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Syntheses of selected heme protein model compounds Morgan, Brian D. 1984

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SYNTHESES OF SELECTED HEME PROTEIN MODEL COMPOUNDS BY BRIAN MORGAN / B.Sc. (Hons), T r i n i t y C o l l e g e , D u b l i n , 1977 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY IN THE FACULTY OF GRADUATE STUDIES (Department of Chemistry) We accept t h i s t h e s i s as conforming to the required standard THE UNIVERSITY OF BRITISH COLUMBIA AUGUST 1984 © B r i a n Morgan 1984 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 i t 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. Department of The University of British Columbia 1956 Main Mall Vancouver, Canada V6T 1Y3 Date 4 T p g y ) / / y f r V ABSTRACT Strapped porphyrins may be defined as those compounds i n which some b r i d g i n g group i s c o v a l e n t l y attached to opposite edges of the porphyrin macrocycle. This c l a s s of compound has been e x t e n s i v e l y studied as models f o r the a c t i v e s i t e s of heme pr o t e i n s such as hemoglobins, cytochrome P450 e t c . Two avenues of approach to the synth e s i s of strapped porphyrins have been used. The strap may be c o v a l e n t l y attached to opposite edges of a preformed p o r p h y r i n , or the two halves of the porphyrin macrocycle may be assembled at each, end of the strap w i t h a f i n a l i n t r a m o l e c u l a r c y c l i z a t i o n f i t t i n g the strap i n t o p l a c e . The l a t t e r approach has been adopted here to provide a general route to those strapped porphyrins bearing f u n c t i o n a l groups i n the b r i d g i n g s t r a p s . Compounds 87a, 87b. and 118a, 118b have been prepared as p o s s i b l e models f o r cytochrome c and c a t a l a s e , while the po r p h y r i n -quinone compounds 143a, 143b. may be used to study e l e c t r o n t r a n s f e r i n donor/acceptor complexes. The syntheses of the v a r i o u s strapped porphyrins a l l o r i g i n a t e from the a - f r e e - i o d o a l k y l p y r r o l e s 44, 64_ which, are r e a d i l y a v a i l a b l e v i a F r i e d e l - C r a f t s a c y l a t i o n of g-free p y r r o l e 1, followed by red u c t i o n and i o d i n a t i o n of the a l k y l chain and m o d i f i c a t i o n of the a-methyl group. For the s u l f i d e - s t r a p porphyrins, r e a c t i o n with, sodium s u l f i d e to give the b i s [ ( p y r r o l - 3 - y l ) a l k y l ] s u l f i d e s 75a, 75b formed the s t r a p . E l a b o r a t i o n to the his-dipyrromethanes 77a, 77b provided a l l the u n i t s necessary f o r porphyrin s y n t h e s i s . S a p o n i f i c a t i o n and decarboxylation followed by h i g h - d i l u t i o n a c i d - c a t a l y z e d i n t r a m o l e c u l a r c y c l i z a t i o n y i e l d e d the strapped porphyrins 87a (9-19%) and 87b (10-18%). Exposure i i to l i g h t during work-up i s believed to be responsible for the formation of the corresponding sulfoxide-strap porphyrins 88a, 88b. b n = i bn=4 Conversion of 44—and 64_ to the corresponding phosphonium s a l t s 94a, 94b followed by a double Wi t t i g reaction under phase-transfer conditions with e i t h e r of the dialdehydes 95_ or 131 gave the bis-alkenes. C a t a l y t i c hydrogenation yielded the b i s ( p y r r o l - 3 - y l ) compounds 113a, 113b and 138a, 138b. Elaboration to the bis-dipyrromethanes was followed by sa p o n i f i c a t i o n , decarboxylation and intramolecular c y c l i z a t i o n to f u r n i s h the strapped porphyrins. These r e l a t i v e l y unstrained compounds were obtained i n good y i e l d : 117a (30-44%), 117b (21-53%), 140a (41-60%), 140b (20-40%). Treatment of the anisole-porphyrin 117a, 117b with boron tribromide furnished the phenol-strapped porphyrin ,118a (76-89%) , 118b (89-95%). Demethylation of the dimethoxybenzene-porphyrin 140a, 140b also with boron tribromide yielded the hydroquinone which was oxidized to the quinone-strapped porphyrin 143a (.82-87%) , 143b (70%) . An attempt was made to incorporate a sui t a b l y substituted imidazole into the bridging strap using the same procedure. However production of the required 1,5-disubstituted imidazole intermediates was hampered by low yi e l d s and d i f f i c u l t y i n p u r i f i c a t i o n . The f a i l u r e to prepare the necessary imidazole bis-aldehyde 170 led to ca n c e l l a t i o n of t h i s attempt. A l l the porphyrins were subjected to elemental a n a l y s i s , high 1 13 resolu t i o n mass spectrometry, and v i s i b l e absorption and H- and C-NMR spectroscopy. A s i m p l i s t i c attempt was made to correlate the spe c t r a l c h a r a c t e r i s t i c s to the structure, length and conformation of the strap. 170 iv H 3Cv y(CH2)nPPh3 I E t 0 V ^ N ^ H 0 H 9 4 a n = 5 9 4 b n = /> 117a n = 6 b n = 5 1J8a n = 6 b n = 5 H3a n = 6 b n = 5 138a n = 6 b n = 5 140a n = 6 b n= 5 0 143a n = 6 b n = 5 v TABLE OF CONTENTS Page Abstract i i Table of Contents y ± L L i s t of Tables i x L i s t of Figures x L i s t of Abbreviations x i v Acknowledgements x v i 1. LITERATURE REVIEW 1 1.1 I n t r o d u c t i o n 2 1.2 Porphyrins w i t h Appended Peptide Fragments . . . . 13 1.3 Chelated Hemes 23 1.3.1 Porphyrins w i t h C o v a l e n t l y Attached Imidazole or P y r i d i n e Ligands 23 1.3.2 Porphyrins w i t h C o v a l e n t l y Attached S u l f u r 1 Ligands 34 1.4 "Picket-Fence" Porphyrins 45 1.4.1 "Picket-Fence" Porphyrins 45 1.4.2 " T a i l e d Picket-Fence" Porphyrins 52 1.5 "Capped" Porphyrins 57 1.5.1 "Capped" Porphyrins 57 1.5.2 "Pocket" and " T a i l e d Pocket" Porphyrins . . 61 v i 1.5.3 "Bis-Pocket" Porphyrins 64 1.6 "Strapped" Porphyrins 67 1.6.1 Non-Functionalized A l k y l Straps 67 1.6.2 Straps Containing Bulky Blocking Groups . 73 1.6.3 Straps Containing Interactive Groups . . . 78 1.6.4 Doubly-Strapped Porphyrins 84 2. RESULTS AND DISCUSSION 96 2.1 Introduction 97 2.2 Synthesis of 5-(5-Ethoxycarbonyl-4-methylpyrrol-3-yl)-l-iodopentane 44_ and i t s Lower Homologue J)4. 110 2.3 Synthesis of Porphyrins Containing a Thioether Strap 135 2.4 Synthesis of Porphyrins Containing a Phenol Strap. 163 2.5 Synthesis of Porphyrins Containing a Quinone Strap 184 2.6 Attempted Synthesis of a Porphyrin Containing an Imidazole Strap 197 3. EXPERIMENTAL 216 3.1 Introduction 217 3.1.1 General Methods 217 3.1.2 Nomenclature of Porphyrins and Intermediate Compounds 218 3.2 Syntheses of Monopyrroles 222 v i i 3.3 Syntheses of Aromatic Bis-Aldehydes _95, 131 and Their Precursors 261 3.4 Syntheses of Chain-Linked Bis-Pyrroles 270 3.5 Syntheses of Chain-Linked Dipyrromethane Dimers . 286 3.6 Syntheses of Strapped Porphyrins 297 3.7 Modifications of Strapped Porphyrins 311 3.8 Syntheses of Imidazole Precursors 319 4. SPECTRAL ASSIGNMENTS AND COMPARISON TABLES 323 4.1 "^H-NMR Data of Strapped Porphyrins 328 /' 13 •' 4.2 C-NMR Data of Strapped Porphyrins .351 4.3 E l e c t r o n i c Absorption Spectra of Porphyrins . . 383 REFERENCES - 400 v i i i LIST OF TABLES TABLE TITLE PAGE I A x i a l L i g a n d s o f S e l e c t e d Heme P r o t e i n s 3 I I Y i e l d s o f t h e S u l f i d e - S t r a p p e d P o r p h y r i n s 87a, 87b and t h e S u l f o x i d e - S t r a p p e d P o r p h y r i n s 88a, 88b. 158 I I I P r e p a r a t i o n of 1 , 5 - D i s u b s t i t u t e d I m i d a z o l e s . . . 204 IV "^H-NMR Data o f S u l f i d e - and S u l f o x i d e - S t r a p p e d P o r p h y r i n s i n CDC1 3 338 V '''H-NMR Data o f A n i s o l e - S t r a p p e d P o r p h y r i n s 117a, 117b and P h e n o l - S t r a p p e d P o r p h y r i n s 118a, 118b i n CDC1 3 339 VI ''"H-NMR D a t a o f Dime t h o x y b e n z e n e - S t r a p p e d P o r p h y r i n s 140a, 140b and Q u i n o n e - S t r a p p e d P o r p h y r i n s 143a, 143b i n CDC1 3 . 3 4 0 V I I ^H-NMR D a t a o f t h e M e t h y l e n e P r o t o n s o f t h e S t r a p p e d P o r p h y r i n s . . . . 341 13 V I I I C-NMR Data o f S u l f i d e - and S u l f o x i d e - S t r a p p e d P o r p h y r i n s i n 10% TFA-CDC1 3 356 13 I X C-NMR Data o f ; n i s o l e - S t r a p p e d P o r p h y r i n s 117a, 117b and P h e n o l - S t r a p p e d P o r p h y r i n s 118a, 118b i n 10% TFA-CDC1 3 357 13 X C-NMR D a t a of Dim e t h o x y b e n z e n e - S t r a p p e d p o r p h y r i n s 140a, -1-4Qb and Q u i n o n e - S t r a p p e d P o r p h y r i n s 143a, 143b i n 10% TFA-CDC1 . . . . . . 358 \ XI Comparison o f E l e c t r o n i c A b s o r p t i o n S p e c t r a l D a t a o f P o r p h y r i n s 386 X I I Comparison o f E l e c t r o n i c A b s o r p t i o n S p e c t r a l Data o f P o r p h y r i n s 387 i x LIST OF FIGURES FIGURE TITLE PAGE 1. Synthesis of the Strapped Porphyrins of Wijesekera et a l . 1 1 0 ' ^ 1 98 2. Attempted Synthesis of the Bis-dipyrromethane _19 . 100 3. Proposed Syntheses of Strapped Porphyrins . . . . 109 4. Synthesis of 5-(5-Ethoxycarbonyl-4-methyl-pyrrol-3-yl)-l-iodopentane 44_ I l l 5. Schematic Representation of the Iodinative Decarboxylation of 4_1_ 117 6. A l t e r n a t i v e Synthesis of 5-(5-Ethoxycarbonyl-4-methylpyrrol-3-yl)-l-iodopentane 44 120 7. Synthesis of 4-(5-Ethoxycarbonyl-4-methylpyrrol-3-yl)-l-iodobutane 6k 122 8. A l t e r n a t i v e Synthesis of 4-(5-Ethoxycarbonyl-4-methylpyrrol-3-yl)-l-iodobutane j54 ........... 127 9. Synthesis of Porphyrins Containing a S u l f i d e Strap 136 10. Synthesis of Sulfide-Strapped Porphyrin 87b v i a Intramolecular C y c l i z a t i o n 149 11. Proposed Mechanism of Sulfoxide-Strapped Porphyrin 88a Formation • 156 12. Schematic Representation of the Active Sites of Peroxidase, Cytochrome c, and some Mutant Hemoglobins 164 13. Synthesis of the Bis-dipyrromethanes 114a and 114b 1 6 7 14. Synthesis of the'Anisole-Strapped Porphyrins 117a and 117b., 181 x 15. S i m p l i f i e d Scheme f o r Photosynthesis i n P l a n t s 1 9 8 185 16. Representative Covalently Linked Porphyrin-Quinone Molecules 186 17. Synthesis of the Bis-dipyrromethanes 139a and 139b 190 18. Synthesis of 22?5r;Diformyl-1,4-dimethoxy-benzene 131 191 19. Synthesis of the Dimethoxybenzene-Strapped Porphyrins 140a and 140b 194 20. Synthesis of the Quinone-Strapped Porphyrins 143a and 143b 196 21. Proposed Synthesis of the Imidazole-Strapped Porphyrin JL54 198 215 22. Synthesis of a-Aminoketones 201 23. Proposed Synthesis of Imidazole-Strapped Porphyrin v i a 1,5-Bis(3-hydroxypropyl) imidazole 112_ 206 24. F i s c h e r and IUPAC Numbering Systems f o r the Porphyrin Nucleus 219 25. Numbering System f o r Dipyrromethanes . . . . . 220 27. Schematic Representation and Abbreviated Names fo r the Strapped Porphyrins . 341 ^ 28. V a r i a t i o n of Porphyrin Ring Methyl Chemical S h i f t s w i t h Strap Length 342 ^ 29. V a r i a t i o n of Meso Proton Chemical S h i f t s w i t h Strap Length 344 30. V a r i a t i o n of Porphyrin Core Protons w i t h -,u Strap Length 346 xi. 31. V a r i a t i o n of Chain Termini and Porphyrin Ethyl Chemical S h i f t s with Strap Length 336 32. Schematic Representation of S t e r i c Crowding i n 117a and 117b 347 33. Separation of Meso Carbon Resonances as a Function of Strap Length . 353 34. 1H-NMR Spectrum (400 MHz) of 87a i n CDC13 . . . . 359 35. 1H-NMR Spectrum (400 MHz) of 87b i n CDC1 3 . . . . . 360 36. H^-NMR Spectrum (400 MHz) of 88a i n CDC13 . . . . 361 37. 1H-NMR Spectrum (400 MHz) of 88b i n CDC13 . . . . 362 38. H^-NMR Spectrum (400 MHz) of 117a i n CDC13 . . . .363 39. H^-NMR Spectrum (400 MHz) of 117b i n CDC1 3 . . . '364 40. 1H-NMR Spectrum (400 MHz) of 118a i n CDC1 3 . . . 365 41. H^-NMR Spectrum (400 MHz) of 118b i n CDC13 . . . 366 42. H^-NMR Spectrum (400 MHz) of 140a i n CDC1 3 . . . 367 43. 1H-NMR Spectrum (400 MHz) of 140b i n CDC1 3 . . . 368 44. 1H-NMR Spectrum (400 MHz) of 143a i n CDC13 . . . 369 45. '''H-NMR Spectrum (400 MHz) of 143b i n CDC13 . . . 370 46. 13C-NMR Spectrum of 87a i n 10% TFA-CDC13 . . . . 371 47. 13C-NMR Spectrum of 8>7b i n 10% TFA-CDC13 . . . . 372 48. 13C-NMR Spectrum of 88a i n 10% TFA-CDC13 . . . . 373 49. 13C-NMR Spectrum of 88b i n 10% •TFA-CDC1 . . . . 374-50. 13C-NMR Spectrum of 117a i n 10% TFA-CDC13 . . . . 375 x i i 51. C-NMR Spectrum of 117b i n 10% TFA-CDC13 . . . . 376 52. 13C-NMR Spectrum of 118a i n 10% TFA-CDC13 . . . . 377 53. 13C-NMR Spectrum of 118b i n 10% TFA-CDC13 . . . . - 378 54. 13C-NMR Spectra of 140a i n 10% TFA-CDC13 . . . . 379 13 55. C-NMR Spectrum of 140b i n 10% TFA-CDC13 . . . . 380 56. 13C-NMR Spectrum of 143a i n 10% TFA-CDC13 . . . . 381 57. 13C-NMR Spectrum of 143b i n 10% -TFA-CDCl^ . . . . 382 58. E l e c t r o n i c Absorption Spectra of 87a 388 59. E l e c t r o n i c Absorption Spectra of 87b 389 60. E l e c t r o n i c Absorption Spectra of 88a 390 61. E l e c t r o n i c Absorption Spectra of 88b 391 62. E l e c t r o n i c Absorption Spectra of 117a 392 63. E l e c t r o n i c Absorption Spectra of 117b 393 64. E l e c t r o n i c Absorption Spectra of 118a 394 65. E l e c t r o n i c Absorption Spectra of 118b 395 66. E l e c t r o n i c Absorption Spectra of 140a 396 67. E l e c t r o n i c Absorption Spectra of 140b 397 68. E l e c t r o n i c Absorption Spectra of.143a 398 69. E l e c t r o n i c Absorption Spectra of 143b 399 x i i i ABBREVIATIONS 13 C-NMR = Carbon-13 nuclear magnetic resonance CT^C^ = Dichloromethane CO = ^Carbon monoxide DABCO = l,4-Diazabicyclo[2.2.2]octane DDQ = 2,3-Dichloro-5,6-dicyano-l,4-benzoquinone DMA = N,N-Dimethylacetamide DMF = N,N-Dimethylformamide DMSO = Dimethyl sulfoxide ee = Enantiomeric excess EPR, ESR = Electron paramagnetic (spin) resonance Et^N = Triethylamine EtOAc = Ethyl acetate "''H-NMR = Proton nuclear magnetic resonance Im = '. d Imidazole KOBu-t = Potassium t-butoxide MCD = Magnetic c i r c u l a r dichroism Q = Oxygen molecule pyr = Pyridine TFA = T r i f l u o r o a c e t i c a c i d THF = Tetrahydrofuran x i v t i c = Thin layer chromatography TMS = Tetramethylsilane Abbreviations i n NMR Assignments S = s i n g l e t m = multiplet d = doublet -bs = broad s i n g l e t t = t r i p l e t bt = broad t r i p l e t q = quartet xv ACKNOWLEDGEMENTS I would l i k e to thank T i l a k Wijesekera, whose work on "strapped" porphyrins provided the i n s p i r a t i o n f o r t h i s e f f o r t , and my supervisor, David Dolphin who provided the f a c i l i t i e s and the necessary encouragement. Thanks should also be extended to Peter Borda of the U.B.C. Mic r o a n a l y t i c a l Laboratory, the s t a f f of the Mass Spectrometry Labora-tory, and p a r t i c u l a r l y the s t a f f of the U.B.C. NMR Centre who provided valuable assistance i n recording some of the spectra. The f a s t and e f f i c i e n t typing of Rani Theeparajah considerably lessened the burden of assemblying t h i s thesis. F i n a l l y I would l i k e to thank B r i d i e Bennett who not only provided constant encouragement, but also helped i n the preparation of the diagrams. x v i 1 CHAPTER I LITERATURE REVIEW 2 1 .1 INTRODUCTION Because of t h e i r ubiquitousness and the v a r i e t y of functions which they carry out, heme proteins have been investigated on a multi-d i s c i p l i n a r y l e v e l . These proteins, a l l containing an i r o n porphyrin as the p r o s t h e t i c group, are responsible for oxygen transport and storage (hemoglobin and myoglobin), electron transport (cytochromes b, c ) , oxygen reduction (cytochrome oxidase), hydrogen peroxide u t i l i z a t i o n and destruction (peroxidases and catalases), substrate oxidation (cytochrome P450). The active s i t e i n each case contains an i r o n porphyrin (usually protoporphyrin IX), the nitrogens of the porphyrin ri n g occupying four e s s e n t i a l l y planar coordination s i t e s of the metal. The d i v e r s i t y of function of the heme proteins must therefore be dictated by the number and nature of the a x i a l ligands, the spin and oxidation state of the i r o n and the nature of the polypeptide chain/ A basic tenet of bioinorganic chemistry i s that the structure and function of large biomolecules may be simulated using simpler inorganic complexes to model the active s i t e s . Obviously to f u l l y understand the mechanisms of heme protein function, a study of i r o n porphyrins must be undertaken i n which the c h a r a c t e r i s t i c s of the metal (spin s t a t e , oxidation state and coordination number) and the s t e r i c and e l e c t r o n i c e f f e c t s of the porphyrin and other ligands are systematically varied. H i s t o r i c a l l y , much of the research on metalloporphyrins has focussed on the mechanism of oxygen binding to myoglobin and hemoglobin. Oxygen binding heme proteins are five-coordinate, high spin (S=2) i r o n ( I I ) species, which upon oxygenation become six-coordinate low spin (S=0). 145 146 TABLE I : A x i a l Ligands of Selected Heme P r o t e i n s ' PROTEIN LIGAND Hemoglobin deoxy His-F8 a oxy His-F8 0 2 carbonmonoxy His-F8 CO Myoglobin - deoxy His-F8 a Cytochrome P450 Cysteine a Cytochrome c - tuna His-18 Met-80 Cytochrome b,. - c a l f l i v e r His-39 His-63 Peroxidase - hor s e r a d i s h His Catalase - beef l i v e r Tyr-357 a) S i x t h l i g a n d s i t e vacant or occupied by water 4 The d i f f i c u l t y in reproducing this behaviour is dominated by two problems: (i) irreversible oxidation of iron(II) porphyrins on exposure to oxygen, and ( i i ) the d i f f i c u l t y in obtaining well-defined five-coordinate iron porphyrins. Simple iron(II) porphyrins cannot reversibly bind oxygen, except at low temperature. At room temperature, and in the absence of a large excess of a sixth ligand, formation of the six-coordinate.iron(II)-— oxygen species i s immediately followed by attack of a second five-coordinate iron(II) complex to give the y-peroxo dimer. This rapidly breaks down, presumably via the fe r r y l intermediate to give the y-oxo dimer in which the iron has been irreversibly oxidized to the f e r r i c 1-4 form (Scheme 1). Therefore, a major role for the polypeptide backbone of heme-proteins is to sheath the oxygen binding site, preventing the close approach of two heme rings and irreversible oxidation via the y-peroxo dimer. That irreversible oxidation of iron(II) porphyrins i s possible by another mechanism is demonstrated by the fact that the body must provide an enzyme to reduce methemoglobin (the oxidized iron(III) hemoglobin incapable of oxygen transport) to the functional iron(II).form. Even so, hemoglobin exists in the body in the f e r r i c form to the extent of about 3%. This alternative oxidation pathway occurs in aqueous acid or under conditions where y-peroxo dimer formation is inhibited, and is believed to involve proton assisted formation of protonated super-S C H E M E 1 B I n •Fe-B - Fe— B B — F e + B B ( l ) + 0 2 Fe — (2) 0, B B in • Fe— + — F e — B — F e — 0 0 — F e — B (3) 0, 0 in _ j . in _ / B — F e — 0 0 — F e : — B I V 2 — F e — B (4) I I V I II B — F e = 0 + F e — B F e — 0 — F e (5) oxide. The peptide chain also stabilizes the Fe(II)-0 2 species by Fe(II) - 0 2 + H + > F e ( I I I > - + H02 (6) Fe(II) + H02 + H + > F e ( I I I ) + (7) 2Fe(II) + H 20 2. + 2H+ • 2 F e ( l I I ) "+ 2^0 (8) enclosing the porphyrin in a hydrophobic pocket to which access by protons i s inhibited. In addition, recent neutron^ and X-ray 8 diffraction studies have indicated that stabilization of the iron-oxygen bQnd in oxyhemoglobin and oxymyoglobin may in part be due to hydrogen bonding between the terminal oxygen atom and the imidazole of the di s t a l histidine (E7). The influence of the protein backbone i s more pervasive than simply providing a barrier to oxidation.:: Conformational changes upon oxygen binding to the active site are believed to be responsible for the remarkable cooperativity exhibited by hemoglobin. Similarly, the arrangement of certain residues on the protein has been postulated to provide an avenue along which electron transfer may occur in the cytochromes. But i t i s the protein's role in maintaining the coordination sphere of the iron porphyrin which determines the functions of the various heme proteins. The second major problem in studying simple iron porphyrins i s the preference of the metal for six-coordination. For example, in solution containing strongly coordinating N-donor ligands, six-coordination is favoured over five coordination, i.e., for the equilibria 9 i n equation 9, K £ > ^ 1 ^ 2 ^ 1 = •*-(^-^^  a P r o t i c solvent at 25°C) . In K, K 2 FellDPor + B FeOOPorB + B ^== i Fe(ll)Por(B)2 (9) benzene at 25°C, the binding constants of pyridine to Fe(II)(TPP) have 3 - 1 4 - 1 been estimated at ^.1.15 x 10 M and K 2^1.9 x 10 M . The s i z e of and i s obviously controlled by the spin state of the i r o n . The four-coordinate iron porphyrin i s i n an intermediate spin (S = 1) state. Addition of one ligand gives the high spin (S = 2) five-coordinate complex which adds a second ligand to form the low spin (S = 0) s i x -coordinate species with a gain i n c r y s t a l f i e l d s t a b i l i z a t i o n energy. ^ ^  In contrast, for Co(II), no s t a b i l i z a t i o n i s gained oil going from f i v e -12 to six-coordinate since Co(II) i s low spin i n both cases, and K >>K . A further consequence of t h i s i s the d i f f i c u l t y of preparing mixed-ligand six-aoordinate iron porphyrins. A t y p i c a l example i s the preparation of models f o r cytochrome c;. where the ir o n i s coordinated by an imidazole (His-18) and a thioether (Met~80). The greater l i g a t i n g power of imidazole coupled with i t s tendency to form six-coordinate bis(imidazole) complexes makes s e l f assembly of the mixed ligand system, Im-Fe-SR^. d i f f i c u l t . Strategies which control coordination are es s e n t i a l f o r preparing a range of heme protein model porphyrins. Numerous approaches have been used to con t r o l oxidation and coordination i n model porphyrin systems. (i) Excess Ligand: The presence of excess base (imidazole, pyridine) w i l l minimize the concentration of five-coordinate heme and reduce y-peroxo dimer formation. B B | I o — F e " — B I I (10) B 0 However i n t h i s case one i s li m i t e d to studying competitive oxygen binding to six-coordinate hemes. B B — F e — + 0 2 f = ± — F e — + B ( n ) B 13— 16 ( i i ) Low Temperatures: Iron(II)-C>2 porphyrin complexes are stable at low temperatures (^60°C) , where the i r r e v e r s i b l e oxidation reactions are su c c e s s f u l l y suppressed. Again one i s reduced to studying competitive oxygen binding as K^/K^ i - n c r e a s e s 3 3 temperature decreases. B B B P n D K, Li K 2 IH 0, L — F e — + B 7-^ — F e — + B -=± — F e — r = z — F e — (12) B ( i i i ) K i n e t i c Measurements: Fast spectroscopy methods may be used to observe r e v e r s i b l e oxygen binding even under conditions where i r r e v e r s i b l e oxidation w i l l occur. Traylor has exploited the s t a b i l i t y of imidazole-heme-CO complexes towards o x i d a t i o n . ^ A so l u t i o n of Im-Hm-CO, equi l i b r a t e d with a mixture of oxygen and carbon monoxide, i s subjected to a short laser pulse which completely removes the carbon monoxide. The deoxy heme then reacts p r e f e r e n t i a l l y with oxygen at a fast but measurable rate ( k ^ > 10^ M ^'s;'''). In 10 3 - 1 0 s , the Im-Hm-O^  complex dissociates and returns to the Im-Hm-CO complex. B r n B 0 B i . ^ i« i . - F e — . — F e — , — F e — (13) k Q C 0 -Pz k-°2 . CO B B o 2 18 The k i n e t i c s are described by: 1 i ° 2 X f = V ° 2 * K B [ 0 2 V . C 0 r r m <"> "return K B K B L C 0 J CO CO Since k^ [CO] i s the rate of return before 0^ i s added, k g [CO] may be accurately determined i n the experiment and k^2 a n d may be calculated from a plo t of ^ / vs 0^ (pressure). return 19 (iv) Metal Substitution: Replacement of i r o n with cobalt or 20 ruthenium leads to metalloporphyrins which are more i n e r t to oxidation and possess d i f f e r e n t coordination properties. Such an approach i s applicable since apoproteins may be reconstituted with Co and Ru porphyrins. In the case of Co, reconstituted Co hemoglobin exhibits cooperative oxygen binding although to a diminished extent. (v) Immobilization: This approach attempts to prevent i r r e v e r s i b l e oxidation by anchoring the porphyrin to a s o l i d support. In Wang's 10 c l a s s i c experiment a heme d i e t h y l ester was embedded i n a matrix of 21 polystyrene and 1-(2-phenylethyl)imidazole. The matrix not only prevented close approach of two hemes but also provided a hydrophobic environment. Reversible oxygen uptake was observed. A l t e r n a t i v e l y , e i t h e r the porphyrin or the ligand may be covalently attached to a r i g i d support. Basolo has undertaken the l a t t e r approach and prepared a s i l i c a gel support which contained 3-imidazolypropyl groups attached 22 to the surface. Reaction with Fe(II)(TPP)(B)^ coordinated the porphyrin and heating i n flowing helium removed the s i x t h a x i a l base (pyridine or piperidine) to give the five-coordinate i r o n ( I I ) porphyrin. However, attempts to observe r e v e r s i b l e oxygen binding were obscured by the physisorption of oxygen by the s i l i c a support. (vi) S t e r i c encumbrance: By s t e r i c a l l y blocking one or both faces of the porphyrin, close approach of two porphyrin rings and therefore u-oxo dimer formation may be prevented. The approach most s i m i l a r to the natural system i s to enfold the porphyrin r i n g i n a polymer chain. This approach has been vigorously pursued i n an attempt to prepare compounds capable of r e v e r s i b l e oxygen binding i n aqueous s o l u t i o n at room temperature. However, doubts about the number and nature of the active s i t e s and the r e v e r s i b i l i t y of oxygenation have made t h i s approach les s f r u i t f u l . In contrast, porphyrins have been synthesized i n which one or both faces of the r i n g i s obstructed by some group(s) covalently bonded to the r i n g . The function of the s t e r i c hindrance i s two-fold: (i) to d i r e c t base binding to the open face, ensuring five-coordina-t i o n , and 11 ( i i ) to allow O2 to bind on the hindered face, s t e r i c hindrance preventing y-oxo dimer formation. Five-coordination may also be ensured i n these systems by using bulky a x i a l bases which cannot bind on the protected face. This approach has been used by many groups to produce a wide va r i e t y of a r c h i t e c t u r a l l y d i f f e r e n t model porphyrins, e.g. picket-fence, capped, cyclophane, crowned, strapped, basket-handle etc. ( v i i ) Chelated Hemes: Covalent attachment of the ligand to the porphyrin periphery allows one to con t r o l the extent of coordination. For poor ligands such as t h i o l a t e , thioether, phenoxide, etc., covalent attachment increases the l o c a l concentration and the l i k e l i h o o d of coordination to the metal without the necessity of a large excess of external ligand. As long as displacement does not occur, addition of a second ligand allows formation of six-coordinate mixed ligand systems. On the other hand, for strong ligands e.g. imidazole, p y r i d i n e , chelation provides a b u i l t - i n 1:1 base/porphyrin stoichiometry. As long as dimerization to form mixtures of s i x - and four-coordinate i s prevented, t h i s approach produces five-coordinate complexes. In the following sections we w i l l examine those porphyrins which employ s t e r i c encumbrance and chelation as models for heme proteins. Several excellent reviews e x i s t which discuss the ligand binding B (15) 12 (16) properties of these models and t h e i r congruency with the natural 11 23—28 systems. ' Instead, here we w i l l concentrate on the strategy and synthetic d e t a i l s of model porphyrin production. To that end, the compounds have heen grouped together more i n terms of structure than of function. 13 1 . 2 PORPHYRINS WITH APPENDED PEPTIDES Perhaps the most obvious approach to the synthesis of heme protein.models i s to reproduce the l o c a l environment of the heme active s i t e by covalently attaching various peptide fragments to a sui t a b l e porphyrin. I f the peptide fragments contain s u i t a b l e amino acids (e.g. h i s t i d i n e , methionine), reproduction of the coordination sphere of the heme protein may be possible. 29 An early example of this, approach, was that of Lautsch et a l . , who coupled various h i s t i d i n e - c o n t a i n i n g t r i p e p t i d e s to the propionic acid side-chains of mesoporphyrin IX l_a (Scheme 2) . A f t e r metal i n s e r t i o n into the porphyrin, intramolecular coordination by the h i s t i d y l imidazole was poss i b l e depending on the length of the peptide chain. S i m i l a r l y , h i s t i d i n e - c o n t a i n i n g peptides were attached to the eth y l side chains of ; mesoporphyrin IX v i a s u l f i d e linkages to give 2, 30 a s i t u a t i o n s i m i l a r to that i n cytochrome c. Losse and H u l l e r coupled L - h i s t i d i n e methyl ester and protohemin _3 with dicyclohexylcarbodiimide i n N,N-dimethylformamide. However, models indicated that, with a single h i s t i d i n e bound to the porphyrin propionic acid, the length of the side chain was too short for coordination of the imidazole to the 31 i r o n centre. Van der Heijden et a l . , coupled various d i - and t r i -peptide fragments (e.g. g-Ala-His; Gly-L-His; L-Ala-L-His; Gly-L-His-Gly-OEt) to protohemin 3_ i n DMF i n the presence of triethylamine and 32 e t h y l chlorocarbonate (Scheme 3). At the same time Warme and Hager prepared porphyrins '.••.containing appended h i s t i d i n e and methionine groups. The reaction of mesohemin 6_ with a SO^/DMF complex 5_ yie l d e d the mesohemin s u l f u r i c anhydride, i n which, one or both of the propionic S C H E M E 2 (a) R = H C - ^ N - C H z - C - ^ O H H N IWR- / \\ C H 2 - C H - N -H 10 R-L-H is-GLy-GLy- OH C - N - C H g - C O j H C H 2 - C H - N - C - C H - N -H II I H 0 C H 3 L-Alo-His-GLy-OH C 0 2 H H C H 3 H . C H z - C H - N - C - C H g - N - C - C H - N -(diR. rC H& ° H N L - A L a - G L y - L - H i s - O H 15 SCHEME 3 I. E t , N / E t C K „ C I J C C II II 0 0 2. R- N H , (a) R-C0 2 C H 3 l_l / C H 2 - C H - N - C - C H 2 - C H 2 - C H 2 - N - 0 - A l a - H i s - O M e N \ 0 ^ C0 2 C H 3 (b) R. A \\ C H 2 - C H - N - C - C H 2 - N - Gly - L - H i s - O M e N ~\  H W  H (0 R- ^ > C 0 2 C H 3 u . C H 2 - C H - N - C - C H - N - l_- A l a - L- H i s - O M e H N _ / H || | H O C H 3 (d) R-O v H X C - N ~ C H 2 - C 0 2 C 2 H 5 C H 2 - C H " N - C - C H - N - G l y - l _ - H i s - G l y - O E t H N _ / 2 H II H y 16 acid side chains had been converted into a sulfuric anhydride. Subse-quent reaction with amino acids such as histidine or methionine methyl ester, yielded either mono- or disubstituted hemins (Scheme 4). A potential cytochrome c model 7e, containing both histidine and methionine covalently attached to the porphyrin was also prepared. Unfortunately preparation and isolation of the products was quite tedious and yields were low. It was also recognized that the peptide-containing side arms were too short to allow unstrained intramolecular coordination. 33 Momenteau et a l . , have synthesized and characterized the coordinating properties of a five-coordinate iron porphyrin. Treatment of deutero-hemin 8^with equimolar quantities of ethylchloroformate and triethylamine, followed by L-histidine methyl ester dihydrochloride and more tr i e t h y l -amine gave, after purification, a mixture of three compounds 9a-c. The desired deuterohemin 6(7) mono-histidine methyl ester _9c was separated from unreacted deuterohemin and deuterohemin 6,7-bis(histidine methyl ester) 9b, and was obtained in 16% yield as a mixture of isomers (Scheme 5). The reduced iron(II.) species was capable of binding oxygen reversibly at low temperature but oxidized irreversibly at room temperature. Furthermore, extensive dimerization of the 5-coordinate species occurred at low temperature. (-60°C),complicating oxygen binding studies. (17) S C H E M E U (c) R = R' = C H 3 - S - C H 2 - C H 2 - C H - N -I H C O 2 C H 3 (d) R = " " , R* = O H C 0 2 C H 3 H I . . N — • C H z - C H - N -le) R - / \\ H . R = C H 3 - S - C H 2 - C H 2 - C H - N -% / I H C 0 2 C H 3 SCHEME 5 SCHEME 6 C02H 11 19 A s i m i l a r dimerization was observed for the iro n ( I I I ) species at room temperature i n concentrated s o l u t i o n s . To t h i s stage a l l the syntheses have yi e l d e d model systems which are 6-coordinate, or mixtures of the 5- and 6-coordinate species, separation of which could be tedious. Castro prepared porphyrin derivatives having two covalently attached imidazoles, by heating deuterohemin 8_ or mesohemin la_ with excess histamine i n vacuo i n the 34 absence of solvent for three hours. The bis-chelated product 10 was obtained i n up to 50% y i e l d a f t e r p u r i f i c a t i o n . Controlled hydrolysis with 2M hydrochloric acid gave a 20% y i e l d of the monoch'elated hemin I I , again as a mixture of isomers (Scheme 6). 35 More recently, Molokoedov et a l . , have used protohemin mono-benzyl ester 13, (obtained from protohemin dibenzyl ester 12_ i n 61% y i e l d by p a r t i a l h y d r o l y s i s ) , to prepare a serie s of h i s t i d i n e - c o n t a i n -ing peptide derivatives 14a-e. Coupling of peptide and hemin was completed by the mixed anhydride method using e t h y l chloroformate and triethylamine. The y i e l d s of product decreased from 47% to 25% as the length of the peptide chain increased, the products heing obtained as a mixture of the 6 and 7 isomers (Scheme 7). The reduced penta-peptide 14d and hexapeptide 14e heme derivatives were reported to be stable for 35-40 minutes at room temperature i n chloroform s o l u t i o n i n the presence of a i r . There have b.een two attempts, to model the active s i t e of cyto-chrome c using heme-peptide compounds. Sequencing of various cytochromes c reveal the segment 14-18 to he in v a r i a n t , with structure 14-Cys-X-X-Cys-His-18. The heme active s i t e i s hound to the polypeptide v i a s u l f i d e bonds to the two cysteine residues .14 and 17, while the 20 SCHEME 7 SCHEME 8 21 imidazole of His-18 provides one of the ligands for the iron atom of the 36 heme. Momenteau and Loock, with a strategy s i m i l a r to that of 29 Lautsch, attached a protected pentapeptide (Cys-Gly-Gly-Cys-His) to the e t h y l side chains of 2,4-a,a'-dibromomesoporphyrin IX 15. (Scheme 8). A f t e r i r o n i n s e r t i o n , o p t i c a l spectra indicated that the imidazole of the h i s t i d i n e could bind to the metal centre. Binding of a methyl thioether e.g. methionine, to the i r o n would then mimic the coordination sphere observed i n the natural cytochrome c. However thioethers are poor ligands for i r o n . An attempt was made to overcome t h i s poor binding by covalently attaching the thioether to the porphyrin. In this case the synthetic porphyrin, tetraphenylporphyrin (.TPP) JL7_ was used. Various cysteine dipeptides were condensed with a TPP d e r i v a t i v e hearing a propenoic acid side chain at a $-pyrrole p o s i t i o n . 3 7 ^ Reaction of a dipeptide containing a terminal S - a l k y l cysteine residue with cis-meso-tetraphenylporphyrin-3-propenoic a c i d , gave a mixture of two a t r o p i s o m e r s , . cis-endo 18 and cis-exo 19 (Scheme 9). In the c i s -endo case, substituents on the peptide chain are disposed i n a favourable conformation for binding to a metal i n the porphyrin. When the dipeptide chain was Gly-(SR)Cys-OEt (R = Me, t r i t y l ) , "''H-NMR and magnetic c i r c u l a r dichroism suggested that a metal s u l f u r bond i n v o l v i n g the cysteine residue might be occurring. However, recent EXAFS data indicated that for the substituted Zn porphyrin, the Zn-s.ulfur i n t e r a c t i o n could only 40 be weak and long range, i f i t occurred at a l l . 22 S C H E M E 9 SR 0 19 E x o - Z n - G l y - ( S R ) C y s O E t S C H E M E 10 SCHEME 11 1.3 CHELATED HEMES 1.3.1 Porphyrins having Covalently Attached Imidazole or Pyridine Ligands Traylor argued that in heme-peptide models the side chains contain-ing the imidazole had either too few or too many atoms to achieve a 41 strain-free iron-imidazole bond. On the other hand he argued that condensation of l-(3-aminopropyl)imidazole 20^with the acid chloride of pyrroporphyrin XV 21_ followed by insertion of iron would give a strain-free five coordinate system Z2_ (Scheme 10). This "chelated" heme was capable of binding dioxygen in a reversible manner in the solid state or when dissolved in a polystyrene film. While capahle of binding oxygen reversibly in solution at -45°C, only irreversible 42 oxidation occurred at room temperature. A series of derivatives of pyrro-, proto- and mesoheme having pyridine or imidazole covalently bound to th.e porphyrin ring through, ester or amide linkages: were investi-43-46 gated. For proto- and mesoheme, the monochelated hemes were 46 easily prepared as shown in Schemes: 11, 12. In one approach the porphyrin dimethyl ester 2_3 was partially hydrolyzed. The purified monoacid 24_ was then coupled to a primary amine or alcohol containing an imidazole or pyridine base using pivaloyl chloride. Alternatively commercially available protohemin _3 was treated with, excess, pivaloyl chloride followed by one equivalent of the base-containing primary amine. The reaction mixture was then quenched with, water or methanol. The monochelated products 26, 27 were isolated by chromatography as a mixture of isomers in up to 30% yield. The dichelated compounds were 24 SCHEME 12 prepared s i m i l a r l y . The v e r s a t i l i t y of the chelated heme approach has allowed the systematic study of the k i n e t i c s of 0^ and CO binding to these compounds. Changes i n solvent, porphyrin side chains, the chelated base, and the length and nature of the chelation arm have, been c o r r e l a t e d with changes 47,48 i n the association and d i s s o c i a t i o n rates of 0^ and CO 33 Unlike the " c h e l a t e d - h i s t i d i n e " system of Momenteau which under-went dimerization at low temperatures, Traylor argued against the presence of any polymeric forms (Scheme 13) at the temperatures and 46 concentrations used i n h i s studies. Indeed, Traylor exploited such S C H E M E 13 B — x B - ^ — — I — ^ 2 — F e — 1  I 2 — F e C O Jt CO F e — B B I Fe-C O r J j rFe I B B Po — \ B 2 — F e jf — F e — 1 B •Fe J dimerization to design a system e x h i b i t i n g cooperativity. For the iro n ( I I I ) protoporphyrin IX d e r i v a t i v e the side chain i s too short to allow intramolecular binding of the pyridine (Scheme 14). While pyridine binds very poorly to hemin, addition of cyanide greatly increases pyridine affinity and vice versa. Therefore ti t r a t i o n of the side-chain pyridine protohemin _28 with cyanide leads to clean conversion to the pyridine-hemin-CN dimer 29_. A H i l l plot (log. Y/l-Y vs. log [CN]) for this titration gave a straight line of slope n = 2.1, indicating cooperativity between the metal centres. Axial base chelation was similarly used to prepare a symmetric diheme."^ Meso-l,2-di-(3-pyridyl)ethylenediamine 30 was coupled with mesoporphyrin monomethyl ester 31_ through the pivaloyl anhydride, follows ed by iron insertion to give the. diheme _32 (Scheme 15) . The reaction with CO exhibits two rate constants, indicating either two environments or a sequential change of environment due to cooperativity. The paramagnetic H^-NMR spectra of the imidazole-cyanide complexes of dichelated protohemins _3_3 and _34 were s t u d i e d . C h e l a t i o n of the imidazole maintains a fixed orientation of the base with, respect to the porphyrin ring, causing different chemical shifts for the methyl and vinyl protons. Comparison of these shifts with, the values published for various heme- proteins provided confirmation for the heme-imidazole orientations proposed in the natural systems. The "''H-NMR analysis of chlorophyll is often complicated by i t s 52 tendency to form dimers or higher aggregates. Sanders and Denriiss removed the phytyl group of chlorophyll-a and converted i t to the mixed anhydride with triethylamine/ethyl chloroformate. Reaction with l-(3-hydroxypropyl)imidazole 35_ resulted in the chelated chlorophyll derivative 36^ (Scheme 16). Intramolecular binding of the imidazole to the magnesium prevented aggregation and gave well resolved ^"H-NMR spectra. A similar "chelated chlorophyll" 37 used by Boxer to model the complex formed when apomyoglobin is reconstituted with chlorophyll , . . 53 derxvatxves. Momenteau has synthesized a similar series of chelated heme 54 compounds. In this series the base is attached to the B-pyrrole position of a tetraphenylporphyrin (TPP) ring, via amide or ester linkages (Scheme 17). Vilsmeier formylation of CuTPP 38"^"* afforded the monoformyl derivative _39_, which was elaborated by a Wittig condensation to yield the aerylate 41_ as a mixture of cis and trans isomers. Demetallation, hydrogenation and saponification gave the propionic acid derivative. Treatment of the corresponding acid chloride 4^ with l-(3-aminopropyl)imidazole 43 or 3-(3-hydroxypropyl)pyridihe _44 r e s u l t e d i n the appropriate chelated porphyrin (70% and 60% respectively) (Scheme 17) . These models were used to study the kinetics of base binding to 56 4- and 5—coordinated iron(II) TPP, and also to study the transient oxygenation of iron(.II) carbonmonoxy TPP after photolytic displacement of CO.57 The same TPP-acrylic acid system was. used by Eaton et al."'^'~^ Treatment of the acid chloride of Cu-TPP acrylic acid \42 with a nitroxyl resulted in the appropriate spin-labelled Cu-TPP derivatives 47 (Scheme 18) . The extent of metal-nitroxyl interaction was investigated by EPR by varying the nature of the nitroxyl, the linkage (amide or ester), and the geometry of the complex (cis or trans). A similar study was carrxed out on a vanadyl porpnyrxn. Collman et a l . h a v e prepared chelated TPP compounds where the chain i s attached to the ortho position of a meso-phenyl ring. Conden-sation of o-nitrohenzaldehyde 48, benzaldehyde 49_ and pyrrole 5_0_ in hot glacial acetic acid gave a 2% yield of the meso-mono-(o-nitrophenyl)-SCHEME 1 7 30 triphenylporphyrin 5_1_ after chromatography. Reduction with stannous chloride produced the mono-o-amino-TPP .52 which was coupled with various imidazole chains (Scheme 19). Collman merely used these compounds as substitutes for the less readily accessible "tailed -picket fence" 62 porphyrins which are discussed in Section 1.4.2. Reed et a l . , used the same chelated TPP compounds to control coordination in a mixed ligand system. Attempts to prepare models for cytochrome c, which contains histidine and methionine as the axial ligands, are frustrated by the greater a f f i n i t y of heme iron for imidazole rather than thioether. By covalently attaching the imidazole to the porphyrin ring a stoichio-metric amount of ligand was: provided; addition of thioether then furnished the mixed six-coordinate system. Reed prepared several complexes, with different t a i l lengths and various thioethers. For the t a i l with tetrahydrothiophene as the thioether, a crystalline I 1 ' iron(II) complex, Fe(ll) (C Im) (TPP) (THT) 5_4, was obtained and i t s crystal structure determined (Scheme 20). Efforts to obtain the corres-ponding iron(III) complex were defeated by "head-to-tail" dimerization. A similar chelated TPP compound 5_5 was used by Walker to study the effect of axial ligand plane orientation'on the "'"H-NMR shifts of the pyrrole protons in iron(III) TPP-bis(imidazole) complexes. In this case the t a i l was much shorter to also study the effect of axial ligand bond strain. In addition Walker and Benson have used mono-(Q:-aminophenyl) triphenylporphyrin 5_2_ to prepare a series of derivatives 4 1 56a-e containing a pyridine ligand bound to a zinc TPP. H-NMR and visible spectroscopy were used to study the displacement of the 3-pyridyl ligand by free 3-picoline (Scheme 21). Ibers^ used mono- (p -hydroxyphenyl) tritolylporphyrin 57_ to 31 SCHEME 19 32 SCHEME 21 SCHEME 23 lol n « 3 lb) n ' 4 33 covalently attach a series of pyridine ligands to the porphyrin ring via an ether linkage. Reaction of o-hydroxyphenyl-TTP with 3-(bromo-alkyl) pyridine hydrobromide 5_8 furnished the chelated porphyrin in 40% yield. The longer chain pyridine compound 62_ prepared through the porphyrin butoxy ester 6J^ was obtained in 27% yield (Scheme 22). The cobalt derivatives reacted reversibly with oxygen at low temperatures (r50°C to -80°C) but the presence of the axial base did not enhance oxygen aff i n i t y . Goff used the same synthetic strategy to prepare 6 6 porphyrins with appended imidazoles. Reaction of 6-hydroxyphenyl TTP 5_7 with a dibromoalkane 63_ forms the corresponding ether, which, when allowed to react with imidazole in DMF solvent (using K^CO^ or Et^N) , gives the required chelated TTP derivative 65_ (Scheme 23) . By varying the length of the alkane chain, "tension" may be introduced into the molecule in the form of t i l t i n g or elongation of the iron-imidazole bond. This was found to have an effect on the sp l i t t i n g and shift of the pyrrole resonances in the H^-NMR spectrum. 1.3.2 Porphyrins having Covalently Attached Sulfur Ligands Because of the poor af f i n i t y of iron(II) porphyrins for mercap-tide anion, models of cytochrome P4.50 have usually consisted of . solutions of porphyrins in the presence of large concentrations of 6 7 excess mercaptide ion. However, Traylor has used the chelated heme approach to covalently attach, mercaptide to the porphyrin periphery, making i t available for binding to the metal without the necessity of excess external ligand (Scheme 24). Protohemin chloride monodimethyl-35 36 amide monoacid 66_ was coupled to l-amino-3-mercaptopropane benzoyl ester 6_7. Addition of sodium hydride and warming removed the benzoyl group and addition of CO resulted in formation of the carbonmonoxy-mercaptide complex 70_. A similar compound 71, containing two masked mercaptides was also prepared and deprotected to give the analogous CO complex 72_. Protection of the mercaptide as the benzoylthio derivative before reduction of Fe(III) was necessary because of the reducing abi l i t y of mercaptans. 2 Fe(lll) + 2 RSH ; = ± 2 Fe(ll) + RSSR + 2 H+ (18) Alternatively protohemin was coupled with bis(3-aminopropyl)-disulf ide 7_3. The resultant disulfide 7_4_ was treated with sodium dithionite, the iron being reduced more quickly than the disulfide. Addition of CO then furnished the carbonmonoxy complex 72. '''H-NMR of the CO complexes indicated that the sulfide underwent intramolecular binding without appreciable dimer formation. (19) CO — F e S" UV/viaible spectroscopy in DMSO solution or aqueous suspension showed a s p l i t Soret (384/460 or 363/446 nm) which, was similar to the spectrum of cytochrome P4S0-CQ. A series of alkyl and aryl "mercaptan-tail" porphyrins has been 6 7 prepared by Collman and Groh. (Scheme 25) . The C, alkyl chain may b.e prepared d i r e c t l y by t r e a t i n g mono-(o-aminophenyl)triphenylporphyrin 52_ with S-acetyl- or S-tritylthiohexanoyl chloride 75. Since the S-protected pentanoic acid derivatives were more d i f f i c u l t to obtain, the bromoalkyl chain was f i r s t attached to the porphyrin and the thio group introduced by treatment with either TrS K + or AcS K +. Deacetylation (MeOH/NH^) or d e t r i t y l a t i o n (Hg(II)/H 2S) gave the free t h i o l . However, a f t e r i r o n i n s e r t i o n , v i s i b l e spectra indicated that the a l k y l chain was too f l e x i b l e to hold mercaptan at the metal s i t e ; the spectra, i n toluene, were s i m i l a r to those of square planar four coordinate iron(II) species. The introduction of CO does lead to the formation of s i x -coordinate low-spin Fe(II)-C0 complexes. To ensure more r i g i d i t y , t a i l s derived from oj-mercaptobenzoic acid _78 or (m-mercaptophenyl)acetic acid 81 were attached to the aminoporphyrin. In t h i s case the p o t e n t i a l t h i o l was introduced as the d i s u l f i d e which was subsequently cleaved with sodium borohydride to give the free a r y l "mercaptan-tail" porphyrins 82, 83. As i n the a l k y l case, the a r y l iron(II) species did not show five-coordination. Furthermore addition of CO gave mixtures of f i v e - and six-coordinate species, depending on the nature of the mercaptan and the temperature, suggesting a t a i l - o f f / t a i l - o n equilibrium. Deprotonation of the mercaptan to give the mercaptide was attempted. The extent of mercaptide formation depended both, on the CO (20) CO CO (21) nature of the base and of the t a i l . Indeed, for most t a i l s only incomplete deprotonation occurred. However for the (m-mercaptophenyl)-acetamide t a i l system 84, deprotonation to the mercaptide was clean and complete using a c e t a n i l i d e anion as base. In the presence of CO t h i s system gave a six-coordinate iron(II)-mercaptide-CO complex 85 whose v i s i b l e spectrum exhibited a s p l i t Soret absorption at 450. and 380 nm, t y p i c a l of cytochrome P450. In section 1.3.1 we r e f e r r e d to Reed's synthesis, of F e ( I I ) -1 ~ ! 