 22. Photocycloaddition of Acetylenes to Aromatic Hydrocarbons CO Me 2 CO Me Grovenstein et al. hν 2 (a) JOC 1969, 34, 2418 MeO2CCO2Me + CO2Me CO2Me 35% F F F CO Me Sket et al. F F F 2 hν JACS 1977, 99, 3504 (b) + Ph C(CH3)3 F F F F CO2Me F F 86% Ph Ph R R Ph R Ph Sasse et al. hν hν Aust. J. Chem. 1969, 22, 1257 (c) Ph Ph + heat R = H, Me, OEt 90%

CO Et 2 EtO C CO2Et 2 Teiti et al. hν (d) Ph Ph + Ph Tetrahedron Lett. 1975, 2299

EtO2C CO2Et EtO2C Ph 15% Of the five-membered heteroaromatic systems, pyrrole adds to dimethyl 1,2- acetylenedicarboxylate and forms a cyclobutene intermediate with subsequent electrocyclic ring- opening to 3,4-disubstituted azepine (Scheme 23a).150, 151 On the other hand, furan reacts with the same acetylene and forms the Diels-Alder adduct resulting from a 2,5-photocycloaddition (Scheme 23b).152 Thiophenes behave similarly but the isolated products is a disubstituted benzene that arises from extrusion of sulfur from the initial photoproduct (Scheme 23c).153, 154 Indene reacts with alkynes under triplet sensitization conditions and gives the cyclobutene adduct (Scheme 24a).155 Similar products were observed for the photochemical cycloaddition of benzothiophene to acetylenes.156 Neckers et al. investigated the photochemical reactions of acetylene and benzo-heteroaromatic systems.157-159 The authors proposed that formation of the major product arises from radical ring-opening followed by bond rotation and radical recombination (Scheme 25).160 Another isolated product is 1,2-disubstituted naphthalene which is most likely formed by electocyclic ring-opening of the 2,3-cycloadduct with subsequent sulfur extrusion upon heating.161

75 Scheme 23. Photochemical Reactions of Acetylenes with Five-Membered Ring Heteroaromatic Hydrocarbons

CO Me H 2 CO2Me N Gandhi et al. hν CO Me Indian J. Chem. 1971, 9, 305 (a) + 2 MeO2CCO2Me CO Me N 2 N H H

O O O O Gandhi et al. CO Me (b) ++hν 2 Chem. Comm. 1968, 552 MeO2CCO2Me CO2Me CO Me 2 CO2Me

S S CO Me 2 kuhn et al. hν CO Me (c) + 2 Chem. Ber. Recueil 1971, 106, 674 MeO2CCO2Me CO2Me CO2Me

40%

Scheme 24. Photochemical Reactions of Acetylenes with Indene and Benzoheteroaromatic Systems

hν Bowman et al. (a) HCN+ Can. J. Chem. 1969, 47, 4503 Benzophenone

CN CH 3 Davis et al. N CO Me X=NCH3 2 JOC 1980, 45, 462 72% CO2Me

X hν O CO Me Tinneman et al. (b) MeO CCOMe X=O 2 2 2 + + isomers JOC 1977, 42, 2374 CO2Me 9%

S CO Me X=S 2 Dopper et al. 51% CO2Me JOC 1971, 36, 3755

76 Scheme 25. Suggested Mechanism for Photocycloaddition of Benzothiophene to Acetylene

S S CO Me hν S 2 MeO CCOMe + hν 2 2 CO Me 2 CO2Me

CO2Me hν

. . S . S CO Me CO Me 2 . 2

CO2Me CO2Me

To the best of our knowledge, none of the literature photocycloaddition reactions produced the tricyclooctene skeleton of 4. Intrigued by the dramatic change in photochemical reactivity of the enediyne moiety and by the intricate polycyclic structure of product 4, we undertook a more detailed study aimed at the elucidation of the mechanism of this reaction. Our original goals were to determine the spin multiplicity of the excited states involved in this transformation, to define its scope and limitations, and to understand the photochemical and photophysical factors controlling the chemical yield and quantum efficiency of this process. Several possibilities were considered a priori: a) a truly one-photon process where concerted formation of the four new bonds is driven by absorption of a single photon, b) a stepwise process where all but the initial step are thermally activated, or c) a sequential multi-photon process with intermediates successfully competing for light with the starting material. Since only one of the triple bonds of the enediyne moiety is involved in the transformation, we tested the reactivity of a family of diaryl monoacetylenes that differ in the acceptor ability and photophysical properties of the aryl substituents. We reasoned that this choice would permit determination of whether the transformation given in Scheme 18 is unprecedented or related to one of the known photocycloaddition pathways.

77 EXPERIMENTAL SECTION

Synthesis of Acetylenes

The diaryl monoacetylenes designed and prepared for mechanistic studies are summarized in Scheme 26. They are roughly organized into three overlapping groups: a) the diarylacetylenes 6- 13, 18 with strong acceptor substituents, b) acetylenes 6-8, 11-16 bearing simple pyridine and pyrazine moieties and c) acetylenes 17,18 with either a phenyl and/or pentafluorophenyl moiety but without a nitrogen-containing heterocycle. These three sets were chosen to probe the role of triple bond polarization as well as the role of the nature of the excited state. We also included diphenylacetylene (tolane) as a useful reference point.

Scheme 26. Choice of Model Substrates and their Abbreviations Used in this Work F F F F F F N N TFP = N F F N N F F F F F F N F F F F

N N PFB = F F F F Pyra-bis-TFP (3) Py-bis-TFP (5) F F F

F F N N N TFP TFP F N 2-Py-TFP (6) Ph-TFP (10) F F Pyra-Ph (16) 2- Py-PFB (13)

N N TFP TFP N N N Tolane (17) 3-Py-TFP (7) Cl Bis-4-Py (14) Pyra-Cl-TFP (11) F F N N TFP TFP N F N 4-Py-TFP (8) Pyra-TFP (12) 4-Py-Ph (15) F F Ph-PFB (18) TFP TFP Bis-TFP (9)

78 Depending on the nature of the aryl substituents, the acetylenes were prepared via two different synthetic routes. Pyridine, pyrazine and pentafluorobenzene substituents were combined with acetylene moiety via a standard Sonogashira protocol,82-84, 162 whereas the TFP moiety was introduced by one-pot sequence which involves fluoride-assisted in situ desilylation of TMS acetylene followed by selective “para” nucleophilic substitution in pentafluoropyridine (Scheme 27).163-166

Scheme 27. Synthesis of Acetylenes 3, 5-16, 18

PdCl2(PPh3)2 Ar X + SiMe Ar SiMe3 3 CuI, Base Yield: 60-85%

PdCl (PPh ) 2 3 2 Ar Ar' Ar SiMe3 + Ar' X CuI, K2CO3 THF/MeOH F N N F F CsF/DMF Ar SiMe3 + Ar N Yield: 40-60% F N F N N Synthetic Procedures and Spectroscopic Details

Materials. 2-Bromopyridine, 3-bromopyridine, 4-bromopyridine hydrochloride, phenylacetylene, 4,4’-dipyridylethylene, pentafluoroiodobenzene, palladium chloride, copper iodide, triphenylphosphine and 1,4-cylohexadiene were purchased from Fisher Scientific. 2- Chloropyrazine, 2,3-dichloropyrazine, bis(trimethylsilyl)acetylene, diphenylacetylene and pentafluoropyridine were purchased from Aldrich Chemical. 2-Ethynylpyridine was purchased from GFS Chemical Inc. Anhydrous DMF over molecular sieves was purchased from Fisher Scientific. Trimethylsilylacetylene was purchased from Petra Research Inc. 1,4-Cyclohexadiene was distilled prior to use. 1,5-Dimethoxy-1,4-cyclohexadiene was provided by Professor Gregory Dudley. Pure trans-stilbene was provided by Professor Jack Slatiel. 2,3- Bis(trimethylsilylethynyl)pyridine was prepared from 3-bromo-2-pyridinol45 and 4,4’- dipyridylacetylene was prepared according to a literature procedure.167

Physical Measurements. 1H NMR spectra were recorded on a 7 Tesla Varian Mercury 300 NMR spectrometer and 13C and 19F spectra were recorded on a 7 Tesla Bruker AC 300

79 multinuclear NMR spectrometer, unless noted otherwise. UV spectra were recorded on a Shimadzu UV-2100 spectrophotometer. Infrared (IR) spectra were recorded on NICOLET AVATAR 360 FT-IR spectrometer. High resolution mass spectra (HRMS) were recorded with a JEOL Model JMS 600H spectrometer using PFK (perfluorokerosene) as internal standard. X- Ray structures were determined using BRUKER SMART ARAX instrument. Flash chromatography was performed using ISCO, Inc. Combi Flash Companion system 1.2.11. Melting points were determined using a Thomas Hoover melting point apparatus.

General Procedure for Sonogashira Coupling. A suspension of the aryl halide (5.8 mmol),

PdCl2(PPh3)2 (0.29 mmol), Cu(I) iodide (0.29 mmol) in 40 mL of amine solvent was degassed three times with freeze/pump/thaw technique in a flame dried Ace pressure tube (for reactions requiring heating) or a rubber stoppered round bottom flask (for room temperature reactions). Acetylenes (1.2 mole excess per halogen atom) were added using a syringe. After total consumption of the aryl halide, the reaction mixture was filtered through Celite. Celite was washed with methylene chloride (3 × 30 mL). The filtrate was washed with saturated solution of

ammonium chloride (2 × 30 mL), water (2 × 30 mL) and dried over anhydrous Na2SO4. Solvent was removed in vacuo. The products were purified by column chromatography on silica gel.

General Procedure for Preparation of Tetrafluoropyridynyl acetylenes: All glassware and syringes were oven-dried prior to use. Round bottom flask equipped with a magnetic stirring bar was charged with potassium or cesium fluoride and heated under vacuo in a sand bath at 250ºC for at least three hours. The flask was cooled down to room temperature under vacuo and filled with argon. The solution of pentafluoropyridine (1.5 mole excess per TMS group) in DMF was transfered through cannula into the reaction flask. A solution of the aryl trimethylsilylacetylene in DMF was added dropwise over 20 hours using a syringe pump. After total consumption of TMS acetylene, the reaction mixture was diluted with saturated solution of ammonium chloride and extracted with methylene chloride. The organic layer was washed with water and dried over anhydrous sodium sulfate. Solvent was removed in vacuo. Products were separated by flash chromatography on silica gel. The products were purified by chromatography on silica gel. Recrystallization afforded pure diaryl acetylene.

80 Pyra-Bis-TFP (3) Synthesis of 2,3-Bis-trimethylsilanylethynyl-pyrazine. The title compound was prepared by Sonogashira coupling of 2,3-dichloropyrazine (0.50 g, 3.36 mmol) and trimethylsilylacetylene

(0.79 g, 8.05 mmol) in 20 mL (i-Pr)2NH at room temperature (r.t.) for 8 hours. The reaction mixture was purified by flash chromatography on silica gel (9:1 hexanes:ethyl acetate) to afford 1 0.84 g (92%) of the desired product as a brown oil; H NMR (300 MHz, CDCl3) į 8.40 (s, 2H), 13 0.26 (s, 18H); C NMR (75.5 MHz, CDCl3) į 142.2, 141.2, 102.6, 99.8, -0.72; UV/Vis

(CH3CN): λmax(lgε) = 305 nm (4.08), 279 (4.23), 265 (4.26), 235 (4.40), 224 (4.32); IR (neat) -1 2961, 1370, 1250, 1125, 845 cm ; HRMS (EI+) calculated for C14H20N2Si2 272.1165, found 272.1166. Synthesis of 2,3-Bis-(2,3,5,6-tetrafluoro-pyridin-4-ylethynyl)-pyrazine (3). The title compound was prepared by reaction of 2,3-bis(trimethylsilylethynyl)pyrazine (2.00 g, 7.35 mmol) with pentafluoropyridine (3.73 g, 11.0 mmol) and KF (2.56 g, 44.1 mmol) in 20 mL DMF. The reaction mixture was purified by column chromatography on silica gel (9:1 hexanes:ethyl acetate) to afford 1.28 g (41%) of the desired product as a white solid. The product 1 was recrystallized from hexanes: mp 128-129 ºC; H NMR (300 MHz, CDCl3) į 8.73 (s, 2H); 13 C NMR (75.5 MHz, CDCl3) į 144.5, 142.0 (dm, J = 267.3 Hz), 143.5 (dm, J = 247.7 Hz), 19 140.3, 115.2 (m), 99.2, 79.3; F NMR (282 MHz, CDCl3) į -89.0 (m), -136.6 (m); UV/Vis -1 (CH3CN): λmax(lgε) = 302 nm (4.54), 286 (4.49), 246 (4.38); IR (neat) 1636, 1472, 963 cm ;

HRMS (EI+) calculated for C18H2N4F8 426.0151, found 426.0134.

Pyra-Cl-TFP (11) Synthesis of 2-Chloro-3-trimethylsilanylethynyl-pyrazine. The title compound was prepared by Sonogashira coupling of 2,3-dichloropyrazine (3.01 g, 20.1 mmol) with trimethylsilylacetylene (2.37 g, 24.2 mmol) in 80 mL (i-Pr)2NH at r.t. for 12 hours. The reaction mixture was purified by flash chromatography on silica gel (20:1 hexanes:ethyl acetate) to afford 1 1.78 g (42%) of the desired product as a brown oil; H NMR (300 MHz, CDCl3) į 8.38 (d, 1H, J 13 = 2.4 Hz), 8.20 (d, 1H, J = 2.4 Hz), 0.21 (s, 9H); C NMR (75.5 MHz, CDCl3) į 150.6, 142.0,

141.8, 138.7, 104.6, 98.6, -0.8; UV/Vis (CH3CN): λmax(lgε) = 296 nm (3.78), 248 (3.71), 289 -1 (3.72), 213 (3.67); IR (neat) 2962, 1366, 845 cm ; HRMS (EI+) calculated for C9H11N2ClSi 210.0380, found 210.0370.

81 Synthesis of 2-Chloro-3-(2,3,5,6-tetrafluoro-pyridin-4-ylethynyl)-pyrazine (11). The title compound was prepared by reaction of 2-chloro-3-trimethylsilylethynylpyrazine (1.01 g, 4.80 mmol) with pentafluoropyridine (1.22 g, 7.20 mmol) and KF (0.83 g, 14.4 mmol) in 20 mL DMF. The reaction mixture was purified by column chromatography on silica gel (20:1 hexanes:ethyl acetate) to afford 0.68 g (50%) of the desired product as a white solid. The product 1 was recrystallized from hexanes: white solid: mp 102-103 ºC; H NMR (300 MHz, CDCl3) į 13 8.61 (d, 1H, J = 2.4 Hz), 8.45 (d, 1H, J = 2.4 Hz); C NMR (75.5 MHz, CDCl3) į 151.5, 143.8, 143.4 (dm, J = 240 Hz), 142.7, 141.7 (dm, J = 268.4 Hz), 137.4, 115.4 (m), 98.9, 79.3; 19F NMR

(282 MHz, CDCl3) į -89.2 (m), -136.3 (m); UV/Vis (CH3CN): λmax(lgε) = 306 nm (4.34), 267 -1 (4.15); IR (neat) 3079, 1639, 1250 cm ; HRMS (EI+) calculated for C11H2N3F4Cl 286.9873, found 286.9867.

Pyra-TFP (12) Synthesis of 2-Trimethylsilanylethynyl-pyrazine.168 The title compound was prepared by Sonogashira coupling of 2-chloropyrazine (5.03 g, 43.7 mmol) with trimethylsilylacetylene (5.14 g, 52.4 mmol) in 100 mL (i-Pr)2NH at 60ºC for 12 hours. The reaction mixture was purified by flash chromatography on silica gel (100:1 hexanes:ethyl acetate) to afford 3.99 g (52%) of the 1 desired product as a brown oil; H NMR (300 MHz, CDCl3) į 8.60 (d, 1H, J = 1.2 Hz), 8.46- 8.44 (dd, 1H, J = 2.7, 1.2 Hz), 8.40-8.39 (d, 1H, J = 2.7 Hz), 0.20 (s, 9H); 13C NMR (75.5 MHz,

CDCl3) į 147.6, 144.1, 142.8, 139.6, 100.5, 99.4, -0.7; UV/Vis (CH3CN): λmax(lgε) = 288 nm (4.09), 243 (4.09), 233 (4.08); IR (neat) 3064, 2960, 1251, 868, 845 cm-1; HRMS (EI+) calculated for C9H12N2Si 176.0770, found 176.0762. Synthesis of 2-(2,3,5,6-Tetrafluoro-pyridin-4-ylethynyl)-pyrazine (12). The title compound was prepared by reaction of 2-trimethylsilylethynylpyrazine (2.90 g, 16.5 mmol) with pentafluoropyridine (4.18 g, 24.7 mmol) and CsF (7.51 g, 49.4 mmol) in 20 mL DMF. The reaction mixture was purified by column chromatography on silica gel (20:1 hexanes:ethyl acetate) to afford 1.45 g (35%) of the desired product as a white solid. The product was 1 recrystallized from hexanes: mp 88-89 ºC; H NMR (300 MHz, CDCl3) į 8.87 (s, 1H), 8.68-8.64 13 (m, 2H); C NMR (75.5 MHz, C6D6) į 148.6, 145.3, 145.2, 143.7 (dm, J = 243.3 Hz), 142.5 19 (dm, J = 265.7 Hz), 138.6, 101.9, 75.9; F NMR (282 MHz, C6D6) į -90.4 (m), -137.4 (m);

82 -1 UV/Vis (CH3CN): λmax(lgε) = 297 nm (4.38), 260 (4.11); IR (neat) 3043, 1637, 1487, 1232 cm ;

HRMS (EI+) calculated for C11H3N3F4 253.0262, found 253.0260.

Pyra-Ph (16) 2-Phenylethynyl-pyrazine (16). The title compound was prepared by Sonogashira coupling of 2-chloropyrazine (1.00 g, 8.73 mmol) with phenylacetylene (1.07 g, 10.5 mmol) in 100 mL (i-

Pr)2NH at 70ºC for 12 hours. The reaction mixture was purified by flash chromatography on silica gel (20:1 hexanes:ethyl acetate) to afford 1.19 g (76%) of the desired product as a brown 1 oil; H NMR (300 MHz, CDCl3) į 8.74 (bs, 1H) 8.56 (bs, 1H) 8.46 (bs, 1H) 7.60 (d, 2H, J = 4.5 13 Hz) 7.39-7.34 (m, 3H); C NMR (75.5 MHz, CDCl3) į 147.5, 144.3, 142.6, 140.1, 131.9, 129.4,

128.3, 121.3, 93.0, 85.8; UV/Vis (CH3CN): λmax(lgε) = 302 nm (4.18), 280 (4.00), 272 (4.02), 266 (401), 217 (3.95); IR (neat) 3063, 2999, 1493, 1141, 847 cm-1; HRMS (EI+) calculated for

C12H8N2 180.0688, found 180.0696.

2-Py-TFP (6) Synthesis of 2-Trimethylsilanylethynyl-pyridine.169 The title compound was prepared by Sonogashira coupling of 2-bromopyridine (5.01 g, 31.6 mmol) with trimethylsilylacetylene (3.72 g, 38.0 mmol) in 100 mL Et3N at 100ºC for 6 hours. The reaction mixture was purified by flash chromatography on silica gel (9:1 hexanes:ethyl acetate) to afford 5.09 g (92%) of the desired 1 product as a brown oil; H NMR (300 MHz, CDCl3) į 8.44-8.42 (d, 1H, J = 4.8 Hz), 7.53-7.45 (t, 1H, J = 7.8 Hz), 7.33-7.26 (d, 1H, J = 7.5 Hz), 7.11-7.07 (dd, 1H, J = 6.6, 5.7 Hz), 0.15 (s, 13 9H); C NMR (75.5 MHz, CDCl3) į 149.6, 142.7, 135.8, 126.9, 122.7, 103.4, 94.4, -0.6;

UV/Vis (CH3CN): λmax(lgε) = 285 nm (3.81), 277 (3.92), 271 (3.88) 245 (4.16) 241 (4.16) 234 -1 (4.13); IR (neat) 2922, 2850, 1275, 750 cm ; HRMS (EI+) calculated for C10H13NSi 175.0817, found 175.0809. Synthesis of 2,3,5,6-Tetrafluoro-4-pyridin-2-ylethynyl-pyridine (6). The title compound was prepared by reaction of 2-trimethylsilylethynylpyridine (1.00 g, 5.71 mmol) with pentafluoropyridine (1.45 g, 8.57 mmol) and CsF (2.60 g, 17.1 mmol) in 25 mL DMF. The reaction mixture was purified by column chromatography on silica gel (20:1 hexanes:ethyl acetate) to afford 0.95 g (66%) of the desired product as a white solid. The product was 1 recrystallized from hexanes: mp 126-127 ºC; H NMR (300 MHz, CDCl3) į 8.71-8.70 (d, 1H, J

83 = 4.2 Hz), 7.81-7.80 (dd, 1H, J = 7.8,7.4 Hz), 7.67-7.64 (d, 1H, J = 7.8 Hz), 7.41-7.37 (dd, 1H, 13 J = 6.9, 5.1 Hz); C NMR (75.5 MHz, CDCl3) į 150.6, 143.4 (dm, J = 254.2), 142.1 (dm, J = 19 271.8), 141.0, 136.5, 128.3, 126.0, 124.7, 104.3, 72.2; F NMR (282 MHz, CDCl3) į -90.0 (m),

-137.2 (m); UV/Vis (CH3CN): λmax(lgε) = 293 nm (4.35), 266 (4.16); IR (neat) 3079, 1637, -1 1492, 965 cm ; HRMS (EI+) calculated for C12H4N2F4 252.0311, found 252.0305.

3-Py-TFP (7) Synthesis of 3-Trimethylsilanylethynyl-pyridine. The title compound was prepared by Sonogashira coupling of 3-bromopyridine (1.00 g, 6.33 mmol) with trimethylsilylacetylene (0.74 g, 7.59 mmol) in 25 mL (i-Pr)2NH at 100ºC for 2 hours. The reaction mixture was purified by flash chromatography on silica gel (20:1 hexanes:ethyl acetate) to afford 0.94 g (85%) of the 1 desired product as a brown oil; H NMR (300 MHz, CDCl3) į 8.67 (bs, 1H), 8.49-8.48 (d, 1H, J = 3.6 Hz), 7.71-7.68 (dd, 1H, J = 8.1, 1.8 Hz), 7.21-7.17 (dd, 1H, J = 7.8, 4.8 Hz), 0.23 (s, 9H); 13 C NMR (75.5 MHz, CDCl3) į 152.4, 148.4, 138.5, 122.6, 120.0, 101.2, 97.9, -0.5; UV/Vis

(CH3CN): λmax(lgε) = 285 nm (3.56), 278 (3.69), 269 (3.62) 245 (4.24); IR (neat) 2960, 2162, -1 1250, 864 cm ; HRMS (EI+) calculated for C10H13NSi 175.0817, found 175.0823. Synthesis of 2,3,5,6-Tetrafluoro-4-pyridin-3-ylethynyl-pyridine (7). The title compound was prepared by reaction of 3-trimethylsilylethynylpyridine (1.00 g, 5.71 mmol) with pentafluoropyridine (1.45 g, 8.57 mmol) and CsF (2.60 g, 17.1 mmol) in 25 mL DMF. The reaction mixture was purified by column chromatography on silica gel (20:1 hexanes:ethyl acetate) to afford 0.81 g (56%) of the desired product as a white solid. The product was 1 recrystallized from hexanes: mp 97-98 ºC; H NMR (300 MHz, CDCl3) į 8.81 (s, 1H), 8.65-8.64 (d, 1H, J = 4.2 Hz), 7.91-7.88 (d, 1H, J = 8.1 Hz), 7.37-7.33 (dd, 1H, J = 8.1, 5.1 Hz); 13C NMR

(75.5 MHz, CDCl3) į 152.7, 150.7, 143.4 (dm, J = 246.1 Hz), 142.1 (dm, J = 265.3 Hz), 139.1, 19 123.2, 117.8, 116.6, 102.7, 78.1; F NMR (282 MHz, CDCl3) į -90.2 (m), -138.0 (m); UV/Vis -1 (CH3CN): λmax(lgε) = 296 nm (4.44), 286 (4.56); IR (neat) 3051, 1636, 1472, 958 cm ; HRMS

(EI+) calculated for C12H4N2F4 252.0311, found 252.0306.

4-Py-TFP (8) Synthesis of 4-Trimethylsilanylethynyl-pyridine.170 The title compound was prepared by Sonogashira coupling of 4-bromopyridine hydrochloride (1.02 g, 5.14 mmol) with

84 trimethylsilylacetylene (0.60 g, 6.17 mmol) in 60 mL 3:1 mixture of THF:(i-Pr)2NH at r.t. for 3 days. The reaction mixture was purified by flash chromatography on silica gel (9:1 hexanes:ethyl 1 acetate) to afford 0.8 g (89%) of the desired product as a brown oil; H NMR (300 MHz, CDCl3) į 8.38-8.36 (d, 2H J = 6.0 Hz), 7.12-7.10 (d, 2H, J = 6.0 Hz), 0.08 (s, 9H); 13C NMR (75.5

MHz, CDCl3) į 149.4, 130.9, 125.5, 101.7, 99.6, -0.6; UV/Vis (CH3CN): λmax(lgε) = 274 nm (3.34), 253 (4.25), 242 (4.26) 245 (4.24); IR (neat) 3038, 2961, 2900, 2166, 1592, 865 cm-1;

HRMS (EI+) calculated for C10H13NSi 175.0817, found 175.0809. Synthesis of 2,3,5,6-Tetrafluoro-4-pyridin-4-ylethynyl-pyridine (8). The title compound was prepared by reaction of 4-trimethylsilylethynylpyridine (1.00 g, 5.71 mmol) with pentafluoropyridine (1.45 g, 8.57 mmol) and CsF (2.60 g, 17.1 mmol) in 25 mL DMF. The reaction mixture was purified by column chromatography on silica gel (hexanes) to afford 0.33 g (23%) of the desired product as a white solid. The product was recrystallized from hexanes: mp 1 110-114 ºC; H NMR (300 MHz, CDCl3) į 8.73-8.71 (d, 1H, J = 5.4 Hz), 7.49-7.47 (d, 1H, J = 13 6.0 Hz); C NMR (75.5 MHz, CDCl3) į 150.2, 143.5 (dm, J = 246.5), 141.9 (dm, J = 141.9), 19 128.4, 125.6, 116.2, 102.5, 76.1; F NMR (282 MHz, CDCl3) į -89.7 (m), -137.5 (m); UV/Vis

(CH3CN): λmax(lgε) = 288 nm (4.40), 273 (4.48), 227 (3.98); IR (neat) 3043, 1639, 1493, 1009, -1 966 cm ; HRMS (EI+) calculated for C12H4N2F4 252.031, found 252.0315.

