THIENOTHIOPHENE-BASED LIQUID CRYSTALS: SYNTHESIS AND COMPARATIVE EVALUATION OF MESOPHASE PROPERTIES

A thesis submitted to Kent State University in partial fulfillment of the requirements for the degree of Master of Science

by Jonathan I. Tietz August, 2012

Thesis written by Jonathan I. Tietz B.S., Kent State University, 2011 M.S., Kent State University, 2012

Approved by ______________________________, Chair, Thesis Committee Dr. Paul Sampson ______________________________, Chair, Thesis Committee Dr. Alexander J. Seed ______________________________, Members, Thesis Committee Dr. Robert J. Twieg ______________________________ Dr. Scott D. Bunge

Accepted by ______________________________, Chair, Department of Chemistry Dr. Michael Tubergen ______________________________, Dean, College of Arts and Sciences Dr. Raymond Craig ii

TABLE OF CONTENTS

LIST OF FIGURES ........................................................................................................... ix LIST OF SCHEMES......................................................................................................... xv LIST OF TABLES .......................................................................................................... xxii LIST OF ABBREVIATIONS ......................................................................................... xxv ACKNOWLEDGEMENTS ......................................................................................... xxxiv CHAPTER 1. INTRODUCTION ....................................................................................... 1 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 Introduction to liquid crystals ........................................................................ 1 Applications of liquid crystals in displays ..................................................... 5 General structure of liquid crystals .............................................................. 15 Sulfur-based heterocycles as liquid crystals ................................................ 21 Thienothiophenes in the literature ............................................................... 23 Previous studies of thienothiophene liquid crystals ..................................... 39 Rationale for selected LC targets ................................................................. 42 Overview of thesis goals .............................................................................. 44

CHAPTER 2. SYNTHESIS OF THIENO[3,2-b]THIOPHENE-2-CARBOXYLATE ESTER-BASED LIQUID CRYSTALS ................................................................ 47 iii

2.1

Rationale for targeting thieno[3,2-b]thiophene-2-carboxylate ester-based liquid crystals ............................................................................................... 47

2.2.1 2.2.2 2.2.3 2.3

Literature routes to thieno[3,2-b]thiophenes................................................ 49 Synthetic plan for target materials ............................................................... 54 Synthesis of alkyl 2-mercaptoacetates ......................................................... 57 Preparation of alkyl thieno[3,2-b]thiophene-2-carboxylate esters under mild conditions via tandem nucleophilic substitution and aldol condensation .... 62

2.4.1 2.4.2

Literature approaches to halogenation of thieno[3,2-b]thiophenes ............. 67 Regioselective C-5 halogenation of thieno[3,2-b]thiophene-2-carboxylate esters 2.3 ...................................................................................................... 76

2.5.1

Thienothiophenes as substrates for Pd(0)-catalyzed cross-coupling in the literature ....................................................................................................... 82

2.5.2

Synthesis of alkyl 5-(4-alkoxyphenyl)thieno[3,2-b]thiophene-2-carboxylate esters via Suzuki coupling ........................................................................... 86

CHAPTER 3. SYNTHESIS OF THIENO[2,3-b]THIOPHENE-2-CARBOXYLATE ESTER-BASED LIQUID CRYSTALS ................................................................ 93 3.1 Rationale for targeting thieno[2,3-b]thiophene-2-carboxylate ester-based liquid crystals ............................................................................................... 93 3.2.1 3.2.2 Literature routes to thieno[2,3-b]thiophenes................................................ 94 Synthetic plan for target materials ............................................................. 113 iv

3.3

Preparation of alkyl 5-bromothieno[2,3-b]thiophene-2-carboxylate esters via mild tandem nucleophilic substitution and aldol condensation ........... 114

3.4.1.

Use of thieno[2,3-b]thiophene substrates in Pd(0)-catalyzed cross-coupling in the literature ........................................................................................... 127

3.4.2

Synthesis of alkyl 5-(4-alkoxyphenyl)thieno[2,3-b]thiophene-2-carboxylate esters via Suzuki coupling ......................................................................... 133

CHAPTER 4. 5-ALKOXYTHIENO[3,2-b]THIOPHENE-2-CARBOXYLATE LIQUID CRYSTALS ........................................................................................................ 135 4.1 4.2 4.3 4.4.1 4.4.2 4.4.3 4.4.4 Rationale for targeting 2-alkoxythieno[3,2-b]thiophenes .......................... 135 Literature routes to 2-alkoxythiophenes and 2-alkoxythienothiophenes ... 137 Initially attempted entries into 2-alkoxythienothiophenes ......................... 143 Synthetic plan for brominated 2-alkoxythiophenes ................................... 154 Preparation of potassium thiophen-2-yltrifluoroborate precursors ............ 155 Oxidation of trifluoroborate salts 4.65 with aqueous Oxone ..................... 162 Preparation of brominated 2-alkoxythiophenes by Mitsunobu etherification of thiophenones 4.9 .................................................................................... 167 4.5.1 Synthesis of 5-alkoxythieno[3,2-b]thiophene-2-carboxylate-based mesogens 4.2 and 4.3 .................................................................................................. 172 4.5.3 Preparation of phenyl analogue of 2-alkoxythieno[3,2-b]thiophene-2carboxylate-based mesogen 4.23 ............................................................... 175 v

CHAPTER 5. TRANSITION TEMPERATURES AND COMPARISON OF TARGETED LIQUID CRYSTALS ................................................................... 178 5.1.1 Transition temperatures of primary alkyl 5-(4-alkoxyphenyl)thieno[3,2b]thiophene-2-carboxylate esters ............................................................... 178 5.1.2 Comparison of primary alkyl thieno[3,2-b]thiophene ester-based liquid crystals ....................................................................................................... 183 5.1.3 Comparison of primary alkyl thieno[3,2-b]thiophene ester-based liquid crystals to analogous mesogens in the literature ........................................ 186 5.2.1 Transition temperatures of primary alkyl 5-(4-alkoxyphenyl)thieno[2,3b]thiophene-2-carboxylate esters ............................................................... 187 5.2.2 Comparison of primary alkyl thieno[2,3-b]thiophene ester-based liquid crystals 5.4a-d ............................................................................................ 189 5.2.3 Comparison of primary alkyl thieno[2,3-b]thiophene ester-based liquid crystals to analogous mesogens in the literature ........................................ 189 5.3.1 Transition temperatures of secondary alkyl 5-(4-alkoxyphenyl)thieno[3,2b]- and [2,3-b]-thiophene-2-carboxylate esters.......................................... 190 5.3.2 Comparison of primary and secondary thieno[3,2-b]- and [2,3-b]thiophene ester- based liquid crystals ......................................................................... 191 5.3.3 Comparison of secondary thieno[3,2-b]- and [2,3-b]thiophene ester-based liquid crystals to analogous mesogens in the literature ............................. 199

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5.4.1

Transition temperatures of novel 2-alkoxythieno[3,2-b]thiophene-2carboxylate mesogens 5.8 and 5.10 ........................................................... 201

5.4.2

Comparison of novel 2-alkoxythieno[3,2-b]thiophene-2-carboxylate-based liquid crystals 5.8 and 5.10 to analogous mesogens in the literature ......... 202

CHAPTER 6. CONCLUSIONS ..................................................................................... 207 6.1.1 Conclusions regarding alkyl 5-(4-alkoxyphenyl)thienothiophene-2carboxylate liquid crystals ......................................................................... 207 6.1.2 Future directions for alkyl 5-(4-alkoxyphenyl)thienothiophene-based LCs .................................................................................................................... 208 6.2 6.2.2 6.3 Conclusions regarding the synthesis of brominated 2-alkoxythiophenes .. 209 Future directions for brominated 2-alkoxythiophenes ............................... 209 Conclusions regarding alkyl 5-alkoxythieno[3,2-b]thiophene-2-carboxylate liquid crystals ............................................................................................. 210 6.3.2 Future directions for alkoxythienothiophenes ........................................... 211

CHAPTER 7. EXPERIMENTAL................................................................................... 213 7.1 7.2 7.3 7.3 7.4 General considerations ............................................................................... 213 Numbering of compounds.......................................................................... 215 Experimental for Chapter 2 ...................................................................... 217 Experimental for Chapter 3 ...................................................................... 247 Experimental for Chapter 4 ...................................................................... 257 vii

CHAPTER 8. REFERENCES ........................................................................................ 288 TABULATED TRANSITION TEMPERATURES OF NOVEL MESOGENS ............ 341

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LIST OF FIGURES Figure 1.1: General sketch of nematic and smectic A and C mesophases .......................... 2 Figure 1.2: Polarization in applied electric fields of (a) paraelectric and (b) ferroelectric materials .................................................................................................................. 4 Figure 1.3: Representation of ray of light as oscillating electric and magnetic fields ........ 6 Figure 1.4: Representation of (a) unpolarized and (b) plane-polarized light ...................... 7 Figure 1.5: Representation of a linear polarizer.................................................................. 7 Figure 1.6: Representation of (a) parallel and (b) crossed polarizers ................................. 8 Figure 1.7: Representation of a twisted nematic (TN) device in (a) off (white) and (b) on (black) states ......................................................................................................... 10 Figure 1.8: Switching behavior in TN and FLC devices .................................................. 13 Figure 1.9: Schematic representation of chevron structure .............................................. 14 Figure 1.10: Previous LCs from our group which were free of chevron defects .............. 15 Figure 1.11: General structure of a calamitic liquid crystal.............................................. 17 Figure 1.12: Influence of central and terminal linkages (Y and Z) on stabilization of the smectic phase in calamitic LCs ............................................................................. 18 Figure 1.13: Effect of extended conjugated systems on mesophase formation ................ 20 Figure 1.14: Influence of heterocyclic systems on core properties .................................. 20 Figure 1.15: Target sulfur-based heterocyclic LCs in our lab .......................................... 21 ix

Figure 1.16: Bend across some sulfur-based heterocycles ............................................... 22 Figure 1.17: Literature examples of sulfur-based heterocycles (1.17 and 1.18 relative to phenyl analogue 1.16) as liquid crystals ............................................................... 22 Figure 1.18: Four isomeric forms of thienothiophene ...................................................... 24 Figure 1.19: Naming of thienothiophenes based on annulations pattern .......................... 24 Figure 1.20: Graphical representation of various aromatic ring substructures in the Reaxys database as of June 2012 .......................................................................... 27 Figure 1.21: Citations in the SciFinder database including thieno[3,2-b]thiophene- and thieno[2,3-b]thiophene-based substrates over time .............................................. 28 Figure 1.22: Literature example of a polymer incorporating thieno[3,2-b]thiophene for energy storage applications ................................................................................... 30 Figure 1.23: Thieno[3,2-b]thiophene-based conducting polymer pBTTT ....................... 31 Figure 1.24: Representative thieno[3,2-b]thiophenes of medicinal interest ..................... 32 Figure 1.25: PEDOT (1.38) and an analogous polymer 1.37 incorporating thieno[2,3b]thiophene ........................................................................................................... 34 Figure 1.26 Application of thieno[2,3-b]thiophenes in nonlinear optics .......................... 35 Figure 1.27: Hypotensive agents based on thieno[2,3-b]thiophene scaffold .................... 35 Figure 1.28: Literature example of thieno[2,3-b]thiophene-based esterase inhibitor ....... 36 Figure 1.29: Thieno[2,3-b]thiophene-based candidates for neurological therapeutic agents ............................................................................................................................... 37 Figure 1.30: Potential antitumor agents based on thieno[2,3-b]thiophene ....................... 37

Figure 1.31: Thieno[2,3-b]thiophene-based compounds of biological interest in the literature ................................................................................................................ 38 Figure 1.32: Thienothiophenes in food chemistry ............................................................ 39 Figure 1.33: Supramolecular liquid-crystalline complexes based on 5-n-decylthieno[3,2b]thiophene-2-carboxylic acid .............................................................................. 40 Figure 1.34: Photoconducting liquid crystals based on benzo[b]thieno[3,2b]benzo[b]thiophene ............................................................................................. 41 Figure 1.35: Previously reported alkyl 5-(4-hexyloxyphenyl)thieno[3,2-b]thiophene-2carboxylate liquid crystals 1.68 ............................................................................ 42 Figure 1.36: Selected target liquid crystals ....................................................................... 42 Figure 1.37: Phenyl analog of target thienothiophene liquid crystal 1.72 ........................ 43 Figure 1.38: Schematic overview of thesis goals.............................................................. 45 Figure 2.1: Previously reported primary alkyl 5-(4-alkoxyphenyl)thieno[3,2-b]thiophene2-carboxylate LCs 2.1 ........................................................................................... 47 Figure 2.2: Target primary alkyl 5-(4-alkoxyphenyl)thieno[3,2-b]thiophene-2carboxylate-based LCs 2.1 .................................................................................... 55 Figure 2.3: Byproducts from esterification of mercaptoacetic acid (2.25) with 1-octanol (2.30a) ................................................................................................................... 60 Figure 2.4: Mechanism of tandem nucleophilic aromatic substitution and intramolecular aldol to give thieno[3,2-b]thiophene 2.3 ............................................................... 66 Figure 2.5: Resonance contributors in the electrophilic aromatic substitution of thieno[3,2-b]thiophene and thiophene .................................................................. 68 xi

Figure 2.6: Relative reactivities of thiophene and thienothiophene sites toward electrophiles .......................................................................................................... 69 Figure 2.7: Mechanism of generation of ICl reactive species by NCS and NaI in acetic acid ........................................................................................................................ 75 Figure 2.8: Diiodinated byproduct from iodination of 2.3................................................ 80 Figure 2.9: Catalytic cycle and mechanism of Pd(0)-catalyzed cross-coupling ............... 83 Figure 3.1: Target 5-(4-alkoxyphenyl)thieno[2,3-b]thiophene-2-carboxylate esters 3.1 and isomeric thieno[3,2-b]thiophene analogues 3.2 ............................................. 94 Figure 3.2: General sketch of pyrolysis approach to thieno[2,3-b]thiophenes ................. 95 Figure 3.3: Strategic disconnection of thieno[2,3-b]thiophenes to carbon disulfide ........ 96 Figure 3.4: Comparison of mercaptoacetate and bromoacetate approaches to thieno[2,3b]thiophenes ........................................................................................................ 111 Figure 3.5: Mechanism of HD rearrangement of 3-lithiothiophene ............................... 117 Figure 3.6: Mechanism of HD rearrangement of 2,5-dibromothiophene ....................... 118 Figure 3.7: Mechanism of tandem nucleophilic aromatic substitution and intramolecular aldol to give thieno[2,3-b]thiophene 3.84 ........................................................... 120 Figure 3.8: Stacked 1H NMR spectra from the synthesis of 3.84b ................................. 122 Figure 3.9: Two diastereomers of the mechanistic intermediate 3.99 in the tandem SNAr/aldol condensation reaction ....................................................................... 123 Figure 3.10: Expansions of crude 1H NMR spectrum in the synthesis of 3.84b after 6 hours, showing integration of peaks ................................................................... 124

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Figure 3.11: Directing influence of the aldehyde functionality in the SNAr attack of 2,5dibromothiophene-3-carbaldehyde ..................................................................... 126 Figure 3.12: Representative mono- and dihalogenated thieno[2,3-b]thiophene-2carboxylates from the literature .......................................................................... 126 Figure 4.1: Targeted alkoxythieno[3,2-b]thiophene-based materials ............................. 135 Figure 4.2: Representative compounds based on 2-alkoxythiophenes ........................... 136 Figure 4.3: Tautomerism of 2-hydroxythiophene ........................................................... 140 Figure 4.4: Literature ligands used for copper-catalyzed alkyl aryl ether synthesis ...... 148 Figure 4.5: General scheme of Chan-Lam and Batey-Quach C-O coupling .................. 153 Figure 4.6: Structure of the Oxone triple salt ................................................................. 164 Figure 4.7: Dependence of yield of oxidation of 3,4-dibromothiophen-2-yltrifluoroborate (4.65d) on reaction time and equivalents of Oxone employed ........................... 166 Figure 4.8: Byproducts obtained from the Mitsunobu reaction of 4.25b ....................... 171 Figure 4.9: Likely mechanism of 2-alkoxythiophene formation .................................... 172 Figure 4.10: Comparison of melting points of 5-subsituted nonyl thieno[3,2-b]thiophene2-carboxylate esters ............................................................................................ 174 Figure 4.11: Phenyl analogues 4.92 and 4.93 of alkoxythienothiophene LCs ............... 175 Figure 5.1: Comparative plot of transition temperatures of primary alkyl ester thieno[3,2b]thiophene LCs 5.1a-i, ordered to show temperature trends based on (a) ester alkyl chain length n and (b) alkoxy alkyl chain length m, (c) clearing point, (d) melting point, (e) SmC width (cooling), and (f) SmA width (cooling)a,b ........... 180

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Figure 5.2: Plot of transition temperatures of novel primary thieno[2,3-b]thiophene ester LCs 5.4a-da ......................................................................................................... 188 Figure 5.3: Comparative plot of transition temperatures (upon heating) for isomeric thieno[2,3-b]thiophene and thieno[3,2-b]thiophene-based LCs ......................... 193 Figure 5.4: Resonance contributors to differences in conjugation between (a) thieno[3,2b]thiophene 5.1 and (b) thieno[2,3-b]thiophene 5.4 ........................................... 194 Figure 5.5: UV-vis spectra of thieno[3,2-b]thiophene-based mesogen 5.1e and thieno[2,3b]thiophene-based mesogen 5.4aa ...................................................................... 195 Figure 5.6: Absorption and emission spectra of (a) thieno[3,2-b]thiophene-based mesogen 5.1e and (b) thieno[2,3-b]thiophene-based mesogen 5.4aa ................. 197 Figure 5.7: Dipoles in thieno[2,3-b]thiophene and thieno[3,2-b]thiophene cores .......... 199 Figure 5.8: Comparative plot of transition temperatures (upon heating) for alkoxythieno[3,2-b]thiophene-based LC 5.8 and phenyl analogue 5.9 .............. 203 Figure 5.9: Comparative plot of transition temperatures (upon heating) for two families of thieno[3,2-b]thiophene-based LCs, 5.8 and 5.1 .................................................. 204 Figure 5.10: Comparison of two families of thieno[3,2-b]thiophene-based LCs, 5.10 and 5.1........................................................................................................................ 205 Figure 5.11: Comparative plot of transition temperatures (upon heating) for alkoxythieno[3,2-b]thiophene-based LC 5.10 and phenyl analogue 5.11 .......... 206

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LIST OF SCHEMES Scheme 1.1: Literature example of a conducting polymer based on thieno[3,2b]thiophene ........................................................................................................... 29 Scheme 1.2: Literature preparation of a conducting polymer incorporating a thieno[2,3b]thiophene monomer ........................................................................................... 33 Scheme 2.1: Previously reported synthesis of thieno[3,2-b]thiophene-based LCs 2.1 .... 48 Scheme 2.2: Literature example of synthesis of substituted thieno[3,2-b]thiophene 2.7 by photodimerization of a cyclopropenethione.......................................................... 50 Scheme 2.3: General strategic approach to substituted thieno[3,2-b]thiophenes from functionalized thiophenes ..................................................................................... 50 Scheme 2.4: Preparation of thieno[3,2-b]thiophene from 3-bromothiophene in the literature ................................................................................................................ 52 Scheme 2.5: Literature example of 3-alkylthieno[3,2-b]thiophene-2-carboxylate ester synthesis ................................................................................................................ 53 Scheme 2.6: Regioselective ring-closing reactions of dibrominated thiophenes ............. 53 Scheme 2.7. Inefficient preparation of ethyl 5-bromothieno[3,2-b]thiophene-2carboxylate 2.21 from aldehyde 2.20 .................................................................... 54 Scheme 2.8. Preparation of benzothiazole-substituted thieno[3,2-b]thiophene 2.23 ....... 54 Scheme 2.9: Synthetic route to novel alkyl 5-(4-alkoxyphenyl)thieno[3,2-b]thiophene-2carboxylate-based LCs 2.1 .................................................................................... 56 xv

Scheme 2.10: General scheme for preparation of thieno[3,2-b]thiophene-2-carboxylate esters 2.3 ............................................................................................................... 63 Scheme 2.11: Synthesis of 3-bromothiophene-2-carbaldehyde 2.24................................ 63 Scheme 2.12: NBS-mediated bromination of thieno[3,2-b]thiophenes by Knochel and coworkers241 .......................................................................................................... 70 Scheme 2.13: Bromination of thieno[3,2-b]thiophenes with elemental bromine in the literature ................................................................................................................ 71 Scheme 2.14: Chlorination of thieno[3,2-b]thiophenes with NCS in the literature.......... 72 Scheme 2.15: Chlorination of thieno[3,2-b]thiophene via lithiation and quenching with PCA in the literature ............................................................................................. 72 Scheme 2.16: Iodination of thieno[3,2-b]thiophenes with NIS in the literature ............... 73 Scheme 2.17: Iodination of thieno[3,2-b]thiophene-2-carbaldehyde with elemental iodine and HgO in the literature267................................................................................... 74 Scheme 2.18: Iodination of thieno[3,2-b]thiophene by lithiation and quenching with elemental iodine in the literature268....................................................................... 74 Scheme 2.19: Iodination of thieno[3,2-b]thiophene in the literature by NCS and NaI .... 75 Scheme 2.20: Iodination of thieno[3,2-b]thiophene-2-carboxylate esters 2.3 using molecular iodine and HgO .................................................................................... 81 Scheme 2.21: Attempted iodination of 2.3 mediated by NCS and NaI ............................ 82 Scheme 2.22: Literature examples of Suzuki-Miyaura coupling of bromothieno[3,2b]thiophenes .......................................................................................................... 84

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Scheme 2.23: Literature example of Suzuki-Miyaura cross-coupling of dibrominated thieno[3,2-b]thiophene .......................................................................................... 85 Scheme 2.24: Literature example of Stille coupling of 2,5-dibromothieno[3,2-b]thiophene ............................................................................................................................... 85 Scheme 2.25: Literature example of Negishi cross-coupling of chlorothieno[3,2b]thiophene derivative 2.70 .................................................................................. 86 Scheme 2.26: Attempted Negishi cross-coupling of brominated thieno[3,2-b]thiophene ester 2.54a and arylzinc chloride 2.75a ................................................................ 87 Scheme 2.27: Suzuki cross-coupling approaches to target compounds 2.1 ..................... 88 Scheme 2.28: Preparation of MIDA boronate 2.76 and aryl trifluoroborate salts 2.29a-c from boronic acid 2.28 .......................................................................................... 89 Scheme 3.1: Efficient pyrolytic preparation of sulflower in the literature ....................... 96 Scheme 3.2: Literature approaches to thieno[2,3-b]thiophenes from diynes ................... 97 Scheme 3.3: General synthetic strategy for the preparation of thieno[2,3-b]thiophenes from carbon disulfide and electron-withdrawing substrates ................................. 97 Scheme 3.4: Literature preparation of tetrasubstituted thieno[2,3-b]thiophenes from alkyl malonates and carbon disulfide ............................................................................. 99 Scheme 3.5: Use of malononitrile and carbon disulfide in the synthesis of thieno[2,3b]thiophenes in the literature .............................................................................. 100 Scheme 3.6: Variability in the literature of success of thieno[2,3-b]thiophene ringbuilding based on substrate structure .................................................................. 101

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Scheme 3.7: Literature preparation of tetrasubstituted thieno[2,3-b]thiophene with distinct C-2 and C-5 substituents ........................................................................ 101 Scheme 3.8: Literature methods for access to 3-chlorothieno[2,3-b]thiophene-2chlorocarbonyl 3.33 via thionyl chloride ............................................................ 102 Scheme 3.9: Comparative literature examples of the use of metallation in the synthesis of thieno[2,3-b]thiophene analogue 3.44 ................................................................ 104 Scheme 3.10: Use of metallation and sulfurization in the literature to prepare thieno[2,3b]thiophene ......................................................................................................... 106 Scheme 3.11: Preparation of thieno[2,3-b]thiophene-2-carboxylic acid 3.53 from dithiocarbamate precursor in the literature ......................................................... 107 Scheme 3.12: Preparation in the literature of [1]benzothieno[2,3-b][1]benzothiophenes 3.58...................................................................................................................... 108 Scheme 3.13: Literature preparations of thieno[2,3-b]thiophenes via an aldol condensation approach ........................................................................................ 109 Scheme 3.14: Aldol approaches to thieno[2,3-b]thiophenes employing bromoacetate ester precursors in the literature .................................................................................. 110 Scheme 3.15: Aldol approaches to thieno[2,3-b]thiophenes employing mercaptoacetate ester precursors in the literature .......................................................................... 111 Scheme 3.16: Acid-catalyzed aldol approaches in the literature to thieno[2,3-b]thiophenes ............................................................................................................................. 112 Scheme 3.17: Synthetic route to novel primary alkyl 5-(4-alkoxyphenyl)thieno[2,3b]thiophene-2-carboxylate-based LCs 3.1 .......................................................... 113 xviii

Scheme 3.18: Literature routes to 2,5-dibromothiophene-3-carbaldehyde .................... 115 Scheme 3.19: Formylation of 3-bromothiophene 3.37 under conditions to discourage HD rearrangement ..................................................................................................... 116 Scheme 3.20: Bromination of thiophene-3-carbaldehyde 3.30 ...................................... 119 Scheme 3.21: Comparative example of Suzuki-Miyaura cross-coupling of brominated thieno[2,3-b]thiophene and thieno[3,2-b]thiophene in the literature .................. 128 Scheme 3.22: Literature examples of Suzuki-Miyaura coupling of thieno[2,3b]thiophenes ........................................................................................................ 129 Scheme 3.23: Comparative influence of substrates on Suzuki-Miyaura and Stille coupling of thieno[2,3-b]thiophene analogues in the literature ......................................... 130 Scheme 3.24: Literature examples of Stille coupling of brominated analogues of thieno[2,3-b]thiophenes ...................................................................................... 131 Scheme 3.25: Literature example of Stille coupling of stannyl derivative of thieno[2,3b]thiophene ......................................................................................................... 132 Scheme 3.26: Literature methods for preparation of 2-bromothiophene-3-carbaldehyde 3.137.................................................................................................................... 134 Scheme 4.1: Examples of literature Ullmann-type and nucleophilic aromatic substitution approaches to 2-alkoxythiophenes ...................................................................... 138 Scheme 4.2. Ring-closing of 1,4-dicarbonyl compounds to afford 5-aryl-2alkoxythiophenes ................................................................................................ 139 Scheme 4.3: Multiple products obtained upon alkylation of hydroxythiophenes by Pedersen and Lawesson ...................................................................................... 140 xix

Scheme 4.4: Literature approaches to 2-alkoxythieno[3,2-b]thiophenes ....................... 141 Scheme 4.5: Representative literature examples of transition-metal catalyzed entry into 3alkoxythiophenes and 3-alkoxythienothiophenes ............................................... 142 Scheme 4.6: Summary of discarded strategies for synthesis of alkoxythienothiophenes143 Scheme 4.7: Chlorination of nonyl thieno[3,2-b]thiophene-2-carboxylate with NCS under acidic conditions ................................................................................................. 144 Scheme 4.8 Attempted nucleophilic aromatic substitution of 4.42 ................................ 146 Scheme 4.9: Attempted copper-catalyzed alkoxylation of 4.47 ..................................... 147 Scheme 4.10: Literature example of an adamantyl phosphine ligand in C-O coupling . 149 Scheme 4.11: Reported preparation of adamantyl phosphine ligand 4.50 ..................... 150 Scheme 4.12: Attempted synthesis of adamantyl phosphine ligand 4.38 ....................... 151 Scheme 4.13: Attempted entry into 2-alkoxythiophene via Batey-modified Chan-Lam coupling............................................................................................................... 154 Scheme 4.14. Synthetic route into brominated 2-alkoxythiophenes............................... 155 Scheme 4.15: General strategy for the preparation of brominated potassium thiophen-2yltrifluoroborates 4.65......................................................................................... 155 Scheme 4.16: Preparation of 2,4-dibromothiophene by halogen dance rearrangement . 160 Scheme 4.17: Preparation of 3,4-dibromothiophene by perbromination and reduction of thiophene ............................................................................................................. 161 Scheme 4.18: Temperature-dependence of regioselectivity in the deprotonation and boronation of 3-bromothiophene ........................................................................ 162

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Scheme 4.19: Literature preparation of alcohols from trifluoroborates by oxidation with Oxone .................................................................................................................. 163 Scheme 4.20: Literature preparation of 2-alkoxythiophene compounds by Mitsunobu etherification ....................................................................................................... 168 Scheme 4.21: Preparation of of 2-alkoxythieno[3,2-b]thiophene-2-carboxylate-based mesogens 4.2 and 4.3 .......................................................................................... 174 Scheme 4.22: Synthesis of phenyl analogue of 4.3 ........................................................ 177

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LIST OF TABLES Table 1.1: Representation of various aromatic ring substructures in the Reaxys database as of June 2012...................................................................................................... 26 Table 2.1: Costs of several alkyl 2-mercaptoacetates 2.26 and mercaptoacetic acid 2.25 from commercial suppliers as of February 2012 .................................................. 58 Table 2.2: Reaction conditions for optimization of mercaptoacetate synthesis................ 59 Table 2.3: Yields of alkyl mercaptoacetates 2.26 prepared by Mastriana ........................ 62 Table 2.4: Synthesis of alkyl thieno[3,2-b]thiophene-2-carboxylate esters 2.3 via tandem nucleophilic aromatic substitution and intramolecular aldol condensation .......... 64 Table 2.5: Commercial availability of N-halosuccinimides from three vendors .............. 76 Table 2.6: Bromination of thieno[3,2-b]thiophene-2-carboxylate esters 2.3 with NBS under acidic conditions ......................................................................................... 78 Table 2.7: Iodination of thieno[3,2-b]thiophene-2-carboxylate esters 2.3 with NIS under acidic conditions ................................................................................................... 79 Table 2.8: Optimization of Pd(0)-catalyzed Suzuki coupling conditions ......................... 91 Table 2.9: Synthesis of target 5-(4-alkoxyphenyl)thieno[3,2-b]thiophene-2-carboxylate ester LCs 2.1a-i via Pd(0)-catalyzed Suzuki cross-coupling with aryltrifluoroborates ............................................................................................... 92 Table 3.1: Preparation of 5-bromothieno[2,3-b]thiophene-2-carboxylate esters 3.84 via tandem nucleophilic aromatic substitution and aldol condensation ................... 119 xxii

Table 3.2: Synthesis of target 5-(4-alkoxyphenyl)thieno[2,3-b]thiophene-2-carboxylate ester LCs 3.1a-f via Pd(0)-catalyzed Suzuki-Miyaura cross-coupling with aryltrifluoroborates 3.85 ..................................................................................... 134 Table 4.1: Relative distribution of products in chlorination of 4.30 ............................... 145 Table 4.2: Preparation of brominated potassium thiophen-2-yltrifluoroborates 4.65 .... 157 Table 4.3: Preparation of brominated thiophen-2(5H)-ones by oxidation of trifluoroborate salts 4.65 with Oxone.......................................................................................... 165 Table 4.4: Mitsunobu etherification of brominated thiophen-2(5H)-ones 4.25a-ea ....... 170 Table 5.1: Transition temperatures of novel 5-(4-alkoxyphenyl)thieno[3,2-b]thiophene-2carboxylate esters 5.1a-i and previously reported esters 5.2a-da,b ..................... 179 Table 5.2: Transition temperatures of phenyl analogues 5.3a-i synthesized by Gray and Goodbya,b ............................................................................................................ 187 Table 5.3: Transition temperatures of novel 5-(4-alkoxyphenyl)thieno[2,3-b]thiophene-2carboxylate esters 5.4a-da ................................................................................... 188 Table 5.4: Transition temperatures of phenyl analogues 5.3e and 5.3g-i synthesized by Gray and Goodbya............................................................................................... 190 Table 5.5: Transition temperatures of novel octan-2-yl 5-(4alkoxyphenyl)thienothiophene-2-carboxylate esters 5.5e-f and 5.6a-ba,b .......... 191 Table 5.6: Transition temperatures of phenyl analogues 5.7a-f synthesized by Gray and Goodbya,b ............................................................................................................ 200 Table 5.7: Transition temperatures of of novel 2-alkoxythieno[3,2-b]thiophene-2carboxylate-based mesogens 5.8 and 5.10 and phenyl analogues 5.9 and 5.11a 201 xxiii

Table 7.1: Comparison of compound numbering across chaptersa................................. 216

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LIST OF ABBREVIATIONS Ac AC AChE Ad AD AIBN Alk A Anal. Calcd atm ATP aq. a.u. cat. Bn b.p. br Bu BuChE acetic alternating current acetylcholinesterase adamantyl Alzheimers disease azobisisobutyronitrile alkyl group amyloid -peptide elemental analysis calculated atmosphere(s) adenosine triphosphate aqueous arbitrary units catalytic benzyl boiling point broad butyl butyrylcholinesterase xxv

c C ca. calcd. cf. conc. Cryst d

cyclic degrees Celsius circa; approximately calculated confer; compare concentrated crystal day(s) doublet

d dd dt ddd DCC DCVC DCU dba DEAD DBN DIAD DIBAL dm

density doublet of doublets doublet of triplets doublet of doublet of doublets N,N'-dicyclohexylcarbodiimide dry column vacuum chromatography dicyclohexylurea dibenzylideneacetone diethyl azodicarboxylate 1,5-diazabicyclo[4.3.0]non-5-ene diisopropyl azodicarboxylate diisobutylaluminum hydride decimeter(s) xxvi

DMAP DMDO DMSO DMF DSC DTAD E+ E1cB EC50 e.g. eq. ESI Et et al. etc. EWG FLC g GA GC GmbH GPR35

4-dimethylaminopyridine dimethyldioxirane dimethylsulfoxide N,N-dimethylformamide differential scanning calorimetry di-tert-butyl azodicarboxylate electrophile unimolecular conjugate base elimination half maximal effective concentration exempli gratia; for example equivalents electrospray ionization ethyl et alii; and others; and coworkers et cetera electron-withdrawing group ferroelectric liquid crystal gram(s) Georgia, USA gas chromatography Gesellschaft mit beschrnkter Haftung G protein-coupled receptor 35 xxvii

HD Hex Hh HIV HMPA HMTA HOMO HPLC hr HRMS h Hz I i.e. Inc. IPS Iso Liq J J kg L LC

halogen dance hexyl Hedgehog human immunodeficiency virus hexamethylphosphoramide hexamine; hexamethylenetetramine highest occupied molecular orbital high-performance liquid chromatography hour(s) high resolution mass spectrometry light hertz iso id est; that is incorporated in-plane switching isotropic liquid Joule(s) coupling constant kilogram ligand liquid crystal xxviii

LCD LDA LUMO m

liquid crystal display lithium diisopropylamide lowest unoccupied molecular orbital meter(s) multiplet

metal molar; mol L-1

Me mg MHz MIDA min mL mm mM mmol mol m.p. MP3 m.s. MW n

methyl milligram(s) megahertz N-methyliminodiacetic acid minute(s) milliliter(s) millimeter(s) millimolar millimole(s) mole(s) melting point MPEG-2 Audio Layer III molecular sieves microwave normal; primary xxix

N NBS NCS NIS NLO nm nM NMP NMR Np n.r. Oct OFET p PAS pBTTT PCA PCC PDI PEDOT pet. Ph

nematic mesophase N-bromosuccinimide N-chlorosuccinimide N-iodosuccinimide nonlinear optics nanometer(s) nanomolar N-methyl-2-pyrrolidone nuclear magnetic resonance neopentyl no reaction octyl organic field-effect transistor para peripheral anionic site poly(2,5-bis(3-alkylthiophen-2-yl)thieno[3,2-b]thiophene) perchloroethane pyridinium chlorochromate polydispersity index poly(3,4-ethylenedioxythiophene) petroleum phenyl xxx

PPA ppm PTSA quant. quint. Rec Recryst rt s s sat. sext Sm SmA SmC SNAr SSFLC STN t t TBAB TBAF

polyphosphoric acid parts per million p-toluenesulfonic acid quantitative quintet recrystallized recrystallized room temperature singlet secondary saturated sextet smectic mesophase smectic A mesophase smectic C mesophase nucleophilic aromatic substitution (addition-elimination) surface stabilized ferroelectric liquid crystal super-twisted nematic time tertiary tetrabutylammonium bromide tetrabutylammonium fluoride xxxi

TFA tfp TFT THF TLC TMS

trifluoroacetic acid trifurylphosphine thin-film transistor tetrahydrofuran thin-layer chromatography trimethyl silyl tetramethylsilane

TN Topo II Ts TTP UV/Vis VAN w X max m

twisted nematic topoisomerase II p-toluenesulfonic thienothiophene ultraviolet/visible spectroscopy vertically aligned nematics weight halogen angstrom(s) chemical shift in ppm extinction coefficient maximum absorption micrometer(s) racemic

reflux xxxii

registered trademark

xxxiii

ACKNOWLEDGEMENTS I would like to thank Kelsey Gerbig for continued patience and support and for listening to more discussion of routine NMR spectra than anyone should have to listen to according to the Universal Declaration of Human Rights. I also thank my parents for support and for instilling in me the value of book-learnin. I thank my brother for advising the use of LaTeX for typesetting, which I unfortunately ignored. For their time, effort, and guidance, I want to thank my advisors, Dr. Paul Sampson and Dr. Alexander J. Seed, whose feedback and encouragement have been essential and constructive during my undergraduate and graduate path here at Kent State. My gratitude goes to numerous members of the Seed/Sampson research group: I thank Dr. Alan Grubb, Pritha Subramanian, and Matthew Barchok for their patience, mentorship, and assistance, all of which made the transition from academic work to lab work and graduate student life easier. I would also like to thank Jamie Mastriana for his contribution to some of the experimental work in this Thesis. Additional thanks go to Bill Wallace and Michael Schmidt for general lab camaraderie and excellent taste in lab music. I thank Dr. Ruth Leslie for help in the interpretation of spectra as well as insightful general discussions. I would also like to thank Dr. Robert J. Twieg for input as well as for the invaluable use of instrumentation, including his DSC, GC-MS, and UVVis. I also thank Dr. Scott Bunge for fruitful discussion as well as glovebox training. I xxxiv

would also like to thank Dr. Mahinda Gangoda for help in the acquisition of some NMR spectra as well as training on the NMR instrumentation. Additionally, Id like to thank numerous members of the chemistry departments support staff for help with research tasks as well as members of Dr. Twiegs research group for discussions. I would like to thank the makers of EndNote for incorporating numerous bugs into their software. Because of the constant crashes and bizarre formatting errors, I was able to occupy my intended free hours with microformatting of this Thesis, which saved me the effort of having to think of something to do for recreation instead. Finally, I would like to express my gratitude to the ancient Ethiopian goat-herd Kaldi, who, as legend has it, noticed his flock of goats chewing on raw coffee berries and observed the agitated state they subsequently entered. His discovery and the resulting brewed beverage of pleasant aroma and vigor has surely been a major contributor to the bulk of all scientific discoveries since. Additionally, I would like to thank anyone taking the time to actually read this Thesis. It picks up. Hang in there. Try coffee.

xxxv

CHAPTER 1. INTRODUCTION 1.1 Introduction to liquid crystals In addition to the more well-known phases of matter (solid, liquid, gas, and plasma), a number of other phases have been characterized, many of which have academically interesting and practically useful properties. Among these are the liquid crystal phases, or mesophases, with properties in between the three-dimensional order of solids and the isotropy of liquids. Liquid crystal-based devices are an essential component of modern life; in a world where 70% of American householders have internet access in their home1 and high-definition streaming video on phones has become commonplace,2 there is naturally a high demand for development of the liquid crystal technology on which many electronic displays are based. Liquid crystal phases. Upon melting from a solid or cooling from an isotropic liquid, a thermotropic mesomorphic material exhibits one or more intermediate liquid crystal phases (mesophases). Though many mesophases have been identified, the most common by far are the nematic (N), smectic A (SmA), and smectic C (SmC) phases. Whichif anyliquid crystal phase is observed for a given material depends on the structural characteristics of the molecule. The nematic, SmA, and SmC phases are sketched in Figure 1.1. The three mesophases differ slightly from each other based on the degree of order present in the material. 1

2 Figure 1.1: General sketch of nematic and smectic A and C mesophases

The SmC phase is the most ordered of the above mesophases: the molecules exist in diffuse layers, in which the molecules have translational motion; molecules are restricted from moving between layers. Within layers, molecules have short-range (on the order of 1.5 nm) but not long-range order.3 In this sense, smectic LCs can be thought of as one-dimensional solids. The SmC phase is differentiated from the SmA phase by the angle that the molecular long axis makes with respect to the layer plane; in the SmA phase this axis is on average perpendicular to the layer plane whereas in the SmC phase it is tilted at a temperature-dependent angle. In the SmA phase, individual molecules reorient about their long axis about 1011 times per second and reorient about their short axis 106 times per second.3 Though they are on average not tilted, any given molecule at any given instant is usually tilted; this results in layer spacing less than the length of the molecule. The rapid reorientation and randomness of the tilt across the bulk material results in normality of the director to the layer plane.3

3 Application of heat to the SmA phase may result in breakdown of the layer structure, although the molecules may still have a net orientation in one direction; this is known as the nematic phase. In the nematic mesophase, molecules have no long-range positional order but do have orientational order.3 This is not to say the molecules all point in the same direction; in fact, on average just as many molecules point in one direction as in the antiparallel direction due to a disordered head-to-tail arrangement in the phase.3 Loss of the orientational order upon further heating finally gives the isotropic liquid phase. Two principal models, neither one entirely satisfactory, have been advanced to explain the tilted smectic C phase in terms of either the molecular dipole or steric interactions. The first, McMillans model,4 posits that lateral molecular dipoles which rotate in the orthogonal SmA phase interact with each other upon cooling, become locked in, and align to give the tilted orientation in the SmC phase. The second, Wulfs model,5 hypothesizes that steric interactions between zig-zag shaped molecules are instead responsible. According to this model, the rigid cores align in the SmA phase while the aliphatic tails move about. Upon cooling, this motion decreases and the molecules tend to align at a tilt (as a result of their zigzag conformation) to maximize packing. However, as Goodby6, 7 has observed, neither model by itself is sufficient; for instance, McMillan neglects to explain SmC phases in molecules without lateral dipoles. A recent model by Goodby8 examines the energy levels associated with dipolar and quadrupolar coupling of molecules as a function of intermolecular separation. In this

4 model, orientations with energy minima are expected to correspond with mesophase formation. Chiral materials may exhibit a special case of the SmC phasethe chiral SmC*. Enantiopure materials, unlike chiral racemic and achiral materials, possess spontaneous polarization. Spontaneous polarization itself refers to the hysteresis loop of a ferroelectric material (Figure 1.2b). A ferroelectric material remains polarized in the absence of an electric field. This is in contrast to a paraelectric material (Figure 1.2a), in which the polarization is proportional to the applied field.9 Figure 1.2: Polarization in applied electric fields of (a) paraelectric and (b) ferroelectric materials (a) paraelectric P (b) ferroelectric P

In the SmC* phase, the director (defined as the vector corresponding to the direction of orientation of a mesogen) rotates slightly in each layer as the molecules form a type of helix.3 The spontaneous polarization rotates with each layer and over the course of one pitch averages itself out to zero. Various strategies exist to avoid this cancelling

5 out, including the application of an electric field (which aligns the molecules and unwinds the helix), mixing the chiral material with achiral host materials (which increases the pitch length), and application of very thin layers of the material (thinner than one pitch length).6 1.2 Applications of liquid crystals in displays The downstream goal of our research is in display applications, and so a brief discussion of liquid crystals in this context is appropriate. Though liquid crystals have seen use as tunable optic filters,10 optical switches,10 optical sensors,11 liquid crystal lenses,10 spatial light modulators,10 components of holographic displays,10 tuners for lasers,10 thermometers including devices for medical thermography,12-15 and mechanical stress testing,16 among others,10 the most familiar and widespread use is in liquid crystal displays (LCDs).17, 18 The LCD is ubiquitous; liquid crystal devices utilized during the writing of this thesis included a color laptop screen, a cell phone touchscreen, a coffee pot display, an insulin pump display, a desk phone display, a Kindle e-reader, a computer LCD projector, a lab timer, a DSC control panel, a short-path distillation apparatus control panel, digital scale readouts, numerous home appliance displays, a personal MP3 player, a fridge thermometer, and a car stereo control panel. Though the basic technology of liquid crystals is still largely the same as it was in the early 1990s,6 consumer demands have pushed research programs towards improvements in display size, weight, viewing angle, brightness, contrast, color palette, response time, and resolution.18 Ferroelectric

6 liquid crystals hold promise for improvement of many of these properties, which lies at the root of our research program. Liquid crystal displays. Liquid crystal displays operate on the principle of polarization of light. As shown in Figure 1.3, light can be represented as an transverse electromagnetic wave consisting of an electric (vector E) and magnetic field (vector B) which propagate while each oscillating perpendicular to each other. Note in Figure 1.3 that the vector sum of the two waves is a wave at a 45 angle to the E and B axes. Figure 1.3: Representation of ray of light as oscillating electric and magnetic fields

direction of propagation

Light which has not been polarized oscillates about the axis of propagation in every orientation (Figure 1.4a). However, light which has been linearly polarized (Figure 1.4b) oscillates with a single orientation. A polarizer confines the electromagnetic oscillation of light to one plane; this is represented conceptually in Figure 1.5. When unpolarized light strikes a polarizer, only 50% of the intensity is

7 transmittedthe vector components of each transverse wave in the plane of the polarizer. This selectivity can then be exploited for displays. Figure 1.4: Representation of (a) unpolarized and (b) plane-polarized light

(a)

(b)

direction of propagation

direction of propagation

Figure 1.5: Representation of a linear polarizer

polarizer

8 When two polarizers are placed in sequence, they can be oriented parallel to each other (Figure 1.6a), perpendicular to each other (Figure 1.6b), or any orientation in between. In the perpendicular (crossed) orientation, no light is transmitted, as light passing through the first polarizer has its plane of polarization at right angles to that of the second polarizer. In the parallel orientation, all light that passes through the first polarizer also passes the second. In this way, on and off states can be enacted. In intermediate orientations, the light intensity is partially transmitted. Figure 1.6: Representation of (a) parallel and (b) crossed polarizers (a)

first polarizer second polarizer

(b)

first polarizer second polarizer

9 Liquid crystal displays exploit the anisotropy of liquid crystals and their ability to twist light in conjunction with polarizers. In a typical display, a mixture of liquid crystals is placed in between two polarizers. Through manipulation of an electric field, the liquid crystals are oriented. Thus, by changing the orientation of the liquid crystals, the polarization of the light passing through the display can be rotated either in-plane with the second polarizer or out-of-plane. Nematics in displays. Despite the promise of ferroelectrics (discussed later), nematic liquid crystals are predominant in displays. The twisted nematic (TN) format, illustrated in Figure 1.7 (reproduced19,20 from sources), and its variants including the super-twisted nematic (STN, etc.) are common and formed the foundation, in the 1970s and onward, of the commercial LCD industry. Newer variants have challenged TN and STN, though TN displays are the cheapest and still widely available. In-plane switching (IPS) displays, for instance, align the LCs in a plane parallel to the substrate.21-23 IPS devices have become very popular recently and form the basis, for instance, of Apples iPhone and iPad Retina displays.24 Though IPS displays give good color reproduction, they suffer from similar disadvantages (i.e. slow response time) to TN displays which ferroelectric displays (discussed later) have the potential to address. Another common variant is the vertically-aligned nematic (VAN) display.22, 23, 25 In this architecture, mesogens align perpendicular (vertical) to the glass substrate. In the absence of an applied field, the display remains dark; an applied voltage, however,

10 induces a variable tilt that allows for a grayscale effect. VAN displays offer higher contrast (deep blacks) than IPS and TN displays with a higher refresh rate and are common in HDTVs. For illustrative purposes, we will consider the TN architecture below. Figure 1.7: Representation of a twisted nematic (TN) device in (a) off (white) and (b) on (black) states (a) (b)

In a TN device with no electrical current applied (Figure 1.7a), the nematic liquid crystal (LC) is positioned between two polymer alignment layers (G) at different angles; the LCs twist gradually from one alignment layer to the other. This results in a twist in the polarization of the incoming light passing through the first polarizer (P2) en route to the second polarizer (P1) which allows the light to pass. If, however, an electrical current is applied to electrodes on either end of the LC material (E1 and E2), the molecules orient

11 in the direction of this current. Thus, the helical twist is destroyed, the polarization of the incoming light is not rotated, and the light is blocked by the second polarizer. This results in a dark state. If the polarizers are parallel instead of perpendicular, the dark/light states for the current being on/off are reversed from the above. One downside to the TN architecture is the response time of the materials. The off and on states are achieved by applying or discontinuing an electric field. Once the field is discontinued, the nematic materials must relax to their stable twisted orientation for the display to change. This is a relatively slow processmuch slower than switching of smectic C* materials.26 Even nematic-based materials with ascribed super-fast LC response times are on the order of a few milliseconds.27, 28 This slow speed limits each subpixel to one color and hence limits resolution, which is a concern in an era of highdefinition television and increasingly detailed small screens.17 Because three red, green, and blue subpixels make up each pixel on the display, the amount of pixels per screen size will always be three times higher than it could optimally be. Ferroelectrics and smectics in displays. Though nematic (and indeed SmA) molecules usually have a net dipole, their bulk materials do not, due to symmetry.9 In contrast, ferroelectric SmC* liquid crystals exhibit a net dipole over the bulk of the material; their alignment can also be quickly switched by application of a current and they remain aligned in the absence of current.9 As previously mentioned, the layers of a SmC* material form a helix and hence the director rotates from layer to layer;

12 interestingly, the material in this helical structure is not ferroelectric (such a phase is termed helielectric). In the most common class of ferroelectric LCDs, surface stabilized ferroelectric liquid crystals (SSFLCs),26 the thickness of the LC material is kept as thin as possible (the period of the SmC* helix9 is on the order of micrometers and so the two glass plates sandwiching the LC are kept about 1.5 m apart) in order to minimize turning of the director.6 In what is known as the surface-stabilized state, a thin layer of molecules between two surfaces are stabilized such that they must lie parallel to the substrate (the bookshelf structure) but may switch direction. This configuration exhibits ferroelectric properties and suppresses the native SmC* helix.9 The contrast in switching behavior between TN devices and ferroelectric liquid crystal (FLC) devices is depicted in Figure 1.8 (reproduced from source9). As shown in the bottom portion of Figure 1.8, the transmitting and non-transmitting states are characterized by opposite applied electric fields (E) which orient the ferroelectric LCs accordingly.

