Mediated Azide-Alkyne Cycloaddition Reactions Using Chelating Azides Wendy S

Home , Glaser coupling, Hexyne, Phenyl azide, Sonogashira coupling

Florida State University Libraries

Electronic Theses, Treatises and Dissertations The Graduate School

2012 Development of Copper(II)-Mediated Azide-Alkyne Cycloaddition Reactions Using Chelating Azides Wendy S. Brotherton

Follow this and additional works at the FSU Digital Library. For more information, please contact [email protected] THE FLORIDA STATE UNIVERSITY

COLLEGE OF ARTS AND SCIENCES

DEVELOPMENT OF COPPER(II)-MEDIATED AZIDE-ALKYNE CYCLOADDITION

REACTIONS USING CHELATING AZIDES

WENDY S. BROTHERTON

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

Degree Awarded: Spring Semester, 2012

Wendy S. Brotherton defended this dissertation on December 8, 2011.

The members of the supervisory committee were:

Lei Zhu Professor Directing Dissertation

P. Bryant Chase University Representative

Gregory B. Dudley Committee Member

Igor V. Alabugin Committee Member

Michael G. Roper Committee Member

The Graduate School has verified and approved the above-named committee members, and certifies that the dissertation has been approved in accordance with university requirements.

This manuscript is dedicated to my mother for all of her encouragement and sacrifices over the many years of my education. I would also like to dedicate this to my fiancé, Travis Ambrose, who has been so supportive and encouraging throughout this entire process.

iii

ACKNOWLEDGEMENTS

I would like to thank Professor Lei Zhu for his guidance, support and assistance over the course of my graduate studies. I would like to express my gratitude to the past and present members of the Zhu group for their support and friendship over the years: Dr. Lu Zhang, Dr. Guichao Kuang, Dr. Pampa Guha, Dr. Sreenath Kesavapillai, Heather Michaels, Ali Younes, and Tyler Simmons. I also would like to thank a very talented undergraduate student, Lisa Stankee, for her assistance. I owe significant thanks to Dr. Clark and his excellent crystallography skills. I would also like to thank him for his guidance/advice regarding crystals and their growth. Thank you to Dr. Dalal and Dr. Shatruk for your roles in understanding the properties of the generated compounds and for the helpful advice and discussions. I would like to thank various people within the chemistry department that have provided training and guidance on different machines/techniques: Hank Hendricks, Umesh Goli, Steve Freitag and Doris Terry. Thank you to my friends and colleagues for their support and advice, specifically Kerry Gilmore, Mioara Larion, Supriya Mathur, and Amy McKenna. Lastly, thank you to my family and Travis for providing constant support and encouragement.

TABLE OF CONTENTS

List of Tables ...... ix

List of Figures ...... xi

List of Abbreviations ...... xxii

Abstract ...... xxv

1. CHAPTER ONE. INTRODUCTION TO THE COPPER(I)-CATALYZED AZIDE- ALKYNE CYCLOADDITION REACTION ...... 1

1.1 Click Chemistry ...... 1

1.2 The Philosophy of Click Chemistry ...... 2

1.3 Click Reactions ...... 3 1.3.1 Cycloaddition Reactions ...... 4

1.4 Copper(I)-Catalyzed Azide-Alkyne Cycloaddition (CuAAC) ...... 5 1.4.1 εeldal’s Copper(I)-Catalyzed Synthesis of Peptidotriazoles ...... 5 1.4.2 Sharpless’ Work on Cu(I) Catalyzed Azide-Alkyne Cycloaddition ...... 7

1.5 Mechanism of CuAAC Reaction ...... 9

1.6 Assisting Ligands with the CuAAC ...... 10

1.7 Selected Applications of CuAAC ...... 11 1.7.1 Synthesis of Small-Molecule Libraries for Drug Discovery ...... 12 1.7.2 Bioconjugation ...... 13 1.7.3 Materials Chemistry ...... 15 1.7.4 Coordination Chemistry ...... 16

1.8 Origin of Present Work ...... 18

2. CHAPTER TWO. APPARENT COPPER(II)-ACCELERATED AZIDE-ALKYNE CYCLOADDITION (AAC) ...... 20

2.1 Summary ...... 20

2.2 Common Copper(I) Source ...... 20 2.2.1 Other Copper Sources ...... 21 Cu(I)-halide salts ...... 21 Cu(0) and Cu(0)/Cu(II) combinations ...... 21 Copper nanoparticles ...... 22

Copper on immobile phases ...... 22 Direct Cu(II) catalysis ...... 23

2.3 Cu(II) Reduction in Alcoholic Solvents ...... 23

2.4 Results and Discussion ...... 24 2.4.1 Preliminary Results ...... 24 2.4.2 Initial Azide and Alkyne Screening ...... 26 2.4.3 Evidence of Copper(II) Reduction ...... 29 2.4.4 Chelating Azides and Triazoles ...... 33

2.5 Conclusions ...... 37

2.6 Experimental Information ...... 37 2.6.1 Materials and General Methods...... 37 2.6.2 Representative Procedures for Table 2.2 ...... 38 2.6.3 Absorption Spectroscopy ...... 38 2.6.4 Electron Paramagnetic Resonance ...... 39 2.6.5 Synthesis of Complex [Cu(2)2(ClO4)CH3CN](ClO4) ...... 40 2.6.6 Characterization of Compounds ...... 40 2.6.7 1H and 13C NMR Spectra ...... 43

3. CHAPTER THREE. STRUCTURAL AND MECHANISTIC ASPECTS OF THE COPPER(II)-ACCELERATED AZIDE-ALKYNE CYCLOADDITION ...... 50

3.1 Summary ...... 50

3.2 Additional Information Leading to Mechanistic Investigation ...... 50 3.2.1 Chelating Azides ...... 51 3.2.2 Assisting Ligand Effect ...... 52 3.2.3 Motivation for Mechanistic Investigation ...... 54

3.3 Results and Discussion ...... 54 3.3.1 Solvent Screening ...... 54

3.3.2 Alkyne Screening ...... 59 3.3.3 Reorganization of Copper Catalyst ...... 62

3.4 Conclusions ...... 63

3.5 Experimental Information ...... 64 3.5.1 Materials and General Methods...... 64 3.5.2 TLC Monitoring Conditions for Tables 3.2 and 3.3 ...... 65 3.5.3 Generation of [Cu4(OAc)4(OCH3)4] Complex ...... 65 3.5.4 Characterization of Compounds ...... 66 3.5.5 1H and 13C NMR Spectra ...... 73

4. CHAPTER FOUR. APPLICATION OF THE Cu(OAc)2-ACCELERATED AAC: SYNTHESES AND STRUCTURAL STUDIES OF MULTIDENTATE LIGANDS FOR TRANSITION METAL IONS ...... 90

4.1 Summary ...... 90

4.2 1,4-Disubstituted-1,2,3-Triazoles as Metal Chelators ...... 91 4.2.1 1,2,3-Triazole Structure and Properties ...... 91 4.2.2 N2 vs. N3 Coordination ...... 92

4.3 Investigating N2 Coordination ...... 93

4.4 Results and Discussion ...... 95 4.4.1 Synthesis ...... 95 4.4.2 Metal Coordination Complexes with 4 ...... 96 4.4.3 Magnetic Properties ...... 104 1 4.4.4 H NMR Titrations of 4 with Fe(ClO4)2 ...... 104 4.4.5 Copper(II)-Organic Azide Complexes ...... 106 4.4.6 Competitive Binding Study ...... 117

4.5 Conclusions ...... 126

4.6 Experimental Information ...... 127 4.6.1 Materials and General Methods...... 127 4.6.2 Ligand Synthesis ...... 127 4.6.3 Synthesis of Complexes ...... 129 1 4.6.4 H NMR Titrations of 4 with Fe(ClO4)2 ...... 132 1 4.6.5 H NMR Titrations of 6 with Zn(ClO4)2 ...... 132 4.6.6 1H and 13C NMR Spectra ...... 133

vii

5. CHAPTER FIVE. SYNTHESIS OF 5-IODO-1,4-DISUBSTITUTED-1,2,3- TRIAZOLES ...... 137

5.1 Summary ...... 137

5.2 5-Iodo-1,4-Disubstituted-1,2,3-Triazoles ...... 138 5.2.1 Synthesis of 1,4,5-trisubstituted-1,2,3-triazoles ...... 138 5.2.2 Uses of 5-iodo-1,2,3-triazoles ...... 141

5.3 Assisting ligand-free synthesis and the development of a one-pot procedure ...... 142

5.4 Results and Discussion ...... 144 5.4.1 Assisting Ligand-Free Synthesis ...... 144 5.4.2 Multi-component One-Pot Reaction to Generate 5-Iodotriazoles ...... 145 In situ generation of CuI and I2 ...... 146 Solvent screening ...... 147 Copper salt screening ...... 149 Alkyne screening ...... 150 Single crystal of 2 ...... 152 Azide screening ...... 155 Time monitored reaction by 1H NMR spectroscopy ...... 157 Possible reaction mechanism ...... 159 One-pot synthesis of 5-allyl-1,4-disubstituted triazole (23) ...... 159 Observation of tetrakis(acetonitrile)copper(I) perchlorate ...... 161 - Observation of triiodide (I3 ) ...... 162 5.4.3 Functionalizing 5-position via Pd coupling reactions ...... 164

5.5 Conclusions ...... 166

5.6 Experimental Information ...... 167 5.6.1 Materials and General Methods...... 167 5.6.2 1H NMR Time Monitored Reaction ...... 168 5.6.3 Absorption Studies ...... 168 5.6.4 Generation of Crystal Complexes ...... 169 5.6.5 Synthesis of 5-Iodo-1,4-disubstituted-1,2,3-triazoles ...... 169 5.6.6 Synthesis of 5-Substituted-1,4-disubstituted-1,2,3-triazoles ...... 170 5.6.7 Characterization of Compounds ...... 171 5.6.8 1H and 13C NMR Spectra ...... 179

REFERENCES ...... 199

BIOGRAPHICAL SKETCH ...... 221

viii

LIST OF TABLES

Table 1.1 Click chemistry criteria ...... 2

Table 1.2 Selected examples of the synthesis of 1,4-disubstituted [1,2,3]-triazoles catalyzed by in situ generated copper(I) ...... 8

Table 2.1 The effects of the copper source and solvent on reaction yield...... 25

Table 2.2 Triazole products generated under developed conditions A and B ...... 28

Table 2.3 Select bond lengths (Å) and angles (°) for [Cu(2)2(ClO4)CH3CN](ClO4) ...... 35

Table 2.4 Crystal data and structural refinement ...... 36

Table 3.1 Selected results of using triazole products 8 and 9 as additives ...... 53

Table 3.2 Solvent screening results of Cu(OAc)2-accelerated AAC of 1 and 2 with phenylacetylene ...... 56

Table 3.3 Effect of Alkyne on the Cu(OAc)2-accelerated AAC reactions with azides 1, 2, and 6 ...... 60

Table 4.1 Selected bond lengths (Å) and angles (°) for [Cu(4)2](ClO4)2 ...... 98

Table 4.2 Crystal data and structural refinement for [Cu(4)2](ClO4)2 ...... 99

Table 4.3 Selected bond lengths (Å) and angles (°) for [Fe(4)2](ClO4)2 ...... 100

Table 4.4 Crystal data and structural refinement for complex [Fe(4)2](ClO4)2 ...... 101

Table 4.5 Selected bond lengths (Å) and angles (°) for [Co(4)2](ClO4)2 ...... 102

Table 4.6 Crystal data and structural refinement for complex [Co(4)2](ClO4)2 ...... 103

Table 4.7 Selected bond lengths (Å) and angles (°) for [Cu2(1)2Cl4] ...... 108

Table 4.8 Crystal data and structural refinement for complex [Cu2(1)2Cl4] ...... 109

Table 4.9 Selected bond lengths (Å) and angles (°) for [Cu(1)2Cl2]...... 111

Table 4.10 Crystal data and structural refinement for complex [Cu(1)2Cl2] ...... 112

Table 4.11 Selected bond lengths (Å) and angles (°) for [Cu(3)Cl2]...... 113

Table 4.12 Crystal data and structural refinement for complex [Cu(3)Cl2] ...... 114

Table 4.13 Bond distances (Å) in the Cu(II) complexes of 1, 3, and 7 ...... 117

Table 4.14 Selected bond lengths (Å) and angles (°) for [Cu(6)2(ClO4)2] ...... 120

Table 4.15 Crystal data and structural refinement for complex 6A [Cu(6)2(ClO4)2] ..... 121

Table 4.16 Selected bond lengths (Å) and angles (°) for [Cu(6)2(CH3CN)2](ClO4)4. .... 122

Table 4.17 Selected bond lengths (Å) and angles (°) for [Cu(6)2(CH3CN)4](ClO4)4..... 123

Table 4.18 Crystal data and structural refinement for complex 6B and 6C ...... 124

Table 5.1 Ligand-free synthesis of 5-iodo-1,2,3-triazoles using 2-picolylazide ...... 145

Table 5.2 Optimization of one-pot conditions to generate 5-iodotriazole 2 ...... 147

Table 5.3 Solvent Screening of one-pot conditions to generate 5-iodotriazole 2 ...... 148

Table 5.4 Copper salt screening of one-pot conditions to generate 5-iodotriazole 2 .. 149

Table 5.5 Alkyne screening of one-pot conditions to generate 5-iodotriazoles ...... 151

Table 5.6 Crystal data and structural refinement for 2 ...... 154

Table 5.7 Azide screening of one-pot conditions to give 5-iodotriazoles ...... 156

LIST OF FIGURES

Figure 1.1 Selection of reactions that meet the click chemistry standards ...... 3

Figure 1.2 (Top) Simplified hetero-Diels-Alder cycloaddition. (Bottom) Azide-alkyne Huisgen 1,3-dipolar cycloaddition ...... 4

Figure 1.3 For the Huisgen cycloaddition, phenyl azide reacted with phenylacetylene and 3,3-diethoxy-1-propyne gave a mixture of products after several days of reaction ...... 4

Figure 1.4 Copper(I)-catalyzed [1,2,3]-triazole formation from propargylic acid resin and various azides with CuI and DIPEA to yield peptidotriazoles. (FGFG: peptide sequence off resin, F: phenylalanine and G: glycine) ...... 6

Figure 1.5 Use of copper(I)-catalyzed [1,2,3]-triazole formation to prepare N-substituted histidine analogs from propargylglycine. i) CuI, DIPEA, ii) 20% piperidine/DMF, iii) 0.1 M NaOH (aq). (FGFG: peptide sequence off resin, F: phenylalanine and G: glycine) ..... 6

Figure 1.6 In situ generation of the active copper(I) species reacted with phenyl propargyl ether and benzyl azide gave the 1,4-disubstituted triazole product ...... 7

Figure 1.7 Proposed mechanism for the CuAAC reaction ...... 9

Figure 1.8 Ligands that have shown to be effective in promoting the Cu(I) catalyzed triazole formation...... 11

Figure 1.9 Compounds 7A-D generated via CuAAC reaction from azide 6 with the hydroxyethylamine peptide core highlighted in red...... 12

Figure 1.10 Examples of CuAAC used in bioconjugation: (A) Two examples of unnatural amino acids being labeled after incorporation into proteins; (B) Two examples of azide and alkyne-derivatized sugars and their infiltration into biosynthetic pathways; (C) Alkyne tagged deoxynucleotide and nucleotide and in vivo labeling of DNA and RNA; (D) Schematic for the strategy of ABPP using click chemistry postlabeling. Star: a label or fluorescent tag (e.g. biotin or Alexa Fluor)...... 14

Figure1.11 Examples of CuAAC reactions being applied in the synthesis of materials: (A) Sequential click reactions generated this dendrimer; (B) CuAAC reaction allowed for functionalization of SWNTs; (C) Generated by CuAAC, this triazolaphane shows uptake

xi of the anion inside its cavity; (D) Active-metal templating with CuAAC yielded desired rotaxane...... 16

Figure 1.12 Unsubstituted imidazole and 1,2,3-triazole (atom numbering shown in red)...... 17

Figure 1.13 Pendant design (top) versus integrated design (bottom) with R being any chemical/biological component to be functionalized with a metal complex. Purple spheres represent metal coordinating groups ...... 17

Figure 1.14 Two triazolyl-containing ligands designed to chelate to metals with the N3 and N2 forming a five-membered ring (blue) and a six-membered ring (red) respectively...... 18

Figure 2.1 Typical CuAAC conditions use a Cu(II) salt (CuSO4) that is in situ reduced to Cu(I) through addition of a reducing agent (sodium ascorbate) ...... 21

Figure 2.2 Yamamoto’s generation of biaryls through use of copper(II) salts and an alcoholic solvent ...... 24

Figure 2.3 Generation of copper(I) via alcohol oxidation proceeding to catalyze the AAC reaction ...... 24

Figure 2.4 Generation of Cu(I) through oxidative homocoupling of a terminal alkyne. . 26

Figure 2.5 2-Picolylazide (1) and propargyl alcohol react rapidly under the developed click conditions ...... 29

Figure 2.6 Reaction of 1 and propargyl alcohol in t-BuOH (A) at the start of the reaction, (B) at ~60 s, and (C) at 90 s ...... 29

Figure 2.7 Absorption spectra of the mixture of 1 (1.0 mmol) and propargyl alcohol (1.5 mmol) in the presence of 5 mol % Cu(OAc)2 in t-BuOH (2.5 mL) during the course of the reaction (4 min). Bold dark blue and light blue traces were collected at the beginning of and after the reaction, respectively ...... 30

Figure 2.8 EPR spectra of Cu(OAc)2 in t-BuOH at room temperature. The purple trace was obtained after the reaction between azide 1 and propargyl alcohol was complete ...... 31

Figure 2.9 EPR spectrum of Cu(OAc)2 with azide 1 in t-BuOH at room temperature overlaid with previous spectra ...... 32

Figure 2.10 Schematic showing the equilibration of copper(II) acetate dimer to monomer. L: arbitrary solvent molecule, pyridine or water ...... 33

xii

Figure 2.11 Dinuclear copper complex [Cu2(1)2Cl4] ...... 34

Figure 2.12 Schematic showing chelation of azide to copper that, during the transition state, renders the azide more electrophilic and facilitates the cycloaddition...... 34

Figure 2.13 ORTEP view shown with 50% probability ellipsoids of [Cu(2)2(ClO4)CH3CN](ClO4). The uncoordinated perchlorate counter ion was omitted for clarity. Carbon atoms are shown in black, nitrogen in blue, oxygen in red, chlorine in green, and copper in orange. Atom labels are shown in purple ...... 35

Figure 2.14 EPR spectra with the calculated (and field-offset corrected) g values. The numbers in bold were calculated using the instrument’s Bruker software. The other values were calculated from the data using Microsoft Excel ...... 39

1 Figure 2.15 300 MHz H NMR Spectrum of compound 1 in CDCl3...... 43

1 Figure 2.16 300 MHz H NMR Spectrum of compound 2 in CDCl3...... 44

13 Figure 2.17 75 MHz C NMR Spectrum of compound 2 in CDCl3 ...... 44

1 Figure 2.18 300 MHz H NMR Spectrum of compound 3 in CDCl3 ...... 45

13 Figure 2.19 75 MHz C NMR Spectrum of compound 3 in CDCl3 ...... 45

1 Figure 2.20 300 MHz H NMR Spectrum of compound 4 in CDCl3 ...... 46

13 Figure 2.21 75 MHz C NMR Spectrum of compound 4 in CDCl3 ...... 46

1 Figure 2.22 300 MHz H NMR Spectrum of compound 5 in CDCl3 ...... 47

1 Figure 2.23 300 MHz H NMR Spectrum of compound 5 in CDCl3 ...... 47

1 Figure 2.24 300 MHz H NMR Spectrum of compound 6a in CDCl3 ...... 48

13 Figure 2.25 75 MHz C NMR Spectrum of compound 6a in CDCl3 ...... 48

1 Figure 2.26 300 MHz H NMR Spectrum of compound 6b in CDCl3...... 49

13 Figure 2.27 75 MHz C NMR Spectrum of compound 6b CD3OD ...... 49

Figure 3.1 (A) Simplified chelation model with copper(II). (B) Copper(I) intermediate prior to the formation of the metallacycle. (C) Selected chelating azides with N, O, and S auxiliary atoms. Py = 2-Pyridyl ...... 52

xiii

Figure 3.2 The best chelating azides under Cu(OAc)2-accelerated conditions ...... 54

Figure 3.3 Azide 1 (A and C) and 2 (B and D) reacted with phenylacetylene in organic solvents (left to right: ACN, THF, DCM, and toluene) at the start of the reaction (top) and after the reactions were completed (bottom) ...... 57

Figure 3.4 Azide 1 (Vials 1-3) and 2 (Vials 4-6) reacted with phenylacetylene in different alcoholic solvents (t-BuOH: 1,4; MeOH: 2,5; i-PrOH: 3,6) at the start of the reaction (A) and five min later at the end of the reaction (B) ...... 57

Figure 3.5 (A) Beginning of reaction with azide 1 (Table 3.2, entry 10); (B) end of reaction after five min; (C) view of yellow organic solid in green aqueous solution ...... 59

Figure 3.6 Known tetranuclear copper(II) cluster [Cu4(OAc)4(OCH3)4]. ORTEP view shown with 50% probability ellipsoids with hydrogens omitted for clarity. Carbon atoms are shown in blue, oxygen in red, and copper in orange. Atom labels are shown in purple. Selected distances (Å): Cu1-O1 1.940, Cu1-O4 1.970, Cu1-O5 1.929, Cu1-O5i 1.919, Cu1-Cu2 2.949, Cu1-Cu1i 2.985 ...... 63

1 Figure 3.7 500 MHz H NMR Spectrum of compound 1b in CDCl3 ...... 73

13 Figure 3.8 125 MHz C NMR Spectrum of compound 1b in CDCl3 ...... 73

1 Figure 3.9 500 MHz H NMR Spectrum of compound 1c in CDCl3 ...... 74

13 Figure 3.10 125 MHz C NMR Spectrum of compound 1c in CDCl3...... 74

1 Figure 3.11 500 MHz H NMR Spectrum of compound 1g in CDCl3...... 75

13 Figure 3.12 125 MHz C NMR Spectrum of compound 1g in CDCl3 ...... 75

1 Figure 3.13 500 MHz H NMR Spectrum of compound 2a in CDCl3 ...... 76

13 Figure 3.14 125 MHz C NMR Spectrum of compound 2a in CDCl3 ...... 76

1 Figure 3.15 500 MHz H NMR Spectrum of compound 2b in CDCl3...... 77

13 Figure 3.16 125 MHz C NMR Spectrum of compound 2b in CDCl3 ...... 77

1 Figure 3.17 500 MHz H NMR Spectrum of compound 2c in CDCl3 ...... 78

13 Figure 3.18 125 MHz C NMR Spectrum of compound 2c in CDCl3 ...... 78

1 Figure 3.19 500 MHz H NMR Spectrum of compound 2d in CDCl3 ...... 79

xiv

13 Figure 3.20 125 MHz C NMR Spectrum of compound 2d in CDCl3 ...... 79

1 Figure 3.21 500 MHz H NMR Spectrum of compound 2e in CDCl3 ...... 80

13 Figure 3.22 125 MHz C NMR Spectrum of compound 2e in CDCl3 ...... 80

1 Figure 3.23 500 MHz H NMR Spectrum of compound 2f in CDCl3 ...... 81

13 Figure 3.24 125 MHz C NMR Spectrum of compound 2f in CDCl3 ...... 81

1 Figure 3.25 500 MHz H NMR Spectrum of compound 2g in CDCl3 ...... 82

13 Figure 3.26 125 MHz C NMR Spectrum of compound 2g in CDCl3 ...... 82

1 Figure 3.27 500 MHz H NMR Spectrum of compound 6a in CD3OD ...... 83

13 Figure 3.28 125 MHz C NMR Spectrum of compound 6a in CD3OD ...... 83

1 Figure 3.29 500 MHz H NMR Spectrum of compound 6b in CD3OD ...... 84

13 Figure 3.30 125 MHz C NMR Spectrum of compound 6b in CD3OD ...... 84

1 Figure 3.31 500 MHz H NMR Spectrum of compound 6c in CD3OD ...... 85

13 Figure 3.32 125 MHz C NMR Spectrum of compound 6c in CD3OD ...... 85

1 Figure 3.33 500 MHz H NMR Spectrum of compound 6d in CD3OD ...... 86

13 Figure 3.34 125 MHz C NMR Spectrum of compound 6d in CD3OD ...... 86

1 Figure 3.35 500 MHz H NMR Spectrum of compound 6e in CD3OD ...... 87

13 Figure 3.36 125 MHz C NMR Spectrum of compound 6e in CD3OD ...... 87

1 Figure 3.37 500 MHz H NMR Spectrum of compound 6f in CD3OD ...... 88

13 Figure 3.38 125 MHz C NMR Spectrum of compound 6f in CD3OD ...... 88

1 Figure 3.39 500 MHz H NMR Spectrum of compound 6g in CD3OD ...... 89

13 Figure 3.40 125 MHz C NMR Spectrum of compound 6g in CD3OD ...... 89

Figure 4.1 Structural properties of the 1,4-disubstituted 1,2,3-triazole ...... 92

Figure 4.2 Triazole-containing ligands that can coordinate through N3 (regular click ligand) or N2 (inverse click ligand). The azide and alkyne starting material components are highlighted in red and blue respectively ...... 93

Figure 4.3 Zinc complexes showing (A) N3 coordination and (B) N2 coordination ...... 93

Figure 4.4 Rapid formation of bidentate ligand 2 from Cu(OAc)2-accelerated CuAAC . 94

Figure 4.5 (A) 2,6-Bis(4-R-1,2,3-triazol-1-ylmethyl)pyridine; (B) 2,6-bis(3,5-R,R- pyrazol-1-ylmethyl)pyridine; (C) β,β’μ6’β”-terpyridine or terpy; (D) 2,6-bis(1-R-1,2,3- triazol-4-yl)pyridine. R: undefined substituent. Nitrogens expected/known to participate in coordination are highlighted in red...... 95

Figure 4.6 Designed ligand with two binding pockets highlighted. Upon introduction of a metal salt, coordination could take place at binding pocket 1 or binding pocket 2. ... 95

Figure 4.7 2,6-bis(azidomethyl)pyridine (3) reacts rapidly with various alkynes to afford the ligand. After minimal purification of 4 or 5, various metal complexes were formed ...... 96

Figure 4.8 ORTEP view shown with 50% probability of [Cu(4)2](ClO4)2. Counter ions and solvent omitted for clarity. Carbon atoms are shown in black, nitrogen in blue, and copper in orange. Atom labels are shown in purple ...... 98

Figure 4.9 ORTEP view shown with 50% probability of [Fe(4)2](ClO4)2. Counter ions and solvent omitted for clarity. Carbon atoms are shown in black, nitrogen in blue, and iron in brick red. Atom labels are shown in purple ...... 100

Figure 4.10 ORTEP view shown with 50% probability of [Co(4)2](ClO4)2. Counter ions and solvent omitted for clarity. Carbon atoms are shown in black, nitrogen in blue, and cobalt in pink. Atom labels are shown in purple...... 102

1 Figure 4.11 H NMR (500 MHz, CD3CN) spectra of 5 in the presence of increasing amount of Fe(ClO4)2 (bottom to top: 0 - 0.5 molar equivalent). R = n-Bu ...... 105

Figure 4.12 ORTEP view shown with 50% probability of [Cu2(1)2Cl4]. Carbon atoms are shown in black, nitrogen in blue, chloride in green, and copper in orange. Atom labels are shown in purple ...... 108

Figure 4.13 The extended chain structure of [Cu2(1)2Cl4]. Carbon atoms are shown in grey, nitrogen in blue, chloride in green, and copper in orange. Weaker interactions between copper(II) and neighboring azido nitrogen are marked with dashed lines ..... 110

xvi

Figure 4.14 ORTEP view shown with 50% probability of [Cu(1)2Cl2]. Carbon atoms are shown in black, nitrogen in blue, chloride in green, and copper in orange. Atom labels are shown in purple ...... 111

Figure 4.15 ORTEP view shown with 50% probability of [Cu(3)Cl2]. Carbon atoms are shown in black, nitrogen in blue, chloride in green, and copper in orange. Atom labels are shown in purple ...... 113

Figure 4.16 The extended structure of [Cu(3)Cl2]. Carbon atoms are shown in grey, nitrogen in blue, chloride in green, and copper in orange. The weaker interactions between copper(II) and terminal nitrogen of adjacent dimer units are marked using dashed black line (γ.β50 Å) and the offset π-π interaction (γ.664 Å) is marked by a dashed red line ...... 115

Figure 4.17 Copper(II) coordinated to chelating azides 1, 3, and 2-(2- azidoethyl)pyridine (7). Counterions (L) are chlorides...... 116

Figure 4.18 Ligand 6 with two binding pockets highlighted and properties of each site ...... 117

Figure 4.19 Rapid formation of ligand 6 from Cu(OAc)2-accelerated CuAAC ...... 118

Figure 4.20 ORTEP view shown with 50 % probability of complex 6A [Cu(6)2(ClO4)2]. Carbon atoms are shown in black, nitrogen in blue, oxygen in red, chloride in green, and copper in orange. Atom labels are shown in purple ...... 120

Figure 4.21 ORTEP view shown with 50% probability of complex 6B [Cu(6)2(CH3CN)2](ClO4)4. Counter ions and hydrogens are omitted for clarity. Carbon atoms are shown in black, nitrogen in blue, and copper in orange. Atom labels are shown in purple...... 122

Figure 4.22 ORTEP view shown with 50% probability of Complex 6C [Cu(6)2(CH3CN)4](ClO4)4. Counter ions and hydrogens are omitted for clarity. Carbon atoms are shown in black, nitrogen in blue, and copper in orange. Atom labels are shown in purple ...... 123

1 Figure 4.23 H NMR spectra (500 MHz, CD3CN) of compound 6 in the presence of increasing concentrations of Zn(ClO4)2. Spectra 1-8: [Zn]/[6] = 0.0, 0.15, 0.30, 0.45, 0.60, 0.75, 0.90, 1.06. Green triangles represent the evolution of HA ...... 125

1 Figure 4.24 300 MHz H NMR Spectrum of compound 3 in CDCl3 ...... 133

13 Figure 4.25 75 MHz C NMR Spectrum of compound 3 in CDCl3 ...... 133

1 Figure 4.26 500 MHz H NMR Spectrum of compound 4 in CDCl3 ...... 134

xvii

13 Figure 4.27 125 MHz C NMR Spectrum of compound 4 in CDCl3 ...... 134

1 Figure 4.28 500 MHz H NMR Spectrum of compound 5 in CDCl3 ...... 135

13 Figure 4.29 125 MHz C NMR Spectrum of compound 5 in CDCl3 ...... 135

1 Figure 4.30 300 MHz H NMR Spectrum of compound 6 in CDCl3 ...... 136

13 Figure 4.31 75 MHz C NMR Spectrum of compound 6 in CDCl3 ...... 136

Figure 5.1 Electrophilic trapping one-pot method developed by Wu et al ...... 138

Figure 5.2 CuI/TTTA catalyzed cycloaddition of organic azides and 1-iodoalkynes developed by Fokin et al ...... 140

Figure 5.3 Fokin’s developed one-pot, two-step method for the generation of 5-iodo- 1,2,3-triazoles ...... 140

Figure 5.4 Proposed mechanisms for the copper(I)-catalyzed azide-iodoalkyne cycloaddition ...... 141

Figure 5.5 Cu(I)-catalyzed azide-haloalkyne cycloaddition of ortho-bis(iodoacetylene) to generate bis(iodotriazoles) that can undergo intramolecular coupling to extend the aromaticity of the system ...... 142

Figure 5.6 Enhancement of N2 binding (in box) with retrosynthetic route to the right ...... 143

Figure 5.7 Left, “classic” conditions to in situ generate Cu(I) to form 5-proto- 1,2,3-triazoles. Right, in situ conditions to generate CuI and I2 to yield 5-iodo-1,2,3- triazoles ...... 143

Figure 5.8 Reaction of 1 with 1-iodophenylacetylene to generate 2 ...... 144

Figure 5.9 (A) ORTEP view (50% ellipsoids) of 2 with the C1-I distance being 2.083 Å. (B) Extended structure of 2. Interactions between I and adjacent Npy and N2 are marked using dashed bonds. The I···Npy-C3/C4 angles are marked by dotted arches153

1 Figure 5.10 H NMR (500 MHz, CD3CN) time monitored reaction of azide 1 with phenylacetylene shown every 50 min...... 158

Figure 5.11 Possible mechanism of the one-pot conditions to generate 5-iodo-1,4- disubstituted-1,2,3-triazole ...... 159

xviii

Figure 5.12 One-pot, multicomponent synthesis of the 1,4,5-trisubstituted 5-allyl-1,2,3- triazole 23 ...... 160

Figure 5.13 ORTEP view (50% ellipsoids) of known tetrakis(acetonitrile)copper(I) complex. The other two tetrakis(acetonitrile)copper(I) groups and perchlorate counterions of the asymmetric unit are omitted for clarity. Carbon atoms are shown in black, nitrogen in blue, chloride in green, oxygen in red, chlorine in green, and copper in orange ...... 161

Figure 5.14 Absorbance of iodine solution (blue), iodine with NaI added (red) and of the reaction mixture of Cu(ClO4)2 with NaI (green). Absorbance values of interest are at 294, 367, and 467 nm ...... 162

Figure 5.15 ORTEP view (50% ellipsoids) of known tetrabutylammonium triiodide complex. Carbon atoms are shown in black, nitrogen in blue, and iodine in purple .... 163

Figure 5.16 Sonogashira coupling of alkynes to 5-iodo-1,2,3-triazole 2 gave a mixture of products that included 24 and 3...... 164

Figure 5.17 Sonogashira coupling of 4-ethynylanisole to 5-iodo-1,2,3-triazole 2 yielding 25 ...... 165

Figure 5.18 Suzuki coupling of 2D with either boronic acid A or the pinacol ester boronic acid B to give trisubstituted products 26 or 27 ...... 166

1 Figure 5.19 500 MHz H NMR Spectrum of compound 2 in CD3CN ...... 179

13 Figure 5.20 125 MHz C NMR Spectrum of compound 2 in CD3CN ...... 179

1 Figure 5.21 500 MHz H NMR Spectrum of compound 4 in CD3CN ...... 180

13 Figure 5.22 125 MHz C NMR Spectrum of compound 4 in CD3CN ...... 180

1 Figure 5.23 500 MHz H NMR Spectrum of compound 5 in CD3CN ...... 181

13 Figure 5.24 125 MHz C NMR Spectrum of compound 5 in CD3CN ...... 181

1 Figure 5.25 500 MHz H NMR Spectrum of compound 6 in CD3CN ...... 182

13 Figure 5.26 125 MHz C NMR Spectrum of compound 6 in CD3CN ...... 182

1 Figure 5.27 500 MHz H NMR Spectrum of compound 7 in CDCl3 ...... 183

13 Figure 5.28 125 MHz C NMR Spectrum of compound 7 in CDCl3 ...... 183

xix

1 Figure 5.29 500 MHz H NMR Spectrum of compound 8 in CDCl3 ...... 184

13 Figure 5.30 125 MHz C NMR Spectrum of compound 8 in CDCl3 ...... 184

1 Figure 5.31 500 MHz H NMR Spectrum of compound 9 in CD3CN ...... 185

13 Figure 5.32 125 MHz C NMR Spectrum of compound 9 in CD3CN ...... 185

1 Figure 5.33 500 MHz H NMR Spectrum of compound 10 in CD3CN ...... 186

13 Figure 5.34 125 MHz C NMR Spectrum of compound 10 in CD3CN ...... 186

1 Figure 5.35 500 MHz H NMR Spectrum of compound 11 in CDCl3 ...... 187

13 Figure 5.36 125 MHz C NMR Spectrum of compound 11 in CDCl3 ...... 187

1 Figure 5.37 500 MHz H NMR Spectrum of compound 12 in CD3CN ...... 188

13 Figure 5.38 125 MHz C NMR Spectrum of compound 12 in CD3CN ...... 188

1 Figure 5.39 500 MHz H NMR Spectrum of compound 13 in CD3CN ...... 189

13 Figure 5.40 125 MHz C NMR Spectrum of compound 13 in CD3CN ...... 189

1 Figure 5.41 500 MHz H NMR Spectrum of compound 14 in CD3CN ...... 190

13 Figure 5.42 125 MHz C NMR Spectrum of compound 14 in CD3CN ...... 190

1 Figure 5.43 500 MHz H NMR Spectrum of compound 17 in CDCl3 ...... 191

13 Figure 5.44 125 MHz C NMR Spectrum of compound 17 in CDCl3 ...... 191

1 Figure 5.45 500 MHz H NMR Spectrum of compound 19 in CD3CN ...... 192

13 Figure 5.46 125 MHz C NMR Spectrum of compound 19 in CD3CN ...... 192

1 Figure 5.47 500 MHz H NMR Spectrum of compound 20 in CD3CN ...... 193

13 Figure 5.48 125 MHz C NMR Spectrum of compound 20 in CD3CN ...... 193

1 Figure 5.49 500 MHz H NMR Spectrum of compound 22 in (CD3)2SO ...... 194

13 Figure 5.50 125 MHz C NMR Spectrum of compound 22 in (CD3)2SO ...... 194

1 Figure 5.51 500 MHz H NMR Spectrum of compound 23 in CD3CN ...... 195

13 Figure 5.52 125 MHz C NMR Spectrum of compound 23 in CD3CN ...... 195

1 Figure 5.53 500 MHz H NMR Spectrum of compound 25 in CDCl3 ...... 196

13 Figure 5.54 125 MHz C NMR Spectrum of compound 25 in CDCl3 ...... 196

1 Figure 5.55 500 MHz H NMR Spectrum of compound 26 in CDCl3 ...... 197

13 Figure 5.56 125 MHz C NMR Spectrum of compound 26 in CDCl3 ...... 197

1 Figure 5.57 500 MHz H NMR Spectrum of compound 27 in CD3CN ...... 198

13 Figure 5.58 125 MHz C NMR Spectrum of compound 27 in CD3CN ...... 198

xxi

LIST OF ABBREVIATIONS

a a axis dd doublet of doublets (spectral)

doublet of doublets of doublets Å angstrom ddd (spectral)

1,8-diazabicyclo[5.4.0]undec-7- AAC azide-alkyne cycloaddition DBU ene

ABPP activity-based protein profiling DIPEA diisopropylethylamine

ACN acetonitrile DMAP N,N-4-dimethylaminopyridine

Anal. elemental analysis DMF dimethylformamide

Aq aqueous DMSO dimethylsulfoxide b b axis molar absorptivity

Bu butyl e.g. example gratia (for example)

electron ionization (in mass bs broad singlet EI spectrometry)

DCM dichloromethane equiv equivalent(s)

electrospray ionization (in mass t-Bu tertiary butyl ESI spectrometry) c c axis et al. et alli (and the others)

°C degrees Celsius EtOAc ethyl acetate

calculated (in mass calcd EDG electron donating group spectrometry)

COSY correlation spectroscopy g grams

copper(I)-catalyzed azide- CuAAC G gauss alkyne cycloaddition

xxii

mechanically interlocked heat, reflux MIM Δ molecule d doublet (spectral) min minute

D debye Mol mole

chemical shift, in parts per million relative to MOF metal-organic framework tetramethylsilane h hour n nano, normal

high-resolution mass HRMS ND not detected spectrometry

Hz hertz NMR nuclear magnetic resonance i iso Nuc nucleophile i.e. id est (that is) p para

coupling constant reported in J Ph phenyl hertz (in NMR spectroscopy)

-pentamethyl- K kelvin PMDETA N, N, N’, N’,N" diethylenetriamine

wavelength ppm parts per million

L liter Pr propyl

µ micro Py pyridine

µeff effective magnetic moment q quartet (spectral)

µB Bohr magnetrons qn quintet (spectral) m multiplet (spectral) RT room temperature m/z mass-to-charge ratio s second, singlet (spectral)

M molar, moles per liter SWNT single walled carbon nanotubes

Me methyl sx sextet (spectral)

xxiii

T tertiary T temperature

- OTf triflate, CF3SO3 td triplet of doublets (spectral)

tris- TBTA TEA triethylamine (benzyltriazolylmethyl)amine

TLC thin layer chromatography UV ultraviolet

tris-(t- vide TTTA see earlier butyltriazolylmethyl)amine supra t triplet vide infra see below

xxiv

ABSTRACT

This dissertation describes the development of copper(II)-mediated azide-alkyne cycloaddition reactions using chelating azides. The first chapter provides an introduction to the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) through describing the history of the CuAAC reaction, its current mechanistic understanding, and selected applications of this widely used reaction. Within the second chapter, the development of copper(II)-accelerated azide-alkyne cycloaddition (AAC) is presented. Therein, 1,4-disubstituted-1,2,3-triazoles were synthesized via the azide-alkyne cycloaddition in good to excellent yields using copper(II) salts in alcoholic solvents. The developed procedures avoided the need for an added reducing agent. Two pathways could be operational to generate copper(I) under these conditions: oxidation of alcoholic solvent or oxidative homocoupling of the alkyne. 2-Picolylazide behaved as a superior substrate under these conditions due to its chelating ability to copper that facilitates the cycloaddition. Preliminary spectroscopic results (EPR, UV-Vis spectroscopy) provided evidence that copper(I) was generated after an induction period. Within the third chapter, the reactivity of other chelating azides and their products as assisting ligands regarding the Cu(OAc)2-accelerated AAC reaction are briefly discussed. This data, combined with the results from the initial study, allowed us to study the mechanism. Results pertaining to solvent screening and alkyne screening are discussed in detail. In regards to solvent, the reaction can proceed in aprotic organic solvents but required longer reaction times than reactions in protic solvents. The

Cu(OAc)2-accelerated AAC reactions were also observed to proceed fairly rapidly in aqueous solvents. The alkyne screening results under preparative, heterogeneous conditions show no clear trend between the structure of the alkyne and efficiency of the reaction. However, under homogeneous conditions used for the kinetics studies, a clear trend was observed where electron-withdrawing substituents on the para-position

xxv of phenylacetylene show shorter induction periods and react very rapidly. During the solvent and alkyne screening, a discontinuous reaction profile was observed suggesting the structure evolution of the catalyst, therefore lowering the catalytic activity.

