Synthesis and Characterization of Polyurethane Dendrimers and Subsequent Click Reactions

Home , Butyne, Dendrimer

MIAMI UNIVERSITY The Graduate School

Certificate for Approving the Dissertation

We hereby approve the Dissertation

Fahad M. Alminderej

Candidate for the Degree

Doctor of Philosophy

______Richard T. Taylor, Director

______C. Scott Hartley, Reader

______Benjamin W. Gung, Reader

______Neil D. Danielson, Reader

______Fazeel Khan, Graduate School Representative

ABSTRACT

SYNTHESIS AND CHARACTERIZATION OF POLYURETHANE DENDRIMERS AND SUBSEQUENT CLICK REACTIONS

Fahad M. Alminderej

The synthesis of polyurethane dendrimers was achieved with a divergent approach, using different cores and building different generations. Diethylene glycol, triethylene glycol, 2-butyne-1,4-diol and 2-butene-1,4-diol were used as cores to synthesize polyurethane dendrimers by using diphenyl phosphoryl azide.

The convergent strategy and the selectivity of the reactions of alkene alcohols on the periphery have been applied to the synthesis of a polyurethane wedges. The first and second generation polyurethane wedges with allyl or pentene peripheries were prepared. The thiol functional group was reacted with an alkene to create first and second generation polyurethane wedges with thiol-ene click periphery. The polyurethane wedges were used to synthesize polyurethane dendrimers.

The synthesis of the first and second generation polyurethane wedges with peripheral alkyne groups was achieved with a convergent approach. The first and second generation polyurethane wedges with a pentyne periphery were prepared. The first generation polyurethane with pentyne periphery was useful for click reaction with boronic acid, 4-azidobenzoic acid, and 3-azido-7-hydroxycoumarin. The first and second generation polyurethane wedges with pentyne or triazoles peripheries were used to prepare several kinds of dendrimers.

SYNTHESIS AND CHARACTERIZATION OF POLYURETHANE DENDRIMERS AND SUBSEQUENT CLICK REACTIONS

A DISSERTATION

Presented to the Faculty of

Miami University in partial

fulfillment of the requirements

for the degree of

Doctor of Philosophy

Department of Chemistry & Biochemistry

Fahad M. Alminderej

The Graduate School Miami University Oxford, Ohio

2016

Dissertation Director: Richard T. Taylor

Fahad M. Alminderej

2016

TABLE OF CONTENTS

CHAPTER PAGE

List of tables viii List of figures ix List of abbreviations & acronyms xii Acknowledgement xiii

I Literature Review of Dendrimers 1 1-1 Theoretical 1

1-2 Synthesis of Dendrimers 2

1-3 Dendrimers review 5

1.4 Polyurethane review 7

1-4-1 Introduction 7

1-4-2 Linear polyurethanes 8

1-4-3 Polyurethane dendrimers and hyperbranched polymers 10

1-4-4 Application of polyurethane dendrimers 16

1-5 Our group research 17

1-6 References 20

II Synthesis of polyurethane dendrimer via divergent approach 23

2-1 Introduction 23

2-1-1 Specific aims 23

2-1-2 Synthetic strategies 23

iii 2-2 Divergent syntheses of polyurethane dendrimers 24

2-2-1 Synthesis of branching monomer 24

2-2-2 Synthesis of polyurethane dendrimer 25

2-2-2-1 Synthesis of diethylene glycol (DEG) polyurethane dendrimer 27

2-2-2-2 Synthesis of triethylene glycol (TEG) polyurethane dendrimer 28

2-2-2-3 Synthesis of 1,4-Bis(2-hydroxyisopropyl)benzene polyurethane dendrimer 29

2-2-2-4 Synthesis of 2-butyne-1,4-diol polyurethane dendrimer 30

2-2-2-5 Synthesis of 2-butene-1,4-diol polyurethane dendrimer 31

2-3 Core effect 32

2-4 Solvent effect 33

2-5 Conclusions 34

2-6 Experimental section 35

2-6-1 Synthesis of branching monomer 35

2-6-2 Synthesis of polyurethane dendrimers 37

2-7 References 44

III Synthesis of alkene polyurethane dendrimer via convergent approach 45

3-1 Introduction 45

3-1-1 Specific aims 46

3-1-2 Synthetic strategies 46

3-2 Synthesis of polyurethane wedge with ally periphery 47

3-2-1 Initial model A 47

iv 3-2-2 Initial model B 49

3-2-3 Synthesis of branching monomer 51

3-2-4 Synthesis of polyurethane wedge with allyl periphery 52

3-2-5 Synthesis of polyurethane dendrimer with allyl periphery 55

3-3 Conclusions 56

3-4 Experimental section 57 3-5 Synthesis of polyurethane with pentene periphery 63

3-5-1 Synthesis of polyurethane wedge with pentene periphery 63

3-5-2 Thiol-ene “click” chemistry of polyurethane wedge with pentene periphery65 3-5-3 Synthesis of polyurethane dendrimers 67

3-5-3-1 Synthesis of polyurethane dendrimers from 4,4'-MDI and 4,4'- biphenyldicarboxylic acid. 68

3-5-3-2 Synthesis of polyurethane dendrimers from trimesic acid 69

3-5-3-3 Synthesis of polyurethane dendrimers from sebacic acid as ester functional group core 70

3-5-3-4 Synthesis of polyurethane dendrimers from porphyrin as ester functional group core 72

3-5-4 Conclusions 74

3-5-5 Experimental section 74

3-6 References 79

IV Synthesis of alkyne polyurethane dendrimer via convergent approach and click chemistry reactions 80

4-1 Introduction 80

v 4-1-1 Specific aims 81

4-1-2 Synthetic strategies 81

4-2 Synthesis of polyurethane with propargyl periphery 83

4-2-1 Synthesis of polyurethane wedge with propargyl periphery 83

4-2-2 Synthesis of polyurethane dendrimers 86

4-3 Conclusions 87

4-4 Experimental section 88 4-5 Synthesis of polyurethane with pentyne periphery 90

4-5-1 Synthesis of polyurethane wedge with pentyne periphery 90

4-5-2 Synthesis of polyurethane wedge with a subsequent click reaction periphery92

4-5-2-1 First generation wedge click reaction with 4-azidobenzoic acid 92

4-5-2-2 First and second generation wedge click reaction with phenyl boronic acid93

4-5-2-3 First generation wedge click reaction with 3-azido-7-hydroxycoumarin 95

4-5-3 Synthesis of polyurethane dendrimers 96

4-5-3-1Synthesis of polyurethane dendrimers from trimesic core with pentyne periphery 97

4-5-3-2 Synthesis of polyurethane dendrimers from trimesic core with phenyl-triazoles periphery 99

4-5-3-3 Synthesis of polyurethane dendrimers from sebacic core with pentyne periphery 100

4-5-3-4 Synthesis of polyurethane dendrimers from sebacic core as ester functional group core 100

vi 4-5-3-5 Synthesis of polyurethane dendrimers from trimesic as ester functional group core 102

3-5-3-6 Synthesis of polyurethane dendrimers from porphyrin as ester functional group core 104

4-6 Conclusions 106

4-7 Experimental section 106

Conclusion and future research 114

4-8 References 115

vii LIST OF TABLES

TABLE PAGE

1. The cores 27

viii

LIST OF FIGURES

FIGURE PAGE

1. Model of dendrimer and hyperbranched polymer 2 2. Schematic of the divergent path 3 3. Schematic of the convergent path 4 4. Polyamine dendrimer synthesis by divergent path 5 5. Poly (ether amide) dendrimers by a divergent path 6 6. Poly (benzyl ether) dendrimers 7 7. Linear polyurethanes synthesized 8 8. Linear polyurethanes synthesized 8 9. Linear polyurethanes synthesized 9 10. Linear polyurethanes synthesized by DPPA 9 11. Polyurethanes synthesized by polymer-supported DPPA 10 12. Polyurethanes synthesized by CDI 10 13. Polyurethane dendrimers by Spindler and Frechet 11 14. Polyurethane dendrimers by Bruchmann et al 12 15. Polyurethane dendrimers by Taylor et al 13 16. Synthesis of alternating urethane and urea aliphatic dendrimers 14 17. Polyurethane dendrimer by Alison Stoddart et al. 15 18. Polyurethane dendrimer by Moeller et al. 16 19. Aliphatic polyurethane dendrimer for drug delivery system 17 20. Porphyrin-cored third generation polyurethane dendrimer 18 21. Divergent synthesis of a polyurethane dendrimer 19 22. Divergent path synthesis strategies 24 23. Synthesis of branching monomer 25 24. Synthesis of isocyanate intermediate 26 25. Diethylene glycol polyurethane dendrimer synthesis 28 26. Triethylene glycol polyurethane dendrimer synthesis 29 27. 1,4-bis(2-hydroxyisopropyl)benzene polyurethane dendrimer synthesis 30 28. 2-butyne-1,4-diol polyurethane dendrimer synthesis 31

ix 29. 2-butyne-1,4-diol polyurethane dendrimer synthesis 32 30. Mechanism of Curtius rearrangement 34 31. Synthetic strategies of alkene wedge and dendrimers 47 32. Synthesis of polyurethane wedge with ally periphery initial model A 48 33. Synthesis of polyurethane wedge with ally periphery initial model B 50 34. Synthesis of branching monomer 52 35. Synthesis of polyurethane wedge with allyl periphery 53 1 13 36. H and C NMR spectrum of 11 in CDCl3-d1 55 37. Synthesis of polyurethane dendrimer with allyl periphery 56 38. Synthesis of polyurethane wedge with pentene periphery 64 1 39. H NMR spectrum of 20 in CDCl3-d1 65 13 40. C NMR spectrum of 21 in CDCl3-d1 65 41. Thiol-ene “click” chemistry of polyurethane wedge 66 1 42. H NMR spectrum of 22 in CDCl3-d1 67 43. Synthesis of polyurethane dendrimers 68 44. 4,4'-MDI and 4,4'-biphenyldicarboxylic acid 68 45. Synthesis of polyurethane dendrimers from trimesic acid 96 46. Synthesis of dendrimers 70 47. Synthesis of polyurethane dendrimers from sebacic acid as ester core 71 48. Synthesis of polyurethane dendrimers from porphyrin as ester core 73 49. Synthetic strategies of alkyne wedge and dendrimers 82 50. Synthesis of first generation wedge with propargyl periphery 83 1 13 51. H and C NMR spectrum of 4 in CDCl3-d1 84 52. Synthesis of second generation wedge with propargyl periphery 85 53. Synthesis of first generation of polyurethane with propargyl periphery 86 54. Synthesis of first generations polyurethane dendrimers 87 55. Synthesis of first and second generation polyurethane wedge with pentyne periphery 91 1 56. H NMR spectrum of 8 in CDCl3-d1 92 57. Synthesis of first generation wedge click reaction with 4-azidobenzoic acid 93

x 58. Synthesis of first and second generation wedge click reaction with phenyl boronic acid 94 1 13 59. H and C NMR spectrum of 12 in CDCl3-d1 95 60. Synthesis of first generation wedge click reaction with 3-azido-7-hydroxycoumarin 96 61. Synthesis of polyurethane dendrimers from trimesic acid 98 62. Synthesis of polyurethane dendrimers with phenyl-triazoles periphery 99 63. Synthesis of polyurethane dendrimers from sebacic core 100 64. Synthesis of polyurethane dendrimers from sebacic core as ester functional group core 102 65. Synthesis of polyurethane dendrimers from trimesic as ester functional group core 103 66. Synthesis of polyurethane dendrimers from porphyrin as ester functional group core 105

xi LIST OF ABBREVIATIONS & ACRONYMS

DPPA Diphenylphosphoryl azide

FT-IR Fourier Transform-Infrared spectroscopy

MALDI-TOF Matrix-assisted laser desorption/ionization-time of flight

MS Mass spectrometry

NMR Nuclear magnetic resonance spectroscopy

TLC Thin-layer chromatography

TBAF Tetra-n-butylammonium fluoride

CDI Carbonyl di-imidazole

DEG Diethylene glycol

TEG Triethylene glycol

xii ACKNOWLEDGEMENTS

I wish to offer my special gratitude and sincerest appreciation to Dr. Richard T. Taylor research advisor, for his invaluable instruction, teaching, and mentoring throughout the duration of my studies. I would like to thank him for the confidence, farsighted guidance, continuous encouragement and support he has to give to me throughout the research and my graduate program.

My sincerest gratitude to my dissertation committee members Dr. C. Scott Hartley, Dr. Benjamin W. Gung, Dr. Neil D. Danielson and Dr. Fazeel Khan for their continual generosity, support, and advice. I would like to thank the faculty and staff in the Department of Chemistry and Biochemistry at Miami University for their guidance and teaching. I wish to thank the Department of Chemistry and Biochemistry of Miami University for giving me the chance to use a variety of advanced scientific instruments and facilities. I appreciate the organic students and lab mate in the chemistry department for their support and advice.

Lastly, I would like to thank my parents greatly for their encouragement and strong support and my brothers and sisters for believing in me. I especially appreciate my wife Wafa Alsaqabi, my sons Basil and Mohammad and my daughters Mayar, Alanoud and Nora for their remarkable patience and support.

xiii Chapter I 1. Literature Review of Dendrimers

1-1. Theoretical

In general, the development synthetic of dendritic polymers establishes two kinds of branched macromolecule: dendrimers, and hyperbranched polymers (Figure 1).1 Dendrimers are usually defined as symmetrical, tree-like macromolecules, monodisperse and perfectly branched.2 Hyperbranched polymers have irregularly branched or imperfectly branched structures with different degrees of branching and are polydisperse in size and structure.3,4 Dendrimers and hyperbranched polymers are formed from the same type of monomers but are synthesized using different techniques. Dendrimers are typically synthesized via a stepwise approach, while hyperbranched polymers are prepared by a one-step polymerization. The properties of dendrimers, such as shape, size, flexibility, polarity, and solubility are easy to control through the choice of the building blocks for the higher generations and the functional groups selected for the periphery. This gives dendrimers an advantage over hyperbranched polymers in that they can be designed with specific, unique properties and structures.5-7

Dendrimer’s comprise the core, the interior branching units, and the periphery or terminal groups. The interior branching unit(s) are called generations (G). The (s) implies and explains that there might be more than one interior branching unit. The core can be multivalent from two or more.

1 Dendrimer Hyperbranched polymer

Figure 1. Models of dendrimer and hyperbranched polymer.

1-2. Synthesis of dendrimers

Dendrimers are often synthesized using two-step reactions. The first step is the building of one generation by an addition of the monomer. The second step involves activating the first generation, and enabling it to react with new monomers to build new generations. There are two main synthetic strategies to the synthesis of dendrimers: divergent and convergent. They are similar in the synthesis steps but differ in dendritic direction.2,8

The divergent path starts from the core which has two or more functional groups and builds up the dendrimer layer by layer towards the periphery. It is an “inside-out” path (Figure 2). In the first step, a monomer should have just one functional group that is reactive. The active functional group reacts with the multi-functionalized core to obtain the first generation dendrimer with an unreactive periphery. In the second step, the unreactive functional groups on the periphery is reactive to get the first generation dendrimer with a reactive periphery which is able to react with other monomers. In the divergent path, the number of reactions increases with every layer. The first generation dendrimer;s reactive functional group periphery reacts with monomers to yield a second generation dendrimer with an unreactive periphery.

2 activation

first generation dendrimer

activation

second generation dendrimer Unreactive group Connect groups

Figure 2. Schematic of the divergent path

The convergent path begins the synthesis by assembly of the macromolecule at the periphery of the dendrimer moving toward the core. The main synthetic strategies of convergent dendrimers build wedges that connect with a core. It is an “outside-in” path (Figure 3). The first step starts from a monomer that contains two or more reactive functional groups and one unreactive functional group. The reactive functional groups react with the periphery of the dendrimer to yield the first generation wedge, leaving the unreactive functional groups unreacted. This is the first generation wedge unreactive. The first generation wedge unreactive is then activated in the second step to form the first generation wedge reactive which is able to react with the core or another monomer. A first generation wedge reactive reacts with a monomer to obtain the second generation wedge unreactive. The second generation wedge is the activated to get the second generation wedge reactive. In the third step, the first generation wedge reactive or second generation wedge reactive reacts with a multifunctional core to produce first generation or second generation

3 dendrimers.

first generation wedge

activation

second generation wedge second generation dendrimer

Terminal groups Unreactive group Connect groups

Figure 3. Schematic of the convergent path

4 1-3. Dendrimers review

Fritz Vogtle et al. have the earliest report of polyamine dendrimer synthesis in 1978.9 Using the divergent path as shown in Figure 4, they used the Michael addition of a primary amine to acrylonitrile to yield a first generation dendrimer with a nitrile periphery. The next step activated the periphery groups via the transformation of the nitrile groups to primary amines. The repetition of this sequence of reactions formed the structure of the second generation dendrimer. Furthermore, the transformation of the nitrile groups to primary amines were straightforward.

R R

N N R CN Co(II), NaBH4

NH2 CH3OH NC CN

NH2 NH2

R R

N N

Co(II), NaBH4

CH3OH N N N N

NC NC CN CN

NH NH NH2 NH2 2 2

Figure 4. Polyamine dendrimer synthesis by divergent path9

In 1985, George R. Newkome and co-workers reported the synthesis of a series of poly(ether amide) dendrimers by a divergent path.10 According to this literature report, the dendrimers formed are multibranched with polar functional groups on the periphery called “Arborols” as shown in Figure 5.

CH2OH C2H5OH / OH CH3(CH2)4CH2CHO R C CH2OH

CH2OH

CH2OH HOH C 2 CH2OH C

HOH2C

CH2OH

CONH C

CH2OH CONH

CH OH CONH 2

C CH2OH CH2OH

CH2OH O CH2OH C

CONH CH2OH O CONH

CH2OH CONH C O CH2OH

CH2OH C CH2OH HOH2C CH2OH

CONH CH2OH

CONH CONH C CH2OH HOH2C C CH2OH HOH C C 2 CH2OH

CH2OH HOH2C CH2OH

Figure 5. Poly (ether amide) dendrimers by a divergent path

In 1990, Jean Fréchet and co-workers reported the first convergent synthetic approach to poly(benzyl ether) dendrimers. The first generation dendritic wedges were synthesized using the Williamson ether synthesis. Benzyl bromide was coupled with the phenolic hydroxyl groups. The 3,5-dihydroxybenzyl alcohol was used as a branching monomer unit and benzyl bromide as the periphery group in the assembly of the dendritic wedges. The molecule 1,1,1-tris(4’- hydroxyphenyl) ethane was used as the core in the assembly of the dendrimer. They achieved the 6th generation dendrimer as shown in Figure 6.11,12

HO OH

O O OH Br HO CBr4, PPh3

Br K2CO3

O O

O HO OH

O K2CO3

O O

Figure 6. Poly (benzyl ether) dendrimers

1-4. Polyurethane review 1-4-1. Introduction

Polyurethane dendrimers14-17 and hyperbranched polymers have been reported by only a few research groups, while the synthesis, properties and potential application of dendritic structures of other functional groups, such as amide13, ester,6 and ether, are widely reported. The monomer branch unit creating urethane dendritic macromolecules often subject to side reaction in the synthesis, hindering the development of this area of research. The synthesis of dendrimers from urethane linked structures has challenges have proven to be too difficult to study due to the generation of functional groups with limited solubility.

7 1-4-2. Linear polyurethanes

Linear polyurethanes are often synthesized from the reaction of isocyanates and alcohols.23 Monomers that contain isocyanate and alcohol functions together in the same molecule are difficult to synthesize because of the isocyanate group’s reactive nature. Thus, the most common synthesis of linear polyurethanes uses two kinds of monomers which are a diisocyanate and a diol. The polymerization is a step-growth polymerization as shown in Figure 7.

O O

1 2 H H HO R OH + OCN R NCO R1 O C N R2 N C O n Diol Diisocyanate Polyurethane

Figure 7. Linear polyurethanes synthesized

In spite of the difficulty in using a monomer which includes an alcohol and an isocyanate together on the molecule, there are some research groups have reported synthesis as an intermediate, but they are unable to isolate the monomer before polymerization.19-22 However, Meijer et al. have reported a method developed using a monomer which includes an alcohol and an isocyanate function together on the molecule by using an in situ polymerization and modifying it to be able to synthesize the polymer as shown in Figure 8.17,22

O O O O [Zr(acac)4] O O O O H HO R NH2 HO R NCO R N C O n

R= (CH2)4 to (CH2)12

Figure 8. Linear polyurethanes synthesized

In a different urethane synthesis, McGhee et al. have reported a procedure to synthesis a small molecule with a carbamate functionality by transformation of the secondary amine to an

8 urethane anion via carbon dioxide which is then subjected to an alkyl chloride or alkyl sulfonate to the obtain a urethane group as shown in Figure 9. 24,25

O O

R2 Cl R1 R2 H R N N O + CO2 + Strong Base N O HBase R1 R1 R1 R

Figure 9. Linear polyurethanes synthesized

The most popular synthesis of the urethane functional group is a procedure known as the Curtius reaction.26 Yamada et al. have reported the transformation of a carboxylic acid function to the urethane function by diphenyl phosphoryl azide (DPPA) and alcohol through the Curtius reaction as shown in Figure 10.