Ph-TFP (10) Synthesis of Trimethylsilanylethynyl-benzene.171 The title compound was prepared by Sonogashira coupling of iodobenzene (5.01 g, 24.5 mmole) with phenylacetylene (2.88 g, 29.4

mmol) in 150 mL (i-Pr)2NH at r.t. for 2 days. The reaction mixture was purified by flash chromatography on silica gel (hexanes) to afford 3.28 g (77%) of the desired product as a brown 1 13 oil; H NMR (300 MHz, CDCl3) į 7.51-7.48 (m, 2H), 7.32-7.31 (m, 3H), 0.28 (s, 9H); C NMR

(75.5 MHz, CDCl3) į 131.9, 128.4, 128.2, 123.1, 105.1, 94.0, -0.03; UV/Vis (CH3CN): λmax(lgε) = 257 nm (4.36), 246 (4.40), 236 (4.17); IR (neat) 3080, 2960, 2160, 1488, 864 cm-1; HRMS

(EI+) calculated for C11H14Si 174.0865, found 174.0865. Synthesis of 2,3,5,6-Tetrafluoro-4-phenylethynyl-benzene (10). The title compound was prepared by reaction of trimethylsilylethynylbenzene (2.00 g, 11.5 mmol) with pentafluoropyridine (2.91 g, 17.2 mmol) and CsF (5.24 g, 34.5 mmol) in 25 mL DMF. The reaction mixture was purified by column chromatography on silica gel (hexanes) to afford 1.85 g

85 (64%) of the desired product as a white solid. The product was recrystallized from hexanes: mp 1 13 119-120 ºC; H NMR (300 MHz, CDCl3) į 7.64-7.61 (d, 1H, J = 8.1 Hz), 7.51-7.40 (m, 3H); C

NMR (75.5 MHz, CDCl3) į 143.3 (dm, J = 244.5), 141.8 (dm, J = 264.1), 132.3, 130.6, 128.6, 19 120.5, 106.6, 73.4; F NMR (282 MHz, CDCl3) į -90.8 (m), -138.6 (m); UV/Vis (CH3CN): -1 λmax(lgε) = 302 nm (4.41), 287 (4.41); IR (neat) 3071, 1472, 957 cm ; HRMS (EI+) calculated for C13H5NF4 251.0358, found 251.0351.

Py-Bis-TFP (5) Synthesis of 2,3-Bis-trimethylsilanylethynyl-pyridine. The title compound was prepared by Sonogashira coupling procedure of 2-bromo-3-pyridinol triflate (1.01 g, 3.27 mmol) with trimethylsilylacetylene (0.77 g, 7.84 mmol) in 30 mL (i-Pr)2NH at 85ºC for 10 hours. The reaction mixture was purified by flash chromatography on silica gel (9:1 hexanes:ethyl acetate) 1 to afford 0.54 g (61%) of the desired product as a brown oil; H NMR (300 MHz, CDCl3) į 8.44- 8.43 (dd, 1H, J = 4.8, 1.8 Hz), 7.71-7.67 (dd, 1H, J = 8.0, 1.8 Hz), 7.14-7.10 (dd, 1H, J = 8.1, 13 4.8 Hz), 0.24 (s, 9H), 0.23 (s, 9H); C NMR (75.5 MHz, CDCl3) į 148.2, 144.2, 138.9, 122.2, 121.6, 101.6, 101.2, 100.2, 98.4, -0.66, -0.74; IR (neat) 2960, 2166, 1413, 1249, 844 cm-1;

HRMS (EI+) calculated for C15H21NSi2 271.1213, found 271.1201. Synthesis of 2,3-Bis-(2,3,5,6-tetrafluoropyridin-4-ylethynyl)-pyridine (5). The title compound was prepared by reaction of 2,3-bis(trimethylsilylethynyl)pyridine (1.10 g, 4.06 mmol) with pentafluoropyridine (2.06 g, 12.2 mmol) and CsF (3.70 g, 24.4 mmol) in 25 mL DMF. The reaction mixture was purified by column chromatography on silica gel (20:1 hexanes:ethyl acetate) to afford 0.98 g (57%) of the desired product as a greenish solid. The 1 product was recrystallized from hexanes: mp 157-158 ºC; H NMR (300 MHz, CDCl3) į 8.78- 8.76 (d, 1H, J = 4.5 Hz), 8.05-8.02 (d, 1H, J = 8.1 Hz), 7.50-7.46 (dd, 1H, J = 8.1, 4.8 Hz); 13C

NMR (75.5 MHz, CDCl3) į 151.1, 143.4 (dm, J = 246.9 Hz), 143.2, 142.0 (m), 140.0, 124.0, 19 121.6, 101.6, 100.4, 80.2; F NMR (282 MHz, CDCl3) į -89.6 (m), -136.9 (m), -137.7; UV/Vis

(CH3CN): λmax(lgε) = 298 nm (4.40), 266 (4.47), 253 (4.41), 233 (4.32); IR (neat) 2919, 2846, -1 1641, 1485 cm ; HRMS (EI+) calculated for C19H3N3F8 425.0199, found 425.0185.

86 4-Py-Ph (15) Synthesis of 4-Phenylethynyl-pyridine (15).172, 173 The title compound was prepared by Sonogashira coupling of 4-bromopyridine hydrochloride (1.01 g, 5.14 mmol) with phenylacetylene (0.63 g, 6.17 mmol) and 6 mL of Et3N in 20 mL CH3CN at r.t. for 3 days. The reaction mixture was purified by flash chromatography on silica gel (9:1 hexanes:ethyl acetate) to afford 0.7 g (76%) of the desired product as a white solid: mp 92-93 ºC ; 1H NMR (300 MHz, 13 CDCl3) į 8.61 (dd, 2H, J = 4.5, 1.5 Hz), 7.57-7.54 (m, 2H), 7.40-7.36 (m, 5H); C NMR (75.5

MHz, CDCl3) į 149.7, 131.8, 131.3, 129.1, 128.4, 125.4, 122.0, 93.9, 86.6; UV/Vis (CH3CN): -1 λmax(lgε) = 296 nm (4.40), 280 (4.45); IR (neat) 3059, 1440, 758 cm ; HRMS (EI+) calculated for C13H9N 179.0735, found 179.0742.

Ph-PFB (18) Synthesis of 1,2,3,4,5-Pentafluoro-6-phenylethynyl-benzene (18). The title compound was prepared by Sonogashira coupling of pentafluoroiodobenzene (2.0 g, 6.9 mmol) with phenylacetylene (0.84 g, 8.28 mmol) in 25 mL of (i-Pr)2NH at r.t. for 24 hours. The reaction mixture was purified by flash chromatography on silica gel (hexanes) to afford 1.78 g (42%) of 173 1 the desired product as a white solid: mp 108-109 ºC (lit. mp 93) ; H NMR (300 MHz, CDCl3) 13 į 7.58 (m, 2H), 7.41 (m, 3H); C NMR (75.5 MHz, CDCl3) į 147.7 (dm, J = 256.7 Hz), 141.4 (dm, J = 261.7 Hz), 137.7 (dm, J = 255.9 Hz), 131.9, 129.6, 128.5, 121.5, 101.6, 100.3, 73.0; 19F

NMR (282 MHz, CDCl3) į -136.1 (m), -153.1 (m), -162.1 (m); UV/Vis (CH3CN): λmax(lgε) = -1 296 nm (4.46), 278 (4.52); IR (neat) 3082, 1495, 982 cm ; HRMS (EI+) calculated for C14H5F5 268.0311, found 268.0311.

2-Py-PFB (13) Synthesis of 2-Pentafluorophenylethynyl-pyridine (13). The title compound was prepared by Sonogashira coupling of pentafluoroiodobenzene (1.01 g, 3.45 mmol) with 2-ethynylpyridine

(0.43 g, 4.14 mmol) in 50 mL Et3N at r.t. for 15 hours. The reaction mixture was purified by flash chromatography on silica gel (20:1 hexanes:ethyl acetate) to afford 0.23 g (25%) of the 1 desired product as a yellowish solid: mp 75-78 ºC ; H NMR (300 MHz, CDCl3) į 8.66-8.65 (d, 1H, J = 4.5 Hz), 7.75-7.70 (ddd, 1H, J = 7.8, 7.65, 1.8 Hz), 7.62-7.59 (d, 1H, J = 7.8 Hz), 7.37- 13 7.29 (ddd, 1H, J = 7.65, 4.8, 0.9 Hz); C NMR (75.5 MHz, CDCl3) į 150.4, 149.2, 145.8, 143.6,

87 141.8, 139.3, 136.2, 135.7, 134.4, 130.3, 127.8, 127.7, 123.9, 99.8, 72.4; 19F NMR (282 MHz,

CDCl3) į , -135.0 (m), -151.3 (m), -161.5 (m); UV/Vis (CH3CN): λmax(lgε) = 300 nm (4.08), 291 (4.12), 284 (4.14), 265 (4.05); IR (neat) 3056, 1497, 779 cm-1; HRMS (EI+) calculated for

C13H4NF5 269.0264, found 269.0256.

Bis-TFP (9) Synthesis of Bis(2,3,5,6-tetrafluoro-pyridin-4-yl)acetylene (9). The title compound was prepared by reaction of bis(trimethysilylethynyl)acetylene (1.02 g, 6.00 mmol) with pentafluoropyridine (3.04 g, 18.0 mmol) and KF (2.09 g, 36.0 mmol) in 25 mL DMF. The reaction mixture was purified by column chromatography on silica gel (100:1 hexanes:methylene chloride) to afford 1.32 g (68%) of the desired product as a white solid. The product was 13 recrystallized from hexanes: mp 154-155 ºC; C NMR (75.5 MHz, CDCl3) į 143.7 (dm, J = 19 248.3), 141.9 (dm, J = 269.7), 114.5, 87.8; F NMR (282 MHz, CDCl3) į -88.4 (m), -135.8 (m);

UV/Vis (CH3CN): λmax(lgε) = 285 nm (4.34), 271 (4.38); IR (neat) 3001, 2921, 1652, 1466, -1 1417, 1101 cm ; HRMS (EI+) calculated for C12N2F8 323.9934, found 323.9967.

General Procedure for Preparative Photochemical Reaction of Acetylenes with 1,4- Cyclohexadiene. Preparative scale irradiation was carried out in a 500 mL reaction vessel equipped with a quartz immersion well (Ace Glass). 450 Watt medium pressure, quartz, mercury-vapor lamp (Ace Glass) was used for irradiation. A Pyrex filter and a 0.001 M solution

of K2CrO4 were used as filters to isolate the 313 nm Hg line, unless stated otherwise. Solutions of acetylenes and 1,4-CHD in acetonitrile were outgassed with bubbling argon overnight. Solutions were irradiated while a constant stream of argon bubbled through the reaction mixture. Solvent was removed in vacuo. The crude product was purified by chromatography on silica gel.

2-(2,3,5,6-Tetrafluoropyridin-4-yl-ethynyl)-3-[2-(2,3,5,6-tetrafluoropyridi-4-yl)-tricyclo [3.2.1.02,7]oct-3-en-3-yl]-pyrazine (4). The title compound was prepared from the photochemical reaction of 2,3-bis(tetrafluoropyridinylethynyl)pyrazine (0.10 g, 0.23 mmol) with 1,4-CHD (2.22 mL, 23.5 mmol) in 400 mL acetonitrile at 20 ºC for 3 hours. The reaction mixture was purified by column chromatography on silica gel (100:1 hexanes:ethyl acetate) to afford 0.044 g (37%) of the desired product as a white solid: mp 171-172 ºC; 1H NMR (300 MHz,

88 F N CDCl3) į 8.41-8.40 (d, 1H, J = 2.1 Hz), 8.24 (d, 1H, J = 2.4 Hz), F F 6.78-6.75 (d, 1H, J = 7.5 Hz), 3.00-2.94 (td, 1H, J = 7.2, 4.8 Hz), F F 2.09 (s, 2H), 1.91-1.86 (dd, 2H, J = 12.0, 4.8 Hz), 1.32-1.25 (d, 2H, 13 F J = 12 Hz); C NMR (75.5 MHz, CDCl3) į 153.7, 143.5 (m), 142.4 N N F N (m), 141.2, 141.1, 140.3(m), 138.9 (m), 134.2, 134.2, 133.7, 128.0, F 114.6, 101.2, 75.1, 30.6, 26.4, 22.3, 21.4; 19F NMR (282 MHz,

CDCl3) į -89.6 (m), -92.2 (m), -136.7 (m), -139.9 (m); UV/Vis (CH3CN): λmax(lgε) = 274 nm (4.38), 257 (4.28); IR (neat) 2962, 2929, 1642, 1455 cm-1; HRMS (EI+) calculated for

C24H10N4F8 506.0777, found 506.0790. The elucidation of the structure for compound 4 was based on the H1-C13 one-bond and long- range couplings, revealed by the ghmqc and ghmbc spectra. The H1-H1 couplings from the H1 spectrum identify the sequence 6.69 – 2.90 – 1.81 – 1.23. The ghmqc spectrum demonstrats that the coupling 1.81–1.23 was a geminal one. The coupling of 2.02 with both 26.4 and 30.7 indicates that its corresponding carbon at 22.3 is adjacent to 26.4. The couplings of 2.02 with the vicinal protons at 1.23 and 1.81 were too small to be resolved in the proton spectrum. The carbon at 21.4 couples with 2.02 and 1.81, thus it is -92.2 adjacent to 22.3. The coupling of 128.1 with 2.90 and F -139.9 142.41 6.69 indicates that 128.1 is adjacent to 133.7. The 138.94 F N 2.02 couplings of 21.4 and 6.69 on one hand and 128.1 and 22.27 1.81 21.42 26.39 2.02 on the other indicate that 21.4 is bonded to 128.1. 134.23 F 1.23 F The 2H intensity of the signals at 2.02, 1.23 and 1.81, 128.04 30.65 8.16 N 2.90 141.07 153.68 133.71 together with the fact that 2.90 couples with two protons 6.69 134.23 141.22 8.33 101.22 F at 1.81, required the doubling of the 22.3 – 26.4 N 75.06 F sequence. Valence pairing requires the cyclopropyl 114.60 moiety. 140.26 N The proton at 2.02 couples with the carbon at 134.2, F 143.51 -136.7 F which is in position 4 of a 2,3,5,6-tetrafluoropyridine -89.6 ring, as indicated by its triplet of triplet (14.3, 2.8 Hz) splitting by F19. The carbon at 21.4 also couples with two fluorine nuclei, with a constant of 2.4 Hz, confirming the bonding to the tetrafluoropyridine ring. Interestingly, coupling with F19

89 splits the carbon at 22.3 as a doublet of doublet (3.9 and 1.0 Hz), indicating that this is a through- space coupling which renders the two ortho-fluorines unequivalent. Quantitative C13 spectra with broadband proton decoupling revealed the alkyne carbons at 101.2 and 75.1. They both are triplets, therefore they are bound to a tetrafluoropyridine moiety. The 4-acetyl-tetrafluoropyridine moiety has one valence which has to be paired to the only one unpaired valence on the pyridazine fragment, to account for the mass seen in the mass spectrum. This pairing agrees with the deshielding of the carbons at 134.2 and 114.6 produced by the alkyne bond. The assignment of the F19 frequencies was made on the basis of the F19-C13 couplings seen in the ghmbc spectrum.

2-Chloro-3-[2-(2,3,5,6-tetrafluoropyridin-4-yl)-tricyclo[3.2.1.02,7]oct-3-en-3-yl]-pyrazine (29). The title compound was prepared from the photochemical reaction of 2-chloro-3- tetrafluoropyridinylethynylpyrazine (0.10 g, 0.35 mmol) with 1,4-CHD (3.28 mL, 34.8 mmol) in 400 mL acetonitrile at 20ºC for 7 hours. The reaction mixture was purified by column chromatography on silica gel (100:1 hexanes:ethyl acetate) to afford 0.029 g (23%) of 29 and 0.066 g (52%) of 27 as white solids. 1 29. mp 145-148 ºC (with decomposition); H NMR (300 MHz, CDCl3) į 8.20-8.19 (d, 1H, J = 2.4 Hz), 8.11-8.10 (d, 1H, J = 2.1 Hz), 6.52-6.49 (d, 1H, J = 7.5 Hz), 2.95-2.92 (td, 1H, J = 7.5, 3.9 Hz), 2.07 (s, 2H), 1.88-1.83 (dd, 2H, J = Cl F 12.0, 4.8 Hz), 1.3-1.25 (d, 2H, J = 12.0 Hz); 13C NMR (75.5 MHz, F N N CDCl3) į 151.6, 148.3, 143.4 (m), 141.5 (dm, J = 297.2 Hz), 141.7, 141.1, F N 19 135.2, 133.6, 129.0, 31.5, 27.6, 23.4, 22.9; F NMR (282 MHz, CDCl3) į F -92.2 (m), -139.7 (m); UV/Vis (CH3CN): λmax(lgε) = 310 nm (3.66), 288 (3.79), 270 (3.92); IR (neat) 2977, 2953, 2918, 2849, 1643, 1453 cm-1; HRMS (EI+) calculated for C17H10N3F4Cl 367.0499, found 367.0503. 2-Chloro-3-[7-(2,3,5,6-tetrafluoropyridin-4-yl)-tetracyclo[3.2.1.02,7.04,6]oct-6-yl]-pyrazine 1 (27). mp 126-130 ºC (decompose); H NMR (300 MHz, CDCl3) į 8.43-

F 8.42 (d, 1H, J = 2.4 Hz), 8.17-8.16 (d, 1H, J = 2.4 Hz), 2.49-2.43 (ddd, N F 2H, J = 13.2, 2.7, 2.4 Hz), 2.7-2.12 (dd, 4H, J = 13.5, 2.1 Hz), 2.06-2.02 N 13 N Cl F (d, 2H, J = 13.2 Hz); C NMR (75.5 MHz, CDCl3) į 152.4, 151.4, F 143.2 (dm, J = 241.6 Hz), 142.2, 142.1, 141.5 (dm, J = 259.7 Hz), 132.6,

90 19 43.2, 34.5, 33.9, 32.5, 24.1; F NMR (282 MHz, CDCl3) į -92.0 (m), -140.5 (m); UV/Vis -1 (CH3CN): λmax(lgε) = 274 nm (3.5); IR (neat) 3036, 2923, 2855, 1642, 1460 cm ; HRMS (EI+) calculated for C17H10N3F4Cl 367.0499, found 367.0483.

2-[2-(2,3,5,6-Tetrafluoropyridin-4-yl)-tricyclo[3.2.1.02,7]oct-3-en-3-yl]pyrazine (30). The title compound was prepared from the photochemical reaction of 2- tetrafluoropyridinylethynylpyrazine (0.10 g, 0.40 mmol) with 1,4-CHD F (3.73 mL, 39.5 mmol) in 400 mL acetonitrile at 20ºC for 2.5 hours. The N F F N reaction mixture was purified by column chromatography on silica gel N F (100:1 hexanes:ethyl acetate) to afford 0.050 g (38%) of the desired 1 product as a white solid: mp 83-86 ºC; H NMR (300 MHz, CDCl3) į 8.58 (bs, 1H), 8.28 (bs, 1H), 8.10 (bs, 1H), 6.52-6.49 (d, 1H, J = 7.5 Hz), 2.95-2.90 (td, 1H, J = 7.2, 4.8, 3.3 Hz), 2.02 (s, 2H), 1.87-1.82 (dd, 2H, J = 12.0, 4.5 Hz), 1.26-1.22 (d, 2H, J = 12.0 Hz); 13C NMR (75.5

MHz, CDCl3) į 153.2, 143.1, 142.9 (m), 142.4, 142.3, 139.0 (m), 137.8, 132.3, 131.0, 31.8, 27.8, 19 23.4, 21.8; F NMR (282 MHz, CDCl3) į -93.4 (m), -140.8 (m); UV/Vis (CH3CN): λmax(lgε) = 267 nm (3.93), 226 (3.86); IR (neat) 2928, 2857, 1642, 1461 cm-1; HRMS (EI+) calculated for

C17H11N3F4 333.0889, found 333.0882.

2-[7-(2,3,5,6-tetrafluoropyridin-4-yl)-tetracyclo[3.2.1.02,7.04,6]oct-6-yl]-pyrazine (28). The title compound was prepared from the photochemical reaction of 2- tetrafluoropyridinylethynylpyrazine (0.10 g, 0.40 mmol) with 1,4-CHD F N F (3.73 mL, 39.5 mmol) in 400 mL acetonitrile at 20ºC for 18 hours using N N F glass filter which cut light below 330 nm. The reaction mixture was F purified by column chromatography on silica gel (100:1 hexanes:ethyl acetate) to afford 0.066 g (50%) of the desired product as a white solid: mp 118-119 ºC; 1H NMR

(300 MHz, CDCl3) į 8.30 (bs, 2H), 8.24 (bs, 1H), 2.39-2.35 (dm, 2H, J = 12.9 Hz), 2.21 (bs, 13 2H), 2.06-2.00 (m, 4H); C NMR (75.5 MHz, CDCl3) į 154.2, 143.4, 143.0 (dm, J = 244.6 Hz), 142.9, 142.0 (dm, J = 264.0 Hz), 141.8, 134.0, 42.5, 35.9, 34.5, 31.1, 24.2; 19F NMR (282 MHz,

CDCl3) į -92.7 (m), -141.8 (m); UV/Vis (CH3CN): λmax(lgε) = 271 nm (3.82), 220 (3.83); IR -1 (neat) 2972, 2898, 2858, 1645, 1467 cm ; HRMS (EI+) calculated for C17H11N3F4 333.0889, found 333.0900.

91

2-[7-(2,3,5,6-tetrafluoropyridin-4-yl)-tetracyclo[3.2.1.02,7.04,6]oct-6-yl]-pyridine (19). The title compound was prepared from the photochemical reaction of 2-

F tetrafluoropyridinylethynylpyridine (0.10 g, 0.40 mmol) with 1,4-CHD N F (3.75 mL, 39.7 mmol) in 400 mL acetonitrile at 20ºC for 1 hours. The N F reaction mixture was purified by column chromatography on silica gel F (100:1 hexanes:ethyl acetate) to afford 0.082 g (62%) of the desired 1 product as a white solid: mp 108-110 ºC; H NMR (300 MHz, CDCl3) į 8.28-8.27 (d, 1H, J = 3.9Hz), 7.49-7.43 (dd, 1H, J = 7.5, 1.8 Hz), 7.03-7.01 (d, 1H, J = 8.1 Hz), 6.98-6.94 (dd, 1H, J = 7.2, 5.1 Hz), 2.36-2.32 (dm, 2H, J = 12.9 Hz), 2.07-2.00 (m, 4H), 1.99-1.95 (d, 2H, J = 12.9 13 Hz); C NMR (75.5 MHz, CDCl3) į 158.7, 149.2, 143.0 (dm, J = 244.0 Hz), 142.2 (dm, J = 19 257.2 Hz), 136.4, 134.9, 122.0, 121.3, 45.1, 34.8, 34.1, 31.6, 24.2; F NMR (282 MHz, CDCl3)

į -93.4 (m), -141.8 (m); UV/Vis (CH3CN): λmax(lgε) = 266 nm (3.75), 223 (3.99); IR (neat) 3050, -1 2915, 2897, 2855, 1644, 1465 cm ; HRMS (EI+) calculated for C18H12N2F4 332.0937, found 332.0930.

3-[7-(2,3,5,6-tetrafluoropyridin-4-yl)-tetracyclo[3.2.1.02,7.04,6]oct-6-yl]-pyridine (20). The title compound was prepared from the photochemicalchemical reaction of 3-tetrafluoropyridinylethynylpyridine (0.10 g, 0.40 mmol) with 1,4-CHD F F N (3.75 mL, 39.7 mmol) in 400 mL acetonitrile at 20ºC for 1.5 hours. The N F reaction mixture was purified by column chromatography on silica gel F (100:1 hexanes:ethyl acetate) to afford 0.072 g (55%) of the desired 1 product as a white solid: mp 152-157 ºC; H NMR (300 MHz, CDCl3) į 8.47 (bs, 1H), 8.36-8.35 (d, 1H, J = 4.2 Hz), 7.53-7.51 (d, 1H, J = 7.8 Hz), 7.12-7.07 (dd, 1H, J = 7.8, 4.8 Hz), 2.38-2.32 13 (dm, 2H, J = 13.2 Hz), 2.02-1.89 (m, 6H); C NMR (75.5 MHz, CDCl3) į 151.2, 148.2, 143.0 (dm, J = 245.4 Hz), 141.7 (dm, J = 233.0 Hz), 137.3, 134.0, 133.3, 123.0, 41.0, 34.1, 32.8, 32.6, 19 24.1; F NMR (282 MHz, CDCl3) į -92.0 (m), -141.9 (m); UV/Vis (CH3CN): λmax(lgε) = 264 nm (3.81); IR (neat) 3028, 2916, 2896, 2855, 1642, 1456 cm-1; HRMS (EI+) calculated for

C18H12N2F4 332.0937, found 332.0944. 4-[7-(2,3,5,6-tetrafluoropyridin-4-yl)-tetracyclo[3.2.1.02,7.04,6]oct-6-yl]-pyridine (21). The title compound was prepared from the photochemical reaction of 4-

92 tetrafluoropyridinylethynylpyridine (0.10 g, 0.40 mmol) with 1,4-CHD F (3.75 mL, 39.7 mmol) in 400 mL acetonitrile at 20ºC for 0.5 hours. The F reaction mixture was purified by column chromatography on silica gel N N F F (100:1 hexanes:ethyl acetate) to afford 0.105 g (80%) of the desired 1 product as a white solid: mp 173-175 ºC; H NMR (300 MHz, CDCl3) į 8.39 (bs, 2H), 7.08 (bs, 13 2H), 2.34-2.30 (dm, 2H, J = 12.6 Hz), 2.01-1.95 (m, 6H); C NMR (75.5 MHz, CDCl3) į 149.7, 147.5, 143.4 (dm, J = 245.4 Hz), 141.7 (dm, J = 257.9 Hz), 133.1, 124.4, 42.6, 34.1, 33.3, 32.3, 19 24.1; F NMR (282 MHz, CDCl3) į -91.9 (m), -141.8 (m); UV/Vis (CH3CN): λmax(lgε) = 263 nm (3.62), 222 (3.88); IR (neat) 3031, 2914, 2897, 2854, 1643, 1461 cm-1; HRMS (EI+)

calculated for C18H12N2F4 332.0937, found 332.0952.

