Verdazyl Radicals As Mediators in Living Radical Polymerizations and As Novel Substrates for Heterocyclic Syntheses

VERDAZYL RADICALS AS MEDIATORS IN LIVING RADICAL POLYMERIZATIONS AND AS NOVEL SUBSTRATES FOR HETEROCYCLIC SYNTHESES

Eric Kuan Yu Chen

A thesis submitted in conformity with the requirements

for the degree of Doctor of Philosophy

Graduate Department of Chemistry

University of Toronto

VERDAZYL RADICALS AS MEDIATORS IN LIVING RADICAL POLYMERIZATIONS AND AS NOVEL SUBSTRATES FOR HETEROCYCLIC SYNTHESES

Degree of Doctor of Philosophy, 2010 Eric Kuan Yu Chen Department of Chemistry, University of Toronto Abstract

Verdazyl radicals are a family of multicoloured stable free radicals. Aside from the defining backbone of four nitrogen atoms, these radicals contain multiple highly modifiable sites that grant them a high degree of derivatization. Despite having been discovered more than half a century ago, limited applications have been found for the verdazyl radicals and little is known about their chemistry. This thesis begins with an investigation to determine whether verdazyl radicals have a future as mediating agents in living radical polymerizations and progresses to their application as substrates for organic synthesis, an application that to date has not been pursued either with verdazyl or nitroxide stable radicals.

The first part of this thesis describes the successful use of the 1,5dimethyl3phenyl6 oxoverdazyl radical as a mediating agent for styrene and nbutyl acrylate stable free radical polymerizations. The study of other verdazyl derivatives demonstrated the impact of steric and electronic properties of the verdazyl radicals on their ability to mediate polymerizations.

The second part of this thesis outlines the initial discovery and the mechanistic elucidation of the transformation of the 1,5dimethyl3phenyl6oxoverdazyl radical into an azomethine imine, which in the presence of dipolarophiles, undergoes a [3+2] 1,3dipolar cycloaddition reaction to yield unique pyrazolotetrazinone structures. The reactivity of the azomethine imine and the scope of the reaction were also examined.

The third part of this thesis describes the discovery and mechanistic determination of a base induced rearrangement reaction that transforms the verdazylderived pyrazolotetrazinone cycloadducts into corresponding pyrazolotriazinones or triazole structures. The nucleophilicity, or the lack thereof, of the base employed leading to various rearrangement products was examined in detail.

The final part of this thesis demonstrates the compatibility of the verdazylinitiated cycloaddition and rearrangement reactions with the philosophy of diversityoriented synthesis in generating libraries of heterocycles. A library of verdazylderived heterocycles was generated in a short amount of time and was tested nonspecifically for biological activity against acute myeloid leukemia and multiple myeloma cell lines. One particular compound showed cellkilling activity at the 250 M range, indicating future potential for this chemistry in the field of drug discovery.

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Acknowledgements

First and foremost, I would like to thank my supervisor Professor Michael Georges.

Words cannot express my gratitude for all you have done for me over the years. The invaluable lessons you have taught me in chemistry, life, or otherwise, will take me long ways from here.

Thank you for unselfishly sharing your knowledge and experience, and thank you for being an excellent scientist, supervisor, teacher and friend.

I would like to thank Dr. Gord Hamer not only for sharing his NMR and DFT expertise, but also for his support through all stages of my degree. I would also like to thank my fellow graduate students Andrea, Joanne, Delphine, Julie, Taka, Matthew, Jeremy and Anna; you have all made my learning and working experience more enjoyable. A special thanks to Julie for paving the path and guiding me through graduate student life. To the postdoctoral fellows

Antoine, Steve and Angela: thank you for enriching and expanding my learning horizons. To the members of my supervisory committee Professor Winnik and Professor Kumacheva, along with the members of my thesis committee Professor Gunning and Professor Chong: thank you for the effort and guidance.

I would like to thank my friends who have stuck by me through times good and bad: Jon,

Sco, Jeff, Selene, Ashley, Lin, Nat, Julie, Richard, Adrienne, Couch, Saad, Ping, Ryan, George and all of you others; thanks for the support and company.

Last but definitely not least I would like to thank my family for the support through it all: my parents Julia and Kevin; my sister Christina. Thank you for being patient and having faith in me. I could not have done this without you guys.

Table of Contents

1 Chapter 1 - Introduction

1.1 Verdazyl Radicals ...... 1 1.1.1 Introduction ...... 1 1.1.2 History, Synthesis, and Characterization of Verdazyl Radicals ...... 2 1.1.3 History of Verdazyl Radical Chemistry ...... 7 1.1.4 History of Verdazyl Radical Applications ...... 8 1.1.5 Concluding Remarks ...... 9 1.2 Stable Free Radical Polymerization ...... 9 1.2.1 Conventional vs. Living Polymerization ...... 9 1.2.2 Introduction to Living Radical Polymerization Systems ...... 14 1.2.3 NitrogenCentered Radicals in Stable Free Radical Polymerizations ...... 27 1.2.4 Concluding remarks ...... 33 1.3 1,3Dipolar Cycloadditions Involving Azomethine Imines ...... 34 1.3.1 Introduction to 1,3Dipolar Cycloadditions ...... 34 1.3.2 Azomethine Imines as Dipoles ...... 37 1.3.3 History of Azomethine Imines ...... 39 1.3.4 Recent Developments in Azomethine Imine Cycloadditions ...... 41 1.3.5 Concluding Remarks ...... 44 1.4 Heterocyclic Rearrangements ...... 45 1.4.1 General Considerations ...... 45 1.4.2 Dimroth Rearrangements ...... 45 1.5 References ...... 54

2 Chapter 2 - Verdazyl-Mediated Living Radical Polymerization of Styrene and n-Butyl Acrylate

2.1 Introduction and Objective ...... 62 2.2 Experimental Section ...... 65

2.2.1 Materials and Equipment ...... 65 2.2.2 Styrene Polymerization Initiated with 1,1’Azobis(cyclohexanecarbonitrile) (Vazo® 88) in the Presence of 1,5Dimethyl3phenyl6oxoverdazyl Radical 16 ...... 67 2.2.3 Styrene Polymerization Initiated with BPO in the Presence of 1,3,5Triphenyl6 oxoverdazyl Radical 17 ...... 67 2.2.4 Synthesis of 2(3Oxo2,4,6triphenyl3,4dihydro1,2,4,5tetrazin1(2H)yl)2 phenylethyl benzoate ( 18 ) ...... 68 2.2.5 Styrene Polymerization Initiated with Unimolecular Initiator 18 ...... 68 2.2.6 Synthesis of 2(2,4Dimethyl3oxo6phenyl3,4dihydro1,2,4,5tetrazin1(2H) yl)2phenylethyl benzoate ( 19 ) ...... 69 2.2.7 Styrene Polymerization Initiated with Unimolecular Initiator 19 ...... 69 2.2.8 nButyl Acrylate Polymerization Initiated with Unimolecular Initiator 19 ...... 69 2.2.9 Reaction of 1,5Dimethyl3phenyl6oxoverdazyl Radical 16 with BPO and Styrene ...... 70 2.2.10 Preparation of Poly( nbutyl acrylatebpolystyrene) from a Poly( nbutyl acrylate) Macroinitiator ...... 70 2.2.11 Preparation of Poly(styrenebnbutyl acrylate) from a Polystyrene Macroinitiator ...... 71 2.2.12 Synthesis of 2(6(4Cyanophenyl)2,4dimethyl3oxo3,4dihydro1,2,4,5 tetrazin1(2H)yl)2phenylethyl benzoate ( 23 ) ...... 71 2.2.13 Styrene Polymerization Initiated with Unimolecular Initiator 23 ...... 72 2.2.14 nButyl Acrylate Polymerization Initiated with Unimolecular Initiator 23 ...... 72 2.2.15 Synthesis of 2(2,4dimethyl6(1methyl1Himidazol2yl)3oxo3,4dihydro 1,2,4,5tetrazin1(2H)yl)2phenylethyl benzoate (24 ) ...... 72 2.2.16 nButyl Acrylate Polymerization Initiated with Unimolecular Initiator 24 ...... 72 2.2.17 Synthesis of 2(2,4Dimethyl3oxo3,4dihydro1,2,4,5tetrazin1(2H)yl)2 phenylethyl benzoate ( 22 ) ...... 73 2.2.18 Reaction of Carbonic Acid Bis(1Methylhydrazide) with 2,6 Dimethylbenzaldehyde ( 29 ) ...... 73 2.2.19 Synthesis of 1(1,5Dimethyl3phenyl6phosphaverdazyl)ethylbenzene Unimolecular Initiator ( 36 ) by ATRA with (1Bromoethyl)benzene ...... 74 2.2.20 Synthesis of 1(1,5Dimethyl3phenyl6phosphaverdazyl)ethylbenzene Unimolecular Initiator ( 36 ) with Sodium Hydride and (1Bromoethyl)benzene ...... 75

2.2.21 nButyl Acrylate Polymerization Initiated with Unimolecular Initiator 36 ...... 75 2.3 Results and Discussion ...... 75 2.3.1 VerdazylMediated Styrene Polymerization with Bimolecular Initiators ...... 75 2.3.2 VerdazylMediated Styrene Polymerization with Unimolecular Initiators ...... 78 2.3.3 VerdazylMediated nButyl Acrylate Polymerization with Unimolecular Initiators ...... 83 2.3.4 Block Copolymer Formation – Chain Extension with VerdazylTerminated Macromolecules ...... 89 2.3.5 Polymerizations with Various 1,5Dimethyl6Oxoverdazyl Radicals ...... 90 2.3.6 Designs and Polymerizations with Other Verdazyl Radicals ...... 98 2.4 Concluding Remarks ...... 103 2.5 Future Work ...... 104 2.6 References ...... 104

3 Chapter 3 - 1,3-Dipolar Cycloaddition via Verdazyl-Derived Azomethine Imines

3.1 Introduction and Objective ...... 107 3.2 Experimental Section ...... 108 3.2.1 Materials and Equipment ...... 108 3.2.2 Synthesis of 2Methyl4,6diphenyl2,6,7,8tetrahydro1Hpyrazolo[1,2 a][1,2,4,5]tetrazin1one ( 20 ) ...... 109 3.2.3 Synthesis of 5Benzyl2,4dimethyl6phenyl4,5dihydro1,2,4,5tetrazin3(2H) one ( 43 ) ...... 110 3.2.4 General Optimized Procedure for the 1, 3Dipolar Cycloaddition of Verdazyl Radical 16 with Various Dipolarophiles ...... 110 3.2.5 Synthesis of Methyl 2methyl1oxo4phenyl2,6,7,8tetrahydro1Hpyrazolo[1,2 a][1,2,4,5]tetrazine6carboxylate ( 21 ) ...... 111 3.2.6 Synthesis of tert Butyl 2methyl1oxo4phenyl2,6,7,8tetrahydro1H pyrazolo[1,2a][1,2,4,5]tetrazine6carboxylate ( 44 ) ...... 111 3.2.7 Synthesis of Methyl 2,6dimethyl1oxo4phenyl2,6,7,8tetrahydro1H pyrazolo[1,2a][1,2,4,5]tetrazine6carboxylate ( 45 ) ...... 112 3.2.8 Synthesis of 2Methyl1oxo4phenyl2,6,7,8tetrahydro1Hpyrazolo[1,2 a][1,2,4,5]tetrazine6carbonitrile ( 46 ) ...... 112

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3.2.9 Synthesis of 2,6Dimethyl1oxo4phenyl2,6,7,8tetrahydro1Hpyrazolo[1,2 a][1,2,4,5]tetrazine6carbonitrile ( 47 ) ...... 113 3.2.10 Synthesis of (6R,7R)Diethyl 2methyl1oxo4phenyl2,6,7,8tetrahydro1H pyrazolo[1,2a][1,2,4,5]tetrazine6,7dicarboxylate ( 48 ) ...... 113 3.2.11 Synthesis of (6S,7R)Diethyl 2methyl1oxo4phenyl2,6,7,8tetrahydro1H pyrazolo[1,2a][1,2,4,5]tetrazine6,7dicarboxylate ( 49 ) ...... 114 3.2.12 Synthesis of (6R,7R)2Methyl1oxo4phenyl2,6,7,8tetrahydro1H pyrazolo[1,2a][1,2,4,5]tetrazine6,7dicarbonitrile ( 50 ) ...... 114 3.2.13 Synthesis of NMethyl Maleimide Cycloadduct ( 51 ) ...... 115 3.3 Results and Discussion ...... 115 3.3.1 [3+2] 1,3Dipolar Cycloaddition Initiated by Verdazyl Radical ...... 115 3.3.2 VerdazylDerived Azomethine Imine ...... 121 3.4 Concluding Remarks ...... 129 3.5 Future Work ...... 129 3.6 References ...... 130

4 Chapter 4 - Rearrangement Reactions of Verdazyl-Derived Cycloadducts

4.1 Introduction and Objective ...... 132 4.2 Experimental Section ...... 133 4.2.1 Materials and Equipment ...... 133 4.2.2 General Procedure for Cycloaddition Reactions ...... 134 4.2.3 Synthesis of 2Methyl4phenyl7,8dihydro1Hpyrazolo[1,2a][1,2,4,5]tetrazine 1,6(2H)dione ( 57 ) ...... 135 4.2.4 Synthesis of (Z)2,3Bis(2,4dimethyl3oxo6phenyl3,4dihydro1,2,4,5tetrazin 1(2H)yl)acrylonitrile ( 58 ) ...... 135 4.2.5 Synthesis of 5Methyl7phenylpyrazolo[1,5d][1,2,4]triazin4(5 H)one ( 67 ) .... 136 4.2.6 Synthesis of Methyl 6acetoxy2methyl1oxo4phenyl2,6,7,8tetrahydro1H pyrazolo[1,2a][1,2,4,5]tetrazine6carboxylate ( 66 ) ...... 136 4.2.7 Synthesis of Methyl 2methyl1oxo4phenyl2,8dihydro1Hpyrazolo[1,2 a][1,2,4,5]tetrazine6carboxylate ( 68 ) ...... 137 4.2.8 Conversion of 66 or 68 to 67 by Heat ...... 137 4.2.9 Conversion of 66 or 68 to 67 by Sodium Hydride ...... 137

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4.2.10 Synthesis of Methyl 5methyl4oxo7phenyl1,2,3,3a,4,5hexahydropyrazolo[1,5 d][1,2,4]triazine3acarboxylate ( 70 ) ...... 137 4.2.11 Conversion of 21 to 70 by Lithium Diisopropylamide ...... 138 4.2.12 Synthesis of Methyl 2(1methyl3phenyl1H1,2,4triazol5yl)ethylcarbamate (76 ) ...... 138 4.2.13 Synthesis of Ethyl 2(1methyl3phenyl1H1,2,4triazol5yl)ethylcarbamate ( 77 ) ...... 139 4.2.14 Synthesis of N,N ,2Trimethyl1oxo4phenyl2,6,7,8tetrahydro1Hpyrazolo[1,2 a][1,2,4,5]tetrazine6carboxamide ( 72 ) ...... 140 4.2.15 Synthesis of N,N ,5Trimethyl4oxo7phenyl1,2,3,3a,4,5hexahydropyrazolo[1,5 d][1,2,4]triazine3acarboxamide ( 73 ) ...... 140 4.3 Results and Discussion ...... 141 4.3.1 Ketene Equivalents and Captodative Olefins in VerdazylInitiated Cycloaddition ...... 141 4.3.2 Rearrangement of Pyrazolotetrazinone to Pyrazolotriazinone ...... 144 4.3.3 Rearrangement of Pyrazolotetrazinone to Triazolyl Carbamate ...... 152 4.4 Concluding Remarks ...... 158 4.5 Future Work ...... 159 4.6 References ...... 160

5 Chapter 5 - Diversity-Oriented Synthesis of Verdazyl-Derived Heterocycles

5.1 Introduction and Objective ...... 161 5.2 Experimental Section ...... 163 5.2.1 Materials and Equipment ...... 163 5.2.2 General Optimized Procedure for the 1, 3Dipolar Cycloaddition of 1,5Dimethyl 6oxoverdazyl Radicals with Various Dipolarophiles ...... 164 5.2.3 General Procedure for the Reduction of Nitriles with in situ t-Boc Protection .... 165 5.2.4 General Procedure for the Amidation of tBoc Protected Amines ...... 165 5.2.5 Synthesis of Dimethyl 2methyl1oxo4phenyl2,6,7,8tetrahydro1H pyrazolo[1,2a][1,2,4,5]tetrazine6,7dicarboxylate ( 86 ) ...... 166 5.2.6 Synthesis of Methyl 4(4cyanophenyl)2methyl1oxo2,6,7,8tetrahydro1H pyrazolo[1,2a][1,2,4,5]tetrazine6carboxylate ( 87 ) ...... 166

5.2.7 Synthesis of Methyl 4(1Himidazol5yl)2methyl1oxo2,6,7,8tetrahydro1H pyrazolo[1,2a][1,2,4,5]tetrazine6carboxylate ( 88 ) ...... 166 5.2.8 Synthesis of 2Methyl4(4nitrophenyl)1oxo2,6,7,8tetrahydro1H pyrazolo[1,2a][1,2,4,5]tetrazine6carbonitrile ( 89 ) ...... 167 5.2.9 Synthesis of 4(4Cyanophenyl)2methyl1oxo2,6,7,8tetrahydro1H pyrazolo[1,2a][1,2,4,5]tetrazine6carbonitrile ( 90) ...... 167 5.2.10 Synthesis of 4(2Methyl1oxo6phenyl2,6,7,8tetrahydro1Hpyrazolo[1,2 a][1,2,4,5]tetrazin4yl)benzonitrile ( 91 ) ...... 167 5.2.11 Synthesis of 2Methyl1oxo4(pyridin2yl)2,6,7,8tetrahydro1Hpyrazolo[1,2 a][1,2,4,5]tetrazine6carbonitrile ( 92 ) ...... 168 5.2.12 Synthesis of 4(4Cyanophenyl)Nisopropyl2methyl1oxo2,6,7,8tetrahydro 1Hpyrazolo[1,2a][1,2,4,5]tetrazine6carboxamide ( 93 ) ...... 168 5.2.13 Synthesis of Dimethyl 5methyl4oxo7phenyl1,2,3,3a,4,5 hexahydropyrazolo[1,5d][1,2,4]triazine3,3adicarboxylate ( 94 ) ...... 168 5.2.14 Synthesis of Methyl 7(4cyanophenyl)5methyl4oxo1,2,3,3a,4,5 hexahydropyrazolo[1,5d][1,2,4]triazine3acarboxylate ( 95 ) ...... 169 5.2.15 Synthesis of Isopropyl 2(3(4cyanophenyl)1methyl1H1,2,4triazol5 yl)ethylcarbamate ( 96 ) ...... 169 5.2.16 Synthesis of Methyl 2(1methyl3(pyridin2yl)1H1,2,4triazol5 yl)ethylcarbamate ( 97 ) ...... 169 5.2.17 Synthesis of Methyl 2(3(3fluoropyridin4yl)1methyl1H1,2,4triazol5 yl)ethylcarbamate ( 98 ) ...... 170 5.2.18 Synthesis of Isopropyl 2(3(3fluoropyridin4yl)1methyl1H1,2,4triazol5 yl)ethylcarbamate ( 99 ) ...... 170 5.2.19 Synthesis of N((2Methyl1oxo4phenyl2,6,7,8tetrahydro1Hpyrazolo[1,2 a][1,2,4,5]tetrazin6yl)methyl) tert butylcarbamate ( 100 ) ...... 170 5.2.20 Synthesis of N((2Methyl1oxo4phenyl2,6,7,8tetrahydro1Hpyrazolo[1,2 a][1,2,4,5]tetrazin6yl)methyl)acetamide ( 101 ) ...... 171 5.2.21 Synthesis of Methyl 4(4(isobutyramidomethyl)phenyl)2methyl1oxo2,6,7,8 tetrahydro1Hpyrazolo[1,2a][1,2,4,5]tetrazine6carboxylate ( 102 ) ...... 171 5.2.22 Synthesis of N(4(2Methyl1oxo6phenyl2,6,7,8tetrahydro1Hpyrazolo[1,2 a][1,2,4,5]tetrazin4yl)benzyl)acetamide ( 103 ) ...... 171 5.2.23 Synthesis of N(4(2Methyl1oxo6phenyl2,6,7,8tetrahydro1Hpyrazolo[1,2 a][1,2,4,5]tetrazin4yl)benzyl)isobutyramide ( 104 ) ...... 172

5.2.24 Synthesis of Methyl 2(3(4(tert butylcarbamoylmethyl)phenyl)1methyl1H 1,2,4triazol5yl)ethylcarbamate ( 105 ) ...... 172 5.2.25 Synthesis of Isopropyl 2(3(4(tert butylcarbamoylmethyl)phenyl)1methyl1H 1,2,4triazol5yl)ethylcarbamate ( 106 ) ...... 172 5.2.26 Synthesis of Methyl 2(3(4(acetamidomethyl)phenyl)1methyl1H1,2,4triazol 5yl)ethylcarbamate ( 107 ) ...... 173 5.2.27 Synthesis of Isopropyl 2(3(4(acetamidomethyl)phenyl)1methyl1H1,2,4 triazol5yl)ethylcarbamate ( 108 ) ...... 173 5.2.28 Synthesis of Methyl 2(3(4(isobutyramidomethyl)phenyl)1methyl1H1,2,4 triazol5yl)ethylcarbamate ( 109 ) ...... 173 5.2.29 Synthesis of Isopropyl 2(3(4(isobutyramidomethyl)phenyl)1methyl1H1,2,4 triazol5yl)ethylcarbamate ( 110 ) ...... 174 5.3 Results and Discussion ...... 174 5.3.1 First Generation Library of VerdazylDerived Heterocycles – VerdazylInitiated Cycloaddition Products ...... 174 5.3.2 Second Generation Library of VerdazylDerived Heterocycles – Rearrangement Products of VerdazylDerived Cycloadducts ...... 175 5.3.3 Third Generation Library of VerdazylDerived Heterocycles – Amide Derivatives from the Reduction of Nitriles and Subsequent Amidation ...... 175 5.3.4 DOS Library of VerdazylDerived Heterocycles ...... 177 5.3.5 Biological Activity Testing ...... 180 5.4 Concluding Remarks ...... 181 5.5 Future Work ...... 181 5.6 References ...... 182

List of Tables

Table 2-1. Summary of the MW and PDI of styrene polymerization initiated with Vazo® 88 and mediated with 1,5dimethyl3phenyl6oxoverdazyl radical 16 ...... 76 Table 2-2. Summary of the MW and PDI of a styrene polymerization initiated with BPO and mediated with 1,3,5triphenyl6oxoverdazyl radical 17 ...... 77 Table 2-3. Summary of the MW and PDI of styrene polymerization initiated with the benzoyl styrene1,3,5triphenyl6oxoverdazyl radical adduct BSV 18 ...... 79 Table 2-4. Summary of the MW and PDI of styrene polymerization initiated with the benzoyl styrene1,5dimethyl3phenyl6oxoverdazyl radical adduct BSV 19 ...... 82 Table 2-5. Summary of the MW and PDI of nbutyl acrylate polymerization initiated with the benzoylstyrene1,5dimethyl3phenyl6oxoverdazyl radical adduct BSV 19 ...... 85 Table 2-6. Summary of the MW and PDI of styrene polymerization initiated with the benzoyl styrene1,5dimethyl3(pCNphenyl)6oxoverdazyl radical adduct BSV 23 ...... 91 Table 2-7. Summary of the MW and PDI of nbutyl acrylate polymerization initiated with the benzoylstyrene1,5dimethyl3(pCNphenyl)6oxoverdazyl radical adduct BSV 23 ...... 92 Table 2-8. Summary of the MW and PDI of nbutyl acrylate polymerization initiated with the benzoylstyrene1,5dimethyl3(methylimidazole)6oxoverdazyl radical adduct BSV 24 ...... 93 Table 2-9. Summary of the MW and PDI of styrene polymerization initiated with the benzoyl styrene1,5dimethyl3hydrogen6oxoverdazyl radical adduct BSV 22 ...... 95 Table 2-10. Summary of the MW and PDI of nbutyl acrylate polymerization initiated with the benzoylstyrene1,5dimethyl3hydrogen6oxoverdazyl radical adduct BSV 22 ...... 96 Table 3-1. Cycloaddition reactions of 1,5dimethyl3phenyl6oxoverdazyl radical 16 with various dipoles; neat or minimal solvent...... 123 Table 3-2. Quantitative DFT calculations of the FMO energies of dipole 41 with dipolarophiles; bolded values represent smallest energy gap...... 126

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List of Figures

Figure 1-1. The verdazyl backbone with known modifications...... 1 Figure 1-2. Xray structures of a nonplanar and a planar verdazyl radical...... 2

Figure 1-3. Mn vs. % conversion plot for a conventional radical polymerization...... 12

Figure 1-4. Mn vs. % conversion plot for a living anionic polymerization...... 13 Figure 1-5. Examples of bi, tri, and tetradentate ligands employed in ATRP...... 17

Figure 1-6. Reversible AdditionFragmentation chain Transfer (RAFT) agent...... 17 Figure 1-7. General structure of a nitroxide radical and TEMPO...... 19

4 Figure 1-8. Comparison of bond strength between TEMPOterminated styrene ( kd = 5.2 x 10 1 5 1 s ) and TEMPOterminated acrylate ( kd = 3.4 x 10 s )...... 22 Figure 1-9. TIPNO and SG1 nitroxides...... 25 Figure 1-10. 1,1Diadamantyl nitroxide...... 26 Figure 1-11. Triazolinyl radical and its spiro derivative...... 29 Figure 1-12. Styrenetriphenylverdazyl bond...... 32 Figure 1-13. Examples of 1,3dipoles...... 34 Figure 1-14. FMO sign and coefficient matchup between a dipole and a dipolarophile...... 35 Figure 1-15. Lowest energy gap set of HOMO/LUMO interaction between a dipole and a dipolarophile...... 36 Figure 1-16. FMO matchup for Sustmann type I, II, and III dipoles with dipolarophiles...... 37 Figure 1-17. Resonance structures of an azomethine imine...... 38 Figure 1-18. Examples of azomethine imines...... 39 Figure 2-1. GPC for the polymerization of styrene initiated with Vazo® 88 and mediated with 1,5dimethyl3phenyl6oxoverdazyl radical 16 (solid3h, dashed5h, dotted6h)...... 76 Figure 2-2. GPC plot of a styrene polymerization initiated with BPO and mediated with 1,3,5 triphenyl6oxoverdazyl radical 17 (solid1h, dashed2h)...... 78 Figure 2-3. GPC of styrene polymerization initiated with the benzoylstyrene1,3,5triphenyl6 oxoverdazyl radical adduct BSV 18 (solid0.5h, dashed1.5h, dotted4h, dash/dotted6h)...... 80 Figure 2-4. GPC of styrene polymerization initiated with the benzoylstyrene1,5dimethyl3 phenyl6oxoverdazyl radical adduct BSV 19 (solid1h, dashed2h, dotted3h, dash/dotted4h, dashed/2dotted5h)...... 83

