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1,3-dipolar cycloadditions with porphyrins Flemming, Jeffrey 2001-12-31

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1,3-Dipolar Cycloadditions with Porphyrins by  Jeffery Flemming B . Sc. (Hons), Wilfrid Laurier University, 1997  A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE In  THE FACULTY OF GRADUATE STUDIES DEPARTMENT OF CHEMISTRY We accept this thesis as conforming to the required standard  THE UNIVERSITY OF BRITISH COLUMBIA August 2001 © Jeffery Flemming, 2001  In presenting this thesis  in partial fulfilment of the requirements for an advanced  degree at the University of British Columbia, I agree that the Library shall make it freely available for reference and study. I further agree that permission for extensive copying of this thesis for scholarly purposes may be granted by the head of my department  or  by  his  or  her  representatives.  It  is  understood  that  copying  or  publication of this thesis for financial gain shall not be allowed without my written permission.  The University of British Columbia Vancouver, Canada  DE-6 (2788)  11  Abstract The  objective  of this work is to use  1,3-dipolar cycloadditions to  synthesize novel aromatic compounds based on meso-phenyl substituted porphyrins. These compounds are potential photosensitizers for use in photodynamic therapy. Tetraphenylporphyrins with a variety of substituents were reacted with selected 1,3-dipoles.  Tetraphenylporphyrin (TPP), 5,10-diphenylporphyrin (DPP), and  tetrakis(pentafluorophenyl)porphyrin (pFTPP) were used in reactions with azomethine ylides, carbonyl ylides, diazoalkanes, nitrile oxides, thiocarbonyl ylides, nitrile ylides, and ozone, with varying results. Centrally metallated porphyrins were also used. Azomethine ylides reacted with p F T P P efficiently giving cycloadducts of F  F  36a-38a pFTPP.  Three n-substituted azomethine ylides (R = benzyl, 3,5-dimethoxybenzyl, and  propyl) were used.  The different substituents on the pyrrolidine ring did not affect the  ultra-violet / visible ( U V - V i s ) spectra of the chlorin.  Ill  Carbonyl ylides form cycloadducts with both T P P and p F T P P . The  F  41  electron deficient p F T P P reacts with non-stabilized carbonyl ylides, while T P P reacts with the electron deficient tetracyano-substituted carbonyl ylide. These results highlight the differences in reactivity of these two porphyrins. hydrolyzed with concentrated hydrochloric acid,  The cyano groups of 42 were  and then methylated  giving  41.  Changes were observed in the U V - V i s spectra as the substituents were modified. Diazomethane  gave  the  cycloadduct  pyrazoline  with  pFTPP  (45).  Compound 45 was then subjected to heat or light, both of which caused the loss of N giving the cyclopropane 46.  2  The U V - V i s a spectrum of the cyclopropane derivative was  IV  red-shifted as compared to the pyrazoline, possibly by distortion in the porphyrin ring system as a result of the cyclopropane ring. F  F  45  46  V  Table of Contents Abstract  ii  Table of Contents  v  List of Figures  viii  List of Schemes  x  List of Tables  xiii  Nomenclature  xiv  List of Abbreviations  xvi  Acknowledgements  xviii  Chapter One 1.1  1.2  Introduction  T e t r a p y r r o l i c Macrocycles  1 1  1.1.1  Introduction  1  1.1.2  Structural Characteristics  4  1.1.3  Reactivity  8  1.1.4  Optical Absorption Spectra of Porphyrins  10  1.1.5  Synthesis of Porphyrins  13  Photodynamic T h e r a p y  19  1.2.1  Introduction  19  1.2.2  Production of a Useful Photosensitizer  21  1.2.3  Mechanism of Photosensitization  22  1.2.4  Singlet Oxygen Production  24  1.2.5  Porphyrin Related Photosensitizers  27  vi Core Modified Water Soluble Porphyrins  27 B P D M A  29 Zinc Tetraruthenated Porphyrin  31  1.3 1,3-Dipolar Cycloadditions  32  1.3.1  Introduction  32  1.3.2  Short History of 1,3-Dipoles  34 Diazomethane  37 Azides  37 Ozone  38 Nitrile Oxides  39  Mechanism and Reactivity of 1,3-Dipoles  40  1.3.3 General Description of Mechanism 1.3.4  Chapter Two  Methods of 1,3-Dipolar Cycloaddition  55 Diazoalkanes  55 Azomethine Ylides  59 Carbonyl Ylides  61 Thiocarbonyl Ylides  62 Nitrile Ylides  64  Results and Discussion  2.1 Introduction 2.1.1  40  65 65  Synthesis of Chlorins from Porphyrins  66 Natural Sources  66 Diels-Alder Reactions  66 Osmium Tetroxide Oxidation  69 1,3-Dipolar Cycloadditions  69  2.2 Results  70  2.2.1  Azomethine Ylides  71  2.2.2  Carbonyl Ylides  78 Tetracyanoethylene Oxide  78 Non-stabilized Carbonyl Ylide  89  Diazoalkanes  86 Diazomethane  86 (Trimethylsilyl)diazomethane  92  2.2.3  2.2.4  Nitrile Oxides  '.  93  2.2.5  Ozone  96  2.2.6  Thiocarbonyl Ylides  97  2.2.7  Nitrile Imines  98  2.2.8  Azides  99  2.2.9  Azaallyl Anions  100  Chapter 3  Conclusions and Suggestions for Further Work  102  Chapter 4  Experimental  104  4.1 Instrumentation and Materials  104  4.2 General Procedures and Data  105  Chapter 5  References  116  List of Figures  Figure 1-1  Tetrapyrrolic Macrocycles  1  Figure 1-2  Structure of Chlorophyll and Heme  2  Figure 1-3  Structure of Poly(vinylidine dichloride)-cobalt-porphyrin  3  Figure 1-4  Chelate Appended Porphyrins  4  Figure 1-5  Aromatic (4n+2) Pathway of Porphyrin  5  Figure 1-6  Tetraphenylporphyrin (6) and Octaethylporphyrin (7)  7  Figure 1-7  Representative Porphyrin Spectra  11  Figure 1-8  U V - V i s i b l e Spectra of Metalloporphyrins  12  Figure 1-9  U V - V i s i b l e Spectra of Chlorin and Bacteriochlorin  13  Figure 1-10  Absorption Intensity of Human Tissue  21  Figure 1-11  Modified Jablonski Diagram of a Photosensitizer  25  Figure 1-12  Singlet State of Molecular Oxygen  26  Figure 1-13  Core Modified Porphyrin Photosensitizers  28  Figure 1-14  Lt-{Me5O-5-10-15-20-tetra(4-pyridyl)porphyrin}-tetrakis-{bis(bipyridine)chlororuthenium(II)}  (26)  32  Figure 1-15  Resonance Structures of 1,3-Dipoles  33  Figure l-15a  Possible 1,3-Dipoles  35  Figure 1-16  Activation Energy Diagram of Early and Late Transition State (T.S.) ..41  Figure 1-17  Symmetry Allowed Interactions of Type One 1,3-Dipolar  Figure 1-18  Cycloadditions  44  Change in Molecular Orbital Energy Upon Substitution  45  ix  Figure 1-19  Symmetry Allowed Interactions of Type Three 1,3-Dipolar Cycloadditions  Figure 1-20  48  Symmetry Allowed Interactions of Type Two 1,3-Dipolar Cycloadditions  49  Figure 1-21  Complex Used for Molecular Orbital Calculations  54  Figure 1-22  Diazomethane Reactions with Electron Rich and Electron Poor Dipolarophiles  Figure 1-23  56  Correlation of the Rates of Reaction of Diazomethane and Diphenyldiazomethane  58  Figure 2-1  Selected Chlorins Tested as P D T Agents  65  Figure 2-2  Results of a, a'di(trimethylsilylmethyl)amine  Reaction with p F T P P and  AgF  73  Figure 2-3  U V - V i s Spectra of  36a, 37a, and 38a  Figure 2-4  Product of A c i d Hydrolysis and Methylation of 40  81  Figure 2-5  Structure of Compound 40  82  Figure 2-6  n-Confused Porphyrin  82  Figure 2-7  U V - V i s Spectra of 40,  Figure 2-8  U V - V i s Spectra of  Figure 2-9  Cyclopropane "Mixed Orbitals"  Figure 2-10  Trimethylsilylazide Cycloaddition Product  40a, and 41  45, 46  77  83 91 91 100  List of Schemes  Scheme 1-1  Electrophilic Substitution of the Porphyrin System  6  Scheme 1-2  Electrophilic Aromatic Substitution  6  Scheme 1-3  Reactions o f the Cross-Conjugated Double Bonds of Porphyrins  10  Scheme 1-4  Synthesis or Uro'gen III  15  Scheme 1-5  Synthesis of Tetraphenylporphyrin (6)  16  Scheme 1-6  Synthesis of Octaethylporphyrin (7)  17  Scheme 1-7  Mechanism for the Synthesis o f Octaethylporphyrin  17  Scheme 1-8  Porphyrin Synthesis from Dipyrrolic Precursors  18  Scheme 1-9  Synthesis of Hematoporphyrin Derivatives  20  Scheme 1-10  Type One Reactions of a Photosensitizer  23  Scheme 1-11  Reactions o f Singlet Oxygen  24  Scheme 1-12  Synthesis of B P D M A  30  Scheme 1-13  Reactions of the Two Types of 1,3-Dipoles  33  Scheme 1-14  Buchners' Proposed Mechanism of the Reaction between Diazoacetic A c i d with Fumaric A c i d  Scheme 1-15  36  Reaction of Methyl Diazoacetate with Dimethyl Acetylenedicarboxylate  36  Scheme 1-16  Reaction o f Diazoacetic A c i d with Methyl Acrylate  36  Scheme 1-17  Structures of Diazomethane and Hydrogen Azide  37  Scheme 1-18  Reaction of Phenyl Azide with Dimethyl Acetylenedicarboxylate  38  Scheme 1-19  The Criegee Mechanism for Ozonolysis  38  xi  Scheme 1-20  Non-concerted 1,3-Dipolar Cycloaddition Mechanism  40  Scheme 1-21  Reaction of Fulminic A c i d with Acetylene and Ethylene  42  Scheme 1-22  Mesomeric Betaines  52  Scheme 1-23  Metal Catalyzed Reaction of Phenyl Nitrile Oxide and 3-Hydroxy-1 -Propene  53  Scheme 1-24  Metal Catalyzed Nitrone Cycloaddition  54  Scheme 1-25  Production of Diazomethane  55  Scheme 1-26  Diradical Mechanism of 1,3-Dipolar Cycloaddition of Diazomethane  57  Scheme 1-27  Electrocyclic Ring Opening Formation of Azomethine Ylides  59  Scheme 1-28  Synthesis of Non-Stabilized Azomethine Ylides  59  Scheme 1-29  Inverse Electron Demand Azomethine Y l i d e 1,3-Dipolar Cycloaddition .60  Scheme 1-30  Reaction of 2-Azaalyl Anion with Anionophile  61  Scheme 1-31  Electrocyclic Ring Opening to form a Carbonyl Ylide  62  Scheme 1-32  Reduction of di-Chloromethylether to form an Unstabilized Carbonyl Ylide  62  Scheme 1-33  Methods of Generating Non-stabilized Thiocarbonyl Ylides  63  Scheme 1-34  Formation of Nitrile Ylides  64  Scheme 2-1  Reaction of Benzoquinonedimethane with T P P  67  Scheme 2-2  Diels-Alder Reactions with Protoporphyrin IX  68  Scheme 2-3  Dihydroxylation of T P P  69  Scheme 2-4  Reaction of Tetraarylporphyrins with Azomethine Ylide  70  Scheme 2-5  Mechanism of Azomethine Ylide Formation  74  xii  Scheme 2-6  Original Assumed Product of T C N E O / T P P Reaction  79  Scheme 2-7  Unstabilized Carbonyl Ylide Reaction with p F T P P to form 44  84  Scheme 2-8  Mechanism of Diazomethane Methylation ( X = O , S, or N )  86  Scheme 2-9  Cyclopropanation of T P P  87  Scheme 2-10  Reaction of Diazomethane with p F T P P  88  Scheme 2-11  Cyclopropane Formation from Pyrazoline  90  Scheme 2-12  Methods of Nitrile Oxide Formation  95  Scheme 2-13  Predicted Products of Porphyrin Ozonolysis  96  Scheme 2-14  Synthesis of Mesomeric Betaine 47  99  Scheme 2-15 Formation of Azaallyl Anions  101  Xlll  List of Tables  Table 1-1  Singlet Oxygen Quantum Yields  Table 1-2  U V - V i s Spectra Showing the Wavelengths of Maximal Absorption of (2) and (3) Compared to the Porphyrin Analogue  27  29  Table 1-3  Frontier Molecular Orbital Energies of Parent 1,3-Dipoles (Type One) ...46  Table 1-4  Relative Rate Constants of Reactions Between Diazomethane and Various Dipolarophiles  47  Table 1-5  Frontier Molecular Orbital Energies of Parent 1,3-Dipoles (Type Three) 49  Table 1-6  Molecular Orbital Energies of Type Three 1,3-Dipoles  Table 1-7  Relative Rate Constants of 1,3-Dipolar Cycloadditions with Phenyl Azide  50  51  XIV  Nomenclature  Monopyrrolic Systems The pyrrolic skeleton is numbered starting from the nitrogen atom as shown.  Positions 2 and 5 are commonly referred to as the " a " and 3 and 4 as the "p"  positions.  Dipyrromethanes are numbered as shown below.  Positions 1 and 9 are  referred to as the " a " positions, while positions 2, 3, 4, and 8 are the "(3" positions. Position 5 is called the "meso" position.  XV  Porphyrins and Related Systems The " a " positions are those at carbons 1,4,6,9,11,14,16, and 19. The "13" positions are those at carbons 2,3,7,8,12,13,17, and 18 and positions 5,10,15, and 20 are referred to as the "meso" positions  List of Abbreviations AgF  silver fluoride  aq.  aqueous  BPD  benzoporphyrin derivative  BPDMA  benzoporphyrin derivative monoacid ring A  CV  cyclic voltammograms  d  doublet  dd  doublet of doublets  DBU  l,8-diazabicyclo[5.4.0.]undec-7-ene  DDQ  2,3-dichloro-5,6,-dicyano-l,4-benzoquinone  DMAD  dimethylacetylene dicarboxylate  DMF  dimethyl formamide  DMSO  dimethylsulfoxide  DNA  deoxyribonucleic acid  DPP  5,15 -diphenylporphyrin  EI  electron impact  EDG  electron donating group  EWG  electron withdrawing group  FMO  frontier molecular orbital  HOMO  highest occupied molecular orbital  HpD  hematoporphyrin derivative  HRMS  high resolution mass spectrometry  Hz  Hertz  LiAlH4  lithium aluminum hydride  LRMS  low resolution mass spectrometry  LUMO  lowest unoccupied molecular orbital  m  multiplet  MS  mass spectrometry  NCS  n-chlorosuccinimide  NMR  nuclear magnetic resonance  /2-N0 -TPP 2  OEP  2-nitro-5,10,15,20-tetraphenylporphyrin 2,3,7,8,12,13,17,18-octaethylporphyrin  PDT  photodynamic therapy  pFTPP  tetrakis(pentafluorophenyl)porphyrin  q  quartet  qu  quintet  s  singlet  t  triplet  TCNEO  tetracyanoethylene oxide  THF  tetrahydrofuran  TLC  thin layer chromatography  TPP  tetraphenylporphyrin  UV-Vis  ultra-violet and visible  XV111  Acknowledgements  I would like to thank Dr. David Dolphin for allowing me to explore the field of porphyrin chemistry as I pleased.  This freedom allowed me challenge my own  limits as a scientist. I would like to thank the Dolphin group, not only for their support and encouragement, but also for the companionship that made the last two years enjoyable. Thanks especially to Angela M . Desjardins, David Fenwick, Dr. Elizabeth Cheu, and Dr. Alison Thompson, for helping me immeasurably with the writing of this thesis. I would also like to thank Ethan Sternberg for his guidance during my time at U . B . C . .  He allowed me to understand, if only in a small way, the world of  porphyrin chemistry.  1  Chapter One: Introduction 1.1  Tetrapyrrolic Macrocycles  1.1.1  Introduction This thesis discusses the chemical reactivity  of porphyrins and 1,3-dipoles.  Porphyrins are members of the tetrapyrrolic macrocycle family.  Some of the other  members of this family are shown in Figure 1-1.  Porphyrin  Chlorin  Isobacteriochlorin  Figure 1-1.  Bacteriochlorin  Corrin  Tetrapyrrolic Macrocycle.  2  A l l of the species shown in Figure 1-1, with the exception of the corrin, are aromatic. The consequences of this will be discussed in Section 1.1.2. Tetrapyrrolic macrocycles are abundant in nature.  The most common uses of  porphyrins and their analogues are related to the fundamental needs of plants and animals. Photosynthesis is the process that is responsible for the presence and  Chlorophyll (1)  Heme (2)  Figure 1-2. Structure of Chlorophyll (1) and Heme (2).  maintenance  of  oxygen  in  the  atmosphere.  Chlorophyll,  which  is  involved  in  photosynthesis, is a purpurin. Purpurins are chlorins with an exocyclic ring as shown in Figure 1-2 (1), and complex to magnesium giving chlorophyll.  Aromatic tetrapyrrolic  macrocycles can complex to many different metals (Section 1.1.2).  The first step of  photosynthesis involves the capture of light by chlorophyll. The light energy is then converted into chemical energy via a cascade of oxidation and reduction processes. Hemoglobin (the prosthetic of which is heme, see Figure 1-2) is used in the transport of oxygen in the human body.  In addition, heme forms the prosthetic group for catalases  3  and peroxidases, peroxide  1  which protect humans from species such as superoxide (O2") and  (O2 "). Nature depends on porphyrins to carry out and control redox processes. 2  Many important uses for porphyrins have been discovered since the elucidation of their structure almost 80 years ago.  One of these is in the use of porphyrins as light  capturing molecules to transform light energy into electrical energy. Another use of porphyrins is in the production of oxygen selective membranes. The  poly(vinylidine  dichloride)-cobalt-porphyrin  membrane  (Figure  investigated for its selectivity of oxygen transport over that of nitrogen.  2  1-3)  was  It was found  that the oxygen sorption amount is 30 times greater than that for nitrogen.  Figure 1-3. Structure of Poly(vinylidine dichloride)-cobalt-porphyrin.  Porphyrins have also been used as reagents to cleave double stranded D N A . Tetra-4-(N-methyl)pyridylporphyrin is known to bind to D N A ,  4  3  therefore compounds 4  and 5 (Figure 1-4) were assessed for their ability to cleave D N A .  The two chelate  4  appended porphyrins were found to induce single respectively of pBR322 plasmid D N A .  and double stranded cleavages  3  5  Figure 1-4. Chelate Appended Porphyrins.  Porphyrin cobalt complexes have also been used as nuclear magnetic resonance (N.M.R.)  shift reagents.  5  Applications of porphyrins are becoming more  widely  developed and applied. 1.1.2 Structural Characteristics The properties and uses of porphyrins have been investigated for many years, but the exact structure has only been known for a relatively short period of time. Kuster first suggested the structure of a porphyrin to be that of a tetrapyrrole in 1912.  8  This theory  was not widely accepted, as a tetrapyrollic structure was thought to be too large to be  5  stable.  In 1929 Fischer, who had originally refuted the tetrapyrrolic structure, completed  6  the total synthesis of heme, and thus Kuster's structure became accepted as the correct one. Porphyrins are aromatic.  This aromaticity defines the unique chemical and  physical properties of the porphyrin. The aromatic system consists of 22 ^-electrons,  yMeso Positions  ,Beta Positions  Figure 1-5. Aromatic (4n+2) Pathway of Porphyrin. which adheres to the (4n+2) rule of Huckel.  7  This aromaticity can be observed in the  N . M . R . spectra of porphyrins. The inner pyrrole protons are shifted significantly upfield, while the meso and yS-protons (Figure 1-5) are shifted downfield.  These effects are  caused by the diamagnetic ring current, which can shift the inner pyrrole protons as far upfield as - 5 ppm, and the meso and /2-protons as far downfield as 10 ppm.  8  The chemical reactions of porphyrins are similar to those o f other aromatic systems.  Electrophilic ( E ) substitution reactions such as nitration, sulfonation, and +  acylation of porphyrins all proceed through a cationic intermediate.  