2,3,5,6-Tetrafluoro-4-(8-phenyl-tetracyclo[3.2.1.02,7.04,6]oct-1-yl)-pyridine (22). The title compound was prepared from the photochemical of

F tetrafluoropyridinylethynylbenzene (0.10 g, 0.40 mmol) with 1,4-CHD F (3.76 mL, 39.8 mmol) in 400 mL acetonitrile at 20ºC for 4 hours. The N F reaction mixture was purified by column chromatography on silica gel F (hexanes) to afford 0.046 g (35%) of the desired product as a white solid: 1 mp 183-187 ºC; H NMR (300 MHz, CDCl3) į 7.30-7.07 (m, 5H), 2.37-2.32 (dm, 2H, J = 12.9 13 Hz), 2.01-1.89 (m, 6H); C NMR (75.5 MHz, CDCl3) į 142.9 (dm, J = 244.8 Hz), 141.8 (dm, J = 257.5 Hz), 138.2, 134.1, 129.8, 128.2, 126.9, 43.8, 33.8, 32.8, 24.3; 19F NMR (282 MHz,

CDCl3) į -92.9 (m), -141.9 (m); UV/Vis (CH3CN): λmax(lgε) = 266 nm (3.62); IR (neat) 3041, -1 2914, 2892, 2853, 1644, 1470 cm ; HRMS (EI+) calculated for C19H13NF4 331.0984, found 331.0979.

2-[7-(2,3,4,5,6-Pentafluorophenyl)-tetracyclo[3.2.1.02,7.04,6]oct-6-yl]-pyridine (24). The title compound was prepared from the photochemical reaction of 2- F pentafluorophenylethynylpyridine (0.10 g, 0.37 mmol) with 1,4-CHD N F (3.51 mL, 37.2 mmol) in 400 mL acetonitrile at 20ºC for 6 hours. The F F reaction mixture was purified by column chromatography on silica gel F (100:1 hexanes:ethyl acetate) to afford 0.026 g (20%) of the desired 1 product as a white solid: mp 89-90 ºC; H NMR (300 MHz, CDCl3) į 8.37-8.36 (d, 1H, J = 4.8

93 Hz), 7.48-7.42 (dd, 1H, J = 7.8, 1.8 Hz), 7.08-7.06 (d, 1H, J = 7.8 Hz), 7.00-6.96 (dd, 1H, J = 7.2, 4.8 Hz), 2.36-2.31 (dm, 2H, J = 12.9 Hz), 2.07-2.06 (m, 2H), 1.97-1.91 (m, 4H, J = 12.9 13 Hz); C NMR (75.5 MHz, CDCl3) į 158.8, 149.0, 146.7 (dm, J = 244.6 Hz), 141.8 (dm, J = 19 241.8 Hz), 136.0, 127.8, 122.9, 121.0, 44.3, 34.0, 33.6, 30.8, 24.0; F NMR (282 MHz, CDCl3)

į -140.0 (m), -157.3 (m), -164.2 (m); UV/Vis (CH3CN): λmax(lgε) = 263 nm (3.76), 214 (4.29); -1 IR (neat) 3042, 2911, 2853, 1497 cm ; HRMS (EI+) calculated for C19H12NF5 349.0890, found 349.0891.

4-[7-Phenyl-tetracyclo[3.2.1.02,7.04,6]oct-6-yl]-pyridine (23). The title compound was prepared from the reaction of 4-phenylethynylpyridine (0.10 g, 0.56 mmol) with 1,4-CHD (5.28 mL, 55.9 mmol) in 400 mL acetonitrile at 20ºC for 16 hours. The reaction mixture was purified by column chromatography on N silica gel (50:1 hexanes:ethyl acetate) to afford 0.044 g (30%) of the desired 1 product as a white solid: mp 69-72 ºC; H NMR (300 MHz, CDCl3) į 8.27-8.25 (d, 2H, J = 5.1 Hz), 7.14-7.10 (m, 5H), 6.92-6.90 (d, 2H J = 6.3 Hz), 2.24-2.18 (dm, 2H, J = 12.9 Hz), 1.94- 13 1.88 (m, 6H, J = 12.9 Hz); C NMR (75.5 MHz, CDCl3) į 149.3, 139.7, 130.2, 128.3, 128.0,

127.6, 124.6, 42.2, 35.1, 33.5, 29.7, 24.1; UV/Vis (CH3CN): λmax(lgε) = 223 nm (4.07), 257 -1 (3.56); IR (neat) 3025, 2923, 2853, 1598 cm ; HRMS (EI+) calculated for C19H17N 259.1361, found 259.1361.

Di-4,4’-[7,6-tetracyclo[3.2.1.02,7.04,6]octyl]-pyridine (25). The title compound was prepared from the photochemical reaction of 4,4’-pyridylacetylene (0.10 g, 0.56 mmol) with 1,4-CHD (5.25 mL, 55.6 mmol) in 400 mL acetonitrile at 20ºC for 10 hours. The reaction mixture was purified by column chromatography N N on silica gel (1:1 hexanes:ethyl acetate) to afford 0.065 g (45%) of the 1 desired product as a white solid: mp 130-132 ºC; H NMR (300 MHz, CDCl3) į 8.26-8.25 (d, 2H, J = 5.4 Hz), 6.88-6.87 (d, 2H J = 6.0 Hz), 2.16-2.15 (dm, 2H, J = 12.9 Hz), 1.97-1.84 (m, 13 6H); C NMR (75.5 MHz, CDCl3) į 149.1, 149.0, 124.4, 41.4, 34.4, 23.7; UV/Vis (CH3CN): -1 λmax(lgε) = 259 nm (3.99), 222 (4.30); IR (neat) 3025, 2924, 2858, 1598 cm ; HRMS (EI+) calculated for C18H16N2 260.1314, found 260.1303.

94 Di-4,4’-[7,6-tetracyclo[3.2.1.02,7.04,6]octyl]-2,3,5,6-tetrafluoropyridine (26). The title compound was prepared from the photochemical reaction of

F F bis(tetrafluoropyridinyl) acetylene (0.10 g, 0.31 mmol) with 1,4-CHD F F (2.92 mL, 30.9 mmol) in 400 mL acetonitrile at 20ºC for 4 hours. The N N F F reaction mixture was purified by column chromatography on silica gel F F (50:1 hexanes:methylene chloride) to afford 0.060 g (48%) of the 1 desired product as a white solid: mp 245-248 ºC; H NMR (300 MHz, CDCl3) į 2.44-2.40 (dm, 13 2H, J = 13.2 Hz), 2.10-2.03 (m, 6H); C NMR (75.5 MHz, CDCl3) į 143.2 (dm, J = 246.0 Hz), 19 141.8 (dm, J = 260.4 Hz), 131.8, 55.5, 34.2, 23.8; F NMR (282 MHz, CDCl3) į -90.8 (m), -

141.7 (m); UV/Vis (CH3CN): λmax(lgε) = 269 nm (3.18), 229 (3.25); IR (neat) 2936, 1646, 1471 -1 cm ; HRMS (EI+) calculated for C18H8N2F8 404.0560, found 404.0560.

1,3-Dimethoxy-di-4,4’-[7,6-tetracyclo[3.2.1.02,7.04,6]octyl]-2,3,5,6-tetrafluoropyridine. The title compound was prepared from the photochemical reaction of MeO OMe bis(tetrafluoropyridinyl) acetylene (0.10 g, 0.31 mmol) with 1,5- F F F F dimethoxy-1,4-CHD (25% mol. equiv., 1.08 g, 7.72 mmol) in 300 mL N N acetonitrile at 20ºC for 4 hours. The reaction mixture was purified by F F F F column chromatography on silica gel (100:1 hexanes:ethyl acetate) to afford 0.057 g (40%) of the desired product as a white solid: mp 222-225 ºC, decompose; 1H

NMR (300 MHz, CDCl3) į 3.32 (s, 6H), 2.80-2.76 (d, 1H, J = 11.7 Hz), 2.69-2.66 (d, 1H, J = 12.0 Hz), 2.57-2.50 (dt, 1H, J = 13.2, 4.8), 2.23-2.19 (d, 1H, J = 13.2 Hz), 2.15-2.13 (d, 2H, J = 13 4.5 Hz); C NMR (75.5 MHz, CDCl3) į 143.3 (dm, J = 246.0 Hz), 143.3 (m), 128.1, 127.5, 19 72.2, 56.8, 37.1, 36.0, 28.3, 25.7; F NMR (282 MHz, CDCl3) į -90.4 (m), -90.8 (m), -138.2

(m), -124.2 (m); UV/Vis (CH3CN): λmax(lgε) = 269 nm (3.78), 224 (3.80); IR (neat) 2931, 2846, -1 1642, 1489, 747 cm ; HRMS (EI+) calculated for C20H12N2O2F8 464.0771, found 464.0771.

1,3-Dimethoxy-3-[7-(2,3,5,6-tetrafluoropyridin-4-yl)-tetracyclo[3.2.1.02,7.04,6] oct-6-yl]- pyridine. The title compound was formed from the photochemical reaction of 2- (tetrafluoropyridinylethynyl)pyridine (0.10 g, 0.40 mmol) with 1,5-dimethoxy-1,4-CHD (25 mol. equiv., 1.39 g, 9.92 mmol) in 300 mL acetonitrile at 20ºC for 3 hours. The reaction mixture was purified by column chromatography on silica gel (100:1 hexanes:ethyl acetate) to afford 0.109 g

95 MeO OMe (70%) of the desired product as a yellowish oil: 1H NMR (300 MHz,

F CDCl3) į 8.3 (d, 1H, J = 4.2 Hz), 7.5 (dd, 1H, J = 7.8 Hz), 7.2 (d, 1H, J = N F 7.8 Hz), 7.0 (d, 1H, J = 7.5, 4.8 Hz), 3.3 (s, 3H), 3.2 (s, 3H), 2.7 (d, 1H, J N F = 11.7 Hz), 2.6 (d, 1H, J = 1.7 Hz), 2.4 (dt, 1H, J = 13.2, 4.8), 2.3 (d, 1H, F 13 J = 4.5 Hz), 2.2 (d, 1H, J = 12.9 Hz); C NMR (75.5 MHz, CDCl3) į 154.8, 149.0, 142.8 (m), 142.2 (m), 135.9, 130.8 (m), 123.1, 121.4, 74.0, 71.1, 56.5, 56.0, 47.4, 19 37.1, 36.3, 28.0, 25.6; F NMR (282 MHz, CDCl3) į -93.2 (m), -93.8 (m), -138.0 (m), 143.1

(m); UV/Vis (CH3CN): λmax(lgε) = 268 nm (3.32), 230 (3.49), 242 (4.26); IR (neat) 2934, 2860, -1 1646, 1462 cm ; HRMS (EI+) calculated for C20H16N2O2F4 392.1148, found 392.11554. 3.19 The elucidation of the structure of compound L4 56.5 was based on the H1-C13 one-bond and long-range 2.55 2.40 28.0 O 25.6 couplings, revealed by the ghmqc and ghmbc 2.65 2.07 3.22 74.0 2.27 56.0 37.1 spectra. The H1-H1 couplings from the H1 2.08 O 71.1 36.3 spectrum identify the sequence 8.22 – 6.95 – 7.46 – F -138.36, -143.23 47.4 7.18 of the pyridine protons, starting with position -93.24, -93.96 7.18 154.8 F 6. The ghmqc spectrum allowed the assignment of 123.1 F N the carbons one bond away. Couplings with the N F 135.9 7.46 protons in positions 6 and 4, identified the carbon in 149.0 121.4 8.22 position 2. The proton at 2.40 displayed a 13.2 Hz 6.95 coupling with its geminal partner at 2.07, and two 5.0 Hz couplings with its vicinal methine protons at 2.27 and 2.08. The proton at 2.40 displayed couplings with carbons three bonds away, at 71.1 and 74.0, which in turn each coupled with the methoxy protons. The methine protons at 2.55 and 2.65 coupled with 74.0, 71.1, 37.1 and 36.3, identifying a 1,3-dimethoxy cyclohexyl moiety with open valences in positions 1,3,4 and 6. A cross-peak in the ghmbc spectrum between 2.27 and 74.0 allowed the assignment of the methoxy groups to positions. The carbon at 47.4 coupled with 7.18, therefore it is bound to position 2 of pyridine. This carbon also couples with 2.55 and 2.08, therefore it is in one of the positions (1 or 3) of the 1,3-dimethoxy cyclohexyl moiety. No cross peaks could be seen for the carbon bound to position 4 of TFP, because of the couplings of this carbon to fluorines. The TFP moiety is silent in the ghmbc experiment, although accounted for in the F19 spectrum, which displayed four signals at -143.23, -138.36, -93.96 and -93.24. These four signals, together with the

96 broadening of the signals at 2.08 and 2.27, suggest restricted rotation of the TFP moiety. The broadening of the fluorine signals precluded the observation of cross peaks in the F19-C13 ghmbc spectrum. Considerations of valence pairing and similarity of the chemical shifts which suggests a high symmetry indicate only two possible structures, L4 and the respective homo Diels-Alder product. The chemical shift of the carbon in position 2 of the 2 pyridyl, 47.4 is impossible for an sp2 carbon, therefore structure of the homo Diels-Alder product has to be discarded. Moreover, the carbons at 37.1 and 36.3 display in the ghmqc spectrum one bond coupling constants of 167.6 and 167.0 Hz respectively, consistent with CH groups on a cyclopropyl ring, while for the carbon at 25.6 the one bond coupling constants are both 130.4 Hz. An nOe between the protons at 2.55 and 2.40 allowed their assignment as trans to the cyclopropyl rings on the six membered ring.

General Procedure for Preparative Photochemical Reaction of Acetylenes with olefins. Preparative scale irradiation was carried out in a 500 mL reaction vessel equipped with a quartz immersion well (Ace Glass). 450 Watt medium pressure mercury-vapor lamp (Ace Glass) was used for irradiation. A Pyrex filter and a 0.001 M solution of K2CrO4 was used as a filter to isolate the 313 nm Hg line, unless stated otherwise. Solutions of acetylenes and olefins (tetramethylethylene, cyclohexene, allyl alcohol and 3,3-dimethylallyl alcohol) in acetonitrile were outgassed with bubbling argon overnight. A constant stream of argon was bubbled through the reaction mixture during irradiation. Solvent was removed in vacuo. The crude product was purified by chromatography on silica gel.

2-Phenyl-1,3-(tetrafluoropyridinyl)naphthalene. The title compound was prepared

TFP photochemical addition of tetrafluoropyridinylethynylbenzene (0.52 g, 0.21 Ph mmol) to allylalcohol (1.78 g, 20.7 mmol) in 20 mL acetonitrile at 20ºC for 5

TFP hours. The reaction mixture was purified by column chromatography on silica gel (7:3 hexanes:ethyl acetate) to afford 5.2 mg (5%) of the product: 1H

NMR (300 MHz, CDCl3) į 8.1 (s, 1H), 8.0 (d, 1H, J = 5.2 Hz), 7.7 (m, 2H), 7.4 (d, 1H, J = 4.8

Hz), 7.2 (m, 3H), 7.0 (d, 1H, J = 4.5 Hz); HRMS (EI+) calculated for C26H10N2F8 502.07160, found 502.07216.

97 General Procedure for Preparative Photochemical Reaction of Acetylenes with Thiophene and Furan. Preparative scale irradiation was carried out in a 500 mL reaction vessel equipped with a quartz immersion well (Ace Glass). 450 Watt medium pressure mercury-vapor lamp (Ace Glass) was used for irradiation. A combination of Pyrex filter and a 0.001 M solution of K2CrO4 was used as a filter to isolate the 313 nm Hg line, unless stated otherwise. Solutions of acetylenes and thiophene or furan in acetonitrile or cylohexane were outgassed with bubbling argon overnight. Solutions were irradiated at 20 ºC while a constant stream of argon bubbled through the reaction mixture. Solvent was removed in vacuo. The crude product was purified by chromatography on silica gel.

2,3,5,6-Tetrafluoro-4-(7-pyridin-2-yl-2-thia-bicyclo[3.2.0]hepta-3,6-dien-1-yl)-pyridine. The title compound was formed from the photochemical N N reaction of 2-(tetrafluoropyridinylethynyl)pyridine (0.10 TFP TFP S or S g, 0.40 mmol) with thiophene (3.33 g, 39.7 mmol) in 400 mL acetonitrile at 20ºC for 18 hours. The reaction mixture was purified by column chromatography on silica gel (95:5 hexanes:ethyl acetate) to afford 3 mg 1 (2%) of the desired product: H NMR (300 MHz, CDCl3) į 8.5 (d, 1H, J = 4.8 Hz), 7.7 (d, 1H, J = 7.5 Hz), 7.6 (d, 1H, J = 7.8 Hz), 7.2 (d, 1H, J = 4.8 Hz), 6.9 (s, 3H), 6.4 (d, 1H, J = 6.3 Hz), 5.7 (dd, 1H, J = 6.0, 2.7 Hz), 4.1 (d, 1H, J = 3 Hz). 2,3,5,6-Tetrafluoro-4-(2-pyridin-2-yl-phenyl)-pyridine. 3 mg (3%): 1H NMR N (300 MHz, CDCl3) į 8.4 (d, 1H, J = 4.2 Hz), 7.8-7.6 (m, 4H), 7.4 (m, 2H), 7.2 (d,

TFP 1H, J = 5.1 Hz); HRMS (EI+) calculated for C16H8N2F4 304.0624, found 304.0621. 1 N 5,7,8-Trifluoro-1,6-diaza-triphenylene. 3 mg (3%): H NMR (300 MHz,

CDCl3) į 8.9 (d, 1H, J = 4.2 Hz), 8.2 (d, 1H, J = 2.1 Hz), 8.0 (dd, 1H, J = 5.6, F 1.8 Hz) 7.9 (dd, 1H, J = 7.5, 1.8 H), 7.8 (dd, 2H, J = 8.4, 5.7 H), 7.5 (dd, 1H, J N F = 5.1, 6.6 Hz); HRMS (EI+) calculated for C16H7N2F3 284.05614, found F 284.05569.

2,3,5,6-Tetrafluoro-4-(7-pyridin-3-yl-2-thia-bicyclo[3.2.0]hepta-3,6-dien-1-yl)-pyridine. The title compound was formed from the photochemical reaction of 3-

98 N N (tetrafluoropyridinylethynyl)pyridine (0.10 g, 0.40 mmol) TFP with thiophene (3.33 g, 39.7 mmol) in 400 mL acetonitrile S TFP or S at 20ºC for 10 hours. The reaction mixture was purified by column chromatography on silica gel (100:1 hexanes:ethyl 1 acetate) to afford 11 mg (8%) of the desired product: H NMR (300 MHz, CDCl3) į 8.5 (d, 1H, J = 4.8 Hz), 7.7 (d, 1H, J = 7.5 Hz), 7.6 (d, 1H, J = 7.8 Hz), 7.2 (d, 1H, J = 4.8 Hz), 6.9 (s, 3H), 6.4 (d, 1H, J = 6.3 Hz), 5.7 (dd, 1H, J = 6.0, 2.7 Hz), 4.1 (d, 1H, J = 3 Hz); HRMS (EI+)

calculated for C16H8N2F4S 336.0344, found 336.0331. 1 N 2,3,5,6-Tetrafluoro-4-(2-pyridin-3-yl-phenyl)-pyridine. 19 mg (16%): H

NMR (300 MHz, CDCl3) į 8.6 (bs, 1H), 8.4 (bs, 1H), 7.7-7.5 (m, 4H), 7.4 (d, 1H,

TFP J = 7.5 Hz), 7.2 (m, 1H); HRMS (EI+) calculated for C16H8N2F4 304.06236,

N found 304.06208. 5,7,8-Trifluoro-1,6-diaza-triphenylene. 15 mg (13%): 1H NMR (300 MHz, F CDCl3) į 9.1 (d, 1H, J = 4.5 Hz), 8.9 (d, 1H, J = 8.4 Hz), 8.0 (d, 1H, J = 8.1 N F Hz) 7.9 (m, 1H), 7.8 (dd, 2H, J = 8.4, 6.9 H), 7.7 (dd, 1H, J = 8.4 4.2 Hz); F HRMS (EI+) calculated for C16H7N2F3 284.05614, found 284.05562.

4-Biphenyl-2-yl-2,3,5-trifluoro-6-methyl-pyridine. The title compound was prepared from the photochemical of tetrafluoropyridinylethynylbenzene (0.10 g, 0.42 mmol) with thiophene (3.51 g, 41.8 mmol) in 400 mL acetonitrile at 20ºC for 15 hours.

TFP The reaction mixture was purified by column chromatography on silica gel 1 (hexanes) to afford 2.4 mg (3%) of the desired product: H NMR (300 MHz, CDCl3) į 7.6-7.5 (m, 3H), 7.4 (d, 1H, J = 7.8 Hz), 7.3 (m, 3H) 7.1 (m, 2H); HRMS (EI+)

calculated for C17H9NF4 303.06711, found 303.06777. 1,3,4-Trifluoro-2-aza-triphenylene. 2.2 mg (3%): 1H NMR (300 MHz, F CDCl3) į 9.1 (d, 1H, J = 4.5 Hz), 8.9 (d, 1H, J = 8.4 Hz), 8.0 (d, 1H, J = 8.1 N F F Hz) 7.9 (m, 1H), 7.8 (dd, 2H, J = 8.4, 6.9 H), 7.7 (dd, 1H, J = 8.4 4.2 Hz);

HRMS (EI+) calculated for C17H8NF3 283.06088, found 283.06028.

1,2-Bis(4-pyridyl)benzene. The title compound was prepared from the photochemical reaction of 4,4’-pyridylacetylene (0.10 g, 0.56 mmol) with thiophene (4.67 g, 41.8 mmol)in 400

99 N mL acetonitrile at 20ºC for 35 hours. The reaction mixture was purified by column chromatography on silica gel (1:1 hexanes:ethyl acetate) to afford 0.065 g 1 (20%) of the desired product: H NMR (300 MHz, CDCl3) į 8.5 (d, 1H, J = 6.0 N Hz), 7.5 (m, 2H), 7.4 (m, 2H), 7.1 (d, 1H, J = 5.7 Hz); HRMS (EI+) calculated for C16H12N2 232.1001, found 232.0990.

1,7-Bis(tetrafluoropyridinyl)-2-thia-bicyclo[3.2.0]hepta-3,6-diene. The title compound was

TFP TFP prepared from the photochemical reaction of bis(tetrafluoropyridinyl) acetylene S (0.10 g, 0.31 mmol) with thiophene (2.60 g, 30.9 mmol) in 300 mL acetonitrile at 20ºC for 8 hours. The reaction mixture was purified by column chromatography on silica gel (100:1 hexanes:ethyl acetate) to afford 12 mg (10%): 1H NMR

(300 MHz, CDCl3) į 6.8 (bs, 1H), 6.3 (d, 1H, J = 6.3 Hz), 5.7 (dd, 1H, J = 6.0, 2.7 Hz), 4.2 (bs, 13 1H); C NMR (75.5 MHz, CDCl3) į 143.8 (m), 141.4 (t, J = 6.6 Hz), 139.9 (m), 132.6 (m), 19 131.1 (d, J = 7.2 Hz), 127.3, 117.6, 67.5, 62.0; F NMR (282 MHz, CDCl3) į -90.3 (m), -91.1

(m), 140.5 (m), -141.6 (m); HRMS (EI+) calculated for C16H4N2F8S 407.9967, found 407.9955. 1,2-Bis(2,3,4,5-tetrafluro-4-pyridnyl) benzene. 75 mg (65%): 1H NMR (300 TFP 13 MHz, CDCl3) į 7.8 (m, 2H), 7.6 (m, 2H); C NMR (75.5 MHz, CDCl3) į 143.6 TFP 19 (m), 139.1 (m), 131.1, 131.0, 126.1; F NMR (282 MHz, CDCl3) į -89.3 (m), -

143.0 (m); HRMS (EI+) calculated for C16H4N2F8 376.0247, found 376.0237. 6,7-Bis(tetrafluoropyridinyl)-2-thia-bicyclo[3.2.0]hepta-3,6-diene. The title compound was

TFP prepared from the photochemical reaction of bis(tetrafluoropyridinyl) acetylene S (0.10 g, 0.31 mmol) with thiophene (2.60 g, 30.9 mmol) and azulene (40.0 mg, TFP 0.31 mmol) in 300 mL acetonitrile at 20ºC for 8 hours. The reaction mixture was purified by column chromatography on silica gel (100:1 hexanes:ethyl acetate) to afford 3.8 mg 1 (3%): H NMR (300 MHz, CDCl3) į 6.4 (d, 1H, J = 6.0 Hz), 5.8 (m, 1H), 5.2 (bs, 1H), 4.8 (bs, 13 1H); C NMR (75.5 MHz, CDCl3) į 143.6 (m), 139.6 (m), 137.2 (m), 139.0, 129.2, 119.7 (t), 19 117.6, 60.8, 52.1; F NMR (282 MHz, CDCl3) į -89.9 (m), -90.0 (m), 139.1 (m), -139.7

(m);HRMS (EI+) calculated for C16H4N2F8S 407.99672, found 407.99650.

