FAGNANI D.Pdf

HYDROGEN BOND DIRECTED SELF-ASSEMBLY OF ARENES

DANIELLE ELIZABETH FAGNANI

A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY

UNIVERSITY OF FLORIDA

2018

To the forthcoming peruser

ACKNOWLEDGMENTS

I first thank my family for their endless cheer and support. My dad, mom, and brother each have been essential in this journey away from home. I am grateful that we can share in all these moments.

My sincerest gratitude goes to my advisor, Prof. Ron Castellano. I thank him for sharing his expertise in conducting scientific research, providing a profound and joyful understanding of chemistry, and offering guidance beyond the molecules. The encouragement he provided throughout the entirety of my doctoral studies is truly appreciated beyond words.

I thank all my labmates for being an excellent group of people to spend my time with in Sisler Hall and for teaching me something new every day. I thank Drs. Raghida

Bou Zerdan and Davita Watkins for their everlasting mentorship and for inspiring me to be a better chemist. I thank Renan for sharing his synthetic prowess, Ashton for her optimism, Asme and Lei for being magnificent teammates, and Ania (and Cher) for always lending a helping hand and never letting a dull moment pass. I thank Dylan for providing me with a wonderful mentoring experience, and Will and Elham for their cheerful energy.

I thank all my collaborators, especially Dr. Jiangeng Xue and his student Daken

Starkenburg. I thank my committee members, Dr. Lisa McElwee-White, Dr. Dan

Talham, Dr. Brent Sumerlin, and Dr. Anthony Brennan for their input and support over the years.

Last but not least, I thank the friends I made in Gainesville for their mutual camaraderie and comedic relief. Graduate school would not have been nearly as enjoyable, nor minimally bearable, without them.

TABLE OF CONTENTS

page

ACKNOWLEDGMENTS ...... 4

LIST OF TABLES ...... 9

LIST OF FIGURES ...... 10

LIST OF SCHEMES ...... 19

LIST OF ABBREVIATIONS ...... 21

ABSTRACT ...... 24

CHAPTER

1 INTRODUCTION ...... 26

Arenes ...... 26 Pi-Pi Interactions ...... 26 Expanding the Pi-Surface ...... 30 Emergent Properties Upon Stacking ...... 32 Optical Properties ...... 32 Charge mobility ...... 34 Redox Properties ...... 35 Using Hydrogen Bonds to Guide Arene Assembly ...... 36 Examples from Nature ...... 37 Synthetic Supramolecular Materials ...... 39 In-Plane Hydrogen Bonding ...... 40 Out-of-plane Hydrogen Bonding ...... 41 Motivation of Dissertation ...... 42

2 STRUCTURE-PROPERTY INVESTIGATION OF NUCLEOBASE CONTAINING PI-CONJUGATED MATERIALS ...... 45

Introductory Remarks...... 45 Molecular Design ...... 46 Synthesis ...... 47 Adenine and Guanine Oligomers ...... 47 Uracil Oligomer ...... 48 Cytosine Oligomer ...... 49 Optoelectronic Properties ...... 50 Computations ...... 50 Absorption ...... 51 Electrochemistry ...... 53 Thermal Properties ...... 54

Self-Association ...... 56 Hetero-Association ...... 60 Adenine and Uracil Base-Pairing ...... 60 Guanine and Cytosine Base-Pairing ...... 62 Concluding Remarks...... 65 Experimental ...... 67 Synthesis ...... 67 Computations ...... 69 UV-Vis Spectroscopy ...... 70 Electrochemistry ...... 70 Thermal Gravimetric Analysis ...... 71 Differential Scanning Calorimetry ...... 71 Binding Studies ...... 71

3 GUANINE TERMINATED LOW ENERGY GAP PI-CONJUGATED OLIGOMERS ...... 73

Introductory Remarks...... 73 Molecular Design ...... 77 Ditopic Design ...... 77 Interior Chromophore Selection ...... 77 Target Molecules ...... 78 Computations ...... 79 Synthesis ...... 80 Purification ...... 82 Metal-Free G-Quartet Formation ...... 85 Photophysical Properties ...... 86 UV-Vis Absorption ...... 86 Emission ...... 88 Thermal Properties ...... 88 Concluding Remarks...... 89 Experimental ...... 91 Synthesis ...... 91 UV-Visible Spectroscopy ...... 103 Fluorescence Spectroscopy ...... 104

4 METHYL SCAN OF GUANINE: TRANSLATING A BIO-INSPIRED MEDICINAL CHEMISTRY APPROACH TO OPTOELECTRONIC MATERIALS DISCOVERY 105

Introductory Remarks...... 105 Molecular Design ...... 108 Conformational Analysis ...... 110 Predicted Self-Association ...... 112 Calculated Electronic Structure ...... 114 Synthesis ...... 116 Concluding Remarks...... 119 Experimental ...... 119

Synthesis ...... 119 Computations ...... 128

5 SIMPLIFIED SYNTHESIS AND OPTOELECTRONIC PROPERTIES OF AN EXTENDED ASYMMETRIC PI-CONJUGATED OLIGOMER ...... 129

Introductory Remarks...... 129 Molecular Design ...... 131 Dipole ...... 132 Oligothiophene Alkyl Group Positioning ...... 134 Synthesis ...... 135 Traditional Step-Wise Route ...... 135 Mixed Cross-Coupling ...... 138 Mixed Knoevenagel Condensation ...... 140 Optical Properties in Solution ...... 143 Hydrogen Bond Capable vs. Benchmark Oligomers ...... 143 Solvatochromism ...... 145 Optoelectronic Properties in the Solid-State ...... 147 Neat Thin Films ...... 147 Organic Photovoltaic Device Performance ...... 148 Concluding Remarks...... 150 Experimental ...... 151 Synthesis ...... 151 Computations ...... 156 UV-Vis Absorption in Solution ...... 156 Absorption in Solid-state...... 156 Organic Photovoltaic Device Fabrication ...... 156

6 HOMOCHIRAL [2.2]PARACYCLOPHANE SELF-ASSEMBLY PROMOTED BY TRANSANNULAR HYDROGEN BONDING ...... 158

Introductory Remarks...... 158 Supramolecular Design...... 160 Tilted Amides ...... 160 Planar Chirality ...... 162 Dipole ...... 163 Synthesis ...... 163 Single Crystal X-Ray Structure ...... 164 Solution Studies ...... 166 NMR Analysis in Mildly Polar Environments (Chloroform) ...... 166 NMR Analysis in Non-Polar Environments (Cyclohexane) ...... 169 Infrared Spectroscopy Analysis ...... 170 Variable Concentration UV-Vis Spectroscopy ...... 172 Variable Temperature UV-Vis Spectroscopy ...... 172 Van’t Hoff analysis of an equal-K model ...... 173 Light Scattering ...... 175 Chromophore Functionalized pCpTA ...... 177

Chromophore Conjugate Design ...... 177 Direct Condensation ...... 178 Click Chemistry ...... 179 Progress Towards Chiral Resolution ...... 180 Improved Synthesis of pCp-4,7,12,15-tetra(carboxylic acid) ...... 181 Synthesis and Chiral Resolution of pCp-4,7,12,15-tetra(ester) Derivatives .... 183 Fisher esterification ...... 183 Acyl substitution under basic conditions ...... 184 Steglich esterification ...... 184 SN2 with carboxylate nucleophile ...... 184 Concluding Remarks...... 186 Experimental ...... 186 Synthesis ...... 186 Computations ...... 195

APPENDIX

A 1HNMR SPECTRA ...... 198

B 13CNMR SPECTRA ...... 219

C COMPUTATIONAL DATA ...... 236

D EXPERIMENTAL DATA ...... 243

E X-RAY DATA ...... 253

LIST OF REFERENCES ...... 255

BIOGRAPHICAL SKETCH ...... 280

LIST OF TABLES

Table page

1-1 Energetic parameters for common benzene configurations from high-level quantum mechanical calculations ...... 29

2-1 DFT calculations on nucleobase-containing oligomers ...... 51

2-2 Electronic properties of nucleobase-containing oligomers ...... 54

2-3 Self- and hetero-association constants of nucleobase-containing oligomers ..... 65

3-1 DFT calculations on guanine-terminated oligomers ...... 80

3-2 Summary of hydrogen bonding distances in unit cell ...... 86

3-3 UV-Vis absorption data collected for guanine and protected guanine terminated oligomers in DMSO ...... 87

3-4 Emission properties of guanine and protected-guanine terminated oligomers ... 88

5-1 DFT Calculation results of monotopic A-D-HB derivatives ...... 132

5-2 Calculation results of oligothiophene alkyl group positioning on compound RCN_T4_G ...... 135

5-3 UV-Vis absorption data collected for RCN_T5-dg_B and DRCNT5-dg in various solvents ...... 145

5-4 Empirical parameters of solvent polarit ...... 146

5-5 Solubility and spin-coating screening results of RCN_T5-dg_B ...... 147

5-6 Summary of BHJ OPV device performance containing RCN_T5-dg_B and PC71BM blended active layers ...... 149

6-1 Halogen-lithium exchange conditions screened on (±)-6-2 ...... 182

6-2 Esterification conditions of (±)-6-3 ...... 185

LIST OF FIGURES

Figure page

1-1 Typical pi-pi interaction geometries of two interacting benzene molecules ...... 27

1-2 Depiction of the electrostatic model utilized by Hunter and Sanders to rationalize pi-pi interactions ...... 28

1-3 Using polycyclic hydrocarbons to probe dispersion effects ...... 31

1-4 Phenylacetylene macrocycle prepared by Moore et al ...... to study the interaction strength of large pi-surfaces in solution ...... 32

1-5 Generalized energy diagram displaying the allowed transitions of H- and J- dimers ...... 33

1-6 The X-ray crystal structures of pentacene packing arrengments ...... 35

1-7 The face-to-face stacked thiophene model system utilized by Collard et al to study the effect of pi-stacking on redox properties ...... 36

1-8 Nucleobase pairs constructed from purine and pyridine backbones shown with conventional numbering scheme ...... 38

1-9 Unraveling of DNA in the absence of dispersion interactions between base pairs during molecular dynamics simulations performed by Hobza et al...... 38

1-10 Chemical structures of BChl c and zinc chlorin model compound and schematic representation of a section of tubular assemblies formed by the interplay of hydrogen bonding, metal oxygen coordination, and pi-pi stacking ... 39

1-11 Molecules used to construct supramolecular pi-functional systems from hydrogen bonding interactions perpendicular to the axis of polymer stacking .... 40

1-12 Molecules used to construct supramolecular pi-functional systems from hydrogen bonding interactions along the axis of polymer stacking ...... 42

1-13 Flowchart demonstrating that non-covalent interactions are central to biological self-assembly and new supramolecular structures ...... 43

2-1 Nucleobase-containing pi-conjugated targets evaluated ...... 47

2-2 Conformational analysis of truncated cytosine oligomer ...... 51

2-3 Overlaid normalized UV-Visible absorption spectra of nucleobase-containing oligomers ...... 52

2-4 TGA data collected for nucleobase-containing compounds...... 55

1 2-5 Concentration-dependent HNMR data collected for 2-1A in CDCl3 at 298 K .... 57

1 2-6 Concentration-dependent HNMR data collected for 2-1U in CDCl3 at 298 K .... 57

1 2-7 Concentration-dependent HNMR data collected for 2-1C in CDCl3 at 298 K .... 58

1 2-8 Concentration-dependent HNMR data collected for 2-1PGa in CDCl3 at 298 K ...... 58

2-9 Concentration-dependent UV-Vis absorption data collected for 2-1G CDCl3 at 298 K ...... 60

2-10 Images of guanine derivatives 2-1G, 2-1PGa, and 2-1PGb in the bulk ...... 60

2-11 Titration 1HNMR data collected for 2-1A (host, 10 mM) upon addition of 2-1U (guest) in CDCl3 at 298 K ...... 61

2-12 Titration 1HNMR data collected for 2-1U (host, 10 mM) upon addition of 2-1A (guest) in CDCl3 at 298 K ...... 62

2-13 Titration 1HNMR data collected for 2-1C (host, 1 mM) upon addition of 2-1G (guest) in CDCl3 at 298 K ...... 63

2-14 Titration UV-Vis absorption spectra collected in chloroform at 298 K of 2-1C (host, 15 M) and upon addition of 2-7 (guest)...... 64

2-15 TitrationUV-Vis absorption spectra collected in chloroform at 298 K of 2-1G (host, 15 M) and upon addition of 2-19 (guest) ...... 65

2-16 The envisioned supramolecular design from integrating nucleobase dimerization into pi-conjugated constructs ...... 67

3-1 Use of self-assembling chromophores in bulk heterojunction solar cells ...... 74

3-2 Guanine self-association into linear and cyclic arrangements ...... 75

3-3 Self-assembled donor-acceptor guanine-containing system utilized for photoinduced charge transfer analysis ...... 76

3-4 Ditopic chromophore design utilized in this work ...... 78

3-5 Donor-Acceptor (D-A) design of pi-conjugated materials...... 79

3-6 Guanine bis-terminated pi-conjugated oligomers evaluated in this study ...... 79

3-7 Silica-gel TLC plate of crude reaction mixture for the synthesis of 3-2PG ...... 83

3-8 Single crystal X-ray structure of guanine templating fragment ...... 85

3-9 UV-Vis absorption spectra of guanine-terminated oligomers ...... 87

3-10 Overlaid TGA data collected for guanine-terminated oligomers ...... 89

3-11 G-quadruplex organic framework reported by Wu, Wasielewski, and co- workers ...... 91

4-1 The major biosynthetic pathway to caffeine from DNA nucleotides ...... 105

4-2 A simplified example of methyl scanning of a cyclic hexapeptide ...... 107

4-3 Guanine (G) and protected guanine (PG) end groups designed with methyl scanning ...... 109

4-4 Simple monotopic and ditopic target compounds evaluated in this work ...... 109

4-5 Conformational analysis of end-groups 4-PG1 and 4-PG5 ...... 110

4-6 Conformational analysis of end-group 4-PG2 ...... 111

4-7 Conformational analysis of end-group 4-PG3 ...... 111

4-8 Possible dimeric and linear hydrogen bonded assemblies of 4-1-PG1 and 4- 1-PG3 and cartoon depictions of the corresponding 2-D arrangement if accommodated by 4-2-PG1 and 4-2-PG3 ...... 113

4-9 Possible dimeric and linear hydrogen bonded assemblies of 4-1-PG1 and 4- 1-PG3 and cartoon depictions of the corresponding 2-D arrangement if accommodated by 4-2-PG1 and 4-2-PG3 ...... 113

4-10 Possible dimeric hydrogen bonded assembly of 4-1-PG4 cartoon depiction of the corresponding 2-D arrangement if accommodated by 4-2-PG4 ...... 114

4-11 Graphical display of calculated HOMO and LUMO energy levels for end groups only, 4-1 series of compounds, and 4-2 series of compounds ...... 115

4-12 Range of calculated HOMO, LUMO, and HOMO-LUMO energy gaps values amongst each set of set of compounds...... 115

5-1 Cartoon representation of the modular design approach available for the construction of self-assembling pi-conjugated oligomers ...... 130

5-2 A series of simple oligomer-like molecules, DRCN4T–DRCN9T, demonstrating exceptional performance in solution-processed solar cells ...... 131

5-3 Generic design of hydrogen bond equipped oligomer-like molecules investigated in this work ...... 131

5-4 Geometry optimized structures of barbiturate containing oligomers with dipoles represented ...... 133

5-5 Molecule used for thienyl alkyl screening ...... 134

5-6 Geometry optimized structures of non-alkylated oligomer RCN_T4_G and substituted derivative RCN_T4-h_G ...... 135

5-7 Synthesis and analysis of bis(aldehyde) terminated oligothiophene ...... 142

5-8 Overlaid normalized absorption spectra of RCN_T5-dg_B and DRCNT5-dg at low concentration (5 ×10-6 M) in chloroform and a chloroform mixture at 298 K ...... 144

5-9 Comparison of RCN_T5-dg_B absorption properties in CHCl3 and CHCl3:o- DCB:DMF (90:5:5) mixture ...... 145

5-10 Overlaid normalized absorption spectra of RCN_T5-dg_B collected as 20 ×10-6 M solutions in THF and a chloroform mixture at 298 K...... 146

6-1 Pi-stacked paracyclophanes (pCps) ...... 159

6-2 The design of pCps capable of self-assembly through hydrogen bonding ...... 160

6-3 Gas-phase, geometry-minimized structures (M06-2X/6-31G*) of amide functionalized paracyclophanes...... 161

6-4 The planar chiral monomers (Sp)-pCpTA and (Rp)-pCpTA dictate the handedness of the respective homochiral assemblies ...... 162

6-5 The dipoles associated with pCpTA conformers and assembly ...... 163

6-6 X-ray crystal structure of pCp-4,7,12,15-tetracarboxamide (±)-6-1a ...... 165

1 6-7 HNMR analysis of (±)-6-1b in CDCl3 ...... 167

6-8 Graphical representation of DOSY data obtained for (±)-6-1b at variable concentrations and temperatures in CDCl3 ...... 169

1 6-9 HNMR analysis of (±)-6-1b in cyclohexane-d12 ...... 170

6-10 Complementary FT-IR analysis of (±)-6-1b and (±)-6-6b ...... 171

6-11 UV-Vis analysis of of (±)-6-1b at increasing concentration (2.5 – 120 × 10-6 M) in MCH at 298 K ...... 172

6-12 Detailed thermal UV-Vis analysis of pCp assembly ...... 174

6-13 Isodesmic (equal-K) treatment of temperature-dependent UV data ...... 175

6-14 Autocorrelation function C(τ) and double exponential fit plotted as a function of lag time τ for scattering angles 30◦-150◦ ...... 176

6-15 Calculated frontier molecular orbital diagrams of pCpTA dimers...... 177

6-16 Molecular design of chromophore functionalized pCpTA ...... 178

6-17 Chiral chromatogram of (±)-6-1b ...... 181

1 A-1 HNMR spectrum of 2-1U in CDCl3 ...... 198

1 A-2 HNMR spectrum of 2-1C in CDCl3 ...... 198

1 A-3 HNMR spectrum of 3-3 in CDCl3 ...... 199

1 A-4 HNMR spectrum of 3-4 in CDCl3 ...... 199

1 A-5 HNMR spectrum of 3-5 in CDCl3 ...... 200

1 A-6 HNMR spectrum of 3-6 (4-1-PG1) in CDCl3 ...... 200

1 A-7 HNMR spectrum of 3-7 in CDCl3 ...... 201

1 A-8 HNMR spectrum of 3-8 in CDCl3 ...... 201

1 A-9 HNMR spectrum of 3-9 in CDCl3 ...... 202

1 A-10 HNMR spectrum of 3-1-PG in CDCl3 ...... 202

1 A-11 HNMR spectrum of 3-1-G in DMSO-d6 ...... 203

1 A-12 HNMR spectrum of 3-2-PG in CDCl3 ...... 203

1 A-13 HNMR spectrum of 3-2-G in DMSO-d6 ...... 204

1 A-14 HNMR spectrum of 3-15 (4-1-G) in DMSO-d6 ...... 204

1 A-15 HNMR spectrum of 4-2-PG1 in CDCl3 ...... 205

1 A-16 HNMR spectrum of 4-8 in CDCl3 ...... 205

1 A-17 HNMR spectrum of 4-9 in CDCl3 ...... 206

1 A-18 HNMR spectrum of 4-10 in CDCl3 ...... 206

1 A-19 HNMR spectrum of 4-6 in CDCl3 ...... 207

1 A-20 HNMR spectrum of 4-4 in CDCl3 ...... 207

1 A-21 HNMR spectrum of 4-1-PG2 in DMSO-d6 ...... 208

1 A-22 HNMR spectrum of 4-2-PG3 in CDCl3 ...... 208

1 A-23 HNMR spectrum of 4-7 in CDCl3 ...... 209

1 A-24 HNMR spectrum of 4-5 in CDCl3 ...... 209

1 A-25 HNMR spectrum of 4-1-PG5 in CDCl3 ...... 210

1 A-26 HNMR spectrum of 5-19 in CDCl3 ...... 210

1 A-27 HNMR spectrum of 5-20 in CDCl3 ...... 211

1 A-28 HNMR spectrum of 5-16 in CDCl3 ...... 211

1 A-29 HNMR spectrum of DRCNT5-dg in CDCl3 ...... 212

1 A-30 HNMR spectrum of RCN_T5-dg_B in 1,1,2,2-tetrachloroethane-d4 ...... 212

1 A-31 HNMR spectrum of 6-10 in CDCl3 ...... 213

1 A-32 HNMR spectrum of 6-11 in CDCl3 ...... 213

1 A-33 HNMR spectrum of 6-8 in CDCl3 ...... 214

1 A-34 HNMR spectrum of 6-15 in CDCl3 ...... 214

1 A-35 HNMR spectrum of 6-16 in CDCl3 ...... 215

1 A-36 HNMR spectrum of 6-14 in CDCl3 ...... 215

1 A-37 HNMR spectrum of (±)-6-13 in methanol-d4 ...... 216

1 A-38 HNMR spectrum of (±)-6-12 in CDCl3 ...... 216

1 A-39 HNMR spectrum of (±)-6-18 in CDCl3 ...... 217

1 A-40 HNMR spectrum of (±)-6-20 in CDCl3 ...... 217

1 A-41 HNMR spectrum of (±)-6-21 in CDCl3 ...... 218

13 B-1 CNMR spectrum of 2-1U in CDCl3 ...... 219

13 B-2 CNMR spectrum of 2-1C in CDCl3 ...... 219

13 B-3 CNMR spectrum of 3-3 in CDCl3 ...... 220

13 B-4 CNMR spectrum of 3-4 in CDCl3 ...... 220

13 B-5 CNMR spectrum of 3-5 in CDCl3 ...... 221

13 B-6 CNMR spectrum of 3-6 in CDCl3 ...... 221

13 B-7 CNMR spectrum of 3-7 in CDCl3 ...... 222

13 B-8 CNMR spectrum of 3-8 in CDCl3 ...... 222

13 B-9 CNMR spectrum of 3-9 in CDCl3 ...... 223

13 B-10 CNMR spectrum of 3-1-PG in CDCl3 ...... 223

13 B-11 CNMR spectrum of 3-2-PG in CDCl3 ...... 224

13 B-12 CNMR spectrum of 4-2-PG1 in CDCl3 ...... 224

13 B-13 CNMR spectrum of 4-8 in CDCl3 ...... 225

13 B-14 CNMR spectrum of 4-10 in CDCl3 ...... 225

13 B-15 CNMR spectrum of 4-6 in CDCl3 ...... 226

13 B-16 CNMR spectrum of 4-4 in CDCl3 ...... 226

13 B-17 CNMR spectrum of 4-7 in CDCl3 ...... 227

13 B-18 CNMR spectrum of 4-5 in CDCl3 ...... 227

13 B-19 CNMR spectrum of 4-1-PG5 in CDCl3 ...... 228

13 B-20 CNMR spectrum of 5-20 in CDCl3 ...... 228

13 B-21 CNMR spectrum of 5-16 in CDCl3 ...... 229

13 B-22 CNMR spectrum of DRCNT5-dg in CDCl3 ...... 229

13 B-23 CNMR spectrum of 6-10 in CDCl3 ...... 230

13 B-24 CNMR spectrum of 6-11 in CDCl3 ...... 230

13 B-25 CNMR spectrum of 6-8 in CDCl3 ...... 231

13 B-26 CNMR spectrum of 6-15 in CDCl3 ...... 231

13 B-27 CNMR spectrum of 6-16 in CDCl3 ...... 232

13 B-28 CNMR spectrum of 6-14 in CDCl3 ...... 232

13 B-29 CNMR spectrum of (±)-6-13 in methanol-d4 ...... 233

13 B-30 CNMR spectrum of (±)-6-12 in CDCl3 ...... 233

13 B-31 CNMR spectrum of (±)-6-18 in CDCl3 ...... 234

13 B-32 CNMR spectrum of (±)-6-20 in CDCl3 ...... 234

13 B-33 CNMR spectrum of (±)-6-21 in CDCl3 ...... 235

C-1 Computational results for 3-1G and 3-1PG including minimized molecular structures, HOMO, and LUMO diagrams ...... 236

C-2 Computational results for 3-2G and 3-2PG including minimized molecular structures, HOMO, and LUMO diagrams ...... 236

C-3 Calculated HOMO and LUMO plots of guanine and protected guanine end groups ...... 237

C-4 Calculated HOMO and LUMO plots of 4-1 series of compounds...... 238

C-5 Calculated HOMO and LUMO plots of 4-2-G...... 238

C-6 Calculated HOMO and LUMO plots of 4-2-PG1 ...... 239

C-7 Calculated HOMO and LUMO plots of conformer 4-2-PG2a ...... 239

C-8 Calculated HOMO and LUMO plots of conformer 4-2-PG2ab ...... 239

C-9 Calculated HOMO and LUMO plots of conformer 4-2-PG2b ...... 240

C-10 Calculated HOMO and LUMO plots of conformer 4-2-PG3a ...... 240

C-11 Calculated HOMO and LUMO plots of conformer 4-2-PG3ab ...... 240

C-12 Calculated HOMO and LUMO plots of conformer 4-2-PG3b ...... 241

C-13 Calculated HOMO and LUMO plots of 4-2-PG4 ...... 241

C-14 Calculated HOMO and LUMO plots of 4-2-PG5 ...... 241

C-15 HOMO and LUMO plots of RCN_T#_G series of compounds ...... 242

D-1 Overlaid UV-Vis absorption spectra of 2-1A in DMF and associated Beer- Lambert plot fit to a linear regression ...... 243

D-2 Overlaid UV-Vis absorption spectra of 2-1U in DMF and associated Beer- Lambert plot fit to a linear regression ...... 243

D-3 Overlaid UV-Vis absorption spectra of 2-1C in DMF and associated Beer- Lambert plot fit to a linear regression ...... 243

D-4 Overlaid UV-Vis absorption spectra of 2-1G in DMF and associated Beer- Lambert plot fit to a linear regression ...... 244

D-5 Cyclic voltammograms of compounds 2-1A, 2-1U, 2-1G, 2-1C, 2-1PGa, and 2-1PGb...... 245

D-6 DSC for compounds 2-1A, 2-1U, 2-1G, 2-1C, 2-1PGa, and 2-1PGb...... 246

D-7 Overlaid UV-Vis absorption spectra of 3-1G, 3-1PG in DMF and associated Beer-Lambert plot fit to a linear regression at pi-pi* transition and charge transfer transition ...... 247

D-8 Overlaid UV-Vis absorption spectra of 3-2G, 3-2PG in DMF and associated Beer-Lambert plot fit to a linear regression at pi-pi* transition and charge transfer transition ...... 248

D-9 Emission spectrum of 3-1G collected in DMSO at 298 K ...... 249

D-10 Emission spectra of 3-1PG collected in DMSO and DCM at 298 K ...... 249

D-11 Emission spectrum of 3-2G collected in DMSO at 298 K ...... 249

D-12 Emission spectra of 3-2PG collected in DMSO and DCM at 298 K...... 250

D-13 UV-Vis of DRCNT5-dg in chloroform ...... 250

D-14 UV-Vis of RCN_T5-dg_B in chloroform ...... 250

D-15 UV-Vis of DRCNT5-dg in chloroform mixture ...... 251

D-16 UV-Vis of RCN_T5-dg_B in chloroform ...... 251

D-17 UV-Vis of RCN_T5-dg_B in THF ...... 251

D-18 Processed DLS data collected for (±)-6-1b 25 mM in methylcyclohexane ...... 252

LIST OF SCHEMES

Scheme page

2-1 Synthesis of adenine-terminated oligomer 2-1A ...... 48

2-2 Synthesis of guanine and protected guanine-terminated oligomers 2-1G, 2- 1PGa, and 2-1PGb ...... 48

2-3 Synthesis of uracil-terminated oligomer 2-1U ...... 49

2-4 Synthesis of 5-hexyl-5’-tributylstannyl-2,2-:5’,2’’-terthiophene ...... 49

2-5 Synthesis of cytosine-terminated oligomer 2-1C ...... 50

3-1 Synthesis of purine-containing building blocks ...... 81

3-2 Synthesis of isoindigo core ...... 81

3-3 Synthesis of extended guanine-terminated pi-conjugated oligomers...... 82

4-1 Synthesis of simple monotopic and ditopic target compounds ...... 116

4-2 Reductive amination of 2-amino-6-methoxy purine (R = n-octyl) ...... 117

4-3 Synthesis of N-methyl-2-amino-6-methoxy purine (R = n-octyl) ...... 118

4-4 Bromination of all methylated guanine derivatives (R = n-octyl) ...... 118

5-1 Synthesis of RCN ...... 136

5-2 Step-wise synthesis of aldehyde-containing oligothiophene fragment ...... 136

5-3 Divergent synthetic route to prepare RCN_T4-df_HB target compounds, in which the hydrogen-bonding unit can be easily exchanged ...... 137

5-4 Attempted borylation of 5-6 and 3-7 ...... 138

5-5 Mixed Stille cross-coupling to obtain precursor for RCN_T5-dg_G ...... 139

5-6 Synthesis of 8-(5'-bromo-4'-octyl-[2,2'-bithiophen]-5-yl)-6-methoxy-9-octyl- 9H-purin-2-amine ...... 139

5-7 One-pot synthesis of A-D-A and A-D-HB oligomers ...... 141

5-8 One-pot synthesis of A-D-A and A-D-HB oligomers ...... 143

6-1 Synthesis of self-assembing pCp-4,7,12,15-tetracarboxamide (±)-6-1 and non-assembling pCp-4-monocarboxamide comparator (±)-6-6b ...... 164

6-2 Retrosynthetic analysis of (±)-6-7 revealing direct condensation route ...... 178

6-3 Synthesis of amino functionalized NI derivative 6-8 ...... 179

6-4 Retrosynthetic analysis of (±)-6-12 revealing a click chemistry route ...... 179

6-5 Synthesis of alkynylated pCp-4,7,12,15-tetracarboxamide ...... 180

6-6 Synthesis of azido-naphthalimide derivative ...... 180

6-7 Synthesis of chromophore functionalized pCp-4,7,12,15-tetracarboxamide by CuAAc ...... 180

6-8 Generalized reaction scheme for the esterification of (±)-6-3 ...... 183

LIST OF ABBREVIATIONS

13CNMR Carbon nuclear magnetic resonance

1HNMR Proton nuclear magnetic resonance

1-D One-dimensional

2-D Two-dimensional

3-D Three-dimensional

A Strong electron acceptor unit

BChl Bacteriochlorophyll

BHJ Bulk heterojunction

CDCl3 Chlorforom-d3

Chl Chlorophyll cryoEM Cryogenic electron microscopy

CV Cyclic voltammetry

D Weak electron donor unit

DART Direct analysis in real time

DCM Dichloromethane

DFT Density functional theory

DMF Dimethylformamide

DMSO Dimethylsulfoxide

DNA Deoxyribose nucleic acid

DOSY Diffusion ordered spectroscopy

DSC Differential scanning calorimetry

EDG Electron donating group

ESI Electrospray ionization

Et2O Diethyl ether

EtOAc Ethyl acetate

EtOH Ethanol eV Electron volts

EWG Electron withdrawing group

H-bond Hydrogen bond

HB Hydrogen bonding unit

HOMO Highest occupied molecular orbital

HPLC High pressure liquid chromatography

IR Infrared spectroscopy

K Kelvin

Ka Association equilibrium constant

Kd Dimerization equilibrium constant

Kel Isodesmic elongation equilibrium constant kcal Kilocalorie kJ Kilojoule

LUMO Lowest unoccupied molecular orbital

MALDI Matrix-assisted laser desorption/ionization

MeOH Methanol mG Milligram mL Milliliter

MO Molecular orbital

NBS N-Bromosuccinimide

NMR Nuclear magnetic resonance

OFET Organic field-effect transistor

OLED Organic light-emitting diode

OPV Organic photovoltaic solar cell

PAH Polycyclic aromatic hydrocarbon

PCBM Phenyl-C61-butyric acid methyl ester pCp [2.2]Paracyclophane

PH Phthalhydrazide

PTFE Polytetrafluoroethylene

Rh Hydrodynamic radius

TFA Trifluoroacetic acid

TGA Thermal gravimetric analysis

THF Tetrahydrofuran

TIPS Triisopropylsilylethynyl

TLC Thin layer chromatography

TMS Tetramethylsilane

TOF Time-of-flight

UV-Vis Ultraviolet-visible spectroscopy

Abstract of Dissertation Presented to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy

HYDROGEN BOND DIRECTED SELF-ASSEMBLY OF ARENES

Danielle Elizabeth Fagnani

May 2018

Chair: Ronald K. Castellano Major: Chemistry

This work describes the design, synthesis, purification, and characterization of new aromatic pi-systems equipped with strong H-bonding groups to effectively guide cofacial pi-stacking interactions. Through fundamental studies on the self-assembly and emergent optical and electronic properties of these molecules, we establish critical design details and practical synthetic methods required to bring these novel materials towards realization in optoelectronic applications.

Chapter 2 describes a bio-inspired approach, which took advantage of both the

H-bonding capabilities and aromatic nature of DNA nucleobases by integrating them into traditional organic semiconductors (e.g., oligothiophene). Of the four nucleobases

4 -1 assessed, guanine showed the strongest self-association in chloroform (Kdim > 10 M ), signatures of pi-pi interactions (red-shifted absorbance), and electron-donating behavior

(lowest oxidation potential), attractive features for construction of self-assembling functional pi-materials for organic optoelectronic applications. These features motivated the synthesis, purification, and photophysical characterization of guanine-terminated isoindigo-centered oligomers discussed in Chapter 3. These oligomers displayed low optical bandgaps (1.72 – 1.75 eV) and internal charge-transfer transitions arising from

the donor-acceptor-donor design. The strong H-bond capability of these oligomers caused strong aggregation in solution, a practical limitation for solution processing of these materials into thin film device architectures. To address this important design criterion, a series of guanine derivatives, in which the H-bonding capability was sequentially deactivated, were designed and presented in Chapter 4. The goal is to thoroughly evaluate the effect of H-bonding on thin film morphology and bulk properties, enabling the selection of a derivative that is most balanced for the specific application.

Chapter 5 discusses alternative synthetic strategies to prepare elongated, H- bond capable, pi-conjugated oligomers, and introduces a novel approach to rapidly access asymmetric low energy-gap oligomers. This approach relies on the one-pot mixed condensation reaction of a bis-carbaldehyde terminated oligothiophene with pi- acceptors (e.g., dicyano rhodanine) and H-bonding moieties (e.g., barbituric acid) containing active methylene groups. By this method, an extended acceptor-donor-H- bonding oligomer was prepared displaying a low optical bandgap (1.92 eV) and interesting solvatochromic behavior.

Chapter 6 introduces the discovery of a new supramolecular archetype based on

[2.2]paracyclophane (pCp), which uniquely promoted the formation of homochiral pi- stacked pCp nanorods through cooperative transannular and intermolecular H-bonding.

CHAPTER 1 INTRODUCTION

Arenes

Marked by the discovery of benzene by Faraday in 18251 and conceptualization of aromaticity by Kekulé in 18652, arenes have been a central topic amongst chemists for nearly two centuries. The unusual stability and distinctive properties of aromatic structures continue to fascinate researchers from both fundamental and applied standpoints.3 The planarity and structural rigidity of arenes make them ideal scaffolds for molecular engineering.4 Furthermore, the delocalized electronic structure and induced ring current give rise to magnetic, optoelectronic, and semiconductive properties.5 Unsurprisingly, nature has taken advantage of these physical and chemical characteristics to construct well-defined biomaterials and effect vital life processes, such as photosynthesis and genetic information storage. Inspired by this knowledge, supramolecular chemists have integrated arenes into fundamental studies which aim to understand the mechanisms and preferences of self-assembling systems. This information is then employed to design new materials for key applications.6-8

Pi-Pi Interactions

When arenes, or heteroarenes, come close in proximity (within van der Waals radii) they uphold geometrically well-defined spatial arrangements by means of attractive non-covalent pi-pi interactions.9 Given its simplicity and familiarity, benzene has been the core subject of many experimental and theoretical investigations aimed at elucidating the nature of these interactions. The classical interaction geometries observed for the benzene dimer are the following: the eclipsed face-to-face “sandwich stack” (E), the face- to-face parallel-displaced “slipped stack” (PD), and the edge-to-face “T-shaped” (T) or “Y-

shaped” arrangements (Y). The face-to-face configurations are co-planar and are formally referred to as “pi-stacking.” The edge-to-face geometry is not truly a pi-pi interaction, but rather a C–H ••• pi interaction that exists between a single pi-surface and peripheral C–H of an adjacent molecule. The benzene dimer geometry is often quantified by its centroid- to-centroid distance, which reflects the extent of horizontal displacement in face-to-face arrangements, and angle between interacting planes for the edge-to-face arrangements.

The average intermolecular parameters of the benzene dimers (obtained from both experiment and theory) are shown in Figure 1-1.10

Figure 1-1. Typical pi-pi interaction geometries of two interacting benzene molecules. Average centroid-to-centroid distances are shown.

The PD and T benzene-benzene dimer interactions are the most thermodynamically stable configurations. The binding energies are nearly isoenergetic, approximately 2.5 – 3 kcal mol-1 in the gas phase. The edge-to-face arrangement is often seen in the solid-state crystal structure of arenes, guiding the common herringbone packing structure, as well as in solution.11,12 Parallel displaced geometries are observed in proteins and other biomolecules, and in the liquid phase.13,14 The eclipsed face-to-face geometry is higher in energy by about 1 kcal mol-1 (in the gas phase). The E geometry is not often observed in neutral arenes, but is found between

donor-acceptor pi-systems or when other non-covalent effects are incorporated (i.e. hydrogen bonding).15,16

While there is still ongoing controversy as to the exact “nature” of pi-pi interactions, early attempts to rationalize preferred interactions of arenes focused on the electrostatic effects associated within the ring. In their seminal electrostatic model from

1990, Hunter and Sanders proposed that charge distribution dictates the geometry of the benzene dimer, and the magnitude of the energetic contribution comes from van der

Waals forces.17 They used the quadrupole moment of benzene to demonstrate that the attractive forces between two benzene rings is the result of pi-σ attractions that balance pi-pi repulsions (Figure 1-2). This intuitive model is harmonious with many experimental accounts.18

Figure 1-2. Depiction of the electrostatic model utilized by Hunter and Sanders to rationalize pi-pi interactions. The arenes are represented as molecular quadrupoles, where the sigma framework is partially positive and the pi electrons are partially negative.

