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Rhodium catalyzed coupling of in situ generated alpha-lactams with indoles and

synthesis and surface immobilization of bis-corannulene molecular receptors

By TITLE PAGE K. G. Upul Ranjan Kumarasinghe

A Dissertation Submitted to the Faculty of Mississippi State University in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy in Chemistry in the Department of Chemistry

Mississippi State, Mississippi

August 2016

Copyright by COPYRIGHT PAGE K. G. Upul Ranjan Kumarasinghe

2016

Rhodium catalyzed coupling of in situ generated alpha-lactams with indoles and

synthesis and surface immobilization of bis-corannulene molecular receptors

By APPROVAL PAGE K. G. Upul Ranjan Kumarasinghe

Approved:

______Andrzej Sygula (Major Professor)

______Keith T. Mead (Committee Member)

______Todd E. Mlsna (Committee Member)

______Dongmao Zhang (Committee Member)

______Stephen C. Foster (Committee Member / Graduate Coordinator)

______Rick Travis Interim Dean College of Arts & Sciences

Name: K. G. Upul Ranjan Kumarasinghe ABSTRACT Date of Degree: August 12, 2016

Institution: Mississippi State University

Major Field: Chemistry

Major Professor: Andrzej Sygula

Title of Study: Rhodium catalyzed coupling of in situ generated alpha-lactams with indoles and synthesis and surface immobilization of bis-corannulene molecular receptors

Pages in Study 194

Candidate for Degree of Doctor of Philosophy

The first section of this dissertation (Chapter I-III) describes the development of new methodologies for the rhodium catalyzed C-N bond formation between sp3 hybridized carbon atom of phenyl substituted alpha-lactams and the nitrogen atom of indole derivatives. Phenyl substituted alpha-lactams generated in situ from the corresponding alpha-bromoamides reacted with indoles in the presence of rhodium catalyst to afford the ring opening products of alpha-lactams. The scope of this methodology was extended to various types of indole derivatives including electron donating and withdrawing substituents. Furthermore, a series of functionalized phenyl substituted alpha-lactams generated in situ reacted with indole to assess the viability of this methodology. The developed method provides an atom-economical approach for the formation of substituted alpha-amino amides in good to excellent yields.

The main goal of the research described in the second section (Chapter IV-VII) is the synthesis of the corannulene-based molecular receptors with polar tethers and their immobilization on silica gel. First, we have considered a preparation of bis- corannulenoanthracene, formally possessing the pentacene core as a potential precursor

for a series of barrelene based bis-corannulene receptors with polar groups. Bis- corannulenoanthracene was synthesized by the double Diels-Alder cycloaddition of isocorannulenofuran with bis-benzyne precursor, followed by deoxygenation of the endoxide adducts. While bis-corannulenoanthracene is stable enough to be isolated and stored, its pentacene core undergoes facile cycloaddition with maleic anhydride to afford bis-corannulene molecular receptor with the barrelene tether adorned with the anhydride

1 moiety. The H NMR titration experiments carried out in chlorobenzene-d5 proved the high binding affinity of the receptor toward C60. In addition, the presence of polar anchors on its tether allowed for its deposition on silica gel through the (3- aminopropyl)triethoxysilane linker.

DEDICATION

To my parents, Mr. Ananda Kumarasinghe and Mrs. Swarnawathi, my wife,

W.Wasanthi Priyanwada De Silva, sister, Mrs. Chandrani Wijesinghe, brother, Rasika

Gayan Kumarasinghe.

ii

ACKNOWLEDGEMENTS

Throughout the following dissertation is an individual work, I could never have reached the heights or explored the depth without the help, support, guidance and efforts of a lot of people.

First and foremost I wish to express my profound appreciation to my advisor Dr.

Andrzej Sygula. I have been amazingly fortunate to have an advisor who gave me tremendous guidance, encouragement, and assistance throughout my years at Mississippi

State University. I also would like to thank Dr. Gerald Rowland, my previous advisor. I greatly appreciate his guidance over the first two and half years of my PhD program. I would also thankful to my graduate committee members Dr. Keith T. Mead, Dr. Todd E.

Mlsna, Dr. Dongmao Zhang and Dr. Stephen C. Foster for their helpful suggestions and discussions throughout my graduate studies.

Appreciation also extended to my former lab mates Dr. Micheal Yanney and Dr.

Peumie L. Abeyratne Kuragama for the encouragement and help given in the laboratory work throughout my PhD. Also, I would like to thank Mrs. Renata Sygula for all her help in the laboratory during the third year of my graduate study. I would like to thank my loving wife, my parents and my family for all the sacrifice that you have made on my behalf. This work would not have been possible without your help and support.

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TABLE OF CONTENTS

DEDICATION ...... ii

ACKNOWLEDGEMENTS ...... iii

LIST OF TABLES ...... viii

LIST OF FIGURES ...... x

LIST OF SCHEMES...... xiii

LIST OF ABBREVIATIONS AND CHEMICALS ...... xvii

CHAPTER

I. RHODIUM CATALYZED COUPLING OF IN SITU GENERATED ALPHA-LACTAMS WITH INDOLES: INTRODUCTION ...... 1

1.1 Synthesis of α-lactams...... 2 1.1.1 (1) Cyclization by dehydrohalogentaion of α-haloamides...... 6 1.1.2 (2) Cycloelimination of N-sulfonyloxy substituted amides...... 6 1.2 Stability of α-lactams ...... 7 1.3 Nucleophilic ring opening reactions of α-lactams ...... 10 1.4 Transition metal catalyzed ring expansion of α-lactams ...... 12 1.5 Ring expansions of aza-oxyallyl cation ...... 14 1.6 N-Functionalization of Indoles and C-N bond formation ...... 15 1.7 Research goals ...... 16

II. RHODIUM CATALYZED COUPLING OF IN SITU GENERATED ALPHA-LACTAMS WITH INDOLES: RESULTS AND DISCUSSION ...... 18

2.1 Synthesis of α-bromoamides ...... 18 2.2 Optimization of the reaction conditions ...... 20 2.3 N-Functionalization of indole derivatives with in situ generated N-tert-butyl-phenylaziridinone (3) ...... 25 2.4 The scope of in situ generated phenyl substituted α-lactams ...... 26 2.5 Proposed catalytic cycle ...... 27 2.6 Conclusions ...... 28

iv

III. RHODIUM CATALYZED COUPLING OF IN SITU GENERATED ALPHA-LACTAMS WITH INDOLES: EXPERIMENTAL ...... 30

3.1 General information ...... 30 3.2 General procedure for the synthesis of α-bromoamides 43, 44, 45, 46, 47, 49 and 50 ...... 30 3.3 Procedure for the synthesis of α-bromoamide 48...... 36 3.4 Reactions of indole derivatives with in situ generated α-lactam ...... 37 3.4.1 General procedure...... 37 3.4.2 Reactions of in situ generated phenyl substituted α-lactams with indole ...... 43

IV. SYNTHESIS AND SURFACE IMMOBILIZATION OF BIS- CORANNULENE MOLECULAR RECEPTORS: INTRODUCTION ...... 49

4.1 Molecular receptors for fullerenes ...... 50 4.2 Corannulene based molecular receptors for fullerenes...... 53 4.3 Acenes and their reactivity towards Diels-Alder cycloaddition ...... 60 4.4 Bis-aryne and corannulyne ...... 64 4.5 Research Goals ...... 68

V. SYNTHESIS OF BIS-CORANNULENOANTHRACENE AND BIS- CORANNULENE RECEPTOR AND ITS BINDING STUDIES USING 1H NMR SPECTROSCOPY ...... 70

5.1 Synthesis of 113 ...... 72 5.2 Synthesis of endoxide adducts 148a and 148b ...... 74 5.2.1 APPI-MS and 1H NMR of syn and anti endoxide adducts ...... 75 5.2.2 Crystal structure of anti isomer (148b) ...... 78 5.2.3 Synthesis of 137 via deoxygenation of 148a and 148b ...... 78 5.2.3.1 UV-Vis and Fluorescence spectra of 137 ...... 79 5.3 Synthesis of molecular receptor 149 ...... 80 5.3.1 APPI-MS and 1H NMR of 149 ...... 81 5.3.2 X-ray crystal structure of 149 ...... 83 5.4 Binding studies of clip 149 using 1H NMR spectroscopy ...... 85 5.4.1 Evaluation of Ka for the 1:1 model (C60@149) in chlorobenzene-d5...... 89 5.4.2 Evaluation of K1 and K2 for the 2:1 model (C60@1492) in chlorobenzene-d5...... 91 5.4.3 F-test ...... 95 5.5 Conclusions ...... 97

VI. IMMOBILIZATION OF BIS-CORANNULENE MOLECULAR RECEPTORS ON SILICA SURFACE ...... 98

6.1 Silica as a solid support and silane coupling agents ...... 99

v

6.2 Modification of silica with APTES ...... 100 6.2.1 DRIFTS analysis of APTES modified silica ...... 101 6.2.2 Elemental analysis and APTES coverage on silica surface ...... 102 6.2.3 TGA analysis of the surface modified silica ...... 103 6.3 Surface immobilization of the model compound 151 ...... 104 6.3.1 DRIFTS analysis of 151 modified silica ...... 105 6.3.2 Elemental analysis of 151 modified silica ...... 107 6.3.3 TGA analysis of adduct 151 grafted silica ...... 108 6.4 Immobilization of 149 on APTES modified silica ...... 108 6.4.1 DRIFTS analysis of 149 modified silica ...... 109 6.4.2 Elemental analysis of 149 modified silica ...... 110 6.4.3 TGA analysis of 149 modified silica ...... 111 6.5 The stir and filter approach to observe the C60 adsorption on the receptor modified silica ...... 112 6.6 Conclusions ...... 113

VII. SYNTHESIS AND SURFACE IMMOBILIZATION OF BIS- CORANNULENE MOLECULAR RECEPTORS: EXPERIMENTAL ...... 115

7.1 General Information ...... 115 7.2 Synthesis of 116 ...... 116 7.3 Synthesis of 142 ...... 116 7.4 Synthesis of 113 ...... 117 7.5 Synthesis of syn (148a) and anti (148b) endoxides ...... 118 7.6 Synthesis of 137 ...... 120 7.7 Synthesis of 149 ...... 120 1 7.8 H NMR titration experiment of clip 149 with C60 in chlorobenzene-d5 ...... 121 7.9 Preparation of silica ...... 126 7.10 Modification of silica surface with APTES linker ...... 127 7.11 Synthesis of cycloadduct 151 ...... 128 7.12 Immobilization of adduct 151 on APTES modified silica ...... 128 7.13 Immobilization of clip 149 on APTES modified silica ...... 129

REFERENCES ...... 130

APPENDIX

A. 1H NMR AND 13C/13C DEPTQ135 NMR OF ALL NEW COMPOUNDS ...... 140

B. X-RAY CRYSTAL STRUCTURES ...... 167

X-ray crystal structure for 148b ...... 168 X-ray crystal structure for 149 ...... 177

C. CALCULATIONS OF SILICA SURFACE COVERAGES ...... 189 vi

Calculation of C/N ratio based on the elemental analysis ...... 190 APTES coverage based on the elemental analysis ...... 190 APTES coverage based on the TGA data148 ...... 190 151 coverage on silica surface based on the elemental analysis ...... 191 Cycloadduct 151 coverage on silica surface based on TGA data ...... 192 Receptor 149 coverage on silica based on elemental analysis ...... 193 C.7 Receptor 149 coverage on silica surface based on TGA ...... 194

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LIST OF TABLES

2.1 Synthesis of α-bromoamides ...... 20

2.2 Optimization of base...... 21

2.3 Optimization of catalyst ...... 23

2.4 Optimization of solvent ...... 24

2.5 N-Functionalization of indole derivatives with in situ generated N- tert-butyl-phenylaziridinone (3) ...... 26

2.6 The scope of in situ functionalized α-lactams ...... 27

5.1 B3LYP/6-311G(d,p) level calculated HOMO-LUMO gap ...... 70

5.2 Maximum observed changes in the chemical shifts of the protons A, B, C, D and E for C60@149 ...... 87

5.3 Estimated values of Ka and ∆δmax using 1:1 model ...... 91

5.4 Estimated values of K1, K2, δΔHG and δΔH2G using 2:1 model ...... 94

5.5 Reduced χ2 values ...... 96

5.6 F-test results...... 96

5.7 Comparison of the binding properties of buckycatchers 93, 99 and 149 in chlorobenzene-d5 ...... 97

6.1 Elemental analysis of APTES modified Cab-O-Sil...... 103

6.2 Elemental analysis results of 151 grafted silica ...... 107

6.3 Elemental analysis results of 149 modified silica ...... 111

1 7.1 H NMR titration data for C60@149 in chlorobenzene-d5 ...... 122

B.1 Crystallographic data, X-ray experimental conditions and structure refinement details for 148b ...... 169

viii

Fractional atomic coordinates (×104) and equivalent Isotropic displacement parameters (Å2×103) for 148b ...... 170

Anisotropic displacement parameters (Å2×103) for 148b ...... 171

Bond lengths for 148b ...... 172

Bond angles for 148b ...... 173

Hydrogen atom coordinates (Å×104) and isotropic displacement parameters (Å2×103) for 148b ...... 176

Crystallographic data, X-ray experimental conditions and structure refinement details for 149 ...... 178

Fractional Atomic Coordinates (×104) and equivalent isotropic displacement parameters (Å2×103) for 149 ...... 179

Anisotropic Displacement Parameters (Å2×103) for 149 ...... 181

Bond Lengths for 149 ...... 183

Bond Angles for 149 ...... 185

Hydrogen Atom Coordinates (Å×104) and Isotropic Displacement Parameters (Å2×103) for 149 ...... 187

ix

LIST OF FIGURES

1.1 Structure of α-lactam ...... 1

1.2 Phenyl substituted α-lactams ...... 10

1.3 Examples of biological active N-functionalized indole derivatives ...... 16

1.4 Reaction of 1,3-di-tert-butylaziridinone and 3-(tert-butyl)-1- tritylaziridinone with indoles ...... 17

2.1 1H NMR of (a) α-bromoamide 43 and (b) in situ generated α-lactam 3 in benzene-d6 ...... 22

4.1 Early supramolecular host molecules crown ether (73), cryptands (74), cavitands (75), and carcerands (76) ...... 50

4.2 Structure of Buckminterfullerene (77) ...... 51

4.3 Chemical structures of the azacrown receptors (78 and 79) for fullerenes ...... 52

4.4 Structures of macrocyclic receptors (80-85) for fullerenes ...... 53

4.5 Structure of corannulene (86, left) and its convex and concave faces (right) ...... 54

4.6 First reported corannulene based receptors (87-89) for fullerenes ...... 55

4.7 Barrelene based molecular receptor 90 ...... 55

4.8 Structure of receptor 94 ...... 57

4.9 Structure of molecular receptor 95 ...... 57

4.10 Structures of molecular receptors 96-98...... 58

4.11 Structure of Buckycatcher II ...... 59

4.12 Molecular receptors 100 and 101 with Kläner’s tethers ...... 60

4.13 Structures of linear acenes (102-107) ...... 61 x

4.14 Products of Diels-Alder cycloaddition of anthracene (108), tetracene (109) and pentacene (110) with maleic anhydride ...... 62

4.15 Structure of bis-corannulenoanthracene (137) ...... 69

5.1 APPI MS of 148a (left) and 148b (right) ...... 76

5.2 1H NMR spectrum of 148a ...... 77

5.3 1H NMR spectrum of 148b...... 77

5.4 Crystal structure of 148b with 50% ellipsoids ...... 78

5.5 APPI MS of 137 ...... 79

5.6 UV-Vis spectra of 113 (blue) and 137 (red) ...... 80

5.7 Fluorescence spectra of 113 (blue) and 137 (red) ...... 80

5.8 APPI MS of clip 149 ...... 81

5.9 1H NMR spectrum of clip 149 ...... 82

5.10 Conformers of molecular receptor 149 and their MM2 calculated relative energies (kcal/mol) ...... 83

5.11 Crystal structure of the toluene solvate of 149 with 50% ellipsoids ...... 84

5.12 MM2 calculated gas phase binding energies (kcal/mol) of receptors 90, 93, 99 and 149 ...... 85

1 5.13 H NMR titration of clip 149 with C60 in chlorobenzene-d5 (downfield protons) ...... 86

1 5.14 H NMR titration of clip 149 with C60 in chlorobenzene-d5 (upfield protons) ...... 87

5.15 Job’s plots for protons A, B, C, D, E and F for the titration of 149 with C60 in chlorobenzene-d5...... 88

5.16 Nonlinear curve regression of the titration of 149 with C60 (1:1 model) ...... 90

5.17 Nonlinear curve regression for the titration of 149 with C60 (2:1 model, downfield protons)...... 93

5.18 Nonlinear curve regression for the titration of 149 with C60 (2:1 model, upfield protons) ...... 94 xi

6.1 Structure of APTES (150) ...... 99

6.2 DRIFT spectrum of unmodified silica ...... 100

6.3 DRIFT spectra of APTES modified silica ...... 102

6.4 TGA thermograms of unmodified silica (blue) and APTES modified silica (red) ...... 104

6.5 DRIFT spectrum of adduct 151 modified silica ...... 106

6.6 DRIFT spectrum of adduct 151 modified silica ...... 106

6.7 IR spectra of adduct 151 ...... 107

6.8 TGA thermogram of 151 grafted silica ...... 108

6.9 DRIFT spectrum of 149 modified silica ...... 110

6.10 IR spectrum of 149 ...... 110

6.11 TGA thermogram of 149 grafted silica ...... 112

6.12 UV-Vis spectra of initial C60 solution (black) recovered C60 solutions after treated with APTES modified silica (red) and receptor 149 modified silica (blue) ...... 113

7.1 Structure of the syn endoxide adduct (148a) ...... 118

7.2 Structure of the anti endoxide adduct (148b) ...... 119

Crystal structure of 148b ...... 168

Crystal structure of 149 ...... 177

xii

LIST OF SCHEMES

1.1 First in situ generated N-tert-butyl-phenylaziridinone (3) and its ring opening reactions ...... 2

1.2 Synthesis of N-tert-butyl-phenylaziridinone (3) ...... 3

1.3 Synthesis of α-lactams from α-haloamides and N-haloamides ...... 4

1.4 Synthesis of 1,3-di-tert-butylaziridinone (8) ...... 4

1.5 Attempted synthesis of 8 using dichlorocarbene ...... 5

1.6 Synthesis of 1-carbobenzoxy-3-benzylaziridinone (12) ...... 5

1.7 The base induced cyclization of α-haloamides ...... 6

1.8 Base promoted 1,3 elimination of N-sulfonyloxyamide ...... 6

1.9 Thermal decomposition of 13 ...... 8

1.10 Thermal decomposition of 8 ...... 8

1.11 Thermal decomposition of 3 ...... 9

1.12 Two paths of nucleophilic ring opening of α-lactams ...... 11

1.13 Rhodium catalyzed ring expansion of 1,3-di-tert-butylaziridinone ...... 12

1.14 Possible mechanism for the ring expansion of 1,3-di-tert- butylaziridinone with [Rh(CO)2Cl]2 ...... 13

1.15 Possible reaction pathway for the ring expansion of 8 with Co2(CO)8 ...... 14

1.16 [4+3] cycloaddition of aza-oxyallyl cation...... 14

1.17 (3+2) dearomative annulation of aza-oxyallyl cation ...... 15

2.1 Synthesis of α-bromoamides (43-50) ...... 18

2.2 Best reaction conditions for the in situ generation of α-lactam 3 and its ring opening with indole ...... 24 xiii

2.3 Proposed catalytic cycle for rhodium catalyzed ring opening of α- lactams ...... 28

3.1 Synthesis of 2-bromo-N-(tert-butyl)-2-phenylacetamide (43) ...... 31

3.2 Synthesis of 2-bromo-N-(tert-butyl)-2-(4-fluorophenyl)acetamide (44) ...... 32

3.3 Synthesis of 2-bromo-N-(tert-butyl)-2-(4-chlorophenyl)acetamide (45) ...... 32

3.4 Synthesis of 2-bromo-2-(4-bromophenyl)-N-(tert-butyl)acetamide (46) ...... 33

3.5 Synthesis of 2-bromo-N-(tert-butyl)-2-(3-chlorophenyl)acetamide (47) ...... 34

3.6 Synthesis of 2-bromo-N-(tert-butyl)-2-(3- (trifluoromethyl)phenyl)acetamide (49) ...... 34

3.7 Synthesis of 2-bromo-N-(tert-butyl)-2-(2-iodophenyl)acetamide (50) ...... 35

3.8 Synthesis of 2-bromo-N-(tert-butyl)-2-(4-methylphenyl)acetamide (48) ...... 36

3.9 Synthesis of N-(tert-butyl)-2-(1H-indol-1-yl)-2-phenylacetamide (51) ...... 37

3.10 Synthesis of N-(tert-butyl)-2-(2-methyl-1H-indol-1-yl)-2- phenylacetamide (52) ...... 38

3.11 Synthesis of N-(tert-butyl)-2-(3-methyl-1H-indol-1-yl)-2- phenylacetamide (53) ...... 39

3.12 Synthesis of N-(tert-butyl)-2-(5-methyl-1H-indol-1-yl)-2- phenylacetamide (54) ...... 39

3.13 Synthesis of N-(tert-butyl)-2-(7-methyl-1H-indol-1-yl)-2- phenylacetamide (55) ...... 40

3.14 Synthesis of N-(tert-butyl)-2-(5-iodo-1H-indol-1-yl)-2- phenylacetamide (56) ...... 41

3.15 Synthesis of N-(tert-butyl)-2-(2-methyl-5-methoxy-1H-indol-1-yl)-2- phenylacetamide (57) ...... 41

3.16 Synthesis of N-(tert-butyl)-2-(2-methyl-5-nitro-1H-indol-1-yl)-2- phenylacetamide (58) ...... 42

xiv

3.17 Synthesis of N-(tert-butyl)-2-(4-fluorophenyl)-2-(1H-indol-1- yl)acetamide (66) ...... 43

3.18 Synthesis of N-(tert-butyl)-2-(4-chlorophenyl)-2-( 1H-indol-1- yl)acetamide (67) ...... 44

3.19 Synthesis of 2-(4-bromophenyl)-N-(tert-butyl)-2-(1H-indol-1- yl)acetamide (68) ...... 45

3.20 Synthesis of N-(tert-butyl)-2-(3-chlorophenyl)-2-( 1H-indol-1- yl)acetamide (69) ...... 45

3.21 Synthesis of N-(tert-butyl)-2-(1H-indol-1-yl)-2-(4- methylphenyl)acetamide (70) ...... 46

3.22 Synthesis of N-(tert-butyl)-2-(1H-indol-1-yl)-2-[4- (trifluoromethyl)phenyl]acetamide (71) ...... 47

3.23 Synthesis of N-(tert-butyl)-2-(1H-indol-1-yl)-2-(2-iodophenyl) acetamide (72) ...... 47

4.1 Synthesis of molecular receptor 93 ...... 56

4.2 Clar’s Synthesis of tetrabenzopentacene (113) ...... 62

4.3 Diels-Alder cycloaddition of 113 ...... 63

4.4 Synthesis of heptacene derivative 117 ...... 64

4.5 Generation of corannulyne 120 and its reactions with different dienophiles ...... 65

4.6 Synthesis of corannulene trimer 123 and tetramer 124 ...... 66

4.7 Synthesis of large polycyclic o-(trimethylsilyl)aryl triflates 128-130 ...... 67

4.8 Generation of polycyclic arynes 131-133 ...... 67

4.9 Synthesis of 135-136 ...... 68

5.1 Attempted acylation of corannulene (86) with pyromellitic dianhydride (112) ...... 71

5.2 Synthesis of phenanthro[9,10,c]furan (140) ...... 72

5.3 Synthesis of endoxide adduct 142 from 1,2,4,5-tetrabromobenzene (141) and 140 ...... 72

xv

5.4 Synthesis of 142 from bis-benzyne precursor 116 and 140 in the presence of TBAF...... 73

5.5 Synthesis of bis-benzyne precursor 116 ...... 73

5.6 Synthesis of endoxide adduct 142 using CsF as a fluoride source ...... 74

5.7 Synthesis of 113 from the endoxide adduct 142 ...... 74

5.8 Synthesis of endoxide adducts...... 75

5.9 Synthesis of isocorannulenofuran (91) ...... 75

5.10 Deoxygenation of 148a and 148b ...... 78

5.11 Synthesis of molecular receptor 149 ...... 81

5.12 2:1 binding model ...... 91

6.1 Modification of silica with APTES ...... 101

6.2 Synthesis of cycloadduct 151 ...... 104

6.3 Immobilization of cycloadduct 151 on APTES modified silica ...... 105

6.4 Immobilization of receptor 149 on APTES modified silica surface ...... 109

7.1 Synthesis of bis-benzyne precursor 116 ...... 116

7.2 Synthesis of endoxide 142 ...... 116

7.3 Synthesis of tetrabenzopentazene (113) ...... 117

7.4 Synthesis of endoxide adducts 148a and 148b...... 118

7.5 Synthesis of bis-corannulenoanthracene (137) ...... 120

7.6 Synthesis of molecular receptor 149 ...... 120

7.7 Modification of silica surface with APTES linker ...... 127

7.8 Synthesis of model compound 151...... 128

7.9 Immobilization of model compound on APTES modified silica ...... 128

7.10 Immobilization of molecular receptor on APTES modified silica ...... 129

xvi

LIST OF ABBREVIATIONS AND CHEMICALS

Et2O Diethyl ether

COD Cyclooctadiene nbd norbornadiene

CO Carbon monoxide

COCl2 Carbonyl dichloride

DIPEA N,N-Diisopropylethylamine

KOH Potassium hydoxide

NaH Sodium hydride

NaHCO3 Sodium bicarbonate t-BuOH Tert-butyl alcohol

NEt3 Triethylamine

MW Microwave

Co2(CO)8 Dicobalt octacarbonyl

[Rh(COD)Cl]2 Chloro(1,5-cyclooctadiene)rhodium(I) dimer [Rh(CO)2Cl]2 Rhodium(I) dicarbonyl chloride dimer

[Ir(COD)Cl]2 Bis(1,5-cyclooctadiene)diiridium(I) dichloride Rh(nbd)2(BF4) Bis(norbornadiene)rhodium(I) tetrafluoroborate Pd(dba)2 Bis(dibenzylideneacetone)palladium(0)

xvii

TGA Thermal Gravimetric Analysis

Bu Butyl

NMR Nuclear Magnetic Resonance

UV Ultraviolet

Vis Visible

IR Infrared Spectroscopy

DCM Dichloromethane

DMF Dimethylformamide

CO Carbon monoxide

MeOH Methanol exTTF extended Tetrathiafulvalene

APPI-MS Atmospheric Pressure Photoionization Mass Spectrometry BE Gas phase binding Energy

PCl3 Phosphorus (III) chloride

SOCl2 Thionyl chloride

MM Molecular Mechanics

Cab-O-Sil Fumed silica

APTES (3-aminopropyl)triethoxysilane

DRIFTS Diffuse Reflectance Infrared Fourier Transform Spectroscopy ESI Electrospray ionization

xviii

CHAPTER I

RHODIUM CATALYZED COUPLING OF IN SITU GENERATED ALPHA-

LACTAMS WITH INDOLES: INTRODUCTION

Small-ring heterocycles have been recognized as useful synthetic targets and as building blocks in the synthesis of complex structures. The most recognized function of these heterocycles is their tendency to undergo ring opening reactions by cleavage of the carbon-heteroatom bond and formation of a new bond with an incoming nucleophile.