Application of the developed Cu(OAc)2-accelerated AAC reaction for the facile and rapid synthesis of tridentate 2,6-bis(1,2,3-triazol-1-ylmethyl)pyridine ligands is described in Chapter 4. Upon coordination with transition metal ions, the pyridyl nitrogen as well as the less Lewis basic N2 nitrogen of the 1,2,3-triazole ring were found to participate in binding. The ligands created in this study complement other well- studied tridentate ligands such as the triazolyl-based terpy motif and the 2,6-bis(pyrazol- 1-ylmethyl)pyridine systems. Additionally, a ligand was designed to include two bidentate binding sites at both the N3 and N2 positions forming a five- and six- membered chelation ring, respectively. Its coordination was studied and showed that metals prefer the 5-membered planar chelation pocket over the puckered 6-membered pocket that contains the N2 nitrogen of the 1,2,3-triazole. Stable copper(II)/organic azide complexes from chelating azides were also observed and their features described. All copper(II)/azide complexes exhibit the alkylated nitrogen atom (Nα) of the azido group coordinating to the copper(II) ion. Analysis of the bond lengths show that copper(II) coordination at Nα enhances the electrophilicity of the terminal N, accelerating the CuAAC reaction. The information gained from this study enhances our knowledge and understanding of the coordination chemistry of 1,4-substituted-1,2,3- triazole molecules, particularly in regards to the N2 atom of the 1,2,3-triazole. Chapter five describes the synthesis of 5-iodo-1,2,3-triazoles. These compounds were synthesized with the intention of functionalizing the 5-position with an electron donating group to enhance the electron density at the N2 position and enhance binding affinity. Unlike previous reports, 5-iodo-1,4-disubstituted-1,2,3-triazoles were generated from 2-picolylazide and iodoalkynes without the need of an assisting ligand. Moderate to good yields of the 5-iodotriazole products were obtained from a small set of iodoalkynes screened. Wanting to circumvent the synthesis of iodoalkynes, a one-pot method was created where copper(II) salts are reduced by NaI. This in situ method generates the necessary copper(I) catalyst as well as the iodinating source. The

xxvi reaction requires an equivalent of base and was able to proceed in a variety of solvents. The reaction performed well with a variety of alkynes and azides, however, the reaction is sensitive to excess base and those with tertiary amines exhibited lower yields due to the formation of protonated triazole. The in situ generating conditions are more reactive than that of the direct addition of CuI and I2. Use of another electrophile, allyl iodide, under these conditions gave the 5-allyl-1,4-disubstituted-1,2,3-triazole in a multicomponent, one-pot reaction. 1,4,5-trisubstituted-1,2,3-triazoles were obtained through palladium cross-coupling reactions, such as the Sonogashira or the Suzuki reactions. However, minor amounts of the dehalogenated triazole by-product complicates purification of these compounds. Further study of 1,4,5-trisubstituted-1,2,3- triazoles is underway in our laboratory.

xxvii

CHAPTER 1

INTRODUCTION TO THE COPPER(I)-CATALYZED AZIDE- ALKYNE CYCLOADDITION REACTION

1.1 Click Chemistry

Formation of carbon-carbon bonds in an aqueous environment is essential for life on this planet. The primary mechanism that nature uses is carbonyl (aldol) chemistry. Carbonyls, the electrophiles, exist along with nucleophiles in an aqueous environment that acts as a perfect medium for proton transfer among reactants. Nature achieves an astonishing amount of structural and functional diversity by relying largely on carbonyl chemistry. From a small library of building blocks, nature is able to use carbonyl chemistry to create biomolecules. Many of these biosynthetic pathways require a unique enzyme for each step. For example, protein synthesis requires an orchestra of assistants that include transfer RNA to activate the amino acid through an ester bond that is produced in an ATP-dependent reaction.1 This is carried out by an aminoacyl tRNA synthetase, a substrate for the ribosome, which catalyzes the attack of the amino group of the elongating protein chain on the ester bond. With billions of years and unlimited resources, nature has created many complex catalysts for formation of products. Kolb, Finn, and Sharpless pointed out in 20012 that while carbonyl-based reactions are appealing, we, as chemists, do not have the time and resources that nature has. Carbonyl chemistry is ill-suited for the rapid discovery of new molecules with desired properties. In the same report, they pointed out that most bioactive natural products are synthetically challenging due to the presence of too many contiguous carbon-carbon bonds. The majority of the 30+ building blocks that nature uses (for formation of nucleic acids, proteins, and polysaccharides) contain, at most, 6 contiguous carbon-carbon bonds. They suggested that perhaps, chemists should, “[take] our cue from nature’s approach,” and focus on a set of, “powerful, highly reliable, and selective

1 reactions for the rapid synthesis of useful new compounds and combinatorial libraries through heteroatom links (C—X—C).” This approach was termed “click chemistry”.2

1.2 The Philosophy of Click Chemistry

Instead of chemist investing so much effort in one particular natural product synthesis that might have desirable pharmaceutical properties, we should follow nature’s lead and look for reactions that efficiently join together smaller molecules. Sharpless and coworkers2 defined a strict set of criteria that these reactions should meet in order to be useful. Those desired properties are listed in Table 1.1. In general, the reaction should have a large thermodynamic driving force that gives almost complete conversion to a single product and that the product is easy to isolate and purify. Some criticisms of click chemistry say that it is just relabeling standard organic chemistry practices and that it is not an idea, but merely common sense.3

Table 1.1 Click chemistry criteria.2

The reaction must be: Desired characteristics:

 Modular  Simple reaction conditions (ideally conditions should be insensitive to O2 and H2O)

 Wide scope  Readily available starting materials and reagents

 Give very high yields  Use of no solvent or benign solvent (e.g. H2O), or easily removed

 Generate only inoffensive by-  Simple product isolation (if products (that can be removed purification is required, it should be through non-chromatographic through nonchromatographic methods methods) such as crystallization or distillation)

1.3 Click Reactions

Despite such strict guidelines, several classes of reactions meet these criteria. These reactions include nucleophilic opening of spring-loaded rings (epoxides, aziridines, aziridinium ions, etc.), non-aldol carbonyl chemistry (formation of ureas, oximes, hydroazones, etc.), additions to carbon-carbon multiple bonds (Michael additions of Nu-H reactants and especially oxidative additions), and cycloaddition (Figure 1.1). .

Figure 1.1 Selection of reactions that meet the click chemistry standards.2

1.3.1 Cycloaddition Reactions

Figure 1.2 (Top) Simplified hetero-Diels-Alder cycloaddition. (Bottom) Azide-alkyne Huisgen 1,3-dipolar cycloaddition.

Cycloaddition reactions, especially those involving heteroatoms, are ideal click reactions. These reactions include the hetero-Diels-Alder and the 1,3-dipolar cycloadditions (Figure 1.2) that allow quick access to five and six-membered rings. Sharpless et al.2 deemed the azide-alkyne Huisgen 1,3-dipolar cycloaddition as the “cream of the crop” of click chemistry. However, the authors note that this reaction has not been given the proper attention from medicinal chemists, presumably due to azidophobia (the fear of potentially explosive azides). While other dipoles work for the 1,3-cycloaddition, the azido group is more appealing because it is an easily installed component that carries on “silently” until a good dipolarophile is present.

Figure 1.3 For the Huisgen cycloaddition, phenyl azide reacted with phenylacetylene and 3,3-diethoxy-1-propyne gave a mixture of products after several days of reaction.4

Despite being labeled “cream of the crop”, there are several drawbacks of the azide-alkyne cycloaddition. Because of its low reaction rate, the reaction must be heated for prolonged periods (hours to days) to afford a mixture of the 1,4- and 1,5- regioisomers (Figure 1.γ). In Huisgen’s review on 1,γ-dipolar cycloadditions,4 he notes that the nature of the substituent affects the regioselectivity to a surprisingly small extent. Typical reaction conditions involve refluxing in toluene, where labile molecules might not survive. Use of the sodium, lithium or magnesium salts of the alkyne allow for lower temperatures to be used but with little success in regards to regioselectivity.5

1.4 Copper(I)-Catalyzed Azide-Alkyne Cycloaddition (CuAAC)

This reaction’s full potential, in the click chemistry context, was not realized until 2002, when Meldal et al.5 from Denmark and Sharpless et al.6 from the U.S. published the copper(I)-catalyzed variant of the azide-alkyne cycloaddition (CuAAC). This version of the reaction proceeds at room temperature and results in the 1,4-substituted triazoles exclusively.

1.4.1 Meldal’s Copper(I)-Catalyzed Synthesis of Peptidotriazoles

Meldal et al.5 presented a mild and efficient method using copper(I) salts to catalyze 1,3-dipolar cycloaddition of azides with terminal alkynes bound to a solid support resin to form peptidotriazoles. The conditions employed copper(I) iodide as the catalyst and N,N-diisopropylethylamine (DIPEA) as a base at room temperature. Using the propargylic acid resin (Figure 1.4), they observed consistently high conversions due to the more reactive electron-deficient alkyne resin. With the propargylglycine resin (Figure 1.5), lower conversion was observed than that of the propargylic acid resin but with slightly higher purities. The developed conditions were fully compatible with Fmoc- and Boc-peptide chemistry. Additionally, they observed that various functional groups (amino, amides, esters, ethers, thioethers, carboxylic acids, t-butyl, trityl, Pmc, Fmoc and Boc) were tolerated by the reaction conditions.

Figure 1.4 Copper(I)-catalyzed 1,2,3-triazole formation from propargylic acid resin and various azides with CuI and DIPEA to yield peptidotriazoles. (FGFG: peptide sequence off resin, F: phenylalanine and G: glycine)

Figure 1.5 Use of copper(I)-catalyzed 1,2,3-triazole formation to prepare N-substituted histidine analogs from propargylglycine. i) CuI, DIPEA, ii) 20% piperidine/DMF, iii) 0.1 M NaOH (aq). (FGFG: peptide sequence off resin, F: phenylalanine and G: glycine)

The formation of the 1,4-substituted triazole was confirmed through comparing the copper(I) catalyzed products to those of the thermal 1,3-dipolar cycloaddition. After refluxing in toluene, the resin in Figure 1.4 with Pmoc-Phe-ψ[CH2N3] gave a mixture of the 1,4- and 1,5-isomer in a 2:1 mixture. The triazole proton of the 1,4-substituted

1,2,3-triazole was found to be almost 0.25 ppm further downfield than that of the 1,5- substituted 1,2,3-triazole, which was consistent with previous NMR observations7 of the 1,4- versus 1,5-substituted 1,2,3-triazole proton. Further evidence was provided through 2D NOE experiments that showed strong NOE effects between the triazole proton and the alkyl group off of the N1 position on the triazole. Only the 1,4-substituted triazole which would allow for this proximity to exist.

1.4.2 Sharpless’ Work on Cu(I)-Catalyzed Azide-Alkyne Cycloaddition

Figure 1.6 In situ generation of the active copper(I) species reacted with phenyl propargyl ether and benzyl azide gave the 1,4-disubstituted triazole product.

Also in 2002, Sharpless et al.6 published their results of using copper(I) to catalyze the 1,3-dipolar cycloaddition. They found that a number of copper(I) salts worked well for the reaction. However, the presence of acetonitrile and an equivalent of an amine base are required for the reactions to proceed. This unfortunately leads to the formation of a number of undesired by-products (diacetylenes, bis-triazoles, etc.). They found the catalyst was better when prepared through in situ reduction of copper(II) salts. The copper(II) salts are often less expensive and of higher purity than their copper(I) counterparts. They found that 0.25 – 2.0 mol % CuSO4·H2O in the presence of a reductant (sodium ascorbate) gave the triazole products in high yields and purity (e.g. Figure 1.6). Similarly to Meldal, they confirmed the regiochemistry via NOE experiments as well as X-ray crystallographic analysis. To compare the results from Figure 1.6, they ran the thermal reaction from those starting materials and obtained a mixture of both 1,4- and 1,5-substituted triazoles in approximately 2:1 ratio respectively. They were able to apply this system to a variety of azide and alkyne substrates (Table 1.2). They also observed no functional group interference.

Table 1.2 Selected examples of the synthesis of 1,4-disubstituted [1,2,3]-triazoles catalyzed by in situ generated copper(I).a

Entry Product Yield [%]

1 92

2 82

3 84

4 88

5 84

6 90

8 88

a Water/t-BuOH solvent, 0.25-0.5 M in reactants, 1 mol % CuSO4 with 10 mol % sodium ascorbate. All were completed within 12-24 h.

1.5 Mechanism of the CuAAC Reaction

Figure 1.7 Proposed mechanism for the CuAAC reaction.

Sharpless et al. proposed a mechanistic cycle that the CuAAC reaction could possibly go through (Figure 1.7).6 The first step is the formation of the copper(I) acetylide (1 in Fig 1.7) since no reaction is observed with internal alkynes. Further DFT studies show that the initial coordination of acetylene to the copper center forming a π 8 complex lowers the pKa of the alkyne proton by almost 10 units. After coordination of the azide (2 in Fig 1.7), the reaction could proceed through the direct [2+3] cycloaddition (route not shown). However, extensive DFT calculations showed that the direct cycloaddition pathway was strongly disfavored by about 12-15 kcal. The favored pathway appears to have nucleophilic attack of acetylide carbon on the terminal nitrogen on the azide generating the unusual six-membered copper(III) metallacycle (3).

Ring contraction affords the copper-triazolide species (4) followed by protonation to release the triazole product (5) to regenerate the catalyst and complete the cycle. Fokin et al. followed these preliminary calculations with detailed kinetic studies. Using benzyl azide and phenylacetylene, they performed pseudo-first-order kinetic experiments.9 With excess copper, the reaction was first-order in azide and between first- and second-order in alkyne. The reaction order for copper was determined to be second order when used in catalytic amount. Both results suggest that multinuclear copper-acetylide species might be involved in the reaction. Recently, Heaney et al. 10 prepared dinuclear alkynylcopper(I) ladderane complexes that function as efficient catalyst in the CuAAC reactions and suggested that the same derivatives be involved in normal CuAAC reactions.

1.6 Assisting Ligands with the CuAAC

Although not required for the CuAAC reaction, assisting ligands are often employed for several reasons. Out of all the common oxidation states of copper (0, +1, and +2), copper(I) is the least thermodynamically stable11 and can be easily oxidized to the catalytically inactive copper(II).12 Therefore, ligands can be used to protect copper(I) from oxidation. The majority of the ligands used contain amines. According to Fokin et al., the primary roles of these amine ligands can be, “(a) to prevent the formation of unreactive polynuclear copper(I) acetylides; (b) to facilitate the coordination of the azide to copper center at the ligand exchange step; and (c) to increase the solubility of the copper complex to deliver higher solution concentrations of the necessary Cu(I)-species.” 11 Many assisting ligands have been used in the CuAAC. A few selected ligands are shown in Figure 1.8. Bipyridine and phenanthroline (1 and 2 Figure 1.8) are moderately capable as assisting ligands.13 They are outperformed by tris(benzyltriazolylmethyl)amine (TBTA, 4 in Figure 1.8). TBTA significantly accelerates the CuAAC reaction and stabilizes the oxidation state of the active copper(I) ion demonstrated by cyclic voltammetry experiments.13 TBTA has also shown to be effective in sequestering copper ions and preventing damage to biological molecules as

10 evident in its successful application in bioconjugation studies.14 However, TBTA is only somewhat soluble in water whereas sulfonated bathophenanthroline (5, Figure 1.8) is water soluble and was successful in assisting the CuAAC small molecules to a cowpea mosaic virus.12 N,N,N’,N’,N”-pentamethyldiethylenetriamine, or PMDETA (3, Figure 1.8) is a flexible tridentate ligand that is predominately used to promote the CuAAC reaction in polymer chemistry.15

Figure 1.8 Ligands that have shown to be effective in promoting the Cu(I) catalyzed triazole formation.

1.7 Selected Applications of CuAAC

Due to its facile introduction of functional groups and wide reaction scope, the CuAAC reaction has found numerous applications in a plethora of areas. The areas that have been influenced the most can be divided into three categories: bioconjugation, material science, and drug discovery.16 Discussed below are a few selected examples of CuAAC applications within those areas.

1.7.1 Synthesis of Small Molecule Libraries for Drug Discovery

When Sharpless first introduced the “click chemistry” philosophy, he envisioned using click chemistry to quickly put together libraries of molecules that could then be screened for reactivity.2 Several groups have employed the CuAAC reaction to do just that.17-23 For example, new HIV protease inhibitors are needed to combat the emergence of drug-resistant mutant HIV proteases. Wong et al.18 produced a small library of compounds for screening. They used a hydroxyethylamine peptide isosteres core (similar to the commercially available HIV protease inhibitor Amprenavir) in which they functionalized with an azide (6 and 7 in Figure 1.9). After reacting with alkynes via CuAAC, over 100 compounds were prepared. Since these compounds were already in aqueous solutions, the crude products were used for screening. Compounds 7A-D (Figure 1.9) derived from azide core 6 showed good activity against HIV-1 PR at 10 nM.

After purification, the most active compounds (7A and 7C) showed very high IC50 values against HIV-1 PR and its mutants (>3 µM, >1 µM respectively).

Figure 1.9 Compounds 7A-D generated via CuAAC reaction from azide 6 with the hydroxyethylamine peptide core highlighted in red.

1.7.2 Bioconjugation

In addition to drug development, tremendous growth has been seen in the applications of CuAAC in labeling and imaging biomolecules.24 Bioconjugation applications, whether in vivo or in vitro, benefit from this approach due to the specificity of the azide-alkyne reaction, the inertness of the reactants under physiological conditions, and overall mild conditions.25 Some examples of bioconjugation using click chemistry can be found in Figure 1.10. Site specific introduction of unnatural amino acids bearing azides or alkynes have been successfully tagged using the CuAAC reaction (Figure 1.10 A).26, 27 Additionally, viruses like the cowpea mosaic virus28 and more recently the tobacco mosaic virus29 have been successfully labeled with either azide or alkyne groups on lysine or cysteine residues that were selectively modified via CuAAC. Furthermore, azido or alkyne labels have also been incorporated onto proteins through post-translational modification and then labeled via the CuAAC reaction to understand the complex process of post- translational modification (Figure 1.10 B).30-33 DNA and RNA nucleotides have both been successfully modified to bear alkyne functional groups that can later be subjected to CuAAC with an azido fluorescent tag for imaging (Figure 1.10 C).34-36 Lipid probes have been modified to have reactive azide or alkyne tags attached through the CuAAC reaction to elucidate the activities of small molecules within the cell.37-39 Activity-based protein profiling (ABPP) has also benefited from the use of click chemistry (Figure 1.10 D).40-42 In ABPP, azide bearing probes are designed to interact with proteins at certain enzyme reactive sites. After the association of the probes, they can then be tagged and manipulated via the CuAAC reaction.

Figure 1.10 Examples of CuAAC used in bioconjugation: (A) Two examples of unnatural amino acids and being labeled after incorporation into proteins; (B) Two examples of azide and alkyne-derivatized sugars and their infiltration into biosynthetic pathways; (C) Alkyne tagged deoxynucleotide and nucleotide and in vivo labeling of DNA and RNA; (D) Schematic for the strategy of ABPP using click chemistry postlabeling. Star: a label or fluorescent tag (e.g. biotin or Alexa Fluor). 14

1.7.3 Materials Chemistry

In addition to biological applications, the CuAAC reaction has shown to be very useful in the field of materials. This includes the fields of polymer and dendrimer synthesis, nanotechnology, and supramolecular chemistry.16 Application of click chemistry in the creation of dendrimers has almost solved the problems associated with purification and separation of impure products that have plagued dendrimer synthesis for over 25 years.16 Fokin’s group showed the first example of utilizing CuAAC in formation of branched dendrimers43 (Figure 1.11 A). CuAAC has also shown to be very useful in the area of polymer synthesis and functionalization as well as formation of organogels.44, 45 The area of nanotechnology has also been aided from use of the CuAAC reaction. It has been employed in DNA nanotechnology,46-49 bioconjugation50 and functionalization51 of nanoparticles and nanotubes. For example, single walled carbon nanotubes (SWNTs) are plagued by solubility problems. Recently, SWNTs bearing alkynes were successfully prepared that were later coupled with azido styrene units through CuAAC, allowing the SWNTs to dissolve in a variety of organic solvents (Figure 1.11 B).52 Supramolecular chemistry has also seen its fair use of click chemistry.53 CuAAC reactions have also been used to modify metal-organic frameworks (MOFs).54-57 Flood and co-workers have used the hydrogen-bonding capability of the triazole ring to bind anions.58 An example of their triazolaphane molecule containing four triazole units is shown in Figure 1.11 C.59 CuAAC reactions were used to construct mechanically interlocked molecules (MIM) such as catenanes and rotaxanes. Leigh et al.60, 61 used the copper center not only as a catalyst but as an “active metal template” to direct the joining of the two dumbbell halves within the macrocycle (Figure 1.11 D). The triazole ring has also served as a docking site for the shuttling of the macrocycle of the rotaxane.62, 63

Figure1.11 Examples of CuAAC reactions being applied in the synthesis of materials: (A) Sequential click reactions generated this dendrimer43; (B) CuAAC reaction allowed for functionalization of SWNTs52; (C) Generated by CuAAC, this triazolaphane shows uptake of the anion inside its cavity58; (D) Active-metal templating with CuAAC to yield desired rotaxane.60, 61

1.7.4 Coordination Chemistry

Most of the applications of CuAAC use the formation of the triazole unit solely to serve as a linker to connect two components. Less attention has been applied to the potential of the 1,2,3-triazole as a ligand. 1,2,3-Triazoles are similar to substituted imidazoles in terms of their coordinative properties (Figure 1.12).25, 64 The CuAAC

16 reaction has been employed in attaching metal complexes to various molecules and materials in a “pendant design” (Figure 1.1γ).65-69 Zhang et al.70 first demonstrated use of pendant designed triazole-based monophosphine ligands (what he termed “ClickPhos”) and their use as palladium ligands for catalyzing the Suzuki-Miyaura coupling and amination reactions of aryl chlorides. Use of the triazole unit as part of the metal chelator in the “integrated design” (Figure 1.1γ) has recently garnered more attention.71 Both N2 and N3 are capable in participating in chelation with metals (see numbering in Figure 1.12). Triazolyl containing ligands have been applied in stabilizing metals for use in catalysis (such as TBTA, vide infra), bioconjugates and anticancer complexes, metal sensing chelators and complexes with interesting electrochemical and photophysical properties.71 Further discussion on triazolyl containing ligands can be found in Chapter 4.

Figure 1.12 Unsubstituted imidazole and 1,2,3-triazole (atom numbering shown in red).

1.8 Origin of Present Work

After iron, zinc is the second most abundant metal in the body. In biological processes, the zinc ion is involved in protein function and neurological activity.72, 73 Zinc deficiency leads to many problems, including gastrointestinal tract erosion, skin lesions, cardiac failure and malformations of the brain.74-76 Dysregulation of free zinc ion has been linked to the formation of beta-amyloid plaques related with Alzheimer’s disease.77 However, the role zinc plays in biological processes is not well understood. This is largely due to its closed shell d10 configuration that renders zinc spectroscopically silent.78 Our group has had a long standing interest in the development of molecular probes for imaging biological zinc(II) ion. Copper(I)-catalyzed azide-alkyne cycloaddition has allowed for the synthesis of several fluoroionophores containing sites capable of binding to zinc(II). Early in our studies, two 1,2,3-triazolyl-containing tetradentate ligands were designed to chelate with zinc(II) though the N3 position and N2 position to form a five-membered and six membered coordination ring, respectively (Figure 1.14).79 An X-ray crystal structure confirmed the coordination to the N3 position whereas suitable crystals were not obtained unequivocally showing binding to the N2 position. However, 1H NMR results indicated that N2 coordination takes place in solution.

Figure 1.14 Two triazolyl-containing ligands designed to chelate to metals with the N3 and N2 forming a five-membered ring (blue) and a six-membered ring (red) respectively.

After these results, several ligands were designed to force binding at the N2 position. Out of several azides, 2-picolylazide quickly became the “go-to” azide due to its straightforward synthesis and highly reactive nature under CuAAC conditions. During the course of these studies, many highly polar polyaza triazolyl-containing probes were being synthesized in our lab that were often difficult to purify. Therefore, we decided to pursue the creation of CuAAC reaction conditions that avoided the use of an added reductant to simplify our purification processes. Using 2-picolylazide, reductant free conditions were developed and those results are discussed in Chapter 2. Insight into the highly reactive nature of 2-picolylazide was shown in its complex with

CuCl2 crystal structure revealing it to be a chelating azide. The high reactivity of 2- picolylazide under these developed conditions and mechanistic insights of this reaction will be addressed in Chapter 3. Taking advantage of the high reactivity of chelating azides, 2-picolylazide and its sister compound, 2,6-bis(azidomethyl)pyridine, were used in the rapid synthesis of bi- and tridentate ligands for first-row transition metal ions. Their synthesis and properties are presented in Chapter 4. To further enhance the binding of the N2 position, functionalization of the 5- position of the triazole moiety was investigated. During this process, we synthesized 5- iodo-1,2,3-triazoles using iodoacetylenes and found that the assisting ligand was unnecessary when using 2-picolylazide. One-pot conditions were developed that avoided prior synthesis of the iodoacetylenes and afforded the 5-iodo-1,2,3-triazoles in good to high yields. The results of 5-position functionalization are shown in Chapter 5.

CHAPTER 2

APPARENT COPPER(II)-ACCELERATED AZIDE-ALKYNE CYCLOADDITION (AAC)

2.1 Summary

1,4-Disubstituted-1,2,3-triazoles were synthesized via azide-alkyne cycloaddition in good to excellent yields using copper(II) salts in alcoholic solvents. The developed procedures avoid the need for an added reducing agent (e.g. sodium ascorbate). Two pathways could be operational to generate copper(I) under these conditions: oxidation of alcoholic solvent or oxidative homocoupling of alkyne. 2-Picolylazide behaved as a superior substrate under these conditions possibly due to its chelating ability to copper that facilitates the cycloaddition. The reaction between 2-picolylazide and propargyl alcohol was highly exothermic and completed within 1-2 min with low copper loading (1- 5 mol %). Preliminary spectroscopic results (EPR, UV-Vis spectroscopy) provided evidence that copper(I) was being generated in an induction period.

2.2 Common Copper(I) Source

The most common conditions for the CuAAC reaction employ in situ generation of Cu(I) through use of CuSO4 and a reducing agent such as sodium ascorbate, ascorbic acid, or tris(2-carboxyethyl)phosphine. A review of published CuAAC articles from 2001 to 2008 included roughly 200 different conditions with almost half being 15 variants of the CuSO4 procedure.

Figure 2.1 Typical CuAAC conditions use a Cu(II) salt (CuSO4) that is in situ reduced to Cu(I) through addition of a reducing agent (sodium ascorbate).

While the CuSO4/sodium ascorbate conditions are typically very successful, there are instances where it must be avoided, often in bioconjugation. Use of sodium ascorbate for the CuAAC reaction in bioconjugation was reported to induce substantial disassembly of proteins.80 Additionally, dehydroascorbate and other ascorbate by- products can react with certain amino acids resulting in modification or aggregation of proteins.81-83 In general, synthesis of 1,4-substituted-1,2,3-triazoles could be improved through avoiding the use of reducing agents. Several methods have been developed that avoid the use of additives either for the concerns of reduction-prone biomolecules or in the interest of catalyst recycling.

2.2.1 Other Copper Sources

Cu(I)-halide salts. Tornoe and Meldal5 used CuI for the CuAAC due to its partial solubility in the solvents used. The efficiencies of copper(I) halide salts rely on the addition of an amine base to form Cu-acetylide complexes.15 This is possibly due to the requirement of a certain concentration of acetylide anion to be present before the reactive complex can form. While not necessary, a reducing agent is often added to convert any oxidized copper(II) species back to the catalytically active copper(I) state.11 The most common copper(I) halide used is CuI in various organic solvents (THF,

CH3CN, or DMSO). In some instances, copper(I) halide reactions are superior to those 15 using CuSO4 in their reaction rate. However, the CuSO4/sodium ascorbate reaction conditions give cleaner products while the copper(I) halide reactions tend to give undesired by-products (diacetylenes, bis-triazoles, and 5-hydroxytriazoles).6 Cu(0) and Cu(0)/Cu(II) combinations. Conditions employing elemental copper, 15 with or without the addition of CuSO4, have shown to be very useful. The Cu(I)

21 catalyst is generated by the comproportionation of Cu(0) and Cu(II).84 When Cu(II) is not directly added to the reaction, comproportionation occurs through the CuO present in the patina on the metal surface.85 The use of straight copper metal is attractive due to being inexpensive and easy to remove post-reaction. However, these reactions 86 require a high loading of catalyst and are generally slow. Adding CuSO4 accelerates the reaction, as well as use of microwave,84, 87 ultrasound, or a combination of microwave and ultrasound.88 Copper metal has been used in several applications due to the easy removal of solid copper.89, 90 Copper nanoparticles. Heterogeneous copper(0) or copper(I) catalysts have also been successfully applied to the click reaction. Copper nanoclusters (0.1% loading) were used as an efficient catalyst for the CuAAC giving high yields without additional base or reducing agent being present.91 Mixed copper/copper oxide nanoparticles proved to be effective catalyst as well (13-20% loading in weight with respect to azide), showing full regioselectivity, short reaction times and mild reaction conditions.85 Copper nanoparticles in aluminum oxyhydroxide nanofiber (3-5 mol % loading) proved to be a recyclable copper catalyst for the AAC reaction. The major drawback from using copper nanoparticles for the CuAAC is that they are not readily available and have to be synthesized, often involving special techniques. Copper on immobile phases. Other heterogeneous copper catalysts have been developed by attaching copper to an immobile phase with the interest of recovery and recycling of catalyst. Girard et al. first reported the use of a reusable polymer- supported catalyst for the CuAAC using dimethylaminomethyl-grafted styrene.92 The amino group on the polymer acted as both a base and a chelator for CuI. Similarly, a functionalized biopolymer, Chitosan, chelated with CuOTf, was also able to catalyze the AAC reaction. But the chelation of the metal varied significantly, causing the metal loading to range from 0.5 to 2.1 mmol of Cu(I)/gram of polymer catalyst.93 Impregnation of activated wood charcoal with Cu(NO3)2 led to a nanoparticle-sized copper/charcoal matrix that was capable of catalyzing the AAC reaction and proved to be reusable multiple times without losing efficiency.94 Similarly, copper(I)-zeolites were prepared and proved to be efficient in catalyzing the AAC reaction.95 Using copper tubing, a copper-flow reactor was developed that allowed for continuous synthesis of 1,4-

22 disubstituted 1,2,3-triazoles96 and has most recently been applied for the synthesis of 1,2,3-triazolyl-containing drug-like macrocycles.97 Similar to copper nanoparticles, the downside of using copper on immobile phases for the CuAAC is that they are not readily available and require significant preparation. Direct Cu(II) catalysis. Unlike the previous examples where either copper(I) was used directly or generated through comproportionation to catalyze the AAC, there have been several reports of copper(II) catalyzing the AAC reaction. Katam et al. reported the use of Cu(OAc)2 in water without adding a reducing agent to provide the 1,4-disubstituted-1,2,3-triazoles in high yields.98 The same group went on to report the use of copper(II) ions immobilized onto a biopolymer as a successful catalyst for the cycloaddition of alkynes with azides.99 Fukuzawa and coworkers reported the use of copper(II) triflate as successful catalyst for the one-pot procedure for formation of the azide from benzylic acetates followed by the 1,3-dipolar cycloaddition.100 Copper(II) salts directly catalyzing the reaction contradicts the copper(I)-based mechanism presented by Sharpless et al. 6 Therefore, these results have been largely dismissed by the click chemistry community as inaccurate11 or that their results are due to the copper(II) salts being contaminated with minor amounts of copper(I).15

2.3 Cu(II) Reduction in Alcoholic Solvents

In the discussion above, the copper(I) catalyst results from either direct use of

Cu(I) salts or through comproportionation of Cu(0) and CuSO4 (or CuO that is present in the patina on the metal). We sought out an alternative method to reduce Cu(II) to the catalytically active Cu(I) species without the use of an added reducing agent. Yamamoto et al. proposed that the oxidizable alcoholic solvents act as reducing agents converting Cu(II) to Cu(I) to catalyze the homocoupling of arylboronic acids (Figure 2.2).101

Figure 2.2 Yamamoto’s generation of biaryls through use of copper(II) salts and an alcoholic solvent.101

Inspired by this work, we developed a hypothesis that use of copper(II) salts in alcoholic solvents would generate the active Cu(I) species necessary for the AAC reaction (Figure 2.3). We then carried out the AAC reaction of 2-picolylazide and phenylacetylene with copper(II) salts in various alcohols to determine if this would be a viable alternative to the in situ reduction of CuSO4 by sodium ascorbate.

Figure 2.3 Generation of copper(I) via alcohol oxidation proceeding to catalyze the AAC reaction.

2.4 Results and Discussion

2.4.1 Preliminary Results

The AAC reactions were screened using 2-picolylazide (1) and phenylacetylene with 5 mol % CuCl2 in the following alcohols: t-BuOH, i-PrOH, EtOH, and MeOH (Table 2.1, entries 1-4). In t-BuOH, the reaction failed to give an identifiable amount of product by TLC after 18 h (entry 1). The reactions in i-PrOH and EtOH proceeded with low conversions (entries 2-3). However, in MeOH, the isolated yield after 18 h was considerably improved to 79% (entry 4). Formation of product was only detected in readily oxidizable alcohols (MeOH, EtOH, and i-PrOH), supporting the hypothesis that a catalytic Cu(I) species was generated via the reduction of CuCl2 (Figure 2.3).

Table 2.1 Effects of the copper source and solvent on reaction yield.a

Entry Copper Source Copper Loading Solvent Yield (%)

b 1 CuCl2 5 mol % t-BuOH ND

2 CuCl2 5 mol % i-PrOH 4

3 CuCl2 5 mol % EtOH 17

4 CuCl2 5 mol % MeOH 79

5 CuSO4 5 mol % MeOH 81

6 CuSO4 5 mol % t-BuOH 6

7 Cu(OAc)2 5 mol % MeOH 90

8 Cu(OAc)2 5 mol % t-BuOH >95

9 CuCl2 + NaOAc 5 mol % t-BuOH 88 a0.2-0.25 mmol of 1 and 0.3 mmol of 2 in 0.5 mL of solvent after 18 h at RT. bNot detectable by TLC.

The counterion effect was studied through using three different Cu(II) salts in

MeOH: CuCl2 (entry 4), CuSO4 (entry 5), and Cu(OAc)2 (entry 7). All three counterions gave satisfactory yields after 18 h. Both CuSO4 and CuCl2 gave miniscule to undetectable amounts of 2 in t-BuOH. However, Cu(OAc)2 in t-BuOH gave the highest amount of product (>95%, entry 8) observed thus far. To check the possibility that

Cu(OAc)2 may have been contaminated with a trace amount of Cu(I), a reaction using 5 mol % ultra-high purity CuCl2 (99.999% pure), that is inactive in t-BuOH (Table 1, entry 1), with 5 mol % NaOAc was added to t-BuOH (entry 9). An 88% yield was isolated, indicating that the reactivity observed with Cu(OAc)2 was not due to contamination of the salt. This observation forced us to revisit our hypothesis on how Cu(I) was being generated in a solvent that is not easily oxidized. In the Glaser reaction, it is known that

25 terminal alkynes may undergo Cu(II)-catalyzed oxidative homocoupling reactions to 102 afford diynes and Cu(OAc)2 is the most active Cu(II) agent in the classical Eglinton protocol.103 In t-BuOH, it is possible that a Glaser-type reaction may be taking place to produce the active Cu(I) species that is catalyzing the AAC reaction (Figure 2.4).

Figure 2.4 Generation of Cu(I) through oxidative homocoupling of a terminal alkyne.

The “catalytic” effect of Cu(OAc)2 on the AAC reactions was reported by Kantam et al. in 200698 (vide supra). In their procedure, satisfactory yields were achieved with 20 mol % catalyst loading in aqueous solutions after 20 h. However, they postulated a direct participation of Cu(II) in the catalysis of the reaction. Comparatively, under the developed conditions, we hypothesize that there are at least two Cu(I)-generating induction processes, alcohol oxidation (Figure 2.3) and terminal alkyne homocoupling (Figure 2.4). These processes generate the active Cu(I) catalyst that necessary for the catalytic cycle proposed by Sharpless, Meldal and others.8, 9, 15, 104-106 It is likely that the efficiency of the reduction process of Cu(II) to Cu(I) is condition-dependent.107 For example, ligands that prefer the tetrahedral coordination have been observed to reduce Cu(II) to Cu(I) resulting in the formation of copper(I) complexes.107-111

2.4.2 Initial Azide and Alkyne Screening

On the basis of either alcohol oxidation or alkyne homocoupling to generate the catalytic Cu(I) species, two reaction conditions that favor either process were selected to evaluate various azide and alkyne substrates. Under condition A (5 mol % CuSO4 in MeOH), copper reduction by methanol is presumably the major process to generate the

Cu(I) species. Whereas in condition B (5 mol % Cu(OAc)2 in t-BuOH), the Glaser-type reaction may result in the reduction of Cu(II). After 18 h, the reactions were filtered through a silica plug and the solvent removed. The results are summarized in Table 2.2.

Overall, the reaction yields were higher under condition B than those of condition

A. This suggests that Cu(OAc)2 is a very potent catalytic Cu(I) source. Benzyl azide performs relatively well under both conditions (entry 5) where octylazide and p- azidoanisole gave decent yields only under condition B when compared to condition A. The sterically hindered 1-azidoadamantane does not show any product under either condition. Under these conditions, 2-picolylazide appears to be a superb substrate (1, Table 2.2, entries 1-4). The facile AAC reactions involving 1 under the normal Cu(I)- catalyzed conditions were also observed by Kosmrlj et al.112

In addition to these conditions (A and B in Table 2.2), an additional third condition 113 was also screened that combined Cu(OAc)2 in MeOH. With this condition (condition C), both the alcohol oxidation and homocoupling pathways are viable options to produce Cu(I). Interestingly, under conditions A and B, di(2-picolyl)propargylamine was unreactive but gave high yields when condition C was used, demonstrating that the reactions are substrate dependent.

Table 2.2 Triazole products generated under developed conditions A and B.a

Entry Product Yield (%)

A: 13 1 B: >95

A: 56 2 B: >95

A: >95 3 B: 92

A: 10b 4 B: 85

A: 68 5 B: 87

A: trace 6 B: 50

A: 25c 7 B: 67c

A: ND 8 B: ND

a A: CuSO4, 5 mol % in MeOH, B: Cu(OAc)2, 5 mol % in t-BuOH. Additional conditions: 0.2 mmol azide (0.6 mmol for entry 4), 0.22-0.3 mmol alkyne, RT, 18 h. b36% monotriazole product was isolated. c40 h reaction time.

2.4.3 Evidence of Copper(II) Reduction

Figure 2.5 2-Picolylazide (1) and propargyl alcohol react rapidly under the developed click conditions.

All reactions listed in Table 2.2 were analyzed after 18 h. However, some reactions may have taken much less time to complete. For instance, the reaction between 1 and propargyl alcohol in the presence of 1-5 mol % Cu(OAc)2 in t-BuOH is complete within 60-120 seconds (Figure 2.5). To our knowledge, this is the fastest CuAAC reaction under classical reaction conditions to date. The reaction between 2-picolylazide and propargyl alcohol displays a dramatic change of color (Figure 2.6). At the start, the reaction is a clear light blue color that quickly heats up and changes to a cloudy bright yellow. The reaction progress can be monitored by UV-Vis spectroscopy (Figure 2.7) by following the d-d band of Cu(II). This band remains unchanged during the induction period but starts to disappear at 65 seconds, suggesting the reduction of Cu(II). Large absorbance values at the end of the reaction were due to the heterogeneity of the sample.