Over the decades, there has been an exorbitant effort by both experimentalists19-

21 and theorists22-26 to further contextualize the “nature” of arene-arene interactions and refine the electrostatic model. The rise of sophisticated computational methods has

enabled a more detailed energetic and geometric description of these interactions.

Sherril et al. made insightful contributions using the symmetry-adapted perturbation theory (SAPT2) to deconstruct the pi-pi binding energy into individual energy components, which are summarized in Table 1-1.27 This theoretical technique dissected interaction energies into individual attractive and repulsive terms governed by electrostatics, London dispersion, induction/polarization, and exchange-repulsion forces.24 This analysis indicated that the electrostatic interaction is most favored by PD and T geometries; moreover, benzene-benzene interactions are dispersion-dominated and this term counteracts the exchange-repulsion term. Comparison of the face-to-face entries to the edge-to-face geometry further indicated that the greater molecular overlap of the E and PD configurations offers them a more stabilizing dispersion term. While the dispersion term dominates in vacuo, it is attenuated in solution where solvent interactions have a large effect.28

Table 1-1. Energetic parameters for common benzene configurations from high-level quantum mechanical calculations.27 Energetic Parameter E PD T Interaction Energy -1.92 -2.95 -2.48 Electrostatic -0.477 -2.77 -1.75 Induction -0.275 -0.882 -0.518 Exchange 4.52 8.58 3.52 Dispersion -5.68 -7.88 -3.73

Ensuing studies on the effect of heteroatoms and substituents indicated that these details have a large influence on the interaction. In this regard, a generated computationally by Wheeler at al. described a “local, direct interaction,” in which the substituent itself directly interacts with the neighboring ring instead of the polarized pi- surface.

Expanding the Pi-Surface

Investigations of benzene–benzene interactions have provided a profound understanding of arene–arene interactions. While this interaction is very pervasive in many chemical systems, it is also relatively weak compared other non-covalent forces.

The fragility of the benzene interaction is evidenced by its thermodynamic properties relative to its saturated counterpart cyclohexane. Both compounds are liquids at room temperature with similar freezing points (5.5 and 6.5 °C) and boiling points (80 and 81

°C). However, an interesting change in properties arises upon expansion of the pi- surface. For instance, it is known that as polycyclic aromatic hydrocarbons (PAHs) becomes larger, they also become more crystalline and increasingly less soluble in common organic solvents compared to saturated counterparts.29 This simple observation indicates that the intermolecular pi-pi interactions become tangibly stronger for larger systems.

The crystallinity of PAHs arises in large part from their molecular rigidity, which facilitates favorable intermolecular contacts. It is generally believed that the larger pi- surface of PAHs is more polarized and can effectively exhibit stronger dispersion effects. In 2006, Zeinalipour-Yazdi and Pullman30 used MP2 methods to compute the binding energy of face-to-face pi-interactions between benzene and aromatics of growing size (Figure 1-3). They studied two series of dimers: the first set contained

PAHs that were extended in two dimensions approaching the limit of graphite (from benzene to circumcoronene), and an analogous second set contained linear (n)- polyacenes (from n = 1 to 11). They found that for both sets of supermolecules, the binding energy increased linearly for lower molecular weight PAHs, and converged as the PAH pi-surface becomes very large. They attributed this phenomenon to the

increased polarizability of fused aromatic rings. However, when pi-surface became too large, the interacting benzene was to far away and unable to polarize the edge of the pi- surface.

Figure 1-3. Using polycyclic hydrocarbons to probe dispersion effects. The binding energies between arenes were calculated (MP2/cc-pVDZ) by Pullman et al.30

An early experimental example of stronger cofacial stacking interactions occurring between pi-systems is the self-association of phenylacetylene macrocycles

(PAMs) observed by Moore et al. (Figure 1-4).31,32 Concentration dependent 1HNMR

-1 analysis showed a dimerization (Kdim) of 60 M in CDCl3, indicating self-association of the rigid planar macrocycle.33 This effect was attributed to the cooperative pi-pi interactions between the several pairs on aromatic rings in a single system. This claim was further supported by the absence of any change in chemical shift (Kdim <1) in benzene-d6, a pi-stacking competitive solvent. Other large planar pi-systems have shown a similar tendency to formed stacked structures and has led to their implementation in various applications, including in optical and electrical sensors. 34

R1 R3

n PAMa, R1-6 = CO2 Bu n n PAMb, R1,3,5 = CO2 Bu, R2,4,6 = O Bu n n PAMc, R1-3 = CO2 Bu, R4-6 = O Bu n PAMd, R1-6 = O Bu n PAMe, R1-6 = CH2O Bu

R6 R4

PAM Figure 1-4. Phenylacetylene macrocycle prepared by Moore et al. to study the interaction strength of large pi-surfaces in solution.31

Emergent Properties Upon Stacking

While aromaticity is a common feature in pi-pi interacting systems, it is not an absolute requirement. In practice, the use of pi-bonds to construct rigid and planar systems facilitates the contact between molecular surfaces and allows for stabilizing pi- pi interactions to occur. Although not aromatic groups, alkenyl, alkynyl, and carbonyl linkages are commonly used in the design of pi-conjugated oligomers and polymers.35

The emergent properties pi-conjugated materials exhibit upon pi-pi complexation are suitable in many applications spanning disciplines from medicine36 to materials science.37,38

Optical Properties

Upon pi-pi complexation, arenes and planar pi-conjugated molecules can display new or enhanced properties. One common effect is the alteration of the absorption spectral profiles of dye molecules by the formation of pi-stacked aggregates, specifically

H- and J-aggregates, which are akin the E and PD arene-arene geometries, respectively.39 Relative to the monomeric dye molecule, H-dimers exhibit hypsochromically shifted absorption spectra and weakened fluorescence due to the prescence of non-radiative decay pathways. Contrastingly, J-dimers exhibit bathochromically shifted absorption spectra and enhanced radiative decay marked by small Stokes shifts and near quantitative quantum yields. These effects are the response of differences in the transition state dipole moments between interacting dye molecules, where the degree of offset between the dimers dictates the allowed excited- state transitions. The allowed transition states differ in energy for the H- and J-dimers, resulting in divergent spectral profiles in accordance with Kasha’s rule, which states that emission occurs in appreciable yield only from the lowest excited state of a given multiplicity emission (Figure 1-5).40

Figure 1-5. Generalized energy diagram displaying the allowed transitions of H- and J- dimers. Adapted from Chan.41

These effects are pertinent in natural systems, where stacks of chlorophyll exhibit demonstrate J-type excitonic coupling phenomena that enable their functionality as light-harvesting materials for photosynthesis.42 As such, J-aggregates have become a widely investigated class of organic materials as their properties are relevant for supramolecular, photochemical, and materials science interests. The intersection of these principles has led to the design new optoelectronic materials towards synthetic light harvesting systems.43-46 Pioneering work by Würthner and co-workers has developed the supramolecular chemistry of perylene bisimide (PBI) dyes so that they can be selectively formed into H- or J-aggregates.47-49 The J-aggregate forms of PBI have demonstrated exceptional exciton transportation and charge separation and are promising for implementation into photonic and photovoltaic applications.

Charge mobility

Organic semiconductors have received significant research attention due to their utility in optoelectronic devices such as organic field effect transistors (OFETs), organic photovoltaics (OPVs), and organic light-emitting diodes (OLEDs). One common feature shared by all of these devices is the requirement for materials capable of efficient charge carrier mobility. Charge carrier mobility is the continuous transport of exitons

(negatively-charged electrons and positively-charged hole pairs) from one pi-conjugated molecule to another until their charges reach the respective termini of the device. The efficiency of this process (whether the charges continue to migrate or recombine) depends on the pi-pi arrangement.50 To achieve efficient charge transport, the pi- surfaces should be in a face-to-face arrangement, achieving optimal pi-orbital overlap.51

Common semiconductive building blocks, such as oligoacenes and oligothiophenes do not stack co-facially, but rather in the herringbone (edge-to-face)

arrangement. This is indeed the case for pentacene, a highly studied PAH.52 However, when functionalized with triisopropylsilylethynyl (TIPS) groups in the 6- and 13- positions, pentacene packs face-to-face and shows improved solid-state electronic properties (Figure 1-6).53 In 2014, Ryno, Risko, and Brédas showed this parallel- displaced “brickwork” packing arrangement of 6,13-bisTIPSpentacene is guided by the steric factors imposed by the TIPS groups, which overcome repulsion forces between interacting pentencene cores.54 While the functionalized and nonfunctionalized parent pentacene display similar electronic properties in solution, the effect of packing structure extends to the polarization properties of solid-state pi-conjugated materials.

Figure 1-6. The X-ray crystal structures of pentacene packing arrengments. The nonfunctionalized compound (left, CSD code: PENCEN01) shows edge-to- face packing why the functionalized derivatives (right, CSD code: VOQBIM) shows parallel-displaced face-to-face stacking.

Redox Properties

Redox chemistry spans its influence in many scientific areas. The conductivity of organic semiconductors is interpreted as an effect of the electronic structure of redox states along the conjugated chain.55 The stability of a redox structure is often depicted by through-bond or, less often, through-space resonance structures. Typically, a cofacial arrangement of aromatic moieties will stabilize a oxidized or reduced state via a cation/pi or anion/pi type-interaction and through-space delocalization of the charge.56

Thiophene is a commonly encountered heteroaromatic p-type (hole transporting) semi-conductive building block and has demonstrated a substantial correlation between long-range order and charge transport properties.57 To directly probe the effects of pi- stacking on redox behaviors and electronic structures of aromatics, Collard et al. utilized a bicyclo-[4.4.1]undecane scaffold (Figure 1-7).58 In this model system, fused thiophene groups were positioned in a face-to-face stacked arrangement. They compared the redox properties of this system to a non-stacking comparator molecule, tetramethylthiophenem and observed a dramatic effect arising from pi-stacking. The comparator molecule showed one irreversible oxidation at +1.39 V, while the stacked analogue underwent two separate 1e- oxidations, including one at a lower potential

+1.09 facilitated by electrostatic stabilization encountered from pi-stacking and another at higher potential +1.59 V impeded by Coulombic repulsion between the charged aromatic tiers.

Figure 1-7. The face-to-face stacked thiophene model system utilized by Collard et al. to study the effect of pi-stacking on redox properties. (CSD code: RESVAN)

Using Hydrogen Bonds to Guide Arene Assembly

Although pi-stacking is a modest interaction in terms of strength, it is one of the most widely recognized molecular forces and is an essential factor in crystal packing

and biomolecule assembly. A reason for this prevalence is that pi-interactions are frequently accompanied stronger and more directional forces, enabling pi-pi interactions to play a supporting role. Undoubtedly pi-stacking and hydrogen bonding often work together synergistically in biology. Furthermore, cooperativity between these non- covalent interactions has been revealed through computational and experimental work, where the thermodynamic stability provided by multiple interactions integrated into a single system is greater than the sum offered by the disconnected components.59-61

Examples from Nature

Hydrogen bonding in-plane of arenes can effectively expand the pi-surface and facilitate dispersive pi-pi interactions, while electrostatic pi-interactions can affect the basicity of heteroatoms and, in turn, H-bond strength. A central example of such pi- stacking and hydrogen bonding synergism is in the DNA double-helix, where the structure is supported by pi-stacked nucleobase pairs. The interaction energy of H- bonded nucleobase pairs has received considerable attention (structures shown in

Figure 1-8).62-65 Geerlings et al. have used high level quantum chemical calculations on experimentally derived structures to study this interplay and observed an increase in hydrogen bonding ability upon stacking of DNA base pairs. This H-bonding ability enhances upon an increase in the number of stacked partners.66 Another interesting computational result generated by Hobza et al. suggested that while the hydrogen bonding interactions are required to template the dimerization between each DNA strand, the helical geometry would unravel without the dispersive pi-pi interactions

(Figure 1-9).67 These data emphasize that embedding the H-bonding recognition sites into the heteroaromatic purine and pyrimidine backbone is a key design factor in DNA double-helix formation.

Figure 1-8. Nucleobase pairs constructed from purine and pyridine backbones shown with conventional numbering scheme.

Figure 1-9. Unraveling of DNA in the absence of dispersion interactions between base pairs during molecular dynamics simulations performed by Hobza et al. Adapted with permission from J. Am. Chem. Soc., 2008, 130 (47), 16055– 16059. Copyright 2008 American Chemical Society.

As previously mentioned, supramolecular organization of chlorophylls (Chls) into

J-aggregates allows these porphyrin-based dye molecules to act as a light-harvesting

antennae system in plants.68 Chlorin, a closely related derivative of porphyrin found in

Bacteriochlorophylls (BCls), likewise functions as a light harvest system in phototrophic bacteria.42 Solid-state NMR and cryogenic electron microscopy (cryoEM) have been used to characterize the self-organization of BCls into tubular structures by multiple weak non-covalent interactions that occur both laterally and orthogonally to the chlorin plane. These non-covalent forces include hydrogen bonding, metal-ligand coordination, and pi-pi stacking.69 As one example, BCh1 c and the self-assembly of its mimetic zinc analog is show in Figure 1-10.70,71

Figure 1-10. Chemical structures of BChl c and zinc chlorin model compound and schematic representation of a section of tubular assemblies formed by the interplay of hydrogen bonding (red arrow), metal oxygen coordination (blue arrow), and pi-pi stacking. Reprinted with permission from Acc. Chem. Res., 2013, 46 (11), 2498–2512. Copyright 2013 American Chemical Society.

Synthetic Supramolecular Materials

There are many examples in the literature of supramolecular assemblies that utilize hydrogen bonds appended to pi-functional materials, typically arenes, to form well-defined pi-stacked nanostructures.72,73 These materials are a promising design strategy to facilitate electron and hole transport in organic electronic devices.74 These hierarchical assemblies can be tuned through rational design of the hydrogen-bonding moiety. Two generalized motifs are that which employ hydrogen bonds that are directed

(1) in the same plane of the arene (perpendicular to the stacking direction) and (2) out of the arene plane (along the stacking direction).

In-Plane Hydrogen Bonding

In-plane hydrogen bonds can be used form discrete H-bonded systems by complementary homodimerization, heterodimerization, or cyclic oligomerization (rosette formation). These enlarged and polarized pi-surfaces can then polymerize into columnar pi-stacks.

Figure 1-11. Molecules used to construct supramolecular pi-functional systems from hydrogen bonding interactions perpendicular to the axis of polymer stacking. a) Structure of an OPV oligomer, H-bonded dimer, and pi-stacked polymer obtained from molecular dynamics simulations,79 b) structure of H-bonded trimer formed between heteroassociation of OPV-DAT and PBI,80 c) trimer rosette formed by cyclic oligomerization of phthalhydrazide upon tautomerization and optical texture columnar discotic mesophases formed by derivatives where R = n-octyl (left) and R = n-decyl (right).83 Sections (a) and (c) are adapted with permission from J. Am. Chem. Soc., 2003, 125 (51), 15941–15949 and J. Am. Chem. Soc., 1998, 120 (37), 9526–9532, Copyright 2003 and 1998 American Chemical Society, respectively.

Renowned examples of each binding motif include the following: homodimerization of oligo(phenylene vinylene)OPVs by quadrupole hydrogen bonds between appended ureidotriazine moieties75,76 which have served as critical model systems to study excitonic migration along pi-pi stacked molecules (Figure 1-11a); 77-79 heterodimization between imides of perylene bisimide (PBI, n-type chromophore) and diaminotriazine functionalized OPV (OPV-DAT, p-type chromophore) assembling into helical stacked polymers, which enabled intermolecular photoinduced charge transfer between the chromophores within the stack (Figure 1-11b);80-82 and the cyclic trimeric rosette formation of phthalhydrazide (PH), which form columnar arrays that have been used to study liquid crystalline phases and template semiconductor assembly in thin films (Figure 1-11c).83-85

Out-of-plane Hydrogen Bonding

Hydrogen bond interactions aligned perpendicular to the arene plane are utilized to guide the assembly of the pendent pi-conjugated chromophore wire-like 1-D structures. This enforced pi-stacked structure, again, facilitates charge transport in organic electronic devices. Whereas in-plane hydrogen bonds are typically accomplished by use of hydrogen bond donors and acceptors built directly into the arene, hydrogen bonds that align perpendicular to the arene plane are typically formed between pendant amide and urea (or thiourea) functional groups that exhibit free rotation.

Returning to a simple and familiar scaffold, benzene-1,3,5-tricarboxamides

(BTAs) are an essential example of this motif, where the amide groups in the 1, 3, and 5 positions rotate out of the benzene plane to form hydrogen bonds with neighboring

molecules that propagate in the pi-stacking direction (Figure 1-12a).86 Substituting the 2,

4, and 6 position allows the formation of supramolecular polymers with selective properties.87-89 Utilizing a similar tri-fold amide hydrogen-bond motif on an intricate multicomponent chromophore, Schmidt, Hildner et al. demonstrated long range energy transport in a single supramolecular wire at room temperature (Figure 1-12b).90

Figure 1-12. Molecules used to construct supramolecular pi-functional systems from hydrogen bonding interactions along the axis of polymer stacking. a) Molecular structure and schematic representation of BTA self-assembly into helical one-dimensional aggregates, which are stabilized by threefold intermolecular H-bonding,86 (b) Multicomponent molecular structure including carbonyl-bridged triarylamine (CBT) core (green); amide moieties (blue) 4-(5- hexyl-2,2′-bithiophene)-naphthalimide (NIBT) periphery (yellow/gold) and schematic representation of self-assembly into nanofibres with an ordered H- aggregated core, driven by pi-stacking of CBTs and stabilized by three chains of hydrogen bonds between the amide groups.90 Sections (a) and (b) are adapted with permission from Chem. Soc. Rev., 2012, 41, 6125–6137 and Nature, 2015, 523, 196–199. Copyright 2012 Royal Society of Chemistry and 2015 Springer nature, respectively.

Motivation of Dissertation

The principles learned from biological self-assembly and simplified model systems allows access to well-defined synthetic assemblies with tunable properties. It is

the fundamental study of these intricate phenomena that will provide access to and innovation in applied technologies (Figure 1-13). From this larger perspective, the fundamental studies on molecular self-assembly of novel pi-conjugated systems, including their design, synthesis, and characterization, is described in this dissertation.

The influence on emergent properties of pi-conjugated materials by tuning the supramolecular structure motivates this work.

Figure 1-13. Flowchart demonstrating that non-covalent interactions are central to biological self-assembly and new supramolecular structures. Adapted with permission from Angew. Chem. Int. Ed. 2004, 43, 668 – 698. Copyright 2004 John Wiley and Sons.91

Specifically, we are developing new pi-systems that are equipped with strong hydrogen-bonding groups to effectively guide cofacial stacking interactions. This investigation begins with a bio-inspired approach, taking advantage of both the hydrogen bonding capability and aromatic nature of DNA nucleobases by integrating them into organic semiconductors. Through fundamental analysis of the molecular recognition and optoelectronic properties, we may identify critical design factors that will dictate the methodology required bring these novel materials into optoelectronic applications. Also presented in this body of work is the development of a new hydrogen-

bonding archetype based on [2.2]paracyclophane, and discovery of its unique supramolecular properties.

CHAPTER 2 STRUCTURE-PROPERTY INVESTIGATION OF NUCLEOBASE CONTAINING PI- CONJUGATED MATERIALS

Introductory Remarks

Nucleobases, nature’s “information rich” building blocks, are mutually responsible for maintaining pristine biomacromolecular structure by formation of hydrogen bonds and pi-contacts, and imparting function by storage of life’s genetic code. The high fidelity of DNA base-pairing (adenine–thymine(uracil) and guanine–cytosine) along with an array of other binding motifs (e.g. self-dimerization and non-Watson-Crick pairing) make nucleobases prototypical assembly units for supramolecular studies.92-94 As consequence, these bioderived building blocks have been adopted by researchers to control the 3-D ordering of synthetic systems, spanning soft materials and solid-state architectures.95,96

Their molecular recognition capabilities are justly applied to control materials properties. For example, complementary base-pairing has been used as a dependable method for cross-linking pendent monomers or polymers97 and patterning nanostructures on surfaces, interfaces, and in solution.98,99 Overshadowed by this morphological control, is their ability to tune the optical and electronic properties of materials by direct incorporation of their aromatic purine/pyrimidine rings into pi- conjugated materials. Along these lines, the Castellano group has developed synthetic methodology to embed the nucleobases adenine, uracil, or guanine into pi-conjugated oligomers, and has shown that indeed, nucleobase identity affects the electronic structure of these molecules by modification of their optical absorbance profile and

HOMO/LUMO energy levels.100 Other work by Kilbey and co-workers has demonstrated

that the regiochemistry (6 vs. 8) of chromophore conjugation has additional influence on the optoelectronic properties of purine-containing compounds.101

While nucleobases are a widespread supramolecular motif, investigation of the intermolecular binding of pi-conjugated nucleobase compounds is seldom performed.102

Recent relevant work comes from González-Rodríquez et al. who quantified the binding strength of lipophilic ribonucleoside-terminated ethylene phenylene oligomers in organic solvents (chloroform and carbon tetrachloride).103 Their results agree with known preferences of nucleobases interactions in organic solvents,104 where adenosine and uridine interact of modest strength (101–102 M-1), and the interaction strength between cytidine and guanosine is significantly stronger (104 M-1). An important aspect of their molecular design, similar to other lipophilic derivatives, is the incorporation of alkylated ribose groups to afford solubility in organic solvents. This bulky group improves solubility by hindering pi-pi interactions between neighboring planar molecules, but this concurrently has an adverse affect on functionality in solid-state device settings that rely on closely pi-stacked chromophores for charge mobility.

Molecular Design

To better understand the potential nucleobase-containing pi-conjugated oligomers hold in optoelectronic device applications, a combined study of the optical and electronic properties and intermolecular binding of device-relevant derivatives is required. To this avail, we have we have designed a novel set of nucleobase-containing oligomers fully conjugated to a terthiophene backbone, a quintessential organic semiconductor (Figure 2-1).105 Each of the canonical nucleobases are installed in a monotopic design, facilitating 1:1 binding analysis. The typical ribose fragments are replaced by a 2-ethylhexyl alkyl chain,106 a solubilizing group commonly utilized by

practitioners in the pi-conjugated materials community. The resulting fundamental characterization of optoelectronic properties and complementary hydrogen bonding interactions are critical to rationally port such materials into solid-state settings and optoelectronic devices, such as in organic photovoltaic cells (OPVs) and field-effect transistors (OFETs).107

Figure 2-1. Nucleobase-containing pi-conjugated targets evaluated.

Synthesis

Adenine and Guanine Oligomers

The synthetic routes to obtain adenine derivative 2-1A and guanine derivatives 2-

1G, 2-1PGa, and 2-1PGb are shown respectively in Schemes 2-1 and 2-2, and have been synthesized and reported by a former Castellano group member, Raghida Bou

Zerdan.108

Scheme 2-1. Synthesis of adenine-terminated oligomer 2-1A.a

Scheme 2-2. Synthesis of guanine and protected guanine-terminated oligomers 2-1G, 2-1PGa, and 2-1PGb.a

Uracil Oligomer

Despite many efforts, the regioselective halogenation of the C(5) thienyl position of uracil derivative 2-13 by either bromination or iodination to provide intermediate 2-14 remains elusive (Scheme 2-3).108 Target compound 2-1U was obtained via Stille cross- coupling between compound 2-12 and terthiophene derivative 2-15 as shown in

a Synthesized by former Castellano group member Dr. Raghida Bou Zerdan

Scheme 2-3. Stannylated compound 2-15 was prepared according to literature procedure from terthiophene and is shown in Scheme 2-4.109

Scheme 2-3. Synthesis of uracil-terminated oligomer 2-1U.

Scheme 2-4. Synthesis of 5-hexyl-5’-tributylstannyl-2,2-:5’,2’’-terthiophene.

Cytosine Oligomer

The synthesis of cytosine-terminated oligomer 2-1C is shown in Scheme 2-5 and was originally prepared by Raghida Bou Zerdan as an inseparable mixture.108 The final product was obtained via Suzuki cross-coupling between compounds 2-22 and 2-3. Due to similar polarities, product 2-1C and starting material 2-22 could not be easily separated. Using chromatographic methods, both compounds co-eluted under several mobile phase conditions (hexanes/ethyl acetate or dichloromethane/methanol mixture) on both silica and neutral alumina. Separation was ultimately achieved using automated

flash chromatography (CombiFlash) using a gradient of 0–20% isopropanol (containing

1% TFA) in hexanes mobile phase and silica gel stationary phase.

Scheme 2-5. Synthesis of cytosine-terminated oligomer 2-1C.

Optoelectronic Properties

Computations

Gas-phase calculations (DFT B3LYP/6-31+G**) were performed on all oligomers to approximate expected HOMO and LUMO energy levels as well as optimized structural geometries.108 Computational results are summarized in Table 2-1. A methyl group was used in place of all alkyl chains to reduce computational time, since they do not significantly affect the equilibrium geometries or electronic properties. Calculations on 2-1A, 2-1U, 2-1G, 2-1PGa/b proceeded with oligomer structures adhering to established preferences of lowest energy conformers of truncated versions. Whereas the aforementioned nucleobases are nearly planar (dihedral angles are < 7° between the nucleobase and terthiophene fragments), the cytosine analog was determined to prefer a twisted orientation between the nucleobase and adjacent thiophene (dihedral

angle ~ 48°, Figure 2-2), disrupting conjugation and resulting in a larger energy gap relative to the other compounds.

Table 2-1. DFT calculations on nucleobase-containing oligomersa,b c Compound HOMO (eV) LUMO (eV) Eg(eV) Torsion Angle (°) 2-1A -5.32 -2.29 3.03 1.7 2-1U -5.28 -2.28 3.00 6.7 2-1C -5.43 -2.17 3.26 48.3 2-1G -5.13 -2.08 3.00 8.3 2-1PGa -5.11 -2.14 2.97 2.9 2-1PGb -5.15 -2.16 2.99 3.6 a All ethylhexyl and hexyl groups have been replaced by methyl groups for the calculations. Geometry optimization and calculation of the HOMO and LUMO energies was performed at the B3LYP/6-31+G** level. b Computations performed by Dr. Raghida Bou Zerdan. c Torsion angle measure between planes on pyrimidine/purine heterocycle and adjacent thiophene.

64.24°

51.71°

2-21-i -986.096124541 a.u. 2-21-ii -986.095435539 a.u. (0.00 kcal/mol) (+0.43 kcal/mol)

Figure 2-2. Conformational analysis of truncated cytosine oligomer. Total energy in hartrees and relative energy in kcal/mol are listed below each conformer.

Absorption

The absorption spectra of all oligomers were measured in dilute DMF (Figure 2-

3) and showed linear Beer-Lambert relationships, indicating no aggregation under these conditions. All spectra displayed a single absorption band corresponding to a pi-pi* transition and some small variance in molar extinction coefficients, though within the

same order of magnitude (2.5–4.5×104 M-1 cm-1). The guanine and protected guanine derivatives 2-1G, 2-1PGa, and 2-1PGb displayed similar absorbance profiles, with absorption maxima ranging from 409-412 nm and identical absorption onsets at 477 nm

(ΔEopt = 2.60 eV). The adenine and uracil derivatives, 2-1A and 2-1U, were slightly blue-shifted relative to guanine, displaying identical absorption maxima at 404 nm, and absorption onsets at 468 and 460 nm (ΔEopt = 2.65 and 2.70 eV), respectively.

Cytosine derivative 2-1C showed the most hypsochromically shifted absorption spectrum, with anabsorption maximum at 382 nm and an onset at 437 nm (ΔEopt = 2.84 eV). The observed differences in absorption spectra, over a range of 30 nm, emphasize the influence of nucleobase identity on the intrinsic optical properties of pi-conjugated systems in solution.

1.0 2-1A 2-1U 2-1C 2-1G 2-1PGa 2-1PGb

0.5 NormalizedAbsorbance (a.u.)

0.0 300 400 500 Wavelength (nm)

Figure 2-3. Overlaid normalized UV-Visible absorption spectra of nucleobase-containing oligomers measured at 20 × 10-6 M in DMF at room temperature.

Electrochemistry

Electrochemical measurements were performed in DMF, again to eliminate aggregation-induced effects on the electronic behavior of the compounds. Compounds

2-1A, 2-1G, 2-1PGa, and 2-1PGb display a single irreversible oxidation, commonly observed for purine derivatives,110-112 and a quasi-reversible reduction band within the accessible solvent window. The pyrimidine derivatives displayed two irreversible oxidations, with 2-1U displaying a quasi-reversible reduction and 2-1C displaying a

onset onset single irreversible reduction band. The key values, Eox and Ered , were determined from the oxidation and reduction onsets, respectively, measured for the compounds in solution versus Fc/Fc+ reference. From these experimentally determined values, EHOMO, ELUMO, and ΔE were estimated following equations 2-1, 2-2, and 2-3, respectively.113-115 Results are summarized in Table 2-2. Compound 2-1G displays a significantly higher HOMO value (-5.31 eV) compared to the other compounds, which narrowly range within 0.1 eV (from -5.52 to -5.61 eV). This data point differs from the optical measurements and the DFT estimations, which suggest 2-1G is nearly identical electronically to comparators 2-1PGa and 2-1PGb. However, this result is in line with previous studies concerning guanine oligothiophene derivatives.116 The LUMO values vary among each entry, with 2-1U displaying the highest level at -3.78 eV and 2-1G the lowest at -3.92 eV. The combination of a high-lying HOMO and low-lying LUMO, as displayed by 2-1G, is favorable to optoelectronic materials requiring a small bandgap.

풐풙 푬푯푶푴푶 = −(푬풐풏풔풆풕 + ퟓ. ퟏ) 풆푽 (2-1)

풓풆풅 푬푳푼푴푶 = −(푬풐풏풔풆풕 + ퟓ. ퟏ) 풆푽 (2-2)

횫푬 = 푬푳푼푴푶 − 푬푯푶푴푶 (2-3)

Table 2-2. Electronic properties of nucleobase-containing oligomers. ox red ECE optical Eonset Eonset HOMO LUMO Eg Eg Entry (V) ± 0.1a (V) ± 0.1a (eV) ± 0.1b (eV) ± 0.1b (eV) ± 0.2 (eV) ± 0.2c 2-1Ad 0.50 -1.23 -5.60 -3.87 1.73 2.65 2-1U 0.42 -1.32 -5.52 -3.78 1.74 2.70 2-1C 0.51 -1.22 -5.61 -3.88 1.73 2.84 2-1Gd 0.21 -1.18 -5.31 -3.92 1.39 2.60 2-1PGad 0.42 -1.23 -5.52 -3.87 1.65 2.60 2-1PGb 0.48 -1.20 -5.58 -3.90 1.68 2.60 a Energies are reported relative to Fc/Fc+ redox couple and are obtained from CV experiments; the solvent employed is N,N-dimethylformamide (DMF) (0.1 mM TBAPF6 at a 100 mV/s scan rate). b Estimated HOMO and LUMO energy levels (relative to vacuum) ox red based on electrochemical potentials (Eonset and Eonset , respectively) determined from CV experiments. c Determined based on UV absorption data in DMF. d Data for these entries was collected by Dr. Raghida Bou Zerdan.

Thermal Properties

The thermal stability of the nucleobase-containing compounds was assessed by thermal gravimetric analysis (TGA). The temperature of 5% weight loss was extrapolated as the onset of decomposition. All compounds exhibited thermal stability at high temperatures (> 200 °C). Compound 2-1U showed 5% loss of its original compound weight at 217 °C. Compound 2-1G appeared displayed multiple weight loss onsets, with a 5% weight loss at 229 °C and a slow decrease in weight until approximately 300 °C where the weight loss transition superimposed those of 2-1PGa/b

(Figure 2-3). High thermal stability was observed for the remaining compounds 2-1A, 2-

1C, 2-1PGa, and 2-1PGb which showed a 5% weight loss at 292, 297, 330, and 303 °C, respectively. This analysis is commonly utilized to obtain a rudimentary estimate of the thermal stability limit; however, underestimated values often result from gradual weight loss onsets. Multiple weight loss onsets were observed for compounds 2-1A, 2-1G, 2-

PGa, and 2-1PGb. In all cases, structural determination of the fragments expelled during heating is required to assign the decomposition pathways.

The melting transition temperatures were determined by differential scanning calorimetry (DSC) performed at a rate of 10 °C/min for one cycle. The melting transitioned ranged between 101–141 °C for all compounds except 2-1G for which no melting transition was observed. This increase in melting temperature is attributed to the stronger self-hydrogen bonding exhibited by 2-1G relative to the other compounds in the solid state. Further DSC analysis, including repeated runs and slower heating/cooling rates, is required to find possible crystallization transitions and correlate these thermal responses to self-association behavior.

Figure 2-4. TGA data collected for nucleobase-containing compounds.

Self-Association

The extent of self-aggregation needs to be determined before evaluating hetero- association between nucleobases. For this purpose, NMR titrations on 2-1A, 2-1U, 2-

1C, and 2-1PGa were carried out in chloroform and the respective dimerization constants were ascertained by fitting the observed change in chemical shift to analyte concentration (Table 2-3).117 The dimerization constants were determined using two methods that resulted in the same absolute values (1) non-linear curve fitting in Origin

8.5 in accord with an dimerization model (equation 2-4) and (2) BindFit “NMR Dimer

Aggregation” online calculator developed by Thordarson and co-workers.118 Adenine

-1 and uracil displayed modest dimerization constants (Kdim <5 M ) by monitoring C(6)–

NH2 and N(3)–H proton shifts, respectively (Figures 2-5 and 2-6). Cytosine displayed a

-1 slightly stronger aggregation (Kdim ~36 M ) and was determined by following the C(4)–

NH2 amino proton shift, which split into two broad peaks, due to restricted rotation upon complexation (Figure 2-7).119 The C(6)O protected guanine derivatives showed no

-1 preference for self-aggregation in chloroform (Kdim <1 M , Figure 2-8).

(2-4)

δobs = measured chemical shift

δd = chemical shift of dimer

δm = chemical shift of monomer

ct = total concentration

Kd = dimer binding constant

1 Figure 2-5. Concentration-dependent HNMR data collected for 2-1A in CDCl3 at 298 K (a) stacked 1HNMR spectra and binding isotherms fit using (b) non-linear curve fitting employed in Origin Pro 8.5 and (c) Bindfit online calculator.

1 Figure 2-6. Concentration-dependent HNMR data collected for 2-1U in CDCl3 at 298 K (a) stacked 1HNMR spectra and binding isotherms fit using (b) non-linear curve fitting employed in Origin Pro 8.5 and (c) Bindfit online calculator.

1 Figure 2-7. Concentration-dependent HNMR data collected for 2-1C in CDCl3 at 298 K (a) stacked 1HNMR spectra and binding isotherms fit using (b) non-linear curve fitting employed in Origin Pro 8.5 and (c) Bindfit online calculator.

1 Figure 2-8. Concentration-dependent HNMR data collected for 2-1PGa in CDCl3 at 298 K (a) stacked 1HNMR spectra and binding isotherms fit using (b) non-linear curve fitting employed in Origin Pro 8.5 and (c) Bindfit online calculator.

The poor solubility of 2-1G in non-polar solvents at mM concentrations precluded its measurement by NMR. Analysis by UV-Vis within solubility range in chloroform (<40

μM) indicates signatures of aggregation in solution (Figure 2-9). Indicative spectral features include a non-linear Beer-Lambert relationship, bathochromic shift of λmax from

399 to 407 nm, and appearance of a shoulder peak at 530 nm upon increasing concentration. These spectral features are characteristic to pi-pi interactions in solution, and that these features are not observed for 2-1G in DMF links the pi-pi interactions to self-hydrogen bonding of the oligomer.

While guanine is known to self-aggregate, most notably as G-quartet arrangement or G-ribbons, related lipophilic guanosine derivatives evaluated González-

Rodríquez and co-workers are sufficiently soluble in non-polar solvents.120 The branched 2-ethylhexyl chain used here, a common solubilizing group for optoelectronic materials, is still less bulky compared to the alkylated ribose solubilizing group, enabling close pipi interactions upon aggregation. Further evidence of the influence of hydrogen bonding on properties can be seen when comparing the optical properties; while 2-1G and 2-1PGa/b displayed nearly identical optical properties and a yellow color when solvated in DMF, the solid-state color of 2-1G differed significantly from 2-1PGa and 2-

1PGb, where 2-1G was deep orange, and the protected derivatives remained dark and bright yellow, respectively (Figure 2-10).

Figure 2-9. Concentration-dependent UV-Vis absorption data collected for 2-1G CDCl3 at 298 K including (a) overlaid UV-Vis absorption spectrum in, (b) related Beer-Lambert plot at multiple wavelengths, and (c) normalized absorption spectra.

2-1G 2-1PGa 2-1PGb

Figure 2-10. Images of guanine derivatives 2-1G, 2-1PGa, and 2-1PGb in the bulk.