2,3-Bis(tetrafluoropyridinyl)-oxoquadricyclane. The title compound was prepared from the photochemical reaction of bis(tetrafluoropyridinyl) acetylene (0.10 g, 0.31 mmol) with furan (6.3

100 O g, 92.6 mmol) in 300 mL acetonitrile at 20ºC for 25 hours. The reaction mixture TFP was purified by column chromatography on silica gel (20:1 hexanes:ethyl acetate) TFP 1 to afford 36 mg (30%): H NMR (300 MHz, CDCl3) į 5.0 (d, 1H, J = 3.3 Hz), 3.0 13 19 (d, 1H, J = 3.0 Hz); C NMR (75.5 MHz, CDCl3) į 71.4, 28.0; F NMR (282 MHz, CDCl3) į -

90.3 (m), 143.0 (m); HRMS (EI+) calculated for C16H4N2F8 392.01957, found 392.01969. 1 O 4,5-Bis(tetrafluoropyridinyl)-oxepine. H NMR (300 MHz, CDCl3) į 6.1 (d, 13 1H, J = 4.8 Hz), 5.4 (d, 1H, J = 4.8 Hz); C NMR (75.5 MHz, CDCl3) į 126.0, 112.9; 19F NMR (282 MHz, CDCl ) -88.6 (m), -141.4 (m). TFP TFP 3 į

2-(2-pyridinyl)-3-(tetrafluoro)-hydroxyfulvene. The title compound was formed from the

H O H photochemical reaction of 2-(tetrafluoropyridinylethynyl)pyridine (0.10 g, N 0.40 mmol) with furan (100 mol. equiv., 2.7 g, 39.7 mmol) in 400 mL acetonitrile at 20ºC for 10 hours. The reaction mixture was purified by TFP column chromatography on silica gel (2:1 hexanes:ethyl acetate) to afford 25 1 mg (20%) of the desired product: H NMR (300 MHz, AcetoneD6) į 18.6 (bs, 1H), 9.2 (s, 1H), 8.5 (bs, 1H), 7.9 (dd, 1H, J = 8.7, 7.5 Hz), 7.6 (d, 1H, J = 8.2 Hz), 7.4 (dd, 1H, J = 6.9, 6.6 Hz), 7.0 (d, 1H, J = 4.2 Hz), 7.3 (d, 1H, J = 3.9 Hz).

2-(2-pyrazinyl)-3-(tetrafluoro)-hydroxyfulvene. The title compound was formed from the

H O H photochemical reaction of 2-(tetrafluoropyridinylethynyl)pyrazine (0.10 g, N 0.40 mmol) with furan (100 mol. equiv., 2.7 g, 39.7 mmol) in 400 mL

N acetonitrile at 20ºC for 15 hours. The reaction mixture was purified by TFP column chromatography on silica gel (2:1 hexanes:ethyl acetate) to afford 6 1 mg (5%) of the desired product: H NMR (300 MHz, C6D6) į 10.3 (s, 1H), 8.3 (d, 1H, J = 4.5 Hz), 8.0 (d, 1H, J = 4.5 Hz), 7.4 (bs, 1H), 7.1 (d, 1H, J = 5.1 Hz), 7.0 (d, 1H, J = 5.1 Hz), 6.8 (d, 1H, J = 4.8 Hz).

101 Determination of Quantum Yields

Stock solutions of acetylenes (1.00 × 10-3 M), 1,4-CHD (0.10 M and 2.00 × 10-3 M) and internal standard (decaline) in acetonitrile were degassed in pyrex 100 × 0.3 mm tubes with three freeze/pump/thaw cycles and flame-sealed under argon. Irradiations were performed in a merry- go-round apparatus174 immersed in a water bath at 25 ºC using the 450-W medium-pressure Hg lamp (Ace Glass) with a Pyrex and a potassium chromate filter solution (0.001 M) to isolate 313 nm light. Duplicate irradiated samples were broken open immediately following the irradiation and analyzed by a Varian Model LP-3800 Gas Chromatograph (column: DB-5MS J&W Scientific, 30 m length, 0.25 mm ID, 0.25 µm film). Photoisomerization of trans-stilbene to cis- 175 stilbene in degassed benzene (φt→c = 0.5) was used for actinometry. Conversion of trans- stilbene to cis-stilbene was less than 7% determined by GC.v When the conversion exceeds 7% the equation suggested by Lamola and Hammond176 was used for back reaction correction.vi

Sensitization and Quenching Studies

-3 Stock solutions of sensitizers (1.5 × 10 M) (benzophenone, ET = 68 kcal/mol; acetophenone, 177 177 ET = 76 kcal/mol; xanthone, ET = 74 kcal/mol) and quenchers (azulene ET = 39 kcal/mol), acetylenes (1.00 × 10-3 M), 1,4-CHD (1.00 × 10-1 and 2.00 × 10-3 M) and internal standard (decalin) were prepared in acetonitrile. Mixtures of the acetylene and sensitizer (2:1 v/v) in Pyrex tubes (100 × 0.3 mm) were degassed with three freeze/pump/thaw cycles and flame-sealed under argon. Sensitized photoreactions were irradiated using a 200 W Hg-Xe lamp (Spectra- Physics, Laser & Photonics Oriel Instrument) and Corning glass filter # 7380 (C.S. 0-52). Quenching experiments were performed using the 200 W Hg-Xe lamp and a long pass filter with a cut-off wavelength 309 nm. Degassed and non-degassed samples were irradiated at the same time to determine the oxygen effect.

v Caution: when benzene is used as solvent do NOT use plastic vials for GC, solvent dissolves the plastic and unwanted peaks are observed in the GC chromatogram. vi Acetylenes with low reactivity required extended time of irradiation to have significant amount of product formed and to determine the quantum yields, thus the conversion of trans-stilbene to the cis-isomer was more than 10% and correction for the back reaction was required.

102 1H NMR Studies

Pyrex NMR tubes (5 mm, WILMAD no. 507-PP) were used. Solutions of acetylenes (5-10

mg) and 1,4-CHD (5 mole excess) in CD3CN (1 mL) were degassed with three freeze/pump/thaw cycles and flame-sealed under argon. Irradiations were performed using the 200 Watts Hg-Xe lamp and a long pass filter with a cut-on wavelength 309 nm. Corning glass filter # 7380 (C.S. 0-52) that transmits light above 340 nm was used for sensitized photoirradiation.

Emission and Absorption Studies

Fluorescence spectra were recorded with a HITACHI F-4500 Fluorescence Spectrophotometer in glassy methylcyclohexane (77 K). Each sample, [acetylene] = 2 × 10-5 M, was prepared in Pyrex NMR tube (WILMAD no. 507-PP) and degassed with three freeze/pump/thaw cycles. Methyl iodide (20 µL) was added to the 1.0 mL solution of acetylene to induce phosphorescence.

Laser Flash Spectroscopy Studies

The pulsed laser spectroscopy system consists of a Nd:YAG laser Spectra-Physics Quanta-Ray DCR3) emitting at 1064 nm (800-900 mJ/pulse) and 10 Hz and at 532 nm by frequency- doubling the fundamental in a nonlinear KDP crystal. 266 nm emission is generated by frequency-doubling the 532 nm output from the YAG laser in a Spectra-Physics WEX (Wavelength EXtender) module. The 4-6 ns 266 nm pulse irradiates the acetylene sample (2 × 10-5 M) and the fluorescence is collected at right angle to the laser axis and detected using a photomultiplier viewing a narrow wavelength region at 450 nm selected by a small monochromator. A 390 nm long pass filter is placed before the monochromator to reduce the laser scatter. The detector signal is then digitized by a LeCroy 9410 two channel, 150 MHz, 100 M sample/second digital storage oscilloscope. Then the signal decay was fitted to a single or double exponential equation using an Oakdale Engineering DataFit program version 5.1.1.

103 Electrochemistry: Cyclic Voltammetry Studies

Electrochemical measurements were obtained using a Princeton Applied Research Model 250 Verastat, which was interfaced to a personal computer running the supplied M270 software. Experiments were performed in spectroscopic grade acetonitrile with tetrabutylammonium hexafluorophosphate as the electrolyte, utilizing a one compartment cell. The working electrode was a platinum disk (Bioanalytical Systems), and the auxiliary electrode consisted of platinum wire sealed in a glass tube. The reference electrode was a homemade saturated sodium calomel electrode (SSCE).

Preparation of Homoquadricyclane-Metal Complexes

Silver nitrate was purchased from MP Biomedicals Inc. Copper(II) Chloride dihydrate was provided to us by Professor Naresh Dalal. All solvents (HPLC grade) were purchased from Aldrich. TGA and DSC experiments were recorded on a SDT 2960 Simultaneous DSC-TGA instrument, TA Instruments. Infrared samples were prepared as KBr pellets and spectra were obtained using a NICOLET AVATAR 360 FT-IR spectrometer.

Synthesis of Complex 1: Complex 1 was synthesized in 80% yield by layering an acetonitrile

solution (3 mL) of L1 (10.0 mg, 0.038 mmol) over a THF solution (3 mL) of AgNO3 (6.5 mg, 0.038 mmol). A white layer of precipitate was formed instantaneously. The vial was covered to reduce solvent evaporation and left in the dark. After three weeks, larger crystals had separated from the white precipitate and X-ray data were collected. IR (KBr pellets): v = 3677 (br), 2921 (m), 2842 (s), 1612 (s), 1383 (m), 1289 (m), 1211 (m), 1027 (m), 826 (s) cm-1. Synthesis of Complex 2: Complex 2 was prepared using a glass U-tube. A chloroform layer (2 mL) was placed in the bottom and a THF solution (2 mL) of L1 (10 mg, 0.038 mmol) was

layered carefully from one end of the tube. An acetonitrile solution (2 mL) of AgNO3 (6.5 mg, 0.038 mmol) was layered on the other end of the chloroform layer. The tube was stoppered at both ends and left in the dark for 30 days. White crystals (30% yield) suitable for X-ray analysis were collected from the THF side of the U-tube suggesting that the metal migrated more efficiently to the ligand layer. IR (KBr pellets): v = 3447 (br), 3022 (m), 2991 (m), 2857 (s), 2362 (m), 1602 (s), 1384 (m), 1318 (m), 1216 (m), 1066 (m), 789 (s) cm-1.

104 Synthesis of Complex 3: A mixture of L3 (10 mg, 0.030 mmol) and silver nitrate (5.2 mg, 0.031 mmol) was dissolved in acetonitrile (10 mL) and left with stirring at room temperature for two hours. The flask was stoppered and the clear solution was allowed to stand in the dark for two weeks. Clear crystals were formed and collected for X-ray analysis (65% yield). IR (KBr pellets): v = 3350 (br), 2935 (m), 2854 (s), 1645 (s), 1613 (s), 1465 (s), 1357 (m), 1136 (m), 970 (m), 883 (s) cm-1. Synthesis of Complex 4: Complex 4 was prepared using a glass U-tube. A chloroform layer (2 mL) was placed in the bottom and an acetonitrile solution (2 mL) of L1 (6.1 mg, 0.023 mmol)

was layered carefully from one end of the tube. A THF solution (2 mL) of CuCl2.2H2O (5.0 mg, 0.029 mmol) was layered on the other end of the chloroform layer. The tube was stoppered at both ends and left in the dark for 30 days. Green crystals (68% yield) suitable for X-ray analysis were collected from bottom of the U-tube. IR (KBr pellets): v = 2997 (s), 2937 (br), 2855 (s), 1615 (s), 1499 (s), 1318 (m), 1219 (s), 1028 (m), 837 (s) cm-1.

RESULTS

Photochemistry of Pyridinyl Aryl Acetylenes

Acetylenes bearing at least one pyridinyl ring as a substituent add to 1,4-cyclohexadiene (1,4-

CHD) when irradiated at 313 nmiii and yield 1,5-diaryl substituted tetracyclo[3.3.0.02,8.04,6]octanes (homoquadricyclanes) in good yields ( Scheme 28 and Table 10). Pyridinyl enediyne 5 provided a mixture (35% overall yield) of inseparable regioisomeric homoquadricyclane adducts where 1,4-CHD adds to either of the triple bonds in 2:1 ratio determined from 1H NMR integration of peaks. Tolane was unreactive under these conditions. This observation agreed with the earlier report that tolane reacts with 1,4-CHD under irradiation at much shorter wavelength and adds to one of the double bonds of the diene to form the cyclobutene adduct.131

105 Scheme 28. Photochemical Reactions of Aryl Pyridinyl Acetylenes with 1,4-CHDa hν

313 nm Ar2 Ar1 Ar2 + CH3CN Ar1 19-26

a The newly formed bonds are shown in blue

The structure of homoquadricyclane adducts was confirmed using a combination of spectroscopic methods, such as 1H, 13C and 19F NMR as well as mass spectrometry and X-ray crystallographic analysis (Figure 18). The presence of the homoquadricyclane products in the 1H NMR of the reaction mixture is revealed by a characteristic doublet of quintets at ~2.4 ppm with geminal coupling of 13.0 Hz corresponding to two protons on the methylene bridges connecting the two cyclopropane rings (Figure 17). Apparently the vicinal and the W-constants for these protons are close in magnitude. The other two protons from these bridges are shifted upfield and are displayed as a rather sharp doublet with the same geminal coupling constant.

Figure 17. The non-aromatic region of the 1H NMR spectra for the homoquadricyclane product.

Since the earlier homoquadricyclane structures reported in litterature were based exclusively on NMR spectra, vide supra, X-ray crystallographic analysis of compounds 19 and 22 for the first time unambiguously confirmed the homoquadricyclane structure of the products. This analysis also revealed interesting structural features of tetracyclo[3.3.0.02,8.04,6]octane moiety.

106 Most interestingly, the two aryl groups defining the hydrophobic cavity are cross-conjugated through the adjacent cyclopropane moieties and are oriented in an almost perfect 60o angle.

19 22

Figure 18. ORTEP presentations of homoquadricyclanes 19 and 22.

Table 10. Conditions and Yields for the Photochemical Cycloaddition of Acetylenes to 1,4- Cyclohexadiene.a,b

c Compounds Product Ar1 Ar2 Irradiation Time, hrs Isolated Yield, % 6 19 2-Py TFP 1 61 7 20 3-Py TFP 1.5 55 8 21 4-Py TFP 0.5 80d 9 26 TFP TFP 0.75 48 10 22 Ph TFP 4 35 13 24 2-Py PFB 20 20 14 25 4-Py 4-Py 10 65 15 23 4-Py Ph 5 25 17 - Ph Ph > 48 No Rxne 18 - Ph PFB > 48 No Rxne a Irradiation was performed at 313 nm in acetonitrile at 25ºC; initial concentrations of acetylenes = 1.0 × 10-3 M and of 1,4-CHD = 0.1 M. b Ph = Phenyl, Py = Pyridinyl, Pyra = Pyrazinyl, TFP = Tetrafluoropyridinyl, PFB = Pentafluorobenzene. c Irradiation time until complete consumption of the acetylene according to TLC analysis. d >95% yield determined by GC. e Acetylenes were completely recovered under these conditions.

Table 10 shows the reaction times and the isolated yields for the photocycloaddition reactions of pyridinyl acetylenes. According to GC analysis, the reaction yields are even higher reaching >95% in the case of 4-Py-TFP acetylene 8. In some of the cases, the combination of high yields

107 of the homoquadricyclane products along with the short irradiation times is quite remarkable and indicates a surprisingly efficient process which contrasts sharply to the observed lack of photochemical reactivity of tolane 17 and Ph-PFB acetylene 18. Monitoring the progress of the reaction with 1H NMR confirms that the reaction is clean and that the homoquadricyclane product is the major product (Figure 19). Since all signals in the product are uniformly moved upfield relative to the starting acetylene, the reaction can be conveniently monitored with NMR. This effect can be attributed either to the loss of conjugation with a strong electron acceptor or, to some extent, to the change in orientation of the two aromatic rings which places the pyridine ring in the vicinity of the aromatic current of the TFP ring.

H d, 8.6ppm hν TFP N 313 nm N TFP H CD3CN d, 8.2ppm 1,4-CHD 6 19

time=0

time=20min

time=1hr

time=1hr40min

time=2.5hrs

time=4.5hrs

8.50 8.00 7.50 7.00 6.50

Figure 19. Changes in the 1H NMR spectra of the aromatic region during irradiation of acetylene 6; [2-Py-TFP] = 0.03 M and [1,4-CHD] = 0.13 M.

Photochemistry of Pyrazinyl Aryl Acetylenes

Under identical conditions, irradiation of diaryl acetylenes 12 and 16 in which one of the aryl substituents is a pyrazinyl, yields tricyclo[3.2.1.04,6]oct-2-ene as the major product—the same

108 product formed in the photochemistry of the pyrazinyl enediyne 3 (Scheme 29 and Table 11, entries 2a and 3).

Scheme 29. Photochemical Reactions of Aryl Pyrazinyl Acetylenes with 1,4-CHDa

hν Ar Ar 313 nm 2 + 2 Ar1 Ar2 + CH3CN Ar1 Ar1 19-28 4,29-31

a The newly formed bonds are shown in blue

The tricyclo[3.2.1.04,6]oct-2-ene products can be easily identified by a characteristic set of 1H NMR signals which includes a doublet in the vinylic region, a doublet of triplets at 3 ppm, and two signals (dd at 1.8 ppm and a doublet at 1.1 ppm) of hydrogens representing two

diastereotopic CH2 groups.

Figure 20. The non-aromatic region of the 1H NMR spectra for the tricyclo[3.2.1.04,6]oct-2-ene product.

Several important mechanistic questions present themselves. Is the tricyclo[3.2.1.04,6]oct-2-ene pathway mechanistically independent in formation from tetracyclo[3.3.0.02,8.04,6]octane? Are tricyclooctene and homoquadricyclane related as primary and secondary photochemical products? Or are they formed through branching from a common intermediate?

109 27 29

Figure 21. ORTEP presentations of homoquadricyclane 27 and tricyclo[3.2.1.0.4,6]oct-2-ene 29.

Fortunately, introduction of a chlorine atom in the pyrazine moiety of acetylene 11 modifies photochemical reactivity in a way where both types of photoproducts are formed at the same time in 23 and 40% yield (Table 11, entries 1a and 1a’). These products were isolated and identified, first spectroscopically and later by X-ray crystallography, as the tricyclo[3.2.1.0.4,6]oct-2-ene 29 and tetracyclo[3.3.0.02,8.04,6]octane 27 adducts (Figure 21).

Table 11. Conditions and Yields for the Photochemical Cycloaddition of Pyrazinyl Acetylenes to 1,4-Cyclohexadiene.a,b

c d Entry Reactants Product Ar1 Ar2 Irradiation Time (hrs) %Yield 1a 11 27 Pyra-2-Cl TFP 7 23 1a’ 11 29 Pyra-2-Cl TFP 7 40 1be 11 27 Pyra-2-Cl TFP 47 90f 1c 27 29 Pyra-2-Cl TFP 1.5 >99f 2a 12 30 Pyra TFP 2 38 2b 12 28 Pyra TFP 2 -g 2c 28 30 Pyra TFP 0.75 >99f 3 16 31 Pyra Ph 48 10h 4 3 4 Pyra-TFPE TFP 5 20

a Irradiation was performed in CH3CN at 313 nm in acetonitrile at 25ºC; initial concentration of acetylenes = 1.0 × -3 b 10 M and of 1,4-CHD = 0.1 M; 1b, 1c, 2b and 2c were performed in CD3CN in an NMR tube. Ph = Phenyl, Py = Pyridinyl, Pyra = Pyrazinyl, TFP = Tetrafluoropyridinyl, TFPE = Tetrafluoropyridinylethynyl. c Irradiation time until total consumption of the acetylene according to TLC analysis. d Isolated yields, unless stated otherwise. e Irradiation at 330 nm. f Yields estimated by 1H NMR. g The product was present in small amounts but could not be isolated from the reaction mixture. h Unreacted acetylene was recovered and product yield was estimated by 1H NMR of the crude reaction mixture.

110 Taking advantage of the observation that, unlike the starting acetylene, the homoquadricyclane product 27 does not absorb light at λ> 330 nm, we repeated the photolysis under these conditions.vii

H s, 8.9ppm hν hν N 330 nm TFP 313 nm TFP TFP N CD CN N N CD CN H 3 H 3 s, 8.3ppm d, 6.5ppm Cl Cl Cl 1,4-CHD N N 29 11 27

time=0

time=1hr

time=9hrs

time=17hrs

time=24hrs

time=47hrs

ÅStop here and change the cut-off filterÆ

Time = 0

Time = 10min

Time = 1hr30min

8.50 8.00 7.50 7.00 6.50 ppm (t1)

Figure 22. Photoreaction of acetylene 11 with 1,4-CHD followed by 1H NMR; [Pyra-Cl-TFP] = 0.04 M and [1,4-CHD] = 0.20 M.

When the reaction progress was monitored with 1H NMR only tetracyclooctane 27 was formed in ca. 90% conversion after 47 hours of irradiation (Table 11, entry 1b). No secondary photochemistry of 27 was observed under these conditions (Figure 22). On the other hand, when the tetracyclooctane was separated from the unreacted starting acetylene and subjected to further

vii A long pass filter with a cut-off wavelength 309 nm. Corning glass filter # 7380 (C.S. 0-52) that transmits light above 340 nm was used for photoirradiation sensitized by benzophenone.

111 irradiation at 313 nm, the homoquadricyclane 27 was cleanly converted into the rearranged tricyclooctene product 29 (Figure 22 and Table 11, entry 1c). As expected, 1,4-CHD was not needed for the latter step. Thus, in this case, the unusual tricyclooctene adduct formation is a result of a photochemical cascade proceeding through homoquadricyclane intermediate. Moreover, the homoquadricyclane intermediate can also be detected in the reaction with the pyrazinyl-TPF acetylene 12 when a less powerful and more tunable light source (200 Watts Hg- Xe lamp) was used for the irradiation (Table 11, entry 2c). According to the NMR analysis of the reaction mixture, ca. 60% of the homoquadricyclane 28 is formed after 2 hours of irradiation at λ>313 nm under these conditions whereas further irradiation (the total of 10 hours of photolysis) led to the reaction mixture which contained ca. 80% of the tricyclooctene 30 (Figure 23).

hν N > 313 nm TFP TFP TFP + N N N CD3CN H H 1,4-CHD H d, 6.5ppm s, 8.9ppm N s, 8.3ppm N 1 12 28 30

0.8

0.6

0.4 Relative Amount

0.2

0 0 100 200 300 400 500 600 700 Time, min

Figure 23. Time evolution of the relative amounts of acetylene 12 (green diamonds), homoquadricyclane 28 (red hollow circles) and tricyclooctene 30 (blue triangles) during photolysis at 313 nm. Slight deviations from the ideal AÆBÆC kinetics are explained by the differences in the absorbance between compounds 12 and 28 and by the quenching effect of 30.

Quantum Efficiency for Formation of Homoquadricyclanes

Quantum yields for the loss of acetylenes and formation of tetracyclooctane and tricyclooctene adducts were determined for 1 mM acetylene solutions using trans-stilbene isomerization in benzene as the actinometer (φ = 0.5).175

112 The quantum yields in presence of 1,4-CHD (0.1 M) correlate well with the time necessary to complete the reaction (Table 10). Reaction efficiency increases in parallel with the electron acceptor ability of the substituents. 2-Py-TFP and 4-Py-TFP are more efficient than 3-Py-TFP and Ph-TFP, but the TFP moiety in non-symmetric acetylenes is, by far, the most effective in increasing quantum efficiency. In this context, the only seemingly surprising observation is that the quantum yield for the formation of homoquadricyclane from the Bis-TFP acetylene is only half of that for 4-Py-TFP acetylene.

Table 12. Quantum Yields for the Disappearance of Acetylene and Formation of Polycyclic Photoadducts.a

2 2 Acetylenes φ acetylenes × 10 φ tetracyclooctane × 10 2-Py-TFP, 6 33.0 ± 0.8 (15.2 ± 0.4) 32.5 ± 0.2 (6.5 ± 0.1) 4-Py-TFP, 8 31.9 ± 0.7 (21.5 ± 0.6) 30.5 ± 0.4 (19.6 ± 0.2) 3-Py-TFP, 7 18.6 ± 0.5 (6.7 ± 0.5) 8.3 ± 0.1 (2.9 ± 0.1) Ph-TFP, 10 17.8 ± 0.6 (6.0 ± 0.2) 5.2 ± 0.1 (1.2 ± 0.1) Bis-TFP, 9 22.5 ± 0.8 (50.2 ± 0.9) 18.4 ± 0.3 (51.2 ± 0.7) Bis-4-Py, 14 2.6 ± 0.9 2.8 ± 0.2 2-Py-PFB, 13 1.2 ± 0.4 0.52 ± 0.05 4-Py-Ph, 15 < 0.5 < 0.5 a Degassed solution in acetonitrile irradiated at 313 nm, 25.0 ºC; initial concentration of acetylene = 1.0 × 10-3 M and of 1,4-CHD = 1.0 × 10-1 M except for the values in parentheses which correspond to concentration of 1,4- CHD = 2.0 × 10-3 M; error limits are average deviation from the mean of several GC traces.

The cases of 2-Py-TFP, 4-Py-TFP and Bis-4-Py acetylenes 6, 8 and 14, respectively, are especially interesting. The quantum efficiencies for the three acetylenes are drastically different – substitution of TFP for Ph decreases the quantum yield by factor of 12 (Table 12). This suggests that the more electron deficient 4-Py-TFP triplet attacks 1,4-CHD noticeably faster. However, the quantum yields for the disappearance of the reactant and the appearance of the product are the same within experimental error in both cases. This indicates that formation of the tetracyclic product is the only photochemical pathway operating for both of these acetylenes and that every excited molecule of these substrates which is not deactivated through competing radiative and radiationless decay options follows an exclusive path to the homoquadricyclane product. In other words, every molecule which enters a reactive path is efficiently converted into the respective homoquadricyclane product.

113 Smaller quantum yields for product formation in the case of other acetylenes may indicate the presence of an intermediate undergoing a slower secondary photochemical process or simply formation of by-products along the thermal reaction paths. The highest observed values of quantum yields of ca. 0.5 indicate that the transformation involves no more than two photochemical steps. In other words, when all information about quantum yields is taken together, it suggests a stepwise process where all steps except for one or two are thermally activated. In the case of a sequential two-photon process, the intermediate should successfully compete for light with the starting material and react very efficiently.