13 Figure 1.8: Switching behavior in TN and FLC devices

Ferroelectric LCDs hold the promise of addressing many issues with TN displays. Indeed, they are good future candidates for LC applications requiring very high speeds, such as electrooptic shutters and real-time spatial light modulators (switching speeds are on the order of microseconds). Moreover, they offer the option of large, high-resolution screens that do not require separate transistors, in contrast to currently common active matrix displays, which employ thin-film transistors (TFTs) in addition to the LC element.9 In contrast to TN displays where a separate subpixel exists for red, green, and

14 blue, FLC devices may employ color sequential illumination, where all three colors are alternatingly emitted to create full color in each single pixel (temporal dither).29 However, the development of smectic FLC devices has proven challenging. Three qualities in smectic materials are temperature dependent: tilt angle, polarization, and layer thickness.9 Of these, the variation in layer thickness is of most detrimental significance. Layer shrinkage on cooling manifests itself as a sort of folding to form a chevron pattern (Figure 1.9); this lowers the switching angle and decreases display brightness and contrast.9 As shown, chevrons can propagate in antiparallel directions. The sites of intersection of two oppositely-running chevrons result in defects in the display that resemble zigzags. Figure 1.9: Schematic representation of chevron structure

Luckily, materials are known which do not show chevron defects9this temperature-independence of layer thickness is known as de Vries behavior. Unfortunately, examples of de Vries materials are scant (fewer than thirty have been reported),30-43 and so rational design of these materials is currently not possible as the structural features responsible for this behavior are unknown. By synthesizing and characterizing more de Vries materials, it is hoped that the structural features leading to de Vries behavior can be discovered. Our own group has discovered a few mesogens

15 (1.1-1.3), containing sulfur-based moieties, that are chevron defect-free;30, 32 these structures are shown in Figure 1.10. Accordingly, a long-term goal of our group is to explore structure-property relationships for a wide range of related sulfur-based mesogens, in an effort to understand which structural features favor the exhibition of de Vries behavior. Figure 1.10: Previous LCs from our group which were free of chevron defects

1.3

General structure of liquid crystals Mesogenic materials are generally categorized by their bulk shape, and commonly

fall into the categories of calamitic, discotic, and sanidic LCs.44 Calamitic LCs are described as rod, lath, or cigar-shaped, and are the most widely studied. Discotic mesogens are disc or sheet-shaped mesogens that tend to stack in columns. Intermediate between these shapes are sanidic LCs, which are described as board-shaped and exhibit some properties both of calamitic and discotic LCs. Of course, many other shapes exist

16 (for instance, conical and bowlic LCs),45 but our research efforts focus on calamitic molecules, as these are the class that produces smectic mesophases. With the wealth of LC knowledge accumulated so far by the research community (by 1998 over 72,000 such materials had been reported,45 and the latest LiqCryst46 databaseversion 5.1is replete with 106,398 compounds), general guidelines for the design of smectic and nematic LCs can be established.6, 45 The structure of a typical calamitic liquid crystal is depicted in Figure 1.11. To illustrate this architecture, previously-mentioned mesogen 1.1 is included and labeled as well. Typically, the liquid crystal is built on an aromatic, heteroaromatic, or aliphatic core (C1 and C2). These two cores may bear lateral substituents (S1 and S2), such as fluorine,47 which are usually installed to fine-tune the phase properties and transition temperatures of a system by modifying the molecules lateral dipole, changing its length-to-breadth ratio and affecting its ability to pack with its neighbors. Linking the core units is oftentimes (but not always) a central flexible linkage (Z) such as an ether or ester moiety. Flanking the cores are flexible terminal linkages (Y1 and Y2) which connect the rigid core to the flexible aliphatic groups (R1 and R2) on either end of the molecule. In some liquid crystals, one or both of these terminal aliphatic groups may be absent and Y may instead by a terminal polar group such as a nitrile.

17 Figure 1.11: General structure of a calamitic liquid crystal

What combinations of chemical features in the aforementioned architecture above give rise to the desired mesophases? A discussion of the structural characteristics of both nematic and smectic LCs is appropriate in order to contextualize our chosen target compounds. Smectics. Goodby and coworkers have previously analyzed the LC literature and constructed loose rules as to which linkages (Y and Z) stabilize the smectic phase,6, 48 as shown in Figure 1.12. Those Y and Z groups we utilized in our target LCs in this study are shown in blue.

18 Figure 1.12: Influence of central and terminal linkages (Y and Z) on stabilization of the smectic phase in calamitic LCs

Schiffs bases, although good at promoting the SmC phase, are usually avoided due to issues of chemical instability. Notably, central linkages (Z) tend to consist of two atoms; this preserves the linearity of the rigid core.45 One-atom central linkages impart a bend to the core that often prevents the formation of smectic phases (this is not always the case, as bent-core mesogens49, 50 are an active area of research). Central linkages which are more polarizable (compare ester and ketone) tend to more easily give smectic phases. Terminal linkages commonly include ethers (for alkoxy groups) and esters, but alkyl terminal chains without a linking group are also often seen.6 The aromatic core can also influence the mesophase, as will be discussed shortly. Aliphatic cores often suppress smectic phases.6

19 Structural influences on transition temperatures. The length and structure of each of the terminal chains is significant, as in homologous series, melting points are highest for very short and very long tails; the lowest temperatures are seen in intermediate ranges.45 Transition temperatures tend to decrease with an increase in the length-tobreadth ratio of the molecule. Alkyl tail lengths of 8 to 15 carbons are optimal for generation of the SmC phase.6 In addition, branching of the tail (i.e. secondary vs. primary alkyl tails) has a marked effect whereby decreasing the mesogens length-tobreadth ratio also decreases transition temperatures.45, 51, 52 The rigid aromatic cores (C1 and C2) can also affect mesophase formation. Larger, more conjugated systems tend to have higher melting points and a stronger tendency for mesophase formation (cf. 1.4, which is not mesogenic to 1.5, which exhibits the nematic phase, and 1.6, which shows both smectic and nematic behavior; Figure 1.13).45, 53, 54

20 Figure 1.13: Effect of extended conjugated systems on mesophase formation

Additionally, various heterocyclic cores change the electronic and dipolar properties of the molecules, which can stabilize mesophases (Figure 1.14; note 1.8, which has a melting point 93 C lower than 1.7 with a clearing point only 8 C lower). Figure 1.14: Influence of heterocyclic systems on core properties

21 1.4 Sulfur-based heterocycles as liquid crystals Sulfur-based heterocycles represent a relatively small subset of the phenyldominated LC literature.55 A current focus of our research group is the synthesis and characterization of liquid crystals incorporating these components; such examples so far have included thiophene-,30, 56-67 1,3-thiazole,32, 61, 68-72 and 1,3,4-thiadiazole-based61, 73-75 mesogens. We also recently extended our efforts to thienothiophenes.76-80 Some typical LCs in progress or completed in our lab are pictured in Figure 1.15. Figure 1.15: Target sulfur-based heterocyclic LCs in our lab

22 Many sulfur-based heterocycles not only possess lateral dipoles but also a marked bend (Figure 1.16).45 Figure 1.16: Bend across some sulfur-based heterocycles

Such compounds thus often have significantly depressed transition temperatures and wide smectic phases relative to their phenyl analogues (cf. 1.16 and 1.17 and 1.18, Figure 1.17).45, 81, 82 Figure 1.17: Literature examples of sulfur-based heterocycles (1.17 and 1.18 relative to phenyl analogue 1.16) as liquid crystals

Additionally, as mentioned previously, our group has discovered recently several LCs based on sulfur heterocycles 1,3-thiazole and thiophene (see 1.1-1.3, Figure 1.10) that are free of chevron defects.

23 An alternative to monocyclic sulfur-based heterocycles are the thienothiophenes (for structures, see Figure 1.18). Though these bicyclic sulfur-based heterocycles share electronic characteristics of monocyclic heterocycles (electron-rich, presence of sulfur, etc.), they differ in that they are a markedly larger ring system that, when substituted appropriately, impart little or no bend in the LC core. Indeed, there is no bend across 2,5disubstituted thieno[3,2-b]thiophene and a very slight bend across 2,5-disubstituted thieno[2,3-b]thiophene according to known crystal structures83-85 (ranging from 9.5 to 15.5 ; compare this to 32.8 for thiophene and 20 for thiazole in Figure 1.16). Given these similarities and differences that thienothiophenes (Figure 1.18) have when compared to the above simple five-membered heterocycles with promising properties, we reasoned that an investigation of thienothiophene-based LCs would add valuable knowledge to the understanding of sulfur-based mesogens. 1.5 Thienothiophenes in the literature Thienothiophenes are materials consisting of two annulated thiophene rings as shown in Figure 1.18. Of the four isomeric ring systems, thieno[3,2-b]thiophene (1.19) and thieno[2,3-b]thiophene (1.20) are the most common, followed by thieno[3,4b]thiophene (1.21). The unusual-looking thieno[3,4-c]thiophene (1.22) is the least common and is difficult to prepare. Historically, thieno[3,2-b]thiophene (1.19) was also called thiophthen, the name introduced in 1904 for 1.19,86 whose X-ray structure was solved in 1949.87 Though by the late 1970s this nomenclature was supplanted by the type

24 shown in Figure 1.18, some reports even in the last two or three years still refer to thiophthen.88, 89 Figure 1.18: Four isomeric forms of thienothiophene

The nomenclature of thienothiophenes is based on the annulation pattern of these fused heterocycles. The numbering schemes of substituent sites for 1.19 and 1.20, the two isomers employed in this thesis, are given above in Figure 1.18. The origin of the naming convention is described below in Figure 1.19; the nomenclature is based on which edges and points of the two rings make up the shared bond. Figure 1.19: Naming of thienothiophenes based on annulations pattern

Thienothiophenes are remarkably underrepresented in the literature. The distribution of hits obtained in a Reaxys database search for various aromatic and heteroaromatic substructures is given in Table 1.1 and plotted against a logarithmic axis in Figure 1.20. These fused-thiophene systems have attracted relatively little attention:

25 there are only 34 examples of thieno[3,4-c]thiophenes, 99 examples of thieno[3,2c]thiophenes, 1296 examples of thieno[2,3-b]thiophenes, and 2080 examples of thieno[3,2-b]thiophenes listed in the Reaxys database. The sharp difference between the two more common thienothiophene isomers and thieno[3,4-c]- and [3,2-c]thiophene is probably due to the synthetic difficulties in preparing the latter two classes of compound.90 As visualized in Figure 1.20, these amounts are 1-5 orders of magnitude smaller than other sulfur-based heterocycles used commonly in materials applications (thiophene, benzothiophene, 1,3-thiazole, 1,3,4-thiadiazole, furan, etc.). Thiophene especially has nearly half a million reported substances, but even thiazole and thiadiazole fall in the 30,000-340,000 range. Industrial applications of thienothiophenes are also far behind those of other sulfur-based heterocycles. Indeed, the proportion of thienothiophene-based substances that appear in patents is low (around 16-21% of all citations for thieno[3,2-b]thiophene, thieno[2,3-b]thiophene, and thieno[3,2-c]thiophene and 0% for thieno[3,4-c]thiophene are patents) compared to other common sulfur-based heterocycles (43% of citations for 1,3,4-thiadiazoles; 41% for 1,3-thiazoles; 40% for benzothiophenes; 31% for thiophenes).

26 Table 1.1: Representation of various aromatic ring substructures in the Reaxys database as of June 2012 Substructure benzene pyridine imidazole pyrrole pyrimidine naphthalene indole thiophene 1,3-thiazole furan quinoline 1,3-oxazole benzofuran benzothiophene 1,3,4-thiadiazole benzimidazole purine thieno[3,2-b]thiophene thieno[2,3-b]thiophene thieno[3,4-b]thiophene thieno[3,4-c]thiophene
a

Type Substancesa Citations Jb Pc monocyclic 11686782 1565915 1289299 264755 monocyclic 1653656 256004 197168 58031 bicyclic 1361901 86930 60676 26051 monocyclic 876957 130151 101879 27768 monocyclic 649462 70200 46477 23479 bicyclic 563973 187801 156249 30238 bicyclic 501310 75776 55437 20121 monocyclic 458313 71000 48712 22105 monocyclic 335757 41417 24257 17073 monocyclic 313394 78621 61207 17280 bicyclic 295145 65415 50955 14169 monocyclic 108465 16213 9117 7000 bicyclic 93227 18650 13876 4721 bicyclic 61873 11560 6887 4630 monocyclic 33138 6744 3816 2918 bicyclic 17676 25960 17108 8825 bicyclic 4482 2769 2108 645 bicyclic 2080 506 401 102 bicyclic 1296 330 277 53 bicyclic 99 38 30 8 bicyclic 34 23 23 0

Number of unique hits in Reaxys database for substances based on listed substructure (substructure search on all atoms). Search criteria: no salts; no mixtures; no isotopes; no charges; no radicals. b J = Number of citations consisting of journal articles. c P = Number of citations consisting of patents.

27 Figure 1.20: Graphical representation of various aromatic ring substructures in the Reaxys database as of June 2012

10000000
Number of substances 1000000 100000 10000 1000 100 10 benzene pyridine imidazole pyrrole pyrimidine naphthalene indole thiophene 1,3-thiazole furan quinoline 1,3-oxazole benzofuran benzothiophene 1,3,4-thiadiazole benzimidazole purine thieno[3,2-b]thiophene thieno[2,3-b]thiophene thieno[3,2-c]thiophene thieno[3,4-c]thiophene Substructure Despite this neglect, there has been a recent surge of interest in thienothiophene systems, particularly since the 1990s. The number of citations per year for thieno[3,2b]thiophene and thieno[2,3-b]thiophene (according to the SciFinder database) are given graphically in Figure 1.21. Thieno[3,2-b]thiophenes have seen a tenfold surge in popularity, growing from 9 citations in 2004 to 97 in 2011. While thieno[2,3b]thiophenes have plainly not seen this same dramatic increase in attention, they have nevertheless become more common since the early 2000s. Interestingly, this increase in

28 attention follows in the wake of the 2000 Nobel Prize in Chemistry, which was awarded for conductive polymers. Polythiophene (and occasionally thienothiophene) units are quite commonly the basis of such materials.91 Figure 1.21: Citations in the SciFinder database including thieno[3,2-b]thiopheneand thieno[2,3-b]thiophene-based substrates over time

100 90 80 Number of citations (via SciFinder) 70 Thieno[2,3-b]thiophene Thieno[3,2-b]thiophene

60
50 40 30 20 10 0 1950 1955 1960 1965 1970 1975 1980 1985 1990 1995 2000 2005 2010 Year Applications of thieno[3,2-b]thiophenes. Materials applications of thieno[3,2-

b]thiophenes have been plentiful. Since 2010 alone, these uses have included organic semiconductors,92-99 organic transistors,100, 101 field-effect transistors,102-107 light-emitting transistors,108 thin-film transistors,109-112 solar cells,113-116 conjugated polymers and photovoltaics,117-126 conducting polymers,127, 128 optical materials,42, 43 thermoelectric

29 materials,129 energy applications,130, 131 electronic applications,132 and liquid crystals (discussed later).77 Other previous applications also include magnetic materials133 and photosensitive receptors.134 In one illustrative example, stannyl thieno[3,2-b]thiophene derivative 1.23 was converted to conducting polymer 1.25 by Stille coupling polymerization (Scheme 1.1). Polymer 1.25 was incorporated into a polymer solar cell which reportedly exhibited promising photovoltaic behavior.135 Scheme 1.1: Literature example of a conducting polymer based on thieno[3,2b]thiophene

Abrua et al. reported 1.27 as part of a study probing chemical and electrochemical properties of redox capacitors for energy storage applications (Figure 1.22).130 The polymer architecture described by the authors is depicted by 1.26, which has a conjugated poly(3,4-ethylenedioxy)thiophene core and what is described as a pendant redox site (R). By virtue of this redox site, polymers of this architecture exhibit much higher energy density than polythiophenes alone (low energy densities are usually a

30 limitation of conjugated polymers). The authors synthesized and characterized 1.27, which was found to have high energy density and to undergo reversible redox processes at positive potentials. Indeed, by the authors estimates based on the electrochemical properties of 1.27, polymer 1.26 would exhibit an energy density comparable to current inorganic battery anodes. Figure 1.22: Literature example of a polymer incorporating thieno[3,2-b]thiophene for energy storage applications

In addition to functioning as a redox site as described above, thienothiophene is often incorporated into material backbones. A common architecture of thieno[3,2b]thiophene-based conjugated polymers is pBTTT (1.28) (Figure 1.23). In one example, de la Fuente Vornbrock et al.111 fabricated organic thin film transistors (TFTs) with a combination of rotogravure and ink-jet printing. The easily manufactured and scaled TFTs, consisting of a pBTTT semiconductor and a poly(4-vinylphenol) dielectric, exhibited some of the highest reported switching speeds for printed transistors.

31 Figure 1.23: Thieno[3,2-b]thiophene-based conducting polymer pBTTT

Biological applications of thieno[3,2-b]thiophenes are numerous and include several candidates in medicinal chemistry studies; several representative examples are discussed presently. For instance, a series of N-(aminodialkyl)thieno[3,2-b]thiophene-2carboxamides were prepared and patented as antidepressants and analgesics in the early 1970s.136 A family of dialkylamino thieno[3,2-b]thiophene sulfonamides 1.29 was tested for anti-glaucoma activity;137 their thieno[2,3-b]thiophene analogs138 were found, however, to have higher efficacy. A series of nucleosides incorporating the thieno[3,2b]thiophene motif (1.30) exhibited virucidal activity and were patented as potential HIV and hepatitis B medications.139 Some other applications include antibiotics140 (such as 1.31),141 and enzyme inhibitors,142, 143 including potential treatments for Alzheimers disease.143 Compound 1.32 was identified as a potent agonist of G protein-coupled receptor 35 (GPR35).144 GPR35 has been implicated in numerous conditions, including hypertension, coronary artery disease, asthma, and cancer. Notably, 1.32 exhibited very potent activity (EC50 = 64 nM) superior to common GPR35 agonists such as Zaprinast. In another example, compound 1.33 exhibited good inhibitory activity of the protein tyrosine phosphatase 1B, an enzyme involved in diseases including diabetes and obesity.145

32 Figure 1.24: Representative thieno[3,2-b]thiophenes of medicinal interest

Recently, at least two studies have identified, by in silico screening, thieno[3,2b]thiophene-based and similar substrates as potential lead compounds for antitumor activity146 or the treatment of trypanosomiasis.147 Though corresponding biological studies have not yet been carried out, such computational methods may increase interest in the thieno[3,2-b]thiophene moiety. Some agricultural applications have also been cultivated: a 1967 patent describes thieno[3,2-b]thiophene-based pesticides.148 Applications of thieno[2,3-b]thiophenes. Thieno[3,2-b]thiophenes generally dominate the materials field in comparison to their [2,3-b] isomers. However, thieno[2,3b]thiophenes have been used for a small number of materials applications, including electrically conductive polymers,128, 149, 150 organic field-effect transistors (OFETs),151, 152 charge transport materials,153 bis-azo dyes,154 and nonlinear optical materials.155-157 They have been incorporated into fluorescent charge-transfer complexes: for example,

33 thieno[2,3-b]thiophene co-crystallizes with 1,2,4,5-tetracyanobenzene to give yellow crystals.158 They also have been used as components of liquid crystalline mixtures159, 160 and as trace components of dyes.161 Thieno[2,3-b]thiophene moieties have been incorporated into polythiophenes (for instance 1.36, prepared by Stille coupling polymerization between 1.34 and 1.35)150, 151 instead of the more fully-conjugated thieno[3,2-b]thiophene unit in order to decrease overall system conjugation and hence protect the materials against oxidative p-type doping by oxygen in air (systems with longer effective -conjugation lengths often see reduced performance in air due to increased susceptibility to this doping) (Scheme 1.2). Scheme 1.2: Literature preparation of a conducting polymer incorporating a thieno[2,3-b]thiophene monomer

Another study took advantage of this reported increased stability and prepared alkoxythiophene polymer 1.37 by electropolymerization (Figure 1.25).149 Polymer 1.37 is a variant of the recently popularized poly(3,4-ethylenedioxythiophene) (PEDOT) (1.38) and displays higher resistivity to oxidationand better aerobic stabilitythan PEDOT. Interest in PEDOT and analogous polymers is currently high162-164 because of a

34 combination of excellent properties (good band gap, low redox potential, optical transparency) and processability. Figure 1.25: PEDOT (1.38) and an analogous polymer 1.37 incorporating thieno[2,3-b]thiophene

Thieno[2,3-b]thiophene-based materials have also found applications in nonlinear optics (NLO). Mashraqui et al.165 prepared push-pull materials, including 1.39-1.42, with thieno[2,3-b]thiophene as the electron-donating component (Figure 1.26). The resulting materials exhibited high thermal stability, which the authors attributed to the thienothiophene core, and nonlinear optic behavioral, attributed as a result of the interaction between thienothiophenes high HOMO and the low LUMO of the electronwithdrawing component of the system.

35 Figure 1.26 Application of thieno[2,3-b]thiophenes in nonlinear optics

Biological applications are more numerous than materials examples. In 1991, Prugh et al.137 at Merck developed a series of thieno[2,3-b]thiophene2-sulfonamides 1.43-1.46 as topical hypotensive agents for glaucoma (Figure 1.27). Specifically, the molecules functioned as carbonic anhydrase inhibitors. Figure 1.27: Hypotensive agents based on thieno[2,3-b]thiophene scaffold

Recently, Conde et al.166 prepared and evaluated a series of glutamic acid derivatives, including thieno[2,3-b]thiophene 1.47, for the treatment of Alzheimers disease (AD) (Figure 1.28). Accessed via thieno[2,3-b]thiophene-2-carbonyl chloride

36 1.48, compound 1.47 was found to inhibit both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), indicating the potential to prevent the aggregation of amyloid -peptide (A ) fibrils characteristic of AD. The electron-rich heteroaryl amide moiety of 1.47 and its analogues was designed to electronically interact with the tryptophan residue of the peripheral anionic site (PAS) of AChE, a site of A aggregation. Figure 1.28: Literature example of thieno[2,3-b]thiophene-based esterase inhibitor

Brunton and coworkers167 synthesized thieno[2,3-b]thiophene derivative 1.50 as part of a family of compounds designed as agonists of the Hedgehog (Hh) signaling pathway (Figure 1.29). As the Hh pathway has been linked to neuronal, embryonic, and bone development, Hh agonists have potential as therapeutic agents for neurological disorders such as Parkinsons disease. Prepared from acyl chloride precursor 1.51, thieno[2,3-b]thiophene 1.50 was found to have higher activity (EC50 = 300 nM) than the initially discovered compound 1.49a (EC50 = 5000 nM). However, structure-activity relationship (SAR) studies revealed compounds with a chlorinated benzothiophene moiety as well as a methylamino group to have better efficacy; for instance, 1.49b has an EC50 = 40 nM.

37 Figure 1.29: Thieno[2,3-b]thiophene-based candidates for neurological therapeutic agents

Liu et al.168 prepared a series of -heterocyclic carboxaldehyde thiosemicarbazones for their evaluation as antitumor agents (Figure 1.30). Many of these compounds showed inhibitory activity against human topoisomerase II (Topo II), a sign of antiproliferative activity, via docking to the ATP-binding site of Topo II. Although 1.53 (which was derived from aldehyde 1.54) displayed moderate activity, its therapeutic potential was vastly outstripped by quinoline-derived 1.52. Figure 1.30: Potential antitumor agents based on thieno[2,3-b]thiophene

Other bioactive compounds containing thieno[2,3-b]thiophene moieties (Figure 1.31) include antibiotics169 (such as 1.55), fibrinogen receptor antagonists170 (such as 1.56), HIV protease inhibitors171, 172 (such as 1.57), medicines for neurological conditions173 such as dementia (such as 1.58), analgesics174, 175 (such as 1.59),

38 hypolipidemic drugs176 (anti-cholesterol medications such as 1.60 and 1.61), and antitumor agents177 (such as 1.62). Figure 1.31: Thieno[2,3-b]thiophene-based compounds of biological interest in the literature

39 Interestingly, thienothiophenes also play a role in food chemistry.178 When 4hydroxy-5-methyl-3(2H)-furanone 1.63 (a compound found in meat sources) is heated under oven-like conditions (140C) with either cysteine (1.64) or H2S (also found abundantly in meats), a rich mixture of volatile components including five distinct thienothiophenes is formed (Figure 1.32). The thienothiophenes were enriched in the cysteine mixture, which tended to have an odor of baconin comparison to the hydrogen sulfide mixture, which had a metallic, medicinal smell. Figure 1.32: Thienothiophenes in food chemistry

1.6

Previous studies of thienothiophene liquid crystals The use of thieno[3,2-b]- and [2,3-b]thiophenes in liquid crystalline materials has

been rather limited. A 1982 study characterized thieno[3,2-b]thiophene dissolved in a commercially available nematic phase mixture by liquid crystal linear dichroism.179 Thienothiophenes have also been patented in liquid crystalline mixtures71, 72 or as liquid crystalline oligothienothiophenes.180, 181 In 1998, Tso et al. reported supramolecular liquid-crystalline complexes based on 5-n-decylthieno[3,2-b]thiophene-2-carboxylic acid 1.65 (Figure 1.33), synthesized through a nine-step pathway.182 The resulting hydrogen-bonded extended mesogens,182,

40
183

mixtures of varying ratios of 1.65 and a hydrogen-bond acceptor 1.66, exhibited both

smectic and nematic mesophases. Thiophene analogs of 1.65 were also reported, which did not show nematic phases in such mixtures and also had substantially lower clearing points. Figure 1.33: Supramolecular liquid-crystalline complexes based on 5-ndecylthieno[3,2-b]thiophene-2-carboxylic acid

In 2000, Mry and coworkers reported benzo[b]thieno[3,2-b]benzo[b]thiophene2,7-dicarboxylate ester derivatives 1.67a-d (Figure 1.34).184 Some of these compounds (1.67a, 1.67b, and 1.67d) exhibited smectic A mesophases with transition temperatures varying widely (1.67a melts at 220 C; 1.67d melts at 83.5 C), and they all exhibited photoconductive behaviorthat is, their electrical conductivity increases upon illumination. The compounds are sanidic liquid crystals that exhibited local columnar order within the smectic layers. This arrangement and the photoconductive behavior are attributed to intermolecular sulfur-sulfur and - interactions.

41 Figure 1.34: Photoconducting liquid crystals based on benzo[b]thieno[3,2b]benzo[b]thiophene

In 2010, our research group reported the preparation and characterization of a family of alkyl 5-(4-hexyloxyphenyl)thieno[3,2-b]thiophene-2-carboxylate liquid crystals 1.68 (Figure 1.35).76, 77 The synthesis of these compounds is briefly discussed in Chapter 2. The mesogens all exhibited the smectic A (SmA) mesophase with melting points ranging between 131.1 C and 140.1 C and clearing points between 154.2 C and 164.2 C. However, none of the compounds exhibited a smectic C (SmC) phase, even upon supercooling.

42 Figure 1.35: Previously reported alkyl 5-(4-hexyloxyphenyl)thieno[3,2-b]thiophene2-carboxylate liquid crystals 1.68

1.7

Rationale for selected LC targets A summary of our selected targets 1.69-1.72 is given in Figure 1.36. Our targets

were designed in order to investigate the nature of the alkyl tails and annulation pattern on mesophase properties of compounds analogous to 1.68. We also sought to prepare the first 2-alkoxythieno[3,2-b]thiophene LCs 1.71-1.72 to probe the mesogenicity of an alkoxythienothiophene core. Figure 1.36: Selected target liquid crystals

In our previously reported series of thieno[3,2-b]thiophene-2-carboxylate-based LCs 1.68 (Figure 1.35),77 a decrease in the melting point was observed with increasing ester tail length (140.1 C for n = 7; 136.3 C for n = 8; 133.5 C for n = 9; 131.1 C for n = 10). The materials only exhibited the SmA mesophase. It was our hope that by

43 changing the alkyl chain lengths at either end of the molecule (see 1.69), we could not only tune the melting point but also induce the formation of the SmC phase. We also desired to investigate the nature of the thienothiophene core on smectic phase stability; accordingly, we targeted thieno[2,3-b]thiophene analogs 1.70. Because chiral materials are required for ferroelectric behavior6 (our ultimate down-the-line goal), we also sought entry into chiral racemic (n = octan-2-yl) variants of 1.69 and 1.70 to probe the mesogenicity of these materials. Because of encouraging results with 2-alkoxythiophene liquid crystals in our group30, 56, 60, 61, 67, 185, 186 as well as the elusive nature of 2-alkoxythienothiophenes, we also sought entry into novel 5-alkoxythieno[3,2-b]thiophene-2-carboxylate ester based compounds 1.71 and 1.72. Compounds 1.71 were targeted due to their architectural similarity to previous sulfur-based heterocyclic liquid crystals reported by our group (see Figure 1.15, compounds 1.2, 1.3, and 1.14). Compounds 1.72 were selected for their similarity to well-known187 phenyl analog 1.73 (Figure 1.37), which exhibits both smectic and nematic phases. Figure 1.37: Phenyl analog of target thienothiophene liquid crystal 1.72

44 1.8 Overview of thesis goals This thesis encompasses five core projects: (I) preparation of a series of primary alkyl thieno[3,2-b]thiophene-2-carboxylate-based liquid crystals; (II) preparation of a series of primary alkyl thieno[2,3-b]thiophene-2-carboxylate-based liquid crystals; (III) preparation of a family of secondary (chiral racemic) alkyl liquid crystals with thieno[3,2-b]thiophene and thieno[2,3-b]thiophene cores; (IV) development of a synthetic approach to brominated 2-alkoxythiophenes; and (V) synthesis of the first 5alkoxythieno[3,2-b]thiophene-2-carboxylates as the first general synthetic entry into 2alkoxythienothiophenes. A brief summary of these projects is presented in Figure 1.38.

45 Figure 1.38: Schematic overview of thesis goals

In Chapter 2, the synthesis of a series of primary and secondary alkyl 5-(4alkoxyphenyl)thieno[3,2-b]thiophene-2-carboxylate LCs is presented (Projects I and III). The preparation of thieno[2,3-b]thiophene analogues to these LCs (both primary and secondary) is next discussed in Chapter 3 (Projects II and III). In Chapter 4, we discuss our development of a strategic route to novel brominated 2-alkoxythiophene building blocks (Project IV). We also describe the preparation of the first alkyl 5alkoxythieno[3,2-b]thiophene-2-carboxylate as well as its elaboration to the first alkoxythienothiophene-based liquid crystals (Project V). In Chapter 5, the mesophase

46 transition temperatures of the abovementioned LC targets are given and discussed in detail, with comparisons to each other and to precedents in the LC literature. The LC properties of all novel materials are recapitulated in a table at the end of this thesis. Lastly, Chapter 6 contains a discussion of the conclusions formed from the above projects as well as suggestions for future directions of research.

CHAPTER 2. SYNTHESIS OF THIENO[3,2-b]THIOPHENE-2-CARBOXYLATE ESTER-BASED LIQUID CRYSTALS 2.1 Rationale for targeting thieno[3,2-b]thiophene-2-carboxylate ester-based

liquid crystals Recently our research group synthesized and characterized the first family of lowmolecular-weight liquid crystals (LCs) built on the thieno[3,2-b]thiophene motif.77 These target compounds 2.1 (Figure 2.1) exhibited the smectic A (SmA) mesophase but not the more desirable tilted smectic C (SmC) phase. As the properties of smectic liquid crystals are substantially dependent on factors related to alkyl tail structure (for instance, lengthto-breadth ratio45), we envisaged that by varying the chain lengths n and m we could tune the materials to exhibit the SmC phase. Additionally, we sought to prepare chiral racemic analogues of 2.1 (secondary esters) to probe their properties, as chirality is required for ferroelectric behavior in liquid crystals.6 Figure 2.1: Previously reported primary alkyl 5-(4-alkoxyphenyl)thieno[3,2b]thiophene-2-carboxylate LCs 2.1

In addition, the previous synthesis of family 2.1 suffered from several challenges which hampered the overall efficiency of their preparation (Scheme 2.1). For instance, 47

48 brominated intermediate 2.4 and cross-coupling product 2.5 were plagued by poor solubility that rendered purification efforts problematic. As a result, compound 2.5 required large amounts of silica for purification (100:1 silica/sample w/w) and could not practically be prepared in large quantities. Though the ensuing hydrolysis of the ethyl ester 2.5 was facile, the low yield of the subsequent DCC/DMAP esterification to the targets 2.1 rendered the whole synthesis inefficient. Additionally, the Negishi crosscoupling to give 2.5 was problematic and in our hands proved capricious when we tried to apply it to a broader base of substrates. It was noticed that the targets 2.1, with longer alkyl tails than 2.5 and 2.4, benefitted from good solubility and easy purification by recrystallization. Thus, we reasoned that if we installed long alkyl tails early on in the synthesis, we could realize a twofold goal of (1) improving the overall synthetic efficiency and (2) tuning the LC properties of the target materials. Scheme 2.1: Previously reported synthesis of thieno[3,2-b]thiophene-based LCs 2.1

49 2.2.1 Literature routes to thieno[3,2-b]thiophenes The preparation of thieno[3,2-b]thiophenes was reviewed in the mid-1970s188 and, more recently, in the mid-2000s.90, 189, 190 There are a few distinct strategic approaches for the construction of the thieno[3,2-b]thiophene ring system. Generally, thieno[3,2b]thiophenes are prepared from either aliphatic precursors or thiophene precursors, though several other specialized methods are also known. Aliphatic precursors, while intellectually interesting, are generally synthetically unappealing. For instance, 2,5-dimethylthieno[3,2-b]thiophene is produced in very low yield (2%) when octane or octene and sulfur react under pressure.191-193 Likewise, thieno[3,2-b]thiophene and thieno[2,3-b]thiophene are produced in complex mixtures when acetylene and sulfur react.194-196 At high temperatures, 1,2-dichloroethylene reacts in a hydrogen sulfide atmosphere to form a mixture of thieno[3,2-b]thiophene and thieno[2,3-b]thiophene in low overall yield (4.5% total).197, 198 Generally, these kinds of methods are advantageous only in that the precursors are extremely inexpensive. The complexity of the reaction mixtures and low yields, however, render them disadvantageous, especially with the wide variety of functionalized thiophenes now readily available. An even less attractive class of precursors for thieno[3,2-b]thiophenes are cyclopropenethiones. For instance, cyclopropenethione 2.6 can photodimerize in benzene to afford 2.7, albeit in only 30% yield199 (Scheme 2.2). Several other similar applications

50 have been reported,200-202 but cyclopropenethiones are difficult to prepare and the low yields make this strategy less than ideal. Scheme 2.2: Literature example of synthesis of substituted thieno[3,2-b]thiophene 2.7 by photodimerization of a cyclopropenethione

Thiophene derivatives provide a much more attractive entry into thieno[3,2b]thiophenes, as thiophene can be easily functionalized. The general strategic approach to these compounds is shown in Scheme 2.3 below. Scheme 2.3: General strategic approach to substituted thieno[3,2-b]thiophenes from functionalized thiophenes

Two slightly divergent examples of this approach are presented in Scheme 2.4. In one example, Rutherford and coworkers203 prepared thieno[3,2-b]thiophene 2.8 via a 5step sequence from 3-bromothiophene (2.2) in a sulfurization-first approach (Scheme 2.4). Intermediate 2.9 was prepared by sequential lithiation, sulfurization, and substitution from 3-bromothiophene (2.2). Vilsmaier-Hack formylation of 2.9 afforded 2.10. On a small scale, this was reasonably efficient (73%) but increasing to a multigram

51 quantity of material dropped the yield substantially (ca. 40%). Aldehyde 2.10 underwent a base-mediated aldol condensation to afford methyl thieno[3,2-b]thiophene-2carboxylate 2.11, which was hydrolyzed and decarboxylated to yield thieno[3,2b]thiophene (2.8). In contrast, Iddon et al.204 utilized a formylation-first approach that was shorter, comprising only 4 steps (51-60% overall yield) in contrast to Rutherfords 6 steps (less than 30% overall yield). Deprotonation of 2.2 by LDA at 0 C (the temperature was important, as deprotonation at -78 C is not regioselective, as Iddon and coworkers found) and quenching with N-formylpiperidine gave aldehyde 2.13. This was readily ring-closed by a tandem nucleophilic aromatic substitution and aldol condensation in the presence of K2CO3 and ethyl thioglycolate to afford 2.14, which was carried on from this point identically to Rutherfords synthesis. This approach had previously been applied successfully to chloro derivatives of thiophene.205-208 Other bases employed in either approach for the ring-closing include DBN,137 sodium ethoxide,205, 209, 210 and potassium hydroxide.207, 208

52 Scheme 2.4: Preparation of thieno[3,2-b]thiophene from 3-bromothiophene in the literature

If ketones are used in lieu of aldehydes in the formylation-first approach, 3alkyl thieno[3,2-b]thiophene-2-carboxylate esters can be prepared, as demonstrated by He and Zhangs synthesis of 2.16 from 2.15 employing ethyl thioglycolate in 85% yield (Scheme 2.5).211 Several other high-yielding analogous approaches employing thiophenyl ketones have been reported.144, 212, 213

53 Scheme 2.5: Literature example of 3-alkylthieno[3,2-b]thiophene-2-carboxylate ester synthesis

In the case of dibrominated thiophene ketones such as 2.17, the nucleophilic aromatic substitution is highly regioselective for the halogen adjacent to the electronwithdrawing carbonyl group.144, 212-214 For instance, Zhang et al.212 achieved a 97% yield in the transformation of 2.17 to 2.18 in the presence of K2CO3 and Wan et al.213 transformed 2.17 (R = C6H13) to 2.19 in 82% yield (Scheme 2.6). Reactions of thiophene aldehydes bearing multiple halogens are also regioselective, but yields tend to be slightly lower (43-73%).215, 216 Scheme 2.6: Regioselective ring-closing reactions of dibrominated thiophenes

Interestingly, however, Iddon and coworkers204 only reported an 8% yield in the reaction of 3,5-dibromothiophene-2-carbaldehyde 2.20 with ethyl thioglycolate to form 2.21 (Scheme 2.7).

54 Scheme 2.7. Inefficient preparation of ethyl 5-bromothieno[3,2-b]thiophene-2carboxylate 2.21 from aldehyde 2.20

Substituents other than esters can be introduced into thieno[3,2-b]thiophenes in this way. For instance, a benzothiazole-substituted thienothiophene 2.23 was created from 2.22, albeit in a disappointing 15% yield (Scheme 2.8).217 Scheme 2.8. Preparation of benzothiazole-substituted thieno[3,2-b]thiophene 2.23

Several other miscellaneous approaches from thiophene have found singular use in the literature but are less applicable to the system targeted in this thesis and are thus beyond the scope of this discussion. These strategies include the use of dithianes,218 thionyl chloride,219-221 metallation/sulfurization,222 and sodium sulfide.223 While interesting, none of these methods have found widespread use. 2.2.2 Synthetic plan for target materials Our target LCs 2.1 built on the thieno[3,2-b]thiophene-2-carboxylate motif are given below in Figure 2.2. We targeted esters with both primary alkyl chains (n = 8-10)

55 as well as branched (chiral racemic 2-octyl) chains in conjunction with primary alkoxy tails (m = 8-10). Figure 2.2: Target primary alkyl 5-(4-alkoxyphenyl)thieno[3,2-b]thiophene-2carboxylate-based LCs 2.1

Our novel approach to these long-chain alkyl targets is presented below in Scheme 2.9. The compounds 2.1 were obtained in 27-64% overall yield from 3bromothiophene (2.2), a tenfold improvement from the 3-4% overall yield seen in the previous route.77

56 Scheme 2.9: Synthetic route to novel alkyl 5-(4-alkoxyphenyl)thieno[3,2b]thiophene-2-carboxylate-based LCs 2.1

The approach exploited an efficient late-stage Pd(0)-catalyzed Suzuki crosscoupling between iodothieno[3,2-b]thiophene-2-carboxylate esters 2.27 and aryltrifluoroborate salts 2.29 which were easily prepared from the corresponding boronic acids 2.28. The alkyl 5-iodothieno[3,2-b]thiophene-2-carboxylate esters 2.27 were synthesized by mild regioselective electrophilic halogenation of non-halogenated precursors 2.3. The long-chain alkyl esters 2.3 were themselves targeted via a tandem nucleophilic aromatic substitution and aldol condensation from 3-bromothiophene-2carbaldehyde 2.24 (made from 3-bromothiophene 2.2) and a series of long-chain alkyl mercaptoacetates 2.26 that were easily prepared by simple azeotropic esterification of mercaptoacetic acid 2.25 and the corresponding alcohols 2.30.

57 2.2.3 Synthesis of alkyl 2-mercaptoacetates In order to prepare thieno[3,2-b]thiophene-2-carboxylate esters 2.3, we required a series of primary long-chain alkyl 2-mercaptoacetates 2.26 (n = 8, 9, 10). Such substrates are admittedly not unknown; costs from several common commercial suppliers (SigmaAldrich, Acros Organics, Alfa Aesar) and more obscure suppliers (TCI America, MP Biomedicals, Pfaltz & Bauer) as of the time of this writing are given below in Table 2.1. The cost for mercaptoacetic acid (2.25) is also given for comparison. Despite the affordability (as low as $0.11/g) of the short-chain mercaptoacetates 2.26 (n = 1, 2) from the larger suppliers (Aldrich, Acros, and Alfa), only Sigma-Aldrich carries long-chain esters (n 8), priced at $100/g. At the time this work was carried out, the esters in

question were not commercially available. However, mercaptoacetic acid 2.25 is available in large quantities at low cost ($0.05/g). It is worth noting that several long-chain (n = 8, 9, 10, 12, 13) alkyl esters 2.26 have recently become available from small suppliers at reasonable cost. For instance, TCI America offers octyl 2-mercaptoacetate (2.26, n = 8) whereas MP Biomedicals supplies 2.26 as the decyl (n = 10) and tridecyl (n = 13) homologues affordably ($2.24-$0.56/g). Additionally, through the rare chemical firm Pfaltz & Bauer, the octyl (n = 8), dodecyl (n = 12), and tridecyl (n = 13) esters 2.26 can be obtained. Interestingly, the nonyl homologue of 2.26 (n = 9) is absent from even the rare-chemical supplier catalogues mentioned. Nonyl mercaptoacetate is commercially available only in 250 mg quantities from Sigma-Aldrich at a synthetically prohibitive $400/g.

58 We thus reasoned that it would be useful to develop a convenient preparation of long-chain alkyl esters 2.26 via esterification from mercaptoacetic acid and the corresponding alcohols. Table 2.1: Costs of several alkyl 2-mercaptoacetates 2.26 and mercaptoacetic acid 2.25 from commercial suppliers as of February 2012

Compound 2.25

2.26

Supplier Pricea Cheapest price Sigma-Aldrich $0.24 - $0.10 / g $0.05 / g Alfa Aesar $0.20 - $0.05 / g Acros Organics $0.08 - $0.07 / g 1 Sigma-Aldrich $4.44 - $0.14 / g $0.11 / g Alfa Aesar $0.62 - $0.11 / g TCI America $0.51 - $0.14 / g Acros Organics $0.27 - $0.14 / g 2 Sigma-Aldrich $4.60 - $3.35 / g $0.13 / g Alfa Aesar $4.12 - $0.13 / g Acros Organics $2.67 - $0.58 / g TCI America $0.54 - $0.24 / g 8 TCI America $2.24 / g $1.02 / g Pfaltz & Bauer $1.02 / g 9 Sigma-Aldrich $400 / g b $400 / g 10 MP Biomedicals $1.10 / g $1.10 / g b Sigma-Aldrich $100 / g 12 Sigma-Aldrich $100 / g b $0.61 / g Pfaltz & Bauer $1.02 - $0.61 / g 13 MP Biomedicals $0.56 / g $0.56 / g Pfaltz & Bauer $1.02 / g n
a b

price as of February 2012 available in 1 g quantities

59 A number of primary alkyl mercaptoacetates 2.26 accessed via acid-catalyzed esterification of mercaptoacetic acid, have been reported in the literature (n = 1,224-226 2,225-229 3-4,226 5,226, 230 6,226 8,226, 231 and 9-10226). In general, these existing reports are characterized by scant experimental or analytical details; yields, characterization data, purity, or byproduct information are typically not reported. Additionally, the aforementioned products were synthesized as intermediates, and, to the best of our knowledge, the esterification procedures had not been optimized. We chose to optimize the synthesis of octyl 2-mercaptoacetate 2.26a. Mercaptoacetic acid 2.25 was heated at reflux in toluene in the presence of 1-octanol (2.30a) and catalytic p-toluenesulfonic acid (PTSA). In order to determine the route that would give the fewest byproducts and would lead to the most convenient purification, the relative amounts of acid and alcohol substrates were varied as detailed below in Table 2.2. In all cases, we employed reflux conditions under argon or nitrogen, using a DeanStark trap to azeotropically remove water and so drive the reaction to completion. Table 2.2: Reaction conditions for optimization of mercaptoacetate synthesis

Entry Conditions Result 2:1 alcohol excess No thioester formation 1 2:1 acid excess, exposure to O2 21% thioester formation 2 2:1 acid excess 11% thioester formation 3 1.1:1 acid excess 6% thioester formation 4 1.5:1 alcohol excess No thioester formation 5

60

It was found that in the presence of an excess of mercaptoacetic acid 2.25 (1.1 to 2 eq.), a thioester byproduct 2.31 tended to form (Figure 2.3). The byproduct, whose structure we tentatively assigned from 1H NMR spectroscopy, forms via thioesterification of the product 2.26a with remaining mercaptoacetic acid 2.25. In contrast, using an excess of the alcohol 2.30a (1.5-2.0 eq. of n-octanol was used in test reactions) yielded the desired product with only leftover octanol as an impurity, which was easily removed by distillation. Figure 2.3: Byproducts from esterification of mercaptoacetic acid (2.25) with 1octanol (2.30a)

In the interest of avoiding purification by distillation if possible, several workups were examined to cleanly cleave the thioester byproduct while leaving the target ester intact. A workup in aq. NaHCO3 left the thioester intact. A workup in the stronger base 0.2 M aq. NaOH cleaved the thioester 2.31 but also cleaved octyl mercaptoacetate 2.26a. Working up the crude product with 0.2 M aq. Na2CO3 showed selective cleavage of the thioester byproduct 2.31, but the workup conditions also caused formation of the disulfide 2.32 (Figure 2.3). A mild reducing agent, such as NaBH4, may be able to selectively cleave the thioester as well, but these conditions were not examined.

61 Regardless, the use of an excess (1.5 eq.) of alcohol 2.30 followed by purification via distillation results in a straightforward, reliable synthesis and purification. The product 2.26a was a colorless liquid that boiled from 74-85C during reduced pressure distillation (3-4 mm Hg), and was isolated in 64% yield (108 mmol scale). Later, another student in our group (Mastriana) applied this methodology to several primary and secondary alcohols to determine its reproducibility.232 High, consistent yields (74-79% for primary alcohols; 63-66% for secondary alcohols) were obtained after vacuum distillation in that study after further optimization; the yields from that study232 are included in Table 2.3 for reference. To discourage aerobic oxidation of the product thiols to symmetrical disulfides 2.32 (Figure 2.3), the products were stored in a freezer (ca. -20 C) under argon or nitrogen. Samples left open to the atmosphere at ambient temperature showed slow oxidation (0.9% disulfide formation relative to thiol after 3 weeks; 1.5% after 7 weeks as determined by 1H NMR analyses).

62 Table 2.3: Yields of alkyl mercaptoacetates 2.26 prepared by Mastriana

Entry R Product Yield (%)a C8H17 76 1 2.26a C9H19 79 2 2.26b C10H21 76 3 2.26c s-C8H17 2.26d 63 4 C11H23 78 5 2.26e C12H25 74 6 2.26f c-C6H11 2.26g 66 7
a

Isolated yields of purified products after vacuum distillation.

2.3

Preparation of alkyl thieno[3,2-b]thiophene-2-carboxylate esters under mild

conditions via tandem nucleophilic substitution and aldol condensation Our general approach into thieno[3,2-b]thiophene esters entailed the reaction of alkyl mercaptoacetates 2.26 with 3-bromothiophene-2-carbaldehyde 2.24 under mild basic conditions (K2CO3 in DMF at room temperature), an approach successfully employed previously by our group76, 77 and in the general literature as discussed previously (Scheme 2.10).

63 Scheme 2.10: General scheme for preparation of thieno[3,2-b]thiophene-2carboxylate esters 2.3

Building block 2.24 is easily prepared by LDA-mediated deprotonation at the C-2 position of 3-bromothiophene 2.2, followed by addition of N-formylpiperidine (DMF has also recently been employed in the literature233, 234). Quenching of the resulting salt with a mild acid (aq. NH4Cl) frees the target compound 2.24 (Scheme 2.11). Described by Fuller and coworkers in 1997,204 this approach has been applied several times in the literature within the last few years in high yield235-237 (79-86%). Our group has found similar success.76, 77 Scheme 2.11: Synthesis of 3-bromothiophene-2-carbaldehyde 2.24

In most cases (2.3a-c) thiophene aldehyde 2.24 was not purified but was instead carried on in crude form (a thick red oil after workup) to the next synthetic step. Crude 2.24 was therefore reacted with the previously described alkyl 2-mercaptoacetates 2.26ac to afford the corresponding alkyl thieno[3,2-b]thiophene-2-carboxylates 2.3a-c in moderate to good yield (56-72%) (Table 2.4). In one case (synthesis of 2.3d), we purified

64 2.24 by Kugelrohr distillation prior to the reaction, which furnished the product in 76% yield. This did not give dramatically higher yields in the subsequent step, but the resulting thienothiophene was easier to purify than the product obtained from the crude starting material. The reaction proceeds at room temperature under ambient atmosphere in the presence of a small excess (1.3 eq.) of K2CO3. Though column chromatography gave materials pure enough for synthetic use, the low melting points of 2.3 (m.p. = 29-36 C for 2.3a-c) made recrystallization for analytical purposes difficult, with low recoveries. Table 2.4: Synthesis of alkyl thieno[3,2-b]thiophene-2-carboxylate esters 2.3 via tandem nucleophilic aromatic substitution and intramolecular aldol condensation

Entry Compound n Yield (%)a 8 56b 1 2.3a 9 64 b 2 2.3b 10 72 b 3 2.3c s-8d 76c 4 2.3d
isolated yield after chromatography two-step yield from 2.2 via crude 2.24 c one-step yield from purified 2.24 d s-8 represents racemic C6H13CH(CH3)b a

Mechanistically, this transformation is believed to involve a tandem SNAr-type nucleophilic aromatic substitution followed by an intramolecular aldol condensation as depicted in Figure 2.4. In the presence of base, the thiolate of 2.26 attacks the

65 electrophilic -carbon of 3-bromothiophene-2-carbaldehyde 2.24. Elimination of bromide sets the stage for an intramolecular aldol condensation which furnishes the second heterocyclic ring. Elimination of water from intermediate 2.34 is driven by the strong incentive of the ring to aromatize, yielding thieno[3,2-b]thiophene 2.3. The mechanism depicted below explains the amount of base (1.3 eq. K2CO3) employed; the first equivalent generates the thiolate, while the remaining base is catalytic and facilitates the aldol condensation.