Subsequently a  proton is removed by a base in order to restore aromaticity (Scheme 1-1). The porphyrin system has two distinct reactive sites, as can be seen from Scheme 1-2. The meso and /^-positions have different reactivities, and often compete  6  Scheme 1-1. Electrophilic Substitution of the Porphyrin System. CHO  Scheme 1-2. Electrophilic Aromatic Substitution. during reactions.  Reactivity can be directed towards either the meso or /^-positions  through metallation o f the inner pyrrole nitrogens of the porphyrin ring. This will be discussed in Section 1.1.3. Different metals have been used to metallate the inner pyrrole nitrogens o f porphyrins (Section 1.1.1).  In fact, almost all of the metals of the periodic table have  been used to form complexes with porphyrins.  9  The size of the ring formed by the four  7  inner pyrrole nitrogens is such that it will accommodate a variety of metals, although some are too large, and must reside outside the plane of the r i n g . deprotonation of the pyrrole nitrogens.  Metallation occurs by  The p K i and p K values are both approximately 2  16, while the p K is 5 and the pIQ is 2. 3  10  11  Thus the porphyrin exists formally as its  dianion in a metal complex. It also exists as a dication in strong a c i d .  13  It is important to  note that the protons on the inner pyrrole nitrogens are not localized on any two nitrogen atoms, but equally on all four. This is due to the fact that porphyrins exist equally a two tautomers. One of the most striking and useful structural features of a porphyrin is the amazing structural diversity that has been attained while maintaining the key features of light absorption and photosensitivity.  This structural diversity becomes obvious by  comparing the structures of natural (Figure 1-2) and synthetic porphyrins (Figure 1-6).  Tetraphenylporphyrin (6)  Octaethylporphyrin (7)  Figure 1-6. Structure of Tetraphenylporphyrin (6) and Octaethylporphyrin (7). Diverse functionalization of both T P P and O E P has been achieved. This includes substitution of the phenyl rings and /^-positions of T P P (6), positions of O E P (7).  13  as well as the B and meso-  The functionalizing of the T P P phenyl rings may occur by using  substrates in the synthesis of T P P which give the desired substitution pattern,  i  n  or by  8  direct substitution o f T P P .  1 4  O E P can also be synthesized with substituents in the /3-  position, but mainly functionalization occurs through chemical reaction with the porphyrin r i n g . These functionalizations enhance the usefulness of porphyrins as briefly 19  discussed in Section 1.1.1. 1.1.3  Reactivity A s mentioned in Section 1.1.2, the chemical reactivity of the free-base porphyrin  is due to its aromaticity.  13  The reactivity of free-base porphyrins is similar to that of  other aromatic systems, however several differences do exist.  The most notable is the  fact that one can easily complex a variety of metals into the core of the porphyrin, and this can have a marked effect on the reactivity at the periphery. The degree of electronegativity at the porphyrin periphery can be controlled via incorporation  of  divalent metals.  Mg>Zn>Cu>Ni>Pd,  15  This  electronegativity  decreases  in the order  and the complexes that are formed tend to be more susceptible to  electrophilic substitution at the meso-positions in the same order. Metals such as Sn(IV) on the other hand, tend to bring substitution to the /^-positions.  This difference in 18  reactivity can be observed in the electrophilic substitutions shown in Scheme 1-2.  The  Vilsmeier reaction (POCI3, D M F ) is known to formylate preferably at the meso-position when the porphyrin is complexed to copper (Cu).'  6  Bromination on the other hand  occurs preferably at the /^-position when the porphyrin is complexed to Sn(IV) or is uncomplexed.  26  The porphyrins are not limited to reacting in the common electrophilic aromatic substitution manner that has been discussed thus far. Figure 1-5 shows that there are two double bonds that are conjugated, but are not a part of the aromatic system.  In other  9 words, these two "cross-conjugated" double bonds can be removed without disturbing the aromaticity of the ring. Chlorins and bacteriochlorins are produced, following removal of either one or both of these double bonds, respectively.  17  One example is the reaction of carbenes with O E P . Carbenes, such as those generated from ethyldiazoacetate,  18  tend to form cyclopropane rings by addition to the B-  double bonds of porphyrins. Some examples of Diels-Alder reactions have been reported to occur with the cross-conjugated double bonds.  13  The double bonds can act either as  the dienophiles or in concert with vinyl substituents to form the diene (Scheme 1-3). Substituents also affect the reactivity of the porphyrin ring. A s mentioned earlier, porphyrins can be functionalized in many ways, and this can be used to effect changes in the reactivity of the porphyrin.  For example, the cross-conjugated double bonds of  tetraphenylporphyrins will react only to a small degree with the most reactive dienes in a Diels-Alder reaction (Scheme 1-3).  19  However, i f tetrakis(pentafluorophenyl)porphyrin  is used then the Diels-Alder reaction occurs much more readily. is observed when porphyrins are reacted with 1,3-dipole. greater detail in Chapter two.  20  21  A similar phenomenon  This will be discussed in  10  Scheme 1-3. Reactions of the Cross-Conjugated Double Bonds of Porphyrins. 1.1.4  Optical Absorption Spectra of Porphyrins One of the main properties of porphyrins is their ability to absorb light, and then  transform this light energy for another use. Because of this property a great deal of study has been devoted to the light absorption patterns of porphyrins. There are two main regions of absorption in the UV-visible spectrum of a porphyrin.  The first is a very strong absorption between 390 nm-425 nm known as the  Soret band, and the second consists of a series of weaker bands between 480 nm-800 nm called the Q-bands.  22  The intensity and exact absorption maxima can reveal significant  information regarding the structure and nature of the porphyrin system.  Usually, there  11  are four Q-bands for non-metallated  porphyrins and two  for the metal porphyrin  complexes or the form with the inner pyrrole nitrogens protonated.  24  Shown in Figure 1-  7 are some representative UV-visible spectra of porphyrins. The etio-type spectrum (see Figure 1-7) is seen in porphyrins where the /?-substituents are all alkyl groups.  The  24  rhodo-type spectrum (see Figure 1-7) occur when electron-withdrawing groups are at the /^-position .  The oxo-rhodo spectrum (see  30  Figure 1-7)  withdrawing groups are on opposite pyrrole units.  30  is observed when electron-  The phyllo-type spectrum  (see  Figure 1-7) is observed when some of the /2-positions are left unsubstituted, or the mesopositions are  filled.  24  Etio  500  550  600  Rhodo  650  700 e  500  550  600  650  700  0)  Oxorhodo  Phyllo  > "53  I  500  I  550  I  600  I  I  650  Wavelength (nm)  700  500  I  550  I  600  I  650  Wavelength (nm)  Figure 1-7. Representative Porphyrin Spectra.  I  700  12  The ratio of the intensity of the two Q-bands in a metal porphyrin complex can also reveal useful information.  Strong Association, Ni(II)  a»3  Weak Association, Cd(II) a>3  c (D CD  13  i  i 500  525  i 550  i 575  i 600  Wavelength (nm)  500  525  550  575  600  Wavelength (nm)  Figure 1-8. UV-Visible Spectra of Metalloporphyrins. This ratio (Figure 1-8) can be used to qualitatively assess the strength o f the metalporphyrin association.  If the or-band (the higher intensity band) is much larger than the  /?-band (the lower intensity one), this shows qualitatively that the metal porphyrin complex is a stable one.  The strength of this metal porphyrin interaction refers to how  easily this complex may be de-metal lated. Chlorins and bacteriochlorins  exhibit UV-visible spectra that are markedly  different from those observed for porphyrins. For both types of compounds, the highest wavelength Q-bands are much more intense relative to the Soret band, and shifted to a lower wavelength  (red-shifted)  examples are shown in Figure 1-9.  than those of the corresponding porphyrin.  Two  A n excellent discussion of the theory behind the U V  spectra of porphyrins, chlorins and bacteriochlorins is given in "The Porphyrins".  13  Bacteriochlorin  Chlorin  350 400 450 500 550 600 650 700  350 400 450 500 550 600 650 700  Wavelength (nm)  Wavelength (nm)  Figure 1-9. UV-Visible Spectra of Chlorin and Bacteriochlorin. 1.1.5  Synthesis of Porphyrins Porphyrins are produced both by natural and synthetic methods. A single reaction  pathway is found for the synthesis of most naturally occurring porphyrins, chlorins and bacteriochlorins found in nature. Methods for synthesizing tetrapyrroles in a laboratory setting are diverse. Naturally occurring porphyrins are ultimately synthesized from 5-aminolaevulinic acid ( A L A ) (11) as shown in Scheme 1-4.  A L A self-condenses to form porphobilinogen  (PGB) (12), which condenses with four other P G B molecules to form uroporphyrinogen III (uro'gen III) (14).  This is accomplished with the help of two enzymes, P B G  deaminase and uro'gen cosynthetase. produced from uro'gen (III).  24  32  Heme, chlorophyll and vitamin B-12 are all  Oxidation of uro'gen (III) to form the porphyrin does not  occur until all peripheral manipulations have been accomplished.  25  In the case of  chlorophyll, the reduction to the chlorin is catalyzed by protochlorophyllide reductase  14  after all functional group manipulation and metal insertion are complete.  Vitamin B-12  is functionally a corrin (Figure 1-1), but it has been found that its synthetic pathway also includes uro'gen (III)  as an intermediate.  27  Uro'gen (III)  is found to be a key  intermediate in the synthesis of many tetrapyrrolic macrocycles that occur in nature. Synthetic porphyrins can be classified into two main groups; those where the /?positions are fully occupied by alkyl groups such as octaethylporphyrin (Figure 1-6), and those where the mew-positions (Figure 1-6).  are fully occupied such as in tetraphenylporphyrin  Both of these species can be synthesized by methods that allow for  relatively large-scale reactions with reasonable yields.  15  Mew-substituted porphyrins are usually synthesized by the condensation of an alkyl  or aryl  aldehyde  with  pyrrole.  Rothemund first  reported that  heating  benzaldehyde and pyrrole in pyridine under high pressure at 1 5 0 ° C gave the desired porphyrin.  29  These conditions were very harsh, and subsequent improvements have been  reported. Alder and Longo reported that refluxing the desired pyrrole and benzaldehyde in propionic acid in air (oxygen in the air being used as the oxidant) gave significantly improved results.  30  Lindsey reported that using D D Q as an oxidant also improves the  yield o f the reaction. The mechanism o f condensation between pyrrole and benzaldehyde is known to  31 proceed via acid catalyzed formation o f an arylpyrrole carbinol (Scheme 1-5).  The  carbinol then loses water to form the corresponding cation, which then condenses with another pyrrole unit, this process continuing until the porphyrinogen is formed. porphyrinogen is then oxidized to the porphyrin in situ. It is important to note  The  15  HO C—  C 0 S C q A  2  r  NH2  ALA Synthase  C0 H glycine (10)  T T  X T  C0 H  2  succinyl C o A (8)  2  O H 0  C0 H  H0 C  2  2  A L A (11)  0  C0 H  2C  2-oxoglutarate (9)  2  2-oxoglutarate  Dehydrogenase then Transaminase  C0 H  C0 H  2  2  >Q NH  NH  2  NH  N  ALA  2  <T^CO H  Dehydrase  2  H0 C  2  2  (  1  2  )  ALA  ALA  H0 C  C0 H  2  2  C0 H 2  C0 H  C0 H 2  H0 C. 2  2  H0 C  Cosynthetase J J Q  2  C0 H  H0 C 2  C0 H  2  2  H0 C 2  C0 H  C0 H  2  2  Uro'gen III (14)  Scheme 1-4.  Hydroxymethylbilane (13)  Synthesis or U r o ' g e n III.  that these are the steps to the desired products, but as there are many other products, there must also be other processes taking place.  16  Ph  Scheme 1-5. Synthesis of Tetraphenylporphyrin (6).  The most common method for the synthesis of O E P is the reduction and subsequent  cyclization of 2-ethoxycarbonyl-3,4-diethylpyrrole  (Scheme  1-6).  32  The  mechanism of this reaction involves the reduction of the ester to an alcohol, followed by a condensation reaction between the alcohol and the pyrrole. This reaction sequence is  17  repeated until the porphyrinogen is formed, which is then oxidized to the porphyrin (Scheme 1-7).  Scheme 1-6. Synthesis of Octaethylporphyrin (7).  Scheme 1-7. Mechanism for the Synthesis of Octaethylporphyrin.  18  Both methods mentioned above are used to make fully symmetrical porphyrins. There are also methods used to synthesize unsymmetrical analogues.  One of these  involves the use of the dipyrroles, dipyrromethenes (15) and dipyrromethanes (16) (Scheme 1-8).  Fischer developed many methods for the use of dipyrromethenes as  precursors to the porphyrins.  33  The MacDonald reaction involves the acid catalyzed  condensation of an a-position di-formyl-substituted dipyrromethane with an a-position non-substituted dipyrromethane (Scheme 1-7).  34  Scheme 1-8. Porphyrins Synthesis from Dipyrrolic Precursors.  19  1.2  Photodynamic T h e r a p y  1.2.1  Introduction Photodynamic therapy (PDT) is a minimally invasive procedure for treatment of  diseases that involve rapid cell growth, such as cancer. steps.  35  This procedure consists of two  First the photosensitizer is administered to the patient.  photosensitizer with lipoproteins then occurs.  Association of the  Since rapidly dividing cells require more  lipoproteins than normal cells, the drug will accumulate preferentially in rapidly dividing tissues. A dose of light of a particular wavelength is then administered to the patient's diseased area, activating the drug and thus destroying the tissue. Activation refers to the production of singlet oxygen from molecular triplet oxygen present, which is thought to be the active agent in P D T . Singlet oxygen undergoes many reactions with biological molecules.  This will be discussed in more detail in Section 1.2.4.  One benefit of this  procedure is that the drug is only activated upon exposure to light of a particular wavelength, so only minimal damage occurs in surrounding tissue. The patient must wait for the drug to be metabolized and excreted before exposing themselves to sunlight because of its ability to make the skin sensitive to light.  36  The phototoxicity of porphyrins has been known for almost 100 years.  47  Meyer-  Betz injected himself with 200 mg of hematoporphyrin derivative ( H p D , Scheme 1-9) in 1913.  37  He experienced extreme photosensitivity for many weeks, including lesions on  his skin, and other reactions to sunlight.  Meyer-Betz was forced to cover every part of  his body i f he wanted to go outside during daylight.  It wasn't until 1924 that Policard  found that porphyrins accumulated in malignant tissues.  38  This  combination  of  20  phototoxicity and preferential accumulation in cancerous tissues, which are two of the fundamental properties of a photodynamic drug, was not fully exploited until 1974, when the first human trials for P D T began.  39  H p D , as well as with a purified form called Photofrin (II), have long been the most commonly used P D T agents. monomers,  dimers  and oligomers  hematoporphyrin (17).  41  40  Both of these are a combination of porphyrin that  are  formed upon the  acid hydrolysis  Molecules with improved characteristics for use as P D T drugs  have since been developed. These will be discussed in detail in Section 1.2.5.  OH 5% H S 0 in A c O H 2  30 min. RT  4  Hematoporphyrin Derivitive Stage 1  Base C0 H 2  of  C0 H 2  Hematoporphyrin (17) Hematoporphyrin Derivative Stage 2 This is the usable drug (a mixture of monomers, oligomers, etc.)  Scheme 1-9. Synthesis of H e m a t o p o r p h y r i n Derivatives.  21  1.2.2 Production of a Useful Photosensitizer The characteristics of a useful P D T agent have been defined after many years of researching their properties. There are seven discussed below. 1.  42  The P D T agent must be a pure compound with a reproducible synthesis. The purity of the compound was one o f the main drawbacks o f the first generation  of photosensitizers (e.g. Photofrin).  They consisted of mixtures of many compounds  where the active constituents are not known.  It is important to know the exact  composition of a drug because impurities may cause side effects that could otherwise be avoided. 2.  The P D T agent must be activated at wavelengths between 650 nm-800 nm. Human tissue is relatively transparent between these wavelengths, while at lower  wavelengths it becomes less transparent (Figure 1-10). must penetrate the tissue before  43  it can sufficiently  This is important because light activate the drug.  Another  consideration is that there is not sufficient energy present in light above 800 nm to produce the active component in P D T , singlet oxygen (see Section 1.2.4).  c  .2 re o  ., . r  c  o  Q_  .2  Q.  re  550  630  700  800  nm  Figure 1-10. Absorption Intensity of Human Tissue.  22  3.  The drug must exhibit minimal dark toxicity. The advantage of P D T drugs is that they can be introduced generally and  activated locally, so that non-diseased tissues are minimally affected. If the drug is active in the absence of light (dark toxicity), then this benefit is lost. 4.  The drug must be an efficient photosensitizer. The drug, when activated, must efficiently generate singlet oxygen (Section  1.2.4).  Singlet oxygen is thought to be the active species in P D T , as the therapy is  ineffective when done in the absence of oxygen. 5.  44  The drug must localize specifically in diseased tissue. This goal has not been attained as of yet, although, preferential accumulation in  diseased tissue does occur with many P D T agents 6.  4 5  The drug must be efficiently metabolized. If this were not the case, one would have to. deal with the same situation as  Meyer-Betz.  47  This was also one o f the problems faced by some o f the first generation  photosensitizers. 