Strained heterocycles, such as epoxides and aziridines, serve as the important intermediates in reactions developed recently in organic chemistry.1-5 α-Lactams

(aziridinones) contribute to another class of strained heterocycles that were first proposed as reactive intermediates by Sheehan and coworkers in 1949.6 These compounds are three-membered rings consisting of the amide function. α-Lactam structure and numbering of the atoms are shown in Figure 1.1. Many of the α-lactam’s chemical and physical properties, either as isolated species or intermediates have been studied up to date.7-15

Figure 1.1 Structure of α-lactam

1

Synthesis of α-lactams, their stability, in situ generation, ring opening and expansion reactions are discussed in this introduction. C-N bond formation and N- functionalization of indoles are also discussed briefly.

1.1 Synthesis of α-lactams.

The first in situ generation of α-lactams was reported by Baumgarten and coworkers in 1961.16 N-tert-butyl-N-chlorophenylacetamide (2) treated with potassium t- butoxide generated N-tert-butyl-phenylaziridinone (3) in situ which subsequently reacted with t-BuO- nucleophile to afford two distinct ring opening products of the α-lactam 3

(Scheme 1.1). In addition, they used IR spectroscopy for the first time to characterize the

α-lactams. The carbonyl stretching frequency of α-lactam which was observed at 1847 cm-1 is in accord with the theoretically predicted frequency (1790-1840 cm-1).17

Scheme 1.1 First in situ generated N-tert-butyl-phenylaziridinone (3) and its ring opening reactions

2

The same research group reported the first isolated α-lactam in 1962.18

Cyclization of intermediate 2 with t-BuOK afforded α-lactam 3 with 31% isolated yield

(Scheme 1.2).18 The purified 3 appeared to be moderately stable and could be stored in a freezer for several weeks.

Scheme 1.2 Synthesis of N-tert-butyl-phenylaziridinone (3)

α-lactams can be prepared by either using α-haloamides or N-haloamides as starting materials. Sheehan and coworkers reported the using of α-haloamides as starting material for synthesis of α-lactams (Scheme 1.3, path (a)) were better than the using of N- haloamides (Scheme 1.3, path (b)) for two reasons.17,19 (1) It is easier to separate the α- lactam formed from α-haloamide than N-haloamide due to the solubility difference between the starting materials and products (2) the anion formation is more favored when the negative charge is situated on the nitrogen atom than when it is on α-carbon atom.17

3

Scheme 1.3 Synthesis of α-lactams from α-haloamides and N-haloamides

Later, Sheehan and co-workers reported a high yield preparation of 1,3-di-tert- butylaziridinone (8) using α-haloamide 6 and t-BuOK (Scheme 1.4).20 The α-lactam 8 exhibit higher stability than the α-lactam 3. As a result, 8 can be distilled under reduced pressure and purified by column chromatography.17,20

Scheme 1.4 Synthesis of 1,3-di-tert-butylaziridinone (8)

4

Besides above methods, Sheehan and co-workers reported another approach to the preparation of 8 using dichlorocarbene and N-neopentylidene-tert-butylamine (9)

(Scheme 1.5).20 However, this method gave only the very low yield of 8 (1%) which was rationalized by the strong steric hindrance of the C-N double bond in 9.

Scheme 1.5 Attempted synthesis of 8 using dichlorocarbene

Another method for synthesis of α-lactam was reported by Miyoshi in 1970.21

Dehydration of N-carbobenzoxy amino acid (11) using phosgene (COCl2) afforded 1- carbobenzoxy-3-benzylaziridinone as crystalline materials (12, Scheme 1.6).

Unfortunately, they did not provide the yield of the α-lactam.

Scheme 1.6 Synthesis of 1-carbobenzoxy-3-benzylaziridinone (12)

Currently, there are two practical methods used to synthesize α-lactams.7

5

1.1.1 (1) Cyclization by dehydrohalogentaion of α-haloamides.

The most common approach to the synthesis of α-lactam is the base-induced cyclization of α-haloamides by bases like t-BuOK, t-BuONa, KOH and NaH. The corresponding α-lactams are formed by an abstraction of the acidic hydrogen from the nitrogen of α-haloamide and subsequent displacement of α-halide (Scheme 1.7).7,9,17 22

Scheme 1.7 The base induced cyclization of α-haloamides

1.1.2 (2) Cycloelimination of N-sulfonyloxy substituted amides.

In this method, N-sulfonyloxyamides are converted to the corresponding α-lactam by base promoted 1,3 elimination (Scheme 1.8).11,23,24

Scheme 1.8 Base promoted 1,3 elimination of N-sulfonyloxyamide

6

1.2 Stability of α-lactams

The carbonyl group of α-lactams adds additional strain to the α-lactam ring as compared to aziridines and epoxides, making them highly reactive.25 The calculated strain energy of α-lactam is approximately 41 kcal mol-1.26,27 Most of the known α- lactams have been stabilized by bulky groups such as tert-butyl or 1-adamantyl on nitrogen atom and C-3 position.9 α-lactams with two bulky groups have shown more stability than their analogs with one bulky group. The enhanced stability may be due to the steric hindrance at the usual reaction sites.17 The higher the steric hindrance of the substituent group on both the nitrogen atom and α-carbon atom, the greater the thermal stability of α-lactam. However, the ease of thermal decomposition does not only depend on steric effect but also on the presence or absence of at least one β-hydrogen in the alkyl group at the C-3 position. α-lactams with at least one β-hydrogen such as 1-tert-butyl-

3,3-dimethylaziridinone (13) decompose quickly in refluxing ether, producing α-β unsaturated amides 14 via β-hydrogen elimination (Scheme 1.9).17 In contrast, α-lactam

8 that does not have any β-hydrogen atoms stabilized by two bulky tert-butyl groups, starts decomposing at ca.140 °C (Scheme 1.10).

7

Scheme 1.9 Thermal decomposition of 13

Scheme 1.10 Thermal decomposition of 8

In addition, α-lactam 3 starts to decompose at 105 °C and produces benzaldehyde

(20), tert-butyl isocyanide (15) and trace amounts of N-benzylidene-tert-butylamine (21) and carbon monoxide (Scheme 1.10).17

8

Scheme 1.11 Thermal decomposition of 3

Nonetheless, if stability depends only on steric effect, 3 would be expected to have similar stability as α-lactam 22 (Figure 1.2) because the steric congestion in these two compounds is not very different. In fact, α-lactam 22 could not be prepared, but a moderately stable α-lactam 3 can be isolated. Hence, the other factors such as electronic effects also influence the stability of α-lactams.17

Only a few α-lactams with aryl groups on C-3 were reported up to date.7,8,17,26,28-34

Some of those were isolated in low yields even with the fast workup procedures. In addition to the synthesis of α-lactam 3, Baumgarten and coworkers reported other phenyl substituted α-lactams at C-3 such as 3-p-chlorophenyl (23), 3-p-bromophenyl (24) and 1- tert-butyl-3,3-diphenylaziridinones (25, Figure 1.2 ). Also, 1-tert-butyl-3(4- biphenyllyl)aziridinone (26) was prepared via the corresponding α-chloroamide only in impure form, because it was not stable enough to be purified under usual conditions. In addition, an attempted synthesis of α-lactam 27 from N-tert-butyl-p-nitrophenylacetamide was unsuccessful.

9

Figure 1.2 Phenyl substituted α-lactams

Therefore, some α-lactams which contain phenyl group at the C-3 position are less stable and nonisolable.7,31 Nevertheless, many α-lactams can be generated in situ and react without the need for isolation. 8,10,22

1.3 Nucleophilic ring opening reactions of α-lactams

Various types of reactions of α-lactams were reported in literature such as reductions35, reaction with Grignard reagent36 and tert-butyl lithium37, alkylation38, pyrolysis39, nucleophilic ring opening8 etc. Among the reported reactions, nucleophilic ring opening reactions of α-lactams with various nucleophiles containing N, O, and S heteroatoms have been studied extensively.8-10 Nucleophile can attack α-lactams either on the sp3 hybridized carbon (C-3) to give secondary amide as a product or on the acyl carbon (C-2) to give 2-amino acid derivatives (Scheme 1.11).8,11,22 In particular, various generalizations were stated for the regioselectivity of a nucleophilic ring opening reaction of α-lactams. 10

Scheme 1.12 Two paths of nucleophilic ring opening of α-lactams

In 1968, Sheehan and coworkers reported that selectivity of the ring opening mainly depends on the nature of the incoming nucleophile.17 Reactions with neutral protic nucleophiles such as water, alcohols, thiols, amines and mineral acids formed amides resulting from the alkyl-nitrogen (C-3-N) bond cleavage. On the other hand, anionic aprotic nucleophiles cause a rupture of the acyl-nitrogen (C-2-N) bond to give amino acid derivatives as the major product. However, in 1998, Yusoff and coworkers reported that steric factors also play a significant role in the regioselectivity of the nucleophilic ring opening of α-lactams.10 Strong, unhindered nitrogen nucleophiles tend to rupture the C-2-N bond, whereas sterically hindered, weaker nucleophiles favor a scission of the C-3-N bond. However, aprotic nucleophiles containing O and S exhibit considerable variation in regioselectivity. In addition, hardness/softness of the nucleophile also effects the regioselectivity of the ring opening reactions.10 Soft nucleophiles like iodide ion attack the soft alkyl carbon of α-lactam and hard nucleophiles such as alkoxide prefer to attack the harder acyl carbon. Clearly, the generalization was not established for the regioselective ring opening of α-lactams.

11

1.4 Transition metal catalyzed ring expansion of α-lactams

Transition metal catalyzed reactions like cycloaddition40, cyclization41, coupling42, ring expansion43, isomerization44, free radical additions45, electrophilic addition46 and nucleophilic ring opening reactions47 have been studied recently. These reactions exhibit a much higher stereo-, regio- and chemo selectivity than the alternative metal free synthetic methodology.

Transition metal catalyzed ring expansion reactions of α-lactams have not been reported widely and to the best of our knowledge, only one example is available in the literature. Roberto and co-workers reported that α-lactam 8 was converted to azetidine-

2,4-dione using Rh(I) and Co(0) complexes. Ring expansion of 8 with Rh(I) was catalytic and with Co(0) stoichiometric.48 The treatment of 8 with CO in the presence of catalytic amount of [Rh(CO)2Cl]2 in dry benzene afforded azetidine-2,4-dione (28) in quantitative yield (Scheme 1.12)

Scheme 1.13 Rhodium catalyzed ring expansion of 1,3-di-tert-butylaziridinone

A proposed mechanism for the ring expansion reaction of 8 is outlined in Scheme

1.13. Insertion of Rh(I) into the C-3-N bond of 8 gives 29 which undergo ligand

12

migration to yield 30. The addition of CO to 30 followed by reductive elimination of

[Rh(CO)2Cl] of 31 affords the azetine-2,4-dione 28.

Scheme 1.14 Possible mechanism for the ring expansion of 1,3-di-tert-butylaziridinone with [Rh(CO)2Cl]2

In addition, treatment of α-lactam 8 with an equimolar amount of Co2(CO)8 in benzene overnight at 65 °C under nitrogen afforded 28 in 90% yield.48 The proposed reaction pathway is outlined in Scheme 1.14. The α-lactam 8 induced the disproportionation of Co2(CO)8 to yield complex 32. The cationic portion of 32 rearrange to the metallacycle 33 and undergo ligand migration to afford complex 34.

Afterward, the reaction of 34 with an excess of Co2(CO)8 and 8 would give product 28 with CO and complex 35 as by-products.

13

Scheme 1.15 Possible reaction pathway for the ring expansion of 8 with Co2(CO)8

1.5 Ring expansions of aza-oxyallyl cation

In addition to the metal catalyzed ring expansion of α-lactams, ring expansion of aza-oxyallyl cation was also reported. Aza-oxyallyl cation is one of the proposed intermediates in α-lactam chemistry.8,49,50 Jeffery and co-workers reported the first example of [4+3] cycloaddition of aza-oxyallyl cation with cyclic dienes (Scheme

1.15).51-53

Scheme 1.16 [4+3] cycloaddition of aza-oxyallyl cation

14

Most recently DiPoto and co-workers reported indole (3+2) dearomative annulation reactions involving aza-oxyallyl cation (Scheme 1.16).54

Scheme 1.17 (3+2) dearomative annulation of aza-oxyallyl cation

1.6 N-Functionalization of Indoles and C-N bond formation

Indole framework is found in a variety of biologically active compounds (Figure

1.3).55-57 Therefore, development of novel methods for selective functionalization of indole has drawn much attention. While most of the research has focused on C-3 functionalization, several methods have also been developed for the N- functionalization.58-62 Since initial publications of Buchwald-Hartwig amination reaction, transition metal catalyzed C-N bond formation has been one of the most utilized transformation in organic synthesis.63-65

15

Figure 1.3 Examples of biological active N-functionalized indole derivatives

In this introduction, we have reviewed several methods of α-lactams preparation, their stability, nucleophilic ring opening reactions, transition metal catalyzed ring expansions and C-N bond formation. We have incorporated some of these concepts to develop a new methodology for transition metal catalyzed regioselective C-N bond formation between α-lactams and indoles.

1.7 Research goals

Nitrogen-containing heterocyclic compounds are extremely important due to their abundance in natural products and synthetic organic compounds that show biological activities. The construction of the C-N bond containing aromatic compounds is particularly important in areas of biologically active compounds. Initially, Rowland’s group has developed a methodology for rhodium-catalyzed regioselective coupling of highly stable 1,3-di-tert-butylaziridinone and 3-(tert-butyl)-1-tritylaziridinone with indole derivatives to construct the new class of compounds which possessed C-N bond and the

16

amino amide function (Figure 1.4). Based on the success of this methodology, we turned our attention to utilize this concept to less stable phenyl substituted α-lactams.66

Figure 1.4 Reaction of 1,3-di-tert-butylaziridinone and 3-(tert-butyl)-1- tritylaziridinone with indoles

Herein we report a new method development for the rhodium catalyzed coupling of less stable phenyl substituted α-lactams with indoles. All the phenyl substituted α- lactams were generated in situ and subsequently reacted with the indoles in the presence of rhodium catalyst. The developed method provides an atom-economical approach for the formation of C-N bond containing substituted α-amino amides with good to excellent yields.

Chapter II discuss the synthesis of α-bromoamides, optimizations of reaction conditions, the scope of indole derivatives, the scope of α-lactams and the proposed catalytic cycle.

Chapter III focuses on experimental procedures and characterization of newly synthesized compounds.

NOTE: This work and the rhodium catalyzed coupling of stable α-lactams with indoles has been published in Tetrahedron 2014, 70, 9709-9717.66 17

CHAPTER II

RHODIUM CATALYZED COUPLING OF IN SITU GENERATED ALPHA-

LACTAMS WITH INDOLES: RESULTS AND DISCUSSION

After the initial findings of the rhodium catalyzed C-N bond formation between the C-3 carbon atom of stable α-lactams and the nitrogen atom of indole derivatives, we turned our attention to the less stable phenyl substituted α-lactams to expand the scope of this methodology. As mentioned in the Introduction, in situ generation is a useful tool for utilization of the less stable α-lactams in nucleophilic ring opening reactions.

2.1 Synthesis of α-bromoamides

In this work, all α-lactams were generated in situ by α-bromoamides as a starting material. All the α-bromoamides reported herein were prepared using a modified procedure reported by Baumgarten and coworkers in 1985 (Scheme 2.1).29

Scheme 2.1 Synthesis of α-bromoamides (43-50)

Synthesis of α-bromoamides begins with well-known Hell-Volhard-Zelinsky reaction. Phenylacetic acid derivatives (35-42, Table 2.1) treated with PCl3 or SOCl2 in 18

the presence of Br2 to afford corresponding α-bromophenylacetyl chlorides. The α- bromophenylacetyl chlorides were then treated with tert-butylamine and diisopropylethylamine in DCM to yield α-bromoamides (43-50) in low to moderate yields (Table 2.1). The unsubstituted phenylacetic acid (35, entry 1), and m-CF3 substituted phenylacetic acid (41, entry 7) provided the highest yields of α-bromoamides.

A drop in yield was noted for the m-chloro-substituted compound (47, entry 5).

However, p-chloro-substituted phenylacetic acid (37) provided the higher yield of α- bromoamide (45) than the m-chloro analogs (entry 3). p-fluoro and o-iodo substituted compounds (36 and 42 respectively) provided moderately high yields of α-bromoamides

(44 and 50 respectively, entry 2 and 8). In addition, p-bromo and p-methyl phenylacetic acid (38 and 40 respectively) provided the lowest yields of α-bromoamides (46 and 48 respectively) when comparing to other para-substituted phenylacetic acid derivatives

(entry 4 and 6). The reactions seem to be not very sensitive to the structure and/or electronic properties of the substituents.

19

Table 2.1 Synthesis of α-bromoamides

2.2 Optimization of the reaction conditions

The optimization of the reaction conditions was done on the model system using

2-bromo-N-(tert-butyl)-2-phenylacetamide (43) as a starting material at room temperature. Unsubstituted indole was used as an indole derivative. We found that there was no significant improvement of the yield at higher temperatures. Potassium tert- butoxide, sodium tert-butoxide and sodium hydride bases were screened for the in situ generation of α-lactam 3 followed by reaction with indole in the presence of

[Rh(COD)Cl]2 in dry benzene (Table 2.2). Potassium tert-butoxide produces the highest yield of the desired ring opening product 51, while sodium tert-butoxide provided the second highest yield (entry 1 and 2). On the other hand, sodium hydride afforded only

20

the trace amount of the corresponding product (entry 3).7 The highest conversion of starting materials were observed when using 1.2 eq of potassium tert-butoxide.

Table 2.2 Optimization of base

In situ generation of α-lactam was confirmed and monitored by 1H NMR. The 1H

NMR of in situ generated N-tert-butyl-phenylaziridinone (3) in benzene-d6 is shown in

Figure 2.1. This study shows that α-bromoamide 43 was converted (> 90 %) into α- lactam 3 in 20-25 minutes. Extending the reaction times did not improve the product yield significantly.

21

Figure 2.1 1H NMR of (a) α-bromoamide 43 and (b) in situ generated α-lactam 3 in benzene-d6

The effects of the transition metal catalysts are summarized in Table 2.3. Based on the findings of rhodium-catalyzed ring opening of 8 with indoles (as mentioned in

Introduction), herein we considered a selected group of catalysts for the screening of their potential for this methodology. Only traces of the product 51 were obtained without the metal catalyst (entry 1). Pd(dba)2, [Ir(COD)Cl]2 and Rh(nbd)2(BF4) also provided the trace amount of the products (entry 2, 3 and 4). On the other hand, 10 mol% of

[Rh(COD)Cl]2 catalyst provided the highest yield of 90% (entry 5). While increasing the catalytic loading gave a slight increase in the product formation, it was not significant enough to justify the additional load of the catalyst for the reaction (entry 6).

22

Table 2.3 Optimization of catalyst

The effects of solvents shown in Table 2.4, indicate that the yield strongly depends on the solvent properties. The reaction in polar aprotic solvents such as THF and 1,4-dioxane provided only trace amounts of the products (entry 1 and 2).

Nonetheless, non-polar toluene and benzene provided the highest yields of 86% and 93% respectively (entry 3 and 4).

23

Table 2.4 Optimization of solvent

In summary, the highest yield for the reaction was achieved when using 1.2 eq of t-BuOK for the in situ generation of α-lactam in 20-25 min, followed by ring opening of

α-lactam with indole in the presence of 10 mol% of [Rh(COD)Cl]2 catalyst in dry benzene for 100 min at room temperature (Scheme 2.2). In addition, excess (0.4 eq) of potassium tert-butoxide was added to the reaction mixture after 70 minutes to convert any unreacted starting materials to corresponding products.

Scheme 2.2 Best reaction conditions for the in situ generation of α-lactam 3 and its ring opening with indole

24

2.3 N-Functionalization of indole derivatives with in situ generated N-tert-butyl- phenylaziridinone (3)

The coupling of a variety of substituted indoles with in situ generated 3 was studied with the optimized reaction conditions described in the previous section (Table

2.5). Relative to the product obtained from unsubstituted indole, moderate yield was observed for the 2-methyl indole (entry 2), an effect likely arising from the steric effects.

A similar explanation can be given to the 3-methyl and 5-methyl indoles giving slightly higher yields relative to the 2-methyl indole (entry 3 and 4 respectively). Surprisingly, with the methyl group in the 7-position an opposite effect was observed, affording the product in 93 % yield (entry 5).

7-iodoindole gives the highest yield of corresponding product (98 %, entry 6).

The reaction provided the desired products in good yields for both electron rich and electron deficient indole derivatives. Indole with the electron donating methoxy group at

5-position gives a similar yield of the product, as compared with the analog with electron withdrawing nitro group at the 5-position (entry 7 and 8).

25

Table 2.5 N-Functionalization of indole derivatives with in situ generated N-tert- butyl-phenylaziridinone (3)

2.4 The scope of in situ generated phenyl substituted α-lactams

The next focus was to determine the reaction scope in terms of the α-lactams

(Table 2.6). A series of α-lactams were generated in situ and then reacted with indole to assess the viability of this method. The reaction seems to be not very sensitive to the substituent size and/or electronic properties. p-Fluoro substituted amide provided the highest yield of desired product (90%, entry 1). Both p-chloro and p-bromo substituted amides produced moderate yields of 81% and 71% respectively (entry 2 and 3).

Increasing the electronegativity of the p-halo substituent seems to have a modest effect on the product yield. This is presumably due to a decrease in the C-N bond strength in

26

the phenyl substituted α-lactam, allowing for the more rapid oxidative addition of the transition metal catalyst to the α-lactam. A slight drop in yield was observed for the m- chloro-substituted amide (entry 4) in comparison with its para-substituted analog.

Moreover, the electron donating p-methyl substituted α-haloamide provided the lowest yield of 60% (entry 5). m-CF3 and o-iodo substituted amides produced 63% and 75% yields respectively (entry 6 and 7).

Table 2.6 The scope of in situ functionalized α-lactams

2.5 Proposed catalytic cycle

Based on the experimental results of this work and other group’s work published, a catalytic cycle is proposed for the rhodium catalyzed ring opening of α-lactams with

48,67,68 indoles (Scheme 2.3). The dimeric [Rh(COD)Cl]2 is cleaved by solvation to afford 27

complex I. Insertion of complex I into the C-3-N bond of the in situ generated α-lactam

II provided complex III. Ligand exchange of indole to complex III followed by a reductive elimination would give the corresponding ring opening product V. Since no rigorous investigation was done on the mechanism of this catalytic reaction, the more detailed description has not been attempted.

Scheme 2.3 Proposed catalytic cycle for rhodium catalyzed ring opening of α-lactams

(Sol represents a solvent molecule)

2.6 Conclusions

The novel rhodium catalyzed method was developed for the coupling of indoles with less stable phenyl substituted α-lactams. All phenyl substituted α-lactams were generated in situ from the corresponding α-bromoamides. The best yields for ring

28

opening products were achieved when using 1.2 eq of t-BuOK for the in situ generation of α-lactam in 20-25 min, followed by ring opening of indole in the presence of 10 mol% of [Rh(COD)Cl]2 catalyst in dry benzene for 100 min at room temperature. The reaction was found to be successful with the electron rich and electron poor indole derivatives.