66 Figure 2.4: Mechanism of tandem nucleophilic aromatic substitution and intramolecular aldol to give thieno[3,2-b]thiophene 2.3

It is worth mentioning that 1H NMR evidence provides support for the above mechanistic pathway; peaks corresponding to an analog of 2.34 are visible early on during the course of the reaction. This evidence was collected in the synthesis of analogous thieno[2,3-b]thiophene-2-carboxylate esters and is presented later in Chapter 3.

67 2.4.1 Literature approaches to halogenation of thieno[3,2-b]thiophenes Thieno[3,2-b]thiophenes react readily with electrophilic halogenating reagents. Consistent with their thiophene cousins, thieno[3,2-b]thiophenes exhibit great selectivity for electrophilic substitution at the C-2 rather than the C-3 position. Attack by an electrophile forms a cationic intermediate preceding the loss of a proton to regenerate aromaticity and yield the electrophile-substituted heterocycle. As shown in Figure 2.5ab, this cationic intermediate in the case of C-2 substitution is stabilized by the delocalization of the positive charge across five resonance contributors; C-3 substitution affords only two resonance contributors. This is consistent with thiophene substitution; as depicted in Figure 2.5c-d, C-2 substitution of thiophene affords an intermediate with three resonance structures in contrast to the two resonance contributors resulting from C3 substitution.

68 Figure 2.5: Resonance contributors in the electrophilic aromatic substitution of thieno[3,2-b]thiophene and thiophene

69 As might be expected from resonance arguments, thieno[3,2-b]thiophenes are more reactive than thiophenes toward electrophilic reagents. In the 1970s, the reactivity order described in Figure 2.6 was determined computationally238 (via quantum chemical methods) and empirically239 (via formylation, acetylation, and chlorination studies). Figure 2.6: Relative reactivities of thiophene and thienothiophene sites toward electrophiles

Not surprisingly, then, methods commonly used for electrophilic halogenation of thiophene have seen analogous use in thieno[3,2-b]thiophene chemistry. Nbromosuccinimide (NBS) has seen several very successful recent applications, some of which are shown in Scheme 2.12. These reactions are typically carried out with good to excellent yields (78-98%) in chloroform,240 DMF,112, 212, 241-243 or a mixture of chloroform and acetic acid,77, 232, 244-249 although THF250 and dichloromethane251, 252 have also been employed.

70 Scheme 2.12: NBS-mediated bromination of thieno[3,2-b]thiophenes by Knochel and coworkers241

It is also possible to regioselectively brominate thieno[3,2-b]thiophenes with bromine,253, 254 such as Bronstein and Chens approach to conjugated system 2.36; however, the increased reactivity of bromine relative to NBS makes this approach more attractive for polybrominated targets204, 255-258 such as 2.37.204, 255 It is worth commenting on the regioselectivity of these reactions; reaction of thieno[3,2-b]thiophene (2.8) with elemental bromine at 0-20 C was sufficient to induce reaction at the C-3 position; however, C-3 substitution with NBS is not seen in thieno[3,2-b]thiophene systems, even under reflux conditions with an excess of the halogenating agent.232

71 Scheme 2.13: Bromination of thieno[3,2-b]thiophenes with elemental bromine in the literature

Precedents for chlorination and iodination are rarer. As depicted in Scheme 2.14, only a handful of instances of chlorination exist: Knochels recent bis-chlorination of thieno[3,2-b]thiophene 2.8 in very high yield (99%),241 Nakayamas chlorination of dimethylthieno[3,2-b]thiophene 2.39 in good yield (77%),252 and Gronowitzs chlorination of thieno[3,2-b]thiophene-2-carboxylic acid 2.12 in reasonable yield (62%).176 These approaches employed N-chlorosuccinimide (NCS), a reagent analogous to NBS, in DMF or acetic acid.

72 Scheme 2.14: Chlorination of thieno[3,2-b]thiophenes with NCS in the literature

The only other example of chlorination comes from a 2005 patent,259 in which thieno[3,2-b]thiophene (2.8) was first lithiated and then treated with perchloroethane (PCA) to afford 2.43 in good yield (75%) (Scheme 2.15). PCA, also known as hexachloroethane, is a source of electrophilic chlorine frequently employed industrially in large-scale chlorination.260 Scheme 2.15: Chlorination of thieno[3,2-b]thiophene via lithiation and quenching with PCA in the literature

73 Like bromination and chlorination, iodination can be accomplished with Niodosuccinimide (Scheme 2.16).261-265 As reported recently,262 treatment of substituted thieno[3,2-b]thiophene 2.44 with N-iodosuccinimide (NIS) affords the corresponding iodothienothiophene 2.45 in good yield (82%). A similar result was obtained by Marder and coworkers,261 who bis-iodinated 2.46 in good yield (80%). Likewise, Wan et al.264 synthesized 2.49 in excellent yield (95%). Scheme 2.16: Iodination of thieno[3,2-b]thiophenes with NIS in the literature

74 Elemental iodine is another useful reagent for this purpose which has seen recent application. The earliest reports of iodothieno[3,2-b]thiophenes in the late 1940s and early 1950s employed I2 with stoichiometric HgO in benzene.195, 266 Though generally neglected in favor of less toxic NIS chemistry, this approach saw recent reuse by Sato et al.,267 who in 2008 prepared 2.51 in this manner from 2.50 in reasonable yield (70%). Scheme 2.17: Iodination of thieno[3,2-b]thiophene-2-carbaldehyde with elemental iodine and HgO in the literature267

Takahashi et al.268 iodinated thieno[3,2-b]thiophene (2.8) regioselectively by metallation with t-butyllithium in diethyl ether followed by quenching with iodine. This afforded the singly iodinated compound 2.52 in quantitative yield. Scheme 2.18: Iodination of thieno[3,2-b]thiophene by lithiation and quenching with elemental iodine in the literature268

In an interesting recent report (2010), Yamamoto et al. described regioselective iodination of electron-rich aromatic compounds, including thieno[3,2-b]thiophene (92% yield), using a 1:1 mixture of N-chlorosuccinimide (NCS) and sodium iodide,269 citing

75 the relatively higher expense of NIS compared to NBS and NCS as the motivation for this combination of reagents (Scheme 2.19). Scheme 2.19: Iodination of thieno[3,2-b]thiophene in the literature by NCS and NaI

The reaction purportedly works through the in situ generation of ICl, an electrophilic source of iodine, via activation of NCS by acetic acid as depicted in Figure 2.7. Figure 2.7: Mechanism of generation of ICl reactive species by NCS and NaI in acetic acid

76 Interestingly, despite the financial argument for this method, the prices of NIS, NCS, and NBS are perhaps not significant. Through NIS is universally more expensive than its bromine or chlorine analogues (Table 2.5), it can be procured very inexpensively from Oakwood Chemicals. Table 2.5: Commercial availability of N-halosuccinimides from three vendors Price ($/100g)a Vendor NIS NBS NCS $464.50 $33.40 $20.90 Sigma-Aldrich $429.90 $23.60 $20.30 Acros Organics Oakwood Chemicals $55.00 $4.40b $15.00
a

based on catalogue prices from May 2012 b based on price for 1 kg

2.4.2

Regioselective C-5 halogenation of thieno[3,2-b]thiophene-2-carboxylate

esters 2.3 With thieno[3,2-b]thiophene-2-carboxylate esters 2.3 in hand, we explored a variety of approaches to 5-halothieno[3,2-b]thiophene-2-carboxylate esters. These heteroaryl halides were to be used as substrates in a cross-coupling step, and so we chose to prepare both brominated 2.54 and iodinated 2.27 thienothiophene adducts in order to (1) optimize the yield of the subsequent cross-coupling and (2) explore the electrophilic halogenation of these heterocycles. Ultimately, we found success with NBS, NIS, and elemental iodine (I2). Bromination with NBS. N-Bromosuccinimide (NBS) is a widely-used halogenating agent that acts as a slow-release source of bromine for electrophilic halogenation. Our group previously found76, 77 that by heating ethyl ester 2.3g (n = 2)

77 under reflux in chloroform and acetic acid (1:1) in the presence of N-bromosuccinimide (NBS), C-5 brominated adduct 2.54g (n = 2) could be obtained regioselectively. We applied this approach to the bromination of long-chain (n = 8, 9, 10) homologues of 2.3g. The reaction conditions were briefly examined. Heating at reflux proved to be necessary. Lower temperature reactions (room temperature and 40 C) were examined, under which the reaction proceeded sluggishly. In both cases, additional portions of NBS had to be added at 48 hours, and time to completion was several days (72 hrs at 40 C, >96 hrs at room temperature). In contrast, heating under reflux gave 95% conversion after 6 hours (as monitored by 1H NMR) and the reaction was complete after 24 hours. Reflux of thieno[3,2-b]thiophene-2-carboxylate esters 2.3 (n = 8, 9, 10) and an excess (1.5 eq.) of NBS in a 1:1 mixture of chloroform and acetic acid thus furnished the expected brominated adducts 2.54a-c in excellent yield (Table 2.6). To our satisfaction, the resulting compounds 2.54a-c were soluble in organic solvents (in contrast to their ethyl analogues) and hence they were easily purified by silica gel chromatography. As with the non-halogenated precursors, brominated thieno[3,2-b]thiophenes 2.54a-c were low-melting and difficult to recrystallize (oiling out of the product usually occurred on heating). Additionally, the halogenated compounds 2.54a-c contained an intensely absorbing green unknown impurity which was difficult to remove by chromatography and recrystallization. Though the presence of this impurity did not interfere with subsequent reactions, the materials could be decolorized via dry column vacuum

78 chromatography (DCVC), a technique often described as the poor mans HPLC, which has seen a recent resurgance in popularity.270 Table 2.6: Bromination of thieno[3,2-b]thiophene-2-carboxylate esters 2.3 with NBS under acidic conditions

Entry n Product Yield (%)a 2.54a 8 88 1 2.54b 9 quant. 2 10 2.54c quant. 3

a

after column chromatography

79 Iodination with NIS. As discussed previously, N-iodosuccinimide (NIS) is an efficient iodinating agent. Analogous to our brominations with NBS, we prepared iodothieno[3,2-b]thiophenes 2.27a-d in high yield (78-91%) using NIS (Table 2.7) in chloroform and acetic acid at room temperature. Table 2.7: Iodination of thieno[3,2-b]thiophene-2-carboxylate esters 2.3 with NIS under acidic conditions

Entry n Product Eq. NIS Yield (%)a 2.27a 8 1.2 78 1 2.27a 8 1.5 38b 2 2.27b 9 1.2 88 3 2.27c 10 1.3 91 4 s-8 2.27d 1.2 90 5
b

after column chromatography after two recrystallizations to remove byproduct 2.55

This approach has been reported recently in the literature for unfunctionalized thienothiophenes271, 272 in similar yields (80-82%) to ours. Although iodination proceeds at room temperature rather than reflux, it is worth noting that the iodination reaction is less regioselective than bromination; portionwise addition of NIS until the reaction is judged to be complete is necessary to prevent over-iodination from the excess reagent. For example, use of 1.5 equivalents of NIS in one portion afforded a 92:8 mixture of the target compound and a di-iodinated material (1H NMR analysis revealed this byproduct

80 to be the 5,6-diiodothieno[3,2-b]thiophene-2-carboxylate ester 2.55); since these two are difficult to separate by chromatography, multiple recrystallizations were required to obtain synthetically pure material, which substantially lowered the yield (Table 2.7, entry 2). Figure 2.8: Diiodinated byproduct from iodination of 2.3

Iodination with elemental iodine. An alternative method of regioselective iodination via elemental iodine (I2) and HgO, recently applied in the literature to a thienothiophene system,267 also proved highly efficient for the preparation of 2.27. Stirring of the precursors 2.3b or 2.3c with 5 equivalents each of I2 and HgO in benzene at room temperature afforded 2.27b and 2.27c regioselectively and in excellent yield (9495%) (Scheme 2.20). Though the reaction is efficient and selective at room temperature, heating is not advantageous here. Reflux with only 1.2 equivalents of each reagent gave only 90% completion, even after 96 hours; in contrast, heating at 75 C with 5 equivalents each of HgO and I2 (as in the literature precedent)267 gave a significant amount of byproduct 2.55 (3.5:1 ratio of desired product 2.27a to di-iodinated product 2.55).

81 Scheme 2.20: Iodination of thieno[3,2-b]thiophene-2-carboxylate esters 2.3 using molecular iodine and HgO

The iodinated product was purified by column chromatography to give a light brown solidthe intense green impurity seen in NIS and NBS halogenations was absent. This method is ideal for small preparations; refluxing conditions are not required and the room temperature reaction gives exclusively mono-iodination. Indeed, the resulting materials are pure enough to use after only a workup. However, the large excess of toxic mercuric oxide and the use of benzene as the solvent render this approach unattractive for large-scale preparations. Other methods. Recently, Yamamoto et al. described regioselective iodination of electron-rich aromatic compounds, including thieno[3,2-b]thiophene, using a 1:1 mixture of N-chlorosuccinimide (NCS) and sodium iodide.269 Though the authors reported a 92% yield for the iodination of thieno[3,2-b]thiophene, when applied to our substrate this method gave a mixture of chlorinated (2.56) and iodinated (2.27) adducts of 2.3 (32:68, respectively), which we did not separate (Scheme 2.21). Given the reactivity of thieno[3,2-b]thiophene-2-carboxylate esters towards chlorination by NCS (see Chapter 4), byproduct 2.56 is reasonably being formed by electrophilic chlorination by NCS.

82 Scheme 2.21: Attempted iodination of 2.3 mediated by NCS and NaI

2.5.1

Thienothiophenes as substrates for Pd(0)-catalyzed cross-coupling in the

literature Palladium-catalyzed cross-coupling, popular variants of which include Negishi coupling (organozincs),273-278 Suzuki-Miyaura coupling (organoborons),279-281 and Stille coupling (organotins),282-284 is a workhorse reaction in modern synthetic organic chemistry in which an aryl (or alkenyl, alkynyl, or alkyl) halide and aryl (or alkenyl, alkynyl, or alkyl) metal species are conjoined. The generally accepted mechanism for this class of reaction is given below in Figure 2.9. As shown, the aryl halide R-X undergoes oxidative addition to the coordinatively unsaturated active Pd(0) catalyst A, giving Pd(II)-complex B. This undergoes transmetallation with the organometallic species R-M, giving C and eliminating M-X. Next, C undergoes reductive elimination, returning the metal to its zero oxidation state and affording the cross-coupling product R-R. Depending on the flavor of the coupling, various additives can influence the catalytic cycle as well.

83 Figure 2.9: Catalytic cycle and mechanism of Pd(0)-catalyzed cross-coupling

Thieno[3,2-b]thiophenes have been reported in aryl-aryl cross-coupling as either the organometallic component or the aryl halide, though there are relatively few examples of this chemistry compared to cross-coupling involving phenyl or other heteroaromatic partners. Suzuki-Miyaura coupling. In one example of Pd(0)-catalyzed Suzuki-Miyaura cross-coupling to a halothieno[3,2-b]thiophene, Gronowitz and coworkers285 coupled 2bromothieno[3,2-b]thiophene (2.57) to uracil-derived boronic acid 2.58 in moderate yield (57%) (Scheme 2.22). Takimiya and coworkers286 successfully coupled

84 dibromothieno[3,2-b]thiophene 2.60 to pentafluorophenylboronic acid 2.61 in similar yield (60%). A few reports of similar cross-couplings can be found in the patent literature263, 287 or the open chemical literature,246, 288, 289 including an unusual patent example263 employing palladium on charcoal as the source of Pd(0). Scheme 2.22: Literature examples of Suzuki-Miyaura coupling of bromothieno[3,2b]thiophenes

Interestingly, Wong et al.262 successfully bis-coupled dihalogenated substrate 2.63 under Suzuki-Miyaura conditions in high yield (81%) (Scheme 2.23); the reaction proceeded readily at both the C-5 and C-4 halogen positions.

85 Scheme 2.23: Literature example of Suzuki-Miyaura cross-coupling of dibrominated thieno[3,2-b]thiophene

There are also a handful of literature examples where the organoboron component is the thieno[3,2-b]thiophene derivative,247, 290-294 with reported yields ranging from 50%291 to 77%.293 Stille coupling. As depicted in Scheme 2.24, Mhaisalkar and coworkers295 found that dibromothieno[3,2-b]thiophene 2.68 readily participated in Stille coupling in high yield (81%) with stannylthiophene 2.67, generated in situ from alkylthiophene 2.66. This in situ stannane approach has found recent use in materials applications,212, 246, 296, 297 but yields can be low (35%296 in one case, 54% in another297). Examples from isolated stannanes also exist,112, 298 with yields ranging from 40%298 to 67%.112 Scheme 2.24: Literature example of Stille coupling of 2,5-dibromothieno[3,2b]thiophene

86 Negishi coupling. Recently, Knochel and coworkers241 reported the Negishi crosscoupling of tetrasubstituted thieno[3,2-b]thiophene 2.70 (Scheme 2.25). Despite the basesensitive ester functional group in 2.70, the compound was successfully magnesiated and transmetallated in situ to the organozinc derivative 2.71, which underwent Negishi coupling with two different aryl iodides in very good (75-83%) yield. The magnesiation (and hence the cross-coupling) was regioselective; one chlorine moiety of 2.70 is left intact in 2.73. Scheme 2.25: Literature example of Negishi cross-coupling of chlorothieno[3,2b]thiophene derivative 2.70

Examples of Heck reactions299 and numerous Sonagashira reactions211, 262, 300-306 of halothieno[3,2-b]thiophenes also exist in the literature but are beyond the scope of this discussion. 2.5.2 Synthesis of alkyl 5-(4-alkoxyphenyl)thieno[3,2-b]thiophene-2-carboxylate

esters via Suzuki coupling Our initial attempts at Pd(0)-catalyzed cross-coupling focused on the Negishi coupling of halogenated thieno[3,2-b]thiophene ester 2.54 and arylzinc intermediate 2.75

87 (derived from the corresponding aryl bromide 2.74) as shown below in Scheme 2.26. This approach was previously used by our group in 51% yield for the shorter chain homologues.76, 77 However, the Negishi coupling of 2.54 proved frustratingly capricious. For one set of substrates 2.75a (n = 8) and 2.54a (n = 8), we obtained a onetime 36% yield. Other attempts at the reaction failed, producing either no product or stopping at low conversions (<20%). In general, Negishi coupling has several drawbacks: the reaction is air- and moisture-sensitive, the organozinc intermediate must be generated in situ, and this generation typically requires use of butyllithium. Due to the unreliable and disappointing nature of these results, the Negishi reaction was discarded in search of a more efficient cross-coupling method. Scheme 2.26: Attempted Negishi cross-coupling of brominated thieno[3,2b]thiophene ester 2.54a and arylzinc chloride 2.75a

Recently, and especially in the last few years, Suzuki cross-coupling of thienothiophenes has gained popularity, as discussed previously. We thus chose to apply Suzuki coupling to our substrates (Scheme 2.27) and to explore variants employing boronic acid analogues such as Molanders aryltrifluoroborates307-309 and Burkes MIDA

88 boronates,310, 311 which have very recently received significant attention but have not been examined with thienothiophene systems. Interestingly, the liquid crystal community has not yet employed these last two methods. Scheme 2.27: Suzuki cross-coupling approaches to target compounds 2.1

Both potassium trifluoroborate salts (BF3Ks) and MIDA boronates operate essentially as protected boronic acids which offer several advantages over their parent class of compounds. Whereas BF3K salts and MIDA boronates exist as easily handled crystalline solids, boronic acids are often waxy and difficult to handleadditionally, their tendency to form mixtures including anhydrides complicates both their stoichiometry and spectroscopic characterization. Additionally, BF3Ks and MIDA boronates are more robust than boronic acids, many of which are unstable even under cross-coupling conditions. Both analogues function mechanistically as a slow-release source,310, 312 liberating the reactive boronic acid slowly while the bulk of the material remains protected from the reaction conditions. Theoretically, then, the same reactions

89 could be performed simply by slow addition of the boronic acid species, but this is not procedurally trivial. Aryl trifluoroborates 2.29 were prepared by treatment of the corresponding boronic acid with KHF2 in methanol and water. MIDA boronate 2.76 was synthesized by azeotropic esterification of the parent boronic acid with N-methyliminodiacetic acid311 (Scheme 2.28). In our hands, the yields for both procedures were moderate (49-64%) from 2.28. It is worth noting that we later discovered some slight modifications to trifluoroborate preparation that significantly increased yields (see Chapter 4 for discussion). Scheme 2.28: Preparation of MIDA boronate 2.76 and aryl trifluoroborate salts 2.29a-c from boronic acid 2.28

The results of our cross-coupling studies are presented below in Table 2.8. We generally found iodinated substrate 2.27 to be a superior cross-coupling substrate as compared to brominated analogue 2.54. Conventional Suzuki coupling using boronic acid 2.28 gave modest results (28-40%, entries 1 and 2 in Table 2.8). Unfortunately, the MIDA boronate approach employing 2.76 (m = 10) failed to yield any cross-coupling

90 product (entries 3 and 4 in Table 2.8) under conditions similar to those employed by Burke.310 We note that this failure may stem from the employed source of palladium: we chose readily available Pd(PPh3)4 whereas Burkes group employed Pd(OAc)2/SPhos. The success we found with readily available, inexpensive organotrifluoroborates led us to forego further attempts at MIDA boronate chemistry. To our delight, aryltrifluoroborate 2.29c gave very good yields of 2.1 (m = 10) (73-81%, entries 5 and 6 in Table 2.8) and relatively clean reactions (few, if any, byproducts were seen by crude 1H NMR). Moreover, in contrast to waxy, often difficultto-characterize boronic acids, aryltrifluoroborate substrates are easily handled, benchtopstable, and readily purified by crystallization, making them attractive substrates for Suzuki cross-coupling applications.307-309 It is worth noting that the yields for preparation of the trifluoroborates 2.29a-c (Scheme 2.28) are modest (49-64%). However, their synthesis is convenient and inexpensive, so the increasing efficiency of the subsequent cross-coupling step compensates for any preparative loss.

91 Table 2.8: Optimization of Pd(0)-catalyzed Suzuki coupling conditions

Entry X Y Br B(OH)2 1 2 3 4 5 6 I B(OH)2

Conditions Pd(PPh3)4 (10%), K2CO3, reflux (1 d), toluene/acetone/water (4:2:1)

Yield (%)a 28 40 73 81

Br B-MIDA Pd(PPh3)4 (10%), K3PO4, 60-80 C (1 d), dioxane/water (5:1) I B-MIDA Br BF3K I BF3K Pd(PPh3)4 (10%), K2CO3, reflux (1 d), toluene/acetone/water (4:2:1)
a

after chromatography

Application of this Suzuki coupling chemistry with a series of aryltrifluoroborates 2.29a-c and iodothieno[3,2-b]thiophene esters 2.27a-d, catalyzed by Pd(PPh3)4 (10 mol %) in the presence of K2CO3 in toluene/acetone/H2O (4:2:1), allowed for the preparation of our final synthetic targets 2.1. Yields for these cross-couplings are given below in Table 2.9. To our knowledge, this synthesis marks the first use of aryltrifluoroborates for cross-coupling within the liquid crystal field. As shown in Table 2.9, isolated yields for most targets were high. However, we realized late in our synthesis that some of the longer-chain products have limited solubility in diethyl ether, which we had been using as our extraction solvent. Accordingly, some yields are uncharacteristically low (i.e. 2.1f

92 and 2.1i). After this realization, we performed all extractions with dichloromethane, with encouraging results (e.g. 2.1c). The target compounds 2.1a-i were all white solids that recrystallized easily from ethyl acetate to give colorless crystals. Table 2.9: Synthesis of target 5-(4-alkoxyphenyl)thieno[3,2-b]thiophene-2carboxylate ester LCs 2.1a-i via Pd(0)-catalyzed Suzuki cross-coupling with aryltrifluoroborates

Entry Product m n Yield (%)a 8 8 80 1 2.1a 8 9 86 2 2.1b 8 10 99 3 2.1c 9 8 89 4 2.1d 9 9 81 5 2.1e 9 10 48 6 2.1f 10 8 74 7 2.1g 10 9 80 8 2.1h 10 10 68 9 2.1i 9 s-8 86 10 2.1j 10 s-8 79 10 2.1k
a

after chromatography

CHAPTER 3. SYNTHESIS OF THIENO[2,3-b]THIOPHENE-2-CARBOXYLATE ESTER-BASED LIQUID CRYSTALS 3.1 Rationale for targeting thieno[2,3-b]thiophene-2-carboxylate ester-based

liquid crystals Of the thienothiophene isomers, thieno[3,2-b]thiophene and thieno[2,3b]thiophene are the most synthetically accessible. The materials community has been more active in pursuing thieno[3,2-b]thiophene targets, with examples discussed previously in Chapter 2. Nevertheless, thieno[2,3-b]thiophenes have found some limited materials applications in electrically conductive polymers,128, 149 polymeric semiconductors,150 organic field-effect transistors (OFETs),151, 152 charge transport materials,153 bis-azo dyes,154 and nonlinear optical materials.155, 156 However, aside from three patents concerning oligothienothiophenes180, 181 and liquid crystal mixtures,159 liquid crystals built on the thieno[2,3-b]thiophene core have not been reported. We considered it worthwhile to pursue a family of 5-(4-alkoxyphenyl)thieno[2,3b]thiophene-2-carboxylate esters 3.1, isomeric analogues to novel series 3.2 (see Chapter 2), in order to (1) synthesize the first family of low-molecular weight LCs built on the thieno[2,3-b]thiophene motif, (2) explore the currently underdeveloped synthetic chemistry of thieno[2,3-b]thiophene systems, and (3) prepare materials that exhibited SmC phases at more favorable transition temperatures than their [3,2-b] analogues 3.2 (Figure 3.1). We targeted materials with long primary alkoxy tails (m = 9, 10) and both 93

94 long chain primary (n = 8, 9, 10) and branched secondary (chiral racemic 2-octyl) alkyl esters. Figure 3.1: Target 5-(4-alkoxyphenyl)thieno[2,3-b]thiophene-2-carboxylate esters 3.1 and isomeric thieno[3,2-b]thiophene analogues 3.2

3.2.1

Literature routes to thieno[2,3-b]thiophenes As with thieno[3,2-b]thiophenes, several distinct strategic approaches to

thieno[2,3-b]thiophenes have been used in the literature. Though thieno[2,3-b]thiophenes are less common in the literature than thieno[3,2-b]thiophenes, there is a greater diversity in methods for their preparation. Reviews on thienothiophene chemistry were published in the mid-1970s188 and, more recently, in the mid-2000s.90, 189, 190 Pyrolysis. As previously discussed, high-temperature approaches provide an inexpensive but inefficient and non-selective route to simple thieno[3,2-b]thiophenes, and for thieno[2,3-b]thiophenes they again fill this role (Figure 3.2). During the latter half of the 20th century, high-temperature methods for thienothiophene synthesis attracted attention, though reports of pyrolysis to afford these targets appear as early as 1916.191,
192, 313, 314

In the 1980s and 1990s, researchers (chiefly in a single Russian lab group)

applied high temperatures (in excess of 350 C) to a variety of precursors (e.g. 1,2dichloroethylene,315, 316 2-chlorothiophene,317-321 2-bromothiophene,321

95 dithienylsulfide,322, 323 thiophene-2-thiol,324 allyl 2-thienylsulfide,325 and di(prop-1enyl)sulfide321) under various gaseous atmospheres (most commonly acetylene,318, 319, 324 H2S,315-318, 322, 323 and dimethyl sulfide317, 318). The resulting yields were typically low (thieno[2,3-b]thiophene was obtained in a mixture in less than 5% yield, for instance315,
316

), with the best reported recovery nearing only 32%.319, 320 While high-temperature

methods are attractive due to the cheap starting materials used, the complex mixtures and low yields make this approach unattractive for preparatory purposes. Figure 3.2: General sketch of pyrolysis approach to thieno[2,3-b]thiophenes

The only recent (post-1995) report of a pyrolytic approach to thieno[2,3b]thiophene-like targets is Nenajdenkos326 synthesis of the first fully heterocyclic circulene, octathio[8]circulene, designated sulflower for its resemblance to a sunflower (Scheme 3.1). Excess LDA and sulfur were first used to introduce sulfur into all free positions of tetrathiophene 3.3. Intermediate 3.4 was then subjected to flash vacuum pyrolysis to afford the target circulene 3.5 in a high two-step yield (80%).

96 Scheme 3.1: Efficient pyrolytic preparation of sulflower in the literature

Approaches from carbon disulfide. Perhaps more practically useful, and most commonly used, are approaches from carbon disulfide. Structurally, carbon disulfide lends itself well to the synthesis of thieno[2,3-b]thiophenes, in which one quaternary carbon is flanked by two sulfur atoms (Figure 3.3). Typically, these methods require reactants with triple bonds (diynes) or electron-withdrawing groups. Instances of each are discussed below. Figure 3.3: Strategic disconnection of thieno[2,3-b]thiophenes to carbon disulfide

An illustration of the use of diynes comes from Otsubo et al.,327 who in 1993 prepared unfunctionalized thieno[2,3-b]thiophene 3.7 in modest yield (47%) (Scheme 3.2). Trimethylsilylpenta-1,3-diyne 3.6 (R = TMS) was added at low temperature to a solution of butyllithium and potassium tert-butoxide; to this mixture was added carbon disulfide and finally tert-butyl alcohol in the presence of HMPA. Generally, this approach has worked as a one-pot entry into a variety of 2-substituted thieno[2,3b]thiophenes 3.8 (R = alkyl, N(alkyl)2, S-alkyl) in similar yields (44-48%).328-330

97 Scheme 3.2: Literature approaches to thieno[2,3-b]thiophenes from diynes

Another general strategy using carbon disulfide is presented below in Scheme 3.3. A 1,3-dicarbonyl compound 3.9 reacts with CS2 under basic conditions to afford the intermediate ketene dithiolate 3.10. This resulting good nucleophile reacts with methylene halide 3.11 to afford the tetrasubstituted thieno[2,3-b]thiophene 3.12. Notably, 3.10 does not need to be isolated in this one-pot procedure. Scheme 3.3: General synthetic strategy for the preparation of thieno[2,3b]thiophenes from carbon disulfide and electron-withdrawing substrates

Examples of this approach are too numerous to list comprehensively. It was initially developed in the 1960s and suffered from low yields,331, 332 but methods reported since then have been more efficient and have found widespread use.154, 333-340 A few such examples are given below.

98 El-Saghier et al.336 reported good to excellent yields (78-93%) via phase-transfer catalysis (using, for instance, Bu4NBr) (EWG = CN, COMe, CO2Et, CONHPh) and carbon disulfide. Later (1999), Mashraqui et al. 333 described a lower-yielding (36-67%) but milder method utilizing anhydrous KF in dry DMF. In 2001, Comel and Kirsch339 applied an analogous approach via K2CO3 in DMF to amino-substituted targets (R1, R2 = NH2 or Me) in good yields (61-87%). Frre et al.341 prepared a series of block copolymers via synthesis of 3,4dialkoxythieno[2,3-b]thiophenes from carbon disulfide (Scheme 3.4). Dimethyl or diethyl malonates 3.12 were first reacted with base and carbon disulfide to give the dithiolate 3.13, which was immediately reacted with either methyl chloroacetate or ethyl bromoacetate and acidified to give dialkyl 3,4-dihydroxythieno[2,3b]thiophenedicarboxylates 3.14. Simple alkylation with alkyl halides under mild conditionstriethylamine and DMFafforded the dialkoxy thieno[2,3-b]thiophene esters 3.15 and 3.17 in good yield (63-71%). These esters were hydrolyzed with sodium hydroxide and decarboxylated via quinoline and Cu2CrO4 under microwave irradiation to give 3,4-dialkoxythieno[2,3-b]thiophenes 3.16 and 3.18.

99 Scheme 3.4: Literature preparation of tetrasubstituted thieno[2,3-b]thiophenes from alkyl malonates and carbon disulfide

Nitriles (e.g. 3.19) rather than dicarbonyls (3.9 and 3.12) may be employed to give 3,4-diamino-substituted thieno[2,3-b]thiophenes (Scheme 3.5). Thus, compound 3.20 (EWG = CN, CO2Me), derived from -bromocrotonic acid, reacts with malonitrile (3.19) to afford tetrasubstituted thieno[2,3-b]thiophene 3.21.337 Malononitrile has been used in several analogous syntheses of tri- and tetrasubtituted thieno[2,3-b]thiophenes.335,
339, 342-349

100 Scheme 3.5: Use of malononitrile and carbon disulfide in the synthesis of thieno[2,3b]thiophenes in the literature

The success of the reaction can vary substantially based on the structure of the substrates. Dong et al.350 reported in 2007 a one-pot synthesis of polysubstituted thieno[2,3-b]thiophenes and thiophenes from carbon disulfide and 1,3-dicarbonyl compounds under aqueous conditions (Scheme 3.6) based on El-Saghiers earlier work.336, 347 The reaction was catalyzed by the addition of tetrabutylammonium bromide (TBAB) as a phase-transfer catalyst. Interestingly, the nature of the 1,3-dicarbonyl compound affected the product obtained; for instance, the majority of substrates 3.22 employed gave sulfur-substituted thiophenes (3.24); only for two substrates (R = Me, Ph) were thieno[2,3-b]thiophenes obtained (3.25).

101 Scheme 3.6: Variability in the literature of success of thieno[2,3-b]thiophene ringbuilding based on substrate structure

The above reactions synthetic versatility is limited by the symmetrical nature of the C-2 and C-5 substituents. However, a variant on this strategy gives separate C-2 and C-5 substituents with regiocontrol. As described by Briel,351 use of only one equivalent of methylene halide 3.26 led to thiolthiophene 3.27. Reaction with an equivalent of a second methylene halide 3.28 furnished unsymmetrical 3.29 (Scheme 3.7). Kirsch et al.352 have also more recently described a similar strategy. Scheme 3.7: Literature preparation of tetrasubstituted thieno[2,3-b]thiophene with distinct C-2 and C-5 substituents

102 Sulfur insertion. The use of sulfurization reagents (commonly thionyl chloride221,
353, 354

or a combination of an organolithium and (PhSO2)2S355-358) to build the final ring is

another common strategy. Thionyl chloride allows access to common pharmaceutical building block359-364 3.33 via a Doebner-modified Knoevenegal condensation of 3-formylthiophene (3.30) and malonic acid (3.31) as reported by Wright,365 Gronowitz,353 and Castle (Scheme 3.8).354 Using these same conditions, analogous compound 3.34 can be prepared from aldehyde 3.35.221 Scheme 3.8: Literature methods for access to 3-chlorothieno[2,3-b]thiophene-2chlorocarbonyl 3.33 via thionyl chloride

Metallation and sulfurization provides another route into thieno[2,3-b]thiophenes, though this approach is used preferentially for tricyclic (or larger) derivatives rather than simpler bicyclic systems. Several comparative examples described below are given in Scheme 3.9.

103 Nenajdenko et al.355 reported a preparation of dithieno[2,3-b:3,2-d]thiophene 3.44 through two approaches. In one route, 2,3,5-tribromothiophene (3.36) was lithiated and treated at -100C with SCl2 to afford 3.42. Removal of two of the bromine substituents with zinc dust afforded 3.43, which could be cyclized via lithiation and reaction with CuCl2. Intermediate 3.43 could alternatively be prepared in similar yield via a one-pot procedure from 3.36. In the second synthetic pathway, lithiation of 3-bromothiophene (3.37) and treatment with CuCl2 gave homocoupling to afford dithiophene 3.41. Bromination to 3.38, followed by lithiation and treatment with either SCl2 at -100C or bis(phenylsulfonyl)sulfide at -70C gave the target 3.44 in low yield (31%). Indeed, the yields of both pathways were low; preparation of 3.44 from 3-bromothiophene (3.37) proceeded in a 20% three-step yield, whereas synthesis from 3.36 proceeded in a 14% three-step yield.

104 Scheme 3.9: Comparative literature examples of the use of metallation in the synthesis of thieno[2,3-b]thiophene analogue 3.44

105 Even with high dilution and low temperatures, the above authors noted significant tar formation in the conversion of 3.38 to target 3.44, which they attributed to the reactivity of the C-5 position of 3.38. More recently, an improvement in yield was made by Cheng et al.,356 who protected the C-5 positions with trimethylsilyl (TMS) groups in order to prevent side reactions at these sites. The silylated bithiophene 3.39 underwent cyclization at a higher efficiency (65% yield) than its unprotected analogue 3.38 (31% yield). As the protection and deprotection steps were both efficient (89% and 98% yields, respectively), the strategy was synthetically favorable. En route to helicenes for materials applications, Racja et al.357 employed an approach similar to that of Nenajdenko.355 From commercially available 3-bromothiophene (3.37), deprotonation with LDA and treatment with bis(phenylsulfonyl)sulfide afforded diaryl thioether 3.43. This intermediate was then lithiated with n-butyllithium, transmetallated with ZnCl2, whence homocoupling using CuCl2 gave 3.44. Interestingly, Nenajdenko and coworkers355 had attempted to produce intermediate 3.43 in this way but obtained only a 15% yield. In a separate study, Racjas synthesis of a thieno[3,2-b]thiophene helicene also utilized a strategy of lithiation and trapping with bis(phenylsulfonyl)sulfide to effect cyclization.358 Hu and coworkers utilized 3-bromobenzo[b]thiophene in the synthesis of sickle-shaped thienothiophene derivatives for materials applications.366 As mentioned, Ph(SO2)2S is used largely for the synthesis of tricyclic annelated thiophenes. However, it is also possible to prepare bicyclic thieno[2,3-b]thiophenes in this manner. Tsuchiya and coworkers367 in 1997 described the synthesis of thieno[2,3-

106 b]thiophene (3.7) (Scheme 3.10). Sonagashira coupling of 3-iodothiophene (3.45) afforded alkynyl thiophene 3.46, which itself was reduced by DIBAL and brominated with N-bromosuccinimide (NBS) to afford (Z)-3-(-bromo-trimethylsilylvinyl)thiophene 3.47. Bis-lithiation of 3.47 generated intermediate 3.48, which cyclized upon treatment with (PhSO2)2S to give the 2-trimethylsilyl thieno[2,3b]thiophene 3.49. The trimethylsilyl moiety was subsequently removed with tertbutylammonium fluoride (TBAF) to furnish 3.7. Scheme 3.10: Use of metallation and sulfurization in the literature to prepare thieno[2,3-b]thiophene

Approaches from dithiocarbamates. In the 1970s, Scheller and Petru368 developed a convenient procedure for the synthesis of thieno[2,3-b]thiophene-2-carboxylic acid 3.53 via reaction of 3-formylthiophene (3.30) with dithiocarbamate 3.50 (Scheme 3.11). Proceeding via intermediate 3.51, this furnished thiol acid 3.52 in quantitative yield. Treatment with iodine afforded the target acid 3.53 in good yield (70%). Schneller and

107 Petru subsequently decarboxylated 3.53 (85% yield), making this a convenient route to unfunctionalized thieno[2,3-b]thiophene. Scheme 3.11: Preparation of thieno[2,3-b]thiophene-2-carboxylic acid 3.53 from dithiocarbamate precursor in the literature

In another dithiocarbamate-driven approach with a roughly analogous family of compounds, the research group of Knochel recently prepared several [1]benzothieno[2,3b][1]benzothiophenes 3.58 via a cyclization with n-butyllithium in high yields (78-90%) (Scheme 3.12).369 The cyclization precursors were prepared ultimately from 3bromobenzo[b]thiophene 3.54 via palladium(0)-coupling to form biaryls 3.56, which were magnesiated at thiophene and reacted with (Me2NC(S)S)2 to afford the dithiocarbamate 3.57. Lithiation and quenching with methanol afforded target 3.58.

108 Scheme 3.12: Preparation in the literature of [1]benzothieno[2,3b][1]benzothiophenes 3.58

Aldol condensation. Aryl substitution followed by aldol condensation is a useful strategy for cyclization to afford thieno[2,3-b]thiophenes and is largely similar to the analogous strategy for thieno[3,2-b]thiophenes. For example, in 1974 Goldfarb et al.209,
370

carried 3,4-dibromothiophene 3.59 through a sequence of formylation, multiple

metallations, sulfurization, and substitution. The intermediate trisubstituted thiophene 3.60, bearing an aldehyde and an enolizable ester, undergoes an intramolecular aldol condensation in the presence of base. Subsequent hydrolysis to acid 3.61 and decarboxylation with copper furnished thieno[2,3-b]thiophene 3.62 (Scheme 3.13). Such a sequence is, along with carbon disulfide-based routes, one of the most common in the preparation of thieno[2,3-b]thiophenes. For instance, 5-phenylthieno[2,3-

109 b]thiophene-2-carboxylic acid371 3.64 and tetrasubtituted thieno[2,3-b]thiophene372 3.66 have been synthesized in this manner. Scheme 3.13: Literature preparations of thieno[2,3-b]thiophenes via an aldol condensation approach

More recently (1991), cyclization via 1,5-diazabicyclo[4.3.0]-non-5-ene (DBN) in methanol afforded methyl thieno[2,3-b]thiophene ester 3.70, an intermediate en route to 2-formylthieno[2,3-b]thiophene (3.72), from the corresponding disubstituted thiophene 3.69 in high yield (82%) (Scheme 3.14).137 Precursor 3.69 was itself prepared via lithiation and substitution of acetal-protected 3-formylthiophene 3.67. This procedure is nearly identical to a classical procedure described by Gronowitz373 (1967) except that the original paper effected the same cyclization via sodium ethoxide and acidic workup, giving a carboxylic acid rather than an ester in high (90%) yield.

110 Scheme 3.14: Aldol approaches to thieno[2,3-b]thiophenes employing bromoacetate ester precursors in the literature

Later methods employed even milder conditions (potassium carbonate at room temperature) to enact nucleophilic substitution of a halothiophene followed by aldol condensation (Scheme 3.15). For instance, Iddon and coworkers374 reacted tribrominated thiophenes 3.73 and 3.75 bearing EWGs at C-3 with ethyl thioglycolate or 2sulfanylacetamide to furnish products 3.74 and 3.76 in moderate to good yield (53-84%). Conveniently, these methods use a mercaptoacetate rather than a bromoacetate, reversing the electrophile/nucleophile roles (Figure 3.4) and obviating the need for lithiation or protection. This shortens such a route from five steps to one.

111 Scheme 3.15: Aldol approaches to thieno[2,3-b]thiophenes employing mercaptoacetate ester precursors in the literature

Figure 3.4: Comparison of mercaptoacetate and bromoacetate approaches to thieno[2,3-b]thiophenes

112 Such cyclizations can also be acid-catalyzed (Scheme 3.16). Dulenko et al.375 reacted substituted thiophene-2-thiol 3.77 with 4-chloro-3-oxobutanoate 3.78 to afford adduct 3.79. This was transformed to a thieno[2,3-b]thiophene tricyclic compound in the presence of an alkyl anhydride and HClO4 to yield 3.80. Alternatively, 2,4-disubstituted target 3.81 may apparently be accessed via cyclization with polyphosphoric acid (PPA) in chlorobenzene; this approach is buried in an obscure patent mentioned in a review.90 Scheme 3.16: Acid-catalyzed aldol approaches in the literature to thieno[2,3b]thiophenes

Miscellaneous. Several other strategies for thieno[2,3-b]thiophene preparation that are less broadly applicable and are beyond the scope of this discussion include a microwave-heating domino approach from malononitrile, elemental sulfur, and a dehydrothiophenone,376 sigmatropic rearrangements of allyl 2-thienylsulfides,377-379 a series of tandem rearrangements of an oxidized propargyl 2-thienylsulfoxide,380 palladium-381 or copper-382 catalyzed cross-coupling, and cyclization with zinc chloride.383

113 3.2.2 Synthetic plan for target materials Our synthetic approach to the target mesogens 3.1 is presented below in Scheme 3.17. Overall, the target alkyl thieno[2,3-b]thiophene LCs 3.1 were obtained in 43-46% overall yield over 4 steps from 3-bromothiophene (3.37). Scheme 3.17: Synthetic route to novel primary alkyl 5-(4-alkoxyphenyl)thieno[2,3b]thiophene-2-carboxylate-based LCs 3.1

Our materials were ultimately prepared via an efficient, reproducibly highyielding Pd(0)-catalyzed Suzuki cross-coupling approach between readily available aryltrifluoroborates 3.85 and 5-bromothieno[2,3-b]thiophene-2-carboxylate esters 3.84. The brominated esters 3.84 were themselves produced in high yield from alkyl mercaptoacetates 3.83 (the synthesis of which was discussed in Chapter 2) and dibrominated thienyl aldehyde 3.82 via a base-mediated tandem nucleophilic aromatic substitution/aldol condensation ring-closing approach. Though this synthesis closely parallels that of the isomeric thieno[3,2-b]thiophene analogues 3.2, the installation of the

114 C-5 bromine in the second step of the synthesis here resulted in a more convergent, efficient overall approach. This approach is approximately parallel to our developed thieno[3,2-b]thiophene synthesis (see Chapter 2) and, while approximately based on Iddons work374 (Scheme 3.15), marks an improvement both in facility and efficiency over previous strategies. 3.3 Preparation of alkyl 5-bromothieno[2,3-b]thiophene-2-carboxylate esters via

mild tandem nucleophilic substitution and aldol condensation Literature routes to 2,5-dibromothiophene-3-carbaldehyde (3.82). Cyclization to cross-coupling precursors 3.84 required preparation of intermediate 3.82, which has been previously prepared in the literature. It is possible to start with 3-methylthiophene 3.86 (reasonably affordable or readily available from isoprene and elemental sulfur384) which undergoes bromination followed by oxidation.385, 386 Another routemore common in recent yearsinvolves bromination with the aldehyde already in place. Though this dihalogenation is relatively inefficient with NBS387, 388 (van Walree and co-workers reported only a 36% yield after 6 additions of NBS for a total of 4.7 equivalents), the use of molecular bromine,389 especially in acidic390 (HBr) or slightly basic391 conditions (NaHCO3), gives good yields (73-75%). This requires thiophene-3-carbaldehyde 3.30, which is itself prepared from 3-bromothiophene 3.37.255, 392

115 Scheme 3.18: Literature routes to 2,5-dibromothiophene-3-carbaldehyde

Synthetic approach to 2,5-dibromothiophene-3-carbaldehyde (3.82). We opted for the most straightforward approach: preparation of 3.82 in two steps from affordable 3bromothiophene (3.37) via thiophene-3-carbaldehyde 3.30. Lithiation of 3.37 followed by quenching with N-formylpiperidine and acidification furnished thiophene-3-carbaldehyde 3.30255, 392 (Scheme 3.19).101, 102 It is worth noting that the choice of solvent was important in order to discourage halogendance (HD) rearrangement,393, 394 which in this case leads to the isomeric byproduct thiophene-2-carbaldehyde. The tendency of 3-lithiothiophenes to undergo HD rearrangements makes direct preparation of 2,5-dibromothiophene-3-carbaldehyde 3.82 by LDA-mediated deprotonation of 2,5-dibromothiophene impossible.395, 396 Two recent reviews of HD rearrangement have been published.397, 398 Lithiation of 3-bromothiophene in a 1:1 mixture of petroleum ether and THF exhibited greatly improved selectivity for C3 formylation (14:1 ratio of C-3 vs C-2 formylation products) in comparison to lithiation in THF alone (5.4:1 ratio). This 1:1 ratio of solvents is hence common in literature preparations of 3-lithiothiophene derivatives.392 The order of addition is also important, as has been noted in the literature;392 addition of n-BuLi to the 3-bromothiophene results in rearrangement whereas this can be largely circumvented by addition of a 3-

116 bromothiophene solution to a solution of n-BuLi (inverse addition). Under these conditions, a constant excess of the organometallic reagent prevents the 3-lithio species from encountering a non-lithiated thiophene and setting of the rearrangement sequence. Scheme 3.19: Formylation of 3-bromothiophene 3.37 under conditions to discourage HD rearrangement

The mechanism by which C-2 formylation occurs is given below in Figure 3.5.128 The rearrangement is fairly straightforward. When a portion of 3-bromothiophene (3.37) is converted to 3-lithiothiophene (3.87), the resulting lithio compound can react with some remaining starting material 3.37 to give the more stable 2-lithio species 3.88 and thiophene 3.89. Thiophene can interact with 3-lithiothiophene (3.87) to finally afford 3.90. As with most metallations, all the reactions here are reversible, though the equilibrium lies always heavily in favor of 2-lithio species. As depicted in Figure 3.5, the rearrangement may be catalyzed either by thiophene or 3-bromothiophene. Addition of the 3-bromothiophene to a sea of organolithium results in essentially no free 3bromothiophene 3.37 or thiophene 3.89, and so the rearrangement does not proceed. As mentioned previously, 2,5-dibromothiophene undergoes HD rearrangement (see Figure 3.6). Even at low temperatures with inverse addition, this rearrangement is so facile that very little, if any, of the 3-lithio species 3.93 is present at equilibrium. We

117 ourselves employed this reaction to our advantage for the preparation of 2,4dibromothiophene (see Chapter 4). Figure 3.5: Mechanism of HD rearrangement of 3-lithiothiophene

118 Figure 3.6: Mechanism of HD rearrangement of 2,5-dibromothiophene

Though 3.30 could be purified via Kugelrohr distillation, this procedure resulted in modest yields (49%) accompanied by the formation of a black tar upon heating. We found it was easier simply to brominate crude 3.30, affording 2,5-dibromothiophene-3carbaldehyde 3.82, which then could be easily purified by column chromatography Bromination was achieved by reaction of 3.30 with 3 equivalents each of bromine and NaHCO3 in chloroform in a procedure (also for 3.82) modified from that described by Jones391 (Scheme 3.20). In this manner, we obtained 3.82 in high yield (65%) over two steps from 3.37.