(A) (B) (C)

Figure 2.6 Reaction of 1 and propargyl alcohol in t-BuOH (A) at the start of the reaction, (B) at ~60 s, and (C) at 90 s.

2.5

2 65 s

1.5 Absorobance Absorobance

0.5 550 600 650 700 750 800 850 Wavelength (nm)

Further evidence of the reduction of Cu(II) was obtained by electron paramagnetic resonance (EPR) measurements given that Cu(II) shows a characteristic EPR signal at a g-value of about 2.2, whereas Cu(I) is EPR-inactive. EPR spectra of

Cu(OAc)2 were taken in t-BuOH with various components of the reaction as well as at the end of the reaction (Figure 2.8). With t-BuOH as the solvent, the spectra in the presence and absence of propargyl alcohol (green and red spectrum respectively) show two overlapping bands (one very broad band and one sharper featureless band). Copper(II) acetate has poor solubility in t-BuOH and the bands are due to two species of copper present: the solvated copper(II) (sharp band) and the suspended solid (broad band). These bands remain unchanged in the presence of alkyne. When the reaction of 1 and phenylacetylene is complete, the copper(II) signals were greatly diminished

(purple spectrum in Figure 2.8). This, along with the absorption data, supports the hypothesis that Cu(II) is converted to Cu(I) enabling the CuAAC reactions.

-2 Copper(II) Acetate -4 Intensity (a.u.) (a.u.) Intensity

Copper(II) Acetate + Alkyne -6

Copper(II) Acetate + Alkyne -8 + Azide (after reaction)

-10 2500 2700 2900 3100 3300 3500 Magnetic Field (G)

Figure 2.8 EPR spectra of Cu(OAc)2 in t-BuOH at room temperature. The purple trace was obtained after the reaction between azide 1 and propargyl alcohol was complete.

-10 Copper(II) Acetate + Azide (1) -20

Intensity (a.u.) (a.u.) Intensity Copper(II) Acetate

-30 Copper(II) Acetate + Alkyne

-40 Copper(II) Acetate + Azide + Alkyne (after reaction) -50 2900 3000 3100 3200 3300 3400 3500 3600 Magnetic Field (G)

Figure 2.9 EPR spectrum of Cu(OAc)2 with azide 1 in t-BuOH at room temperature overlaid with previous spectra.

The EPR spectrum of copper(II) acetate with 1 EPR was also taken. A significant enhancement of the copper signal was observed (shown separately in Figure 2.9 due to the intensity difference from Figure 2.8). This increase in signal can be attributed to the fact that copper(II) acetate can exist in both the dimer and monomeric form (Figure 2.10). In most organic solvents, copper(II) acetate exists primarily the dimer form and gives little to no absorption for EPR.114 With increasing amounts of water or pyridine, observed enhancement in the EPR signal suggests the formation of the monomeric copper(II) acetate species.115, 116 Therefore, coordination of 2-picolylazide in the axial position increases the amount of copper(II) acetate monomer in solution, therefore enhancing the signal. The g values for all copper bands (2.13, 2.10, and ~2.09) are in agreement with values previously reported for copper(II) acetate.114 Hyperfine splitting

32 was also observed around 3400 G. The splitting pattern and g value of 2.006 are consistent with those reported for nitroxide radicals.117 The intensities of the peaks are very weak and suggest that they are a very minor component of the system (<5%). If this is indeed a nitroxide radical, its appearance in the system is not well understood and future EPR work is planned.

Figure 2.10 Schematic showing the equilibration of copper(II) acetate dimer to monomer. L: arbitrary solvent molecule, pyridine or water.

2.4.4 Chelating Azides and Triazoles

Crystals suitable for X-ray diffraction were obtained from 1 and copper(II) chloride (Figure 2.11). This dinuclear copper structure is presented fully and discussed in detail in Chapter 4. The coordination of the pyridyl nitrogen and the alkylated nitrogen (Nα) to the copper center was observed. We proposed that this coordination mode renders the azide more electrophilic and facilitates the attack from the acetylide (Figure 2.12). Additionally, reactions involving 1 gave multidentate ligands for copper. This is evident in the crystal structure of the Cu(II) complex of 2 with copper(II) perchlorate. The N2 of the triazole units (labeled N2 and N22 in Figure 2.13) are coordinated to the metal. The Cu(II) complex displays a Jahn-Teller distorted octahedral geometry. Within the octahedral, the nitrogens in the square plane have a ligand-to-metal distance of 2.02 Å (Table 2.3). The apical ligand-to-metal distances are elongated with a distance of 2.34 Å and 2.68 Å for the acetonitrile nitrogen (labeled N41 in Figure 2.12) and perchlorate oxygen (labeled O4). Despite the affinity to Cu(II), product inhibition in the AAC reactions was not observed.

Figure 2.11 Dinuclear copper complex [Cu2(1)2Cl4].

Figure 2.12 Scheme showing chelation of azide to copper that, during the transition state, renders the azide more electrophilic and facilitates the cycloaddition.

Table 2.3 Select bond lengths (Å) and angles (°) for [Cu(2)2(ClO4)CH3CN](ClO4).

Cu1 Distance Angles N2 2.004 (2) N22 2.004 (2) 17.31 (12) N4 2.057 (3) 88.26 (10) 92.73 (10) N24 2.058 (3) 92.05 (10) 87.01 (10) 179.39 (11) N41 2.338 (3) 95.73 (12) 89.86 (12) 90.33 (11) 88.11 (11) O4 2.677 (3) 90.55 (11) 84.06 (11) 81.49 (10) 99.04 (11) 169.54 (11) Cu1 N2 N22 N4 N24 N41

Table 2.4 Crystal data and structural refinement.

[Cu(2)2(ClO4)CH3CN](ClO4)

Formula C30H27CuN9O8Cl2 Formula weight 776.06

Space group P212121 Crystal system Orthorhombic a/ Å 11.422(3) b/ Å 16.075(4) c/ Å 17.832(5) α/° 90.000 ° 90.000 /° 90.000 V/Å3 3274.1(15) Z 4 -3 Dc/g cm 1.574 µ(Mo-Kα)/ mm-1 0.895 T/K 173(2) Crystal size (mm) 0.05 x 0.13 x 0.33 θ range (°) 2.1, 22.0

Rint 0.020 Total reflections 23550 Unique reflections 3990 Parameters refined 452

R1 [I > βσ(I)] 0.0267

wR2 0.0827 GOF on F2 0.720

2.5 Conclusions

Copper(II) salts are able to accelerate the AAC reaction without deliberate addition of reducing agents. After an induction period, the active copper(I) is being generated either through alcohol oxidation or through oxidative homocoupling of alkynes. Spectroscopic evidence of copper(I) generation was provided through UV-Vis spectroscopy and EPR. Azides capable of chelation, like 2-picolylazide, demonstrated high reactivity under these developed conditions. For example, the reaction with 2- picolylazide and propargyl alcohol is very rapid, reaching completion in less than two min. To our knowledge, the aforementioned reaction is one of the fastest AAC reactions to date under classical conditions. High yields were obtained for pyridyl- containing multidentate ligands for copper(II) with no product inhibition observed.

2.5 Experimental Information

2.5.1 Materials and General Methods

Caution: Low molecular weight carbon azides used in this study are potentially explosive. Proper handling and appropriate precautions should be observed when using these compounds. Reagents and solvents were purchased from various commercial sources and used without further purification unless otherwise stated. The purities of Cu(II) salts used are: CuCl2 - > 99.999%; Cu(OAc)2 - > 99.0%; and CuSO4 - > 98%. Analytical thin-layer chromatography (TLC) was performed using pre-coated TLC plates with silica gel 60 F254 (EMD) or with aluminum oxide 60 F254 neutral (EMD). Flash column chromatography was performed using 40-6γ m (βγ0-400 mesh ASTM) silica gel (EMD) or alumina (80-200 mesh, pH 9-10, EMD) as the stationary phases. Silica and alumina gel were flame-dried under vacuum to remove absorbed moisture before use. 1H and 13C NMR spectra were recorded at 300 MHz and 75 MHz, respectively, on a Varian εercury spectrometer. All chemical shifts were reported in units relative to tetramethylsilane. CDCl3 was treated with alumina gel prior to use. High resolution mass spectra (ESI) were obtained on a JEOL AccuTof spectrometer at the

Mass Spectrometry Laboratory at FSU. Absorption spectra were collected on a Varian Cary 100 Bio UV-Visible Spectrophotometer.

2.5.2 Representative Procedures for Table 2.2

Method A: 2-Picolylazide (27 mg, 0.2 mmol) was added to a 2-dram sample vial. A stock solution of phenylacetylene (0.5 mL, 0.6 M in MeOH, 0.3 mmol) was then added to the vial while stirring. The addition of CuSO4 (25 δ, 0.4 ε solution in H2O, 10 mol) was followed and the reaction mixture was capped and stirred for 18 h. After checking by TLC (50/50 DCM/EtOAc), the reaction mixture was directly loaded onto a short plug of silica gel. After elution with EtOAc, the solvent was removed under vacuum and a 1H NMR was taken. If needed, the product was further chromatographed using a finer solvent gradient to afford the analytically pure product.

Method B: 2-Picolylazide (27 mg, 0.2 mmol) was added to a 2-dram sample vial. A stock solution of phenylacetylene (0.5 mL, 0.6 M in t-BuOH, 0.3 mmol) was then added to the vial while stirring. After the addition of Cu(OAc)2 (β5 δ, 0.4 ε solution in H2O, 10 mol), the reaction mixture was capped and stirred for 18 h. The reaction was checked by TLC (50/50 DCM/EtOAc) to confirm completion. The reaction mixture was loaded directly onto a short plug of silica gel. After elution with EtOAc, the solvent was removed under vacuum and a 1H NMR was obtained. If needed, the product was further chromatographed using a finer solvent gradient to afford the analytically pure product.

2.5.3 Absorption Spectroscopy

2-Picolylazide (1β0 δ, d = 1.1γ, 1.0 mmol) and propargyl alcohol (λ0 δ, d = 0.λ4λ, 1.5 mmol) were dissolved in t-BuOH (2.5 mL) in a spectrophotometer cuvette. Upon addition of Cu(OAc)2 (1β6 δ, 0.4 ε in H2O, 0.05 mmol) and brief mixing, the absorption spectrum of the reaction mixture was taken every 22 seconds. The spectrum did not alter much during the first minute and the d-d transition of Cu(II) was clearly identifiable. At ~ 65 s, the blue color of the reaction mixture quickly faded before it rapidly turned into

38 a bright-yellow color within seconds. The band for the d-d transition disappeared. The absorption in the recorded window at that point was mainly due to the scattering of a heterogeneous sample. The spectrum taken at the 65 s was discontinuous because the reaction was occurring during the scan.

2.5.4 Electron Paramagnetic Resonance

~2.17 20

2.0063 10 2.1933 2.0963

0 2.1306 -10 2.0732 Copper(II) Acetate + Azide (1) -20 ~2.09

Intensity (a.u.) (a.u.) Intensity Copper(II) Acetate ~2.03 -30 Copper(II) Acetate + Alkyne

-40 Copper(II) Acetate + Azide + Alkyne (after reaction) -50 2500 2700 2900 3100 3300 3500 Magnetic Field (G)

EPR measurements were made using a commercial (Bruker E-line) spectrometer at X- band (~9.4 GHz) using a standard TE102 cavity at room temperature. The microwave power and magnetic field modulation amplitude were optimized for signal intensity and resolution. Typical values were: microwave power: 10 mW, modulation frequency 100

39 kHz, modulation amplitude: 10 gauss peak to peak, scan range: 1000 G/5 min; number of scans added: 4. Samples for EPR were prepared in vials separately and then transferred to EPR tubes for analysis. Sample solutions: Copper(II) acetate (40 δ of

0.4 M Cu(OAc)2 stock in H2O) and t-BuOH (0.5 mδ); Copper(II) acetate (40 δ of 0.4 ε

Cu(OAc)2 stock in H2O), propargyl alcohol (0.5 mmol, γ0 δ) and t-BuOH (0.5 mL);

Copper(II) acetate (40 δ of 0.4 ε Cu(OAc)2 stock in H2O), 2-picolylazide (0.5 mmol, 60

δ) and t-BuOH (0.5 mδ); Copper(II) acetate (40 δ of 0.4 ε Cu(OAc)2 stock in H2O), 2- picolylazide (0.β mmol, β4 δ), propargyl alcohol (0.γ mmol, 0.5 mδ of 0.6 ε stock in t- BuOH).

2.5.5 Synthesis of Complex [Cu(2)2(ClO4)CH3CN](ClO4)

Compound 2 (β0.5 mg, 86.8 mol) was dissolved in acetonitrile (~5 mδ). To that solution, copper(II) perchlorate (86.8 δ, 0.05 ε Cu(ClO4)2 solution in acetonitrile was added. Upon mixing the solution changed from blue to green. The solvent was removed and the green solid rinsed with diethyl ether (3 x 10 mL). After drying thoroughly, the complex was dissolved in acetonitrile (~ 2 mL) and filtered through glass microfiber. Vapor diffusion with diethyl ether overnight gave green colored crystals.

2.5.6 Characterization of Compounds

Compound 1.118 2-Picolylchloride hydrochloride (8.20 g, 50 mmol), 18-crown-6 (cat.), and tetrabutylammonium iodide (cat.) were dissolved in DMF (15 mL). To this stirred solution, diisopropylethylamine (8.5 mL) was added. Lastly, sodium azide (3.57 g, 55 mmol) was added and the solution was left stirring for overnight (~ 12 h). The solution was then diluted with EtOAc (100 mL), rinsed with basic brine (100 mL × 3, pH > 10) followed by washing with ammonium chloride solution (100 mL, 1.0 M). The organic layer was then dried over Na2SO4 and the solvent removed to afford the pure product as 1 a yellow oil. The yield was between 60-80%. H NMR (300 MHz, CDCl3)μ /ppm 8.61 (d,

J = 4.2 Hz, 1H), 7.73 (td, J = 1.8, 7.8 Hz, 1H), 7.35 (d, J = 7.8 Hz, 1H), 7.26 (m, 1H), 4.50 (s, 2H).

1 Compound 2. H NMR (300 MHz, CDCl3)μ /ppm 8.61 (d, J =4.8 Hz, 1H), 7.λ4 (s, 1H), 7.83 (d, J = 7.2 Hz, 2H), 7.69 (td, J =1.8, 7.8 Hz, 1H), 7.41 (t, J = 7.2 Hz, 2H), 7.31-7.27 13 (m, 1H), 7.27-7.25 (m, 1H), 5.70 (s, 2H). C NMR (75 MHz, CDCl3)μ /ppm 154.7, 149.9, 148.4, 137.5, 130.7, 129.0, 128.3, 125.9, 123.6, 122.6, 120.3, 55.9. HRMS (ESI): calcd [M+H]+ 237.1140, found 237.1104.

1 Compound 3. H NMR (300 MHz, CDCl3)μ /ppm 8.5λ (d, J = γ.6 Hz, 1H), 7.67 (td, J = 1.8, 7.8 Hz, 1H), 7.41 (s, 1H), 7.30-7.20 (m, 1H), 7.14 (d, J = 7.8 Hz, 1H), 5.61 (s, 2H), 2.71 (t, J = 7.2 Hz, 2H), 1.64 (m, 2H), 1.37 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H). 13C NMR

(75 MHz, CDCl3)μ ppm 155.1, 14λ.8, 14λ.1, 1γ7.4, 1βγ.4, 1ββ.4, 1β1.γ, 55.6, γ1.6, 25.5, 22.4, 13.9. HRMS (ESI): calcd [M+H]+ 217.1453, found 217.1466.

1 Compound 4. H NMR (300 MHz, CDCl3)μ /ppm 8.5λ (d, J = 4.8 Hz, 1H), 7.7γ-7.65 (m, 2H), 7.30-7.24 (m, 1H), 7.21 (d, J = 7.8 Hz, 1H), 5.64 (s, 2H), 4.80 (s, 2H). 13C NMR

(75 MHz, CDCl3)μ /ppm 154.5, 149.8, 148.5, 137.6, 123.6, 122.7, 56.4, 55.7. HRMS (ESI): calcd [M+H]+ 191.0933, found 191.0918.

1 Compound 5. H NMR (300 MHz, CDCl3)μ /ppm 8.5λ (d, J = 4.β Hz, 1H), 7.68 (td, J = 1.8, 7.8 Hz, 1H), 7.62 (s, 1H), 7.29-7.23 (m, 1H), 7.16 (d, J = 7.8 Hz, 1H), 5.65 (s, 2H),

13 3.60 (s, 2H), 2.26 (s, 6H). C NMR (75 MHz, CDCl3)μ /ppm 158.λ, 154.0, 14λ.λ, 141.6, 127.6, 127.3, 126.6, 59.9, 58.7, 49.4. HRMS (ESI): calcd [M+H]+ 218.1406, found 218.1432.

1 Compound 6a. H NMR (300 MHz, CDCl3)μ /ppm 8.58 (d, J = 4.8 Hz, βH), 7.67 (td, J = 1.8, 7.8 Hz, 2H), 7.42 (s, 2H), 7.28-7.22 (m, 2H), 7.14 (d, J = 7.8 Hz, 2H), 5.61 (s, 4H), 13 2.74 (m, 4H), 1.74 (m, 4H). C NMR (75 MHz, CDCl3)μ /ppm 154.8, 149.7, 148.4, 137.3, 123.3, 122.2, 121.4, 55.5, 28.9, 25.4. HRMS (ESI): calcd [M+H]+ 375.2046, found 375.2047.

1 Compound 6b. H NMR (300 MHz, CDCl3)μ /ppm 8.60 (d, J = 4.8 Hz, 1H), 7.6λ (td, J = 1.8, 7.8 Hz, 1H), 7.44 (s, 1H), 7.27 (m, 1H), 7.16 (d, J = 7.8 Hz, 1H), 5.62 (s, 2H), 2.74 (t, J = 7.2 Hz, 2H), 2.22 (td, J = 2.4, 7.2 Hz, 2H), 1.93 (t, J = 2.4 Hz, 1H), 1.86-1.74 (m, 13 2H), 1.65-1.55 (m, 2H). C NMR (75 MHz, CD3OD)μ /ppm 155.4, 14λ.λ, 150.6, 1γ8.5, 124.2, 123.2, 84.1, 69.0, 55.3, 28.8, 28.4, 25.1, 18.1. HRMS (ESI): calcd [M+Na]+ 263.1282, found 263.1273.

119 1 Compound 7. H NMR (300 MHz, CDCl3)μ /ppm 7.4γ-7.30 (m, 3H), 7.30- 7.20 (m, 2H), 7.18 (s, 1H), 5.49 (s, 2H), 2.69 (t, J = 7.8 Hz, 2H), 1.62 (m, 2H), 1.36 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H).

120 1 Compound 8. H NMR (300 MHz, CDCl3)μ /ppm 7.77 (d, J = 7.β Hz, βH), 7.67 (s, 1H), 7.36 (t, J = 7.2 Hz, 2H), 7.26 (t, J = 7.2 Hz, 1H), 4.33 (t, J = 7.5 Hz, 2H), 1.88 (m, 2H), 1.24 (m, 10H), 0.80 (t, J = 7.2 Hz, 3H).

120 1 Compound 9. H NMR (300 MHz, CDCl3)μ /ppm 8.11 (s, 1H), 7.λ1 (d, J = 7.β Hz, 2H), 7.69 (d, J = 9.0 Hz, 2H), 7.46 (t, J = 7.2 Hz, 2H), 7.37 (t, J = 7.2 Hz, 1H), 7.05 (d, J = 9.0 Hz, 2H), 3.84 (s, 3H).

2.5.7 1H and 13C NMR Spectra

1 Figure 2.15 300 MHz H NMR Spectrum of compound 1 in CDCl3.

1 Figure 2.16 300 MHz H NMR Spectrum of compound 2 in CDCl3.

13 Figure 2.17 75 MHz C NMR Spectrum of compound 2 in CDCl3.

1 Figure 2.18 300 MHz H NMR Spectrum of compound 3 in CDCl3.

13 Figure 2.19 75 MHz C NMR Spectrum of compound 3 in CDCl3. 45

1 Figure 2.20 300 MHz H NMR Spectrum of compound 4 in CDCl3.

13 Figure 2.21 75 MHz C NMR Spectrum of compound 4 in CDCl3.

1 Figure 2.22 300 MHz H NMR Spectrum of compound 5 in CDCl3.

13 Figure 2.23 75 MHz C NMR Spectrum of compound 5 in CDCl3.

1 Figure 2.24 300 MHz H NMR Spectrum of compound 6a in CDCl3.

13 Figure 2.25 75 MHz C NMR Spectrum of compound 6a in CDCl3.

1 Figure 2.26 300 MHz H NMR Spectrum of compound 6b in CDCl3.

13 Figure 2.27 75 MHz C NMR Spectrum of compound 6b CD3OD.

CHAPTER 3

STRUCTURAL AND MECHANISTIC ASPECTS OF THE COPPER(II)-ACCELERATED AZIDE-ALKYNE CYCLOADDITION

3.1 Summary

The reactivity of other chelating azides and their products as assisting ligands in regards to the Cu(OAc)2-accelerated AAC reaction were studied by other members in the group and their results are briefly discussed. This data, combined with the results from the initial study, allowed us to study the mechanism. Results pertaining to solvent screening and alkyne screening are discussed in detail. In regards to solvent, the reaction can proceed in aprotic organic solvents but required longer reaction times than reactions in protic solvents. The Cu(OAc)2-accelerated AAC reactions were observed to proceed fairly rapidly in aqueous solvents which shows promise for possible use in bioconjugation applications. The alkyne screening results under preparative, heterogeneous conditions show no clear trend between the structure of the alkyne and efficiency of the reaction. However, under homogeneous conditions used for the kinetics studies, a clear trend was observed where electron-withdrawing substituents on the para-position of phenylacetylene show shorter induction periods and react very rapidly. During the solvent and alkyne screening, a discontinuous reaction profile was observed suggesting the structure evolution of the catalyst, therefore lowering the catalytic activity. A known copper cluster structure [Cu4(OAc)4(CH3O)4] was isolated and discussed in regards to catalyst reorganization over the course of the reaction.

3.2 Additional Information Leading to Mechanistic Investigation

From the initial study of copper(II)-accelerated AAC reaction, it was observed that (1) 2-picolylazide and 2-(azidomethyl)quinoline were superior substrates possibly

50 due to their ability to coordinate to copper(II) thus facilitating the reaction and, (2) despite creating products that serve as ligands for copper, no product inhibition was observed, suggesting the possibility of the products serving as assisting ligands during the reaction. In the next two subsections, the results of experiments to test the reactivities of chelating azides and the ligand acceleration effect are discussed.

3.2.1 Chelating Azides

Chelating azides coordinate to copper(II) via the alkylated nitrogen of the azido group (Figure 3.1A); therefore, the catalytic copper(I) species generated during the induction process is biased to bind at the alkylated nitrogen. It has been observed that copper(I) may preferentially coordinate with the terminal nitrogen of the azido group.121 The coordination mode (Figure 3.1 A) enhances the electrophilicity of the azido group thereby accelerating the nucleophilic attack by the copper acetylide and the following formation of the metallacycle intermediate (Figure 3.1 B). To test the hypothesis that chelation-enhanced reactivity was generally applicable, other azides capable of forming chelate complexes with copper were studied.122 Several azides were designed to have auxiliary heteroatoms near the azido group that could assist in coordination to copper (Figure 3.1 A) and studied in the copper(II) acetate AAC reaction. In general, chelating azides were more reactive than non-chelating azides. In fact, nitrogen bearing donor ligands were more reactive than those of oxygen (e.g. azide 6) or sulfur (e.g. azide 7). Azides capable of forming a five-membered ring when chelated with copper show a higher reactivity than those forming six-membered rings. Several control experiments demonstrate the significance of chelation over basicity. 1- Azidooctane, p-ethynylanisole, and one equivalent of base (pyridine or N- methylpyrrolidine) showed very low conversions over extended reaction times. The addition of a base (pyridine or N-methylpyrrolidine) to reactions of 2-picolylazide (1) and N-(2-azidoethyl)pyrrolidine (2) with phenylacetylene led to considerably longer reaction times when compared to the reactions without base added.

3.2.2 Assisting Ligand Effect

During the development of the CuAAC reactions, Fokin and coworkers observed that the reaction rates of certain polyvalent substrates were very high and that the reactions appeared to be autocatalytic.13 It was proposed that the resulting polytriazole products (such as TBTA) served as rate accelerating ligands for copper(I).

During the initial study of Cu(OAc)2-accelerated AAC reactions, multidentate ligands for copper were synthesized without any observed product inhibition. It is possible that a similar autocatalytic processes may be operational in the Cu(OAc)2- accelerated AAC reaction in that the bidentate triazole products serve as accelerating ligands. To test this, Kuang et al.122 used different compounds generated from 2- picolylazide (e.g. 8 and 9) as additives (10 mol %) to reactions that scarcely proceeded under typical Cu(OAc)2 conditions. Moderate acceleration of the AAC reaction was observed when compared to reactions without additives (Table 3.1 contains select

52 examples) suggesting the possibility of autocatalysis. However, a significant acceleration was observed when TBTA was used as an assisting ligand showing full conversions with short reaction times (Table 3.1).

Table 3.1 Selected results of using triazole products 8 and 9 as additives.a

Product Time Yield (%)b Additive

3 h 13 None

3 h 38 8 TBTA 1 h 98 (10 mol %)

24 h 13 None

24 h 23 8 TBTA 2 h 93 (2 mol %)

4 h 17 None

4 h 40 9 TBTA 2 h 95 (2 mol %) a Reaction conditions: azide (0.2 mmol), alkyne (0.2-0.22 mmol), t-BuOH (0.5 mL), and Cu(OAc)2 (β5 δ, b 0.4 M solution in H2O). Isolated yields.

3.2.3 Motivation for Mechanistic Investigation

From the investigations on the copper(II) acetate based conditions,113, 122 there were two key observations that motivated us to investigate the mechanism. The first being that chelating azides (1, 2, 6, and 10-12 shown in Figure 3.2) are superior substrates under the Cu(OAc)2-accelerated conditions. Secondly, copper(II) acetate is the most effective copper(II) precatalyst when compared to other counterions for copper(II). Therefore, we sought out to understand the roles that chelating azides and copper(II) acetate during the course of the reaction. The mechanistic study was led by G.-C. Kuang in our lab and his kinetics studies results will not be discussed in detail in this chapter. My contribution to this work focused on solvent and structural studies for their effects on the efficiency of Cu(OAc)2-accelerated AAC reaction. These results allowed for the selection of appropriate conditions to be used for the kinetic experiments that employed fluorescence and 1H NMR assays.

Figure 3.2 The best chelating azides under Cu(OAc)2-accelerated conditions.

3.3 Results and Discussion

3.3.1 Solvent Screening

We have postulated that under the Cu(OAc)2-accelerated CuAAC conditions the catalytic copper(I) species is generated after a short induction period either through oxidation of the alcoholic solvent or by oxidative homocoupling (OHC) of terminal

54 alkynes. Direct observations of the homocoupled diyne products and the formation of the aldehyde species under similar CuAAC conditions by us122, Mizuno et al.123, and Heaney et al.10, 124 support our hypothesis on the processes operating to generate the catalyst. During the initial study, it was observed that some reactions were complete in far less time than the allotted 18 h reaction time and that the reaction between 2- picolylazide and phenylacetylene proceeded to a certain extent in acetonitrile. It was then warranted to determine the reaction times of the Cu(OAc)2-accelerated CuAAC reaction in the alcoholic solvents as well as in other organic solvents and aqueous conditions. Chelating azides 2-picolylazide (1) and N-(2-azidoethyl)pyrrolidine (2) and their reactions with phenylacetylene were screened in various solvents and their results presented in Table 3.2. The solvents in Table 3.2 are divided into two groups; aprotic organic solvents and protic solvents. The reaction times were monitored by TLC until the disappearance of 1 or 2 followed by confirmation of full conversion by 1H NMR.

The first group, aprotic organic solvents, includes CH2Cl2, CH3CN, THF and toluene (Table 3.2, entries 1-4). These reactions are heterogeneous and start out as a light blue solution (Figure 3.3 A and B). As the reactions proceed, for most cases, the solutions change to a green-blue color (Figure 3.3, C and D). The fading of the blue color is indicative of the copper(II) precatalyst being transformed into the copper(I) catalyst.113, 123 Reactions involving azide 1 were finished between 55 min to 5 h where reactions involving azide 2 were completed in 2.75 h to 8 h. The fastest reaction time for the aprotic organic solvents was observed for azide 1 in CH3CN and demonstrated a dramatic color change (Figure 3.3 A and C) when compared to the other reactions. 125 Copper(II) is a stronger oxidant in CH3CN than in most other solvents, therefore the solvent is providing a thermodynamic driving force for copper(II) reduction. Some reactions show an initial rapid conversion followed by a slower phase to reach completion. This type of discontinuous kinetic profile is indicative of the deactivation of the catalyst over the course of the reaction,126, 127 which will be discussed in more detail in Section 3.3.3. The second group contains the protic solvent reactions (Table 3.2, entries 5-11). The reactions in alcoholic solvents (Table 3.2, entries 5-7) are more homogeneous than

55 the previous set of reactions. Reactions in alcoholic solvents all undergo drastic color changes (Figure 3.4). In general, the reactions start out as a light blue color (Figure 3.4 A) and end as yellow-green color (Figure 3.4 B). All reactions in alcoholic solvents are complete within five min without discernible difference between the reactivity of azide 1 or 2.

Table 3.2 Solvent screening results of Cu(OAc)2-accelerated AAC of 1 and 2 with phenylacetylene.a

Entry Solvent Time R:1b Time R:2b

1 CH3CN 55 min 3.5 h 2 THF 5 h 3.5 h

3 CH2Cl2 60 min 2.75 h 4 Toluene 3 h 8 h (58%)c 5 t-BuOH <5 min <5 min 6 MeOH <5 min <5 min 7 i-PrOH 5 min <5 min 8 Water 40 min 30 min 9 NaOAc (0.05 M, pH 7) <25 min 30 min 10 HEPES buffer (0.5 M, pH 7) <5 min 2 h (89%)c NaOAc (0.05 M), 11 <5 min 2 h (85%)c HEPES (0.5 M, pH 7) a Reaction conditions: Azide 1 or 2 (0.2 mmol), phenylacetylene (0.22 mmol), Cu(OAc)2•H2O (5 mol %), room temperature. b Time that the azide was observed to disappear on TLC. c Incomplete conversion with percent conversion from 1H NMR in parentheses.

Reactions in alcoholic solvents are consistently faster than those of aprotic organic solvents. There may be several reasons the reactions are apparently faster in alcoholic solvents. Firstly, the induction period in aprotic organic solvents might be longer probably because of only having the OHC reaction to generate copper(I), whereas alcoholic solvents have two pathways (OHC reaction and alcohol oxidation) operable to generate the active catalyst. Secondly, the alcoholic solvents allow for rapid protonation of the copper(I) triazolide, which could affect the overall rate.127, 128 Reactions in aprotic organic solvents might be slower due to the proton sources in the reaction media being scarce. The sources are limited to the terminal alkyne proton, protonated azides 1 and 2 (pyridinium or pyrrolidinium formed from the deprotonation of alkyne), or the minimum amount of water introduced with the Cu(OAc)2. Lastly, the exchange process between the counterion and the azide/alkyne may be faster in protic solvents when compared to aprotic solvents. This exchange has been noted as important in the CuAAC reactions.127, 129 The reactions also proceed well in aqueous solvents (Table 3.2, entries 8-11). These reactions also undergo a dramatic color change from light blue to a yellow-green colored solution with a yellow precipitate (Figure 3.5). The reactions had relatively short reaction times in deionized water (Table 3.2, entry 8) or water with sodium acetate added (Table 3.2, entry 9). The reaction time for azide 1 was significantly shortened in an aqueous buffered solution with or without sodium acetate present (Table 3.2, entries 10 and 11). However, the time for azide 2 increased significantly and did not go to completion. More than likely, this is due to azide 2 being a stronger base (pKa of N- methylpyrrolidinium 10.5) than that of azide 1 (pyridinium pKa 5.2), thus being protonated by the buffer to maintain pH and disabling its auxiliary chelation with the copper center. The reactions in aqueous solvents are reasonably rapid when compared to the 20 h reaction time reported for the aqueous CuAAC reaction conditions used by 98 Reddy et al. The results of the Cu(OAc)2-accelerated AAC reaction in aqueous conditions show potential for applying this reaction in bioconjugation studies.

From the solvent screening results, methanol and acetonitrile were selected as representative solvents for the alkyne screening and the kinetic studies. It was expected that the protic solvent would have a shorter induction time than that of aprotic organic solvent (vide supra).

Figure 3.5 (A) Beginning of reaction with azide 1 (Table 3.2, entry 10); (B) end of reaction after five min; (C) view of yellow organic solid in green aqueous solution.

3.3.2 Alkyne Screening

Reactivities of various alkynes with azides 1, 2, and 6 were studied in both

CH3OH and CH3CN and the results are presented in Table 3.3. The reactions were carried out at benchtop conditions with vigorous stirring and small aliquots being routinely removed for TLC analysis.

Table 3.3 Effect of alkyne on the Cu(OAc)2-accelerated AAC reaction with azides 1, 2, and 6.a

Entry

CH3OH CH3CN CH3OH CH3CN CH3OH CH3CN

8 h 8 h 1 <5 min 55 min <5 min 3.5 h (84%)c (92%)c

8 h 2 <5 min 10 min 5 min 30 min 2.5 h (94%)c

3 <5 min 30 min <5 min 30 min 8 h 60 min

4 <5 min < 5 min <5 min 60 min 30 min 90 min

8 h 8 h 8 h 5 <5 min < 5 min No Rxn (93%)c (92%) c (75%) c

8 h 8 h 8 h 6 2.5 h 3.5 h 25 min (81%)c (94%)c (72%)c

8 h 8 h 8 h 8 h 8 h 7 2 h (84%)c (18 %)c (96%)c (22%)c (3%)c

a Reaction conditions: azide (0.2 mmol), alkyne (0.22 mmol), Cu(OAc)2 (5 mol %), solvent (0.5 mL), room temperature. For reactions involving azide 6, TEA (0.2 mmol) was added. bObserved time for azide to disappear on TLC, followed by confirmation of full conversion by 1H NMR. cIncomplete reaction with % conversion as determined by 1H NMR noted in parentheses.

Regardless of azide or solvent, no apparent correlation between alkyne structure and reactivity was observed. The only exception was 3,3-dimethylbutyne (Table 3.3, entry 7) whose reactivity was consistently low. This is more than likely due to the steric effect imposed by the t-butyl group. Azide 1 consistently had shorter reaction times when compared to the tertiary amino-containing azide 2 or the carboxylate-containing azide 6 in either solvent but particularly more noticeable in CH3CN. It was routinely observed (especially with azides 2 and 6) that a rapid conversion to product (within 5-30 min) was followed by a slower phase to reach completion. This discontinuous profile is possibly due to the reorganization of the catalyst (see Section 3.3.3) over the course of the reaction that alters, often lowers, the catalytic activity.126 The results of the unsubstituted and para-substituted phenylacetylene (Table 3.3, entries 1-3) show no clear trend with the electron donating dimethylamino group (alkyne b, entry 2) or the electron withdrawing nitro substituent (alkyne c, entry 3). For instance, with azide 1 in CH3CN, the 4-ethynyl-N,N-dimethylaniline (alkyne b, entry 2) reaction was faster than the 1-ethynyl-4-nitrobenzene reaction (alkyne c, entry 3) whereas the opposite is true for the reactions with azide 6 in the same solvent. However, under the homogeneous conditions used for the kinetic experiments, a clear trend of the para-substituent effect on phenylacetylene was observed (NO2 > F > H > 130 MeO > Me2N). When the para-substituent is an electron-withdrawing group, the induction period was significantly reduced and the reaction is faster. These electronic effects are similar to those previously reported for the OHC reaction almost 50 years ago131 as well as previous reports that electron-withdrawing substituents on the alkyne accelerate the CuAAC.5, 132, 133 This data, together with a primary deuterium isotope effect,130 suggests that alkyne deprotonation is kinetically significant in both the OHC reaction in the induction period and during the reaction phase of the copper(II) acetate- accelerated CuAAC.

 Conditions: [1] = 20 mM, [alkyne] = 20 mM, and [Cu(OAc)2 ▪ H2O] = 1 mM in CD3CN at 40 °C in NMR spectrometer without spinning NMR tube. 61

3.3.3 Reorganization of Copper Catalyst

In our studies, and others in general, mechanistic conclusions are drawn from data taken from a limited view of the reaction. For example the kinetic orders determined over the initial phase of the reaction or the distance between copper centers of the dinuclear catalyst/precatalyst introduced at the beginning of the reaction. In reality, kinetic orders, copper-copper distance and other mechanistic parameters change over the course of the reaction.11 Caution must be taken when applying mechanistic conclusions drawn from data obtained during the initial phase to the full reaction profile.134 Results from sections 3.3.1 and 3.3.2 often showed a discontinuous reaction profile where the reaction goes through a rapid initial phase that was followed by a slower phase to reach completion. The structure of the precatalyst/catalyst 11 Cu(OAc)2 may change as the reaction proceeds, altering the mechanism. An example of the copper(II) acetate structure evolution was provided during an attempt to prepare the Cu(OAc)2 complex with 1 in CH3OH. However, a known 135-139 tetranuclear copper(II) cluster [Cu4(OAc)4(OCH3)4] (Figure 3.6) was obtained in crystal form after several days. Without the alkyne to complete the reaction, it is possible that 1 deprotonates CH3OH to methoxide and the methoxide can then displace an acetate moiety to form the copper cluster. Therefore, if the CuAAC reaction time scale is longer than this transformation, it is probable that the reaction mechanism will change. An additional example was also provided in a separate experiment.130 When copper(II) acetate was reacted with 3,3-dimethylbutyne in CH3OH, a copper(I)14 cluster surrounded by acetate and deprotonated 3,3-dimethylbutyne ligands was produced. It is well known that 3,3-dimethylbutyne creates alkynyl/copper(I) cluster structures due to the steric effect imposed by the t-butyl groups preventing aggregation of copper(I)- 140-142 acetylide. In addition to the copper(I)14 cluster crystal, the homocoupled diyne product (2,2,7,7-tetramethylocta-3,5-diyne) was also co-crystallized. Without an azide component, or with an azide of low reactivity, the copper center preferentially interacts with the alkyne to alter the catalytic structure, often impairing reactivity.

135-139 Figure 3.6 Known tetranuclear copper(II) cluster [Cu4(OAc)4(OCH3)4]. ORTEP view shown with 50% probability ellipsoids with hydrogens omitted for clarity. Carbon atoms are shown in blue, oxygen in red, and copper in orange. Atom labels are shown in purple. Selected distances (Å): Cu1-O1 1.940, Cu1-O4 1.970, Cu1-O5 1.929, Cu1- O5i 1.919, Cu1-Cu2 2.949, Cu1-Cu1i 2.985.

3.4 Conclusions

In conclusion, chelating azides are more reactive under the copper(II) acetate- accelerated CuAAC conditions and the most reactive chelating azides were presented. The multidentate products generated from the CuAAC reactions have a modest assisting effect that accounts for the observed lack of product inhibition. Various solvents were screened and the reaction times for azide 1 and 2 were determined. The reactions are very rapid in alcoholic solvents where both oxidative homocoupling of the terminal alkynes and oxidation of the solvent generate copper(I) during a very short

63 induction period. Aprotic organic solvents require longer reaction times due to being limited to only OHC reaction to generate the catalyst, lack of proton sources for protonation of the copper(I)-triazolide, and hindered exchange between the counterion and the azide or alkyne substrate to the copper center. The reactions proceed fairly rapidly in aqueous conditions and show potential for use in bioconjugation applications. Under typical benchtop conditions with heterogeneous reactions, the results from the alkyne screening show no general trend whereas under the conditions for the kinetic studies there is an observable trend showing short induction periods and fast reactions for electron withdrawing substituents on the para-position of phenylacetylene. During both the solvent and the alkyne screening, a discontinuous reaction profile was observed. This two-phase reaction profile is indicative of a reorganization of the copper catalyst. A known [Cu4(OAc)4(CH3O)4] cluster structure was isolated and discussed in regards to catalyst evolution during the progression of the reaction.