Hetero-Association

Adenine and Uracil Base-Pairing

The base-pairing interaction between 2-1A and 2-1U was assessed in chloroform using conventional host guest titrations while monitoring with 1HNMR. Both situations, using 2-1A as the host (10 mM) and 2-U (50 mM) (Figure 2-11) as the guest and vice versa (Figure 2-12), were performed. Analyzing the change in chemical shift of the atom involved in hydrogen bonding C(6)–NH2 for 2-1A and N(3)–H for 2-1U provided data for association constant determination. The association constants were determined using two methods that resulted in the same absolute values (1) non-linear curve fitting in

Origin 8.5 in accord with an association model (equation 2-5)121 and (2) BindFit “NMR

1:1” online calculator developed by Thordarson and co-workers.118 The association

-1 constants determined for both host-guest roles were in agreement, Ka ~35 M . This

value differs by an order of magnitude compared to that determined for related compounds, 2-aminodenosine and uridine (102 M-1), however it is important to distinguish that the naturally occurring hydrogen-bonding form of adenine, 6-amino purine, was used in this work, whereas a closely related 2,6-diamino purine derivative was used by González-Rodríquez and co-workers.103

ퟐ ퟐ (푲풂([푯]+[푮])+ퟏ) −ퟒ푲풂 ∗[푯]∗[푮] 휹풐풃풔 = 휹푯 + (휹푯푮 − 휹푯) ∗ ((푲풂([푯] + [푮]) + ퟏ)) − √ (2-5) ퟐ푲풂[푯]

δobs = measured chemical shift

δH = chemical shift of empty host solution

δHG = chemical shift of fully occupied host solution

[H] = total host concentration

[G] = total guest concentration

Ka = binding constant

Figure 2-11. Titration 1HNMR data collected for 2-1A (host, 10 mM) upon addition of 2- 1U (guest) in CDCl3 at 298 K including (a) raw spectra and binding isotherms fit using (b) non-linear curve fitting employed in Origin Pro 8.5 and (c) Bindfit online calculator.

Figure 2-12. Titration 1HNMR data collected for 2-1U (host, 10 mM) upon addition of 2- 1A (guest) in CDCl3 at 298 K including (a) raw spectra and binding isotherms fit using (b) non-linear curve fitting employed in Origin Pro 8.5 and (c) Bindfit online calculator.

Guanine and Cytosine Base-Pairing

Quantification of the association constant governing the interaction between 2-1C and 2-1G was more challenging due to the limited solubility of the aggregate. NMR titration between 2-1C (host) and 2-1G (guest) was performed using NMR. The initial concentration of 2-1C used was 1 mM, lowered relative to 2-1A/2-1U to exclude host dimerization from the experiment, as determined by the dimerization constant. Changes in chemical shift indicative of base-pairing were observed, including peak splitting, downfield shift from 5.5 to 10.0 ppm of the C(4)–NH2 resonance of 2-1C, and an upfield

shift the N(1)–H resonance of 2-1G (Figure 2-13). The species were only soluble up to a

1:0.6 host:guest ratio, and due to this limited solubility of the heterodimers, an exact Ka could not be determined in chloroform by NMR titrations. This limited solubility is attributed to stacking of the increased pi-surface that arises upon base-pairing of oligomers or formation of higher aggregates.122 The reverse situation, using 2-1G as the host and 2-1C as the guest, was not possible using NMR given the inability to collect a zero-point (free host) measurement for 2-1G at an appropriate concentration (>10-4 M).

Figure 2-13. Titration 1HNMR data collected for 2-1C (host, 1 mM) upon addition of 2- 1G (guest) in CDCl3 at 298 K including (a) raw spectra and (b) changes in chemical shift upon addition of guest

A parallel UV-Vis experiment, where alkylated guanine derivative 2-7 was titrated as a UV “silent” guest into a 2-1C host solution, did not produce any changes in the absorption spectrum (Figure 2-14). Though, when 2-1G was used as a host (15 uM)

and alkylated cytosine derivative 2-19 as the “silent” guest, a hypsochromic shift from

405 to 402 nm and disappearance of the slight shoulder band near 500 nm was observed (Figure 2-15). These trends are opposite to those observed upon increasing concentrations of 2-1G in the self-association analysis. Taken together, these results indicate that 2-19 disrupts guanine self-aggregation and effectively solvates 2-1G by capping the hydrogen bonding edges. These results are in agreement with the known preference for base-pairing over self-association of guanine and cytosine. Interestingly, while a 1:1 mixture of 2-1G:2-1C is only sparsely soluble in chloroform, an analogous mixture of 2-1G:2-19 is very soluble, supporting the notion that extending the pi-surface of the natural nucleobases increases their propensity to aggregate.

Figure 2-14. Titration (a) UV-Vis absorption spectra collected in chloroform at 298 K of 2-1C (host, 15 M) and upon addition of 2-7 (guest) and (b) plot of absorption versus addition of host monitored at 386 nm.

Figure 2-15. Titration (a) UV-Vis absorption spectra collected in chloroform at 298 K of 2-1G (host, 15 M) and upon addition of 2-19 (guest) and (b) plot of absorption versus addition of host monitored at selected wavelengths.

Table 2-3. Self- and hetero-association constants of nucleobase-containing oligomers. -1 -1 Compound Kdim (M )a Guest Kdim (M )a 2-1A <5 1U 33 ± 3 2-1U <5 1A 38 ± 4 2-1G >104 b 2-19 >104 c 2-1C 36 ± 4 1G >104 b 2-1PGa <1 - - 2-1PGb <1 - - 1 a Determined by HNMR titrations in CDCl3 at 298 K, b Estimated from UV-Vis titrations performed in CHCl3 at 298 K, c Estimated from NMR titrations performed in CHCl3 at 298 K. Concluding Remarks

A library of novel monotopic nucleobase-containing pi-conjugated oligomers has been synthesized. This set of compounds incorporates device-relevant moieties, including an oligothiophene chromophore and an 2-ethylhexyl solubilizing group. As in

previous studies, the identity of the nucleobase had an influence on the intrinsic optoelectronic properties of the oligomer, with guanine derivatives showing the lowest energy optical absorbance and cytosine displaying the highest. These observations agree with DFT estimations, which indicate that cytosine would have a higher energy absorbance due to a twisted conformation that disrupts pi-conjugation within the oligomer. Furthermore, the electrochemical analysis indicates that guanine has a higher-lying HOMO relative to the other derivatives, including protected guanine- derivatives, suggesting that the naturally occurring form of guanine is especially electron-rich and would be useful as a donor fragment in pi-conjugated materials.

To probe the base-pairing fidelity of these lipophilic compounds, the supramolecular properties were evaluated in an organic solvent. The modest binding strength of self-association and hetero-association of adenine and uracil derivatives allowed for their facile analysis in chloroform using 1HNMR techniques. While the self- association of cytosine could be similarly determined using 1HNMR, its hetero- association with its complementary base-pair, 2-1G, was complicated due to significantly strengthened binding, increasing aggregation, and poor solubility for thorough analysis. In accord, the strong self-association of 2-1G conferred pi-stacking interactions in chloroform, evidenced by bathochromic optical absorbance upon increasing concentration. Similarly, its strong hetero-association with 2-1C was overcome by aggregation, causing the assembly to precipitate from non-polar solvents.

These results indicate that the less-sterically hindered 2-ethylhexyl solubilizing group, as envisioned, allows pi-interactions of the conjugated chromophore to accompany hydrogen bonding. This effect urges the implementation of such

nucleobase-containing pi-conjugated optoelectronic materials into solid-state applications that rely on ordered arrays of molecules (Figure 2-16) for unhindered charge carrier mobility.

Figure 2-16. The envisioned supramolecular design from integrating nucleobase dimerization into pi-conjugated constructs. Adapted from González-Rodríquez and Schenning.73

Experimental

Synthesis

General

Reagents and solvents were purchased from commercial sources and used without further purification unless otherwise specified. THF, diethyl ether, CH2Cl2, toluene, and

DMF, were degassed in 20 L drums and passed through two sequential purification columns (activated alumina; molecular sieves for DMF) under a positive argon atmosphere. Thin-layer chromatography (TLC) was performed on SiO2-60 F254 aluminum plates with visualization by UV light. Flash column chromatography was

1 13 performed using SiO2-60, 230−400 mesh. H( C) NMR spectra were recorded on

300(75) MHz or 500(125) MHz spectrometers as specified. Chemical shifts (δ) are given in parts per million (ppm) relative to TMS and referenced to residual protonated solvent

(CDCl3: δH 7.26 ppm, δC 77.23 ppm; DMSO-d6: δH 2.50 ppm, δC 39.50 ppm).

Abbreviations used are s (singlet), d (doublet), t (triplet), q (quartet), quin (quintet), sep

(septet), b (broad), and m (multiplet). Compounds were purchased from commercial resources and used without further purification: 5’-hexyl-2,2’-bithiophene-5-boronic acid pinacol ester (2-3) (Sigma-Aldrich), tetrakis(triphenylphosphine) palladium (0) (Sigma-

Aldrich), trans-bis(triphenylphosphine) palladium (II) chloride (Sigma-Aldrich), and triphenylbismuth (Strem Chemical). The following compounds were synthesized in accordance with literature procedures: 2-1A,108 2-1G,108 2-1PGa,108 2-1PGb,108 2-22,108

2-12,100 and 2-15.109

Synthesis of (±)-1-(2-ethylhexyl)-5-(5''-hexyl-[2,2':5',2''-terthiophen]-5- yl)pyrimidine-2,4(1H,3H)-dione (2-1U)

In a dry round-bottom flask under inert atmosphere, compounds 2-12 (0.10 g,

0.34 mmol), 2-15 (0.25 g, 0.51 mmol), and Pd(PPh3)2Cl2 (0.024 g, 0.034 mmol) were dissolved in dry and degassed dioxane (10 mL) then stirred at 100 °C for 18 hours. The reaction mixture was cooled to room temperature, then concentrated under reduced pressure. The crude product was purified on an automatic silica gel column (0-100 % gradient of ethyl acetate in hexanes to afford product as a yellow solid (0.12 g, 63%). 1H

NMR (500 MHz, CDCl3): δ 8.66 (s, 1H), 7.46 (s, 1H), 7.33 (d, J = 3.9 Hz, 1H), 7.08 (dd,

J = 5.4, 3.9 Hz, 2H), 6.99 (dd, J = 8.8, 3.6 Hz, 2H), 6.68 (d, J = 3.6 Hz, 1H), 3.71 (d, J =

7.5 Hz 2H), 2.79 (t, J = 7.6 Hz, 2H), 1.81 (hept, J = 6.7, 6.2 Hz, 1H), 1.68 (p, J = 7.5 Hz,

13 2H), 1.45 - 1.23 (m, 16H), 0.98 - 0.86 (m, 9H); C NMR (125 MHz, CDCl3): δ 161.18,

149.89, 145.89, 139.43, 137.24, 137.18, 135.31, 134.53, 132.10, 125.03, 124.99,

124.48, 123.75, 123.58, 123.50, 109.55, 77.41, 77.16, 76.91, 52.85, 39.04, 31.71,

30.34, 30.17, 28.90, 28.54, 23.54, 23.12, 22.72, 14.23, 14.18, 10.56. HRMS (ESI) calc’d

+ for C30H38N2O2S3 [M+H] : 555.2168, found: 555.2168.

Synthesis of (±)-4-amino-1-(2-ethylhexyl)-5-(5''-hexyl-[2,2':5',2''-terthiophen]-5- yl)pyrimidin-2(1H)-one (2-1C)

Pd(PPh3)4 (0.067 g, 0.058 mmol), 2-22 (0.25 g, 0.58 mmol), 2-3 (0.38 g, 0.87 mmol), and Cs2CO3 (0.57 g, 1.7 mmol) were dissolved in degassed THF (9 mL), followed by addition of degassed H2O (3 mL). The mixture was heated at 66 °C for 16 hours. The reaction mixture was diluted with DCM (50 mL). The organic layer was separated from the aqueous phase and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure, the crude product was purified by silica gel column chromatography

(EtOAc) to yield the product 2-1C as a yellow solid (80% pure by NMR). The product was further purified on an automatic silica gel column (0-20% gradient of isopropanol

(+1% TFA) in hexanes to yield the pure product as a mixture of regioisomers (0.11 g, 34

1 %). H NMR (500 MHz, CDCl3): δ 8.12 (s, 1H), 7.28 (s, 1H), 7.11 (d, J = 3.6 Hz, 1H),

7.05 (d, J = 3.7 Hz, 1H), 7.00 (dd, J = 6.1, 3.7 Hz, 2H), 6.96 (d, J = 3.7 Hz, 1H), 6.69 (d,

J = 3.5 Hz, 1H), 5.65 (s, 1H), 3.67 (d, J = 7.3 Hz, 2H), 2.79 (t, J = 7.6 Hz, 2H), 1.92–

1.78 (m, 2H), 1.68 (p, J = 7.6 Hz, 2H), 1.44–1.19 (m, 16H), 0.97–0.81 (m, 9H).; 13C

NMR (125 MHz, CDCl3): δ 163.97, 155.96, 146.10, 145.55, 138.41, 137.68, 134.53,

134.31, 132.63, 128.17, 125.02, 124.86, 124.12, 123.76, 123.71, 100.76, 54.11, 38.60,

31.69, 30.33, 30.31, 28.88, 28.57, 23.62, 23.16, 22.71, 14.22, 14.19, 10.57. HRMS

+ (ESI) calc’d for C30H39N3OS3 [M+H] : 554.2328, found: 554.2332.

Computations

Starting geometries were obtained from semi-empirical calculations using the

MM2 method as implemented in Chem3D Pro v. 13.0.0.3015 for Windows. The ground

state geometries, energies and orbital energies were then obtained from DFT calculations at the B3LYP/6-31+G** level as implemented in Gaussian 09,123 accessed through the UF High-Performance Computing Center. Frequency calculations were performed at the same computational level, and no imaginary frequencies were found.

Molecular orbital plots were made using GaussView v. 5.0.8124 from the Gaussian output files. Computations were performed by Raghida Bou Zerdan.108

UV-Vis Spectroscopy

Absorption spectra were measured on a Perkin-Elmer Lambda 25 dual beam absorption spectrometer and a Cary 100 Bio spectrophotometer using 1 cm quartz cells.

All solvents were spectroscopic grade (purchased from Fisher) and stored over 4 Å molecular sieves. The absorption intensity at λmax was then plotted against the concentration in all cases to confirm, by linearity, that the compounds followed Beer’s law. Molar extinction coefficients (ε) were determined from the linear plot for each compound (where A = εbc). Values for λonset were determined from the intercept of the decreasing slope of λmax absorption and the baseline.

Electrochemistry

Cyclic Voltammetry (CV) measurements were performed at a scan rate of 100 mV/s using a single-compartment three-electrode cell with a gold counter electrode, a

Ag/Ag+ reference electrode, and a platinum disk (0.02 cm2) as the working electrode.

Electrodes were purchased from either BASi, Inc. or CH Instruments.

Tetrabutylammonium hexafluorophosphate (TBAPF6) was purchased from Aldrich and kept dry under vacuum. DMF was collected from an Innovative Technologies solvent system, sparged with Ar and passed over two columns of 5 Å activated sieves. The oligomer solid was dissolved to a concentration of 2 mM in a 0.1 M TBAPF6/DMF

electrolyte. Potential sweeps were controlled by a Princeton Applied Research

Versastat II potentiostat.

Thermal Gravimetric Analysis

Thermal gravimetric analysis (TGA) was performed using a TA Instruments TGA

Q5000-0121 V3.8 Build 256 at a heating rate of 10 °C/min using 1–3 mg of sample in a

100 μL platinum pan (under nitrogen).

Differential Scanning Calorimetry

Differential Scanning Calorimetry (DSC) was performed using a TA Instruments

DSC Q1000-0620 V9.9 at a heating/cooling rate of 10 °C/min using 1–3 mg of sample in a sealed aluminum pan, with respect to an empty aluminum reference pan.

Binding Studies

Determination of dimerization strength by NMR

NMR dilutions were performed at 298 K on an Inova 500 spectrometer (500

MHz) in CDCl3, purchased from Cambridge Isotope Laboratories. Individual concentrated solutions of 2-1A, 2-1U, 2-1C, and 1PGa were prepared in 375 μL of

CDCl3. By micropipette, calculated equivalents of deuterated solvent were added into the NMR tube and the 1HNMR spectrum of the diluted solution measured. The 1HNMR experiments were continued until the dilutions yielded chemical shifts within the 20–80% saturation range. Dilution-induced chemical shifts of adenine 6-NH2, uracil N(3)–H, cytosine NH2, and guanine 2-NH2 of 2-1A, 2-1U, 2-1C, and 2-1PGa, respectively, were monitored for fitting. The dimerization constants were determined using two methods that resulted in the same absolute values (1) non-linear curve fitting in Origin 8.5 in accord with a dimerization model (Equation 2-4) and (2) BindFit “NMR Dimer

Aggregation” online calculator developed by Thordarson and co-workers.118

Determination of the association strength of nucleobase pairing by NMR

NMR dilutions were performed at 298 K on an Inova 500 spectrometer (500

MHz) in CDCl3, purchased from Sigma-Aldrich. The host was dissolved in CDCl3, and

375 μL of the resulting solution (10 mM or 1 mM) was added to the NMR tube. The remainder of the host solution was used to dissolve the guest to ensure the host concentration remained constant throughout the titration. By micropipette, the host- guest solution was added in calculated amounts to the NMR tube containing the original host solution. The binding constants were determined using two methods that resulted in the same absolute values (1) non-linear curve fitting in Origin 8.5 in accord with an association model (Equation 2-5)121 and (2) BindFit “NMR 1:1” online calculator developed by Thordarson and co-workers.118

UV-Vis Titrations

Absorption spectra were measured on a Perkin-Elmer Lambda 25 dual beam absorption spectrometer and a Cary 100 Bio spectrophotometer equipped with a Peltier

1  1 Cell Holder to maintain isothermal conditions. The host was dissolved in HPLC grade chloroform (purchased from Sigma-Aldrich), and 2.5 mL of the resulting solution was added to a quartz cuvette closed with a screw cap. The remainder of the host solution was used to dissolve the guest to ensure the host concentration remained constant throughout the titration. By micropipette, the host-guest solution was quickly added in calculated amounts to the cuvette containing the original host solution.

CHAPTER 3 GUANINE TERMINATED LOW ENERGY GAP PI-CONJUGATED OLIGOMERS

Introductory Remarks

Organic pi-conjugated molecules have attracted research interest owing to their unique optical and semiconductive properties, which have launched applications in electronic and optoelectronic devices (e.g., OLEDS, OPVs, and OFETs).125 A significant research emphasis has been placed on tuning the electronic and optical properties of individual pi-systems by introducing structural changes, particularly the exploration of diverse conjugated moieties with varying electron-affinities.126,127 While these investigations have led to significant advancements in the construct of pi-conjugated materials with tailored intrinsic properties, there has been relatively small consideration of tuning the supramolecular packing of these systems in the bulk – a property intimately linked with their function.107,128,129 The ability to predict and control the three- dimensional morphological structure of organic semiconductors is best accomplished using a bottom-up self-assembly approach.130,131 In this regard, a general paradigm is envisioned in which a robust hydrogen-bonding unit is covalently linked to a pi- conjugated chromophore, generating an oligomer able to be directed into a distinct supramolecular assembly on the molecular scale and retain order in the bulk.

Our group first utilized this strategy to construct the active layer of a bulk- hetereojunction (BHJ)132 organic photovoltaic (OPV), an organic solar cell in which the light absorpting layer consists of a blend of p-type (DONOR) and n-type (ACCEPTOR) materials (Figure 3-1a). In the original design, the DONOR material consisted of a phthalhydrazide (PH) hydrogen-bonding unit (HB) covalently linked to the terminus of a branched (1st generation)84 and linear (2nd generation)84 quaterthiophene chromophore

(DONOR unit) (Figure 3-1b). These molecules formed discrete disk-shaped aggregates,133 templated by tautomerization-induced self-assembly of PH into trimers, and then pi-stacked arrays. This topology then uniquely accommodated spherical fullerene (C60 or C70) additives in thin film blends (the common ACCEPTOR material in

BHJ OPVs) (Figure 3-1c). These primary investigations have yielded encouraging results. In particular, it was shown that the morphology resulting from hydrogen-bonding enhanced absorptivity and red-shifted the absorption in solid-state films. This morphology also promoted vertically oriented pi-stacks on surfaces, retained order and orientation in fullerene blends, improved charge collection efficiency and carrier mobility, and consequently increased device performance (PCE) two-fold.

Figure 3-1. Use of self-assembling chromophores in bulk heterojunction solar cells, (a) Cartoon representation of the state-of-the art BHJ solar cell, (b) phthlahydrazide hydrogen-bonding unit capable of forming trimers, and (c) schematic representation of the monotopic design used in previous work.

The next phase of this investigation is to test the modularity of this approach by applying the same design principles across different classes of chromophores and hydrogen-bonding units. As described in chapter 2, nucleobases arise as compelling

bio-inspired hydrogen-bonding units for this purpose, as the aromatic purine (guanine and adenine) and pyrimidine (cytosine and uracil) heterocycles are equipped with high- precision molecular recognition sites that can guide supramolecular packing while mutually tuning the intrinsic optoelectronic properties on the pi-conjugated molecules.

Among the previously studied nucleobase-containing pi-conjugated systems, guanine derivatives showed the strongest electron donating character, evidenced by a red- shifted absorption spectra and more narrow bandgap relative to the other nucleobase containing oligomers, an attractive feature for application OPVs. Additionally, guanine units are capable of self-complementary hydrogen bonding. Guanine is known to be polymorphic, displaying various hydrogen-bonding arrangements, most commonly G- ribbons (linear arrangement) and the desired cyclic G-quartet arrangement (Figure 3-

2).91,134 The latter is selectively formed in the presence of an alkali metal (Na+, K+, or

Cs+).

Figure 3-2. Guanine self-association into linear and cyclic arrangements.

Figure 3-3. Self-assembled donor-acceptor guanine-containing system utilized for + photoinduced charge transfer analysis. (a) Independent hole (h ) and electron – (e ) transport in a core–shell columnar assembly of donor–bridge–acceptor molecules. (b) Cation-induced formation of a guanine (G)-quartet and a G- quadruplex. (c) A C -symmetric G-quadruplex based on the GPDI conjugate. 4 Aliphatic substituents in the quadruplex are omitted for clarity. Copied with permission from (Wu, Y.-L.; Brown, K. E.; and Wasielewski, M. R., J. Am. Chem. Soc., 2013, 135 (36), pp 13322–13325). Copyright (2013) American Chemical Society.

Guanine has been recognized by researchers as a compelling building block to construct pi-conjugated materials. Systems incorporating guanosine, both directly conjugated135,136 and cross-linked with a short saturated bridge,137,138 have been utilized to control the assembly of the peripheral chromophores upon central G-quartet and G- quadruplex formation. Alkylated guanine derivatives, in which the lipophilic ribose group is substituted with a linear alkyl chain, have also been directly conjugated to pi-donor and pi-acceptors for a similar purpose.139,140,141 In all of these systems mentioned, a metal cation was used to induce G-quartet assembly in solution. Seminal work from

Wu, Wasielewski, et al. has demonstrated that guanine-based self-assembled donor-

acceptor systems can generate efficient charge separation upon photoexcitation, where the electron-rich G-quadruplex platform can effectively transport holes and the peripheral electron-defficient perylene diimide (PDI) units can channel electrons (Figure

3-3).140,141 The exemplary precedent of the G-quartet to both template extended pi- chromophore assembly and accommodate photoinduced charge separation/transfer, reiterates the impetus for further development of guanine into functional pi-systems.

Molecular Design

Ditopic Design

The next generation of the modular design utilizes a ditopic design, positioning self-complementary hydrogen-bonding units at each terminus of a linear pi-conjugated chromophore composing an oligomer with C2h symmetry. The ditopic oligomer is expected to form a non-covalent 2-D conjugated framework, providing pores able to accommodate fullerene additives (Figure 3-4). This general motif offers supramolecular tunability by interchanging the hydrogen-bonding units (affecting framework shape) and pi-chromophore (affecting pore size). Installing guanine (G) units at both termini would template a square lattice network analogous the cartoon framework shown in Figure 3-

4. Preparation of a comparator derivative, in which a methyl protecting group is installed in the C(6)O position of guanine (PG), would generate a non-G-quartet forming derivative suitable for paralleled analysis.

Interior Chromophore Selection

An isoindigo centered oligothiophene, of the common donor-acceptor-donor (D-

A-D) oligomer pattern, was selected as the interior pi-conjugated backbone in this design (Figure 3-5a). Isoindigo is an electron acceptor unit popularized by Reynolds and co-workers142-146 for use in organic electronic materials.147-151 The alternating D-A (weak

electron donor (D) and strong electron acceptor (A)) pi-conjugated oligomer (or polymer) design is a rational approach to narrow the bandgap of an oligomer (or polymer) thereby harnessing a large portion of visible light. This can be accomplished by incorporating electron acceptor units (i.e. isoindigo) to lower the LUMO and electron donor units (i.e. thiophene) to raise the HOMO (Figure 3-5b).126 The electron-rich guanine end-groups may then contribute congruously with the thiophene units to the electronic properties of the molecule.

Figure 3-4. Ditopic chromophore design utilized in this work.

Target Molecules

Two sets of oligomers were designed for this study (Figure 3-6). All compounds contain a central isoindingo core. The first set, 3-1, has a single thiophene spacer between the HB terminal groups and isoindigo core and achiral n-octyl solubilizing groups installed in all four R positions. The second set, 3-2, utilizes a bis(thiophene) spacer and branched racemic 2-ethylhexyl chains in all R positions to improve solubility.

Each set includes derivatives terminated with either fully hydrogen bond capable G or hydrogen bond compromised PG heterocycles.

Figure 3-5. Donor-Acceptor (D-A) design of pi-conjugated materials. (a) isoindigo based oligothiophenes of both a D-A-D and A-D-A design investigated by Reynolds and co-workers (R = 2-ethylhexyl),142 and (b) schematic representation of how incorporating alternating electron donor and acceptor units in a single extended design narrows the overall bandgap of the system.

Figure 3-6. Guanine bis-terminated pi-conjugated oligomers evaluated in this study.

Computations

Gas-phase calculations (DFT B3LYP/6-31+G*) were performed on all oligomers to approximate expected HOMO and LUMO energy levels and results are summarized in Table 3-1. A methyl group was used in place of all alkyl chains to reduce computational time, since they do not significantly affect the equilibrium geometries or electronic properties. The frontier molecular orbital diagrams show the HOMO is

distributed throughout the entire molecule and LUMO is centralized on the isoindigo acceptor fragment. The calculated energy gaps are similar between each set of chromophores, 3-1G and 3-1PG are ~2.22 eV, and 3-2G and 3-2PG are ~2.05 eV. The narrowed band gap of the 3-2 compound set is expected given the extended the conjugation length.

Table 3-1. DFT calculations on guanine-terminated oligomers.a

calculated Compound HOMO (eV) LUMO (eV) Eg (eV)

3-1G -5.25 -3.03 2.22

3-1PG -5.33 -3.12 2.21

3-2G -5.15 -3.09 2.07

3-2PG -5.15 -3.11 2.04 a All ethylhexyl and hexyl groups have been replaced by methyl groups for the calculations. Geometry optimization and calculation of the HOMO and LUMO energies was performed at the B3LYP/6-31+G* level.

Synthesis

All purine-containing building blocks were synthesized using methodology developed within the Castellano group (Scheme 3-1).116 Stille-coupling reactions were performed on brominated compounds, 2-6, 3-5, and 2-9 to extend the conjugated of the end groups. Isoindigo was synthesized, alkylated, and borylated according to literature procedures (Scheme 3-2).142 Comparator targets 3-1PG and 3-2PG were prepared through Suzuki-Miyaura cross-coupling reactions between respective brominated thienyl and borylated isoindigo components (Scheme 3-3). Initial attempts to demethylate

protected guanine derivative using BCl3 in dichloromethane proved unsuccessful; switching to a stronger Lewis acid, BBr3, in chloroform generated target compounds 3-

1G and 3-2G as mixtures of stereoisomers.

Scheme 3-1. Synthesis of purine-containing building blocks.

Scheme 3-2. Synthesis of isoindigo core.

Scheme 3-3. Synthesis of extended guanine-terminated pi-conjugated oligomers.

Purification

A substantial challenge faced during synthesis was purification of the target compounds. The large size of the oligomers and presence of “sticky” hydrogen-bonding groups precluded purification using standard silica gel column chromatography.

Compound 3-2PG, the first pi-extended chromophore synthesized in this series resulted in a reaction mixture containing many products, typical of cross-coupling reactions and exaggerated by the bis(cross-coupling) utilized to prepare the target compounds (Figure

3-7). Compound 3-2PG was initially purified on a neutral alumina column using a 0 –

100% gradient of chloroform in hexanes, followed by washing extensively with hexanes and then methanol. While this sufficiently purified the compound, a large amount of

chloroform was required to remove 3-2PG from the alumina stationary phase due to

“dragging” of the molecule.

Figure 3-7. Silica-gel TLC plate of crude reaction mixture for the synthesis of 3-2PG eluted with DCM.

Pure 3-2PG material was then used to prepare 3-2G. Although the deprotection reaction was much cleaner relative to the cross-coupling chemistry, product 3-2G still carried impurities, evident in the aromatic region of the 1HNMR spectrum. These minor impurities could not be easily removed. Due to the more limited solubility of 3-2G, additional solvents (e.g. chloroform, acetone) were used to wash the crude material.

Routinely washing the crude solid 3-2G with hot solvents (hexanes, acetone, chloroform, and methanol) in a filter flask, until the filtrate passed through cleanly, did not effectively remove the impurities, which remained evident in the aromatic region of the 1HNMR spectrum. As a desperate final attempt to purify compound 3-2G, column chromatography utilizing inert sand as the stationary phase was attempted. Sand was selected because this was the only available stationary phase that did not irreversibly adsorb 3-2G. To great satisfaction, this approach proved successful. Chloroform was passed through the column until the eluent passed clean, and then a 10:1 mixture of chloroform:methanol was used to remove the target compound from the sand. Purity was confirmed by 1HNMR. One major drawback of this method was the slow

evaporation of solvent while passing through the frit of the column, leading to gradual film formation that completely halted solvent flow. This was also evident during hot vacuum filtration through a Büchner funnel. Although burdensome during filtration, these observed films are an indirect indication of desired extended 2-D network formation.

It is believed that aromatic impurities are physically entrapped between the large- conjugated target molecules (likely adsorbed via pi-pi interactions and hydrogen bonding). Solids must then be physically separated to allow solvents to completely solubilize all impurities during washing. Inspired by the initial success of utilizing sand as a stationary phase in column chromatography, a generalized method was developed utilizing a Soxhlet-extractor for the purification of these compounds: (1) a solid dispersion of 0.5-1 weight % was prepared by depositing the crude material on a solid support (e.g., alumina, sand), (2) impurities were washed away in a Soxhlet extractor, and (3) compound was removed from solid support using an appropriate solvent system.

This method proved particularly useful for 3-2G. The use of the Soxhlet apparatus greatly improved the efficiency of this purification. The use of sand as a solid- support allowed for facile removal of hydrogen-bonding compounds, which were adsorbed irreversibly to other materials (e.g., alumina, Florisil®). Saturation of the apparatus with solvent vapors prevented premature precipitation of the ditopic molecule.

The recycling of clean solvent during this process considerably reduced the amount required for purification (from approximately 4 L to 200 mL on a 100 mg scale).

Furthermore, this technique avoided the use of sublimation protocols that threaten to

decompose large compounds before volatilization. This technique was then applied to compounds 3-2PG, 3-1PG, and 3-1G.

Metal-Free G-Quartet Formation

Guanine is known to be polymorphic, displaying various hydrogen-bonding arrangements, most commonly G-ribbons (linear arrangement) and the desired cyclic

G-quartet arrangement.17–19 The latter is selectively formed in the presence of an alkali metal (Na+, K+, or Cs+).20 It has also been reported that the presence of bulky groups in the N-9 position and large aromatic groups at the C-8 position favors the formation of the G-quartet.21,22 Single crystal analysis of the oligomer templating fragment 3-15 supports sterically driven G-quartet formation (Figure 3-8 and Table 3-2).a This data suggests that the desired 2-D solid-state arrangement can be obtained without any alkali additives.

Figure 3-8. Single crystal X-ray structure of guanine templating fragment. (a) molecular structure of 3-15, (b) molecules in unit cell shown with numbering scheme, (c) hydrogen bonded G-quartet observed in crystal structure, and (d) parallel displaced packing of G-quartets.

a X-ray data collected and refined by Dr. Khalil Abboud at The Center for X-ray Crystallography at the University of Florida

Table 3-2. Summary of hydrogen bonding distances in unit cell.

D—H - - - A D—H (Å) H - - - A (Å) D - - - A (Å) D—H - - - A (°) N1A—H1A - - - O10B 0.862 1.996 2.849 170 N11A—H11B - - - N7B 0.866 2.094 2.939 165 N1B—H1B - - - O10A 0.858 1.965 2.813 169 N11B—H11D - - - N7A 0.835 2.170 2.977 162

Photophysical Properties

UV-Vis Absorption

The optical absorbance of each target compound was measured in DMSO to suppress any intermolecular hydrogen bonding (Figure 3-9). The associated Beer-

Lambert plots were linear for all compounds confirming the absence of aggregation events occurring at the concentrations evaluated in the H-bond suppressing solvent.

The solution absorption profiles were qualitatively similar for all compounds, each displaying a high energy absorption maximum corresponding to a pi-pi* transition, and a lower energy absorption maximum indicative of intramolecular charge transfer (see

Table 3-3).144,152 The pi-pi* maxima occurred at 396 and 399 nm for 3-2G and 3-2PG, respectively, red-shifted by ~30 nm relative to the truncated derivatives 3-1G and 3-

1PG. This is expected as increasing the conjugation length of pi-conjugated oligomers provides a bathochromic shift in optical absorbance. There was also a similar trend but of a smaller magnitude observed for the charge transfer band of 3-2G and 3-1G, which occurred at 606 and 593 nm, respectively. Interestingly, the charge-transfer band occurs at the same wavelength, 604 nm, for both protected-guanine terminated compounds 3-2PG and 3-1PG. While the molar absorptivities varied for slightly amongst the compounds, the guanine-terminated compounds showed approximately equal absorptivities at both transitions, while the protected-guanine derivatives both showed

stronger absorptions at the pi-pi* transition. Additionally, the optical bandgap, as determined by the onset of absorption, was slightly narrowed for derivatives with longer conjugation length derivatives, 1.72 eV for 3-2G and 3-2PG versus 1.74 eV for 3-1G and1.75 eV for 3-1PG. Even though these values are lower than computational results, \ the conjugation length trends agree.

Table 3-3. UV-Vis absorption data collected for guanine and protected guanine terminated oligomers in DMSO.

optical λmax-1 ε1 λmax-2 ε2 λonset Eg Compound (nm) (M-1 cm-1) (nm) (M-1 cm-1) (nm) (eV) 3-1G 361 3.1 × 104 593 3.3 × 104 712 1.74 3-1PG 363 1.8 × 104 604 1.7 × 104 708 1.75 3-2G 396 4.6 × 104 606 4.5 × 104 722 1.72 3-2PG 399 3.9 × 104 604 3.6 × 104 720 1.72

3-1G 1.0 3-1PG 3-2G 3-2PG

0.5 NormalizedAbsorbance (a.u.)

0.0 300 400 500 600 700 800 Wavelength (nm)

Figure 3-9. UV-Vis absorption spectra of guanine-terminated oligomers.

Emission

The emission spectrum of each target compound was measured in DMSO and all displayed a single emission band from short-wavelength excitation (Figures 3-15 to

3-18). The more soluble protected guanine derivatives 3-1PG and 3-2PG were also measured in DCM and displayed dual emission from short-wavelength excitation, now including long-wavelength emission arising from an internal charge-transfer (ICT) state

(Figure 3-16 and Figure 3-18). In all cases, the fluorescence quantum yield was

144 relatively weak (ΦF < 0.1%) typical of isoindigo compounds. Further investigation of the fluorescence characteristics is in progress, including emission with low-energy excitation and transient absorption spectroscopy.

Table 3-4. Emission properties of guanine and protected-guanine terminated oligomers.a

Compound Solvent λex (nm) em λmax (nm) Stokes shift (nm) ΦF 3-1G DMSO 397 490 129 0.0086 3-1PG DMSO 394 483 120 0.0067 3-1PG DCM 380 464, 719 - 0.0050 3-2G DMSO 352 530 134 0.0059 3-PG DMSO 352 511 112 0.0063 3-2PG DCM 352 461,516, 742 - 0.0066

Thermal Properties

The thermal stability of the nucleobase-containing compounds was assessed by thermal gravimetric analysis (TGA) using a constant heating ramp of 10 °C per minute

(Figure 3-10). The temperature of 5% weightloss was extrapolated as the onset of decomposition. All compounds exhibited thermal stability at high temperatures (> 300

a Fluorescence experiments were performed by James D. Bullock from the Schanze Research Group in the UF Department of Chemistry

°C) relevant for optoelectronic applications. Compounds 3-2G, 3-2PG, and 3-1PG showed nearly identical decomposition onsets at 356, 358, and 359 °C, respectively.

Compound 3-1G displayed a slightly lowered onset at 338 °C.

100 95 %

60 3-1G 3-1PG 3-2G

40 3-2PG Weight (%)

0 100 200 300 400 500 600 Temperature (°C)

Figure 3-10. Overlaid TGA data collected for guanine-terminated oligomers.

Concluding Remarks

In summary, novel guanine-containing pi-conjugated oligomers have been prepared and showed desirable properties for use as p-type optoelectronic materials, including a low energy optical absorbance and thermal stability. Their limited solubility has delayed their fabrication into diagnostic OPV devices

Wu, Waszeliwski et al. reported a similar chemical concept in 2017, posterior to the preparation of these compounds (Figure 3-11).153 They confirmed the envisioned design of an ordered pi-stacked framework in single crystals and demonstrated that the ordered electron-rich and electron-poor regions could produce long-lived mobile charge carriers upon photoexcitation. The G-quadruplex organic frameworks can also

accommodate various core arene units to tune photochemical properties.154 They concluded their work by stating “further development of these materials towards optoelectronic applications will require the fabrication of thin films and quantitation of charge-carrier mobilities and yields” – a tantamount conclusion to this chapter as well.

The large size of the compounds 3-1G, 3-1PG, 3-2G, and 3-2PG precluded the possibility of vacuum deposition, and solution processing of these guanine-containing oligomers into thin-films is challenging due to their poor solubility. Just as these pi- extended H-bond capable compounds required non-traditional purification methods, they will also require refined processing conditions to fabricate them into thin films.