The scope of this method was extended to the various phenyl substituted α-lactams including ortho, para, and meta substituted groups. The developed method provided desired C-3-N ring opening products in good to excellent yields. The produced α-amino amides would provide a new class of compounds to further functionalization and/or to be screened for their biologically-active properties.

29

CHAPTER III

RHODIUM CATALYZED COUPLING OF IN SITU GENERATED ALPHA-

LACTAMS WITH INDOLES: EXPERIMENTAL

3.1 General information

All reactions were performed using oven-dried glassware under Ar or N2 atmosphere. The reactions were monitored by TLC using Sorbent technology silica gel

TLC plates (UV 254). Flash chromatography was performed on a Biotage Isolera One system using silica gel. The following reagents were purchased and used as received.

Indole derivatives (Sigma-Aldrich), benzene (Sigma-Aldrich; anhydrous) and chloro

(1,5-cyclooctadiene) rhodium (I) dimer (Strem). The 1H NMR and 13C NMR were recorded on a Bruker AVANCE III 300 MHz and Bruker AVANCE III 600 MHz spectrometers. The chemical shifts were reported in ppm relative to the internal standard tetramethylsilane (TMS). High-resolution mass spectra (HRMS) were recorded on a

Bruker UHPLC-Micro-Q/T of MS/MS instrument. IR spectra were recorded on a

Thermo IR100 FT-IR. Melting points were determined using DigiMelt MPA160 melting point apparatus.

3.2 General procedure for the synthesis of α-bromoamides 43, 44, 45, 46, 47, 49 and 50

A two neck oven dried round bottom flask equipped with a magnetic stirrer and reflux condenser capped with a calcium chloride drying tube was charged with the

30

substituted phenylacetic acid (1.0 eq) and phosphorous trichloride (1.0 eq) in DCM.

Bromine (2.0 eq) was added dropwise at 0 °C, and the mixture was stirred at 70-90 °C for

1.5 h. After this time, an excess of bromine (0.4-0.6 eq) was added and the mixture was stirred further for 18 h. The reaction mixture was cooled to room temperature, poured into 150 mL of ice water, extracted with toluene (2 × 150 mL) and dried over anhydrous

Na2SO4. The residual bromine and toluene were removed under reduced pressure and the crude bromophenylacetyl chloride was used directly for the next step.

To a solution of tert-butylamine (1.0-1.1eq) in DCM, was added N,N’- diisopropylethylamine/triethylamine (1.0-2.0 eq) at room temperature. The mixture was cooled to 0 °C and the crude bromo(phenyl)acetyl chloride was added dropwise over 45-

60 min. The reaction mixture was warmed up to room temperature, and the mixture was stirred for further 3-5 h. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (hexanes/DCM) to afford α-bromoamide.

Scheme 3.1 Synthesis of 2-bromo-( N- tert-butyl)-2-phenylacetamide (43)

Phenyl acetic acid (15.0 mmol), phosphorous trichloride (15.0 mmol), bromine

(30.0 mmol, excess 9.0 mmol), tert-butylamine (15.0 mmol), N,N’-diisopropylethylamine

º (30.0 mmol), DCM (75 mL). White solid, 3.3g, 81% yield, mp: 134-136 C; Rf =

1 0.45(hexane/DCM = 1:3); H NMR (600 MHz, CDCl3) δ 7.43 (d, 2H, J = 7.2 Hz), 7.34-

13 7.29 (m, 3H), 6.56 (s, 1H), 5.33 (s, 1H), 1.37 (s, 9H); C NMR (600 MHz, CDCl3) δ 31

166.1, 137.8, 128.9, 128.8, 128.2, 52.1, 51.9, 28.4 ;IR: 3294, 1655, 1556, 1450, 1361,

-1 + 1260, 1222, 711, 694, 575 cm ; HRMS (ESI) m/z calculated for C12H17BrNO [M+H] :

270.0494; found: 270.0495.

Scheme 3.2 Synthesis of 2-bromo-( N- tert-butyl)-2-(4-fluorophenyl)acetamide (44)

(4-Fluorophenyl) acetic acid (18.0 mmol), phosphorous trichloride (18.0 mmol), bromine (36.0 mmol, excess 11 mmol), tert-butylamine (18.0 mmol), N,N’- diisopropylethylamine (36.0 mmol), DCM (75 mL). White solid, 2.9g, 56% yield, mp:

º 1 133-135 C; Rf = 0.41 (EtOAc/hexane 1:4); H NMR (600 MHz, CDCl3) δ 7.41 (dd, 2H, J

= 5.4, 8.4 Hz), 7.02 (t, 2H, J = 8.4 Hz), 5.32 (s, 1H), 1.39 (s, 9H); 13C NMR (600 MHz,

CDCl3) δ 165.9, 163.6 (d, J = 990 Hz), 133.8 (d, J = 12 Hz), 130.2 (d, J = 36 Hz), 115.9

(d, J = 84 Hz), 52.2, 50.8, 28.4; IR: 3295, 3072, 2982, 1653, 1555, 1507, 1361, 1224,

-1 + 1157, 760, 619, 534 cm ; HRMS (ESI) m/z calculated for C12H15BrFNO [M+H] :

288.0399; found: 288.0407.

Scheme 3.3 Synthesis of 2-bromo-( N- tert-butyl)-2-(4-chlorophenyl)acetamide (45)

32

(4-chlorophenyl) acetic acid (30.0 mmol), phosphorous trichloride (30.0 mmol), bromine (60.0 mmol, excess 11mmol), tert-butylamine (68.0 mmol), N,N’- diisopropylethylamine (77.0 mmol), DCM (50 mL). White solid, 6.6g, 72% yield, mp:

º 1 156-158 C. Rf=0.38 (EtOAc /hexane 1:4); H NMR (600 MHz, CDCl3) δ 7.37 (d, 2H, J =

8.4 Hz), 7.32 (d, 2H, J = 8.4 Hz), 6.48 (s, 1H), 5.28 (s, 1H), 1.39 (s, 9H); 13C NMR (600

MHz, CDCl3) δ 165.6, 136.5, 134.9, 129.7, 129.1, 52.3, 50.9, 28.4; IR: 3286, 3077, 2961,

1658, 1556, 1455, 1221, 1093, 835, 747, 607 cm-1; HRMS (ESI) m/z calculated for

+ C12H15BrClNNaO [M+Na] : 327.9903; found: 327.9901.

Scheme 3.4 Synthesis of 2-bromo-2-(4-bromophenyl)-N-(tert-butyl)acetamide (46)

(4-bromophenyl) acetic acid (4.9 mmol), phosphorous trichloride (4.9 mmol), bromine (9.8 mmol, excess 2.5 mmol), tert-butylamine (5.1 mmol), triethylamine (7.0

º mmol), DCM (50 mL). White solid, 0.5g, 30% yield, mp: 177-179 C; Rf = 0.38 (EtOAc

1 /hexane 1:4); H NMR (600 MHz, CDCl3) δ 7.49 (d, 2H, J = 8.4 Hz), 7.31 (d, 2H, J = 8.4

13 Hz), 6.48 (s, 1H), 5.27 (s, 1H), 1.39 (s, 9H); C NMR (600 MHz, CDCl3) δ 165.5, 137.0,

132.1, 129.9, 123.1, 52.3, 50.9, 28.39; IR: 3287, 3068, 2974, 1657, 1556, 1220, 1072,

-1 + 744, 603 cm ; HRMS (ESI) m/z calculated for C12H15Br2NNaO [M+Na] : 371.9398; found: 371.9394.

33

Scheme 3.5 Synthesis of 2-bromo-( N- tert-butyl)-2-(3-chlorophenyl)acetamide (47)

(3-chlorophenyl) acetic acid (18 mmol), phosphorous trichloride (18 mmol), bromine (36 mmol, excess 11mmol), tert-butylamine (18 mmol), N,N’- diisopropylethylamine (36 mmol), DCM (75 mL). White solid, 3.1g, 56% yield. mp:

º 1 124-127 C; Rf = 0.38 (EtOAc /hexane 1:4); H NMR (600 MHz, CDCl3) δ 7.41 (s, 1H),

13 7.30 (m, 3H), 6.56 (s, 1H), 5.26 (s, 1H), 1.40 (s, 9H); C NMR (600 MHz, CDCl3) δ

165.4, 139.7, 134.6, 130.2, 129.1, 128.5, 126.5, 52.3, 50.6, 28.4: IR: 3291, 3077, 2961,

1659, 1556, 1363, 1225, 1088, 830, 748 cm-1 ; HRMS (ESI) m/z calculated for

+ C12H15BrClNNaO [M+Na] : 327.9903; found: 327.9910.

Scheme 3.6 Synthesis of 2-bromo-( N- tert-butyl)-2-(3- (trifluoromethyl)phenyl)acetamide (49)

[3-(trifluoromethyl) phenyl] acetic acid (44.1 mmol), phosphorous trichloride

(44.1 mmol,), bromine (88.2 mmol, 2.0 eq, excess 22.0 mmol), tert-butylamine (48.5 mmol), triethylamine (66.2 mmol), DCM (250 mL). White solid, 12.7g, 85% yield. mp:

º 1 97-100 C; Rf = 0.38 (EtOAc /hexane 1:4); H NMR (600 MHz, CDCl3) δ 7.67 (s, 1H),

34

7.64 (d, 1H, J = 7.8 Hz), 7.59 (d, 1H, J = 7.8 Hz), 7.50 (t, 1H, J = 7.8Hz), 6.55 (s, 1H),

13 5.33 (s, 1H), 1.40 (s, 9H); C NMR (600 MHz, CDCl3) δ 165.3, 139.0, 131.8, 131.3 (q, J

= 132 Hz), 129.5, 125.7 (q, J = 12.0 Hz), 125.1 (q, J = 18.0 Hz), 124.6 (q, J = 1086.0

Hz), 52.4, 50.3, 28.4; IR: 3281, 3077, 2974, 1653, 1560, 1326, 1226, 1162, 1072, 786,

-1 + 694, 652, 576 cm ; HRMS (ESI) m/z calculated for C13H15BrF3NNaO [M+Na]

360.0187; found: 360.0180.

Scheme 3.7 Synthesis of 2-bromo-( N- tert-butyl)-2-(2-iodophenyl)acetamide (50)

(2-iodophenyl) acetic acid (10.0 mmol), phosphorous trichloride (10.0 mmol), bromine (20.0 mmol, 2.0 eq, excess 5.0 mmol), tert-butylamine (10.0 mmol, 1.0 eq),

N,N’-diisopropylethylamine (20.0 mmol, 2.0 eq), DCM (50 mL). White solid, 2.6 g, 64%

º 1 yield. mp: 118-120 C; Rf = 0.51 (DCM/hexane 3:1); H NMR (600 MHz, CDCl3) δ 7.83

(d, 1H, J = 8.4 Hz), 7.55 (d, 1H, J = 7.8 Hz), 7.35 (t, 1H, J = 7.8 Hz), 6.97 (t, 1H, J = 7.8

13 Hz), 6.58 (s, 1H), 5.65 (s, 1H), 1.40 (s, 9H); C NMR (600 MHz, CDCl3) δ 165.2, 140.6,

139.8, 130.3, 129.1, 129.1, 100.7, 56.0, 52.3, 28.3; IR: 3266, 3063, 2961, 1647, 1550,

1354, 1223, 1010, 747, 725, 646, 558 cm-1; HRMS (ESI) m/z calculated for

+ C12H15BrINNaO [M+Na] : 417.9279; found: 417.9279.

35

3.3 Procedure for the synthesis of α-bromoamide 48.

Scheme 3.8 Synthesis of 2-bromo-( N- tert-butyl)-2-(4-methylphenyl)acetamide (48)

2-bromo-N-(tert-butyl)-2-(4-methylphenyl)acetamide (48) was prepared from a slightly modified general procedure. To a solution of (4-methylphenyl)acetic acid (12 mmol) in chloroform (15 mL) was added dimethylformamide (2 drops) at room temperature. The mixture was cooled to 0 ºC and thionyl chloride (18 mmol) was added slowly. The mixture was allowed to warm to room temperature. After 2 h, bromine

(14.4 mmol, excess 11 mmol) was added dropwise, and the resulting mixture was allowed to stir at 80 ºC for 16 h. The reaction mixture was cooled to room temperature, poured into 150 mL of ice water, extracted with toluene (2 × 150 mL) and dried over anhydrous Na2SO4. The residual bromine and solvent were removed under reduced pressure and crude 2-bromo-2-(methylphenyl)acetyl chloride was used directly for the next step. N,N’-diisopropylethylamine (24 mmol) was charged to a solution of tert- butylamine (18 mmol) in DCM (50 mL). The reaction mixture was cooled to 0ºC and the crude 2-bromo-2-(methylphenyl)acetyl chloride was added slowly over 45-60 min. The reaction mixture was allowed to warm up to room temperature and the mixture was stirred for further 3-5 h. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (hexanes/EtOAc). White solid, 0.8 g, 24%

º 1 yield. mp: 135-138 C; Rf = 0.44 (EtOAc/hexane 1:4); H NMR (600 MHz, CDCl3) δ 7.32 36

(d, 2H, J = 7.8 Hz), 7.17 (d, 2H, J = 7.8 Hz), 6.53 (s, 1H), 5.33 (s, 1H), 2.33 (s, 3H), 1.39

13 (s, 9H); C NMR (600 MHz, CDCl3) δ 166.1, 139.0, 134.9, 129.6, 128.1, 52.2, 52.1,

28.4, 21.2; IR: 3300, 3072, 2965, 2922, 1655, 1556, 1449, 1358, 1208, 757, 641 cm-1 ;

+ HRMS (ESI) m/z calculated for C13H18BrNNaO [M+Na] : 306.0469; found: 306.0457.

3.4 Reactions of indole derivatives with in situ generated α-lactam

3.4.1 General procedure.

2-bromo-N-(tert-butyl)-2-phenylacetamide (43) (0.19 mmol) and t-BuOK (0.23 mmol) were placed in a screw top vial while indole derivatives (0.095 mmol) and

[Rh(COD)Cl]2 (0.0095 mmol) were placed in a separate vial under argon. Benzene (0.7 mL) was then added to the mixture of 43 and t-BuOK, and the mixture was stirred at room temperature for 20-25 minutes. After this time, benzene (0.8 mL) was added to the mixture of indole derivative and [Rh(COD)Cl]2 and the solution was transferred to the vial containing in situ generated α-lactam. The reaction mixture was stirred at room temperature for 100 minutes. (excess 0.4 eq t-BuOK was added after 70 min). After this time, the reaction mixture was diluted with DCM and filtered through a plug of silica gel.

The crude reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (hexanes/DCM).

Scheme 3.9 Synthesis of N-(tert-butyl)-2-(1H-indol-1-yl)-2-phenylacetamide (51)

37

º White solid, 26.2 mg, 90% yield, mp = 174-177 C; Rf = 0.25 (DCM/hexane 1:1);

1 H NMR (600 MHz, CDCl3) δ 7.64 (d, 1H, J = 7.8 Hz), 7.39-7.33 (m, 6H), 7.23 (t, 1H, J

= 7.8 Hz), 7.15 (t, 1H, J = 7.8 Hz), 6.86 (d, 1H, J = 3.0 Hz), 6.52 (d, 1H, J = 3.0 Hz), 6.01

13 (s, 1H), 5.35 (s, 1H), 1.25 (s, 9H); C NMR (600 MHz, CDCl3) δ 168.2, 136.6, 135.6,

129.0, 128.9, 128.8, 128.7, 126.0, 122.3, 121.3, 120.5, 109.6, 103.1, 64.7, 51.8, 28.5; IR:

3287, 3081, 2971, 1649, 1557, 1478, 1362, 1214, 796, 757, 702 cm-1; HRMS (ESI) m/z

+ calculated for C20H22N2NaO [M+Na] : 329.1630; found: 329.1623.

Scheme 3.10 Synthesis of N-(tert-butyl)-2-(2-methyl-1H-indol-1-yl)-2-phenylacetamide (52)

º White solid, 20.5 mg, 67% yield, mp =161-164 C; Rf = 0.21 (DCM/hexane 1:1);

1 H NMR (600 MHz, CDCl3) δ 7.53 (d, 1H, J = 7.2 Hz), 7.31-7.25 (m, 3H), 7.22 (d, 2H, J

= 7.2 Hz), 7.06 (dd, 1H, J = 7.8, 6.6 Hz), 6.99 (dd, 1H, J = 8.4, 6.6 Hz), 6.96 (d, 1H, J =

7.8 Hz), 6.37 (s, 1H), 6.10 (s, 1H), 5.48 (s, 1H), 2.35 (s, 3H), 1.26 (s, 9H); 13C NMR (600

MHz, CDCl3) δ 167.4, 137.1, 136.3, 135.5, 128.8, 128.6, 128.0, 127.9, 121.2, 120.2,

120.0, 111.0, 102.7, 62.5, 51.8, 28.5, 13.7; IR: 3329, 3064, 2956, 1661, 1542, 1497,

-1 1368, 1218, 1021, 718, 691, 629 cm ; HRMS (ESI) m/z calculated for C21H25N2O

[M+H]+: 321.1967; found: 321.1966.

38

Scheme 3.11 Synthesis of N-(tert-butyl)-2-(3-methyl-1H-indol-1-yl)-2-phenylacetamide (53)

º White solid , 24.3 mg, 80% yield, mp = 186-189 C; Rf = 0.18 (DCM/hexane 1:1);

1 H NMR (600 MHz, CDCl3) δ 7.57 (d, 1H, J = 7.8 Hz), 7.40-7.36 (m, 3H), 7.34-7.30 (m,

3H), 7.23 (t, 1H, J = 7.8 Hz), 7.16 (t, 1H, J = 7.8 Hz), 6.61 (s, 1H), 5.96 (s, 1H), 5.39 (s,

13 1H), 2.26 (s, 3H), 1.25 (s, 9H); C NMR (600 MHz, CDCl3) δ 168.5, 137.0, 135.9,

129.3, 129.0, 128.7, 128.6, 123.3, 122.3, 119.8, 119.3, 112.3, 109.5, 64.5, 51.7, 28.5, 9.7;

IR: 3307, 3085, 2970, 1651, 1553, 1464, 1360, 1223, 1196, 796, 741, 694 cm-1; HRMS

+ (ESI) m/z calculated for C21H25N2O [M+H] : 321.1967; found: 321.1964.

Scheme 3.12 Synthesis of N-(tert-butyl)-2-(5-methyl-1H-indol-1-yl)-2-phenylacetamide (54)

39

º White solid, 23.4 mg, 77% yield, mp =187-189 C; Rf= 0.21 (DCM/hexane 1:1);

1 H NMR (600 MHz, CDCl3) δ 7.42 (s, 1H), 7.39- 7.32 (m, 5H), 7.24 (dd, 1H, J = 9.6, 1.2

Hz), 7.06 (dd, 1H, J = 8.4, 1.2 Hz), 6.81 (d, 1H, J = 3.6 Hz), 6.43 (d, 1H, J = 3.0 Hz),

13 5.98 (s, 1H), 5.37 (s, 1H), 2.44 (s, 3H), 1.25 (s, 9H); C NMR (600 MHz, CDCl3) δ

168.3, 135.7, 135.0, 129.7, 129.2, 129.0, 128.7, 128.7, 126.0, 123.9, 120.9, 109.3, 102.6,

64.8, 51.7, 28.5, 21.4; IR: 3286, 3085, 2970, 1649, 1559, 1477, 1452, 1362, 1214, 1034,

-1 + 869, 702, 608 cm ; HRMS (ESI) m/z calculated for C21H25N2NaO [M+Na] : 343.1786; found: 343.1763.

Scheme 3.13 Synthesis of N-(tert-butyl)-2-(7-methyl-1H-indol-1-yl)-2-phenylacetamide (55)

º White solid, 28.2 mg, 93% yield, mp =170-173 C; Rf= 0.29 (DCM/hexane 1:1);

1 H NMR (600 MHz, CDCl3) δ 7.47 (d, 1H, J = 7.8 Hz), 7.40-7.36 (m, 3H), 7.32 (d, 2H, J

= 7.2 Hz), 7.03 (t, 1H, J = 7.2 Hz), 6.97 (d, 1H, J = 7.2 Hz), 6.73 (s, 1H), 6.56 (s, 1H),

13 6.49 (s, 1H), 5.19 (s, 1H), 2.75 (s, 3H), 1.25 (s, 9H); C NMR (600 MHz, CDCl3) δ

169.2, 136.6, 135.8, 129.9, 129.0, 128.9, 128.6, 126.6, 125.7, 121.2, 120.6, 119.5, 103.6,

66.3, 51.7, 28.4, 20.3; IR: 3300, 3060, 2930, 1665, 1547, 1452, 1392, 1306, 1223, 1203,

-1 + 1082, 781, 722, 696 cm ; HRMS (ESI) m/z calculated for C21H25N2O [M+H] : 321.1967; found: 321.1973.

40

Scheme 3.14 Synthesis of N-(tert-butyl)-2-(5-iodo-1H-indol-1-yl)-2-phenylacetamide (56)

º White solid , 40.2 mg, 98% yield, mp = 206-208 C; Rf = 0.18 (DCM/hexane 1:1);

1 H NMR (600 MHz, CDCl3) δ 7.96 (s, 1H), 7.46 (d, 1H, J = 8.4 Hz), 7.39 (d, 3H, J = 5.4

Hz), 7.29 (d, 2H, J = 6.0 Hz), 7.11 (d, 1H, J = 8.4 Hz), 6.86 (d, 1H, J = 3.0 Hz), 6.44 (d,

13 1H, J = 3.0 Hz), 5.94 (s, 1H), 5.36 (s, 1H), 1.27 (s, 9H); C NMR (600 MHz, CDCl3) δ

167.6, 135.6, 135.2, 131.4, 130.5, 130.1, 129.1, 128.9, 128.5, 127.0, 111.5, 102.2, 84.0,

64.7, 51.9, 28.5; IR: 3290, 3077, 2965, 1648, 1557, 1452, 1362, 1218, 1090, 794, 772,

-1 + 693 cm ; HRMS (ESI) m/z calculated for C21H21IN2NaO [M+Na] : 455.0596 ; found:

455.0558.

Scheme 3.15 Synthesis of N-(tert-butyl)-2-(2-methyl-5-methoxy-1H-indol-1-yl)-2- phenylacetamide (57)

º White solid , 23.2 mg, 70% yield, mp =131-133 C; Rf= 0.20 (DCM/hexane 1:1);

1 H NMR (600 MHz, CDCl3) δ 7.31-7.29 (m, 3H), 7.22 (d, 2H, J = 7.2 Hz), 6.99 (s, 1H), 41

6.79 (d, 1H, J = 9.0 Hz), 6.64 (dd, 1H, J = 7.2, 1.8 Hz), 6.29 (s, 1H), 6.04 (s, 1H), 5.47

13 (s,1H), 3.81 (s, 3H), 2.34 (s, 3H), 1.26 (s, 9H); C NMR (600 MHz, CDCl3) δ 167.4,

154.3, 137.8, 135.6, 131.3, 129.4, 128.6, 128.0, 127.9, 111.8, 110.8, 102.4, 102.2, 62.6,

55.7, 51.7, 28.6, 13.7; IR: 3313, 3076, 2965, 1660, 1509, 1451, 1331, 1290, 1216, 1071,

-1 + 751, 726, 696 cm ; HRMS (ESI) m/z calculated for C22H26N2NaO2 [M+Na] : 373.1892; found: 373.1877.

Scheme 3.16 Synthesis of N-(tert-butyl)-2-(2-methyl-5-nitro-1H-indol-1-yl)-2- phenylacetamide (58)

º 1 White solid, 22.0 mg, 63% yield, mp = 73-75 C; Rf= 0.15 (DCM/hexane 1:1); H

NMR (600 MHz, CDCl3) δ 8.45 (d, 1H, J = 1.8 Hz), 7.91 (dd, 1H, J = 9.0, 1.8 Hz), 7.35

(d, 3H, J = 4.8 Hz), 7.18 (d, 2H, J = 4.8 Hz), 7.04 (d, 1H, J = 9.0 Hz), 6.54 (s, 1H), 6.10

13 (s, 1H), 5.50 (s, 1H), 2.41 (s, 3H), 1.32 (s, 9H); C NMR (600 MHz, CDCl3) δ 166.3,

141.9, 140.8, 139.5, 134.7, 129.1, 128.7, 128.0, 127.7, 116.9, 116.8, 110.9, 104.4, 63.2,

52.3, 28.5, 13.8; IR: 3313, 3068, 2965, 1660, 1509, 1451, 1331, 1290, 1216, 1071, 752,

-1 + 726, 696 cm ; HRMS (ESI) m/z calculated for C21H23N3NaO3 [M+Na] : 388.1637; found: 388.1623.

42

3.4.2 Reactions of in situ generated phenyl substituted α-lactams with indole

α-bromoamide (0.19 mmol) and t-BuOK (0.23 mmol) were placed in a screw top vial while indole (0.095 mmol) and [Rh(COD)Cl]2 (0.0095 mmol) were placed in a separate vial under argon. Benzene (0.7 mL) was then added to the mixture of α- bromoamide and t-BuOK, and the mixture was stirred at room temperature for 20-25 minutes. After this time, benzene (0.8 mL) was added to the mixture of indole derivative and [Rh(COD)Cl]2 and the solution was transferred to the vial containing in situ generated α-lactam. The reaction mixture was stirred at room temperature for 100 minutes (excess 0.4 eq t-BuOK was added after 70 min). After this time, the reaction mixture was diluted with DCM and filtered through a plug of silica gel. The crude reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (hexanes/DCM).

