verdazyl radicals as mediators in living radical ......verdazyl radicals as mediators in living...

VERDAZYL RADICALS AS MEDIATORS IN LIVING RADICAL

POLYMERIZATIONS AND AS NOVEL SUBSTRATES FOR HETEROCYCLIC

SYNTHESES

By

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

© Copyright by Eric Kuan Yu Chen 2010

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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 1,5-dimethyl-3-phenyl-6-

oxoverdazyl radical as a mediating agent for styrene and n-butyl 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.

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The second part of this thesis outlines the initial discovery and the mechanistic elucidation of the

transformation of the 1,5-dimethyl-3-phenyl-6-oxoverdazyl radical into an azomethine imine,

which in the presence of dipolarophiles, undergoes a [3+2] 1,3-dipolar 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 verdazyl-derived 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 verdazyl-initiated cycloaddition

and rearrangement reactions with the philosophy of diversity-oriented synthesis in generating

libraries of heterocycles. A library of verdazyl-derived heterocycles was generated in a short

amount of time and was tested non-specifically for biological activity against acute myeloid

leukemia and multiple myeloma cell lines. One particular compound showed cell-killing activity

at the 250 µM 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.

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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 Nitrogen-Centered Radicals in Stable Free Radical Polymerizations .................... 27

1.2.4 Concluding remarks ................................................................................................ 33

1.3 1,3-Dipolar Cycloadditions Involving Azomethine Imines ........................................... 34

1.3.1 Introduction to 1,3-Dipolar 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

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2.2.1 Materials and Equipment ........................................................................................ 65

2.2.2 Styrene Polymerization Initiated with 1,1’-Azobis(cyclohexanecarbonitrile) (Vazo® 88) in the Presence of 1,5-Dimethyl-3-phenyl-6-oxoverdazyl Radical 16 ............. 67

2.2.3 Styrene Polymerization Initiated with BPO in the Presence of 1,3,5-Triphenyl-6-oxoverdazyl Radical 17 ......................................................................................................... 67

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) ..................................................................................................... 68

2.2.5 Styrene Polymerization Initiated with Unimolecular Initiator 18 ........................... 68

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) ............................................................................................ 69


2.2.8 n-Butyl Acrylate Polymerization Initiated with Unimolecular Initiator 19 ............ 69

2.2.9 Reaction of 1,5-Dimethyl-3-phenyl-6-oxoverdazyl Radical 16 with BPO and Styrene ................................................................................................................................. 70

2.2.10 Preparation of Poly(n-butyl acrylate-b-polystyrene) from a Poly(n-butyl acrylate) Macroinitiator ........................................................................................................................ 70

2.2.11 Preparation of Poly(styrene-b-n-butyl acrylate) from a Polystyrene Macroinitiator .. ................................................................................................................................. 71

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) .................................................................... 71



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) ........................................................ 72


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) ..................................................................................................... 73

2.2.18 Reaction of Carbonic Acid Bis(1-Methylhydrazide) with 2,6-Dimethylbenzaldehyde (29) .................................................................................................. 73

2.2.19 Synthesis of 1-(1,5-Dimethyl-3-phenyl-6-phosphaverdazyl)ethylbenzene Unimolecular Initiator (36) by ATRA with (1-Bromoethyl)benzene ................................... 74

2.2.20 Synthesis of 1-(1,5-Dimethyl-3-phenyl-6-phosphaverdazyl)ethylbenzene Unimolecular Initiator (36) with Sodium Hydride and (1-Bromoethyl)benzene .................. 75

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2.3 Results and Discussion ................................................................................................... 75

2.3.1 Verdazyl-Mediated Styrene Polymerization with Bimolecular Initiators .............. 75

2.3.2 Verdazyl-Mediated Styrene Polymerization with Unimolecular Initiators ............ 78

2.3.3 Verdazyl-Mediated n-Butyl Acrylate Polymerization with Unimolecular Initiators . ................................................................................................................................. 83

2.3.4 Block Copolymer Formation – Chain Extension with Verdazyl-Terminated Macromolecules ..................................................................................................................... 89

2.3.5 Polymerizations with Various 1,5-Dimethyl-6-Oxoverdazyl 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 2-Methyl-4,6-diphenyl-2,6,7,8-tetrahydro-1H-pyrazolo[1,2-a][1,2,4,5]tetrazin-1-one (20) .............................................................................................. 109

3.2.3 Synthesis of 5-Benzyl-2,4-dimethyl-6-phenyl-4,5-dihydro-1,2,4,5-tetrazin-3(2H)-one (43) ............................................................................................................................... 110

3.2.4 General Optimized Procedure for the 1, 3-Dipolar Cycloaddition of Verdazyl Radical 16 with Various Dipolarophiles ............................................................................. 110

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) ................................................................................ 111

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) .......................................................... 111

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) .......................................................... 112

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) ................................................................................ 112

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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) ................................................................................ 113

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) .................................................... 113

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) .................................................... 114

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) .................................................... 114

3.2.13 Synthesis of N-Methyl Maleimide Cycloadduct (51) ........................................... 115

3.3 Results and Discussion ................................................................................................. 115

3.3.1 [3+2] 1,3-Dipolar Cycloaddition Initiated by Verdazyl Radical .......................... 115

3.3.2 Verdazyl-Derived Azomethine Imine ................................................................... 121


3.5 Future Work ................................................................................................................. 129

3.6 References .................................................................................................................... 130

4 Chapter 4 - Rearrangement Reactions of Verdazyl-Derived Cycloadducts




4.2.2 General Procedure for Cycloaddition Reactions ................................................... 134

4.2.3 Synthesis of 2-Methyl-4-phenyl-7,8-dihydro-1H-pyrazolo[1,2-a][1,2,4,5]tetrazine-1,6(2H)-dione (57) ............................................................................................................... 135

4.2.4 Synthesis of (Z)-2,3-Bis(2,4-dimethyl-3-oxo-6-phenyl-3,4-dihydro-1,2,4,5-tetrazin-1(2H)-yl)acrylonitrile (58) ................................................................................................... 135

4.2.5 Synthesis of 5-Methyl-7-phenylpyrazolo[1,5-d][1,2,4]triazin-4(5H)-one (67) .... 136

4.2.6 Synthesis of Methyl 6-acetoxy-2-methyl-1-oxo-4-phenyl-2,6,7,8-tetrahydro-1H-pyrazolo[1,2-a][1,2,4,5]tetrazine-6-carboxylate (66) .......................................................... 136

4.2.7 Synthesis of Methyl 2-methyl-1-oxo-4-phenyl-2,8-dihydro-1H-pyrazolo[1,2-a][1,2,4,5]tetrazine-6-carboxylate (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 5-methyl-4-oxo-7-phenyl-1,2,3,3a,4,5-hexahydropyrazolo[1,5-d][1,2,4]triazine-3a-carboxylate (70) .................................................................................. 137

4.2.11 Conversion of 21 to 70 by Lithium Diisopropylamide ......................................... 138

4.2.12 Synthesis of Methyl 2-(1-methyl-3-phenyl-1H-1,2,4-triazol-5-yl)ethylcarbamate (76) ............................................................................................................................... 138

4.2.13 Synthesis of Ethyl 2-(1-methyl-3-phenyl-1H-1,2,4-triazol-5-yl)ethylcarbamate (77) ............................................................................................................................... 139

4.2.14 Synthesis of N,N,2-Trimethyl-1-oxo-4-phenyl-2,6,7,8-tetrahydro-1H-pyrazolo[1,2-a][1,2,4,5]tetrazine-6-carboxamide (72) .............................................................................. 140

4.2.15 Synthesis of N,N,5-Trimethyl-4-oxo-7-phenyl-1,2,3,3a,4,5-hexahydropyrazolo[1,5-d][1,2,4]triazine-3a-carboxamide (73) ................................................................................ 140


4.3.1 Ketene Equivalents and Captodative Olefins in Verdazyl-Initiated Cycloaddition ... ............................................................................................................................... 141

4.3.2 Rearrangement of Pyrazolotetrazinone to Pyrazolotriazinone ............................. 144

4.3.3 Rearrangement of Pyrazolotetrazinone to Triazolyl Carbamate ........................... 152


4.5 Future Work ................................................................................................................. 159

4.6 References .................................................................................................................... 160

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




5.2.2 General Optimized Procedure for the 1, 3-Dipolar Cycloaddition of 1,5-Dimethyl-6-oxoverdazyl 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 t-Boc Protected Amines ....................... 165

5.2.5 Synthesis of Dimethyl 2-methyl-1-oxo-4-phenyl-2,6,7,8-tetrahydro-1H-pyrazolo[1,2-a][1,2,4,5]tetrazine-6,7-dicarboxylate (86) .................................................... 166

5.2.6 Synthesis of Methyl 4-(4-cyanophenyl)-2-methyl-1-oxo-2,6,7,8-tetrahydro-1H-pyrazolo[1,2-a][1,2,4,5]tetrazine-6-carboxylate (87) .......................................................... 166

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5.2.7 Synthesis of Methyl 4-(1H-imidazol-5-yl)-2-methyl-1-oxo-2,6,7,8-tetrahydro-1H-pyrazolo[1,2-a][1,2,4,5]tetrazine-6-carboxylate (88) .......................................................... 166

5.2.8 Synthesis of 2-Methyl-4-(4-nitrophenyl)-1-oxo-2,6,7,8-tetrahydro-1H-pyrazolo[1,2-a][1,2,4,5]tetrazine-6-carbonitrile (89) .......................................................... 167

5.2.9 Synthesis of 4-(4-Cyanophenyl)-2-methyl-1-oxo-2,6,7,8-tetrahydro-1H-pyrazolo[1,2-a][1,2,4,5]tetrazine-6-carbonitrile (90) .......................................................... 167

5.2.10 Synthesis of 4-(2-Methyl-1-oxo-6-phenyl-2,6,7,8-tetrahydro-1H-pyrazolo[1,2-a][1,2,4,5]tetrazin-4-yl)benzonitrile (91) ............................................................................. 167

5.2.11 Synthesis of 2-Methyl-1-oxo-4-(pyridin-2-yl)-2,6,7,8-tetrahydro-1H-pyrazolo[1,2-a][1,2,4,5]tetrazine-6-carbonitrile (92) ................................................................................ 168

5.2.12 Synthesis of 4-(4-Cyanophenyl)-N-isopropyl-2-methyl-1-oxo-2,6,7,8-tetrahydro-1H-pyrazolo[1,2-a][1,2,4,5]tetrazine-6-carboxamide (93) .................................................. 168

5.2.13 Synthesis of Dimethyl 5-methyl-4-oxo-7-phenyl-1,2,3,3a,4,5-hexahydropyrazolo[1,5-d][1,2,4]triazine-3,3a-dicarboxylate (94) ...................................... 168

5.2.14 Synthesis of Methyl 7-(4-cyanophenyl)-5-methyl-4-oxo-1,2,3,3a,4,5-hexahydropyrazolo[1,5-d][1,2,4]triazine-3a-carboxylate (95) ............................................ 169

5.2.15 Synthesis of Isopropyl 2-(3-(4-cyanophenyl)-1-methyl-1H-1,2,4-triazol-5-yl)ethylcarbamate (96) ......................................................................................................... 169

5.2.16 Synthesis of Methyl 2-(1-methyl-3-(pyridin-2-yl)-1H-1,2,4-triazol-5-yl)ethylcarbamate (97) ......................................................................................................... 169

5.2.17 Synthesis of Methyl 2-(3-(3-fluoropyridin-4-yl)-1-methyl-1H-1,2,4-triazol-5-yl)ethylcarbamate (98) ......................................................................................................... 170

5.2.18 Synthesis of Isopropyl 2-(3-(3-fluoropyridin-4-yl)-1-methyl-1H-1,2,4-triazol-5-yl)ethylcarbamate (99) ......................................................................................................... 170

5.2.19 Synthesis of N-((2-Methyl-1-oxo-4-phenyl-2,6,7,8-tetrahydro-1H-pyrazolo[1,2-a][1,2,4,5]tetrazin-6-yl)methyl)tert-butylcarbamate (100) .................................................. 170

5.2.20 Synthesis of N-((2-Methyl-1-oxo-4-phenyl-2,6,7,8-tetrahydro-1H-pyrazolo[1,2-a][1,2,4,5]tetrazin-6-yl)methyl)acetamide (101) ................................................................. 171

5.2.21 Synthesis of Methyl 4-(4-(isobutyramidomethyl)phenyl)-2-methyl-1-oxo-2,6,7,8-tetrahydro-1H-pyrazolo[1,2-a][1,2,4,5]tetrazine-6-carboxylate (102) ................................ 171

5.2.22 Synthesis of N-(4-(2-Methyl-1-oxo-6-phenyl-2,6,7,8-tetrahydro-1H-pyrazolo[1,2-a][1,2,4,5]tetrazin-4-yl)benzyl)acetamide (103) ................................................................. 171

5.2.23 Synthesis of N-(4-(2-Methyl-1-oxo-6-phenyl-2,6,7,8-tetrahydro-1H-pyrazolo[1,2-a][1,2,4,5]tetrazin-4-yl)benzyl)isobutyramide (104) ........................................................... 172

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5.2.24 Synthesis of Methyl 2-(3-(4-(tert-butylcarbamoylmethyl)phenyl)-1-methyl-1H-1,2,4-triazol-5-yl)ethylcarbamate (105) .............................................................................. 172

5.2.25 Synthesis of Isopropyl 2-(3-(4-(tert-butylcarbamoylmethyl)phenyl)-1-methyl-1H-1,2,4-triazol-5-yl)ethylcarbamate (106) .............................................................................. 172

5.2.26 Synthesis of Methyl 2-(3-(4-(acetamidomethyl)phenyl)-1-methyl-1H-1,2,4-triazol-5-yl)ethylcarbamate (107) ................................................................................................... 173

5.2.27 Synthesis of Isopropyl 2-(3-(4-(acetamidomethyl)phenyl)-1-methyl-1H-1,2,4-triazol-5-yl)ethylcarbamate (108) ........................................................................................ 173

5.2.28 Synthesis of Methyl 2-(3-(4-(isobutyramidomethyl)phenyl)-1-methyl-1H-1,2,4-triazol-5-yl)ethylcarbamate (109) ........................................................................................ 173

5.2.29 Synthesis of Isopropyl 2-(3-(4-(isobutyramidomethyl)phenyl)-1-methyl-1H-1,2,4-triazol-5-yl)ethylcarbamate (110) ........................................................................................ 174


5.3.1 First Generation Library of Verdazyl-Derived Heterocycles – Verdazyl-Initiated Cycloaddition Products ........................................................................................................ 174

5.3.2 Second Generation Library of Verdazyl-Derived Heterocycles – Rearrangement Products of Verdazyl-Derived Cycloadducts ...................................................................... 175

5.3.3 Third Generation Library of Verdazyl-Derived Heterocycles – Amide Derivatives from the Reduction of Nitriles and Subsequent Amidation ................................................ 175

5.3.4 DOS Library of Verdazyl-Derived Heterocycles ................................................. 177

5.3.5 Biological Activity Testing ................................................................................... 180


5.5 Future Work ................................................................................................................. 181

5.6 References .................................................................................................................... 182

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List of Tables

Table 2-1. Summary of the MW and PDI of styrene polymerization initiated with Vazo® 88 and mediated with 1,5-dimethyl-3-phenyl-6-oxoverdazyl radical 16. .......................................... 76

Table 2-2. Summary of the MW and PDI of a styrene polymerization initiated with BPO and mediated with 1,3,5-triphenyl-6-oxoverdazyl radical 17. ............................................................. 77

Table 2-3. Summary of the MW and PDI of styrene polymerization initiated with the benzoyl-styrene-1,3,5-triphenyl-6-oxoverdazyl radical adduct BSV 18. ................................................... 79

Table 2-4. Summary of the MW and PDI of styrene polymerization initiated with the benzoyl-styrene-1,5-dimethyl-3-phenyl-6-oxoverdazyl radical adduct BSV 19. ....................................... 82

Table 2-5. Summary of the MW and PDI of n-butyl acrylate polymerization initiated with the benzoyl-styrene-1,5-dimethyl-3-phenyl-6-oxoverdazyl radical adduct BSV 19. ......................... 85

Table 2-6. Summary of the MW and PDI of styrene polymerization initiated with the benzoyl-styrene-1,5-dimethyl-3-(p-CN-phenyl)-6-oxoverdazyl radical adduct BSV 23. .......................... 91

Table 2-7. Summary of the MW and PDI of n-butyl acrylate polymerization initiated with the benzoyl-styrene-1,5-dimethyl-3-(p-CN-phenyl)-6-oxoverdazyl radical adduct BSV 23. ............ 92

Table 2-8. Summary of the MW and PDI of n-butyl acrylate polymerization initiated with the benzoyl-styrene-1,5-dimethyl-3-(methylimidazole)-6-oxoverdazyl radical adduct BSV 24. ...... 93

Table 2-9. Summary of the MW and PDI of styrene polymerization initiated with the benzoyl-styrene-1,5-dimethyl-3-hydrogen-6-oxoverdazyl radical adduct BSV 22. ................................... 95

Table 2-10. Summary of the MW and PDI of n-butyl acrylate polymerization initiated with the benzoyl-styrene-1,5-dimethyl-3-hydrogen-6-oxoverdazyl radical adduct BSV 22. ..................... 96

Table 3-1. Cycloaddition reactions of 1,5-dimethyl-3-phenyl-6-oxoverdazyl 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. X-ray structures of a non-planar 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 Addition-Fragmentation chain Transfer (RAFT) agent. ............................... 17

Figure 1-7. General structure of a nitroxide radical and TEMPO. ............................................. 19

Figure 1-8. Comparison of bond strength between TEMPO-terminated styrene (kd = 5.2 x 10-4

s-1) and TEMPO-terminated acrylate (kd = 3.4 x 10-5 s-1). ............................................................ 22

Figure 1-9. TIPNO and SG1 nitroxides. ..................................................................................... 25

Figure 1-10. 1,1-Diadamantyl nitroxide. .................................................................................... 26

Figure 1-11. Triazolinyl radical and its spiro- derivative. .......................................................... 29

Figure 1-12. Styrene-triphenylverdazyl bond. ............................................................................ 32

Figure 1-13. Examples of 1,3-dipoles. ........................................................................................ 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 1,5-dimethyl-3-phenyl-6-oxoverdazyl radical 16 (solid-3h, dashed-5h, dotted-6h). .................... 76

Figure 2-2. GPC plot of a styrene polymerization initiated with BPO and mediated with 1,3,5-triphenyl-6-oxoverdazyl radical 17 (solid-1h, dashed-2h). ........................................................... 78

Figure 2-3. GPC of styrene polymerization initiated with the benzoyl-styrene-1,3,5-triphenyl-6-oxoverdazyl radical adduct BSV 18 (solid-0.5h, dashed-1.5h, dotted-4h, dash/dotted-6h). ........ 80

Figure 2-4. GPC of styrene polymerization initiated with the benzoyl-styrene-1,5-dimethyl-3-phenyl-6-oxoverdazyl radical adduct BSV 19 (solid-1h, dashed-2h, dotted-3h, dash/dotted-4h, dashed/2dotted-5h). ....................................................................................................................... 83

xiv

Figure 2-5. GPC of an n-butyl acrylate polymerization initiated with the benzoyl-styrene-1,5-dimethyl-3-phenyl-6-oxoverdazyl radical adduct BSV 19 (solid-2.5h, dashed-5.5h, dotted-8.5h, dash/dotted-12h, dashed/2dotted-18h, dashed-28h). .................................................................... 86

Figure 2-6. Custom-designed sealed tube to prevent monomer evaporation. ............................. 88

Figure 2-7. GPC plot of polystyrene-b-(n-butyl 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(n-butyl acrylate)-b-styrene 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 1,5-dimethyl-6-oxoverdazyl radical moieties in the corresponding BSV unimolecular initiators. ....................................................................... 91

Figure 2-10. GPC of styrene polymerization initiated with the benzoyl-styrene-1,5-dimethyl-3-(p-CN-phenyl)-6-oxoverdazyl radical adduct BSV 23 (solid-1h, dashed-2h, dotted-3h, dash/dotted-10h). .......................................................................................................................... 92

Figure 2-11. GPC of n-butyl acrylate polymerization initiated with the benzoyl-styrene-1,5-dimethyl-3-(p-CN-phenyl)-6-oxoverdazyl radical adduct BSV 23 (solid-1h, dashed-2h, dotted-4h, dash/dotted-6h, dashed/2dotted-24h). ........................................................................................... 93

Figure 2-12. GPC of n-butyl acrylate polymerization initiated with the benzoyl-styrene-1,5-dimethyl-3-(methylimidazole)-6-oxoverdazyl radical adduct BSV 23 (solid-1h, dashed-2h, dotted-3h, dash/dotted-4h, dashed/2dotted-5h). ............................................................................ 94

