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Studies toward the chemistry of N-confused oligopyrroles Liu, Runchang 2011

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Studies toward the Chemistry of Nconfused Oligopyrroles by Runchang Liu M.Sc. Nankai University, 2001 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE STUDIES (Chemistry)  THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) March 2011 © Runchang Liu, 2011  Abstract The objectives of this work were to explore the synthesis of linear N-confused (αmeso-β) oligopyrrolic pigments (variants of the corresponding α,α‟-linear oligopyrrolic pigments), as well as to study the stability, optical properties and cyclization reactivity of these unprecedented N-confused oligopyrrole structures. MSA (methanesulfonic acid)-catalyzed condensation of aryl aldehydes with a variety of electron-withdrawing group (EWG)-substituted pyrroles to afford the corresponding meso-aryl N-confused diacyl dipyrromethanes was established. The directing effect of these EWGs for α-meso-β-linkage formation in N-confused dipyrromethanes was evaluated. The key for the successful transformation appears to depend upon the reactivities of the aldehyde and the electron-poor pyrrole substrates used. This novel one-pot synthetic approach for construction of α-meso-β-linkages between pyrroles is a substantial improvement over the classic multi-step synthesis (Chapter 2). Oxidation of an N-confused dipyrromethane to the corresponding conjugated dipyrrin system was explored by applying different oxidants. An efficient DDQ-mediated benzylic C-H activation for hydroxylation, alkoxylation and heteroarylation of meso-aryl DPMs (three different forms) to the corresponding meso-modified dipyrromethanes (DPMs) was established. Mechanistic study shows the reaction proceeds through a highly-unstable protonated dipyrrin intermediate (Chapter 3). Exploration of the oxidation process of the dipyrromethane allows discussion of the meso-steric effect observed during the oxidation, where substituents on the 2- and 6positions of the meso-aryl group play important roles in producing and stabilizing the  ii  conjugated pyrrolemethene. N-confused (α-meso-β) dipyrrins were studied with regards to their synthesis, stability, reactivity, and configurational interconversion. The Nconfused dipyrrinodiol can be imbedded as a building block into oligopyrrole frameworks efficiently with retention of the Z-syn N-confused moiety, which provides a concise way to create higher N-confused oligopyrrolic pigments (Chapter 4). Subsequently, in chapter 5, we report our synthesis of the conjugated N-confused oligopyrrolic macrocycle [12] tripyrrin (0.1.1) via an oxidative amination cyclization. As a macrocycle constructed purely of meso-aryl groups and pyrrole, N-confused [12] tripyrrin (0.1.1) was synthesized using an unprecedented head-to-tail cyclization. Also, linear N-confused tri- and tetrapyrrolemethenes were synthesized and fully characterized by X-ray analysis. Conversion of α,α‟-linear oligopyrroles to their corresponding Nconfused counterparts was achieved despite their presumed instability.  iii  Table of Contents Abstract .............................................................................................................................. ii Table of Contents ............................................................................................................. iv List of Tables .................................................................................................................. viii List of Figures ................................................................................................................... ix Lists of Schemes ............................................................................................................. xiii List of Abbreviations ..................................................................................................... xvi Nomenclature ............................................................................................................... xviii Acknowledgements ........................................................................................................ xxi Chapter 1 Introduction ...................................................................................................... 1 1.1 Introduction ................................................................................................................. 2 1.2 Linear Oligopyrrole Chemistry ................................................................................. 4 1.2.1 Introduction of α,α‟-Dipyrrins and Their Derivatives ........................................... 6 1.2.1.1 Structures of α,α‟-Dipyrrins and Their Derivatives ........................................ 6 1.2.1.2 Preparation of Dipyrrin and Its Derivatives .................................................... 7 1.2.1.3 α,β- and β,β‟-Dipyrrins ................................................................................... 9 1.2.2 Reactivity of Dipyrrin Derivatives......................................................................... 9 1.2.2.1 Protonation and Deprotonation ..................................................................... 10 1.2.2.2 Dipyrrin as Ligand for Coordination Chemistry ........................................... 11 1.2.2.3 Nucleophilic and Electrophilic Reactions on Dipyrrin Derivatives ............. 12 1.3 Introduction of α,α’-Tripyrrins ............................................................................... 13 1.3.1 Free-base Tripyrrin Derivatives ........................................................................... 13 1.3.2 Synthesis of Tripyrrin Derivatives ....................................................................... 14 1.3.3 Tripyrrins as Ligands for Coordination Chemistry .............................................. 15 1.4 Introduction of α,α’-Tetrapyrrolic Pigments ......................................................... 16 1.4.1 Synthesis of Bilindiones ...................................................................................... 17 1.4.2 Synthetic Tetrapyrrolic Pigments ........................................................................ 19 1.4.2.1 Application of Biladiene-ac 1-28 as Precursor for Corrole 1-30 .................. 19 1.4.2.2 Application of Seccorrin 1-31 as Precursor for Corrin 1-33......................... 20 1.5 Introduction of α,α’-Oligopyrroles Higher than Tetrapyrrole. ............................ 20 1.5.1 Synthesis of Meso-aryl Pentapyrrin 1-34 ............................................................. 21 1.5.2 Application of Pentapyrrin 1-34 as Precursor for Sapphyrin 1-35 ...................... 22 1.5.3 Application of Higher Linear Oligopyrroles for Preparation of Expanded Porphyrins ..................................................................................................................... 23 1.6 Optical Properties of the Fully-conjugated Oligopyrrole Products ..................... 25 1.7 Summary of α,α’-Linear Oligopyrroles .................................................................. 26  iv  1.8 Introduction of N-confused Oligopyrroles.............................................................. 27 1.8.1 Properties and Reactivities of NCTPP ................................................................. 28 1.8.2 Reactivities of the N-confused Moiety ................................................................ 30 1.8.2.1 Electrophilic Reactions of NCTPP ............................................................... 30 1.8.2.2 Nucleophilic Addition Reaction of NCTPP .................................................. 32 1.8.2.3 Diels-Alder Reaction of NCTPP ................................................................... 32 1.8.2.4 Oxidative Degradation Reaction of NCTPP ................................................. 33 1.8.3 Confusing a Ring in NCTPP ................................................................................ 34 1.9 Contracted N-confused Oligopyrrole Macrocycles................................................ 34 1.10 Summary .................................................................................................................. 37 1.11 Research Objectives and Thesis Preview .............................................................. 38 Chapter 2 the Synthesis of N-confused Dipyrromethanes—Confusion of One of the Pyrroles in Dipyrromethanes ........................................................................................... 44 2.1 Introduction to the Synthesis of meso-Aryl Dipyrromethanes (DPM) ................ 45 2.1.1 Introduction to the Synthesis of meso-Aryl α,α‟-DPMs ...................................... 45 2.1.2 Application of Protected Pyrroles for the Synthesis of α,α‟-DPMs..................... 46 2.1.2.1 Electron-donating Groups (EDG) as Blocking Groups ................................ 46 2.1.2.2 Electron-withdrawing Groups (EWG) as Blocking Groups ......................... 47 2.1.3 N-confused DPM ................................................................................................. 48 2.1.3.1 Rational Synthesis of N-confused DPMs ..................................................... 49 2.2 Results and Discussion .............................................................................................. 51 2.2.1 Design the Directing Strategy for Synthesis of N-confused DPM ...................... 51 2.2.2 Preliminary Screening for Substrates and Catalysts ............................................ 54 2.2.3 Characterization of the N-confused DPMs .......................................................... 55 2.2.4 Survey of the Catalysts and Reaction Conditions ................................................ 58 2.2.5 Scope of the Reaction .......................................................................................... 63 2.2.5.1 Scope of the meso-Aryl Group ..................................................................... 63 2.2.5.2 Scope of the Pyrrole Substrates .................................................................... 67 2.2.5.3 Effect of EWG on the Nitrogen .................................................................... 71 2.3 Summary .................................................................................................................... 74 Chapter 3 DDQ-Mediated Modification of Meso-aryl Dipyrromethanes ...................... 75 3.1 Introduction ............................................................................................................... 76 3.2 Results and Discussion .............................................................................................. 77 3.2.1 Characterization of Hydroxylated Product 3-1 .................................................... 77 3.2.2 Exploration of the Oxidation Reaction ................................................................ 80 3.2.2.1 Exploration of the Oxidants for N-confused Dipyrrins ................................ 80 3.2.2.2 Exploration of the Meso-aryl Effect on the Reactivity of N-confused DPMs ................................................................................................................................... 81 3.2.2.3 meso-steric Effect on α,α‟- and β,β‟-DPMs .................................................. 84 3.2.3 The meso-steric Effect Analysis in the NMR Spectra ......................................... 87  v  3.2.4 DDQ-mediated Modification of the meso-Position of DPMs.............................. 88 3.2.5 DDQ-mediated C-O Bond Formation on the meso-Position ............................... 89 3.2.6 C-C Bond Formation on the meso-position Mediated by DDQ .......................... 91 3.2.7 Mechanism Discussion ........................................................................................ 94 3.2.8 Conclusion ........................................................................................................... 96 Chapter 4 N-confused Dipyrrins- a More Flexible Dipyrryl System ............................. 97 4.1 Introduction ............................................................................................................... 98 4.2 Results and Discussion .............................................................................................. 99 4.2.1 Synthesis of the N-confused Dipyrrin.................................................................. 99 4.2.2 Characterization of the Free-Base N-confused Dipyrrin ................................... 101 4.2.2.1 Structure Determination of 4-1 by NMR Spectroscopy ............................. 101 4.2.2.2 Structure Determination of 4-1 by X-ray Analysis ..................................... 102 4.2.3 Configurational Study of N-confused Dipyrrin by DFT Calculation ................ 104 4.3 Studies of Configuration Change in N-confused Dipyrrins: Alkoxylation Reaction at the α-Position ............................................................................................ 105 4.3.1 DDQ-Promoted Oxidative Alkoxylation at the α-Position of N-confused Dipyrrins ..................................................................................................................... 106 4.3.1.1 Structure Determination of Lactim N-confused Dipyrrin by NMR Spectroscopy ........................................................................................................... 107 4.3.1.2 Structure Determination of Lactim N-confused Dipyrrin by X-ray Diffraction Analysis................................................................................................................... 108 4.3.2 Exploration of the Scope of meso-Aryl Groups ................................................. 110 4.3.3 Exploration of Various Alcohols ....................................................................... 111 4.3.4 Mechanism of the Alkoxylation Reaction ......................................................... 114 4.3.5 Optical Absorption Spectra of N-confused Dipyrrin Derivatives...................... 115 4.4 Reactivities of the N-confused Dipyrryl System ................................................... 116 4.5 Oxidative Dimerization Reaction on the N-confused Dipyrrin .......................... 120 4.5.1 Characterization of Tetrapyrrolic Product 4-27a ............................................... 121 4.5.1.1 Structure Determination of 4-27a by NMR Spectroscopy.......................... 121 4.5.1.2 Structure Determination of 4-27a by X-ray Analysis ................................. 123 4.5.2 Survey of the Scope of the Oxidative dimerization Reaction ............................ 123 4.5.3 Proposed Mechanism ......................................................................................... 124 4.6 Conclusion ............................................................................................................... 126 Chapter 5 N-confused [12]Tripyrrin(0.1.1) and Linear N-confused Oligopyrroles….128 5.1 1+1 Strategy for Producing Porphyrin and Oligopyrrolic Analogues ............... 132 5.2 Results and Discussion............................................................................................ 133 5.2.1 Exploration of the Reaction Conditions ............................................................. 135 5.2.2 N-confused [12]Tripyrrin(0.1.1) 5-3a ................................................................ 136 5.2.2.1 Structure Determination of 5-3a by NMR Spectroscopy ............................ 136 5.2.2.2 Structure Determination of 5-3a by X-ray Analysis ................................... 138  vi  5.2.2.3 Reactivity and Stability of 5-3a .................................................................. 140 5.2.2.4 Survey of the Scope of Substrates for Macrocycle Formation ................... 141 5.2.2.5 Proposed Mechanism for Producing 5-3a ................................................... 144 5.2.3 Structure Determination of Tetrapyrrin 5-4 ....................................................... 145 5.2.4 Structure Determination of Tripyrrin 5-5a ......................................................... 147 5.3 N-confused Tripyrrane ........................................................................................... 149 5.4 N-confused Tripyrrin.............................................................................................. 152 5.4.1 Structure Determination of 5-9a and 5-9b by X-ray Analysis ........................... 152 5.4.2 Optical Absorption Spectra of the N-confused tripyrrin 5-9a and 5-9b ............ 155 5.5 Conclusion ............................................................................................................... 157 Chapter 6 Conclusion .................................................................................................... 159 6.1 Summary and Conclusion ...................................................................................... 160 6.2 Future Work ............................................................................................................ 161 Bibliography ................................................................................................................... 164 Appendices ...................................................................................................................... 172 Experimental ................................................................................................................. 173 A.1 Instrumentation and General Materials .............................................................. 173 A.2 Experimental Data for Chapter 2 ......................................................................... 174 A.2.1 General Procedure ............................................................................................. 174 A.2.2 1H and 13C NMR Data for DPM Products ........................................................ 176 A.2.3 Crystal Data for 2-23, 2-28 ............................................................................... 187 A.3 Experimental Data for Chapter 3 ......................................................................... 189 A.3.1 1H and 13C NMR Data for DPM Products ........................................................ 190 A.3.2 Crystal Data for 3-8, 3-9 ................................................................................... 203 A.4 Experimental Data for Chapter 4 ......................................................................... 205 A.4.1 1H and 13C NMR data........................................................................................ 205 A.4.2 Crystal Data for 4-1, 4-11, 4-27a ...................................................................... 217 A.5 Experimental Data for Chapter 5 ......................................................................... 220 A.5.1 1H and 13C NMR Data ....................................................................................... 222 A.5.2 Crystal Data for 5-3a, 5-3b, 5-4, 5-5b, 5-9a, 5-9b, 5-11b ................................. 226 References ...................................................................................................................... 233  vii  List of Tables  Table 2.1 Survey of acid catalysts for the condensation reaction. .................................... 59 Table 2.2 Yields of N-confused DPMs. ............................................................................ 64 Table 2.3 Survey of the α-EWG effect. ............................................................................ 69 Table 2.4 Directing group promoted β,β‟-DPM products. ............................................... 70 Table 2.5 Applying the N-protected pyrrole as substrate. ................................................ 72 Table 3.1 Survey of oxidants for an N-confused meso-aryl diacyl DPM. ........................ 81 Table 3.2 DDQ-mediated hydroxylation on N-confused diacyl DPMs. ........................... 82 Table 3.3 DDQ-mediated reaction on α,α‟- and β,β‟-diacyl DPMs. ................................ 85 Table 3.4 Selected 1H and 13C NMR of meso-H and -C for DPM substrates. .................. 87 Table 3.5 DDQ-mediated meso-alkoxylation on an α,β-DPM. ........................................ 90 Table 3.6 DDQ-mediated meso-C-C bond formation on DPMs....................................... 92 Table 4.1 DDQ-promoted dehydrogenation of N-confused DPM.................................. 100 Table 4.2 Exploration of alkoxylation conditions........................................................... 106 Table 4.3 N-confused dipyrrin as substrate for alkoxylation. ......................................... 111 Table 4.4 DDQ-promoted alkoxylation of the N-confused dipyrromethane. ................. 112 Table 4.5 Relationship between hydrogen-bonding strength and stereochemistry. ....... 113 Table 5.1 One-pot synthesis of the corresponding macrocycles and oligopyrroles. ...... 141  viii  List of Figures Figure 1.1 Natural products constituted of oligopyrroles. .................................................. 2 Figure 1.2 Acyclic oligopyrrolic structures. ....................................................................... 5 Figure 1.3 Dipyrrin systems. ............................................................................................... 6 Figure 1.4 Hydrogen bonding of triflic acid protonated dipyrrin complex 1-1. ............... 10 Figure 1.5 Coordination chemistry of dipyrrins. .............................................................. 11 Figure 1.6 Free-base tripyrrin derivatives. ........................................................................ 13 Figure 1.7 Bilin derivatives: Biliverdin 1-20, Bilirubin 1-21 and Phytochrome 1-22. ..... 17 Figure 1.8 UV absorption ranges of di-, tri-, tetra- and pentapyrrin. ................................ 25 Figure 1.9 α-Azafulvene and β-azafulvene structures. ..................................................... 26 Figure 1.10 The NCTPP structure 1-40 and TPP structure 1-41. ..................................... 27 Figure 1.11 Two tautomers of NCTPP 1-40A, 1-40B ...................................................... 28 Figure 1.12 UV absorption spectra of TPP and NCTPP ................................................... 30 Figure 1.13 Factors affecting the stabilities of N-confused oligopyrrolic structures. ...... 37 Figure 2.1 The three constitutional isomers of dipyrromethanes. .................................... 45 Figure 2.2 Reactivity of 2-EDG substituted pyrroles calculated by Lindsey. .................. 53 Figure 2.3 1H NMR spectrum of N-confused DPM 2-16 in CDCl3. ................................ 56 Figure 2.4 13C NMR spectrum of N-confused DPM 2-16 in CDCl3. ............................... 56 Figure 2.5 1H-1H COSY spectrum of N-confused DPM 2-31 in CDCl3. ......................... 57 Figure 2.6 X-ray crystal structure of N-confused DPM 2-23. .......................................... 58 Figure 2.7 Total distribution of DPM 2-16 (α,β:β,β‟ DPMs = 2.56:1) after chromatography ........................................................................................................ 60  ix  Figure 2.8 1H NMR spectrum of the DPM products (α,β:β,β‟ = 7:1, catalyzed by MSA, table 2.1, entry 7). ..................................................................................................... 62 Figure 2.9 1H NMR spectrum of β,β‟-DPM 2-24b. .......................................................... 66 Figure 2.10 1H NMR spectrum of α,α‟-DPM 2-39. .......................................................... 73 Figure 2.11 X-ray crystal structure of α,α‟-DPM 2-39. .................................................... 74 Figure 3.1 1H NMR spectrum of hydroxylated DPM 3-1 in CDCl3. ................................ 78 Figure 3.2 13C NMR spectrum of hydroxylated DPM 3-1 in CDCl3. ............................... 79 Figure 3.3 X-ray structure of the meso-modified N-confused DPM 3-9. ......................... 79 Figure 3.4 1H NMR spectrum of lactam dipyrromethene 3-10 in CDCl3. ........................ 83 Fugure 3.5 13C NMR spectrum of lactam dipyrromethene 3-10 in CDCl3....................... 83 Figure 3.6 X-ray structure of the conjugated structure 3-8. .............................................. 84 Figure 3.7 X-ray structure of 3-16. ................................................................................... 86 Figure 3.8 1H NMR spectrum of 3-32 in CDCl3............................................................... 93 Figure 3.9 13C NMR spectrum of 3-32 in CDCl3.............................................................. 93 Figure 4.1 Configurations of the α,β-dipyrrins. .............................................................. 101 Figure 4.2 1H-1H COSY spectrum of N-confused dipyrrin 4-1 in CDCl3. ..................... 102 Figure 4.3 ORTEP representation of the X-ray structure of N-confused dipyrrin 4-1, a top view (left) and a side view (right), the vibrational ellipsoids are represented at 50% probability. .............................................................................................................. 103 Figure 4.4 Hydrogen-bonding interaction in crystal-packing of 4-1. ............................. 104 Figure 4.5 1H-1H COSY NMR spectrum of 4-5 in CDCl3. ............................................ 108 Figure 4.6 ORTEP drawing of N-confused dipyrrin 4-11, a top view (left) and a side view (right), the vibrational ellipsoids are represented at 50% probability. .................... 109  x  Figure 4.7 1H NMR spectrum of 4-20 (Z-anti: Z-syn =4:1) in CDCl3............................ 114 Figure 4.8 Electronic spectra of N-confused dipyrrin derivatives in CH2Cl2. ................ 116 Figure 4.9 1H NMR spectrum of tetrapyrrole 4-24 in CDCl3. ........................................ 120 Figure 4.10 a) 1H NMR spectrum of tetrapyrrole 4-27a in CDCl3, b) 13C NMR spectrum of the tetrapyrrole 4-27a in CDCl3. ......................................................................... 122 Figure 4.11 ORTEP drawing of 4-27a, the vibrational ellipsoids are represented at 50% probability. .............................................................................................................. 123 Figure 5.1 One-pot strategies for the synthesis of oligopyrrolic structures. ................... 133 Figure 5.2 Products of the one-pot strategy .................................................................... 135 Figure 5.3 1H-1H COSY NMR spectrum of compound 5-3a in CDCl3. ......................... 137 Figure 5.4 HMQC NMR spectrum of compound 5-3a in CDCl3. .................................. 138 Figure 5.5 ORTEP representations of 5-3a, a top view (left) and a side view (right), the vibrational ellipsoids are represented at 50% probability. ...................................... 139 Figure 5.6 ORTEP representations of 5-3b, a top view (left) and a side view (right), the vibrational ellipsoids are represented at 50% probability. ...................................... 142 Figure 5.7 The UV absorption spectrum of the compound 5-3a in CDCl3..................... 143 Figure 5.8 1H NMR spectrum of 5-4 in CDCl3............................................................... 146 Figure 5.9 X-ray crystal structures of 5-4, the vibrational ellipsoids are represented at 50% probability. ...................................................................................................... 147 Figure 5.10 1H-1H COSY NMR spectrum of 5-5a in CDCl3.......................................... 148 Figure 5.11 X-ray crystal structure of 5-5b, the vibrational ellipsoids are represented at 50% probability. ...................................................................................................... 149  xi  Figure 5.12 ORTEP representation of X-ray crystal structure of 5-11b, the vibrational ellipsoids are represented at 50% probability. ........................................................ 151 Figure 5.13 X-ray crystal structures of 5-9a, a top view (left) and a side view (right), the vibrational ellipsoids are represented at 50% probability. ...................................... 153 Figure 5.14 X-ray crystal structures of 5-9b, a top view (left) and a side view (right), the vibrational ellipsoids are represented at 50% probability. ...................................... 153 Figure 5.15 1H NMR spectrum of 5-9a in CDCl3. .......................................................... 154 Figure 5.16 1H NMR spectrum of 5-9b in CDCl3........................................................... 155 Figure 5.17 Electronic absorption spectrum of 5-9a in CH2Cl2...................................... 156 Figure 5.18 Electronic absorption spectrum of 5-9b ...................................................... 157 Figure 6.1 Proposed coordination modes of N-confused dipyrrin. ................................. 162  xii  Lists of Schemes Scheme 1.1 Conformers of dipyrrin.................................................................................... 6 Scheme 1.2 Two strategies for preparation of α,α‟-dipyrrins: a) MacDonald coupling strategy; b) Oxidation from the meso-aryl dipyrromethane. ....................................... 8 Scheme 1.3 Oxidation of N-confused DPM and a meso-alkyl substituted α,α‟-DPM. ...... 9 Scheme 1.4 Protonation and deprotonation of dipyrrins. ................................................. 10 Scheme 1.5 Synthesis of 1-9 from α,α‟-dipyrrins. ............................................................ 12 Scheme 1.6 Synthesis of tripyrrin derivatives. ................................................................. 14 Scheme 1.7 Coordination chemistry of tripyrrin derivatives. ........................................... 16 Scheme 1.8 Macdonald coupling reaction for bilindione 1-20. ........................................ 18 Scheme 1.9 Synthesis of the linear tetrapyrrole bilindione 1-27. ..................................... 19 Scheme 1.10 Cyclization of biladiene-ac 1-28 to yield corrole 1-30. .............................. 19 Scheme 1.11 From 1-31 to 1-33, electrocyclic ring closure study by Eschenmoser. ....... 20 Scheme 1.12 Synthesis of meso-aryl pentapyrrin 1-34. .................................................... 21 Scheme 1.13 Pentapyrrin 1-34 as precursor for sapphyrin 1-35. ...................................... 23 Scheme 1.14 Intramolecular and intermolecular oxidative coupling for cyclization of 136 and 1-38. .............................................................................................................. 24 Scheme 1.15 The tautomerization of NCTPP. .................................................................. 29 Scheme 1.16 Electrophilic substitution reactions on the confused moiety: a) Alkylation reaction. b) Bromination and fusion reaction............................................................ 31 Scheme 1.17 Nucleophilic addition reactions of Ni(II) NCTTP. ..................................... 32 Scheme 1.18 Diels-Alder reaction on Ni(II) NCTPP. ...................................................... 33 Scheme 1.19 Oxidative degradation reaction on NCTPP. ................................................ 33  xiii  Scheme 1.20 One-pot reaction for preparation of NCTPP. .............................................. 34 Scheme 1.21 N-confused corrorin 1-50 and the oxyindolophyrin 1-51. .......................... 35 Scheme 2.1 The failed synthetic route to N-confused dipyrrin 2-2. ................................. 43 Scheme 2.2 Synthesis of the N-confused dipyrromethane for oxidation study. ............... 44 Scheme 2.3 Lindsey‟s protocol for synthesis of meso-aryl α,α‟-DPMs and A2B2 TPP. .. 46 Scheme 2.4 EDG as blocking groups for α,α‟-DPM synthesis......................................... 47 Scheme 2.5 EWGs as blocking groups for α,α‟-DPM synthesis ...................................... 48 Scheme 2.6 Multi-step synthesis of meso-aryl N-confused DPM. ................................... 50 Scheme 2.7 Multi-step synthesis of meso-aryl N-confused DPM from the aryl aldehyde. ................................................................................................................................... 51 Scheme 2.8 Strategies for regioselective modification of the β-position of pyrrole. ....... 51 Scheme 2.9 Reaction employing a more electron-poor pyrrole substrate. ....................... 71 Scheme 3.1 Oxidation of the α,α‟-DPMs to the corresponding dipyrrins ........................ 77 Scheme 3.2 DDQ-oxidation of disulfonyl α,α‟-DPM 2-36. ............................................. 87 Scheme 3.3 Proposed mechanism of alkoxylation of α,β-DPMs. .................................... 95 Scheme 3.4 Mechanism study of hydroxylation of α,β-DPMs. ........................................ 96 Scheme 4.1 Proposed mechanism for DDQ-mediated addition reaction. ...................... 115 Scheme 4.2 Reactivities of N-confused dipyrrins........................................................... 118 Scheme 4.3 Oxidative dimerization reaction of N-confused DPM. ............................... 121 Scheme 4.4 Oxidative N-C bond formation in the dipyrrin system. .............................. 124 Scheme 4.5 Proposed mechanism for the oxidative dimerization reaction of N-confused dipyrrin. ................................................................................................................... 125  xiv  Scheme 5.1 Inter- and intramolecular oxidative coupling for the construction of oligopyrrolic macrocycles. ...................................................................................... 129 Scheme 5.2 Inter- and intramolecular oxidative amination for the construction of oligopyrrolic macrocycles. ...................................................................................... 130 Scheme 5.3 Synthesis of N-confused oligopyrranes for further oxidation studies. ........ 131 Scheme 5.4 Resonance forms of N-confused tripyrrin 5-3a. .......................................... 140 Scheme 5.5 Ring-opening attempt under the standard reaction conditions. ................... 140 Scheme 5.6 Proposed mechanism for cyclization of 5-3a. ............................................. 145 Scheme 5.7 Preparation of β-α-β-β connected tripyrrane 5-10a. .................................... 150 Scheme 5.8 Intramolecular oxidative amination reaction............................................... 152 Scheme 6.1 Proposed synthetic route for EWG substituted oligopyrrole macrocycles. 162  xv  List of Abbreviations  Anal.  Analytical  br  Broad (NMR)  Calcd  Calculated  conc.  Concentrated  COSY  Correlated spectroscopy  d  Doublet  DDQ  2,3-Dichloro-5,6-Dicyano-1,4-Benzoquinone  DFT  Density Functional Theory  DMF  N,N-Dimethylformamide  EI  Electron Impact Ionization  equiv.  Equivalent  h  Hour(s)  HMQC  Heteronuclear Multiple Quantum Coherence  HRMS  High Resolution Mass Spectrometry  m  Meta  m  Multiplet  m/z  Mass/charge  min  Minute(s)  MS  Mass Spectrometry  MSA  Methanesulfonic Acid  xvi  N2CP  Doubly N-Confused Porphyrin  NBS  N-Bromosuccinimide  NCP  N-Confused Porphyrin  NCTPP  N-Confused Tetraphenyl Porphyrin  NFP  N-Fused Porphyrin  NMR  Nuclear Magnetic Resonance  o  Ortho  OEP  Octaethylporphyrin  ORTEP  Oak Ridge Thermal Ellipsoid Plot  p  Para  r.t  Room Temperature  s  Singlet  t  Triplet  TEA  Triethylamine  TFA  Trifluoroacetic Acid  TLC  Thin-Layer Chromatography  TPP  meso-Tetraphenylporphyrin  UV-vis  Ultraviolet-visible  xvii  Nomenclature The nomenclature of oligopyrrolic compounds has undergone much revision over the past several decades. The most recent IUPAC recommendations are listed here.  Monopyrrolic systems The parent of the monopyrrole is numbered as below. The Greek letters α and β are used to distinguish between the two different carbon positions in all pyrrolic systems.  Labelling of monopyrrolic systems.  Dipyrrolic systems  Labelling and nomenclature of dipyrrolic systems.  xviii  Tripyrrolic systems  Labelling and nomenclature of tripyrrolic systems.  Tetrapyrrolic systems  Labelling and nomenclature of tetrapyrrolic systems.  Pentapyrrolic systems  Labelling and nomenclature of pentapyrrolic systems.  xix  Porphyrin and N-confused porphyrin systems The parent porphyrin system is called porphine. The numbering of the ring positions is shown below. Positions 1, 4, 6, 9, 11, 14, 16 and 19 are termed the “α” positions; 2, 3, 7, 8, 12, 13, 17 and 18 are the “β” positions and 5,10,15 and 20 are the “meso” positions.  Labelling and nomenclature of porphyrin and N-confused porphyrin systems.  