3.5 Experimental Information

3.5.1 Materials and General Methods

Caution: Low molecular weight carbon azides used in this study are potentially explosive. Proper handling and appropriate precautions should be observed when using these compounds. Reagents and solvents were purchased from various commercial sources and used without further purification. The Cu(OAc)2•H2O used had a purity greater than 99%. Analytical thin-layer chromatography (TLC) was performed using TLC plates pre-coated with silica gel 60 F254 (EMD) or aluminum oxide 60 F254 neutral (EMD). Flash column chromatography was performed using 40-63 µm (230-400 mesh ASTM) silica gel (EMD) or alumina (80-200 mesh, pH 9-10, EMD) as the stationary phase. 1H and 13C NMR spectra were recorded at 500 and 125 MHz. All chemical shifts were reported in units relative to tetramethylsilane. Azides and triazoles products that are not listed in the section 3.5.4 were previously reported.113, 122

3.5.2 TLC Monitoring Conditions for Tables 3.2 and 3.3

To an azide solution (0.2 mmol in 0.5 mL) in 1 dram vials was added an alkyne (0.22 mmol) and Cu(OAc)2 (β5 L, 0.4 M in H2O). The reactions were stirred between 500- 600 rps and TLCs were typically taken every five min for shorter reaction times and every 15 to 30 min for longer reactions to monitor the disappearance of the azide starting material. Completion time varied depending on the stirring rate, size and shape of stir bar, and the reaction container due to the heterogeneous nature of the reactions. Therefore, in order to obtain consistent reaction completion times, the same type of container and stirring rate were used for all the reactions. All experiments were conducted in triplicate or more.

Reactions involving 2-picolylazide (1). Disappearance of the 2-picolylazide was monitored on silica TLC plates (1/1 EtOAc/DCM) and visualized under a UV lamp.

Reactions involving 1-(2-azidoethyl)pyrrolidine (2). Reactions were monitored on an alumina TLC plate (1:9 EtOAc/DCM) and stained with iodine.

Reactions involving 3-azidopropanoic acid (6). Reaction aliquot was diluted with DCM (100-β00 δ) and several drops of p-toluene sulfonic acid in MeOH were added. The developed silica TLC plates (1/1 EtOAc/DCM) were stained with a bromocresol green solution.

3.5.3 Generation of [Cu4(OAc)4(OCH3)4] Complex

2 Picolylazide 1 (50 mg, 0.37 mmol) was dissolved in CH3CN (~1 mL). Separately, Cu(OAc) O (74.4 mg, 0.37 mmol) was dissolved in a mixed solvent of CH CN and ‐ 2 ▪ H2 3 CH3OH. The two solutions were combined, and the solvent was removed under vacuum. The resulting powder was washed with diethyl ether (3 x 15 mL). The product was then dissolved with a minimal amount of CH3OH, filtered through a small plug of glass microfiber and set up in vapor diffusion chambers with diethyl ether. After 3 4

‐ 65 days, blue crystals that were suitable for X ray diffraction formed. Upon solving the structure, it was determined to be the known compound [Cu (OAc) (OCH ) ]. ‐ 4 4 3 4

3.5.4 Characterization of Compounds

General procedure. Due to the amount of material lost during TLC monitoring, the following new compounds were characterized separately from the screenings. To a solution of azide (0.2 mmol) in acetonitrile (0.5 mL) was added alkyne (0.22 mmol) and

Cu(OAc)2 (β5 L, 0.4 M in H2O). Triethylamine (1 equiv, 0.2 mmol) was added to reactions involving azide 6. The reactions were stirred for 18 h and then filtered through either a silica or alumina plug. Unless otherwise noted, no column or further workup was necessary.

Compound 1b. The product was isolated in 94% yield (52.6 mg) as an off-white 1 powder. H NMR (500 MHz, CDCl3)μ /ppm 8.5λ (ddd, J = 4.9, 1.7, 0.9 Hz, 1H), 7.76 (s, 1H), 7.69 (dt, J = 9.0, 2.2 Hz, 2H), 7.65 (td, J = 7.8, 1.8 Hz, 1H), 7.23 (ddd, J = 7.5, 7.5, 1.0 Hz, 1H), 7.18 (d, J = 7.8 Hz, 1H), 6.74 (dt, J = 9.0, 2.1 Hz, 2H), 5.66 (s, 2H), 2.96 (s, 13 6H). C NMR (125 MHz, CDCl3)μ /ppm 155.1, 150.7, 14λ.8, 148.λ, 1γ7.4, 1β6.λ, 123.4, 122.4, 119.1, 118.8, 112.7, 55.8, 40.6. HRMS [M+H]+: 280.1562 (calcd), 280.1563 (found).

Compound 1c. The product was isolated in 98% yield (55.6 mg) as a light yellow solid. 1 H NMR (500 MHz, CDCl3)μ /ppm 8.6γ (ddd, J = 5.0, 1.8, 0.9 Hz, 1H), 8.27 (dt, J = 8.9, 2.2 Hz, 2H), 8.13 (s, 1H), 8.00 (dt, J = 8.9, 2.2 Hz, 2H), 7.73 (td, J = 7.8, 1.8 Hz, 1H), 13 7.34-7.28 (m, 2H), 5.73 (s, 2H). C NMR (125 MHz, CDCl3)μ /ppm 154.0, 150.β, 147.5, 146.2, 137.7, 137.0, 126.3, 124.5, 123.9, 122.9, 122.0, 56.0. HRMS [M+H]+: 282.0991 (calcd), 282.0994 (found).

Compound 1g. The product was isolated in 73% yield (31.7 mg) as a cloudy solid. 1H

NMR (500 MHz, CDCl3)μ /ppm 8.61 (d, J = 4.7 Hz, 1H), 7.69 (t, J = 7.0 Hz, 1H), 7.40 (s, 1H), 7.30-7.25 (m, 1H), 7.17 (d, J = 7.8 Hz, 1H), 5.63 (s, 2H), 1.35 (s, 9H). 13C NMR

(125 MHz, CDCl3)μ /ppm 158.γ, 155.1, 14λ.8, 1γ7.5, 1βγ.4, 1ββ.5, 11λ.β, 55.7, γ0.λ, 30.5. HRMS [M+Na]+: 239.1273 (calcd), 239.1271 (found).

Compound 2a. The product was isolated in 97% yield (47.1 mg) as a clear filmy solid. 1 H NMR (500 MHz, CDCl3)μ /ppm 7.λ0 (s, 1H), 7.8γ (dt, , J = 7.2, 1.3, 2H), 7.41 (t, J = 7.6, 2H), 7.32 (tt, J = 7.4, 1.6, 1H), 4.51 (t, J = 6.6, 2H), 2.98 (t, J = 6.5, 2H), 2.58-2.53 13 (m, 4H), 1.81-1.75 (m, 4H). C NMR (125 MHz, CDCl3)μ /ppm 147.7, 1γ0.λ, 1β8.λ, 128.1, 125.8, 120.3, 55.7, 54.3, 49.6, 23.7. HRMS [M+H]+: 243.1610 (calcd), 243.1609 (found).

Compound 2b. The product was isolated in 86% yield (48.9 mg) as an off-white solid. 1 H NMR (500 MHz, CDCl3)μ /ppm 7.74 (s, 1H), 7.70 (d, J = 9.0 Hz, 2H), 6.77 (d, J = 9.0 Hz, 2H), 4.50 (t, J = 6.9 Hz, 2H), 2.99-2.96 (m, 8H), 2.58-2.54 (m, 4H), 1.81-1.75 (m, 13 4H). C NMR (125 MHz, CDCl3)μ /ppm 150.5, 148.γ, 1β6.8, 11λ.β, 118.λ, 11β.7, 55.8, 54.4, 49.6, 40.7, 23.8. HRMS [M+H]+: 286.2032 (calcd), 286.2030 (found).

Compound 2c. The product was isolated in 95% yield (54.5 mg) as a light yellow solid. 1 H NMR (500 MHz, CDCl3)μ /ppm 8.γ0 (d, λ.0 Hz, βH), 8.07 (s, 1H), 8.0β (d, λ.0 Hz, 2H), 4.56 (t, 6.3 Hz, 2H), 3.01 (t, 6.3 Hz, 2H), 2.61-2.55 (m, 4H), 1.83-1.77 (m, 4H). 13C

NMR (125 MHz, CDCl3)μ /ppm 147.4, 145.6, 1γ7.4, 1β6.γ, 1β4.5, 1ββ.0, 55.6, 54.3, 49.8, 23.8. HRMS [M+H]+: 288.1460 (calcd), 288.1457 (found).

Compound 2d. The product was isolated in 78% yield (30.7 mg) as a clear oil. 1H

NMR (500 MHz, CDCl3)μ /ppm 7.70 (s, 1H), 4.77 (d, J = 1.9 Hz, 2H), 4.47 (td, J = 6.6, 0.9 Hz, 2H), 2.90 (td, J = 6.7, 0.8 Hz, 2H), 2.59-2.50 (m, 4H), 1.83-1.75 (m, 4H). 13C

NMR (125 MHz, CDCl3)μ /ppm 147.λ, 1ββ.6, 56.4, 55.7, 54.γ, 4λ.5, βγ.7. HRεS [M+H]+: 197.1402 (calcd), 197.1404 (found).

Compound 2e. The product was isolated in 69% yield (30.8 mg) as a yellow, oily solid. 1 H NMR (500 MHz, CDCl3)μ /ppm 7.64 (s, 1H), 4.46 (td, J = 6.5, 1.9 Hz, 2H), 3.60 (d, J = 2.0 Hz, 2H), 2.93 (td, J = 6.7, 1.6 Hz, 2H), 2.55-2.50 (m, 4H), 2.25 (d, J = 2.4 Hz, 6H), 13 1.79-1.73 (m, 4H). C NMR (125 MHz, CDCl3)μ /ppm 144.7, 1βγ.4, 55.7, 54.4, 54.β, 49.5, 45.1, 23.6. HRMS [M+H]+: 224.1875 (calcd), 224.1881 (found).

Compound 2f. The product was isolated in 76% yield (34.0 mg) as a clear solid. 1H

NMR (500 MHz, CDCl3)μ /ppm 7.γ6 (s, 1H), 4.4β (t, J = 6.8 Hz, 2H), 2.92 (t, J = 6.8 Hz, 2H), 2.69 (t, J = 7.7 Hz, 2H), 2.55-2.50 (m, 4H), 1.80-1.73 (m, 4H), 1.67-1.59 (m, 2H), 13 1.41-1.32 (m, 2H), 0.91 (t, J = 7.4 Hz, 3H). C NMR (125 MHz, CDCl3)μ /ppm 148.4, 121.2, 55.8, 54.3, 49.4, 31.8, 25.5, 23.7, 22.5, 14.0. HRMS [M+H]+: 223.1924 (calcd), 223.1923 (found).

Compound 2g. The product was isolated in 96% yield (37.7 mg) as a light yellow solid. 1 H NMR (500 MHz, CDCl3)μ /ppm 7.γ4 (s, 1H), 4.45 (t, J = 7.0 Hz, 2H), 2.96 (t, J = 7.0 Hz, 2H), 2.59-2.53 (m, 4H), 1.83-1.77 (m, 4H), 1.36 (s, 9 H). 13C NMR (125 MHz, + CDCl3)μ /ppm 157.8, 11λ.1, 55.λ, 54.4, 4λ.5, γ0.λ, γ0.6, βγ.8. HRεS [M+H] : 223.1923 (calcd), 223.1911 (found).

Compound 6a. The crude product was subjected to acidic workup (pH ~1). The acidic aqueous solution was neutralized with sodium bicarbonate and then the compound was extracted using EtOAc. The organic layer was dried with Na2SO4 and, after removal of the solvent, gave the pure product in 100% yield (43.4 mg) as a white solid. 1H NMR

(500 MHz, CD3OD)μ /ppm 8.β6 (s, 1H), 7.78 (dt, J = 7.2, 1.3 Hz, 2H), 7.41 (t, J = 7.5 Hz, 2H), 7.32 (tt, J = 7.4, 1.4 Hz, 1H), 4.70 (t, J = 6.7 Hz, 2H), 3.01 (t, J = 6.6 Hz, 2H). 13 C NMR (125 MHz, CD3OD)μ /ppm 17γ.λ, 148.λ, 1γ1.λ, 1γ0.1, 1βλ.4, 1β6.8, 1ββ.8, 47.3, 35.3. HRMS [M+Na]+: 240.0749 (calcd), 240.0744 (found).

Compound 6b. The crude product was dissolved in EtOAc and subjected to acidic workup (pH ~1). The organic layer was discarded and the acidic aqueous layer was neutralized with sodium bicarbonate and then the compound was extracted with fresh

EtOAc. The organic layer was dried with Na2SO4 and, after the solvent was removed, gave the pure product in 76% yield (39.4 mg) as a light pink solid. 1H NMR (500 MHz,

CD3OD): /ppm 8.1β (s, 1H), 7.6β (J = 8.7 Hz, 2H), 6.80 (d, J = 8.7 Hz, 2H), 4.67 (t, J = 13 6.6 Hz, 2H), 3.04-2.97 (m, 8H). C NMR (125 MHz, CD3OD)μ /ppm 174.γ, 15β.γ, 149.5, 127.7, 121.2, 119.9, 113.9, 47.3, 40.9, 35.5. HRMS [M+Na]+: 283.1171 (calcd), 283.1175 (found).

Compound 6c. The crude product was dissolved in EtOAc and subjected to acidic workup (pH ~1). The organic layer was dried with Na2SO4 and, after the solvent was removed, gave the pure product in 69% yield (36.2 mg) as a light yellow solid. 1H NMR

(500 MHz, CD3OD): /ppm 8.55 (s, 1H), 8.γβ (d, J = 8.9 Hz, 2H), 8.07 (d, J = 8.9 Hz, 13 2H), 4.74 (t, J = 6.5 Hz, 2H), 3.04 (t, J = 6.5 Hz, 2H). C NMR (125 MHz, CD3OD): /ppm 17γ.λ, 148.8, 146.6, 1γ8.γ, 1β7.4, 1β5.4, 1β4.7, 47.8, γ5.1. HRεS [ε+Na]+: 285.0600 (calcd), 285.0600 (found).

Compound 6d. The crude product was dissolved in MeOH and the solvent was removed under reduced pressure to remove residual TEA. This was repeated several times until there was no trace of TEA by 1H NMR. The pure product was isolated in 50%

1 yield (17.2 mg) as a yellow solid. H NMR (500 MHz, CD3OD)μ /ppm 7.λβ (s, 1H), 13 4.68-4.60 (m, 4H), 2.82 (t, J = 6.8 Hz, 2H). C NMR (125 MHz, CD3OD)μ /ppm 176.0, 149.0, 124.6, 56.6, 48.0, 37.2. HRMS [M+Na]+: 194.0542 (calcd), 194.0538 (found).

Compound 6e. The crude product was dissolved in MeOH and the solvent was removed under reduced pressure to remove residual TEA. This was repeated several times until there was no trace of TEA by 1H NMR. The pure product was isolated in 98% 1 yield (38.8 mg) as a white solid. H NMR (500 MHz, CD3OD)μ /ppm 8.16 (s, 1H), 4.68 (t, J = 6.5 Hz, 2H), 4.25 (s, 2H), 2.79 (t, J = 6.7 Hz, 2H), 2.72 (s, 6H). 13C NMR (125 + MHz, CD3OD)μ /ppm 177.7, 1γλ.γ, 1β7.8, 5β.7, 4γ.γ, γ8.6. HRεS [ε+H] : 199.1195 (calcd), 199.1191 (found).

Compound 6f. The crude product was dissolved in EtOAc and subjected to acidic workup (pH ~1). The organic layer was dried with Na2SO4 and, after removal of the solvent, the pure product was obtained in 31% yield (12.3mg) as a yellow oil. 1H NMR

(500 MHz, CD3OD)μ /ppm 7.βγ (s, 1H), 4.61 (t, J = 6.5 Hz, 2H), 2.94 (t, J = 6.5 Hz, 2H), 2.68 (t, J = 7.5 Hz, 2H), 1.68-1.59 (m, 2H), 1.42-1.33 (m, 2H), 0.95 (t. J = 7.4 Hz, 3H). 13 C NMR (125 MHz, CD3OD)μ /ppm 174.1, 14λ.β, 1βγ.7, 47.1, γ5.4, γβ.λ, β6.1, βγ.4, 14.3. HRMS [M+H]+: 198.1243 (calcd), 198.1239 (found).

Compound 6g. The crude product was dissolved in EtOAc and subjected to acidic workup (pH ~1). The organic layer was dried with Na2SO4 and the solvent removed to give the pure product in 90% yield (35.5 mg) as a yellow oil. 1H NMR (500 MHz,

CD3OD)μ /ppm 7.75 (s, 1H), 4.61 (t, J = 6.6 Hz, 2H), 2.95 (t, J = 6.7 Hz, 2H), 1.33 (s, 13 9H). C NMR (125 MHz, CD3OD)μ /ppm 174.0, 158.5, 1β1.7, 47.0, γ5.γ, γ1.7, γ0.8. HRMS [M+Na]+: 220.1062 (calcd), 220.1064 (found).

3.5.5 1H and 13C NMR Spectra

1 Figure 3.7 500 MHz H NMR Spectrum of compound 1b in CDCl3.

13 Figure 3.8 125 MHz C NMR Spectrum of compound 1b in CDCl3.

1 Figure 3.9 500 MHz H NMR Spectrum of compound 1c in CDCl3.

13 Figure 3.10 125 MHz C NMR Spectrum of compound 1c in CDCl3.

1 Figure 3.11 500 MHz H NMR Spectrum of compound 1g in CDCl3.

13 Figure 3.12 125 MHz C NMR Spectrum of compound 1g in CDCl3.

1 Figure 3.13 500 MHz H NMR Spectrum of compound 2a in CDCl3.

13 Figure 3.14 125 MHz C NMR Spectrum of compound 2a in CDCl3.

1 Figure 3.15 500 MHz H NMR Spectrum of compound 2b in CDCl3.

13 Figure 3.16 125 MHz C NMR Spectrum of compound 2b in CDCl3.

1 Figure 3.17 500 MHz H NMR Spectrum of compound 2c in CDCl3.

13 Figure 3.18 125 MHz C NMR Spectrum of compound 2c in CDCl3.

1 Figure 3.19 500 MHz H NMR Spectrum of compound 2d in CDCl3.

13 Figure 3.20 125 MHz C NMR Spectrum of compound 2d in CDCl3.

1 Figure 3.21 500 MHz H NMR Spectrum of compound 2e in CDCl3.

13 Figure 3.22 125 MHz C NMR Spectrum of compound 2e in CDCl3.

1 Figure 3.23 500 MHz H NMR Spectrum of compound 2f in CDCl3.

13 Figure 3.24 125 MHz C NMR Spectrum of compound 2f in CDCl3.

1 Figure 3.25 500 MHz H NMR Spectrum of compound 2g in CDCl3.

13 Figure 3.26 125 MHz C NMR Spectrum of compound 2g in CDCl3. 82

1 Figure 3.27 500 MHz H NMR Spectrum of compound 6a in CD3OD.

13 Figure 3.28 125 MHz C NMR Spectrum of compound 6a in CD3OD. 83

1 Figure 3.29 500 MHz H NMR Spectrum of compound 6b in CD3OD.

13 Figure 3.30 125 MHz C NMR Spectrum of compound 6b in CD3OD.

1 Figure 3.31 500 MHz H NMR Spectrum of compound 6c in CD3OD.

13 Figure 3.32 125 MHz C NMR Spectrum of compound 6c in CD3OD.

1 Figure 3.33 500 MHz H NMR Spectrum of compound 6d in CD3OD.

13 Figure 3.34 125 MHz C NMR Spectrum of compound 6d in CD3OD.

1 Figure 3.35 500 MHz H NMR Spectrum of compound 6e in CD3OD.

13 Figure 3.36 125 MHz C NMR Spectrum of compound 6e in CD3OD.

1 Figure 3.37 500 MHz H NMR Spectrum of compound 6f in CD3OD.

13 Figure 3.38 125 MHz C NMR Spectrum of compound 6f in CD3OD. 88

1 Figure 3.39 500 MHz H NMR Spectrum of compound 6g in CD3OD.

13 Figure 3.40 125 MHz C NMR Spectrum of compound 6g in CD3OD.

CHAPTER 4

APPLICATION OF THE Cu(OAc)2-ACCELERATED AAC: SYNTHESES AND STRUCTURAL STUDIES OF MULTIDENTATE LIGANDS FOR TRANSITION METAL IONS

4.1 Summary

Use of 1,4-disubstituted-1,2,3-triazoles as metal chelators has recently garnered much interest. The N3 position of the 1,2,3-triazole unit typically participates in binding with metal ions due to the higher electron density at that position. Application of the developed Cu(OAc)2-accelerated AAC reaction allowed for facile and rapid synthesis of tridentate 2,6-bis(1,2,3-triazol-1-ylmethyl)pyridine ligands. Upon coordination with transition metal ions, the pyridyl nitrogen as well as the less Lewis basic N2 nitrogen of the 1,2,3-triazole ring were found to participate in binding. The ligands created in this study complement other well-studied tridentate ligands such as the triazolyl-based terpy motif and the 2,6-bis(pyrazol-1-ylmethyl)pyridine systems. Stable copper(II)/organic azide complexes from chelating azides were produced and their features described. All copper(II)/azide complexes exhibit the alkylated nitrogen atom (Nα) of the azido group coordinating to the copper(II) ion. Analysis of the bond lengths shows that copper(II) coordination at Nα enhances the electrophilicity of the terminal N, accelerating the CuAAC reaction. Additionally, a ligand was designed to include two bidentate binding sites at both the N3 and N2 positions forming a five- and six-membered chelation ring, respectively. Its coordination was studied and showed that metal ions prefer the 5- membered planar chelation pocket over the puckered 6-membered pocket that contains the N2 nitrogen of the 1,2,3-triazole. The information gained from this study enhances our understanding of the coordination chemistry of 1,4-substituted-1,2,3-triazole molecules, particularly in regards to the N2 atom of the 1,2,3-triazole.

4.2 1,4-Disubstituted-1,2,3-Triazoles as Metal Chelators

As mentioned in Chapter 1, the majority of the applications of CuAAC uses the triazole formation solely as a linker to connect two components. The rapid application of this reaction to numerous scientific disciplines may have overshadowed the intriguing metal coordination chemistry of the 1,2,3-triazole unit until recently.71 Indicative of the increasing popularity of the application of triazoles as ligands is the use of clever phrases for this approach. Some simply refer to the CuAAC reaction in generation of triazole metal chelators as “click to chelate”64 or others simply refer to the products as “click chelators”143-148 or simply “clickates.”149, 150

4.2.1 1,2,3-Triazole Structure and Properties

1,4-Disubstituted-1,2,3-triazoles have interesting properties. Having the three electronegative nitrogens positioned on one side of the ring lowers the electronegativity of the C5 carbon and increases the acidity of the C5 proton. It also creates a large dipole moment of 5 debye.25 Together, these two features make the triazole unit a good anion receptor (Figure 4.1).58, 151 Where the unsubstituted 1,2,3-triazole ring offers three sites for metal coordination and can bridge metal ions in five different modes,152 the 1,4- disubstituted-1,2,3-triazoles, generated via CuAAC, offers only two sites for metal coordination, N2 and N3 (Figure 4.1).153, 154 The electrons on N1 are involved in the aromatic system of the ring and not available for coordination.

Figure 4.1 Structural properties of the 1,4-disubstituted 1,2,3-triazole.

4.2.2 N2 vs. N3 Coordination

At the beginning of this project, the majority of the 1,2,3-triazole ligands reported coordinated through the N3 position of the triazole. In 2006, Schibli et al. reported triazole-containing chelators with technetium-99m for the radiolabeling of biomolecules.64 Ligands were prepared that could coordinate to the metal through N3 (termed regular click ligands) or N2 (inverse click ligands) of the triazole. A higher inverse ligand concentration was required to achieve complete conversion of the metal precursor to the product compared to regular click ligands. This result suggests, and later confirmed by DFT calculations, that the highest electron density is located on the N3 of the triazole. Further DFT studies have also revealed that the N3 nitrogen possessed the highest electron density regardless of the substituents.145 Therefore, early examples of N2 binding are almost non-existent. The only structure providing unambiguous proof of N2 coordination is a dinuclear copper(I) complex with two TBTA ligands where both N2 and N3 were coordinated to a copper center.155

4.3 Investigating N2 Coordination

Within our group, ligands were developed to act as metal ion responsive fluorophores.79 Upon coordination with zinc, complexes in which N3 of the triazole ligand participates in binding (Figure 4.3 A) demonstrated a dramatic increase in fluorescence. Other ligands were designed where coordination to N3 is sterically difficult, therefore the metal must coordinate to the N2 (Figure 4.3 B). Fluorescence titrations with these ligands also show an increase in fluorescence, suggesting coordination through the N2 of the triazole. At the time, a crystal suitable for X-ray crystallography was not obtained.

Figure 4.3 Zinc complexes showing (A) N3 coordination and (B) N2 coordination.

 A crystal has since been successfully grown and the structure indeed verified N2 coordination. 93

The Cu(OAc)2-accelerated AAC conditions has allowed for the rapid synthesis of multidentate ligands.113 The coordination involving the pyridyl and the N2 of the triazolyl in metal chelation was confirmed by X-ray crystallography and gave a non-planar six- membered chelate ring.113, 122 Metal complexes of bidentate ligand 2 (Figure 4.4) were reported by us in 2009, Crowley et al. shortly thereafter,156 and several others since.143, 156-159

Figure 4.4 Rapid formation of bidentate ligand 2 from Cu(OAc)2-accelerated CuAAC.

Due to the rapid reactions involving 1 and the interesting coordination chemistry of 2, we proposed that 2,6-bis(azidomethyl)pyridine would also be just as reactive under the Cu(OAc)2-accelerated CuAAC reaction. We anticipated that the tridentate products (Figure 4.5 A) would show a similar chelation mode to that of 2,6-bis(3,5-R,R-pyrazol-1- ylmethyl)pyridine (Figure 4.5 B).160 Like ligand 2, the less Lewis basic N2161 on the triazole rings would participate in metal coordination. This coordination would be assisted by the nearby pyridyl ligand. This tridentate ligand would complement the previously developed terpy (Figure 4.5 C) triazole analogs, 2,6-bis(1-R-1,2,3-triazol-4- yl)pyridine, where N3 participates in binding (Figure 4.5 D).149, 162 Transition metal complexes of these ligands with transition metals were studied, as well as copper(II) complexes with azides 1 and 3. To further examine N2 versus N3 coordination in a more challenging structural context, a ligand was designed to offer more than one binding pocket that could coordinate to a metal ion. The results of these binding studies are discussed below.

Figure 4.6 Designed ligand with two binding pockets highlighted. Upon introduction of a metal salt, coordination could take place at binding pocket 1 or binding pocket 2.

4.4 Results and Discussion

4.4.1 Synthesis

When compared to 2-picolylazide, 2,6-bis(azidomethyl)pyridine also reacts very rapidly with various acetylenes in the presence of 5 mol % Cu(OAc)2·H2O in either t- BuOH or MeOH to afford the symmetrically substituted tridentate ligands (Figure 4.7).

For phenylacetylene and 1-hexyne, the reactions were complete within a matter of min with full conversions. Purification simply involved filtering the reaction mixture through a small silica plug followed by removal of the solvent. The total time for the reaction to reach completion and isolation of the product took around 30 min. This is a highly efficient process, even by the “click chemistry” standards.2 Generation of the transition- metal complexes of 4 were prepared by combining solutions of the metal perchlorate hexahydrate salt (metals: CuII, FeII, CoII) at half molar equivalents with a solution of 4.

Vapor diffusion of diethyl ether into the CH3CN solutions of the complexes gave single crystals suitable for X-ray diffraction after one or two days.

Figure 4.7 2,6-bis(azidomethyl)pyridine (3) reacts rapidly with various alkynes to afford the ligand. After minimal purification of 4 or 5, various metal complexes were formed.

4.4.2 Metal Coordination Complexes with 4

All of the metal perchlorate complexes of ligand 4 crystallize in the same triclinic space group P1. Within their asymmetric units, they all have discrete mononuclear complexes having the general formula [M(4)2](ClO4)2 where M = Cu(II), Fe(II), and Co(II). The three complexes display octahedral coordination geometry about the metal centers. For the [Cu(4)2](ClO4)2 complex (Figure 4.8), the expected Jahn-Teller

2+ distortion is observed. The six-membered chelation rings in [M(4)2] adopt boat conformations similar to the coordination modes of the 2-(pyrazole-1-ylmethyl)pyridine ligands.160, 163-166 The boat conformation, rather than the chair, allows for the preferred bond angles within the ring with minimal angle strain.167 2+ For [Cu(4)2] , the two pyridyl nitrogens (Npy, shown as N4 and N34 in Figure 4.8) from two different ligands and two triazole N2 nitrogens (N32 and N36) from the same ligand occupy the square plane about the copper center. The nitrogens in this plane have shorter bonds (1.966 – 2.105 Å, Table 4.1), while the remaining two triazolyl N2 nitrogens of the other ligand (N2 and N6) have longer bonds (2.422, 2.345 Å) at the apical positions as a result of Jahn-Teller distortion. This renders the two ligands chemically different in regards to their binding strength to the copper center. 2+ 2+ The complexes [Fe(4)2] (Figure 4.9) and [Co(4)2] (Figure 4.10) are isomorphous in that they (a) have the same space group and unit-cell dimensions and (b) the types and arrangement of atoms are the same in both except for the metal center.168 The octahedral sites around the metal ion are occupied by the four N2 nitrogens of the triazole and the two Npy atoms of the two ligands. The triazole nitrogen 2+ 2+ atoms occupy the four sites in the basal plane ([Fe(4)2] : N2, N6, N9, N13; [Co(4)2] : 2+ N2, N6, N33, N36) and the axial positions contain the Npy ([Fe(4)2] : N4, N11; 2+ 2+ [Co(4)2] : N4, N34). In [Fe(4)2] , the average N2 triazole bond distance is 1.954 Å 2+ (Table 4.3), where the [Co(4)2] triazole N2 bonds are slightly longer at an average of 2.093 Å (Table 4.4). In both structures the axial bonds are slightly elongated by 0.08- 0.10 Å. This is interesting considering the N2 is less Lewis basic and should be a 169 weaker donor than the Npy and the N3 of the triazole. The steric congestion caused between the methylene and the axially coordinated ligands more than likely lengthens the bond between the metal and Npy. A similar situation has been observed with 2,6- bis(pyrazole-1-ylmethyl)pyridine (see core structure in Figure 4.5 B) metal complexes with the metal-to-Npy bond distances being slightly longer (average of 2.274 Å) than the metal-to-pyrazolyl nitrogen bond (average of 2.173 Å). However, the overall M-N distances reported are longer than that of the Fe(II) complex.170, 171

Table 4.1 Selected bond lengths (Å) and angles (°) for [Cu(4)2](ClO4)2.

Cu1 Distance Angles N32 1.9663 (20) N36 1.9925 (20) 177.92 (9) N4 2.0762 (20) 92.00 (8) 86.22 (8) N34 2.1048 (20) 90.68 (8) 91.09 (8) 177.19 (8) N6 2.3454 (22) 94.60 (8) 84.51 (8) 95.35 (8) 83.57 (8) N2 2.4219 (22) 83.19 (8) 98.01 (8) 94.76 (7) 86.41 (7) 169.72 (7) Cu1 N32 N36 N4 N34 N6

Table 4.2 Crystal data and structural refinement for [Cu(4)2](ClO4)2

[Cu(4)2](ClO4)2·CH3CN

Formula C48 H41CuN15Cl2 O8 Formula weight 1090.4 Space group P1 Crystal system Triclinic a/ Å 11.6858(7) b/ Å 12.5597(8) c/ Å 17.8088(11) α/° 70.093(1) ° 78.667(1) /° 79.742(1) V/Å3 2392.1(3) T/K 173(2) Z 2 -3 Dc/g cm 1.514 µ (Mo-Kα)/mm-1 0.641 Crystal size (mm) 0.24 x 0.25 x 0.27 θ range (°) 1.8, 27.1

Rint 0.027 Total reflections 26975 Unique reflections 10453 Parameters refined 668 Data with I > βσ(I) 8465 R1 [I > βσ(I)] 0.0465

wR2 0.1148 GOF on F2 0.99

Table 4.3 Selected bond lengths (Å) and angles (°) for [Fe(4)2](ClO4)2.

Fe1 Distance Angles N2 1.9445 (28) N6 1.9543 (28) 178.74 (12) N9 1.9554 (27) 86.49 (11) 94.28 (11) N13 1.9638 (26) 95.96 (11) 83.29 (11) 177.06 (12) N4 2.0255 (25) 90.15 (11) 90.87 (11) 87.61 (11) 90.76 (11) N11 2.0352 (25) 87.22 (11) 91.78 (11) 90.89 (11) 90.85 (11) 177.05 (11) Fe1 N2 N6 N9 N13 N4

100

Table 4.4 Crystal data and structural refinement for complex [Fe(4)2](ClO4)2.

[Fe(4)2](ClO4)2·Et2O·CH3CN

Formula C52H51FeN15O9Cl2 Formula weight 1156.83 Space group P1 Crystal system Triclinic a/ Å 12.4446(9) b/ Å 14.6888(10) c/ Å 17.0173(12) α/° 114.150(1) ° 101.255(1) /° 96.187(1) V/Å3 2722.0(3) Z 2 -3 Dc/g cm 1.411 µ(Mo-Kα)/mm-1 0.445 T/K 173(2) Crystal size (mm) 0.11 x 0.15 x 0.42 θ range (°) 1.9, 23.8

Rint 0.036 Total reflections 19804 Unique reflections 8347 Parameters refined 715

R1 [I > βσ(I)] 0.0542

wR2 0.0900 GOF on F2 2.003

101

Table 4.5 Selected bond lengths (Å) and angles (°) for [Co(4)2](ClO4)2.

Co1 Distance Angles N6 2.0876 (15) N2 2.0903 (15) 178.34 (6) N32 2.0952 (15) 88.12 (6) 93.50 (6) N36 2.0979 (14) 93.02 (6) 85.37 (6) 177.70 (6) N4 2.1859 (13) 90.45 (5) 89.24 (5) 88.44 (5) 93.54 (5) N34 2.1972 (14) 87.91 (5) 92.46 (5) 89.36 (5) 88.69 (5) 177.30 (5) Co1 N6 N2 N32 N36 N4

102

Table 4.6 Crystal data and structural refinement for complex [Co(4)2](ClO4)2.

[Co(4)2](ClO4)2·Et2O·CH3CN

Formula C52H50CoN15O9Cl2 Formula weight 1158.9 Space group P1 Crystal system Triclinic a/ Å 12.3100(8) b/ Å 14.6560(9) c/ Å 17.4106(11) α/° 114.703(1) ° 101.989(1) /° 94.290(1) V/Å3 2744.9(3) Z 2 -3 Dc/g cm 1.402 µ(Mo-Kα)/mm-1 0.480 T/K 173(2) Crystal size (mm) 0.14 x 0.25 x 0.35 θ range (°) 1.9, 28.3

Rint 0.024 Total reflections 32788 Unique reflections 13224 Parameters refined 704

R1 [I > βσ(I)] 0.0444

wR2 0.0809 GOF on F2 2.372

103

4.4.3 Magnetic Properties

In collaboration with Dr. Shatruk’s group, the magnetic properties of the complexes were studied. Observation of short Fe-N bonds (1.94-2.04 Å) for

[Fe(4)2](ClO4)2 was indicative of a low-spin complex. Confirmation was provided through the magnetic susceptibility measurement that indicated a diamagnetic Fe(II) center. This is in contrast to the complementary high-spin Fe(II) complex with 2,6- bis(3,5-dimethylpyrazol-1-ylmethyl)pyridine (see core structure in Figure 4.5 B) where the Fe-N bond elongation can be attributed to the sterics imposed by methyl substituents of the dimethylpyrazole171, 172 resulting in a high-spin iron(II).173 On the 167 other hand, the [Co(4)2](ClO4)2 complex is high-spin. This spin assignment is consistent given its metal-to-nitrogen bond distances were longer than those in the

[Fe(4)2](ClO4)2 complex.

1 4.4.4 H NMR Titrations of 4 with Fe(ClO4)2

1 Due to [Fe(4)2](ClO4)2 complex being low-spin, H NMR titration experiments were performed. Because of the congestion in the aromatic region with ligand 4, ligand 5 was used in its place. 1H NMR spectra were collected as increments of

Fe(ClO4)2·6H2O were added into the CD3CN solution of 5 (Figure 4.11). A new set of signals were apparent upon the first addition of Fe(II). This separate set of signals suggests that the association equilibrium of the complex is slow on the 1H NMR time scale. The broadening of the methylene signal at 5.54 ppm (Hd in Figure 4.11) suggests that the flipping of the six-membered chelation rings is on the time scale of the 1 170 H NMR experiment. The aromatic signals (Ha-c in Figure 4.11) undergo significant downfield shifts upon complex formation with Fe(II) which can be attributed to the deshielding effect of the Fe(II) cation. In contrast, the aliphatic hydrogens of the butyl group move upfield. This may be due to the shielding they experience from the nearby aromatic system on the other ligand after complex formation.174-176 Upon adding 0.5 molar equivalent of iron(II) into the sample, the signals from the free ligand 5 disappear indicating a 2:1 (ligand:metal) binding stoichiometry.

104

2 ) 4 in the presence of increasing amount of amount Fe(ClO of presence increasing in the 5

Bu -

d n d CN) spectra spectra of CN) 3

H NMR (500H NMR CD MHz, 1 a

b Figure 4.11 0(bottom equivalent).molar top: to 0.5 - R =

105

4.4.5 Copper(II)-Organic Azide Complexes

For the following discussion on copper(II) complexes, it is worth mentioning that the copper(II) coordination chemistry is a very rich area. Copper(II) has the ability to adopt a coordination number of four, five or six.177 With a coordination number five, copper(II) geometry can vary from trigonal bipyramidal (TBP), through a series of distorted structures, to square pyramidal (SP).178 From this variation along the TBP-SP continuum, methods have been developed to help distinguish between the

179-182 180 geometries. A semiquantitative criterion, τ5 value, was developed. The τ5 parameter calculation is shown in Eq. 4.1 where is the largest X-Cu-X bond angle and

α is the second largest X-Cu-X angle. For regular square pyramidal structures, τ5 = 0 and will increase to 1.0 as the trigonal bipyramidal distortion increases. 166, 180, 183 Application of this parameter assists with the geometry assignment for pentacoordinate copper(II) complexes reported herein.

τ5 (4.1)

The chelation-assisted coordination between the copper catalyst and the alkylated nitrogen in 1 and 3 was recognized for accelerating the CuAAC reactions. Determined structures of copper(II) complexes of azides 1 and 3 show the alkylated nitrogen (Nα, Figure 4.4) bound to the copper(II) ion. Along with a few other examples,122, 184 these copper complexes of azides 1 and 3 are remarkably stable. Organic azides in transition metal complexes are known to rapidly break down to the 185 nitrene species. The dinuclear copper(II) complex of 1, [Cu2(1)Cl4], was mentioned briefly in Chapter 2. The complex crystallizes in the P1 space group and shows a pentacoordinate copper center with a τ5 = 0.05, indicating square pyramidal geometry

(Figure 4.12). Similar to other copper(II) dinuclear structures containing a Cu2Cl2 core,186, 187 the two square pyramids share a base-to-apex edge but show parallel basal planes. Coordination geometry about the copper center is essentially square pyramidal.

106

The apical chlorides (Cl2 and Cl2a) have elongated Cu-Cl bond lengths (Table 4.7) and they bridge with the adjacent copper(II) center. The copper(II) center does not lie within the N2Cl2 square base; it is instead 0.159 Å above it. The extended structure (Figure 4.13), shows the Cu(II) ion weakly interacts with a neighboring alkylated nitrogen within the azido group (3.308 Å). When using a different stoichiometry (2:1 ratio of ligand to metal), the mononuclear copper complex [Cu(1)2Cl2] was also isolated (Figure 4.14). This crystallized in the P21/n space group. In this structure, a distorted Jahn-Teller octahedral geometry for the copper ion was observed. The pyridyl nitrogens and chlorides (N1, N5, Cl1, and Cl2) reside in the square plane with the copper center and the alkylated nitrogens (N2 and N6) in the apical positions. Unlike the dinuclear

[Cu2(2)2Cl4] complex, the azido groups in this complex are significantly bent off the copper square plane by 66.03°. The N-N bond (1.129 Å) is longer than that in

[Cu2(2)2Cl4]

Additionally, a 1:1 reaction of azide 3 with CuCl2 yields [Cu(3)Cl2] (Figure 4.15) and it shows a pentacoordinate complex. The complex has a distorted square pyramidal geometry about the copper(II) center indicated by its τ5 = 0.21 value.

Chelation of Npy (N1) and Nα (N2, and N5) to the copper center yields two five- membered coordination rings. The copper is slightly deviated from its square base (0.426 Å). Expansion of the matrix (Figure 4.16) shows a weak apical interaction between the copper(II) center and the terminal nitrogen of one azido group (3.250 Å). Furthermore, an offset π-π stack of the pyridyl rings (γ.664 Å) was observed.

107

Figure 4.12 ORTEP view shown with 50% probability of [Cu2(1)2Cl4]. Carbon atoms are shown in black, nitrogen in blue, chloride in green, and copper in orange. Atom labels are shown in purple.