O O O R2 OH + 1 2 P R R R1 OH Et3N N O PhO N3 H PhO

Figure 10. Linear polyurethanes synthesized by DPPA

Our group’s synthesis of diphenyl phosphoryl azide (DPPA) from a phenol resin and phenyl phosphonic dichloride to generate the polymer-supported DPPA should be noted. The preparation of a urethane group from a carboxylic acid, the polymer-supported DPPA and an alcohol by the Curtius rearrangement are shown in Figure 11.27

9 O O O dry DCM NaN3, 15-crown-5 OH PhO P Cl O P Cl O P N3 r.t., 8 h dry DCM, reflux, 24 h Cl OPh OPh

O O O R2 OH 1 2 + O P N3 R R R1 OH Et3N N O H OPh

Figure 11. Polyurethanes synthesized by polymer-supported DPPA

Carbonyl di-imidazole (CDI) can be used to synthesize urethanes. Primary and secondary alcohols were reacted with CDI to generate imidazole carboxylic esters. The imidazole carboxylic esters were then reacted with primary and secondary amines to afford the urethanes. Staab also reported that imidazole carboxylic esters with amines in the presence of alcohol form urethanes as shown in Figure 12.26,27

O N N O N N 2 1 R NH2 R 2 R1 R 1 CDI O N R OH N O N H

Figure 12. Polyurethanes synthesized by CDI

1-4-3. Polyurethane dendrimers and hyperbranched polymers

The first reported synthesis of a polyurethane hyperbranched polymer was achieved by Spindler and Frechet in 1993.18 They synthesized a monomer containing two kinds of functional groups which are two isocyanates and one alcohol. They were used in an in-situ polymerization of this monomer to obtain hyperbranched polyurethane. They achieved molecular weights of polyurethane over 30 000 Da at low concentrations as shown in Figure 13.

10 H H OCN NCO R O N N O

O O HO

HO OH

O O

O NH HN O

O O O

HN O NH N O HN O H O O O O O O O H H O N NH HN N O HN N O H O O O O

O O

O O NH HN O O

O NH HN O H H O N N O HN NH O H H O N O O N O HN O O O O N O H O O O O HO HN O O NH

O O

O N N O HN NH H H O O O O

Figure 13. Polyurethane hyperbranched polymer by Spindler and Frechet18

In 1995, Bruchmann et al. reported the synthesis of a polyurethane dendrimer from 2,4-toluylene diisocyanate and trimethylolpropane. Different reactive molecules of trimethylolpropane were used to prepare wedges and used as a core as shown in Figure 14.30

11 O

O O HO O NCO + NH O O

ONC ONC

HO HO O OH O

NH OH

O NH O

O O

H O N N O H

HN O

OH OH

Figure 14. Polyurethane dendrimers by Bruchmann et. al.30

In 2001, Taylor et. al. reported the synthesis of a first generation aliphatic urethane dendrimer. This is synthesized via modification of the McGhee process as shown in Figure 15.16

12 NO2

H N

O S O PhSH, K2CO3, DMF

N O O

O O Et2N NEt2 O O

O O Et2N NEt2

CO2, 5c, DBU, MeCN

CO2,TfO(CH2)3OTf DBU, MeCN

NO2

Et N 2 NEt2 O O

O O O S O

N N

O O O O

(CH ) 2 3 O O N N O O O O NEt2 Et2N O N O O O O O

O O NEt2 NEt2

O O Et2N NEt2

Figure 15. Polyurethane dendrimers by Taylor et al16

In 2001, Meijer et al. published the synthesis of alternating urethane and urea aliphatic dendrimers. They used two types of monomers, diisocyanate and triol, to generate a first generation urethane dendrimer with an isocyanate periphery. In the second steps, the first generation urethane dendrimer with an isocyanate function periphery reacted with secondary amine diol to get the second generation urethane-urea dendrimer with an alcohol periphery. These steps were repeated to get the divergent urethane-urea dendrimer as shown in Figure 16.17

13 OCN

NCO NH O HO O O OCN O NH HO OH Zr(IV)acac O O NCO NH

NCO

O O HN N O HN H N O N O O O NH O HN O O NH O N H NH O N O 1) HO OH NH

NCO 2) Zr(IV)acac NH O O HN OCN N N H O N HN 3) O O O O HN O O O HN NH O HN N O NH NH O N NH N O N

Figure 16. Synthesis of alternating urethane and urea aliphatic dendrimers

In 2003, Alison Stoddart et al. reported the synthesis of aliphatic polyurethane dendrimers. A convergent path was used to prepare the dendrimers. They first described the convergent synthesis of the aliphatic polyurethane and then the synthesis of the third generation

14 dendrimer up to the fourth generation. The core nitrogen atom was used as shown in Figure 17.31,32

O O

NH NH

O O CDI N N

O OH O O

NH NH N N O O O

NH2 O

O NH N O

N O N H H2N NH2

O NH O

HN N O O

N O HN N O H N H O O O

H N N O O O HN

Figure 17. Polyurethane dendrimer by Alison Stoddart et al.32

Moeller et al. published a synthesis of aliphatic polyurethane dendrimers. They prepared dendrons by reacting a hexamethylene diisocyanate (HDI) uretdione with an alcohol. The second step was a ring opening of the uretdione via an amino alcohol to get a dendron which has urea in the center, two urethane functionalities and a hydroxyl group at the terminal, as shown in Figure 18.33,34

15 O NCO N

N OCN O

R1OH

O H N O O N R

R N O O N H O

HO NH2

HN O O O

H R R1 N N 1 O N N O H H O

Figure 18. Polyurethane dendrimer by Moeller et. al.33,34

1-4-4. Applications of polyurethane dendrimers

There are many applications of polyurethane dendrimers. According to Moeller et. at, aliphatic polyurethane dendrimers can be used for self-assembled films on silicon oxide.34 Long and coworkers have reported that linear and highly branched segmented poly(urethane urea) can be materials for the electrospinning process, yielding elastic fibers.35 Voit et al. reported that hydroxyl group terminated aliphatic and aromatic hyperbranched polyurea-urethanes might be used as a model coating composition.35 Bruchmann and coworkers studied the ability of using hyperbranched polyurethane-polyisocyanates polymeric stabilizers.37 Hyperbranched polyurethanes worked as a printing system on both polar and non-polar materials.38 Santi Mukul Santra showed that aliphatic polyurethane dendrimers, which are synthesized via the convergent

16 approach, might be used as a drug delivery system for ovarian cancer treatment as shown in Figure 19.39

O O O O O

NH O O O NH NH O O O O O O

O O BENOMYL O N N Anti-cancer NH H H Drug O O O O O O H O H N N N H O

NH O N N O O O O N O H O O O O O O NH O O O O NH NH H N O O N H O O O HN O O O O O O HN HN O H O N O O O O O O O HN HN O HN O O

O O O O O

Figure 19. Aliphatic polyurethane dendrimer for drug delivery system39

1-5. Our group’s research

Our group has published a convergent synthesis of a polyurethane dendrimer in 1998 (Figure 20) involving a wedge dendrimer was prepared from 5-(t-butyldiphenylsiloxy)propyloxyisophthalic

17 acid and DPPA by the Curtius rearrangement. These polyurethane dendrimers contain alkyl moieties as the terminal group and porphyrin or trimesic acid as the core.40

Figure 20. Porphyrin-cored third generation polyurethane dendrimer.

In 2004, our group reported a divergent synthesis of the polyurethane dendrimer (Figure 21). The dendrimer was prepared from 3,5-bis-(3-methoxy propoxy)benzoic acid, DPPA and different aliphatic alcohols as a core. All layers were built by a Curtius rearrangement of 3,5-bis-

18 (3-methoxy propoxy) benzoic acid and polymer-supported diphenyl phosphoryl azide (DPPA).41 In this dissertation, the design, synthesis and properties of some new polyurethane dendrimers and wedges by using DPPA will be reported. In chapter two we desire a divergent strategy for dendrimer preparation based on similar chemistry from our group. In the later chapter, we present new synthetic pathway designs to allow the preparation of structurally diverse dendrimers from common late stage intermediates.

OAc

AcO O O O O

OAc AcO

M M

O O

M M

AcO O O OAc Core

AcO O O OAc

M M

O O

M M

OAc OAc

O O O O OAc

AcO

AcO AcO

O(CH2)3OH

HO OH O HO(H2C)3O O(CH2)3OH

O OH HO O

HO(H2C)3O O(CH2)3OH

Figure 21. Divergent synthesis of a polyurethane dendrimer

19 1-6. References

1. Frechet, J. M. J.; Hawker, C. J. Synthesis and Properties of Dendrimers and

Hyperbranched Polymers, in Comprehensive Polymer Science, 2n d Suppl., 1996, p 71.

2. Newkome, G. R.; Moorefield, C. N.; Vogtle, F. Dendritic Molecules: Concepts,

Syntheses and Perspectives; VCH: Weinheim, 1996.

3. Hult, A.; Johansson, M.; Malmstrom, E. Adv. Polym. Sci. 1999,143, 1.

4. Tu C. Le, B. D. Todd, P. J. Daivis, A. Uhlherr, Journal of Chemical Physics 2009, 130, 7.

5. Mourey, T. M.; Turner, S. R.; Rubinstein, M ; Frechet, J. M. J.; Hawker, C. J.;

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22 Chapter II

Synthesis of polyurethane dendrimer via divergent approach

2-1. Introduction

In this chapter will be studying effect of different cores on synthesis polyurethane dendrimer using a divergent path when use DPPA. While our previous work used similes reaction, all previous synthesis were convergent.

2-1-1. Specific aims

The aims of this polyurethane dendrimer synthesis are listed below:

i- A synthesis of the branching monomer. ii- Starting the synthesis from different cores. iii- Study the effect of the core on polyurethane dendrimer divergent path synthesis.

2-1-2. Synthetic strategies

The divergent path synthesis was chosen to study the polyurethane dendrimer synthesis. The starting monomer for the synthesis is active on one side. The core, which has di-hydroxyl functional groups, is reacted with two branching monomers to generate the first generation of polyurethane dendrimer which is inactive before activation. The next step is the activation of the first generation which is then reacted with four branching monomers to yield the second generation of polyurethane dendrimer as shown in Figure 22.

23 HO OH AcO OAc AcO OAc

DPPA, Et3N core solvent, reflux

COOH NCO

Monomer

OH OAc O O HO N H AcO N Deprotection O O H O O N OH N OAc H H O O HO AcO

first generation dendrimer

AcO OAc

AcO OAc OAc AcO HN O NH O O O N NCO O O O H O N O O H O HN O HN OAc AcO AcO OAc second generation dendrimer

Figure 22. Divergent path synthesis strategies

2-2. Divergent syntheses of polyurethane dendrimers

2-2-1. Synthesis of branching monomer

The synthesis of the branching monomer begins from the iodination of 3- chloro-1-propanol (1) by NaI in acetone without isolation of the intermediate 2. 3,5- Dihydroxybenzoic acid methyl ester (3) was coupled with 3-iodo-1-propanol 2 in the presence of K2CO3 in acetone to produce 3,5-bis-(3-hydroxypropoxy)benzoic acid

24 methyl ester 4. This was then hydrolyzed with a mixture of NaOH solution and THF at 60 oC to generate 3,5-bis-(3-hydroxypropoxy)benzoic acid 5. Protection of 3,5-bis- (3-hydroxypropoxy)benzoic acid 5 carried out by acetic anhydride in pyridine yielding 3,5-bis-(3- acetoxypropoxy)benzoic acid 6.1 3,5-bis-(3- acetoxypropoxy)benzoic acid 6 is the branching monomer for the polyurethane dendrimer synthesis as shown in Figure 23.

O HO O

NaI 3 , K CO OH 2 3 Cl OH acetone, 24 h I OH acetone, reflux, 24 h

1 2

O O O OH

2.5 M NaOH / THF

60 oC, 24 h HO O O OH HO O O OH

4 5

O OH

acetic anhydride O O pyridine, 48 h O O O O

Figure 23. Synthesis of branching monomer.

2-2-2. Synthesis of polyurethane dendrimers

The modified Curtius reaction of 3,5-bis-(3-acetoxypropoxy)benzoic acid 6 by

DPPA and Et3N in benzene generated theacyl azide 7. The Curtius rearrangement of acyl azide 7 provided the isocyanate intermediate branching monomer 8 (Figure 24). The dihydroxyl compound (Table 1) was added as a core to obtain the first generation of polyurethane dendrimer with acetoxy periphery groups 9. The compound 9 was

25 hydrolyzed to get the first generation of polyurethane dendrimer with hydroxyl periphery groups. The first generation of polyurethane dendrimer with hydroxyl groups periphery was added to the isocyanate intermediate branching monomer 8 to afford the second generation of polyurethane dendrimer with acetoxy groups periphery. The hydrolysis was repeated to get the second generation of polyurethane dendrimer with hydroxyl groups on the periphery.2

O OH O N3

O O O O Et3N, DPPA reflux

O O O O O O O O

6 7

R O

O O NH C R OH

N O O

O O O O O O

O O O O 9 8

Figure 24. Synthesis of isocyanate intermediate.

26 Table 1. The cores.

Name structure diethylene glycol (DEG) O HO OH triethylene glycol (TEG) O OH HO O

1,4-Bis(2- HO OH hydroxyisopropyl)benzene

2-butyne-1,4-diol OH HO

2-butene-1,4-diol OH HO

2-2-2-1. Synthesis of diethylene glycol (DEG) polyurethane dendrimer

Two moles of the isocyanate 8 (Figure 24) were reacted with one mole of diethylene glycol (DEG) to get the diethylene glycol first generation of polyurethane dendrimers with acetoxy groups on the periphery 10. Compound 10 was obtained in an excellent yield of 95%. Hydrolysis via K2CO3 in MeOH/H2O generated diethylene glycol first generation of polyurethane dendrimers with hydroxyl groups on the periphery 11. 11 was then reacted with four equivalents of isocyanate intermediate branching monomer 8 to afford the second generation of polyurethane dendrimers with acetoxy groups on the periphery 12 and the yield was 86% as shown in Figure 25.

27 AcO

HO OH O OAc NH 8 O O O O O OH K2CO3 (5 mol% ) O O O NH HO O O MeOH / H2O (2:1) HN O O AcO O DEG O O O O HN HO 10 O OAc 11

AcO

O O OAc

NH O O

O N O O O H

O AcO O 8 H H N O O N O OAc O O O O H O O O N O O O HN AcO

O O 12

OAc

Figure 25. Diethylene glycol polyurethane dendrimer synthesis

2-2-2-2. Synthesis of triethylene glycol (TEG) polyurethane dendrimer

Long chain triethylene glycol was used as the long-chain core to synthesize first and second generation polyurethane 13. The same synthesis was started with triethylene glycol reacting with two moles of isocyanate intermediate branching monomer 8 as shown in Figure 26. The first and second generation of polyurethane dendrimers with acetoxy groups on the periphery 13 & 15 were synthesized with yields of 87% and 80% respectively.

28 OH OAc HO OH AcO

O O O H O O O H O N N K2CO3 (5 mol% ) O O 8 O O O O N O O N MeOH / H2O (2:1) O H O O O H O O O

OH HO OAc 14 HO TEG AcO 13

AcO

O O

OAc NH

O O O O O N H O O AcO O 8 H N O O H O O N OAc O O O H O O N O O O O O AcO HN

O 15 O

OAc

Figure 26. Triethylene glycol polyurethane dendrimer synthesis

2-2-2-3. Synthesis of 1,4-Bis(2-hydroxyisopropyl)benzene polyurethane dendrimer

1,4-Bis(2-hydroxyisopropyl)benzene (16) is rigid in comparison to DEG or TEG when used as a core. The synthesis of the first and second generation of polyurethane dendrimers 17 & 19 began by reacting 1,4-bis(2- hydroxyisopropyl)benzene with the isocyanate intermediate branching monomer 8 as shown in Figure 27. The first and second generation of polyurethane dendrimers with acetoxy groups on the periphery 17& 19 were synthesized with yields of 55% and 45% respectively.

29 AcO HO

O OAc O OH

OH NH 8 O NH K2CO3 (5 mol% ) O O O O O MeOH / H2O (2:1) O O O O O

HN O HO HN

16 AcO O HO O 17 18

OAc OH

AcO

O NH

O O O O AcO OAc O O N O H 8 O H O N O O N O H O H O N O O AcO OAc O O O O

HN O

19 O

OAc OAc

Figure 27. 1,4-Bis(2-hydroxyisopropyl)benzene polyurethane dendrimer synthesis

2-2-2-4. Synthesis of 2-butyne-1,4-diol polyurethane dendrimer

2-Butyne-1,4-diol (20) was used as a core and reacted with isocyanate intermediate branching monomer 8 to generate the first generation of polyurethane dendrimers with acetoxy groups on the periphery 21. Hydrolysis was then performed to get the first generation of polyurethane dendrimers with hydroxyl groups on the periphery 22. The yield was 77%. The first generation of polyurethane dendrimers with hydroxyl groups on the periphery 22 was not soluble in benzene and toluene, which impeded synthesis of the second generation of polyurethane dendrimers 23 as shown in Figure 28.

30 O O HO

O O O O OH NH HO O NH 8 O O O O K2CO3 (5 mol% ) O O O O O O OH HN MeOH / H2O (2:1) O 20 HN O O O HO O

21 O 22 O OH

AcO

O O

OAc

NH O O O N O H O O

O AcO O

H H 8 N O O N OAc O O O O H O O O N O O O HN AcO 23 O O

OAc

Figure 28. 2-butyne-1,4-diol polyurethane dendrimer synthesis

2-2-2-5. Synthesis of 2-butene-1,4-diol polyurethane dendrimer

The first generation of polyurethane dendrimers with acetyl groups on the periphery was synthesized from a 2-butene-1,4-diol core (24). The yield was 80%. As with the 2-butyne-1,4-diol that the first generation of polyurethane dendrimers with hydroxyl groups on the periphery 26 was not soluble in benzene and toluene as shown in Figure 29.

31 O O HO

O O OH O O NH O O HO O NH OH O O O K2CO3 (5 mol% ) O O HN O MeOH / H2O (2:1) O O O 24 O HN O O O

O HO O 25 26 OH

AcO

O O

OAc NH O O O O O N O H AcO O 8 O H N O H O N O O OAc O H O O N O O O O O AcO HN

O O

OAc 27 OAc

Figure 29. 2-butyne-1,4-diol polyurethane dendrimer synthesis

2-3. Core effect

Proton and 13C NMR were used to characterize the polyurethane dendrimers. MALDI-TOF MS was used to determine the molecular weights of polyurethane.3,4 Diethyl glycol and triethylene glycol achieved excellent yields for both first and second generations. 2-Butyne-1,4-diol and 2-butene-1,4-diol were able to be used for the first generation polyurethane dendrimers in benzene or toluene solvents. The first generation of polyurethane dendrimers with hydroxyl groups on the periphery from 2-butene-1,4-diol or 2-butyne-1,4-diol were not soluble in benzene and toluene which caused a problem for synthesizing the second generation for both these cores. 1,4-Bis(2-hydroxy isopropyl) benzene was use to synthesize the first and second generations of polyurethane dendrimers with a good yield. Therefore, the flexible cores such as diethyl glycol and triethylene glycol were better cores for the divergent synthesis of polyurethane dendrimers when compared with 2-butyne-1 4-diol, 2-butene-1 4-diol and 1,4-Bis(2-hydroxy isopropyl)benzene.

2-4. Solvent effect

The solvent had an effect on the synthesis of the polyurethane dendrimers. The first generation of polyurethane dendrimers with hydroxyl groups on the periphery from 2-butene-1,4-diol or 2-butyne-1,4-diol was not soluble in benzene or toluene. That impeded the synthesis of the second generation of polyurethane dendrimers, and the major product was compound 28. The first generation of polyurethane dendrimers with hydroxyl groups on the periphery from 2-butene-1,4- diol or 2-butyne-1,4-diol was soluble in a polar solvent such as THF and 1,4-dioxane.5 Unfortunately, the major product was compound 28.6 Therefore, using polar and poor solvents led to the major undesired product (compound 28).5,6 The compound 28 was formed from reacted between isocyanate intermediate branching monomer 8 and a carboxylic acid molecule 6. It is important that conversion of all carboxylate to acyl azide be complete before formation of the isocyanate in order to avoid side reactions 28. Isocyanate formation is promoted by polar solvents, so the beast polar solvent that dissolves the starting material is ideal. From our work, it appears the most polar solvent valid for the reaction is 1,4-dioxane (Figure 30).