Whereas most pi-conjugated molecules are processed using standard solvents (i.e. chloroform, dichlorobenzene), the limited solubility of these compounds prevented their thin film fabrication using the community-standard methods (spin-coating from a single source solvent containing both DONOR and ACCEPTOR materials). As alluded to in the preceding discussion, these compounds are soluble in DMF, DMSO, and partially soluble in mixtures of chloroform and methanol, but PCBM in insoluble in these solvents.155 Alternative solvents and solvent mixtures are under investigation. In addition to sufficient solubility, the effects of evaporation of multi-solvent systems should to be taken into consideration. For example, in a two-solvent system (A:B), where solvent A solubilizes HB-pi and solvent B solubilizes PCBM, the relative rate of evaporation, A>>B, A<

Figure 3-11. G-quadruplex organic framework reported by Wu, Wasielewski, and co- workers. The construction of G-quadruplex organic frameworks was achieved through a two-step process that consists of a cross-coupling reaction (3–4 equiv. of Boc3GBr with Pd(PPh3)4/CuI catalysts, 43–50% yield) and protecting group removal (CF3CO2H in CH2Cl2, followed by vapour exchange with MeOH for slow crystallization, quantitative). The ordered pi stacks of chromophores offer segregated conduits for hole and electron transport. Boc = tert- butyloxycarbonyl, THF = tetrahydrofuran, TFA = CF3COOH. (Copied with permission from Wu, Y.-L.; Brown, K. E.; and Wasielewski, M. R., Nature Chemistry volume 9, pages 466–472 (2017)). Copyright 2017 Springer Nature.

Experimental

Synthesis

General Information

Reagents and solvents were purchased from commercial sources and used without further purification unless otherwise specified. THF, diethyl ether, CH2Cl2, toluene, and

DMF, were degassed in 20 L drums and passed through two sequential purification columns (activated alumina; molecular sieves for DMF) under a positive argon atmosphere. Tetrakis(triphenylphosphine) palladium(0) was purchased from Sigma-

Aldrich and used as received. Thin-layer chromatography (TLC) was performed on

SiO2-60 F254 aluminum plates with visualization by UV light. Flash column

1 13 chromatography was performed using SiO2-60, 230−400 mesh. H( C) NMR spectra were recorded on 300(75) MHz or 500(125) MHz spectrometers as specified. Chemical shifts (δ) are given in parts per million (ppm) relative to TMS and referenced to residual protonated solvent (CDCl3: δH 7.26 ppm, δC 77.23 ppm; DMSO-d6: δH 2.50 ppm, δC

39.50 ppm). Abbreviations used are s (singlet), d (doublet), t (triplet), q (quartet), quin

(quintet), sep (septet), b (broad), and m (multiplet). Compounds 3-10,142 3-11,142 3-

13,143 were synthesized in accordance with literature procedures.

Synthesis of (±)-6-chloro-9-(2-ethylhexyl)-9H-purin-2-amine (2-4)

K2CO3 (7.3 g, 53 mmol, 3 equiv) was added to a solution of 6-chloro-9H-purin-2-amine

(3.0 g, 17.7 mmol, 1 equiv) in 250 mL dry DMF, then stirred at rt for 1 h. 2-Ethylhexyl bromide (3.5 mL, 19 mmol, 1.1 equiv) was then added, and the solution was allowed to stir for 16 h. The solvent was removed under reduced pressure and the resulting crude mixture was purified by silica gel column chromatography with gradient elution

(EtOAc:hexanes 30:70 to 50:50) to yield a white solid (3.0 g, 10.6 mmol, 60% yield).

1 HNMR (500 MHz, CDCl3): δ 7.71 (s, 1H), 5.32 (s, 2H), 3.95 (d, J = 7.0 Hz, 2H), 1.88–

13 1.86 (m, 1H), 1.28–1.24 (m, 8H), 0.90–0.83 (m, 6H); CNMR (125 MHz, CDCl3): δ

159.2, 154.3, 151.2, 142.9, 125.2, 47.3, 39.6, 30.4, 28.5, 23.7, 23.0, 14.1, 10.5; HRMS

+ (ESI) calc’d for C13H21ClN5 [M+H] : 282.1485, found: 282.1472.

Synthesis of 6-chloro-9-octyl-9H-purin-2-amine (3-3)

K2CO3 (2.4 g, 17.7 mmol, 3 equiv) was added to a solution of 6-chloro-9H-purin-2-amine

(1.0 g, 5.9 mmol, 1 equiv) in dry DMF, then stirred at rt for 1 h. Compounds 1-octyl bromide (1.3 g, 6.5 mmol, 1.1 equiv) was then added, and the solution was allowed to

stir for 16 h. The solvent was removed under reduced pressure and the resulting crude mixture was purified by silica gel column chromatography with gradient elution

(EtOAc:hexanes 30:70 to 50:50) to yield a white solid (0.86 g, 3.1 mmol, 52% yield). 1H

NMR (500 MHz, CDCl3) δ 7.74 (s, 1H), 5.28 (s, 2H), 4.05 (t, J = 7.2 Hz, 2H), 1.88 – 1.78

13 (m, 2H), 1.36 – 1.16 (m, 12H), 0.85 (t, J = 7.0 Hz, 3H); C NMR (126 MHz, CDCl3) δ

159.17, 153.95, 151.28, 142.47, 125.41, 43.98, 31.79, 29.77, 29.16, 29.07, 26.71,

+ 22.68, 14.15; HRMS (ESI) calc’d for C13H20ClN5 [M+H] : 282.1480, found: 282.1476.

Synthesis of (±)-9-(2-ethylhexyl)-6-methoxy-9H-purin-2-amine (2-5)

Alkylated guanine derivative 2-4 (2.5 g, 8.9 mmol,1 equiv) was added to a solution of

NaOMe (0.96 g, 18 mmol, 2 equiv) in dry MeOH, then stirred at room temperature overnight. The reaction mixture was then poured into deionized water, extracted with chloroform, and dried over anhydrous MgSO4. The crude product was purified by silica get chromatography (EtOAc:hexanes 30:70 to 60:40) to yield a white solid (2.1 g, 7.7

1 mmol, 87% yield). H NMR (500 MHz, CDCl3): δ 7.54 (s, 1H), 4.88 (s, 2H), 4.06 (s, 3H),

3.92 (d, J = 7.2 Hz, 2H), 1.87 (quin, J = 6.6 Hz, 1H), 1.31–1.24 (m, 8H), 0.86 (dt, J =

14.0, 7.2 Hz, 6H).; 13C NMR (125 MHz, CDCl3): δ 161.65, 159.35, 154.35, 139.87,

115.64, 53.92, 47.04, 39.66, 30.41, 28.53, 23.77, 23.02, 14.11, 10.57.; HRMS (ESI)

+ calc’d for C14H23N5O [M+H] : 278.1975, found: 278.1969.

Synthesis of 9-octyl-6-methoxy-9H-purin-2-amine (3-4)

Alkylated guanine derivative 3-3 (0.51g, 1.8 mmol, 1 equiv) was added to a solution of

NaOMe (0.20 g, 3.6 mmol, 2 equiv) in 15 mL dry MeOH, then stirred at room temperature overnight. The reaction mixture was then poured into deionized water, extracted with chloroform, and dried over anhydrous MgSO4. The crude product was

purified by silica get chromatography (EtOAc:hexanes 30:70 to 70:30) to yield a white

1 solid (0.42 g, 1.5 mmol, 84% yield). H NMR (500 MHz, CDCl3) δ 7.74 (s, 1H), 5.28 (s,

2H), 4.07 (s, 3H), 4.05 (t, J = 7.2 Hz, 2H), 1.88 – 1.78 (m, 2H), 1.36 – 1.16 (m, 12H),

13 0.85 (t, J = 7.0 Hz, 3H); C NMR (126 MHz, CDCl3) δ 159.17, 153.95, 151.28, 142.47,

125.41, 53.96, 43.98, 31.79, 29.77, 29.16, 29.07, 26.71, 22.68, 14.15; HRMS (ESI)

+ calc’d for C14H23N5O [M+H] : 278.1975, found: 278.1971.

Synthesis of (±)-8-bromo-9-(2-ethylhexyl)-6-methoxy-9H-purin-2-amine (2-6)

NBS (0.97 g, 8.3 mmol, 1.1 equiv) was added portion wise to a solution of 2-5 (2.08 h,

7.5 mmol, 1 equiv) in 100 mL DMF and stirred at rt for 1 h. The reaction mixture was then poured into deionized water (~100 mL), extracted with ethyl acetate, washed with a solution of 5% Na2S2O4, and dried over anhydrous MgSO4. The solvent was removed under reduced pressure and the product further purified using silica gel chromatography

(EtOAc:hexanes 40:60) to yield an orange oil (2.4 g, 6.8 mmol, 90% yield). 1H NMR

(500 MHz, CDCl3): δ 4.86 (s, 2H), 4.05 (s, 3H), 3.93 (d, J = 7.6 Hz, 2H), 2.00 (quin, J =

6.1 Hz, 1H), 1.35–1.22 (m, 8H), 0.87 (dt, J = 13.9, 7.3 Hz, 6H).; 13C NMR (125 MHz,

CDCl3): δ 160.5, 159.2, 155.3, 125.9, 115.9, 54.1, 48.2, 39.1, 30.4, 28.5, 23.8, 23.1,

+ 14.1, 10.7; HRMS (ESI) calc’d for C14H22BrN5O [M+Na] : 356.1080, found: 356.1094.

Synthesis of 8-bromo-9-octyl-6-methoxy-9H-purin-2-amine (3-5)

NBS (0.18 g, 1.4 mmol, 1.1 equiv) was added portion wise to a solution of 3-4 (0.38 g,

1.5 mmol, 1 equiv) in DMF and stirred at rt for 1 h. The reaction mixture was then poured into deionized water (20 mL), extracted with ethyl acetate, washed with a solution of 5% Na2S2O4 (15 mL), and dried over anhydrous MgSO4. The solvent was removed under reduced pressure and the product further purified using silica gel

chromatography (EtOAc:hexanes 30:70 to 60:40) to yield an orange solid (0.46, 1.3

1 mmol, 86% yield). H NMR (500 MHz, CDCl3) δ 7.75 (s, 1H), 5.10 (s, 2H), 4.07 (t, J =

7.3 Hz, 2H), 1.84 (p, J = 7.5 Hz, 2H), 1.38 - 1.22 (m, 6H), 0.94 - 0.80 (m, 3H); 13C NMR

(126 MHz, CDCl3) δ 159.09, 153.96, 151.39, 142.49, 125.54, 44.03, 31.32, 29.79,

+ 26.42, 22.59, 14.09; HRMS (ESI) calc’d for C14H22BrN5O [M+H] : 356.1080, found:

356.1097.

Synthesis of (±)-9-(2-ethylhexyl)-6-methoxy-8-(thiophen-2-yl)-9H-purin-2-amine (2-

Brominated guanine derivative 2-6 (2.6 g, 7.3 mmol, 1 equiv), Ph3Bi (0.32 g, 0.73 mmol,

0.1 equiv), and Pd(PPh3)4 (0.84 g, 0.73 mmol, 0.1 equiv) were dissolved in 80 mL dry degassed xylenes, along with 2-(tributylstannyl)thiophene (5.6 mL, 18 mmol, 2.4 equiv).

The reaction vessel was heated to reflux and stirred overnight. The solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (EtOAc:hexane 20:80 to 50:50) to yield a thick yellow oil ( 72% yield).

1 H NMR (500 MHz, CDCl3): δ 7.53 (d, J = 3.6 Hz, 1H), 7.44 (d, J = 5.0 Hz, 1H), 7.12 (t,

J = 4.3 Hz, 1H), 4.86 (s, 2H), 4.21 (d, J = 7.6 Hz, 2H), 4.08 (s, 3H), 1.95–1.89 (m, 1H),

13 1.29–1.16 (m, 8H), 0.83–0.78 (m, 6H); C NMR (125 MHz, CDCl3): δ 161.3, 159.2,

156.2, 144.6, 132.9, 128.0, 127.7, 127.6, 115.4, 54.0, 47.5, 38.9, 30.3, 28.3, 23.8, 23.1,

+ 14.2, 10.7; HRMS (ESI) calc’d for C18H25N5OS [M+H] : 360.1853, found: 360.1850.

Synthesis of 9-octyl-6-methoxy-8-(thiophen-2-yl)-9H-purin-2-amine (3-6)

Brominated guanine derivative 3-5 (0.26 g, 0.73 mmol, 1 equiv), Ph3Bi (0.032 g, 0.073 mmol, 0.1 equiv), and Pd(PPh3)4 (0.084 g, 0.073 mmol, 0.1 equiv) were dissolved in dry degassed xylenes, and 2-(tributylstannyl)thiophene (0.56 mmol, 1.76 mmol, 2.4 equiv)

was added. The reaction vessel was heated to reflux and stirred overnight. The solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (EtOAc:hexane 30:70 to 50:50) to yield an off-white solid (0.17

1 g, 0.47 mmol, 63% yield). H NMR (500 MHz, CDCl3) δ 7.53 (d, J = 3.7 Hz, 1H), 7.45 (d,

J = 5.1 Hz, 1H), 7.17 - 7.13 (m, 1H), 4.88 (s, 2H), 4.35 - 4.26 (m, 2H), 4.09 (s, 3H), 1.87

- 1.78 (m, 2H), 1.41 - 1.16 (m, 12H), 0.87 (t, J = 6.8 Hz, 3H). 13C NMR (125 MHz,

CDCl3): δ 161.23, 159.16, 155.56, 144.28, 132.61, 128.01, 127.75, 127.32, 115.45,

53.96, 43.66, 31.85, 29.80, 29.24, 29.19, 26.75, 22.72, 14.19. HRMS (ESI) calc’d for

+ C18H25N5OS [M+H] : 360.1853, found: 360.1871.

Synthesis of (±)-8-(5-bromothiophen-2-yl)-9-(2-ethylhexyl)-6-methoxy-9H-purin-2- amine (2-9)

Glacial acetic acid (20 mL) was added to a solution of 2-8 (1.6 g, 4.4 mmol, 1 equiv) in

20 mL dry THF, then the contents of the reaction vessel were cooled to 0 °C in an ice- water bath. Next, NBS (0.57 g, 4.9 mmol, 1.1 equiv) was added portion wise over 5 minutes and the reaction was slowly warmed to rt over 1.5 h. The solvent was removed under reduced pressure to yield the crude product, which was subsequently diluted with

EtOAc, washed with a solution of 5% Na2S2O4, and with brine. The organic phase was dried over anhydrous MgSO4, filtered, and evaporated. The crude product was purified by silica gel column chromatography (EtOAc:hexanes 30:70 to 50:50) to yield a sticky

1 orange solid (1.6 g, 3.7 mmol, 83% yield). H NMR (500 MHz, CDCl3): δ 7.25 (s, 1H),

7.08 (d, J = 4.0 Hz, 1H), 4.86 (s, 2H), 4.17 (d, J = 7.7 Hz, 2H), 4.08 (s, 3H), 1.91 (quin, J

13 = 7.2 Hz, 1H), 1.30–1.16 (m, 8H), 0.82 (t, J = 7.4 Hz, 6H).; C NMR (125 MHz, CDCl3):

δ 161.2, 159.2, 156.0, 143.2, 134.5, 130.5, 127.3, 115.2, 115.1, 53.9, 47.4, 38.8, 30.2,

+ 28.2, 23.6, 22.9, 14.0, 10.5; HRMS (ESI) calc’d for C18H24BrN5OS [M+H] : 438.0958, found: 438.0970.

Synthesis of 8-(5-bromothiophen-2-yl)-9-octyl-6-methoxy-9H-purin-2-amine (3-7)

Glacial acetic acid (10 mL) was added to a solution of 3-6 (0.46 g, 1.3 mmol, 1 equiv) in

10 mL dry THF, then the contents of the reaction vessel were cooled to 0 °C in an ice- water bath. Next, NBS (0.17 g, 1.4 mmol, 1.1 equiv) was added portion wise over 5 minutes and the reaction was slowly warmed to rt over 1.5 h. The solvent was removed under reduced pressure to yield the crude product, which was subsequently diluted with

1 orange solid (0.33 g, 0.76 mmol, 60% yield). H NMR (500 MHz, CDCl3) δ 7.22 (d, J =

3.9 Hz, 1H), 7.07 (d, J = 3.9 Hz, 1H), 4.97 (s, 2H), 4.27 - 4.14 (m, 2H), 4.06 (s, 3H), 1.81

- 1.70 (m, 2H), 1.26 (dd, J = 22.5, 15.5 Hz, 11H), 0.89 - 0.82 (m, 3H);13C NMR (126

MHz, CDCl3) δ 161.29, 159.30, 155.50, 143.02, 134.40, 130.65, 127.14, 115.44,

115.27, 54.00, 43.60, 31.83, 29.76, 29.21, 29.16, 26.71, 22.71, 14.18; HRMS (ESI)

+ calc’d for C18H24BrN5OS [M+H] : 438.0958, found: 438.0970.

Synthesis of (±)-8-([2,2'-bithiophen]-5-yl)-9-(2-ethylhexyl)-6-methoxy-9H-purin-2- amine (3-8)

Brominated derivative 2-9 (1.6 g, 3.6 mmol, 1 equiv), Ph3Bi (0.16 g, 0.36 mmol, 0.1 equiv), and Pd(PPh3)4 (0.42 g, 0.36 mmol, 0.1 equiv) were dissolved in dry degassed xylenes, along with 2-(tributylstannyl)thiophene (2.8 mL, 8.8 mmol, 2.4 equiv). The reaction vessel was heated to reflux and stirred overnight. The solvent was removed

under reduced pressure. The crude product was purified by silica gel column chromatography (EtOAc:hexane 30:70 to 50:50) to yield a sticky yellow solid (1.4 g, 3.2

1 mmol, 87% yield). H NMR (500 MHz, CDCl3) δ 7.43 (s, 1H), 7.18 (s, 2H), 7.09 - 6.99

(m, 1H), 5.05 (s, 2H), 4.24 (s, 2H), 4.10 (s, 3H), 1.99 (s, 1H), 1.62 (s, 1H), 1.27 (s, 8H),

13 0.88 (d, J = 39.6 Hz, 6H); C NMR (126 MHz, CDCl3) δ 161.11, 159.06, 156.10, 143.96,

139.54, 136.60, 131.32, 128.03, 127.56, 125.15, 124.42, 123.87, 115.26, 53.98, 47.54,

38.95, 30.34, 28.37, 23.78, 23.10, 14.15, 10.67.

Synthesis of (±)-8-(5'-bromo-[2,2'-bithiophen]-5-yl)-9-(2-ethylhexyl)-6-methoxy-9H- purin-2-amine (3-9)

Glacial acetic acid (15 mL) was added to a solution of 3-8 (1.4 g, 3.2 mmol, 1 equiv) in

15 mL dry THF, then the contents of the reaction vessel were cooled to 0 °C in an ice- water bath. Next, NBS (0.62 g, 3.5 mmol, 1.1 equiv) was added portion wise over 5 minutes and the reaction was slowly warmed to rt over 1.5 h. The solvent was removed under reduced pressure to yield the crude product, which was subsequently diluted with

1 orange solid (1.36 g, 2.6 mmol, 83% yield). H NMR (500 MHz, CDCl3) δ 7.42 (s, 1H),

7.12 (s, 1H), 7.00 (s, 2H), 5.07 (s, 2H), 4.24 (s, 2H), 4.12 (s, 3H), 1.99 (s, 1H), 1.26 (d, J

13 = 37.6 Hz, 12H), 0.86 (s, 8H). C NMR (126 MHz, CDCl3) δ 161.17, 159.11, 156.10,

143.70, 138.35, 138.08, 131.95, 130.84, 127.43, 124.48, 124.12, 115.32, 111.87, 53.87,

47.40, 38.80, 30.19, 28.22, 23.64, 22.96, 14.02, 10.54.

Synthesis of (E)-6,6'-dibromo-1,1'-dioctyl-[3,3'-biindolinylidene]-2,2'-dione (3-12)

Isoindigo 3-10 was bis-N-alkylated in accordance with a literature procedure,142 using 1- octyl bromide as the alkylating agent, purified using silica gel chromatography

(DCM:hexanes 50:50 to 100:0) and obtained as a fluffy red solid (87% yield). 1H NMR

(500 MHz, CDCl3) δ 9.08 (d, J = 8.6 Hz, 1H), 7.17 (d, J = 9.3 Hz, 1H), 6.93 (s, 1H), 3.72

(d, J = 7.5 Hz, 2H), 1.68 (p, J = 7.2 Hz, 2H), 1.46 - 1.13 (m, 12H), 0.86 (s, 3H); 13C NMR

(126 MHz, CDCl3) δ 167.89, 145.94, 132.81, 131.34, 126.89, 125.29, 120.58, 111.47,

40.44, 31.92, 29.38, 29.31, 27.54, 27.14, 22.77, 14.23.

Synthesis of (E)-1,1'-dioctyl-6,6'-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-

[3,3'-biindolinylidene]-2,2'-dione (3-14)

Alkylated isoindigo derivative 3-12 was borylated in accordance with a Miyaura

Borylation procedure found in the literature143 and obtained as a dark red solid (63%

1 yield). H NMR (500 MHz, CDCl3) δ 9.15 (d, J = 8.4 Hz, 1H), 7.48 (d, J = 7.9 Hz, 1H),

7.15 (s, 1H), 3.79 (t, J = 7.5 Hz, 2H), 1.71 (dt, J = 14.8, 7.1 Hz, 2H), 1.32 (d, J = 52.9

13 Hz, 24H), 0.87 (t, J = 6.3 Hz, 3H). C NMR (126 MHz, CDCl3) δ 167.83, 144.17, 134.48,

129.07, 124.42, 113.26, 84.26, 40.17, 31.94, 29.43, 29.33, 27.67, 27.14, 25.02, 22.77,

14.24.

Synthesis of (E)-6,6'-bis(5-(2-amino-6-methoxy-9-octyl-9H-purin-8-yl)thiophen-2- yl)-1,1'-dioctyl-[3,3'-biindolinylidene]-2,2'-dione (3-1PG)

Borylated isoindigo derivative 3-13 (0.18 g, 0.24 mmol, 1 equiv), brominated guanine derivative 3-9 (0.22 g, 0.50 mmol, 2.1 equiv), K2CO3 (0.10 g, 0.71 mmol, 3 equiv), and Pd(PPh3)4 (27 mg, 0.024 mmol, 0.1 equiv) were dissolved in degassed toluene:water (10:1). Aliquot 336 (~3 drops) was added and the reaction was stirred under reflux for 20 hours. The crude reaction was concentrated under reduced

pressure, dissolved in DCM, washed with water, washed with brine, dried with MgSO4, and filtered. Neutral alumina was poured into the solution and the solvent removed under reduced pressure to prepare a solid dispersion. Using a Soxhlet set-up, the crude product was washed with hexanes, followed by methanol until the solvents no compound was being removed (detection with UV light). The compound was then removed using chloroform and the solvent removed under reduced pressure to yield a

1 dark blue product (220 mg, 0.18 mmol, 77% yield). H NMR (500 MHz, CDCl3) δ 9.22

(d, J = 8.4 Hz, 1H), 7.52 - 7.47 (m, 1H), 7.46 (d, J = 3.8 Hz, 1H), 7.34 (d, J = 9.7 Hz,

1H), 7.02 (s, 1H), 4.92 (s, 2H), 4.36 - 4.29 (m, 2H), 4.11 (s, 3H), 3.83 (t, J = 6.5 Hz, 2H),

1.94 - 1.83 (m, 2H), 1.81 - 1.71 (m, 3H), 1.44 - 1.19 (m, 24H), 0.91 - 0.84 (m, 7H); 13C

NMR (126 MHz, CDCl3) δ 168.29, 161.36, 159.04, 146.06, 145.59, 143.81, 137.13,

133.23, 132.25, 130.69, 127.53, 125.03, 121.77, 119.33, 115.67, 104.99, 54.11, 43.87,

40.38, 31.96, 31.92, 29.85, 29.51, 29.32, 29.29, 27.80, 27.28, 26.86, 22.79, 14.24.

+ HRMS (MALDI) calc’d for C H N O S [M + H] : 1201.6566; found: 1201.2759. 68 88 12 4 4

Synthesis of (E)-6,6'-bis(5-(2-amino-9-octyl-6-oxo-6,9-dihydro-1H-purin-8- yl)thiophen-2-yl)-1,1'-dioctyl-[3,3'-biindolinylidene]-2,2'-dione (3-1G)

In a dry round-bottom flask under an inert atmosphere, a solution of pentamethylbenzene (74 mg, 0.50 mmol, 5 equiv) and protect compound 3-1PG (120 mg, 0.10 mmol, 1 equiv) in dry degassed CHCl3 was cooled to −40 °C and then a 1.0 M solution of BBr3 in CH2Cl2 (0.6 mL, 0.60 mmol, 6 equiv) was added slowly over 15 min.

The solution was stirred at −40 °C for 30 min then slowly brought to room temperature over 30 min, followed by the addition of methanol (25 mL) to quench the reaction. After

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quenching with MeOH, sand was poured into the crude reaction mixture and all solvent removed under reduced pressure to prepare a solid dispersion. Using a Soxhlet set-up, the crude product was washed with hexanes, followed by acetone, and chloroform until the solvents no compound was being removed (detection with UV light). The compound was then removed using a 1:1 mixture of chloroform:methanol and the solvent removed under reduced pressure to yield a dark purple product (55 mg, 0.047 mmol, 47% yield).

1 H NMR (500 MHz, DMSO-d6): δ 10.47 (s, 1H), 9.19 (d, J = 8.4 Hz, 1H), 7.77 (d, J = 3.9

Hz, 1H), 7.58 – 7.53 (m, 1H), 7.43 – 7.37 (m, 1H), 7.35 (s, 1H), 6.39 (s, 2H), 4.32 – 4.22

(m, 2H), 3.97 – 3.84 (m, 2H), 1.80 – 1.69 (m, 4H), 1.38 (dq, J = 13.9, 7.9, 6.7 Hz, 4H),

1.25 (dd, J = 14.8, 8.0 Hz, 16H), 0.83 (t, J = 6.1 Hz, 6H). 13CNMR spectrum collection was unsuccessful due to the poor solubility of the compound. HRMS (MALDI) calc’d for

+ C66H84N12O4S2 [M + H] : 1173.6653; found: 1173.6653.

Synthesis of (E)-6,6'-bis(5'-(2-amino-9-(2-ethylhexyl)-6-methoxy-9H-purin-8-yl)-

[2,2'-bithiophen]-5-yl)-1,1'-bis(2-ethylhexyl)-[3,3'-biindolinylidene]-2,2'-dione (3-

2PG)

Borylated isoindigo derivative 3-13 (0.29 g, 0.40 mmol, 1 equiv), brominated guanine derivative 3-9 (0.43 g, 0.83 mmol, 2.1 equiv), K2CO3 (0.16 g, 1.2 mmol, 3 equiv), and

Pd(PPh3)4 (46 mg, 0.040 mmol, 0.1 equiv) were dissolved in degassed toluene:water

(10:1). Aliquat 336 (~3 drops) was added and the reaction was stirred under reflux for

20 hours. The crude reaction was concentrated under reduced pressure, dissolved in

DCM, washed with water, washed with brine, dried with MgSO4, filtered and the solvent removed under reduced pressure. The crude solid was further purified by depositing the material on neutral alumina and washing with hexanes, followed by methanol until the

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solvents no compound was being removed (detection with UV light). The compound was then removed using chloroform and the solvent removed under reduced pressure

1 to yield a dark blue product (130 mg, 0.095 mmol, 24% yield). HNMR (500 MHz,

DMSO-d ): δ 9.16 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 3.7 Hz, 1H), 7.58 (d, J = 3.8 Hz, 1H), 6

7.50 (d, J = 3.7 Hz, 1H), 7.45 (d, J = 3.7 Hz, 1H), 7.38 (d, J = 8.5 Hz, 1H), 7.23 (s, 1H),

6.25 (s, 2H), 4.25 (d, J = 7.6 Hz, 2H), 4.03 (s, 3H), 3.78 (s, 2H), 1.91 (m, 2H), 1.45 -

1.11 (m, 16H), 0.96 (t, J = 7.4 Hz, 3H), 0.88 (t, J = 7.1 Hz, 3H), 0.80 (dt, J = 13.2, 7.2

13 Hz, 6H); CNMR (125 MHz, CDCl3): δ 168.77, 161.42, 159.20, 156.38, 145.97, 144.06,

143.79, 139.35, 137.38, 137.23, 132.19, 131.91, 130.57, 127.84, 125.65, 125.28,

124.30, 121.59, 119.08, 115.68, 104.76, 47.67, 44.44, 39.18, 38.09, 31.16, 30.52,

29.86, 29.09, 28.50, 24.55, 23.95, 23.26, 23.11, 14.25, 14.10, 11.03, 10.71; HRMS

+ (MALDI) calc’d for C H N O S [M + H] : 1365.6320, found: 1365.6372. 76 92 12 4 4

Synthesis of (E)-6,6'-bis(5'-(2-amino-9-(2-ethylhexyl)-6-oxo-6,9-dihydro-1H-purin-8- yl)-[2,2'-bithiophen]-5-yl)-1,1'-bis(2-ethylhexyl)-[3,3'-biindolinylidene]-2,2'-dione (3-

2G)

In a dry round-bottom flask under an inert atmosphere, a solution of pentamethylbenzene (71 mg, 0.048 mmol, 5 equiv) and protect compound 3-2PG (130 mg, 0.095 mmol, 1 equiv) in 15 mL dry degassed CHCl3 was cooled to −40 °C and then a 1.0 M solution of BBr3 in CH2Cl2 (0.57 mL, 0.57 mmol, 6 equiv) was added slowly over

15 min. The solution was stirred at −40 °C for 30 min then slowly brought to room temperature over 30 min, followed by the addition of methanol (25 mL) to quench the reaction. After quenching with MeOH, sand was poured into the crude reaction mixture

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and all solvent removed under reduced pressure to prepare a solid dispersion. Using a

Soxhlet set-up, the crude product was washed with hexanes, followed by acetone, and chloroform until the solvents no compound was being removed (detection with UV light).

The compound was then removed using a 1:1 mixture of chloroform:methanol and the solvent removed under reduced pressure to yield a dark blue product (71 mg, 0.053

1 mmol, 56% yield). H NMR (500 MHz, DMSO-d ): δ 10.47 (s, 1H), 9.15 (d, J = 8.3 Hz, 6

1H), 7.70 (d, J = 2.9 Hz, 1H), 7.47 (d, J = 9.3 Hz, 2H), 7.44 – 7.40 (m, 1H), 7.37 (d, J =

8.4 Hz, 1H), 7.22 (s, 1H), 6.35 (s, 1H), 4.17 (d, J = 7.0 Hz, 2H), 3.77 (s, 2H), 1.89 (dd, J

= 14.1, 6.5 Hz, 2H), 1.40 – 1.07 (m, 16H), 0.96 (t, J = 7.3 Hz, 3H), 0.88 (t, J = 6.9 Hz,

3H), 0.81 (q, J = 7.5 Hz, 6H); 13CNMR spectrum collection was unsuccessful due to the

+ poor solubility of the compounds. HRMS (MALDI) calc’d for C H N O S [M + H] : 74 92 12 4 4

1337.6006, found: 1337.6011.

Computations

Starting geometries were obtained by molecular mechanics minimizations as implemented in Spartan Student version 5.0.2 for Macintosh. The structural geometries of all monomers and multimers were optimized at the B3LYP/6-31+G* level of theory as implemented in Gaussian 09,156 accessed through the UF High- Performance

Computing Center. Molecular orbital plots were made using Visual Molecular Dynamics

(VMD)157 software from the Gaussian output files.

UV-Visible Spectroscopy

Absorption spectra were measured for 2.5, 5, 10, 15, 20, and 30 μM solutions on a Cary

100 Bio spectrophotometer using 1 cm quartz cells. All solvents were HPLC grade

(purchased from Fisher). The absorption intensity at λmax was then plotted against the

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concentration in all cases to confirm, by linearity, that the compounds followed Beer’s law. Molar extinction coefficients (ε) were determined from the linear plot for each compound (where A = εbc). Values for λonset were determined form the intercept of the decreasing slope of λmax absorption and the baseline.

Fluorescence Spectroscopy

Corrected steady state photoluminescence spectra were obtained using a

Fluorolog-3 spectrophotometer with a xenon arc lamp and collected by a Horiba photomultiplier tube detector at 90º relative to the excitation beam. Solution samples were made with an optical density of approximately 0.1 at the excitation wavelength.

For solution quantum yield measurements, the samples were measured using

2+ [Ru(bpy)3] (Φ = 0.038). The choice of excitation wavelength was based on exciting the higher energy absorption band and where it had the same optical density as the

2+ standard [Ru(bpy)3] .

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CHAPTER 4 METHYL SCAN OF GUANINE: TRANSLATING A BIO-INSPIRED MEDICINAL CHEMISTRY APPROACH TO OPTOELECTRONIC MATERIALS DISCOVERY

Introductory Remarks

Methyl scanning is a bio-inspired chemical design approach in which the proton sites of biomolecules are replaced with methyl groups, imparting a structural change and influencing functionality.158,159 This is a naturally occurring phenomenon, where methyltransferases, a large class of enzymes, serve to methylate biomolecules including histones,160 peptides,161 DNA/RNA,162 and other natural products.163 In addition to consequences on genetics and protein regulation, many naturally methylated products show unique antibiotic and therapeutic properties – all testaments to the importance of these processes. There are a myriad of instances of methylation processes occurring within life’s taxonomy; a steadfast example – the methyltransferase enabled biosynthesis of caffeine from purine nucleotides – is shown below in Figure 4-1.

Figure 4-1. The major biosynthetic pathway to caffeine from DNA nucleotides.164

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Instinctively, medicinal chemists have adopted this approach to modulate the biological function of synthetic peptides and other pharmacophores.165-172 In the laboratory, methyl scanning involves the systematic preparation of a library of methylated derivatives of a compound by advanced synthetic methods, followed by biological assays to identify regions of the biomolecule important for biological activity.167 This is commonly performed by the N-methylation of peptides, where methylation of the primary peptide sequence contrives a profound modification to the overall structural biology. These effects are achieved by adjusting a few physical chemical parameters including: (i) conformational flexibility – using steric factors to influence entropic effects, binding affinities, and substrate selectivity (ii) hydrogen bonding capability – destabilizing secondary structure and limiting intermolecular interactions, and (iii) solubility/hydrophobicity – influencing oral bioavailability and cell permeability.159 A generalized example is shown below in Figure 4-2.

These same parameters – conformational flexibility, hydrogen bonding capability, and hydrophobicity – are fundamental criteria to consider when engineering synthetic self-assembling systems. Since supramolecular chemistry has a widespread presence in scientific applications,173 it is propitious that this structural screening approach can find implications beyond medicine and into materials and nanotechnology. A suitable research area to pilot this concept is in the rational design on pi-conjugated materials, where in addition to intrinsic optoelectronic properties

(primary structure), the macroscale assembly of molecules (secondary packing structure) has a profound influence on materials properties in applied settings.

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Figure 4-2. A simplified example of methyl scanning of a cyclic hexapeptide. Shown is the (a) generic scheme, (b) conformationally flexible non-methylated cyclic peptide compatible with many substrates, and (c) N-methylated cyclic peptide conformationally locked and selective towards a single substrate.

In this study we extend this biochemical approach to materials development, where guanine-containing pi-conjugated oligomers arise as exceptionally befitting substrates for a methyl scanning investigation. The chemodiversity of the purine building block allocates an array of atomic positions to probe.174 Many methylated purine analogs are known natural products,164 and, in congruence, the vast synthetic methodology established in the biochemical community makes selective methylation readily accessible. Furthermore, these bio-derived building blocks have been shown to

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contribute to the electronic structure and facilitate charge transfer when embedded in pi- conjugated materials.100,110,175 Of considerable impetus, the tribulations previously encountered while attempting to fabricate guanine-containing pi-conjugated materials into optoelectronic devices indicates a clear area for innovation.

Methodically blocking each hydrogen-bonding site of guanine (G) by installing methyl groups sequentially modulates the solid-state templating ability of each purine building-block (PG1–PG5, Figure 4-3). Expanding from a simple control (“h-bond on” and “h-bond off”) to a more intricate analysis will serve to elucidate how the hydrogen bond strength and geometry (monitored in the bulk and in solution) is ported into solid- state thin films. This understanding can then be utilized to quantify how these design factors evolve in macroscale morphology and have a systematic affect on optoelectronic device performance.

Molecular Design

The periphery of the guanine unit contains a diverse array of hydrogen bond donor and acceptor atoms (Figure 4-3). While the keto form of guanine is preferred,176-

178 O-methylation at the C(6) position imposes the enol form while removing one hydrogen bond donor. Further mono- and di-N-methylation at the C(2) amino group sequentially removes the remaining hydrogen bond donors to render a comparator,

PG5, incapable of forming hydrogen bonds. Protected guanine comparators PG1, PG2,

PG3, and PG4, retain some of the hydrogen bonding capability relative to the fully hydrogen bond capable derivative G.

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Figure 4-3. Guanine (G) and protected guanine (PG) end groups designed with methyl scanning.

In this study, both a simple monotopic and ditopic set of guanine-terminated thiophenes are evaluated (Figure 4-4). As in Chapter 2, thiophene is selected due to its relevance in pi-conjugated materials. The monotopic derivatives serve as model compounds to probe association strength in solution and interaction geometries in bulk solids (dimeric, cyclic, or linear self-association patterns). The information learned from the monotopic derivatives (4-1 series) will serve as a basis for understanding the possible long-range aggregation of C2h symmetric ditopic compounds (propagating linear or 2-D network formation). The ditopic compounds (4-2 series) will be evaluated in solution, as bulk solids, and in thin films.

Figure 4-4. Simple monotopic and ditopic target compounds evaluated in this work.

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Conformational Analysis

A conformational analysis on the end groups was performed to determine preferred orientation of the methy groups relative to the purine scaffold. Gas-phase geometry optimization calculations (DFT B3LYP/6-31+G*) were performed on all possible conformations, followed by comparison of the differences between calculated total energy. In each case, the N(9) alkyl chain was replaced with a methyl group to reduce computational time, since the substitution does not significantly affect the equilibrium geometry or electronics of individual molecules in the gas-phase.