62 (C Im) (TPP) (THT) 54_ as a model for cytochrome c . Buckingham and Rauchfuss adopted the a l t e r n a t i v e strategy of attaching the thioether 69 ligand to the porphyrin periphery. Reaction of (p-aminophenyl)tri-phenylporphyrin 5_2_ with the corresponding anhydrides 86_ afforded the t a i l e d porphyrins 87,containing thioether, sulfoxide, or sulfone groups i n 60-90% '(Scheme 26). A f t e r i r o n i n s e r t i o n and reduction, apectro-photometric t i t r a t i o n with base allowed the following ordering of ligand a f f i n i t i e s : R 2S0 > R 2S > R 2 S 0 2 - T h e e a s y displacement of s u l f i d e by pyridine or imidazole precluded t h i s system as. an e f f e c t i v e model for cytochrome c. Smith and Bisset have also used the chelated heme approach, to synthesize a p o t e n t i a l P450 model, 7^ but i n t h i s case the substituents were attached to the meso p o s i t i o n of an octalkylp(3rphyrinv. A meso-acefbxymethyl substituent i s susceptible to n u c l e o p h i l i c displacement at the " b e n z y l i c " carbon atom l e a d i n g to the ready i n t r o d u c t i o n of s u i t a b l y f u n c t i o n a l i z e d chains. Heating the acetoxymethylporphyrin 88 i n a melt w i t h 1,6-hexanediol gave the ether 89_ w i t h no s i g n of dimer formation (Scheme 27). Conversion to the bromide followed by r e f l u x i n g w i t h t h i o u r e a afforded the thiouronium s a l t , the h y d r o l y s i s of which was accompanied by o x i d a t i o n to give the d i s u l f i d e 9_1_. U n f o r t u n a t e l y , attempts to generate the c h a r a c t e r i s t i c RS -Fe(II)-CO spectrum from the i r o n ( I I I ) - d i s u l f i d e complex were un s u c c e s s f u l . A l t e r n a t i v e l y , treatment of acetoxymethylporphyrins w i t h d i t h i o l s y i e l d e d only the meso-porphyrins. Treatment of meso-acetoxymethyl o c t a e t h y l p o r p h y r i n w i t h excess l-(3-aminopropyl) imidazole J20_ i n r e f l u x i n g t e t r a h y d r o f uran c o n t a i n i n g a suspension of sodium hydride provided the meso-chelated imidazole porphyrin 93, a p o t e n t i a l model f o r T-state hemoglobin. The success of the chelated heme approach to model heme p r o t e i n s i s due to i t s a b i l i t y to c o n t r o l the c o o r d i n a t i o n of a meta l l o p o r p h y r i n . For p o o r l y b i n d i n g ligands e.g. mercaptide, t h i o e t h e r , covalent a t t a c h -ment to the porphyrin increases the l o c a l c oncentration and enhances b i n d i n g without the need of excess e x t e r n a l l i g a n d . In the case of st r o n g l y b i n d i n g l i g a n d s e.g. imid a z o l e , p y r i d i n e , c h e l a t i o n can be used to dampen the b i n d i n g a b i l i t y . A d d i t i o n of one eq u i v a l e n t of base to an i r o n p orphyrin r e s u l t s i n a mixture of fo u r - and s i x - c o o r d i n a t e s p e c i e s , simee^K ••> K- dsn equation 22. B B — Fe + B — F e — + B F e — (22) B 43 However 'covalent attachment of the base to the porphyrin provides a stoichiometric equivalent of base which w i l l bind intramolecularly to give the desired five-coordinate species, provided dimerization i s not s i g n i f i c a n t . B F e — I — F e — — ^ B z — * B — F e — ( 2 3 ) c Fe-B Addition of a. second ligand then gives the mixed ligand complex. As models for hemoglobin or myoglobin the chelated hemes of Traylor were found to bind oxygen r e v e r s i b l y i n so l u t i o n at low temperature (-40°C) and the k i n e t i c s of oxygen binding at room temperature could be measured. However the oxygen complexes were not stable at room temperature, i r r e v e r s i b l e oxidation to the u~oxo dimer occurring. In an attempt to prepare stable oxygen-binding complexes i t was r e a l i z e d that s t e r i c hindrance about one face of the porphyrin might prevent i r r e v e r s i b l e oxidation. I f a base bound to the open face and oxygen bound at the s t e r i c a l l y hindered face, close approach of two porphyrin rings would be discouraged, preventing ^a-oxovdimer formation. B — F e B — F e — 0 2 ^ > B — F e — 0 2 F e — B (24) Such, an approach has been followed by many groups to produce an array of di f f e r e n t model porphyrins e.g. picket-fence, capped, cyclophane, crowned, strapped, basket-handle etc. S C H E M E 2 8 1.4 "PICKET-FENCE" PORPHYRINS 1.4.1 "Picket-Fence" Porphyrins Perhaps the most successful of the heme protein' a c t i v e s i t e models i s the "picket-fence" porphyrins of Collman. S t e r i c encumbrance about the metal s i t e of these substituted TPP molecules depends on two fa c t o r s : (i) due to s t e r i c repulsion, the TPP w i l l adopt a conformation i n which the four meso phenyl rings are almost perpendicular to the porphyrin r i n g ; substituents at the ortho p o s i t i o n s of the phenyl rings w i l l l i e above and below the porphyrin plane , a n c * ( i i ) f o r TPP molecules containing mono-ortho-substituted phenyl rings, separation and, depending on the bulk of the substituent, i n t e r -conversion of the four possible atropisomers may be achieved. Collman reasoned that synthesis, of a substituted iron(II)TPP having four pivalamido groups located on the same side of the porphyrin r i n g would give a "protected pocket". Ligands e.g. imidazole, could bind to the metal on the unencumbered face but could not penetrate the pocket, thereby ensuring five-coordination even i n the presence of excess ligand. The much, smaller dioxygen molecule would not be s t e r i c a l l y retarded and a six-coordinate complex could form. This oxygenated complex should be stable since the bulky pivalamido groups would prevent i r r e v e r s i b l e oxidation through close approach of two porphyrins to form a y-peroxo dimer. Condensation of pyrrole 50 and four equivalents, of <o-nitrobenz— . 46 aldehyde 48_ i n a c e t i c a c i d gave meso-tetra(9-nitrophenyl)porphyrin 95 "Picket-fence" O Oxygen -binding Pocket B-Fe-02 94 < B—Fe —0 ^ -Fe—B (25) which was reduced by stannous c h l o r i d e to the meso-tetra (o-aminophenyl)-71 72 , porphyrin (Scheme 28). ' The four atropisomers (aaaa, aaaB, 2aaB3) were separated by chromatography, the slowest moving of which was the de s i r e d aaaa isomer 9_6. I n t e r c o n v e r s i o n of the atropisomers was s u f f i c i e n t l y slow at room temperature to a f f o r d clean s e p a r a t i o n . Then r e f l u x i n g the unwanted products i n toluene for 20 minutes e f f e c t e d r e -e q u i l i b r a t i o n to the s t a t i s t i c a l m i x t u r e . a l l o w i n g f u r t h e r i s o l a t i o n of the aaaa isomer. Reaction of the amino groups w i t h p i v a l o y l c h l o r i d e gave the " p i c k e t - f e n c e " porphyrin a,a,a,a-H^TpivPP 97, i n which the c o n f i g u r a t i o n i s frozen by the bulky s u b s t i t u e n t s , ( e q u i l i b r a t i o n r e q u i r e d s e v e r a l hours i n b o i l i n g x y l e n e ) . Treatment with. FeBr^, followed by r e d u c t i o n w i t h CrCacac)^ gave the Fe(JI) (.a, a, a,a,-TpivPP) . Although, a d d i t i o n of st r o n g f i e l d l i g a n d s gave low s p i n s i x -coordinate complexes, FeB 2(a,a,a,a-TpivPP), i t was suspected that the bi n d i n g constant of the base on the " p i c k e t - f e n c e " side was l e s s than that on the "open" s i d e . A s e r i e s of s i x - c o o r d i n a t e compounds were prepared (B = Im, l-Melm, l-n-Bulm, l - t r i t y l l m , 4-t-BuIm, , 1,2-Me2'lm, 72 p y r i d i n e , p i p e r i d i n e , tetrahydrothiophene, t e t r a h y d r o f u r a n ) . A l l of these showed r e v e r s i b l e oxygen b i n d i n g behaviour i n benzene s o l u t i o n at 25°C, without appreciable amounts of decomposition. Indeed the 47 oxygen complexes, Fe(TpivPP)(N-RIm)(0^) were stable for long periods Cti^ 2-3 months) i n s o l u t i o n provided 2-4 equivalents of a x i a l base were present to protect the unshielded face. Furthermore, a n a l y t i c a l l y pure, NI/B sy (26) c r y s t a l l i n e dioxygen complexes could be obtained 72 The c r y s t a l structures of Fe(II) (TpivPP). (l-Melm) (.0 ) 9 8 a , 7 2 ' 7 3 Fe(II)(TpivPP)-74 (2-MeIm)'EtOH and i t s dioxygen adduct have been determined. Further a B b B c B d B 1-MeIm 1-BuIm THF THT s t r u c t u r a l information was ohtained by I.R. 7 3' 7^ 7 ^ and Mos.sb.auer 6 8 73 spectroscopy and magnetic s u s c e p t i b i l i t y measurements. ' I. Binding of a second base on the "picket-fence" side of the porphyrin prevented determination of oxygen binding to the f i v e - c o o r d i -nate heme i n s o l u t i o n . However, c r y s t a l s of Fe(II)(TpivPP)(1-MeIM)-' (0^) could be deoxygenated under vacuum to give the five-coordinate species which could be re-oxygenated. This c y c l i n g between 0^ and vacuum produced no observable i r r e v e r s i b l e oxidation over many cycles Similar r e v e r s i b l e oxygenation was demonstrated by s o l i d samples, of Fe (TpivPP) B (B = 2-MeIm, 1,2-MeIm). From the H i l l p l o t (log Y/i-Y vs. 78 log V Q ^ ) i t was observed that s o l i d state oxygen binding for these two compounds showed two regions of non-cooperative binding (at high and low pressures) and an intermediate region of cooperative binding. Collman r a t i o n a l i z e d t h i s i n terms of a shrinking of the molecules' dimensions on oxygenation as the i r o n and i t s bound imidazole move towards the porphyrin r i n g . "As increasing numbers of molecules i n the s o l i d oxygenate this change i n molecular dimensions presumably induces s u f f i c i e n t s t r a i n i n the c r y s t a l l i t e to induce a conformational change i n the s o l i d which enhances the oxygen a f f i n i t y of the remaining deoxy s i t e s . This behaviour i s reminiscent of the cooperative oxygen binding of hemoglobin. Various other s t e r i c a l l y hindered TPP derivatives have been prepared by the condensation of meso-a, a, a, a-tetra(.o-aminophenyl)-porphyrin 96^ and bulky acid c h lorides. Collman has also prepared the compounds, H,,^. , PP 101 and H. T^ PP 102, by reaction of H_T PP 96 r 2 Phth — — 2 Tos ' J 2 Am — with iso-phthaloyl d i c h l o r i d e 9_9_ and p-toluenesulfonyl chloride 100 respectively (Scheme 29). Despite the bulky "picket-fence", the ferrous. complexes of both, compounds exhibited only i r r e v e r s i b l e oxidation on exposure to oxygen at 25°C. This was at t r i b u t e d to the a c i d i c amide protons which, were presumably directed into the cavity, allowing proto-72 nation of the coordinated dioxygen and consequent heme oxidation. A s i m i l a r s e r i e s of TPP derivatives 103a-g have been synthesized under 79 80 i d e n t i c a l conditions by Bogatskii et a l . ' Ortho-substituted TPP derivatives have been used as b.inuclear ligand systems by choosing s u i t a b l e substituents on the phenyl r i n g s . For example, treatment of H„T. PP 96 with maleic anhydride gave the z Am — tetra(o-maleamoylphenyl)porphyrin 104 ,in 90% y i e l d (Scheme 30). In aqueous DMF t h i s porphyrin undergoes copper i n s e r t i o n at a rate much fas t e r than for unsubstituted porphyrins. Rapid complexation of the copper by the carboxylates holds the metal ion i n a p o s i t i o n favourable 81 for rapid intramolecular transfer to the porphyrin nucleus. Binuclear porphyrins capable of binding i r o n and copper have been investigated as synthetic models f o r the iron/copper s i t e of cytochrome oxidase. One such model 106 consists of a tetraphenylporphyrin r i n g with a covalently attached t e t r a p y r i d i n e ligand system, obtained by t r e a t i n g a , a , a , a-H 2T PP'9_6 with excess n i c o t i n i c anhydride 1 0 5 - (Scheme 82 31). The mixed metal compound with iron inserted i n t o the porphyrin r i n g and copper coordinated to the four nicotinamide groups was prepared, 83 and the ESR and magnetic s u s c e p t i b i l i t y of the complex examined. In contrast, E l l i o t t and Kr.ebs claim that the conditions necessary for metal i n s e r t i o n into t h i s complex cause isomerization of the nicotinamide 84 groups. Instead, these authors have coordinateddRu(II) to the n i c o t i n -amide groups, which locks the "pickets" i n t o place allowing more fo r c i n g conditions to be used for the introduction of divalent and t r i v a l e n t f i r s t - r o w t r a n s i t i o n metals into the porphyrin r i n g , without fear of isomerization. Iron porphyrin catalysis; of epoxidation and hydroxylation using iodosylarenes as oxidants i s believed to proceed v i a a reactive iron-oxo intermediate. Groves has attempted the c a t a l y t i c asymmetric epoxidation of o l e f i n s using s u i t a b l y substituted c h i r a l "picket-fence" porphyrins to c o n t r o l the stereochemistry of approach, of the substrate 1, o l e f i n to 85 the iron-oxo species. The c h i r a l porphyrins were prepared by s t i r r i n g &» g, a, g - H o T A p p 1 ° 7 with an o p t i c a l l y a ctive acid chloride (Scheme 32) . With a (R)-2-phenylpropanamido group as the c h i r a l appendage the SCHEME 32 porphyrin- 108a was formed in high yield (95%). However, in the epoxida-tion of various olefins with iodosylbenzene very l i t t l e selectivity was obtained (%ee, 9-31%). Instead the binaphthyl group was chosen as an appendage which could form a large and relatively r i g i d chiral cavity about the porphyrin core. The diacid chloride of 1,1'-binaphthyl-2,2'-dicarboxylic acid 109 was reacted with a, 6 , a , B-I^T PP 107, followed by methanolysis and iron insertion. This catalyst was more successful and enantiomeric excesses of 20-50% were observed for variously substituted styrenes and aliphatic olefins. 1.4.2 "Tailed Picket-Fetyce''- Porphyrins While the direct oxygenation of five-coordinate Fe(II) "picket-fence" was observable in the solid state, such, studies i n solution were not possible since the "picket-fence" couldnnot prevent six-coordination in the presence of excess sterically unhindered base. (Excess base is necessary to ensure complete coordination on the "open" face and prevent y-oxo dimer formation). To control coordination, Collman et a l . , adopted the "chelated heme" approach.. Dispensing with external ligand, the b.ase was covalently attached to the ortho-phenyl position of TPP, and so constrained into a position promoting intramolecular binding to the porphyrin metal. The other three meso-phenyl rings carry the "pickets" necessary to prevent irreversible oxidation. Treating a,a,a,a-T PP 96 with 3.2 equivalents of pivaloyl chloride gave the "3-picket" a-aminophenylporphyrin 110 (35%) (Scheme 33). Refluxing in benzene solution for 2 hours equilibrated the free 53 54 amine-phenyl group to a 1:1 mixture of the a and B atropisomers 110, 111 which were separated by chromatography. (The unwanted a- isomer could be r e - e q u i l i b r a t e d to increase the y i e l d of the B- product). Using amide or urea linkages an imidazole was attached to the B-amino porphyrin by chains of varying length. D i r e c t metal i n s e r t i o n using anhydrous F e B ^ gave nearly quantitative y i e l d s of the five-coordinate iron(II) 61 1 " t a i l picket-fence" porphyrin. H-NMR spectra confirmed the proposed five-coordinate high spin (S = 2) iron(II) formulation, but on decreasing the temperature (-25° C) peaks due to a diamagnetic (S = 0.) complex were observed, presumably due to a dimerization process. (Momenteau, but not Traylor, had observed such, dimerization i n the chelated heme systems). /-B ^-B f i ( \ 2 i — F e — ; = = 1 F e — (27) B Fe S = 2 S=0 S = 1 Addition of oxygen to solutions: of the high, s.pin five-coordinate iron(II) compounds gave the expected diamagnetic spectra for the oxygenated species 115. The peak pattern for the "pickets" suggests that the oxygen may be ordered i n these complexes, presumably towards the open side of the pocket, a claim which, i s awaiting confirmation by X-ray crystallography. A s i m i l a r s e r i e s of " t a i l picket-fence" porphyrins 114 has been synthesized with a pyridine covalently attached to the porphyrin periphery 0 2 and C 61,86-88 86 v i a urea linkages. 0^ and CO binding to both, s e r i e s of porphyrins has been ca r r i e d out The use of meso-(o-aminophenyl)triphenylporphyrin 9^ to prepare a series of alkyl and aryl mercaptan-tail porphyrins as cytochrome P450 models has been described in Section 1.3.2. The same series of compounds has been prepared by acylation of the tripivalamide-6-amino-phenylporphyrin 117 to give the alkyl mercaptan "tailed picket-fence" 6 8 porphyrins 120 (Scheme 34). A similar compound 121 with an appended thioether chain has also been prepared and is reportedly capable of reversibly binding oxygen.^ 56 57 1.5 "CAPPED" PORPHYRINS 1.5.1 "Capped" Porphyrins The direct condensation of aromatic aldehydes and pyrrole to form tetraphenylporphyrins was exploited by Baldwin and co-workers to prepare a "capped" porphyrin. In this molecule a benzene ring was covalently attached to a l l four ortho positions of the meso-phenyl rings, enclosing a volume of space above one face of the porphyrin ring. If the cap was sufficiently tight the binding of bases (e.g. alkylimidazoles, pyridine) should be prevented on the enclosed face; binding on the open face would result in a five-coordinate species. On the.other hand, the smaller dioxygen molecule would be. able to f i t under the cap, which, would provide a physical barrier to u-oxo.dimer formation. It was recognized that attempts to condense a b.enzene ring with a porphyrin by four ester linkages would probably result in very low yields. Instead the necessary units were attached to the "cap" to give a tetraaldehyde which, was condensed with, pyrrole to give the "capped" porphyrin. Unlike the "picket-fence" porphyrin, cyclization of the porphyrin ring i s the last step of the synthesis, so chromato-graphic separation of atropisomers is not required. The required tetraaldehyde 122 was. prepared by alkylation of salicylaldehyde with bromoethanol, followed by condensation with pyromellitoyl chloride 123. Reaction of the tetraaldehyde with, pyrrole in refluxing propionic acid yielded the "capped" porphyrin 124 after 89 90 chromatographic purification (_Scheme 35). ' The same reaction sequence using 2-(3-hydroxypropoxy)benzaldehyde yielded the correspond-SCHEME 36 ing "homologous" or "C^-capped" porphyrin 125 in which there is an 90 extra methylene group in each link of the cap. In this latter case the yield of the cyclization reaction was much lower (5%), probably reflecting the extra entropy factors required to form the larger cap. To provide steric hindrance on the uncapped face a "naphthyl-C^-capped" 90 porphyrin 129 was similarly prepared (Scheme 36). Insertion of iron into the '^-capped" porphyrin, followed by reduction, gave a crystalline four-coordinate high spin iron(II) porphyrin. In solutions containing excess axial base the five-coordinate heme was formed which was capable of reversible dioxygen binding at 25°C. The stability of the dioxygen adduct depended on the nature and concentration of the axial base and the position of the equilibria in 89 Scheme 37. Unlike the "C^-capped" porphyrin 124 which could only SCHEME 37 bind a single axial base, the larger size of the "C^Cap" '-125 permitted binding of two axial bases, provided that they were small, e.g., propyl-amine. For intermediate size bases such, as l-Melm, i t appeared that a second base could weakly coordinate to the iron, probably through, the side of the cap. Oxygen binding was s t i l l reported to occur, giving a 91-93 pseudo-seven-coordinate complex. (28) The 0^ and CO a f f i n i t i e s of a series of Fe(II) and Co(II) capped 90 porphyrins have been studied, CO (CH2)n\ \ 0 C ^ 0 . 0 0 It was found that 0^ a f f i n i t i e s were A B c C 2 -Cap V24 n = 2 Pheny l H C 3-Cap 125 n = 3 Pheny l H C 2 -CapN0 2 130 n = 2 Pheny l N0 2 NapC 2-Cap 129 n = 2 Naphthyl H much, lower than those of natural porphyrins and other synthetic models e.g.,T(p-0CH3)PP > NapC 2 - Cap 129_ > C 2 - Cap 124 > C £ - CapN02 130 > C^ - Cap 125. In contrast CO bound more quickly than 0 2, and the rate of binding was independent of the cap s i z e and comparable to unhindered 96 model porphyrins. This was r a t i o n a l i z e d i n terms of a s t e r i c e f f e c t 97 of the cap. Although the c r y s t a l structures of both. H 2(C 2~Cap) and ,98 Fe(III)Cl(CJ 2-Cap) indicated that the phenyl cap-porphyrin separation was too small to accommodate e i t h e r CO or 0 2 ,"• .a considerably more expanded v e r s i o n must e x i s t i n s o l u t i o n . That the l i n e a r Fe-C-0 system could be accommodated under the cap argued against a " c e n t r a l " s t e r i c e f f e c t . However the bent Fe-0-0 system might be d e s t a b i l i z e d by a " p e r i p h e r a l " s t e r i c e f f e c t of the methylene chain l i n k a g e s . Central (29) A recent study ' of the paramagnetic s h i f t s i n the H-NMR of Co(II)Cap porphyrins was used to deduce the cap-porphyrin se p a r a t i o n . The r e l a t i v e c a v i t y s i z e was i n the order NapC2-Cap>C2-Cap>C.j-Cap, which c o r r e l a t e s w i t h the r e l a t i v e oxygen a f f i n i t y of the i r o n ( I I ) "capped" porphyrins. 1.5.2 "Pocket" and " T a i l e d Pocket" Porphyrins To prepare a system which, d i s c r i m i n a t e s against the b i n d i n g of CO r e l a t i v e to that of 0^, Collman has used a combination of the " p i c k e t -fence" and the "capped" porphyrin approach, to prepare a s e r i e s of "pocket" porphyrins '"*"^ 2 As above, a phenyl r i n g i s used to provide s t e r i c encumbrance at one face of the porphyrin, but i n t h i s case i t i s l i n k e d to only three meso-phenyl r i n g s , l e a v i n g an open s i d e . Oxygen may bind within the pocket by orientation of the bent Fe-O-0 unit toward the open side. Carbon monoxide may only be accomodated by bending and/or t i l t i n g of the linear Fe-C-0 unit leading to decreased CO a f f i n i t y . Treatment of a,a,a,'^ ""^ ''"Am^ ^ — w ^ t l 1 slightly more than one equivalent of pivaloyl chloride formed the "mono-pocket" porphyrin 131 (Scheme 38). Condensation with a phenyl tri-acid chloride 132 under high dilution conditions afforded the pocket porphyrins 133 in good yield (>60%). The volume of the pocket was dictated by the choice of acid chloride and the presence of the single picket provided protection against irreversible oxidation. A similar strategy was employed to prepare the "tailed-pocket" porphyrins 134. However, in these compounds, the remaining ortho-amino group is used to attach the base leaving no protection on the open face of the pocket. In contrast to the "tailed picket-fence" porphyrins, these complexes undergo rapid oxidation to the y-oxo dimer. For the iron(II) "pocket" porphyrins, the coordination state of the iron depended on the size of the pocket. Visible absorption and MCD spectral data showed that Fe(H)PocPiv remained five coordinate even in the presence of excess base. Although the medium and large size pockets showed increasing six-coordination, concentration ranges could be determined within which five-coordinate iron(II) was the dominant species. The 0^  and CO binding of the "pocket" and "picket-103 fence" porphyrins were compared. While the 0^ a f f i n i t i e s for both systems were similar, the "pocket" porphyrins showed a reduced CO af f i n i t y . Since electronic and solvent effects were similar in the two model systems, the reduction in CO af f i n i t y was attributed to the 63 64 s.teric hindrance of the cap which d i s t o r t e d the Fe-C-0 unit from l i n e a r i t y . 1.5.3 "Bis-Pocket" Porphyrins Eventual i r r e v e r s i b l e oxidation of both the "picket-fence " and the "capped" porphyrins occurs because s t e r i c encumbrance i s present only on one side of the;molecule. To avoid t h i s , octa-ortho-suhstituted TPP compounds have heen prepared. By choosing the correct s t e r i c bulk for the ortho substituents a protected pocket may he formed on both sides of the porphyrin r i n g . The pockets could s t i l l be penetrated by a x i a l bases and gaseous ligand, but would form a b a r r i e r to the close approach of two metal centres, thus s t a b i l i z i n g the oxygenated porphyrin. 135 Vaska and Amudsen have prepared [T-(2,4,6-MeO)^PP]Fe(II) and 136 [T-(2,4,6-EtO) 3PP]Fe(II) by condensation of the appropriate t r i -substituted benzaldehyde with p y r r o l e . B a l c h has shown by "''H-NMR that although the ortho methoxy substituents prevent y-oxo dimer forma-ti o n , oxidation at room temperature proceeds to form PFe(III)_OH and 4 PF e ( I I I ) C l . A more hindered complex was prepared by Suslick and Fox,'^ '^'" who condensed 2,4,6-triphenylbenzaldehyde with pyrrole i n r e f l u x i n g propionic acid to obtain fcheiporphyrin i n 1% y i e l d . M e t a l l a t i o n and reduction gave the four-coordinate i r o n ( I I ) species [ T-(2,4,6-Ph) -PP]Fe(II) 137 i n 80% y i e l d . Addition of the s t e r i c a l l y hindered base, 1,2-dimethylimidazole gave a five-coordinate i r o n ( I I ) complex which was capable of completely r e v e r s i b l e oxygenation i n non-polar solvents at 30°C. However, the oxygen a f f i n i t y i s very low compared to oth.er model complexes and the natural systems, an observation which was attributed to the non-polar nature of the binding site. Covalent attachment of a group to the four ortho positions of TPP may also be used to prepare porphyrin complexes having a r i g i d 44 structure. Such an approach was adopted by Lindsey and Hauzerall to prepare a cofacial porphyrin-quinone system where the separation between ° 106 the two rings was estimated to b.e 10A. The quinone-tetraaldehyde 136 was prepared by alkoxylation of fluoranil 135, and then reacted with a,a,a,a-H„T4 PP 96. The reversibility and the intramolecular nature of 2 Am — J the Schiff base reaction were responsible for the high yield of the reaction; 85% yield of the "capped" porphyrin 137a after stirring at room temperature for 24 hours. Subsequent reduction of the Schiff bases with NaBH^CN yielded the desired porphyrin-quinone in 80-95% yield. (Scheme 39). Acetylation of the amino groups and metal insertion furnished ZnPQ(OAc)^ 138. The photochemical properties of this compound were investigated and the rate constant for electron transfer - 10.7 from porphyrin to quinone was estimated. S C H E M E 39 n'6-10.12 2 0 - 3 0 % 1.6 STRAPPED PORPHYRINS The strapped porphyrln^class of heme protein' models embraces a l l those compounds in which, some group is covalently linked to two corners (usually diagonally opposite) of a porphyrin macrocycle. The usual synthetic strategy has been to t i e the strap to an already formed porphyrin, thus allowing great v e r s a t i l i t y in the types of structures made (e.g. cyclophane, crowned, pagoda, basket-handle etc.). The porphyrins may be singly- or doubly-strapped and may be classified according to the nature of the chain: (i) • Simple non-functionalized alkyl chains whose role is to span one face of the porphyrin, discouraging y-oxo dimerization and providing a more hydrophobic environment. (i i ) Straps incorporating some bulky group which w i l l provide more steric encumbrance than a simple alkyl chain. ( i i i ) Functionalized straps which incorporate some group capable of binding to or interacting with the metal at the porphyrin core. These may be used to maintain five-coordination or to form six-coordinate mixed ligand systems L-M-L', where one ligand binds poorly to the metal. 1.6.1 Non-Functionalized Alkyl Straps A number of research, groups have reported the syntheses of simple strapped porphyrins. D-goshi"*"^ condensed long-chain diamines with, a difunctional etio-type porphyrin in the presence of iso-butyl chloroformate and triethylamine under high dilution to obtain the strapped porphyrins (n = 6rl0,12) in 20-30% yield after chromatography (Scheme 40.) . On the basis of visible absorption spectroscopy i t was claimed that, for short straps, binding of a second bulky axial ligand under the strap was inhibited, giving five-coordinate iron(ll) species. Attempts to observe oxygen binding to the ferrous porphyrins at 15°C resulted in rapid formation of the u-oxo dimer. Battersby^^ used the same strategy, reacting the bis-acid chloride of mesoporphyrin II with 1,12-aminododecane under high dilution to give the bridged porphyrin in 25% yield (Scheme 41). Alternatively, elaboration of the porphyrin carboxyl side chains by ester or amide formation, followed by Intra-molecular oxidative coupling or Cieckmann* .condensation? :gave• 'the= ester-, or amide-linked strapped porphyrins 144, 145 in good yield. Not surprisingly, attempts to oxygenate the ferrous complexes in THF or aqueous acetone at 20°C showed only rapid irreversible oxidation to the 112 ferric state. Chang has also prepared an amide-linked csrt,rapp.ed .pqrphyrin 146. In this instance the system was used as a cytochrome P450 model to investigate the porphyrin-catalyzed hydroxylation of unactivated alkanes by iodosyl benzene (Scheme 42). A similar series of amide-linked strapped porphyrins 147 have also been prepared containing 5-7 113 methylene units in the strap. Such models were prepared in an attempt to mimic the differentiation of 0^ and CO displayed by the natural systems. Using resonance Raman spectroscopy a correlation between increased steric strain (shorter straps) and the Fe-CO stretch-114 ing and Fe-C-0 bending vibrations has been observed. 69 7 0 71 A different synthetic strategy was adopted by Baldwin et a l . , to prepare strapped porphyrins where the ortho positions of opposite meso-phenyl rings are linked. ^ Unlike the previous syntheses, i t is the strap which is prepared i n i t i a l l y and the two halves of the porphyrin attached to both ends. In the f i n a l step the porphyrin ring is formed by intramolecular cyclization and the strap is stretched into position (Scheme 43). Condensation of the anion of salicylaldehyde with 1,12— dibromododecane gave the "strapped-dialdehyde" 148. Acid catalyzed condensation with benzyl 3,4-dimethylpyrrole-2-carboxylate 149 afforded the chain-linked bis-dipyrromethane, which after hydrogenolysis gave the unstable tetraacid 151. This was immediately condensed with trimethyl orthoformate to give the "alky1-strapped" porphyrin 152 in 23% overall yield. As in the previous examples the alkyl strap was not able to enforce five-coordination of the iron(II) complex. In the presence of excess base the six-coordinate species 153 was formed which did not bind oxygen. Reducing the concentration of base led to an increase of the four-coordinate species 152 which underwent irreversible oxidation. While reversible oxygenation was observed at -55°C as for unhindered porphyrins, warming to room temperature caused y-oxo dimer formation (Scheme 44). 117 118 A similar approach was used by Dolphin and Wijesekera, ' who were attempting to strap a porphyrin with very short alkyl chains -short enough to cause deformation of the porphyrin. Obviously in this case, linking opposite corners of a preformed porphyrin would, at best, give very poor yields. Instead the two halves of the porphyrin were assembled at each end of the strap, and only at the last step was the porphyrin 157 formed by acid-catalyzed intramolecular cyclization under SCHEME 45 (a) n = 11 (b) n = 10 ( c ) n = 9 high dilution conditions (Scheme 45). Visible and H-NMR spectroscopy and X-ray crystallography a l l point to increasing distortion of the ring as the length of the strap is decreased (n = 11,10,9). A chain length of nine methylene units appears to be the lower limit; attempts to prepare even more strained porphyrins with shorter straps were unsuccess-f u l . Ligand binding to the metal complexes showed that the straps provided no steric protection. 1.6.2 Straps Containing Bulky Blocking Groups Porphyrins strapped with simple alkyl chains are poor models for oxygen binding heme proteins. In most cases the strap is too "floppy" and can be pushed to one side allowing y-oxo dimer formation. In addition, base is not prevented from binding under the strap, leading to oxygen binding on the open face and, consequently, irreversible oxidation. The logical extension is to incorporate some bulky group into the strap to increase the steric encumbrance about one face. One of the i n i t i a l examples of the strapped porphyrin approach 1 1 9 to heme protein models-was the cyclophane"porphyrin 160 of T r a y l o r . In this example steric encumbrance was provided by a biphenyl group in the strap. To ensure a tightly f i t t i n g strap, porphyrin cyclization was delayed until the f i n a l step (Scheme 46). Because of poor yield (5% for the cyclization step after repeated chromatographic purification) this porphyrin was not used as a heme p r o t e i n model. i n s t e a d ari anthracene was strapped across a preffirmed porphyrin 163 by means of 120 amide linkages (Scheme 47). For the anthracene-heme[6,6]cyclophane S C H E M E 46 75 S C H E M E Ul 2 . B r 2 , H C 0 2 H 3.6NHCI. Reflux 4. nBuOH, HCI OnBu 155 164 the two aromatic rings were estimated to be ^4.5 A apart. Performing a Diels-Alder addition on the anthracene with l-phenyl-triazine-2,5-dione 165 gave the "pagoda porphyrin" 166 possessing an even tighter pocket. Binding of a second axial base underneath the anthracene ring was not observed, the iron(II) complex being five-coordinate even in IM l-Melm. The anthracene-heme[6,6]cyclophane and the homologous[7,7] compound were used to study the binding of i s o n i t r i l e s , CO and 0^  within the pocket as models for the distal side steric effects in heme-120-122 proteins. Baldwin adapted his strapped porphyrin synthesis to prepare a 116 system 167 with a phenyl ring above one face (Scheme 48). Although structurally similar to the "C^-capped" porphyrin 124, the absence of the two extra linkages resulted in a "floppy" strap which did not prevent six-coordination by ligands such as l-Melm or pyridine and which did not prevent y-oxo dimer formation. An even more bulky strap, incorporating a naphthalene ring 168, was no more successful. Dolphin^ 7' has prepared a series of strapped porphyrins with a durene group protecting one face. Since short chains could be synthesized by this method i t was hoped that a sufficiently r i g i d strap could be obtained to enforce five-coordination. While the durene group did discriminate against bulky ligands such as 1,5-dicyclohexylimidazole, sterically unhindered ligands (l-Melm, pyridine) gave six-coordinate species. 77 1.6.3 Straps Containing Interactive Groups 78 The incorporation of potential ligands into the porphyrin strap has three advantages. (i) A stoichiometric amount of ligand is built into the system, ensuring five-coordination without the addition of external ligand. In the case of nitrogen bases, mixtures of six- and four-coordinate complexes are not obtained. (i i ) For ligands which bind poorly to iron(II) (e.g. thiolate), coordina-tion would be favoured by constraining the ligand into a position suitable for binding to the metal. ( i i i ) Because the strap is fixed in two positions, complications due to ligand replacement or dissociation w i l l be minimized. The strapped-porphyrin approach is also useful for orientating other interactive groups (e.g.,metal binding sites, electron donor/ acceptor groups) into specific geometries with respect to the porphyrin. Battersby has prepared a series of strapped porphyrins bearing 123 variously substituted pyridine ligands. Reaction of the porphyrin bis-acid chloride 141 with the corresponding pyridine diol 169 gave the ester-linked pyridine straps 170 in up to 38% yield (Scheme 49). A 124 cytochrome P450 model was prepared similarly (Scheme 50). A suitably functionalized diol 173 was reacted under high dilution with the bis-acid chloride of mesoporphyrin II 141 to give the strapped porphyrin 174 in 25% yield. The protected-sulfur» derivative 175 was obtained by displace-79 merit of the tosyloxy group with potassium thioacetate. After iron insertion and reduction to the iron(II) state, the S-acetyl group was cleaved with dimsyl sodium to produce the five-coordinate iron(II) species. On exposure to CO a six-coordinate iron(II) species 176 was formed whose visible absorption spectrum reproduced the major character-i s t i c s of the carbonmonoxy cytochrome P450 spectrum - a s p l i t Soret 13 13 band with an intense band at 450 nm. The C-NMR spectrum of the CO complex also supported the RS -Fe(II)-C0 formulation. Several binucleating strapped porphyrins have been prepared, which are capable of binding two metal ions in close proximity. The "crowned" 125 porphyrin 179 of Chang, formed by the addition of a bis-amino crown ether to the bis-acid chloride of deuteroporphyrin II 177, may bind a transition metal ion (in the porphyrin ring) and a group IA or IIA cation (in the diaza-18-crown-6.ring) (Scheme 51). Apart from i t s metal binding capability the crown ether also exerts some steric control over one face of the porphyrin. For the iron(II) complexes, bulky ligands (e.g.,1-triphenylmethylimidazole) bind only on the unhindered face of the porphyrin to give a five-coordinate species. Oxygen may then bind under the crown to give a reasonably stable oxygen species (t > .1 hr.-.at:-^0^ inf/DMA). h The combination of crown ether and porphyrin has recently been 126 extended by Lehn. The macrotetracyclic cryptand 182 was prepared by condensation of the biphenyl-linked bis-crown ether 180 with the di-p-nitrophenyl ester porphyrin 181 in pyridine at 55°C under high dilution conditions (45-54% after chromatography). Reduction to the tetra-amine 183 was effected by treating the zinc complex with diborane followed by demetallation. This multisite complexing species is S C H E M E 51 0 82 capable of selective substrate binding: transition metal cations are bound by the porphyrin and alkyl diammonium salts, +HJSI (CH0) NH„ +(n = ' 3 2 n 3 8-10), within the central cavity. That binding within the cavity does indeed occur was evidenced by the large upfield shifts of the methylene protons due to the shielding effects of the porphyrin and biphenyl rings. A copper binding site has been covalently attached to a porphyrin in an attempt to mimic the ESR characteristics of the iron-copper site 127 of cytochrome oxidase. The copper-binding strap was a bis-thiazole derivative 185, obtainable from phthalylglycine 184 i n high yield. Because of the need for a non-square-planar copper binding site, the strap was attached to one side of the porphyrin ring rather than to opposite corners. Condensation of the diamino thiazole sulfide 185 with mesoporphyrin XII bis-acid chloride 186 under high dilution gave the strapped porphyrin 187 in 72% yield after chromatography (Scheme 53). Metal ions could be differentially introduced into the porphyrin and into the strap to give a dinuclear metal complex containing a high spin iron(III) and a copper(II) ion. The extent of coupling between the two 128 metal centres was investigated by ESR. Gunter et a l . , used a somewhat different approach to prepare a similar Fe/Cu strapped porphyrin (Scheme 54). Condensation of the tetramethyldipyrromethane 188 with d-nitrobenzaldehyde 48^ , followed by oxidation afforded the 5,15-meso-(o-nitrophenyl)porphyrin 189. After reduction to the amino derivative the atropisomers were separated by chromatography. The a,ai-isomer 189 was fi n a l l y condensed with 2.6-pyridylbis(4'-:thla-5'-pentahoyll chloride) 190, arid gave the strapped porphyrin. Insertion of iron and copper and the introduction of bridging ligands gave species of the type 192, whose 83 84 , 129 magnetic properties were investigated. As a model for photosynthetic and electron-transfer systems, S a n d e r s 3 ^ has prepared a quinone-capped porphyrin. Using the Battersby group approach, 1,4-dialkoxybenzene 193 derivatives were reacted with mesoporphyrin II bis-acid chloride 141 to give the strapped porphyrins 194 in 7 and 15% yield depending on strap length (Scheme 55). Deprotection with boron trichloride afforded the hydro-quinones which were oxidized to the quinones 195 with lead dioxide. H^-NMR studies on the magnesium complexes suggest that the quinone carbonyl binds to the metal ion and that therefore the quinone and 132 porphyrin chromophores are perpendicular. 1.6.4 Doub jy-Strapped Porphyrins We have already seen that sterically encumbered porphyrins may s t i l l be susceptible to y-oxo dimer formation i f any four-coordinate species in solution binds oxygen on the open face. Steric encumbrance on both faces of the porphyrin, as in the "bis-pocket" porphyrin systems of Vaska'''^ and Suslick, may prevent this bimolecular oxidation pathway. Momenteau has used a combination of approaches to prepare TPP :e 115,116 133 derivatives having two straps on each porphyrin ring. In a strategy reminiscent of Baldwin's "capped" and "strapped" porphyrin syntheses, the sodium salt of salicylaldehyde was reacted with a variety of dibromoalkyl and p-(dibromoalkyl)benzene derivatives 193 to give chain-linked dialdehydes 194. The TPP ring was then formed by condensing the 8 5 S C H E M E 55 OR 86 dialdehydes with pyrrole in refluxing propionic acid (Scheme 56). After removal of polymeric materials, three isomers were obtained by chromatography in low overall yield. The unwanted adjacent cis-linked product 195c was often the predominant isomer. To increase the yield of the more interesting cross trans-linked isomers, formation of the bridges was delayed u n t i l after the porphyrin-forming condensation. Tetra-(d-methoxyphenyl)porphyrin 196 was obtained from pyrrole and p-methoxybenzaldehyde (10% yield) and demethylated to provide the tetra-(o-hydroxyphenyl)porphyrin 197. Alkylation with the dibromo derivatives 193 under high dilution in DMF at 100°C, followed by chromatography led to the isolation of the three porphyrin isomers 195. In this case the major product of each reaction was the desired cross trans-linked isomer 195a (Scheme 57). (The starting T(0H)PP was used as a mixture of the four possible atropisomers since the conditions of the condensa-tion would lead to equilibration). The degree of steric encumbrance is illustrated by the rates of metallation and oxidation of the various isomers. The adjacent cis-linked isomer 195c has one face unhindered and is easily metallated. In contrast the other isomers, where both faces are hindered undergo iron insertion reluctantly. While not preventing ligation of nitrogenous bases or gases, the chains do inhibit irreversible oxidation at room temperature. For the four-coordinate iron(II) cross trans-linked isomer 195a the t i . for oxidation to the hematin derivative PFe(III)-0H is 1.5-10.5 minutes compared to 7-54 seconds for oxidation of the less hindered isomers to the u-oxo dimer. Similarly, in toluene at 25°C under 0„ (1 atm), t,, for oxidation of the six-coordinate iron(II) complex 2 % i s 11-25 minutes for the cross trans-linked isomer compared to 1.5-12 minutes for the other two isomers. A similar doubly-strapped porphyrin has been reported by ~ 135 Bogatskii. The a, 8>a,3 atropisomer of meso-tetra (o-aminophenyl)-porphyrin 107 was acylated"with t r i g l y c o l i c dichloride at room temperature in the presence of pyridine, conditions that do not cause significant isomeri-zation of the atropisomer. The doubly-strapped porphyrin was obtained in 32% yield after chromatography (Scheme 58). A further refinement to the production of heme protein models was the synthesis of doubly-strapped models containing different straps. As models for hemoglobin or myoglobin, incorporation of a nitrogen base into one strap would simulate the proximal face of the natural system while the steric encumbrance provided by the second strap would be analogous to the distal, oxygen binding face. Momenteau's route to doubly-strapped porphyrins was easily adapted to produce compounds in which an axial base was incorporated into one 136 of the straps. Condensation of tetra(o-hydroxyphenyl)porphyrin 197 (mixture of four isomers) with one equivalent of 1,12-dibromododecane gave a mixture of two singly-linked porphyrins, depending on whether adjacent 199, or opposite 198 meso-phenyl groups were linked. This mixture was reacted with 3,5-bis(3-bromopropyl)pyridine 200 and the desired cross trans-linked isomer 201 isolated by preparative t i c (5% overall) (Scheme 59). A similar porphyrin 203 was prepared from a,B, a,B-tetra(o-aminophenyl)porphyrin 107; in this case the straps were tied to the porphyrin skeleton by amide linkages. Following iron insertion and reduction, both visible absorption and '''H-NMR spectra of both compounds were consistent with a five-coordinate high spin (S = 2) • ' iron(II) complex. The rate constants for the association and dissociation of 0^  and CO were determined by laser flash photolysis. The 0^  a f f i n ity of the "amide" linked system was higher than that of the "ether" linked 0 'compound (Pt ^ 18.6 vs 2) as a result of a difference of a factor of ca. 10 in the 0 o dissociation rates (k .... 4 vs 0.5). This increase in z or r s t a b i l i t y of the "amide" oxygenated species was attributed to the presence of the N-H group and the possibility of hydrogen-bonding with the terminal oxygen atom. The low temperature (-27 °C) H^-NMR spectrum was used to support this thesis, the observed inequivalence of the pyrrole protons as well as the shifts of the amide protons suggesting a 137 preferred orientation of the oxygen molecule towards the amide N-H's. To better model the hemoglobin and myoglobin active sites a doubly-strapped porphyrin 204 was prepared incorporating a pendant 138 imidazole (Scheme 60). The iron(II) derivative was capable of binding oxygen to give a relatively stable oxygenated species (lifetime was about one day in dry toluene under 1 atm 0^). The kinetics of 0^  and CO binding have been determined and i n i t i a l comparisons with the comparable "pendant pyridines" porphyrins show: (i) 0^ and CO combination rates are practically-constant in the three pendant base porphyrins, and ( i i ) a reduction in k ^ in the imidazole porphyrin due to a combina-tion of hydrogen bonding with the amide N-H and the greater basicity of imidazole over pyridine. Comparison of the pendant imidazole model with myoglobin or isolated hemoglobin chains shows that the model reacts 10 times faster with 0 92 S C H E M E 6 0 93 and that the dissociation rate is ^100 times faster than in the natural systems. With the availability of the differentially protected copro-' -. . . porphyrin II205, Battersby adapted his syntheses to the. production of doubly-139 strapped porphyrins (Scheme 61). Reaction of the bis-acid chloride 205 with 3,5-bis(3-hydroxypropyl)pyridine yielded the pyridine-strapped porphyrin 206 (33%) . Hydrogenolysis of the benzyl esters and acid chloride formation was followed by condensation with the anthracene diol 207 to give the doubly-bridged porphyrin 208 (27%). Iron insertion was found to be d i f f i c u l t so the metal was inserted after the introduction of the pyridine strap. Reduction with aqueous dithionite furnished the iron(II) species which on the basis of the visible absorption spectrum was judged to be high spin (S = 2) five-coordinate. Exposure to oxygen gave an oxygenated compound with a ti ^ of 1^5 minutes at room temperature in CH^Cl^. In DMF a more stable oxygenated species was formed (ti^ 2^ hr at 20 C). The 0^ could be displaced by passing CO into the solution, and, surprisingly, regeneration of the oxygenated species was. accomplished h.y passage of 0^. Such 02-C0 cycles could be repeated six times without significant irreversible oxidation. This was in contrast to the resistance of unhindered CO-porphyrin complexes to displacement of CO by 0 £. The further refinement of incorporating an imidazole ligand has 140 been recently reported. As before, the differentially protected coproporphyrin 205 was reacted with the anthracene diol 207 to give the porphyrin 209 (57%). After removal of the benzyl esters and treatment with oxalyl chloride, the bis-acid chloride was reacted with the N-substi-tuted imidazole diol 210. The doubly-bridged porphyrin 211 was obtained 94 95 in 22% yield (Scheme 62). The iron(II) complex was capable of reversible oxygen binding, four cycles of oxygenation-deoxygenation (by reducing the pressure) being possible before significant irreversible oxidation occurred. The ti^ for the oxygenated species was ca. 24 hr sat room temperature in DMF solution. Recognizing that the pendant-imidazole strap was s t i l l somewhat floppy, more r i g i d straps containing a 1,5-disubstituted imidazole 212 140 were prepared as before (Scheme 62). Coupling l,5-bis(4-hydroxybutyl)-212a or 1,5-bis(3-hydroxypropyl)imidazole 212b- with the bis-acid chloride of the anthracene-strapped porphyrin gave the doubly-bridged systems 213 in 23% and 6% yield. Distortion of the porphyrin ring, from planarity to accommodate the "shorter strap was held responsible for the low yield in the latter case and also for the lesser stability of the oxygenated iron(II) species. For the n = 4 case, the iron(II) complex could reversibly bind oxygen in DMF solution at ambient temperature. Ten oxygenation-deoxygenation cycles could be performed before irreversible oxidation was significant,-arid • only 20% irreversible oxidation after 2 days in solution. CHAPTER 2 RESULTS AND DISCUSSION 2 . 1 INTRODUCTION Wijesekera has already devised a strategy for the synthesis of porphyrins strapped with non-functionalized hydrocarbon chains, and a durene cap.