7.  46  The drug must be soluble in the bodies' tissue fluids as to be easily administered  and transported to disease areas. Recently discovered P D T agents will be discussed in Section 1.2.5. 1.2.3  Mechanism of Photosensitization How can one explain why Meyer-Betz became so sensitive to sunlight after  injecting himself with hematoporphyrin derivative?  The reason is that this and many  other tetrapyrollic macrocycles are photosensitizers.  Photosensitizers (PS) absorb light,  which excites the molecule to an excited triplet state ( PS). Tissue damage is caused by 3  23  reaction o f the excited porphyrin with other molecules in the area ( S U B - H ) by either type one or type two processes. ' 47  Type one processes can occur either by either oxidation  62  of, or hydrogen abstraction from a molecule in the vicinity (Scheme 1-10). The 3  PS  +  SUB-H  Scheme 1-10. Type One Reactions of a Photosensitizer.  photosensitizer is then able to react with molecular oxygen to form reactive species, which can in turn generate radicals, and start a free chain radical reaction which could cause a great deal of damage in the b o d y . ' 61  48  Free radicals formed by hydrogen  abstraction, can interact with oxygen to form many different oxidized products, which could in turn initiate free radical chain reactions themselves.  '  The other method by which photosensitizers can be harmful to tissue is through what is known as a type two  reaction. ' 61  62  In this process, the excited triplet  photosensitizer, interacts directly with oxygen to form singlet oxygen. allowed process, and thus is very efficient. ' 61  62  This is a spin  Singlet oxygen is able to react with  24  biological molecules in a variety of ways.  61,62  Since this process is thought to be the  dominant one occurring during P D T , it will be discussed in more detail in Section 1.2.4 1.2.4  Singlet Oxygen Production After a photosensitizer absorbs light, it can transfer this energy to an oxygen  molecule to form singlet oxygen. This occurs by promotion of an electron in the ground state triplet oxygen to an excited state, forming singlet oxygen (Figure 1-11). There are two possible singlet states for oxygen.  One is a high energy (37.5 kcal/mol) and short  lived (< 10~ s), while the other is lower in energy (22.5 kcal/mol) and longer lived (4 u.s u  in water). ' 61  62  The second state is thought to be the one involved in P D T . This high  energy oxygen species can then undergo many reactions with functional groups in proteins, carbohydrates, D N A , etc. Scheme 1-11.  Some reactions of singlet oxygen are shown in  After a short period of time, these reactions, and similar ones, will cause  irreparable damage to a cell.  Hydrogen Abstraction and Oxygen Addition  Cycloaddition  Oxygenation  Scheme 1-11. Reactions of Singlet Oxygen.  25  The process by which the energy transfers from light to oxygen is only one o f many possible processes that can occur in the presence of a photosensitizer (Figure 1-11). The modified Jablonski diagram in Figure 1-11 gives a brief description of this process. The mechanism by which the energy is transferred from the photosensitizer to oxygen is not yet completely understood.  Internal Conversion  S-i  Intersystem Crossing Fluorescence Phosphorescence  Type 1 Process  Emission •  Absorption  Figure 1-11. Modified Jablonski Diagram of a Photosensitizer. Figure 1-11 shows a variety of processes that a photosensitizer can undergo once it has become activated. A l l of these involve the loss of energy to achieve the most stable ground state.  Energy can be lost either as heat (internal conversion), or as light  (fluorescence).  Another option is a spin-forbidden process in which the first excited  26  triplet state (Ti) is formed (this process also occurs with the loss of heat).  The triplet  state is much longer lived than that of any singlet state, as all routes to the ground state are spin forbidden.  Other possibilities include phosphorescence, type one or type two  processes. The singlet state of oxygen is shown in Figure 1-12.  In*  In*  3a  3a  In  In  2a*  2a* hv  2a  2a  la*  la"  la  la  Triplet Ground State  Figure 1-12.  Singlet Excited State  Singlet State of Molecular Oxygen.  A photosensitizer must have a long lived triplet state, as well as having the ability to transfer this energy to oxygen before phosphorescence occurs (Figure 1-11).  The  ability to transfer absorbed energy to oxygen through a non-radiative spin exchange is  27  quantified as the singlet oxygen quantum yield (OA)  4 9  A few examples are listed in  Table 1-1. Photosensitizer  Solvent  ® A (wavelength)  Hematoporphyrin  CH3OD  0.74 (546+576 n m )  CH3OD  0.70 (532 n m )  60  PB/1  0.79 (692 n m )  51  50  Derivative (HpD) OTe50-tetrakis(4sulfonatophenyl)porphyrin (TPPS) Benzoporphyrin  derivative  monoacid ring a ( B P D M A )  %TX100  (1% octylphenol ethylene oxide condensate ( T X 100) and phosphate buffer (PB)) PB  Chlorin e6  0.75 (660)  62  Table 1-1. Singlet Oxygen Q u a n t u m Yields. 1.2.5 Porphyrin Related Photosensitizers There are a variety of ways to generate photosensitizers which have the qualities deemed necessary as discussed in Section 1.2.2. Photofrin has already been discussed but the more recent and effective compounds will be discussed-in Section 1.2.5.  Core Modified Water-Soluble Porphyrins Two  of the core modified porphyrins (Figure 1-13)  photosensitizing  ability  dithiaporphyrin  (18)  are and  5, 5,  10, 10,  15, 15,  investigated  for their  20-tetrakis(4-sulfonatophenyl)-21,  23-  20-tetrakis(4-sulfonatophenyl)-21,  23-  28  diselenaporphyrin (19).  These species were tested in response to the fact that the  porphyrin 5, 10, 15, 20-tetrakis(4-sulfonatophenyl)porphyrin (TPPS4) (Table 1-2) found to accumulate in tumors almost selectively, neurotoxin.  52  was  but has been reported to be a  It was hoped that core modification would eliminate this neurotoxicity,  while maintaining the photosensitizing properties. The two core modified porphyrins 18 and 19, have similar absorption spectra (Table 1-2).  Their U V - V i s absorption spectra are analogous to that of a porphyrin, with  the exception that the high wavelength Q-bands are significantly red-shifted (shifted to a higher wavelength), as compared to that of a porphyrin (Table 1-2).  This is significant as  human tissue is more transparent (Figure 1-10) at 695 nm than at the 630 nm absorption maxima of the porphyrin (Table 1-2).  53  5, 10, 15, 20-tetrakis(4-sulfonatophenyl) -21, 23-dithiaporphyrin (18)  5, 10, 15, 20-tetrakis(4-sulfonatophenyl) "  2 1  > 23-diselenaporphyrin (19)  Figure 1-13. Core Modified Porphyrin Photosensitizers.  29  A,  nm (s x 10" cm" mol" L ) in water 3  max  1  1  Compound  Soret  Band I V  Band III  Band II  Band I  TPPS4  411(464)  513 (15.5)  549 (7.0)  577 (6.5)  630 (3.9)  18  434(190)  513 (19.3)  546 (5.5)  633 (2.0)  695 (4.0)  19  434 (221)  513 (22.4)  546 (6.2)  631 (2.2)  695 (4.5)  54  Table 1-2. UV-Vis Spectra Showing the Wavelengths of Maximal Absorption of (18) and (19) Compared to TPPS4. It was found that 18 causes significant tumor damage and no alterations to the skin,  55  in  fact 18 was found to be a more effective tumor photosensitizer than chlorin e6 (Figure 21), which has been used as a P D T agent for many years. N o neurotoxicity was observed upon administration of 18 when P D T effective doses of were administered.  55  Compound  19 was not an effective photosensitizer. B P D M A The Diels-Alder reaction of protoporphyrin I X dimethyl ester (20) with dimethyl acetylenedicarboxylate gives a 1,4 diene benzoporphyrin adduct (21).  56  The 1,4-diene  benzoporpyrin adduct, under strongly basic conditions, rearranges giving the conjugated 1.3- diene (23).  The ester group on the carbon adjacent to that of the angular methyl is  then isomerized with diazabicyclo[5.4.0]undec-7-ene ( D B U ) to form 24. The final step is hydrolysis of the methyl esters giving B P D M A (25) (Scheme 1-12).  57  The purpose of forming the chlorin is to increase the intensity of absorption at long wavelengths.  The most intensely absorbing Q-band in the U V - V i s spectrum of the  1.4- diene (21) is 666 nm, while the maxima for the 1,3-diene (23) is 688 n m . ' 5 8  absorption is in the optimal range for tissue penetration (Figure 1-10).  7 7  This  C0 Me  C0 Me  2  C0 Me 21  2  2  Protoporphyrin IX Dimethyl Ester (20)  C0 Me 2  C0 Me 20% 2  C0 Me  C0 Me C0 Me 22 20% 2  2  C0 Me  C0 Me  2  23 24  2  2  90%  90% 25% HC1  C0 Me  C0 Mf  2  2  ^ O n e of These is Hydrolyzed to the Acid 25  Scheme 1-12.  40%  Synthesis of B P D M A .  31  Even with comparable electronic spectra, not all o f the 1,3-diene analogues are equally efficient photosensitizers.  24 is not active, and 25 is five times more active than the di-  1(\ 7*7 acid.  "7A "7"7  Additionally, 25 is metabolized and excreted within 72 h, '  '  and has a high  singlet oxygen quantum yield (0.78 in homogeneous solution, 0.46 in vivo). ' 76  58  This  drug has recently been approved in the United States for use in treating A M D (agerelated macular degeneration). The structure of 25 lends itself to the possibility of chemical modification so as to take advantage of the chlorin chromophore, while changing the physical properties o f the drug. The free acid group can be functionalized in many ways to produce a wide variety of photosensitizers with different physical properties. Zinc Tetraruthenated Porphyrin Synthesis o f novel "site specific photosensitizers" has been pursued.  59  PDT  agents, to date, are not site-specific and cause cessation o f cellular activity via damage to the entire cell. This can be undesirable because it is difficult to know what area o f the cell the drug is acting on. Ideally, site-specific P D T agents will be more effective as only targeted  cellular  processes  would  be  effected.  //-{me5 o-5-10-15-20-Tetra(4,  pyridyl)porphyrin}-tetrakis-{bis-(bipyridine) chlororuthenium(II)} (26) has been found to associate strongly with D N A .  6 0  In the presence o f D N A and oxygen 26, efficiently  photo-catalyzes the oxidation o f 2'-deoxyguanosine. deoxyguanosine  61  This reaction yields 8-oxo-2'-  and 4-hydroxy-8-oxo-dihydro-2'-deoxyguanosine.  77  These are the  products of a type two reaction where singlet oxygen was delivered specifically to the 2'deoxyguanosine residue.  Thus, in vitro, this is one example o f a photosensitizer that  reacts specifically with 2'-deoxyguanosine.  32  L  i  N  l  L  26 Figure 1-14. //-{meso-5-10-15-20-Tetra(4-pyridyl)porphyrin}-tetrakis-{bis(bipyridine)chlororuthenium(II)} (26). 1.3 1,3-Dipolar Cycloadditions 1.3.1 Introduction The  reaction between  cycloaddition (Scheme 1-13).  a "dipole" and a "dipolarophile" is  a  1,3-dipolar  The dipolarophile includes a 7i-bond, while the dipole  includes at least three atoms with four electrons in three consecutive p-orbitals. These porbitals overlap to produce an allyl anion molecular orbital that is the reactive part of the molecule. A dipole, consists o f a positively charged central heteroatom (usually oxygen or nitrogen, but can be sulfur or phosphorus) which compensates for the negative charge that is distributed evenly on the two terminal atoms. This results in a species with no net charge.  61  Figure 1-15 depicts some of the resonance structures o f allyl and allenyl type  1,3-dipoles.  It is possible to show the positive and negative charges localized at the  termini (Figure 1-15). This represents the "ambivalence" in the dipole.  Ambivalence  33  refers to the fact that the termini can be represented either as nucleophilic or electrophilic, depending on which resonance structure is observed.  A l l y l Type  A l l e n y l Type  0 ©  0 © A-B=C  A-B=C D E  D E  E  E  D=E  A' C  A''V  D=E  D-E  a  A- -C D-E B  A- "C D=E B  Scheme 1-13. Reactions of the Two Types of 1,3-Dipoles.  © 0  © 0  A=B-C Full Octets  -  - A-B-C Sextet on A  A l l y l Type  © 0  © 0  A=B-C  A=B"C  Full Octets  Sextet on A  Allenyl Type  Figure 1-15. Resonance Structures of 1,3-Dipoles.  A s shown in Scheme 1-13, the dipole can be that of a propargylic - allenylic, or an allylic form.  The difference  is that the allenylic type has an extra 7i-orbital  perpendicular to the plane of the allyl anion molecular orbital.  82  The central atom can be  that of either group V or V I (e.g. nitrogen or oxygen) in the allyl type, but only of group  34  V (e.g. nitrogen) in the allenyl type. charged in their quaternary state.  This is because only group V atoms are positively  61  Keeping the description and requirements for the structure of 1,3-dipoles in mind, while also restricting oneself to discussing the first row elements only, a table of possible 1,3-dipoles can be formulated (Figure l-15a). Even with the restriction of only using the first row elements, the possibilities are quite numerous (Figure 1-15a), and i f one were to include higher row elements such as sulfur and phosphorus the diversity of this chemistry, becomes even more apparent. 1.3.2 A Short History of 1,3-Dipoles 1,3-Dipoles as a species have been known since 1883,  62  but up until 1958, when  the classification shown in Figure l-15a was conceived, only five cycloadditions with 1,3-dipoles had been described.  61  The original 1,3-dipolar cycloaddition reaction was  reported from the family of diazoalkanes.  79  35 Propargyl-Allenyl Type Nitrilium Betaines — C  S  ©  © ©y N - C  ©  © 0/  © © © ©  © ©  Oxides  Betaines ©  © © N=N~C ©  ©  N=N=C  \  © ©  N=N~N ©  Nitrile  C=N=0  —C=N-0  ©  Nitrile Imines  •C=N=N  —C^N-N  Diazonium  Nitrile Ylides  \  N  ©  N=N~0  ~*  "  Diazoalkanes  \  N=N=N  Azides  © © N=N=0  Nitrous  Oxide  Allyl Type N i t r o g e n as C e n t r a l A t o m \ /  C  /  = N - N  C  © © = N - 0  -  \ © © / ^N=N-N \  ©  \ /  \ x  x  © © / C=0-N  \ \  \  © © © © / N=0-N © ©  N=0-0 ©  ©  0=0-0  y  I  \ ©  ©  "  /  Ylides  Azomethine  Imines  Nitrones 0  ©  /  Azimines Azoxy  N~N=0  ©  Azomethine  x  N"N=N / ©i  Comounds  ©  /0-N= -  V  I ©  .C-N=N  x  = N - 0  c=o-c  \©  V "  O x y g e n as C e n t r a l A t o m \ © © / /  x  \ ©  "  ©0 0  \® © / .C-N=C  / C - N =  ©  N=N-0  /  -  X  C  \ /  © © / = N - C  Nitro  0  Compounds  -  \0 © /  c-o=c  \© © / C - O ^ \©  / /  ©  \© © / N-0=N \©  Carbonyl Ylides  x  ©  C a r b o n y l Imines Carbonyl  Oxides  Nitrosimines  N-0=0  Nitrosoxides  © © 0-0=0  Ozone  Figure l-15a. Possible 1,3-Dipoles.  36  Eduard Buchner was reported to be the first person to accomplish a 1,3-dipole reaction.  63  Buchner reacted ethyl diazoacetate with unsaturated carboxylic esters which  gave a cycloadduct and N2 was expelled upon heating this cycloadduct (Scheme 1-14). rrC0 H  +  N  N-r-C0 H  2  C0 H  L  2  2  C0 H  °  H  2  2  C  N-LCC^H  Scheme 1-14. Buchners' Proposed Mechanism of the Reaction Between Diazoacetic Acid and Fumaric Acid.  Buchner then reacted methyl diazoacetate with dimethyl acetylenedicarboxylate ( D M A D ) (Scheme cycloadduct. 15).  1-15), however no N2 was expelled upon heating the resultant  Buchner realized in 1893 that the product was the pyrazole (Scheme 1-  64  MeQ C-C-N^N + e 0 C - ^ - C Q M e 2  M  2  H  e  a  .  t  2  ® ®  M e ^ O - ^ N Me0 C  C0 Me  2  2  Scheme 1-15. Reaction of Methyl Diazoacetate and Dimethyl Acetylenedicarboxylate.  Buchner then proceeded to react methyl diazoacetate with methyl acrylate, and this yielded a 2-pyrazoline, which had been formed in a rearrangement from the initially formed 1-pyrazoline (Scheme 1-16).  H C0 C-g-N=N 3  H  2  3  C 0  2  C ^ ^ N  H  C0 CH 2  = - C 0  2  C H  3  C 0  2  C - ^ % H  3  3  Scheme 1-16. Reaction of Diazoacetic Acid with Methyl Acrylate.  C0 CH 2  3  37 Diazomethane Von  Pechmann  diazomethane  synthesized  diazomethane  with dimethyl fumarate  incorrect structures.  65  in  The structure of diazomethane, 69  Pechmann  61  and dimethyl maleate,  determined the 1930's using electron diffraction data. (Scheme  1894.  reacted  but assigned  the  being linear or cyclic,  was  66  The colourless cyclic diazirine  1-17) was synthesized in 1960, and as diazomethane is a yellow gas, this  confirmed the structure of diazomethane as linear and not c y c l i c .  67 Azides Azides have a history that is closely related to that of the diazoalkanes. Although not yet proven, much of the structural evidence points towards a linear, as opposed to cyclic structure,  13  as for the aliphatic diazo compounds (Scheme 1-17).  68  Unlike the  structure for diazomethane, the cyclic structure for the azide has not been ruled out (Scheme 1-17). azide  69  and  1 5  The bulk of the structural evidence comes from the reactivity of the  N labeling experiments as reported by Clausius and Weisser.  70  0©  0©  NH=N=N  HC=N=NH N  OR Cyclic Diazirine N HN-N Resonance Structures of  Possible Structures of  Diazomethane  Hydrogen Azide  Scheme 1-17. Structures of Diazomethane and Hydrogen Azide.  38 Michael was the first to report the reaction of phenyl azide with dimethyl acetylenedicarboxylic acid ester, and realized that this reaction was closely related to Buchners' reaction (Scheme 1-18).  71  C0 CH || 2  H N=N-N-C H 6  3  ^  N^JN  5  © 0  C0 CH 2  H C0 C  3  3  C0 CH  2  2  3  Scheme 1-18. Reaction of Phenyl Azide with Dimethyl Acetylenedicarboxylate. Ozone Ozone can be used as a reagent for the cleavage of double bonds.  72  The  o  mechanism of the reaction between ozone and a double bond has been a source of a great deal of controversy.  Criegee in 1953 did much work towards elucidating this  mechanism, and theorized that it involved a 1,3-dipolar cycloaddition, a 1,3-dipolar cycloreversion, and a 1,3-cycloaddition sequence (Scheme 1-19). '  73 61  The 1,2,3-trioxane  structure of the intermediate ozonide was established in 1966 by Bailey et al. using tertbutyl groups and establishing their equivalence using N M R .  ^-Bu  ~  H  ©a> o  H  7 4  ,00  t-BuVli O  '-  Bu  © H  X°Y'~  '•B»0-0H Scheme 1-19. The Criegee Mechanism for Ozonolysis.  BU  39  Still debates continued over the identity of the intermediates in the reactions o f ozone.  