Scheme 3.17 Synthesis of N-(tert-butyl)-2-(4-fluorophenyl)-2-( 1H-indol-1-yl)acetamide (66)

º White solid, 27.6 mg, 90% yield, mp = 174-177 C; Rf = 0.38 (DCM/hexane 3:1);

1 H NMR (600 MHz, CDCl3) δ 7.65 (d, 1H, J = 7.8 Hz), 7.34-7.30 (m, 3H), 7.24 (t, 1H, J

= 7.8 Hz), 7.17 (t, 1H, J = 7.8 Hz), 7.07 (t, 2H, J = 8.4 Hz), 6.86 (d, 1H, J = 3.0 Hz), 6.54

13 (d, 1H, J = 3.0 Hz), 5.99 (s, 1H), 5.35 (s, 1H), 1.25 (s, 9H); C NMR (600 MHz, CDCl3)

43

δ 168.0, 163.6 (d, J = 990 Hz), 136.5, 131.5 (d, J = 12 Hz), 130.5 (d, J = 36 Hz), 129.0,

125.8, 122.5, 121.4, 120.6, 116.1 (d, J = 84 Hz), 109.6, 103.4, 63.9, 51.9, 28.5; IR: 3283,

3081, 2969, 1648, 1508, 1460, 1217, 1161, 810, 763, 742 cm-1; HRMS (ESI) m/z

+ calculated for C20H21FN2NaO [M+Na] : 347.1536; found 347.1514.

Scheme 3.18 Synthesis of N-(tert-butyl)-2-(4-chlorophenyl)-2-( 1H-indol-1-yl)acetamide (67)

º White solid, 26.1 mg, 81% yield, mp = 143-146 C; Rf = 0.35 (DCM/hexane 3:1);

1 H NMR (600 MHz, CDCl3) δ 7.65 (d, 1H, J = 7.8 Hz), 7.35 (d, 2H, J = 8.4 Hz), 7.32 (d,

1H, J = 7.8 Hz), 7.24-7.20 (m, 3H), 7.16 (t, 1H, J = 7.2 Hz), 6.87 (d, 1H, J = 3.0 Hz),

6.55 (d, 1H, J = 3.0 Hz), 5.98 (s, 1H), 5.35 (s, 1H), 1.25 (s, 9H); 13C NMR (600 MHz,

CDCl3) δ 167.7, 136.5, 134.7, 134.2, 130.0, 129.2, 129.0, 125.8, 122.5, 121.4, 120.7,

109.6, 103.6, 63.9, 51.9, 28.5; IR: 3283, 3085, 2969, 1648, 1557, 1460, 1362, 1217,

-1 + 1094, 805, 763, 742 cm ; HRMS (ESI) m/z calculated for C20H21ClN2NaO [M+Na] :

363.1240; found: 363.1228.

44

Scheme 3.19 Synthesis of 2- (4-bromophenyl)-N-(tert-butyl)-2-(1H-indol-1- yl)acetamide (68)

º White solid, 26.1 mg, 71% yield, mp = 159-161 C; Rf = 0.38 (DCM/hexane 3:1);

1 H NMR (600 MHz, CDCl3) δ 7.65 (d, 1H, J = 7.8 Hz), 7.51 (d, 2H, J = 7.8 Hz), 7.32 (d,

1H, J = 8.4 Hz), 7.24 (d, 1H, J = 7.8 Hz), 7.20-7.15 (m, 3H), 6.87 (s, 1H), 6.55 (s, 1H),

13 5.96 (s, 1H), 5.34 (s, 1H), 1.25 (s, 9H); C NMR (600 MHz, CDCl3) δ 167.6, 136.4,

134.7, 132.2, 130.3, 128.9, 125.8, 122.9, 122.5, 121.4, 120.7, 109.6, 103.6, 64.0, 51.9,

28.5; IR: 3291, 3081, 2969, 1647, 1557, 1489, 1460, 1217, 1074, 1013, 800, 734, 713 cm-

1 + HRMS (ESI) m/z calculated for C20H21BrKN2O [M+K] :423.0474; found: 423.0453.

Scheme 3.20 Synthesis of N-(tert-butyl)-2-(3-chlorophenyl)-2-( 1H-indol-1-yl)acetamide (69)

White solid, 22.8 mg, 70% yield, mp = 195-198 ºC; Rf = 0.38 (DCM/hexane

3:1); 1H NMR (600 MHz, CDCl3) δ 7.65 (d, 1H, J = 8.4 Hz), 7.35-7.30 (m, 4H), 7.25 (t,

1H, J = 7.2 Hz), 7.21 (d, 1H, J = 7.2 Hz), 7.17 (t, 1H, J = 7.2 Hz), 6.89 (d, 1H, J = 3.0

45

Hz), 6.57 (d, 1H, J = 3.0 Hz), 5.98 (s, 1H), 5.35 (s, 1H), 1.26 (s, 9H); 13C NMR (600

MHz, CDCl3) δ 167.4, 137.6, 136.5, 134.9, 130.2, 129.0, 128.9, 128.8, 126.8, 125.8,

122.6, 121.4, 120.7, 109.5, 103.6, 64.0, 51.9, 28.5; IR: 3283, 3090, 2965, 1651, 1561,

-1 1461, 1214, 782, 762, 738 cm ; HRMS (ESI) m/z calculated for C20H21ClN2NaO

[M+Na]+: 363.1240; found: 363.1236.

Scheme 3.21 Synthesis of N-(tert-butyl)-2-(1H-indol-1-yl)-2-(4- methylphenyl)acetamide (70)

White solid, 18.2 mg, 60% yield, mp = 162-165 ºC; Rf = 0.36 (DCM/hexane 3:1);

1H NMR (600 MHz, CDCl3) δ 7.65 (d, 1H, J = 7.8 Hz), 7.37 (d, 1H, J = 7.8 Hz), 7.26 (d,

3H, J = 8.4 Hz), 7.21 (d, 2H, 7.8 Hz), 7.16 (t, 1H, J = 7.8 Hz), 6.86 (d, 1H, J = 3.0 Hz),

6.52 (d, 1H, J = 3.0 Hz), 5.98 (s, 1H), 5.33 (s, 1H), 2.36 (s, 3H), 1.25 (s, 9H); 13C NMR

(600 MHz, CDCl3) δ 168.4, 138.7, 136.4, 132.4, 129.7, 128.8, 128.6, 125.9, 122.2,

121.2, 120.4, 109.6, 102.9, 64.4, 51.7, 28.4, 21.2; IR: 3283, 3081, 2974, 2922, 1647,

1556, 1453, 1307, 1208, 787, 752, 741 cm-1; HRMS (ESI) m/z calculated for

+ C21H24N2NaO [M+Na] : 343.1786; found: 343.1794.

46

Scheme 3.22 Synthesis of N-(tert-butyl)-2-(1H-indol-1-yl)-2-[4- (trifluoromethyl)phenyl]acetamide (71)

º White solid, 22.4 mg, 63% yield, mp = 188-191 C; Rf = 0.47 (DCM/hexane 3:1);

1 H NMR (600 MHz, CDCl3) δ 7.66 (d, 1H, J = 7.8 Hz), 7.63 (d, 2H, J = 5.4 Hz), 7.52-

7.49 (m, 2H), 7.34 (d, 1H, J = 7.8 Hz), 7.27 (d, 1H, J = 7.2 Hz), 7.18 (t, 1H, J = 7.8 Hz),

6.86 (d, 1H, J = 3.0 Hz), 6.58 (d, 1H, J = 3.0 Hz), 6.06 (s, 1H), 5.37 (s, 1H), 1.26 (s, 9H);

13 C NMR (600 MHz, CDCl3) δ 167.3, 136.7, 136.5, 132.0, 131.3 (q, J = 132.0 Hz),

129.5, 128.9, 125.6, 125.5, 124.7, 122.9, 122.7, 121.5, 120.8, 109.5, 103.9, 64.0, 52.0,

28.5; IR: 3296, 3076, 2965, 1657, 1552, 1458, 1329, 1207, 1163, 1122, 1074, 743, 700

-1 + cm ; HRMS (ESI) m/z calculated for C21H21F3N2NaO [M+Na] : 397.1504; found:

397.1474.

Scheme 3.23 Synthesis of N-(tert-butyl)-2-(1H-indol-1-yl)-2- (2-iodophenyl) acetamide (72)

47

º White solid, 30.7 mg, 75% yield, mp = 189-191 C; Rf = 0.19 (DCM/hexane 3:1);

1 H NMR (600 MHz, CDCl3) δ 7.90 (d, 1H, J = 7.8 Hz), 7.66 (d, 1H, J = 7.8 Hz), 7.39-

7.37 (m, 2H), 7.23 (t, 2H, J = 7.8 Hz), 7.22 (d, 1H, J = 7.8 Hz), 7.17 (t, 1H, J = 7.8 Hz),

7.06 (t, 1H, J = 7.8 Hz), 6.84 (d, 1H, J = 3.0 Hz), 6.57 (d, 1H, J = 3.0 Hz), 6.17 (s, 1H),

5.39 (s, 1H), 1.28 (s, 9H); 13C NMR (600 MHz, CDCl3) δ 167.4, 140.1, 138.6, 136.5,

130.3, 129.0, 128.8, 128.6, 125.4, 122.4, 121.2, 120.5, 109.7, 103.3, 101.4, 68.5, 51.9,

28.4;IR: 3292, 3051, 2952, 1656, 1544, 1457, 1310, 1221, 1010, 733, 575 cm-1; HRMS

+ (ESI) m/z calculated for C20H21IN2NaO [M+Na] : 455.0596; found: 455.0588.

48

CHAPTER IV

SYNTHESIS AND SURFACE IMMOBILIZATION OF BIS-CORANNULENE

MOLECULAR RECEPTORS: INTRODUCTION

Supramolecular chemistry (chemistry beyond the molecule) is the branch of chemistry concerned with the interplay between the intermolecular forces and designed molecular assemblies.69,70 Non-covalent interactions such as hydrogen bonding, Van der

Waals forces, etc., are responsible for holding together the molecules of supramolecular complexes. Hydrogen bonding is a specific type of electrostatic interaction that involves the interaction between hydrogen atom bound to small highly electronegative atom such as nitrogen, oxygen or fluorine, and other nearby electronegative atom. Van der Waals forces are driven by dipole-dipole, dipole-induced dipole and London dispersion forces.

The concept of supramolecular chemistry was first proposed by Fisher in 1890s for biological systems and he introduced the idea of molecular recognition and host-guest chemistry for the enzyme-substrate interactions.71 Based on the findings of non-covalent interactions of natural systems, scientists began to study synthetic systems based on non- covalent interactions. Cram, Lehn, and Pedersen, 1987 Nobel Prize winners, examined the inclusion chemistry of simple molecular hosts such as crown ether (73), cryptands

(74), cavitands (75), and carcerands (76, Figure 4.1).72-77

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Figure 4.1 Early supramolecular host molecules crown ether (73), cryptands (74), cavitands (75), and carcerands (76)

These hosts bind to a variety of guests through noncovalent interactions. Crown

+ + 74 ether (73) and cryptands (74) form host-guest complexes with cations like K and NH4 .

Cavitands (75) and carcerands (76) form complexes with small molecules such as benzene, chloroform, and acetonitrile.72

4.1 Molecular receptors for fullerenes

Fullerenes (77), representing the third known allotrope of carbon, were discovered in the mid 1980s.78 The 1996 Nobel Prize in chemistry was awarded to Smalley, Carl, and Kroto for their discovery of fullerenes. Most famous fullerene molecule is C60 with sixty sp2 hybridized carbon atoms forming the 3D network containing 20 hexagonal and

12 pentagonal rings (Figure 4.2).78

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Figure 4.2 Structure of Buckminterfullerene (77)

One of the active fields in fullerene chemistry is the development of molecular receptors that can form stable complexes in the solid state and in solutions. There are at least two major reasons to design and synthesize molecular receptors for fullerenes: (1)

For the separation of different size and/or shape fullerenes, and (2) amalgamation of fullerenes with receptors for the novel materials, potentially applicable in nanoscale electronic devices.79 The unique physical and chemical properties (electronic, magnetism, conductivity, etc.) of fullerenes have promised their potential applications in nanotechnology and material chemistry.

Stabilization of the supramolecular complexes of fullerenes depends essentially on van der Waals and solvophobic interactions between fullerenes and their receptors.

The first receptor for fullerenes was designed and synthesized by Ringsdorf, Diederich and coworkers in 1992.80 They utilized aza-crown ethers (78 and 79, Figure 4.3) as macrocyclic scaffolds and decorated with lipophilic fragments through N-alkylation or acylation.

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Figure 4.3 Chemical structures of the azacrown receptors (78 and 79) for fullerenes

The ability of other macrocyclic moieties such as calix[6]arenes (80)81, calix[5]arenes (81)82, double calix[5]arenes (82)83, porphyrin (83)84, π-extended tetrathiafulvalene (ex-TTF, 84)85 and cyclotriveratrylenes86 (85) to associate with fullerenes has also been studied (Figure 4.4).

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Figure 4.4 Structures of macrocyclic receptors (80-85) for fullerenes

4.2 Corannulene based molecular receptors for fullerenes.

Corannulene (86) is the smallest subunit of the fullerenes, containing 20 carbon and 10 hydrogen atoms, which still maintains a curved surface (Figure 4.5).87 Highly nonplanar corannulene consists of five benzene rings arranged around the central five- membered ring with concave and convex faces of the carbon network (Figure 4.5). The curvature of corannulene gives unique properties that are not observed in planar polyaromatic hydrocarbon analogs.

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Figure 4.5 Structure of corannulene (86, left) and its convex and concave faces (right)

Molecular receptors with corannulene pincers have attracted considerable interest in host-guest complex formation with fullerene because the concave face of corannulene nicely fits the convex fullerene surface. This type of interaction between the fullerene surface and corannulene provides the favorable π-π stacking interactions which can be utilized in the design and synthesis of the efficient receptors. Moreover, molecular receptors with two or more corannulene pincers can be designed to encapsulate fullerene much more effectively than the single corannulene analogs.

The first corannulene-based receptor for fullerene was reported by Mizyed and coworkers in 2001 (Figure 4.6).87 The association constant estimated by 1H NMR

-1 titration experiments in toluene-d8 was 1,420 ± 54 M for C60@89. However, the association constants of receptors 87 and 88 were much lower in comparison with 89.88

The relatively high association constant for C60@89 was attributed to the presence of peripheral electron donating groups in 89, most likely due to favorable interactions with the electron deficient C60.

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Figure 4.6 First reported corannulene based receptors (87-89) for fullerenes

In 2003, Sygula and coworkers synthesized the first potential molecular receptor

(90) for fullerenes with two corannulene pincers preorganized on the barrelene tether

(Figure 4.7).89 Unfortunately, the complexation of 90 with fullerenes was not detected neither in solution nor in the solid state.

Figure 4.7 Barrelene based molecular receptor 90

The successful molecular receptor for fullerene based on corannulene was synthesized by Sygula and co-workers in 2007 and it was named “Buckycatcher I” (93).

55

This molecular receptor consists of two corannulene subunits linked through a tetrabenzocyclooctatetraene tether (Scheme 4.1).90 The molecular receptor 93 forms

-1 stable 1:1 inclusion complexes with C60, with Ka = 2,780 ± 80 M in toluene-d8, and 520

-1 91 ± 20 M in chlorobenzene-d5. Formation of a C60@93 complex was also observed in the solid state by X-ray crystal structure determination.

Scheme 4.1 Synthesis of molecular receptor 93

In 2013, Yanney and Sygula reported another example for corannulene-based molecular receptor (94) for fullerenes (Figure 4.8), possessing three corannulene pincers linked to the cyclotriveratrylene tether via ether bonds.92 1H NMR titration experiment in toluene-d8 suggested the formation of 1:1 fullerene@94 complexes and provided the Ka

-1 of 1,500 ± 50 and 1,180 ± 30 M for C60 and C70 respectively. Nonetheless, receptor 94 has a lower affinity for fullerenes as compared to buckycatcher 93, even though 94 has an additional corannulene unit. This variation of binding affinity was explained by the severe entropy and solvation penalties associated with the supramolecular complex formation in solution.92

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Figure 4.8 Structure of receptor 94

Another type of the molecular tweezers with corannulene pincers was reported by

Alvarez and coworkers.93 Tweezer 95 consist of 1,2-bis(diphenylphosphino)ethane ligand (dppe) and two ethynyl units with corannulene groups coordinated to a platinum metal center to form a square planar complex (Figure 4.9). This receptor shows a high

-1 binding affinity towards C70 (Ka = 20,700 ± 600 M ) but significantly lower affinity

-1 towards C60 (Ka = 4,600 ± 100 M ).

Figure 4.9 Structure of molecular receptor 95 57

In 2015, the same research group reported the synthesis of molecular receptors using “click chemistry” between ethynyl corannulene and various azides (Figure 4.10).94

-1 -1 The binding affinities of 96 and 97 for C60 were 2,150 ± 300 M and 2,190 ± 50 M respectively. Receptor 98 consist of two corannulene subunits linked to hexahelicene has a binding affinity of 2,550 ± 140 M-1. All three receptors exhibiting very similar affinity towards C60; again underlining the importance of a proper alignment of the pincers.

Figure 4.10 Structures of molecular receptors 96-98

A molecular receptor with two corannulene subunits and a norbornadiene tether

95 “Buckycatcher II” (99, C51H24, Figure 4.11) was recently synthesized in our group.

This receptor forms the usual 1:1 C60@99 inclusion complexes as well as a trimeric

C60@992 complex that shows a remarkable nanometric universal joint structure in the solid state. The measured binding constants of C60 in chlorobenzene-d5 are 10,000 ±

-1 -1 1,000 M and 1,200 ± 600 M for K1 and K2 respectively.

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Figure 4.11 Structure of Buckycatcher II

Most recently, two novel bis-corannulene molecular receptors 100 and 101 with

Kläner’s tethers were synthesized by our group (Figure 4.12).96 1H NMR titration experiments in chlorobenzene-d5 demonstrated that while receptor 100 binds both C60 and

C70 with similar affinity to the previously reported corannulene-based receptors, 101 shows the record-breaking affinity towards fullerenes with the association constant higher by approximately two orders of magnitude.96 Similarly to 99, both the usual 1:1

C70@101 inclusion complex and the trimeric C70@1012 complex are formed in

-1 chlorobenzene-d5. The estimated values for C70@101 were K1 = 200,000 ± 70,000 M

-1 and K2 = 33,000 ± 9,000 M .

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Figure 4.12 Molecular receptors 100 and 101 with Kläner’s tethers

In summary, various types of bis- and tris-corannulene based efficient receptors for fullerenes preorganized on different tethers have been reported by us and other groups. Learning from these reports, we turned our attention to synthesize efficient molecular receptors for fullerenes with polar groups on their tethers. The presence of polar groups on tethers allow to immobilize these receptors on solid support like silica gel. The synthesis of these receptors can be achieved from the Diels-Alder cycloaddition of corannulene-based polyaromatic hydrocarbon which possessed pentacene core with proper dienophiles. These PAHs with pentacene core can be synthesized by benzyne chemistry. The next sections of this Introduction focused on the acenes, bis-arynes and their reactivity towards Diels-Alder cycloaddition reactions.

4.3 Acenes and their reactivity towards Diels-Alder cycloaddition

Acenes are the most extended class of fused polyaromatic hydrocarbons (PAHs).

The smallest unit is naphthalene (102), followed by anthracene (103), tetracene (104),

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pentacene (105) etc.97 The structures of some linear acenes are shown in Figure 4.13.

Recently, larger acenes have received much attention for their electronic properties.98

However, in comparison with other aromatic hydrocarbons with the same number of rings, linear acenes have smaller HOMO-LUMO gap that affect their stabilities and the gaps decrease when introducing more aromatic rings to their backbones.98 Thus, the largest well characterized linear acene is pentacene (105) containing five linearly fused benzene rings. Pentacenes serve as highly efficient dienes in the Diels-Alder cycloaddition reactions. The 6,13 positions of pentacene 105 are highly reactive towards various dienophiles. However, synthesis, characterization and application of acenes larger than pentacene is limited by their solubility, poor light and oxygen stability and difficult synthetic approaches.98

Figure 4.13 Structures of linear acenes (102-107)

The addition of activated dienophiles like maleic anhydride to an acene was first demonstrated with anthracenes, which reacts in boiling xylene and form the maleic 61

anhydride adduct 108 (Figure 4.14).99 Tetracene and pentacene also react readily with maleic anhydride to form corresponding adducts 109 and 110. The reactivity of acenes on their central benzene rings can be explained by the Clar’s aromatic sextet rule.99

Figure 4.14 Products of Diels-Alder cycloaddition of anthracene (108), tetracene (109) and pentacene (110) with maleic anhydride

In contrast to the linear acenes, acenes containing angularly fused benzene rings show much higher stability. In 1956, E. Clar reported the synthesis of tetrabenzopentacene (113) from the Friedel-Crafts acylation of octahydrophenanthrene

(111) with pyromellitic dianhydride (112, Scheme 4.2).100 Interestingly, this compound was stable enough to be isolated and stored.

Scheme 4.2 Clar’s Synthesis of tetrabenzopentacene (113)

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On the other hand, the central benzene ring of the 113 is reactive towards Diels-

Alder cycloaddition with maleic anhydride to afford adduct 114 (Scheme 4.3).100

Subsequently, more examples of the synthesis, characterization and Diels-Alder cycloadditions of acenes with angularly fused benzene rings were reported by Clar and coworkers.99,101,102

Scheme 4.3 Diels-Alder cycloaddition of 113

In 2003, Wudl and co-workers reported the efficient synthesis of heptacene derivative 117, termed as twistacene, by double Diels-Alder cycloaddition of bis-aryne precursor 116 with pyrano-diphenylcyclopentadione 115 in the presence of tetrabutylammoniumfluoride (TBAF, Scheme 4.4).103 This compound shows no sign of decomposition even after 3 years of storage at ambient conditions.103 This stability was rationalized by the twist topology of 117 arising from the presence of the phenyl substituents. There are other examples of the sterically congested acenes that display distortions from planarity and are more stable than their planar analogs.97,104

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Scheme 4.4 Synthesis of heptacene derivative 117

4.4 Bis-aryne and corannulyne

Arynes are currently the common building blocks for the preparation of

PAHs.105,106 In particular, their reactivity and highly electrophilic character as dienophiles in Diels-Alder reactions has been utilized in the area of complex natural products and in the preparation of novel polycyclic aromatic systems.105,107 A few examples of corannulene-based arynes were reported by our group. In 2008, Sygula and co-workers demonstrated the generation of corannulyne 120 from 2- trimethylsilylcorannulene triflate (119) in the presence of cesium fluoride followed by reactions with different dienes such as furan and isocorannulenofuran (Scheme 4.5).108

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Scheme 4.5 Generation of corannulyne 120 and its reactions with different dienophiles

Furthermore, in 2012 Yanney and co-workers reported the synthesis of corannulene trimer 123 from in situ generated 120 in the presence of palladium catalyst which subsequently reacted with another corannulyne to produce a tetrameric structure

124 (Scheme 4.6).109,110

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Scheme 4.6 Synthesis of corannulene trimer 123 and tetramer 124

Most of the work published in the last decade used fluoride induced elimination of o-(trimethylsilyl)aryl triflates to generate arynes under mild conditions. This methodology was first described by Kobayashi and coworkers in 1983.111 In addition to the using of arynes, bis-arynes also have much attention in the Diels-Alder cycloaddition reactions. Some of the reported bis-arynes were generated from the fluoride-induced elimination of bistriflate 116.103,106,111 As mentioned in section 4.4, twistacene 117 was synthesized with 22% yield using bis-triflate 116 and pyrano-diphenylcyclopentadione

115 in the presence of tetra-butylammonium fluoride (TBAF) as a fluoride source

(Scheme 4.4). 66

In 2015, Rodrígues-Lojo and co-worker synthesized large polycyclic o-

(trimethylsilyl)aryl triflates by controlled [4+2] stepwise cycloadditions between cyclopentadienones and 116 in 44-60% yield (Scheme 4.7).105

Scheme 4.7 Synthesis of large polycyclic o-(trimethylsilyl)aryl triflates 128-130

These compounds are useful precursors to generate large polycyclic arynes,

(Scheme 4.8) which can be used to synthesize novel acene derivatives via cycloadditions.

Scheme 4.8 Generation of polycyclic arynes 131-133

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In addition to the bis-triflate 116, compound 134 was also utilized as a bis- benzyne precursor to afford large polycyclic o-(trimethylsilyl)aryl triflates 135 and 136

(Scheme 4.9).105

Scheme 4.9 Synthesis of 135-136

In this introduction, we have discussed various types of molecular receptors and their binding affinities towards fullerenes, the stability of acenes and their reactivity towards Diels-Alder cycloadditions, arynes and their applications in corannulene-based systems, and bis-arynes. We have incorporated some of these concepts in designing and synthesizing novel molecular receptors which can be utilized in future applications.

4.5 Research Goals

The main goal of this research is to construct molecular receptors with a high binding affinity towards fullerenes and with polar tethers that can be immobilized on a solid support like silica gel. In this context, we turn our attention to the synthesis of bis- corannulenoanthracene, (137, C50H22, Figure 4.15) formally containing a pentacene core.