End groups 4-G and 4-PG4 only possess one possible conformation. Derivatives

4-PG1 and 4-PG5 each posses two similar possible orientations of the C(6)O methyl group, where the methyl group is (i) pointed towards the N(1) position or (ii) towards the

N(7) position (Figure 4-5). In both cases, geometry (i) is preferred by ~2.5 kcal/mol, and thus, this geometry was used for subsequent analysis.179 The free rotation of the C(2) secondary amine in 4-PG2 enables two possible conformers, 4-PG2a and 4-PG2b, where the former is favored by ~0.3 kcal/mol (Figure 4-6). Given this difference is small, both conformers were considered for this study.

Figure 4-5. Conformational analysis of end-groups 4-PG1 and 4-PG5; total energy in hartrees and relative energy in kcal/mol are listed below each conformer.

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Figure 4-6. Conformational analysis of end-group 4-PG2; total energy in hartrees and relative energy in kcal/mol are listed below each conformer.

Derivative 4-PG3, incorporating both the C(6)O methyl and C(2) secondary amine, can display four possible conformations (Figure 4-7). The energy difference between these conformers agree with the other comparators, where C(6)O methyl position (i) is favored over (ii) by ~2.5 kcal/mol and C(2) methylamino group orientation

(a) is favored to (b) by ~0.4 kcal/mol. Following suit, only the two isomers 4-PG3a-i and

4-PG3b-i were considered for further analysis.

Figure 4-7. Conformational analysis of end-group 4-PG3; total energy in hartrees and relative energy in kcal/mol are listed below each conformer.

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Predicted Self-Association

As discussed in chapter 3, monotopic guanine can form linear arrangements, ribbon A and ribbon B, or the cyclic G-quartet. Transcribed by a corresponding ditopic derivative, the ribbon B templated assembly would form a closed-packed 2-D arrangement, and the G-quartet would form a porous square lattice network (Figure 4-

8). Meanwhile, the ribbon A form would be too sterically congested to be accommodated by a ditopic derivative.

Interesting, derivatives capped with PG2 groups have the same capabilities as G depending upon the rotation of the 2-amino functionality.180,181 As drawn in Figure 4-8,

4-1-PG2a could form ribbon B linear arrangement and 4-1-PG2b can form the G-quartet

In fact, both Wu et al182,183 and Davis et al.184 simultaneously demonstrated cation templated G-quartet formation by C(8), N(2) substituted guanosine derivatives.

Important aspects to consider about PG2 derivatives are how the additional R group, relative to G, can aid in solubility for solution-processing and how the rotational dynamics between PG2a and PG2b may influence controlled self-assembly.

Likewise, protected lactim units PG1 and PG3 are capable of parallel hydrogen bond interactions, including dimer formation between N(3) and N(2)–H and a linear arrangement between N(7) and N(2)–H. Proliferation of these arrangements by the ditopic derivatives would lead to linear assemblies (Figure 4-9). Furthermore, alteration between interaction could lead to branch points of the 1-D assemble or grain boundaries in thin films. 4-1-PG4 would only be capable of forming a dimer between interacting lactam moieties, leading to a linear arrangement for 4-2-PG4 (Figure 4-10).

Derivatives terminated with PG5 end groups would be incapable of hydrogen bond driven assembly.

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Figure 4-8. Possible (a) dimeric and (b) linear hydrogen bonded assemblies of 4-1-PG1 and 4-1-PG3 and cartoon depictions of the corresponding 2-D arrangement if accommodated by 4-2-PG1 and 4-2-PG3, respectively.

Figure 4-9. Possible (a) dimeric and (b) linear hydrogen bonded assemblies of 4-1-PG1 and 4-1-PG3 and cartoon depictions of the corresponding 2-D arrangement if accommodated by 4-2-PG1 and 4-2-PG3, respectively.

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Figure 4-10. Possible dimeric hydrogen bonded assembly of 4-1-PG4 cartoon depiction of the corresponding 2-D arrangement if accommodated by 4-2-PG4.

Calculated Electronic Structure

Gas-phase calculations (DFT B3LYP/6-31+G**) were performed on all oligomers to approximate expected HOMO and LUMO energy levels and results are summarized graphically in Figure 4-11. In each case, the N(9) alkyl chain was replaced with a methyl group to reduce computational time, since the substitution does not significantly affect the equilibrium geometry or electronics of individual molecules in the gas-phase. There is some variance amongst the calculated HOMO and LUMO energy levels of each end group, however these fluctuations are tempered upon increasing the conjugation length, with the 4-2 series more closer to being isoelectronic than the 4-1 series and end-group only structures (Figure 4-12). This normalization of the electronic structure upon extending conjugation suggests that solid-state packing, as opposed to a solely intrinsic effect, is expected to dominate emergent properties of the 4-2 series in thin films.

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Figure 4-11. Graphical display of calculated HOMO and LUMO energy levels for end groups only (black), 4-1 series of compounds (red), and 4-2 series of compounds (blue). Additional entries in 4-2 series represent mixed conformer derivatives 4-2-PG2a/b and 4-2-PG3a/b.

End Group Only 4-1 series 4-2 series

0.4

0.2 EnergyRange (eV)

0.0 HOMO LUMO FMO Gap

Figure 4-12. Range of calculated HOMO, LUMO, and HOMO-LUMO energy gaps values amongst each set of set of compounds.

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Synthesisa

The synthesis of target compounds 4-1-PG1 and 4-1-G has been previously reported (compounds 3-6 and 3-15 in chapter 3). Ditopic compounds 4-2-G and 4-2-

PG1 are synthesized in a similar manner, where the 4-2-PG1 is formed via Stille cross- coupling between 3-5 and 5,5’-bis(trimethylstannyl)-2,2’-bithiophene 4-3, followed by

Lewis acid assisted demethylation to yield compound 4-2-G. The remaining derivatives could also be synthesized using the same methodology from relevant 2-methyl amino and 2-dimethylamino purine precursors (Scheme 4-1).

Scheme 4-1. Synthesis of simple monotopic and ditopic target compounds.

a Synthesis performed by Dylan Holst, undergraduate researcher in the Castellano Research Group

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The synthesis of N-methyl and N,N-dimethyl amino purine building blocks was adapted from methodology reported by Gundersen et al. to synthesize heteromine natural products.185 Similar to their findings, N,N-dimethylation of 2-amino-6-methoxy purine (compound 3-4 in this work) can be accomplished though the reductive amination of formaldehyde in large excess (35 equivalents, 3 days). Monomethylation was not possible using similar conditions under stoichiometric control, the use of 1.5 equivalents of formaldehyde for a prolonged time (7 days) afforded only dimethylated product and unreacted starting material (Scheme 4-2). This observation suggests that the monomethylated secondary amine is more reactive than the primary amine towards reductive amination. It is possible that introduction of the first methyl group does not have a significant steric effect on reactivity, but instead increases the nucleophilicity of the nitrogen atom under aqueous conditions. A similar effect was observed by Mayr et al., who determined that the nucleophilicity of ammonia in water increased upon methylation (nucleophilicity parameter (N) = 9.48 for NH3, 13.82 for MeNH2, and 17.12

186 for Me2NH). The authors reasoned this increase in nucleophilicity as an effect of a respective decrease in hydration energy as the ammonia protons are replaced by methyl groups.187

Scheme 4-2. Reductive amination of 2-amino-6-methoxy purine (R = n-octyl).

The monomethylated derivative 4-6 was ultimately obtained following a similar strategy to Gundersen et al, where the N(2) amino group of 3-4 was first protected by a

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benzoyl group by reaction with benzoyl chloride in a pyridine/DCM mixture. A small amount of aryl methoxy cleaved by-product 4-9 was observed in the product mixture, likely due to the presence of pyridine hydrochloride.188 The desired product 4-8 was isolated and methylated using methyl iodide under basic conditions to yield 4-10.

Treatment with sodium methoxide in methanol then yielded target compound 4-6.

Scheme 4-3. Synthesis of N-methyl-2-amino-6-methoxy purine (R = n-octyl).

Both compounds 4-6 and 4-7 were brominated using NBS, similar to 3-4. The electrophilic aromatic substitution went to completion relatively quickly in ~15 minutes on substrate 4-7, whereas 3-4 and 4-6 took at least 2 hours to proceed. This difference in reaction rates speaks to the electronic effect induced by the electron rich dimethylamino group present in 4-7.175

Scheme 4-4. Bromination of all methylated guanine derivatives (R = n-octyl).

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Concluding Remarks

The full characterization of these compounds in both solution and solid-state is currently in progress. These studies will include UV-Vis absorption in both chloroform and a hydrogen-bond suppressing solvent to quantify the optical properties in solution, electrochemical analysis to analyze the electrochemical properties, and determination of association strength in chloroform. The bulk solids will be subjected to thermal analysis to correlate binding strength to materials transitions in the solid-state, and IR analysis to identify signatures of hydrogen bonding. Additionally, we plan to make thing films from the 4-2 series, and observe the impact of molecular recognition patterns on bulk properties in thin films through characterization of surface morphology (AFM, XRD) and solid-state optical properties. This study has the potential to reveal an innovative approach to the design of functional materials and can lead to substantial advances in the use of organic materials for solar energy conversion.

Experimental

Synthesis

General Information

Reagents and solvents were purchased from commercial sources and used without further purification unless otherwise specified. THF, diethyl ether, dichloromethane, toluene, and DMF were degassed in 20 L drums and passed through two sequential purification columns (activated alumina; molecular sieves for DMF) under a positive argon atmosphere. All synthetic manipulations were carried out under an atmosphere of argon using standard Schlenk line techniques unless otherwise noted.

Tetrakis(triphenylphosphine) palladium (0) and trans- bis(triphenylphosphine)palladium(II) chloride were purchased from Sigma-Aldrich and

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used as received. Thin-layer chromatography (TLC) was performed on SiO2-60 F254 aluminum plates with visualization by UV light. Flash column chromatography was performed manually or automatically on a CombiFlash Rf system (Teledyne Isco) using

1 13 SiO2-60, 230−400 mesh. H( C) NMR spectra were recorded on 300(75) MHz or

500(125) MHz spectrometers as specified. Chemical shifts (δ) are given in parts per million (ppm) relative to TMS and referenced to residual protonated solvent (CDCl3: δH

7.26 ppm, δC 77.16 ppm; DMSO-d6: δH 2.50 ppm, δC 39.50 ppm). Abbreviations used are s (singlet), d (doublet), t (triplet), q (quartet), quin (quintet), dt (doublet of triplets), b

(broad), and m (multiplet). ESI0 and ESITOF-MS spectra were recorded on a single quadrupole spectrometer. Compound 4-3189 was synthesized in accordance with literature procedures. Synthesis of compounds 4-1-PG4, 4-2-PG2, and 4-2-PG4 are in progress.

Synthesis of 9-octyl-6-methoxy-8-(thiophen-2-yl)- 1,9-dihydro-6H-purin-6-one (4-1-

Compound 4-1-PG (0.168 g, 0.467 mmol, 1 equiv) was dissolved in dry CH2Cl2 and cooled to -78 °C and then a 1.0 M solution of BBr3 in CH2Cl2 (2.80 mL, 2.80 mmol, 6 equiv) was added slowly over 15 min. The solution was stirred at -40 °C for 30 min then slowly brought to room temperature over 30 minutes, followed by the addition of methanol to quench the reaction. After quenching with MeOH, the solvent was removed under reduced pressure and the product washed with chloroform to yield a pale yellow

1 solid (0.120 g, 74 % yield). H NMR (300 MHz, DMSO-d6) ) δ 11.25 (s, 1H), 7.99 (dd, J

= 5.0, 0.9 Hz, 1H), 7.79 (dd, J = 3.6, 0.9 Hz, 1H), 7.32 (dd, J = 5.0, 3.8 Hz, 1H), 6.00 (s,

43H), 4.25 – 4.15 (m, 2H), 1.77 – 1.62 (m, 2H), 1.18 (s, 12H), 0.82 (t, J = 6.6 Hz, 3H).

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Synthesis of ,8'-([2,2'-bithiophene]-5,5'-diyl)bis(6-methoxy-9-octyl-9H-purin-2- amine) (4-2-PG1)

Compound 3-5 (0.61 g, 1.7 mmol, 2.2 equiv.), 4-3 (0.38 g, 0.78 mmol, 1 equiv), Ph3Bi

(34 mg, 0.078 mmol, 0.1 equiv), and Pd(PPh3)4 (90 mg, 0.078 mmol, 0.1 equiv) were dried under vacuum and dissolved in degassed xylenes. The reaction was heated to reflux and stirred overnight. The solvent was removed under reduced pressure, and the crude solid washed with boiling hexanes followed by boiling methanol. The filtrate was further purified on a neutral alumina column with gradient elution (MeOH:DCM 0:100 to

2:98) to yield an orange solid (0.190 g, 0.27 mmol, 34 % yield). 1H NMR (500 MHz,

DMSO-d6) δ 7.58 (d, J = 4.0 Hz, 1H), 7.50 (d, J = 3.9 Hz, 1H), 6.57 (s, 2H), 4.30 (t, J =

6.9 Hz, 2H), 3.99 (s, 3H), 1.82 – 1.63 (m, 2H), 1.37 1.10 (m, 10H), 0.82 (t, J = 6.9 Hz,

13 3H). C NMR (126 MHz, DMSO-d6) δ 160.36, 159.89, 155.75, 141.71, 137.09, 132.27,

127.29, 125.73, 113.61, 53.22, 42.65, 31.11, 28.83, 28.53, 28.45, 25.91, 22.03, 13.88.

Synthesis of 8,8'-([2,2'-bithiophene]-5,5'-diyl)bis(2-amino-9-octyl-1,9-dihydro-6H- purin-6-one) (4-2-G)

Compound 4-2-PG1 (0.190 g, 0.265 mmol, 1 equiv) was dissolved in dry DMF and cooled to -40 °C and then a 1.0 M solution of BBr3 in CH2Cl2 (1.59 mL, 1.59 mmol, 6 equiv) was added slowly over 15 min. The solution was stirred at -40 °C for 30 min then slowly brought to room temperature over 30 minutes, followed by the addition of methanol to quench the reaction. After quenching with MeOH, sand was poured into the crude reaction mixture and all solvent was removed under reduced pressure to prepare a solid dispersion. Using a Soxhlet set-up, the crude materials was with hexane, followed by acetone, and chloroform until there was no further indication of impurities

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being removes (detection with UV light). The compounds was then removed using a 1:1 mixture of chloroform:methanol and the solvent removed under reduced pressure to yield an bright orange solid ( 0.087 g, 0.127 mmol, 48 % yield). Initial 1HNMR and

13 CNMR analysis showed trace impurities, further purification is in progress.

Synthesis of N-(6-methoxy-9-octyl-9H-purin-2-yl)benzamide (4-8)

In a dry round bottom flask under an inert atmosphere, anhydrous benzoyl chloride (1.1 mL, 9.5 mmol, 2.4 equiv) and anhydrous pyridine (0.77 mL, 9.5 mmol, 2.4 equiv) was added to dry DCM and stirred for 10 min. The solution was then transferred via syringe to another round bottom flask under an inert atmosphere containing dissolved compound 3-4 (1.1 g, 4.0 mmol, 1 equiv) in anhydrous DCM and stirred at rt overnight.

The reaction mixture was concentrated under reduced pressure to a volume of ~1-2 mL, then a 5 mL portion of hexanes was added and the flask was placed under reduced pressure to remove the DCM. The precipitate was collected by filtration, sonicated in hexanes, and then filtered to yield the product as a colorless solid (1.380 g, 3.616 mmol,

1 91 % yield). H NMR (500 MHz, CDCl3) δ 8.49 (s, 1H), 7.94 (d, J = 7.2 Hz, 2H), 7.82 (s,

1H), 7.57 (t, J = 7.4 Hz, 1H), 7.50 (t, J = 7.5 Hz, 2H), 4.17 (t, J = 7.3 Hz, 2H), 4.17 (s,

3H), 1.94 – 1.85 (m, 2H), 1.37 – 1.18 (m, 10H), 0.86 (t, J = 6.9 Hz, 3H); 13C NMR (126

MHz, CDCl3) δ 165.25, 161.41, 153.04, 152.12, 141.76, 134.86, 132.31, 128.89,

127.58, 118.62, 54.58, 44.20, 31.84, 29.94, 29.24, 29.14, 26.78, 22.73, 14.19. HRMS

+ (DART) calc’d for C21H28N5O2 [M+H] :382.2238, found: 382.2243.

Synthesis of N-(9-octyl-6-oxo-6,9-dihydro-1H-purin-2-yl)benzamide (4-9)

4-9 was observed as a by-product in the crude reaction mixture from the synthesis of 4-

1 8. H NMR (300 MHz, CDCl3) δ 12.08 (s, 1H), 8.59 (s, 1H), 7.94 (d, J = 8.6 Hz, 2H),

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7.67 (d, J = 6.6 Hz, 2H), 7.57 (t, J = 7.6 Hz, 2H), 4.04 (t, J = 7.3 Hz, 2H), 1.91 – 1.76 (m,

2H), 1.41 – 1.19 (m, 12H), 0.87 (t, J = 6.6 Hz, 3H).

Synthesis of N-(6-methoxy-9-octyl-9H-purin-2-yl)-N-methylbenzamide (4-10)

Compound 4-8 (1.1 g, 2.9 mmol, 1 equiv) and NaH (0.17 g, 4.3 mmol, 1.5 equiv) were dissolved in dry THF under an inert atmosphere and stirred for 20 min. Methyl iodide

(0.90 mL, 14.4 mmol, 5 equiv) was then added and the reaction vessel was heated to

50 °C and stirred for 30 min. The reaction mixture was then quenched with methanol, poured into deionized water, extracted with DCM, and dried over anhydrous MgSO4.

The solvent was removed under reduced pressure and the resulting mixture was purified by silica gel column chromatography with gradient elution (EtOAc:hexanes

0:100 to 70:30) to yield compound 4-10 as a colorless solid (1.04 g, 2.6 mmol, 91 %

1 yield). H NMR (500 MHz, CDCl3) δ 7.74 (s, 1H), 7.36 (d, J = 7.1 Hz, 2H), 7.29 – 7.26

(m, 1H), 7.19 (t, J = 7.5 Hz, 2H), 3.96 (t, J = 7.2 Hz, 2H), 3.69 (s, 3H), 3.63 (s, 3H), 1.62

(p, J = 7.3 Hz, 2H), 1.34 – 1.15 (m, 12H), 0.87 (t, J = 7.0 Hz, 3H); 13C NMR (126 MHz,

CDCl3) δ 172.69, 160.34, 156.34, 152.62, 142.05, 138.43, 129.82, 127.95, 127.81,

118.32, 54.10, 44.02, 34.93, 31.83, 29.71, 29.21, 28.98, 26.66, 22.71, 14.17. HRMS

+ (DART) calc’d for C22H30N5O2 [M+H] :396.2394, found: 396.2404.

Synthesis of 6-methoxy-N-methyl-9-octyl-9H-purin-2-amine (4-6)

In a dry round bottom flask under an inert atmosphere, sodium methoxide in methanol

(30 wt%, 1.2 mL, 6.4 mmol, 5.05 equiv) was added to a solution of 4-10 (0.5 g, 1.3 mmol, 1 equiv) in anhydrous methanol.and stirred at rt for 48 h. The reaction mixture was then added to deionized water, extracted with DCM, and dried over anhydrous

MgSO4. The solvent was removed under reduced pressure, and the resulting mixture was purified by silica gel column chromatography with gradient elution (EtOAc:hexanes

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0:100 to 100:0) to yield compound 4-10 as a colorless solid (0.20 g, 0.69 mmol, 55 %

1 yield). H NMR (500 MHz, CDCl3) δ 7.53 (s, 1H), 4.87 (bs, 1H), 4.07 (s, 3H), 4.04 (t, J =

7.2 Hz, 2H), 3.02 (d, J = 5.0 Hz, 3H), 1.88 – 1.80 (m, 2H), 1.35 – 1.19 (m, 10H), 0.86 (t,

13 J = 6.9 Hz, 3H); C NMR (126 MHz, CDCl3) δ 161.38, 159.97, 154.30, 138.91, 115.16,

53.68, 43.53, 31.88, 29.91, 29.24, 29.14, 28.93, 26.73, 22.75, 14.21. HRMS (ESI) calc’d

+ for C15H26N5O [M+H] :292.2132, found: 292.2119.

Synthesis of 8-bromo-6-methoxy-N-methyl-9-octyl-9H-purin-2-amine (4-4)

NBS (0.067 g, 0.38 mmol, 1.1 equiv) was added portion wise to a solution of 4-6 (0.1 g,

0.34 mmol, 1 equiv) in dry DMF and stirred at rt for 2 h. The reaction mixture was then poured into deionized water, extracted with ethyl acetate, washed with a solution of 5%

Na2S2O4, and dried over anhydrous MgSO4. The solvent was removed under reduced pressure and the mixture was purified by silica gel column chromatography with gradient elution (EtOAc:hexanes 0:100 to 50:50) to yield compound 4-4 as a an off-

1 white solid (0.11 g, 0.29 mmol, 85% yield). H NMR (500 MHz, CDCl3) δ 4.90 (d, J = 4.6

Hz, 1H), 4.07 (s, 5H), 3.00 (d, J = 5.0 Hz, 3H), 1.79 (p, J = 6.7 Hz, 2H), 1.38 – 1.18 (m,

13 10H), 0.87 (t, J = 6.9 Hz, 3H); C NMR (126 MHz, CDCl3) δ 160.15, 159.72, 155.16,

124.63, 115.32, 77.41, 77.16, 76.91, 53.79, 44.10, 31.89, 29.28, 29.23, 29.15, 28.85,

+ 26.59, 22.75, 14.21. HRMS (DART) calc’d for C15H25BrN5O [M+H] :370.1237, found:

370.1242.

Synthesis of 6-methoxy-N-methyl-9-octyl-8-(thiophen-2-yl)-9H-purin-2-amine (4-1-

PG3)

Compound 4-4 (0.05 g, 0.14 mmol, 1 equiv), Ph3Bi (0.005 g, 0.014 mmol, 0.1 equiv), and Pd(PPh3)4 (0.015 g, 0.014 mmol, 0.1 equiv) were dissolved in dry degassed

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xylenes, along with 2-(tributylstannyl)thiophene (0.10 mL, 0.32 mmol, 2.4 equiv). The reaction vessel was heated to reflux and stirred overnight. The solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (EtOAc:hexanes 0:100 to 80:20) to yield the product as an off-white solid (0.043 g, 0.115 mmol, 85 % crude yield). Initial 1HNMR and 13CNMR analysis showed trapped solvents and trace impurities, further purification is in progress. HRMS

+ (ESI) calc'd for C19H27N5OS [M+H] : 374.2009, found: 374.2013.

Synthesis of 2-(methylamino)-9-octyl-8-(thiophen-2-yl)-1,9-dihydro-6H-purin-6-one

(4-1-PG2)

In a dry round-bottom flask under an inert atmosphere, a solution of 4-1-PG3 (20 mg,

0.053 mmol, 1 equiv) in dry degassed CHCl3 was cooled to −40 °C and then a 1.0 M solution of BBr3 in CH2Cl2 (0.32 mL, 0.32 mmol, 6 equiv) was added slowly over 15 min.

The solution was stirred at −40 °C for 30 min then slowly brought to room temperature over 30 min, followed by the addition of methanol (25 mL) to quench the reaction. The solvent was removed under reduced pressure and the product washed with methanol to

1 yield an off-white solid (5 mg, 0.014 mmol, 26 % yield). H NMR (500 MHz, DMSO-d6) δ

13.75 (s, 1H), 10.71 (s, 1H), 7.67 (dd, J = 5.2, 0.6 Hz, 1H), 7.54 – 7.50 (m, 1H), 7.19

(dd, J = 5.0, 3.8 Hz, 1H), 6.38 (d, J = 4.3 Hz, 1H), 4.29 – 4.20 (m, 2H), 2.84 (d, J = 7.0

Hz, 3H), 1.75 – 1.64 (m, 2H), 1.33 – 1.08 (m, 14H), 0.82 (t, J = 7.0 Hz, 3H). HRMS (ESI)

+ calc’d for C18H25N5OS [M+Na] : 382.1672, found: 382.1683.

Synthesis of 8,8'-([2,2'-bithiophene]-5,5'-diyl)bis(6-methoxy-N-methyl-9-octyl-9H- purin-2-amine) (4-2-PG3)

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Compound 4-4 (0.257 g, 0.696 mmol, 2.5 equiv.), 4-3 (0.137 g, 0.78 mmol, 1 equiv),

Ph3Bi (12 mg, 0.028 mmol, 0.1 equiv), and Pd(PPh3)4 (32 mg, 0.028 mmol, 0.1 equiv) were dried under vacuum and dissolved in degassed xylenes. The reaction was heated to reflux and stirred overnight. The solvent was removed under reduced pressure, and the crude solid washed with boiling hexanes followed by boiling methanol. The filtrate was further purified on a neutral alumina column with gradient elution (MeOH:DCM

0:100 to 2:98) to yield an orange solid (0.170 g, 0.23 mmol, 30 % yield). 1H NMR (500

MHz, DMSO-d6) δ 7.43 (d, J = 3.7 Hz, 1H), 7.24 (d, J = 3.9 Hz, 1H), 4.94 (s, 1H), 4.34

(t, J = 7.9 Hz, 2H), 4.09 (s, 3H), 3.05 (s, 3H), 1.94 – 1.78 (m, 2H), 1.46 – 1.17 (m, 12H),

+ 0.87 (t, J = 6.7 Hz, 3H). HRMS (ESI) calc’d for C38H52N10O2S2 [M+H] : 745.3789, found:

745.3778.

Synthesis of 6-methoxy-N,N-dimethyl-9-octyl-9H-purin-2-amine (4-7)

Compound 3-4 (1.0 g, 3.6 mmol, 1 equiv), NaCNBH3 (1.4 g, 22.7 mmol, 6.3 equiv), and paraformaldehyde (3.8 g, 126 mmol, 35 equiv) were added to solution of methanol (30 mL) and water (20 mL) in a sealed tube. Glacial acetic acid (4.7 mL, 83 mmol, 23 equiv) was then added, the flask was sealed, and the reaction vessel was heated to 50 °C and stirred for 70 h. The reaction mixture was poured into deionized water and extracted with chloroform and dried over anhyrdrous MgSO4. The solvent was removed under reduced pressure, and the resultant crude mixture was purified by silica gel column chromatography with an ethyl acetate mobile phase to yield compound 4-7 as a yellow

1 liquid (0.835 g, 2.737 mmol, 76 % yield). H NMR (500 MHz, CDCl3) δ 7.53 (s, 1H), 4.08

(s, 3H), 4.04 (m, 2H), 3.19 (s, 6H), 1.88 – 1.79 (m, 2H), 1.35 – 1.18 (m, 10H), 0.86 (t, J

13 = 6.8 Hz, 3H); C NMR (126 MHz, CDCl3) δ 160.70, 159.46, 154.46, 138.74, 113.82,

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53.45, 43.40, 37.45, 31.86, 29.79, 29.20, 29.09, 26.67, 22.73, 14.18. HRMS (DART)

+ calc’d for C16H27N5O [M+H] :306.2288, found: 306.2298.

Synthesis of 8-bromo-6-methoxy-N,N-dimethyl-9-octyl-9H-purin-2-amine (4-5)

NBS (0.68 g, 3.82 mmol, 1.4 equiv) was added portion wise to a solution of 4-7 (0.84 g,

2.7 mmol, 1 equiv) in dry DMF and stirred at rt for 15 min. The reaction mixture was then poured into deionized water, extracted with ethyl acetate, washed with a solution of

5% Na2S2O4, and dried over anhydrous MgSO4. The solvent was removed under reduced pressure and the mixture was purified by silica gel column chromatography with gradient elution (EtOAc:hexanes 0:100 to 50:50) to yield a yellow liquid (0.82 g, 2.2

1 mmol, 79% yield). H NMR (500 MHz, CDCl3) δ 3.89 (d, J = 7.2 Hz, 5H), 3.04 (s, 6H),

1.71 – 1.61 (m, 2H), 1.24 – 1.06 (m, 11H), 0.74 (t, J = 6.8 Hz, 3H); 13C NMR (126 MHz,

CDCl3) δ 159.07, 158.61, 154.91, 123.83, 113.74, 53.09, 43.51, 36.96, 31.55, 28.87,

28.80, 28.76, 26.19, 22.40, 13.85. HRMS (DART) calc’d for C16H26BrN5O

[M+H]+:384.1393, found: 384.1403.

Synthesis of 6-methoxy-N,N-dimethyl-9-octyl-8-(thiophen-2-yl)-9H-purin-2-amine

(4-1-PG5)

Compound 4-5 (0.10 g, 0.26 mmol, 1 equiv), Ph3Bi (0.011 g, 0.026 mmol, 0.1 equiv), and Pd(PPh3)4 (0.030 g, 0.026 mmol, 0.1 equiv) were dissolved in dry degassed xylenes, along with 2-(tributylstannyl)thiophene (0.20 mL, 0.63 mmol, 2.4 equiv). The reaction vessel was heated to reflux and stirred overnight. The solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (EtOAc:hexanes 0:100 to 80:20) to yield the product as a light yellow

1 solid (0.069 g, 0.18 mmol, 68 % yield). H NMR (500 MHz, CDCl3) δ 7.51 (d, J = 3.7 Hz,

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1H), 7.40 (d, J = 5.1 Hz, 1H), 7.11 (t, J = 4.4 Hz, 1H), 4.30 (t, J = 7.5 Hz, 2H), 4.09 (s,

13 3H), 3.21 (s, 7H), 1.81 (s, 2H), 1.24 (m, 13H), 0.87 (s, 3H). C NMR (126 MHz, CDCl3)

δ 160.33, 159.20, 156.09, 143.44, 133.24, 127.62, 127.47, 126.72, 113.68, 77.41,

77.16, 76.91, 53.42, 43.35, 37.44, 31.86, 29.58, 29.19, 29.10, 26.74, 22.73, 14.19.

Computations

Starting geometries were obtained by molecular mechanics minimizations as implemented in Spartan Student version 5.0.2 for Macintosh. The structural geometries of all monomers and multimers were optimized at the B3LYP/6-31+G** level of theory as implemented in Gaussian 09,156 accessed through the UF High- Performance

Computing Center. Frequency calculations were performed at the same computational level, and no imaginary frequencies were found. Molecular orbital plots were made using Visual Molecular Dynamics (VMD)157 software from the Gaussian output files.

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CHAPTER 5 SIMPLIFIED SYNTHESIS AND OPTOELECTRONIC PROPERTIES OF AN EXTENDED ASYMMETRIC PI-CONJUGATED OLIGOMER

Introductory Remarks

The supramolecular approach developed by the Castellano group to tailor the

BHJ OPV active layer morphology (Figure 3-1) retains the opportunity to enhance the performance of organic solar cells through continued exploration of the modularity of the design.84,85,133 Exchanging the hydrogen bonding unit can modify the rosette geometry and effective pi-surface area of the assembly. Incorporating state-of-the-art chromophores can tune the intrinsic optoelectronic properties of the oligomer.

Progressing from an asymmetric monotopic to a symmetric ditopic design offers expanded morphological control in the activate layer blend (Figure 5-1). As discussed in chapters 3 and 4, judiciously implementing the envisioned ditopic design into thin film architectures rouses practical challenges and thus a fundamental investigation of ditopic model compounds is in pursuit. Nevertheless, given the success of the original monotopic derivatives, revisiting the asymmetric design holds immediate promise for further advancement.

There is an abundance of planar self-complementary hydrogen-units known in the supramolecular community that is amendable in this design. A few of these units include the following: the previously investigated phthalhydrazide (PH) unit which provided a rosette with 3-fold radial symmetry; guanine (G) which can provide a G- quartet templated rosette of 4-fold symmetry; and barbituric acid (B), a widely investigated unit by Yagai et al. in pi-conjugated contexts, which can form 6-fold symmetric cyclic assemblies (Figure 5-1a).190-193

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Figure 5-1. Cartoon representation of the modular design approach available for the construction of self-assembling pi-conjugated oligomers.

There has been an astounding amount of advancements in the performance of organic photovoltaics over the past decade enabled by the introduction of contemporary molecular building blocks into pi-conjugated polymers or oligomers.194-198 Chen et al. have recently reported a record breaking performance for single-junction small molecule

OPV of 10 % PCE. Their devices utilized small molecules based on oligothiophenes containing 2-(1,1-dicyanomethylene)rhodanine (RCN) acceptor units in an A-D-A

(acceptor–donor–acceptor) design (Figure 5-2). Inspired by the simplicity and exceptional performance of the RCN containing oligothiophenes, and by the improvements hydrogen bonding had on quaterthiophene performance in OPVs, we have designed novel thiophene-based oligomers incorporating both of these features in an A-D-HB (acceptor–donor–hydrogen bonding) design (Figure 5-3).

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Figure 5-2. A series of simple oligomer-like molecules, DRCN4T–DRCN9T, demonstrating exceptional performance in solution-processed solar cells.199

Figure 5-3. Generic design of hydrogen bond equipped oligomer-like molecules investigated in this work.

Molecular Design

The molecules featured in this study adhere to an A-D-HB design in which the electron acceptor is RCN, the electron donor is an oligothiophene, and the hydrogen bonding unit is either a guanine or barbiturate unit (Figure 5-3). Model compounds of

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varying oligothiophene lengths were evaluated computationally (DFT B3LYP/6-31+G*) to determine equilibrium geometries and estimate the effects of conjugation length on electronic properties. The R groups on RCN and G units were substituted with methyl groups and non-alkylated oligothiophene units were used. Conformers were drawn in accordance with literature precedent. Results are summarized below in Table 5-1.

Table 5-1. DFT Calculation results of monotopic A-D-HB derivatives.

Compound HB n HOMO (eV) LUMO (eV) Eg (eV) Name

RCN_T4_G G 4 -5.35 -3.30 2.04

RCN_T5_G G 5 -5.25 -3.31 1.94

RCN_T6_G G 6 -5.17 -3.32 1.85

RCN_T7_G G 7 -5.11 -3.33 1.78

RCN_T4_B B 4 -5.63 -3.34 2.29

RCN_T5_B B 5 -5.46 -3.27 2.20

RCN_T6_B B 6 -5.64 -3.51 2.13

RCN_T7_B B 7 -5.50 -3.48 2.02

Dipole

For the guanine derivatives (RCN_T#_G series), the HOMO levels heighten with increasing conjugation while the LUMO levels remain unchanged, indicating that the narrowing energy gap is an effect of elongating the electron donating region. Whereas the guanine end group is an electron donor, maintaining a simple A-D motif, the electron withdrawing nature of barbiturate causes it to behave as an electron acceptor, creating a more complex A-D-A’ motif. Thus, the barbiturate derivatives (RCN_T#_B series) also

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show a decrease in energy gap with increasing conjugation length, but both the HOMO and LUMO levels are altered. Barbiturate entries with an even number of thiophenes have a HOMO of ~5.6 eV and odd numbered oligothiophenes have a HOMO of ~5.5 eV. Within each odd and even thiophene number set, the LUMO lowers by a similar magnitude upon increasing the thiophene spacer length resulting in a decreased energy gap (n = 4 to n = 6, ΔLUMO = -0.17 eV, ΔEg = -0.16 eV ; n = 5 to n = 7, ΔLUMO = -0.21

a eV, ΔEg = -0.18 eV). Due to the defined E/Z configuration of the end groups, the symmetry of the molecule changes with the number of thiophene units, affecting the total molecular dipole magnitude (Figure 5-4). Even numbered thiophene derivatives have a dipole of ~5 Debye and odd numbered thiophene derivatives have a ipole of

~9.5 Debye. Similarly, Chen et al. noted a correlation between dipole and electronic properties in the DRCNnT series of compounds.199 Therefore, it is likely that both donor spacer length and overall molecular dipole will have an effect on the electronic properties of the barbiturate terminated oligomers.

Figure 5-4. Geometry optimized structures of barbiturate containing oligomers with dipoles represented.

a E/Z configurations were drawn in accordance with literature precedent; RCN configuration is under investigation by Castellano group members Dr. Asmerom Weldeab and Lei Li.

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Oligothiophene Alkyl Group Positioning

The oligothiophene spacers offer additional opportunity to improve solubility by incorporation of alkylated thiophene units. To approximate how the regiochemistry of the alkyl groups may affect the electronic properties (due to both inductive effects and torsion angle influences), a computational screening of regioisomers in the HB = guanine, n = 4 family was performed, with methyl groups substituting longer alkyl chains in each position as demonstrated in Figure 5-5. Results of this screening are listed in

Table 5-2. Only minor perturbation of the electronic structure is found in each position

(ΔEg < 0.05 eV), except for the “h” position (4’’’) directly adjacent to the HB unit (ΔEg

+0.14 eV). Due to sterics effects, the dihedral angle between the oligothiophene and guanine units increases from 0° to 50°, disrupting the conjugation (Figure 5-6). Since the alkyl position did not have a large influence on the electronic structure in the other positions, synthetic targets with alkylated thiophene fragments were selected based on the synthetic accessibility of commercially available thiophene reagents.

Figure 5-5. Molecule used for thienyl alkyl screening. IUPAC numbering is abbreviated by letters a-h for simplicity.

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Table 5-2. Calculation results of oligothiophene alkyl group positioning on compound RCN_T4_G. (DFT B3LYP/6-31+G*)

Thiophene Position Group Electronic Properties

HB n a b c d e f g h HOMO LUMO Eg (eV) (eV) (eV) G 4 H H H H H H H H -5.35 -3.30 2.04 G 4 Me H H H H H H H -5.32 -3.26 2.06 G 4 H Me H H H H H H -5.30 -3.25 2.04 G 4 H H Me H H H H H -5.32 -3.23 2.09 G 4 H H H Me H H H H -5.35 -3.29 2.07 G 4 H H H H Me H H H -5.30 -3.24 2.06 G 4 H H H H H Me H H -5.30 -3.29 2.01 G 4 H H H H H H Me H -5.28 -3.26 2.02 G 4 H H H H H H H Me -5.49 -3.31 2.18

Figure 5-6. Geometry optimized structures of non-alkylated oligomer RCN_T4_G and substituted derivative RCN_T4-h_G.