119 Scheme 3.20: Bromination of thiophene-3-carbaldehyde 3.30

With 3.82 in hand, we proceeded analogously to our ring-closing strategy described in Chapter 2. Primary and secondary alkyl 2-mercaptoacetates 3.83, the synthesis of which was described in Chapter 2, were reacted at room temperature with 2,5-dibromothiophene-3-carbaldehyde 3.82 in DMF in the presence of K2CO3 (1.3 eq.) under ambient atmosphere. Thus, synthetic intermediates 3.84 were obtained in high yield (80-84%) after chromatography (Table 3.1). Table 3.1: Preparation of 5-bromothieno[2,3-b]thiophene-2-carboxylate esters 3.84 via tandem nucleophilic aromatic substitution and aldol condensation

Entry Product R1 Yield (%)a C8H17 82 1 3.84a C9H19 84 2 3.84b C10H21 80 3 3.84c b 82 4 3.84d CH(CH3)C6H13
a

after chromatography b chiral racemic

120 Mechanistically, the preparation of compounds 3.84 is analogous to their thieno[3,2-b]thiophene analogues and is depicted in Figure 3.7. In the presence of base, the thiolate attacks the electrophilic -carbon at the C-2 position of 2,5dibromothiophene-3-carbaldehyde 3.82. Elimination of bromide sets the stage for an intramolecular aldol condensation which furnishes the second heterocyclic ring. Elimination of water from intermediate 3.99 is driven by the strong incentive for the ring to aromatize, yielding thieno[3,2-b]thiophene 3.84. Figure 3.7: Mechanism of tandem nucleophilic aromatic substitution and intramolecular aldol to give thieno[2,3-b]thiophene 3.84

It is worth noting that 1H NMR spectral evidence supports the above mechanism. In Figure 3.8, three stacked and expanded 1H NMR traces are given for the reaction

121 leading to 3.84b: Figure 3.8a is a crude spectrum after 6 hours, Figure 3.8b is a crude spectrum after 24 hours, and Figure 3.8c is a sample of 3.84b purified by chromatography. Peaks corresponding to solvents (DMF is the reaction solvent; CH2Cl2 was used for workup of a sample for 1H NMR) and the product and intermediates (tentatively assigned) are marked appropriately.

122 Figure 3.8: Stacked 1H NMR spectra from the synthesis of 3.84b

A DMF (solvent) B CH2Cl2 (solvent) C CHCl3 (solvent) 3.84b (R = C9H19)

3.99 (R = C9H19)

123 As shown above, two intermediates (diastereomers; marked E and F) are visible 6 hours into the reaction but have disappeared by 24 hours. These sets of peaks E and F correspond to the two possible diastereomers of 3.99 in the mechanism, redrawn in Figure 3.9, and are consistent with these structures. Each has one aromatic peak and two midfield aliphatic peaks clearly visible and separated from other peaks. The integrals and coupling constants are consistent with the presence of a 3:2 mixture of diastereomers (see Figure 3.10), though it is unknown whether cis or trans is in excess. The major isomer (E) displays a coupling constant of J = 4.0 Hz whereas the minor isomer (F) shows a constant of J = 5.6 Hz. Analysis of configuration of 5-membered rings by J-values is much more complicated than analysis of 6-membered rings, which follow the Karplus curve and can be determined in a straightforward manner.399 However, in general, calculations have shown that trans-protons usually exhibit larger coupling constants than cis-protons in five-membered systems.400 Thus, we tentatively propose that compound E (the major isomer) is the trans compound whereas F corresponds to the cis isomer. The presence of these peaks in the spectrum points suggests that the elimination of water from 3.99 is the rate-determining step in the overall mechanism. Figure 3.9: Two diastereomers of the mechanistic intermediate 3.99 in the tandem SNAr/aldol condensation reaction

124 Figure 3.10: Expansions of crude 1H NMR spectrum in the synthesis of 3.84b after 6 hours, showing integration of peaks

(integrals)

(integrals)

125 This marks the first preparation of long-chain alkyl 5-bromothieno[2,3b]thiophene-2-carboxylate esters. Notably, this preparation is considerably more facile than most previous syntheses of thieno[2,3-b]thiophene-2-carboxylate esters, which typically proceed in modest overall yield through lithiation, sulfurization, nucleophilic substitution, deprotection, and aldol condensation from acetal-protected 3formylthiophene.137, 373 Conveniently, the presence of two bromine atoms in precursor 3.82 obviated the need for a subsequent halogenation prior to cross-coupling; overall, the shifting of the C-5 bromination step earlier in the synthesis (relative to the synthesis of 3.2, in which the bromination occurred after ring-closing) gave a more convergent, efficient process. Despite the presence of two bromine atoms at the -position of thiophene, our ring closing reaction proceeds regioselectively. This is presumably due to the directing influence of the formyl group, which decreases electron density at the desired reaction site, enhancing its electrophilicity and its reactivity toward SNAr-type attack by the thiolate, as depicted in Figure 3.11. No evidence for reaction at the C-5 position was seen in crude 1H NMR spectra.

126 Figure 3.11: Directing influence of the aldehyde functionality in the SNAr attack of 2,5-dibromothiophene-3-carbaldehyde

It is interesting that, despite the widespread use of similar mild conditions for the construction of thieno[3,2-b]thiophene-2-carboxylate esters, the only reported analogous preparation for thieno[2,3-b]thiophenes under the same conditions is by Hawkins and coworkers,215 who synthesized the ethyl 4,5-dibromo analogue 3.74 in only modest yield (58%). The literature is actually almost entirely devoid of 5-halothieno[2,3-b]thiophene2-carboxylates, with the only other previous example being 5-chlorothieno[2,3b]thiophene-2-carboxylic acid 3.100, 176 a potential hypolipidemic agent (Figure 3.12). Figure 3.12: Representative mono- and dihalogenated thieno[2,3-b]thiophene-2carboxylates from the literature

127 3.4.1. Use of thieno[2,3-b]thiophene substrates in Pd(0)-catalyzed cross-coupling in the literature Consistent with the paucity of thieno[2,3-b]thiophene applications in the literature, very few examples of Pd(0)-catalyzed cross-coupling of thieno[2,3b]thiophenes are known. Among these handful, Suzuki-Miyaura and Stille coupling are the most popular. However, very few of the reported Pd(0)-couplings of thieno[2,3b]thiophenes are efficient; the highest reported yield is 75%. Suzuki-Miyaura coupling. Generally, Suzuki-Miyaura coupling can be performed with success with brominated thieno[2,3-b]thiophenes. Representative examples are given in Schemes 3.21 and 3.22 below. In one particularly illustrative example, 2bromothieno[2,3-b]thiophene 3.104 was coupled to uracil-derived boronic acid 3.102 under Suzuki-Miyaura conditions by Gronowitz et al.285 (Scheme 3.21). The thieno[3,2b]thiophene-based analogue 3.101 was also coupled. Essentially identical yields were obtained for thieno[2,3-b]thiophene 3.105 (60%) and thieno[3,2-b]thiophene 3.103 (57%).

128 Scheme 3.21: Comparative example of Suzuki-Miyaura cross-coupling of brominated thieno[2,3-b]thiophene and thieno[3,2-b]thiophene in the literature

In addition to Gronowitzs work,285 Wang et al.401 prepared cross-coupled derivatives of bromothieno[2,3-b]thiophene analogue 3.106 in decent yield (62-66%). Campbell and coworkers402 used a Suzuki-Miyaura approach to prepare fluorenethienothiophene electroluminescent liquid crystalline polymer 3.110. Wang and coworkers403 prepared 3.113 by Suzuki-Miyaura coupling of 3.111 to 3thiophenylboronic acid (3.112); the yield here varied depending on the nature of the terminal R group of 3.111 (R = H, 67%; R = Ph, 28%). Notably, no examples of Suzuki-Miyaura coupling of thieno[2,3-b]thiophenederived boronic acids exist.

129 Scheme 3.22: Literature examples of Suzuki-Miyaura coupling of thieno[2,3b]thiophenes

Stille coupling. Despite some successes of Suzuki-Miyaura coupling and the toxicity of stannyl compounds, Stille coupling has found acceptance as a general tactical approach for cross-coupling reactions involving bromothieno[2,3-b]thiophenes. In the preparation of a series of organic field-effect transistors, Hu and coworkers404 synthesized compounds 3.116 and 3.119 as synthetic intermediates (Scheme 3.23). Whereas 2thienylboronic acid (3.115, M = B(OH)2) would not undergo coupling to substrate 3.114, the stannyl thiophene derivative (3.115, M = SnBu3) underwent Stille coupling in 50%

130 yield. Interestingly, while phenylboronic acid (3.118) participated in Suzuki-Miyaura coupling with 3.117 (R = H) in 75% yield, no product was obtained with the aldehyde analogue (3.117, R = CHO). Scheme 3.23: Comparative influence of substrates on Suzuki-Miyaura and Stille coupling of thieno[2,3-b]thiophene analogues in the literature

Sotgiu et al.405 prepared compound 3.122 via Stille coupling in only 51% yield using tributylstannylbenzene with tetrakis(triphenylarsine)palladium(0) as the catalyst (Scheme 3.24). The authors did not discuss the reason for the use of triphenylarsine as the palladium ligand here (triphenylarsine is ~6 times more expensive than triphenylphosphine from Sigma-Aldrich), but AsPh3 complexes often exhibit improved Stille coupling reactivity relative to PPh3 complexes.406, 407 Hergu and Frre149 crosscoupled bis-brominated 3,4-dialkoxythieno[3,2-b]thiophene 3.123 (readily prepared from 3.16) under Stille conditions to yield 3.125 in only 18% yield. Contributing to the low

131 yield, however, may have been the rather low stability of compound 3.125, which decomposed unless handled under an inert atmosphere. Otsubo et al.327 themselves prepared the symmetrical dimer 3.128 from brominated thieno[2,3-b]thiophene 3.126 and trimethylstannyl derivative 3.127. Their optimized procedure afforded 3.128 in only a 13% yield. In contrast to 3.125, where decomposition of the product could account for the low yield, symmetrical compound 3.128 is quite stable and high-melting. Scheme 3.24: Literature examples of Stille coupling of brominated analogues of thieno[2,3-b]thiophenes

In stark contrast to Suzuki-Miyaura coupling (where boronate derivatives of thieno[2,3-b]thiophenes have not been employed as substrates), stannyl derivatives of

132 thieno[2,3-b]thiophene have been employed in Stille coupling. Hummelen et al.408 used this approach in the preparation of polymer 3.131 in 87% yield from 2,5bis(trimethylstannyl)thieno[2,3-b]thiophene 3.133 (Scheme 3.25). This was a 20% improvement over the preparation by the same group of the identical polymer by Suzuki methodology (67% yield) from monomer 3.129. Additionally, the Stille approach gave a polymer with a lower polydispersity (PDI; a PDI value closer to 1 indicates a polymer with a narrower range of molecular weights). Scheme 3.25: Literature example of Stille coupling of stannyl derivative of thieno[2,3-b]thiophene

To the best of our knowledge, no examples of Negishi coupling or Sonagashira coupling of thieno[2,3-b]thiophenes exist. In summary, it can be seen that there is only a limited range of literature describing Pd(0)-cross-coupling reactions of thieno[2,3-b]thiophenes, and many of these examples proceed in moderate-to-poor yields. The lack of good, efficient precedents for Pd(0)-coupling of thieno[2,3-b]thiophenes provided incentive for the study of crosscoupling of this class of compounds as part of our approach to the thieno[2,3b]thiophene-based LCs targeted in this Chapter.

133 3.4.2 Synthesis of alkyl 5-(4-alkoxyphenyl)thieno[2,3-b]thiophene-2-carboxylate

esters via Suzuki coupling Previously, we prepared alkyl 5-(4-alkoxyphenyl)thieno[3,2-b]thiophene-2carboxylate LCs 3.2 by an efficient cross-coupling step between aryl trifluoroborate salts and 5-iodothieno[3,2-b]thiophene-2-carboxylate esters (Chapter 2). We utilized the same conditions here for the cross-coupling of halogenated thieno[2,3-b]thiophene derivatives and aryl trifluoroborates (Table 3.2), with one exception: we utilized brominated thieno[2,3-b]thiophene-2-carboxylate esters 3.84 rather than their iodo counterparts. This was a matter of convenience, as the proposed preparation of the iodinated analogues would have required the inconvenient preparation (via oxidation409, 410 from 3.135, chemoselective magnesiation411, 412 of 3.136, or bromination and Sommelet oxidation413 from 3.86) or prohibitively expensive purchase ($307.60/g from Acros Organics) of 2bromothiophene-3-carbaldehyde 3.137 (Scheme 3.26). Fortunately, the brominated esters 3.84 proved excellent cross-coupling substrates, reacting uniformly in high yields (8091%) with 1.3 equivalents of an aryltrifluoroborate salt 3.85, K2CO3, and catalytic Pd(PPh3)4 (ca. 10 mol %) in a mixture of toluene, acetone, and water (4:2:1) (Table 3.2). In this way our target mesogens 3.1a-f were obtained directly. The mechanism of SuzukiMiyaura coupling and the use of aryltrifluoroborate salts therein were discussed previously in Chapter 2.

134 Scheme 3.26: Literature methods for preparation of 2-bromothiophene-3carbaldehyde 3.137

Table 3.2: Synthesis of target 5-(4-alkoxyphenyl)thieno[2,3-b]thiophene-2carboxylate ester LCs 3.1a-f via Pd(0)-catalyzed Suzuki-Miyaura cross-coupling with aryltrifluoroborates 3.85

Entry Compound m n Yield (%)a 9 9 85 1 3.1a 10 8 87 2 3.1b 10 9 86 3 3.1c 10 10 86 4 3.1d b 9 s-8 91 5 3.1e b 10 s-8 80 6 3.1f
b

after chromatography s-8 refers to racemic C6H13CH(CH3)-

CHAPTER 4. 5-ALKOXYTHIENO[3,2-b]THIOPHENE-2-CARBOXYLATE LIQUID CRYSTALS 4.1 Rationale for targeting 2-alkoxythieno[3,2-b]thiophenes Though ferroelectric smectic LC devices hold great promise for display applications, their usage has been limited by display defects rooted in the temperaturedependence of smectic layer spacing (for a discussion, see Chapter 1).9 However, several reports414-418 have described defect-free materials (so-called de Vries behavior) displaying temperature-independent layer spacing. The structural basis of this behavior is not presently clear. However, recent (yet unpublished) results in our lab have included de Vries-like materials (displaying chevron-free smectic C phases upon cooling from the SmA phase) based on sulfur-containing heterocycles including alkoxythiophenes and alkoxythiazoles. Thus, the exploration of alkoxythienothiophenes was a natural extension of this work. We chose to target compounds 4.1, 4.2, and 4.3 (Figure 4.1), of which 4.2 and 4.3 were expected to display mesogenic behavior. Figure 4.1: Targeted alkoxythieno[3,2-b]thiophene-based materials

Though several direct approaches from halothienothiophenes were tried, we ultimately found that brominated 2-alkoxythiophene materials (see Scheme 4.21) were 135

136 first required for entry into our alkoxythienothiophene targets, which necessitated development of an efficient method for the synthesis of this class of compounds. Alkoxythiophene subunits have recently attracted attention in a variety of materials applications. These subunits predominantly consist of more synthetically accessible 3-alkoxythiophenes, which have found particular application in conducting polymers419-423 for photovoltaic and nonlinear optic applications. Notable examples of 2alkoxythiophenes include liquid crystals,185, 424, 425 photochromic materials,426 components of organometallic complexes with nonlinear optical properties,427 and bioactive targets428-431; a few such examples are given in Figure 4.2. Figure 4.2: Representative compounds based on 2-alkoxythiophenes

137 4.2 Literature routes to 2-alkoxythiophenes and 2-alkoxythienothiophenes Few 2-alkoxythiophenes exist. Common literature approaches to the alkoxylation of heteroaromatic systems include Ullmann-type copper-mediated reactions and nucleophilic aromatic substitution (Scheme 4.1). Despite several examples of highyielding alkoxylation to afford C-3 thiophene ethers241, 423, 432-436 (reported yields range from 40-90% from but are typically above 80%), these approaches are not amenable to functionalization at the C-2 position of the thiophene ring. Indeed, though 2methoxylation437-449 and 2-ethoxylation438, 450-452 of halothiophenes can sometimes be efficient (yields vary substantially from 10-88% depending on the substrate but are typically modest; see 4.12,437-439 4.14,449 4.16, 438, 440 4.18,442 4.20,441 and 4.22445 in Scheme 4.1), increasing the alkyl tail length results in reduced yields,425, 453 even under aggressive conditions. Additionally, reactions of dibromothiophenes proceed with poor regioselectivity.438

138 Scheme 4.1: Examples of literature Ullmann-type and nucleophilic aromatic substitution approaches to 2-alkoxythiophenes

Efficient entry into 2-alkoxythiophenes is possible by reaction of 1,4-dicarbonyl species 4.23 with Lawessons reagent in the manner described by Seed et al. (Scheme 4.2); however, this approach requires an aryl substituent at the C-5 position of the resulting 2-alkoxythiophene.186 Other similar approaches with other sulfurization reagents suffer from low yield/reproducibility or problematic mixtures of products.454, 455

139 Scheme 4.2. Ring-closing of 1,4-dicarbonyl compounds to afford 5-aryl-2alkoxythiophenes

In contrast to good results commonly obtained with phenolic systems, Williamson etherification of hydroxythiophenes (which exist as thienones456 unless intramolecular hydrogen bonding is possible) gives mixtures of products due to unwanted reaction at the C-3 and C-5 sites (Scheme 4.3).457 These side reactions are the consequence of hydroxythiophenes existing predominantly as their thienone isomers456 (Figure 4.3). The extent of this isomerism is such that the dominant thiophen-2(5H)-one isomer is the only one detectable in solution by 1H NMR spectroscopy. Unlike phenolates, then, which undergo O-alkylation with alkyl halide electrophiles,458 the conjugate bases of hydroxythiophenes behave more like enolates; thus, frontier orbital interactions lead to Calkylation by the soft alkyl halide electrophile.

140 Scheme 4.3: Multiple products obtained upon alkylation of hydroxythiophenes by Pedersen and Lawesson

Figure 4.3: Tautomerism of 2-hydroxythiophene

Thus, the preparation of 2-alkoxythiophene building blocks bearing bromine functional handles (which we required for our ultimate route into 2alkoxythienothiophenes) is a synthetic challenge; this has been discussed in reviews by Gronowitz459 and Hrnfeldt.460 Even rarer than 2-alkoxythiophenes are 2-alkoxythienothiophenes. Only two examples of 2-alkoxythieno[3,2-b]thiophenes exist in the literature, as depicted in Scheme 4.4. In one instance, 2-bromo-3,4-dimethylthieno[3,2-b]thiophene 4.31 was methoxylated by Boldt et al.461 with sodium methoxide in the presence of copper(II) oxide and sodium iodide. The reaction took 120 hours at reflux and produced 4.32 in only 47% yield. Kobayashi and coworkers462 prepared symmetrical t-butyl ether 4.34 en route to quinone derivatives of thieno[3,2-b]thiophene. In this case, lithiation of dibromothienothiophene 4.33, transmetallation to the corresponding Grignard reagent,

141 and reaction with t-butyl perbenzoate gave 4.34 in only 42% yield. There are no examples of 2-alkoxythieno[2,3-b]thiophenes in the literature. Scheme 4.4: Literature approaches to 2-alkoxythieno[3,2-b]thiophenes

Despite a recent surge in publications related to transition metal (Pd or Cu) catalyzed aryl alkyl ether synthesis, no reports exist in the literature of these metal/ligand (N or P-based) catalyst systems being applied to the synthesis of 2-alkoxythiophenes. Some stoichiometric copper-mediated methods without N ligands have been utilized, as discussed previously. A few such systems (examples depicted in Scheme 4.5) have been used for 3-alkoxythiophene synthesis, including palladium-based systems (Buchwalds RockPhos463 ligand) and copper-based systems (ligands include 1,10-phenanthroline464,
465

, tetramethylphenanthroline241, 466, and lutidine467). In general, conditions are harsh for

these catalytic systems, which typically employ a base such as Cs2CO3 at temperatures in excess of 90-100 C, and the ligands are in most cases expensive. Interestingly,

142 Buchwalds tetramethylphenanthroline ligand was successfully applied by Knochel and coworkers241 towards 3-butoxythieno[3,2-b]thiophene, albeit in only 40% yield. Scheme 4.5: Representative literature examples of transition-metal catalyzed entry into 3-alkoxythiophenes and 3-alkoxythienothiophenes

143 4.3 Initially attempted entries into 2-alkoxythienothiophenes A variety of literature procedures were initially attempted on halothienothiophene substrates with no success, as detailed herein. Strategically, these approaches are summarized in Scheme 4.6. Scheme 4.6: Summary of discarded strategies for synthesis of alkoxythienothiophenes

Nucleophilic aromatic substitution. Our first attempted route involved nucleophilic aromatic substitution, shown strategically in Scheme 4.6a. We chose to utilize chlorinated substrate 4.42 (Scheme 4.7) to give the best chance of success in this reaction (aryl chlorides react more readily in this type of reaction than aryl bromides or

144 iodides). This required the synthesis of 4.42 as depicted in Scheme 4.7. In analogy with our developed method for bromination and iodination, we treated 4.41 with Nchlorosuccinimide (NCS) in a 1:1 mixture of glacial acetic acid and chloroform under reflux. Scheme 4.7: Chlorination of nonyl thieno[3,2-b]thiophene-2-carboxylate with NCS under acidic conditions

In contrast to the bromination of thieno[3,2-b]thiophene-2-carboxylate esters 4.41 (Chapter 2), which was regioselective even with an excess of the halogenating agent, chlorination is less trivial, as regioselectivity is much poorer. Indeed, as shown in Table 4.1, GC analysis showed the presence of di-chlorinated material 4.43 even before the starting material 4.41 had been consumed. Additional aliquots of NCS were added to drive the reaction to completion, eventually giving the composition shown in Entry 5 (Table 4.1) after workup. As 4.42 and 4.43 were not separable by column chromatography in our hands, we purified 4.42 by recrystallization from a 1:1 mixture of diethyl ether and petroleum ether. Not only was this difficult due to the low melting point of 4.42 (the material oiled out quite easily), but recovery was low. Thus, 4.42 was isolated in only 39% yield.

145 Table 4.1: Relative distribution of products in chlorination of 4.30

Entry Time (h) 17 23 46 94 106 NCS (eq.) 0.99 0.99 1.25 1.33 1.41
a

1 2a 3a 4a 5b

4.41 25% 25% 8% 3% 1%

4.42 71% 71% 87% 91% 90%

4.43 4% 4% 5% 6% 9%

Ratios by GC analysis. b Ratios by NMR analysis.

With 4.42 in hand, we examined several conditions for nucleophilic aromatic substitution. As pictured below (Scheme 4.8), neither substitution with an alkoxide in refluxing anhydrous THF or under the same conditions with CuO and KI additives (according to a precedent32 from another worker in our group for thiazole systems) produced any traces of product. When the reaction was conducted at room temperature rather than at reflux, transesterification product 4.46 was observed. At reflux, decomposition to poorly soluble byproducts was seen, with only a single spot at the baseline visible by TLC. The reaction solvent had a slight influence; when an alkoxide was reacted with 4.42 in DMF at 70 C,428 a trace set of peaks corresponding to the desired product was seen by 1H NMR. When CuO and KI additives were added, these peaks were no longer seen. Given the lack of success in any of these preliminary studies, we abandoned this approach in favor of an alternate strategy.

146 Scheme 4.8 Attempted nucleophilic aromatic substitution of 4.42

While the above method would have been convenient, it is perhaps not surprising that it failed. The ester functionality in substrate 4.42 is probably too sensitive to the harsh basic conditions employed. Additionally, the thienothiophene system is electronrich and reacts readily with electrophilesreaction with nucleophiles is hence discouraged even in the presence of the electron-withdrawing ester moiety. Moreover, copper is a common reagent for thienothiophene decarboxylation,204, 339, 468, 469 which may have presented an interfering pathway under the aggressive conditions used.

147 Copper-catalyzed coupling of aryl halides. Our second strategy is depicted in Scheme 4.6b. Copper-catalyzed routes to alkyl aryl ethers have recently been popularized by Buchwalds group, among others.241, 464-467, 470 Given the successful synthesis of 3-alkoxythiophenes with some of these systems, we chose to probe some literature procedures with our thienothiophene-based systems. In 2002, Buchwald and coworkers465 reported a simple system for alkyl aryl ether synthesis involving catalytic CuI with 1,10-phenanthroline as a ligand in the presence of Cs2CO3 in toluene. This approach was used in 2003 for an intramolecular 2-alkoxylation of a 2-bromothiophene by Hellberg and coworkers, albeit in only 29% yield after 68 hours.470 In our hands (Scheme 4.9) we obtained none of the desired product 4.45, instead obtaining the transesterification product 4.48. We also attempted the same reaction using p-cresol in toluene; no discernable ether product or transesterification product were seen, though the reaction mixture contained the protodehalogenation product nonyl thieno[3,2b]thiophene-2-carboxylate. Scheme 4.9: Attempted copper-catalyzed alkoxylation of 4.47

A few other ligands have been reported for this type of coupling (Figure 4.4), including 3,4,7,8-tetramethyl-1,10-phenanthroline,241, 471 and N,N-dimethylglycine.472

148 However, the cost of these ligands (especially 3,4,7,8-tetramethyl-1,10-phenanthroline, which reportedly works better than 1,10-phenanthroline) and the lack of any sign of product in the abovementioned reaction led us to abandon this route. Figure 4.4: Literature ligands used for copper-catalyzed alkyl aryl ether synthesis

Palladium-catalyzed coupling. Our third strategy is presented in Scheme 4.6c. Recently, there has been a surge in popularity of palladium-catalyzed coupling approaches to alkyl aryl ethers; this method, which employs biaryl phosphine ligands, has largely been developed by Buchwald.473-476 Though methods for the coupling of aryl halides to tertiary473 and secondary or primary463, 474-478 alcohols have been reported, these reactions are often complicated by ligand choice. Seemingly minor variations in ligand structure can strongly affect the success of these reactions, making the selection of ligands nontrivial476 (and potentially expensive if the wrong ligand is purchased). Additionally, these methods are primarily developed for phenyl systems. One ligand system caught our attention prior to beginning our study. Beller and coworkers478 reported in 2010 that the use of ligand 4.50 allowed for efficient C-O crosscoupling (Scheme 4.10). A variety of primary alcohols (see 4.52) were successfully coupled. A few heterocyclic examples were also shown, such as (relatively) electron-poor

149 4.53 (96% yield) and (relatively) electron-rich 4.54 (57% yield). We chose thus to probe this chemistry with our bromothienothiophene substrate. Scheme 4.10: Literature example of an adamantyl phosphine ligand in C-O coupling

Moreover, the ligand 4.50 was touted by Beller et al.478 for its ease of preparation in an efficient, essentially two-pot synthesis (Scheme 4.11). As described by the authors, 1,3-dicarbonyl compound 4.55 was carried through a three-step one-pot process of bromination to 4.56, amination to 4.57, and reaction with phenyl hydrazine to form heterocyclic system 4.58 in 70% yield. Intermediate 4.58 was subsequently deprotonated with n-butyllithium and reacted with electrophilic diadamantylphosphine chloride (Ad2PCl) to furnish adamantyl phosphine ligand 4.50 in high yield (86%).

150 Scheme 4.11: Reported preparation of adamantyl phosphine ligand 4.50

In our hands, the abovementioned synthesis was not so trivial. Our attempt at the one-pot procedure described above did not result in the described precipitation of 4.58; indeed, 1H NMR analysis of the crude mixture failed to show any 4.58. As the paper479 cited by Beller and coworkers as the precedent for 4.58 used a more concentrated reaction mixture, we tried these conditions479 as well to no avail. Finally, we opted to pursue a longer but more surefire approach (Scheme 4.12). We first brominated 4.55 with NBS in acetonitrile, giving 4.56 in 89% yield. The brominated material was reacted with pyrazole in NMP at room temperature to afford 4.57 in 91% yield. Next, this was condensed with phenylhydrazine overnight, affording 4.58 in 79% yield. Though this 64% three-step yield was not much lower than Bellers 70%, the use of three discrete steps was a source of inconvenience.

151 Scheme 4.12: Attempted synthesis of adamantyl phosphine ligand 4.38

The subsequent lithiation and P-alkylation required the use of di(1adamantyl)chlorophosphine (4.62). As this material is prohibitively expensive on a preparatory scale ($204/g, Sigma-Aldrich), it was necessary to prepare the material. This proved deceptively capricious. Adamantane (4.59) was chlorinated at reflux with phosphorus trichloride in the presence of a stoichiometric amount of aluminum chloride.480-482 Removal of the excess PCl3 and quenching with water afforded 4.60. Interestingly, the reaction was sensitive to seemingly inconsequential experimental details. When heating was performed with a heating mantle attached to a variable AC controller, a complex mixture of 5 products (by 31P NMR) was obtained as a brown solid.

152 When heated with an oil bath, the desired product was obtained in quantitative yield (99%) as a yellow solid. Reduction of 4.60 with lithium aluminum hydride next afforded 4.61 in high yield (88%) as a white solid.481, 482 The seemingly simple next step, chlorination of 4.61 by mild heating in CCl4, proved agonizingly elusive. We communicated with two groups who had reported this chemistry;483-485 they reported similar caprice and attributed it either to impurities appearing in the reduction from 4.60 to 4.61, to moisture in the CCl4, or to reaction sensitivity to the amount of solvent present. Despite addressing these issues and employing a variety of precautionary measures, including rigorous purification and drying of CCl4, freeze-pump-thaw degassing of the solvent, high-vacuum drying of 4.61, and reaction workup in an inert glovebox environment, an unpredictable mixture of products was obtained in all cases. The difficulties encountered in obtaining a sufficiently pure sample of 4.62 led us to abandon this route when a later alternate strategy proved feasible. Chan-Lam coupling of aryl trifluoroborates. Our fourth strategy is shown in Scheme 4.6d. Aryl boronic acids may be oxidatively coupled to aryl alcohols in what is known as the Chan-Lam (or Chan-Evans-Lam) coupling486 (Figure 4.5a). Developed in the late 1990s, the use of boronic acids generally does not allow construction of alkyl aryl ethers (aryl aryl ethers are readily made). However, a more recent variant by Batey and Quach487 allows for the preparation of alkyl aryl ethers via aryltrifluoroborate salts (Figure 4.5b). Both methods employ catalytic copper under an oxygen atmosphere.

153 Figure 4.5: General scheme of Chan-Lam and Batey-Quach C-O coupling

As Bateys method487 employed affordable reagents, was operationally facile, and had been employed to synthesize a 3-alkoxythiophene, we were encouraged. However, we obtained disappointing results. As depicted in Scheme 4.13, we obtained a 75% yield of 4.64 when we treated potassium 4-octyloxyphenyltrifluoroborate (4.63) with copper acetate, 1-octanol, powdered 4 molecular sieves, and a catalytic amount of DMAP in chloroform at room temperature under oxygen. In contrast, potassium thiophen-2yltrifluoroborate (4.65a) gave instead thiophene (4.66)the product of protodeboronationwith only barely detectable amounts of the desired material 4.67a. The failure of this route may not be unexpected. In the field of organocuprate chemistry, 2-thienyl ligands are often employed in mixed organocuprate reagents as nontransferable dummy ligands in conjugate addition reactions.488-490 Thus, the affinity of copper for the 2-thienyl ligand may prevent the reductive elimination which would furnish the desired product 4.67a.

154 Scheme 4.13: Attempted entry into 2-alkoxythiophene via Batey-modified ChanLam coupling

4.4.1

Synthetic plan for brominated 2-alkoxythiophenes Our final successful route into brominated 2-alkoxythiophenes is presented below

in Scheme 4.14. By modification of two recently reported procedures429, 491 in the literature, we oxidized a variety of trifluoroborate salts 4.65 using Oxone (DuPont trade name of the potassium peroxymonosulfate triple salt) to their corresponding thiophen2(5H)-ones 4.25. These compounds subsequently underwent an efficient Mitsunobu etherification with a chosen test alcohol (1-octanol) in the presence of diisopropyl azodicarboxylate (DIAD) and PPh3, yielding 4.67. In this way, we have developed the first efficient synthetic route into long-chain brominated 2-alkoxythiophenes.

155 Scheme 4.14. Synthetic route into brominated 2-alkoxythiophenes

4.4.2

Preparation of potassium thiophen-2-yltrifluoroborate precursors The synthesis of brominated thiophen-2(5H)-ones 4.25 required the preparation of

a series of brominated potassium thiophen-2-yltrifluoroborate salts 4.65. Generally, this was accomplished by treatment with an organometallic reagent to form the respective boronic acid, which was converted to the requisite aryltrifluoroborate by an established literature protocol (Scheme 4.15).492 The intermediate boronic acids 4.69 typically did not require purification but could be simply treated with KHF2 in methanol and water to furnish 4.65. Additionally, compounds 4.65 were easily purified by recrystallization from acetone and diethyl ether, making the overall procedure easy to scale up and inexpensive. Scheme 4.15: General strategy for the preparation of brominated potassium thiophen-2-yltrifluoroborates 4.65

The results of our trifluoroborate syntheses are given below in Table 4.2. As shown, when the intermediate boronic acid was not purified, the desired compounds were

156 obtained in good yields (61-70%, two steps) after recrystallization. We prepared 4.65c at a variety of scales and noted that, in our hands, better yields were seen at a larger scale (61-62% yield when employing ca. 0.5 g of starting material; 72% yield when employing ca. 2 g of starting material; 84% yield when employing ca. 10 g of starting material). In some uncommon cases, boronic acid intermediates 4.69 can contain diaryl borinic acid impurities (diaryl borinic acids are prepared under similar conditions to aryl boronic acids493). We posit that this can occur if the addition of trimethyl borate is too slow and the aryllithium in solution attacks the newly-generated electrophilic boronic ester; accordingly, rapid quenching with B(OMe)3 is recommended. Borinic acidcontaminated compounds 4.69, when carried on to the next step, contain an impurity attributable to the diaryl potassium difluoroborate (compounds of this nature have been reported494 in the literature with NMR spectral features consistent with our identified byproduct). Though this impurity can complicate NMR analysis, we found that it does not interfere with the subsequent chemistry and the material may be treated as if it were simply the desired compound. In the majority of cases, we did not observe this byproduct at all.

157 Table 4.2: Preparation of brominated potassium thiophen-2-yltrifluoroborates 4.65

Entry Product X1 X2 X3 X4 Step 1 conditions Yield (%)a H H H H 52b 1 4.65a n-BuLi, THF, -78 C Br H H H 64 2 4.65b LDA, THF, -78 C H Br H Br i-PrMgCl LiCl, THF, 0 C 61 3 4.65c 62 4 i-PrMgCl, THF, 0 C H Br Br H 63 5 4.65d LDA, THF, -78 C H H Br H 70 6 4.65e LDA, THF, 0 C
b

Two-step yield from 4.65 after recrystallization. Intermediate 4.69 was also isolated and recrystallized.

Potassium thiophen-2-yltrifluoroborate 4.65a was prepared by deprotonation of thiophene at the C-2 position with butyllithium at low temperature (dry ice/acetone) followed by treatment with trimethyl borate and hydrolysis with aqueous acid as described by Burrell et al.495 to give the boronic acid, which we recrystallized from water (78% yield). Subsequent treatment of this boronic acid with KHF2/MeOH/H2O gave the trifluoroborate 4.65a in 67% yield (52% two-step yield). Potassium 5-bromothiophen-2-yltrifluoroborate 4.65b was prepared analogously; 2-bromothiophene was deprotonated with lithium diisopropylamide (LDA) and carried through an analogous sequence, giving 4.65b in a 64% two-step yield. The intermediate boronic acid was not purified here or in any subsequent cases. We found it was best to utilize the crude boronic acid immediately; if left for a few days on the benchtop, it decomposed by protodeboronation to a brown liquid that contained primarily the starting

158 material 2-bromothiophene. The intermediate boronic acid has also been reported in the literature by lithiation with n-butyllithium of 2,5-dibromothiophene in anhydrous diethyl ether;496 however, this procedure does not report a yield. No reports using LDA for this compound have been issued, so we believe this marks a novel, easy alternative approach into this compound (2-bromothiophene is very affordable at $74 / 100g, Aldrich). The preparation of compound 4.65c required some development. Initially we sought to lithiate 2,4-dibromothiophene at the C-2 position with n-butyllithium in order to prepare this compound. However, after the addition of trimethylborate and hydrolysis, the crude reaction mixture contained the desired boronic acid and an unknown impurity in an approximately 5:1 ratio. This led to a low yield (12%) of pure 4.65c after treatment with KHF2 and recrystallization. Lawesson496 also prepared 4.65c in this way in 1957 and reported a 56% yield. However, reaction of 2,4-dibromothiophene with isopropylmagnesium chloride in THF followed by reaction with trimethylborate and hydrolysis gave the desired boronic acid product as a pure white solid which was converted to the corresponding trifluoroborate 4.65c in a 62% two-step yield. As mentioned previously, this yield was higher on scaleup. It is worth noting that, despite the presence of the two bromine atoms in 2,4-dibromothiophenes, the magnesiation was completely regioselective; no evidence of C-4 metallation was seen by 1H NMR analysis of the crude reaction product. It is known that for bromothiophenes, 2-bromothiophene undergoes magnesiation 103-104 times faster than 3-bromothiophene, which is often sluggish.497, 498 The reaction was carried out at 0 C, so the combination of high

159 reactivity, regioselectivity, and the lack of any need for cryogenic conditions make this an attractive approach. We also probed the use of Knochels TurboGrignard reagent (i-PrMgCl LiCl complex in THF), which recently gained such popularity as to be named the e-EROS Best Reagent for 2011.497, 499 The reagent is touted for its increased rate of reaction (relative to isopropylmagnesium chloride without lithium chloride in solution) and ease of use. We found no significant difference in yield when using this reagent (Table 4.2, compare entries 3 and 4); the rate of halogen-metal insertion is fast enough for our substrate that the use of the more reactive reagent does not make a noticeable difference. Given the threefold cost difference between iPrMgCl ($39/100mL of 2.0 M solution in THF) and the TurboGrignard i-PrMgCl LiCl ($78/100mL of 1.3 M solution in THF, Aldrich) we opted not to use the TurboGrignard for preparative work here. The disadvantage of compound 4.65c is that it must be prepared from 2,4dibromothiophene. As shown in Scheme 4.16, 2,4-dibromothiophene (4.68c) is expensive ($28/g through Alfa Aesar; $90/g from Acros Organics) but can be conveniently prepared. Simple treatment of inexpensive 2,5-dibromothiophene (4.68b) with LDA affords 4.68c in high yield (87-94%) by halogen dance rearrangement as described in the literature by Kano396 (halogen dance rearrangement of halothiophenes was discussed previously in Chapter 2 and is driven by the increased stability of 2lithiothiophenes compared to 3-lithiothiophenes).

160 Scheme 4.16: Preparation of 2,4-dibromothiophene by halogen dance rearrangement

Potassium 3,4-dibromothiophen-2-yltrifluoroborate 4.8d was prepared analogously to the above compounds. Metallation was accomplished by treatment of 3,4dibromothiophene with LDA to deprotonate the C-2 position. In this way, 4.8d was prepared in a 63% two-step yield. As with compound 4.8c we here opted to prepare the bromothiophene precursor, as 3,4-dibromothiophene is also prohibitively expensive ($22/g through Alfa Aesar; $30/g from Acros Organics). Fortunately, as shown in Scheme 4.17, 3,4-dibromothiophene can be conveniently prepared. Thiophene (4.68a) was first perbrominated as described in the literature,500 giving tetrabromothiophene (4.70) as large plate crystals in good yield (78%) after recrystallization from ethanol. A modified literature procedure500 was next used to reduce the C-2 and C-5 carbon-bromine bonds and afford 3,4-dibromothiophene 4.68d in high yield (86-95%). Tetrabromothiophene (4.70) was heated with zinc in a mixture of acetic acid and water in a flask equipped with a Dean-Stark trap. As the reaction progressed, the pure product 4.68d collected in the Dean-Stark trap. Our procedure as modified offers several advantages over the many reported instances of this zinc-driven reduction.500-507 The reported procedures are all somewhat lower-yielding (62-92%) than our method (86-95%) and generally require an aqueous

161 workup and vacuum distillation to isolate the product.500, 503 In contrast, with our modification (use of a Dean-Stark trap), the resulting material could be simply drained from the trap and was not only pure but also sufficiently dry to use in the subsequent LDA reaction; no aqueous workup or distillation are required. As vacuum distillation can be a lengthy procedure, we believe this simple modification to be quite useful. Scheme 4.17: Preparation of 3,4-dibromothiophene by perbromination and reduction of thiophene

Lastly, potassium 3-bromothiophen-2-yltrifluoroborate (4.65e) was prepared from 3-bromothiophene. Treatment of 3-bromothiophene (4.68e) with LDA at 0 C afforded boronic acid 4.69e with complete regioselectivity (Scheme 4.18). The temperature of addition was crucial at this stage. As shown in Scheme 4.18, deprotonation at -78 C resulted in a 59:41 mixture of the two possible -regioisomers 4.69e and 4.69c. Simply raising the deprotonation temperature to 0 C, however, gave 4.69e with no traces of 4.69c. A similar temperature dependence was noted previously by Iddon and coworkers204 in the formylation of 3-bromothiophene. This is presumably a result of thermodynamic vs. kinetic control in the deprotonation of 4.68e; at the higher temperature, equilibration to the more thermodynamically-stable 2-lithio derivative occurs. Presumably, there is not a very large kinetic preference for either the 2-lithio or 5-

162 lithio derivative of 4.68e, as evidenced by the roughly 1:1 mixture obtained at low temperatures. This LDA-mediated preparation of 4.69e marks a more convenient and efficient procedure than the previously reported preparation by Lawesson, who used nbutyllithium and 2,3-bromothiophene, giving a 51% yield.496 Scheme 4.18: Temperature-dependence of regioselectivity in the deprotonation and boronation of 3-bromothiophene

Boronic acid 4.69e was then treated as described above with KHF2 to afford 4.65e in a high two-step yield (70%). 4.4.3 Oxidation of trifluoroborate salts 4.65 with aqueous Oxone Our attention was drawn to a recent (2011) report by Molander and Cavalcanti,491 which described the oxidation of a variety of aryl, heteroaryl, alkenyl, and alkyl trifluoroborate salts R-BF3K to their corresponding R-OH adducts via simple treatment of a solution of the trifluoroborate in acetone with a solution of Oxone in water (Scheme

163 4.19). The reactions were complete in about 2 minutes and a simple silica plug filtration following workup reportedly gave the desired R-OH adducts as pure substances. Some representative heterocyclic compounds produced by this method are depicted in Scheme 4.19. Though Molander and Cavalcanti did not include any examples of oxidation of thiophen-2-yltrifluoroborates, their report was encouraging. Their targets included a furan-2(5H)-one (4.73), a thiophen-3(2H)-one (4.74), and a benzothiophen-2(3H)-one (4.75). Additionally, several examples containing aryl halogen substitutents (e.g. 4.75 and 4.77) were described. We thus reasoned that this chemistry could be easily extended to our brominated 2-thiophenyltrifluoroborate salts 4.65. Scheme 4.19: Literature preparation of alcohols from trifluoroborates by oxidation with Oxone

Oxone is the DuPont trade name of potassium peroxymonosulfate and is the most common name for the substance in use. Technically, Oxone consists of the triple salt shown in Figure 4.6, where KHSO5 is the active oxidant.

164 Figure 4.6: Structure of the Oxone triple salt

Oxone is a crystalline compound that is air-stable, inexpensive, possesses fewer safety risks than other comparable oxidants such as H2O2 or hydroxylamine (both of which are potentially explosive and are handled in solution). Indeed, Oxone is commonly used as a clarifier in swimming pools, reducing the need for chlorine.508 In the veterinary medicine community, it is marketed under the name Virusnip (Novartis) as a broad spectrum virucide, fungicide, and bactericide.509 In chemistry, Oxone has found widespread use for epoxidation, generation of dioxiranes such as DMDO, Baeyer-Villeger oxidation, oxidation of alcohols to ketones, oxidation of aldehydes to acids or nitriles, oxidation of amines to nitro compounds, preparation of oxaziridines, a coreagent in alkenyl chlorination, oxidation of thioethers to sulfones or sulfoxides, alkene and alkyne cleavage, conversion of nitromethyl groups to carboxylic acids, and oxidation of thiols to disulfides, among other uses that have been reviewed.510 In our hands, a slightly modified version of Molanders procedure worked quite well on substrates 4.65a-e. Each trifluoroborate salt 4.65 was dissolved in acetone (0.2 M) and mixed immediately with an equal volume of a 0.4 M (relative to peroxymonosulfate) aqueous solution of Oxone (2 equivalents). After a period of time (5 minutes or 60 minutes, depending on the substrate), the reaction was quenched with dilute (0.0625 M) aqueous hydrochloric acid. The product was extracted with

165 dichloromethane and filtered through a silica plug to yield 4.25 in high yield (71-79% under optimized conditions) (see Table 4.3). Table 4.3: Preparation of brominated thiophen-2(5H)-ones by oxidation of trifluoroborate salts 4.65 with Oxone

Entry Product X1 X2 X3 Oxone (eq.) Time (min) Yield (%)b H H H 2 5 71 1 4.25a Br H H 2 5 79d 2 4.25b 1 5 71d 3 H Br H 2 5 79 4 4.25c 1 60 59 5 2 60 c 6 H Br Br 2 30 63 7 4.25d 2 60 77 8 H H Br 2 60 76 9 4.25e
a

Conditions: Substrate (0.2 M in acetone), Oxone (0.4 M in H2O if 2 eq., 0.2 M if 1 eq.), rt, ambient atmosphere. b Isolated yield after silica plug filtration (petroleum ether). c Significant (>10%) presence of byproducts after silica plug filtration. d Product decomposes upon storage.

Though good yields (71-79%) were obtained for 4.25a-c after only 5 minutes of reaction, the formation of 4.25d was slower, requiring an hour to reach a comparable yield (Table 4.3, entries 7 and 8). Compound 4.65e was also allowed to react for this time. Having initially obtained a low yield (37%) upon oxidation of 4.65d under conditions comparable to the oxidation of other trifluoroborates, we varied the reaction

166 time in a series of experiments (Figure 4.7) on a small scale. We noticed that a yield plateau occurred after about 45 to 60 minutes of the reaction. Thus, we extended the reaction time for 4.65e. We also noticed a modest but noticeable boost in the yield of 4.25b or 4.25d when two equivalents of Oxone were employed (see Figure 4.7 for 4.25d and Table 4.3, entries 2 and 3 for 4.25b). As a result, other reactions were conducted using 2 equivalents of Oxone. Figure 4.7: Dependence of yield of oxidation of 3,4-dibromothiophen-2yltrifluoroborate (4.65d) on reaction time and equivalents of Oxone employed 100 90 80 70

1 eq. Oxone

2 eq. Oxone

Yield (%)

60 50 40 30 20 10 0 0 50 100 150 200 250 Time (min) Interestingly, when 4.65c was allowed to react with two equivalents of Oxone for

an hour, a significant (ca. 10%) amount of an unidentified byproduct formed, as seen by

1

H NMR (Table 4.3, Entry 6); it was thus important to limit the reaction time to 5

167 minutes for this substrate. This byproduct formation was not seen for 4.25d-e; reaction times were not extended to an hour for 4.25a-b due to concerns about their instability. If the reaction time was extended to an hour with only one equivalent of Oxone (entry 5), we did not note byproduct formation, but the yield was lower than that obtained after 5 minutes with 2 equivalents of Oxone (entry 4). Unlike 4.25a (liquid)511 and 4.25b (solid, m.p. = 23 C),512 which were somewhat air-sensitive and decomposed even upon storage in the freezer, thiophen-2(5H)-ones 4.25c-e are high-melting (ca. 80-114 C) air-stable solids that crystallize easily. Thus, the orange or red solids obtained after silica plug filtration could be purified by recrystallization from ethyl acetate and petroleum ether; however, this was not typically necessary, as the silica plug tended to give pure compounds. 4.4.4 Preparation of brominated 2-alkoxythiophenes by Mitsunobu etherification

of thiophenones 4.25 For the etherification of thiophenones 4.25, we adapted a procedure reported recently by Harris and coworkers.429 In their original report, Harris et al. prepared a variety of 2-alkoxythiophenes by the Mitsunobu etherification of thiophen-2(5H)-one (4.25a) with di-tert-butyl azodicarboxylate (DTAD) and polystyrene-supported PPh3 (Scheme 4.20). A number of compounds were prepared in this manner for the purposes of a medicinal chemistry study, and several representative compounds 4.9 and 4.79-4.84 are given in Scheme 4.20. In Harriss study, yields varied widely, though a methyl (4.79) and a cyclopentyl (4.80) ether were each produced in excellent yield (94% and 83%,

168 respectively). Though several alcohols were studied, the only thiophenone substrate employed was 4.25a. We thus reasoned that by applying an analogous procedure to our materials we had an opportunity to expand the scope of this chemistry. Scheme 4.20: Literature preparation of 2-alkoxythiophene compounds by Mitsunobu etherification

Though thiophen-2(5H)-onea heterocyclic enoneperhaps looks like an odd substrate for the Mitsunobu reaction, which is traditionally between carboxylic acids and alcohols,513 alkyl aryl ethers can also be produced under Mitsunobu conditions; several reviews on this topic have been published.514-518 It has been noted empirically that Mitsunobu reactions involving DIAD or DEAD reagents simply require a nucleophilic component (carboxylic acid, phenol, etc.) with a pKa below 11 (other azodicarboxylate

169 analogues are available for less acidic reagents).518 Compound 4.25 was determined by Harris and coworkers to have a pKa of 10.63 and is thus a suitable substrate.429 The question remained, however, whether brominated analogues 4.25b-e would be sufficiently acidic to participate in this reaction. Fortunately, they were; electronegative C-3 and C-4 halogens stabilize the C-5 anion of 4.25c-e through the inductive effect. The results of our Mitsunobu study are presented in Table 4.4. Our procedure was modified from that originally reported by Harris: we utilized diisopropyl azodicarboxylate (DIAD) rather than DTAD due to the differences in cost ($600 / 100 g vs. $87 / 100 g, respectively, from Aldrich). Harris et al. employed polystyrene-supported PPh3; we simply used PPh3 and noted no difficulty in the separation of residual PPh3 and its oxide byproduct from the desired product. After adding 1-octanol to a previously generated solution of PPh3 and DIAD at slightly lowered temperature (-10 C), thiophenone 4.25 was added. After an hour, the reaction mixture was simply concentrated and eluted through a silica plug with petroleum ether. The major byproducts of the reaction are either polar, colored azo compounds or triphenylphosphine oxide, which is insoluble in petroleum ether; these were hence removed by the plug. The resulting crude products 4.67 could easily be further purified by column chromatography to afford airstable, colorless liquids. Using this method, we prepared 4.67a and 4.67c-e in excellent yields (80-86%). This reaction was amenable to scaleup (ca. 2 g quantities of 4.67c and 4.67d were prepared) with no change in yield.