^^ 7'^^^ His goal was to make the hydrocarbon straps as short as p o s s i b l e , tying back the porphyrin and d i s t o r t i n g the aromatic r i n g . Such d i s t o r t i o n of the porphyrin macrocycle has been suggested to play a r o l e i n heme protein functioning e.g. doming of hemes during R *—* T state changes i n hemoglobin. C l e a r l y any attempt to l i n k opposite corners of a ..preformed porphyrin with a hydrocarbon chain short enough to cause d i s t o r t i o n of the r i n g was doomed to f a i l u r e or very low y i e l d s . Furthermore, such a chain could probably only be "snapped" i n place using ester or amide linkages. For short straps the system would be s u f f i c i e n t l y taut that such linkages would be inherently unstable. In addition the amide linkage would make the compound l e s s soluble. Wijesekera's strategy ( F i g . 1) was to synthesize the strap f i r s t and attach i t to two g-free pyrroles _1_ v i a F r i e d e l - C r a f ts acylation.'''^ 7' ^  Modification of the a-methyl and a'-ester groups of the b i s - p y r r o l e _4 enabled the chain-linked bis-dipyrromethane _7 to be formed. With dipyrromethane formation a l l the elements necessary f o r construction of the porphyrin were i n place. D e - e s t e r i f i c a t i o n and deprotection of the a,a'-functional groups, followed by thermal decarboxylation yielded the chain-linked a-free, a'-formyl bis-dipyrromethane _8. High d i l u t i o n acid-catalyzed intramolecular c y c l i z a t i o n furnished the intermediate 3 porphodimethene 9^  which, due to the two sp carbon bridges, was r e l a t i v e l y unstrained. In s i t u oxidation of 9_ gave the strapped porphyrin J^O, the increase i n s t r a i n energy being traded off against the resonance s t a b i l i z a t i o n of the aromatic r i n g . Wijesekera prepared 98 F i g . 1: Synthesis of the Strapped Porphyrins of Wijesekera et a l . in good yield where n = 11 (22-52%), 10 (29-37%), 9 (20-25%). Where the chain was -(CH^)^-durene-(CH^)^-, yields were also good (22-31%) for the f i n a l cyclization step. With a chain length of eleven methylene units or a - ( C ^ ) ^ -durene- (CH^),.- chain, the strapped porphyrin was essentially undistorted and yields from the cyclization step were similar. Decreasing the length of the chain led to a corresponding decrease in yield as distor-tion became more severe. We anticipated that the above" strategy could be used to prepare a strapped porphyrin containing a -(CH^)^-S-(CH^)^- chain. It was hoped that this compound would be a good model for cytochrome c. We have already referred in sections 1.3.1 and 1.3.2 to the d i f f i c u l t y of preparing the mixed ligand system, N-Fe-S, as a model for the active site of cytochrome c where methionine 80 and histidine 18 coordinate to the heme iron. Unless one of the ligands i s covalently attached to the porphyrin periphery only the symmetric complex is obtained. In our case the sulfide i s incorporated into a strap which is slightly more than eleven methylene units long; long enough to produce a virtually planar, strain-free porphyrin, yet short enough to ensure that the sulfur atom would bind to the iron of the corresponding heme. The series of reactions outlined in Fig. 2 was attempted. Refluxing 2,4-dimethyl-iodopentylpyrrole 11 with 1.5 equiv. of sodium sulfide in aqueous THF gave the bis(pyrrol-3-yl)pentyl: sulfide _12 in 94% yield. Saponification with potassium hydroxide in aqueous propanol gave, after 2 hours reflux, the bis(a-carboxypyrrol-3-yl)pentyl sulfide 13. This compound was not purified or characterized but was immediately decarboxylated in refluxing >N,N-dimethylformamide. The course of the H3CN,ICH2^I H 3C N,[CH 2^SICH 2I 5 N,CH3 E,0V9^CH3 H°0/T9HF° • E,0V9^H3 ^ '^ V0* 11 -F i g . 2: Attempted Synthesis of the Bis-dipyrromethane '-19 reaction was followed by UV spectroscopy, disappearance of the band at 283 nm being indicative of complete decarboxylation. Vilsmeier formylation of the crude b i s ( a - f r e e - p y r r o l - 3 - y l ) p e n t y l l sulfide 14 was carried out in situ using phosphorous oxychloride and N,N-dimethyl-formamide. The crude product _15_ was treated with malononitrile and cyclohexylamine, protecting the a-formyl function as the 2,2-dicyano-vinyl derivative 16. Only at this stage was the product isolated and purified by column chromatography. Compound _16 was treated with 2 equivalents of sulfuryl chloride to form the bis-chloromethyl compound _17_, followed by addition of the a-fre e pyrrole _18 and refluxing of the reaction mixture. Typically, dipyrromethanes such as compound _19_ show up on t i c as bright yellow spots which turn violet on exposure to bromine. Tic of the reaction mixture, however,showed such a spot only faintly; there were many other compounds, one being due to unreacted a - f r e e pyrrole 18. ''H-NMR examination of the crude reaction product showed only a weak signal at 3.92 6 (the bridge -CEL^  P r o t o n s °f dipyrromethanes occur at 3.9-4.0 6), with a large doublet at 6.53 6 due to the a-H of the unconsumed a - f r e e pyrrole 18. The failure of this reaction indicated that chloromethyla-tion of _16 was not occurring as anticipated. This result was not surprising in view of the known reactivity of sulfides with sulfuryl 142 chloride to produce a-chlorosulfides. The reaction is believed to proceed by a mechanism involving chlorosulfonium salts I as inter-143 mediates. Such sulfur-chlorine complexes are stable at low temperatures (-78 to -40°C) and even at 0°C for short periods. However on warming to room temperature they decompose to give the a-chlorosul-fides II. Alternatively, hydrolysis at low temperature (-78°C) produces 102 the corresponding sulfoxide I I I , 144 S C H E M E 6 3 -CH 2 -S-CH 2 -S 0 2 C 1 2 + -70°C 95% EtOH -70°C „ J I -CHo-S-CH-n The f a i l u r e of the chloromethylation reaction of the L b i s ( p y r r o l -3-:yl)pentyl s u l f i d e 16 with 2 equivalents of s u l f u r y l chloride at room temperature and higher was thought to be due to competing dechlorination of the s u l f i d e chain. The reaction was repeated at low temperature using 3 equivalents of s u l f u r y l c h l o r i d e , one each for the two a-methyl groups and one for the formation of the -chlorosulfonium s a l t which would be transformed to a sulfoxide during work-up. The b i s ( p y r r o l - 3 - y l ) p e n t y l s u l f i d e 1_6 was dissolved i n dichloro-methane and cooled to -60°C. The s u l f u r y l c hloride was added and the 16 R' 17 R' s o l u t i o n s t i r r e d at -60°C for 2 hours, then at -40°C overnight. A solu t i o n of the a-free pyrrole JJ3 i n dichloromethane and g l a c i a l a c e t i c acid was added and the s o l u t i o n allowed to warm to room temperature. Aft e r work-up neither H^-NMR nor t i c showed any s i g n i f i c a n t amount of desired bis-dipyrromethane 19. Dipyrromethanes may also be synthesized by the condensation of a-acetoxymethyl and a-free pyrroles i n the presence of aci d . Thus the chain-linked b i s ( p y r r o l - 3 - y l ) p e n t y l s u l f i d e 16^ was treated with 4 equivalents of lead tetraacetate to give 20. A crude product was is o l a t e d and allowed to react with, the a-free pyrrole 1_8_. Again examination of the reaction mixture by t i c and ^H-NMR gave no evidence of s i g n i f i c a n t formation of the desired bis-dipyrromethane 19. As with, s u l f u r y l c h l o r i d e , s u l f i d e s are attacked by lead t e t r a -acetate. Depending on the nature of the solvent the i n i t i a l l y formed 148 acyloxysulfonium cation IV may rearrange to the a-substituted s u l f i d e 149 y or the sulfoxide VI. Likewise the a-acetoxymethyl pyrrole route was: not pursued since, i f any bis-dipyrromethanes were produced, i t would be a mixture of products. At t h i s stage i t was considered that Wijesekera 1s synthetic strategy might not be d i r e c t l y applicable to the synthesis of strapped porphyrins containing non-inert straps. It was considered that the 104 SCHEME 6 4 •CH 2 -S-CH 2 -Pb(OAc) A - C H - S T C H 2 -N ChU - C H ^ S - C H 2 -L V . -OAc - CH 2 - S -CH 2 -0 , CH. C = 0 I E | "OAc •CH 2-S-CH 2- j j -0 + A c 2 0 - C H - S - C H 2 -0 , H,C c = o route contained two p o t e n t i a l l y troublesome steps: ( i ) The F r i e d e l - C r a f t s a c y l a t i o n of a 3-free p y r r o l e 1_ using stannic c h l o r i d e as c a t a l y s t , and ( i i ) the use of s u l f u r y l c h l o r i d e to prepare the c h a i n - l i n k e d a-chloro-methyl pyrr o l e , dimer, the precursor of the protected b i s - d i p y r r o -methane. Obviously the use of s t a n n i c c h l o r i d e and the necessary formation of a b i s - a c i d c h l o r i d e might not be compatible w i t h formation of strapped porphyrins bearing a c i d s e n s i t i v e f u n c t i o n a l i t i e s i n the chain. S u l f u r y l c h l o r i d e presented two problems. This reagent has been widely used f o r the s i d e - c h a i n halogenations of p o l y s u b s t i t u t e d a-methyl 105 pyrroles The r e s u l t i n g a-chloromethyl pyrroles have been used as intermediates i n the preparation of a number of pyrrole oligomers such as dipyrromethanes, dipyrromethenes and porphyrins. Despite t h e i r importance, l i t t l e a ttention has been paid to the mechanisms of these halogenations. In one instance, side-chain c h l o r i n a t i o n with s u l f u r y l c h l o r i d e was assumed to occur by a free r a d i c a l mechanism.'''^ ''' I l l u m i n a t i et a l . , recently suggested that the mechanism of s u l f u r y l chloride 152 153 action might be s i m i l a r to that of molecular chlorine and bromine, and might proceed by an e l e c t r o p h i l i c mechanism. They studied the c h l o r i n a t i o n of s p e c i a l l y selected a-methyl pyrroles with molecular ch l o r i n e at low temperatures (-28°C) and i n the dark. The r e s u l t s suggested that the o v e r a l l process consists of two main steps, i . e . , e l e c t r o p h i l i c nuclear attack and subsequent rearrangement of the halogen from ei t h e r the adjacent g- or the vinylogous a'- p o s i t i o n to the side-*-chain. That a r a d i c a l -mechanism did not hold was supported by the f a c t that the results: were unaffected by sunlight and r a d i c a l scavengers such, as g a l v i n o x y l . Furthermore t h e i r r e s u l t s provided some analogies with, the nonconventional e l e c t r o p h i l i c substitutions of highly activated 154 methyl substituted aromatics leading to side-chain c h l o r i n a t i o n . Unlike the pyrrole case, halogenation of alkylbenzenes has been extensively studied. With, l e s s substituted benzene rings and under i l l u m i n a t i o n the reaction proceeds through a free r a d i c a l mechanism. Lee"^^^ has; studied the l i g h t induced c h l o r i n a t i o n of alkylbenzenes i n carbon t e t r a c h l o r i d e at 40°C using s u l f u r y l c h l o r i d e . The suggested course of the reaction i s as follows where hydrogen abstraction i s by 156 the. c h l o r o s u l f i n y l r a d i c a l . 106 R -H + R- + In contrast the dark reaction of polyalkylated benzenes proceeds by an electrophilic mechanism. Thus, reaction of hexamethylbenzene with, chlorine involves electrophilic nuclear attack to give the benzene-onium ion which, decomposes, via rearrangement of the chlorine from the nucleus to the side-chain, to give the a-chloromethyl benzene. SCHEME 6 5 Cl CH 2 Cl These results suggested that any attempt to monochlorinate the a-meth.yl groups of compounds 2\_ and 23_ with sulfuryl chloride might also lead to chlorination of the substituted benzene ring (equations 34 and 35). Wijesekera"''"''7 had shown that exclusive pyrrole side-chain chlorina-tion could take place even in the presence of a hexasubstituted benzene in the reaction of compound 25_ with sulfuryl chloride in the dark (equation 36). However, although the pyrrole nucleus is known to be highly reactive towards electrophilic attack, the presence of electron donating methoxy groups might make the benzene ring sufficiently reactive to compete with i t . By this time we were aware that sulfuryl chloride could react •sop so2ci2 + R' + S 0 2 + HCI > R-Cl + 'S0 2 CI so2ci2 i so2 + cr (30) (31) (32) 107 SCHEME 6 6 (33) (34) (35) (36) V with, s u l f i d e s to form a - c h l o r o s u l f i d e s and/or s u l f o x i d e s , depending on r e a c t i o n c o n d i t i o n s . This was demonstrated by our f a i l u r e to form the b i s (oi-chloromethyl), p y r r o l e .17. Furthermore we wished to prepare strapped porphyrins with, an a n i s o l e or a bis-methoxybenzene r i n g incorporated i n t o the s t r a p ; demethylation would then give a compound w i t h a phenol or a quinone r i n g r e s p e c t i v e l y , c o v a l e n t l y l i n k e d to a porphyrin. For t h i s purpose compounds 22 and 24 would be r e q u i r e d . However from the above co n s i d e r a t i o n s i t seemed d o u b t f u l i f s e l e c t i v e c h l o r i n a t i o n of the a-methyl groups could be e f f e c t e d . For these reasons i t was decided that chlorination of a pyrrole a-methyl function should occur before chains incorporating susceptible groups are set in place. To this end we devised an alternative synthetic route which was a variation on Wijesekera's strategy. In this alterna-tive reaction scheme both the Friedel-Crafts acylation and the modifica-tion of the pyrrole a-methyl group are carried out before the strap is s:et in place CFig. 3). The various porphyrin syntheses a l l start from a common intermediate 44 of 64, which is easily obtained in pure form and in large quantities By known reactions. 87a n = 5 b n = 4 118a n = 6 b n = 5 U3a n = 6 b n = 5 Fig. 3: Proposed Syntheses of Strapped Porphyrins 110 2.2 SYNTHESIS OF 5-(5-ETH0XYCARB0NYL-4-METHYLPYRR0L-3-YL)-l-IODOPENTANE 44 AND ITS LOWER HOMOLOGUE 64 Heating ethyl hydrogen glutarate with excess thionyl chloride formed the acid chloride 27, which was immediately used in the Friedel-Crafts acylation of g-free pyrrole 1_ (Fig. 4). Stannic chloride was added dropwise to a cold solution of the crude acid chloride 27_ and the pyrrole 1^ . When t i e indicated complete consumption of starting pyrrole the reaction mixture was poured into 2M hydrochloric acid and the dichloromethane layer separated. - Extraction with sodium bicarbonate aolution removed any -unreacted acid chloride. The crude keto-ester 28 was recrystallized from aqueous ethanol to give a 84% yield. Reduction of the keto-ester 2j5 to the hydroxypentyl pyrrole 30 may be carried out in one or two steps. Thus keto-ester 28 was l dissolved in dry tetrahydrofuran and 2.0 equivalents of sodium boro-hydride added. Boron trifluoride etherate (2.8 equivalents) was then added dropwise over a period of 20 minutes. The course of the reaction was followed by t i c as the starting material was reduced f i r s t to the pentyl ester pyrrole '29_ and then to the hydroxypentyl pyrrole .30. The reaction was carried out without cooling and was complete after stirring for 2 hours. The excess diborane was quenched by the careful addition of glacial acetic acid (extreme caution is necessary at this stage especially i f the reaction is being carried out on a large scale). After work-up and recrystallization a yield of 85% was obtained. The reduction of the keto group appears to proceed more quickly than that of the ester group. If the diborane reduction is carried out in a mixture of tetrahydrofuran and ethyl acetate, reduction of the ester H 3 C v , H E t o y C A c H C , 0 C , C H ^ C 0 ^ o H 3 1 27 SnCl, 0 ° C E t O H 3 C . . C ( C H 2 ) 3 C 0 2 E t 0 H 28 C H , H 3 C . ^ { C H ^ O H B O ^ N X C H 0 H • * 30 N a B H i N a B H 4 B F 3 E t 2 0 t E tOAc H 3Cv x ( C H 2 ) 4 C 0 2 E t B F 3 E t 2 0 EtOYsNAcH H 29 CH3S02CI E t 3 N 0°C 0 II H 3 C v ^ ( C H 2 ) 5 0 S C H 3 H 3 C v . ( C H 2 ) 5 C l E t 0 V C X c ° • E t 0 v C X , 0 H 35 U C H 3 ( CH 3 ) 2 C=0 0 H A 36 H 3 C \ _ / ( C H 2 ^ Et0^iXH 3 0 H 40 1) 3 S 0 2 C l 2 2) H 2 0 / ( C H 3 ) 2 C = 0 H 3 C . . (CH 2 ) 5 I E t O O H J 43 _ N a H C Q 3 / K I / I 2 "H2O/CUCH2)2CI H 3 C v . ( C H 2 ) 5 X E t O ^ / . N X c o H 41 X = I 42 X=Cl HI E tOH E t O (CH 2 ) 5 I 44 F i g . 4: Synthesis of 5-C5-Ethoxycarb.onyl-4-me.th.ylpyrrol-3-yl)-1-iodopentane 44 function i s suppressed and the product 29, a r i s i n g from reduction of the keto group only, i s obtained. Reduction of the ester to the a l c o h o l l may then be ca r r i e d out i n THF under the same conditions;and with a s i m i l a r y i e l d (Fig. 4). In retrospect, i t was r e a l i z e d that i t was not necessary to use the a c i d c h l o r i d e of et h y l hydrogen glutarate - the b i s - a c i d chloride of g l u t a r i c acid would have worked equally well. Previous work'''"'7 had shown that the reaction of g-free pyrrole 1_ with s u c c i n i c and g l u t a r i c acid b i s - a c i d chlorides r e s u l t s i n the formation of the p y r r o l y l keto acid 33_ as the major product (Scheme 67) . Presumably SCHEME 6 7 H CIOC(CH2)nCOCl H3C C(CH2)„CCI EtO CH 3 E tO CH3 0-r-C=0 0 32 0 0 0 I  33 113 the intermediate p y r r o l y l keto acid chloride 31_ can c y c l i z e to an enol lactone 3_2_ which, upon work-up, hydrolyzes to 3_3. For s u c c i n i c and g l u t a r i c acids (n = 2 and 3), the lactones are 5 and 6 membered rings r e s p e c t i v e l y , r a t i o n a l i z i n g t h e i r ease of formation. The product 3_3 i s e a s i l y separated from any unreacted b i s - a c i d chloride or 3-free pyrrole 1_, and also from the more i n s o l u b l e bis-acylated product 34. Reduction of the p y r r o l y l keto acid 3_3 with diborane i n the usual way would give the required hydroxyalkyl pyrrole 30. The -mesylate 35_ was prepared by the method of Crossland and 15 8 Seryis;. The hydroxypentyl pyrrole 30_ and 1.5 equivalents of t r i e t h y l -amine were dissolved i n dichloromethane and cooled to 0°C. Methane-s u l f o n y l chloride (1.2 equivalents) was added dropwise and the s o l u t i o n allowed to warm to room temperature. Work-up included extraction with d i l u t e a c i d and saturated sodium bicarbonate to remove excess triethyl.-? amine, and methanesulfonyl chloride r e s p e c t i v e l y . The crude product was r e c r y s t a l l i z e d from aqueous ethanol for a 92% y i e l d . 0 H 3 C . . (CH 2 )sOSCH3 H 3 C . , ( C H 2 ) 5 C l B O N ^ N X C H E t 0 V ^ X C H 0 H 0 H 35 3_6 Although, t i c of the crude product i n several solvent systems showed only a s i n g l e spot, the product may have been contaminated with the cb.irresponding chlo'ropentyl pyrrole 36. If the hydroxyoctyl pyrrole 37_ was treated with triethylamine (1.5 equiv) and methanesulfonyl chloride (1.5 equiv,) , and the crude product refluxed with, potassium bromide i n 114 acetone then a mixture of the bromide 38_ and chloride _39_ was obtained. The chloride was presumably formed during the mesylation reaction, bromide not being sufficiently nucleophilic to effect substitution during the subsequent S 2 reaction. Whether or not the chloropentyl pyrrole 3_6 was formed in any of the mesylation reactions was never established since the crude mesylate was usually carried forward to the next stage without characterization. Thus refluxing with sodium iodide (4 equiv.) in acetone gave the iodo-pentyl pyrrole 40. After work-up the crude product was recr.ystallized from ethanol to give a f i r s t crop yield of 79%; a second crop (13%) was obtained from the mother liquor. It was found that sodium iodide was more efficient for the reaction than potassium iodide due to the greater solubility of the former in acetone. Efficient mechanical stir r i n g was required for medium-to-large scale reactions as a heavy gelatinous precipitate was produced which, caused severe bumping. Any chloropentyl pyrrole 36 contaminant present in the crude mesylate would have reacted with, the more nucleophilic iodide ion to give the desired product 40. Conversion of the a-methyl-iodopentyl pyrrole 4Q_ to the corres-ponding a -free pyrrole 44 was effected by- trichlorination of the a-methyl S C H E M E 6 8 37 38 39 group, hydrolysis to the a-carboxy pyrrole 4_1_, and decarboxylation via the ct-iodo pyrrole 43. The extent of chlorination can be controlled by the stoichiometry of the reaction. Mono-, d i - , and t r i - chlorination may be effected using one, two and three equivalents of sulfuryl chloride respectively. Chlorination of the (3-methyl group is much, more sluggish, so there is. l i t t l e danger of g-chloromethyl pyrrole formation during trichloro-methylation even i f a moderate excess of sulfuryl chloride is used. Choice of solvent for the trichlorination reaction is important. It has been reported that the use of chlorocarbon solvents alone leads 159 to incomplete reaction and impure products. This was attributed to the hydrogen chloride liberated during the reaction. Use of ether gave variable results. The ether appears to solvate the liberated hydrogen chloride preventing reaction with the product, but ether is known to react with sulfuryl chloride and therefore can compete for reagent. The reaction was carried out according to the reported method of 160 Battersby et a l . , where a compromise was struck between the desired solubility of pyrroles in dichloromethane and the solvating property of ether on the one hand and the adverse reactivity of ether with, sulfuryl chloride on the other. Thus the a-methyl-iodopentyl pyrrole 40_ was. dissolved in a 50:50 dichloromethane/diethyl ether mixture. A solution of sulfuryl chloride (3.3 equiv) in dichloromethane was added dropwise. AO 43 116 Addition was f a i r l y rapid to ensure that the hindered, less reactive a-dichloromethyl pyrrole could compete with the ether for the oxidant. The solution darkened and warmed slightly as the reaction proceeded. After removal of solvents and excess sulfuryl chloride the crude trichloromethyl pyrrole intermediate was immediately hydrolyzed by refluxing in 20% aqueous acetone. Removal of most of the acetone led to the precipitation of the crude a-carboxy pyrrole. Proton nmr of the crude product showed complete disappearance of the singlet at 2.20 6 due to the a-methyl group and no evidence of other peaks which, might be attributed to the hydrolysis products of mono- or dichlorination. However, not only was there a t r i p l e t at 3.20. 6 due to -CH^I, but i n some cases there was also a significant tr i p l e t at 3.56 <5 due to -CH^Cl. This chloride substitution presented only a minor i r r i t a t i o n since the chloropentyl pyrrole 42 may be reconverted to the iodopentyl pyrrole 41 at this or any subsequent stage by refluxing with, sodium iodide in acetone. Although a-carboxy pyrroles are known to undergo thermal decarboxyla-tion, i t has been accepted that a two step sequence involving iodinative decarboxylation and de-iodination gives better yields and cleaner 159 products. The iodinative decarboxylation was carried out in a two-phas.e reaction system (illustrated schematically in Fig. 5). The a-carboxy-41 X = I h2 X = ci 40 F i g . 5: SchematicRiRepcesenl5at±onf-:6ftbheilddteM"i've D e c a r b o x y l a t i o n o f 41 118 iodopentyl pyrrole 4_1_ was dissolved i n the basic aqueous phase of a water/dichloroethane system. Addition of potassium iodide and iodine formed KI^ i n the aqueous phase which was subjected to n u c l e o p h i l i c attack by the pyrrole nucleus to give the sigma adduct 4_5. This adduct could break down to regenerate the a-carboxy pyrrole 4_1, or i t could lose carbon dioxide to form the a-iodo pyrrole 4_3 which was then extracted into the lower organic phase, preventing the formation of 161 s o l i d p yrrole-iodine charge transfer complexes. The r e a c t i o n mixture was vigorously s t i r r e d and then-_-iref luxedV dichioroethane,being used rather than dichloromethane since i t s higher b o i l i n g point gave the optimum temperature for reaction. Work-up of the reaction was simple. Excess iodine was destroyed by addition of sodium b i s u l f i t e and the two layers separated. Evaporation of the organic layer yielded the crude a-iodo-iodopentyl pyrrole 43 which, was r e c r y s t a l l i z e d from 50% ethanol/water, or more frequently c a r r i e d on to the next stage without p u r i f i c a t i o n . The r e c r y s t a l l i z e d product y i e l d , was 78-84%. De-iodination was accomplished using hydriodic a c i d . The a-iodo pyrrole 4_3 was dissolved i n ethanol and the hydriodic acid generated i n situ from potassium iodide and hydrochloric acid; .'-Alternatively the s t a r t i n g material was dissolved i n g l a c i a l a c e t i c acid and 47% hydriodic a c i d added. Again the equilibrium was pushed to the r i g h t by consuming the l i b e r a t e d iodine with hypophosphorous a c i d . N e u t r a l i z a t i o n of the acids and extraction gave the crude product. Chromatographic p u r i f i c a t i o n was c a r r i e d out at t h i s stage, reactions on a 20 g scale being convenient-l y p u r i f i e d . The red contaminant (due to b i p y r r o l e by-products) was retained at the o r i g i n and the pure a-free~iodopentyl pyrrole 4_4 eluted quickly from the column with, dichloromethane as solvent. Evaporation of 119 the f r a c t i o n s gave a s l i g h t l y yellow s o l i d (84%) . The o v e r a l l y i e l d of a-free-iodopentyl pyrrole 4_4_ from the s t a r t i n g 2,4-dimethyl-iodopentyl pyrrole 40_ was 66%. The a-free-iodopentyl pyrrole 44 was also prepared by an a l t e r n a -t i v e route where the sequence of reactions was changed s l i g h t l y ( F i g . 6). Thus the hydroxypentyl pyrrole 30_ was converted to the acetate 46_ which was used as a protecting group f o r the t r i c h l o r i n a t i o n reaction. Treat-ment with 3.2 equivalents of s u l f u r y l chloride followed by hydrolysis with aqueous acetone produced the a-carboxy pyrrole 48_. Unfortunately, during the hydrolysis stage the reaction mixture was s u f f i c i e n t l y a c i d i c to cause p a r t i a l removal of the acetate group. This presented only a minor inconvenience since the acetate could be f u l l y restored a f t e r i o dinative decarboxylation, or preferably, at the a-free pyrrole stage. The t r i c h l o r i n a t i o n was also repeated but using a mixture of acetone and aqueous sodium bicarbonate s o l u t i o n to carry out the hydrolysis under basic conditions. Under those conditions the acetate remained i n t a c t . However, strongly basic conditions should be avoided for the hydrolysis reaction since these have been reported to lead to considerable pyrrocol 54_ formation. Iodinative decarboxylation and de-iodination proceeded exactly as outlined for the corresponding iodopentyl pyrroles. The crude a-free pyrrole 51_ was p u r i f i e d by column chromatography. The y i e l d s for the decarboxylation and de-iodination were 77% and 80% 120 EtO H3Cv ^ICH^OH f\ Pyr/(CH3CO)20 0 H 30 H 3C. ,(CH2)5OR Etov(Ai 0 H 49 R= H 50 R= OAc KI/HCl/EtOH HI/CH3C02H H3Cx ,(CH2)5OR E t O > A X H 0 H 51 R=H 52 R=OAc H 3C. .(CH2)50CCH3 P in Jl \ 0 " II 0 H 46 1) 3S0 2Cl 2 2) H20/(CH3)2C=0' NaHC0 3/KI/I 2 H 20/Cl(CH 2) 2Cl H 3 C . , ( C H 2 ) 5 O R E t 0 5^H C ° 2 H 47 R =H 48 R =OAc 5% H2S04/MeOH H3C\ ytCHzlsOH EIONV^ NKH I H H 51 CH3S02CI Et3N 0°C EtO H 3 C X y(CH 2) 5OSCH 3 V ^ N A H Nal H 53 (CH3)2C=0 A H j C v . J C H ^ - I E t 0 V ( A H 0 H UL F i g . 6: Al t e r n a t i v e Synthesis of 5-(5-Ethoxycarb.onyl-4-methylpyrrol-3-yl)-1-iodopentane 44 121 r e s p e c t i v e l y . The acetate was removed by s t i r r i n g i n 5% s u l f u r i c acid/methanol and the a-free-hydroxypentyl pyrrole 51_ converted to the mesylate 53 using the same methanesulfonyl chloride/triethylamine procedure as before. Refluxing the crude mesylate with sodium iodide in acetone gave the desired a-free-iodopentyl pyrrole 44. The y i e l d s i n the two r e a c t i o n sequences were comparable. However due to the l a b i l i t y of the acetate function under the conditions of some reactions and also due to the r e l a t i v e i n s t a b i l i t y of the a-free hydroxypentyl and a-free methanesulfonylpentyl pyrroles, 5_1_ and 53_, the r e a c t i o n sequence using iodopentyl pyrroles was: more convenient. 4-(5-Ethoxycarbonyl-4-methylpyrrol-3-yl)-l-iodobutane 64_ was. prepared by the same reaction sequence as for i t s higher homologue 44 ( F i g . 7). The acid chloride of ethyl hydrogen succinate 55 was, prepared using t h i o n y l chloride and used i n the Friedel-Crafts. a c y l a t i o n of g-free pyrrole l_.with. stannic c h l o r i d e . After work-up and r e c r y s t a l l i -zation from ethanol a 73% y i e l d of the keto-ester 5_6 was obtained which was reduced using diborane, generated i n s i t u from sodium borohydride and boron t r i f l u o r i d e etherate. R e c r y s t a l l i z a t i o n of the crude product from 50% aqueous ethanol y i e l d e d the h.ydroxybutyl pyrrole 57 (72%) . The mesylate 5_8 was obtained using methanesulf onyl chloride/triethylamine and was c r y s t a l l i z e d from 50% aqueous ethanol (88%, 2 crops). No evidence was observed for the presence of the contaminant chlorobutyl pyrrole 59_. Refluxing the mesylate 5_8 with sodium iodide (4 equivalents) i n acetone formed the iodobutyl pyrrole 60, which was r e c r y s t a l l i z e d from 20% aqueous ethanol C88%, 2 crops). The t r i c h l o r i n a t i o n of 60 was carried out exactly as for 40, using 0 H a C v / H H 3 C w C ( C H 2 ) 2 C 0 2 E t Ftn i V ClOC(CH2)2C02Et — ^ //Iv 0 " 55 0 H 1 56 NaBH, ^ H 3C^(CH 2) 4X ] } ^ H 3 C (CH2)4X BF,Et 20 E t O y C j j X ^ 2 ) N a I , ( CH 3) 2C = 0 E t ° V ^ \ C 0 H 57 X - 0 H C I V - / - M 0 3) 3S02CU 5-1 X _ C l 58X = OSCH, « H20/(CH3)2C=0 II 3 0 59 X = Cl 60X= I 62 X = 1 NaHC03/KI/I2 H 3Cy_^(CH 2 U H I H 3C^/(CH 2)J H3C H2O/CUCH2)2C. B O ^ X J " ^ o T T ^ t O v ^ X H Et°vV 0 H 6J . 64 6 5 H2/ 10%Pd-C NaOAc / MeOH H 3 C N , ( C H 2 ) 4 I H 3 C v . (CH2)3CH3 E t o ^ i A H E t o v C A n 0 H 0 H 66 64 F i g . 7: Synthesis of 4-(5-Ethoxycarb.onyl-4'-methylpyrrol-3-yl). iodohutane 64 sulfuryl chloride (3.2 equivalents). In general the "butyl pyrrole" compounds appeared to be less soluble than the corresponding "pentyl pyrrole" compounds. In some trichlorination reactions the starting iodobutyl pyrrole 60_ was not completely soluble in a reasonable volume of the reaction solvent, 1:1 dichloromethane/diethyl ether. In those cases the starting material was simply suspended in the solvent mixture and the sulfuryl chloride added. As the reaction proceeded and the mixture warmed the solution became homogeneous. After hydrolysis the crude product was refluxed with sodium iodide in acetone to ensure that none of the chlorobutyl pyrrole 6_1 was present. The a-carboxy pyrrole 62^was obtained from the reaction mixture in 80-90% yield. Iodinative decarboxylation proceeded as expected under the same conditions as before, the a-iodo pyrrole 63_ being obtained in 73-87% yield after recrystallization from ethanol. Unlike i t s longer chain counterpart, de-iodination of a-iodo-iodo-butyl pyrrole 63; presented some problems. The starting material was dissolved in ethanol by heating gently on a steam-bath.. Without further heating hydriodic acid was added, the solution becoming very dark as. iodine was liberated, indicating that the reaction was proceeding. The liberated iodine was destroyed by addition of hypophosphorous acid, but t i c indicated incomplete reaction so more hydriodic acid was added. When t i c confirmed complete reaction, water was added and the mixture le f t standing. The solid which precipitated was collected and dried, and purified by column chromatography. The f i r s t fractions from the column comprised pure a-free iodobutyl pyrrole 64, the desired product. However later fractions showed the product to be contaminated with a second compound. This second compound was isolated and identified. H^-NMR confirmed the presence of an ester and a 4-methyl group. However the spectrum displayed no doublet at 6.72 6 due to the a-free proton at po s i t i o n 2 of the pyrrole r i n g , nor did i t display a t r i p l e t at 3.24 6 due to the -CH^I group. Mass spectrometry showed a parent peak at 207 and t h i s fact coupled with the ''H-NMR evidence suggested that the contaminant had the structure 65. This intramolecular c y c l i z a t i o n appeared to occur excl u s i v e l y during the de-iodination reaction (Scheme 69, equation 39); there was: no evidence f o r the formation of 65 during the i o d i n a t i v e decarboxylation react i o n . S i m i l a r l y there was no observation of intramolecular c y c l i z a t i o n during the de-iodination of the corresponding a-iodo-iodopentyl pyrrole 43, formation of seven-membered rings being a less favoured process (equation 40). De-iodination may also be ca r r i e d out by c a t a l y t i c hydrogenation over palladium on charcoal with sodium acetate present to prevent poisoning of the c a t a l y s t . Accordingly the a-iodo pyrrole was dissolved i n methanol, sodium acetate and 10% palladium on charcoal added, and s t i r r e d under hydrogen overnight. T i c of the reaction mixture showed a single spot which, was not s t a r t i n g material. However, af t e r work-up, subsequent reactions showed that the product was not homogeneous but was a mixture of the two compounds 6k_ and 66_ i n approximately equal amounts. That only two products-were obtained from the. hydrogenation 64 63 65 125 SCHEME 69 126 suggested that the pyrrole iodine was more l a b i l e than the side-chain iodine. With c a r e f u l monitoring i t might have been possible to follow the course of the reaction and interrupt i t a f t e r a l l the p y r r o l i c iodine had been removed but before any s i g n i f i c a n t de-iodination of the chain had occurred. Although contaminated with either the b u t y l pyrrole 6j6 or the r i n g pyrrole 65, samples of the a-free pyrrole 64_ were pushed through to the next steps since the contaminants were e a s i l y removed from subsequent products by chromatography. To circumvent the problem of de-iodination, the a-free-iodobutyl pyrrole 64_ was synthesized using the acetate route (Fig. 8). The acetate of 2,4-dimethyl-hydroxypentyl pyrrole 5_7 was prepared using pyridine and a c e t i c anhydride.(85%). The t r i c h l o r i n a t i o n with, s u l f u r y l c h l o r i d e was c a r r i e d out as before and the intermediate trichloromethyl pyrrole was hydrolyzed by r e f l u x i n g i n aqueous acetone which, contained some sodium bicarbonate. However the NMR spectrum of the crude product showed i t to be a mixture of _68_ and ^69. This presented no problem as the mixture of products was c a r r i e d through, the decarboxylation and de-iodination reactions to give '7_2_ and 73_. Before chromatographic p u r i f i c a t i o n the mixture was. converted to the, acetate 72,, then p u r i f i e d (55% y i e l d from 67). De-iodination of 71 was also c a r r i e d out by hydro-genation over 10% palladium on charcoal i n the presence of sodium acetate (9.1-9.5%) . The acetate group was removed by s t i r r i n g 72 with. 5% s u l f u r i c acid/methanol and the. product was obtained by extraction of the reaction mixture with ethyl acetate to give a brown s o l i d C93% crude). The crude hydroxyhutyl pyrrole 73 was not p u r i f i e d but c a r r i e d on to the mesylation step. Methanesulfonyl c h l o r i d e was added to a cold s o l u t i o n of crude 73 and triethylamine i n dichloromethane. After 127 H 3 C V . ( C H 2 ) P H H3C. .(CH2VOCCH3 r- ~ in p / r / <CH3CO)20 f~{ 0 0 n 0 H 57 67 H 3 C N J C H ^ O R D 3 S Q 2 C l 2 ^ " ^ V - / ' " " ' ' F C " N Q H C Q 3 / K I / I 2 2) H 2 0 / ( C H 3 ) 2 C = 0 E t O v y ^ N X c 0 2 H H 2 0 / C U C H 2 ) 2 C I H3Cv J C H ^ O R H 68 R= H 69 R= A c 0 H 7_0 R = H 71 R = A c 70 H 3 C . • <CH 2 ) i OCCH 3 H 2 n o % p d - c N a O A c / M e O H E t O ^ M ^ 0 H 72 71 H I EtOH J 5 % H 2 S 0 4 / M e O H H 3 C . ^ (CH 2 ) 4 OH 6 H 73 E t 3 N 0 ° C H 3 C . , (CH 2 ) 4 OSCH 3 E t O s ^ X ^ 74 N a l / (CH 3 ) 2 C=0 A H 3 C . y ( C H 2 U Et 0 vCX H 0 H 64 F i g . 8: A l t e r n a t i v e Synthesis of 4 - ( 5-Ethoxycarbonyl - - 4-methylpyrrol - 3 -y l ) - i - i o d o b u t a n e 6^ 4 128 30 minutes t i c indicated complete consumption of s t a r t i n g material, the reaction was terminated and the product TJ*_ i s o l a t e d as a red o i l . This crude product was dissolved i n reagent grade acetone, sodium iodide (2.0 equivalents) added and the mixture refluxed and s t i r r e d for 18.5 hours. T i c (10% EtOAS/CR^Cip showed a s i n g l e spot which was believed to be the desired a-free-iodobutyl pyrrole 6j4. The crude product was obtained from the reaction mixture as a brown s o l i d and was p u r i f i e d by column chromatography on 'a s i l i c a gel (BDH 60-120; 200 g) column. The column was eluted f i r s t with dichloromethane and then, since the compound was moving slowly down the column, the p o l a r i t y of the eluant was increased to 10% ethyl acetate/dichloromethane. 'The f i r s t f r a c t i o n s from the column were c o l o r l e s s and were shown to contain a s i n g l e compound. Later f r a c t i o n s however contained two compounds, the desired product 64 and the undesired intramolecular c y c l i z a t i o n product 65. The y i e l d of pure 64_ from the hydroxyhutyl pyrrole 7_3 was. 43% and the impure fractions, gaye a s i m i l a r quantity of the mixture. Obviously, i n t h i s case, intramolecular c y c l i z a t i o n occurred during mesylate formation or during the subsequent S^2 reaction of the mesylate with iodide i n r e f l u x i n g acetone. Since compound j)4 was the branch point for the various porphyrin syntheses i t was important to asc e r t a i n where intramolecular c y c l i z a t i o n was occurring and what steps could be taken to avoid i t . Formation of 66 64 cyclohexyl pyrrole &5_ during the de-iodination of 63_ with hydriodic acid was already noted. However de-iodination of the corresponding acetoxy pyrrole 7_1_ gave no observable amount of 65_. Also intramolecular 64 from the a-free-hydroxybutyl pyrrole 7_3 v i a the mesylate 7_4_. Because mesylate formation was c a r r i e d out at 0°C i t was f e l t that the c y c l o -hexyl pyrrole 65_ was formed during the S^2 reaction when the mesylate was heated i n r e f l u x i n g acetone for long periods. Moreover i t was shown that r e f l u x i n g the a-free-iodobutyl pyrrole 64_ i n acetone i n the presence of sodium iodide for ^70 hours produced only a trace of 65, as indicated by t i c . The phosphonium iodide 94b. was prepared from 64 by ' treatment with, triphenylphosphine i n r e f l u x i n g toluene for 16-24 hours. It was feared that a major part of either the smarting material or the product would be consumed i n the formation of the undesired cyclohexyl pyrrole 65 during the prolonged r e f l u x times. Such a s i t u a t i o n was p o t e n t i a l l y disastrous i . since the phosphonium iodide was a key s t a r t i n g m a terial for two porphyrin syntheses and r e l a t i v e l y large amounts were required. Fortunately the phosphonium s a l t appeared to be quite stable under the conditions of i t s formation; r e f l u x i n g a small sample i n toluene for ^30 hours produced only trace of cyclohexyl pyrrole 65_ as shown by t i c . A small sample of a-free-iodobutyl pyrrole 64_ was s i m i l a r l y refluxed c y c l i z a t i o n occurred during the formation of a-free-iodobutyl pyrrole + 94a n = 5 94b n = /> 130 i n toluene for 24 hours and t i c examination showed only a trace of 65. Reflux was maintained for a further 70 hours during which time most of the toluene evaporated and the reaction mixture was concentrated to ^2 mL. At that stage t i c showed no trace of the s t a r t i n g material 64, but a major spot due to 65_ and a second u n i d e n t i f i e d material with a higher Rf value. SCHEME 70 0 II H 3 Cv . (CHAOSCH 3 iri 0 EtO> 74 NaT H3Cv AC\ (CH3)2C=0 E t r > A 5 H 64 (CH 2)J + H,C EtO 0 H 65 (41) H3Cv ,(CH2)J BOV^ AH 0 t 64 Nal HoC A/(CH 3) 2C=0 EtO or A/ C 7 H 8 0 II \ N H 65 Trace (42) H3Cy_,(CHAPPh 3r A / C 7 H 8 0 H 94 b H 3 CK3 E t O ^ N ^ 0 H 65 Trace (43) These observations may be r a t i o n a l i z e d i n terms of the leaving a b i l i t y of the group at.the chain's terminus, and the number and po s i t i o n of electron-donating and electron-withdrawing groups on the pyrrole nucleus. Thus, i n the de-iodination of 63, the 2-iodo group renders the pyrrole r i n g s u f f i c i e n t l y electron rich, to undertake displacement of the iodide group at the chain's terminus.,leading to an 1 3 1 SCHEME 7 1 H 3Cx_ylCH 2lI H 3C./(CH 2) 4I H3Cx/(CH2>4I EtoV^Xi " E t ov^Ai H " E tOvO\ H 0 H 0 H 0 H 63 H 3 C J C H ^ I H 3 C \ _ / — \ BOY^ XH ° (CH 3 ) 2 C=O ' E»OV(AH + ET0V^^ 74 A ° 64 m Q J 9 r ° 65 m i n ° r H 3 C ^ , ( C H 2 U N Q I / A H 3 C ^ _ / ( C H 2 ) J ^ z y Y - \ E t O N ^ N A H ( C H 3 ) 2 C = O ' E t O v ^ A N A H + Et0 -y<|3 ' 0 H or C 7 H 8 0 H 0 H T r a c e 64 7 8 64 m a J ° r 65 H 3 C \ _ / I C H 2 V P P h 3 l " H 3 C N , ( C H 2 ) 4 P P h 3 I ~ H 3 C , EtOyCXn C 7 H e / A ' E t 0 V Q \ H + E t 0 v O 94b ONLY 62 65 ( 4 4 ) (45) E t O v ^ N X j E t O N^AwXy EtO 0 H 0 *" 63 6_5 HjCv^JCHjliOCCHa H3Cv_/(CH2)4OCCH3 0 H 0 H 71 72 9: H 3C N.(CH 2) tOSCH 3 H,C^/(CH 2)J H 3C V ( 4 7 ) (48) (49) H 3 C W < C H 2 U N q H C q A / H 3 C W - A ET0V<JJSH " E T 0 V ^ N > - ^ ( 5 0 ) 0 H 2 ' x 0 H ONI 132 intermediate cyclohexyl-pyrrolonium ion which collapses to the cyclohexyl pyrrole 65_ (Scheme 71, equation 45). However, displacement of the poorer leaving acetate group does not occur and de-iodination occurs without formation of fr5 (equation 46). In the case of the a-free butylpyrroles the n u c l e o p h i l i c behaviour of the pyrrole r i n g i s considerably lessened and the q u a l i t a t i v e r e s u l t s may be explained by considering the leaving a b i l i t y of the terminal group. Thus a small but s i g n i f i c a n t amount of the cyclohexyl pyrrole <65 i s formed on r e f l u x i n g the mesylate 6^ i n acetone with, sodium iodide. However extended r e f l u x of iodobutyl pyrrole 6>4_ under the same conditions produces only a trace of 65_ as; shown by t i c (equation 48). S i m i l a r l y iodobutyl pyrrole 64 or the phosphonium iodide 9.4b i n r e f l u x i n g toluene produce only traces of 65. Although, one would expect the phosphonium s a l t to be a good leaving group, s t e r i c hindrance by the bulky phenyl groups probably prevents n u c l e o p h i l i c attack by the pyrrole r i n g . Introduction of electron withdrawing groups decreases the nucleo-p h i l i c i t y of the p y r r o l e . Therefore no intramolecular c y c l i z a t i o n was observed in the decarboxylation of 2-carboxy pyrrole 62^  (equation 50). These observations are analogous to the r e s u l t s reported by Smith. 169 et a l . , who showed that the transformation of c e r t a i n 2-hydroxyethyl pyrroles into the corresponding 2-haloethyl pyrroles proceeded with, scrambling of the two carbons i n the side-chain (Scheme 72). A mechanism was suggested involving neighbouring group p a r t i c i p a t i o n by the e l e c t r o n - r i c h p yrrole nucleus to give an ethylenepyrrolonium ion, the course of the reactions depending on the leaving a b i l i t y of the group at the chain's terminus and the s u b s t i t u t i o n pattern on the. 133 SCHEME 72 (51) R = CH3 R = H X = Br.CI D D.OH H3C\—^~ Ac;0/C5H5N PhCHzON^NAf-o or 0 H ^ 3 CH3S02CI/ C5H5N P OR R = Ac R = S O J C H J (53) (54) 134 pyrrole r i n g . Contamination of the desired a-free-iodobutyl pyrrole 64_ with cyclohexyl pyrrole 65_ was a major problem. In a l l the solvent systems tested the two compounds had s i m i l a r Rf values so that complete chromato-graphic separation was not possible. Separation of the two compounds by c r y s t a l l i z a t i o n was not attempted since there was no obvious difference i n t h e i r s o l u b i l i t i e s . Indeed, i t was more convenient to carry the crude a-free-iodobutyl pyrrole 6j4 to the next stage, formation of either the phosphonium iodide 9,4b or the b l s ( p y r r o l - 3 - y l ) b u t y l s u l f i d e 75b. At this stage the unwanted cyclohexyl pyrrole 65_ was e a s i l y separated from the desired products. 64 65 + 94b 75b 135 2.3. SYNTHESIS OF PORPHYRINS CONTAINING A THIOETHER STRAP With the a v a i l a b i l i t y of the key intermediates 4_4 and 64, the thioether strapped porphyrins 87a and 87b are conveniently produced i n several steps (Fig.9) . ^Dimerization of 44 or 64.produces the chain-linked b i s - p y r r o l e 75_ which incorporates not only the strap and rings A and C of the porphyrin, but also two a-free positions to which the eventual pyrrole rings B and D of the porphyrin may be attached. Therefore with 76 and 44 (or 64) i n hand, a l l the units necessary for porphyrin construction are a v a i l a b l e . Refluxing the a-free-iodopentyl pyrrole 44_ with, sodium s u l f i d e (1.5-^2.0 equivalents) i n aqueous tetrahydrof uran (THF/^O 100 :4Q) f o r 14-28 hours gave the bis (lpyrr o l - 3 - y l ) p e n t y l s u l f i d e 75a i n high y i e l d . In the i n i t i a l experiments ^4 was inadvertantly<contaminated with the corresponding chloropentyl pyrrole which did not react with the sodium s u l f i d e . In those cases the tetrahydrofuran was removed and the crude product i s o l a t e d by extraction with, ethyl acetate. The unreacted chloropentyl pyrrole 36_ was e a s i l y removed by column chromatography and the desired product was obtained as a white s o l i d (72-89%). When pure s t a r t i n g material was used the chromatographic p u r i f i c a t i o n was, unnecessary. Removal of the tetrahydrofuran led to the separation of a yellow o i l which was redissolved by addi t i o n of acetone. Addition of 75a 3 6 136 88a n= 5 b n= U F i g . 9_; Synthesis of Porphyrins: Containing a Sulfide Strap 137 water p r e c i p i t a t e d a white s o l i d which was c o l l e c t e d and dried (81-97%). Although the thioether 75a was formed under basic conditions, s a p o n i f i -cation of the pyrrole ethyl esters was not observed. However i t had been previously demonstrated that the conditions of t h i s reaction were s u f f i c i e n t to hydrolyze a dicyanovinyl protecting group, and therefore the thioether chain was set i n place before formation of the dipyrro-methane 77a. Unsymmetric dipyrromethanes may be prepared by the reaction of an a-free pyrrole 80 with a p y r r y l c a r b i n y l cation 7_9_ which may be derived from a v a r i e t y of precursors _78_ (Scheme 73). Procedures using bromo-78 80 X = Br, Cl. 0CH3, OAc, etc. B C B C 76 NC CN 82 CN 138 methyl-, chloromethyl-, and acetoxymethyl pyrroles under a v a r i e t y of conditions and solvents have already been published. Wijesekera,'''''7 using the a-free pyrrole 81_ and the chloromethyl-dicyanovinyl pyrrole 76 as a model system, had evaluated these procedures and had found that the y i e l d s were low (<46%) and/or the products required chromato-graphic p u r i f i c a t i o n . On the other hand he found that simply heating 81 and 7_6 i n g l a c i a l a c e t i c acid at 70°C for 20 minutes under nitrogen produced the required dipyrromethane 82_ i n high y i e l d (>87%) . The product was recovered from the re a c t i o n mixture by c r y s t a l l i z a t i o n a f t e r concentration and addition of methanol. Tic indicated that only a sin g l e dipyrromethane had been formed; no rearrangement products were observed. The bis-dipyrromethane 77a was prepared by Wijesekera's method. The b i s ( p y r r o l - 3 - y l ) p e n t y l s u l f i d e 75a and the a-chloromethyl pyrrole 76 b n = 4 (2.05 equivalents) were suspended i n g l a c i a l a c e t i c a c i d (5 mL)_ and heated at 70°C under nitrogen. After 10-20 minutes a l l the solids, dissolved to give a deep red s o l u t i o n . The solution was cooled, methanol (15-25 mL) added and the mixture stored i n the freezer overnight. The orange-red s o l i d which, p r e c i p i t a t e d was c o l l e c t e d and dried (.81-84%) . T i c exhibited a s i n g l e major yellow spot which, turned purple when the. 139 plate was exposed to bromine vapour. (This test i s diagnostic f o r dipyrromethanes on t i c plates as exposure to bromine oxidizes any dipyrromethane spots to the more highly coloured dipyrromethene). The crude product was also contaminated with small amounts of u n i d e n t i f i e d pyrrole compounds but there was no sign of any unreacted 75a. In an a l t e r n a t i v e work-up procedure the cooled reaction mixture was poured into aqueous sodium bicarbonate to n e u t r a l i z e the ac e t i c a c i d . The orange s o l i d which, p r e c i p i t a t e d was f i l t e r e d , washed with, water and dried. R e c r y s t a l l i z a t i o n from dichloromethane/methanol gave an orange/ red s o l i d (.74%). As before t i c of t h i s product showed a sing l e major spot due to the dipyrromethane 77a with smaller amounts of pyrrole contaminants. The chain-linked bis-dipyrromethane 77a contained a l l the features necessary f o r the synthesis of the strapped porphyrin (Fig. 9). Since compounds 83a and 84a were neither i s o l a t e d nor characterized, compound 77a was the d i r e c t precursor for the strapped porphyrin 87a. Hydrolysis under strongly basic conditions to remove the dicyanovinyl protecting group and saponify the ester, followed by thermal decarboxyla-t i o n yielded the a-free,a'—formyl bis-dipyrromethane 84a. This was then c y c l i z e d using an acid c a t a l y s t , the c y c l i z a t i o n being c a r r i e d out under conditions of high, d i l u t i o n to encourage intramolecular rather than intermolecular c y c l i z a t i o n and to minimize the formation of polymeric by-products. Esters at the 2-pyrrole p o s i t i o n are more d i f f i c u l t to hydrolyze than the corresponding a l i p h a t i c esters. This was exemplified i n the. formation of the b i s ( p y r r o l - 3 - y l ) p e r i t y l . s u l f i d e 75a where the ester groups survived i n t a c t the basic conditions of the reaction. However i n the 140 aliphatic analogue 85_ reaction under the same conditions led to complete SCHEME % Et OEt H 3 C X / ( C H ^ I H 3 C N / ( C H 2 - ) 5 S ( C H 2 ) 5 N X H 3 W Na 2 S-9H 2 0 W W 0 V < N A H H 2 0 / T H F " E t 0 V ^ N ^ H H A N " V 0 H A o H n 0 44 7 5 a (55) E t0 2 C (CH 2 ) 5 B r N a 2 S - 9 H 2 0 ^ H 0 2 C ( C H 2 ) 5 S ( C H 2 ) 5 C 0 2 H (56) H 2 0 / T H F 85 A, 86 saponification. Moreover i t had already been demonstrated that the hydrolysis of the 2-ester group of dipyrromethanes was sluggish, in aqueous ethanol.