Synthesis

Traditional Step-Wise Route

The RCN acceptor unit was synthesized according to literature procedure200 and was reacted with a 2-carbaldehyde thiophene derivative to demonstrate the generation of the condensed product (Scheme 5-1).201,202

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Scheme 5-1. Synthesis of RCN

The initial synthetic plan involved a divergent synthetic route, in which a large portion of the molecule containing the aldehyde functionality for downstream RCN condensation chemistry could be gradually built outwards (Scheme 5-2). Then separately, a small hydrogen bonding containing fragment could be synthesized.

Finally, the two units would be joined through cross-coupling to yield the final target

(Scheme 5-3). By this approach, the oligothiophene spacer could be modified by including additional thiophene units through successive step-wise cross-coupling, and the hydrogen bonding unit could be varied by changing the coupling partner in the final step. For simplicity, the quaterthiophene derivative with octyl groups in positions d(4’) and f(4’’) was pursued.

Scheme 5-2. Step-wise synthesis of aldehyde-containing oligothiophene fragment.

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Scheme 5-3. Divergent synthetic route to prepare RCN_T4-df_HB target compounds, in which the hydrogen-bonding unit can be easily exchanged.

Obtaining crucial intermediate 5-9 proved troublesome. It was imagined either the stannylated or borylated derivative could be obtained from 5-8 following standard procedures.203-206 However, the bromination of 5-7 resulted in an inseparable mixture of products. Likewise, the direct lithiation of 5-7 did not proceed. While the bromination reaction of 5-7 was under optimization,a the borylation of intermediate 5-6 was explored with the intention of translating these conditions to 5-8 (Scheme 5-4). Following known literature conditions,207 the desired product 5-12 was not observed and the protonated by-product 5-5 was obtained. Switching the coupling partners through use of a metalated HB fragment (guanine) suffered from the same drawbacks, where neither a stannylatedb nor a borylated derivative was obtained following standard procedures.

Continued efforts to optimize the step-wise synthesis of key aldehyde-containing oligothiophene precursors were performed by Asmerom Weldeab and Lei Li.

a Optimization of the bromination of 5-7 was later performed by Dr. Asmerom Weldeab. b Stannylation of protected guanine containing derivatives was previously explored by Dr. Raghida Bou Zerdan

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Scheme 5-4. Attempted borylation of 5-6 and 3-7.

Mixed Cross-Coupling

In an attempt to expedite the synthesis of an A-D-HB derivative with readily available reagents, a convergent mixed Stille cross-coupling was performed (Scheme 5-

5). This reaction utilized 1 equivalent each of aryl bromides 5-6 and 5-14 (synthesis shown in Scheme 5-6), and 0.95 equivalent of bis(trimethyltin)thiophene 5-15. Although this route would result in a predictably low yield of the desired compound 5-17 (the precursor to final compound RCN_T5-dg_G), the overall atom economy would be equivalent to or improved from a traditional step-wise route. Relative to a traditional step-wise approach208 this route would potentially ascribe to the principles of green chemistry209 by recognizing the following features: (1) improving atom economy, (2) consuming less energy by lowered reaction time due to fewer steps, (3) generating less waste by lowering the number of intermediates to purify, (4) reducing the consumption of precious materials, (5) utilizing readily available reagents, (6) utilizing catalysts, and

(7) reducing exposure to hazardous reagents by reducing the number of steps requiring organotin reagents.210

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Scheme 5-5. Mixed Stille cross-coupling to obtain precursor for RCN_T5-dg_G.

The mixed Stille cross-coupling reaction resulted in a complex reaction mixture, as expected given the complexity of the major products and generation of by-products common in Stille cross-coupling of pi-conjugated materials.203,211,212 Attempts to purify the reaction mixture were performed using automated column chromatography, in which the stationary phase was silica gel and the mobile phase transitioned from a 0-

100% DCM in hexanes gradient to a 0-10% MeOH in DCM gradient. Three major fractions eluted during this run: fraction 1 at 60% DCM in hexanes, fraction 2 at 100%

DCM, and fraction 3 at 5% MeOH in DCM. After analysis of all three fractions, desired compound 5-17 was not observed. Only the bis(aldehyde) compound 5-16 could be identified and isolated from fraction 2, necessitating an alternative synthetic route.

Scheme 5-6. Synthesis of 8-(5'-bromo-4'-octyl-[2,2'-bithiophen]-5-yl)-6-methoxy-9-octyl- 9H-purin-2-amine

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Mixed Knoevenagel Condensation

Inspired by the ability to rapidly access the bis(aldehyde) pentathiophene derivative 5-16 by a convergent method, a mixed Knoevanagel condensation route was designed to obtain A-D-HB target RCN_T#_B. Conveniently, both RCN and barbituric acid contain active methylene groups which can undergo quantitative condensation reactions with aldehyde-containing thiophene derivatives to afford the respective condensation products.213,214 In the redesigned route (Scheme 5-7) compound 5-16 would be reacted with 1.5 equivalents of RCN until all of the acceptor was consumed to yield two products, the mono- and disubstituted adducts. Addition of barbituric acid would then only be able to react with compounds containing a free aldehyde. The final result would be access to two products, a ditopic A-D-A derivative DRCN and an asymmetric A-D-HB oligomer RCN_T#_B, in one-pot. The difference in binding affinity of each product to a stationary phase through hydrogen bonding interactions (or lack thereof) allows the two compounds to be easily separated by chromatography or

Soxhlet extraction. This route would also avoid unnecessary derivatization because the

DRCN by-product could serve as a benchmark comparator, since its conjugated molecular framework is identical to the high performing oligomer prepared by Chen et al.199

This route was investigated using 5-16 as the bis(aldehyde) starting material, which was synthesized directly via Stille cross-coupling of compounds 5-6 and 5-15 (5-

7a). Purification was performed using column chromatography and verified by TLC analysis (single spot) and 13CNMR (1 aldehyde, 10 aromatic, and 8 aliphatic signals were observed). However, an anomaly was observed in the 1HNMR; all expected peaks were observed, but the singlet (7.25 ppm) corresponding to the central thiophene proton

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integrated lower than the other protons (0.8:1) and two additional doublets (7.21 and

7.35 ppm) integrating to the difference (0.2:1) appeared (Figure 5-7b). After further scrutiny, it was determined that the purified material was actually a mixture containing

~80% of the cross-coupled pentathiophene derivative 5-16 and ~20% of the homo- coupled hexathiophene derivative 5-21 – an undesired by-product typical of Stille cross- coupling methodology.211,212 This composition was confirmed my mass-spectrometry, which revealed ions corresponding to both species in a single sample ([5-16+H]+ theoretical: 693.2018, observed: 692.2017 (0.1 ppm) amu; ([5-21+H]+ theoretical:

775.1895, observed: 775.1884 (1.4 ppm) amu). Indeed, upon further optimization of

TLC conditions (reducing the polarity and repeated elution) the two compounds were resolved (Figure 5-7c). The desired compound was then isolated repeated column chromatography.

Scheme 5-7. One-pot synthesis of A-D-A and A-D-HB oligomers.

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Figure 5-7. Synthesis and analysis of bis(aldehyde) terminated oligothiophene including (a) reaction scheme demonstrating generation of cross-coupled 5-16 and 1 homo-coupled side product 5-21, (b) HNMR spectrum taken in DMSO-d6 at 298 K zoomed into the aromatic region, and (c) TLC analysis comparing “normal polarity” and “less polar” mobile phases, inset shows image of 5-16 as a bulk solid after repeated column chromatography.

After purification of intermediate 5-16, the mixed Knovenagel condensation was performed using 1.55 equivalents of RCN until all RCN was consumed, and then 0.55 equivalents of barbituric acid was added and allowed to react (Scheme 5-8). The crude mixture was then deposited on a neutral alumina stationary phase followed by Soxhlet extraction to first isolate DRCNT5-dg. Compound RCN_T5-dg_B could then be removed by switching to a hydrogen bond competing solvent system, effectively separating the two products.

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Scheme 5-8. One-pot synthesis of A-D-A and A-D-HB oligomers.

Optical Properties in Solution

Hydrogen Bond Capable vs. Benchmark Oligomers

The UV-Vis absorption spectra of RCN_T5-dg_B and DRCNT5-dg were initially measured in chloroform to compare their optical properties. Compound DRCNT5-dg displayed a single low-energy absorption with λmax at 538 nm and a linear Beer-Lambert plot. RCN_T5-dg_B showed also displayed a single absorption with a λmax at lower energy (551 nm) but the Beer-Lambert plot was not linear, indicative of aggregation in solution. Furthermore, a red-shifted absorption shoulder appeared at 699 nm, indicative of pi-pi interactions between aggregated molecules. Typical hydrogen-bond suppressing solvents, DMF and DMSO, did not solvate both compounds, so alternative solvent mixtures were explored. A mixture containing chloroform, 1,2-dichlorobenzene (o-DCB), and DMF in a 90:5:5 ratio by volume was chosen to incorporate pi-pi stacking and hydrogen-bonding competing solvents. NO change in the absorption profile of DRCNT5- dg was observed in this solvent mixture. As shown in Figure 5-8, the λmax of RCN_T5-

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-6 dg_B matched that of DRCNT5-dg at low concentration (λmax = 538 at 2.5 – 10 ×10

M). At increased concentrations, however, a slight bathochromic shift (λmax = 542 at 40

×10-6 M, Δλ = 4 nm) and appearance of the shoulder at 669 nm was observed (Figure 5-

9). This change suggests that RCN_T5-dg_B begins to aggregate within this concentration range in the solvent mixture, but the association strength is not as strong as in pure chloroform. In a monomeric state, both DRCNT5-dg and RCN_T5-dg_B display similar absorption onsets corresponding to optical band gaps of 1.94 and 1.92 eV, respectively. While DRCNT5-dg displayed a higher extinction coefficient, the difference occurs within the same order of magnitude (104 M-1). The UV-Vis absorption properties are listed in Table 3-5.

DRCNT -dg in CHCl 5 3 DRCNT -dg in CHCl :o-DCB:DMF 5 3 RCN_T -dg_B in CHCl 5 3 RCN_T -dg_B in CHCl :o-DCB:DMF 1.0 5 3

0.5 NormalizedAbsorbance (a.u.)

0.0 300 400 500 600 700 800 Wavelength (nm)

Figure 5-8. Overlaid normalized absorption spectra of RCN_T5-dg_B and DRCNT5-dg at low concentration (5 ×10-6 M) in chloroform and a chloroform mixture at 298 K. Inset: an image of the solutions.

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a) b) 0.6 CHCl 3 CHCl 3 CHCl :o-DCB:DMF 3 CHCl :o-DCB:DMF 1.0 3

0.8 0.4

0.6

0.4 0.2 Absorbance(a.u.)

NormalizedAbsorbance (a.u.) 0.2

0.0 0.0 400 600 800 0 10 20 30 40 Wavelength (nm) Concentration (µM)

Figure 5-9. Comparison of RCN_T5-dg_B absorption properties in CHCl3 and CHCl3:o- DCB:DMF (90:5:5) mixture including a) overlaid normalized absorption spectra at high concentration (40 ×10-6 M) at 298 K and b) Beer-Lambert plot at 669 nm.

Table 5-3. UV-Vis absorption data collected for RCN_T5-dg_B and DRCNT5-dg in various solvents. optical λmax ε λonseta Eg Compound Solvent (nm) (M-1 cm-1) (nm) (eV)

4 DRCNT5-dg CHCl3 538 7.4 × 10 637 1.95 4 RCN_T5-dg_B CHCl3 538 4.3 × 10 660 1.88 4 DRCNT5-dg CHCl3:o-DCB:DMFb 551 7.0 × 10 640 1.94 4 RCN_T5-dg_B CHCl3:o-DCB:DMFb 538 - 542 5.2 × 10 646 1.92 4 RCN_T5-dg_B THF 515 5.2 × 10 617 2.01 aDetermined from absorption spectrum of 5 ×10-6 M solutions. bChloroform, 1,2- dichlorobenzene, and N,N-dimethylformamide used as a 90:5:5 by volume mixture.

Solvatochromism

In the chloroform solvent mixture RCN_T5-dg_B displayed a deep purple color

(λmax = 538 nm), while in THF the compound formed a bright red solution and showed a hypsochromically shifted absorption spectrum (λmax = 515 nm) (Figure 5-10). This positive solvatochromism (Δλ = 23 nm) likely occurs because the chloroform solvent mixture is more polar than THF, as indicated by ET(N) value of each component (values

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215 listed in Table 5-4). In the case of RCN_T5-dg_B, a dipolar solute, the more polar solvent is better able to stabilize the excited state relative to the ground state, resulting in a bathochromic shift.216,217

THF CHCl :o-DCB:DMF 1.0 3  = 515 nm  = 540 nm max max

0.5 NormalizedAbsorbance (a.u.)

0.0 400 600 800 Wavelegnth (nm)

Figure 5-10. Overlaid normalized absorption spectra of RCN_T5-dg_B collected as 20 ×10-6 M solutions in THF and a chloroform mixture at 298 K. Insets: images of each solution.

Table 5-4. Empirical parameters of solvent polarity.215

Solvent ET(30) ETN

Chloroform 39.1 0.259

1,2-dichlorobenzene 38.0 0.225

N,N-dimethylformamide 43.2 0.386

tetrahydrofuran 37.4 0.207

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Optoelectronic Properties in the Solid-State

Neat Thin Filmsa

The solubility of RCN_T5-dg_B was screened in different solvents and solvent mixtures that would be suitable as co-solvents with PCBM derivatives. Five of these conditions were used to prepare neat thin films by spin coating, two of which led to films of thicknesses relevant for OPV devices. The results from this solvent screening and best spin-coating conditions are listed below in Table 5-5.

Table 5-5. Solubility and spin-coating screening results of RCN_T5-dg_B. Solubility Film Thickness Solvent Spin Condition (mg/mL) (nm) HFIP < 1 - -

CHCl3 < 1 - - Chlorobenzene (CB) ~ 4 500 RPM, dynamic 37 ± 3 o-DCB ~ 4 500 RPM, static N/Aa Toluene < 2 - - Acetonitrile < 2 - - THF ~6 1000 RPM, static N/Ab MeOH < 1 - -

CHCl3:HFIP (80:20) < 2 - -

CHCl3:o-DCB:DMF (90:5:5) ~4 - -

CHCl3:o-DCB:MeOH (90:5:5) < 2 - - o-DCB:DMF (50:50) > 10 500 RPM, static N/Aa

CHCl3:THF (75:25) ~ 6.5 1000 RPM, dynamic 55 ± 2

CHCl3:MeOH (50:50) < 1 - -

CHCl3:DMF (50:50) < 1 - -

CHCl3:DMF (50:50) < 1 - - aFilm was too thin to measure. bFilm quality was not suitable for device fabrication due to aggregation and could not be accurately measured.

a Solid-state characterization was performed by Daken J. Starkenburg from the Xue Research Group in the UF Department of Materials Science and Engineering

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Neat films of RCN_T5-dg_B were prepared by spin coating from chlorobenzene

(CB) and a CHCl3:THF (3:1) solvent mixture. The absorption spectra of these neat films are shown below in Figure 5-11. The absorption maxima appeared at 595 nm, red- shifted 57 nm relative to the solvated form. The absorption onsets of the neat films occur at 698 nm and 704 nm, corresponding to optical band gaps of 1.78 eV and 1.74 eV for CB and CHCl3:THF, respectively. The thin film absorption onsets are approximately 0.14 – 0.18 eV lower in energy compared to the solvated molecule. The film absorbance spectra also showa shouldering at ~650 nm, similar to the shouldering observed upon aggregation in solution and further indicating enhanced molecular overlap.

Solution in CHCl :o-DCB:DMF (90:5:5) 3 1.4 0.4 (a.u.) Absorbance Solution Film from CB Film from CHCl :THF (3:1) 1.2 3 0.3 1.0

0.8 0.2 0.6

0.4 FilmAbsorbance (a.u.) 0.1 0.2

0.0 0.0 300 400 500 600 700 800 900 Wavelength (nm)

Figure 5-11. Optical absorbance of RCN_T5-dg_B in thin films and in solution.

Organic Photovoltaic Device Performance

Bulk heterojunction organic solar cells were prepared on ITO substrates coated with an PEDOT:PSS layer. Although RCN_T5-dg_B films showed a thickness of ~50 nm when fabricated into neat films from a CHCl3:THF solution, the film thickness decreased to ~15 nm when spin-coated as a mixture with PC71BM onto the device

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substrate. These devices did not show a measurable power conversion efficiency due to low donor content in this thin active layer (entries 1 and 2 in Table 5-6). Spin-coating from a THF:CB (4:1) solution resulted in thicker films of 80 – 100 nm and permissible device performance with maximum efficiency reaching 0.8 % (entries 3-5 in Table 5-7).

Unfortunately, the performance was limited again due to low donor content in the film.

Optical absorbance of the device films showed spectral features which overlapped with neat PC71BM films; that is, neat film RCN_T5-dg_B absorbance features were not observed in the blended active layer absorbance (Figure 5-12). Ultimately, the low solubility of RCN_T5-dg_B restricts its incorporation into blended thin film and limits the device performance.

Table 5-6. Summary of BHJ OPV device performance containing RCN_T5-dg_B and PC71BM blended active layers. Spin Active Jsc Coat Layer 2 a a PCE Device Solvent (mA/cm ) Voc (V) FF a Speed Thickness a (%) (RPM) (nm)

CHCl3:THF 0.006 ± 0.42 ± 0.18 ± 0.00 ± 1 500 16 ± 3 (3:1) 0.001 0.01 0.01 0.00

CHCl3:THF 0.005 ± 0.42 ± 0.21 ± 0.00 ± 2 1000 15 ± 3 (3:1) 0.001 0.06 0.01 0.00

THF:CB 2.19 ± 0.86 ± 38.5 ± 0.73 ± 3 1000 86 ± 2 (4:1) 0.18 0.01 0.4 0.07

THF:CB 1.72 ± 0.89 ± 35.4 ± 0.55 ± 4 500 101 ± 15 (4:1) 0.18 0.01 0.9 0.07

THF:CB 1.51 ± 0.88 ± 34.3 ± 0.46 ± 5 500 98 ± 9 (4:1) 0.3 0.01 1.6 0.11 aShort-circuit density (Jsc ), open-circuit voltage (Voc), fill factor (FF), and power conversion efficiency (PCE).

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Figure 5-12. Neat and blended film absorbance of RCN_T5-dg_B and PC71BM.

Concluding Remarks

A monotopic A-D-HB type molecule with extended pi-conjugation (RCN_T5- dg_B) was synthesized in 6 total steps. Synthesis was accomplished by a convergent strategy involving the generation of ditopic bis(aldehyde) pentathiophene (D) derivative and performing a mixed Knoevenagel condensation to install the acceptor (RCN) and hydrogen bonding unit (B). This synthetic approach is exclusively available to end groups containing active methylene groups. This streamlined synthetic approach is appealing as it allows rapid access to monodisperse, pi-conjugated materials with an improved overall yield. For perspective, synthesizing an analog containing a different hydrogen bonding unit by the traditional approach, such as the guanine analog

RCN_T5-dg_G, could take up to 21 overall synthetic steps.

Compound RCN_T5-dg_B showed attractive properties for use in optoelectronic devices, including a low optical band-gap and indication of pi-pi stacking in the solid- state. However, the limited solubility of the compound lowered its incorporation into

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OPV active layer blends, thus limiting it’s performance. Future work in this area includes the synthesis of a pentathiophene oligomer containing additional alkyl chains for improved solution processing. The synthesis of a shorter terthiophene derivative amenable to vacuum deposition is also envisioned. For these compounds, avoiding

Stille cross-coupling reactions in order to eliminate the generation of homo-coupled by- products during the bis(aldehyde) precursor synthesis is under consideration.

Experimental

Synthesis

General Information

Thin-layer chromatography (TLC) was performed on SiO2-60 F254 aluminum plates with visualization by UV light. Flash column chromatography was performed manually or automatically on a CombiFlash Rf system (Teledyne Isco) using SiO2-60, 230−400 mesh. 1H(13C) NMR spectra were recorded on 300(75) MHz or 500(125) MHz spectrometers as specified. Chemical shifts (δ) are given in parts per million (ppm) relative to TMS and referenced to residual protonated solvent (CDCl3: δH 7.26 ppm, δC

77.16 ppm; DMSO-d6: δH 2.50 ppm, δC 39.50 ppm). Abbreviations used are s (singlet), d (doublet), t (triplet), q (quartet), quin (quintet), dt (doublet of triplets), b (broad), and m

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(multiplet). ESI0 and ESITOF-MS spectra were recorded on a single quadrupole spectrometer.

The preparation of the following compounds has been reported by Asmerom

Weldeab:218 Z)-2-(5-((5-bromothiophen-2-yl)methylene)-3-octyl-4-oxothiazolidin-2- ylidene)malononitrile (5-2), tributyl(4-octylthiophen-2-yl)stannane (5-4), 4'-octyl-[2,2'- bithiophene]-5-carbaldehyde (5-5), 5'-bromo-4'-octyl-[2,2'-bithiophene]-5-carbaldehyde

(5-6), 4',4''-dioctyl-[2,2':5',2''-terthiophene]-5-carbaldehyde (5-7), and 5''-bromo-4',4''- dioctyl-[2,2':5',2''-terthiophene]-5-carbaldehyde (5-8), 2-(3-octyl-4-oxothiazolidin-2- ylidene)malononitrile (RCN). The following compounds were obtained from commercial sources and used without further purification: 5-bromothiophene-2-carbaldehyde (5-1,

Sigma-Aldrich), 3-octylthiophene (5-3, TCI America), and 2,5- bis(trimethylstannyl)thiophene (5-15, Sigma-Aldrich).

Synthesis of 6-methoxy-9-octyl-8-(4'-octyl-[2,2'-bithiophen]-5-yl)-9H-purin-2-amine

(5-19)

Brominated guanine derivative 3-7 (0.20 g, 0.46 mmol, 1 equiv), Ph3Bi (0.020 g, 0.046 mmol, 0.1 equiv), and Pd(PPh3)4 (0.053 g, 0.046 mmol, 0.1 equiv) were dissolved in 30 mL dry degassed xylenes, and compound 5-4 (0.53 g, 1.1 mmol, 2.4 equiv) was added.

The reaction vessel was heated to reflux and stirred overnight. The solvent was removed under reduced pressure. The crude product was purified by automated flash chromatogpraphy using silica gel and the gradient optimizer (EtOAc:hexane 0:100 to

100:0) to yield a yellow solid (0.23 g, 0.41 mmol, 91 % yield). 1H NMR (500 MHz,

CDCl3) δ 7.36 (d, J = 3.9 Hz, 1H), 7.10 (d, J = 3.9 Hz, 1H), 7.03 (s, 1H), 6.80 (s, 1H),

4.96 (s, 2H), 4.23 (t, J = 7.5 Hz, 2H), 4.04 (s, 3H), 2.54 (t, J = 7.5 Hz, 2H), 1.78 (p, J =

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7.6 Hz, 2H), 1.58 (p, J = 7.5 Hz, 2H), 1.41 – 1.15 (m, 20H), 0.83 (dt, J = 10.3, 6.8 Hz,

+ 6H); HRMS (ESI) calc’d for C H N OS [M + H] theoretical: 554.2982, observed: 30 43 5 2

554.2986.

Synthesis of 8-(5'-bromo-4'-octyl-[2,2'-bithiophen]-5-yl)-6-methoxy-9-octyl-9H- purin-2-amine (5-20)

Glacial acetic acid (1 mL) was added to a solution of 5-19 (0.23 g, 0.42 mmol, 1 equiv) in 10 mL dry THF, then the contents of the reaction vessel were cooled to 0 °C in an ice-water bath. Next, NBS (0.081 g, 0.46 mmol, 1.1 equiv) was added portion wise over

5 minutes and the reaction was slowly warmed to rt over 1.5 h, then heated to 60 °C and stirred overnight. The solvent was removed under reduced pressure to yield the crude product, which was subsequently diluted with EtOAc, washed with a solution of

5% Na2S2O4, and with brine. The organic phase was dried over anhydrous MgSO4, filtered, and evaporated. The crude product was purified by silica gel column chromatography (EtOAc:hexanes 0:100 to 100:0) to yield an orange solid (0.23 g, 0.37

1 mmol, 89 % yield). H NMR (500 MHz, CDCl3) δ 7.39 (d, J = 3.9 Hz, 1H), 7.10 (d, J =

3.9 Hz, 1H), 6.92 (s, 1H), 5.11 (s, 2H), 4.31 – 4.25 (m, 2H), 4.09 (s, 4H), 2.57 – 2.49 (m,

2H), 1.86 – 1.78 (m, 2H), 1.64 – 1.55 (m, 2H), 1.29 (m, 20H), 0.88 (m, 6H). 13C NMR

(126 MHz, CDCl3) δ 161.30, 159.35, 155.34, 143.62, 143.33, 139.07, 136.00, 131.28,

127.54, 125.30, 124.01, 115.48, 108.81, 54.07, 43.73, 31.99, 31.87, 29.80, 29.73,

29.67, 29.48, 29.35, 29.33, 29.27, 29.20, 26.71, 22.78, 22.73, 21.09, 14.23, 14.20.

+ HRMS (ESI) calc’d for C H BrN OS [M + H] theoretical: 634.2200, observed: 30 42 5 2

634.2057.

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Synthesis of 3''',4'-dioctyl-[2,2':5',2'':5'',2''':5''',2''''-quinquethiophene]-5,5''''- dicarbaldehyde (5-16)

Compounds 5-6 (1.1 g, 2.9 mmol, 2.5 equiv), 5-15 (0.47 g, 1.15 mmol, 1 equiv), and

Pd(PPh3)4 (0.26 g, 0.23 mmol, 0.2 equiv) were dissolved in 150 mL toluene and stirred at 100 °C for 36 hours. The reaction mixture was, concentrated under reduced pressure, and purified by repeated silica gel chromatography (EtOAc:hexanes 0:100 to

10:90) to yield a deep orange solid (170 mg, 0.25 mmol, 22 % yield). 1H NMR (500

MHz, CDCl3) δ 9.86 (s, 1H), 7.67 (d, J = 3.9 Hz, 1H), 7.24 (d, J = 3.9 Hz, 1H), 7.21 (s,

1H), 7.14 (s, 1H), 2.86 – 2.74 (m, 2H), 1.69 (p, J = 7.6 Hz, 2H), 1.47 – 1.20 (m, 11H),

13 0.86 (s, 3H); C NMR (126 MHz, CDCl3) δ 182.56, 146.92, 141.81, 141.27, 137.49,

135.95, 133.90, 129.29, 126.82, 124.24, 32.04, 30.65, 29.72, 29.67, 29.57, 29.43,

+ 22.83, 14.27. HRMS (ESI) calc’d for C H O S [M + H] theoretical: 693.2018, 38 44 4 5 observed: 692.2017.

Synthesis of 2,2'-((5Z,5'Z)-((3''',4'-dioctyl-[2,2':5',2'':5'',2''':5''',2''''- quinquethiophene]-5,5''''-diyl)bis(methaneylylidene))bis(3-octyl-4-oxothiazolidine-

5,2-diylidene))dimalononitrile (DRCNT5-dg)

A solution of 5-16 (175 mg, 0.25 mmol, 1 equiv), RCN (108 mg, 0.39 mmol, 1.55 equiv.), and ammonium acetate (58 mg, 0.75 mmol, 3 equiv) in 16 mL acetic was stirred at 100 °C for 48 °C. Then barbituric acid (16 mg, 0.13 mmol, 0.5 equiv) was added and the reaction continued to stir at 100 °C. After 24 h, 20 mL chloroform was added to the reaction to aid in solubility, and the reaction continued stirring for 24 h. The reaction mixture was cooled to room temperature. Neutral alumina was added to the crude reaction mixture and all solvent removed under reduced pressure to prepare a solid

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dispersion. Using a Soxhlet set-up, the crude product was washed with chloroform overnight to remove compound DRCNT5-dg. The compound was further purified on a silica gel column (70:30 DCM in hexanes) to yield a dark purple solid (75 mg, 0.062

1 mmol, 25 % yield). H NMR (500 MHz, CDCl3) δ 8.04 (s, 1H), 7.41 (d, J = 4.1 Hz, 1H),

7.27 (s, 1H), 7.25 (s, 1H), 7.17 (s, 1H), 4.27 – 4.17 (m, 2H), 2.87 – 2.79 (m, 2H). 13C

NMR (126 MHz, CDCl3) δ 165.91, 165.46, 146.20, 141.20, 136.79, 135.86, 135.27,

133.16, 132.68, 129.34, 128.43, 126.35, 124.94, 113.47, 112.29, 55.82, 45.46, 32.03,

31.82, 30.56, 30.00, 29.94, 29.62, 29.50, 29.19, 29.17, 28.88, 26.08, 22.82, 22.73,

14.26, 14.19, 1.13.

Synthesis of (Z)-2-(5-((3''',4'-dioctyl-5''''-((2,4,6-trioxotetrahydropyrimidin-5(2H)- ylidene)methyl)-[2,2':5',2'':5'',2''':5''',2''''-quinquethiophen]-5-yl)methylene)-3-octyl-

4-oxothiazolidin-2-ylidene)malononitrile (RCN_T5-dg_B)

From the same reaction mixture containing DRCNT5-dg, RCN_T5-dg_B was removed from the alumina dispersion by was washing with a 50:50 mixture of chloroform:methanol for 24 hours. The compound was dried under vacuum to yield a

1 dark purple solid (80 mg, 0.75 mmol, 30 % yield). H NMR (500 MHz, C2D2Cl4) δ 8.60

(bs, 1H), 8.06 (bs, 1H), 7.89 (bs, 1H), 7.77 (bs, 1H), 7.67 (bs, 1H), 7.44 (bs, 2H), 7.40

(bs, 1H), 7.32 (bs, 1H), 7.29 (bs, 1H), 7.24 (bs, 2H), 4.26 (bs, 2H), 2.86 (bs, 4H), 1.77

(bs, 8H), 1.44 (m, 122H), 0.94 (bs, 9H). 13CNMR spectrum collection was unsuccessful due to the poor solubility of the compound. HRMS (MALDI) calc’d for C56H63N5O4S6 [M

+ + H] theoretical: 1061.3198, observed: 1061.3198 (1.6 ppm).

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Computations

UV-Vis Absorption in Solution

Absorption spectra were measured for 2.5, 5, 10, 15, 20, and 40 μM solutions on a

Cary 100 Bio spectrophotometer using 1 cm quartz cells. All solvents were HPLC grade

(purchased from Fisher). The absorption intensity at λmax was then plotted against the concentration in all cases to inspect, by linearity, if the compounds followed Beer’s law.

Molar extinction coefficients (ε) were determined from the linear plot for each compound

(where A = εbc). Values for λonset were determined form the intercept of the decreasing

-6 slope of λmax absorption and the baseline for spectrum collected at 5 ×10 M.

Absorption in Solid-state

To measure solid-state (thin film) absorption, monochromatic light was shone incident on to the film and chopped by a mechanical chopper and absorbance was measured using a Newport 818 UV detector connected to a pre-amp and lock-in amplifier.

Organic Photovoltaic Device Fabrication

Glass substrates containing pre-patterned indium tin oxide electrodes were sonicated in deionized water and soap, deionized water, acetone, and isopropyl alcohol

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for 15 minutes each. The substrates were then dried with air and subjected to a 15 minute ultraviolet ozone treatment. Following this treatment, PEDOT:PSS (Clevios

4083) was spin coated on to the substrates and annealed in air at 145 °C for 20 minutes resulting in a 40 nm film, as measured by profilometry. Following the anneal, the substrates were passed into a nitrogen glovebox where the active layer was cast via spin coating. After spin coating the active layer, the devices were put under high vacuum and a 100 nm Al layer was deposited to complete the device structure. The devices were then characterized in air.

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CHAPTER 6 HOMOCHIRAL [2.2]PARACYCLOPHANE SELF-ASSEMBLY PROMOTED BY TRANSANNULAR HYDROGEN BONDINGa

Introductory Remarks

[2.2]Paracyclophane (pCp; Figure 6-1a) has enticed academic and commercial curiosity for over half a century.219,220 The rigid connectivity and close positioning of its

“bent and battered benzene rings”221 are the basis for through-space (transannular pi– pi) and through-bond [σ(bridge)–pi(deck)] interactions222,223 which strongly perturb the chemical, optical, and electronic properties of the molecule. The synthetic chemistry of pCp is quite mature and allows functional groups to be precisely positioned on the rings and bridges221,224—two common ring substitution patterns are shown in Figure 6-1b.

Synthetic organic chemists continue to use the planar chirality associated with appropriately functionalized pCps225 in ligand and catalyst design to great effect,226 while work by the groups of Bazan,227,228 Chujo,229-232 Collard,233-235 and others236-238 has beautifully evaluated the consequences of through-space conjugation on the properties of covalent pi-conjugated oligomers and polymers featuring embedded pCps.

Indeed, the pCp building block remains attractive for organic optoelectronic applications ranging from nonlinear optics239 to photovoltaics.240

The prospect of delocalized electronic states emerging for extended pi-stacked cyclophanes dates back to the seminal work of the groups of Chow,241 Misumi,242,243 and Staab,244 whose tediously prepared multitiered structures (e.g., Figure 6-1c) showed, for example, longer wavelength absorption and emission maxima upon

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increasing the number of intervening benzene rings. The single-molecule conductance of such constructs has only recently been measured. 245 Covalent systems which enforce much looser interactions between pCp rings229-231,233,234,238 nonetheless show evidence for delocalized “phane” states through pi-stacking (Figure 6-1d). It therefore comes as a surprise that unlike many pi-conjugated molecules for which robust self- assembly recipes have been established246 to encourage their predictable and even chiral one-dimensional (1D) supramolecular ordering in solution and the solid state, pCps have hardly been studied in this regard.247

Reported here is the first self-assembly strategy to promote the stacking of

[2.2]paracyclophanes to produce 1D supramolecular architectures. The design relies on judiciously installed transannular hydrogen-bonding (H-bonding) interactions—hitherto unstudied in this class of molecules—which predispose the chiral monomers for stereospecific, noncovalent polymerization

Figure 6-1. Pi-stacked paracyclophanes (pCps). a) (top) structure of [2.2]paracyclophane (pCp) and its standard carbon numbering, (bottom) X-ray crystal structure (data at 15 K) of pCp (CCDC 1036460) with transannular distances and benzene ring deformation indicated, b) familiar names of pCp substitution patterns; planar chiral structures are indicated (±), c) covalent bonds promote strong transannular interactions between p-stacked benzene rings in a “six-fold layered” cyclophane,242 d) Stacking of pseudo-geminal pCps in p-conjugated polymers provides access to a delocalized “phane” electronic state.234

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Supramolecular Design

Tilted Amides

Our pCp self-assembly design borrows conceptually from benzene-1,3,5- tricarboxamides (BTAs), molecules which reliably form 1D assemblies through threefold

H-bonding between the tilted amides of adjacent pi-stacked monomers (Figure 6-2).

The BTA assembly paradigm has found numerous applications across the materials and biomedical sciences,86 and is sufficiently robust for classroom experiments.248 One approach to porting the motif to [2.2]paracyclophane employs pCp-4,7,12,15- tetracarboxamide (pCpTA, Figure 6-2). The substitution pattern together with the pCp bridged structure demand formation of intramolecular N−H⋅⋅⋅O=C hydrogen bonds between pseudo-ortho-disposed amides. Reminiscent of the work of Nuckolls and co- workers with persubstituted (crowded) BTAs, 249 the pCp monomer becomes preorganized for intermolecular H-bonding with two pi-stacked neighbors.

Figure 6-2. The design of pCps capable of self-assembly through hydrogen bonding: Intramolecular (transannular) hydrogen bonds (dashed lines) in a pCp- 4,7,12,15-tetracarboxamide (pCpTA) predispose the molecule for self- complementary association with a stacked neighbor (left); the design draws inspiration from the popularized benzene-1,3,5-tricarboxamide (BTA) assembly motif (right); both form 1-D stacks of multi-tiered arenes (center).

Gas-phase calculations (DFT M06-2X/6-31G*)250,251 of a representative monomer

(Figure 6-3), where R = CH3, identify two C2-symmetric low-energy conformations, anti

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and syn, which differ with respect to their H-bonding (i.e., amide carbonyl) directionality and energy (the former is more stable by 0.2 kcal mol−1). The amide torsion angles

(defined by the C=O and pCp aryl planes), ϕ1– ϕ4, are similar between the isomers (ϕ1 ≈

ϕ3 ≈ 35°; ϕ2 ≈ ϕ4 ≈ −154°) and support good linearity and optimized distances

(N⋅⋅⋅C=O≈2.9 Å) between the H-bond donors and acceptors. Comparison of the pCpTA conformations to those of comparators pCp-4-monocarboxamide (ϕ1 ≈ 30°, ϕ1’ ≈ 157°), pCp-4,12-dicarboxamide (ϕ1 ≈ 154°, ϕ2 ≈ 37°), and pCp-4,16-dicarboxamide (ϕ1 ≈ 158°,

ϕ2 ≈ 29°) (Figure 6-3) further shows that the estimated intramolecular H-bond energy (~

8 kcal mol−1) more than compensates for a slightly unfavorable amide positioning in the

H-bonded arrangement (which costs ~1 kcal mol−1).

Figure 6-3. Gas-phase, geometry-minimized structures (M06-2X/6-31G*) of amide functionalized paracyclophanes: (Rp)-anti and (Rp)-syn pCpTA monomers (left), and comparators (Rp)-pCp-4-monocarboxamide (top, right), (Rp)-pCp- 4,12-dicarboxamide and pCp-4,16-dicarboxamide (bottom, right), where R=CH3, hydrogen atoms are not shown for clarity, and total energies are normalized within each set of isomers.