33 N N O OH N N O N O N

Et3N, DPPA

AcO O O OAc AcO O O OAc AcO O O OAc

R O O

C HN O

N R-OH heat

-N2 AcO O O OAc

AcO O O OAc 9 8

O OH

AcO O O OAc 6

OAc OAc

O O

AcO O N N O OAc H H

Figure 30. Mechanism of Curtius rearrangement

2-5. Conclusions

The synthesis of polyurethane dendrimers in the divergent approach was carried out with different cores and different generations. Dendrimers with flexible cores such as diethyl glycol and triethylene glycol were achieved with excellent yields. 2-Butyne-1,4- diol and 2-butene-1,4-diol were used to synthesize first generation polyurethane dendrimers. Due to a solvent effect, the synthesis of first generation polyurethane dendrimers from these cores was unable to be achieved. 1,4-Bis(2-hydroxy isopropyl) benzene was used to synthesize the first and second generations polyurethane dendrimers with good yield. All of the generations of these polyurethane dendrimers were characterized via proton and 13C NMR and the molecular weights determined by MALDI- TOF mass spectrometry. Solvents were also important in the synthesis. Compared to

34 toluene and benzene with THF and 1,4-dioxane are better solvent in the divergent synthesis of polyurethane dendrimers in the presence of DPPA.

2-6. Experimental section

2-6-1. Synthesis of branching monomer

O HO O O O

NaI , K CO OH 2 3 Cl OH acetone I OH acetone, reflux, 24 h HO O O OH 4

Preparation of 3,5-bis-(3-hydroxypropoxy)benzoic acid methyl ester (4). To a 100 mL round bottom flask, 3-chloro-1-propanol (2 mL, 24 mmol, 1 eq), NaI (10.75 g, 71.7 mmol, 3 eq) and acetone (50 mL) were added. The mixture was stirred and heated to 50 oC for 24 hours. The reaction mixture was filtered and was washed with acetone (10 mL). Solvent was removed by rotary evaporation to get 3-iodo-1- propanol 2. 3-Iodo-1-propanol 2 was dissolved in acetone (50 mL) and added methyl

3,5-dihydroxybenzoate (1.70 g, 10 mmol, 1.0 eq), K2CO3 (3.32 g, 24 mmol, 2.4 eq) and stirred and refluxed under nitrogen for 24 hours. The solvent was removed and a crude product was washed with water (100 mL) and ether (100 mL) to obtain 3,5- bis-(3-hydroxypropoxy)benzoic acid methyl ester 4 in a 70% yield. 1H-NMR (300

MHz; aceton-d6): δ 2.03-1.90 (m, 4H), 3.05-2.77 (m, 2H), 3.77-3.70 (m, 4H), 3.89-3.84 (m, 3H), 4.18-4.11 (m, 4H), 6.78-6.74 (m, 1H), 7.17-7.14 (m, 2H).

35 O O O OH

2.5 M NaOH / THF

60 oC, 24 h

HO O O OH HO O O OH 4 5 Preparation of 3,5-bis-(3-hydroxypropoxy)benzoic acid (5). To a solution of 3,5- bis-(3-hydroxypropoxy)benzoic acid methyl ester 4 in 20 mL of THF was added 25 mL of NaOH solution (2.5 M). The mixture was stirred and heated to 60 oC overnight. The reaction mixture was separated, and the aqueous layer was acidified to neutral pH by concentrated HCl. A white solid was obtained by rotary evaporation, which was product and NaCl. A mixture of a white solid and 50 mL of acetone was stirred overnight. The mixture was filtered and washed carefully with acetone (100 mL). The solvent was removed under vacuum to give a white solid as crude product.

O OH O OH

acetic anhydride O O

pyridine, 48 h HO O O OH O O O O 5 6

Preparation of 3,5-bis-(3-acetoxypropoxy)benzoic acid (6). To a round bottom flask was equipped with a magnetic stirrer and a nitrogen inlet was added a mixture of pyridine and acetic anhydride (20 mL, 20 mol% of acetic anhydride). 3,5-Bis-(3- hydroxypropoxy)benzoic acid 5 was added and stirred at room temperature for two days. Water (20 mL) was added and the reaction mixture was acidified to pH=2 by concentrated hydrochloric acid. The mixture was extracted with ethyl acetate. The combined organic layers were washed with hydrochloric acid solution and water. The solvent was removed under vacuum to give a white solid as crude product. 1H NMR (CDCl3, 300 MHz) 2.08(s, 6H), 2.14 (quint, J = 6.2 Hz, 4H), 4.096 (t, J = 6.2 Hz, 4H), 4.279 (t, J = 6.3 Hz, 4H), 6.70 (m, 1H), 7.26 (d, J = 2.1 Hz, 2H), 9.62 (br, 1H); 13C NMR (CDCl3, 75 MHz) 20.814, 28.548, 61.148, 64.801, 107.542, 108.382, 131.403, 159.875,

36 170.957, 171.003.

2-6-2. Synthesis of polyurethane dendrimers

General method one: For the syntheses of polyurethane dendrimers with acetoxy groups on the periphery. A mixture of 3,5-bis-(3-acetoxypropoxy)benzoic, polymer- supported DPPA or DPPA and Et3N with toluene was stirred at room temperature for 40 minutes under a nitrogen atmosphere. The temperature was raised to 65 °C and stirred for 3 hours. The core or first generation polyurethane dendrimers with hydroxyl groups on the periphery were added and the mixture refluxed for 24 h. The solution was cooled to room temperature, was filtered and the resin washed with EtOAc (60 mL). The combined organic layers were washed with aqueous NaOH solution (1 M, 20 mL x 3), distilled water (25 mL x 3) and brine (25 mL) and dried over MgSO4.The solvent was removed under vacuum to give the crude product.

General method two for the hydrolysis of polyurethane dendrimers with acetoxy groups on the periphery into polyurethane dendrimers with hydroxyl groups on the periphery. To a solution of 5 mol% of K2CO3 in a mixture of MeOH and distilled water (2:1) (50 mL) was added the polyurethane dendrimers with acetoxy groups on the periphery. The mixture was stirred for 2 hours and evaporated to obtain a white solid. The white solid was dissolved in (45 mL) of an acetone and stirred overnight at room temperature. The mixture was filtered, and washed (100 mL) with more acetone. The combined filtrates were concentrated to give a crude product which is polyurethane dendrimers with hydroxyl groups on the periphery.

Preparation of the first generation of diethylene glycol cored with acetoxy groups on the periphery. The general method one was carried out on a mixture of 3,5-bis-(3-acetoxypropoxy)benzoic acid (0.159 g, 0.45 mmol, 2.5 eq), DPPA (0.296 g,

37 1.077 mmol, 6 eq) and Et3N (0.193 g, 1.9 mmol, 9.0 eq) with toluene (10 mL). The mixture was stirred at room temperature and under a nitrogen atmosphere for 40 minutes. The temperature was raised to 65 °C and the solution stirred for 3 hours. Diethylene glycol (0.019 g, 0.2 mmol, 1.0 eq) was added and refluxed for 24 h. Purification was performed by silica-gel column chromatography (1:1 to 1:2 hexanes/EtOAc) to give pure diethylene glycol core the first generation. 1H NMR

(CDCl3, 300MHz) 2.09 (m, 20H), 3.79 (t, J = 6.1 Hz, 4H), 4.02 (t, J = 3.5 Hz, 8H), 4.24 (t, J = 3.3 Hz, 8H), 4.36 (t, J = 4.2 Hz, 4H), 6.19 (t, J = 2.0 Hz, 2H), 6.65 (d, J = 2.1 Hz, 4H),

6.81 (br, 2H); 13C NMR (CDCl3, 75 MHz) 20.82, 28.58, 61.20, 64.11, 64.51, 69.36,

97.00, 97.83, 139.57, 153.17, 160.35, 170.90; MALDI-TOF MS m/z [M+Na+] calculated for C38H52N2O17Na+ 831.32, found 831.5.

Preparation of the first generation of diethylene glycol cored with hydroxyl groups on the periphery. The general method two was followed using the first generation of diethylene glycol core with acetoxy groups on the periphery which was added to a solution of K2CO3 (5 mol%) in a mixture of MeOH and water (2:1) (50 mL) and stirred for 2.5 hours. Purification was performed by silica-gel column chromatography (10:1 CHCl3/MeOH) to give diethylene glycol cored the first generation - OH: 1H NMR (acetone-d6, 300 MHz) 1.97 (quint, 8H), 3.55 (t, J = 5.0 Hz, 16H), 3.66 (t, J = 4.4 Hz, 8H), 3.74 (t, 4.4 Hz, 4H), 4.13 (t, 6.3 Hz, 4H), 5.47 (br, 2H), 6.74 (t, J = 2.3 Hz, 2H), 7.15 (d, J = 2.3 Hz, 4H).

Preparation of the second generation of diethylene glycol cored with acetoxy groups on the periphery. The general method one was carried out on a mixture of 3,5-bis-(3-acetoxypropoxy)benzoic acid (0.166 g, 0.47 mmol, 5 eq), DPPA (0.387 g,

1.4 mmol, 15 eq) and Et3N (0.19 g, 1.9 mmol, 20 eq) with toluene (10 mL). The mixture was stirred at room temperature and under a nitrogen atmosphere for 40 minutes. The temperature was raised to 65 °C and the solution stirred for 3 hours. The mixture was added into the first generation of diethylene glycol cored with hydroxyl groups

38 on the periphery (0.06 g, 0.1 mmol, 1.0 eq) and the mixture refluxed for 24 h. Purification was performed by silica-gel column chromatography (1:1, 1:2 to 1:2 hexanes/EtOAc) to give pure diethylene glycol core the first generation, as a white viscous solid (0.18 g, 87% yield): 1H NMR (CDCl3, 300 MHz) 2.11 (m, 48H), 3.76 (m, 4H), 3.98 (m, 24H), 4.22 (m, 24H), 4.27 (m, 4H), 6.16 (m, 6H), 6.65 (m, 9H), 7.2 (m,

8H), 7.6 (m, 6H) 7.56 (br, 4H); 13C NMR (CDCl3, 75 MHz) 20.97, 21.46, 28.53, 29.71, 61.27, 61.29, 64.32, 64.38, 96.49, 98.61, 120.04,120.08, 125.29, 125.77, 128.23, 129.026, 129.85, 129.94, 137.85, 140.47, 160.24, 160.27, 171.140, 171.194; MALDI-

+ + TOF MS m/z [M+Na ] calculated for C98H128N6O41Na 2067.80, found 2062.7 and

+ + [M+K ] calculated for C98H128N6O41K 2083.78, found 2089.7.

Preparation of the first generation of triethylene glycol cored with acetoxy groups on the periphery. The general method one was carried out on a mixture of 3,5-bis-(3-acetoxypropoxy)benzoic acid (0.166 g, 0.47 mmol, 2.5 eq), DPPA (0.309 g,

1.12 mmol, 6 eq) and Et3N (0.171 g, 1.6 mmol, 9 eq) with toluene (10 mL). The mixture was stirred at room temperature and under a nitrogen atmosphere for 40 minutes. The temperature was raised to 65 °C and the solution stirred for 3 hours. Then was added triethylene glycol (0.028 g, 0.19 mmol, 1.0 eq) and the mixture refluxed for 24 h. Purification was performed by silica-gel column chromatography (1:1 to 1:2 hexanes/EtOAc) to give pure triethylene glycol cored the first generation – OAc (TEG-

FG-OAc) as colorless oil (0.15 g, 87% yield): 1H NMR (CDCl3, 300 MHz) 2.08 (m, 19H), 3.62 (t, J = 3.9 Hz, 4H), 3.75 (t, J = 4.5 Hz, 4H), 4.07 (t, J = 6.0 Hz, 8H), 4.24 (t, J = 6.3 Hz, 8H), 5.72 (br, 2H), 6.55 (t, J = 2.4 Hz, 2H), 7.24 (t, J = 2.1 Hz, 4H); 13C NMR

(CDCl3, 75 MHz) 20.77, 28.57, 61.24, 61.49, 64.59, 70.29, 70.37, 72.59, 105.60, 107.96, 125.22, 128.14, 128.94, 136.33, 136.36, 159.55,170.64, 170.94; MALDI-TOF

+ MS m/z [M+Na+] calculated for C40H56N2O18Na 875.34, found 875.43 and [M+K+]

+ calculated for C40H56N2O18K 891.32, found 891.39.

39 Preparation of the first generation of triethylene glycol cored with hydroxyl groups on the periphery. The general method two was followed using the first generation of diethylene glycol cored with acetoxy groups on the periphery added to a solution of 5 mol% of K2CO3 in a mixture of MeOH and distilled water (2:1) (50 mL)

1 which was stirred for 2 hours. H-NMR (300 MHz; CDCl3): δ 2.14-2.03 (m, 18H), 3.76- 3.61 (m, 17H), 4.07 (t, J = 6.1 Hz, 7H), 4.24 (t, J = 6.3 Hz, 8H), 5.72 (s, 4H), 6.55 (dd, J = 3.1, 1.6 Hz, 2H), 7.24 (d, J = 2.4 Hz, 3H).

Preparation of the second generation of triethylene glycol cored with acetoxy groups on the periphery. The general method one was carried out on a mixture of 3,5-bis-(3-acetoxypropoxy)benzoic acid (0.155 g, 0.44 mmol, 5 eq), DPPA (0.362 g,

1.3 mmol, 15 eq) and Et3N (0.177, 1.7 mmol, 20 eq) with toluene (10 mL). The mixture was stirred at room temperature and under a nitrogen atmosphere for 40 minutes. The temperature was raised to 65 °C and the solution stirred for 3 hours. The mixture was added into the first generation of triethylene glycol cored with hydroxyl groups on the periphery (0.06 g, 0.09 mmol, 1.0 eq) and the mixture refluxed for 24 h. 1H-NMR

(300 MHz; CDCl3): δ 2.17-2.04 (m, 41H), 2.16-2.05 (m, 3H), 3.80-3.65 (m, 5H), 3.80-3.65 (m, 76H), 4.13-4.05 (m, 14H), 4.12-4.08 (m, 1H), 4.29-4.24 (m, 16H), 4.31-4.22 (m, 16H), 6.61-6.59 (m), 6.61-6.59 (m, 3H), 7.21-7.18 (m, 1H), 7.21-7.18 (m, 9H), 7.28-7.25 (m,

13 1H), 7.28-7.25 (m, 13H). C-NMR (75 MHz, CDCl3): δ 8.55, 20.84, 28.59, 45.05, 61.20, 61.23, 64.62, 70.28, 70.30, 70.38, 106.04, 108.08, 159.59, 170.97.

Preparation of the first generation of 1,4-bis(2-hydroxyisopropyl)benzene cored with acetoxy groups on the periphery. The general method one was carried out on a mixture of 3,5-bis-(3-acetoxypropoxy)benzoic acid (0.182 g, 0.5 mmol, 2.5 eq),

DPPA (0.34 g, 1.2 mmol, 6 eq) and Et3N (0.188 g, 1.9 mmol, 9 eq) with toluene (10 mL). The mixture was stirred at room temperature and under a nitrogen atmosphere for 40 minutes. The temperature was raised to 65 °C and the solution stirred for 3

40 hours. Then was added 1,4-bis(2-hydroxyisopropyl)benzene (0.04 g, 0.2 mmol, 1.0 eq)

1 and the mixture refluxed for 24 h. H-NMR (300 MHz; CDCl3): δ 2.17-2.08 (m, 20H), 4.09 (t, J = 6.1 Hz, 8H), 4.27 (t, J = 6.3 Hz, 8H), 6.67-6.65 (m, 2H), 7.25 (d, J = 2.1 Hz,

13 3H), 7.48 (s, 7H). C-NMR (75 MHz, CDCl3): δ 8.53, 20.89, 45.11, 64.67, 72.41, 106.85, 108.20, 147.47, 159.76, 171.07. MALDI-TOF MS m/z [M+H+] calculated for

+ C46H60N2O16H 896.39, found 896.40.

Preparation of the first generation of 1,4-bis(2-hydroxyisopropyl)benzene cored with hydroxyl groups on the periphery. The general method two was followed using the first generation of 1,4-bis(2-hydroxyisopropyl)benzene core with acetoxy groups on the periphery was added to a solution of K2CO3 (5 mol%) in a mixture of MeOH and water (2:1) (45 mL) and stirred for 2 hours.

Preparation of the second generation of 1,4-bis(2-hydroxyisopropyl)benzene cored with acetoxy groups on the periphery. The general method one was carried out on a mixture of 3,5-bis-(3-acetoxypropoxy)benzoic acid (0.146 g, 0.41 mmol, 5 eq), DPPA (0.34 g, 1.2 mmol, 15 eq) and Et3N (0.167, 1.6 mmol, 20 eq) with toluene (10 mL). The mixture was stirred at room temperature and under a nitrogen atmosphere for 40 minutes. The temperature was raised to 65 °C and the solution stirred for 3 hours. The mixture was added into the first generation of 1,4-bis(2- hydroxyisopropyl)benzene core with hydroxyl groups on the periphery (0.06 g, 0.08

1 mmol, 1.0 eq) and the mixture refluxed for 24 h. H-NMR (500 MHz; CDCl3): δ 1.87 (s, 10H), 2.08 (d, J = 8.6 Hz, 63H), 3.99 (t, J = 5.9 Hz, 23H), 4.24 (t, J = 6.2 Hz, 24H), 6.17 (s, 6H), 6.61 (d, J = 1.7 Hz, 9H), 7.19 (t, J = 5.9 Hz, 17H), 7.28 (dt, J = 7.4, 3.7 Hz, 17H).

13 C-NMR (126 MHz, CDCl3): δ 20.97, 21.46, 28.53, 61.27, 61.30, 64.34, 96.61, 98.77, 125.29, 128.22, 129.00, 129.03, 129.94, 137.86, 140.35, 160.23, 160.26, 171.17, 171.19, 171.23.

Preparation of the first generation of 2-butyene-1,4-diol cored with acetoxy

41 groups on the periphery. The general method one was carried out on a mixture of 3,5-bis-(3-acetoxypropoxy)benzoic acid (0.188 g, 0.5 mmol, 2.5 eq), DPPA (0.35 g, 1.3 mmol, 6 eq) and Et3N (0.19 g, 1.9 mmol, 9.0 eq) with toluene (10 mL). The mixture was stirred at room temperature and under a nitrogen atmosphere for 40 minutes. The temperature was raised to 65 °C and the solution stirred for 3 hours. Then was added 2-Butyene-1,4-diol (17 mg, 0.2 mmol, 1.0 eq) and the mixture refluxed for 24 h.

1 H-NMR (500 MHz; CDCl3): δ 2.04-2.13 (m, 33H), 4.026 (t, J = 6.13 Hz, 8H), 4.256 (t, J = 6.32 Hz, 8H), 4.819 (s, 3H), 6.204 (t, J = 2.14 Hz, 2H), 6.798 (d, J = 2.21 Hz, 2H), 7.03-

13 7.03(m, 4H). C-NMR (126 MHz, CDCl3): δ 8.450, 20.964, 21.457, 28.522, 28.58, 45.623, 61.23, 61.368, 64.412, 81.095, 96.985, 97.550, 120.245, 120.285, 123.259, 125.293,

128.219, 129.028, 129.197, 160.019, 160.284, 171.110. MALDI-TOF MS m/z [M+Na+]

+ calculated for C38H48N2O16Na 811.3, found 811.181.

Preparation of the first generation of 2-butyene-1,4-diol cored with hydroxyl groups on the periphery. The general method two was followed using the first generation of 2-butyene-1,4-diol core with acetoxy groups on the periphery was added to a solution of 5 mol% of K2CO3 in a mixture of MeOH and distilled water (2:1) (50 mL) and stirred for 2 hours. 1H-NMR (500 MHz; aceton-d): δ 1.98-1.93 (m, 8 H), 3.735 (t, J = 6.07 Hz, 8H), 4.077 (t, J = 6.32 Hz, 8H), 4.831 (s, 3H), 6.236(s, 1H), 6.828 (d, J = 1.54Hz, 3H), 8.028 (s, 2H), 8.780 (s, 1H). 13C-NMR (126 MHz, aceton-d): δ 32.412, 51.918, 58.156, 64.722, 78.300, 81.080, 95.843, 97.328, 140.508, 152.519, 160.662.

+ + MALDI-TOF MS m/z [M+Na ] calculated for C30H40N2O12Na 643.16, found 643.122 + + and [M+K ] calculated for C30H40N2O12K 659.26, found 659.088.

Preparation of the first generation of 2-butene-1,4-diol cored with acetoxy groups on the periphery. The general method one was carried out on a mixture of 3,5-bis- (3-acetoxypropoxy)benzoic acid (0.34 g, 0.96 mmol, 2.5 eq), DPPA (0.63 g, 2.3 mmol,

6 eq) and Et3N (0.35 g, 3.4 mmol, 9.0 eq) with toluene (10 mL). The mixture was stirred at room temperature and under a nitrogen atmosphere for 40 minutes. The

42 temperature was raised to 65 °C and the solution stirred for 3 hours. Then was added 2-butene-1,4-diol (31.5 mg, 0.38 mmol, 1.0 eq) and the mixture refluxed for 24 h. 1H-

NMR (500 MHz; CDCl3): δ 2.06 (d, J = 5.0 Hz, 21H), 3.97 (dt, J = 10.5, 5.4 Hz, 8H), 4.28- 4.21 (m, 10H), 4.79-4.72 (m, 3H), 6.17 (d, J = 13.1 Hz, 2H), 6.61 (d, J = 13.8 Hz, 4H).