Figure 2-13. GPC plot of styrene polymerization initiated with the benzoyl-styrene-1,5-dimethyl-3-hydrogen-6-oxoverdazyl radical adduct BSV 22 (solid-1h, dashed-2h, dotted-3h, dash/dotted-5h, dashed/2dotted-7h). ............................................................................................. 96

Figure 2-14. GPC of n-butyl acrylate polymerization initiated with the benzoyl-styrene-1,5-dimethyl-3-hydrogen-6-oxoverdazyl radical adduct BSV 22 (solid-1h, dashed-2h, dotted-4h, dash/dotted-8h). ............................................................................................................................ 97

Figure 2-15. 1,5-Dimethyl-3-phenylverdazyl 31. ..................................................................... 101

Figure 3-1. Expected trapped products from diradical mechanism; not observed. ................... 118

Figure 3-2. Structural similarities between 1,5-dimethyl-3-phenyl-6-oxoverdazyl 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

xv

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: yellow-high; blue-low). ..................................................................................................................................... 127

Figure 3-8. Reactions between verdazyl radicals containing electron-withdrawing (para-cyanophenyl, para-fluoro) substituents with electron-rich dipolarophiles (pyrrolidino-1-cyclopentene and 1-morpholinocyclohexene). ........................................................................... 128

Figure 3-9. Verdazyl radicals bearing 3-pentafluorophenyl- and 1,5-dibenzyl- substituents. .. 130

Figure 4-1. Captodative olefins E-2-methylthio-phenylacrylonitrile 61, α-acetoxyacrylonitrile 62, and methyl α-acetoxy acrylate (MAA) 63. ........................................................................... 143

Figure 4-2. Cycloadducts bearing an acidic hydrogen α- to electron-poor phenyl rings. ........ 159

Figure 5-1. Compound 50, synthesized from 1,5-dimethyl-3-phenyl-6-oxoverdazyl radical 16 and fumaronitrile. ........................................................................................................................ 163

Figure 5-2. First generation DOS library of verdazyl-derived heterocycles; verdazyl-initiated cycloadducts. ............................................................................................................................... 177

Figure 5-3. Second generation DOS library of verdazyl-derived heterocycles; rearrangement products of verdazyl-derived cycloadducts. ............................................................................... 178

Figure 5-4. Third generation DOS library of verdazyl-derived heterocycles; amido-derivatives from reduction of nitrile-containing verdazyl-derived heterocycles. ......................................... 179

Figure 5-5. Dose response curve of compound 50 for acute myeloid leukemia (AML) and multiple myeloma (LP) cell lines. ............................................................................................... 180

xvi

List of Schemes

Scheme 1-1. Formazan alkylation attempt; synthesis of triarylverdazyl radicals. ........................ 3

Scheme 1-2. Synthesis of 6-oxotetrazinones. ................................................................................ 3

Scheme 1-3. Oxidation of tetrazinones through the intermediacy of leucoverdazyl..................... 4

Scheme 1-4. Formation of undesired bis-hydrazide. ..................................................................... 4

Scheme 1-5. Synthesis of 1,3,5-triaryl-6-oxotetrazinones. ........................................................... 5

Scheme 1-6. Synthesis of 6-phosphaverdazyls. ............................................................................ 6

Scheme 1-7. Synthesis of 3-phosphaverdazyl radicals. ................................................................. 6

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

Scheme 1-9. Synthesis of 1,5-diisopropyl-6-oxoverdazyl radicals. .............................................. 7

Scheme 1-10. Decomposition products of triphenylverdazyl radical. .......................................... 8

Scheme 1-11. Dimerization of 1,5-dimethyl-3-phenyl-6-oxoverdazyl 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 Addition-Fragmentation chain Transfer (RAFT) process. ................. 18

Scheme 1-18. BPO-initiated styrene polymerization. ................................................................. 20

Scheme 1-19. BST-initiated styrene polymerization. .................................................................. 20

Scheme 1-20. TEMPO-mediated 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. Base-catalyzed enolization of α-hydroxycarbonyl compounds to the corresponding ene-diol; used as a reducing agent for nitroxides. ................................................. 24

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

xvii

Scheme 1-25. Irreversible decomposition of nitroxides bearing α-hydrogen (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. Triphenylverdazyl-mediated SFRP system. ......................................................... 31

Scheme 1-30. Hydrogen abstraction of triphenylverdazyl from a polymethacrylate radical forming leucoverdazyl 11. ............................................................................................................ 32

Scheme 1-31. 1,3-Dipolar 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 3-pyrazolidone and carbonyl compounds. ....... 39

Scheme 1-34. An azomethine imine reported by Oppolzer. ....................................................... 40

Scheme 1-35. An azomethine imine designed to undergo intramolecular 1,3-dipolar 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 1,3-dipolar cycloaddition with alkenes. .......................................................................................................................................... 40

Scheme 1-38. A sugar-derived chiral azomethine imine. ............................................................ 41

Scheme 1-39. Zirconium-catalyzed formation and 1,3-dipolar cycloaddition of an azomethine imine. ............................................................................................................................................ 42

Scheme 1-40. Copper-catalyzed formation and 1,3-dipolar 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 15N-label 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

xviii

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

Scheme 1-49. The Dimroth rearrangement reactions of 6-amino-4-oxopyrano[3,4-d] [1,2,3]thiadiazoles to 6-hydroxy-4-oxo-[1,2,3]thiadiazolo[4,5-c]pyridines. ................................ 49

Scheme 1-50. Nucleophile-assisted vs. heat-assisted 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 with1,3-dipolar cycloadditions involving azomethine ylides. ......................................................................................................................... 53

Scheme 2-1. Methyl methacrylate polymerization initiated with the triphenylverdazyl-AIBN adduct 10 at 60 ºC. ........................................................................................................................ 64

Scheme 2-2. Styrene polymerizations initiated with the triphenylverdazyl-AIBN adduct 10 at 110 ºC. ........................................................................................................................................... 64

Scheme 2-3. Unimolecular initiator exchange reaction between BST and 1,3,5-triphenyl-6-oxoverdazyl radical 17. ................................................................................................................. 79

Scheme 2-4. Synthesis of 1,5-dimethyl-3-phenyl-6-oxoverdazyl radical 16. ............................. 81

Scheme 2-5. Synthesis of the unimolecular initiator 19 via exchange reaction between BST and 1,5-dimethyl-3-phenyl-6-oxoverdazyl radical 16 with ascorbic acid. .......................................... 81

Scheme 2-6. Unimolecular initiator 19 synthesis from 1,5-dimethyl-3-phenyl-6-oxoverdazyl 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. n-Butyl acrylate polymerization initiated with the unimolecular initiator 19; isolation of 21. .............................................................................................................................. 88

Scheme 2-9. Hydrogen-abstraction mechanism of 1,5-dimethyl-6-oxoverdazyl; oxidation of resulting leucoverdazyl 25 by atmospheric oxygen. ..................................................................... 98

Scheme 2-10. Attempted synthesis of 1,5-dimethyl-3-(2,6-dimethylphenyl)-6-oxoverdazyl radical 28 yielding bis(hydrazone) 29. .......................................................................................... 99

Scheme 2-11. Synthesis of 1,5-dibenzyl-3-phenyl-6-oxoverdazyl radical 30. ......................... 100

Scheme 2-12. Proposed syntheses of 32, the precursor to verdazyl radical 31, or 33, the protected analogue of 32. ............................................................................................................ 101

xix

Scheme 2-13. Synthesis of 6-phosphaverdazyl 35. ................................................................... 102

Scheme 2-14. ATRA and nucleophilic substitution syntheses of styrene-6-phosphaverdazyl unimolecular initiator 36 with (1-bromoethyl)benzene and 6-phospha-leucoverdazyl 34 or 6-phosphaverdazyl radical 35. ........................................................................................................ 102

Scheme 3-1. Synthesis of unimolecular initiator 19 with 1,5-dimethyl-3-phenyl-6-oxoverdazyl radical 16, styrene, and BPO; 20 recovered as major product. ................................................... 115

Scheme 3-2. Formation of 20 with 1,5-dimethyl-3-phenyl-6-oxoverdazyl radical 16 without BPO. ............................................................................................................................................ 117

Scheme 3-3. Postulated diradical mechanism for the formation of 20 with 1,5-dimethyl-3-phenyl-6-oxoverdazyl radical 16 and styrene. ............................................................................ 117

Scheme 3-4. Postulated single electron transfer mechanism of 1,5-dimethyl-3-phenyl-6-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-dimethyl-3-phenyl-6-oxoverdazyl 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-dimethyl-3-phenyl-6-oxoverdazyl radical 16 and methyl methacrylate. .................................... 121

Scheme 4-1. Reaction between 1,5-dimethyl-3-phenyl-6-oxoverdazyl radical 16 and 1-chloroacrylonitrile. ...................................................................................................................... 141

Scheme 4-2. Mechanism for the formation of 58, the radical addition/trapping product between 1,5-dimethyl-3-phenyl-6-oxoverdazyl radical 16 and 1-chloroacrylonitrile. ............................. 142

Scheme 4-3. Reaction between TEMPO and 1-chloroacrylonitrile. ......................................... 143

Scheme 4-4. Reaction between 1,5-dimethyl-3-phenyl-6-oxoverdazyl radical 16 and α-acetoxyacrylonitrile. .................................................................................................................... 143

Scheme 4-5. Reaction between 1,5-dimethyl-3-phenyl-6-oxoverdazyl radical 16 and MAA. 144

Scheme 4-6. Postulated cycloaddition reaction between 1,5-dimethyl-3-phenyl-6-oxoverdazyl 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 1,5-dimethyl-3-phenyl-6-oxoverdazyl radical 16 and methyl propiolate. ................................................................................................................................... 146

Scheme 4-10. Treatment of methyl acrylate cycloadduct 21 with heat. ................................... 147

Scheme 4-11. Sodium hydride-induced rearrangement of 21 to 70. ......................................... 147

Scheme 4-12. Loss of methyl ester from 21 and 70 from treatment with sodium hydride. ...... 148

xx

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 verdazyl-initiated cycloaddition and rearrangement. .... 162

Scheme 5-2. Reduction and subsequent amidation of a nitrile functionality. ........................... 163

Scheme 5-3. Cycloadducts derived from various 1,5-dimethyl-6-oxoverdazyl radicals and dipolarophiles bearing nitriles and acidic α-protons. ................................................................. 174

Scheme 5-4. Base and nucleophile-induced rearrangements of verdazyl-derived cycloadducts to pyrazolotriazinones and triazoles. ............................................................................................... 175

xxi

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 t-Boc protection of nitrile reduction and subsequent amidation. .............. 176

Scheme 5-8. 1,5-Dibenzyl-3-phenyl-6-oxoverdazyl radical undergoing 1,3-dipolar 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 acrylonitrile-derived cycloadducts with amines. ..................................................................................................................................................... 182

xxii

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 1-Benzoyloxy-2-phenyl-2-(2’,2’,6’,6’-tetramethyl-1’-piperidinyloxy)ethane

BSV 1-Benzoyloxy-2-phenyl-2-(6-oxoverdazyl)ethane

DCC Dynamic combinatorial chemistry

de

DFT

Diastereomeric excess

Density functional theory

DMF Dimethyl formamide

DMSO Dimethyl sulfoxide

DOS Diversity-oriented 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

xxiii

K Kelvin

K Equilibrium constant for the SFRP system

kc Rate constant for the cross-coupling reaction between the persistent and transient radical

kd Rate constant for the bond dissociation reaction for the SFRP process

ki

kp

L

Rate constant for the initiator bond dissociation reaction

Rate constant for the polymerization process

Ligand

LDA Lithium diisopropylamide

LUMO Lowest unoccupied molecular orbital

MAA Methyl α-acetoxy 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

xxiv

SG1 N-tert-Butyl-N-[1-diethylphosphono-(2,2-dimethylpropyl)]nitroxide

t Time

TEMPO 2,2,6,6-Tetramethyl-1-piperidinyloxy

THF Tetrahydrofuran

TIPNO 2,2,5-Tri-methyl-4-phenyl-3-azahexane-3-nitroxide

TLC Thin layer chromatography

Vazo® 88 1,1’-Azobis(cyclohexanecarbonitrile)

MW Molecular weight

X· Persistent radical

1

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 six-membered ring containing four

nitrogen atoms at the 1, 2, 4, 5 positions (Figure 1-1).1 The radical, which resides in π orbitals, is

stabilized by the delocalization of the spin density over the four nitrogen atoms2-5 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

2

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 non-planar (Figure 1-2).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. X-ray structures of a non-planar 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 1-1).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.

3

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 6-oxo and 6-thioxoverdazyl radicals were reported.19 Alkyl

(mainly methyl- and benzyl-) hydrazines were reacted with phosgene or thiophosgene to form

the bis-alkylhydrazides of carbonic acid or thiocarbonic acid, respectively, which were readily

isolated as white solids. These bis-alkylhydrazide 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 1-2).

Scheme 1-2. Synthesis of 6-oxotetrazinones.

Tetrazinones, the precursors to the 6-oxoverdazyl 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

4

intermediate, the leucoverdazyl, which is readily oxidized by atmospheric oxygen and therefore

virtually impossible to isolate (Scheme 1-3).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 1-4).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 bis-alkylhydrazide intermediate

is now part of the standard syntheses of 6-oxo- and 6-thioxoverdazyl radicals.

Scheme 1-4. Formation of undesired bis-hydrazide.

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

In 1994, Milcent et al. published the synthesis of 1,3,5-triaryl-6-oxoverdazyl radicals

(Scheme 1-5).8 It was demonstrated that the undesired chemoselectivity of arylhydrazines could

5

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 1-5). This synthetic route

provides easy access to 1,3,5- symmetric and asymmetric triaryl-6-oxoverdazyl radicals.

Scheme 1-5. Synthesis of 1,3,5-triaryl-6-oxotetrazinones.

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 1-6). Alternatively, starting with the bis(1-methylhydrazide) 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 1-7). In contrast to the

6

leucoverdazyl form of the 6-oxoverdazyl radicals, which is readily oxidized by oxygen, the

leucoverdazyl form of the phosphaverdazyls is inert to atmospheric oxygen.

Scheme 1-6. Synthesis of 6-phosphaverdazyls.22

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

In addition to introducing phosphorus into verdazyl radicals, Hicks et al. also

incorporated boron to produce borataverdazyl radical salts (Scheme 1-8).24

Scheme 1-8. Synthesis of 6-borataverdazyl 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 1-9).21 t-Butylcarbazate, 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

7

protected with a tert-butoxycarbonyl (t-Boc) protecting group, nullifying its nucleophilicity.25

Nucleophilic substitution reactions of these protected alkylhydrazines with phosgene followed by

removal of the t-Boc protecting group with acid gave the corresponding bis(1-alkylhydrazides)

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 1,5-diisopropyl-6-oxoverdazyl 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

8

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

In 1988, 1,5-dimethyl-3-phenyl-6-oxoverdazyl was reported to dimerize when treated

with formic acid (Scheme 1-11).26 However, only a low yield of 8% was observed after 48 hours.

Scheme 1-11. Dimerization of 1,5-dimethyl-3-phenyl-6-oxoverdazyl 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

end-group analysis.28 In 1994, Yamada et al. attempted to exploit verdazyl radicals as mediating

9

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 transition-metal 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.30-33

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, 1,3-dipolar cycloadditions,

heterocyclic rearrangements, and diversity-oriented 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.34-36 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

10

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 1-12). 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. α-Methylstyrene polymerizations predominantly

undergo disproportionation termination reactions.35

11

I I 2 I

M

Pn

Initiation Propagation

PnPm + dead chains

Termination

R Rm RRn

R R

R R

m

n

Termination by coupling

Termination by disproportionation

R Rm RR

n

R

H

R Rm

RRR

n+H

MIM

Scheme 1-12. Conventional radical polymerization process.

Although conventional radical polymerization is one of the most used processes

industrially, it is not without limitations. Well-defined 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 1-3).

12

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 1,3-butadiene 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 1-4); 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.

13

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 1-13) or

degenerative transference (Scheme 1-14) of the active propagating species.

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

14

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 Addition-Fragmentation chain Transfer (RAFT, 1998).45 Examples of

other notable living radical polymerization systems are degenerative transfer polymerization with

alkyl iodides,46,47 cobalt-mediated radical polymerization,48-50 organotellurium-mediated radical

polymerization,51,52 organostibine-mediated radical polymerization53 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

15

60 ºC in the presence of a ruthenium catalyst.43 This process utilizes the reversible redox reaction

of RuII, which in the presence of an alkyl halide, is oxidized to RuIII. At the same time, the alkyl

halide undergoes homolytic cleavage of the C-X 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 1-15).

R X CuILn

R

CuIIXLn

Initiation

Addition

R' RR'

RR'

X

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

Pn-X. An equilibrium between the active and the dormant species is established to keep this

process going (Scheme 1-16).

16

R X CuILn

R

CuIIXLn

Pn

Pn X

M

Pn

M

CuILn

CuIIXLn

Initiation

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 Nitrogen-based 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 1-5).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 copper-based.59

17

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 1-6, Scheme 1-17).

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

18

Scheme 1-17. Reversible Addition-Fragmentation 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 Pm•. 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.

19

1.2.2.3 Stable Free Radical Polymerization (SFRP)

The field of stable free radical polymerization has flourished since Georges’

demonstration of 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO)-mediated styrene

polymerization. TEMPO, 2, (Figure 1-7) 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 1-18).41 Alternatively, nitroxide-derived unimolecular initiators, referred to as

alkoxyamines, such as benzoyl styryl TEMPO (BST) 3 can be employed (Scheme 1-19).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 125-135 ºC, as compared to a conventional radical

polymerization which typically runs between 60-95 ºC. The need for the high temperature is

two-fold – 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.

20

Scheme 1-18. BPO-initiated styrene polymerization.

Scheme 1-19. BST-initiated 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 step-wise monomer addition and minimal termination (Scheme 1-20). At

equilibrium, the typical concentration of the dormant propagating chain [P-X] 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

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

recombination kc is between 106 and 108 M-1s-1.63 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.

21

Ph O

O

O Ph

O

Ph O

O2

Ph O

O

Ph

Ph O

O

Ph

N

O

ON

Ph O

O

Ph

NO

Ph

+

Ph O

O

Ph Ph

ON Ph

Ph O

O

Ph Ph

ON

n

BST

Initiation

Propagation / Reversible termination

Ph

Ph O

O

Ph

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

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

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

1-1). 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

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

of 5.2 x 10-4 s-1 and kc value of 2.8 x 108 M-1s-1 (values based on small molecule alkoxyamine

model compounds at 393 K).63,65,66

Equation 1-1. Equilibrium constants and concentrations.

22

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

nearly 10-fold lower homolytic dissociation rate constant kd (3.4 x 10-5 s-1 in comparison to that

of styrene, 5.2 x 10-4 s-1)65 of the C-ON bond between TEMPO and the acrylate unit, bond

cleavage does not occur to any large extent to allow propagation (Figure 1-8).65,67,68

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

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 TEMPO-mediated styrene polymerizations can be explained by the

Mayo reaction, an auto-initiation reaction of styrene (Scheme1-21).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

23

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

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

of styrene and n-butyl acrylate.72 If the strong acrylate-TEMPO bond resulting from the low kd

value was the only reason that inhibits TEMPO-mediated 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 TEMPO-mediated living radical polymerization of n-butyl 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 1-22)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.

24

Owing to the intrinsic inefficiency and impracticality of the continuous ascorbic acid

addition method, Georges et al. further improved upon the TEMPO-mediated acrylate

polymerization system with the ab-initio addition of α-hydroxycarbonyl compounds with base.74

The α-hydroxycarbonyl functionality undergoes enolization, catalyzed by base, to give the ene-

diol form of the compound (Scheme 1-23), which then reduces TEMPO in a similar manner to

ascorbic acid.

Scheme 1-23. Base-catalyzed enolization of α-hydroxycarbonyl compounds to the corresponding ene-diol; used as a reducing agent for nitroxides.

Various α-hydroxycarbonyl compounds (benzoin, anisoin, 3-hydroxy-2-butanone, 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 n-butyl acrylate, a 63% monomer conversion was achieved in 3

hours with a final molecular weight of 26,400 g mol-1 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

25

library of nitroxides, the two notable nitroxides with good success in acrylate polymerizations

are 2,2,5-trimethyl-4-phenyl-3-azahexane-3-nitroxide (TIPNO) 4 and N-tert-butyl-N-[1-

diethylphosphono-(2,2-dimethylpropyl)]nitroxide (SG1) 5 (Figure 1-9).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

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

2006, Braslau et al. published a piece of key evidence detailing a decomposition reaction of

nitroxides bearing an α-hydrogen, a feature shared by TIPNO and SG1, at elevated temperatures

(~120 ºC) (Scheme 1-25).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.