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Figure 2-5. GPC of an nbutyl acrylate polymerization initiated with the benzoylstyrene1,5 dimethyl3phenyl6oxoverdazyl radical adduct BSV 19 (solid2.5h, dashed5.5h, dotted8.5h, dash/dotted12h, dashed/2dotted18h, dashed28h)...... 86 Figure 2-6. Customdesigned sealed tube to prevent monomer evaporation...... 88 Figure 2-7. GPC plot of polystyreneb(nbutyl acrylate) diblock formation mediated with verdazyl 16 . Starting homopolymer (MW = 6,250 g mol 1, PDI = 1.20, solid), resulting block copolymer (MW = 8,800 g mol 1, PDI = 1.26, dashed)...... 89 Figure 2-8. GPC plot of poly( nbutyl acrylate)bstyrene diblock formation mediated with verdazyl 16 . Starting homopolymer (MW = 10,400 g mol 1, PDI = 1.20, solid), resulting block copolymer (MW = 13,200 g mol 1, PDI = 1.30, dashed)...... 90 Figure 2-9. Derivatization at the 3 position of the 1,5dimethyl6oxoverdazyl radical moieties in the corresponding BSV unimolecular initiators...... 91 Figure 2-10. GPC of styrene polymerization initiated with the benzoylstyrene1,5dimethyl3 (pCNphenyl)6oxoverdazyl radical adduct BSV 23 (solid1h, dashed2h, dotted3h, dash/dotted10h)...... 92 Figure 2-11. GPC of nbutyl acrylate polymerization initiated with the benzoylstyrene1,5 dimethyl3(pCNphenyl)6oxoverdazyl radical adduct BSV 23 (solid1h, dashed2h, dotted4h, dash/dotted6h, dashed/2dotted24h)...... 93 Figure 2-12. GPC of nbutyl acrylate polymerization initiated with the benzoylstyrene1,5 dimethyl3(methylimidazole)6oxoverdazyl radical adduct BSV 23 (solid1h, dashed2h, dotted3h, dash/dotted4h, dashed/2dotted5h)...... 94 Figure 2-13. GPC plot of styrene polymerization initiated with the benzoylstyrene1,5 dimethyl3hydrogen6oxoverdazyl radical adduct BSV 22 (solid1h, dashed2h, dotted3h, dash/dotted5h, dashed/2dotted7h)...... 96 Figure 2-14. GPC of nbutyl acrylate polymerization initiated with the benzoylstyrene1,5 dimethyl3hydrogen6oxoverdazyl radical adduct BSV 22 (solid1h, dashed2h, dotted4h, dash/dotted8h)...... 97 Figure 2-15. 1,5Dimethyl3phenylverdazyl 31 ...... 101 Figure 3-1. Expected trapped products from diradical mechanism; not observed...... 118 Figure 3-2. Structural similarities between 1,5dimethyl3phenyl6oxoverdazyl radical 16 and TIPNO 4 in bearing an α hydrogen relative to two adjacent heteroatoms...... 118 Figure 3-3. Comparison of substitution pattern between azomethine imine 41 and two other azomethine imines containing the carbonyl functionality...... 122 Figure 3-4. Postulated qualitative FMO analysis of dipole 41 with generic dipolarophiles. .... 125 Figure 3-5. Qualitative representation of DFT calculated FMO analysis of dipole 41 with 1 pyrrolidinocyclopentene and methyl acrylate...... 126

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Figure 3-6. Qualitative representation of DFT calculated FMO analysis of dipole 41 with styrene and methyl acrylate...... 126

Figure 3-7. DFT calculated electrostatic potential map of dipole 41 (electron density: yellowhigh; bluelow) ...... 127 Figure 3-8. Reactions between verdazyl radicals containing electronwithdrawing ( para cyanophenyl, para-fluoro) substituents with electronrich dipolarophiles (pyrrolidino1 cyclopentene and 1morpholinocyclohexene)...... 128 Figure 3-9. Verdazyl radicals bearing 3pentafluorophenyl and 1,5dibenzyl substituents. .. 130

Figure 4-1. Captodative olefins E2methylthiophenylacrylonitrile 61 , αacetoxyacrylonitrile 62 , and methyl αacetoxy acrylate (MAA) 63 ...... 143

Figure 4-2. Cycloadducts bearing an acidic hydrogen α to electronpoor phenyl rings...... 159 Figure 5-1. Compound 50 , synthesized from 1,5dimethyl3phenyl6oxoverdazyl radical 16 and fumaronitrile...... 163 Figure 5-2. First generation DOS library of verdazylderived heterocycles; verdazylinitiated cycloadducts...... 177 Figure 5-3. Second generation DOS library of verdazylderived heterocycles; rearrangement products of verdazylderived cycloadducts...... 178 Figure 5-4. Third generation DOS library of verdazylderived heterocycles; amidoderivatives from reduction of nitrilecontaining verdazylderived heterocycles...... 179 Figure 5-5. Dose response curve of compound 50 for acute myeloid leukemia (AML) and multiple myeloma (LP) cell lines...... 180

List of Schemes

Scheme 1-1. Formazan alkylation attempt; synthesis of triarylverdazyl radicals...... 3 Scheme 1-2. Synthesis of 6oxotetrazinones...... 3 Scheme 1-3. Oxidation of tetrazinones through the intermediacy of leucoverdazyl...... 4 Scheme 1-4. Formation of undesired bishydrazide...... 4 Scheme 1-5. Synthesis of 1,3,5triaryl6oxotetrazinones...... 5 Scheme 1-6. Synthesis of 6phosphaverdazyls...... 6 Scheme 1-7. Synthesis of 3phosphaverdazyl radicals...... 6 Scheme 1-8. Synthesis of 6borataverdazyl radical salts...... 6 Scheme 1-9. Synthesis of 1,5diisopropyl6oxoverdazyl radicals...... 7 Scheme 1-10. Decomposition products of triphenylverdazyl radical...... 8 Scheme 1-11. Dimerization of 1,5dimethyl3phenyl6oxoverdazyl radical...... 8 Scheme 1-12. Conventional radical polymerization process...... 11 Scheme 1-13. General scheme for a reversible termination polymerization...... 13 Scheme 1-14. General scheme for a degenerative transfer polymerization...... 14 Scheme 1-15. The Atom Transfer Radical Addition (ATRA) process...... 15 Scheme 1-16. The Atom Transfer Radical Polymerization (ATRP) process...... 16 Scheme 1-17. Reversible AdditionFragmentation chain Transfer (RAFT) process...... 18 Scheme 1-18. BPOinitiated styrene polymerization...... 20 Scheme 1-19. BSTinitiated styrene polymerization...... 20 Scheme 1-20. TEMPOmediated Stable Free Radical Polymerization (SFRP) of styrene...... 21 Scheme 1-21. Autoinitiation reaction of styrene (Mayo reaction)...... 23 Scheme 1-22. Ascorbic acid reduction of TEMPO radical to the corresponding hydroxyamine...... 23

Scheme 1-23. Basecatalyzed enolization of αhydroxycarbonyl compounds to the corresponding enediol; used as a reducing agent for nitroxides...... 24 Scheme 1-24. Pyridine catalyzed enolization of glyceraldehyde dimer...... 24

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Scheme 1-25. Irreversible decomposition of nitroxides bearing αhydrogen (TIPNO is shown)...... 26 Scheme 1-26. Ring contraction of leucoverdazyl to triazolinyl radical...... 28 Scheme 1-27. Alternative synthetic methods to triazoline...... 28 Scheme 1-28. Thermal decomposition of triazolinyl radical 7 to give a triazole and a phenyl radical...... 29 Scheme 1-29. Triphenylverdazylmediated SFRP system...... 31 Scheme 1-30. Hydrogen abstraction of triphenylverdazyl from a polymethacrylate radical forming leucoverdazyl 11 ...... 32 Scheme 1-31. 1,3Dipolar cycloaddition between an azomethine imine and a dipolarophile. ... 38 Scheme 1-32. [3+3] Dimerization of an azomethine imine...... 38 Scheme 1-33. Azomethine imine derived from 3pyrazolidone and carbonyl compounds...... 39 Scheme 1-34. An azomethine imine reported by Oppolzer...... 40 Scheme 1-35. An azomethine imine designed to undergo intramolecular 1,3dipolar cycloaddition...... 40 Scheme 1-36. Structure of sydnone as first proposed by Earl et al ...... 40 Scheme 1-37. Sydnone, as proposed by Huisgen, undergoing a 1,3dipolar cycloaddition with alkenes...... 40 Scheme 1-38. A sugarderived chiral azomethine imine...... 41 Scheme 1-39. Zirconiumcatalyzed formation and 1,3dipolar cycloaddition of an azomethine imine...... 42 Scheme 1-40. Coppercatalyzed formation and 1,3dipolar cycloaddition of an azomethine imine...... 43 Scheme 1-41. The use of an azomethine imine in the total synthesis of saxitoxin...... 43 Scheme 1-42. The use of an azomethine imine in the total synthesis of massadine...... 44 Scheme 1-43. The use of an azomethine imine in the total syntheses of nankakurines A and B.44 Scheme 1-44. The 15 Nlabel experiment verifying the rearrangement mechanism proposed by Dimroth...... 46 Scheme 1-45. The translocation of heteroatoms in a fused bicyclic system...... 46 Scheme 1-46. An example of a Dimroth rearrangement pathway involving a highly conjugated intermediate...... 46 Scheme 1-47. The Dimroth rearrangement alkyl or alkoxyadenines to purines...... 47 xvii

Scheme 1-48. A Dimroth rearrangement favouring the product with the highest thermodynamic stability...... 48 Scheme 1-49. The Dimroth rearrangement reactions of 6amino4oxopyrano[3,4d] [1,2,3]thiadiazoles to 6hydroxy4oxo[1,2,3]thiadiazolo[4,5c]pyridines...... 49 Scheme 1-50. Nucleophileassisted vs. heatassisted ring fission in a Dimroth rearrangement. 49 Scheme 1-51. A schematic representation of DCC...... 51 Scheme 1-52. A DCC library of compounds involving hydrazal formation...... 51 Scheme 1-53. A DOS library of compounds containing the same scaffold R...... 52 Scheme 1-54. An example of a DOS library of compounds containing different scaffolds and different orthogonal functionalities...... 53 Scheme 1-55. DOS library of compounds built with1,3dipolar cycloadditions involving azomethine ylides...... 53 Scheme 2-1. Methyl methacrylate polymerization initiated with the triphenylverdazylAIBN adduct 10 at 60 ºC...... 64 Scheme 2-2. Styrene polymerizations initiated with the triphenylverdazylAIBN adduct 10 at 110 ºC...... 64 Scheme 2-3. Unimolecular initiator exchange reaction between BST and 1,3,5triphenyl6 oxoverdazyl radical 17 ...... 79 Scheme 2-4. Synthesis of 1,5dimethyl3phenyl6oxoverdazyl radical 16 ...... 81 Scheme 2-5. Synthesis of the unimolecular initiator 19 via exchange reaction between BST and 1,5dimethyl3phenyl6oxoverdazyl radical 16 with ascorbic acid...... 81 Scheme 2-6. Unimolecular initiator 19 synthesis from 1,5dimethyl3phenyl6oxoverdazyl 16, styrene, and BPO; major product 20 ...... 87 Scheme 2-7. Styrene polymerization initiated with the unimolecular initiator 19 ; isolation of 20 ...... 87 Scheme 2-8. nButyl acrylate polymerization initiated with the unimolecular initiator 19 ; isolation of 21 ...... 88 Scheme 2-9. Hydrogenabstraction mechanism of 1,5dimethyl6oxoverdazyl; oxidation of resulting leucoverdazyl 25 by atmospheric oxygen...... 98 Scheme 2-10. Attempted synthesis of 1,5dimethyl3(2,6dimethylphenyl)6oxoverdazyl radical 28 yielding bis(hydrazone) 29 ...... 99 Scheme 2-11. Synthesis of 1,5dibenzyl3phenyl6oxoverdazyl radical 30 ...... 100 Scheme 2-12. Proposed syntheses of 32 , the precursor to verdazyl radical 31 , or 33 , the protected analogue of 32 ...... 101

xviii

Scheme 2-13. Synthesis of 6phosphaverdazyl 35 ...... 102 Scheme 2-14. ATRA and nucleophilic substitution syntheses of styrene6phosphaverdazyl unimolecular initiator 36 with (1bromoethyl)benzene and 6phosphaleucoverdazyl 34 or 6 phosphaverdazyl radical 35 ...... 102 Scheme 3-1. Synthesis of unimolecular initiator 19 with 1,5dimethyl3phenyl6oxoverdazyl radical 16 , styrene, and BPO; 20 recovered as major product...... 115 Scheme 3-2. Formation of 20 with 1,5dimethyl3phenyl6oxoverdazyl radical 16 without BPO...... 117 Scheme 3-3. Postulated diradical mechanism for the formation of 20 with 1,5dimethyl3 phenyl6oxoverdazyl radical 16 and styrene...... 117 Scheme 3-4. Postulated single electron transfer mechanism of 1,5dimethyl3phenyl6 oxoverdazyl radical 16 with styrene for the formation of 20 ...... 119 Scheme 3-5. Postulated mechanism for the formation of azomethine imine 41 from 1,5 dimethyl3phenyl6oxoverdazyl radical 16 and its formation of cycloadduct 20 with styrene...... 120 Scheme 3-6. Benzylation trapping experiment of leucoverdazyl 42 from cycloaddition of 1,5 dimethyl3phenyl6oxoverdazyl radical 16 and methyl methacrylate...... 121 Scheme 4-1. Reaction between 1,5dimethyl3phenyl6oxoverdazyl radical 16 and 1 chloroacrylonitrile...... 141 Scheme 4-2. Mechanism for the formation of 58 , the radical addition/trapping product between 1,5dimethyl3phenyl6oxoverdazyl radical 16 and 1chloroacrylonitrile...... 142 Scheme 4-3. Reaction between TEMPO and 1chloroacrylonitrile...... 143

Scheme 4-4. Reaction between 1,5dimethyl3phenyl6oxoverdazyl radical 16 and α acetoxyacrylonitrile...... 143 Scheme 4-5. Reaction between 1,5dimethyl3phenyl6oxoverdazyl radical 16 and MAA. 144 Scheme 4-6. Postulated cycloaddition reaction between 1,5dimethyl3phenyl6oxoverdazyl radical 16 and MAA...... 145 Scheme 4-7. Isolable intermediates 66 and 68 leading to rearranged product 67 via heat...... 146 Scheme 4-8. Intermediate 66 or 68 leading to rearranged product 67 via sodium hydride...... 146 Scheme 4-9. Reaction between 1,5dimethyl3phenyl6oxoverdazyl radical 16 and methyl propiolate...... 146 Scheme 4-10. Treatment of methyl acrylate cycloadduct 21 with heat...... 147 Scheme 4-11. Sodium hydrideinduced rearrangement of 21 to 70 ...... 147 Scheme 4-12. Loss of methyl ester from 21 and 70 from treatment with sodium hydride...... 148

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Scheme 4-13. Rearrangement of methyl acrylate cycloadduct 21 with excess LDA...... 148 Scheme 4-14. Treatment of methyl methacrylate cycloadduct 45 with base...... 149 Scheme 4-15. Treatment of N,N dimethyl acrylamide cycloadduct 72 with potassium tert butoxide...... 149 Scheme 4-16. Postulated intermolecular rearrangement mechanism for the conversion of 68 to 67 ...... 150 Scheme 4-17. Proposed intramolecular rearrangement mechanism for the conversion of 68 to 67 ...... 151 Scheme 4-18. Proposed intramolecular rearrangement mechanism for the conversion of 21 to 70 ...... 152 Scheme 4-19. Rearrangement of 21 to 76 via sodium methoxide...... 153 Scheme 4-20. Rearrangement of 21 to 77 via sodium ethoxide...... 153 Scheme 4-21. Treatment of methyl methacrylate derived from cycloadduct 45 with sodium methoxide...... 154 Scheme 4-22. Rearrangement of 70 to 76 in the presence of sodium methoxide...... 154 Scheme 4-23. Postulated mechanism for the rearrangement of cycloadducts 21 (and 70 ) to 76 in the presence of sodium methoxide...... 155 Scheme 4-24. Treatment of styrene cycloadduct 20 with alkoxides, LDA, or tert butyllithium...... 156 Scheme 4-25. Rearrangement of acrylonitrile cycloadduct 46 with sodium methoxide and ethoxide...... 156 Scheme 4-26. Rearrangement of N,N dimethyl acrylamide cycloadduct 72 with potassium tert butoxide...... 157 Scheme 4-27. Treatment of cycloadducts 48 , 49 , and 50 with sodium methoxide...... 158 Scheme 4-28. Reaction of cycloadduct acrylonitrile cycloadduct 46 with benzylamine...... 158

Scheme 4-29. Triazole rearrangement of cycloadducts bearing an acidic α hydrogen induced by other nucleophiles...... 160 Scheme 5-1. DOS strategy involving verdazylinitiated cycloaddition and rearrangement. .... 162 Scheme 5-2. Reduction and subsequent amidation of a nitrile functionality...... 163 Scheme 5-3. Cycloadducts derived from various 1,5dimethyl6oxoverdazyl radicals and dipolarophiles bearing nitriles and acidic αprotons...... 174 Scheme 5-4. Base and nucleophileinduced rearrangements of verdazylderived cycloadducts to pyrazolotriazinones and triazoles...... 175

Scheme 5-5. Dimerization between an amine and a nitrile...... 176 Scheme 5-6. Dimerization between an amine and an imine...... 176 Scheme 5-7. In situ tBoc protection of nitrile reduction and subsequent amidation...... 176 Scheme 5-8. 1,5Dibenzyl3phenyl6oxoverdazyl radical undergoing 1,3dipolar cycloaddition with butyl acrylate...... 182 Scheme 5-9. The Suzuki coupling reaction of bromo containing cycloadducts and boronic acids...... 182 Scheme 5-10. The rearrangement reaction of acrylonitrilederived cycloadducts with amines...... 182

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List of Abbreviations

Heat

[M] t Monomer concentration at time t

[M] 0 Initial monomer concentration AIBN Azobisisobutyronitrile AML Acute myeloid leukemia atm Atmospheric ATRA Atom transfer radical addition ATRP Atom transfer radical polymerization B: Base BPO Benzoyl peroxide BST 1Benzoyloxy2phenyl2(2’,2’,6’,6’tetramethyl1’ piperidinyloxy)ethane BSV 1Benzoyloxy2phenyl2(6oxoverdazyl)ethane DCC Dynamic combinatorial chemistry de Diastereomeric excess DFT Density functional theory DMF Dimethyl formamide DMSO Dimethyl sulfoxide DOS Diversityoriented synthesis

Ea Energy of activation EDG Electron donating group EWG Electron withdrawing group FMO Frontier molecular orbital GPC Gel permeation chromatography HRMS High resolution mass spectrometry HOMO Highest occupied molecular orbital

xxii

K Kelvin K Equilibrium constant for the SFRP system kc Rate constant for the crosscoupling reaction between the persistent and transient radical kd Rate constant for the bond dissociation reaction for the SFRP process ki Rate constant for the initiator bond dissociation reaction kp Rate constant for the polymerization process L Ligand LDA Lithium diisopropylamide LUMO Lowest unoccupied molecular orbital

MAA Methyl αacetoxy acrylate MMA Methyl methacrylate MO Molecular orbital MP Multiple myeloma

Mn Number average molecular weight

Mw Weight average molecular weight NMR Nuclear magnetic resonance Nu Nucleophile

Pn Polymer composed of n number of monomer units P Propagating polymer radical PDI Polydispersity index PMDETA N,N,N’,N’,N”Pentamethyldiethylenetriamine R Transient radical RAFT Radical atom fragmentation chain transfer rt Room temperature SET Single electron transfer SFRP Stable free radical polymerization

xxiii

SG1 Ntert ButylN[1diethylphosphono(2,2 dimethylpropyl)]nitroxide t Time TEMPO 2,2,6,6Tetramethyl1piperidinyloxy THF Tetrahydrofuran TIPNO 2,2,5Trimethyl4phenyl3azahexane3nitroxide TLC Thin layer chromatography Vazo® 88 1,1’Azobis(cyclohexanecarbonitrile) MW Molecular weight X Persistent radical

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Chapter 1

1 Introduction

1.1 Verdazyl Radicals

1.1.1 Introduction

The family of verdazyl radicals has garnered a lot of interest since their discovery in the

1960’s. While most radicals have lifetimes long enough just for their detection and characterization, the family of verdazyl radicals is among the elite few whose stability allows isolation and storage. The general verdazyl backbone is a sixmembered ring containing four nitrogen atoms at the 1, 2, 4, 5 positions (Figure 11).1 The radical, which resides in π orbitals, is stabilized by the delocalization of the spin density over the four nitrogen atoms 25 and is sterically protected by the R groups at the 1, 3, 5 positions. Over the years a broad range of synthetic methods have been developed for the synthesis of verdazyls leading to a wide variety of unique structures.

Figure 1-1. The verdazyl backbone with known modifications.

The colours of various verdazyl radicals range from green (the ver- portion itself comes from vert , or green, the colour of the first verdazyl radical discovered), 6 to reddish orange, 7 to

purple.8 The stabilities of various verdazyl radicals range from being transient, where they decay too quickly to be isolable, 9 to being stable for years.10 The conformation of various verdazyl radicals, depending on the substituents attached, can be planar or nonplanar (Figure 12).11,12

Applications of verdazyl radicals range from being radical traps,13,14 molecular magnets,15 living radical polymerization mediators, 16 organic synthesis substrates, 17 to ultimately sacrificing their own backbones to form unique heterocyclic structures.18

Figure 1-2. Xray structures of a nonplanar and a planar verdazyl radical. 12

1.1.2 History, Synthesis, and Characterization of Verdazyl Radicals

1.1.2.1 History and Synthesis of Triarylverdazyl Radicals

The first verdazyl radical was serendipitously discovered in 1963 by Kuhn and

Trischmann in their attempt to alkylate formazan 1 (Scheme 11). 6 Shortly thereafter, research on verdazyl radicals focused on their synthesis and characterization. The first derivatives of the verdazyl radicals were of the triaryl variety.

Scheme 1-1. Formazan alkylation attempt; synthesis of triarylverdazyl radicals. 6

1.1.2.2 History and Synthesis of 6-Oxo- and 6-Thioxoverdazyl Radicals

In 1983, the syntheses of 6oxo and 6thioxoverdazyl radicals were reported.19 Alkyl

(mainly methyl and benzyl) hydrazines were reacted with phosgene or thiophosgene to form the bisalkylhydrazides of carbonic acid or thiocarbonic acid, respectively, which were readily isolated as white solids. These bisalkylhydrazide intermediates were then used to prepare a broad range of verdazyl radicals with varying functionalities at the 3 position, as determined by the alkyl or arylaldehyde used during the subsequent condensation step (Scheme 12).

Scheme 1-2. Synthesis of 6oxotetrazinones.

Tetrazinones, the precursors to the 6oxoverdazyl radicals, are generally stable under atmospheric oxygen and can be oxidized to the corresponding radicals with any number of different oxidants. The most common oxidants used are lead oxide, potassium ferricyanide, and periodates. The oxidation is a three electron process and proceeds through a partially oxidized

intermediate, the leucoverdazyl, which is readily oxidized by atmospheric oxygen and therefore virtually impossible to isolate (Scheme 13).1,20

Scheme 1-3. Oxidation of tetrazinones through the intermediacy of leucoverdazyl.

Although this synthetic method allows for derivatization at the 3 position, its drawback lies in the limitation of functionalities that can be incorporated at the 1, 5 positions. The electronic and steric properties of many potential monosubstituted hydrazine precursors forbid the reaction of phosgene with the secondary nitrogen (Scheme 14).21 For example, in the case of arylhydrazines, incorrect chemoselectivity may result from the preference of nucleophilic attack by the primary nitrogen over the conjugated, weakly nucleophilic secondary nitrogen. For bulky alkylhydrazines, the same consequence may result from steric effects obstructing the nucleophilic attack of the secondary nitrogen. Nonetheless, the bisalkylhydrazide intermediate is now part of the standard syntheses of 6oxo and 6thioxoverdazyl radicals.

Scheme 1-4. Formation of undesired bishydrazide.

1.1.2.3 History and Synthesis of 1,3,5-Triaryl-6-Oxoverdazyl Radicals

In 1994, Milcent et al . published the synthesis of 1,3,5triaryl6oxoverdazyl radicals

(Scheme 15).8 It was demonstrated that the undesired chemoselectivity of arylhydrazines could

be overcome by first converting the arylhydrazines to the corresponding arylhydrazones. Such a conversion allows the correct nucleophilic substitution with one molar equivalent of phosgene.

Subsequent nucleophilic substitution with a molar equivalent of arylhydrazine afforded the corresponding tetrazane after intramolecular ring closure (Scheme 15). This synthetic route provides easy access to 1,3,5 symmetric and asymmetric triaryl6oxoverdazyl radicals.

Scheme 1-5. Synthesis of 1,3,5triaryl6oxotetrazinones.

The triaryloxoverdazyl derivatives are known to be the most stable verdazyl radicals. No decomposition of these verdazyl radicals has been reported to date.

1.1.2.4 History and Synthesis of Inorganic Verdazyl Radicals

The verdazyl radical family was further expanded by Hicks et al ., who designed a series of inorganic phosphaverdazyls, a class of verdazyl radicals containing phosphorus.22 The phosphorus center can be introduced at either the 3 or the 6 position. Starting with the bis(1 methylhydrazide) of phenylphosphonic acid, 23 condensation can be carried out with trimethyl orthobenzoate to afford the corresponding stable leucoverdazyl, which can then be oxidized with periodate via a one electron oxidation to the corresponding radical with phosphorus at the 6 position (Scheme 16). Alternatively, starting with the bis(1methylhydrazide) of carbonic acid, condensation can be carried out with trichlorodiphenylphosphorane in the presence of triethylamine to afford the corresponding stable leucoverdazyl, which again can be oxidized via a one electron oxidation to the corresponding radical (Scheme 17). In contrast to the

leucoverdazyl form of the 6oxoverdazyl radicals, which is readily oxidized by oxygen, the leucoverdazyl form of the phosphaverdazyls is inert to atmospheric oxygen.