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Planar Chirality

Upon pCpTA monomer self-assembly, as shown schematically in Figure 6-2, two

(as opposed to three for the BTAs) strands of H-bonds will helically “lace up” a 1D supramolecular structure, evocative of both polypeptides and duplex DNA. Unlike the

BTA system, for which the monomer is inherently achiral and assembly stereocontrol can only be achieved through remote chiral induction (e.g., the introduction of chiral side chains), the helical sense of pCpTA assembly is dictated by the planar chirality of the monomers (Rp or Sp). One consequence is that pCpTA linear assembly is homochiral,

252 that is, each member of a propagating 1D stack must share the same absolute stereochemistry. The system joins just a handful of others whereby chiral self-sorting in supramolecular polymerization is realized in the absence of chiral carbon centers.49,253-

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Figure 6-4. The planar chiral monomers (Sp)-pCpTA and (Rp)-pCpTA dictate the handedness of the respective homochiral assemblies.

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Dipole

A final distinction between the pCpTAs and BTAs worth noting is related to their assembly polarity. While the latter boasts a permanent assembly macrodipole (which amplifies upon assembly growth) regardless of amide directionality, only the syn conformation of pCpTA (with its amides pointed in the stacking direction) is expected to behave similarly (Figure 6-5). The anti conformation, while polar as a monomer, should lead to effectively nonpolar nanorods upon 1D noncovalent polymerization. It is interesting to consider if the reduction in dipole which accompanies assembly can drive pCpTA self-association in a nonpolar solvent.

Figure 6-5. The dipoles associated with pCpTA conformers and assembly: (Rp)-anti- pCpTA (left) and (Rp)-syn-pCpTA (right). Molecular dipole moments are calculated from gas-phase geometry-minimized structures (M06-2X/6-31G*).

Synthesis

The synthesis of (±)-6-1 (see Scheme 6-1) progressing through intermediates 6-

2–6-5 began from commercially available pCp, which was tetrabrominated in the manner reported by Reich and Cram,256 converted into its tetraacid through lithium– halogen exchange followed by quenching with CO2, as reported by Rozenberg and co- workers for the synthesis of pCp mono- and diacids,257,258 and finally converted into the aliphatic amide derivatives (±)-6-1a and (±)-6-1b using standard chemistry. The hexyl version affords particularly good solubility in organic solvents. A similar synthetic

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approach was used to prepare monoamide (±)-6-6b, which is useful as a comparator molecule to report on the hydrogen-bonding properties of (±)-6-1.

O 1) n-BuLi O 1) (COCl)2, O O Br2 (excess), Br Br (8 equiv), DMF (cat), HO OH RHN NHR I2 (cat), Et2O DCM rt, 8 days HO OH RHN NHR Br Br 2) CO2 (g) 2) RNH2, 32% DIPEA 50% O O O O pCp (±)-6-2 (±)-6-3 30–50% (±)-6-1

a R = C3H7 b R = C H 1) n-BuLi O 1) (COCl)2, O 6 13 Br (1.05 equiv), 2 Br (2.1 equiv), DMF (cat), Fe (cat), DCM, Et2O OH DCM NHC6H13

rt, 15 min 2) CO2 (g) 2) C6H13NH2 70% quant 49% (±)-6-4 (±)-6-5 (±)-6-6b

Scheme 6-1. Synthesis of self-assembing pCp-4,7,12,15-tetracarboxamide (±)-6-1 and non-assembling pCp-4-monocarboxamide comparator (±)-6-6b.

Single Crystal X-Ray Structure

Slow evaporation of an ethanol solution of (±)-6-1a produced needle-like crystals of sufficient quality for single-crystal X-ray diffraction. The data (Figure 6-6), after extensive refinement (due to primarily side-chain disorder), unambiguously confirms the

a intended pCpTA assembly design. Three configurationally equivalent [i.e., (Rp)-6-1aanti or (Sp)-6-1aanti] but crystallographically independent pCpTA molecules constitute the asymmetric unit. The trimer stacks derived from (Sp)-6-1aanti and (Rp)-6-1aanti are shown in Figure 6-6a. Revealed experimentally is an average intramolecular (transannular) H- bond (N···C=O) distance of 2.81 Å, nearly identical to the average intermolecular H- bond distance of 2.77 Å. Accompanying the well-optimized H-bonding distances are average amide torsion angles (ϕ1 ≈ −38°; ϕ2 ≈ −141°) which are reasonably consistent with those predicted from DFT calculations. While the average intramolecular distance

a X-ray data collected and refined by Dr. Khalil Abboud at The Center for X-ray Crystallography at the University of Florida

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between aryl ring centroids (3.1 Å) is fixed and consequently short, the intermolecular centroid-to-centroid distances are on-average larger, 3.8 Å (the closest intermolecular

Caryl···Caryl distance is 3.4 Å). The increased distance reflects some monomer-to- monomer wobbling along the 1D chain, presumably a result of the molecules’ negotiating favorable H-bonding interactions and unfavorable repulsions between the distorted aromatic ring surfaces. Even so, dynamic solution environments likely support transiently close (and more typical) pi-stacking distances for assembled pCpTAs.

Figure 6-6. X-ray crystal structure of pCp-4,7,12,15-tetracarboxamide (±)-6-1a. a) Unit cell containing each enantiomorphic asymmetric unit. The two helical H-bond laces are denoted with differently colored dashed lines. Centroid-to-centroid benzene distances and H-bonding distances are shown. b) Wire frame representation of the asymmetric unit; side view (left) and top-down view (right) showing overlap of central benzene rings. c) pCp packing; side view of extended pCp stacks (atoms participating in H-bonding are shown as spheres for clarity. Alkyl chains and disorder have been omitted for clarity. d) Side view of extended pCp stack shown with planes drawn through the top of each benzene ring to more clearly visualize “wobbling” along the stack. e) Packing diagram showing multiple (Sp)-6-1a (light blue) and (Rp)-1a (dark gray) stacks from a top-down view (top) and tilted side view (bottom). Heteroatoms are shown as spheres for clarity.

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While the anti conformation of the pCpTA monomer is perhaps slightly favored, its selection in the crystal is probably governed by longer range interactions which also dictate the columnar packing arrangement. The helical sense of the antiparallel H- bonding laces between the homochiral stacks, [(Rp)-6-1aanti]n or [(Sp)-6-1aanti]n, are naturally opposite as dictated by monomer planar chirality. The [(Rp)-6-1aanti]n and [(Sp)-

6-1aanti]n stacks closely pack as shown in Figure 6-6d (the alkyl side chains have been removed for clarity). Interesting to note is that while the interface between the individual columns is filled with alkyl side chains, the interface associated with the shortest intercolumnar distance (10 vs. 12 Å) involves amides pointing in the same and not opposite directions.

Solution Studies

NMR Analysis in Mildly Polar Environments (Chloroform)

1 H NMR data acquired for soluble (±)-6-1b in CDCl3 from 0.1–30 mm (Figure 6-7) shows concentration-dependent chemical shift changes consistent with the self- assembly shown by X-ray crystallography. Specifically, upon increasing the concentration, the amide NH resonance [which, assuming the anti conformation, represents the weighted average of three NH environments: solvent exposed (Ha), intramolecularly H-bonded (Hb), and intermolecularly H-bonded (Hc)] shifts downfield (to

~ 8.1 ppm; Δδ ~. 0.6 ppm), and the time-averaged aromatic pCp protons (Hd and He) shift upfield (to ~ δ = 6.6 ppm; Δδ ~ 0.3 ppm). Smaller, but equally informative upfield shifts are observed for the diastereotopic methylene protons (Hf-i) on the bridges. Given that significant monomer conformational changes are not expected upon assembly, the upfield C−H shifts presumably arise from the ring current effect induced by pi-stacking.

The downfield shift of the amide proton is diagnostic of H-bonded assembly, and

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nonlinear curve fitting of the concentration-dependent data to an isodesmic (equal-K,

259,260 −1 equations 6-1 and 6-2) self-assembly model provides Kel = 63 ± 5 M (similar values are obtained from the other protons; see the Supporting Information). The results contrast with those of (±)-6-6b, which shows an upfield (δ = 5.5 ppm in CDCl3) and concentration invariant (from 0.1–30 mm) amide NH resonance.

1 Figure 6-7. HNMR analysis of (±)-6-1b in CDCl3. a) Molecular structure of 6-1b with proton labeled, b) non-linear curve fitting of concentration-dependent –NH chemical shift data fit to an isodesmic model, and c) 1HNMR spectrum of (±)- -3 6-1b at variable concentrations (0.1–30 × 10 M) in CDCl3 at 25 °C.

Kel pCpTA (pCpTA) n (6-1)

(6-2) δobs = measured chemical shift δm = chemical shift of monomer δagg = chemical shift of aggregate ct = total concentration Kel = elongation equilibrium constant

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The equilibrium constant for (±)-1 b is relatively small in chloroform, but reasonable given the number of intermonomer H-bonding interactions, and a bit larger

261 −1 than some BTAs (K = 15 ± 5 M ). Indeed, DOSY NMR measurements in CDCl3

(Figure 6-8) could be used to verify supramolecular growth through translational diffusion coefficients (D) obtained at various concentrations and temperatures. For (±)-

6-1b at 25 °C, D (10−10 m2 s−1) decreases from 6.7 ±0 .1 at 1 mm, to 5.5 ± 0.1 at 15 mm, to 5.1 ± 0.1 at 30 mm. The latter value expectedly decreases further (to 2.7±0.1) upon lowering the temperature to −10 °C. The trends, consistent with pCp self-assembly, are alternatively expressed through estimated hydrodynamic volumes relative to a non- aggregating internal reference tetramethylsilane (TMS) as described by Wu, X. et al.262

The changes observed in relative volume, V6-1b /VTMS, upon variation of concentration and temperature [36 ± 2 (1 mm, 25 °C), 50 ± 2 (15 mm, 25 °C), 56 ± 2 (30 mm, 25 °C),

112 ± 9 (30 mm, −10 °C)], are consistent with pCp self-association and the trends discussed above. The diffusion data treatment to determine relative volume, V6-1b /VTMS, is as follows:

The diffusion coefficients were related to hydrodynamic radius by the Stokes-

Einstein equation (equation 6-3), where D = the diffusion coefficient, kB =

Bolztman constant, T = temperature in Kelvin, η = dynamic viscosity, and rH =

hydrodynamic radius:

k T D = B (6-3) 6phrH

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When referenced to TMS as an internal standard, equation 6-3 can be reduced

to equation 6-4 to estimate the relative radius of the analyte (pCp) relative to

TMS:

r D pCp = TMS (6-4) rTMS DpCp Then, considering the volume of a sphere (equations), the volume of (±)-6-1b

relative to TMS can be estimated (eq. 6):

4 V = pr3 (6-5) 3

(6-6)

) Diffusion Relative Volume

-1

s )

2 6 100

TMS

-10 1b

2 Relative Volume (V Volume Relative 0 0 Diffusion Coefficient (10 Coefficient Diffusion 1 mM 15 mM 30 mM 30 mM 25 °C 25 °C 25 °C -10 °C

Figure 6-8. Graphical representation of DOSY data obtained for (±)-6-1b at variable concentrations and temperatures in CDCl3, indicating a decrease in the diffusion coefficient and increase of hydrodynamic radius relative to a TMS standard upon aggregation.

NMR Analysis in Non-Polar Environments (Cyclohexane)

A dramatic change in solution behavior is observed when (±)-6-1b is dissolved in a less-polar hydrocarbon solvent (e.g., cyclohexane or methylcyclohexane). Even at

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mM concentrations, the solutions are considerably viscous, a hallmark macroscopic property of H-bonded supramolecular polymers,263 thus suggesting a significant boost in association strength. While this is expected from the standpoint of H-bonding, it must also mean that the pCp pi-stacking is, at the very least, accommodated under these conditions. The solution spectroscopic data is consistent with the macroscopic result. 1H

NMR analysis in cyclohexane-d12, for example, shows concentration invariant chemical shifts for (±)-6-1b between 0.1–1.0 Mm. The result confirms a persistent aggregated state at even this level of dilution, further evidenced by slow monomer exchange on the

NMR timescale which affords two broad and downfield (δ Hb = 9.6 ppm; δHc=8.8 ppm)

NH resonances. Meanwhile, the amide NH resonance of (±)-6-6b remains upfield (δ =

5.2 ppm, 30 mM in cyclohexane-d12).

1 Figure 6-9. HNMR analysis of (±)-6-1b in cyclohexane-d12. Molecular structure of 6-1b with protons labeled (left), and 1HNMR spectrum of (±)-6-1b at variable -3 concentrations (0.1–1.0 × 10 M) in cyclohexane-d12 at 25 °C.

Infrared Spectroscopy Analysis

Further evidence for self-association by H-bonding in different environments comes through complementary FT-IR analysis (Figure 6-10).264 In the solid state, a predominant and broad N−H stretch is observed for (±)-6-6b at 3276 cm−1 (associated with intermolecular H-bonding), while two broad N−H stretches [ascribable to weaker,

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intermolecular (3215 cm−1) and stronger, intramolecular (3052 cm−1) H-bonding] are found for (±)-6-1b. At 30 mM in CHCl3, (±)-6-6b shows only a sharp, solvent-exposed

N−H stretch (3442 cm−1), a resonance also found for (±)-6-1b (3437 cm−1). Two additional broad N−H stretches are observed for (±)-6-1b (3257 and 3068 cm−1), consistent with H-bond association at these concentrations. FT-IR data in cyclohexane is fully consistent with the 1H NMR data, showing exclusively two H-bonded N−H stretches for (±)-6-1b mirroring the solid-state behavior and one solvent-exposed N−H stretch for (±)-6-6b. Worth noting, while the N−H stretch of (±)-6-1b associated with intramolecular H-bonding (3063 cm−1) in cyclohexane is comparable to chloroform

(3068 cm−1), the intermolecularly H-bonded NH shows a stretch at lower energy (3222 cm−1) consistent with stronger H-bonding in this solvent.

Figure 6-10. Complementary FT-IR analysis of (±)-6-1b and (±)-6-6b. N–H stretch region of a) both (±)-6-1b and (±)-6-6b in solid-state, b) (±)-6-1b in chloroform at variable concentrations (1 – 30 × 10-3 M), c) (±)-6-1b in cyclohexane at variable concentrations (1 – 30 × 10-3 M), and d) (±)-6-6b in chloroform and cyclohexane (30 × 10-3 M).

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Variable Concentration UV-Vis Spectroscopy

4 −1 1 The larger Kel value (>10 M , estimated from the H NMR dilution data) provides the opportunity to evaluate assembly by UV-Vis spectroscopy, which can report on both inter- and intramolecular pCp electronic interactions. The high-energy band and cyclophane band for (±)-6-1b maintain the same absorption maxima (λ = 207 nm and

287 nm, respectively) and obey Beer's law (Figure 6-11) in methylcyclohexane (MCH) across a broad concentration range (2.5 – 120 μm). Taken together with the 1H NMR dilution data for (±)-6-1b in cyclohexane-d12, this data indicates that the concentration range remains above what is required to observe concentration-dependent aggregation behavior. In other words the solvated species remain in largely aggregated form within this range at 25 °C.

Figure 6-11. UV-Vis analysis of of (±)-6-1b at increasing concentration (2.5 – 120 × 10-6 M) in MCH at 298 K. a) overlaid absorption spectra. Arrows indicate direction of increasing concentration, b) Beer’s plot of high-energy transition, and c) Beer’s plot of cyclophane band.

Variable Temperature UV-Vis Spectroscopy

Absorption spectra of (±)-6-1b (40 μm) recorded at various temperatures (15–

90 °C) in methylcyclohexane (MCH) show a hypsochromic shift of the higher energy

(λmax = 208 nm at 90 °C; 204 nm at 15 °C) transition and bathochromic shift of the lower

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energy (λmax = 280 nm at 90 °C; 287 nm at 15 °C) transition, with clean isosbestic points, upon cooling (aggregation; Figure 6-12a). The former absorption presumably originates from a pi–pi* transition involving H-aggregated benzene decks (Figure 6-12b) ,40,265 while the latter cyclophane band reports on the distance between and the deformation of the pCp benzene rings,266 deformation which occurs upon assembly (Figure 6-12c). A bathochromic shift and attenuated intensity of the cyclophane band has been reported as paracyclophane decks are positioned closer in space.267 A similar trend of the cyclophane band is observed for (±)-6-1b (40 μm) when comparing chloroform (λmax =

283 nm) and methylcyclohexane (λmax = 287 nm) spectra, where the latter solvent is able to support stronger hydrogen bonds (Figure 6-12d) As further evidence that the temperature-dependent absorption energy changes are induced by self-assembly, no hypso- or bathochromic shifts are observed for either (±)-6-6b in methylcyclohexane

(Figure 6-12e) or for (±)-6-1b in ethanol (Figure 6-12f), a solvent which effectively competes for hydrogen bonds.

Van’t Hoff analysis of an equal-K model

The temperature-dependent spectral changes of the high-energy band, which report on the degree of polymerization, do not cleanly fit an equal-K model as demonstrated by Schenning, Meijer et al. (Figure 6-13).259 This analysis was performed following a temperature-dependent isodesmic model using the absorption data collected for (±)-6-1b (40 × 10-6 M in MCH) collected while cooling at a rate of 1 °C per minute

(Figure 6-13a). The absorption maxima at the lowest and highest temperatures (204 nm and 208 nm, respectively), which adhere to Beer’s Law at 298 K (Figure 6-13b), were selected for analysis. The degree of aggregation (α) estimated from the normalized absorbance at variable temperature, assuming the highest degree of aggregation (α =

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1) at low temperature and no aggregation (α = 0) at high temperature (Figure 6-13c).

The number-average degree of polymerization (DPN) approximated from the degree of aggregation according to equation 6-7 (Figure 6-13d) and the temperature-dependent equilibrium constant (Ke) approximated from according to equation 6-8 (Figure 6-13e).

The resultant Van’t Hoff plot displayed a non-linear relationship (Figure 6-13f). This plot is expected to be linear if the data conforms to an isodesmic model, thus suggesting a more complex relationship between the absorption changes and assembly mechanism at this concentration and temperature range in MCH.

Figure 6-12. Detailed thermal UV-Vis analysis of pCp assembly. a) Temperature- dependent absorption spectra of (±)-6-1b (40 × 10-6 M in MCH) collected with a constant cooling rate of 1 °C per minute. Arrows indicate the direction of decreasing temperature., b) Temperature-dependent absorption spectra of (±)-6-1b zoomed into high-energy absorption, and c) zoomed into cyclophane band, d) overlaid normalized absorption spectra of (±)-6-1b (40 × 10-6 M) in CHCl3 and MCH at 298 K, e) temperature-dependent absorption spectra of (±)-6-6b (40 × 10-6 M in MCH) collected with a constant cooling rate of 1 °C per minute, and f) temperature-dependent absorption spectra of (±)-6-1b (40 × 10-6 M in ethanol) collected with a constant cooling rate of 1 °C per minute.

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Figure 6-13. Isodesmic (equal-K) treatment of temperature-dependent UV data. (a) Overlaid absorption spectra of (±)-6-1b (40 × 10-6 M in MCH) collected at variable temperatures while cooling at a rate of 1 K/min. The absorption maxima at the lowest and highest temperatures (204 nm and 208 nm, respectively) were selected for analysis, (b) Beer-Lambert plot of (±)-6-1b in MCH at 298 K monitored at 204 nm and 208 nm, (c) degree of aggregation estimated from the normalized absorbance at the selected wavelengths, (d) number-average degree of polymerization (DPN) approximated from the degree of aggregation, (e) temperature-dependent equilibrium constant (Ke) approximated from the DPN using an isodesmic model, (f) Van’t Hoff plot, the equilibrium constant was divided by the molar volume of methylcyclohexane (0.128 M-1) to provide a dimensionless value.

1 퐷푃 = (6-7) 푁 √1−훼

1 1 퐷푃 = + √4퐾 푐 + 1 (6-8) 푁 2 2 푒 푡 Light Scattering

Dynamic light scattering analysis was conducted on a 25 mM sample of (±)-6-1b in MCH.a Measurements were performed between scattering angles of 30°–150° and

a Dynamic light scattering analysis was performed by Ian R. Smith from the Savin Research Group in the UF Department of Chemistry

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data was fit to a double exponential for analysis (Figure 6-14). These preliminary results indicated the presence of nanostructures in solution with a hydrodynamic radius (Rh) of

~ 6 nm, consistent with elongating stacking of the monomers. The correlation function also indicated the presence of larger aggregated species. These larger species may form by interactions between homochiral stacks as presented in the crystal structure

((Rp)-6-1aanti or (Sp)-6-1aanti), or may the effect of other conformations present in solution

(i.e. (Rp)-6-1asyn or (Sp)-6-1asyn). Detailed light scattering analyses on lower concentrations is currently in progress to better elucidate the structure and dynamics of the assembly in solution.

0.4 30 () 38 () 46 () 54 () 62 () 70 () 78 () 86 () 94 () 102 () 110 () 118 () 126 () 134 () 142 () 150 ()

0.3

) 0.2



( C

0.1

0.0 0.1 1 10 100 1000 10000 100000  (ms)

Figure 6-14. Autocorrelation function C(τ) and double exponential fit plotted as a function of lag time τ for scattering angles 30◦-150◦. The data are represented by the filled symbols, and the double exponential fits are the solid curves. With the exception of 38 not being able to fit a double exponential, the data at low angles look to have a better fit. There looks to be another “decay” between lag times of 0.1-1.0 ms that could be related to the sample. Though, due to the small size of your sample (Rh = 6 nm), this could also be the limit for the detector and correlator to build a correlation function at such short lag times.

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Chromophore Functionalized pCpTA

Chromophore Conjugate Design

Preliminary frontier MO analysis of [(Rp)-6-1anti]2 in the gas phase (DFT M06-

2X/6-31G*) shows that through-space (intermonomer) orbital delocalization could accompany dimerization (Figure 6-15). In order to probe the unique optical properties of the assembly, detailed photophysical studies by fluorescence spectroscopy, ultrafast spectroscopy and transient absorption are pursued. These techniques are limited to species which absorb visible light > 300 nm, requiring a pCpTA derivative tagged with a suitable chromophore. The molecular design is shown in Figure 6-16, where the pCpTA core is functionalized at each of the four amides with a chromophore, allowing for the desired absorption. Specifically, 4-dialkylamino-1,8-naphthalimide (NI) was selected for it’s established visible absorption and electroluminescent properties,268,269 prevalence in optoelectronic applications,270,271 and synthetic feasibility.272,273 NI can be readily appended to pCpTA at the N-imido position, and installation of aliphatic chains at the 4- amino position allows for increased solubility in non-polar solvents.

Figure 6-15. Calculated frontier molecular orbital diagrams of pCpTA dimers. a) HOMO and LUMO plots of [(Rp)-anti-pCpTA]2, and b) HOMO and LUMO plots of [(Rp)-syn-pCpTA]2 calculated from gas-phase geometry-minimized structures (M06-2X/6-31G*).

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Figure 6-16. Molecular design of chromophore functionalized pCpTA.

Direct Condensation

Similar to (±)-6-1, target compound (±)-6-7 could be synthesized via direct condensation between pCp tetra(acid), (±)-6-3, of an amino functionalized NI derivative

6-8 (Scheme 6-2). Compound 6-8 was synthesized as shown in Scheme 6-3.

Unfortunately, condensation with (±)-6-3 (via the acyl chloride intermediate generated in situ) yielded a complex mixture, from which the target compound could not be identified or isolated. It is plausible that the ethylene spacer did not significantly compensate enough for the steric bulk imposed by the large chromophore.

Scheme 6-2. Retrosynthetic analysis of (±)-6-7 revealing direct condensation route.

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Scheme 6-3. Synthesis of amino functionalized NI derivative 6-8.

Click Chemistry

Copper(I) catalyzed alkyne-azide cycloaddition (CuAAc) 274 has been successfully utilized in multivalent and macromolecular functionalizations and, thus, is an appealing method of synthesizing chromophore-tagged pCpTA.275,276 The redesigned route utilizing click chemistry to generate target compound (±)-6-12 is shown in Scheme 6-4. Precursor (±)-6-13 was synthesized via propargyl amine addition to the acyl chloride (Scheme 6-5) and 6-14 was prepared from 6-10 in three steps

(Scheme 6-6). It was found that a THF:H2O (10:1) mixed solvent system was crucial for the CuAAc reaction, giving the product in 44 % yield (Scheme 6-7). Recrystallization from a MCH:DCM:MeOH solvent mixture yielded the pure product. The photophysical properties of (±)-6-12 in solution are currently under investigation, as are single crystal growth attempts.

Scheme 6-4. Retrosynthetic analysis of (±)-6-12 revealing a click chemistry route.

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Scheme 6-5. Synthesis of alkynylated pCp-4,7,12,15-tetracarboxamide.

Scheme 6-6. Synthesis of azido-naphthalimide derivative.

Scheme 6-7. Synthesis of chromophore functionalized pCp-4,7,12,15-tetracarboxamide by CuAAc.

Progress Towards Chiral Resolution

The in-depth analysis of the stereospecific association of pCpTA requires both the racemic and optically pure samples in useful quantities. The chiral resolution of tetra substituted pCp derivatives prepared from the brominated starting material (±)-6-2 has been achieved, but proceeds through generation of a phenolic derivative that could not be easily transformed into pCpTA.277 Furthermore, pCpTA has yet to be fully

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resolved by analytical chiral HPLC, limiting both the use of this compound for definitive confirmation of optical purity and the possibility for semi-preparative resolution (Figure

6-17). Thus, it is appropriate to chemically resolve and analyze precursors to pCpTA, where the carboxylic acid derivative, (±)-6-3, arises as the suitable choice. Several methods to resolve related pCp carboxylic derivatives by chiral auxiliaries are known, including: the resolution of 4-pCp-monocarboxylic acid by it’s diastereomeric ammonium salt,257,278,279 pseudo-ortho substituted 4,12-pCp-dicarboxylic acid by esterification with a camphanyl template to afford separable diastereomers279 or with achiral p- bromophenol to afford enantiomers separable by semi-prep chiral HPLC.280

Figure 6-17. Chiral chromatogram of (±)-6-1b. Performed on a Chiralpak 1A column, flow rate = 1 mL/min, mobile phase = 5 % isopropanol in hexanes.a

Improved Synthesis of pCp-4,7,12,15-tetra(carboxylic acid)

As reflected by relatively lower yields (Scheme 6-1), the synthesis of tetrasubstituted pCp derivatives is non-trivial due to the inevitable generation of by-products with undesired substitution patterns. This is indeed the case for the synthesis of (±)-6-3, where the crude reaction mixture contains several impurities, likely including mono-, di-, and tri- carboxylated products, that would surely complicate crystallization of their

a Analysis by chiral HPLC was performed with the assistance from Kathryn L. Olsen from the Aponick Research Group in the UF Department of Chemistry

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diastereomeric ammonium salts. Reverse-phase chromatography was initially used to purify (±)-6-3, however this method was not effective on a larger scale. Thus, alternative purification methods were pursued. The use of normal-phase chromatography on silica gel with an acidic mobile phase improved the purification, but resulted in low yields (<

20% recovery) containing trace impurities.281

Since (±)-6-3 could not be easily purified, we sought an improved method of synthesizing the desired compound. Several accounts utilize n-BuLi for the halogen- lithium exchange of mono- and di-substituted brominated pCps, however, Lützen et al. found that the lithium-halogen exhange was the limiting step in the synthesis of 4,15- disubstituted pCp and that switching to t-BuLi at the base improved in the yield of the reaction.282 We tried the same approach and, likewise, observed improvements in crude reaction yield and purity (Table 6-1).

Table 6-1. Halogen-lithium exchange conditions screened on (±)-6-2. Crude Organolithium Equiv. Time Temp. Crude Crude Solvent Yielda Reagent (R-Li) of R-Li (h) (° C) Puritya Appearancea (%)

n-BuLi 8 Et2O 2 25 20 – 50 poor yellow

n-BuLi 8 Et2O 1 25 20 – 50 poor yellow

t-BuLi 8 THF 1 -78 41 poor yellow

t-BuLi 10 Et2O 1 -78 – 0 75 – 85 good off-white

t-BuLi 10 THF 1 -78 – 0 75 – 85 good off-white a Crude results were evaluated on (±)-6-3 following work-up.

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Synthesis and Chiral Resolution of pCp-4,7,12,15-tetra(ester) Derivatives

Since the optical purity of neither (±)-6-3 nor (±)-6-1 could be accurately evaluated by chiral HPLC, an esterified derivative was sought. Esterification of (±)-6-3 proved to be non-trivial. A generalized reaction is shown in Scheme 6-8, and accompanied results are listed in Table 6-2 and described herein.

Scheme 6-8. Generalized reaction scheme for the esterification of (±)-6-3. Reaction conditions and results are listed in Table 6-2.

Fisher esterification

Standard Fischer esterification utilizing methanol or ethanol and a catalytic amount of sulfuric acid did not proceed (Entries 1 and 2, Table 6-2). To minimize moisture during the reaction, an azeotropic Fisher esterification was tried using a Dean-

Starke setup with 1-butanol as the alcohol source and toluene to remove water while heating (Entry 3, Table 6-2). The product (±)-6-20 was initially obtained as an oil, however purification by repeated column chromatography was unsuccessful.

Additionally, these results were not reproducible, with the reaction conditions often resulting in no product formation. Presumably, the bulky steric environment of (±)-6-3 is preventing for Fisher esterification from occurring due to the close proximity of the C(4) carboxylic acid with the C(12) carboxylic acid during the transition state.

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Acyl substitution under basic conditions

Nucleophilic substitution of an acid chloride was reported by Meyer-Eppler et al. to prepare pCp diesters with 4,12 and 4,15 substitution patterns.280,282 Following this precedent, we reacted pCp tetra acid chloride (prepared in situ) with 4-bromophenol under basic conditions. This resulted in a complex mixture, in which the product could identified by 1HNMR but not sufficiently isolated (Entry 4, Table 6-2). Changing the alcohol component from 4-bromophenol to ethanol gave similar results (Entry 5, Table

6-2). The use of sodium methoxide in methanol as both the nucleophile and base resulted in the formation of the desired product, (±)-6-18, however, only trace product was isolated following purification (Entry 6, Table 6-2).

Steglich esterification

In a second attempt to obtain the (±)-6-21, N,N'-Dicyclohexylcarbodiimide (DCC) was applied as a coupling agent with 4-bromophenol and a catalytic amount of base

(Entry 7, Table 6-2).283 This had a similar result to the acyl chloride condensation route, in which the product could not be sufficiently purified from the complex reaction mixture.

SN2 with carboxylate nucleophile

The best results were obtained through the generation of the carboxylate form of

(±)-6-3 under basic conditions and subsequent reaction of this intermediate with a methyl electrophile to afford product (±)-6-18 (Entries 8 and 9, Table 6-2). While use of

K2CO3 as the base resulted in relatively low yields, cesium fluoride gave the pure product in up to 40% isolated yield.284 Exploration of the synthetic utility of this derivative, including hydrolysis, transesterification with a chiral secondary alcohol, and direct amidation are under investigation. Preparation of an ester through use of a diol is of additional interest.

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Table 6-2. Esterification conditions of (±)-6-3. Isolated “Alcohol” Entry Reagents Conditions Product Yield Component (%)

H2SO4 (cat.) neat 1 MeOH (±)-6-18 NR reflux, 72 h

H2SO4 (cat.) neat 2 EtOH (±)-6-19 NR reflux, 72 h

n-BuOH:toluene H2SO4 (cat.) 3 n-BuOH (1:1) (±)-6-20 0 – 20a

reflux, 24 – 72 h

4-BrPh (8 equiv.) , 4- DCM 4 TEA (12 equiv.), (±)-6-21 N/Ac bromophenol rt, overnight b

EtOH (excess), 5 EtOH DCM (±)-6-19 N/Ac DIPEA (excess), rt, overnight b

NaOMe (5.4 M in 6 MeOH DCM (±)-6-18 2 MeOH, 20 equiv.) rt, overnight b

DCC (6 equiv.), DMAP (0.25 4- DMF 7 equiv.), 4-BrPh (6 (±)-6-21 N/Ac bromophenol rt, 48 h equiv.)

K2CO3 (12 DMF equiv.), 8 MeI 50 – 100 °C, (±)-6-18 14 MeI (8 equiv.) overnight

CsF (6 equiv.), DMF 9 MeI MeI (80 equiv.) (±)-6-18 21 – 40 50 °C, overnight aIsolated result. bPerformed on acyl chloride intermediate. cResulted in a mixture of products, accurate yield of desired product could not be accurately determined due to insufficient purity.

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Concluding Remarks

This molecule, pCp‐4,7,12,15‐tetracarboxamides (pCpTAs), is the first pCp derivative capable of spontaneous organization into well‐defined supramolecular assemblies. The 1D arrangements are homochiral, with each column comprising monomers sharing the same planar‐chiral configuration, and helically laced‐up by two strands of anti‐parallel hydrogen bonds. A single‐crystal X‐ray structure has confirmed the supramolecular arrangement in the solid state and NMR, IR, and UV/Vis spectroscopic measurements have shown its persistence in solution. The molecular design is the first to feature cooperative transannular (intramolecular) and intermolecular H‐bonds along a propagating stack of aromatic molecules. Important derivatives required to enable detailed spectroscopic studies have been synthesized.

Efforts are underway to elucidate supramolecular polymerization mechanism details and explore possible long‐range, through‐space charge/energy transport.

Experimental

Synthesis

General Information

Reagents and solvents were purchased from commercial sources and used without further purification unless otherwise specified. Diethyl ether, THF, toluene, and dichloromethane were degassed in 20 L drums and passed through two sequential purification columns (activated alumina; molecular sieves for DMF) under a positive argon atmosphere. All synthetic manipulations were carried out under an atmosphere of argon using standard Schlenk line techniques unless otherwise noted. Thin-layer chromatography (TLC) was performed on SiO2-60 F254 aluminum plates with visualization by UV light. Flash column chromatography was performed using SiO2-60,

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230−400 mesh. Automated chromatography was performed on a CombiFlash Rf system

(Teledyne Isco). 1H(13C) NMR spectra were recorded on 300(75) MHz or 500(125) MHz spectrometers as specified. Chemical shifts (δ) are given in parts per million (ppm) relative to TMS and referenced to residual protonated solvent (CDCl3: δH 7.26 ppm, δC

77.16 ppm; DMSO-d6: δH 2.50 ppm, δC 39.50 ppm). Abbreviations used are s (singlet), d (doublet), t (triplet), q (quartet), quin (quintet), sx (sextet), dt (doublet of triplets), b

(broad), and m (multiplet). Compounds (±)-6-1, (±)-6-2, (±)-6-3, (±)-6-4, (±)-6-5, (±)-6-6, were synthesized in accordance with literature procedures.285 Compound 6-9 was purchased from Sigma-Aldrich and used without further purification.

Synthesis of 6-(dihexylamino)-1H,3H-benzo[de]isochromene-1,3-dione (6-10)

In a three-neck round bottom flask, compound 6-9 (1.3 g, 4.69 mmol)

and CuSO4·5H2O ( 0.059 g, 0.235 mmol) were dissolved in DMF

(100 mL). Dihexylamine (4.35 g, 23.5 mmol) was added and the

reaction stirred at 130 °C for 4 hours. The reaction was cooled to room temperature, diluted with DCM, washed 3 x H2O, 2 x 1 M HCl, and 2 x brine. The organic layer was dried with MgSO4, filtered and concentrated under reduced pressure.

The crude product was further purified on an automatic silica gel column (0 – 5% ethyl acetate in hexanes gradient). The final product was obtained as a bright yellow powder

(0.74 g, 42 % yield). 1H NMR (500 MHz, Chloroform-d) δ 8.56 (d, J = 7.2 Hz, 1H), 8.45

(dd, J = 8.4, 2.4 Hz, 2H), 7.71 – 7.64 (m, 1H), 7.18 (d, J = 8.3 Hz, 1H), 3.47 – 3.34 (m,

4H), 1.68 – 1.55 (m, 4H), 1.26 (m, J = 8.4 Hz, 12H), 0.84 (t, J = 6.7 Hz, 6H); 13C NMR

(125 MHz, Chloroform-d) δ 161.76, 160.83, 157.07, 134.55, 133.30, 133.07, 132.58,

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126.77, 125.32, 119.47, 116.47, 110.09, 53.78, 31.63, 27.27, 26.91, 22.69, 14.10;

+ HRMS (ESI) calc’d for C24H32NO3 [M + H ]: 382.2377, found: 382.2376.

Synthesis of tert-butyl (2-(6-(dihexylamino)-1,3-dioxo-1H-benzo[de]isoquinolin-

2(3H)-yl)ethyl)carbamate (6-11)

Triethylamine (0.140 g, 1.37 mmol) and tert-butyl N-(2-

aminoethyl)carbamate (0.110 g, 0.688 mmol) and were added to a

solution of 6-10 (0.175 g, 0.459 mmol) in toluene (18 mL) and the

mixture was refluxed for 40 hours. The reaction mixture was cooled to

room temperature and concentrated under reduced pressure. The

crude product was further purified on an automatic silica gel columns

(default 0 – 100 % ethyl acetate in hexanes gradient). The final product was obtained as sticky orange solid (0.23 g, 95% yield). 1H NMR (500 MHz, Chloroform-d) δ 8.57 (d, J =

8.1 Hz, 1H), 8.47 (d, J = 8.2 Hz, 1H), 8.42 (dd, J = 8.4, 0.9 Hz, 1H), 7.64 (dd, J = 8.3,

7.4 Hz, 1H), 7.19 (d, J = 8.2 Hz, 1H), 4.35 (t, J = 5.2 Hz, 2H), 3.58 – 3.44 (m, 2H), 3.35

(t, J = 7.3, 4H), 1.57 (p, J = 7.2 Hz, 4H), 1.30 (s, 9H), 1.23 (m, 12H), 0.83 (t, J = 6.9 Hz,

6H); 13C NMR (125 MHz, Chloroform-d) δ165.13, 164.60, 156.16, 155.94, 132.45,

131.41, 131.22, 130.56, 127.19, 125.16, 123.06, 116.83, 115.21, 77.41, 77.16, 76.91,

53.90, 40.19, 39.62, 31.68, 28.39, 27.15, 26.95, 22.70, 14.11; HRMS (ESI) calc’d for

+ C31H46N3O4 [M + H ]: 546.3302, found: 546.3306.