Preparation of the first generation of 2-butene-1,4-diol cored with hydroxyl groups on the periphery. The general method two was followed using the first generation of 2-butene-1,4-diol core with acetoxy groups on the periphery was added to a solution of 5 mol% of K2CO3 in a mixture of MeOH and distilled water (2:1) (50 mL) and stirred for 2 hours. MALDI-TOF MS m/z [M+Na+] calculated for

+ C30H42N2O12Na 645.17, found 645.232.

43 2-7. References

1. Greene, T. W. and Wuts, P. G. In “Protective groups in organic synthesis” John Wiley & Sons: New York, 1999, p 150.

2. Greene, T. W. and Wuts, P. G. In “Protective groups in organic synthesis” John Wiley & Sons: New York, 1999, p 154.

3. Paupaiboon, U.; Taylor, R. T. and Jai-Nhuknan, J. “Structural confirmation of polyurethane dendritic wedges and dendrimers using post source decay matrix- assisted laser desorption/ ionization time-of-flight mass spectrometry” Rapid Commun. Mass Spectrom. 1999, 13, 516-520.

4. Paupaiboon, U. and Taylor, R. T. “Characterization and monitoring reaction of polyurethane dendritic wedges and dendrimers using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry” Rapid Commun. Mass Spectrom. 1999, 13, 508-515.

5. Iskander, M. J. “Solvent effect in the Curtius rearrangement of cinnamoyl azide” Z. Phys. Chem., Leipzig 1981, 262, 76-82.

6. Ninomiya, K.; Shioiri, T. and Yamada, S. “Phosphorus in organic synthesis – VII Diphenyl phosphorazidate (DPPA). A new convergent reagent for a modified Curtius reaction” Tetrahedron 1974, 30, 2151-2157.

44 Chapter III

Synthesis of alkene polyurethane dendrimer via convergent approach

3-1. Introduction

Dendrimers have achieved success in applications ranging from medicine to nanoengineering.1-4 The challenge is to develop workable syntheses of highly branched macromolecules. “Click” chemistry has received the most attention because it can easily yield elaborate molecules with high efficiency and orthogonal reactions.5 In recent research thiol-ene click reactions have received attention due to their ability to selectively functionalize and modify molecular structures.6 In dendritic fashion, Hawker and coworkers reported the synthesis of fourth generation dendrimers synthesized in the divergent fashion dependent upon a thiol-ene reaction.7 Nilsson and coworkers have shown the effect thiol-ene reaction on the properties of first generation dendritic cores.8 Both current convergent and divergent syntheses of the dendrimer, in general, suffer from limitations. If one desires to undertake structure activity studies of any dendritic system, it is an important set of molecules. The most important structural variants and the peripheral groups and the core. In the divergent synthesis, the core is chosen in stage one. Any variation in the core requires a new synthesis. The divergent strategy allows peripheral reaction easily that most the core. In the convergent synthesis, the opposite problem arises, the core is on end-stage choice, but the peripheral groups are determined in step one. The strategy we advance in chapter III allow both groups to be served late in the synthesis. By using thiol-ene click chemistry, a convergent synthesis retains the late choice of the core but introduces a facile method for adjusting the peripheral groups past construction. In their way, the objection of late stage choice both core and periphery is realized.

45 3-1-1. Specific aims

The aims of this polyurethane dendrimer synthesis are listed below:

i- A synthesis of the branching monomer containing two different functional groups, two carboxylic acids and one protected hydroxyl group. ii- A synthesis of the polyurethane wedge which contains alkene groups at the periphery via the convergent path. iii- A synthesis of the polyurethane dendrimers from the polyurethane wedge and different cores. iv- Thiol-ene click chemistry of polyurethane dendrimers with thiol functional groups. v- Characterization and study of the properties of the polyurethane dendrimer.

3-1-2. Synthetic strategies

A branched monomer with two carboxylic acids was reacted with DPPA and Et3N to generate an isocyanate monomer. The first generation polyurethane wedge with peripheral alkene groups was prepared from reaction of an isocyanate monomer and a hydroxyl alkene. The first generation of polyurethane wedge with peripheral alkene groups was deprotected to get the first generation of polyurethane wedge with hydroxyl groups. Two first generation polyurethane wedges were reacted with an isocyanate monomer to obtain a second generation polyurethane wedge with peripheral alkene groups. Repeating the deprotection step afforded a second generation of polyurethane wedges with peripheral alkene groups and hydroxyl groups. The polyurethane dendrimers were synthesized from a reaction of core and the first or second generation of polyurethane wedges with alkene groups periphery. The polyurethane dendrimers and the first or second generation of polyurethane wedges with alkene groups periphery were reacted with 1-octanethiol as thiol-ene click reaction.

HOOC COOH OCN NCO HO DPPA, Et3N

solvent, reflux

O(P) O(P)

Monomer

H H O N N O H H O N N O Deprotection O O O O O(P) OH first generation wedge

O O

OCN NCO HN O O NH

HN NH H H O N N O O(P) Deprotection O O O O O O

second generation wedge

first generation wedge HOOC COOH first generation dendrimer

DPPA, Et3N solvent, reflux second generation dendrimer COOH second generation wedge

Figure 31. Synthetic strategies of alkene wedge and dendrimers.

3-2. Synthesis of polyurethane wedge with ally periphery

3-2-1. Initial model A

In the initial strategy (Figure 32), 5-hydroxyisophthalic acid (1) was protected by acetic anhydride and pyridine to get 5-acetoxy isophthalic acid 2. The first

47 generation wedge with a allyl periphery was formed from a reaction of 5-acetoxy isophthalic acid 2 with DPPA and Et3N in refluxing benzene followed by the addition of allyl alcohol. Deprotection of the first generation wedge with allyl periphery 3 by

K2CO3 in methanol and water provided the first generation wedge with allyl periphery 4. The above procedure was repeated with the first generation wedge with allyl periphery 4 to obtain the second generation wedge with allyl periphery 5 as shown in Figure 32.

O O O O

O O HO OH HO OH 1) DPPA, Et3N O pyridine 2) HO

OH OAc

1 2

H H O N N O H H O N N O C C C C 2.5% K2CO3 O O O O MeOH/H2O

OAc OH

3 4

O O

C C HN O OAc O NH

O O

HN O N N O NH DPPA H H

Et3N C C O O O O 2

Figure 32. Synthesis of polyurethane wedge with ally periphery initial model A

48 The first generation with the allyl periphery was made and analyzed by proton NMR and 13C NMR. Unfortunately, the second generation with the allyl periphery synthesis failed perhaps due to steric effect of the first generation on both sides of diisocyanate monomer. Moreover, the first generation with the allyl periphery was not completely soluble in benzene and toluene. Therefore, a flexible chain, such as propane, on the hydroxyl group, might allow for the successful synthesis of the second generation dendrimer with peripheral allyl groups.

3-2-2. Initial model B

The synthesis of the initial monomer (Figure 33) was envisioned to begin with available 5-hydroxyisophthalic acid (1). Protection of dicarboxylic acid by H2SO4 and methanol began the synthesis, generating dimethyl-5-hydroxyisophthalate 6. The coupling of dimethyl 5-hydroxyisophthalate 6 with 3-chloro-1-propanol in the presence of potassium iodide and potassium carbonate in DMF under reflux for 4 h would afford dimethyl 5-(3-hydroxypropoxy) isophthalate 7. Deprotection of 3 by mixture of 1 M NaOH solution and THF at 60 oC for 5h afforded 5-(3-hydroxypropoxy) isophthalic acid 8. Protection of 8 as a hydroxyl group by acetic anhydride in pyridine at room temperature for 40 hours would generate 5-(3-acetoxypropoxy) isophthalic acid 9. The first generation wedge with allyl periphery 10 would be prepared by a reaction 5-(3-acetoxypropoxy) isophthalic acid 9 with Et3N and DPPA in benzene followed by the addition of allyl alcohol. Deprotection of the first generation wedge with allyl periphery 10 via of K2CO3 in a mixture of MeOH and distilled water (2:1) yielding the first generation wedge with allyl periphery and propanol 11. The above procedure would be repeated with the first generation wedge with allyl periphery 11 to obtain the second generation wedge with allyl periphery 12.

49 O O O O O O

HO OH MeO OMe MeO OMe H SO 2 4 KI, K2CO3, DMF

MeOH Cl OH

OH OH O

6 1

OH 7

O O O O

O O HO HO OH OH 1M NaOH/THF O 1) DPPA, Et3N pyridine 2) HO O O

OH OAc 8 9

H H H H O N N O O N N O C C C C

O O O O 2.5% K2CO3

MeOH/H2O O O

OAc OH

10 11

O O

C C O HN O NH

HN O O NH 2.5% K2CO3 C O O H C MeOH/H2O H O O N N O O DPPA O Et3N O

9 O

OH 12 Figure 33. Synthesis of polyurethane wedge with ally periphery initial model B

50 In practice, 5-(3-acetoxypropoxy) isophthalic acid 9 was prepared and used to generate the first generation wedge with allyl periphery and propyl acetate. Deprotonation of the first generation wedge with allyl periphery and propyl acetate offered a few challenges, when K2CO3 with methanol and water were used to get the first generation wedge with allyl periphery and propanol. Unfortunately, the reaction was not selective and the deprotection happened with both side acetoxypropoxy and carboxamide and produced the hydroxyl and methylester, respectively. To solve this problem, we tried acid deprotonation using p-toluenesulfonic acid. p-toluenesulfonic acid worked better than the basic conditions but was low yielding. Therefore, other protecting groups are needed to increase the yield of the first and second generation wedge with allyl periphery and propanol.

3-2-3. Synthesis of branching monomer

The synthesis of monomer 7 (Figure 34) begins with dimethyl 5-(3- hydroxypropoxy) isophthalate 7 which was synthesized using the same method as previously reported (Figure 3-3). Protection of alcohol 7 took place by reacting it with tert-butyl(chloro)diphenylsilane in the presence of imidazole in DMF at room temperature for 24 hours to afford dimethyl 5-(oxy-propane-tert-butyl diphenyl siloxyl) isophthalate 13. Deprotection of 13 by a mixture of 1 M NaOH solution and THF at 60 oC for 5h gave access to 5-(oxy-propane-tert-butyl diphenyl siloxyl) isophthalic acid 14. Note that 7 could be also produced by chlorotriphenylsilane to give dimethyl 5-(oxy-propane-triphenyl siloxyl) isophthalate. However, the tert- butyl(chloro)diphenylsilane produced a better yield than chlorotriphenylsilane.

51 O O O O O O

MeO OMe MeO OMe HO OH

TBDPSCl, imidazole 1M NaOH/THF DMF

O O O

OH 13 OTBDPS OTBDPS 14 7

Figure 34. Synthesis of branching monomer

3-2-4. Synthesis of polyurethane wedge with allyl periphery

14 was reacted with Et3N until it dissolved in toluene followed by the addition of DPPA and stirring for 30 minutes. It was heated to reflux to generate the isocyanate intermediate 15. The allyl alcohol was added and the mixture was stirred overnight to obtain the first generation wedge with allyl periphery and TBDPS protecting group 16. Without any purification, 16 was directly dissolved in THF and a tetrabutylammonium fluoride solution (1.0 M in THF) was added to get the first generation wedge with allyl periphery and hydroxyl group 11. The above procedure was repeated with the first generation wedge with allyl periphery 12 to obtain the second generation wedge with allyl periphery 12 as shown in Figure 35.

52 O O O O C C N N HO OH

DPPA, Et3N HO

O O

OTBDPS OTBDPS 14 15

H H O N N O H H O N N O C C C C

O O TBAF O O THF O O

OTBDPS OH 16 11

O O C O O C HN H O O H N N O O TBAF NH THF O DPPA O

Et3N HN O O C 14 O NH C O O

Figure 35. Synthesis of polyurethane wedge with allyl periphery

53 The first and second generation wedges with allyl periphery were analyzed by 1H-NMR and 13C NMR. A difference between the first and second generation wedges are in the number of proton and carbons because they are symmetrical molecules. However, the chemical shifts are close between the first and second generation wedges. There is insufficient precision in the 1H NMR integrates to distinguish the first and second generation. Thus, the 1H-NMR and 13C NMR spectra did not give enough information to fully characterize the products. On other hand, the matrix- assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS) was used to measure the first and second generation wedges with allyl periphery.

The first generation wedge with allyl periphery and hydroxyl group 11 was confirmed by the appearance of peaks at δ 7-7.4 ppm, corresponding to the protons of aromatic ring and the appearance of peaks at δ 7.8 corresponding to the protons of NH in the 1H NMR spectroscopy (Figure 36). Furthermore, the appearance of peak at 159 corresponding to the carbon of carbamate in the 13C NMR spectroscopy (Figure 2). The first generation of a wedge with allyl periphery and propanol 11 was successfully isolated and it was analyzed. The mass spectrum of the first generation wedge with allyl periphery and propanol 11 displays a peak at m/z = 372.68 with the isotope pattern corresponding to [M + Na]+ and a peak at m/z = 388.72 corresponding to [M + K]+. Furthermore, the second generation wedge with allyl periphery and propanol 12 was successfully isolated. The mass spectrum of the second generation wedge with allyl periphery and propanol 12 displays a peak at m/z = 957.103 with the isotope pattern corresponding to [M + Na]+ and a peak at m/z = 973.101 corresponding to [M + K]+. Both the first and second generation wedges with allyl periphery and propanol (11&12) afforded low isolated yield, 10% and 15% respectively after column chromatography. Benzene, toluene, THF and 1,4-dioxane were used to attempt to improve the yield. The best yields were obtained with benzene and toluene.9

1 13 Figure 36. H and C NMR spectrum of 11 in CDCl3-d1

3-2-5. Synthesis of polyurethane dendrimer with allyl periphery

The synthesis of the first generation dendrimer with allyl periphery started from a reaction of 1,3,5-benzene tricarboxylic acid (17) with DPPA in the presence of

Et3N in toluene to obtain tri-isocyanate intermediate. The first generation wedge with allyl periphery and propanol 11 was added to get first generation dendrimer with allyl periphery 18 as shown in Figure 37.

55 H H O N N O

O O

O O O

O O NH O HO OH 1) DPPA, Et3N O O NH O 2) 11 O N N O O HN H H O

HO O NH O O 17 HN O

O O

Figure 37. Synthesis of polyurethane dendrimer with allyl periphery

The first generation dendrimer with allyl periphery 18 was analyzed by proton and 13C NMR and MALDI-TOF MS after column chromatography. The yield was 10% and mass spectrum of the first generation dendrimer with allyl periphery and trimesic core displays a peak at m/z = 1274.431 with the isotope pattern corresponding to [M + Na]+ and a peak at m/z = 1290.461 corresponding to [M + K]+.

3-3. Conclusions

The convergent path and the selectivity of the reactions of allyl alcohol periphery have been applied in the synthesis of a polyurethane dendrimers. The first and second generation polyurethane wedge with allyl periphery have been prepared. Unfortunately, there is a low yield of the first and second generation wedges polyurethane with allyl periphery.9 The first generation polyurethane dendrimers

56 with allyl periphery have been prepared. In addition, the structures were characterized by NMR and mass spectrometry.

3-4. Experimental section

O O O O

HO OH O O H2SO3

MeOH

OH OH

6 Preparation of dimethyl-5-hydroxyisophthalate 6. A mixture of 5- hydroxyisophthalic acid (20 g, 108.5 mmol), 16 mL of H2SO4, and MeOH (350 mL) was stirred at room temperature for 2 days. The solvent was removed and a crude product was dissolved in 50% v/v of water and ether. The organic layer was separated and the aqueous layer was extracted with ether (3 x100mL). The combined organic layers were washed with water, saturated sodium chloride and dried over MgSO4. The solvent was removed in vacuum to give a white solid as crude product.

O O O O

KCO3,KI, DMF

Cl OH

OH O

OH Preparation of dimethyl-5-oxy-propanol-isophthalate 6. In a 250 mL round bottom flask, dimethyl-5-hydroxyisophthalate (4.0 g, 19.0 mmol, 1.0 eq), K2CO3 (3.16 g, 22.8 mmol, 1.2 eq), potassium iodide (3.79 g, 22.8 mmol, 1.2 eq), 3- chloro-1- propanol (2.16 g, 22.8 mmol, 1.2 eq) and DMF (50 mL) were placed. The reaction mixture was refluxed for 3h under nitrogen. The solvent was removed on a rotary

57 evaporator and a crude product was dissolved in 50% v/v of water and EtOAc. The combined organic layers were washed with water, saturated sodium chloride and dried over MgSO4. The solvent was removed in vacuum to obtain a colorless oil as crude product 90%.

O O O O

O O O O imidazole / TBDPSCl

DMF O O

OH OTBDPS Preparation of dimethyl-(5-oxy-propane-tert-butyldiphenylsiloxy) isophthalate 13. In a 100 mL round bottom flask, dimethyl-5-oxy-propanol- isophthalate (3.0 g, 11.2 mmol, 1.0 eq), imidazole (1.9 g, 28.0 mmol, 2.5 eq), and DMF (30 mL) were placed. The reaction mixture was stirred under a nitrogen atmosphere until completely dissolved and then was added tert-Butyl(chloro)diphenylsilane (3.4 g, 12.3 mmol, 1.1 eq). The reaction mixture was stirred overnight. Water (50 mL) was added, the reaction mixture was extracted with DCM (3 x 40 mL). The combined organic layers were washed with water, saturated sodium chloride and dried over

MgSO4. The solvent was removed in vacuum to give a yellow oil as crude product.

O O O O

HO OH O O 1M NaOH

THF

O O

OTBDPS OTBDPS

58 Preparation of 5-(oxy-propane-tert-butyl diphenyl siloxyl) isophthalic acid 14. To a solution of dimethyl-(5-oxy-propane-tert-butyldiphenylsiloxy)isophthalate 13 (6.0 g, 11.8 mmol) in THF (20 mL) was added NaOH (30 mL of 1M). The reaction mixture was stirred at 50 oC for 5 h. Water (50 mL) was added and the reaction mixture was acidified with 1% H2SO4. The reaction mixture was extracted with EtOAc

(3 x 30 mL). The combined organic layers were dried over MgSO4. The solvent was removed in vacuum to give a white solid as crude product. 1H-NMR (500 MHz; acetone-d6): δ 1.05 (d, J = 1.7 Hz, 11H), 2.14 (q, J = 6.0 Hz, 2H), 3.98-3.95 (m, 2H), 4.34 (t, J = 6.1 Hz, 2H), 7.47-7.39 (m, 7H), 7.71 (dt, J = 6.4, 1.6 Hz, 3H), 7.81-7.78 (m, 4H),

13 8.32-8.30 (m, 1H). C-NMR (126 MHz, acetone-d6): δ 13.63, 18.76, 18.86, 19.96, 26.18, 26.32, 26.35, 35.20, 41.60, 59.67, 60.02, 60.34, 119.55, 119.56, 120.48, 121.95, 122.84, 127.45, 127.71, 127.73, 127.77, 127.86, 129.20, 129.71, 129.78, 132.36, 133.45, 133.53, 134.67, 134.73, 135.30, 135.37, 136.39, 157.69, 165.97, 166.05, 166.06, 170.04. MALDI-

+ TOF MS calculated for C27H30O6Si 478.18, found 501.123 [M+Na ].

Experimental Procedure (A) for syntheses of dendritic ether urethane wedges with alkene groups on the periphery.A mixture of 5-(oxy-propane-tert- butyldiphenylsiloxyisloxyisophthalic acid) 14 (1.0 equiv), triethylamine (6.0 equiv), and dry toluene (30 mL/g) was stirred under a nitrogen atmosphere until dissolved, then diphenylphosphoryl azide (4.0 equiv) was added. The mixture was stirred at room temperature for 25 minutes and the mixture was refluxed for 3h. Alkene alcohol (2.1 equiv) was added, refluxed and stirred overnight. The mixture was allowed to cool down to room temperature. The solvent was removed in a rotary evaporator to give a crude product and was dissolved in ethyl acetate. The solution was washed with water, a solution of saturated NaCl and dried over MgSO4 and evaporated.

The crude product was dissolved in THF be for addition of 1.0 M tetrabutylammonium fluoride hydrate (3.775 equiv). The mixture was stirred at 40 oC overnight. The solvent was removed in a rotary evaporator and dissolved in EtOAc, washed with water, solution of saturated NaCl, dried over MgSO4 and evaporated.