xx  Acknowledgements  I would first like to extend gratitude to my supervisor, Professor David Dolphin for the advice, guidance and academic freedom he offered me to explore the chemistry of oligopyrrolic pigments. It is also my wish to thank past and present colleagues of the Dolphin lab and other research groups for their assistance and friendship. Special thanks go to Mr. Andrew Tovey for his diligent proof-reading of this thesis and for providing invaluable critique during its writing. Also, this work would not have been possible without the help of many people in the UBC Chemistry Department. I would like to acknowledge Dr. Brian Patrick for his X-ray structure determinations, Mrs. Ezhova for performing the NMR analyses and Dr. Yun Ling for the mass and elemental analyses. Additionally, I am grateful for the fruitful discourse provided by Dr. Yakun Chen during our theoretical chemistry discussions. Finally, I would like to thank my wife Annie, who has provided continual support and encouragement during the course of my studies. Financial support in the form of a research assistantship from NSERC is greatly appreciated.  xxi  Chapter 1 Introduction  1  1.1 Introduction In organic chemistry there are few, if any, classes of natural products that have held more fascination for investigators than pyrrole pigments during the past century. Studies of oligopyrrolic systems containing several pyrrolic moieties linked through methylene or methane fragments at the α-position originated from the isolation of naturally-occurring pyrrolic pigments. These natural pigments, containing four or fewer pyrrolic fragments arranged in a cyclized or linear fashion, are represented by heme, chlorophyll and the corresponding linear bile pigments such as biliverdin, bilirubin and phytochrome (Figure 1.1).1  Figure 1.1 Natural products constituted of oligopyrroles.  2  Among these natural oligopyrrolic structures, the linear, conjugated oligopyrrolic pigments, represented by propentdyopent, prodigiosins, phytochrome and bile pigments, have attracted much interest during the past century. 2 These biological pigments are formed in many organisms and play important roles in nature. For example, the sensor system of phytochrome in plants governing photomorphogenesis (light-mediated development in plants) includes a green tetrapyrrolic bile pigment.3 Another example is the linear oligopyrrole bilirubin produced in vertebrates of which each person yields approximately 400 mg each day through degradation of hemoglobin. 4 Throughout the twentieth century the interesting photochemical properties and bioactivities of these naturally-occurring oligopyrrole pigments have attracted the interest of many chemists and continue to provide fertile ground for new discoveries and inventions in related research fields. Besides these naturally-occurring oligopyrrolic pigments, considerable efforts have been devoted to the synthesis and study of artificial oligopyrrole systems. These cyclic and linear π-conjugated oligopyrrolic systems attract growing interest due to their expanded π-conjugated systems, 5 which have found various applications in the anion binding,6 cation coordination,7 conducting polymer,8 liquid crystal,9 and nonlinear optics research areas.10 Concentrating on the predominant aspects of synthesis, structure and reactivity, this introduction presents an overview of the development of linear oligopyrrolic pigments. Both natural and artificial oligopyrrolic pigments are covered in this account.  3  1.2 Linear Oligopyrrole Chemistry Studies of linear oligopyrroles have largely focused on the chemistry of naturallyoccurring bile pigments due to their extensive occurrence in both animals and plants. Despite studies of oligopyrrolic pigments dating back to the beginning of the last century, detailed information of the structures of these pigments has been gleaned only recently from advanced modern spectroscopic studies. Great strides have been made since the introduction of X-ray diffraction analysis. The crystal structure of bilirubin was reported by Bonnett in 1976,11 and its biliverdin derivative was solved by Sheldrick in the same year. 12 Following these advances, the structure of biliprotein C-phycocyanin from Agmenellum quadruplicatum was reported by Huber in 1987.13 In 2005, the Vierstra and Forest labs published a three-dimensional structure of the photosensory domain of the Deinococcus phytochrome.14 These discoveries are important milestones for natural linear oligopyrrolic chemistry and have stimulated a continued growth of study in this field. Successful elucidation of these oligopyrrolic pigments brought about a surge of natural product synthesis in the early seventies in synthetic chemistry. After the total synthesis of heme,15 the total synthesis of a more complicated tetrapyrrole, chlorophyll, was successfully accomplished by Woodward in 1960.  16  The total synthesis of  chlorophyll showed a significant advance over Fischer‟s total synthesis of heme, and this milestone event in oligopyrrole chemistry contributed not only to pyrrole chemistry, but also extended the frontier of synthetic chemistry at the time. Their accomplishment subsequently contributed to myriad advancements in oligopyrrole chemistry and related disciplines. Encouraged by the successful synthesis of chlorophyll, total syntheses of the linear tetrapyrrole bilin derivatives of phycocyanobilin, phycoerythrobilin and  4  phytochromobilin were subsequently solved by Albert Gossauer and coworkers in the early seventies.17, 18, 19 The methods for the preparation of useful oligopyrroles, either from naturally-derived tetrapyrroles or from pyrrole subunits are described in their reports.  Figure 1.2 Acyclic oligopyrrolic structures.  A wealth of novel strategies were generated to synthesize the intricate network of mono-, di-, tri- and tetrapyrrolic intermediates for the total synthesis of the structures mentioned above, which offered opportunities to discover and invent new research areas in oligopyrrole chemistry and related disciplines. Among the oligopyrrolic frameworks  5  being created, fully conjugated oligopyrrolic derivatives such as dipyrrin, tripyrrin and tetrapyrrin were widely studied in various fields owing to their extended π-electron delocalization on a flexible molecular framework (Figure 1.2).4 1.2.1 Introduction of α,α’-Dipyrrins and Their Derivatives 1.2.1.1 Structures of α,α’-Dipyrrins and Their Derivatives  Figure 1.3 Dipyrrin systems.  Composed of a pyrrole ring and an azafulvene linked via their α-positions, α,α‟dipyrrin is essentially one-half of the porphyrin structure (Figure 1.3). The two pyrrole rings and the methine bridge create a rigid, planar and conjugated structure bearing 12π delocalized electrons.  Scheme 1.1 Conformers of dipyrrin.  The coexistence of both imine and enamine functionalities gives dipyrrin an amphoteric character and it may exist in three distinct forms (neutral, cationic and anionic). As there is always an exocyclic double bond at the meso-position in dipyrrin,  6  two configurations, (E) and (Z), are possible according to the relative orientation of exocyclic double bond. The three possible forms are described as the Z-syn, Z-anti and Esyn isomers (Scheme 1.1). Due to the strong hydrogen-bonding interaction in free-base meso-aryl dipyrrins, there is a rapid exchange of the two tautomers resulting from the sharing of a hydrogenatom between the two pyrrole nitrogen atoms (Scheme 1.1). In contrast, the Z-anti and Esyn conformers are reported only in the complex form induced by coordination or hydrogen-bonding interaction.20 Dipyrrins exhibit very different acid-base properties, and free-base dipyrrins are regarded as relatively strong bases. The pKa of the hydrogen atom bound to the nitrogen atom is greatly affected by electron-withdrawing and electron-donating groups on dipyrrins21 and this significantly affects the coordination ability of dipyrrin derivatives.22 1.2.1.2 Preparation of Dipyrrin and Its Derivatives Reaction of a 2-formyl pyrrole with a β-substituted pyrrole bearing an unsubstituted α-position, by acid-catalyzed condensation, affords the β-substituted and meso-unsubstituted dipyrrin in high yield. This reaction provides a reliable method for preparation of all β-position-substituted dipyrrins (Scheme 1.2 a), 23 and is frequently referred to as the MacDonald coupling, named after the Canadian porphyrin chemist Stewart Ferguson MacDonald. The MacDonald coupling reaction is the most frequently used method for the preparation of asymmetrical β-substituted and meso-unsubstituted dipyrrins. Among various acids used, hydrobromic acid is commonly employed, and the dipyrrin products prepared in this way are isolated as salts.  7  Scheme 1.2 Two strategies for preparation of α,α‟-dipyrrins: a) MacDonald coupling strategy; b) Oxidation from the meso-aryl dipyrromethane.  Dipyrrins bearing aryl groups at the 5- or meso-position display enhanced stability, in comparison with β-substituted and meso-unsubstituted dipyrrins, and such free-base meso-aryl dipyrrins can be isolated and stored at room temperature. Preparation of mesoaryl dipyrrins involves oxidation of 5-aryl-substituted dipyrromethanes to yield the freebase dipyrrins (Scheme 1.2 b). Development of reliable methods for the preparation of dipyrrins by oxidation of the corresponding dipyrromethanes has been a very important advance in dipyrrin chemistry. As a result of the reliable one-pot strategy developed for preparation of meso-aryl-substituted dipyrromethanes by Lindsey and coworkers, 24 , 25 many substrates for different 5-aryl-substituted dipyrrins are available. Oxidation of meso-aryl dipyrromethanes to dipyrrins may be achieved with a number of quinone oxidants, such as p-chloranil and 2,3-dichloro-5,6-dicyano-1,4benzoquinone (DDQ), with the latter being the most commonly used. It is worthwhile to note the hydrogen elimination reaction is highly substituent-dependent. The oxidation of meso-aryl N-confused dipyrromethanes 26 and 5-alkyl-β-unsubstituted dipyrromethanes 27  8  give none of the desired products, as the reaction leads to the decomposition of the starting materials (Scheme 1.3).  Scheme 1.3 Oxidation of N-confused DPM26 and a meso-alkyl substituted α,α‟-DPM.27 1.2.1.3 α,β- and β,β’-Dipyrrins Reports regarding α,β- and β,β‟-dipyrromethene analogues are rather rare, with instability and the lack of an efficient synthetic route hampering the study of these α,α‟dipyrrin counterparts. Falk indicated that the β,β‟-dipyrrin is only stable in the protonated form; when deprotonated, it soon forms the dimer linked through the meso-positions.28 The constitution, nature and number of substituents remarkably affect the stability of a dipyrrin. Thus, for α,β- or β,β‟-dipyrrins, stability is the key hurdle to overcome before further studies can be reasonably pursued. 1.2.2 Reactivity of Dipyrrin Derivatives As the simplest oligopyrrolic system, free-base dipyrrins are readily protonated to yield the salt and protonated β-substituted and meso-unsubstituted type dipyrrins are more stable than their corresponding free-base counterparts. Interestingly, protonation of meso-aryl dipyrrin, which exists in the Z-syn configuration, generates the E-anti form of meso-aryl dipyrrin cation 1-1, as shown in Scheme 1.4 a and figure 1.4.20  9  1.2.2.1 Protonation and Deprotonation  Scheme 1.4 Protonation and deprotonation of dipyrrins.  Figure 1.4 Hydrogen bonding in triflic acid protonated dipyrrin complex 1-1 (Source: Inorg. Chem. 2008, 766).20  Meso-groups affect the protonation and tautermerization profoundly. For example, when deprotonating meso-alkyl or benzyl dipyrrins, the resulting free-base dipyrrin tautomerizes to generate dipyrrole 1-2 as the product (Scheme 1.4 b).29, 30 The relative acidity of the meso-alkyl proton promotes the generation of dipyrrole 1-2 from the freebase dipyrrin under strongly basic conditions. This unexpected result demonstrates that the meso-alkyl dipyrrins have rather distinct acid-base properties when compared with their meso-aryl and meso-H counterparts.  10  1.2.2.2 Dipyrrin as Ligand for Coordination Chemistry  Figure 1.5 Coordination chemistry of dipyrrins.  The two nitrogen atoms in a dipyrrin are ideally arranged to chelate metal cations and thus readily form metal dipyrrin complexes. As monoanionic bidentate ligands, dipyrrins are employed to generate complexes such as 1-3 (for divalent metal ions) and 14 (for trivalent metal ions) (Figure 1.5). 31 Beyond these classic coordination motifs, additional coordination modes have been recently reported, which have greatly expanded the coordination chemistry of dipyrrins. For example, by installing additional ligating groups on the two α-positions, the meso-aryl dipyrrin can be converted into a tetradentate ligand with an NNNO coordination mode for divalent metals such as Ni(II) to create square planar architectures (1-5).32, 33 Modification of the peripheral meso-aryl group may introduce further coordination positions and generate a diversity of supramolecular architectures when coordinated with metal ions. Construction of discrete or infinite supramolecular architectures such as 1-6 has been achieved by Cohen and coworkers.34 Formation of complexes with a variety of metal ions has provided new avenues to explore in dipyrrin chemistry.  11  1.2.2.3 Nucleophilic and Electrophilic Reactions on Dipyrrin Derivatives Both nucleophilic and electrophilic substitution reactions can occur at the αposition of dipyrrin substrates owing to their π-conjugation.  35 , 36 , 15, 37  These modified  dipyrrin derivatives have been employed extensively in the synthesis of porphyrins and linear oligopyrroles. For example, the classic reaction of cyclizing dipyrrin derivatives 17 and 1-8 to the corresponding porphyrin 1-9 was developed in the total synthesis of heme by H. Fischer (Scheme 1.5).15 The most remarkable feature of Fischer‟s synthesis is the fusion of the two dipyrrin components in the presence of acid. The acidification of the free-base of dipyrrin 1-8 induced the nucleophilic substitution of 1-7 to the α-position of 1-8, and thus the cyclic porphyrin skeleton 1-9 was created in a single step by two C-C bond formations.  Scheme 1.5 Synthesis of 1-9 from α,α‟-dipyrrins.15  These unique reactions of dipyrrin render dipyrrin derivatives almost indispensable building blocks in oligopyrrole chemistry. The corresponding higher tri-, tetra- and penta-oligopyrroles can be constructed in a stepwise fashion from the corresponding dipyrrin and pyrrole substrates by employing successive MacDonald couplings.  12  1.3 Introduction of α,α’-Tripyrrins Bearing one more conjugated pyrrole moiety than their dipyrrin counterparts, tripyrrin compounds are also found in nature. For example, biotripyrrin 1-10 is secreted in urine as the degradation product of heme (Figure 1.6). 38 Also, the red tripyrrolic pigment prodigiosin 1-12, a compound from Bacillus prodigiosus, is comprised of a dipyrrin coupled to a pyrrole group (Figure 1.6).39  Figure 1.6 Free-base tripyrrin derivatives.  In synthetic chemistry, tripyrranes (saturated tripyrrins) are building blocks in the construction of various porphyrinoids. However, the corresponding unsaturated tripyrrin derivatives, in comparison to the wealth of chemistry for di- and tetrapyrrolic pigments, have been minimally pursued in the literature. 1.3.1 Free-base Tripyrrin Derivatives Systematic approaches toward generating the oxidized form of tripyrranes have not, as yet, been reported. The tripyrrin system cannot be produced by oxidizing the corresponding tripyrrane due to the instability of the tripyrrin products and, therefore, a multi-step synthesis via MacDonald coupling is necessary for preparation of the βsubstituted and meso-unsubstituted type of tripyrrin derivatives. Also, stability is found on a case-by-case basis depending on the substituents present in the resulting product. In 13  spite of their instability, the application of tripyrrin derivatives as ligands for divalent metals has rendered them rather promising newcomers to supramolecular chemistry.40 1.3.2 Synthesis of Tripyrrin Derivatives Reports of fully characterized free-base tripyrrin derivatives are very rare, which is somewhat surprising considering the long history of oligopyrrole chemistry. No reports of preparation of free-base meso-aryl tripyrrins were found in the literature until very recently. Gazezowski and coworkers have reported that meso-aryl tripyrrin 1-13 can be created by oxidizing a meso-aryl tripyrrane precursor 1-11 under basic conditions (KOH/MeOH) (Scheme 1.6 a).41 The methoxy group is added to the α-position of the produced tripyrrin to give the lactim form of free-base tripyrrin 1-13, which is stable in both solution and the solid state. Although this approach produces the meso-aryl tripyrrin directly, the large number of by-products (more than 50) limits the practical preparation of meso-aryl tripyrrins using this strategy.  Scheme 1.6 Synthesis of tripyrrin derivatives.  14  It was not until 2004 that the first free-base of a β-substituted and mesounsubstituted tripyrrin (1-14) was fully characterized by Bröring and coworkers (Scheme 1.6 b).42 In their synthesis, a stable free-base tripyrrin 1-14 is generated by reaction of a bulky t-butyl group protected 3,4-diethyl-substituted pyrrole with a 2,5-pyrrole dialdehyde in the presence of acid. The structure is assigned as (Z-syn, Z-syn) with the two terminal pyrroles in the imine form as shown by X-ray crystallography. 1.3.3 Tripyrrins as Ligands for Coordination Chemistry Rational exploration into the coordination chemistry of tripyrrins is hampered due to the susceptibility of the α-positions to both electrophilic and nucleophilic attack. This characteristic is unique to tripyrrins and bears only faint resemblance to other oligopyrrolic systems. The pioneering work using tripyrrins for coordination chemistry was conducted by Sessler and coworkers. 43 By mixing tripyrrane 1-15 and copper(II) under oxidizing conditions, a tripyrrinone-Cu (II) complex 1-16 was isolated and characterized by X-ray analysis (Scheme 1.7 a). Rath et al. discovered that oxidation of an iron oxaphlorin complex 1-17 proceeded beyond the ring opening to yield tripyrrolic complex 1-18 (Scheme 1.7 b).44 This unexpected result suggests that tripyrrins can be promising ligands in coordination chemistry. However, it remains to be seen whether linear tripyrrolic systems can be rationally employed as metal-complexation ligands to the same extent as dipyrrins.  15  Scheme 1.7 Coordination chemistry of tripyrrin derivatives.  The coordination chemistry of tripyrrin was recently established by Bröring‟s group. 45 Rationally synthesized tripyrrin may serve as a tridentate ligand for divalent metal ions such as Co(II), Cu(II), Zn(II) and Pd(II) to yield tripyrrin complexes (Scheme 1.7 c). As a T-shaped tridentate ligand for metal ions, tripyrrins provide three pyrrolic nitrogens for coordination, which makes it a unique synthon in coordination chemistry. 1.4 Introduction of α,α’-Tetrapyrrolic Pigments Extension of the π-conjugation of linear tetrapyrrolic systems has attracted much interest. As the most widely studied linear oligopyrroles, tetrapyrrins or bilins are 16  biological pigments formed in many organisms as the metabolites of various porphyrins. The vast majority of studies on linear tetrapyrrins have largely focused on the biochemistry of naturally-occurring bile pigments such as biliverdin 1-20, bilirubin 1-21 and phytochrome 1-22 (Figure 1.7).  Figure 1.7 Bilin derivatives: Biliverdin 1-20, Bilirubin 1-21 and Phytochrome 1-22. 1.4.1 Synthesis of Bilindiones In addition to the bioactivities of the bilin derivatives, many other aspects of synthetic conjugated tetrapyrrole derivatives have been studied. Examples include: photochemical isomerization and energy transfer, 46 coordination properties, 47 chiral frameworks for various enantioselective processes, 48 as well as molecular electronic materials.49 In the vast majority of these studies, two synthetic routes, to obtain fully conjugated tetrapyrrole derivatives, have been developed (Schemes 1.8 and 1.9). The βsubstituted and meso-unsubstituted bilindione 1-20 requires a multi-step synthesis owning to the low symmetry of the molecule (Scheme 1.8).50 Despite the reliability of the MacDonald coupling reaction for extension of the oligopyrrole system, the challenging  17  multi-step synthesis and uncertain stability render the linear tetrapyrrolic bilindiones less frequently employed as a scaffold compared to the well-studied porphyrins.  Scheme 1.8 Macdonald coupling reaction for bilindione 1-20.50  To avoid a long synthetic route, a straightforward method for preparation of symmetric meso-aryl bilindione 1-27 has been developed by Mizutani‟s group. 51 This strategy uses an oxidative degradation pathway under aerobic conditions by employing the synthetic meso-aryl TPP-type of metal porphyrin 1-25 as precursor (Scheme 1.9). At room temperature iron(II) TPP 1-25 was treated with pyridine, ascorbic acid and dioxygen, and the biladienone 1-26 was produced in 63% yield along with by-product biladienone 1-27. The preparation of the meso-aryl 1,19-bilindione derivatives using an oxidative degradation pathway from synthetic porphyrin precursor 1-25 in a single step encouraged further studies toward fully conjugated tetrapyrroles.  18  Scheme 1.9 Synthesis of the linear tetrapyrrole bilindione 1-27.51 1.4.2 Synthetic Tetrapyrrolic Pigments 1.4.2.1 Application of Biladiene-ac 1-28 as Precursor for Corrole 1-30 Chemistry relating to oligopyrrolic macrocycle synthesis involving acyclic tetrapyrrin precursors has accumulated during the past few decades. The tetrapyrrin pigments not only demonstrate interesting properties, but also they provide precursors for unique carbon-linked oligopyrrole macrocycles. For example, oxidative cyclization of biladiene-ac 1-28 to yield fully β-substituted corrole 1-30 was investigated by Dolphin et al.52 A variety of free-radical initiators and one-electron oxidizing agents proved effective for ring closure of biladiene-ac 1-28 to create 1-30. The presence of base is essential for this reaction since the cyclization process is initiated by meso-position hydrogen abstraction (Scheme 1.10).  Scheme 1.10 Cyclization of biladiene-ac 1-28 to yield corrole 1-30.52 19  1.4.2.2 Application of Seccorrin 1-31 as Precursor for Corrin 1-33 Another conjugated tetrapyrrin derivative, secocorrin (1-31), serving an important role in the vitamin B12 total synthesis, provides an acyclic precursor for corrin 1-33. As one of the most well studied metal coordinated tetrapyrrolic structures,53 secocorrin was employed as the key precursor for A/D ring closure to generate the corrin core in the total synthesis of vitamin B12.54 The metal ion templates the linear tetrapyrrole 1-31 to create the (Z,Z,Z) configuration in a somewhat helical shape, which enables one hydrogen atom of the ring D α-methylene group to be placed above the exocyclic azafulvene bond. This delicate arrangement enables the subsequent photo-induced electrocyclic ring closure reaction to occur and stereoselectively generate the cyclized corrin 1-33 (Scheme 1.11).55  Scheme 1.11 From 1-31 to 1-33, electrocyclic ring closure study by Eschenmoser.53 1.5 Introduction of α,α’-Oligopyrroles Higher than Tetrapyrrole. Fully conjugated oligopyrrolic macrocycles consisting of as many as 24 pyrrole rings have been synthesized and fully-characterized by X-ray diffraction analysis. 56 Conversely, the corresponding longest fully-characterized linear oligopyrrin only consists of five pyrrolic units due to increasing instability of the linear structure with longer conjugation.  20  1.5.1 Synthesis of Meso-aryl Pentapyrrin 1-34 Recently, meso-aryl pentapyrrin 1-34 was generated by a solvent-free condensation of pyrrole and pentafluorobenzaldehyde, and was fully characterized by Xray diffraction analysis (Scheme 1.12).57 As noted above, the stability of fully conjugated oligopyrroles is highly substitution-dependent, and the nature of the meso-substituent has been shown to be crucial for the stabilization of certain structures with high reactivity. In 1-34, pentafluorophenyl groups at the meso-positions of the meso-aryl pentapyrrin not only decrease the electron density of the conjugated system, but also provide the mesopositions steric protection from possible nucleophilic or electrophilic addition reactions.  Scheme 1.12 Synthesis of meso-aryl pentapyrrin 1-34.57  Composed solely of pyrroles bridged by one unsaturated meso-methine carbon in an alternating fashion, 1-34 is the largest fully characterized acyclic oligopyrromethene synthesized to date. This pentapyrrin shows C2 symmetry in the solid state, and the entire molecule adopts an overall helical shape. The two terminal pyrroles overlap each other, a typical feature shared by other helical molecular systems. The configuration of 1-34 is assigned (Z,Z,Z,Z) according to the exocyclic double bonds shown in the X-ray analysis.  21  1.5.2 Application of Pentapyrrin 1-34 as Precursor for Sapphyrin 1-35 Higher oligopyrroles bearing unsubstituted α-positions on the two terminal pyrroles may be used as precursors for the construction of macrocycles through oxidative coupling. Construction of novel expanded porphyrinoids is of interest to synthetic chemists; however the number of synthetic approaches toward the cyclization of oligopyrrolic macrocycles remains quite limited. The molecular constitution and shape of 1-34 resemble the sapphyrin macrocycle and the two closely overlapped terminal pyrrole rings render it a promising precursor for further oxidative coupling cyclizations through the two unsubstituted α-positions. A facile oxidative cyclization of the pentapyrrin 1-34 to yield sapphyrin 1-35 with either Na2Cr2O7 or I2/O2 as oxidant has been developed by Gross and coworkers (Scheme 1.13).58  22  Scheme 1.13 Pentapyrrin 1-34 as precursor for sapphyrin 1-35.58 1.5.3 Application of Higher Linear Oligopyrroles for Preparation of Expanded Porphyrins Sessler and coworkers utilized β-substituted and meso-unsubstituted oligopyrrins with unsubstituted α-positions on the terminal pyrroles, such as 1-36 and 1-38, as the precursors of carbon-linked macrocycles 1-37 and 1-39, through an oxidative coupling approach.59 Both an intramolecular and an intermolecular oxidative C-C bond formation are apparent in their synthesis of 1-37 and 1-39 (Scheme 1.14). Briefly, the linear oligopyrrole 1-36 was obtained by condensation of the diformyl hexamethylterpyrrole precursor with 2.5 equivalents of tetramethylbipyrrole under acidcatalyzing conditions. Treated with aqueous Na2Cr2O7 in TFA, 1-36 affords the oxidative ring closure product 1-37 smoothly with 43% yield. This was the first time oxidative methodology was applied for ring closure in expanded macrocycle system, and it provides a reasonably efficient way (in terms of steps) for application of linear oligopyrrole with unsubstituted α-positions to generate macrocyclic products.  23  Scheme 1.14 Intramolecular and intermolecular oxidative coupling for cyclization of 136 and 1-38.59 Higher oligopyrroles can serve as precursors for novel macrocycle construction, which has attracted the attention of porphyrin chemists. However, with an increase in length, the stability of oligopyrroles decreases, complicating the synthesis and purification processes. There are few reports regarding the existence of fully conjugated hexapyrrins except in the case of a bipyrrole-connected hexapyrrole structure.60  24  1.6 Optical Properties of the Fully-conjugated Oligopyrrole Products  Figure 1.8 UV absorption ranges of di-, tri-, tetra- and pentapyrrin.  As coloured pigments, one of the most important feature of conjugated oligopyrrole compounds is their optical properties. The relationship of absorption or absorption change with structure may provide important information regarding the structural features of fully conjugated oligopyrroles (Figure 1.8). The effect of molecular structure, especially the stereochemistry, upon the spectroscopic properties of these naturally-occurring systems has received much attention.61 Generally, the optical properties of these oligopyrroles are governed by the following factors: 1) The length of the conjugated system: the number of conjugated pyrroles is the decisive factor affecting absorption wavelength. The UV-absorptions of fully conjugated  25  oligopyrroles range from 300 nm to 800 nm depending on the length of these conjugated systems (Figure 1.8); 2) Configuration and conformation play secondary roles in absorption properties, but even so, in bilin chemistry, configurational change is critical to the photosynthetic process.61 3) Other factors affecting the absorption properties of oligopyrrolic pigments include the electronic properties of the substituents,62 the protonation and deprotonation states,63 and tautomerism.64 1.7 Summary of α,α’-Linear Oligopyrroles Significant achievements have been made in the chemistry of α,α‟-oligopyrrolic pigments during the past several decades. The assembly of the pyrrolic groups by exploiting the much higher nucleophilicity of the 2-position of pyrrole, relative to that of the 3-position, leads to the α,α‟-oligopyrrole network (Figure 1.9).  Figure 1.9 α-Azafulvene and β-azafulvene structures.  Beyond the traditional α,α‟-oligopyrrole frameworks, a synthetic oligopyrrolic macrocycle-N-confused porphyrin (NCP) was reported in 1994. 65, 66 This system, which contains an inverted pyrrolic subunit, was, at that time, only the second example of a  26  porphyrin isomer, and showed distinct characteristics that immediately attracted the interest of porphyrin chemists. 1.8 Introduction of N-confused Oligopyrroles The isolation of the N-confused tetraaryl porphyrin (NCTPP) 1-40 as a byproduct of a standard preparative method for tetraaryl porphyrin (TPP) 1-41 was an important and unexpected development in porphyrin chemistry (Figure 1.10). The unique α-meso-β linkage renders one pyrrole "confused" with its nitrogen atom oriented outside of the macrocycle; this significantly changes the properties and reactivities of the N-confused macrocycle.  Figure 1.10 The NCTPP structure 1-40 and TPP structure 1-41.  Considerable progress has been made in understanding the unique properties of NCP and its analogues during the last decade. Some of the most attractive properties include long wavelength absorptions that can possibly lead to applications in photodynamic therapy, 67 the ability to act as dianionic and trianionic ligands, and the potential use of NCP complexes as catalysts. 68 Also, coordination complexes and hydrogen-bonding interactions through the external nitrogen oriented outside of the macrocycle allow the formation of supramolecular architectures.69 27  Systematically confusing more pyrrole rings in the oligopyrrole macrocycle system provides unprecedented N-confused porphyrinoid analogues. Isomers, multiple NCPs and expanded NCPs, have opened up new realms of NCP chemistry. 70 The following introduction gives a brief review of the predominant aspects of the syntheses, properties and reactivities of N-confused systems. 1.8.1 Properties and Reactivities of NCTPP The N-confused tetraphenyl porphyrin (NCTPP) 1-40 contains 18π-electrons delocalized within the tetrapyrrole macrocycle plane and exhibits aromaticity similar to that of TPP 1-41. X-ray diffraction analysis showed that the skeleton deviates from planarity with the confused pyrrole ring tilted out of the average plane constituted by other three pyrroles nitrogens by 26.9º. (Figure 1.11, 1-40A). This deviation from planarity appears to result from the repulsion of the three inner hydrogen atoms.  Figure 1.11 Two tautomers of NCTPP 1-40A, 1-40B.71  The NCTTP can exhibit different conjugations and optical properties with three possible tautomeric forms (Scheme 1.15 1-40A, 40B, 40C); however, only tautomers 140A and 1-40B have been observed. 71 NCPs are commonly isolated as the fully  28  conjugated imine-type tautomer 1-40A, but this species is only slightly more stable than the less aromatic enamine-type tautomer 1-40B which is favoured in polar aprotic solvents. Crystals of tautomer 1-40A and 1-40B were obtained by crystallization of 1-40 in nonpolar or polar solvents, with both forms characterized by X-ray diffraction analysis.  Scheme 1.15 The tautomerization of NCTPP.  In the electronic spectra of NCTPP, the Soret- (corresponding to a wavelength of maximum absorption) and Q-type transitions (corresponding to weak absorptions between 500-750 nm) of NCTPP are broadened and bathochromically-shifted to longer wavelengths (439 and 725 nm as compared to the corresponding TPP (419 and 647 nm) (Figure 1.12). The general trend of the N-confused oligopyrrole macrocycle toward bathochromic-shifting in contrast to the corresponding regular porphyrin suggests the Nconfused oligopyrrolic macrocycle as promising photodynamic therapy (PDT) agents, which are generally photoactive at wavelengths between 650 nm and 800 nm.  29  Figure 1.12 UV absorption spectra of TPP and NCTPP (absorbance between 484 nm and 800 nm is shown with a 5 times greater intensity for clarity). 1.8.2 Reactivities of the N-confused Moiety Confusing a ring in the TPP system leads to a higher energy system in comparison to the corresponding TPP,72 and also increases the reactivity of the system. The unusual reactivity of the confused pyrrole is a consequence of the conjugation through the αmeso-β linkage in the macrocycle. 1.8.2.1 Electrophilic Reactions of NCTPP Modifying the N-confused moiety in the NCTPP can be readily achieved by electrophilic or nucleophilic substitution at three sites (N(2), C(3), and C(21)). One notable characteristic of NCTPP is that the peripheral nitrogen atom of the N-confused ring presents a tempting target for functionalization. For example, the enamine-type tautomer (1-40B) in polar solvents is more reactive than the imine-type tautomer (1-40A).  30  By using Cs2CO3 as the base along with polar DMF as the solvent, a variety of nitrogen alkylated NCPs (1-42) are created in high yield without using a large excess of reagent or base (Scheme 1.16 a). 73 Also, N-confused pyrrole carbon C(3) and C(21) can be brominated using NBS to give 1-43 in high yield. By taking advantage of this high reactivity at the C(21) and C(3) positions of the N-confused moiety, the brominated NCP framework can be further modified. For example, the first N-fused porphyrin (NFP) 1-44, was spontaneously obtained from a pyridine solution of brominated NCP 1-43 at room temperature. (Scheme 1.16 b). 74 NFP 1-44 possesses a characteristic fused [5.5.5] tripentacyclic ring in the macrocyclic core and the most remarkable feature is that it exhibits an unusually long wavelength absorption near 1000 nm in the infrared region.  Scheme 1.16 Electrophilic substitution reactions on the confused moiety: a) Alkylation reaction.73 b) Bromination and fusion reaction.74  31  1.8.2.2 Nucleophilic Addition Reaction of NCTPP As an aromatic macrocycle, Ni(II) NCTPP also undergoes nucleophilic addition reactions. For example, reaction of Ni(II) NCTPP with NaOCH3 and DDQ resulted in the unexpected inner C(21) cyanide addition product 1-46 as the major product, with minor product 1-45 presumably formed by addition of methoxide to 1-46 at C(3) followed by DDQ oxidation (Scheme 1.17). 75 The high regioselectivity of Ni(II) NCTPP toward nucleophiles is attributed to the peripheral iminium character of the carbon-nitrogen bond of the N-confused moiety.  Scheme 1.17 Nucleophilic addition reactions of Ni(II) NCTTP.75 1.8.2.3 Diels-Alder Reaction of NCTPP Diels-Alder reactions of NCTPP have been investigated by Dolphin et al.76 The N-confused ring of Ni(II) NCTPP is capable of undergoing Diels–Alder reactions with activated dienes such as orthobenzoquinodimethane to yield adduct 1-47 (Scheme 1.18). The high regioselectivity of the peripheral carbon-nitrogen bond over the carbon-carbon bonds is attributed to its resonance contribution to the overall structure of the Ni(II) NCTPP.  32  Scheme 1.18 Diels-Alder reaction on Ni(II) NCTPP.76 1.8.2.4 Oxidative Degradation Reaction of NCTPP Furuta and coworkers reported that when NCTPP and Cu (II) were refluxed in toluene for 24 hours, under aerobic conditions, the degradation product tripyrrinone complex 1-48 was obtained in 34% yield. 77 1-48 can be demetalated using concentrated H2SO4 and the resulting free tripyrrin, as a tetradentate ligand, can be remetalated with a variety of transition metals (Scheme 1.19). Mechanistic studies show that the cleavage of the macrocycle happens regioselectively at the meso 5-position instead of the 20-position. It was also shown that when NCP derivatives bearing a sterically-hindered group such as 2,6-dimethylphenyl, 2,6-dimethoxyphenyl, pentafluorophenyl, and 2-chlorophenyl, were subjected to the same reaction conditions, none of the corresponding tripyrrin complexes could be detected.  