18

16 y = 0.0255x + 3.2397 2 R = 0.9826

φ 14 1/ 12

10 y = 0.0072x + 3.1762 2 8 R = 0.9828

6

4

2

0 0 100 200 300 400 500

1/[1,4-CHD], M-1

Figure 24. Limiting quantum yields for the consumption of 2-Py-TFP acetylene 6 (solid line) and formation of the corresponding tetracyclooctane product 19 (dashed line); [2-Py-TFP] = 1.0 × 10-3 M.

We have also measured the quantum yields in presence of lower concentration of 1,4-CHD (2.0× 10-3 M) (Table 12 values in parentheses). In the case of the more reactive 4-Py-TFP acetylene 8, a 50-fold decrease in the 1,4-CHD concentration leads to only ca. 30% decrease in the quantum yields. The photocycloaddition of the less reactive 3-Py-TFP and Ph-TFP acetylenes 7 and 10 is more sensitive to the concentration of the diene and the same decrease in the 1,4-CHD concentration leads to ca. 60% decrease in the quantum efficiency. However, the most surprising behavior is displayed by the Bis-TFP acetylene 9 where the 50-fold decrease in the concentration of 1,4-CHD leads to more than 30% increase in the quantum yield for the

114 disappearance of the acetylene and to more than 3-fold increase in the quantum yield for the formation of the respective homoquadricyclane product. In order to understand this peculiar behavior, we have investigated the effect of 1,4-CHD concentration on the reaction with 2-Py- TFP and Bis-TFP acetylenes in more detail and determined the limiting quantum yields for these processes.

In the case of 2-Py-TFP acetylene 6, φlim for the consumption of acetylene and the formation of tetracyclooctane adduct were 0.32 ± 0.03 and 0.31 ± 0.05, respectively (Figure 24). These data are tabulated in Table 13. A linear relationship obtained when 1/φ was plotted against 1/[1,4- CHD] indicates that the mechanism does not change at higher concentrations of CHD.

Table 13. Quantum Yields for the Consumption of 2-Py-TFP 6 and Bis-TFP 9 Acetylenes and the Formation of the Tetracyclooctane Products at Different Concentration of 1,4-CHD.a

2 2 [1,4-CHD], mM φ acetylenes × 10 φ tetracyclooctane × 10 2-Py-TFP acetylene, 6 2.1 15.2 ± 0.4 6.5 ± 0.5 5.1 22.6 ± 0.3 13.0 ± 0.1 10.0 25.5 ± 0.1 14.9 ± 0.3 20.1 26.5 ± 0.1 19.8 ± 0.1 50.8 29.3 ± 0.6 30.7 ± 0.1 100.6 33.0 ± 0.8 32.5 ± 0.3 TFP-TFP acetylene, 9 2.1 50.2± 0.9 51.2 ± 0.7 6.3 42.6 ± 0.5 47.3 ± 0.6 11.3 32.4 ± 0.3 39.4 ± 0.4 29.1 28.6 ± 0.2 28.0 ± 0.1 47.2 26.4 ± 0.1 21.4 ± 0.2 84.5 27.7 ± 0.1 16.6 ± 0.1 117.2 22.5 ± 0.8 18.4 ± 0.3 a Degassed solution in acetonitrile irradiated at 313 nm, 25 °C; initial concentration of acetylene = 1.0 × 10-3 M; error limits are average deviation from the mean of several GC traces.

In sharp contrast, the analogous relationship between 1/φ and 1/[1,4-CHD] is clearly nonlinear in the case of Bis-TFP acetylene 9. Figure 25 compares the dependence of quantum yield for the formation of tetracyclooctane products for acetylenes 6 and 9. At 1.0 mM concentration of the

115 acetylene, the quantum efficiency of the photoaddition reaches its maximum at 2-5 fold molar excess of 1,4-CHD. The lower quantum yields at the higher concentrations of 1,4-CHD suggests a change in mechanism. GC analysis shows that new products are formed at higher concentration of 1,4-CHD at the expense of the tetracyclooctane adduct.

25 8

φ 1/

4 20

φ

1/ 0 15 0306090 1/[1,4-CHD], M-1

y = 0.0255x + 3.2397 10 R2 = 0.9826

5

0 0 100 200 300 400 500

1/[1,4-CHD], M-1

Figure 25. Limiting quantum yields for the formation of the tetracyclooctane products from 2- Py-TFP (hollow circles) and TFP-TFP (diamonds) acetylenes; [Bis-TFP] = 1.0 × 10-3 M.

Quantum Efficiency for Formation of Tricyclooctenes

Quantum yields were determined similarly for the photochemical reactions of TFP-pyrazine acetylenes (Table 14). The overall quantum yield for the formation of tricyclooctene from enediyne 3 is rather low (less than 0.01). We also determined the quantum yields for the two sequential steps of acetyleneÆhomoquadricyclaneÆtricyclooctene transformation separately. The first step is comparable in efficiency to photocycloaddition of pyridinyl acetylenes and has a similar dependence from the diene concentration as in the case of nonsymmetric Ar-TFP acetylenes. The quantum yields for the secondary transformation are in the order of 0.1, indicating a moderately efficient process.

116 Table 14. Quantum Yields for the Disappearance of Acetylene and Formation of Polycyclic Photoadducts in Pyrazinyl Acetylenes.a

2 2 2 Acetylenes φ-acetylenes × 10 φ-tetracyclooctane × 10 φ-tricyclooctene × 10 Pyra-2,3-TFP, 3 10.0 ± 0.4 - b 0.76 ±0.04c Pyra-2-Cl-3-TFP, 11 28.3 ± 1.1 (8.1 ± 0.1) 18.8 ± 0.4 (4.3 ± 0.1) 8.0 ±0.1d Pyra-2-TFP, 12 27.3 ± 0.3 13.6 ± 0.3 7.7 ±0.1d a Degassed solution in acetonitrile irradiated at 313 nm, 25.0 ºC; initial concentration of acetylenes = 1.0 × 10-3 M and of 1,4-CHD = 1.0 × 10-1 M except values in parentheses are for [1,4-CHD] = 2.0 × 10-3 M; error limits are average deviation from the mean of several GC traces. b Photoproduct not detectable, φ < 5 × 10-3. c The overall quantum yield for acetylene/CHD – tricyclooctene transformation. d Quantum yields determined for the photorearrangement of homoquadricyclane to tricyclooctene adduct.

Low Temperature Phosphorescence

Low temperature emission spectra of six acetylenes (four reactive and two unreactive) were recorded at 77 K in Pyrex NMR tubes in methylcyclohexane glass after three freeze/pump/thaw degassing cycles. Under these conditions, emission spectra of the acetylenes show two sets of signals (Figure 26). The set at the shorter wavelengths is a mirror image of the excitation spectrum and corresponds to the fluorescence spectrum whereas the second set of peaks at lower energy (λ>450 nm) corresponds to phosphorescence. Importantly, both the strong 0-0 band and the vibronic structure in the phosphorescence spectra of all acetylenes are almost identical to each other and to the literature spectrum of tolane 17.178 Such spectral similarity suggests that the electronic structures of the lowest triplet excited states are close as well and indicates a πX→πX* absorption. Although phosphorescence could not be sensitized in glassy methylcylohexane through triplet energy transfer using conventional triplet sensitizers (benzophenone, ET = 68 kcal/mol; 177 acetophenone, ET = 74 kcal/mol; and xanthone, ET = 74 kcal/mol), we found it to be sensitive to the presence of MeI (Figure 26).viii Remarkably, adding MeI175 to the methylcyclohexane glasses enhanced initially very weak phosphorescence of reactive acetylenes 6, 9, 10 and 12 (at the expense of their fluorescence) but did not lead to a similar phosphorescence enhancement in the case of unreactive Ph-PFB 18 and Ph-Ph acetylenes 17. These differences between reactive

viii 20 microliter of MeI was added to 1.0 mL of acetylene solution.

117 and unreactive acetylenes further suggest that intersystem crossing (ISC) efficiency and the dynamics of triplet state formation are important for the homoquadricyclane formation.

(a) 8000 F F 1400

N 700 10 F F 6000

0 λ , 330 nm 425 450 475 500 525 550 575

Relative Intensity Intensity Relative det 4000

λexc, 300 nm λexc, 313 nm 2000

0 200 250 300 350 400 450 500 550 600

Wavelength, nm

(b) 8000 F F F F

N N

F F 9 F F 6000

λdet, 357 nm λexc, 300 nm 4000 Relative Intensity Intensity Relative λ , 300 nm exc

2000

0 200 250 300 350 400 450 500 550 600

Wavelength, nm

Figure 26. Excitation (dotted red line) and emission (solid blue line) spectra from 10-5 M of acetylene solutions in the absence and presence of methyl iodide (dashed green line): (a) Ph-TFP 10; (b) Bis-TFP 9; (c) Pyra-TFP 12; (d) 2-Py-TFP 6; (e) Tolane 17; (f) Ph-PFB 18 in frozen methylcyclohexane glass (77 K). Both excitation and detection wavelengths are shown.

118 (c) 8000 F F N N λexc, 300 nm N 12 F F 6000

Relative Intensity Intensity Relative 4000 λ , 300 nm exc λdet, 479 nm

2000

0 200 250 300 350 400 450 500 550 600

Wavelength, nm

(d) 1200 8000 F F N N

6 F F 600 6000

0 440 465 490 515 540 4000 Relative Intensity Intensity Relative λ , 326 nm det λexc, 300 nm λexc, 300 nm 2000

0 200 250 300 350 400 450 500 550 600

Wavelength, nm

Figure 26. Continues

119 (e) 8000 110 0

17 550 6000

λdet, 324 nm 0 4000 445 465 485 505 525 Relative Intensity Intensity Relative

λexc, 300 nm 2000 λexc, 300 nm

0 200 250 300 350 400 450 500 550 600

Wavelength, nm

(f) 8000 F F 600

F

18 F F 300 6000

0 440 480 520 560

Relative Intensity 4000 λdet, 326 nm λexc, 300 nm 2000 λexc, 290 nm

0 200 250 300 350 400 450 500 550 600

Wavelength, nm

Figure 26. Continues

Laser Flash Spectroscopy Studies

Transient absorption of diaryl acetylenes under laser flash photolysis (LFP) using 266 nm excitation was monitored at 450 nm. The triplet lifetimes were determined by fitting the decays

120 with a single or, when necessary, a double exponential function. The results for selected excited acetylenes in argon and oxygen saturated acetonitrile solutions are shown in Table 15.

o Table 15. Lifetimes of Excited Species Determined by LFP, CH3CN, 25 C in Argon and Oxygen Saturated Saturated Solutions.

Argon Saturated Oxygen Saturated Acetylene τ1 (µs) τ2 (µs) τ1 (µs) τ2 (µs) 2-Py-TFP, 6 71.8 - 24.0 - Ph-TFP, 10 4.06 - < 1.5 - Ph-PFB, 18 25.6 5.2 < 1.5 - Pyra-TFP, 12 22.6 4.36 10.8 < 1.5 TFP-TFP, 9 1.82 - < 1.5 - 4-Py-4-Py, 14 1.72 - < 1.5 -

Interestingly, 2-Py-TFP acetylene 6 which has triplet excited state with the longest life time also has the highest cycloaddition quantum yield. In all of the cases, saturation of solutions with oxygen leads to noticeable decrease in the lifetime of the excited species. It is worth mentioning that argon saturated solutions of acetylenes changed color after flash spectroscopy (yellowish in the case of Ph-TFP acetylene and yellow reddish in the case of 2-Py-TFP acetylene). The color change is less pronounced in oxygen saturated solutions. This indicates that the acetylenes reacted when irradiated with the laser pulse and that the reactive species, presumably the triplet excited state of the acetylene, is quenched with oxygen. We found that dimerization of acetylene is the major reaction when acetylene were irradiated in absence of 1,4-CHD (Scheme 30).

Scheme 30. Photochemical Dimerization of Diaryl Acetylenes F F TFP X R hν 2 N CH CN 3 X TFP F F X = CH, R = Ph, 35% X = N, R = 2-Py, 20% The 1,2,3-triarylnaphthalene product is most likely formed from the triplet excited state of acetylene which reacts with another acetylene where one of the radical centers attacks the aryl ring followed by a 1,5-hydrogen shift (Scheme 31). The structure of the product was determined

121 by 1H NMR spectroscopy and confirmed by X-ray crystallography (Figure 27). Similar product was observed in the case of 2-Py-TFP.

Figure 27. Ball and stick representation of 1,2,3-triarylnaphthalene. The crystal used in the X- ray analysis was not suitable for achieving good structure optimization.

Interestingly, the triplet states of more electron-deficient 2-Py-TFP 6 and Pyra-TFP 12 acetylenes are quenched by oxygen rather inefficiently compared to the triplet of Ph-PFB 18 acetylene. The slower quenching is consistent with different electronic properties of the respective triplet states, e.g., higher electrophilicity and greater oxidative potential of the TFP triplets.179-182 Unfortunately, the two symmetric acetylenes have lifetimes shorter than our instrument response which precluded us from estimating the efficiency of triplet quenching with oxygen using available instrumentation. The efficiency of singlet oxygen formation has been 183 used in the literature as a tool to study electronic properties and nature of T1 states. For example, these efficiencies vary from 0.3 to 0.5 for n-π* excited ketones,123, 184-187 whereas in the cases of π-π* excited ketones and π-π*excited aromatic hydrocarbons, these values are generally close to unity (0.8-1).188

Scheme 31. Photodimerization of Diaryl Acetylenes

TFP TFP H TFP . H Ph Ph . 1,5-hydrogen Ph hν . Ph TFP shift TFP TFP . TFP

These data suggest that, besides the ISC efficiency, sufficiently long triplet lifetime and electron deficiency of triplet state are the two conditions favoring the photocycloaddition. In the

122 ideal case of 2-Py-TFP acetylene, both of these conditions are satisfied. In the case of short-lived triplets, the role of electrophilicity becomes essential as illustrated by comparison of the results for the two symmetric acetylenes 9 and 14: although the lifetimes of Bis-TFP 9 and Bis-4-Py 14 triplets are very close, the quantum yield for the formation of homoquadricyclane product is considerably higher in the case of the more electron deficient and, thus, more reactive Bis-TFP acetylene.

DISCUSSION

Aryl Substituent Effect on the Photocycloaddition Reaction

Although the presence of the strong acceptor TFP moiety is beneficial and leads to the more efficient photocycloadditions (especially in nonsymmetric acetylenes) the electron deficiency and overall polarization of the triple bond per se are neither necessary nor sufficient for the reaction to occur. For example, the highly polarized Ph-PFB acetylene 18 does not react whereas a symmetric Bis-4-Py acetylene 14 undergoes photoreaction with 1,4-CHD which proceeds relatively slow but in a high yield. Since the ground state polarization of the triple bond is not a prerequisite for the cycloaddition, the lack of reactivity in the case of tolane lies elsewhere. Taken together, these trends in reactivity suggest that presence of a nitrogen atom in a six- membered aryl ring represents a key requirement for the photocyclization. An intriguing possible rationale for these observations is that the reactivity of diarylacetylenes correlates with the availability and electronic structure of n,π* excited states in pyridinyl/pyrazinyl acetylenes and with the absence of this state in diphenylacetylenes lacking nitrogen atoms. The presence of the nitrogen atom may allow entry to triplet intermediates of a different electronic nature and, thus, provides an alternative to carbonyl- and carboxy- substituted acetylenes. Two mechanisms for the n,π* state involvement are possible. The most obvious route is a direct change in the nature of the reactive excited state from π,π* to n,π* - the two states which are well-known to have different reactivities.189 The second indirect possibility is based on differences in photophysical properties of the involved states – such as different

123 efficiencies of the reactive triplet state formation which may be based on the differences in the ISC rates between π,π* singlet excited state and the n,π* and π,π* triplets.190

Nature of the Excited States

The spin multiplicity of the excited state involved in the formation of polycyclic photoadducts and their subsequent rearrangement was determined using quenching and sensitization experiments. Whereas the homoquadricyclaneÆtricyclooctene rearrangement is not affected by triplet sensitizers and quenchers and, thus, should proceed through a singlet excited state, formation of homoquadricyclanes can be sensitized by benzophenone (ET = 68 kcal/mol) and acetophenone (ET = 74 kcal/mol) and quenched by azulene (ET = 39 kcal/mol) and molecular oxygen. For instance, non-degassed samples showed significant decrease in conversion than degassed samples under identical conditions (Figure 28). The latter observation is important from a practical point of view because, due to the quenching effect of oxygen, degassing is essential for reaching high conversions and reaction yields.

35.00

30.00

25.00

20.00

15.00 % Product Yield 10.00

5.00

0.00 Pyra-TFP Pyra-TFP 3-Py-TFP Pyra-Cl-TFP [1,4-CHD] = 0.5 M [1,4-CHD] = 2.1 M [1,4-CHD] = 2.10 M [1,4-CHD] = 2.1 M

Degassed Not Degassed

Figure 28. Oxygen effect on conversion of acetylenes to the corresponding homoquadricyclane products; [Pyra-TFP] = 1.08 × 10-3 M, [3-Py-TFP] = 1.10 × 10-3 M and [Pyra-Cl-TFP] = 1.06 × 10-3 M.

Interestingly, despite the accelerating effects of the acceptor groups mentioned above, the reaction can be performed not only in polar solvents (acetonitrile) but also in non-polar solvents (cyclohexane). The quantum yields for the conversion of Pyra-TFP acetylene 12 was determined

124 in acetonitrile and in cyclohexane to be (27.3 ± 0.4) × 10-2 and (26.9 ± 0.3) × 10-2, respectively. Together, these results clearly suggest that the photocycloaddition step proceeds through an acetylene triplet excited state without formation of charged intermediates.

Competition between Triplet and Photoelectron Transfer Pathways

Fast intersystem crossing (ISC) to the triplet excited state is likely to be responsible for the absence of radical-anionic C1C5 cyclization in the case of enediyne 3. Fast ISC rate in this molecule is consistent with the drastically reduced quantum yield of fluorescence in the pyrazine enediynes (0.01 for 3 vs. 0.90 for 1).ix Electron transfer from cyclohexadiene to the lower energy triplet excited state of enediynes is less favorable than photoelectron transfer (PET) to the singlet excited state of enediyne 3.

Table 16. Reduction Potentials, Energies of Singlet and Triplet Excited States and PET Free Energies for Selected Diaryl Acetylenes.

- a *b *b *c *c Acetylenes Epc A/A (V) ES ET ∆GET ,S ∆GET ,T Ph-PFB, 18 -2.1 93 62 -5.7 25.2 2-Py-TFP, 6 -1.4 88 63 -16.9 8.1 Ph-TFP, 10 -1.6 90 62 -15.4 14.6 TFP-TFP, 9 -1.0 85 64 -23.1 -2.1 Pyra-TFP, 12 -1.2 89 61 -21.4 6.6 a The reduction is irreversible, peak potentials are measured vs SCE in DMF, [acetylene] = 1× 10-2 M. b Values in kcal/mol estimated from low temperature fluorescence and phosphorescence spectra. c Values in kcal/mol + calculated from the Rehm-Weller equation taking wp = 1.3 kcal/mol, and E1/2 (D /D) = 1.74 (vs. SCE) for 1,4- CHD.

The thermodynamics of the PET can be calculated using the Rehm-Weller equation:191

+ - ∆GET = 23.06 [E1/2 (D /D) - E1/2 (A/A )] - wp - ∆G00 where ∆GET is the energy of electron transfer (ET) process, E1/2 are oxidation and reduction potentials for the donor (D) and acceptor (A), and ∆G00 is the excited state energy; E1/2 (1,4- 192 CHD) = 1.74 V (vs. SCE) , E1/2 (3) = -1.07 V (vs. SCE), E1/2 (1) = -1.22 V (vs. SCE).

According to this estimate, ∆GET is equal to -26 and +3 kcal/mol respectively for the singlet and

ix Measured by Professor J. Kauffman at the University of Missouri-Columbia.

125 triplet excited states of enediynes 3 (Table 16). In order to estimate efficiency of PET in these systems, quenching of fluorescence of Bis-TFP acetylenes 9 with 1,4-CHD was investigated in acetonitrile and cyclohexane (Figure 29).

2500000

2000000 Increase [1,4-CHD]

1500000 Relative Intensity Intensity Relative

1000000

500000

0 280 320 360 400 440 480 520 560

Wavelength, nm

Figure 29. Quenching of the fluorescence of Bis-TFP acetylene 9 by 1,4-CHD in acetonitrile at room temperature irradiated at 285 nm; [Bis-TFP] = 2.02 × 10-4 M.

4 Et 3N (Acetonitrile) y = 109.83x + 0.9832 1,4-CHD (Acetonitrile) 2 y = 78.986x + 1.097 R = 0.9989 3 R2 = 0.9902 /A 0 A

2

1,4-CHD (Cyclohexane) y = 50.976x + 1.0259 1 R2 = 0.9906

0 0 0.005 0.01 0.015 0.02 0.025 0.03 0.035

3 [1,4-CHD]*10 , M

Figure 30. Stern-Volmer plots for fluorescence quenching of Bis-TFP acetylene with 1,4-CHD in acetonitrile (diamonds) and cyclohexane (squares) and with Et3N in acetonitrile (triangles).

126 Stern-Volmer plots are linear with slopes of kqτ = 79 and 51 M in acetonitrile and cyclohexane, respectively (Figure 30). Since the excited states of 1,4-CHD are higher in energy than the respective excited states of the acetylene, electron transfer should be the main photophysical mechanism for fluorescence quenching. Consistent with this notion, the quenching is ca. 5 times less efficient in cyclohexane than in acetonitrile (assuming that the lifetimes are similar in the two solvents). Stern-Volmer plot for a much stronger donor, Et3N, (∆GET = -30 kcal/mol) shows 40% increase in the efficiency of fluorescence quenching indicating that PET in the case of 1,4-CHD is very fast but not diffusion controlled.

Scheme 32. Competing Photophysical Pathways for the Reaction of 1,4-CHD and Diaryl Acetylenesa S1

D 21 ISC PET 23

T1 85 D+ Ac-...D+

S0

a Energies of states relative to S0 are given in kcal/mol for the case of Bis-TFP acetylene 9 in acetonitrile; (D=donor) (Ac=Acetylene)

These results provide an explanation for the “anomalous” plot in Figure 25 and show that reaction efficiency is a compromise between the rate of intersystem crossing forming the reacting triplet and unproductive interception of the singlet excited state through electron transfer from 1,4-cyclohexadiene (Scheme 32). In the case of the strongly acceptor Bis-TFP acetylene 9 and high concentrations of 1,4-CHD, PET successfully competes with ISC leading to the observed decrease in cycloaddition efficiency. For the less electron deficient acetylenes, this competition is less important (Table 16).

Reaction Mechanisms: Formation of Homoquadricyclanes

Literature reports describing the photochemical transformation of acetylenes into homoquadricyclanes are scarce. There are no mechanistic studies aimed at elucidation of factors controlling the efficiency of this reaction as well as the nature of excited states (singlet vs.

127 triplet) involved in this transformation. The reaction yields are generally low and quantum yields for the formation of the products were never measured. The only conclusion regarding the reaction mechanisms which could be derived from the earlier literature data is that formation of homoquadricyclanes from acetylenes requires the presence of a C=O moiety in the excited reagent, either in the diene or in the acetylene. This observation supports the notion that presence of a long lived and electron deficient triplet excited state is essential for these photocycloadditions and agrees well with our experimental data for diarylacetylenes. One can also speculate that the other key requirements are efficient formation of the triplet state upon excitation and inefficient ISC of the triplet 1,4-diradical intermediate formed by addition of excited acetylene to alkene to its singlet counterpart. Depending on their conformation, singlet 1,4-diradicals are expected to undergo either the Grob fragmentation or to close into the cyclobutene products (Scheme 33).193

Scheme 33. Most Common Reactions of Singlet 1,4-Biradicalsa . . .

.

a Differences in hybridization of non-bonding orbitals at sp3 and sp2 carbon centers are neglected

Although the phosphorescence studies suggest that all diaryl acetylenes have lowest excited states of similar nature, the oxygen quenching in LFP experiments and contrasting MeI effects on phosphorescence suggest that differences in dynamics and electronic properties exist between reactive and unreactive acetylenes. Computational analysis of these species using unrestricted B3LYP/6-31(d,p) methods predict that the energies of all of the excited triplet states of acetylenes are quite close and all of the triplet states are dominated by π-π* configuration.194 As a result, one has to ask the question about the origin of the dramatic difference in reactivity of pyridinyl and pyrazinyl acetylenes and whether the presence of higher energy n,π* state in azaheterocycles play any role in this phenomenon. Since 3n,π* is not the lowest triplet state, it should undergo fast radiationless decay into the lowest energy 3π,π* state in accordance with the Kasha’s rules195-198 and, thus, is unlikely to play a direct role in photochemical reactivity. However, its presence plays an important role in the

128 efficiency of 3π,π* triplet excited state formation. In seminal studies, El-Sayed had shown that the first order spin-orbit coupling (SOC) is forbidden between states of the same configuration and developed a set of selection rules, commonly known as El-Sayed rules, for ISC in compounds possessing π-π* and n-π* states. El-Sayed postulated that transition between 1π,π* and 3n,π* states in nitrogen-containing heterocyclic molecules proceeds up to three orders fold faster (~10-9 s) in pyridines than ISC between 1π,π* and 3π,π* states (~10-6 s) and radiative decay back to the ground state (~10-7 s). Since transitions between 3π,π* and 3n,π* are known to be very fast (~10-11 s), the overall effect of the 3n,π* state presence is a dramatic increase in the

efficiency of S1ÆT1 triplet state formation (Scheme 34). This increase effectively “blocks” side reactions associated with singlet excited state reactivity.