The carbonyl oxide was initially thought to be the zwitterionic intermediate  (Scheme 1-19). The correct structure of the intermediate was finally established as the carbonyl oxide capable of syn, anti - isomerism in 1975.  75  This structure is analogous to  that of the azomethine oxide, which was originally reported in 1918.  61  The mechanism of  ozonolysis is still contentious. In a recent paper the occurrence of a 1,3-dipole reaction in the ozonolysis mechanism was refuted by Schank et a l .  76 Nitrile Oxides The history o f nitrile oxides follows the discovery of formonitrile oxide and benzonitrile oxide.  Gay-Lassac and Liebig first reported the former, while Werner and  Buss first synthesized benzonitrile oxide in 1894.  77  Nitrile oxides have been found over  the years to be one of the most reactive of the 1,3-dipoles, and not only react with a TR  variety of dipoles and heterodipolarophiles, but also dimerizes to form furoxans.  This  competing dimerization was found to be slowed considerably by 2,6-disubstitution on the aromatic ring o f the benzonitrile oxide,  79  and with this di-substitution, many of these 1,3-  dipoles are stable even at r.L. The number o f uses of nitrile oxides in 1,3-dipolar cycloaddition chemistry is rapidly growing.  One use is a method to introduce isoxazole or 2-isoxazolines into a  molecule with good control over its regio- and stereochemistry. used in natural product synthesis.  80  form the isoxazole or 2-isoxazoline.  Often nitrile oxides are  In many instances no other reactions could be used to  40  1.3.3  Mechanism and Reactivity of 1,3-Dipoles Section 1.3.3  of the thesis will describe both the mechanism of the 3 + 2  cycloaddition of 1,3-dipoles and the theory behind the observed reactivity. General Description o f Mechanism The main controversy surrounding the mechanism of 1,3-dipolar cycloadditions is whether or not these reactions are concerted. The mechanism of reaction of a 1,3-dipole reaction is generally thought of as a suprafacial cycloaddition o f the 3 p orbitals from the z  dipole to the 2 p  orbitals of the dipolarophile. Woodward-Hoffman rules predict that  z  cycloadditions will be thermally allowed i f it proceeds by a concerted mechanism.  A  concerted mechanism provides rationale for the observed stereoselectivity of these 1,3-  81 dipolar reactions.  In other words, cis-l,2-disubstituted  dipolarophiles give  cis-  substituted pentacycles, and trans-1,2-disubstituted dipolarophiles give trans-substituted  R i R R  3  f  2 R  R  4 .  y,ce  Ob  3 4  R3 R2  R  \R y—^R A. ® {  K©  2  B-C  B-C  0  "  3 4_ R ! - ^ - R R  A.  R3  R  B  X  0  R  2  2  A. X B  Scheme 1-20. Non-concerted 1,3-Dipolar Cycloaddition Mechanism.  41  pentacycles.  103  A few exceptions do exist and were observed because of the lack of  stereoselectivity observed in the product (Scheme 1-20).  Examples of these will be  discussed in Sections The mechanism of 1,3-dipolar cycloadditions is not synchronous.  This means that the degree to which each of the new bonds are formed in  the transition state is not the same. 1,3-Dipolar cycloadditions are said to proceed via "early transition states".  61  Thus the transition state occurs early along the reaction coordinate of an activation energy diagram (Figure 1-16). This has the effect of making the transition state "reactant  >  Early T.S.  Late T . S .  o <' r-t.  5' 3 ffl 3 n> i-t  era  iiii,l».LUJilui ll^iM»» i,u»i.;yMiij»Nl..MWyw-i»ii»i'ii»m >  m  t  r  Reaction Coordinate  Figure 1-16. Activation Energy Diagram of Early and Late Transition State (T.S.). like",  while a late transition state is referred to as "product like".  postulate,  The Hammond  states that the transition state structure will be more similar in structure to  the species that is energetically closer to it. The calculation of the energies of reaction between fulminic acid and ethylene and acetylene provides some evidence of the early transition state.  The heat of reaction  is much lower for the isoxazole than it is for the 2-isoxaline as determined by ab-initio calculations.  This is rationalized, as the aromatic system isoxazole is more stable  42  © 0 HON-0.  Nonaromatic  Aromatic  Scheme 1-21. Reaction of Fulminic Acid with Acetylene and Ethylene.  than the non-aromatic 2-isoxaline (Scheme 1-21). for both the reactions are similar.  115  115  The calculated activation energies  This would suggest, according to the Hammond  postulate, that the transition state of isoxazole  does not benefit from the aromatic  stabilizing effect as much as would be expected i f the reaction had a late transition state.  131  Early transition states of 1,3-dipole reactions are observed as advantageous in the Perturbation Molecular Orbital ( P M O ) theory.  The P M O theory states that as two  molecules approach one another, mutual perturbation consists of three terms;  86  1.  Closed shell repulsion stems from the interaction of filled orbitals.  2.  Coulombic forces can be repulsive or attractive depending on the polarities of the  reactant pair. 3.  The "second order perturbation term" consists of attractive interactions between  all the occupied and unoccupied M O s of the reactants as long as these orbitals are of the correct symmetry. P M O theory is most often used to compare reaction sequences and since terms one and two are considered constant within a series, only the second order perturbation term needs to be considered.  61  43  This process can be further simplified when one considers that the highest occupied molecular orbital ( H O M O ) and lowest unoccupied molecular orbital ( L U M O ) of the reacting species have the lowest energy separation, and should therefore contribute most to the second order perturbation t e r m .  This enables one to consider solely the  112  frontier molecular orbitals ( F M O ) when discussing the differences in activities in a series of reactions.  The energies of these orbitals, as well as their orbital coefficients,  determined from various theoretical methods.  61  are  Transition states can be extrapolated  from the first differential reaction element as early transition states (Figure 1-16) allow prediction of reactivity for a wide range of processes.  118  Sustmann used F M O description to categorize three groups, type one, two and three reactions.  1,3-dipolar cycloadditions into  These assignments are based on the  predominant F M O interaction. Type  one  reactions  interacting with the H O M O  are characterized by the of the dipole.  120  LUMO  of the dipolarophile  This is also referred to as an " H O  controlled" reaction (Figure 1-17). Figure 1-17 shows the symmetry allowed molecular orbital interactions.  Figure 1-17 also shows the lowest energy (solid arrow) and higher  energy symmetry allowed interactions (dotted arrow). The lowest energy gap represents the interaction that is most likely to lead to a reaction, in this case an H O controlled interaction. A n H O controlled reaction will be accelerated by an electron donating group (edg) on the 1,3-dipole, and an electron withdrawing group (ewg) on the dipolarophile. The reason is that as electrons are donated into the H O M O of the dipole it becomes less  44  Dipole  Dipolarophile  Figure 1-17. Symmetry Allowed Interactions of Type One 1,3-Dipolar Cycloadditions.  stable, and rises in energy towards the L U M O of the dipolarophile. O n the other hand, ewgs on the dipolarophile will lower the energy of the L U M O towards the H O M O of the dipole. The H O M O and L U M O energies of the dipolarophiles can be varied by adding electron withdrawing or donating substituents.  Figure 1-18 shows how the energies of  the M O s are affected by different substituents.  The cases where the H O M O energy is  increased will be the most useful for type one dipoles.  45  I* LUMO  CN  Conjugation  Alkyl Subst.  Electron Donor Electron Acceptor  OO  HOMO  CN  Figure 1-18. Change in Molecular Orbital Energy Upon Substitution.  The energies (see F i g 1-18) of the H O M O ' s are calculated from the ionization oo  potentials, while the L U M O ' s were estimated by Houk.  The sizes o f the lobes reflect  calculated atomic orbital coefficients. These coefficients are determined by the orbital interaction responsible for the reaction.  A s seen in Figure 1-18, substituents not only  exert an effect on the energy of the orbitals, but also on atomic orbital coefficients. coefficients  have  cycloaddition,  61  been  reported  to  effect  the  regiochemistry  of  a  These  1,3-dipolar  as the atom of the dipole with the largest molecular orbital coefficient  associates with the atom of the dipolarophile also with the largest orbital coefficient.  46  1,3-Dipole  e(eV) H O M O  Method  e(eV) L U M O  Method  HCNCH  -7.7  Estimate  0.9  Estimate  -9.0  Photoelectron  1.8  Estimate  1.4  CNDO/2  2  Nitrile Ylide NNCH  2  Diazomethane  H2CNHCH2  Spectroscopy -6.9  CNDO/2 Calculation  Azomethine  Calculation ' 1  8  Ylide H CNHNH 2  -8.6  Estimate  0.3  Estimate  -7.1  Estimate  0.4  Estimate  -8.6  Estimate  -0.2  Estimate  Azomethine Imine  H2CCOCH2 Carbonyl Ylide H CONH 2  Carbonyl Imine  Table 1-3. Frontier Molecular Orbital Energies of Parent 1,3-Dipoles (Type One).  The F M O energies of typical type one 1,3-dipoles are listed in Table 1-3. energy of their H O M O ' s (estimated from experimental ionization potentials)  90  61  The  are high  enough that the interaction with the L U M O of the dipolarophile with the H O M O of the  47  dipole is the dominant one. These dipoles are often referred to as nucleophilic because of their preference to react with electron deficient dipolarophiles.  Some o f these species  will be discussed individually in Section 1.3.4. Examples o f type one reactivity are shown in Table 1-4. Monosubstituted Ethylene, R C H = C H R=  C0 C2H  1-Substituted Butadienes CH =CR-CH=CH 2  2  2  11200  R = C0 CH  C6H5  43  C6H5  21  H  20  H  10.7  10.7  CH  C4H9  .44  OCH3  OC4H9  .01  N(C H )  2  CH = CH  5  2  2  2570  2.43  3  1.34  2  Olefinic Carboxylic Esters  3  5  .06  2  /^Substituted Styrenes, R C H = C H - P h  Ethyl Acrylate  112000  R = H  44.5  Methyl  6270  C6H5  1.01  Methyl Crotonate  641  CH(CH )  Methyl Cinnamate  264  N(CH )  Methacrylate  3  2  2  4  .29 .03  Table 1-4. Relative Rate Constants of Reactions Between Diazomethane and Various Dipolarophiles. This table shows the relative rate constants of reactions between diazomethane, and  a host of dipolarophiles.  91  Diazomethane is shown to react more quickly with  electron deficient rather than electron rich or neutral dipolarophiles.  48  Type three 1,3-dipoles react in a manner opposite to that of the type one 1,3dipoles.  In these cases the L U M O  of the dipole react with the H O M O  of the  dipolarophile, or in a " L U controlled" manner (Figure 1-19). In other words, the H O M O of the dipole is of such low energy that the interaction between the L U M O of the dipole and H O M O of the dipolarophile is the dominant one.  61  Thus edgs on the dipolarophile  and ewgs on the dipole will accelerate the reaction.  Dipole  Dipolarophile  Figure 1-19. Symmetry Allowed Interactions of Type Three 1,3-Dipolar Cycloadditions. These dipoles are referred to as electrophilic because they tend to react more efficiently with electron rich dipolarophiles. controlled manner are listed in Table 1-5.  115  Parent 1,3-dipoles that react in a L U  49  1,3-Dipole  e(eV) H O M O  Method  e(eV) L U M O  Method  NNO  -12.9  Photoelectron  -1.1  Estimate  -2.2  Negative  Azoxy OOO  Spectroscopy Photoelectron  -13.5  Ozone  of  Electron  Spectroscopy  Affinity  Table 1-5. Frontier Molecular Orbital Energies of Parent 1,3-Dipoles (Type Three). The final group of 1,3-dipoles is made up of those dipoles that react neither by L U or H O controlled reactions (Figure 1-20). These are type two 1,3-dipoles. The energies  8-TH  m Dipole  Dipolarophile  Figure 1-20. Symmetry Allowed Interactions of Type Two 1,3-Dipolar Cycloadditions.  O f these H O M O ' s and L U M O ' s are intermediate to those of type one and three 1,3dipolar cycloadditions (Table 1-6).  50  Adding either an edg or ewg to the dipole or dipolarophile can accelerate these reactions.  Type two molecular orbital energies are shown in Table 1-6.  on making either the H O or L U interaction predominate.  115  The focus is  This will lower the energy  difference between one of the interactions, thus increasing the reaction rate. example of type two reactivity is shown with phenyl azide (Table 1-7). shows "parabolic" reactivity.  A good Table 1-7  Reactivity like this is common among type two dipoles.  Dipolarophiles that are very electron deficient (i.e. D M A D ) react well with phenyl azide, while dipolarophiles that are electron rich (i.e. pyrrolidinocyclopentene) also react well with phenyl azide, and to a much greater degree.  "Non-activated" (i.e. cyclohexene)  dipolarophiles do not react well. This is an example of substituting the dipolarophile to control reactivity. 1,3-Dipole  s(eV)  Method  e(eV)  Method  HCNNH  -9.2  Estimate  0.1  Estimate  -10.8  Photoelectron  -0.5  Estimate  0.1  Estimate  Nitrile Imines HCNO  Spectroscopy  Nitrile Oxides NNNH  -10.7  Photoelectron Spectroscopy  Azides H CNHO  -9.7  Estimate  -0.5  Estimate  H COO  -10.3  Estimate  -0.9  Estimate  2  2  Table 1-6. Molecular Orbital Energies of Type Three 1,3-Dipoles.  51  Monosubstituted Ethylenes C H = C H R  Electron-Poor Ethylenes  R = C0 C H  9.85  Diethyl fumarate  8.36  CN  1.07  Maleic anhydride  7.20  C6H5  .40  n-Phenylmaleimide  27.6  C5H11  .24  Methyl methacrylate  .72  OC4H9  .40  Ethyl crotonate  .27  2  2  2  5  Electron Rich Ethylenes  Cycloalkanes  Butyl vinyl ether  .40  Cyclopentene  1.86  Ethoxycyclopentene  .49  Cyclohexene  .033  1 -Morpholinocyclopentene  2580  Bicyclo(2.2.2)octene  .90  1 -Pyrrolidinocyclohexene  9930  Norbornene  188  1 -Pyrrolidinocyclopentene  115000  Norbornadiene  194  Acetylenic Dipolarophiles Dimethyl  25.4  acetylenedicarboxylate Methyl Propiolate  10.4  Phenylacetylene  .29  Table 1-7. Relative Rate Constants of 1,3-Dipolar Cycloadditions with Phenyl Azide. Another way of controlling reactivity is by adding substituents that will change the energies of the molecular orbitals of the dipoles. ' 93  94  This process accomplishes the  52  same goals as modification of the dipolarophiles in the phenyl azide reactions shown in Table 1-7. Azomethine ylides are typical type one, nucleophilic dipoles.  Section  describes an example of electron deficient azomethine ylides that react more efficiently with electron rich dipolarophiles. Another example of this "inverse electron demand" is the mesomeric betaines containing pyrrolo- or imidazo-triaziniumolate system (Scheme 1-22).  95  dipole.  These molecules react functionally as azomethine imines, a typical type one In this  dipolarophiles.  case though, the  reactions  are more  facile  with electron  rich  34  Pyrrolotriaziniumolate  Imidazotriaziniumolate  \  Scheme 1-22.  Mesomeric Betaines.  The explanation for this change in reactivity comes from the energies of the molecular orbitals. The calculated H O M O - L U M O gap is smaller for the L U M O of the dipole H O M O of the electron rich dipolarophile (enamine) than the H O M O o f the dipole  53  L U M O of the electron deficient dipolarophile ( D M A D ) . rate of the reaction.  This causes the increase in the  108  Another method of controlling the reactivity of 1,3-dipoles outside o f substituent manipulation is the use of transition metals. Metals generally coordinate on the dipole or dipolarophile thus, changing the orbital energies. Transition metals are also often used in conjunction with chiral ligands in order to induce stereoselectivity, not be presented here.  but this aspect will  96  Two examples that will be discussed are magnesium alkoxides  reacting with nitrile oxides and transition metal catalysis of nitrone cycloadditions. Nitrile oxides are considered to be type two dipoles, and will react if there is an "activated" dipolarophile present.  In cases where the dipolarophile is internal and non-  activated, the yields of these reactions are low, as nitrile oxides dimerize giving  Ph Cl  H  ,OH  >=N  +  / V  0  Ph  Ph  I  BrMg  H  0  N rf  O  EtMgBr THF  Br © 0 Ph-C^N-0  OMgBr  x  THF  0  v p^  Scheme 1-23. Metal Catalyzed Reaction of Phenyl Nitrile Oxide and 3-Hydroxy1-Propene. furoxans.  97  The magnesium catalyzed process shown in Scheme 1-23, was compared to  that of the non-catalyzed, triethylamine promoted reaction. The non-catalyzed reaction, had a relative rate o f 0.09, while the relative rate of the magnesium catalyzed process was  54  14.  This is an increase in rate of over 100 times. The rationale for the rate increase is  based on molecular orbital calculations.  The calculations were based on the complex  shown in Figure 1-21, which approximates the complex shown in Scheme 1-23, with the exception of H2O replacing T H F and C l replacing Br. HCNO^ ci Mg-OH  2  H 0 Takes the Place of T H F for Ease of 2  Calculation  Figure 1-21. Complex Used for Molecular Orbital Calculations.  The energies of the F M O ' s change dramatically with the addition o f metal, so much so that the process becomes a type three reaction ( L U controlled). The complex formation, according to ab initio calculations, induced an increase of the H O M O - L U M O energies of the dipolarophile from -0.396 and 0.176 hartree to -0.349 and 0.188 Hartee, respectively.  111  The energies of the dipole decreased .107 and .048 Hartree for the  H O M O and L U M O respectively.  This was enough to change the reaction from H O  controlled to L U controlled. The energy gap o f the L U controlled reaction went from 0.572 to 0.477 Hartree, while the H O controlled process is much higher in energy, 0.671 Hartree.  160  A  second example involves the reaction of a nitrone with an electron rich  dipolarophile (Scheme 1-24)." This reaction, normally H O controlled  0 Ph.  .0  .OR .OR  "  A  1  Ph  O  OR  Scheme 1-24. Metal Catalyzed Nitrone Cycloaddition.  55  became a L U controlled process via inverse-electron demand by the addition of a chiral aluminum catalyst.  