Scheme 1.19 Oxidative degradation reaction on NCTPP.77 33  1.8.3 Confusing a Ring in NCTPP NCTPP 1-40 was obtained using a modification of the well-known synthesis of TPP that involves the acid-catalyzed condensation between benzaldehyde and pyrrole (Scheme 1.20). Following the discovery of NCTPP, great efforts have been made to increase the yields of NCTPPs by modifying the reaction conditions. By exploring various acid catalysts, Lindsey and coworkers 78 found that a strong organic acid, methanesulfonic acid (MSA), increased the yield of NCTPP significantly at a concentration of 7 mM. The reaction conditions for NCTPP 1-40a are also applicable to various electron-donating aryl aldehydes such as p-tolyl, p-anisyl, etc. The yields can reach as high as 30-40% under Lindsey‟s conditions.  Scheme 1.20 One-pot reaction for preparation of NCTPP.78 1.9 Contracted N-confused Oligopyrrole Macrocycles Contracted porphyrins are porphyrinoid analogues containing pyrrole and methine groups in sub-tetrapyrrolic macrocycles. Incorporation of confusion, namely α-meso-βlinkages, into the contracted framework is of synthetic interest. However, among the contracted macrocycles, those bearing N-confused moieties are very rare. Presumably, higher reactivity, unfavourable ring strain and lack of stability greatly decrease the chances of producing these conjugated structures. Only serendipitous syntheses of N-  34  confused contracted oligopyrrolic macrocycle compounds such as 1-50 and 1-51 have been reported (Scheme 1.21).79  Scheme 1.21 N-confused corrorin 1-50 and the oxyindolophyrin 1-51.79  In one of Furuta's reports, the synthesis of the first N-confused corrole isomer, “corrorin 1-50”, and its transformation into an oxy- derivative of “indolophyrin 1-51” is described.85 The doubly N-confused corrole isomer “Corrorin” 1-50 was obtained as a major  product  (13%)  from  the  acid-catalyzed  condensation  of  N-confused  dipyrromethane and pentafluorobenzaldehyde followed by DDQ oxidation (Scheme 1.21). The structure of 1-50 was determined by X-ray diffraction analysis, which revealed a nonplanar structure wherein the two N-confused dipyrrin moieties are connected directly to the α,α‟-position and two pyrrolic rings of the bipyrrole were substantially distorted.  35  The air stable corrorin 1-50 can be transformed into the novel N-confused aromatic macrocycle oxyindolophyrin 1-51 when a benzene solution of 1-50 is refluxed for 8 hours with 5 equivalents of the Lewis acid SnCl2. This unusual reactivity of the Nconfused moiety was attributed as the lower stability or higher reactivity of the Nconfused corrole 1-50, which has been shown to be less stable than the parent macrocycle “corrole” using DFT calculations.79 X-ray diffraction analysis of oxyindolophyrin 1-51 shows a planar structure bearing an oxo-substituted indolizine moiety and dipyrromethene unit in the framework.79 One of the remarkable features of this tripyrrolic macrocycle is that 1-51 exhibits aromaticity, which is presumably due to the contribution of a zwitterionic canonical form that has an 18 π-electron circuit in the macrocycle structure. The bonding mode in 1-51 is beyond the traditional α-meso-α‟ sequence in porphyrinoid macrocycles and is also beyond the α-meso-β mode in N-confused oligopyrroles. In 1-51 the confused pyrrole group itself provides the 1, 2, and 3 positions for modification and this provides a hint towards other modes for construction of conjugated pyrrole macrocycles yet to be made.  36  1.10 Summary NCP and analogues bearing N-confused moieties exhibit diverse characteristic structures in comparison to the traditional porphyrin structure. Incorporation of confusion into the normal α-meso-α‟ linked oligopyrrolic system significantly changes the properties and reactivities of these oligopyrrole pigments. With regard to the stability and reactivity of N-confused macrocycles, some conclusions can be drawn (Figure 1.13): 1) There are special requirements for the meso-aryl groups in N–confused oligopyrrolic macrocycle syntheses. The presence of certain substituents often aids the generation of macrocyclic products and the nature of the meso-substituent has been shown to be crucial for the stabilization of certain structures with high reactivities. For example, in doubly Nconfused porphyrin and expanded N-confused oligopyrroles, a pentafluorophenyl group appears to be important.  Figure 1.13 Factors affecting the stabilities of N-confused oligopyrrolic structures.  2) Fusion of an N-confused moiety into [5.5.5] tripentacyclic ring on the macrocycle helps to release ring strain and stabilize the final product. The fusion reaction is a common phenomenon in tetrapyrrolic macrocycles and other mid-sized N-confused macrocycles.  37  3) Nucleophilic addition of an alkoxy group to the C(3) position of the N-confused moiety is an effective way to increase the stability of the resulting product. In expanded N-confused oligopyrrole macrocycles, especially those higher than pentaphyrin, the Nconfused moiety adopts the lactim or lactam structure to participate in a hydrogenbonding interaction with the pyrrole nitrogen atom to stabilize the macrocycle frame. In short, the studies of linear oligopyrrolic pigments are fueled by four areas of research: 1) the biochemistry related to natural tetrapyrrole derivatives; 2) the coordination chemistry of supramolecular architectures; 3) the unique optical and electronic properties for application in material chemistry and; 4) the provision of specific building blocks for novel oligopyrrolic macrocycle synthesis. Given the intensity with which α-meso-α‟-linked linear oligopyrroles have been investigated, it is somewhat surprising that α-meso-β-linked analogues that further expand upon the „„confused‟‟ aspect of these NCP macrocycles have not been reported previously. The construction of linear fully conjugated N-confused oligopyrrole pigments has been a serious challenge owing to the instability of the conjugated α-meso-β linkage. However, the rich and interesting chemistry of well-defined α-meso-α‟-linked oligopyrroles requires solutions regarding the instability of their N-confused oligopyrrole “cousins”. 1.11 Research Objectives and Thesis Preview The objectives of the research described in this thesis are to pursue the synthesis of linear N-confused oligopyrroles (cousins of the corresponding α,α‟-linear oligopyrroles) and to study the stability, optical properties and cyclization reactivity of such new N-confused oligopyrrole structures.  38  Studies toward the chemistry of N-confused oligopyrroles were initiated by the one-pot synthesis of N-confused dipyrromethane. In chapter 2, MSA-catalyzed condensation of aryl aldehydes with a variety of electron-withdrawing group-substituted pyrroles to afford the corresponding meso-aryl N-confused diacyl dipyrromethanes has been established. As well, the directing effect of these EWG groups for α-meso-β linkages has been evaluated. The key for the successful transformation apparently depends upon the reactivity of the aldehyde and the electron-poor pyrrole substrates used. This novel one-pot synthesis for construction of the α-meso-β linkage between pyrroles represents a substantial improvement of the reported multi-step synthesis of N-confused DPMs.25 Oxidation of the N-confused dipyrromethane has been tested to screen substituent effects in order to obtain stabilized N-confused dipyrrins. An unprecedented, DDQinduced C-H oxidation reaction was discovered. In chapter 3, we describe a highly efficient protocol to introduce a C-O or C-C bond at the meso-position of DPMs via DDQ-mediated benzylic C-H activation. The efficiency of the reaction is greatly affected by the nature of the meso-aryl substituents. Mechanistic studies show the reaction proceeds through a highly-unstable protonated dipyrrin intermediate. The results of studies of the oxidation process of the dipyrromethane allows a discussion of the meso-steric effect observed during oxidation, where substituents on the 2- and 6- positions of the meso-aryl group play an important role in producing and stabilizing the conjugated pyrrolemethene. Thusly, N-confused dipyrrins have been synthesized and fully characterized by placing steric aryl groups such as 2,6-  39  dichlorophenyl on the meso-position. As well, higher oligopyrroles were constructed by employing the N-confused dipyrrinone as a building block (Chapter 4). Subsequently, in chapter 5, we present our results on the synthesis of the conjugated N-confused oligopyrrolic macrocycle [12] tripyrrin (0.1.1) and other fully conjugated linear N-confused oligopyrroles. As a macrocycle constructed purely from meso-aryl and pyrrole moieties, N-confused [12] tripyrrin (0.1.1) was synthesized using an unprecedented head to tail cyclization via oxidative amination. Also, linear Nconfused tri- and tetrapyrrolemethene were synthesized and fully characterized by X-ray diffraction analysis. Modification of linear oligopyrroles to their corresponding Nconfused counterparts has been achieved despite their long-believed instability.  40  Chapter 2 the Synthesis of N-confused Dipyrromethanes  41  The simplest π-conjugated N-confused oligopyrrole pigment is the N-confused dipyrrin or 2,3‟-dipyrrin, which remains an important synthetic target to clarify the intrinsic role of the confused pyrrole unit in linear oligopyrroles. In comparison to the well-studied α,α‟-dipyrrin chemistry, “2,3-and 3,3-dipyrrins have been prepared only in very rare instances. They are not well characterized and seem to be stable only in their protonated case.”2 Based on the traditional preparation methods of α,α‟-dipyrrins, Dolphins‟ group reported their attempts to synthesize the β-substituted and meso-unsubstituted N-confused dipyrrin by reaction of an α-pyrrole aldehyde with a β-unsubstituted pyrrole, or a βpyrrole aldehyde with an α-unsubstituted pyrrole under acid-catalyzed conditions. 80 However, tripyrrolic compounds 2-1 and 2-3 were generated as the main products instead of the desired N-confused dipyrrin product 2-2 (Scheme 2.1), suggesting instability of the meso position of β-substituted and meso-unsubstituted N-confused dipyrrins.  42  Scheme 2.1 The failed synthetic route to N-confused dipyrrin 2-2.80  Postulating that the meso-aryl N-confused dipyrrin is likely to be more stable than the corresponding β-substituted and meso-unsubstituted dipyrrin, 81 we designed an oxidation pathway for generating the corresponding N-confused dipyrrins. Our studies commenced with investigation of the oxidation of rationally synthesized meso-aryl Nconfused DPMs 2-8 and 2-9 in CH2Cl2. However, attempts to oxidize these N-confused DPMs led to their immediate decomposition (Scheme 2.2).26 Apparently, as opposed to the established preparation of meso-aryl α,α‟-dipyrrins via an oxidation pathway, oxidation of N-confused DPMs via hydrogen elimination is dependent upon the nature and number of substituents present. Therefore, we envisaged that adjusting the electronic nature and the steric bulk of the DPM substituents would help to generate an oxidation  43  pathway to N-confused dipyrrins since the oxidation process is initiated from an electron transfer from the electron-rich pyrrole to the oxidant.  Scheme 2.2 Synthesis of the N-confused dipyrromethane for oxidation study.  To evaluate substituent effects, a full investigation of the oxidation of variously substituted N-confused meso-aryl DPMs needed to be undertaken. As described in scheme 2.2, N-confused dipyrromethanes 2-8 and 2-9 were synthesized rationally from N-(benzenesulfonyl)pyrrole 2-4 utilizing a protection/deprotection strategy. In this protocol, the meso-aryl group is introduced in the third step while the pyrrole substituent is added in the fifth step or later. The long synthetic route and tedious purification after each step have limited the efficiency of introducing various substituents to the DPM. The absence of any direct protocols to synthesize these compounds led us to consider the development of a straightforward method to bridge the gap between the synthesis of α,α‟-  44  DPMs and α,β-DPMs. Given the important applications of N-confused dipyrromethanes in N-confused porphyrin chemistry, a straightforward strategy for the synthesis of mesoaryl N-confused DPMs bearing different substituents would also greatly promote further investigation into the chemistry of N-confused porphyrins. 2.1 Introduction to the Synthesis of meso-Aryl Dipyrromethanes (DPM) 2.1.1 Introduction to the Synthesis of meso-Aryl α,α’-DPMs There are three types of DPM isomers with the following constitutions: α,α‟-DPM, α,β-DPM and β,β‟-DPM (Figure 2.1). Historically, α,α‟-DPMs have been the most widely studied because of their important application as building blocks in porphyrin chemistry.82 Interest in α,β-DPMs has seen a increase since the discovery of N-confused porphyrins in 1994, where the N-confused DPMs serve as important precursors for Nconfused oligopyrrolic macrocycles.83 Their counterparts, β,β‟-DPMs, are often employed as precursors for bis(dipyrrin)s, which have seen application as ligands in supramolecular chemistry.84, 85  Figure 2.1 The three constitutional isomers of dipyrromethanes.  A number of stepwise syntheses of α,α‟-dipyrromethanes lacking β-substituents have been developed,  86 , 87 , 88  and the more direct routes have employed one-flask  condensations of pyrrole and the desired aldehyde. As described by Lindsey and  45  coworkers, reaction of an aryl aldehyde with EDG substituted pyrroles provides a simple one-pot strategy for preparation of symmetric meso-aryl-substituted dipyrromethanes (Scheme 2.3). 89,  90, 91  Lindsey found that the optimal synthetic conditions for a one-pot synthesis of α,α‟-DPMs are a 40-fold excess of pyrrole with a catalytic amount of acid (TFA or BF3·OEt2, 0.03-0.3 equivalents) at room temperature in the absence of any other solvent.92 High yields of 5-substituted α,α‟-symmetric dipyrromethanes are the result of the much higher nucleophilicity of the α-position versus the β-position of the pyrrole, and large-scale preparation of various meso-substituted DPMs has been achieved to the extent that the need for chromatographic purification is unnecessary.  Scheme 2.3 Lindsey‟s protocol for synthesis of meso-aryl α,α‟-DPMs and A2B2 TPP.91 2.1.2 Application of Protected Pyrroles for the Synthesis of α,α’-DPMs 2.1.2.1 Electron-donating Groups (EDG) as Blocking Groups α(2)-EDG substituted, β(3,4)-unsubstituted pyrroles as substrates for DPM synthesis have been widely applied, with the most studied being methyl substituted pyrrole (Scheme 2.4).93 Owing to the directing and activating effect of the 2-EDG to the 5-position of pyrrole toward electrophiles, reaction of 2-EDG substituted pyrroles with  46  aryl aldehyde in the presence of acid results in high yields of 1,9-disubstituted α,α‟DPMs.  Scheme 2.4 EDG as blocking groups for α,α‟-DPM synthesis.93, 94  Besides alkyl substituted pyrroles, there are only a few examples of other 2-EDGprotected pyrroles as substrates for DPM synthesis. Recently, Lindsey and coworkers investigated an alkylthio group-protected pyrrole for 1,9-protected α,α‟-DPMs synthesis, and their study revealed that alkylthio groups are also good directing and protecting groups for preparation of α,α‟-DPMs.94 2.1.2.2 Electron-withdrawing Groups (EWG) as Blocking Groups Reports utilizing α-EWG substituted and β-unsubstituted pyrrole substrates for synthesis of α,α‟-DPMs are rare. In sharp contrast to the widely-studied α-EDG substituted pyrroles as substrates for α,α‟-DPM synthesis, only two 1,9-di-EWGsubstituted and β-unsubstituted α,α‟-meso-aryl dipyrromethanes have been synthesized via a one-pot approach (Scheme 2.5). Reaction of pyrrole-2-carboxylate esters with 4-nitrobenzaldehyde in the presence of acid was investigated by Setsune and coworkers. Catalyzed by the Lewis acid TiCl4, the α,α‟-1,9-diester DPM 2-10 was obtained in a 51% yield as the major product (Scheme 2.5 a). 95 Recently, Cohen and coworkers reported their synthesis of a 1,9-diamidesubstituted α,α‟-DPM using p-TSA catalysis. By reacting benzaldehyde with a pyrrole-247  amide the corresponding 1,9-diamide-substituted α,α‟-DPM 2-11 was produced in a 78% yield (Scheme 2.5 b).33 Both cases suggest that EWGs such as alkoxy carbonyls and amides still favour the α,α‟-DPM products, although harsh reaction conditions are necessary.  Scheme 2.5 EWGs as blocking groups for α,α‟-DPM synthesis.95, 33 2.1.3 N-confused DPM Upon examining the acid-catalyzed condensation of benzaldehyde in excess pyrrole using various reaction conditions, the distribution of the pyrrolemethane in the crude products in relation to the preparative conditions used was rationalized by Lindsey and coworkers. The resulting products were found to consist of two types of dipyrromethanes: (a) α,α‟-dipyrromethanes and (b) N-confused dipyrromethanes (2,3dipyrromethane). Their study unambiguously proved that traces of N-confused dipyrromethanes were produced in the traditional one-pot protocol for synthesis of α,α‟DPMs.92  48  The highest yield for N-confused DPMs reaches a 10% gas chromatography (GC) yield (whereas the α,α‟-DPM represents 80% of the GC analysis) by treatment of benzaldehyde and pyrrole (1:25) with BF3·OEt2 in CH2Cl2, while under optimized reaction conditions for preparing α,α‟-DPMs the N-confused DPM yield is only 2% of the overall crude products (GC yield).92 The low yield and difficulty in separating the small amount of N-confused DPM from the dominant α,α‟-DPM product render this onepot strategy for preparation of N-confused DPMs impractical. 2.1.3.1 Rational Synthesis of N-confused DPMs Formation of the asymmetric Cα-Cmeso-Cβ bond between the two pyrroles is an essential step for the preparation of N-confused DPMs, and efficient protocols for syntheses of meso-aryl N-confused DPMs are rather limited. To date, the only strategy to achieve meso-aryl N-confused DPMs is a multi-step approach following a protection/deprotection procedure (Scheme 2.6).92 Starting from the N-protected pyrrole and the acid chloride, this stepwise approach provides the meso-aryl N-confused DPM 213 in five steps. Specifically, the triisopropylsilyl (TIPS) N-protected 3-acyl pyrrole 2-12 is formed followed by acylation of the desired β-position of the protected pyrrole. Nconfused DPM 2-13 is generated by reaction of an in situ produced β-pyrrole carbinol with another pyrrole in the presence of acid. Acylation of the N-confused DPM 2-13 to create 1,9-diacyl N-confused DPM 2-14 represents a further challenge due to the presence of three active unsubstituted pyrrole positions. Furuta‟s group reported that the 1,9-disubstituted N-confused DPM 2-14 was produced in only a 14% yield from corresponding N-confused DPM.96  49  Scheme 2.6 Multi-step synthesis of meso-aryl N-confused DPM.90  An alternate route to N-confused DPMs originates from the reaction of β-lithiated pyrrole with aryl aldehydes (Scheme 2.7).92 This reaction provides access to the β-pyrrole carbinol, and is particularly useful when the reduction step involves steric benzoyl groups. N-confused meso-mesityl substituted dipyrromethane 2-15 was synthesized from the sterically demanding mesityl aldehyde and the anion derived from 3-bromo-1(triisopropylsilyl) pyrrole in six steps from pyrrole. The overall yield is less than 10% based on the starting pyrrole and use of air sensitive reagents makes this route inconvenient for large-scale preparation of N-confused DPMs.  50  Scheme 2.7 Multi-step synthesis of meso-aryl N-confused DPM from the aryl aldehyde.92 2.2 Results and Discussion 2.2.1 Design the Directing Strategy for Synthesis of N-confused DPM Improving Cα-Cmeso-Cβ bond formation is necessary for the one-pot synthesis of unsymmetric N-confused DPMs. Increasing the selectivity and yield of the addition reactions to the β-position of the pyrrole may provide guidance for one pot synthesis of N-confused DPMs. However, the preferential α-nucleophilicity over β-nucleophilicity of pyrroles makes the regioselective modification at the β-position rather difficult. Despite these inherent difficulties, three strategies are available to enhance β-substitution (Scheme 2.8).  Scheme 2.8 Strategies for regioselective modification of the β-position of pyrrole. 97, 98, 99  51  The most common method is a protecting and directing strategy using pyrroles bearing an electron-withdrawing group at the α- or N-position (Scheme 2.8 a).97 In addition to this directing approach, metallation can realize selective modification on the β-position: for example, the pentaammineosmium(II) system forms thermally-stable η2complexes with pyrroles, and has been used for a variety of organic transformations.98 Applying this osmium methodology, dihaptocoordinated pyrrole complex 4,5-η2[Os(NH3)5(1-methylpyrrole)]OTf2 can be converted to a β-vinylpyrrole complex in good yield (93%) via a Lewis-acid promoted aldol reaction with acetone (Scheme 2.8 b). As well, the catalytic regioselective β-alkylation of pyrroles in one step by reaction of readily available alkynes with electron-rich N-methylpyrroles and HSiEt3 with the aid of indium(III) catalysis was developed recently (Scheme 2.8 c).99 Apparently, the regioselective result is attributed to η2-complex and carbocation formation during the reaction. These strategies, providing reliable protocols for the regioselective modification of the β-position of pyrrole, might be applicable to a one-pot N-confused DPM synthesis. We envisaged that the substituent-tunable nucleophilicity of the pyrrole α-position versus the β-position renders a directing strategy for the one-pot synthesis of N-confused DPM possible. For example, 2-methylpyrrole gives exclusively α,α‟-DPM as product,93 whereas the α(5)-position of 2-alkylthiopyrroles has an intermediate nucleophilicity between pyrrole and 2-methylpyrrole, which leads to production of N-confused DPM. Lindsey and coworkers reported that N-confused DPMs were observed as minor products by reaction of aryl aldehydes with an alkylthio-substituted pyrrole for the DPM synthesis and the resulting α,α‟-DPMs and N-confused DPMs were produced in a ratio between  52  3.3:1 to 6:1 (Figure 2.2).94 This suggests a subtle relationship between the activation ability of the directing group on the α-position of the pyrrole substrate and the yields of the corresponding N-confused DPMs.  Figure 2.2 Reactivity of 2-EDG substituted pyrroles calculated by Lindsey. (Source: J. Org. Chem. 2006, 903).94  However, at this point, the extent of the regioselectivity was too low for developing a reliable synthetic pathway for N-confused DPM, as such a ratio still favours synthesis of the 1,9-diprotected α,α‟-DPM. Still, a direct method for synthesis of Nconfused DPMs is required to avoid additional synthetic steps and extensive chromatographic separation. Despite considerable efforts toward increasing the yield of the α,α‟-DPMs in a one-pot reaction, very little attention has been paid to the acidcatalyzed aryl aldehyde and EWG-substituted pyrrole condensation in the preparation of N-confused DPMs. Reaction of 2-EWG-substituted pyrroles lacking substituents at the 3- and 4positions with aryl aldehyde in the presence of acid for preparation of DPMs is expected to present three problems. Firstly, electron-withdrawing substituents remarkably deactivate the pyrrole ring inductively or through resonance which renders further reactions sluggish. Additionally, these substituents may also change the orientation of  53  substitution on the pyrrole ring. In contrast to electron-donating groups at the 2-position strongly favouring substitution at the 5-position, electron-withdrawing groups direct the incoming electrophile to both the 4-and 5-positions. 100 The extent of selectivity is dependent upon the nature of the 2-position substituents and the conditions of the substitution reaction. Finally, acid-promoted rearrangement of the 2-position group to the other positions causes additional concern. 101 Nevertheless, after weighing these three issues, EWGs at the 2-position are still highly desirable as directing groups in construction of an α-meso-β linkage between two pyrroles for DPM synthesis. 2.2.2 Preliminary Screening for Substrates and Catalysts The use of α-EWG substituted pyrrole such as 2-alkoxy carbonyl pyrrole and 2amide substituted pyrrole as substrates for the preparation of α,α‟-DPM has been previously reported. Indeed, these pyrroles are successful substrates for one-pot α,α‟DPM synthesis in terms of yield.95, 33 Stronger electron-withdrawing group-substituted pyrroles such as 2-acyl pyrrole as substrate for one-pot aldehyde and pyrrole condensation is unprecedented and we conceived a relative stronger EWG might change the condensation pathway to yield the N-confused DPM in one step. Catalyzed by various acid catalysts, benzaldehyde and commercially available 2acetylpyrrole were selected to model the reaction. Providing increased stability in the strongly acidic reaction conditions than the carboxylate ester and amide groups, the acyl group makes the pyrrole ring less active, which makes developing a methodology for the synthesis of EWG-substituted DPMs in one step a challenge owing to the poor nucleophilicity of the deactivated pyrrole ring. However, treatment of benzaldehyde and 2-acetylpyrrole with a Lewis acid, BF3.OEt2, or an organic acid (methanesulfonic acid  54  (MSA)) at relatively high concentrations does give DPMs as major products. After quenching the reaction with aqueous NaOH, three fractions were separated by silica column chromatography. The first fraction was recovered 2-acetylpyrrole, the second fraction included the DPM, and the third fraction (14%) was revealed to be a mixture of tripyrranes by mass spectroscopic and 1H NMR analysis. In the work described below, only recovered pyrrolic substrates and DPM products were isolated and analyzed in order to evaluate the efficiency of the reaction. 2.2.3 Characterization of the N-confused DPMs N-confused DPMs 2-16 were isolated as the major product by analysis of the DPM fraction and, surprisingly, in all cases, no α,α‟-DPM was observed on the TLC plate. The 1H NMR analysis of product 2-16 showed four different pyrrolic CH proton signals appearing between 6 and 7 ppm (Figure 2.3). Also, data from the  13  C NMR analysis  showed two different sets of acetyl signals, appearing at 25.07, 25.40, 187.53, and 188.09 ppm (Figure 2.4). Further NMR data (1H-1H COSY) from a later isolated DPM product 2-31 revealed the each of the N-H protons correlated with two of the pyrrolic protons (Figure 2.5). Together, these data are consistent with the formation of α-meso-β linkage between the two pyrrole moieties. The meso-sp3 H(4) proton appears at 5.38 ppm and the H(2), H(3), H(5) and H(6) are located at 6.74, 5.99, 6.86, 6.70 ppm, respectively, in 2-16 (Figure 2.3).  55  Figure 2.3 1H NMR spectrum of N-confused DPM 2-16 in CDCl3.  Figure 2.4 13C NMR spectrum of N-confused DPM 2-16 in CDCl3.  56  Figure 2.5 1H-1H COSY spectrum of N-confused DPM 2-31 in CDCl3.  57  Subsequently, single-crystal X-ray analysis of compound 2-23 confirmed the Nconfused structure (Figure 2.6). Thus the α-meso-β linkage between the two pyrrole substrates was unambiguously proven.  Figure 2.6 X-ray crystal structure of N-confused DPM 2-23. 2.2.4 Survey of the Catalysts and Reaction Conditions The influence of catalysts in the condensation reaction of benzaldehyde with 2acetylpyrrole in CH2Cl2 is summarized in Table 2.1. Lindsey‟s conditions (condensation of 0.25 M benzaldehyde and 2.2 equivalents 2-alkylthiopyrrole in CH2Cl2 containing 0.1 M TFA at room temperature) for synthesis of alkylthio-masked α,α‟-DPMs were modified and applied. The 2-acetyl group enables the use of a 1.5 equivalents amount of substituted pyrrole in CH2Cl2. The order of addition is critical for the transformation of the pyrrole substrates, presumably, efficient formation of the protonated aryl aldehyde by mixing the aldehyde and acid together,102 prior to the addition of the pyrrole, is the key to the yields obtained in this reaction.  58  Table 2.1 Survey of acid catalysts for the condensation reaction.  a  Reaction conditions: room temperature, 0.25 M benzaldehyde, 0.375 M 2-acetylpyrrole, 0.375 M  acid catalyst.  b  Room temperature, 2.5 M benzaldehyde, 3.75 M 2-acetylpyrrole, 3.75 M acid catalyst.  c  Same conditions as b except -10 0C. d Isolated DPM yields based on consumed 2-acetylpyrrole.  The exploration was initiated with the combination of 0.25 M aryl aldehyde and 0.0375 M (0.15 equivalents) acid catalysts in CH2Cl2. At room temperature, using TFA as catalyst, the most common acid catalyst for condensation of aryl aldehydes and electron-rich pyrroles, did not induce any reaction after 24 hours. The same result was obtained with the use of the weak Lewis acid Yb(OTf)3 or the strong inorganic acid HCl (Table 2.1, entries 2 and 3). After a number of unsuccessful results using various Lewis and Bronsted acids, a small amount of DPM products were observed when the catalyst was changed to 0.0375 59  M BF3·OEt2 (0.15 equivalents). However, after work up, the consumption of the pyrrole substrate was just 15% (Table 2.1, entry 4). Eventually, by increasing the acid concentration to 0.375 M (1.5 equivalents), a significant increase in the yield of DPM was observed and the consumption of the pyrrolic substrate was 55%. The yield of the total DPMs is 61% based on the consumed pyrrole, and the ratio of the α,β:β,β‟ DPMs in the overall DPM products is 2.56:1 (Table 2.1, entry 5, figure 2.7).  Figure 2.7 Total distribution of DPM 2-16 (α,β:β,β‟ DPMs = 2.56:1) after chromatography (catalyzed by BF3·OEt2, table 2.1, entry 5).  Careful optimization of the acid catalysts might provide a good protocol for narrowing the distribution of the undesired β,β‟-DPM, thus opening a route to more efficient synthesis of N-confused DPMs. In the synthesis of NCTPP, methanesulfonic acid (MSA) was found to be the most effective acid catalyst in increasing the yield (35%)  60  of NCTPP via a one-pot strategy.78 It was thus expected that MSA may induce Cα-CmesoCβ bond formation more efficiently than other acid catalysts. Subsequent studies revealed that additional refinements could be made by employing the stronger acid MSA (pKa = 2.6) rather than BF3·OEt2. The use of 0.375 M (1.5 equivalents) of MSA as catalyst, generates an acceptable (51%) conversion (Table 2.1, entry 6), and the N-confused DPM 2-16 is produced in a 58% yield (measured by integration of the 1H NMR spectrum of isolated (α,β-and β,β‟)-DPM products) based on consumed pyrrolic substrate (51%) (Figure 2.8). No α,α‟-DPM was observed under any of the reaction conditions; however, a minor product β,β‟-DPM was present and represented 12% of the total DPM products after chromatography (α,β:β,β‟ DPMs = 7:1). The existence of the β,β‟-DPM as a minor product seems universal in these reactions, and further chromatography on alumina exploiting the different affinity of the α,β-and β,β‟-DPMs on this support is needed to separate the N-confused DPM.  61  Figure 2.8 1H NMR spectrum of the DPM products (α,β:β,β‟ = 7:1, catalyzed by MSA, table 2.1, entry 7). Subsequent optimization of the reaction conditions suggested that high concentration will best facilitate conversion of the pyrrole substrate. A 10-fold increase of the aldehyde concentration from 0.25M to 2.5M along with 3.75M MSA improved the conversion to 78% (Table 2.1, entry 7). However, some uncharacterized impurities were also observed, and the yield (using integration of the 1H NMR spectrum of isolated DPM products) of the desired N-confused DPM was decreased (45%) based on the consumed pyrrole substrate. Decreasing the temperature to -10 0C, generated the N-confused DPM in 56% yield (using integration of the 1H NMR spectrum of isolated DPM products) based on a 71% consumption of the pyrrolic substrate (Table 2.1, entry 8). Thus, a straightforward synthetic protocol providing the facile and regioselective construction of  62  an asymmetric bridge between the α- and β-positions of two pyrroles in one pot has been achieved. 2.2.5 Scope of the Reaction 2.2.5.1 Scope of the meso-Aryl Group Subsequently, the scope of this reaction was examined by varying the aryl aldehyde, which in turn may allow introduction of a variety of meso-aryl groups to Nconfused DPMs (Table 2.2, entries 1-11). Similar to the synthesis of regular α,α‟-DPMs, the choice of meso-aryl group is also an important factor affecting the N-confused DPM yields. Halogens, methoxy-, cyano- and formyl-groups all survive the harsh reaction conditions and give satisfactory yields of N-confused DPMs (Table 2.2, entries 2-9, 33%52%). It is noteworthy that if the meso-aryl position bears an electron-withdrawing group, such as pentafluorophenyl, the reaction proceeds smoothly with a higher conversion of the pyrrolic substrate owing to the more reactive aldehyde group (entries 36, 75%-82%). On the other hand, electron-donating substituents on the meso-aryl such as a methoxy group retarded the condensation reaction, and resulted in a lower conversion (Table 2.2, entry 2, 55%).  63  Table 2.2 Yields of N-confused DPMs.  a 0  at -10 C.  Reaction conditions: 2.5 M benzaldehyde, 3.75 M 2-acetylpyrrole, 2.5 M acid catalyst, 24 hours b  Same conditions as a except room temperature. c Same conditions as b except 8 hours. d Isolated  yields based on consumed pyrrole substrates. e Yields based on the integration of 1H NMR of isolated DPM products according to consumed pyrrole substrate.  f  Isolated yields after recrystallization based on  consumed pyrrole substrate.  Meso-steric aryl group substituted N-confused DPMs such as 2,6-dichlorophenyl N-confused DPM cannot be synthesized using a rational synthesis from the acid chloride owing to the difficulty in reduction resulting from the steric hindrance of the acyl group. Thus, it is highly desirable to synthesize steric meso-aryl-substituted N-confused DPMs via the one-pot approach using aryl aldehyde as reactant. Upon treatment of 2,6dichlorobenzaldehyde and 2-acetylpyrrole with MSA, the 2,6-dichlorophenyl was  64  incorporated into the meso-position of the N-confused DPM readily in a 41% yield without any β,β‟-DPM observed under the reaction conditions (Table 2.2, entry 8). In the mesitaldehyde case the electron-donating and steric substituent effects make the reaction sluggish and decreased consumption of 2-acetylpyrrole (64%) was observed. N-confused DPM 2-24a was isolated in a 33% yield, and an increase of the β,β‟-DPM 2-24b was also observed, which was easily separated by alumina column chromatography in a 14% yield (Table 2.2, entry 9, figure 2.9).  65  2.41 N H  N H  O  11  10  9  8  2.18 5.73  10.40  6.89 6.83 6.78  2.31  O  7 6 Chemical Shift (ppm)  5  4  3  2  Figure 2.9 1H NMR spectrum of β,β‟-DPM 2-24b.  DPMs bearing a formyl group on the meso-aryl position are useful building blocks in both porphyrin and supramolecular chemistry, and have previously only been prepared in a rational synthetic way.93 Direct synthesis of N-confused DPM 2-20 (41%) bearing a formyl group on the para-position of the meso-aryl group suggests the possibility of incorporating various sensitive unprotected functional groups onto the DPM unit (Table 2.2, entry 5).  66  Such a synthesis is particularly attractive as it offers a very short route to introduce specific meso-aryl groups into the N-confused DPM system. Meso-heteroarylsubstituted DPMs offer attractive applications, particularly with regard to metal complexation and as precursors for porphyrins. 103 To examine the potential for introducing meso-heteroaryl groups onto the meso-position of N-confused DPM by a one-pot strategy, the 2-pyridine and 4-pyridine aldehydes were employed as substrates. Under the modified reaction conditions (3 equivalents acid catalyst) these heterocyclic aryl groups were successfully incorporated into the meso-position at room temperature with isolated yields of 38% and 32%, respectively (Table 2.2, entries 10 and 11). There is no β,β‟-DPM observed and the small amount of α,α‟-DPM product can be easily removed by standard silica column chromatography. The direct introduction of heteroaryl groups into the meso-position of DPMs using aldehydes as substrates provides advantages such as short synthetic route and higher atom economy. 2.2.5.2 Scope of the Pyrrole Substrates This methodology offers versatility in the substitution pattern of the meso-aryl Nconfused DPMs, but still suffers from the difficulties associated with the substituents on the pyrrole α–position, and thus was further explored to provide other 1,9-electronwithdrawing functional group substituted N-confused DPMs (Table 2.3, entries 1-12). We sought to prepare pyrrole derivatives bearing a series of –COR groups on the α– position, where R= H, C6H5, C6F5, and 2,6-Cl2C6H3, and to test their reactivity in a onepot N-confused DPM synthesis.  