Table 4.7 Selected bond lengths (Å) and angles (°) for [Cu2(1)2Cl4].

Cu1 Distance Angles N1 2.0282 (13) N2 2.0305 (14) 77.96 (5) Cl1 2.2323 (04) 96.94 (4) 165.50 (4) Cl2 2.2659 (04) 168.34 (4) 90.53 (4) 93.78 (2) Cl2a 2.7181 (04) 88.89 (4) 93.64 (4) 99.87 (2) 93.80 (1) Cu1 N1 N2 Cl1 Cl2

108

Table 4.8 Crystal data and structural refinement for complex [Cu2(1)2Cl4].

[Cu2(1)2Cl4]

Formula C12H12Cl4Cu2N8 Formula weight 537.18 Space group P1 Crystal system Triclinic a/ Å 6.8184(3) b/ Å 8.0206(3) c/ Å 9.7388(3) α/° 68.060(1) ° 71.710(1) /° 89.378(1) V/Å3 465.63(3) Z 1 -3 Dc/g cm 1.916 µ(Mo-Kα)/mm-1 2.872 T/K 173 Crystal size (mm) 0.20 x 0.23 x 0.29 θ range (°) 2.4, 28.3

Rint 0.017 Total reflections 6699 Unique reflections 2249 Parameters refined 119

R1 [I > βσ(I)] 0.0210

wR2 0.0504 GOF on F2 2.71

109

110

Figure 4.14 ORTEP view shown with 50% probability of [Cu(1)2Cl2]. Carbon atoms are shown in black, nitrogen in blue, chloride in green, and copper in orange. Atom labels are shown in purple.

Table 4.9 Selected bond lengths (Å) and angles (°) for [Cu(1)2Cl2].

Cu1 Distance Angles N1 2.0019 (92) N5 2.0019 (92) 180.00 (22) Cl1 2.3172 (25) 89.97 (25) 90.03 (25) Cl2 2.3172 (25) 90.03 (25) 89.97 (25) 180.00 N6 2.4097 (93) 104.06 (32) 75.95 (32) 86.87 (23) 93.13 (23) N2 2.4098 (93) 75.95 (32) 104.05 (32) 93.13 (23) 86.87 (23) 180.00 (27) Cu1 N1 N5 Cl1 Cl2 N6

111

Table 4.10 Crystal data and structural refinement for complex [Cu(1)2Cl2].

[Cu(1)2Cl2]

Formula C12H12Cl2CuN8 Formula weight 402.74

Space group P21/n Crystal system Monoclinic a/ Å 8.306(3) b/ Å 9.366(3) c/ Å 9.997(4) α/° 90 ° 100.815(10) /° 90 V/Å3 763.9(5) Z 2 -3 Dc/g cm 1.751 µ(Mo-Kα)/mm-1 1.790 T/K 173(2) Crystal size (mm) 0.18 x 0.18 x 0.26 θ range (°) 3.0, 23.4

Rint 0.033 Total reflections 8675 Unique reflections 572 Parameters refined 106

R1 [I>βσ(I)] 0.0536

wR2 0.1792 GOF on F2 1.13

112

Figure 4.15 ORTEP view shown with 50% probability of [Cu(3)Cl2]. Carbon atoms are shown in black, nitrogen in blue, chloride in green, and copper in orange. Atom labels are shown in purple.

Table 4.11 Selected bond lengths (Å) and angles (°) for [Cu(3)Cl2].

Cu1 Distance Angles N1 1.9677 (14) N5 2.0978 (15) 77.64 (6) N2 2.0997 (14) 78.48 (6) 146.78 (6) Cl2 2.2127 (05) 159.62 (4) 95.59 (4) 98.86 (4) Cl1 2.3697 (05) 95.96 (4) 103.72 (4) 101.42 (5) 104.34 (2) Cu1 N1 N5 N2 Cl2

113

Table 4.12 Crystal data and structural refinement for complex [Cu(3)Cl2].

[Cu(3)Cl2]

Formula C7H7Cl2CuN7 Formula weight 323.64 Space group P1 Crystal system Triclinic a/ Å 7.1364(4) b/ Å 9.0635(5) c/ Å 10.3618(5) α/° 108.756(1) ° 94.270(1) /° 107.286(1) V/Å3 595.15(6) Z 2 -3 Dc/g cm 1.806 µ(εo Kα)/mm-1 2.271 T/K 173(2) Crystal size (mm) 0.09 x 0.21 x 0.22 θ range (°) 2.1, 33.1

Rint 0.019 Total reflections 8719 Unique reflections 3312 Parameters refined 154

R1 [I > βσ(I)] 0.0247

wR2 0.0593 GOF on F2 1.00

114

Figure 4.16 The extended structure of [Cu(3)Cl2]. Carbon atoms are shown in grey, nitrogen in blue, chloride in green, and copper in orange. The weaker interactions between copper(II) and terminal nitrogen of adjacent dimer units are marked using dashed black line (3.250 Å) and the offset π-π interaction (γ.664 Å) is marked by a dashed red line.

115

Free aliphatic azides have bond lengths Nα-N of ~1.22 Å and N-N of ~1.13 Å.188, 189 Comparison of the reported values with those of the crystal structures for organic azides reported here, as well as another organic azide from our group122 (Figure

4.17), show a slightly longer Nα-N bond lengths indicating they carry more single bond like character (Table 4.13). Additionally, the N-N lengths are shorter than those reported for free aliphatic azides indicating more triple bond character is present. The complex [Cu2(1)2Cl4] has the longest Nα-N distance at 2.57 Å and the shortest N-N bond at 1.113 Å. Interestingly, the complex of [Cu(1)2Cl2] shows the shortest Nα-N distance at 2.234 Å and the longest N-N distance at 1.129 Å that are closer to those reported for the free aliphatic azide. The complexes of [Cu2(1)2Cl4], [Cu2(7)2Cl4], and

[Cu(3)Cl2] support the hypothesis that copper(II) coordination favors the resonance structure of the azide shown in Figure 4.17. This coordination mode facilitates the nucleophilic attack from the copper(I) acetylide on the N position.

Figure 4.17 Copper(II) coordinated to chelating azides 1, 3, and 2-(2- 122 azidoethyl)pyridine (7). Counterions (L) are chlorides.

116

Table 4.13 Bond distances (Å) in the Cu(II) complexes of 1, 3, and 7.

122 [Cu2(1)2Cl4] [Cu(1)2Cl2] [Cu2(7)2Cl4] [Cu(3)Cl2] Cu1-N1 (pyridyl) 2.028 1.995 1.994 1.968

Cu1-N2 (azido Nα) 2.030 2.424 2.201 2.100

Cu1-N5 (azido Nα) ------2.098

N2-N3 (Nα-N) 1.257 1.234 1.243 1.245

N3-N4 (N-N) 1.113 1.129 1.123 1.119

N5-N6 (Nα-N) ------1.252

N6-N7 (N-N) ------1.122

4.4.6 Competitive Binding Study

To further examine N2 versus N3 coordination in a more challenging structural context, compound 6 was designed (Figure 4.18). Ligand 6 contains two binding sites that could coordinate to a metal ion. Site 1 offers a planar, five-membered binding pocket. This site also contains the more electron dense N3 nitrogen.64, 71, 145 The second site offers a non-planar, six-membered chelation ring as well as coordination with the N2 of the triazole. The Cu(OAc)2-accelerated CuAAC reaction conditions allow for the rapid synthesis (10 min) of the ligand 6 From 1 and 2-ethynylpyridine (Figure 4.19). As with ligands 4 and 5, simple filtration through a plug of silica gel afforded the pure compound.

Figure 4.18 Ligand 6 with two binding pockets highlighted and properties of each site.

117

Figure 4.19 Rapid formation of ligand 6 from Cu(OAc)2-accelerated CuAAC.

Complex 6A ([Cu(6)2(ClO4)2]) was obtained from the reaction of Cu(ClO4)2•6H2O with 6 in a 2:1 ligand to metal stoichiometry (Figure 4.20). This mononuclear complex showed a distorted Jahn-Teller octahedral geometry about the copper(II) ion. Two bidentate ligands are coordinated about the Cu(II) trans to one another. The pyridyl nitrogens, as well as the N3 nitrogens (N5, N5a, N4 and N4a), lie in the square plane surrounding the metal with an average distance of 2.033 Å. Copper(II) preferentially binds to the planar, five-membered binding pocket 1 in both ligands. Adjusting the stoichiometry to 1:1 ligand to metal gives the dinuclear complex where copper can be found in both binding pockets. The asymmetric unit for this complex showed two discrete dinuclear copper(II) complexes (Figure 4.21 6B and Figure 4.22 6C). In both structures the ligands were oriented trans to each other. Each copper center was bound to one 5-membered binding pocket from one ligand and a 6- membered binding pocket of the other ligand. In both complexes, the six-membered ring adopted a boat conformation characteristic of these types of ligands.113, 122, 146, 159 However, the coordination geometry was significantly different between the two complexes. Complex 6B was pentacoordinate and its geometry is difficult to describe.

Its calculated τ5 value is 0.55, suggesting it has distorted trigonal bipyramidal geometry. An additional method to distinguish between geometries based on the dihedral angles in

179, 181 ideal polyhedra has been applied, along with the τ5, to help assign geometry. Using an approximation of this method,182 from the angles listed in Table 4.15, the trigonal bipyramidal distortion of 6B is 49% along the Berry pseudorotation pathway toward square pyramid. It is clear from these two parameters that the coordination of the ligands are imposing significant departures from the idealized geometries.179 The axial position on each metal center has a slightly longer bond to a CH3CN molecule.

118

The metal to metal distance in this complex is 4.079 Å. Complex 6C showed a distorted octahedral geometry about the copper(II) centers. Each copper center in this complex has two CH3CN molecules coordinated in the axial positions. The copper-copper distance in this complex is slightly shorter (4.053 Å) possibly due to its different molecular geometry about the copper centers. Other cases where the triazolyl groups bridge metal ions have been observed for copper(I) complexes.155, 190 Recently Crowley et al. reported156 the use of ligand 6 to create a dinuclear silver(I) complex. Like complexes 6B and 6C, the silver centers are enveloped by the 8 nitrogens from the two ligands. However, despite using the same ligand (6), the distance between the two silver metals was significantly larger (4.98 Å) when compared to that of 6B or 6C possibly due to the larger metal ion used.

119

Figure 4.20 ORTEP view shown with 50% probability of complex 6A [Cu(6)2(ClO4)2]. Carbon atoms are shown in black, nitrogen in blue, oxygen in red, chloride in green, and copper in orange. Atom labels are shown in purple.

Table 4.14 Selected bond lengths (Å) and angles (°) for [Cu(6)2(ClO4)2].

Cu1 Distance Angles N5 2.0381 (14) N4 2.0269 (14) 99.35 (6) N4a 2.0269 (14) 80.65 (6) 180.00 N5a 2.0381 (14) 180.00 80.65 (6) 99.35 (6) O1 2.4192 (14) 97.29 (5) 89.00 (5) 89.00 (5) 82.71 (5) O1a 2.4192 (14) 82.71 (5) 89.00 (5) 91.01 (5) 97.29 (5) 180.00 Cu1 N5 N4 N4a N5a O1

120

Table 4.15 Crystal data and structural refinement for complex 6A [Cu(6)2(ClO4)2].

[Cu(6)2(ClO4)2]

Formula C26H22Cl2CuN10O8 Formula weight 736.98

Space group P21/c Crystal system Monoclinic a/ Å 7.7090(8) b/ Å 15.0327(15) c/ Å 12.5632(13) α/° 90 ° 91.942(1) /° 90 V/Å3 1455.1(3) Z 2 -3 Dc/g cm 1.682 µ(Mo-Kα)/mm-1 1.004 T/K 173(2) Crystal size (mm) 0.08 x 0.09 x 0.34 θ range (°) 2.1, 27.1

Rint 0.026 Total reflections 15949 Unique reflections 3189 Parameters refined 214

R1 [I > βσ(I)] 0.0283

wR2 0.0771 GOF on F2 1.05

121

Table 4.16 Selected bond lengths (Å) and angles (°) for [Cu(6)2(CH3CN)2](ClO4)4.

Cu1 Distance Angles N7 2.146 (4) N4 2.004 (4) 90.41 (15) N3 1.997 (4) 89.81 (15) 173.46 (15) N1 2.005 (4) 129.15 (15) 97.64 (15) 87.27 (15) N6 2.036 (4) 90.48 (15) 80.33 (15) 93.13 (15) 140.37 (16) Cu1 N7 N4 N3 N1

122

Figure 4.22 ORTEP view shown with 50% probability of complex 6C [Cu(6)2(CH3CN)4](ClO4)4. Counter ions and hydrogens are omitted for clarity. Carbon atoms are shown in black, nitrogen in blue, and copper in orange. Atom labels are shown in purple.

Table 4.17 Selected bond lengths (Å) and angles (°) for [Cu(6)2(CH3CN)4](ClO4)4.

Cu2 Distance Angles N8 2.051 (5) N10 2.076 (5) 79.7 (2) N11 2.016 (4) 98.15 (16) 156.8 (3) N13 1.972 (5) 173.37 (19) 93.66 (16) 88.1 (2) N14 2.686 (6) 90.7 (2) 74.43 (19) 82.5 (2) 88.0 (2) N15 2.206 (6) 90.5 (2) 103.7 (2) 99.4 (2) 90.6 (2) 177.57 (19) Cu1 N8 N10 N11 N13 N14

123

Table 4.18 Crystal data and structural refinement for complex 6B and 6C.

[Cu(6) (CH CN) ](ClO ) , 2 3 2 4 4 [Cu(6)2(CH3CN)4](ClO4)4

Formula C64H126Cu4N26Cl8O32 Formula weight 2277.16

Space group P21/c Crystal system Monoclinic a/ Å 12.8536(8) b/ Å 17.8381(12) c/ Å 19.0070(12) α/° 90 ° 90.832(1) /° 90 V/Å3 4357.5(5) Z 2 -3 Dc/g cm 1.736 µ(Mo-Kα)/mm-1 1.310 T/K 173(2) Crystal size (mm) 0.15 x 0.20 x 0.25 θ range (°) 2.0, 25.2

Rint 0.045 Total reflections 39440 Unique reflections 7781 Parameters refined 626

R1 [I > βσ(I)] 0.0610

wR2 0.1999 GOF on F2 1.46

124

Using 1H NMR, the coordination chemistry of 6 was further investigated (Figure 4.23). Due to the paramagnetic nature of copper(II), zinc(II) was used as a diamagnetic analogue. The peaks for ligand 6 in spectrum 1 were assigned based on the 2D-COSY experiment. The figure insert in Figure 4.23 shows the protons associated with the coordination pockets of 1 and 2 color coded in blue and red, respectively.

Upon the initial addition of Zn(ClO4)2, the hydrogens from the pocket 2 (red) retain their splitting character whereas the pyridyl hydrogens in pocket 1 (blue) show shifting and broadening (spectrum 2). Further addition of zinc shows a reemergence and downfield shift of signals for these protons. The protons that show the most change during the first half of the titration are HI as well as the triazole proton HF. The methylene proton HE remains relatively unchanged up to this point. When the metal to

125 ligand ratio exceeds 1:2 (spectra 5), the picolyl protons (red) then begin to show changes and shift downfield as well, indicating occupation of pocket 1 by the zinc(II) ion. This indicates that the solution behavior of ligand 6 mirrors the observations in the solid state. Metals preferably coordinate with the five-membered, planar pocket 1, but with increasing metal concentrations will then occupy binding pocket 2.

4.5 Conclusions

Facile and rapid synthesis of tridentate 2,6-bis(1,2,3-triazol-1-ylmethyl)pyridine ligands were achieved through the application of our developed Cu(OAc)2-accelerated AAC reaction. The ligands showed the pyridyl nitrogen as well as the less Lewis basic N2 nitrogen of the 1,2,3-triazole ring coordinating to transition metal ions; copper(II), iron(II), and cobalt(II). These ligands complement the triazolyl-based terpy motif where N3 participates in coordination. Additionally, the boat-like, six-membered chelation is similar to those observed for the 2,6-bis(pyrazol-1-ylmethyl)pyridine systems. Stable copper(II)/organic azide complexes were described. The alkylated nitrogen atom (Nα) of the azido group was coordinated to copper(II). Analysis of the bond lengths show that copper(II) coordination at Nα nitrogen enhances the electrophilicity of the terminal N, accelerating the CuAAC reaction. Additionally, a ligand was designed to offer binding sites at both the N2 and N3 positions forming a six- and five-membered chelation ring, respectively. Its coordination with metals were studied and found that both copper(II) and zinc(II) prefer the 5-membered planar chelation pocket that includes N3 atom over the 6-membered, puckered pocket with the N2 nitrogen of the 1,2,3-triazole. The information gained from this study enhances our knowledge and understanding of the coordination chemistry of 1,4-substituted-1,2,3-triazole molecules.

126

4.6 Experimental Information

4.5.1 Materials and general methods

CDCl3 was treated with alumina gel prior to use. Mass spectra were obtained at the Mass Spectrometry Laboratory at FSU. The absorption spectra were recorded on a Varian Cary 100 Bio UV-Visible Spectrophotometer. Elemental analysis data were collected at Atlantic Microlab, Inc.

4.5.2 Ligand Synthesis

Compound 3. In a round-bottom flask, 2,6-bis(chloromethyl)pyridine (0.18 g, 1.0 mmol), 18-crown-6 (catalytic amount), and tetrabutylammonium iodide (catalytic amount) were dissolved in DMF (10 mL). To this stirred solution, sodium azide (0.16 g, 2.5 mmol) was added and the solution was left stirring overnight (12 h). The reaction mixture was then diluted with ethyl acetate (100 mL) and washed sequentially with a saturated NaHCO3 solution (100 mL x 3) and an NH4Cl solution (2 M, 100 mL). The organic fraction was dried over Na2SO4 and the solvent was subsequently removed to afford the product as a pale yellow oil that solidified upon storage at -20 °C. Yield = 0.18

127

1 g, 95%. HNMR (300 MHz, CDCl3): δ (ppm) 7.77 (t, J = 7.8 Hz, 1H), 7.31 (d, J = 7.8 Hz, 13 2H), 4.50 (s, 4H). C NMR (125 MHz, CDCl3): δ (ppm) 156.1, 138.2, 121.3, 55.6.

Compound 4. To a solution of 3 (0.076 g, 0.40 mmol) in CH3OH (1 mL) were added phenylacetylene (0.11 mL, 1.0 mmol) and Cu(OAc)2·H2O (50 mL, 0.4M solution in H2O) at RT. The reaction was completed as the reaction mixture turned to a yellow solid in ~3 min. The mixture was diluted with CH2Cl2 and loaded onto a short plug of silica gel. After elution with ethyl acetate, the solvent was removed under vacuum to afford the 1 pure product as a white solid. Yield = 0.15 g, 98%. H NMR (300 MHz, CDCl3): δ (ppm) 7.87 (s, 2H), 7.81 (d, J = 6.6 Hz, 4H), 7.71 (t, J = 7.8 Hz, 1H), 7.42–7.30 (m, 6H), 7.20 13 (d, J = 7.8 Hz, 2H), 5.70 (s, 4H). C NMR (125 MHz, CDCl3): δ (ppm) 155.0, 148.6, 139.0, 130.6, 129.1, 128.5, 126.0, 122.2, 120.4, 55.6. HRMS [M+Na]+: 416.1600 (calcd), 416.1621 (found).

Compound 5. To a solution of 2,6-bis(azidomethyl)pyridine (0.038 g, 0.20 mmol) in t-

BuOH (0.5 mL) were added 1-hexyne (56 δ, 0.50 mmol) and Cu(OAc)2·H2O (25 mL,

0.4M solution in H2O) at RT. From TLC, the reaction was completed in 7 min. The reaction mixture was diluted with CH2Cl2 and loaded onto a short plug of silica gel. After elution with ethyl acetate, the solvent was removed under vacuum to afford the pure 1 product as a white solid. Yield = 0.058 g, 82%. H NMR (300 MHz, CDCl3): δ (ppm) 7.66 (t, J = 7.8 Hz, 1H), 7.37 (s, 2H), 7.07 (d, J = 7.8 Hz, 2H), 5.61 (s, 4H), 2.73 (t, J = 7.8 Hz, 4H), 1.66 (m, 4H), 2.09 (m, 4H), 0.93 (t, J = 7.2 Hz, 6H). 13C NMR (125 MHz,

CDCl3): δ (ppm) 155.2, 149.2, 138.8, 121.8, 121.4, 55.3, 31.7, 25.6, 22.5, 14.0. HRMS [M+H]+: 354.2406 (calcd), 354.2414 (found).

128

Compound 6. Picolylazide (1 mmol, 0.1368 g) and 2-ethynylpyridine (1.1 mmol, 120 L) were dissolved in t-BuOH (2.5 mL). To that solution, copper(II) acetate (25 L, 0.4 M in water) was added. After ten min, the reaction was complete and filtered through a short silica plug with DCM/MeOH to afford the pure product as a yellow solid in 98% 1 yield. H NMR (300 MHz, CDCl3)μ /ppm 8.6 (dd, J = 4.8, 15.0 Hz, βH), 8.β7 (s, 1H), 8.19 (d, J = 8.4 Hz, 1H), 7.79 (td, J = 1.5, 7.8 Hz, 1H), 7.70 (td, J = 1.5, 7.5 Hz, 1H), 13 7.30-7.22 (m, 3H), 5.74 (s, 2H). C NMR (75 MHz, CDCl3)μ /ppm 154.4, 150.γ, 150.0, 149.5, 148.9, 137.5, 137.0, 123.6, 123.0, 122.9, 122.5, 120.4, 55.9. HRMS [M+H]+: 238.1093 (calcd), 238.1093 (found).

4.5.1 Synthesis of Complexes

Synthesis of complex [Cu(4)2](ClO4)2

Solutions of Cu(ClO4)2•6H2O (0.012 g, 0.032 mmol, in 2 mL CH3OH) and ligand 4

(0.025 g, 0.064 mmol, in 10 mL CH3OH) were combined and stirred for several min. The solvent was subsequently removed under reduced pressure. The resulting green solid was washed with diethyl ether (3 x 20 mL) to afford the complex in powder form in 96% yield (0.032 g). The product was dissolved in a minimal amount of CH3CN and filtered through a piece of glass microfiber. Vapor diffusion of diethyl ether into the CH3CN solution gave dark green crystals that were suitable for X-ray diffraction. MS (ESI+, + + CH3CN, 0.1% formic acid), m/z: 456.1 ([Cu(4)] ), 501.1 ([Cu(4)(HCO2)] ), 849.3 + + + 3 -1 - ([Cu(4)2] ), 894.3 ([Cu(4)2(HCO2)] ), 948.2 ([Cu(4)2(ClO4)] ). max/nm (max/dm mol cm 1 ) (CH3CN), 650 (160). µeff, 300 K: 1.89 µB. Anal. Calcd. for C46H38Cl2CuN14O8·CH3CN: C, 52.87; H, 3.79; N, 19.27. Found: C, 52.62; H, 3.91; N, 19.32%.

Synthesis of complex [Fe(4)2](ClO4)2

Complex [Fe(4)2](ClO4)2 was obtained in 87% yield (0.029 g) by following a procedure analogous to that for preparing [Cu(4)2](ClO4)2. The product was dissolved in a minimal amount of CH3CN and filtered through a piece of glass microfiber. Vapor diffusion of

129 diethyl ether into the CH3CN solution gave rose colored crystals that were suitable for 2+ 3 -1 - X-ray diffraction. MS (ESI+, CH3OH), m/z: 421.1 ([Fe(4)2] . max/nm (max/dm mol cm 1 ) (CH3CN), 550 (210). Anal. Calcd. for C46H38Cl2FeN14O8•βH2O: C, 51.27; H, 3.93; N, 18.20. Found: C, 51.56; H, 3.82; N, 8.44%.

Synthesis of complex [Co(4)2](ClO4)2

Complex [Co(4)2](ClO4)2 was obtained in 88% yield (0.033 g) by following a procedure analogous to that described for [Cu(4)2](ClO4)2. The product was dissolved in a minimal amount of CH3CN and filtered through a piece of glass microfiber. Vapor diffusion of diethyl ether into the CH3CN solution gave yellow colored crystals that were suitable for 2+ X-ray diffraction. MS (ESI+, CH3CN, 0.1% formic acid), m/z: 422.6 ([Co(4)2] ), 890.3 + + 3 -1 -1 ([Co(4)2(HCO2)] ), 944.2 ([Co(4)2(ClO4)] ). max/nm (max/dm mol cm ) (CH3CN), 545

(415). µeff, 300 K: 4.95 µB. Anal. Calcd. for C46H38Cl2CoN14O8·2H2O: C, 51.99; H, 3.79; N, 18.45. Found: C, 51.56; H, 3.86; N, 17.90%.

Synthesis of complex [Cu(1)2Cl2]

Solutions of compound 3 (0.025 g, 0.18 mmol, in 5 mL CH3OH) and CuClβ•2H2O (0.015 g, 0.092 mmol, in 5 mL CH3OH) were combined. An immediate green precipitate separated out. The green solid was filtered off and was washed with diethyl ether (3 x 20 mL) to give the powdered complex in 93% yield (0.069 g). This solid was then dissolved in CH3OH and filtered through a piece of glass microfiber. Vapor diffusion of diethyl ether into the solution in CH3OH gave well-formed blue X-ray diffraction quality single crystals. A batch of crystals always contains various amounts of green crystals that were determined to be the dimeric complex [Cu2(1)2Cl4]. Therefore, the elemental + analysis of this complex was not attempted. MS (ESI+,CH3CN) 501.0 ([Cu2(1)2Cl3] ). 3 -1 -1 max/nm (max/dm mol cm ) (CH3CN), 690 (462).

Synthesis of complex [Cu(3)Cl2]

Solutions of CuCl2·2H2O (0.023 g, 0.13 mmol, in 2 mL CH3OH) and ligand 3 (0.025 g,

0.13 mmol, in 2mLCH3OH) were combined and stirred for several min. The solvent was subsequently removed under reduced pressure and the green solid was washed with

130 diethyl ether (3 x 20 mL) to afford the complex in powder form in 76% yield (0.32 g). The product was dissolved in a minimal amount of CH3CN and filtered through a piece of glass microfiber. Vapor diffusion of diethyl ether into the solution in CH3CN gave green- colored crystals that were suitable for X-ray diffraction. MS (ESI+, CH3CN), m/z: 287.1 + + 3 -1 -1 ([Cu(3)Cl] ), 609.1 ([Cu2(3)2Cl3] ). max/nm (max/dm mol cm ) (CH3CN), 705 (480).

Anal. Calcd. for C7H7Cl2CuN7: C, 25.98; H, 2.18; N, 30.30. Found: C, 26.22; H, 1.95; N, 30.09%.

Complex 6A. The ligand 6 (0.21 mmol, 50 mg) was dissolved in acetonitrile (1 mL). Copper(II) perchlorate hexahydrate (0.21 mmol, 77.8 mg) in acetonitrile (1 mL) was added dropwise to the ligand solution and stirred for several min. The solvent was then removed and the complex was rinsed with diethyl ether (3 x 10 mL). The complex was then dissolved in minimal acetonitrile, filtered through glass microfiber and set up for vapor diffusion with diethyl ether. Anal. Calcd for C26H22Cl2CuN10O8 ([Cu(6)2(ClO4)2]) C, 3 - 4β.γ7; H, γ.01; N, 1λ.01. Foundμ C, 4β.5λ; H, γ.01; N, 1λ.08%. max/nm (max/dm ·mol 1 -1 ·cm ) (CH3CN), 680 (310).

Complex 6B. The ligand (0.21 mmol, 50 mg) was dissolved in acetonitrile (~1 mL). Copper(II) perchlorate hexahydrate (0.105 mmol, 38.9 mg) in acetonitrile (~1 mL) was added dropwise to the ligand solution and stirred for several min. The solvent was then removed and the complex was rinsed with diethyl ether (3 x 10 mL). The complex was then dissolved in minimal 50/50 acetonitrile/methanol, filtered through glass microfiber and set up for vapor diffusion with diethyl ether. Anal. Calcd for C30H28Cl4Cu2N12O16

([Cu2(6)2(CH3CN)2](ClO4)4) C, 33.32; H, 2.61; N, 15.54. Found: C, 33.43; H, 2.71; N, 3 -1 -1 15.β7%. max/nm (max/dm ·mol ·cm ) (CH3CN), 675 (280).

131

1 4.5.4 H NMR Titrations of 5 with Fe(ClO4)2

Ligand 5 (5.8 mg, 0.016 mmol) was dissolved in CD3CN in a 5 mL volumetric flask to a concentration of 3.3 mM. This solution (1 mL) was added to a screw-cap NMR tube completed with a septum. Fe(ClO4)2•6H2O (0.100 g, 0.276 mmol) was dissolved with

CD3CN in a 1-mL volumetric flask to the final concentration of 276 mM. The Fe(ClO4)2 solution was titrated into the NMR tube and 1H NMR spectra were recorded with a wait time between titrations of 5 min. Fourteen data points were taken with the total volume of addition being 6.5 µL which covered the molar ratio ([FeII]/[5]) range from 0 to 0.54.

1 4.5.5 H NMR Titrations of 6 with Zn(ClO4)2

Ligand 6 (9.1 mg, 0.038 mmol) was dissolved in CD3CN in a 1 mL volumetric flask to a concentration of 38.35 mM. This solution (1 mL) was added to a screw-cap NMR tube completed with a septum. Zn(ClO4)2•6H2O (108.1 mg, 0.29 mmol) was dissolved with

CD3CN in a 1-mL volumetric flask to the final concentration of 290.31 mM. The 1 Zn(ClO4)2 solution was titrated into the NMR tube and H NMR spectra were recorded with a wait time between titrations of 5 min. Eight data points were taken with the total volume of addition being 140 µL which covered the molar ratio ([ZnII]/[6]) range from 0 to 1.06.

132

4.5.6 1H and 13C NMR Spectra

1 Figure 4.24 300 MHz H NMR Spectrum of compound 3 in CDCl3.

13 Figure 4.25 75 MHz C NMR Spectrum of compound 3 in CDCl3.

133

1 Figure 4.26 500 MHz H NMR Spectrum of compound 4 in CDCl3.

13 Figure 4.27 125 MHz C NMR Spectrum of compound 4 in CDCl3.

134

1 Figure 4.28 500 MHz H NMR Spectrum of compound 5 in CDCl3.

13 Figure 4.29 125 MHz C NMR Spectrum of compound 5 in CDCl3.

135

1 Figure 4.30 300 MHz H NMR Spectrum of compound 6 in CDCl3.

13 Figure 4.31 75 MHz C NMR Spectrum of compound 6 in CDCl3.

136

CHAPTER 5

SYNTHESIS OF 5-IODO-1,4-DISUBSTITUTED-1,2,3- TRIAZOLES

5.1 Summary

Unlike previous reports, 5-iodo-1,4-disubstituted-1,2,3-triazoles were generated from 2-picolylazide and iodoalkynes without the need of an assisting ligand. Moderate to good yields of the 5-iodotriazole products were obtained from a small set of iodoalkynes screened. Wanting to circumvent the synthesis of iodoalkynes, a one-pot method was created where copper(II) salts are reduced by NaI. This in situ method generates the necessary copper(I) catalyst as well as the iodinating source. The reaction requires an equivalent of base and was able to proceed in a variety of solvents. However, solvents that are moderately coordinating and less prone to disproportionate

Cu(I) to Cu(II)/Cu(0) (CH3CN, THF, and acetone) gave the highest yields of product. The reaction performed well with a variety of alkynes and azides. However, the reaction is sensitive to excess base and those with tertiary amines exhibited lower yields due to the formation of protonated triazole. Insight into the mechanism was provided by time monitored 1H NMR experiments as well as isolation of know complexes (tetrakis(acetonitrile)copper(I) perchlorate and tetrabutylammonium triiodide). Observation of these two known complexes help explain why the in situ generating conditions are more reactive than that of the direct addition of CuI and I2. Use of another electrophile, allyl iodide, under these conditions gave the 5-allyl-1,4- disubstituted-1,2,3-triazole in a multicomponent, one-pot reaction. 1,4,5-trisubstituted- 1,2,3-triazoles were obtained through palladium cross-coupling reactions, such as the Sonogashira or the Suzuki reactions. However, minor amounts of the dehalogenated triazole by-product complicates purification of these compounds. Further synthesis and study of 1,4,5-trisubstituted-1,2,3-triazoles is underway in our laboratory.

137

5.2 5-Iodo-1,4-Disubstituted-1,2,3-Triazoles

The synthesis of 1,4-disubstituted-1,2,3-triazoles using copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC)5, 6 has shown numerous applications in many fields due to its ability to easily form 1,2,3-triazoles in high yields.11, 15 The CuAAC reaction has been studied now for many years and, as discussed in the previous chapters, there are many different conditions that have been developed. However, the synthesis of 1,4,5-trisubstituted-1,2,3-triazoles has not been well studied. A 5-iodo-1,4-disubstituted- 1,2,3-triazole has been observed as a by-product in some reactions where CuI is used as a catalyst.191 The synthesis of 1,4,5-trisubstituted-1,2,3-triazoles through various approaches has only recently garnered interest.192

5.2.1 Synthesis of 1,4,5-trisubstituted-1,2,3-Triazoles

Wu et al. in 2005,193 reported the first synthesis of 1,4,5-trisubstituted-1,2,3- triazoles through a one-pot reaction strategy. Based off the mechanism proposed by Fokin et al.,6, 11 Wu and coworkers proposed that the copper-triazolide intermediate in the CuAAC mechanistic cycle could be trapped through use of electrophiles. Using iodine as the electrophile, in the presence of a base and stoichiometric amounts of CuI, they were able to isolate the 5-iodo-1,4-disustituted-1,2,3-triazole in low yields. Switching to the more electrophilic iodine monochloride showed a dramatic increase in the yield (up to 80%). Through varying the substrates, they were able to synthesize different 5-iodo-1,4-disubstituted-1,2,3-triazoles in varying yields (34-82%).

Figure 5.1 Electrophilic trapping one-pot method developed by Wu et al.193

138

Also in 2005, Rutjes and coworkers194 reported a copper(I) catalyzed coupling of bromoalkynes and organic azides to generate the 5-bromo-1,4-disubstituted-1,2,3- triazoles in high yields. In cases where CuI was used, they observed a small amount of the 5-iodotriazole product being formed. Therefore, the optimized catalyst for this system was determined to be a combination of CuBr and Cu(OAc)2 (5 mol % each) in THF at room temperature. They attempted to synthesize the 5-iodotriazoles through use of the iodoacetylenes; however, they were unsuccessful and noted that the iodoacetylenes might be too unstable to survive the reaction conditions. The following year, Porco et al.195 observed the unexpected formation of 5- alkynyl-1,2,3-triazoles while investigating the effects of amine ligands on the solubility of copper(I) salts in the CuAAC. They reported the optimized conditions for generation of the 5-alkynyl-1,2,3-triazoles with a 2:1 ratios of Cu(I)/N-methylmorpholine oxide as well as 1 equivalent of Hunig’s base (DIPEA) under an oxidative atmosphere. Products were obtained in 20 min. However, due to the competing Glaser coupling, they were only able to obtain low to moderate yields (31-61%). There have been two variants published of Wu’s one-pot, electrophilic trapping reaction. Hsung et al.196 reported the use of allyliodides as electrophilic trapping agents for the cuprate-triazolide intermediate. Their optimized conditions used 8 equivalents of allyl iodide, 1 equivalent of CuBr, and 2 equivalents of base (2,6-lutidine). However, their reactions were very sluggish (2 days) and the yields were low to moderate (26- 78%). Zhang et al.197 synthesized 5-iodotriazoles through use of CuI and NBS in relatively short reaction times (3-5 h) with good yields (81-90%). Their optimized conditions used a ratio of alkyne, azide, CuI and NBS in a 1:1.1:1.1:1.2 ratio with 1 equivalent of DIPEA added. Most recently, Fokin and coworkers have reported a facile method for the generation of 5-iodo-1,4-disubstituted-1,2,3-triazoles. They developed a system for the generation of stable 1-iodoalkynes that were used with organic azides in the presence of TTTA (an assisting ligand, see Figure 5.2) and CuI to undergo cycloaddition (Figure 5.2). Low catalyst loading and short reaction times gave the 5-iodo-1,2,3-triazole products in good to high yields (73-99%). The CuI/TTTA catalyst system was active in a wide range of protic solvents, including water. They were able to further apply this

139 method for a one-pot, two step synthesis for the generation of iodoalkynes and the formation of 5-iodo-1,2,3-triazoles (Figure 5.3).

Figure 5.2 CuI/TTTA catalyzed cycloaddition of organic azides and 1-iodoalkynes developed by Fokin et al.198

Figure 5.3 Fokin’s developed one-pot, two-step method for the generation of 5-iodo- 1,2,3-triazoles.

There are several key observations from this reaction. The reactivities of 1- iodoalkynes appear to surpass that of terminal alkynes.11, 198 Without an amine ligand, the reaction does not proceed and the 5-iodo-1,2,3-triazole products were isolated exclusively. Although a detailed mechanistic study was not presented, they did provide a mechanistic proposal (Figure 5.4). One possible pathway is similar to that of the CuAAC (Path A, Figure 5.4) where it involves the formation of the copper(I) acetylide. The reaction proceeds to the copper triazolide, where they propose a Cu-I exchange via σ-bond metathesis with iodoalkyne which completes the cycle. The alternate proposed

140 pathway (Path B, Figure 5.4) involves formation of a π-complex that, after introduction of the azide, proceeds through a vinylidine-like intermediate shown in brackets to give the iodotriazole product. Within path B, the carbon-iodine bond is never severed. Based off their observations (mainly the lack of H-triazole formed), the authors favored path B. However, this pathway does not explain the observation of Rutjes et al. where they also used an internal alkyne (bromoalkynes) catalyzed by CuI and observed formation of iodotriazoles.194

Figure 5.4 Proposed mechanisms for the copper(I)-catalyzed azide-iodoalkyne cycloaddition.

5.2.2 Uses of 5-Iodo-1,2,3-Triazoles

5-iodo-1,2,3-triazoles are aryl halides that can be further functionalized using palladium cross-coupling. Iodotriazoles have been successfully coupled with a variety of organoboronic acids, terminal alkenes, and terminal acetylenes through use of Suzuki, Heck and Sonogashira reactions, respectively.199 Fokin et al. employed a Suzuki cross-coupling reaction immediately after the generation of iodotriazoles and were able to obtain several triaryltriazoles in 70-73% yields.198 Generation of 5-iodo- 1,2,3-triazole-containing macrocycles were achieved using copper tubing as the

141 catalyst.200 These macrocycles were further functionalized using Suzuki, Heck and Sonogashira reactions. In addition to functionalizing the 5-position, Rowan and coworkers have recently fused nearby 5-iodo-1,2,3-triazoles in order to extend aromaticity. The bis(triazole) system is analogous to the bis(phenyl) system that can have its aromaticity extended through use of the Bergman cyclization201, 202 or cyclodehyrogenation.203, 204 Use of ortho-bis(iodoacetylenes) coupled with organic azides under previously reported conditions198 gave the bis(iodotriazoles) in 39-82% (see example in Figure 5.5). The bis(iodotriazoles) were subjected to an intramolecular homocoupling reaction using a palladacycle catalyst (Figure 5.5) that was previously described in the literature.205 The fused product was confirmed by 1H NMR and by the appearance of a red-shifted shoulder in the UV-Vis spectrum.

Figure 5.5 Cu(I)-catalyzed azide-haloalkyne cycloaddition of ortho-bis(iodoacetylene) to generate bis(iodotriazoles) that can undergo intramolecular coupling to extend the aromaticity of the system.

5.3 Assisting-Ligand Free Synthesis and the Development of a One- Pot Procedure

To further study the coordinating ability of the N2 position, we proposed that installing an electron donating group (EDG) at the 5-position would increase the electron density at the N2 nitrogen (Figure 5.6). We envisioned that the 1,4,5- trisubstituted product could be obtained via palladium cross-coupling of the 5-iodo- 1,2,3-triazole and that the 5-iodotriazole could be generated via the Cu(I)-catalyzed azide-iodoalkyne cycloaddition (Figure 5.6).

142

Figure 5.6 Enhancement of N2 binding (in box) with retrosynthetic route to the right.

During the course of this study, reactions of 2-picolylazide with iodoacetylenes gave 5-iodotriazoles in good to excellent yields without the need of an assisting ligand. An alternative one-pot method was developed that allowed for the formation of 5- iodotriazoles without the pre-synthesis of the iodoalkyne. The classical CuAAC conditions form copper(I) from in situ reduction of copper(II) by sodium ascorbate (Figure 5.7 left), whereas the developed conditions provide an in situ method to reduce copper(II) by sodium iodide forming copper(I) iodide and iodine (Figure 5.7 right). The CuI can then catalyze the reaction where iodine serves as the iodinating reagent. These 5-iodotriazoles were then able to be functionalized at the 5-position via palladium coupling.