^ 7 To ensure complete saponification extended refluxing was required providing the opportunity for decarboxylation and material-consuming side reactions to occur. In an attempt to decrease the length, of reaction by increasing the reaction temperature. but at the same time retain some miscib.ility, the ethanol was, replaced by the higher boiling n-propanol. It was then found that deprotection and saponification of a-ester,a'-dicyanovinyl dipyrromethanes was complete in ^3 hours and no major side reactions occurred. The protected dipyrromethane 77a was stirred in n-propanol (50 mL) 7 7 q R = C 0 2 E t , R* = C H = ( C N ) 2 8 3 a R = C 0 2 H , R ' = C H O 8 4 a R = H , R J = C H O 141 and a s o l u t i o n of potassium hydroxide (14 g, M60 equivalents) i n water (100 mL) was added. The reaction was s t i r r e d and refluxed under argon, the course of the r e a c t i o n being monitored by UV/visible spectroscopy. A spectrum of the s t a r t i n g dipyrromethane i n methanol showed two major bands at 406.0 and 276.8 nm with, a shoulder at 250 nm. The band at 406.0 nm was believed to be due to the pyrrole ring containing the dicyanovinyl. group while the band at 276.8 nm was due to the pyrrole ester group. As the reaction proceeded the band at 40.6.0. nm decreased i n i n t e n s i t y and a new band grew i n at 316.8 nm, due to the pyrrole aldehyde; the band at 276.8 nm moved to 268.4 nm. T y p i c a l l y , a f t e r 3 hours, r e f l u x no further s p e c t r a l change was observed and the reaction was; deemed complete. The n-propanol was boiled o f f and the. r e a c t i o n mixture cooled down. At t h i s stage a brown o i l y s o l i d p r e c i p i t a t e d from s o l u t i o n , presumably the potassium s a l t of the a-carhoxy di p y r r o -methane 83a. For smaller scale reactions this, s o l i d could be redissolved by addition of more water. However for larger scale reactions, the most convenient procedure was as follows:. The cooled reaction mixture containing the p r e c i p i t a t e d s o l i d was f i l t e r e d and the brown s o l i d which, was retained on the f i l t e r paper was washed with, copious: amounts of water u n t i l i t a l l redissolved. T y p i c a l l y , by t h i s stage the volume of s o l u t i o n was V500 mL. A c i d i f i c a t i o n with, g l a c i a l a c e t i c a c i d (15 mL) formed the a-carboxy,a'-formyl bis-dipyrromethane 83a which, separated from s o l u t i o n as a brown gelatinous s o l i d . This was c o l l e c t e d by f i l t r a t i o n and dried overnight i n vacuo. The crude product was neither characterized nor p u r i f i e d but c a r r i e d on to the penultimate step -thermal decarboxylation of the a-carboxy group. Thermal decarboxylation was c a r r i e d out by r e f l u x i n g the -142 a-carboxy,a'-formyl dipyrromethane 83a in N,N-dimethylformamide under argon for 3 hours. Since the product 84a undergoes indiscriminate acid catalyzed reaction, care must be exercised to ensure that the product does not come into contact with acid before the high dilution intra-molecular cyclization step. Therefore only spectral grade DMF should be used for the decarboxylation reaction. In one instance reagent grade DMF was used, leading to premature cyclization due to traces of formic acid in the solvent; after work-up no strapped porphyrin was obtained-. Furthermore, a l l glassware used in the decarboxylation should be given an a l k a l i rinse. The course of the reaction may be monitored by UV spectroscopy although i t was found that the reaction was complete after 3 hours reflux. The spectrum of the starting material 83a in dichloromethane exhibited two bands at 320.0 and 280.0. nm due to the pyrrole aldehyde and pyrrole carboxylic acid respectively. During the course of the decarboxylation the band at 280.0. nm steadily declined and the band at 320.0 nm moved slightly to the blue. The spectrum of the product showed a single major band at 312.0. nm and a shoulder at 272.8 nm. The reaction mixture was then cooled down under argon and the DMF was removed using a rotary evaporator attached to a vacuum pump (bath, temperature 50°C). a-Free,a'-formyl dipyrromethanes are known to be unstable so the compound was not evaporated to dryness:. When almost a l l the DMF was removed the residue was immediately dissolved in dichloromethane. This solution was extracted with, water to remove the remaining DMF, then dried over anhydrous sodium sulfate, f i l t e r e d and diluted with dichloromethane to a predetermined volume depending on the scale of reaction. 143 7.7a R C 0 2 E t , R ' C 0 2 H , R ' H . R' C H = ( C N ) 2 C H O ( C H 2 ) 5 83a R C H 3 84a R C H O R R ' The whole strategy of the strapped porphyrin synthesis depended on delaying the formation of the porphyrin r i n g u n t i l the l a s t step. Having assembled a l l the necessary subunits i n the precursor b i s - d i p y r r o -methane 77_a_ the success of t h i s scheme depended on three fa c t o r s : ( i ) Clean and complete removal of the ester and dicyanovinyl protecting groups. Even i f only a small percentage of the product 83a contained an unhydrolyzed a-group, such, blocked molecules would react with v i a b l e molecules to form large amounts of polymeric products and decrease the y i e l d . ( i i ) Clean and complete decarboxylation of 83a to 84a. Furthermore 84a required protection from exposure to acid otherwise i n t e r -molecular c y c l i z a t i o n would occur. ( i i i ) The acid-catalyzed reaction of 84a had to be performed i n a manner that promoted intramolecular 2 + 2 c y c l i z a t i o n . If only one of the four r e a c t i v e a-positions reacted i n an intermolecular fashion r i n g closure to the strapped porphyrin would be impossible and polymeric materials would r e s u l t . Clearly i t was necessary to e f f e c t the f i n a l c y c l i z a t i o n to the strapped porphyrin under conditions of high, d i l u t i o n . T y p i c a l l y the reactions were carried out on a 1.2 - 17.0 x 10 mole scale. After decarboxylation the solution of the crude a-free,a'-formyl bis-dipyrro-methane 84a in dichloromethane was diluted to 250 mL for reactions on -4 -3 a l . 2 - 8 . O x 10 mole scale, and to 500 mL for 1.0 - 1.7 x 10 mole reactions. The solution was loaded into 4 gas-tight syringes each. capable of holding 50-60 mL. The contents of the syringes were then injected into four Erlenmeyer flasks each containing a solution of p-toluenesulfonic acid (4 g) in methanol (25 mL) and dichloromethane (.600 mL) To ensure constant slow addition a syringe pump was used to empty the syringes. At i t s slowest speed the pump emptied the syringes over a period of approximately twelve hours, the contents of the syringes being delivered to each, reaction flask by means of tygon tubing inserted into a capillary tube which was held just above the surface of the liquid in the flask. The contents of the syringes were therefore added drop-wise rather than in a continuous fashion. If the tip of the capillary was placed below the surface of the liquid in the flask i t generally became blocked, leading to spillage. The degree of dilution was determined by the concentration of acid in the flask, the concentration of 84a in the syringe, the speed of the syringe pump and the diameter of the capillary tube. With the exception of the latter the other factors were maintained constant. Generally addition was complete and the reaction work-up carried out within a 48 hour period. To isolate the product the contents of the reaction flasks were concentrated, then washed with, sodium bicarbonate to neutralize the acid and convert the protonated porphyrins to their free base forms:. This was accompanied by a change in the colour of the solution from deep red—purple to a brown-red colour. The organic layer was separated, 145 dried and then evaporated to dryness to obtain the crude product. Chromatographic purification was attempted using a variety of types and activities of s i l i c a gel and alumina. The following procedure was found to be the most convenient. The crude product was placed on a Merck Kieselgel 60 s i l i c a , gel column (75-150 g) and eluted with 1% methanol-dichloromethane as solvent. Several small pink bands, due to metallo-porphyrin and other unidentified material ran ahead of the main bulk of material and were discarded. The porphyrin eluted from the column as a broad dark band and was collected in fractions of ^150 mL. After most of the material had been eluted the polarity of the solvent was increased to 2% methanol-dichloromethane to move any more porphyrin which might be adhering to the column. The fractions were then examined by t i c and the i n i t i a l and later fractions were found to contain large amounts of brown material. (Interestingly the later fractions were also found to contain two major porphyrin bands). This impure porphyrin was crudely purified by means of preparative t i c (.2% MeOH/CR^Cl^) and com-bined with, the bulk of the product. This was then placed on a-column of Merck neutral alumina 90 (activity III, 40-50 g) and eluted with dichloromethane. The porphyrin moved quickly down the column, any brown material being adsorbed at the top of the column. As mentioned above the porphyrin separated into two bands; a fast running major band followed by a minor band. By adjusting the flow rate of the column and the size of the fractions i t was possible to separate the two bands, with, minimal overlap. The front running major band was due to the deaired thioether strapped porphyrin 87a as shown by mass spectrometry (m/e 592). The mass spectrum of the slower moving minor compound displayed a parent 146 0 I! 87a 88a peak at 608 i n d i c a t i n g that i t was due to a strapped porphyrin i n which, the s u l f i d e had been oxidized to a sulfoxide. This was confirmed by high r e s o l u t i o n mass spectrometry, elemental a n a l y s i s , and '''H and 13 C-NMR. The combined y i e l d of 87a and 88a, that i s the t o t a l c y c l i z a t i o n y i e l d , was 9.5 - 19.5%, based on precursor 77a. The lower homologue 87b was prepared i n exactly the same mariner. The bis (pyrrole.-3-yl)butyl s u l f i d e 75b was obtained from the a-free iodo-butyl pyrrole 64 by r e f l u x i n g with sodium s u l f i d e i n aqueous.THF. In most cases a y i e l d could not be determined because 75b. was contamina-ted with either the cyclohexyl pyrrole 65_ or the butyl pyrrole 66. Fortunately these impurities were e a s i l y separated from the required product. In one instance, where pure 64 was used the product was obtained from the reaction mixture as a s l i g h t l y pink s o l i d (.94.4% crude). The bis-dipyrromethane 77b was prepared as before by heating 66 75b 65 147 75b with 76 (2.1 equivalents) in glacial acetic acid at 80-90°C for 1 hour. After work-up 77b was obtained as an orange solid (82-92% crude). Again t i c displayed a single major yellow spot which turned purple on exposure to bromine vapour. The deprotection-decarboxylation-cyclization sequence was carried out exactly as described above. Cyclization was carried out under the same conditions and similar concentrations to those used for 87a. After work-up t i c of the crude product showed two major purple spots and a faster running green spot. The crude product was placed on a column (75-100 g) and eluted with. 2% methanol/dichloromethane. As usual faint bands due to metalloporphyrins and otTier compounds came off the column f i r s t and were discarded. These were followed by a green band and then f i n a l l y by the strapped porphyrin. A visible spectrum of the green material gave an unrecognizable spectrum totally unlike that of an etio-type porphyrin. Fractions containing hoth. green material and strapped porphyrins were stirred in a i r overnight whereupon t i c indicated complete disappearance of the green material. Similarly, when fractions containing only the unknown green material were stirred in air for 48 hours t i c showed the presence of strapped porphyrin. Attempts to isolate and purify this green material by preparative t i c failed, only porphyrin and other blue, purple and brown bands appearing on the plate. The partially purified product was placed on a column of Merck neutral alumina 90 (activity III) and eluted with, dichloromethane. The f i r s t material from the column was an unidentified blue compound, followed by the thioether strapped porphyrin 87b and the corresponding sulfoxide porphyrin 88b; a l l the brown impurities remained at the head of the column. 148 0 87 b ^ Although, no hard evidence was: obtained we can speculate as to the identity of the transient green material obtained from the column. The intramolecular cyclization.reaction proceeds via a b-bilene 89 to a porphodimethene 9Q_ (Fig. 10). Generally such, compounds undergo facile oxidation by air to yield the corresponding porphyrin. However i t is. conceivable that, i f the strap was very short, the molecule might be locked into a conformation where oxidation to the planar porphyrin would be more d i f f i c u l t . Wijesekera, in his preparation of the equally strained porphyrin 9J_ bearing a 9-carb.on chain did not report the occurrence of a possible porphodimethene intermediate. In his purifica-tion procedure the crude porphyrin was placed in a s i l i c a gel column (Woehlm, activity I) for several hours, a situation which, might be expected to enhance oxidation of a porphodimethene to the porphyrin. In our case purification was accomplished by flash chromatography and the crude product was on the column for less, than 30. minutes. However in the absence of more evidence the discussion remains merely speculative. The synthesis of the 8-carb.on thioether strapped porphyrin was attempted three times and the total cyclization yield (i.e. yield of Fig, 10: Synthesis of Sulfide-Strapped Porphyrin 87b Intramolecular Cyclization 150 thioether 87b and sulfoxide 88b) was 12.0, 18.6 and 21.6%. Unexpectedly the y i e l d s were s i m i l a r to those obtained for the corresponding homologues 87a and 88a (9.0 - 19.5%). These y i e l d s were disappointingly low when compared to syntheses of si m i l a r porphyrins containing only a methylene strap (9_2 u 22-52%, _91 : 20-25%). Obviously the pu r i t y of the precursor bis-dipyrromethanes 77a and 77b must be suspected since most c y c l i z a t i o n s were performed using crude samples. However, the samples would have to be grossly contaminated to bring about the 50% decrease i n y i e l d f or 87a. The fact that some sulfoxide was produced may hint that other reactions besides decarboxylation and hydrolysis are occurring p r i o r to the intramolecular c y c l i z a t i o n . Other reactions, such as breaking of the thioether chain, would s e r i o u s l y reduce the y i e l d . Wijesekera's work set the l i m i t on the length, of a methylene chain strapping a porphyrin (91, y i e l d 20-25%). The fact that both 87a and 87b are produced i n s i m i l a r y i e l d s (9-20% and 12-22% respectively) may set the l i m i t for the more f r a g i l e thioether chain, i r r e s p e c t i v e of i t s length.. It would be i n t e r e s t i n g to determine at what stages i n F i g . 9, decomposition and/or oxidation of the s u l f i d e linkage could occur. 165 Unlike ethers, s u l f i d e s are r e a d i l y r e a c t i v e . Various a l i p h a t i c s u l f u r compounds can be decomposed to o l e f i n s at 55°C i n a KOBu-t/DMSO s (CH2)n 77a n = 5 b n = 4 CN 151 medium. Thus Wallace et a l . , observed that aryl. alkyl sulfides and sulfoxides undergo base-catalyzed 1,3-rearrangements and subsequent 3-eliminations to stilbene derivatives in dipolar solvents (Scheme 75, 167 equation 57). However, while Fenton and Ingold have shown that olefin SCHEME 7 5 (57) (58) production from simple aliphatic sulfones in the presence of KOH requires a reaction temperature of 200°C or higher, aliphatic sulfoxides and sulfides are not decomposed by KOH under these conditions. In contrast, 168 Wallace et a l . , . have reported that some aliphatic sulfur compounds may be decomposed to olefins in the presence of KOH. at 80°C in hexa-methylphosphoramide after extended heating (Scheme 75, equation 58). Therefore formation of the sulfide 75_ and formation of the his-dipyrro-methane 77_ employ conditions unlikely to lead to decomposition. Similarly the sulfide bond should be stable under conditions used for hydrolysis of 77_ i.e.,KOH in aqueous propanol at 80°C for 3-4 hours. However thermal decarboxylation of 8_3_ uses more drastic conditions, refluxing N,N-dimethylformamide. The cleavage of the C-S bond of 152 169 sulfides is known to occur in thermal reactions, but in general the temperature required is quite high. Thus ethyl sulfide decomposes at 83 o. n = 5 c q R,__ c H Q b n = U 2 84 a n = 5 b n = U R = H , R ' C H O 400°C, and, after 2 hours in kerosene at 23Q°C in the presence of molybdenum sulfide, the decomposition of propyl sulfide was 26%. However the extent of decomposition after 4 hours in N,N-dimethylformamide at 153°C cannot be ascertained without isolation of the unstable a-free, a'-formyl bis-dipyrromethane 84. Many methods are available for the oxidation of sulfides to sulfoxides ^9,170 industrially sulfoxides are prepared by the direct air oxidation of sulfides catalyzed by nitrogen dioxide."''7"'' However samples of 75_ and 77_ which, had been in contact with air for several months showed no evidence for sulfoxide formation. Indeed "''H-NMR and mass spectral analysis seem to indicate that no appreciable amount of sulfoxide i s produced prior to hydrolysis of the bis-dipyrromethanes 77, and i t i s unlikely that sulfoxide formation occurs during the hydrolysis step. Although, the thermal decarboxylation of 83_ is carried out under argon the high temperatures of the reaction may enable the sulfide to react with traces of oxygen present, or to abstract oxygen from the solvent (Scheme 76, equation 59.).. The latter would he analogous to the reported oxidation of organic sulfides in dimethyl 153 sulfoxide at 160-172°C (equation 60). SCHEME 76 V s + R / 0 II H N - C H 3 I C H , R R V i S=0 + N(CHo) 3'3 (59) R CH 3 0=S \ CH, R x C H 3 S=0 + S R 7 X C H 3 (60) A more a t t r a c t i v e proposition i s that oxidation of the s u l f i d e to the sulfoxide does not occur u n t i l a f t e r formation of the porphyrin r i n g . Since most free hase porphyrins are good sensitizers: of s i n g l e t oxygen i t i s l i k e l y that the sulfoxides 88_ are produced by the photo-173 oxidation of 87. Schenck and Krauch f i r s t reported that d i a l k y l s u l f i d e s undergo se n s i t i z e d photooxidation to give 2 mol of s u l f o x i d e 174 per mol of absorbed oxygen. Recently, Foote et a l . , have i n v e s t i -gated the s i n g l e t oxygen oxidation of d i e t h y l s u l f i d e i n various solvents (methanol, benzene, and a c e t o n i t r i l e ) , zinc tetraphenylporphyrin and free base tetraphenylporphyrin being used as s e n s i t i z e r s i n the benzene s o l u t i o n . Sulfide photooxygenation i s of p a r t i c u l a r i n t e r e s t because methionine i s one of the amino acids attacked most r a p i d l y i n photodynamic action (i.e., the destructive action of dye sensitizers,, l i g h t and oxygen on organisms) and the photosensitized deactivation of several enzymes e.g..,chyjnotrypsin, has been correlated with the 176 photooxidation of methionine to the corresponding sulfoxide. As 87 was s y n t h e s i z e d t o model t h e b i n d i n g o f m e t h i o n i n e t o t h e heme of cytochrome e t h i s o x i d a t i o n was o f p a s s i n g i n t e r e s t . 87 Q n = 5 88a n = 5 b n = 4 b n = 4 J o r i e t a l . , " ' ' 7 7 have c a r r i e d out a k i n e t i c i n v e s t i g a t i o n of the p h o t o o x i d a t i o n o f m e t h i o n i n e by i r r a d i a t i o n i n t h e p r e s e n c e o f a s e r i e s of p o r p h y r i n s . C o n v e r s i o n t o t h e s u l f o x i d e was observed t o he q u a n t i t a t i v e and a r e a c t i o n mechanism i n v o l v i n g s i n g l e t oxygen was proposed. W h i t t e n and co-workers have s t u d i e d t h e p h o t o o x i d a t i o n o f p r o t o p o r p h y r i n IX, bo t h i n s o l u t i o n and i n o r g a n i z e d media.178,179 The p o r p h y r i n a c t i v a t e d oxygen m a i n l y by p r o d u c t i o n of s i n g l e t oxygen. While t h e p o r p h y r i n can r e a c t w i t h the s i n g l e t oxygen t o g i v e e i t h e r n e t quenching or p h o t o o x i d a t i o n p r o d u c t s , t h e r e a c t i v i t y i s low, so t h a t p r o t o p o r p h y r i n IX can f u n c t i o n as a good s e n s i t i z e r f o r t h e photo-179 o x i d a t i o n of o t h e r p o t e n t i a l s u b s t r a t e s . I t was a l s o observed t h a t t h e p h o t o o x i d a t i o n of p r o t o p o r p h y r i n IX i n n a t u r a l membrane systems y i e l d e d p r o d u c t s ^ which d i d not i n c l u d e the " u s u a l " s i n g l e t oxygen 180 p r o d u c t s . W h i t t e n and K r i e g m o d e l l e d t h e k i n e t i c b e h a v i o u r observed i n the n a t u r a l membrane systems by u s i n g an o i l / w a t e r m i c r o e m u l s i o n as a s o l v e n t and addi n g v a r i o u s amino a c i d s . The r e s u l t s of t h i s study suggested t h a t p o r p h y r i n s s e n s i t i z e s i n g l e t oxygen e f f i c i e n t l y but t h a t t h e s i n g l e t oxygen i s r a p i d l y 155 scavenged by substrates such as methionine and other amino acids. The oxygenated amino acids then act as agents to oxidize the porphyrins by attacking the porphyrin r i n g d i r e c t l y . To demonstrate that the sulfoxide strap porphyrin 88a i s formed by the photooxidation of 87a the following very crude experiment was ca r r i e d out. Two solutions containing 87a i n dichloromethane were prepared and placed i n stoppered v i a l s (10 mL). One so l u t i o n was kept i n the dark while the other was subjected to laboratory l i g h t . A f t e r 3 days the illuminated sample was examined by t i c (.2% MeOH/CH^Cl^) . It showed no trace of the s u l f i d e strap porphyrin 87a, only a spot due to sulfoxide 88a and a large spot at the o r i g i n , presumably due to decomposition products. The sample kept i n the dark showed only a spot due to s u l f i d e 87a with no trace of sulfoxide 88a or decomposition. A further three equimolar solutions of s u l f i d e strap porphyrin 87a i n dichloromethane were prepared and stored i n stoppered v i a l s . One was stored i n the dark, another was subjected to laboratory l i g h t i n g as before and the t h i r d had some diazabicyclooctane (.DABCO) added and subjected to laboratory l i g h t i n g . A f t e r 12 hours the dark sample showed no change on t i c . The illuminated sample containing only porphyrin showed no trace of the s u l f i d e 87a, only sulfoxide 88a and decomposition. The illuminated sample containing DABCO showed no trace of sulfoxide 88a formation. This i s consistent with, the known a b i l i t y of DABCO to act as a "quenching" agent i.e.^ i t destroys s i n g l e t oxygen and the molecular excited states leading to s i n g l e t oxygen formation. The above crude experiments suggest that the porphyrin ring acts as a s e n s i t i z e r to produce s i n g l e t oxygen which can then oxidize the. 156 hv (CH2)„ (CH 2)„ 1 NH HN 1 8 7 a (C.H2>n (CH2)„ + 3 0 2 • NH HN 1 (CH 2)„ (CH2)„ + 1 0 2 NH HN-0" (CH 2) n (CH,), 2'n -NH HN-(CH 2)„ • 3 0 , NH HN-(CH2>„ (CH2)„ ' NH HN ' 0 II •s (CH,), 2'n <CH2)„ 2 (CH2)„ (CH -NH HN-2'n -NH HN-88a Fig. 1 1 : Proposed Mechanism of Sulfoxide-Strapped Porphyrin 8 8 a Formation 157 s u l f i d e strap to the corresponding s u l f o x i d e . F i g . 11, i s i n analogy to the mechanism of photooxidation of d i e t h y l s u l f i d e proposed by 174 Foote et a l . No s i g n i f i c a n c e can be attached to the observation that more sulfoxide appears to be produced during the formation of 87b than during the formation of the longer chain 87a (Table I I ) . The length and l e v e l s of i l l u m i n a t i o n varied considerably during work-up. Sulfoxides can be oxidized to sulfones but with a f a r lower rate compared to that of s u l f i d e s to sulfoxides."' 7 3'"' 7^ No observable amount of the sulfones 93a and 93b was formed during porphyrin prepara-t i o n and p u r i f i c a t i o n . 0 ,0 ^ / < C H2>n— S — ( C H 2 ) n 93a n= 5 b n= 4* While formation of the sulfoxide porphyrins 88a, 88b complicated somewhat the p u r i f i c a t i o n of the s u l f i d e porphyrins 87a_, c8Sb_ the problem was not a major one since many methods are known for reducing sulfoxides to s u l f i d e s . As we had already used o x a l y l chloride/dimethyl sulfoxide for the oxidation of alcohols to aldehydes (cf. Section 2.4), a sense of symmetry prompted us to use an o x a l y l chloride/sodium iodide system to 181 e f f e c t the sulfoxide deoxygenation. The reaction of sulfoxides with, o x a l y l chloride occurs to give intermediate VII which, can undergo 158 TABLE I I : Yie l d s of the Sulfide-Strapped Porphyrins 87a, 87b and the Sulfoxide-Strapped Porphyrins 88a, 88b % YIELDS RUN 87a 88a 87b 88b % 88a/87a % 88b/87b 1 9.5 0.8 8.4 2 14.2 0.9 6.3 3 18.7 0.8 4.3 4 8.8 0.7 8.0 5 13.0 2.6 20.0 6 10.1 1.9 18.8 7 17.5 4.6 26.3 8 16.5 2.1 12.7 159 elimination to give chlorinated sulfide, VIII. The presence of sodium iodide prevents c h l o r i n a t i o n by trapping intermediate VII before elimination occurs or by reducing any chlorine as soon as i t i s formed (Scheme 77). SCHEME 7 7 o RCH 2 SCH 2 R + (COCl) 2 Cl I RCH 2SCH 2R + I Cl I RCHSCH 2R 0 0 IIII OCCCl I RCH 2 SCH 2 R + 1 E E o o I I OCCCl I RCHoSCHLR I I RCH 2 SCH 2 R Oxalyl chloride was added dropwise to a s o l u t i o n of the sulfoxide 88a and sodium iodide i n cold a c e t o n i t r i l e . There was an immediate evolution of gas and l i b e r a t i o n of iodine following which the s o l u t i o n was s t i r r e d for a further . 20 minutes. After quenching with aqueous sodium t h i o s u l f a t e and work-up the r e s u l t s were v a r i a b l e . In some instances t i c indicated complete reduction to the s u l f i d e 87a. However 160 in other cases some sulfoxide 88a s t i l l persisted. It was not establish-ed whether this was due to incomplete reduction or to re-oxidation of the sulfide 87a on exposure to light during chromatography. Neverthe-less an alternative reduction method was sought. Because of i t s v e r s a t i l i t y , the use of iodotrimethylsilane was considered. This reagent was attractive since i t could be used not only for sulfoxide deoxygenation but also for the demethylation of 182 alkyl aryl ethers (cf Section 2.4). Since iodotrimethylsilane is a relatively expensive commercial reagent and is subject to decomposition on standing, several methods for i t s in situ generation have been developed. The use of methyltrichlorosilane/sodium iodide as an iodo-183 trimethylsilane equivalent has been described by Olah. Addition of trichloromethylsilane to an acetonitrile solution of anhydrous sodium iodide gives a yellow solution with, precipitation of sodium chloride and formation of complex IX. Subsequent reaction with, a sulfoxide may proceed through intermediates X-XII resulting in reduction to the sulfide and liberation of iodine. Reduction of the sulfoxide strap porphyrin 88a was conveniently carried out using a large excess of methyltrichlorosilane and sodium iodide. After s t i r r i n g for 2 hours the reaction was quenched and the porphyrin purified by chromatography on an alumina column (7Q.7%). Tic and mass spectrometry indicated complete reduction to the sulfide strap porphyrin 87a. For the shorter chain homologue 88b reduction to the sulfide 87b. was more complicated. Addition df 88b to a solution of excess methyl-trichlorosilane and. sodium iodide in acetonitrile was followed by 2 hours stirring before the reaction was quenched by addition of aqueous. SCHEME 78 161 H 3CSiCl 3 + Nal + CH3CN -Cl CH3C = N-Si-CH 3 + I Cl RSR II 0 CH3 I Cl-Si -Cl A* II R R I" + NaCl J X CH 3 I J Cl-Si -Cl I 0 I R-S-R I I xr CH 3 CH 3 I I C^Si y+^Si Cl 2 0 I R-S-R I 1 -1, R-S-R + Cl2CH3Si -O-SiCh^Clj 162 sodium t h i o s u l f a t e s o l u t i o n . T i c at t h i s stage showed not only the presence of the desired porphyrin 87b, but also a pink/brown spot with a higher Rf value. The crude product was placed on an alumina column and eluted with dichloromethane. The i n i t i a l f r a c t i o n s from the column, when examined by t i c (2% MeOH/CH^Cl^), were a mixture of a green and a red/pink m a t e r i a l . The o p t i c a l spectrum of t h i s mixture displayed a broad band at 590 nm with two more intense bands at 350 and 401 nm. Continued e l u t i o n with, dichloromethane gave f r a c t i o n s containing only the s u l f i d e porphyrin 87b. The i n i t i a l fractions, were combined, protected from exposure to l i g h t , and s t i r r e d overnight i n a i r . Both t i c and the v i s i b l e spectrum of the s o l u t i o n showed the disappearance of both, the green and pink/red materials; the strapped porphyrin 87b was the only material present. A l l the porphyrin f r a c t i o n s were combined and further p u r i f i e d by preparative t i c to give a 74% y i e l d of the s u l f i d e porphyrin 87b. Previously we had observed the formation of a green material during the preparation of the s u l f i d e strap porphyrin 87b which, on s t i r r i n g i n a i r , was oxidized to the porphyrin. We speculated that the short strap retarded porphyrin formation and s t a b i l i z e d the intermediate porphodimethene 90. For the strained C^~sulfoxide strap porphyrin 88b i t would appear that reduction of the sulfoxide to the s u l f i d e i s accompanied by reduction of the porphyrin ring.. That t h i s occurs for 88b but not for the longer chain 88a r e f l e c t s the highly strained nature of 88b. 163 2.4 SYNTHESES OF PORPHYRINS CONTAINING A PHENOL STRAP Tyrosine plays a r o l e i n several hemeproteins, and therefore the production of s u i t a b l e porphyrin-phenol models i s desirable. Catalase i s an enzyme which protects aerobic organisms from the toxic e f f e c t s of hydrogen peroxide by catalyzing reaction 61. 2 H 2 0 2 • 2 H 2 0 + 0 2 ( 6 i ) The X-ray c r y s t a l structure of beef l i v e r catalase shows that the f i f t h , proximal ligand of the heme ac t i v e s i t e i s the phenol of Tyr-357, presumably deprotonated. There i s no sixth, ligand but residues on 184 the d i s t a l side include His-74, which, i s e s s e n t i a l f o r enzyme a c t i v i t y . Tyrosine also acts as a heme ligand i n c e r t a i n mutant hemoglobins, where e i t h e r the proximal or d i s t a l h i s t i d i n e i s replaced by tyrosine 185 which binds to the heme i r o f i ( I I I ) . In a d d i t i o n , the proximity of a tyrosine (Tyr-67 of horse cyto-chrome e) to the heme of cytochrome e has suggested a r o l e for t h i s 186 residue as a d e l i v e r e r of electrons to the metal centre. Porphyrins with coordinated phenoxides have been previously prepared. Sugimoto and co-workers prepared a s e r i e s of i r o n (.III) porphyrins with various 4-substituted phenoxides as a x i a l ligands, — 186 [Fe(III)(Pot)(4-X-C,H.O )] (Por = OEP, TPP). A l l the compounds were o 4 five-coordinate high, spin complexes. A re l a t e d s e r i e s of iro n ( I I I ) phenoxides, Fe(III)(PPIXDBE)(phenoxide) has been prepared by Ainscough. 185 and co-workers. While the five-coordinate complexes were e a s i l y PROXIMAL Hb HYDE PARK Hb IWATE 164 CYTOCHROME C F i g . 12: Schematic Representation of the A c t i v e S i t e s of Peroxidase, Cytochrome c, and Some Mutant Hemoglobins 165 p r e p a r e d as i n e q u a t i o n 62, attempts to study the base a d d i t i o n [Fe(l l l)(PPlXDBE)] 20 + 2H0Ar • ( 6 2 ) 2[Fe(lll){PPIXDBE)("0Ar)] + H 20 r e a c t i o n a t room temperature were c o m p l i c a t e d by the f o r m a t i o n o f m i x t u r e s of [ F e ( I I I ) ( P P I X D B E ) ( ~ O A r ) ] , [ F e ( I I I ) ( P P I X D B E ) ( ~ O A r ) ( L ' ) ] and [ F e ( I I I ) (PPIXDBE) ( L ' ^ ] + . [Fe(lll)lPPIXDBE)rOAr)] + L . ( 6 3 ) [Fe(lll)(PPIXDBE)("OAr)(Ll] L = IMelm, C 5 H 5 N A l l attempts to p r e p a r e the f i v e - c o o r d i n a t e i r o n ( I I ) phenoxide complexes, f a i l e d , s p e c t r a a t t r i b u t a b l e to t h e s i x - c o o r d i n a t e weak f i e l d systems, [Fe(II)(PPIXDBE)(~OAr) ] 2 ~ , b e i n g o n l y observed. I t was hoped t h a t t h e p r e p a r a t i o n of a p o r p h y r i n with, an appended p h e n o l would g i v e g r e a t e r c o n t r o l over c o o r d i n a t i o n , l e a d i n g not o n l y to the c h a r a c t e r i z a t i o n o f f i v e - c o o r d i n a t e i r o n ( I I ) and i r o n ( I I I ) phenoxides as model's f o r c a t a l a s e and HBM Boston, but a l s o the mixed l i g a n d systems, Fe(.Por.( O A r ) ( L ' ) . 166 As i n the synthesis of the s u l f i d e strap porphyrins 87a and 87b, the synthesis of porphyrins containing a phenol strap proceeded from the same bu i l d i n g blocks, a-free-iodoalkyl pyrroles 44_ and 64_ (Fig. 13). This reaction sequence constituted a f l e x i b l e approach to the synthesis of porphyrins containing f u n c t i o n a l i z e d hydrocarbon straps, the method being l i m i t e d only by the a v a i l a b i l i t y of suitable dialdehydes to incorporate into the strap. The key reaction i n t h i s route was the double Wittig reaction between the a-free pyrrole phosphonium iodide 94 and the dialdehyde 95. The dialdehyde 95, 2,6-diformyl-4-methylanisole, was prepared by 187 published procedures (Scheme 79). Treatment of p-cresol 9j6 with. SCHEME 7 9 F i g . 13: Synthesis of the Bis-dipvrromethanes. 114a and 114b. 168 formaldehyde and potassium carbonate at 50°C gave the desired 2,6-b.w.s(hydroxymethyl)-4-methylphen61 97 i n modest y i e l d (34-43%). Despite the low y i e l d the reaction was e a s i l y c a r r i e d out on a large scale using r e a d i l y a v a i l a b l e s t a r t i n g materials to give large quantities of pure product. The phenol 9_7_ was protected as i t s methyl ether by reaction with dimethyl s u l f a t e . Despite the high published y i e l d s (84-95%), Cram's 187 procedure i n our hands gave v a r i a b l e y i e l d s . Thus 2,6-bis(hydroxy-methyl) -4-methylphenol 9_7 was s t i r r e d with, dimethyl s u l f a t e (1.1 equiva-lents) and potassium carbonate i n acetone at room temperature f o r 24 hours. After work-up and r e c r y s t a l l i z a t i o n from chloroform or d i c h l o r o -methane y i e l d s v a r i e d from 24-75%. Using sodium hydroxide as base or re f l u x i n g the reaction mixture lead to poorer y i e l d s . No attempt was made to maximize the y i e l d since s u f f i c i e n t q uantities of 98 were obtained for further work. Oxidation of the hydroxymethyl functions using pyridinium dichro-188 mate gave disappointing r e s u l t s (21-53%). However, oxidation using dimethyl s u l f o x i d e / o x a l y l chloride/triethylamine gave uniformly good 189 y i e l d s (71-93% crude). The crude product was r e c r y s t a l l i z e d from 1:1 (v:v) carbon tetrachloride/cyclohexane to give f i n e colourless: needles. The a-free pyrrole phosphonium iodide 94a was prepared by refl u x i n g the a-free-iodopentyl pyrrole 44_ with excess triphenylphosphine i n toluene. In the i n i t i a l experiments the s t a r t i n g material was. contamina-ted with the corresponding a - f r e e chloropentyl pyrrole which- decreased the y i e l d . Furthermore the crude phosphonium iodide 94a separated from s o l u t i o n as a red or brown viscous: o i l . When the reac t i o n was. 169 H 3 C V _ / (CH2)5Cl (CH 2) 5PPh 3 I E t O H E t O H 94a judged complete the solvent was decanted and the viscous product was triturated several times with, diethyl ether to remove unreacted triphenyl-phosphine and the a-free chloropentyl pyrrole. On drying in vacuo the viscous o i l turned into a hardened foam which was collected. A l t e r -natively, trituration with heptane solidified the product but this was a very tedious process. Although, these samples gave poor elemental analyses they were used without further purification since they were being used in excess in subsequent reactions. In more recent prepara- . tions, using purer samples of a-free iodopentyl . pyrrole 44, the product phosphonium iodide 94a precipitated from the reaction medium as a tan powder which, was fi l t e r e d and dried. Yields ranged from Preparation of the corresponding butyl phosphonium iodide 94b was complicated by a lack of pure starting material. As mentioned in Section 2.2, preparation of a-free iodobutyl pyrrole 64 was always accompanied by formation of the cyclohexyl pyrrole 65_ or the a-free-75-97%. 66 64 65 170 butyl pyrrole 66_. Refluxing triphenylphosphine and 6^4 in toluene invariably led to the separation of the product 94b as a brown viscous o i l . After trituration with diethyl ether and decanting the supernatant liquid, the o i l was dried on a vacuum line to give a hardened foam (85-90% crude). The success of the reactions in Fig. 13 depended upon the yield and ease of preparation of the bis-alkenes 9_9_. One of the most versatile 190 reactions for carbon-carbon bond formation is the Wittig reaction. Thus treatment of a phosphonium salt 100 with, base leads to formation of the ylide 101 which is allowed to react with a carbonyl compound 102 to form the olefinic product 1Q3 and triphenylphosphine oxide 104 via the intermedia&y of the betaine 105. Phosphorous ylides are a unique form of carbanion in which, the charge is modified by possible dir-pn bonding (Scheme 80, 101a » 101b.) . The dipolar ylide focm 101a gives the ylide i t s nucleophilic character which is then modified by the 1 2 nature of R and R . Thus electron-withdrawing groups w i l l stabilize the carbanion and reduce the reactivity of the ylide, whereas electron donating groups w i l l enhance i t . For this reason ylides have been classified as "stable" or "reactive". Similarly the strength of base required to generate the ylide w i l l depend on the acidity of the hydrogen on the a-carbon atom. Stable ylides, with, electron-withdrawing groups on the a-carbon are easily deprotonated with, dilute aqueous alkai or neat amines. Reactive ylides, with, electron-donating, groups on the a-carbon (e.g. alkyl groups), require metal alkyls or hydrides to effect ylide formation. Moreover these ylides are oxygen and moisture sensitive and -must be used immediately. 171 SCHEME 80 Ph 3P-CH 100 R Base Ph 3 P-C \ 2 101a R / R ,1 Ph 3P=C \ 2 101b V 0=C I V P h 3 P — C R 1 2 'o-c ^ V c=c . 2 / V 4 R*103 102 105 Ph 3P=0 104 The y l i d e derived from phosphonium s a l t 94a was c l e a r l y of the react i v e kind and, i n i t i a l l y , b u t y l l i t h i u m was used for deprotonation of the a-carbon. Thus a solution of 94a i n fr e s h l y d i s t i l l e d t e t r a -hydrofuran was cooled to -78°C and s t i r r e d under argon. n-B.utyl l i t h i u m was added dropwise v i a syringe. The solution changed c o l o r r from clear orange to cloudy white to, f i n a l l y , a c l e a r orange/red as the pyrrole nitrogen and then the a-carbon were deprotonated to form the y l i d e . Dropwise addition of 2,6-diformyl-4-methylanisole 95 discharged the orange/red color to give a yellow s o l u t i o n as the y l i d e reacted. After warming to room temperature the reaction was quenched and worked-up. The product was i s o l a t e d by column chromatography. The f i r s t material from the column was shown by H^-NMR to be a p y r r o l i c by-product. The presence of t r i p l e t s at 0.90 <5 and 5.38 <5 suggested structure 106 which, was further confirmed by a parent peak of 277 i n the mass spectrum. The second material from the column was usually unreacted dialdehyde 95. Unfortunately the. desired bis-alkene 99a ran quite c l o s e l y a f t e r the dialdehyde so care had to be taken to avoid overlap of the two materials. Optimum y i e l d of product (.61-79%) was obtained when two equivalents of butyl l i t h i u m per pyrrole phosphonium iodide 94a were used. Experiments using 1.5, 3.0 and 4.0 equivalents of b u t y l l i t h i u m per pyrrole gave lower y i e l d s (<42%). The p o s s i b i l i t y of using a more convenient reaction which, would 173 avoid formation of by-product 106 was prompted by the reports of Delmas, Le Bigot and Gaset who published a simplified Wittig reaction 191 192 using a solid-liquid phase-transfer process. ' Phase-transfer catalysis had previously been applied to the Wittig reaction. Markl 193 and Merz showed that non-stabilized phosphonium salts could be deprotonated with aqueous sodium hydroxide in dichloromethane. Thus addition of 50% caustic soda to a vigorously stirred mixture of aldehyde and phosphonium iodide led to a weakly exothermic reaction SCHEME 81 N q Q H / H 2 Q , P h 2 P C H R 2 R 3 R 1 C H 0 + P h 3 P C H R 2 R 3 0 107 N a O H R 1 C H = C R 2 R 3 C H 2 C 1 2 / H 2 0 1 1 1 P h 3 P = 0 R1 R2 R3 % YIELD Z/E ARYL/STYRYL Ph H 72-88 -1 ARYL /STYRYL CH 3 H 21-51 -which, was complete in ca. 10. minutes. Separation of the organic layer and removal of the solvent gave the crude product. Since phosphonium salts are themselves phase-transfer catalysts, no ammonium salt was 174 necessary. In the presence of aldehydes the Wittig reaction was faster than the undesired degradation to phosphine oxide 107 (Scheme 81). ':• 194 Boden was able to introduce some stereoselectivity into the reaction using a solid-liquid transfer process catalyzed by crown ethers. Addition of aldehyde and 18-crown-6 to a solution of phosphonium salt and potassium t-butoxide (or potassium carbonate) in tetrahydrofuran (or dichloromethane) gave the desired alkene. SCHEME 82 R 1 C H 0 + Ph 3 PCH 2 R 2 • R1CH = CHR 2 R 1 R 2 SOLVENT Z / E B A S E % Y I E L D C 6 H 5 THF 22/78 t -BuOK or 96 C H 2 C l 2 3 0 / 7 0 K 2 C 0 3 97 C 6 H 5 C H 3 THF 85/15 96 C H 2 C l 2 22/78 93 C 2 H 5 C 6 H 5 T H F 25/75 t - B u O K 82 K 2 C 0 3 94 C H 2 C l 2 46/54 t - B u O K or 92 K 2 C 0 3 In the absence of crown ether l i t t l e or no product formation was 191 observed. Delmas, Le Bigot and Gaset found that similar results (yields, stereochemistry) could be obtained i f the crown ether were replaced by stoichiometric amounts of water (Scheme 83). Similarly no product was obtained in the absence of added water. Indeed, while 175 SCHEME 83 RCHO + Ph 3P(CH 2) 3CH 3 Br" 0.02mol 0.02 mo! % YI ELD OF ALKENE R = C 6 H 5 R = CH3(CH2)6 DICYCLOHEXYL-18-CROWN-6 98 67 WATER ( 0.4 mL) 98 68 K 2 C0 3 » 0.03 mol O/90°C RCH=CH(CH2)2CH3 * Ph 3PO v a r y i n g amounts of b.aae (sodium hydroxide or potassium carbonate), d i d not a f f e c t the y i e l d or length, of the r e a c t i o n , i t was found that maximum y i e l d was obtained when between one and two equivalents of water was used per molecule of aldehyde. The published procedure was 195 extremely simple. A mixture of phosphonium s a l t (.0.02 mol), sodium hydroxide (.3 g) , water (0.3 mL) and aromatic aldehyde (0..0.2 mol) was r e f l u x e d i n 1,4-dioxane. F i l t r a t i o n , s o l v e n t e v a p o r a t i o n and f l a s h chromatography y i e l d e d t h e p u r e a l k e n e s . The s i m p l i c i t y o f t h e r e a c t i o n and work-up, c o u p l e d w i t h t h e h i g h y i e l d s , even f o r l o n g -c h a i n a l i p h a t i c phosphonium s a l t s , recommended t h i s method f o r o u r d o u b l e W i t t i g r e a c t i o n . The i n i t i a l r e s u l t s were not e n c o u r a g i n g . U s i n g sodium h y d r o x i d e as b a s e , t h e phosphonium s a l t 94a and t h e d i a l d e h y d e 95 were h e a t e d i n 50:1 d i o x a n e / w a t e r (18 e q u i v a l e n t s o f w a t e r p e r a l d e h y d e ) a t 70°C. "''H-NMR e x a m i n a t i o n o f t h e c r u d e r e a c t i o n m i x t u r e a f t e r work-up gave no i n d i c a t i o n o f a l k e n e f o r m a t i o n , n o r was: any u n r e a c t e d d i a l d e h y d e o b s e r v e d . 