59 O O

C C H H HO OH 1) DPPA, Et3N, toluene O N N O 2) HO O O O 3)p-toluenesulfonic acid , OH THF/ H2O (2:1) O

Preparation of allyl periphery first generation (4). A mixture of 5-(acetyloxy)- isophthalic acid (0.5 g, 2.2 mmol, 1.0 eq), triethylamine (1.35 g, 13.1 mmol, 6.0 eq), and dry toluene (20 mL/g) was stirred under a nitrogen atmosphere until dissolved. Diphenylphosphoryl azide (2.45 g, 8.9 mmol, 4.0 eq) was added. The mixture was stirred at room temperature 25 minutes and the mixture was refluxed for 3h. Allyl alcohol (0.27 g, 4.7 mmol, 2.1 eq) was added and the mixture stirred overnight. The mixture was allowed to cool down to room temperature. The solvent was removed in a rotary evaporator to give a crude product and it was dissolved in ethyl acetate. The solution was washed with water, brine, dried over MgSO4 and evaporated.

The crude product was dissolved in a solution of 1 mol% of p-toluenesulfonic acid in a mixture of THF and distilled water (2:1) (50 mL). The mixture was stirred at room temperature overnight. The organic layer was separated and the aqueous layer was extracted with EtOAc several times. The combined organic layers were washed with water and dried over MgSO4 and evaporated. Purification was performed by silica-gel

1 column chromatography (1:1 to 1:2 hexanes/EtOAc). H-NMR (500 MHz; acetone-d6): δ 4.65-4.61 (m, 4H), 5.39-5.20 (m, 4H), 6.01-5.98 (m, 2H), 7.73-7.70 (m, 2H), 8.01 (t, J =

13 1.4 Hz, 1H). C-NMR (126 MHz, aceton-d6): δ 51.51, 115.15, 119.07, 119.43, 119.46, 119.92, 119.94, 119.98, 120.95, 128.66, 129.28, 129.86, 131.65, 132.76, 165.95.

60 O O H H O N N O C C HO OH 1) DPPA, Et3N, toluene 2) O O HO O O 3) TBAF, THF

HO TBDPSO

Preparation of allyl periphery first generation (11). The experimental procedure (A) was followed using 5-(oxy-propane-tert-butyldiphenylsiloxyisloxyisophthalic acid) (1 g, 2.1 mmol, 1.0 eq), Et3N (1.27 g, 12.5 mmol, 6.0 eq) and DPPA (2.3 g, 8.4 mmol, 4.0 eq) with toluene (30 mL). Allyl alcohol (0.25 g, 4.4 mmol, 2.1 eq) was then added and the mixture was refluxed for 24 h. Pure compound 11 was obtained by silica gel column chromatography (1:1 DCM/EtOAc) as a yellowish oil; Yield 10%. 1H

NMR (aceton-d6, 500 MHz) 1.98 (m, J = 6.0 Hz, 2H), 2.92 (br, 1H), 3.75 (t, J = 6.0 Hz, 2H), 4.07 (t, J = 4.0 Hz, 4H), 4.63 (dd, J = 3.5 Hz, 4H), 5.28 (dd, J = 4.0 Hz, 4H), 6.00 (m, J = 4.5 Hz, 2H), 7.00 (d, J = 1.5 Hz, 2H) 7.30 (d, J = 1.5 Hz, 2H) 8.69 (br, 2H); 13C NMR

(aceton-d6, 125 MHz) 32.42, 58.18, 64.67, 64.82, 99.33, 100.89, 116.73, 133.32,

140.53, 153.15, 160.09. MALDI-TOF MS calculated for C17H22N2O6 350.15, found 372.68 [M+Na+] and 388.72[M+K+].

O O O O C C O O C NH HN HN O O NH C O HO OH 1) DPPA, Et3N, toluene O O O 2)FG_Allyl_OH

O O O 3) TBAF, THF NH HN O O

O TBDPSO

61 Preparation of allyl periphery second generation (12). The experimental procedure (A) was followed using 5-(oxy-propane-tert- butyldiphenylsiloxyisloxyisophthalic acid) (0.3 g, 0.63 mmol, 1.0 eq), Et3N (0.38 g, 3.8 mmol, 6.0 eq) and DPPA (0.69 g, 2.5 mmol, 4.0 eq) with toluene (30 mL). Allyl periphery first generation 11 (0.46 g, 1.3 mmol, 2.1 eq) was then added and the mixture refluxed for 24 h. Pure compound 12 was obtained by silica gel column chromatography (1:1 to 1:2 DCM/EtOAc) as a yellowish oil; Yield 15%. 1H-NMR (500

MHz; CDCl3): δ 2.12-1.69 (m, 26H), 3.74 (s, 2H), 3.94 (d, J = 28.7 Hz, 6H), 4.20-4.11 (m, 14H), 5.03-4.96 (m, 8H), 5.78 (ddt, J = 17.0, 10.3, 6.7 Hz, 4H), 6.81 (s, 5H), 7.09-7.06 (m,

3H), 7.33 (s, 3H), 7.72 (t, J = 0.4 Hz, 2H). 13C NMR (acetone-d6, 125 MHz) 12.97, 18.39, 32.43, 58.18, 61.14, 64.24, 64.70, 64.81, 64.85, 70.33, 99.34, 100.92, 116.72, 127.46, 133.32, 140.54, 140.59, 153.17, 159.86, 160.08. MALDI-TOF MS calculated for

+ + C45H54N6O16 934.36, found 957.103 [M+Na ] and 973.101[M+K ].

Preparation of first generation of 1,3,5-benzene tricarboxylic acid with allyl groups on the periphery. A mixture of 1,3,5-benzene tricarboxylic acid (0.07 g, 0.3 mmol, 1.0 eq), Et3N (0.24 g, 2.3 mmol, 7.0 eq) and dry toluene (10 mL/g) was stirred under a nitrogen atmosphere until dissolved. DPPA (0.46 g, 1.7 mmol, 5.0 eq) was added. The mixture was stirred at room temperature for 25 minutes and the mixture was then refluxed for 45 minutes. 11 (0.385 g, 1.1 mmol, 3.3 eq) was added and the solution stirred overnight. The solvent was removed and a crude product was dissolved in ethyl acetate. The solution was washed with water, brine, dried over

MgSO4. and evaporated. By removal of solvent on a rotary evaporator (10%) of a

1 yellowish oil was obtained; H NMR (500 MHz; CDCl3): δ 2.05-1.93 (m, 7H), 3.96-3.95 (m, 7H), 4.01 (dt, J = 5.8, 2.9 Hz, 6H), 4.65 (d, J = 4.1 Hz, 12H), 5.40-5.27 (m, 12H), 6.02- 5.90 (m, 6H), 6.75 (d, J = 16.7 Hz, 6H), 6.80 (s, 3H), 7.07 (s, 3H). MALDI-TOF MS

+ + calculated for C60H69N9O21 1251.46, found 1274.431 [M+Na ] and 1290.461 [M+K ].

62 3-5. Synthesis of polyurethane with pentene periphery 3-5-1. Synthesis of polyurethane wedge with pentene periphery

Many attempts were made to improve the yield of the allyl wedge and dendrimer, but unfortunately none were successful. An attempt to increase yield using long chains was investigated. Fortunately, 4-pentene-1-ol gave better yield than allyl alcohol and was the best candidate to prepare first and second generation wedges with a good yield. Using the same procedure as noted above, first and second generation wedges with pentene periphery were synthesized as shown in Figure 38.

63 O O H H O N N O C C HO OH O O

1) DPPA, Et3N

2) O HO O

OTBDPS OTBDPS 14 19

H H O N N O C C

O O TBAF TBAF THF THF O DPPA Et3N

OH 20

O O C O O C H H HN O O N N O O NH

O O

HN O O O NH C C O O

Figure 38. Synthesis of polyurethane wedge with pentene periphery

The conformation of the first and second generation wedge with pentene periphery and propanol (20&21) were carefully monitored by 1H NMR as shown in Figure 39 and 40. The products were analyzed with proton and 13C NMR and MALDI- TOF MS after column chromatography. The first generation wedge with pentene periphery and propanol 20 yield was 49% and the mass spectrum displays a peak at m/z = 429.050 with the isotope pattern corresponding to [M + Na]+. The second

64 generation wedge with pentene periphery and propanol 21 yield was 21.7 % and the mass spectrum displays a peak at m/z = 1069.576 with the isotope pattern corresponding to [M + Na]+.

1 Figure 39. H NMR spectrum of 20 in CDCl3-d1

1 Figure 40. H NMR spectrum of 21 in CDCl3-d1

3-5-2. Thiol-ene “click” chemistry of polyurethane wedge with pentene periphery The overall synthetic strategy is highlighted in (Figure 38), starting from the first and second generation wedges with pentene periphery. 1-Octanethiol was

65 appropriately chosen for its thiol functionality and its miscibility with 20 or 21. The first generation wedge with pentene periphery was reacted with 1-octanethiol in the presence AIBN in dry DCM to generate the first generation wedge with thiol-ene “click” chemistry periphery as shown in Figure 41.10, 11

H H H H O N N O S O N N O S R R

O O AIBN, 1-octanethiol O O DCM O O

OH OH

20 22

R= C8H17

R R S S TBAF, THF DPPA/ Et3N 14

O O

HN O O NH

HN H H NH O O N N O O

O O O O O O

S S

R R OH

Figure 41. Thiol-ene “click” chemistry of polyurethane wedge

The thiol-ene “click” chemistry reaction was carried out for both the first and second generation wedges with pentene periphery 20 and 21. Unfortunately, it worked solely with the first generation wedge 19, perhaps due to the radical initiation. The second generation wedge 23 can be synthesized using the first generation thiol-ene on the periphery 22 from a reaction the first generation wedge with thiol-ene “click” chemistry periphery 22 with 14 in the presence of DPPA and

Et3N in toluene followed by deprotection. Characterization of the purified products of each generation by a combination of 1H NMR and 13C NMR and MALDI-TOF mass

66 spectrometry. The first generation wedge 22 yield was 30% and the mass spectrum displays a peak at m/z = 721.539 with the isotope pattern corresponding to [M + Na]+ and a peak at m/z = 737.555 corresponding to [M + K]+. The second generation wedge 23 yield was 20% and the mass spectrum displays a peak at m/z = 1654.027 with the isotope pattern corresponding to [M + Na]+. The first generation wedge with thiol-ene “click” chemistry periphery 22 was confirmed by the disappearance of peaks at δ 4.8- 6 ppm, corresponding to the protons of alkene and the appearance of peaks at δ 2.5 corresponding to the protons of (-CH2SCH2-) in the 1H NMR spectroscopy (Figure 42).

1 Figure 42. H NMR spectrum of 22 in CDCl3-d1

3-5-3. Synthesis of polyurethane dendrimers

The multi-carboxylic acid cores were reacted with Et3N and DPPA in dry benzene or toluene, then heated to reflux to generate the isocyanate intermediate. The first and second generation wedges were added to the mixture, and it was refluxed overnight to obtain the first and second generation polyurethane dendrimers as shown in Figure 43. Characterization of the purified products of each generation was carried out by a combination of 1H NMR and 13C NMR and MALDI-TOF mass spectrometry.

H H O N N O H H S O N N O S O O O O O O

N O 1) 3 O O DPPA/ Et O 2) DPPA/ C NH 19 Et 1) 3 N NH C FG_Pentene_dendrimer O FG_Ene_click_dendrimer C

OH N 3 Et 1) DPPA/ DPPA/ 1) Et 20 3 N S 2) S

O O O O HN NH HN O NH O O O

HN H H NH H H O O O N N O O HN O O N N O O NH O O O O O O O O O O O O O

S S O O O O C NH C NH

SG_Pentene_dendrimer SG_Ene_click_dendrimer

Figure 43. Synthesis of polyurethane dendrimers

3-5-3-1. Synthesis of polyurethane dendrimers from 4,4'-MDI and 4,4'- biphenyldicarboxylic acid.

4,4'-MDI and 4,4'-biphenyldicarboxylic acid (Figure 44) were insoluble in toluene and benzene. Thus, these were not suitable for dendrimer formation.

O O

HO OH OCN NCO

4,4'-MDI 4,4'-biphenyldicarboxylic acid

Figure 44. 4,4'-MDI and 4,4'-biphenyldicarboxylic acid

68 3-5-3-2. Synthesis of polyurethane dendrimers from trimesic acid

Trimesic acid was successful in confessing the first generation dendrimer with pentene periphery 25 (Figure 45). 25 mass calculated for C72H93N9O21 1419.65 displays a peak at m/z = 1442.600 with the isotope pattern corresponding to [M + Na]+ and a peak at m/z = 1458.645 corresponding to [M + K]+. Unfortunately, the second generation dendrimer with pentene periphery and trimesic core, and the first generation dendrimer with octanethiol periphery and trimesic core were reacted at just one site of trimesic acid. This might be to the steric effect of a wedge.

H H O N N O

O O

O OH O O

1) DPPA, Et3N

HO O 2) 20 O HN HN O O O

O O O HN O O O OH O NH

HN O 24 O O NH

Figure 45. Synthesis of polyurethane dendrimer from trimesic acid

To solve the problem of reaction between the first and second generation wedges with a core, a new strategy was coupling between the wedge and core as an ester functional group. The new strategy of synthesis of dendrimers is shown in

69 Figure 46. The multi-carboxylic acid groups core were reacted with thionyl chloride or oxalyl chloride to generate multi-acyl chloride, followed by the addition of the first or second generation wedges to obtain the first or second generation dendrimers.

H H O N N O

O O O O SOCl2 or (CO)2Cl2 FG_Pentene_OH C C O base OH n Cl n C O O

Figure 46. Synthesis of dendrimers

3-5-3-3. Synthesis of polyurethane dendrimers from sebacic acid as ester functional group core.

The synthesis of the sebacic core dendrimers (Figure 47) begins with sebacic acid. To begin the transformation of dicarboxylic acid (26) by oxalyl chloride in the presence of DMF in DCM, this combination was refluxed for 24 hours to generate sebacoyl chloride 27. Esterification of sebacoyl chloride 27 with the first or second generation wedge in the presence of poly(4-vinylpyridine) in DCM was done by refluxing for 24 h to obtained the first or second generation sebacic 28 and 29, as ester functional group, core dendrimers.

70 O O

O (COCl)2 O HO Cl CH2Cl2, DMF

OH 27 Cl

O NH

O O O 20 O NH HN O O O poly(4-vinylpyridine) O O O DCM

HN O

O NH

O NH O O O O HN O

O O HN O O NH O O O 21 O 27 HN O O poly(4-vinylpyridine) O O NH DCM O O O O HN O O NH O O

O NH O O O N O H O N H O 29

Figure 47. Synthesis of polyurethane dendrimers from sebacic acid as ester core

The sebacic core, the first generation dendrimer 28 mass spectrum displays a peak at m/z = 1001.879 with the isotope pattern corresponding to [M + Na]+. The second generation dendrimer 29 yield was 20% and the mass spectrum displays a peak at m/z = 2282.092 with the isotope pattern corresponding to [M + Na]+.

3-5-3-4. Synthesis of polyurethane dendrimers from porphyrin as ester functional group core.

The reaction of 4,4′,4′′,4′′′-(porphine-5,10,15,20-tetrayl)tetrakis(benzoic acid) (30) with oxalyl chloride in the presence of DMF in THF gives 4,4′,4′′,4′′′- (porphine-5,10,15,20-tetrayl)tetrakis(benzoyl chloride) 31. Then, esterification by reaction with the first generation wedge in the presence of poly(4-vinylpyridine) in THF and refluxing to obtain the first generation porphyrin, as ester functional group, core dendrimers 32 (Figure 48).

72 O OH O Cl

Cl HO NH N NH N OH Cl (COCl)2, DMF O O N HN N HN O THF O

O Cl O OH

30 31

H H O N N O

O O

O O C O O HN 20 O poly(4-viylpyridine), THF N HN HN O O O O C C O O O NH N O NH

NH O O C O O

O O

O N N O H H 32

Figure 48. Synthesis of polyurethane dendrimers from porphyrin as ester core

73 The 4,4′,4′′,4′′′-(porphine-5,10,15,20-tetrayl)tetrakis(benzoic acid) core as aromatic-ester core unit with the first generation polyurethane wedge with pentene periphery mass spectrum displays a peak at m/z = 2366.997 with the isotope pattern corresponding to [M + Na]+ and a peak at m/z = 2381.509 corresponding to [M + K]+.

3-5-4. Conclusions

The convergent route was useful in the synthesis of the first and second generation polyurethane wedges with pentene periphery. The polyurethane wedges were afforded in good yield. The thiol functional group was reacted with an alkene to get first and second generation polyurethane wedges with thiol-ene click periphery.

Trimesic acid was useful for synthesis of dendrimers with an aromatic- urethane core unit. Sebacic acid and 4,4′,4′′,4′′′-(porphine-5,10,15,20- tetrayl)tetrakis(benzoic acid) was used to prepared dendrimers with an aromatic- ester core unit. All polyurethane wedges and dendrimers were characterized via proton and 13C NMR. MALDI-TOF mass spectra was useful to determine the molecular weight and identity of these wedges and polyurethane dendrimers.

3-5-5. Experimental section Preparation of pentene periphery first generation (20). The Experimental Procedure (A) was followed using 5-(oxy-propane-tert- butyldiphenylsiloxyisloxyisophthalic acid) (1 g, 2.1 mmol, 1.0 eq), Et3N (1.27 g, 12.5 mmol, 6.0 eq) and DPPA (2.3 g, 8.4 mmol, 4.0 eq) in toluene (30 mL). 4-Penten-1-ol (0.38 g, 4.4 mmol, 2.1 eq) was added and the mixture refluxed for 24 h. Pure compound 20 was obtained by silica gel column chromatography (ether) as a

1 1 yellowish oil; Yield 49 %. H NMR H-NMR (500 MHz; CDCl3): δ 1.76 (quintet, J = 7.2 Hz, 4H), 1.98 (t, J = 6.0 Hz, 2H), 2.15 (q, J = 7.1 Hz, 4H), 2.47 (s, 1H), 3.80 (t, J = 5.9 Hz, 2H), 4.06 (t, J = 6.0 Hz, 2H), 4.16 (t, J = 6.6 Hz, 4H), 5.07-4.99 (m, 4H), 5.82 (ddt, J =

74 13 17.0, 10.3, 6.7 Hz, 2H), 6.80 (s, 2H), 7.04 (s, 3H). C-NMR (126 MHz, CDCl3): δ 28.07, 29.95, 31.91, 59.98, 64.71, 65.51, 99.95, 99.98, 100.03, 100.05, 100.09, 100.13, 101.37, 101.40, 101.45, 109.98, 115.31, 137.43, 139.53, 153.65, 159.91. MALDI-TOF MS

+ calculated for C21H30N2O6 406.21, found 429.050 [M+Na ].

Preparation of pentene periphery second generation (21). The Experimental Procedure (A) was followed using 5-(oxy-propane-tert- butyldiphenylsiloxyisloxyisophthalic acid) (0.2 g, 0.42 mmol, 1.0 eq), Et3N (0.25 g, 2.5 mmol, 6.0 eq) and DPPA (0.46 g, 1.7 mmol, 4.0 eq) with toluene (30 mL). Pentene periphery first generation (20) (0.36 g, 0.88 mmol, 2.1 eq) was then added and the mixture refluxed for 24 h. Pure compound (21) was obtained by silica gel column

1 chromatography (ether) as a yellowish oil; Yield 21.7 %. H NMR (CDCl3-d, 500 MHz) 1.72 (t, J = 6.5 Hz, 8H), 1.93 (t, J = 5.5 Hz, 6H), 2.09 (t, J = 7.0 Hz, 8H), 3.74 (br, 2H), 3.91 (br, 2H), 4.14 (m, J = 4.0 Hz, 8H), 4.20 (br, 4H), 5.00 (m, J = 9.5 Hz, 8H), 5.76 (m, J

13 = 3.0 Hz, 4H), 6.81 (br, 6H) 7.06 (br, 3H) 7.72 (br, 2H); C NMR (CDCl3-d, 125 MHz) 14.20, 21.06, 28.01, 28.66, 29.92, 31.88, 59.72, 60.48, 61.67, 64.26, 64.73, 65.23, 100.02, 101.49, 115.31, 137.45, 139.59, 153.87, 159.79. MALDI-TOF MS calculated for

+ C53H70N6O16 1046.48, found 1069.576 [M+Na ].

Thiol-ene “Click” Chemistry

Experimental Procedure (B) for syntheses of dendritic ether urethane wedges with Thiol-ene “Click” Chemistry on the periphery.To a solution of dendritic ether urethane wedges with alkene groups on the periphery (1.0 equiv) in 5 mL of dichloromethane was added (2.1 equiv) of thiol compounds and (0.02 equiv) 2,20- azobis(isobutyronitrile). The mixture was stirred under a uv light lamp and nitrogen at room temperature overnight. The solvent was removed on a rotary evaporator to obtain a crude product. This product was dissolved in ethyl acetate and washed with water and dried over MgSO4 and evaporated. Purification was performed by silica-gel

75 column chromatography DCM than (1:1 DCM/EtOAc) to give pure dendritic ether urethane wedges with thiol-ene “click” chemistry on the periphery.