26

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

To further argue against a low kd value being the culprit in hindering TEMPO-mediated

acrylate polymerizations, Georges et al. prepared a severely sterically hindered nitroxide, the

1,1-diadamantyl nitroxide 6 (Figure 1-10),77 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. 1,1-Diadamantyl nitroxide.

Styrene polymerizations were successful with the 1,1-diadamantyl 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

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

27

hours with n-butyl 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 ene-diols, 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, di-tert amyl peroxide,

a high temperature initiator, was employed to provide a successful polymerization of n-butyl

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 radicals79 and triazolinyl radicals80-82 have been shown to mediate

living radical polymerizations with different degrees of success. Of these candidates, the

triazolinyl radical, a family of nitrogen-centered 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 1,3,5,6,6-pentaphenylleucoverdazyl was treated with formic acid.83 Ring contraction gave

28

the nitrogen centered stable free radical, which contains the 1,2,4-triazoline backbone, in 17%

yield (Scheme 1-26).

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

Alternative synthetic routes to the triazoline (Scheme 1-27), 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 living-radical

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

29

reaction would be two-fold; 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 1-11) was designed to decompose at 130 ºC to generate the

phenyl radical along with 1,3,5-triphenyl-1H-1,2,4-triazole. The driving force for this

decomposition reaction is the aromatization of the triazole backbone (Scheme 1-28).

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 TEMPO-mediated

polymerization systems.

The two triazolinyl radicals were used as mediators in styrene81 and MMA80

polymerizations initiated by BPO. Styrene polymerizations mediated by the spirotriazolinyl

radical 8 at 140 ºC showed similar behaviour to that of TEMPO-mediated polymerizations with

30

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 auto-initiation 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 auto-initiation 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 60-80% of the chains were terminated with triazolinyl moieties,

which indicated that up to 40% irreversible termination reactions had occurred.

31

1.2.3.2 Stable Free Radical Polymerizations Mediated by Verdazyl Radicals

As introduced previously, verdazyl radicals are another family of nitrogen-centered stable

free radicals. Shortly after Georges et al.41 reported the TEMPO-mediated 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 1-29).

Scheme 1-29. Triphenylverdazyl-mediated SFRP system.28

For the triphenylverdazyl-mediated 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 1-30).

32

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 styryl-verdazyl C-N bond does not dissociate to allow monomer addition

(Figure 1-12).

Figure 1-12. Styrene-triphenylverdazyl bond.

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

(110 ºC) with the same AIBN-derived 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

33

(>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 1-10)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 living-radical 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 living-radical 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 n-butyl acrylate can be achieved with the appropriate choice of verdazyl radical.

34

1.3 1,3-Dipolar Cycloadditions Involving Azomethine Imines

1.3.1 Introduction to 1,3-Dipolar Cycloadditions85-87

The 1,3-dipolar cycloaddition reaction, as the name suggests, involves the cycloaddition

reaction between a 1,3-dipole (shown in the zwitterion form of a three-atom molecule) (Figure 1-

13) and a dipolarophile (a dienophile equivalent) to form a five-membered ring. The 1,3-dipolar

cycloaddition reaction is classified as a [3+2] cycloaddition for the number of atoms in the

participating molecules. In contrast to the Diels-Alder [4+2] cycloaddition reaction where the

diene almost invariably acts as the nucleophile, the dipoles used in 1,3-dipolar cycloaddition

reactions are able to act as either the nucleophile or the electrophile, depending upon their

substituents and the dipolarophiles used. 1,3-Dipoles 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 1,3-dipolar cycloaddition reaction is one of the most prevalent methods of

synthesizing heterocyclic compounds. Even though the 1,3-dipole 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 1,3-dipoles.

35

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

(MO) interactions of the reactants as stated by Woodward and Hoffmann.88-90 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 1,3-dipolar

cycloaddition, reactions. First, FMO signs between the reactants must match in a symmetry-

allowed fashion for the reaction to occur (Figure 1-14). 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 1-15). 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 1-14).

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

36

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. Electron-rich substituents, such as alkoxy or amino groups, raise both the HOMO

and the LUMO energy levels; electron-withdrawing 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 electron-rich dipole using its high energy HOMO to

interact with the low energy LUMO of an electron-poor dipolarophile. This HOMO/LUMO

interaction is considered the “regular” cycloaddition, as most 1,3-dipoles – nitrilimines,96

nitrones,97 diazoalkanes,98 azides,99 and sydnones100 – follow this pattern. A reaction that occurs

with this particular set of MO interaction is sometimes referred to as a dipole-HO controlled

reaction. Electron-rich 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 azide99,101 and more recently, phthalazinium

37

dicyanomethanide102,103 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

electron-rich 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 1-16).

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

The regioselectivity of an asymmetric 1,3-dipolar 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 Dipoles85-87

Azomethine imines are a class of 1,3-dipoles containing one carbon and two nitrogen

atoms. They are isoelectronic to an allyl anion and as such, have corresponding resonance

structures (Figure 1-17). Even though some of the resonance structures represent the charges on

38

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

Furthermore, like most 1,3-dipoles, 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] 1,3-dipolar cycloaddition reactions with a range of

dipolarophiles, usually in high yields with good stereoselectivity, to yield saturated or

unsaturated heterocyclic structures (Scheme 1-31).

Scheme 1-31. 1,3-Dipolar 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 1-32).

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

39

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 1-18).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 3-pyrazolidone and carbonyl compounds (Scheme 1-33).108,109

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

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

(Scheme 1-34).110,111 This azomethine imine was generated in situ with a dipolarophile

incorporated in the same molecule designed to undergo an intramolecular 1,3-dipolar

cycloaddition reaction to form a fused heterocyclic structure (Scheme 1-35).111

40

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

Scheme 1-35. An azomethine imine designed to undergo intramolecular 1,3-dipolar 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 1-36).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 alkenes113 and alkynes.114 Decarboxylation reactions of

sydnone cycloadducts derived from alkenes and alkynes are facile and yield pyrazolines and

pyrazoles, respectively (Scheme 1-37).

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

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

41

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 near-pure (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

pentabenzoyl-D-glucose and its corresponding cycloadduct with methyl acrylate (Scheme 1-38).

Scheme 1-38. A sugar-derived 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 1,3-dipolar cycloaddition reactions with azomethine imines by the addition of a

chiral zirconium/BINOL complex.116 Reported yields typically ranged from 60-100%, with

>90% ee, depending on the catalyst used. The built-in intramolecular dipolarophiles were of the

unactivated variety (alkenes) while the intermolecular dipolarophiles were of the electron-rich

variety (vinyl ethers, vinyl thioethers). The fact that no electron-poor dipolarophiles were

42

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 1-39).

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

Fu et al.117 reported the first example of copper catalysis of 1,3-dipolar cycloaddition

reactions with azomethine imine. It was shown that in the presence of copper (I) and a P, N

ligand, phosphaferrocene-oxazoline, 94-99% yield and 81-96% ee could be achieved in

cycloaddition reactions of azomethine imines with methyl propiolate. (Scheme 1-40). 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.

43

Scheme 1-40. Copper-catalyzed formation and 1,3-dipolar 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 1,3-dipolar cycloaddition reaction from the corresponding azomethine

imine (Scheme 1-41). 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 1-42). 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 α-ketoester and a thiosemicarbazide. The cycloadduct was isolated and

subsequently converted to the final target.

44

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

More recently, Overman and Rohde121 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 1-43).

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


It is evident that azomethine imines are excellent precursors to nitrogen-containing

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 1,3-dipolar cycloaddition reaction as well as subsequent rearrangement reactions gave rise to

heterocycles containing a variety of scaffolds.

45

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.

Nitrogen-containing 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 fused-ring 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 well-documented 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 15N-label studies (Scheme 1-44) 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 1-45).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.

46

Scheme 1-44. The 15N-label 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 newly-introduced electron density from the

nucleophile. By the same token, ring fission can be more favourable if the resulting intermediate

is highly conjugated (Scheme 1-46).127

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

47

In 1971, Fujii et al.130,131 reported the first isolated intermediate of the Dimroth

rearrangement (Scheme 1-47). 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 re-cyclized 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 1-47).131,132 It is now well-documented 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

48

rearrangement rate. It is also agreed that the rate affected is that of the ring fission step of the

rearrangement. Both Brown133 and more recently Fujii128 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 1-alkyl-2-

alkyliminopyrimidines rearrangement reaction performed by Brown et al.,134,135 both the starting

material and the product were designed to be non-aromatic. 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 1-48), 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 Fabian136 reported the transformations of 6-amino-4-oxopyrano[3,4-d]

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

(Scheme 1-49).

49

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

Initially it was shown that the above-mentioned rearrangement reaction occurs with

morpholine or piperidine under heating conditions, classifying it as a typical nucleophile-assisted

ring fission Dimroth rearrangement (top of Scheme 1-50). However, the same results were

obtained from experiments performed in freshly purified and dry DMF under argon without

morpholine or piperidine, which ruled out nucleophile-assistance during the ring fission step.

The authors then proposed a new thermal ring fission mechanism involving a carbamoyl ketene

intermediate 15 (bottom of Scheme 1-50).

Scheme 1-50. Nucleophile-assisted vs. heat-assisted 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 24-34 kcal/mol and is spontaneous under

50

heating conditions. The authors also showed that the nucleophile-assisted ring fission is

5 kcal/mol less favourable than the heat-assisted ring fission. Therefore, it was concluded that

this particular example of the Dimroth rearrangement took place via a heat-assisted ring fission

pathway.


Even though the Dimroth rearrangement reaction is well-documented, 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 nucleophile-assisted 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 drug-like 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.

51

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

diversity-oriented 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 target-bound complex for characterization and structure-to-activity

relationship elucidation (Scheme 1-51, Scheme 1-52).

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

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

52

1.5.2 Diversity-Oriented Synthesis (DOS)

Contrasting the traditional target-oriented 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 1-53). 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 multi-component 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

53

orthogonal functionalities (Scheme 1-54). 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 1,3-dipolar cycloaddition reaction applicable to DOS

is shown below (Scheme 1-55).145 The use of the 1,3-dipolar cycloaddition reaction in DOS is

relevant to the work of this thesis.

Scheme 1-55. DOS library of compounds built with1,3-dipolar 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

54

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 two-fold. 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.

1.5 References

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(2) Glazer, R. L.; Poindexter, E. H. J. Chem. Phys. 1971, 55, 4548-4554.

(3) Mukai, K.; Yamamoto, T.; Kohno, M.; Azuma, N.; Ishizu, K. Bull. Chem. Soc. Jpn. 1974, 47, 1797-1798.

(4) Neugebauer, F. A.; Brunner, H. Tetrahedron 1974, 30, 2841-2850.

(5) Mukai, K.; Shikata, H.; Azuma, N.; Kuwata, K. J. Magn. Res. 1979, 35, 133-137.

(6) Kuhn, R.; Trischmann, H. Angew. Chem. Int. Ed. Engl. 1963, 2, 155-155.

(7) Kursmitteilung, F. A.; Neugebauer, F. A.; Fischer, H. Angew. Chem. Int. Ed. Engl. 1980, 19, 724-725.

(8) Milcent, R.; Barbier, G. J. Heterocycl. Chem. 1994, 31, 319-324.

(9) Griller, D.; Ingold, K. U. Acc. Chem. Res. 1976, 9, 13-19.

(10) Neugebauer, F. A. Angew. Chem. Int. Ed. Engl. 1973, 12, 455-464.

55

(11) Williams, D. E. Acta Cryst. B 1973, 29, 96-103.

(12) Neugebauer, F. A.; Fischer, H.; Krieger, C. J. Chem. Soc. Perkin Trans. 2 1993, 2, 535-544.

(13) Otsu, T.; Yamada, B.; Ishikawa, T. Macromolecules 1991, 24, 415-419.

(14) Yamada, B.; Kageoka, M.; Otsu, T. Macromolecules 1991, 24, 5234-5236.

(15) Brook, D. J. R.; Lynch, V.; Conklin, B.; Fox, M. A. J. Am. Chem. Soc. 1997, 119, 5515-5162.

(16) Chen, E. K. Y.; Teertstra, S. J.; Chan-Seng, D.; Otieno, P. O.; Hicks, R. G.; Georges, M. K. Macromolecules 2007, 40, 8609-8616.

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

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(18) Chapter 4 of this thesis.

(19) Neugebauer, F. A.; Fischer, H.; Siegel, R.; Krieger, C. Chem. Ber. 1983, 116, 3461-3481.

(20) The leucoverdazyl precursors of phosphorus-containing verdazyl radicals are unique in their stability under atmospheric oxygen.

(21) Pare, E. C.; Brook, D. J.; Brieger, A.; Badik, M.; Schinke, M. Org. Biomol. Chem. 2005, 3, 4258-4261.

(22) Hicks, R. G.; Hooper, R. Inorg. Chem. 1999, 38, 284-286.

(23) Majoral, J. P.; Kraemer, R.; Navech, J.; Mathis, F. Tetrahedron 1976, 32, 2633-2644.

(24) Gilroy, J. B.; Ferguson, M. J.; McDonald, R.; Patric, B. O.; Hicks, R. G. Chem. Commun.

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62

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 well-known; 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

63

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.7-12 Furthermore, various substituents are known to affect the stabilities, sterics and

three-dimensional 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 2-1) and styrene polymerizations, initiated with the unimolecular

initiator adduct 10 obtained through the reaction of AIBN and the 1,3,5-triphenylverdazyl 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 1-30).13 In the case of styrene polymerization,

no hydrogen abstraction was observed but the polymerizations still only gave low monomer

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

64

Scheme 2-1. Methyl methacrylate polymerization initiated with the triphenylverdazyl-AIBN 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 2-2), a temperature high enough for the

styryl-verdazyl bond to dissociate and allow propagation. However, the PDI values of the

resulting polystyrene were generally greater than 2 and end-group 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 triphenylverdazyl-AIBN 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

65

radical 9 to perform as desired did not provide sufficient evidence to rule out other verdazyl

radical derivatives. In this chapter, results from the verdazyl-mediated SFRP system using

various 6-oxoverdazyl radicals are provided and discussed. Successful living-radical

polymerizations are demonstrated for styrene and n-butyl acrylate monomers.15

2.2 Experimental Section

2.2.1 Materials and Equipment

All ACS grade reagents and solvents were purchased from Sigma-Aldrich, 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 n-butyl acrylate, respectively, by passing the monomers through a short column

packed with the appropriate inhibitor remover resin purchased from Sigma-Aldrich. The

inhibitor-free 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 40-63 µm)

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

Benzoyl-Styrene-TEMPO (BST) adduct was synthesized according to an unpublished procedure

66

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 INOVA-500 spectrometer at 20 ºC, operating at

500 MHz for 1H NMR and 125 MHz for 13C NMR in CDCl3 (Aldrich, 99.8% atom D) with

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

million (ppm) referenced to TMS (0 ppm) for 1H NMR spectra and CDCl3 (77.0 ppm) for 13C

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 70S-250 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 Perkin-Elmer

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

67

Waters model 410 differential refractometer (RI) detector and Styragel HR4 (7.8 x 300 mm,

effective MW range 5,000-600,000), HR2 (4.6 x 300 mm, effective MW range 500-20,000), and

HR1 (4.6 x 300 mm, effective MW range 100-5,000) columns calibrated with polystyrene

standards in the range Mn = 400-188,000 g mole-1. 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 1,5-dimethyl-3-phenyl-6-oxoverdazyl 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 1,3,5-triphenyl-6-oxoverdazyl radical 17

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

68

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 1,3,5-triphenyl-6-oxoverdazyl 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: 143-144 ºC). In solution 18 exists as

two conformers (C-N rotamers). 1H NMR (500 MHz, acetone-d6, 0 ºC), major conformer (92%)

δ: 6.92-8.27 (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: 6.92-8.27 (m, 25H), 5.00 (dd, J = 4.1, 10.3, 1H), 4.80

(dd, J = 10.3, 12.0, 1H), 4.52 (dd, J = 4.1, 12.0, 1H). 13C NMR (125 MHz, acetone-d6), major

conformer δ: 165.8, 152.8, 149.0, 120-144, 56.6, 62.3; minor conformer δ: 165.9, 152.9, 149.6,

120-144, 67.5, 63.7. Anal. Calcd for C35H28N4O3 (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-

triphenyl-6-oxoverdazyl-stabilized styrene (10 mL, 87 mmol) and unimolecular initiator 18 (100

mg, 0.18 mmol) was heated at 130 ºC for 6 h.

69

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:

97-98 ºC). The yield could be improved to 45% with the addition of 350 mg ascorbic acid. In

solution 19 exists as two conformers (C-N rotamers). 1H NMR (500 MHz, CDCl3, -20 ºC),

major conformer (78%), δ: 7.22-8.28 (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:

7.22-8.28 (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,

11.6, 1H), 3.05 (s, 3H), 2.71 (s, 3H). 13C NMR (125 MHz, CDCl3), major conformer δ: 166.1,

157.2, 147.2, 127-135, 64.3, 62.1, 40.4, 35.6; minor conformer δ: 166.0, 159.4, 149.2, 127-136,

63.8, 63.2, 40.0, 36.7. Anal. Calcd for C25H24N4O3 (428.48): C, 70.08; H, 5.65; N, 13.08. Found:

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


Using the same experimental procedure described in section 2.2.2, a solution of 1,5-

dimethyl-3-phenyl-6-oxoverdazyl-stabilized 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-

dimethyl-3-phenyl-6-oxoverdazyl-stabilized n-butyl acrylate (15 mL, 100 mmol) and

unimolecular initiator 19 (100 mg, 0.23 mmol) was heated at 130 ºC for 28 h.

70

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

a pale yellow oil. 1H NMR (500 MHz, CDCl3), δ: 7.44-7.38 (m, 2H), 7.45-7.28 (m, 2H), 7.26-

7.20 (m, 2H), 7.18-7.11 (m, 3H), 6.92-6.86 (m, 2H), 4.71 (dd, J = 4.9, 8.6, 1H), 4.37-4.30 (m,

1H), 3.64-3.57 (m, 1H), 3.19 (s, 3H), 2.58-2.49 (m, 1H), 2.22-2.14 (m, 1H). 13C NMR (125

MHz, CDCl3), 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 C18H19N4O [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 verdazyl-stabilized styrene (10 mL, 87 mmol) and 1,5-dimethyl-3-phenyl-

6-oxoverdazyl-terminated poly(n-butyl acrylate) (Mn = 6,250 g mol-1, PDI = 1.14, 1.42 g, 0.23

mmol), purified from three cycles of methanol precipitation, was degassed by argon for 1 h and

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

1.26.

71

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

Macroinitiator

A solution of verdazyl-stabilized n-butyl acrylate (15 mL, 110 mmol) and 1,5-dimethyl-

3-phenyl-6-oxoverdazyl-terminated polystyrene (Mn = 10,400 g mol-1 , PDI = 1.20, 2.50 g, 0.24

mmol), purified from three cycles of methanol precipitation, was degassed by argon for 1 h and

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



141-143 ºC). In solution 23 exists as two conformers (C-N rotamers). 1H NMR (500 MHz,

CDCl3, -20 ºC), major conformer (81%), δ: 8.20-8.10 (m, 2H), 8.00-7.93 (m, 2H), 7.76-7.71 (m,

1H), 7.65-7.58 (m, 2H), 7.56-7.53 (m, 2H), 7.40-7.38 (m, 3H), 7.23-7.19 (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: 8.00-7.93 (m, 2H), 7.89-7.86 (m, 2H), 7.74-7.70 (m, 2H), 7.69-7.65

(m, 1H), 7.54-7.50 (m, 2H), 7.46-7.42 (m, 3H), 7.42-7.38 (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). 13C NMR (100

MHz, CDCl3), 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 C26H23N5O3 (455.18): C,

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

72


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.



stabilized n-butyl 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)

The title compound was prepared using the same unimer exchange experimental



156-159 ºC). 1H NMR (400 MHz, CDCl3, 25 ºC), δ: 8.05-7.90 (d, J = 8.8, 2H), 7.60-7.30 (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,

6H). 13C NMR (100 MHz, CDCl3), 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 C23H24N6O3

M+, 432.1901; found, 432.1901.



stabilized n-butyl acrylate (10 mL, 70 mmol) and unimolecular initiator 24 (85 mg, 0.20 mmol)


73

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 1,5-Dimethyl-6-oxoverdazyl 26 (500 mg, 3.9

mmol), benzoic acid 2-bromo-2-phenyl-ethyl ester6 (1.07 g, 3.9 mmol), and

pentamethyldiethylenetriamine (120 mg, 0.70 mmol) were dissolved in 15 mL of toluene in a

three neck round-bottom 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 (Cu0)

(22 mg, 3.5 mmol) and CuBr2 (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

white crystalline solid (610 mg, 44%, mp: 102-104 ºC). 1H NMR (500 MHz, CDCl3, 20 ºC) δ:

7.34-8.06 (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

(s, 3H), 2.91 (s, 3H). 13C NMR (125 MHz, CDCl3) δ: 166.1, 156.9, 134.5, 128-138, 64.8, 62.8,

38.5, 36.2. Anal. Calcd for C19H20N4O3 (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 2,6-dimethylbenzaldehyde (1.10 g, 8.56 mmol) in 500 mL ethanol was

added to a solution of carbonic acid bis(1-methylhydrazide) (1.00 g, 8.56 mmol) in 150 mL

74

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(1-methylhydrazone)

(1.99 g, 67%). 1H NMR (500 MHz, CDCl3), δ: 7.89 (s, 2H), 7.11-7.06 (m, 2H), 7.01-6.97 (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

6-Phosphaverdazyl 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 (1-bromoethyl)benzene (250 mg, 1.4 mmol),

pentamethyldiethylenetriamine (40 mg, 1.7 mmol), copper powder (Cu0) (100 mg, 1.5 mmol),

CuBr2 (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: 135-137

ºC). 1H NMR (400 MHz, CDCl3, 25 ºC), δ: 7.84-7.67 (m, 3H), 7.59-7.50 (m, 2H), 7.50-7.41 (m,

3H), 7.41-6.14 (br, m, 7H), 4.40 (br, 1H), 3.31 (br, 3H), 3.00 (br, 3H), 1/03 (br, 3H). 13C NMR

(100 MHz, CDCl3), δ: 132.5, 132.4, 132.3, 132.2, 128.6-128.0, 59.8, 37.0, 36.9, 34.0, 20.4. Anal.