67  Formyl- and benzoyl- groups were found to tolerate the modified reaction conditions; however, there is a significant increase in the β,β‟-DPM produced when the aryl aldehyde was reacted with pyrrole-2-aldehyde (Table 2.3, entry 1-3). In all of the cases employing pyrrole-2-aldehyde, the α,β:β,β‟ ratio of the resulting DPM products is 2:1 as shown by integration of the 1H NMR spectrum. Under the same reaction conditions the 2-benzoyl pyrrole substrates provided Nconfused DPMs as the sole DPM products with isolated yields ranging from 22% to 51% (Table 2.3, entries 4-6 and 8-10). The decrease in yield is attributed to the increased production of tripyrromethanes, which are observed on the TLC plate. Even though these EWG-substituted pyrroles led to an increase of by-products such as tripyrromethanes, the desired N-confused DPM products are generated in acceptable yields, suggesting the generality of this strategy.  68  Table 2.3 Survey of the α-EWG effect.  a  Reaction conditions: 2.5 M benzaldehyde, 3.75 M susbstituted pyrrole, 2.5 M acid catalyst, 24  hours at -10 0C.  b  Same conditions as a except room temperature. c Same conditions as b except 8 hours.  Isolated yields based on consumed pyrrole substrate.  e  d  Yields based on the integration of 1H NMR of  isolated DPM products and based on consumed pyrrole substrate.  Our attempts to extend this method to a more electron-withdrawing group substituted  pyrrole  substrate,  2-pentafluorobenzoyl  pyrrole,  afforded  meso-  pentafluorophenyl N-confused DPM 2-33a in low yield (20%), and subsequent studies revealed that there was a significant increase of β,β‟-DPM product 2-33b (31%) (Table 2.3, entry 7). In contrast, changing the substrate to the 2-(2,6-dichlorobenzoyl)pyrrole and condensing it with the same aryl aldehyde leads to a higher N-confused DPM yield (51%) 69  without the β,β‟ counterpart being produced (Table 2.3, entry 8). Apparently, the yields of N-confused DPM are highly dependent upon the electronic and steric characteristics of the 2-EWG on the pyrrole substrate. Unfortunately, this strategy does not appear to be applicable to some combinations due to the creation of by-products or the instability of the produced DPMs in the strongly acidic reaction environment. For example, no desired N-confused DPM was observed when 2-alkoxy carbonyl substituted pyrrole was employed as substrate under the standard reaction conditions (Table 2.3, entry 11). Hydrolysis of the alkoxy carbonyl group under these conditions renders the reaction sluggish and this is also the case for the 2-cyanopyrrole. Following these results, the directing effect of an even more electron-withdrawing group was examined. The trifluoroacetyl group enables a dramatic alteration to the reaction pathway to give exclusively β,β‟-DPM in good yields (54-58%) with BF3·OEt2 as catalyst (Table 2.4). Table 2.4 Directing group promoted β,β‟-DPM products.  a  Reaction conditions: room temperature, 48 hours, 0.25 M benzaldehyde, 0.375 M 2-  trifluoroacetylpyrrole, 0.25 M acid catalyst. b Isolated yield.  70  Utilizing a more electron-poor substrate such as N-sulfonated-2-cyanopyrrole provided no reaction after refluxing in acetonitrile for 24 hours (Scheme 2.9). The electron deficiency of this pyrrole substrate apparently leaves the unsubstituted pyrrole position inert to further electrophilic attack.  Scheme 2.9 Reaction employing a more electron-poor pyrrole substrate. 2.2.5.3 Effect of EWG on the Nitrogen Having established that our methodology can be used for the efficient formation of diacyl N-confused DPMs, we turned our attention to expand this strategy to Nsubstituted DPM synthesis. To examine the directing effect of the EWG on the pyrrole nitrogen, a series of experiments were designed, where N-(benzenesulfonyl)pyrrole was reacted with aryl aldehydes under acid-catalyzed conditions (Table 2.4). The benzenesulfonyl group is an electron-withdrawing group and decreases the electron density of the pyrrole substrate significantly and the steric effect of sulfonyl group may strongly direct incoming electrophiles to the β-position. Thus we envisaged that the sulfonyl group may be an ideal protecting group and greatly facilitate further modification and application of the resulting N-confused DPM or β,β‟-DPMs. The use of a sulfonyl group as a protecting and directing group seems a reasonable strategy but due to the strong decrease in electron density on the pyrrole, direct synthesis of the Nsulfonyl dipyrromethane from the sulfonyl pyrrole is unprecedented in the literature. A recent report indicated that “attempts to decrease the reactivity of one of the pyrrole rings  71  in the dipyrromethane by selective N-tosylation of the dipyrromethane, or preparation of an N-tosylated dipyrromethane from N-tosylpyrrole, were unsuccessful.”104 In  our  hands,  the  reaction  of  4-nitrobenzaldehyde  with  N-  (benzenesulfonyl)pyrrole catalyzed by BF3·OEt2 took four days to completion, with the yields of the resulting DPMs ranging from 42% to 45% (Table 2.5). Table 2.5 Applying the N-protected pyrrole as substrate.  a  Reaction conditions: 0.25 M aryl aldehyde, 0.375 M N-(benzenesulfonyl)pyrrole, 0.375 M  BF3·OEt2, 96 hours at room temperature. b Isolated yield.  Spectroscopic studies (1H NMR, 13C NMR) revealed the DPM product 2-39 as a symmetric molecule with the meso-H appearing at 5.49 ppm (Figure 2.10).  72  7.33  2008012903_001000fidf1so2aa.esp  7.49 O  S  O  7.31  F  N S  12  11  10  9  8  7 Chemical Shift (ppm)  6  5.44  6.04 6.02  6.59  7.27 7.29  6.65  O  6.03  7.51  O  6.68  N  5  4  3  Figure 2.10 1H NMR spectrum of α,α‟-DPM 2-39.  Eventually single crystal X-ray analysis of 2-39 revealed the sole product was the conventional α,α‟-DPM (Figure 2.11). This result indicates the electronic effect of 2EWG is crucial to facilitate the synthesis of N-confused DPMs, but EWG on the nitrogen position do not help in generating the corresponding N-confused DPMs.  73  2  Figure 2.11 X-ray crystal structure of α,α‟-DPM 2-39. 2.3 Summary In summary, the MSA-catalyzed condensation of electron-poor pyrroles with aryl aldehydes to synthesize the corresponding N-confused dipyrromethanes in a single step was developed. This work represents the first practical preparation of a variety of Nconfused diacyl DPMs in a one-flask approach and may lead to an acceleration of further investigation into the myriad applications for these compounds in synthetic and coordination chemistries.  74  Chapter 3 DDQ-Mediated Modification of MesoAryl Dipyrromethanes  75  3.1 Introduction In the previous chapter an efficient strategy was described to connect two pyrrole moieties, via a meso-aryl group, to the α- and β- positions to afford the corresponding Nconfused dipyrromethanes. With the series of compounds available, a detailed examination of the electronic and steric effects of the substituents on the properties of these systems is possible. Development of reliable methods for the preparation of dipyrrins by oxidation of the corresponding dipyrromethanes has been a very important advance in dipyrrin chemistry. meso-Aryl-α,α‟-dipyrrins are normally synthesized by oxidation of the corresponding DPMs and the well established oxidation pathway for their preparation is outlined in scheme 3.1. Regardless of the electron-withdrawing or the electron-donating nature of the group, the R group on the two α- positions does not affect the outcome, and meso-aryl dipyrrins are obtained in high yields as the sole products through the oxidation pathway. For example, treatment of 1,9-dimethyl-substituted DPMs with DDQ gives the hydrogen eliminated dipyrrin in 70% yield,93 while changing the substrates to the structurally similar 1,9-dialkylthio-substituted DPMs affords the corresponding dipyrrin in 60% yield.90 Besides the EDG-substituted DPMs, Cohen and coworkers reported the DDQ oxidation of the 1,9-diamide α,α‟-DPM, a EWG substituted DPM, producing the corresponding dipyrrin in 90% yield.33 At this point, it seems both EWG and EDG substituted meso-aryl α,α‟-DPMs give the corresponding dipyrrins via the oxidation pathway.  76  Scheme 3.1 Oxidation of the α,α‟-DPMs to the corresponding dipyrrins.90, 93, 94  Despite the fact that N-confused DPMs are used as building blocks for conjugated oligopyrrolic macrocycle pigments, there is little known about the oxidation of Nconfused DPMs without macrocycle formation. At this point, it remains an open question whether they can be oxidized to give the corresponding conjugated product. 3.2 Results and Discussion 3.2.1 Characterization of Hydroxylated Product 3-1 With a variety of meso- and pyrrole-substituted N-confused DPMs in hand, exploration of an oxidation pathway for preparation of N-confused dipyrrin could proceed. Attempts to oxidize N-confused diacetyl DPM 2-16 were carried out in CH2Cl2 at room temperature, but, despite employing various reaction conditions, no expected dipyrrin pigment was observed. Interstingly, exposure of N-confused DPM 2-16 to DDQ in CH2Cl2, a rather polar spot was observed on TLC with quantitative transformation after 10 minutes. Mass spectrometric analysis of this product 3-1 revealed an M+ peak that was 16 mass units heavier than the starting material. Spectroscopic studies (1H NMR) showed the proton at the meso-position had disappeared in the product, while a new proton  77  resonance appeared at 5.49 ppm which could be exchanged with D2O (Figure 3.1). As well, the absence of the meso-H signal is accompanied by the presence of a new carbon resonance at 74.36 ppm in the 13C NMR spectrum (Figure 3.2). Together, these data are consistent with the formation of a hydroxy group substituted on a tertiary sp3 carbon.  Figure 3.1 1H NMR spectrum of hydroxylated DPM 3-1 in CDCl3.  78  Figure 3.2 13C NMR spectrum of hydroxylated DPM 3-1 in CDCl3.  Later, unambiguous proof for C-O bond formation on the meso-position for this oxidation reaction was provided by X-ray diffraction analysis of 3-9 (Figure 3.3).  Figure 3.3 X-ray structure of the meso-modified N-confused DPM 3-9.  79  3.2.2 Exploration of the Oxidation Reaction 3.2.2.1 Exploration of the Oxidants for N-confused Dipyrrins At this point, whether the oxidation process could be manipulated to afford the conjugated dipyrryl structure was uncertain. Investigation of the oxidation reaction was carried out using various oxidants in CH2Cl2. Traditional metal oxidants such as CrO3, KMnO4 and (NH4)4Ce(SO4)4 did not result in any oxidation (Table 3.1, entries 1-3). Hydroxylated product 3-1 was the sole product (produced in low yield) after 4 days when 2-16 was subjected to one equivalent benzoyl peroxide (11%, Table 3.1, entry 4) along with a considerable amount of unconsumed 2-16 remaining. The combination of pchloranil and iron(III) chloride, an efficient system for the oxidation of α,α‟-DPMs, was fruitless as well. None of the oxidants mentioned above altered the reaction pathway to create the hydrogen-eliminated N-confused dipyrrin product.  80  Table 3.1 Survey of oxidants for an N-confused meso-aryl diacyl DPM.  a  0.025 M 2-16, 0.1 M oxidants, room temperature.  b  DCM/MeOH=3/1.  c  Same as  a  except 0.025M  oxidant. d Isolated yield.  3.2.2.2 Exploration of the Meso-aryl Effect on the Reactivity of N-confused DPMs To explore the substituent effects on the oxidation process, further investigation was carried out by varying the meso-aryl groups under the same reaction conditions for hydroxylation of DPMs and the results are summarized in table 3.2. Functional groups such as halogens, cyano-, formyl- and nitro-groups are well-tolerated with this process and provide the corresponding hydroxylated N-confused DPMs in high yields (72-82%). Surprisingly, the meso-4-methoxyphenyl substituted N-confused DPM decomposed immediately upon addition of the DDQ (Table 3.2, entry 10), suggesting that a careful balance of electron-donating and -withdrawing substituents is crucial to this reaction.  81  Table 3.2 DDQ-mediated hydroxylation on N-confused diacyl DPMs.  a  0.025 M DPM, 0.1 M DDQ, room temperature, 2 hours. b Same as a except 24 hours. c Isolated yield.  It is noteworthy that a red nonpolar product 3-9 was obtained in 42% yield along with the hydroxylated product 3-3 (25% yield) when a steric aryl group such as a pentafluorophenyl group was present (Table 3.2, entry 3). In response to this interesting observation, substrates with increasingly steric 2,6-substituents on the meso-aryl position such as 2,6-dichlorophenyl and 1,3,5-trimethylphenyl N-confused DPMs (Table 3.2, entries 5 and 9) were examined and red products 3-10 and 3-11 were also produced as the sole products in 56% and 53% yields, respectively. The absence of the meso-proton resonance in the 1H NMR spectrum (Figure 3.4) and the presence of a lactam resonance at 166.70 ppm in the  13  C NMR spectrum (Figure 3.5) of 3-10 are consistent with the  formation of a conjugated product.  82  Figure 3.4 1H NMR spectrum of lactam dipyrromethene 3-10 in CDCl3.  Fugure 3.5 13C NMR spectrum of lactam dipyrromethene 3-10 in CDCl3.  83  A crystal of the isolated compound suitable for X-ray diffraction analysis was grown via the evaporation of solvent from a CH2Cl2/hexane solution. The structure was confirmed to be that of 3-8, an N-confused lactam dipyrrinone (Figure 3.6).  Figure 3.6 X-ray structure of the conjugated structure 3-8. The steric effect of the meso-aryl groups suggests that regardless of the electronwithdrawing or electron-donating characteristics, the presence of ortho-substituents on the meso-aryl group of N-confused DPM is required for effective preparation of conjugated N-confused dipyrrin derivatives with DDQ. 3.2.2.3 meso-steric Effect on α,α’- and β,β’-DPMs In order to test whether hydroxylation is unique to N-confused DPMs or that it may be extended to other types of DPMs, experiments to probe the scope of application to DPM isomers were designed (Table 3.3). The steric effect was also observed when α,α‟-diacyl DPMs were reacted with DDQ, and hydroxylated α,α‟-DPMs 3-12-3-14 were obtained in high yields (71-78%) from non-steric meso-aryl substrates (Table 3.3, entries  84  1-3). Also, increasing the steric bulk of the meso-aryl 2,6-disubstituted group, such as with the 2,6-dichlorophenyl group (Table 3.3, entry 5), led to a higher yield (55%) of the dipyrrin 3-17. The conjugated dipyrryl structure was unambiguously proven by X-ray diffraction analysis of 3-16 (Figure 3.7).  Table 3.3 DDQ-mediated reaction on α,α‟- and β,β‟-diacyl DPMs.  a  0.025 M DPM, 0.1 M DDQ, room temperature, 2 hours. b Same as a except 24 hours. c Isolated yield.  85  Figure 3.7 X-ray structure of 3-16.  Subsequent studies indicate there is little difference in the reactivity between the β,β‟-diacyl DPMs and α,α‟-DPMs (see entries 2, 6, 7 in table 3.3). The hydroxylated DPMs 3-18 and 3-19 were obtained as the sole products in yields of 68-71% when nonsteric meso-aryl groups were present (Table 3.3, entries 6 and 7). Further investigations of substituent effects were carried out by reaction of α,α‟disulfonyl DPM 2-36 with DDQ (Scheme 3.2). However, upon treatment of α,α‟disulfonyl DPM 2-36 with four equivalents DDQ, only starting material was recovered (Scheme 3.2), suggesting the nitrogen lone pairs are sufficiently delocalized into the sulfonyl groups that the pyrrolic rings are too electron-deficient to allow for an initial electron transfer or to stabilize an electron-deficient intermediate.  86  0.025 M DPM, 0.1M DDQ, CH2Cl2, room temperature.  Scheme 3.2 DDQ-oxidation of disulfonyl α,α‟-DPM 2-36. 3.2.3 The meso-steric Effect Analysis in the NMR Spectra The effect of substituents at the ortho-positions of the meso-aryl group of DPMs is mirrored in their 1H and 13C NMR spectra (Table 3.4). Table 3.4 Selected 1H and 13C NMR of meso-H and -C for DPM substrates.  If the 2- and 6-positions of the meso-phenyl group are substituted, the resonances of the meso-proton are shifted downfield (from 5.37 to 6.33 ppm) owing to their interaction with these meso-aryl substituents. Meanwhile, the inductive effect of the meso-aryl group renders the 13C NMR of the meso-carbon upfield-shifted (from 43.22 to 32.27 ppm).  87  3.2.4 DDQ-mediated Modification of the meso-Position of DPMs It is known that porphyrin derivatives containing saturated meso-carbon(s) are important intermediates in biosynthesis and the metabolism of natural porphyrins. 105 However, direct modification of the meso-carbon of the porphyrin ring is still rare owing to the poor electrophilicity of the conventional porphyrins used so far.106 Pre-installation of a functional group onto the meso-position of DPMs is a practical way for preparing precursors of meso-saturated porphyrin analogues, such as calix[4] phyrins.107 However, difficulty in modifying the meso-position of DPMs, to use as appropriate precursors, has limited this strategy. As an electron-rich heterocyclic compound, DPM is more sensitive to acid than pyrrole owing to the facile acid-catalyzed cleavage of the pyrrole-meso-carbon bond. Also, electrophilic substitution easily occurs if the DPM has an unsubstituted position on the pyrrole moiety. Under such circumstances the electrophile will attack the most active pyrrole position, which is usually the αposition.108, 109 On the other hand, owing to its relative electron-richness, it is difficult to trigger a nucleophilic substitution on DPMs. Finally, the meso-aryl DPM cannot be simply treated as a compound bearing a benzylic C-H due to the electron-releasing effect of the two pyrrole heterocycles. Due to these specific characteristics, introducing a functional group on the meso-position of DPMs still remains a challenge. Benzylic oxidation is a reaction of fundamental importance in organic chemistry. 110  DDQ-mediated cross-dehydration-coupling (CDC) reactions through benzylic C-H  activation have been developed and have greatly added to synthetic methodologies.111, 113, 114  112,  The efficient strategy of introducing a hydroxy group to the meso-position inspired  88  us to develop a protocol to modify the meso-position of DPMs by introducing C-O and C-C bonds via benzylic C-H activation. 3.2.5 DDQ-mediated C-O Bond Formation on the meso-Position The great challenge in developing a strategy for functionalization of the mesoposition of DPMs is discovering conditions that support C-H cleavage and functionalization of the resulting intermediate at the same time. Attempts to react Nconfused DPM 2-16 with nucleophiles such as thioalkyl compounds and alkyl amines using DDQ as oxidant were unsuccessful, only starting materials were recovered. Following extensive unsuccessful exploration, it was found that reaction of N-confused DPM 2-16 with DDQ and MeOH in CH2Cl2 at room temperature allowed the formation of meso substituted N-confused DPM 3-20 in 72% yield (Table 3.5, entry 1).  89  Table 3.5 DDQ-mediated meso-alkoxylation on an α,β-DPM.  a  0.025 M 2-16, 0.025 M R-OH, 0.05 M DDQ, room temperature, 2 hours. b Isolated yield.  Various alcohols were reacted with 2-16 in CH2Cl2, and the corresponding results are listed in Table 3.5. The reaction conditions were broadly applicable to different alkoxylation reagents (Table 3.5), both primary and secondary alcohols are effective in the reaction. Alcohol substrates other than methanol, such as ethanol, benzylic alcohol, and cyclohexanol, were incorporated onto the meso-position of the N-confused DPM 216 successfully by applying the same protocol, however, owning to steric effect the yield from the substitution of cyclohexanol is significantly low (26%). As well, in the case of pyridyl derivative, the yield of 31% is significantly lower than the benzyl alcohol (48%), and presumably the basicity of the pyridyl group is responsible for this result.  90  Alcohols bearing oxidizable functional groups were subjected to this reaction, and the compatibility with various functional groups such as benzyl, pyridyl, thiophene, alkyne, alkene and hydroxyl demonstrated the generalizability of this reaction (Table 3.5, entries 3, 4, 8-10 and 12). It is noteworthy that reaction of carboxylic acid substrates with 2-16 and DDQ were fruitless under the same reaction conditions, as were alcohol-bearing amines, suggesting acidic conditions are crucial for the reaction and neutral or weakly basic species best facilitate the hydroxylation reaction. 3.2.6 C-C Bond Formation on the meso-position Mediated by DDQ Subsequently, C-C bond formation at the meso-position via C-H activation was explored. Nucleophiles such as simple ketones and malonate esters were subjected to the reaction conditions but all attempts to induce the C-C bond formation failed. Perhaps enolate formation, which requires a basic environment, suppressed the formation of the DPM carbocation intermediate. In an effort to promote C-C bond formation at the meso-position, electron-rich heterocycles such as pyrrole were chosen as the nucleophile. Following the protocol for alkoxylation of N-confused DPMs, treatment of 2-16 with two equivalents DDQ and one equivalent pyrrole in CH2Cl2 at room temperature gave the C-C bond formation product 3-32 in 78% yield (Table 3.6, entry 1).  91  Table 3.6 DDQ-mediated meso-C-C bond formation on DPMs.  a  0.025 M DPM, 0.025 M heteroaryl, 0.05 M DDQ, room temperature, 2 hours. b Isolated yield. c Substrate= meso-4-nitrophenyl α,α‟-DPM.  The formation of 3-32 from N-confused DPM 2-16 was clearly evident from the analysis of the 1H NMR spectrum of 3-32 (CDCl3): three N-H broad peaks at 8.14, 9.18, and 9.66 ppm respectively, and the absence of meso-H around 5.5 ppm indicated that the heterocycle had been attached to the meso-position (Figure 3.8). Moreover, the absence of the meso-H was accompanied by the presence of a resonance at 50.50 ppm in the 13C NMR spectrum (Figure 3.9). All these data are consistent with the formation of heteroarylation product 3-32.  92  N H  H N  2.38 2.41  2009051209_004000fidphch3abpyrrole.esp  O  HN  10  9  6.76 6.69 6.22 6.21 6.08 6.07 6.01  8.14  7.33 11  9.18  9.66 12  7.14 7.29 7.13  7.31  O  8 7 Chemical Shift (ppm)  6  5  4  3  2  128.18  Figure 3.8 1H NMR spectrum of 3-32 in CDCl3.  O  128.57  NH H N O  25.47 25.16  108.02  50.50  140  130.41  160  132.11 134.39  143.66 144.59  187.72 188.39 180  117.21  128.78  127.38 124.50 117.03 116.81 111.15 109.00 108.38  N H  120  100 Chemical Shift (ppm)  80  60  40  20  13  Figure 3.9 C NMR spectrum of 3-32 in CDCl3.  93  Electron-rich heterocycles such as indole and 2,5-alkyl substituted pyrrole were smoothly added to the DPM meso-position via their β-positions in 57% and 73% yields, respectively (Table 3.6, entries 4 and 6). However, TIPS-protected pyrrole and electronpoor heteroaryls such as thiophene did not react under the same conditions, presumably owing to their poor nucleophilicity resulting from both a steric and electronic standpoint. Various 1,9- substituted DPMs were subjected to the standard reaction conditions, and there was little difference in the reactivity between formyl-substituted and acetylsubstituted N-confused DPMs (Table 3.6, entries 2 and 6). Subsequent studies demonstrated that α,α‟-DPM can also be modified under the same reaction conditions to give 3-34 in 68% yield (Table 3.6, entry 3). 3.2.7 Mechanism Discussion A tentative mechanism for the benzylic C-H activation reaction is proposed in Scheme 3.3. Heterocycles such as pyrrole will react by an initial electron-transfer during oxidation, 115 and this is the case when DPMs are dehydrogenated to afford the corresponding dipyrrins (Scheme 3.3, pathway a). However, meso-hydrogen atom transfer may initially occur when there is an EWG on the pyrrole (Scheme 3.3, pathway b or c). Neither of these radical intermediates in pathway a and c are likely to react directly with water (but possibly with dioxygen) and both will be oxidized to create resonancestabilized cation I (Scheme 3.3, Ia and Ib). I is merely a canonical form of the protonated dipyrromethene which seems the most likely intermediate to undergo nucleophilic attack. Indeed, nucleophilic addition reactions at the meso-position of meso-unsubstituted and βsubstituted dipyrromethene salts have been previously reported,116, 117and reduction with sodium borohydride is a well known reaction of dipyrromethenes to give the  94  corresponding dipyrromethanes. Depending upon the steric requirements of the meso-aryl group, the nucleophile will attack the meso- or α-position of I to give the mesoalkoxylation product or lactam (after further oxidation).  Scheme 3.3 Proposed mechanism of alkoxylation of α,β-DPMs.  Experimental observations provide some support for the proposed mechanism. An 18  O-labelled molecular ion at 324 was observed when H218O was added under the  reaction conditions employing 2-16 as substrate, which confirms that water is the source of the hydroxy group instead of O2 (Scheme 3.4). Furthermore, when hydroxylated pentafluorophenyl α,α‟-DPM 3-15 was treated with TFA, the corresponding dehydrated dipyrromethene 3-16 was observed which was in turn rehydrated to hydroxylated DPM 3-15 with TFA/H2O. Moreover, the conditions used during the reaction, particularly the pH, are crucial. Thus, a small amount of base or the addition of pyridine prevents any reaction. These observations are consistent with the mechanisms outlined in Scheme 3.3.  95  Scheme 3.4 Mechanism study of hydroxylation of α,β-DPMs. 3.2.8 Conclusion In conclusion, a comprehensive exploration of the oxidation of N-confused DPMs has been carried out and the electronic and the steric effects of the substituent groups have been elucidated. As expected, the course of the oxidation shows a striking dependence on the steric bulk of meso-substituents, with the substituents on the orthopositions of the meso-aryl group being crucial for producing conjugated N-confused dipyrrinone structures. An efficient protocol for introducing C-O and C-C bonds at the meso-position (sp3) of α,β-, α,α‟- and β,β‟- meso-aryl DPMs has been developed via DDQ-mediated benzylic C-H activation at room temperature. The advantages of this method include: (1) mild reaction conditions at room temperature; (2) tolerance of various functional groups; (3) no metal catalysts employed and; (4) high regioselectivity at the meso-position. By unveiling the meso C-H as a “functional group,” novel disconnections can be envisioned, which may streamline future syntheses of complex pyrrolic precursors in oligopyrrole chemistry.  96  Chapter 4 N-confused Dipyrrins— a More Flexible Dipyrryl System  97  4.1 Introduction Extension of conjugation to generate linear oligopyrroles through the β-position of the pyrrole has represented a considerable challenge and it remains an open question whether these enticing dipyrrin analogs can actually be prepared and exist as a stable dipyrryl chromophore. The lack of a general method to prepare stable N-confused dipyrrins has hindered advancement in this field. In the previous chapters, the successful preparation of various meso-aryl substituted N-confused dipyrromethanes and the subjection of them to oxidation has helped to shine light on the factors affecting the preparation of the corresponding N-confused dipyrrins. Indeed, the lactam forms of Nconfused meso-aryl dipyrrins were successfully synthesized and characterized as described in chapter 3. However, free-base N-confused dipyrrin, namely, a dipyrrin constructed by α-azafulvene and a confused pyrrole or a β-azafulvene and a pyrrole, has not yet been achieved and remains an important target, the synthesis of which may help clarify the role of the confused pyrrole unit in linear oligopyrroles. In this work, following the 4C strategy in oligopyrrole chemistry (from Constitution to Configuration and Conformation, and then Crystal-packing), we report detailed studies of N-confused dipyrrins and a thorough evaluation of the properties and reactivities of N-confused dipyrrin derivatives.  98  4.2 Results and Discussion 4.2.1 Synthesis of the N-confused Dipyrrin We have shown that substituent effects are critical for the oxidation of DPMs, and the presence of steric meso-aryl groups and EWGs on the α-positions is required for generation of the corresponding stabilized N-confused conjugated oligopyrrole structures. Systematically studying the oxidation of N-confused dipyrromethanes may provide further insight for preparation of the conjugated dipyrrin by fulfilling these prerequisites (EWG on the α-position, meso-steric aryl group substituted) in the dipyrromethane precursors. A series of diacyl dipyrromethanes bearing steric meso-aryl groups and EWGs on the α-positions were subjected to various oxidation conditions and the results are summarized in Table 4.1. Treatment of 2,6-dichlorophenyl N-confused DPM 2-23 with traditional oxidants such as benzoyl peroxide, phenyliodine bis(trifluoroacetate) (PIFA), CrO3, KMnO4 and (NH4)4Ce(SO4)4 did not lead to Nconfused dipyrrins, and several attempts to prepare the N-confused dipyrrin with the milder oxidant tetrachloro-1,4-benzoquinone (p-chloranil) were unsuccessful. Upon treatment of meso-2,6-dichlorophenyl N-confused DPM 2-23 with one equivalent of the stronger oxidant DDQ in CH2Cl2, and careful inspection of the process by TLC, a yellow product 4-1, later proven to be the N-confused dipyrrin, was obtained in a 15% yield after chromatography. Mass spectrometric analysis of 4-1 revealed an M+ peak that was two mass units less than the starting material. Spectroscopic (1H,  13  C NMR) studies are  consistent with the formation of an N-confused dipyrrin structure. The low yield is attributed to the susceptibility of the resulting N-confused dipyrrin 4-1 toward DDQ,  99  which can undergo further oxidation to generate the lactam form of the N-confused dipyrrin. Table 4.1 DDQ-promoted dehydrogenation of N-confused DPM.  a  reaction conditions: room temperature, 0.025 M N-confused DPM, 0.025 M DDQ. b Isolated yield.  Subsequent studies indicated that using CH3CN as solvent suppresses further oxidation of the dipyrrins and significantly improves the yields of N-confused dipyrrins (Table 4.1, 12-48%). The efficiency of the oxidation reaction for preparation of Nconfused dipyrrin is highly-dependent upon the meso-aryl group (Table 4.1).  100  4.2.2 Characterization of the Free-Base N-confused Dipyrrin Several configurational forms of α,β-dipyrrins such as Z-anti A, Z-syn B, Z-syn C can be expected from the hydrogen elimination reaction (Figure 4.1). The configuration of a dipyrrin is dependent upon the nature of the substituents on the meso- or β-position, the nature and position of hydrogen-bonding, and the state of protonation. In the present work, the DDQ dehydrogenation process allows the highly stereoselective production of the free-base Z-anti conformation (Z-anti A) of N-confused dipyrrins (Figure 4.1).  Figure 4.1 Configurations of the α,β-dipyrrins. 4.2.2.1 Structure Determination of 4-1 by NMR Spectroscopy Proton NMR spectroscopic studies (1H NMR, 1H-1H COSY) of 4-1 were carried out in CDCl3. The unsymmetrically substituted N-confused dipyrrin 4-1 has four distinct proton resonances, one for each of the pyrrolic protons, between 6.5-7.8 ppm (Figure 4.1), suggesting the N-confused dipyrrin has a delocalized conjugated dipyrryl structure instead of being a simple azafulvene compound. The hydrogen bound to the pyrrolic nitrogen atom, which is generally not observed in the NMR spectra of free-base conventional α,α‟-dipyrrins, is readily located at 10.51 ppm for the N-confused dipyrrin 4-1. In addition, 1H-1H COSY correlations between the NH proton (10.51 ppm) and the C(8)H, and C(10)H signals (7.71 ppm and 7.94 ppm) along with the strong correlation  101  between two β adjacent protons C(4)H, C(5)H (6.71 ppm, 7.02 ppm) establishes the presence of the active hydrogen (NH) localized on the confused pyrrole ring (Figure 4.2).  Figure 4.2 1H-1H COSY spectrum of N-confused dipyrrin 4-1 in CDCl3. 4.2.2.2 Structure Determination of 4-1 by X-ray Analysis Slow diffusion of hexanes into a CH2Cl2 solution of 4-1 produced crystals suitable for X-ray analysis and the ORTEP representation of 4-1 is presented in figure 4.3. Consistent with the spectroscopic analysis, the molecular structure of 4-1 is essentially planar. The confused pyrrole is connected to the β-position with an α-azafulvene moiety via the meso-methine bridge, with the meso-phenyl group tilted down 82ºfrom the mean plane composed by the two pyrrole rings. An important feature in this structure is that the two pyrrole rings in the molecular are in the Z-anti conformation. This observation is  102  consistent with the spectral analysis, and is highly significant as it correlates well with the observed preference for one isomeric form (Z-syn) in conventional free-base α,α‟dipyrrins.118  Figure 4.3 ORTEP representation of the X-ray structure of N-confused dipyrrin 4-1, a top view (left) and a side view (right), the vibrational ellipsoids are represented at 50% probability.  N-confused dipyrrin 4-1 exists as a single tautomer with the α-pyrrole bearing the imine nitrogen form and the confused pyrrole in the enamine form. The C(3)-N(1)-C(6) angle 105.10º of the α-azafulvene moiety, is a typical inner angle for an imine structure in conjugated pyrrole systems (Figure 4.3). In the crystal-packing (Figure 4.4), 4-1 exists as a dimer, connected by strong intermolecular duplex hydrogen-bonding between the C=O(02)∙∙∙H-N(2).  103  Figure 4.4 Hydrogen-bonding interaction in crystal-packing of 4-1. 4.2.3 Configurational Study of N-confused Dipyrrin by DFT Calculation To gain insight into the conformation and the location of the NH atoms in Nconfused dipyrrin 4-1, DFT calculations were performed on the two possible configuration forms (Z-anti, Z-syn) of free-base N-confused dipyrrin 4-1. Further evidence of the selective production of the Z-anti conformation of N-confused dipyrrin 41 is obtained through theoretical calculations. A B3LYP/cc-pVDZ level DFT calculation was carried out based on the crystal structure of the 4-1 (DFT calculation was conducted by Dr. Yakun Chen).119 The result indicates that Z-anti monomer A (Figure 4.1) is more stable than Z-syn diastereomer B in solution while less stable in the gaseous phase. The duplex intermolecular hydrogen-bonding interactions have a significant stabilizing effect when considering the Z-anti A configuration as a hydrogen-bonding dimer in solution, which may decrease the overall energy by 9.9 kcal/mol compared to the two independent monomers. In contrast, conformation C (Figure 4.1) is far less stable than A and B due to the unfavourable H-H steric interactions and, possibly, due to the lack of planarity. In  104  response to the calculations, attempts to change the configuration of N-confused dipyrrins were carried out by varying the temperature. Only slight decomposition was observed by 1  H NMR analysis when 4-1 was heated to 180 ºC in 1,2-dichlorobenzene under argon and  the Z-syn N-confused dipyrrin form was not observed despite its inferred stability in the gas state (based on theoretical calculations). 4.3 Studies of Configuration Change in N-confused Dipyrrins: Alkoxylation Reaction at the α-Position The configuration and tautomeric interconversion of oligopyrrolic pigments have been widely studied. For example, configuration change in tetrapyrrole pigments plays an important role in the absorption of light in nature.120 Also, tautomerization significantly affects the reactivity of the inverted pyrrole in NCP.121 As well, configuration is crucial in the conjugated α,α‟-dipyrryl system for metal-catalyzed cross-coupling reaction on the pyrrole ring.122 Accordingly, it is expected that N-confused dipyrrins can be further modified on the unsubstituted α-position of the confused pyrrole ring, and that the tautomerization can possibly be adjusted from one end to the other via hydrogen-shifting. 123 Introducing a hydrogen-bonding acceptor such as an oxygen atom on the α-position of the confused pyrrole ring might induce configuration change and tautomer interconversion. In synthetic chemistry, protocols to introduce an oxygen atom at the α-position of polypyrrolic systems are dependent upon the substrates. Generally, synthesis of a linear oligopyrrole system bearing an α-oxygen requires a multi-step condensation from a simple precursor or from oxidative ring opening of the corresponding polypyrrolic macrocycle.124  105  In some respects the addition of alcohols directly to the α-position of pyrrolic moieties provides a straightforward approach. Chemical functionalization of the αposition of certain oligopyrroles has been accomplished on certain substrates. For example, oxidative alkoxylation of N-confused porphyrins was reported by employing DDQ as promoter by Dolphin‟s group,75 and recently Cohen and coworkers also reported hydroquinone-promoted alkoxylation on the α-position of the α,α‟-meso aryl dipyrrin in combination with a transition metal catalyst.125 In the present work we sought a similar oxidative alkoxylation reaction to introduce a hydrogen-bonding acceptor at the αposition of the confused pyrrole to control configurational interconversion of the Nconfused dipyrrin. 4.3.1 DDQ-Promoted Oxidative Alkoxylation at the α-Position of N-confused Dipyrrins Table 4.2 Exploration of alkoxylation conditions.  