Thiol-ene “Click” Chemistry first generation (22). The Experimental Procedure (B) was followed using pentene periphery first generation 20 (0.2 g, 0.49 mmol, 1.0 eq), AIBN (2 mg, 0.01 mmol, 0.02 eq) and 1-octanethiol (0.15 g, 1.0 mmol, 2.1 eq) with DCM (5 mL). The mixture was stirred under uv light lamp and nitrogen at room

1 temperature for overnight. Yield 30 %; H-NMR (500 MHz; CDCl3): δ 0.88 (d, J = 13.8 Hz, 6H), 1.33-1.30 (m, 20H), 1.42-1.35 (m, 5H), 1.51-1.43 (m, 4H), 1.71-1.55 (m, 14H), 2.04-1.98 (m, 2H), 2.54-2.44 (m, 8H), 3.82 (t, J = 5.9 Hz, 2H), 4.08 (t, J = 6.0 Hz, 2H),

13 4.14 (t, J = 6.6 Hz, 4H), 6.80 (s, 2H), 6.93 (s, 2H), 7.03 (s, 1H); C NMR (CDCl3-d, 125 MHz) 14.10, 22.65, 25.20, 28.56, 28.97, 29.20, 29.23, 29.29, 29.72, 31.82, 31.95, 31.98, 32.23, 60.28, 65.21, 65.72, 99.93, 101.29, 139.52, 153.48, 159.99. MALDI-TOF MS

+ + calculated for C41H74N2O6S2 698.44, found 721.539 [M+Na ] and 737.555[M+K ].

Thiol-ene “Click” Chemistry second generation (23). The Experimental Procedure (A) was followed using 5-(oxy-propane-tert- butyldiphenylsiloxyisloxyisophthalic acid) (0.1 g, 0.21 mmol, 1.0 eq), Et3N (0.13 g, 1.3 mmol, 6.0 eq) and DPPA (0.23 g, 0.8 mmol, 4.0 eq) with toluene (10 mL). Thiol-ene “Click” Chemistry first generation 22 (0.31 g, 0.4 mmol, 2.1 eq) was then added and the mixture refluxed for 24 h. Purification was performed by silica-gel column

1 chromatography DCM than (1:1 DCM/EtOAc). Yield 20 %; H-NMR (500 MHz; CDCl3): δ 0.89 (d, J = 13.3 Hz, 13H), 2.08-1.34 (m, 90H), 2.52 (tdd, J = 9.1, 5.7, 3.8 Hz, 16H),

13 4.27-3.84 (m, 17H), 7.22-6.76 (m, 13H); C NMR (CDCl3-d, 125 MHz) 14.11, 22.66, 25.20, 28.55, 28.98, 29.21, 29.24, 29.29, 29.72, 31.83, 31.98, 32.23, 60.24, 64.48, 65.30, 65.69, 100.09,109.37, 120.06, 129.82, 139.51, 150.48, 153.71, 159.94. MALDI-

TOF MS calculated for Chemical Formula: C85H142N6O16S4 1630.94, found 1654.027 [M+Na+].

76 Preparation of first generation of 1,3,5-benzene tricarboxylic acid with pentene groups on the periphery 25. A mixture of 1,3,5-benzene tricarboxylic acid (0.04 g,

0.19 mmol, 1.0 eq), Et3N (0.14 g, 1.3 mmol, 7.0 eq) and dry toluene (10 mL/g) was stirred under a nitrogen atmosphere until dissolved, before addition of DPPA (0.26 g, 1.0 mmol, 5.0 eq). The mixture was stirred at room temperature for 25 minutes and the mixture was refluxed for 45 minutes. 20 (0.26 g,0.63 mmol, 3.3 eq) was added and the solution stirred overnight. The solvent was removed and a crude product was dissolved in ethyl acetate. The solution was washed with water, solution of saturated

NaCl and dried over MgSO4. and evaporated. By removal of solvent on a rotary

1 evaporator (15%) of a yellowish oil was obtained; H-NMR (500 MHz; CDCl3): δ 1.71 (t, J = 6.5 Hz, 13H), 1.97 (dt, J = 1.6, 0.7 Hz, 6H), 2.08 (t, J = 6.9 Hz, 14H), 4.20-3.90 (m, 26H), 5.02-4.95 (m, 12H), 5.82-5.73 (m, 6H), 7.09-6.78 (m, 10H). 13C-NMR (126 MHz,

CDCl3): δ 28.65, 30.00, 48.18, 63.29, 64.55, 64.61, 66.00, 66.05, 99.93, 101.46, 115.30, 119.99, 120.03, 120.07, 120.11, 125.40, 125.69, 129.80, 129.88, 137.45, 139.69, 139.72,

150.39, 150.45, 153.72, 153.76, 159.64. MALDI-TOF MS calculated for C72H93N9O21 1419.65, found 1442.600 [M+Na+] and 1458.645 [M+K+].

Preparation of first generation of sebacic core with pentene groups on the periphery 28. A mixture of sebacic acid (0.12 g, 0.59 mmol, 1.0 eq), oxalyl chloride (0.3 g, 2.4 mmol, 4.0 eq) and 10 µm of DMF in dry DCM (10 mL) was stirred at 45 oC. After 30 min, 10 µm of DMF was added and stirred for 24 h. Then, excess of oxalyl chloride via evaporation solvent was removed to get sebacoyl chloride. Sebacoyl chloride was dissolved in DCM and added to 20 (0.35 g, 0.9 mmol, 2.1 eq) and poly vinyl pyridine 0.1 g. Refluxing was needed for 24 h to get 28. 1H-NMR (500 MHz;

CDCl3): δ 1.28-1.25 (m, 16H), 1.75 (dt, J = 6.9, 3.6 Hz, 8H), 2.04-1.96 (m, 6H), 2.14-2.11 (m, 9H), 3.79-3.72 (m, 4H), 4.05-3.96 (m, 3H), 4.16-4.11 (m, 12H), 5.06-4.98 (m, 8H),

13 5.85-5.77 (m, 4H), 6.84-6.80 (m, 3H), 7.10-7.02 (m, 4H). C-NMR (126 MHz, CDCl3): δ 14.17, 18.46, 21.02, 28.07, 29.68, 29.93, 31.96, 60.43, 64.66, 100.04, 100.07, 115.28, 127.62, 129.40, 134.81, 137.43, 139.57, 139.59, 153.65, 159.93, 171.24. MALDI-TOF MS

+ calculated for C52H74N4O14 978.52, found 1001.879 [M+Na ].

Preparation of second generation of sebacic core with pentene groups on the periphery 29. A mixture of sebacoyl chloride (0.04 g, 0.14 mmol, 1.0 eq) was dissolved in DCM and added to 21 (0.15 g, 0.14 mmol, 2.1 eq) and poly vinyl pyridine

1 0.1 g. refluxing for 24 h to get 29. H-NMR (500 MHz; CDCl3): δ 1.33-1.26 (m, 28H), 1.82-1.59 (m, 28H), 2.20-1.97 (m, 30H), 2.38-2.28 (m, 8H), 2.48-2.44 (m, 2H), 3.86-3.80 (m, 3H), 4.30-4.02 (m, 39H), 5.10-4.99 (m, 16H), 5.88-5.77 (m, 8H), 6.84 (s, 9H), 7.03 (d,

13 J = 0.5 Hz, 10H). C-NMR (126 MHz, CDCl3): δ 24.66, 28.06, 28.68, 28.69, 28.89, 28.94, 28.98, 29.71, 29.95, 33.81, 64.79, 99.95, 99.98, 100.07, 101.31, 115.33, 137.42, 139.52, 153.56, 153.60, 153.63, 159.81, 159.91, 178.08. MALDI-TOF MS calculated for

+ C116H154N12O34 2260.07, found 2283.076 [M+Na ].

Preparation of first generation of 4,4′,4′′,4′′′-(porphine-5,10,15,20- tetrayl)tetrakis(benzoic acid) with pentene groups on the periphery 32. A mixture of 4,4′,4′′,4′′′-(porphine-5,10,15,20-tetrayl)tetrakis(benzoic acid) (0.01 g, 0.01 mmol, 1.0 eq), oxalyl chloride (1 mL) and 10 µm of DMF in dry THF (10 mL) was stirred and refluxed. After 30 min, 10 µm of DMF was added and the solution stirred for 24 h. Then, excess of oxalyl chloride wasremoved via evaporation of the solvent to generate 4,4′,4′′,4′′′-(porphine-5,10,15,20-tetrayl)tetrakis(benzoyl chloride). Then was dissolved in THF and added to 20 (0.03 g, 0.1 mmol, 6.3 eq) and poly vinyl

1 pyridine 0.2 g. Refluxing was needed for 24 h to get 32. H-NMR (500 MHz; CDCl3): δ 1.83-1.76 (m, 19H), 2.07-2.01 (m, 7H), 2.20-2.15 (m, 20H), 3.87-3.85 (m, 8H), 4.17 (dt, J = 15.5, 7.3 Hz, 24H), 5.10-5.02 (m, 17H), 5.89-5.80 (m, 8H), 6.60 (s, 5H), 6.82 (s, 5H), 7.03 (t, J = 0.8 Hz, 3H), 7.39-7.37 (m, 4H), 7.68-7.66 (m, 4H). 13C-NMR (126 MHz,

CDCl3): δ 19.20, 21.21, 23.91, 26.86, 29.20, 30.32, 31.88, 34.24, 59.91, 64.71, 65.43, 67.63, 99.96, 99.98, 100.03, 101.47, 107.89, 115.34, 125.53, 127.66, 129.58, 135.53,

137.44, 139.56, 153.77, 159.88. MALDI-TOF MS calculated for C132H142N12O28 2344.01, found 2366.857 [M+Na+] and 2381.785 [M+K+].

78 3-6. References

1. Tomalia, D. A.; Fréchet, J. M. J. J. Polym. Sci., Part A: Polym. Chem. 2002, 40, 2719– 2728.

2. Grayson, S. M.; Fréchet, J. M. J. Chem. ReV. 2001, 101, 3819–3868.

3. Helms, B.; Meijer, E. W. Science 2006, 313, 929–930.

4. Almutairi, A.; Guillaudeu, S. J.; Berezin, M. Y.; Achilefu, S.; Fréchet, J. M. J. J. Am. Chem. Soc. 2008, 130, 444–445.

5. Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed. 2001, 40, 2004– 2021.

6. Dondoni, A. Angew. Chem. Int. Ed. 2008, 47, 8995-8997.

7. Killops, K. L.; Campos, L. M.; Hawker, C. J. J. Am. Chem. Soc. 2008, 130, 5062-5064.

8. Nilsson, C.; Simpson, N.; Malkoch, M.; Johansson, M.; Malmstrom, E. J. Polym. Sci. Part A: Polym. Chem. 2008, 46, 1339-1348.

11. Francis, T.; Thorne, M. P., Can. J. Chem. 1975, 54, 24.

10. Robert M. Stolz and Brian H. Northrop, J. Org. Chem. 2013, 78, 8105−8116.

12. Kato L. Killops, Luis M. Campos, and Craig J. Hawker, J. Am. Chem. Soc. 2008, 130, 5062–5064.

79 Chapter IV

Synthesis of alkyne polyurethane dendrimer via convergent approach and click chemistry reactions

4-1. Introduction

Triazoles are a very important class of organic compounds for both organic synthetic and biochemistry.1-3 Triazoles are the result of using the 1,3-dipolar cycloaddition of organic azides with alkynes.4,5 Cu(I)- catalysis for azide–alkyne 1,3- dipolar cycloaddition has received attention because of the reaction’s ability to form 1,4-substituted-1,2,3-triazoles in excellent yield under mild reaction conditions,6,7 with high regioselectivity. Such triazoles have shown good biological properties.8-11 Organic azides are beneficial intermediates in the preparation of different heterocyclic compounds such as 1,2,3-triazoles.12-17 The synthesis of alkyl azides is simple while the synthesis of aryl azides is rather limited. They are synthesized from amines via their diazonium salts,18,19 or the reaction of organometallic aryls with tosyl azides.20,21 Recently, some researchers have reported copper catalyzed coupling of

22 23 aryl amines, halides, and boronic acids with azide sources such as NaN3, TMSCN

24-27 and TfN3. Both current convergent and divergent syntheses of the dendrimer, in general, suffer from limitations. If one desires to undertake structure activity studies of any dendritic system, it is an important set of molecules. The most important structural variants and the peripheral groups and the core. In the divergent synthesis, the core is chosen in stage one. Any variation in the core requires a new synthesis. The divergent strategy allows peripheral reaction easily that most the core. In the convergent synthesis, the opposite problem arises, the core is on end-stage choice, but the peripheral groups are determined in step one. The strategy we advance in chapter IV allow both groups to be served late in the synthesis. By using azide-alkyne click chemistry, a convergent synthesis retains the late choice of the core but

80 introduces a facile method for adjusting the peripheral groups past construction. In their way, the objection of late stage choice both core and periphery is realized.

4-1-1. Specific aims

i- A synthesis of the branching monomer containing two different functional groups: two carboxylic acid groups and one hydroxyl protecting group. ii- A synthesis of polyurethane wedges containing peripheral alkyne groups via the convergent path. iii- A synthesis of polyurethane dendrimers from polyurethane wedges and a different core. iv- Click chemistry of inspired synthesis of polyurethane dendrimers. v- Characterization and study of polyurethane dendrimer

4-1-2. Synthetic strategies

Two carboxylic acids on the monomer branch were reacted with DPPA and

Et3N to generate an isocyanate monomer (Figure 49). The first generation polyurethane wedge with peripheral alkyne groups was formed from a reaction of the isocyanate monomer and the hydroxyl alkyne. The first generation polyurethane wedge with peripheral alkyne groups then underwent deprotection to afford the first generation polyurethane wedge with peripheral alkyne groups and hydroxyl group. Two equivalents of first generation polyurethane wedge were reacted with the isocyanate monomer to obtain the second generation polyurethane wedge with peripheral alkyne groups. The deprotection step was repeated to get a second generation of polyurethane wedge with alkyne groups on the periphery and a hydroxyl group. Polyurethane dendrimers were synthesized from reacting a core and a first or second generation polyurethane wedge with peripheral alkyne groups. A click reaction was then performed between the first generation polyurethane wedge

81 and the azido compound to give the first generation polyurethane wedge with peripheral triazole groups. The synthesis was repeated with the second generation polyurethane wedge and second generation polyurethane dendrimer.

HOOC COOH OCN NCO HO DPPA, Et3N

solvent, reflux

O(P) O(P)

Monomer

H H O N N O H H O N N O Deprotection O O O O O(P) OH first generation wedge

O O

OCN NCO HN O O NH

HN NH H H O N N O O(P) Deprotection O O O O O O

second generation wedge

first generation wedge HOOC COOH first generation dendrimer

DPPA, Et3N solvent, reflux second generation dendrimer COOH second generation wedge

Figure 49. Synthetic strategies of alkyne wedge and dendrimers

82 4-2. Synthesis of polyurethane with propargyl periphery

4-2-1. Synthesis of polyurethane wedge with propargyl periphery

The initial reaction was between 5-(oxy-propane-tert-butyl diphenyl siloxyl) isophthalic acid 1 and propargyl alcohol in the presence of Et3N and DPPA in toluene to afford the first generation polyester wedge with peripheral propargyl groups 2. The purpose of the synthesis was to get the first generation polyurethane wedge peripheral propargyl groups 3. Deprotection of 2 by a TBAF solution in THF took place to obtain the first generation polyester wedge with peripheral propargyl groups and propanol 4 and the yield was 5% as shown in Figure 50.

O O O O O O C C C C O HO OH O O O 1) DPPA, Et3N 2) HO TBAF, THF

O O O

OTBDPS OTBDPS OH 2 4 1

H H O N N O C C

O O

Intended 3 OTBDPS

Figure 50. Synthesis of first generation wedge with propargyl periphery

The first generation polyester wedge with peripheral propargyl groups and propanol 4 was confirmed by the appearance of peaks at δ 7.7-8.4 ppm, corresponding to the protons of aromatic ring and the appearance of peaks at δ 7.8 corresponding to the protons of NH in the 1H NMR spectroscopy. Furthermore, the appearance of peak at 164 corresponding to the carbon of ester in the 13C NMR

83 spectroscopy (Figure 51). The mass spectrum of the first generation polyester wedge with peripheral propargyl groups and propanol 4 displays a peak at m/z = 338.668 with the isotope pattern corresponding to [M + Na]+ and a peak at m/z = 354.723 corresponding to [M + K]+ .The isolated yield of 5% after column chromatography was low.

1 13 Figure 51. H and CNMR spectrum of 4 in CDCl3-d1

The first generation polyester wedge with peripheral propargyl groups and propanol 4 was reacted with 5-(oxy-propane-tert-butyl diphenyl siloxyl) isophthalic acid 1 in the presence of Et3N and DPPA in toluene. This was then deprotected by TBAF in THF to afford the second generation polyester-urethane wedge peripheral propargyl groups and propanol 5 as shown in Figure 52.

O O O O O O

C C HO OH C C O O O O 1) DPPA, Et3N 2) 4

O H 3) H O TBAF, THF O O N N O C C

O O

OTBDPS O 1

OH 5

Figure 52. Synthesis of second generation wedge with propargyl periphery

The mass spectrum of the second generation polyester-urethane wedge peripheral propargyl groups and propanol 5 displays a peak at m/z = 889.129 with the isotope pattern corresponding to [M + Na]+ and a peak at m/z = 906.171 corresponding to [M + K]+.

Terminal propargyl groups were used to prepare the polyurethane wedge via the convergent path. Unfortunately, initial models did not generate the desired polyurethane wedge. Most of the yield was ester functional groups. The ester formation was thought to be a result of the interception of a DPPA intermediate. To solve this problem an alternative method to get carbamate functional groups was considered. Isobutyl chloroformate and sodium azide were a candidates to get the acyl azide. The acyl azide was heated to give the isocyanate. The propargyl alcohol was added to obtain the first generation of polyurethane with propargyl periphery.

85 Unfortunately, while the first generation of polyurethane with propargyl periphery was obtained, it was synthesized in very low yields as shown in Figure 53.

O O O O H H N3 N3 O N N O HO OH C C Et3N HO isobutyl chloroformate O O than NaN O O 3 O

TBDPSO TBDPSO OTBDPS 3 1

Figure 53. Synthesis of first generation of polyurethane with propargyl periphery

To reduce the number of reaction steps, use of excess propargyl alcohol was done. 5-(Oxy-propane-tert-butyl diphenyl siloxyl) isophthalic acid 1 was reacted with isobutyl chloroformate in the percent of Et3N. Sodium azide was added to get the acyl azide and propanol. The propargyl alcohol was added shape of different ratios (2.2, 11& 20) equivalent. There was competition between hydroxyl of propargyl and 5-(3- hydroxypropoxy) phthalate. The polymer was formed when both 0 and 2.5 equivalents of the alcohol were used. A mixture of first and second generation wedges (whichever it is) with peripheral properly groups along with other compounds was obtained when 11 and 20 equivalents of the alcohol was used, but at 20 equivalents only the first generation was produced. Unfortunately, purification of these compounds was very difficult.

4-2-2. Synthesis of polyurethane dendrimers

The first generation polyester-urethane dendrimer with propargyl periphery was prepared from a reaction between the first generation polyester wedge with propargyl periphery 4 and 1,3,5-benzene tricarboxylic acid. A 1,3,5-benzene

86 tricarboxylic acid (6) was transformed to the tri-isocyanate intermediate by Et3N and DPPA in benzene. The first generation polyester wedge with a propargyl periphery 4 was then added to afford the first generation polyester-urethane dendrimer 7 as shown in Figure 54.

O O

HO OH O O

C C 1)DPP, O O 2) 4 Et HO O 3 N, benzene 6 O

O O O C

H C O O N NH O

O O

C HN O O C O O C O

C O O

Figure 54. Synthesis of first generations polyurethane dendrimers

The mass spectrum of the first generation polyester-urethane core peripheral propargyl groups and 1,3,5-benzene 7 displays a peak at m/z = 1172.367 with the isotope pattern corresponding to [M + Na]+ and a peak at m/z = 1188.349 corresponding to [M + K]+.

4-3. Conclusions

The convergent path and the selectivity of the reactions of terminal propargyl alcohols have been used in the synthesis of polyurethane dendrimers. The first

87 generation polyester wedge with propargyl periphery and propanol synthesized when DPPA was used. The second generations polyurethane/ester wedge with propargyl periphery and propanol have been prepared. Unfortunately, there is a low yield of the first and second generations wedges polyurethane or polyester with propargyl periphery. The first generations polyester dendrimers with propargyl periphery have been prepared. In addition, the structures were characterized by NMR and mass spectrometry.