Figure 5.7 Left, “classic” conditions to in situ generate Cu(I) to form 5-proto-1,2,3- triazoles. Right, in situ conditions to generate CuI and I2 to yield 5-iodo-1,2,3-triazoles.

143

5.4 Results and Discussion

5.4.1 Assisting ligand-free synthesis

Iodoalkynes were easily prepared following a procedure described in the literature.206 Preliminary attempts to synthesize 5-iodotriazoles with azide 1 and 1- iodophenylacetylene with Cu(OAc)2 (5 mol %) in methanol gave the desired product 2 in 41% yield after an extended reaction period (2 days). Upon switching to the conditions similar to those reported by Fokin198 but with no added base or TTTA, the 5-iodo-1,2,3- triazole 2 was obtained in good yields (90%) with a significantly shorter reaction time (Figure 5.8). Under these conditions, Fokin et al. reported that no reaction occurred without an amine ligand being present.11, 198 It is possible that the chelating azides/products are serving as assisting ligand similar to what we have observed for 113, 122, 130 these products in the Cu(OAc)2-accelerated AAC reaction.

Figure 5.8 Reaction of 1 with 1-iodophenylacetylene to generate 2.

Reacting a small set of iodoalkynes with 2-picolylazide (Table 5.1) gave moderate to good yields (2, 4-8 55-84%, Table 5.1) of the 5-iodo-1,2,3-triazole. Of the reactions studied, only 4-(iodoethynyl)anisole (entry 2, Table 5.1) and 3-iodo-N,N- dimethylpropargyl-amine (entry 6, Table 5.1) did not go to completion, resulting in lower isolated yields.

144

Table 5.1 Ligand free synthesis of 5-iodo-1,2,3-triazoles using 2-picolylazide.a

Entry Iodoalkyne Yield (%)

1 2, 90

2 4, 62b

3 5, 77

4 6, 84

5 7, 73

6 8, 55b aReaction conditions: azide (0.4 mmol), iodoalkyne(0.5 mmol), CuI (5 mol %), THF (2 mL), RT, 4 h. bReaction did not go to completion.

5.4.2 Multi-Component One-Pot Reaction to Generate 5-Iodotriazoles

Previous work by Wu193 and Fokin198 leads to formation of 5-iodo-1,2,3-triazoles through either electrophilic trapping or a one-pot, 2-step synthesis. However, these methods require expensive, not to mention hazardous and corrosive, iodinating reagents and/or the additional synthesis of unstable iodoacetylenes.194 We therefore developed a method to generate the selective formation of 5-iodo-1,2,3-triazoles

145 through use of one-pot CuAAC via in situ generation of CuI and I2 from inexpensive, readily available copper(II) salts and sodium iodide.

207 In situ generation of CuI and I2. In the 1λ60’s, Kauffman and Pinnell found that copper(II) sulphate, in the presence of potassium iodide, gave copper(II) iodide initially (eq 1) but decomposed almost immediately to yield copper(I) iodide and free iodine (eq 2).

2 CuSO4 + 4 KI  2 CuI2 + 2 K2SO4 (1)

2 CuI2  2 CuI + I2 (2)

Inspired from this work, copper(II) perchlorate and sodium iodide were used with azide 1 and phenylacetylene in THF. Encouragingly, exclusive formation of the iodotriazole product was observed after a 6 h reaction time, albeit in low yield (Table 5.2, entry 1). Upon addition of triethylamine (entry 2), the yield dramatically increased to 97%. Unlike Wu193 and Fokin’s198 results, only one equivalent of base was needed. Excess base leads to the formation of the undesired H-triazole product 2 (entry 3). Other organic bases were also examined but only diethylamine, DMAP, and DBU showed results comparable to that of TEA. Of the inorganic bases screened (Table 5.2, entries 9-10), sodium carbonate showed selectivity but poor conversion. However, doping sodium carbonate with TEA showed complete conversion and selectivity for the 5-iodo-1,2,3- triazole product. Interestingly, even though there is excess base in this last entry, the undesired H-triazole product wasn’t formed.

146

Table 5.2 Optimization of one-pot conditions to generate 5-iodotriazole 2.a

Entry Additive Equiv. 2/3b Yield (%)c

1 None ---- 1:0 19

2 TEA 0.5 3.5:1[d] 68

3 TEA 1.0 1:0 97

4 TEA 1.5 9:1 84

5 Et2NH 1.0 1:0 91

6 Pyridine 1.0 3.5:1 79

7 DMAP 1.0 1:0 96

8 DBU 1.0 1:0 90

9 NaHCO3 1.0 3.5:1 60

d 10 Na2CO3 1.0 1:0 68

11 TEA/Na2CO3 0.5/5.0 1:0 96 a 2-picolylazide (0.2 mmol), phenylacetylene (0.23 mmol), Cu(ClO4)2 (0.4 mmol), NaI (0.8 mmol), THF (1 mL), RT, 6 h. bProduct ratio determined by 1H NMR. cYield of 1 isolated. dReaction did not go to completion.

Solvent screening. In the work by Kauffman and Pinnell,207 water was used as the solvent due to the insolubility of CuI, allowing for easy isolation of the copper salt product from the iodine solution. For the developed reaction, various solvents were screened using TEA as the base (Table 5.3). The reaction proceeds in all sovents screened. While not all went to completion, all showed selectivity for the formation of the 5-iodo-1,2,3-triazole product, even in protic solvents (Table 5.3, entries 8-10). A closer look at the solvent properties of Table 5.3 shows that non-coordinating solvents 208 (Toluene and CH2Cl2, entries 1 and 3, respectively) generate the least amount of product. The rest of the solvents used are coordinating solvents,208 however, they 147 stabilize Cu(I) to different degrees. This influences the disproportionation process where copper(I) ions participate in a bimolecular redox process to yield Cu(II) and elemental copper.209 Water and DMF are both strongly coordinating solvents, however, copper(I) ions in water have a higher propensity to disproportionate when compared to the solvents with the highest isolated product yields (e.g. acetone and CH3CN, entries 5 and 6).209

Table 5.3 Solvent Screening of one-pot conditions to generate 5-iodotriazole 2.a

Entry Solvent 2/3b Yield (%)c

1 Toluene 2:1 58

2 EtOAc 1:0 74

d 3 CH2Cl2 1:0 44

4 THF 1:0 97

5 Acetone 1:0 90

6 CH3CN 1:0 93

7 DMF 1:0 86

8 Isopropanol 13:1 40d

9 Methanol 1:0 68d

10 Water 2:1 23d a 2-picolylazide (0.2 mmol), phenylacetylene (0.23 mmol), Cu(ClO4)2 (0.4 mmol), NaI (0.8 mmol), TEA (0.2 mmol), solvent (1 mL), RT, 6 h. bProduct ratio determined by 1H NMR. cYield of 1 isolated. dReaction did not go to completion.

148

Copper salt screening. Various copper salts were also screened (Table 5.4). All copper(II) salts appear to be able to convert to the active catalyst CuI, although some better than others. Copper salts with weakly coordinating anions, like copper(II) perchlorate and copper(II) triflate (Table 5.4, entries 1 and 6) appear to be better choices as the copper source with the exception of copper(II) tetrafluoroborate (entry 5). The in situ generation of CuI and iodine is superior to that of directly using CuI and iodine (entry 7). The direct use of CuI/I2 showed significant amounts of left-over azide 1 as well as slight formation of 3. This low reactivity of the direct addition of CuI and I2 has also been observed by others.193,197

Table 5.4 Copper salt screening of one-pot conditions to generate 5-iodotriazole 2.a

Entry Cu(II) 2/3b Yield (%)c

1 Cu(ClO4)2 1:0 97

2 CuSO4 4.5:1 87

3 CuCl2 16:1 82

4 Cu(OAc)2 4:1 70

5 Cu(BF4)2 1.8:1 53

6 Cu(CF3SO3)2 13:1 89 7c CuI 13:1 55e a1 (0.2 mmol), phenylacetylene (0.23 mmol), Cu(II) salt (0.4 mmol), NaI (0.8 mmol), TEA (0.2 mmol) THF (1 mL), RT, 6 h. bProduct ratio determined by 1H NMR. cYield of 2 isolated. d1 (0.2 mmol), phenylacetylene (0.23 mmol), CuI (0.2 mmol), I2 (0.2 mmol), TEA (0.2 mmol), THF (1 mL), RT, 6 h. eReaction did not go to completion.

149

Alkyne screening. A plethora of alkynes were subjected to the developed conditions with 2-picolylazide (Table 5.5). All proceeded to give the iodotriazole selectively, with the exception of entry 4 and entry 9. Entry 4 was found to proceed to completion even in absence of an added base and with similar distribution of products observed by 1H NMR. Using two equivalents of 2-picolylazide in the presence of 1,3-diethynylbenzene gave the diiodotriazole compound in one pot. compound 14, as well as compound 22 (vide infra), are similar to compounds recently reported via a multistep synthesis and have comparable yields but avoids the synthesis of iodoacetylenes and with much shorter reaction times for the AAC reacction.210

150

Table 5.5 Alkyne screening of one-pot conditions to generate 5-iodotriazoles.a

Entry Product Yield (%)b Entry Product Yield (%)b

1 83 7 84

2 74

8 93

3 97

9 75 4 51

5 78 10 53

6 88

a 1 (0.2 mmol), phenylacetylene (0.23 mmol), Cu(ClO4)2 salt (0.4 mmol), NaI (0.8 mmol), TEA (0.2 mmol), ACN (1 mL), RT, 6 h. bYield of product isolated.

151

Single crystal of 2. While characterizing these compounds, single crystals suitable for X-ray diffraction were grown in an NMR tube after the sample had been briefly heated and allowed to cool to room temperature. The solved structure (Figure 5.9) shows the iodo-substituent located at the 5-position of the triazole ring. The 5-iodo-1,2,3-triazole unit is not co-planar with the phenyl moiety (20.1° out of plane). This has also been observed in complexes of the H-triazole ligand 3 (e.g. Chapter 2

[Cu(3)2(ClO4)CH3CN](ClO4)2 complex). The crystal structure packing shows several π- π interactions that vertically stack the molecules. It also shows an intermolecular interaction between the pyridyl nitrogen and the iodo-substituent of an adjoining molecule with a Npy-I distance of 2.879 Å and an Npy···I-C1 angle of 168.43°. There may also be a secondary interaction between the N2 nitrogen and the iodo-substituent (N2-I: 3.800 Å and N2···I-C1: 131.45°) that is causing the pyridine unit not to be coplanar with the C1—I unit and the C3-Npyr···I or C4-Npyr···I angles to be off from the expected 120°.211

152

153

Table 5.6 Crystal data and structural refinement for 2.

Formula C14H11IN4 Formula weight 362.17 Space group Pbca Crystal system Orthorhombic a/ Å 8.2998(7) b/ Å 12.7159(11) c/ Å 24.849(2) α/° 90.00 ° 90.00 /° 90.00 V/Å3 2622.6(4) T/K 173(2) Z 8 -3 Dc/g cm 1.834 µ (Mo-Kα)/mm-1 2.433 Crystal size (mm) 0.04 x 0.06 x 0.20 θ range (°) 2.95, 28.35

Rint 0.019 Total reflections 29065 Unique reflections 3276 Parameters refined 172 Data with I > βσ(I) 2836 R1 [I > βσ(I)] 0.0177

wR2 0.0435 GOF on F2 0.99

154

Azide screening. The optimized conditions were also applied in selection of azides with phenylacetylene (Table 5.7). Benzylazide (entry 1) as well as trifluoromethyl substituted benzylazide (entry 2) showed high reactivity under the developed conditions. With some of the less reactive azides (entries 3-7) and only slight excess of phenylacetylene, the reactions showed mainly starting material azides, some 5-iodo- 1,2,3-triazole product and homocoupled acetylene after 12 h. Recent reports note that CuI/Iodine in the presence of terminal alkynes are good conditions to yield 1,3- diynes.212 To overcome this side reaction, the amount of phenylacetylene was doubled and the reactions then went to completion. The reaction involving azidoadamantane (entry 7) showed mainly starting material and trace amounts of 5-iodo-1,2,3-triazole product. This poor reactivity of azidoadamantane can be attributed to sterics. The iodo product was obtained as the sole product in most cases with a few exceptions. Pyrrolidine azide (entry 6) gave rather significant amounts of 5-proto-1,2,3- triazole. This is not entirely surprising considering the pyrrolidine azide starting material is a base and the outcome of products appear to be sensitive to the amount of amine bases present in the system. Excess TEA (Table 5.2, entry 4) in the reaction shows formation of the H-product. Additionally, the reaction of 1 with dimethylpropargylamine (Table 5.5, entry 4) showed significant formation of the protonated triazole. However, the reaction tolerates pyridine as evident by the reactions involving azide 1 and/or ethynylpyridines (Table 5.5), possibly because pyridine is not as basic as TEA, pyrrolidine, etc. Wu’s one-pot method also showed an increase of H-triazole product formed with the increase of TEA present.193 It has also been observed for normal CuAAC reactions, that excess base in the presence of CuI gives particularly high yields of the protonated triazole.133 Although it is not entirely clear as to the exact reason of why excess base gives rise to the formation of protonated triazole, it does appear to be consistent with reports in the literature.

155

Table 5.7 Azide screening of one-pot conditions to give 5-iodotriazoles.a

Entry Product Yield (%)b

1 93

2 93

3 70c

4 98c

5 58c,d

6 65c

7 Tracec,d

8e 69 a Azide (0.2 mmol), phenylacetylene (0.23 mmol), Cu(ClO4)2 (0.4 mmol), NaI (0.8 mmol), DBU (0.2 mmol), ACN (1 mL), RT, 12 h. bYields of isolated products. cAzide (0.2 mmol), phenylacetylene (0.5 mmol), d Cu(ClO4)2 (0.4 mmol), NaI (0.8 mmol), DBU (0.2 mmol), ACN (1 mL), RT, 12 h. Reaction did not go to e completion. Azide (0.2 mmol), phenylacetylene (0.5 mmol), Cu(ClO4)2 (0.8 mmol), NaI (1.6 mmol), DBU (0.4 mmol), ACN (1 mL), RT, 12 h.

156

Time monitored reaction by 1H NMR spectroscopy. Under the developed conditions, a reaction to form compound 2 was set up in deuterated acetonitrile. After the last component was added to the reaction mixture, an aliquot of the reaction was diluted with additional deuterated acetonitrile. This was then monitored by 1H NMR over the duration of the reaction (Figure 5.10). This experiment showed only the formation of 2 and not that the reaction was proceeding through a 5-proto-1,2,3-triazole intermediate under these conditions. Control experiments verified that 3 was not being formed and then iodinated under the conditions. In these experiments, the protonated 1,2,3-triazole 3 was subjected to the reaction conditions from Table 5.5 or 5.7 with TEA or DBU used as the base, respectively. After 6 h, 3 was recovered from both experiments with no evidence of 2 formed.

157

with phenylacetylene with 1 CN) time monitored reaction of azide of monitored time reaction CN) 3

. H NMR (500 H NMR CD MHz, 1

Figure 5.10 everyshown min 50 0 min 0 min 75

158

Possible reaction mechanism. The proposed mechanism follows that of the CuAAC reaction proposed by Sharpless, Fokin and coworkers.6, 8 The copper(II) salt in the presence of sodium iodide converts to copper(I) iodide (or other forms of copper(I) (vide infra) and iodine. Deprotonation of the terminal alkyne allows for the formation of the copper acetylide. The azide can coordinate with the copper acetylide and then form the unusual six-membered metallacycle. Upon ring contraction, the copper triazolide is formed. At this point in the normal CuAAC reaction, the regular triazole product would be obtained via proteolysis. Under these conditions, iodine (or triiodide, vide infra) serve as the electrophilic trapping agents to give the 5-iodo-1,2,3-triazole products. This proposed mechanism is similar to that of path A (Figure 5.4) proposed by Fokin and coworkers.198

Figure 5.11 Possible mechanism of the one-pot conditions to generate 5-iodo-1,4- disubstituted-1,2,3-triazole.

One-pot synthesis of 5-allyl-1,4-disubstituted triazole (23). To test other electrophilic trapping agents in addition to I2, the loading of copper(II) and NaI were reduced and an electrophile, allyl iodide, was added to the reaction of 1 and hexyne. Formation of the 2-((5-allyl-4-butyl-1,2,3-triazol-1-yl)methyl)pyridine (23) was observed

159 when 15 mol % copper loading was used in acetonitrile. The reaction did not proceed to completion after 12 h and showed a mixture of the 5-iodo-1,2,3-trizole product (2) and 23. Increasing the loading to 0.5 equiv of copper increased conversion but also increased the formation of 2. In Kauffman and Pinnell’s synthesis of CuI from copper(II) 207 salts and NaI, the isolated CuI was always contaminated by I2. To overcome this contamination, sodium thiosulfate was added prior to the reaction to remove the unwanted I2. Thus, sodium thiosulfate was also added to our reaction mixture with 0.5 equiv copper(II) and, after 12 h, the reaction showed full conversion to the trisubstituted 1,2,3-triazole product. However, 2 is still formed, albeit in lower amounts (~25% vs. ~40%). Determination of 2 from the crude 1H NMR spectrum was always approximate due to spectral overlap of 2 with an allyl peak from the product 23. The limited success of the addition of sodium thiosulfate is due to its reduced solubility in the organic solvents used. Switching to a solvent where sodium thiosulfate has increased solubility (MeOH) did reduce the amount of 2 formed (~15%), however, also showed formation of the protonated triazole 3 (~10%). Formation of 3 is extremely undesired due to increased complications in purification of the products. Therefore, using sodium thiosulfate and 0.5 equiv of Cu(ClO4)2 in ACN gave the 5-allyl-1,2,3-triazole product 23 in 76% (Figure 5.12).

Figure 5.12 One-pot, multicomponent synthesis of the 1,4,5-trisubstituted 5-allyl-1,2,3- triazole 23.

Use of other electrophiles (benzoyl chloride, iodobenzene, acrolein, acetyl chloride, methane sulfonyl chloride, and iodomethane) were unsuccessful under these developed conditions and mixtures of starting materials, 2 and 3 were recovered. Benzyl bromide gave a mixture of the trisubstituted product and 3. While we were

160 unable to purify the product from 3, formation of the trisubsitituted product was confirmed from MS of the mixture of products. Further work in this reaction is underway in our laboratory.

Observation of tetrabutylammonium triiodide. In an attempt to isolate a crystal from a mixture of 1, Cu(ClO4)2 and NaI in acetonitrile, an off-white precipitate of CuI was observed along with a green precipitate (presumably oxidized Cu+ to Cu2+). In addition to this, large amounts of the known tetrakis(acetonitrile)copper(I) perchlorate crystal213 were grown. The solvation of the copper(I) by acetonitrile is favored due to the back- donation of electrons from copper and the protection of copper(I) from oxidation to Cu(II).214 However, the acetonitrile ligands are not bound very strongly to the copper ion and therefore this complex serves as a precursor for other copper(I) complexes.215 The observation of the tetrakis(acetonitrile)copper(I) suggests that in addition to the freshly prepared CuI, a solvated copper(I) species could also be present and catalyzing the reaction.

Figure 5.13 ORTEP view (50% ellipsoids) of known tetrakis(acetonitrile)copper(I) complex.213 The other two tetrakis(acetonitrile)copper(I) groups and perchlorate counterions of the asymmetric unit are omitted for clarity. Carbon atoms are shown in black, nitrogen in blue, chloride in green, oxygen in red, chlorine in green, and copper in orange.

161

- Observation of triiodide (I3 ). The observation of the tetrakis(acetonitrile)copper(I) complex led us to investigate the nature of the remaining iodine. The absorption trace of Cu(ClO4)2 and NaI after reacting in ACN shows two bands at 294 and 367 nm with no appearance of a copper(II) band in the 700 nm range (Figure 5.14). Iodine in the - presence of iodide is known to from triiodide (I3 ) shown in eq 3.

- - I2 + I I3 (3)

Triiodide has characteristic absorption bands at 362 and 292 nm in acetonitrile.216-218 Iodine in acetonitrile also shows these two absorption bands but an additional band at 218-220 467 nm for I2. Addition of NaI to the I2 solution shows a decrease in the 467 nm band and an increase in the 362 and 292 nm bands suggesting a shift in the equilibria - toward that of I3 .

1.5

* Iodine 1 Iodine + NaI

* Cu(ClO4)2 + NaI

Absorbance 0.5

0 200 300 400 500 600 700 800 Wavelength (nm)

Figure 5.14 Absorbance of iodine solution (blue), iodine with NaI added (red) and of the reaction mixture of Cu(ClO4)2 with NaI (green). Absorbance values of interest (294, 367, and 467 nm) are marked.

162

- A structure containing I3 was obtained by switching the counterion from sodium + to the bulkier tetrabutylammonium (Bu4N ). Reacting copper(II) perchlorate with Bu4NI in MeOH gave CuI as an off-white precipitate that was filtered off. Slow evaporation of the solvent gave red-black crystals. The solved structure for the crystal was determined 221 to be the known Bu4NI3 structure.

Figure 5.15 ORTEP view (50% ellipsoids) of known tetrabutylammonium triiodide complex.221 Carbon atoms are shown in black, nitrogen in blue, and iodine in purple.

Use of triiodide as an iodinating reagent has been well studied in the iodination of acetone.222 This reaction is either acid or base catalyzed and proceeds through an - enolate intermediate. The enolate collapses and attacks the I3 forming the iodoacetone - 223 - and releasing two I . It is possible in our reaction that the I3 could also be serving as the electrophilic iodine for the copper(I) triazolide intermediate. Two parallel reactions were set up involving azide 1, phenylacetylene, CuI (0.5 equiv) with DBU in ACN where one contained Bu4NI3 and the other I2. The reaction with I2 was not complete after 20 h (29% azide still present by 1H NMR) and showed a mixture of 2 and 3 (68% and 3%, respectively). The reaction involving Bu4NI3 showed complete conversion to 2 with no

163

- evidence of 3. These results suggest that I3 is a better electrophile than I2 under these conditions.

5.4.3 Functionalizing 5-Position via Pd coupling reactions

Attempts to functionalize the 5-position of the 5-iodo-1,2,3-triazole utilized the Sonogashira coupling reaction described by Wu et al.199 The coupling reactions were plagued with problems. The crude reaction was typically a mixture of the desired 1,4,5- trisubstituted-1,2,3-triazoles (24 in Figure 5.16), the iodo-starting material (2), and the product of protodehalogenation (3). The protodehalogenation of 5-iodo-1,2,3-triazoles in the presence of palladium was also observed by Rowan et al.210 in their 5-iodotriazole model compound analogous to 2. They proposed that the desired product was not formed due to the steric hindrance imposed by the substituents at the 1- and 4- positions, which could also be hindering the formation of our desired product 3. Further complications were encountered in the isolation of the 1,4,5-trisubstituted-1,2,3-triazole in that it was virtually inseparable from the 5-H-triazole by-product (4) via chromatography. Therefore, the 1,4,5-trisubstituted-1,2,3-triazole products resulting from this Sonogashira reaction condition were never isolated in pure form.

Figure 5.16 Sonogashira coupling of alkynes to 5-iodo-1,2,3-triazole 2 gave a mixture of products that included 24 and 3.

The above conditions are for the copper-free Sonogashira. These conditions are often used to help avoid the homocoupled alkyne by-product. Limited success was obtained when using the Pd/Cu catalyst system. Using the same palladium salt with the addition of CuI and DIPEA, 4-ethynylanisole was successfully coupled to the 1,2,3-

164 triazole ring giving product 25. However, the product 25 was isolated only in a 43% yield due to the dehalogenated triazole by-product still being formed.

Figure 5.17 Sonogashira coupling of 4-ethynylanisole to 5-iodo-1,2,3-triazole 2 yielding 25.

Use of Suzuki coupling of the 5-iodo-1,2,3-triazoles to arylboronic acids gave the trisubstituted products in high yields (Figure 5.18). The 5-iodo-1,2,3-triazole 6 with either arylboronic acid A or pinacol ester boronic acid, B, gave primarily the 1,4,5- trisubstituted product 26 or 27 respectively. This palladium catalyzed reaction also gave minor amounts of the protodeiodinated compound. Again, isolated products of 5A and 5B always contained minor amounts (<3% by 1H NMR) of protodehalogenated triazole due to their inseparability on the column. The protodehalogenated compounds generated in the presence of palladium catalysts has also been observed by others.224- 227 Recently, successful isolation of the Suzuki product without the dehalogenated triazole by-product was obtained via preparatory TLC, however, this process is time consuming and limited in the amount of material that may be purified. Further synthesis and study of 5-functionalized ligands generated from 5-iodotriazoles is underway in our laboratory.

165

Figure 5.18 Suzuki coupling of 6 with either boronic acid A or the pinacol ester boronic acid B to give trisubstituted products 26 or 27.

5.5 Conclusions

In summary, 5-iodo-1,4-disubstituted-1,2,3-triazoles were generated from 2- picolylazide and iodoalkynes without the need of an assisting ligand. Of the small set of iodoalkynes screened, moderate to good yields of the 5-iodotriazole product were obtained. Wanting to avoid the synthesis of iodoalkynes, a one-pot method was created where copper(II) salts are reduced by NaI. This in situ method generates the necessary copper(I) catalyst as well as the iodinating source. The reaction requires an equivalent of base (e.g. TEA, DMAP, DBU, etc.) and excess amine base in the reaction mixture leads to the undesired formation of the protonated triazole. The reaction proceeds in a variety of solvents. However, solvents that are moderately coordinating and less prone to disproportionate Cu(I) to Cu(II)/Cu(0) (CH3CN, THF, acetone) gave the highest yields. The reaction performed well with a variety of alkynes and azides, however, the reaction is sensitive to excess base and those with tertiary amines showed lower yields due to the formation of protonated triazole. The time monitored reaction by 1H NMR as well as control experiments, show the reaction is proceeding to form the 5-iodo-1,2,3-triazole and does not proceed through a protonated triazole intermediate. A possible reaction mechanism was proposed where iodine could serve as an electrophilic trap for the copper(I) triazolide intermediate. Use of another electrophile, allyl iodide was used and

166 the 5-allyl-1,4-disubstituted-1,2,3-triazole was obtained, thus supporting our proposed mechanism. Observation of the tetrakis(acetonitrile)copper(I) complex suggest that, in certain solvents, the solvated copper(I) species is present and possibly increasing the - effective copper(I) catalyst available in solution. Additionally, the observed I3 could also serve as the electrophile. These two observations could explain why the in situ conditions are more reactive than that of the direct addition of CuI and I2. Use of palladium cross-coupling reactions like the Sonogashira or the Suzuki reaction generated the 1,4,5-trisubstituted products. However, minor amounts of the dehalogenated triazole by-product complicates purification of these compounds. Further study of these 1,4,5-trisubstituted-1,2,3-triazoles is underway in our laboratory.

5.6 Experimental Information

5.6.1 Materials and general methods

Warning! Low molecular weight organic azides and metal perchlorate salts used in this study are potentially explosive. Appropriate protective measures should always be taken when handling these compounds. Reagents and solvents were purchased from various commercial sources and used without further purification unless otherwise stated. Analytical thin-layer chromatography (TLC) was performed using pre- coated TLC plates with silica gel 60 F254 (EMD) or with aluminium oxide 60 F254 neutral (EMD). Flash column chromatography was performed using 40-6γ m (βγ0-400 mesh ASTM) silica gel (EMD) or alumina (80-200 mesh, pH 9-10, EMD) as the stationary phases. Silica and alumina gel were flame dried under vacuum to remove absorbed moisture before use. 1H and 13C NMR spectra were recorded on Bruker AvanceIII-500 Spectrometer and the chemical shifts () are expressed in parts per 1 million relative to residual CHCl3 or acetonitrile as internal standards. H NMR spectra were recorded at 500 MHz and carbon spectra were recorded at 125 MHz and both were acquired at 295 K unless otherwise noted. Spectrophotometric measurements were obtained on a Varian Cary 100 Bio UV-Visible Spectrophotometer. High resolution

167 mass spectra (ESI) were obtained on a JEOL AccuTOF spectrometer at the Mass Spectrometry Laboratory at FSU. Synthesis of iodoalkynes followed a procedure reported in the literature.206 Iodoalkynes synthesized were all previously reported (1- (iodoethynyl)benzene,228, 229 4-(iodoethynyl)anisole,229, 230 2-(iodoethynyl)pyridine,229 1- iodohexyne,231 3-iodo-N,N-dimethylpropargylamine,198 and [(3-iodo-2-propynyl)oxy]- benzene232)

5.6.2 1H NMR Time Monitored Reaction

In a vial of 1 (0.2 mmol, 26.8 mg), deuterated acetonitrile (1 mL), NaI (120 mg),

Cu(ClO4)2 (148 mg) were added. To that, TEA (30 µL) was added and the reaction stirred for several min. Phenyl acetylene (40 µL) was added, the vial inverted several times, and an aliquot of the reaction (20 µL) was diluted with deuterated acetonitrile (750 µL) in an NMR tube and quickly placed into the spectrometer. Data was acquired every five min with shimming between scans for the first 3-4 scans until solvent peak was a well-defined pentet. The reaction was monitored for a total of 12.5 h.

5.6.3 Absorption Studies

All spectra were collected in baseline correction mode using CH3CN as the reference scanning from 800 – 200 nm. Iodine (25.4 mg, 0.1 mmol) was dissolved in CH3CN and diluted to 10 mL to afford a stock solution of 10 mM. The working solution of iodine was prepared by diluting β0 δ stock up to 1 mδ with CH3CN to give a working solution of 0.2 mM. After the spectrum was collected, sodium iodide (15 mg, 0.1 mmol) was added to this solution. The spectrum was collected but its absorbance was far too intense. An aliquot of this solution (40 δ) was diluted with CH3CN up to 1 mL and the spectrum was collected. Sodium iodide (60 mg, 0.4 mmol) was dissolved in CH3CN (~1 mL). Copper(II) perchlorate was added (74 mg, 0.2 mmol) and then the solution was diluted with CH3CN up to 10 mL. After all components had reacted, the stock solution (15 δ) was diluted with CH3CN up to 5 mL and the spectrum collected.

168

5.6.4 Generation of Crystal Complexes

Crystal of 2. Crystals of 2 were inadvertently obtained from a concentrated NMR sample. Compound 2 (~25 mg) had been dissolved in hot acetonitrile (~1 mL) and the sample heated to 323 K within the spectrometer. Upon gradual cooling to room temperature (many h), crystals suitable for X-ray diffraction were obtained.

Crystal of Bu4NI3. n-Bu4NI (148 mg) and Cu(ClO4)2 were combined in MeOH (2 mL) and stirred for several min until reaction mixture was dark red-orange and a fine off- white precipitate had evolved (presumably CuI). This solution was filtered through a glass microfiber plug. Gradual evaporation of solvent gave dark red-black crystals that were suitable for X-ray diffraction.

Crystal of tetrakis(acetonitrile)copper(I) perchlorate. Azide 1 (0.4 mmol, 53.6 mg),

NaI (0.8 mmol, 120 mg) and Cu(ClO4)2 (0.4 mmol, 148 mg) were combined in acetonitrile (10 mL). After the solution turned dark red-orange, it was divided up into chambers for vapour diffusion with diethyl ether. Large, light yellow needle-like crystals were obtained overnight as well as small off-white clusters, and a fine green precipitate. The large needle crystals were suitable for X-ray diffraction and, upon solving the structure, turned out to be the known tetrakis(acetonitrile)copper(I) perchlorate complex.

5.6.5 Synthesis of 5-Iodo-1,4-disubstituted-1,2,3-triazoles

Assisting ligand free conditions: A freshly prepared stock of iodoacetylene (0.5 mmol) in THF (2 mL) was added to azide 1 (0.4 mmol, 53.7 mg). A catalytic amount of CuI (<2 mg) was added and the reaction stirred for 4 h. The reaction was diluted with DCM and flushed through a silica plug with DCM/EtOAc often yielding the pure compound. If necessary, the compound was purified on a silica column eluted with DCM/EtOAc.

169

General procedure for one-pot synthesis of 2: Azide 1 (26.8 mg, 0.2 mmol) was weighed in a 2 dram vial and dissolved with THF (1 mL). To that solution, NaI (120 mg,

0.8 mmol) and Cu(ClO4)2 (148 mg, 0.4 mmol) were added. This solution was allowed to stir for ~5 min before TEA (γ0 δ, 0.β mmol) and phenylacetylene (β5 δ, 0.βγ mmol) was added. This solution was allowed to stir at room temperature for 6 h. After this time, the contents of the vial were treated with a 10% NH4OH solution (100 mL) and saturated brine solution (25 mL). The organic components were extracted with EtOAc (3 x 50 mL) and DCM (1 x 50 mL) and dried with sodium sulphate. The solvent was removed via reduced pressure giving the crude product as a light yellow powder. The product was purified on a silica column eluted with DCM/EtOAc (or recrystallized from hot acetonitrile) as a white powder in 97% yield (70.3 mg).

5.6.6 Synthesis of 5-substituted-1,4-disubstituted-1,2,3-triazoles

Copper-free Sonogashira conditions.199 To a flame-dried round bottom and stir bar, dry THF (5 mL), 5-iodo-1,2,3-triazole 2 (0.2 mmol, 72.4 mg), alkyne (0.4 mmol),

(PPh3)2PdCl2 (0.02 mmol, 14 mg), and K2CO3 (0.3 mmol, 42 mg) were added. The reaction was heated to 70 °C for 12 h and then cooled to RT. The mixture was filtered through a silica plug (DCM/EtOAc). If the crude 1H NMR indicated product formation, attempts to purify the product on a silica column eluted with DCM/EtOAc failed to separate the product from the dehalogenated 1,2,3-traizole.

Sonogashira conditions. To a flame-dried round bottom and stir bar, dry THF (12 mL), 5-iodo-1,2,3-triazole 2 (0.4 mmol, 144.9 mg), DIPEA (1.2 mL), 4-ethynylanisole

(0.44 mmol, 60 δ), (PPh3)2PdCl2 (0.02 mmol, 14 mg), and CuI (0.02 mmol, 4 mg) were added. The reaction was heated to reflux for 6 h and then cooled to RT. The mixture was filtered through a silica plug (DCM/EtOAc). The pure product was obtained by purification on a silica column held at 5% EtOAc/DCM. The fractions containing the pure product were combined to give 23 in 43% yield (62.3 mg).

170

Suzuki conditions.199 To a flame-dried round bottom and stir bar, dry THF (3 mL) was added and bubbled with argon for 10 min. 5-iodo-1,2,3-triazole 2 (0.2 mmol, 72.4 mg), boronic acid (0.3 mmol), (PPh3)2PdCl2 (0.008 mmol, 6 mg), and KOH (0.4 mmol, 22.4 mg) were added to the reaction flask. The reaction was heated to 70 °C for 12 h and then cooled to RT. The mixture was filtered through a silica plug (DCM/EtOAc). The pure product was obtained by purification on a silica column eluted with increasing EtOAc in DCM. The fractions containing the pure product were combined to give 26 or 27.

5.6.7 Characterization of Compounds

1 Compound 2. H NMR (500 MHz, CD3CN)μ /ppm 8.5β (ddd, J = 4.8, 1.7, 0.9 Hz, 1H), 7.95-7.91 (m, 2H), 7.77 (td, J = 1.8, 7.7 Hz, 1H), 7.54-7.48 (m, 2H), 7.44 (tt , J = 1.6, 7.4, 1H), 7.33-7.29 (m, 1H), 7.18 (d, J = 7.8 Hz, 1H), 5.80 (s, 2H). 13C NMR (125 MHz,

CD3CN, γβγ K) /ppm 155.8, 151.1, 150.8, 138.4, 132.1, 129.8, 129.8, 128.6, 124.4, 123.1, 79.8, 56.7. HRMS (ESI-TOF) (m/z): [M+H]+ calcd 363.0107, found 363.0116.

Compound 4. Isolated as an off-white solid in 83% yield (65.0 mg). 1H NMR (500 MHz,

CD3CN, γγγ K)μ /ppm 8.5γ (d, J = 4.4 Hz, 1H), 7.87 (dt, J = 2.5, 9.0 Hz, 2H), 7.75 (td, J = 1.8, 7.7, 1 H), 7.29 (dd, J = 4.9, 7.6, 1H), 7.17 (d, J = 7.9 Hz, 1H), 7.05 (dt, J = 2.6, 13 8.9 Hz. 2H), 5.77 (s, 2H), 3.85 (s, 3H). C NMR (125 MHz, CD3CN, 333 K) /ppm 161.5, 156.0, 151.1, 150.8, 138.4, 130.1, 124.6, 124.4, 123.2, 115.4, 78.9, 56.8, 56.4. HRMS (ESI-TOF) (m/z): [M+H]+ calcd 393.0212, found 393.0219.

171

Compound 5. Isolated a light yellow solid in 74% yield (54.0 mg). 1H NMR (500 MHz,

CD3CN)μ /ppm 8.66 (bs, 1H), 8.5β (d, J = 4.9 Hz, 1H), 8.11 (bs, 1H), 7.87 (t, J = 7.6 Hz, 1H), 7.76 (td, J = 1.9, 7.7 Hz, 1H), 7.35 (bs, 1H), 7.32-7.27 (m, 1H), 7.18 (d, J = 7.92 Hz, 1H), 5.83 (s, 2H). 13C NMR (125 MHz, CD3CN, 323 K) /ppm 155.8, 151.γ, 150.8, 150.1, 149.6, 138.3, 138.0, 124.4, 124.3, 123.0, 122.7, 80.5, 56.5. HRMS (ESI- TOF) (m/z): [M+H]+ calcd 364.0059, found 364.0065.

Compound 6. Isolated as a yellow oil in 97% yield (66.1 mg). 1H NMR (500 MHz,

CD3CN, γβγ K)μ /ppm 8.5β (d, J = 3.8 Hz, 1H), 7.73 (td, J = 1.8, 7.7 Hz, 1H), 7.28 (dd, J = 5.0, 7.6 Hz, 1H), 7.07 (d, J = 7.9 Hz, 1H), 5.68 (s, 2H), 2.66 (t, J = 7.5 Hz, 2H), 1.71- 13 1.63 (m, 2H), 1.43-1.34 (m, 2H), 0.95 (t, J = 7.37 Hz, 3H). C NMR (125 MHz, CD3CN, γβγ K) /ppm 155.0, 15γ.β, 150.7, 1γ8.β, 1β4.β, 1ββ.λ, 80.λ, 56.4, γβ.0, β6.7, βγ.0, 14.2. HRMS (ESI-TOF) (m/z): [M+H]+ calcd 343.0420, found 343.0410.

Compound 7. Isolated as a beige solid in 73% yield (117.2 mg). 1H NMR (500 MHz,

CDCl3)μ /ppm 8.5λ (d, J = 4.8 Hz, 1H), 7.65 (td, J = 7.7, 1.8 Hz, 1H), 7.33-7.27 (m, 2H), 7.24 (dd, J = 7.8, 5.0 Hz, 1H), 7.04 (d, J = 8.0 Hz, 2H), 6.98 (t, J = 7.3 Hz, 1H), 13 6.93 (d, J = 7.9 Hz, 1H), 5.76 (s, 2H), 5.16 (s, 2H). C NMR (125 MHz, CDCl3) /ppm 158.4, 154.1, 149.8, 148.1, 137.4, 129.6, 123.4, 121.7, 121.5, 115.2, 81.7, 61.9, 55.8. HRMS (EI+) (m/z): [M]+ calcd 392.0134, found 392.0124.

172

Compound 8. Isolated as a pale yellow solid in 55% (76.2 mg). 1H NMR (500 MHz,

CDCl3)μ /ppm 8.56 (d, J = 4.8 Hz, 1H), 7.62 (td, J = 1.8, 7.8 Hz, 1H), 7.21 (dd, J = 5.0, 7.2 Hz, 1H), 6.85 (d, J = 7.9 Hz, 1H), 5.74 (s, 2H), 3.55 (s, 2H), 2.29 (s, 6H). 13C NMR

(125 MHz, CDCl3) /ppm 154.4, 149.7, 148.9, 137.2, 123.2, 121.4, 81.9, 55.6, 54.0, 45.2. HRMS (ESI-TOF) (m/z): [M+H]+ calcd 344.0372, found 344.0372.

Compound 9. Isolated as a white powder in 78% yield (49.2 mg). 1H NMR (500 MHz,

CD3CN, γβγK)μ /ppm 8.52 (d, J = 4.6 Hz, 1H), 7.75 (td, J = 1.8, 7.7 Hz, 1H), 7.30 (dd, J = 5.0, 7.7 Hz, 1H), 7.13 (d, J = 7.9 Hz, 1H), 5.71 (s, 2H), 4.60 (s, 2H). 13C NMR (125

MHz, CD3CN, γβγ K) /ppm 155.8, 15β.5, 150.7, 1γ8.γ, 1β4.4, 1βγ.1, 81.λ, 57.0, 56.4. HRMS (ESI-TOF) (m/z): [M+H]+ calcd 316.9899, found 316.9904.