161  N o kinetic studies have yet been reported on this procedure, but  the reaction was more efficient with electron rich dipolarophiles, and it was observed that regio- and diastereoselectivity increased upon the addition of the catalyst.  100  1.3.4 Methods of 1,3-Dipolar Cycloaddition Many of the 1,3-dipoles used today in organic synthesis are very reactive species, and must be generated in situ. What follows is a short collection of the methods used for generating 1,3-dipoles, along with a discussion of the mechanisms that are specific to each species. A n emphasis will be on those 1,3-dipoles that appear in this thesis. Diazoalkanes The  simplest diazoalkane, diazomethane, is usually generated by the  reaction of a base with « - m e t h y l n-nitroso amines (Scheme 1-25). This reaction generates the yellow gas in a solution of ether where it can be safely handled and used in further reactions.  101  Diazald  MNNG  KOH  0  2  N - N ^  © 0  NH  HC=N=N  o H 0 2  ©O H M N N G = l-methyl-3-nitro-l-nitrosoguanidine  Scheme 1-25. Production of Diazomethane.  56  Analogues of diazomethane are also widely used in cycloaddition chemistry. These  include  ethyldiazoacetate  phenyldiazomethane,  trimethlysilyldiazomethane,  and  which are all more or less stable at r.t., and can be directly reacted  102  with dipolarophiles . The mechanism of the diazomethane 1,3-dipolar cycloaddition has been a source of controversy for many years. T o this day, there are results that are difficult to explain with even the most sophisticated theory. The original disagreement came in the late 1970's and early 1980's. H u i s g e n ,  103  was the first person to systematically look at the reactivities of many of the 1,3-dipoles. Firestone disagreed however, about the concertedness of the 1,3-dipolar cycloadditions of N  = \ CH N 2  2  +  " E  D  N (  G  •  'N«  EWG  \_J EDG  E W G OR E D G EWG  Figure 1-22. Diazomethane Reactions with Electron Rich and Poor Dipolarophiles.  diazomethane that Huisgen initially reported o n .  1 0 4  Huisgen had done a great deal of  work involving 1,3-dipolar reactions, and maintained that the reaction mechanism was a concerted process.  In  1976,  Firestone  suggested that the  diazomethane  reaction  underwent a non-concerted process, where the intermediate was a diradical (Figure 122).  134  The discussion was based on the fact that diazomethane reacts with both electron  rich and poor dipolarophiles to give the  1-pyrazoline.  The diradical mechanism,  according to Firestone would result in the observed results, while a concerted, but not  57  synchronous mechanism would result in opposite orientations for electron rich and poor dipolarophiles in the resultant product.  140  This stems from the fact that the diradical  intermediate will be stabilized more efficiently i f the radical is next to an activating group. The concerted process is governed by F M O theory, and this predicts the reaction will be most efficient with electron poor dipolarophiles. Huisgen in 1977 reported that the reaction is stereospecific  and this is an insurmountable obstacle for the diradical  mechanism as the ring closure must be faster than rotation around bond B as shown in Scheme 1-26.  105  H H  H  H  -N=N< H  R V ^ ° 2 R c  -N=N' c  h  h  3  P7B^ ,  R  C0 CH 2  3  MIXTURE OF PRODUCTS  Scheme 1-26 Diradical Mechanism for 1,3-Dipolar Cycloaddition with Diazomethane Huisgen reported evidence that supported a di-radical mechanism that would give products of mixed stereochemistry. FMO  calculations  106  at a high level  Rastelli et a / . of theory,  107  using a slightly modified form of  and assuming that only  concerted  mechanisms were possible, they were able to predict the formation of only the 1pyrazoline for both ewgs and edgs.  108  The mechanism of reaction of aliphatic diazo compounds is not appreciably affected by steric bulk.  A graph showing the reaction rates o f diazomethane and  diphenyldiazomethane is shown in Figure 1-23.  There is good correlation between the  reactivity of the two dipoles, which differ in structure by 2 phenyl groups. This suggests that not only do the reactions go through the same mechanism, but that the phenyl groups  58  have no appreciable effect on reactivity. phenyl groups have cycloadditions.  109  on reactivity is the  The reason for the minimal effect that the early transition state of the  1,3-dipolar  In this case, the bonds of the product are not formed to a significant  extent in the transition state, thus steric effects do not play a role in the kinetics of the reaction.  JZO&Us  7 + log k2 (Diphenyldiazomethane) Figure 1-23. Correlation of the Rates of Reaction of Diazomethane and Diphenyldiazomethane.  59 Azomethine Ylides One of the most common ways to generate azomethine ylides is the electrocyclic ring opening of aziridines (Scheme 1-27). no  R  K  A  2  Scheme 1-27.  Rs N ©  5  N K  o  r  h  ©  v  R  3  R  2  3  Electrocyclic Ring Opening Formation of Azomethine Ylides.  Other methods include the formation of an imine between an « - a l k y l amino acid and an aldehyde,  followed  by  decarboxylation  to  decarboxylation of/?-lactams (Scheme 1-28).  form  an  un-stabilized  ylide  and  The cycloaddition of such a species is  111  used to form a pyrrolidine, and has been used synthetically in the stereoselective synthesis of /^-lactams.  112 -H 0 2  H0 C. 2  H .N.  + +  -0  U  CHoO 2 M  U  H0 C. ^ 2  2  I fa - C 0 . N ^ ^  2  I „ ,!,© /"V  Heat  o-^Y  °  C0 R 2  Scheme 1-28.  -> o c  o^i  3  fi  Co R  C0 R  2  2  Synthesis of Non-Stabilized Azomethine Ylides.  The mechanism of azomethine ylide 1,3-dipolar cycloaddition is concerted, and 113  some reactions are characterized by stereospecificity  of the products.  examples of this reaction where the products obtained are non-stereospecific.  There are  60  The most recent example of a non-stereospecific azomethine ylide 1,3-dipolar cycloaddition was investigated by Bohm et a / .  114  This paper describes the reaction of an  electron deficient azomethine ylide with an electron rich dipolarophile in a L U controlled process. Azomethine ylides are generally type one, nucleophilic dipoles, but this can be changed with the addition of electron withdrawing groups.  The reaction as shown in  Scheme 1-29 has good conversion, but the selectivity is poor. Almost equal amounts of the cis and trans products are formed. (Scheme 1-20).  This suggests a non-concerted mechanism  151  A P P R O X I M A T E L Y 50:50  Scheme 1-29. Inverse Electron Demand Azomethine Ylide 1,3-Dipolar Cycloaddition.  Kinetic studies were performed on these electron deficient azomethine ylides of the type shown in Scheme 1-29.  115  These studies showed that the ylides reacted more  efficiently with electron rich dipolarophiles than with electron poor. This is what would be expected from a L U controlled 1,3-dipolar cycloaddition.  130  A M I calculations of the  M O ' s confirmed the reason for this reactivity. The H O M O / L U M O energies of the parent  61  azomethine ylide from Table-1 are -6.9 eV/1.4 eV.  The energies for the  electron  deficient azomethine ylide are -7.77 eV/-1.54 eV. The energy of the L U M O o f the ylide is 3 e V less for the electron deficient species, while the H O M O is 0.8 e V less.  The  lowering o f the L U M O causes the reaction to be L U controlled, and accounts for the ylide reacting with electron rich dipolarophiles more efficiently than electron poor. This may also provide an explanation for a non-concerted mechanism.  152  In cases where the reaction of an azomethine ylide is not possible, or does not yield the desired products, a new method for 3+2-cycloaddition can be used.  The  reaction of a 2-azaallyl anion forms a pyrrolidine, but this 2-azaallyl anion reacts with electron rich dipolarophiles, instead of electron poor. This makes the 2-azaallyl anions a complimentary method to the azomethine ylides (Scheme 1-30).  116  Scheme 1-30. Reaction of 2-Azaalyl Anion with Anionophile.  The reactions of the 2-azaallyl anions are designated as concerted [TT4S + n2s], mechanism.  These generally proceed with conservation of stereochemistry.  131  It is  interesting to note that the products of the reaction can be quenched with an electrophile giving ^-substituted pyrrolidines. Carbonyl Ylides Stabilized and non-stabilized carbonyl ylides can be generated for reactions with dipolarophiles.  Stabilized carbonyl ylides can be generated by first order thermal  62  electrocyclic ring opening (Scheme 1-31) via the cleavage of the carbon-carbon bond of electron deficient epoxides.  117  These species are known to react mainly with electron  rich systems.  O  Heat  N C - ^ ^ C N NC CN  Q  N C ^ V C N  '  NC  CN  .  Scheme 1-31. Electrocyclic Ring Opening to form a Carbonyl Ylide.  Non-stabilized methods.  118  carbonyl  ylides  can  also  be  generated  through  different  One example is the two-electron oxidation of a di-chloromethylether using  Mn/PbCl and N a T  1 1 9  2  Mn/PbCl  ci^o  ©  2  ^ Y>  ci Nal  u  Scheme 1-32. Reduction of di-Chloromethylether to form an Unstabilized Carbonyl Ylide.  Non-stabilized carbonyl ylides react with both electron poor dipolarophiles and electron r i c h .  160  This is not expected as the parent carbonyl ylide is a type one dipole. 120  The reaction proceeds in a concerted manner, and yields stereoselective products. Thiocarbonyl ylides Unstabilized thiocarbonyl ylides can be generated by thermal decomposition of di(methyltrimethylsilyl)sulfoxide to the thiocarbonyl y l i d e , chloromethyl trimethylsilylmethyl sulfide.  122  121  or by the desilylation of  63  TMS^S^TMS  A  0 V  +  \ /  +  i  8  \  Si  \  ^Si " C l  CsF  0,  ,Q  TMS TMS  +  CsCl  TMS-F  ©  Scheme 1-33. Methods of Generating Unstabilized Thiocarbonyl Ylides.  These reactions of the non-stabilized ylides are useful.  They undergo ready  cycloaddition with electron poor dipolarophiles, and react via a concerted mechanism. This was observed from the fact that the stereochemistry in the dipolarophile is conserved during reaction.  123  It has also been noted in some examples that thiocarbonyl ylides undergo nonstereospecific reactions, which is rationalized by a non-concerted mechanism.  124  Such  reactions proceed with an electron rich thiocarbonyl ylide reacting with electron poor 125  dipolarophiles such as dicyanomaleate and dicyanofumarate. Thiocarbonyl ylides like most 1,3-dipoles react via an early transition state. This can be observed from ab-initio calculations which showed, even though the  1,3-dipolar  cycloaddition of the thiocarbonyl ylide was much more exothermic than the thiocarbonyl imine, the transition state energy (activation energy) was higher.  126  This suggests that the  relative energy of the product that is formed has very little effect on the energy of the transition state, and thus it must occur early.  This is in line with what was discussed  earlier about the transition state of these reactions.  64 Nitrile Ylides There are several different ways to generate a nitrile ylide, but the most common are the thermal extrusion of carbon dioxide, 34).  and dehydrohalogenation (Scheme  1-  128 Q  Tn  ^ M e - N ^  p^CN  N  _  C  H  P  C  h  Base  Me-<  P  h  N  ©  Ph  ^Me^=N-K Cl  U  Scheme 1-34. F o r m a t i o n of Nitrile Ylides.  The reaction has all the characteristics of the other 1,3-dipoles, except that there are no surprises with this one. These reactions occur strictly diastereospecifically.  129  The nitrile  ylides is considered to be one of the most nucleophilic, and will react very quickly with electron deficient dipolarophiles (the reaction is H O controlled). profile is similar to that of diphenyldiazomethane.  In fact, its reactivity  130  Recently, metallo-nitrile ylides have been investigated, and are another example of metal coordination changing the landscape of the M O ' s , in that these dipoles react with electron rich dipolarophiles,  131  as did both the nitrile oxides (Scheme 1-23) and  nitrones (Scheme 1-24). The above discussion has given a brief overview of the 1,3-dipole cycloaddition chemistry that has been investigated during this thesis. If there are any questions about this chemistry, there are reviews and books to consult.  132  65  Chapter 2: Results and Discussion 2.1  Introduction One of the most important methods for the production o f new photosensitzers is  the synthesis o f chlorins.  The reason for this is that chlorins absorb light intensely at  wavelengths where human tissue is most transparent (Figures 1-9 and 1-10).  wTHPC  28  Figure 2-1. Selected Chlorins Tested as PDT Agents. Chlorins  such  as  BPDMA  hydroxyphenyl)chlorin  134  (26),  chlorin  e6  1  3  3  (27)  and  /neso-tetrapheny^m-  ( m T H P C , 28) are all useful photsensitizers (see Figure 2-1).  66  The most apparent method to generate a chlorin is to dihydrogenate a cross-conjugated double bond. This is generally done via a diimide reduction. porphyrins has been extensively reviewed.  136  135  The dihydrogenation of  Some other examples  of methods to  synthesize chlorins will be presented in Section 2.1.1. 2.1.1 Formation of Chlorins from Porphyrins Natural Sources One method for obtaining chlorins for use in P D T is from natural sources. Chlorophyll (Figure 1-2) is a chlorin that occurs abundantly in many plants and in some animals. The main function of chlorophyll is as a photosynthetic agent and chlorophyll can be extracted from leaves and algae by boiling in methanol.  Chlorophyll is then  purified by column chromatography. The isolation and purification of chlorophylls has been reviewed extensively.  137 Diets-Alder Reactions A Diels-Alder reaction is a [4TI + 2n ] electrocyclization between a diene and a S  s  dienophile. In the case of a porphyrin, the cross-conjugated double bond could act as a dienophile.  The cross-conjugated double bond could also act as part of a diene,  in  concert with a conjugated double bond at the P-position. Scheme  2-1  shows  an example  of the  cross-conjugated  double  bond  tetraphenylporphyrin (TPP) reacting as a dienophile. This reaction between T P P and  of  67  Naphthoporphyrin  Bacteriochlorin  Scheme 2-1. Reaction of Benzoquinonedimethane with TPP.  benzoquinondimethane is the first example of this type of Diels-Alder reaction. temperatures are required for the extrusion of S02( ) from the benzoquinone g  which then reacts as the diene to form the chlorin. yields  the  naphthoporphyrin.  tetrakis(pentafluorophenyl)porphyrin  High  sulfone,  Oxidation of the resultant chlorin  Bacteriochlorins (pFTPP) was  138  would  be  observed  if  used as the dipolarophile in the  68  reaction described in Scheme 2-1.  This suggests that the cross-conjugated double bonds  of the electron deficient porphyrin (pFTPP) are more reactive towards cycloaddition then the double bonds of T P P .  1 8 1  There have also been examples  of the  cross-conjugated double bonds  of  porphyrins being used in concert with an exocyclic double bond to form a diene in a Diels-Alder reaction.'^Protoporphyrin IX dimethyl ester is a common diene and has been used in reactions with tetracyanoethylene, ' D M A D , 8  9  C0 Me 2  C0 Me 2  C0 Me 2  1 0  and urazines (Scheme 2-2)."  C0 Me 2  C0 Me 2  Scheme 2-2. Diels-Alder Reaction with P r o t o p o r p h y r i n I X .  C0 Me 2  69 Osmium Tetroxide Oxidation Osmium tetroxide can be used to dihydroxylate the cross-conjugated bonds of porphyrins. " 143  145  double  This procedure involves using a stoichiometric amount of the  osmium tetroxide/pyridine complex and reducing the resulting osmate ester with H2S (Scheme 2-3).  13  Scheme 2-3. Dihydroxylation of T P P . 1,3 -Dipolar Cycloadditions One example in the literature of 1,3-dipolar cycloadditions being used to form chlorins from porphyrins was reported by Cavaleiro et al}  92  reactions  between tetraarylporphyrins, namely  Cavaleiro reported that  T P P and p F T P P ,  azomethine ylides resulted in yields of the chlorin from 10 - 60 % .  1 4 6  and unstabilized T P P and p F T P P  were refluxed with sarcosine and paraformaldehyde. The resulting imine that formed from the reaction between the alpha amino acid and formaldehyde, decarboxylated to  70  produce the parent azomethine ylide (Scheme 2-4).  T P P formed the chlorin in 12 %  yield, while p F T P P gave 61 % chlorin and 11 % bacteriochlorin.  192  Scheme 2-4. Reaction of Tetraarylporphyrins with Azomethine Ylide.  2.2 Results Sections 2.2.1-2.2.9 provides a synopsis of the work done in the course of this research. Explanations of the results are included. Different dipolarophiles were used in the course of this research, including p F T P P . This dipolarophile is interesting not only because of its reactivity, but also because of the effect that fluorine substituents can have on the biological activity of a d r u g .  147  Fluorine  and hydrogen atoms have comparable V a n der Waals radii, thus may be biologically indistinguishable and yet chemically quite different.  Fluorinated compounds can have  some interesting biological properties because of this. Fluorine substitution can increase  71  lipophilicity, and the rate at which biologically active compounds move across lipid membranes. 2.2.1  195  Azomethine Ylides Azomethine ylides were discussed in Section  The most general way of  synthesizing the unstabilized ylide is through the sequential double desilylation of the a,a'-di(trimethylsilylmethyl)amines (Figure 2-2). synthesize  cycloadducts  using  many  different  148  This procedure has been used to  dipolarophiles.  Most  of  these  dipolarophiles are electron poor double bonds, although there are cases where the reaction  has  proceeded  with  heterodipolarophiles.  This  195  procedure yields  unstabilized azomethine ylide, meaning there are no substituents pyrrolidine  carbon atoms  o f the  product.  