a  reaction conditions: room temperature, 0.025 M 4-1, 0.025 M MeOH, 0.025 M DDQ. b DCM/MeOH 3:1. c 1 equivalent MeONa. d Isolated yield.  106  The alkoxylation reaction was carried out in CH2Cl2 by reaction of meso-2,6dichlorophenyl substituted N-confused dipyrrin 4-1 with one equivalent of methanol and oxidant (Table 4.2). Treatment of N-confused dipyrrin 4-1 with common oxidants such as Ce4+, MnO2, PIFA, benzoyl peroxide and p-chloranil did not bring about any reaction. The reaction of N-confused dipyrrin 4-1 with DDQ and MeONa (Table 4.2, entry 5) afforded the desired alkoxylated N-confused dipyrrin 4-5 in 11% yield. Subsequent studies showed that treatment of 4-1 with MeOH and DDQ in CH2Cl2 gave alkoxylated product 4-5 in 81% yield after chromatography, suggesting that the formation of the alkoxy-substituted N-confused dipyrrin did not require the presence of base but did require a quinone oxidant. Further investigation of solvent effects was carried out: solvents such as EA, CH3CN, and THF made the reaction sluggish, whereas in CH2Cl2 and CHCl3 the reaction proceeded smoothly. 4.3.1.1 Structure Determination of Lactim N-confused Dipyrrin by NMR Spectroscopy Mass spectrometric analysis indicates a molecular ion (M+) of 402 corresponding to the alkoxylation product and 1H, 13C NMR studies of 4-5 suggest it exists as a single tautomer in CDCl3. As expected, the methoxy group was introduced to the α-position of the confused pyrrole, and an active N-H proton is present on the regular pyrrole moiety, which is consistent with the correlations between the two β-proton resonances (6.12 ppm, 6.83 ppm) with the active N-H resonance (12.30 ppm) in the 1H-1H COSY study (Figure 4.5). The downfield shift to 12.30 ppm in the 1H NMR spectrum (Figure 4.5) is postulated to be caused by strong intramolecular hydrogen-bonding between the  107  introduced oxygen atom and the enamine NH and, therefore, only the Z-syn configuration satisfies the necessary geometry.  Figure 4.5 1H-1H COSY NMR spectrum of 4-5 in CDCl3. 4.3.1.2 Structure Determination of Lactim N-confused Dipyrrin by X-ray Diffraction Analysis Later, crystals of butyl alkoxylated N-confused dipyrrin 4-11 were obtained by diffusion of hexanes into a CH2Cl2 solution and the structure was determined by X-ray crystallography (Figure 4.6). The crystal structure reveals several interesting structural  108  features, which again distinguish the compound from the parent unsubstituted Nconfused dipyrrin 4-1. As expected, 4-11 exists in the Z-syn form, and the X-ray structure demonstrates the two pyrrole rings are coplanar. Consistent with the 1H NMR analysis of 4-11, the structure exists as a single tautomer in the solid state with the hydrogen localized on the nitrogen of the unmodified pyrrole. The strong intramolecular hydrogen-bonding interaction from O(3)∙∙∙H-N(1) (2.705 Å) facilitates the coplanarity and this phenomenon is fairly common in conjugated dipyrryl systems. The bond length (1.377 Å) between C(7)-C(8), a typical C=C bond distance, is consistent with the formation of the postulated β-azafulvene structure. The inner angle of 104.80ºfor the confused pyrrole C(11)- N(2)-C(10), is typical of the inner angle of the imine type of pyrrole, and also supports the formation of a β-azafulvene structure in the confused pyrrole group (Figure 4.6).  Figure 4.6 ORTEP drawing of N-confused dipyrrin 4-11, a top view (left) and a side view (right), the vibrational ellipsoids are represented at 50% probability.  109  This system represents the first characterized β-azafulvene moiety in linear oligopyrrolic pigments, and reveals a distinct asymmetry in the bond lengths of the bipyrrolic chromophore. In the lactim pyrrole ring, the bond lengths are C(7)-C(8) 1.377 Å, C(11)-C(8) 1.491 Å, C(11)-N(2) 1.289 Å, N(2)-C(10) 1.418 Å, C(9)-C(10) 1.364 Å, C(8)-C(9) 1.433 Å, displaying the alternating double bond/single bond sequence, while in the α-connected pyrrole ring the bond lengths are similar due to the delocalization (Figure 4.6). 4.3.2 Exploration of the Scope of meso-Aryl Groups ortho-Substituted meso-aryl dipyrromethanes were selected to explore the steric and electronic effects of the oxidation reaction and the results are summarized in table 4.3. The alkoxylation reaction occurred readily regardless of the electron-withdrawing or electron-donating nature of the 2,6-substituents (Table 4.3), and alkoxylation products 46 to 4-8 were obtained with high stereoselectivity as the Z-syn products. It is worthwhile to note that thiolation on the α-position was also achieved using a thiol as substrate under the same reaction conditions (Table 4.3, entry 5), although both diastereomers (Z-anti: Zsyn = 1.34:1) were present. Production of the two diastereomers suggests the hydrogenbonding interaction and tautomerization are the decisive factors for controlling the configuration of the N-confused dipyrrin system since the sulfur atom is a weak hydrogen-bonding acceptor in comparison to the oxygen atom.  110  Table 4.3 N-confused dipyrrin as substrate for alkoxylation.  a  Reaction conditions: room temperature, 0.025 M dipyrrin, 0.025 M RXH, 0.025 M DDQ.  Isolated yield.  c  b  Determined based on integral ratio of 1H NMR from the mixture of Z-syn and Z-anti  products.  4.3.3 Exploration of Various Alcohols DDQ serves as both a oxidation reagent for producing the dipyrrin and as the mediator for the alkoxylation reaction and thus, a cascade reaction combining the two steps together was developed in CH2Cl2. At room temperature, treatment of DPM substrate 2-23 and methanol with two equivalents DDQ enables completion of the reaction within two hours, giving the alkoxylated product 4-5 in a 66% yield (Table 4.4, entry 1). Subsequently, a variety of alcohols were investigated under the standard reaction conditions to explore their participation in this process. The reaction conditions were broadly applicable to different alkoxylation reagents (Table 4.4): alcohol substrates other than methanol, such as ethanol, propanol, and cyclohexanol, were incorporated onto the  111  α-position of the N-confused dipyrrin successfully, however, owing to steric effects there is 10% of the Z-anti isomer present after the substitution of cyclohexanol. Additionally, oxidizable functional groups such as hydroxy, alkyne and alkene groups were welltolerated in the reaction and gave the corresponding stereoselective Z-syn lactim products in good yields (Table 4.4, entry 5-7). The formation of the lactim N-confused dipyrrin is shown to be general and can be performed on N-confused DPMs with various steric meso-aryl substituents with a variety of alcohols.  Table 4.4 DDQ-promoted alkoxylation of the N-confused dipyrromethane.  a  reaction conditions: room temperature, 0.025 M 2-23, 0.025 M ROH, 0.05 M DDQ. b Isolated  yields. c Z-anti observed as 10% of the total product.  4.3.4 Hydrogen-bonding Controlled Configuration Changes It is of interest to have control over the stereochemistry of the N-confused dipyrrin. Since strong hydrogen-bonding interactions control the stereochemistry of the  112  products in the above reactions, it is expected that reducing the hydrogen-bonding interaction between the introduced oxygen atom and NH may alter the stereochemistry of the final products.  Table 4.5 Relationship between hydrogen-bonding strength and stereochemistry.  a  reaction conditions: room temperature, 0.025 M 2-23, 0.025 M ROH, 0.05 M DDQ.  b  Isolated yields. c Determined based on the integral ratio of 1H NMR from the mixture of Z-syn and Z-anti products.  Because of the tunability of oxygen as a hydrogen-bonding acceptor, three primary alcohols bearing different electron-withdrawing groups (-CN, -Cl, -CF3) on the β-position of the alcohols were selected to examine whether they can be used to control the stereochemistry of the resulting lactim N-confused dipyrrins (Table 4.5, entries 1-3). Under standard reaction conditions, β-chloro-ethanol gave the completely stereoselective result with the Z-syn lactim N-confused dipyrrin 4-17 as the sole product, whereas βcyano-ethanol gave a 5% increase of the Z-anti form dipyrrin in the overall dipyrrin products (Table 4.5, entry 2). Interestingly, both the Z-syn (C) and Z-anti (A)  113  diastereomers were present in the resulting lactim products in a 1:4 ratio demonstrated by 1  H NMR analysis of the resulting lactim N-confused dipyrrin 4-20 (Figure 4.7) when the  weakest hydrogen-bond acceptor CF3CH2OH was reacted as the nucleophile. The relationship between the ability of the alcohol oxygen atom as hydrogen-bond acceptor and the dipyrrin configuration proves the crucial role of hydrogen-bonding interactions for the stereochemistry of N-confused dipyrrins.  Figure 4.7 1H NMR spectrum of 4-20 (Z-anti: Z-syn =4:1) in CDCl3. 4.3.4 Mechanism of the Alkoxylation Reaction Overall, the essential components of the present reaction have been elucidated and a plausible mechanism to rationalize the alkoxylation reaction on the N-confused dipyrrin is depicted in scheme 4.1. Firstly, mediated by DDQ, the alcohol nucleophile is introduced to the α-position of the N-confused dipyrrin to yield the species I. In this step the extent of conjugation between the methine and the pyrrole moiety decreases and free  114  rotation of the confused pyrrole group occurs around the methine pyrrole C-C bond. The strong hydrogen-bonding interaction between the nitrogen acceptor and the oxygen donor enforces the conformation of the resulting intermediate II. Further oxidation of species II with DDQ leads to loss of a hydride to yield intermediate III, a protonated lactim Nconfused dipyrrin. Intramolecular hydrogen shift should be easily occurred in species III to give species IV. Followed by deprotonation, a highly stereoselective Z-syn configuration lactim form of N-confused dipyrrin is produced.  Scheme 4.1 Proposed mechanism for DDQ-mediated addition reaction. 4.3.5 Optical Absorption Spectra of N-confused Dipyrrin Derivatives The optical properties of the N-confused dipyrrin derivatives were assessed in CH2Cl2 and the UV-vis absorption spectra are presented in figure 4.8. A broad peak at 422 nm was observed in the UV-vis spectrum of N-confused dipyrrin 4-1 (Figure 4.8, curve 1), whereas the α,α‟-dipyrrin 3-17 appears at 462 nm (Figure 4.8, curve 6), indicating the blue shift tendency of the N-confused dipyrrin compared to the conventional α,α‟-dipyrrin. The extinction coefficient of the N-confused dipyrrin 4-1 is 115  44640 M-1 cm-1 at 422 nm, and lactim N-confused dipyrrin 4-5 has the extinction coefficient 36984 M-1 cm-1 at 416 nm, while the extinction coefficient of the α,α‟-dipyrrin 3-17 at 462 nm is 22320 M-1 cm-1. The UV-vis spectra of the lactim form of dipyrrins have broad absorption peaks at 415 nm, which are slightly shifted to higher energy in comparison to that of the corresponding unsubstituted N-confused dipyrrin 4-1. Such observation is consistent with an α-alkoxylated α,α‟-dipyrrin.125 All of the lactim Nconfused dipyrrin UV-vis spectra display a shoulder at 380 nm, which again distinguishes them from the parent unsubstituted N-confused dipyrrins. The absorption spectra of the Z-syn and Z-anti diastereomers are almost identical (Figure 4.8, curves 2 and 4) and cannot be differentiated by their optical absorption spectra, suggesting that configuration change does not significantly affect the conjugation of the lactim N-confused dipyrrins.  Figure 4.8 Electronic spectra of N-confused dipyrrin derivatives in CH2Cl2. 4.4 Reactivities of the N-confused Dipyrryl System Further functionalization of N-confused dipyrrins was examined as described in scheme 4.2. By treatment of DPM 2-23 with NBS in CH2Cl2, dibrominated DPM 4-25 116  was produced regioselectively with bromine at the two β-positions. Surprisingly, 4-25 was resistant to oxidation in the presence of two equivalents of DDQ, with increased redox potential resulting from the two bromo-substituents presumably accounting for this. An N-confused tetrapyrrole macrocycle 4-26 was constructed by reaction of N-confused dipyrromethane diol with a bipyrrole in the presence of acid, however, 4-26 was unstable and further oxidation reactions did not generate the corresponding fully conjugated Nconfused corrole. Interestingly, interaction of the lactim forms of N-confused dipyrrins 4-5 or 4-19 with silica gel quantitatively generates the lactam form of N-confused dipyrrin 3-10. Similar to NCP, the alkylation of the nitrogen in the confused pyrrole of 4-1 is easily achieved in 71% yield by reaction of N-confused dipyrrin 4-1 with 4-cyanobenzyl bromide in the presence of K2CO3 in DMF. The synthetic route to N-confused dipyrrin derivatives described here may prove useful, upon further optimization, for the preparation of interesting chromophores containing this functional group.  117  Scheme 4.2 Reactivities of N-confused dipyrrins. Given that the acetyl group may serve as both an electron-withdrawing group, and it is capable of being reduced, reduction of the dipyrrin system was examined. Upon the treatment of 4-1 with four equivalents of NaBH4, a complex mixture was observed on TLC, presumably owing to the susceptibility of the conjugated system toward the hydride. In sharp contrast, when the substrate was changed to the lactam dipyrrin 3-10 the selectively reduced product 4-22 is produced in 91% yield (Scheme 4.2). As a stable compound bearing both the oxidized moiety (dipyrrinone) and the reduced moiety (diol),  118  the configuration-fixed dipyrryl carbinol 4-22 can further react with nucleophiles such as pyrrolic derivatives to afford oligopyrroles 4-23 and 4-24 in 28% and 61% yields, respectively, with retention of the Z-syn configuration of the N-confused dipyrryl moiety (Scheme 4.2). The stereochemistry (retention of the Z-syn dipyrryl moiety) of 4-24 is clearly reflected in the characteristically sharp resonance at 13.75 ppm for the NH of the N-confused moiety in the 1H NMR spectrum (Figure 4.9).  119  Figure 4.9 1H NMR spectrum of tetrapyrrole 4-24 in CDCl3. 4.5 Oxidative Dimerization Reaction on the N-confused Dipyrrin Dipyrrins and N-confused porphyrins are known to be rather reactive owing to the exposed α-positions, which are susceptible to further transformations.74, 75In the same way, N-confused dipyrrins demonstrate higher reactivity than the corresponding α,α‟-dipyrrins as the result of presence of the α-meso-β linkage and the reactive α-position.126 Under acidic or basic conditions, both the free-base form of N-confused dipyrrins and the lactim form of N-confused dipyrrins are stable. However, under oxidative conditions, upon treatment of 1,9-dibenzoyl meso-2,6-dichlorophenyl N-confused DPM 2-32 with two equivalents of DDQ followed by addition of 0.1 equivalents of triethyl amine (TEA), a green tetrapyrrolic product, 4-27a, was produced in 41% yield. HRMS analysis indicated that dimerization of two dipyrrin molecules had occurred (Scheme 4.3). 120  4.5.1 Characterization of Tetrapyrrolic Product 4-27a 4.5.1.1 Structure Determination of 4-27a by NMR Spectroscopy  Scheme 4.3 Oxidative dimerization reaction of N-confused DPM.  1  H NMR analysis showed a broad proton resonance at 8.49 ppm and seven proton  resonances between 5.52 ppm-6.82 ppm, corresponding to the N-H proton and pyrrolic protons, respectively, in the tetrapyrrole structure of 4-27a (Figure 4.10 a). In addition, 1  H-1H COSY studies reveal that two proton resonances (5.48 and 6.81ppm) are correlated  to each other along with the N-H (8.49 ppm), suggesting there is only one enamine-type pyrrole moiety within this molecule. The available structural information, although still limited, is consistent with the formulation of 4-27a as intermolecular oxidative amination structure I (Scheme 4.3). However, the 74.19 ppm shift in the 13C NMR spectrum (Figure 4.10 b), ascribed as the non-aromatic C-H carbon, cannot be explained by the proposed structure I.  121  Figure 4.10 a) 1H NMR spectrum of tetrapyrrole 4-27a in CDCl3, b) 13C NMR spectrum of the tetrapyrrole 4-27a in CDCl3.  122  4.5.1.2 Structure Determination of 4-27a by X-ray Analysis Crystals of compound 4-27a were obtained by diffusion of hexanes into a CH2Cl2 solution and the structure was determined by X-ray crystallography (Figure 4.11). The crystal structure revealed several interesting structural features, which again proved the high reactivity of the α-positions of the N-confused moiety. As expected, an oxidative dimerization product was confirmed, in addition a further intramolecular N-H-C addition reaction has occurred on the N-confused moiety to create a tertiary center and the two Nconfused dipyrrin moieties are fused in a tripyrrolic macrocycle.  Figure 4.11 ORTEP drawing of 4-27a, the vibrational ellipsoids are represented at 50% probability. 4.5.2 Survey of the Scope of the Oxidative dimerization Reaction Various N-confused DPMs were examined in this oxidative reaction using DDQ (2 equivalents) as oxidant in CH2Cl2 at room temperature (Scheme 4.4). The results indicate that both benzoyl and acetyl group substituted N-confused DPMs afford the cyclized products in good yields (41%-61%). However, owing to the increase in steric  123  bulk when changing the benzoyl group to the 2,6-dichlorobenzoyl group, there is no corresponding dimerization product observed. As well, treatment of 1,9-diformyl substituted meso-2,6-dichlorophenyl N-confused DPM with DDQ and TEA under the same reaction conditions only afforded a small amount of N-confused dipyrrinone and no N-H-C coupling product was observed. It is worthwhile to note that in all of the above reactions there are no dimerization products observed in the absence of base, suggesting the basic conditions are critical for this oxidative N-C bond formation reaction.  Scheme 4.4 Oxidative N-C bond formation in the dipyrrin system. 4.5.3 Proposed Mechanism Oxidative C-C bond formation between two pyrrole moieties is a common and fundamental reaction in either single pyrrole or oligopyrrole systems. 127 The strategic application of selective C-H oxidation reactions has been demonstrated to increase diversity in porphyrinoid systems. However, the intermolecular oxidative C-N bond formation between the oligopyrrole systems is unusual, and while the exact mechanism of the N-H-C coupling reaction in the oligopyrrole system is not clear, a proposed mechanism is given in scheme 4.5.  124  Scheme 4.5 Proposed mechanism for the oxidative dimerization reaction of N-confused dipyrrin.  A plausible mechanism consistent with the above observations might involve the following (Scheme 4.5): The initial oxidation of the N-confused DPM could generate an intermediate such as N-confused dipyrrin. This could be followed by an addition reaction from the nitrogen of N-confused pyrrole from another molecule N-confused DPM to give a dimerized species I. In earlier studies, we have shown that N-confused dipyrrins tautomerise. Thus we suggest that there is a hydrogen shift following the formation of species I to yield species II. Further oxidation of II with DDQ leads to loss of a “hydride” to give intermediate V, a DPM substituted N-confused dipyrrin. Bearing one 125  saturated meso C-H, V should easily be oxidized to VI, a N-confused dipyrrin dimer bearing one α-position unsubstituted on one of the N-confused pyrroles. Such exposed αpositions are known to be highly reactive in the presence of oxidant and base, and indeed this has been verified in our earlier studies during the oxidative alkoxylation of the Nconfused dipyrrins. Upon intramolecular addition of one pyrrole nitrogen to this specific α-position, 4-27b would be obtained as the cyclized product. The inherent preference of pyrrole derivatives to oxidatively dimerize at the αcarbon, regardless of whether as a single pyrrole or an oligopyrrolic system, makes the oxidative construction of a N-C bond a great challenge. The strategies for oxidative N-C bond formation described above serve not only to introduce a new type of oligopyrrole but also to challenge that conventional C-C bond formation in oligopyrroles is the only result from classic oxidative coupling conditions. With the established oxidative N-C bond forming reaction, aspects of the chemistry such as further extension and cyclization of a number of previously unknown oligopyrrole systems can be explored. 4.6 Conclusion In summary, the first genuine free-base N-confused dipyrrin has been synthesized and fully characterized. As well, DDQ-mediated alkoxylation on the α-position of Nconfused dipyrrins was achieved through a cascade reaction from N-confused DPMs. This approach offers considerable flexibility in the choice of the resulting stereochemistry of the N-confused dipyrrin, affording both the Z-syn and Z-anti configurations of N-confused dipyrrins by manipulation of hydrogen-bonding interactions. It is possible that these new dipyrrin analogues, like the conventional α,α‟-  126  dipyrrins that preceded them, will provide a portal into a new and rich area of dipyrrin related research. The reactivities of the N-confused dipyrrin have also been investigated. Specifically, selective reduction of the lactam form of N-confused dipyrrin has been achieved and the resulting lactam N-confused dipyrrindiol provides a building block for partially-conjugated N-confused oligopyrroles. The principles for stabilizing the freebase of N-confused dipyrrins and concise synthesis of higher N-confused oligopyrroles may provide guidance for the further N-confused oligopyrrole studies.  127  Chapter 5 N-confused [12]Tripyrrin(0.1.1) and Linear N-confused Oligopyrroles— Oxidative Amination and Ring Closure  128  Extension of the π-conjugated oligopyrrole macrocyclic system has continued to attract the attention of porphyrin chemists. Such systems often exhibit interesting physical properties and these studies have opened up new areas of physical organic and functional material chemistry.128 For example, various porphyrinic macrocycles have been synthesized and investigated for medical applications such as anion recognition, 129 , 130 magnetic resonance imaging (MRI),131 and photodynamic therapy (PDT).132.  The strategic application of selective C-H oxidation of linear oligopyrrole precursors has been demonstrated to increase the diversity of porphyrinoid systems. C-C bond oxidative coupling reactions for ring closure have been used in the formation of several conjugated oligopyrrolic macrocycles (e.g., corroles, sapphyrins, rubyrins, heptaphyrin and octaphyrin) under Rothemund-like conditions,133 and have been used to prepare bipyrrole itself.134  Scheme 5.1 Inter- and intramolecular oxidative coupling for the construction of oligopyrrolic macrocycles.  129  The number of synthetic methods that can be used to construct oligopyrrolic macrocyclic structures bearing bipyrrole feature remains rather limited. The inherent preference of pyrrole derivatives to oxidatively couple at the α-carbon in either single or oligopyrrole systems provides a fundamental protocol for ring closure of such systems but also renders the oxidative construction of other connection types a great challenge. With the advent of reliable N-H-C amination on N-confused dipyrrin systems, an oxidative N-C formation strategy for ring closure in elongated oligopyrrole systems to create the corresponding fully-conjugated cyclized products might be developed, thus providing a new category of N-confused oligopyrrolic macrocycles (Scheme 5.2).  Scheme 5.2 Inter- and intramolecular oxidative amination for the construction of oligopyrrolic macrocycles.  Having determined that N-confused DPMs can be oxidized by DDQ and that the N-confused pyrrole ring shows higher reactivity for further transformation, we investigated the utility of longer N-confused oligopyrroles as precursors for oxidized Nconfused oligopyrrins. Oligopyrroles bearing the α-meso-β-linkage with various substituents such as N-confused tripyrrane 5-1 and 5-2 were synthesized. With the necessary constitution in place, a variety of oxidation (basic and acidic) conditions were 130  screened (Scheme 5.2). Despite numerous attempts using oxidants such as DDQ and pchloranil under various reaction conditions, oxidized products analogous to N-confused dipyrrins were not observed with only starting materials being detected by TLC analysis (Scheme 5.3).  Scheme 5.3 Synthesis of N-confused oligopyrranes for further oxidation studies. Preceding studies indicate that steric meso-aryl groups and EWGs on the αposition were required for the generation of N-confused oligopyrrolic structures and attempts to synthesize the corresponding 2,6-dichlorophenyl-substituted N-confused tetrapyrrane  starting  from  1,9-bis-2,6-dichlorobenzoyl  substituted  meso-  pentafluorophenyl N-confused DPM 2-33 were carried out (Scheme 5.3). Unexpectedly, owing to the steric hindrance from the 2,6-dichlorophenyl group, the reduction of the benzoyl group was problematic, where even strong reducing agents (LiAlH4) under refluxing reaction conditions were unsuccessful (Scheme 5.3). The 2,6-dichlorophenyl groups and corresponding EWGs could not at, this point, be introduced onto an oligopyrrole framework by rational synthesis. The lack of an  131  efficient method for rational synthesis of longer N-confused pyrrolemethanes bearing steric meso-aryl groups and EWGs on the pyrrole moiety continued to hinder advancement. One remedy against such difficulties was the utilization of a traditional one-pot, two step strategy. 5.1 1+1 Strategy for Producing Porphyrin and Oligopyrrolic Analogues Pyrrole-aldehyde condensations catalyzed by acid has emerged as a versatile process and has led to a seemingly endless source of macrocyclic porphyrinoid analogues over the past few decades. In a series of largely accidental discoveries, a wealth of oligopyrrole macrocyclic products have been isolated from the crude black mixtures that are typically obtained prior to workup as the results of pyrrole–aldehyde condensations (Figure 5.1). Among them, the one-pot syntheses of N-confused porphyrins, corroles and expanded porphyrins have all been well documented (Figure 5.1). 135 Not surprisingly, these porphyrin analogues have been both the subject of attention for synthetic chemists and a source of conceptual inspiration. The development of one-pot synthetic pathways for novel oligopyrrolic macrocycles with different conjugations and π-electron systems has a healthy future.  132  Figure 5.1 One-pot strategies for the synthesis of oligopyrrolic structures (Source: Angew. Chem., Int. Ed. 2004, 1918).135 5.2 Results and Discussion The studies discussed here explore the hypothesis that π-extended N-confused oligopyrrolic structures may be created by the directing effect of electron-withdrawing groups (EWG) on the pyrrole α-position via a one-pot, two step protocol. With the breakthrough in the one-pot synthesis of N-confused DPM and thorough investigation of the oxidation conditions, a [1+1] strategy might be applied to the preparation of  133  conjugated N-confused oligopyrrolic macrocyles by treatment of EWG-substituted pyrroles with aryl aldehydes under one-pot reaction conditions. Initially, we sought to react 2-acetylpyrrole with sterically encumbered aryl aldehydes under acid-catalyzed conditions to explore the hypothesis. Typically the onepot pyrrole-aldehyde condensation is conducted between aryl aldehyde and electron rich pyrrole or their analogues under dilute conditions, whereby the resulting porphyrinogens can then be oxidized to yield a fully-conjugated macrocycle. The use of 2-acetylpyrrole fulfills the prerequisites for efficient N-confused oligopyrrolic macrocycle formation via the one-pot, two step reaction. Firstly, as an EWG, the acetyl group can stabilize the longer conjugated oligopyrrolic structure, using the fact that previous reports suggest that EWG on the meso-position may stabilize expanded porphyrin analogues. 136 Secondly, the 2-acetyl group can deactivate the pyrrole and direct the next electrophilic substitution to the β-position as well;100 hence the other two unsubstituted pyrrole positions (4, 5) could, theoretically, be incorporated with the incoming meso-aryl group to generate the α-mesoβ or β-meso-β linkage. Finally, the acetyl group is a relatively small group which should not generate much of a steric interaction between itself and the meso-aryl group in the resulting oligopyrrolic structures. Reaction of 2-acetylpyrrole with aryl aldehyde under the acidic condensation reaction conditions followed by DDQ oxidation, gave ring confused macrocycles and linear pyrrolemethenes, 5-3 through 5-7, in roughly 3-8% yields by the one-pot, two step strategy (Figure 5.2). These oligopyrroles are unprecedented with macrocycle 5-3a representing the first example of an N-confused tripyrrolic macrocycle structure composed of a 12 π-electron framework with only pyrrole and meso-aryl moieties.  134  Additionally, the free-base N-confused oligopyrrolemethenes 5-4 through 5-5 can be seen as mutants of the α,α‟-oligopyrromethenes.  Figure 5.2 Products of the one-pot strategy. 5.2.1 Exploration of the Reaction Conditions Various conditions for the acid-catalyzed condensation of 2-acetylpyrrole and ortho-substituted  aryl  aldehyde  such  as  pentafluorobenzaldehyde  and  2,6-  dichlorobenzaldehyde were examined. After extensive screening, we determined that MSA still served as the best acid for catalysis. Briefly, the 2,6-dichlorobenzaldehyde was condensed with 2 equivalents of 2-acetylpyrrole under conditions of acid catalysis (1 equivalent MSA) to furnish a linear oligopyrrole precursor. This oligopyrrole intermediate, although apparently stable, was not isolated. After removal of acid by chromatography through a short basic alumina column, the eluate was treated immediately with DDQ/TEA. Under these conditions, analogous to those used in the previous work to produce N-H-C dimerization products from N-confused dipyrrins, oxidative ring closure occurs spontaneously to afford N-confused tripyrrin 5-3a in an overall 2.1% yield.  135  Both the catalysis and the oxidization processes are important for the outcome and removal of the acid before the oxidation procedure turned out to be the most critical step for the successful preparation of the conjugated oligopyrromethene structures. Further studies of the oxidation step indicated that 0.1 equivalents (relative to 2-acetylpyrrole) of DDQ/TEA gave the best yields, while excess DDQ caused decomposition. The basicity of the oxidation procedure has a profound influence to the N-H-C amination cyclization step; in particular, no cyclization product was observed without addition of TEA. Under these optimized conditions, three pigments 5-3a, 5-4 and 5-5a were generated in roughly 3% yields by reaction of 2,6-dichlorobenzaldehyde with 2-acetylpyrrole. 5.2.2 N-confused [12]Tripyrrin(0.1.1) 5-3a 5.2.2.1 Structure Determination of 5-3a by NMR Spectroscopy Mass spectrometric analysis of green product 5-3a indicated an M+ of 637, corresponding to a two aryl and three pyrrole constitution. Spectroscopic measurements (1H NMR,  13  C NMR) suggest it has as a conjugated but non-aromatic structure. The 1H  NMR analysis shows three singlet pyrrolic peripheral CH signals between 5.5-7.0 ppm and one NH proton signal at 14 ppm in CDCl3, suggesting strong hydrogen-bonds are present in the structure. As well, the observation of an NH signal at low field is, in itself, considered diagnostic of the nonaromatic nature of 5-3a. 1H-1H COSY studies reveal the proton resonance at 5.55 ppm has weak correlation with the NH resonance (Figure 5.3), and HMQC studies prove the signals between 5.5-7.0 ppm are from the pyrrole rings (Figure 5.4), indicating there is only one enamine-type pyrrole ring in the structure.  136  Figure 5.3 1H-1H COSY NMR spectrum of compound 5-3a in CDCl3.  137  Figure 5.4 HMQC NMR spectrum of compound 5-3a in CDCl3. 5.2.2.2 Structure Determination of 5-3a by X-ray Analysis Eventually, the structure of 5-3a was ascertained by single crystal X-ray analysis (Figure 5.5). The crystal structure reveals several interesting structural features, which again prove the high reactivity of the α-positions of the N-confused moiety. Consistent with the above observations, 5-3a has a non-aromatic conjugated macrocyclic structure with two confused pyrrole rings (A and C) present in the tripyrrolic macrocycle (Scheme 5.4). The A and C rings are confused and imbedded within the macrocyclic framework, and thus satisfies the unique head-to-tail N-C cyclization pattern of the macrocycle.  138  Following nomenclature rules, a conjugated macrocycle with 12 π-electrons comprised of two meso-sp2 carbons and three pyrroles is named the N-confused [12]tripyrrin(0.1.1).  Figure 5.5 ORTEP representations of 5-3a, a top view (left) and a side view (right), the vibrational ellipsoids are represented at 50% probability.  As the smallest oligopyrrolic macrocycle constructed purely from meso-aryl and pyrrole moieties, 5-3a bears interesting features. The B and C pyrroles are fused together to create a tricyclic [5.5.5] structure to relieve strain, and the three pyrrole groups are coplanar due to the fusion and intramolecular hydrogen-bonding. The two aryl groups are tilted down 65.43ºand 89.05ºfrom the tripyrrolic mean plane, respectively. While not formally aromatic, 5-3a does contain the expected cyclized π-electron conjugation pathway (Scheme 5.4). The strong intramolecular hydrogen-bonding (O(04)···H-N(2) 2.607 Å) between the C=O bond of C ring and the cofacial A ring NH causes the NH resonance to be shifted downfield to 13.97 ppm, suggesting 5-3a is weakly zwitterionic  139  (Scheme 5.4). A longer bond distance of C(03)=O(04) (1.237 Å) and C(01)-C(03)=O (1.438) compared to the typical C=O (1.20 Å) and C-C (1.45 Å) bonds are consistent with the zwitterionic character of the vinylogous amide form of 5-3a.137 The zwitterionic character is further supported by the C(06)-N(3)-C(01) angle of 104.08º, typical of the imine form of pyrrole, and is consistent with resonance structure II of 5-3a (Scheme 5.4).  Scheme 5.4 Resonance forms of N-confused tripyrrin 5-3a. 5.2.2.3 Reactivity and Stability of 5-3a  Scheme 5.5 Ring-opening attempt under the standard reaction conditions.  Despite bearing two N-confused pyrrole rings in the structure, 5-3a appears to be stable under normal laboratory conditions. A typical reaction for opening the tripentacyclic moiety of NCP in the presence of sodium methoxide was not effective in  140  this case (Scheme 5.5),138 possibly owing to the strong intramolecular hydrogen-bonding interaction of the A and C rings. 5.2.2.4 Survey of the Scope of Substrates for Macrocycle Formation Table 5.1 One-pot synthesis of the corresponding macrocycles and oligopyrroles.  This oxidative intramolecular cyclization reaction was then examined with pyrrole substrates bearing different electron-withdrawing groups on the α-position and the results are summarized in Table 5.1. These results suggest that the reactivity patterns leading to these macrocycles are highly dependent on both meso-substitution and pyrrole substitution. Certain substituted pyrroles, such as 2-acetylpyrrole and non-steric benzoylpyrroles, may facilitate the construction of the cyclized tripyrrins, while 2-pyrrole aldehyde and the steric group-protected benzoyl pyrroles (i.e. 2-(2,6-dichlorophenyl benzoyl)pyrrole) are not capable of generating the corresponding macrocycles. Changing 2,6-dichlorobenzaldehyde to the pentafluorobenzaldehyde under the same reaction conditions was also tested. Interestingly, we were unable to isolate any macrocyclic products from reactions involving pentafluorophenyl aldehyde, which afforded only  141  small amounts of a linear tripyrrin product 5-5b (Figure 5.2). This observation indicates that the presence of ortho-chloro substituents on the meso-aryl groups is required for effective ring closure. To study the peripheral substituent effect, a 2-benzoylpyrrole constructed macrocycle 5-3b was characterized by X-ray analysis (Figure 5.6). The most remarkable feature is that there is a π-π stacking interaction between the meso-2,6-dichlorophenyl group within the tripentacyclic moiety and the β-substituted benzoyl group on the peripheral position, with the other characteristics strongly resembling the acetyl substituted 5-3a.  Figure 5.6 ORTEP representations of 5-3b, a top view (left) and a side view (right), the vibrational ellipsoids are represented at 50% probability.  142  5.2.2.5 Optical Absorption Spectra of N-confused [12]Tripyrrin(0.1.1) 5-3a. The optical spectrum of 5-3a was investigated in CH2Cl2. The UV-vis spectrum shows that 5-3a has an intense absorption band at 371 nm, along with two weak absorption bands at 445 nm and 651 nm, respectively (Figure 5.7). Lack of an intense Sband in the spectrum distinguishes it from the conventional carbon-carbon connected oligopyrrole structures. The spectrum changes insignificantly upon addition of one equivalent of trifluoroacetic acid and this behavior is expected, since 5-3a contains no protonatable imine nitrogen sites.  