195 Gaset e t a l . , s u g g e s t e d t h a t p o t a s s i u m c a r b o n a t e was more s u i t a b l e as a base i n t h e p h a s e - t r a n s f e r W i t t i g r e a c t i o n s i n c e ( i ) i t i s a poo r c a t a l y s t f o r a l d o l c o n d e n s a t i o n s i f a l i p h a t i c a l d e h y d e s a r e b e i n g u s e d , and ( i i ) t h e r e i s l e s s l i k l i h o o d o f a competing Cannizzaf.o r e a c t i o n i f e l e c t r o n - r i c h a r o m a t i c a l d e h y d e s a r e u s e d . A c c o r d i n g l y , u s i n g anhydrous p o t a s s i u m c a r b o n a t e as b a s e , t h e phosphonium i o d i d e 94a and t h e d i a l d e h y d e 95 were r e f l u x e d i n 50:1 d i o x a n e / w a t e r (50 e q u i v a -l e n t s o f w a t e r p e r al d e h y d e ) f o r 20 h o u r s . T h i s t i m e "''H-NMR o f t h e cr u d e r e a c t i o n m i x t u r e i n d i c a t e d some a l k e n e f o r m a t i o n . However a f t e r chromatography t h e major p r o d u c t was de m o n s t r a t e d nofuto.nbe t h e d e s i r e d b i s - a l k e n e 99a but r a t h e r t h e mono-alkene 108. T h i s was formed i n 7.1% y i e l d . I n a s i m i l a r r e a c t i o n , u s i n g anhydrous p o t a s s i u m c a r b o n a t e as. base , e x c e s s phosphonium i o d i d e C4 e q u i v a l e n t s ) and 2 e q u i v a l e n t s o f wa t e r p e r a l d e h y d e f u n c t i o n , t h e s t a r t i n g d i a l d e h y d e was r e c o v e r e d q u a n t i t a t i v e l y . By c o n t r a s t , when t h i s r e a c t i o n was r e p e a t e d b o t h mono-a l k e n e 108 (74%) and b i s - a l k e n e 99a (18%) were o b t a i n e d ; 27% of t h e 177 s t a r t i n g dialdehyde 95_ was recovered unchanged. CH 3 (CH2)4CH=CH CHO EtO OCH 3 0 H 108 In none of the reactions was any unreacted phosphonium iodide 94a recovered unchanged, even wheni excess was used. This suggested that some side reaction might be consuming the phosphonium iodide 94a as quickly as i t was reacting with, the dialdehyde. Accordingly s i n g l e equivalents each of 94a and potassium carbonate were added to a s o l u t i o n of dialdehyde 95_ i n r e f l u x i n g dioxane over a period of time. To avoid any doubt about the amount of water present, hydrated potassium carbonate was used as base, the water necessary f o r the reaction being present as water of c r y s t a l l i z a t i o n (K CO -l^H 0). The f i r s t equiva-lent of 94a and potassium carbonate was added and the mixture refluxed for 12 hours before the second equivalent was added. Aft e r a further 8 hours t i c indicated the complete disappearance of dialdehyde 9_5_ and the presence of both, mono-alkene 10.8 and bis-alkene 99a products. Addition of a t h i r d equivalent of 94a and potassium carbonate and a further 18 hours r e f l u x gave e s s e n t i a l l y complete reaction; the desired CH 3 (CH2) CH=CH CH=CH(CH?) EtO 0CH 3 OEt H 9 9 a 178 bis --alkene 99a predominated with only a t race of the mono-alkene 108 apparent. Similar reactions using incremental addition of 94a gave the bis-alkene 99a i n 60-72% y i e l d a f t e r chromatographic p u r i f i c a t i o n . These y i e l d s compared favourably with, those reported by Gaset et a l . , for single W i t t i g reactions on substituted benzaldehydes (73-88%) 195 These authors subsequently confirmed our observations on the SCHEME 84 0HC-(\ />-CH0 + 109 ( P h ) 3 P C H 2 R Br" K 2 C 0 3 0 H C ~ \ _ / ~ C H = C H R 110 K ,C0 (Ph) 3 PCH 2 R Br" 2 ^ 3 CH=CHR CH=CHR 111 (Ph) 3 PCH 2 R' Br -CH=CHR CH=CHR 112 s l u g g i s h n e s s o f t h e p h a s e - t r a n s f e r W i t t i g r e a c t i o n when they r e p o r t e d 196 t h e r e a c t i o n s o f t e r e p h t h a l a l d e h y d e 109 i n heterogeneous media. Because o f t h e i r h i g h e r r e a c t i v i t y i n anhydrous homogeneous media, phosphorus y l i d e s r e a c t w i t h d i a l d e h y d e s to y i e l d e x c l u s i v e l y t h e d i - o l e f i n s . In heterogeneous media, however, t h e r e a c t i v i t y i s much l e s s . Once one o f the c a r b o n y l f u n c t i o n s r e a c t s t o form the mono-o l e f i n t h e n t h e e l e c t r o n d e n s i t y on t h e r e m a i n i n g c a r b o n y l group i n c r e a s e s s u f f i c i e n t l y t o d i s c o u r a g e n u c l e o p h i l i c a t t a c k by a second phosphof.us y l i d e . Gaset e t a l . , were a b l e t o e x p l o i t t h e d i f f e r e n c e i n r e a c t i v i t y o f t h e two c a r b o n y l s (k_^> k^) to i s o l a t e and p u r i f y t h e mo n o - o l e f i r i 110. T h i s c o u l d then be r e a c t e d with, excess o f the same, or a d i f f e r e n t , phosphonium s a l t , t o form symmetric o r unsymmetric d i -o l e f i n s 11_1, 112 (Scheme 84). In t h e cas.e o f 2,6- d i f o r m y I - 4 - m e t h y l -a n i s o l e 9_5_ t h e p r e s e n c e of two e l e c t r o n - d o n a t i n g groups: on the benzene r i n g may account f o r t h e r e l u c t a n c e of t h e second c a r b o n y l group t o r e a c t and t h e lower y i e l d s o f d i - o l e f i n . I t has been r e p o r t e d t h a t the p h a s e - t r a n s f e r W i t t i g r e a c t i o n i n 192 d i p o l a r s o l v e n t s y i e l d s p r e d o m i n a n t l y t h e c i s isomer (Z/E ^80/20). Such s t e r e o s e l e c t i v i t y i s o f no consequence f o r our double W i t t i g r e a c t i o n s as t h r e e p o s s i b l e i s o m e r i c p r o d u c t s may be formed (ZZ, ZE, EE) . S i n c e t h e '''H-NMR c h e m i c a l s h i f t s and c o u p l i n g c o n s t a n t s i n each isomer a r e s i m i l a r , the o l e f i n i c p r o t o n s appear as a d o u b l e t and a d o u b l e t of t r i p l e t s a t 6.51 <5. and 5.70 6. r e s p e c t i v e l y . However c h e m i c a l s h i f t s 13 i n C-NMR a r e more s e n s i t i v e t o s m a l l changes i n m o l e c u l a r geometry. The p r e s e n c e of t h r e e g e o m e t r i c isomers i n the pure p r o d u c t gave a more c o m p l i c a t e d p a t t e r n o f peaks i n t h e o l e f i n and a r o m a t i c r e g i o n o f t h e 13 C-NMR spectrum. The s t e r e o s e l e c t i v i t y o f t h e W i t t i g r e a c t i o n was of no c o n s i d e r a -tion since the next step was hydrogenation of the double bonds. Stirring the bis-alkene 99a in tetrahydrofuran under hydrogen with 10% palladium on charcoal as catalyst resulted in complete reduction. Removal of catalyst and solvent and flash chromatography gave the chain-linked bis-pyrrole 113a in high yield (85-97%). With, sufficient quantities of 113a in hand, elaboration to the corresponding strapped porphyrin 9.2a followed the same sequence of reactions as outlined in Section 2.3 for formation of the thioether strapped porphyrin 87a (Fig. 14). Heating the bis-pyrrole 113a with the a-chloromethyl-dicyanovinyl pyrrole _76 (2.1 equivalents) at 80°C in glacial acetic acid for 1 hour formed the chain-linked bis-dipyrromethane 114a in high yield. Tic o f the crude product showed a major yellow spot which turned violet on exposure to bromine vapour (diagnostic for dipyrromethanes). Since t i c showed the presence of small amounts of other colored materials, the product was purified by chromatography (84-94%). Hydrolysis of 114a with, potassium hydroxide in a water/n-propanol mixture removed the ester and dicyanovinyl groups to give the.a-carboxy,a'-formyl bis-dipyrro-methane 115a. Thermal decarboxylation in refluxing N,N-dimethylformamide yielded the a-free,a'-formyl bis-dipyrromethane 116a. As before this intermediate was not isolated but used immediately for the porphyrin synthesis. Slow injection of a dichloromethane solution of 116a into a 113a 117b n = 5 Fig. 14: Synthesis of the Phenol-Strapped Porphyrins 117a and 117b. 182 large volume of dichloromethane containing p-toluenesulfonic acid favoured intramolecular cyclization to the strapped porphyrin 117a. In this case the spanning strap is sufficiently long that l i t t l e or no deformation of the porphyrin ring is observed. Because of this yields of the unstrained porphyrin 117a (30-44%) are higher than those of the more strained thioether strapped porphyrins (10-22%). Synthesis of the shorter chain homologue 117b followed the same sequence of reactions as shown in Figs.13, 14. The step-wise double Wittig reaction of phosphonium iodide 94b and dialdehyde 9_5_ gave lower yields of the b is-alkene 9_9b_ (.43-52%) after chromatographic purification. However, fractions containing impure product were retained and purified after catalytic reduction of the double bonds. In this way overall yields of 43-53% were obtained for the two step reaction 94b. —» 9.9b —• 113b. The bis-dipyrromethane 114b. was prepared in 76-95% yield after chromatography. After deprotection, decarboxylation and intramolecular cyclization, the strapped porphyrin 117b was obtained in 21-53% yield. With the formation of the porphyrin ring the f i n a l step required removal of the methoxy group to generate the free phenol. Iodotri-methylsilane has been used as a mild reagent for the demethylation of 183 alkyl aryl ethers. Since the iodotrimethylsilane equivalent, Cl^MeSi/ Nal, had already been used to effect the deoxygenation of the sulfoxide porphyrins 88, this reagent was investigated. Addition of methyltri-chlorosilane to a solution of sodium iodide in freshly d i s t i l l e d aceto-n i t r i l e generated the iodotrimethylsilane equivalent, giving a yellow solution with precipitated sodium chloride. After dropwise addition of a solution of porphyrin 117a in dichloromethane, the solution was lef t stirring for 4 hours before the reaction was quenched and the 183 product isolated by preparative t i c . Mass spectrometry indicated complete demethylation. However when the reaction was carried out on a larger scale under the same conditions a mixture of starting material 117a and product 118a was obtained. Furthermore, two attempts to demethylate porphyrin 117b under the same conditions led to mixtures of starting material' and product. These variations in results were attributed to traces of moisture in the system. 117a n = 6 1_18a n = 6 • - b n = 5 b n = 5 The use of boron tribromide to effect the demethylation gave more reproducible results. The boron tribromide was added dropwiae to a solution of the anisole porphyrin 117a in dichloromethane at -78°C. The reaction mixture was stirred at -78°C for 30 minutes, allowed to warm to room temperature and stirred for a further 1 hour. After work-up and chromatographic purification on an alumina column (Merck 90 neutral, activity III) the phenol porphyrin 118a was obtained in 76-89%. The lower homologue 117b. was demethylated under the same-conditions, 118b being obtained in 89-95% after chromatography. 184 2.5 SYNTHESES OF PORPHYRINS CONTAINING A QUINONE STRAP Although the exact details of photosynthesis have not a l l been elucidated, the essential features of the process are believed to include the following. Incident light is harvested by a complex antenna system of chlorophyll (bacteriochlorophyll in photosynthetic bacteria) and other pigments, and used to excite a special (bacterio)-chlorophyll center to the singlet state. An electron is then transferred from the excited (bacterio)chlorophyll through a series of intermediate compounds [(bacterio)pheophytin, Fe-S clusters] to an acceptor. In photosynthetic bacteria and in photosystem II of green plants this electron acceptor is a quinone molecule, ubiquinone and plastoquinone 197 respectively. As shown in the simplified scheme (Fig. 15), the net 198 result is a reduction of NADP and the oxidation of water to oxygen. Not surprisingly attempts have been made to mimic this light-induced separation of charge in the laboratory using various porphyrin-quinone models. The models generally belong to two types. The quinone may be attached to the porphyrin by a single covalent chain (Jig. 16, 197 199—203 119-125). ' The f l e x i b i l i t y of the chain, while discouraging the formation, w i l l enhance the lifetime of the charge-separated species by reducing the recombination reaction. The alternative, using porphyrin with attached "quinone caps" (Fig. 16, 126, 127) is: attractive since the relative orientation and separation of.the porphyrin and v. w f n , 106,107,130-132 quxnone may be better controlled. More sophisticated models have recently been produced allowing for greater stabilization of the charge separated species. In the bis-quinone system 128 (Scheme 85) of Sakata and co-workers a two step 18 5 -0.6 r ACCEPTOR * (Fe S P r o t e i n ) - - 2 e " o o LU + 0.4 + 0.8 Y CNADP .slADPH + H + \ -\ \ hv •* PHOTOSYSTEM I (P700) C Y T O C H R O M E b3 / i PLASTOQUI NONE / / / / / fie' 2e" HoO hv s 2 • PHOTOSYSTEM E ( P680 ) ( 1/2 0 2 + 2H + Fig. 15: Simplified Scheme of Photosynthesis in Plants 186 Fig. 16: Representative Covalently Linked Porphyrin - Quinone Molecules charge transfer is believed to occur to give the long-lived P 4Q4Q* species, a situation analogous to the multistep electron transfer which 204 occurs in vivo. The spectroscopic behaviour of the carotenoid-205 porphyrin-quinone (CPQ) system 129 of Moore et a l . , has been inter-SCHEME 85 P4Gl4a' — • P4Q4QL~ preted as in Scheme 86. Charge recombination is: inhibited by electron transfer from the carotenoid to the porphyrin cation radical, to give a long-lived (ys scale) C -P-Q species. The interest in electron transfer systems and our goal of preparing porphyrins bearing functionalized straps prompted us to synthesize a strapped porphyrin in which, a quinone was incorporated into the strap. Sanders and Ganesh. had already reported the synthesis of a strapped porphyrin-quinone 126, using the more common synthetic strategy of attaching a 2,5-disubstituted-l,4-dimethoxybenzene 144 131 to a preformed porphyrin ring 145 by ester linkages (Scheme 87). The authors discovered that demethylation of the subsequent strapped 188 C P Q i hv c-'p-a c - P-a *• c- p - a" porphyrin 146 f a i l e d . Oxidative deprotection using eerie ammonium n i t r a t e gave a meso-nitrated .porphyrin, while argentic oxide,- amongst other reactions, inserted s i l v e r into the porphyrin. Boron tribromide and t r i m e t h y l s i l y l iodide also f a i l e d to deprotect without damage. This was not s u r p r i s i n g since t r i m e t h y l s i l y l iodide i s known to be an.extremely e f f i c i e n t reagent for the de-alkylation of esters 183 They repeated 189 SCHEME 87 lAJa R = C H 2 0 C H 3 n = 2 t h e i r work masking the quinone with, the more l a b i l e methoxymethyl ether (MME = OCH^OMe) protecting group. In t h i s case they were able to remove the protecting groups from the strapped porphyrin 148 and oxidize the cap to the desired quinone 126. Y i e l d s for the strapped porphyrin 148 were 7-8% (n = 2) and 15-20% (n = 3) . To demonstrate the v e r s a t i l i t y of our synthetic strategy we attempted a synthesis of a s i m i l a r quinone-strapped porphyrin (Tig. 17). We decided to protect the quinone as the b.is-methoxy ether rather than Fig. 17: Synthesis of the Bls-djpyrromethanes 139a and 139b.. as the bis-methoxymethyl ether since the former would be more stable •' over the reaction sequence. Furthermore, since the product porphyrin 140 would contain only hydrocarbon linkages demethylation might be easier to e f f e c t without damage to the molecule. In addition we believed that our strategy was more f l e x i b l e i n allowing shorter chain lengths and higher y i e l d s of the. strapped porphyrin. Since the required pyrrole phosphonium iodide';:9.4a and 9.4b. were already on hand i t only remained to synthesize the required aldehyde 131. Treatment of 1,4-dimethoxybenzene 132 with, formaldehyde, hydrogen chloride and hydrochloric acid yielded the 2,5-bis(chloromethyl)-1,4-206 dimefihoxybenzene 133 i n good y i e l d (57%) ( F i g . 18). This compound was converted into the corresponding diacetate 134 with sodium acetate Fig. 18: Synthesis of 2,5-Diformy1-1,4-dimethoxybenzene 192 i n r e f l u x i n g a c e t i c acid (72-90%), then saponified with sodium hydroxide to give the di-hydroxymethyl compound 135. 207 Oxidation with dimethyl s u l f o x i d e / o x a l y l chloride smoothly oxidized both alcohols to the aldehyde i n high y i e l d (94-96% crude). Vacuum sublimation furnished the pure compound 100 (83-87%) as a yellow s o l i d . In t h i s case the double Wittig reaction between the dialdehyde 131 and the phosphonium iodide 94_ was somewhat more convenient to follow and work-up. As before the phosphonium iodide 9_4_ and potassium carbonate were added i n one equivalent increments to a r e f l u x i n g solution of the dialdehyde 131 i n p-dioxane, the course of the reaction being monitored by t i c . Since 131 i s intensely yellow i t s eventual consumption i s e a s i l y noted. The presence of the p a r t i a l l y reacted mono-alkene 136 can be detected since i t fluoresces on the plates under UV l i g h t . When t i c indicated that reaction was complete the dioxane was, removed and the crude reaction product obtained as: a yellow o i l . Sometimes on standing t h i s o i l s o l i d i f i e d . Addition of d i c h l o r o -methane did not completely redissolve i t and the white s o l i d which, was f i l t e r e d off was found to he the required bis-alkene 137. More product was obtained by chromatographic p u r i f i c a t i o n of the f i l t r a t e . The bis-alkene 137 seemed to be unusually insoluble compared to the analogous anisole compound 99. For t h i s reason room temperature c a t a l y t i c hydro-genation was not attempted. Instead, transfer hydrogenation was c a r r i e d 0CH3 136a n = U b n = 3 193 out where the bis-alkene 137 was refluxed i n a mixture of ethanol and 208 cyclohexene, with 10% palladium/charcoal as c a t a l y s t . When the reaction was complete the hot s o l u t i o n was f i l t e r e d through a C e l i t e pad to remove the c a t a l y s t . As the f i l t r a t e cooled down the product 138 pr e c i p i t a t e d from sol u t i o n as a white s o l i d which was c o l l e c t e d by Q C H 3 H 3 C v . ( C H 2 ) C H = C H ^ ~ V - C H = C H ( C H 2 1 I v . C H B O ^ A H \ ) C H 3 H / N \ / 0 E t 137Q n = L 137b n = 3 f i l t r a t i o n . Further product was obtained from concentration of the f i l t r a t e . For the longer chain b i s - p y r r o l e 138a the combined o v e r a l l y i e l d s for the two steps :94a—>• 137a —> 138a were excellent (.67-84%). However for the shorter chain 138b the o v e r a l l y i e l d was much, poorer (.42%). ' Q Q ( _ | 0 H H 0 138a n =6 138b_ n = 5 The synthesis, of the bis-dipyrromethane 139_ was c a r r i e d out as usual i n hot g l a c i a l a c e tic a c i d . Compound 139a was obtained i n good y i e l d (76-88%) a f t e r chromatography, while the le s s soluble 139b. pre c i p i t a t e d from the reaction mixture i n a n a l y t i c a l l y pure form (.91%). Once prepared the bis-dipyrromethanes 139 were subjected to hydrolysis, decarboxylation and high, d i l u t i o n c y c l i z a t i o n under the same conditions 194 Fig. 19: Synthesis of the Dimethoxybenzene-Strapped Porphyrins 140a and 140b. 195 as outlined previously (Fig. 19). Aft e r work-up and chromatography the strapped porphyrins 140a and 140b were obtained i n 41-60% and 20-40% y i e l d r e s p e c t i v e l y . The methoxy functions were conveniently demethylated using boron tribromide. After s t i r r i n g 140a with, a large excess of boron tribromide at -78°C for 1.5 hours, t i c (10% EtOAc/hexanes) showed the presence of two compounds., neither of which, was s t a r t i n g material. They were believed to be the desired porphyrin-hydroquinone 141a and the porphyrin 142a i n which, only one methoxy group had reacted. This was by analogy to the reports of Loach., who had demonstrated s e l e c t i v e 199 demethylation under s i m i l a r conditions. After warming to room temperature the mixture was s t i r r e d for a further hour by which, time the reaction was complete. Attempts to p u r i f y the crude hydroquinone 141a by chromatography on alumina i n v a r i a b l y l e d to p a r t i a l oxidation, mixtures of hydroquinone 141a and quinone 143a being obtained. Since the quinone was the desired product, the hydroquinone 141a was oxidized f u l l y to 143a before chromatographic p u r i f i c a t i o n . Both. DDQ and lead dioxide were used as oxidants, the l a t t e r being more convenient as i t was e a s i l y removed by f i l t r a t i o n . The crude porphyrin-quinone 143a was then p u r i f i e d by chromatography on alumina (82-87%). Demethylation of 140b was c a r r i e d out i n exactly the same way. Aft e r chromatography, the quinone 143b was r e c r y s t a l l i z e d from toluene f or a 70% y i e l d . 196 O C H , ( C H 2 ) n I O C H , " I (CH 2'n • N H H N • B B r 3 - 7 8 ° C UOQ n = 6 140b n = 5 F i g . 20: Synthesis of the Quinone-Strapped Porphyrins -I43a and 243b, 197 2.6 ATTEMPTED SYNTHESIS OF A PORPHYRIN CONTAINING AN IMIDAZOLE STRAP Obviously the most desirables strapped porphyrin would be that bearing an imidazole ring incorporated into the bridging strap. Such a model would have widespread applicability since the imidazole of a histidine residue is a heme ligand in many heme proteins. Incorporation of the imidazole into the strap would provide a distinct five-coordinate species, avoiding the problem of six-coordination when using free imidazole. In addition, i f the strap was sufficiently "tight" to secure the imidazole in place, the problems of dissociation and head-to-t a i l dimerization associated with imidazole chelated hemes would also be avoided. Examination of molecular models: indicated that maximum overlap would occur betwen the imidazole nitrogen lone pair orbital and orbitals on the metal at the porphyrin core i f the imidazole was attached to the porphyrin through, i t s 1,5 positions. Strap lengths of 7 or 8 methylene units each, would secure the imidazole in place without causing deformation of the porphyrin ring or allowing excessive motion of the strap. Unfortunately, of a l l the substitution patterns of imidazoles, 209 210 the 1,5 disubstituted appears to be the least accessible. ' Our i n i t i a l efforts were directed towards preparing the 1,5 disubstituted imidazole 152, which has the two straps already in place. It was hoped that the two halves of the porphyrin could be built up at the chain termini to give, after intramolecular cyclization, the imidazole strapped porphyrin (Fig. 21). Attempts were made to prepare 152 by a 211 variation of the Marckwald synthesis, i.e.^condensation of an 1 9 8 Fig. 21; Proposed Synthesis of the. Imidazole - Strapped Porphyrin 154 a-amino ketone 150 and an a l k y l isothiocyante 149 to give"the imidazoline-2-thione 151 which could be desulfurized at any subsequent convenient stage. The oj-carbalkoxyalkyl isothiocyanates were e a s i l y prepared from the c y c l i c ketones 155. Beckmann rearrangement to the lactam 156 SCHEME 88 o 1) NH20H-HCl u fl 1) HCI/H20 K 2 C0 3 " " ^ 2) HCl/MeOH CH 2 ) n 2) H 2 S C \ V ( C H 2 ) n 155 156 CS 2/Et 3N Me0 2 C(CH 2 ) n NH 2 HCl • Me0 2C(CH 2) nNCS ClC0 2 Et 157 n = 6 149 n= 6 followed by r i n g opening and e s t e r i f i c a t i o n furnished the (ajramino '212 ester 157 (Scheme 83). i' Condensation with carbon-disulfide. iri.,the presence of e t h y l chloroformate and triethylamine yielded the i s o t h i o -213 cyanate 149. While the isothiocyanate 149 was. r e a d i l y a v a i l a b l e , convenient large-scale preparation of the a-amino ketone 15Q presented''a more formidable task. I n i t i a l l y the method of Schrecker and T r a i l was 214 investigated. D i - t - b u t y l acetamidomalonate 158 was acylated by r e f l u x i n g with sodium hydride followed by treatment with, a s u i t a b l e acid c h l o r i d e 159 (Scheme. 89.) . Decarboxylation was effected by heating the crude reaction mixture with t r i f l u d r o a c e t i c a c i d , the 200 SCHEME 89 o HII h k / N C C H g 1) N a H WW 13 W INUI I "X 2) E t 0 2 C ( C H 2 ) n C O C l 0 0 1 5 9 a n = 6 158 TFA b n= 3 0 0 II u II E t 0 2 C ( C H 2 ) n C ^ N C C H 3 w 0 0 0 0 0 , II II 6N H C l II E t 0 2 C ( C H 2 ) n C C H 2 N C C H 3 • H 0 2 C ( C H 2 ) n C C H 2 N H 2 - HC l 1 6 0 a n = 6 161a n = 6 b n = 3 ' b n= 3 r e s u l t i n g a-acetamido ketone I6Q b e i n g i s o l a t e d by column chromato-graphy b e f o r e a c i d h y d r o l y s i s f u r n i s h e d t h e a-amino ketone h y d r o -c h l o r i d e 161 i n ^ 1 3 % y i e l d o v e r a l l . A more a t t r a c t i v e r o u t e appeared t o be t h a t proposed by Evans 215 and Sidebottom ( F i g . 2 2 ) . Treatment 'of e t h y l h i p p u r a t e I62a w i t h two e q u i v a l e n t s o f l i t h i u m d i i s o p r o p y l a m i d e formed t h e d i a n i o n which was r e a c t e d w i t h a s e r i e s o f a n h y d r i d e s t o form t h e a c y l a t e d p r o d u c t . A c i d h y d r o l y s i s y i e l d e d t h e a-amino ketone h y d r o c h l o r i d e s i n 40% o v e r -a l l y i e l d . In our case r e a c t i o n of the. d i a n i o n w i t h , t h e mixed a n h y d r i d e I63a gave v a r i a b l e r e s u l t s . I n a s m a l l s c a l e (20 mmol) r e a c t i o n t h e 201 0 1_62a R = Et b R= B z LDA - 7 8 ° C 163a R1=^ E t 0 2 C ( C H 2 ) 6 R2= EtO 163b R 1= R = (CH 2 ) 3 R l C \ 0 0 R2-Q 0 0 |_j ^ A N ^ / ( C H 2 ) n C 0 2 E t R 0 2 C ( C H 2 ) n \ c ^ 0 0 165 n= 6 6N H C l / H 2 0 0 R1 = B z , R 2 = E t n =6 R 1=Et, R 2 = E t , n = 6 H 0 2 C ( C H 2 ) n C C H 2 N H 2 - H C l 1_61 a n =6 b n =3 E t O H HCl 0 " E t 0 2 C ( C H 2 ) n C C H 2 N H 2 - H C l 166a b n = 6 n = 3 Fig. 22: Synthesis of a-Aminoketones. i n i t i a l acylated product 164a was i s o l a t e d by column chromatography (^20%) p r i o r to the a c i d i c hydrolysis to the a-amino ketone hydro-chloride 161a. However, for larger scale (0.2 mol) reactions the products of the a c y l a t i o n step were refluxed i n 6M hydrochloric acid without p u r i f i c a t i o n . Extraction of the reaction mixture with ethyl acetate removed some of the impurities and the a-amino ketone hydro-chloride 161 was p r e c i p i t a t e d by addi t i o n of acetone to the concentrated aqueous phase. The crude y i e l d varied from 20-40%. When g l u t a r i c anhydride 163b was used the a-amino ketone hydrochloride 161b was 215 obtained i n 21.5% o v e r a l l y i e l d (33.4% reported y i e l d ) . In an attempt to s i m p l i f y work-up the dianion of benzyl hippurate 162b was reacted with the mixed anhydride 163a. Hydrogenation of the crude product brought about d e e s t e r i f i c a t i o n and decarboxylation to give the a-benzamido ketone 165 which was p u r i f i e d by column chromatography (.33%) . Subsequent hydrolysis provided the a-amino ketone hydrochloride 161a. R e - e s t e r i f i c a t i o n was accomplished by s t i r r i n g i n ethanolic hydrogen ch l o r i d e (v70%). The formation of the imidazoline—2-thione 151 was ca r r i e d out by 216 the method of A l t l a n d and Doney. Condensation of a-amino ketone 166a and the a l k y l isothiocyanate 149a occurred i n r e f l u x i n g toluene i n the presence of triethylamine with, azeotropic removal of the water formed during the re a c t i o n . A f t e r work-up and chromatography the desired product was obtained i n 27-35% y i e l d (Scheme 9.0.) . The d i f f i c u l t y of obtaining large quantities of the pure a-amino ketone 166 coupled with the poor y i e l d s of the imidazoline-2-thione condensation prompted us to inve s t i g a t e other methods of obtaining 1,5-disubstituted imidazoles. Our attention was focussed on the SCHEME 90 o E t0 2 C(CH 2 ) n C 166a n = 6 ^ N H 2 b n = 3 HCI E t0 2 C(CH 2 ) n / (CH 2 ) n C0 2Me N r U9a n= 6 * — b n = 3 S Et 3N C 7 H 8 A 1_51a n= 6 b n= 3 v (CH ? ) n CO ? Me \ _ N Us H 219. report of Van Leusen et a l . These workers had studied the use of tosylmethyl isocyanide (TosMIC) in the preparation of various hetero-cyclic ring systems. The reaction of TosMIC with aldimines in the presence of base (I^CO , t-BuNH^) reportedly provided 1,5-disiibstituted imidazoles in high yield. Following Van Leusen's published procedure a preformed aldimine 167 was reacted with. TosMIC 168 in the presence 1 2 of base (Scheme 91). However, despite variation of R and R , type and quantity of base, and stoichiometry and reaction time, the yields of imidazole 169 were uniformly disappointing (^40% crude yield). These low yields were i n i t i a l l y attributed to the instability of the aldimine under the ^basic condition of the reaction. Aldimines from primary aldehydes which, contain a -CH2-C=N- group undergo aldol-type 22Q condensations easily to give polymers.' It was noted that the high. 204 TABLE I I I : Preparation of l-Butyl-5-Propylimidazole H + TosMIC •N 'N BASE mmol ALDIMINE mmol TosMIC mmol SOLVENT hrs/°C % YIELD n-BuNH„ i 2.0 4.1 1.1 1.1 1.1 2.2 MeOH DME 14/RT 24/RT 30.3 19.0 K 2C0 3 2.0 2.0 1.6 1.1 1.1 1.1 1. 1 1.1 1.1 MeOH DME DME 18-/RT 52/RT 83/RT 9.7 2.5 37.3 t-BuNH„ 3.8 1.1 2.2 DME 23/RT 12.5 C6 H13 N 1.5 1. 1 1.1 DME 45/RT . 27.0 Et 3N 1.6 1.1 1. 1 DME 45/RT 4.5 NaH 1.4 1. 1 1.1 DMSO/DME 4/RT BuLi 1.0 1.1 1. 1 THF - 7 8 ° C SCHEME 91 205 0 yields reported by Van Leusen et a l . , were for aldimines containing methyl, isopropyl, or t-butyl groups. Alternatively, addition of the aldehyde to a solution of TosMIC and excess amine in methanol gave excellent yields of the corresponding 221 imidazole (Scheme 9.2) . Using a stoichiometric amount of the primary amine and triethylamine as base also gave equally good yields. These results prompted us to attempt the preparation of imidazole bis-aldehyde 170, which could be subjected to a double Wittig reaction with the pyrrole phosphonium iodide 94a and elaborated to form the strapped porphyrin as in the phenol and quinone cases (Fig. 23). Our i n i t i a l target molecule was the imidazole bis-ester 171 which, might be reduced to the bis-alcohol 172 and oxidized to the aldehyde 206 EtO 0 173 + E t O ^ ^ N H 2 0 TosMIC E« 3N Et0 2C!CH 2) 2 x J C H ^ C O j E t N 171 OL 175 0 ^ ^ - N H 2 176 TosMIC E t 3 N B*0(CH,) 3 (CH 2 ) 3 OBr 174 H O ( C H 2 ) 3 v _ N , ( C H 2 ) 3 O H 172 OHC(CH 2) 2. N / ( C H 2 ) 2 C H O O m F i g , 23: Proposed Synthesis of Imidazole - Strapped Porphyrin v i a 1,5-Bis(3-hydroxypropyl)imidazole 172 207 SCHEME 9 2 CH3(CH2)5CHO • CH3ICH2)3NH2 _ ! ! ^ ^ C H3< C H2>5>_ N /(CH 2 ) 3 CH 3 TosMIC // A -90% CH3ICH2)5CHO + H2N(CH2)5C02Et - C H 3 ( C H 2 ) 5 v _ N / ICH^COjEt TosMIC (HJ> ~ 7 ? % CH3(CH2)2CHO + H2N(CH2)3CH3 » C H 3 C H 2 /(CH2)2CH3 ^ X S N CH3CH2CHO +' H2N(CH2)3CH3 - CH 3CH 2 |CH2)2CH3 xs TosM,c O 170. Model reactions on a related system suggested that this, was possible (equation 64). However, as we anticipated d i f f i c u l t i e s i n CH3(CH2)2 (CH 2) 5C0 2Et 1) LiAlH^ CH 3(CH 2) 2. N / (CH 2 ) 5 CHO N 2) (C0CI)2/DMS0 N Et3N (64) preparing the succinaldehyde 173, we decided to prepare the hi s - a l c o h o l 222 172 from the his-henzyl ether 174, a route developed by Battersby. Both, the aldehyde 175 and the amine 176 necessary for formation of 1,5-bis.(.3-benzyloxypropyl)imidazole 174_ were e a s i l y prepared. Treatment of 1,4-butanediol with 0.5 equivalents of sodium and 0..3 208 equivalents of benzyl chloride furnished the 3-benzyloxybutan-l-ol 177 223 in 44-70% yield, which was oxidized to the aldehyde 175 using 189 dimethyl sulfoxide/oxalyl chloride (65-83% after vacuum d i s t i l l a t i o n ) . SCHEME 93 (C0C I ) 9 /DMS0 . ^ ^ Q ^ ^ Y ^ (65) Et 3N ^ 0 175 <Q)-CH 20H V78 176 (66) Obtaining the amine 176 proved to b.e somewhat more d i f f i c u l t . The n i t r i l e 178 was easily prepared by adding acrylonitrile to sodium 224 benzylate, the product being obtained by vacuum d i s t i l l a t i o n (.67%). Attempts to reduce the n i t r i l e to the corresponding amine 176 met with varying success. Both diborane and lithium aluminum hydride reductions 232 failed, the latter presumably due to removal of the henzyloxy group. 225 I n i t i a l l y borane/dimethyl sulfide gave reasonable yields (.57-66% 209 crude product) of the amine, but the yield decreased to zero on repetition for some inexplicable reason. While tetra-n-butylammonium 226 borohydride did reduce the n i t r i l e , the crude product was contamina-ted with tetra-n-butylammonium salts. The yields varied (30.-68%) depending on the scale of the reaction, large scale reactions being tedious to work-up due to solubility problems. Eventually alane was 227 found to carry out the reaction in high, yield (80-90%). The imidazole 174 was prepared by stirring equimolar amounts of the. aldehyde 175, amine 176 and TosMIC with 4-5 equivalents of triethylamine in methanol for 70.-168 hours. The solvent was removed and the residue partitioned between ethyl acetate and 3M hydrochloric acid. Neutralization of the aqueous layer and back-extraction with, ethyl acetate gave a very crude product, which, was purified somewhat by column chromatography to give a yellow o i l . "''H-NMR of the product at this stage showed a l l the necessary signals, but the presence of other rresonances and the appearance of other spots on t i c showed i t to be s t i l l crude. The imidazole cyclization was judged to have proceeded in 30-50% yield based on the weight of this crude product which was carried through, to the next stage without further purification. The low yields of imidazole 174 were both, disappointing and puzzling. The preparation of imidazoles bearing non—functionalized alkyl chains had, under the same reactions, given* excellent yields. Why itfihe introduction of the benzyl ether functions resulted in such, a lowering of yield remains unclear. Furthermore, reaction of TosMIC with, a pre-formed aldimine 179 under essentially similar conditions gave equally disappointing yields (Scheme 94). Hydrogenolysis of the b nzyl et rs using palladium-charcoal as 210 SCHEME 94 £3~ C H 2 ° I C H 2'3 N H 2 catalyst resulted in, at test, only partial deprotection; presumably some by-product was poisoning the catalyst. Similarly, transhydro-genation using cyclohexene and a catalytic quantity of palladium-charcoal in refluxing ethanol gave a mixture of starting material and 208 products. Only on addition of stoichiometric amounts of the catalyst could complete hydrogenolysis be effected. A more convenient procedure was to carry out a reductive cleavage 228 of the benzyl ethers using sodium in liquid ammonia. Complete removal was achieved but isolation of the 1,5-bis(3-hydroxypropyl)-imidazole 172 was hampered by it s low solubility in non-polar solvents. Using methanol to recover the product led to contamination of the product with the ammonium chloride used to quench the reduction. Never-theless samples of the imidazole were obtained by chromatography (60-70%). H^-NMR was used to confirm the removal of the benzyl ethers. With samples of the 1, 5-bis(3-hydroxylpropyl)imidazole 172 avail-ablel i t was decided to push ahead to the oxidation step since only small quantities of the dialdehyde 170 would be required in the conver-O H C ( C H 2 ) 2 V N / ( C H 2 ) 2 C H O H O ( C H 2 ) 3 v N / ( C H 2 ) 3 O H v m o m gent porphyrin synthesis. However oxidation of 172 to 170, proved to be 188 f r u i t l e s s . Stirring with, pyridinium dichromate for 12 hours in dichloromethane/tetrahydrofuran (10:1) or dichloromethane/pyridine (1:1), followed by f i l t r a t i o n through, a short s i l i c a gel plug to remove the chromium salts did not lead to the isolation of any recognizable 229 product. Similarly refluxing 172 with, tetrahutylammonium chromate in tetrahydrofuran gave no recognizable product after work-up. 230 Likewise Oppenauer oxidation with aluminum isopropoxide and henzo-h phenone showed no sign of the his-aldehyde product 170. Oxidation using DMSO/Et^N/CCOCl)^ was examined more closely since these reagents had previously been used to oxidize a hydroxyalkyl imidazole 180 to the corresponding aldehyde 181 (equation 67). Addition of oxalyl chloride to a solution of dimethyl sulfoxide in dichloromethane CH3(CH2)2. N/(CH2)6OH CH3(CH2)2. N (CH2)5CHO f j (C0CI)2/DMS0 Fl N IN Et3N ( 6 7 ) 180 .. 181 K } 212 at -78°C was accompanied by an increase i n temperature and the evolution of gas as the i n i t i a l l y formed species I decomposed to the dimethyl-sulfonium chloride II (Scheme 95). On addition of the 1,5-bis(3-hydroxy-propyl)imidazole 172 i n CI^Cl /DMSO sol u t i o n , a white p r e c i p i t a t e appeared, presumably due to formation of the dimethyl alkoxysulfonium SCHEME 95 H 3 C \ * . H 3 C \ + H 3 C V . S - 0 + (COCDo • / S - O C C C l • X-c i H 3 C H 3 C nil H 3 ^ C f Tl H 3 C V HO(CH 2 J 3 |CH 2 ) 3 OH H 3 C X . .s-ci •+ f \ • ; S - O C H 2 R c r H 3 C H . C 7 H 172 HI + H 3 C N + v H 3 C X / S - O T C H - R CI' • / S + EtNHCl + RCHO H 2C v l H 3 C /  z l \ H ? UL V ; N E t 3 s a l t I I I . Subsequent addition of triethylamine led to a temporary disappearance of the white p r e c i p i t a t e , which, then returned due to formation of triethylammonium chloride. The reaction mixture was allowed to warm to room temperature then quenched by addition of water. Extraction of the reaction mixture with, d i l u t e hydrochloric acid, followed by n e u t r a l i z a t i o n , back-extraction into ethyl acetate and removal of the solvent gave only a minute amount of material showing several spots on t i c . 2 1 3 Fearing that the product had b een lost in the aqueous phase during work-up, the oxidation was repeated under the same conditions. This time however, after quenching with water, the entire reaction mixture was taken to dryness. Again t i c showed many spots and '''H-NMR of the residue showed no indication of any aldehyde peaks. Other combinations of conditions were employed. In one instance the reaction was quenched by addition of water while s t i l l at -78°C, and in another, the solution containing the dimethyl alkoxysulfonium s a l t I I I was allowed to warm to 0°C before" addition of triethylamine. In neither case was any of the desired aldehyde observed. Furthermore, improving the solubility of 172 by increasing the quantity of dimethyl sulfoxide, or cancelling the aqueous quench, gave no sign of product. Replacement of triethylamine with diisopropylamine resulted in no improvement. In only one instance was: a recognizable carbonyl product obtained. 1,5-Bis(.3-hydroxypropyl)imidazole 1_72^  (p..4 g) was subjected to the usual oxidation procedure and quenched with water. After work-up of both the aqueous and organic layers, t i c showed a large spot for dimethyl sulfoxide which was preceeded by a smaller spot. This material was isolated by chromatography to give an off-white solid. The "''H-NMR 172 214 of t h i s product did show a peak i n the aldehyde region, but i t was a s i n g l e t rather than the expected t r i p l e t . This f a c t , coupled with the absence of t r i p l e t s at ^2.6 and 3.8-4.0 6 indicated that the product was not the desired bis-aldehyde 170. Indeed the pattern of resonances [2.6-2.9 (m, 2a ) , -2 .9 -3.1 On, 2H), 4.88 (d, 2H), 6.86 (m, 2H), 7.42 (bs, IH), 9.42 (s, IH)] was more consistent with, the b i c y c l i c imidazole product 182, formed by intramolecular a l d o l condensation. The assign-ment was further confirmed by mass, spectrometry (m/e 162) and by two bands i n the i n f r a - r e d spectrum at 1675 and 1630 cm \ due to the carbonyl and imine bonds re s p e c t i v e l y . These f a i l u r e s : led us to believe that s u i t a b l e conditions could not be found to produce 170 i n s a t i s f a c t o r y yields. . Since the formation of the 1,5-disuhstituted imidazoles had also been t y p i f i e d by poor y i e l d s and d i f f i c u l t i e s i n p u r i f i c a t i o n , further e f f o r t s i n t h i s f i e l d were postponed. With, the p u b l i c a t i o n by Momenteau"''38 and by Battershy 1^ 2 1 5 of heme models containing a "pendant" and a "strapped" imidazole r e s p e c t i v e l y , our attempts to prepare a strapped imidazole porphyrin were abandoned. CHAPTER 3 EXPERIMENTAL 217 3.1 INTRODUCTION 3.1.1 GENERAL METHODS Melting point determinations were obtained using a Thomas-Hoover Unimelt o i l - b a t h / c a p i l l a r y tube apparatus, and a l l the quoted r e s u l t s are uncorrected. A Cary (Model 1756) spectrophotometer was used to record UV and v i s i b l e spectra. Elemental analysis, was; c a r r i e d out by Kr. P. Borda of the Micro a r i a l y t i c a l Laboratory, U.B.C. Mass Spectra were recorded on a Varian MAT CH 4-B spectrometer or a Kratos/AEI MS-902 spectrometer. High r e s o l u t i o n measurements were obtained on a Kratos/AEI MS-50 spectrometer. In a l l cases the i o n i z a t i o n voltage was 70 eV. The "''H NMR spectra of a l l the monopyrroles were obtained at 100 MHz with a Varian XL-100. spectrometer under Fourier-transform conditions. The spectra of the chain-linked bis-pyrroles were recorded at 270 MHz with a U.B.C. NMR Centre modified Nicolet-Oxford H-270. spectrometer. The spectra of the chain-linked his-dipyrromethanes and the strapped porphyrins were recorded at 400 MHz on a Bruker WH—400 spectrometer. For the substituted benzene and imidazole compounds the spectra were recorded on a Varian EM-360L or XL-100 spectrometer. The chemical s h i f t s were recorded with tetramethylsilane (.TMS) as an i n t e r n a l standard. 13 Most of the C-NMR spectra were obtained with, a Varian CFT-2Q spectrometer using TMS as the i n t e r n a l standard. Compounds: 113b., 138a and 138b were recorded on a Bruker WP-80 instrument operating at 20..15 MHz 218 and using deuterochloroform (6 = 77.0) as i n t e r n a l standard. Of the strapped porphyrins, 87b, 88b, 117a, 118a and 118b were recorded on a Var ia.n CFT—20 spectrometer i the others were recorded on a Brulcer WH—400 spectrometer. The samples were 0.012-0.082M i n 10% TFA-CDC13 with TMS as an i n t e r n a l standard. Column chromatography on s i l i c a gel was performed using BDH s i l i c a gel (60-120 mesh), Merck K i e s e l g e l 60H, or Merck K i e s e l g e l 60 (70-230 mesh). For the f i n a l p u r i f i c a t i o n of the porphyrin samples Merck aluminum oxide 90 (70-230 mesh, neutral, a c t i v i t y III) was used. Thin layer chromatography ( t i c ) was performed using precoated s i l i c a gel plates (Analtech-Uniplate, 250u) , and the compounds were usually detected by UV l i g h t (254 nm) and/or exposure to iodine. Mixtures of solvents used i n chromatography are expressed as volume:volume percentages. 3.1.2 Nomenclature of Porphyrins and Intermediate Compounds The strapped porphyrins have been numbered i n accordance with the IUPAC recommendations on "Nomenclature of Tetrapyrroles" as indicated i n 233 Fi g . 24. For consistency i n the diagrams the strap has been attached to p o s i t i o n s 3 arid 13 of the porphyrin r i n g . For convenience and c l a r i t y , a l l the pyrroles and dipyrromethane compounds have been named as de r i v a t i v e s of the fun c t i o n a l i z e d alkane chain. Numbering of both, the pyrrole r i n g and the alkane chain has been kept constant; thus the alkane chain has been always numbered as attached to p o s i t i o n 3 of the pyrrole r i n g and the ethoxycarb.onyl group at p o s i t i o n 219 F i g . 24: F i s c h e r (a) and IUPAC (b) Numbering Systems f o r P o r p h y r i n s 5. F o r example compounds such as .183, ( F i g . 25), haye b.een c o n s i s t e n t l y d e s c r i b e d as 5 - ( 5 - e t h o x y c a r b o n y l - 2 , 4 - d i m e t h y l p y r r o l - 3 — y l ) p e n t a n e d e r i v a -t i v e s . The c h a i n - l i n k e d h i s - p y r r o l e s have been numbered i n s i m i l a r f a s h i o n . Thus 75a has been named as b i s [ 5 - ( 5 - e t h o x y c a r b o n y l - 4 - m e t h y l -p y r r o l e - 3 - y l ) p e n t y l ] s u l f i d e . T h i s name i s more i n f o r m a t i v e and l e s s u nwieldy t h a n the c o r r e s p o n d i n g IUPAC o r Chemical A b s t r a c t names. In k e e p i n g w i t h Chemical A b s t r a c t s nomenclature the d i p y r r o -methanes have been named as s u b s t i t u t e d ( p y r r o l e - 2 - y l ) m e t h y l p y r r o l e s 184 ( F i g . 2 6 ) . The p y r r o l e n u c l e i were numbered so as to a s s i g n 2 and 2' t o t h e methane b r i d g e d a - p o s i t i o n s . The numbers 2', 3' e t c . have been used on one p y r r o l e r i n g o n l y f o r the purpose o f d i s t i n g u i s h i n g the analogous p o s i t i o n s on t h e two r i n g s i n s p e c t r a l a s s i g n m e n t s . Thus the b i s - d i p y r r o m e t h a n e 77a ( F i g . 26) was named as b i s { . 5 - ( 5 - e t h o x y c a r b o n y l -220 75a F i g . 25: Numbering System for P y r r o l i c Intermediates -2[ (5-(2 ,2-dicyanovinyl) -3^-ethyl-4-methylpyrrol-2-yl)methylJ-4-methyl-p y r r o l - 3 - y l ) p e n t y l s u l f i d e . 184 222 3.2 SYNTHESES OF MONOPYRROLES H 3C 0 C(CH 2 ) 3 C0 2 Et EtO CH 3 28 Ethyl 5-(5-Ethoxycarbonyl-2,4-dimethylpyrrol-3-yl)-5-pxopentanoate 28 Ethyl hydrogen glutarate (96.0 g, 0.54 mol ) and thionyl chloride (120 mL, 1.6 mol ) were placed in a round bottom flask _ equipped with a reflux condenser -and a drying tube and heated on a steam bath for 2 hours. The excess thionyl chloride was removed by rotary evaporation with carbon tetrachloride (2 x 100 mL) to give a dark yellow o i l . This crude acid chloride was used without purification. 5-Ethoxycarbonyl-2,4-dimethylpyrrole 1_ (75.0 g, 0.45 mol) was dissolved in dichloromethane (.750 mL) in a 2-liter Erlenmeyer flask equipped with a Claisen adapter, nitrogen inlet, pressure-equalizing dropping funnel and drying tube. The crude acid chloride was added and the mixture stirred under nitrogen and cooled in an ice-bath. Stannic chloride (.58.0 mL, Q.50. mol) was added dropwise over a period of 35 minutes and the solution was then l e f t s t i r r i n g for 1.5 hours. By this stage t i c (.10% EtOAc/CR^Cl^ indicated complete consumption of starting material. The reaction mixture was poured into 2M hydrochloric acid (40.0 mL) and the dichloromethane layer was separated. This was; extracted with. sodium bicarbonate so l u t i o n to remove unreacted acid chloride, then dried over anhydrous sodium s u l f a t e , f i l t e r e d and evaporated. The resultant dark red o i l was dissolved i n ethanol (500 mL). Addition of water p r e c i p i t a t e d a s o l i d which was c o l l e c t e d by f i l t r a t i o n and dried to give 116.8 g (84.1%). The product was contaminated with a trace of s t a r t i n g pyrrole but was used without further p u r i f i c a t i o n . An a n a l y t i c a l l y pure sample was prepared by column chromatography on s i l i c a gel with. 10% Et0Ac/CH 2Cl 2 as eluant. MP; 68.0-70.0°C. 2H-NMR (4, CDC1 3): 1.26 (t , 3H, J = 7.0 Hz, chain -0CH2<IH3), 1.38 (t, 3H, J = 7.0 Hz, pyrrole -QQL^ CHy, 2.08 Cq, 2H, J = 7 Hz, chain 3-CH 2), 2.43 (t , 2H, J = 7 Hz, chain 2-CH 2), 2.54 Cs, 3H, A-CK^, 2.60 Cs, 3H, 2-CH 3), 2.80 ( t , 2H, J = 7 Hz, chain 4-CH 2), 4.16 (.q, 2H, J = 7.0 Hz, chain -OGH^CH^ , 4.37 Cq, 2H, J = 7.0 Hz, pyrrole -OCf^CH^, 9.38 (bs, IH, N-H). 13 C-NMR C&, CDC1 3): 197.0.5 (chain 5-C, C = Q), 173.41 (chain 1-C, C! = 0), 162.10 (pyrrole ester, C = Q), 138.53 (pyrrole 2-C), 129.16 . (pyrrole 4-C), 123.21 (pyrrole 3-C), 118.09 (pyrrole 5-C), 60.28 (pyrrole and chain ester, -0CH 2CH 3), 41.54 (chain 4-C), 33.57 (chain 2-C), 19.45 (chain 3-C), 14.86 (2-CH 3), 14.32 (pyrrole ester, -0CH 2CH 3), 14.20 (chain ester, -OCH^H }, 12.71 (4-CH 3). Anal. Calcd. for C 1 6 H 2 3 N 0 5 : c> 62.12; H, 7.49; N, 4.53. Found: C, 62.15; H, 7.52; N, 4.59. 224 Mass. Spectrum: (m/e, r e l a t i v e i n t e n s i t y ) : 30.9 (M +, 28), 264-(.24), 222 (10) , 209 (.7), 19.4 (83), 148 (.100.). Ethyl 4^ - (5-Ethoxycarb.onyl-2,4-dimethylpyrrol-3-yl)-4-oxohutanoate 56 This was prepared from 5-ethoxycarbonyl-2,4-dimethylpyrrole _1_ (20.0 g, 0.12 mol). and ethyl s u c c i n y l chloride 55 (23.6 g, 0.14 mol) by the same procedure as for the homologous pyrrole 28. The crude product was r e c r y s t a l l i z e d from the minimum amount of hot ethanol to give a white c r y s t a l l i n e s o l i d as a f i r s t crop (25.7 g, 0 C ( C H 2 ) 2 C 0 2 E t 5 6 72.8%). MP: 144.Q - 145.5°C. RVNMR (<S., CDC13) : 1.28 ( t , 3H., J =7.0 Hz, chain -OC^CH. ), 1.39. ( t , 3H, J = 7.0 Hz, pyrrole -0CH2CH ),'2.55 (s, 3H, 4-CH ), 2.60 (s, 3H, 2-CH 3), 2.72 ( t , 2H, J = 6.Hz, chain 2-CH 2), 3.08 ( t , 2H, J = 6 Hz, chain 3-CH 2), 4.19 (q, 2H, J = 7.0 Hz, chain -OCH^CH.^, 4.37 (q, 2H, J = 7.0. Hz, pyrrole -CH 2CH 3), 9L.14 (bs, IH, N-H). 13 C-NMR OS, CDC1 3): 195.49 (chain 5-C, C = 0), 173.35 (chain 1-C, C = 225 0), 162.08 (p y r r o l ester, C = 0), 138.65 (pyrrole 2-C), 129.32 (pyrrole 4-C), 123.03 (pyrrole 3-C), 118.22 (pyrrole 5-C), 60.55 (pyrrole ester, -0CH 2CH 3), 60.45 (chain ester -OCH^CRy , 37.51 (chain 3-C), 28.42 (chain 2-C), 15.12 (2-CH 3), 14.46 (pyrrole ester, -0CH 2CH 3), 14.22 (chain ester, -OCR^CH^), 12.86 (4-CRy . Anal. Calcd. for C 1 CH N0 C: C, 61.00; H, 7.17; N, 4.74. Found: 15 21 5 C, 61.06; H, 7.26; N, 4.71. Mass Spectrum (m/e'relative i n t e n s i t y ) : 295 (M +, 39), 250 (34), 222 (8), 194 (.76), 166 (13), 149 (.100). 5-C5-Ethoxycarbonyl-2,4-dlmethylpyrrol-3-yl)-l-pentanol 30 E t h y l 5-(5-ethoxycarbonyl-2,4-dimethylpyrr©l-3-yl)^5-oxopenta-noate 2J3 (56.3 g, 0.18 mol) was d i s s o l v e d i n f r e s h l y d i s t i l l e d t e t r a -hydrofuran (300 mL) and s t i r r e d under n i t r o g e n i n a 1 - l i t e r Erlenmeyer f l a s k equipped w i t h a p r e s s u r e - e q u a l i z i n g a d d i t i o n f u n n e l . Sodium borohydride (14.5 g, 0.38 mol) was added, followed by dropwise a d d i t i o n of boron t r i f l u o r i d e etherate (62.7 mL, 0.51 mol) over a period of 20 minutes. No e x t e r n a l c o o l i n g was a p p l i e d and the r e a c t i o n 226 temperature rose to ^ 50°C. The reaction was l e f t s t i r r i n g for 2 hours. The reaction was quenched by the slow, careful addition of glacial acetic acid ( 50 mL) followed by the addition of water unt i l the solution became a clear red. The tetrahydrofuran was removed on a rotary evaporator and the red o i l which then separated was extracted with, dichloromethane (300 mL). The dichloromethane solution was dried over anhydrous sodium sulfate, filtered and evaporated to give a dark red o i l . Dissolving this in ethanol (.100 mL) and adding water precipitated a pink solid which, was fil t e r e d and air-dried to yield 39.2 g (85.0%). MP: 84.Q-85.0°C. 2H-NMR (6, CDC13): 1.36 (t, 3H, J = 7.0 Hz, -OCH^H.^), 1.2-1.7 (m, 7H, chain 2-, 3-, 4-CH2, 0-H), 2.21 (s, 3H, 2-CH^, 2.28 (s, 3H, 4-CH3), 2.39 (t, 2H, chain 5-CH2), 3.69 (t, 2H, J = 6 Hz, 1-CH2), 4.32 (q, 2H, J = 7.0. Hz, -0CH2CH3), 8.64 (bs, IH, N-H) 13C-NMR (<5, CDC13): 162.35 (C = 0), 130.26 (pyrrole 2-C) , 127 .0.7 (pyrrole 4-C), 122.06 (pyrrole 3-C), 116.75 (pyrrole 5-C), 62.66 (chain 1-C), 59.62 (-OCI^CH ), 32.74 (chain 2-C), 30.77 (chain 4-C), 25.66 (chain 3-C), 24.04 (chain 5-C), 14.57 (-OC^CH^, '11.36 .(2-CH ), 10.75 (4-CH3). Arial. Calcd. forC,.H N0o: C, 66.37; H, 9.15; N, 5.53. Found: 14 23 3 C, 66.41; H, 9.12; N, .5.50. 227 Mass Spectrum (m/e, r e l a t i v e i n t e n s i t y ) : 253 (M +, 34), 208 (8), 180 (100), 134 (69). 4-(5-Ethoxycarbonyl-2,4-dimethylpyrrol-3-yl)-l-butanol 57 This was prepared i n the same way as 30, from ethyl 4-(5-ethoxy-carbonyl-2,4-dimethylpyrrol-3-yl)-4-oxobutanoate 56 (14.4 g, 0.05 mol), sodium borohydride (7.4 g, 0.2 mol) and boron t r i f l u o r i d e etherate (37.0 mL, 0.3 mol). Afte r work-up a yellow o i l was obtained which, slowly c r y s t a l l i z e d to a white s o l i d . The crude product was r e c r y s t a l l i z e d from 50% water/ ethanol (100 mL) to give 8.4 g (72.1%): 5 7 MP: 117.0-119.Q°C. 1 H-NMR CS, CDC1 3): 1.36 ( t , 3H, J =7.0 Hz, -OCH2CH_3) , 1.5-1.7 (m, 5H, chain 2-, 3-CH2, 0-H), 2.21 (s, 3H, 2-CH 3), 2.28 (,s, 3H, 4-CH 3), 2.40 ( t , 2H, chain 4-CH 2), 3.67 ( t , 2H, chain 1-CH 2), 4.32 (.q, 2H, J = 7.0 Hz, -OCH 2CH 3), 8.7 (bs, IH, N-H). 13 C-NMR CS, CDC1 3): 162.12 (C = 0), 129.94 (pyrrole 2-C), 127.08 (pyrrole 4-C), 121.87 (pyrrole 3-C), 116.85 (pyrrole 5-C), 62.81 (chain 1-C), 59.65 (-OCH CH ), 32.49 (chain 2-C), 27.02 (chain 3-C), 23.82 (chain 4-C), 14.60 (-OCH^CHy , 11.45 (2-CH ), 10.71 (4-CH ). Anal. Calcd. for C 1 3 H 2 1 N 0 3 : c> 65.24; H, 8.85; N, 5.85. Found: C, 65.24; H, 8.86; N, 5.81. Mass Spectrum (m/e, relative intensity): 239 (M+, 38), 194 (11), 180 (100), 166 (4), 134 (.88). J5^(5-Ethoxycarhonyl-2,4-dimethylpyrrol-3-yl)-l-pentylmethanesulfonate 35_ 5-(5-Ethoxycarbonyl-2,4-dimethylpyrrol-3-yl)==l-pentanol 3(3 (39.2 . 0.16 mol) and triethylamine (32.3 g, 0.23 mol), were dissolved in dichloromethane (500 mL) in a 3-neck flask equipped with i a nitrogen inlet, overhead stirrer and pressure-equalizing addition funnel. The solution was stirred under nitrogen and cooled to 0loC in an ice-bath.. Methanesulfonyl chloride (18.5 mL, 0.1SL mol) was: added dropwise over a period of 10 minutes, and the reaction mixture was then allowed to warm to room temperature. Tic (.50% EtOAc/CH CI ) indicated complete reaction. The reaction mixture was extracted i n turn with water (200 mL), cold 2M hydrochloric a c i d (200 mL), saturated sodium bicarbonate s o l u t i o n and f i n a l l y saturated sodium chloride s o l u t i o n . The d i c h l o r o -methane so l u t i o n was dried over anhydrous sodium s u l f a t e , f i l t e r e d and evaporated. A dark red o i l was obtained. Dissolving i n the minimum amount of hot ethanol and adding water p r e c i p i t a t e d a pink s o l i d . This was f i l t e r e d and a i r - d r i e d (47.1 g, 91.8%). The product was ca r r i e d to the next stage without further p u r i f i c a t i o n . An a n a l y t i c a l l y pure sample was prepared by column chromatography on s i l i c a gel with 20% E t O A c / C H ^ C l ^ as.eluant. MP: 68.0,-70.0°C. 1 H-NMR 05, CDC1 3): 1.35 ( t , 3H, J =7.0 Hz, -OC^CH^), 1.2-1.9 (m, 6H, chain 2-, 3-, 4-CH 2), 2.20 (s, 3H, 2-CH ),.2.27 (s, 3H, 4-CH 3), 2.39 (m, 2H, chain 5-CH 2), 2.99 (s, 3H, -OS02CH_3), 4.23 (t, 2H, J = 7 Hz, chain 1-CH2) , 4.24 (q, 2H, J = 7.0 Hz, -OCH^CH^, 8.79 (bs, IH, N-H) . 