This  is  the  on either of the  important in reactions  with  tetraarylporphyrins, as the aryl rings are rotating, and institute a large steric requirement to any reactions at the P-position. Since the parent ylide is a typical type one dipole, it was decided that the best results would be obtained with p F T P P and not T P P as the dipolarophile. The electron withdrawing ability of the 20 fluorine atoms of p F T P P makes the cross-conjugated double bonds amenable to a type one reaction (Section 1.3.3). This is coupled with the fact that Cavaleiro et al. reported this porphyrin to be responsive in both D i e l s - A l d e r and 1,3-dipolar cycloadditions.  164  159  The reason for this difference in reactivity between  p F T P P and T P P can be explained by looking at the H O M O and L U M O energies.  198  Cyclic voltammograms ( C V ) show the voltages at which porphyrins undergo two one-electron oxidations and two one-electron reductions. the H O M O and the L U M O of the compound.  198  149  These give the energies of  The C V of Z n T P P  1 9 9  (Zn being a redox-  72  inactive metal)  shows that the oxidations occur at 0.80 V and 1.16 V , while  reductions occur at -1.33 V and -1.66 V .  the  The first oxidation represents the energy  required to remove an electron from the H O M O , thus the energy of the H O M O of Z n T P P is -0.80 e V while the energy of the L U M O is 1.33 eV. The H O M O of p F T P P is -1.37 e V and the L U M O is 0.95 eV. These results show that the energies o f both o f the sets o f molecular orbitals are lower in the case of the fluorinated species, suggesting that p F T P P will react as a type one dipolarophile (see Section  The stabilization of the  L U M O o f the dipolarophile makes the energy difference between the L U M O of the dipolarophile and the H O M O of the dipole smaller. This should have a positive effect of the rate of the reaction. The  a,«'-di(trimethylsilylmethyl)amines  procedure as reported in the literature.  166  were  prepared  according  to  the  The amines were refluxed in dry acetonitrile,  with two equivalents of chloromethyltrimethylsilane and two equivalents o f K 2 C O 3 .  201  The a,a'-di(trimethylsilylmethyl)amine 39 was synthesized from 36 via a V o n Braun reaction. dry  150  Cyanogen bromide was dissolved in dry  CH2CI2 was slowly added.  27  CH2CI2 and then a solution of 36 in  73  Figure 2-2. Results of a,a'-Di(trimethylsilylmethyl)amine Reaction with pFTPP and AgF.  74  The 1,3-dipolar cycloadditions were done with a large excess of amine and A g F . The amines  (36-39)  were added as solutions in T H F to p F T P P dissolved in T H F .  AgF  was then added to the resultant solution under a stream of N2 in the dark. The mixture was continuously stirred under N2 for 0.1-1 h.  Once the reaction was complete, the  products were purified by column chromatography.  1  0^©^  2Me SiF 3  2  A  S  Scheme 2-5. Mechanism of Azomethine Ylide Formation.  During the course of the reaction, it was observed that a silver mirror formed on the inside of the reaction flask. This suggests that the A g F was reduced to metallic silver (Scheme 2-5).  This was seen in the reaction of compound 39, even though no product  was obtained (see Figure 2-2).  75  Compound 36 was reacted as shown in Scheme 2-5 with p F T P P to yield two spots on a silica 60 thin layer chromatographic (tic) plate.  The least polar (Rf 0.7, 60 %  CH^Cb/hexane) green spot gave a characteristic chlorin spectrum (Soret; 405.9 nm, Q bands; 504, 600 and 654 nm, with 654 nm being the most intense).  The N . M . R . data  suggest a high degree of symmetry within the compound with only three P-proton peaks observed at 8.70 (2H, d, J = 4.78 Hz), 8.48 (2H, s) and 8.38 ppm (2H, d, J = 4.78 Hz). The phenyl peaks of the benzyl amine are observed at 7.25 and 7.08 ppm. A multiplet observed in the spectrum which integrated for two protons at 5.17 ppm are assigned to the pyrrolidine protons of the chlorin, while signals of the pyrrolidine protons of the cycloadduct are observed at 3.09 (2H, m) and 2.56 ppm (2H, m). A singlet observed at 3.41 ppm (2H, s) was assigned to the benzylic protons. The mass spectrum of 36a gave a peak of 1108 m/z , which corresponds to the molecular mass of the desired chlorin, and the high resolution spectrum confirmed the molecular formula of C53H20F20N5.  These  data suggest the formation of 36a. Compound 37 reacted similarly as 36 to give two spots on silica tic plate.  The  most polar of which (Rf 0.7, 20 % EtOAc/hexane) gave a similar chlorin U V - V i s spectrum to that of 36a.  The N . M . R . data showed a high degree of symmetry within the  compound with only three P-proton peaks observed at 8.70 (2H, d, J = 4.78 Hz), 8.47 (2H, s) and 8.36 ppm (2H, d, J = 4.78 Hz). The phenyl peaks of the benzylamine are observed at 6.30 ( I H , s) and 6.16 ppm (2H, s). The methoxy group protons are observed at 3.57 ppm (6H, s).  The pyrrolidine protons of the chlorin are observed at 5.15 ppm  (2H, m), while the pyrrolidine protons of the cycloadduct are observed at 3.34 (2H, m) and 3.10 ppm (2H, m). The mass spectrum of this compound gave a peak at 1168 m/z,  76  which is the expected  mass of the desired product 37a.  High resolution mass  spectroscopy confirmed the molecular formula to be C 5 5 H 2 5 F 2 0 N 5 O 2 .  These data suggest  the formation of 37a. Compound 38 reacted similarly as 37 and 36 and gave two products.  The less  polar of which (Rf 0.7 20 % EtOAc/hexane) gave a similar chlorin spectrum as 37a.  The  N . M . R . data showed a high degree of symmetry for the compound, with only three peaks for the (3-protons at 8.70 (2H, d, J = 4.78 Hz), 8.47 (2H, s) and 8.38 ppm (2H, d, J = 4.75 Hz). The signal of the pyrrolidine protons of the chlorin were observed at 5.20 ppm (2H, m) and the pyrrolidine protons of the cycloadduct were observed at 3.15 (2H, m) and 2.51 ppm (2H, m).  The alkyl amine protons were observed at 2.24 (2H, d, J =  7.5 Hz), 1.30 (2H, m), 1.19 (2H, m) and 0.80 ppm (3H, t, J = 7.5 Hz).  The mass  spectrum o f this compound gave a peak at 1074 m/z, which is the mass of desired product.  The high resolution mass spectrum confirmed the molecular formula to be  C50H23N5F20.  These data suggest the formation of 38a.  N o isolable products were  obtained between 39 and pFTPP. The structures of the products of these three reactions are shown in Figure 2-2 and are the products of the expected cycloadditions. One main side product was observed in each of these reactions.  These were purple compounds which were more polar (Rf 0.6  60 % CH2Cl2/hexane) than the cycloadducts and exhibited non-porphyrin-like U V - V i s spectra. Identification of these compounds has not at this point been completed. The U V - V i s spectra of all three azomethine cycloaddition products are shown in Figure 2-3. N o difference was observed between these three U V - V i s spectra. It might be expected that different substituents would result in a change in the orbital energies, thus  77  resulting in a difference in the observed spectra, however, this does not seem to be the case.  Figure 2-3. U V - V i s Spectra of 36a, 37a and 38a.  The  reaction  of  36  was  cobalt(II)tetraphenylporphyrin (CoTPP).  also  carried  out  with  TPP  and  The reaction of 36 with T P P gave only one  product. The red spot on a silica tic plate was less polar than that of the starting material (Rf  0.6,  50 % CiUCb/hexane)  and had a characteristic  metalloporphyrin  UV-Vis  spectrum. This compound was assumed to be the silver(I) metallated porphyrin and the reaction was discontinued. The reaction with C o T P P gave no product. Differences in molecular orbital energies may be used to explain the different reactivities observed between dipoles and dipolarophiles.  The unstabilized azomethine  ylides react very well with electron deficient dipolarophiles (Section 1.3.3). observed in the yields of the reactions between 36 - 38 and p F T P P .  This is  N o reaction was  78  observed between 39 and p F T P P , even though the initial silver(I) oxidation was observed to occur, implied by the formation of the A g mirror. This suggested that the azomethine ylide was formed. The electron withdrawing cyano group may alter the energies of the dipole, and possibly cause 39 to become a type two or three dipole. This may be the reason that the non-stabilized azomethine ylide no longer reacts with the electron deficient dipolarophile pFTPP.  It was hoped, though, that this change in molecular  orbital energies would cause the dipole to react with T P P or C o T P P . Unfortunately, this was not the case, and the cyano N-substituted dipole remained unreactive. The outcome o f the reaction between  36-38 and T P P was not unexpected. The  cross-conjugated double bonds o f T P P are not as electron deficient as those of p F T P P . This causes them to be not as reactive towards type one dipoles that usually react with electron deficient double bonds. 2.2.2  Carbonyl Ylides Carbonyl ylides are discussed in Section Two different 1,3-dipoles were  used in reactions with porphyrin dipolarophiles. Firstly, the electron deficient carbonyl ylide obtained from heating tetracya^oethyleneoxide (Scheme 1-31), unstabilized  carbonyl  ylide  obtained  a  two  electron  and secondly, the of  a,oC-  In 1965, Linn and Benson found that upon heating tetracyanoethylene  oxide  dichloromethylether (Figure 1-32).  from  151  reduction  152 Tetracyanoethylene Oxide  153  ( T C N E O ) undergoes first order electrocyclic ring opening reactions. carbonyl  ylide  was  found to  react with  olefins,  acetylenes  The resulting  and benzene.  34  The  experimental conditions consisted of refluxing T C N E O with the dipolarophile at 100 ° C  79  for  a period between 4-24 h.  The reaction  proceeds  well  for many  dipolarophiles, including aromatic systems such as naphthalene and benzene.  different 171  The  dicyanocyclopropylchlorin (40) was previously assumed to be the product synthesized from the reaction between T C N E O and TPP in this l a b .  154  Scheme 2-6. O r i g i n a l Assumed Product of T C N E O / T P P Reaction. This potential  functionalization of the  cycloadduct 40  was  intriguing. For  example, the cyano groups may be hydrolyzed to the carboxylic acids, and then decarboxylation of one of the carboxylic moieties would leave one acid group available for derivitization. The procedure for hydrolysis-was to reflux 40 in cone. H C l f o r 6 h .  1 5 5  This gave a  very polar (Rf 0.6 49 % 49 % 2 % acetone/CF^C^/acetic acid) light blue spot on a silica tic plate.  The product 40a was very insoluble and difficult to purify.  The U V - V i s  spectrum was characteristic of that of a chlorin (Soret; 418.0 nm, Q-bands; 518.0, 546.0, 596.0 and 645.9 nm, 654.6 nm being the most intense Q-band). Crude 40a was isolated and reacted further to methylate the acid groups so as the resultant product would be  80  easier to purify. 40a was heated in D M S O , in the presence of excess dimethyl sulfate and potassium carbonate.  156  This reaction gave two products, both of which were less polar  than 40a, a more polar product with a characteristic chlorin U V - V i s spectrum (41), and a less polar blue spot. The U V - V i s spectrum of the product isolated from the more polar spot 41 on a tic plate gave a characteristic chlorin spectrum (Soret; 416 nm, Q-band; 518, 544, 592 and 646.1 nm, 646.1 nm being the most intense of the Q-bands). The N . M . R . data showed a high degree a symmetry in the isolated product, with only 3 P-proton peaks observed at 8.60 (2H, d, J = 4.89 Hz), 8.45 (2H, s) and 8.28 ppm (2H, d, J = 4.89 Hz). The signals observed for the phenyl protons were between 8.13-7.66 ppm (20H, m), while the signal assigned to the N H protons was at 1.96 ppm (2H, s).  The most striking parts of the  observed N . M . R . spectrum were the signals assigned to the pyrrolidine protons at 6.02 ppm (2H, s), the T H F ring protons assigned to the signal at 4.92 ppm (2H, s) and the methoxy protons assigned to 3.53 ppm (6H, s). The two proton singlet observed at 4.92 ppm was unexpected.  The proposed cyclopropane ring structure (Scheme 2-6) would  yield an N . M . R . spectrum without the observed singlet at 4.92 ppm.  L o w resolution  mass spectrometry gave the M of this product to be 775 m/z, while high resolution mass +  spectral data confirmed the molecular formula to be C 5 0 H 3 8 N 4 O 5 .  These suggest a  structure as shown in Figure 2-4. These data seem to conflict with the proposed structure of 40.  The dicyanocyclopropanochlorin shown in Scheme 2-6 has also recently been  synthesized independently by another method, and again, the spectroscopic data conflict with the data originally obtained from compound 40.  157  81  Compound 40 was re-submitted for mass spectrometry.  Initially, the mass  spectrum was obtained by electron impact (E.I.). This method may make it more difficult to obtain the molecular ion, due to the high energy mass ions produced. L S I M S (liquid secondary ion mass spectrometry) was then chosen as a second attempt to obtain a mass spectrum of the compound.  The L S I M S spectrum gave a molecular ion of 759 m/z,  which corresponds to the molecular mass of 41, suggesting the structure of the dipolar cycloadduct.  1,3-  The peak that corresponds to the dicyanocyclopropyl cycloadduct  ion was not observed in this mass spectrum. It seems that the initial characterization was incorrect.  Figure 2-4. Product of Acid Hydrolysis and Methylation of 40.  The structure of 40 proposed with the mass spectral data obtained from this thesis work is as shown in Figure 2-5. The  reaction  dipolarophiles.  outlined  in  Scheme  2-6  was  attempted  with  a variety  of  The reaction of T C N E O with C o T P P was attempted at - 78 ° C , 100 ° C ,  and 0 ° C . The only product that was recovered from these reactions was a brown, oily  40 Figure 2-5. Structure of Compound 40.  compound that did not give a U V - V i s spectrum characteristic to that of a porphyrin, and could not purified. observed.  Using polar solvent conditions and silica tic, a brown smear was  N o reason could be found for why this decomposition reaction was  vigorous, even at low temperatures.  The reaction of  so  N i T P P with T C N E O in toluene  gave T P P , and no other discernible compounds. The reaction of n-confused porphyrin 43  43 Figure 2-6. n-Confused porphyrin.  83  (Figure 2-6) gave many different products that in the end could not be purified, but looked interesting for future work.  N o reaction was observed between T C N E O and  pFTPP. O f the products that were obtained (40, 40a and 41) it is interesting to note the differences in their U V - V i s spectra. 1.4 n 1.2 1 u c 0.8 (8 -Q O 0.6 -  41  </)  n  <  0.4 0.2 0 350  400  450 500  550 600  650 700  750 800  Wavelength (nm)  Figure 2-7. U V - V i s Spectra of 40, 40a and 41.  The major difference is seen between the U V - V i s spectra of 40 and 40a.  A s the cyano  groups are hydrolyzed, and replaced with carboxylic acids, the U V - V i s spectra show a "red-shifting" of the Soret and the Q-bands.  This could represent a difference in the  electron withdrawing ability of the acid groups as compared to a cyano groups, or the difference in the steric requirements.  A change to the acid groups decreases the gaps  between the orbitals responsible for the absorption peaks, which would manifest itself in the observed red-shift.  84 Unstabilized Carbonyl Ylide Unstabilized carbonyl ylides are discussed in Section The reaction used in this experiment to synthesize the ylide was the two electron oxidation of the a,oCdichloromethylether  (Scheme  1-32).  This reaction has been used for  1,3-dipolar  158 cycloadditions  with  many  dipolarophiles.  This  includes  electron  deficient  dipolarophiles such as ester substituted double bonds, and electron rich dipolarophiles such as phenyl sulfide substituted double bonds. F  176  F  Scheme 2-7. Unstabilized Carbonyl Ylide Reaction with pFTPP to form 44.  The only reaction that was successful in this set of experiments was with pFTPP. The reaction yielded two products that were of similar polarity on silica tic (Rf 0.5 50 % CFbCVhexane).  The U V - V i s spectrum of the less polar compound was typical of a  chlorin (Soret; 414 nm, Q-bands; 506, 602 and 656 nm, 656 nm being the most intense Q-band).  The N . M . R . spectrum of this product showed a highly symmetrical structure.  85  The signals for the ^-protons are located at 8.70 (2H, d, J = 4.9 Hz), 8.47 (2H, s) and 8.38 ppm (2H, d, J = 4.9 Hz). The signals of the protons located on the pyrrolidine ring are observed at 5.33 ppm (2H, t, J = 4.36 Hz).  The peaks representing the T H F ring are  observed at 4.20 (2H, t, J = 8.17 Hz) and 3.92 ppm (2H, dd, J = 4.36 H z and 8.17 Hz). These three sets of protons show correlations to one another in the ' H C O S Y spectrum. The mass spectrum o f this compound has a parent ion at 1019 m/z, which corresponds to the molecular mass of the desired cycloaddition product, suggesting its formation. The more polar product gave a typically bacteriochlorin spectrum (Soret; 374 nm, Q-bands; 506, 582 and 732 nm, 732 nm being the most intense Q-band) but in the course of purifying this mixture, the bacteriochlorin product could not be obtained in large enough quantities to be fully characterized. unstabilized carbonyl ylides (Scheme  Other dipolarophiles used in the reactions with 2-7)  were N i T P P , Z n T P P , diphenylporphyrin  (DPP), tetra(p-nitrophenyl)porphyrin and /^nitro-tetraphenylporphyrin all of which gave no satisfactory results. The results of the above reactions are good examples of the differences between type one, two and three 1,3-dipolar cycloaddition reactions. The stabilized carbonyl ylide reacted very well with the electron rich cross-conjugated double bond o f T P P , while the unstabilized carbonyl ylide did not react at all. p F T P P , on the other hand, reacted very well with the unstabilized carbonyl ylide, but not with the tetracyano-substituted carbonyl ylide.  It is presumed that the four cyano groups cause the carbonyl ylide to react more  like a type three dipole, which would allow it to react with the relatively electron rich TPP.  The electron withdrawing groups lower the L U M O of the dipole to the point at  which the dominant interaction becomes the L U M O of the dipole, and the H O M O of the  86  dipolarophile (Section 1.3.3). The unstabilized ylide, reacts as a type one dipole, as one would expect (Section 1.3.3).  