170 Table 4.4: Mitsunobu etherification of brominated thiophen-2(5H)-ones 4.25a-ea

Entry Product X1 X2 X3 Time Yield (hr) (%)b H H H 1 83 1 4.67a Br H H 24 d 2 4.67b H Br H 1 86c 3 4.67c H Br Br 1 87c 4 4.67d H H Br 1 80 5 4.67e
a

Conditions: (a) PPh3 (3 eq.), CH2Cl2, -10C, (b) DIAD (3 eq.), -10C, 10 min., (c) 1-octanol (3 eq.), 10C, 30 min., (d) substrate 4.25 (1 eq.), -10Crt, 1 hr, unless otherwise stated. b Isolated yield after column chromatography (petroleum ether). c Average of two experiments ( 1-2%). d Only trace amounts of product detected by 1H NMR.

Our optimized reaction conditions involved stirring the reaction mixture for one hour before filtration. We also tried extending the reaction time to 24 hours; no significant change in yield was seen, and so a one-hour reaction time was chosen for convenience. Interestingly, thiophenone 4.25b did not react to give 4.67b. When 4.25b was subjected to the above conditions, a mixture was obtained that surprisingly contained dioctyl ether (4.85) as a major product (Figure 4.8). Other minor components of the reaction mixture included 2-octyloxythiophene (4.67a), 1-octanol, and the starting material 4.25b. The desired product 4.67b was seen only as a trace peak by 1H NMR. The formation of dioctyl ether 4.85 is admittedly unusual under these conditions, but dialkyl ethers have been reported from Mitsunobu reactions.516

171 Figure 4.8: Byproducts obtained from the Mitsunobu reaction of 4.25b

Why, then, is target 4.67b so elusive by this method? Some mechanistic speculation is appropriate. As previously mentioned, Mitsunobu reactions involving DIAD or DEAD reagents require an acid or aryl alcohol with a pKa below 11,518 and thiophen-2(5H)-one 4.25a was reported to have a pKa of 10.63.429 Thus, the zwitterionic intermediate in the mechanism (Figure 4.9) can successfully deprotonate the thiophenone (step B), allowing the eventual formation of the product. The presence of C-3 and C-4 bromine atoms on the thiophenone enhances the C-5 acidity by the inductive effect for 3and 4-substituted thiophenones 4.25c-e. However, a C-5 bromine is bulky, lying geminal to the proton in question. Bromine is relatively electronegative and so it should slightly increase the C-5 protons acidity, so the steric bulk is likely responsible for the poor reactivity of 4.25b.

172 Figure 4.9: Likely mechanism of 2-alkoxythiophene formation

4.5.1

Synthesis of 5-alkoxythieno[3,2-b]thiophene-2-carboxylate-based mesogens

4.2 and 4.3 With an efficient synthetic route to brominated 2-alkoxythiophenes 4.67 in hand, we turned our attention to our original target family of compounds: 5-alkoxythieno[3,2b]thiophene-2-carboxylates. As mentioned previously, no previous strategies existed for the synthesis of this family, or indeed for 2-alkoxythieno[3,2-b]thiophenes in general. Our synthetic route into these materials is depicted in Scheme 4.21. We first deprotonated 4-bromo-2-octyloxythiophene (4.67c) with LDA in THF at 0 C. Treatment with N-formylpiperidine and subsequent hydrolysis gave aldehyde 4.86. This aldehyde could be purified by column chromatography (88-92% yield) or simply used crude in the next step. When 4.86 was treated with potassium carbonate and nonyl mercaptoacetate (4.87) in DMF at room temperature under ambient atmosphere for several days in

173 analogy with our chemistry described in Chapter 2, thieno[3,2-b]thiophene 4.44 was obtained. When 4.86 was used in crude form rather than in pure form, a 52% two-step yield was obtained. However, when 4.86 was purified before use, this two-step yield jumped to 70-76%. Interestingly, when crude 4.86 was used the reaction was complete in three days. In contrast, when a pure sample of 4.86 was used, even after 6 days, mild heating had to be applied (ca. 65 C) with an additional portion of mercaptoacetate 4.87 added to drive the sluggish reaction to completion, ultimately giving 4.44 in 79% yield. In a separate trial, we used an excess (ca. 20%) of 4.86 and heated the reaction at 65 C under argon for the entire time. Under these conditions, the reaction was complete in 14 hours and a very good yield was obtained (86%). Significantly, the preparation of 4.44 marks the first long-chain alkyl alkoxythieno[3,2-b]thiophene to be reported. Our approach is extremely attractive for several reasons: (1) mercaptoacetates 4.87 with various chain lengths can be easily prepared (or sometimes purchased) as described in Chapter 2, (2) the alkoxy moiety on the thieno[3,2-b]thiophene can be changed by using different alcohols at the Mitsunobu stage of the preparation, (3) the ring-closing reaction from 4.86 to 4.44 is not only highyielding but is also easy to perform, requiring no special equipment, low temperatures, or exclusion of water. Thus, a variety of homologues of 4.44 should be easily synthetically accessible.

174 Scheme 4.21: Preparation of of 2-alkoxythieno[3,2-b]thiophene-2-carboxylate-based mesogens 4.2 and 4.3

As an interesting side note, alkoxythienothiophene 4.44, despite having a significantly longer length and somewhat higher molecular weight than bromo- and iodothienothiophene analogues 4.47 and 4.91, displays a melting point range (38.6-40.2 C) intermediate between the two halo compounds (33.2-34.5 C for bromo compound 4.47; 46.1-47.1 C for iodo compound 4.91) (Figure 4.10). Figure 4.10: Comparison of melting points of 5-subsituted nonyl thieno[3,2b]thiophene-2-carboxylate esters

175 With novel material 4.44 in hand, we sought to demonstrate its usefulness by the construction of the first alkoxythieno[3,2-b]thiophene-based liquid crystals. As alkoxythiophenes have attracted major attention in the materials community, we saw this as an opportunity to probe this potentially fruitful class of materials. As shown above in Scheme 4.21, we first hydrolyzed the ester 4.44 to give 5octyloxythieno[3,2-b]thiophene-2-carboxylic acid 4.88 in 80% yield; it is our intent to optimize this reaction in the future. Acid 4.88 was subjected to Steglich esterification conditions519 to furnish target mesogens 4.2 and 4.3 in good to excellent yields (77% and 99%, respectively. 4.5.2 Preparation of phenyl analogue of 2-alkoxythieno[3,2-b]thiophene-2-

carboxylate-based mesogen 4.23 We desired to compare our thienothiophene-based mesogens to phenyl analogues (see Chapter 5) (Figure 4.11), as phenyl compounds comprise the bulk of the LC literature. Though analogue 4.93 has been prepared and characterized in several studies,187, 520-525 compound 4.92 has not been reported. We thus sought to prepare this target. Figure 4.11: Phenyl analogues 4.92 and 4.93 of alkoxythienothiophene LCs

176 The synthesis of 4.92 (Scheme 4.22) was straightforward and facile. From commercially available 4-hydroxybenzoic acid (4.94), 4-octyloxybenzoic acid (4.95) was produced in modest yield (62%) by reflux of 4.94 with 1-bromooctane in the presence of sodium hydroxide in a 2:1 ethanol:water mixture.526 The pure product was obtained after simple filtration and washing of the resulting precipitate. From precursor 4.94, octyl 4hydroxybenzoate (4.89) was also obtained in 71% after chromatography by simple Fischer esterification with 1-octanol in refluxing toluene with azeotropic removal of water using a Dean-Stark trap; this is a marked improvement in yield from comparable syntheses of 4.89 in the literature (for instance, Owen et al.527 employed H2SO4 as the acid catalyst and achieved only a 58% yield). With intermediates 4.89 and 4.95 in hand, we prepared phenyl target 4.92 via a simple DCC/DMAP Steglich esterification, delivering the target in 75% yield after recrystallization.

177 Scheme 4.22: Synthesis of phenyl analogue of 4.3

CHAPTER 5. TRANSITION TEMPERATURES AND COMPARISON OF TARGETED LIQUID CRYSTALS 5.1.1 Transition temperatures of primary alkyl 5-(4-alkoxyphenyl)thieno[3,2-

b]thiophene-2-carboxylate esters Transition temperatures of the novel series of 5-(4-alkoxyphenyl)thieno[3,2b]thiophene-2-carboxylate esters 5.1a-i are presented in Table 5.1 and plotted in Figures 5.1a-f. Also in Table 5.1 are given transition temperatures of a previously reported,77 shorter-chain series of 5-(4-alkoxyphenyl)thieno[3,2-b]thiophene-2-carboxylate esters 5.2a-d for comparison. All of the targeted thieno[3,2-b]thiophene esters 5.1a-i display tilted smectic C (SmC) and orthogonal smectic A (SmA) mesophases. The shorter-chain compounds 5.1a-d display monotropic SmC phases whereas the higher chain homologues 5.1e-i are enantiotropic.

178

179 Table 5.1: Transition temperatures of novel 5-(4-alkoxyphenyl)thieno[3,2b]thiophene-2-carboxylate esters 5.1a-i and previously reported esters 5.2a-da,b

Compound 5.1a 5.1b 5.1c 5.1d 5.1e 5.1f 5.1g 5.1h 5.1i 5.2a 5.2b 5.2c 5.3d

m 8

n 8 9 10

Cryst 143.7 (51.97) 138.0 (40.48) 134.4 (35.84) 144.5 (20.16) 140.7 (31.90) 135.9 (42.33) 141.5 (71.12) 142.3 (75.39) 139.7 (78.97) 140.1 (48.64) 136.3 (47.51) 133.5 (41.89) 131.1 (53.38)
a

SmC ( ( ( ( 140.7) (0.4978) 137.2) (0.4215) 132.2) (0.1038) 144.4) (0.7552) 141.5 (0.5418) 137.0 (0.6135) 144.7 (0.9773) 142.6 (0.4637) 139.9

SmA 153.1 (19.04) 150.3 (16.00) 147.5 (14.56) 149.8 (6.721) 147.1 (10.48) 144.3 (14.38) 147.5 (23.94) 145.6 (21.32) 142.9 (24.96) 164.2 (22.85) 160.7 (24.13) 157.2 (22.31) 154.2 (29.54)

Iso Liq Recryst. 132.9 130.5 128.0 137.6 131.1 128.5 133.4 134.1 132.6 132.5 129.8 128.2 127.8

8 9 10

10

8 9 10

6 6 6 6

7 8 9 10

( ) indicates a monotropic transition numbers italicized below transition temperatures refer to enthalpies (J g -1)

180 Figure 5.1: Comparative plot of transition temperatures of primary alkyl ester thieno[3,2-b]thiophene LCs 5.1a-i, ordered to show temperature trends based on (a) ester alkyl chain length n and (b) alkoxy alkyl chain length m, (c) clearing point, (d) melting point, (e) SmC width (cooling), and (f) SmA width (cooling)a,b

(a) ordered by n 120 5.1a 5.1b 5.1c Compound 5.1d 5.1e 5.1f 5.1g

130

Temperature ( C) 140 150

160
m = 8, n = 8
n=9 n = 10 m = 9, n = 8 n=9 n = 10 m = 10, n = 8 n=9 n = 10

Cryst SmC SmA IsoLiq

5.1h 5.1i
a

Top bar for each compound represents heating; lower bar represents cooling. b =m+n

181 (b) ordered by m 120 130 5.1a 5.1d 5.1g Compound 5.1b 5.1e Temperature ( C) 140 150

160
m = 8, n = 8 m=9 m = 10 m = 8, n = 9

Cryst

SmC
SmA IsoLiq

m=9
m = 10 m = 8, n = 10 m=9 m = 10

5.1h 5.1c 5.1f 5.1i

(c) ordered by clearing point Temperature ( C) 120 130 140 150 5.1a 5.1b 5.1d Compound 5.1g 5.1c 5.1e

160
m = 8, n = 8 = 16 m = 8, n = 9 = 17 m = 9, n = 8 = 17 m = 10, n = 8 = 18 m = 8, n = 10 = 18 m = 9, n = 9 = 18 m = 10, n = 9 = 19 m = 9, n = 10 = 19 m = 10, n = 10 = 20

Cryst SmC SmA IsoLiq

5.1h 5.1f 5.1i

a

Top bar for each compound represents heating; lower bar represents cooling. b =m+n

182 (d) ordered by melting point 120 130 5.1c 5.1f 5.1b Compound 5.1i 5.1e 5.1g Temperature ( C) 140 150

160
m = 8, n = 10 = 18 m = 9, n = 10 = 19 m = 8, n = 9 = 17 m = 10, n = 10 = 20 m = 9, n = 9 = 18 m = 10, n = 8 = 18 m = 10, n = 9 = 19 m = 8, n = 8 = 16 m = 9, n = 8 = 17

Cryst

SmC
SmA IsoLiq

5.1h 5.1a 5.1d

(e) ordered by SmC width (cooling) 120 130 5.1c

Temperature ( C) 140 150 160

m = 8, n = 10 = 18 m = 9, n = 8 = 17 m = 8, n = 9 = 17 m = 10, n = 10 = 20 m = 8, n = 8 = 16 m = 10, n = 9 = 19 m = 9, n = 10 = 19 m = 9, n = 9 = 18 m = 10, n = 8 = 18

5.1d
5.1b Compound 5.1i 5.1a

Cryst SmC SmA IsoLiq

5.1h 5.1f 5.1e 5.1g

a

Top bar for each compound represents heating; lower bar represents cooling. b =m+n

183 (f) ordered by SmA width (cooling) 120 5.1g 5.1i 130

Temperature ( C)
140 150 160
m = 10, n = 8 = 18 m = 10, n = 10 = 20 m = 10, n = 9 = 19 m = 9, n = 8 = 17 m = 9, n = 9 = 18 m = 9, n = 10 = 19 m = 8, n = 8 = 16 m = 8, n = 9 = 17 m = 8, n = 10 = 18

5.1h
Compound 5.1d 5.1e 5.1f 5.1a

Cryst

SmC
SmA IsoLiq

5.1b
5.1c
a

Top bar for each compound represents heating; lower bar represents cooling. b =m+n

5.1.2

Comparison of primary alkyl thieno[3,2-b]thiophene ester-based liquid

crystals Varying the length of alkyl tails was seen to have only a small effect on the transition temperatures of target LCs 5.1a-i. The melting points of 5.1a-i generally decrease with an increase in the ester alkyl chain length (n). For 5.1a, 5.1b, and 5.1c (m = 8), increasing n from 8 to 9 results in a 5.7 C decrease in the melting point, followed by a further 3.6 C decrease from n = 9 to n = 10. For 5.1d, 5.1e, and 5.1f (m = 9), the melting point decreases by 3.8 C from n = 8 to n = 9 and a further 4.8 C from n = 9 to n = 10. For 5.1g, 5.1h, and 5.1i (m = 10) the

184 melting point increases by 0.8 C as n increases from 8 to 9. From n = 9 to n = 10, the melting point decreases by 2.6 C. Increasing the alkoxy chain length (m) of 5.1a-i typically results in an increase in the melting point. For 5.1a, 5.1d, and 5.1g (n = 8), a 0.8 C increase is seen from m = 8 to m = 9, but a 3.0 C decrease is seen from m = 9 to m = 10. For 5.1b, 5.1e, and 5.1h (n = 9), the melting point increases by 2.7 C from m = 8 to m = 9 and by 1.6 C from m = 9 to m = 10. For 5.1c, 5.1f, and 5.1i (n = 10), the melting point increases by 1.5 C from m = 8 to m = 9 and by 3.8 C from m = 9 to m = 10. When the ester chain length (n) increases, the temperature of the SmC-SmA transition decreases for all mesogens 5.1a-i, as illustrated in Figure 5.1a. For 5.1a, 5.1b, and 5.1c (m = 8), increasing n from 8 to 9 results in a decrease in this temperature by 3.5 C; a further 5.0 C decrease is seen from n = 9 to n = 10. For 5.1d, 5.1e, and 5.1f (m = 9), a 2.9 C decrease is seen from n = 8 to n = 9 and a 4.5 C decrease is seen from n = 9 to n = 10. For 5.1g, 5.1h, and 5.1i (m = 10), the transition temperature drops by 2.1 C from n = 8 to n = 9 and drops by 2.7 C from n = 9 to n = 10. Increasing the alkoxy chain length (m) leads to an increase in the temperature of the SmC-SmA transition for all targets 5.1a-i, as seen in Figure 5.1b. For 5.1a, 5.1d, and 5.1g (n = 8), the SmC-SmA transition temperature increases by 3.7 C from m = 8 to m = 9 and by 0.3 C from m = 9 to m = 10. For 5.1b, 5.1e, and 5.1h (n = 9), the SmC-SmA transition temperature increases by 4.3 C from m = 8 to m = 9 and by 1.1 C from m = 9

185 to m = 10. For 5.1c, 5.1f, and 5.1i (n = 10), the SmC-SmA transition temperature increases by 4.8 C from m = 8 to m = 9 and by 2.9 C from m = 9 to m = 10. For all target mesogens 5.1a-i, increasing the ester chain length (n) leads to a decrease of the clearing point (SmA-Iso Liq). This can be plainly seen in Figure 5.1a. For 5.1a, 5.1b, and 5.1c (m = 8), the clearing point decreases by 2.8 C from n = 8 to n = 9 and decreases a further 2.8 C from n = 9 to n = 10. For 5.1d, 5.1e, and 5.1f (m = 9), the clearing point decreases by 2.7 C from n = 8 to n = 9 and by 2.8 from n = 9 to n = 10. For 5.1g, 5.1h, and 5.1i (m = 10), a 1.9 C decrease in the clearing point is seen from n = 8 to n = 9 and a 2.7 C decrease is seen from n = 9 to n = 10. The clearing points of 5.1a-i also decrease as the alkoxy chain (m) is lengthened. This trend can be seen clearly in Figure 5.1b. For 5.1a, 5.1d, and 5.1g (n = 8), the clearing point decreases by 3.3 C from m = 8 to m = 9 and by 2.3 C from m = 9 to m = 10. For 5.1b, 5.1e, and 5.1h (n = 9), a decrease of 3.2 C is seen from m = 8 to m = 9 and 1.5 C from m = 9 to m = 10. For 5.1c, 5.1f, and 5.1i (n = 10), a decrease of 3.2 C is seen from m = 8 to m = 9 and 1.4 C from m = 9 to m = 10. Both Figure 5.1c and Figure 5.1d illustrate an interesting generalization. Any increase in the molecular weight (as measured by the sum of m and n) results in a decrease of the clearing point (Figure 5.1c) for mesogens 5.1a-i. No such trend is seen for the melting point (Figure 5.1d). No discernable trend is seen for the width of the SmC phase (Figure 5.1e); however, the SmA phase tends to widen with a decreasing alkoxy chain length m (Figure 5.1f).

186 5.1.3 Comparison of primary alkyl thieno[3,2-b]thiophene ester-based liquid

crystals to analogous mesogens in the literature The transition temperatures of a previously reported analogous series of 5-(4alkoxyphenyl)thieno[3,2-b]thiophene-2-carboxylate esters 5.2a-d are given in Table 5.1. Below, the transition temperatures for the phenyl analogues 5.3a-i synthesized previously by Gray and Goodby7, 528 are presented in Table 5.2. Our target series 5.1a-i benefits from exhibiting the smectic C mesophase not seen in our previously reported shorter-chain analogues 5.2a-d. Consistent with our observation that increasing the alkoxy chain length (m) acts to decrease the clearing point, the series 5.1a-i (m = 8, 9, 10) display lower clearing points than 5.2a-d (m = 6). We also observed that increasing m usually increases the melting point; consistently, 5.1a-i (m = 8, 9, 10) have higher melting points than their analogues of equal n 5.2b-d. Mesogens 5.1a-i display higher transition temperatures than their phenyl analogues 5.3a-i synthesized by Gray and Goodby7, 528 (Table 5.2). The melting points of 5.1a-c are 64 C, 59 C, and 59 C higher than those of their phenyl analogues 5.3a-c, respectively. The melting points of 5.1d-f are 59 C, 55 C, and 52 C higher than those of the phenyl analogues 5.3d-5.3f. Likewise, the melting points of 5.1g-i are 59 C, 56 C, and 55 C higher than those of their phenyl analogues 5.3g-i, respectively. The SmCSmA transitions occur 78 C, 91 C, and 86 C higher, respectively, in 5.1g-i than in 5.3g-i (virtual transition temperatures were recorded for a number of the phenyl analogues reported by Gray and Goodby). Also, the clearing points of 5.1a-c are 73 C,

187 70 C, and 69 C higher, respectively, than those of 5.3a-c. The clearing point of 5.1g is 70 C higher than the clearing point of 5.3g. For 5.1h-i and 5.3h-i a direct comparison of the clearing point is not possible as the phenyl analogues are non-mesogenic. Table 5.2: Transition temperatures of phenyl analogues 5.3a-i synthesized by Gray and Goodbya,b

Compound m n Cryst SmC SmA Iso Liq Recryst. 8 8 80 80) 80 5.3a ( 8 9 79 80 73 5.3b 8 10 75 79 69 5.3c c 9 8 86 36] ] 84 5.3d [ [ c 9 9 86 ] 84 5.3e [ c 9 10 84 ] 82 5.3f [ 10 8 83 67] 78 78 5.3g [ c 10 9 86 52] ] 83 5.3h [ [ c 10 10 85 54] ] 83 5.3i [ [
( ) indicates a monotropic transition b [ ] indicates a virtual transition c virtual transition temperature not determined
a

5.2.1

Transition temperatures of primary alkyl 5-(4-alkoxyphenyl)thieno[2,3-

b]thiophene-2-carboxylate esters Transition temperatures of the novel target 5-(4-alkoxyphenyl)thieno[2,3b]thiophene-2-carboxylate ester LCs 5.4a-d are presented in Table 5.3 and plotted in Figure 5.2. All of the targeted primary thieno[2,3-b]thiophene esters 5.4a-d display tilted smectic C (SmC) and orthogonal smectic A (SmA) mesophases; both the SmC and SmA mesophases are enantiotropic.

188 Table 5.3: Transition temperatures of novel 5-(4-alkoxyphenyl)thieno[2,3b]thiophene-2-carboxylate esters 5.4a-da

Compound

Cryst

SmC

SmA

Iso Liq

Recryst.

5.4a 5.4b 5.4c 5.4d

9 10 10

9 8 9

10 10
a

119.0 (58.39) 115.5 (53.68) 120.7 (80.15) 119.7 (37.91)

141.0 (0.7816) 143.8 c 142.2 (0.7478)b 139.4 c

145.1 (20.95) 145.6 (29.18) 143.6 (28.50)b 141.0 (13.51)

114.8 113.2 116.7 115.2

numbers italicized below transition temperatures refer to enthalpies (J g -1) b enthalpies obtained at a cooling rate of 1 C min-1 c peak overlaps with SmA-IsoLiq transition on the DSC trace

Figure 5.2: Plot of transition temperatures of novel primary thieno[2,3-b]thiophene ester LCs 5.4a-da Temperature ( C) 120 130 140

100 5.4a Compound 5.4b 5.4c 5.4d

110

150

160 Cryst SmC

SmA
IsoLiq

Top bar for each compound represents heating; lower bar represents cooling.

189 5.2.2 Comparison of primary alkyl thieno[2,3-b]thiophene ester-based liquid

crystals 5.4a-d In general, the primary alkyl thieno[2,3-b]thiophene-2-carboxylate esters 5.4a-d display little variation in their transition temperatures. No general trend in the melting point is discernable across 5.4b-d as the ester chain length is increased. However, the SmC-SmA transition decreases in temperature with increasing chain length; increasing n from 8 to 9 results in a 1.6 C drop followed by a further 2.8 C drop from n = 9 to n = 10. A similar trend is seen for the clearing point, which decreases by 2.0 C from n = 8 to n = 9 and a further 2.6 C as n increases from 9 to 10. This is consistent with the corresponding trends for thieno[3,2-b]thiophene analogues 5.1a-d. 5.2.3 Comparison of primary alkyl thieno[2,3-b]thiophene ester-based liquid

crystals to analogous mesogens in the literature Transition temperatures of some phenyl analogues 5.3g-i and 5.3e reported by Goodby and Gray7, 528 are given in Table 5.2 and are reproduced below for convenience in Table 5.4. All transition temperatures for the novel thieno[2,3-b]thiophenes 5.4a-d are higher than their phenyl analogues. The melting points of 5.4a-d are uniformly higher (33-35 C) than those of 5.3e and 5.3g-i (5.4a is 33 C higher than 5.3e; 5.4b is 33 C higher than 5.3g; 5.4c is 35 C higher than 5.3h; and 5.4d is 35 C higher than 5.3i). The SmC-SmA transition is much higher for 5.4b-d than for 5.3g-i (77 C higher for 5.4b compared to 5.3g; 90 C higher for 5.4c compared to 5.3h; 85 C higher for 5.4d

190 compared to 5.3i); the SmC-SmA transition cannot be compared between 5.4a and 5.3e because 5.3e was not mesogenic and a virtual transition temperature was not determined. Additionally, the clearing point of 5.4b is 68 C higher than its analogue 5.3g. Table 5.4: Transition temperatures of phenyl analogues 5.3e and 5.3g-i synthesized by Gray and Goodbya

Compound m n Cryst SmC SmA Iso Liq Recryst. c 9 9 86 ] 84 5.3e [ 10 8 83 67] 78 78 5.3g [ c 10 9 86 52] ] 83 5.3h [ [ c 10 10 85 54] ] 83 5.3i [ [
c

[ ] indicates a virtual transition virtual transition temperature not determined

5.3.1

Transition temperatures of secondary alkyl 5-(4-alkoxyphenyl)thieno[3,2-b]-

and [2,3-b]-thiophene-2-carboxylate esters The transition temperatures of the secondary alkyl 5-(4alkoxyphenyl)thienothiophene-2-carboxylate esters 5.5e-f and 5.6a-b are given below in Table 5.5. The secondary alkyl thieno[2,3-b]thiophene-2-carboxylate esters 5.5e-f and secondary alkyl thieno[3,2-b]thiophene-2-carboxylate ester 5.6a display only monotropic SmA and SmC phases; compound 5.6b exhibits only a monotropic SmA phase with very narrow supercooling.

191 Table 5.5: Transition temperatures of novel octan-2-yl 5-(4alkoxyphenyl)thienothiophene-2-carboxylate esters 5.5e-f and 5.6a-ba,b

Compound

TTP

Cryst

SmC

SmA

Iso Liq

5.5e 5.5f 5.6ac 5.6bd

a

9 10 9 10

101.4 (21.21) 97.4 (27.07) 100.0 e 97.6 e

( ( (

89.8 (1.553) 90.1 (1.698)f 86.9 e ( e

92.9) (12.43) 92.1) (15.50)f 90.2) (49.94) 89.9) (55.74)

( ) indicates a monotropic transition numbers italicized below transition temperatures refer to enthalpies (J g -1) c Transition temperatures for 5.6a were recorded at a cooling rate of 10 C min-1. At a cooling rate of 5 C min-1 crystallization occurred in tandem with the formation of the SmA phase and the SmC phase was not visible. Cooling at 10 C min-1 revealed the SmC phase but again crystallization occurred at the same time as the phase formed d SmA and recrystallization were seen in tandem for 5.6b. The SmC phase was not observed even at a cooling rate of 15 C min-1. e All three transitions overlap on the DSC trace. f Enthalpies obtained at a cooling rate of 1 C min-1.
b

5.3.2

Comparison of primary and secondary thieno[3,2-b]- and [2,3-b]thiophene

ester- based liquid crystals The secondary alkyl esters 5.5e-f and 5.6a-b display only monotropic mesophases. There is remarkably little difference in the transition temperatures of octan2-yl thieno[2,3-b]thiophene esters 5.5e-f and their [3,2-b] analogues 5.6a-b (5.5e has a 1.4 C higher melting point, 2.9 C higher SmA-SmC transition, and 2.7 C higher clearing point than 5.6a; 5.5f has a 0.2 C lower melting point and 2.2 C higher clearing

192 point than 5.6b). This stands in contrast to the 20-26 C difference in melting points observed between primary [2,3-b] esters 5.4a-d and isomeric [3,2-b] LCs 5.1e and 5.1g-i. The melting point of the [2,3-b] LCs 5.5e and 5.5f decreases by 4.0 C from m = 9 to m = 10 as the alkoxy chain length is varied. The increase in alkoxy chain length is also accompanied by an increase of 0.3 C in the SmC-SmA transition and a decrease of 0.8 C in the clearing point. For the [3,2-b] LCs 5.6a and 5.6b, there is a corresponding decrease of the melting point by 2.4 C from m = 9 to m = 10 as well as a 0.3 C decrease in the clearing point. The clearing points of [2,3-b] targets 5.4a-d show almost negligible decreases when compared to the previously reported [3,2-b] analogues 5.1e, 5.1g, 5.1h, and 5.1i (2.0 C lower for 5.4a compared to 5.1e; 1.9 C lower for 5.4b compared to 5.1g; 2.0 C lower for 5.4c compared to 5.1h; 1.9 C lower for 5.4d compared to 5.1i). The SmCSmA transitions for 5.4a-d are also barely lower than the corresponding SmC-SmA transitions of 5.1e, 5.1g, 5.1h, and 5.1i (0.5 C lower for 5.4a compared to 5.1e; 0.9 C lower for 5.4b compared to 5.1g; 0.4 C lower for 5.4c compared to 5.1h; 0.5 C lower for 5.4d compared to 5.1i). However, the melting points of 5.4a-d are markedly lower than their [3,2-b] analogues (21.7 C lower for 5.4a compared to 5.1e; 26.0 C lower for 5.4b compared to 5.1g; 21.6 C lower for 5.4c compared to 5.1h; 20.0 C lower for 5.4d compared to 5.1i). As illustrated in Figure 5.3, the combined effect of barely changing the clearing point while appreciably dropping the melting point is a significant broadening of the desired SmC mesophase. Whereas the SmC phase was exhibited across

193 a range of only 0.2 C to 3.2 C for thieno[3,2-b]thiophenes 5.1e, 5.1g, 5.1h, and 5.1i, the isomeric LCs 5.4a-d display this phase over a much wider 19.7 C to 28.3 C range (22.0 C for 5.4a; 28.3 C for 5.4b; 21.5 C for 5.4c; 19.7 C for 5.4d). Figure 5.3: Comparative plot of transition temperatures (upon heating) for isomeric thieno[2,3-b]thiophene and thieno[3,2-b]thiophene-based LCs

100 5.4a 5.4b Compound 5.4c 5.4d 5.1e 5.1g 5.1h 5.1i

110

Temperature ( C) 120 130

140

150 Cryst SmC SmA IsoLiq

The similarity in clearing points and mesophase transitions between [2,3-b] isomers 5.4 and [3,2-b] isomers 5.1 despite a marked difference in melting points is worth comment. This is interesting in light of the different electronic properties of the two systems. The conjugation of these systems is shown via resonance structures in Figure 5.4. Whereas thieno[3,2-b]thiophenes 5.1 possess extended conjugation from the

194 electron-donating alkoxy moiety to the electron-withdrawing carboxylate group (Figure 5.4a), the thieno[2,3-b]thiophenes 5.4 lack this extended conjugation, which is interrupted by the central double bond of the thieno[2,3-b]thiophene moiety (Figure 5.4b). Figure 5.4: Resonance contributors to differences in conjugation between (a) thieno[3,2-b]thiophene 5.1 and (b) thieno[2,3-b]thiophene 5.4

As expected based on these resonance arguments (Figure 5.4), the UV-vis spectra of two isomeric analogues 5.1 and 5.4 differ markedly (Figure 5.5) according to the extent of -conjugation. Whereas the fully-conjugated thieno[3,2-b]thiophene system 5.1 displays a broad peak with a maximum absorption max = 350 nm, a blue shift of 67 nm is observed for the more poorly conjugated thieno[2,3-b]thiophene system 5.4 (max = 283 nm). This is a more accentuated difference than that seen between the parent heterocyclic

195 cores themselves, which differ in absorption maxima by 37-55 nm (thieno[3,2b]thiophene max = 260, 269, 278 nm529; thieno[2,3-b]thiophene max = 223 nm327, 339). Figure 5.5: UV-vis spectra of thieno[3,2-b]thiophene-based mesogen 5.1e and thieno[2,3-b]thiophene-based mesogen 5.4aa

1.2 5.1e 5.1 1 5.4a 5.4

Absorbance (a.u.)

0.8 0.6 0.4 0.2 0

200

250

300 350 Wavelength (nm)

400

450

Spectra normalized to maximum absorbance of 5.4a based on extinction coefficients

196 Interestingly, both 5.1e and 5.4a exhibit a fluorescence emission maximum at 422 nm in chloroform, resulting in a much larger Stokes shift for 5.4a (139 nm) compared to 5.1e (72 nm) (Figure 5.6). Both of the above families of LCs displayed fluorescent emissions around 422 nm (blue light). While we did not measure the quantum yield of the fluorescence, it may be worth investigating, as fluorescent LC systems have attracted some attention in the literature with the potential for brighterand cheaperdisplays.530,
531

One recent report contained compounds with similar absorption and emission maxima

to ours.532

197 Figure 5.6: Absorption and emission spectra of (a) thieno[3,2-b]thiophene-based mesogen 5.1e and (b) thieno[2,3-b]thiophene-based mesogen 5.4aa
(a) 1.2

Absorbance 1 Intensity (a.u.) 0.8 0.6 0.4 0.2 0 240 290 340 390 440 Wavelength (nm) 490 540 Emission

(b) 1.2

Absorbance Emission

1 Intensity (a.u.) 0.8 0.6 0.4

0.2
0 240 290 340 390 440 Wavelength (nm) 490 540

Spectra normalized to maximum absorbance.

198 The difference in conjugation of these two systems has previously been exploited in the design of materials; for instance, thieno[2,3-b]thiophene moieties have been incorporated into polythiophenes150 to decrease overall system conjugation and hence protect the materials against oxidative p-type doping by oxygen in air (systems with longer effective -conjugation lengths often see reduced performance in air due to increased susceptibility to this doping). The decreased -conjugation of 5.4 reduces the polarizability of the system. Typically, this should lead to a decrease in the transition temperatures of the mesogens. However, it is our conjecture that the strong lateral dipole imparted by the thieno[2,3b]thiophene moiety (absent in the thieno[3,2-b]thiophene system), as shown in Figure 5.7, counteracts the effect of the reduced conjugation length by increasing dipole-dipole interactions of 5.4 within the LC phases. Thus, the similar transition temperatures of the isomeric forms may be the result of the subtle interplay of polarizability and polarity. Despite the lower symmetry of the thieno[2,3-b]thiophene core compared to thieno[3,2b]thiophene, it is unlikely that the improved mesophase properties of 5.4 result from a bend imparted by this core; previously reported83-85 X-ray structures of 2,5-disubstituted thieno[2,3-b]thiophenes show the C-2 and C-5 substituents to possess high colinearity (the bend across the system is 9.5 , 11.8 , and 15.5 for each of those structures previously reported).

199 Figure 5.7: Dipoles in thieno[2,3-b]thiophene and thieno[3,2-b]thiophene cores

5.3.3

Comparison of secondary thieno[3,2-b]- and [2,3-b]thiophene ester-based

liquid crystals to analogous mesogens in the literature The observed drops in melting and clearing points for 5.5e-f and 5.6a-b compared to their primary alkyl analogues are consistent with the phenyl analogues 5.7a-f of Goodby and Gray7, 528 (temperatures for these analogues are given in Table 5.6). Upon going from primary to secondary alkyl esters 5.7 (Table 5.6), similar decreases were seen in the melting point (26 C lower for 5.7a compared to 5.7d; 23 C lower for 5.7b compared to 5.7e; 18 C lower for 5.7c compared to 5.7f) and the SmC-Iso Liq transition (53 C lower for 5.7a compared to 5.7d; 43 C lower for 5.7b than 5.7e; 43 C lower for 5.7c than 5.7f). Indeed, the temperature-lowering effect of branching of the alkyl chain (which decreases the mesogens length-to-breadth ratio and thus decreases transition temperatures) is well-known within the liquid crystal field and has been described previously.45, 51, 52 As with the primary series, secondary [2,3-b] and [3,2-b] esters 5.5e-f and 5.6a-b display higher transition temperatures than their phenyl analogues. Direction comparisons of mesophase morphologies are not possible, as the nonyloxy- and decyloxyphenyl variants of 5.8 have not been reported.

200 Table 5.6: Transition temperatures of phenyl analogues 5.7a-f synthesized by Gray and Goodbya,b

Compound m n Cryst SmC SmA Iso Liq Recryst. 8 s-7 61 30] 50 5.7a [ 8 s-8 57 37] 41 5.7b [ 8 s-9 61 37] 44 5.7c [ 8 7 87 46] 83) 79 5.7d [ ( 8 8 80 80) 80 5.7e ( 8 9 79 80 73 5.7f
a

( ) indicates a monotropic transition b [ ] indicates a virtual transition

201 5.4.1 Transition temperatures of novel 2-alkoxythieno[3,2-b]thiophene-2-

carboxylate mesogens 5.8 and 5.10 The transition temperature of novel 2-alkoxythieno[3,2-b]thiophene-2carboxylate-based mesogens 5.8 and 5.10 are given along with the transition temperatures of their phenyl analogues 5.9 (newly reported) and 5.11 (reported187 previously) in Table 5.7. Table 5.7: Transition temperatures of of novel 2-alkoxythieno[3,2-b]thiophene-2carboxylate-based mesogens 5.8 and 5.10 and phenyl analogues 5.9 and 5.11a

Compound 5.8 5.9 5.10 5.11

Cryst I 76.4 (52.66) 60.5 (59.70) 54.6 (6.36) 63.3

b

Cryst II 88.6 (58.64)

SmC 109.7 (0.447) 73.8

b

SmA 116.2 (12.72) 69.2 (11.94) 116.8 (1.068)

N 123.8 (5.154) 93.1

b

Iso Liq

Recryst. 56.8 37.8 61.6 51.2

b

numbers italicized below transition temperatures refer to enthalpies (J g ) b enthalpies not listed in the literature

-1

Compound 5.8 exhibits only an enantiotropic SmA mesophase, which is present from 76.4 C to 116.2 C (39.8 C range). Compound 5.8 also exhibits substantial supercooling, recrystallizing at 56.8 C on cooling, a full 19.6 C below its melting point.

202 Compound 5.10 exhibits enantiotropic SmC, SmA, and nematic (N) mesophases. Additionally, a crystal-crystal transition is seen for this material. The SmC phase is seen from 88.6 C to 109.7 C (21.1 C wide), the SmA mesophase is seen from 109.7 C to 116.8 C (7.1 C wide), and the N phases is seen from 116.8 C to 123.8 C (7.0 C wide). Notably, compound 5.10 is, to the best of our knowledge, the first low molecular weight thienothiophene-based LC to exhibit the nematic phase. 5.4.2 Comparison of novel 2-alkoxythieno[3,2-b]thiophene-2-carboxylate-based

liquid crystals 5.8 and 5.10 to analogous mesogens in the literature A very striking comparison can be made between ester 5.8 and its newly-prepared phenyl analog 5.9 as visualized in Figure 5.8. As is consistent with every other phenyl/thienothiophene analog comparison, the thienothiophene-based mesogen 5.8 melts at a higher temperature than 5.9 (15.9 C higher). The difference in clearing points is much more accentuated; whereas phenyl compound 5.9 clears at 69.2 C (giving an 8.7 C wide SmA phase), alkoxythienothiophene 5.8 displays a clearing point of 116.2 Ca temperature 47.0 C higher than 5.9 and resulting in a SmA phase with a width of 39.8 C. Both 5.8 and its phenyl analog 5.9 exhibit substantial supercooling; 5.8 recrystallizes 19.6 C below its melting point whereas 5.9 recrystallizes 22.7 C below its melting point.

203 Figure 5.8: Comparative plot of transition temperatures (upon heating) for alkoxythieno[3,2-b]thiophene-based LC 5.8 and phenyl analogue 5.9 Temperature ( C) 60 80 100

0 Compound 5.8

20

40

120

140 Cryst SmA

5.9

Iso Liq

Despite the absence of a SmC mesophase, the properties of 5.8 are promising. This is aptly illustrated by comparison with our first family of low-molecular weight thieno[3,2-b]thiophene-based LCs, 5.1 (Figure 5.9). While they do not have the exact same molecular weight, 5.8 and 5.1a have identical tail lengths. However, there is a radical difference in transition temperatures. Compound 5.1a melts only at 143.7 C and clears at 153.1 Ca high temperature mesophase with a width of only 9.4 C. Compound 5.1a does display an SmC phase, but this is monotropic only. In contrast, alkoxythienothiophene LC 5.8 melts at 76.4 Ca full 67.3 C lower than its analogue! Though 5.8 does not exhibit a SmC phase, its SmA phase is much wider than for 5.1a: 76.4 C to 116.2 C (39.8 C range). This marks the widest mesophase seen for any of

204 our thienothiophene-based liquid crystals as well as the lowest melting point for any of our thienothiophene-based liquid crystals; previous families 5.1, 5.4, 5.6, and 5.7 have melted at temperatures in excess of 97 C. It is likely possible to produce homologues of 5.8 that will exhibit the SmC mesophase by merely changing the alkyl tail lengths. For instance, compare 5.2d (enantiotropic SmA phase only), 5.1c (enantiotropic SmA and monotropic SmC phase), 5.1f (enantiotropic SmA and SmC phase), and 5.1i (enantiotropic SmA and SmC phase), which differ only in alkyl tail lengths of a few carbons. Figure 5.9: Comparative plot of transition temperatures (upon heating) for two families of thieno[3,2-b]thiophene-based LCs, 5.8 and 5.1 Temperature ( C) 80 100 120

40 Compound 5.8

60

140

160 Cryst SmA

5.1a

Iso Liq

Compound 5.10 exhibits promising mesophase properties compared to thieno[3,2b]thiophene precedents 5.1 and phenyl analogue 5.11 (Figure 5.10 and Figure 5.11). As

205 illustrated below, 5.10 exhibits a greater diversity of phases (SmC, SmA, N) than 5.1 (SmC, SmA). The presence of the nematic phasea first for this class of materialsis beneficial, as it allows for easier alignment of the resulting LCs. Additionally, 5.10 melts at a significantly lower temperature (88.6 C) than 5.1a (143.7 C), a 55.1 C decrease. While the width of the SmC phase is similar (21.1 C range) to that seen for thieno[2,3b]thiophene-based LCs 5.4a-d (19.7 C - 28.3 C range), 5.10 has a markedly lower melting point than these materials (5.4a-d melt at 115.5 C - 120.7 C, a range of 26.9 C 32.1 C higher than for novel material 5.10). This makes 5.10 the lowest-melting material reported herein to exhibit the SmC mesophase. Figure 5.10: Comparison of two families of thieno[3,2-b]thiophene-based LCs, 5.10 and 5.1 Temperature ( C) 90 110 130

50 Compound 5.10 5.1a

70

150

170

Cryst SmC SmA N IsoLiq

206 Target LC 5.10 also exhibits a greater diversity of phases than phenyl analogue 5.11 (Figure 5.11). Whereas 5.11 only exhibits SmC and N mesophases, thienothiophene LC 5.10 also shows a SmA phase. Alkoxythienothiophene 5.10 displays a higher melting point than 5.11 (25.3 C higher) but also a higher clearing point (30.7 C higher). Moreoever, the SmC phase is much wider (21.1 C wide for 5.10; 10.5 C wide for 5.11), though the nematic mesophase is narrower (7.0 C wide for 5.10; 19.3 C wide for 5.11). Figure 5.11: Comparative plot of transition temperatures (upon heating) for alkoxythieno[3,2-b]thiophene-based LC 5.10 and phenyl analogue 5.11 Temperature ( C) 90 110

50 Compound 5.10 5.11

70

130

150 Cryst SmC SmA N IsoLiq

From the comparison of alkoxythienothiophene LCs 5.8 and 5.10 to their phenyl analogues (Figure 5.8 and Figure 5.11), it can be seen that the thienothiophene materials tend to have higher melting points and clearing points than their phenyl analogues. However, the difference in clearing points is larger than the difference in melting points, giving rise to wider mesophases in thienothiophene-based materials.

CHAPTER 6. CONCLUSIONS 6.1.1 Conclusions regarding alkyl 5-(4-alkoxyphenyl)thienothiophene-2-

carboxylate liquid crystals We have reported the synthesis and mesophase evaluation of three families of alkyl 5-(4-alkoxyphenyl)thienothiophene-2-carboxylate-based LCs. Primary alkyl 5-(4-alkoxyphenyl)thieno[3,2-b]thiophene-2-carboxylate mesogens were synthesized in good yield via a route that was considerably more efficient than the one previously used for their homologous precedents.77 The target LCs all exhibited SmA phases as well as either monotropic (for some shorter-chain compounds) or enantiotropic SmC phases. Primary alkyl 5-(4-alkoxyphenyl)thieno[2,3-b]thiophene-2-carboxylate mesogens were also synthesized by a slightly more efficient pathway similar to that used for their [3,2-b] analogs. The mercaptoacetate-driven ring-closing strategy we employed marked the most efficient preparation of thieno[2,3-b]thiophene-2-carboxylate systems to date, being much shorter and higher yielding than the classical approaches in the literature. The target LCs had markedly lower melting points and only slightly lower clearing points than their [3,2-b] analogs, resulting in a significant broadening of the SmC mesophase. All the target mesogens displayed enantiotropic SmA and SmC phases. We hypothesized that the subtle interplay of reduced polarizability and increased lateral dipole was responsible for this broadening.

207

208 Both of the above families of LCs displayed fluorescent emissions around 422 nm (blue light). While we did not measure the quantum yield of the fluorescence, it may be worth investigating, as fluorescent LC systems have attracted some attention in the literature with the potential for brighterand cheaperdisplays.530, 531 One recent report contained low-molecular-weight LCs based on a benzothiophene and 1,3,4-oxadiazole core with similar absorption and emission maxima to ours.532 We also prepared chiral racemic octan-2-yl analogs of the above two families, as chirality is necessary for ferroelectric behavior. Disappointingly, the chiral racemic compounds were only weakly mesogenic in comparison to their primary alkyl analogs. For both the secondary [2,3-b] and [3,2-b] compounds, only monotropic SmA and SmC phases were seen over a narrow range, and one compound did not display the SmC mesophase. Interestingly, the inclusion of the secondary ester destroyed any influence of the annulations patterns of the cores on the mesophase properties. This may be due to the close proximity of the branched octan-2-yl group to the thienothiophene units, which could disrupt molecular packing due to steric interactions. 6.1.2 Future directions for alkyl 5-(4-alkoxyphenyl)thienothiophene-based LCs The inclusion of a fluorine lateral substituent often has a pronounced effect on the melting point of calamitic LCs; this has been shown empirically in our group. Fluorothiazoles,32 for instance, display depressed transition temperatures and melting points compared to their non-fluorinated analogs. Thus, it may be worth incorporating a fluorine moiety to reach more favorable transition temperatures with these materials.

209 6.2 Conclusions regarding the synthesis of brominated 2-alkoxythiophenes We have developed a general method for the synthesis of 3- and 4-brominated 2alkoxythiophenes. Unlike any previous routes, our strategy allowed regioselective preparation of 2-alkoxythiophenes with no competing C-3 alkylation or etherification at the bromine sites. This method involves the mild room-temperature oxidation by Oxone of various brominated potassium thiophen-2-yltrifluoroborate salts to a series of thienones which participate in a Mitsunobu reaction to afford the desired 2-alkoxythiophenes in good twostep yield. The methods are easily performed, requiring no chromatography until the last step, and are easily scaled, as cryogenic conditions are not required and reaction times are brief. Bromine substituents at the C-3 and C-4 positions are tolerated quite well; interestingly, the Mitsunobu reaction completely fails in the presence of a C-5 bromine. This strategy is thus complementary to our groups previously developed ringclosing of -ketoesters via Lawessons reagent,424, 533 which is useful for C-5 substituted 2-alkoxythiophenes. 6.2.2 Future directions for brominated 2-alkoxythiophenes Several avenues of exploration suggest themselves. The selective lithiation of brominated alkoxythiophenes, for example, could be used as a route into fluorothiophenes, which our group has previously established to be promising ring systems to be incorporated into materials. The scope of the reaction should be probed to see what other substituents, besides bromine, might be compatible with our

210 oxidation/Mitsunobu etherification approach to 2-alkoxythiophenes. Also, if the sites of cross-coupling and lithiation on 3,4-dibromo-2-alkoxythiophene can be controlled, then orthogonal substitution would be possible, allowing a diverse array of tetrasubstituted thiophenes to be prepared with selectivity by only a handful of methods in a diversityoriented synthesis approach recently popularized by Schreiber.534 This should be a reasonable goal, as the alkoxy group should serve as an ortho-director for lithiation under the proper conditions. The two C-Br moieties in 3,4-dibromo-2-octyloxythiophene differ in electron-richness, as the alkoxy group donates electrons into only one by resonance. Thus, the less electron-rich site should be more amenable to oxidative addition and, under the right conditions, should participate in regioselective cross-coupling. Regioselective cross-coupling of polybrominated thiophenes has attracted recent attention.535-537 6.3 Conclusions regarding alkyl 5-alkoxythieno[3,2-b]thiophene-2-carboxylate

liquid crystals We have elaborated 4-bromo-2-octyloxythiophene into the first long-chain 5alkoxythieno[3,2-b]thiophene-2-carboxylate (which is also the first long-chain alkyl 2alkoxythienothiophene) in very good yield in analogy with our previously developed chemistry for thieno[3,2-b]thiophene-2-carboxylate esters. This operationally facile route marks the first strategic entry into 2-alkoxythienothiophenes as well as the first preparation of 5-alkoxythieno[3,2-b]thiophene-2-carboxylate esters. The length of the alkyl tail can be modified at either end of these esters quite easily. These compounds have strong potential as building blocks for materials applications.