Calcd for C23H25N4OP (404.18): C, 68.30; H, 6.23; N, 13.85. Found: C, 68.21; H, 6.20; N, 14.00.

75

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

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

1,2,5,6-Tetrahydro-1,5-dimethyl-3,6-diphenyl-1,2,4,5,6-tetrazaphosphorine 6-oxide (6-

phospha-leucoverdazyl) 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. (1-Bromoethyl)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%).



stabilized n-butyl acrylate (6.5 mL, 50 mmol) and unimolecular initiator 36 (65 mg, 0.16 mmol)


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 2-1, Figure 2-1).18 Polymerizations with lower

76

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 1,5-dimethyl-3-phenyl-6-oxoverdazyl radical 16.18

Reaction time (h) Mn (g mol-1) MnTH (g mol-1) PDI Conversion (%)

3 1280 1700 1.5 6 5 15900 17900 1.5 63 6 18800 19600 1.4 69

MV

10.00

20.00

30.00

40.00

50.00

Minutes

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

Figure 2-1. GPC for the polymerization of styrene initiated with Vazo® 88 and mediated with 1,5-dimethyl-3-phenyl-6-oxoverdazyl radical 16 (solid-3h, dashed-5h, dotted-6h).

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

77

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 re-synthesize 16,

the polymerization-mediating 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 2-2,

Figure 2-2).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 2-2). 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 1,3,5-triphenyl-6-oxoverdazyl radical 17.18


1 24500 8700 1.67 23

78

2 23900 7900 1.72 21

MV

0.00

20.00

40.00

60.00

80.00

100.00

120.00

140.00

Minutes

22.00 24.00 26.00 28.00 30.00 32.00 34.00 36.00 38.00 40.00 42.00

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

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 2-3).15 The result was a near-

quantitative exchange of the terminating agents, which can be rationalized by the lower kd value

of the styryl-verdazyl bond (7.4 x 10-5 s-1, 393 K)19 compared to that of the styryl-TEMPO bond

(5.5 x 10-4 s-1, 393 K).20 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 2-3, Figure 2-3).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

79

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 1,3,5-triphenyl-6-oxoverdazyl radical 17.18

Table 2-3. Summary of the MW and PDI of styrene polymerization initiated with the benzoyl-styrene-1,3,5-triphenyl-6-oxoverdazyl radical adduct BSV 18.18


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

80

Figure 2-3. GPC of styrene polymerization initiated with the benzoyl-styrene-1,3,5-triphenyl-6-oxoverdazyl radical adduct BSV 18 (solid-0.5h, dashed-1.5h, dotted-4h, dash/dotted-6h).

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 2-4). 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 reduced21 (refer to

Scheme1-22) and thus shift the equilibrium towards BSV 19 (Scheme 2-5).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 BST-verdazyl exchange reaction, a yield improvement of 50% was

observed.

MV

0.00

20.00

40.00

60.00

80.00

100.00

120.00

140.00

Minutes 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

BSV

18

0.5 h

1.5 h

4 h

6 h

81

Scheme 2-4. Synthesis of 1,5-dimethyl-3-phenyl-6-oxoverdazyl radical 16.

Scheme 2-5. Synthesis of the unimolecular initiator 19 via exchange reaction between BST and 1,5-dimethyl-3-phenyl-6-oxoverdazyl radical 16 with ascorbic acid.

In contrast to the polymerizations mediated by 17, those mediated by 16 were well-

controlled (Table 2-4, Figure 2-4).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

82

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 s-1, 393 K vs. 2.6 x 10-3 s-1, 393 K, respectively).19 These results thus show that, as

hypothesized, there is a variation in the polymerization-mediating 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 benzoyl-styrene-1,5-dimethyl-3-phenyl-6-oxoverdazyl radical adduct BSV 19.15


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

83

MV

5.00

10.00

15.00

20.00

25.00

30.00

35.00

40.00

45.00

50.00

Minutes

28.00 30.00 32.00 34.00 36.00 38.00 40.00 42.00 44.00 46.00 48.00

Figure 2-4. GPC of styrene polymerization initiated with the benzoyl-styrene-1,5-dimethyl-3-phenyl-6-oxoverdazyl radical adduct BSV 19 (solid-1h, dashed-2h, dotted-3h, dash/dotted-4h, dashed/2dotted-5h).

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

n-Butyl acrylate polymerization was also demonstrated to proceed with living

characteristics when initiated with the verdazyl-derived unimolecular initiator BSV 19 (Table 2-5,

Figure 2-5).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 n-butyl acrylate polymerizations. First, the n-butyl 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 six-fold increase in

polymerization time was required for the n-butyl acrylate system. This can be accounted for by

comparing the kd values for the two polymerizations: the kd value of the acryloyl-verdazyl bond

(2.9 x 10-5 s-1, 393 K)19 is roughly two orders of magnitude lower than the styryl counterpart (2.6

x 10-3 s-1, 393 K).19 As a consequence, the verdazyl terminating agents required more energy to

dissociate from the chain ends which slowed down the n-butyl acrylate polymerization.

84

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 n-butyl acrylate polymerization over the first 18 hours (Figure 2-5), 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 2-4).

The third difference between the styrene and the n-butyl acrylate polymerizations is that

while the n-butyl 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

Section 1.2.2.4).22,23 While the low kd value for the acryloyl-verdazyl 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 28-hour polymer sample (Figure 2-5). 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

85

suppress the accumulation of terminating agents as described previously (see Scheme 1-21).24

Additives such as ascorbic acid are known to accelerate TEMPO-mediated acrylate

polymerizations by reducing the TEMPO concentration.22,23 A similar effect was also observed

when ascorbic acid was added to the verdazyl-mediated 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 n-butyl acrylate polymerization initiated with the benzoyl-styrene-1,5-dimethyl-3-phenyl-6-oxoverdazyl radical adduct BSV 19.15


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

86

MV

2.00

3.00

4.00

5.00

6.00

7.00

8.00

9.00

10.00

11.00

Minutes

28.00 30.00 32.00 34.00 36.00 38.00 40.00 42.00 44.00 46.00 48.00

Figure 2-5. GPC of an n-butyl acrylate polymerization initiated with the benzoyl-styrene-1,5-dimethyl-3-phenyl-6-oxoverdazyl radical adduct BSV 19 (solid-2.5h, dashed-5.5h, dotted-8.5h, dash/dotted-12h,

dashed/2dotted-18h, dashed-28h).

It is interesting to speculate why the polymerization of n-butyl 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

nitroxides such as TIPNO and SG1.2 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 2-6).26

87

Scheme 2-6. Unimolecular initiator 19 synthesis from 1,5-dimethyl-3-phenyl-6-oxoverdazyl 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 verdazyl-mediated styrene and n-butyl acrylate polymerization mixtures in methanol,

respectively (Scheme 2-7, 2-8).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.

88

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

As can be observed in Table 2-5, the experimental molecular weights of the poly(n-butyl

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(n-butyl 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 n-butyl

acrylate polymerization compared to the styrene polymerization. To resolve this issue,

polymerizations were performed in custom-made sealed tubes to prevent any evaporation of

monomers (Figure 2-6).

argon in whenvalve opensealed by

J-Young valve

Figure 2-6. Custom-designed sealed tube to prevent monomer evaporation.

89

A verdazyl-mediated n-butyl acrylate polymerization reaction was carried out at 130 ºC

in the sealed tube without interruption for 40 hours. Results showed consistency between the

experimental and theoretical molecular weights (Mn = 12,900 g mol-1 vs. MnTH = 13,200 g mol-1

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 n-butyl acrylate polymerizations without the need for

additives, the n-butyl 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 verdazyl-mediated polymerization systems,

verdazyl-terminated polystyrene and poly(n-butyl acrylate) were chain extended with n-butyl

acrylate and styrene, respectively (Figure 2-7, 2-8). The homopolymers, or macroinitiators, were

purified from the initial polymerization mixture by several precipitation cycles from methanol

prior to the chain extension reactions.

MV

0.00

5.00

10.00

15.00

20.00

25.00

30.00

35.00

40.00

45.00

50.00

Minutes

30.00 31.0032.0033.00 34.0035.0036.00 37.0038.0039.0040.00 41.0042.0043.00 44.0045.00 46.0047.0048.00

Figure 2-7. GPC plot of polystyrene-b-(n-butyl 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).

90

MV

5.00

10.00

15.00

20.00

25.00

30.00

Minutes

28.0029.0030.0031.0032.0033.0034.0035.0036.0037.0038.0039.0040.0041.0042.0043.0044.0045.0046.0047.00

Figure 2-8. GPC plot of poly(n-butyl acrylate)-b-styrene 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 3-position 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 2-9) were prepared via BST-exchange or

ATRA27,28 reactions with the corresponding verdazyl radicals.

91

Figure 2-9. Derivatization at the 3 position of the 1,5-dimethyl-6-oxoverdazyl radical moieties in the corresponding BSV unimolecular initiators.

Table 2-6. Summary of the MW and PDI of styrene polymerization initiated with the benzoyl-styrene-1,5-dimethyl-3-(p-CN-phenyl)-6-oxoverdazyl radical adduct BSV 23.


1 1700 1900 1.13 5 2 3000 3900 1.09 10 3 3900 6300 1.09 16

10 6600 17700 1.14 45

92

MV

0.00

10.00

20.00

30.00

40.00

50.00

Minutes

30.0031.0032.0033.0034.0035.0036.0037.0038.0039.0040.0041.0042.0043.0044.0045.0046.0047.0048.00

Figure 2-10. GPC of styrene polymerization initiated with the benzoyl-styrene-1,5-dimethyl-3-(p-CN-phenyl)-6-oxoverdazyl radical adduct BSV 23 (solid-1h, dashed-2h, dotted-3h, dash/dotted-10h).

Table 2-7. Summary of the MW and PDI of n-butyl acrylate polymerization initiated with the benzoyl-styrene-1,5-dimethyl-3-(p-CN-phenyl)-6-oxoverdazyl radical adduct BSV 23.


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

93

MV

2.00

4.00

6.00

8.00

10.00

12.00

14.00

16.00

18.00

20.00

Minutes

30.0031.0032.0033.0034.0035.0036.0037.0038.0039.0040.0041.0042.0043.0044.0045.0046.0047.0048.00

Figure 2-11. GPC of n-butyl acrylate polymerization initiated with the benzoyl-styrene-1,5-dimethyl-3-(p-CN-phenyl)-6-oxoverdazyl radical adduct BSV 23 (solid-1h, dashed-2h, dotted-4h, dash/dotted-6h,

dashed/2dotted-24h).

Table 2-8. Summary of the MW and PDI of n-butyl acrylate polymerization initiated with the benzoyl-styrene-1,5-dimethyl-3-(methylimidazole)-6-oxoverdazyl radical adduct BSV 24.


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

94

MV

2.00

3.00

4.00

5.00

6.00

7.00

8.00

9.00

10.00

11.00

Minutes

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

Figure 2-12. GPC of n-butyl acrylate polymerization initiated with the benzoyl-styrene-1,5-dimethyl-3-(methylimidazole)-6-oxoverdazyl radical adduct BSV 23 (solid-1h, dashed-2h, dotted-3h, dash/dotted-4h,

dashed/2dotted-5h).

While certain substitution on the 3 position, for example para-cyanophenyl (initiator 23),

showed minimal impact on the polymerization-mediating 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 (3-methyl 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 2-8, Figure 2-12). Two possibilities may account for these results. First, this

particular verdazyl radical may undergo faster decomposition than the 3-phenyl 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.

95

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 2-9, Figure 2-13).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 C-N 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 kd values between the 3-Ph

(2.6 x 10-3 s-1, 397 K) and the 3-H (2.7 x 10-3 s-1, 397 K) verdazyl unimolecular initiators.19

Therefore, the difference in polymerization results is not caused directly by the steric effects

surrounding the styryl-verdazyl bond.

Table 2-9. Summary of the MW and PDI of styrene polymerization initiated with the benzoyl-styrene-1,5-dimethyl-3-hydrogen-6-oxoverdazyl radical adduct BSV 22.15


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

96

MV

2.00

4.00

6.00

8.00

10.00

12.00

14.00

16.00

18.00

20.00

22.00

24.00

Minutes

28.00 30.00 32.00 34.00 36.00 38.00 40.00 42.00 44.00 46.00 48.00

Figure 2-13. GPC plot of styrene polymerization initiated with the benzoyl-styrene-1,5-dimethyl-3-hydrogen-6-oxoverdazyl radical adduct BSV 22 (solid-1h, dashed-2h, dotted-3h, dash/dotted-5h,

dashed/2dotted-7h).

Even more interesting is the inability of the verdazyl radical 26 (see Scheme 2-9) to

mediate the polymerization of n-butyl 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 2-14).15

Table 2-10. Summary of the MW and PDI of n-butyl acrylate polymerization initiated with the benzoyl-styrene-1,5-dimethyl-3-hydrogen-6-oxoverdazyl radical adduct BSV 22.15


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

97

MV

2.00

4.00

6.00

8.00

10.00

12.00

Minutes

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

Figure 2-14. GPC of n-butyl acrylate polymerization initiated with the benzoyl-styrene-1,5-dimethyl-3-hydrogen-6-oxoverdazyl radical adduct BSV 22 (solid-1h, dashed-2h, dotted-4h, dash/dotted-8h).

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 n-butyl 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 n-butyl 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 air-exposed polymerization mixture provided a match for a standard sample of the 3-H

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,

98

which accounted for the observed colour change and the appearance of the verdazyl radical 26 on

the TLC plate (Scheme 2-9).

Scheme 2-9. Hydrogen-abstraction mechanism of 1,5-dimethyl-6-oxoverdazyl; 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 n-butyl 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

99

precursor to the verdazyl radical. In the reaction of bis-methylhydrazide and 2,5-

dimethylbenzaldehyde, the major product was 29 while the anticipated product 27 was not

observed (Scheme 2-10).

Scheme 2-10. Attempted synthesis of 1,5-dimethyl-3-(2,6-dimethylphenyl)-6-oxoverdazyl radical 28 yielding bis(hydrazone) 29.

Although the formation of the bis-hydrazone 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 bis-methylhydrazide and the aldehyde.

However, in the case of the 2,6-dimethylbenzaldehyde, both potential solutions to suppress the

formation of 27 were taken to the extreme (20-fold 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 1-2 for

general overview of the verdazyl synthesis).

100

The 1,5-dibenzyl-6-oxoverdazyl 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 procedure6 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 2-11).

Scheme 2-11. Synthesis of 1,5-dibenzyl-3-phenyl-6-oxoverdazyl radical 30.

The 1,5-dimethyl-6-methyleneverdazyl radical 31 (Figure 2-15) was of interest due to its

structural difference compared to the 1,-5-dimethyl-6-oxoverdazyl 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 bis-hydrazine or its protected analogue precursor to the verdazyl radical 31, modifications to

the analogous synthetic route for the synthesis of 6-oxoverdazyls 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 2-12).

101

Figure 2-15. 1,5-Dimethyl-3-phenylverdazyl 31.

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

The 6-phosphaverdazyl 35 (Scheme 2-13) 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 2-14) but product yields were generally less than 5%. However, the radical

precursor, leucoverdazyl 34, of the 6-phosphaverdazyl radical 35 is stable in air unlike other

leucoverdazyls (Scheme 2-14). The stability of the 6-phospha-leucoverdazyl 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 (1-bromoethyl)benzene, the 6-

phosphaleucoverdazyl 34 yielded the unimolecular initiator 36 in 45% (Scheme 2-14).

102

Scheme 2-13. Synthesis of 6-phosphaverdazyl 35.

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

Several n-butyl acrylate polymerizations were attempted with unimolecular initiator 36,

under typical polymerization conditions as used with other verdazyl unimolecular initiators at

115-120 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 n-butyl acrylate polymerizations mediated by the

1,5-dimethyl-3-phenyl-6-oxoverdazyl 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 living-radical

polymerization conditions. It was observed that verdazyl radicals containing different

substituents showed varying degrees of success as mediators in living-radical polymerization

systems. This observation is consistent with the fact that various nitroxides, depending upon

their structures, also behave differently as mediators in living-radical polymerization systems.

104

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 polymerization-mediating abilities. For a complete assessment of the verdazyl-

mediated SFRP process, one should design a systematic study of the SFRP mediating-ability 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 6-phosphaverdazyl 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 6-oxoverdazyl 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 kd and Ea values should be determined in order to form structure-to-

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


(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, 5929-5939.

105

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

- Polym. Chem. 2002, 40, 3264-3283.

(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 20060524-enddate 20060526; Society of Polymer Science: 2006; Vol. 55, pp 442.

(6) Debuigne, A.; Chan-Seng, D.; Li, L.; Hamer, G. K.; Georges, M. K. Macromolecules 2007,

40, 6224-6232.





(11) Milcent, R.; Barbier, G. J. Heterocycl. Chem. 1994, 31, 319-324.

(12) Pare, E. C.; Brook, D. J.; Brieger, A.; Badik, M.; Schinke, M. Org. Biomol. Chem. 2005, 3, 4258-4261.

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

A31, 351-366.

(14) Yamada, B.; Nobukane, Y.; Miura, Y. Polym. Bull. (Berlin) 1998, 41, 539-544.

(15) Chen, E. K. Y.; Teertstra, S. J.; Chan-Seng, D.; Otieno, P. O.; Hicks, R. G.; Georges, M. K. Macromolecules 2007, 40, 8609-8616.

(16) Hicks, R. G.; Hooper, R. Inorg. Chem. 1999, 38, 284-286.

(17) Matyjaszewski, K.; Woodworth, B. E.; Zhang, X.; Gaynor, S. G.; Metzner, Z. Macromolecules 1998, 31, 5955-5957.

(18) Teertstra, S. J.; Chen, E. K. Y.; Chan-Seng, D.; Otieno, P. O.; Hicks, R. G.; Georges, M. K. Macromol. Symp. 2007, 248, 117-125.

(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, 9201-9207.

(21) Paleos, C. M.; Dais, P. J. Chem. Soc. , Chem. Commun. 1977, 345-346.

106


(23) Debuigne, A.; Radhakrishnan, T.; Georges, M. K. Macromolecules 2006, 39, 5359-5363.


Chem. 1995, 8, 301-305.

(25) Unpublished results.


2008, 4571-4574.

(27) Curran, D. P. Comprehensive Organic Synthesis 1991, 4, 715-735.

(28) Matyjaszewski, K. Current Organic Chemistry 2002, 6, 67-82.

(29) Majoral, J. P.; Kraemer, R.; Navech, J.; Mathis, F. Tetrahedron 1976, 32, 2633-2644.