4-4. Experimental section

Preparation of the first generation polyester wedge with peripheral propargyl groups 4. The experimental procedure (A) (in chapter III) was followed using 5-(oxy- propane-tert-butyldiphenylsiloxyisloxyisophthalic acid) (1 g, 2.1 mmol, 1.0 eq), Et3N (1.27 g, 12.5 mmol, 6.0 eq) and DPPA (2.3 g, 8.4 mmol, 4.0 eq) with toluene (30 mL). Propargyl alcohol (0.25 g, 4.4 mmol, 2.1 eq) was then added and the mixture refluxed for 24 h. Pure compound 4 was obtained by silica gel column chromatography (1:1

1 DCM/ether) as a yellowish oil; Yield 5 %. H-NMR (500 MHz; CDCl3): δ 2.09 (quintet, J = 5.9 Hz, 2H), 2.23 (s, 1H), 2.57 (s, 2H), 3.89 (t, J = 5.8 Hz, 2H), 4.22 (t, J = 5.9 Hz,

13 2H), 4.95 (s, 4H), 7.79 (s, 2H), 8.32 (s, 1H). C-NMR (126 MHz, CDCl3): δ 31.82, 52.88, 59.73, 65.92, 75.43, 77.37, 102.29, 120.33, 123.39, 131.08, 158.98, 164.78. MALDI-TOF

+ + MS calculated for C17H18N2O6 316.09, found 338.668 [M+Na ] and 354.723[M+K ].

Preparation of the second generation polyester-urethane wedge peripheral propargyl groups and propanol 5. The Experimental Procedure (A) was followed using 5-(oxy-propane-tert-butyldiphenylsiloxyisloxyisophthalic acid) (0.3 g, 0.6 mmol, 1.0 eq), Et3N (0.38 g, 3.8 mmol, 6.0 eq) and DPPA (0.69 g, 2.5 mmol, 4.0 eq) with toluene (10 mL). Propargyl periphery first generation (FG-Propargyl-OH) (0.42 g, 1.3 mmol, 2.1 eq) was then added and the mixture refluxed for 24 h. MALDI-TOF

+ + MS calculated for C45H42N2O16 866.25, found 889.129 [M+Na ] and 906.171[M+K ].

Preparation of the first generation polyester-urethane core peripheral propargyl groups and 1,3,5-benzene 7. A mixture of 1,3,5-benzene tricarboxylic acid (10 mg, 0.05 mmol, 1.0 eq), Et3N (0.03 g, 0.3 mmol, 7.0 eq) and dry benzene (10 mL) was stirred under a nitrogen atmosphere until dissolved. DPPA (0.07 g, 0.2 mmol, 5.0 eq) was then added. The mixture was stirred at room temperature for 25 min and then the mixture was refluxed for 45 minutes. 4 (0.054 g, 0.2 mmol, 3.3 eq) was added and the solution stirred overnight. The solvent was removed and the crude product was dissolved in ethyl acetate. The solution was washed with water, a solution of

1 saturated NaCl, dried over MgSO4. and evaporated. H-NMR (500 MHz; CDCl3): δ 2.10 (dd, J = 12.0, 6.0 Hz, 8H), 3.90 (t, J = 5.9 Hz, 6H), 4.22 (t, J = 6.0 Hz, 8H), 4.96 (d, J = 2.4 Hz, 18H), 7.37 (s, 5H), 7.80 (d, J = 1.3 Hz, 8H), 8.33 (s, 4H).MALDI-TOF MS

+ + calculated for C60H51N3O21 1149.30, found 1172.367 [M+Na ] and 1188.349[M+K ].

89 4-5. Synthesis of polyurethane with pentyne periphery

4-5-1. Synthesis of polyurethane wedge with pentyne periphery

The first generation wedge having two pentyne-terminals was synthesized from 5-(oxy-propane-tert-butyl diphenyl siloxyl) isophthalic acid 1 via a Curtius rearrangement with pentyne alcohols in the presence of DPPA and Et3N. Deprotection of the first generation polyurethane wedge pentyne periphery by TBAF generated the first generation polyurethane wedge wedge with peripheral pentyne groups and propanol 8. This first generation wedge was then reacted with the diisocyanate intermediate to obtain the second generation wedge with four terminal pentyne groups. Deprotection followed to afford the second generation wedge with four terminal pentyne groups and a hydroxyl group 9 as shown in Figure 55.

90 O O

H H HO OH O N N O

1 )DPPA, Et3N, toluene O O

2) O O OH

3)TBAF, THF OH

8 OTBDPS 1

O O O O O O O O O O NH NH HN HN HO OH

O 1) DPPA, Et N, toluene 3 O 2) 8

O 3) TBAF, THF O O

NH NH O O

O OTBDPS

1 OH 9 Figure 55. Synthesis of first and second generation polyurethane wedge with pentyne periphery.

The conformation the first generation polyurethane wedges peripheral pentyne groups and propanol 8 was carefully monitored by 1H NMR as shown in Figure 56. The mass spectrum of the first generation polyurethane wedges peripheral pentyne groups and propanol 8 displays a peak at m/z = 402.748 with the isotope pattern corresponding to [M + H]+, a peak at m/z = 424.699 with the isotope pattern corresponding to [M + Na]+ and a peak at m/z = 440.770 corresponding to [M + K]+. Furthermore, the second generation polyurethane wedges with peripheral pentyne groups and propanol 9 was successfully isolated and the mass spectrum displays a peak at m/z = 1061.705 with the isotope pattern corresponding to [M + Na]+ . Both the first and second generation wedges peripheral pentyne groups and propanol (8 & 9) afforded low isolated yields, 55% and 25% respectively after column

91 chromatography.

1 13 Figure 56. H and CNMR spectrum of 8 in CDCl3-d1

4-5-2. Synthesis of polyurethane wedge with a subsequent click reaction periphery.

The first generation polyurethane wedge with peripheral pentyne groups and propanol 8 was reacted with an azide using a click reaction to obtain the first generation wedge with triazoles periphery and propanol. 4-Azidobenzoic acid, phenyl boronic acid and 3-azido-7-hydroxycoumarin were used for the click reaction.

4-5-2-1. First generation wedge click reaction with 4-azidobenzoic acid.

Compound 8 was reached with 4-azidobenzoic acid in the presence of CuSO4 and ascorbic acid in THF/H2O (1:1) at room temperature for 24 h. After that, the first generation wedge having two terminal triazoles and hydroxyl-functionalized was obtained 10 as shown in Figure 57.

92 OH HO

O O

N N H H O O N N O N H H N O N N O N3 N N

O O OH O O CuSO4, HAsc THF/H2O O O

OH OH

8 10

Figure 57. Synthesis of first generation wedge click reaction with 4-azidobenzoic acid

The mass spectrum of the first generation polyurethane wedges peripheral 4- triazolebenzoic acid and propanol 10 displays a peak at m/z = 751.226 with the isotope pattern corresponding to [M + Na]+ and a peak at m/z = 767.227 corresponding to [M + K]+.

4-5-2-2. First and second generation wedge click reaction with phenyl boronic acid.

In a one-pot reaction, phenylboronic acid (11), CuSO4 and NaN3 were reacted in methanol for 20 h at room temperature.28 Water, ascorbic acid, and compound 8 were then added to the reaction mixture to afford the first generation wedge with triazoles periphery and propanol 12 (Figure 58). This was then reacted with the diisocyanate intermediate to generate the second generation wedge with peripheral triazoles and TBDPS. Deprotection of the TBDPS group by TBAF followed to afford the hydroxyl group 13.

93 HO OH N N B

N H H N NaN3, CuSO4, HAsc O N N O N N then 8 O O

11 O

N N OCN NCO 1) N N N

N O

O O OTBDPS HN O NH 2) TBAF O

HN O NH

O O O O O

H H O N N O N

O O N N N N N O

OH 13

Figure 58. Synthesis of first and second generation wedge click reaction with phenyl boronic acid

The conformation the first generation wedge with triazoles periphery and propanol 12 was carefully monitored by 1H NMR as shown in Figure 59. The mass spectrum of the first generation polyurethane wedges peripheral triazolephenayl and propanol 12 displays a peak at m/z = 641.095 with the isotope pattern corresponding to [M + H]+, a peak at m/z = 663.120 with the isotope pattern corresponding to [M + Na]+ and a peak at m/z = 679.111 corresponding to [M + K]+. Furthermore, the second

94 generation polyurethane wedge peripheral triazolephenayl and propanol 13 was successfully isolated and the mass spectrum displays a peak at m/z = 1515.743 with the isotope pattern corresponding to [M + H]+, a peak at m/z = 1537.769 with the isotope pattern corresponding to [M + Na]+ and a peak at m/z = 1553.767 corresponding to [M + K]+.

1 13 Figure 59. H and CNMR spectrum of 12 in CDCl3-d1

4-5-2-3. First generation wedge click reaction with 3-azido-7- hydroxycoumarin.

3-Azido-7-hydroxycoumarin was synthesized and used for the click reaction.29

Compound 8 was reacted with 3-azido-7-hydroxycoumarin in the presence of CuSO4 and ascorbic acid in THF/H2O (1:1) at room temperature for 48 h to afford the first generation wedge with triazole-7-hydroxycoumarin periphery and propanol as shown in Figure 60.

95 O H N OH

HO O HO O O 15 O O O 1) HCl/EtOH O O 2) NaNO2 NaOAc, Ac2O N N O 3 OH H 3) NaN3 150 C, 4.5h 17 14 16

N N N N HO OH H H CuSO , H ase N H H N O N N O 4 O N N O O O O O HO O O O O O O O O N3 17 OH

8 OH 18

Figure 60. Synthesis of first generation wedge click reaction with 3-azido-7- hydroxycoumarin

The mass spectrum of the first generation polyurethane wedges peripheral 4- triazole-7-hydroxycoumarin and propanol 18 displays a peak at m/z = 809.320 with the isotope pattern corresponding to [M + H]+ and a peak at m/z = 831.347 corresponding to [M + Na]+.

4-5-3. Synthesis of polyurethane dendrimers

The first and second generation polyurethane wedges with peripheral pentyne groups and propanol 8 & 9 were reacted with different cores to obtain the first and second generation polyurethane dendrimers with peripheral pentyne groups. Also, the first and second generation wedge having two and four triazoles - terminals were reacted with a core to get the first and second generation dendrimers with terminal triazoles. Trimesic acid, sebacic acid, 4,4-biphenyldicarboxylic acid, 4,4'-MDI and porphyrin were used as the cores. The 4,4-biphenyldicarboxylic acid and 4,4'-MDI reaction was not successful due to solubility issues.

96 4-5-3-1. Synthesis of polyurethane dendrimers from trimesic core with pentyne periphery

The first and second generation polyurethane wedge with pentyne periphery 8 and 9 respectively, were used to synthesize polyurethane dendrimers. The core of polyurethane dendrimers was trimesic acid 19. The synthesis was started from the transformation of trimesic acid 19 to the tri-isocyanate intermediate by DPPA and

ET3N in toluene. After that was added 8 or 9 to get the first and second generation polyurethane dendrimers with pentyne periphery 20 and 21 respectively as shown in Figure 61.

97 O NH O O O NH

O O HN

NH O O O NH O NH O O O O NH O O NH HN O O OH benzene O O 3N, Et O 1) DPPA,

2) 8 20 HO O

O OH O O NH 19 H N O 1) DPPA, O O 2) O 8 Et 3 N, benzene HN O O O O HN O O O NH O O HN NH O O O O N O H

O O O O H HN N O O NH O O NH HN O O O

O H H O O NH O O N O O N O O HN HN O NH O O O O O

O O O N O N H O H 21

Figure 61. Synthesis of polyurethane dendrimers from trimesic acid

The mass spectrum of the first generation polyurethane dendrimer peripheral pentyne groups and 1,3,5-benzene 20 displays a peak at m/z = 1430.653 corresponding to [M + Na]+. Moreover, the second generation polyurethane dendrimer peripheral pentyne groups and 1,3,5-benzene 21 was successfully isolated

98 and the mass spectrum displays a peak at m/z = 3341.773 with the isotope pattern corresponding to [M + Na]+.

4-5-3-2. Synthesis of polyurethane dendrimers from trimesic core with phenyl- triazoles periphery

The trimesic acid 19 was reacted with DPPA and ET3N in benzene to get the tri-isocyanate intermediate. Compound 12 was then added to afford the first generation polyurethane dendrimers with phenyl-triazoles periphery 22 as shown in Figure 62.

N N N N N H H N O N N O

N O O N N O

O OH O O O O N H N HN O O N NH N 1) DPPA/Et3N O 2) 2 HO O O HN O HN O O O NH O O OH O

19 O NH N O N N

N N N

22 Figure 62. Synthesis of polyurethane dendrimers with phenyl-triazoles periphery

The mass spectrum of the first generation polyurethane dendrimer peripheral triazolephenyl and 1,3,5-benzene core 22 displays a peak at m/z = 2144.882 with the isotope pattern corresponding to [M + Na]+.

99 4-5-3-3. Synthesis of polyurethane dendrimers from sebacic core with pentyne periphery

In the initial synthesis, sebacic acid (23) was reacted with DPPA in the presence of Et3N and 8 was added into mixture and refluxed for 24h to get the first generation dendrimer with pentyne periphery 24 (Figure 63). Note, the yield of the dendrimer 24 was low, possibly due to formation of isocyanate in the presence of DPPA and carboxylic acid. Also, the sebacic acid 23 is a flexible chain that is easy to cyclize, which also could have been a problem.

O H N O O O O H OH 1)DPPA/Et3N N O HO O O HN 2) 8 NH O O O O N H O O O 23 N H O

Figure 63. Synthesis of polyurethane dendrimers from sebacic core.

The mass spectrum of the first generation polyurethane dendrimer peripheral pentyne groups and sebacic core 24 displays a peak at m/z = 1023.872 with the isotope pattern corresponding to [M + Na]+ and a peak at m/z = 1038.846 with the isotope pattern corresponding to [M + K]+.

4-5-3-4. Synthesis of polyurethane dendrimers from sebacic core as ester functional group core.

The problem of synthesis of dendrimers from sebacic acid as urethane functional group needed to be solved. This led us to a synthesis of dendrimers from sebacic acid-derived ester functional groups. It started with the conversion of sebacic acid (23) to sebacoyl chloride 25 via oxalyl chloride in the presence of DMF in DCM under reflux for 24 hours. Esterification of sebacoyl chloride 24 with 8 or 9 in the

100 presence of poly(4-vinylpyridine) in DCM under reflux for 24 hours afforded the first or second generation dendrimers sebacic core, as ester functional groups, core dendrimers 25, 26 respectively as shown in Figure 64.

O O O HO (COCl)2 O Cl CH2Cl2, DMF OH Cl 23 25

O NH

O O 8 O

poly(4-vinylpyridine) HN O O O O NH DCM O O O

HN O

101 O NH O O NH O O HN O O

O O HN O O NH O O O 9 O HN O O 25 O O poly(4-vinylpyridine) NH O DCM O O O HN O O

O NH O

O O NH O O N O H O N H O

Figure 64. Synthesis of polyurethane dendrimers from sebacic core as ester functional group core

The mass spectrum of the first generation polyurethane dendrimer peripheral pentyne groups and sebacic core 26 displays a peak at m/z = 993.489 corresponding to [M + Na]+. Moreover, the mass spectrum of the second generation polyurethane dendrimer peripheral pentyne groups and sebacic core 27 was successfully isolated and the mass spectrum displays a peak at m/z = 2274.924 with the isotope pattern corresponding to [M + Na]+ and a peak at m/z = 2288.651 with the isotope pattern corresponding to [M + K]+.

4-5-3-5. Synthesis of polyurethane dendrimers from trimesic as ester functional group core

Transformation of trimesic acid to 1,3,5-benzenetricarbonyl trichloride by thionyl chloride in DCM was done. 1,3,5-Benzenetricarbonyl trichloride was reacted with 8 in the presence of poly(4-vinylpyridine) in DCM under reflux for 24 hours to

102 afford the first generation dendrimer trimesic, as ester functional group as shown in Figure 65.

O OH O Cl

SOCl2 8. poly(4-vinylpyridine)

DCM, reflux,12h DCM, reflux, 24h O OH O Cl

OH O Cl O

19 28

O O O O

HN NH

O O

H H O N O O O O N O

O O O O

O NH HN O

O O

29 Figure 65. Synthesis of polyurethane dendrimers from trimesic as ester functional group core

The mass spectrum of the first generation polyurethane dendrimer peripheral pentyne groups and 1,3,5-benzene core 29 displays a peak at m/z = 1385.555 with the isotope pattern corresponding to [M + Na]+.

103 3-5-3-6. Synthesis of polyurethane dendrimers from porphyrin as ester functional group core

The transformation of 4,4′,4′′,4′′′-(porphine-5,10,15,20- tetrayl)tetrakis(benzoic acid) (27) to 4,4′,4′′,4′′′-(porphine-5,10,15,20- tetrayl)tetrakis(benzoyl chloride) 28 by oxalyl chloride and DMF in THF was done. After that, esterification 4,4′,4′′,4′′′-(porphine-5,10,15,20-tetrayl)tetrakis(benzoyl chloride) 28 with a first generation wedge in the presence of poly(4-vinylpyridine) in THF and refluxed afforded the first generation dendrimer with porphyrin core 29 (Figure 66).

104 O OH O Cl

HO NH N (COCl)2, DMF Cl NH N OH Cl O O N HN O THF N HN O

O OH O Cl

31 30

H H O N N O

O O

O O C O O HN 8 O poly(4-viylpyridine), THF N HN HN O O O O C C O O O NH N O NH

NH O O C O O

O O

O N N O H H

32 Figure 66. Synthesis of polyurethane dendrimers from porphyrin as ester functional group core

The mass spectrum of the first generation polyurethane dendrimer peripheral pentyne groups and porphyrin core 32 displays a peak at m/z = 2328.155 with the isotope pattern corresponding to [M + H]+.

105

4-6. Conclusions

The convergent path and the selectivity of the reactions of pentyne alcohol periphery have been used in the synthesis of a polyurethane dendrimers. The first and second generation polyurethane wedges with pentyne periphery were made using DPPA with a good yield. The first generation polyurethane with pentyne periphery was useful for click reactions with boronic acid, 4-azidobenzoic acid, and 3-azido-7-hydroxycoumarin. Also, the first and second generations polyurethanes with pentyne or triazoles on the periphery were useful for synthesis dendrimers. Trimesic acid, sebacic acid, and 4,4′,4′′,4′′′-(porphine-5,10,15,20- tetrayl)tetrakis(benzoic acid) were used as the core for dendrimers. In addition, the structures were characterized by NMR and mass spectrometry.

4-7. Experimental section Preparation of the first generation polyurethane core peripheral pentyne groups and propanol 8. The Experimental Procedure (A) was followed using 5-(oxy- propane-tert-butyldiphenylsiloxyisloxyisophthalic acid) (1 g, 2.1 mmol, 1.0 eq), Et3N (1.27 g, 12.5 mmol, 6.0 eq) and DPPA (2.3 g, 8.4 mmol, 4.0 eq) with toluene (30 mL). 4-Pentyn-1-ol (0.37 g, 4.4 mmol, 2.1 eq) was then added and the mixture was refluxed for 24 h. Pure compound 8 was obtained by silica gel column chromatography

1 (DCM:ethyl ether) as a yellowish oil; Yield 55%. H-NMR (500 MHz; CDCl3): δ 1.89- 1.83 (m, 4H), 1.94 (quintet, J = 6.0 Hz, 2H), 2.01 (t, J = 3.8 Hz, 2H), 2.28 (dd, J = 14.1, 2.6 Hz, 4H), 2.82 (s, 1H), 3.76 (t, J = 6.0 Hz, 2H), 4.00 (t, J = 6.0 Hz, 2H), 4.22 (t, J = 6.3

13 Hz, 4H), 6.77 (s, 2H), 7.03 (s, 1H). C-NMR (126 MHz, CDCl3): δ 15.10, 27.74, 31.88, 59.71, 63.73, 65.32, 69.25, 83.12, 100.09, 100.14, 100.18, 100.28, 101.56, 101.58, 101.61, 101.64, 101.68, 101.73, 131.62, 139.47, 153.63, 153.73, 159.85. MALDI-TOF MS

+ + calculated for C21H26N2O6 402.18, found 402.748 [M + H] , 424.699 [M+Na ]and 440.770 [M + K]+.

106

Preparation of the second generation polyurethane core peripheral pentyne groups and propanol 9 The Experimental Procedure (A) was followed using 5-(oxy- propane-tert-butyldiphenylsiloxyisloxyisophthalic acid) (0.2 g, 0.4 mmol, 1.0 eq),

Et3N (0.25 g, 2.5 mmol, 6.0 eq) and DPPA (0.46 g, 1.7 mmol, 4.0 eq) with toluene (30 mL). The first generation polyurethane core with peripheral pentyne groups and propanol 8 (0.35 g, 0.9 mmol, 2.1 eq) were then added and the mixture refluxed for 24 h. Pure compound 9 was obtained by silica gel column chromatography (DCM than

1 ethyl ether) as a yellowish oil; Yield 25%. H-NMR (500 MHz; CDCl3): δ 1.91-1.84 (m, 10H), 2.03-1.94 (m, 12H), 2.30 (dtd, J = 10.6, 7.3, 3.0 Hz, 9H), 3.81 (q, J = 5.4 Hz, 2H), 3.99 (dq, J = 19.6, 6.3 Hz, 4H), 4.06 (t, J = 6.0 Hz, 2H), 4.29-4.23 (m, 12H), 6.80 (d, J =

13 5.6 Hz, 5H), 7.03 (d, J = 11.3 Hz, 3H), 7.25 (s, 2H). C-NMR (126 MHz, CDCl3): δ 15.11, 15.13, 27.74, 28.68, 31.90, 59.79, 60.03, 63.75, 63.80, 64.38, 65.54, 69.19, 69.25, 69.29, 83.06, 83.11, 100.10, 100.15, 100.21, 101.47, 101.55, 139.44, 139.47, 139.55, 153.46,

153.60, 153.63, 159.80, 159.82, 159.92. MALDI-TOF MS calculated for C53H62N6O16 1038.42, found 1061.705 [M+Na+].