Scheme 1-6. Synthesis of 6phosphaverdazyls. 22

Scheme 1-7. Synthesis of 3phosphaverdazyl radicals. 22

In addition to introducing phosphorus into verdazyl radicals, Hicks et al . also incorporated boron to produce borataverdazyl radical salts (Scheme 18).24

Scheme 1-8. Synthesis of 6borataverdazyl radical salts. 24

1.1.2.5 History and Synthesis of 1,5-Diisopropyl-6-Oxoverdazyl Radicals

In 2005, Brook et al . revisited the synthesis of dialkyloxoverdazyls to overcome the aforementioned limitation of bulky alkylhydrazines in nucleophilic substitution reactions with phosgene (Scheme 19).21 tButylcarbazate, a protected derivative of hydrazine, can afford various hydrazones by condensation reactions with corresponding aldehydes or ketones.

Reduction with sodium cyanoborohydride gives alkylhydrazines with the primary nitrogen

protected with a tert butoxycarbonyl (tBoc) protecting group, nullifying its nucleophilicity.25

Nucleophilic substitution reactions of these protected alkylhydrazines with phosgene followed by removal of the tBoc protecting group with acid gave the corresponding bis(1alkylhydrazides) of carbonic acid, which could then undergo condensation reactions with various aldehydes to form tetrazinones. Oxidation of the tetrazinones yields the verdazyl radicals.

Scheme 1-9. Synthesis of 1,5diisopropyl6oxoverdazyl radicals. 21

1.1.3 History of Verdazyl Radical Chemistry

Few chemical reactions have been reported with verdazyl radicals. Aside from radical coupling reactions with alkyl radicals, the only other notable chemical reactions were reported by

Neugebauer. In 1973 it was reported that triphenylverdazyl, when heated at 80 ºC, contracts to give a substituted triazole which at 200 ºC further breaks down and eliminates aniline (Scheme 1

10).1

Scheme 1-10. Decomposition products of triphenylverdazyl radical. 1

In 1988, 1,5dimethyl3phenyl6oxoverdazyl was reported to dimerize when treated with formic acid (Scheme 111).26 However, only a low yield of 8% was observed after 48 hours.

Scheme 1-11. Dimerization of 1,5dimethyl3phenyl6oxoverdazyl radical. 26

Little explanation and no mechanisms were offered, and these seemingly interesting reactions were not further pursued. While the work of this thesis does not directly investigate these reactions, the principle theories outlined in Chapter 3 may be applicable in explaining these decomposition reactions.

1.1.4 History of Verdazyl Radical Applications

The verdazyl radicals found their first application as radical traps in kinetic experiments to determine initiation rates of AIBN in styrene, methyl methacrylate (MMA), acrylonitrile, and vinyl chloride polymerizations. 13,14,27 Verdazyl radicals have also been used as targets in polymer endgroup analysis. 28 In 1994, Yamada et al . attempted to exploit verdazyl radicals as mediating

agents in living radical polymerization;28,29 however, initial results were not fruitful. This work will be discussed in greater detail in Section 1.2.3.2.

The first reported transitionmetal coordination complex of a verdazyl radical was reported in 1997. 15 Since then, the magnetic properties of verdazyl radicals have been well studied and research in the area of using verdazyl radicals as molecular magnets has grown. 3033

The magnetochemistry of the verdazyl radicals bears little relevance to the work of this thesis and therefore will not be discussed.

1.1.5 Concluding Remarks

The chemistry and the use in applications of verdazyl radicals have been largely unexplored. With the unique properties of these radicals and the potential for their further exploitation in consideration, the work of this thesis will focus on the successful use of verdazyl radicals in four different fields: living radical polymerizations, 1,3dipolar cycloadditions, heterocyclic rearrangements, and diversityoriented synthesis. Below are introductions to each of these fields, and a brief prologue to how verdazyl radicals interweave them.

1.2 Stable Free Radical Polymerization

1.2.1 Conventional vs. Living Polymerization

1.2.1.1 Conventional Polymerization

Vinyl radical polymerizations are widely used in industry. 3436 Due to the high reactivity and poor selectivity of radicals, the range of polymerizable vinyl monomers is broad. In addition, these polymerizations require minimal monomer purification and are tolerant of water, enabling

them to be performed under emulsion and suspension conditions, two factors that make them very amenable to large scale processes.

There are three stages to radical polymerization: initiation, propagation, and termination

(Scheme 112). The polymerization begins with an initiation species, such as a peroxide or an azo compound, which generates primary radicals either thermally, photolytically, or by a redox reaction. The highly reactive primary radical then adds to a monomer unit, forming a reactive alkyl radical. Propagation occurs rapidly as vinyl monomers add to the highly reactive propagating chain end. Monomer addition is facile due to the formation of a strong σ bond at the expense of a weaker π bond. Propagation continues until either the monomer is depleted or chain termination occurs by either a coupling or a disproportionation reaction. Coupling termination arises when two propagating chains react irreversibly with each other at the reactive carbon radical centres to form a σ bond. Examples of polymers that predominantly undergo termination by coupling are styrene and (meth)acrylates. 35 Termination by disproportionation arises when a propagating radical from one chain abstracts a hydrogen atom from the carbon α to the radical centre of another propagating radical, resulting in one polymer chain with a saturated end and another with an unsaturated end. αMethylstyrene polymerizations predominantly undergo disproportionation termination reactions. 35

Initiation Propagation M M II 2 I IM Pn

Termination

Pm + Pn dead chains

Termination by coupling

R R n

m n R R R R m R R

Termination by disproportionation

H H n + n m R R m R R R R R R R R Scheme 1-12. Conventional radical polymerization process.

Although conventional radical polymerization is one of the most used processes industrially, it is not without limitations. Welldefined polymers and polymers of complex architectures cannot be prepared by this method due to the unavoidable termination reactions that occur throughout the polymerization process. Unwanted termination by combination and disproportionation limits the polydispersity index (PDI), the measure of molecular weight distribution, to a theoretical low of 1.5,35 although PDI values as high as 5.0 or 6.0 are commonly observed in typical conventional radical polymerizations. Moreover, due to a fast propagation rate, uncontrolled growing polymer chains reach high molecular weights in a short period of time.

Thus, even after very short reaction times, high molecular weight polymers are present in the reaction. This notable characteristic of conventional radical polymerizations is typically represented in the exponential plot of molecular weight vs. % conversion (Figure 13).

Figure 1-3. Mn vs. % conversion plot for a conventional radical polymerization.

1.2.1.2 Living Anionic Polymerization

Living anionic polymerization was first developed in 1956 by Szwarc.37 Anionic polymerizations are void of termination reactions and therefore PDI values as low as 1.02 can be achieved. As a consequence, the experimental number average molecular weights can be very close to the theoretical molecular weights predicted on the basis of the amount of initiator and monomer used. The range of monomer that can be used in anionic polymerizations is not as broad as in the case of radical polymerization but monomers such as styrene and its derivatives,

(methyl)acrylate and dienes, such as 1,3butadiene and isoprene, are readily polymerized.

As the field of anionic polymerizations matured, a set of criteria was established for the classification of livingness. 35,38 A polymerization is considered living if a) the polymerization proceeds until all the monomer is consumed, and restarts if more monomer is added; b) the number of living chains remains constant; c) a linear molecular weight increase with % conversion is observed (Figure 14); d) the concentration of active species remains constant

(linear ln([M] o/[M] t vs. time plot); e) low PDI value is observed (if ki >> kp); f) the polymers are chain extendable to block copolymers and g) end group fidelity is retained.

Figure 1-4. Mn vs. % conversion plot for a living anionic polymerization.

However, stringent monomer and solvent purification to get rid of any protic impurities, severe reaction conditions, including in some cases temperatures as low as 78 ºC, aqueous incompatibility, as well as the restricted choice of monomers and functionalities have limited the applications of anionic polymerization.

1.2.1.3 Living Radical Polymerization

The concept of living radical polymerization was first proposed in the 1950’s.39,40 To achieve such a system, the unwanted radical termination reactions have to be eliminated, or at least largely suppressed. Since the activation energy of a radical coupling reaction is much less than that of a monomer addition reaction, the concentration of the active radical species has to be kept low in order to force propagation and avoid termination – a feat that could be attained with a mediating agent that participates in either the reversible termination (Scheme 113) or degenerative transference (Scheme 114) of the active propagating species.

Scheme 1-13. General scheme for a reversible termination polymerization.

Scheme 1-14. General scheme for a degenerative transfer polymerization.

The first successful demonstration of a living radical polymerization system to meet the aforementioned criteria was published in 1993 by Georges et al .41,42 Since then, research in living radical polymerization has exploded into one of the largest areas in the polymer community. Several living radical polymerization systems have emerged over the years, each with its advantages and disadvantages. The three most prominent systems are Stable Free

Radical Polymerization (SFRP, 1993), 41 Atom Transfer Radical Polymerization (ATRP,

1995),43,44 and Reversible AdditionFragmentation chain Transfer (RAFT, 1998). 45 Examples of other notable living radical polymerization systems are degenerative transfer polymerization with alkyl iodides, 46,47 cobaltmediated radical polymerization,4850 organotelluriummediated radical polymerization,51,52 organostibinemediated radical polymerization 53 and organobismuthine mediated radical polymerization.54 All these systems operate on the principle of minimizing termination reactions. In the following sections ATRP and RAFT are briefly discussed, followed by a more detailed discussion of SFRP since its principles set the foundation for the work described in this thesis.

1.2.2 Introduction to Living Radical Polymerization Systems

1.2.2.1 Atom Transfer Radical Polymerization (ATRP)

The concept of ATRP was first independently reported by both Sawamoto et al .43 and

Matyjaszewski et al .44 in 1995. Polymerization of MMA was performed by Sawamoto et al . at

60 ºC in the presence of a ruthenium catalyst. 43 This process utilizes the reversible redox reaction of Ru II , which in the presence of an alkyl halide, is oxidized to Ru III . At the same time, the alkyl halide undergoes homolytic cleavage of the CX bond, generating a carbon radical that propagates in the presence of monomers. In the same year, Matyjaszewski et al . reported a living radical polymerization process with the use of copper and alkyl chlorides, and the process was referred to as ATRP. 44 ATRP was derived from atom transfer radical addition (ATRA), 55,56 which utilizes a reversible redox process between a transition metal, typically copper, and an alkyl halide (Scheme 115).

Initiation X I R' RX Cu Ln R

II Cu XLn

R' R R' R

Addition Scheme 1-15. The Atom Transfer Radical Addition (ATRA) process.

In the ATRP process, an alkyl halide is used as an initiator. The copper catalyst is oxidized as it homolytically strips away the halide to form the reactive R• group that undergoes propagation in the presence of monomer. The copper catalyst is then reduced and at the same time, the bond reforms between the halogen and propagating radical to give the dormant species

PnX. An equilibrium between the active and the dormant species is established to keep this process going (Scheme 116).

Initiation CuIL CuIL RX n Pn X n

II II Cu XLn Cu XLn

M M

R Pn Pn

Propagation Scheme 1-16. The Atom Transfer Radical Polymerization (ATRP) process.

Since its initial discovery, a variety of transition metals (Ti, Mo, Re, Fe, Ru, Os, Rh, Co,

Ni, Pd, Cu) have been applied in the mediation of ATRP systems.35,57 Of these, copper complexes have been found to be most efficient for a broad range of monomers. It is also the least expensive of the metals studied.

The choice of ligand is another consideration in the ATRP process. The ligands serve two purposes: to solubilize the metal ion in the organic media and to control the extent of metal activation by altering the reduction potential of the complex. 35,36 Nitrogenbased ligands are typically used, and can range from bidentate, tridentate to tetradentate; an example of each are: bipyridine, pentamethyldiethylenetriamine, and tris[2(dimethylamino)ethyl]amine, respectively

(Figure 15). 58 Monodentate ligands are generally not employed due to their low activity, which is related to their poor chelating ability. In a few cases, phosphorus ligands are employed for systems that are not copperbased. 59

Figure 1-5. Examples of bi, tri, and tetradentate ligands employed in ATRP.

A broad range of monomers (styrenes, (meth)acrylates, acrylamides, acrylonitriles, butadienes, but not vinyl acetates) can be polymerized by the ATRP process. Temperatures employed for ATRP range from 60 ºC to 130 ºC, depending on the initiator, monomer, and ligand.

1.2.2.2 Reversible Addition-Fragmentation chain Transfer (RAFT)

The RAFT process was first reported by Moad et al . in 1998. 45,60,61 Dithioester or dithiocarbamates are used as reversible chain transfer agents to mediate the polymerization

(Figure 16, Scheme 117).

Figure 1-6. Reversible AdditionFragmentation chain Transfer (RAFT) agent.

Scheme 1-17. Reversible AdditionFragmentation chain Transfer (RAFT) process.

A conventional initiator is used to form primary radicals. In the presence of monomer they react to form IP•, which adds more monomer to give the propagating radical chain Pn•. At some point Pn• reacts with the RAFT agent; a facile reaction due to the stability of the resulting radical flanked by three activating groups. The driving force to homolytically expel the R• group is the reformation of the dithioester or dithiocarbamate double bond. The R• group then initiates a new chain to give P m•. The cycle repeats to afford polymers in a living fashion. A broad range of monomers (styrenes, (meth)acrylates, acrylamides, acrylonitrile, vinyl esters, vinyl acetate, vinyl amides) can be used in the RAFT process. Temperatures employed in the RAFT process range from ambient to 140 ºC, depending on the monomer and RAFT agent selection.

1.2.2.3 Stable Free Radical Polymerization (SFRP)

The field of stable free radical polymerization has flourished since Georges’ demonstration of 2,2,6,6tetramethylpiperidine1oxyl (TEMPO)mediated styrene polymerization. TEMPO, 2, (Figure 17) is a prominent member of the nitroxide family and is known to be very stable, even up to 150 ºC in solution.

Figure 1-7. General structure of a nitroxide radical and TEMPO.

Two initiation systems have been developed in the SFRP process. The first system utilizes conventional radical initiators such as benzoyl peroxide (BPO) or azobisisobutyronitrile

(AIBN) (Scheme 118).41 Alternatively, nitroxidederived unimolecular initiators, referred to as alkoxyamines, such as benzoyl styryl TEMPO (BST) 3 can be employed (Scheme 119).62 The former initiation system is more practical and economical because it lacks the extra synthetic step required to obtain the alkoxyamines. However, the alkoxyamines boast more accurate control over molecular weights because the molar equivalents of propagating radicals and terminating agents are predetermined. The temperatures for initiation and polymerization are higher for the TEMPO system, between 125135 ºC, as compared to a conventional radical polymerization which typically runs between 6095 ºC. The need for the high temperature is twofold – i) it ensures fast initiation in the case of conventional initiators thus enabling all polymer chains to begin growth simultaneously, and ii) it ensures the bond between the propagating chain end and TEMPO is sufficiently labile to regenerate sufficient propagating chains for the polymerization process to proceed at an acceptable rate.

Scheme 1-18. BPOinitiated styrene polymerization.

Scheme 1-19. BSTinitiated styrene polymerization.

During polymerization, the addition of a thermally reversible terminating agent establishes an equilibrium such that the concentration of the propagating species is maintained low and constant, but more importantly, the lifetime of the propagating species is kept short.

This ensures controlled stepwise monomer addition and minimal termination (Scheme 120). At equilibrium, the typical concentration of the dormant propagating chain [PX] is about 10 2 M, the typical concentration of the active propagating chain [P•] ranges from 10 8 to 10 7 M, while the typical concentration of the terminating agent [X•] ranges from 10 5 to 10 4 M.63 The

4 1 1 homolytic rate of dissociation kd ranges from 10 to 10 s , while the homolytic rate of

6 8 1 1 63 recombination kc is between 10 and 10 M s . The rate of recombination is generally considered to be near diffusion controlled, 35,64 although this statement is of course not without exceptions, as in the case with sterically bulky terminating agents.

Initiation O O O O Ph 2 Ph O O Ph Ph O Ph O Ph

Propagation / Reversible termination O N

O O O N + N O O Ph O Ph O Ph O Ph Ph Ph BST

O O N N Ph O Ph O Ph O Ph O n Ph Ph Ph Ph

Scheme 1-20. TEMPOmediated Stable Free Radical Polymerization (SFRP) of styrene.

An equilibrium constant K can be inferred from the concentration of participating species

12 10 in the range of 10 to 10 M, in accordance with K calculated from kd and kc values (Equation

11). K values typically range from 10 11 to 10 9 M for living radical polymerizations with reversible termination mechanism, depending on the terminating agent and monomer. 63 As a

12 reference, the TEMPOmediated styrene polymerization has a K value of 1.9 x 10 M, kd value

4 1 8 1 1 of 5.2 x 10 s and kc value of 2.8 x 10 M s (values based on small molecule alkoxyamine model compounds at 393 K).63,65,66

Equation 1-1. Equilibrium constants and concentrations.

1.2.2.4 Stable Free Radical Polymerization of Acrylates Mediated by Nitroxides

Despite its success in mediating polymerizations of styrene and its derivatives, TEMPO was found ineffective in mediating acrylate polymerizations; oligomers of acrylates can be prepared, but the polymerization stalls shortly after initiation. Two theories were presented for the inability of TEMPO to mediate acrylate polymerizations. One theory stated that, with the

5 1 nearly 10fold lower homolytic dissociation rate constant kd (3.4 x 10 s in comparison to that of styrene, 5.2 x 10 4 s1)65 of the CON bond between TEMPO and the acrylate unit, bond cleavage does not occur to any large extent to allow propagation (Figure 18). 65,67,68

4 1 Figure 1-8. Comparison of bond strength between TEMPOterminated styrene ( kd = 5.2 x 10 s ) and 5 1 65 TEMPOterminated acrylate ( kd = 3.4 x 10 s ).

The other theory for the inability of TEMPO to mediate acrylate polymerizations stated that due to inevitable termination reactions, the concentration of TEMPO builds up and results in a shift in the polymerization equilibrium towards the dormant polymer chains, inhibiting the polymerization.69 Successful TEMPOmediated styrene polymerizations can be explained by the

Mayo reaction, an autoinitiation reaction of styrene (Scheme121). 70 The Mayo reaction has been shown to generate alkyl radicals that are able to initiate new polymer chains which in turn consume the excess TEMPO and therefore, help maintain the equilibrium concentration of

TEMPO.71

Scheme 1-21. Autoinitiation reaction of styrene (Mayo reaction).70

Hawker et al . demonstrated that TEMPO is able to mediate the random copolymerization

72 of styrene and nbutyl acrylate. If the strong acrylateTEMPO bond resulting from the low kd value was the only reason that inhibits TEMPOmediated acrylate SFRP systems, the random copolymerization of the said two monomers would have stalled as soon as TEMPO terminated chains ending with the acrylic functionality. However, that was not observed.

Georges et al . presented irrefutable proof against the kd argument by reporting the successful TEMPOmediated living radical polymerization of nbutyl acrylate with the continuous addition of ascorbic acid. 69 Molecular weights of 10,000 g mol 1 and 51 % conversion were achieved in 7 hours at 133 ºC. The premise of this publication argued that ascorbic acid readily reduced TEMPO to its hydroxylamine form (Scheme 122) 73 and lowered the concentration of excess TEMPO which accumulated due to the unavoidable irreversible termination reactions that occurred throughout the polymerization. Once the TEMPO concentration was restored, the polymerization equilibrium was shifted back towards the active propagating species which allowed the polymerization to proceed.

Scheme 1-22. Ascorbic acid reduction of TEMPO radical to the corresponding hydroxyamine.

Owing to the intrinsic inefficiency and impracticality of the continuous ascorbic acid addition method, Georges et al . further improved upon the TEMPOmediated acrylate polymerization system with the ab-initio addition of αhydroxycarbonyl compounds with base. 74

The αhydroxycarbonyl functionality undergoes enolization, catalyzed by base, to give the ene diol form of the compound (Scheme 123), which then reduces TEMPO in a similar manner to ascorbic acid.

Scheme 1-23. Basecatalyzed enolization of αhydroxycarbonyl compounds to the corresponding ene diol; used as a reducing agent for nitroxides.

Various αhydroxycarbonyl compounds (benzoin, anisoin, 3hydroxy2butanone, acetol, glycoaldehyde, glyceraldehyde) were evaluated with various bases (dimethylaminopyridine, pyridine), with the glyceraldehyde dimer paired with pyridine giving the best results (Scheme 1

24). Using this system with nbutyl acrylate, a 63% monomer conversion was achieved in 3 hours with a final molecular weight of 26,400 g mol1 and a PDI value of 1.4. The resulting polyacrylate underwent a clean chain extension reaction with styrene, demonstrating its ability to continue to add monomer in a living manner.

Scheme 1-24. Pyridine catalyzed enolization of glyceraldehyde dimer.

In order to design acrylate polymerization systems that do not require additives, new nitroxides and unimolecular initiators continue to be synthesized and investigated. Out of a

library of nitroxides, the two notable nitroxides with good success in acrylate polymerizations are 2,2,5trimethyl4phenyl3azahexane3nitroxide (TIPNO) 4 and Ntert butylN[1 diethylphosphono(2,2dimethylpropyl)]nitroxide (SG1) 5 (Figure 19).75

Figure 1-9. TIPNO and SG1 nitroxides.

These two particular nitroxides are reported to enable styrene polymerization at temperatures as low as 85 ºC, a feature attributed to their steric bulk. Moreover, these two nitroxides also mediate acrylate polymerizations at 95 ºC without additives, a feature some

67 attributed to the high kd values associated with these two nitroxides and the monomer units. In

2006, Braslau et al . published a piece of key evidence detailing a decomposition reaction of nitroxides bearing an αhydrogen, a feature shared by TIPNO and SG1, at elevated temperatures

(~120 ºC) (Scheme 125). 76 In this publication, Braslau et al . built upon the conclusions reached by Georges et al .69,74 in that a decomposition reaction can provide a mechanism to counteract the accumulation of nitroxides resulting from inevitable termination reactions throughout the polymerization. Consequently, the polymerization equilibrium shifts back towards the propagating polymer species, allowing propagation to continue.

Scheme 1-25. Irreversible decomposition of nitroxides bearing an αhydrogen (TIPNO is shown). 76

To further argue against a low kd value being the culprit in hindering TEMPOmediated acrylate polymerizations, Georges et al . prepared a severely sterically hindered nitroxide, the

77 1,1diadamantyl nitroxide 6 (Figure 110), to raise the kd value between the nitroxide and acrylate. This particular nitroxide was designed to be stable even at elevated temperatures (~120

ºC) and thus would accumulate in the polymerization solution as inevitable termination reactions of the polymeric chains occurred.

Figure 1-10. 1,1Diadamantyl nitroxide.

Styrene polymerizations were successful with the 1,1diadamantyl nitroxide as the mediating agent at temperature as low as 104 ºC (21,000 g mol 1, 85% conversion, PDI 1.17 after

5 hours with benzoic acid/glyceraldehydes additives), indicating the steric bulk enabled an

º increase in kd value. However, only 6% monomer conversion was achieved at 104 C after 6

hours with nbutyl acrylate. At 124 ºC, higher monomer conversion was observed but the PDI value increased and the molecular weight remained constant as the polymerization proceeded.

The success of acrylate polymerizations has been shown to be dependent upon keeping the nitroxide concentration constant. There are two approaches to achieve this. First, the judicious addition of additives, such as enediols, to destroy excess nitroxide can be employed.

The addition of additional initiating species to the reaction solution to generate new propagating chains is also included in this category. 78 In the latter case, as an example, ditert amyl peroxide, a high temperature initiator, was employed to provide a successful polymerization of nbutyl acrylate. Both a linear dependence of ln([M] 0/[M]) vs. time, as well as predictable molecular weights, were observed. Alternatively, an inherently unstable terminating agent can be designed to counteract its accumulation throughout the polymerization. This would allow for a self regulating system and the complications associated with additives, such deciphering both appropriate concentration of additives to use and addition rates, would be avoided.

Nitroxides are not alone in enabling the SFRP process; other families of stable free radicals such as galvinoxyl radicals 79 and triazolinyl radicals 8082 have been shown to mediate living radical polymerizations with different degrees of success. Of these candidates, the triazolinyl radical, a family of nitrogencentered free radicals, will be reviewed as it closely relates to the verdazyl work presented in later chapters.

1.2.3 Nitrogen-Centered Radicals in Stable Free Radical Polymerizations

1.2.3.1 Stable Free Radical Polymerizations Mediated by Triazolinyl Radicals

The triazolinyl radical family was first discovered by Neugebauer and Fischer in 1989 when 1,3,5,6,6pentaphenylleucoverdazyl was treated with formic acid. 83 Ring contraction gave

the nitrogen centered stable free radical, which contains the 1,2,4triazoline backbone, in 17% yield (Scheme 126).

Scheme 1-26. Ring contraction of leucoverdazyl to triazolinyl radical. 83

Alternative synthetic routes to the triazoline (Scheme 127), with improved yields as high as 72%, were subsequently reported by the same authors.84 Oxidation of the triazoline by oxidants such as lead oxide or potassium ferricyanide afforded the corresponding radical.

Scheme 1-27. Alternative synthetic methods to triazoline. 84

Despite being an unusually stable radical, it was not until 1998 that Klapper et al . sought to use the triazolinyl radical as a thermally reversible terminating agent for the livingradical polymerization of styrene initiated with BPO. 80,81 Klapper reiterated the two properties, as already conceptually described by Georges et al ., 69,74 required by the stable free radical to successfully mediate living radical polymerization. First, the stable free radical must be stable enough during polymerization conditions to participate in the reversible termination of propagating species. Second, should its concentration increase in the polymerization, the stable free radical must decompose to counterbalance its accumulation. Klapper further stated that to counteract the accumulation of the stable free radical, its decomposition mechanism must generate a radical species capable of initiating a new chain. The effect of such a decomposition

reaction would be twofold; both the decomposition itself, as well as the new chain initiation, would result in a decrease in the stable free radical concentration, allowing the polymerization to proceed uninhibited by the presence of excess free mediating radical.