Synthesis of this hydrocarbon should allow for the preparation of a series of barrelene- based bis-corannulene receptors with polar groups if 137 can be used as a diene in the

Diels-Alder cycloaddition with proper dienophiles. Herein we describe the synthesis of 68

bis-corannulenoanthracene and its facile cycloaddition with maleic anhydride to afford novel bis-corannulene receptor for fullerene. In addition, we demonstrate the possibility of deposition of these receptors on silica gel.

Figure 4.15 Structure of bis-corannulenoanthracene (137)

Chapter V focuses on the synthesis of bis-corannulenoanthracene, the synthesis of bis-corannulene receptor with polar tether and binding studies performed on this receptor

1 with C60 using H NMR spectroscopy.

NOTE: This work has been published in Org. Lett. 2016, 18, 3054-3057.112

Chapter VI describes immobilization of bis-corannulene receptor on silica gel and its characterization using Diffused Reflectance Infrared Fourier Transform Spectroscopy

(DRIFT), elemental analysis, and Thermogravimetric Analysis (TGA).

Chapter VII focuses on experimental procedures and characterization of newly synthesized compounds which related to the research work on synthesis and surface immobilization of bis-corannulene molecular receptors.

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CHAPTER V

SYNTHESIS OF BIS-CORANNULENOANTHRACENE AND BIS-CORANNULENE

RECEPTOR AND ITS BINDING STUDIES USING 1H NMR SPECTROSCOPY

As mentioned in Chapter IV, synthesis of bis-corannulenoanthracene (137) will allow for the preparation of novel molecular receptors with polar tethers. Considering the well-known stability limits of larger linear acenes the question arises whether 137, containing a pentacene core, would be stable enough to be isolated. However, previously reported fused tetrabenzopentacene (113) was found to be considerably less reactive than pentacene, but it still reacted readily with dienophile like maleic anhydride to form a cycloadduct (Chapter IV).100 Therefore, the potential reactivity/stability of 137 in comparison to pentacene (105) and 113 was assessed by calculating the HOMO-LUMO gaps for the three hydrocarbons (Table 5.1).112 (Calculations of HOMO-LUMO gaps of hydrocarbons were done by Sygula)

Table 5.1 B3LYP/6-311G(d,p) level calculated HOMO-LUMO gap

Compound HOMO-LUMO gap /eV Pentacene (105) 2.20 Tetrabenzopentacene (113) 2.64 Bis-corannulenoanthracene (137) 2.65

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At B3LYP/6-311G(d,p) level the calculated gap for 137 is almost identical to the one calculated for 113. Both these numbers are significantly higher than the HOMO-

LUMO gap calculated for the parent pentacene 105, indicating that the anticipated stability of 137 should be similar to 113 rather than to 105.

The synthesis of previously reported 113 started with the Friedel-Craft acylation of octahydrophenanthrene (111) with pyromellitic dianhydride (112) (Chapter IV,

Scheme 4.2).100 However, the acylation of corannulene with the 112 led to the formation of extremely insoluble products, presumably polyquinones, which resisted their reduction to afford expected product (Scheme 5.1).

Scheme 5.1 Attempted acylation of corannulene (86) with pyromellitic dianhydride (112)

Thus, we turned our attention to utilize benzyne chemistry for the synthesis of

137. Considering the high cost of corannulene derivatives, we decided to synthesize tetrabenzopentacene (113) as a model compound starting from the phenanthro[9,10,c]furan (140) which was synthesized by previously reported method

(Scheme 5.2).112

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Scheme 5.2 Synthesis of phenanthro[9,10,c]furan (140)

5.1 Synthesis of 113

First, we attempted to synthesize 113 starting from cycloaddition of 140 with

1,2,4,5-tetrabromobenzene (141) as a bis-benzyne precursor. Bis-benzyne can be generated in situ from 141 using n-BuLi at -78 °C.113,114 The one pot double-Diels-Alder cycloaddition of 140 with 141 afforded endoxide adduct 142 in low yield (10% , Scheme

5.3).

Scheme 5.3 Synthesis of endoxide adduct 142 from 1,2,4,5-tetrabromobenzene (141) and 140

As described in Chapter IV, Wudl and co-workers reported the synthesis of heptacene derivative 117 using o-(trimethylsilyl)aryl triflates (116) as a bis-benzyne precursor (Chapter IV, Scheme 4.4).103 Based on the success of utilizing 116 as a bis- benzyne precursor in a large polyaromatic systems like 117, we turned our attention to 72

the use of 116 as a bis-benzyne precursor for our systems. Interestingly, when using 116, an endoxide adduct was obtained with the higher yield than when use of 141 as bis- benzyne precursor (40%, Scheme 5.4). Bis-benzyne was formed sequentially by the action of tetrabutylammonium fluoride (TBAF) on a 116. The precursor 116 was synthesized by a slightly modified Wudl’s procedure (Scheme 5.5).103

Scheme 5.4 Synthesis of 142 from bis-benzyne precursor 116 and 140 in the presence of TBAF

Scheme 5.5 Synthesis of bis-benzyne precursor 116

The highest yield (53%) of endoxide adducts was achieved using CsF as a fluoride source and reaction temperature of 40 °C for 3h (Scheme 5.6). Deoxygenation of endoxide adduct was achieved by trimethylsilyl iodide (TMSI) which was generated in situ from TMSCl and NaI (Scheme 5.7) to afford 113 as a red solid.

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Scheme 5.6 Synthesis of endoxide adduct 142 using CsF as a fluoride source

Scheme 5.7 Synthesis of 113 from the endoxide adduct 142

5.2 Synthesis of endoxide adducts 148a and 148b

Synthesis of 137 was attempted using the conditions optimized by the model reaction. One-pot double cycloaddition of isocorannulenofuran (91) to the bis-benzyne, formed sequentially by the action of CsF on the precursor 116, produced a mixture of two isomeric endoxide adducts 148a and 148b (ca. 5:3) in a combined yield of 61% (Scheme

5.8). Isocorannulenofuran (91), a useful synthon for the preparation of larger systems that containing corannulene subunits, was used as the diene in these reactions. The synthesis of 91 is shown in Scheme 5.9.115 The separation of the stereoisomers (148a and

148b) while not necessary for the synthesis of 137, was easily achieved due to the significantly different solubilities of the two adducts in DCM. The syn isomer, 148a, was soluble and the anti-isomer, 148b, was only sparingly soluble in this solvent.

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Scheme 5.8 Synthesis of endoxide adducts

Scheme 5.9 Synthesis of isocorannulenofuran (91)

5.2.1 APPI-MS and 1H NMR of syn and anti endoxide adducts

Both the isomers were separately characterized by both 1H and 13C NMR spectroscopy as well as MS. The APPI-MS showed m/z of 654.1609 and 654.1614 corresponding to the mass of the compounds 148a and 148b respectively (C50H22O2,

Figure 5.1).

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Figure 5.1 APPI MS of 148a (left) and 148b (right)

1 H NMR spectra of 148a and 148b show the singlets for aromatic protons ‘a1’ and

‘a2’at 7.39 ppm and 7.07 ppm respectively (Figure 5.2 and 5.3). The protons next to the oxygen, ‘b1’ and ‘b2’, are observed as singlets at 6.47 ppm and 6.30 ppm for 148a and

148 b respectively. The corannulene protons ‘c1’ and ‘c2’ are observed at 7.70 ppm and

7.71 ppm with the characteristic corannulene coupling constants of 8.4 Hz. The other corannulene protons were observed in a usual range of 7.5-7.8 ppm for both the endoxide adducts.

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Figure 5.2 1H NMR spectrum of 148a

Figure 5.3 1H NMR spectrum of 148b

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5.2.2 Crystal structure of anti isomer (148b)

The X-ray quality crystals of 148b were grown by a slow evaporation of toluene/DCM solvent mixture. X-ray crystal structure determination of 148b provided the proof for its anti-configuration of two corannulene pincers (Figure 5.4).

Figure 5.4 Crystal structure of 148b with 50% ellipsoids

5.2.3 Synthesis of 137 via deoxygenation of 148a and 148b

Deoxygenation of both 148a and 148b was achieved by in situ generated trimethylsilyl iodide (TMSI) in CH3CN:DCM (1:1) to afford 137 as a bright red solid in

83% yield (Scheme 5.10).

Scheme 5.10 Deoxygenation of 148a and 148b

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As expected, 137 is only sparingly soluble in organic solvents, which prevents the characterization by NMR spectroscopy. However, it was characterized by MS, IR, UV-

Vis and fluorescence spectroscopies. The APPI-MS showed m/z of 622.1721 corresponding to the mass of the compound 137 (C50H22, Figure 5.5).

Figure 5.5 APPI MS of 137

5.2.3.1 UV-Vis and Fluorescence spectra of 137

UV-Vis absorption and fluorescence spectra of 137 in 1,2,4-trichlorobenzene

(TCB) were recorded and compared to the spectra of previously reported 113. Both hydrocarbons exhibit very similar spectral patterns of the absorption (Figure 5.6) and emission spectra (Figure 5.7) with 137 displaying a slight red shift as compared with 113.

The longest wavelength absorptions λmax for 137 and 113 are 510 and 504 nm respectively. The both λmax values are considerably shorter wavelength than in pentacene

105 (582-585 nm), indicating the larger HOMO-LUMO gap in the compounds 137 and

113. In addition, both 137 and 113 are strongly fluorescent and show small Stokes shifts of 6 and 3 nm, respectively. 79

Figure 5.6 UV-Vis spectra of 113 (blue) and 137 (red)

Figure 5.7 Fluorescence spectra of 113 (blue) and 137 (red)

5.3 Synthesis of molecular receptor 149

In analogy to tetrabenzopentacene 113, pentacene core of 137 undergoes facile

Diels-Alder cycloaddition with proper dienophiles to yield novel molecular receptors

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with barrelene type tethers. Clip 149 was synthesized by reacting 137 with a large excess of maleic anhydride in refluxing xylene for 24 h and 149 afforded in 52% yield (Scheme

5.11). APPI-MS showed m/z 720.1725 which corresponded to the molecular ion of 137

1 (C54H24O3, Figure 5.8). Also, H NMR spectrum showed the expected number of protons upon integration (Figure 5.9).

Scheme 5.11 Synthesis of molecular receptor 149

5.3.1 APPI-MS and 1H NMR of 149

Figure 5.8 APPI MS of clip 149

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Figure 5.9 1H NMR spectrum of clip 149

Since 149 contains two corannulene pincers that are bowl shaped with a low barrier for bowl-to-bowl inversion, four distinct conformers are expected (Figure 5.10).

The relative topology of corannulene pincers are bis-concave, convex-concave, concave- convex and bis-convex for 149a, 149b, 149c and 149d respectively. Molecular mechanics calculations performed with MM2 show that in the gas phase all four conformers 149a-149d are virtually isoenergetic (within 1.0 kcal/mol). In addition, these conformers can interconvert quickly due to the low barrier of bowl-to-bowl inversion of corannulene (ca.11 kcal/mol).116,117

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Figure 5.10 Conformers of molecular receptor 149 and their MM2 calculated relative energies (kcal/mol)

5.3.2 X-ray crystal structure of 149

X-ray crystal structure determination of the crystal grown from a toluene-DCM solution of 149 shows that bis-convex conformation of the clip (149d) is preferred for the toluene solvate in the solid state (Figure 5.11). A similar conformation was previously observed in the crystal structure of the smaller dicorannulene analog 90, which did not show measurable association with fullerene in toluene.89

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Figure 5.11 Crystal structure of the toluene solvate of 149 with 50% ellipsoids

Nonetheless, bis-concave conformation 149a is of special interest for the association of fullerenes, since it would employ both concave faces of the corannulene pincers to accommodate the guest carbon cage. Due to the low bowl-to-bowl inversion barriers for corannulene, it is expected that conformer 149a could be preferred in the association of fullerenes in solution.

We calculated the MM2 binding energies of receptors 90, 93, 99 and 149 in order to assess their potential binding affinities for fullerenes. MM2 calculated gas-phase binding energies for C60@90, C60@93, C60@99 and C60@149 are 19.2, 24.7, 25.9 and

25.0 kcal/mol respectively (Figure 5.12).

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Figure 5.12 MM2 calculated gas phase binding energies (kcal/mol) of receptors 90, 93, 99 and 149

MM2 calculated binding energy of 149 with C60 is significantly higher than that of the receptor 90 which did not show any binding affinity with fullerenes in solutions.

In addition, the binding energy of 149 is virtually identical with the original buckycatcher

93 and only slightly lower than the more efficient buckycatcher II (99), predicting the strong affinity of 149 towards fullerenes. Moreover, the more sophisticated B97-

D/QZVP*//B97-D/TZVP calculations performed by Sygula reproduced the trends in the

112 MM2 gas phase binding energies of C60 with the considered receptors.

5.4 Binding studies of clip 149 using 1H NMR spectroscopy

1 H NMR titration carried out by the addition of C60 to clip 149 in chlorobenzene- d5 solution suggested that C60 and 149 were binding in solution. Changes in chemical shifts of the 149 were observed upon addition of C60 (Figure 5.13 and 5.14). The

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chemical shifts of protons A, B, C, D and E moved upfield and proton F moved downfield upon titration of 149 with C60. The maximum chemical shift changes of all protons are shown in Table 5.2.

1 Figure 5.13 H NMR titration of clip 149 with C60 in chlorobenzene-d5 (downfield protons)

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1 Figure 5.14 H NMR titration of clip 149 with C60 in chlorobenzene-d5 (upfield protons)

Table 5.2 Maximum observed changes in the chemical shifts of the protons A, B, C, D and E for C60@149

Protons A B C D E F

Δδ (C60@149) ppm -0.080 -0.089 -0.036 -0.026 -0.060 0.125

The binding stoichiometries for the inclusion complexes for C60 were assessed by continuous variation (Job) plot analysis (Figure 5.15). The Job’s plots derived from the titration data have their maxima ca. 0.5 molar fraction of the receptor, indicating the predominance of the 1:1 stoichiometry of the binding of 149 with C60. On the other hand, some asymmetry of these curves is observed at the receptor molar fractions higher than

0.5. This asymmetry of Job’s plots can be attributed to minor contributions from the trimeric C60@1492 complex formation. Previously studied buckycatchers 93 and 99 87

90,95 exhibited different modes of association with fullerenes in chlorobenzene-d5. The more efficient Buckycatcher II (99) forming both 1:1 and 2:1 complexes while only 1:1 association of Buckycatcher I (93) with C60 were detected in solution. However, receptor

149 seems to represent a borderline case between the 93 and 99. Therefore, non-linear curve fitting was attempted for both 1:1 and the stepwise 2:1 complexation models and F- statistics was then used to determine the better fitting model.

Figure 5.15 Job’s plots for protons A, B, C, D, E and F for the titration of 149 with C60 in chlorobenzene-d5

88

5.4.1 Evaluation of Ka for the 1:1 model (C60@149) in chlorobenzene-d5.

Association constant (Ka) was evaluated from the changes in chemical shifts of the six symmetry independent protons (A-F) by applying a nonlinear curve-fitting equation shown in eq 5.1. This equation was derived using equations of 5.2 and 5.3 by considering 1:1 inclusion complex formation.112

1⁄ 2 2 2 2 2 ∆훿푚푎푥(1+퐾푎× [퐺]0+퐾푎×[퐻]0)−(∆훿푚푎푥 ×(1+퐾푎×[퐺]0+퐾푎×[퐻]0) −4퐾푎[퐺]0[퐻]0∆훿푚푎푥 ) ∆훿 = (5.1) 2퐾푎[퐻]0 where

Δδ = δ - δh

[G]0 = Total concentration of the guest

[H]0 = Total concentration of the host

∆δmax; That is ∆δ at 100% complexation

[Hg] 퐾 = 푎 [H]×[퐆] (5.2)

훿 = 푥훿푐 + (1 − 푥)훿ℎ (5.3)

x = [HG] / [H]0 = mole fraction of the inclusion complex

δ = observed chemical shift of a specific nucleus in 149

δh = chemical shifts of a specific nucleus in 149 in the free form

δc = chemical shifts of a specific nucleus in 149 when bound to the guest

Ka and ∆훿푚푎푥 were optimized as parameters in the nonlinear curve fitting using Origin©

(v. 8.0). All non-linear curve regression (1:1 model) for the titration of 149 with C60 are given in the Figure 5.16.

89

Figure 5.16 Nonlinear curve regression of the titration of 149 with C60 (1:1 model)

The estimated Ka and ∆δmax for all six protons were given in the Table 5.3.

90

Table 5.3 Estimated values of Ka and ∆δmax using 1:1 model

-1 Proton / ppm Ka / M ∆δmax / Hz H(8.62 (1)) 6292 ± 951 55 H (8.62 (2)) 3676 ± 357 68 H(8.18) 6070 ± 990 25 H(7.85) 6614 ± 1131 18 H(5.32) 4700 ± 654 44 H(3.55) 3612 ± 382 96

-1 The estimated weighted average Ka was 4159 ± 224 M for C60@149 complex and it was calculated using eq 5.4.

∑ 푊푖퐾푖 Weighted average Ka = (5.4) ∑ 푊푖

1 푤 = 𝑖 휎2 (5.5)

1 휎푤푎푣 = (5.6) √∑ 푊푖 where,

Ki = The association constant of (Ka) for each experiments

σ = The uncertainty for each experiment

σwav = The weighted average uncertainty

5.4.2 Evaluation of K1 and K2 for the 2:1 model (C60@1492) in chlorobenzene-d5.

Scheme 5.12 2:1 binding model

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The association constants K1 and K2 were estimated using the 2:1 binding model

(Scheme 5.12) and binding equation 5.7.

2 훿∆퐻퐺[퐺]0퐾1[퐻] +2훿∆퐻2퐺[퐺]0퐾1퐾2 [퐻] ∆훿 = 2 (5.7) [퐻]0(1 + 퐾1[퐻]+퐾1퐾2[퐻] )

K1 = The first stepwise association constant

K2 = The second stepwise association constant

δΔHG = δHG – δh

δΔH2G = δH2G – 2δh

δh - chemical shift of a given proton in free host (buckycatcher)

δHG - chemical shift of the same proton in 1:1 complex

δH2G - chemical shift of the same proton in 2:1 complex

Δδ= δexp – δh

[G]0 = The total concentration of the guest

[H]0 = The total concentration of the host

[H] = Molar concentration of the free host

For a given set of K1, K2, [G]0 and [H]0 the concentration of free host [H] was calculated by solving the following cubic equation:

A[H]3 + B[H]2 + C[H] + D = 0 (5.8) where:

A = (K1K2)

B = K1(2K2[G]0 - K2[H]0 + 1)

C = K1([G]0 - [H]0) + 1

D = -[H]0

[H]0 = [H] + [HG] + 2[H2G] 92

K1, K2, δΔHG and δΔH2G were optimized as parameters in the non-linear curve fitting using

Origin© (v. 8.0). All non-linear curve regression (2:1 model) for the titration of 149 with

C60 are given in the Figure 5.17 and 5.18.

Figure 5.17 Nonlinear curve regression for the titration of 149 with C60 (2:1 model, downfield protons)

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Figure 5.18 Nonlinear curve regression for the titration of 149 with C60 (2:1 model, upfield protons)

The estimated association constants K1 and K2 for all protons given in the Table

5.4. The equation 5.4 was used to estimate the weighted average K1 and K2 of C60@

-1 1492. The estimated weighted average association constants were 3609 ± 23 M and

-1 1997 ± 118 M for K1 and K2 respectively.

Table 5.4 Estimated values of K1, K2, δΔHG and δΔH2G using 2:1 model

-1 -1 Proton / ppm K1 / M K2 / M δΔHGmax / Hz δΔH2G / Hz H(8.62 (1)) 3977 ± 47 2358 ± 215 62 32 H (8.62 (2)) 3150 ± 31 1595 ± 197 74 30 H(8.18) 5252 ± 125 1898 ± 402 26 13 H(7.85) 5349 ± 119 2063 ± 367 19 10 H(5.32) 3974 ± 85 2305 ± 441 47 20 H(3.55) 3960 ± 105 2161 ± 429 98 32

Even though the standard errors of the average K, values calculated by the

Origin© (v. 8.0) fitting procedures are quite small, they should be treated with some caution. The K, values calculated for six independent protons of 149 differ significantly

94

more than their estimated standard errors (Table 5.4). At this point we are not able to offer any convincing explanation for the discrepancies.

5.4.3 F-test

F-test is used to test group variance against the null hypothesis and its often used to comparing nested models.118 In this context, 1:1 model which consist of two parameters is nested by the four parameter 2:1 model. Null hypothesis is that the 2:1 model does not provide a significantly better fit than 1:1 model. The null hypothesis is rejected if the F calculated from the titration data is greater than the critical value of F distribution (Fυ1,υ2) at a given confidence level α (0.05 or 0.01). F-values for each protons were calculated using equation 5.9.118,119

휒 2−휒 2 ( 1 2 ) 휌2−휌1 F = 휒 2 (5.9) ( 2 ) 푛−(휌2+1) where,

υ1 = degrees of freedom of the numerator = (ρ2 - ρ1) = (4-2) = 2

υ2 = degrees of freedom of the denominator = (n – (ρ2+1)) = (16-(4+1)) = 11

ρ1 = no of parameters for the 1:1 model (2)

ρ2 = no of parameters for the 2:1 model (4)

n = number of experiments (16)

2 2 χ1 = reduced χ values for the two-parameter 1:1 model (Table 5.5)

2 2 χ2 = reduced χ values for the four-parameter 2:1 model (Table 5.5)

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Table 5.5 Reduced χ2 values

2 2 Proton / ppm Reduced χ1 Reduced χ2 H(8.62 (1)) 1.20401 0.11383 H (8.62 (2)) 0.67813 0.10634 H(8.18) 0.28917 0.08074 H(7.85) 0.16431 0.03523 H(5.32) 0.62116 0.16854 H(3.55) 1.5721 0.37457

119 The critical value of F distribution is 3.98 (95%) or 9.65 (99%) for F(2,11). The calculated F values are significantly higher for all six experiments than the critical values

(Fcalc>> F(2,11)) implying the statistical significance of the 2:1 four parameter association model (Table 5.6).112

Table 5.6 F-test results

Proton / ppm H(8.62 (1)) H(8.62 (2)) H(8.18) H(7.85) H(5.32) H(3.55)

Fcalc (2,11) 52.7 29.6 14.2 20.2 14.8 17.6

Clip 149 shows strong affinity towards C60, significantly higher than

Buckycatcher I (93), even though the calculated gas phase binding energies for both clips are almost identical (Table 5.7). The Gibbs free energy of the 1:1 complexation of C60

-1 with 149 in chlorobenzene-d5 at room temperature is 1.1 kcal mol more exergonic than

Buckycatcher I (Table 5.7, 93). In addition, 2:1 complexation of 149 is significant as compared to 93 under the conditions of NMR titration experiment. On the other hand,

149 is not as efficient receptor for fullerene as Buckycatcher II (99), with the Gibbs free

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energy less exergonic by ca. 0.6 kcal mol-1 for the 1:1 inclusion complex formation

(Table 5.7).112

Table 5.7 Comparison of the binding properties of buckycatchers 93, 99 and 149 in chlorobenzene-d5

-1 complex K1/ M (BE kcal/mol) K2

90 C60@93 520 ± 20 (41.8) not detected

95 C60@99 10,040 ± 110 (42.5) 1,180 ± 640

C60@149 3,610 ± 20 (41.7) 2,000 ± 120

5.5 Conclusions

Bis-corannulenoanthracene (137), which contains pentacene core was synthesized by the Diels-Alder cycloaddition of isocorannulenofuran and in situ generated bis- benzyne followed by deoxygenation of the endoxide adducts. Hydrocarbon 137 is stable enough to be isolated and stored, despite the presence of pentacene subunit in its core.

On the other hand, the central benzene ring of 137 undergoes facile cycloaddition with maleic anhydride to form a bis-corannulene molecular receptor 149 with polar group

1 substituted tether. H NMR titration experiments carried out in chlorobenzene-d5 shows the formation of both 1:1 and 2:1 inclusion complexes of 149 with C60. The estimated association constants are 3,610 ± 20 and 2,000 ± 120 for K1 and K2 respectively. In addition to being the efficient molecular receptor for fullerenes, 149 possesses the polar group on its tether, which would allow for its deposition on a solid support like silica gel.

Surface immobilized molecular receptors can be applied in the areas of fullerene separations and nanoscale organic electronic devices.

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CHAPTER VI

IMMOBILIZATION OF BIS-CORANNULENE MOLECULAR RECEPTORS ON

SILICA SURFACE

We have been developing synthetic methodologies to construct molecular receptors with corannulene pincers. As mentioned in the previous sections these receptors, if immobilized on a solid support, could be used for two major applications (1) as stationary phases in liquid chromatography for the separation of various types and/or size fullerenes and (2) as buckycatcher-fullerene complexes in photovoltaic applications.120

There are many stationary phases available for separation of fullerenes.121-125

However, corannulene-based receptors have not yet been utilized for this purpose.

Specially designed molecular receptors with polar groups on their tethers such as 149 are good candidates for their immobilization on solid support like silica gel.