107

Chapter 3

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


In the previous chapter, the 1,5-dimethyl-6-oxoverdazyl radical 16 was shown to mediate

living radical polymerizations of styrene and n-butyl acrylate. It is known that styrene

polymerizations1 can be mediated by nitroxides, such as TEMPO, due to the Mayo autoinitiation

reaction2,3 (see Scheme 1-21) which is absent in acrylate polymerizations. For acrylate

polymerizations to be successful under SFRP conditions, the mediating radical must be capable

of undergoing decomposition4 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 1,5-dimethyl-6-oxoverdazyl radical 16 into a

structurally unique azomethine imine which, in the presence of styrene and electron-poor

108

dipolarophiles, undergoes [3+2] 1,3-dipolar 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 1,5-dimethyl-3-phenyl-6-oxoverdazyl-initiated 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.



All ACS grade reagents and solvents were purchased from Sigma-Aldrich, 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.





Verdazyl radicals were synthesized according to published procedures.9

109


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

operating at 400 MHz for 1H NMR and 100 MHz for 13C NMR in CDCl3 (Aldrich, 99.8% atom

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

per million (ppm) referenced to TMS (0 ppm) for 1H NMR spectra and CDCl3 (77.0 ppm) for 13C











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-

83 ºC). 1H NMR (500 MHz, CDCl3), δ: 7.93-7.88 (m, 2H), 7.48-7.43 (m, 3H), 7.37-7.31 (m, 3H),

7.27-7.26 (m, 2H), 4.06 (s, 2H), 3.04 (s, 3H), 2.98 (s, 3H). 13C NMR (125 MHz, CDCl3), 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 C17H19N4O [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. 1,5-Dimethyl-3-phenyl-6-oxoverdazyl 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 O2. 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

as a yellow crystalline solid (315 mg, 74%, mp: 115-117 ºC). 1H NMR (500 MHz, CDCl3), δ:

7.67-7.62 (m, 2H), 7.47-7.42 (m, 1H), 7.42-7.37 (m, 2H), 4.24 (dd, J = 3.9, 9.0, 1H), 4.22-4.17

(m, 1H), 3.56 (s, 3H), 3.52-3.46 (m, 1H), 3.37 (s, 3H), 2.48-2.39 (m, 1H), 2.27-2.20 (m, 1H).

13C NMR (125 MHz, CDCl3), 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 C14H16N4O3 [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-


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


as a yellow crystalline solid (315 mg, 74%, mp: 109-110 ºC). 1H NMR (500 MHz, CDCl3), δ:

7.67-7.63 (m, 2H), 7.46-7.42 (m, 1H), 7.42-7.37 (m, 2H), 4.28-4.21 (m, 1H), 4.15 (dd, J = 3.9,

8.6, 1H), 3.43-3.36 (m, 1H), 3.34 (s, 3H), 2.45-2.36 (m, 1H), 2.25-2.17 (m, 1H), 1.32 (s, 9H).

112

13C NMR (125 MHz, CDCl3), 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 C17H22N4O3 [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-

125 ºC). 1H NMR (500 MHz, CDCl3), δ: 7.66-7.61 (m, 2H), 7.46-7.41 (m, 1H), 7.41-7.35 (m,

2H), 4.01-3.93 (m, 1H), 3.83-3.75 (m, 1H), 3.63 (s, 3H), 3.35 (s, 3H), 2.58-2.50 (m, 1H), 1.97-

1.89 (m, 1H), 1.29 (s, 3H). 13C NMR (125 MHz, CDCl3), 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 C15H19N4O3

[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


as a pale yellow crystalline solid (234 mg, 62%, mp: 184-186 ºC). 1H NMR (500 MHz, CDCl3),

δ: 7.79-7.74 (m, 2H), 7.52-7.47 (m, 1H), 7.47-7.42 (m, 2H), 4.44-4.37 (m, 1H), 4.32 (dd, J = 3.4,

9.2, 1H), 3.50-3.43 (m, 1H), 3.39 (s, 3H), 2.56-2.48 (m, 1H), 2.45-2.38 (m, 1H). 13C NMR (125

MHz, CDCl3), 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 C13H13N5O [M]+, 255.1120; found, 255.1127.

113

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


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

pale yellow crystalline solid (275 mg, 74%, mp: 94-96 ºC). 1H NMR (400 MHz, CDCl3), δ:

7.83-7.78 (m, 2H), 7.52-7.40 (m, 3H), 4.23-4.13 (m, 1H), 3.69-3.61 (m, 1H), 3.39 (s, 3H), 2.73-

2.64 (m, 1H), 2.18-2.10 (m, 1H), 1.42 (s, 3H). 13C NMR (100 MHz, CDCl3), 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

C14H15N5O [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,

CDCl3), δ: 7.74-7.70 (m, 2H), 7.48-7.39 (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). 13C NMR (125 MHz,

CDCl3), 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 C18H22N4O5 [M+], 374.1590; found, 374.1593.

114

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,

CDCl3), δ: 7.65-7.60 (m, 2H), 7.48-7.44 (m, 1H), 7.43-7.38 (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,

J = 7.2, 3H). 13C NMR (125 MHz, CDCl3), 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 C18H22N4O5 [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

mg, 69%, mp: 161-162 ºC). 1H NMR (500 MHz, CDCl3), δ: 7.83-7.76 (m, 2H), 7.56-7.45 (m,

3H), 5.00 (m, 1H), 4.59-4.55 (m, 1H), 3.67-3.58 (m, 2H), 3.42 (s, 3H). 13C NMR (100 MHz,

CDCl3), 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 C14H12N6O [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 N-methyl 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,

56%, mp: 224-226 ºC). 1H NMR (500 MHz, CDCl3), δ: 7.86-782. (m, 2H), 7.53-7.47 (m, 2H),

7.47-7.44 (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

(dd, J = 8.5, 12.4, 1H), 3.30 (s, 1H), 2.91, (s, 3H). 13C NMR (125 MHz, CDCl3), 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 C15H16N5O3 [M+H]+, 314.1247; found, 314.1262.


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

3.3.1.1 Discovery

As previously noted (see Scheme 2-6, Scheme 2-7), compound 20 was isolated from a

verdazyl-containing unimolecular initiator synthesis reaction mixture, as well as from a styrene

polymerization involving verdazyl radical 16 as the moderating stable radical (Scheme 3-1).

Scheme 3-1. Synthesis of unimolecular initiator 19 with 1,5-dimethyl-3-phenyl-6-oxoverdazyl 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 3-2). Two potential mechanisms were contemplated for the formation of 20,

one involving a diradical intermediate and the other involving a 1,3-dipole 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 head-to-tail 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 1,3-dipolar 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 1,5-dimethyl-3-phenyl-6-oxoverdazyl 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 3-3).

Scheme 3-3. Postulated diradical mechanism for the formation of 20 with 1,5-dimethyl-3-phenyl-6-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 3-1), 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 3-1). Therefore, the diradical

mechanism was rejected.

118

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 radicals4 (see Scheme 1-25), 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 3-2).

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

41, which could react with styrene to form the bicyclic product 20 (Scheme 3-4).

Figure 3-2. Structural similarities between 1,5-dimethyl-3-phenyl-6-oxoverdazyl 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 1,5-dimethyl-3-phenyl-6-oxoverdazyl 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 3-5), 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

120

other 1,3-dipolar cycloadditions, the formation of 20 was readily rationalized via the mechanism

shown in Scheme 3-5.

Scheme 3-5. Postulated mechanism for the formation of azomethine imine 41 from 1,5-dimethyl-3-phenyl-6-oxoverdazyl 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 3-6).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.

121

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

3.3.2 Verdazyl-Derived Azomethine Imine

3.3.2.1 Optimization of Reaction and Solvent Effects

The initial verdazyl-initiated 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 3-5). 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 3-5).

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.

122

3.3.2.2 Scope of Reaction

Azomethine imines are a class of well-studied 1,3-dipoles known to undergo 1,3-dipolar

cycloaddition reactions with a wide range of dipolarophiles of both electron-rich and electron-

poor nature. Various azomethine imines with various attached substituents display different

reactivities towards dipolarophiles. The verdazyl-derived 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 imines13,14 in that its carbonyl functionality is attached to

the centre rather than the terminal nitrogen of the azomethine imine moiety (Figure 3-3).

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 electron-poor dipolarophiles (Table 3-1) proceeded

to give products in high yields.11 In contrast, cycloaddition reactions with electron-rich olefins

such as vinyl ether, pyrrolidino-1-cyclopentene and 1-morpholinocyclohexene and unactivated

olefins such as 1-hexene and cyclohexene gave no appreciable yields of cycloadduct.12

123

Table 3-1. Cycloaddition reactions of 1,5-dimethyl-3-phenyl-6-oxoverdazyl radical 16 with various dipoles; neat or minimal solvent.11

Compound Substrate Product % Yield

20 Ph

N

N N

NMe

O

Ph Ph

63

21

74

44

82

45

84

46

62

47

74

124

48

83

49

42

50

69

51 N

O

O

N

N N

NMe

O

PhN

O

O

56

3.3.2.3 Assessment of Reactivity

It was surprising that even though the cycloaddition reaction proceeded smoothly with

electron-poor 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 1-16) 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 electron-rich dipolarophiles are too large (Figure 3-4).

125

LUMO

HOMO

LUMO

HOMO

LUMO

HOMO

dipole41

electron poordipolarophile

electron richdipolarophile

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 electron-rich

dipolarophiles (Figure 3-5) are comparable, if not smaller, than the electron-poor dipolarophiles.

This suggests that the transition states for the reactions between 41 and the electron-rich 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 3-2) showed that while reactions of 41 with

electron-poor 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 3-6). 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.

126

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 p-HOMO LUMO LU(d) – HO (p) LU (p) – HO (d)

LU-dipole

controlled

HO-dipole

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

127

1-Mopholinocyclohexene -0.1896 0.0426 0.12204 0.24467 1-Pyrrolidinocyclopentene -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 3-7), 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: yellow-high; 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,

128

cannot be completely omitted from the equation.17 We can speculate that while the negative

electrostatic potential of azomethine imine 41 is complementary to electron-poor dipolarophiles

and thus reaction is favourable, electrostatic repulsion would hinder its reaction with electron-

rich dipolarophiles.

It can be envisioned that with more electron-withdrawing substituents on the azomethine

imine the negative electrostatic potential at the 1,3-dipole site would be reduced. To that end,

verdazyl radicals 52 and 53, known to undergo 1,3-dipolar cycloaddition reactions with methyl

acrylate,12 were synthesized and tested with electron-rich dipolarophiles such as pyrrolidino-1-

cyclopentene and 1-morpholinocyclohexene (Figure 3-8). Still, no cycloadducts were observed.

Figure 3-8. Reactions between verdazyl radicals containing electron-withdrawing (para-cyanophenyl, para-fluoro) substituents with electron-rich dipolarophiles (pyrrolidino-1-cyclopentene and 1-

morpholinocyclohexene).

Nevertheless, the electrostatic potentials of the azomethine imines corresponding to these

verdazyl radicals have not yet been calculated, and the electron-withdrawing 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.

129


In conclusion, structurally unique azomethine imines were generated from verdazyl

radicals to participate with styrene and electron-poor dipolarophiles in 1,3-dipolar 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 electron-rich dipolarophiles.

3.5 Future Work

The verdazyl-derived azomethine imine 1,3-cycloaddition 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 electron-withdrawing derivatives such as 54 should be, and are, being synthesized

and characterized by DFT calculations to elucidate the compatibility of the azomethine imine

with electron-rich dipolarophiles. Other verdazyl series, such as the 1,5-dibenzyl-6-oxoverdazyl

radicals 55 should be, and are being synthesized for their compatibility for this cycloaddition

reaction (Figure 3-9). Catalysis and asymmetric synthesis should be investigated in order to

improve the efficiency of this reaction and also to find potential applications.

130

N

N N

NMe Me

O

F

F

F

F

F

N

N N

NBn Bn

O

R

54

55

Figure 3-9. Verdazyl radicals bearing 3-pentafluorophenyl- and 1,5-dibenzyl- substituents.

3.6 References

(1) Georges, M. K.; Veregin, R. P. N.; Kazmaier, P. M.; Hamer, G. K. Macromolecules 1993, 26, 2987-2988.

(2) Mayo, F. R. J. Am. Chem. Soc. 1968, 90, 1289-1295.


Chem. 1995, 8, 301-305.



(6) Yamada, B.; Kageoka, M.; Otsu, T. Macromolecules 1991, 24, 5234-5236.

(7) Otsu, T.; Yamada, B.; Ishikawa, T. Macromolecules 1991, 24, 415-419.



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


2008, 4571-4574.


(13) Dorn, H.; Otto, A. Angew. Chem. Int. Ed. Engl. 1968, 7, 214-215.

131


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

Perkin Trans. 1 2001, 1391-1397.

(16) Butler, R. N.; Coyne, A. G.; Burke, L. A. J. Chem. Soc. Perkin Trans. 2 2001, 1781-1784.

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

132

Chapter 4

4 Rearrangement Reactions of Verdazyl-Derived Cycloadducts


In Chapter 3, the 1,5-dimethyl-3-phenyl-6-oxoverdazyl radical 16 was demonstrated to

form an azomethine imine in situ, which could undergo 1,3-dipolar 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 electrophile-assisted 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 verdazyl-derived cycloadducts described in Chapter 3 appeared stable at high

temperatures. The synthetic procedure for their formation that gave the best yields was the one

133

in which the reaction was refluxed in toluene (~110 ºC). In addition, as demonstrated,

cycloadducts could be isolated from styrene and n-butyl acrylate living-radical polymerizations

that were conducted at temperatures as high as 135 ºC. The first rearrangement reaction of the

verdazyl-derived 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.










Verdazyl radicals3, E-2-methylthio-phenylacrylonitrile4 and methyl α-acetoxy acrylate5

were synthesized according to published procedures. α-Acetoxyacrylonitrile was purchased

from Sigma-Aldrich.

134
















4.2.2 General Procedure for Cycloaddition Reactions

The dipolarophile (20 mmol) was placed neat or in a minimal amount of solvent

(typically THF) 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. 1,5-Dimethyl-3-phenyl-6-

oxoverdazyl radical 16 (203 mg, 1 mmol) was added as a solid to the flask with minimal

exposure to air and the reaction solution was heated and stirred at ambient temperature for 24 h

135

under an atmosphere of O2. Excess olefin was removed in vacuo and the products were purified

by flash silica gel chromatography.

4.2.3 Synthesis of 2-Methyl-4-phenyl-7,8-dihydro-1H-pyrazolo[1,2-a][1,2,4,5]tetrazine-

1,6(2H)-dione (57)

The title compound was synthesized according to the general cycloaddition procedure.

Hydrolysis of the initially formed cycloaddition product 56 appeared to occur during silica gel

chromatography (1:9 ethyl acetate/methylene chloride). Recrystallization from ethyl

acetate/hexane gave the title compound as a white crystalline solid (110 mg, 45%, mp: 108-111

ºC). 1H NMR (500 MHz, CDCl3), δ: 7.75-7.65 (m, 2H), 7.50-7.35 (m, 3H), 4.18 (t, J = 8.14,

2H), 3.43 (s, 3H), 2.71 (t, J = 8.14, 2H). 13C NMR (125 MHz, CDCl3) δ: 169.3, 156.9, 141.4,

131.3, 128.7, 128.6, 127.5, 42.5, 37.5, 30.2. HRMS (EI) (m/z): calculated for C12H12N4O2 M+,

244.0960; found, 244.0960.

4.2.4 Synthesis of (Z)-2,3-Bis(2,4-dimethyl-3-oxo-6-phenyl-3,4-dihydro-1,2,4,5-tetrazin-

1(2H)-yl)acrylonitrile (58)

The title compound was synthesized according to the general cycloaddition procedure

and purified by silica gel column chromatography (1:1 ethyl acetate/hexane) and recrystallized

from ethyl acetate to give a white crystalline solid (160 mg, 35%, mp: 172-174 ºC). 1H NMR

(500 MHz, CDCl3), δ: 7.70-7.35 (m, 10H), 6.80 (s, 1H), 3.32 (s, 3H), 3.26 (s, 3H), 3.19 (s, 3H),

3.15 (s, 3H). 13C NMR (125 MHz, CDCl3) δ: 156.3, 155.2, 142.3, 141.6, 131.8, 130.7, 129.4,

128.8, 127.4, 127.2, 114.3, 91.5, 39.1, 37.5, 36.8, 34.4. HRMS (EI) (m/z): calculated for

C23H23N9O2 M+, 457.2000; found, 457.1975. mp: 172-174 ºC. The Z- configuration was

determined by the chemical shift of the vinyl hydrogen.

136

4.2.5 Synthesis of 5-Methyl-7-phenylpyrazolo[1,5-d][1,2,4]triazin-4(5H)-one (67)


with the slight modification that less MAA (1065 mg, 7.5 mmol) was used relative to 1,5-

dimethyl-3-phenyl-6-oxoverdazyl 16 (203 mg, 1.0 mmol). The excess monomer was removed in

vacuo. Purification by silica gel chromatography (hexane/ethyl acetate 3:1) and recrystallization

from ethyl acetate/hexane gave the product as a white crystalline solid (96 mg, 32%, mp: 119-

121 ºC). The yield can be increased up to 89% if the reaction is performed in refluxing ethyl

acetate. 1H NMR (500 MHz, CDCl3), δ: 8.15-8.05 (m, 2H), 8.015 (d, J = 1.94, 1H), 7.60-7.50

(m, 3H), 7.226 (d, J = 1.94, 1H), 3.83 (s, 3H). 13C NMR (125 MHz, CDCl3) δ: 153.7, 143.7,

138.5, 134.6, 131.0, 129.4, 128.8, 128.5, 106.5, 37.9. HRMS (ESI) (m/z): calculated for

C12H11N4O [M+H]+, 227.0929; found, 227.0927.

4.2.6 Synthesis of Methyl 6-acetoxy-2-methyl-1-oxo-4-phenyl-2,6,7,8-tetrahydro-1H-



with the modification that the reaction was stopped after 3 h. Purification by silica gel column

chromatography (hexanes/ethyl acetate 3:1) gave 66 as a colorless liquid. 1H NMR (400 MHz,

CDCl3), δ: 7.65-7.70 (m, 2H), 7.45-7.35 (m, 3H), 4.37-4.28 (m, 1H), 3.61-3.51 (m, 1H), 3.43 (s,

3H), 3.21-3.10 (m, 1H), 3.17 (s, 3H), 2.49-2.40 (m, 1H), 2.03 (s, 3H). A 13C NMR spectrum was

not recorded due to the rapid decomposition of this compound.

137

4.2.7 Synthesis of Methyl 2-methyl-1-oxo-4-phenyl-2,8-dihydro-1H-pyrazolo[1,2-


Spontaneous elimination of acetic acid from 66 occurred in quantitative yield at room

temperature over 3 h to give the title compound as a colorless liquid. 1H NMR (400 MHz,

CDCl3) δ: 7.58-7.54 (m, 2H), 7.43-7.36 (m, 3H), 5.90 (t, J = 2.78, 1H), 4.70 (d, J = 2.78, 2H),

3.34 (s, 3H), 3.30 (s, 3H). 13C NMR (125 MHz, CDCl3) δ: 159.0, 146.1, 134.2, 131.7, 130.4,

129.4, 128.6, 127.1, 113.3, 52.0, 51.3, 36.8. HRMS (ESI) (m/z): calculated for C14H14N4O3

[M+H]+, 287.1125; found, 287.1138.

4.2.8 Conversion of 66 or 68 to 67 by Heat

Product 66 or 68 (20 mg, 0.07 mmol) was refluxed in 5 mL of ethyl acetate for 2 h. The

solvent was removed in vacuo to give 67 (14 mg, 89%).

4.2.9 Conversion of 66 or 68 to 67 by Sodium Hydride

Product 66 or 68 (20 mg, 0.07 mmol) was dissolved in 3 mL of dry THF. Excess solid

sodium hydride (20 mg) was added and the reaction was allowed to proceed at room temperature

for 5 h. The reaction mixture was cooled in an ice bath and quenched with methanol. The THF

was removed in vacuo. The reaction mixture was taken up in ethyl acetate (10 mL) and washed

with a cold brine solution (10 mL). The ethyl acetate solution was dried over Na2SO4 and the

solvent was removed in vacuo to give 67 (12 mg, 76%).