Figure 5.7 The UV absorption spectrum of the compound 5-3a in CDCl3.  143  5.2.2.5 Proposed Mechanism for Producing 5-3a The cyclization of linear oligopyrroles accompanied by oxidation (DDQ), is depicted in Scheme 5.6. According to the constitution of 5-3a, a linear oligopyrrolic tripyrrane precursor I (Scheme 5.6) was first produced during the acid-catalyzed process. Catalyzed by the strong acid MSA, the α-acetyl group on the B ring rearranges to the βposition,139 with which two unsubstituted α-positions are capable of connecting the A and C rings via meso-aryl substitution. Thus, in the resulting tripyrrane I, the A, B, and C pyrrole rings are connected by meso-aryl groups via a β-α-α-β sequence, providing the geometry necessary for oxidative N-H-C cyclization. After removal of the acid, the oxidation reaction at the meso-position is induced by DDQ. The in situ produced tripyrrin II is highly reactive and the addition of the pyrrolic nitrogen from the N-confused C ring to the α-position of the N-confused A pyrrole is further induced, and a final tandem reaction enables the resulting macrocycle to undergo a further oxidative amination reaction to afford 5-3a.  144  Scheme 5.6 Proposed mechanism for cyclization of 5-3a. 5.2.3 Structure Determination of Tetrapyrrin 5-4 Oxidation of the residue of the one–pot reaction with 2,3-dichloro-5,6-dicyano-pbenzoquinone (DDQ) followed by chromatography on silica gel led to isolation of another green pigment 5-4 in 3% yield. A signal at m/z=886.0227 in the HRMS spectrum indicated the green pigment 5-4 was constituted from three aryl and four pyrrolic units. 1  H NMR analysis revealed that four singlet pyrrole proton signals appeared between 6-7  ppm in CDCl3, along with three NH proton signals at 12.79, 9.07 and 8.69 ppm (Figure 5.8). This suggests a non-aromatic structure with a strong intramolecular hydrogenbonding interaction present.  145  Figure 5.8 1H NMR spectrum of 5-4 in CDCl3.  Consistent with the above observation, X-ray analysis of 5-4 disclosed it to be a linear tetrapyrrin structure constructed from two fused tricyclic [5.6.5] structures via a meso-aryl group (Figure 5.9). All spectroscopic data for 5-4 are consistent with the assigned tetrapyrrin structure. The inner N-H signal of B ring appears at 5.34 ppm in the 1  H NMR spectrum owing to the shielding of the two adjacent phenyl groups, suggesting  the conformation observed in the solid state is largely preserved in solution.  146  Figure 5.9 X-ray crystal structures of 5-4, the vibrational ellipsoids are represented at 50% probability. 5.2.4 Structure Determination of Tripyrrin 5-5a Apart from the above mentioned pigments, a purple product 5-5a was further eluted from the silica gel chromatography column. Mass spectrometric analysis of 5-5a indicates it is made up of three pyrroles and two meso-aryl substituents according to the M+ peak at 621.0357. Four pyrrolic proton signals appear between 6-7 ppm in the 1H NMR spectrum, along with two NH peaks at 8.80 and 11.72 ppm. There is only one set of doublet peaks, corresponding to two adjacent β-protons of the oligopyrrole, appearing at 6.65 ppm and 7.13 ppm in 1H NMR spectrum (Figure 5.10).  147  Figure 5.10 1H-1H COSY NMR spectrum of 5-5a in CDCl3. The exact structure of 5-5 is confirmed by the X-ray crystallographic data. X-ray crystallography of pentafluorophenyl substituted analogue 5-5b reveals it to have a linear meso-aryl fused tripyrromethene structure (Figure 5.11). Three pyrrole rings in 5-5b are connected in a planar arrangement through the fused tricyclic [5.6.5] structure. All spectroscopic data for 5-5a are consistent with the assigned structure, with the 1H-1H COSY spectrum clearly indicating the correlation between C(9)-H-H-N(1) and C(17)-HH-N(2) (Figure 5.10).  148  Figure 5.11 X-ray crystal structure of 5-5b, the vibrational ellipsoids are represented at 50% probability. 5.3 N-confused Tripyrrane The successful preparation of N-confused oligopyrrolic pigments using a one-pot strategy inspired us to use preformed tripyrranes as precursors to create N-confused oligopyrrolic macrocycles. The use of N-confused oligopyrrolemethanes as general precursors for macrocycle have been reported, 140 but controlled head-to-tail cyclization remains largely uninvestigated except for a recently reported synthesis of N-confused sapphyrin.141 Having confirmed that acid-catalyzed condensation of 2-acetylpyrrole and aldehyde in a one-pot reaction can generate the N-confused oligopyrrole and the resulting tripyrrolemethane with two α-unsubstituted terminal N-confused pyrroles can serve as precursor for N-H-C oxidative ring closure, we investigated the use of synthesized oligopyrrole 5-10a, a tripyrrolemethane bearing two terminal N-confused pyrroles, for ring closure reaction (Scheme 5.7). During the condensation reaction there are 14%  149  tripyrrolemethanes produced as a regioisomeric mixture, which includes 5-10a and 5-10b. Among the N-confused tripyrrane regioisomers, the major component 5-10a is of interest to us as it is conceived to be a useful precursor for N-confused macrocycles with two terminal pyrroles connected to the β-position, resembling the precursor for macrocycle 53a.  Scheme 5.7 Preparation of β-α-β-β connected tripyrrane 5-10a.  Difficulty in separation of the two isomers hindered further work with them. We sought to establish a method in which unwanted product 5-10b could be removed from the regioisomer mixture, leaving desired 5-10a purified. In tripyrrane 5-10b the α,α‟dipyrromethane moiety is capable of coordinating with tin(II) to yield a tin(II) complex  150  5-11a, resembling that of the 1,9-diacyl α,α‟-DPM.142 Using this property, a coordination strategy was developed to remove minor product 5-10b (Scheme 5.7). Treatment of the tripyrrane mixtures 5-10a and 5-10b with tin(II) under basic conditions resulted in complete formation of complex 5-11a within 5 minutes, which was easily removed by chromatography from the starting materials owing to its low polarity. Therefore, purified 5-10a was obtained by this coordination strategy. Direct evidence of the connection of the middle pyrrole of such tripyrranes came from the crystal structure of 5-11b. For crystallographic purposes, 2-chloro-6fluorophenyl-substituted complex 5-11b was produced, and a crystal suitable for X-ray analysis was obtained by diffusion of hexanes into the CH2Cl2 solution. X-ray analysis of the tin complex unambiguously proved the constitution of the tripyrrane ligand, with the middle pyrrole connected at the 4- and 5- positions, and the two terminal pyrrole rings connected to the α- and β- positions, respectively (Figure 5.12).  Figure 5.12 ORTEP representation of X-ray crystal structure of 5-11b, the vibrational ellipsoids are represented at 50% probability. 151  5.4 N-confused Tripyrrin Bearing two terminal pyrroles connected through the β-positions, the unique β-αβ-β connection of tripyrrane 5-10a affords a promising geometry for head-to-tail cyclization. Attempts at intramolecular cyclization of tripyrrolemethane 5-10a were carried out in CH2Cl2 (Scheme 5.8) under modified conditions (4 equivalents DDQ). Oxidation of 5-10a to give the corresponding oxidized products 5-9a and 5-9b proceeded in good yields (Scheme 5.8, 41% and 42%), unlike the nonsteric meso-phenyl tripyrrane 5-1 and 5-2 discussed previously, supporting the hypothesis that the steric meso-groups and EWG groups on the pyrrole ring considerably promote oxidation in oligopyrroles.  Scheme 5.8 Intramolecular oxidative amination reaction. 5.4.1 Structure Determination of 5-9a and 5-9b by X-ray Analysis Mass spectrometric analysis indicates both 5-9a and 5-9b have an M/Z peak at 702, suggesting they have the same molecular constitution, and are constructed from three pyrroles, two aryl groups and two chlorine atoms. The assignment of the exact structure of 5-9a and 5-9b relied upon X-ray crystallography. Both products were crystallized after slow diffusion of hexanes into their CH2Cl2 solutions, and suitable crystals were selected for X-ray diffraction analysis.  152  ORTEP representations of 5-9a and 5-9b are shown in figures 5.13 and 5.14, respectively. Interestingly, X-ray analysis revealed that 5-14a and 5-14b are E/Z isomers of fused Nconfused tripyrrins instead of the proposed cyclization products.  Figure 5.13 X-ray crystal structures of 5-9a, a top view (left) and a side view (right), the vibrational ellipsoids are represented at 50% probability.  Figure 5.14 X-ray crystal structures of 5-9b, a top view (left) and a side view (right), the vibrational ellipsoids are represented at 50% probability.  The crystal structure reveals several interesting structural features, which again prove the high reactivity of the α-positions in the N-confused moiety. The same tripentacyclic group constructed through the α-meso-β linkage is present in the two  153  products, which is then further connected the third pyrrole group in an E or Z configuration for 5-9a and 5-9b, respectively. Synthesis of N-confused tripyrrins is rare and, to our knowledge, this is the first time aryl-substituted N-confused tripyrrins have been synthesized and characterized by X-ray diffraction analysis. The spectroscopic studies are fully consistent with the assigned structures. The tripentacyclic moiety produces a relatively strong hydrogen-bonding interaction which causes the shift of the tripentacyclic NH signals to 9.77 and 9.70 ppm in the 1H NMR spectrum (Figure 5.15, 5.16). As confirmed by the 1H NMR analysis, the E-anti conformation of 5-9a and Z-syn conformation of 4-9b observed in the solid state are largely preserved in solution, leading to observable shielding of the peripheral protons in the molecule.  Figure 5.15 1H NMR spectrum of 5-9a in CDCl3.  154  Figure 5.16 1H NMR spectrum of 5-9b in CDCl3.  The mutual shielding of the two phenyl rings causes a significant upfield-shift (6.84 ppm-7.08 ppm) of the meso-aryl phenyl proton signals in the 1H NMR spectrum of 5-9a (Figure 5.15). Also, the shielding of the pyrrole by the phenyl ring is reflected in the 1  H NMR of 5-9b as the chemical shift of the pyrrole proton moves further upfield to 6.28  ppm (Figure 5.16) in contrast to the corresponding peak in 5-9a at 6.60 ppm (Figure 5.15). These data strongly indicate that the E-anti conformation of 5-9a and Z-syn conformation of 5-9b are preserved even in solution. 5.4.2 Optical Absorption Spectra of the N-confused tripyrrin 5-9a and 5-9b N-confused tripyrrins 5-9a and 5-9b are both red-violet in solution. The most notable feature of their UV-vis spectra is the strong maximum absorption around 477 nm (Figure 5.17, λmax (5-9a) = 477 nm, figure 5.18, λmax (5-9b) = 476 nm). In contrast to the  155  conventional α,α‟,α‟-tripyrrin (λmax = 545 nm),41 the maximum absorptions of 5-9a and 59b displayed significant hypsochromic shifts, suggesting the confused structure in a linear oligopyrrolic structure may lead to a blue-shift of the maximum absorption peak as compared to the conventional α,α‟-oligopyrrin.  Figure 5.17 Electronic absorption spectrum of 5-9a in CH2Cl2.  156  Figure 5.18 Electronic absorption spectrum of 5-9b in CH2Cl2. 5.5 Conclusion The synthesized N-confused oligopyrromethene derivatives support the hypothesis of the directing strategy: (a) the stability and reactivity of N-confused oligopyrroles are dependent on the peripheral and meso-substituents; (b) the oxidative amination induced by DDQ/TEA provides a novel ring closure strategy for cyclization of the conjugated oligopyrroles. In summary, we have succeeded in extending the π-conjugated network of Nconfused oligopyrrolic systems. The syntheses of novel N-confused oligopyrroles, prepared using an N-H-C oxidative amination procedure, are described. This oxidative CN bond formation cyclization strategy serves not only to introduce a new type of oligopyrrolic macrocycle but also to challenge the hitherto commonly accepted conception that conventional C-C bond formation ring closed oligopyrrolic macrocycles  157  are the only products that result from classic [1+1] pyrrole, aryl aldehyde oxidative condensations. The strategy developed here for confusing the pyrrole moiety as well as stabilizing the N-confused oligopyrrole framework can also serve as a guide for rational synthesis of unique π-conjugated systems. We remain optimistic that additional Nconfused oligopyrrolic macrocycles will be designed and synthesized by extending the conjugation of N-confused oligopyrroles.  158  Chapter 6 Conclusion  159  6.1 Summary and Conclusion MSA (methanesulfonic acid)-catalyzed condensation of aryl aldehydes with a variety of electron-withdrawing group (EWG)-substituted pyrroles to afford the corresponding meso-aryl N-confused diacyl dipyrromethanes was established. The directing effect of these EWGs for α-meso-β-linkage formation in N-confused dipyrromethanes was evaluated. The key for the successful transformation appears to depend upon the reactivities of the aldehyde and the electron-poor pyrrole substrates used. This novel one-pot synthetic approach for construction of α-meso-β-linkages between pyrroles is a substantial improvement over the classic multi-step synthesis (Chapter 2). Oxidation of an N-confused dipyrromethane to the corresponding conjugated dipyrrin system was explored by applying different oxidants. Instead of the assumed hydrogen-elimination reaction, an unexpected substitution reaction at the meso-position in the presence of DDQ was observed. An efficient DDQ-mediated benzylic C-H activation for hydroxylation, alkoxylation and heteroarylation of meso-aryl DPMs (three different forms) to the corresponding meso-modified dipyrromethanes (DPMs) was established. Mechanistic study shows the reaction proceeds through a highly-unstable protonated dipyrrin intermediate (Chapter 3). A route to asymmetric α-substituted meso-aryl N-confused dipyrrins has been discovered and investigated. N-confused (α-meso-β) dipyrrins, variants of the α,α‟dipyrrins, were studied with regards to their synthesis, stability and reactivity. The Nconfused dipyrrinodiol can be imbedded as a building block into oligopyrrole frameworks with retention of the Z-syn configuration, which provides a concise way to create higher N-confused oligopyrrolic pigments (Chapter 4).  160  Subsequently, in chapter 5, we report our synthesis of the conjugated N-confused oligopyrrolic macrocycle [12]tripyrrin (0.1.1), 5-3a, via an oxidative amination cyclization. As a macrocycle constructed purely of meso-aryl groups and pyrrole, Nconfused [12]tripyrrin (0.1.1) was synthesized using an unprecedented head-to-tail cyclization. The presence of steric meso-aryls and EWGs such as acetyl and benzoyl is required for the efficient formation of the corresponding fully conjugated N-confused oligopyrroles. In short, conversion of α,α‟-linear oligopyrroles to their corresponding Nconfused counterparts was achieved despite their long-believed instability. Our studies indicate that the N-confused oligopyrroles, as variants of the corresponding α,α‟oligopyrrolic structures, show interesting properties and serve as building blocks for fully conjugated macrocycles as well. It is possible that these new oligopyrrin analogues, like the conventional α,α‟-linear counterparts that preceded them, will provide a portal into a new and rich area of related research. 6.2 Future Work α,α‟-dipyrrins are an important class of bispyrrolic ligands that have received considerable attention over the past few years. In particular, luminescent 143 as well as porous materials based on dipyrrin derivatives have been reported.3 4 One of the most important allpications involves their borondifluoride complexes. For example, borondifluoride complexes of α,α‟-dipyrrins which utilized their intense fluorescence for the study of gas chromatographic processes. 144 ,  145  The generally high fluorescence  quantum yields, with tunable emission maxima wavelengths and good photochemical stability, allow these borondifluoride dipyrrinato complexes to be used in biological  161  staining and dye laser applications, making them the most commercially important examples of dipyrrinato complexes.  Figure 6.1 Proposed coordination modes of N-confused dipyrrin. As essentially one-half of an N-confused porphyrin, N-confused dipyrrins may serve as a versatile new class of ligands in the area of nonporphyrinic pyrrole-based compounds that merit further investigation. Resembling an α-substituted 1,9diamidodipyrrin ligand,33 the fully characterized α-substituted N-confused dipyrrin may serve as a novel bispyrrolic ligand for coordination chemistry by providing four atoms as chelating sites. Coordination modes such as NCOO, NNNC, NNOC or NNC beyond the traditional coordination chemistry can be developed by introducing the carbon atom as a coordination site (Figure 7.1) thus allowing applications in organometallic chemistry.  Scheme 6.1 Proposed synthetic route for EWG substituted oligopyrrole macrocycles. In the acid-catalyzed one-pot, two-step protocol for synthesis of porphyrin analogues, not only the aldehyde components, but also the pyrrole components, can be widely varied in this reaction. For example, 3,4-diaryl pyrroles and 3,4-dialkoxy pyrroles, 162  3,4-difluoropyrrole, and 3,4-bis(methylsulfanyl)pyrrole have all been condensed with aldehydes to yield the corresponding β-octaaryl, 146 and β-octaalkoxy porphyrins, 147 βoctafluoroporphyrins,  148  and  β-octakis(methylsulfanyl)porphyrins.  149  Systematic  mechanistic studies of pyrrole-aldehyde condensations are clearly an important goal in this field.  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Lett. 1997, 291.  171  Appendices  172  Experimental A.1 Instrumentation and General Materials All starting materials for syntheses were purchased from Sigma-Aldrich Fine Chemicals, Acros Chemicals or Fisher Scientific. Solvents were reagent grade and used without further purification unless otherwise stated. When necessary, chemicals were synthesized and purified by published procedures. The silica gel was 230-400 mesh (Silicycle). Activity III basic alumina was obtained by adding 6% water to Brockman activity I basic alumina, 60-325 mesh (Fisher). Electronic absorption spectra were recorded on a Varian Cary 50 scan UV-vis spectrophotometer using 1 cm quartz cells. Nuclear magnetic resonance (NMR) spectra were obtained on a Bruker WH-400, or a Bruker AMX-500. Chemical shifts are reported in parts per million (ppm) and are referenced to the residual solvent. Coupling constants are reported in hertz (Hz). Spectral splitting patterns are designated as s: singlet, d: doublet, t: triplet, q: quartet, m: multiplet and br: broad. High-resolution mass spectra were measured with a KRATOS Concept IIHQ Hybrid mass spectrometer. Elemental analyses were performed on a Carlo Erba Elemental analyzer. X-ray crystallographic analyses were made using a Rigabu/ADSC CCD.  173  A.2 Experimental Data for Chapter 2 Materials 2-Benzoyl pyrrole and N-(benzenesulfonyl)pyrrole were prepared from the corresponding acid chlorides and pyrrole, as described in the literature.1 Aryl aldehydes, 2-acetylpyrrole, 2-formylpyrrole and anhydrous DCM were used as purchased. A.2.1 General Procedure General Procedure I for the Condensation Reaction for Preparation of N-confused DPM 1.34 g (10 mmol) 1,4-benzenedicarboxaldehyde was dissolved in 4 mL anhydrous DCM and 1.42 g (15 mmol) MSA was added dropwise. The reaction was allowed to stir at room temperature for 5 minutes. To this solution, 1.64 g (15 mmol, 1.5 equivalents relative to the aldehyde) 2-acetylpyrrole was added, and the reaction was cooled to -10°C and allowed to stir for another 24 hours. Upon completion, the reaction mixture was quenched with 10% aqueous NaOH. The mixture was extracted with CH2Cl2 (3 × 100 mL), dried over anhydrous Na2SO4, and the solvent was removed under vacuum. The residue was separated by silica column chromatography (CH2Cl2: ethyl acetate 4:1). 0.30 g (2.7 mmol) recovered 2-acetylpyrrole was obtained. Collection of the N-confused DPM band afforded 2-20 0.84 g (2.52 mmol), a 41% yield based on the consumed 2acetylpyrrole (1.34 g, 12.3mmol). Products 2-23-2-26, 2-30-2-36 were made following the same procedure. General procedure II for preparation of poorly separating N-confused DPM products 1.06 g (10 mmol) benzaldehyde was dissolved in 4 mL anhydrous DCM and 1.42 g (15 mmol) MSA was added dropwise. The reaction mixture was allowed to stir at room temperature for 5 minutes, 1.64 g (15 mmol) 2-acetylpyrrole was added, and the mixture was stirred at room temperature for another 5 minutes. The reaction was cooled to -10 °C and stirred for another 24 hours. Upon completion, the reaction mixture was quenched with 100 mL10% aqueous NaOH. The mixture was extracted with CH2Cl2 (3 × 100 mL), dried over anhydrous Na2SO4, and the solvent was removed under vacuum. The residue  174  was chromatographed on silica gel (CH2Cl2: ethyl acetate = 4:1). 0.47g (4.31 mmol) unreacted 2-acetylpyrrole was recovered, and collection of the N-confused DPM band gave 1.05 g (3.4 mmol) (64% yield based on the consumption of 2-acetylpyrrole) DPM products, in which the N-confused DPM to β,β‟-DPM ratio is 6.7:1 based on the 1H NMR analysis. The N-confused DPM yield is calculated as 54% by integration of the 1H NMR of the total DPM products based on the consumption of pyrrole substrate (1.17 g, 10.65mmol). Due to almost identical Rf values for the α,β and β,β‟-DPM products, complete separation was difficult. Further careful chromatography on alumina (CH2Cl2: ethyl acetate = 4:1) twice was necessary. Collection of the purified product afforded 0.40 g 2-16 (24% yield based on the consumption of 2-acetylpyrrole). Products 2-16-2-18, 221 and 2-17-2-19 were made following this procedure. General Procedure III for Preparation of β,β’-DPM 2-37 and 2-38 0.47g (5 mmol) BF3·OEt2 was added dropwise into a solution of 0.53 g (5 mmol) 4-cyanobenzaldehyde in anhydrous CH3CN (20 mL). After 5 minutes, 1.23g (7.5 mmol) 2-(trifluoroacetyl)pyrrole was added, and the mixture was stirred at room temperature for 48 hours. Upon completion, the reaction mixture was quenched with 10% aqueous NaOH. The mixture was extracted with CH2Cl2 (3 × 100 mL), dried over anhydrous Na2SO4, and the solvent was removed under vacuum. The residue was purified by chromatography (CH2Cl2: ethyl acetate = 95:5). Collection of the DPM band gave 1.17g (2.18 mmol) β,β‟DPM product, yield 54%. Products 2-38 and 2-39 were made following this procedure. General Procedure IV for Preparation of α,α’-DPM 2-39 and 2-40 3.75 mmol BF3·OEt2 was added to a solution of 0.31g (2.5 mmol) 4fluorobenzaldehyde in 10 mL anhydrous DCM. The reaction mixture was allowed to stir at room temperature for 5 minutes, and 0.77 g (3.75 mmol) N-(benzenesulfonyl)pyrrole was added. The reaction mixture was stirred at room temperature for 96 hours. Upon completion, the mixture was treated with 10% aqueous NaOH. The organic layer was removed and dried over Na2SO4 and the solvent was evaporated under vacuum. The residue was chromatographed on silica gel (CH2Cl2: hexanes = 4:1). Collection of the  175  DPM band gave 0.41g (0.78 mmol) 2-39, yield 42%. Products 2-39 and 2-40 were made following this procedure. A.2.2 1H and 13C NMR Data for DPM Products 2-16 1-(4-((5-acetyl-1H-pyrrol-2-yl)(phenyl)methyl)-1H-pyrrol-2-yl)ethanone According to general procedure II, 1.06 g DPM (yield 64%) was obtained from reacted 2-acetylpyrrole (1.16 g). N-confused DPM yield 54% was calculated by integration of the 1H NMR of the total DPM products (N-confused DPM: β,β‟-DPM = 6.7 : 1) based on consumption of pyrrole substrate. 0.56 g 2-16 was isolated (yield 34%) after chromatography on alumina using 3 columns. Transparent oil after evaporation, treatment with CH2Cl2/hexaness produces a white powder. mp 170-173°C; 1H NMR (300 MHz, CDCl3) δ 2.37 (s, 3H), 2.39 (s, 3H), 5.38 (s, 1H), 5.99 (s, 1H), 6.70 (s, 1H); 6.74 (s, 1H), 6.86 (s, 1H), 7.20-7.33 (m, 5H), 9.24 (br, 1H), 9.65 (br, 1H); 13C NMR (100 MHz, CDCl3) δ 25.07, 25.40, 43.22, 109.87, 116.21, 117.55, 123.62, 126.80, 127.08, 128.27, 128.73, 131.50, 132.31, 141.98, 187.53, 188.09; HRMS (EI) Calcd for C19H18N2O2: 307.1406. Found: 307.1400; Anal. Calcd for C19H18N2O2: C, 74.49; H, 5.92; N, 9.14. Found C, 74.78; H, 6.34; N, 8.68.  2-17  1-(4-((5-acetyl-1H-pyrrol-2-yl)(4-methoxyphenyl)methyl)-1H-pyrrol-2-  yl)ethanone According to general procedure II, 0.71 g (yield 62%) DPM was obtained from reacted 2-acetylpyrrole 0.90 g. N-confused DPM yield 48% was calculated by integration of the 1H NMR of the total DPM products (N-confused DPM: β,β‟-DPM = 3.35: 1) based on consumption of pyrrole substrate. 0.34 g (yield 30%) 2-17 was isolated after chromatography on alumina. A transparent oil after evaporation, treatment with CH2Cl2/Hexanes produces an amorphous powder. 1H NMR (300 MHz, CDCl3) δ 2.38 (s, 3H), 2.39 (s, 3H), 3.81 (s, 3H), 5.31 (s, 1H), 5.98 (s, 1H), 6.68 (s, 1H), 6.72 (s, 1H), 6.85 (d, 2H, J = 9.0 Hz), 7.10 (d, 2H, J = 9.0 Hz), 8.94 (br, 1H), 9.23 (br, 1H); 13C NMR (100 MHz, CDCl3) δ 25.06, 25.39, 42.34, 55.23, 109.68, 114.04, 116.31, 117.65, 123.75, 127.17, 129.25, 131.39, 132.22, 134.14, 142.55, 158.51, 187.53, 188.15; HRMS (EI)  176  Calcd for C20H20N2O3: 336.1474. Found: 336.1474. Anal. Calcd for C20H20N2O3: C, 71.41; H, 5.99; N, 8.33. Found C, 71.08; H, 6.18; N, 7.95.  2-18  1-(4-((5-acetyl-1H-pyrrol-2-yl)(4-fluorophenyl)methyl)-1H-pyrrol-2-  yl)ethanone According to general procedure II, 1.22 g DPM (yield 63%) was obtained from 1.32 g reacted 2-acetylpyrrole. N-confused DPM yield 52% was calculated by integration of the 1H NMR of the total DPM products (N-confused DPM: β,β‟-DPM = 3.35: 1) based on consumption of pyrrole substrate. 0.31 g (yield 32%) 2-18 was isolated after chromatography on alumina. A transparent oil after evaporation, treatment with CH2Cl2/MeOH produces a white powder. mp 166-169°C; 1H NMR (300 MHz, CDCl3) δ 2.37 (s, 3H), 2.39 (s, 3H), 5.37 (s, 1H), 5.96 (s, 1H), 6.67 (s, 1H), 6.72 (s, 1H), 6.86 (s, 1H), 7.00-7.04 (m, 2H), 7.15-7.20 (m, 2H), 9.19 (br, 1H), 9.55 (br, 1H);  13  C NMR (100  MHz, CDCl3) δ 25.11, 25.43, 42.48, 109.89, 115.47, 115.83, 117.44, 123.21, 126.65, 129.74, 129.85, 131.63, 132.48, 137.99, 141.50, 160.35, 163.61, 187.57, 188.01; HRMS m/z (EI).Calcd for C19H17FN2O2: 324.1274. Found: 324.1268; Anal. Calcd for C19H17FN2O2 : C, 70.36; H, 5.28; N, 8.64. Found C, 70.61; H, 5.58; N, 8.17.  2-19  1-(4-((5-acetyl-1H-pyrrol-2-yl)(perfluorophenyl)methyl)-1H-pyrrol-2-  yl)ethanone According to general procedure II, 1.45 g DPM (yield 60%) obtained from 1.34 g reacted 2-acetylpyrrole. After recrystallization (dichloromethane/hexanes 1:2), 1.16 g purified 2-19 was isolated, yield 48%. mp 125-128°C; 1H NMR (300 MHz, CDCl3) δ 2.40 (s, 6H), 5.80 (s, 1H), 6.06 (s, 1H), 6.80 (s, 1H), 6.87 (s, 1H), 6.96 (s, 1H), 9.72 (br, 1H), 9.98 (br, 1H);  13  C NMR (100 MHz, CDCl3) δ 25.14, 25.43, 32.27, 109.73, 115.61,  117.51, 122.44, 123.34, 131.83, 132.57, 137.65, 187.81, 188.09; HRMS (EI) Calcd for C19H13F5N2O2: 394.0740. Found: 394.0741. Anal. Calcd for C19H13F5N2O2: C, 57.58; H, 3.31; N, 7.07. Found C, 57.96; H, 2.92; N, 7.03.  177  2-20 4-((5-acetyl-1H-pyrrol-2-yl)(5-acetyl-1H-pyrrol-3-yl)methyl)benzaldehyde According to general procedure I, 0.83g 2-20 was obtained from 1.34g reacted 2acetylpyrrole, isolated yield 41%. 1H NMR (300 MHz, CDCl3) δ 2.35 (s, 6H), 2.39 (s, 3H), 5.50 (s, 1H), 5.97 (s, 1H), 6.67 (s, 1H); 6.76 (s, 1H), 6.86 (t, 1H), 7.37-7.40 (d, 2H, J = 9.0 Hz), 7.80-7.84 (d, 2H J = 9.0 Hz), 9.77 (br, 1H), 9.99 (s, 1H), 10.06 (br, 1H); 13C NMR (100 MHz, CDCl3) δ 25.13, 25.42, 43.28, 110.07, 116.19, 117.77, 123.79, 125.75, 128.99, 130.10, 131.74, 132.40, 135.26, 140.97, 149.07, 187.87, 188.21, 191.70; HRMS (EI) Calcd for C20H18N2O3: 334.1317. Found: 334.1319; Anal. Calcd for C20H18N2O3: C, 71.84; H, 5.43; N, 8.38. Found C, 71.83; H, 5.61; N, 8.14.  2-21 4-((5-acetyl-1H-pyrrol-2-yl)(5-acetyl-1H-pyrrol-3-yl)methyl)benzonitrile According to general procedure II, 1.15 g DPM (yield 62%) was obtained from 1.23 g reacted 2-acetylpyrrole. N-confused DPM yield 50% was calculated by integration of the 1H NMR of the total DPM products (N-confused DPM: β,β‟-DPM = 4.26 : 1) based on consumption of pyrrole substrate. 0.52 g of 2-21 was isolated (yield 28%) after chromatography on alumina. A transparent oil after evaporation, treatment with CH2Cl2/hexanes produces an amorphous powder. 1H NMR (300 MHz, CDCl3) δ 2.38 (s, 6H), 2.40 (s, 3H), 5.45 (s, 1H), 5.95 (d, 1H, J = 3.0 Hz), 6.65 (s, 1H); 6.73 (s, 1H), 6.876.88 (d, 1H, J = 3.0 Hz), 7.31-7.34 (d, 2H, J = 6.0 Hz), 7.62-7.64 (d, 2H, J = 6.0 Hz), 9.31 (br, 1H), 9.59 (br, 1H); 13C NMR (100 MHz, CDCl3) δ 25.16, 25.46, 43.22, 110.16, 111.12, 115.67,117.49, 118.57,123.25, 125.32, 129.10, 131.89, 132.56, 140.07, 147.45, 187.78, 188.03; HRMS (EI).Calcd for C20H17N3O2: 331.1321. Found: 331.1310.  2-22  1-(4-((5-acetyl-1H-pyrrol-2-yl)(2-chloro-6-fluorophenyl)methyl)-1H-pyrrol-2-  yl)ethanone According to general procedure II, 1.07 g DPM (yield 58%) was obtained from 1.06 g reacted 2-acetylpyrrole. After recrystallization (dichloromethane/hexanes 1:2), 0.78 g purified 2-22 was isolated, yield 45%. mp 118-120°C; 1H NMR (300 MHz, CDCl3) δ 2.37 (s, 6H), 2.38 (s, 3H), 6.02-6.05 (m, 2H), 6.85 (m, 2H), 6.97 (m, 2H), 7.21 (m, 2H), 9.59 (br, 1H), 10.37 (br, 1H); 13C NMR (100 MHz, CDCl3) δ 25.04, 25.36, 36.54, 109.45,  178  115.16, 115.46, 116.40, 117.56, 117.60, 123.25, 124.02, 125.75, 125.79, 128.92, 129.05, 131.35, 132.15, 134.49, 139.68, 159.73, 163.05, 187.45, 188.17; HRMS (EI) Calcd for C19H16ClFN2O2: 358.0884. Found: 358.0882.  2-23  1-(4-((5-acetyl-1H-pyrrol-2-yl)(2,6-dichlorophenyl)methyl)-1H-pyrrol-2-  yl)ethanone According to general procedure I, 0.98 g 2-23 was obtained from 1.29 g reacted 2-acetylpyrrole, isolated yield 44%. A pale yellow oil after evaporation, treatment with CH2Cl2/hexanes produces a crystalline solid. mp decomposed above 200°C; 1H NMR (300 MHz, CDCl3) δ 2.40 (s, 6H), 2.41 (s, 3H), 6.04 (s, 1H), 6.33 (s, 1H), 6.88 (s, 1H), 6.91 (s, 1H), 7.01 (s, 1H), 7.17-7.21 (m, 1H), 7.34-7.36 (m, 2H), 9.10 (br, 1H), 9.49 (br, 1H); 13C NMR (100 MHz, CDCl3) δ 25.33, 25.68, 39.46, 109.87, 116.63, 116.71, 117.93, 122.31, 123.93 124.12, 129.23, 131.35, 132.43, 135.94, 137.03, 139.47, 187.59, 188.22; HRMS (EI) Calcd for C19H14Cl2N2O2: 374.0403. Found: 374.0415; Anal. Calcd for C19H16Cl2N2O2 : C, 60.81; H, 4.30; N, 7.47. Found C, 60.79; H, 4.34; N, 7.37.  2-24a 1-(4-((5-acetyl-1H-pyrrol-2-yl)(mesityl)methyl)-1H-pyrrol-2-yl)ethanone 1  H NMR (300 MHz, CDCl3): δ (ppm) 2.08 (s, 6H), 2.28 (s, 3H), 2.38 (s, 6H), 5.77  (s, 1H), 6.04-6.05 (m, 1H), 6.75 (s, 1H), 6.78 (s, 6H), 6.86 (s, 3H), 9.06 (br, 1H), 9.87 (br, 1H);  13  C NMR (100 MHz, CDCl3): δ (ppm) 20.98, 21.05, 25.26, 25.64, 36.77, 37.92,  109.51, 116.70, 117.95, 123.97, 124.30, 130.59, 131.23, 132.51, 134.76, 136.93, 137.10, 142.25, 187.40, 188.24; HRMS (EI) Calcd for C22H24O2N2: 348.1837. Found: 348.1835.  2-24b 1,1'-(4,4'-(mesitylmethylene)bis(1H-pyrrole-4,2-diyl))diethanone 1  H NMR (300 MHz, CDCl3): δ (ppm) 2.08 (s, 6H), 2.31 (s, 3H), 2.41 (s, 6H), 5.73  (s, 1H), 6.78 (m, 2H), 6.83 (m, 2H), 6.89 (s, 2H), 10.04 (br, 2H);  13  C NMR (100 MHz,  CDCl3): δ (ppm) 20.71, 21.35, 25.39, 36.48, 117.06, 124.23, 127.78, 131.83, 135.72, 136.68, 137.09, 188.30; HRMS (EI) Calcd for C22H24O2N2 348.1832. Found: 348.1834.  179  2-25 1-(4-((5-acetyl-1H-pyrrol-2-yl)(pyridin-2-yl)methyl)-1H-pyrrol-2-yl)ethanone According to general procedure I, 0.62 g 2-25 was isolated, a 38% yield based on 1.16 g reacted pyrrole. A transparent oil after evaporation, treatment with CH2Cl2/hexanes produces an amorphous powder. 1H NMR (300 MHz, CDCl3) δ 2.34 (s, 6H), 2.38 (s, 3H), 5.46 (s, 1H), 6.07 (d, 1H, J = 3.0 Hz), 6.73 (s, 1H), 6.73 (s, 1H), 6.81 (s, 1H), 6.83-6.84 (d, 1H, J = 3.0 Hz), 7.16-7.19 (m, 1H), 7.23-7.25 (m, 1H), 7.62-7.66 (m, 1H), 8.60-8.62 (d, 1H J = 6.0 Hz), 9.99 (br, 1H), 10.17 (br, 1H);  13  C NMR (100 MHz,  CDCl3) δ 25.38, 25.68, 43.44, 110.39, 111.36, 115.91, 117.73, 118.80, 115.91, 117.73, 118.80, 123.49, 125.56, 129.34, 132.80, 140.30, 147.68, 188.02, 188.26; HRMS (EI) Calcd for C18H17N3O2: 307.1320. Found: 307.1334.  2-26 1-(4-((5-acetyl-1H-pyrrol-2-yl)(pyridin-4-yl)methyl)-1H-pyrrol-2-yl)ethanone According to general procedure I, 0.67 g 2-16 was isolated, a 32% yield based on 1.42 g reacted pyrrole substrate. A transparent oil after evaporation, treatment with CH2Cl2/hexanes produces an amorphous powder. 1H NMR (300 MHz, CDCl3) δ 2.37 (s, 3H), 2.40 (s, 3H), 5.39 (s, 1H), 5.98 (d, 1H, J = 3.0 Hz), 6.66 (s, 1H), 6.76 (s, 1H), 6.87 (d, 1H, J = 3.0 Hz), 7.13-7.15 (d, 2H, J = 6.0 Hz), 8.55-8.57 (d, 2H, J = 6.0 Hz), 9.49 (br, 1H), 9.78 (br, 1H);  13  C NMR (100 MHz, CDCl3) δ 25.16, 25.46, 42.16, 110.18, 115.87,  117.63, 123.43, 123.55, 124.87, 131.89, 132.59, 139.82, 149.32, 149.85, 151.29, 187.86, 188.11; HRMS (EI) Calcd for C18H17N3O2: 307.1320. Found: 307.1319.  2-27 4,5'-((4-methoxyphenyl)methylene)bis(1H-pyrrole-2-carbaldehyde) Due to the polymerization of pyrrole-2-aldehyde under the strongly acidic reaction conditions the reaction time was reduced to 8 hours at room temperature. 0.61 g DPM (yield 44%) was obtained from 0.87 g reacted pyrrole-2-aldehyde. N-confused DPM 28% yield was calculated by integration of the 1H NMR of the total DPM products (N-confused DPM: β,β‟-DPM = 1.78 : 1) based on consumption of pyrrole substrate. 0.26 g 2-27 was isolated after chromatography on alumina, yield 18%. A transparent oil after evaporation, treatment with CH2Cl2/hexanes produces an amorphous powder. 1H NMR (300 MHz, CDCl3) δ 3.81 (s, 3H), 5.38 (s, 1H), 6.06-6.07 (d, 1H, J = 3.0 Hz), 6.77-6.78  180  (d, 1H, J = 3.0 Hz), 6.85 (m, 1H), 6.86-6.88 (d, 2H, J = 6.0 Hz), 6.91-6.93 (m, 1H), 7.127.14 (d, 2H, J = 6.0 Hz), 9.29 (b, 1H), 9.40 (s, 1H), 9.43 (s, 1H), 9.59 (br, 1H), 9.79 (br, 1H);  13  C NMR (100 MHz, CDCl3) δ 42.35, 55.30, 110.57, 114.26, 120.43, 122.17,  125.17, 127.67, 129.30, 132.21, 132.95, 133.47, 143.96, 158.77, 178.64, 179.36; HRMS (EI) Calcd for C18H16N2O3: 308.1160. Found: 308.1160.  2-28 4,5'-(phenylmethylene)bis(1H-pyrrole-2-carbaldehyde) 2-28 was synthesized following the same procedure as 2-27. 0.56 g DPM (yield 51%) was obtained from 1.0 g reacted pyrrole-2-aldehyde. N-confused DPM 36% yield was calculated by integration of the 1H NMR of the total DPM products (N-confused DPM: β,β‟-DPM = 2.33 : 1) based on consumption of pyrrole substrate. 0.28 g 2-28 was isolated after chromatography on alumina, yield 21%. A transparent oil after evaporation, treatment with CH2Cl2/hexanes produces an amorphous powder. 1H NMR (300 MHz, CDCl3) δ 5.42 (s, 1H), 6.05-6.07 (m, 1H), 6.77 (s, 1H), 6.85 (s, 1H), 6.90-6.92 (m, 1H), 7.19-7.22 (m, 2H), 7.29-7.35 (m, 3H), 9.37 (s, 1H), 9.39 (s, 1H), 9.45 (br, 1H), 9.95 (br, 1H);  13  C NMR (100 MHz, CDCl3) δ 43.31, 110.87, 120.71, 122.38, 125.50, 127.44,  127.49, 128.44, 129.02, 132.41, 133.09, 141.56, 143.82; HRMS (EI) Calcd for C17H14N2O2: 278.1142. Found: 278.1146.  2-29 4,5'-((4-fluorophenyl)methylene)bis(1H-pyrrole-2-carbaldehyde) 2-29 was synthesized following the same procedure as 2-27. N-confused DPM 28% yield was calculated by integration of the 1H NMR analysis of the total DPM products (N-confused DPM: β,β‟-DPM = 1.78 : 1) based on consumption of pyrrole substrate. 0.26 g 2-29 was isolated after chromatography on alumina, yield 18%. A transparent oil after evaporation, treatment with CH2Cl2/hexanes produces an amorphous powder. 1H NMR (300 MHz, CDCl3) δ 5.41 (s, 1H), 6.05-6.06 (m, 1H), 6.77 (s, 1H), 6.84 (s, 1H), 6.91-6.93 (m, 1H), 7.01-7.06 (m, 2H), 7.16-7.22 (m, 2H), 9.16 (b, 1H), 9.42 (s, 1H), 9.46 (s, 1H), 9.52 (br, 1H);  13  C NMR (100 MHz, CDCl3) δ 42.63, 110.93, 115.94,  116.08, 120.11, 120.54, 122.21, 124.98, 127.28, 130.03, 130.08, 132.09, 133.31, 137.35, 137.37, 143.23, 161.36, 162.99, 178.98, 179.55; HRMS (EI) Calcd for C17H13FN2O2: 296.1011. Found 296.1015.  181  2-30  (4-((5-benzoyl-1H-pyrrol-2-yl)(4-fluorophenyl)methyl)-1H-pyrrol-2-  yl)(phenyl)methanone According to general procedure I, 0.24 g 2-30 was obtained from 0.65 g reacted 2-benzoyl pyrrole (0.77 g, 4.5mmol added), isolated yield 28%. A transparent oil after evaporation, treatment with CH2Cl2/hexanes produces a pale yellow powder. mp 155157°C; 1H NMR (300 MHz, CDCl3) δ 5.55 (s, 3H), 6.03 (s, 1H), 6.70 (s, 1H), 6.84 (s, 1H), 6.95 (m, 2H), 7.19-7.21 (m, 2H), 7.39-7.55 (m, 5H), 7.80-7.82 (d, 2H, J = 6.0 Hz), 7.87-7.89 (d, 2H, J = 6.0 Hz), 10.77 (br, 1H), 10.83 (br, 1H);  13  C NMR (100 MHz,  CDCl3) δ42.60, 110.33, 115.39, 115.61, 118.79, 120.63,124.44, 127.15 128.24, 128.33, 128.92, 129.84, 129.91, 130.62, 131.26, 137.73, 138.00, 138.33, 142.83, 160.55, 162.99, 184.59, 184.82; HRMS (EI) Calcd for C29H21FN2O2: 448.1587. Found: 448.1593.  