Figure 1-11. Triazolinyl radical and its spiro derivative. 80

Triazolinyl radical 780 (Figure 111) was designed to decompose at 130 ºC to generate the phenyl radical along with 1,3,5triphenyl1H1,2,4triazole. The driving force for this decomposition reaction is the aromatization of the triazole backbone (Scheme 128).

Scheme 1-28. Thermal decomposition of triazolinyl radical 7 to give a triazole and a phenyl radical. 80

The spirotriazolinyl radical 8, with its connected phenyl rings, was designed not to decompose under the same conditions and was applied as a control to mimic TEMPOmediated polymerization systems.

The two triazolinyl radicals were used as mediators in styrene 81 and MMA 80 polymerizations initiated by BPO. Styrene polymerizations mediated by the spirotriazolinyl radical 8 at 140 ºC showed similar behaviour to that of TEMPOmediated polymerizations with

linear molecular weight increases versus % conversion and ln([M] o/[M] t versus time plots, albeit the PDI value reached as high as 1.49, suggesting some loss of control. The final molecular weights were in the 60,000 g mol 1 range.

However, MMA polymerization mediated by the spirotriazolinyl radical 8 gave only a

2% conversion after 22 hours. This result was attributed to the lack of an autoinitiation reaction from the MMA monomer. As a consequence, no new radicals were generated to react with and consume excess stable radials, which were formed as a result of the ever present termination reactions that occur between the propagating chains.

In contrast, MMA polymerization mediated by the triazolinyl radical 7 showed molecular weight growth over time (final polymers after 7 h: 78,700 g mol 1, 48% conversion, PDI = 1.60), demonstrating that propagation was possible despite the absence of an autoinitiation reaction from the monomer. This result was attributed to the decomposition of the triazolinyl radical 7 into radical products capable of initiating new chains, each of which consumed a stable radical molecule.

Although the system mediated by triazolinyl radical 7 displayed moderate living characteristics for styrene and MMA (linear ln( M0/M) vs. time, increase in molecular weight over time, linearity in Mn vs. conversion plot and chain extendibility), the PDI values were high, between 1.4 and 1.8 for homopolymers and upwards of 2.5 for copolymers. Furthermore, end group analysis showed that only 6080% of the chains were terminated with triazolinyl moieties, which indicated that up to 40% irreversible termination reactions had occurred.

1.2.3.2 Stable Free Radical Polymerizations Mediated by Verdazyl Radicals

As introduced previously, verdazyl radicals are another family of nitrogencentered stable free radicals. Shortly after Georges et al .41 reported the TEMPOmediated polymerization of styrene, Yamada et al .28 in 1994 sought to use the triphenylverdazyl radical 9 to mediate the polymerizations of styrene and MMA (Scheme 129).

Scheme 1-29. Triphenylverdazylmediated SFRP system. 28

For the triphenylverdazylmediated polymerization of MMA conducted at 60 ºC, adduct

10 , prepared from the coupling reaction between the triphenylverdazyl radical 9 with the isobutyronitrile radical derived from AIBN, was employed as a unimolecular initiator. After 24 hours, the polymerization produced polymers of low molecular weights (less than 5,000 g mol 1) at low monomer conversions (less than 10%). Furthermore, the initial colourless polymerization solutions gradually turned green, which indicated the accumulation of the verdazyl radical. The authors attributed this accumulation to a low recombination rate of the verdazyl radicals with the propagating polymer chains. The green colour intensified in air, which was an indication that leucoverdazyl 11 also formed in the reaction solution and oxidized in air to form more verdazyl radical. Presumably, the formation of the leucoverdazyl resulted from a hydrogen abstraction reaction by the verdazyl radical from a propagating polymethacrylate chain end (Scheme 130).

Scheme 1-30. Hydrogen abstraction of triphenylverdazyl from a polymethacrylate radical forming leucoverdazyl 11 .

As shown in the above mechanism, the hydrogen abstraction reaction destroys the propagating species and stops polymer growth of that particular chain. Due to these results the triphenylverdazyl radical was deemed unsuitable for MMA SFRP systems.

The same authors also attempted to use the triphenylverdazyl radical in the mediation of styrene SFRP systems.28 At 60 ºC, polymerizations did not occur even after 24 h, suggesting that once formed, the styrylverdazyl CN bond does not dissociate to allow monomer addition

(Figure 112).

Figure 1-12. Styrenetriphenylverdazyl bond.

In 1998, Yamada et al .29 revisited the polymerization of styrene at higher temperatures

(110 ºC) with the same AIBNderived triphenylverdazyl adduct 10 used in the previous study.

The resulting polymers showed an increase in molecular weight with conversion, which suggested that initiation and propagation reactions were possible with this particular verdazyl radical as a reversible terminating agent at this elevated temperature. However, the PDI values

(>1.5) were rather high. End group analysis of the polymers by NMR showed that roughly only

40% of the chain ends contained the triphenylverdazyl moiety, which indicated that a significant amount of irreversible bimolecular chain termination had occurred. The authors attributed this result to the decomposition of the triphenylverdazyl radical at 110 ºC (Scheme 110) 10 leaving insufficient amounts of terminating agent to cap all the propagating chains in a timely fashion, resulting in irreversible bimolecular termination of the propagating polymer chains. It was suggested by the authors that a structurally modified triphenylverdazyl radical with sufficient stability would be able to mediate the SFRP process. Whether that was true or not at the time was not clear but what was evident was that the verdazyl radicals warranted further study as mediators for livingradical polymerizations.

1.2.4 Concluding remarks

From the extensive investigations of the nitroxide family as mediators for the SFRP process, it is clear that structurally different nitroxides have varying degrees of success as thermally reversible terminating agents. With the wealth of information and diverse modifications available to the verdazyl family, it appeared conceivable that a verdazyl could be designed to successfully mediate the livingradical polymerization of various monomers. The second chapter of this thesis details our efforts at using verdazyl radicals as mediators for living radical polymerizations and in the process, it is shown that successful polymerizations of styrene and nbutyl acrylate can be achieved with the appropriate choice of verdazyl radical.

1.3 1,3-Dipolar Cycloadditions Involving Azomethine Imines

1.3.1 Introduction to 1,3-Dipolar Cycloadditions 8587

The 1,3dipolar cycloaddition reaction, as the name suggests, involves the cycloaddition reaction between a 1,3dipole (shown in the zwitterion form of a threeatom molecule) (Figure 1

13) and a dipolarophile (a dienophile equivalent) to form a fivemembered ring. The 1,3dipolar cycloaddition reaction is classified as a [3+2] cycloaddition for the number of atoms in the participating molecules. In contrast to the DielsAlder [4+2] cycloaddition reaction where the diene almost invariably acts as the nucleophile, the dipoles used in 1,3dipolar cycloaddition reactions are able to act as either the nucleophile or the electrophile, depending upon their substituents and the dipolarophiles used. 1,3Dipoles contain either a double or triple bond and are heteroatomic in nature, containing a combination of C, N, O and S atoms. It is not surprising then that the 1,3dipolar cycloaddition reaction is one of the most prevalent methods of synthesizing heterocyclic compounds. Even though the 1,3dipole designation suggests that the charges have a 1,3 relation, dipoles are typically shown in their ylide form with the charges on adjacent atoms.

Figure 1-13. Examples of 1,3dipoles.

The rate and regioselectivity of cycloaddition reactions are governed by molecular orbital

(MO) interactions of the reactants as stated by Woodward and Hoffmann.8890 Coulombic forces play little role in most cycloadditions reactions. 91 Fukui simplified the MO theory to the frontier molecular orbital (FMO) theory, which takes into account only the interaction between the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital

(LUMO) of the species involved. 92,93 The FMO theory is adequate in predicting the outcome of most cycloaddition reactions, although its accuracy is limited when predicting reactions where secondary orbital interactions, steric interactions, and solvent interactions play a large role. 94,95

For the most part, the FMO theory will be used in discussing the results of this work.

Three main conditions govern the outcome of pericyclic, and thus 1,3dipolar cycloaddition, reactions. First, FMO signs between the reactants must match in a symmetry allowed fashion for the reaction to occur (Figure 114). Second, the reactants must react in accordance to the set of HOMO/LUMO interaction with the lowest energy gap, which ensures the greatest transition state stabilization possible (Figure 115). Lastly, the reactants must align in a manner dictated by the relative size of their orbital coefficients; the atoms with larger coefficients interact with each other, and vice versa. The proper coefficient interactions give rise to a predictable regioselectivity (Figure 114).

Figure 1-14. FMO sign and coefficient matchup between a dipole and a dipolarophile.

Figure 1-15. Lowest energy gap set of HOMO/LUMO interaction between a dipole and a dipolarophile.

The relative energy levels of both the dipole and the dipolarophile are dictated by their substituents. Electronrich substituents, such as alkoxy or amino groups, raise both the HOMO and the LUMO energy levels; electronwithdrawing substituents, such as ester or nitrile groups, lower both the HOMO and the LUMO energy levels; conjugated substituents such as phenyl rings and polyenes raise the HOMO energy level but lower the LUMO energy level. Depending upon the relative energy levels of a particular dipole, three different MO interaction scenarios with various dipolarophiles are possible.

The first scenario describes an electronrich dipole using its high energy HOMO to interact with the low energy LUMO of an electronpoor dipolarophile. This HOMO/LUMO interaction is considered the “regular” cycloaddition, as most 1,3dipoles – nitrilimines, 96 nitrones, 97 diazoalkanes, 98 azides, 99 and sydnones 100 – follow this pattern. A reaction that occurs with this particular set of MO interaction is sometimes referred to as a dipole-HO controlled reaction . Electronrich dipolarophiles are not suitable in this instance, as the interaction between their high energy LUMO and the dipole HOMO would not provide sufficient stabilization for the transition state. In the second scenario, a dipole with the appropriate HOMO and LUMO energy levels can act as either an electron donor or acceptor, depending on the FMO’s of the dipolarophiles. Comprehensive studies with phenyl azide 99,101 and more recently, phthalazinium

dicyanomethanide 102,103 show they fit into this scenario. The third scenario describes an electron poor dipole which uses its low energy LUMO to interact with the high energy HOMO of an electronrich dipolarophile. This HOMO/LUMO interaction leads to what is known as an inverse electron demand cycloaddition reaction, which is also referred to as a dipole-LU controlled reaction . The three types of interactions described above can also be used to classify dipoles as Sustmann type 1, 2, 3 dipoles, respectively (Figure 116).

Figure 1-16. FMO matchup for Sustmann type I, II, and III dipoles with dipolarophiles.

The regioselectivity of an asymmetric 1,3dipolar cycloaddition is determined by orbital sizes, or coefficients, of the dipole and the dipolarophile species involved, which will vary according to any attached substituents. Both the energy levels and the coefficients can be qualitatively estimated as described by Fleming. 91 More recently, these values have been more accurately calculated by density function theory (DFT) calculations. 104

1.3.2 Azomethine Imines as Dipoles 8587

Azomethine imines are a class of 1,3dipoles containing one carbon and two nitrogen atoms. They are isoelectronic to an allyl anion and as such, have corresponding resonance structures (Figure 117). Even though some of the resonance structures represent the charges on

the 1 and 3 positions, azomethine imines are generally shown in the imine ylide 12 form.

Furthermore, like most 1,3dipoles, azomethine imines are typically considered to be overall neutral, which allows them to participate as any of the three Sustmann type dipoles assuming proper MO interactions with dipolarophiles.

Figure 1-17. Resonance structures of an azomethine imine.

Azomethine imines undergo [3+2] 1,3dipolar cycloaddition reactions with a range of dipolarophiles, usually in high yields with good stereoselectivity, to yield saturated or unsaturated heterocyclic structures (Scheme 131).

Scheme 1-31. 1,3Dipolar cycloaddition between an azomethine imine and a dipolarophile.

However, in the absence of dipolarophiles, certain reactive azomethine imines have been reported to dimerize via a [3+3] cycloaddition reaction (Scheme 132).

Scheme 1-32. [3+3] Dimerization of an azomethine imine.

1.3.3 History of Azomethine Imines

The first azomethine imine reported was by Schad in 1893, 105 but its potential to participate in cycloaddition reactions was not demonstrated until 1917.106 Few reports on azomethine imines were published for the next few decades and it was not until 1963 that a comprehensive review on azomethine imines was published by Huisgen. Below are some specific examples of azomethine imines (Figure 118).107

Figure 1-18. Examples of azomethine imines.

In 1968, Otto et al . reported another example of an azomethine imine, derived from the reaction of 3pyrazolidone and carbonyl compounds (Scheme 133).108,109

Scheme 1-33. Azomethine imine derived from 3pyrazolidone and carbonyl compounds. 108,109

Another example of an azomethine imine was reported by Oppolzer et al . in 1970

(Scheme 134).110,111 This azomethine imine was generated in situ with a dipolarophile incorporated in the same molecule designed to undergo an intramolecular 1,3dipolar cycloaddition reaction to form a fused heterocyclic structure (Scheme 135).111

Scheme 1-34. An azomethine imine reported by Oppolzer. 110,111

Scheme 1-35. An azomethine imine designed to undergo intramolecular 1,3dipolar cycloaddition. 111

Sydnones, cyclic azomethine imines formed by the treatment of various derivatives of N nitrosophenylglycine with acetic anhydride, were first synthesized and reported in 1936 by Earl et al . as a highly strained bicyclic structure (Scheme 136). 112 In 1962, Huisgen recognized the structure proposed by Earl as an azomethine imine and successfully employed it as a dipole in cycloaddition reactions with various alkenes 113 and alkynes. 114 Decarboxylation reactions of sydnone cycloadducts derived from alkenes and alkynes are facile and yield pyrazolines and pyrazoles, respectively (Scheme 137).

Scheme 1-36. Structure of sydnone as first proposed by Earl et al .112

Scheme 1-37. Sydnone, as proposed by Huisgen, undergoing a 1,3dipolar cycloaddition with alkenes. 113

1.3.4 Recent Developments in Azomethine Imine Cycloadditions

1.3.4.1 Stereoselective Synthesis

The first report of stereoselective syntheses with chiral azomethine imines were reported in 1992 by Stanovnik et al .115 A dihydropyrazole was reacted with aldehydo sugars to form stable chiral azomethine imines which, in the presence of methyl acrylate, gave pure (>95% de) or nearpure (90% de) stereoisomers in over 60% yield. It was deduced that the diastereoselectivity resulted from the dipolarophile reacting with the less hindered side of the azomethine imine. The example shown below illustrates the azomethine imine formed from pentabenzoylDglucose and its corresponding cycloadduct with methyl acrylate (Scheme 138).

Scheme 1-38. A sugarderived chiral azomethine imine. 115

1.3.4.2 Metal-Catalyzed 1,3-Dipolar Cycloadditions

Kobayashi et al . was one of the first groups to report the metal catalysis of inter and intramolecular 1,3dipolar cycloaddition reactions with azomethine imines by the addition of a chiral zirconium/BINOL complex. 116 Reported yields typically ranged from 60100%, with

>90% ee, depending on the catalyst used. The builtin intramolecular dipolarophiles were of the unactivated variety (alkenes) while the intermolecular dipolarophiles were of the electronrich variety (vinyl ethers, vinyl thioethers). The fact that no electronpoor dipolarophiles were

reported would suggest a likely scenario that the coordinated zirconium metal withdrew electron density from the azomethine imine. As a consequence, the LUMO energy of the azomethine imine was lowered such that the azomethine imine could only display Sustmann type III characteristics in its selection of dipolarophiles. The example shown below illustrates a zirconium catalyzed intramolecular cycloaddition reaction of a dipole with neutral and electron rich dipolarophiles (Scheme 139).

Scheme 1-39. Zirconiumcatalyzed formation and 1,3dipolar cycloaddition of an azomethine imine. 116

Fu et al .117 reported the first example of copper catalysis of 1,3dipolar cycloaddition reactions with azomethine imine. It was shown that in the presence of copper (I) and a P, N ligand, phosphaferroceneoxazoline, 9499% yield and 8196% ee could be achieved in cycloaddition reactions of azomethine imines with methyl propiolate. (Scheme 140). The mechanism of catalysis by copper on the alkynyl substrates was presumed to go through a transient formation of a copper acetylide, a well known intermediate exemplified by “click” chemistry. 118 The copper acetylide intermediate, acting as a dipolarophile, has a much lower

LUMO energy level compared to the corresponding alkyne and as a consequence, the reaction proceeds with the azomethine imine acting as a Sustmann type I dipole.

Scheme 1-40. Coppercatalyzed formation and 1,3dipolar cycloaddition of an azomethine imine. 117

1.3.4.3 Total Synthesis

Azomethine imines have proven to be useful tools in targeted/total syntheses. Jacobi et al .119 recognized that a key intermediate in the synthesis of saxitoxin contains a pyrolidine ring that could be formed by a 1,3dipolar cycloaddition reaction from the corresponding azomethine imine (Scheme 141). The azomethine imine was formed by the reaction of a hydrazide derivative with glyoxylate hemiacetal in the presence of a Lewis acid. Once the pyrolidine ring was synthesized by the cycloaddition, its transformation to saxitoxin was straightforward. This was the first example of applying an azomethine imine in a total synthesis.

Scheme 1-41. The use of an azomethine imine in the total synthesis of saxitoxin. 119

In 2006, Overman et al .120 reported the use of an azomethine imine intramolecular 1,3 dipolar cycloaddition reaction as a key step in the synthesis of the diguanidine alkaloid massadine (Scheme 142). It was recognized that the cis fused pyrazolidine could be constructed from a thiosemicarbazide derived azomethine imine, prepared in situ by the thermal condensation of an αketoester and a thiosemicarbazide. The cycloadduct was isolated and subsequently converted to the final target.

Scheme 1-42. The use of an azomethine imine in the total synthesis of massadine. 120

More recently, Overman and Rohde 121 reported another case of an azomethine imine 1,3 dipolar cycloaddition reaction as a key step in the total synthesis of nankakurines A and B.

Starting from a hydrazine derivative, a hydrazone formation was performed with formaldehyde and base to give the azomethine imine, which then underwent an intramolecular cycloaddition to give a fused ring intermediate in 82% yield. The cycloadduct was subsequently converted into nankakurines A and B (Scheme 143).

Scheme 1-43. The use of an azomethine imine in the total syntheses of nankakurines A and B. 121

1.3.5 Concluding Remarks

It is evident that azomethine imines are excellent precursors to nitrogencontaining heterocycles. As such, novel azomethine imines expand the arsenal of precursors in heterocyclic designs, encouraging structural diversity and utility of the resulting cycloadducts. In the third chapter of this thesis, a structurally unique azomethine imine was discovered and its participation in a 1,3dipolar cycloaddition reaction as well as subsequent rearrangement reactions gave rise to heterocycles containing a variety of scaffolds.

1.4 Heterocyclic Rearrangements

1.4.1 General Considerations

Heterocyclic structures are abundant and important in synthetic chemistry. Incorporated within these ring structures are heteroatoms that govern the unique reactivities of heterocycles by properties such as electronegativity, anomeric effect, or neighbouring group participation.

Nitrogencontaining rings are of particular interest due to the nucleophilic nature of the heteroatom, as well as their lone pair inversions which allow for extra flexibility. These properties are exemplified in fusedring systems containing multiple nitrogen atoms that undergo inter or intramolecular rearrangement reactions. If understood correctly, heterocyclic rearrangements can prove invaluable in designing ring systems that would otherwise be difficult to construct.

1.4.2 Dimroth Rearrangements

A welldocumented example of a heterocyclic rearrangement is the Dimroth rearrangement, first observed by Rathke in 1888. 122 However, its mechanism was not correctly interpreted until 1909 by Dimroth.123 In 1961, Brown et al .124 substantiated the proposed mechanism by 15 Nlabel studies (Scheme 144) and named the reaction the Dimroth rearrangement.125,126 The Dimroth rearrangement is classified as an isomerization process whereby exo and endocyclic heteroatoms are translocated on a heterocyclic ring. 127 Two main classifications exist: one is the translocation that occurs in a single heterocyclic ring and the second is the translocation that occurs in a fused bicyclic ring system (Scheme 145).128 Due to the relevance of the latter class to the work presented in this thesis, the chemistry of this reaction will be introduced in further detail.

Scheme 1-44. The 15 Nlabel experiment verifying the rearrangement mechanism proposed by Dimroth.124

Scheme 1-45. The translocation of heteroatoms in a fused bicyclic system. 128

1.4.2.1 Nucleophile-Assisted Ring Fission

The Dimroth rearrangement can be induced via acid, base, heat, or light. In the former two conditions, the nucleophilic attack from an external nucleophile is responsible for the initial ring fission. Faster rearrangement rates are generally observed in heterocycles that contain more electronegative atoms or electron withdrawing groups. This observation can be rationalized by the ability of these systems to delocalize the newlyintroduced electron density from the nucleophile. By the same token, ring fission can be more favourable if the resulting intermediate is highly conjugated (Scheme 146).127

Scheme 1-46. An example of a Dimroth rearrangement pathway involving a highly conjugated intermediate. 129

In 1971, Fujii et al .130,131 reported the first isolated intermediate of the Dimroth rearrangement (Scheme 147). Alkyl and alkoxyadenines were converted to the corresponding purines upon being refluxed in water. However, when the adenines were treated with water at approximately 5 ºC instead, ring fission occurred to yield the corresponding isolable monocyclic derivative 13 . The monocyclic derivatives in the overall rearrangements were confirmed to be intermediates as they recyclized to the purine products when heated in refluxing water.

Scheme 1-47. The Dimroth rearrangement alkyl or alkoxyadenines to purines. 130,131

Interestingly, it was reported in the same series of experiments that the initial alkyladenines, when protonated, undergo ring fission at a much higher rate than their neutral counterparts (Scheme 147).131,132 It is now welldocumented that Dimroth rearrangements occur at a higher rate for protonated compounds or compounds containing electron withdrawing substituents. This increase in rate is due to the facile delocalization of the electron density introduced by the nucleophile. Conversely, electron donating substituents reduce the

rearrangement rate. It is also agreed that the rate affected is that of the ring fission step of the rearrangement. Both Brown 133 and more recently Fujii 128 have compiled data to suggest that heterocyclic compounds, when protonated or carrying electron withdrawing substituents, are also more electron deficient and therefore are more susceptible to attack by nucleophiles.

Another driving force for the Dimroth rearrangement is the higher thermodynamic stability of the product relative to the starting heterocycle. In the investigation of 1alkyl2 alkyliminopyrimidines rearrangement reaction performed by Brown et al ., 134,135 both the starting material and the product were designed to be nonaromatic. When lacking aromaticity as a decisive driving force, the system equilibrates and favours the product with higher thermodynamic stability. For example, in the equilibrium shown below (Scheme 148), structure

14 is the more stable product due to the accommodation of the larger group R on the exocyclic nitrogen, and is therefore the favoured product.

Scheme 1-48. A Dimroth rearrangement favouring the product with the highest thermodynamic stability. 134,135

1.4.2.2 Heat-Assisted Ring Fission

Dimroth rearrangements can also be initiated thermally without nucleophiles. In a recent example, Subbotina and Fabian 136 reported the transformations of 6amino4oxopyrano[3,4d]

[1,2,3]thiadiazoles to the corresponding 6hydroxy4oxo[1,2,3]thiadiazolo[4,5c]pyridines

(Scheme 149).

Scheme 1-49. The Dimroth rearrangement reactions of 6amino4oxopyrano[3,4d] [1,2,3]thiadiazoles to 6hydroxy4oxo[1,2,3]thiadiazolo[4,5c]pyridines. 136

Initially it was shown that the abovementioned rearrangement reaction occurs with morpholine or piperidine under heating conditions, classifying it as a typical nucleophileassisted ring fission Dimroth rearrangement (top of Scheme 150). However, the same results were obtained from experiments performed in freshly purified and dry DMF under argon without morpholine or piperidine, which ruled out nucleophileassistance during the ring fission step.

The authors then proposed a new thermal ring fission mechanism involving a carbamoyl ketene intermediate 15 (bottom of Scheme 150).

Scheme 1-50. Nucleophileassisted vs. heatassisted ring fission in a Dimroth rearrangement.

DFT calculations showed that the formation of the ketene intermediate 15 , which is the rate determining step, has an activation barrier of 2434 kcal/mol and is spontaneous under

heating conditions. The authors also showed that the nucleophileassisted ring fission is

5 kcal/mol less favourable than the heatassisted ring fission. Therefore, it was concluded that this particular example of the Dimroth rearrangement took place via a heatassisted ring fission pathway.

1.4.3 Concluding Remarks

Even though the Dimroth rearrangement reaction is welldocumented, novel pathways and structures are continually being proposed and reported. As the definition of Dimroth rearrangement spotlights structural features rather than the mechanistic pathway, it is possible for a reaction to be categorized as a Dimroth rearrangement but still go through a novel mechanism.

The fourth chapter of this thesis will focus on a heterocyclic rearrangement that is structurally classified as a Dimroth rearrangement; however the mechanism proposed differs drastically from the nucleophileassisted ring fission that is typical of Dimroth rearrangements.

1.5 Advances in Small Molecules Libraries

1.5.1 General Considerations

Small molecules have shown their usefulness in biological chemistry not just as mechanistic study tools, but also as therapeutic drugs. Traditionally, libraries of small molecules resembling known drugs have been successfully employed as probes for known targets of interest, such as specific proteins or receptors. Ironically, the druglike structural properties of the compounds in these libraries limit the structural diversity therein, and thus the variety of biological targets they can interact with also becomes severely limited.

Recently, techniques have been developed to further expand the structural diversity in small molecule libraries to allow greater chances of success in probing unknown biological targets. At the frontier of these techniques are dynamic combinatorial chemistry (DCC) 137,138 and diversityoriented synthesis (DOS); 139,140 with the latter technique having more relevance to our research interests. DCC utilizes building blocks that undergo reversible reactions to construct molecules. The most thermodynamically stable molecule or one that provides the most favourable and irreversible binding to the target can then be purified out of the reaction as a single product or as a targetbound complex for characterization and structuretoactivity relationship elucidation (Scheme 151, Scheme 152).

Scheme 1-51. A schematic representation of DCC. 138

Scheme 1-52. A DCC library of compounds involving hydrazal formation. 141

1.5.2 Diversity-Oriented Synthesis (DOS)

Contrasting the traditional targetoriented syntheses that rely on retrosynthetic analyses, the DOS strategy does not target specific molecules. In order to increase the chance of observing any biological activities during screening, DOS libraries require structural diversity and complexity. Currently, three main design philosophies exist for DOS. 139 First, a sole starting material is treated with different substrates to create a library of derivatives containing the same scaffold (Scheme 153). Second, a similar method with a sole starting material is employed to create a library of stereoisomers in which all the stereoisomers contain the same scaffold. While structural complexity can be integrated into the products with appropriate structurally complex starting materials and substrates, the structural diversity of these libraries is still limited to one scaffold.