211 As proof of concept, we carried the ester through hydrolysis to its carboxylic acid derivative followed by Steglich esterification to afford two novel LCs 4.2 (m = n = 8) and 4.3 (m = n = 8) (Figure 6.1). These compounds mark not only the first LC applications of 2-alkoxythienothiophenes, but indeed the first materials applications of this family of compounds. The presence of a strong electron donor conjugated to a system which has found recent popular application in electronic materials suggests that these compounds could find widespread use. Notably, our targets 4.2 (m = n = 8) and 4.3 (m = n = 8) exhibited promising properties. Ether 4.2 displayed the SmC, SmA, and N phases, making it the first monomeric thienothiophene-based LC to do so. Ester 4.3 exhibited the SmA phase over a wider temperature range than our previously reported thienothiophene-based LCs. Both compounds melted below 90 C, making them the lowest-melting thienothiophene-based LCs we have prepared to date. 6.3.2 Future directions for alkoxythienothiophenes Our initial exploration into alkoxythienothiophene LCs suggests several avenues of exploration. The synthesis of a complete family of analogues of 4.2 (m, n = 8-12) should be completed; these targets should display SmC, SmA, and N phases, will provide a range of transition temperatures. A chiral analog (n = s-8) should also be prepared and characterized in order to probe the potential of these materials as ferroelectric LCs. Also, it stands to reason that we can possibly reach lower melting points and wider mesophases

212 via a thieno[2,3-b]thiophene analogue, as this change in the thienothiophene core in alkyl 5-(4-alkoxyphenyl)thienothiophene-5-carboxylate LCs had this effect. Compound 4.3 (m = n = 8) displayed only a SmA mesophase, but the low transition temperatures (nearly 70 C lower than its alkyl 5-(4-alkoxyphenyl)thieno[3,2b]thiophene-5-carboxylate analog) are encouraging. As we noted previously that the SmC phase could be induced by changing alkyl tail lengths, access to a complete homologous family 4.3 (m, n = 8-12) would be useful. Alternatively, since we noted significant stabilization of the SmC phase with thieno[2,3-b]thiophenes compared to their thieno[3,2-b]thiophene analogs, the synthesis of the thieno[2,3-b]thiophene analogues may provide compounds with near-room temperature mesophase properties, especially if fluorination of the heteroaryl core is accomplished.

CHAPTER 7. EXPERIMENTAL 7.1 General considerations Confirmation of the structures of intermediates and products was obtained by 1H (400 MHz, Bruker Avance 400 MHz spectrometer using Topspin version 2.1 software; tetramethylsilane was used as internal standard) and 13C (100 MHz) NMR spectroscopy in CDCl3, unless another solvent is stated. Elemental analyses were performed by Atlantic Microlab Inc. (Norcross, GA). High-resolution mass spectrometry was performed by The Ohio State University. The progress of reactions was monitored using either TLC [aluminium backed silica gel plates (Sigma-Aldrich, 200 m layer thickness, 2-25 m particle size and 60 pore size)], GC [Shimadzu gas chromatograph GC-14A with a Restek RTX-5 capillary column (30 m) and Shimadzu class VP software] or NMR. Column chromatography was performed with Fisher Scientific silica gel (Davisil,17 0-400 Mesh, Type 60A, Grade 1740). Transition temperatures of the final products were measured using a Mettler FP82HT hot-stage and FP90 control unit in conjunction with a Leica Laborlux 12PolS polarizing microscope. All transitions are quoted from microscopic measurements and are given upon cooling at a rate of 5 C per minute. For all compounds melting points were recorded using the same apparatus at a heating rate of 5 C per minute. The control unit was calibrated with three Merck standards (benzophenone, benzoic acid and 213

214 caffeine). Differential scanning calorimetry (DSC) measurements were performed using a TA Instruments Differential Scanning Calorimeter 2920 at heating and cooling rates of 5 C per minute (unless otherwise stated) with indium as internal standard. UV/Vis spectra were recorded on an Agilent 8453 spectrophotometer using UVVis ChemStation software. Samples were dissolved in HPLC-grade chloroform (Fisher Scientific) in a Spectrosil quartz cuvette (1/Q/10, path length 10 mm, Starna Cells, Inc.). Fluorescence spectra were recorded on a Carey Eclipse fluorescence spectrometer using Carey Eclipse software. Samples were dissolved in HPLC-grade chloroform (Fisher Scientific) in a Spectrosil quartz fluorescence cuvette (101-QS, path length 10 mm, Hellma GmbH). Anhydrous tetrahydrofuran (THF) was dried by distillation over sodium metal and benzophenone under argon or nitrogen. Anhydrous diisopropylamine was distilled from calcium hydride under nitrogen. Anhydrous dichloromethane was distilled from CaH2 under argon. Ethyl acetate and petroleum ether were distilled prior to use. Nbromosuccinimide was recrystallized from water and dried under high vacuum (P2O5) prior to use. All other reagents were used without further purification. All densities are quoted at 25 C unless otherwise stated. Compounds 7.4,204 7.8a-c,538, 539 7.9a-c,538 7.13,255 7.14,391 7.17a,495 7.18a,492, 540 7.19,396, 535 7.21,500, 502, 503 7.22a,541, 542, 7.22b,512 7.22e,543, 544 7.27,545, 546 7.28,527 7.30,547,
548

7.33,549 7.34,549 7.35,549 7.36,480-482 and 7.37,481 have been previously reported and

215 characterized. Compounds 7.2a,231 7.2e,550 7.2g,551 7.17b,496, 552 7.17c,496 7.17e,503 and 7.22c543 have been reported but complete analytical data were not supplied. 7.2 Numbering of compounds Several of the compounds presented in this experimental chapter have been mentioned previously in multiple chapters. For the sake of ease of reference, Table 7.1 below contains a list of each compound in this section and its equivalent number(s) in previous chapters. Compounds are given in this chapter with their chemical structures immediately preceding their preparative procedures.

216 Table 7.1: Comparison of compound numbering across chaptersa Ch. 1 Ch. 2 2.25 2.26 2.2 2.24 2.3 2.54
2.27 2.77 2.28 2.29 2.76 2.1

Ch. 3 3.83 3.37

Ch. 4 4.87 4.68e 4.47

Ch. 5

Ch. 7 7.1 7.2 7.3 7.4 7.5 7.6

7.7 7.8 7.9 7.10 7.11 7.12 7.13 7.14 7.15 7.16 7.17 7.18 7.19 7.20 7.21 7.22 7.23 7.24 7.25 7.26 7.27 7.28 7.29 7.30 7.31 7.32 7.33 7.34 7.35 7.36 7.37 7.38

3.85 3.2 3.30 3.82 3.84 3.1 4.69 4.65 4.68c 4.70 4.68d 4.25 4.67 4.86 4.44 4.88 4.95 4.89 4.92 4.90 4.3 4.2 4.56 4.57 4.58 4.60 4.61 4.42 5.1b 5.6c

1.69

1.70

5.4b 5.5c

5.9 5.8 5.10

1.71 1.72

Compounds in red are target or novel mesogens. b Primary alkyl chains. c Secondary alkyl chains.

2.56

217 7.3 Experimental for Chapter 2

Octyl 2-mercaptoacetate (7.2a) Mercaptoacetic acid (7.70 mL, d = 1.326 g mL-1, 111 mmol), 1-octanol (26.0 mL, d = 0.827 g mL-1, 165 mmol), p-toluenesulfonic acid monohydrate (2.17 g, 11.4 mmol) and toluene (200 mL) were stirred and heated at reflux under nitrogen with azeotropic removal of water via a Dean-Stark trap (3.5 hours). The reaction mixture was allowed to cool to room temperature before being washed with saturated NaHCO3 (sat.; 4 50 mL). The organic layer was dried (MgSO4), filtered, and concentrated at reduced pressure. The resulting liquid was distilled under reduced pressure (4-9 mm Hg) to yield a colorless liquid (b.p. = 70C 82.5C). Yield: 17.19 g (76%). 1H NMR (CDCl3) 0.88 (t, 3H, J =

218 6.8 Hz), 1.22-1.41 (m, 10H), 1.65 (quint, 2H, J = 7.0 Hz), 2.01 (t, 1H, J = 8.2 Hz), 3.25 (d, 2H, J = 8.4 Hz), 4.13 (t, 2H, J = 6.8 Hz). 13C NMR (CDCl3) 14.0, 22.7, 25.8, 26.3, 28.4, 29.1 (2C), 32.8, 65.6, 170.7. Anal. Calcd for C10H20O2S: C, 58.78; H, 9.87. Found: C, 59.03; H, 9.71. Nonyl 2-mercaptoacetate (7.2b) Compound 7.2b was prepared in the same manner as compound 7.2a from 1-nonanol. Quantities: mercaptoacetic acid (7.70 mL, d = 1.326 g mL-1, 111 mmol), 1-nonanol (28.8 ml, d = 0.827 g mL-1, 165 mmol), p-toluenesulfonic acid monohydrate (2.17 g, 11.4 mmol), toluene (200 mL). The product was distilled under reduced pressure (0.5-1.0 mm Hg) to yield a colorless liquid (b.p. = 86.5C - 88C). Yield: 19.19 g (79%). 1H NMR (CDCl3) 0.88 (t, 3H, J = 8.2 Hz), 1.22-1.41 (m, 12H), 1.64 (quint, 2H, J = 6.9 Hz), 2.02 (t, 1H, J = 8.2 Hz), 3.24 (d, 2H, J = 8.4 Hz), 4.11 (t, 2H, J = 6.8 Hz). 13C NMR (CDCl3) 13.9, 22.5, 25.7, 26.3, 28.4, 29.1, 29.4 (2C), 31.7, 65.5, 170.5. Anal. Calcd for C11H22O2S: C, 60.51; H, 10.16. Found: C, 60.77; H, 10.21. Decyl 2-mercaptoacetate (7.2c) Compound 7.2c was prepared in the same manner as compound 7.2a from 1-decanol. Quantities: mercaptoacetic acid (7.70 mL, d = 1.326 g ml-1, 111 mmol), 1-decanol (31.5 ml, d = 0.829 g mL-1, 165 mmol), p-toluenesulfonic acid monohydrate (2.17 g, 11.4 mmol), toluene (200 mL). The product was distilled under reduced pressure (0.5-1.0 mm Hg) to yield a colorless liquid (b.p. = 101C - 102C). Yield: 19.56 g (76%). 1H NMR

219 (CDCl3) 0.88 (t, 3H, J = 6.8 Hz), 1.20-1.40 (m, 14H), 1.64 (quint, 2H, J = 7.0 Hz), 2.01 (t, 1H, J = 8.2 Hz), 3.24 (d, 2H, J = 8.4 Hz), 4.11 (t, 2H, J = 6.6 Hz). 13C NMR (CDCl3) 14.0, 22.6, 25.8, 26.3, 28.5, 29.15, 29.22 (2C), 29.4, 31.8, 65.6, 170.6. Anal. Calcd for C12H24O2S: C, 62.02; H, 10.41. Found: C, 62.28; H, 10.50. Undecyl 2-mercaptoacetate (7.2d) Compound 7.2d was prepared in the same manner as compound 7.2a from 1-undecanol. Quantities: mercaptoacetic acid (7.70 mL, d = 1.326 g mL-1, 111 mmol), 1-undecanol (34.25 mL, d = 0.830 g mL-1, 165 mmol), p-toluenesulfonic acid monohydrate (2.17 g, 11.4 mmol), toluene (200 mL). The product was distilled under reduced pressure (4-9 mm Hg) to yield a colorless liquid (b.p. = 109C - 113C). Yield: 21.34 g (78%). 1H NMR (CDCl3) 0.87 (t, 3H, J = 6.8Hz), 1.20-1.41 (m, 16H), 1.64 (quint, 2H, J = 7.0Hz), 2.01 (t, 1H, J = 8.2Hz), 3.23 (d, 2H, J = 8.4Hz), 4.11 (t, 2H, J = 6.8Hz). 13C NMR (CDCl3) 14.0, 22.6, 25.7, 26.3, 28.5, 29.2, 29.3 (2C), 29.4, 29.5, 31.8, 65.5, 170.5. Anal. Calcd for C13H26O2S: C, 63.37; H, 10.64. Found: C, 63.50; H, 10.81. Dodecyl 2-mercaptoacetate (7.2e) Compound 7.2e was prepared in the same manner as compound 7.2a from 1-dodecanol. Quantities: mercaptoacetic acid (7.70 mL, d = 1.326 g mL-1, 111 mmol), 1-dodecanol (36.9 mL, d = 0.833 g mL-1, 165 mmol), p-toluenesulfonic acid monohydrate (2.17 g, 11.4 mmol), toluene (200 mL). The product was distilled under reduced pressure (4-9 mm Hg) to yield a colorless liquid (b.p. = 115C - 120C). Yield: 21.32 g (74%). 1H

220 NMR (CDCl3) 0.88 (t, 3H, J = 6.8 Hz), 1.20-1.40 (m, 18H), 1.65 (quint, 2H, J = 7.1 Hz), 2.00 (t, 1H, J = 8.2 Hz), 3.25 (d, 2H, J = 8.4 Hz), 4.13 (t, 2H, J = 6.8 Hz). 13C NMR (CDCl3) 14.0, 22.6, 25.8, 26.4, 28.5, 29.2, 29.3 (2C), 29.46, 29.52, 29.6, 31.9, 65.6, 170.7. Anal. Calcd for C14H28O2S: C, 64.56; H, 10.84. Found: C, 64.71; H, 10.98. Octan-2-yl 2-mercaptoacetate (7.2f) Compound 7.2f was prepared in the same manner as compound 7.2a from racemic 2octanol. Quantities: mercaptoacetic acid (7.70 mL, d = 1.326 g mL-1, 111 mmol), 2octanol (26.2 mL, d = 0.819 g mL-1, 165 mmol), p-toluenesulfonic acid monohydrate (2.17 g, 11.4 mmol), toluene (100 mL). The product was distilled twice under reduced pressure (~1 mm Hg) to yield a colorless liquid (b.p. = 98C - 100C). Yield: 14.26 g (63%). 1H NMR (CDCl3) 0.88 (t, 3H, J = 6.9 Hz), 1.23 (d, 3H, J = 6.3 Hz), 1.21-1.39 (m, 8H), 1.45-1.67 (m, 2H), 1.98 (t, 1H, J = 8.2 Hz), 3.23 (d, 2H, J = 8.2 Hz), 4.92 (sextet, 1H, J = 6.4 Hz). 13C NMR (CDCl3) 13.9, 19.6, 22.4, 25.1, 26.6, 28.9, 31.6, 35.7, 72.2, 170.1. Anal. Calcd for C10H20O2S: C, 58.78; H, 9.87. Found: C, 58.90; H, 9.77. Cyclohexyl 2-mercaptoacetate (7.2g) Compound 7.2g was prepared in the same manner as compound 7.2a from cyclohexanol. Quantities: mercaptoacetic acid (7.70 mL, d = 1.326 g mL-1, 111 mmol), cyclohexanol (17.4 mL, d = 0.984 g ml-1, 165 mmol), p-toluenesulfonic acid monohydrate (2.17 g, 11.4 mmol), toluene (100 mL). The product was distilled twice under reduced pressure (~1

221 mm Hg) to yield a colorless liquid (b.p. = 85C - 87C). Yield: 12.85 g (66%). 1H NMR (CDCl3) placeholder. 13C NMR (CDCl3) 23.7, 25.4, 26.8, 31.4, 73.8, 170.2. Anal. Calcd for C8H14O2S: C, 55.14; H, 8.10. Found: C, 55.44; H, 8.12. 3-Bromothiophene-2-carbaldehyde (7.4) A procedure similar to Iddon et al. was employed.204 To an oven-dried 3-neck flask (1 L) were added anhydrous diisopropylamine (26.0 ml, d = 0.722 g ml-1, 0.186 mol) and anhydrous THF (300 mL). The vessel was cooled to ca. -68C before n-butyllithium (10 M in hexanes, 18.0 mL, 0.18 mol) was added by syringe over 2 hours at a range of -68C to -65C. After allowing the mixture to warm to 0C, 3-bromothiophene (17.5 mL, d = 1.74 g mL-1, 0.187 mol) was added by syringe pump over 1.5 hours from 0C to 3C. Stirring was maintained at this temperature for another hour before N-formylpiperidine (20 mL, d = 1.019 g mL-1, 0.18 mol) was added by syringe pump from -2 C to 2 C over 1.5 hours. The vessel was allowed to warm to room temperature overnight before a solution of sat. aq. NH4Cl (50 mL) was added to the white suspension and stirring was maintained for 2 hours. The layers were then separated. The organic layer was washed with water (2 50 mL). The aqueous layer was extracted with diethyl ether (2 50 mL). The combined organic layers were washed with brine (100 mL), dried over MgSO4, filtered, and concentrated in vacuo to give a red liquid (39.72 g). The product was purified by Kugelrohr distillation (110C, ca. 1 mm Hg) to afford 7.4 as a light yellow liquid (17.32 g, 50%) whose analytical data were consistent with the literature.204 1H

222 NMR (CDCl3) 7.15 (1H, d, J = 5.1 Hz), 7.73 (1H, dd, J = 1.2, 5.1 Hz), 9.98 (1H, d, J = 1.2 Hz). Octyl thieno[3,2-b]thiophene-2-carboxylate (7.5a) To a stirred, room temperature mixture of octyl 2-mercaptoacetate 7.2a (6.37 g, 31.2 mmol) and anhydrous potassium carbonate (4.99 g, 36.1 mmol) in DMF (50 mL) was added dropwise a solution of crude 3-bromothiophene-2-carbaldehyde 7.4 (5.16 g) in DMF (15 mL). The reaction mixture was left to stir under argon at room temperature for 3 days. The potassium salts were removed by vacuum filtration and the red crude mixture was diluted with diethyl ether (300 mL) and washed with water (2 100 mL) and brine (100 mL). The combined aqueous washings were extracted with diethyl ether (3 75 mL). The combined organic washings were dried over MgSO4 and concentrated at reduced pressure to yield a red liquid which was purified by column chromatography (300 g silica; 7% diethyl ether in petroleum ether) to give an orange solid. Recrystallization from petroleum ether and drying under high vacuum (P2O5) yielded white crystals for analysis. Yield: 5.38 g (56%, two-step yield based on 3bromothiophene), m.p. 34.4-35.8 C (from petroleum ether). 1H NMR (CDCl3): 0.89 (t, 3H, J = 6.9 Hz), 1.23-1.40 (m, 8H), 1.44 (quint, 2H, J = 7.4 Hz), 1.76 (quint, 2H, J = 7.1 Hz), 4.32 (t, 2H, J = 6.7 Hz), 7.28 (dd, 1H, J = 5.3 Hz, 0.6 Hz), 7.58 (d, 1H, J = 5.3 Hz), 7.99 (d, 1H, J = 0.6 Hz). 13C NMR (CDCl3): 14.1, 22.7, 26.0, 28.7, 29.1, 29.24, 31.8, 65.5, 119.8, 125.5, 131.6, 135.3, 138.8, 143.9, 162.8. Anal. Calcd for C15H20O2S2: C, 60.77; H, 6.80. Found: C, 60.80; H, 6.80.

223 Nonyl thieno[3,2-b]thiophene-2-carboxylate (7.5b) Compound 7.5b was prepared in the same manner as 7.5a from nonyl 2-mercaptoacetate 7.2b. Quantities: nonyl 2-mercaptoacetate 7.2b (6.75 g, 30.9 mmol), anhydrous potassium carbonate (5.01 g, 36.2 mmol), DMF (50 mL), crude 3-bromothiophene-2carbaldehyde 7.4 (5.20 g) in DMF (15 mL). The crude red mixture was purified by column chromatography (250 g silica; 5% diethyl ether in petroleum ether) to yield a red liquid which solidified upon standing. Recrystallization from petroleum ether and drying under high vacuum (P2O5) yielded off-white crystals for analysis. Yield: 4.60 g (64%, two-step yield based on 3-bromothiophene), m.p. 28.5-30.4 C (from petroleum ether).
1

H NMR (CDCl3): 0.88 (t, 3H, J = 6.9 Hz), 1.22-1.39 (m, 10H), 1.43 (quint, 2H, J = 7.1

Hz), 1.76 (quint, 2H, J = 7.1 Hz), 4.32 (t, 2H, J = 6.7 Hz), 7.27 (d, 1H, J = 5.3 Hz), 7.57 (d, 1H, J = 5.3 Hz), 7.98 (d, 1H, J = 0.4 Hz). 13C NMR (CDCl3): 14.1, 22.7, 26.0, 28.7, 29.25, 29.27, 29.5, 31.9, 65.5, 119.7, 125.5, 131.6, 135.3, 138.7, 143.9, 162.7 Anal. Calcd for C16H22O2S2: C, 61.90; H, 7.14. Found: C, 62.10; H, 7.20. Decyl thieno[3,2-b]thiophene-2-carboxylate (7.5c) Compound 7.5c was prepared in the same manner as 7.5a from decyl 2-mercaptoacetate 7.2c. Decyl 2-mercaptoacetate 7.2c (7.13 g, 30.7 mmol) and K2CO3 (5.04 g, 36.5 mmol) were dissolved in DMF (100 mL). To the flask was then added dropwise crude 3bromothiophene-2-carbaldehyde 7.4 (6.72 g), and the reaction was allowed to stir at room temperature under argon. After 4 days, the potassium salts were filtered off and the filtrate was concentrated at reduced pressure. The crude product was diluted with diethyl

224 ether (100 mL) and washed with water (2 50 mL) and brine (75 mL). The organic layer was dried over MgSO4, filtered, and concentrated at reduced pressure to give an orange liquid which was purified by column chromatography (250 g silica; 1.5% ethyl acetate in petroleum ether) to afford a yellow solid. Recrystallization from petroleum ether and drying under high vacuum (P2O5) yielded white crystals for analysis. Yield: 7.21 g (72%), m.p. 32.0-32.2 C (from petroleum ether). 1H NMR (CDCl3): 0.88 (3H, t, J = 6.8 Hz), 1.22-1.38 (12H, m), 1.43 (2H, quint, J = 7.2 Hz), 1.75 (2H, quint, J = 7.1 Hz), 4.31 (2H, t, J = 6.7 Hz), 7.27 (1H, dd, J = 0.6, 5.3 Hz), 7.57 (1H, d, J = 5.3 Hz), 7.98 (1H, d, J = 0.6 Hz). 13C NMR (CDCl3): 14.1, 22.7, 26.0, 28.7, 29.27, 29.32, 29.5, 31.9, 65.5, 119.7, 125.5, 131.6, 135.3, 138.7, 143.9, 162.7. Anal. Calcd for C17H24O2S2: C, 62.92; H, 7.45. Found: C, 63.17; H, 7.49. ( )-Octan-2-yl thieno[3,2-b]thiophene-2-carboxylate (7.5f) A mixture of ( )-octan-2-yl mercaptoacetate 7.2f (3.02 g, 14.8 mmol), K2CO3 (2.64 g, 19.1 mmol), and 7.3 (2.82 g, 14.8 mmol) in DMF (40 mL) was stirred at room temperature for 2 days. The inorganic salts were then filtered off and the mixture was concentrated. The crude concentrate was diluted with diethyl ether (50 mL) and washed with water (2 25 mL). The aqueous washings were extracted with diethyl ether (2 25 mL). The combined organic layers were then washed with brine (40 mL), dried (MgSO4), filtered, and concentrated to afford 9 as a red liquid which was purified twice by column chromatography (silica gel; 4% ethyl acetate in petroleum ether) to afford a yellow liquid (3.38 g, 77%). A sample for analysis was purified by preparatory TLC. Found: C, 61.02;

225 H: 6.82. Calc. for C15H20O2S2: C, 60.77; H, 6.80%. 1H NMR (CDCl3): 0.88 (t, 3H, J = 6.9 Hz), 1.22-1.46 (m, 8H), 1.34 (d, 3H, J = 6.3 Hz), 1.54-1.79 (m, 2H), 5.13 (apparent sext, 1H, J = 6.3 Hz), 7.27 (dd, 1H, J = 5.3, 0.4 Hz), 7.56 (d, 1H, J = 5.3 Hz), 7.97 (d, 1H, J = 0.6 Hz). 13C NMR (CDCl3): 14.1, 20.1, 22.6, 25.4, 29.1, 31.7, 36.0, 72.5, 119.7, 125.3, 131.4, 154.9, 138.7, 143.8, 162.4. Octyl 5-bromothieno[3,2-b]thiophene-2-carboxylate (7.6a) To a stirred, room temperature solution of octyl thieno[3,2-b]thiophene-2-carboxylate 7.5a (1.04 g, 3.51 mmol), chloroform (15 mL), and acetic acid (15 mL) was added Nbromosuccinimide (882.3 mg, 4.959 mmol). The mixture was stirred at reflux under argon for 24 hours. The crude product was diluted with diethyl ether (100 mL) and washed with aqueous NaHCO3 (sat., 50 mL), water (2 50 mL), and brine (50 mL). The combined organic layers were then dried over MgSO4, filtered, and concentrated at reduced pressure to give a green liquid which was purified via silica plug filtration (2% ethyl acetate in petroleum ether) to give a light green solid. Recrystallization from a 1:1 mixture of petroleum ether and diethyl ether followed by drying under high vacuum (P2O5) yielded white crystals for analysis. Yield: 1.16 g (88%), m.p. 43.9-45.7 C (from petroleum ether/diethyl ether). 1H NMR (CDCl3): 0.88 (t, 3H, J = 6.9 Hz), 1.22-1.38 (m, 8H), 1.42 (quint, 2H, J = 7.4 Hz), 1.75 (quint, 2H, 7.1 Hz), 4.31 (t, 2H, J = 6.7 Hz), 7.28 (d, 1H, 0.4 Hz), 7.86 (d, 1H, J = 0.5 Hz). 13C NMR (CDCl3): 14.1, 22.6, 26.0, 28.7, 29.19, 29.22, 31.8, 65.7, 118.4, 122.5, 124.9, 134.6, 138.9, 142.8, 162.5. Anal. Calcd for C15H19BrO2S2: C, 48.00; H: 5.10. Found: C, 47.98; H, 5.13.

226 Nonyl 5-bromothieno[3,2-b]thiophene-2-carboxylate (7.6b) Compound 7.6b was prepared in the same manner as compound 7.6a from nonyl thieno[3,2-b]thiophene-2-carboxylate 7.5b. Quantities: nonyl thieno[3,2-b]thiophene-2carboxylate 7.5b (1.54 g, 4.96 mmol), acetic acid (10 mL), chloroform (10 mL), Nbromosuccinimide (1.29 g, 7.25 mmol). The crude green solid was purified by silica plug filtration (petroleum ether followed by dichloromethane) to afford a light green solid. Recrystallization from a 1:1 mixture of petroleum ether and diethyl ether followed by drying under high vacuum (P2O5) yielded white crystals for analysis. Yield: 2.02 g (quant.), m.p. 33.2-34.5 C (from petroleum ether/diethyl ether). 1H NMR (CDCl3): 0.88 (t, 3H, J = 6.9 Hz), 1.23-1.38 (m, 10H), 1.42 (quint, 2H, J = 7.4 Hz), 1.75 (quint, 2H, J = 7.0 Hz), 4.31 (t, 2H, J = 6.7 Hz), 7.29 (s, 1H), 7.87 (s, 1H). 13C NMR (CDCl3): 14.1, 22.7, 26.0, 28.7, 29.2, 29.5, 31.9, 65.7, 118.4, 122.5, 124.9, 134.6, 138.9, 142.8, 162.6. Anal. Calcd for C16H21BrO2S2: C, 49.35; H, 5.44. Found: C, 49.39; H, 5.43. Decyl 5-bromothieno[3,2-b]thiophene-2-carboxylate (7.6c) Compound 7.6c was prepared in the same manner as compound 7.6a from decyl thieno[3,2-b]thiophene-2-carboxylate 7.5c. Quantities: decyl thieno[3,2-b]thiophene-2carboxylate 7.5c (1.01 g, 3.11 mmol), acetic acid (10 mL), chloroform (10 mL), Nbromosuccinimide (0.85 g, 4.8 mmol). The crude green solid was purified by silica plug filtration (petroleum ether followed by dichloromethane) to afford a light green solid. Recrystallization from a 1:1 mixture of petroleum ether and diethyl ether followed by drying under high vacuum (P2O5) yielded white crystals for analysis. Yield: 1.30 g

227 (quant.). m.p. 41.8-42.7 C (from petroleum ether/diethyl ether). 1H NMR (CDCl3): 0.88 (t, 3H, J = 6.9 Hz), 1.20-1.38 (m, 12H), 1.43 (quint, 2H, J = 7.2 Hz), 1.75 (quint, 2H, J = 7.1 Hz), 4.31 (t, 2H, J = 6.7 Hz), 7.29 (d, 1H, J = 0.6 Hz), 7.87 (d, 1H, J = 0.6 Hz). 13C NMR (CDCl3): 14.1, 22.7, 26.0, 28.7, 29.26, 29.31, 29.5, 31.9, 65.7, 118.4, 122.5, 124.9, 134.7, 138.9, 142.8, 162.6. Anal. Calcd for C17H23BrO2S2: C, 50.62; H, 5.75. Found: C, 50.85; H, 5.81. Octyl 5-iodothieno[3,2-b]thiophene-2-carboxylate (7.7a) Octyl thieno[3,2-b]thiophene-2-carboxylate 7.7a (587.5 mg, 1.982 mmol), Niodosuccinimide (534.3 mg, 2.375 mmol), chloroform (10 mL) and acetic acid (10 mL) were stirred at room temperature for 2 days. The reaction mixture was then diluted with diethyl ether (30 mL) and washed with aqueous NaHCO3 (sat., 15 mL), aqueous Na2S2O3 (sat., 15 mL), water (2 15 mL), and brine (20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated at reduced pressure to afford a green solid which was purified by silica plug filtration (2% ethyl acetate in petroleum ether). Recrystallization from a 1:1 mixture of petroleum ether and diethyl ether followed by drying under high vacuum (P2O5) yielded white crystals for analysis. Yield: 655.4 mg (78%), m.p. 44.2-48.4 C (from petroleum ether/diethyl ether). 1H NMR (CDCl3): 0.88 (t, 3H, J = 6.9 Hz), 1.22-1.38 (m, 8H), 1.42 (quint, 2H, J = 7.4 Hz), 1.75 (quint, 2H, J = 7.1 Hz), 4.31 (t, 2H, J = 6.7 Hz), 7.45 (d, 1H, J = 0.6 Hz), 7.88 (d, 1H, J = 0.6 Hz). 13C NMR (CDCl3): 14.1, 22.7, 26.0, 28.7, 29.19, 29.22, 31.8, 65.7, 80.5, 124.4, 128.8,

228 135.0, 143.4, 144.0, 162.7. Anal. Calcd for C15H19IO2S2: C, 42.66; H, 4.53. Found: C, 42.82; H, 4.60. Nonyl 5-iodothieno[3,2-b]thiophene-2-carboxylate (7.7b) Compound 7.7b was prepared in the same manner as compound 7.7a from nonyl thieno[3,2-b]thiophene-2-carboxylate 7.5b. Quantities: nonyl thieno[3,2-b]thiophene-2carboxylate 7.5b (1.96 g, 6.31 mmol), N-iodosuccinimide (1.7195 g, 7.6429 mmol), chloroform (10 mL), acetic acid (10 mL). The crude green liquid was purified by silica plug filtration (2% ethyl acetate in petroleum ether) to give an off-white solid. Recrystallization from a 1:1 mixture of petroleum ether and diethyl ether followed by drying under high vacuum (P2O5) yielded white crystals for analysis. Yield: 2.43 g (88%), m.p. 46.1-47.1 C (from petroleum ether/diethyl ether. 1H NMR (CDCl3): 0.88 (t, 3H, J = 6.9 Hz), 1.20-1.38 (m, 10H), 1.42 (quint, 2H, J = 7.1 Hz), 1.75 (quint, 2H, J = 7.0 Hz), 4.31 (t, 2H, J = 6.7 Hz), 7.44 (d, 1H, J = 0.6 Hz), 7.88 (d, 1H, J = 0.6 Hz). 13C NMR (CDCl3): 14.1, 22.7, 26.0, 28.7, 29.2, 29.3, 29.5, 31.9, 65.7, 80.5, 124.4, 128.8, 135.0, 143.3, 144.0, 162.9. Anal. Calcd for C16H21IO2S2: C, 44.04; H, 4.85. Found: C, 44.26; H, 4.91. Decyl 5-iodothieno[3,2-b]thiophene-2-carboxylate (7.7c) Decyl thieno[3,2-b]thiophene-2-carboxylate 7.5c (1.45 g, 4.47 mmol), iodine (5.66 g, 22.3 mmol), and HgO (4.62 g, 21.3 mmol) were dissolved in benzene (50 ml) and stirred at room temperature under argon for 18 hours. The reaction mixture was then shaken

229 with saturated Na2S2O3 (30 mL). The layers were separated and the organic layer was washed with water (2 30 mL) and brine (30 mL). The combined organic layers were dried over MgSO4 and concentrated to afford a brown solid which was pure by NMR. Recrystallization from a 1:1 mixture of petroleum ether and diethyl ether followed by drying under high vacuum (P2O5) yielded white crystals for analysis. Yield: 1.92 g (95%), m.p. 58.9-59.6 C (from petroleum ether/diethyl ether). 1H NMR (CDCl3): 0.88 (t, 3H, J = 6.9 Hz), 1.20-1.38 (m, 12H), 1.42 (quint, 2H, J = 7.2 Hz), 1.75 (quint, 2H, J = 7.1 Hz), 4.31 (t, 2H, J = 6.7 Hz), 7.45 (d, 1H, J = 0.6 Hz), 7.88 (d, 1H, J = 0.6 Hz). 13C NMR (CDCl3): 14.1, 22.7, 26.0, 28.7, 29.25, 29.31, 29.5, 31.9, 65.7, 80.5, 124.8, 128.8, 135.0, 143.4, 144.0, 162.7. Anal. Calcd for C17H23IO2S2: C, 45.33; H, 5.15. Found: C, 45.62; H, 5.24. ( )-Octan-2-yl 5-iodothieno[3,2-b]thiophene-2-carboxylate (7.7f) A mixture of 7.5f (1.3515 g, 4.5589 mmol), N-iodosuccinimide (1.0460 g, 4.6493 mmol), chloroform (10 mL), and glacial acetic acid (10 mL) was stirred under argon at room temperature in a flask wrapped in foil to exclude light. GC analysis after 22 h showed 85% conversion and so additional NIS (185.7 mg, 0.8254 mmol) was added. GC analysis after a further 44 h showed >98% conversion. The reaction mixture was then diluted with diethyl ether (50 mL) and washed with Na2S2O3 (saturated aqueous, 15 mL) and NaHCO3 (saturated aqueous, 3 15 mL). The combined aqueous washings were extracted with diethyl ether (2 15 mL). The combined organic extracts were washed with brine (25 ml), dried over MgSO4, filtered, and concentrated to yield a green liquid (2.23 g).

230 Purification by column chromatography (silica gel; 3% ethyl acetate in petroleum ether) gave 7.7f as a green liquid that was pure by NMR; the material could be decolorized by dry column vacuum chromatography (ethyl acetate/petroleum ether, gradient elution) or preparatory TLC (10% ethyl acetate in petroleum ether). Yield: 1.7410 g (90%). Found: C, 43.01; H: 4.62. Calc. for C15H19IO2S2: C, 42.66; H, 4.53%. 1H NMR (CDCl3): 1H NMR (CDCl3): 0.87 (t, 3H, J = 6.8 Hz), 1.23-1.45 (m, 8H), 1.34 (d, 3H, J = 6.2 Hz), 1.54-1.78 (m, 2H), 5.12 (apparent sext, 1H, J = 6.3 Hz), 7.41 (d, 1H, J = 0.4 Hz), 7.86 (d, 1H, J = 0.5 Hz). 13C NMR (CDCl3): 14.1, 20.1, 22.6, 25.3, 29.1, 31.7, 26.0, 72.6, 80.4, 124.1, 128.7, 135.5, 143.3, 143.8, 162.3. 1-Bromo-4-(octyloxy)benzene (7.8a) Compound 7.8a was prepared in the method of Seed and Nassif.538 To a stirred, room temperature solution of 4-bromophenol (7.93 g, 45.8 mmol) and K2CO3 (14.83 g, 107.3 mmol) in 2-butanone (80 mL) was added dropwise 1-bromooctane (11.48 g, 59.44 mmol). The mixture was heated under reflux for 3 days (an aliquot was taken and GC analysis indicated completion). The heat was then removed, the potassium salts were filtered off, and the solvent was removed by rotary evaporation. The crude product was then diluted with diethyl ether (100 mL) and washed with water (2 50 mL) and brine (50 mL). The combined organic layers were dried over MgSO4, which was filtered off before the product was concentrated at reduced pressure to afford a light yellow liquid (14.33 g), which was purified by Kugelrohr distillation (150C, 1 mm Hg) to yield a light yellow liquid that was pure by 1H NMR; analytical data were consistent with the

231 literature.539 Yield: 10.74 g (82%). 1H NMR (CDCl3): 0.89 (t, 3H, J = 6.5 Hz), 1.231.37 (m, 8H), 1.43 (quint, 2H, J = 7.1 Hz), 1.75 (quint, 2H, J = 7.0 Hz), 3.89 (t, 2H, J = 6.6 Hz), 6.75 (d, 2H, J = 9.0 Hz), 7.34 (d, 2H, J = 9.0 Hz). 13C NMR (CDCl3): 14.1, 22.7, 26.0, 29.19, 29.24, 29.4, 31.8, 68.3, 112.5, 116.3, 132.2, 158.3. 1-Bromo-4-(nonyloxy)benzene (7.8b) Compound 7.8b was prepared in the manner of 7.8a from 1-bromononane. Quantities: 4bromophenol (7.93 g, 45.8 mmol), K2CO3 (14.45 g, 104.6 mmol), 2-butanone (80 mL), 1bromononane (12.15 g, 58.65 mmol). The crude reaction product was purified twice by Kugelrohr distillation (166C then 170C, 1 mm Hg) to yield a light yellow liquid that was pure by 1H NMR. Yield: 11.40 g (83%). 1H NMR (CDCl3): 0.88 (t, 3H, J = 6.9 Hz), 1.22-1.40 (m, 10H), 1.43 (quint, 2H, J = 7.2 Hz), 1.76 (quint, 2H, J = 7.0 Hz), 3.90 (t, 2H, J = 6.6 Hz), 6.76 (d, 2H, J = 9.0 Hz), 7.35 (d, 2H, J = 9.0 Hz). 13C NMR (CDCl3): 14.1, 22.7, 26.0, 29.2, 29.3, 29.4, 29.5, 31.9, 68.2, 112.5, 116.3, 132.2, 158.3. 1-Bromo-4-(decyloxy)benzene (7.8c) Compound 7.8c was prepared in the manner of 7.8a from 1-bromodecane. Quantities: 4-bromophenol (7.92 g, 45.8 mmol), K2CO3 (14.54 g, 105.2 mmol), 2-butanone (80 mL), 1-bromodecane (12.92 g, 58.41 mmol). The crude reaction product was purified twice by Kugelrohr distillation (154C then 169C, 1 mm Hg) to yield a light yellow liquid that was pure by 1H NMR. Yield: 10.32 g (72%). 1H NMR (CDCl3): 0.88 (t, 3H, J = 6.8 Hz), 1.21-1.37 (m, 12H), 1.42 (quint, 2H, J = 7.1 Hz), 1.74 (quint, 2H, J = 7.0 Hz), 3.87

232 (t, 2H, J = 6.6 Hz), 6.74 (d, 2H, J = 9.0 Hz), 7.33 (d, 2H, J = 9.0 Hz). 13C NMR (CDCl3): 14.1, 22.7, 26.0, 29.2, 29.36, 29.42, 29.6 (2C), 31.9, 68.2, 112.5, 116.2, 132.1, 158.3. 4-(Octyloxy)phenylboronic acid (7.9a) Compound 7.9a was prepared in the method of Seed and Nassif.538 A solution of 1bromo-4-octyloxybenzene 7.8a (8.10 g, 28.4 mmol) in anhydrous THF (150 mL, distilled from sodium/benzophenone under argon) was stirred under argon at -72C. To the flask was added n-butyllithium (2.2 M in cyclohexane; 17.0 mL, 37.4 mmol) dropwise by syringe with the reaction temperature maintained at -72 to -65C. After addition was complete, the reaction mixture was allowed to stir a further 35 minutes at this temperature before an aliquot was taken (GC analysis indicated complete lithiation). Neat trimethyl borate (5.87 g, 56.5 mmol) was then added dropwise by syringe with the reaction temperature maintained at -72 to -64C. The reaction vessel was then allowed to warm to room temperature overnight. Aqueous HCl (10%, 100 mL) was added to the flask; the resulting cloudy mixture was stirred for 2 hours, during which the organic layer turned clear. The layers were separated; the organic layer was concentrated and the aqueous layer was extracted with diethyl ether (3 50 mL). The combined organic layers were concentrated to a volume of approximately 100 mL before being washed with water (2 50 mL) and brine (60 mL), dried over MgSO4, and concentrated under reduced pressure at afford a near-white solid. Yield: 6.54 g (92%). 1H NMR (CDCl3): 0.90 (t, 3H, J = 6.7 Hz), 1.22-1.41 (m, 8H), 1.47 (quint, 2H, J = 6.8 Hz), 1.82 (quint, 2H, J = 7.0

233 Hz), 4.04 (t, 2H, J = 6.6 Hz), 7.00 (d, 2H, J = 8.6 Hz), 8.15 (d, 2H, J = 8.6 Hz). (The boronic acid signal was not detected; peaks from impurities not included). 4-(Nonyloxy)phenylboronic acid (7.9b) Compound 7.9b was prepared in the manner of 7.9a from 1-bromo-4-nonyloxybenzene 7.8b; the reaction mixture employed a mixture of THF and petroleum ether for solubility purposes. Quantities: 1-bromo-4-nonyloxybenzene 7.8b (8.99 g, 30.0 mmol), THF (230 mL), petroleum ether (100 mL, dried previously over 4 molecular sieves), nbutyllithium (2.2 M in cyclohexane; 18.2 mL, 40. mmol), trimethyl borate (6.19 g, 59.6 mmol). A near-white solid was obtained. Yield: 7.99 g (quant.) 1H NMR (CDCl3): 0.89 (t, 3H, J = 6.9 Hz), 1.21-1.43 (m, 10H), 1.47 (quint, 2H, J = 7.1 Hz), 1.82 (quint, 2H, J = 7.0 Hz), 4.04 (t, 2H, J = 6.6 Hz), 7.00 (d, 2H, J = 8.6 Hz), 8.15 (d, 2H, J = 8.6 Hz). (The boronic acid signal was not detected; peaks from impurities not included). 4-(Decyloxy)phenylboronic acid (7.9c) Compound 7.9c was prepared in the manner of 7.9a from 1-bromo-4-decyloxybenzene 7.8c; the reaction mixture employed a mixture of THF and petroleum ether for solubility purposes. Quantities: 1-bromo-4-decyloxybenzene 7.8c (8.96 g, 28.6 mmol), THF (350 mL, distilled over sodium metal), petroleum ether (100 mL, dried previously over 4 molecular sieves), n-butyllithium (2.2 M in cyclohexane; 19.2 mL, 42.4 mmol), trimethyl borate (6.05 g, 58.2 mmol). A near-white solid was obtained. Yield: 7.61 g (96%). 1H NMR (CDCl3): 0.89 (t, 3H, J = 6.8 Hz), 1.21-1.41 (m, 12H), 1.47 (quint, 2H, J = 7.2

234 Hz), 1.82 (quint, 2H, J = 7.0 Hz), 4.04 (t, 2H, J = 6.6 Hz), 7.00 (d, 2H, J = 8.7 Hz), 8.15 (d, 2H, J = 8.6 Hz). (The boronic acid signal was not detected; peaks from impurities not included). Potassium 4-(octyloxy)phenyltrifluoroborate (7.10a) In a plastic reaction vessel were added 4-(octyloxy)phenylboronic acid 7.9a (5.96 g, 23.8 mmol) and methanol (9 mL) to give an off-white slurry. The reaction vessel was then chilled in an ice-water bath. Next, neat KHF2 (4.79 g, 61.3 mmol) was added in one portion, followed by the dropwise addition of water (12 ml). The reaction mixture, a thick white slurry, was stirred manually with a glass rod periodically over the course of an hour. The crude product was then isolated by filtration and washed with cold methanol. The product was recrystallized from acetone and dried under high vacuum (P2O5) afford white crystals. Yield: 3.65 g (49%), m.p. >250C (from acetone). 1H NMR (DMSO-d6): 0.86 (t, 3H, J = 6.9 Hz), 1.21-1.34 (m, 8H), 1.39 (quint, 2H, J = 7.1 Hz), 1.66 (quint, 2H, J = 7.0 Hz), 3.86 (t, 2H, J = 6.5 Hz), 6.63 (d, 2H, J = 8.0 Hz), 7.19 (d, 2H, J = 8.4 Hz).
13

C NMR (DMSO-d6): 13.9, 22.0, 25.5, 28.6, 28.7, 28.8, 31.1, 66.8, 112.4, 132.1, 141.5

(br), 156.5. Anal. Calcd for C14H21BF3KO: C, 53.86; H, 6.78. Found: C, 54.01; H, 6.76. Potassium 4-(nonyloxy)phenyltrifluoroborate (7.10b) Compound 7.10b was prepared in the same manner as compound 7.10a from 4(nonyloxy)phenylboronic acid 7.9b; stirring was maintained for 2 hours. Quantities: 4(nonyloxy)phenylboronic acid 7.9b (6.79 g, 25.7 mmol), methanol (9 mL), KHF2 (5.13 g,

235 65.7 mmol), water (12 mL). The product was recrystallized from acetone and dried under high vacuum (P2O5) to afford white crystals. Yield: 5.40 g (64%), m.p. >250C (from acetone). 1H NMR (DMSO-d6): 0.86 (t, 3H, J = 6.9 Hz), 1.20-1.34 (m, 10H), 1.39 (quint, 2H, J = 7.1 Hz), 1.66 (quint, 2H, J = 7.0 Hz), 3.86 (t, 2H, J = 6.5 Hz), 6.63 (d, 2H, J = 8.0 Hz), 7.19 (d, 2H, J = 8.3 Hz).13C NMR (100 MHz, DMSO-d6): 13.9, 22.0, 25.5, 28.6, 28.74, 28.79, 28.9, 31.1, 66.8, 112.4, 132.1, 141.1, 156.5. Potassium 4-(decyloxy)phenyltrifluoroborate (7.10c) Compound 7.10c was prepared in the same manner as compound 7.10a from 4(decyloxy)phenylboronic acid 7.9c. Quantities: 4-(decyloxy)phenylboronic acid 7.9c (6.45 g, 23.2 mmol), methanol (9 mL), KHF2 (4.53 g, 58.0 mmol), water (12 mL). The product was recrystallized from acetone and dried under high vacuum (P2O5) to afford white crystals. Yield: 4.54 g (58%), m.p. >250C (from acetone). 1H NMR (DMSO-d6): 0.86 (t, 3H, J = 6.8 Hz), 1.21-1.33 (m, 12H), 1.39 (quint, 2H, J = 7.1 Hz), 1.66 (quint, 2H, J = 6.9 Hz), 3.86 (t, 2H, J = 6.5 Hz), 6.63 (d, 2H, J = 8.0 Hz), 7.19 (d, 2H, J = 8.4 Hz). 13C NMR (DMSO-d6): 13.9, 22.0, 25.5, 28.6, 28.7, 28.77, 28.86, 28.92, 31.2, 66.8, 112.4, 132.1, 141.7 (br), 156.5. 4-(Decyloxy)phenyl MIDA boronate (7.11c) A mixture of 4-decyloxyphenylboronic acid 7.9c (0.98 g, 3.5 mmol), Nmethyliminodiacetic acid (MIDA) (0.64 g, 4.3 mmol), toluene (45 mL), and DMSO (5 mL) was stirred under argon at reflux for 12 hours; water was azeotropically removed

236 during reflux with a Dean-Stark trap. The heat was then removed and the mixture was concentrated at reduced pressure to afford an orange solid. Recrystallization from acetone and diethyl ether followed by drying under high vacuum (P2O5) afforded the target compound as a white solid. Yield: 745.9 mg (55%), m.p. 108.7-110.3 C. 1H NMR (CDCl3): 0.88 (t, 3H, J = 6.8 Hz), 1.19-1.40 (m, 12H), 1.45 (quint, 2H, J = 7.4 Hz), 1.78 (quint, 2H, J = 7.1 Hz), 3.74 (d, 2H, J = 16.4 Hz), 3.88 (d, 2H, J = 16.4 Hz), 3.96 (t, 2H, J = 6.6 Hz), 6.92 (d, 2H, J = 8.4 Hz), 7.43 (d, 2H, J = 8.4 Hz). 13C NMR (CDCl3): 14.1, 22.7, 26.1, 26.3, 29.3, 29.4, 29.6, 31.9, 47.3, 61.6, 67.9, 114.5, 133.7, 160.7, 167.1. Anal. Calcd for C21H32BNO5: C, 64.79; H, 8.29; N, 3.60. Found: C, 64.60; H, 8.14; N, 3.67. Octyl 5-(4-(octyloxy)phenyl)thieno[3,2-b]thiophene-2-carboxylate (7.12a) To a mixture of octyl 5-iodothieno[3,2-b]thiophene-2-carboxylate 7.7a (410.2 mg, 0.9713 mmol) and toluene (20 mL) were added potassium 4-(octyloxy)phenyltrifluoroborate 7.10a (398.7 mg, 1.277 mmol), K2CO3 (376.2 mg, 2.722 mmol), tetrakis(triphenylphosphine)palladium(0) (103.1 mg, 0.08922 mmol), acetone (10 mL) and water (5 mL). The solvents were sparged for >15 minutes with argon prior to addition. The reaction mixture was stirred under argon and heated under reflux for 24 hours. The reaction mixture was then diluted with dichloromethane (30 mL) and shaken with water (30 mL). The aqueous layer was extracted with dichloromethane (3 30 mL). The combined organic extracts were washed with brine (50 mL), dried over MgSO4, filtered, and concentrated at reduced pressure to afford a brown solid. Purification by