These reactions provide insight into assessing which  dipoles will react with which porphyrin dipolarophile. Electron deficient dipoles seem to react more efficiently with TPP, while the relatively electron rich dipoles react better with pFTPP. 2.2.3  Diazoalkanes Diazoalkanes were discussed in Section  Two diazoalkanes will be  discussed in this section, diazomethane and trimethlysilyldiazomethane. Diazomethane Diazomethane is synthesized by the reaction o f n-methyl-n-nitroso amines with a base (Scheme 1.25). reagents.  216  Other  Diazomethane has been used in reactions with many different  than  the  cycloaddition reaction  diazomethane is also a very efficient methylating agent.  that 159  will  be  discussed  here,  Diazomethane first acts as a  base to remove the proton from the heteroatom that it will be replacing and then methylates the heteroatom (Scheme 2-8).  Scheme 2-8. Mechanism of Diazomethane Methylation (X = O, S, or N). Diazomethane has been used for cycloaddition reactions with a variety of dipolarophiles giving pyrazolines including alkenes (electron rich and poor), dienes, heterodipolarophiles, heterocumulenes  and triple b o n d s .  diazomethane is a well established synthetic process.  160  '  213  The cycloaddition of  87  Pyrazolines eliminate N  2  to form cyclopropane rings.  The pyrolytic elimination  of N covers an activation energy range from a low of 15-20 kcal/mol to a high of 40-45 2  kcal/mol.  214  This activation energy difference translates into decomposition temperatures  that range from - 1 0 0 ° C to 3 0 0 ° C .  1 6 1  N extrusion can also be achieved photochemically. 2  Previous work involving the reaction of porphyrins with diazomethane did not yield the pyrazoline.  215  Callot et al. have reported on reactions between diazomethane  and porphyrins using a copper catalyst.  162  Through this method the cyclopropane ring  cycloadduct was obtained in 30 % yield (Scheme 2-9).  Scheme 2-9. Cyclopropanation of T P P .  Diazomethane, a type one dipole, reacts much more efficiently with electron poor dipolarophiles, thus a reaction with p F T P P would be more likely to yield the desired cycloadduct.  A large excess of diazomethane was added to a  CH2CI2 solution of the  dipolarophile p F T P P . A more polar (R 0.7, 50 % CH Cl2/hexane) green spot compared f  2  with the less polar spot of the precursor was observed on a silica tic plate.  Upon  purification on a silica preparatory tic plate, the product was found to have a U V - V i s spectrum characteristic to that of a chlorin (Soret; 402 nm, Q-bands; 504, 598, 648 nm,  88  648 nm being the most intense Q-band). The N . M . R . data did not show a symmetrical product as compared to the previous examples. The signals that represent the /^-protons are found at 8.80 ( I H , d, J = 4.89 Hz), 8.77 ( I H , d, J = 4.89 Hz), 8.61 ( I H , d, J = 4.89 Hz), 8.53 (2H, s) and 8.44 ppm ( I H , d, J = 4.89 Hz). The signal observed for one of the pyrrolidine peaks of the chlorin appears at 7.72 ppm ( I H , d, J = 8.8 Hz). Along with correlation of this proton to the adjacent pyrrolidine proton, this peak also shows a weak *H C O S Y correlation to one of the pyrazoline protons. proton adjacent to the azo-nitrogens.  This signal was assigned to the  A peak observed at 5.11 ppm (2H, m) was assigned  to both the other pyrrolidine proton and a pyrazoline proton. The other pyrazoline proton is found at 4.92 ppm ( I H , m). The N H pyrrole proton signals are observed at -2.09 ppm (2H, s).  The mass spectrum of the chlorin gave a molecular ion of 988 m/z, which  corresponds to the calculated mass of the desired cycloadduct.  High-resolution mass  spectral analysis confirmed the molecular formula to be C45H12N6F20, which is the molecular formula of the expected product 45. F  F  F  F  F  45  Scheme 2-10.  Reaction of Diazomethane with pFTPP.  89  The  reaction shown in Scheme 2-10  has the possibility of producing two  enantiomers, as the attack of diazomethane is possible from either side of the plane of the porphyrin ring.  The long range coupling between the pyrazoline protons and the  pyrrolidine proton adjacent to the azo-nitrogens mentioned on the previous page is due to homo-allylic coupling, which is common in these types of compounds. Compound 45 is stable at r.t. for long periods of time (9 months), however under certain conditions, N 2 will be  eliminated.  A n initial  attempt  to  synthesize  the  cyclopropane from the pyrazoline (45) consisted of refluxing a toluene solution of the pyrazoline overnight. N o observable change was noted on a tic plate as compared to the starting material.  The solvent was then changed to mesitylene, and this solution was  refluxed (Scheme 2-11). After 1 h, silica tic showed no starting material, and only a less polar product ( R f 0.8, 20 % CEbCb/hexane) that was green on a silica tic plate. This product had a U V - V i s spectrum characteristic to that of a chlorin (Soret; 410 nm, Q bands; 508, 606.1 and 662.0 nm, 662.0 nm being the most intense Q-band) and N . M . R . data suggest a symmetrical structure. There are only three signals that correspond to the /^protons at 8.67 (2H, d, J - 4.78 Hz), 8.43 (2H, s) and 8.40 ppm (2H, d, 4.78 Hz). The signals assigned to the cyclopropane are located at 3.90 (2H, dd, J = 4.10 Hz), 1.90 (1H, m) and 0.84 ppm (1H, m). The mass spectrum of this chlorin shows a M H m/z, and confirms the molecular formula to be C45H12N4F20 cyclopropane adduct 4 6 .  +  peak at 988  which suggests the  90  Scheme 2-11. Cyclopropane Formation from Pyrazoline. The same product 46 is formed when a dilute sample of 45 (1 mg in 2 m L of toluene de) is placed in sunlight for 1 h. Both photochemical and thermal reactions are clean, forming only the cyclopropane cycloadduct. The U V - V i s spectra of the pyrazoline and the cyclopropyl group chlorins are quite different (Figure 2-8).  The peaks observed in the spectrum of the cyclopropyl  chlorin are red-shifted as compared with that of the spectrum of the pyrazoline chlorin. The reason for this is not well understood. ring is highly strained (Figure 2-9).  One reason could be that the cyclopropane  91  350  400  450  500  550  600  650  700  750  800  Wavelength (nm)  Figure 2-8. U V - V i s Spectra of 45 and 46.  This strain causes what would normally be considered to be sp orbitals in an 3  aliphatic compound, to resemble sp orbitals. These "intermediate orbitals" (Figure 2-9) 2  may then be able to conjugate to the porphyrin ring, in much the same way a double bond would. This resultant conjugation may shift the absorption bands to higher wavelengths. Another reason could be the strained cyclopropyl ring may distort the porphyrin ring, and through this causes a change in the electronic spectra.  Overlapping  Propane sp Orbitals 3  Cyclopropane "Mixed" Orbitals  Figure 2-9. Cyclopropane " M i x e d Orbitals".  92  Zinc tetraphenylporphyrin (ZnTPP), T P P , O E P , lutidine acetylacetate porphyrin (Lu(acac)TPP) diazomethane,  and  D P P were  however,  used  no observable  as  starting  materials  in  the  reaction  with  products were obtained, and only starting  materials were recovered. (Trimethvlsilyl)diazomethane (Trimethylsilyl)diazomethane is a substituted diazoalkane that is stable at r.t. and can be used similarly as diazomethane for cycloaddition reactions.  178  A large number of 216  cycloaddition reactions with trimethlysilyldiazomethane have been reported. This reagent was used in reactions with T P P and p F T P P . observable product in the T P P reaction.  There was  no  The reaction with p F T P P was carried out in  refluxing hexane using a large excess of the (trimethylsilyl)diazomethane. A new spot on a tic plate began to appear after 24 h of reaction, and was observed to be more polar than the starting material. This product was found to have U V - V i s spectrum characteristic to that of a chlorin (Soret; 450 nm, Q-bands; 505.0, 595.0 and 649.9 nm, 649.9 nm being the most intense Q-band). This spectrum is very similar to the spectrum of the pyrazoline product from the reaction of diazomethane with p F T P P .  Only a M A L D I - T O F (matrix  assisted laser desorption time of flight spectrometry) mass spectrum was obtained which showed a molecular ion at 1017.5 m/z, which corresponds to the calculated mass of the diazomethane cycloaddition product 45. It is possible that the trimethylsilyl group could have been cleaved at some point during the reaction. Further work is required with this reaction. Diazomethane, being less sterically hindered, reacts more efficiently with the electron deficient double bonds of p F T P P than does (trimethylsilyl)diazomethane.  The  93  trimethylsilyl group is a relatively large molecule as compared to the hydrogens on diazomethane, and would hamper the approach of the reactive center to the dipolarophile. The trimethylsilyl group is also electron donating and should have an opposite effect on reactivity to that of the steric factor. The electron donating group would destabilize the HOMO  of the dipole thus decreasing its energetic  dipolarophile.  distance to the L U M O  of the  This effect should increase the rate of the 1,3-dipolar cycloaddition. In  this case, it seems that the steric consideration is the more important factor in determining the rate of the reaction, as the diazomethane reaction was shown to be more efficient. 2.2.4 Nitrile Oxides Nitrile oxides are discussed in detail in "1,3-Dipolar Cycloaddtion Chemistry". There are many ways to synthesize nitrile oxides.  181  The methods described in this thesis  are dehydrohalogenation of hydroximoylchlorides,  217  dehydration of aliphatic nitro  917  groups,  163  917  and diazotation of ethyl diazoacetate  (Scheme  2-12).  Nitrile oxides  dimerize rapidly. The only way to combat this is to ensure that the generation of the 1,3dipole is very slow, and that the concentration of the nitrile oxide remains low (Scheme 2-12). Several methods significant  results  hydroximoylchlorides.  of dehydrohalogenation  acquired  from  were attempted.  dehydrohalogenation  There were no  reactions  with  aryl  The dehydration of aliphatic nitro groups was attempted in the  presence of many different dipolarophiles. A reaction of 1-nitropropane was attempted with phenyl isocyanate in the presence of T P P , N i T P P , /?-nitro tetraphenylporphyrin, tetrakis(p-nitrophenyl)porphyrin, Z n T P P or p F T P P .  The only reaction that gave a result  was the reaction with pFTPP. A spot more polar than the starting material was observed  94  on the tic plate and the U V - V i s spectrum of the crude product showed the longest wavelength absorption band growing more intense as the reaction progressed, but nothing was isolated from this reaction. The diazotation of ethyldiazoacetate to form the nitrile oxide was done in the presence of p F T P P or T P P . The reaction with p F T P P was unsuccessful.  The reaction  with T P P , gave a more polar green spot on a silica tic plate, however, a product could not be isolated. The reactions with nitrile oxides were not fruitful. The reason for this presumably is that the reactive intermediates have exceedingly short lifespans, due to their tendency to dimerize. This makes it very difficult to promote a reaction with such an unreactive dipolarophile as a porphyrin.  95  Ph-T$  •NEti R  =0  ©  '00  > 7N:  2  R-  n  0H  H ^ Et0 C-C-N=N  N=0  OH  2  s  0 ©  CI ^ ^  NaN0 HC10  2  4  Ph.  ©0  H © Et0 C-CTN^N7N^O  R-C=N-0 © HNEt  2  TP^ 3  © Ph  Dehydrohalogenation  G? N  Ph  ,  N H / ^  H  P  h  H ©/ Et0 C-C=N-NjN OH i  2  -HoO  ©0 Ph-C=N-0 C0  H ^ Et0 C-C=l^N=N 2  ^ © 2  Ph~NH  H,0'  y  2  Dehydration of Aliphatic Nitro Compounds  2.2.5  Ozone  E t 0  ©©  2  C ^ N - 0  Diazotation of Ethyldiazoacetate  Scheme 2 - 1 2 . Methods of Nitrile Oxide F o r m a t i o n .  H  2  0  96  Being a type three dipole, it was thought that ozone might give some interesting products in reactions with porphyrins. Electrical arcing o f oxygen produces Ph  Ph  Scheme 2-13. Predicted Products of Porphyrin Ozonolysis.  ozone, and a variety of porphyrins were reacted with ozone. In these reactions, dimethyl sulfide was used to reduce the ozonide.  This allows the ozonide to form two aldehydes  (Scheme 2-13). If the reactions were to succeed on a porphyrin, a sechochlorin would be formed.  164  These reactions were performed at 0 ° C , samples were taken from the reaction flask at regular time intervals, quenched with dimethylsulfide, and the products were observed using silica tic.  Initially, T P P was used as the dipolarophile, and during the  97 reaction, the observed tic plates showed two different spots, starting material, and a polar baseline spot.  The U V - V i s spectrum showed an increasingly chlorin-like spectrum  (intense high wavelength  absorption).  Upon work-up though, none of the chlorin  spectrum, as evidenced by U V - V i s spectral analysis and the portions of the reaction that were left the longest, showed no porphyrin characteristics in the U V - V i s spectrum.  It  was determined that the intense high wavelength band resulted from protonation of the inner pyrrole nitrogens of the porphyrins. The only products that were obtained in the reaction with T P P , Z n T P P , D P P , N i T P P and Lu(acac)TPP were decomposition products, with no fine structure observable in the U V - V i s spectra. 2.2.6 Thiocarbonyl Ylides Thiocarbonyl ylides are discussed in Section  Being a typical type one  dipolarophile, it was thought the thiocarbonyl ylides would react best with the electron poor dipolarophile pFTPP.  Two methods  for the  synthesis  of the  unstabilized  thiocarbonyl ylide were used in this thesis. The  first method for synthesis of the  thiocarbonyl ylide was  the  double  desilylation of a,a'-di(trimethylsilylmethyl)sulfide with A g F . It was thought that the azomethine ylides could be synthesized via this procedure, thus possible to synthesize thiocarbonyl ylides in the same manner.  The « , « ' - d i ( t r i m e t h y l s i l y l m e t h y l ) s u l f i d e was  synthesized by reacting Na2S with chloromethyltrimethylsilane.  165  The cycloaddition  reaction was performed in a similar manner to that of the azomethine ylides (Section 2.2.1). A g F and p F T P P were stirred under N  2  in T H F and the sulfide was added to this  solution in T H F . A silver mirror on the inside of the reaction flask appeared after stirring the reaction mixture overnight.  Only one reaction product was observed on a silica tic  98  plate (Rf 0.5,  50 % C F L C V h e x a n e ) .  This product, after purification, exhibited a  characteristic metallo-porphyrin U V - V i s spectrum. The reaction was discontinued after two weeks. The other method for the synthesis of the thiocarbonyl ylide is the elimination of disiloxane from bis(trimethylsilyl)methyl sulfoxide (Scheme 1-33).  166  This method has  been used in cycloaddition reactions with many dipolarophiles, and works well with electron poor species, thus a reaction was attempted with p F T P P . synthesized via NaI04 oxidation of the sulfide.  222  The sulfoxide was  The sulfoxide and the p F T P P , both  dissolved in H M P A , were then added to H M P A at 1 0 0 ° C .  Only starting material and  silica tic baseline material were recovered. This reaction was discontinued. 2.2.7 Azomethine Imines Grashey discusses the reactions of azomethine imines in detail. investigated in this thesis, mesomeric betaines, functionally azomethine  185  167  The example  is detailed in Section They are  imines, and are intriguing because of their preference for  reacting with electron rich dipolarophiles.  126  The pyrrolotriaziniumolate systems utilized  in this thesis were synthesized by the method shown in Scheme 2-14.  The cycloaddition  reaction was attempted by heating 47 with a selected dipolarophile in toluene.  pFTPP,  T P P and D P P were all used as dipolarophiles. The D P P reactions were attempted both with and without M g B ^ l U O as a catalyst. The catalyst is thought to act by coordinating 168  to the carbonyl oxygen to lower the L U M O level of the dipole, three cycloaddition more facile.  thus making the type  99  A l l of the reactions that were attempted failed to yield any products. It is possible that the steric congestion that occurs when using such a large dipole was the dominating factor.  f \  NH NHC0 Et 2  2  H  f \  N  H  m  F  NaH(O.leq)  H  f \ ^  N  . N H  Mel(lOeq)/ K CO, 2  Or  N  00  X  ©  N  47  Scheme 2-14. Synthesis of Mesomeric Betaine 47.  2.2.8  Azides ( N O Lwowski  discusses  azides  in detail.  169  dipolarophiles are stereospecific and reversible.  187  The cycloadditions  of  azides  to  Azides are type two dipolarophiles,  and can react efficiently with both electron rich and poor dipolarophiles. Azides were reacted with both p F T P P and T P P . A n excess of trimethylsilylazide was refluxed with either p F T P P or T P P in T H F . The reaction with p F T P P gave a more polar red spot on a silica tic plate. The compound that corresponds to this spot had a U V V i s spectrum characteristic to that of a chlorin.  Unfortunately, the amount of the  compound isolated was small and no other structural characterizations were obtained. The possible 1,3-dipole cycloadduct structure is shown in Figure 2-10. The second type of azide that was used in a reaction with T P P and p F T P P is NaN3.  61  This reactant undergoes 3"+2 cycloadditions where the products are negatively  Figure 2-10.  anion  orbital,  Unfortunately,  in the none  PossibleTrimethylsilylazide Cycloadditon Product.  same o f the  way  as  reactions  the  azaallyl anions  react  yielded products, thus  (Section  the  reactions  were  discontinued. 2.2.9  Azaallyl Anions Azaallyl anions are discussed in Section  These reactive intermediates  have been used to react with many different dipolarophiles. both electron rich and electron poor dipolarophiles.  