Scheme 1-53. A DOS library of compounds containing the same scaffold R. 142

The third design overcomes the aforementioned limitation. The more ambitious DOS designs involve two or multicomponent reactions where each component tolerates various orthogonal functionalities. A library of compounds can be generated with the same scaffold but different combinations of functionalities. Additionally, the single scaffold is designed to be able to undergo a number of distinct transformations under various conditions such that each member from the first library can generate new derivatives with varying scaffolds while retaining the

orthogonal functionalities (Scheme 154). Furthermore, these orthogonal functionalities can be derivatized to increase the library size.

Scheme 1-54. An example of a DOS library of compounds containing different scaffolds and different orthogonal functionalities. 143,144

An example of an azomethine ylide 1,3dipolar cycloaddition reaction applicable to DOS is shown below (Scheme 155).145 The use of the 1,3dipolar cycloaddition reaction in DOS is relevant to the work of this thesis.

Scheme 1-55. DOS library of compounds built with1,3dipolar cycloadditions involving azomethine ylides. 145

The general requirements for DOS reactions are that they must be high yielding with easy to purify products.140 As a consequence, large libraries of compounds with high degrees of structural complexity and diversity for biological probing can be easily and rapidly generated. If

biological activity is observed with a particular compound from the screening, the select compound would undergo further assessment and derivatization to maximize its potency.

The impact of DCC and DOS techniques is twofold. Aside from the primary goal of generating libraries of compounds, new reactions are continually being developed to provide structural diversity while old reactions are improved upon for higher efficiency and functional group tolerance.140

The final chapter of this thesis will demonstrate how the newly developed reactions from this thesis meet the requirements of DOS; preliminary efforts have shown high potential for these reactions in creating unique libraries of structurally complex and diverse compounds over a short period of time.

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Chapter 2

2 Verdazyl-Mediated Living Radical Polymerization of Styrene and n-Butyl Acrylate

2.1 Introduction and Objective

Living radical polymerizations have been an integral part of the polymer community since the early 1990’s. Combining the living characteristics of low PDI values and chain extendable polymers from anionic polymerization with the synthetic ease, monomer versatility and aqueous compatibility of conventional radical polymerizations, living radical polymerizations have become a very versatile method for constructing polymers with complex architecture. The three prominent living radical polymerization systems are SFRP, ATRP, and

RAFT.

Nitroxides are the most extensively studied stable free radicals in the SFRP system.

Among nitroxides, TEMPO, TIPNO, and SG1 are wellknown; the former for its commercial availability and straightforward use in styrene polymerizations, the latter two for their ability to mediate styrene and acrylate polymerizations without additives at low temperatures (~85 ºC).

Even though recent studies have linked the success of TIPNO and SG1 in acrylate polymerizations to their inherent instabilities under polymerization conditions, 1 it is evident that structurally different nitroxides exhibit different degrees of success in mediating SFRP systems. 2

6 Therefore, it can be envisioned that other families of stable free radicals with the potential for

diverse structures may improve polymerization conditions (lower temperatures, shorter time) and expand the range of monomers (to include monomers such as methacrylates and vinyl acetate) in the SFRP system.

The family of verdazyl radicals has had a long history since their discovery and there exists an extensive repertoire of synthetic methods that enables much derivatization for these radicals.712 Furthermore, various substituents are known to affect the stabilities, sterics and threedimensional structures of the verdazyl radicals, 10 features known to affect the SFRP mediating ability of nitroxides. To that end, the verdazyl radicals would appear to be promising candidates as mediators for the SFRP process.

Although Yamada et al .13,14 attempted to use verdazyl radicals as mediators for living radical polymerizations first in 1994 and again in 1998, the study was not particularly exhaustive.

Methyl methacrylate (Scheme 21) and styrene polymerizations, initiated with the unimolecular initiator adduct 10 obtained through the reaction of AIBN and the 1,3,5triphenylverdazyl radical

9, were initially studied at 60 ºC. While 10 did appear to dissociate and initiate polymerizations, the overall results of the polymerizations were unsatisfactory. In the case of methyl methacrylate polymerization, the triphenylverdazyl radical 9 favoured hydrogen abstraction over recombination with the propagating polymethacrylate chains resulting in low molecular weights and low monomer conversions (refer to Scheme 130).13 In the case of styrene polymerization, no hydrogen abstraction was observed but the polymerizations still only gave low monomer

13 conversions, presumably due to the low kd value of the styrylverdazyl bond at 60 ºC.

Scheme 2-1. Methyl methacrylate polymerization initiated with the triphenylverdazylAIBN adduct 10 at 60 ºC.

In 1998, Yamada et al .14 revisited the polymerization of styrene with 10 , this time performing the polymerizations at 110 ºC (Scheme 22), a temperature high enough for the styrylverdazyl bond to dissociate and allow propagation. However, the PDI values of the resulting polystyrene were generally greater than 2 and endgroup analysis showed that roughly

60% of the polymer chains had been terminated by an irreversible bimolecular chain coupling reaction. On the basis of these results, the authors concluded that a living radical polymerization could not be realized with verdazyl radicals as the mediating agents.

Scheme 2-2. Styrene polymerizations initiated with the triphenylverdazylAIBN adduct 10 at 110 ºC.

Despite the aforementioned effort and results from Yamada et al ., the multitude of modifications affordable by the verdazyl radical family still made a further study of these molecules interesting. Just as the initial inability of TEMPO to mediate acrylate polymerization led to the study of other nitroxides such as TIPNO and SG1, the inability of triphenylverdazyl

radical 9 to perform as desired did not provide sufficient evidence to rule out other verdazyl radical derivatives. In this chapter, results from the verdazylmediated SFRP system using various 6oxoverdazyl radicals are provided and discussed. Successful livingradical polymerizations are demonstrated for styrene and nbutyl acrylate monomers. 15

2.2 Experimental Section

2.2.1 Materials and Equipment

All ACS grade reagents and solvents were purchased from SigmaAldrich, EMD

Chemicals, and Caledon Chemicals unless otherwise stated. Argon was purchased from BOC

Canada. TEMPO was used as received from ZD Chemipan (Poland). 2,2’Azobis(2,4 dimethylpentanenitrile) (Vazo® 52) was provided by the Xerox Research Centre of Canada

(XRCC) and used as received. 1,1’Azobis(cyclohexanecarbonitrile) (Vazo® 88) (Aldrich, 98%) was used as received. tert Butylcatechol and hydroquinone monomethyl ether were removed from styrene and nbutyl acrylate, respectively, by passing the monomers through a short column packed with the appropriate inhibitor remover resin purchased from SigmaAldrich. The inhibitorfree monomers were stabilized with added stable free radical (TEMPO or verdazyl radical corresponding to that used in specific polymerizations) at a concentration of 0.042 M.

Flash column chromatography was performed using Silica Gel 60 (particle size 4063 m) purchased from EMD Chemicals. Thin layer chromatography analyses were performed using aluminum plates coated with silica (pore size of 60Å) and fluorescent indicator, purchased from

EMD Chemicals, and visualized under UV (254 nm) light.

Verdazyl radicals were synthesized according to published procedures. 10,11,16 The

BenzoylStyreneTEMPO (BST) adduct was synthesized according to an unpublished procedure

utilizing the TEMPO promoted dissociation of BPO. In this procedure, TEMPO and BPO (1:2 molar ratio) were reacted at high concentrations and at ambient temperatures in neat styrene monomer. The reaction was exothermic, and was repeatedly cooled by lowering the reaction flask into an ice bath in order to keep the reaction temperature at ~25 ºC. Once the exotherm stopped, the reaction was left overnight. The styrene monomer was then removed by a stream of air. BST was recovered in roughly 40% yield after flash column chromatography with methylene chloride as the solvent.

NMR data were obtained using a Varian INOVA500 spectrometer at 20 ºC, operating at

1 13 500 MHz for H NMR and 125 MHz for C NMR in CDCl 3 (Aldrich, 99.8% atom D) with

0.03% (v/v) tetramethylsilane (TMS) standard. Chemical shifts ( δ) are reported in parts per

1 13 million (ppm) referenced to TMS (0 ppm) for H NMR spectra and CDCl 3 (77.0 ppm) for C

NMR. Coupling constants (J) are reported in hertz (Hz). Spin multiplicities are indicated by the following abbreviations: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet) and br

(broad). Accurate mass determination mass spectra (HRMS) were obtained from AIMS laboratory, Department of Chemistry, University of Toronto using a Micromass 70S250 sector mass spectrometer or ABI/Sciex Qstar mass spectrometer. Elemental analyses were performed by the ANALEST facility, Department of Chemistry, University of Toronto on a PerkinElmer

Series II model 2400 CHNS/O analyzer equipped with a Mettler MT5 micro analytical balance, operating in the CHN mode. Samples were calibrated against an internal standard, acetanilide (C,

71.09; H, 6.71; N, 10.3) before and after running samples. Melting points were determined on an electrothermal capillary melting point apparatus and are uncorrected.

Polymer molecular weights and polydispersity indices (PDI) were estimated by gel permeation chromatography (GPC) using a Waters 2690 separations module equipped with a

Waters model 410 differential refractometer (RI) detector and Styragel HR4 (7.8 x 300 mm, effective MW range 5,000600,000), HR2 (4.6 x 300 mm, effective MW range 50020,000), and

HR1 (4.6 x 300 mm, effective MW range 1005,000) columns calibrated with polystyrene

1 standards in the range Mn = 400188,000 g mole . THF was used as eluent at 40 ºC and a flow rate of 0.35 mL min 1. GPC was performed on samples taken directly from the reaction mixture without any prior precipitation that may remove low molecular weight chains. Excess monomer was removed by evaporation with a stream of air before GPC analysis. Percentage conversions were determined gravimetrically.

2.2.2 Styrene Polymerization Initiated with 1,1’-Azobis(cyclohexanecarbonitrile) (Vazo®

88) in the Presence of 1,5-Dimethyl-3-phenyl-6-oxoverdazyl Radical 16

In a typical polymerization experiment, styrene (10 mL, 87 mmol), Vazo® 88 (30 mg,

0.12 mmol), and 1,5dimethyl3phenyl6oxoverdazyl radical 16 (100 mg, 0.49 mmol) were placed in a 25 mL three neck round bottom flask fitted with a thermometer, a condenser with a gas outlet adapter, and a septum through which argon was introduced and samples were withdrawn via syringe. The solution was purged with argon for 30 min and then heated to

125 ºC for 5 h under a slow stream of argon.

2.2.3 Styrene Polymerization Initiated with BPO in the Presence of 1,3,5-Triphenyl-6-

oxoverdazyl Radical 17

Using the same experimental procedure described in section 2.2.2, a solution of styrene

(10 mL, 87 mmol), BPO (28 mg, 0.12 mmol), and 1,3,5triphenyl6oxoverdazyl radical 17

(100 mg, 0.29 mmol) was heated at 110 ºC under argon for 2 h.

2.2.4 Synthesis of 2-(3-Oxo-2,4,6-triphenyl-3,4-dihydro-1,2,4,5-tetrazin-1(2H)-yl)-2-

phenylethyl benzoate (18)

In a typical exchange reaction, argon was bubbled through a solution of BST 3 (750 mg,

2 mmol) and 1,3,5triphenyl6oxoverdazyl radical 17 (1.38 g, 4 mmol) in chlorobenzene for 30 min, after which the solution was heated under argon at 120 ºC for 2 h. The solvent was removed in vacuo and the product was obtained from the resulting oil by silica gel column chromatography (1:3 ethyl acetate/hexane). Recrystallization from isopropanol gave the title compound as a white crystalline solid (990 mg, 90%, mp: 143144 ºC). In solution 18 exists as

1 two conformers (CN rotamers). H NMR (500 MHz, acetoned6, 0 ºC), major conformer (92%)

δ: 6.928.27 (m, 25H), 4.86 (dd, J = 3.9, 10.6, 1H), 4.78 (dd, J = 10.6, 11.7, 1H), 4.50 (dd, J =

3.9, 11.7, 1H); minor conformer (8%) δ: 6.928.27 (m, 25H), 5.00 (dd, J = 4.1, 10.3, 1H), 4.80

13 (dd, J = 10.3, 12.0, 1H), 4.52 (dd, J = 4.1, 12.0, 1H). C NMR (125 MHz, acetoned6), major conformer δ: 165.8, 152.8, 149.0, 120144, 56.6, 62.3; minor conformer δ: 165.9, 152.9, 149.6,

120144, 67.5, 63.7. Anal. Calcd for C 35 H28 N4O3 (552.62): C, 76.07; H, 5.11; N, 10.14. Found:

C, 76.08; H, 5.47; N, 10.30.

2.2.5 Styrene Polymerization Initiated with Unimolecular Initiator 18

Using the same experimental procedure described in section 2.2.2, a solution of 1,3,5 triphenyl6oxoverdazylstabilized styrene (10 mL, 87 mmol) and unimolecular initiator 18 (100 mg, 0.18 mmol) was heated at 130 ºC for 6 h.

2.2.6 Synthesis of 2-(2,4-Dimethyl-3-oxo-6-phenyl-3,4-dihydro-1,2,4,5-tetrazin-1(2H)-yl)-

2-phenylethyl benzoate (19)

The title compound was prepared, using the same unimer exchange experimental procedure described in section 2.2.4, purified by silica gel chromatography (1:3 ethyl acetate/hexane) and recrystallized from isopropanol to give a white crystalline solid (30%, mp:

9798 ºC). The yield could be improved to 45% with the addition of 350 mg ascorbic acid. In

1 solution 19 exists as two conformers (CN rotamers). H NMR (500 MHz, CDCl 3, 20 ºC), major conformer (78%), δ: 7.228.28 (m, 15H), 5.04 (dd, J = 10.8, 11.9, 1H), 4.63 (dd, J = 4.1,

11.9, 1H), 4.50 (dd, J = 4.1, 10.8, 1H), 3.34 (s, 3H), 2.65 (s, 3H); minor conformer (22%), δ:

7.228.28 (m, 15H), 5.08 (dd, J = 10.3, 11.6, 1H), 4.77 (dd, J = 3.8, 10.3, 1H), 4.53 (dd, J = 3.8,

13 11.6, 1H), 3.05 (s, 3H), 2.71 (s, 3H). C NMR (125 MHz, CDCl 3), major conformer δ: 166.1,

157.2, 147.2, 127135, 64.3, 62.1, 40.4, 35.6; minor conformer δ: 166.0, 159.4, 149.2, 127136,

63.8, 63.2, 40.0, 36.7. Anal. Calcd for C 25H24N4O3 (428.48): C, 70.08; H, 5.65; N, 13.08. Found:

C, 70.06; H, 5.55; N, 13.08.

2.2.7 Styrene Polymerization Initiated with Unimolecular Initiator 19

Using the same experimental procedure described in section 2.2.2, a solution of 1,5 dimethyl3phenyl6oxoverdazylstabilized styrene (10 mL, 87 mmol) and unimolecular initiator 19 (100 mg, 0.23 mmol) was heated at 125 ºC for 6 h.

2.2.8 n-Butyl Acrylate Polymerization Initiated with Unimolecular Initiator 19

Using the same experimental procedure described in section 2.2.2, a solution of 1,5 dimethyl3phenyl6oxoverdazylstabilized nbutyl acrylate (15 mL, 100 mmol) and unimolecular initiator 19 (100 mg, 0.23 mmol) was heated at 130 ºC for 28 h.

2.2.9 Reaction of 1,5-Dimethyl-3-phenyl-6-oxoverdazyl Radical 16 with BPO and Styrene

A solution of radical 16 (1.00 g, 4.9 mmol) dissolved in styrene (10 mL, 90 mmol) was added to a three neck round bottom flask equipped with a gas inlet, thermometer and a stir bar.

The reaction solution was purged with nitrogen for 20 min. BPO (1.00 g, 4.1 mmol) was added to the reaction mixture producing an exotherm of about 10 ºC two minutes after the addition.

The reaction was allowed to continue at ambient temperature for 24 h after which the excess styrene was removed by a stream of air. Products 19 and 20 were purified by silica gel chromatography (3:7 ethyl acetate/hexane). Product 19 was recrystallized from isopropanol (220 mg, 10%): for full characterization see section 2.2.4. Product 20 (422 mg, 28%) was isolated as

1 a pale yellow oil. H NMR (500 MHz, CDCl 3), δ: 7.447.38 (m, 2H), 7.457.28 (m, 2H), 7.26

7.20 (m, 2H), 7.187.11 (m, 3H), 6.926.86 (m, 2H), 4.71 (dd, J = 4.9, 8.6, 1H), 4.374.30 (m,

1H), 3.643.57 (m, 1H), 3.19 (s, 3H), 2.582.49 (m, 1H), 2.222.14 (m, 1H). 13 C NMR (125

MHz, CDCl 3), δ: 155.0, 147.3, 139.4, 131.5, 130.1, 128.2, 128.1, 127.8, 127.4, 127.2, 66.0, 44.8,

+ 36.4, 33.2. HRMS (ESI) ( m/z ): calculated for C 18 H19 N4O [M+H] , 307.1553; found, 307.1551.

2.2.10 Preparation of Poly( n-butyl acrylate-b-polystyrene) from a Poly( n-butyl acrylate)

Macroinitiator

A solution of verdazylstabilized styrene (10 mL, 87 mmol) and 1,5dimethyl3phenyl

1 6oxoverdazylterminated poly( nbutyl acrylate) ( Mn = 6,250 g mol , PDI = 1.14, 1.42 g, 0.23 mmol), purified from three cycles of methanol precipitation, was degassed by argon for 1 h and

1 heated at 125 ºC for 7 h. The resulting diblock copolymer had Mn = 8,800 g mol and PDI =

1.26.

2.2.11 Preparation of Poly(styrene-b-poly( n-butyl acrylate)) from a Polystyrene

Macroinitiator

A solution of verdazylstabilized nbutyl acrylate (15 mL, 110 mmol) and 1,5dimethyl

1 3phenyl6oxoverdazylterminated polystyrene ( Mn = 10,400 g mol , PDI = 1.20, 2.50 g, 0.24 mmol), purified from three cycles of methanol precipitation, was degassed by argon for 1 h and

1 heated at 135 ºC for 4 h. The resulting diblock copolymer had Mn = 13,200 g mol and PDI =

1.30.

2.2.12 Synthesis of 2-(6-(4-Cyanophenyl)-2,4-dimethyl-3-oxo-3,4-dihydro-1,2,4,5-tetrazin-

1(2H)-yl)-2-phenylethyl benzoate (23)

The title compound was prepared using the same unimer exchange experimental procedure described in section 2.2.4, purified by silica gel chromatography (1:3 ethyl acetate/hexane) and recrystallized from isopropanol to give a white crystalline solid (30%, mp:

141143 ºC). In solution 23 exists as two conformers (CN rotamers). 1H NMR (500 MHz,

CDCl 3, 20 ºC), major conformer (81%), δ: 8.208.10 (m, 2H), 8.007.93 (m, 2H), 7.767.71 (m,

1H), 7.657.58 (m, 2H), 7.567.53 (m, 2H), 7.407.38 (m, 3H), 7.237.19 (m, 2H), 5.02 (t, J =

11.1, 1H), 4.65 (dd, J = 4.1, 12.0, 1H), 4.40 (dd, J = 4.1, 10.8, 1H), 3.37 (s, 3H), 2.67 (s, 3H); minor conformer (19%), δ: 8.007.93 (m, 2H), 7.897.86 (m, 2H), 7.747.70 (m, 2H), 7.697.65

(m, 1H), 7.547.50 (m, 2H), 7.467.42 (m, 3H), 7.427.38 (m, 2H), 5.02 (t, J = 11.1, 1H), 4.68

(dd, J = 4.1, 12.0, 1H), 4.55 (dd, J = 4.1, 10.8, 1H), 3.10 (s, 3H), 2.77 (s, 3H). 13 C NMR (100

MHz, CDCl 3), δ: 166.1, 156.4, 144.5, 135.5, 134.1, 133.7, 132.5, 129.6, 129.3, 128.8, 128.6,

127.8, 127.5, 118.3, 113.6, 65.1, 62.4, 40.2, 36.0. Anal. Calcd for C 26 H23N5O3 (455.18): C,

68.86; H, 5.11; N, 15.44. Found: C, 68.73; H, 5.26; N, 15.57.

2.2.13 Styrene Polymerization Initiated with Unimolecular Initiator 23

Using the same experimental procedure described in section 2.2.2, a solution of verdazyl stabilized styrene (10 mL, 870 mmol) and unimolecular initiator 23 (100 mg, 0.23 mmol) was heated at 125 ºC for 10 h.

2.2.14 n-Butyl Acrylate Polymerization Initiated with Unimolecular Initiator 23

Using the same experimental procedure described in section 2.2.2, a solution of verdazyl stabilized nbutyl acrylate (15 mL, 100 mmol) and unimolecular initiator 23 (100 mg, 0.23 mmol) was heated at 130 ºC for 24 h.

2.2.15 Synthesis of 2-(2,4-dimethyl-6-(1-methyl-1H-imidazol-2-yl)-3-oxo-3,4-dihydro-

1,2,4,5-tetrazin-1(2H)-yl)-2-phenylethyl benzoate (24)

1 156159 ºC). H NMR (400 MHz, CDCl 3, 25 ºC), δ: 8.057.90 (d, J = 8.8, 2H), 7.607.30 (m,

8H), 7.16 (s, 1H), 6.95 (s, 1H), 5.03 (br, 2H), 4.69 (dd, J = 4.9, 11.0, 1H), 3.70 (s, 3H), 2.96 (br,

13 6H). C NMR (100 MHz, CDCl 3), δ: 166.1, 138.0, 135.8, 133.1, 129.8, 129.7, 129.0, 128.7,

128.5, 128.3, 125.1, 65.4, 63.4, 39.6, 36.5, 35.8. HRMS (EI) ( m/z ): calculated for C23 H24 N6O3

M+, 432.1901; found, 432.1901.

2.2.16 n-Butyl Acrylate Polymerization Initiated with Unimolecular Initiator 24

Using the same experimental procedure described in section 2.2.2, a solution of verdazyl stabilized nbutyl acrylate (10 mL, 70 mmol) and unimolecular initiator 24 (85 mg, 0.20 mmol) was heated at 120 ºC for 5 h.

2.2.17 Synthesis of 2-(2,4-Dimethyl-3-oxo-3,4-dihydro-1,2,4,5-tetrazin-1(2H)-yl)-2-

phenylethyl benzoate (22)

The title compound was prepared using a modified version of the ATRA reaction originally reported by Matyjaszewski et al .17 1,5Dimethyl6oxoverdazyl 26 (500 mg, 3.9 mmol), benzoic acid 2bromo2phenylethyl ester 6 (1.07 g, 3.9 mmol), and pentamethyldiethylenetriamine (120 mg, 0.70 mmol) were dissolved in 15 mL of toluene in a three neck roundbottom flask equipped with a reflux condenser, a septum, and a thermometer.

Argon was bubbled through the solution for 30 min before the addition of copper powder (Cu 0)

(22 mg, 3.5 mmol) and CuBr 2 (16 mg, 0.070 mmol). The reaction was carried out at 60 ºC for 40 h. The reaction mixture was filtered to remove solid copper residues, and the solvent was removed in vacuo . The crude mixture was redissolved in methylene chloride, washed three times with water, dried over sodium sulfate, and filtered. The methylene chloride was removed in vacuo , and the product was purified from the resulting oil by silica gel column chromatography (1:3 ethyl acetate/hexane) and recrystallized from isopropanol/hexane to give a

1 white crystalline solid (610 mg, 44%, mp: 102104 ºC). H NMR (500 MHz, CDCl 3, 20 ºC) δ:

7.348.06 (m, 10H), 6.78 (s, 1H), 4.91, 4.76, 4.60 (ABC spin system, J = 11.8, 9.1, 5.2, 3H), 3.01

13 (s, 3H), 2.91 (s, 3H). C NMR (125 MHz, CDCl 3) δ: 166.1, 156.9, 134.5, 128138, 64.8, 62.8,

38.5, 36.2. Anal. Calcd for C 19 H20N4O3 (352.15): C, 64.76; H, 5.72; N, 15.90. Found: C, 65.01;

H, 5.90; N, 15.69.

2.2.18 Reaction of Carbonic Acid Bis(1-Methylhydrazide) with 2,6-Dimethylbenzaldehyde

(29)

A solution of 2,6dimethylbenzaldehyde (1.10 g, 8.56 mmol) in 500 mL ethanol was added to a solution of carbonic acid bis(1methylhydrazide) (1.00 g, 8.56 mmol) in 150 mL

isopropanol at a rate of 1 drop per ~5 seconds at 82 ºC. Upon complete addition, the solvent was removed in vacuo and the product was purified from the resulting oil by silica gel chromatography (1:5 ethyl acetate/hexane) to give the corresponding bis(1methylhydrazone)

1 (1.99 g, 67%). H NMR (500 MHz, CDCl 3), δ: 7.89 (s, 2H), 7.117.06 (m, 2H), 7.016.97 (m,

4H), 3.44 (s, 6H), 2.32 (s, 12H).

2.2.19 Synthesis of 1-(1,5-Dimethyl-3-phenyl-6-phosphaverdazyl)ethylbenzene

Unimolecular Initiator (36) by ATRA with (1-Bromoethyl)benzene

6Phosphaverdazyl 34 was synthesized according to a literature procedure reported by

Hicks et al .16 The ATRA reaction was carried out using the same experimental procedure described in section 2.2.5 with (1bromoethyl)benzene (250 mg, 1.4 mmol), pentamethyldiethylenetriamine (40 mg, 1.7 mmol), copper powder (Cu 0) (100 mg, 1.5 mmol),

CuBr 2 (8 mg, 0.035 mmol) and an estimated amount of phosphaverdazyl 34 in a minimal amount of ethyl acetate (250 mg, 0.83 mmol). The solvent was removed in vacuo and the title compound was purified from the resulting oil by silica gel column chromatography (ethyl acetate) and recrystallized from isopropanol/hexane to give a white crystalline solid (24 mg, 4%, mp: 135137

1 ºC). H NMR (400 MHz, CDCl 3, 25 ºC), δ: 7.847.67 (m, 3H), 7.597.50 (m, 2H), 7.507.41 (m,

3H), 7.416.14 (br, m, 7H), 4.40 (br, 1H), 3.31 (br, 3H), 3.00 (br, 3H), 1/03 (br, 3H). 13 C NMR

(100 MHz, CDCl 3), δ: 132.5, 132.4, 132.3, 132.2, 128.6128.0, 59.8, 37.0, 36.9, 34.0, 20.4. Anal.