13C-NMR (6, CDC1 3): 162.14 (C = Q), 130.11 (pyrrole 2-C), 126.83 (pyrrole 4-C), 121.63 (pyrrole 3-C), 116.90 (pyrrole 5-C), 70.20 (chain 1-CH 2), 59.61 (-OCH2CH3), 37.22 (-OSO^CH^, 30.29 (chain 4-C), 29.15 (chain 3-C), 25.19 (chain 2-C), 23.85 (chain 5-C), 14.60 (-0CH 2£H 3), 11.36 (2-CH 3), 10.72 C4-CH 3). Anal. Calcd. f o r C I 5 H 2 5 N 0 5 S : c» 54.36; H, 7.60; N, 4.23; S, 9.68. 230 Found: C, 54.22; H, 7.66; N, 4.26; S, 9.55. Mass Spectrum (m/e, relative intensity): 331 (M+, 12), 286 (2), 281 (16), 252 (3), 251 (4), 236 (4), 206 (5), 180 (100), 134 (32). 4-(5-Ethoxycarbonyl-2,4-dimethylpyrrol-3-yl)-l-hutylmethanesulfonate 58 4-(5-Ethoxycarbonyl-2,4-dimethylpyrrol-3-yl)-l-butanol 5_7 (8.4 g, 35 mmol) in dichloromethane (.250. mL) was treated with, triethylamine (7.3 mL, 52 mmol) and methanesulfonyl chloride (4.8 mL, 48 mmol) as outlined for the analogous compound 35_ above. Recrystallization from 50% ethanol/water gave a white flaky solid (8.2 g, 74.0%). A second crop (1.5 g, 13.7%) was obtained from the mother liquors. MP: 82.0-83.5°C. H^-NMR (jS, CDC13): 1.36 (t, 3H., J =7.0 Hz, -OCH^H^), 1.4-1.9 (m, 4H, chain 2-, 3-CH2), 2.21 (s, 3H, 2-CH ) , ; 2 . 2 8 (s, 3H, 4-CH.^ ) , 2.43 (t, 2H, chain 4-CH2), 3.00 (s, 3H, -0S02CH3), 4.27 (t, 2H, J = 6 Hz, chain 1-CH2), 4.33 (q, 2H, J =7.0 Hz, -OCIL^CH^, 8.58 (bs, IH, N-H). " C-NMR (.6, CDC13): 162.00 (C = 0), 129.98 (pyrrole 2-C), 126.85 (pyrrole 4-C), 121.10 (pyrrole 3-H), 116.99 (pyrrole 5-C), 70.10 (chain 1-C), 59.66 (-OCI^CH^ , 37.32 (-0S02CH3),.28.76 (chain 3-C), 26.56 (chain 2-C), 23.39 (chain 4-C), 14.60 (-OCI^CRy , 11.42 (2-CH3), 10.71 C4-CH }. Anal. Calcd. for C 1 4 H 2 3 N 0 5 S : c> 52.98; H,.7.30; N, 4.41; S, 10.10. Found: C, 53.26; H, 7.37; N, 4.32; S, 9.95. Mass; Spectrum (m/e, relative intensity): 3.17 (M+, 11), 281 (.6), 272 (3), 267 (4), 239 (.4) , 238 (3), 222 (2), 192 (6) , 180 (.100) , 134 (88). 5-(5-Ethoxycarbonyl-4-methylpyrrol-3-yl)-l-pentylmethanesulfonate 53 This was prepared from 5-(5-ethoxycarbonyl-4-methylpyrrol-3-yl)-1-pentanol 51_ (3.22 g, 13.4 mmol), triethylamine (2.8 mL, 20.1 mmol) and methanesulfonyl chloride (1.61 mL, 16.0 mmol) as outlined for compound 35 above. The crude product, after work-up was obtained as a reddish o i l which, slowly crystallized to a pink solid (4.25 g, 99.5%) . This was carried to the next step without purification. A small sample, 232 recrystallized from 50% ethanol/water, was retained for analysis. MP: 74.5-76.0 C. "''H-NMR (.6, CDG13): 1.37 (t, 3H, J =7.0 Hz, -OCH^iy , 1.4-1.9 (m, 6H, chain 2-, 3-, 4-CH2>, 2.30 (s, 3H, 4-CH3), 2.44 (t, 2H, J = 7 Hz, chain 5-CH2), 3.02 (s, 3H, -OSO^H^ , 4.26 (t, 2H, J =7.0 Hz, chain 1-CH2), 4.34 (.q, 2H, J = 7.0 Hz, -OCH^C^), 6.70 (d, IH, J = 3.Q Hz, 2-H), 8.8 (bs, IE, N-H). 1 3 C-NMR C6, CDC13): 161.84 (C = 0!), 125.88 (pyrrole 3-C), 125.16 (pyrrole 4-C), 119.84 (pyrrole 2-C) , 119_.41 (pyrrole 5-C), 70.12 (chain 1-C), 59.82 (-OCH2CH3), 37.32 (-OSO^H^ , 29.75 Cchain 4-C), 29.0.5 (chain 3-C), 25.18 (chain 2-C), 24.79 (chain 5-C), 14.54 (.-0CH2CH3), 10.31 C4-CH3). Anal. Calcd. for C 1 4 H 2 3 N ° 5 S : C ' 52.98;' H, 7.30.; N, 4.41; S, 10.10. Found: C, 52.92; H, 7.43; N, 4.28; S, 10.00 Mass Spectrum (m/e, relative intensity): 317 (M , 31), 272 (7), 244 (11), 238 (.10), 222 (6), 208 (.2), 192 (.17), 180. (4), 166 (.100), 120 (.88). 233 4-(5-Ethoxycarbonyl-4-methylpyrrol-3-yl)-1-butylmethanesulfonate 74 This was prepared from 4-(5-ethoxycarbonyl-4-methylpyrrol-3-yl)-1-butanol 73 (9.79 mL, 43 mmol), triethylamine (10.0 mL, 72 mmol), and methanesulfonyl chloride (6.0 mL, 60 mmol). The crude product, obtained as a deep red o i l was c a r r i e d to the next stage without p u r i f i c a t i o n . An a n a l y t i c a l l y pure sample was obtained by column chromatography on s i l i c a g e l with. 10% EtOAc/CH^Cl^ as eluant. MP: '46.0-48.0°C. ^H-NMR (.6, CDC1 3): 1.36 ( t , 3H, J = 7.0. Hz, -OC^CH^), 1.5-1.9 (m, 4H, chain 2-, 3-CH 2), 2.29 (s, 3H., 4-CH 3), 2.47 ( t , 2H, chain 4-CH 2), 3.00. (s, 3H, -0S0 2CH 3), 4.26 (t, 2H, J = 7.0 Hz, chain 1-CH 2), 4.33 (q, 2H, J = 7.0 Hz, -OCH 2CH 3), 6.69 (d, IH, J = 3.0 Hz, 2-H), 8.95 (bs, 1, N-H) I3C-NMR (<5, CDC13) : 161.85 (C = 0), 125.85 (pyrrole 3-C), 124.57 (pyrrole 4-C), 119.97 (pyrrole 2-C), 119.46 (pyrrole 5-C), 70.07 (chain 1-C), 59.86 (-0CH2CH3), 37.31 (-OS02CH3) , 28.79 (chain 3-C), 26.16 234 (chain 2-C), 24.37 (chain 4-C), 14.53 (-OCR^CRy , 10.31 (4-CRy. Anal. Calcd. for C 1 3 H 2 1 N 0 5 S : c» -51.47; H, 6.98; N, 4.62; S, 10.57. Found: C, 51.50; H, 6.95; N, 4.64; S, 10.39. Mass Spectrum (m/e, relative intensity): 303 (M+, 22), 267 (18), 258 (7), 253 (.18) , 224 (13), 208 (7), 207 (.7), 206 (.4), 178 (,22), 166 (100), 120 (100.) , 134 (20) . 5-(5-Ethoxycarbonyl-2,4-dImetfrylpyrrol-3-yl)-1-iodopentane 40 5-(5-Ethoxycarbonyl-2,4-dimethylpyrrol-3-yl)-1-pentylmethane-sulfonate 35_ (46.6 g, 0.14 mol) and sodium iodide (84.0 g, 0.56 mol) were suspended in acetone (750 mL) and, with vigorous stirring, were refluxed for 16 hours. Tic (10% Et0Ac/CH 2Cl 2) indicated complete reaction. The reaction mixture was cooled to room temperature and the solid which, had precipitated during the course of the reaction was fi l t e r e d off. The f i l t r a t e was reduced in volume to approximately 20.0 mL, and addition of water (.200 mL) precipitated a red solid which, was collected by f i l t r a t i o n . While s t i l l damp the crude product was recrystallized from hot ethanol to give a pink solid (40.5 g, 79.3%). A second crop (6.4 g, 12.5%) was obtained by adding water to the mother liquor. MP: 79.0-80.0°C. 2H-NMR (<$, CDC13): 1.35 (t, 3H, J = 7.0 Hz, -OCT^CH ), 1.3-1.5 and 1.7-2.0 (m, 6H, chain 2-, 3-, 4-CH2), 2.20 (s, 3H, 2-CH3), 2.27 (s, 3H, 4-CH ), 2.2-2.5 (m, 2H, chain 5-CH ), 3.19 (t, 2H, J =7.0 Hz, chain 1-CH2), 4.31 (.q, 2H, J = 7.0 Hz, -OCH CH ). 13C-NMR C<5, CDC13): 162.QQ (C = 0), 129.79 (pyrrole 2-C), 126.82 (. (pyrrole 4-C), 121.75 (pyrrole 3-C), 116.87 (pyrrole 5-C), -59.58 C-0CH2CH3), 33.50 (chain 2-C), 30.34 (chain 4-C), 29.76 C.chain 3-C), 23.88 (chain 5-C), 14.61 (-0CH2CH3), 11.47 ( 2 - O y , 10.71 C4-CH3) , 6.78 (chain 1-C). Anal. Calcd. for C 1 4H 2 2N0 2I: C, 46.29; H, 6.11; N, 3.86; I, 34.9.4. Found: C, 46.50; H, 6.17; N, 3.68; I, 34.71. Mass Spectrum (m/e, relative intensity): 363 (M , 38), 318 (14), 236 (.69) , 180 (100), 134 (95) . 4- C5-Ethoxycarbonyl-2,4-dimeth_ylpyrrol-3-yl) -1-iodohutane 60 This was prepared from 4-(5-ethoxycarbonyl-2,4-dimethylpyrrol-3-yl)-1-butylmethanesulfonate 58_ (.9.2 g, 0.0.3 mol) by the method outlined .for compound 40. The crude product was r e c r y s t a l l i z e d from 20% ethanol/water to give a white flaky s o l i d (.8.2 g, 80.2%). A second crop (0.8 g, 7.9%) was obtained from the mother l i q u o r . MP: 81.0.-82.0°C. 1H-NMR (6, CDC13) : 1.36 ( t , 3H, J = 7.0 Hz, - O C ^ C y , .1.4-2.0 (in, 4H, chain 2-, 3-CH ) , 2.22 (s, 3H, 2-CH ) , 2.28 (s, 3H, 4-CH.j), 2.39 (t, 2H, J = 7.4 Hz, chain 4-CH ), 3.20 ( t , 2H, J = 7.2 Hz, chain 1-CH ), 4.32 (q, 2H, J = 7.0 Hz, -OCR^CH ) , 8.62 (bs, IH, N-H). 13C-NMR (6, CDC1 3): 162.07 (C = 0), 129.92 (pyrrole 2-C), 126.86 (pyrrole 4-C), 121.34 (pyrrole 3-C), 116.94 (pyrrole 5-C), 59.64 C-QCH CH ), 33.16 (chain 2-C), 31.57 (chain 3-C), 22.98 Cchaln 4-C), 14.60 (-OCH Ol ), 11.48 (2-CH-), 10.71 (4-CH 3), 6.77 (chain 1-C). 237 Anal. Calcd. for' C 1 3H NO I : C, 44.71; H, 5.77; N, 4.01; I, 36.34. Found: C, 44.96; H, 5.87; N, 4.01; I, 36.22. + Mass Spectrum (m/e, relative intensity): 349 (M , 60), 304 (9), 222 (.19), 180 (100), 148 (17), 134 (94). 5-(5-Ethoxycarb.onyl-2,4-dimethylpyrrol-3-yl).-l-acetoxypentane 46 5-(5-Ethoxycarbonyl-2,4-dimethylpyrrol-3-yl)-1-pentanol 30^  (9.2 g, 36 mmol) was stirred overnight in a mixture of pyridine (.16 mL) and acetic anhydride (.21 mL) . The mixture was then poured into water (100 mL) and extracted with, ethyl acetate (10.0. mL) . The organic layer was washed with 2M hydrochloric acid (100 mL), saturated sodium bicarbonate solution and saturated sodium chloride solution. After drying over anhydrous sodium sulfate and f i l t e r i n g , the s:olvent was removed to give a red o i l . This was dissolved in ethanol (.50. mL) and addition of water precipitated a pink solid (.8.0 g, 74.8%). A second crop (.2.1 g, 19.6%) was also obtained. MP: 56.5-57.Q°C. 1 H-NMR (6, CDC13): 1.36 (t, 3H, J = 7.0 Hz, -OC^CH^), 1.3-1.8 (m, 6H, chain 2-, 3-, 4-CH2) , 2.06 (s, 3H, - O ^ C i y , 2.20 (s, 3H, 2-CH3) , 2.28 (s, 3H, 4 - C H 3 ) , 2.38 (t, 2H, 5.-CH ) , 4.08 (t, 2H, J = 7.0 Hz, chain 1-a y , 4.32 (q, 2H, J = 7.0 Hz, -OCH^CH,^ , 8.58 (bs, I H , N-H). 13 C-NMR (<5, CDC13) : 171.14 (acetate, C = 0) , 161.79 (pyrrole ester, C = 0), 129.39 (.pyrrole 2-C), 127.01 (pyrrole 4-C), 121.99 (pyrrole 3-C), 116.92 (pyrrole 5-C), 64.58 (chain 1-C), 59.58 C-QCI^CH ), 30.51 (chain 4-C), 28.64 (chain 3-C), 25.76 (chain 2-C), 23.96 (chain 5-C)., 20.96 (-02CCH3), 14.63 (-OO^O^), 11.52 (2-CH.^), 10.64 (4-CH.j). Anal. Calcd. for C I 6 H 2 5 N 0 4 : c> 6 5 - 0 6 ; H» 8.53; N, 4.74. Found: C, 65 .04 ; H, 8 . 6 1 ; N, 4 . 6 9 . Mass Spectrum (m/e, relative intensity): 295 (M+, 48), 250 (7), 222 (.3), 180 (100) , 134 (60) (CH 2) 4OCCH 3 0 6 7 4-(5-Ethoxycarbonyl-2,4-dimethylpyrrol-3-yl)-1-acetoxybutane 67 4-(5-Ethoxycarbonyl-2,4-dimethylpyrrpl-3-yl)-.l-butanol 5_7 (18.0 g, 75 mmol) was stirred overnight in dichloromethane (10.0. mL) in the 239 presence of pyridine (30 mL) and acetic anhydride (35 mL). The work-up of the reaction was the same as for compound 46 above. The crude product was precipitated from aqueous ethanol to give a white flaky solid (15.8 g, 74.5%). A second crop (2.3 g, 10.8%) was also obtained. MP: 59.0-60.0°C H-NMR (.6;, CDC13): 1,38 Ct, 3H, J = 7.0 Hz, -0CH2CH_3) , 1.4-1.8 (m, 4H, chain 2-, 3-CH2), 2.04 (s, 3H, -0 CCH ), 2.21 (s, 3H, 2-CH3), 2.27 Cs, 3H, 4-CH3), 2.40 (t, 2H, J = 7 Hz, chain 4-CH2), 4.09 (t, 2H, J = 7.0 Hz, chain 1-CH2), 4.32 (q, 2H, J = 7.0 Hz, -OCH^CH^ , 8.78 (bs, IH, N-H). 13 C-NMR (6, CDC13) : 171.0.9 (acetate, C = 0), 162,11 (pyrrole ester, £ = 0), 130.00 (pyrrole 2-C), 126.86 (pyrrole 4-C), 121.49 (pyrrole 3-C), 116.96 (pyrrole 5-C), 64.42 (chain 1-C), 59.59 (-0CH2CH3), 28.33, 27.09, Cchain, 2-C,. 3-C), 23.63 (chain 4-C), 20.90 (-O^CH^, 14.61 (-0CH2CH3), 11.37 (2-CH3), 10.71 (4-CH3). Anal. Calcd. for C^H^NO^ C, 64.03; H, 8.24; N, 4.98. Found: C, 64.11; H, 8.16; N, 4,93. Mass Spectrum (m/e, relative intensity): 281 CM , 47), 236 (10), 208 (.5), 192 (8), 180 (100), 134 (87). 240 5-(5-Ethoxycarbonyl-2-carboxy-4-methylpyrrol-3-yl)-l-iodopentane 41 5-(5-Ethoxycarbonyl-2,4-dimethylpyrrol-3-yl)-l-iodopentane 40_ (30.0 g, 83 mmol) was dissolved in dichloromethane (250 mL) in a 1-liter Erlenmeyer flask equipped with a magnetic stir r e r bar, Claisen head, pressure-equalizing dropping funnel and nitrogen i n l e t . Anhydrous diethyl ether (250 mL) was added. With rapid stirring, a solution of sulfuryl chloride (21.2 mL, 270 mmol) in dichloromethane (100 mL) was added dropwise over a period of 15 minutes. The solution darkened and warmed slightly and was le f t s t i r r i n g for a further 15 minutes. The solvents were removed by rotary evaporation and a 20% water-acetone solution (300 mL) was added to the residue. The yellow solution which resulted was refluxed for 45 minutes. After cooling, the acetone was removed, whereupon the crude product precipitated as a tan solid. Although t i c (10% Et0Ac/CH 2Cl 2) showed no trace of starting material, H^-NMR showed that the product was contaminated with, the corresponding "chloropentyl" compound 42_. Complete conversion to the iodide was effected by refluxing the crude product with, sodium iodide (37 g, 0.25 mmol) in acetone (500 mL) for 12 hours. The reaction 241 mixture was then reduced in volume to approximately half, and addition of water (200 mL) precipitated a brown solid. The crude product was fi l t e r e d off, and while s t i l l wet, was dissolved in a mixture of methanol (200 mL) and saturated sodium bicarbonate solution (200 mL) by heating on a steam bath. After cooling the solution was extracted with ethyl acetate. The aqueous layer was separated, fi l t e r e d and acidified with 6M hydrochloric acid which precipitated a cream-colored solid. This was collected by f i l t r a t i o n , washed with water and air-dried to give 27.1 g (83.4%). An analytically pure sample was obtained by one more r e c r y s t a l l i -zation. MP: 145.0-147.0°C. 2H-NMR (6, DMS0-dr/CDClo) : 1.37 (t, 3H, J = 7.0 Hz, -OCH^CHj, 1.3-o 3 2 — J 2.0 (m, 6H, chain 2-, 3-, 4-CH ), 2.29 (s, 3H, 4-CH ), 2.76 (t, 2H, chain 5-CH2), 3.20 (t, 2H, J = 7.0 Hz, chain l-CH^ , 4.36 (q, 2H, J = 7.0 Hz, -0CH_2CH3), 9.52 (bs, IH, N-H). Anal. Calcd. for C^H NO I: C, 42.76; H, 5.13; N, 3.56; I, 32.27. Pound: C, 42.51; H, 5.11; N, 3.44; I, 32.15. Mass Spectrum (m/e, relative intensity): 393 (M+, 62), 348 (.6), 266 (11), 222 (13), 210 (75), 164 (100), 120 (15). 242 H 3 C (CH 2 ) A I EtO C 0 2 H 62 4-(5-Ethoxycarbonyl-2-carboxy-4-methylpyrrol-3-yl)-l-iodobutane 62 This compound was prepared in a similar manner as for compound 41 using 4- (5-ethoxycarhonyl-2,4-dimethylpyrrol-3-yl) -1-iodobutane 6_0 (.8.3 g, 23.6 mmol) and sulfuryl chloride (.6.1 mL, 75.6 mmol). To ensure that the product was not contaminated with, any of the corresponding "chlorobutyl" compound 61_, the crude product was dissolved in acetone (.250 mL) , sodium iodide (.4 g, 26 mmol) added and the mixture refluxed for 13 hours. After cooling, addition of water (200 mL) precipitated a white solid which was fi l t e r e d and dried (.8.1 g, 90.5%). The crude product was carried on to the next step without purification. MP: 157.0-159.0°C. 243 2.Q (m, 4H, chain 2-, , 2.20 (s, 3H, 4-CH ), 2.71 (t, 2H, chain 4-CH2), 3.14 Ct, 2H, chain 1-CH ) , 4.27 (q, 2H, J = 7.0 Hz, -OCH CH ) , 9.60 (hs, IH, N-H). Mass. Spectrum (m/e, relative intensity): 379 (M+, 41), 363 (5), 332 (5), 316 (5), 252 (9), 210 (100), 208 (16), 164 (78), 120 (14). H 3 C V /(CHJcOCCH, 5-(5:~Ethoxycarbonyl-2-carboxy-4-methylpyrrol-3-yl)-l-acetoxypentane 4 8 5-(5-Ethoxycarbonyl-2,4-dimethylpyrrol-3-yl)-1-acetoxypentane 46 (3.5 g, 12 mmol) was treated with sulfuryl chloride (5.2 g, 38 mmol) as described for compound 41. After removal of solvents and unreacted sulfuryl chloride, acetone (80 mL) and a solution of sodium bicarbonate (2.8 g) in water (20 mL) were, added to the dark red o i l r esidue. The mixture was refluxed for 1 hour then cooled to room temperature. The solution was acidified with acetic acid, water (100 mL) added and the mixture cooled in a freezer. The cream solid which precipitated was collected and dried (3.4 g, 88.0%). MP: 112.0-115.0°C. 244 IH-NMR (6, CDC1 3): 1.38 ( t , 3H, J = 7.0 Hz, -OC^CH^), 1.2-1.9 (m, 6H, c h a i n 2-, 3-, 4-CH 2) , 2.03 ( s , 3H, - O ^ C t y , 2.28 ( s , 3H, 4-CH 3) , 2.78 ( t , 2H, c h a i n 5-CH 2), 4.08 ( t , 2H, c h a i n 1-CH 2), 4.38 ( q , 2H, J = 7.0 Hz, -0CH 2 C H 3 ) , 9.5 ( b s , IH, N-H). 1 3 C-NMR (6, CDC1 3): 171.31 ( a c e t a t e C = 0 ) , 160.96 ( p y r r o l e e s t e r C = 0 ) , 133.68, 126.85, 123.03, 120.46 ( p y r r o l e 2-, 3-, 4-, 5-C), 64.60 ( c h a i n 1-C), 60.77 (-0CH 2CH 3), 30.14 ( c h a i n 4-C), 28.50 ( c h a i n 3-C), 25.77 ( c h a i n 2-C), 24.40 ( c h a i n 5-C), 20.96 (-0 CCH ) , 14.41 (-OC^CH^, 10.04 ( 4 - C H 3 ) . A n a l . C a l c d . f o r C 1 C H N 0 C : C, 59.06; H, 7.12; N, 4.31. Found: l b 2.3 o C, 58.93; H, 7.19; N, 4.31. Mass Spectrum (m/e, r e l a t i v e i n t e n s i t y ) : 325 ( M + , 1 0 0 ) , 309 ( 6 ) , 307 ( 7 ) , 281 ( 2 6 ) , 265 (27), 236 ( 2 1 ) , 220 ( 3 0 ) , 210 ( 8 0 ) , 192 ( 2 3 ) , 166 (.38) , 164 (100) . 5 - ( 5 - E t k Q x y c a r b o n y l - 2 - i o d o - 4 - m e t h y l p y r r o l - 3 - y l ) - l - i o d o p e n t a n e 43 5 - ( 5 - E t h o x y c a r b o n y l - 2 - c a r b o x y - 4 - m , e t h y l p y r r o l - 3 - y l ) - l - i o d o p e n t a n e 245 41 (13.4 g, 34 mmol) and sodium bicarbonate (11.4 g, 136 mmol) were suspended in a mixture of water (150 mL) and dichloroethane (80 mL) in a 1-liter Erlenmeyer flask, and heated on a steam bath u n t i l a l l the solid dissolved. The mixture was cooled to room temperature and vigorously stirred while a solution of potassium iodide (16.9 g, 102 mmol) and iodine (9.5 g, 37 mmol) in water (80 mL) was rapidly added dropwise. The solution was refluxed for 30 minutes and the excess iodine was destroyed by the addition of a sodium b i s u l f i t e solution. (The color of the solution changed from deep purple to straw yellow) . The solution was cooled and dichloromethane (100 mL) added. The organic phase was separated, dried over anhydrous magnesium sulfate, f i l t e r e d and evaporated to dryness. The crude product was dissolved in hot ethanol (100 mL) and water was added u n t i l crystallization began. The solid which precipitated was fi l t e r e d , washed with. 50% ethanol/water and air-dried to give a slightly yellow solid (13.6 g, 84.3%). MP: 92.0-93.5°C. 2H-NMR (<5, CDC13): 1.38 (t, 3H, J = 7.0 Hz, -OCH^H^), 1.3-2.0. (m, 6H, chain 2-, 3-, 4-CH2), 2.32 (s, 3H, 4-CH3), 2.39 (t, 2H, chain 5-CH2), 3.21 (t, 2H, J = 7.0 Hz, chain 1-CH2), 4.36 (q, 2H, J = 7.0 Hz, -0CH2CH3), 8.84 (bs, IH, N-H). I3C-NMR (.5, CDC13) : 160.98 (C_ = 0), 130.23 (pyrrole 3-C), 126.39 . (pyrrole 4-C), 124.01 (pyrrole 5-C), 73.46 (pyrrole 2-C), 60.31 (-OCI^CH^, 246 33.39 (chain 2-C), 30.17 (chain 4-C), 29.11 (chain 3-C), 26.30 (chain 5-C), 14.55 (-0CH2CH3), 19.98 (4-CH ), 6.70 (chain 1-C). Anal. Calcd. for C.-H,QN0 T : i j iy 2 2 C, 32.86; H, 4.03; N, 2.95; I, 53.42. Found: C, 32.64; H, 3.84; N, 2.78; I, 53.38. Mass Spectrum (m/e, relative intensity): 475 (M+, 100), 430 (8), 348 (15), 292 (60), 246 (68), 166 (47). 4-(5-Ethoxycarbonyl-2-iodo-4-methylpyrrol-3-yl)-l-iodobutane 63 This was prepared i n the same way as for 43, from 4-(5-ethoxycarbonyl-2-carboxy-4-methylpyrrol-3-yl)-l-iodobutane 62_ (6.4 g, 17 mmol). After work-up the crude brown product was recrystallized once from hot ethanol to yield 6.6 g (85.5%), which was carried to the next stage without fur-ther purification. H-NMR (6, CDC13): 1.36 (t, 3H, J = 7.0 Hz, -0CH2CH_3) , 1.5-2.0 (m, 4H, chain 2-, 3-CH2), 2.31 (s, 3H, 4-CH3), 2.38 (t, 2H, chain 2-CH2), 3.21 (t, 2H, J = 7.0 Hz, chain 1-CH2) , 4.33 (q, 2H, J = 7.0 Hz, -OC^CH^, 247 8.86 (bs, IH, N-H) 13C-NMR (6; CDC13): 160.92 (C = 0), 129.75 (pyrrole 3-C), 126.35 (pyrrole 4-C), 124.04 (pyrrole 5-C), 73.53 (pyrrole 2-C), 60.32 (-OCH2CH3), 32.94 (chain 2-C), 30.91 (chain 3-C), 25.40 (chain 4-C), 14.52 (-OCH2CH3), 10.95 (4-CH3>, 6.65 (chain 1-4). Mass Spectrum (m/e, relative intensity): 461 (M+, 83), 416 (6), 334 (5), 292 (60), 246 (100), 207 (69), 166 (60), 120 (39). 5-(5-Ethoxycarbonyl-2-iodo-4-methylpyrrol-3-yl)-l-acetoxypentane 50 This compound was prepared from 5-(5-ethoxycarbonycl)-2-carbbxy-4-methylpyrrol-3-yl)-l-acetoxypentane 48_ (3.4 g, 10.5 mmol) exactly as outlined for compound 43_ . The crude product was recrystallized from 50% ethanol/water ( 150 mL) to yield pure product (3.3 g, 76.9%). MP: 79.0-80.0°C. H^-NMR (<5, CDClj): 1-35 (t, 3H, J = 7.0 Hz, -0CH2CH_3), 1.2-1.8 (m, 6H, chain 2-, 3-, 4-CH.), 2,00 (s, 3H, -0 CCH ), 2.28 (s, 3H, 4-CH ), 2.38 248 (t, 2H, chain 5-CH2), 4.08 (t, 2H, chain 1-CH ), 4.33 (q, 2H, J = 7.0 Hz, -0CH2CH3), 8.95 (bs, IH, N-H). 13C-NMR (6, CDC13): 171.14 (acetate C = 0), 160.88 (pyrrole ester C = 0), 130.36 (pyrrole 3-C), 126.46 (pyrrole 4-C), 124.01 (pyrrole 5-C), 73.20 (pyrrole 2-C), 64.53 (chain 1-C), 60.24 (-0CH2CH3), 29.85 (chain 4-C), 28.55 (chain 3-C), 26.40 (chain 2-C), 25.62 (chain 5-C), 20.97 (-02CCH3), 14.54 (-0CH CH ), 10.97 (4-CH ). Anal. Calcd. for C H HO I: C, 44.24; H, 5.45; N, 3.44; I, 31.16. Found: C, 44.46; H, 5.43; N, 3.41; I, 31.00. Mass Spectrum (m/e, relative intensity): 407 (M+, 77), 361 (8), 292 (80), 280 (8), 246 (100), 234 (29), 220 (32), 192 (22), 174 (19), 166 (46), 120 (43). H3Cv / (CH 2 ) 5 I 44 5-(5-Ethoxycarbonyl-4-methylpyrrol-3-yl)-l-iodopentane 44 Method A 5-(5-Ethoxycarbonyl-2-iodo-4-methylpyrrol-3-yl)-l-iodopentane 43_ 249 (22.7 g, 47.8 mmol) was dissolved in ethanol (250 mL) by heating on a steam-bath. A solution of potassium iodide (12.7 g, 76.5 mmol) in water (20 mL) and concentrated hydrochloric acid (20 mL) was added, the solution darkening as iodine was liberated. Addition of hypophosphorous acid (20 mL) lightened the color as i t destroyed the liberated iodine. Heating was continued for a further 15 minutes. Water (250 mL) was added and the cloudy pink solution was extracted with ethyl-acetate (100 mL). The organic layer was dried over anhydrous magnesium sulfate, and after f i l t e r i n g and removing the solvent, a pink solid was obtained. The crude product was placed on a s i l i c a gel column (Merck Kieselgel 60H, 120 g) and eluted with dichloromethane. The colored impurities remained at the origin, while the product was obtained as a slightly orange solid (14.6 g, 87.5%). Method B 5- (5-Ethoxycarbonyl-4-methylpyrrol-3-yl)-l-pentylmethanesulfonate -53 (3.6 g, 11.4 mmol) and sodium iodide (6.8 g, 45.4 mmol) were refluxed in acetone (100 mL) for 2.5 hours. About half the volume of acetone was removed by rotary evaporation. Addition of water (50 mL) precipi-tated a yellow solid which was fi l t e r e d and dried and used without further purification. MP: 74.0-75.0°C. H-NMR ( s , CDC13): 1.35 (t, 3H, J = 7.0 Hz, -OCH^H^ , 1.49 and 1.86 (m, 6H, chain 2-, 3-, 4-CH2), 2.28 (s, 3H, 4-CH3), 2.42 (t, 2H, chain 250 5-CH2), 3.20 (t, 2H, J = 7.0 Hz, chain 1-CH ), 4.32 (q, 2H, J = 7.0 Hz, -OCH CH ), 6.67 (d, IH, J = 3 Hz, 2-H), 8.76 (bs, IH, N-H). 13C-NMR (6J, CDC13): 161.85 (C = 0), 125.89 (pyrrole 3-C), 125.29 (pyrrole 4£C) , 119.73 (pyrrole 2-C), 119.41 (pyrrole 5-C), 59.81 (-0CH CH^ , 33.44 (chain 2-C), 30.28 (chain 4-C), 29.25 (chain 3-C), 24.83 (chain 5-C), 14.55 (-OCH2CH3), 10.31 (4-CH ), 6.78 (chain 1-C). Anal. Calcd. for c 1 3 H 2 0 N O 2 I : C> 4 4 - 7 1 J ' H> 5.77;. N, 4.01; I , 36.34. Found: C, 44.59.; H, 5.66; N, 3.89; I , 36.12. Mass Spectrum (m/e, relative intensity): 349 (M+, 27), 304 (7), 222 (57), 194 (3), 166 (55), 120 (100). 4-(5-Ethoxycarbonyl-4-methylpyrrol-3-yl)-l-iodobutane 64 Method A 4- (5-Ethoxycarbonyl-2-iodo-4-methylpyrrol-3-yl)-l-iodobutane 6_3 (7.3 g, 16 mmol) was dissolved in ethanol (100 mL) by heating on a steam-bath. The solution was removed from the steam-bath and hydriodic 251 acid (25 mL) added. The liberated iodine was destroyed by addition of hypophosphorous acid (10 mL). Tic (5% EtOAc/Toluene) showed that about 50% reaction had occurred with no sign of intramolecular c y c l i -zation. More hydriodic acid (20 mL) and hypophosphorous acid (10 mL) was added, t i c then showing only a trace of starting material. "A third portion of hydriodic acid (10 mL) was added and the solution l e f t stand-ing for 1 hour. Water (100 mL) was added to the reaction mixture and the dark red solid which precipitated was fi l t e r e d and dried. The crude product was placed on a s i l i c a gel column (BDH SiO^ 60-120 mesh, 150 g) and eluted with dichloromethane. At f i r s t the eluant was colorless and was shown by t i c to contain only the desired product 64. These fractions were combined and evaporated to give 2.3 g (43.4%). Increasing the polarity of the eluant to 10% EtOAc/CR^C^ gave fractions which were orange colored and contained not only the desired product 64, but also the unwanted contaminant 65_. This impure material (2.1 g) was retained. 4-(5-Ethoxycarbonyl-4-methylpyrrol-3-yl)-l-butylmethanesulfonate 74 (14.2 g, 47 mmol) and sodium iodide were dissolved in acetone (200 mL) and refluxed with s t i r r i n g for 18.5 hours. The solution was cooled and the precipitated solid removed by 65 Method B 252 f i l t r a t i o n . The f i l t r a t e was evaporated and the resultant dark brown o i l was dissolved in ethyl acetate (100 mL). The solution was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, f i l t e r e d and evaporated. The crude product was obtained as a brown o i l which slowly s o l i d i f i e d . The crude product was placed on a s i l i c a gel column (BDH SiO^ 60-120 mesh, 200 g) andueluted with dichloromethane. The f i r s t fractions were colorless and contained the desired pure product 64_. These were combined and evaporated to give 6.3 g,(40.1%) of a slightly yellow solid. Increasing polarity to 10% EtOAc/CH^Cl^ eluted orange colored fractions. Tic showed that these contained not only the product 64 but also thevunwanted impurity 65_. This impure material was collected (5.8 g) . MP: 68.5-70.0°C. H^-NMR (6, CDC13): 1.38 (t, 3H, J = 7.0 Hz, -OO^CH^) , 1.5-2.1 (m, 4H, chain 2-, 3-CH2), 2.31 (s, 3H, 4-CH3), 2.47 (t, 2H, chain 4-CH2), 3.24 (t, 2H, J = 7.0 Hz, chain 1-CH2), 4.36 (q, 2H, J = 7.0 Hz, -0CH_2CH3) , 6.72 (d, IH, J = 3 Hz, 2-H), 8.8 (bs, IH, N-H). 13C-NMR (5, CDC13): 16.1.87 (C = 0), 125.90 (pyrrole 3-C), 124.85 (pyrrole 4-C), 119.78 (pyrrole 2-, 5-C), 59.86 (-0CH CH ), 33.16 (chain 2-C), 31.15 (chain 3-C), 23.95 (chain 4-C), 14.5.4 (-OCH^ JH ) , 10.34 (4-CH3), 6.68 (chain 1-C). Anal. Calcd. for C H NO T: C, 43.00; H, 5.41; N, 4.18; I, 37.86. 253 Found: C, 43.16; H, 5.31; N, 4.14; I, 37.77. Mass Spectrum (m/e, relative intensity): "335 (M+, 44), 290 (7), 208 (27), 166 (85), 162 (12), 134 (17),. 120 (100). 5-(5-Ethoxycarbonyl-4-methylpyrrol-3-yl)-l-acetoxypentane 52 5-(5-Ethoxycarbonyl-2-iodo-4-methylpyrrol-3-yl)-l-acetoxypentane 50 (3.8 g, 9.4 mmol) was dissolved in glacial acetic acid (25 mL). With stirring, hydriodic acid (20 mL) was added, the solution instantly turning dark red due to liberated iodine. The color was discharged by addition of hypophosphorous acid (20 mL) to give a yellow solution which was stirred for 30 minutes. Tic (10% EtOAc/CH2Cl2) showed two spots - the faster running material due to the desired product and the slower material due to product with the acetate removed. The reaction mixture was approximately neutralized with potassium hydroxide solution, then extracted with ethyl acetate (100 mL). The organic layer was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate, f i l t e r e d and evaporated to get a yellow o i l . The crude product was dissolved in dichloromethane (100 mL) and 0 acetic anhydride (10 mL) and pyridine (10 mL) added. The mixture was stirred for 3 hours to reconvert a l l the product to the acetate. After work-up the crude acetate was placed on a column (Kieselgel 60, 150 g) and eluted with 10% EtOAc/CH 2Cl 2. The product came off cleanly * fractions showing a single spot on t i c were combined and evaporated to give a yellow o i l which s o l i d i f i e d to a light yellow solid (2.1 g, 80.4%). MP: 43.0-45.0°C. H^-NMR (6, CDC13): 1.35 (t, 3H, J = 7.2 Hz, -0CH2CH_3) , 1.2-1.8 (m, 6H, chain 2-, 3-, 4-CH2) , 2.04 (s, 3H, - O ^ C i y , 2.28 (s, 3H, ^-CH^, 2.43 (bt, 2H, chain 5-CH2), 4.08 (t, 2H, J = 6.6 Hz, chain 1-CH2), 4.33 (q, 2H, J = 7.2 Hz, -0CH2CH3), 6.68 (d, IH, J = 3 Hz, 2-H), 8.83 (bs, IH, N-H) . 13C-NMR (6, CDC13): 171.15 (acetate C = 0), 161.77 (pyrrole ester, C = 0), 125.96 (pyrrole 3-C), 125.54 (pyrrole 4-C), 119.54 (pyrrole 2-C), 119.11 (pyrrole 5-C), 64.54 (chain 1-C), 59.80 (-OC^CH^ , 29.99 (chain 4-C), 28.55 (chain 3-C), 25.72 (chain 2-C), 24.90 (chain 5-C), 20.97 (-02CCH3), 14.55 (-0CH2CH3), 10.27 (4-CH^. Anal. Calcd. for C 1 5 H 2 3 N 0 4 : c> 64.03; H, 8.24; N, 4.98. Found: C, 64.29; H, 8.36; N, 4.90. Mass Spectrum (m/e, relative intensity): 281 (M , 44), 236 (10), 221 (5), 208 (6), 192 (14), 167 (65), 166 (91), 120 (100). 255 EtO 0 " 4- (5-Ethoxycarbonyl-4-methylpyrrol-3-yl)-l-acetoxybutane 72 (a) Trichlorination 4- (5-Ethoxycarbonyl-2,4-dimethylpyrrol-3-yl) -1-acetoxybutane 67_ (7.0 g, 24.9 mmol) was treated with sulfuryl chloride (6.4 mL, 79.5 mmol) and worked-up as described for compound 48. After refluxing in basic aqueous acetone the solution was cooled to room temperature and acidified with 6M hydrochloric acid. The acetone was removed and the aqueous solution was extracted with dichloro-methane (200 mL). The organic layer was separated, dried over anhydrous sodium sulfate, f i l t e r e d and concentrated to 20 mL. Addition of hexanes (200 mL) precipitated a light tan solid which was collected and dried. This crude product was carried to the next stage without purification or characterization. (b) Iodinative Decarboxylation This step was carried out exactly as for compound 50_. The crude product was obtained as a dark brown o i l which was carried on to the next stage. 256 (c) De-iodination The above product was dissolved in glacial acetic acid (25 mL). Hydriodic acid (20 mL) was added and the liberated iodine was destroyed by addition of hypophosphorous acid (20 mL). The reaction mixture was stirred for 1 hour at which point t i c (10% Et0Ac/CH 2Cl 2) indicated complete reaction. As before t i c indicated some loss of the acetate group. The reaction mixture was roughly neutralized with potassium hydroxide solution and extracted with dichloromethane (200 mL). The organic layer was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate, f i l t e r e d and concentrated to 50 mL. Acetic anhydride (5 mL) and pyridine (5 mL) were added and the solution stirred overnight. The solution was extracted with 3M hydrochloric acid (40 mL) and saturated sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate, f i l t e r e d andpevaporated to get a dark brown o i l . The crude product was placed on a column (Kieselgel 60, 150 g) and eluted with 10% EtOAc/CH 2Cl 2. Evaporation of the eluant gave a light brown o i l which crystallized (3.7 g, 55.5%). MP: 48.0-50.0°C. 1H-NMR fcfij, CDC13): 1.36 (t, 3H, J = 7 Hz, -0CH2CH_3) , 1.5-1.7 (m, 4H, chain 2-, 3-CH ), 2.05 (s, 3H, -02CCH_3), 2.29 (s, 3H, 4-CH3) , 2.49 (t, 2H, 4-CH ), 4.01 (t, 2H, chain 1-CH ), 4.33 (q, 2H, J = 7 Hz, 257 -OCH2CH3), 6.69 (d, IH, J = 3 Hz, 2-H), 8.9 (bs, IH, N-H). 13C-NMR (6, CDC13): 171.14 (acetate C = 0), 161.89 (pyrrole ester C = 0), 125.87 (pyrrole 3-C), 125.03 (pyrrole 4-C), 119.48 (pyrrole 20C), 119.10 (pyrrole 5-C), 64.40 (chain 1-C), 59.79 (-0CH2CH3), 28.36 (chain 3-C), 26.68 (chain 2-C), 24.63 (chain 4-C), 20.91 (-0 CCH ), 14.56 (-OO^CH ), 10.31 (.4-CH ) . Anal. Calcd. for C 1 4 H 2 1 N ° 4 : C» 6 2- 9 05 H » 7 - 9 2 J N> 5.24. Found: C, 63.18; H, 7.80; N, 5.24. Mass Spectrum (m/e, relative intensity): 267 (M+, 59), 224 (4), 222 (11), 207 (4), 194 (4), 179 (19), 166 (98), 134 (21), 120 (100). 5-(5-Ethoxycarbonyl-4-methylpyrrol-3-yl)-1-triphenylphosphoniumpentane  iodide (n = 5) 94a A mixture of 5-(5-ethoxycarbonyl-4-methylpyrrol-3-yl)-l-iodo-pentane 44_ (7.2 g, 21 mmol) and triphenylphosphine (16.5 g, 60 mmol) in toluene (250 mL) was refluxed under argon for 25 hours. As the reaction proceeded the product precipitated from solution as a cream solid. After 25 hours, t i c (25% EtOAc/Tol) showed no trace of the starting pyrrole. The reaction mixture was cooled to room temperature. The solid product was collected by f i l t r a t i o n , washed with diethyl ether and dried to yield 12.2 g (96.6%). This crude product was used without purification. An analytical sample was prepared by chromatography on s i l i c a gel with 10% Me0H/CH2Cl2 as eluant. MP: 191.0-193.0°C. 2H-NMR (.6, CDC13): 1.34 (t, 3H, J = 7.0 Hz, -OCH CH ) , 1.4-1.8 (m, 6H, chain 2-, 3-, 4-CH2), 2.21 (s, 3H, 4-CH3), 2.36 (m, 2H, chain 5-CH2), 3.4-3.6 (m, 2H, chain 1-CH2) , 4.30 Cq, 2H, J = 7.0 Hz, -OCH^CH^, 6.76 (d, IH, J = 3.0 Hz, 2-H), 7.6-8.0 (m, 15H, C ^ ) , 8.86 (bs, IH, N-H). 13C-NMR C6, CDC13): 161.61 ( C = 0), 135.23 (d, J = 2.4 Hz, phenyl 4-C), 138.68 (d, J = 10.4 Hz, phenyl 2-C), 130.67 (d, J = 12.2 Hz;, phenyl 3-C), 125.89 (pyrrole 3-C), 124.66 (pyrrole 4-C), 120.52 (pyrrole 2-C), 119.00 (pyrrole 5-C), 118.10 (d, J = 86.0 Hz, phenyl 1-C), 59.65^ (-0CH2CH3), 30.46 (chain 4-C), 30.03 (d, J = 17.2 Hz, chain 3-C), 24.47 (chain 5-C), 23.20 (d, J = 51.0 Hz, chain 2-C), 14.61 (-OCH^H^, 10.32 (4-CH3). Anal. Calcd. for C 3 1 H 3 5 N 0 2 P I : C> 6 0 - 8 7 ; H> 5.77; N, 2.29; I, 20.75. Found: C, 60.57; H, 5.80; N, 2.27; I, 20.87. 259 4-(5-Ethoxvcarbonyl-4-methylpvrrol-3-vl)-1-triphenylphosphoniumbutane  iodide (n = 4) 94b 4-(5-Ethoxycarbonyl-4-methylpyrrol-3-yl)-l-iodobutane 64_ (3.3 g, 9.7 mmol) and triphenylphosphine (10.2 g, 40 mmol) were dissolved in toluene (70 mL) and refluxed while stirring under nitrogen for 19.5 hours. As the reaction proceeded a purple o i l separated from solution. When t i c (10% EtOAc/Tol) indicated complete consumption of starting material the solution was cooled to room temperature and the supernatant liquid was decanted. The o i l was triturated with diethyl ether but no solid developed. The crude product was placed on a s i l i c a gel column ( Merck Kieselgel 60, 200 g) and eluted with 5% MeOH/CH2Cl2. The colored impurities were retained at the head of the column and the product was collected as a clear o i l which was dried under vacuum (5.0 g, 86.2%). MP: 103-106°C. 1H-NMR (.$,-CDCl3): 1.36 (t, 3H, J = 7.0 Hz, -OCH^^), 1.5-2.0 Cm, 4H, chain 2-, 3-CH ), 2.18 (s, 3H, 4-CH3), 2.46 (t, 2H, chain 4-CH2>, 3.5-3.8 (m, 2H, chain 1-CH ), 4.32 (q, 2H, J = 7.0 Hz, -OCH^CH^, 6.84 (d, IH, J = 3.0 Hz, 2-H), 7.6-7.9 (m, 15H, C H^), 9.00 (bs, IH, N-H). C-NMR (.6, CDC13): 161.63 (C = 0), 135.21 (d, J = 2.2 Hz, phenyl 4-C), 133.67 (d, J = 10.0 Hz, phenyl 2-C), 130.64 (d, J = 12.8 Hz, phenyl 3-C), 125.98 (pyrrole 3-C), 123.73 (pyrrole 4-C), 120.78 (pyrrole 2-C), 119.10 (pyrrole 5-C), 118.09 (d, J = 86.2 Hz, phenyl 1-C), 59.72 (-0CH2CH3), 30.35 (d, J = 15.4 Hz, chain 3-C), 24.13, 21.74 (chain . 2-, 4-C), 22.94 (d, 47.8 Hz, chain 1-C), 14.63 (-OC^ CH.^ ) , 10.40 (4-CH3) . Anal. Calcd. for C 3 0 H 3 3 N O 2 P I : C> 60.31; H, 5.57; N, 2.34; I, 21.24. Found: C, 60.47; H, 5.64; N, 2.14; I, 21.10. 261 3.3 SYNTHESES OF AROMATIC BIS-ALDEHYDES 95, 131 AND THEIR PRECURSORS 2,6-Bis (hydroxymethyl)-4-methylphenol 9.7 This compound was prepared hy the method described by Cram et a l . ^ A mixture of p—cresol (40 g, 0.37 mol) and potassium carbonate (.60. g, 0.43 mol) in water (.600 mL) was heated to 50°C and stirred under argon. Aqueous formaldehyde solution (37%, 120 mL, .1.48 mol) was added dropwise over a period of 10 minutes. The solution was then maintained at 50°C for a further 3.5 hours. The heating was removed and carbon dioxide was hub.bJ.ed through, the clear yellow solution un t i l i t turned very cloudy. The solution was then extracted with ethyl acetate (2 x 200 mL). The ethyl acetate washings were combined, dried over anhydrous sodium sulfate, f i l t e r e d and evaporated to give a viscous yellow, o i l which, solidified on cooling. This crude product was. recrystallized from ethyl acetate (.150 mL) to give a white solid (.24.8 g, 39.9%). OH MP: .123.0-124.5°C; L i t . 187 123-124°C. 4.68 (bs, 2H, -CH2OH), 6.97 (s, 2H, ArH) . Anal. Calcd. for CgH^Cy C, 64.27; H, 7.19. Found: C, 64.20; H, 7.05. Mass Spectrum (m/e, relative intensity): 168 (M+, 65), 150 (74), 149 (60), 122 (51), 121 (.100), 107 (51), 91 (47), 79 (51), 77 (.51). 2,6-Bis(hydroxymethyl)-4-methylanisole 98 This compound was prepared by the method described by Cram A mixture of 2,6-fais(hydroxymethyl)-4-methylphenol 97 (.5.0 g, 29.8 mmol), potassium carbonate (.6.2 g, 45 mmol) and dimethyl sulfate (.3.3 mL, 35.3 mmol) in spectral grade acetone (100 mL) was stirred under nitrogen at room temperature for 24 hours. The reaction mixture was filtered and the acetone removed. The residue was dissolved, with d i f f i c u l t y , in ethyl acetate (.50 mL) and water (.50 mL) , and the organic layer was washed with, saturated sodium chloride solution. After drying over anhydrous magnesium sulfate and f i l t e r i n g , the solvent was removed to give a white solid. This was et a l . 187 263 crystallized from dichloromethane (150 mL) to yield colorless needles (4.1 g, 75.5%). Four other reactions on similar scales and under the same conditions gave yields of 22.5, 37.1, 42.1 and 61.4%. MP: 105.0-107.0°C; L i t . 1 8 7 103-10.4° C. 1 H-NMR (6, acetone-d>6): 2.27 (s, 3H, ArCH ), 3.73 (s, 3H, -OCH ), 4.60 (ba, 4H, -CH20H.), 7.17 (s, 2H, ArH). Anal. Calcd. for C^H^O^ C, 65.91; H, 7.74. Found: C, 65.83; Mass Spectrum (m/e, relative intensity): 182 (M , 1Q0), 163.(18), 151 (.19), 149 (35), 147 (.19), 135 (41), 123 (27), 121 (.24), 119 (16), 105 (.31), 91 (47), 79 (.17), 77 (.37). 2,6-Diformyl-4-methylanisole 95 Oxalyl chloride (3.5 mL, 10. mmol). was added to freshly d i s t i l l e d H, 7.66. 95 0CH 3 264 dichloromethane (200 mL) in an oven-dried 3-neck flask equipped with nitrogen inlet, pressure-equalizing dropping funnel and drying tube. The solution was cooled to -78°C in a dry ice/acetone bath. A solution of dimethyl sulfoxide (5.2 mL, 73 mmol) in dichloro-methane (10 mL) was added dropwise over a period of 5 minutes. The solution was l e f t s t i r r i n g for 5 minutes. A solution of 2,6-bis(hydroxy-methyl) -4-methylanisole 98_ (.3.01 g, 17 mmol) in dimethyl sulfoxide (5 mL) and dichloromethane (.20 mL) was, then added dropwise. After stirring for 15 minutes, triethylamine (.23 mL, 165 mmol) was added and the reaction mixture was allowed to warm gradually to room temperature. Addition of water (20 mL) and removal of the dichloromethane on a rotary evaporator led to the precipitation of a waxy solid which, was filt e r e d and dried (.2.74 g, 93.1%). The crude product was recrystallized from 1;1 carbon tetrachloride/ cyclohexane to yield a f i r s t crop of white needles (1.51 g, 51.5%). A second crop (.0.57 g, 19.4%) was obtained from the mother liquid. MP: 91.5-92.5°C: L i t . 1 8 7 88-89°C. H-NMR (5, CDC13):2.43 Cs, 3H, ArCH^), 4.07 (s, 3H, -0CH3), 7.92 (s, 2H, ArH), 10.42 (s, 2H, CHO). I3C-NMR (.&, CDC13): 188.54 (g_ = 0), 163.60 (1-C), 135.36 (3,5-C), 134.96 (2,6-C), 129.84 (4-C), 66.71 (-0CH3), 20.52 (-CH3). Mass Spectrum (m/e, relative.intensity): 178 (M , 100), 150. (35), 149 (35), 132 (38), 119- (.27), 105 (35), 91 (43), 77 (57). 265 2,5-Bis (chloromethyl)-l ,4-dimethoxybenz,ene 133 206 This compound was; prepared b.y the method of Wood and Gibson. A 1-liter three-neck flask was equipped with, gas bubbler, dropping funnel and mechanical stirr e r , and was charged with. 1,4-dimethoxyb.enzene (51.5 g, 0.37 mmol), p-dioxane • (3QQ mL) and concentrated hydrochloric acid (50 mL). Hydrogen chloride gas was bubbled through, the solution and three portions- (25 mL each) of 37% formaldehyde solution were added at 30 minute intervals. Stirring and gas addition was continued for 3 hours after the last formaldehyde addition. The solution was then lef t standing overnight. The white solid which, precipitated was fi l t e r e d and washed with, water, and was recrystallized from acetone (50.1 g, 57.2%). MP: 158.Q-160.0°C; L i t . 2 0 6 167.0-167.5°C. Anal. Calcd. for .C^H 2C1 0 : C,51.08; H, 5.15; CI, 30.16. Found: C, 50.88; H, 5.14; CI, 30.05. Mass Spectrum (m/e, relative intensity): 236 (45), 234 (.70.), 221 (.9.), 266 219 (7), 201 (34), 199 (100), 171 (15), 160 (20), 144 (36), 91 (24). OCH, 9 j\ 9 C H 3 C C O H 2 C — £ > - C H 2 0 C C H 3 2,5-Bi.s. (acetoxymethyl) -1,4 -d ime thoxyhenz ene 134 20.7 This compound was prepared by the method of Marx et a l . 2,5-Bis(chloromethyl)-1,4-dimethoxybenzene 133 (25.0 g, 0.11 mmol), anhydrous sodium acetate (32.3 g, 0.39 mol) and glacial acetic acid (.300 mL) were placed in a 1-liter two-neck flask. The mixture was stirred and refluxed for 18 hours,. After cooling the reaction mixture was poured into water (1.5 L) The white precipitate was: fi l t e r e d , dried and recrystallized from methanol (26.9 g, 89.7%). 907 MP: 114.0-116.0°C; L i t . 116-118°C. '''H-NMR (.6, CDC13): 2.12 (s, 6H, -02CCH ), 3.83 (s, 6H, -0CH3), 5,13 (s, 4H, -CH20Ac), 6.88 (s, 2H, ArH). 13C-NMR 05, CDC13): 170:,82 (C = 0), 151.50 (1,4-C), 125.23 (2,5-C), 113.03 (3,6-C), 61.48 (.-0CH3), 56.28 (-C^OAc), 20.97 (.-02CCH_3) . 2 67 Anal. Calcd. for C,,H,„Cv : C, 59.56; H, 6.43. Found: C, 59.85; H, 6.42. Mass Spectrum (m/e, relative intensity): 236 (45), 234 (70), 221 (9), 219 (7), 201 (.34), 199 (100), 171 (13), 169 (20), 144 (36), 91 (24). 2,5-Bis (hydroxymethyl) -1,4-dimethoxyb.enzene 135 2,5-Bis(,acetoxymethyl)-l,4-djmethoxybenzene 134 (15.0 g, 53 mmol) was suspended in methanol (100 mL) and 10% sodium hydroxide solution (.60 mL), and the mixture was: refluxed for 4 hours. Tic showed complete consumption of starting material. The reaction was; allowed to cool to room temperature. The solid which, crystallized out was f i l t e r e d and dried (8.6 g, 81.9%) and used without further purification. MP: 159.0-160.5°C; L i t . 20.7 164-165°C. Anal. Calcd. for C^H.,.0. : C, 60.59.; H, 7.12. Found: C, 60.71; H, 7.12. 268 Mass Spectrum (m/e, relative intensity): 198 (M+, 100), 151 (14), 139 (19), 137 (19), 125 (26), 110 (14). 2,5-Bisformyl-1,4-dimethoxybenzene 131 Oxalyl chloride (.3.1 g, 24 mmol), was added to dichloromethane (20Q mL) in a 3-neck flask equipped with, nitrogen inlet, pressure-equaliz-ing addition funnel, magnetic s t i r r e r bar.and drying tube. . Stirring -under nitrogen, the solution was cooled to -70°C in a dry-ice/acetone bath.. Dimethyl sulfoxide (3.5 g, 44 mmol) was added dropwise and the solution then l e f t s t i r r i n g for 5 minutes. Carbon dioxide evolution was observed. 2,5-Bis(hydroxymethyl)-l ,4-dimethoxybenzene 135_ (.2.Q g, 10. mmol) was dissolved in 2:1 dimethyl sulfoxide/dichloromethane (15 mL) and added dropwise to the oxidizing solution over a period of 5 minutes.. After stirring for 15 minutes, triethylamine (14 mL, 0.1 mmol) was added, a bright yellow color immediately being formed. The solution was allowed to warm to room temperature before, water (20 mL) was added to quench the reaction. Removal of the dichloromethane precipitated a bright yellow solid, which, was fil t e r e d and dried (1.83 g, 93.7%). The crude product was purified by vacuum sublimation. 269 MP: 203.0-205.0°C; L i t . 205-209°C, 205°C. Anal. Calcd. for C^H^O : C, 61.85; H, 5.19. Found: C, 61.58; H, 5.20. Mass Spectrum (m/e. relative intensity): 194 (M+, 100), 179 (20), 176 (10), 151 (16), 148 (.20). 270 3.4 SYNTHESES OF CHAIN-LINKED BIS-PYRROLES EtO OEt Bis[5-(5-ethoxycarboriyl-4-methylpyrrol-3-yl)pentyl]sulfide (n = 5) 75a 5-(5-Ethoxycarb.onyl-4-methylpyrrol-3-yl)-1—iodopentane 44_ (.6.7 g, 19 mmol) was dissolved in tetrahydrof uran (10.0. mL) . A solution of sodium sulfide (7.0 g, 30 mmol) in water (40 mL) was added and the mixture was stirred and refluxed for 18 hours. At this stage t i c (10% EtOAc/CH2Cl2) showed the presence of some unconsumed starting material. Refluxing was continued and small amounts of sodium sulfide were added u n t i l reaction was complete (.28 hours). The tetrahydrofuran was removed on a rotary evaporator causing the product to separate out as a yellow o i l . Sufficient acetone was added to obtain a homogeneous solution and addition of an equal volume of water led to the precipitation of a white solid. This was collected and dried (4.4 g, 97%) and used without further purification. An analytical sample was purified by column chromatography on s i l i c a gel (.10% EtOAc/CH 2Cl 2). MP: 76.0.-78.5°C. 1 H-NMR (6, CDC13) : 1.34 (t, 6H, J = 7.0 Hz, -OCH2CH ), 1.3-1.7 (in, 12H, chain 2-, 3-, 4-CH2>, 2.26 (s, 6H, 4-CH ), 2.39 (t, 4 H, J = 7.0 Hz, chain 5-CH2>, 2.49 (t, 4H, J = 7.0 Hz, chain 1-CH ), 4.29 (q, 4H, J = 7.0 Hz, -OCH^ CH ), 6.62 (d, 2H, J = 2.8 Hz, 2-H), 8.87 (bs, 2H, N-H). 13C-NMR (6, CDC13): 161.93 (C = 0), 125.96 (pyrrole 3-C), 125.53 (pyrrole 4-C), 119.84 (pyrrole 2-C), 119.34 (pyrrole 5-C), 59.80 (.-0CH2CH ), 32.21 (chain 1-C), 29.99 (chain 4-C), 29.66, 28.70. (chain 2-, 3-C), 24.91 (chain 5-C), 14.54 (r0CH2CH ), 10.33 (.4-CH3) . Anal. Calcd. for C^H N20 S: C, 6.5.51; H, 8.48; N, 5.88; S, 6.73. Found: C, 65.20; H, 8.54; N, 5.68; S, 6.55. Mass Spectrum (m/e relative intensity): 476 (M+, 70), 430 (27), 222 (95), 166 (51), 120 (100). Bis[4-(5-ethoxycarb,onyl-4-methylpyrrol-3-yl)-butyl]sulfide (n = 4) 75b. 4-(5-Ethoxycarb.onyl-4-methylpyrrol-3-yl)-l-iodohutane 64 (3.0 g, 9 mmol) and sodium sulfide (3.2 g, 13.3 mmol) were refluxed for 22 hours in a mixture of tetrahydrofuran (30 mL) and water (70 mL). After cooling the tetrahydrofuran was removed on a rotary evaporator and the aqueous solution was extracted with, ethyl acetate. The ethyl acetate layer was washed with, water and saturated sodium chloride,solution, dried over anhydrous souiunrsulfate, then-filtered. Removal of the solvent gave a pink solid (1.9 g, 94.4%) which was used without purification. An analytical sample was prepared by column chromatography on s i l i c a gel (10% EtOAc/CH 2Cl 2). MP: 96.5-97.5°C. H-NMR (A CDC13): 1.36 (,t, 6H, J = 7.0 Hz, -OCH^iy, 1.63 (m, 8H, 2-, 3-CH2), 2.29 Cs, 6H, 4-CH3), 2.42 (m, 4H, chain 4-CH2), 2.53 (m, 4H, chain 1-CH2), 4.33 Cq, 4H, J =7.0 Hz, -OCH^CH^, 6.68 C.d, 2H, J = 3.0 Hz, 2-H), 8.84 (bs, 2H, N-H). a3C-NMR (.6, CDC13): 161.91 (C = a), 125.99 (pyrrole 3-C), 125.31 (pyrrole 4-C), 119.78 (pyrrole 2-C), 119.46 (pyrrole 5-C), 59.83 ;. C-0CH2CH3), 32.16 (chain 1-C), 29.48 (chain 2-, 3-C), 24.65 (chain 4-C), 14.55 (-OCH^^), 10.32 (4-CH3) . Anal. Calcd. for C 0 /H 0,N„0.S: C, 64.25; H, 8.09; N, 6.25; S, 7.15. 24 36 2 4 Found: C, 64.00; H, 7.97; N, 6.21; S, 7.25. Mass Spectrum (m/e,..relat ive intensity): 448 (M , 56), 403 (13), 40.2 (19), 240. (.13), 208 (.47), 206 (3D, 179 C25), 166 (75), 134 (.66), 120 (.100) . 273 2 , 6 - B i s [ 6 - ( 5 - e t h o x y c a r b o n y l - 4 - m e t h y l p y r r o l - 3 - y l ) - l - h e x e n y l ] - 4 - m e t h y l -a n i s o l e (n = 4) 99a Method A 4 - ( 5 - E t h o x y c a r b o n y l - 4 - m e t h y l p y r r o l - 3 - y l ) - l - t r i p h e n y l p h o s p h o n i u m -pentane i o d i d e 94a (1.2 g, 2.0 mmol) was d i s s o l v e d i n f r e s h l y d i s t i l l e d t e t r a h y d r o f u r a n (60 mL) i n a 3-neck f l a s k e q u i p p e d w i t h a m a g n e t i c s t i r r e r b a r , a rgon i n l e t and r u b b e r septum. W i t h s t i r r i n g under a r g o n t h e s o l u -t i o n was c o o l e d t o -78°C by p l a c i n g t h e f l a s k i n a d r y i c e - a c e t o n e b a t h . A s o l u t i o n - of • b u t y l l i t h i u m i n hexane (1.45M) was., added, d r o p w i s e t o t h e s o l u t i o n v i a s y r i n g e . The s o l u t i o n changed i n c o l o r f r o m c l e a r o range t o c l o u d y w h i t e ,*• t o f i n a l l y , c l e a r o r a n g e / r e d when 3.0 mL (4.4 mmol, 2 e q u i v a l e n t s p e r p y r r o l e ) o f b u t y l l i t h i u m was added. The s o l u t i o n was l e f t s t i r r i n g a t -78°C f o r 15 m i n u t e s . 2 , 6 - D i f o r m y l - 4 - m e t h y l a n i s o l e 95 (0.16 g, 0.92 mmol). was d i s s o l v e d i n t e t r a h y d r o f u r a n (10 mL) and added d r o p w i s e t o t h e above s o l u t i o n v i a s y r i n g e . When a d d i t i o n was complete t h e o r a n g e / r e d c o l o r was d i s c h a r g e d and t h e r e s u l t i n g y e l l o w s o l u t i o n was a l l o w e d t o warm t o room t e m p e r a t u r e o v e r a p e r i o d o f 2 h o u r s . The r e a c t i o n was quenched b.y a d d i t i o n o f w a t e r (20 mL). and t h e tetrahydrofuran removed on a rotary evaporator. The residue was dissolved in ethyl acetate (100 mL) and the solution was washed with water, dilute hydrochloric acid, saturated sodium bicarbonate solution and saturated sodium chloride solution. After drying over anhydrous sodium sulfate and f i l t e r i n g , the ethyl acetate was removed to give a yellow o i l . Thin layer chromatography (25% EtOAc/Tol) showed a major spot (Rf ^ 0.62) which was believed to be the desired product. The crude reaction product was placed on a s i l i c a gel column (Merck Kieselgel 60H; 100 g). Eluting with, dichloromethane washed off a by-product which, was identified by mass spectrometry and *H-NMR to be 106. The p o l a r i t y of the eluant was increased to 2% ethyl acetate/ dichloromethane and the desired product was c o l l e c t e d . Removal of the solvent gave a pink s o l i d (0.34 g, 62.8%). The reaction was repeated twice on s i m i l a r scales and under the same conditions to give y i e l d s of 79.3% and 60.9% a f t e r chromatographic i s o l a t i o n . 