4.2.10 Synthesis of Methyl 5-methyl-4-oxo-7-phenyl-1,2,3,3a,4,5-hexahydropyrazolo[1,5-

d][1,2,4]triazine-3a-carboxylate (70)

Cycloadduct 21 (140 mg, 0.5 mmol) was dissolved in 15 mL of dry THF in a dry 3-neck

round bottom flask equipped with a stir bar. The reaction solution was cooled to 0 ºC and

138

degassed with N2 for 30 min. Sodium hydride (20 mg, 1.0 mmol) was added. The reaction

mixture was allowed to warm to room temperature and then left at that temperature for an

additional 0.5 h. Three drops of methanol were added to quench the remaining sodium hydride

and the THF was removed in vacuo. The resulting oil was dissolved in ethyl acetate and washed

with a cold brine solution. The organic layer was dried over Na2SO4 and the solvent was

removed in vacuo to give the title compound as an oil (118 mg, 82%). 1H NMR (400 MHz,

CDCl3) δ: 7.70-7.62 (m, 2H), 7.40-7.32 (m, 3H), 5.40 (br, 1H), 3.81 (s, 3H), 3.40-3.30 (m, 1H),

3.21 (dt, J = 13, 3, 1H), 2.85 (s, 3H), 2.86-2.80 (m, 1H), 2.09 (dt, J = 13, 5, 1H). 13C NMR (100

MHz, CDCl3) δ: 168.6, 150.2, 147.6, 129.5, 127.9, 127.8, 127.6, 85.6, 52.6, 36.9, 36.7, 27.4.

HRMS (ESI) (m/z): calculated for C14H17N4O3 [M+H]+, 289.1295; found, 289.1297.

4.2.11 Conversion of 21 to 70 by Lithium Diisopropylamide


round bottom flask equipped with a stir bar. The reaction solution was cooled to 0 ºC in an ice

bath and degassed with N2 for 30 min. Lithium diisopropylamide (0.1 mL, 0.2 mmol in

THF/heptane/ethylbenzene) was added dropwise via syringe over 30 seconds. The reaction

mixture was allowed to warm to room temperature after 15 min at 0 ºC. TLC (3:1

dichloromethane/ethyl acetate) of the reaction mixture showed no remaining starting material.

The THF was removed in vacuo. The resulting solid was washed with CDCl3 and the NMR

spectrum of the crude reaction mixture matched the spectrum previously obtained for 70.

4.2.12 Synthesis of Methyl 2-(1-methyl-3-phenyl-1H-1,2,4-triazol-5-yl)ethylcarbamate (76)

Cycloadduct 21 (140 mg, 0.5 mmol) was dissolved in 20 mL of methanol in a round

bottom flask equipped with a stir bar. A few freshly-cut pieces of sodium metal was added and

the reaction mixture was stirred for 2 h. The solvent was removed in vacuo. A saturated

139

ammonium chloride solution (5 mL) was added to the remaining solids and the title compound

was extracted with 3 x 10 mL of ethyl acetate. The ethyl acetate extractions were combined,

washed with brine and dried over sodium sulphate. Removal of the ethyl acetate in vacuo gave a

solid that was recrystallized from methylene chloride/hexane to give a white crystalline solid

(125 mg, 89%, mp: 78-80 ºC). 1H NMR (400 MHz, CDCl3) δ: 8.07-8.02 (m, 2H), 7.45-7.35 (m,

3H), 5.71 (br, 1H), 3.82 (s, 3H), 3.73-3.63 (m, 4H), 2.94 (t, J = 6.19, 2H). 13C NMR (100 MHz,

CDCl3), δ: 160.6, 157.0, 154.2, 130.8, 128.9, 128.4, 126.0, 52.0, 38.2, 34.9, 26.1. HRMS (ESI)

(m/z): calculated for C13H17N4O2 [M+H]+, 261.1346; found, 261.1334.

4.2.13 Synthesis of Ethyl 2-(1-methyl-3-phenyl-1H-1,2,4-triazol-5-yl)ethylcarbamate (77)

A few freshly-cut pieces of sodium metal was added to a solution of the cycloadduct 21

(140 mg, 0.5 mmol) in 20 mL of ethanol in a round bottom flask equipped with a stir bar. After

2 h the solvent was removed in vacuo. A saturated ammonium chloride solution (5 mL) was

added to the remaining solid, and the title compound was extracted with 3 x 10 mL of ethyl

acetate, washed with brine, and recrystallized from methylene chloride/hexane to give a white

crystalline solid (119 mg, 87%, mp: 75-77 ºC). 1H NMR (400 MHz, CDCl3) δ: 8.11-8.02 (m,

2H), 7.49-7.35 (m, 3H), 5.56 (br, 1H), 4.11 (q, J = 7.02, 2H), 3.85 (s, 3H), 3.68 (q, J = 6.04, 2H),

2.97 (t, J = 6.04, 2H), 1.23 (t, J = 7.02, 2H). 13C NMR (100 MHz, CDCl3), δ: 160.6, 156.6,

154.2, 130.8, 128.9, 128.4, 126.0, 60.7, 38.1, 34.9, 26.2. HRMS (ESI) (m/z): calculated for

C14H19N4O2 [M+H]+, 275.1502; found, 275.1507.

140

4.2.14 Synthesis of N,N,2-Trimethyl-1-oxo-4-phenyl-2,6,7,8-tetrahydro-1H-pyrazolo[1,2-

a][1,2,4,5]tetrazine-6-carboxamide (72)


and purified by recrystallization from ethyl acetate to give a dark yellow crystalline solid (253

mg, 84%, mp: 141-143 ºC). 1H NMR (400 MHz, CDCl3) δ: 7.70-7.63 (m, 2H), 7.47-7.35 (m,

3H), 4.58-4.54 (m, 1H), 4.31-4.20 (m, 1H), 3.53-3.43 (m, 1H), 3.38 (s, 3H), 2.71 (s, 3H), 2.51 (s,

3H), 2.40-2.28 (m, 1H), 2.16-2.04 (m, 1H). 13C NMR (100 MHz, CDCl3) δ: 170.2, 153.6, 146.0,

131.4, 130.5, 128.4, 127.7, 59.5, 44.5, 36.7, 36.4, 35.5, 30.0. HRMS (ESI) (m/z): calculated for

C15H20N5O2 [M+H]+, 302.1616; found, 302.1611.

4.2.15 Synthesis of N,N,5-Trimethyl-4-oxo-7-phenyl-1,2,3,3a,4,5-hexahydropyrazolo[1,5-

d][1,2,4]triazine-3a-carboxamide (73)


round bottom flask equipped with a stir bar. Potassium tert-butoxide (26 mg, 0.2 mmol) was

added in small portions. The reaction mixture was stirred at room temperature for 0.5 h. The

THF was removed in vacuo. Ethyl acetate (3 mL) was added to the remaining solid and three

drops of saturated ammonium chloride was added to the suspension. The organic layer was

washed twice with brine, dried over Na2SO4 and evaporated in vacuo to give the title compound

as an oil (24 mg, 80%). 1H NMR (400 MHz, CDCl3) δ: 7.73-7.65 (m, 2H), 7.42-7.32 (m, 3H),

5.06 (br, 1H), 3.43 (dt, J = 12.1, 4.6, 1H), 3.38-3.30 (m, 1H), 3.23 (br, 3H), 3.02 (br, 3H), 2.79 (s,

3H), 2.69 (dd, J = 12.5, 3.5, 1H), 2.11-2.00 (m, 1H). 13C NMR (100 MHz, CDCl3) δ: 168.3,

151.2, 149.1, 129.7, 128.9, 128.0, 127.4, 85.1, 38.1 (br), 37.7 (br), 37.3, 36.5, 25.1. HRMS (ESI)

(m/z): calculated for C15H20N5O2 [M+H]+, 302.1626; found, 302.1611.

141


4.3.1 Ketene Equivalents and Captodative Olefins in Verdazyl-Initiated Cycloaddition

In an effort to introduce more functionality in the verdazyl-derived cycloadducts, 1-

chloroacrylonitrile was used as a ketene equivalent dipolarophile in the cycloaddition reaction

with verdazyl radical 16 (Scheme 4-1). It was anticipated that hydrolysis of cycloadduct 56

would yield the carbonyl-containing cycloadduct 57. Surprisingly, only a trace amount of

cycloadduct 57 was observed. The major product of the reaction was identified as 58, a

compound with a structural pattern not previously observed.

N

N N

N

O

Me Me

Ph

+

1) O2, 10 min.

2) rt, 24 h

N

N N

N

O

Me

PhCl CN

O

N

N N

N

O

Me Me

Ph

N

N N

N

O

Me Me

PhCN

+

16 57 58

<5% 35%

N

N N

N

O

Me

Ph

56

ClCN

H2O

Scheme 4-1. Reaction between 1,5-dimethyl-3-phenyl-6-oxoverdazyl radical 16 and 1-chloroacrylonitrile.

Because the double bond in 58 is flanked by two verdazyl molecules at their respective

radical centres, it is easy to envision the 1-chloroacrylonitrile undergoing a radical addition

reaction with 16 followed by a radical trapping reaction with another molecule of 16. A

subsequent E1 reaction to eliminate hydrogen chloride would yield the product 58, where the

driving force for the elimination reaction is the high degree of conjugation of the resulting double

bond. The overall postulated mechanism is shown below (Scheme 4-2).

142

N

N N

N

O

Ph

+

1) O2, 10 min.

2) rt, 24 h

N

N N

N

O

PhCl CN

O

N

N N

N

O

Ph

N

N N

N

O

PhCN

+

N

N N

N

O

Ph

N

N N

N

O

PhCNCl

N

N N

N

O

Ph

CN

Cl

- HCl

N

N N

N

O

Ph

16 57 58

<5%

59 60

35%

16

Scheme 4-2. Mechanism for the formation of 58, the radical addition/trapping product between 1,5-dimethyl-3-phenyl-6-oxoverdazyl radical 16 and 1-chloroacrylonitrile.

The verdazyl radical addition step of the mechanism was very interesting since we had

not up to that point observed verdazyl radicals adding to double bonds. Stable free radicals are

not generally known to undergo initiation reactions with olefins, although there is at least one

exception in which TEMPO added to the double bond of styrene.6 However, the addition of the

verdazyl radical to the double bond of 1-chloroacrylonitrile can be readily rationalized if the

intermediate radical 59 is viewed as a captodative radical, where the chlorine atom acts as an

electron donor and the nitrile group acts as an electron withdrawing group. The increased

stability of the radical resulting from the initiation step could explain the formation of

intermediate 59. Due to the unique nature of this reaction, we sought to duplicate the results by

replacing verdazyl radical 16 with TEMPO. However, no reaction was observed even at

temperatures as high as 80 ºC (Scheme 4-3).

143

Scheme 4-3. Reaction between TEMPO and 1-chloroacrylonitrile.

Attempts were also made to repeat the addition reaction with verdazyl radical 16 with

other captodative olefins such as E-2-methylthio-phenylacrylonitrile4 61, α-acetoxyacrylonitrile

62, and methyl α-acetoxy acrylate5 (MAA) 63 (figure 4-1).

Figure 4-1. Captodative olefins E-2-methylthio-phenylacrylonitrile 61, α-acetoxyacrylonitrile 62, and methyl α-acetoxy acrylate (MAA) 63.

Olefin 61 underwent the cycloaddition with the verdazyl radical and no radical addition

product analogous to 58 was observed. Cycloadduct 57 was isolated from the reaction of

verdazyl radical 16 with dipolarophile 62, presumably through a cycloadduct intermediate

analogous to 56 (Scheme 4-4). While the intention was to use 62 as another captodative olefin,

the fact that it turned out to be a ketene equivalent dipolarophile was not surprising. It would

seem that the 1-chloroacrylonitrile reaction with verdazyl radical 16 yielding 58 is unique.

Scheme 4-4. Reaction between 1,5-dimethyl-3-phenyl-6-oxoverdazyl radical 16 and α-acetoxyacrylonitrile.

144

4.3.2 Rearrangement of Pyrazolotetrazinone to Pyrazolotriazinone

4.3.2.1 Discovery of the Rearrangement of a Pyrazolotetrazinone Product to a

Pyrazolotriazinone Structure

From the experiments with various captodative olefins described above, it was found that

the reaction between verdazyl radical 16 with MAA yielded neither the anticipated radical

addition products (64, 65) nor the cycloaddition product 66. Instead, compound 67 was isolated

and characterized via single crystal X-ray diffraction (Scheme 4-5).

Scheme 4-5. Reaction between 1,5-dimethyl-3-phenyl-6-oxoverdazyl radical 16 and MAA.

Even though there was no experimental information at the time to support any particular

mechanistic pathway for the formation of 67, in order to elucidate a mechanism it was presumed

that the cycloaddition product 66 initially formed and then underwent a rearrangement reaction.

To see if that was the case, the reaction of verdazyl radical 16 with MAA was reinvestigated with

the mindset to try to identify and isolate intermediates along the rearrangement pathway.

145

Scheme 4-6. Postulated cycloaddition reaction between 1,5-dimethyl-3-phenyl-6-oxoverdazyl radical 16 and MAA.

4.3.2.2 Isolation of Intermediates from the Reaction of Verdazyl Radical 16 with MAA

Working up the cycloaddition reaction between verdazyl radical 16 with MAA after just

3 hours allowed the isolation of cycloadduct 66, albeit in low yield. After it was isolated,

cycloadduct 66 rapidly eliminated acetic acid at room temperature to give the stable α,β-

unsaturated ester 68 (Scheme 4-7). The 1H NMR spectrum of a sample of 66 that was allowed to

sit at room temperature for 2 hours in an NMR tube showed clear evidence for the formation of

acetic acid with the appearance of peaks at 2.10 ppm (s, 3H) and 11.50 ppm (s, 1H). When

independently heated in refluxing ethyl acetate, both 66 and 68 converted in near quantitative

yields to the rearranged product 67 (Scheme 4-7). Alternatively, treatment of 66 or 68 with

sodium hydride at 0 ºC also gave 67 in near quantitative yields. From these experiments, it can

be deduced that both 66 and 68 are intermediates in the formation of product 67.

146

Scheme 4-7. Isolable intermediates 66 and 68 leading to rearranged product 67 via heat.

Scheme 4-8. Intermediate 66 or 68 leading to rearranged product 67 via sodium hydride.

In a parallel project, the cycloaddition reaction between verdazyl radical 16 and methyl

propiolate 69 gave the same α,β-unsaturated ester 68 intermediate which upon heating, also

converted to the rearranged product 67 (Scheme 4-9).7

Scheme 4-9. Reaction between 1,5-dimethyl-3-phenyl-6-oxoverdazyl radical 16 and methyl propiolate.

147

4.3.2.3 Generalization of the Rearrangement Reaction – Saturated Derivatives

The translocation of the nitrogen and carbon atoms going from 68 to 67, combined with

the fact that the saturated derivative 21 is stable under the same heating conditions (Scheme 4-

10), suggested that the rearrangement reaction might have been occurring via a carbanion centred

at the carbon containing the ester group. If that were the case, 21 should be able to undergo a

similar ring rearrangement reaction with an analogous carbanion formation. Indeed, treatment of

21, previously prepared by the reaction of verdazyl radical 16 with methyl acrylate, in THF at

0 ºC with 2 equivalent of sodium hydride gave the rearranged product 70 in 82 % yield (Scheme

4-11).

Scheme 4-10. Treatment of methyl acrylate cycloadduct 21 with heat.

Scheme 4-11. Sodium hydride-induced rearrangement of 21 to 70.

It is interesting to note that the rearrangement of the original unsaturated compound 68

gave the aromatized product 67 (Scheme 4-7), while aromatization did not occur in the case of

the rearrangement of 21 (Scheme 4-10). However, upon treatment with excess sodium hydride,

148

21 de-esterified to give 71. In addition, 70 also de-esterified to give 71 upon treatment with

excess sodium hydride (Scheme 4-12).

N

N N

N

O

Me

Ph CO2CH3

THF, 0 oC

excess NaH N

N N

O

Me

Ph

NH

N

N N

O

Me

Ph

NH

CO2CH3

or

21

70

71

Scheme 4-12. Loss of methyl ester from 21 and 70 from treatment with sodium hydride.

Rearrangement of 21 was repeated with lithium diisopropylamide (LDA) at 0 ºC (Scheme

4-13) although under these conditions, even with excess base only product 70 formed.

Scheme 4-13. Rearrangement of methyl acrylate cycloadduct 21 with excess LDA.

From the above series of experiments, it was concluded that the carbanion formation is

vital to the rearrangement reaction. This is further confirmed by the lack of reactivity of the

methyl methacrylate cycloadduct 45 under similar conditions (Scheme 4-14). However, the loss

of the methyl ester moiety appears to rely on either aromatization (see Scheme 4-7 to structure

67) as a driving force or treatment with excess sodium hydride and warrants further examination.

149

Scheme 4-14. Treatment of methyl methacrylate cycloadduct 45 with base.

In order to examine the generality of the above-described ring rearrangement reaction,

cycloadduct 72 was prepared by the reaction of verdazyl radical 16 and N,N-dimethyl acrylamide.

Treatment of 72 with sodium hydride resulted in no rearrangement even at temperatures as high

as 66 ºC; however, treatment of 72 with potassium tert-butoxide at 0 ºC gave the desired

rearranged product 73.

Scheme 4-15. Treatment of N,N-dimethyl acrylamide cycloadduct 72 with potassium tert-butoxide.


On a structural basis, the above-described ring rearrangement reaction is reminiscent of a

Dimroth rearrangement, which is generally defined as an isomerization process whereby

heteroatoms are translocated in a heterocyclic ring (refer to Scheme 1-45).2 However, in the

typical Dimroth rearrangement involving basic conditions, nucleophilic catalysts such as

alkoxides or pyridine are generally used. In our base-induced rearrangement reactions, non-

nucleophilic bases were used for the sole purpose of forming the carbanion.

150

To eliminate the possibility of a base-initiated intermolecular self-catalytic mechanism

(Scheme 4-16) in the conversion of 68 to 67, a qualitative concentration dependence experiment

was performed. Under the same temperature and time conditions as a typical cycloaddition

reaction, a solution of 68 in deuterated chloroform at 10 times the dilution of a regular

cycloaddition reaction achieved roughly the same near quantitative yield of 67.

Scheme 4-16. Postulated intermolecular rearrangement mechanism for the conversion of 68 to 67.

The concentration independence of this rearrangement reaction strongly suggests the

likelihood of an intramolecular mechanism, as opposed to an intermolecular one. The

intramolecular rearrangement mechanism we propose for the conversion of 68 to 67 is shown

below (Scheme 4-17).

151

Scheme 4-17. Proposed intramolecular rearrangement mechanism for the conversion of 68 to 67.

In the above mechanism (Scheme 4-17), the deprotonation leading to the carbanion

formation is the first step. It can be shown with a stick model (Darling Models™) that the

carbanion is able to reach the carbonyl centre with relative ease due to the lone pair inversion of

the nitrogen atoms in the ring that allows them to flip and as a consequence, the two rings are

able to approach each other in a butterfly-type conformation. The resulting 4-membered

intermediate 74 is highly strained, and can presumably collapse to either form the starting

material or the product. However, the forward reaction should be favoured due to the formation

of the carbon-carbon bond and greater stabilization of the negative charge on the nitrogen atom

as seen in intermediate 75. This proposed mechanism is also viable for the saturated analogue

(Scheme 4-18). In a parallel theoretical assessment of the mechanism by DFT calculations,

conformations and energy levels of all intermediates and transition states from both the

unsaturated and the saturated cycloadducts were shown to be reasonable when undergoing the

rearrangement reaction.7

152

Scheme 4-18. Proposed intramolecular rearrangement mechanism for the conversion of 21 to 70.

Despite the structural classification of this rearrangement as a Dimroth rearrangement,

the proposed mechanism is novel. It can be envisioned that other flexible scaffolds may be

designed to undergo similar rearrangement reactions as a novel strategy for creating heterocycles

that would otherwise be difficult to synthesize.

4.3.3 Rearrangement of Pyrazolotetrazinone to Triazolyl Carbamate

4.3.3.1 Discovery of the Rearrangement of a Pyrazolotetrazinone Product to a Triazolyl

Carbamate Structure

In a search for a weaker base to induce the rearrangement reaction of pyrazolotetrazinone

to pyrazolotriazinone, cycloadduct 21 was treated with excess sodium methoxide. Surprisingly,

a structurally different isomeric product from the previous rearrangement product 70 was

isolated in near quantitative yield. Even though the high resolution mass spectrometry analysis

indicated the same molecular formula as 70 for this new product, the 1H, 13C, and 2-dimensional

NMR peaks were distinctly different. In the end, single crystal X-ray diffraction was relied on to

determine the structure of this new product to be 76 (Scheme 4-19).

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Scheme 4-19. Rearrangement of 21 to 76 via sodium methoxide.

Since the starting pyrazolotetrazinone 21 and the product triazolyl carbamate 76 are

structural isomers, it was intuitive to conclude that the elemental composition of the product

came from the starting material. However, no mechanism could be deduced simply by

rearranging atoms of 21 without the participation and the incorporation of the methoxide as a

reagent. Replacing the sodium methoxide with sodium ethoxide in the reaction afforded the

corresponding ethyl carbamate analogue 77 (Scheme 4-20), which indicated that the alkoxide

participated in this rearrangement reaction not only as a base, but also as a nucleophile.