2-31  (4-((5-benzoyl-1H-pyrrol-2-yl)(perfluorophenyl)methyl)-1H-pyrrol-2-  yl)(phenyl)methanone According to general procedure I, 0.32 g 2-31 was obtained from 0.57 g reacted 2-benzoyl pyrrole (0.77 g, 4.5 mmol added), isolated yield 36%. A transparent oil after evaporation, treatment with CH2Cl2/hexanes produces a crystalline solid. mp decomposed above 200°C; 1H NMR (300 MHz, CDCl3) δ 5.88 (s, 3H), 6.13-6.14 (d, 1H, J = 3.0 Hz), 6.79 (s, 1H), 6.84 (d, 1H, J = 3.0 Hz), 7.08 (s, 1H), 7.45-7.50 (m, 4H), 7.54-7.59 (m, 2H), 7.84-7.88 (m, 4H), 10.03 (br, 1H), 10.23 (br, 1H); 13C NMR (100 MHz, CDCl3) δ 32.48, 110.11, 118.28, 120.35, 122.92, 124.17, 128.30, 128.44, 128.92, 128.93, 130.86, 131.38, 131.91, 132.16, 137.79, 138.05, 138.31, 184.66, 184.81; HRMS (EI) Calcd for C29H17F5N2O2; 520.1210. Found: 520.1206. 2-32  (4-((5-benzoyl-1H-pyrrol-2-yl)(2,6-dichlorophenyl)methyl)-1H-pyrrol-2-  yl)(phenyl)methanone Following general procedure I, 2-32 was isolated in 32% yield. A transparent oil after evaporation, treatment with CH2Cl2/hexanes produces a white solid. 1H NMR (300 MHz, CD3CN) δ 6.13-6.14 (s, 1H), 6.42 (s, 1H), 6.83-6.86 (m, 1H), 6.97 (s, 1H), 7.147.19 (m, 2H), 7.33-7.36 (m, 2H), 7.44-7.57(m, 6H), 7.87-7.91 (m, 4H), 9.55 (br, 1H),  182  10.10 (br, 1H);  13  C NMR (100 MHz, CDCl3) δ39.43, 110.22, 19.15, 120.53, 122.57,  124.76, 128.21, 128.37, 128.86, 129.01, 130.17, 131.07, 131.60, 131.98, 135.75, 136.75, 138.03, 138.42, 140.02, 184.24; HRMS (EI) Calcd C29H20Cl2N2O2: 500.0872. Found: 500.0874.  2-33a  (4-((5-(perfluorobenzoyl)-1H-pyrrol-2-yl)(perfluorophenyl)methyl)-1H-  pyrrol-2-yl)(perfluorophenyl)methanone Following general procedure I, 2-33a was isolated in 10% yield. A transparent oil after evaporation, treatment with CH2Cl2/hexanes produces an amorphous powder. 1H NMR (300 MHz, CDCl3) δ 5.83 (s, 3H), 6.16 (s, 1H), 6.64 (s, 1H), 6.68 (s, 1H), 7.19 (s, 1H), 10.47 (br, 1H), 10.56 (br,1H); 13C NMR (100 MHz, CDCl3) δ 32.29, 110.81, 113.36, 114.87, 120.05, 122.84, 123.69, 127.07, 131.39, 131.87, 136.43-145.17 multiple broad peaks due to F/C coupling, 172.40, 173.03; HRMS (EI) Calcd for C29H7F15N2O2: 700.0268. Found: 700.0267.  2-33b  4,4'-((perfluorophenyl)methylene)bis(1H-pyrrole-4,2-  diyl)bis((perfluorophenyl)methanone) Following general procedure I, 2-33b was isolated in 31% yield. A transparent oil after evaporation, treatment with CH2Cl2/hexanes produces a crystalline solid. mp 126128°C; 1H NMR (300 MHz, CDCl3) δ 5.66 (s, 1H), 6.62 (s, 2H), 7.15 (s, 2H), 10.80 (br, 2H);  13  C NMR (100 MHz, CDCl3) δ 30.98, 120.14, 126.56, 126.87, 131.62, 135-147  multiple broad peaks due to C/F coupling,172.91; HRMS (EI) Calcd for C29H7F15N2O2: 700.0268. Found: 700.0265.  2-34  (4-((5-(2,6-dichlorobenzoyl)-1H-pyrrol-2-yl)(perfluorophenyl)methyl)-1H-  pyrrol-2-yl)(2,6-dichlorophenyl)methanone Isolated yield 51%. 1H NMR (300 MHz, CDCl3): δ (ppm) 5.77 (s, 1H), 6.02 (m, 1H), 6.45-48 (m, 2H), 7.12 (s, 1H), 7.34-7.40 (m, 6H), 9.93 (br, 1H), 10.08 (br, 1H); 13C NMR (100 MHz, CDCl3): δ (ppm) 32.39, 110.97, 119.09, 121.19, 123.19, 125.65, 128.04, 128.19, 130.65, 130.89, 130.98, 131.50, 132.34, 132.39, 136.76, 137.08, 140.06, 180.68, 181.24; HRMS (EI) Calcd for C29H13Cl4F5N2O2: 655.9651. Found: 655.9629.  183  2-35  (4-((5-(2,6-dichlorobenzoyl)-1H-pyrrol-2-yl)(4-fluorophenyl)methyl)-1H-  pyrrol-2-yl)(2,6-dichlorophenyl)methanone According to general procedure I, 0.36 g 2-35 was obtained from 0.98 g reacted 2-(2,6-dichlorobenzoyl)pyrrole (1.08 g, 4.5 mmol added), isolated yield 37%. 1H NMR (300 MHz, CDCl3): δ (ppm) 5.44 (s, 1H), 5.95-5.97 (m, 1H), 6.39 (s, 1H), 6.39 (s, 1H), 6.48 (s, 1H), 6.89-6.95 (m, 3H), 7.31-7.35 (m, 4H), 10.16 (br, 1H), 10.63 (br, 1H);  13  C  NMR (100 MHz, CDCl3): δ (ppm) 41.77, 110.83, 115.21, 120.06, 121.52, 121.57, 127.35, 127.39, 128.60, 128.64, 129.96, 130.48, 131.23, 132.31, 132.38, 137.16, 137.29, 144.62, 160.49, 162.93, 180.36, 181.20; HRMS (EI) Calcd for C29H17Cl4FN2O2: 585.99987. Found: 585.99995.  2-36a  (4-((5-(2,6-dichlorobenzoyl)-1H-pyrrol-2-yl)(2,6-dichlorophenyl)methyl)-1H-  pyrrol-2-yl)(2,6-dichlorophenyl)methanone According to general procedure I, 0.56 g 2-36a was obtained from 0.87 g reacted 2-(2,6-dichlorobenzoyl)pyrrole (1.08 g, 4.5 mmol added), isolated yield 45%. 1H NMR (300 MHz, CDCl3): δ (ppm) 6.11-6.13 (m, 1H), 6.41 (s, 1H), 6.83-6.84 (m, 1H), 6.96 (s, 1H), 7.17-7.25 (m, 3H), 7.35-7.91 (m, 6H), 9.35 (br, 1H), 9.67 (br, 1H);  13  C NMR (100  MHz, CDCl3): δ (ppm) 39.39, 110.89, 120.02, 121.19, 122.85, 126.13, 127.97, 129.30, 130.32, 130.72, 131.16, 132.47, 136.18, 137.03, 137.40, 141.73, 180.13, 181.01. HRMS (EI) Calcd for C29H16Cl6N2O2: 633.9298. Found 633.9296.  2-36b  (4,4'-((2,6-dichlorophenyl)methylene)bis(1H-pyrrole-4,2-diyl))bis((2,6-  dichlorophenyl)methanone) According to general procedure I, 0.10 g 2-36b was obtained from 0.87 g reacted 2-(2,6-dichlorobenzoyl)pyrrole (1.08 g, 4.5 mmol added), isolated yield 8%. 1H NMR (300 MHz, (CD3)2CO): δ (ppm) 6.14 (s, 1H), 6.39 (s, 2H), 6.98 (s, 2H), 7.20 (m, 31H), 7.33-7.44 (m, 6H), 10.72 (br, 2H); 13C NMR (100 MHz, CDCl3): δ (ppm) 30.36, 117.55, 126.53, 128.82, 129.49, 131.13, 131.65, 132.23, 135.87, 138.07, 139.08, 180.31, 195.05; HRMS (EI) Calcd for C29H16Cl6N2O2: 633.9298. Found 633.9295.  184  2-37  1,1'-(4,4'-((perfluorophenyl)methylene)bis(1H-pyrrole-4,2-diyl))bis(2,2,2-  trifluoroethanone) According to general procedure III, 1.17 g 2-37 was obtained from (1.23 g, 7.5 mmol) 2-(trifluoroacetyl)pyrrole, yield 58%. A transparent oil after evaporation, treatment with CH2Cl2/hexanes produces a white solid. mp 166-168°C; 1H NMR (300 MHz, CD3CN) δ 5.77 (s, 1H), 7.08 (s, 2H), 7.22 (s, 2H), 10.50 (br, 2H); 13C NMR (100 MHz, CD3CN) δ 31.80, 112.30, 116.13, 118.37, 119.95, 121.02, 123.77, 126.45, 127.94, 129.66, 137.43-147.63 multiple broad peaks due to C/F coupling, 169.64-170.59 multiple peaks belong to the carbonyl group; HRMS (EI) Calcd C19H7F11N2O2: 540.0332. Found: 540.0323. Anal. Calcd for C19H7F11N2O2: C, 45.26; N, 5.56; H, 1.40. Found: C, 45.37; N, 5.58; H, 1.45.  2-38 4-(bis(5-(2,2,2-trifluoroacetyl)-1H-pyrrol-3-yl)methyl)benzonitrile Following general procedure III, 0.89 g 2-38 was obtained from (1.23 g, 7.5 mmol) 2-(trifluoroacetyl)pyrrole, yield 54%. A transparent oil after evaporation, treatment with CH2Cl2/hexanes produces a white solid. mp decomposed over 200°C; 1H NMR (300 MHz, CD3CN) δ 5.46 (s, 1H), 7.00 (d, 2H, J = 3.0 Hz), 7.12 (d, 2H, J = 3.0 Hz), 7.42-7.45 (d, 2H, J = 6.0 Hz) 7.66-7.78 (d, 2H, J = 6.0 Hz), 10.51 (br, 2H);  13  C  NMR (100 MHz, CD3CN) δ 42.49, 111.28, 116.14, 118.38, 119.76, 119.97, 126.53, 129.80, 130.19, 130.78, 133.61, 150.73, 170.05, 170.52 multiple peaks belong to the carbonyl group; HRMS (EI) Calcd for C20H11F6N3O2: 439.0756. Found: 439.0744; Anal. Calcd for C20H11F6N3O2: C, 54.68; H, 2.52; N, 9.57; Found C, 54.89; H, 2.41; N, 9.50.  2-39 4,5'-((4-fluorophenyl)methylene)bis(1-(phenylsulfonyl)-1H-pyrrole) Following general procedure IV, 0.41g 2-39 was obtained from (0.77 g, 3.75 mmol) N-(benzenesulfonyl)pyrrole, yield 42%. mp 175-177°C; 1H NMR (300 MHz, CDCl3) δ 5.44 (s, 2H), 6.03 (d, 2H, J = 3.0 Hz), 6.59 (s, 1H), 6.65-6.68 (m, 4H), 7.297.33 (m, 6H), 7.45-7.51 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 39.88, 110.92, 114.87, 115.08, 115.74, 123.05, 126.87, 128.89, 130.05, 133.18, 135.35, 136.31, 136.35, 138.64, 160.42, 162.86; HRMS (EI) Calcd for C27H21FN2O4S2: 520.0927. Found: 520.0924.  185  2-40 4,5'-((4-nitrophenyl)methylene)bis(1-(phenylsulfonyl)-1H-pyrrole) Following general procedure IV, 0.46 g 2-40 was obtained from (0.77 g, 3.75 mmol) N-(benzenesulfonyl)pyrrole, yield 45%. mp 169-170°C; 1H NMR (300 MHz, CDCl3) δ 5.46 (s, 2H), 6.06-6.07 (m, 2H), 6.71 (s, 1H), 6.85-6.87 (d, 2H, J = 6.0 Hz), 7.28-7.32 (m, 4H), 7.36 (s, 2H), 7.46-7.52 (m, 6H), 7.79-7.81 (d, 2H, J = 3.0 Hz);  13  C  NMR (100 MHz, CDCl3) δ 40.46, 111.09, 116.32, 123.31, 123.52, 126.83, 128.98, 129.31, 133.46, 133.70, 138.55, 148.09; HRMS (EI) Calcd for C27H21N3O6S2: 547.0871. Found: 547.0869; Anal. Calcd for C27H21N3O6S2: C, 59.22; H, 3.87; N, 7.67. Found C, 59.29; H, 3.94; N, 7.48.  186  A.2.3 Crystal Data for 2-23, 2-28 ORTEP Plot of Crystal Structure of 2-23: C19H16N2O2Cl2, Mw = 375.24, triclinic, space group P-1; dimensions: a = 12.3256(12) Å, b = 12.7825(13) Å, c = 13.4665(13) Å, α = 66.884(5)º, β = 62.843(5)º, γ = 79.514(6)º, V = 1736.2(3) Å3; Z = 4; 34710 reflections measured at 100 K; independent reflections: Unique: 8411 (Rint = 0.028); R1 = 0.056, wR2 = 0.117, S = 1.04; highest residual electron density 0.56 e-/Å3 (all data R1 = 0.041; wR2 = 0.106).  187  ORTEP Plot of Crystal Structure of 2-38: C27H21N2O4FS2, Mw = 520.58, orthorhombic, space group Pca21; dimensions: a = 16.3617(10) Å, b = 7.6051(5) Å, c = 19.7607(11) Å, α = 90.0º, β= 90.0º, γ = 90.0º, V = 2458.9(3) Å3; Z = 4; 23981 reflections measured at 100 K; independent reflections: Unique: 5072 (Rint = 0.029); R1 = 0.048, wR2 = 0.032, S = 1.03; highest residual electron density 0.27 e-/Å3.  188  A.3 Experimental Data for Chapter 3 Materials: All DPM substrates were prepared according to the literature. DDQ, anhydrous DCM and alcohols were used as purchased from Aldrich.  General Procedure for Preparation of Hydroxylated Dipyrromethanes (DPMs): 1-(4-((5-acetyl-1H-pyrrol-2-yl)(4-fluorophenyl)methyl)-1H-pyrrol-2-yl)ethanone 2-18 (0.16 g, 0.5 mmol) was dissolved in 20 mL DCM and DDQ (0.44 g, 2 mmol) was added. The resulting mixture was stirred at room temperature for 2 h. After complete consumption of the starting material as indicated by TLC, the reaction mixture was quenched with 0.3 mL Et3N. After concentration, flash chromatography on silica using ethyl acetate/CH2Cl2 (2:1) afforded the crude product which was rechromatographed on silica (ethyl acetate/CH2Cl2 (1:2-3:2)) to produce a viscous oil 3-2 (0.13 g, 0.38 mmol), yield 81%. After treatment with hexanes/CH2Cl2,an amorphous powder was produced. Syntheses of 3-1-3-7, 3-12-3-15, 3-18 and 3-19 were made following the same procedure.  General Procedure for Conjugated Dipyrromethenes: 1-(4-((5-acetyl-1H-pyrrol-2-yl)(perfluorophenyl)methyl)-1H-pyrrol-2-yl)ethanone 2-19 (0.20 g, 0.5 mmol) was dissolved in 20 mL anhydrous DCM. To this solution, DDQ (0.44 g, 2 mmol) was added. The resulting mixture was stirred at room temperature for 24 hours. After complete consumption of the starting material as indicated by TLC, the solvent was removed under vacuum. Flash chromatography on silica using ethyl acetate/CH2Cl2 (1:4) afforded the crude product, which was rechromatographed on silica using ethyl acetate/CH2Cl2 (1:5-1:3) to produce a red powder 3-16 (0.09 g, 0.21 mmol), yield 35%. Syntheses of 3-10, 3-11, 3-16 and 3-17 were made following this procedure.  General Procedure for Alkoxylation of DPMs: 1-(4-((5-acetyl-1H-pyrrol-2-yl)(phenyl)methyl)-1H-pyrrol-2-yl)ethanone  2-16  (0.15 g, 0.5 mmol) and (0.5 mmol) 1-butanol were dissolved in 20 mL anhydrous DCM, DDQ (0.23 g, 1 mmol) was added. The resulting mixture was stirred at room temperature  189  for 2 hours. After complete consumption of the starting material as indicated by TLC, the reaction mixture was quenched using 0.3 mL Et3N. After concentration, flash chromatography on silica using ethyl acetate/CH2Cl2 (1:1) afforded the crude product which was rechromatographed on silica using ethyl acetate/CH2Cl2 (1:5-1:3) to produce a viscous oil. After treatment with hexanes/CH2Cl2, an amorphous powder 3-21 was produced (0.13 g 0.35 mmol), yield 71%. Syntheses of 3-20-3-31 were made following the same procedure.  General Procedure for Arylation of DPMs: 1-(4-((5-acetyl-1H-pyrrol-2-yl)(phenyl)methyl)-1H-pyrrol-2-yl)ethanone  2-16  (0.15 g, 0.5 mmol) and DDQ (0.46 g, 2 mmol) were dissolved in 20 mL anhydrous DCM and, after stirring for 5 minutes, 1.0 mmol pyrrole was added. The resulting mixture was stirred at room temperature for 2 hours. After complete consumption of the starting material as indicated by TLC, the reaction mixture was quenched using 0.3 mL Et3N. After concentration, the reaction mixture was chromatographed on silica using ethyl acetate/CH2Cl2 (1:5-1:3) to produce a viscous oil. An amorphous powder was produced after treatment with hexanes/CH2Cl2, yields 48-78%. Syntheses of 3-32-3-37 were made following the same procedure. A.3.1 1H and 13C NMR Data for DPM Products 3-1  1-(4-((5-acetyl-1H-pyrrol-2-yl)(hydroxy)(phenyl)methyl)-1H-pyrrol-2-  yl)ethanone Transparent oil after evaporation. Treatment with CH2Cl2/hexanes produces a white powder. Yield 75% 1  H NMR (300 MHz, CDCl3): δ (ppm) 2.32 (s, 3H), 2.36 (s, 3H), 5.49 (s, 1H),  5.84 (s, 1H), 6.72 (s, 1H), 6.81(s, 1H), 6.84 (s, 1H), 7.27-7.32 (m, 3H), 7.37-7.39 (m, 2H), 10.08 (br, 1H), 10.89 (br, 1H); 13C NMR (100 MHz, CDCl3): δ (ppm) 25.08, 25.32, 74.36, 110.66, 116.21, 118.07, 124.22, 126.57, 127.63, 128.00, 131.34, 131.96, 132.12, 145.20, 146.11, 188.76, 188.89; HRMS (EI) Calcd for C19H18N2O: 322.1317. Found: 322.1315; mp 102-104 °C; Anal. Calcd for C19H18N2O: C, 70.79; H, 5.63; N, 8.69. Found: C, 70.77; H, 5.76; N, 8.20.  190  3-2  1-(4-((5-acetyl-1H-pyrrol-2-yl)(4-fluorophenyl)(hydroxy)methyl)-1H-pyrrol-2-  yl)ethanone Transparent oil after evaporation. Treatment with CH2Cl2/hexanes produces an amorphous powder. Yield 81%. 1H NMR (300 MHz, CDCl3): δ (ppm) 2.32 (s, 3H), 2.37 (s, 3H), 5.79-5.81 (m, 2H), 6.72 (s, 1H), 6.81 (s, 1H), 6.85 (m, 1H), 6.98-7.01 (m, 2H), 7.35-7.37 (m, 2H), 10.43 (br, 1H), 11.07 (br, 1H); 13C NMR (100 MHz, CDCl3): δ (ppm) 25.11, 25.43, 73.99, 110.65, 114.64, 114.92, 115.99, 118.11, 124.03, 128.41, 128.51, 131.43, 132.07, 141.09, 145.86, 160.52, 163.78, 188.73, 189.00; HRMS (EI) Calcd for C19H17FN2O3: 340.1223. Found: 340.1221; Anal. Calcd for C19H17FN2O3: C, 67.05; H, 5.03; N, 8.23; Found: C, 67.25; H, 5.41; N, 7.80.  3-3 1-(4-((5-acetyl-1H-pyrrol-2-yl)(hydroxy)(perfluorophenyl)methyl)-1H-pyrrol-2yl)ethanone Transparent oil after evaporation. Treatment with CH2Cl2/hexanes produces a white powder. Yield 25%. 1H NMR (300 MHz, CDCl3): δ (ppm) 2.40 (s, 3H), 2.42 (s, 3H), 5.07 (s, 1H), 5.98 (s, 1H), 6.87 (s, 2H), 6.93 (s, 1H), 9.89 (br, 1H), 10.49 (br, 1H); 13  C NMR (100 MHz, CDCl3): δ (ppm) 25.19, 25.39, 72.29, 109.84, 114.87, 117.84,  123.02. 129.30, 131.83, 132.27, 142.78, 188.61, 189.11; HRMS (EI) Calcd for C19H13F5N2O3:412.0846. Found: 412.0837; mp 143-145 °C.  3-4 4,5'-((4-fluorophenyl)(hydroxy)methylene)bis(1H-pyrrole-2-carbaldehyde) Transparent oil after evaporation. Treatment with CH2Cl2/hexanes produces an amorphous powder. Yield 78%. 1H NMR (300 MHz, CDCl3): δ (ppm) 5.69 (b, 1H), 5.92 (s, 1H), 6.81 (s,1H), 6.85 (s,1H), 6.90 (s,1H), 6.94-7.00 (m, 2H), 7.32-7.36 (m, 2H), 9.27 (s, 2H), 10.69 (br, 1H), 10.94 (br, 1H);  13  C NMR (100 MHz, CDCl3): δ (ppm) 74.05,  110.81, 114.78, 115.07, 120.62, 123.08, 126.07, 128.33, 128.44, 131.74, 132.31, 132.58, 140.52, 147.02, 160.56, 163.83, 179.72, 179.93; HRMS (EI) Calcd for C17H13FN2O3: 312.0910. Found: 312.0916.  191  3-5  1-(4-((5-acetyl-1H-pyrrol-2-yl)(hydroxy)(4-nitrophenyl)methyl)-1H-pyrrol-2-  yl)ethanone Transparent oil after evaporation. Treatment with CH2Cl2/hexanes produces a white powder. Yield 72%. 1H NMR (300 MHz, CDCl3): δ (ppm) 2.34 (s, 3H), 2.39 (s, 3H), 5.50 (br, 1H), 5.85 (s, 1H), 6.76 (m, 5H), 6.87 (s, 1H), 7.61-7.63 (d, 2H, J = 6.0 Hz), 8.17-8.19 (d, 2H, J = 6.0 Hz), 10.00 (br, 1H), 10.83 (br, 1H);  13  C NMR (100 MHz,  CDCl3): δ (ppm) 25.21, 25.38, 74.01, 110.77, 115.60, 118.30, 123.28, 123.87, 127.64, 131.07, 131.68, 132.30, 144.48, 147.33, 152.08, 188.68, 189.25; HRMS (EI) Calcd for C19H17N3O5: 367.1168. Found: 367.1169; mp 136-138 °C.  3-6  4-((5-acetyl-1H-pyrrol-2-yl)(5-acetyl-1H-pyrrol-3-  yl)(hydroxy)methyl)benzonitrile Transparent oil after evaporation. Treatment with CH2Cl2/hexanes produces a white powder. Yield 82%. 1H NMR (300 MHz, CDCl3): δ (ppm) 2.32 ( s, 3H), 2.37 ( s, 3H), 5.80 (s, 1H), 5.93 (s, 1H), 6.74 (s, 1H), 6.77 (s, 1H), 6.86 (s, 1H), 7.52-7.55 (d, 2H, J = 9.0 Hz), 7.60-7.63 (d, 2H, J = 9.0 Hz), 10.47 (br, 1H), 11.04 (br, 1H); 13C NMR (100 MHz, (CD3)2CO): δ (ppm) 25.94, 26.12, 75.16, 110.91, 112.35, 116.33, 117.46, 119.92, 124.77, 129.10, 132.43, 133.13, 133.85, 145.16, 153.06, 188.12, 188.33; HRMS (EI) Calcd for C20H17N3O3: 347.1270. Found: 347.1271; mp 143-145 °C.  3-7 4,5'-(hydroxy(4-nitrophenyl)methylene)bis(1H-pyrrole-2-carbaldehyde) Transparent oil after evaporation. Treatment with CH2Cl2/hexanes produces an amorphous powder. Yield 75%. 1H NMR (300 MHz, CDCl3): δ (ppm) 5.55 (s, 1H), 5.98 (s, 1H), 6.83 (s, 1H), 6.91 (s, 1H), 6.96 (s, 1H), 7.62-7.65 (d, 2H, J = 9.0 Hz), 8.17-8.20 (d, 2H, J = 9.0 Hz), 9.34 (s, 1H), 9.36 (s, 1H), 10.37 (br, 1H), 10.87 (br, 1H);  13  C NMR  (100 MHz, CDCl3): δ (ppm) 74.09, 110.85, 119.54, 122.92, 123.48, 125.23, 127.55, 131.37, 132.07, 133.01, 145.26, 147.52, 151.35, 179.73, 179.87; HRMS (EI) Calcd for C17H13N3O5: 339.0855. Found: 339.0859.  192  3-8 (Z)-5-acetyl-3-((5-acetyl-1H-pyrrol-2-yl)(4-fluorophenyl)methylene)-1H-pyrrol2(3H)-one Red powder, only a trace of the product separated from a 10 fold scale reaction. 1  H NMR (300 MHz, CDCl3): δ (ppm) 2.28 (s, 3H), 2.56 (s, 3H), 6.03 (s, 1H), 6.17 (d, 1H,  J = 3.0 Hz), 6.88 (s, 1H), 7.22-7.37 (m, 4H), 8.06 (s, 1H), 15.09 (br, 1H); 13C NMR (100 MHz, CDCl3): δ (ppm) 24.51, 26.36, 114.63, 115.32, 115.61, 116.01, 122.73, 125.83, 131.15, 131.25, 135.31, 136.62, 161.32, 164.64, 166.81, 188.27, 188.58.  3-9  (Z)-5-acetyl-3-((5-acetyl-1H-pyrrol-2-yl)(perfluorophenyl)methylene)-1H-  pyrrol-2(3H)-one Red powder. Yield 42%. 1H NMR (300 MHz, CDCl3): δ (ppm) 2.36 (s, 3H), 2.56 (s, 3H), 5.94 (s, 1H), 6.19 (d, 1H, J = 3.0 Hz), 6.90 (d, 1H, J = 3.0 Hz), 8.43 (s,1H), 14.80 (br, 1H);  13  C NMR (100 MHz, CDCl3): δ (ppm) 24.81, 26.32, 111.76, 116.55, 120.78,  127.93, 130.74, 133.31, 135.97, 137.01, 137.29, 139.31-145.78 multiple weak peaks due to C-F coupling, 166.22, 188.33, 188.41; HRMS (EI) Calcd for C19H11F5N2O3: 410.0690. Found: 410.0699; mp decomposed above 160°C; Anal. Calcd for C19H11F5N2O3: C, 55.62; H, 2.70; N, 6.83; Found: C.55.77; H, 2.80; N, 6.64.  3-10  (Z)-5-acetyl-3-((5-acetyl-1H-pyrrol-2-yl)(2,6-dichlorophenyl)methylene)-1H-  pyrrol-2(3H)-one Red powder. Yield 56%. 1H NMR (300 MHz, CDCl3): δ (ppm) 1H NMR (300 MHz, CDCl3): δ (ppm) 2.30 (s, 3H), 2.56 (s, 3H), 5.83 (s, 1H), 6.08 (s, 1H), 6.87 (s, 1H), 7.42-7.52 (m, 3H), 8.19 (s, 1H), 14.83 (br, 1H);  13  C NMR (100 MHz, CDCl3): δ (ppm)  24.66, 26.32, 112.60, 116.50, 120.44, 126.26, 128.38, 130.72, 133.57, 134.75, 135.49, 136.51, 136.63, 141.95, 166.70, 188.32; HRMS (EI) Calcd for C19H14Cl2N2O3: 388.0382. Found: 388.0383; mp 116-118°C.  193  3-11 (Z)-5-acetyl-3-((5-acetyl-1H-pyrrol-2-yl)(mesityl)methylene)-1H-pyrrol-2(3H)one Red powder. Yield 53%. 1H NMR (300 MHz, CDCl3): δ (ppm) 1H NMR (300 MHz, CDCl3): δ (ppm) 2.04 (s, 6H), 2.26 (s, 3H), 2.39 (s, 3H), 2.55 (s, 3H), 5.88-5.89 (d, 1H, J = 3.0 Hz), 6.08-6.09 (d, 1H, J = 3.0 Hz), 6.82-6.83 (d, 1H, J = 3.0 Hz), 6.98 (s, 2H), 8.07 (s, 1H), 14.98 (s, 1H);  13  C NMR (100 MHz, CDCl3): δ (ppm) 19.58, 21.12, 24.57,  26.29, 114.01, 116.34, 121.19, 125.57, 128.37, 134.29, 134.80, 135.48, 135.64, 136.49, 138.17, 148.73, 188.41, 188.47; HRMS (EI) Calcd for C22H22N2O3: 362.1630. Found: 362.1636; mp decomposed over 120 °C.  3-12 4-(bis(5-acetyl-1H-pyrrol-2-yl)(hydroxy)methyl)benzonitrile Transparent oil after evaporation. Treatment with CH2Cl2/hexanes produces a white powder. Yield 71%. 1H NMR (300 MHz, (CD3)2CO): δ (ppm) 2.30 (s, 6H), 3.04 (b, 1H), 5.96 (s, 2H), 6.91 (s, 2H), 7.75 (s, 4H), 10.83 (br, 2H);  13  C NMR (100 MHz,  (CD3)2CO): δ (ppm) 25.84, 74.86, 112.42, 112.60, 117.95, 119.59, 128.86, 133.01, 133.62, 143.36, 150.49, 188.88; HRMS (EI) Calcd for C20H17N3O3: 347.1270. Found: 347.1274; mp 145-147°C.  3-13  1,1'-(5,5'-((4-fluorophenyl)(hydroxy)methylene)bis(1H-pyrrole-5,2-  diyl))diethanone Transparent oil after evaporation. Treatment with CH2Cl2/hexanes produces a white powder. Yield 75%. 1H NMR (300 MHz, CDCl3): δ (ppm) 2.35 (s, 6H), 5.82-5.84 (m, 2H), 6.03 (b, 1H), 6.80-6.82 (m, 2H), 7.00-7.02 (m, 2H), 7.32-7.33 (m, 2H), 10.47 (br, 1H); 13C NMR (100 MHz, CDCl3): δ (ppm) 25.16, 73.95, 110.75, 114.86, 115.15, 117.65, 128.43, 128.54, 131.73, 139.23, 143.26, 160.78, 164.06, 188.91; HRMS (EI) Calcd for C19H17FN2O3: 340.1223. Found: 340.1231; mp decomposed above 105°C.  194  3-14  1,1'-(5,5'-(hydroxy(4-nitrophenyl)methylene)bis(1H-pyrrole-5,2-  diyl))diethanone Transparent oil after evaporation. Treatment with CH2Cl2/hexanes produces a white powder. Yield 78%. 1H NMR (300 MHz, CDCl3): δ (ppm) 2.32 (s, 6H), 5.85-5.86 (m, 2H), 5.92 (b,1H), 6.80-6.81(m, 2H), 7.64-7.66 (d, 2H, J = 9.0 Hz), 8.17-8.20 (d, 2H, J = 9.0 Hz), 10.80 (br, 1H); 13C NMR (100 MHz, CDCl3): δ (ppm) 25.24, 73.70, 111.05, 117.89, 123.34, 127.55, 132.01, 142.46, 147.53, 149.85, 189.26; HRMS (EI) Calcd for C19H17N3O5: 367.1168. Found: 367.1167; mp 154-156°C;  3-15  1,1'-(5,5'-(hydroxy(perfluorophenyl)methylene)bis(1H-pyrrole-5,2-  diyl))diethanone Transparent oil after evaporation. Treatment with CH2Cl2/hexanes produces a white powder. Yield 25%. 1H NMR (300 MHz, CDCl3): δ (ppm) 2.38 (s, 6H), 5.96-5.98 (m, 2H), 6.39 (s, 1H), 6.85-6.87 (m, 2H), 10.54 (br, 1H); 13C NMR (100 MHz, CD3CN): δ (ppm) 26.00, 72.70, 110.54, 118.10, 118.57, 133.70, 141.34, 189.59; HRMS (EI) Calcd for C19H13F5N2O3: 412.0846. Found: 412.0844; mp 118-120°C.  3-16  (Z)-1-(2-((5-acetyl-1H-pyrrol-2-yl)(perfluorophenyl)methylene)-2H-pyrrol-5-  yl)ethanone Red powder. Yield 35%. 1H NMR (300 MHz, CDCl3): δ (ppm) 2.68 (s, 6H), 6.566.57 (d, 2H, J = 3.0 Hz), 6.95-6.96 (d, 2H, J = 3.0 Hz), 12.69 (br, 1H);  13  C NMR (100  MHz, CDCl3): δ (ppm) 26.15, 121.38, 128.17, 136-155 multiple peaks due to C-F coupling, 192.38; HRMS (EI) Calcd for C19H11F5N2O2: 394.0741. Found 394.0747; mp decomposed above 160°C; Anal. Calcd for C19H11F5N2O2: C, 57.88; H, 2.81; N, 7.10; Found: C, 57.92; H, 2.90; N, 6.94.  3-17 (Z)-1-(2-((5-acetyl-1H-pyrrol-2-yl)(2,6-dichlorophenyl)methylene)-2H-pyrrol-5yl)ethanone Red powder. Yield 55%. 1H NMR (300 MHz, CDCl3): δ (ppm) 2.67 (s, 6H), 6.446.45 (d, 2H, J = 3.0 Hz), 6.91-6.92 (d, 2H, J = 3.0 Hz), 7.30-7.50 (m, 3H), 12.68 (br, 1H);  195  13  C NMR (100 MHz, CDCl3): δ (ppm) 26.13, 120.91, 128.01, 128.13, 130.88, 133.42,  135.29, 138.53, 143.29, 192.46; HRMS (EI) Calcd for C19H14Cl2N2O2: 372.0432. Found: 372.0436; mp decomposed above 168°C; Anal. Calcd for C19H14Cl2N2O2: C, 61.14; H, 3.78; N, 7.51; Found C, 61.53; H, 3.89; N, 7.39.  3-18  1,1'-(4,4'-(hydroxy(phenyl)methylene)bis(1H-pyrrole-4,2-diyl))bis(2,2,2-  trifluoroethanone) Transparent oil after evaporation. Treatment with CH2Cl2/hexanes produces a white powder. Yield 71%. 1H NMR (300 MHz, CD3CN): δ (ppm) 4.35 (b, 1H), 7.02 (s, 2H), 7.11 (s, 2H), 7.26-7.44 (m, 5H), 10.52 (br, 2H);  13  C NMR (100 MHz, CDCl3): δ  (ppm) 74.11, 119.55, 120.08, 125.77, 126.29, 127.49, 127.89, 128.35, 135.23, 145.43, 170.42; HRMS (EI) Calcd for C19H12F6N2O3: 430.0752. Found: 430.0764; mp 82-84°C.  3-19  1,1'-(4,4'-((4-fluorophenyl)(hydroxy)methylene)bis(1H-pyrrole-4,2-  diyl))bis(2,2,2-trifluoroethan-one) Transparent oil after evaporation. Treatment with CH2Cl2/hexanes produces a white powder. Yield 68%. 1H NMR (300 MHz, CD3CN): δ (ppm) 4.31 (br, 1H), 7.01(s, 2H), 7.10 (m, 4H), 7.41-7.44 (m, 2H), 10.46 (br, 2H);  13  C NMR (100 MHz, CD3CN): δ  (ppm) 73.84, 115.22, 115.43, 116.41, 119.28, 120.26, 126.08, 129.12, 129.27, 129.35, 136.33, 144.05, 163.91; HRMS (EI) Calcd for C19H11F7N2O3: 448.0658. Found: 448.0662; mp 115-118°C.  3-20  1-(4-((5-acetyl-1H-pyrrol-2-yl)(methoxy)(phenyl)methyl)-1H-pyrrol-2-  yl)ethanone Transparent oil after evaporation. Treatment with CH2Cl2/hexanes produces an amorphous powder. Yield 72%. 1H NMR (300 MHz, CDCl3): δ (ppm) 2.38 (s, 3H), 2.40 (s, 3H), 3.15 (s, 3H), 6.16 (m, 1H), 6.78 (s, 1H), 6.84 (m, 1H), 6.93 (s, 1H), 7.30-7.36 (m, 3H), 7.45-7.48 (m, 2H), 9.40 (br, 1H), 10.08 (br, 1H);  13  C NMR (100 MHz, CDCl3): δ  (ppm) 25.21, 25.40, 51.79, 79.46, 110.57, 116.88, 117.21, 125.42, 126.54, 126.89, 127.53, 127.98, 128.15, 131.27, 131.88, 141.83, 142.93, 187.77, 188.52; HRMS (EI) Calcd for C20H20N2O3: 336.1474. Found: 336.1480.  196  3-21  1-(4-(butoxy(phenyl)(5-(prop-1-en-2-yl)-1H-pyrrol-2-yl)methyl)-1H-pyrrol-2-  yl)ethanone Transparent oil after evaporation. Treatment with CH2Cl2/hexanes produces an amorphous powder. Yield 71%. 1H NMR (300 MHz, CDCl3): δ (ppm) 0.88-0.92 (t, 3H, J = 6.0 Hz), 1.39-1.45 (m, 2H), 1.58-1.63 (m, 2H), 2.40 (s, 3H), 3.20-3.26 (m, 2H), 6.156.18 (m, 1H), 6.79 (s, 1H), 6.85 (s, 1H), 6.94 (s, 1H), 7.31-7.33 (m, 3H), 7.48-7.50 (m, 2H), 9.38 (br, 1H), 10.21 (br, 1H). 13C NMR (100 MHz, CDCl3): δ (ppm) 13.90, 19.46, 25.17, 25.38, 32.02, 63.61, 78.76, 110.42, 116.80, 117.14, 125.30, 126.83, 127.40, 127.59, 128.04, 131.14, 131.80, 142.35, 143.53, 187.65, 188.43; HRMS (EI) Calcd for C23H26N2O3: 378.1943. Found: 378.1935.  3-22 1-(4-(phenoxy(phenyl)(5-(prop-1-en-2-yl)-1H-pyrrol-2-yl)methyl)-1H-pyrrol-2yl)ethanone Transparent oil after evaporation. Treatment with CH2Cl2/hexanes produces an amorphous powder. Yield 48%. 1H NMR (300 MHz, CDCl3): δ (ppm) 2.39 (s, 3H), 2.41 (s, 3H), 4.29-4.39 (q, 2H, J = 6.0 Hz), 6.25-6.27 (m, 1H), 6.84 (s, 1H), 6.87 (m, 1H), 6.99 (s, 1H), 7.30-7.38 (m, 8H), 7.54-7.57 (m, 2H), 9.35 (br, 1H), 9.77 (br, 1H);  13  C NMR  (100 MHz, CDCl3): δ (ppm) 25.26, 25.44, 66.12, 79.51, 110.82, 116.76, 116.84, 124.97, 126.90, 127.30, 127.42, 127.56, 128.27, 128.36, 131.52, 132.04, 138.27, 141.60, 143.19, 187.74, 188.36; HRMS (EI) Calcd for C26H24N2O3: 412.1787. Found: 412.1796.  3-23  1-(4-(phenyl(5-(prop-1-en-2-yl)-1H-pyrrol-2-yl)(pyridin-3-yloxy)methyl)-1H-  pyrrol-2-yl)ethan-one Transparent oil after evaporation. Treatment with CH2Cl2/hexanes produces an amorphous powder. Yield 31%. 1H NMR (300 MHz, CDCl3): δ (ppm) 2.39 (s, 3H), 2.41(s, 3H), 4.34-4.4 (q, 2H, J = 6.0 Hz), 6.27-6.29 (m, 1H), 6.83 (s, 1H), 6.88 (m, 1H), 7.00 (s, 1H), 7.29-7.38 (m, 4H), 7.52-7.55 (d, 2H), 7.67-7.69 (m, 1H), 8.55 (s, 2H), 9.34 (br, 1H), 9.92 (br, 1H); 13C NMR (100 MHz, CDCl3): δ (ppm) 25.26, 25.46, 63.75, 79.81, 111.05, 116.50, 116.73, 123.35, 124.80, 126.79, 127.14, 127.82, 128.36, 131.70, 132.18,  197  133.85, 135.10, 140.99, 142.86, 148.73, 188.25; MS (ESI) Calcd for C25H23N3O3: 412. Found: (M+23) 435.1.  3-24  1-(4-((5-acetyl-1H-pyrrol-2-yl)(ethoxy)(phenyl)methyl)-1H-pyrrol-2-  yl)ethanone Transparent oil after evaporation. Treatment with CH2Cl2/hexanes produces an amorphous powder. Yield 68%. 1H NMR (300 MHz, CDCl3): δ (ppm) 1.21-1.23 (t, 3H, J = 6.0 Hz), 2.38 (s, 3H), 2.40 (s, 3H), 3.23-3.29 (q, 2H, J = 6.0 Hz), 6.12-6.14 (m, 1H), 6.77 (s, 1H), 6.84 (m, 1H), 6.90 (s, 1H), 7.26-7.38 (m, 3H), 7.46-7.49 (d, 2H), 9.37 (br, 1H), 9.86 (br, 1H);  13  C NMR (100 MHz, CDCl3): δ (ppm) 15.33, 25.22, 25.40, 59.58,  78.98, 110.29, 116.87, 116.97, 125.06, 126.88, 127.51, 127.75, 128.15, 131.15, 131.68, 142.44, 143.31, 188.39; HRMS (EI) Calcd for C21H22N2O3: 350.1630. Found: 350.1628.  3-25  1-(4-((5-acetyl-1H-pyrrol-2-yl)(2-chloroethoxy)(phenyl)methyl)-1H-pyrrol-2-  yl)ethanone Transparent oil after evaporation. Treatment with CH2Cl2/hexanes produces an amorphous powder. Yield 57%. 1H NMR (300 MHz, CDCl3): δ (ppm) 2.38 (s, 3H), 2.40 (s, 3H), 3.48-3.53 (t, 2H, J = 6.0 Hz), 3.62-3.65 (m, 2H), 6.20-6.22 (d, 1H, J = 3.0 Hz), 6.80 (s, 1H), 6.84-6.86 (d, 1H, J = 3.0 Hz), 6.97 (m, 1H), 7.29-7.36 (m, 3H), 7.49-7.51 (m, 2H), 9.47 (br, 1H), 10.14 (br, 1H); 13C NMR (100 MHz, CDCl3): δ (ppm) 25.24, 25.42, 43.27, 64.24, 79.33, 110.79, 116.72, 116.87, 125.22, 126.76, 127.00, 127.69, 128.20, 131.57, 132.02, 141.07, 142.97, 187.76, 188.47; HRMS (EI) Calcd for C21H21ClN2O3: 384.1241. Found: 384.1247.  3-26  1-(4-((5-acetyl-1H-pyrrol-2-yl)(phenyl)(2,2,2-trifluoroethoxy)methyl)-1H-  pyrrol-2-yl)ethanone Transparent oil after evaporation. Treatment with CH2Cl2/hexanes produces an amorphous powder. Yield 29%. 1H NMR (300 MHz, CDCl3): δ (ppm) 2.38 (s, 3H), 2.41 (s, 3H), 3.59-3.70 (m, 2H), 6.26 (s, 1H), 6.80 (s, 1H), 6.86 (s, 1H), 6.98 (s, 1H), 7.27-7.37 (m, 3H), 7.47-7.49 (m, 2H), 9.30 (br, 1H), 10.13 (br, 1H); 13C NMR (100 MHz, CDCl3): δ (ppm) 25.29, 25.43, 61.82, 80.15, 111.33, 116.51, 116.65, 125.89, 126.10, 126.55,  198  126.62, 127.68, 128.04, 128.09, 128.47, 132.07, 132.28, 139.47, 141.92, 145.14, 187.97, 188.60; HRMS (EI) Calcd for C21H19F3N2O3: 404.1348. Found: 404.1340.  3-27  1-(4-((5-acetyl-1H-pyrrol-2-yl)(but-3-ynyloxy)(phenyl)methyl)-1H-pyrrol-2-  yl)ethanone Transparent oil after evaporation. Treatment with CH2Cl2/hexanes produces an amorphous powder. Yield 65%. 1H NMR (300 MHz, CDCl3): δ (ppm) 2.38 (s, 3H), 2.40 (s, 3H), 2.49-2.51 (t, 2H, J = 6.0 Hz), 3.34-3.38 (t, 2H, J = 6.0 Hz), 6.19-6.21 (d, 1H, J = 3.0 Hz), 6.78 (s, 1H), 6.84 (d, 1H, J = 3.0 Hz), 6.94 (s, 1H), 7.27-7.34 (m, 3H), 7.50-7.52 (m, 2H), 9.58 (br, 1H), 9.81 (br, 1H); 13C NMR (100 MHz, CDCl3): δ (ppm) 20.01, 25.28, 25.42, 62.30, 70.02, 81.76, 110.64, 116.80, 116.88, 125.12, 126.76, 127.22, 127.59, 128.13, 131.48, 131.99, 141.47, 143.34, 188.36; HRMS (EI) Calcd for C23H22N2O3: 374.1630. Found: 374.1629.  3-28  1-(4-((5-acetyl-1H-pyrrol-2-yl)(pent-4-enyloxy)(phenyl)methyl)-1H-pyrrol-2-  yl)ethanone Transparent oil after evaporation. Treatment with CH2Cl2/hexanes produces an amorphous powder. Yield 67%. 1H NMR (300 MHz, CDCl3): δ (ppm) 1.67-1.76 (m, 2H), 2.12-2.19 (m, 2H), 2.38 (s, 3H), 2.40 (s, 3H), 3.22-3.28 (m, 2H), 4.93-5.04 (m, 2H), 5.75-5.81 (m, 1H), 6.15-6.17 (d, 1H, J = 3.0 Hz), 6.77 (s, 1H), 6.83 (d, 1H, J = 3.0 Hz), 6.92 (s, 1H), 7.27-7.33 (m, 3H), 7.47-7.49 (m, 2H), 9.36 (br, 1H), 10.15 (br, 1H);  13  C  NMR (100 MHz, CDCl3): δ (ppm) 25.19, 25.39, 29.10, 30.44, 63.23, 78.86, 110.48, 114.68, 116.79, 117.08, 125.24, 126.83, 127.45, 127.53, 128.08, 131.23, 131.85, 138.17, 142.20, 143.45, 188.43; HRMS (ESI) Calcd for C24H26N2O3Na: 413.1841. Found: 413.1832.  3-29  1-(4-((5-acetyl-1H-pyrrol-2-yl)(5-hydroxypentyloxy)(phenyl)methyl)-1H-  pyrrol-2-yl)ethanone Transparent oil after evaporation. Treatment with CH2Cl2/hexanes produces an amorphous powder. Yield 58%. 1H NMR (300 MHz, CDCl3): δ (ppm) 1.48-1.65 (m, 6H), 2.37 (s, 3H), 2.40 (s, 3H), 3.20-3.26 (t, 2H, J = 6.0 Hz), 3.63-3.67 (t, 2H, J = 6.0 Hz),  199  6.15 (d, 1H, J = 3.0 Hz), 6.76 (s, 1H), 6.85 (d, 1H, J = 3.0 Hz), 6.90 (m, 1H), 7.30-7.33 (m, 3H), 7.46-7.49 (m, 2H), 9.54 (br, 1H), 9.98 (br, 1H); 13C NMR (100 MHz, CDCl3): δ (ppm) 22.46, 25.24, 25.42, 29.44, 32.28, 62.50, 63.55, 78.85, 110.49, 117.23, 125.33, 126.53, 126.86, 127.47, 128.10, 131.14, 131.81, 142.57, 143.44, 187.97, 188.50; HRMS (ESI) Calcd for C24H28N2O4Na: 431.1947. Found: 431.1958.  3-30  1-(4-((5-acetyl-1H-pyrrol-2-yl)(cyclohexyloxy)(phenyl)methyl)-1H-pyrrol-2-  yl)ethanone Transparent oil after evaporation. Treatment with CH2Cl2/hexanes produces an amorphous powder. Yield 26%. 1H NMR (300 MHz, CDCl3): δ (ppm) 0.80-1.66 (m, 10H), 2.40 (s, 3H), 2.42 (s, 3H), 3.47-3.53 (m, 1H), 6.21-6.23 (d, 1H, J = 3.0 Hz), 6.86 (s, 1H), 6.95 (d, 1H, J = 3.0 Hz), 6.96 (m, 1H), 7.28-7.33 (m, 3H), 7.51-7.54 (m, 2H), 9.34 (br, 1H), 9.97 (br, 1H); 13C NMR (100 MHz, CDCl3): δ (ppm) 24.41, 25.22, 25.40, 25.42, 25.56, 33.90, 35.48, 72.54, 78.47, 110.57, 116.81, 117.36, 125.40, 126.54, 126.96, 127.37, 127.94, 128.00, 128.68, 131.07, 131.45, 131.71, 132.05, 142.89, 144.82, 145.20, 188.52; HRMS (EI) Calcd for C25H28N2O3: 404.2100. Found: 404.2090.  3-31  1-(4-((5-acetyl-1H-pyrrol-2-yl)(phenyl)(thiophen-2-ylmethoxy)methyl)-1H-  pyrrol-2-yl)ethanone Transparent oil after evaporation. Treatment with CH2Cl2/hexanes produces an amorphous powder. Yield 58%. 1H NMR (300 MHz, CDCl3): δ (ppm) 2.39 (s, 3H), 2.41 (s, 3H), 4.45-4.52 (m, 2H), 6.24-6.25 (d, 1H, J = 3.0 Hz), 6.85-6.87 (m, 1H), 6.92 (d, 1H, J = 3.0 Hz), 6.95-6.97 (m, 2H), 7.01 (s, 1H) 7.30-7.37 (m, 3H), 7.54-7.56 (m, 2H), 9.38 (br, 1H), 9.99 (br, 1H); 13C NMR (100 MHz, CDCl3): δ (ppm) 25.26, 25.46, 61.49, 79.71, 110.79, 116.74, 125.03, 125.35, 125.40, 126.88, 127.27, 128.29, 131.58, 132.11, 141.03, 141.29, 142.96, 188.40; HRMS (EI) Calcd for C24H22N2O3S: 418.1351. Found: 418.1353.  3-32  1-(4-((5-acetyl-1H-pyrrol-2-yl)(phenyl)(1H-pyrrol-2-yl)methyl)-1H-pyrrol-2-  yl)ethanone Transparent oil after evaporation. Treatment with CH2Cl2/hexanes produces an amorphous powder. Yield 78%. 1H NMR (300 MHz, CDCl3): δ (ppm) 2.38 (s, 3H), 2.41  200  (s, 3H), 6.01 (s, 1H), 6.07-6.08 (d, 1H, J = 3.0 Hz), 6.21-6.22 (d, 1H, J = 3.0 Hz), 6.69 (s, 1H), 6.76 (s, 2H), 6.88 (s, 1H), 7.13-7.14 (d, 2H, J = 3.0 Hz), 7.29-7.33 (m, 3H), 8.14 (b, 1H), 9.18 (br, 1H), 9.66 (br, 1H);  13  C NMR (100 MHz, CDCl3): δ (ppm) 25.17, 25.47,  50.50, 108.37, 109.00, 111.14, 116.80,117.03, 117.62, 124.49, 127.38, 128.17, 128.57, 130.41, 131.11, 132.11, 134.38, 143.65, 144.59, 146.66, 187.71, 188.38; HRMS (EI) Calcd for C23H21N3O2: 371.1634. Found: 418.1628.  3-33 2,3'-(phenyl(1H-pyrrol-2-yl)methylene)bis(1H-pyrrole-5-carbaldehyde) Transparent oil after evaporation. Treatment with CH2Cl2/hexanes produces an amorphous powder. Yield 72%. 1H NMR (300 MHz, CDCl3): δ (ppm) 6.00 (s, 1H), 6.146.15 (d, 1H, J = 3.0 Hz), 6.20-6.21 (d, 1H, J = 3.0 Hz), 6.76 (s, 1H), 6.80 (s, 1H), 6.83 (s, 1H), 6.94 (s, 2H), 7.11-7.12 (d, 2H, J = 3.0 Hz) 7.31-7.33 (m, 3H), 8.03 (br, 1H), 9.15 (br, 1H), 9.43 (s, 1H), 9.44 (s, 1H), 9.74 (br, 1H);  13  C NMR (100 MHz, CDCl3): δ (ppm);  50.55, 108.59, 109.18, 111.88, 117.89, 121.10, 121.21, 126.04, 127.63, 128.35, 128.54, 131.00, 131.98, 132.69, 133.82, 144.08, 145.20, 178.90, 179.61; HRMS (EI) Calcd for C25H25N3O2: 399.1947. Found: 399.1952.  3-34  1,1'-(5,5'-((4-nitrophenyl)(1H-pyrrol-2-yl)methylene)bis(1H-pyrrole-5,2-  diyl))diethanone Transparent oil after evaporation. Treatment with CH2Cl2/hexanes produces an amorphous powder. Yield 68%. 1H NMR (300 MHz, CDCl3): δ (ppm) 2.25 (s, 6H), 6.01 (s, 2H), 6.15 (s, 1H), 6.79 (s, 3H), 7.94-7.96 (d, 2H, J = 6.0 Hz), 8.20-8.21 (d, 2H, J = 6.0 Hz), 9.76 (br, 1H), 11.37 (br, 2H);  13  C NMR (100 MHz, CDCl3): δ (ppm); 25.25,  52.12, 108.05, 108.88, 111.62, 118.34, 118.79, 123.20, 129.94, 131.74, 132.25, 142.37, 146.99, 149.50, 188.28; HRMS (EI) Calcd for C23H20N4O4: 416.1485. Found: 416.1494.  3-35  1-(4-((5-acetyl-1H-pyrrol-2-yl)(1H-indol-3-yl)(phenyl)methyl)-1H-pyrrol-2-  yl)ethanone Transparent oil after evaporation. Treatment with CH2Cl2/hexanes produces an amorphous powder. Yield 73%. 1H NMR (300 MHz, CDCl3): δ (ppm) 2.34 (s, 3H), 2.39 (s, 3H), 6.09-6.11 (m, 1H), 6.67-6.71 (m, 3H), 6.87-6.90 (m, 3H), 7.13-7.19 (m, 3H),  201  7.27 (m, 4H), 7.35-7.38 (m, 1H), 8.12 (br, 1H), 8.98 (br, 1H), 9.26 (br, 1H);  13  C NMR  (100 MHz, CDCl3): δ (ppm); 25.17, 25.46, 111.32, 117.00, 117.17, 117.70, 119.74, 121.73, 121.83, 122.23, 124.64, 126.38, 126.91, 127.97, 128.82, 131.03, 131.14, 131.90, 137.05, 144.52, 145.10, 188.20; HRMS (EI) Calcd for C27H23N3O2 : 421.1790. Found: 421.1787.  3-36  1-(4-((5-acetyl-1H-pyrrol-2-yl)(2,5-dimethyl-1H-pyrrol-3-yl)(phenyl)methyl)-  1H-pyrrol-2-yl)ethanone Transparent oil after evaporation. Treatment with CH2Cl2/hexanes produces an amorphous powder. Yield 57%. 1H NMR (300 MHz, CDCl3): δ (ppm) 1.64 (s, 3H), 2.20 (s, 3H), 2.40 (s, 3H), 2.45 (s, 3H), 5.34 (d, 1H, J = 3.0 Hz), 6.11-6.12 (d, 1H, J = 3.0 Hz), 6.74 (s, 2H), 6.92 (s, 1H), 7.21-7.22 (m, 2H), 7.30 (m, 3H), 7.74 (br, 1H), 9.11 (br, 1H), 9.54 (br, 1H); 13C NMR (100 MHz, CDCl3): δ (ppm); 12.89, 25.14, 25.44, 49.61, 108.35, 110.93, 117.17, 117.59, 122.92, 123.75, 124.08, 124.65, 126.46, 127.70, 128.84, 130.60, 131.80, 132.48, 145.72, 146.11, 187.44, 188.30; HRMS (EI) Calcd for C25H25N3O3 399.1947. Found 399.1950.  3-37  2,3'-((2,5-dimethyl-1H-pyrrol-3-yl)(phenyl)methylene)bis(1H-pyrrole-5-  carbaldehyde) Transparent oil after evaporation. Treatment with CH2Cl2/hexanes produces an amorphous powder. Yield 48%. 1H NMR (300 MHz, CDCl3): δ (ppm) 1.61 (s, 3H), 2.17 (s, 3H), 5.31 (s, 1H), 6.17 (s, 1H), 6.78 (s, 1H), 6.82 (s, 1H), 6.95 (s, 1H), 7.14-7.16 (m, 2H), 7.29 (m, 3H), 7.67 (br, 1H), 9.08 (br, 1H), 9.44 (s, 2H), 9.54 (br, 1H);  13  C NMR  (100 MHz, CDCl3): δ (ppm) 49.64, 111.79, 122.48, 122.92, 123.26, 124.20, 126.57, 127.75, 128.74, 131.30, 132.28, 132.98, 145.66, 147.58, 178.60, 179.58; HRMS (EI) Calcd for C23H21N3O2: 371.1634. Found: 371.1632.  202  A.3.2 Crystal Data for 3-8, 3-9 ORTEP Plot of Crystal Structure of 3-9: The material crystallizes with disordered methylene chloride in the lattice and the PLATON/SQUEEZE program was used to correct the data for any unresolved electron density found in void spaces in the lattice. The SQUEEZE output suggests approximately one molecule of CH2Cl2 in the asymmetric unit. C20H15N2O3F5Cl2, Mw = 497.24, monoclinic, space group P21/c; dimensions: a = 10.7839(7) Å, b = 11.6313(6) Å, c = 19.2701(11) Å, α = 90.0º, β = 100.542(3)º, γ = 90.0º, V = 2376.3(2) Å3; Z = 4; 24728 reflections measured at 100 K; independent reflections: Unique: 5725(Rint = 0.034); R1 = 0.049, wR2 = 0.139, S = 1.13; highest residual electron density 0.36 e-/Å3 (all data R1 = 0.075; wR2 = 0.147).  