Compound 10. Isolated as a white solid in 88% yield (60.4 mg). 1H NMR (500 MHz,

CD3CN, γβγ K)μ /ppm 8.5β (d, J = 4.6 Hz, 1H), 7.73 (td, J = 1.8, 7.7 Hz, 1H), 7.28 (dd, J = 5.0, 7.6 Hz, 1H), 7.04 (d, J = 7.9 Hz, 1H), 5.70 (s, 2H), 1.47 (s, 9H). 13C NMR (125

MHz, CD3CN, γβγ K) /ppm 158.1, 156.β, 150.7, 1γ8.γ, 1β4.β, 1ββ.λ, 76.7, 56.5, γβ.7, 30.2. HRMS (ESI-TOF) (m/z): [M+H]+ calcd 343.0420, found 343.0417.

173

Compound 11. Isolated as a dark blue/green solid in 84% (68.3 mg). 1H NMR (500

MHz, CDCl3)μ /ppm 8.61 (d, J = 3.8 H 1H), 7.88 (dt, J = 2.5, 9.0 Hz, 2H), 7.65 (td, J = 1.7, 7.3 Hz, 1H), 7.24 (dd, J = 5.2, 7.1, 1H), 6.93 (d, J = 7.8 Hz, 1H), 6.80 (dt, J = 2.4, 13 8.9 Hz, 2H), 5.81 (s, 2H), 3.01 (s, 6H). C NMR (125 MHz, CDCl3) /ppm 154.8, 150.8, 150.7, 149.8, 137.4, 128.4, 123.2, 121.6, 118.2, 112.2, 75.8, 55.9, 40.6. HRMS (ESI- TOF) (m/z): [M+H]+ calcd 406.0529, found 406.0517.

Compound 12. Isolated as a light yellow solid in 93% yield (75.8 mg). 1H NMR (500

MHz, CD3CN)μ /ppm 8.5γ (d, J = 4.5 Hz, 1H), 8.33 (dt, J = 2.3, 9.1 Hz, 2H), 8.25 (dt, J = 2.2, 9.1 Hz, 2H), 7.78 (td, J = 1.8, 7.7 Hz, 1H), 7.32 (dd, J = 5.2, 7.4 Hz, 1H), 7.24 (d, 13 J = 7.9 Hz, 1H), 5.83 (s, 2H). C NMR (125 MHz, CD3CN, γβγ K) /ppm 155.7, 151.0, 149.3, 149.2, 138.5, 138.5, 129.3, 125.2, 124.6, 123.4, 81.4, 57.0. HRMS (ESI-TOF) (m/z): [M+H]+ calcd 407.9957, found 407.9954.

Compound 13. Isolated as a white powder in 75% yield (54.3 mg). 1H NMR (500 MHz,

CD3CN)μ /ppm λ.14 (s, 1H), 8.61 (d, J = 4.2 Hz, 1H), 8.52 (d, J = 4.7 Hz, 1H), 8.27 (ddd, J = 7.9, 2.4, 1.6 Hz, 1H), 7.78 (td, J = 7.7, 1.8 Hz, 1H). 7.45 (ddd, J = 8.0, 4.9, 0.7 Hz, 1H) 7.33-7.29 (m, 1H), 7.22 (d, J = 7.9 Hz, 1H), 5.81 (s, 2H). 13C NMR (125 MHz,

CD3CN, γβγ K) /ppm 155.4, 150.6, 150.5, 14λ.1, 148.4, 1γ8.β, 1γ5.5, 1β7.8, 1β4.6, 124.3, 123.0, 80.9, 56.5. HRMS (ESI-TOF) (m/z): [M+H]+ calcd 364.0059, found 364.0056.

174

Compound 14. Isolated as an off-white solid in 53% (68.5 mg). 1H NMR (500 MHz,

CD3CN)μ /ppm 8.57-8.52 (m, 3H), 8.04 (dd, J = 1.8, 7.8 Hz, 2H), 7.77 (td, J = 1.8, 7.7 Hz, 2H), 7.65 (t, J = 7.9 Hz, 1H), 7.34-7.28 (m, 2H), 7.21 (d, J = 7.8 Hz, 2H), 5.82 (s, 13 4H). C NMR (125 MHz, CD3CN, γγγ K) /ppm 155.λ, 150.λ, 150.8, 1γ8.4, 1γβ.6, 130.4, 128.7, 127.2, 124.4, 123.2, 80.0, 56.9. HRMS (ESI-TOF) (m/z): [M+Na]+ calcd 668.9480, found 668.9473.

Compound 15.193 Isolated as a white solid in 93% yield (67.4 mg). 1H NMR (500 MHz,

CD3CN)μ /ppm 7.λ5-7.85 (m, 2H), 7.55-7.46 (m, 2H), 7.46-7.31 (m, 4H), 7.30-7.25 (m, 2H), 5.70 (s, 2H).

Compound 16.198 Isolated as a white solid at 93% yield (80.1 mg). 1H NMR (300 MHz,

CD3CN)μ /ppm 7.λ6-7.88 (m, 2H), 7.70-7.40 (m, 7H), 5.77 (s, 2H).

Compound 17. Isolated as an iridescent white solid in 70% yield (52.0 mg). 1H NMR

(500 MHz, CDCl3, γβγ K)μ /ppm 8.06-8.00 (m, 2H), 7.53-7.40 (m, 5H), 7.08 (dt, J = 2.9, 13 8.9 Hz, 2H), 3.92 (s, 3H). C NMR (125 MHz, CDCl3, γβ8 K) /ppm 161.γ, 150.4,

175

130.7, 130.5, 128.9, 128.8, 128.2, 128.0, 114.8, 78.4, 55.9. HRMS (ESI-TOF) (m/z): [M+H]+ calcd 378.0103, found 378.0114.

Compound 18.193 Isolated as a light yellow solid in 98% yield (76.7 mg). 1H NMR (500

MHz, CD3CN)μ /ppm 7.λβ-7.87 (m, 2H), 7.53-7.46 (m, 2H), 7.45-7.40 (m, 1H), 4.44 (t, J = 7.2 Hz, 2H), 1.96-1.86 (m, 2H), 1.40-1.22 (m, 10H), 4.44 (t, J = 7.2 Hz, 3H).

Compound 19. Isolated as a white powder in 58 % yield (45.5 mg). 1H NMR (500

MHz, CD3CN)μ /ppm 7.λ1-7.87 (m, 2H), 7.52-7.47 (m, 2H), 7.42 (tt, J = 7.4, 1.5 Hz, 1H), 7.30-7.24 (m, 2H), 6.95 (tt, J = 7.4, 1.0 Hz, 1H), 6.91-6.87 (m, 2H), 4.83 (t, J = 5.3 13 Hz, 2H), 4.50 (t, J = 5.3 Hz, 2H). C NMR (125 MHz, CD3CN, γβγ K) /ppm 15λ.4, 150.7, 132.0, 130.7, 129.8, 129.7, 128.7, 122.5, 115.9, 80.0, 67.4, 51.3. HRMS (EI+) (m/z): [M]+ calcd 391.0182, found 391.0174.

Compound 20. Isolated as a light brown solid in 65% yield (47.8 mg). 1H NMR (500

MHz, CD3CN)μ /ppm 7.λβ-7.88 (m, 2H), 7.52-7.47 (m, 2H), 7.43 (tt, J = 1.69, 7.39 Hz, 1H), 4.55 (t, J = 6.62 Hz, 2H), 2.97 (t, J = 6.60 Hz, 2H), 2.58-2.53 (m, 4H), 1.74-1.69 (m, 13 4H). C NMR (125 MHz, CD3CN, γβγ K) /ppm 150.5, 1γβ.β, 1βλ.8, 1β9.7, 128.6, 79.1, 56.1, 55.0, 51.2, 24.7. HRMS (ESI-TOF) (m/z): [M+H]+ calcd 369.0576, found 369.0573.

176

Compound 22. Isolated as an off-white solid in 69% yield (89.1 mg). 1H NMR (500

MHz, (CD3)2SO, γγγ K)μ /ppm 7.λ0-7.82 (m, 5H), 7.50-7.35 (m, 6H), 7.19 (d, J = 7.72 13 Hz, 2H), 5.79 (s, 4H). C NMR (125 MHz, (CD3)2SO, γγγ K) /ppm 154.β, 148.5, 138.0, 130.4, 128.1, 127.8, 126.7, 120.7, 81.4, 54.4. HRMS (EI+) (m/z): [M]+ calcd 644.9635, found 644.9630.

Compound 23. Isolated as a yellow oil in 76% yield (39.0 mg). 1H NMR (500 MHz,

CD3CN)μ /ppm 8.50 (d, J = 4.3 Hz, 1H), 7.73 (td, J = 7.8, 1.8 Hz, 1H), 7.28 (dd, J = 7.8, 5.1 Hz, 1H), 7.13 (d, J = 7.9 Hz, 1H), 5.75-5.65 (m, 1H), 5.2 (s, 2H), 4.97 (dq, J = 10.2, 1.6 Hz, 1H), 4.86 (dq, J = 17.2, 1.6 Hz, 1H), 3.39 (dt, J = 6.0, 1.7 Hz, 2H) 2.57 (t, J = 7.6 Hz, 2H), 1.60-1.52 (m, 2H), 1.36-1.27 (m, 2H), 0.89 (t, J = 7.3 Hz, 3H). 13C NMR (125

MHz, CD3CN) /ppm 156.1, 150.6, 146.6, 1γ8.4, 1γ4.β, 132.4, 124.2, 123.2, 117.4, 53.8, 32.6, 27.2, 25.3, 23.1, 14.2. HRMS (EI+) (m/z): [M]+ calcd 257.1766, found 257.1763.

Compound 25. Isolated as a white solid in 43% yield (62.3 mg). 1H NMR (500 MHz,

CDCl3)μ /ppm 8.65 (bs, 1H), 8.24-8.19 (m, 2H), 7.68 (t, J = 7.7 Hz, 1H), 7.50-7.44 (m, 2H), 7.43-7.35 (m, 3H), 7.26 (bs, 1H), 7.09 (bs, 1H), 6.90 (d, J = 8.8 Hz, 2H), 5.86 (bs, 13 2H), 3.84 (s, 3H). C NMR (125 MHz, CDCl3) /ppm 160.λ, 1γ7.4, 1γγ.5, 1γ0.5, 1β8.λ,

177

128.8, 126.4, 118.4, 114.4, 113.5, 103.3, 74.4, 55.6. HRMS (ESI-TOF) (m/z): [M+H]+ calcd 357.1559, found 367.1555.

Compound 26. Isolated as a yellow oil in 86% yield (50.4 mg). 1H NMR (500 MHz,

CD3CN, γ1γK)μ /ppm 8.44 (bs, 1H), 7.64 (td, J = 7.7, 1.6 Hz, 1H), 7.45-7.40 (m, 3H), 7.33-7.28 (m, 2H), 7.21 (dd, J = 7.1, 5.0 Hz, 1H), 6.97 (d, J = 7.7 Hz, 1H), 5.50 (s, 2H), 2.62 (t, J = 7.6 Hz, 2H), 1.59 (qn, J =7.5 Hz, 2H), 1.29 (sx, J = 7.4 Hz, 2H), 0.83 (t, J = 13 7.4 Hz, 3H). C NMR (125 MHz, CDCl3, γ1γ K) /ppm. 155.λ, 14λ.6, 146.β, 1γ7.0, 135.1, 129.8, 129.4, 129.0, 127.6, 122.9, 121.6, 53.6, 31.8, 25.0, 22.5, 13.9. HRMS (EI+) (m/z): [M]+ calcd 292.1688, found 292.1683.

Compound 27. Isolated as a brown oil in 91% yield (57.8 mg). 1H NMR (500 MHz,

CD3CN, γ1γK)μ /ppm 8.45 (d, J = 4.8 Hz, 1H), 7.65 (t, J = 7.7 Hz, 1H), 7.21 (dd, J = 7.5, 5.1 Hz, 1H), 7.02-6.97 (m, 2H), 6.94 (d, J = 7.9 Hz, 1H), 6.68-6.63 (m, 2H), 5.47 (s, 2H), 4.37 (bs, 2H), 2.59 (t, J = 7.7 Hz, 2H), 1.59 (qn, J = 7.6 Hz, 2H), 1.30 (sx, J = 7.4 13 Hz, 2H), 0.85 (t, J = 7.5 Hz, 3H). C NMR (125 MHz, CD3CN, γ1γ K) /ppm. 157.1, 150.4, 150.1, 146.0, 138.0, 136.5, 131.7, 123.9, 122.7, 116.4, 115.4, 54.0, 32.6, 25.7, 23.1, 14.2. HRMS (EI+) (m/z): [M]+ calcd 307.1797, found 307.1796.

178

5.6.8 1H and 13C NMR Spectra

1 Figure 5.19 500 MHz H NMR Spectrum of compound 2 in CD3CN.

13 Figure 5.20 125 MHz C NMR Spectrum of compound 2 in CD3CN.

179

1 Figure 5.21 500 MHz H NMR Spectrum of compound 4 in CD3CN.

13 Figure 5.22 125 MHz C NMR Spectrum of compound 4 in CD3CN.

180

1 Figure 5.23 500 MHz H NMR Spectrum of compound 5 in CD3CN.

13 Figure 5.24 125 MHz C NMR Spectrum of compound 5 in CD3CN.

181

1 Figure 5.25 500 MHz H NMR Spectrum of compound 6 in CD3CN.

13 Figure 5.26 125 MHz C NMR Spectrum of compound 6 in CD3CN.

182

1 Figure 5.27 500 MHz H NMR Spectrum of compound 7 in CDCl3.

13 Figure 5.28 125 MHz C NMR Spectrum of compound 7 in CDCl3.

183

1 Figure 5.29 500 MHz H NMR Spectrum of compound 8 in CDCl3.

13 Figure 5.30 125 MHz C NMR Spectrum of compound 8 in CDCl3.

184

1 Figure 5.31 500 MHz H NMR Spectrum of compound 9 in CD3CN.

13 Figure 5.32 125 MHz C NMR Spectrum of compound 9 in CD3CN.

185

1 Figure 5.33 500 MHz H NMR Spectrum of compound 10 in CD3CN.

13 Figure 5.34 125 MHz C NMR Spectrum of compound 10 in CD3CN.

186

1 Figure 5.35 500 MHz H NMR Spectrum of compound 11 in CDCl3.

13 Figure 5.36 125 MHz C NMR Spectrum of compound 11 in CDCl3.

187

1 Figure 5.37 500 MHz H NMR Spectrum of compound 12 in CD3CN.

13 Figure 5.38 125 MHz C NMR Spectrum of compound 12 in CD3CN.

188

1 Figure 5.39 500 MHz H NMR Spectrum of compound 13 in CD3CN.

13 Figure 5.40 125 MHz C NMR Spectrum of compound 13 in CD3CN.

189

1 Figure 5.41 500 MHz H NMR Spectrum of compound 14 in CD3CN.

13 Figure 5.42 125 MHz C NMR Spectrum of compound 14 in CD3CN.

190

1 Figure 5.43 500 MHz H NMR Spectrum of compound 17 in CDCl3.

13 Figure 5.44 125 MHz C NMR Spectrum of compound 17 in CDCl3.

191

1 Figure 5.45 500 MHz H NMR Spectrum of compound 19 in CD3CN.

13 Figure 5.46 125 MHz C NMR Spectrum of compound 19 in CD3CN.

192

1 Figure 5.47 500 MHz H NMR Spectrum of compound 20 in CD3CN.

13 Figure 5.48 125 MHz C NMR Spectrum of compound 20 in CD3CN.

193

1 Figure 5.49 500 MHz H NMR Spectrum of compound 22 in (CD3)2SO.

13 Figure 5.50 125 MHz C NMR Spectrum of compound 22 in (CD3)2SO.

194

1 Figure 5.51 500 MHz H NMR Spectrum of compound 23 in CD3CN.

13 Figure 5.52 125 MHz C NMR Spectrum of compound 23 in CD3CN. 195

1 Figure 5.53 500 MHz H NMR Spectrum of compound 25 in CDCl3.

13 Figure 5.54 125 MHz C NMR Spectrum of compound 25 in CDCl3.

196

1 Figure 5.55 500 MHz H NMR Spectrum of compound 26 in CDCl3.

13 Figure 5.56 125 MHz C NMR Spectrum of compound 26 in CDCl3.

197

1 Figure 5.57 500 MHz H NMR Spectrum of compound 27 in CD3CN.

13 Figure 5.58 125 MHz C NMR Spectrum of compound 27 in CD3CN.

198

REFERENCES

1. Voet, D.; Voet, J. G., Biochemsitry. 3rd ed.; John Wiley & Sons, Inc.: 2004; Vol. 1.

2. Kolb, H. C.; Finn, M. G.; Sharpless, K. B., Click Chemistry: Diverse Chemical Function from a Few Good Reactions. Angew. Chem., Int. Ed. 2001, 40, 2004- 2021.

3. Ball, P., The click concept. Chem. World 2007, 4, 46-51.

4. Huisgen, R., 1,3-Dipolar Cycloadditions Past and Future. Angew. Chem., Int. Ed. 1963, 2, (10), 565-632.

5. Tornoe, C. W.; Christensen, C.; Meldal, M., Peptidotriazoles on Solid Phase: [1,2,3]-Triazoles by Regiospecific Copper(I)-Catalyzed 1,3-Dipolar Cycloaddition of Terminal Alkynes to Azides. J. Org. Chem. 2002, 67, 3057-3064.

6. Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B., A Stepwise Huisgen Cycloaddition Process: Copper(I)-Catalyzed Regioselective "Ligation" of Azides and Terminal Alkynes. Angew. Chem. Int. Ed. 2002, 41, (14), 2596-2599.

7. Alonso, G.; Garcia-δopez, ε. T.; Garcıa-Munoz, G.; Madronero, R.; Rico, M., Heterocyclic N-glycosides. The reaction of flycosyl azides with propiolic acid and methyl propiolate. J. Heterocycl. Chem. 1970, 7, 1269-1272.

8. Himo, F.; Lovell, T.; Hilgraf, R.; Rostovtsev, V. V.; Noodleman, L.; Sharpless, K. B.; Fokin, V. V., Copper(I)-Catalyzed Synthesis of Azoles. DFT Study Predicts Unprecedented Reactivity and Intermediates. J. Am. Chem. Soc. 2005, 127, 210- 216.

9. Rodionov, V. O.; Fokin, V. V.; Finn, M. G., Mechanism of the Ligand-Free Cu(I)- Catalyzed Azide-Alkyne Cycloaddition Reaction. Angew. Chem., Int. Ed. 2005, 44, 2210-2215.

10. Buckley, B. R.; Dann, S. E.; Heaney, H., Experimental Evidence for the Involvement of Dinuclear Alkynylcopper(I) Complexes in Alkyne-Azide Chemistry. Chem. Eur. J. 2010, 16, 6278-6284.

199

11. Hein, J. E.; Fokin, V. V., Copper-catalyzed azide-alkyne cycloaddition (CuAAC) and beyond: new reactivity of copper(I) acetylides. Chem. Soc. Rev. 2010, 39, 1302-1315.

12. Wu, P.; Fokin, V. V., Catalytic Azide-Alkyne Cycloaddition: Reactivity and Applications. Aldrchim ACTA 2007, 40, 7-17.

13. Chan, T. R.; Hilgraf, R.; Sharpless, K. B.; Fokin, V. V., Polytriazoles as Copper(I)- Stabilizing Ligands in Catalysis. Org. Lett. 2004, 6, 2853-2855.

14. Michaels, H. A.; Zhu, L., N,N,N-Tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine (TBTA). In Encyclopedia of Reagents for Organic Synthesis [Online], John Wiley & Sons Ltd.: 2011.

15. Meldal, M.; Tornoe, C. W., Cu-Catalyzed Azide-Alkyne Cycloaddition. Chem. Rev. 2008, 108, 2952-3015.

16. Moses, J. E.; Moorhouse, A. D., The Growing Applications of Click Chemistry. Chem. Soc. Rev. 2007, 36, 1249-1262.

17. Tornoe, C. W.; Sanderson, S. J.; Mottram, J. C.; Coombs, G. H.; Meldal, M., Combinatorial Library of Peptidotriazoles: Identification of [1,2,3]-Triazole Inhibitors against a Recombinant Leishmania mexicana Cysteine Protease. J. Comb. Chem 2004, 6, 312-324.

18. Brik, A.; Muldoon, J.; Lin, Y. C.; Elder, J. H.; Goodsell, D. S.; Olson, A. J.; Fokin, V. V.; Sharpless, K. B.; Wong, C. H., Rapid diversity-oriented synthesis in microtiter plates for in situ screening of HIV protease inhibitors. ChemBioChem 2003, 4, 1246-1248.

19. Brik, A.; Alexandratos, J.; Lin, Y. C.; Elder, J. H.; Olson, A. J.; Wlodawer, A.; Goodsell, D. S.; Wong, C. H., 1,2,3-triazole as a peptide surrogate in the rapid synthesis of HIV-1 protease inhibitors. ChemBioChem 2005, 6, 1167-1169.

20. Wang, J.; Uttamchandani, M.; Li, J.; Hu, M.; Yao, S. Q., Rapid Assembly of Matrix Metalloprotease Inhibitors Using Click Chemistry. Org. Lett. 2006, 8, 3821- 3824.

21. Srinivasan, R.; Uttamchandani, M.; Yao, S. Q., Rapid Assembly and in Situ Screening of Bidentate Inhibitors of Protein Tyrosine Phosphatases. Org. Lett. 2006, 8, 713-716.

200

22. Lee, L. V.; Mitchell, M. L.; Huang, S. J.; Fokin, V. V.; Sharpless, K. B.; Wong, C. H., A Potent and Highly Selective Inhibitor of Human α-1,3-Fucosyltransferase via Click Chemistry. J. Am. Chem. Soc. 2003, 125, 9588.

23. Tron, G. C.; Pilrali, T.; Billington, R. A.; Canonico, P. L.; Sorba, G.; Genazzani, A. A., Click Chemistry Reactions in Medicinal Chemistry: Applications of the 1,3- dipolar Cycloaddition Between Azides and Alkynes. Med. Res. Rev. 2008, 28, (2), 278-308.

24. Best, M. D., Click Chemistry and Bioorthogonal Reactions: Unprecedented Selectivity in the Labeling of Biological Molecules. Biochemistry 2009, 48, (28), 6571-6584.

25. Kolb, H. C.; Sharpless, K. B., The growing impact of click chemistry on drug discovery. Drug Discovery Today 2003, 8, 1128-1137.

26. Krishenbaum, K.; Carrico, I. S.; Tirrell, D. A., Biosynthesis of proteins incorporating a versatile set of phenylalanine analogs. ChemBioChem 2002, 3, 235-237.

27. Link, A. J.; Vink, M. K. S.; Agard, N. J.; Prescher, J. A.; Bertozzi, C. R.; Tirrell, D. A., Discovery of aminoacy-tRNA synthetase activity through cell surface display of noncanonical amino acids. Proc. Natl. Acad. Sci. USA 2006, 103, 10180- 10185.

28. Wang, Q.; Chan, T. R.; Hilgraf, R.; Fokin, V. V.; Sharpless, K. B.; Finn, M. G., Bioconjugation by Copper(I)-Catalyzed Azide-Alkyne [3+2] Cycloaddition. J. Am. Chem. Soc. 2003, 125, 3192-3193.

29. Bruckman, M. A.; Kaur, G.; Lee, L. A.; Xie, F.; Sepulveda, J.; Breitenkamp, R.; Zhang, X.; Joralemon, M.; Russell, T. P.; Emrick, T.; Wang, Q., Surface Modification of Tobacco Mosaic Virus with "Click" Chemistry. ChemBioChem 2008, 9, 519-523.

30. Luchansky, S. J.; Argade, S.; Hayes, B. K.; Bertozzi, C. R., Metabolic functionalization of recombinant glycoproteins. Biochemistry 2004, 43, 12358- 12366.

31. Hsu, T. L.; Hanson, S. R.; Kishikawa, K.; Wang, S. K.; Sawa, M.; Wong, C. H., Alkynyl sugar analogs for the labeling and visualization of glycoconjugates in cells. Proc. Natl. Acad. Sci. USA 2007, 104, 2614-2619.

201

32. Chang, P. V.; X., C.; Smyrniotis, C.; Xenakis, A.; Hu, T.; Bertozzi, C. R.; Wu, P., Metabolic labeling of sialic acids in living animals with alkynyl sugars. Angew. Chem. Int. Ed. 2009, 48, 4030-4033.

33. Hanson, S. R.; Greenberg, W. A.; Wong, C. H., Probing glycans with the copper(I)-catalyzed [3+2] azide-alkyne cycloaddition. QSAR Comb. Sci. 2007, 26, 1243-1252.

34. Gierlich, J.; Burley, G. A.; Gramlich, P. M. E.; Hammond, D. M.; Carrell, T., Click chemistry as a reliable method for the high-density postsynthetic functionalization of alkyne-modified DNA. Org. Lett. 2006, 8, 3639-3642.

35. Salic, A.; Mitchison, T. J., A chemical method for fast and sensitive detection of DNA synthesis in vivo. Proc. Natl. Acad. Sci. USA 2008, 105, 2415-2420.

36. Jao, C. Y.; Salic, A., Exploring RNA transcription and turnover in vivo by using click chemistry. Proc. Natl. Acad. Sci. USA 2008, 105, 15779-15784.

37. Neef, A. B.; Schultz, C., Selective fluorescence labeling of lipids in living cells. Angew. Chem. Int. Ed. 2009, 48, 1498-1500.

38. Best, M. D.; Rowland, M. M.; Bostic, H. E., Exploiting Bioorthogonal Chemistry to Elucidate Protein-Lipid Binding Interactions and Other Biological Roles of Phospholipids. Acc. Chem. Res. 2011, 44, 686-698.

39. Smith, M. D.; Sudhahar, C. G.; Gong, D.; Stahelin, R. V.; Best, M. D., Modular synthesis of biologically active phosphatidic acid probes using click chemistry. Mol. BioSyst. 2009, 5, 962-972.

40. Speer, A. E.; Adam, G. C.; Cravatt, B. F., Activity-based protein profiling in vivo using a copper(I)-catalyzed azide-alkyne 3+2 cycloaddition. J. Am. Chem. Soc. 2003, 125, 4686-4687.

41. Cravatt, B. F.; Wright, A. T.; Kozarich, J. W., Activity-based protein profiling: From enzyme chemistry. Annu. Rev. BioChem 2008, 77, 383-414.

42. Salisbury, C. M.; Cravatt, B. F., Click chemistry-led advances in high content functional proteomics. QSAR Comb. Sci. 2007, 26, 1229-1238.

43. Wu, P.; Feldman, A. K.; Nugent, A. K.; Hawker, C. J.; Scheel, A.; Voit, B.; Pyun, J.; Frechet, J. M. J.; Sharpless, K. B.; Fokin, V. V., Efficiency and Fidelity in a Click-Chemistry Route to Triazole Dendrimers by the Copper(I)-Catalyzed Ligation of Azides and Alkynes. Angew. Chem. Int. Ed. 2004, 43, 3928-3932.

202

44. Evans, R. A., The Rise of Azide-Alkyne 1,3-Dipolar 'Click' Cycloaddition and its Application to Polymer Science and Surface Modification. Aust. J. Chem. 2007, 60, 384-395.

45. Binder, W. H.; Sachsenhofer, R., 'Click' Chemistry in Polymer and Materials Science. Macromol. Rapid Commun. 2007, 28, 15-54.

46. Lundberg, E. P.; Plesa, C.; Wilhelmsson, L. M.; Lincoln, P.; Brown, T.; Norden, B., Nanofabrication Yields. Hybridization and Click-Fixation of Polycyclic DNA Nanoassemblies. ACS Nano 2011, 7565-7575.

47. Qing, G.; Xiong, H.; Seela, F.; Sun, T., Spatially Controlled DNA Nanopatterns by "Click" Chemistry Using Oligonucleotides with Different Anchoring Sites. J. Am. Chem. Soc. 132, (43), 15228-15232.

48. Voigt, N. V.; Torring, T.; Rotaru, A.; Jacobsen, M. F.; Ravnsbaek, J. B.; Subramani, R.; Mamdouh, W.; Kjems, J.; Mokhir, A.; Besenbacher, F.; Gothelf, K. V., Single-molecule chemical reactions on DNA origami. Nat Nano 2010, 5, (3), 200-203.

49. El-Sagheer, A. H.; Brown, T., Click chemistry with DNA. Chem. Soc. Rev. 2010, 39, (4), 1388-1405.

50. Algar, W. R.; Prasuhn, D. E.; Stewart, M. H.; Jennings, T. L.; Blanco-Canosa, J. B.; Dawson, P. E.; Medintz, I. L., The Controlled Display of Biomolecules on Nanoparticles: A Challenge Suited to Bioorthogonal Chemistry. Bioconjugate Chem. 2011, 22, 825-858.

51. Perrier, T.; Saulnier, P.; Benoît, J.-P., Methods for the Functionalization of Nanoparticles: New Insights and Perspectives. Chem. Eur. J. 2010, 16, (38), 11516-11529.

52. Li, H.; Cheng, F.; Duft, A. M.; Adronov, A., Functionalization of Single-Walled Carbon Nanotubes with Well-Defined Polystyrene by "Click" Coupling. J. Am. Chem. Soc. 2005, 127, 14518-14524.

53. Fahrenbach, A. C.; Stoddart, J. F., Reactions under the Click Chemistry Philosophy Employed in Supramolecular and Mechanostereochemical Systems. Chem. Asian. J. 2001.

54. Savonnet, M.; Kockrick, E.; Camarata, A.; Bazer-Bachi, D.; Bats, N.; Lecocq, V.; Pinel, C.; Farrusseng, D., Combinatorial synthesis of metal-organic frameworks libraries by click-chemistry. New J. Chem. 2011, 35, (9), 1892-1897.

203

55. Goto, Y.; Sato, H.; Shinkai, S.; Sada, K., "Clickable" Metal-Organic Framework. J. Am. Chem. Soc. 2008, 130, (44), 14354-14355.

56. Gadzikwa, T.; Farha, O. K.; Malliakas, C. D.; Kanatzidis, M. G.; Hupp, J. T.; Nguyen, S. T., Selective Bifunctional Modification of a Non-catenated Metal- Organic Framework Material via "Click" Chemistry. J. Am. Chem. Soc. 2009, 131, (38), 13613-13615.

57. Gassensmith, J. J.; Erne, P. M.; Paxton, W. F.; Valente, C.; Stoddart, J. F., Microcontact Click Printing for Templating Ultrathin Films of Metal-Organic Frameworks. Langmuir 2011, 27, (4), 1341-1345.

58. Hua, Y.; Flood, A. H., Click chemistry generates privileged CH hydrogen-bonding triazoles: the latest addition to anion supramolecular chemistry. Chem. Soc. Rev. 2010, 39, (4), 1262-1271.

59. Zahran, E. M.; Hua, Y.; Lee, S.; Flood, A. H.; Bachas, L. G., Ion-Selective Electrodes Based on a Pyridyl-Containing Triazolophane: Altering Halide Selectivity by Combining Dipole-Promoted Cooperativity with Hydrogen Bonding. Anal. Chem. 2010, 83, (9), 3455-3461.

60. Aucagne, V.; Berna, J.; Crowley, J. D.; Goldup, S. M.; Hanni, K. D.; Leigh, D. A.; Lusby, P. J.; Ronaldson, V. E.; Slawin, A. M. Z.; Viterisi, A.; Walker, D. B., Catalytic "Active-Metal" Template Synthesis of [2]Rotaxanes, [3]Rotaxanes, and Molecular Shuttles, and Some Observations on the Mechanism of the Cu(I)- Catalyzed Azide-Alkyne 1,3-Cycloaddition. J. Am. Chem. Soc. 2007, 129, (39), 11950-11963.

61. Crowley, J. D.; Goldup, S. M.; Lee, A. L.; Leigh, D. A.; McBurney, R. T., Active Metal Template Synthesis of Rotaxanes, Catenanes and Molecular Shuttles. Chem. Soc. Rev. 2009, 38, 1530-1541.

62. Zheng, H.; Zhou, W.; Lv, J.; Yin, X.; Li, Y.; Liu, H.; Li, Y., A Dual-Response [2]Rotaxane Based on a 1,2,3-Triazole Ring as a Novel Recognition Station. Chem. Eur. J. 2009, 15, (47), 13253-13262.

63. Hanni, K. D.; Leigh, D. A., The application of CuAAC 'click' chemistry to catenane and rotaxane synthesis. Chem. Soc. Rev. 2010, 39, (4), 1240-1251.

64. Mindt, T. L.; Struthers, H.; Brans, L.; Anguelov, T.; Schweinsberg, C.; Maes, V.; Tourwe, D.; Schibli, R., "Click to Chelate": Synthesis and Installation of Metal Chelates into Biomolecules in a Single Step. J. Am. Chem. Soc. 2006, 128, 15096-15097.

204

65. Dijkgraaf, I.; Rijnders, A. Y.; Soede, A.; Dechesne, A. C.; van Esse, G. W.; Brouwer, A. J.; Corstens, F. H. M.; Boerman, O. C.; Rijkers, D. T. S.; Liskamp, R. M. J., Synthesis of DOTA-conjugated multivalent cyclic-RGD peptide dendrimers via 1,3-dipolar cycloaddition and their biological evaluation: implications for tumor targeting and tumor imaging purposes. Org. Biomol. Chem. 2007, 5, 935-944.

66. Bryson, J. M.; Chu, W.-J.; Lee, J. H.; Reineke, T. M., A b-Cyclodextrin “click cluster” decorated with seven paramagnetic chelates containing two water exchange sites. Bioconjugate Chem 2008, 19, 1505-1509.

67. Casas-Solvas, J. M.; Vargas-Berenguel, A.; Capitain-Vallvey, L. F.; Santoyo- Gonzalez, F., Convenient Methods for the Synthesis of Ferrocene-Carbohydrate Conjugates. Org. Lett. 2004, 6, 3687-3690.

68. Viguier, R. F. H.; Hulme, A. N., A sensitized Europium Complex Generated by Micromolar Concentrations of Copper(I): Toward the Detection of Copper(I) in Biology. J. Am. Chem. Soc. 2006, 128, 11370-11371.

69. Yim, C.-B.; Dijkgraaf, I.; Merkx, R.; Versluis, C.; Eek, A.; Mulder, G. E.; Rijkers, D. T. S.; Boerman, O. C.; Liskamp, R. M. J., Synthesis of DOTA-Conjugated Multimeric [Tyr3]Octreotide Peptides via a Combination of Cu(I)-Catalyzed "Click" Cycloaddition and Thio Acid/Sulfonyl Azide "Sulfo-Click" Amidation and Their in Vivo Evaluation. J. Med. Chem. 2010, 53, (10), 3944-3953.

70. Liu, D.; Gao, W.; Dai, Q.; Zhang, X., Triazole-Based Monophosphines for Suzuki- Miyaura Coupling and Amination Reactions of Aryl Chlorides. Org. Lett. 2005, 7, 4907-4910.

71. Struthers, H.; Mindt, T. L.; Schibli, R., Metal chelating systems synthesized using the copper(I) catalyzed azide-alkyne cycloaddition. Dalton Trans. 2010, 39, 675- 696.

72. Sekler, I.; Sensi, S. L.; Hershfinkel, M.; Silverman, W. F., Mechanism and Regulation of Cellular Zinc Transport. Mol. Med. 2007, 13, 337-343.

73. Frederickson, C. J.; Koh, J.-Y.; Bush, A. I., The neurobiology of zinc in health and disease. Nat. Rev. Neurosci. 2005, 6, (6), 449-462.

74. Hambridge, M., Human Zinc Deficiency. J. Nutr. 2000, 130, 13445-13495.

75. Maret, W.; Sandstead, H. H., Zinc requirements and the risks and benefits of zinc supplementation. J. Trace. Elem. Med. Biol. 2006, 20, 3-18.

205

76. MacDonald, R. S., The role of zinc in growth and cell proliferation. J. Nutr. 2000, 130, 15005-15085.

77. Cherny, R. A.; Atwood, C. S.; Zilinas, M. E.; Gray, D. N.; Jones, W. D.; McLean, C. A.; Barnham, K. J.; Volitakis, I.; Fraser, F. W.; Kim, Y.; Huang, X.; Goldstein, L. E.; Moir, R. D.; Lim, J. T.; Beyreuther, K.; Zheng, H.; Tranzi, R. E.; Masters, C. L.; Bush, A. I., Treatment with a copper-zinc chelator markedly and rapidly inhibits beta-amyloid accumulation in Alzheimer's disease transgenic mice. Neuron 2001, 30, 641-642.

78. Richard B, T., Studying zinc biology with fluorescence: ain't we got fun? Curr. Opin. Chem. Biol. 2005, 9, (5), 526-532.

79. Huang, S. H.; Clark, R. J.; Zhu, L., Highly Sensitive Fluorescent Probes for Zinc Ion Based on Triazolyl-Containing Tetradentate Coordination Motifs. Org. Lett. 2007, 9, 4999-5002.

80. Wang, Q.; Chan, T. R.; Hilgraf, R.; Fokin, V. V.; Sharpless, K. B., Bioconjugation by Copper(I)-Catalyzed Azide-Alkyne [3+2] Cycloaddition. J. Am. Chem. Soc. 2003, 125, 1392-3193.

81. Hong, V.; Presolski, S. I.; Ma, C.; Finn, M. G., Analysis and Optimization of Copper-Catalyzed Azide-Alkyne Cycloaddition for Bioconjugation. Angew. Chem. Int. Ed. 2009, 48, 9879-9883.

82. Levengood, M. R.; Kerwood, C. C.; Chatterjee, C.; van der Donk, W. A., Investigation of the Substrate Specificity of Lacticin 481 Synthetase by Using Nonproteinogenic Amino Acids. ChemBioChem 2009, 10, 911-919.

83. Nagaraj, R. H.; Sell, D. R.; Prabhakaram, M.; Ortwerth, B. J.; Monnier, V. M., High Correlation between pentosidine protein crosslinks and pigmentation implicates ascorbate oxidation in human lens senescence and cataractogenesis. Proc. Natl. Acad. Sci. USA 1991, 88, 10257-10261.

84. Appukkuttan, P.; Dehaen, W.; Fokin, V. V.; Van der Eycken, E., A Microwave- Assisted Click Chemistry Synthesis of 1,4-Disubstituted 1,2,3-Triazoles via a Copper(I)-Catalyzed Three-Component Reaction. Org. Lett. 2004, 6, 4223-4225.

85. Molteni, G.; Bianchi, C. L.; Marinoni, G.; Santo, N.; Ponti, A., Cu/Cu-oxide nanoparticles as catalyst in the "click" azide-alkyne cycloaddition. New. J. Chem. 2006, 30, 1137-1139.

206

86. Orgueira, H. A.; Fokas, D.; Isome, Y.; Chan, P. C.-M.; Baldino, C. M., Regioselective synthesis of [1,2,3]-triazoles catalysed by Cu(I) generated in situ from Cu(0) nanosize activated powder and amine hydrochloride salts. Tet. Lett. 2005, 46, 2911-2914.

87. Moorhouse, A. D.; Moses, J. E., Microwave Enhancement of a 'One-Pot' Tandem Azidation-'Click' Cycloaddition of Anilines. Synlett 2008, 2089-2092.

88. Cravotto, G.; Fokin, V. V.; Garella, D.; Binello, A.; Boffa, L.; Barge, A., Ultrasound-Promoted Copper-Catalyzed Azide-Alkyne Cycloaddition. J. Comb. Chem 2010, 12, 13-15.

89. Deiters, A.; Schultz, P. G., In vivo incorporation of an alkyne into proteins in Escherichia coli. Bioorg. Med. Chem. Lett. 2005, 15, 1521-1524.

90. Bonnet, D.; Ilien, B.; Galzi, J.-L.; Riche, S.; Antheaune, C.; Hibert, M., A rapid and Versatile Method to Label Receptor Ligands Using "Click" Chemistry: Validation with the Muscarinic M1 Antagonist Pirenzepine. Bioconjugate Chem 2006, 17, 1618-1623.

91. Pachon, L. D.; van Maarseveen, J. H.; Rothenberg, G., Click Chemistry: Copper Clusters Catalyse the Cycloaddition of Azides with Terminal Alkynes. Adv. Synth. Catal. 2005, 347, 811-815.

92. Girard, C.; Onen, E.; Aufort, M.; Beauviere, S.; Samson, E.; Herscovici, J., Reusable Polymer-Supported Catalyst for the [3+2] Huisgen Cycloaddition in Automation Protocols. Org. Lett. 2006, 8, 1689-1692.

93. Chtchigrovsky, M.; Primo, A.; Gonzalez, P.; Molvinger, K.; Robitzer, M.; Quignard, F.; Taran, F., Functionalized Chitosan as Green, Recyclable, Biopolymer-Supported Catalyst for the [3+2] Huisgen Cycloaddition. Angew. Chem. Int. Ed. 2009, 48, 5916-5920.