237 column chromatography (40 g silica; 25% dichloromethane in petroleum ether) afforded a white solid. Recrystallization from ethyl acetate and drying under high vacuum (P2O5) yielded white crystals for analysis. Yield: 391.0 mg (80%). Transitions (C) Cryst 143.7 (SmC 140.7) SmA 153.1 Iso Liq (Rec. 132.9). 1H NMR (CDCl3): 0.890 (t, 3H, J = 6.5 Hz), 0.892 (t, 3H, J = 6.5 Hz), 1.23-1.41 (m, 16H), 1.41-1.52 (m, 4H), 1.76 (quint, 2H, J = 7.7 Hz), 1.80 (quint, 2H, J = 7.4 Hz), 3.99 (t, 2H, J = 6.6 Hz), 4.31 (t, 2H, J = 6.7 Hz), 6.94 (d, 2H, J = 8.8 Hz), 7.36 (s, 1H), 7.56 (d, 2H, J = 8.8 Hz), 7.94 (s, 1H). 13C NMR (CDCl3): 14.1, 22.7, 26.00, 26.04, 28.7, 29.22, 29.25, 29.4, 31.8, 65.5, 68.2, 114.3, 115.0, 125.7, 126.6, 127.4, 133.7, 137.1, 145.0, 150.8, 159.7, 162.8. Anal. Calcd for C29H40O3S2: C, 69.56; H, 8.05. Found: C, 69.68; H, 7.87. Nonyl 5-(4-(octyloxy)phenyl)thieno[3,2-b]thiophene-2-carboxylate (7.12b) Compound 7.12b was prepared in the same manner as compound 7.12a from nonyl 5iodothieno[3,2-b]thiophene-2-carboxylate 7.7b; the workup was performed with diethyl ether rather than dichloromethane. Quantities: nonyl 5-iodothieno[3,2-b]thiophene-2carboxylate 7.7b (426.2 mg, 0.9767 mmol), toluene (20 mL), potassium 4(octyloxy)phenyltrifluoroborate 7.10a (402.6 mg, 1.289 mmol), K2CO3 (383.0 mg, 2.771 mmol), tetrakis(triphenylphosphine)palladium(0) (101.1 mg, 0.08749 mmol), acetone (10 mL), water (5 mL), The crude brown solid was purified by column chromatography (40 g silica; 25% dichloromethane in petroleum ether) to afford a white solid. Recrystallization from ethyl acetate and drying under high vacuum (P2O5) yielded white crystals for analysis. Yield: 434.2 mg (86%). Transitions (C) Cryst 138.0 (SmC 137.2) SmA 150.3

238 Iso Liq (Rec. 130.5). 1H NMR (CDCl3): 0.88 (t, 3H, J = 6.8 Hz), 0.89 (t, 3H, J = 6.8 Hz), 1.22-1.41 (m, 18H), 1.41-1.51 (m, 4H), 1.79 (quint, 2H, J = 7.3 Hz), 1.83 (quint, 2H, J = 7.4 Hz), 3.99 (t, 2H, J = 6.6 Hz), 4.31 (t, 2H, J = 6.7 Hz), 6.93 (d, 2H, J = 8.8 Hz), 7.36 (d, 1H, J = 0.6 Hz), 7.55 (d, 2H, J = 8.8 Hz), 7.93 (d, 1H, J = 0.5 Hz). 13C NMR (CDCl3): 14.1, 22.7, 26.00, 26.05, 28.8, 29.25 (5 overlapping C signals), 29.29, 29.4, 29.5, 31.8, 31.9, 65.5, 68.2, 114.3, 115.1, 125.7, 126.7, 127.4, 133.7, 137.1, 145.0, 150.9, 159.7, 162.8. Anal. Calcd for C30H42O3S2: C, 69.99; H, 8.22. Found: C, 69.93; H, 8.12. Decyl 5-(4-(octyloxy)phenyl)thieno[3,2-b]thiophene-2-carboxylate (7.12c) Compound 7.12c was prepared in the same manner as compound 7.12a from decyl 5iodothieno[3,2-b]thiophene-2-carboxylate 7.7c. Quantities: decyl 5-iodothieno[3,2b]thiophene-2-carboxylate 7.7c (306.7 mg, 0.6810 mmol), toluene (20 mL), potassium 4(octyloxy)phenyltrifluoroborate 7.10a (273.1 mg, 0.8747 mmol), K2CO3 (252.6 mg, 1.828 mmol), tetrakis(triphenylphosphine)palladium(0) (70.0 mg, 0.0606 mmol), acetone (10 mL), water (5 mL). The crude brown solid was purified by column chromatography (40 g silica; 25% dichloromethane in petroleum ether) to afford a white solid. Recrystallization from ethyl acetate and drying under high vacuum (P2O5) yielded white crystals for analysis. Yield: 355.6 mg (99%). Transitions (C) Cryst 134.4 (SmC 132.2) SmA 147.5 Iso Liq (Rec. 128.0). 1H NMR (CDCl3): 0.88 (t, 3H, J = 7.0 Hz), 0.89 (t, 3H, J = 6.7 Hz), 1.22-1.41 (m, 20H), 1.41-1.50 (m, 4H), 1.76 (quint, 2H, J = 7.7 Hz), 1.80 (quint, 2H, J = 7.4 Hz), 3.99 (t, 2H, J = 6.6 Hz), 4.31 (t, 2H, J = 6.7 Hz), 6.93 (d, 2H, J = 8.8 Hz), 7.36 (s, 1H), 7.55 (d, 2H, J = 8.7 Hz), 7.93 (s, 1H). 13C NMR (CDCl3):

239 14.1, 22.67, 22.69, 25.99, 26.04, 28.8, 29.23, 29.24, 29.28, 29.32, 29.4, 29.5, 31.8, 31.9, 65.5, 68.2, 114.2, 115.1, 125.7, 126.6, 127.4, 133.7, 137.1, 145.0, 150.9, 159.7, 162.7. Anal. Calcd for C31H44O3S2: C, 70.41; H, 8.39. Found: C, 70.46; H, 8.33. Octyl 5-(4-(nonyloxy)phenyl)thieno[3,2-b]thiophene-2-carboxylate (7.12d) Compound 7.12d was prepared in the same manner as compound 7.12a from potassium 4-(nonyloxy)phenyltrifluoroborate 7.10b. Quantities: octyl 5-iodothieno[3,2-b]thiophene2-carboxylate 7.7a (414.6 mg, 0.9817 mmol), toluene (20 mL), potassium 4(nonyloxy)phenyltrifluoroborate 7.10b (414.5 mg, 1.270 mmol), K2CO3 (351.1 mg, 2.540 mmol), tetrakis(triphenylphosphine)palladium(0) (100.8 mg, 0.08723 mmol), acetone (10 mL), water (5 mL). The crude brown solid was purified by column chromatography (40 g silica; 25% dichloromethane in petroleum ether) to afford a white solid. Recrystallization from ethyl acetate and drying under high vacuum (P2O5) yielded white crystals for analysis. Yield: 451.4 mg (89%). Transitions (C) Cryst 144.5 (SmC 144.4) SmA 149.8 Iso Liq (Rec. 137.6). 1H NMR (CDCl3): 0.89 (t, 6H, J = 6.8 Hz), 1.21-1.40 (m, 18H), 1.40-1.51 (m, 4H), 1.76 (quint, 2H, J = 7.2 Hz), 1.80 (quint, 2H, J = 7.2 Hz), 3.99 (t, 2H, J = 6.6 Hz), 4.31 (t, 2H, J = 6.7 Hz), 6.94 (d, 2H, J = 8.8 Hz), 7.36 (d, 1H, J = 0.6 Hz), 7.55 (d, 2H, J = 8.8 Hz), 7.94 (d, 1H, J = 0.6 Hz). 13C NMR (CDCl3): 14.1, 22.66, 22.68, 25.99, 26.0, 28.7, 29.21, 29.25, 29.27, 29.4, 29.5, 31.8, 31.9, 65.5, 68.2, 114.2, 115.0, 125.7, 126.6, 127.4, 133.7, 137.1, 145.0, 150.8, 159.7, 162.8. Anal. Calcd for C30H42O3S2: C, 69.99; H, 8.22. Found: 69.85; H, 8.24.

240 Nonyl 5-(4-(nonyloxy)phenyl)thieno[3,2-b]thiophene-2-carboxylate (7.12e) Compound 7.12e was prepared in the same manner as compound 7.12a from potassium 4-(nonyloxy)phenyltrifluoroborate 7.10b and nonyl 5-iodothieno[3,2-b]thiophene-2carboxylate 7.7b; the workup was performed with diethyl ether rather than dichloromethane. Quantities: nonyl 5-iodothieno[3,2-b]thiophene-2-carboxylate 7.7b (427.6 mg, 0.9799 mmol), toluene (20 mL), potassium 4-(nonyloxy)phenyltrifluoroborate 7.10b (421.7 mg, 1.293 mmol), K2CO3 (364.0 mg, 2.634 mmol), tetrakis(triphenylphosphine)palladium(0) (104.6 mg, 0.09052 mmol), acetone (10 mL), water (5 mL), The crude brown solid was purified by column chromatography (40 g silica; 25% dichloromethane in petroleum ether) to afford a white solid. Recrystallization from ethyl acetate and drying under high vacuum (P2O5) yielded white crystals for analysis. Yield: 420.8 mg (81%). Transitions (C) Cryst 140.7 SmC 141.5 SmA 147.1 Iso Liq (Rec. 131.1). 1H NMR (CDCl3): 0.885 (t, 3H, J = 6.3 Hz), 0.894 (t, 3H, J = 5.4 Hz), 1.21-1.41 (m, 20H), 1.41-1.52 (m, 4H), 1.76 (quint, 2H, J = 7.6 Hz), 1.80 (quint, 2H, J = 7.3 Hz), 3.99 (t, 2H, J = 6.6 Hz), 4.31 (t, 2H, J = 6.7 Hz), 6.93 (d, 2H, J = 8.8 Hz), 7.36 (s, 1H), 7.55 (d, 2H, J = 8.8 Hz), 7.94 (s, 1H).
13

C NMR (CDCl3): 14.1, 22.7,

25.99, 26.03, 28.7, 29.2, 29.3, 29.4, 29.51, 29.54, 31.9, 65.5, 68.2, 114.2, 115.0, 125.7, 126.6, 127.4, 133.7, 137.1, 145.0, 150.8, 159.7, 162.7. Anal. Calcd for C31H44O3S2: C, 70.41; H, 8.39. Found: C, 70.28; H, 8.65. max(CHCl3)/nm 350 (/dm3 mol-1 cm-1 3.7 104).

241 Decyl 5-(4-(nonyloxy)phenyl)thieno[3,2-b]thiophene-2-carboxylate (7.12f) Compound 7.12f was prepared in the same manner as compound 7.12a from potassium 4-(nonyloxy)phenyltrifluoroborate 7.10b and decyl 5-iodothieno[3,2-b]thiophene-2carboxylate 7.7c; the workup was performed with diethyl ether rather than dichloromethane. Quantities: decyl 5-iodothieno[3,2-b]thiophene-2-carboxylate 8c (399.8 mg, 0.8877 mmol), toluene (20 mL), potassium 4-(nonyloxy)phenyltrifluoroborate 13b (373.7 mg, 1.145 mmol), K2CO3 (310.6 mg, 2.247 mmol), tetrakis(triphenylphosphine)palladium(0) (95.5 mg, 0.0826 mmol), acetone (10 mL), water (5 mL). The crude brown solid was purified by column chromatography (40 g silica; 25% dichloromethane in petroleum ether) to afford an off-white solid. Recrystallization from ethyl acetate and drying under high vacuum (P2O5) yielded white crystals for analysis. Yield: 229.0 mg (48%). Transitions (C) Cryst 135.9 SmC 137.0 SmA 144.3 Iso Liq (Rec. 128.5). 1H NMR (CDCl3): 0.88 (t, 3H, J = 6.9 Hz), 0.89 (t, 3H, J = 6.9 Hz), 1.21-1.40 (m, 22H), 1.40-1.51 (m, 4H), 1.76 (quint, 2H, J = 7.3 Hz), 1.80 (quint, 2H, J = 7.4 Hz), 3.99 (t, 2H, J = 6.6 Hz), 4.31 (t, 2H, J = 6.7 Hz), 6.93 (d, 2H, J = 8.8 Hz), 7.36 (d, 1H, J = 0.6 Hz), 7.55 (d, 2H, J = 8.8 Hz), 7.94 (d, 1H, J = 0.6 Hz). 13C NMR (CDCl3): 14.1, 22.7, 25.99, 26.03, 28.7, 29.2, 29.27, 29.32, 29.4, 29.5, 31.89, 31.90, 65.5, 68.2, 114.2, 115.0, 125.7, 126.6, 127.4, 133.7, 137.1, 145.0, 150.8, 159.7, 162.8. Anal. Calcd for C32H46O3S2: C, 70.80; H, 8.54. Found: C, 70.65; H, 8.44.

242 Octyl 5-(4-(decyloxy)phenyl)thieno[3,2-b]thiophene-2-carboxylate (7.12g) Compound 7.12g was prepared in the same manner as compound 7.12a from potassium 4-(decyloxy)phenyltrifluoroborate 7.10c; the workup was performed with diethyl ether rather than dichloromethane. Quantities: octyl 5-iodothieno[3,2-b]thiophene-2carboxylate 7.7a (400.9 mg, 0.9492 mmol), toluene (20 mL), potassium 4(decyloxy)phenyltrifluoroborate 7.10c (432.5 mg, 1.271 mmol), K2CO3 (354.4 mg, 2.564 mmol), tetrakis(triphenylphosphine)palladium(0) (94.3 mg, 0.0816 mmol), acetone (10 mL), water (5 mL). The crude brown solid was purified by silica gel chromatography (40 g silica, 25% dichloromethane in petroleum ether) to afford a white solid. Recrystallization from ethyl acetate and drying under high vacuum (P2O5) yielded white crystals for analysis. Yield: 370.1 mg (74%). Transitions (C) Cryst 141.5 SmC 144.7 SmA 147.5 Iso Liq (Rec. 133.4). 1H NMR (CDCl3): 0.88 (t, 3H, J = 6.6 Hz), 0.89 (t, 3H, J = 6.9 Hz), 1.22-1.40 (m, 20H), 1.41-1.50 (m, 4H), 1.76 (quint, 2H, J = 7.4 Hz), 1.80 (quint, 2H, J = 7.2 Hz), 3.99 (t, 2H, J = 6.6 Hz), 4.31 (t, 2H, J = 6.7 Hz), 6.93 (d, 2H, J = 8.7 Hz), 7.36 (s, 1H), 7.55 (d, 2H, J = 8.6 Hz), 7.94 (s, 1H). 13C NMR (CDCl3): 14.1, 22.67, 22.69, 26.00, 26.04, 28.8, 29.22, 29.25, 29.33, 29.4, 29.6, 31.8, 31.9, 65.5, 68.2, 114.3, 115.1, 125.7, 126.7, 127.4, 133.7, 137.1, 145.0, 150.9, 159.7, 162.8. Anal. Calcd for C31H44O3S2: C, 70.41; H, 8.39. Found: C, 70.16; H, 8.30. Nonyl 5-(4-(decyloxy)phenyl)thieno[3,2-b]thiophene-2-carboxylate (7.12h) Compound 7.12h was prepared in the same manner as compound 7.12a from potassium 4-(decyloxy)phenyltrifluoroborate 7.10c and nonyl 5-iodothieno[3,2-b]thiophene-2-

243 carboxylate 7.7b; the workup was performed with diethyl ether rather than dichloromethane. Quantities: nonyl 5-iodothieno[3,2-b]thiophene-2-carboxylate 7.7b (418.8 mg, 0.9597 mmol), toluene (20 mL), potassium 4-(decyloxy)phenyltrifluoroborate 7.10c (438.8 mg, 1.290 mmol), K2CO3 (383.7 mg, 2.776 mmol), tetrakis(triphenylphosphine)palladium(0) (98.6 mg, 0.0853 mmol), acetone (10 mL), water (5 mL). The crude brown solid was purified by column chromatography (40 g silica; 25% dichloromethane in petroleum ether) to afford an off-white solid. Recrystallization from ethyl acetate and drying under high vacuum (P2O5) yielded white crystals for analysis. Yield: 416.2 mg (80%). Transitions (C) Cryst 142.3 SmC 142.6 SmA 145.6 Iso Liq (Rec. 134.1). 1H NMR (CDCl3): 0.88 (t, 6H, J = 6.8 Hz), 1.22-1.40 (m, 22H), 1.46 (quint, 4H, J = 7.6 Hz), 1.76 (quint, 2H, J = 7.1 Hz), 1.80 (quint, 2H, J = 9.6 Hz), 3.99 (t, 2H, J = 6.6 Hz), 4.31 (t, 2H, J = 6.7 Hz), 6.93 (d, 2H, J = 8.8 Hz), 7.35 (s, 1H), 7.55 (d, 2H, J = 8.8 Hz), 7.93 (s, 1H) . 13C NMR (CDCl3): 14.1, 22.7, 25.99, 26.03, 28.7, 29.2, 29.26, 29.29, 29.33, 29.5, 29.5, 29.57, 29.58, 31.88, 31.91, 65.5, 68.2, 114.2, 115.0, 125.7, 126.6, 127.4, 133.7, 137.1, 145.0, 150.8, 159.7, 162.7. Anal. Calcd for C32H46O3S2: C, 70.80; H, 8.54. Found: C, 70.71; H, 8.55. Decyl 5-(4-(decyloxy)phenyl)thieno[3,2-b]thiophene-2-carboxylate (7.12i) Compound 7.12i was prepared in the same manner as compound 7.12a from potassium 4(decyloxy)phenyltrifluoroborate 7.10c and decyl 5-iodothieno[3,2-b]thiophene-2carboxylate 7.7c; the workup was performed with diethyl ether rather than dichloromethane. Quantities: decyl 5-iodothieno[3,2-b]thiophene-2-carboxylate 7.7c

244 (433.2 mg, 0.9618 mmol), toluene (20 mL), potassium 4-(decyloxy)phenyltrifluoroborate 7.10c (437.5 mg, 1.286 mmol), K2CO3 (362.3 mg, 2.621 mmol), tetrakis(triphenylphosphine)palladium(0) (98.9 mg, 0.0856 mmol), acetone (10 mL), water (5 mL). The crude brown solid was purified by column chromatography (40 g silica; 25% dichloromethane in petroleum ether) to afford a white solid. Recrystallization from ethyl acetate and drying under high vacuum (P2O5) yielded white crystals for analysis. Yield: 365.2 mg (68%). Transitions (C) Cryst 139.7 SmC 139.9 SmA 142.9 Iso Liq (Rec. 132.6). 1H NMR (CDCl3): 0.88 (t, 6H, J = 6.2 Hz), 1.21-1.40 (m, 24H), 1.46 (quint, 4H, J = 7.3 Hz), 1.76 (quint, 2H, J = 7.3 Hz), 1.79 (quint, 2H, J = 7.1 Hz), 3.98 (t, 2H, J = 6.5 Hz), 4.31 (t, 2H, J = 6.6 Hz), 6.92 (d, 2H, J = 8.7 Hz), 7.35 (s, 1H), 7.54 (d, 2H, 8.6 Hz), 7.93 (s, 1H). 13C NMR (CDCl3): 14.1, 22.7, 26.00, 26.04, 28.8, 29.2, 29.28, 29.33, 29.4, 29.6, 31.9, 65.4, 68.2, 114.2, 115.1, 125,7, 126.6, 127.4, 133.7, 137.1, 145.0, 150.9, 159.7, 162.7. Anal. Calcd for C33H48O3S2: C, 71.18; H, 8.69. Found: C, 71.10; H, 8.79. ( )-Octan-2-yl 5-(4-nonyloxyphenyl)thieno[3,2-b]thiophene-2-carboxylate (7.12j) Compound 7.12j was prepared in the same manner as 7.12a from 7.7f and potassium 4nonyloxyphenyltrifluoroborate 7.10b. Quantities: 7.7f (469.9 mg, 1.113 mmol), potassium 4-nonyloxyphenyltrifluoroborate 7.10b (470.3 mg, 1.442 mmol), K2CO3 (439.7 mg, 3.181 mmol), tetrakistriphenylphosphine palladium(0) (139.1 mg, 0.1204 mmol), toluene (20 mL), acetone (10 mL) and water (5 mL). The crude brown solid was purified by column chromatography (silica gel; 25% dichloromethane in petroleum ether)

245 to afford 7.12j as a white solid. The product was recrystallized from ethyl acetate and dried in vacuo (P2O5) to afford white crystals. Yield: 494.8 mg (86%) Transitions ( C) Cryst 100.0 (SmC 86.9 SmA 90.2) Iso Liq (Rec.89.6); Transition temperatures were recorded at a cooling rate of 10 C min-1). At a cooling rate of 5 C min-1 crystallization occurred in tandem with the formation of the SmA phase and the SmC phase was not visible. Cooling at 10 C min-1 revealed the SmC phase but again crystallization occurred at the same time as the mesophase formed). Found: C, 70.18; H, 8.15. Calc. for C30H42O3S2: C, 69.99; H, 8.22%. 1H NMR (CDCl3): 0.88 (t, 3H, J = 6.9 Hz), 0.89 (t, 3H, J = 6.8 Hz), 1.23-1.41 (m, 18H), 1.35 (d, 3H, J = 6.3 Hz), 1.46 (quint, 2H, J = 7.2 Hz), 1.57-1.75 (m, 2H), 1.80 (quint, 2H, J = 7.0 Hz), 3.99 (t, 2H, J = 6.6 Hz), 5.13 (apparent sext, 1H, J = 6.3 Hz), 6.93 (d, 2H, J = 8.8 Hz), 7.36 (d, 1H, J = 0.52 Hz), 7.55 (d, 2H, J = 8.8 Hz), 7.92 (d, 1H, J = 0.56 Hz). 13C NMR (CDCl3): 14.07, 14.12, 20.1, 22.6, 22.7, 25.4, 26.0, 29.16, 29.23, 29.28, 29.4, 29.5, 31.8, 31.9, 36.1, 68.2, 72.3, 114.2, 115.0, 125.5, 126.6, 127.3, 134.3, 137.1, 144.9, 150.7, 159.6, 162.3. ( )-Octan-2-yl 5-(4-decyloxyphenyl)thieno[3,2-b]thiophene-2-carboxylate (7.12k) Compound 7.12k was prepared in the same manner as 7.12a from 7.7f and potassium 4decyloxyphenyltrifluoroborate 7.10c. Quantities: 7.7f (413.7 mg, 0.9795 mmol), potassium 4-decyloxyphenyltrifluoroborate 7.10c (438.3 mg, 1.288 mmol), K2CO3 (384.5 mg, 2.782 mmol), tetrakistriphenylphosphine palladium(0) (113.1 mg, 0.09787 mmol), toluene (20 mL), acetone (10 mL) and water (5 mL). The crude brown solid was purified by column chromatography (silica gel; 25% dichloromethane in petroleum ether) to

246 afford 7.12k as a white solid. The product was recrystallized from ethyl acetate and dried in vacuo (P2O5) to afford white crystals. Yield: 410.7 mg (79%). Transitions ( C) Cryst 97.6 (SmA 89.9) Iso Liq (Rec. 89.4; the SmA phase and recrystallization were seen in tandem. The SmC phase was not observed even at a cooling rate of 15 C min-1). Found: C, 70.30; H, 8.45. Calc. for C31H44O3S2: C, 70.41; H, 8.39%. 1H NMR (400 MHz, CDCl3): 0.879 (t, 3H, J = 6.9 Hz), 0.883 (t, 3H, J = 6.9 Hz), 1.23-1.42 (m, 20H), 1.34 (d, 3H, J = 6.2 Hz), 1.46 (quint, 2H, J = 7.3 Hz), 1.54-1.75 (m, 2H), 1.79 (quint, 2H, J = 7.0 Hz), 3.98 (t, 2H, J = 6.6 Hz), 5.13 (apparent sext, 1H, J = 6.3 Hz), 6.92 (d, 2H, J = 8.8 Hz), 7.34 (d, 1H, J = 0.40 Hz), 7.54 (d, 2H, J = 8.8 Hz), 7.92 (d, 1H, J = 0.44 Hz).
13

C NMR (100 MHz, CDCl3): 14.08, 14.13, 20.1, 22.6, 22.7, 25.4, 26.0, 29.16, 29.23,

29.3, 29.4, 29.58, 29.59, 31.8, 31.9, 36.1, 68.2, 72.3, 114.2, 115.0, 125.5, 126.7, 127.4, 134.3, 137.1, 144.9, 150.7, 159.7, 162.4.

247 7.3 Experimental for Chapter 3

3-Formylthiophene (7.13) Compound 7.13 was prepared in a manner similar to Archer255 (we used 1:1 petroleum ether:THF as solvent and N-formylpiperidine rather than DMF as the formylating agent). To an oven-dried flask were added petroleum ether (50 mL, dried over 4 molecular sieves) and anhydrous THF (50 mL). The stirred mixture was cooled to -72 C before nbutyllithium (10 M in hexanes, 5.00 mL, 50. mmol) was added in one portion by syringe while not exceeding -66 C. A solution of 3-bromothiophene (7.3973 g, 45.371 mmol) in THF (12 mL) was then added by syringe pump over 1.5 hours between -76 C and -72 C. After a further 30 min. of stirring, N-formylpiperidine (7.24 g, 64.0 mmol) was added dropwise by syringe pump over 1 hour with the reaction temperature maintained between -74 C and -70 C. The clear mixture was then allowed to warm to room temperature overnight. The resulting white suspension was poured into aq. NH4Cl (sat., 100 mL) and

248 stirred vigorously for 1 hour to afford a deep red bisphasic mixture. The organic layer was separated and washed with water (3 50 mL) before the combined aqueous layers were extracted with diethyl ether (2 50 mL). The combined organic extracts were then washed with brine (50 mL), dried (MgSO4), filtered, and concentrated to afford a brown liquid (7.20 g) which was used in the next step without further purification. Analytical data were consistent with the literature.255, 392 Yield: 7.20 g. 1H NMR (CDCl3): 7.39 (dd, 1H, J = 4.9, 2.9 Hz), 7.55 (dd, 1H, J = 5.1, 1.0 Hz), 8.12 (dd, 1H, J = 2.9, 1.1 Hz), 9.94 (s, 1H) (Signals from impurities not included). 2,5-Dibromo-3-formylthiophene (7.14) Compound 7.14 was prepared in the manner of Jones and co-workers.391 To a stirred mixture of crude 7.13 (7.20 g), NaHCO3 (11.50 g, 136.9 mmol), and chloroform (100 mL) was added dropwise under argon, over approximately 2 hours, a solution of Br2 (7.00 mL, d = 3.119 g mL-1 at 25 C, 137 mmol) in chloroform (100 mL). The mixture was allowed to stir overnight before it was washed with water (2 100 mL) and sodium thiosulfate (saturated aqueous, 100 mL). The aqueous washings were extracted with dichloromethane (100 mL) and the combined organic layers were then dried (MgSO4) and concentrated in vacuo to yield a dark red-brown liquid (12.40 g). Purification by column chromatography (silica gel; 5% ethyl acetate in petroleum ether) afforded 7.14 as a yellow solid; analytical data were consistent with the literature.391 Yield: 7.94 g (65% two-step yield). 1H NMR (CDCl3): 7.34 (s, 1H), 7.97 (s, 1H).

249 Octyl 5-bromothieno[2,3-b]thiophene-2-carboxylate (7.15a) A mixture of octyl mercaptoacetate 7.2a (2.16 g, 10.6 mmol), K2CO3 (1.92 g, 13.9 mmol), and 7.14 (2.86 g, 10.6 mmol) in DMF (40 ml) was stirred under an open atmosphere at room temperature for 2 days. The potassium salts were filtered off and the crude product was concentrated in vacuo. The crude material was diluted with diethyl ether (100 mL) and washed with water (3 20 mL). The combined aqueous washings were extracted with diethyl ether (3 20 mL). The combined organic layers were then washed with brine (40 mL), dried over MgSO4, filtered, and concentrated in vacuo to afford a brown liquid (3.67 g) that solidified upon standing. Purification by column chromatography (silica gel; 3% ethyl acetate in petroleum ether) afforded 7.15a as a yellow solid. The product was recrystallized from a 1:1 mixture of diethyl ether and petroleum ether before being dried in vacuo (P2O5) to afford off-white crystals for analysis. Yield: 3.27 g (82%). mp 39.4-40.7 C. Found: 48.00; H, 5.16. Calc. for C15H19BrO2S2 : C, 48.00; H, 5.10%. 1H NMR (CDCl3): 0.88 (t, 3H, J = 6.9 Hz), 1.201.38 (m, 8H), 1.42 (quint, 2H, J = 7.4 Hz), 1.75 (quint, 2H, J = 7.1 Hz), 4.30 (t, 2H, J = 6.7 Hz), 7.25 (s, 1H), 7.83 (s, 1H). 13C NMR (CDCl3): 14.1, 22.7, 26.0, 28.7, 29.20, 29.22, 31.8, 65.6, 114.7, 123.4, 125.1, 136.2, 142.5, 145.0, 162.2.

250 Nonyl 5-bromothieno[2,3-b]thiophene-2-carboxylate (7.15b) Compound 7.15b was prepared in same manner as 7.15a from nonyl mercaptoacetate 7.2b. Quantities: nonyl mercaptoacetate 7.2b (2.52 g, 11.5 mmol), K2CO3 (2.08 g, 15.0 mmol), 7.14 (3.12 g, 11.6 mmol) and DMF (40 mL). The resulting crude brown liquid was purified by column chromatography (silica gel; 3% ethyl acetate in petroleum ether) to afford a yellow solid. The product was recrystallized from a 1:1 mixture of petroleum ether and diethyl ether before being dried in vacuo (P2O5) to afford 7.15b as white crystals for analysis. Yield: 3.79 g (84%). mp 34.6-36.6 C. Found C, 49.27; H, 5.45. Calc. for C16H21BrO2S2: C, 49.35; H, 5.44%. 1H NMR (CDCl3): 0.88 (t, 3H, J = 6.8 Hz), 1.22-1.38 (m, 10H), 1.45 (quint, 2H, J = 7.0 Hz), 1.75 (quint, 2H, J = 7.0 Hz), 4.31 (t, 2H, J = 6.6 Hz), 7.28 (s, 1H), 7.84 (s, 1H). 13C NMR (CDCl3): 14.1, 22.7, 26.0, 28.7, 29.2, 29.3, 29.5, 31.9, 65.7, 114.7, 123.4, 125.1, 136.2, 142.5, 145.0, 162.2. Decyl 5-bromothieno[2,3-b]thiophene-2-carboxylate (7.15c) Compound 7.15c was prepared in same manner as 7.15a from decyl mercaptoacetate 7.2c. Quantities: decyl mercaptoacetate 7.2c (2.58 g, 11.1 mmol), K2CO3 (2.01 g, 14.5 mmol), 7.14 (3.00 g, 11.1 mmol) and DMF (40 ml). The resulting crude brown liquid was purified by column chromatography (silica gel; 3% ethyl acetate in petroleum ether) to afford a peach solid. The product was recrystallized from a 1:1 mixture of petroleum ether and diethyl ether before being dried in vacuo (P2O5) to afford 7.15c as white crystals for analysis. Yield: 4.59 g (80%). mp 42.4-47.9 C. Found: C, 50.72; H, 5.84. Calc. for C17H23BrO2S2: C, 50.62; H, 5.75%. 1H NMR (CDCl3): 0.88 (t, 3H, J = 6.8

251 Hz), 1.21-1.37 (m, 12H), 1.42 (quint, 2H, J = 7.2 Hz), 1.75 (quint, 2H, J = 7.0 Hz), 4.30 (t, 2H, J = 6.7 Hz), 7.26 (s, 1H), 7.83 (s, 1H). 13C NMR (CDCl3): 14.1, 22.7, 26.0, 28.7, 29.25, 29.31, 29.5, 31.9, 65.7, 114.7, 123.4, 125.1, 136.2, 142.5, 145.0, 162.2. One carbon signal was obscured due to accidental equivalence. ()-Octan-2-yl 5-bromothieno[2,3-b]thiophene-2-carboxylate (7.15f) Compound 7.15f was prepared in the same manner as 7.15a from octan-2-yl mercaptoacetate 7.2f. Quantities: octan-2-yl mercaptoacetate 7.2f (1.5267 g, 7.4717 mmol), K2CO3 (1.3775 g, 9.9667 mmol), 7.14 (2.0392 g, 7.5543 mmol) and DMF (20 ml). The crude orange liquid was purified by column chromatography (silica gel, 3% ethyl acetate in petroleum ether) to yield 7.15f as a light yellow liquid. Yield: 2.31 g (82%). Found: 48.32; H, 5.22. Calc. for C15H19BrO2S2: C, 48.00; H, 5.10%. 1H NMR (CDCl3): 0.88 (t, 3H, J = 6.8 Hz), 1.22-1.45 (m, 8H), 1.34 (d, 3H, J = 6.2 Hz), 1.551.79 (m, 2H), 5.12 (apparent sext, 1H, J = 6.3 Hz), 7.26 (s, 1H), 7.83 (s, 1H). 13C NMR (CDCl3): 14.1, 20.1, 22.6, 25.3, 29.1, 31.7, 36.0, 72.7, 114.6, 123.4, 124.9, 136.7, 142.4, 145.0, 161.8. Nonyl 5-(4-nonyloxyphenyl)thieno[2,3-b]thiophene-2-carboxylate (7.16a) To an oven-dried 3-neck flask were added, under argon, 7.15b (396.3 mg, 1.018 mmol) and toluene (20 mL; sparged previously for 25 minutes with argon). Next were added potassium 4-nonyloxyphenyltrifluoroborate (431.2 mg, 1.322 mmol), K2CO3 (378.5 mg, 2.739 mmol), tetrakis(triphenylphosphine) palladium(0) (128.1 mg, 0.1109 mmol),

252 acetone (10 mL; sparged previously for 20 minutes with argon) and water (5 mL; sparged previously for 20 minutes with argon). The mixture was brought to reflux with vigorous stirring. After 19 hours (NMR verified completion of the reaction) heating was discontinued and the cooled crude mixture was poured into dichloromethane (30 mL) and shaken with water (30 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (3 30 mL). The combined organic layers were washed with brine (50 mL), dried over MgSO4, filtered, and concentrated to afford a brown solid. Purification by column chromatography (silica gel; 25% dichloromethane in petroleum ether) afforded 7.16a as a white solid. The product was recrystallized from ethyl acetate and dried in vacuo (P2O5) to afford white crystals for analysis. Yield: 458.1 mg (85%). Transitions ( C) Cryst 119.0 SmC 141.0 SmA 145.1 Iso Liq (Rec. 114.8). Found: C, 70.70; H, 8.48. Calc. for C31H44O3S2: C, 70.41; H, 8.39%. max(CHCl3)/nm 283 (/dm3 mol-1 cm-1 4.2 104), 311sh. 1H NMR (CDCl3): 0.884 (t, 3H, J = 6.3 Hz), 0.887 (t, 3H, J = 6.3 Hz), 1.23-1.40 (m, 20H), 1.40-1.51 (m, 4H), 1.77 (quint, 2H, J = 7.4 Hz), 1.80 (quint, 2H, J = 7.1 Hz), 3.98 (t, 2H, J = 6.6 Hz), 4.31 (t, 2H, J = 6.7 Hz), 6.92 (d, 2H, J = 8.8 Hz), 7.31 (s, 1H), 7.51 (d, 2H, J = 8.8 Hz), 7.89 (s, 1H). 13C NMR (CDCl3): 14.1, 22.7, 25.98, 26.04, 28.7, 29.3, 29.4, 29.51, 29.55, 31.9, 65.5, 68.2, 114.9, 115.0, 126.0, 126.7, 127.3, 135.8, 141.8, 146.7, 148.4, 159.3, 162.4; the remaining 6 aliphatic signals are accidentally equivalent and appear as a broad signal at 29.2-29.35.

253 Octyl 5-(4-decyloxyphenyl)thieno[2,3-b]thiophene-2-carboxylate (7.16b) Compound 7.16b was prepared in the same manner as 7.16a from 7.15a and potassium 4decyloxyphenyltrifluoroborate 7.10c. Quantities: 7.15a (427.0 mg, 1.138 mmol), potassium 4-decyloxyphenyltrifluoroborate 7.10c (500.5 mg, 1.471 mmol), K2CO3 (443.4 mg, 3.208 mmol), tetrakis(triphenylphosphine) palladium(0) (129.8 mg, 0.1123 mmol), toluene (20 mL), acetone (10 mL) and water (5 mL). The crude brown solid was purified by column chromatography (silica gel; 25% dichloromethane in petroleum ether) to afford 7.16b as a white solid. The product was recrystallized from ethyl acetate and dried in vacuo (P2O5) to afford white crystals for analysis. Yield: 520.7 mg (87%). Transitions ( C) Cryst 115.5 SmC 143.8 SmA 145.6 Iso Liq (Rec. 113.2). Found: C, 70.38; H, 8.49. Calc. for C31H44O3S2: C, 70.44; H, 8.39%. 1H NMR (CDCl3): 0.885 (t, 3H, J = 6.9 Hz), 0.889 (t, 3H, J = 7.2 Hz), 1.22-1.40 (m, 20H), 1.40-1.51 (m, 4H), 1.76 (quint, 2H, J = 7.1 Hz), 1.79 (quint, 2H, J = 7.0 Hz), 3.98 (t, 2H, J = 6.6 Hz), 4.31 (t, 2H, J = 6.7 Hz), 6.92 (d, 2H, J = 8.7 Hz), 7.31 (s, 1H), 7.51 (d, 2H, J = 8.7 Hz), 7.89 (s, 1H). 13C NMR (CDCl3): 14.12, 14.13, 22.67, 22.70, 25.99, 26.04, 28.7, 29.2, 29.3, 29.4, 29.58, 29.59, 31.8, 31.9, 65.5, 68.2, 114.87, 115.00, 126.0, 126.7, 127.3, 135.8, 141.8, 146.7, 148.5, 159.4, 162.4; 2 aliphatic signals are obscured due to accidental equivalence. Nonyl 5-(4-decyloxyphenyl)thieno[2,3-b]thiophene-2-carboxylate (7.16c) Compound 7.16c was prepared in the same manner as 7.16a from 7.15b and potassium 4decyloxyphenyltrifluoroborate 7.10c. Quantities: 7.14c (477.8 mg, 1.227 mmol), potassium 4-decyloxyphenyltrifluoroborate 7.10c (548.1 mg, 1.611 mmol), K2CO3 (478.8

254 mg, 3.464 mmol), tetrakis(triphenylphosphine) palladium(0) (148.0 mg, 0.1281 mmol), toluene (20 mL), acetone (10 mL) and water (5 mL). The resulting crude brown solid was purified by column chromatography (silica gel; 25% dichloromethane in petroleum ether) to afford 7.16c as a white solid. The product was recrystallized from ethyl acetate and dried in vacuo (P2O5) to afford white crystals for analysis. Yield: 574.2 mg (86%) Transitions ( C) Cryst 120.7 SmC 142.2 SmA 143.6 Iso Liq (Rec. 116.7). Found: C, 70.77; H, 8.58. Calc. for C32H46O3S2: C, 70.80; H, 8.54%. 1H NMR (CDCl3): 0.88 (t, 6H, J = 6.9 Hz), 1.23-1.40 (m, 22H), 1.40-1.50 (m, 4H), 1.76 (quint, 2H, J = 7.2 Hz), 1.79 (quint, 2H, J = 7.0 Hz), 3.98 (t, 2H, J = 6.6 Hz), 4.31 (t, 2H, J = 6.7 Hz), 6.92 (d, 2H, J = 8.8 Hz), 7.30 (s, 1H), 7.50 (d, 2H, J = 8.8 Hz), 7.89 (s, 1H). 13C NMR (CDCl3): 14.1, 22.7, 25.98, 26.04, 28.7, 29.24, 29.25, 29.28, 29.34, 29.4, 29.5, 29.57, 29.59, 31.88, 31.91, 65.5, 68.2, 114.9, 115.0, 126.0, 126.7, 127.3, 135.8, 141.8, 146.7, 148.4, 159.3, 162.4; 2 aliphatic signals are obscured due to accidental equivalence. Decyl 5-(4-decyloxyphenyl)thieno[2,3-b]thiophene-2-carboxylate (7.16d) Compound 7.16d was prepared in the same manner as 7.16a from 7.15c and potassium 4decyloxyphenyltrifluoroborate 7.10c. Quantities: 7.15c (434.0 mg, 1.076 mmol), potassium 4-decyloxyphenyltrifluoroborate 7.10c (479.0 mg, 1.408 mmol), K2CO3 (424.5 mg, 3.071 mmol), tetrakis(triphenylphosphine) palladium(0) (131.5 mg, 0.1138 mmol), toluene (20 mL), acetone (10 mL) and water (5 mL). The crude light orange solid was purified by column chromatography (silica gel; 25% dichloromethane in petroleum ether) to afford 7.16d as a white solid. The product was recrystallized from ethyl acetate and

255 dried in vacuo (P2O5) to afford white crystals for analysis. Yield: 514.7 mg (86%). Transitions ( C) Cryst 119.7 SmC 139.4 SmA 141.0 Iso Liq (Rec. 115.2). Found: C, 71.23; H, 8.64. Calc. for C33H48O3S2: C, 71.18; H, 8.69%. 1H NMR (CDCl3): 0.881 (t, 3H, J = 6.3 Hz), 0.884 (t, 3H, J = 6.3 Hz), 1.21-1.40 (m, 24H), 1.40-1.51 (m, 4H), 1.76 (quint, 2H, J = 7.1 Hz), 1.79 (quint, 2H, J = 7.0 Hz), 3.97 (t, 2H, J = 6.6 Hz), 4.31 (t, 2H, J = 6.7 Hz), 6.92 (d, 2H, J = 8.8 Hz), 7.30 (s, 1H), 7.50 (d, 2H, J = 8.8 Hz), 7.88 (s, 1H).
13

C NMR (CDCl3): 14.1, 22.7, 25.99, 26.04, 28.7, 29.24, 29.28, 29.33, 29.4, 29.55,

29.58, 29.59, 31.9, 65.5, 68.2, 114.85, 114.99, 125.99, 126.7, 127.3, 135.8, 141.8, 146.7, 148.4, 159.3, 162.4; 5 aliphatic signals are obscured due to accidental equivalence. ( )-Octan-2-yl 5-(4-nonyloxyphenyl)thieno[2,3-b]thiophene-2-carboxylate (7.16e) Compound 7.16e was prepared in the same manner as 7.16a from 7.15f and potassium 4nonyloxyphenyltrifluoroborate. Quantities: 7.15f (424.4 mg, 1.131 mmol), potassium 4nonyloxyphenyltrifluoroborate 7.10b (479.6 mg, 1.470 mmol), K2CO3 (429.8 mg, 3.110 mmol), tetrakis(triphenylphosphine) palladium(0) (128.7 mg, 0.1114 mmol), toluene (20 mL), acetone (10 mL) and water (5 mL). The crude yellow-brown solid was purified by column chromatography (silica gel; 25% dichloromethane in petroleum ether) to afford a white solid. The product was recrystallized from ethyl acetate and dried in vacuo (P2O5) to afford 7.16e as white crystals for analysis. Yield: 529.5 mg (91%). Transitions ( C) Cryst 101.4 (SmC 89.8 SmA 92.9) Iso Liq (Rec. 78.0). Found: C, 70.09; H, 8.28. Calc. for C30H42O3S2: C, 69.99; H, 8.22%. 1H NMR (CDCl3): 0.88 (t, 3H, J = 6.8 Hz), 0.89 (t, 3H, J = 6.8 Hz),1.23-1.41 (m, 18H), 1.34 (d, 3H, J = 6.2 Hz), 1.46 (quint, 2H, J = 7.1

256 Hz), 1.55-1.75 (m, 2H), 1.79 (quint, 2H, J = 7.0 Hz), 3.97 (t, 2H, J = 6.6 Hz), 5.13 (apparent sext, 1H, J = 6.3 Hz), 6.91 (d, 2H, J = 8.8 Hz), 7.30 (s, 1H), 7.50 (d, 2H, J = 8.8 Hz), 7.87 (s, 1H). 13C NMR (CDCl3): 14.08, 14.12, 20.1, 22.6, 22.7, 25.4, 26.0, 29.15, 29.25, 29.3, 29.4, 29.6, 31.8, 31.9, 36.0, 68.2, 72.4, 114.9, 115.0, 125.8, 126.8, 127.3, 136.4, 141.7, 146.7, 148.4, 159.3, 162.0. ( )-Octan-2-yl 5-(4-decyloxyphenyl)thieno[2,3-b]thiophene-2-carboxylate (7.16f) Compound 7.16f was prepared in the same manner as 7.16a from 7.15d and potassium 4decyloxyphenyltrifluoroborate 7.10c. Quantities: 7.15d (410.8 mg, 1.094 mmol), potassium 4-decyloxyphenyltrifluoroborate 7.10c (479.6 mg, 1.409 mmol), K2CO3 (431.5 mg, 3.122 mmol), tetrakistriphenylphosphine palladium(0) (121.8 mg, 0.1054 mmol), toluene (20 mL), acetone (10 mL) and water (5 mL). The crude red-brown solid was purified by column chromatography (silica gel; 25% dichloromethane in petroleum ether) to afford a white solid. The product was recrystallized from ethyl acetate and dried in vacuo (P2O5) to afford 7.16f as white crystals for analysis. Yield: 465.4 mg (80%). Transitions ( C) Cryst 97.4 (SmC 90.1 SmA 92.1) Iso Liq (Rec. 77.1). Found C, 70.70; H, 8.41. Calc. for C31H44O3S2: C, 70.41; H, 8.39%. 1H NMR (CDCl3): 0.880 (t, 3H, J = 6.8 Hz), 0.884 (t, 3H, J = 6.8 Hz), 1.23-1.41 (m, 20H), 1.35 (d, 3H, J = 6.2 Hz), 1.46 (quint, 2H, J = 7.2 Hz), 1.56-1.75 (m, 2H), 1.80 (quint, 2H, J = 7.0 Hz), 3.99 (t, 2H, J = 6.6 Hz), 5.13 (sext, 1H, J = 6.3 Hz), 6.93 (d, 2H, J = 8.8 Hz), 7.31 (s, 1H), 7.51 (d, 2H, J = 8.8 Hz), 7.88 (s, 1H). 13C NMR (CDCl3): 14.08, 14.13, 20.1, 22.6, 22.7, 25.4, 26.0, 29.1, 29.2, 29.3, 29.4, 29.58, 31.7, 31.9, 36.0, 68.2, 72.4, 115.0, 125.8, 126.8, 127.3,

257 136.4, 141.7, 146.7, 148.4, 159.3, 162.0; 1 aliphatic and 1 aromatic signal are obscured from view due to accidental equivalence. 7.4 Experimental for Chapter 4

Thiophen-2-ylboronic acid (7.17a) The boronic acid was prepared in the manner of Burrell and coworkers,495 except that trimethyl borate was used instead of triisopropyl borate. A solution of thiophene (10.05 g, 119.4 mmol) in anhydrous THF (140 mL; distilled under argon from sodium/benzophenone) was stirred under argon and cooled to -76 C before nbutyllithium (12.0 mL; 10 M in hexanes, 120 mmol) was added dropwise by syringe with the reaction temperature maintained at -76 C to -72 C. The solution was allowed to stir 30 minutes further at this range before the resulting off-white suspension was allowed to warm to -20 C. Upon warming, the suspension became a transparent solution, which was again chilled to -76 C. The solution was then transferred slowly by cannula (positive pressure) to a solution of trimethyl borate (17.44 g, 167.8 mmol) in dry THF (80 mL) from -70 C to -64 C. The resulting mixture was allowed to warm to room temperature and stirred overnight before being hydrolyzed with aq. HCl (17 mL conc. HCl diluted to 100 mL) for one hour. The layers were then separated and the aqueous phase was extracted with dichloromethane (4 100 mL). The combined organic extracts

258 were dried (MgSO4), filtered, and concentrated to give a yellow solid. Recrystallization from H2O yielded light grey crystals which were pure (mix of acid and anhydride) by NMR. Analytical data were consistent with previously reported data.310 Yield: 11.93 g (78%). 1H NMR (DMSO-d6): 7.18 (dd, 1H, J = 4.7, 3.4 Hz), 7.70 (dd, 1H, J = 3.4, 0.9 Hz), 7.74 (dd, 1H, J = 4.7, 0.9 Hz), 8.23 (s, 2H). Potassium thiophen-2-yltrifluoroborate (7.18a) A suspension of thiophen-2-ylboronic acid 7.17a (7.00 g, 54.7 mmol) in methanol (16 mL) was stirred under ambient atmosphere and cooled in an ice/water bath before KHF2 (12.85 g, 164.5 mmol) was added in one portion. Next, H2O (36 mL) was added dropwise. The cooling bath was removed and the resulting mixture was stirred at room temperature for 15 minutes before being concentrated by rotary evaporation and dried overnight. The resulting grey-green solid was extracted with boiling acetone (200 mL) and filtered. The filtrate was concentrated and the resulting solid was recrystallized from acetone/diethyl ether and dried under high vacuum (P2O5) to afford the pure product as light grey crystals. Analytical data were consistent with previously reported data.492, 540 Yield: 6.95 g (67%). 1H NMR (DMSO-d6): 6.83-6.88 (m, 1H), 6.89-6.93 (m, 1H), 7.21 (d, 1H, J = 4.6 Hz).