Scheme 4-20. Rearrangement of 21 to 77 via sodium ethoxide.


From the results of the two alkoxides experiments, it became clear that the nucleophilic

base used in the reaction ended up being incorporated into the carbamate portion of the product,

which would explain the absence of such a product from the previous reactions that employed

bases of non-nucleophilic nature, such as sodium hydride and lithium diisopropylamide. In

addition, treatment of cycloadduct 45 with sodium methoxide (Scheme 4-21) gave no reaction.

The lack of the acidic α-hydrogen in cycloadduct 45 and its non-reactivity insinuated that the

154

first rearrangement reaction to pyrazolotriazinone 70 must be an intermediate on the pathway

from pyrazolotetrazinone 21 to triazolyl carbamate 76 (Scheme 4-19). Indeed, treatment of 70

with sodium methoxide gave 76 in near quantitative yields (Scheme 4-22).

Scheme 4-21. Treatment of methyl methacrylate derived from cycloadduct 45 with sodium methoxide.

Scheme 4-22. Rearrangement of 70 to 76 in the presence of sodium methoxide.

The fact that cycloadduct 45 is not affected by the methoxide treatment also indicates that

the bis-hydrazidyl carbonyl functionality is not electrophilic. Therefore the translocation of the

nitrogen and carbon atoms in the initial rearrangement product 70 appears to enhance the

electrophilicity of the same carbonyl functionality. Below is our proposed mechanism (Scheme

4-23) for the rearrangement of 21 to 76.

155

Scheme 4-23. Postulated mechanism for the rearrangement of cycloadducts 21 (and 70) to 76 in the presence of sodium methoxide.

The mechanism begins with an α-deprotonation by the sodium methoxide, similar to the

reaction depicted earlier with sodium hydride (Scheme 4-18), to give the rearranged structure 70

as an intermediate. Since sodium hydride cannot act as a nucleophile, the earlier described

reaction ends at this rearranged product 70. However the methoxide anion, which can act as a

nucleophile, attacks the hydrazidyl carbonyl carbon of 70 to break the pyrazolotriazinone

backbone in a ring opening reaction. The hydrazide in 78 acts as a better leaving group than the

methoxide due to the strong electron withdrawing ability of the entire hydrazidinyl moiety.8 The

156

resulting amide anion and ester in 79 are set up for a facile intramolecular 5-membered ring

closure by a nucleophilic substitution reaction that forms a carbamate. The resulting negative

charge in 80 is well-stabilized as a carbanion α- to the ester group as well as the hydrazidinyl

moiety. As shown from the resonance structures of 80, an intramolecular ring closure reaction

initiated by the terminal nitrogen anion forms a triazoline structure that then aromatizes by de-

esterification to give the final product. The mechanism of the de-esterification step is not clear at

this time.

4.3.3.3 Generalization of the Reaction – Other Cycloadducts and Bases

In order to examine the scope of the reaction, cycloadducts bearing an acidic α-hydrogen

20, 46, and 72 were treated with various bases and alkoxides.

Scheme 4-24. Treatment of styrene cycloadduct 20 with alkoxides, LDA, or tert-butyllithium.

Scheme 4-25. Rearrangement of acrylonitrile cycloadduct 46 with sodium methoxide and ethoxide.

157

Scheme 4-26. Rearrangement of N,N-dimethyl acrylamide cycloadduct 72 with potassium tert-butoxide.

Cycloadduct 20 was not reactive towards LDA, tert-butyllithium or any alkoxides

presumably due to the high pKa value of its hydrogen α- to the phenyl group, since the phenyl

group is not a great electron withdrawing substituent (Scheme 4-24). Cycloadduct 46 yielded the

expected triazoles 76 and 77 upon treatment with the corresponding alkoxides; however, the

postulated intermediate pyrazolotriazinone 81 was not isolable (Scheme 4-25). Cycloadduct 72

was not reactive with methyl, ethyl, and isopropyl alkoxides, even when refluxed in the

corresponding alcohol. However, as previously noted (Scheme 4-15), it does react with

potassium tert-butoxide to give the rearranged product 73, but does not further rearrange to give

the triazole (Scheme 4-26).

The reactivities of other cycloadducts bearing an acidic α-hydrogen, such as 48, 49 and

50, were also examined with sodium methoxide in methanol (Scheme 4-27). After an hour into

the reactions, TLC analyses showed that no starting materials remained in the reaction mixtures.

However, multiple products had formed in all the reactions and efforts to separate them were not

fruitful. Furthermore, the corresponding target triazolyl carbamates were not detected in the 1H

NMR spectra of the reaction mixtures. It is possible in all these rearrangement reactions that the

anticipated products had formed, but the reactivity of the acidic hydrogen α- to the R’ group led

to further anion formation and other reactions such as intermolecular condensation reactions with

either the starting material or the product.

158

Scheme 4-27. Treatment of cycloadducts 48, 49, and 50 with sodium methoxide.

In another ongoing project to expand the library of heterocycles using this chemistry, the

triazolyl urea 82 was isolated from the reaction of cycloadduct 46 with benzylamine at 130 ºC.

This result suggested that the triazole rearrangement with weaker nucleophilic bases may occur

with more forcing conditions (Scheme 4-28).7

Scheme 4-28. Reaction of cycloadduct acrylonitrile cycloadduct 46 with benzylamine.


In conclusion, pyrazolotetrazinone cycloadducts bearing an acidic α-hydrogen were

shown to rearrange into the corresponding pyrazolotriazinone or triazolyl carbamate structures,

depending on reaction conditions. These rearrangement reactions were unexpected, although not

surprising, considering the wealth of heteroatoms contained in the flexible parent heterocycles.

Although the pyrazolotriazinone rearrangement is structurally classified as a Dimroth

rearrangement, its intramolecular rearrangement mechanism and the absence of nucleophilic

catalysts are unique compared to other reported Dimroth rearrangement reactions. Experiments

159

were conducted to verify the proposed mechanism for these rearrangement reactions while

eliminating other possibilities. In combination with the wealth of diversity from the verdazyl

radicals, as well as the wide range of dipolarophiles available, these rearrangement reactions

leading to the various unique scaffolds provide the opportunity to increase the number of our

heterocyclic structures.

4.5 Future Work

The two rearrangement reactions outlined in this chapter are still only in their exploratory

stages. The scope of both rearrangement reactions may potentially be broadened with more

cycloadducts bearing an acidic α-hydrogen, perhaps next to an electron deficient benzene ring

(Figure 4-2). In addition, the scope of the triazole rearrangement reaction may also be

potentially broadened with the introduction of other nucleophilic bases such as amines, sulfides,

or even organometallics like butyllithiums in forming the corresponding ureas, thiocarbamates,

and amides, respectively (Scheme 4-29).

Figure 4-2. Cycloadducts bearing an acidic hydrogen α- to electron-poor phenyl rings.

160

Scheme 4-29. Triazole rearrangement of cycloadducts bearing an acidic α- hydrogen induced by other nucleophiles.

4.6 References


2008, 4571-4574.

(2) El Ashry, E. S. H.; El Kilany, Y.; Rashed, N.; Assafir, H. Adv. Heterocyl. Chem. 2000, 75, 79-165.


(4) Feit, B.; Haag, B.; Schmidt, R. R. J. Org. Chem. 1987, 52, 3825-3831.

(5) Wolinky, J.; Novak, R.; Vasileff, R. J. Org. Chem. 1964, 29, 3596-3598.

(6) Connolly, T. J.; Scaiano, J. C. Tet. Lett. 1997, 38, 1133-1136.



161

Chapter 5

5 Diversity-Oriented Synthesis of Verdazyl-Derived Heterocycles


The previous two chapters provided new synthetic strategies for the synthesis of novel

heterocyclic compounds based on the use of a verdazyl radical that undergoes a transformation

into an azomethine imine, which in turn is capable of readily undergoing 1,3-dipolar

cycloaddition reactions with a variety of dipolarophiles. With the broad range of verdazyl

radicals and dipolarophiles available, different structures containing the pyrazolotetrazinone

motif can be designed and synthesized1 and then, with subsequent reactions with bases and

nucleophiles, these products can be transformed into new compounds constructed of

pyrazolotriazinone or triazole motifs.

The compound-generating strategy described above is in perfect sync with the philosophy

of diversity-oriented synthesis (DOS). DOS focuses on expanding structural diversity in small

molecule libraries for non-specific biological activity probing.2,3 The structural diversity can

originate from different generation libraries of compounds. For example, a first generation

library of compounds can be designed using one reaction with a wide range of starting materials,

which would provide structures with the same scaffold but different functionalities. A second

generation library of compounds can then be designed by the successive transformation of the

common scaffold, which would mimic the first generation library of structures but with different

162

scaffolds. A third generation library of compounds can also be realized if any functionalities

from the first two libraries of compounds can be derivatized (see Section 1.5.2). From the

perspective of this project, the three reactions for the three corresponding generation libraries of

compounds are represented by the verdazyl-initiated cycloaddition reaction (see Chapter 3), the

rearrangement reaction of verdazyl-derived cycloadducts (see Chapter 4), and derivatizations of

any functionalities present (see below), respectively (Scheme 5-1).

N

N N

NR1

O

R1

R2(fn)

N

N N

NR1

O

R2(fn)R3(fn)

R3(fn)

B

Nu

N

N

N

R2(fn)

R1

NH

O

Nu

N

N N

R1

O

R2(fn)

NH

R3(fn)

first generation

second generation

N

N N

R1

O

R2(fn)

NH

R3(fn)

N

N

N

R2(fn)

R1

NH

O

Nu

R4

R4

third generationmodifiable sites: R1, R2, R3, R4, Nu(fn) - derivatizable functionality

Scheme 5-1. DOS strategy involving verdazyl-initiated cycloaddition and rearrangement.

The reaction of choice for the derivatization step was selected on the basis of its

simplicity and degree of derivatization possible. Additionally, in accordance with the Lipinski’s

Rule of Five for evaluating drug-likeness of small molecules, hydrogen-bond donors were

desirable in the compounds.4 The reaction chosen to fulfill all the aforementioned requirements

was the acid chloride amidation of amines. The amino group can in turn be introduced by the

reduction of a nitrile group easily incorporated into our cycloaddition products by using nitrile

substituted verdazyl radicals or dipolarophiles (Scheme 5-2).

163

Scheme 5-2. Reduction and subsequent amidation of a nitrile functionality.

This chapter will describe the DOS approach to generating a small library of verdazyl-

derived heterocycles. Over the course of one month, 25 new compounds were synthesized,

purified and characterized, demonstrating the compatibility of our substrates with DOS.

Combined with the compounds prepared from the work of the previous two chapters, a library of

43 compounds were prepared and tested against acute myeloid leukemia and multiple myeloma

cell lines. One particular compound, 50 (Figure 5-1, see Table 3-1), was able to decrease the

viability of the cells tested in both strains at the 250 µM range, which is an encouraging result

worth further pursuit.

Figure 5-1. Compound 50, synthesized from 1,5-dimethyl-3-phenyl-6-oxoverdazyl radical 16 and fumaronitrile.






164





Verdazyl radicals were synthesized according to published procedures.5-7







following abbreviations: s (singlet), d (doublet), t (triplet), q (quartet), sept (septet), m (multiplet)

and br (broad).

5.2.2 General Optimized Procedure for the 1, 3-Dipolar Cycloaddition of 1,5-Dimethyl-6-

oxoverdazyl Radicals with Various Dipolarophiles

Cycloaddition reactions were performed according to the general procedure (refer to

Section 3.2.4) with the modification of refluxing the reaction mixture in toluene to enable faster

reaction rates. Under these conditions reactions were typically completed after 3 h, as compared

to the 24 h reaction times that were initially required when the reactions were performed at

ambient temperature. Yields were typically 70% or higher under these conditions.

165

5.2.3 General Procedure for the Reduction of Nitriles with in situ t-Boc Protection

The nitrile-containing compound (100-200 mg, 0.30-0.40 mmol) was dissolved in 30 mL

of absolute ethanol. Roughly 100 mg of wet Raney nickel and 100 mg of ammonium chloride

were added to the solution. The mixture was cooled in an ice bath to 0 ºC and 5 molar excess of

di-tert-butyl dicarbonate was added to the stirred reaction mixture. Sodium borohydride was

then added in roughly 10 mg increments, with thorough mixing on a vortex mixer in between,

until the starting material was no longer visible on TLC. The reaction mixture was then filtered

through Celite and rinsed with ethyl acetate. The solvent was removed in vacuo and 20 mL of

ethyl acetate was added to the mixture. The suspension was washed with 5 mL saturated

solution of sodium bicarbonate, 5 mL of brine, and 5 mL of water. Ethyl acetate was removed in

vacuo and the product was purified by silica gel chromatography to give yields of 70% or higher.

5.2.4 General Procedure for the Amidation of t-Boc Protected Amines

The t-Boc protected amine (0.2 mmol) was stirred for 1 hour in a 5 mL (1:1 v/v) mixture of

trifluoroacetic acid (TFA) and methylene chloride. The acid and solvent were removed in vacuo

and the mixture was dissolved in 2 mL of pyridine. The acid chloride or acid anhydride of

choice (0.21 mmol) was then added to the reaction with gentle stirring for 15 minutes. The

solvent was removed in vacuo and 2 mL of water was added to the remaining oil. The

suspension was extracted with 3 x 4 mL of ethyl acetate. The combined organic layer was

washed with 1 mL saturated solution of ammonium chloride, 1 mL of brine, and 1 mL of water.

Ethyl acetate was removed in vacuo and the product was purified by silica gel chromatography

where necessary to give yields of 90% or higher.

The following verdazyl-derived heterocycles were synthesized with the procedures

described above. Due to structural similarities to other previously reported and fully

166

characterized verdazyl-derived heterocycles, the following were identified by their 1H and 13C

NMR data.

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

a][1,2,4,5]tetrazine-6,7-dicarboxylate (86)

1H NMR (400 MHz, CDCl3), δ: 7.73-7.69 (m, 2H), 7.49-7.38 (m, 3H), 4.66 (d, J = 3.5, 1H),

4.56-4.50 (m, 1H), 3.82 (s, 3H), 3.68-3.62 (m, 1H), 3.58 (s, 3H), 3.54-3.48 (m, 1H), 3.36 (s, 3H).

13C NMR (100 MHz, CDCl3), δ: 170.8, 169.9, 155.8, 153.4, 133.3, 130.9, 128.7, 127.4, 64.5,

52.9, 52.6, 47.3, 16.9, 36.7.

5.2.6 Synthesis of Methyl 4-(4-cyanophenyl)-2-methyl-1-oxo-2,6,7,8-tetrahydro-1H-


1H NMR (400 MHz, CDCl3), δ: 7.81-7.76 (m, 2H), 7.71-7.67 (m, 3H), 4.29-4.17 (m, 2H), 3.57 (s,

3H), 3.50-3.41 (m, 1H), 3.38 (m, 3H), 2.52-2.41 (m, 1H), 2.32-2.22 (m, 1H). 13C NMR (100

MHz, CDCl3), δ: 170.9, 153.7, 143.5, 135.3, 132.3, 127.6, 118.1, 113.9, 62.1, 52.4, 44.1, 36.9,

29.5.

5.2.7 Synthesis of Methyl 4-(1H-imidazol-5-yl)-2-methyl-1-oxo-2,6,7,8-tetrahydro-1H-


1H NMR (400 MHz, CDCl3), δ: 10.05 (s, br, 1H), 7.11 (t, J = 1.5, 1H), 7.08 (dd, J = 1.3, 2.2, 1H),

5.28 (dd, J = 3.7, 8.9), 3.87-3.78 (m, 1H), 3.68, (s, 3H), 3.62-3.52 (m, 1H), 3.26 (s, 3H), 2.61-

2.50 (m, 1H), 2.33-2.25 (m, 1H). 13C NMR (100 MHz, CDCl3), δ: 171.6, 154.4, 138.8, 138.2,

129.9, 117.4, 61.2, 52.4, 43.0, 36.2, 29.2.

167

5.2.8 Synthesis of 2-Methyl-4-(4-nitrophenyl)-1-oxo-2,6,7,8-tetrahydro-1H-pyrazolo[1,2-


1H NMR (400 MHz, CDCl3), δ: 8.36-8.26 (m, 2H), 8.00-7.92 (m, 2H), 4.47-4.38 (m, 1H), 4.37-

4.31 (m, 1H), 3.53-3.46 (m, 1H), 3.44 (s, 3H), 2.66-2.54 (m, 1H), 2.51-2.41 (m, 1H). 13C NMR

(100 MHz, CDCl3), δ: 153.0, 149.2, 141.3, 135.9, 134.6, 127.8, 124.0, 116.7, 50.2, 44.2, 37.4,

30.3.

5.2.9 Synthesis of 4-(4-Cyanophenyl)-2-methyl-1-oxo-2,6,7,8-tetrahydro-1H-pyrazolo[1,2-



4.00 (m, 1H), 3.63-3.54 (m, 1H), 3.36 (s, 3H), 3.27-3.18 (m, 1H), 2.36-2.26 (m, 1H). 13C NMR

(100 MHz, CDCl3), δ: 155.8, 148.8, 140.3, 131.4, 130.5, 128.4, 127.5, 127.4, 62.5, 44.5, 37.0,

28.9.

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

a][1,2,4,5]tetrazin-4-yl)benzonitrile (91)


4.62 (m, 1H), 4.36-4.26 (m, 1H), 3.75-3.66 (m, 1H), 3.25 (s, 3H), 2.64-2.54 (m, 1H), 2.28-2.18

(m, 1H). 13C NMR (100 MHz, CDCl3), δ: 154.7, 145.2, 138.8, 136.1, 131.8, 128.4, 128.3, 127.7,

127.3, 118.2, 113.2, 66.7, 45.2, 36.8, 33.3.

168

5.2.11 Synthesis of 2-Methyl-1-oxo-4-(pyridin-2-yl)-2,6,7,8-tetrahydro-1H-pyrazolo[1,2-


1H NMR (400 MHz, CDCl3), δ: 8.59 (d, J = 4.7, 1H), 8.05 (d, J = 7.9, 1H), 7.78 (dt, J = 1.9, 7.8,

1H), 7.35 (ddd, J = 1.0, 4.9, 7.9, 1H), 5.35 (dd, J = 3.2, 9.0, 1H), 4.30-4.21 (m, 1H), 3.53-3.43

(m, 1H), 3.38 (s, 3H), 2.66-2.55 (m, 1H), 2.47-2.38 (m, 1H). 13C NMR (100 MHz, CDCl3), δ:

153.4, 148.9, 148.7, 142.7, 136.9, 124.8, 122.0, 117.8, 51.1, 43.1, 37.0, 30.0.

5.2.12 Synthesis of 4-(4-Cyanophenyl)-N-isopropyl-2-methyl-1-oxo-2,6,7,8-tetrahydro-1H-

pyrazolo[1,2-a][1,2,4,5]tetrazine-6-carboxamide (93)

1H NMR (400 MHz, CDCl3), δ: 7.81-.75 (m, 2H), 7.71-7.66 (m, 2H), 5.37 (d, br, J = 8.0, 1H),

4.13-7.03 (m, 1H), 4.00-3.93 (m, 1H), 3.93-3.84 (m, 1H), 3.64-3.53 (m, 1H), 3.37 (s, 3H), 2.39-

2.19 (m, 2H), 1.05 (d, J = 6.8, 3H), 0.88 (d, J= 6.8, 3H). 13C NMR (100 MHz, CDCl3), δ: 168.5,

153.4, 144.1, 135.5, 132.3, 127.9, 118.0, 113.8, 64.5, 44.7, 41.6, 36.9, 29.9, 22.3, 22.2.

5.2.13 Synthesis of Dimethyl 5-methyl-4-oxo-7-phenyl-1,2,3,3a,4,5-hexahydropyrazolo[1,5-

d][1,2,4]triazine-3,3a-dicarboxylate (94)

1H NMR (400 MHz, CDCl3), δ: 7.71-7.58 (m, 2H), 7.45-7.31 (m, 3H), 5.49 (d, br, J = 5.9, 1H),

3.84 (s, 3H), 3.82-3.79 (m, 1H), 3.75 (s, 3H), 3.55-3.78 (m, 1H), 3.39-3.33 (m, 1H), 2.83 (s, 3H).

13C NMR (100 MHz, CDCl3), δ: 168.9, 167.5, 149.7, 147.3, 129.6, 128.1, 128.1, 127.6, 127.5,

86.8, 53.0, 52.3, 38.8, 37.9, 36.5.