Calcd for C 23 H25N4OP (404.18): C, 68.30; H, 6.23; N, 13.85. Found: C, 68.21; H, 6.20; N, 14.00.

2.2.20 Synthesis of 1-(1,5-Dimethyl-3-phenyl-6-phosphaverdazyl)ethylbenzene

Unimolecular Initiator (36) with Sodium Hydride and (1-Bromoethyl)benzene

1,2,5,6Tetrahydro1,5dimethyl3,6diphenyl1,2,4,5,6tetrazaphosphorine 6oxide (6 phosphaleucoverdazyl) 35 was synthesized according to a literature procedure reported by Hicks et al .16 A solution of 35 (250 mg, 0.83 mmol) in dry THF (50 mL) was degassed with argon for

30 min. Sodium hydride (30 mg, 1.3 mmol) was added to the solution, which turned from colourless to bright orange, presumably due to the anion formation. (1Bromoethyl)benzene

(150 mg, 0.90 mmol) in 5 mL dry THF was added to the solution, which turned from bright orange to pale yellow. The solvent was removed in vacuo and the title compound was purified from the resulting oil by silica gel column chromatography (ethyl acetate) and recrystallized from isopropanol/hexane to give a white crystalline solid (152 mg, 45%).

2.2.21 n-Butyl Acrylate Polymerization Initiated with Unimolecular Initiator 36

Using the same experimental procedure described in section 2.2.2, a solution of verdazyl stabilized nbutyl acrylate (6.5 mL, 50 mmol) and unimolecular initiator 36 (65 mg, 0.16 mmol) was heated at 120 ºC for 3 h.

2.3 Results and Discussion

2.3.1 Verdazyl-Mediated Styrene Polymerization with Bimolecular Initiators

Preliminary polymerization experiments with styrene under SFRP conditions were performed at 110 ºC with verdazyl radical 16 , supplied by Professor Robin Hicks from the

University of Victoria, as the mediating agent. Vazo® 88 was used as the initiator, with a verdazyl/Vazo® 88 molar ratio of 3.2:1 (Table 21, Figure 21). 18 Polymerizations with lower

molar ratios of verdazyl to initiator were also attempted but they led to exotherms and high conversion within the first hour even at polymerization temperatures as low as 80 ºC.

Table 2-1. Summary of the MW and PDI of styrene polymerization initiated with Vazo® 88 and mediated with 1,5dimethyl3phenyl6oxoverdazyl radical 16 .18

1 TH 1 Reaction time (h) Mn (g mol ) Mn (g mol ) PDI Conversion (%) 3 1280 1700 1.5 6 5 15900 17900 1.5 63 6 18800 19600 1.4 69

50.00

40.00

30.00 MV

20.00

10.00

24.00 26.00 28.00 30.00 32.00 34.00 36.00 38.00 40.00 42.00 44.00 46.00 Minutes

Figure 2-1. GPC for the polymerization of styrene initiated with Vazo® 88 and mediated with 1,5 dimethyl3phenyl6oxoverdazyl radical 16 (solid3h, dashed5h, dotted6h).

Styrene polymerizations performed with the verdazyl/Vazo® 88 molar ratio of 3.2:1 at

110 ºC gave a monomer conversion well over 50% and a molecular weight of over 15,000 g mol 1 after 5 hours. However, the system was considered to be inefficient due to its high verdazyl/initiator molar ratio, the high PDI values (greater than 1.5) of the resulting polymers, and the high viscosity of the polymerization mixture. The encouraging outcome from these

preliminary results was that a molecular weight growth over time was observed, which suggested further investigation was worth pursuing.

Due to a temporary unavailability of the starting materials required to resynthesize 16 , the polymerizationmediating potential of verdazyl radical 17 , prepared according to the procedure of Milcent et al.,11 was investigated. Styrene polymerizations were performed with

BPO as the bimolecular initiator and verdazyl radical 17 as the mediating agent (Table 22,

Figure 22). 18 In a typical polymerization, a verdazyl/BPO molar ratio of 2.25:1 was used at

110 ºC. A monomer conversion of 20% was reached after only 30 minutes. A monomer conversion that high in a living radical polymerization, over such a short reaction time, suggested that not enough verdazyl radicals were present to trap the propagating species. However, increasing the verdazyl/BPO molar ratio to 2.7:1 gave virtually the same result. High molecular weights exceeding 25,000 g mol 1 with high PDI values (greater than 1.6) were obtained for all experiments under these reaction conditions. Furthermore, no visible growth of molecular weight over time was observed, which indicated that the propagating species were not being regenerated (Figure 22). These results were reminiscent of a conventional radical polymerization process and suggested that 17 was an ineffective mediator for these polymerizations under these conditions.

Table 2-2. Summary of the MW and PDI of a styrene polymerization initiated with BPO and mediated with 1,3,5triphenyl6oxoverdazyl radical 17 .18

1 TH 1 Reaction time (h) Mn (g mol ) Mn (g mol ) PDI Conversion (%) 1 24500 8700 1.67 23

2 23900 7900 1.72 21

140.00 120.00 100.00 80.00 MV 60.00 40.00 20.00 0.00 22.00 24.00 26.00 28.00 30.00 32.00 34.00 36.00 38.00 40.00 42.00 Minutes

Figure 2-2. GPC plot of a styrene polymerization initiated with BPO and mediated with 1,3,5triphenyl 6oxoverdazyl radical 17 (solid1h, dashed2h).

2.3.2 Verdazyl-Mediated Styrene Polymerization with Unimolecular Initiators

Recognizing that unimolecular initiation systems are superior in terms of accurately introducing the molar ratio of propagating species and terminating agents, our attention turned to the verdazyl analogue of BST 3, BSV 18 . BSV 18 was prepared by an exchange reaction with

BST and verdazyl radical 17 at 120 ºC in chlorobenzene (Scheme 23). 15 The result was a near quantitative exchange of the terminating agents, which can be rationalized by the lower kd value of the styrylverdazyl bond (7.4 x 10 5 s1, 393 K) 19 compared to that of the styrylTEMPO bond

4 1 20 (5.5 x 10 s , 393 K). The low kd value of the BSV 18 could be inferred from the GPC plot of the polymerizations where even after 4 hours at 130 ºC, the unimolecular initiator species was still present in the polymerization mixture (Table 23, Figure 23). 15 Furthermore, over the course of the polymerization, the PDI values were high and the polymers showed no molecular weight growth. These poor livingness features of the system were attributed to the slow dissociation of the verdazyl radicals from the polymer chain ends. Having attempted both

bimolecular and unimolecular initiation systems, it was decided that verdazyl radical 17 is not suitable for mediating styrene SFRP systems.

Scheme 2-3. Unimolecular initiator exchange reaction between BST and 1,3,5triphenyl6oxoverdazyl radical 17 .18

Table 2-3. Summary of the MW and PDI of styrene polymerization initiated with the benzoylstyrene 1,3,5triphenyl6oxoverdazyl radical adduct BSV 18 .18

1 TH 1 Reaction time (h) Mn (g mol ) Mn (g mol ) PDI Conversion (%) 0.5 17400 1000 1.7 2 1.5 25100 4500 1.8 9 4 30500 11100 1.7 22 6 32700 20000 1.6 39

140.00 0.5 h 120.00 BSV 100.00 1.5 h 18 80.00 MV 60.00 4 h 40.00 6 h 20.00 0.00 20.00 22.00 24.00 26.00 28.00 30.00 32.00 34.00 36.00 38.00 40.00 42.00 44.00 46.00 48.00 Minutes

Figure 2-3. GPC of styrene polymerization initiated with the benzoylstyrene1,3,5triphenyl6 oxoverdazyl radical adduct BSV 18 (solid0.5h, dashed1.5h, dotted4h, dash/dotted6h).

Upon receiving adequate reagents, we decided to revisit styrene polymerization with verdazyl radical 16 , employing the unimolecular initiation strategy. Verdazyl radical 16 was prepared using the procedure reported by Neugebauer et al .10 with the modification of replacing phosgene gas with the safer triphosgene solid (Scheme 24). BSV 19 was prepared by an exchange reaction with BST and verdazyl radical 16 at 120 ºC as described above; however, the observed yield of 30% was somewhat low in comparison to the near quantitative yield from the synthesis of BSV 18 . In order to increase the yield of the exchange reaction, ascorbic acid was added to the reaction mixture in anticipation that TEMPO would be reduced 21 (refer to

Scheme122) and thus shift the equilibrium towards BSV 19 (Scheme 25). 15 While ascorbic acid is also known to reduce verdazyl radicals, 7 it was observed qualitatively that the colour of the verdazyl persisted much longer than that of TEMPO in the presence of ascorbic acid, which suggested that the reduction of verdazyl radicals is slower than that of TEMPO. When ascorbic acid was added to the BSTverdazyl exchange reaction, a yield improvement of 50% was observed.

Scheme 2-4. Synthesis of 1,5dimethyl3phenyl6oxoverdazyl radical 16 .

Scheme 2-5. Synthesis of the unimolecular initiator 19 via exchange reaction between BST and 1,5 dimethyl3phenyl6oxoverdazyl radical 16 with ascorbic acid.

In contrast to the polymerizations mediated by 17 , those mediated by 16 were well controlled (Table 24, Figure 24). 15 At 125 ºC, fast initiation, a feature of living polymerization systems, could be inferred from the GPC plot – the unimolecular initiator peak had completely disappeared after an hour, which indicated complete dissociation. In a typical styrene polymerization mediated with verdazyl radical 16 , a monomer conversions of 40% and polymer

molecular weights of 12,000 g mol 1 , with a PDI value as low as 1.2 were attainable after a reaction time of 5 hours.

It is evident that the methyl substitutions at the 1 and 5 positions of the verdazyl radical, when compared to its diphenyl analogue, affected the chemistry of the verdazyl radical enough to alter its polymerization mediating abilities. From a kinetics perspective, substitution from 1,5 diphenyl to dimethyl in the verdazyl radical increased the kd value by two orders of magnitude

(0.074 x 10 3 s1, 393 K vs. 2.6 x 10 3 s1, 393 K, respectively). 19 These results thus show that, as hypothesized, there is a variation in the polymerizationmediating abilities between verdazyl radicals, similar to what has been observed with different nitroxide derivatives.

Table 2-4. Summary of the MW and PDI of styrene polymerization initiated with the benzoylstyrene 1,5dimethyl3phenyl6oxoverdazyl radical adduct BSV 19 .15

1 TH 1 Reaction time (h) Mn (g mol ) Mn (g mol ) PDI Conversion (%) 1 4200 4600 1.13 12 2 7700 8900 1.14 23 3 9800 11600 1.19 30 4 11200 13500 1.22 35 5 12100 15500 1.22 40

50.00 45.00 40.00 35.00 30.00

MV 25.00 20.00 15.00 10.00 5.00

28.00 30.00 32.00 34.00 36.00 38.00 40.00 42.00 44.00 46.00 48.00 Minutes

Figure 2-4. GPC of styrene polymerization initiated with the benzoylstyrene1,5dimethyl3phenyl6 oxoverdazyl radical adduct BSV 19 (solid1h, dashed2h, dotted3h, dash/dotted4h, dashed/2dotted5h).

2.3.3 Verdazyl-Mediated n-Butyl Acrylate Polymerization with Unimolecular Initiators

nButyl acrylate polymerization was also demonstrated to proceed with living characteristics when initiated with the verdazylderived unimolecular initiator BSV 19 (Table 25,

Figure 25). 15 In a typical polymerization, a 40% monomer conversion, molecular weight of

14,300 g mol 1, and a PDI value of 1.20 were reached after the polymerization was allowed to continue for 28 hours at 130 ºC. Several distinct differences were observed in comparing the styrene and the nbutyl acrylate polymerizations. First, the nbutyl acrylate polymerization time was significantly longer than that of styrene systems; to reach the same monomer conversion and roughly the same molecular weight as the styrene polymerization, a sixfold increase in polymerization time was required for the nbutyl acrylate system. This can be accounted for by comparing the kd values for the two polymerizations: the kd value of the acryloylverdazyl bond

(2.9 x 10 5 s1, 393 K) 19 is roughly two orders of magnitude lower than the styryl counterpart (2.6 x 10 3 s1, 393 K).19 As a consequence, the verdazyl terminating agents required more energy to dissociate from the chain ends which slowed down the nbutyl acrylate polymerization.

The second difference between the styrene and the n-butyl acrylate polymerizations is that while no tailing was observed in the low molecular weight region in the GPC’s of samples taken from the nbutyl acrylate polymerization over the first 18 hours (Figure 25), tailing in the low molecular weight region was observed for each of the polymer samples in the GPC in the case of the styrene polymerization (Figure 24).

The third difference between the styrene and the n-butyl acrylate polymerizations is that while the nbutyl acrylate polymerization rate decreased over time, the styrene polymerization rate remained more or less consistent over time (2,000 g mol 1 growth from 18 – 28 h in the n- butyl acrylate polymerization vs. 2,000 g mol 1 growth from 5.5 – 8.5 h in the styrene polymerization).

The latter two observations can be attributed to the accumulation of the verdazyl radical due to the unavoidable irreversible coupling termination reactions throughout the polymerization, which inhibits the polymerization by shifting the equilibrium towards the dormant species (see

22,23 Section 1.2.2.4). While the low kd value for the acryloylverdazyl bond should reduce the concentration of the propagating radical species at any given time, and thus lower the occurrence of coupling termination reaction, inevitable termination reactions did appear to have occurred over the course of the polymerization as evidenced by the prominent tailing observed in the GPC plot for the 28hour polymer sample (Figure 25). Each time a termination reaction occurred, two verdazyl radical molecules also accumulated. The accumulation of verdazyl radicals over time slowed down the polymerization, which accounted for the slow molecular growth towards the end of the polymerization. The accumulation of terminating agents also occurred in the styrene polymerizations; however, its effects were less prominent due to the shorter polymerization period and due to the existence of the Mayo autoinitiation reaction that helped to

suppress the accumulation of terminating agents as described previously (see Scheme 121). 24

Additives such as ascorbic acid are known to accelerate TEMPOmediated acrylate polymerizations by reducing the TEMPO concentration. 22,23 A similar effect was also observed when ascorbic acid was added to the verdazylmediated acrylate polymerizations: the monomer conversion increased from 40% to 53% in a 5 hour polymerization. 25 This result was anticipated as ascorbic acid is also known to reduce verdazyl radicals. 7

Table 2-5. Summary of the MW and PDI of nbutyl acrylate polymerization initiated with the benzoyl styrene1,5dimethyl3phenyl6oxoverdazyl radical adduct BSV 19 .15

1 TH 1 Reaction time (h) Mn (g mol ) Mn (g mol ) PDI Conversion (%) 2.5 3000 3600 1.58 5.9 5.5 5900 6900 1.36 12 8.5 7900 9800 1.29 17 12 9600 14400 1.27 25 18 12200 18500 1.22 32 28 14300 23000 1.20 40

11.00 10.00 9.00 8.00 7.00 MV 6.00 5.00 4.00 3.00 2.00 28.00 30.00 32.00 34.00 36.00 38.00 40.00 42.00 44.00 46.00 48.00 Minutes

It is interesting to speculate why the polymerization of nbutyl acrylate was achievable with verdazyl radical 16 in contrast to TEMPO, which without additives, cannot moderate the polymerization. The inability of TEMPO to mediate acrylate polymerizations has been attributed to its stability under polymerizations conditions. Acrylate polymerizations have been successful with TEMPO in the presence of ascorbic acid as a reductant, or with inherently unstable

2 nitroxides such as TIPNO and SG1. In contrast, stable nitroxides with high kd values have shown little success in mediating acrylate polymerizations. 6 Thus, the ability of verdazyl radical

16 to mediate acrylate polymerizations without additives would suggest that the verdazyl radical possesses some form of instability under polymerization conditions. This hypothesis was somewhat validated when, in a unimolecular initiator synthesis analogous to that for BST, the bicyclic compound 20 was isolated as the major product (Scheme 26). 26

Scheme 2-6. Unimolecular initiator 19 synthesis from 1,5dimethyl3phenyl6oxoverdazyl 16 , styrene, and BPO; major product 20 .26

The incorporation of the verdazyl moiety into compound 20 suggested that the radical had reacted with the monomer, but not in a coupling reaction with a monomer radical at the end of a propagating polymer chain. It was speculated that this reaction also occurred under polymerization conditions and contributed to the consumption of extra verdazyl radical that accumulated as a result of the unavoidable coupling termination reaction previously discussed.

Indeed, compounds 20 and 21 were isolated from the filtrates obtained from the precipitation of the verdazylmediated styrene and nbutyl acrylate polymerization mixtures in methanol, respectively (Scheme 27, 28). 25 The nature and exact mechanism of the reaction will be discussed in the following chapter, but it was safe to assume at this point that the verdazyl radicals did more than just reversibly terminate propagating polymer chains.

Scheme 2-7. Styrene polymerization initiated with the unimolecular initiator 19 ; isolation of 20 .

Scheme 2-8. nButyl acrylate polymerization initiated with the unimolecular initiator 19 ; isolation of 21 .

As can be observed in Table 25, the experimental molecular weights of the poly( nbutyl acrylate) as determined by GPC did not agree with the theoretical molecular weights calculated based on monomer conversions, a discrepancy not evident in the styrene polymerizations. The actual poly( nbutyl acrylate) molecular weights were consistently lower than the theoretical molecular weights by as much as 40%. It was suspected that this discrepancy arose from the evaporation of the monomer due to the steady argon flow that was maintained in the reaction vessel over the polymerization period; a period significantly longer in the case of the nbutyl acrylate polymerization compared to the styrene polymerization. To resolve this issue, polymerizations were performed in custommade sealed tubes to prevent any evaporation of monomers (Figure 26).

argon in when sealed by valve open J-Young valve

Figure 2-6. Customdesigned sealed tube to prevent monomer evaporation.

A verdazylmediated nbutyl acrylate polymerization reaction was carried out at 130 ºC in the sealed tube without interruption for 40 hours. Results showed consistency between the

1 TH 1 experimental and theoretical molecular weights ( Mn = 12,900 g mol vs. Mn = 13,200 g mol based on 34% conversion, PDI = 1.22), 15 proving our aforementioned hypothesis in regards to monomer evaporation. Thus, while it has been clearly demonstrated that verdazyl radical 16 is capable of mediating both styrene and nbutyl acrylate polymerizations without the need for additives, the nbutyl acrylate polymerizations are slower than desired and further work in this area is required.

2.3.4 Block Copolymer Formation – Chain Extension with Verdazyl-Terminated

Macromolecules

To further demonstrate the livingness of the verdazylmediated polymerization systems, verdazylterminated polystyrene and poly( nbutyl acrylate) were chain extended with nbutyl acrylate and styrene, respectively (Figure 27, 28). The homopolymers, or macroinitiators, were purified from the initial polymerization mixture by several precipitation cycles from methanol prior to the chain extension reactions.

50.00 45.00 40.00 35.00 30.00

MV 25.00 20.00 15.00 10.00 5.00 0.00 30.00 31.00 32.00 33.00 34.00 35.00 36.00 37.00 38.00 39.00 40.00 41.00 42.00 43.00 44.00 45.00 46.00 47.00 48.00 Minutes

Figure 2-7. GPC plot of polystyreneb(nbutyl acrylate) diblock formation mediated with verdazyl 16 . Starting homopolymer (MW = 6,250 g mol 1, PDI = 1.20, solid), resulting block copolymer (MW = 8,800 g mol 1, PDI = 1.26, dashed).

30.00

25.00

20.00

MV 15.00

10.00

5.00

28.00 29.00 30.00 31.00 32.00 33.00 34.00 35.00 36.00 37.00 38.00 39.00 40.00 41.00 42.00 43.00 44.00 45.00 46.00 47.00 Minutes

Figure 2-8. GPC plot of poly( nbutyl acrylate)bstyrene diblock formation mediated with verdazyl 16 . Starting homopolymer (MW = 10,400 g mol 1, PDI = 1.20, solid), resulting block copolymer (MW = 13,200 g mol 1, PDI = 1.30, dashed).

In both chain extension experiments, small shoulders in the low molecular weight region can be observed in the resulting block copolymers, which can be attributed to unreacted or terminated starting homopolymers. It is clear though, that the controlled growth of the second blocks were achieved as significant molecular weight increases were observed from both chain extension reactions while low PDI values were preserved.

2.3.5 Polymerizations with Various 1,5-Dimethyl-6-Oxoverdazyl Radicals

The ease of derivatizing the 3position of the verdazyl radicals provided an opportunity to study the effects of substituents on the rate and livingness of various polymerizations. To that end, a series of unimolecular initiators (Figure 29) were prepared via BSTexchange or

ATRA 27,28 reactions with the corresponding verdazyl radicals.

Figure 2-9. Derivatization at the 3 position of the 1,5dimethyl6oxoverdazyl radical moieties in the corresponding BSV unimolecular initiators.

Table 2-6. Summary of the MW and PDI of styrene polymerization initiated with the benzoylstyrene 1,5dimethyl3(pCNphenyl)6oxoverdazyl radical adduct BSV 23 .

1 TH 1 Reaction time (h) Mn (g mol ) Mn (g mol ) PDI Conversion (%) 1 1700 1900 1.13 5 2 3000 3900 1.09 10 3 3900 6300 1.09 16 10 6600 17700 1.14 45

50.00

40.00

30.00 MV 20.00

10.00

0.00 30.00 31.00 32.00 33.00 34.00 35.00 36.00 37.00 38.00 39.00 40.00 41.00 42.00 43.00 44.00 45.00 46.00 47.00 48.00 Minutes

Figure 2-10. GPC of styrene polymerization initiated with the benzoylstyrene1,5dimethyl3(pCN phenyl)6oxoverdazyl radical adduct BSV 23 (solid1h, dashed2h, dotted3h, dash/dotted10h).

Table 2-7. Summary of the MW and PDI of nbutyl acrylate polymerization initiated with the benzoyl styrene1,5dimethyl3(pCNphenyl)6oxoverdazyl radical adduct BSV 23 .

1 TH 1 Reaction time (h) Mn (g mol ) Mn (g mol ) PDI Conversion (%) 1 2500 3900 1.50 7 2 3500 5000 1.35 9 4 5000 7200 1.23 13 6 6200 8900 1.20 16 24 11500 22000 1.17 40

20.00 18.00 16.00 14.00 12.00

MV 10.00 8.00 6.00 4.00 2.00 30.00 31.00 32.00 33.00 34.00 35.00 36.00 37.00 38.00 39.00 40.00 41.00 42.00 43.00 44.00 45.00 46.00 47.00 48.00 Minutes

Figure 2-11. GPC of nbutyl acrylate polymerization initiated with the benzoylstyrene1,5dimethyl3 (pCNphenyl)6oxoverdazyl radical adduct BSV 23 (solid1h, dashed2h, dotted4h, dash/dotted6h, dashed/2dotted24h).

Table 2-8. Summary of the MW and PDI of nbutyl acrylate polymerization initiated with the benzoyl styrene1,5dimethyl3(methylimidazole)6oxoverdazyl radical adduct BSV 24 .

1 TH 1 Reaction time (h) Mn (g mol ) Mn (g mol ) PDI Conversion (%) 1 1600 1800 3.07 4 2 3700 4000 4.83 9 3 15700 9400 3.46 21 4 43200 18800 2.02 42 5 56000 25500 2.06 57

11.00 10.00 9.00 8.00 7.00 MV 6.00 5.00 4.00 3.00 2.00 22.00 24.00 26.00 28.00 30.00 32.00 34.00 36.00 38.00 40.00 42.00 44.00 46.00 48.00 50.00 Minutes

Figure 2-12. GPC of nbutyl acrylate polymerization initiated with the benzoylstyrene1,5dimethyl3 (methylimidazole)6oxoverdazyl radical adduct BSV 23 (solid1h, dashed2h, dotted3h, dash/dotted4h, dashed/2dotted5h).

While certain substitution on the 3 position, for example para cyanophenyl (initiator 23 ), showed minimal impact on the polymerizationmediating ability of the verdazyl, other substituents, for example methyl imidazole and hydrogen, had greater effects. In the case of n butyl acrylate polymerizations initiated with 24 (3methyl imidazole derivative), it is apparent that even though the corresponding verdazyl radical allows a much faster polymerization rate compared to verdazyl radical 16 , its ability to control the polymerization is inferior, resulting in polymers with PDI as high as 2 and above, while showing little growth in molecular weight over time (Table 28, Figure 212). Two possibilities may account for these results. First, this particular verdazyl radical may undergo faster decomposition than the 3phenyl derivative, resulting in a decrease in the concentration of terminating agent at a rate too fast to allow for a controlled polymerization. Alternatively, the methyl group extending from the imidazole moiety may sterically hinder the recombination reaction of the verdazyl radical with the propagating radical chain end, causing uncontrolled growth and unwanted termination.

When styrene polymerizations were initiated with unimolecular initiator 22 in which the

3 position of the verdazyl radical is a hydrogen atom, higher molecular weights, higher monomer conversions and lower PDI values were achieved in roughly the same amount of time compared to the styrene polymerizations initiated by 19 (Table 29, Figure 213). 15 This result was somewhat surprising due to our initial hypothesis that with less steric crowding from a hydrogen atom at the 3 position of the verdazyl moiety, the CN bond between the verdazyl and styrene moieties would require more energy to dissociate and consequently slow down the polymerization. However, kinetics data show minimal difference in k d values between the 3Ph

(2.6 x 10 3 s1, 397 K) and the 3H (2.7 x 10 3 s1, 397 K) verdazyl unimolecular initiators. 19

Therefore, the difference in polymerization results is not caused directly by the steric effects surrounding the styrylverdazyl bond.

Table 2-9. Summary of the MW and PDI of styrene polymerization initiated with the benzoylstyrene 1,5dimethyl3hydrogen6oxoverdazyl radical adduct BSV 22 .15

1 TH 1 Reaction time (h) Mn (g mol ) Mn (g mol ) PDI Conversion (%) 1 1720 2160 1.11 5.6 2 5220 5850 1.09 15 3 10300 12100 1.08 31 5 15200 16700 1.09 43 7 19900 23000 1.09 59

24.00 22.00 20.00 18.00 16.00 14.00 MV 12.00 10.00 8.00 6.00 4.00 2.00 28.00 30.00 32.00 34.00 36.00 38.00 40.00 42.00 44.00 46.00 48.00 Minutes

Figure 2-13. GPC plot of styrene polymerization initiated with the benzoylstyrene1,5dimethyl3 hydrogen6oxoverdazyl radical adduct BSV 22 (solid1h, dashed2h, dotted3h, dash/dotted5h, dashed/2dotted7h).