230  170  They are able to react with  The reaction that was attempted in 171  this thesis required the formation of the azaallyl anion from (2-azaallyl)silanes. The procedure consisted of first forming the (2-azaallyl)silane in situ at r.t., and then cleaving the silyl group with H F . p y r at 5 0 ° C (Scheme 2-15).  The reaction was  101  attempted  with  trimethylsilylmethylamine  and  z'so-valeraldehyde  to  azaallyl)silane while p F T P P and D P P were used as the dipolaophiles. not provide any product, only starting material was recovered. discontinued.  form  the  (2-  The reaction did  The reactions were  102  Chapter Three: Conclusions and Suggestions For Future Work In this thesis, the synthesis, isolation and characterization of novel chlorins were investigated.  Initially the reactions between carbonyl ylides and porphyrins were The T P P reaction with T C N E O yielded compound 40 in moderate yield,  performed.  which was then hydrolyzed and methylated to form compound 41. The p F T P P reaction with non-stabilized carbonyl ylide, synthesized from a,a'-dichloromethylether, yielded compound 44 in moderate yield.  These results suggest that electron rich T P P will  undergo 1,3-dipolar cycloaddition with electron poor carbonyl ylides in what might be a LU  controlled process,  while  the  electron  poor p F T P P  will undergo  1,3-dipolar  cycloaddition with non-stabilized carbonyl ylides in an H O controlled process.  This  concept could be investigated further with the variety of dipoles and dipolarophiles available. Novel chlorins were then synthesized via reaction between electron pFTPP  and  non-stabilized  azomethine  ylides  synthesized  from  deficient a,ol-  di(trimethylsilylmethyl)amines to form compounds 36a-38a. These results are evidence that electron deficient porphyrins are required to undergo 1,3-dipolar cycloaddition with type one dipoles such as azomethine ylides, as many porphyrins were investigated, with only p F T P P yielding a successful reaction. In continuation of this research, there are a variety  of  amines  available  for  use  in  the  synthesis  of  a,d-  di(trimethylsilylmethyl)amines which could then be used in 1,3-dipolar cycloadditions with various electron deficient porphyrins.  103  Diazomethane  was  cycloaddition with p F T P P .  used  to  synthesize  novel  chlorin  45 via  1,3-dipolar  45 was then subjected to heat in refluxing mesitylene, or  sunlight, both o f which caused the extrusion of N2 to form 46. Again, the successful 1,3dipolar cycloaddition reaction between diazomethane and p F T P P shows the requirement for electron deficient porphyrins in reaction with type one dipoles, as this reaction has never been reported to be successful with T P P or other electron rich porphyrins.  In  continuation of this research, other electron deficient porphyrins could be investigated in 1,3-dipolar cycloadditions with diazomethane. The purpose of this thesis was to synthesize novel chlorins for their use as photosensitizers in P D T .  Investigation of the chlorins synthesized in the course of this  thesis for use in P D T would yield insight into the physical properties o f photosensitizers as the fluorinated chlorins have not been investigated for this purpose.  104  Chapter 4: Experimental 4.1 Instrumentation and Materials Mass Spectra Mass spectrometric analyses were carried out by the B . C . Regional Mass Spectrometry Center at the University of British Columbia, Department of Chemistry. L o w and high resolution mass spectra were obtained by liquid secondary ion mass spectrometry (LSIMS), and were determined on a K R A T O S Concept IIHQ hybrid mass spectrometer. Molecular ions are designated as M H . +  UV-Vis Spectra U V - V i s spectra were taken on a Carey 50. maximum (X ) max  Wavelengths for each absorption  are reported in nanometers (nm).  Nuclear Magnetic Resonance Spectrometry Proton nuclear magnetic resonance spectra ( ' H - N M R ) were recorded on the following spectrometers:  Bruker WH-400 (400 M H z ) , Bruker A V - 4 0 0 (400 M H z ) and  Bruker A M X - 5 0 0 (500 M H z ) .  The positions of the signals are given as chemical shifts  (8) in parts per million (ppm) with respect to tetramethylsilane; however, the internal reference standard used in each case was the residual proton signal present in the deuterated solvent.  Reported chemical shifts are followed  in parentheses by the  multiplicity of the peak, the coupling constant in H z , and the number of protons. In some cases, ' H C O S Y experiments were used in order to ascertain structures.  Chromatography Chromatographic purification's of compounds were carried out using silica gel 60, 70-230 mesh, supplied by E . Merck Co.. Thin layer chromatography (tic) was carried out  105  on pre-coated silica gel plates (Merck 60, 230-400 mesh) with aluminum backing and fluorescent indicator (F254).  Preparative thin layer chromatography was performed on  pre-coated 10 cm x 10 cm, 1 or 2 mm thick Merck silica gel plates.  Reaction conditions Due to inherent light sensitivity of these compounds, all reactions were performed in a dark fumehood or surrounded by aluminum foil.  Reagents and Solvents Unless  otherwise specified,  reagents were used as supplied by the  Aldrich  Chemical Company. Solvents were reagent grade and purified using standard literature procedures when necessary.  Deuterated solvents were supplied by Cambridge Isotope  Laboratory.  4.2 General Procedures and Data Tetraarylporpyrin Synthesis Tetra(para-nitrophenyl)porphyrin method.  172  synthesized by  Alder's  The method involves the refluxing of the appropriate benzaldehyde  pyrrole in propionic acid (500 m L ) . filtered  (T(p-NC>2)PP) was  through  silica  gel.  The  and  This solution was concentrated to 100 m L and filtrate  is  concentrated  again  and purified  by  chromatography on silica gel (50 % C ^ C b / h e x a n e ) . Tt>-N0 )PP: R 0.77 (silica; C H C 1 ) ; U V - V i s ( C H C 1 ) ^ 2  f  2  2  2  2  m a x  422, 518, 554, 592,  648; ' H - N M R (400 M H z , CDCI3, ppm) 8 = 8.75 (s, 8H), 8.68 (d, J = 6.86 H z , 8H), 8.59 (d, J = 6.84 H z , 8H). p F T P P was synthesized by the method of D r e n t h .  173  This method proceeds by  adding 800 m L of distilled C H C 1 to a 2 L flask. To this 100 m L of 0.10 M pyrrole and 2  2  106  100 m L of 0.10 M benzaldehyde are added and the solution was purged with N 5 min.  for  2  After 5 min. 4 m L of 0.5 M BF3»Et20 was then added, and the solution was  stirred in the dark under N for 24 h. 7.4 mol of D D Q was then added to the solution, and 2  stirred for another 1 h, after which the solution is concentrated (200 m L ) under reduced pressure and 20 g of alumina was added.  The product is then purified by column  chromatography on neutral alumina (30 % CHCls/hexane).  pFTPP: R 0.77 (silica; 50 % CH Cl /hexane); U V - V i s ( C H C 1 ) ^ f  2  2  2  2  m a x  ( l o g s) 411  (4.52), 507 (4.37), 584 (3.99), 658 (3.79); ' H - N M R (200 M H z , C D C l , p p m ) 5 = 8.80 (s, 3  8H), -2.50 (s, 2H). Zinc 2-nitro-5, 10, 15, 20-tetraphenylporphyrin (y3-N0 TPP) was produced by the 2  following procedure.  Z n T P P is dissolved in 50 % C H C 1 / C H 3 C N and stirred under N  174  2  in the absence of light. dissolved in C H C l 2 . 2  AgN0  2  was dissolved in C H 3 C N and was followed by I  2  2  2  The reaction was left for 2 h in the dark, and then concentrated  under reduced pressure. The final product was then purified by column chromatography on silica gel (75 % CHC^/hexane). P-NO2TPP:  U V - V i s (CHCI3)  X ax m  (log s) 425 (5.28), 558 (4.20), 603 (4.14), H [  N M R (200 M H z , C D C 1 , ppm) 8 = 9.18 (s, IH), 8.80 (br s, 6H), 7.95-8.25 (m, 8H), 7.53  7.85 (m, 12H).  Synthesis of a;a'-(disilylmethyi)amines  TMS—\  175  (36,37 and 38).  TMS—\  TMS—\  MeO  36  37  38  107  A solution of benzylamine (2 g, 18.6 mmol), chloromethyltrimethylsilane (4.56 g, 37.3 mmol)  and potassium  carbonate  (5.14 g,  37.3 mmol)  were  refluxed  in dry  acetonitrile under N for 68 h. The potassium carbonate was filtered off, and the mixture 2  was concentrated under reduced pressure. chromatography.  The crude product was purified by column  The yield of the final product 36 was 76 %.  Compound 37 was  produced in the same manner using 3.12 g (18.6 mmol) of 3,5-dimethoxybenzylamine, 4.56 g  (37.3 mmol)  of chloromethyltrimethylsilylamine and 5.14 g (37.3 mmol)  of  potassium carbonate. The yield was 51 %. Compound 38 required 1.36 g (18.6 mmol) of n-butylamine, 4.5 g (37.2 mmol) of chloromethyltrimethylsilane and 5.14 g (37.2 mmol) of potassium carbonate. The yield of 38 was 59 %. 36: R 0.6 (silica; 20 % EtOAc/hexane); ' H - N M R (400 M H z , C D C 1 , ppm) 8 = f  3  7.20 (m, 5H), 3.40 (s, 2H), 1.80 (s, 4H), 0.00 (2, 18H). 37: R 0.6 (silica; 20 % EtOAc/hexane); ' H - N M R (400 M H z , C D C 1 , ppm) 5 = f  3  6.52 (d, J = 1 H z , 2H), 6.32 (t, J = 1 H z , 1H), 3.72 (s, 6H), 3.30 (s, 2H), 1.85 (3, 4H), 0.00 (s, 18H). 38: R 0.5 (silica; 20 % EtOAc/hexane); ' H - N M R (400 M H z , C D C 1 , ppm) 8 = f  3  2.23 (t, J = 7.08 H z , 2H), 1.86 (m, 4H), 1.31 (m, 4H), 0.88 (t, J = 7.08 H z , 2H), 0.00 (s, 18H).  Synthesis of a;a'-(disilymethyl)-n-cyanomethylamine (39) A solution of 37 (500 mg, 1.79 mmol) in dry CH2CI2 (5 m L ) was added to a solution of cyanogen bromide (209 mg, 1.97 mmol) slowly at r.t..  Almost immediately,  silica tic showed complete consumption of 37, and the reaction was halted.  2 m L of  triethylamine was added to the reaction mixture, which was then washed twice with  108  0.5 M HC1, and then twice with H 0 . 2  The crude product was purified using column  chromatography on silica gel (5 % EtOAc/hexane) to give the pure product in 58 % yield. 39: R 0.7 (silica; 20 % EtOAc/hexane); ' H - N M R (400 M H z , C D C 1 , ppm) 8 = f  3  2.5 (s, 4H), 0.20 (s, 18H).  M S (EI) m/z calculated for C H22N Si2: 214.13216, found 9  2  214.13265 m/z ( M H = 100 %). +  Reaction of a;a'-(disilylmethyl)amines with p F T P P .  1 9 4  F  OMe  36a  37a  38a  F  36a-38a  Two dry round bottom flasks are fitted with N2 inlets. T o one was added 50 mg (0.0513 mmol) of p F T P P and 129 mg (1.026 mmol) of A g F . 177.7 mg (0.636 mmol) of dry 36.  T o the other was added  1 m L of T H F was added to both flasks, and the  solution of amine 36 was added to the other flask drop-wise via syringe. was stopped after 1 h and A g F was  filtered.  The reaction  The products were purified by column  chromatography on silica gel (20 % EtOAc/hexane). Two products were collected 36a  109  (33 mg, 58 %) and 36b (7 mg).  The reaction of 37 with p F T P P proceeded in a similar  manner with 50 mg (0.0513 mmol) of p F T P P , 200 mg (1.58 mmol) o f A g F and 200 mg (0.589 mmol) of 37.  The reaction was left for 1 h.  The products were purified in the  same manner as 36a, yielding 37a (19 mg, 33 %) and 37b (5 mg). The reaction between 38 and p F T P P proceeded in a similar manner to that o f 36 with 50 mg (0.0513 mmol) of p F T P P , 200 mg (1.58 mmol) of A g F and 150 mg (0.607 mmol) of 38. The products were purified in the same manner as 36a, yielding 38a (38 mg, 67 %). 36a: R 0.7 (silica; 60 % CH Cl /hexane); ' H - N M R (400 M H z , C D C 1 , ppm) 5 = f  2  2  3  8.70 (d, J = 4.78 H z , 2H), 8.48 (s, 2H), 8.38 (d, J = 4.78 H z , 2H), 7.25 (m, 2H), 7.08 (m, 3H), 5.17 (m, 2H), 3.41 (s, 2H), 3.09 (m, 2H), 2.56 (m, 2H), -1.80 (s, 2H). (CHC1 ) 3  (rel. intensity) 405  Timax  UV-Vis  (1.00), 504 (0.08), 600 (0.02), 654 (0.283).  MS  ( L S I M S ) dev. in ppm from mass calculated for C 5 3 H F N 5 : 0.15, found 1108.15575 m/z 22  20  ( M H = 100%). +  37a: R 0.7 (silica; 20 % EtOAc/hexane); ' H - N M R (400 M H z , C D C 1 , ppm) 5 = f  3  8.70 (d, J = 4.78 H z , 2H), 8.47 (s, 2H), 8.38 (d, J = 4.78 H z , 2H), 6.3 (s, 1H), 6.16 (s, 2H), 5.15 (m, 2H), 3.57 (s, 6H), 3.34 (s, 2H), 3.10 (m, 2H), 2.56 (m, 2H), -1.80 (s, 2H). U V - V i s (CHCI3) A™* (rel. intensity) 405 (1.00), 504 (0.09), 600 (0.03), 654 (0.284). M S ( L S I M S ) dev. in ppm from mass calculated for C s s l f e F ^ N ^ : -1.39, found 1168.17509 m/z ( M H = 100%). +  38a: R 0.7 (silica; 60 % CH Cl /hexane); ' H - N M R (400 M H z , C D C 1 , ppm) 5 = f  2  2  3  8.70 (d, J = 4.78 H z , 2H), 8.48 (s, 2H), 8.38 (d, J = 4.78 H z , 2H), 5.20 (m, 2H), 3.15 (m, 2H), 2.51 (m, 2H), 2.24 (d, J = 7.5 H z , 2H), 1.3 (m, 2H), 1.19 (m, 2H), 0.80 (t, J = 7.5 H z , 3H), -1.86 (s, 2H). U V - V i s (CHC1 ) ? w (rel. intensity) 405 (1.00), 504 (0.09), 3  110  600 (0.03),  654 (0.290).  M S (LSIMS)  dev. in ppm from mass calculated for  C oH23F oN : 1.59, found 1074.17295 ( M H = 100 %). +  5  2  5  Reaction of tetracyanoethylene oxide with TPP to form 40  40  A solution o f 200 mg (0.325 mmol) of T P P was refluxed in 50 m L of toluene. T C N E O (200 mg, 1.4 mmol) was then added to the solution.  The mixture was refluxed  for 1 h, concentrated under reduced pressure, and purified by preparatory tic on 2 m m silica gel plates (50 % CT^C^/hexane). The product 40 was obtained in 20 % yield. 40: R 0.7 (silica; 50 % CH Cl /hexane); ' H - N M R (400 M H z , C D C 1 , ppm) 8 = f  2  2  3  8.70 (d, J = 4.89 H z , 2H), 8.50 (s, 2H), 8.38 (d, J = 4.89 H z , 2H), 8.13 - 7.66 (m, 20H), 6.00 (s, 2H), -2.05 (s, 2H). U V - V i s (CHC1 ) ^max (rel. intensity) 416 (1.0), 514 (0.14), 3  554 (0.18), 586 (0.10), 642 (0.22). L R M S (LSIMS) 759 m/z ( M H = 100 %). +  Ill  Hydrolysis and methylation of 40 to form 41  A solution of 40 in concentrated HC1 (5 m L ) , was refluxed for 8 h, and the HC1 was removed under reduced pressure. in 2 m L of D M S O , potassium carbonate.  with 66  The resulting polar products were then dissolved  u L of dimethylsulfate  and 100 mg (0.723 mmol)  of  This solution was heated until no more baseline material was  observed using silica tic. Purification on preparatory tic gave two products, one of which was 41, 10 mg, 10% yield. 41: R 0.7 (silica; 60 % CH Cl /hexane); H - N M R (400 M H z , C D C 1 , ppm) 5 = 1  f  2  2  3  8.60 (d, J = 4.89 H z , 2H), 8.45 (s, 2H), 8.28 (d, J = 4.89 H z , 2H), 8.13 - 7.66 (m, 20H), 6.02 (s, 2H), 4.92 (s, 2H), 3.53 (s, 6H), -1.96 (s, 2H).  U V - V i s (CHC1 ) X 3  max  (rel.  intensities) 416 (1.00), 518 (0.10), 544 (0.09), 592 (0.07), 646 (0.14). M S (LSIMS) dev. in ppm for mass calculated for C 3 H o F o N : 0.30, found 775.29228 m/z ( M H = 100 %). +  5  2  2  5  112  Synthesis of a,a'-(dichIoromethyI)ether  176  A 100 m L round bottom reaction flask was cooled in ice, 16.8 m L of cone. HC1 was added to the flask, after which 24 g of paraformaldehyde was added  slowly.  45.2 m L of chlorosulfonic acid was added slowly to the mixture while stirring.  The  mixture is stirred for 4 h at r.t.. The less dense organic layer was then separated from the more dense aq. layer, and was washed with H 0 twice, and with 40 % N a O H until just 2  alkaline.  The product was dried over potassium carbonate and potassium hydroxide at  0 ° C . The product was then used without further purification. 44a: ' H - N M R (200 M H z , CDC1, ppm) 5 = 5.45 (s, 4H).  Reaction of unstabilized carbonyl ylide with pFTPP to form 44  44  A suspension of lead P b C ^ with M n was stirred in 15 m L of dry T H F for 1 h. To the mixture 50 mg (0.05 mmol) of p F T P P was added followed by 3 g (0.02 mol) N a i and 1.14 g of the a,a'-(dichloromethyl)ether.  The reaction is left to stir overnight under N2,  113  and stopped 12 h later. The reaction was quenched with water, and the organic products were then separated into C H 2 C I 2 . The organic layer was dried with MgSCu and purified by preparatory tic on 2 mm silica gel plates (50 % CHCl /hexane). 3  The product 44 was  obtained in 38 % yield. 44: R 0.5 (silica; 50 % CH Cl /hexane); ' H - N M R (400 M H z , C D C 1 , ppm) 8 = f  2  2  3  8.70 (d, J = 4.90 H z , 2H), 8.47 (s, 2H), 8.38 (d, J = 4.90 H z , 2H), 5.33 (t, J = 4.36 H z , 2H), 4.20 (t, J = 8.17 H z , 2H), 4.20 (t, J = 8.17 H z , 2H), 3.92 (dd, J = 4.36 H z and 8.17 H z , 2H), -1.50 (s, 2H).  U V - V i s (CHC1 ) X 3  max  (rel. intensities) 414 (1.00), 506  (0.03), 603 (0.01), 656 (0.128). L R M S (LSIMS) 1019 m/z ( M H = 100 %). +  Reaction of p F T P P with Diazomethane to give 45 F  45 2 g (9.33 mmol) of Diazald ® was dissolved in 16 m L of diethyl ether.  This is  added dropwise into the reaction chamber of a diazomethane apparatus containing 8 m L of H 2 O , 8 m L E t O H and 2 g (0.0338 mmol) of K O H . The resulting gas was condensed with ether at - 7 8 ° C into a flask containg 50 mg of p F T P P dissolved in 2 m L of dry  114  CH2CI2. After all of the Diazald ® is exhausted, the reaction was sealed under positive N2 pressure and left to stir overnight.  The reaction is repeated 24 h later. The solution  was then concentrated under reduced pressure, and the crude product was purified by preparatory tic on 2 mm silica gel plates (20 % Qr^Cb/hexane). The compound 45 was obtained in 60 % yield. 45: R 0.7 (silica; 50 % CH Cl /hexane); ' H - N M R (400 M H z , C D C 1 , ppm) 8 = f  2  2  3  8.80 (d, J = 4.89 H z , IH), 8.77 (d, J = 4.89 H z , IH), 8.61 (d, J = 4.89 H z , IH), 8.52 (s, 2H), (m,  8.44 (d, J= 4.89 H z , IH), 4.92 (s, 2H), 7.72 (d, J = 8.8 H z , IH), 5.11 (m, 2H), 4.92 IH), -2.09 (s, 2H). U V - V i s (CHC1 ) ^ 3  (0.01), 648 (0.181).  m a x  (rel. intensities) 402 (1.00), 504 (0.09), 598  M S (LSIMS) dev in ppm from mass calculated for C 4 H i 2 F o N : 5  0. 58. found 1017.08882 m/z ( M H  +  2  6  = 100 %).  Nitrogen Elimination from Compound 45 to form 46 Compound 45 (5 mg) was subjected to the following two experiments. 1.  Compound 45 was dissolved in mesitylene and refluxed under N2 for 1 h.  2.  Compound 45 was dissolved in toluene-dg, this was then irradiated with sunlight  for 1 h. Both reactions gave the same product 46 in nearly quantitative yield. The products were used directly for analysis without any purification. 46: R  f  0.8 (silica; 20 % CH Cl /hexane); ' H - N M R (400 M H z , CDCI3, 2  2  ppm) 8 = 8.67 (d, J = 4.78 H z , 2H), 8.43 (s, 2H), 8.40 (d, J = 4.78 H z , 2H), 3.90 (dd, J = 4.10 H z , 2H), 1.90 (m, IH), .84 (s, IH), -1.73 (s, 2H). intensities) 410 (1.00), 508 (0.14), 606 (0.08), 662 (0.30).  U V - V i s (CHC1 ) X 3  m a x  (rel.  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