Thus, we turned our attention to immobilize molecular receptor 149, which shows high binding affinities for fullerenes, on silica gel. Chapter VI focuses on the modification of silica surface with (3-aminopropyl)triethoxysilane linker (APTES, 150) and immobilization of the model compound (151) as well as of the molecular receptor

149 on APTES modified silica gel. To the best of our knowledge, this is the first example of immobilization of corannulene-based molecular receptors on a solid support like silica gel. The surface modified silica was characterized by Diffused Reflectance

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Infrared Fourier Transform Spectroscopy (DRIFTS), Thermogravimetric Analysis (TGA) and elemental analysis. In addition, the crude estimation of surface coverages were obtained based on the elemental analysis and TGA data.

6.1 Silica as a solid support and silane coupling agents

Silica is a highly porous material and one of the most used material for supporting various types of molecules. It has many advantages such as ease of surface modification, ease of characterization, availability, and low cost.126 The attachment of organic functional groups on silica has received much attention recently because it shows some advantages such as high thermal resistance, strong resistance to organic solvents and the availability of various types of silylating agents for the functionalization of its surface.126-

129 Chemical modification of silica surface with silane coupling agents has been extensively studied in the past two decades.127,130-132 APTES is one of the most utilized silylating agent employed for the modification of surfaces (Figure 6.1).133-137 APTES consist of two types of functionalities. (1) Hydrolyzable ethoxy groups (-OEt) that can be condensed with silanol groups on silica to form siloxane linkages (2) The amino group

(–NH2) can be used to bind the proper functional groups.

Figure 6.1 Structure of APTES (150)

99

6.2 Modification of silica with APTES

M-5 grade Cab-O-Sil was used as the silica source for surface modification with

APTES. Cab-O-Sil, one of the most utilized types of silica gel in research, has a small particle size, well-defined surface area, and high purity.138-140 The DRIFT spectrum of unmodified silica is shown in Figure 6.2. Silica exhibits absorption bands for the Si-O-Si stretching and bending at 1100 cm-1 (strong) and 810 cm-1 (weak) respectively.141,142 The peaks corresponding to the silanol –OH groups and adsorbed or hydrogen bonded water molecules appear in the range of 3700-3000 cm-1.

Figure 6.2 DRIFT spectrum of unmodified silica

The Cab-O-Sil surface was modified with the linker by treatment with APTES at

80 °C overnight in toluene (Scheme 6.1).128,133,143 The ethoxy groups of APTES were reacted with surface hydroxyl groups of silica to form durable bonds between silica and the APTES.127,136,141,144,145 It is possible for APTES to form one, two or three bonds with

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the silica surface. The linker-modified silica was sonicated, washed with toluene, DCM,

DMF, acetone, CH3OH, hexane and again with DCM and dried at 60 °C for 24 h. The dried APTES modified silica was characterized by DRIFT, TGA, and elemental analysis.

The surface coverage of APTES immobilized silica was estimated based on the results of elemental analysis and TGA.146-148

Scheme 6.1 Modification of silica with APTES

6.2.1 DRIFTS analysis of APTES modified silica

The DRIFT spectra of APTES modified silica (5 wt% in KBr) is shown in Figure

6.3. The C-H stretching vibration frequencies of APTES moiety appeared in the range of

2850-3000 cm-1.141 In addition, The C-H bending vibration peak shows at 1488 cm-1.

Two stretching vibration bands of the primary amine group of APTES are found at 3299 cm-1 and 3367 cm-1.141 The bending vibration band of –N-H group is found at 1560 cm-1, further confirming the presence of –N-H group.136,141 The C-N stretching vibration peak in the range of 1000-1200 cm-1 was not observed due to the overlap of absorption peaks arise from the Si-O-Si stretching vibrations of silica.141

101

Figure 6.3 DRIFT spectra of APTES modified silica

6.2.2 Elemental analysis and APTES coverage on silica surface

The elemental analysis provided the percentages of carbon, nitrogen and hydrogen in the APTES modified silica surface (Table 6.1). The experimental C/N ratio of 3.35 (Appendix C.1) of APTES modified silica, compared with the theoretical C/N ratio of 3.00 indicates that almost all the ethoxy groups in APTES were condensed with the hydroxyl groups of silica to bond in a tridentate fashion.149 Since the only source of nitrogen is APTES, the surface coverage of modified silica was calculated using N%.

The calculated surface coverage is 0.88 mmol/g or 2.65 molecules of APTES per nm2

(Appendix C.2). The surface coverages of 0.8 - 1.3 mmol/g are reported in the literature.149-153 Since there is 0.88 mmol/g APTES available on the silica surface, the percentages of carbon and hydrogen calculated from the linker loading should be 3.17% and 0.70% respectively. The higher experimental C% and H% values 3.54% and 0.85%

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(Table 6.1) could be due to the presence of the unreacted ethoxy groups of APTES and the presence of moisture in the silica.

Table 6.1 Elemental analysis of APTES modified Cab-O-Sil

Element %

C 3.54

H 0.85

N 1.23

6.2.3 TGA analysis of the surface modified silica

TGA performed under a nitrogen flow at a heating rate of 5 °C/min from room temperature up to 1000 °C, gives the percentage mass loss due to the volatility of the materials. Figure 6.4 shows the weight loss thermograms of unmodified silica (blue) and

APTES modified silica (red). The TGA thermogram of the unmodified silica gives a mass loss of 2.1 % in the range of 25 °C – 1000 °C likely due to the moisture loss and the condensation reaction of the surface hydroxyl groups of silica.154,155 For APTES modified silica, the total weight loss was 6.8% which corresponds to both water and

APTES release from the silica surface. The APTES coverage was estimated using procedure reported by Halhalli et al148 and found to be 0.90 mmol/ g (Appendix C.3) and it is in a good agreement with the surface coverage obtained from the elemental analysis.

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Figure 6.4 TGA thermograms of unmodified silica (blue) and APTES modified silica (red)

6.3 Surface immobilization of the model compound 151

Due to the high cost of corannulene-based molecular receptors, we first attempted to immobilize cycloadduct 151 to silica gel as a model reaction. Cycloadduct 151, which also possessed an anhydride functionality on its tether, was synthesized by the previously reported procedure (Scheme 6.2).156

Scheme 6.2 Synthesis of cycloadduct 151

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Cycloadduct 151 was grafted to the APTES modified silica in the presence of triethylamine in refluxing toluene for 24 h (Scheme 6.3).157,158 The 151 grafted silica was then sonicated, filtered and washed with toluene, DCM, acetone, MeOH and again with

DCM. The silica was dried under vacuum at 60 °C for 24 h and characterized by DRIFT,

TGA, and elemental analysis.

Scheme 6.3 Immobilization of cycloadduct 151 on APTES modified silica

6.3.1 DRIFTS analysis of 151 modified silica

DRIFT spectra of 151 modified silica (5 wt% in KBr) was recorded with 5%

APTES modified silica in KBr (Figure 6.5) and 5% unmodified silica in KBr (Figure 6.6) as the reference materials. The characteristic signals related to carbonyl asymmetric stretching frequencies of the imide moiety can be found at 1770 cm-1 and 1697 cm-1.157-

160 The characteristic anhydride carbonyl frequencies of 151 at 1861 cm-1 and 1775 cm-1

(Figure 6.7) disappeared after immobilization on the silica surface. In addition, comparing the IR spectrum of 151 (Figure 6.7) and DRIFT spectrum of 151 grafted silica

105

(Figure 6.5) suggests the presence of the aromatic C-H stretching bands at 3000-3100 cm-

1 and the sp3 hybridized C-H bands at 2900-3000 cm-1 on the 151 grafted silica.

Furthermore, the characteristic bands for C-H and N-H stretching vibration frequencies of unreacted APTES can be found in the ranges of 2850-3000 cm-1 and 3200-3400 cm-1 respectively (Figure 6.6).

Figure 6.5 DRIFT spectrum of adduct 151 modified silica

(5% APTES modified silica in KBr as the reference)

Figure 6.6 DRIFT spectrum of adduct 151 modified silica

(5% silica in KBr as the reference) 106

Figure 6.7 IR spectra of adduct 151

6.3.2 Elemental analysis of 151 modified silica

As expected elemental analysis of 151 modified silica shows the higher carbon and hydrogen percentages than the APTES modified silica, which further confirms the attachment of 151 on the surface (Table 6.2). Li reported the weight adjustment method to calculate the ligand coverages on silica surface based on the elemental analysis data.147

A similar approach was used to estimate the 151 coverage and the calculation is shown in

Appendix C.4. The calculated surface coverage of the adduct 151 on silica surface is

0.44 mmol/g or 1.3 molecules of 151 per nm2 and it was calculated using carbon percentages.

Table 6.2 Elemental analysis results of 151 grafted silica

Element % C 12.64 H 1.20 N 1.09

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6.3.3 TGA analysis of adduct 151 grafted silica

TGA of 151 grafted silica gives the total weight loss of 17.5% which shows significantly higher weight loss than for the APTES modified silica (Figure 6.8). The

APTES loading per one gram of 151 modified silica should be less than the initial

APTES coverage (0.88 mmol/g) due to the weight gain from the adduct 151. The estimated new APTES loading on 151 grafted silica is 0.78 mmol/g (Appendix C.5).

Therefore, the estimated 151 surface coverage is 0.50 mmol/g (Appendix C.5) and it is good agreement with the surface coverage obtained from the elemental analysis.

Figure 6.8 TGA thermogram of 151 grafted silica

6.4 Immobilization of 149 on APTES modified silica

We performed preliminary studies to attach the corannulene based receptor 149 on APTES modified silica using the methodology applied for the model compound

(Scheme 6.4).

108

Scheme 6.4 Immobilization of receptor 149 on APTES modified silica surface

6.4.1 DRIFTS analysis of 149 modified silica

DRIFT spectrum of 149 grafted silica (5 wt% in KBr) was recorded with 5%

APTES modified silica in KBr (Figure 6.9) as the reference material. As expected, a spectral pattern similar to the 151 grafted silica was observed for the receptor 149 modified silica. The characteristic carbonyl asymmetric stretching frequencies of imide moiety are observed at 1695 cm-1 and 1776 cm-1.158-160 The formation of the imide moiety confirmed the immobilization of 149 on APTES modified silica. In addition, sp3 hybridized C-H stretching (2900 - 3000 cm-1), aromatic C-H stretching (3000-3100 cm-1) and aromatic C=C stretching (1400-1500 cm-1) frequencies were also observed in DRIFT spectra. For comparing the IR spectrum of receptor 149 is shown in Figure 6.10.

109

Figure 6.9 DRIFT spectrum of 149 modified silica

(5% APTES modified silica in KBr as the reference)

Figure 6.10 IR spectrum of 149

6.4.2 Elemental analysis of 149 modified silica

The elemental analysis of 149 modified silica (Table 6.3) provided higher carbon percentage than the APTES and 151 modified silica confirming the attachment of 149 on

110

the surface. A similar method as for the model compound was used to estimate the coverage which found to be 0.21 mmol/g or 0.6 molecules per nm2 (Appendix C.6).147

Table 6.3 Elemental analysis results of 149 modified silica

Element % C 16.86 H 1.16 N 0.88

6.4.3 TGA analysis of 149 modified silica

For the 149 modified silica, the observed total weight loss was 23.8% (Figure

6.11). This significantly higher weight loss than the APTES modified silica further confirmed the immobilization of receptor 149 on the surface. Similar to the 151 modified silica (section 6.3.3), the APTES coverage of 149 modified silica should be less than the initial APTES coverage because of the weight gain from the receptor. The estimated new

APTES coverage of 149 modified silica is 0.63 mmol/g and it was calculated by nitrogen percentage obtained from the elemental analysis (Appendix C.7). Based on the new

APTES coverage, the calculated weight loss due to the release of 149 is 20.1%

(Appendix C.7). Therefore, the estimated coverage of 149 is 0.29 mmol/g (Appendix

C.7) which is acceptable agreement with the coverage calculated from the elemental analysis (0.21 mmol/g).

111

Figure 6.11 TGA thermogram of 149 grafted silica

6.5 The stir and filter approach to observe the C60 adsorption on the receptor modified silica

The stir and filter approach (SAFA) was performed to observe the adsorption of

161 C60 on the receptor modified silica. The solution of C60 (1.39 mM) was prepared in toluene and subsequently added to the 15 mg of the receptor modified silica.

Simultaneously, the same C60 solution (1.39 mM) was treated with the APTES modified silica for the control experiment. After 30 min of stirring, the suspensions were separately filtered and washed with 1.0 mL of MeOH. Both the filtrates were collected and the solvent was evaporated under the reduced pressure. The recovered C60 was redissolved in 3.00 mL of toluene. The UV-Vis spectra were recorded for recovered C60 solutions and compared with the initial C60 solution (Figure 6.12)

112

Figure 6.12 UV-Vis spectra of initial C60 solution (black) recovered C60 solutions after treated with APTES modified silica (red) and receptor 149 modified silica (blue)

As expected UV-Vis absorbance of the C60 recovered from the receptor modified silica (Figure 6.12, blue) is lower than the absorbance of C60 recovered from the APTES modified silica (Figure 6.12, red) and the initial C60 solution (Figure 6.12, black). These preliminary results indicate the receptor modified silica adsorbed more C60 than the

APTES modified silica. This approach provided further evidence for the attachment of molecular receptors on silica surface.

6.6 Conclusions

Silica surface was modified with APTES linker prior to the immobilization of the molecular receptors. The characteristic absorption bands of DRIFT spectra of APTES- modified silica confirmed attachment of the linker to the silica surface. The estimated

APTES coverage on silica surface based on elemental analysis was 0.88 mmol/g in good

113

agreement with the coverage calculated from TGA data (0.90 mmol/g). Cycloadduct 151 was successfully immobilized on the linker modified silica surface as confirmed by

DRIFT spectra. The estimated surface coverage calculated from the elemental analysis was 0.42 mmol/g. Using the conditions of the model reaction, the molecular receptor 149 was also immobilized on APTES modified silica. Surface modification was confirmed by the appearance of the characteristic imide carbonyl asymmetric stretching bands. The estimated surface coverage was 0.21 mmol/g based on the elemental analysis. In addition, stir and filter experiment was performed and it showed that more C60 was retained on receptor modified silica than on the APTES modified silica. Future studies will investigate the possibility of separation of various types/size fullerenes using corannulene-based receptors immobilized on the silica surface.

114

CHAPTER VII

SYNTHESIS AND SURFACE IMMOBILIZATION OF BIS-CORANNULENE

MOLECULAR RECEPTORS: EXPERIMENTAL

7.1 General Information

All reagents and solvents were purchased from Sigma Aldrich or Alfa-Aesar.

Cab-O-Sil (M-5, Scintillation grade, surface area 200 m2/g) were purchased from Acros

Organics. Reaction solvents were further purified by Innovative Technology solvent purification system or by distillation. All reactions were performed under either nitrogen or argon atmosphere. All flash chromatography was done using silica gel 60 (particle size 0.040-0.063 mm and 230-400 mesh ASTM). 1H and 13C NMR spectra were recorded on 600 and 300 MHz Bruker Avance III spectrometers. Chemical shifts are reported in ppm using chloroform-d, chlorobenzene-d5 residual signals as standards. APPI Mass

Spectra were recorded on Bruker UHPLC-Micro-Q-TOF MS/MS instrument. IR and

DRIFT spectra were recorded on Thermo Nicolet 6700 FT-IR. UV-Vis absorption and fluorescence spectra were recorded on Shimadzu 2550 UV-VIS and Fluoromax 4 spectrofluorometers respectively. Modified and unmodified silica samples were analyzed on a Perkin-Elmer TGA-7 Thermogravimetric analyzer under the nitrogen atmosphere.

The temperature range of room temperature to 1000 °C was analyzed at a rate of 5 °C per minute. Elemental analyses were performed by Atlantic Microlab, Inc. (Norcross, GA).

Modified silica samples were analyzed for carbon, hydrogen and nitrogen content.

115

7.2 Synthesis of 116

Scheme 7.1 Synthesis of bis-benzyne precursor 116

Synthesis of triflate 116 was successfully achieved following the slightly modified procedure developed by Wudl et al.103,162

7.3 Synthesis of 142

Scheme 7.2 Synthesis of endoxide 142

54 mg (0.10 mmol) of triflate 116, 52g (0.24 mmol) phenanthro[9, 10-c]furan 140 and 46 mg (0.30 mmol) of CsF were heated for 1.5 h at 40 C in 12 mL of CH3CN:DCM

(1:1). After this time, the second portion of CsF (46 mg, 0.30 mmol) was added and stirring was continued for an additional 1.5 h. The reaction mixture was cooled to room temperature, water was added and the organic products were extracted using DCM. The organic layer was dried with anhydrous Mg2SO4 and the solvent was removed under

116

reduced pressure. The crude solid materials were redissolved in DCM and product was isolated by column chromatography on silica gel with DCM:cyclohexane (1:1) with the

1 yield of 53% ; 27 mg; Yellow solid; H NMR (300 MHz, CDCl3, ppm) δ 8.55 (d, J = 7.8

Hz, 4H), 7.91 (d, J = 7.8 Hz, 4H), 7.58-7.48 (m, 10H), 6.54 (s, 4H); ); HRMS (APPI) m/z

+ calculated for [M] C38H22O2: 510.1620; found: 510.1630.

7.4 Synthesis of 113

Scheme 7.3 Synthesis of tetrabenzopentazene (113)

10 mg (0.020 mmol) of 142, 30 mg (0.20 mmol) of NaI and 26 µL (0.390 mmol) of TMSCl in 6 mL of degassed CH 3CN:DCM (1:1) was stirred for 18 h at room temperature under nitrogen. The red color suspension was filtered through filter paper, washed several times with degassed DCM and dried under vacuum; Yield 78%, 7 mg,

1 Red solid. H NMR (600 MHz, toluene-d8, ppm) δ 9.18 (s, 4H), 8.69 (s, 2H), 8.67 (d, J =

7.8 Hz, 4H), 8.31 (d, J = 7.2 Hz, 4H), 7.50 (t, J = 7.2 Hz, 4H), (t, J = 7.8 Hz, 4H). Very low solubility of 113 in common deuterated solvents prevented its characterization by 13C

NMR, IR: 3020, 1620, 1410, 1388, 1290, 1200, 910, 815, 782, 680, 630 cm-1; HRMS

+ (APPI) m/z calculated for [M] C38H22: 478.1722; found: 478.1715

117

7.5 Synthesis of syn (148a) and anti (148b) endoxides

Scheme 7.4 Synthesis of endoxide adducts 148a and 148b

52 mg (0.10 mmol) of triflate 116, 64mg (0.22 mmol) isofurancorannulene 91 and

46 mg (0.30 mmol) of CsF were heated for 1.5 h at 40 C in 12 mL of CH3CN:DCM

(1:1). After this time, the second portion of CsF (46 mg (0.30 mmol)) was added and stirring was continued for an additional 1.5 h. The reaction mixture was cooled to room temperature, water was added and the organic products were extracted using DCM. The organic layer was dried with anhydrous Mg2SO4 and the solvent was removed under reduced pressure. The crude solid materials was suspended in 5 mL of DCM, sonicated briefly and 15 mg of anti-isomer was isolated by filtration. 25 mg of the second isomer was obtained by column chromatography on silica gel with DCM:cyclohexane (1:1) with the combined yield of 61%.

Syn isomer (148a)

Figure 7.1 Structure of the syn endoxide adduct (148a) 118

1 25 mg; Yellow solid; H NMR (600 MHz, CDCl3) δ 6.47 (s, 4H), 7.39 (s, 2H),

7.56 (s, 8H), 7.65 (d, J = 8.4 Hz, 4H), 7.70 (d, J = 8.4 Hz, 4H); 13C DEPT-Q135 (600

MHz, CDCl3) δ 81.5, 113.9, 123.4, 125.9, 127.0, 127.5, 130.2, 130.7, 134.1, 134.7,

135.3, 147.5, 148.6; IR: 3034, 2998, 2954, 2920, 1432, 1328, 1279, 1206, 1134, 998,

-1 + 970, 828, 767, 673 cm ; HRMS (APPI) m/z calculated for [M] ; C50H22O2: 654.1620; found: 654.1609

Anti isomer (148b)

Figure 7.2 Structure of the anti endoxide adduct (148b)

1 15 mg; White solid; H NMR (600 MHz, CDCl3) δ 6.30 (s, 4H), 7.07 (s, 2H), 7.71

13 (d, J = 8.4 Hz, 4H), 7.76 (m, 12H); C DEPT-Q135 (600 MHz, CDCl3) δ 81.4, 113.6,

123.0, 127.1, 127.1, 127.3, 127.7, 130.7, 131.1, 134.7, 134.9, 136.0, 147.1, 149.0; IR:

3031, 3000, 2951, 2924, 1431, 1325, 1268, 1215, 1150, 1001, 980, 831, 767, 670 cm-1;

+ HRMS (APPI) m/z calculated for [M] ; C50H22O2: 654.1620; found: 654.1614

119

7.6 Synthesis of 137

Scheme 7.5 Synthesis of bis-corannulenoanthracene (137)

38 mg (0.058 mmol) of a mixture of 148a/148b, 87 mg (0.580 mmol) of NaI and

74 µL (0.580 mmol) of TMSCl in 12 mL of degassed CH3CN: DCM (1:1) was stirred for

24 h at room temperature under nitrogen. The bright red color suspension was filtered through filter paper, washed several times with degassed DCM and dried under vacuum and directly used for the next step; Yield 83%, 30 mg; Red solid; IR: 3024, 1615, 1417,

1396, 1286, 1209, 913, 825, 790, 675, 637 cm-1; HRMS (APPI) m/z calculated for [M]+;

C50H22: 622.1722 found: 622.1721. Very low solubility of 137 in common deuterated solvents prevented its characterization by NMR.

7.7 Synthesis of 149

Scheme 7.6 Synthesis of molecular receptor 149

120

A suspension of 25 mg of bis-corannulenoanthracene 137 with ca.10 fold excess of maleic anhydride was heated under reflux in 20 mL of degassed xylene for 24 h. After this time reaction mixture was cooled, washed with water and brine solution (3 times).

The organic layer dried with anh. Mg2SO4 and solvent removed under reduced pressure.

The residue was chromatographed on silica gel with DCM. Yield 52%; 15 mg; Light

1 yellow solid; H NMR (600 MHz, CDCl3) δ 3.82 (s, 2H), 5.41 (s, 2H), 7.75-7.79 (m, 4H),

7.80 (q, J = 8.4 Hz, 4H), 7.85 (d, J = 8.4 Hz, 2H), 7.93 (d, J = 8.4 Hz, 2H), 8.15 (d, J =

8.4 Hz, 2H), 8.21 (d, J = 8.4 Hz, 2H), 8.69 (s, 2H), 8.74 (s, 2H); 13C DEPT-Q135 (600

MHz, CDCl3) δ 45.9, 48.3, 121.0, 121.9, 124.0, 124.2, 127.1, 127.1, 127.2, 127.2, 127.2,

127.6, 127.8, 128.3, 128.3,128.4, 130.5, 130.5, 130.7, 130.8, 132.3, 132.7, 134.7, 135.2,

135.3, 136.6, 137.4, 139.1, 170.3; IR: 3040, 2961, 2923, 2851, 1867, 1778, 1440, 1260,

1223, 1073, 1020, 918, 830, 802, 674 cm-1

+ HRMS (APPI) m/z calculated for [M] ; C54H24O3: 720.1725; found: 720.1715

1 7.8 H NMR titration experiment of clip 149 with C60 in chlorobenzene-d5

A stock solution of 149 was prepared by dissolving 0.25 mg of the clip 139 in

-4 1.00 mL of chlorobenzene-d5 (3.47 × 10 M). 600 µL of the above solution was subsequently titrated with 10, 20, 30, 40, 50, 60, 70, 80, 100, 150, 200, 300, 400, 500 and

-3 1 1500 µL of 1.37 × 10 M solution of C60 in chlorobenzene-d5 and H NMR spectra were recorded after each addition. Association constants K1 and K2 were estimated from the changes in chemical shifts using the non-linear curve fitting tool in Origin 8.0.