203  ORTEP Plot of Crystal Structure of 3-8: C38.5H31N4O2F2Cl, Mw = 719.12, triclinic, space group P-1; dimensions: a = 10.8406(6) Å, b = 12.7715(8) Å, c = 13.7003(9) Å, α = 75.717(3)º, β = 68.411(4)º, γ = 75.393(4)º, V = 1681.6(2) Å3; Z = 2; 33669 reflections measured at 100 K; independent reflections: Unique: 8073(Rint = 0.025); R1 = 0.041, wR2 = 0.100, S = 1.02; highest residual electron density 0.37 e-/Å3 (all data R1 = 0.056; wR2 = 0.110).  204  A.4 Experimental Data for Chapter 4 All DPM substrates were prepared according to the method developed in chapter 2. Oxidants and alcohols were purchased from Aldrich and used as received.  General Procedure for Preparation of Free-Base N-confused Dipyrrins DDQ (0.11 g, 0.5 mmol) was added to 1-(4-((5-acetyl-1H-pyrrol-2-yl)(2,6dichlorophenyl)methyl)-1H-pyrrol-2-yl)ethanone 2-23 (0.19 g, 0.5 mmol) in CH3CN (20 mL) and the resulting mixture was allowed to stir at room temperature for 2 hours. After concentration, the residue was purified by silica column chromatography (DCM/EA= 4:1) and 0.09 g yellow product 4-1 was obtained, yield 48%. Products 4-1-4-4 were made following this procedure.  General Procedure for Preparation of Lactim N-confused Dipyrrins 0.22 g (1 mmol) DDQ was added to a mixture of 0.19 g (0.5 mmol) 1-(4-((5acetyl-1H-pyrrol-2-yl)(2,6-dichlorophenyl)methyl)-1H-pyrrol-2-yl)ethanone 2-23 and 0.5 mmol methanol in DCM (20 mL). The resulting mixture was allowed to stir at room temperature for 2 hours. After concentration, the residue was purified by alumina column chromatography (DCM/EA= 4:1) and 0.16 g yellow lactim dipyrrin product 4-5 was obtained, yield 81%. Products 4-5-4-20 were made following this procedure. A.4.1 1H and 13C NMR data 4-1 (Z)-1-(2-((5-acetyl-1H-pyrrol-3-yl)(2,6-dichlorophenyl)methylene)-2H-pyrrol-5yl)ethanone Yellow powder. Yield 48%. 1H NMR (300 MHz, CDCl3) δ 2.49 (s, 3H), 2.77 (s, 3H), 6.61-6.63 (d, 1H, J = 3.0 Hz), 7.00-7.01 (d, 1H, J = 3.0 Hz), 7.40-7.49 (m, 3H), 7.60 (s, 1H), 7.77 (s, 1H), 10.41 (br, 1H); 13C NMR (100 MHz, CDCl3) δ 25.56, 26.04, 120.13, 123.02, 124.77, 128.09, 130.48, 132.54, 133.88, 134.76, 135.08, 135.75, 145.53, 152.46, 167.55, 188.96, 197.52; HRMS (EI) Calcd for C19H14N2O2Cl2: 372.0432. Found: 372.0425; Anal. Calcd for C19H14Cl2N2O2 : C, 61.14; H, 3.78; N, 7.51. Found C, 60.63; H, 3.92; N, 7.23.  205  4-2  (Z)-1-(2-((5-acetyl-1H-pyrrol-3-yl)(2-chloro-6-fluorophenyl)methylene)-2H-  pyrrol-5-yl)ethanone Yellow powder. Yield 38%. 1H NMR (300 MHz, CDCl3) δ 2.48 (s, 3H), 2.76 (s, 3H), 6.67-6.68 (d, 1H, J = 3.0 Hz), 7.00-7.01 (d, 1H, J = 3.0 Hz), 7.18-7.20 (m, 1H), 7.25-7.45 (m, 2H), 7.61 (s, 1H), 7.82 (s, 1H), 10.45 (br, 1H); 13C NMR (100 MHz, CDCl3) δ 25.53, 26.03, 114.15, 119.85, 123.64, 124.83, 125.50, 132.30, 133.30, 134.61, 135.41, 141.69, 152.73, 158.91, 161.39, 167.62, 188.76, 197.49; HRMS (EI) Calcd for C19H14N2O2ClF: 356.0734. Found: 356.0742.  4-3  (Z)-1-(2-((5-acetyl-1H-pyrrol-3-yl)(perfluorophenyl)methylene)-2H-pyrrol-5-  yl)ethanone Yellow powder. Yield 12%. 1H NMR (300 MHz, CDCl3) δ 2.42 (s, 3H), 2.69 (s, 3H), 6.95-6.96 (d, 1H, J = 3.0 Hz), 7.02-7.03 (d, 1H, J = 3.0 Hz), 7.85 (s, 1H), 8.16 (s, 1H), 11.76 (br, 1H); 13C NMR (100 MHz, CDCl3) δ 25.78, 26.13, 117.87, 120.28, 123.82, 128.38, 133.89, 134.15, 136.52, 168.90, 188.45; HRMS (EI) Calcd for C19H11F5N2O2: 394.0741. Found 394.073.  4-4 (Z)-1-(2-((5-acetyl-1H-pyrrol-3-yl)(mesityl)methylene)-2H-pyrrol-5-yl)ethanone Yellow powder. Yield 35%. 1H NMR (300 MHz, CDCl3) δ 2.08 (s, 6H), 2.38 (s, 3H), 2.47 (s, 3H), 2.76 (s, 3H), 6.65 (d, 1H, J = 3.0 Hz), 6.96 (m, 3H), 7.58 (s, 1H), 7.78 (s, 1H), 9.70 (br, 1H); 13C NMR(100 MHz, CDCl3) δ 19.95, 21.12, 26.06, 91.18, 119.89, 123.90, 124.82, 128.13, 123.21, 134.65, 135.62, 135.83, 138.02, 188.56, 203.04; HRMS (EI) Calcd for C22H22N2O2: 346.1681. Found: 346.1680.  4-5  (Z)-1-(3-((5-acetyl-1H-pyrrol-2-yl)(2,6-dichlorophenyl)methylene)-2-methoxy-  3H-pyrrol-5-yl)ethanone Red powder. Yield 81%. 1H NMR (300 MHz, CDCl3): δ (ppm) 2.42 (s, 3H), 2.54 (s, 3H), 4.46 (s, 3H), 6.05 (s, 1H), 6.12 (d, 1H, J = 3.0 Hz), 6.83 (d, 1H, J = 3.0 Hz), 7.47 (m, 3H), 12.32 (br, 1H);  13  C NMR (100 MHz, CDCl3): δ (ppm) 25.42, 26.53, 57.37,  110.39, 116.08, 117.13, 121.75, 128.01, 128.25, 130.41, 131.58, 134.36, 135.87, 136.51,  206  140.73, 149.07, 164.76, 188.20, 194.42; HRMS (EI) Calcd for C20H16N2O23Cl2: 402.0538. Found: 402.0542.  4-6  (Z)-1-(3-((5-acetyl-1H-pyrrol-2-yl)(2-chloro-6-fluorophenyl)methylene)-2-  methoxy-3H-pyrrol-5-yl)ethanone Red powder. Yield 76%. 1H NMR (300 MHz, CDCl3): δ (ppm) 2.40 (s, 3H), 2.52 (s, 3H), 4.44 (s, 3H), 6.09 (s, 1H), 6.14 (d, 1H, J = 3.0 Hz), 6.81 (d, 1H, J = 3.0 Hz), 7.16-7.45 (m, 3H), 12.33 (br, 1H);  13  C NMR (100 MHz, CDCl3): δ (ppm) 26.03, 26.77,  57.61, 114.20, 114.49, 116.18, 117.58, 122.31, 125.56, 130.98, 131.09, 134.50, 136.77, 149.25, 158.21, 161.53, 164.90, 188.43, 194.65; HRMS (EI) Calcd for C20H16ClFN2O3: 388.0804. Found 388.0813.  4-7 (Z)-1-(3-((5-acetyl-1H-pyrrol-2-yl)(perfluorophenyl)methylene)-2-methoxy-3Hpyrrol-5-yl)ethanone Red powder. Yield 62%. 1H NMR (300 MHz, CDCl3): δ (ppm) 2.42 (s, 3H), 2.54 (s, 3H), 4.41 (s, 3H), 6.01 (s, 1H), 6.14 (d, 1H, J = 3.0 Hz), 6.80 (d, 1H, J = 3.0 Hz), 12.36 (br, 1H);  13  C NMR (100 MHz, CDCl3): δ (ppm) 26.06, 26.92, 57.85, 116.21,  122.32, 137.22, 149.99, 188.42; HRMS (EI) Calcd for C20H13F5N2O3: 424.0846. Found 424.0848.  4-8 (Z)-1-(3-((5-acetyl-1H-pyrrol-2-yl)(mesityl)methylene)-2-methoxy-3H-pyrrol-5yl)ethanone Red powder. Yield 54%. 1H NMR (300 MHz, CDCl3): δ (ppm) 2.01 (s, 3H), 2.36 (s, 3H), 2.37 (s, 3H), 2.52 (s, 3H), 4.44 (s, 3H), 6.09 (s, 1H), 6.12 (d, 1H, J = 3.0 Hz), 6.77 (d, 1H, J = 3.0 Hz), 6.93 (s, 2H), 12.33 (br, 1H);  13  C NMR (100 MHz, CDCl3): δ  (ppm) 19.66, 21.09, 25.99, 26.55, 57.36, 116.17, 118.94, 122.66, 127.73, 128.23, 133.55, 135.11, 135.34, 136.54, 138.14, 147.60, 148.56, 164.58, 188.54, 194.38; HRMS (EI) Calcd for C23H24N2O3: 376.1787. Found 376.1784.  207  4-9 (Z)-1-(3-((5-acetyl-1H-pyrrol-2-yl)(2,6-dichlorophenyl)methylene)-2-(butylthio)3H-pyrrol-5-yl)ethanone Red powder. Yield 63%. Two sets of NMR signals from Z-syn and Z-anti diastereomers (1.3:1) in the 1H NMR spectrum (300 MHz, CDCl3): δ (ppm) 0.86-0.93, 1.26-1.36 1.59-1.67, 2.48, 2.52, 2.57, 2.77, 3.10-3.15, 3.98-4.00, 4.21-4.24, 6.61-6.62, 6.72-6.73,  6.97-7.01,  7.41-7.53,  7.70,  8.49,  9.10;  HRMS  (EI)  Calcd  for  C23H22Cl2N2O2S:460.0779. Found 460.0785.  4-10  (Z)-1-(3-((5-acetyl-1H-pyrrol-2-yl)(2,6-dichlorophenyl)methylene)-2-propoxy-  3H-pyrrol-5-yl)ethanone Red powder. Yield 70%. 1H NMR (300 MHz, CDCl3): 1H NMR (300 MHz, CDCl3): δ (ppm) 1.11-1.16 (t, 3H, J = 6.0 Hz), 2.24-2.28 (m, 2H), 2.40 (s, 3H), 2.52 (s, 3H), 4.73-4.77 (t, 2H, J = 6.0 Hz), 6.01 (s, 1H), 6.08 (d, 1H, J = 3.0 Hz), 6.83 (d, 1H, J = 3.0 Hz), 7.42-7.48 (m, 3H), 12.17 (br, 1H); 13C NMR (100 MHz, CDCl3): δ (ppm) 10.55, 21.88, 26.03, 26.77, 73.27, 116.57, 116.97, 121.90, 128.19, 128.22, 129.01, 130.54, 132.44, 134.62, 136.78, 140.54, 188.28, 194.71; HRMS (EI) Calcd for C22H20Cl2N2O3: 430.0851. Found 430.0853.  4-11  (Z)-1-(3-((5-acetyl-1H-pyrrol-2-yl)(2,6-dichlorophenyl)methylene)-2-ethoxy-  3H-pyrrol-5-yl)ethanone Red powder. Yield 68%. 1H NMR (300 MHz, CDCl3): 1H NMR (300 MHz, CDCl3): δ (ppm) 1.79-1.84 (t, 3H, J = 6.0 Hz), 2.39 (s, 3H), 2.52 (s, 3H), 4.83-4.84 (q, 2H, J = 6.0 Hz), 6.01 (s, 1H), 6.09 (d, 1H, J = 3.0 Hz), 6.83 (d, 1H, J = 3.0 Hz), 7.37-7.48 (m, 3H), 12.21 (br, 1H);  13  C NMR (100 MHz, CDCl3): δ (ppm) 14.50, 26.06, 26.80,  67.63, 116.55, 116.97, 121.91, 126.95, 128.23, 129.02, 130.57, 132.44, 134.65, 136.80, 140.59, 188.33; HRMS (EI) Calcd for C21H18Cl2N2O3: 416.0695. Found 416.0692.  208  4-12  (Z)-1-(3-((5-acetyl-1H-pyrrol-2-yl)(2,6-dichlorophenyl)methylene)-2-butoxy-  3H-pyrrol-5-yl)ethanone Red powder. Yield 55%. 1H NMR (300 MHz, CDCl3): 1H NMR (300 MHz, CDCl3): δ (ppm) 1.06-1.08 (t, 3H), 1.55-1.64 (m, 2H), 2.20-2.23 (m, 2H), 2.40 (s, 3H), 2.52 (s, 3H), 4.78-4.82 (t, 2H, J = 3.0 Hz), 6.00 (s, 1H), 6.08 (s, 1H), 6.82 (s, 1H), 7.427.48 (m, 3H), 12.16 (br, 1H);  13  C NMR (100 MHz, CDCl3): δ (ppm) 14.1, 18.7, 27.7,  28.0, 32.4, 62.8, 114.20, 114.49, 116.18, 117.58, 122.31, 125.56, 130.98, 131.09, 134.50, 136.77, 149.25, 158.21, 161.53, 164.90, 188.43, 194.65; HRMS (EI) Calcd for C23H22Cl2N2O3: 444.1008. Found 444.1006.  4-13  (Z)-1-(3-((5-acetyl-1H-pyrrol-2-yl)(2,6-dichlorophenyl)methylene)-2-(but-3-  ynyloxy)-3H-pyrrol-5-yl)ethanone Red powder. Yield 57%. 1H NMR (300 MHz, CDCl3): 1H NMR (300 MHz, CDCl3): δ (ppm) 2.04 (s, 1H), 2.41 (s, 3H), 2.53 (s, 3H), 3.16-3.19 (t, 2H, J = 6.0 Hz), 4.48-4.91(t, 2H, J = 6.0 Hz), 6.03 (s, 1H), 6.11-6.12 (d, 1H, J = 3.0 Hz), 6.81-6.83 (d, 1H, J = 3.0 Hz), 7.42-7.47 (m, 3H), 12.07 (br, 1H);  13  C NMR (100 MHz, CDCl3): δ (ppm)  23.3, 27.7, 60.6, 69.7, 81.4, 114.20, 114.49, 116.18, 117.58, 122.31, 125.56, 130.98, 131.09, 134.50, 136.77, 149.25, 158.21, 161.53, 164.90, 188.43, 194.65; HRMS (EI) Calcd for C23H18Cl2N2O3: 440.0695. Found 440.0703. Anal. Calcd for C23H18Cl2N2O3: C, 62.60; H, 4.11; N, 6.35; found: C, 62.93; H, 4.17; N, 6.29.  4-14  (Z)-1-(3-((5-acetyl-1H-pyrrol-2-yl)(2,6-dichlorophenyl)methylene)-2-(pent-4-  enyloxy)-3H-pyrrol-5-yl)ethanone Red powder. Yield 55%. 1H NMR (300 MHz, CDCl3): 1H NMR (300 MHz, CDCl3): δ (ppm) 2.32-2.36 (m, 4H), 2.40 (s, 3H), 2.52 (s, 3H), 4.79-4.82 (t, 2H, J = 3.0 Hz), 5.02-5.04 (d, 1H, J = 3.0 Hz), 5.12-5.14 (d, 1H, J = 3.0 Hz), 5.88-5.97 (m,1H), 6.01 (s, 1H), 6.09 (d, 1H, J = 3.0 Hz), 6.82 (d, 1H, J = 3.0 Hz), 7.42-7.47 (m, 3H), 12.15 (br, 1H); 13C NMR (100 MHz, CDCl3): δ (ppm) 24.66, 26.32, 26.6, 29.9, 63.3, 115.8, 112.60, 116.50, 120.44, 126.26, 128.38, 130.72, 133.57, 134.75, 135.49, 136.50, 136.51, 136.63,  209  141.95, 166.70, 188.32; HRMS (EI) Calcd for C24H22Cl2N2O3 456.1008. Found: 456.1016. Anal. Calcd C, 63.03; H, 4.85; N, 6.13; found: C, 63.19; H, 4.85; N, 6.15.  4-15  (Z)-1-(3-((5-acetyl-1H-pyrrol-2-yl)(2,6-dichlorophenyl)methylene)-2-(5-  hydroxypentyloxy)-3H-pyrrol-5-yl)ethanone Red powder. Yield 61%. 1H NMR (300 MHz, CDCl3): 1H NMR (300 MHz, CDCl3): δ (ppm) 1.65-1.79(m,4H), 2.25-2.30 (m,2H), 2.39 (s, 3H), 2.51 (s, 3H), 3.72 (m, 2H), 4.79-4.83 (t, 2H, J = 6.0 Hz), 6.00 (d, 1H, J = 3.0 Hz), 6.09 (d, 1H, J = 3.0 Hz), 6.82 (s, 1H), 7.42-7.48 (m, 3H), 12.13 (br, 1H); 13C NMR (100 MHz, CDCl3): δ (ppm) 22.54, 26.06, 26.78, 28.32, 32.34, 62.53, 71.81, 116.78, 117.08, 121.96, 128.22, 129.03, 130.58, 132.50, 134.61, 136.33, 136.75, 140.60, 149.50, 164.93, 188.21; HRMS (EI) Calcd for C24H24Cl2N2O4: 474.1113. Found: 474.1117.  4-16  (Z)-1-(3-((5-acetyl-1H-pyrrol-2-yl)(2,6-dichlorophenyl)methylene)-2-  (cyclohexyloxy)-3H-pyrrol-5-yl)ethanone Red powder. Yield 57%. 1H NMR (300 MHz, CDCl3): 1H NMR (300 MHz, CDCl3): δ (ppm) 1.55-1.63 (m, 6H), 1.93-1.96 (m,4H), 2.40 (s, 3H), 2.52 (s, 3H), 5.44 (m, 1H), 5.98 (s, 1H), 6.06 (d, 1H, J = 3.0 Hz), 6.82 (d, 1H, J = 3.0 Hz), 7.42-7.48 (m, 3H), 12.25 (br, 1H); 13C NMR (100 MHz, CDCl3): δ (ppm) 24.84, 25.29, 26.04, 26.89, 32.19, 80.93, 116.56, 116.66, 128.22, 129.74, 130.49, 132.59, 134.67, 136.51, 136.68, 140.22, 149.83, 164.26, 188.29; HRMS (EI) Calcd for C25H24Cl2N2O3: 470.1164. Found: 470.11635.  4-17  (Z)-1-(3-((5-acetyl-1H-pyrrol-2-yl)(2,6-dichlorophenyl)methylene)-2-(2-  chloroethoxy)-3H-pyrrol-5-yl)ethanone Red powder. Yield 66%. 1H NMR (300 MHz, CDCl3): δ (ppm) 2.42 (s, 3H), 2.55 (s, 3H), 4.02-4.08 (t, 2H, J = 6.0 Hz), 4.82-5.86 (t, 2H, J = 6.0 Hz), 6.05 (s, 1H), 6.16 (d, 1H, J = 3.0 Hz), 6.84 (s, 1H), 7.42-7.51 (m, 3H), 12.07 (br, 1H);13C NMR (100 MHz, CDCl3): δ (ppm) 26.06, 26.85, 41.26, 70.55, 116.50, 117.38, 122.44, 128.13, 128.27, 130.69, 132.23, 134.61, 136.15, 137.12, 148.94, 163.84, 188.49, 194.60; HRMS (EI)  210  Calcd for C21H17Cl3N2O3: 450.0305. Found: 450.0309; Anal. Calcd for C21H17Cl3N2O3 C, 55.84; H, 3.79; N, 6.20; found: C, 56.12; H, 3.84; N, 6.11.  4-18 (Z)-3-(5-acetyl-3-((5-acetyl-1H-pyrrol-2-yl)(2,6-dichlorophenyl)methylene)-3Hpyrrol-2-yloxy)propanenitrile Red powder. Yield 61%. 1H NMR (300 MHz, CDCl3): δ (ppm) 2.40 (s, 3H), 2.54 (s, 3H), 3.38-3.41 (t, 2H, J = 6.0 Hz,), 5.02-5.06 (t, 2H, J = 6.0 Hz,), 6.07 (s, 1H), 6.14 (d, 1H, J = 3.0 Hz), 6.83-6.84 (d, 1H, J = 3.0 Hz), 7.46-7.48 (m, 3H), 11.96 (br, 1H);13C NMR (100 MHz, CDCl3): δ (ppm) 18.09, 26.00, 26.84, 65.21, 116.56, 116.75, 117.67, 122.74, 128.29, 5.92, 137.16, 141.94; HRMS (EI) Calcd for C22H17Cl2N3O3: 441.0647. Found: 441.0643.  4-19  (E)-1-(2-((5-acetyl-2-(2,2,2-trifluoroethoxy)-1H-pyrrol-3-yl)(2,6-  dichlorophenyl)methylene)-2H-pyrrol-5-yl)ethanone Red powder. Yield 63%. Two sets of signals (Ratio 3:7) Z-syn 1H NMR (300 MHz, CDCl3): 1H NMR (300 MHz, CDCl3): δ (ppm) 2.40 (s, 3H), 2.52 (s, 3H), 5.20-5.22 (q, 2H, J = 6.0 Hz), 5.81 (s, 1H), 6.24 (d, 1H, J = 3.0 Hz), 6.82 (d, 1H, J = 3.0 Hz), 7.427.48 (m, 3H), 11.33 (br, 1H); Z-anti 1H NMR (300 MHz, CDCl3): δ (ppm) 2.50 (s, 3H), 2.52 (s, 3H), 4.54-4.56 (q, 2H, J = 6.0 Hz), 6.07 (d, 1H, J = 3.0 Hz), 6.98-6.99 (d, 1H, J = 3.0 Hz), 7.13 (s, 1H), 7.42-7.48 (m, 3H), 9.14 (b, 1H); HRMS (EI) Calcd for C21H15Cl2F3N2O3: 470.0412. Found: 470.0409.  4-21 (E)-4-((2-acetyl-4-((5-acetyl-2H-pyrrol-2-ylidene)(2,6-dichlorophenyl)methyl)1H-pyrrol-1-yl)methyl)benzonitrile 1  H NMR (300 MHz, CDCl3): δ (ppm) 1H NMR (300 MHz, CDCl3): δ (ppm) 2.42  (s, 3H), 2.72 (s, 3H), 5.63 (s, 2H), 6.62-6.63 (d, 1H, J = 3.0 Hz), 7.01-7.02 (d, 1H, J = 3.0 Hz), 7.22-7.49 (m, 3H), 7.50-7.51 (d, 2H, J = 3.0 Hz), 7.62-7.63 (d, 2H, J = 3.0 Hz), 7.68 (s, 1H), 7.70 (s, 1H);  13  C NMR (100 MHz, CDCl3): δ (ppm) 53.25, 117.76, 118.42,  120.86, 127.44, 131.99, 132.63, 134.86, 135.53, 142.19, 144.38, 152.90, 167.88, 197.19; HRMS (EI) Calcd for C27H19Cl2N3O2: 487.0854. Found: 487.0864.  211  4-20  (E)-1-(2-((5-acetyl-2-(2,2,2-trifluoroethoxy)-1H-pyrrol-3-  yl)(perfluorophenyl)methylene)-2H-pyrrol-5-yl)ethanone Red powder. Yield 67%. Two sets of signals (Ratio 3:7) Z-syn 1H NMR (300 MHz, CDCl3): 1H NMR (300 MHz, CDCl3): δ (ppm) 2.46 (s, 3H), 2.56 (s, 3H), 5.18-5.26 (q, 2H, J = 9.0 Hz), 6.15 (s, 1H), 6.34 (d, 1H, J = 3.0 Hz), 6.89 (d, 1H, J = 3.0 Hz), 11.40 (br, 1H); Z-anti 1H NMR (300 MHz, CDCl3): δ (ppm) 2.53 (s, 3H), 2.54 (s, 3H), 4.604.69 (q, 2H, J = 9.0 Hz), 6.74-6.76 (d, 1H, J = 6.0 Hz), 7.01-7.03 (d, 1H, J = 6.0 Hz), 7.06 (s, 1H), 9.49 (b, 1H); HRMS (EI) Calcd for C21H12F8N2O3: 492.0720. Found: 492.0721.  4-22 (Z)-3-((2,6-dichlorophenyl)(5-(1-hydroxyethyl)-1H-pyrrol-2-yl)methylene)-5-(1hydroxyethyl)-1H-pyrrol-2(3H)-one 1.95 g (5 mmol) 2,6-dichlorophenyl N-confused dipyrrinone 3-10 was dissolved in anhydrous THF/MeOH (50 mL 4:1). 4.3 g (108.0 mmol) NaBH4 was added and the reaction was stirred for 1 hour at room temperature. After the starting material was consumed as confirmed by TLC analysis, 50 mL water was added. The aqueous layer was extracted with dichloromethane (3 x 50 mL) and the combined extracts were washed with brine and dried over anhydrous Na2SO4. After evaporation, 1.80 g biscarbinol derivative of N-confused dipyrrinone 4-22 was obtained, yield 92%. 1  H NMR (300 MHz, C2D6CO): δ (ppm) 1.33-1.35 (d, 3H, J = 6.0 Hz), 1.53-1.55  (d, 3H, J = 6.0 Hz), 4.31 (s, 1H), 4.50 (s, 1H), 4.57 (q, 1H, J = 3.0 Hz), 4.91 (s, 1H), 4.98 (q, 1H, J = 3.0 Hz), 5.76 (d, 1H, J = 3.0 Hz), 6.08 (d, 1H, J = 3.0 Hz), 7.48-7.59 ( m, 3H), 9.28 (br, 1H); 14.28 (br, 1H); 13C NMR (100 MHz, CDCl3): δ (ppm) 22.67, 23.94, 64.33, 64.72, 100.19, 108.89, 118.55, 123.16, 129.50, 130.60, 131.49, 135.99, 138.70, 144.97, 145.68, 170.50; HRMS (EI) Calcd for C19H18Cl2N2O3: 392.0695. Found: 392.0694. Synthesis of 4-23 and 4-24 0.98 g (2.5 mmol) biscarbinol derivative of N-confused dipyrrinone 4-22 and 0.2 g (2.5 mmol) pyrrole were dissolved into CH2Cl2 (50 mL) and trifluoroacetic acid (92 μL, 0.88 mmol) was added. After stirring at room temperature for one hour, the reaction was quenched with 10% aqueous NaOH. The organic phase was removed and washed with  212  water, dried over Na2SO4, and evaporated under vacuum. Then crude compound was purified by silica column chromatography (DCM/EA= 4:1) to afford 0.34 g N-confused tetrapyrrole 4-23, yield 28%. 1.04 g 4-24 was obtained following the same procedure by reaction of 4-22 with pentafluorophenyl DPM, yield 61%. 4-23 1H NMR (300 MHz, CDCl3): δ (ppm) 1.44-1.46 (d, 3H, J = 6.0 Hz), 1.701.72 (d, 3H, J = 6.0 Hz), 3.80-3.82 (d, 1H), 4.28-4.30 (q, 1H, J = 3.0 Hz), 4.93 (s, 1H), 5.89 (s, 1H), 6.02 (s, 1H), 6.04 (s, 1H), 6.12 ( s, 2H), 6.18 (s. 1H), 6.69 (m, 2H), 7.327.45(m, 3H), 8.00 (br, 1H), 8.13 (br, 1H), 13.92 (br, 1H); HRMS (EI) Calcd for C27H24Cl2N4O: 490.1327. Found: 490.1329. 4-24 1H NMR (300 MHz, CDCl3): δ (ppm) 1.37-1.39 (d, 3H, J = 6.0 Hz), 1.68170 (d, 3H, J = 9.0 Hz), 4.25-4.27 (q, 1H, J = 3.0 Hz), 4.52-4.54 (q, 1H, J = 3.0 Hz), 4.94 (s, 1H), 5.87-5.96 (m, 3H), 6.08 (m, 3H), 6.14 (s, 1H), 6.59 (s, 1H), 7.34-7.45 (m, 3H), 8.49 (s, 1H), 8.64 (s, 1H), 9.28 (s, 1H), 13.75 (br, 1H); 13C NMR (100 MHz, CDCl3): δ (ppm) 19.99, 21.43, 32.68, 33.23, 63.93, 101.02, 105.81, 106.85, 108.16, 108.42, 109.44, 117.78, 119.83, 119.98, 127.99, 128.54, 129.18, 129.72, 133.97, 134.91, 136.93, 137.55, 140.05, 144.28, 169.09; HRMS (EI) Calcd for C34H25Cl2F5N4O2: 686.1275. Found: 686.1271.  4-25  1-(5-((5-acetyl-1H-pyrrol-3-yl)(2,6-dichlorophenyl)methyl)-3,4-dibromo-1H-  pyrrol-2-yl)ethanone 0.37 g (1 mmol) 1-(4-((5-acetyl-1H-pyrrol-2-yl)(2,6-dichlorophenyl)methyl)-1Hpyrrol-2-yl)ethanone 2-23 was dissolved in 20 mL CH2Cl2. To this solution, 0.54 g (3 mmol) NBS was added and the mixture was stirred at room temperature for 3 hours. After removal of the solvent, the residue was dissolved in a small amount of dichloromethane and passed through a short alumina column using DCM/EA (3:1) as eluent. 0.30 g 4-25 was isolated as a white powder, yield 57%. 1  H NMR (300 MHz, CDCl3): δ (ppm) 1H NMR (300 MHz, CDCl3): δ (ppm) 2.36  (s, 3H), 2.39 (s, 3H), 6.16 (s, 1H), 6.73 (s, 1H), 6.90 (s, 1H), 7.19-7.38 (m, 3H), 8.95 (s,  213  1H), 9.69 (br, 1H); mp decomposed over 200°C. HRMS (EI) Calcd for C19H14Br2Cl2N2O2: 529.8810. Found: 529.8815. Synthesis of 4-26 1.85 g (5 mmol) 1-(4-((5-acetyl-1H-pyrrol-2-yl)(2,6-dichlorophenyl)methyl)-1Hpyrrol-2-yl)ethanone 2-23, was dissolved in 50 mL of anhydrous THF/MeOH (4:1), 4.3 g (108.0 mmol) NaBH4 was added and the mixture was allowed to stir for 3 hours at room temperature. After the starting material was consumed as confirmed by TLC analysis, 50 mL water was added, and the aqueous layer was extracted with CH2Cl2 (3 x 50 mL). The combined extracts were washed with brine and dried over anhydrous Na2SO4. After evaporation, the bis-carbinol derivative of N-confused dipyrromethane was obtained. The crude bis-carbinol derivative of N-confused dipyrromethane is unstable and was used directly in the next step. Crude bis-carbinol derivative of N-confused dipyrromethane (2.5 mmol) and bipyrrole (2.5mmol) were dissolved into 50 mL CH2Cl2 and trifluoroacetic acid (92 μL, 0.88 mmol) was added.2 The reaction was allowed to stir at room temperature for 2 h. After quenching with 10% aqueous NaOH, the organic phase was washed with water, dried over Na2SO4, and evaporated under vacuum. The residue was chromatographed on silica gel (CH2Cl2: hexanes = 7:3) to afford 0.28 g N-confused tetrapyrrole macrocycle 426, yield 12%. 4-26 1H NMR (300 MHz, CDCl3): δ (ppm) 1H NMR (300 MHz, CDCl3): δ (ppm) 1  H NMR (300 MHz, CDCl3) δ 1.61 (d, 3H, J = 3.0 Hz), 1.62 (d, 3H, J = 3.0 Hz), 4.15-  4.19 (m, 2H), 6.02-6.03 (s, 1H), 6.05 (s, 1H), 6.12-6.13 (m, 1H), 6.16 (m, 1H), 6.36 (d, 1H, J = 3.0 Hz), 6.50 (d, 1H, J = 3.0 Hz), 6.71-6.75 (m, 2H), 7.08-7.14 (m, 1H), 7.317.33 (m, 2H), 7.77 (br, 1H), 7.89 (br, 1H), 8.18 (br, 1H), 8.36 (br, 1H); HRMS (EI) Calcd for C25H24Cl2N2O3 :474.1378. Found: 474.1375.  General Procedure for Dimerization Reaction on DPMs: 0.19 g (0.5 mmol) (4-((5-benzoyl-1H-pyrrol-2-yl)(2,6-dichlorophenyl)methyl)1H-pyrrol-2-yl)(phenyl)methanone 2-32 was dissolved in 5 mL anhydrous DCM. To this solution, 0.22 g (1 mmol) DDQ and 0.05 mmol Et3N were added and the resulting  214  mixture was stirred at room temperature for 2 hours. After concentration, the residue was chromatographed on silica gel (DCM/EA=4:1) to afford the crude product, which was rechromatographed on alumina (ethyl acetate/CH2Cl2 = 1:20). 0.1 g 4-27a was produced as a green powder, yield 41%. 4-27b and 4-27c were made following the same procedure. 4-27a Yield 41%. 1H NMR (300 MHz, CDCl3): δ (ppm) 5.50 (m, 1H), 6.20 (s, 1H), 6.42 (s, 1H), 6.46-6.47 (d, 1H, J = 3.0 Hz), 6.54 (s, 1H), 6.70-6.71 (d, 1H, J = 3.0 Hz), 6.81-6.82 (m, 1H), 7.18-7.57 (m, 18H), 7.61-7.63 (d, 2H, J = 6.0 Hz), 7.82-7.84 (d, 2H, J = 6.0 Hz), 8.08-8.10 (d, 2H, J = 6.0 Hz), 8.15-8.16 (d, 2H, J = 6.0 Hz), 8.49 (br, 1H);  13  C NMR (100 MHz, CDCl3): δ (ppm) 110.81, 115.19, 117.10, 120.68, 120.85,  121.72, 124.73, 127.61, 128.43, 128.74, 128.89,128.94, 129.59, 130.03, 130.77, 131.04, 131.16, 131.47, 132.14, 132.22, 132.89, 133.27, 133.45, 133.49, 134.52, 134.63, 134.74, 135.71, 135.78, 136.10, 136.57, 137.23, 137.81, 137.88, 137.95, 139.24, 144.13, 153.69, 155.74, 183.50, 183.74, 185.88, 188.17. HRMS (ESI) Calcd for C58H35N4O4Cl4: 991.1412. Found: 991.1399.  4-27b Yield 61%.  1  H NMR (300 MHz, CDCl3): δ (ppm) 2.31 (s, 3H), 2.43 (s,  3H), 2.45 (s, 3H), 2.53 (s, 3H), 5.10-5.12 (m, 1H), 6.16 (d, 1H, J = 3.0 Hz), 6.29 (s, 1H), 6.32 (s, 1H), 6.41 (d, 1H, J = 3.0 Hz), 6.66-6.68 (s, 1H), 6.94-6.95 (m, 1H), 7.36-7.57 (m, 6H), 8.29 (br, 1H);  13  C NMR (100 MHz, CDCl3): δ (ppm) 25.36, 27.38, 27.91, 28.74,  75.25, 110.92, 111.63, 117.15, 118.20, 119.54, 125.39, 128.30, 128.67, 129.12, 129.24, 131.10, 131.26, 132.71, 132.78, 133.12, 134.44, 134.61, 134.93, 135.21, 135.99, 136.16, 137.80, 138.17, 138.92, 144.92, 154.84, 87.24, 187.56, 191.45, 196.38; HRMS (ESI) Calcd for C38H27N4O4Cl4: 743.0786. Found: 743.0768. 4-27c Yield 58%. 1H NMR (300 MHz, CDCl3): δ (ppm) 2.35 (s, 3H), 2.39 (s, 3H), 2.41 (s, 3H), 2.45 (s, 3H), 5.45-5.47 (m, 1H), 6.15 (s, 1H), 6.38 (s, 1H), 6.43-6.45 (d, 1H, J = 3.0 Hz), 6.52 (s, 1H), 6.67-6.68 (d, 1H, J = 3.0 Hz), 6.78-6.80 (m, 1H, J = 3.0 Hz), 6.98-7.00 (d, 2H, J = 6.0 Hz), 7.24-7.57 (m, 12H), 7.73-7.76 (d, 2H, J = 6.0 Hz), 8.028.04 (d, 2H, J = 6.0 Hz), 8.06-8.08 (d, 2H, J = 6.0 Hz), 8.46 (br, 1H);  13  C NMR (100  MHz, CDCl3): δ (ppm) 21.62, 21.68, 21.78, 74.17, 110.72, 114.95, 116.95, 120.38, 121.50, 128.23, 128.35, 128.70, 128.78, 128.85, 128.90, 129.06, 129.10, 129.17,129.24,  215  129.79, 130.16, 130.94, 131.00, 131.05, 131.52, 133.34, 133.42, 134.20, 134.51, 134.59, 134.76, 134.79, 134.90, 135.21, 135.51, 135.78, 135.85, 136.15, 137.70, 139.40, 142.80, 142.84, 143.68, 144.28, 153.70, 183.28, 183.43, 185.64, 187.75; HRMS (ESI) Calcd for: C62H43N4O4Cl4:1047.2038. Found: 1047.2031.  216  A.4.2 Crystal Data for 4-1, 4-11, 4-27a ORTEP Plot of Crystal Structure of 4-1: C19H14N2O2Cl2, Mw = 373.22, monoclinic, space group P21/n; dimensions: a = 12.0302(6) Å, b = 7.3077(4) Å, c = 19.9392(10) Å, α = 90.0º, β = 100.746(3)º, γ = 90.0º, V = 1722.18(15) Å3; Z = 4; 14970 reflections measured at 100 K; independent reflections: Unique: 3402(Rint = 0.044); R1 = 0.083, wR2 = 0.159, S = 1.03; highest residual electron density 0.66 e-/Å3.  217  ORTEP Plot of Crystal Structure of 4-11: C23H22Cl2N2O3, Mw = 444.10, triclinic, space group P-1; dimensions: a = 8.239 Å, b = 11.273 Å, c = 11.754 Å, α = 81.82°, β = 86.92°, γ = 84.17°, V = 1074.1 Å3; Z = 2; 21134 reflections measured at 100 K; independent reflections: Unique 4994 [R(int) = 0.0314]; R1 = 0.1036, wR2 = 0.2592, S = 1.142; highest residual electron density 2.596 e-/Å3.  218  ORTEP Plot of Crystal Structure of 4-27a: C58H35Cl4N4O4, Mw = 991.14, monoclinic, space group P-1; dimensions: a = 10.9122(8) Å, b = 21.1111(15) Å, c = 26.294(2) Å, α = 109.646(5)º, β = 95.702(5)º, γ = 90.437(5)º, V = 5671.0(7) Å3; Z = 4; 146646  reflections measured at 100 K;  independent reflections: Unique: 120318 (Rint = 0.000); R1 = 0.0843, wR2 = 0.2079; S = 1.067; highest residual electron density 1.093 e-/Å3 (all data R1 = 0.1239, wR2 = 0.2336).  219  A.5 Experimental Data for Chapter 5 Materials. Aryl aldehydes, 2-acetylpyrrole, 2-formylpyrrole and anhydrous DCM were purchased from Aldrich and used as received.  General Procedure 5-1 is synthesized according to the literature procedure 3 Synthesis of 5-2 1.52 g (40 mmol) NaBH4 was added to 2.75g (10 mmol) 2,4-dibenzoyl pyrrole in 50 mL anhydrous THF/MeOH (3:1) under argon and the reaction was allowed to stir at room temperature for 2 hours. Upon completion, the reaction was quenched with 100 mL saturated aqueous NH4Cl, and the system was extracted with DCM (3 x 100 mL). After drying over anhydrous Na2SO4, the solvent was removed under vacuum. The residue was dissolved in 100 mL DCM and 0.97 g (10 mmol) 2,5-dimethylpyrrole was added. 1 mmol TFA (as acid catalyst) was added dropwise. The reaction was stirred at room temperature for 2 hours and then treated with 10% aqueous NaOH. The organic layer was dried (Na2SO4) and the solvent was removed under vacuum. The residue was chromatographed on silica gel (DCM/EA = 6:1) to afford 0.94 g tripyrrane 5-2 as an amorphous powder, yield 65%.  Synthesis of 5-3a 3.5 g (20 mmol) 2,6-dichlorobenzaldehyde and 1.92 g (20 mmol) MSA were dissolved in 20 mL anhydrous DCM. To this solution, 4.36 g (40 mmol) 2-acetylpyrrole was added. The brown mixture was stirred for an additional 72 hours at room temperature in the dark. The reaction mixture was quenched with 10% NaOH aqueous and extracted with dichloromethane (3 × 150 mL). Volatile components were removed using a rotary evaporator, leaving a green-red residue. The resulting products were purified via column chromatography on silica gel (DCM: EA = 4:1). Recovered starting material was discarded, and the porphyrinogen and pyrrolemethane bands between the starting  220  material and the tripyrromethane were collected. After concentration, the solution was dried under vacuum and dissolved into CH2Cl2 (100 mL). 2.2 g (10 mmol) DDQ and 2 mmol Et3N were added and the resulting solution was stirred at room temperature for 2 hours. After concentration, the residue was chromatographed on silica gel (DCM: EA = 20:1) to afford 0.18 g green product 5-3a, yield 2.1%. Using the same eluent, an additional 0.21 g green product 5-4 was collected, yield 2.4%. By increasing the polarity of the eluent (DCM: EA = 10:1), 0.23 g red product 5-5 was isolated, yield 2.8%. Finally, 1.94 g of yellow dipyrrin product 4-1 was collected, yield 7%. 5-3b, 5-3c, 5-5b, 5-6, 5-7 were synthesized following the same procedure by reaction of pyrrole substrates with steric meso-aryl aldehydes.  Synthesis of 5-10a and 5-11a Tripyrromethane mixtures (5-10a as major product) were isolated from acidcatalyzed condensation of 2,6-dichlorophenyl aldehyde with 2-acetylpyrrole in 14% yield. To purify 5-10a, 1 equivalent of dibutyltin(II) dichloride and 1.2 g (20mmol) tripyrrane were dissolved in DCM (10 mL). To this solution, 0.5 mL of Et3N was added and the reaction was allowed to stir at room temperature for 1 hour. Upon completion, the mixture was concentrated and passed through a short silica column using DCM as eluent. 0.1g nonpolar tin complex 5-11a was isolated. 1.01g 5-10a was collected after increasing the polarity of the eluent (EA/DCM = 1:1).  Synthesis of 5-9a and 5-9b 0.92 g (4 mmol) DDQ was added to 0.64 g (1 mmol) tripyrrane 5-10a in anhydrous DCM (100 mL) at room temperature, and the reaction mixture was stirred for 72 hours. Upon completion, the reaction was quenched with 0.1 mmol Et3N. After removal of the solvent, the residue was dissolved in a small amount of DCM and passed through a short silica column using ethyl acetate as eluent. After concentration, the mixture was further chromatographed on silica gel column (DCM/EA = 3:1). The first red coloured band was collected to afford 0.28 g 5-9a, yield 41% and the second fraction was 0.29 g 5-9b, yield 42%.  221  A.5.1 1H and 13C NMR Data Compound 5-2 Yield 65%. 1H NMR (300 MHz, CDCl3) δ 1.11-1.14 (m, 6H), 1.89-1.93 (m, 6H), 2.17-2.18 (m, 6H), 2.40-2.48 (m, 4H), 5.37 (s, 1H), 5.49 (s, 1H), 5.83 (s, 1H), 6.31 (s, 1H), 7.22-7.38 (m, 10H), 7.79 (br, 1H); 13C NMR(100 MHz, CDCl3) δ 9.17, 11.08, 17.76, 29.68, 30.88, 41.62, 42.38, 107.78, 115.69, 119.88, 121.04, 124.56, 125.78.  Compound 5-3a Yield 2.1%. 1H NMR (300 MHz, CDCl3) δ 2.11 (s, 3H), 2.18 (s, 3H), 2.47 (s, 3H), 5.61 (s, 1H), 5.84 (s, 1H), 6.75 (s, 1H), 7.19-7.49 (m, 6H), 13.97 (br, 1H); 13C NMR(100 MHz, CDCl3) δ 25.21, 26.83, 27.17, 104.84, 110.12, 118.31, 118.72, 120.02, 123.32, 127.75, 127.81, 128.37, 128.79, 129.10, 130.27, 131.03, 132.16, 132.46, 132.80, 136.30, 136.41, 138.33, 138.52, 142.22, 185.69, 187.93, 191.83; HRMS (EI) Calcd for C32H20N3O3Cl4: 634.0259. Found 634.0248. Compound 5-3b Yield 6%. 1H NMR (300 MHz, CDCl3): δ (ppm) 5.70 (d, 1H, J =3.0 Hz), 5.95 (s, 1H), 6.51 (s, 1H), 7.09-7.72 (m, 21H), 14.10 (br, 1H);  13  C NMR (100 MHz, CDCl3): δ  (ppm) 104.04, 110.45, 120.14, 121.17, 122.59, 122.89, 127.21, 127.73, 128.06, 128.32, 128.49, 128.51, 128.67, 129.09, 129.25, 130.15, 131.14, 131.40, 131.73, 132.07, 132.58, 132.81, 135.39, 135.94, 135.98, 136.72, 137.67, 137.83, 139.24, 139.63, 142.18, 182.33, 186.13; HRMS (EI) Calcd for C47H26N3O3Cl4: 820.0728; Found: 827.0750. Compound 5-3c Yield 3.8%. 1H NMR (300 MHz, CDCl3): δ (ppm) 2.18 (s, 3H), 2.30 (s, 3H), 2.38 (s, 3H), 2.41 (s, 3H), 5.70 (d, 1H, J = 3.0 Hz), 5.95 (s, 1H), 6.51 (s, 1H), 6.99-7.63 (m, 18H), 14.06 (br, 1H); 13C NMR (100 MHz, CDCl3): δ (ppm) 21.50, 21.53, 21.54, 103.92, 110.31, 120.83, 122.12, 127.30, 127.62, 128.10, 128.66, 128.73, 128.79, 129.01, 129.47, 130.24, 130.67, 32.60, 134.21, 135.19, 135.42, 136.02, 142.35, 143.50, 188.37; HRMS (EI) Calcd for C50H32N3O3Cl4: 826.1198. Found: 862.1215.  222  Compound 5-4 Yield 3.1%. 1H NMR (300 MHz, CDCl3) δ 2.53 (s, 3H), 2.57 (s, 3H), 2.60 (s, 3H), 2.88 (s, 3H), 5.34 (s, 1H), 6.01 (s, 1H), 6.60 (s, 1H), 6.96 (s, 1H), 7.27-7.70 (m, 9H), 8.69 (s, 1H), 9.07 (s, 1H), 12.79 (s, 1H);  13  C NMR(100 MHz, CDCl3) δ 12.16, 13.15,  25.78, 26.04, 103.92, 107.49, 107.93, 109.07, 110.39, 120.59, 125.89, 126.13, 132.85, 128.51, 141.13, 185.96, 190.35; HRMS (EI) Calcd for C45H28N4O3Cl6: 886.0234. Found: 886.0227.  Compound 5-5a Yield 3.5%. 1H NMR (300 MHz, CDCl3) δ 2.31 (s, 3H), 2.58 (s, 3H), 2.67 (s, 3H), 6.63-6.65 (d, 1H, J = 6.0 Hz), 6.98-7.00 (d, 1H, J = 6.0 Hz), 6.71 (s, 1H), 6.81 (s, 1H), 7.49-7.62 (m, 6H), 8.80 (s, 1H), 11.72 (s, 1H);  13  C NMR(100 MHz, CDCl3) δ 13.57,  25.84, 25.92, 108.30, 109.07, 114.19, 114.69, 124.85, 128.11, 128.57, 129.15, 129.74, 129.96, 130.78, 133.70, 134.04, 134.27, 135.75, 136.55, 137.76, 138.21, 139.03, 165.89, 190.55, 196.24; HRMS (ESI) Calcd for C32H21N3O2Cl4: 621.0358. Found: 621.03574. Compound 5-5b Yield 3.0%. 1H NMR (300 MHz, CDCl3) δ 2.53 (s, 3H), 2.61 (s, 3H), 2.71 (s, 3H), 6.75-6.76 (d, 1H, J = 6.0 Hz), 6.85 (s, 1H), 6.92 (s, 6H), 7.09 (d, 1H, J = 6.0 Hz), 8.97 (s, 1H), 11.79 (s, 1H); 13C NMR(100 MHz, CDCl3) Due to the C/F coupling the signals of C are not good. HRMS (EI) Calcd for C32H15N3O2F10: 663.1005. Found: 663.1008. Compound 5-9a Yield 41%. 1H NMR (300 MHz, CDCl3) δ 2.36 (s, 6H), 2.54 (s, 3H), 2.55 (s, 3H), 6.60 (s, 1H), 6.84 -7.08 (m, 7H), 8.45 (s, 1H), 9.70 (br, 1H); 13C NMR(100 MHz, CDCl3) δ 24.91, 28.16, 109.63, 111.17, 118.15, 119.10, 120.62, 123.49, 123.80, 128.10, 128.54, 129.30, 129.48, 130.08, 132.57, 136.62, 137.20, 187.05, 189.93; HRMS (EI) Calcd for C32H19N3O3Cl6: 702.9558. Found: 702.9552.  223  Compound 5-6 Yield 6%. 1H NMR (300 MHz, CDCl3): δ (ppm) 6.68 (d, 1H, J = 3.0 Hz), 7.18 (d, 1H, J = 3.0 Hz), 7.22 (s, 1H), 7.40-7.89 (m, 14H), 7.88-7.90 (m, 2H), 8.42-8.44 (m, 2H), 10.05 (br, 1H);  13  C NMR (100 MHz, CDCl3): δ (ppm) 120.28, 124.51, 126.37, 127.14,  128.48, 129.45, 130.88, 131.42, 133.28, 133.86, 134.19, 135.81, 136.24, 143.19, 143.81, 145.12; HRMS (EI) Calcd for C29H18O2N2Cl2: 498.0717. Found: 498.0716. Compound 5-7 Yield 8%. 1H NMR (300 MHz, CDCl3): δ (ppm) 2.43 (s, 3H), 2.44 (s, 3H), 6.67 (d, 1H, J = 3.0 Hz), 7.16 (d, 1H, J = 3.0 Hz), 7.20 (s, 1H), 7.42-7.48 (m, 3H), 7.61 (s, 1H), 7.70 (s, 1H), 7.84-7.86 (d, 4H), 8.39-8.41 (d, 4H), 9.95 (br, 1H);  13  C NMR (100 MHz,  CDCl3): δ (ppm) 21.70, 21.76, 121.25, 123.62, 127.47, 128.16, 128.78, 129.25, 130.46, 131.12, 134.29, 134.36, 134.69, 135.01, 136.04, 143.15, 143.48, 145.02; HRMS (EI) Calcd for C31H22O2N2Cl2: 526.1029. Found: 526.10414. Compound 5-9b Yield 42%. 1H NMR (300 MHz, CDCl3) δ 2.08 (s, 6H), 2.36 (s, 3H), 2.54 (s, 6H), 6.60 (s, 1H), 6.84 (m, 1H), 6.98-7.08 (m, 2H), 8.45 (b, 1H), 9.70 (br, 1H); 13C NMR (100 MHz, CDCl3) δ 25.01, 25.81, 27.98, 110.90, 117.87, 121.83, 123.34, 124.63, 127.32, 127.90, 128.62, 128.72, 128.79, 129.62, 130.87, 130.98, 131.34, 133.14, 135.41, 136.36, 136.95, 137.19, 187.03, 187.19, 189.95; HRMS (EI) Calcd for C32H19N3O3Cl6: 706.9498. Found: 706.9506. Compound 5-10a 1  H NMR (300 MHz, CDCl3) δ 2.32 (s, 3H), 2.34 (s, 3H), 2.39 (s, 3H), 5.73 (s,  1H), 6.14 (s, 1H), 6.54 (s, 1H), 6.62 (s, 1H), 6.74 (s, 1H), 6.84 (m, 1H), 7.09-7.32 (m, 6H), 9.07 (br, 1H), 9.28 (br, 1H), 9.62 (br, 1H); HRMS (EI) Calcd for 639.0650. Found: 639.0637. Changing the substrate to 2-benzoyl pyrrole produce the corresponding β-α-β-β connected tripyrromethane in 18% yield with no other isomers observed. 1H NMR (300 MHz, CDCl3) δ 5.72 (s, 1H), 6.23 (s, 1H), 6.65 (s, 1H), 6.69-6.70 (m, 1H), 6.87 (s, 1H),  224  6.93 (s, 1H), 7.04(s, 1H), 7.06-7.30 (m, 6H), 7.41-7.94 (m, 10H), 9.34 (br, 1H), 9.59 (br, 1H), 9.79 (br, 1H); 13C NMR (100 MHz, CDCl3) δ 37.75, 39.11, 118.53, 119.44, 121.42, 121.66, 122.12, 124.39, 124.80, 125.75, 127.80, 128.22, 128.31, 128.50, 128.87, 128.90, 128.98, 130.72, 131.65, 131.79, 132.08, 137.96, 138.37, 184.65; HRMS (ESI) Calcd for C47H31N3O3Cl4Na 848.1017. Found: 848.0988.  225  A.5.2 Crystal Data for 5-3a, 5-3b, 5-4, 5-5b, 5-9a, 5-9b, 5-11b Crystal Structure of 5-3a: C32H20Cl4NO3, Mw = 634.02, monoclinic, space group P21/n; dimensions: a = 13.9882(8) Å, b = 14.1324(7) Å, c = 20.2525(11) Å, α = 76.443(3)°, β = 70.996(2)°, γ = 69.190(2)°, V = 3506.4(3) Å3; Z = 8; 70799 reflections measured at 100 K; independent reflections: Unique: 16609 (Rint = 0.0356); R1 = 0.0751, wR2 = 0.2426, S = 1.115.  226  Crystal Structure of 5-3b: C47H26Cl4N3O3, Mw = 820.07, monoclinic, space group C2/c: b1; dimensions: a = 31.430Å, b = 11.253 Å, c = 20.903 Å, α = 90°, β = 102.17°, γ = 90°, V = 7226.8 Å3; Z = 4; 58548 reflections measured at 100 K; independent reflections: Unique: 10629 (Rint = 0.0283); R1 = 0.0639, wR2 = 0.1708, S = 1.021.  227  Crystal Structure of 5-4: C47H26N3O3Cl4, Mw =820.07, triclinic, space group P-1; dimensions: a = 12.4730 Å, b = 29.7360 Å, c = 33.5230 Å, α = 107.637°, β = 95.011°, γ =102.004°, V = Å3; Z = 4; 177518 reflections measured at 100 K; independent reflections: Unique: 41621(Rint = 0.0634); R1 = 0.1229, wR2 = 0.4212, S = 1.58.  228  Crystal Structure of 5-5b: C32H15F10N3O3, Mw = 663.1008, monoclinic, space group P-1; dimensions: a = 10.8150(16) Å, b = 13.673(2) Å, c = 20.805(3) Å, α = 97.781(7)°, β = 93.163(7)°, γ = 101.960(8)°, V = 2971.0(8) Å3; Z = 2; 28994 reflections measured at 100 K; independent reflections: Unique: 8116(Rint = 0.0634); R1 = 0.0615, wR2 = 0.1389, S = 1.021.  229  ORTEP Plot of Crystal Structure of 5-11b: C40H40Cl2F2N3O3Sn, Mw = 838.84, triclinic, space group P-1; dimensions: a = 13.2940(11) Å, b = 13.3270(11) Å, c = 15.3600(15) Å, α = 113.575(4)°, β = 94.515(4)°, γ = 118.780(4)°, V = 2057.7(3) Å3; Z = 2; 30613 reflections measured at 100 K; independent reflections: Unique: 9793 [R(int) = 0.0226]; 3745 [R(int) = 0.0220]; R1 = 0.0657, wR2 = 0.1980, S = 1.097.  230  ORTEP Plot of Crystal Structure of 5-9a: C32H19Cl6N3O3, Mw = 702.96, monoclinic, space group P-1; dimensions: a = 10.2231(5) Å, b = 13.2106(7) Å, c = 14.0341(7) Å, α = 96.761(3)º, β = 92.689(3)º, γ = 99.153(2)º, V = 1854.04(16) Å3; Z = 3; 35759 reflections measured at 100 K; independent reflections: Unique: 8591(Rint = 0.0292); R1 = 0.0769, wR2 = 0.2245, S = 1.034.  231  ORTEP Plot of Crystal Structure of 5-9b: The structure of 5-12b was solved by direct methods. The material crystallizes with disordered methylene chloride in the lattice. This disordered is too extensive to be properly modeled, therefore the PLATON/SQUEEZE program was used to correct the data for any unresolved electron density found in void spaces in the lattice. The SQUEEZE output suggests approximately two molecule of CH2Cl2 in the asymmetric unit. C32H19Cl6N3O3, Mw = 702.96, monoclinic, space group P-1; dimensions: a = 9.3090(12)Å, b = 11.6760(17)Å, c = 17.163(3)Å, α = 78.720(5)º, β = 83.900(5)º, γ = 89.870(5)º, V = 1818.8(5) Å3; Z = 2; 22987 reflections measured at 100 K; independent reflections: Unique: 6679 (Rint = 0.0425); R1 = 0.0448, wR2 = 0.1201, S = 1.038.  232  References  1. Xu, R. X.; Anderson, H. J.; Gogan, N. J.; Loader, C. E.; McDonald, R. Tetrahedron Lett. 1981, 22, 4899. 2. Dohi, T.; Morimoto, K.; Maruyama, A.; Kita, Y. Org. Lett. 2006, 8, 2007. 3. Gazezowski, M.; Jazwinski, J.; Lewtak, J.; Gryko, D. T. J. Org. Chem. 2009, 74, 5610.  233  

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