4-(5-Ethoxycarbonyl-4-methylpyrrol-3-yl)-l-triphenylphosphonium-pentane iodide 94a (0.35 g, 0.58 mmol), 2,6-diformyl-4-methylanisole 95 (0.10 g, 0.58 mmol) and potassium carbonate (0.10 g, 0.59 mmol) were suspended in p-dioxane (50 mL\ and refluxed while stirring under nitrogen. After 20 hours, t i c (10% EtOAc/Tol) showed two major spots; Method B 275 the faster running due to unconsumed dialdehyde 95_ and the slower spot due to the "mono-alkene" 108. One equivalent each, of the phosphonium iodide 94a and potassium carbonate was added to the mixture and reflux continued for a further 9 hours. By this stage t i c showed complete consumption of the starting dialdehyde 95, and two major products identified as the "mono-alkene" 108 and the desired "bis-alkene" 9.9a. A third equivalent each, of phosphonium iodide 94a and potassium carbonate was added and the solution refluxed for 15 hours. Tic s t i l l showed a trace of the "mono-alkene" 108. Phosphonium iodide 94a (0.18 g, 0.29 mmol) was added, and after a further 6 hours reflux, the reaction proceeded to completion. The reaction mixture was cooled to room temperature and the p-dioxane removed on a rotary evaporator. The residue was dissolved in ethyl acetate (50 mL) and water (50 mL). The organic layer was washed with, water, dilute sodium hydroxide solution and saturated sodium chloride solution. After drying over ahydrous sodium sulfate and f i l t e r i n g , the solvent was removed to leave a dirty brown o i l . The crude product was placed on a s i l i c a gel column (Merck Kieselgel 60H; 30 g) and eluted with, dichloromethane. The f i r s t material off the column was a small amount of an unidentified by-product. Fractions containing pure product were combined and the solvent removed C H 3 CHO 108 276 to yield 0.21 g (60.4%). The reaction was repeated three times on similar scales and under the same conditions to give yields of: 56.3, 60.1 and 71.8% after chromatographic isolation of the product. MP: 125.0-128.0°C. ""•H-NMR (6, CDC13): 1.34 (t, 6H, J = 7.0 Hz, -OCH^H ), 1.4-1.6 (m, 8H, chain 4-, 5-CH2), 2.26 (s, 6H, pyrrole 4-CH3), 2.2-2.3 (m, 4H, chain 3-CH2), 2.30 (.s, 3H, phenyl 4-CH3), 2.39 (t, 4H, J =7.0. Hz, chain 6-CH2), 3.60 (s, 3H, -0CH3), 4.30 (q, 4H, J =7.0 Hz, -0CH2CH3), 5.70 (d of t, 2H, J A T ) = 8 Hz, JT 0 = 12 Hz, -CH_CH = CH) , 6.51 (d, 2H, J = 12 Hz, AB BC 2 — AB -CH2CH=CH), 6.62 (d, 2H, J = 3 Hz, pyrrole 2-H), 6.96 (s, 2H, phenyl 3-H, 5-H), 8.74 (bs, 2H, N-H). 13C-NMR (<5, CDC13): . 161.84 (C = 0), 153.9.8 (phenyl 1-C), 133.20 (-CH = CH-CH2-), 132.01 (phenyl 4-C), 130.73 (phenyl 2-, 6-C), 129.56, (phenyl 3-, 5-C), 125.99 (pyrrole 5-C), 125.60 (pyrrole 4-C), 124.62 (.-CH. = CH-CH2~), 119.69 (pyrrole 2-C), 119.36 (pyrrole 5-C), 60.67 (-0CH3), 59.77 (-OCH2CH3), 29.93, 29.58, 28.57 (chain 3-, 4-, 5-C), 24.87 (chain 6-C) , 21.05 (phenyl 4-CH^ , 14.56 (-OC^C^) , 10.30 (pyrrole 4-CH3) . Anal. Calcd. for C o,H / oN o0 c: C, 73.44; H, 8.21; N, 4.76. Found: 36 4o z 5 C, 73.69; H, 8.33; N, 4.57. Mass Spectrum (m/e, relative intensity): 588 (M , 8), 542 (.16), .515 (.8), 514 (6), 496 (14), 469 (13), 468 (.15), 441 (6), 220 (41), 218 (13), 192 (16), 167 (42), 166 (44), 120 (100). 2,6-Bis[5-(5-ethoxycafbbriyl-4-methylpyrrol-3-yl)-l-peritenyl]-4- methylanisole (n = 3) 99b 4-(5-Ethoxycarbonyl-4-methylpyrrol-3-yl)-1-triphenylphosphonium-butane iodide 94b (0.31 g, 0.57 mmol), 2,6-diformyl-4-methylanisole 95 (.0.10 g, 0.56 mmol) and potassium carbonate CO.10 g, 0.59 mmol) were refluxed in p-dioxane (50 mL) under nitrogen for 18 hours. A second equivalent each of 94b (Q.34 g, 0.58 mmol) and potassium carbonate (0.10 g, 0.59 mmol) was added and reflux maintained for 8 hours. Tic (10% EtOAc/Tol) showed complete consumption of the starting dialdehyde and two major spots due to "mono-alkene" and "bis-alkene" products. A third equivalent each of 94b and potassium carbonate was added. After 19 hours reflux t i c showed complete reaction. The reaction mixture was cooled and the p-dioxane removed by rotary evaporation. The residue was dissolved in ethyl acetate (.100 mL) and water (.50 mL) and the organic layer was washed with, saturated sodium chloride solution. Removal of the solvent gave a dirty brown o i l . The crude product was placed on a s i l i c a gel column (.80 g) and eluted with. 10% EtOAc/CIL^Cl,,. The front-running by-products were separated cleanly from the desired product. A l l the fractions showing a single spot on t i c were combined and the solvent removed to give a pink o i l CO.15 g, 47.1%). Later fractions from the column were contaminated with a slower-moving material. This contaminated product was purified after hydro-genation to the reduced product 113b. Repetition of the reaction on similar scales and under the same conditions gave yields in the range 42-52%. H^-NMR (S, CDC13): 1.34 (t, 6H, J = 7.0 Hz, -0CH2CH3), 1.6-1.8 (m, 4H, chain 4-CH2>, 2.25 (s, 6H, pyrrole 4-CH3>, 2.27 (s, 3H, phenyl 4-CH3>, 2.2-2.4 (m, 4H, chain 3-CH2>, 2.41 (t, 4H, J =7.0 Hz, chain 5-CH ), 3.61 "(a, 3H, -0CH_3) , 4.27 (q, 4H,.J'= 7.0 Hz, -OCH^CH.^ , 5.69 (d of t , 2H,.. J = 8 Hz, J = 11 Hz, -CH.CH = CH-), 6.49 (d, 2H, JT = 11 Hz, -CH„CH = AB BC 2 — AB. 2 CH-), 6.54 (d, 2H, J = 3 Hz, pyrrole 2-H), 6.87 (s, 2H, phenyl 3-, 5-H), 8.76 Cbs, 2H, N-H). I3C-NMR (.6, CDC13) : 161.87 Cl = 0), 154.00 (phenyl 1-C), 132.92 C.-CH=CH-CH2-), 132.10 (phenyl 4-C), 130.71 (phenyl 2-, 6-C);, 129.54 --s '(phenyl 3-,5-C) , 126.01 (pyrrole 3-C), 125.60 (pyrrole 4-C), 124.91 (,-CH=CH-CH - ) , 119.84 (pyrrole 2-C), 119.46 (pyrrole 5-C), 60.70 (-0CH3), 59.80 (-0CH2CH3), 30.45, 28.45 (chain 3-,4-C), 24.70 (chain 5-C), 20.98 (phenyl 4-CH3), 14.56 (-0CH2CH3), 10.31 (pyrrole 4-CH3). Anal. Calcd. for C 3 4 H 4 4 N 2 0 5 : C, 72.83; H, 7.91; N, 5.00. Found: C, 73.10; H, 8.02; N, 5.03. Mass Spectrum (m/e, relative intensity): 560 (M , 5), 514 (54), 487 (13), 468 (8), 441 C7), 206 (81), 180 C8), 167 ClOO), 166 (71), 120. (.61). 279 2,6-Bis[6-(5-ethoxycarb.onyl-4-roethylpyrrol-3-yl)hexyl]-4-methylanisole 'Cn = 6) 113a 2,6-Bis[6-(5-ethoxycarbonyl-4-methylpyrrol-3-yl)-l-hexenyl]-4-methylanisole 99a (0.46 g, 0.78 mmol) was dissolved in tetrahydrofuran (100 mL). 10% Palladium/charcoal catalyst and three drops of t r i e t h y l -amine were added and the mixture was stirred under hydrogen for 24 hours. The solution was fi l t e r e d through. Celite to remove the catalyst, then evaporated to yield a yellow o i l . The crude product was placed on a s i l i c a gel column (Kieselgel 60.H, 30 g) and eluted with 10% ethyl acetate/dichloromethane. Fractions exhibiting a single spot on t i c were combined and evaporated to yield a colorless o i l which, slowly c r y s t a l l i -zed (0.45 g, 96.7%) . Four other reactions on similar scales gave yields of 53.1, 84.7, 88.3 and 95.1%. MP: 81.0-83.5°C. -H-NMR C<5, CDC13): 1.34 (t, 6H, J =7.5 Hz, -OCH^H^) , 1.2-1.7 (m, 16H, chain 2-, 3-, 4-, 5-CH2), 2.26 (s, 3H, phenyl 4-CH3), 2.27 (s, 6H, pyrrole 4-CH.j), 2.39 Ct, 4H, J = 7.6 Hz, chain 6-CH2), 2.57 (t, 4H, J = 7.9 Hz, chain 1-CH2), 3.70 (s, 3H, -OCH^), 4.31 (q, 4H, J = 7.5 Hz, -OCH2CH3), 6.66 (d, 2H, J..= 2.5 Hz, pyrrole 2-H), 6.84 (s, 2H, phenyl 3-, 5-H), 8.96 (bs, 2H, N-H). I3C-NMR (<5„ CDC13): 161.84 (C = 0), 154.31 (phenyl 1-C), 135.34 (phenyl 2-, 6-C), 133.07 (phenyl 4-C), 128.32 (phenyl 3-, 5-C), 126.04 (pyrrole 3-C), 125.94 (pyrrole 4-C), 119.64 (pyrrole 2-C), 119.37 (pyrrole 5-C), 61.19 C-OCHg), 59.97 (.-OCH CH ) , 30.94, 30.34, 29.90, 29.70, 29.36 (chain lr-, 2w-, 3-, 4-, 5-C), 25.03 (chain 6-C), 20.89 (phenyl 4-CH ) , 14.57 C'-OCH CH ) , 10.30 (pyrrole 4-CH3) . Anal. Calcd. for C 3 6 H 5 2 N 2 ° 5 : C> 7 2- 9 4> H> 8.84; N, 4.73. Found: C, 73.03; H, 8.83; N, 4.62. Mass Spectrum (m/e, relative intensity): 592 (M+, 47), 546 (.35) , 519 (.12), 515 (9), 500. '(13), 473 (24), 445 (9), 220 (9), 167 (.73), 166 (.73), 120 (.100), 94 (46). 2,6-Bis[5-(5-ethoxycarbonyl-4-methylpyrrol-3-yl)pentylj-4-methyl-. anisole (n = 5) 113b 2,6-Bis[5-(5-ethoxycarbony1-4-methylpyrrol-3-yl)-1-pent enylj-4-methylanisole 9.9a was hydrogenated as described for 113a above. Five 281 reactions were carried out on 0.15-0.32 g scales under the same conditions and with identical work-up and purification procedures. The yields were 79.9, 82.6, 91.7, 97.3 and 97.7% before recrystallization from aqueous ethanol. MP: 92.0-94.0°C 2H-NMR (<5, CDC13) : 1.33 (t, 6H, J =7.2 Hz, -OCH^H^) , 1.4-1.5 (m, 4H, chain 3-CH ), 1.5-1.7 (m, 8H, chain 2-, 4-CH ), 2.24 Cs, 3H, phenyl 4-CH ) , 2.27 (s, 6 H , pyrrol.4-CH 3), 2.39 (t, 4 H , J = 7.7 Hz, chain 5-CH2), 2.56 (t, 4H, J = 8.0 Hz, chain 1-CH2), 3.67 Cs, 3H, -OCiy , 4.27 Cq, 4H, J = 7.2 Hz, -0CH2CH3), 6.60 (d, 2H, J =2.8 Hz, pyrrole 2-H), 6.78 (,s, 2H, phenyl 3-, 5-H) , 8.92 (bs, 2H, N-H). 1 3 C-NMR (.6, CDC13) : 162.40 (C = 0), 154.70 Cphenyl l^C) , 135.60, (phenyl 2- , 6-C), 133.40 (phenyl 4-C), 128.58 (phenyl 3-, 5-C), 126.25 (pyrrole 3- C), 126.06 (pyrrole 4-C), 120.00 (pyrrole 2-C), 119.48 (pyrrole 5-C), 61.00 (.-0CH3), 59.54 (-OCH2CH3) , 30.36, 29.81, 29.40, 29.14 Xchain 1-, 2-, 3-, 4-C), 24.45 (chain 5-C), 20.36 (phenyl 4-CH3), 13.96 (-OCE^ay, 9.73 (pyrrole 4-CH3). Anal. Calcd. for C 0 /H / 0N 0 : C, 72.31; H, .8.57; N, 4.96. Found: C, 72.24; H, 8.59; N, 4.96. Mass. Spectrum (m/e, relative intensity): 564 (M+, 5), 563 (.14) , 519 (18), 492 (.20), 472 (.17), 445 (26), 417 (14), 208 (10), 206 (13), 167 (.64), 166 (.69), 134 (36) , 120 (100), 94 (78) . 282 2,5-Bis [6- (,5-ethoxycarboriyl-4-methylpyrrol-3-yl)hexyl] -1,4-dimethbxy- benzene (n = 6) 138a 5-(5-Ethoxycarbonyl-4-methylpyrrol-3-yl)-l-triphenylphosphonium iodide 94a (0.65 g, 1.1 mmol), 1,4-diformyl-2,5-dimethoxybenzene 131 (0.21 g, 1.1 mmol) and potassium carbonate (0.16 g, 1.0 mmol) were refluxed in p-dioxane (50 mL) under nitrogen for 6.5 hours. A second equivalent each, of 9.4a and potassium carbonate was added and the mixture refluxed overnight (16 hours). By this stage t i c (10% EtOAc/Tol) showed almost complete reaction. Potassium carbonate (0.05 g, 0.3 mmol) and 94a (0.20 g, 0.3 mmol) were added and the solution refluxed for a further 4.5 hours unti l t i c indicated complete reaction. The solution was cooled to room temperature and the p-dioxane removed. The residue was dissolved in ethyl acetate (100 mL) and washed with water, dilute sodium hydroxide solution and saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, f i l t e r e d and evaporated to give a yellow o i l which, sol i d i f i e d on standing. Addition of dichloromethane (yliO mL) did not dissolve a l l the crude product. The insoluble material was filtered off and shown by t i c to be almost pure product. The f i l t r a t e was concentrated and placed on a s i l i c a gel column (Kieselgel 60H, ^40 g) and eluted with 10% ethyl acetate/dichloromethane. Fractions showing a single product spot on t i c were combined and concentrated to about 50 mL. The solid product was added and the solution diluted with ethanol (150 mL). Cyclohexene (.25 mL) and 10% palladium/charcoal catalyst were added and the mixture refluxed for 6.5 hours. While s t i l l hot the solution was filt e r e d through Celite and the Celite pad washed well with hot ethanol. As the f i l t r a t e cooled down a white solid precipitated which was collected by f i l t r a t i o n (.0.42 g, 64.1%). Concentration of the f i l t r a t e yielded a second crop of product (0.12 g, 18.6%). Three other reactions, carried out under similar conditions, gave yields of 78.0, 67.3 and 84.8%. MP: 144.0-145.0°C. H-NMR (<5, CDC13): 1.35 (t, 6H, J =7.0. Hz, -OCT^a^) , 1.3-1.4 (m, 8H, < chain 3-, 4-CH2), 1.4-1.6 (m, 8H, chain 2-, 5-CH2), 2.27 (s, 6H, 4-CH3), 2.39 Ct, 4H, J = 7.0 Hz, chain 6-CH2), 2.56 (t, 4H, J =7.7 Hz, chain 1-CH2), 3.76 (s, 6H, -OCH^ ) , 4.30 (q, 4H, J =7.0 Hz, -OCH_2CH3), 6.64 Cs, 4H, pyrrole 2-H, phenyl 3,6-H), 8.75 (bs, 2H, N-H). 13C-NMR (.6, CDC13): 151.83 (phenyl 1,4-C), 129.61 (phenyl 2, 5-C)., 126.38 (pyrrole 3, 4-C), 119.80 (pyrrole 2, 5-C), .113.36 (phenyl 3, 6-C), 59.61 (.-0CH2CH3), 56.06 C'-OCjy., 29.92, 29..82, 29.08, 28.96 (chain 1, 2, 3, 4, 5-C), 24.48 (chain 6-C), 14.0.7 (,-OCI^ CH ), 9.74 (4-CH3) . 284 Anal. Calcd. for C o,H_„N o0 c: C,71.02; H, 8.62; N, 4.60. Found: — Jo DL I o C, 70.70; H, 8.89; N, 4.55. Mass Spectrum (m/e, relative intensity): 608 (M+, 100), 562 (6), 535 (6), 516 (8), 489 (14), 340 (6), 220 (9), 167 (35) , 166 (37), 134 (12) , 120 (52) , 108 (10), 94 (.22) . 2 ,5-BisE5-(5-ethoxycarb.oriyl-4-raethylpyrrol-3-yl) perityl j - l ,4-dimethoxy-benzene (n = 5) 138b This was prepared as: described for compound 138a above in 42.4% yield. MP: 136.0-137.Q°C. -'"H-NMR (5, CDC13) : 1.34 (t, 6H., J = 7.0Hz, -0CH2CH3), 1.3-1.5 (m, 4H, chain 3-CH2), 1.5-1.7 (m, 8H, chain 2-, 4-CH2), 2.27 (s, 6H, 4-CH ), 2.39 (t, 4H, J =7.4 Hz, chain 5-CH2), 2.55 (t, 4H, J = 7.7 Hz, chain 1-CH ),-3.74 (s, 6H, -0CH3) , 4.28 (q, 4H, J =7.0 Hz, -OC^C^) , 6.61 (s, 4H, pyrrole 2-H, ,phenyl 3, 6-H), 8.76 (bs, 2H, N-H). 13C-NMR (&, CDC13): 162.39. (c = Q) , 151.83 (phenyl 1, 4-C), 129-.62 (phenyl 2, 5-C), 126.26 (pyrrole 3, 4-C) , 119:. 9,4 (pyrrole 2-C), .119.60 (pyrrole 5-C), 113.39 (phenyl 3, 6-C), 59.61 (-0CH2CH3), 56.06 (-0CH3), 285 22.8Q, 29.0.2. (chain 1, 2, 3, 4-C), 24.52 (chain 5-C), 14.07 (-OCH^H ) , 9.76 (4-CH3). Anal. Calcd. for 0,.H/oNo0,: C, 70.31; H, 8.33; N, 4.82; Found: 3H W I. b C, 70.15; H, 8.19; N, 4.73. Mass Spectrum (m/e, relative intensity) : 580 (M+, 100) , 534 (.4), 507 (12), 488 (10), 461 (.23), 433 (11)., 401 (14), 328 (.9), 326 (.7), 220 (.4), 206 (.14), 167 (.41), 166 (.54), 148 (.15) , 134 (.22), 120 (.84), 94 (35). 286 3.5 SYNTHESES OF CHAIN-LINKED DIPYRROMETHANE DIMERS Bis.{ 5 - ( , 5 - e t h o x y c a r b o n y l - 2 - [ ( " 5 - ( . 2 , 2 - d i c y a n o v i n y l ) - 3 - e t h y l - 4 - m e t h y l -p y r r o l - 2 - y l ) m e t h y l ] - 4 - m e t h y l p y r r o l - 3 - y l ) p e n t y l } s u l f i d e (n = 5) 77a B i s [ 5 - ( 5 - e t h o x y c a r b o n y l - 4 - m e t h y l p y r r o l - 3 - y l ) p e n t y l ] s u l f i d e 75a (0.50 g, 1.05 mmol) and 2 - c h l o r o m e t h y l - 5 - ( 2 , 2 - d i c y a n o v i n y l ) - 3 - e t h y l -4 - m e t h y l p y r r o l e 76 (0.50 g, 2.15 mmol) were suspended i n g l a c i a l a c e t i c a c i d (5 mL) and s t i r r e d under n i t r o g e n . The r e a c t i o n m i x t u r e was h e a t e d a t 70°C f o r 10 m i n u t e s whereupon a l l t h e s o l i d s d i s s o l v e d t o g i v e a deep r e d s o l u t i o n . The s o l u t i o n was c o o l e d t o room t e m p e r a t u r e , m e t h a n o l (^15 mL) added, t h e n c o o l e d i n t h e f r e e z e r . A d a r k o i l s e p a r a t e d w h i c h l a t e r s o l i d i f i e d . T h i s s o l i d was t r i t u r a t e d w i t h more m e t h a n o l and an orange s o l i d (0.77 g, 83.7%) c o l l e c t e d by f i l t r a t i o n . MP: 152.0-154.5°C. 287 1H-NMR (6, CDC1 )'.: 1.05 ( t , 6H, J = 7.6 Hz, 3'-CH 2CH 3), 1.33 ( t , 6H, J = 7.0 Hz, -0CH 2CH 3), 1.30-1.45 and 1.50-1.60 (m, 12H, chain 2-, 3-, 4-CH 2), 2.16 (s, 6H, 4'-CH ), 2.29 (s, 6H, 4-CH ), 2.35-2.48 (m, 12H, chain 1-, 5-CH 2 > 3»-CH 2CH ), 3.97 (s, 4H, bridge CH ) , 4.29 (q, 4H, J = 7.0 Hz, -0CH 2CH 3), 7.35 [s, 2H, C(H)=C(CN) ], 8.55 (bs, 2H, 1-NH), 9.19 (bs, 2H, l'-NH). 13C-NMR (.6, CDC13) : 162.14 (C = 0), 140.74 [C(H)=C(CN) ], 14Q.39 (pyrrole 2»-C), 136.01 (pyrrole 4'-C), 127.27 (pyrrole 4-C), 126.61, 126.42 (pyrrole 2-C, 3'-C), 124.16 (pyrrole 5'-C), 123.43 (pyrrole 3-C), 118.89 (pyrrole 5-C), 116.80, 115.96 (C=N), 64.15 [C(H)=C(CN)^, 59.94 HDCH 2CH 3), 32.20 (chain 1-C), 30.48 (chain 4-C), 29.68, 28.79 (chain 2-, 3-C), 24.07 (bridge CH 2, chain 5-C), 17.12 (.3 '-rj^CH ), 14.67 (3'-CH 2CH 3), 14.43 (-0CH2CH3), 10.72 C4-CH3) , 9.42 ( A ' - C H ^ . Anal. Calcd. for C^H^NgO^: C, 68.93; H, 7.17; N, 12.86; S, 3.68. Found: C, 68.81; H, 7.04; N, 12.82; S, 3.68. Mol. Wt. Calcd. f o r C C„H. oN o0.S: 870.4615. Found by high, r e s o l u t i o n 50 62 8 4 J . O mass spectrometry: 870.4604. Bi s{5-(5-e thoxycarb ony1-2-[(5-(2,2-dicyanovinyl)-3-ethyl-4-methyl-pyrrbl-2-yl)methyl]-4-methylpyrrol-3-yl)butyl}sulfide (n = 4) 77b. Bis[5-(5-ethoxycarb.onyl-4'-methylpyrrol-3-yl) -b.utyl]sulfide 75b 288 (.1.01 g, 2.25 mmol) and 2-chloromethyl-5-(.2,2-dicyanovinyl) -3-ethyl-4-methylpyrrole 76 (1.11 g, 4.74 mmol) were suspended in glacial acetic acid (20 mL) and heated at 80°C for 1 hour while s t i r r i n g under nitrogen. After several minutes heating a l l the solids dissolved and on continu-ing heating some product precipitated from solution. The reaction mixture was cooled, methanol (.50 mL) was added and then placed in the freezer overnight. The orange-brown solid which, precipitated was fil t e r e d and dried (1.71 g, 90.0%). The product was used without further purification hut a sample was recrystallized from 50% dichloromethane/methanol for elemental analysis. MP: 185.Q-187.0.°C. "^ H-NMR (.6, CDC13) : 1.0.4 (t, 6H, J =7.6 Hz, 3 '-C^CH ), 1.33 (t, 6H, J = 7.0. Hz, -0CH2CH3), 1.4-1.6 (m, 8H, chain 2-, 3-CH2) , 2.15 (s, 6H., 4'-CH ),.2.26 (s, 6H, 4-CH3) , 2.35-2.42 (m, 12H., chain 1-, 5-CH2, 3'-CH2CH3), 3.93 (s, 4H, bridge CH2), 4.26 (q, 4H, J = 7.0. Hz, -0CH2CH3) , 7.32 [s, 2H, C(H)=C(.CN)2], 8.55 (bs, 2H, 1-NH), 9.19 (bs, 2H, l'-NH). 1 3 C-NMR (.6, CDC13): 161.98 ( C = 0) , 140.87 £C(H)=C(CN)2] , 139 .91 ; (pyrrole 2'-C), 135.95 (pyrrole 4*-C), 127.31 (pyrrole 4-C), 126.49, 126.23 (pyrrole 2-C, 3'-C), 124.26 (pyrrole 5'-C), 123.23 (pyrrole 3-C), 119.00. (pyrrole 5-C), 116.85, 115.82 (.C_=N)., 64.59. [C(H)=C(CN) ], 60.04 (-OCH2CH3), 32.13 (chain 1-C), 29.97, 29.41 (chain 2-, 3-C), 23.79 (bridge CH2, chain 4-C), 17.14 (3 '-CH CH ) , 14.72 (3 '-CH^CH^, 14.48 (-OCH2CH3), 10.70 (4-CH3), 9.45 (A'-CH^. 289 "Anal. Calcd. f o r C H N g0 S: C, 68.38; H, 6.93; N, 13.29; S, 3.80. Found: C, 67.71; H, 6.89; N, 13.15. Calculated f o r C. QH c oN o0.S-0.5CH„0H <4 0 j i ) o 4 o C, 67.80; H, 7.04; N, 13.04. Mol. Wt. Calcd. f o r C / oH_ oN o0.S: 842.4302. Found by high r e s o l u t i o n 48 58 8 4 mass spectrometry: 842.4279. 2,6-Bis[6-{5-ethoxycarbonyl-2-[(5-(2,2-dlcyanovinyl)-3-ethyl-4-methylT-pyrrol-2-yl)methyl]-4-methylpyrrol-3-yl}hexyl]-4-methylariisole Cn = 6) 114a 2,6-B.is[6-(5-ethoxycarbonyl-4-methylpyrrol-3-yl).hexyl]-4-methyl-anisole 113a (0.20 g, 0.34 mmol) and 2-chloromethyl-5-(2,2-dicyanovinyl)-3-ethyl-4-methylpyrrole 76_ CO.17 g, 0.73 mmol) were suspended i n g l a c i a l a c e t i c acid (5 mL) and s t i r r e d under nitrogen. The reac t i o n mixture was heated at 80°C for 1 hour. The s o l u t i o n was cooled to room temperature then poured into 290 sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was dried, fi l t e r e d and evaporated to give a dark red o i l . The crude product was placed on a column (Kieselgel 60, 50 g) and eluted with 10% ethyl acetate/toluene. Many small red and yellow bands eluted off the column i n i t i a l l y . These were followed by a bright red band immediately proceeding "the product, which eluted off. as a broad yellow band. Those fractions displaying a single yellow spot on t i c were collected. The fractions were combined and evaporated to give an orange o i l (.0.29. g, 85.2%), which was recrystallized from 50% dichloromethane/methanol to give an orange solid. Three other syntheses on similar scales gave yields of 84.1, 91.2 and 94.2% after chromatographic purification. MP: 146.5-150.Q°C. "^  H-NMR (6, CDC13) : .1.0.4 (t, 6H., J = 7.6 Hz, ,3'-CH2CH3), 1,30 (t, 6H, J = 7.2 Hz, -0CH2CH_3), 1.25-1.45 (m, 12H, chain 3-, 4-, 5-CH2), 1.48-1.60 Cm, 4H, chain 2-CH2) , 2.10 Cs, 6H, 4'-CH ),'2.26 (s, 9H, 4-CH3, phenyl 4-CH3), 2.32-2.42 (m, 4H, chain 6-CH2), 2.42 (q, 4H, J = 7.8 Hz, 3'-CH2CH3), 2.54 (ht, 4H, chain 1-CH2), 3.67 (s, 3H, -0CH3), 3.97 (s, 4H, bridge CH2) , 4.19 (_q, 4H, J = 7.2 Hz, -OCH^CH^ , 6.80. (s, 2H, phenyl 3-, 5-H), 7.25 [s, 2H, C(.H)=C(.CN)2J, 9.26 (bs, 2H, 1-NH), 9.50 (bs, 2H, . 1 '-NH) . *3C-NMR 0$, CDC13): 162.10 (C = 0), 154.23 (phenyl 1-C), 140.73 [C^CHi^CCN)^, 140.28 (pyrrole 2'-C), 135.93 (pyrrole 4'-Cl, 135.28 Cphenyl 2-, 6-C), 133.07 (phenyl 4-C), 128.26 (phenyl 3-, 5-C), .127.35 (pyrrole 4-C), 126.42 (pyrrole 2-, 3'-C), 124.17 (pyrrole 5'-C), 123.73 (pyrrole 3-C), 118.91 (pyrrole 5-C), 116.81 115.91 (CEN), 64.31 [C(H)=£(CN)2], .61.19 (-OCH3) , 59.95 (-OO^CH^ , 30.91, 30.27, 29.87, 29.77, 29.45 (chain 1-, 2-, 3-, 4-, 5-C), 24.20, 23.94 (bridge CH , chain 6-C) , 20.87 (phenyl 4-Ciy , 17.12 (3'-CH2CH3), 14.69 O'-O^CR^), .14.46 (-0CH2CH3), 10.68 (4-oy , 9.87 (4'-CH3). Anal. Calcd. for C^ H-.N-O,.: C, 72.99; H, 7.56; N, 11.35. Found: oU IH o 5 C, 73.28; H, 7.42; N, 11.24. Mol. Wt. Calcd. for C,.H.J o0 c: 986.5782. Found by high, resolution 6 0 /H o 5 mass spectrometry: 986.5849. 2,6-Bis[5-{5-ethoxycarbonyl-2-[(5-(2,2-dicyanovinyl)-3-e.thyl-4-methyl-pyrrol-2-yl)methyl]-4-methylpyrrol-3-yl}pentyl]-4-methylanisole (n = 5) 114b This compound was prepared from 113b and 76_ exactly as de'sc-ribed for compound 114a. In four reactions the yields of product after chromatographic purification were 76.4, 83.9, 91.7 and 95.2%. MP: 181.5-182.5°C. :H-NMR (6, CDC1 l.:'"l.Q5 (t, 6R, J = 7.6 Hz, 3'-CH2CH3) , 1.34 (t, 6H, 292 J = 7.2 Hz, -OC^CH ), 1.3-1.5 (m, 8H, chain 3-, 4-CH2> , 1.5-1.6 (m, 4H, chain 2-CH2>, 2.14 (s, 6H, 4'-CH ), 2.25 (s, 3H, phenyl 4-CH3>, 2.27 (s, 6H, 4-CH), 2.38 (t, 4H, chain 5-CH2), 2.42 (q, 4H, J = 7.6 Hz, 3'-CH2CH3), 2.54 (bt, 4H, chain 1-CH2), 3.67 (s, 3H, -OCH ), 3.94 (s, 4H, bridge CH_2) , 4.27 (q, 4H, J = 7.2 Hz, -OCH^ CH ), 6.79 (s, 2H, phenyl 3-, 5-H), 7.29 [s, 2H, C(.H)=C(CN) ], 8.67 (bs, 2H, 1-NH), 9.17 (bs, 2H, l'-NH). 13C-NMR (.6, CDC13) : 162.19'(6 = 0), 154.27 (phenyl 1-C) , 140.69 [C(H) = C(CN) 2], 140.51 (pyrrole 2'-C), 136.02 (pyrrole 4'-C), 135.19 (phenyl 2-, 6-C), 133.10 (phenyl 4-C), 128.37 (phenyl 3-, 5-C),, 127.36 (pyrrole 4-C), 126.60, 126.42 (pyrrole 2-, 3'-C), 124'.16' (pyrrole 5'-C), 123.69 (pyrrole 3-C), 118.89 (pyrrole 5-C), 116.76, 116.01 (C=N), 64.09 [C(H)= C(.CN)2], 61.24 (-0CH3), 59.93 C-OC^Ctt^, 30.82, 29.86, 29.76 (chain 1-, 2-, 3-, 4-C), 24.16, 23.90 (bridge CH2, chain 5-C), 20.85 (phenyl 4-CH3), 17.10 (3'-CH2CH3),. 14.65 C3'-CH Ol ), 14.45 (-OC^CH^ , 10.71 (4-CH3) , 9.36 (4'-CH3). Anal. Calcd. for C c oH N O : C, 72.62; H, 7.36; N, 11.68. Found: io /U o j C, 72.84; H, 7.48; N, 11.38. Mol. Wt. Calcd. for C^H^N.O,.: 958.5469. Found by high resolution 58 /U o 5 mass spectrometry: 958.5511. 293 2 , 5 - B i s [ 6 - { 5 - e t h o x y c a r b o n y l - 2 - [ ( 5 - ( 2 , 2 - d i c y a n o v i n y l ) - 3 - e t h y l - 4 ^ m e t h y l -p y r r o l - 2 - y l ) m e t h y l ] - 4 - m e t h y l p y r r o l - 3 - y l ' } h e x y l ] , - l ,4-dimethoxybenzene (n = 6) 139a The compound was. p r e p a r e d from 138a and 7_6_ e x a c t l y as d e s c r i b e d f o r compound 114a & •. „0f f i v e r e a c t i o n s ;:t.h'eiSyie!Myo"-&lprodu:ct'l'roduct a f t e r c h r o m a t o g r a p h i c p u r i f i c a t i o n was 75.9-87.6%. MP: 165.0-168.0°C. ^H-NMR (.6, CDC1 3): 1.0.4 ( t , 6H, J = 7.6 Hz, 3'-CH 2CH 3), 1.30 ( t , 6H, J = 7.0 Hz, -OCH^H ) , 1.25-1.41 (m, 12H, c h a i n 3-, 4-, 5-CH 2>, 1.45-1.56 (m, 4H, c h a i n 2-CH 2), 2.10. ( s , 6H, 4'-CH ) , 2.25 ( s , 6H, 4-CH 3), 2.38 ( b t , 4H, c h a i n 6-CH 2), 2.41 ( q , 4H, J = 7.6 Hz, 3'-CH 2CH 3)., 2.51 b t , 4H, c h a i n 1-CH 2), 3.74 ( s , 6H, -OCH^), 3.9.4 Cs , 4H, b r i d g e C i y , 4.21 C q , 4H, J = 7.0 Hz, -0CH 2CH 3), 6.62 ( s , 2H, p h e n y l 3-, 6-H), 7.26 294 [ s , 2H, C(H)=C(CN 2 L. 9.15, 9.19 ( b s , 4H, 1-NH, l'-NH). 1 3C-NMR (6, CDC1 3): 162.12 (C = 0 ) , 151.32 ( p h e n y l 1-, 4-C), 140.81 [C(H)=C(CN) 2], 140.21 ( p y r r o l e 2'-C), 136.00 ( p y r r o l e 4'-C), 129.25 ( p h e n y l 2-, 5-C), 127.36 ( p y r r o l e 4-C), 126.39 ( p y r r o l e 2-, 3'-C), 124.19 ( p y r r o l e 5'-C), 123.84 ( p y r r o l e 3-C), 118.92 ( p y r r o l e 5-C), 116.94, 115.89 C ^ N ) , 113.14 ( p h e n y l 3-, 6-C) , 64.38 [C(H)=C(CN) 2], 60.02 (-0CH 2CH 3), 56.27 (-0CH 3), 30.88, 30.27, 29.53 ( c h a i n 1-, 2-, 3-, 4-, 5-C), 24.22, 23.97 ( b r i d g e CRy c h a i n 6-C), 17.16 C3'-CH 2CH 3), 14.73 (3' - C H 2 C H 3 ) , 14.51 (-0CH 2£H 3), 10.69 ( 4 - C H 3 ) , 9.40 ( 4 ' - C H ^ . A n a l . C a l c d . f o r C ^ H ^ N g O ^ C, 71,83; H, 7.44; N, 11.17, Found; C, 71.91; H, 7.35; N, 11.06. M o l . Wt, C a l c d . f o r C , A . N o 0 , : 1002.5731. Found by h i g h , r e s o l u t i o n 60 74 8 6 J O mass s p e c t r o m e t r y : 1002.5728. 2 , 5 - B i s [ 5 - { 5 - e t h o x y c a r b o n y l - 2 - J ( 5 - ( 2 , 2 - d i c y a n o v i n y l ) - 3 - e t h y l - 4 - m e t h y l -p y r r o l - 2 - y l ) m e t h y l ] - 4 - m e t h y l p y r r o l - 3 - y l } p e n t y l ] - l , 4 - d i m e t h o x y b e n z e n e (n = 5) 139b 2 , 5 - B i s [ 5 - ( 5 - e t h o x y c a r h o n y l - 4 - m e t h y l p y r r o l - 3 - y l ) p e n t y l ] - ! , 4 -dimethoxyb.enzene 138b CO.24 g, 0.41 mmol) and 2- c h l o r o m e . t h y l - 5 - ( 2 , 2 -d i c y a n o v i n y l ) - 3 - e t h y l - 4 - m e . t h y l p y r r o l e 76_ C0.20. g, 0.87 mmol) were suspended i n g l a c i a l a c e t i c a c i d (5 mL) and s t i r r e d under n i t r o g e n . The m i x t u r e was h e a t e d a t 80°C f o r 1 h o u r . A f t e r a few m i n u t e s a l l t h e s o l i d s d i s s o l v e d t o g i v e a d a r k r e d s o l u t i o n , b u t d u r i n g t h e c o u r s e of t h e r e a c t i o n an orange s o l i d p r e c i p i t a t e d f r o m s o l u t i o n . The r e a c t i o n m i x t u r e was c o o l e d t o room t e m p e r a t u r e , m e t h a n o l (20 mL) added and t h e n c o o l e d o v e r n i g h t i n th e f r e e z e r . The p r e c i p i t a t e d p r o d u c t was c o l l e c t e d by f i l t r a t i o n , washed w e l l w i t h m e t h a n o l and d r i e d t o g i v e a y e l l o w powder (.0.36 g, 90.. 0%). MP: >215° Idee). H-NMR CS, CDC1 3): 1,04 Ct, 6H, J = 7 . 6 Hz, 3'-C^CH^) , 1.32 (t, 6H, J = 7.4 Hz, -0CH 2CH 3), 1.36-1.47 (m, 8H, c h a i n 3-, 4-CH 2), 1.47-1.58 (m, 4H, c h a i n 2-CH 2), 2.12 ( s , 6H, 4*-CH ) , 2.25 ( s , 6H, 4-CH ),.2.37 Ct, 4H, c h a i n 5-CH ) , 2.40 ( q , 4H, J = 7.4 Hz, 3'^CH 2CH ) , 2.50 ( h t , 4H, c h a i n 1-CH 2), 3.73 ( s , 6H, -OCH ) , 3.93 ( s , 4H, b r i d g e C H 2 ) , 4.28 ( q , 4H, J = 7.3 Hz, -OCH^CH ) , 6.71 ( s , 2H, p h e n y l 3-, 6-H), 7.29 [ s , 2H, C ( H ) = C ( C N ) 0 ] , 8.81 ( b s , 2H, 1-NH), 9.18 ( b s , 2H, l ' - N H ) . 1 3C-NMR (S, CDC1 3): 161.94 (@= 0 ) , 151.41 ( p h e n y l 1-, 4-C), 140.87 [C(.H)=C(CN) 2], 139.81 ( p y r r o l e 2'-C), 135.89 ( p y r r o l e 4'-C), 129.26 ( p h e n y l 2-, 5-C), 127.41 ( p y r r o l e 4-C), 126.48, 126.16 ( p y r r o l e 2-, 3 124.25 ( p y r r o l e 5'-C), 123.89 ( p y r r o l e 3-C), 119.12 ( p y r r o l e 5-C), 116.79, 115.96 (C^N), 113.25 ( p h e n y l 3-, 6-C), 64.80 [C(.H)=CCCN) 2], 60.00 C-OCH 2CH 3), 56.29 (-0CH 3), 30.78, 30.20, 29.56 ( c h a i n 1-, 2-, 3-, 4-C), 24.04 ( b r i d g e CH 2, c h a i n 5-C), 17.14 C3*-CH^CH ) , 14.71 (.3' CH2CH3), 14.54 (-OCH2CH3), 10.65 (4-CH ), 9.39 (4'-CH ). 296 Anal. Calcd. for CrDH_, 2SL0.: C, 71.43; H, 7.24; N, 11.49. Found: 5o 70 o 6 C, 71.19; H, 7.32; N, 11.28. Mol. Wt. Calcd. for C__H N 0 • 974.5418. Found by high resolution 5o /U o 6 mass spectrometry: 974.5402. 297 3.6 SYNTHESES OF STRAPPED PORPHYRINS s 13 87 7,17-Diethyl-2,8,12,18-tetramethyl-3,13-[thiob.is (pentamethylene) ]- porphyrin (n = 5) 87a (i) Saponification: Bis{ 5-(5-ethoxycarbonyl-2-[(5-(.2,2-dicyanovinyl)-3-ethyl-4-methylpyrrol-2-yl)methyl]-4-methylpyrrol-3-yl)pentyl}s.ulfide 77a (1.312 g, 1.51 mmol) was placed in an Erlenmeyer flask equipped with a Claisen head and a nitrogen i n l e t . A solution of potassium hydroxide (14 g) in water. (100 mL) and n-propanol (50 mL) was added and the mixture stirred. A small quantity of this, starting mixture was withdrawn, diluted with, methanol and a uv-visible spectrum recorded. Two major bands were observed at 406.0 nm and at 276.8 nm. The mixture was heated to reflux and stirred under nitrogen, the- course of the reaction being followed spectrophotometrically. After 3 hours reflux the reaction was judged complete. The spectrum of the f i n a l solution showed complete disappearance of the band 40.6.Q. nm and the appearance of a new band at 316.8 nm; the band at 276.8 nm moved to 268.4 nm. 298 A l l the propanol was boiled off from the two-phase reaction mixture and more water (200 mL) was added, after which the solution was allowed to come to room temperature. The cooled solution, contain-ing an oily precipitate, was filtered and the material which, remained on the f i l t e r was washed with water u n t i l i t a l l redissolved (final volume 500 mL). The f i l t r a t e was acidified with glacial acetic acid which caused the formation of a rust-brown gelatinous precipitate. This crude bis:.{5-(5-carb.oxy-2-[(5-formyl-3-ethyl-4-methylpyrrol-2-yl) methyl]-4-methylpyrrol-3-yl)pentyl}sulfide 83a was collected by f i l t r a t i o n and dried overnight in a vacuum desiccator. ( i l ) Decarboxylation The crude a-carb.oxy,a'-formyl b.js-dlpyrromethane 83a was dissolved in spectral grade N,N-dimethylformamide (150. mL) in an Erlenmeyer flask equipped with, a Claisen head and an argon inlet. The uv spectrum of a sample of this solution in dichloromethane showed two bands at 320.0. nm and 280.Q. nm in the ratio 1:1.3. The solution was stirred and refluxed under argon for 3 hours after which no further spectral change occurred. In the f i n a l spectrum the band i n i t i a l l y at 320.0 nm shifted to 312.0 nm and the 280.0 nm band decreased in intensity and moved to 272.8 nm; the ratio: of the two bands was now 1:0.5. The reaction mixture was cooled under argon then evaporated almost to dryness under reduced pressure. The residue was. dissolved in dichloromethane (.100 mL) and extracted with, water (3 x 200 -mL) and saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, f i l t e r e d and diluted to 500 mL with dichloro-methane. ( i i i ) Cyclization Four .. l ^ l i t e r Erlenmeyer flasks were wrapped in aluminum f o i l and each was charged with, p-toluenesulfonic acid (4 g) , methanol (.25 mL) and dichloromethane (600 mL) and stirred in subdued lighting. Tne solution of the a-free,a'-formyl bis-dipyrromethane 84a was injected slowly into the flasks over a period of 48 hours using a syringe pump. When addition was complete the. four wine colored solutions were concentrated to approximately 250 mL. This was then extracted with saturated sodium bicarbonate solution to neutralize the acid and convert the protonated porphyrin to i t s free base form (the color of the solution changed from wine to red/brown). The organic layer was; dried over anhydrous sodium sulfate, filtered and evaporated to dryness (. a vacuum pump was used to remove any traces of DMF). (Iv) Purification The crude product was placed on a s i l i c a gel column (Kieselgel 60, 150 g). Elution with dichloromethane washed off a small amount of metalloporphyrin and other minor bands which were discarded; most of the material remained at the top of the column. The polarity of the eluant was increased to 1% methanol/dichloromethane whereupon the porphyrin was washed off the column. When the eluant' was almost colorless the polarity was increased to V5% methanol/dichloromethane. Tic (.2% MeOH/Cn^Cl^ showed that the later fractions, obtained with the most polar eluant, were contaminated with a brown impurity and the corresponding sulfoxide strapped porphyrin 88a. These later fractions were combined and partially purified on another s i l i c a gel column (Kieselgel 60, 50 g) before being combined with the main bulk of the product. The crude strapped porphyrin was placed on a column of activity III alumina (Merck 90 neutral, 40 g) and eluted with dichloromethane. The brown impurities remained at the head of the column and the porphyrin came off the column i n two bands with l i t t l e overlap. The faster major band was due to the desired sulfide strapped porphyrin 87a, and the slower band was due to the corresponding sulfoxide strapped porphyrin 88a. Combination and evaporation of the various, fractions and drying on the vacuum line gave 166.9 mg (18.7%) of porphyrin 87a and 7.5 mg of 88b.. In nine attempts the total overall yield (i.e. yield of sulfide and sulfoxide) for the saponification - decarboxylation — cyclization sequence varied between 9.5% and 19.5%. MP: 28Q-283°C. Mol. Wt. Calcd. for C 0 0H / 0N.S: 592.3599. Found by high resolution jo HO H mass spectrometry: 592.3587. Anal. Calcd. for C_0H./0N,S: C, 76.9.8; H, 8.16; N, 9.45; S, 5.41. 3o HO H Found: 76.68; H, 8.07; N, 9.23; S, 5.39. 2H-NMR (:6:, CDC13): 9.93 (a, 2H, methine 10, 20-H), 9.82 (s, 2H, methine 5, 15-H), .4.09 (m,. 4H., -C^C^) , 3.97 (m, 2H, chain 5-CH2), 3.63 (.a, m, 8H, two CH3, chain 5-CH2>, 3.36 (s, 6H, two C R ^ , 1.86 (t, 6H, -CH2CH), 1.42 (m, 4H, chain 4-CH2), 0.17 (m, 2H, chain 3-CH2), -0.13 Cm, 2H, chain 3-CH2) , -1.46 (m, 2H, chain 2-0^), -1.56 (m, 2H, chain 1-CH2) , -1.85 (m, 2H, chain 2-CH2), -2.02 (m, 2H, chain 1-CH2), -3.38 Cbs, 2H, N-H). J'3C-NMR (.6, 10% TFA-CDC13): 146.87, 144.79, 143.55, 141.73, 141.07, 140.00, 139.71, 139.47 (16C, a- and 6-pyrrolic carbons), 100.52, 99.19, C.4C, meso carbons), 29.41, 27.35, 27.0.6, 26.04, 24.12 (10C, chain carbons), 20.48 (2C,, a^CHy , 16.51 (2C, CH2CH3) , 12.28, 11.89.C4C, CH3). Visible Spectrum ( C H ^ l ^ : \ (nm) , 40Q.0 502.0 539.0 570.0. 624.2 max log e , 5.22 4.0.3 4.03 3.79. 3.52 7,17-Diethyl-2,8,12,18-tetramethyl-3,13-[thiobis(tetramethylene)]- porphyrin (n = 4) 87b The saponification, decarboxylation and cyclization reactions were carried out oh 77b exactly as described for the synthesis of the 302 thiobis(pentamethylene) porphyrin 87a. After work-up the crude product was placed on a s i l i c a gel column (Kieselgel 60, 100 g) and eluted with 2% methanol/dichloromethane. A small amount of metalloporphyrin came off the column f i r s t and was discarded. This was followed by a major green band and then by the purple strapped porphyrin band. The eluant was collected in fractions (100-200 mL) and examined by t i c (.2% MeOH/CH^Cl^ . Those fractions: containing green and purple material were stirred overnight in dichloro-methane in a i r , whereupon t i c indicated disappearance of the green material. Fractions containing just green material were combined and evaporated. Attempts to purify this by preparative t i c failed. Only strapped porphyrins were obtained from the plate. The partially purified strapped porphyrin samples were combined and placed on a column of activity III alumina (Merck 90 neutral, 100 g) and eluted with, dichloromethane. A l l brown impurities remained at the head of the column. The porphyrin came off the column in two bands. The f i r s t , due to the sulfide porphyrin 87b, was slightly contaminated with, a faster running blue material but most fractions (y5 mL) contained pure sulfide porphyrin... The second, slower moving band was due to the sulfoxide strapped porphyrin 88b. In these preparations the yields of 87b were 10.1%, 17.5% and 16.5%. When the quantity of 88b was included, the total overall yield was 12.0%, 21.6% and 18.6%. MP: >270°C (dec). 'Mol. 'Wt. C a l c d . f o r Cn,H,.N,S:' 564.3287. Found by h i g h r e s o l u t i o n 36 44 4 mass s p e c t r o m e t r y : 564.3277. A n a l . C a l c d . f o r C 0,H,.N.S: C, 76.55; H, 7.85; N, 9.92; S, 5.68. 36 44 4 Found: C, 76.40; H, 7.58; N, 9.87; S, 5.51. *H-NMR QS, CDC1 3): 9.72 ( s , 2E, m e t h i n e 10, 20-H), 9.40. (s;, 2H, me t h i n e 5, 15-H), 3.99 Cm, 4H, -CH_ 2CH 3), 3.56 ( s , 6H, two.CH ), 3.44 (m, 2H, c h a i n 4-CH 2), 3.03 Cs, m, 8H, two CH 3, c h a i n 4-CH 2), 1.83 ( t , 6H, - C H ^ ^ ) , 0.93 (m, 2H, c h a i n 3-CH 2), 0.79 (m, 2H, c h a i n 3-CH 2), -0.62 (m, 2H, c h a i n 2-CH )•, -0.86 (m, 2H, c h a i n 2-CH ) , -3.11 ( b s , 2H, N-H), -3.74 ( t , 4H, c h a i n l-CHp. a 3C-NMR (6, 1 0 % TFA-CDC1 3): 146.96, 145.85, 143.79, 141.7.1, 1 3 9 . 9 5 , 139.7.1, 133.91 (16C, a- and g - p y r r o l i c c a r b o n s ) , 10.0.99, 9.8.67,(40, meso c a r b o n s ) , 29.97, 26.90, 25.72, 23.68 (8C, c h a i n c a r b o n s ) , 20.24 (2C, CH 2CH ) , 16.25 (2C, CH2_CH ) , 11.68 (4C, CH 3) . V i s i b l e Spectrum ( C H 2 C 1 2 ) : X (nm) , 405.6 512.6 551.0 576.0 630.0 max l o g e , 5.16 3.84 4.01 3.79: 3.32 304 7,17—Djethyl-2,8,12,18—tetramethyl-3,13-[2-^methoxy-5-methylphenylene- 1,3-Bis(hexamethylene)]porphyrin (n = 6) 117a The s a p o n i f i c a t i o n , decarboxylation and c y c l i z a t i o n reactions were c a r r i e d out on 114a as described f or 87a. The product was p u r i f i e d f i r s t on a s i l i c a gel column (Kieselgel 60, 100 g), e l u t i n g with 1% methanol/dichloromethane. The p a r t i a l l y p u r i f i e d porphyrin was then placed on an a c t i v i t y I I I alumina column (Merck 90 neutral, 40 g) and eluted with, dichloromethane. The pure porphyrin was c o l l e c t e d and evaporated to dryness. In four preparations the y i e l d s were 30.0%, 39.7%, 40.4% and 43.7%. MP: 233-234°C. Mol. Wt. Calcd. for C H NO: 708.4767. Found by high r e s o l u t i o n 305 mass spectrometry: 708.4793. Anal. Calcd. for C/oR\nN.0: C, 81.31; H, 8.53; N, 7.90; 0, 2.26. Found: C, 81.21; H, 8.62; N, 7.75; 0, 2.35. H^-NMR (.6, CDC13) : 10.02 (s, 2H, methine 5, 15-H), 10.QO. (s, 2H, methine 10., 20-H), 5.60. (s, 2H, phenyl 4, 6-H),4.36 (m, 2H, chain 6-CH2), 4.13 (m, 2H, -CH_2CH3), .4.06 (m, 2H., -CH2CH3), 3.94 (m, 2H, chain 6-CH2), 3.63 (s, 6H, two-CH3), 3.58 (s, 6H, tw.o-CH3), 2.19 (m, 2H, chain 5-CH2), 2.0.2 (m, 2H, chain 5-CH2), 1.88 (t, 6H, -C^CH^), 1.69 (s, 3H, phenyl 5-CH3), 0.89 (m, 2H, chain 4-CH2), 0.84 (m, 2H, chain 4-CH2), 0.7.1 (m, 2H, chain 3-CH2), 0..5Q. (m, 2H, chain 1-CH2), 0.42 (m, 2H, chain 3-CH2), 0.27 (m, 2H, chain 2-CH2), 0.18 (m, 2H, chain 1-CH ), 0.03 (m, 2H, chain 2-CH2), -2.70. (>, 3H, -0CH3), -3.77 (hs, 2H, N-H). 13C-NMR (6, 1Q% TFA-CDC13): 150..9.6 (IC, phenyl 2-C), 147.0J, .144.07, 143.46, 142.19, 141.37, 141.19, 140.13, 139.9.7 (16C, a - and g-pyrrolic carbons), 135.09 (2C, p h e n y l1 , 3-C), 134.76 (IC, phenyl 5-C), 128.76 (2C, phenyl 4, 6HC), 100.42, 99.35 (4C, meso carbons), 60.64 (IC, -0CH3), 31.66, 30.52, 29.59, 29.08, 28.40, 26.36 (12C, chain carbons), 20.39 (2C, CH2CH3), 20.23 (IC, phenyl 5-CH3), 16.65 (2C, CH2CH3), 12.40, 11.80. (4C, -CH3) . 567.2 620.6 3.82 3.70. V i s i b l e Spectrum (CH 2C1 2): X (nm) 397.2 49.7.2 530.6 max log e 5.21 4.13 3.99 306 ene-This was prepared exactly as described for 87a and 117a. In two preparations the yields of porphyrin before recrystallization were 24.1% and 53.0%; a third preparation yielded 20.7% after recrystalliza-tion from dichloromethane/hexanes. MP: 253-256 C. Mol. Wt. Calcd. for C.,.Hr.N,0: 680,4454. Found by high resolution 46. 56 4 mass spectrometry: 680.4439. Anal. Calcd. for C.,H_.N.O: C, 81.13; H, 8.29; N, 8.23; 0, 2.35. 4o D O 4 Found: C, 81.28; H, 8.20; N, 8.26; 0, 2.16. 1 H-NMR (.$., CDC13) : 10.04 (s, 2H., methine 10, 20-H), 10..01. Cs;, 2H, methine 5, 15-H), 5.20 (s, 2H, phenyl 4, 6-H), 4.23 (m, 2H, chain 5-CH2), 4.16 (m, 2H, -CH2CH3), 4.07 (m, 2H, -CH2CH3), 3.88 (m, 2H, chain 5-CH2), 3.64 (s, 6H, two -CH3), 3.52 (s, 6H, two-CH3), 2.04 (m, 2H, chain 4-CH2), 1.89 (t, m, 8H, -CH2CH3, chain 4-CH2), 1.41 (s, 3H, phenyl 5-CH^., 0.94 Cm, 2H, chain 3-CH2), 0.86 (m, 2H, chain 3-CH2), 0.68 (m, 2H, 307 chain 1-CH2), 0.20 (m, 2H, chain 1-CH ) , 0.79 (m, 2H, chain 2-CH ) , -1.10 (m, 2H, chain 2-CH^), -2.07 (s, 3H, -OCH ) , -3.77 (bs, 2H, N-H). 13C-NMR (6, 10% TFA-CDC13): 146.44, 143.87, 143.70, 143.32, 141.44, 141.29, 140.02, 139.58 (16C, a- and g-pyrrolic carbons), 132.93 (IC, phenyl 5-C), 131.81 (2C, phenyl 1, 3-C), 126.45 (2C, phenyl 4, 6-C), 100.04, 99.65 (4C, mes.o carbons), 58.89 (IC, -OCH ), 29.30, 28.65, 27.74, 27.25, 26.97 (IOC, chain carbons), 20.22 (2C, CH2CH3), 19.81 (IC, phenyl 5-CH ), 16,34 (2C, CH 2£H 3), 12.29, 11.59 (4C, CH ). Visible Spectrum (CH 2C1 2): A (nm) 397.2 497.8 533.6 56.7.2 620.8 max log e 5.18 4.07 3.98 3.78 3.63 7,17-Dlethyl-2,8,12,18-tetramethyl-3,13-[2,5-dimethoxyphenylene-l,4- bis(hexamethylene) ]porphyrin Cn = 6) : 140a The synthesis and purification was carried out oh 139a as described 308 f o r 87a and 117a. Of s i x preparations the y i e l d s before r e c r y s t a l l i z a -t i o n were 19.2%, 41.3%, 49.2% and 60.2%. The compound was r e c r y s t a l l i z e d from dichloromethane/hexanes. MP: 271-274°C. Mol. Wt. Calcd. f o r C/oH._N.0 • 724.4716. Found by high, r e s o l u t i o n 48 60 4 2 mass spectrometry: 724.4695. Ar i a l . Calcd. f o r C , X n N ( 0 ^ : C, 79.52] H, 8.34; N, 7.73; 0, 4.41. 48 60. 4 2 ' ' ' 1 Found: C, 79.64; H, 8.40; N, 7.64; 0, 4.44. 1 H-NMR C.6, CDC13) : 10.00 Cs, 2H, methine 5, 15-H), 9.98 (s, 2H, methine 10, 20-H), 4.43 (m, 2H, chain 6-CH 2), 4.12 (m, 2H, -CH_2CH3), 4.0.4 (m, 2H, -CH 2CH 3), 3.91 (s, 2H, phenyl 3, 6-H), 3.72 (m, 2H, chain 6-CH 2), 3.60 ( s , 6H, two-CH 3), 3.59 ( s , 6H, two-CH^, 2.32 (m, 4H, chain 5-CH 2), l'.87 ( t , 6H, -CH 2CH 3), 1.58 ( s , 6H, -0CH_3), 1.50 (m, 2H, chain 4-CH 2), 1.22 Cm, 2H, chain 4-CH 2), 0.82 (m, 4H, chain 3-CH 2), 0.40 (m, 3H, chain 1-CH 2), 0.21 (m, 2H, chain 1-CH 2), 0.11 (m, 2H, chain 2-CH 2), -0.10 (m, 2H, chain 2-CH 2), -3.99 (bs, 2H, N-H). 13C-NMR (.6, 10% TFA-CDC13) : 145.89, 142.96, 142.73, 142.12, 140.92, 139.64, 138.67, 138.28 (16C, a- and B - p y r r o l i c carbons), 99.00, 97.72 (4C, meso carbons), 31.88, 28.68, 28.43, 26.28 (chain carbons), 20.28 (2C, jCH 2CH 3), 16.22 (2C, CH 2CH 3), 12.09, 11.61 (4C, CH 3). 309 V i s i b l e Spectrum (CR^Cl ) : A (nm) 397.2 496.6 530.0 565.6 620.8 max lo g e 5.19 4.11 3.99 3.80 3.72 7,17-Diethy1-2,8,12,18-tetramethyl-3,13[2,5-dlmethoxyphenylene-l,4- bis(pentamethylene)]porphyrin (n = 5) 140b The synthesis and p u r i f i c a t i o n was c a r r i e d out on 139b. as; described f o r 87a and 117a. The y i e l d was 39.5%. MP: 264-267°C. Mol. Wt. Calcd. f o r C,,Hr,N,0o: 69.6.4403. Found by high, r e s o l u t i o n — 46 56 4 2 mass spectrometry: 69.6.4365. Ana l . Calcd. f o r C.,H CN 0 : C, 79.27] H, 8.10] N, 8.0.4] 0, .4.59,. 46 56 4 2 Found: C, 79.40; H, 8.11] N, 8.02] 0, 4.44. ^H-NMR (8, CDC13) : 9.97 (a, 2H, methine 5, 15-H), 9.93 (a, 2H, methine 10, 20-H)-, 4.25 Cm, 2H, chain 5-CH2) , 4.17 (m, 2H, -CH^ CH.^ ) , 4.0.7 (m, 2H, -CH 2CH 3), 3.9.3 (m, 2H, chain 5-CH 2), 3.80. ( s , 2H, phenyl 3, 6-H), 3.62 Cs, 6H, two-CH 3), 3.54 ( s , 6H, two-CH 3), 2.22 (m, 2H, chain 4-CH 2), 1.9.1, 1.88 Cs, t, m, 14H, -0CH_3, -0CH2CH_3, chain 4-CH 2), 1.07 (m, 2H, 3 chain 3-CH2), 0.96 (m, 2H, chain 1-CH2), 0.88 (m, 2H, chain 3-CH ), 0.53 (m, 2H, chain 1-CH ), -0.31 (m, 2H, chain 2-CH ), -1.13 (m, 2H, chain 2-CH2), -3.90 (bs, 2H, N-H). I3C-NMR (6, 10% TFA-CDG13): 150.01 (IC, phenyl 2,5-G), 146.29, 143.75, 143.45, 143.30, 141.23, 140.91, 140.11, 139.37 (16C, a- and g-pyrrolic carbons), 128.40 (2C, phenyl 1,4-C), 113.56 (2C, phenyl 3,6-C), 99.94, 99.42 (4C, meso carbons), 57.10 (2C, -OCH ), 29.70, 28.80, 28.15, 28.08 27.02 (IOC, chain carbons), 20.30 (2C, CH2CH3), 16.52 (2C, CHjCH ), 12.34, 11.73 (4C, CH ). Visible Spectrum (CH 2C1 2): XX (nm) 39.8.4 498.4 532.4- 567.2 621.8 max log e 5.20 4.10 4.0.1 3.80. 3.68 311 3.7 MODIFICATIONS OF STRAPPED PORPHYRINS 7,17 jDieth.y 1-2,8,12,18-tetramethyl-3 ,13- [2-hydroxy-5-methylphenylene- 1,3-bis(hexamethylene)]porphyrin (n = 6) 118a Anisole strapped porphyrin 117a (153 mg, 0.22 mmol) was dissolved in dry dichloromethane (10 mL) in an oven-dried 3-neck flask equipped with magnetic s t i r r e r bar, pressure-equalizing dropping funnel, argon inlet and drying tube. Stirring under argon, the solution was cooled to -78'°C in a dry ice/acetone bath. Boron tribromide (0.3 mL, 3.2 mmol) was dissolved in dichloro-methane (5 mL) in the dropping funnel and was added dropwise to the porphyrin solution over a period of 5 minutes. The reaction mixture was l e f t s t i r r i n g at —78°C for 2 hours, then at room temperature for a further 1 hour. The reaction was quenched with, water (10.mL) and extracted with. dtchloromethane (50 mL). The organic layer was washed with, sodium 312 bicarbonate s o l u t i o n and saturated sodium chloride s o l u t i o n , then dried over anhydrous sodium s u l f a t e , f i l t e r e d and evaporated to dryness. The crude product was placed on a neutral alumina column (Merck 90, a c t i v i t y III) and eluted with dichloromethane. Fractions contain-ing a single product were combined and evaporated (123 mg, 82.1%). The product was r e c r y s t a l l i z e d from dichloromethane/hexanes as purple plates (.67 mg, 54.3%). MP: 260-263°C. Mol. Wt. Calcd. for C . X J J : 694.460.6. Found by h i g h r e s o l u t i o n H/ J O 4 mass spectrometry: 624.4611. Anal. Calcd. for C , X J ( 0 : C, 81.22; H, 8.41; N, 8.0.6; 0, 2.30. 4/ JO 4 Found: CQ.81,40; H, 8.47; N, 7.97; 0, 2.40. 1 H-NMR (6, CDC13) : 10.04, 10.01 Cs:, 4H, methine 5 ,10,15,20-H) , 5.51 (s, 2H, phenyl 4,6-H), 4.46 (m, 2H, chain 6-CH 2), 4.0.2 (m, 4H, -CIj^CH.^ , 3.95 (m, 2H, chain 6-CH 2), 3.64 Cs, 6H, two-CH 3), 3.62 (s, 6H, two-CH 3), 2.39 (m, 2H, chain 5-CH 2), 2.24 (m, 2H, chain 5-CH 2), 1.88 ( t , 6H, -CH2CH_3), 1.51 (s, 3H, phenyl 5-CH3) , 1.26 (m, 4H, chain 4-CH 2), 0.84 (m, 2H, chain 3-CH2) , 0.47 (m, 2H, chain 3-CH 2), 0.0. (m, 2H, chain 2-CH 2), -0.35 (m, 2H, chain 2-CH 2), -Q.44 (m, 2H, chain 1-CH 2), -0.94 (m, 2H, chain 1-CH2) , -2.56 (bs, IH, phenyl -OH), -3.68 (bs., 2H, -NH). 13C-NMR CS, 10% TFA-CDC1 3): 159.51 (IC, phenyl 2-C), 145.70, 144.72, 313 142.91,' 142.60, 142.13, 140.91, 138.81, 138.10 (16C, a- and S-pyrrolic carbons), 134.08, 132.61, 127.81 (5C, phenyl carbons), 98.79, 97.61 (4C, meso carbons), 30.89, 30.52, 30.29, 29.64, 28.74, 26.22 (12C, chain carbons), 20.25 (3C, CH2CH3 and phenyl 5-CH3), 16.33 (2C, CH2CH3), 11.92, 11.61 (4C, CH3). Visible Spectrum (CH„C1J : 1 2 2 A (nm) 398.0 498.0 534.8 564.4 618.0 max log. e 5.24 4.12 4.00 3.84 3.69 7,17-Diethyl-2,8,12,18-tetramethyl-3,13-[:2-hydroxy-5-methylphenylene-1,3-bis(pentamethylene) jporphyrin (n = 5) 118b The demethylation was carried out on a 0.15 mmol scale, exactly as described for . 1 1 8 a . a b M t e r work-up theucru'de p.roduqt' w a s . was. purified by chromatography on a neutral alumina column [Merck 90., activity III] using dichloromethane as eluant (89.8 mg, 88.9%). The product was recrystallized from dichloromethane/hexanes (72.2 mg, 72.2%). MP: 225-298°C Mol. Wt. Calcd. for C.cHr,N.O: 666.4298. Found by high, resolution 45 54 4 mass spectrometry: 666.4293. 314 Anal. Calcd. for C^H N 0 : C, 81.04; H, 8.16; N, 8.40; 0, 2.40. Found: C, 78.70; H, 8.27; N, 8.04; 0, 4.70. Calcd. for C45 H54 N4°* 1 H2° : C ' 7 8 ' 9 1 ' H> 8 ' 2 4 ^ N> 8' 1 85 °> 4 - 6 7 -H^-NMR 0$, CDC1 ):• 10.22 (s, 2H, methine 5,15-H), 10.08 (a, 2H, methine 15,20-H), 5.33 (s, 2H, phenyl 4,6-H), 4.24 (m, 2H, chain 5-CH ), 4.21, 4.Q8 (m, 4Hv. -CH CH ),'4.Q0 (m, 2H, chain 5-CH ) , 3.64, 3.50 (s, 12H, four-CH 3), 2.22 (m, 2H, chain 4-CH ), 1.88 (t, 6H, -CH2CH ) , .1.61 (m, 2H, chain 4-CH2), 1.24-1.40. (m, 4H, chain 3-CH ) , 1.37 (a/ 3H, phenyl 5-CH3) , -0.15 (m, 2H, chain 1-CH2), -Q.48 (m, 2H, chain 2-CH2) , -1.60. (m, 2H, chain 1-CH2), -1.94 Cm, 2H, chain 2-CH2), -3.84 (bs, 2H, -NH). I3C-NMR 05, 10.% TFA-CDC1 ) : 158.87 (IC, phenyl 2-C), 146.42, 144.73, 143.42, 143.12, 141.66, 141.37, 140.56, 140.02 (16C, a- and g-pyrrolic carbons), 131.32, 127.33, 126.52 (5C, phenyl carbons), 100.76, 100.10, C4C, meso carbons), 29.08, 28.67, 28.13, 27.77, 27.65 (IOC, chain carbons), 20.36 (2C, CH2CH3), 19.42 (IC, phenyl 5-CH3), 16.65 (2C, CH2_CH3), 12.31, 11.85 C4C, CH3) . Visible Spectrum C^CH2C12) : A (nm) 397.2 49.9.2 535.2 563.6 617.6 max " log e 5.25 4.1Q 4.01 3.84 3.59. The bis(methoxy)benzene porphyrin 140a (101 mg, 0.14 mmol) was dissolved in freshly d i s t i l l e d dichloromethane (30 mL) in a 3-neck flask equipped with argon inlet, pressure-equalizing addition funnel, drying tube and magnetic st i r r e r bar. The solution was stirred under argon and cooled to -78°C in a dry ice/acetone bath. A solution of boron tribromide (.0.5 mL, 5.3 mmol) in dichloro-methane (.10 mL) was placed in the addition funnel and added dropwise to the porphyrin solution over a period of 10 minutes. The solution was l e f t s t i r r i n g at -78°C for 1.25 hours, allowed to reach, room temperature and stirred for a further 1.5 hours. At this stage, t i c (10% ethyl acetate/hexanes) showed no sign of the starting material. The reaction was; quenched by the addition of water (IQ mL) and the mixture extracted with 6M hydrochloric acid, sodium bicarbonate s o l u t i o n and saturated sodium chloride s o l u t i o n . The organic layer was dried over anhydrous sodium s u l f a t e , f i l t e r e d and evaporated to dryness. The hydroquinone was oxidized to the quinone by s t i r r i n g i n dichloromethane with lead dioxide for approximately 10 minutes. When t i c indicated complete reaction the oxidant was f i l t e r e d o f f . The crude product was placed on a neutral alumina column [Merck 90, a c t i v i t y I I I ] , E l u t i o n with, dichloromethane yielded the quinone-strapped porphyrin 143a (79.8 mg, 82.2%) which, was r e c r y s t a l l i z e d from toluene (58.8 mg, 60.6%). MP: >260°C (dec). Mol. Wt. Calcd. for C,,H ,N,0 : 694.4247. Found by high, r e s o l u t i o n 46 54 4 2 mass spectrometry: 694.4249. Anal. Calcd. for C ^ H ^ N ^ : C, 79.50; H, 7.83; N, 8.06; 0, 4.60. Found: C, 79.24; H, 8.00; N, 7.9.4; 0, 4.80. H^-NMR (6, CDC13) : 10.03 (s, 2H,, methine 5,15-H), 10.02 (s, 2E, methine 10,20-H), 4.40 (m, 2H, chain 6-CH 2), 4.12 Cq, 4H, -O^Oy, 3.63-3.75 Cm, 2H, chain 6-CH2) , 3.68, 3.60. (s, 12H, f o u r - a y , 2.76 C.s, 2H, quinone 3,6-H), 2.51 (m, 4H, chain 5 rCH 2), 1.89 ( t , 6H, -CH2CH_3) , 1.73 (m, 2H, chain 4-CH 2), 1.51 (m, 2H, chain 4-CH 2), 1.11 (m, 2H, chain 3-CH 2), 0.95 (m, 2H, chain 3-CH 2), 0.27 (m, 2H, chain 1-CH 2), 0.05 to -0.15 (m, 4H, chain 2-CH2) , -Q.72 (m, 2H., chain 1-CH 2), -4.00 (bs, 2H, -NH) . 13C-NMR (6, 10% TFA-CDC13): 188.19 (2C, C = 0), 148.61 (2C, quinone . I, 4-C), 145.71, 142.69, 142.57, 142.21, 141.39, 141.05, 139.39, 138.46 (16C, a- and g-pyrrolic carbons), 132.42 (2C, quinone 3,6-C), 99.14, 98.10 (4C, meso carbons), 31.32, 27.51, 27.28, 27.17, 26.93, 26.29 (12C, chain carbons), 20.30 (2C, CH^CHy, 16.32 (2C, CI^CH.^), 12.27, II. 68 (4C, CH3). Visible Spectrum X (nm) max log e (CH 2C1 2): 258.';4.4 397.?2 ' 2 497.2^.