121

1 Table 7.1 H NMR titration data for C60@149 in chlorobenzene-d5

C60 added (μl) [10] M [C60] M

0 0.000347 0

10 0.000341 0.0000225

20 0.000336 0.0000442

30 0.000330 0.0000652

40 0.000325 0.0000856

50 0.000320 0.0001054

60 0.000315 0.0001245

70 0.000311 0.0001431

80 0.000306 0.0001611

100 0.000297 0.0001957

150 0.000277 0.0002740

200 0.000260 0.0003425

300 0.000231 0.0004567

400 0.000208 0.0005480

500 0.000189 0.0006227

1500 0.000099 0.0009786

122

Table 7.1 (Continued)

Proton A Δδ of A Proton B Δδ of B Proton C Δδ of C (ppm) (Hz) (ppm) (Hz) (ppm) (Hz)

8.62 0.00 8.62 0.00 8.175 0.00

8.616 2.40 8.616 2.40 8.173 1.20

8.611 5.40 8.611 5.40 8.171 2.40

8.607 7.80 8.607 7.80 8.169 3.60

8.603 10.2 8.603 10.2 8.167 4.80

8.6 12.0 8.6 12.0 8.1655 5.70

8.597 13.8 8.597 13.8 8.164 6.60

8.593 16.2 8.593 16.2 8.163 7.20

8.591 17.4 8.591 17.4 8.161 8.40

8.586 20.4 8.586 20.4 8.16 9.00

8.577 25.8 8.577 25.8 8.156 11.4

8.57 30.0 8.57 30.0 8.153 13.2

8.562 34.8 8.559 36.6 8.149 15.6

8.558 37.2 8.552 40.8 8.146 17.4

8.554 39.6 8.547 43.8 8.144 18.6

8.54 48.0 8.531 53.4 8.139 21.6

123

Table 7.1 (Continued)

Proton D Δδ of D Proton E Δδ of E Proton F Δδ of E (ppm) (Hz) (ppm) (Hz) (ppm) (Hz)

7.847 0.00 5.323 0.00 3.550 0.00

7.845 1.08 5.321 1.20 3.556 3.60

7.844 1.74 5.317 3.60 3.563 7.80

7.843 2.40 5.314 5.40 3.568 10.8

7.841 3.60 5.311 7.20 3.573 13.8

7.84 4.20 5.308 9.00 3.578 16.8

7.839 4.80 5.306 10.2 3.583 19.8

7.838 5.40 5.304 11.4 3.587 22.2

7.837 6.00 5.303 13.2 3.591 24.6

7.836 6.60 5.299 14.4 3.598 28.8

7.833 8.40 5.293 18.0 3.610 36.0

7.831 9.60 5.288 21.0 3.620 42.0

7.828 11.4 5.281 25.2 3.635 51.0

7.826 12.6 5.276 28.2 3.644 56.4

7.825 13.2 5.273 30.0 3.652 61.2

7.821 15.6 5.263 36.0 3.675 75.0

124

Table 7.1 (Continued)

Mole fraction (MR) MR × Δδ (Hz) of A MR × Δδ of B MR × Δδ of C

1.000 0.000 0.000 0.000

0.9382 2.258 2.252 1.126

0.8836 4.772 4.772 2.121

0.8351 6.514 6.514 3.006

0.7916 8.074 8.074 3.800

0.7523 9.028 9.028 4.288

0.7169 9.893 9.893 4.731

0.6846 11.09 11.09 4.929

0.6550 11.40 11.40 5.502

0.6030 12.30 12.30 5.427

0.5032 12.98 12.98 5.736

0.4317 12.95 12.95 5.698

0.3361 11.70 12.30 5.244

0.2752 10.24 11.23 4.789

0.2330 9.228 10.21 4.334

0.0920 4.414 4.911 1.986

125

Table 7.1 (Continued)

Mole fraction (MR) MR × Δδ of D MR × Δδ of E MR × Δδ of f

1.000 0.000 0.000 0.000

0.9382 1.013 1.126 3.378

0.8836 1.538 3.181 6.893

0.8351 2.004 4.509 9.019

0.7916 2.850 5.699 10.92

0.7523 3.160 6.771 12.64

0.7169 3.441 7.312 14.19

0.6846 3.697 7.804 15.20

0.6550 3.930 8.646 16.11

0.6030 3.980 8.683 17.38

0.5032 4.226 9.057 18.11

0.4317 4.144 9.065 18.13

0.3361 3.832 8.471 17.14

0.2752 3.468 7.762 15.52

0.2330 3.076 6.990 14.26

0.0920 1.435 3.310 6.899

7.9 Preparation of silica

Cab-O-Sil (5 g) was refluxed with concentrated HCl (100 mL) for 6 h. After this time, silica was filtered, washed with water and dried at 150 °C under vacuum for 24 h.

-1 -1 -1 IR: 810 cm (νSi-O-Si bending), 1100 cm (νSi-O-Si streching), 3700-3000 cm (νSi-OH and νH2O)

126

7.10 Modification of silica surface with APTES linker

Scheme 7.7 Modification of silica surface with APTES linker

The dried Cab-O-Sil (2 g) was suspended in 100 mL anhydrous toluene and 6 mL of (3-aminopropyl)triethoxysilane (APTES) under nitrogen at 80 °C overnight.158 The mixture was then sonicated for 20 min, filtered, washed with toluene, DCM, DMF, acetone, CH3OH, cyclohexane, again with DCM and dried at 60 °C under vacuum for 24 h. The dried APTES modified silica was characterized by DRIFT, TGA, and elemental

-1 -1 analysis. IR: 1488 cm (νC-H bending), 1560 cm-1 (νN-H bending), 2850-3000 cm (νC-H

-1 -1 stretching), 3299 cm and 3367 cm (νNH2 )

127

7.11 Synthesis of cycloadduct 151

Scheme 7.8 Synthesis of model compound 151

Cycloadduct 151 was synthesized using previously reported procedure.156

7.12 Immobilization of adduct 151 on APTES modified silica

Scheme 7.9 Immobilization of model compound on APTES modified silica

50 mg of APTES modified silica, cycloadduct 151 (20 mg) and triethylamine (50

μL) was stirred in anhydrous toluene (20 mL) under reflux for 24 h.158 After this time mixtue was sonicated for 20 min, filtered and the silica was washed with toluene, DCM,

128

acetone, MeOH and again with DCM. The adduct 151 immobilized silica was dried under vacuum at 60 °C for 24 h. The dried 151 grafted silica was characterized by

-1 -1 DRIFT, TGA and elemental analysis. IR: 1697 cm and 1770 cm (νC=O imide), 2900-

-1 -1 3000 cm (νaliphatic C-H stretching), 3000-3100 cm (νaromatic C-H stretching).

7.13 Immobilization of clip 149 on APTES modified silica

Scheme 7.10 Immobilization of molecular receptor on APTES modified silica

35 mg of APTES modified silica, clip 149 (22 mg) and triethylamine (50 μL) was stirred in anhydrous toluene (15 mL) under reflux for 24 h. After this time mixtue was sonicated for 20 min, filtered and the silica was washed with toluene, DCM, acetone,

MeOH and again with DCM. The receptor 149 immobilized silica was dried under vacuum at 60 °C for 24 h. The dried clip 149 grafted silica was characterized by DRIFT,

-1 -1 -1 TGA and elemental analysis. IR: 1695 cm and 1776 cm (νC=O imide), 2900-3000 cm

-1 (νaliphatic C-H stretching), 3000-3100 cm (νaromatic C-H stretching).

129

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1H NMR AND 13C/13C DEPTQ135 NMR OF ALL NEW COMPOUNDS

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149

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X-RAY CRYSTAL STRUCTURES

167

X-ray crystal structure for 148b

Crystal structure of 148b

X-ray data were collected at T = 101 K with CuKα radiation on a Bruker Kappa

APEX-II DUO diffractometer to θmax = 72.3°, yielding 3994 independent reflections.

Crystal data monoclinic P21/n, a = 11.0215(5) Å, b = 13.1109(6) Å, c = 15.1972(7) Å, β

= 111.193(2)° , Z = 2, R = 0.1111, 3704 refined parameters. Disordered solvent contribution was removed using the SQUEEZE procedure, amounting to about 2.8 molecules of toluene per molecule of 148b.

168

Table B.1 Crystallographic data, X-ray experimental conditions and structure refinement details for 148b

Empirical formula C50H22O2 Formula weight 654.67 Temperature/K 100.99 Crystal system monoclinic

Space group P21/n a/Å 11.0215(5) b/Å 13.1109(6) c/Å 15.1972(7) α/° 90 β/° 111.193(2) γ/° 90 Volume/Å3 2047.50(16) Z 2 3 ρcalcg/cm 1.062 μ/mm-1 0.500 F(000) 676.0 Crystal size/mm3 0.19 × 0.12 × 0.09 Radiation CuKα (λ = 1.54178) 2Θ range for data collection/° 9.19 to 144.604 Index ranges -12 ≤ h ≤ 13, -16 ≤ k ≤ 16, -18 ≤ l ≤ 18 Reflections collected 35868

Independent reflections 3994 [Rint = 0.0536, Rsigma = 0.0254] Data/restraints/parameters 3994/6/236 Goodness-of-fit on F2 1.054

Final R indexes [I>=2σ (I)] R1 = 0.1111, wR2 = 0.2901

Final R indexes [all data] R1 = 0.1157, wR2 = 0.2936 Largest diff. peak/hole / e Å-3 0.54/-0.39

169

Fractional atomic coordinates (×104) and equivalent Isotropic displacement parameters (Å2×103) for 148b

Atom x y z U(eq) O1 3049(3) 3046(2) 4861.2(19) 26.3(6) C1 2523(3) 3190(3) 1760(2) 17.6(7) C2 3581(3) 2512(3) 2089(3) 19.4(7) C3 4146(3) 2440(3) 1356(3) 20.0(7) C4 3408(4) 3098(3) 604(3) 21.1(8) C5 2412(3) 3574(3) 852(2) 18.4(7) C6 2093(3) 3764(3) 2380(3) 19.9(7) C7 2703(4) 3455(3) 3304(3) 23.0(8) C8 3765(3) 2804(3) 3642(3) 20.0(7) C9 4317(4) 2357(3) 3034(3) 22.2(8) C10 5635(4) 1976(3) 3214(3) 21.0(8) C11 6147(4) 1922(3) 2522(3) 25.6(8) C12 5403(4) 2217(3) 1537(3) 24.7(8) C13 5901(4) 2528(3) 828(3) 27.4(9) C14 5215(4) 3170(3) 94(3) 26.2(9) C15 3954(4) 3546(3) 5(2) 21.5(8) C16 3302(4) 4465(3) -433(3) 30.1(10) C17 2345(4) 4928(3) -203(2) 27.4(9) C18 1954(4) 4517(3) 521(2) 23.4(8) C19 1309(4) 5034(3) 1078(3) 23.1(8) C20 1367(4) 4657(3) 1950(3) 24.4(8) C21 2577(4) 3891(3) 4218(3) 24.5(8) C22 3754(3) 4612(3) 4633(2) 23.6(8) C23 4850(3) 3977(3) 4951(2) 17.2(7) C24 4259(3) 2903(3) 4707(2) 18.5(7) C25 3880(4) 5665(3) 4682(2) 19.9(7)

Ueq is defined as 1/3 of the trace of the orthogonalised UIJ tensor

170

Anisotropic displacement parameters (Å2×103) for 148b

Atom U11 U22 U33 U23 U13 U12 O1 23.2(14) 30.6(14) 26.4(14) 2.2(11) 10.7(11) -3.5(11) C1 13.4(16) 14.6(15) 21.7(17) -6.3(13) 2.8(13) -4.5(12) C2 20.1(17) 14.2(16) 24.6(18) -0.6(13) 8.8(14) -8.0(13) C3 19.9(17) 20.2(17) 23.1(17) -2.4(14) 11.7(14) -5.0(14) C4 28.2(19) 17.9(16) 21.1(17) -3.4(13) 13.6(15) -13.1(14) C5 17.0(16) 24.4(18) 9.4(14) -4.3(13) -0.6(12) -5.7(13) C6 15.5(16) 21.2(17) 23.2(17) -6.2(14) 7.0(13) -11.2(13) C7 19.6(18) 15.7(16) 31(2) -4.9(14) 6.3(15) -8.9(13) C8 19.1(17) 19.1(17) 21.3(17) -2.2(13) 6.9(14) -5.9(13) C9 29(2) 13.8(16) 25.7(18) 1.4(13) 12.5(15) 3.0(14) C10 23.0(18) 17.5(16) 25.8(18) -1.3(14) 12.7(15) 2.9(14) C11 29(2) 26.5(19) 24.3(19) 0.2(15) 13.9(16) 2.1(15) C12 28(2) 25.0(19) 22.3(18) -4.1(15) 9.8(15) -6.6(15) C13 24.8(19) 34(2) 21.5(18) -9.9(15) 5.7(15) -4.3(16) C14 27(2) 38(2) 19.4(17) -7.8(15) 15.7(15) -16.3(16) C15 27.1(19) 20.2(17) 17.3(16) -7.1(13) 8.1(14) -12.6(14) C16 40(2) 33(2) 11.9(16) 1.8(15) 2.8(15) -18.4(18) C17 35(2) 28(2) 11.7(16) -0.4(14) -0.5(15) -4.1(16) C18 23.3(18) 24.2(18) 12.1(15) -6.0(13) -6.5(13) -1.9(14) C19 21.5(18) 23.9(18) 17.9(17) 2.7(14) -0.2(13) -0.5(14) C20 22.1(18) 28.6(19) 21.0(18) -5.8(15) 5.9(15) -1.5(15) C21 17.3(17) 31(2) 28.9(19) 1.7(16) 12.8(15) 1.1(15) C22 15.3(17) 37(2) 17.3(16) -4.2(15) 4.0(13) 12.4(15) C23 16.9(13) 21.5(14) 16.4(12) -3.2(11) 10.1(10) 6.9(11) C24 19.6(17) 18.0(17) 22.0(17) 1.1(13) 12.4(14) 9.0(13) C25 21.7(17) 22.9(17) 15.8(16) -0.8(13) 7.8(13) 4.0(14) The anisotropic displacement factor exponent takes the form: 2 2 2 2π [h a* U11+2hka*b*U12+…]

171

Bond lengths for 148b

Atom Atom Length/Å Atom Atom Length/Å O1 C21 1.444(5) C9 C10 1.465(5) O1 C24 1.448(4) C10 C11 1.364(5) C1 C2 1.407(5) C11 C12 1.475(5) C1 C5 1.431(5) C12 C13 1.434(5) C1 C6 1.415(5) C13 C14 1.383(6) C2 C3 1.463(5) C14 C15 1.435(6) C2 C9 1.386(5) C15 C16 1.437(6) C3 C4 1.427(5) C16 C17 1.367(6) C3 C12 1.343(6) C17 C18 1.426(6) C4 C5 1.426(5) C18 C19 1.454(6) C4 C15 1.389(5) C19 C20 1.395(5) C5 C18 1.361(5) C21 C22 1.544(6) C6 C7 1.380(5) C22 C23 1.401(5) C6 C20 1.435(5) C22 C25 1.387(6) C7 C8 1.388(5) C23 C24 1.540(5) C7 C21 1.555(5) C23 C251 1.388(5) C8 C9 1.405(5) C25 C231 1.388(5)

C8 C24 1.515(5)

172

Bond angles for 148b

Atom Atom Atom Angle/˚ Atom Atom Atom Angle/˚ C21 O1 C24 96.7(3) C10 C11 C12 122.4(4) C2 C1 C5 109.6(3) C3 C12 C11 114.8(3) C2 C1 C6 122.2(3) C3 C12 C13 115.5(4) C6 C1 C5 121.5(3) C13 C12 C11 127.8(4) C1 C2 C3 107.2(3) C14 C13 C12 122.2(4) C9 C2 C1 124.1(3) C13 C14 C15 120.9(3) C9 C2 C3 122.0(3) C4 C15 C14 115.3(4) C4 C3 C2 107.2(3) C4 C15 C16 113.3(4) C12 C3 C2 123.3(3) C14 C15 C16 129.5(3) C12 C3 C4 122.9(3) C17 C16 C15 123.8(3) C5 C4 C3 108.8(3) C16 C17 C18 120.4(4) C15 C4 C3 121.5(4) C5 C18 C17 116.9(4) C15 C4 C5 123.0(4) C5 C18 C19 113.8(3) C4 C5 C1 107.2(3) C17 C18 C19 128.3(4) C18 C5 C1 124.4(3) C20 C19 C18 121.5(3) C18 C5 C4 121.2(3) C19 C20 C6 123.2(3) C1 C6 C20 113.4(3) O1 C21 C7 101.3(3) C7 C6 C1 111.4(3) O1 C21 C22 98.7(3) C7 C6 C20 133.5(3) C22 C21 C7 104.8(3) C6 C7 C8 126.3(4) C23 C22 C21 105.6(3) C6 C7 C21 129.3(3) C25 C22 C21 133.2(3) C8 C7 C21 103.3(3) C25 C22 C23 121.1(4) C7 C8 C9 121.4(3) C22 C23 C24 102.9(3) C7 C8 C24 105.8(3) C25 C23 C22 123.8(4) C9 C8 C24 131.6(3) C25 C23 C24 133.1(3) C2 C9 C8 112.9(3) O1 C24 C8 100.8(3) C2 C9 C10 114.3(3) O1 C24 C23 100.2(3) C8 C9 C10 131.0(3) C8 C24 C23 107.0(3) C11 C10 C9 122.2(4) C22 C25 C23 115.1(3)

173

Table B.5 (continued)

O1 C21 C22 C23 34.5(3) C7 C8 C9 C10 154.8(4) O1 C21 C22 C25 -149.4(4) C7 C8 C24 O1 35.1(3) C1 C2 C3 C4 0.7(4) C7 C8 C24 C23 -69.2(3) C1 C2 C3 C12 152.6(4) C7 C21 C22 C23 -69.7(4) C1 C2 C9 C8 10.8(5) C7 C21 C22 C25 106.4(4) C1 C2 C9 C10 -156.0(3) C8 C7 C21 O1 -31.2(3) C1 C5 C18 C17 157.0(3) C8 C7 C21 C22 71.1(3) C1 C5 C18 C19 -12.9(5) C8 C9 C10 C11 -154.7(4) C1 C6 C7 C8 10.9(5) C9 C2 C3 C4 -151.5(3) C1 C6 C7 C21 177.4(3) C9 C2 C3 C12 0.4(6) C1 C6 C20 C19 -12.1(5) C9 C8 C24 O1 -157.7(4) C2 C1 C5 C4 1.6(4) C9 C8 C24 C23 98.0(4) C2 C1 C5 C18 -148.9(3) C9 C10 C11 C12 -1.7(6) C2 C1 C6 C7 -9.1(5) C10 C11 C12 C3 -6.6(6) C2 C1 C6 C20 158.1(3) C10 C11 C12 C13 157.1(4) C2 C3 C4 C5 0.2(4) C11 C12 C13 C14 -152.4(4) C2 C3 C4 C15 152.4(3) C12 C3 C4 C5 -151.8(3) C2 C3 C12 C11 7.2(5) C12 C3 C4 C15 0.4(6) C2 C3 C12 C13 -158.5(3) C12 C13 C14 C15 -0.8(6) C2 C9 C10 C11 9.1(5) C13 C14 C15 C4 -9.7(5) C3 C2 C9 C8 158.3(3) C13 C14 C15 C16 153.7(4) C3 C2 C9 C10 -8.5(5) C14 C15 C16 C17 -155.9(4) C3 C4 C5 C1 -1.1(4) C15 C4 C5 C1 -152.8(3) C3 C4 C5 C18 150.5(3) C15 C4 C5 C18 -1.1(5) C3 C4 C15 C14 10.1(5) C15 C16 C17 C18 1.2(6) C3 C4 C15 C16 -156.0(3) C16 C17 C18 C5 -10.4(5) C3 C12 C13 C14 11.2(6) C16 C17 C18 C19 157.8(4) C4 C3 C12 C11 154.8(3) C17 C18 C19 C20 -158.3(4) C4 C3 C12 C13 -10.9(5) C18 C19 C20 C6 2.3(6) C4 C5 C18 C17 10.4(5) C20 C6 C7 C8 -152.7(4) C4 C5 C18 C19 -159.5(3) C20 C6 C7 C21 13.8(6) C4 C15 C16 C17 7.7(5) C21 O1 C24 C8 -53.4(3) C5 C1 C2 C3 -1.4(4) C21 O1 C24 C23 56.3(3) -171.2(3) C5 C1 C2 C9 150.1(3) C21 C7 C8 C9

174

175

Table B.5 (Continued)

C5 C1 C6 C7 -157.5(3) C21 C7 C8 C24 -2.3(4) C5 C1 C6 C20 9.6(5) C21 C22 C23 C24 0.0(3) C5 C4 C15 C14 158.3(3) C21 C22 C23 C251 175.6(3) C5 C4 C15 C16 -7.8(5) C21 C22 C25 C231 -174.7(4) C5 C18 C19 C20 10.2(5) C22 C23 C24 O1 -34.6(3) C6 C1 C2 C3 -153.1(3) C22 C23 C24 C8 70.2(3) C6 C1 C2 C9 -1.6(5) C23 C22 C25 C231 1.0(5) C6 C1 C5 C4 153.5(3) C24 O1 C21 C7 51.9(3) C6 C1 C5 C18 3.1(5) C24 O1 C21 C22 -55.2(3) C6 C7 C8 C9 -1.9(6) C24 C8 C9 C2 -174.8(3) C6 C7 C8 C24 166.9(3) C24 C8 C9 C10 -10.8(7) C6 C7 C21 O1 160.0(3) C25 C22 C23 C24 -176.7(3) C6 C7 C21 C22 -97.8(4) C25 C22 C23 C251 -1.1(6) C7 C6 C20 C19 151.3(4) C251 C23 C24 O1 150.4(4) C7 C8 C9 C2 -9.2(5) C251 C23 C24 C8 -104.9(4)

Hydrogen atom coordinates (Å×104) and isotropic displacement parameters (Å2×103) for 148b

Atom x y z U(eq) H10 6149 1759 3833 25 H11 7015 1686 2680 31 H13 6729 2285 863 33 H14 5585 3365 -357 31 H16 3549 4767 -911 36 H17 1939 5528 -528 33 H19 837 5644 841 28 H20 902 5008 2276 29 H21 1708 4174 4157 29 H24 4819 2330 5066 22 H25 3150 6110 4479 24

176

X-ray crystal structure for 149

Crystal structure of 149

10 as the toluene solvate. X-ray data were collected at T =90 K with CuKα radiation on a Bruker Kappa APEX-II DUO diffractometer to θmax =62.3°, yielding 3116 independent reflections. Crystal data monoclinic P21/m, a = 10.8890(4) Å, b =

13.3104(6)Å, c = 13.9583(6)Å, β = 106.526(2), Z = 2, R = 0.046, 538 refined parameters and 530 restraints. The main molecule lies across a mirror plane and is disordered by a tilt of approximately 11 degrees from the mirror. The anydride C2O3 moiety is further disordered into two orientations with 71:29 relative population. The toluene molecule is also disordered.