259

5-Bromothiophen-2-ylboronic acid (7.17b) To a solution of anhydrous diisopropylamine (3.10 mL, d = 0.722 g mL-1 at 25C, 22.1 mmol) and anhydrous THF (60 mL), stirred under argon and cooled using a dry ice/acetone bath, was added n-butyllithium (2.05 M in cyclohexane, 9.80 mL, 20.1 mmol) dropwise by syringe; the reaction temperature was maintained at -70C to -65C. Stirring was maintained at this temperature range for 45 minutes before a solution of 2bromothiophene (3.00 g, 18.4 mmol) in anhydrous THF (30 mL) was added by syringe pump over 1.5 hours with the reaction temperature maintained at -77C to -75C. After 45 minutes of further stirring, trimethyl borate (4.10 mL, d = 0.932 g mL-1 at 25C, 36.8 mmol) was added dropwise by syringe with the reaction temperature maintained at -76C to -73C. The cooling bath was then removed and the mixture was allowed to warm to room temperature overnight. The product was hydrolyzed with aq. HCl (1 M, 75 mL, 75. mmol) for 15 minutes. The layers were separated and the organic layer was washed with sat. aq. NH4Cl (2 50 mL). The combined aqueous washings were extracted with diethyl ether (3 75 mL). The combined organic extracts were washed with brine (50 mL), dried (MgSO4), filtered, and concentrated by rotary evaporation to afford the crude product as a brown solid (2.89 g) that was used without further purification. Yield: 2.89 g. 1H NMR

260 (DMSO-d6): 7.23 (d, 1H, J = 3.6 Hz), 7.49 (d, 1H, J = 3.6 Hz). The peak from the boronic acid signal was not detected. Potassium 5-bromothiophen-2-yltrifluoroborate (7.18b) In a plastic vessel was suspended crude 5-bromothiophen-2-ylboronic acid 7.17b (2.70 g, ca. 13.1 mmol) in methanol (3.8 mL). The suspension was stirred vigorously under an open atmosphere and cooled in an ice bath before KHF2 (4.08 g, 52.2 mmol) was added in one portion. Water (8.8 mL) was next added dropwise to the cooled suspension. The ice bath was removed and the mixture was stirred at room temperature for 30 minutes. The suspension was then transferred to a flask, concentrated by rotary evaporation, and dried under a stream of air overnight. The resulting light brown solid was finely crushed and suspended in acetone (20 mL), heated in a water bath at ca. 55 C, and filtered. This extraction process was repeated twice more with the residual solids (2 20 mL acetone). The combined filtrates were concentrated and recrystallized from acetone and diethyl ether and dried under high vacuum (P2O5) to afford the target material as a white solid in two crops. Yield: 2.98 g (64% two-step yield from 2-bromothiophene). 1H NMR (DMSO-d6): 6.62 (d, 1H, J = 3.2 Hz), 6.89-6.92 (m, 1H). 13C NMR (DMSO-d6): 108.5, 127.6, 129.6, 154.7 (br). HRMS (ESI/[M+K]+) calcd. for C4H210BBrF3KS: 305.8416. Found: 305.8416.

261

2,4-Dibromothiophene (7.19) A modified literature396 procedure was used. To an oven-dried 3-neck flask under argon were added dry diisopropylamine (7.50 mL, d = 0.722 g mL-1, 53.5 mmol; distilled under N2 from CaH2) and anhydrous THF (100 mL; distilled under argon from sodium/benzophenone) under argon with stirring. The solution was cooled via a dry ice/acetone bath before n-butyllithium (10 M in hexanes, 5.00 mL, 50. mmol) was added dropwise by syringe from -70 C to -60 C. After 20 minutes of stirring at this same temperature range, 2,5-dibromothiophene (9.98 g, 41.3 mmol) was added dropwise by syringe from -72 C to -70 C. Stirring was maintained for a further 30 minutes, after which the reaction was quenched with H2O (10 mL), added dropwise from -70 C to -65 C. The mixture was stirred and allowed to warm to room temperature. The mixture was then washed with aq. NH4Cl (sat., 50 mL 2). The combined aqueous washings were extracted with diethyl ether (2 30 mL). The combined organic extracts were washed with brine (50 mL), dried (MgSO4), filtered, and concentrated by rotary evaporation to afford an orange liquid that was ~95% the desired product (ca. 5% non-HD starting material). Analytical data were consistent with the literature.535 Yield: 9.37 g (94%). 1H NMR (CDCl3): 6.98 (d, 1H, J = 1.5 Hz), 7.15 (d, 1H, J = 1.6 Hz).

262 4-Bromothiophen-2-ylboronic acid (7.17c) To a solution of 2,4-dibromothiophene 7.19 (9.52 g, 39.4 mmol) in anhydrous THF (100 mL) under argon, cooled via a brine/ice bath, was added dropwise by syringe isopropylmagnesium chloride (2.0 M in THF, 24.0 mL, 48. mmol) over 20 minutes with the reaction temperature maintained at -2 C to 1 C. After stirring for 40 minutes, trimethyl borate (8.6 mL, d = 0.932 g mL-1 at 20 C, 77 mmol) was added by syringe in one portion (temperature rose from -2 C to 12 C), and a white suspension immediately formed. After 35 minutes of further stirring, aq. HCl (2 M, 75 mL) was added in one portion (temperature rose from 0 C to 18 C). The cooling bath was removed and stirring was maintained for 10 minutes. The layers were then separated and the aqueous layer was extracted with diethyl ether (3 50 mL). The combined organic layers were

concentrated to afford the crude product as a white solid which was used without further purification. Yield: 11.88 g. 1H NMR (DMSO-d6): 7.61 (d, 1H, J = 1.2 Hz), 7.84 (d, 1H, J = 1.2 Hz), 8.41 (s, 2H). Potassium 4-bromothiophen-2-yltrifluoroborate (7.18c) Crude 4-bromothiophen-2-ylboronic acid 7.17c (10.94) was suspended in methanol (15 mL) in a plastic vessel and cooled using an ice bath. Solid KHF2 (16.48 g, 211.0 mmol) was added in one portion before H2O (35 mL) was added dropwise. The cooling bath was removed and stirring was maintained at room temperature for 1.5 hours. The mixture was then concentrated by rotary evaporation and the resulting off-white solid was dried under

263 a stream of air for 2 hours. The resulting solids were extracted with hot acetone (3 30

mL, solids crushed during each extraction). The combined filtrates were concentrated and redissolved in acetone (10 mL). Addition of diethyl ether (60 mL) induced crystallization of a white solid which was isolated by filtration and dried under high vacuum (P2O5). Yield: 8.20 g (84%, two-step yield). 1H NMR (DMSO-d6): 6.74 (s, 1H), 7.30 (s, 1H).
13

C NMR (DMSO-d6): 107.9, 121.8, 129.2, 153.5 (br). HRMS (ESI/[M+K]+) calcd. for

C4H10BBrF3KS: 305.8416. Found: 305.8406.

2,3,4,5-Tetrabromothiophene (7.20) Compound 7.20 was prepared in the manner of Araki and coworkers.500 To a vigorously stirred mixture of thiophene (10.00 g, 118.8 mmol) and chloroform (4 mL) was added dropwise by addition funnel bromine (27.5 mL, d = 3.119 g mL-1, 0.537 mol). The resulting mixture was allowed to stir at room temperature overnight (ca. 18 hrs). During the course of the reaction additional CHCl3 (ca. 30 mL total) was added periodically to allow stirring (the product precipitated). The next day, the solid/liquid mixture was

264 heated at reflux for 1.5 hours. The reaction mixture was then allowed to cool to room temperature before a solution of KOH (12.01 g, 214.0 mmol) in ethanol (70 mL) was added dropwise by addition funnel (an exothermic reaction occurred upon addition). The resulting solid/liquid mixture was heated at reflux for 4 hours, allowed to cool to room temperature, and poured onto ice (250 g). The product was collected by vacuum filtration as a yellow precipitate (46.80 g) which was purified by recrystallization with ethanol to afford white needles. Yield: 37.10 g (78%) 3,4-Dibromothiophene (7.21) To a vigorously stirred mixture of glacial acetic acid (25 mL) and water (50 mL) under argon were added tetrabromothiophene (31.79 g, 79.53 mmol, prepared as described in the literature500, 553) and zinc dust (325 mesh; 16.83 g, 257.4 mmol) alternatingly in small portions at room temperature. The flask was equipped with a Dean-Stark trap and the mixture was heated overnight under reflux. The product collected in the trap as a dense colorless liquid (ca. 8.8 mL) which was shown by NMR to be the pure product. The material was sufficiently pure to use in the subsequent step without further drying or purification. Analytical data were consistent with previously reported data.500, 502, 503 Yield: 18.28 g (95%). 1H NMR: 7.30 (s, 2H). 13C NMR: 113.9, 123.8. 3,4-Dibromothiophen-2-ylboronic acid (7.17d) To stirred solution of anhydrous diisopropylamine (1.20 mL, d = 0.722 g mL-1 at 25C, 8.56 mmol) and anhydrous THF (20 mL) under argon, cooled using a dry ice/acetone

265 bath, was added n-butyllithium (2.05 M in cyclohexane, 3.40 mL, 6.97 mmol) dropwise by syringe with the reaction temperature maintained at -75 C to -70 C. After stirring for 45 minutes at this temperature range, a solution of 3,4-dibromothiophene 7.21 (1.5074 g, 6.2307 mmol) in anhydrous THF (10 mL) was added dropwise by syringe with the reaction temperature maintained at -75 C to -73 C. Stirring was maintained for 45 minutes, after which neat trimethyl borate (1.40 mL, d = 0.932 g mL-1 at 25 C, 12.6 mmol) was added dropwise by syringe with the reaction temperature maintained at -73 C to -71 C. The mixture was allowed to stir and warm to room temperature overnight. The brown solution was hydrolyzed with aq. HCl (25 mL, 1 M) for 15 minutes. The layers were then separated; the organic layer was washed with sat. aq. NH4Cl (2 mL). The combined aqueous washings were extracted with diethyl ether (2 20

25 mL).

The combined organic extracts were washed with brine (40 mL), dried (MgSO4), filtered and concentrated by rotary evaporation to afford a burgundy oil (2.0315 g). Addition of H2O (ca. 5 mL) to this oil gave the product as waxy brown solid which was isolated by filtration and used without further purification. Yield: 1.6330 g. 1H NMR (DMSO-d6): 7.87 (s, 1H). The peak from the boronic acid signal was not detected. Potassium 3,4-dibromothiophen-2-yltrifluoroborate (7.18d) In a plastic vessel was suspended 3,4-dibromothiophen-2-ylboronic acid 7.17d (1.3924 g, 4.8728 mmol) in methanol (1.4 mL). The suspension was stirred vigorously under open atmosphere and cooled in an ice bath before KHF2 (1.18 g, 15.1 mmol) was added in one

266 portion. Water (3.3 mL) was next added dropwise to the cooled suspension. Following addition, the ice bath was removed and the mixture was stirred at room temperature for 30 minutes (after about 10 minutes a light brown precipitate had formed and so stirring was performed manually via a glass stir rod). The suspension was then transferred to a flask, concentrated at reduced pressure, and dried under a stream of air (ca. 30 minutes). The resulting light brown solid was finely crushed and suspended in acetone (20 mL), heated in a water bath at ca. 50 C, and filtered. This was repeated two more times (20 mL acetone 2) with the residual solids. The combined filtrates were then concentrated

and recrystallized from acetone/diethyl ether and dried under high vacuum (P2O5) to give the pure product as pale grey crystals in three crops. Yield: 1.1752 g (63%, two-step yield). 1H NMR (DMSO-d6): 7.52 (1H, s). 13C NMR (DMSO-d6): 111.9, 112.4, 123.2, 147.9 (br). HRMS (ESI/[M+K]+) calcd. for C4H11B(79,81)Br2F3KS: 386.7465. Found: 386.7451.

3-Bromothiophen-2-ylboronic acid (7.17e) A solution of anhydrous diisopropylamine (1.00 mL, d = 0.722 g mL-1 at 25 C, 7.14 mmol) in anhydrous THF (20 mL) was stirred and cooled using a dry ice/acetone bath under argon. Next n-butyllithium (2.05 M in cyclohexane, 2.80 mL, 5.74 mmol) was added dropwise by syringe with the reaction temperature maintained at -70 C to -65 C.

267 After 30 minutes of stirring at this temperature range, the reaction mixture was transferred to an ice/salt bath and warmed to 0 C over 15 minutes. A solution of 3bromothiophene (981.4 mg, 6.019 mmol) in anhydrous THF (10 mL) was added dropwise by syringe pump over 1 h with the reaction temperature maintained at -3 C to 1 C. Stirring at this range continued for 1 more hour before trimethyl borate (1.00 mL, d = 0.932 g mL-1 at 25 C, 8.97 mmol) was added dropwise by syringe over 15 minutes with the reaction temperature maintained at -1 C to 1 C. The reaction mixture was allowed to warm to room temperature overnight. Aq. HCl (1M, 25 mL) was added and the resulting biphasic mixture was stirred vigorously. The layers were then separated and the organic layer was washed with sat. aq. NH4Cl (2 washings were extracted with diethyl ether (2 25 mL). The combined aqueous

25 mL). The combined organic extracts

were washed with brine (40 mL), dried (MgSO4), filtered and concentrated by rotary evaporation to afford the desired product as a brown solid (1.13 g) that was used without further purification. Yield: 1.13 g. 1H NMR (DMSO-d6): 7.14 (d, 1H, J = 4.8 Hz), 7.77 (d, 1H, J = 4.8 Hz), 8.18 (s, 2H). Potassium 3-bromothiophen-2-yltrifluoroborate (7.18e) In a plastic vessel, a solution of crude 3-bromothiophen-2-ylboronic acid 7.17e (958.4 mg) in methanol (1.3 mL) was stirred under ambient atmosphere. The solution was cooled in an ice/water bath before neat KHF2 (1.52 g, 19.5 mmol) was added in one portion. Water (3.10 mL) was next added slowly dropwise (temperature was not

268 monitored). After addition was complete, the reaction vessel was removed from the cooling bath and allowed to stir at room temperature for 30 minutes. The solvents were then removed by rotary evaporation to give an off-white solid. The crude material was crushed, dissolved in acetone (ca. 10-20 mL) and heated on the rotary evaporator at 55 C (no vacuum was applied) for 3-5 minutes before being filtered. This process was repeated twice with the residual solids. The combined filtrates were concentrated and recrystallized from acetone/diethyl ether and dried under high vacuum (P2O5) to afford the pure product as a white solid in two crops. Yield: 906.3 mg (70%, two-step yield). 1H NMR (DMSO-d6): 6.85 (dd, 1H, J = 4.8 Hz, 1.1 Hz), 7.27 (d, 1H, J = 4.8 Hz). 13C NMR (DMSO-d6): 108.9, 125.4, 130.4, 145.4. HRMS (ESI/[M+K]+) calcd. for C4H10BBrF3KS: 305.8416. Found: 306.8405.

Thiophen-2(5H)-one (7.22a) To a solution of potassium thiophen-2-yltrifluoroborate 7.18a (106.0 mg, 0.5578 mmol) in acetone (2.8 mL, 0.2 M) was added a solution of Oxone (340.6 mg, 1.109 mmol based on active oxidant) in H2O (2.8 mL, 0.4 M) in one portion at room temperature. The resulting mixture was vigorously stirred for 5 minutes under ambient atmosphere before

269 aq. HCl (0.0625 M, 4.5 mL, 0.28 mmol) was added. The product was extracted with dichloromethane (3 5 mL) before the combined organic extracts were dried (MgSO4)

and eluted through a silica plug (CH2Cl2). The eluant was concentrated by rotary evaporation to afford the pure product as a pale yellow liquid. The analytical data for this compound are consistent with previously reported data.541, 542 Yield: 39.6 mg (71%). 1H NMR (CDCl3): 4.15 (dd, 2H, J = 2.8, 2.1 Hz), 6.40 (dt, 1H, J = 6.0, 2.1 Hz), 7.59 (dt, 1H, J = 5.9, 2.8 Hz). 13C NMR (CDCl3): 38.6, 133.5, 153.9, 200.4. 5-Bromothiophen-2(5H)-one (7.22b) Compound 7.22b was prepared in the manner of 7.22a from 7.18b. Quantities: potassium 5-bromothiophen-2-yltrifluoroborate 7.18b (228.2 mg, 0.8485 mmol), Oxone (519.8 mg, 1.691 mmol). Concentration of the silica plug eluant furnished the pure product as a brown liquid. The 1H NMR spectrum was consistent with previously reported data.512 Yield: 120.3 mg (79%). 1H NMR (CDCl3): 6.34 (dd, 1H, J = 2.9, 1.1 Hz), 6.36 (dd, 1H, J = 5.9, 1.1 Hz), 7.60 (dd, 1H, J = 5.9, 2.9 Hz). 13C NMR (CDCl3): 48.3, 131.4, 155.9, 195.5. 4-Bromothiophen-2(5H)-one (7.22c) Compound 7.22c was prepared in the manner of 7.22a from 7.18c. Quantities: potassium 4-bromothiophen-2-yltrifluoroborate 7.18c (111.2 mg, 0.4135 mmol), Oxone (252.2 mg, 0.8205 mmol). Concentration of the silica plug eluant afforded the pure product as a

270 light orange solid. Yield: 58.3 mg (79%). 1H NMR (CDCl3): 4.27 (d, 2H, J = 1.8 Hz), 6.54 (t, 1H, J = 1.8 Hz). 13C NMR (CDCl3): 43.1, 133.9, 148.0, 195.3. (Gram-scale synthesis of 7.22c) Compound 7.2c was prepared according to the general procedure described above. Quantities: 4-bromothiophen-2-yltrifluoroborate 1c (3.01 g, 11.2 mmol), Oxone (6.88 g, 22.4 mmol, acetone (56 mL), water (56 mL), aq. HCl (0.0625 M, 90. mL, 5.6 mmol). Concentration of the silica plug eluant afforded the pure product as a red solid. A small sample for melting point analysis was recrystallized from ethyl acetate/petroleum ether. Yield: 1.61 g (81%). 3,4-Dibromothiophen-2(5H)-one (7.22d) Compound 7.22d was prepared in the manner of 7.22a from 7.18d, except that stirring was maintained for 1 hour before the addition of aq. HCl. Quantities: potassium 3,4dibromothiophen-2-yltrifluoroborate 7.18d (2.95 g, 8.48 mmol), Oxone (5.22 g, 17.0 mmol). Concentration of the silica plug eluant afforded the pure product as a pale yellow solid. A small sample for melting point analysis was recrystallized from ethyl acetate/petroleum ether. Yield: 1.69 g (77%), mp = 112.8-113.5 C. 1H NMR (CDCl3): 4.23 (2H, s). 13C NMR (CDCl3): 40.5, 126.6, 145.9, 188.5. HRMS (ESI/[M+Na]+) calcd. for C4H2Br2OS: 278.8091. Found: 278.8086.

271 3-Bromothiophen-2(5H)-one (7.22e) Compound 7.22e was prepared in the manner of 7.22a from 7.18e, except that stirring was maintained for 1 hour before the addition of aq. HCl. Quantities: potassium 3bromothiophen-2-yltrifluoroborate 7.18e (497.5 mg, 1.850 mmol), Oxone (1.15 g, 3.74 mmol). Concentration of the silica plug eluant afforded the pure product as a light red solid. A small sample for melting point analysis was recrystallized from ethyl acetate/petroleum ether. The analytical data were consistent with previously reported data.544 Yield: 252.0 mg (76%), mp = 79.7-82.1 C (lit.544 81-82 C). 1H NMR (CDCl3): 4.03 (d, 2H, J = 3.1 Hz), 7.67 (1H, t, J = 3.1 Hz). 13C NMR (CDCl3): 36.1, 124.7, 151.2, 192.6. HRMS (ESI/[M+Na]+) calcd. for C4H3BrOS: 200.8986. Found: 200.8991. 2-Octyloxythiophene (7.23a) To a stirred solution of PPh3 (8.81 g, 33.6 mmol) in anhydrous CH2Cl2 (50 mL) under argon, cooled via an ice/salt bath, was added DIAD (6.60 mL, d = 1.027 g mL-1 at 25 C, 33.5 mmol) dropwise by syringe with the reaction temperature maintained at -10 C to -8 C. The solution was stirred at this temperature range for 10 minutes before 1-octanol (4.40 g, 33.8 mmol) in anhydrous CH2Cl2 (10 mL) was added dropwise by syringe with the reaction temperature maintained at -12 C to -9 C. After another 20 minutes of stirring, a solution of thiophen-2(5H)-one 7.22a (1.1225 g, 11.209 mmol) in anhydrous CH2Cl2 (10 mL) was added dropwise by syringe with the reaction temperature maintained at -10 C to -8 C. The resulting dark blue solution was removed from the

272 ice/salt bath and allowed to stir at room temperature for one hour. The reaction mixture was then filtered through a short silica plug (petroleum ether) and concentrated onto silica. The product was purified twice by column chromatography (75 g silica; petroleum ether) to afford the pure product as a colorless liquid. Yield: 1.9650 g (83%). 1H NMR (CDCl3): 0.89 (t, 3H, J = 6.8 Hz), 1.21-1.38 (m, 8H), 1.44 (quint, 2H, J = 7.3 Hz), 1.77

(quint, 2H, J = 7.0 Hz), 4.0 (t, 2H, J = 6.5 Hz), 6.19 (dd, 1H, J = 3.7, 1.4 Hz), 6.52 (dd, 1H, J = 5.8, 1.4 Hz), 6.70 (dd, 1H, J = 5.8, 3.8 Hz). 13C NMR (CDCl3): 14.1, 22.7, 25.9, 29.2 (2C), 29.3, 31.8, 74.0, 104.5, 111.7, 124.7, 165.9. HRMS (ESI/[M+H]+) calcd. for C12H20OS: 213.1313. Found: 213.1323. 4-Bromo-2-octyloxythiophene (7.23c) Compound 7.23c was prepared in the manner of 7.23a from 7.22c. Quantities: PPh3 (245.8 mg, 0.9371 mmol), DIAD (0.20 mL, d = 1.027 g mL-1 at 25C, 1.0 mmol), 1octanol (125.3 mg, 0.9621 mmol), 4-bromothiophen-2(5H)-one 7.22c (55.1 mg, 0.308 mmol). Purification by column chromatography (10 g silica; petroleum ether) afforded the pure product as a colorless liquid. Yield: 76.9 mg (86%). 1H NMR (CDCl3): 0.89 (t, 3H, J = 6.8 Hz), 1.23-1.38 (m, 8H), 1.38-1.46 (m, 2H), 1.76 (quint, 2H, J = 7.0 Hz), 3.99 (t, 2H, J = 6.5 Hz), 6.12 (d, 1H, J = 1.8 Hz), 6.46 (d, 1H, J = 1.7 Hz). 13C NMR: 14.1, 22.7, 25.8, 29.0, 29.19, 29.23, 31.8, 73.8, 107.0, 107.3, 108.6, 165.5. HRMS (ESI/[M+H]+) calcd. for C12H19BrOS: 291.0418. Found: 291.0405. (Gram-scale synthesis of 7.23c) Quantities: PPh3 (4.83 g, 18.4 mmol), DIAD (3.65 mL, d = 1.027 g mL-1at 25 C, 18.5 mmol), 1-octanol (2.41 g, 18.5 mmol), 4-bromothiophen-

273 2(5H)-one 7.22c (1.1053 g, 6.1735 mmol). Purification twice by column chromatography (180 g/100 g silica; petroleum ether) afforded the pure product as a colorless liquid. Yield: 1.56 g (87%). 3,4-Dibromo-2-octyloxythiophene (7.23d) Compound 7.23d was prepared in the manner of 7.23a from 7.22d. Quantities: PPh3 (4.54 g, 17.3 mmol), DIAD (3.45 mL, d = 1.027 g mL-1at 25 C, 17.5 mmol), 1-octanol (2.27 g, 17.4 mmol), 3,4-dibromothiophen-2(5H)-one 7.22d (1.50 g, 5.82 mmol). Purification by column chromatography (160 g silica; petroleum ether) afforded the pure product as a colorless liquid. Yield: 1.91 g (89%). 1H NMR (CDCl3): 0.89 (t, 3H, J = 6.9 Hz), 1.23-1.40 (m, 8H), 1.46 (quint, 2H, J = 7.3 Hz), 1.80 (quint, 2H, J = 7.0 Hz), 4.09 (t, 2H, J = 6.5 Hz), 6.74 (s, 1H). 13C NMR (CDCl3): 14.1, 22.6, 25.7, 29.2 (3C), 31.8, 75.6, 96.0, 109.1, 111.4, 158.3. 3-Bromo-2-octyloxythiophene (7.23e) Compound 7.23e was prepared in the manner of 7.23a from 7.22e. Quantities: PPh3 (656.4 mg, 2.503 mmol), DIAD (0.50 mL, d = 1.027 g mL-1at 25 C, 2.5 mmol), 1octanol (335.7 mg, 2.578 mmol), 3-bromothiophen-2(5H)-one 7.22e (150.3 mg, 0.8395 mmol). Purification by column chromatography (30 g silica; petroleum ether) afforded the pure product as a colorless liquid. Yield: 195.1 mg (80%). 1H NMR (CDCl3): 0.89 (t, 3H, J = 6.8 Hz), 1.23-1.40 (m, 8H), 1.47 (quint, 2H, J = 7.0 Hz), 1.80 (quint, 2H, J = 7.1 Hz), 4.08 (t, 2H, J = 6.6 Hz), 6.64 (d, 1H, J = 6.0 Hz), 6.73 (d, 1H, J = 6.0 Hz). 13C

274 NMR (CDCl3): 14.1, 22.7, 25.8, 29.19, 29.23, 29.3, 31.8, 76.1, 92.5, 112.6, 127.6, 158.1.

3-Bromo-5-(octyloxy)thiophene-2-carbaldehyde (7.24) A solution of LDA was generated by the addition of n-butyllithium (2.18 M in cyclohexane, 1.50 mL, 3.27 mmol) to dry diisopropylamine (distilled under N2 from CaH2; 0.51 mL, d = 0.722 g mL-1, 3.6 mmol) in anhydrous THF (18 mL; distilled under argon from sodium/benzophenone) with the reaction temperature maintained at -72 C to -66 C under argon. The resulting LDA solution was transferred to an ice/brine bath and the reaction mixture was allowed to warm to -4 C. Next, a solution of 4-bromo-2octyloxythiophene 7.23c (841.3 mg, 2.889 mmol) in anhydrous THF (4 mL) was added dropwise by syringe over 8 minutes with the reaction temperature maintained at -4 C to 2 C. After an hour of stirring at this temperature range, N-formylpiperidine (0.45 mL, d = 1.019 g mL-1 at 25 C, 4.1 mmol) was added by syringe from -2 C to 0 C. The cooling bath was removed and the reaction mixture was allowed to warm to room temperature overnight (ca. 18.5 hours). The next day, the reaction was quenched with aq.

275 NH4Cl (sat., 10 mL). The layers were separated and the organic layer was washed with aq. NH4Cl (sat., 10 mL ether (3 2). The aqueous washings were next extracted with diethyl

10 mL). The combined organic layers were last dried (MgSO4), filtered,

concentrated onto silica, and purified by column chromatography (30 g silica; 5% ethyl acetate in petroleum ether) to afford the pure product as a yellow liquid that slowly solidified upon standing. Yield: 851.2 mg (92%). 1H NMR (CDCl3): 0.89 (t, 3H, J = 6.9 Hz), 1.22-1.40 (m, 8H), 1.44 (quint, 2H, J = 7.5 Hz), 1.82 (quint, 2H, J = 7.0 Hz), 4.11 (t, 2H, J = 6.5 Hz), 6.30 (s, 1H), 9.77 (s, 1H). 13C NMR (CDCl3): 14.3, 22.8, 25.9, 29.0, 29.3, 32.0, 74.6, 77.3, 110.8, 121.4, 123.8, 174.0, 182.1. HRMS (ESI/[M+Na]+) calcd. for C13H19BrO2S: 341.0187. Found: 381.0181. Nonyl 5-(octyloxy)thieno[3,2-b]thiophene-2-carboxylate (7.25) A solution of nonyl mercaptoacetate 7.2b (830.0 mg, 3.801 mmol), 4-bromo-2octyloxythiophene-5-carbaldehyde 7.24 (983.6 mg, 3.081 mmol), and K2CO3 (592.9 mg, 4.290 mmol) in DMF (40 mL) was heated at 65 C under argon for 14 hours. Heating was then discontinued (NMR indicated completion of the reaction) and the carbonate salts were filtered off. The resulting mixture was partitioned between water (300 mL), brine (100 mL), and diethyl ether (50 mL). The organic layer was separated and the aqueous layer was extracted with diethyl ether (3 50 mL). The combined organic

extracts were washed with brine (50 mL), dried (MgSO4), filtered, and concentrated to afford a red solid (1.47 g). Purification of the crude material by column chromatography (60 g silica; 3% diethyl ether in petroleum ether) yielded the product as a light peach

276 solid. A small portion was recrystallized from ethyl acetate and dried under high vacuum (P2O5) to give white crystals for analysis. Yield: 1.1580 g (86%), mp = 38.6-40.2 C.
max

= 328 nm ( = 2.2 104 M-1 cm-1), 296 nm ( = 1.0 104 M-1 cm-1). 1H NMR (CDCl3):

0.88 (t, 3H, J = 6.9 Hz), 0.89 (t, 3H, J = 6.9 Hz), 1.23-1.39 (m, 18H), 1.39-1.49 (m, 4H), 1.74 (quint, 2H, J = 7.1 Hz), 1.82 (quint, 2H, J = 7.0 Hz), 4.12 (t, 2H, J = 6.5 Hz), 4.28 (t, 2H, J = 6.7 Hz), 6.42 (d, 1H, J = 0.5 Hz), 7.82 (d, 1H, J = 0.5 Hz). 13C NMR (CDCl3): 14.10, 14.12, 22.65, 22.68, 25.8, 26.0, 28.8 29.0, 29.18, 29.22, 29.25, 29.29, 29.5, 31.8, 31.9, 65.2, 74.1, 97.5, 126.2, 126.3, 130.1, 142.4, 162.7, 170.4. HRMS (ESI/[M+Na]+) calcd. for C24H38O3S2: 461.2160. Found: 461.2157. 5-(Octyloxy)thieno[3,2-b]thiophene-2-carboxylic acid (7.26) To a solution of nonyl 5-(octyloxy)thieno[3,2-b]thiophene-2-carboxylate (921.2 mg, 2.100 mmol) in ethanol (6.0 mL), heated at reflux under ambient atmosphere, was added a solution of NaOH (665.2 mg, 16.63 mmol) in H2O (3.0 mL) in one portion. The mixture was stirred at reflux for 2 hours 20 minutes, at which point heating was discontinued and the reaction vessel was placed in an ice/water bath. A cream-colored precipitate formed, which was filtered and washed with cold water and petroleum ether. The resulting solid was dissolved in glacial acetic acid (75 mL) heated at 100 C (external temperature). When all of the solid had gone into solution, ice (ca. 100 g) was added to the solution and heating was discontinued. The resulting white precipitate was isolated by filtration. The mother liquors from both filtrations were combined and concentrated. A second crop of white solid was recovered in the manner described above.

277 The solids were dried under high vacuum (P2O5). Yield: 524.8 mg (80%). 1H NMR (CDCl3): 0.86 (t, 3H, J = 6.9 Hz), 1.20-1.35 (m, 8H), 1.40 (quint, 2H, J = 7.2 Hz), 1.75 (quint, 2H, J = 6.9 Hz), 4.16 (t, 2H, J = 6.5 Hz), 6.80 (s, 1H), 7.94 (s, 1H), 12.87 (s, 1H).
13

C NMR (CDCl3): 13.8, 22.0, 26.2, 28.2, 28.5 (2C), 31.1, 73.6, 98.1, 125.5, 126.8,

130.5, 141.6, 163.1, 169.4.

4-Octyloxybenzoic acid (7.27) Compound 7.27 was prepared according to the procedure of Hirai and coworkers.545 A mixture of 4-hydroxybenzoic acid (2.02 g, 14.6 mmol), 1-bromooctane (2.83 g, 14.7 mmol), NaOH (1.30 g, 32.5 mmol) in water (10 mL) and ethanol (20 mL) was heated under reflux under open atmosphere. After 24 hours, heating was discontinued. The reaction mixture was cooled to room temperature, at which point a white precipitate formed. The mixture was acidified (ca. pH = 2) with conc. HCl and the product was

278 isolated by vacuum filtration, washed with cold water and petroleum ether, and dried in vacuo (P2O5, paraffin shavings) to afford the desired product as a white solid whose analytical data were consistent with the literature.546 Yield: 2.26 g (62%). 1H NMR (CDCl3): 0.89 (t, 3H, J = 6.9 Hz), 1.24-1.40 (m, 8H), 1.46 (quint, 2H, J = 7.3 Hz), 1.81 (quint, 2H, J = 7.1 Hz), 4.02 (t, 2H, J = 6.6 Hz), 6.93 (d, 2H, J = 9.0 Hz), 8.06 (d, 2H, J = 8.9 Hz). Octyl 4-hydroxybenzoate (7.28) A mixture of 4-hydroxybenzoic acid (4.16 g, 30.1 mmol), 1-octanol (7.89 g, 60.6 mmol), and p-toluenesulfonic acid monohydrate (0.48 g, 2.5 mmol) in toluene (100 mL) was stirred and heated under reflux under argon. Water was removed azeotropically with a Dean-Stark trap. After 12 hours, heating was discontinued (NMR indicated completion of the reaction). The toluene was removed by rotary evaporation and the crude product was diluted with diethyl ether (50 mL). The ether was washed with aq. NaHCO3 (sat., 2 mL). The combined washings were extracted with diethyl ether (2 50 mL). The 50

combined organic layers were then washed with brine (50 mL), dried (MgSO4), filtered, and concentrated to yield a yellow liquid. This was purified by column chromatography (200 g silica; 10-20% ethyl acetate/petroleum ether) to afford a pale yellow liquid (7.65 g) that by NMR was shown to be a ca. 49:51 mixture of the desired product and octanol. The octanol was removed via short-path Kugelrohr distillation (~1 mm Hg, oven temperature = 130 C, t = 40 min) to afford the product as a liquid that formed colorless crystals upon cooling. Analytical data were consistent with the literature.527 Yield: 5.33 g

279 (71%). 1H NMR (CDCl3): 0.88 (t, 3H, J = 6.9 Hz), 1.23-1.38 (m, 8H), 1.43 (quint, 2H, J = 7.2 Hz), 1.75 (quint, 2H, J = 7.1 Hz), 4.28 (t, 2H, J = 6.7 Hz), 5.55 (br s, 1H), 6.86 (d, 2H, J = 8.8 Hz), 7.96 (d, 2H, J = 8.8 Hz). Octyl 4-(4-(octyloxy)benzoyloxy)benzoate (7.29) A solution of 4-octyloxybenzoic acid (256.7 mg, 1.025 mmol) and octyl 4-hydrobenzoate (257.0 mg, 1.027 mmol) in dichloromethane (30 mL) was stirred under argon. Next were added DCC (229.6 mg, 1.113 mmol) and DMAP (13.1 mg, 0.107 mmol) in one portion. The reaction mixture was stirred at room temperature for 21 hours (precipitation of DCU was noted after ca. 15 minutes). The reaction was then filtered through silica (CH2Cl2) to afford a nearly-pure (by TLC) solid (0.62 g). This was recrystallized from n-propanol to give the desired product. A sample for analysis was recrystallized again and dried under high vacuum (P2O5, paraffin shavings) to afford white crystals (236.7 mg). Yield: 372.9 mg (75%). 1H NMR (CDCl3): 0.89 (t, 3H, J = 6.9 Hz), 0.90 (t, 3H, J = 6.9 Hz), 1.241.41 (m, 16H), 1.43-1.50 (m, 4H), 1.77 (quint, 2H, J = 7.1 Hz), 1.82 (quint, 2H, J = 7.0 Hz), 4.05 (t, 2H, J = 6.6 Hz), 4.32 (t, 2H, J = 6.7 Hz), 6.98 (d, 2H, J = 9.0 Hz), 7.29 (d, 2H, J = 8.8 Hz), 8.13 (m, 4H). 13C NMR(CDCl3): 14.1, 22.7, 26.0, 26.1, 28.7, 29.1, 29.21, 29.22, 29.26, 29.33, 31.8, 65.3, 68.4, 114.4, 121.1, 121.8, 128.0, 131.1, 132.4, 154.7, 163.8, 164.4, 166.0.

280

4-Octyloxyphenol (7.30) A portion of 1-benzyloxy-4-octyloxybenzene (4.70 g, 15.0 mmol) was dissolved in ethyl acetate (100 mL) and ethanol (100 mL). The solution was stirred under argon at room temperature for 10 minutes before palladium (10% Pd/C, wet Degussa type, 0.28 g) was added in one portion. The mixture was then stirred vigorously and degassed under house vacuum for 25 minutes before being placed under an atmosphere of hydrogen. After 18 hours, 450 mL H2 had been consumed (120 mL at 30 minutes; 400 mL at 3 hours) and the hydrogen atmosphere was removed. The reaction mixture was filtered through Celite and concentrated to afford a yellow solid (3.83 g). Recrystallization from petroleum ether afforded the pure product as white crystals in three crops. Analytical data were consistent with data reported in the literature.547 Yield: 3.06 g (92%). 1H NMR (CDCl3): 0.88 (t, 3H, J = 6.9 Hz), 1.23-1.39 (m, 8H), 1.44 (quint, 2H, J = 7.4 Hz), 1.75 (quint, 2H, J = 7.1 Hz), 3.89 (t, 2H, J = 6.6 Hz), 4.45 (s, 1H), 6.72-6.81 (m, 4H).

281

4-(Octyloxycarbonyl)phenyl 5-(octyloxy)thieno[3,2-b]thiophene-2-carboxylate (7.31) To a solution of 5-(octyloxy)thieno[3,2-b]thiophene-2-carboxylic acid 7.26 (104.8 mg, 0.3354 mmol) and octyl 4-hydroxybenzoate 7.28 (86.6 mg, 0.346 mmol) in dichloromethane (15 mL), stirred under argon, were added DCC (90.4 mg, 0.438 mmol) and DMAP (5.0 mg, 0.041 mmol) in one portion. The resulting solution was stirred at room temperature. A white precipitate began to form after ca. 25 minutes. After 54 hours, the white precipitate (DCU) was removed by filtration and the filtrate was concentrated to give a white solid. This was concentrated onto silica and purified by column chromatography (30 g silica; 50% dichloromethane in petroleum ether) to afford an offwhite solid. A sample for analysis was recrystallized from n-propanol and dried under high vacuum (P2O5) to yield white crystals. Yield: 181.5 mg (99%). 1H NMR (CDCl3): 0.889 (t, 3H, J = 6.9 Hz), 0.895 (t, 3H, J = 7.0 Hz), 1.24-1.40 (m, 16H), 1.40-1.50 (m, 4H), 1.77 (quint, 2H, J = 7.1 Hz), 1.84 (quint, 2H, J = 7.0 Hz), 4.15 (t, 2H, J = 6.5 Hz), 4.32 (t, 2H, J = 6.7 Hz), 6.47 (d, 1H, J = 0.5 Hz), 7.31 (d, 2H, J = 8.8 Hz), 8.02 (d, 1H, J = 0.4 Hz), 8.11 (d, 2H, J = 8.8 Hz). 13C NMR (CDCl3): 14.1, 22.6, 25.8, 26.0, 28.7,

282 29.0, 29.17, 29.20, 29.3, 31.77, 31.80, 65.3, 74.2, 97.5, 121.7, 126.5, 127.9, 128.07, 128.10, 131.1, 144.1, 154.3, 160.3, 165.9, 171.5. 4-(Octyloxy)phenyl 5-(octyloxy)thieno[3,2-b]thiophene-2-carboxylate (7.32) Compound 7.32 was prepared in the manner of 7.31 from 7.30. Quantities: 5(octyloxy)thieno[3,2-b]thiophene-2-carboxylic acid 7.26 (101.9 mg, 0.3261 mmol), 4octyloxyphenol 7.30 (74.5 mg, 0.335 mmol), DCC (88.0 mg, 0.427 mmol), DMAP (10.8 mg, 0.0884 mmol), CH2Cl2 (15 ml). Purification by column chromatography (30 g silica; 40% dichloromethane in petroleum ether) afforded the product as a pure off-white solid. A sample for analysis was prepared by recrystallization from n-propanol and drying under high vacuum (P2O5) to yield white crystals. Yield: 126.6 mg (77%). 1H NMR (CDCl3): 0.892 (t, 3H, J = 6.8 Hz), 0.894 (t, 3H, J = 6.8 Hz), 1.23-1.40 (m, 16H), 1.401.51 (m, 4H), 1.78 (quint, 2H, J = 7.0 Hz), 1.84 (quint, 2H, J = 7.0 Hz), 3.95 (t, 2H, J = 6.6 Hz), 4.14 (t, 2H, J = 6.5 Hz), 6.46 (d, 1H, J = 0.5 Hz), 6.91 (d, 2H, J = 9.1 Hz), 7.12 (d, 2H, J = 9.1 Hz), 7.99 (d, 1H, J = 0.5 Hz). 13C NMR (CDCl3): 14.1, 22.65, 22.67, 25.8, 26.1, 29.0, 29.18, 29.22, 29.26, 29.29, 29.4, 31.78, 31.83, 68.5, 74.2, 97.6, 115.1, 122.4, 126.4, 127.6, 128.7, 143.5, 144.1, 156.9, 161.3, 171.1.

283

2-Bromo-1,3-diphenylpropane-1,3-dione (7.33) Compound 7.33 was prepared by a modified procedure of Singer and coworkers (we employed NBS instead of pyridinium tribromide).549 To a dry 3-neck flask equipped with stir bar, argon inlet, and septum were added 1,3-diphenyl-1,3-propanedione (0.96 g, 4.3 mmol) and acetonitrile (6 mL). The mixture was cooled to ca. 10C before a solution of N-bromosuccinimide (0.90 g, 5.1 mmol) in acetonitrile (9 mL) was added by syringe pump over ca. 1 hour. TLC after 2.5 hours showed completion, so methanol (5 mL) was added, followed by water (10 mL) dropwise over 15 minutes to promote crystallization. Stirring was maintained in an ice bath for ca. 1 hr. Next, the product was isolated by filtration and dried under high vacuum (P2O5) to afford a white solid that was pure by NMR and whose analytical data were consistent with data in the literature.549 Yield: 1.15 g (89%)

284 1,3-Diphenyl-2-(1H-pyrazol-1-yl)propane-1,3-dione (7.34) Compound 7.34 was prepared in the manner of Singer and coworkers.549 To a roundbottom flask were added 2-bromo-1,3-diphenylpropane-1,3-dione 7.33 (0.98 g, 3.2 mmol), stir bar, and NMP (2 mL). Next was added pyrazole (0.66 g, 9.7 mmol) in small portions at room temperature. The mixture was allowed to stir at room temperature for 2 days, after which point water (11 mL) was slowly added dropwise over 10 minutes to crystallize the product. The suspension was stirred in an ice bath for 1.5 hours, after which it was filtered and washed with cold water to give off-white crystals that displayed analytical data consistent with data in the literature.549 Yield: 0.85 g (91%) 1-(1,3,5-Triphenyl-1H-pyrazol-1-yl)-1H-pyrazole (7.35) Compound 7.35 was prepared largely in the manner of Singer and coworkers.549 To a clean round-bottom flask (25 mL) equipped with stir bar were added 1,3-diphenyl-2-(1Hpyrazol-1-yl)propane-1,3-dione 7.34 (0.82 g, 2.8 mmol), methanol (2 mL), and glacial acetic acid (2 mL). To this suspension was added a solution of phenylhydrazine (0.47 g, 4.4 mmol) in methanol (1 mL) dropwise. The mixture was stirred under argon at room temperature. The next day, the product had precipitated. Water (5 mL) was added dropwise to complete precipitation. Stirring was maintained for 2 hours before the product was isolated by filtration and washed with water, cold methanol, cold petroleum ether, and dried on the vacuum filter (overnight) to afford off-white crystals that displayed analytical data consistent with data in the literature.549 Yield: 0.81 g (79%)

285 Di-1-adamantylphosphinic chloride (7.36) Compound 7.36 was prepared in the manner of Goerlich et al.481 To an oven-dried roundbottom flask (25 mL) under argon were added adamantane (0.995 g, 7.30 mmol), aluminum trichloride (1.036 g, 7.770 mmol), and phosphorus trichloride (3.25 mL, d = 1.574 g mL-1, 37.2 mmol). The mixture was stirred and heated to reflux with an oil bath. After 5.5 hours, the excess of phosphorus trichloride was distilled off and the residual orange solid in the reaction flask was allowed to cool to room temperature. Chloroform (8 mL) was added; the mixture was cooled to ca. 0C in an ice bath and water (5 mL) was added cautiously. After 20 minutes of stirring, the orange slurry was poured into a separatory funnel. The layers were separated and the organic phase was dried over MgSO4, filtered, and concentrated by rotary evaporation to afford a yellow solid that was the desired product; analytical data were consistent with the literature.480, 481 Yield: 1.28 g (99%) . 1H NMR (CDCl3): 1.74-1.78 (m, 6H), 2.04-2.09 (m, 3H), 2.14-2.19 (m, 6H).
31

P NMR (CDCl3): 86.5. 13C NMR (CDCl3): 27.8 (d, J = 10.8 Hz), 36.3 (d, J = 1.4

Hz), 36.9 (d, J = 1.8 Hz). Di-1-adamantylphosphine (7.37) Compound 7.37 was prepared in the manner of Goerlich et al.481 To an oven-dried 3-neck flask (25 mL) under argon were added di-1-adamantylphosphinic chloride (301.0 mg, 0.8530 mmol) and anhydrous THF (5 mL; distilled over sodium/benzophenone). The solution was cooled to -14 C via CryoCool before lithium aluminum hydride (2.4 M in THF, 0.85 mL, 2.0 mmol) was added dropwise by syringe over a range of -14 C to -12

286 C. The reaction was then allowed to warm to room temperature overnight. The next day, the mixture was cooled in the same manner to -12 C before being hydrolyzed slowly with aqueous HCl (1.2 M, 2.0 mL, 2.4 mmol) between -12 C and 2 C. After stirring for ca. 30 minutes while the mixture warmed to room temperature, the mixture was diluted with diethyl ether (10 mL) and water (10 mL), and the layers were separated. The organic layer was dried (MgSO4), filtered, and concentrated to give the desired product as a white solid who analytical data were consistent with the literature.481, 554 Yield: 225.5 mg (87%). 13P NMR (CDCl3): 18.17.

Nonyl 5-chlorothieno[3,2-b]thiophene-2-carboxylate (7.38) To a three-neck flask equipped with stir bar and condenser were added nonyl thieno[3,2b]thiophene-2-carboxylate 7.5b (1.78 g, 5.73 mmol), N-chlorosuccinimide (760.5 mg, 5.695 mmol), chloroform (10 mL), and glacial acetic acid (10 mL). The mixture was brought to reflux under an open atmosphere. Successive portions of N-chlorosuccinimide (194.7 mg; 60.5 mg; 61.2 mg; total of all portions = 1.08 g, 8.09 mmol, ~1.4 eq.) were added as needed over the course of the next several days until the starting material had been almost completely consumed (~1% remaining. Notably, the presence of a dichlorinated byproduct was seen before complete consumption of the starting material). The contents of the reaction vessel were transferred to a separatory funnel and diluted

287 with dichloromethane (40 mL) before being neutralized to pH = 7 with saturated aq. NaHCO3 (25 mL). The organic layer was then washed with water (3 30 mL). The combined organic layers were washed with brine (40 mL) and dried over MgSO4. The drying agent was filtered off and the product was concentrated by rotary evaporation to afford a brown liquid (1.7908 g) that was shown by NMR to be a 1:90:9 mixture of starting material to product to dichlorinated byproduct. As reasonable separation between the product and the dichlorinated byproduct was not achieved with any eluents in TLC, the product was purified by recrystallization from 1:1 diethyl ether/petroleum ether to afford a shiny brown solid. Yield: 0.7679 g (39%). 1H NMR (CDCl3): 0.88 (t, 3H, J = 6.9 Hz), 1.21-1.39 (m, 10H), 1.43 (quint, 2H, J = 7.1 Hz), 1.75 (quint, 2H, J = 7.1 Hz), 4.31 (t, 2H, J = 6.7 Hz), 7.17 (d, 1H, J = 0.6 Hz), 7.87 (d, 1H, J = 0.6 Hz).

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TABULATED TRANSITION TEMPERATURES OF NOVEL MESOGENS

Compound m n Cryst SmC SmA N Iso Liq Recryst.

5.1a (7.12a) 5.1b (7.12b) 5.1c (7.12c) 5.1d (7.12d) 5.1e (7.12e) 5.1f (7.12f) 5.1g (7.12g) 5.1h (7.12h) 5.1i (7.12i)

8 8 8 9 9 9 10 10 10

8 9 10 8 9 10 8 9 10

143.7 138.0 134.4 144.5 140.7 135.9 141.5 142.3 139.7

( ( ( (

140.7) 137.2) 132.2) 144.4) 141.5 137.0 144.7 142.6 139.9

153.1 150.3 147.5 149.8 147.1 144.3 147.5 145.6 142.9

132.9 130.5 128.0 137.6 131.1 128.5 133.4 134.1 132.6

(racemic)

5.6a (7.12j) 5.6b (7.12k)

9 10

100.0 97.6

86.9 (

90.2) 89.9)

5.4a (7.16a) 5.4b (7.16b) 5.4c (7.16c) 5.4d (7.16d)

9 10 10 10

9 8 9 10

119.0 115.5 120.7 119.7

141.0 143.8 142.2 139.4

145.1 145.6 143.6 141.0

114.8 113.2 116.7 115.2

(racemic)

5.5e (7.16e) 5.5f (7.16f)

9 10

101.4 97.4

( (

89.8 90.1

92.9) 92.1)

5.10 (7.32)

88.6

109.7

116.8

123.8

61.6

5.8 (7.31)

76.4

116.2

56.8

5.9 (7.29)

60.5

69.2

37.8

341