Even more interesting is the inability of the verdazyl radical 26 (see Scheme 29) to mediate the polymerization of nbutyl acrylate. At the typical polymerization temperature of

133 ºC, the polymerization was fast and uncontrolled. Lowering the polymerization temperature to 125 ºC provided more control, but the PDI value remained high, typically above 1.5 (Table 2

10, Figure 214). 15

Table 2-10. Summary of the MW and PDI of nbutyl acrylate polymerization initiated with the benzoyl styrene1,5dimethyl3hydrogen6oxoverdazyl radical adduct BSV 22 .15

1 TH 1 Reaction time (h) Mn (g mol ) Mn (g mol ) PDI Conversion (%) 1 1550 2530 2.53 7.1 2 2460 3570 2.20 10 4 10800 11000 1.96 31 8 23200 24300 1.54 68

12.00

10.00

8.00

MV 6.00

4.00

2.00

26.00 28.00 30.00 32.00 34.00 36.00 38.00 40.00 42.00 44.00 46.00 48.00 50.00 Minutes

Figure 2-14. GPC of nbutyl acrylate polymerization initiated with the benzoylstyrene1,5dimethyl3 hydrogen6oxoverdazyl radical adduct BSV 22 (solid1h, dashed2h, dotted4h, dash/dotted8h).

It was speculated that the verdazyl radical 26 is more susceptible to abstract hydrogen from the carbon adjacent to the propagating radical, forming leucoverdazyl 25 , which causes a substantial decrease in the verdazyl concentration during polymerization. In the case of styrene polymerization, this decrease in verdazyl radical concentration is beneficial as it speeds up the polymerization. In the case of nbutyl acrylate polymerization, however, the rate of propagation is generally faster than that of styrene polymerizations and when combined with a rapid decrease of the terminating agent, the polymerization goes out of control. Supporting this speculation is the observation that the nbutyl acrylate polymerization mixtures turned from colourless to pale yellow, the colour of verdazyl radical 26 , upon removal of the excess monomer. This is what would be expected to happen if the reaction mixtures contained the colourless leucoverdazyl which would immediately oxidize to the verdazyl radical upon exposure to air. TLC analysis of the airexposed polymerization mixture provided a match for a standard sample of the 3H verdazyl radical. It can be rationalized that once a verdazyl radical abstracted a hydrogen atom from a propagating chain end during the polymerization, it became leucoverdazyl 25 . Upon exposure to atmospheric oxygen, the leucoverdazyl 25 was oxidized back to the radical form,

which accounted for the observed colour change and the appearance of the verdazyl radical 26 on the TLC plate (Scheme 29).

Scheme 2-9. Hydrogenabstraction mechanism of 1,5dimethyl6oxoverdazyl; oxidation of resulting leucoverdazyl 25 by atmospheric oxygen.

While verdazyl radical 26 acting as a good hydrogen abstractor can account for the polymerization results, the hydrogen abstracting property of this radical can also be rationalized.

Due to the lack of steric hindrance near the radical centre, hydrogen abstraction may be a much more facile reaction for verdazyl radical 26 as compared to other verdazyl radicals. The facile hydrogen abstraction reaction of the verdazyl radical would compete against the reversible termination reaction and thus provide less control over the polymerization. From this sterics perspective, it would appear that the substituent at the 3 position can alter the hydrogen abstracting ability of the verdazyl radical and affect the reversible terminating reactions of the verdazyl radical with the propagating chains.

2.3.6 Designs and Polymerizations with Other Verdazyl Radicals

Syntheses of other verdazyl radical derivatives were attempted to study their reactivities in styrene and nbutyl acrylate polymerizations. Verdazyl radical 28 was designed to increase the steric bulk around the radical site so as to raise the kd value of the corresponding unimolecular initiator. However, difficulty arose in the synthesis of the tetrazinone 27, the

precursor to the verdazyl radical. In the reaction of bismethylhydrazide and 2,5 dimethylbenzaldehyde, the major product was 29 while the anticipated product 27 was not observed (Scheme 210).

Scheme 2-10. Attempted synthesis of 1,5dimethyl3(2,6dimethylphenyl)6oxoverdazyl radical 28 yielding bis(hydrazone) 29 .

Although the formation of the bishydrazone is a common side reaction in other tetrazinone (verdazyl radical precursor) syntheses, it can usually be suppressed via a slow addition of the aldehyde and dilution of both the bismethylhydrazide and the aldehyde.

However, in the case of the 2,6dimethylbenzaldehyde, both potential solutions to suppress the formation of 27 were taken to the extreme (20fold dilution and addition of the aldehyde over 30 hours) with no success. It would seem that due to the steric bulk near the carbonyl and hydrazone centre caused by the two methyl substituents, intermolecular condensation is more favourable than the intramolecular ring closing condensation reaction (see Scheme 12 for general overview of the verdazyl synthesis).

100

The 1,5dibenzyl6oxoverdazyl 30 was initially of interest for study as a polymerization moderator due to its high instability as reported in the literature. 8 But decomposition of this verdazyl radical in a modified oxidation procedure 6 occurred even as it was warmed from 78 ºC to room temperature, which suggested it would be too unstable for mediating polymerizations carried out at over 100 ºC (Scheme 211).

Scheme 2-11. Synthesis of 1,5dibenzyl3phenyl6oxoverdazyl radical 30 .

The 1,5dimethyl6methyleneverdazyl radical 31 (Figure 215) was of interest due to its structural difference compared to the 1,5dimethyl6oxoverdazyl radicals. It was hypothesized that with the lack of a carbonyl functionality, verdazyl radical 31 would have a different reactivity and perform differently as a terminating agent. In the attempts to synthesize 32 or 33 , the bishydrazine or its protected analogue precursor to the verdazyl radical 31 , modifications to the analogous synthetic route for the synthesis of 6oxoverdazyls were made. Methylene bromide or methylene iodide was used in place of triphosgene and the reaction was performed at ambient temperatures rather than at 78 ºC. However, neither 32 nor 33 were formed in these reactions (Scheme 212).

101

Figure 2-15. 1,5Dimethyl3phenylverdazyl 31 .

Scheme 2-12. Proposed syntheses of 32 , the precursor to verdazyl radical 31 , or 33 , the protected analogue of 32 .

The 6phosphaverdazyl 35 (Scheme 213) was successfully synthesized according to the procedure of Hicks et al .16,29 However, the radical is only stable in solution and attempts to isolate the pure verdazyl by removing the solvent (ethyl acetate or methylene chloride) resulted in decomposition. The synthesis of the unimolecular initiator 36 was attempted via an ATRA reaction (Scheme 214) but product yields were generally less than 5%. However, the radical precursor, leucoverdazyl 34 , of the 6phosphaverdazyl radical 35 is stable in air unlike other leucoverdazyls (Scheme 214). The stability of the 6phosphaleucoverdazyl 34 was exploited in an alternative synthesis of 36 , where 34 was deprotonated with a strong base to form a nitrogen anion which was able to participate in a substitution reaction with the subsequently added electrophile. In its reaction with sodium hydride and (1bromoethyl)benzene, the 6 phosphaleucoverdazyl 34 yielded the unimolecular initiator 36 in 45% (Scheme 214).

102

Scheme 2-13. Synthesis of 6phosphaverdazyl 35 .

Scheme 2-14. ATRA and nucleophilic substitution syntheses of styrene6phosphaverdazyl unimolecular initiator 36 with (1bromoethyl)benzene and 6phosphaleucoverdazyl 34 or 6phosphaverdazyl radical 35 .

Several nbutyl acrylate polymerizations were attempted with unimolecular initiator 36 , under typical polymerization conditions as used with other verdazyl unimolecular initiators at

115120 ºC. After an hour, a sample of the polymerization mixture was withdrawn and dried under a stream of air to remove monomer. No reaction appeared to have occurred as no polymeric materials remained in the sample vial after the monomer had been removed. However, initiation occurred prior to the end of the second hour resulting in the polymerization mixture

103

becoming very viscous. The monomer conversion at that point was found to be greater than 50%.

These results suggest that this initiator may have a higher kd value than the corresponding 6 oxoverdazyl, but it is not able to reversibly terminate the propagating chains, and therefore the polymerization could not be controlled.

2.4 Concluding Remarks

In conclusion, successful styrene and nbutyl acrylate polymerizations mediated by the

1,5dimethyl3phenyl6oxoverdazyl 16 were demonstrated. Due to its ability to mediate n butyl acrylate polymerizations with no additives, verdazyl radical 16 is speculated to possess some inherent instability under the polymerization conditions. Byproducts containing the verdazyl moiety were isolated from both unimolecular initiator syntheses and polymerization reactions, confirming the hypothesis. The nature and exact mechanism of formation of these byproducts will be discussed in the next chapter.

Various other verdazyl radicals with different substituents at the 1, 3, 5 or 6 positions were designed. Some of these verdazyl radicals were synthesized in a straightforward manner while others could not be synthesized. The successfully synthesized verdazyl radicals were transformed into the corresponding unimolecular initiators and evaluated under livingradical polymerization conditions. It was observed that verdazyl radicals containing different substituents showed varying degrees of success as mediators in livingradical polymerization systems. This observation is consistent with the fact that various nitroxides, depending upon their structures, also behave differently as mediators in livingradical polymerization systems.

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2.5 Future Work

By no means did these experiments exhaust the potential of verdazyl radicals in mediating the stable free radical polymerization process. What was shown was that similar to nitroxides, verdazyl radicals with various substituents possess different reactivities and in turn, different polymerizationmediating abilities. For a complete assessment of the verdazyl mediated SFRP process, one should design a systematic study of the SFRP mediatingability of not only the verdazyl radicals currently reported in the literature, but new verdazyl radicals constructed with different combinations of substituents at various positions. Thus, for example, it would be worthwhile to perform a study on a group of 6phosphaverdazyl radicals with various substituents at the 3 position, similar to what was done in Section 2.3.5., or to perform a study on a group of 6oxoverdazyl radicals where the 3 position substituent is kept constant while the alkyl groups at the 1 and 5 positions are varied. For each polymerization system studied, parallel kinetic parameters such as k d and E a values should be determined in order to form structureto mediating ability correlations for each of the verdazyl radicals. It is envisioned that, with the broad range of derivatization available to the verdazyl radical family, a whole new series of verdazyl radicals can be found that could moderate the polymerization of any number of different monomers.

2.6 References

(1) Nilsen, A.; Braslau, R. J. Polym. Sci. Part A - Polym. Chem. 2006 , 44 , 697717.

(2) Benoit, D.; Chaplinski, V.; Braslau, R.; Hawker, C. J. J. Am. Chem. Soc. 1999 , 121 , 3904 3920.

(3) Benoit, D.; Grimaldi, S.; Robin, S.; Finet, J. P.; Tordo, P.; Gnanou, Y. J. Am. Chem. Soc. 2000 , 122 , 59295939.

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(4) Ananchenko, G. S.; Souaille, M.; Fischer, H.; Mericier, C. L.; Tordo, P. J. Polym. Sci. Part A - Polym. Chem. 2002 , 40 , 32643283.

(5) Fukuda, K.; Mannan, M. A.; Miura, Y. The ability of a cyclic nitroxide having a bulky substituent at the 2-position to control the polymerization of butyl acrylate; 55th SPSJ Annual Meeting, start date 20060524enddate 20060526; Society of Polymer Science: 2006; Vol. 55, pp 442.

(6) Debuigne, A.; ChanSeng, D.; Li, L.; Hamer, G. K.; Georges, M. K. Macromolecules 2007 , 40 , 62246232.

(7) Neugebauer, F. A.; Fischer, H. Angew. Chem. Int. Ed. 1973 , 12 , 455464.

(8) Neugebauer, F. A.; Fischer, H.; Siegel, R.; Krieger, C. Chem. Ber. 1983 , 116 , 34613481.

(9) Neugebauer, F. A.; Fischer, H.; Seigel, R. Chem. Ber. 1988 , 121 , 815822.

(10) Neugebauer, F. A.; Fischer, H.; Krieger, C. J. Chem. Soc. Perkin Trans. 2 1993 , 2 , 535544.

(11) Milcent, R.; Barbier, G. J. Heterocycl. Chem. 1994 , 31 , 319324.

(12) Pare, E. C.; Brook, D. J.; Brieger, A.; Badik, M.; Schinke, M. Org. Biomol. Chem. 2005 , 3 , 42584261.

(13) Yamada, B.; Tanaka, H.; Konishi, K.; Otsu, T. J. Macromol. Sci. , Pure Appl. Chem. 1994 , A31 , 351366.

(14) Yamada, B.; Nobukane, Y.; Miura, Y. Polym. Bull. (Berlin) 1998 , 41 , 539544.

(15) Chen, E. K. Y.; Teertstra, S. J.; ChanSeng, D.; Otieno, P. O.; Hicks, R. G.; Georges, M. K. Macromolecules 2007 , 40 , 86098616.

(16) Hicks, R. G.; Hooper, R. Inorg. Chem. 1999 , 38 , 284286.

(17) Matyjaszewski, K.; Woodworth, B. E.; Zhang, X.; Gaynor, S. G.; Metzner, Z. Macromolecules 1998 , 31 , 59555957.

(18) Teertstra, S. J.; Chen, E. K. Y.; ChanSeng, D.; Otieno, P. O.; Hicks, R. G.; Georges, M. K. Macromol. Symp. 2007 , 248 , 117125.

(19) Lukkarila, L. PhD Thesis: Nitroxide and Verdazyl Stable Free Radicals: Synthesis, Kinetics and Polymerization Studies, University of Toronto, Toronto, Canada, 2009.

(20) Li, L.; Hamer, G. K.; Georges, M. K. Macromolecules 2006 , 39 , 92019207.

(21) Paleos, C. M.; Dais, P. J. Chem. Soc. , Chem. Commun. 1977 , 345346.

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(22) Georges, M. K.; Lukkarila, J. L.; Szkurhan, A. R. Macromolecules 2004 , 37 , 12971303.

(23) Debuigne, A.; Radhakrishnan, T.; Georges, M. K. Macromolecules 2006 , 39 , 53595363.

(24) Georges, M. K.; Kee, R. A.; Veregin, R. P. N.; Hamer, G. K.; Kazmaier, P. M. J. Phy. Org. Chem. 1995 , 8 , 301305.

(25) Unpublished results.

(26) Yang, A.; Kasahara, T.; Chen, E. K. Y.; Hamer, G. K.; Georges, M. K. Eur. J. Org. Chem. 2008 , 45714574.

(27) Curran, D. P. Comprehensive Organic Synthesis 1991 , 4 , 715735.

(28) Matyjaszewski, K. Current Organic Chemistry 2002 , 6 , 6782.

(29) Majoral, J. P.; Kraemer, R.; Navech, J.; Mathis, F. Tetrahedron 1976 , 32 , 26332644.

Chapter 3

3 1,3-Dipolar Cycloaddition via Verdazyl-Derived Azomethine Imines

3.1 Introduction and Objective

In the previous chapter, the 1,5dimethyl6oxoverdazyl radical 16 was shown to mediate living radical polymerizations of styrene and nbutyl acrylate. It is known that styrene polymerizations 1 can be mediated by nitroxides, such as TEMPO, due to the Mayo autoinitiation reaction 2,3 (see Scheme 121) which is absent in acrylate polymerizations. For acrylate polymerizations to be successful under SFRP conditions, the mediating radical must be capable of undergoing decomposition 4 so as to keep its concentration at a level that allows it to control the reversible termination reaction between itself and the propagating chain without inhibiting the polymerization. 5 It should then follow that verdazyl radicals capable of mediating acrylate polymerizations must be similarly unstable under polymerization conditions.

Verdazyl radicals are generally perceived as stable radicals and virtually all their known reactions involve radical coupling reactions with alkyl radicals. 6,7 Otherwise, the general chemistry of verdazyl radicals is largely unexplored. Even though a few decomposition products have been reported, little explanation has been offered for their formation. 8 This chapter highlights the unique transformation of the 1,5dimethyl6oxoverdazyl radical 16 into a structurally unique azomethine imine which, in the presence of styrene and electronpoor

107

108

dipolarophiles, undergoes [3+2] 1,3dipolar cycloaddition reactions to give pyrazolotetrazinone heterocycles. It is noteworthy that this reaction is one of the rare examples of stable free radicals employed as substrates in organic synthesis and as such, presents a novel opportunity to synthesize a new class of heterocycles. Moreover, evidence suggests that the verdazyl radical undergoes this cycloaddition during styrene and acrylate polymerizations and as a consequence, helps to reduce the concentration of the excess verdazyl radicals that accumulate due to the unavoidable termination reactions that occur under SFRP conditions.

This chapter deals with the origin and discovery of the cycloaddition reaction involving the 1,5dimethyl3phenyl6oxoverdazylinitiated azomethine imine. The thought process that went into delineating the reaction mechanism for the formation of the azomethine imine, while eliminating other possible mechanisms, is highlighted. The reactivity of the azomethine imine and scope of this cycloaddition reaction is also examined.

3.2 Experimental Section

3.2.1 Materials and Equipment

All ACS grade reagents and solvents were purchased from SigmaAldrich, Alfa Aesar, and Caledon Chemicals unless otherwise stated. Nitrogen was purchased from BOC Canada.

Inhibitors were not removed from monomers or dipolarophiles for the cycloaddition reactions.

EMD Chemicals, and visualized under UV (254 nm) light.

Verdazyl radicals were synthesized according to published procedures. 9

109

NMR data were obtained using a Varian INOVA500 spectrometer at 20 ºC, operating at

500 MHz for 1H NMR and 125 MHz for 13 C NMR or a Bruker Avance III spectrometer at 23 ºC,

1 13 operating at 400 MHz for H NMR and 100 MHz for C NMR in CDCl 3 (Aldrich, 99.8% atom

D) with 0.03% (v/v) tetramethylsilane (TMS) standard. Chemical shifts ( δ) are reported in parts

1 13 per million (ppm) referenced to TMS (0 ppm) for H NMR spectra and CDCl 3 (77.0 ppm) for C

NMR. Coupling constants (J) are reported in hertz (Hz). Spin multiplicities are indicated by the following abbreviations: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet) and br

Series II model 2400 CHNS/O analyzer equipped with a Mettler MT5 micro analytical balance, operating in the CHN mode. Samples were calibrated against an internal standard, acetanilide (C,

71.09; H, 6.71; N, 10.3) before and after running samples. Melting points were determined on an electrothermal capillary melting point apparatus and are uncorrected.

3.2.2 Synthesis of 2-Methyl-4,6-diphenyl-2,6,7,8-tetrahydro-1H-pyrazolo[1,2-

a][1,2,4,5]tetrazin-1-one (20)

To a 50 mL round bottom flask equipped with a stir bar, verdazyl radical 16 (1.0 g, 4.9 mmol) was dissolved in styrene (10 mL, 90 mmol). The reaction was allowed to continue at room temperature for 24 hours after which excess styrene was removed by a stream of air. The title compound was purified by silica gel chromatography (3:7 ethyl acetate/hexane) (392 mg,

26%). The full characterization of 20 was presented in Section 2.2.9.

110

3.2.3 Synthesis of 5-Benzyl-2,4-dimethyl-6-phenyl-4,5-dihydro-1,2,4,5-tetrazin-3(2H)-one

(43)

To a 50 mL round bottom flask equipped with a stir bar, verdazyl radical 16 (300 mg,

1.47 mmol) was dissolved in 10 molar equivalents of methyl methacrylate. The resulting solution was purged for 20 min with argon. The cycloaddition reaction was allowed to continue for 24 h at ambient temperature, after which a suspension of sodium hydride (250 mg, 10.4 mmol) in 3 mL of THF was added via syringe. Benzyl bromide (0.88 mL, 7.4 mmol) was added 5 minutes later via syringe. After 20 minutes the reaction mixture was quenched with a few drops of methanol and the solvent was removed in vacuo . The resulting mixture was diluted with a saturated solution of ammonium chloride (5 mL) and extracted with ethyl acetate (3 x 5 mL).

The combined organic fraction was dried over sodium sulfate then concentrated in vacuo . The title compound was purified by silica gel chromatography (2:3 ethyl acetate/hexane) and recrystallized from ethyl acetate/hexane to give a white crystalline solid (157 mg, 36%, mp: 80

º 1 83 C). H NMR (500 MHz, CDCl 3), δ: 7.937.88 (m, 2H), 7.487.43 (m, 3H), 7.377.31 (m, 3H),

13 7.277.26 (m, 2H), 4.06 (s, 2H), 3.04 (s, 3H), 2.98 (s, 3H). C NMR (125 MHz, CDCl 3), δ:

156.2, 147.5, 134.9, 130.8, 130.4, 129.8, 128.8, 128.4, 128.3, 127.2, 55.3, 36.3, 35.7. HRMS

+ (ESI) ( m/z ): calculated for C 17 H19 N4O [M+H] , 295.1553; found, 295.1560.

3.2.4 General Optimized Procedure for the 1, 3-Dipolar Cycloaddition of Verdazyl

Radical 16 with Various Dipolarophiles

The dipolarophile (20 mmol) was placed neat or in minimal solvent in a three neck round bottom flask, equipped with a septum and an adaptor that was connected to a gas bubbler, and cooled in an ice bath. Oxygen was bubbled into the reaction flask for 30 minutes via a syringe needle pierced through the septum. 1,5Dimethyl3phenyl6oxoverdazyl radical 16 (300 mg,

111

1.47 mmol) was added as a solid to the flask with minimal exposure to air and the reaction solution was stirred at ambient temperature for 24 h under an atmosphere of O 2. Solvent and excess olefin were removed in vacuo and the products were purified by flash silica gel chromatography.

3.2.5 Synthesis of Methyl 2-methyl-1-oxo-4-phenyl-2,6,7,8-tetrahydro-1H-pyrazolo[1,2-

a][1,2,4,5]tetrazine-6-carboxylate (21)

The title compound was synthesized according to the general procedure using methyl acrylate as the dipolarophile. Purification by silica gel chromatography (2:3 ethyl acetate/methylene chloride) and recrystallization from ethyl acetate/hexane afforded the product

1 as a yellow crystalline solid (315 mg, 74%, mp: 115117 ºC). H NMR (500 MHz, CDCl 3), δ:

7.677.62 (m, 2H), 7.477.42 (m, 1H), 7.427.37 (m, 2H), 4.24 (dd, J = 3.9, 9.0, 1H), 4.224.17

(m, 1H), 3.56 (s, 3H), 3.523.46 (m, 1H), 3.37 (s, 3H), 2.482.39 (m, 1H), 2.272.20 (m, 1H).

13 C NMR (125 MHz, CDCl 3), δ: 171.3, 154.2, 146.0, 130.9, 130.9, 128.7, 127.5, 62.1, 52.4, 44.1,

+ 36.7, 29.8. HRMS (EI) ( m/z ): calculated for C 14 H16 N4O3 [M] , 288.1222; found, 288.1218.

3.2.6 Synthesis of tert -Butyl 2-methyl-1-oxo-4-phenyl-2,6,7,8-tetrahydro-1H-pyrazolo[1,2-

a][1,2,4,5]tetrazine-6-carboxylate (44)

The title compound was synthesized according to the general procedure using tert butyl acrylate as the dipolarophile. Purification by silica gel chromatography (1:9 ethyl acetate/methylene chloride) and recrystallization from ethyl acetate/hexane afforded the product

1 as a yellow crystalline solid (315 mg, 74%, mp: 109110 ºC). H NMR (500 MHz, CDCl 3), δ:

7.677.63 (m, 2H), 7.467.42 (m, 1H), 7.427.37 (m, 2H), 4.284.21 (m, 1H), 4.15 (dd, J = 3.9,

8.6, 1H), 3.433.36 (m, 1H), 3.34 (s, 3H), 2.452.36 (m, 1H), 2.252.17 (m, 1H), 1.32 (s, 9H).

112

13 C NMR (125 MHz, CDCl 3), δ: 169.9, 154.3, 145.9, 130.9, 130.8, 128.6, 127.6, 82.7, 63.1, 44.3,

+ 36.7, 29.8, 27.7. HRMS (EI) ( m/z ): calculated for C 17 H22 N4O3 [M] , 330.1692; found, 330.1694.

3.2.7 Synthesis of Methyl 2,6-dimethyl-1-oxo-4-phenyl-2,6,7,8-tetrahydro-1H-

pyrazolo[1,2-a][1,2,4,5]tetrazine-6-carboxylate (45)

The title compound was synthesized according to the general procedure using methyl methacrylate as the dipolarophile. Filtration upon reaction completion and recrystallization from ethyl acetate/hexane afforded the product as a yellow crystalline solid (375 mg, 84%, mp: 122

1 125 ºC). H NMR (500 MHz, CDCl 3), δ: 7.667.61 (m, 2H), 7.467.41 (m, 1H), 7.417.35 (m,

2H), 4.013.93 (m, 1H), 3.833.75 (m, 1H), 3.63 (s, 3H), 3.35 (s, 3H), 2.582.50 (m, 1H), 1.97

13 1.89 (m, 1H), 1.29 (s, 3H). C NMR (125 MHz, CDCl 3), δ: 172.6, 155.4, 146.8, 132.1, 130.6,

128.4, 128.1, 69.7, 52.3, 44.0, 38.5, 36.7, 23.4. HRMS (ESI) ( m/z ): calculated for C 15 H19 N4O3

[M+H] +, 303.1451; found, 303.1459.

3.2.8 Synthesis of 2-Methyl-1-oxo-4-phenyl-2,6,7,8-tetrahydro-1H-pyrazolo[1,2-

a][1,2,4,5]tetrazine-6-carbonitrile (46)

The title compound was synthesized according to the general procedure using acrylonitrile as the dipolarophile. Purification by silica gel chromatography (1:20 ethyl acetate/methylene chloride) and recrystallization from ethyl acetate/hexane afforded the product

1 as a pale yellow crystalline solid (234 mg, 62%, mp: 184186 ºC). H NMR (500 MHz, CDCl 3),

δ: 7.797.74 (m, 2H), 7.527.47 (m, 1H), 7.477.42 (m, 2H), 4.444.37 (m, 1H), 4.32 (dd, J = 3.4,

9.2, 1H), 3.503.43 (m, 1H), 3.39 (s, 3H), 2.562.48 (m, 1H), 2.452.38 (m, 1H). 13C NMR (125

MHz, CDCl 3), δ: 153.4, 143.9, 131.4, 129.9, 128.9, 127.4, 117.1, 50.3, 44.1, 37.1, 30.5. HRMS

+ (EI) ( m/z ): calculated for C 13 H13 N5O [M] , 255.1120; found, 255.1127.