Scheme 34. The Role of a “Phantom” 3n,π* State in Enhancing ISC in Diaryl Acetylenes

S1 π-π* T n Fast 3n,π* Very fast Slow [2+2] and T1 ISC other byproducts 3π,π*

S0 Several photochemical routes summarized in Scheme 35 can account for the formation of homoquadricyclane adducts. In every case, the initially formed first singlet excited state of diaryl acetylenes (S1) undergoes intersystem crossing (ISC) to the first triplet excited state (T1). High efficiency of ISC is consistent with the drastically reduced fluorescence and with the observed lack of photochemical reactivity (C1C5 cyclization) derived from PET from 1,4-CHD to the enediyne moiety of 3. Unlike the highly exothermic PET to the singlet excited state, PET from 1,4-CHD to the triplet excited state becomes endothermic due to the lower energy of the latter state, vide supra. In contrast with the earlier photochemical reactions of enediynes where 1,4- CHD serves as a source of electrons and/or hydrogen atoms, the triplet excited state of enediyne 3 and related monoacetylenes finds yet another way to engage 1,4-CHD in a photochemical reaction by attacking one of the two double bonds of cyclohexadiene moiety. Although lack of PET from 1,4-CHD is readily explained by the lower energy of triplet state, the switch from

129 hydrogen-atoms abstraction to the attack on the π-system provides direct insight into the electronic structure of the triplet acetylenes and deserves an additional comment.

Scheme 35. Suggested Mechanism of the Homoquadricyclanes Formation in Photocycloaddition of Diaryl Acetylenes to 1,4-CHDa

. . Ar2 Ar1 . . 3-exo Ar Ar 2 ISC 1 A 33-endo 33-exo

Ar Ar . . Ar2 1 1 Ar ISC hν ISC . 2 Ar S * . 1 1 . Ar 37 Ar 5-exo 1 38 2 . Ar C Ar2 2 Ar1 32 T * ISC 1 . hν 3-exo Ar2 B . Ar1 . 35 ISC

Ar2 ISC Ar Ar 2 . 1 Ar 34 36, endo or exo 1

a Note that Intersystem Crossing (ISC) should occur somewhere along the reaction hypersurface in order to reach the final product 37. The lack of [2π+2π] adducts suggests that ISC occurs after the initially formed diradical 32 undergoes one of the further steps in the cyclization cascade. Five possible ISC points are shown but it is possible that ISC occurs even before these points.

In general, such a competition between hydrogen-atom abstraction and addition to a double bond is a typical feature of radical processes. Although radicals can participate in both of the above reactions, they often exhibit a preference towards a particular pathway depending on their nucleophilic or electrophilic character.199-204 The fact that triplet acetylenes choose for the attack a position of increased electron density (the π-bond) rather than the partially positive hydrogen atom of C-H bonds strongly suggests electrophilic nature of the triplet diaryl acetylenes, a notion which is in a perfect agreement with the observed quantum yield increase for acetylenes with electron acceptor substituents (Table 12). After addition of the triplet acetylene to the double bond, the initially formed diradical intermediate 32 can undergo three different intramolecular cyclizations. In the most “economic”

130 mechanism A, the radical on the cyclohexenyl moiety “comes back” to the former acetylenic moiety in a 3-exo-trig fashion205-207 with formation of a carbene 33. Insertion of the carbene into the remaining double bond will lead directly to the tetracyclooctane adduct 37. The insertion can be either stepwise or concerted depending on the multiplicity nature of the carbene (triplet or singlet carbene), which, in turn, is determined by the relative ISC timing. The carbene mechanism is supported by an earlier finding that photochemical reaction of 1,2-dimethyl acetylenedicarboxylate with ethylene128 resulted in a 9:1 mixture of cyclobutene and dicyclopropane adducts where the latter product was suggested to be formed through a similar cyclopropane-carbene intermediate (Scheme 19c).

Scheme 36. Photocycloaddition of Diaryl Acetylenes to Olefins F F N hν F Py TFP + CH3CN Py

Ar hν Ar Ar Ar' + + CH CN 3 Ar' Ar = Py, Ph Ar' Ar' = TFP, PFB [2+2] hν Photoycloaddition -HF Dehydrodehalogenation Ring opening

F F N F F N F hν F F F Photocyclization H

The main problem with extending this mechanism to our system is that in the intramolecular version of this process the first cyclization step should lead to formation of a mixture of two carbene isomers (exo- and endo-) shown in Scheme 35 and, according to the simple geometric considerations, only one of these isomer can insert into the double bond. Although the “unreactive” isomer 33-exo can be “recycled” back to the 1,4-diradical 32, one would expect

131 that if carbene 33 and diradical 32 were in an equilibrium, the latter would sooner or later undergo ISC to a ground state 1,4-diradical which should close to the cyclobutene product of formal [2π+2π] cycloaddition. We do not observe such a product as well as any other products derived from 33-exo carbene in reactions with cyclohexadiene. The [2π+2π] adducts are readily formed in reactions with alkenes such as cyclohexene and tetramethyl ethylene (Scheme 36). In the case of reaction with cyclohexene, the initially formed cyclobutene product reacts under further irradiation and undergoes a facile photocyclization with concomitant dehydrodehalogenation reaction and form the phenantherene adduct. These reactions are well known in literature especially for cis-stilbene like compounds.208, 209 In a recent work, Tomioka et al. had shown that triplet diaryl carbenes readily abstract hydrogen from 1,4-CHD.210 Our effort to trap the carbene intermediate by insertion into an O-H bond also failed.211 Irradiation of acetylene in presence of allyl alcohol or 3,3-dimethyl allyl alcohol form the cyclobutene adduct (Scheme 37) the expected [2π+2π] addition of acetylene to olefins. Similarly, photocyclization-dehydrodehalogenation reaction follows and the major product is a phenanthrene adduct. It is noteworthy that this latter molecule are interesting especially as DNA intercalators due to their planarity nature.212, 213

Scheme 37. Photocycloaddition of Diaryl Acetylenes to Allyl Alcohol F F N TFP R R Ph R R Ph hν F O + OH + X R R CH3CN OH TFP Ar' TFP Ar R = H, CH 3 In a second possible mechanism B, the radical at the cyclohexene moiety of 32 reacts via another 3-exo-trig pathway with the remaining double bond of 1,4-CHD to give a new diradical 34. The newly formed radical centers can combine after ISC to give a stable intermediate 36. Control experiments ruled out thermal homo-Diels-Alder reaction between 1,4-CHD and acetylene which is the other way to form compound 36. This intermediate would require further photochemical excitation in order to undergo a [2π+2σ] transformation to the homoquadricyclane product.214

132 The final possibility C is the 5-exo-trig cyclization of the vinyl radical 32 leading to a 1,3- diradical 35. According to the empirical “rule of five”215-218 which is a paraphrase of the Baldwin rules,219 this should be the most likely pathway. This cyclization opens two new directions. In the first, the diradical undergoes ISC and closes to form the cyclopropane 36 which needs to absorb another photon for the transformation to the final product 37 as described in the previous paragraph. Alternatively, one of the radical centers of 35 reacts with the double bond to give diradical 38, and the two radical centers recombine only at the final stage providing the homoquadricyclane product 37. In this process, each of the two unpaired electrons generated at the triple bond by photochemical excitation eventually comes back to the same carbon atoms as a boomerang. Again, ISC is needed somewhere along this reaction path to arrive to the final product.

Scheme 38. Retrosynthetic Analysis of the Photochemical Approach to Homoquadricyclanes Based on the Triplet Photocycloaddition of Diaryl Acetylenes and 1,4-CHD

Ar1

C C Ar1 . . . . Ar2 4 unpaired electrons Ar1 Ar 2 2 π-bonds Ar 2

Scheme 39. Topological Analysis of the “Boomerang” Reaction of Vinyl-1,2-diyl with Two Double Bonds

hν

a b c

Triplet diradical is formed, (b) Two new sigma bonds and two new radicals are formed at the expense of two π-bonds of 1,4- CHD, c) The new radical centers complete the cyclic bond-forming route

Our computational studies suggest that , at least, two converging pathways may be responsible for the formation of the observed products, the bulk of computational results does suggest that 5- exo cyclization at the triplet hypersurface is the most likely reaction pathway. It is possible that ISC may also be important in controlling the partitioning between the alternative mechanisms.220- 228 However, from a practical perspective, all of the mechanisms converge to the same product and differ only in a sequence of bond-forming steps and, thus, topologically, one can think about

133 this transformation as cyclopropanation of both double bonds of a 1,4-diene by a 1,2-bicarbene synthone (Scheme 38). Mechanistically, this transformation occurs through a “boomerang” reaction of a vinyl-1,2-diyl diradical with two double bonds where the two radical centers “self- annihilate” after completing a circular cascade of bond-forming events (Scheme 39).

Reaction Mechanisms: Homoquadricyclanes-Tricyclooctene Rearrangement

The most probable mechanism for the transformation of homoquadricyclanes to the tricyclo[3.2.1.04,6]oct-2-enes is shown in Scheme 40. Photochemical excitation of homoquadricyclane 37 results in the regioselective C-C rupture in the cyclopropyl group attached to the pyrazinyl ring and formation of 1,3-diradical 39. The source of this selectivity is unknown at this moment but is perfectly consistent with the absence of homoquadricyclane- tricyclooctene rearrangement in the case of pyridinyl substituted homoquadricyclanes. This process is likely to proceed through a singlet excited state. The reaction yield is not affected when the rearrangement is performed in presence of triplet quencher such as azulene or molecular oxygen. Similarly, there was no improvement when sensitizers such as benzophenone, acetophenone or xanthone, were added to the reaction mixture. This transformation is followed by a 1,2-carbon shift directly leading to tricyclooctene 40.

Scheme 40. Secondary Photochemistry of Pyrazinyl Homoquadricyclanes

C1-C2 Ar hν Ar alkyl shift 2 2 Ar2 Ar = Pyrazine . Ar1 1 Ar1 . Ar1 37 39 40

Ar 2 Ar2 Ar 1 Ar 1

134 PHOTOCYCLOADDITION REACTIONS OF DIARYL ACETYLENES WITH HETEROAROMATIC FIVE-MEMBERED RING COMPOUNDS

So far, we have shown that a new family of diaryl acetylene, where at least one of the aryl groups bears a nitrogen atom in its ring, undergoes photocycloaddition to 1,4-CHD. Unlike the reactions reported in literature, the yield for the photochemical cycloaddition is excellent and the quantum efficiency can reach 0.5 for some cases. Intrigued by these results, we decided to expand the scope of our studies to include photochemical reaction with five-membered heteroaromatic compounds that can be considered as “masked dienes”. In this section, we describe our results on photocycloaddition of diaryl acetylenes to thiophene and furan. As mentioned earlier in the introduction section, photochemical addition of acetylene to fused heteroaromatic compounds were investigated extensively in literature, vide supra. The major products in these reactions are cyclobutene products formed via a [2π+2π] addition of the acetylene and the carbon-carbon double bond of the five-membered heteroaromatic ring. However, it has been reported that these cyclobutene products are prone to secondary photochemical and thermal rearrangements.

Reactions with Thiophene

In 1969, Neckers et al. reported the photochemical reaction of dimethyl acetylenedicarboxylate to benzo[b]thiophenes.229 The authors proposed that the cyclobutene product is initially formed by a [2π+2π] photocycloaddition followed by a photorearrangement (Scheme 25). Later the same year, Sasse et al. reported the photocycloaddition reaction of tolane to benzo[b]thiophenes, and isolated the cyclobutene product formed from simple [2π+2π] photocycloaddition, in addition to the rearranged isomer.156 In both studies, the cyclobutene adducts undergo facile thermal sulfur exclusion to form 1,2-disubstituted naphthalenes. Mechanistic studies suggest that the photocycloaddition occurs from the triplet excited state of benzo[b]thiophene and results in the formation of the unrearranged cyclobuytene adduct which irreversibly rearranged to the isolated major product.160, 161

Irradiation of pyridinyl acetylenes in acetonitrile at 313 nmiii formed the corresponding rearranged cyclobutene 41 (3-8%), the 1,2-diaryl benzene 42 (3-60%) and a triphenylene derivative 43 (3-16%) in relatively low yields (Scheme 41 and Table 17, entries 1-3).

135 Analogous to the mechanism described in Scheme 36 for the formation of the triphenylene products from photocycloaddition of diaryl acetylenes and olefins, vide supra, the triphenylene derivatives, 43, arise from the photochemical dehydrodehalogenation reaction of 1,2-diaryl benzene 42. The latter product is most likely to be formed by sulfur-atom exclusion either from the cyclobutene product 41 or from another intermediate formed in the photochemical process.

Scheme 41. Photocycloaddition of Diaryl Acetylenes with Thiophene

Ar' Ar 1 2 Ar Ar S S 1 1 hν Ar1 Ar2 + + + CH CN 3 Ar2 Ar' 41 42 43 2 Ar = 2-Py, 3-Py, 4-Py, TFP 1 hν Ar2 = TFP, 4-Py -HF

Table 17. Conditions and Yields for the Photochemical Cycloaddition of Acetylenes to Thiophene.a,b

Isolated Products Irradiation Time Ratio of Entry Acetylene Solvent Additive (% Yields) (hrs) 41:42d SMc 41 42 43 1 2-Py-TFP 18 Acetonitrile - 11 2 3 3 1:1 2 3-Py-TFP 10 Acetonitrile - - 8 16 13 1:2 3 Bis-4-Py 35 Acetonitrile - - 2 20 - 1:8 4 Ph-TFP 15 Acetonitrile - 13 - 3 3 0:1 5 Ph-PFBe 45 Acetonitrile - 85 - - - - 6 2-Py-TFPf 10 Cyclohexane - 5 - trace - 0:1 7 Bis-TFP 8 Acetonitrile - 1 10 65 - 1:5 8 Bis-TFP 8 Cyclohexane - 2 trace 25 - 1:10 9 Bis-TFPg 8 Cyclohexane Azulene 8 3 6 - 1:2 10 Bis-TFPf 8 Acetonitrile Azulene 10 - - - 1:1 a Irradiation was performed at 313 nm in acetonitrile at 25ºC; initial [acetylenes] = 1.0 × 10-3 M and [thiophene] = 0.1 M. b Ph = Phenyl, Py = Pyridinyl, TFP = Tetrafluoropyridinyl, PFB = Pentafluorobenzene. c Percentage for the recovered unreacted acetylene. d Ratio determined from 1H NMR spectra of the reaction mixture. e Starting material was recovered f Products were not separated from the reaction mixture. g The unrearranged product 44 was isolated in 3% yield.

136 Although the photochemical reactions described in literature formed similar products, it is important to notice that the excited species are not the same. Neckers et al. studied the photocycloaddition of excited benzo[b]thiophene which, according to the authors, undergoes ISC to the triplet state which adds to the acetylenes. However, in our studies, irradiation is performed at a wavelength (313 nm) where only the acetylene molecules absorb but not thiophene. For that reason, we decide to investigate in more details the photocycloaddition reaction of diaryl acetylenes and thiophene. We aimed to verify whether the mechanism described in literature is relevant to our system or another path that leads to the same products is possible through the excited acetylene. In parallel with the results for photocycloaddition of acetylene to 1,4-CHD, irradiation of Ph- PFB acetylene with thiophene for 45 hrs in acetonitrile lead to total recovery of the acetylene (Table 17, entry 5). Moreover, Bis-TFP acetylene was the most reactive among the acetylene and formed the two major products 41 and 42 in 10 and 65% yield, respectively (Table 17, entry 7). However, unlike the reaction with 1,4-CHD, 3-Py-TFP acetylene reacted with thiophene more efficiently than 2-Py-TFP acetylene with higher yields and shorter irradiation time (Table 17, entries 1 and 2). On the other hand, irradiation of Ph-TFP acetylene with thiophene formed only 42 and 43 as the sole detected products in the reaction mixture with no trace for the cyclobutene adduct (Table 17, entry 4). When the irradiation was performed in cyclohexane (a non-polar solvent) 1,2-diaryl benzene 42 was formed almost exclusively (Table 17, entries 6 and 8). In the case of Bis-TFP acetylene, the non-polar solvent favored the formation of 1,2-diaryl benzene 42 over the cyclobutene product 41 (Table 17, entries 7 and 8). However, when these reactions were 177 repeated in presence of azulene as a triplet quencher (ES ∼ 40 kcal/mol and ET ∼ 30 kcal/mol) both products were formed in almost equal amounts (Table 17, entries 9 and 10). Interestingly, irradiation of Bis-TFP acetylene with thiophene in presence of azulene in cyclohexane formed, in addition to 41 and 42, the unrearranged cyclobutene product 44 which was isolated in 3% yield (Table 17, entries 8). These results enabled us to confirm whether the rearranged cyclobutene product 41 is a result of a secondary photorearrangement of its cyclobutene 44 or there is another path for its formation. Indeed, irradiation of cyclobutene 44 in acetonitrile leads to its complete rearrangement to isomer 41 within few minutes (Figure 31) But when the reaction mixture was exposed to extended time of irradiation, the rearranged cyclobutene product 44 disappears from the reaction mixture with not evidence for formation of

137 a new compound. This observation suggests that cyclobutene 44 is photo-unstable and explains the low yield in these photochemical reactions. Furthermore, these results indicate that cyclobutene isomers 41 and 44 are not precursors for 1,2-diaryl benzene 42, thus different mechanism might be responsible for the formation of 42.

Ha TFP TFp TFP S S hν Hd Hd' TFP Hb' Ha' Hc Hb Hc' 44 41

time = 0 min

Ha' Hd' Hd Hc Hc' Ha Hb Hb' time = 3 min

time = 4 min

time = 5 min

time = 6 min

7.00 6.50 6.00 5.50 5.00 4.50 4.00 ppm(t ) 1

Figure 31. Photorearrangement of cyclobutene adduct 44 to 41 monitored by 1H NMR in CD3CN.

Although more conclusive experiments are needed to elucidate the mechanism for photocycloaddition reactions of diaryl acetylenes and thipohene, based on our preliminary results, we propose that thiophene reacts with diaryl acetylenes in two different ways. The first one is through the triplet excited state of diaryl acetylene. We have shown in previous sections that singlet diaryl acetylenes undergo fast intersystem crossing (ISC) to the triplet state due to the presence of the “phantom” n,π* triplet state. Similar to the mechanism proposed for the photocycloaddition to 1,4-CHD, triplet acetylene adds stepwise to thiophene and forms the formal Diel-Alder adduct 45 which can easily lose sulfur atom and generate the aromatic ring

138 (Scheme 42). This pathway results in the formation of 1,2-diaryl benzene 42 which reacts under further irradiation and forms the triphenylene adduct 43. Khun et al. reported the thermal addition of dimethyl acetylenedicarboxylate to thiophene and suggested the formation of the Diels-Alder adduct intermediate which yields 1,2-dimethyl benzenedicarboxylate as the major product.154

Scheme 42. Our Proposed Mechanism for Photocycloaddition of Diaryl Acetylene to Thiophene

* S S S Ar1 . Ar1 Ar Ar Ar . 1 1 -S 1 . . hν ISC Ar -HF 2 Ar2 Ar Ar2 2 * Ar2 Ar 1T 45 42 43 Ar1 1 4 hν + Ar - . Ar 2 . Ar 2 Ar 2 Ar 1 S Ar1 S S 1 S 1 S hν + Ar 44 2 41 Ar 2

Stern-Volmer plots in Figure 32 show that thiophene efficiently quenches the fluorescence of Bis-TFP acetylene in acetonitrile. These results suggest that the singlet excited state of acetylene can be reduced efficiently by thiophene, thus precluding ISC to the triplet state. Consequently, we suggest that the second pathway for the photochemical reaction of diaryl acetylenes with thiophene is through a photoelectron transfer (PET) mechanism. In this case, thiophene reduces the singlet excited state of acetylene to form a radical anion/radical cation exciplex (Scheme 42). The latter undergoes a sequence of reactions that leads to the formation of cyclobutene 44 which upon absorption of another photon rearranges to the final cyclobutene product 41. Our results in Table 17 are consistent with both mechanisms. For instance, irradiation in non- polar solvents suppresses the formation of cyclobutene product at the expense of the 1,2-diaryl benzene. However, addition of triplet quencher decreases the yield of 1,2-diaryl benzene in polar and non-polar solvents. It is worth to mention that, in earlier literature reports, formation of charged intermediate was proposed for the mechanism of photocycloaddition of benzothiophene to acetylene.161

139 6 Et3N (Acetonitrile) y = 109.54x + 0.9906 5 R2 = 0.999

/A 4 0 A Thiophene (Acetonitrile) 3 y = 101.2x + 1.1316 R2 = 0.9946 2

1

0 0 0.005 0.01 0.015 0.02 0.025 0.03 0.035 0.04 0 [1,4-CHD]*103, M

Figure 32. Stern-Volmer plots for fluorescence quenching of Bis-TFP acetylene in acetonitrile by thiophene (triangles) and with Et3N (squares).

Reactions with Furan

Irradiation of 2-Py-TFP acetylene and furan in acetonitrile yielded the hydroxyfulvene 45 in 20% yield (Scheme 43). The structure of the product was elucidated by 2D NMR experiments performed in collaboration with Dr. Ion Ghiviriga at University of Florida, Gainesville. This aldehyde can also be considered with another resonance structure 45b, a hydroxyfulvene. Such molecules are interesting molecules because they exhibit intramolecular hydrogen bonding known as resonance assisted hydrogen-bond (RAHB).

Scheme 43. Photochemical Reactions of 2-Py-TFP Acetylenes with Furan H O H H O H H O H N O .. + TFP + hν N N N CH3CN

TFP TFP TFP 45, 20% RAHB

Photocycloaddition reactions of acetylenes to furans are scarce in literature. Nonetheless, photocycloaddition of benzo[b]furans to acetylenes was reported by Neckers et al. The authors showed that, similar to their thiophene analogues, benzo[b]furans add to acetylenes and form the cyclobutene adducts, vide supra.159 Furthermore, Prinzbach et al. prepared the oxanorbornadiene

140 derivative 46 (75% yield) by the thermal Diels-Alder reaction of furan and dimethyl acetylenedicarboxylate (Scheme 44).230 The authors studied the photochemically isomerization reaction of 2,3-dimethyl oxanorbornadienedicarboxylate 46 to the corresponding oxaquadricyclane 47 (60 % yield). When the latter compound is heated, it rearranges to the oxepin derivative 48 with 70-75% yield (Scheme 44). The authors proposed a electrocyclic cleavage of the two cyclopropane rings in oxaquadricyclane 48 forming the zwiterionic intermediate 49 which leads eventually to the oxepin 48.231

Scheme 44. Proposed Mechanism for the Photochemical Reactions of Acetylenes with Furan and 1H NMR Chemical Shifts for 46, 47 and 48

O O - O H 6.27 ppm CO2Me MeO C O MeO C MeO C 2 ∆ 2 hν 2 ∆ H + 5.06 ppm Furan H H MeO2C MeO2C H H 7.17 ppm MeO2C 5.57 ppm 4.88 ppm MeO2C CO2Me CO2Me 2.65 ppm 46 47 49 48

H O H O O

MeO2C OMe MeO C - + 2 . . CO Me 51 2 50 Interestingly, Prinzbach et al. also speculated that one of the cyclopropyl rings in oxaquadricyclane 48 may heterolytically or homolytically open to the charged intermediate 50 which after a series of transformations leads to the hydroxyfulvene 51.231 Similar to the hydroxyfulvene 45 formed from the photochemical reaction of 2-Py-TFP and furan, hydroxyfulvenes 51 also exhibits resonance assisted hydrogen-bond. These hydroxyfulvenes are also interesting because they can display excited-state intramolecular proton transfer. Such fast tautomarization is known to result in reorganization of charge distribution in the molecule, thus rendering them attractive in the design of fluorescence sensors,232, 233 laser dyes,234, 235 UV filters236-239 and molecular switches.240-243 Because photochemical reaction involving the formation of hydroxyfulvenes with structure similar to 45 has not been reported yet in literature, we decided to investigate the scope and mechanism of this photochemical reaction. We tested the photochemical reactivity for selected diaryl acetylenes with furan under identical conditions.

141 3-Py-TFP and Ph-TFP acetylenes did not react with furan and starting material was recovered after 45 hours irradiation. In the case of Ph-TFP, dimerization product also formed, vide supra. However, Pyra-TFP acetylene undergoes photocycloaddition with furan and forms similar hydroxyfulvene product, though in lower yield (5%). Bis-TFP acetylene reacts with furan when irradiated at 313 nm and forms the oxaquadricyclane derivative 51 in 30% yield (Scheme 45). The structure of the product was determined based on 1H and 19F NMR and mass spectrometry analysis. The 1H NMR spectrum

of 51 in CDCl3 contains two doublets (Jab = 3.0-3.3 Hz) at 5.0 and 3.0 ppm (shown in Scheme 45) which indicates a highly symmetrical molecule. The base peak in the EI-MS spectrum refers to a 1:1 adduct with m/z = 392 (M+). Furthermore, a simple comparison of chemical shifts to the

oxaquadricyclane 47 (Jab = 3.5 Hz) reported by Prinzbach et al. confirms our structure assignment (Scheme 44).

Scheme 45. Photochemical Reactions of Bis-TFP Acetylenes with Furan and 1H NMR Chemical Shifts for 52 and 53 O H O 6.12 ppm O hν TFP r.t. TFP TFP + H CH CN 5.42 ppm 3 TFP H H 5.04 ppm 3.04 ppm TFP TFP 52 53

Accidentally, the NMR tube containing oxaquadricyclane 51 in CDCl3 was left on the bench 1 for two weeks. H NMR spectra showed the formation of two new doublets (Jab = 4.8 Hz) at 6.1 and 5.4 ppm, in addition to those for oxaquadricyclane 51. Consequently, we concluded that our oxaquadricyclane 51 rearranged to the corresponding oxepin 53. The ratio for the two compounds is 1:1 and the protons signals are shifted down-field, in accordance with Prinzbach et al. assignment (Scheme 44). Finally, as I have mentioned earlier, more experiments should be conducted in order to elucidate a rational mechanism for these reactions. Nonetheless, these preliminary experiments show that the interesting photochemical behavior of the diaryl acetylenes studied in this work is not limited to reactions with cyclohexadienes and paves the way for more interesting chemistry.

142 HOMOQUADRICYCLANES AS NEW SUPRAMOLECULAR SCAFFOLDS

In this section, we describe our attempts to use homoquadricyclane molecules, synthesized from the photocycloaddition of diaryl acetylenes to 1,4-CHD, as building blocks in supramolecular chemistry. Recently, the field of metal-directed supramolecular coordination chemistry has seen significant development due to their useful applications in biological molecular recognition, new dynamic material and catalysis.