94. Lipshutz, B. H.; Taft, B. R., Heterogeneous Copper-in-Charcoal-Catalyzed Click Chemistry. Angew. Chem. Int. Ed. 2006, 45, 8235-8238.

95. Chassaing, S.; Kumarraja, M.; Sido, A. S. S.; Pale, P.; Sommer, J., Click Chemistry in Cu(I)-zeolites: The Huisgen [3+2]-Cycloaddition. Org. Lett. 2007, 9, 883-886.

96. Bogdan, A. R.; Sach, N. W., The Use of Copper Flow Reactor Technology for the Continuous Synthesis of 1,4-Disubstituted 1,2,3-Triazoles. Adv. Synth. Catal. 2009, 351, 849-854.

207

97. Bogdan, A. R.; James, K., Synthesis of 5-Iodo-1,2,3-triazole-Containing Macrocycles Using Copper Flow Reactor Technology. Org. Lett. 2011, 13, (15), 4060-4063.

98. Reddy, K. R.; Rajgopal, K.; Kantam, M. L., Copper(II)-Promoted Regioselective Synthesis of 1,4-Disubstituted 1,2,3-Triazoles in Water. Synlett 2006, 957-959.

99. Reddy, K. R.; Rajgopal, K.; Kantam, M. L., Copper-alginates: a biopolymer supported Cu(II) catalyst for 1,3-dipolar cycloaddition of alkynes with azides and oxidative coupling of 2-naphthols and phenols in water. Catal. Lett. 2007, 114, 36-40.

100. Fukuzawa, S.-I.; Shimizu, E.; Kikuchi, S., Copper(II) Triflate as a Double catalyst for the One-Pot Click Synthesis of 1,4-Disubstituted 1,2,3-Triazoles from Benzylic Acetates. Synlett 2007, 15, 2436-2438.

101. Kirai, N.; Yamamoto, Y., Homocoupling of Arylboronic Acids Catalysed by 1,10- Phenanthrolin-Ligated Copper Complexes in Air. Eur. J. Org. Chem. 2009, 1864- 1867.

102. Siemsen, P.; Livingston, R. C.; Diederich, F., Acetylenic Coupling: A Powerful Tool in Molecular Construction. Angew. Chem., Int. Ed. 2000, 39, 2632-2657.

103. Eglinton, G.; Galbraith, A. R., Cyclic diynes. Chem. Ind. 1956, 737-738.

104. Straub, B. F., m-Acetylide and m-alkenylidene ligands in "click" triazole syntheses. Chem. Commun. 2007, 3868-3870.

105. Nolte, C.; Mayer, P.; Straub, B. F., Isolation of a Copper(I) Triazolide: A "Click" Intermediate. Angew. Chem., Int. Ed. 2007, 46, (2101-2103).

106. Ahlquist, M.; Fokin, V. V., Enhanced Reactivity of Dinuclear Copper(I) Acetylides in Dipolar Cycloadditions. Organometallics 2007, 26, 4380-4391.

107. Kitagawa, S.; Munakata, M.; Higashie, A., Autoreduction of copper(II) complexes of 6.6'-diakyl-2,2'-bipyridine and characterization of their copper(I) complexes. Inorg. Chim. Acta. 1984, 84, 79-84.

108. Musker, W. K.; Olmstead, M. M.; Kessler, R. M., Influence of ligand structure on the mechanism of oxidation of dithioethers by copper(II). X-ray crystal structure of bis(2-hydroxy-1,5-dithiacyclooctane)copper(II) perchlorate. Inorg. Chem. 1984, 23, 1764-1768.

208

109. Benzekri, A.; Cartier, C.; Latour, J.-M.; Limosin, D.; Rey, P.; Verdaguer, M., Structural and electrochemical studies of dicopper complexes of a binucleating ligand involving sulfides and benzimidazoles. Inorg. Chim. Acta. 1996, 252, 413- 420.

110. Malachowski, M. R.; Adams, M.; Elia, N.; Rheingold, A. L.; Kelly, R. S., Enforcing geometrical constraints on metal complexes using biphenyl-base ligands: spontaneous reduction of copper(II) by sulfur-containing ligands. J. Chem. Soc., Dalton Trans. 1999, 2177-2182.

111. Sarkar, S.; Patra, A.; Drew, M. G.; Zangrando, E.; Chattopadhyay, P., Copper(II) complexes of tetradentate N2S2 donor sets: Synthesis, crystal structure characterization and reactivity. Polyhedron 2009, 28, 1-6.

112. Urankar, D.; Kosmrlj, J., Concise and Diversity-Oriented Synthesis of Ligand Arm-Functionalized Azoamides. J. Comb. Chem 2008, 10, 981-985.

113. Brotherton, W. S.; Michaels, H. A.; Simmons, J. T.; Clark, R. J.; Dalal, N. S.; Zhu, L., Apparent Copper(II)-Accelerated Azide-Alkyne Cycloaddition. Org. Lett. 2009, 11, 4954-4957.

114. Sharrock, P.; Melnik, M., Copper(II) acetates: from dimer to monomer. Can. J. Chem. 1985, 63, 52-56.

115. Nakasuka, N.; Azuma, K.; Tanaka, M., Complex formation of copper(II) acetate with pyridine bases in anhydrous acetic acid. Inorg. Chem. Acta. 1995, 238, 83- 87.

116. Szpakowska, M.; Uruska, I., Solvent effect on u.v.-vis and EPR spectra and on the relative stability of mononulear and binuclear complexes of Cu(II) acetate with pyridine derivatives. Spectrochim. Acta A 1987, 43A, 763-769.

117. Likhtenshtein, G. I.; Yamauchi, J.; Nakatsuji, S.; Smirnov, A. I.; Tamura, R., Nitroxides: applications in chemistry, biomedicine and materials. Wiley-VCH: Weinheim, 2008.

118. Ritschel, J.; Sasse, F.; Maier, M. E., Synthesis of a Benzolactone Collection using Click Chemsitry. Eur. J. Org. Chem. 2007, 78-87.

119. Zhang, L.; Chen, X.; Xue, P.; Sun, H. H.; Williams, I. D.; Sharpless, K. B.; Fokin, V. V.; Jia, G., Ruthenium-catalyzed cycloaddition of alkynes and organic azides. J. Am. Chem. Soc. 2005, 127, 15998-15999.

209

120. Park, I. S.; Kwon, M. S.; Kim, Y.; Lee, J. S.; Park, J., Heterogeneous Copper Catalyst for the Cycloaddition of Azides and Alkynes without Additives under Ambient Conditions. Org. Lett. 2008, 10, 497-500.

121. Dias, H. V.; Polach, S. A.; Goh, S.-K.; Archibong, E. F.; Marynick, D. S., Copper and Silver Complexes Containing Organic Azide Ligands: Syntheses, Structures, and Theoretical Investigation of [HB(3,5-(CF3)2Pz)3CuNNN(1-Ad) and [HB(3,5- (CF3)2Pz)3AgN(1-Ad)NN (where Pz = pyrazolyl, and 1-Ad = 1-adamantyl). Inorg. Chem. 2000, 39, 3894-3901.

122. Kuang, G.-C.; Michaels, H. A.; Simmons, J. T.; Clark, R. J.; Zhu, L., Chelation- Assisted, Copper(II)-Acetate-Accelerated Azide-Alkyne Cycloaddition. J. Org. Chem. 2010, 75, 6540-6548.

123. Kamata, K.; Nakagawa, Y.; Yamaguchi, K.; Mizuno, N., 1,3-Dipolar Cycloaddition of Organic Azides to Alkynes by a Dicopper-Substituted Silicotungstate. J. Am. Chem. Soc. 2008, 130, (46), 15304-15310.

124. Buckley, B. R.; Dann, S. E.; Harris, D. P.; Heaney, H.; Stubbs, E. C., Alkynylcopper(I) polymers and their use in a mechanistic study of alkyne-azide click reactions. Chem. Commun. 2010, 46, 2274-2276.

125. Kratochvil, B.; Zatko, D. A.; Markuszewski, R., Copper(II) as an Analytical Oxidant in Acetonitrile. Anal. Chem. 1966, 38, (6), 770-772.

126. Blackmond, D. G.; Rosner, T.; Plfaltz, A., Comprehensive kinetic screening of catalysts using reaction calorimetry. Org. Process Res. Dev. 1999, 3, 275-280.

127. Rodionov, V. O.; Presolski, S. I.; Daz, D.; Fokin, V. V.; Finn, M. G., Ligand- Accelerated Cu-Catalyzed Azide-Alkyne Cycloaddition: A Mechanistic Report. J. Am. Chem. Soc. 2007, 129, (42), 12705-12712.

128. Nolte, C.; Mayer, P.; Straub, B., Isolation of a Copper(I) Triazolide: A "Click" Intermediate. Angew. Chem. Int. Ed. 2007, 46, 2101-2103.

129. Presolski, S. I.; Hong, V.; Cho, S.-H.; Finn, M. G., Tailored Ligand Acceleration of the Cu-Catalyzed Azide-Alkyne Cycloaddition Reaction: Practical and Mechanistic Implications. J. Am. Chem. Soc. 2010, 132, (41), 14570-14576.

130. Kuang, G.-C.; Guha, P. M.; Brotherton, W. S.; Simmons, J. T.; Stankee, L. A.; Nguyen, B. T.; Clark, R. J.; Zhu, L., Experimental Investigation on the Mechanism of Chelation-Assisted, Copper(II) Acetate-Accelerated Azide-Alkyne Cycloaddition. J. Am. Chem. Soc. 2011, 133, 13984-14001.

210

131. Bohlmann, F.; Schonowsky, H.; Inhoffen, E.; Grau, G., Polyacetylenverbindungen, LII. Über den Mechanismus der oxydativen Dimerisierung von Acetylenverbindungen. Chem. Ber. 1964, 97, 794-800.

132. Collman, J. P.; Devaraj, N. K.; Chidsey, C. E. D., Clicking Functioinality onto Electrode Surfaces. Langmuir 2004, 20, 1051-1053.

133. Bock, V. D.; Hiemstra, H.; van Maarseveen, J. H., Cu(I)-Catalyzed Alkyne-Azide "Click" Cycloadditions from a Mechanistic and Synthetic Perspective. Eur. J. Org. Chem. 2006, 51-68.

134. Rosner, T.; Pfaltz, A.; Blackmond, D. G., Observation of Unusual Kinetics in Heck Reactions of Aryl Halides: The Role of Non-Steady-State Catalyst Concentration. J. Am. Chem. Soc. 2001, 123, 4621-4622.

135. Simonov, Y. A.; Matuzenko, G. S.; Botoshanskii, M. N.; Yampol'skaya, M. A., Crystal and molecular structure of a square cluster of tetrakis[-methoxo-- acetato(O,O')copper(II)]. Doklady Akademii Nauk SSSR 1980, 250, 99-102.

136. Gerbeleu, N. V.; Indrichan, K. M.; Yampol'skaya, M. A.; Matuzenko, G. S., Mass spectrometric study of copper(II) methoxo carboxylato complexes. Koordinats Kim 1986, 12, 1056-1059.

137. Wu, L. P.; Kuroda-Sowa, T.; Maekawa, M.; Suenaga, Y.; Munakata, M., An unusual tetranuclear copper(II) acetate structure with an open cubane Cu4O4 framework. J. Chem. Soc., Dalton Trans. 1996, 2179-2180.

138. Andrew, J. E.; Blake, A. B.; Fraser, L. R., Magnetic properties of polynuclear complexes. Part III. Alkoxo-bridged complexes of copper(II). J. Chem. Soc., Dalton Trans. 1976, 477-480.

139. Koval, I. A.; Gamez, P.; Roubeau, O.; Driessen, W. L.; Lutz, M.; Spek, A. L.; Reedjik, J., Century-known copper calt Cu(OAc)(OMe) proven to be a unique magnetic lattice composed of tetranuclear copper(II) species with a rare binding mode of the acetate anion. Inorg. Chem. 2003, 42, (3), 868-872.

140. Chui, S. S. Y.; Ng, M. F. Y.; Che, C.-M., Structure Determination of Homoleptic Au(I), Ag(I) and Cu(I) Coordination Polymers by X-ray Powder Diffraction. Chem. Eur. J. 2005, 11, 1739-1749.

141. Olbrich, F.; Kopf, J.; Weiss, E., Novel Alkynylcopper(I) Complexes and Lithium Alkynyl Cuprates. Angew. Chem. Int. Ed. 1993, 32, 1077-1079.

211

142. Baxter, C. W.; Higgs, T. C.; Bailey, P. J.; Parsons, S.; McLachlan, F.; McPartlin, M.; Tasker, P. A., Copper(I) Alkynyl Clusters, [Cux+y(hfac)x(C[TRIPLE BOND]CR)y], with Cu(10)–Cu(12) Cores. Chem. Eur. J. 2006, 12, 6166-6174.

143. Fu, Y.; Li, H.; Chen, X.; Qin, J., A linear Cu(II) coordination polymer based on a simple click chelator. Inorg. Chem. Commun. 2011, 14, (1), 268-270.

144. Chevry, A.; Teyssot, M.-L.; Maisonial, A.; Lemoine, P.; Voiossat, B.; Traikia, M.; Aitken, D. J.; Alves, G.; Morel, L.; Nauton, L.; Gautier, A., Click Chelators - The Behavior of Platinum and Palladium Complexes in the Presence of Guanosine and DNA. Eur. J. Inorg. Chem. 2010, 2010, 3513-3519.

145. Maisonial, A.; Serafin, P.; Traikia, M.; Debiton, E.; Thery, V.; Aitken, D. J.; Lemoine, P.; Viossat, B.; Gautier, A., Click Chelators for Platinum-Based Anticancer Drugs. Eur. J. Inorg. Chem. 2008, 2008, (2), 298-305.

146. Crowley, J. D.; Bandeen, P. H.; Hanton, L. R., A one pot multi-component CuAAC "click" approach to bidentate and tridentate pyridyl-1,2,3-triazole ligands: Synthesis, X-ray structures and copper(II) and silver(II) complexes. Polyhedron 2010, 29, 70-83.

147. Fu, Y.; Liu, Y.; Fu, X.; Zou, L.; Li, H.; Li, M.; Chen, X.; Qin, J., Synthesis of Click- Chelator via Cu(I)-Catalyzed Alkyne-Azide Cycloaddition. Chin. J. Chem. 2010, 28, (11), 2226-2232.

148. Teyssot, M.-L.; Nauton, L.; Canet, J.-L.; Cisnetti, F.; Chevry, A.; Gautier, A., Aromatic Nitrogen Donors for Efficient Copper(I)-NHC CuAAC under Reductant- Free Conditions. Eur. J. Org. Chem. 2010, 2010, 3507-3515.

149. Meudtner, R. M.; Ostermeier, M.; Goddard, R.; Limberg, C.; Hecht, S., Multifunctional "Clickates" as Versatile Extended Heteroaromatic Building Blocks: Efficient Synthesis via Click Chemistry, Conformational Preferences, and Metal Coordination. Chem. Eur. J. 2007, 13, 9834-9840.

150. Tamanini, E.; Flavin, K.; Motevalli, M.; Piperno, S.; Gheber, L. A.; Todd, M. H.; Watkinson, M. W., Cyclam-Based "Clickates": Homogeneous and Heterogeneous Fluorescent Sensors for Zn(II). Inorg. Chem. 2010, 49, 3789- 3800.

151. Li, Y.; Flood, A. H., Strong, Size-Selective, and Electronically Tunable C-H Halide Binding with Steric Control over Aggregation from Synthetically Modular, Shape- Persisten [34]Triazolophanes. J. Am. Chem. Soc. 2008, 130, 12111-12122.

212

152. Aromi, G.; Barrios, L. A.; Roubeau, O.; Gamez, P., Triazoles and tetrazoles: Prime ligands to generate remarkable coordination materials. Coord. Chem. Rev. 2011, 255, 485-546.

153. Moore, D. S.; Robinson, S. D., Catenated Nitrogen Ligands Part II. Transition Metal Derivatives of Triazoles, Tetrazoles, Pentazoles, and Hexazine. In Advances in Inorganic Chemistry, Sykes, A. G., Ed. London, 1988; Vol. 32.

154. Rachwal, S.; Kratritzky, A. R., 1,2,3-Triazoles. In Comprehensive Heterocyclic Chemistry III, Katritzky, A. R.; Ramsden, C. A.; Scriven, E. F. V.; Taylor, R. J. K., Eds. Elsevier: Oxford, 2008; Vol. 5, pp 1-158.

155. Donnelly, P. S.; Zanatta, S. D.; Zammit, S. C.; White, J. M.; Williams, S. J., 'Click' cycloaddition catalysts: copper(I) and copper(II) tris(triazolylmethyl)amine. Chem. Commun. 2008, 2459-2461.

156. Crowley, J. D.; Bandeen, P. H., A multicomponent CuAAC "click" approach to a library of hybrid polydentate 2-pyridyl-1,2,3-triazole ligands: new building blocks for the generation of metallosupramolecular architectures. Dalton Trans. 2010, 39, 612-623.

157. Bratsos, I.; Urankar, D.; Zangrando, E.; Genova-Kalou, P.; Kosmrlj, J.; Alessio, E.; Turel, I., 1-(2-Picolyl)-substituted 1,2,3-triazole as novel chelating ligand for the preparation of ruthenium complexes with potential anticancer activity. Dalton Trans. 2011, 40, 5188-5199.

158. Urankar, D.; Pevec, A.; Turel, I.; Kosmrlj, J., Pyridyl Conjugated 1,2,3-Triazole is a Versatile Coordination Ability Ligand Enabling Supramolecular Associations. Cryst. Growth Des. 2010, 10, 4920-2927.

159. Urankar, D.; Pinter, B.; Pevec, A.; De Proft, F.; Turel, I.; Kosmrlj, J., Click- Triazole N2 Coordination to Transition-Metal Ion Assisted by a Pendant Pyridine Substituent. Inorg. Chem. 2010, 49, 4820-4829.

160. Mukherjee, R., Coordination chemistry with pyrazole-based chelating ligands: molecular structural aspects. Coord. Chem. Rev. 2000, 203, 151-218.

161. El Ghomari, M. J.; Mokhlisse, R.; Laurence, C.; Le Questel, J.-Y.; Berthelot, M., Basicity of Azoles: Complexes of Diiodine with Imidazoles, Pyrazoles and Triazoles. J. Phy. Org. Chem. 1997, 10, 669-674.

213

162. Li, Y.; Huffman, J. C.; Flood, A. H., Can Terdentate 2,6-Bis(1,2,3-triazol-4- yl)pyridines form Stable Coordination Compounds? Chem. Commun. 2007, 2692-2694.

163. Lal, T. K.; Mukherjee, R. N., New Cobalt(II) and Nickel(II) Complexes with 2- (pyrazole-1-ylmethyl)pyridine. Stereochemical variations in Cobalt(II) Complexes and X-ray Crystal Structure of Bis[2-(pyrazol-1-ylmethyl)pyridine]dichloro- cobalt(II) Tetrahydrate. Polyhedron 1997, 16, 3577-3583.

164. Lal, T. K.; Gupta, R.; Mahpatra, S.; Mukherjee, R. N., Synthesis, Spectra and Redox Properties of Mononuclear Five-Coordinate Copper(II) Complexes with Non-Communicable Pyrazole/Pyridyl Containing Ligands. X-ray Structure of [2,6- bis(3,5-dimethylpyrazol-1-ylmethyl)pyridine][2-(3,5-dimethylpyrazol-1- ylmethyl)pyridine]-copper(II) Perchlorate. Polyhedron 1999, 18, 1743-1750.

165. Bai, S.-Q.; Gao, E.-Q.; He, Z.; Fang, C.-J.; Yan, C.-H., Crystal structures and magnetic behavior of three new azido-bridged dinuclear cobalt(II) and copper(II) complexes New J. Chem. 2005, 29, 935-941.

166. Manikandan, P.; Thomas, K. R. J.; Manoharan, P. T., Structural and spectral diversities in copper(n) complexes of 2,6-bis(3,5-dimethylpyrazol-l- ylmethyl)pyridine. J. Chem. Soc., Dalton Trans. 2000, 2779-2785.

167. Brotherton, W. S.; Guha, P. M.; Phan, H.; Clark, R. J.; Shatruk, M.; Zhu, L., Tridentate complexes of 2,6-bis(4-substituted-1,2,3-triazol-1-ylmethyl)pyridine and its organic azide precursors: an application of the copper(II) acetate- accelerated azide–alkyne cycloaddition. Dalton Trans. 2011, 40, 3655-3665.

168. Glusker, J. P.; Lewis, M.; Rossi, M., Crystal Structure Analysis for Chemists and Biologists. Wiley VCH: New York, 1994.

169. Bastero, A.; Font, D.; Pericas, M. A., Assessing the Suitability of 1,2,3-Triazole Linkers for Covalent Immobilization of Chiral Ligands: Application to Enantioselective Phenylation of Aldehydes. J. Org. Chem. 2007, 72, 2460-2468.

170. House, D. A.; Steel, P. J.; Watson, A. A., Synthesis and metal complexes of 2,6- bis(pyrazol-1-ylmehtyl)pyridine and chiral derivatives. Inorg. Chim. Acta. 1987, 130, 167-176.

171. Mahapatra, S.; Butcher, R. J.; Mukherjee, R. N., Observation of the longest Fe- II 1 N(pyridine)bond in an Fe N6 Chromophore. Crystal Structure and H Nuclear Magnetic Resonance Studies of [FeL2][ClO4]2 [L = 2-(3,5-dimethylpyrazole-1- ylmethyl)-6-(pyrazol-1-ylmethyl)pyridine]. J. Chem. Soc., Dalton Trans. 1993, 3723-3726.

214

172. Mahapatra, S.; Gupta, N.; Mukherjee, R. N., Consequences of Incremental Steric II Crowding at the Fe N6 (S=2) Coordination Sphere. Synthesis, Spectra, and Electrochemistry. J. Chem. Soc., Dalton Trans. 1991, 2911-2915.

173. Oliver, J. D.; Mullica, D. F.; Hutchinson, B. B.; Milligan, W. O., Iron-nitrogen bond lengths in low-spin and high-spin iron(II) complexes with poly(pyrazolyl)borate ligands. Inorg. Chem. 1980, 19, 165-169.

174. Crowley, J. D.; Gavey, E. L., Use of di-1,4-substituted-1,2,3-triazole "click" ligands to self-assemble dipalladium(II) coordinatively saturated, quadruply stranded heliccate cages. Dalton Trans. 2010, 39, 4035-4037.

175. Prodi, A.; Chiorboli, C.; Scandola, F.; Iengo, E.; Alessio, E.; Dobrawa, R.; Wurthner, F., Wavelength-Dependent Electron and Energy Transfer Pathways in a Side-to-Face Ruthenium Porphryin/Perylene Bisimide Assembly. J. Am. Chem. Soc. 2005, 127, 1454-1462.

176. Michaels, H. A.; Murphy, C. S.; Clark, R. J.; Davidson, M. W.; Zhu, L., 2- Anthryltriazolyl-Containing Multidentate Ligands: Zinc-Coordination Mediated Photophysical Processes and Potential in Live-Cell Imaging Applications. Inorg. Chem. 2010, 49, 6540-6548.

177. Lawrance, G. A., Introduction to Coordination Chemistry. Wiley: Chichester, 2010.

178. Mackay, K. M.; Mackay, R. A.; Henderson, W., Introduction to modern inorganic chemistry. 6th ed.; CRC Press: 2002.

179. Muetterties, E. L.; Guggenberger, L. J., Idealized Polytopal Forms. Description of Real Molecules Referenced to Idealized Polygons or Polyhedra in Geometric Reaction Path Form. J. Am. Chem. Soc. 1974, 96, 1748-1756.

180. Addison, A. W.; Rao, T. N.; Reedijk, J.; van Rijn, J.; Verschoor, G. C., Synthesis, structure, and spectroscopic properties of copper(II) compounds containing nitrogen–sulphur donor ligands; the crystal and molecular structure of aqua[1,7- bis(N-methylbenzimidazol-β′-yl)-2,6-dithiaheptane]copper(II) perchlorate J. Chem. Soc., Dalton Trans. 1984, 1349-1356.

181. Holmes, R. R.; Deiters, J. A., Structural Distortions of Cyclic Phosphoranes and the Berry Exchange Coordinate. A Quantitative Description. J. Am. Chem. Soc. 1977, 99, 3318-3326.

215

182. Bassindale, A. R.; Sohail, M.; Taylor, P. G.; Koryukov, A.; Arkhipov, D. E., Four independent structures of a pentacoordinate silicon species at different points on the Berry pseudorotation pathway. Chem. Commun. 2010, 46, 3274-3276.

183. Reinen, D.; Friebel, C., Cu in 5-coordination: a case of a second-order Jahn- Teller effect. 2. CuCl and other CuL complexes: trigonal bipyramid or square pyramid? Inorg. Chem. 1984, 23, 791-798.

184. Barz, M.; Herdtweck, E.; Thiel, W. R., Transition Metal Complexes with Organoazide Ligands: Synthesis, Structural Chemistry, and Reactivity. Angew. Chem. Int. Ed. 1998, 37, 2262-2265.

185. Cenini, S.; Gallo, E.; Caselli, A.; Ragaini, F.; Fantauzzi, S.; Piangiolino, C., Coordination chemistry of organic azide and amination reactions catalyzed by transition metal complexes. Coord. Chem. Rev. 2006, 250, 1234-1253.

186. Rodriguez, M.; Llobet, A.; Corbella, M.; Martell, A. E.; Reibenspies, J., Synthesis, Structure, and Magnetic Properties of New Chloro-Bridged Dimer [Cu2(dpt)2Cl2] with an Unusual Structure and Ferromagnetic Coupling. Inorg. Chem. 1999, 38, 2328-2334.

187. Burger, K.-S.; Chaudhuri, P.; Wieghardt, K., Exchange Coupling in Symmetrically syn,syn-Mono(carboxylato)-Bridged Dinuclear Copper(II) Complexes. Inorg. Chem. 1996, 35, 2704-2707.

188. Zhang, X.-R.; Xu, M.-H.; Li, X.-M.; Zhang, S. S., Ethyl 2-(4-phenyl-1H-1,2,3- triazol-1-yl)acetate. Acta Cryst. 2006, E62, o3278-o3279.

189. Chesterton, A. K. S.; Jenkinson, S. F.; Jones, N. A.; Fleet, G. W.; Watkin, D. J., (2S, 4S)-4-Azido-1-benzyl-2-[(S)-2,2-dimethyl-1,3-dioxolan-4-yl]pyrrolidine. Acta Cryst. 2006, E62, o2983-o2985.

190. Manbeck, G. F.; Brennessel, W. W.; Evans, C. M.; Eisenberg, R., Tetranuclear Copper(I) Iodide Complexes of Chelating Bis(1-benzyl-1H-1,2,3-triazole) Ligands: Structural Characterization and Solid State Photoluminescence. Inorg. Chem. 2010, 49, 2834-2843.

191. Bock, V. D.; Perciaccante, R.; Jansen, T. P.; Hiemstra, H.; van Maarseveen, J. H., Click Chemistry as a Route to Cyclic Tetrapeptide Analogues: Synthesis of cyclo-[Pro-Val-Ïˆ(triazole)-Pro-Tyr]. Organic Letters 2006, 8, (5), 919-922.

216

192. Spiteri, C.; Moses, J. E., Copper-Catalyzed Azide-Alkyne Cycloaddition: regioselective Synthesis of 1,4,5-Trisubstituted 1,2,3-Triazoles. Angew. Chem. Int. Ed. 2010, 49, 31-33.

193. Wu, Y.-M.; Deng, J.; Li, Y.; Chen, Q.-Y., Regiospecific Synthesis of 1,4,5- Trisubstituted-1,2,3-triazole via One-Pot Reaction Promoted by Copper(I) Salt. Synthesis 2005, 1314-1318.

194. Kuijpers, B. H. M.; Dijkmans, G. C. T.; Groothuys, S.; Quaedflieg, P. J. L. M.; Blaauq, R. H.; van Delft, F. L.; Rutjes, F. P. J. T., Copper(I)-Mediated Synthesis of Trisubstituted 1,2,3-Triazoles. Synlett 2005, 3059-3062.

195. Gerard, B.; Ryan, J.; Beeler, A. B.; Porco Jr., J. A., Synthesis of 1,4,5- trisubstituted-1,2,3-triazoles by copper-catalyzed cycloaddition-coupling of azides and terminal alkynes. Tetrahedron 2006, 62, 6405-6411.

196. Zhang, X.; Hsung, R. P.; Li, H., A Triazole-templated ring-closing metathesis for constructing novel fused and bridged triazoles. Chem. Commun. 2007, 2420- 2422.

197. Li, L.; Zhang, G.; Zhu, A.; Zhang, L., A convenient Preparation of 5-Iodo-1,4- disubstituted-1,2,3-triazole: Multicomponent One-Pot Reaction of Azide and Alkyne Mediated by CuI-NBS. J. Org. Chem. 2008, 73, 3630-3633.

198. Hein, J. E.; Tripp, J. C.; Krasnova, L. B.; Sharpless, K. B.; Fokin, V. V., Copper(I)-Catalyzed Cycloaddition of Organic Azides and 1-Iodoalkynes. Angew. Chem. Int. Ed. 2009, 48, 8018-8021.

199. Deng, J.; Wu, Y.-M.; Chen, Q.-Y., Cross-Coupling Reaction of Iodo-1,2,3- triazoles Catalyzed by Palladium. Synthesis 2005, 16, 2730-2738.

200. Bogdan, A. R.; James, K., Efficient Access to New Chemical Space Through Flow-Construction of Druglike Macrocycles Through Copper-Surface-Catalyzed Azide-Alkyne Cycloaddition Reactions. Chem. Eur. J. 2010, 16, 14506-14512.

201. Nath, M.; Pink, M.; Zaleski, J. M., Controlling Both Ground- and Excited-State Thermal Barriers to Bergman Cyclization with Alkyne Termini Substitution. J. Am. Chem. Soc. 2005, 127, 478-479.

202. Bowles, D. M.; Anthony, J. E., A Reiterative Approach to 2,3-Disubstituted Napthalenes and Anthracenes. Org. Lett. 2000, 2, 85-87.

217

203. Wu, J.; Pisula, W.; Mullen, K., Graphenes as Potential Material for Electronics. Chem. Rev. 2007, 107, (3), 718-747.

204. Otero, G.; Biddau, G.; Sanchez-Sanchez, C.; Caillard, R.; Lopez, M. F.; Rogero, C.; Palomares, F. J.; Cabello, N.; Basanta, M. A.; Ortega, J.; Mendez, J.; Echavarren, A. M.; Perez, R.; Gomez-Lor, B.; Martin-Gago, J. A., Fullerenes from aromatic precursors by surface-catalysed cyclodehydrogenation. Nature 2008, 454, (7206), 865-868.

205. Luo, F.-T.; Jeevanandam, A.; Basu, M. K., Efficient and high turnover homocoupling reaction of aryl iodide by the use of palladacycle catalyst. A convenient way to prepare poly-p-phenylene. Tet. Lett. 1998, 39, (43), 7939- 7942.

206. Armatore, C.; Blart, E.; Genet, J. P.; Jutand, A.; Lemaire-Audoire, S.; Savignac, M., New Synthetic Applications of Water-Soluble Acetate Pd/TPPTS Catalyst generated in Situ. Evidence for a True Pd(0) Species Intermediate. J. Org. Chem. 1995, 60, 6829-6839.

207. Kauffman, G. B.; Pinnell, R. P., Copper(I) Iodide. Inorg. Synth. 1960, 6, 3-6.

208. Diaz-Torres, R.; Alvarez, S., Coordinating ability of anions and solvents towards transition metals and lanthanides. Dalton Trans. 2011, 40, 10742-10750.

209. Tsarevsky, N. V.; Braunecker, W. A.; Matyjaszewski, K., Electron transfer reactions relevant to atom transfer radical polymerization. J. Organomet. Chem. 2007, 692, 3212-3222.

210. Juricek, M.; Stout, K.; Kouwer, P. H. J.; Rowan, A. E., Fusing Triazoles: Toward Extending Aromaticity. Org. Lett. 2011, 13, (13), 3494-3497.

211. Metrangolo, P.; Resnati, G.; Pilati, T.; Biella, S.; Metrangolo, P.; Resnati, G., Halogen Bonding in Crystal Engineering Halogen Bonding. In Springer Berlin / Heidelberg: 2008; Vol. 126, pp 105-136.

212. Li, D.; Yin, K.; Li, J.; Jia, X., CuI/iodine-mediated homocoupling reaction of terminal alkynes to 1,3-diynes. Tetrahedron Lett. 2008, 49, 5918-5919.

213. Csoregh, I.; Kierkegaard, P.; Norrestam, R., Copper(I) tetraacetonitrile perchlorate. Acta Cryst. 1975, B31, 314-317.

214. Izutsu, K., Electrochemistry in Nonaqueous Solutions. 2nd ed.; Wiley: Weinheim, 2009.

218

215. Kubas, G. J.; Monzyk, B.; Crumbliss, A. L., Tetrakis(acetonitrile)Copper(1+) Hexafluorophosphate(1-). In Reagents for transition metal complex and organometallic syntheses, Angelici, R. J., Ed. Wiley: New York, 1990; Vol. 28.

216. Nishiyama, Y.; Terazima, M.; Kimura, Y., Photo-dissociation and recombination of triiodide in room temperature ionic liquids. Chem. Phys. Lett. 2010, 491, 164- 168.

217. Wei, Y.-J.; Liu, C.-g.; Mo, L.-P., Ultraviolet Absorption Spectra of Iodine, Iodide Ion and Triiodide Ion. Spectrosc. Spec. Anal. 2005, 25, 86-88.

218. Lyon, E. J.; Musie, G.; Reibenspies, J. H.; Darensbourg, M. Y., Sulfure Site Iodine Adduct of a Nickel Thiolate Complex. Inorg. Chem. 1998, 37, 6942-6946.

219. Ufimtsev, A. V.; Soroka, N. V.; Bagiyan, G. A., Tunneling Transfer of an Electron - - in Oxidation of the HS ion by and I3 Complex in Aqueous Solution. Bull. Russ. Acad. Sci. 1992, 41, 522-536.

220. Reiller, P.; Mercier-Bion, F.; Gimenez, N.; Barre, N.; Miserque, F., Iodination of humic acid samples from different origins. Radiochim. Acta 2006, 94, 739-745.

221. Herbstein, F. H.; Kaftory, M.; Kapon, M.; Saenger, W., Crystal structures of polyiodide salts and molecular complexes. Part III. Structures of three crystals containing approximately linear chains of triiodide ions. Tetra(n-butyl)ammonium triiodide, bis(benzamide) hydrogen triiodide, caffeine monohydrate hydrogen triiodide. Z. Kristallogr. 1981, 154, 11-30.

222. Lapworth, A., The action of halogens on compounds containing the carbonyl group. J. Chem. Soc. 1904, 85, 30-42.

223. Hu, B.; Baird, J. K., Reaction Kinetics and Critical Phenomena: Iodination of Acetone in Isobutyric Acid + Water near the Consolute Point. J. Phys. Chem. A 2010, 114, 355-359.

224. Baudoin, O.; Herrbach, A.; Gueritte, F., The Palladium-Catalyzed C-H Activation of Benzylic gem-Dialkyl Groups. Angew. Chem. Int. Ed. 2003, 42, (46), 5736- 5740.

225. Molander, G. A.; Yun, C.-S.; Ribogorda, M.; Biolatto, B., B-Alkyl Suzuki-Miyaura Cross-Coupling Reactions with Air-Stable Potassium Alkyltrifluoroborates. J. Org. Chem. 2003, 68, (14), 5534-5539.

219

226. Andersen, N. G.; Keay, B. A., 2-Furyl Phosphines as Ligands for Transition- Metal-Mediated Organic Synthesis. Chem. Rev. 2001, 101, 997-1030.

227. Kesharwani, T.; Larock, R. C., Benzylic C-H activation and C-O bond formation via aryl to benzylic 1,4-palladium migrations. Tetrahedron 2008, 64, (26), 6090- 6102.

228. Luithle, J. E. A.; Pietuszka, J., Synthesis of Enantiomerically Pure cis- Cyclopropylboronic Esters. Eur. J. Org. Chem. 2000, 14, 2557-2526.

229. Reddy, K. R.; Venkateshwar, M.; Maheswari, C. U.; Kumar, P. S., Mild and efficient oxy-iodination of alkynes and phenols with potassium iodide and tert- butyl hydroperoxide. Tet. Lett. 2010, 51, 2170-2173.

230. Naskar, D.; Roy, S., 1-Haloalkynes from Propiolic Acids: A Novel Catalytic Halodecarboxylation Protocol. J. Org. Chem. 1999, 64, 6896-6897.

231. Yan, J.; Li, J.; Cheng, D., Novel and Efficient Synthesis of 1-Iodoalkynes. Synlett 2007, 15, 2442-2444.

232. Sladkov, A. M.; Ukhin, L. Y.; Gorshkova, G. N.; Chubarova, M. A.; Makhsumov, A. G.; Kasatochkin, V. I., Synthesis and spectra of iodo- and bromoacetylenic derivatives. Russ. J. Org. Chem. 1965, 1, 415-421.

220

BIOGRAPHICAL SKETCH

Birth Place

Champaign, IL, December 13, 1983

Education

Florida State University Berea College Tallahassee, Florida Berea, Kentucky PhD Candidate, Organic Chemistry BA in Chemistry 2006-Present 2002-2006

Publications

1. Brotherton, W. S.; Zhu, L. Multicomponent, One-Pot Reaction for the Preparation of 5-Iodo-1,4-disubstituted-1,2,3-triazoles Through In situ Generation of CuI and I2. In preparation.

2. Guha, P. M.; Phan, H; Kinyon, J; Brotherton, W. S.; Kesavapillai, S.; Simmons, J. T.; Clark, R. J.; Dalal, N. S.; Shatruk, M.; Zhu, L. Structurally Diverse Copper(II) Complexes of Polyaza Ligands Containing 1,2,3-Triazoles – Site Selectivity and Magnetic Properties. Submitted.

3. Kuang, G.-C.; Guha, P.; Brotherton, W. S.; Simmons, J. T.; Stankee, L. A.; Nguyen, B. T.; Clark, R. J.; Zhu. L. Experimental Investigation on the Mechanism of Chelation-Assisted, Copper(II) Acetate-Accelerated Azide-Alkyne Cycloaddition. J. Am. Chem. Soc. 2011, 133, 13984-14001.

4. Brotherton, W. S.; Guha, P.; Phan, H.; Clark, R. J.; Shatruk, M.; Zhu, L. Tridentate Complexes of 2,6-Bis(4-substituted-1,2,3-triazol-1-ylmethyl)pyridine and its Organic Azide Precursors – An Application of Copper(II) Acetate Accelerated Azide-Alkyne Cycloaddition. Dalton Trans., 2011, 40, 3655-3665.

5. Brotherton, W. S.; Zhu, δ. “Nanostructuresμ Bottom-Up Approach.” Encyclopedia of Supramolecular Chemistry. Edited by Jerry L. Atwood, Jonathan W. Steed, and Karl Wallace. 2011. 1-20. http://www.informaworld.com/10.1081/E-ESMC-120045448

6. Brotherton, W. S.; Michaels, H. A.; Simmons, J. T.; Clark, R. J.; Dalal, N. S.; Zhu, L. Apparent Copper(II)-Accelerated Azide−Alkyne Cycloaddition. Org. Lett. 2009, 4954–4957.

221

Formal Presentations

08.24.10 ACS National Meeting and Exposition, Boston, Massachusetts. Talk “Apparent Copper(II) Catalyzed Azide-Alkyne Cycloaddition”

05.15.10 Florida ACS Annual Meeting and Exposition, Tampa, Florida. Talk “Apparent Copper(II) Catalyzed Azide-Alkyne Cycloaddition”

10.03.09 Florida Inorganic and Materials Symposium, Gainesville, Florida Talk “Investigation of εetal Coordination to 1, β, γ-Triazoles”

05.16.09 Florida Annual Meeting and Exposition, Orlando, Florida. Talk “Investigation of εetal Coordination to 1, 2, 3-Triazoles”

05.08.08 Florida Annual Meeting and Exposition, Orlando, Florida Poster “Thermal Cross-Linking for Increasing Stability of DNA-Based Assemblies” 09.22.07 Florida Inorganic and Materials Symposium, Gainesville, Florida Poster “Thermal Cross-Linking for Increasing Stability of DNA-Based Assemblies” 10.21.05 6th Annual Berea College Research Presentations, Berea College Talk “Occurrence and Distribution of εercury in εammoth Cave National Park” 10.19.05 Geological Society of America National Conference, Salt Lake Talk City, Utah “REU Siteμ Summer Research Experience for Undergraduates in the εammoth Cave/Upper Green River Watershed” 12.05.04 Kentucky Academy of Science, Murray University, Kentucky Poster “Synthesis of Cationic Anti-Microbial Peptide (PKP)4”

10.29.04 5th Annual Berea College Research Presentations, Berea College, Poster Kentucky “Synthesis of Cationic Anti-Microbial Peptide (PKP)4”

222