“Click” Chemistry Experimental Procedure (C) for syntheses of dendritic ether urethane wedges with one-pot triazole from boronic acid. In a 50 mL round bottom flask, phenylboronic acid (1.0 eq), CuSO4 (0.2 eq), NaN3 (1.2 eq) and methanol (5 mL) were placed. The reaction mixture was stirred for 14 hours at room temperature. Ascorbic acid (0.5 eq), (3 mL) and the first or second generation polyurethane wedge with peripheral pentyne groups and propanol (8 or 9) (0.4 eq) were added into the reaction mixture. The reaction mixture was stirred for 4 hours. The reaction mixture was filtered and washed with MeOH before removal of the solvent on a rotary evaporator. Purification was performed by silica-gel column chromatography (EtOAc then 5% MeOH in EtOAc) to obtain the first or second generation polyurethane wedge with peripheral triazole groups and propanol.

107 Preparation the first generation polyurethane wedges peripheral 4- triazolebenzoic acid and propanol 10. A mixture of 4-azidobenzoic acid (0.097 g, 0.6 mmol, 2.4 eq), CuSO4 (0.024 g, 0.1 mmol, 0.6 eq), ascorbic acid (0.026 g, 0.1 mmol, 0.6 eq), the first generation polyurethane wedge peripheral pentyne groups and propanol 8 (0.1 g, 0.2 mmol, 1.0 eq), THF (5 mL) and H2O (3 mL) was stirred at room temperature for overnight. The reaction mixture was filtered and washed with THF and the combined filtrates were vacuum evaporated to afford crude product. 1H-NMR

(500 MHz; DMSO-d6): δ 1.82 (dt, J = 22.2, 6.5 Hz, 4H), 2.05 (t, J = 7.4 Hz, 2H), 2.29 (td, J = 7.1, 2.6 Hz, 2H), 2.52 (t, J = 6.2 Hz, 3H), 2.82 (dt, J = 2.6, 1.3 Hz, 1H), 2.85 (t, J = 7.6 Hz, 2H), 3.36 (d, J = 0.9 Hz, 10H), 3.54 (t, J = 6.1 Hz, 2H), 3.94 (t, J = 6.4 Hz, 2H), 4.15 (dt, J = 25.4, 6.4 Hz, 4H), 6.56-6.54 (m, 1H), 6.79-6.78 (m, 2H), 7.25-7.21 (m, 2H), 7.63- 7.61 (m, 1H), 7.98-7.96 (m, 1H), 8.03 (d, J = 8.5 Hz, 2H), 8.14-8.11 (m, 2H), 8.73 (s, 1H),

13 9.59 (d, J = 15.5 Hz, 2H), 12.87 (s, 1H). C-NMR (126 MHz, DMSO-d6): δ 14.90, 22.05, 27.96, 28.59, 30.87, 32.54, 57.75, 63.18, 63.86, 64.87, 72.11, 83.92, 99.44, 101.48, 113.01, 119.62, 119.95, 120.86, 127.75, 130.78, 131.47, 131.51, 131.66, 140.12, 140.73, 140.78, 144.40, 147.34, 148.13, 153.58, 153.77, 153.88, 159.60, 166.87, 167.94. MALDI-TOF MS

+ + calculated for C35H36N8O10 728.26, found 751.226 [M+Na ] and 767.227 [M+K ].

Preparation of the first generation polyurethane wedges peripheral triazolephenyl groups and propanol 12. The Experimental Procedure (C) was followed using phenylboronic acid (0.05 g, 0.4 mmol, 1.0 eq), CuSO4 (0.013 g, 0.08 mmol, 0.2 eq), NaN3 (0.032 g, 0.5 mmol, 1.2 eq) and methanol (5 mL). Ascorbic acid (0.04 g, 0.2 mmol, 0.5 eq), (3 mL) and the first generation polyurethane wedge peripheral pentyne groups and propanol 8 (0.066 g, 0.16 mmol, 0.4 eq) were added

1 into the reaction mixture. H-NMR (500 MHz; CDCl3): δ 1.96 (quintet, J = 5.9 Hz, 2H), 2.11-2.05 (m, 5H), 2.21 (t, J = 2.0 Hz, 2H), 2.87 (t, J = 7.5 Hz, 4H), 3.02 (s, 1H), 3.79 (t, J = 5.8 Hz, 2H), 4.03 (t, J = 5.9 Hz, 2H), 4.20 (t, J = 6.0 Hz, 4H), 6.83 (s, 2H), 7.11 (s, 1H), 7.39 (t, J = 7.4 Hz, 2H), 7.47 (t, J = 7.8 Hz, 4H), 7.68 (d, J = 7.7 Hz, 5H), 7.80 (s,

13 2H). C-NMR (126 MHz, CDCl3): δ 22.03, 28.56, 31.95, 59.70, 60.44, 64.07, 64.10, 64.13, 65.38, 99.98, 100.01, 100.04, 119.40, 120.31, 120.35, 128.55, 129.67, 137.01, 139.64,

108 147.68, 153.78, 159.90. MALDI-TOF MS calculated for C33H36N8O6 640.28, found 641.095 [M+H+], 663.120 [M+Na+] and 679.111[M+K+].

Preparation of the second generation polyurethane wedges peripheral triazolephenyl and propanol 13. The Experimental Procedure (C) was followed using phenylboronic acid (0.1 g, 0.8 mmol, 1.0 eq), CuSO4 (0.026 g, 0.16 mmol, 0.2 eq),

NaN3 (0.064 g, 1.0 mmol, 1.2 eq) and methanol (5 mL). Ascorbic acid (0.087 g, 0.5 mmol, 0.5 eq), (3 mL) and the second generation polyurethane wedge peripheral pentyne groups and propanol 9 (0.341 g, 0.33 mmol, 0.4 eq) were added into the reaction mixture. MALDI-TOF MS calculated for C77H82N18O16 1514.62, found 1515.743 [M+H+], 1537.769 [M+Na+] and 1553.767 [M+K+].

Preparation of 3-azido-7-hydroxycoumarin. A mixture of 2,4- dihydroxybenzaldehyde (3.5 g, 25.3 mmol, 1.0 eq), N-acetylglycine (2.97 g, 25.3 mmol, 1 eq) and sodium acetate (10.34 g, 76.0 mmol, 3 eq) in acetic anhydride (100 mL) was refluxed for 4 h. Then was added ice water into the mixture to get a yellowish precipitate. The precipitate was filtered washed with ice water and dried to obtain crude yellowish solid. Then the crude yellowish solid was dissolved in a solution of concentrated HCl and ethanol (15 mL, 2:1 v/v) and refluxed for 1 h. After that, the solution was diluted with ice water (20mL) and cooled in an ice bath. NaNO2 (0.90 g,

13.0 mmol, 2 eq) was added to the mixture. After 20 min, NaN3 (1.27 g, 19.5 mmol, 3 eq) was added in the mixture as portions and stirring for 20 min. A crude brownish solid was filtered with water and dried to get 3-azido-7-hydroxycoumarin. IR: 3051,

-1 1 2112, 1684, 1613, 1462, 1304, 1154, 1125, 742 cm . H-NMR (500 MHz; aceton-d6): δ 6.82 (d, J = 2.1 Hz, 1H), 6.90 (dd, J = 8.5, 2.3 Hz, 1H), 7.46 (s, 1H), 7.50 (d, J = 8.5 Hz,

13 1H), 9.50 (s, 1H). C-NMR (126 MHz, acetone-d6): δ 102.25, 112.03, 113.64, 113.65, 122.17, 127.17, 129.02, 153.28, 157.34, 160.13.

109 Preparation of the first generation polyurethane wedges peripheral 4-triazole- 7-hydroxycoumarin and propanol 18. A mixture of 3-azido-7-hydroxycoumarin

(0.107 g, 0.53 mmol, 2.2 eq), CuSO4 (0.38 g, 2.4 mmol, 10.0 eq), ascorbic acid (0.84 g, 4.78 mmol, 20.0 eq), the first generation polyurethane wedge peripheral pentyne groups and propanol 8 (0.096 g, 0.24 mmol, 1.0 eq), THF (5 mL) and H2O (5 mL) was stirred at room temperature for 24 h. The reaction mixture was filtered and washed with THF and the combined filtrates were vacuum evaporated to afford crude

1 product. H-NMR (500 MHz; aceton-d6): δ 1.87 (t, J = 6.7 Hz, 2H), 1.98-1.95 (m, 2H), 2.12 (t, J = 7.1 Hz, 4H), 2.41-2.31 (m, 3H), 3.74 (dd, J = 4.8, 0.6 Hz, 2H), 4.07 (d, J = 6.2 Hz, 2H), 4.22 (dt, J = 14.6, 6.5 Hz, 4H), 6.91 (d, J = 1.8 Hz, 1H), 7.02-6.98 (m, 3H), 7.78 (d, J = 8.5 Hz, 2H), 8.38 (s, 1H), 8.49 (s, 1H), 8.65 (s, 2H), 9.85 (s, 1H). 13C-NMR (126

MHz, DMSO-d6): δ 25.53, 31.05, 62.39, 67.46, 68.79, 73.61, 75.08, 88.22, 91.72, 105.84, 109.46, 118.35, 152.85, 153.40, 171.17, 173.21. MALDI-TOF MS calculated for

+ + C39H36N8O12 808.25, found 809.320 [M+H ] and 831.347 [M+Na ].

Dendrimers Preparation of the first generation polyurethane dendrimer peripheral pentyne groups and 1,3,5-benzene core 20. The Experimental Procedure (A) was followed using 1,3,5-benzene tricarboxylic acid (0.04 g, 0.2 mmol, 1.0 eq), Et3N (0.135 g, 1.3 mmol, 7.0 eq), DPPA (0.26 g, 1.0 mmol, 5.0 eq) and dry benzene (10 mL). The first generation polyurethane wedge with peripheral pentyne groups and propanol 8

(0.253 g, 0.6 mmol, 3.3 eq) was added and the solution stirred overnight. 1H-NMR

(500 MHz; CDCl3): δ 1.88 (quintet, J = 6.5 Hz, 16H), 2.01 (q, J = 5.9 Hz, 9H), 2.18-2.10 (m, 10H), 2.31 (dt, J = 6.8, 3.5 Hz, 16H), 3.98 (t, J = 5.6 Hz, 6H), 4.25 (d, J = 12.2 Hz,

13 16H), 4.49-4.41 (m, 9H), 6.78 (s, 5H), 7.07 (s, 3H). C-NMR (126 MHz, CDCl3): δ 15.14, 27.77, 29.94, 30.00, 63.31, 63.67, 65.94, 65.98, 69.22, 83.08, 99.88, 99.89, 101.33, 120.01, 120.05, 120.09, 120.13, 125.41, 129.83, 129.89, 139.56, 150.37, 150.39, 150.43, 150.45,

153.41, 159.69. MALDI-TOF MS calculated for C72H81N9O21 1407.55, found 1430.653 [M+Na+].

110 Preparation of the the first generation polyurethane dendrimer peripheral triazolephenyl and 1,3,5-benzene core 22. The Experimental Procedure (A) was followed using 1,3,5-benzene tricarboxylic acid (0.02 g, 0.1 mmol, 1.0 eq), Et3N (0.067 g, 0.7 mmol, 7.0 eq), DPPA (0.131 g, 0.5 mmol, 5.0 eq) and dry benzene (10 mL). The first generation polyurethane wedges peripheral triazolephenayl groups and propanol 12 (0.201 g, 0.3 mmol, 3.3 eq) was added and the solution stirred overnight.

+ MALDI-TOF MS calculated for C108H111N27O21 2122.85, found 2144.882 [M+Na ].

Preparation of the first generation polyurethane dendrimer peripheral pentyne groups and sebacic core 24. The Experimental Procedure (A) was followed using sebacic acid (16 mg, 0.1 mmol, 1.0 eq), Et3N (0.055 g, 0.5 mmol, 7.0 eq), DPPA (0.11 g, 0.4 mmol, 5.0 eq) and dry benzene (7 mL). The first generation polyurethane wedge with peripheral pentyne groups and propanol 8 (0.100 g, 0.2 mmol, 3.3 eq) was added and the solution stirred overnight. 1H-NMR (500 MHz;

CDCl3): δ 1.28-1.24 (m, 7H), 1.45-1.44 (m, 5H), 1.86 (quintet, J = 6.6 Hz, 8H), 1.96 (quintet, J = 6.0 Hz, 3H), 2.00 (t, J = 2.6 Hz, 4H), 2.28 (td, J = 7.0, 2.5 Hz, 8H), 3.17 (q, J = 6.7 Hz, 3H), 3.77 (t, J = 6.0 Hz, 3H), 4.03 (t, J = 6.0 Hz, 3H), 4.23 (dd, J = 8.0, 4.3 Hz,

13 8H), 6.86-6.80 (m, 4H), 7.07 (d, J = 11.3 Hz, 2H). C-NMR (126 MHz, CDCl3): δ 15.12, 26.50, 28.96, 29.39, 30.31, 31.98, 41.02, 59.74, 63.65, 65.36, 83.11, 100.06, 100.08, 100.10, 101.48, 101.50, 101.58, 139.59, 149.75, 149.81, 153.60, 156.50, 159.91. MALDI-

+ TOF MS calculated for C52H68N6O14 1000.48, found 1023.872 [M+Na ] and 1038.846 [M+K+].

Preparation of sebacoyl chloride. A mixture of sebacic acid (0.120 g, 0.59 mmol, 1.0 eq) and oxalyl chlorid (0.3 g, 2.4 mmol, 4.0 eq) in DCM 10 mL was stirred and refluxed. After 30 min, DMF (10 uL) was added; then the mixture was stirred and refluxed

1 overnight. H-NMR (500 MHz; CDCl3): δ 1.37-1.33 (m, 8H), 1.71 (quintet, J = 7.2 Hz,

13 4H), 2.89 (t, J = 7.3 Hz, 4H). C-NMR (126 MHz, CDCl3): δ 24.96, 28.26, 28.75, 47.03, 173.82.

111 Preparation of the first generation polyurethane dendrimer peripheral pentyne groups and sebacic core 26. In a 25 mL round bottom flask, sebacic chloride (17 mg, 0.06 mmol, 0.5 eq), the first generation polyurethane wedge peripheral pentyne groups and propanol 8 (0.050 g, 0.1 mmol, 2.1 eq) and DCM (5 mL) were placed. The reaction mixture was then stirred and refluxed for overnight. The reaction mixture was filtered and removal of solvent on a rotary evaporator was

+ done. MALDI-TOF MS calculated for C52H66N4O14970.46, found 993.489 [M+Na ].

Preparation of the second generation polyurethane dendrimer peripheral pentyne groups and sebacic core 27. A mixture of sebacoyl chloride (7 mg, 0.024 mmol, 0.5 eq) was dissolved in DCM and then added to the second generation polyurethane wedge peripheral pentyne groups and propanol 9 (0.05 g, 0.048 mmol, 2.1 eq) and 0.1 g polyvinylprydine. Refluxing for 24 h gave the second generation of sebacic core with penetyne groups on the periphery. MALDI-TOF MS calculated for

+ + C116H138N12O34 2243.95, found 2274.924 [M+Na ] and 2288.651 [M+K ].

Preparation of the second generation polyurethane dendrimer peripheral pentyne groups and 1,3,5-benzene core 21. The Experimental Procedure (A) was followed using 1,3,5-benzene tricarboxylic acid (0.01 g, 0.048 mmol, 1.0 eq), Et3N (0.04 g, 0.4 mmol, 8.0 eq), DPPA (0.09 g, 0.3 mmol, 5.0 eq) and dry benzene (5 mL). The second generation polyurethane wedge peripheral pentyne groups and propanol

9 (0.16 g, 0.2 mmol, 3.3 eq) was added and the solution stirred overnight. 1H-NMR

(500 MHz; aceton-d6): δ 1.87 (quintetd, J = 6.6, 3.5 Hz, 24H), 1.99-1.94 (m, 5H), 2.08 (td, J = 6.3, 2.2 Hz, 22H), 2.16-2.11 (m, 13H), 2.32 (td, J = 7.1, 2.7 Hz, 24H), 2.39 (q, J = 2.5 Hz, 12H), 4.08 (dt, J = 13.5, 6.6 Hz, 17H), 4.21 (td, J = 6.3, 1.9 Hz, 25H), 4.31 (t, J = 6.2 Hz, 15H), 7.01-6.98 (m, 17H), 7.28 (d, J = 1.6 Hz, 9H), 8.67 (s, 17H). 13C-NMR (126 MHz, aceton-d6): δ 14.54, 27.93, 58.18, 61.15, 62.97, 64.23, 64.65, 64.87, 69.52, 76.58, 82.99,

99.24, 99.26, 140.61, 153.40, 159.84. MALDI-TOF MS calculated for C168H189N21O51 3317.29, found 3341.773 [M+Na+].

112 Preparation of The mass spectra of the first generation polyurethane dendrimer peripheral pentyne groups and 1,3,5-benzene core 29. A mixture of 1,3,5-benzenetricarbonyl trichloride (70 mg, 0.26 mmol, 1.0 eq) was dissolved in DCM and then added the first generation polyurethane wedge peripheral pentyne groups and propanol 8 (0.53 g, 1.3 mmol, 5.0 eq) and 0.1 g polyvinylpyridine. Refluxing for 24 h gave the first generation dendrimer with penetyn groups on the

1 periphery. H-NMR (500 MHz; CDCl3): δ 1.89 (ddt, J = 9.8, 6.5, 3.3 Hz, 16H), 2.00 (t, J = 2.6 Hz, 7H), 2.30 (dtd, J = 15.0, 8.0, 3.9 Hz, 23H), 4.10 (ddt, J = 16.5, 11.1, 5.6 Hz, 8H), 4.24 (tt, J = 12.2, 6.1 Hz, 15H), 4.59 (dt, J = 15.0, 6.2 Hz, 6H), 6.80 (s, 6H), 6.89 (s, 4H),

13 7.00 (s, 4H). C-NMR (126 MHz, CDCl3): δ 15.26, 28.46, 32.16, 41.47, 63.61, 63.78, 64.55, 65.85, 69.19, 69.21, 83.02, 83.04, 99.79, 101.24, 131.96, 132.69, 134.84, 135.48, 136.68, 137.40, 138.14, 139.46, 139.51, 139.54, 153.24, 153.26, 153.29, 153.31, 159.72,

159.75, 159.85, 163.57, 164.32, 166.73. MALDI-TOF MS calculated for C72H78N6O21 1362.52, found 1385.555 [M+Na+].

Preparation of The mass spectra of the first generation polyurethane dendrimer peripheral pentyne groups and 4,4′,4′′,4′′′-(porphine-5,10,15,20- tetrayl)tetrakis(benzoyl). A mixture of 4,4′,4′′,4′′′-(porphine-5,10,15,20- tetrayl)tetrakis(benzoyl chloride) (10 mg, 0.01 mmol, 1.0 eq), the first generation polyurethane wedge peripheral pentyne groups and propanol 8 (0.03 g, 0.1 mmol, 6.0 eq) and 0.2 g polyvinylprydine in THF was stirred and refluxed for 24h. MALDI-TOF

+ MS calculated for C132H142N12O28 2344.01, found 2328.155 [M+H ].

113 Conclusion and future research

Our work in this dissertation builds on previous studies. A divergent preparation of polyurethane dendrimers from multiple core molecule has been demonstrated.

The possibility of a powerful method for structural reactions of dendrimers has been established. Both thiol-ene and azide-alkyne click chemistry have been shown to provide late stage reactions of peripheral groups in a convergent synthesis.

Fluorescent has important in proteomics, functional genomics, cell biology and another research area. Fluorescents have many applications such as detection tag, fluorescent dyes, and purification of the ligated product.29 In future work, additional fluorophores in azide-alkyne click chemistry should be investigated as shown below. Multiple fluorophores on the same dendrimer should be examined for fluorescence transfer (including fluorescent cores).

HO O O O O O N O O N O O

N 3 N3 N3 N3

O O O

O N3

Also, additional to alkene-alkene olefin metathesis reaction of polyurethane alkene wedges and dendrimers should be investigated as shown below.

+ W R W R

Dendrimer or wedge

114 4-8. References 1. M. S. Costa, N. Boechat, E. A. Rangel, F. D. C. da Silva, A. M. T. de Sousa, C. R. Rodrigues, H. C. Castro, I. N. Junior, M. C. S. Lourenco, S. M. S. V. Wardell and V. F. Ferreira, Bioorg. Med. Chem., 2006, 14, 8644–8653;

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