Supramolecular Chemistry: An Overview

From a practical point of view, photocycloaddition reactions of acetylenes to 1,4-CHD are interesting because “capping” of the triple bond with the polycyclic framework orients the terminal aryl (4-pyridyl, 4-tetrafluoropyridyl, phenyl etc.) groups in an almost perfect 60º angle rendering such molecules promising supramolecular building blocks in the design and synthesis of metal coordination polymers. In this context, it is interesting to quote a recent paper by Stang and coworkers: “The relative dearth of triangles synthesized to-date can be explained by the difficulty in finding the appropriate corner unit… there exist no single-center complex that possesses a 60o angle between coordinated ligands.”244 Intrigued by these comments, we decided to investigate the supramolecular chemistry of 1,5-(4,4’-dipyridyl) homoquadricyclane 25 (Scheme 26) which has potential to serve as a corner unit for such supramolecular triangles or rhomboids245, 246 and provides other examples of V-shape textons that exhibit interesting solid state packing motifs.247, 248 Several groups have adopted a tactic for the synthesis of molecular triangles which uses a suitable ligand as the corner units and metal coordination acting as the linker between these ligands.249-252 We prepared a family of organometallic coordination polymers based on pyridine-metal interaction. Silver (I) is frequently used as the metal in crystal engineering because the flexibility of its coordination sphere can produce a large array of coordination architectures.253-256 The ability to modify the ligand-to-metal ratio, the counterions and noncovalent interactions reflects this flexibility.257-261 Different types of spacers (e.g. rigid, semirigid and flexible) were utilized in the construction of coordination polymers and supramolecular complexes with potential application in crystal engineering.

143 X-Ray Crystallography Interpretation: Basic Homoquadricyclane Units

Photocycloadditions of Bis-4-Py acetylene, Bis-TFP acetylene and 4-Py-TFP acetylene to 1,4- cyclohexadiene (1,4-CHD) afford 1,5-diaryl homoquadricyclanes 25 (L1), 21 (L2) and 26 (L3) in good isolated yields (Table 10). The structures of L1, L2 and L3 were determined using spectroscopic techniques and confirmed by single crystal X-ray analysis (Figure 33 and Figure 34).

The first interesting structural feature of L1 is the high (C2v) symmetry of the molecule – a generally useful property in supramolecular chemistry. The two pyridine rings form a diverging cavity with an angle of 63.2° (Figure 33). The distance between the two nitrogens is 6.05 Å and the dihedral angle formed by the C1(Ar)-C6(Hq)-C7(Hq)-C1(Ar’) carbon bonds is 0°.

60 oC

Figure 33. ORTEP representation of the geometry of 1,5-(4,4’-dipyridyl) homoquadricyclane 24 (L1) [di-4,4’-[7,6-tetracyclo[3.2.1.02,7.04,6] octyl]-pyridine] (left) and a side view showing molecular symmetry and the angle formed by the planes of the two pyridine rings (right).

The torsional angle between the two pyridyl rings in homoquadricyclane L2 is 1.1° (Table 18). Despite this slight distortion, the angle between the two electron deficient TFP rings flanking the cavity is essentially unchanged (62.9°). A similar situation is observed in the case of unsymmetric 1,5-diaryl homoquadricyclane L3 (Table 18), where the angle formed by the two aryl rings of different acceptor abilities (TFP and 4-Py) is 63.3°. The distance between the two pyridyl nitrogens is 6.02 Å and the dihedral angle is 2.64°. Comparison of selected distances, angles and torsional angles of ligands L1, L2 and L3 in Table 18 suggests that the main geometrical features of the scaffold remain nearly intact in these structural modifications. Symmetry, shape and electronic properties of the hydrophobic cavity control packing of the diaryl homoquadricyclanes in the crystals (Figure 35). In L1, the cavity formed by the pyridyl

144 rings accommodates C-H bonds from the polycyclic homoquadricyclane moiety, possibly due to weak CH-π interactions of the aromatic moieties and the homoquadricyclane CH bonds.262-267 L1 also shows π-π stackings of parallel pyridyl rings in an offset fashion with a distance of ca. 3.37 Å.268, 269 Interestingly, the pyridine rings are twisted inward by ca. 5°, thus opening up the cavity from one side.

(b) (a)

Figure 34. ORTEP representation of (a) L2 [Di-4,4’-[7,6-tetracyclo[3.2.1.02,7.04,6]octyl]-2,3,5,6- tetrafluoropyridine] and (b) L3 [4-[7-(2,3,5,6-tetrafluoropyridin-4-yl)-tetracyclo [3.2.1.02,7.04,6]oct-6-yl]-pyridine].

(c) (a) (b)

Figure 35. Crystal packing of Homoquadricyclanes L1, L2 and L3.

By contrast, the electron deficient cavity of Bis-TFP ligand L2 is occupied by the edge of another TFP molecule. This is due to the stabilizing interaction between the electron deficient π- system and the lone pairs of the fluorine atoms that supplement the π-π interactions by providing

145 intermolecular forces in the solid state. The most regular and well-defined packing is in the mixed Py-TFP ligand L3 which is controlled by face-to-face stacking interactions between the electron acceptor TFP and the electron donor Py rings (Figure 35c).93, 270, 271 Finally, hydrogen bond interactions between aromatic hydrogens of 4-Py rings and fluorine atoms provide additional stabilization to the crystal network.66, 272, 273

Table 18. Selected distances (Å) and angles (deg) for homo-quadricyclanes L1, L2 and L3 and for complexes 1, 2, 3 and 4.

C8 C3

C1 C2 C5 C4

C7 C6 C2 C1 C1 C2

C3 Ar' Ar C3 N N L1 L2 L3 1 2 3 4 Angles (deg) L1 (corner) L1 (linker) Ar-Ar’ 63.2 62.9 63.3 65.7 71.8 69.6 60.9 65.4 C1(Ar)-C6(Hq)-C1(Ar’) average 121.2 120.8 120.9 123.1 126.7 121.9 121.5 121.1 Torsion Angles (deg) C1(Ar)-C6(Hq)-C7(Hq)-C1(Ar’) 0 1.14 2.64 5.8 4.5 11.6 7.08 4.20 C2(Ar)-C1(Ar)-C6(Hq)-C7(Hq) 85.3 103.9 101.2 119.7 162.4 126.9 131.52 103.5 C2(Ar)-C1(Ar)-C6(Hq)-C7(Hq) 85.3 75.6 94.1 58.2 82.9 58.1 119.60 70.2 Distances (Å) π−π Ar1-Ar2 3.37 3.34 3.62 - - - 3.97 - N(Ar)-N(Ar’) 6.05 5.99 6.02 6.19 6.54 6.44 5.87 6.15 H at C1 (Hq1) - N(Ar2) 2.62 - 2.58 - - - - - H at C3 (Hq1) - F at C1 (Ar2) - 2.57 2.60 - - - - - F at C2 (Ar1)-F at C3 (Ar12) - 2.76 ------N(Ar1)-C1(Ar2) - 3.06 ------

146 (a) (b)

(c)

Figure 36. Distances, angles and torsion angles of homoquadricyclanes L1, L2 and L3.

X-Ray Crystallography Interpretation: Metal Complexes and Packing

Homoquadricyclanes L1 and L3 readily form silver complexes when mixed with AgNO3.

Interestingly, L1 produces different AgNO3 complexes at different L1:AgNO3 ratios. When a

THF solution of L1 is layered on top of a CH3CN solution of AgNO3 in a 1:1 ratio, almost instantaneously, a white precipitated is formed between the two layers. However, slow diffusion affords X-ray quality single crystals of a 1:1 complex.

147

Figure 37. Alternating layers of organic and inorganic molecules in the crystal structure of complex 1 (1:1 ratio L1:AgNO3).

Figure 38. Distances, valence and torsion angles in complex 1.

X-ray analysis shows that silver cations are shared between two pyridine moieties from two different homoquadricyclane molecules which pack in infinite zigzag layers (Figure 37). The structure of 1 shows the coordination sphere of Ag to be almost linear with a L1-Ag-L1 angle of 171.26°. The average Ag-N distance is 2.15 Å indicating strong coordination between the - pyridyl nitrogen and the silver cation. Although, NO3 is usually a relatively strong coordinating anion,274 it interacts rather weakly with Ag+ in this system where the shortest Ag-O distance in - complex 1 is only 2.90 Å. The NO3 positions itself perpendicularly to the L1-Ag-L1 plane, thus

148 providing pseudosquare planar geometry at Ag+ (Ag-O-N 96.6°) (Figure 38). The nitrate counterions complete the “salt” inorganic layers which are sandwiched between the hydrophobic organic layers of silver complexes. Furthermore, the nitrate ions bridge the adjacent Ag-L1 chains through two of their oxygen atoms. The packing of this interesting composite material which combines two potentially tunable and interchangeable organic and inorganic moieties is shown in Figure 37. Silver cations and nitrate anions alternate through the packing layers forming polar rods which are separated by organic relatively nonpolar “pipes”. A slight change in the crystallization conditions (slow diffusion of ligand and inorganic salt through a U-tube) leads to formation of a different complex, 2, with the 3:2 L1:AgNO3 ratio

(Figure 39). X-ray analysis of this complex also indicates presence of disordered CHCl3 molecules (not shown).

Figure 39. View of the basic trimeric unit [Ag2(L1)3(NO3)2 (CHCl3)2] of complex 2.

Thermal gravimetric analysis (TGA) suggests that there are two molecules of chloroform per each (L1)3/(AgNO3)2 unit (Figure 39 and Figure 42). In this complex, two pyridine moieties are assembled into rhomboids by coordination with two Ag+ ions. Each of the two Ag+ ions which occupy two opposite corners of the rhomboid (Ag-Ag = 11.544 Å), is also coordinated with an oxygen atom of a nitrate anion and with the third Bis-Py ligand that bridges it to an analogous adjacent (Bis-Py)2 - (AgNO3)2 unit. As a result, the silver cation adopt a distorted tetrahedral coordination sphere where each Ag cation coordinates with pyridyl nitrogens belonging to three - different L1 molecules and an oxygen atom from the NO3 anion (Ag-O = 2.54 Å) (Table 18). All three Ag-N distances (Ag-N(1) = 2.31 Å, Ag-N(2) = 2.35 Å, Ag-N(3) = 2.26 Å) are significantly longer than in the linear 1:1 complex, vide supra. The distance between the parallel

149 pyridine rings which form the four sides of the rhomboid are 8.01 Å and 7.45 Å. The chains of interconnected rhomboids pack in a highly porous structure with large cavities that are also rhomboid (Figure 41). These large voids are occupied by disordered solvent molecules to sustain the structure. The dimensions of the cavities are as follows: the diagonal distances (from one corner to the opposite one) are 14.92 Å and 14.70 Å and distances from one edge of the rhomboid to the opposite one are 10.46 Å and 8.09 Å. In both complexes 1 and 2 the geometry of the homoquadricyclane L1 is altered from the geometry of the free ligand as shown in Table 18.

Figure 40. Distances, angles and torsion angles of the basic unit in complex 2.

Figure 41. “Beads on a string” packing of supramolecular rhomboids in complex 2. Different colors show three different strings forming the cavities. Hydrogens are omitted for clarity.

150 Figure 42 compares the Thermal Gravimetric Analysis (TGA) plots for L1 and complexes 1 and 2. As a reference point, we have also included data for L1 alone. L1 sublimes almost completely at 500°C. In contrast, complexes 1 and 2 show only 40% and 75% loss of weight at 500°C, respectively. The remaining weight is consistent with the amount of silver nitrate present in the complexes. Most interestingly, the thermal analysis for complex 2 (black line in Figure 42) shows a shoulder between 190o C and 200o C which is absent for both L1 and complex 1. This

18% loss is consistent with loss of two molecules of CHCl3 from the silver rhomboid. The TGA data suggest that the 1:1 complex 1 may also contain an acetonitrile molecule.

100

80 % Weight % Weight 60

40

20

0 0 50 100 150 200 250 300 350 400 450 500

o Temperature, C

Figure 42. TGA plots for L1 (blue line) and complexes 1 (red line), 2 (black line) and 3 (green line). Complex 2 shows a shoulder where the weight loss is 18%, corresponding to two CHCl3 molecules in complex 2.

Reaction of L1 with copper(II) chloride dihydrate (CuCl2.2H2O) forms rhomboids, complex 3, where the ligand occupy opposite corners of the rhomboids and Cu(II) occupies the other two (Figure 43). Copper(II) adopt a distorted tetrahedral geometry with two chlorine atoms occupying two vertices and two pyridine nitrogens from different L1 molecules occupy the other two vertices. The tetrahedron angles are as follows: N1-Cu-N2 (137.45 º), N1-Cu-Cl1 (98.27 º), N2-Cu-Cl2 (94.34 º) and Cl1-N-Cl2 (141.60). Chlorides anions are stronger coordinating ligands than nitrates with an average Cu-Cl distance of 2.23 Å. The Cu-N distance is 2.00 Å.

151

Figure 43. View of the basic unit [Cu2(L1)2Cl4(CHCl3)] of complex 3.

Unlike other complexes, the angle formed by the two pyridine rings in complex 3 is decreased compared to the free ligand (63.2 º for L1 and 60.9 º for complex 3, Table 18). Furthermore, the nitrogen distance of the two pyridine rings is decrease by ca. 1 Å. Also, Figure 44 shows the π−π stacking between two pyridine rings of different rhomboids.

Figure 44. Distances, angles and torsion angles of the basic unit in complex 3. Chloroform molecules were omitted for clarity reasons.

The dimension of the cavity formed by rhomboid 3 is smaller than the one in complex 2. In complex 3, the distance between two parallel pyridine rings forming the edges of the rhomboid are 6.55 Å and 6.79 Å and a Cu-Cu distance of 7.32 Å. Chloroform molecules are present in the crystal packing and situated between the layers formed by the rhomboid units (Figure 45).

152

Figure 45. Crystal packing of supramolecular rhomboids, complex 3.

Although water molecules could not be optimized in the X-ray analysis, TGA plot for complex 3 shows the loss of solvent molecules upon heating (Figure 42). Complex 3 loses one molecule of chloroform at ca. 90 ºC (12.3% weight) followed by a small shoulder of 2.7% weight loss corresponding to two molecules of H2O. As a result, complex 3 can be identified as

2CuCl2.2H2O.2L1.CHCl3. Equally interesting is the possibility of changing the symmetry and coordinating properties of the homoquadricyclane ligands. Not surprisingly, homoquadricyclane L2 does not react with silver nitrate due to the low donor ability of the TFP nitrogen atoms. However, cocrystallization of 4-Py-TFP homoquadricyclane L3 with AgNO3 resulted in formation of complex 4 in a 2:1

L3/AgNO3 ratio. In complex 4, only nitrogen in the stronger donor Py moiety participates in coordination with the silver ions. Similar to complex 1, the silver ions in 4 adopt a square planar geometry (L3-Ag-L3 = 180.0° and Ag-N = 2.16 Å) where each Ag coordinates with two L3 molecules and two nitrate oxygens. As a result, the layers of AgNO3 are separated by thicker - “organic walls” (Figure 46). Disordered nitrate anions bridge two Ag ions (Ag-O (NO3 ) = 2.59 Å) providing communication between the layers which form a stair-like network.

153

Figure 46. Thicker “walls” between the inorganic layers in the 2:1 (L1/AgNO3) complex 4. Nitrate anions are disordered.

Substitution on the Homoquadricyclane Unit Controls Rotation of Aryl Groups

The data in Table 18 suggest that the homoquadricyclane framework possesses significant flexibility to accommodate geometric requirements in respective complexes. Remarkably, this flexibility can be readily fine-tuned by substituent effects. We found that rather subtle modifications in the homoquadricyclane skeleton may fine-tune the shape and conformational properties of the cavity flanked by the two aryl groups. This sensitivity makes substituted diaryl homoquadricyclanes interesting scaffolds for molecular recognition.

Scheme 46. Photocycloaddition of Diaryl Acetylenes to 1,5-Diemthoxy-1,4-Cyclohexadiene

O O H C CH O O 3 3 Ar TFP + hν Ar F F CH3CN F N F

Ar = L4: 2-Py (70%) L5: TFP (40%) Photocycloaddition reaction of diaryl acetylenes to substituted 1,4-CHD formed homoquadricyclane products bearing substituents on the polycyclic moiety. 2-Py-TFP and Bis- TFP acetylenes were irradiated with 1,5-dimethoxy-1,4-cyclohexadiene in acetonitrile and the products were isolated in good yields (Scheme 46). The structure of compound L4 shown in

154 Figure 47 was elucidated based on the H1-C13 one-bond and long-range couplings, revealed by the ghmqc and ghmbc spectra. Interestingly, the 19F NMR of TFP moiety in these dimethoxy substituted diaryl homoquadricyclanes displays four signals at -143.23, -138.36, -93.96 and -93.24 (Figure 48). These four signals suggest restricted rotation of the TFP moiety.

3.19 56.5

2.65 2.55 O 2.40 2.07 28.0 25.6 74.0 2.27 37.1 56.0 3.22 71.1 2.08 O 36.3 F -138.36, -143.23 47.4 -93.24, -93.96 154.8 F 123.1 F N 7.18 N F 135.9 7.46 8.22 149.0 121.4 6.95

Figure 47. NMR chemical shifts assignments for L4.

(a) (b)

Figure 48. 19F NMR spectrum for (a) L4 and (b) L5.

155 CONCLUSIONS

This study significantly expanded the utility of the photochemical conversion of acetylenes to homoquadricyclanes and, for the first time, provided a mechanistic rationale for this intriguing and atom-economical cascade transformation. Photoirradiation of pyridine substituted acetylenes in presence of 1,4-CHD yielded 1,5-diaryl substituted tetracyclo[3.3.0.02,8.04,6]octanes in good yields. The spin multiplicity of the excited state involved in the formation of polycyclic photoadducts and their subsequent photorearrangement was determined using quenching and sensitization experiments. These experiments unambiguously confirmed that formation of homoquadricyclanes proceeds through a triplet excited state. Electron-accepting substituents increase the efficiency of the reaction by enhancing electrophilic character of triplet acetylene moiety. However, electron acceptor properties of the acetylene moiety must be balanced in such a way that ISC to the triplet exited state would proceeds faster than electron transfer between excited acetylene and 1,4-diene moieties. Lack of such balance can lead to the situation when in the case of larger concentrations of dienes, the singlet excited state of acetylene is intercepted through electron transfer before it is transformed into the triplet and, thus, efficiency of the triplet photocycloaddition decreases. Sufficiently long triplet lifetime and electron deficiency of triplet state are the two conditions favoring the photocycloaddition. Acetylenes where both of these conditions are satisfied react with 1,4-CHD very efficiently. In the case of short-lived triplets, the role of electrophilicity becomes essential as illustrated by comparison of the results for the two symmetric acetylenes: although the lifetimes of Bis-TFP and Bis-4-Py triplets are very close, the quantum yield for the formation of homoquadricyclane product is considerably higher in the case of the more electron deficient Bis-TFP acetylene. In the triplet excited state produced from Ph-PFB acetylene, relative polarization of the triple bond does not change compared to the ground state whereas in the case of 4-Py-Ph and Ph-TFP triplets, there is an inversion of the ground state polarization of the triple bond. Influence of these electronic effects on the observed trends in reactivity should also depend on the relative rates of ISC in the two types of acetylenes. El-Sayed rules suggest that phantom n,π* excited state plays an important role in accelerating ISC and blocking competing side reactions.

156 The reaction cascade is complicated and several reasonable possibilities exist for the formation of the homoquadricyclanes. From these possibilities, the 5-exo cyclization of the initially formed 1,4-diradical seems the most likely. In the case of pyrazyl substituted aryl acetylenes, secondary photoreaction of homoquadricyclane singlet excited state leads to tricyclooctene adduct via a 1,2-carbon shift. These results provide the new insight needed for rational design and better control of this intriguing class of photochemical cycloadditions. Photocycloaddition reactions of acetylenes to thiophene formed a [2π+2π] cyclobutene adduct and 1,2-diaryl benzene. Two mechanisms may be responsible for the formation of products. The first involves triplet excited state of acetylene which adds to the double bond of thiophene with the formation of the formal Diels-Alder adduct followed by a rapid sulfur-atom exclusion to yield the 1,2-Diaryl benzene. On the other hand, cyclobutene products are suggested to be formed through a charged intermediate complex formed by PET process between singlet excited of acetylene and thiophene. Photochemical reaction of 2-Py-TFP acetylene with furan forms a very interesting hydroxyfulvene product. These kinds of molecules are interesting due to their ability to display resonance assisted hydrogen-bonding which may be important in the design of molecules with interesting applications, such as molecular switches and dyes. Symmetry and geometry of Bis-pyridinyl homoquadricyclane ligands render them promising supramolecular scaffolds for preparation of self-assembling metal-coordination polymers and rhomboids. Reaction with silver nitrate and copper(II) chloride produces metal coordinate polymers in which the silver coordination sphere is sensitive to the ligand:metal ratio. Electronic properties and rigidities of the scaffolds can be modified by appropriate substitution. For example, homoquadricyclanes bearing substituents on their aliphatic polycyclic framework displayed restricted rotation of the aryl groups, thus indicating a possibility for controlling the rigidity of the hydrophobic cavity by such substituents.

157 APPENDIX A: 1H NMR SPECTRA

Chapter I

O H O

O S CF3 O O O S CF3 O

158 O H Si

Si

159 O H

160 NO2 Si

Si

161 NO2

162 O

CF3 NH Br

Br

163 O

CF3 NH Si

Si

164 NH2

165 OCD3 I

NO2

166 OCD3 I

NH2

167 OCD3 I

I

168 OCD3 Si

Si

169 OCD3

170 OMe

171 OMe

172 O

173 CD2H OCD3 OD

+

4:1

174 CD 3 O

175 D D O D

176 Chapter II

8,395 7,260 0,262

3500 0

SiMe3 N 3000 0

N 2500 0 SiMe3

2000 0

1500 0

1000 0

5000

0

2.00 17.79

5.0 0.0 ppm (t1)

177 0,213 8,379 8,371 8,207 8,199 7,260 2500 0

SiMe3 N

2000 0 N Cl

1500 0

1000 0

5000

0

1.000.95 9.08

5.0 0.0 ppm (t1)

178 8,600 8,595 8,458 8,450 8,445 8,399 8,390 7,260 0,204

30000

SiMe3 N

25000 N

20000

15000

10000

5000

0

1.001.001.00 9.31

8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 ppm (t1)

179 8,441 8,425 7,528 7,502 7,476 7,331 7,305 7,260 7,108 7,089 7,067 0,150 1000 0

N

SiMe3

5000

0

0.96 1.181.151.00 8.89

9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0 ppm (f1)

180 8,656 8,489 8,477 7,709 7,688 7,682 7,209 7,193 7,183 7,167 7,260 0,226 2500 0

N

SiMe3 2000 0

1500 0

1000 0

5000

0

1.171.11 1.00 9.15

9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0 ppm (f1)

181 8,382 8,362 7,260 7,122 7,117 7,102 0,078 40000

N SiMe3

30000

20000

10000

0 1.99 2.07 8.97

8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0 ppm (t1)

182 7,508 7,501 7,490 7,476 7,325 7,318 7,308 0,284

15000

SiMe3

10000

5000

0 2.00 2.91 8.99

8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0 -1.0 ppm (t1)

183 8,438 8,422 8,416 8,432 7,705 7,700 7,679 7,673 7,260 7,142 7,126 7,115 7,099 0,244 0,232

2000 0

SiMe3 N

1500 0

SiMe3

1000 0

5000

0

1.00 1.03 1.05 18.00

9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0 ppm (f1)

184 8,732 7,260

F F N

F N F (3) F N F

N 500 0 F F

0

2.00

10.0 5.0 0.0 ppm (f1)

185 8,614 8,606 8,454 8,446 7,260

7000

F F N N 6000 N Cl F F

(11) 5000

4000

3000

2000

1000

0

1.000.98

10.0 5.0 0.0 ppm (t1)

186 8,639 7,260 8,866 8,679 5000

F F N 4000 N N F F (12)

3000

2000

1000

0

1.001.92

10.0 5.0 0.0 ppm (f1)

187

8,741 8,550 8,463 7,604 7,589 7,385 7,372 7,357 7,345 3000

N

N 2500 (16)

2000

1500

1000

500

0 1.00 1.04 1.10 2.48 3.48

9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0 ppm (t1)

188 7,406 7,389 7,366 7,261 8,700 7,806 7,780 7,755 7,666 7,640 8,714

300 0

F F N 250 0 N

(6) F F 200 0

150 0

100 0

500

0

1.00 1.101.051.01

10.0 5.0 0.0 ppm (f1)

189 7,329 7,260 7,908 7,902 7,875 7,372 7,355 7,345 8,812 8,653 8,639 250 0

F F N N 200 0 (7) F F

150 0

100 0

500

0

1.000.91 0.83 0.85

10.0 5.0 ppm (t1)

190

6000 8,728 8,710 7,489 7,469 7,261 F F

N N 5000

(8) F F

4000

3000

2000

1000

0 1.09 1.00

10.0 5.0 0.0 ppm (t1)

191

7,502 7,486 7,475 7,459 7,260 8,765 8,049 8,022 8,780

300 0 F F N

F N 250 0 F (5) F F 200 0 N F F

150 0

100 0

500

0

1.00 0.93 0.98

10.0 5.0 0.0 ppm (t1)

192

7,402 7,395 7,260 7,485 7,475 7,462 7,449 7,425 7,510 7,505 7,498 7,639 7,617 7,612

300 0

F F 250 0 N

(10) F F 200 0

150 0

100 0

500

0

2.002.86

9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0 ppm (t1)

193 8,608 7,260 7,396 7,388 7,380 7,360 8,613 8,598 8,593 7,572 7,565 7,554 7,540

600 0

500 0 N

(15) 400 0

300 0

200 0

100 0

0

2.00 1.954.95

9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0 ppm (t1)