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3.2.9 Synthesis of 2,6-Dimethyl-1-oxo-4-phenyl-2,6,7,8-tetrahydro-1H-pyrazolo[1,2-

a][1,2,4,5]tetrazine-6-carbonitrile (47)

The title compound was synthesized according to the general procedure using methacrylonitrile as the dipolarophile. Purification by silica gel chromatography (1:20 ethyl acetate/methylene chloride) and recrystallization from ethyl acetate afforded the product as a

1 pale yellow crystalline solid (275 mg, 74%, mp: 9496 ºC). H NMR (400 MHz, CDCl 3), δ:

7.837.78 (m, 2H), 7.527.40 (m, 3H), 4.234.13 (m, 1H), 3.693.61 (m, 1H), 3.39 (s, 3H), 2.73

13 2.64 (m, 1H), 2.182.10 (m, 1H), 1.42 (s, 3H). C NMR (100 MHz, CDCl 3), δ: 154.4, 144.9,

131.4, 131.2, 128.5, 128.5, 120.2, 60.2, 43.7, 40.0, 37.0, 25.7. HRMS (EI) ( m/z ): calculated for

+ C14 H15 N5O [M] , 269.1277; found, 269.1281.

3.2.10 Synthesis of (6R,7R)-Diethyl 2-methyl-1-oxo-4-phenyl-2,6,7,8-tetrahydro-1H-

pyrazolo[1,2-a][1,2,4,5]tetrazine-6,7-dicarboxylate (48)

The title compound was synthesized according to the general procedure using diethyl fumarate as the dipolarophile. Purification by silica gel chromatography (3:7 ethyl acetate/hexane) afforded the product as a yellow oil (459 mg, 83%). 1H NMR (500 MHz,

CDCl 3), δ: 7.747.70 (m, 2H), 7.487.39 (m, 3H), 4.64 (d, J = 3.3, 1H), 4.52 (dd, J = 9.0, 11.8,

1H), 4.27 (dq, J = 1.4, 7.1, 2H), 4.05 (dq, J = 0.5, 7.1, 2H), 3.67 (dd, J = 5.5, 11.8, 1H), 3.53

3.48 (m, 1H), 3.35 (s, 3H), 1.33 (t, J = 7.1, 3H), 1.13 (t, J = 7.1, 3H). 13 C NMR (125 MHz,

CDCl 3), δ: 170.4, 169.5, 153.8, 145.4, 130.9, 130.5, 128.7, 127.4, 64.6, 62.1, 62.0, 47.4, 47.1,

+ 36.7, 14.1, 13.8. HRMS (EI): calculated for C 18 H22 N4O5 [M ], 374.1590; found, 374.1593.

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3.2.11 Synthesis of (6S,7R)-Diethyl 2-methyl-1-oxo-4-phenyl-2,6,7,8-tetrahydro-1H-

pyrazolo[1,2-a][1,2,4,5]tetrazine-6,7-dicarboxylate (49)

Diethyl maleate was first purified by column chromatography (1:8 ethyl acetate/hexane).

The title compound was synthesized according to the general procedure with the modification of using 8 equivalents of purified diethyl maleate. Purification by silica gel chromatography (3:7 ethyl acetate/hexane) afforded the product as a yellow oil (132 mg, 24%). 1H NMR (500 MHz,

CDCl 3), δ: 7.657.60 (m, 2H), 7.487.44 (m, 1H), 7.437.38 (m, 2H), 4.46 (dd, J = 8.8, 11.3, 1H),

4.38 (d, J = 7.9, 1H), 4.14 (q, J = 7.1, 2H), 4.12 (dq, J = 7.1, 10.8, 1H), 4.04 (dq, J = 7.1, 10.8,

1H), 3.83 (dd, J = 9.7, 11.3, 1H), 3.64 (q, J = 8.6, 1H), 3.31 (s, 1H), 1.22 (t, J = 7.1, 3H), 1.17, (t,

13 J = 7.2, 3H). C NMR (125 MHz, CDCl 3), δ: 168.5, 168.3, 154.4, 144.7, 131.0, 130.6, 128.7,

+ 127.4, 63.1, 61.9, 61.6, 47.1, 46.5, 36.8, 13.9, 13.8. HRMS (EI): calculated for C 18 H22 N4O5 [M ],

374.1590; found, 374.1582.

3.2.12 Synthesis of (6R,7R)-2-Methyl-1-oxo-4-phenyl-2,6,7,8-tetrahydro-1H-pyrazolo[1,2-

a][1,2,4,5]tetrazine-6,7-dicarbonitrile (50)

The title compound was synthesized according to the general procedure with the modification of adding minimal THF to solubilize the reaction mixture containing fumaronitrile as the dipolarophile. Purification by silica gel chromatography (1:3 ethyl acetate/hexane) and recrystallization from ethyl acetate/hexane afforded the product as a yellow crystalline solid (362

1 mg, 69%, mp: 161162 ºC). H NMR (500 MHz, CDCl 3), δ: 7.837.76 (m, 2H), 7.567.45 (m,

3H), 5.00 (m, 1H), 4.594.55 (m, 1H), 3.673.58 (m, 2H), 3.42 (s, 3H). 13 C NMR (100 MHz,

CDCl 3), δ: 151.8, 142.3, 131.9, 129.2, 128.8, 127.1, 116.3, 114.2, 54.1, 48.1, 37.2, 34.0. HRMS

+ (EI): calculated for C 14 H12 N6O [M ], 280.1073; found, 280.1068.

115

3.2.13 Synthesis of N-Methyl Maleimide Cycloadduct (51)

The title compound was synthesized according to the general procedure modified by the addition of 5 mL of THF to solubilize the reaction mixture containing Nmethyl maleimide as the dipolarophile. Purification by silica gel chromatography (1:4 ethyl acetate/methylene chloride) and recrystallization from ethyl acetate afforded the product as a white crystalline solid (260 mg,

1 56%, mp: 224226 ºC). H NMR (500 MHz, CDCl 3), δ: 7.86782. (m, 2H), 7.537.47 (m, 2H),

7.477.44 (m, 1H), 4.82 (dd, J = 0.8, 12.4, 1H), 4.41 (d, J = 7.7, 1H), 3.57 (t, J = 7.9, 1H), 3.44

13 (dd, J = 8.5, 12.4, 1H), 3.30 (s, 1H), 2.91, (s, 3H). C NMR (125 MHz, CDCl 3), δ: 174.8, 171.5,

154.1, 145.7, 131.2, 130.0, 128.7, 127.4, 62.4, 48.1, 45.6, 36.9, 25.2. HRMS (ESI) ( m/z ):

+ calculated for C 15 H16 N5O3 [M+H] , 314.1247; found, 314.1262.

3.3 Results and Discussion

3.3.1 [3+2] 1,3-Dipolar Cycloaddition Initiated by Verdazyl Radical

3.3.1.1 Discovery

As previously noted (see Scheme 26, Scheme 27), compound 20 was isolated from a verdazylcontaining unimolecular initiator synthesis reaction mixture, as well as from a styrene polymerization involving verdazyl radical 16 as the moderating stable radical (Scheme 31).

Scheme 3-1. Synthesis of unimolecular initiator 19 with 1,5dimethyl3phenyl6oxoverdazyl radical 16, styrene, and BPO; 20 recovered as major product.

116

In the unimer synthesis reaction, the yield of 28% for 20 was far higher than our anticipated product 19 at 10%. Since this type of novel bicyclic compound had never been observed in the analogous BST synthesis, and its formation appears to contribute to the success of the verdazyl mediate acrylate polymerization, our focus shifted to investigating the formation of this product to better understand the chemistry occurring in this reaction.

3.3.1.2 Elucidation of Mechanism

The aforementioned unimolecular synthesis reaction was repeated without BPO and without nitrogen, in the former case to see if BPO was a participant in the reaction and in the latter case to understand whether the formation of 20 occurred via a radical mechanism. After 24 hours, the reaction still gave a 26% yield of 20 , eliminating the participation of BPO in its formation (Scheme 32). Two potential mechanisms were contemplated for the formation of 20 , one involving a diradical intermediate and the other involving a 1,3dipole intermediate. The absence of the regioisomer of 20 , 37 , supported both mechanisms. From radical polymerizations, it is known that when a radical adds to an olefin, it tends to do so in a headtotail fashion due to the proper matchup of the molecular orbital signs and coefficients of both species. The same principles can be used to rationalize the regioselectivity of the formation of 20 through a diradical mechanism. On the other hand, the regioselectivity of 1,3dipolar cycloadditions is also known to be governed by the molecular orbital signs and coefficients of the two reacting species.

117

Scheme 3-2. Formation of 20 with 1,5dimethyl3phenyl6oxoverdazyl radical 16 without BPO.

The postulated diradical mechanism would involve a hydrogen abstraction reaction as its first step. The resulting diradical would then react via a radical addition reaction with styrene to form the bicyclic product (Scheme 33).

Scheme 3-3. Postulated diradical mechanism for the formation of 20 with 1,5dimethyl3phenyl6 oxoverdazyl radical 16 and styrene.

However, several pieces of evidence argued against this mechanism. Since the verdazyl radical itself is a radical trap the formation of 38 should have led to the formation of compound 39

(Figure 31), but it was not observed. By the same token, the benzoyloxy radical formed from

BPO, used in the initial reaction, should also have provided some variant of compound 38 , such as compound 40 , but again this was not observed (Figure 31). Therefore, the diradical mechanism was rejected.

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Figure 3-1. Expected trapped products from diradical mechanism; not observed.

Next, a single electron transfer (SET) reaction, similar to what has been observed with nitroxide radicals 4 (see Scheme 125), leading to an ionic mechanism for the formation of 20 , was considered. Due to the structural similarity between the verdazyl radical 16 and the nitroxide 4 (TIPNO) in that they both bear an α hydrogen relative to the two adjacent heteroatoms, it seemed reasonable that an analogous mechanism would occur (Figure 32).

Deprotonation following the single electron transfer reaction would provide a 1,3dipole species,

41 , which could react with styrene to form the bicyclic product 20 (Scheme 34).

Figure 3-2. Structural similarities between 1,5dimethyl3phenyl6oxoverdazyl radical 16 and TIPNO 4 in bearing an α hydrogen relative to two adjacent heteroatoms.

119

Scheme 3-4. Postulated single electron transfer mechanism of 1,5dimethyl3phenyl6oxoverdazyl radical 16 with styrene for the formation of 20 .

However, in our correspondence with Professor Hicks at the University of Victoria regarding the above mechanism, it was pointed out that the reduction potential of the verdazyl radical is too low for this redox reaction to occur spontaneously at room temperature. 10 In contrast, nitroxides are well known for their ability to act as oxidants. Therefore, what is a reasonable mechanism for the nitroxide family is not applicable to the verdazyls, and the single electron transfer mechanism was rejected.

During the discussion of the formation of intermediate 41 (Scheme 35), the hydrogen abstraction pathway was under investigation by preliminary DFT calculations by another group member, Dr. Gordon Hamer. These calculations showed that a hydrogen abstraction reaction would lead directly to the azomethine imine 41 , without the necessity of invoking the intermediacy of a diradical species. Since styrene is an example of a dipolarophile used in many

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other 1,3dipolar cycloadditions, the formation of 20 was readily rationalized via the mechanism shown in Scheme 35.

Scheme 3-5. Postulated mechanism for the formation of azomethine imine 41 from 1,5dimethyl3 phenyl6oxoverdazyl radical 16 and its formation of cycloadduct 20 with styrene.

The hydrogen abstraction step that results in the formation of leucoverdazyl 42 was verified by an in situ benzylation experiment (Scheme 36). 11 Since leucoverdazyl 42 is stable in the absence of oxygen, its presence in the reaction mixture was shown by trapping it as its N benzylated derivative. After a cycloaddition reaction was allowed to occur between 41 and methyl methacrylate over 24 h under an atmosphere of argon, sodium hydride and benzyl bromide were added to the reaction mixture. Compound 43 was isolated from this reaction mixture in 36% yield relative to the starting verdazyl radical.

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Scheme 3-6. Benzylation trapping experiment of leucoverdazyl 42 from cycloaddition of 1,5dimethyl3 phenyl6oxoverdazyl radical 16 and methyl methacrylate.

3.3.2 Verdazyl-Derived Azomethine Imine

3.3.2.1 Optimization of Reaction and Solvent Effects

The initial verdazylinitiated cycloaddition reactions were performed at room temperature under an atmosphere of oxygen for 24 hours in neat dipolarophile or with the dipolarophile dissolved in a minimal amount of methylene chloride or THF. 12 Oxygen allows the oxidation of the leucoverdazyl 42 back to the verdazyl radical 16 (Scheme 35). The minimal use of solvent allows the cycloaddition reaction to proceed relatively quickly by allowing optimal intermolecular hydrogen abstraction between two verdazyl radical molecules (Scheme 35).

Refluxing the reaction mixture in toluene allowed the reaction time to be reduced to 3 hours. 12

The role of solvent in the reaction was also studied in the cycloaddition reaction of azomethine imine 41 with styrene. Cycloaddition reactions conducted at room temperature for

24 hours in acetone, dimethyl sulfoxide and methylene chloride gave 20 in 51, 53 and 45% yields, respectively. 12 This lack of difference in yields is consistent with the fact that solvents have little or no effect on cycloaddition reactions in general.

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3.3.2.2 Scope of Reaction

Azomethine imines are a class of wellstudied 1,3dipoles known to undergo 1,3dipolar cycloaddition reactions with a wide range of dipolarophiles of both electronrich and electron poor nature. Various azomethine imines with various attached substituents display different reactivities towards dipolarophiles. The verdazylderived azomethine imine 41 is structurally unique in its tetrazinonyl backbone which, when incorporated into cycloaddition products, provide novel heterocyclic structures. The azomethine imine 41 also has a different substitution pattern than other existing azomethine imines 13,14 in that its carbonyl functionality is attached to the centre rather than the terminal nitrogen of the azomethine imine moiety (Figure 33).

Figure 3-3. Comparison of substitution pattern between azomethine imine 41 and two other azomethine imines containing the carbonyl functionality. 13,14

Cycloaddition reactions with various electronpoor dipolarophiles (Table 31) proceeded to give products in high yields. 11 In contrast, cycloaddition reactions with electronrich olefins such as vinyl ether, pyrrolidino1cyclopentene and 1morpholinocyclohexene and unactivated olefins such as 1hexene and cyclohexene gave no appreciable yields of cycloadduct. 12

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Table 3-1. Cycloaddition reactions of 1,5dimethyl3phenyl6oxoverdazyl radical 16 with various dipoles; neat or minimal solvent. 11

Compound Substrate Product % Yield O Me N N 20 63 Ph NN Ph Ph

21 74

44 82

45 84

46 62

47 74

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48 83

49 42

50 69

O O Me N N O 51 N NN 56 N O Ph O

3.3.2.3 Assessment of Reactivity

It was surprising that even though the cycloaddition reaction proceeded smoothly with electronpoor dipolarophiles, little or no reactivity was observed with unactivated and electron rich dipolarophiles. With such a selectivity of dipolarophiles, azomethine imine 41 is categorized as a Sustmann type I (see Figure 116) dipole. Initially we sought to explain this phenomenon with FMO theory; that the energy gap between the azomethine imine and electron poor dipolarophiles are smaller and much more favourable thus allowing the reaction to occur, while the gaps with electronrich dipolarophiles are too large (Figure 34).

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LUMO LUMO

LUMO HOMO HOMO electron rich dipolarophile dipole HOMO 41 electron poor dipolarophile Figure 3-4. Postulated qualitative FMO analysis of dipole 41 with generic dipolarophiles.

In association with another member of the group, Dr. Gordon Hamer, a parallel assessment of the cycloaddition reactions was conducted using DFT calculations. Energy levels of the azomethine imine, as well as some dipolarophiles, were calculated with methods reported in the literature and the energy of the dipolarophiles matched consistently with literature values. 15,16 Interestingly, the energy gaps between the azomethine imine 41 and electronrich dipolarophiles (Figure 35) are comparable, if not smaller, than the electronpoor dipolarophiles.

This suggests that the transition states for the reactions between 41 and the electronrich olefins are at least as stable, if not more stable, than the transitions states between 41 and the electron poor olefins. In fact, on the basis of FMO theory, azomethine imine 41 should be a Sustmann type II dipole and should be able to react with dipolarophiles of any electronic properties. In agreement with this theory, DFT calculations (Table 32) showed that while reactions of 41 with electronpoor dipolarophiles are in the classification of dipole-HO controlled cycloaddition reactions, the reaction of 41 with styrene is in the contrasting dipole-LU controlled classification

(Figure 36). On this basis, it is evident that this azomethine imine 41 is a Sustmann type II dipole. The fact that it only displays Sustmann type I characteristics is a puzzle we can only speculate on.

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Figure 3-5. Qualitative representation of DFT calculated FMO analysis of dipole 41 with 1 pyrrolidinocyclopentene and methyl acrylate.

Figure 3-6. Qualitative representation of DFT calculated FMO analysis of dipole 41 with styrene and methyl acrylate.

Table 3-2. Quantitative DFT calculations of the FMO energies of dipole 41 with dipolarophiles; bolded values represent smallest energy gap.

Dipolarophile pHOMO LUMO LU(d) – HO (p) LU (p) – HO (d) LU-dipole HO-dipole controlled controlled Verdazyl dipole 0.20207 0.06756

Styrene 0.2217 0.0305 0.15414 0.17157 Methyl acrylate 0.2822 0.044 0.21464 0.15807 Acrylonitrile 0.2892 0.0563 0.22164 0.14577 MMA 0.2652 0.0368 0.19764 0.16527 Dimethyl fumarate 0.2913 0.0814 0.22374 0.12067

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1Mopholinocyclohexene 0.1896 0.0426 0.12204 0.24467 1Pyrrolidinocyclopentene 0.1678 0.0842 0.10024 0.28627

In an attempt to rationalize why the azomethine imine 41 does not react with electron rich dipolarophiles despite the proper FMO configurations, its electrostatic potential properties were investigated with DFT calculations. According to these DFT calculations, the electrostatic potential of the azomethine imine moiety of 41 is highly negative (Figure 37), which contrasts with typical azomethine imines that are generally known to be fairly neutral. 17

Figure 3-7. DFT calculated electrostatic potential map of dipole 41 (electron density: yellowhigh; blue low).

Even though most cycloaddition reactions operate on the principles of FMO theory, electrostatic interactions, which are typically ignored due to the neutrality of the dipole species involved,

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cannot be completely omitted from the equation. 17 We can speculate that while the negative electrostatic potential of azomethine imine 41 is complementary to electronpoor dipolarophiles and thus reaction is favourable, electrostatic repulsion would hinder its reaction with electron rich dipolarophiles.

It can be envisioned that with more electronwithdrawing substituents on the azomethine imine the negative electrostatic potential at the 1,3dipole site would be reduced. To that end, verdazyl radicals 52 and 53 , known to undergo 1,3dipolar cycloaddition reactions with methyl acrylate, 12 were synthesized and tested with electronrich dipolarophiles such as pyrrolidino1 cyclopentene and 1morpholinocyclohexene (Figure 38). Still, no cycloadducts were observed.

Figure 3-8. Reactions between verdazyl radicals containing electronwithdrawing ( para cyanophenyl, para-fluoro) substituents with electronrich dipolarophiles (pyrrolidino1cyclopentene and 1 morpholinocyclohexene).

Nevertheless, the electrostatic potentials of the azomethine imines corresponding to these verdazyl radicals have not yet been calculated, and the electronwithdrawing substituents may either be too weak or too far from the reactive centre to have enough impact. Therefore, the experiments are inconclusive at this point and future work is needed.

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3.4 Concluding Remarks

In conclusion, structurally unique azomethine imines were generated from verdazyl radicals to participate with styrene and electronpoor dipolarophiles in 1,3dipolar cycloadditions.

This discovery is not only exciting because it is a rare example of incorporating stable free radicals as substrates in organic synthesis, but also because it opens the door to new libraries of structurally unique heterocycles. Experiments were performed to verify the proposed mechanism in the formation of cycloadduct 20 and a range of dipolarophiles were tested to explore the scope of the reaction. The reactivity of the azomethine imine 41 was assessed by both experimental data and theoretical calculations. It was hypothesized that even though the azomethine imine 41 is theoretically a Sustmann type II dipole on the basis of FMO analysis, it only displays Sustmann type I characteristics presumably due to restrictions from its negative electrostatic repulsions with electronrich dipolarophiles.

3.5 Future Work

The verdazylderived azomethine imine 1,3cycloaddition reaction is only in its exploratory stage. An ongoing effort in broadening the range of dipolarophiles is being made in order to further expand this library of unique heterocycles – as elaborated in the upcoming chapter. More electronwithdrawing derivatives such as 54 should be, and are, being synthesized and characterized by DFT calculations to elucidate the compatibility of the azomethine imine with electronrich dipolarophiles. Other verdazyl series, such as the 1,5dibenzyl6oxoverdazyl radicals 55 should be, and are being synthesized for their compatibility for this cycloaddition reaction (Figure 39). Catalysis and asymmetric synthesis should be investigated in order to improve the efficiency of this reaction and also to find potential applications.

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O O Me Me Bn Bn N N N N NN NN

F F R 55 F F F 54 Figure 3-9. Verdazyl radicals bearing 3pentafluorophenyl and 1,5dibenzyl substituents.

3.6 References

(1) Georges, M. K.; Veregin, R. P. N.; Kazmaier, P. M.; Hamer, G. K. Macromolecules 1993 , 26 , 29872988.

(2) Mayo, F. R. J. Am. Chem. Soc. 1968 , 90 , 12891295.

(3) Georges, M. K.; Kee, R. A.; Veregin, R. P. N.; Hamer, G. K.; Kazmaier, P. M. J. Phy. Org. Chem. 1995 , 8 , 301305.

(4) Nilsen, A.; Braslau, R. J. Polym. Sci. Part A - Polym. Chem. 2006 , 44 , 697717.

(5) Georges, M. K.; Lukkarila, J. L.; Szkurhan, A. R. Macromolecules 2004 , 37 , 12971303.

(6) Yamada, B.; Kageoka, M.; Otsu, T. Macromolecules 1991 , 24 , 52345236.

(7) Otsu, T.; Yamada, B.; Ishikawa, T. Macromolecules 1991 , 24 , 415419.

(8) Neugebauer, F. A.; Fischer, H. Angew. Chem. Int. Ed. 1973 , 12 , 455464.

(9) Neugebauer, F. A.; Fischer, H.; Krieger, C. J. Chem. Soc. Perkin Trans. 2 1993 , 2 , 535544.

(10) Gilroy, J. B.; McKinnon, S. D. J.; Koivisto, B. D.; Hicks, R. G. Org. Lett. 2007 , 9 , 4837 4840.

(11) Yang, A.; Kasahara, T.; Chen, E. K. Y.; Hamer, G. K.; Georges, M. K. Eur. J. Org. Chem. 2008 , 45714574.

(12) Unpublished results.

(13) Dorn, H.; Otto, A. Angew. Chem. Int. Ed. Engl. 1968 , 7 , 214215.

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(14) Oppolzer, W. Tet. Lett. 1970 , 11 , 21992205.

(15) Butler, R. N.; Coyne, A. G.; McArdle, P.; Cunningham, D.; Burke, L. A. J. Chem. Soc. Perkin Trans. 1 2001 , 13911397.

(16) Butler, R. N.; Coyne, A. G.; Burke, L. A. J. Chem. Soc. Perkin Trans. 2 2001 , 17811784.

(17) Fleming, I. In Frontier Orbitals and Organic Chemical Reactions; John Wiley & Sons: Great Britain, 1976.

Chapter 4

4 Rearrangement Reactions of Verdazyl-Derived Cycloadducts

4.1 Introduction and Objective

In Chapter 3, the 1,5dimethyl3phenyl6oxoverdazyl radical 16 was demonstrated to form an azomethine imine in situ , which could undergo 1,3dipolar cycloaddition reactions with various dipolarophiles to yield structurally unique heterocycles. 1 Heterocycles in general are known to be prone to rearrangement reactions due to their facile ability to undergo ring fission, bond rotation and ring closure. A number of factors, or any combination thereof, contribute to this ability. For example, i) external nucleophile or electrophileassisted ring fission reactions may be facilitated by any electrophilic functionalities or nucleophilic atoms, respectively, incorporated in the heterocycle; ii) intramolecular ring fission reactions may be facilitated by the flexibility of the heterocycle due to the inversion of lone pair electrons on nitrogen atoms; iii) ring fission reactions may be facilitated by stable intermediates conjugated through the orbitals of the heteroatoms. 2 When properly exploited, heterocyclic rearrangements provide an array of compounds that would otherwise be difficult to synthesize by conventional routes. Typically, heat or nucleophilic catalytic reagents, such as pyridine or alkoxides, are used to induce many of these rearrangement reactions. 2

The initial verdazylderived cycloadducts described in Chapter 3 appeared stable at high temperatures. The synthetic procedure for their formation that gave the best yields was the one

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in which the reaction was refluxed in toluene (~110 ºC). In addition, as demonstrated, cycloadducts could be isolated from styrene and nbutyl acrylate livingradical polymerizations that were conducted at temperatures as high as 135 ºC. The first rearrangement reaction of the verdazylderived cycloadducts was serendipitously discovered in a project originally initiated to produce a variety of cycloaddition products containing different functionalities.

This chapter outlines two interesting heterocyclic rearrangement reactions and shows the role these rearrangement reactions play in expanding the scaffold diversity of the verdazyl derived heterocycles. A unique mechanism is proposed for one of these rearrangement reactions.

4.2 Experimental Section

4.2.1 Materials and Equipment

All ACS grade reagents and solvents were purchased from SigmaAldrich, Alfa Aesar, and Caledon Chemicals unless otherwise stated. Nitrogen was purchased from BOC Canada.

Inhibitors were not removed from monomers or dipolarophiles for the cycloaddition reactions.

EMD Chemicals, and visualized under UV (254 nm) light.

Verdazyl radicals 3, E2methylthiophenylacrylonitrile 4 and methyl αacetoxy acrylate 5 were synthesized according to published procedures. αAcetoxyacrylonitrile was purchased from SigmaAldrich.

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