177

Crystallographic data, X-ray experimental conditions and structure refinement details for 149

Empirical formula C54H24O3  C7H8 Formula weight 812.86 Temperature/K 90.0 Crystal system monoclinic Space group P21/m a/Å 10.8890(4) b/Å 13.3104(6) c/Å 13.9583(6) α/° 90 β/° 106.526(2) γ/° 90 Volume/Å3 1939.50(14) Z 2 3 ρcalcg/cm 1.392 μ/mm-1 0.662 F(000) 844.0 Crystal size/mm3 0.35 × 0.24 × 0.14 Radiation CuKα (λ = 1.54184) 2Θ range for data collection/° 6.60 to 122.54 Index ranges -11 ≤ h ≤ 12, -12 ≤ k ≤ 15, -15 ≤ l ≤ 14 Reflections collected 19440

Independent reflections 3116 [Rint = 0.0394, Rsigma = 0.0226] Data/restraints/parameters 3116/530/538 Goodness-of-fit on F2 1.043

Final R indexes [I>=2σ (I)] R1 = 0.0460, wR2 = 0.1381 Final R indexes [all data] R1 = 0.0509, wR2 = 0.1445 Largest diff. peak/hole / e Å-3 0.24/-0.18

178

Fractional Atomic Coordinates (×104) and equivalent isotropic displacement parameters (Å2×103) for 149

Atom x y z U(eq) O1 3817(2) 2500 3227.4(16) 68.2(7) O2 3998.2(16) 833.2(16) 3425.3(14) 77.9(6) C1 4246(2) 1642(2) 3790.0(18) 62.0(7) O1A 7093(7) 2500 5522(5) 82(2) O2A 6853(6) 834(4) 5443(4) 97.1(18) C1A 6362(8) 1645(6) 5291(5) 82(2) C2 4957.1(16) 1925.8(13) 4848.5(12) 57.9(4) C3 4209.8(15) 1520.3(12) 5571.4(11) 54.9(4) C4 2884.1(15) 1972.4(12) 5201.3(10) 50.2(4) C5 1753.2(15) 1452.8(13) 4843.9(11) 55.3(4) C17 4867.3(15) 1972.6(13) 6581.0(12) 57.6(4) C18 5472.4(16) 1453.1(17) 7433.4(13) 69.4(5) C6 612(6) 1843(16) 4469(6) 47(2) C6A 546(6) 2929(16) 4521(5) 47(2) C7 -548(10) 1243(7) 4049(11) 48(2) C7A -682(11) 3437(8) 4089(11) 51(2) C8 -1670(4) 1766(4) 3825(3) 50.6(18) C8A -1739(3) 2830(5) 3859(2) 50.6(18) C9 -2817(7) 1412(5) 3134(6) 54.5(16) C9A -2913(6) 3118(5) 3192(5) 51.2(14) C10 -3569(4) 2243(3) 2747(3) 56.0(16) C11 -4445(4) 2244(3) 1821(3) 61(2) C12 -4672(7) 1269(5) 1355(6) 62.9(17) C12A -4799(7) 3190(5) 1402(6) 64.5(18) C13 -3920(6) 441(4) 1749(5) 63.2(14) C13A -4178(5) 4070(5) 1802(5) 57.6(14) C14 -2876(7) 509(6) 2651(5) 54.3(16) C14A -3116(7) 4037(6) 2703(6) 54.0(17) C15 -1760(7) -113(4) 2990(6) 58.1(16) C15A -2086(7) 4730(5) 3047(6) 54.7(15) C16 -647(9) 244(7) 3655(8) 55.1(19) C16A -918(9) 4447(7) 3716(8) 56(2) Ueq is Defined as 1/3 of of the trace of the orthogonalised UIJ tensor

179

Table B.8 (Continued)

C19 6098(9) 2161(5) 8360(6) 46(3) C19A 6074(8) 3244(6) 8283(6) 49(2) C20 6797(7) 1640(5) 9268(5) 57.1(16) C20A 6807(7) 3839(5) 9155(5) 53.3(16) C21 7269(6) 2245(4) 10080(4) 54(3) C21A 7270(5) 3313(4) 10031(4) 57.2(19) C22 8286(5) 1956(5) 10918(4) 61.3(12) C22A 8279(6) 3671(6) 10830(4) 62.5(14) C23 8909(4) 2830(3) 11381(3) 66.5(16) C24 10166(5) 2840(4) 11917(4) 71(2) C25 10749(7) 1890(6) 12118(4) 75.2(16) C25A 10751(7) 3800(6) 12029(4) 78.5(18) C26 10160(6) 1005(6) 11686(4) 73.4(16) C26A 10127(5) 4663(5) 11509(3) 73.0(13) C27 8890(6) 1044(6) 10982(4) 69.5(17) C27A 8874(6) 4575(5) 10815(4) 68.5(14) C28 8278(6) 352(5) 10222(5) 68.5(13) C28A 8276(5) 5190(4) 9970(4) 64.8(12) C29 7286(7) 631(5) 9386(5) 61.0(16) C29A 7289(6) 4847(4) 9177(5) 62.4(15) C30 11465(4) 2635(13) 8167(3) 51(3) C31 10833(4) 2678(13) 7151(3) 64(3) C32 9518(4) 2521(12) 6817(2) 83(3) C33 8835(4) 2320(11) 7498(3) 69(4) C34 9467(5) 2277(15) 8514(3) 98(3) C35 10782(5) 2434(15) 8849(2) 74(4) C36 12895(6) 2705(8) 8588(5) 61(3) C30A 9806(5) 2661(15) 7521(5) 80(5) C31A 11023(7) 2778(19) 7401(6) 64(3) C32A 12100(5) 2640(30) 8210(9) 106(7) C33A 11961(8) 2380(20) 9139(7) 102(5) C34A 10744(11) 2265(15) 9259(5) 94(5) C35A 9667(7) 2405(17) 8450(6) 98(3) C36A 8586(12) 2881(11) 6677(10) 126(5)

180

Anisotropic Displacement Parameters (Å2×103) for 149

Atom U11 U22 U33 U23 U13 U12 O1 48.1(12) 113(2) 41.0(12) 0 9.2(10) 0 O2 56.8(10) 106.9(16) 65.9(11) -32.6(11) 10.8(8) 1(1) C1 42.9(12) 96(2) 47.1(13) -11.3(13) 13.2(10) 2.9(12) O1A 91(5) 84(5) 80(4) 0 38(4) 0 O2A 119(4) 83(4) 100(4) 8(3) 49(3) 25(3) C1A 121(6) 72(5) 69(4) -2(3) 54(4) 11(5) C2 52.4(9) 70.9(10) 48.3(9) -4.0(8) 11.3(7) 5.6(8) C3 58.7(9) 53.1(10) 48.4(9) 5.1(7) 7.9(7) 2.3(7) C4 54.4(9) 58.0(8) 37.0(8) 3.3(6) 11.0(6) -1.8(7) C5 63.6(10) 61.5(10) 38.8(8) 7.6(7) 11.4(7) -7.6(8) C17 51.9(9) 74.8(10) 43.9(9) 6.6(7) 10.0(7) 0.3(7) C18 53.7(10) 100.0(15) 51.3(11) 17.9(10) 9.8(8) -1.4(9) C6 53.1(10) 58(8) 31.5(9) -0.1(12) 12.6(8) 1.2(14) C6A 53.1(10) 58(8) 31.5(9) -0.1(12) 12.6(8) 1.2(14) C7 55(3) 53(6) 37(3) 3(4) 14(2) -6(4) C7A 65(4) 54(5) 37(2) -6(4) 20(3) 4(3) C8 50.1(10) 68(6) 36.6(9) -0.7(10) 16.3(8) -3.2(11) C8A 50.1(10) 68(6) 36.6(9) -0.7(10) 16.3(8) -3.2(11) C9 58(3) 61(5) 49(3) -8(4) 22(3) -12(3) C9A 50(3) 67(4) 40(2) 6(3) 20(2) 5(3) C10 50.0(17) 71(5) 48.8(18) -2.1(18) 16.9(14) -5.9(18) C11 49.1(19) 74(7) 58(2) -8(2) 13.5(17) -10.2(19) C12 51(3) 82(5) 52(3) -1(4) 8(2) -15(4) C12A 50(3) 83(6) 58(3) -8(5) 11(2) 1(4) C13 60(3) 68(3) 64(3) 3(3) 21(2) -13(3) C13A 47(3) 74(4) 50(3) -5(3) 10(2) 5(3) C14 54(4) 59(4) 50(3) 10(3) 14(3) -10(3) C14A 52(3) 60(5) 53(3) -11(4) 20(3) 3(3) C15 73(4) 47(3) 53(2) 13(3) 16(3) -10(3) C15A 59(4) 50(4) 53(3) -13(3) 14(3) 6(3) C16 62(4) 55(5) 46(3) 11(3) 12(3) -12(3) C16A 58(4) 64(7) 45(3) -16(4) 16(3) 2(3) The Anisotropic displacement factor exponent takes the form: - 2 2 2 2π [h a* U11+2hka*b*U12+…] 181

Table B.9 (Continued)

C19 53(2) 47(9) 38(2) -1(2) 9.2(15) -3(3) C19A 52(2) 48(6) 46(3) 5(3) 10.5(17) 7(3) C20 59(2) 64(4) 51(4) 4(3) 19(2) -1(3) C20A 54(3) 64(5) 38(3) -8(3) 7(2) 4(4) C21 54.3(18) 69(11) 40.7(17) 4(3) 14.1(13) -2(3) C21A 57(2) 76(6) 37(2) -1(3) 12.7(18) 6(3) C22 61(3) 86(3) 40(3) 8(3) 20(2) -4(3) C22A 58(3) 90(4) 37(2) -5(3) 11(3) 4(4) C23 64(2) 102(5) 34.5(17) 5.2(19) 14.5(17) 0(2) C24 65(3) 112(6) 35(2) 6(2) 10(2) -7(3) C25 68(4) 118(5) 38(3) 14(3) 11(3) 0(4) C25A 63(4) 133(5) 35(3) 5(4) 7(2) 3(5) C26 72(4) 102(5) 47(3) 19(4) 18(3) -5(4) C26A 70(3) 105(4) 41(2) -8(3) 10.6(18) -3(3) C27 61(4) 103(5) 45(3) 24(3) 15(3) 1(4) C27A 69(3) 94(4) 38(3) -12(3) 9(2) 5(3) C28 76(3) 73(4) 61(4) 14(3) 26(3) 0(3) C28A 66(2) 78(3) 46(2) -19(3) 8.9(18) 3(3) C29 61(3) 67(5) 53(3) 22(3) 12(3) 4(4) C29A 61(2) 60(4) 60(3) -14(3) 7(2) 5(3) C30 94(5) 17(10) 44(3) -7(3) 22(4) -5(5) C31 74(2) 71(8) 49(3) -12(5) 23(2) -4(3) C32 86(5) 116(7) 52(3) -41(10) 27(3) -38(11) C33 78(4) 72(12) 65(3) -17(4) 33(3) -11(4) C34 110(4) 119(9) 76(3) -13(4) 47(2) -17(5) C35 85(5) 80(10) 70(4) -39(12) 41(4) -37(9) C36 62(3) 56(10) 63(3) -3(3) 14(3) 6(3) C30A 78(5) 72(15) 96(6) 4(7) 36(5) -25(8) C31A 74(2) 71(8) 49(3) -12(5) 23(2) -4(3) C32A 94(10) 60(20) 132(12) -7(10) -22(9) -10(14) C33A 123(9) 60(13) 90(7) -10(9) -24(6) 5(10) C34A 114(9) 44(10) 129(11) -8(9) 43(8) -13(6) C35A 110(4) 119(9) 76(3) -13(4) 47(2) -17(5)

182

Bond Lengths for 149

Atom Atom Length/Å Atom Atom Length/Å O1 C11 1.389(3) C15 C16 1.384(10) O1 C1 1.389(3) C15A C16A 1.400(10) O2 C1 1.189(3) C19 C19A 1.445(7) C1 C2 1.508(3) C19 C20 1.455(10) O1A C1A 1.374(9) C19A C20A 1.480(10) O1A C1A1 1.374(9) C20 C21 1.366(8) O2A C1A 1.197(8) C20 C29 1.437(7) C1A C2 1.524(9) C20A C21A 1.374(8) C2 C21 1.529(4) C20A C29A 1.438(7) C2 C3 1.562(2) C21 C22 1.416(7) C3 C17 1.512(2) C21 C21A 1.423(9) C3 C4 1.513(2) C21A C22A 1.407(8) C4 C5 1.376(2) C22 C27 1.371(9) C4 C41 1.404(3) C22 C23 1.408(7) C5 C6 1.310(7) C22A C27A 1.370(9) C17 C18 1.372(2) C22A C23 1.419(8) C17 C171 1.404(4) C23 C24 1.361(6) C18 C19 1.588(7) C24 C25 1.408(8) C6 C6A 1.450(4) C24 C25A 1.416(10) C6 C7 1.468(11) C25 C26 1.393(10) C6A C7A 1.467(11) C25A C26A 1.424(8) C7 C8 1.363(10) C26 C27 1.452(8) C7 C16 1.431(9) C26A C27A 1.436(7) C7A C8A 1.367(9) C27 C28 1.420(8) C7A C16A 1.437(9) C27A C28A 1.431(7) C8 C8A 1.420(5) C28 C29 1.397(8) C8 C9 1.424(8) C28A C29A 1.383(7) C8A C9A 1.404(7) C30 C31 1.3900 C9 C14 1.371(8) C30 C35 1.3900 C9 C10 1.391(8) C30 C36 1.503(7) C9A C14A 1.387(7) C31 C32 1.3900 C9A C10 1.414(7) C32 C33 1.3900 C10 C11 1.371(6) C33 C34 1.3900 C11 C12A 1.396(8) C34 C35 1.3900 183

Table B.10 (Continued)

C11 C12 1.440(8) C30A C31A 1.3900 C12 C13 1.390(7) C30A C35A 1.3900 C12A C13A 1.388(9) C30A C36A 1.533(12) C13 C14 1.439(8) C31A C32A 1.3900 C13A C14A 1.448(9) C32A C33A 1.3900 C14 C15 1.434(7) C33A C34A 1.3900 C14A C15A 1.426(7) C34A C35A 1.3900

184

Bond Angles for 149

Atom Atom Atom Angle/˚ Atom Atom Atom Angle/˚ C11 O1 C1 110.6(3) C16 C15 C14 121.4(6) O2 C1 O1 120.2(2) C16A C15A C14A 121.9(6) O2 C1 C2 129.6(2) C15 C16 C7 122.2(7) O1 C1 C2 110.1(2) C15A C16A C7A 121.9(8) C1A O1A C1A1 111.9(9) C19A C19 C20 122.2(7) O2A C1A O1A 120.4(8) C19A C19 C18 122.5(8) O2A C1A C2 129.7(7) C20 C19 C18 115.1(5) O1A C1A C2 109.9(6) C19 C19A C20A 118.6(7) C1 C2 C21 104.50(13) C21 C20 C29 114.6(5) C1A C2 C21 104.2(3) C21 C20 C19 115.0(5) C1 C2 C3 109.27(15) C29 C20 C19 129.1(6) C1A C2 C3 107.5(3) C21A C20A C29A 114.6(5) C21 C2 C3 110.22(9) C21A C20A C19A 115.8(6) C17 C3 C4 108.22(13) C29A C20A C19A 128.6(6) C17 C3 C2 105.60(13) C20 C21 C22 123.1(5) C4 C3 C2 105.30(12) C20 C21 C21A 123.7(6) C5 C4 C41 120.17(10) C22 C21 C21A 107.4(6) C5 C4 C3 126.32(15) C20A C21A C22A 122.7(5) C41 C4 C3 113.44(9) C20A C21A C21 123.1(7) C6 C5 C4 126.5(9) C22A C21A C21 108.1(6) C18 C17 C171 120.27(12) C27 C22 C23 122.8(4) C18 C17 C3 126.21(17) C27 C22 C21 122.9(6) C171 C17 C3 113.46(9) C23 C22 C21 108.4(5) C17 C18 C19 113.3(3) C27A C22A C21A 123.4(5) C5 C6 C6A 115.5(12) C27A C22A C23 122.9(6) C5 C6 C7 123.7(15) C21A C22A C23 108.1(6) C6A C6 C7 120.8(7) C24 C23 C22 122.6(4) C6 C6A C7A 119.5(7) C24 C23 C22A 123.1(5) C8 C7 C16 114.9(8) C22 C23 C22A 107.9(5) C8 C7 C6 115.3(7) C23 C24 C25 115.3(4) C16 C7 C6 128.4(10) C23 C24 C25A 114.8(5) C8A C7A C16A 114.6(9) C25 C24 C25A 128.7(6) C8A C7A C6A 115.6(7) C26 C25 C24 123.2(4)

185

Table B.11 (Continued)

C16A C7A C6A 128.9(10) C24 C25A C26A 122.5(5) C7 C8 C8A 123.6(7) C25 C26 C27 119.6(6) C7 C8 C9 122.9(6) C25A C26A C27A 120.1(6) C8A C8 C9 107.9(5) C22 C27 C28 114.3(6) C7A C8A C9A 122.8(7) C22 C27 C26 115.1(6) C7A C8A C8 123.3(7) C28 C27 C26 129.5(7) C9A C8A C8 107.3(4) C22A C27A C28A 114.1(5) C14 C9 C10 124.5(6) C22A C27A C26A 115.1(6) C14 C9 C8 122.2(6) C28A C27A C26A 129.2(5) C10 C9 C8 107.8(5) C29 C28 C27 122.6(6) C14A C9A C8A 123.6(6) C29A C28A C27A 122.6(5) C14A C9A C10 121.3(6) C28 C29 C20 121.2(6) C8A C9A C10 108.5(6) C28A C29A C20A 121.4(5) C11 C10 C9 122.8(4) C31 C30 C35 120.0 C11 C10 C9A 122.9(4) C31 C30 C36 123.6(4) C9 C10 C9A 108.4(5) C35 C30 C36 116.2(4) C10 C11 C12A 115.5(5) C32 C31 C30 120.0 C10 C11 C12 114.2(4) C31 C32 C33 120.0 C12A C11 C12 129.2(5) C34 C33 C32 120.0 C13 C12 C11 122.0(6) C33 C34 C35 120.0 C13A C12A C11 123.3(6) C34 C35 C30 120.0 C12 C13 C14 121.7(6) C31A C30A C35A 120.0 C12A C13A C14A 120.1(5) C31A C30A C36A 122.3(8) C9 C14 C15 115.3(5) C35A C30A C36A 117.6(8) C9 C14 C13 113.6(6) C30A C31A C32A 120.0 C15 C14 C13 129.5(6) C33A C32A C31A 120.0 C9A C14A C15A 113.9(6) C32A C33A C34A 120.0 C9A C14A C13A 115.5(6) C35A C34A C33A 120.0 C15A C14A C13A 129.0(7) C34A C35A C30A 120.0

1+X,1/2-Y,+Z

186

Hydrogen Atom Coordinates (Å×104) and Isotropic Displacement Parameters (Å2×103) for 149

Atom x y z U(eq) H2 5852 1658 5035 69 H2A 4604 1650 4158 69 H3 4190 770 5590 66 H5 1774 739 4844 66 H18 5493 740 7425 83 H12 -5356 1190 760 75 H12A -5499 3234 813 77 H13 -4099 -186 1413 76 H13A -4451 4695 1484 69 H15 -1786 -784 2752 70 H15A -2196 5404 2814 66 H16 75 -188 3856 66 H16A -261 4935 3931 67 H25 11585 1849 12570 90 H25A 11591 3871 12468 94 H26 10588 379 11851 88 H26A 10541 5299 11622 88 H28 8555 -328 10285 82 H28A 8568 5861 9954 78 H29 6928 145 8886 73 H29A 6922 5286 8634 75 H31 11300 2816 6686 77 H32 9086 2551 6123 100 H33 7936 2213 7270 82 H34 9000 2140 8980 117 H35 11214 2405 9543 89 H36A 13126 2657 9319 91 H36B 13300 2154 8324 91 H36C 13192 3349 8397 91 H36D 13286 2783 8041 91 H36E 13112 3286 9036 91 H36F 13220 2091 8963 91

187

Table B.12 (Continued)

H32A 12931 2717 8128 127 H33A 12697 2286 9692 122 H34A 10649 2090 9894 113 H35A 8836 2326 8532 117 H36G 7834 2752 6912 189 H36H 8586 3585 6473 189 H36I 8557 2445 6105 189 H36J 8817 3102 6081 189 H36K 8065 2270 6520 189 H36L 8095 3410 6889 189

188

CALCULATIONS OF SILICA SURFACE COVERAGES

189

Calculation of C/N ratio based on the elemental analysis

Carbon percentage based on the elemental analysis = 3.54%

Number of moles of C in 100 g of silica = 3.54 g/12 g mol-1 = 0.295 mol

Nitrogen percentage based on the elemental analysis = 1.23%

Number of moles of N in 100 g of silica= 1.23 g/14 g mol-1 = 0.088 mol

C/N ratio = 0.295 mol/0.088 mol = 3.35

APTES coverage based on the elemental analysis

Number of moles of N in 1 g of silica = 0.088 mol/100 = 0.88 mmol

Therefore, APTES coverage on silica surface = 0.88 mmol g-1

Average specific surface area of silica = 200 m2 g-1

Number of linker molecules per nm2

0.88 푚푚표푙 푚2 × 6.02 × 1023 푚표푙−1 × 10−18 = 2.65 -2 = 200 푚2 푛푚2 molecules nm

APTES coverage based on the TGA data148

%푊 ( 퐴푃푇퐸푆 ) × 100 − %푊 100 − %푊 푠𝑖푙𝑖푐푎 = 퐴푃푇퐸푆 푀푊 표푓 푣표푙푎푡푎푙푒 푓푟푎푔푚푒푛푡 × 100

6.8 ( )×100−2.1 = 100−6.8 = 0.0009 푚표푙 푔−1 -1 58×100 = 0.90 mmol g

%WAPTES = Total weight loss of APTES modified silica = 6.8% (Figure 6.4)

%WSilica = Total weight loss of unmodified silica = 2.1% (Figure 6.4)

Molecular weight of volatile components of APTES (assuming all APTES groups were attached to the surface via tridentate binding mode)

=(12 (C) × 3 + 14 (N) × 1 + 8 (H) × 1) = 58 푔 푚표푙−1

190

151 coverage on silica surface based on the elemental analysis

Weight adjusted procedure for the calculation of 151 coverage on silica.147

Step 1

First assume that weight gain is negligible. The model compound 151 coverage can be calculated using the carbon percentages

퐶% 표푓 ퟏퟓퟏ 푚표푑𝑖푓𝑖푒푑 푠𝑖푙𝑖푐푎−퐶%표푓 퐴푃푇퐸푆 푚표푑𝑖푓𝑖푒푑 푠𝑖푙𝑖푐푎 = 푛표 표푓 푐푎푟푏표푛 푎푡표푚푠 푝푒푟 퐴푃푇퐸푆 푚표푙푒푐푢푙푒 × 푎푡표푚𝑖푐 푤푒𝑖푔ℎ푡 표푓 푐푎푟푏표푛 × 100

(12.64−3.54) 𝑔 = = 0.00042 mol g-1 = 0.42 mmol g-1 18 ×12 𝑔 푚표푙−1 ×100 𝑔

Step 2

Using this surface coverage to adjust for weight change of the silica

To prepare 100 g of 151 modified silica, needs 100 g – 100 × 0.00042 × 276 (molar mass of 151) + 100×0.00042×18 (molar mass of H2O) = 89.2 g of APTES modified silica , as the reaction of APTES modified silica with 151 loss of one H2O molecule (Scheme 6.3).

Step 3

Recalculate the surface coverage considering this weight change.

Since it required 89.2 g of APTES modified silica to make 100 g of 151 grafted silica the coverage is

89.2 (12.64−3.54× )𝑔 = 100 = 0.00044 푚표푙 푔−1 -1 18 ×12 𝑔 푚표푙−1 ×100 𝑔 = 0.44 mmolg

Step 4

Repeat step 2 and 3 until convergence of the results.

After two iterations 151 coverage on surface = 0.44 mmolg-1

Average specific surface area of silica = 200 m2/g

191

Number of 151 molecules per nm2

0.44 푚푚표푙 푚2 × 6.023 × 1023 푚표푙−1 × 10−18 = 1.3 -2 = 200 푚2 푛푚2 molecules nm

Cycloadduct 151 coverage on silica surface based on TGA data

Due to the immobilization of 151 on silica surface, the APTES loading per gram of silica should be less than the initial APTES coverage (0.88 mmol g-1). A new APTES coverage on 151 grafted silica can be calculated by N% obtained from the elemental analysis.

N% obtained from the elemental analysis (after immobilization of 151) = 1.09%

Number of moles of N per 100g of silica = 1.09 g/14 g mol-1 = 0.078 mol

Number of moles of N per 1g of silica = 0.078 mol/100 = 0.78 mmol

New APTES coverage = 0.78 mmol g-1

Calculated weight loss from the APTES on 151 modified silica (based on 0.78 mmol g-1 coverage)

= 0.78 × 10-3 mol g-1 × 58 g mol-1 × 100%= 4.5%

Therefore, %weight loss due to 151 release

= 17.5% – 4.5% = 13.0%

Molecular weight of volatile components of 151 (assuming all ethoxy groups were attached to the surface via tridentate binding mode)

=(12 (C) × 18 + 16 (O) × 2 + 12(H) × 1) = 260 푔 푚표푙−1

Surface coverage of adduct 151 on silica surface

13.0 1 푚푚표푙 = ( × × 103 ) = 0.50 푚푚표푙 푔−1 100 푔 푠𝑖푙𝑖푐푎 260 푔 푚표푙−1 푚표푙

192

Receptor 149 coverage on silica based on elemental analysis

Weight adjusted procedure for the calculation of 149 coverage147

Step 1

First assume that weight gain is negligible. The 149 coverage can be calculated using carbon percentages

퐶% 표푓 ퟏퟒퟗ 푚표푑𝑖푓𝑖푒푑 푠𝑖푙𝑖푐푎 −퐶%표푓 퐴푃푇퐸퐸푆 푚표푑𝑖푓𝑖푒푑 푠𝑖푙𝑖푐푎 = 푛표 표푓 푐푎푟푏표푛 푎푡표푚푠 푝푒푟 푙𝑖푛푘푒푟 × 푎푡표푚𝑖푐 푤푒𝑖푔ℎ푡표푓 푐푎푟푏표푛 × 100

(16.86−3.54) 𝑔 = = 0.00021 mol g-1 = 0.21 mmol g-1 54 ×12 𝑔 푚표푙−1 ×100 𝑔

Step 2

Using this surface coverage to adjust for weight change of the silica

To prepare 100 g of 149 modified silica, 100 g – 100 × 0.00021 × 720 (molar mass of

149) + 100×0.00021×18 (molar mass of H2O) = 84.5 g of APTES modified silica, as the reaction of APTES modified silica and 149 loss of one H2O molecule (Scheme 6.4).

Step 3

Recalculate the surface coverage considering this weight change.

Since it required 85.3 g APTES modified silica to make 100 g of 151 grafted silica the coverage is

84.5 (16.86−3.54× ) 𝑔 = 100 = 0.00021 푚표푙 푔−1 -1 54 ×12 𝑔 푚표푙−1 ×100 𝑔 = 0.21 mmol g

Step 4

Repeat step 2 and 3 until convergence of the results.

After two iterations, 149 coverage on surface = 0.21 mmol g-1

Average specific surface area of silica = 200 m2 g-1

193

Number of 149 molecules per nm2

0.21 푚푚표푙 푚2 × 6.023 × 1023 × 10−18 = 0.6 -2 = 200 푚2 푛푚2 molecules nm

C.7 Receptor 149 coverage on silica surface based on TGA

Due to the immobilization of 149 on silica surface, the APTES loading per gram of silica should be less than the initial APTES coverage (0.88 mmol g-1). A new APTES coverage on 149 grafted silica can be calculated by N% obtained from the elemental analysis.

N% obtained from the elemental analysis (after immobilization of 149) = 0.88%

Number of moles of N in 100g of silica = 0.88 g/14 g mol-1 = 0.063 mol

Number of moles of N per gram of silica = 0.063 mol/100 = 0.63 mmol

New APTES coverage = 0.63 mmol g-1

Calculated weight loss from APTES moiety of 149 modified silica (based on 0.63 mmol g-1 coverage)

= 0.63 × 10-3 mol g-1 × 58 g mol-1× 100 %= 3.7%

Therefore, %weight loss due to 149 release = 23.8% – 3.7% = 20.1%

Molecular weight of volatile components of 149 (assuming all APTES groups were attached to the surface via tridentate binding mode)

=(12 (C) × 54 + 16 (O) × 2 + 24 (H) × 1) = 704 푔 푚표푙−1

Surface coverage of 149 on silica surface

20.1 1 푚푚표푙 = ( × × 103 ) = 0.29 푚푚표푙 푔−1 100 푔 푠𝑖푙𝑖푐푎 704 푔 푚표푙−1 푚표푙

194