194 7,261 7,334 7,309 7,293 7,322 7,313 7,297 7,374 7,350 7,338 7,695 7,615 7,593 7,567 8,664 8,649 7,752 7,746 7,726 7,720 7,700

300 0

F F N 250 0 F

F F (13) 200 0

150 0

100 0

500

0

1.00 1.221.431.48

9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0 ppm (t1)

195

7,576 7,411 7,260 2000

F F

F

F F 1500 (18)

1000

500

0 2.23 3.18

9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0 ppm (t1)

196 600 0 1,251 2,999 2,944 1,282 2,959 2,091 1,912 1,896 1,872 1,857 1,322 2,983 2,970 8,235 7,260 6,776 6,751 8,407 8,400 8,243

F 500 0 N F F F F 400 0

F N N F N

F 300 0 (4)

200 0

100 0

0 2.21 3.14 1.02 1.91 1.00 0.89 0.88

8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 ppm (t1)

197

F N F F F F

F N N F N

F (4)

198 F N F F F F

F N N F N

F (4)

199 F N F F F F

F N N F N

F (4)

200 F N F F F F

F N N F N

F (4)

201 F N F F F F

F N N F N

F (4)

202 F N F F F F

F N N F N

F (4)

203 F N F F F F

F N N F N

F (4)

204 350 0 2,062 2,018 2,125 2,119 2,170 2,163 2,459 2,493 2,485 2,476 2,450 2,441 2,433 2,467 8,426 8,418 8,172 8,164 7,260

300 0 F N F N 250 0 N Cl F F (27) 200 0

150 0

100 0

500

0 2.45 4.21 2.65 1.00 0.95

9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0 ppm (t1)

205 2,950 2,937 2,925 2,071 1,885 8,202 8,194 8,109 8,101 6,518 6,493 1,870 1,846 1,830 1,327 1,287 1,247

400 0

Cl F F N N F N 300 0 F (29)

200 0

100 0

0

1.000.88 0.91 1.07 2.142.40 3.38

5.0 0.0 ppm (t1)

206 1,256 1,216 2,895 2,023 1,872 1,857 1,833 1,817 2,951 2,935 2,922 2,911 8,580 8,283 8,097 7,260 6,518 6,493 350 0

300 0

F F N 250 0 F N N F (30) 200 0

150 0

100 0

500

0

1.26 1.230.92 1.00 1.03 2.112.71 2.48

9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0 ppm (f1)

207 8,300 8,244 7,263 2,389 2,346 2,208 2,061 2,042 1,998

1500

F N F N N F (28) F 1000

500

0 3.00 2.09 1.91 3.57

9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 ppm (t1)

208 2,005 1,990 1,947 2,363 2,356 2,320 2,073 6,955 6,938 7,034 7,007 6,979 6,960 7,489 7,484 7,464 7,458 7,438 7,432 7,260 8,282 8,269

500 0

F 400 0 N F N F F (19) 300 0

200 0

100 0

0

0.84 0.89 1.77 2.19 6.00

8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0 ppm (f1)

209 1,894 2,324 2,023 1,980 1,928 1,921 2,384 2,376 2,368 2,341 2,332 7,073 7,260 7,115 7,099 7,089 8,472 8,361 8,347 7,533 7,507 800 0

700 0

F 600 0 F N N F 500 0 F (20)

400 0

300 0

200 0

100 0

0

1.000.88 0.88 0.85 2.05 3.852.02

9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0 ppm (t1)

210 8,389 7,261 7,078 2,344 2,302 2,014 1,967 1,949

250 0

F F 200 0 N N F F (21) 150 0

100 0

500

0 2.00 5.81 1.82 1.70

5.0 0.0 ppm (t1)

211 2,325 2,009 1,987 1,966 1,888 7,101 7,091 7,067 2,368 7,260 7,240 7,216 7,177 7,155 7,129 7,114 7,302 7,286 300 0

250 0 F F N F 200 0 F (22)

150 0

100 0

500

0

5.00 2.09 3.861.95

8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 ppm (t1)

212

7.260 2.439 2.431 2.404 2.395 2.104 2.070 2.026

F F F F N N F F F F (26) 2.46 6.00

7.0 6.0 5.0 4.0 3.0 2.0 ppm (f1)

213

8,264 8,246 6,879 6,859 2,157 2,123 2,114 2,106 1,965 1,906 1,898 1,889 1,879 1,835 2,149 3500

3000

N N (25) 2500

2000

1500

1000

500

0 4.09 4.00 2.55 6.95

-500

9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0 ppm (t1)

214 1,914 2,058 2,051 1,969 1,926 2,362 2,353 2,327 2,319 2,311 6,951 7,084 7,058 6,992 6,973 6,968 7,483 7,477 7,457 7,451 7,431 7,425 7,260 8,369 8,353 350 0

300 0 F N F

F F 250 0 F (24)

200 0

150 0

100 0

500

0 7.01 2.51 1.00 1.17 1.08 1.01

8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 ppm (t1)

215 300 0 8,265 8,248 7,260 7,138 7,126 7,103 6,925 2,243 6,904 2,235 2,227 2,201 2,192 2,184 1,937 1,894 1,884 1,878 2,218 2,210 2175

250 0

N (23) 200 0

150 0

100 0

500

0 6.07 2.52 2.00 4.98 1.95

8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 ppm (t1)

216 7,260 3,315 5,300 2,800 2,761 2,691 2,651 2,558 2,541 2,530 2,514 2,498 2,234 2,190 2,149 2,134 500 0

MeO OMe

F F F F 400 0 N N F F F F (L3) 300 0

200 0

100 0

0 6.00 1.10 1.08 1.15 2.87

8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 ppm (t1)

217

8,273 8,259 7,502 7,477 7,451 7,259 7,225 7,199 6,988 6,972 6,947 3,289 3,247 3,173 2,736 2,697 2,646 2,607 2,445 2,429 2,418 2,401 2,385 2,274 2,259 2,133 2,164 2,121 600 0

MeO OMe 500 0 F N F N F 400 0 F (L4)

300 0

200 0

100 0

0 6.10 2.36 1.29 1.15 2.05 1.03 1.12 0.96 1.01

8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0 ppm (t1)

218 TFP Ph

TFP

219 N

F

N F F

220 N

TFP

221 N N TFP TFP S or S

222 N

N or F F

N N F F F F

223 N

TFP

224 N N TFP S TFP or S

225 TFP

TFP

226 TFP TFP S

227 TFP S

TFP

228 O TFP

TFP

229 O O TFP + TFP TFP TFP

230 N

N

231 H O H N

TFP

232 H O H N

N TFP

233 APPENDIX B: 13C NMR SPECTRA

Chapter I

O H O

O S CF3 O O O S CF3 O

234 O H Si

Si

235 O H

236 NO2 Si

Si

237 NO2

238 O

CF3 NH Br

Br

239 O

CF3 NH Si

Si

240 NH2

241 OCD3 I

NO2

242

OCD3 I

NH2

243 OCD3 I

I

244 OCD3 Si

Si

245 OCD3

246 Chapter II

76,365 -0,718 77,212 76,790 102,606 99,751 142,217 142,097

3500 0

SiMe3 N 3000 0 N SiMe 3 2500 0

2000 0

1500 0

1000 0

5000

0

150 100 50 0 ppm (t1)

247 77,427 77,000 76,572 -0,767 150,551 141,953 141,801 138,686 104,606 98,578

SiMe3 N 1000 0

N Cl

5000 0

0

150 100 50 0 ppm (t1)

248 77,474 147,615 144,054 142,817 139,607 100,472 99,384 77,048 76,622 -0,688

3000 0 SiMe3 N

N 2500 0

2000 0

1500 0

1000 0

5000

0

150 100 50 0 ppm (t1)

249 149,597 142,710 135,789 126,943 122,747 103,420 94,361 77,425 77,201 77,000 76,575 -0,560 6000 0

N

SiMe3 5000 0

4000 0

3000 0

2000 0

1000 0

0

150 100 50 0 ppm (f1)

250 152,375 152,262 148,452 148,345 138,501 122,587 120,004 101,161 97,931 77,221 76,798 76,374 -0,460

2500 0 N

SiMe3

2000 0

1500 0

1000 0

5000

0

150 100 50 0 ppm (t1)

251 N SiMe3

252 600 0 131,923 128,446 128,163 123,094 105,098 94,038 77,423 77,000 76,576 -0,027

500 0

SiMe3

400 0

300 0

200 0

100 0

0

150 100 50 0 ppm (t1)

253 148,184 144,161 138,876 122,191 121,594 101,595 101,236 100,158 98,403 77,000 76,576 76,152 -0,665 -0,745

SiMe3 2000 0 N

SiMe3 1500 0

1000 0

5000

0

150 100 50 0 ppm (f1)

254

F F N

F N F (3) F N F

N F F

255

F F N N N Cl F F (11)

256

F F N N N F F (12)

257 N

N (16)

258 F F N N

(6) F F

259

F F N N

(7) F F

260 F F

N N

(8) F F

261

F F N

F N F (5) F F

N F F

262 145,231 145,049 144,873 143,749 143,362 143,275 142,001 141,810 141,762 140,248 139,879 139,780 132,293 130,600 128,650 120,493 106,621 106,570 77,423 77,000 76,575 73,350

8000 0

F F 7000 0

N 6000 0 (10) F F

5000 0

4000 0

3000 0

2000 0

1000 0

0

-1000 0

150 100 50 0 ppm (t1)

263 N

(15)

264

F F N F

F F (13)

265 F F

F

F F (18)

266 F F F F

N N

F F F F (9)

267

F N F F F F

F N N F N

F (4)

268 F N F F F F

F N N F N

F (4)

269 F N F F F F

F N N F N

F (4)

270

F N F N N Cl F F (27)

271 Cl F F N N F N F (29)

272 F N F F N N F (30)

273 F N F N N F (28) F

274 158,682 149,243 144,950 144,755 136,365 144,534 144,141 121,974 121,293 143,710 141,751 141,523 140,733 140,304 134,888 77,679 77,256 76,832 45,129 34,810 34,144 24,245

2000 0

F N F N F 1500 0 F (19)

1000 0

5000

0

150 100 50 0 ppm (f1)

275 F F N N F F (20)

276 F F N N F F (21)

277 F F N F F (22)

278 F F F F N N F F F F (26)

279 1000 0 149,122 77,424 148,986 124,406 77,000 76,576 41,375 34,409 23,718

N N (25)

5000

0

150 100 50 0 ppm (t1)

280 F N F

F F F (24)

281 N (23)

282 MeO OMe

F F F F N N F F F F (L3)

283

MeO OMe

F N F N F F (L4)

284 APPENDIX C: 19F NMR SPECTRA

F F N

F N F (3) F N F

N F F

285

F F N N N Cl F F (11)

286 F F N N N F F (12)

287 F F N N

(6) F F

288 F F N N

(7) F F

289 F F

N N

(8) F F

290

F F N

F N F (5) F F

N F F

291 F F

N

(10) F F

292 F F N F

F F (13)

293 F F

F

F F (18)

294 F F F F

N N

F F F F (9)

295

F N F F F F

F N N F N

F (4)

296 F N F F F F

F N N F N

F (4)

297 F N F N N Cl F F (27)

298 Cl F F N N F N F (29)

299 F N F F N N F (30)

300 F N F N N F (28) F

301 F N F N F F (19)

302 F F N N F F (20)

303 F F N N F F (21)

304 F F N F F (22)

305 F F F F N N F F F F (26)

306

F N F

F F F (24)

307 MeO OMe

F F F F N N F F F F (L3)

308 MeO OMe

F N F N F F (L4)

309 APPENDIX D: DERIVATION OF RATE CONSTANTS

Derivations of Equations 1-7:

. k 1 k2 NO NO 2 NO2 2 k 1,4-CHD -1 . A B C

k3

D (by-products) d[A] = −k [A] + k [B] A1 dt 1 −1 d[C] = k [HD][B] A2 dt 2 d[D] = k [B] A3 dt 3 d[B] = k [A] − k [B] − k [B] − k [HD][B] A4 dt 1 −1 3 2 d[B] Under Steady State Approximation conditions, = 0 dt

So, k1[A] − k−1[B] − k3[B] − k2 [HD][B] = 0 k [A] Then, [B] = 1 A5 k2 [HD] + k−1 + k3

d[A] 1kk −1[A] Equation A1 becomes, −= k1[A] + dt k2 [HD] + k−1 + k3

d[A] ⎛ kk 21 [HD] + kk 31 ⎞ This results to, = −[A]⎜ ⎟ A6 dt ⎝ k2 [HD] + k−1 + k3 ⎠ Integration of Equation A6 gives,

(− eff tk ) A kk 21 [HD] + kk 31 [A] = [A]0 e Eq. 1 ; where keff = Eq. 3 k2 [HD] + ()k−1 + k3

If 1,4-CHD is in excess, k2 and k-1 become more important than k3,

310 kk 21 [HD] Thus, keff = Eq. 6 k2 [HD] + k−1 Substitution of Eq.n A5 in Eq. A2 results, d[C] ⎛ kk 21 [HD] ⎞ = [A]⎜ ⎟ A7 dt ⎝ k2 [HD] + k−1 + k3 ⎠

C kk 21 [HD] Thus, keff = Eq. 4 k2 [HD] + ()k−1 + k3

If 1,4-CHD is in excess, k2 and k-1 become more important than k3,

Thus [A] = [A]0 −[C] A8 Substitution of Eq. A8 in Eq. A7 and integration of E. A7 gives ⎛ [P ] ⎞ kk [HD] ⎜ inf ⎟ 21 ln()X = ln⎜ ⎟ = keff t 2; where keff = Eq. 5 ⎝[Pinf ] −[P]⎠ k2 [HD] + k−1 Substitution of Eq. A5 in Eq. A3 results, d[D] ⎛ kk 31 ⎞ = [A]⎜ ⎟ A9 dt ⎝ k2 [HD] + k−1 + k3 ⎠

D kk 31 Thus, keff = A10 k2 [HD] + ()k−1 + k3 1 k 1 The inverse of Eq. 6 leads = −1 + Eq. 6 keff kk 21 [HD] k1

311 Derivations of Equations 8 and 9:

H(D) . H(D) O H(D)

k OR OR 3 OR' H(D) . . C k1 k 1,4-CHD -1 . 1,4-CHD A B 1,4-CHD D H k2 R' = CH , CD H R = CH , CD 3 2 3 3 Monoradical d[A] = −k [A] + k [B] A11 dt 1 −1 d[B] = k [A] − k [B] − k [HD][B] − k [B] − k [B] A12 dt 1 −1 2 3 4 d[B] Under Steady State Approximation conditions, = 0 dt

So, k1[A] − k−1[B] − k2 [HD][B] − k3[B] − k4 [B] = 0 k [A] which leads to [B] = 1 A13 k−1 + k3 + k4 + k2 [HD] d[A] k [A] Equation A11 becomes, −= k [A] + 1 dt 1 k + k + k + k [HD] −1 3 4 2 d[A] ⎛ k + k + k [HD] ⎞ ⎜ 3 4 2 ⎟ This results to, −= [A]⎜k1 ⎟ A14 dt ⎝ k−1 + k3 + k4 + k2 [HD]⎠

k + k2 [HD] and kapp = k1 Eq. 8 k−1 + k + k2 [HD] where k = k3 + k4 and Equation 8 is dependent on [HD]

When intramolecular reactions are much faster than intermolecular processes (k3 >> k4 and k3 >> k2[HD])

kk 31 Equation 8 becomes, kapp = Eq. 9 k−1 + k3 Equation 9 is independent on [HD]

312 APPENDIX E: X-RAY CRYSTALLOGRAPHIC ANALYSIS

F F F Cl F N F N F F F N N N N N F F F N Cl F N F F F F formula C18 H12 F4 N2 C19 H13 F4 N C17 H10 Cl F4 N3 C17 H10 Cl F4 N3 FW 332.30 331.30 367.73 367.73 λ (Ǻ) 0.71073 0.71073 0.71073 0.71073 crystal system Triclinic Orthorhombic Monoclinic Triclinic space group P-1 Pnma P2(1)/n P-1 a (Ǻ) 7.711(2) 7.5926(12) 13.958(3) 6.8075(7) b (Ǻ) 11.939(4) 12.408(2) 7.5579(17) 9.0631(10) c (Ǻ) 15.819(5) 15.483(3) 15.236(3) 13.4888(15) α (deg) 91.697(6) 90 90 70.863(2) β (deg) 90.421(5) 90 114.600(4) 78.833(2) γ ( deg) 98.628(5) 90 90 75.604(2) V (Ǻ3) 1439.1(7) 1458.7(4) 1461.4(6) 755.80(14) Z 4 4 4 2 3 Dcalc (g/cm ) 1.534 1.509 1.671 1.616 µ mm−1) ( 0.128 0.124 0.313 0.303 F(000) 680 680 744 372 reflns collected 19896 18894 19407 10529 unique reflns 7134 1899 3630 3720 max and min 0.80148 0.54365 0.8621 0.5355 0.98535 0.64643 0.86250 transa R1 [I > 2σ(I)] 0.0461 0.0654 0.0470 0.0372 wR2 0.1242 0.1471 0.1195 0.1006 a Or the ratio of minimum to maximum transmission

313

F F F F F F N N N N N N F F F F F F formula C18 H16 N2 C18 H8 F8 N2 C18 H12 F4 N2 FW 260.33 404.26 332.30 λ (Ǻ) 0.71073 0.71073 0.71073 crystal system Orthorhombic Triclinic Monoclinic space group Pnma P-1 P2(1)/n a (Ǻ) 11.3748(9) 8.0015(7) 7.7667(6) b (Ǻ) 15.1163(12) 8.1970(7) 14.8121(12) c (Ǻ) 7.6120(6) 11.9516(10) 12.6730(10) α (deg) 90 85.903(2) 90 β (deg) 90 81.555(2) 99.8570(10) γ ( deg) 90 75.332(2) 90 V (Ǻ3) 1308.84(18) 749.63(11) 1436.4 Z 4 2 4 3 Dcalc (g/cm ) 1.321 1.791 1.537 µ mm−1) ( 0.078 0.177 0.128 F(000) 100(2) 173(2) 173(2) reflns collected 552 404 680 unique reflns 16961 10295 19245 max and min transa 0.8090 0.8490 0.8474 R1 [I > 2σ(I)] 0.0568 0.0581 0.0670 wR2 0.1448 0.1405 0.1805 a Or the ratio of minimum to maximum transmission

314

Complex 1 Complex 2 Complex 3 Complex 4 formula C18 H16 Ag N3 O3C27 H24 Ag N4 O3C36 H36 Cu2 Cl4 N4 C36 H24 Ag F8 N5 O3 FW 430.21 560.37 793.41 834.47 λ (Ǻ) 0.71073 0.71073 0.71073 0.71073 crystal system Monoclinic Orthorhombic Triclinic Monoclinic space group P2/c Pccn P-1 P2(1)/n a (Ǻ) 9.6811(6) 34.8648(17) 8.6528(7) 6.7893(4) b (Ǻ) 8.1066(5) 10.9050(5) 11.0091(9) 7.6743(5) c (Ǻ) 12.6643(9) 15.1589(7) 12.2088(10) 31.3763(18) α (deg) 90 90 70.4320(10) 90 β (deg) 121.3020(10) 90 70.4850(10) 93.5760(10) γ ( deg) 90 90 84.2940(10) 90 V (Ǻ3) 849.23(10) 5763.4(5) 1032.78(10) 1631.62(17) Z 2 8 2 2 3 Dcalc (g/cm ) 1.682 1.292 1.596 1.699 µ mm−1)( 1.209 0.730 1.646 0.711 F(000) 173(2) 173(2) 501 100(2) reflns collected 432 2280 14122 836 unique reflns 11302 7186 5108 21.666 max and min transa 0.8591 0.8768 0.8631 0.8819 R1 [I > 2σ(I)] 0.0905 0.0948 0.0453 0.0513 wR2 0.1514 0.2302 0.1316 0.1055 a Or the ratio of minimum to maximum transmission

315 APPENDIX F: UV SPECTRA

2-Py-TFP (6) [ ] = 6.35 × 10-5 M 4 İ293 = 2.23 × 10 L/mol.cm log İ293 = 4.35 4 İ265.5 = 1.44 × 10 L/mol.cm log İ266 = 4.16

3-Py-TFP (7) [ ] = 4.365 × 10-5 M 4 İ296 = 2.76 × 10 L/mol.cm log İ296 = 4.44 4 İ286 = 2.86 × 10 L/mol.cm log İ286 = 4.46

316

4-Py-TFP (8) [ ] = 1.86 × 10-5 M 4 İ288 = 2.50 × 10 L/mol.cm log İ288 = 4.40 4 İ273 = 3.00× 10 L/mol.cm log İ273 = 4.48 4 İ227 = 0.96× 10 L/mol.cm log İ227 = 3.98

Ph-TFP (10) [ ] = 6.18 × 10-5 M 4 İ302 = 2.57 × 10 L/mol.cm log İ296 = 4.41 4 İ287 = 2.58 × 10 L/mol.cm log İ287 = 4.41

317

Bis-TFP (9) [ ] = 2.01 × 10-5 M 4 İ285 = 2.20 × 10 L/mol.cm log İ285 = 4.34 4 İ271 = 2.38 × 10 L/mol.cm log İ271 = 4.38

4-Py-Ph (15) [ ] = 7.8 × 10-5 M 4 İ296 = 2.5 × 10 L/mol.cm log İ296 = 4.40 4 İ280 = 2.8× 10 L/mol.cm log İ280 = 4.45

318

Py-bis-TFP (5) [ ] = 4.35 × 10-5 M 4 İ298 = 2.5 × 10 L/mol.cm log İ298 = 4.40 4 İ266 = 2.95 × 10 L/mol.cm log İ266 = 4.47 4 İ253 = 2.6 × 10 L/mol.cm log İ253 = 4.41 4 İ233 = 2.1 × 10 L/mol.cm log İ233 = 4.32

Pyra-TFP (12) [ ] = 4.6 × 10-5 M 4 İ297 = 2.4 × 10 L/mol.cm log İ297 = 4.38 4 İ260 = 1.3 × 10 L/mol.cm log İ260 = 4.11

319

Pyra-Cl-TFP (11) [ ] = 5.6 × 10-5 M 4 İ306 = 2.2 × 10 L/mol.cm log İ306 = 4.34 4 İ267 = 1.4 × 10 L/mol.cm log İ267 = 4.15

Pyra-bis-TFP (3) [ ] = 2.3 × 10-5 M 4 İ302 = 3.5 × 10 L/mol.cm log İ302 = 4.54 4 İ256 = 3.1 × 10 L/mol.cm log İ256 = 4.49 4 İ246 = 2.4 × 10 L/mol.cm log İ246 = 4.38

320

Ph-PFB (18) [ ] = 5.8 × 10-5 M 4 İ296 = 2.87 × 10 L/mol.cm log İ296 = 4.46 4 İ278 = 3.33 × 10 L/mol.cm log İ278 = 4.52

Pyra-Ph (16) [ ] = 2.29 × 10-5 M 4 İ302 = 1.50 × 10 L/mol.cm log İ301 = 4.18 4 İ280 = 1.00 × 10 L/mol.cm log İ280 = 4.00 4 İ272 = 1.06 × 10 L/mol.cm log İ272 = 4.02 4 İ266 = 1.02 × 10 L/mol.cm log İ266 = 4.01

321 4 İ217 = 0.90 × 10 L/mol.cm log İ217 = 3.95

2-Py-PFB (13) [ ] = 1.11× 10-4 M 4 İ300 = 1.22 × 10 L/mol.cm log İ300 = 4.08 4 İ291 = 1.32 × 10 L/mol.cm log İ291 = 4.12 4 İ284 = 1.36 × 10 L/mol.cm log İ284 = 4.14 4 İ265 = 1.12 × 10 L/mol.cm log İ265 = 4.05

4-Py-TFP-Tetra (21)

322 [ ] = 2.89 × 10-5 M 4 İ263 = 0.42 × 10 L/mol.cm log İ263 = 3.62 4 İ222 = 0.75 × 10 L/mol.cm log İ222 = 3.88

Bis-4-Py-Tetra (25) [ ] = 6.68 × 10-5 M 4 İ259 = 0.98 × 10 L/mol.cm log İ259 = 3.99 4 İ222 = 1.99 × 10 L/mol.cm log İ222 = 4.30

2-Py-PFB-Tetra

323 [ ] = 2.29 × 10-5 M 4 İ263 = 0.58 × 10 L/mol.cm log İ263 = 3.76 4 İ214 = 1.97 × 10 L/mol.cm log İ214 = 4.29

4-Py-Ph-Tetra (23) [ ] = 5.56 × 10-5 M 4 İ223 = 1.18 × 10 L/mol.cm log İ223 = 4.07 4 İ257 = 0.36 × 10 L/mol.cm log İ257 = 3.56

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345 BIOGRAPHICAL SKETCH

Tarek A. Zeidan was born and raised in Saida (Saidon), Lebanon. He attended Raffic Harriri High School in Saida (formally known as New Saidon School). After his graduation (June 1997), he moved to the capital, Beirut, and attended the American University of Beirut (AUB) as an undergraduate in the Department of Chemistry. He was first introduced to organic chemistry research through an undergraduate project during summer 1999 in organic synthesis under the guidance of Professor Makhlouf J. Haddadin. He worked on the synthesis of quinoxaline 1,4- dioxides used as therapeutic agents in hypoxia. This work was in collaboration with Professor Hala Mohtasseb in the Biology Department at AUB. During his last semester at AUB, he worked on the synthesis of chlorosulfonyl chalcones using Michael addition under the supervision of Professor Paul Bassin. He graduated from AUB in the spring 2000 term. He received a teaching assistantship from Florida State University and moved to Tallahassee, Florida, to join the graduate program in organic chemistry there. Since then, he has worked under the supervision of Professor Igor V. Alabugin on mechanistic and kinetic studies of interesting photochemical and thermal reactions of enediynes. He accepted a postdoctoral fellowship at Northwestern University. Starting in October 2005, he will be working under the supervision of Professor Frederick D. Lewis on DNA molecular photonics. Tarek A. Zeidan is a member in the American Chemical Society, the Inter-American Photochemical Society and the Sigma Xi Society. He is married to Nadine Tassabehji.

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