169

5.2.14 Synthesis of Methyl 7-(4-cyanophenyl)-5-methyl-4-oxo-1,2,3,3a,4,5-

hexahydropyrazolo[1,5-d][1,2,4]triazine-3a-carboxylate (95)

1H NMR (400 MHz, CDCl3), δ: 7.77-7.73 (m, 2H), 7.65-7.61 (m, 2H), 5.62 (d, J = 5.3, 1H), 3.81

(s, 3H), 3.43-3.33 (m, 1H), 3.29-3.17 (m, 1H), 2.88 (s, 3H), 2.88-2.85 (m, 1H), 2.14-2.05 (m,

1H). 13C NMR (100 MHz, CDCl3), δ: 170.2, 155.3, 141.3, 135.1, 131.8, 128.0, 117.7, 112.8,

62.4, 52.2, 36.3, 27.2, 13.9.

5.2.15 Synthesis of Isopropyl 2-(3-(4-cyanophenyl)-1-methyl-1H-1,2,4-triazol-5-

yl)ethylcarbamate (96)

1H NMR (400 MHz, CDCl3), δ: 8.20-8.14 (m, 2H), 7.74-7.68 (m, 2H), 5.33 (t, br, J = 6.0, 1H),

4.91 (p, J = 6.0, 1H), 3.88 (s, 3H), 3.67 (q, J = 6.4, 2H), 2.99 (t, J = 6.4, 2H), 1.64 (s, br, 1H),

1.22 (d, J = 6.0, 6H). 13C NMR (100 MHz, CDCl3), δ: 159.0, 156.2, 154.9, 135.1, 132.3, 126.4,

118.7, 112.2, 68.2, 38.1, 35.2, 26.3, 22.0.

5.2.16 Synthesis of Methyl 2-(1-methyl-3-(pyridin-2-yl)-1H-1,2,4-triazol-5-


1H NMR (400 MHz, CDCl3), δ: 8.72 (d, J = 4.7, 1H), 8.08 (d, J = 8.2, 1H), 7.78 (dt, J = 1.9, 7.8,

1H), 7.35 (ddd, J = 1.0, 4.9, 7.9, 1H), 5.58 (t, br, J = 6.1, 1H), 3.91 (s, 3H), 3.72 (q, J = 6.1, 2H),

3.67 (s, 3H), 3.01 (t, J = 6.6, 2H). 13C NMR (100 MHz, CDCl3), δ: 160.2, 157.0, 154.6, 149.8,

149.6, 136.6, 123.6, 121.2, 52.0, 38.2, 35.2, 26.2.

170

5.2.17 Synthesis of Methyl 2-(3-(3-fluoropyridin-4-yl)-1-methyl-1H-1,2,4-triazol-5-


1H NMR (400 MHz, CDCl3), δ: 8.59 (d, J = 2.8, 1H), 8.49 (d, J = 4.9, 1H), 7.97 (dd, J = 4.9, 6.3,

1H), 5.54 (t, br, J = 7.5, 1H), 3.92 (s, 3H), 3.70 (q, J = 6.2, 2H), 3.68 (s, 3H), 3.02 (t, J = 6.2, 2H).

13C NMR (100 MHz, CDCl3), δ: 157.5, 157.0, 155.1, 155.0, 154.6, 145.7, 145.6, 139.6, 139.3,

125.8, 125.7, 122.7, 52.1, 38.1, 35.4, 26.1.

5.2.18 Synthesis of Isopropyl 2-(3-(3-fluoropyridin-4-yl)-1-methyl-1H-1,2,4-triazol-5-


1H NMR (400 MHz, CDCl3), δ: 8.60 (s, 1H), 8.50 (d, J = 4.6, 1H), 7.98 (t, J = 5.7, 1H), 5.37 (t,

br, J = 6.5, 1H), 4.91 (sept, J = 6.3, 1H), 3.93 (s, 3H), 3.68 (q, J = 6.1, 2H), 3.03 (t, J = 6.1, 2H),

1.22 (d, J = 6.3, 6H). 13C NMR (100 MHz, CDCl3), δ: 157.5, 156.2, 155.0, 155.0, 154.7, 145.7,

145.6, 139.6, 139.3, 125.8, 125.7, 122.7, 68.3, 38.1, 35.4, 26.2, 22.0.

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

a][1,2,4,5]tetrazin-6-yl)methyl)tert-butylcarbamate (100)


4.02-3.90 (m, 2H), 3.58-3.48 (m, 1H), 3.34 (s, 3H), 3.07 (t, J = 6.7, 2H), 2.31-2.19 (m, 1H),

1.93-1.83 (m, 1H), 1.32 (s, 9H). 13C NMR (100 MHz, CDCl3), δ: 156.6, 155.4, 147.9, 131.2,

130.7, 128.6, 127.4, 79.5, 61.3, 43.8, 43.3, 36.9, 28.4, 28.0.

171

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

a][1,2,4,5]tetrazin-6-yl)methyl)acetamide (101)


4.08-4.00 (m, 1H), 4.00-3.93 (m, 1H), 3.58-3.48 (m, 1H), 3.36 (s, 3H), 2.35-2.24 (m, 1H), 2.04

(d, J = 8.8, 2H), 1.91-1.81 (m, 1H), 1.72 (s, 3H). 13C NMR (100 MHz, CDCl3), δ: 170.1, 156.6,

147.6, 131.2, 130.9, 128.8, 127.2, 60.9, 43.9, 42.4, 37.0, 28.6, 22.8, 22.5.

5.2.21 Synthesis of Methyl 4-(4-(isobutyramidomethyl)phenyl)-2-methyl-1-oxo-2,6,7,8-

tetrahydro-1H-pyrazolo[1,2-a][1,2,4,5]tetrazine-6-carboxylate (102)


4.50-4.44 (m, 2H), 4.26-4.15 (m, 2H), 3.57 (s, 3H), 3.50-3.41 (m, 1H), 3.35 (s, 3H), 2.48-2.36 (m,

2H), 2.29-2.18 (m, 2H), 1.20 (dd, J = 2.5, 7.2, 6H). 13C NMR (100 MHz, CDCl3), δ: 176.8,

171.1, 154.1, 145.5, 141.5, 130.0, 128.0, 127.8, 127.7, 62.0, 52.3, 44.0, 42.9, 36.6, 35.5, 29.6,

19.5, 18.7.

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

a][1,2,4,5]tetrazin-4-yl)benzyl)acetamide (103)

1H NMR (400 MHz, CDCl3), δ: 7.44-7.34 (m, 2H), 7.21-7.10 (m, 5H), 6.95-6.86 (m, 2H), 6.12 (t,

br, J = 5.6, 1H), 4.72-4.66 (m, 1H), 4.40 (d, J = 6.0, 2H), 4.36-4.27 (m, 1H), 3.65-3.56 (m, 1H),

3.16 (s, 3H), 2.61-2.49 (m, 1H), 2.25-2.14 (m, 1H), 2.03 (s, 3H). 13C NMR (100 MHz, CDCl3),

δ: 169.9, 155.0, 146.9, 140.6, 139.4, 130.8, 128.2, 127.9, 127.7, 127.4, 127.2, 66.0, 44.8, 43.1,

36.4, 33.1, 23.1.

172

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

a][1,2,4,5]tetrazin-4-yl)benzyl)isobutyramide (104)

1H NMR (400 MHz, CDCl3), δ: 7.40-7.35 (m, 2H), 7.19-7.10 (m, 5H), 6.93-6.87 (m, 2H), 5.99 (t,

br, J = 6.1, 1H), 4.73-4.64 (m, 1H), 4.40 (d, J = 6.1, 2H), 4.36-4.27 (m, 1H), 3.65-3.56 (m, 1H),

3.16 (s, 3H), 2.62-2.50 (m, 1H), 2.46-2.35 (m, 1H), 2.25-2.15 (m, 1H), 1.18 (d, J = 7.1, 6H). 13C

NMR (100 MHz, CDCl3), δ: 176.4, 155.0, 149.6, 147.0, 140.9, 139.4, 135.9, 130.7, 128.2, 127.9,

127.8, 127.7, 127.3, 127.2, 123.6, 66.0, 44.8, 42.8, 36.4, 35.5, 33.2, 19.5.

5.2.24 Synthesis of Methyl 2-(3-(4-(tert-butylcarbamoylmethyl)phenyl)-1-methyl-1H-1,2,4-

triazol-5-yl)ethylcarbamate (105)


4.94 (, t, br, J = 7.0, 1H), 4.34 (d, J = 5.8, 2H), 3.83 (s, 3H), 3.70,-3.63 (m, 5H), 2.95 (t, J = 6.6,

2H), 1.47 (s, 9H). 13C NMR (100 MHz, CDCl3), δ: 160.4, 157.0, 155.8, 154.2, 139.7, 129.9,

127.5, 126.2, 79.4, 52.0, 44.4, 38.2, 34.9, 28.2, 26.1.

5.2.25 Synthesis of Isopropyl 2-(3-(4-(tert-butylcarbamoylmethyl)phenyl)-1-methyl-1H-

1,2,4-triazol-5-yl)ethylcarbamate (106)


5.01-4.84 (m, 2H), 4.35 (d, J = 5.6, 2H), 3.85 (s, 3H), 3.66 (q, J = 6.1, 2H), 2.96 (t, J = 6.1, 2H),

1.47 (s, 9H), 1.22 (d, J = 6.4, 6H). 13C NMR (100 MHz, CDCl3), δ: 160.4, 156.2, 155.8, 154.3,

139.7, 130.0, 127.5, 126.2, 79.4, 68.1, 44.4, 38.1, 34.9, 28.3, 26.2, 22.0.

173

5.2.26 Synthesis of Methyl 2-(3-(4-(acetamidomethyl)phenyl)-1-methyl-1H-1,2,4-triazol-5-


1H NMR (400 MHz, CDCl3), δ: 8.06-7.96 (m, 2H), 7.37-7.29 (m, 2H), 5.82 (br, 1H), 5.63 (t, br,

J = 6.0, 1H), 4.47 (d, J = 5.6, 2H), 3.85 (s, 3H), 3.72-3.63 (m, 5H), 2.96 (t, J = 6.5, 2H), 2.05 (s,

3H). 13C NMR (100 MHz, CDCl3), δ: 169.8, 160.3, 157.0, 154.2, 138.9, 130.2, 127.9, 126.3,

68.0, 53.3, 43.4, 38.2, 35.0, 23.2.

5.2.27 Synthesis of Isopropyl 2-(3-(4-(acetamidomethyl)phenyl)-1-methyl-1H-1,2,4-triazol-

5-yl)ethylcarbamate (108)

1H NMR (400 MHz, CDCl3), δ: 8.00 (d, J = 8.1, 2H), 7.33 (d, J = 8.1, 2H), 5.92 (s, br, 1H), 5.45

(t, br, J = 6.3, 1H), 4.90 (sept, J = 6.4, 1H), 4.46 (d, J = 5.8, 2H), 3.85 (s, 3H), 3.65 (q, J = 6.0,

2H), 2.97 (t, J = 7.2, 2H), 2.04 (s, 3H), 1.21 (d, J = 6.4, 6H). 13C NMR (100 MHz, CDCl3), δ:

169.8, 160.2, 156.2, 154.3, 138.9, 130.2, 127.9, 126.3, 68.1, 43.4, 38.2, 35.0, 26.2, 23.1, 22.0.

5.2.28 Synthesis of Methyl 2-(3-(4-(isobutyramidomethyl)phenyl)-1-methyl-1H-1,2,4-


1H NMR (400 MHz, CDCl3), δ: 8.00 (d, J = 8.1, 2H), 7.33 (d, J = 8.1, 2H), 5.81 (t, br, J = 6.0,

1H), 5.65 (t, br, J = 5.4, 1H), 4.47 (d, J = 6.1, 2H), 3.84 (s, 3H), 3.71-3.64 (m, 5H), 2.96 (t, J =

5.8, 2H), 2.41 (sept, J = 6.1, 1H), 1.20 (d, J = 6.9, 6H). 13C NMR (100 MHz, CDCl3), δ: 176.7,

160.3, 157.0, 154.2, 169.3, 130.1, 127.8, 126.3, 52.0, 43.1, 38.2, 35.6, 35.0, 26.1, 19.5.

174

5.2.29 Synthesis of Isopropyl 2-(3-(4-(isobutyramidomethyl)phenyl)-1-methyl-1H-1,2,4-



5.45 (t, br, J = 6.3, 1H), 4.90 (sept, J = 5.6, 1H), 4.47 (d, J = 5.9, 2H), 3.84 (s, 3H), 3.65 (q, J =

6.2, 2H), 2.96 (t, J = 6.2, 2H), 2.41 (sept, J = 7.0, 1H), 1.26-1.16 (m, 12H). 13C NMR (100 MHz,

CDCl3), δ: 176.7, 160.3, 156.2, 154.3, 139.3, 130.1, 127.8, 126.3, 68.1, 43.1, 38.2, 35.5, 35.0,

26.2, 22.0, 19.5.


5.3.1 First Generation Library of Verdazyl-Derived Heterocycles – Verdazyl-Initiated

Cycloaddition Products

Targeted cycloadducts bearing nitrile functionalities for amidation, as well as acidic α-

protons for rearrangement reactions, were prepared via the general cycloaddition procedure (see

Section 5.2.2) with the corresponding verdazyl radicals and dipolarophiles (Scheme 5-3).

Scheme 5-3. Cycloadducts derived from various 1,5-dimethyl-6-oxoverdazyl radicals and dipolarophiles bearing nitriles and acidic α-protons.

175

5.3.2 Second Generation Library of Verdazyl-Derived Heterocycles – Rearrangement

Products of Verdazyl-Derived Cycloadducts

Rearrangement reactions of verdazyl-derived cycloadducts to the corresponding

pyrazolotriazinones were performed with sodium hydride or potassium tert-butoxide in dry THF

according to the general procedures (see Sections 4.2.10, 4.2.15). Rearrangement reactions of

verdazyl-derived cycloadducts to the corresponding triazoles were performed with methyl, ethyl,

and isopropyl alkoxides according to the general procedure (see Section 4.2.12) (Scheme 5-4).

Scheme 5-4. Base and nucleophile-induced rearrangements of verdazyl-derived cycloadducts to pyrazolotriazinones and triazoles.

5.3.3 Third Generation Library of Verdazyl-Derived Heterocycles – Amide Derivatives

from the Reduction of Nitriles and Subsequent Amidation

Several nitrile reduction procedures were attempted. The Raney nickel catalyst was

paired with reducing agents such as hydrazine, formic acid,8 hydrazinium monoformate,9 sodium

cyanoborohydride, and sodium borohydride.10,11 Optimal results (>70% yield) were achieved by

sodium borohydride with Raney nickel catalysis. However, attempts at the direct reduction to

the amine often resulted in a side product which was suspected to be a dimer between the fully

reduced amine with the nitrile (Scheme 5-5) or the partially reduced imine (Scheme 5-6) due to

176

the roughly two-fold increase in molecular weight as observed in its mass spectrometry data

(theoretical: 317.34 g mol-1; actual: 631.33 g mol-1).

Scheme 5-5. Dimerization between an amine and a nitrile.

Scheme 5-6. Dimerization between an amine and an imine.

To prevent this suspected dimerization reaction, t-Boc anhydride was added to the

reduction reaction mixture in situ to yield the t-Boc protected amine 83 in a one pot reaction,

which also added one extra derivative per reduction reaction. Trifluoroacetic acid (TFA)

removal of the protecting group provided the trifluoroacetate salt of the free amine 84, which

was deprotonated with base and reacted in near quantitative yields with acid chlorides and acid

anhydrides to give the corresponding amides 85 (Scheme 5-7).

Scheme 5-7. In situ t-Boc protection of nitrile reduction and subsequent amidation.

177

5.3.4 DOS Library of Verdazyl-Derived Heterocycles

Using the above described procedures, 25 compounds were synthesized over the period

of one month (Figure 5-2, Figure 5-3, Figure 5-4). Combined with the work of the previous two

chapters, this library of 43 compounds was tested for biological activity in cell lines of acute

myeloid leukemia and multiple myeloma.

Figure 5-2. First generation DOS library of verdazyl-derived heterocycles; verdazyl-initiated cycloadducts.

178

Figure 5-3. Second generation DOS library of verdazyl-derived heterocycles; rearrangement products of verdazyl-derived cycloadducts.

179

N

N N

N

O

NHC5H9O2*

N

N N

N

O

NH

ON

N N

N

O

CO2CH3

NH

O

N

N N

N

O

Ph

NH

O

N

N N

N

O

Ph

NH

O

N

NN

NH

O

O

*O2C5H9HN

N

NN

NH

O

O

*O2C5H9HN

N

NN

NH

O

O

HN

O

N

NN

NH

O

O

HN

O

N

NN

NH

O

O

HN

O

N

NN

NH

O

O

HN

O

100 101 102 103 104

105 106

107 108

109 110

*C5H9O2 - ter t-butoxycarbonyl

Figure 5-4. Third generation DOS library of verdazyl-derived heterocycles; amido-derivatives from reduction of nitrile-containing verdazyl-derived heterocycles.

180

5.3.5 Biological Activity Testing

The library of 43 compounds that were synthesized were tested for their ability to kill

cells at concentrations of 5000 and 500 µM with cell lines of acute myeloid leukemia and

multiple myeloma. Out of the 43 verdazyl-derived heterocycles, compound 50 (Figure 5-1, see

Table 3-1) showed the most promising results, decreasing the viability of the cells tested at 100%

at the lower (500 µM) concentration for both cell lines. A dose response experiment was

performed to find the lowest concentration at which this compound could be used to kill these

cancer cells. For both cell lines, compound 50 was active at concentrations as low as 250 µM

(Figure 5-5). While these results are promising, they are not good enough to define a new cancer

drug. However, it should be noted that on a relative basis, the sample size of compounds that

were tested was very small relative to the many cases where hundreds of compounds in a series

are tested. Since we were not targeting compounds with known active structures, the fact that

one of the synthesized compounds showed some activity is encouraging and warrants further

work in this area.

Figure 5-5. Dose response curve of compound 50 for acute myeloid leukemia (AML) and multiple myeloma (LP) cell lines.

181


In conclusion, novel cycloaddition and rearrangement reactions involving verdazyl

radicals were demonstrated to be viable as a DOS library generation strategy. In a rapid and

straightforward manner, 25 compounds were synthesized, demonstrating the potential of

introducing much larger libraries of structurally unique heterocycles. In testing the biological

activity of a library of 43 verdazyl-derived heterocycles, one particular compound was able to

decrease the viability of the cells tested at the 250 µM range in acute myeloid leukemia and

multiple myeloma cell lines.

5.5 Future Work

The DOS approach was demonstrated to be compatible with the chemistry described in

the previous chapters of this thesis. The initial results with the chemistry and biological testing

are encouraging enough to warrant further work to build larger libraries of heterocycles with

other verdazyl derivatives, dipolarophiles, and derivable functionalities. To that end, 1,5-

dibenzyl-6-oxoverdazyls have been shown to undergo the 1,3-dipolar cycloaddition reaction

(Scheme 5-8); Suzuki coupling reactions have been attempted with moderate success on

bromine-containing verdazyl-derived cycloadducts (Scheme 5-9); amines have been used as

nucleophiles to form triazolyl urea compounds (Scheme 5-10) as opposed to the aforementioned

carbamates. The long term plan is to test non-specifically for biological activity from any new

compounds that result from this extension of the initial work in this area. If any compounds

should show promising results, further assessment and derivatization will be pursued.

182

Scheme 5-8. 1,5-Dibenzyl-3-phenyl-6-oxoverdazyl radical undergoing 1,3-dipolar cycloaddition with butyl acrylate.

Scheme 5-9. The Suzuki coupling reaction of bromo- containing cycloadducts and boronic acids.

Scheme 5-10. The rearrangement reaction of acrylonitrile-derived cycloadducts with amines.

5.6 References


2008, 4571-4574.

(2) Schreiber, S. L. Science 2000, 287, 1964-1969.

(3) Tan, D. S. Nature Chem. Bio. 2005, 1, 74-84.

(4) Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J. Adv. Drug Del. Rev. 1997, 23, 3-25.



183


(8) Gowda, D. C.; Gowda, A. S. P.; Baba, A. R.; Gowda, S. Synth. Comm. 2000, 30, 2889-2895.

(9) Gowda, S.; Gowda, D. C. Tetrahedron 2002, 58, 2211-2213.

(10) Wu, B.; Zhang, J.; Yang, M.; Yue, Y.; Ma, L.; Yu, X. Arkivoc 2008, 12, 95-102.

(11) Pogorelic, I.; Filipan-Litvic, M.; Merkas, S.; Ljubic, G.; Cepanec, I.; Litvic, M. J. Molecular

Catalysis A: Chemical 2007, 274, 202-207.

verdazyl radicals as mediators in living radical ......verdazyl radicals as mediators in living...

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