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Synthesis of 2-(2-aminoethyl)-6-(dihexylamino)-1H-benzo[de]isoquinoline-1,3(2H)- dione (6-8)

TFA (1 mL) was added to a solution of 6-11 (180 mg, 0.334 mmol) in 5

mL DCM and stirred at room temperature for 1 hour. The crude

reaction mixture was concentrated under reduced pressure to remove

excess TFA, then passed through a silica plug (100 % DCM eluent).

The product was dried under vacuum to yield the product as a thick orange oil (140 mg, 0.334 mmol, quantitative yield). 1H NMR (500 MHz, Chloroform-d) δ

8.63 (d, J = 8.4 Hz, 1H), 8.57 (d, J = 6.9 Hz, 1H), 8.51 (d, J = 7.3 Hz, 1H), 7.74 (t, J =

7.7 Hz, 1H), 7.44 (d, J = 7.6 Hz, 1H), 4.54 (s, 2H), 3.75 – 3.33 (m, 6H), 1.49 (p, J = 7.9,

7.4 Hz, 4H), 1.21 (m, 13H), 0.79 (t, J = 6.8 Hz, 6H). 13C NMR (125 MHz, Chloroform-d)

δ 165.31, 164.87, 161.24, 160.93, 132.56, 130.43, 130.05, 127.02, 126.50, 122.40,

64.49, 56.84, 40.27, 38.14, 31.29, 26.45, 26.22, 22.47, 13.88. HRMS (ESI) calc’d for

+ C26H37N3O2 [M + H ]: 424.2959, found: 424.2942.

Synthesis of 6-(dihexylamino)-2-(2-hydroxyethyl)-1H-benzo[de]isoquinoline-

1,3(2H)-dione (6-15)

The following method was adapted from a literature procedure.286

Ethanolamine (0.12 g, 1.97 mmol) was added to a solution of 6-10

(0.25 g, 0.655 mmol) in DMF (5 mL) and the mixture was stirred at 80

°C for 6 hours. The reaction mixture was cooled to room temperature,

diluted with ethyl acetate, washed with brine, dried with MgSO4, filtered, and concentrated under reduced pressure. The crude product was further purified on an automatic silica gel column (default 0 – 100 % ethyl acetate in hexanes

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gradient). The final product was obtained as an orange oil (0.24 g, 86 % yield). 1H NMR

(500 MHz, Chloroform-d) δ 8.54 (dd, J = 7.2, 1.0 Hz, 1H), 8.45 (d, J = 8.2 Hz, 1H), 8.41

(d, J = 8.4 Hz, 1H), 7.62 (dd, J = 8.3, 7.4 Hz, 1H), 7.17 (d, J = 8.2 Hz, 1H), 4.42 (t, J =

5.3 Hz, 2H), 3.95 (s, 2H), 3.35 (t, J = 7.5 Hz, 4H), 2.88 (s, 1H), 1.57 (q, J = 7.5, 7.0 Hz,

4H), 1.22 (s, 12H), 0.82 (t, J = 6.8 Hz, 6H); 13C NMR (125 MHz, Chloroform-d) δ 165.54,

165.08, 156.12, 132.57, 131.44, 131.35, 130.49, 126.97, 125.07, 122.87, 116.62,

114.81, 62.10, 53.80, 42.75, 31.61, 27.12, 26.88, 22.63, 14.05. HRMS (ESI) calc’d for

+ C26H36N2O3 [M + H ]: 425.2799, found: 425.2807.

Synthesis of 2-(2-bromoethyl)-6-(dihexylamino)-1H-benzo[de]isoquinoline-1,3(2H)- dione (6-16)

The following method was adapted from a literature procedure.287

Phosphorus tribromide (0.160 mL,1.65 mmol) was added dropwise to

a solution of 6-15 (0.200 g, 0.471 mmol) in chloroform at 0 °C. The

reaction was slowly brought to room temperature while stirring for 3 h.

The reaction mixture was concentrated under reduced pressure. The reaction mixture was slowly added to ice water and basified by slow addition of saturated NaHCO3. The aqueous phase was extracted with DCM, dried with MgSO4, filter, and concentrated under reduced pressure. The crude product was further purified by silica gel chromatography (0 – 10 % ethyl acetate in hexanes to yield an orange oil.

(167 mg, 0.344 mmol, 73 % yield). 1H NMR (500 MHz, Chloroform-d) δ 8.57 (d, J = 7.7

Hz, 1H), 8.48 (d, J = 8.2 Hz, 1H), 8.44 (d, J = 8.5 Hz, 1H), 7.69 – 7.58 (m, 1H), 7.24 –

7.15 (m, 1H), 4.60 – 4.46 (m, 2H), 3.82 (t, J = 6.9 Hz, 2H), 3.35 (t, J = 7.4 Hz), 1.57 (q, J

= 7.3, 6.7 Hz, 4H), 1.23 (s, 14H), 0.83 (t, J = 6.4 Hz, 6H); 13C NMR (125 MHz,

190

Chloroform-d) δ 164.63, 164.01, 156.12, 132.54, 131.46, 131.40, 130.57, 127.15,

125.15, 122.86, 116.74, 114.85, 53.85, 41.16, 40.69, 31.65, 27.16, 26.93, 22.68, 14.09.

Synthesis of 2-(2-azidoethyl)-6-(dihexylamino)-1H-benzo[de]isoquinoline-1,3(2H)- dione (6-14)

Compound 6-16 (0.160 g, 0.328 mmol) was dissolved in DMF (10 mL)

and NaN3 (0.065 g, 0.985 mmol) was slowly added. The reaction mixture

was stirred at 80 °C for 24 h, cooled to room temperature, then

concentrated under reduced pressure. The crude reaction mixture was

poured into water then extracted with ethyl acetate. The combined organic layers were dried with MgSO4, filtered, and concentrated under reduced pressure to yield an orange oil (0.135 g, 0.302 mmol, 92 % yield). 1HNMR (500 MHz, Chloroform-d) δ

8.59 (d, J = 6.1 Hz, 1H), 8.49 (d, J = 8.3 Hz, 1H), 8.44 (d, J = 8.3 Hz, 1H), 7.66 (t, J =

8.3 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 4.43 (t, J = 6.8 Hz, 2H), 3.65 (t, J = 6.4 Hz, 2H),

3.42 – 3.29 (m, 4H), 1.66 – 1.57 (m, 4H), 1.26 (d, J = 19.2 Hz, 13H), 0.84 (t, J = 6.5 Hz,

6H); 13C NMR (125 MHz, Chloroform-d) δ 164.81, 164.19, 156.16, 132.59, 131.52,

131.44, 130.63, 127.20, 125.20, 122.90, 116.79, 114.91, 110.14, 53.91, 49.13, 38.78,

+ 31.70, 27.20, 26.97, 22.72, 14.13. HRMS (DART) calc’d for C26H35N5O2 [M + H ]:

450.2864, found: 450.2870.

Synthesis of (±)-4,7,12,15-tetra(n-prop-2-yn-1yl)amide[2.2]paracyclophane ((±)-6-

13)

191

Oxalyl chloride (0.16 mL, 1.9 mmol) was added to a solution of

(±)-6-3 (0.166 g, 0.432 mmol) in DCM (15 mL). A catalytic

amount of DMF was added and the mixture was stirred at

room temperature for 2 hours. The solvent was removed under reduced pressure and the (±)-4,7,12,15-tetra(acyl chloride)[2.2]paracyclophane intermediate dried under vacuum, dissolved in DCM (15 mL) and cooled to 0 °C.

Freshly distilled N-propargyl amine (0.476 g, 8.64 mmol) was added dropwise and the reaction warmed to room temperature while stirring overnight. The solvent was removed under reduced pressure. The solid was washed with DCM. The off-white precipitate was slowly recrystallized from methanol to yield a white crystalline product (0.033g, 14 %

1 yield). H NMR (500 MHz, Methanol-d4) δ 7.07 (s, 1H), 4.24 (qd, J = 17.4, 2.5 Hz, 2H),

3.71 (sx, J = 5.3 Hz, 1H), 2.73 (sx, J = 5.3 Hz, 1H), 2.71 (t, J = 2.5 Hz, 1H); 13C NMR

(125 MHz, Methanol-d4) δ 170.41, 140.62, 139.19, 133.51, 80.49, 72.24, 49.51, 49.34,

49.17, 49.00, 48.83, 48.66, 48.49, 34.97, 29.82. HRMS (ESI) calc’d for C32H29N4O4 [M +

H+]: 533.2189, found: 533.2186.

Synthesis of (±)-4,7,12,15-tetra(n-((1-(2-(6-(dihexylamino)-1,3-dioxo-1H- benzo[de]isoquinolin-2(3H)-yl)ethyl)-1H-1,2,3-triazol-4-yl)methyl))carboxamide

[2.2]paracyclophane ((±)-6-12)

Compound (±)-6-13 (23 mg, 0.044 mmol), copper(II) sulfate pentahydrate (11 mg, 0.044 mg), and sodium ascorbate (18 mg, 0.88 mmol) were dissolved in a mixture of 1 mL

THF and 0.1 mL water and stirred at room temperature for 10 minutes. Compound 6-14

(0.100 g, 0.22 mmol) was added as a solution in THF (0.5 mL) and the reaction was stirred at 40 °C for 24 hours. The solvent was removed under reduced pressure and the

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crude reaction mixture was purified on a silica gel column using three component solvent mixture with gradient elution (50:50:0 to 50:45:5 hexanes:DCM:MeOH). The product was obtained as an orange solid of 98% + purity (45 mg, 0.019 mmol, 44 % yield). The compound could be further purified by precipitation from slow evaporation of the 50:45:5 hexanes:DCM:MeOH solvent mixture. 1HNMR (500 MHz, Chloroform-d) δ

8.44 – 8.32 (m, 3H), 8.07 (t, J = 4.9 Hz, 1H), 7.93 (s, 1H), 7.60 – 7.53 (m, 1H), 7.12 (d, J

= 8.2 Hz, 1H), 6.96 (s, 1H), 4.81 – 4.58 (m, 7H), 3.69 – 3.59 (m, 1H), 3.36 – 3.28 (m,

5H), 2.56 – 2.45 (m, 1H), 1.57 (s, 13H), 1.23 (s, 15H), 0.83 (t, J = 6.8 Hz, 7H); 13CNMR

(125 MHz, Chloroform-d) δ 168.72, 164.39, 163.78, 156.10, 144.90, 139.00, 137.91,

132.71, 132.48, 131.35, 130.47, 126.98, 125.06, 123.36, 122.53, 116.57, 114.51, 53.79,

48.09, 39.74, 35.68, 34.09, 31.65, 27.14, 26.91, 22.68, 14.10. HRMS (MALDI) calc’d for

+ C136H168N24O12 [M + Na] : 2352.237, found: 2353.234.

Synthesis of (±)-4,7,12,15-tetra(methylester) [2.2] paracyclophane (±)-6-18

Compound (±)-6-3 (0.160 g, 0.411 mmol) and CsF (0.380 g, 2.5 mmol) were dried under vacuum, dissolved in 5 mL DMF, and stirred at 50 °C for 5 minutes. Methyl iodide

(2 mL, 32 mmol) was added and the reaction continued stirring overnight. The solution was cooled to room temperature, diluted with ethylacetate, washed with brine, dried with

MgSO4, and filtered. The crude reaction mixture was concentrated under reduced pressure and purified on an automatic silica gel column (0 – 10 % ethyl acetate in hexanes gradient elution). The product was then recrystallized from methanol to yield a white solid (0.072 g, 0.16 mmol, 40 % yield). 1HNMR (500 MHz, Chloroform-d) δ 7.18

(s, 1H), 4.03 (sx, J = 5.3 Hz, 1H), 3.92 (s, 3H), 3.05 (sx, J = 5.3 Hz, 1H); 13CNMR (125

MHz, Chloroform-d) δ 166.55, 142.85, 136.00, 133.96, , 52.21, 34.72. HRMS (DART)

193

+ + calc’d for C24H24O8 [M + H] , [M + NH4] : 441.1544, 458.1809; found: 441.1533,

453.1786.

Synthesis of (±)-4,7,12,15-tetra(n-butylester) [2.2] paracyclophane (±)-6-20

In Dean-Stark apparatus, compound (±)-6-3 (0.174 g, 0.453 mmol) was dissolved in a mixture of 15 mL 1-butanol and 10 mL toluene and stirred at 90 °C. After 48 hours, the mixture was cooled to room temperature and concentrated under reduced pressure.

The mixture was redissolved in DCM and was with saturated NaHCO3 and brine, then dried with MgSO4 and filtered. The product was isolated using automated silica gel chromatography (0 – 10% ethyl acetate in hexanes). The product was obtained as a pale yellow oil of ~90 % purity, estimated from NMR. 1HNMR (500 MHz, Chloroform-d)

δ 7.17 (s, 1H), 4.31 (ddt, J = 33.6, 10.8, 6.9 Hz, 2H), 3.98 (sx, J = 5.3 Hz, 1H), 3.06 (sx,

J = 5.3 Hz, 1H), 1.83 – 1.73 (quin, J = 4.9 Hz, 2H), 1.47 (sx, J = 7.4 Hz, 2H), 1.00 (t, J =

7.4 Hz, 3H); 13CNMR (125 MHz, Chloroform-d) δ 166.30, 142.53, 135.81, 134.02,

65.13, 34.91, 30.91, 19.47, 13.92.

Synthesis of (±)-4,7,12,15-tetra(4-broomophenylester) [2.2] paracyclophane ((±)-6-

21)

Oxalyl chloride (0.046 mL, 0.54 mmol) was added to a solution of (±)-6-3 (0.047 g, 0.12 mmol) in DCM (5 mL). A catalytic amount of DMF was added and the mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure and the (±)-4,7,12,15-tetra(acylchloride)[2.2]paracyclophane intermediate dried under vacuum, dissolved in DCM (10 mL) and cooled to 0 °C. Triethylamine (0.20 mL, 1.5 mmol) and 4-bromophenol (0.170 g, 0.98 mmol) were added to the reaction mixture, and it was stirred while warming to room temperature overnight. The reaction

194

was diluted with ethyl acetate, washed with 1N HCl and brine, and the organic layer dried with MgSO4 and filtered. The product was isolated using repeated automated silica gel chromatography (0 – 30% ethyl acetate in hexanes). The product was obtained as an off-white solid of ~70 % purity, estimated from NMR. 1HNMR (500 MHz,

Chloroform-d) δ 7.56 (s, 1H), 7.54 (d, J = 8.8 Hz, 2H), 7.10 (d, J = 8.8 Hz, 2H), 4.14 (sx,

J = 5.3 Hz, 1H), 3.23 (sx, J = 5.3 Hz, 1H); 13CNMR (125 MHz, Chloroform-d) δ 164.23,

149.64, 143.92, 136.53, 133.76, 132.89, 123.53, 119.65, 35.10.

Computations

Starting geometries of monomers were obtained from manually varying dihedral angles

(0°, 90°, 180°, and 270°) of an N-methylamido group substituted on

[2.2]paracyclophane crystal structure coordinates (CCDC database) in Spartan Student version 5.0.2 for Macintosh. Starting geometries of multimers were obtained from manually stacking minimized monomer structures in Spartan. The structural geometries of all monomers and multimers were optimized at the M06-2X/6-31+G* level of theory251

(as implemented in Gaussian 09).156 Frequency calculations were performed at the same computational level, and no imaginary frequencies were found. Dihedral angles were measured in Mercury CSD 3.6 (Build RC6). Molecular orbital plots were made using Visual Molecular Dynamics (VMD) software from the Gaussian output files.157

Infrared Spectroscopy

Solution phase IR spectra were collected under N2 atmosphere using a Bruker Vertex

80v with a sealed 1 mm pathlength CaF2 solution cell (PIKE Technologies). Solutions were prepared using HPLC grade chloroform and cyclohexane purchased from Sigma-

Aldrich and dried over activated molecular sieves (4 Å) prior to use. Solid-state IR

195

spectra were collected using using a Bruker Vertex 80v equipped with a GladiATR™ attachment (PIKE Technologies). Solid samples were dried under vacuum prior to measurement. All measurements were taken using Opus 7.0 software.

NMR Studies

Variable concentration NMR studies were performed at 298 K on an Inova 500 MHz spectrometer with a Varian 5 mm conventional probe H1/P31-N15. Variable temperature and DOSY NMR studies were performed on an Inova 500 MHZ spectrometer with a Varian 5 mm triple resonance indirect detection probe H1/C13/P31-

N15. DOSY spectra were recorded by performing a series of pulsed field gradient (PFG) stimulated echo experiments at 263 K and 298 K, using a bipolar pulse-pair stimulated- echo pulse sequence with a gradient strength of 2 ms and diffusion delay of 50 ms.

DOSY data was processed using Vnmrj software to obtain diffusion coefficients.

Contour plots were prepared using the Bayesian DOSY Transform feature in MNova.

CDCl3 with 0.01% TMS was purchased from Cambridge Isotope Laboratories and dried over activated molecular sieves (4 Å) prior to use. Cyclohexane-d12 was purchased from

Sigma-Aldrich. Association constants were calculated using non-linear curve fitting in

Origin 8.5 in accord with a dimerization and isodesmic polymerization association model.

UV-Vis Studies

Absorption measurements were taken on a Cary 100 Bio UV-Visible spectrophotometer controlled by Cary Win UV software and equipped with a Peltier 1  1 Cell Holder using

1 cm quartz cells. CHROMASOLV® HPLC grade cyclohexane and methylcyclohexane was purchased from Sigma-Aldrich. Temperature-dependent UV data in

196

methylcyclohexane was measured using a constant cooling ramp of 1 K per minute and the data was treated with an isodesmic (equal-K) model as described by P. van der

Schoot, E. W. Meijer, and co-workers.259 The temperature-dependent density constants for solvents used in variable temperature experiments were used to correct for effective

“dilution” of samples due to solvent expansion at elevated temperatures.288

Dynamic Light Scattering

Multi-angle dynamic light scattering (DLS) measurements were performed on

Brookhaven Instruments BI-200SM goniometer, which consisted of an avalanche photodiode detector and a laser operating at a wavelength of 휆 = 632.8 푛푚 and scattering angles from 휃 = 30 − 150°. Fluctuations in the scattering intensity were measured via a TurboCorr correlator, and analyzed via the intensity autocorrelation function (g(2)(τ)). A double exponential fit was used to analyze the data, and the mutual diffusion coefficient was calculated through the relation

2 Γ = 푞 퐷푚 where Γ is the average decay rate of the autocorrelation function and q2 is the scalar magnitude of the scattering vector. The hydrodynamic radius (Rh) was calculated through the Stokes-Einstein equation

푘퐵푇 퐷푚 ≈ 퐷푡 = 6휋휂푠푅ℎ

Where Dm is the mutual diffusion coefficient, Dt is the tracer diffusion coefficient, kB is the Boltzmann constant, T is the absolute temperature, and ηs is the solvent viscosity.

The sample was filtered through a 0.45 μm PTFE filter (Millipore) directly into scattering cells prior to measurement.

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APPENDIX A 1HNMR SPECTRA

1 Figure A-1. HNMR spectrum of 2-1U in CDCl3.

1 Figure A-2. HNMR spectrum of 2-1C in CDCl3.

198

1 Figure A-3. HNMR spectrum of 3-3 in CDCl3.

1 Figure A-4. HNMR spectrum of 3-4 in CDCl3.

199

1 Figure A-5. HNMR spectrum of 3-5 in CDCl3.

1 Figure A-6. HNMR spectrum of 3-6 (4-1-PG1) in CDCl3.

200

1 Figure A-7. HNMR spectrum of 3-7 in CDCl3.

1 Figure A-8. HNMR spectrum of 3-8 in CDCl3.

201

1 Figure A-9. HNMR spectrum of 3-9 in CDCl3.

1 Figure A-10. HNMR spectrum of 3-1-PG in CDCl3.

202

1 Figure A-11. HNMR spectrum of 3-1-G in DMSO-d6.

1 Figure A-12. HNMR spectrum of 3-2-PG in CDCl3.

203

1 Figure A-13. HNMR spectrum of 3-2-G in DMSO-d6.

1 Figure A-14. HNMR spectrum of 3-15 (4-1-G) in DMSO-d6.

204

1 Figure A-15. HNMR spectrum of 4-2-PG1 in CDCl3.

1 Figure A-16. HNMR spectrum of 4-8 in CDCl3.

205

1 Figure A-17. HNMR spectrum of 4-9 in CDCl3.

1 Figure A-18. HNMR spectrum of 4-10 in CDCl3.

206

1 Figure A-19. HNMR spectrum of 4-6 in CDCl3.

1 Figure A-20. HNMR spectrum of 4-4 in CDCl3.

207

1 Figure A-21. HNMR spectrum of 4-1-PG2 in DMSO-d6.

1 Figure A-22. HNMR spectrum of 4-2-PG3 in CDCl3.

208

1 Figure A-23. HNMR spectrum of 4-7 in CDCl3.

1 Figure A-24. HNMR spectrum of 4-5 in CDCl3.

209

1 Figure A-25. HNMR spectrum of 4-1-PG5 in CDCl3.

1 Figure A-26. HNMR spectrum of 5-19 in CDCl3.

210

1 Figure A-27. HNMR spectrum of 5-20 in CDCl3.

1 Figure A-28. HNMR spectrum of 5-16 in CDCl3.

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1 Figure A-29. HNMR spectrum of DRCNT5-dg in CDCl3.

1 Figure A-30. HNMR spectrum of RCN_T5-dg_B in 1,1,2,2-tetrachloroethane-d4.

212

1 Figure A-31. HNMR spectrum of 6-10 in CDCl3.

1 Figure A-32. HNMR spectrum of 6-11 in CDCl3.

213

1 Figure A-33. HNMR spectrum of 6-8 in CDCl3.

1 Figure A-34. HNMR spectrum of 6-15 in CDCl3.

214

1 Figure A-35. HNMR spectrum of 6-16 in CDCl3.

1 Figure A-36. HNMR spectrum of 6-14 in CDCl3.

215

1 Figure A-37. HNMR spectrum of (±)-6-13 in methanol-d4.

1 Figure A-38. HNMR spectrum of (±)-6-12 in CDCl3.

216

1 Figure A-39. HNMR spectrum of (±)-6-18 in CDCl3.

1 Figure A-40. HNMR spectrum of (±)-6-20 in CDCl3.

217

1 Figure A-41. HNMR spectrum of (±)-6-21 in CDCl3.

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APPENDIX B 13CNMR SPECTRA

13 Figure B-1. CNMR spectrum of 2-1U in CDCl3.

13 Figure B-2. CNMR spectrum of 2-1C in CDCl3.

219

13 Figure B-3. CNMR spectrum of 3-3 in CDCl3.

13 Figure B-4. CNMR spectrum of 3-4 in CDCl3.

220

13 Figure B-5. CNMR spectrum of 3-5 in CDCl3.

13 Figure B-6. CNMR spectrum of 3-6 in CDCl3.

221

13 Figure B-7. CNMR spectrum of 3-7 in CDCl3.

13 Figure B-8. CNMR spectrum of 3-8 in CDCl3.

222

13 Figure B-9. CNMR spectrum of 3-9 in CDCl3.

13 Figure B-10. CNMR spectrum of 3-1-PG in CDCl3.

223

13 Figure B-11. CNMR spectrum of 3-2-PG in CDCl3.

13 Figure B-12. CNMR spectrum of 4-2-PG1 in CDCl3.

224

13 Figure B-13. CNMR spectrum of 4-8 in CDCl3.

13 Figure B-14. CNMR spectrum of 4-10 in CDCl3.

225

13 Figure B-15. CNMR spectrum of 4-6 in CDCl3.

13 Figure B-16. CNMR spectrum of 4-4 in CDCl3.

226

13 Figure B-17. CNMR spectrum of 4-7 in CDCl3.

13 Figure B-18. CNMR spectrum of 4-5 in CDCl3.

227

13 Figure B-19. CNMR spectrum of 4-1-PG5 in CDCl3.

13 Figure B-20. CNMR spectrum of 5-20 in CDCl3.

228

13 Figure B-21. CNMR spectrum of 5-16 in CDCl3.

13 Figure B-22. CNMR spectrum of DRCNT5-dg in CDCl3.

229

13 Figure B-23. CNMR spectrum of 6-10 in CDCl3.

13 Figure B-24. CNMR spectrum of 6-11 in CDCl3.

230

13 Figure B-25. CNMR spectrum of 6-8 in CDCl3.

13 Figure B-26. CNMR spectrum of 6-15 in CDCl3.

231

13 Figure B-27. CNMR spectrum of 6-16 in CDCl3.

13 Figure B-28. CNMR spectrum of 6-14 in CDCl3.

232

13 Figure B-29. CNMR spectrum of (±)-6-13 in methanol-d4.

13 Figure B-30. CNMR spectrum of (±)-6-12 in CDCl3.

233

13 Figure B-31. CNMR spectrum of (±)-6-18 in CDCl3.

13 Figure B-32. CNMR spectrum of (±)-6-20 in CDCl3.

234

13 Figure B-33. CNMR spectrum of (±)-6-21 in CDCl3.

235

APPENDIX C COMPUTATIONAL DATA

Figure C-1. Computational results for 3-1G and 3-1PG including minimized molecular structures, HOMO, and LUMO diagrams.

Figure C-2. Computational results for 3-2G and 3-2PG including minimized molecular structures, HOMO, and LUMO diagrams.

236

Figure C-3. Calculated HOMO and LUMO plots of guanine and protected guanine end groups.

237

Figure C-4. Calculated HOMO and LUMO plots of 4-1 series of compounds.

Figure C-5. Calculated HOMO and LUMO plots of 4-2-G.

238

Figure C-6. Calculated HOMO and LUMO plots of 4-2-PG1.

Figure C-7. Calculated HOMO and LUMO plots of conformer 4-2-PG2a.

Figure C-8. Calculated HOMO and LUMO plots of conformer 4-2-PG2ab.

239

Figure C-9. Calculated HOMO and LUMO plots of conformer 4-2-PG2b.

Figure C-10. Calculated HOMO and LUMO plots of conformer 4-2-PG3a.

Figure C-11. Calculated HOMO and LUMO plots of conformer 4-2-PG3ab.

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Figure C-12. Calculated HOMO and LUMO plots of conformer 4-2-PG3b.

Figure C-13. Calculated HOMO and LUMO plots of 4-2-PG4.

Figure C-14. Calculated HOMO and LUMO plots of 4-2-PG5.

241

Figure C-15. HOMO and LUMO plots of RCN_T#_G series of compounds.

242

APPENDIX D EXPERIMENTAL DATA

1.6  = 404 nm in DMF 5 µM max 1.4 1.5 4 -1 -1 10 µM  = (3.6 ± 0.03) ×10 M cm 15 µM 1.2 r2 = 0.99982 20 µM 1.0 30 µM 40 µM 1.0

0.8

0.6 0.5

Absorbance(a.u.) 0.4 Absorbance(a.u.)

0.2

0.0 0.0 200 400 600 800 0 10 20 30 40 Wavelength (nm) Concentration (µM)

Figure D-1. Overlaid UV-Vis absorption spectra of 2-1A in DMF (left) and associated Beer-Lambert plot fit to a linear regression (right).

2.5  = 404 nm in DMF 5 µM max 10 µM  = (3.7 ± 0.02) ×104 M-1 cm-1 2.0 2 20 µM r2 = 0.99995 40 µM

1.5 60 µM

1.0 1 Absorbance(a.u.) 0.5 Absorbance(a.u.)

0.0 0 200 400 600 800 0 10 20 30 40 50 60 Wavelength (nm) Concentration (µM)

Figure D-2. Overlaid UV-Vis absorption spectra of 2-1U in DMF (left) and associated Beer-Lambert plot fit to a linear regression (right).

1.8 2.0 5 µM  = 382 nm in DMF 1.6 max 10 µM 4 -1 -1  = (2.7 ± 0.02) ×10 M cm 1.4 20 µM 1.5 2 40 µM r = 0.99996 1.2 60 µM 1.0

1.0

0.8

0.6 Absorbance(a.u.)

Absorbance(a.u.) 0.5 0.4

0.2

0.0 0.0 200 400 600 800 0 10 20 30 40 50 60 Wavelength (nm) Concentration (µM)

Figure D-3. Overlaid UV-Vis absorption spectra of 2-1C in DMF (left) and associated Beer-Lambert plot fit to a linear regression (right).

243

1.4 1.5  = 409 nm in DMF 5 µM max 1.2 10 µM  = (3.2 ± 0.02) ×104 M-1 cm-1 15 µM 2 1.0 r = 0.99998 20 µM 1.0 30 µM

0.8 40 µM

0.6 0.5

0.4

Absorbance(a.u.) Absorbance(a.u.)

0.2

0.0 0.0 200 400 600 800 0 10 20 30 40 Wavelength (nm) Concentration (µM)

Figure D-4. Overlaid UV-Vis absorption spectra of 2-1G in DMF (left) and associated Beer-Lambert plot fit to a linear regression (right).

244

Figure D-5. Cyclic voltammograms of compounds (a) 2-1A, (b) 2-1U, (c) 2-1G, (d) 2- 1C, (e) 2-1PGa, and (f) 2-1PGb.

245

Figure D-6. DSC for compounds (a) 2-1A, (b) 2-1U, (c) 2-1G, Tmelting not observed, (d) 2- 1C, (e) 2-1PGa, and (f) 2-1PGb. The first heating and cooling cycle is shown for each.

246

Figure D-7. Overlaid UV-Vis absorption spectra of a,d) 3-1G, 3-1PG in DMF and associated Beer-Lambert plot fit to a linear regression at b,e) pi-pi* transition and c,f) charge transfer transition.

247

Figure D-8. Overlaid UV-Vis absorption spectra of a,d) 3-2G, 3-2PG in DMF and associated Beer-Lambert plot fit to a linear regression at b,e) pi-pi* transition and c,f) charge transfer transition.

248

40000

30000

20000

Intensity(a. u.) 10000

0 500 600 700 800 Wavelength (nm)

Figure D-9. Emission spectrum of 3-1G collected in DMSO at 298 K.

Figure D-10. Emission spectra of 3-1PG collected in a) DMSO and b) DCM at 298 K.

Figure D-11. Emission spectrum of 3-2G collected in DMSO at 298 K.

249

Figure D-12. Emission spectra of 3-2PG collected in a) DMSO and b) DCM at 298 K.

a) b) 40 M 3 20 M 3 15 M 10 M 5 M

2 2.5 M 2

1 1 Absorbance(a.u.) λ = 538 nm max Absorbance(a.u.) 4 -1 -1 ε = 7.4 × 10 M cm 2 R =0.999 0 0 400 600 800 0 10 20 30 40 Wavelength (nm) -6 Concentration (10 M)

Figure D-13. UV-Vis of DRCNT5-dg in chloroform.

a) 2 b) 2.0 40 M 20 M 15 M 10 M 1.5 5 M 2.5 M

1 1.0

Absorbance(a.u.) λ = 551 nm 0.5 max Absorbance(a.u.) 4 -1 -1 ε = 4.3 × 10 M cm 2 R = 0.992 0 0.0 400 600 800 0 10 20 30 40 Wavelength (nm) -6 Concentration (10 M)

Figure D-14. UV-Vis of RCN_T5-dg_B in chloroform.

250

a) b) 3 3 40 M 20 M 15 M 10 M 2 5 M 2

2.5 M

1 1 Absorbance(a.u.) λmax = 538 nm Absorbance(a.u.) 4 -1 -1 ε = 7.0 × 10 M cm 2 R = 0.999 0 0 400 600 800 0 10 20 30 40 Wavelength (nm) -6 Concentration (10 M)

Figure D-15. UV-Vis of DRCNT5-dg in chloroform mixture.

a) b)

40 M 2.0 20 M 2 15 M 10 M 1.5 5 M

2.5 M

1.0 1

Absorbance(a.u.) λ = 538 - 542 nm Absorbance(a.u.) 0.5 max 4 -1 -1 ε = 5.2 × 10 M cm 2 R = 0.996 0 0.0 400 600 800 0 10 20 30 40 Wavelength (nm) -6 Concentration (10 M)

Figure D-16. UV-Vis of RCN_T5-dg_B in chloroform.

a) b) 2.2 2.5 µM 2.0 2.0 5 µM 1.8 10 µM 15 µM 1.6 20 µM 1.5 1.4 40 µM

1.2

1.0 1.0 0.8

Absorbance(a.u.) 0.6

Absorbsance(a.u.) 0.5 λmax = 515 nm 0.4 4 -1 -1 ε = 5.2 × 10 M cm 0.2 2 R =0.998 0.0 0.0 400 600 800 0 10 20 30 40 Wavelength (nm) Concentration (uM)

Figure D-17. UV-Vis of RCN_T5-dg_B in THF.

251

4 3.0x10 1.0x10-10

2.5x104 8.0x10-11

2.0x104 -11

) 6.0x10 /s

) 4

1.5x10 2

-1

s (

( -11

4.0x10

 eff

1.0x104 D

2.0x10-11 5.0x103

0.0 0.0 14 14 14 14 14 14 14 14 0.0 0.0 2.0x10 4.0x10 6.0x10 8.0x10 2.0x10 4.0x10 6.0x10 8.0x10 2 -2 2 -2 q (m ) q (m ) Figure D-18. Processed DLS data collected for (±)-6-1b 25 mM in methylcyclohexane. (Left) Relaxation rate Γ plotted against the square of the scattering vector q for angles 30°-150°. The mutual diffusion coefficient Dm was extracted from the linear slope of the data set. The Γ values were calculated by performing a double exponential analysis on the autocorrelation functions, (Right) The effective diffusion coefficient Deff plotted against the square of the scattering 2 vector q for scattering angles 30°-150°. The Deff slightly fluctuated with q , which implies that there is very little dispersity in the size of the crystals in methylcyclohexane.

252

APPENDIX E X-RAY DATA

General Information

X-Ray Intensity data were collected at 100 K on a Bruker DUO diffractometer using MoK radiation ( = 0.71073 Å) and an APEXII CCD area detector.

Raw data frames were read by program SAINT and integrated using 3D profiling algorithms. The resulting data were reduced to produce hkl reflections and their intensities and estimated standard deviations. The data were corrected for Lorentz and polarization effects and numerical absorption corrections were applied based on indexed and measured faces.

The structure was solved and refined in SHELXTL2014v/6, using full-matrix least- squares refinement. The non-H atoms were refined with anisotropic thermal parameters and all of the H atoms were calculated in idealized positions and refined riding on their parent atoms. The asymmetric unit consists of two chemically equivalent but crystallographically independent molecules, labeled A and B. They differ only by the orientation of the C8 chain oriented out of the average plane of the molecule as in A, and in the plane of the molecule as in A. The two molecules crystallize as dimers by a donor- acceptor Hydrogen bonding pattern. There are traces of a chlorine atom bonded to C15 of molecule A (fixed at 3% occupation. Molecule B has no traces of chlorine. In the final cycle of refinement, 7887 reflections (of which 6378 are observed with I > 2 (I)) were used to refine 466 parameters and the resulting R1, wR2 and S (goodness of fit) were

3.41%, 8.89% and 1.046, respectively. The refinement was carried out by minimizing the

2 wR2 function using F rather than F values. R1 is calculated to provide a reference to the conventional R value but its function is not minimized.

253

Crystal data and structure refinement for 3-15. Identification code dfagn2 Empirical formula C17 H22.99 Cl0.02 N5 O S Formula weight 345.98 Temperature 100(2) K Wavelength 0.71073 Å Crystal system Triclinic Space group P -1 Unit cell dimensions a = 9.3351(4) Å = 115.3251(9)°. b = 14.4655(7) Å = 102.3320(9)°. c = 14.9860(7) Å = 98.7097(9)°. Volume 1718.10(14) Å3 Z 4 Density (calculated) 1.338 Mg/m3 Absorption coefficient 0.205 mm-1 F(000) 737 Crystal size 0.345 x 0.213 x 0.038 mm3 Theta range for data collection 1.582 to 27.499°. Index ranges -12≤h≤12, -18≤k≤18, -19≤l≤19 Reflections collected 30491 Independent reflections 7887 [R(int) = 0.0266] Completeness to theta = 25.242° 100.0 % Absorption correction Analytical Max. and min. transmission 0.9928 and 0.9624 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 7887 / 0 / 466 Goodness-of-fit on F2 1.046 Final R indices [I>2sigma(I)] R1 = 0.0341, wR2 = 0.0889 [6378] R indices (all data) R1 = 0.0463, wR2 = 0.0939 Extinction coefficient n/a Largest diff. peak and hole 0.335 and -0.285 e.Å-3

254

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BIOGRAPHICAL SKETCH

Danielle Fagnani was born and raised in Philadelphia, PA. In 2008, she began college at Drexel University in Philly where she earned her Bachelor of Science degree in chemistry. She received an NSF S-STEM scholarship, which included mentorship by a Drexel faculty mentor, Prof. Lynn Penn, who first suggested that she venture into the world of research. At the end of her freshman year, Danielle began doing biochemistry research with Prof. Jun Xi. Additionally, she participated in Drexel’s Co-op program, which promotes hands-on learning through the alternation of full-time study with full-time employment. This program allowed her to spend six months at Progenra Inc., a small company learning organic synthesis, six months at Solvay (formerly Rhodia Inc.), a large specialty chemical R&D facility learning polymer characterization techniques, and six months in Prof. Caroline Schauer’s laboratory in the Department of Materials

Science and Engineering developing chemical sensors. These diverse experiences encouraged her passion for scientific research and collaboration, motivating her to pursue a graduate degree. In 2013, she moved Gainesville, FL to attend graduate school at the University of Florida Department of Chemistry as a UF NIMET

(Nanoscience Institute for Medical & Engineering Technology) fellow. In Sisler Hall, where she spent most her days, she studied physical organic and supramolecular chemistry under the tutelage of Prof. Ron Castellano. Upon completion of her doctoral degree in 2018, Danielle will continue onto postdoctoral research at The University of

Michigan with Prof. Anne McNeil. She plans to pursue a career where she can share her excitement for scientific discovery, learning, and chemistry.

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