^2530.4^ • 567.2 "'- 621.6 4.72 5.21 4.08 3.94 3.79 3.63 7,17-Diethyl-2,8,12,18-tetramethyl-3,13^[2J5-dioxophenylene-l,4- his(pentamethylene)]porphyrin Cn = 5) 143b The bis(methoxy)benzene porphyrin 140b (61.6 mg, 0.09 mmol) was demethylated under the conditions outlined for compound 143a . The crude product was oxidized with, lead dioxide and purified by chromatography to give 58.9 mg (98.6%). Recrystallization from toluene afforded 41.2 mg (69.9%) of the quinone-strapped porphyrin,143b. MP: >270°C (dec). Mol. Wt. Calcd. for C H N 0 • 666.3934. Found by high, resolution 318 mass spectrometry: 666.3984. Anal. Calcd. for C^H QN 0 : C, 79.24; H, 7.56; N, 8.40; 0, 4.80. Found: C, 77.00; H, 7.44; N, 8.00; 0, 6.77. Calcd. for C 4 4 H 5 0 N 4 ° 2 ' 1 H 2 0 : C> 77.16; H, 7.65; N, 8.18; 0, 7.0.1. 1H-NMR (6, CDC13): 9.47 (s, 4H, methine 5,10,15,20-H), 4.30 (m, 2H, chain t 4.08-4.25 (m, 4H, '-CH^CH^, 3,97 (m, 4H, chain 5-CH ), 3.70, 3.57 (s, 12H, four-CH 3), 2,94 Cs, 2H, quinone 3,6-H), 2.33 (m, 2H, chain 4-CH2), 1.93 (t and m, 8H, -C^CH^. and chain 4-CH2), 1.25 (m, 2H, chain 3-CH2), 1.14 (m, 2H, chain 3-CH2), 0.65 (m, 2H, chain 1-CH2), -0.02 On, 2H, chain l-CH }, -Q.32 (m, 2H, chain 2-CH ), -1.29 (m, 2H, chain 2-CH ), -3.91 (he, 2H, N-H). 13C-NMR C6, 10% TFA-CDC13) : 186.33 (2C, quinone 2,5-C), 147.0.5 (2C, quinone 1,4-C), 146.15, 142.99, 142.81, 142.05, 141.92, 140.86, 140.17, 139.62 (16C, a- and g-pyrrolic carbons), 131.45 (2C, quinone 3,6-C), 99.85, 98.72 (4C, meso carbons),•28.66, 27.00, 26.86, 25.99, 25.92, (IOC, chain carbons), 20.43 C2C, CH2CH3), 16.54 (2C, CH2CH3), 12.20. 11.80 (4C, CH3). Visible Spectrum.: (CH2C12) : X m „ v (nm) .260.0 396.8 498.0 534.8 567.2 620.8 log e 4.47 5.21 4.07 3.98 3.82 3.58 319 3.8 SYNTHESES OF IMIDAZOLE PRECURSORS OH 177 4-Benzyloxy-l-butanol 177 Sodium metal (.40.1 g, 1.7 mol) was washed in dry xylene and was added in small pieces • (yl g) to a solution of butanediol (476.5 g, 5.3 mol) in dry xylene (160 mL) at 120°C. When a l l the sodium had dissolved, benzyl chloride (218.1 mL, 1.9 mol) was added dropwise over a period of 3 hours, the temperature of the reaction mixture being maintained at 120°C. The solut ion was heated at 120°C for a further 1 hour, then allowed to cool to room temperature. The precipitate was filtered off and the xylene was removed from the f i l t r a t e by rotary evaporation. The residue was d i s t i l l e d under reduced pressure (.10 mmHg) . The unreacted butanediol d i s t i l l e d over f i r s t and the product was collected at 152-165°C (10 mmHg) as a clear colorless liquid (179.3 g, 52.5%). BP: 152-165°C @ 10 mmHg; L i t . 234 98-107° C @ 1 mmHg ^ H-NMR (.6, CDC13) : 1.5-1.8 (m, 4H, 1-, 3-CH2), 2.59 (bs, IH, -OH), 3.51, 3.61 (t, 4H, 1-, 4-CH2), 4.52 (s:, 2H, C^CH^, 7.34 (s, 5H, Anal. Calcd. for C^H^O^: C, 73.30; H, 8.95. Found: C, 73.12; H, 8.88. Mass Spectrum (m/e, relative intensity): 180 (M , 7), 137 (3), 107 (73), 91 (100), 79 (14), 77 (7), 71 (17). 4-Benzyloxybutyraldehyde 175 Oxalyl chloride (.27.8 mL, 0..32 mmol) was added to dry dichloro-methane (150 mL) in a 3-neck flask equipped with, overhead st i r r e r , nitrogen inlet and pressure equalizing addition funnel. The mixture was cooled to <v-7Q°C in a dry ice/acetone bath.. With stirring, a solution of dimethyl sulfoxide (47.2 mL, 0.67 mmol) in dichloromethane (150 mL) was added dropwise, gas evolution being observed. 4-Benzyloxy-l-b.utanol 177 (.50.0. g, 0.28 mmol) was dissolved in dichloromethane (200 mL) and added dropwise to the above solution. The solution was l e f t s t i r r i n g for 10 minutes while a cloudy white precipitate developed. Triethylamine (19.4.4 mL, 1.4 mmol) was: added. A dense white precipitate formed and the solution was le f t stirring at -70°C for 1 hour before warming to room temperature. The reaction mixture was transferred to a separatory funnel and H 3 2 1 washed with 2M hydrochloric acid (200 mL) , saturated sodium bicarbonate solution (200 mL), water (200 mL) and saturated sodium chloride solution (200 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to give a slightly yellow o i l . The crude product was d i s t i l l e d under reduced pressure. The clear colorless liquid d i s t i l l i n g at 105-108°C (4 mmHg) was collected (43.8 g, 88.5%). BP: 105-108°C @ 4 mmHg. 1H-NMR (6, CDC13): 1.7-1.8 (m, 2H, 3-CH2), 2.44 (t, 2H, 2-CH2), 3.42 (t, 2H, J = 6 Hz, 4-CH„), 4.40 (s, 2H, C.H_CHj, 7.24 (s, 5H, C.H_), z o _) —z o J 9.68 (t, IH, -C(H)=0). Anal. Calcd. for  c 1 1 E 1 i i ° 2 : C > 7 4 - I 3 J H> 7 - 9 2 - F o u n d : c> 73.94; H, 8.02. Mass Spectrum (m/e, relative intensity): 178 (M+, 8), 150. (9.), 107 (35), 91 (100), 87 (.10), 79 (.12), 77 (4), 71 (11). 178 3-Berizylbxypropibnitrile 178 Methanol (10. mL) was. placed in a 3-neck. flasrk. equipped with, nitro-gen inlet, magnetic stirrer bar, thermometer and pressure-equalizing 322 addition funnel. With stirring, sodium metal (1.5 g) was added. When hydrogen evolution slowed down, benzyl alcohol (240 mL, 2.28 mol) w a s added and the solution stirred until a l l the sodium dissolved. The solution was cooled in an ice-bath to 35°C and acrylonitrile (150 mL, 2.28 mol) added, keeping the temperature at 30-35°C. The mixture was le f t stirring at room temperature for 1 hour then acidified with glacial acetic acid. The mixture was d i s t i l l e d through, a 1-foot Vigreux column under reduced pressure. The product was collected as a clear colorless liquid d i s t i l l i n g in the range 115-123°C @ 5 mmHg (.268.1 g, 73.0%). 0 0/ BP: 115-123°C @ 5 mmHg. L i t . 114-116°C @ 0.5 mmHg. H^-NMR (6, CDC13): 2.50 (t, 2H, 2-CH2), 3.58 Ct, 2H, 3-CH2),;4.48 (a, 2H, C^H.CH), 7.30 (s, 5H, C L ) . 6 D l- 6 -* Anal. Calcd. for C^H^NO: C, 74.50; H, 6.88; N, 8.69. Found: C, 74.50; H, 7.09; N, 8.85. Mass Spectrum (m/e relative intensity): . 161 (M , 39), 132 (.7), 10.6 (22), 104 (10), 91 (100), 79 (.30), 77 (21). -323 176 3-Benzyloxyp ropyIamine 176 A 1 - l i t e r 3-neck flask., equipped with, nitrogen i n l e t and mechanical s t i r r e r , was charged with anhydrous d i e t h y l ether (30.0 mL) and cooled i n an ice-bath.. Lithium aluminum hydride (21.2 g, 0.56 mol) was added and the mixture s t i r r e d . Aluminum t r i c h l o r i d e (.62.0 g, 0.47 mol) ..was weighed into -a 5 0 mL Erlenmeyer f l a s k which, was then attached to one neck of the reaction flask, by a length, of wide bore Tygon tubing. This enabled the aluminum chloride to be added i n small portions. When addi t i o n was completed the f l a s k and tubing were replaced with, a pressure equalizing dropping funnel. A s o l u t i o n of 3-b.enzyloxypropionitrile 178 (.50.0. g, 0..31 mol) i n anhydrous d i e t h y l ether (200 mL) was added dropwise, and the s o l u t i o n l e f t s t i r r i n g overnight. A 30% potassium hydroxide s o l u t i o n (30.0. mL) was added (slowly at f i r s t ) and, a f t e r b r i e f l y s t i r r i n g , the two layers were allowed to separate. The ether layer was decanted, and the aqueous layer was extracted with more ether (2 x 200 mL) . The aether solutions ~ were combined, dried over anhydrous sodium s u l f a t e , f i l t e r e d and evaporated to obtain a yellow o i l . - 324 The crude product was d i s t i l l e d under reduced pressure (96-98°C at 4 mmHg) to y i e l d a co l o r l e s s l i q u i d (44.8 g, 87.3%). BP: 96-98°C @ 4 mmHg; L i t . :.2-32 103°C @ 2 mmHg. H-NMR (.6, CDC1 3): 1.58 (s, 2H, -NH^), 1.70 (q, 2H, J = 6 Hz, 2-CH ), 2.75 ( t , 2H, J = 6 Hz, 1-CH 2), 3.50 ( t , 2H, J = 6 Hz, 3-CH ), 4.45 Cs, 2H, C 6H 5CH 2-), 7.28 (s, 5H, C H^). Anal. Calcd. f o r -ClrtH__N0: C, 72.62; H, 9.15; N, 8.48. Found: 10. 15 C, 72.89; H, 9.08; N, 8.60. Mass: Spectrum (m/e, r e l a t i v e Intensity),; 166 (M +, 1), 108 .'(16) , 10.7 (15), 91 (.10.0.), 79. (.24), 77 C20.), 74 (75). l,5-Bis.(.3-henzyloxypropyl) imidazole 174 A solution of 3-b.enzyloxyb.utyraldeh.yde 177 CO..54 g, 3.Q mmol) and triethylamine (1.27 g, 12.6 mmol) i n dry methanol C25 mL) was added dropwise to a so l u t i o n of 4 -ben z y 1 oxy p r opy 1 am i n e 176 (CL49 g, 3.0. mmol) and tosylmethyl isocyanide (0.61 g, 3.1 mmol) i n dry methanol (40 mL) BrO(CH 2 ) 3 (CH 2 ) 3 0Br 174 325 over a period of 30 minutes. The mixture was l e f t stirring for 70 hours. The solvent was removed and the residue placed on a s i l i c a gel column (Merck Kieselgel 60H, 20 g). The column was eluted f i r s t with dichloromethane but the product only came off when the polarity of the eluant was increased to 10% acetone/dichloromethane. Those fractions in which the desired product predominated were combined and evaporated to give a yellow o i l (0.43 g, 39.4%). Mass. Spectrum (m/e, relative intensity): 364 (M , 13), 273 C20.), 167 (19), 139 (.16), 124 (26), 91 (10.0). Im-2H) . 1,5-Bis (3-hydroxypropyl)imidazole ; 172 A 3-neck flask was, equipped with, ammonia and nitrogen inlets, pressure-equalizing addition funnel and magnetic stirrer bar. With cooling in a dry ice/acetone bath, ammonia was introduced into the flask u n t i l about 25 mL of liquid had collected. l,5-Bis(3-benzyloxypropyl)imidazole 174 (0.39 g, 1.1 mmol) was dissolved in freshly d i s t i l l e d tetrahydrofuran (50 mL) and added dropwise to the solution which was stirring under nitrogen. Sodium metal was cut into small pieces and added in portions un t i l the reaction mixture attained a deep blue color. After stirring for 30 .: .: minutes the blue color was discharged by the addition of solid ammonium chloride and the solution allowed to warm to room temperature under a stream of nitrogen. 20% Methanol/dichloromethane was added to the solid residue and the insoluble material removed by f i l t r a t i o n . The f i l t r a t e was placed on a s i l i c a gel column (Merck Kieselgel 60, 50 g) and eluted with. 20% methanol/dichloromethane. Those fractions containing pure product were combined and evaporated to give a yellow o i l (0.11 g, 57.4%). ^ H-NMR (6, CDClo/DMS0-d,) : 1.4-1.8 (m, 4H., chain 2-CH_) , 2.40 (t, 2H, ' J o ' z Im-5C-CH2), 2.30, 2.39 (t, 4H, 3-CH2), 3.76 (t, 2H, Im-N-CH2), 6.48 (bs, IH, Im-4H), 7.23 (bs, IH, Im-2H) Mass Spectrum (m/e, relative intensity): 184 (M , 22), 140 (39), 96 (100) . CHAPTER 4 .SPECTRAL ASSIGNMENTS AND COMPARISON TABLES 32& 4.1 H-NMR DATA OF STRAPPED PORPHYRINS In t h i s and subsequent s e c t i o n s t h e s t r a p p e d p o r p h y r i n s w i l l be r e f e r r e d t o by t h e t r i v i a l names i n d i c a t e d i n F i g . 27. C h e m i c a l s h i f t s s t a t e d w i t h o u t i n d i c a t i o n o f t h e u n i t s r e f e r t o ppm on the 6 s c a l e . When compared t o t h e i r n o n - s t r a p p e d a n a l o g u e , e t i o p o r p h y r i n I I 185, t h e "'"H-NMR o f t h e s t r a p p e d p o r p h y r i n s d i s p l a y t h e e x p e c t e d f e a t u r e s . Because o f i t s symmetry, e t i o p o r p h y r i n I I has a s i m p l e s p e c t r u m w i t h , the f o u r r i n g m e t h y l s a t t h e 2,8,12,18 p o s i t i o n s o c c u r r i n g as a s i n g l e t a t 3.62 and t h e e t h y l groups as a t r i p l e t and q u a r t e t a t 1,87 and 4,11 235 r e s p e c t i v e l y . A l t h o u g h , two s i g n a l s would be e x p e c t e d , t h e f o u r meso p r o t o n s (5',10,15,20) o c c u r as a s i n g l e t a t 10.11. The i n n e r N-41 p r o t o n s appear u p f i e l d o f TMS a t -3,67 due. t o e x t e n s i v e s h i e l d i n g by t h e p o r p h y r i n r i n g c u r r e n t . I n t r o d u c t i o n of t h e b r i d g i n g s t r a p , which, i s e q u i v a l e n t t o j o i n i n g t h e e t h y l groups a t p o s i t i o n s 3 and 13 o f e t i o I I , l e a d s t o a d e c r e a s e i n symmetry and a s p l i t t i n g o f the. meso, r i n g m e t h y l and met h y l e n e r e s o n a n -c e s . I t has been a l r e a d y n o t e d t h a t t h e s p l i t t i n g o f the r i n g m e t h y l s i g n a l s shows a d e f i n i t e t r e n d depending on s t r a p length."'""''7 W h i l e t he u n s t r a p p e d e t i o . : H shows a s i n g l e m e t h y l r e s o n a n c e a t 3.62, t h e p r e s e n c e o f t h e s t r a p r e s u l t s i n a s p l i t t i n g and an u p f i e l d s h i f t a s i l l u s t r a t e d i n F i g . 28. I n g e n e r a l t h e two m e t h y l r e s o n a n c e s move u p f i e l d a t d i f f e r i n g r a t e s as t h e s t r a p l e n g t h , i s d e c r e a s e d . The res o n a n c e a t h i g h e r f i e l d may be a s s i g n e d t o t h e m e t h y l groups a t t h e 2,12 p o s i t i o n s b.y a n a l o g y t o N - a l k y l a t e d p o r p h y r i n s . S t u d i e s have shown t h a t s u b s t i t u e n t s on t h e N - a l k y l a t e d p y r r o l e r i n g appear u p f i e l d r e l a t i v e t o s i m i l a r s u b s t i -t u e n t s on t h e n o n - a l k y l a t e d r i n g s . S i n c e the N - a l k y l a t e d r i n g i s t i l t e d 329 117a n = 6 Cr-OCH„ 6 3 b n = 5 C 5-OCH 3 118a n = 6 C -OH. 6 b n = 5 C5~OH. F i g . 27: Schematic Representation and Abbreciated Names f o r the Strapped Porphyrins C4 S C4 10 c 5 s c 5 11 b C -Durene C5-OH C6-(OMe)2 C,.-Quinone C5-OCH3 C5-(OMe)2 Cr-Quinone o C,-0CH. 6 3 C^ -OH 6 Etio II b i—r 3-7 3-6 35 i — i — r 3-2 "T 3-1 (a) Ref 235 (b) Ref 117 1 1 30 34 3-3 6 Fig. 28: Variation of Porphyrin Ring Methyl Chemical Shifts with Strap Length o 331 • from t h e p o r p h y r i n p l a n e t h i s d i f f e r e n c e i n c h e m i c a l s h i f t s r e f l e c t s t h e d i f f e r e n c e i n p o s i t i o n o f t h e s u b s t i t u e n t s w i t h r e s p e c t t o t h e p o r p h y r i n r i n g c u r r e n t . ' 2 ^ S i m i l a r l y d e c r e a s i n g t h e s t r a p l e n g t h w i l l t i l t r i n g s A and C so t h a t t h e m e t h y l groups a t the 2,12 p o s i t i o n s no l o n g e r e x p e r i e n c e t h e f u l l d e s h i e l d i n g e f f e c t o f t h e p o r p h y r i n and move u p f i e l d . F o r t h e l o n g e r s t r a p s , t h e d i s t o r t i o n o f r i n g s B and D i s m i n i m a l and t h e m e t h y l s a t t h e 8,18 p o s i t i o n s r e s o n a t e c l o s e t o the p o s i t i o n f o r t h e u n s t r a i n e d e t i o l l . O n ly as t h e s t r a p becomes v e r y s h o r t ( 10 c a r b o n atoms) i s t h e r e a s i g n i f i c a n t u p f i e l d s h i f t o f t h i s s i g n a l . Two e x c e p t i o n s t o t h i s b e h a v i o u r a r e n o t e d . When a quinone i s i n c o r p o r a t e d i n t o t h e s t r a p t h e s i g n a l f o r the 8,18 m e t h y l groups e x p e r i e n c e s a s i g n i f i c a n t d o w n f i e l d s h i f t . These m e t h y l groups may e x p e r i e n c e a d e s h i e l d i n g e f f e c t from the quinone c a r b o n y l s . The m e t h y l groups a t t h e 2,12 p o s i t i o n s a l s o e x p e r i e n c e t h i s d e s h i e l d i n g , b u t t h e e f f e c t i s o v e r r i d d e n by t h e o u t - o f - p l a n e s h i f t . F o r t h e dimethoxybenzene p o r p h y r i n s 117a,b t h e 8,18 m e t h y l s e x p e r i e n c e a s l i g h t u p f i e l d s h i f t . From e x a m i n a t i o n o f CPK models, c o n f o r m a t i o n s o f the s t r a p a r e p o s s i b l e i n w h i c h t h e benzene r i n g i s above r i n g s B and D. I n t h o s e c a s e s t h e d e s h i e l d i n g e f f e c t o f t h e r i n g c u r r e n t a t t h e p o r p h y r i n p e r i p h e r y may be opposed by a s h i e l d i n g e f f e c t o f t h e benzene r i n g , r e s u l t i n g i n a n e t ... u p f i e l d s h i f t . I n t r o d u c t i o n o f t h e s t r a p d i s r u p t s t h e c o i n c i d e n c e o f t h e meso p r o t o n s i g n a l s o b s e r v e d i n e t i o I I . As w i t h t h e m e t h y l groups d e c r e a s i n g t h e s t r a p l e n g t h l e a d s t o u p f i e l d s h i f t s and an i n c r e a s i n g s e p a r a t i o n between tfthe -meso s i g n a l s ( F i g . 2 9 ) . I n d i v i d u a l r e s o n a n c e s were a s s i g n e d i n most c a s e s u s i n g d e c o u p l i n g e x p e r i m e n t s ; i r r a d i a t i o n o f the m u l t i p l e t c. sc. 4 4 c i o b c 5sc 5 C,. -Durene^ " 11 C5-(OMe)2 C6-(OMe)2 C,-OCH. 6 3 C,-Quinone o C,-OH 6 C,-OCH. o 3 C^-Quinone C5~OH Etio II 10-2 100 9-8 10,20 meso protons . 5,15 meso protons H X H (a) M a (b) ~s Cc). /13 (d) resonances' was'-n'ot obtained 9-6 9-4 Fig. 29: Variation of Meso Proton Chemical Shifts with Strap Length 333 - / due t o t h e e t h y l m e thylene groups r e s u l t s i n an enhancement o f t h e s i g n a l f o r t h e 5,15 meso protons;. I n g e n e r a l , f o r t h e l o n g e r c h a i n , t he u p f i e l d s h i f t and t h e s p l i t t i n g o f the s i g n a l s i s q u i t e s m a l l , and i t i s th e 10,20 s i g n a l w h i c h i s f u r t h e r u p f i e l d . On d e c r e a s i n g t h e s t r a p l e n g t h b o t h s i g n a l s c o n t i n u e t o move u p f i e l d , but a t d i f f e r i n g r a t e s , so t h a t e v e n t u a l l y i t i s t h e 5,15 meso s i g n a l w h i c h i s f u r t h e r , u p f i e l d . Examina-t i o n o f CPK models s u g g e s t s t h a t , when an a r o m a t i c r i n g i s : i n c o r p o r a t e d i n t o t h e s t r a p , t h e r e a r e c o n f o r m a t i o n s o f t h e s t r a p i n which, the a r o m a t i c r i n g i s d i r e c t l y above t h e 10,20 meso p o s i t i o n s . At t h e s e p o s i t i o n s t he d e s h i e l d i n g e f f e c t of t h e p o r p h y r i n r i n g c u r r e n t i s p a r t i a l l y o f f s e t by the s h i e l d i n g e f f e c t o f t h e a r o m a t i c r i n g , r e s u l t i n g i n a s l i g h t u p f i e l d s h i f t f o r t h e s e p r o t o n s compared t o t h e 5,15 p r o t o n s , whose u p f i e l d s h i f t i s d e t e r m i n e d s o l e l y by d i s r u p t i o n o f the p o r p h y r i n r i n g c u r r e n t . As t h e d i s r u p t i o n becomes more s e v e r e i n the s h o r t e r s t r a p s (11-9 c a r b o n atoms) and the i n f l u e n c e o f t h e p h e n y l r i n g i s removed, the 5,15 meso p r o t o n s e x p e r i e n c e a g r e a t e r u p f i e l d s h i f t . Some e x c e p t i o n s o c c u r t o t h i s s i m p l i s t i c e x p l a n a t i o n n o t a b l y f o r C^.-OH, where the 5,15 p r o t o n s d i s p l a y a u n e x p e c t e d d o w n f i e l d s h i f t and f o r t h e C^-durene and C^-OMe^ where t h e o r d e r o f t h e s i g n a l s i s r e v e r s e d d e s p i t e t h e s i m i l a r i t y o f t h e s t r a p s . The same r e v e r s a l o f s i g n a l s i s a l s o o b s e r v e d f o r t h e C -OCH o 3 and C^-OCH^ p a i r . For t h e C<.-quinone sample t h e meso s i g n a l s were c o i n c i d e n t . I f t he u p f i e l d s h i f t o f t h e p o r p h y r i n m e t h y l and meso p r o t o n s i s th e r e s u l t o f the p e r t u r b a t i o n o f t h e p o r p h y r i n TT e l e c t r o n c l o u d on i n t r o d u c t i o n o f the s t r a p , t h e n a c o r r e s p o n d i n g d o w n f i e l d s h i f t o f t h e N-H p r o t o n s s h o u l d be o b s e r v e d due t o a d e c r e a s e d s h i e l d i n g a t the p o r p h y r i n c o r e . On t h e whole t h i s i s what i s o b s e r v e d ( F i g . 3 0 ) . F o r ;.cio :c sc C,--OH 6 C5,-'0H C,-Quinone 6 ' •C6-(OMe)2. ,Cc-Quinone ^ 5-(OMe) 2 C^-Durene C6-OCH3 E t i o I l a (a) Ref. 235 Cb) Ref. 117 -3 -0 1 -. 1 -i 1 1 1 ' 1 - 3 - 2 - 3 - U - 3 - 6 - 3 - 8 - 4 - 0 6 F i g . 30: V a r i a t i o n of Porphyrin Core Protons w i t h Strap Length 4^  335 straps bearing a dimethoxybenzene 140a,b or quinone ring 143a,b there i s a further upfield shift due to the shielding effect of the rings. With the anisole porphyrins 117a,b the N-H protons resonate at a similar position to etio II (3.77), indicating that the phenyl ring may be perpendicular to the porphyrin. While hydrogen bonding to the phenol may explain the downfield shift of the N-H protons in C^ -OH, the upfield shift in C^ -OH is unexpected. When the complicating effect of a benzene or quinone ring in the strap i s removed the downfield shift of the N-H resonance corresponds directly to the decrease in chain length. The ethyl methylene protons of etio II appear as a simple quartet at 4.11. Introduction of the strap, which is equivalent to linking diagonally opposite ethyl groups, results in a pair of multiplets for the methylene groups adjacent to the porphyrin. That the protons at the strap's terminus appear as complex multiplets indicates that flipping of the strap above and below the porphyrin plane is relatively slow (Scheme 96). Otherwise the n,n' protons would give simple triplets 132 from coupling to i t s adjacent pair. From Fig. 31 i t can be seen that for unstrained porphyrins the signals for the chain terminal protons are evenly distributed about the resonance position of the ethyl methylene protons of etio !!• As the chain length decreases and rings A and C are t i l t e d out of the plane, both signals experience similar upfield shifts. The -.asymmetry of the strapped porphyrins also results in an inequivalence of the methylene protons of the 7,17 ethyl groups, which occur as a pair of complex multiplets. Similar diastereotopic behaviour by the ethyl methylene protons has been observed in a number of monomeric and dimeric scandium and thallium porphyrins. 1 1 >^ "10 in the case of the thallium porphyrin 187 the asymmetry results both from C4 S C4 c 5 s c 5 10 r b , c C 5-OCH 3 C5-OH C 5-(OMe) 3 -Quinone C,-0CHo o 3 C,-0H 6 C,-Quinone o C 6-(0Me) 2 E t i o I I b a — " r — Terminal CH 2 of Strap 7,17 - CH 2CH 3 [7 (a) if r (b) N 1 H X N" H (c) N N 4-4 42 40 3-8 3-6 I 3-4 (d) Ref. 235 Ref. 117 p o s i t i o n of -CEL^ CH.^  not determined exact p o s i t i o n obscured by overlap 3-2 3 0 F i g . 31: V a r i a t i o n of Chain Termini and Porphyrin E t h y l Chemical S h i f t s SCHEME 96 337 13 7[ i f \ H / \ I 18/ 1 \ ^ 17J Tl3 17[ H X H ^ N / N 12 187 the d i f f e r e n c e i n t h e a x i a l l i g a n d s : and from t h e s i z e o f the. t h a l l i u m i o n w h i c h i s t o o l a r g e t o s i t i n the p o r p h y r i n p l a n e . F o r t h e s t r a p p e d p o r p h y r i n s i r r a d i a t i o n o f the t r i p l e t a t 1.6-1.9, due t o the e t h y l m e t h y l p r o t o n s , l e a d s t o the c o l l a p s e o f the m u l t i p l e t s t o g i v e an AB q u a r t e t . The o n l y e x c e p t i o n t o t h i s b e h a v i o u r was o b s e r v e d i n the C,-quinone case 6 where the methylene p r o t o n s appeared as a q u a r t e t c e n t e r e d a t 4.12. I r r a d i a t i o n o f t h e t r i p l e t a t 1.89 t h e n y i e l d e d a s i n g l e t . The c h e m i c a l s h i f t s o f each p a i r o f p r o t o n s i n t h e s t r a p have been i d e n t i f i e d by d e c o u p l i n g e x p e r i m e n t s ( T a b l e V I I ) . H a v i n g a s s i g n e d the two m u l t i p l e t s i n t h e r e g i o n 3.1-4.5 t o t h e protons, a t t h e s t r a p ' s t e r m i n u s , i r r a d i a t i o n o f e a c h m u l t i p l e t i n t u r n i d e n t i f i e d t h o s e p r o t o n s on the a d j a c e n t c a r b o n . S y s t e m a t i c i r r a d i a t i o n o f e a c h m u l t i p l e t TABLE I V : H-NMR Data o f S u l f i d e - and S u l f o x i d e - S t r a p p e d P o r p h y r i n s ( i n CDC1 3) GROUP 87a (n = 5) 87b (n = 4) 88a (n = 5) 88b (n = .10,20 M e t h i n e H's 9.93 9.72 9.98* 9.78* 9.96 9.50 5,15 M e t h i n e H's 9.82 9.40 9.89 9.47 9.88 -CH„CH 4.09 3. 99 4.02 4.01 —2 3 -CH 0 3.63 3.56 3.67 3.58 3.36 3.03 3.66 3.09 3.43 3.05 3.40 -CH 0CH. 1.86 1.83 1.88 1.87 Z J 1.87 N-H -3.38 -3.11 - -C h a i n 1-CH. -2.02 -3.74 -3.98* -5.69* z -1.56 -3.45 -5.35 -2.89 -2.49 C h a i n 2-CH„ -1.85 -0.86 -1.91 -2.30 z -1.46 -0.62 -0.74 -1.10 C h a i n 3-CH„ -0.13 0.79 -0.3 t o -0.6 +0.26 2. 0.17 0.93 -0.07 0.35 +0.47 0.54 Ch a i n 4-CH„ 1.42 3.08 1.22 1.4 - 1.6 z 3.44 1.50 2.90 1.82 3.3 - 3.5 Chain 5-CH^ 3.63 _ 3.6 - 3.7 3.6 - 3.7 z 3.97 3.8 - 4.0 * Resonances n o t a s s i g n e d 339 TABLE V: H-NMR Data o f A n i s o l e - and P h e n o l - S t r a p p e d P o r p h y r i n s ( i n CDC1 3) • i GROUP 117a (n = 6) 117b (n = 5) 118a (n = 6) 118b (n : 10,20 M e t h i n e H 1 s 10. 00 10. 04 10.04 10.08 5,15 M e t h i n e H's 10.02 10.01 10.01 10.22 P h e n y l 4,6-H 5.60 5.20 5.51 5.33 -CH„CH„ 4.13 4.16 4.09 4.21 -2 3 4.06 4.07 4.08 -CH„ 3.63 3.64 3.64 3.64 j 3.58 3.52 3.62 3.50 " C H 2 C H 3 1.88 1.89 1.88 1.88 P h e n y l 5-CH 3 1.69 1.41 1.51 1.37 P h e n y l 2-0CH 3 -2.70 -2.07 - -N-H -3.77 -3.77 -3.68 -3.84 C h a i n 1-CH„ 0.18 0.20 -0.94 -1.60 z 0.50 0.68 -0.44 -0.15 C h a i n 2-CH„ 0.03 -1.10 -0.35 -1.94 z 0.27 -0. 79 0. 0 -0.48 C h a i n 3-CH 0 0.42 0.86 0.47 1.24 z 0.71 0.94 0.84 1.40 C h a i n 4-CH 0 0.84 1.89 1.26 1.60 2 0.89 2.04 2.22 C h a i n 5-CH„ 2.02 3.88 2.24 4.00 z 2.19 4.23 2.39 4.24 C h a i n 6-CH„ 3.94 - 3.95 -z 4.36 4.46 -340 TABLE V I : H-NMR Data o f Dimethoxybenzene- and Q u i n o n e - S t r a p p e d P o r p h y r i n s ( i n CDC1 3) ( C H , I „ GROUP 140a (n = 6) 140b (n = 5) 143a (n = 6) 143b ( n = 5 ) 10,20 M e t h i n e H's 9.98 9.93 10.02 5,15 M e t h i n e H's 10.00 9.97 10.03 10.05 " - 2 C H 3 til "Al 4.12 4.08-4.25 4.04 4.07 P h e n y l 3,6-H 3.91 3.80 -CH 3.60 3.62 3.68 3.70 3.59 3.54 3.60 3.57 Quinone 3,6-H - - 2.76 2.94 -CH 2CH 3 ' 1.87 1.88 1.89 1.93 P h e n y l 2,5-OCH 3 1.58 1.91 N-H -3.99 -3.90 -4.00 -3.91 C h a i n 1-CH 0.70 0.53 0.27 0.65 0.21 0.96 -0.70 0.0 Ch a i n 2-CH -0.10 -1.13 0.05-0.15 -1.29 0.11 -0.31 -0.32 C h a i n 3-CH 0.82 0.88 0.95 1.14 1.07 1.11 1.25 C h a i n 4-CH 1.22 1.91 1.51 1.93 1.50 2.22 1.73 2.33 Chain 5-CH 2.32 3.93 2.51 3.97 4.25 4.30 Chain 6-CH 3.72 - 3.63-3.75 4.43 4.40 TABLE V I I : H-NMR Da t a f o r t h e M e t h y l e n e P r o t o n s o f t h e S t r a p p e d P o r p h y r i n s ( i n CDC1 3) i <CH 2) n •NHHN- 1 n \ n + 2 x 87a (n = 3) -2.02 -1.56 •1.85 •1.46 -0. 13 0.17 4 1.42 3.63 3.97 87b (n = 2) -3.74 -0.86 -0.62 0.79 0.93 3.08 3.44 O C H , 117a (n = 4) 0.18 0.50 117b (n = 3) 0.20 0.68 0.03 0.27 -1.10 -0.79 0.42 0.71 0.86 0.94 0.84 0.89 1.89 2. 04 2.02 2.19 3.88 4.23 3.94 4.36 118a (n = 4) -0.94 -0.44 118b (n = 3) -1.60 -0. 15 -0.35 0.0 -1.94 -0.48 0.47 0.84 1.24 1.40 1.26 1.61 2. 22 2.24 2.39 4.00 4.24 3.95 4.46 C o n t i n u e d TABLE VII: (CONTINUED) X 1 2 3 0 . 2 1 - 0 . 1 0 Q 8 2 0 . 7 0 0 . 1 1 0 . 5 3 - 1 . 1 3 0 . 8 8 0 . 9 6 - 0 . 3 1 1 . 0 7 - ° - 7 0 0 . 0 5 - 0 . 1 5 ° ' 9 5 0 . 2 7 1 . 1 1 0 . 0 - 0 . 3 2 1 . 1 4 0 . 6 5 - 1 . 2 9 1 . 2 5 4 5 6 1 . 22 3 2 3 . 7 2 1 . 5 0 4 . 4 3 1 .91 3 . 9 3 2 . 2 2 4 . 2 5 1 .51 S . . 6 3 - 3 . 7 5 1 . 73 4 . 4 0 1 . 93 3 . 9 7 2 . 3 3 4 . 3 0 -343 C -quinone undecoupled Simultaneous I r r a d i a t i o n at 1.89 i d e n t i f i e d each, pair of protons on the strap. Attempts to extract s t r u c t u r a l information from the chemical s h i f t s of the strap protons were complicated by the i n t e r p l a y of several f a c t o r s . A l l protons i n the strap w i l l experience an u p f i e l d s h i f t due to shielding by the porphyrin r i n g current. Since t h i s e f f e c t " Y X 344 decreases along both x-and y-axes, the largest u p f i e l d s h i f t should be experienced by the protons at the center of the strap. However when the strap i s func t i o n a l i z e d t h i s u p f i e l d s h i f t may be opposed by the deshielding e f f e c t of the functional group. Thus, for G\.SG\., the methy-lene protons adjacent to the s u l f u r occur further downfield (-1.56 and 2.02) than expected compared to a non-functionalized carbon strap ( e . g . j C ^ , -2.23, -5.87). Since the s h i e l d i n g e f f e c t of the porphyrin decreases also along the y-axis the conformation of the strap w i l l determine chemical s h i f t s . Those protons which are directed into the cav i t y bounded by the porphyrin and the strap w i l l experience a greater sh i e l d i n g and u p f i e l d s h i f t than those directed away. This has been exemplified by the methylene chain porphyrins where a p a r t i c u l a r conformation 184 has been invoked to explain the pattern of u p f i e l d 117 132 s h i f t s . ' Although the porphyrin r i n g current has i t s greatest e f f e c t at the porphyrin core, l o c a l maxima associated with, i n d i v i d u a l j pyrrole rings may also account for the a l t e r n a t i n g pattern of u p f i e l d 132 s h i f t s . Therefore for fu n c t i o n a l i z e d straps the chemical s h i f t s of the straps' protons depend on the following f a c t o r s : 345-(i) the shielding effect of the porphyrin ( i i ) the deshielding effect of the functional group ( i i i ) the conformation of the strap (iv) the length of the strap (v) the presence of local ring current maxima Since these factors may reinforce or cancel each other i t i s d i f f i c u l t to extract useful information from the chemical shift data alone. For the C^-quinone porphyrin the protons appear further upfield than the protons (Table VII). How much of this can be attributed to the deshielding effect of the quinone, or to a conformation in which the protons are directed outside the cavity and the protons inside, i s unclear. For the C^.—quinone the protons are at +0.27 and -0.70 while the C^ . protons both occur at 0.05-0.15. If the influence of the quinone i s the same in both compounds then in C -quinone 6 the strap has adopted a conformation in which one proton of/C is point-ing into the cavity while both protons- of are on the outside. However this data does not suggest any order for the porphyrin-quinone separation in the two compounds. Observation of CPK molecular models suggests that the longer, more flexible chain in C^-quinone can accomodate a shorter porphyrin-quinone separation, which is analogous to Baldwin's "cap" and 99 100 "homo-cap" porphyrins. This: i s reinforced by the larger upfield shift of the quinone proton in C^,-quinone (2.76) compared to C^-quinone 132 (2.94). A similar situation was observed by Sanders. For both dimethoxybenzene porphyrins, C^ -OMe^  and C^ -OMe^ , the conformation of the chain appears to be similar with the protons on H.H H H NHHN 5 •NHHN-C^-quinone Y 5 > Y 6 C^-quinone the outside of the c a v i t y and the C^ protons d i r e c t e d i n s i d e . A l t e r -n a t i v e l y , the d e s h i e l d i n g e f f e c t of the phenyl r i n g current may cancel the s h i e l d i n g e f f e c t of the porph y r i n , r e s u l t i n g i n a net downfield s h i f t of the protons compared to those on • In t h i s instance the phenyl proton (C, 3.91, C r 3.80) and the methoxy protons (C, 1.58, 6 5 o C,. 1.88) o f f e r c o n f l i c t i n g estimates of. the porphyrin-phenyl separation. S i m i l a r arguments may be advanced to e x p l a i n the more downfield p o s i t i o n of the protons r e l a t i v e to those on f o r the a n i s o l e porphyrins, GV-^ OCH,, and C,-OCH,. I f the chemical s h i f t s of the phenyl 5 3 6 3 (C, 5.60, C c 5.20) and methyl protons (C, 1.69, C c 1.41) may be taken 6 5 6 5 as i n d i c a t o r s of s e p a r a t i o n , then i n C^-OCH^ the phenyl is. c l o s e r to the porphyrin than i n C^-OCH^. That the methoxy group occurs at -2.70 i n C,-0CH„ compared to -2.07 i n C -OCH may he as c r i b e d to s t e r i c crowding 6 3 5 3 i n the l a t t e r system. In the more crowded C^-OCH^ the methoxy methyl i s constrained i n t o p o s i t i o n s outside the c a v i t y and experiences a l e s s e r u p f i e l d s h i f t compared to the " l o o s e r " C^-OCH^ which can accommo-date the methoxy group w i t h i n the c a v i t y ( F i g . 32). Removal of the methoxy group to give C^-OH and C^ -OH. r e s u l t s i n a dramatic change i n the chemical s h i f t s of the C^  and C^ protons. One may speculate that formation of the phenol r e s u l t s i n e i t h e r a r e l i e f 347 F i g . 32: Schematic R e p r e s e n t a t i o n o f S t e r i c Crowding i n 117a and 117b o f s t e r i c c o n g e s t i o n o r hydro gen-^bonding between the p h e n o l and N-H p r o t o n s . The phenyl-moves c l o s e r t o t h e p o r p h y r i n c o r e , and the subsequent c o n f o r m a t i o n a l change i n the s t r a p r o t a t e s t h e C^ p r o t o n s i n s i d e t h e c a v i t y , r e s u l t i n g i n a l a r g e u p f i e l d s h i f t . The p o s i t i o n o f t h e p h e n y l (C, 5.51, C c 5.33) and m e t h y l p r o t o n s (C, 1.51, C c 1.37) b 5 b J b o t h suggest t h a t t h e p h e n y l r i n g i s c l o s e r t o t h e p o r p h y r i n i n the C..-OH c a s e . One anomaly i s t h e d o w n f i e l d s h i f t o f the p h e n y l p r o t o n on g o i n g from C 5-OCH 3 (5.20.) t o C 5"0H ( 5 . 3 3 ) . The o r i g i n o f t h i s e f f e c t i s u n c l e a r . 348* The p a t t e r n o f peaks f o r t h e C^SC^ p o r p h y r i n s u g g e s t s t h a t t h e m o l e c u l e may adopt a c o n f o r m a t i o n s i m i l a r t o t h a t shown i n 185ij where . the p r o t o n s a r e d i r e c t e d i n s i d e t h e c a v i t y w i t h the s u l f u r and t h e C„ p r o t o n s p o i n t i n g away fr o m the p o r p h y r i n . F o r the C SC 186 p o r p h y r i n i t a p p e a rs t h a t both. and have one p r o t o n d i r e c t e d i n s i d e the c a v i t y and one o u t s i d e . •. E t i o p o r p h y r i n redisplays symmetry and so we o b s e r v e a s i n g l e r esonance f o r t h e m e t h y l and e t h y l m e t h y l e n e p r o t o n s and two c o i n c i d e n t s i g n a l s f o r t h e meso p r o t o n s . I n t r o d u c t i o n o f t h e s t r a p a c r o s s one f a c e o f the p o r p h y r i n d e c r e a s e s the. symmetry o f the m o l e c u l e . The s t r a p p e d p o r p h y r i n s a r e c h i r a l and o c c u r as a r a c e m i c m i x t u r e o f t h e two e n a n t i o m e r s . F o r t h e quinone 143a,b. and dimethoxybenzene p o r p h y r i n s 140a,b , . a l l c o n f o r m a t i o n s o f t h e s t r a p ( e x c e p t one) r e n d e r the m o l e c u l e c o m p l e t e l y a s y m m e t r i c . That o n l y two s i g n a l s a r e s t i l l o b s e r v e d f o r the meso and m e t h y l p r o t o n s i m p l i e s t h a t the p o r p h y r i n and the quinone o r benzene it±irgs.-*are s t r i c t l y p a r a l l e l , o r t h a t t h e r e i s r a p i d a v e r a g i n g o f a l e a s t two conformations.. S i m i l a r l y , f o r t h e a n i s o l e 117a,h and p h e n o l p o r p h y r i n s 118a,b, ..the p o r p h y r i n 'and -t-he»rphenyl-1ri5igsr£mus-.t be •349 s t r i c t l y perpendicular or rapid averaging i s occurring. The consequences of molecular symmetry were demonstrated in the H^-NMR spectra of a series of porphyrins with a sulfur functional group incorporated into the strap. For C^SC^ 87a the molecule displays effective symmetry and two signals each are observed for the meso and methyl protons, and ten multiplets for each of the pairs of protons on the strap. On oxidation to the tetrahedral sulfoxide the porphyrin contains no symmetry elements at a l l . Four signals each are observed for the meso and methyl protons, with two triplets for the ethyl methyl groups and twenty multiplets for each proton of the strap. Further oxidation to the sulfone restores the symmetry of the molecule and only two signals each are observed for the meso and methyl protons and ten multiplets for the strap protons. Recent X-ray crystal structure determinations of C^SC^ 87a and C.SC. 87b have been carried out. For the shorter chain C.SC, 87b the 4 4 — , 4 4 porphyrin ring is significantly distorted from planarity. This distortion, while much less, i s s t i l l apparent for the longer chain C^SC^ 87a. These results are in agreement with the conclusions drawn from visible and """H-NMR spectroscopy. The conformations of the straps in the crystal are also similar to those conformations 185, 186 deduced from a simplistic interpretation of the """H-NMR case. Thus for C^SC^ the strap carbons adjacent to the sulfur are close to the porphyrin ring. The protons on these carbons are directed into the cavity and experience a large upfield shift. For C..SC,-, the unit -C2-C -S-C^ -C"2- appears to be almost linear, and one proton each from and C2 is directed into the cavity experienc-ing larger upfield shifts compared to the protons directed outside. 350 3.51 4.2 C-NMR DATA OF STRAPPED PORPHYRINS The H-NMR spectra of porphyrins are dominated by the^ring current e f f e c t s of the macrocycle, the r e s u l t i n g s h i f t s being of the same 13 magnitude as the-observed range of chemical s h i f t s (a.10 ppm) . For C-NMR the ri n g current s h i f t s are of the same magnitude as for '''H-NMR, but since 13 the observed range of C chemical s h i f t s i s about 200 ppm, the e f f e c t i s l e s s dramatic. 13 The C-NMR spectra of the strapped porphyrins may be divided into four regions. Signals f o r the g- substituents and the methylene carbons of the strap occurred i n the region 10-52 6V- The .methoxy groups of the dimethoxybenzene 14Qa,b. and the. anisole porphyrins 117a,b are located at 57-60 6. The meso carbons were confined to a narrow region at 97-100 while the a- and g-pyrrolic carbons and the phenyl carbon occurred from 110-160 6. ' In general the spectra showed small u p f i e l d s h i f t s ( 4 ppm) for the carbons i n the straps functional group compared to the corresponding bis-dipyrromethanes or b i s - p y r r o l e s . Furthermore, for the anisole and phenol porphyrins t h i s u p f i e l d s h i f t was more pronounced i n the C,. rather than the Cr strap. This supported the arguments based on "''H-NMR o that the phenyl r i n g i s closer to the porphyrin i n the shorter strap molecule. For the quinone porphyrins 143a, 143b the upfield. s h i f t (.1-2 ppm) of the quinone carbons on decreasing the strap length from 6 to 5 c o n f l i c t e d with '''H-NMR evidence which suggested that i t was with the longer, more f l e x i b l e strap that the quinone could approach, more c l o s e l y to the porphyrin. For the strapped porphyrins displaying C symmetry there were'"'•four . 352 d i s t i n c t carbons each for the a- and g-pyrrolic p o s i t i o n s . When a spectrum of C^SC^ was recorded i n deuterochloroform no signals were observed for the quarternary a - p y r r o l i c carbons. This f a i l u r e to observe sharp resonances had previously been a t t r i b u t e d to N-H tautomeri-237 13 zation. The use of 10% TFA-CDC13 as solvent to record the C-NMR spectra of the strapped porphyrins was prompted not by s o l u b i l i t y considerations alone (indeed the samples appear to be s u f f i c i e n t l y soluble i n deuterochloroform), but to allow observation of the a-carbons by forming the d i c a t i o n and preventing tautomerization. Under these conditions the f u l l eight signals were observed although i t was not possible to assign the i n d i v i d u a l resonances. The chemical s h i f t s of the meso carbons are s e n s i t i v e to the su b s t i t u t i o n pattern on the porphyrin periphery. These signals were used to confirm the homogeneity of the sample, the observation of only two peaks i n the region 98-100 p&ij i n d i c a t i n g that rearrangement during the a c i d catalyzed intramolecular condensation had not occurred. Two exceptions were the asymmetric C,_-sulf oxide 88a and C^-sulfoxide 88b where three ( r a t i o 2:1:1) and four meso signals were observed r e s p e c t i v e l y . These compounds also showed sixteen signals for the ,:a- and g-pyrrolic carbons as expected. Attempts to cor r e l a t e the chemical s h i f t s of the meso carbons and the strap length met with only l i m i t e d success. For hydrocarbon and s u l f i d e straps: the separation of the two signals increased with decreasing strap length (Fig. 33). Introduction of a phenyl or quinone r i n g into the strap resulted "in no .obvious rends.. The positions of the porphyrin ethyl (^ 20. and 16 "5 r) and methyl (Nil p6-)i)did not appear to be affected by introduction of the strap, appearing close to the values observed for etioporphyrin I I . In most 353^ (a) Ref. 235 C b 1 1 a Et i o I I a (b) Ref. 117 0 0.5 1.0 1.5 2.0 2.5 6 F i g . 33: Separation of Meso Carbon Resonances as a Function of Strap Length cases two signals wereobserved for the two d i s t i n c t methyl groups. For C^SC^ the two signals are coincident, while for the asymmetric C,.-sulfoxide four signals were, observed. The spectrum of C -(0Me)„ 140a was anomalous. When run i n 10% TFA-6 2 CDCl^ a l l the si g n a l s for the porphyrin carbons appeared at the expected po s i t i o n s . However none of the dimethoxybenzene signals appeared and for the strap carbons only two sharp signals (31.88, 26.28) were observed with two broad signals at 28.67 and 28.43. Introduction of a 3s pulse delay resulted i n no improvement of the spectrum. In contrast, the spectrum of C,--(0Me)2 140b i n the same solvent displayed a l l the expected signals. Three explanations presented themselves: (i) the samples of C -(OMe) were contaminated with some paramagnetic impurity, 354 ( i i ) t h e dimethoxybenzene r i n g had been o x i d i z e d t o t h e r a d i c a l , o r ( i i i ) the dimethoxybenzene r i n g and the s t r a p were s l o w l y i n t e r c o n v e r t -i n g among s e v e r a l c o n f o r m a t i o n s l e a d i n g t o b r o a d e n i n g o f the s i g n a l s . P o s s i b i l i t y ( i ) was c o n s i d e r e d u n l i k e l y s i n c e t he absence o f the peaks had been o b s e r v e d u s i n g d i f f e r e n t samples o f C -(OMe) and 6 2 d i f f e r e n t b a t c h e s o f s o l v e n t s . F u r t h e r m o r e C -(OMe) 140b, p r e p a r e d under i d e n t i c a l c o n d i t i o n s , showed a l l t h e e x p e c t e d p e a k s . A h i g h t e m p e r a t u r e (80°C) s p e c t r u m ( F i g . 54) was r u n i n 10% TFA-T o l u e n e - d c i n an attempt t o speed up i n t e r c o n v e r s i o n between the v a r i o u s 8 c o n f o r m e r s l e a d i n g t o sharp s i g n a l s f o r an " a v e r a g e " c o n f o r m a t i o n . A l t h o u g h t h e r e was some s h a r p e n i n g f o r t h e s t r a p c a r b o n s (3 peaks a t 32.28, 29.07 and 26 . 4 7 ) , t h e dimethoxybenzene c a r b o n s were s t i l l v e r y b r o a d . However, when t h e sp e c t r u m was r u n i n CDCl^ a t room t e m p e r a t u r e , a l l t h e e x p e c t e d r e s o n a n c e s were o b s e r v e d ( t h e a - p y r r o l i c c a r b o ns were broadened due t o N-H t a u t o m e r i z a t i o n ) . '''H-NMR d i s p l a y e d c o m p l i m e n t a r y b e h a v i o u r . I n CDCl^ a l l t h e p r o t o n r e s o n a n c e s were^bbserved,-but'in TFA-CDC1„ o r T F A - T o l u e n e - d D , t h e r e was a b r o a d e n i n g o r d i s a p p e a r a n c e o f 3 o a l l t h e dimethoxybenzene p r o t o n s and some o f t h e s t r a p m e t h y l e n e p r o t o n s . I t w o u l d appear t h a t f o r t h e f r e e - b a s e form t h e s t r a p o f C ^ - ^ M e ^ can. r o t a t e f r e e l y among a.-number of conf o r m a t i o n s o g i v i n g i r i s e v t o sharp.arp s i g n a l s f o r the av e r a g e c o n f o r m a t i o n . On p r o t o n a t i o n however, t h i s r o t a t i o n i s r e s t r i c t e d and t h e s i g n a l s f o r t h e s t r a p a r e broadened. T h i s r e s t r i c t e d r o t a t i o n may be due t o e i t h e r o r b o t h o f the f o l l o w i n g : ( i ) h y d r o g e n - b o n d i n g between t h e oxygen o f the methoxy group and the 355 i' N-H, o r ( i i ) r u f f l i n g of the p y r r o l e r i n g s on p r o t o n a t i o n may h i n d e r r o t a t i o n of the s t r a p . 356 13 TABLE V I I I : C-NMR Data o f S u l f i d e - and S u l f o x i d e - S t r a p p e d P o r p h y r i n s ( i n 10% TFA-CDC1 3) GROUP a- and g-p y r r o l i c c a r b o n s 87a (n = 5) 8;7b (n = 4) Meso carbons C h a i n c a r b o n s -CH 2CH 3 -CH 2CH 3 -CH„ 146.87 144.79 143.55 141.73 141.07 140.00 139.91 139.47 100.52 99.18 29.41 27.35 27.06 26.04 24.12 20.48 16.65 12.28 11.89 146.96 145.85 143.79 141.71 139.95 139.71 (139.71) 133.91 100.99 98.67 29.97 26.90 25.72 23.68 20.24 16.33 16.27 11.68 88a (n = 5) 88b (n = : 4) 145.68 144. 17 146. 75 146.48 143.44 142. 96 146. 37 145.51 142.86 142. 80 145. 00 143.76 142.56 141. 56 142. 72 142.60 141.20 139. 02 141. 09 140.78 138.79 138. 46 139. 44 139.36 138.20 137. 56 137. 59 137.01 136.75 132. 60 131.10 99^50 100.78 (99. 50) 99. 93 98. 18 98. 37 98. 14 97. 87 .49.56 .48. 61 51. 75 49.35 26.54 26. 25 28. 78 26.28 26.24 25. 65 25. 70 25.14 25.47 24. 17 . 20. 71 20.24 16. 25 16. 09 12. 06 11. 60 11. 99 11. 37 11. 77 11. 70 357 TABLE IX: 13 C-NMR Data of A n i s o l e - and P h e n o l - S t r a p p e d P o r p h y r i n s ( i n 10% TFA-CDC1 3) GROUP a- and g-p y r r o l i c c a r b o n s 117a (n = 6) 117b (n = 5 ) 118a (n = 6) 118b (n = 5) 147.01 144.07 143.46 142.19 141.37 141.19 140.13 139.97 146.44 143.87 143.70 143.32 141.44 141.29 140.02 139.58 145.70 144.79 142.91 142.60 142.13 140.91 138.81 138.10 146.42 144.73 143.42 143.12 141.66 141.37 140.56 140.02 P h e n y l c a r b ons 2-C 1,3-C 5-C 4,6-C 150.96 133.09 134.76 128.78 131.81 132.93 126.45 159.51 134.08 132.61 127.81 158.87 127.33 131.32 126.52 Meso c a r b o n s P h e n y l 2-0CH 3 C h a i n c a r b o n s 100.42 99.35 60.64 31.66 30.52 29.59 29.08 28.40 26.36 100.04 99.65 58.89 29.30 28.65 27. 74 27.25 26. 97 98.79 97.61 30.89 30.52 30.29 29.64 28.74 26.22 100.76 100.16 29.08 28.67 28.13 27.77 27.65 -CH 2CH 3 P h e n y l 5-CH„ -CH 2CH 3 -CH„ 20.39 20.23 16.65 12.40 11.80 20.22 19.81 16.34 12.29 11.59 20.25 20.25 16.33 11.92 11.61 20.36 19.42 16.65 12.31 11.85 358 GROUP 1 4 0 a (n = 6) 1 40b (n = 5) 1 4 3 a (n = 6) 1 43b (n = 5) a- and g-p y r r o l i c carbons 145.90 142.96 142.12 140.92 139.64 138.67 138.28 146.29 143.75 143.45 143.30 141.23 140.91 140.11 139.37 145.71 142.69 142.57 142.21 141.39 141.05 139.39 138.46 146.15 142.99 142.81 142.05 141.92 140.86 140.17 139.62 -2,5rC. Phenyl 1,4-C carbons 3,6-C Meso carbons Phenyl 2,5-0CH3 Chain carbons 99.00 97.72 31.88 28.68 28.43 26.28 150.01 128.40 113.56 99.94 99.42 57.10 29. 70 28.80 28.15 28.08 27.20 188.19 148.61 132.42 99.14 98.10 31.32 27.51 27.28 27.17 26.93 26.29 186.33 147.05 131.45 99.85 98.72 28.66 27.00 26.86 25.99 25.92 -CH 2CH 3 -CH^H -CH„ 20.28 16.22 12.09 11.61 20.30 16.52 12.34 11.73 20.30 16.32 12.27 11.68 20.43 16.54 12.20 11.80 Resonances not observed 87a n = 5 10 - r 9 T" 8 T" 7 i 1 1 r r 3 2 6 I i 1 1 i r 1 0 - 1 - 2 -3 -4 F i g . 34: H NMR Spectrum of 87a i n CDCI, LO , Ln 87b n = 4 88b n = A ~ r ~ 1 1 1 1 1 — i r 10 9 8 7 6 5 A 3 6 Fig. 37: 1H NMR Spectrum of 88b in CDC1„ 3 u> (S3 1 l2 l„-VL|CB2'n^ O C H 3 J 117 b n= 5 - I J _ J 10 9 8 7 6 5 U 3 2 1 0 -1 -2 -3 -4 6 Fig. 39: H NMR Spectrum of 1175 in CDC1. Fig. 40: H NMR Spectrum of 118a in CDC1 IAJV. J L - r 0 -1 — r -2 - 3 — r -A OJ ON On Fig. 41: H. NMR Spectrum of 118b in CDC1 All 8 T -5 Fig. 43: H NMR Spectrum of 140b. in CDC1 Fig. 44: IH NMR Spectrum of 143a in CDC1. .00 • j . csv KO: 13 Fig. 46: C NMR Spectrum of 87a in 10% TFA-CDC10 w ' 3 -~J Fig. 47: C NMR Spectrum of 87b. in 10% TFA-CDC1 0 88a n = 5 A I 150 I — 100 50 0 Fig. 48: 1 3 C Spectrum of 88a in 10% TFA-CDC13 49: C NMR Spectrum of 88b in 10% TFA-CDC1 Fig. 51; I 3 C NMR Spectrum of 117b. in 10% TFA-CDC1 w Fig. 53: C NMR Spectrum of II8b in 10% TFA-CDC1 00 F i g . 54: 13 C-NMR Spectra of 140a; A B C i n 10% TFA-CDC13 at Room Temperature i n 10% TFA-Toluene-dg at 80°C i n CDCl^ at Room Temperature 383 • 4.3: ELECTRONIC ABSORPTION SPECTRA OF PORPHYRINS The e l e c t r o n a b s o r p t i o n s p e c t r u m o f a p o r p h y r i n d e r i v a t i v e i s dominated by an i n t e n s e band between 380 and 420 nm. T h i s band, commonly c a l l e d t h e S o r e t band, has a m o l a r e x t i n c t i o n c o e f f i c i e n t f r o m 2 t o 4 x 10^ M ^cm ^. F o r f r e e base p o r p h y r i n s f o u r l e s s i n t e n s e bands, d e s i g n a t e d I - I V i n o r d e r o f i n c r e a s i n g e n e r g y , a r e o b s e r v e d i n the r e g i o n 450-650 nm. I n s e r t i o n of a m e t a l o r p r o t o n a t i o n of the n i t r o g e n s a t the. p o r p h y r i n c o r e r e s u l t s i n a s i m i l a r change i n t h e s p e c t r u m . B o t h m e t a l l o p o r p h y r i n s and p o r p h y r i n d i c a t i o n s s t i l l d i s p l a y an i n t e n s e S o r e t band, b u t o n l y two bands, a and g, a r e o b s e r v e d i n t h e r e g i o n 500-600 nm. T h i s d r a m a t i c change i s a t t r i b u t e d t o an i n c r e a s e i n symmetry o f t h e p o r p h y r i n . F o r t h e f r e e base p o r p h y r i n s : t h e p a t t e r n o f i n t e n s i t i e s of bands I - I V may be c o r r e l a t e d w i t h t h e s u b s t i t u t i o n p a t t e r n on the< p o r p h y r i n 147 p e r i p h e r y . S t e r n and c o w o r k e r s used t h e terms e t i o , r h o d o, oxorhodo and p h y l l o t o c l a s s i f y t h e i n t e n s i t y p a t t e r n s shown i n Scheme 97. ( i ) E t i o - t y p e S p e c t r a : The p a t t e r n IV > I I I > I I > I i s f o u n d i n a l l p o r p h y r i n s where a t l e a s t s i x p e r i p h e r a l s i t e s a r e s u b s t i t u t e d by a l k y l groups and t h e r e m a i n i n g s i t e s a r e u n s u b s t i t u t e d . ( i i ) Rhodo-type S p e c t r a : I n t r o d u c t i o n of an e l e c t r o n - w i t h d r a w i n g group ( e . g . c a r b o x y l i c a c i d , a l d e h y d e ) r e s u l t s i n an i n c r e a s e i n i n t e n s i t y o f band I I I r e l a t i v e t o band I V , i . e . , I l l > IV > I I > I . T h i s change i s accompanied by a s h i f t i n a b s o r p t i o n t o l o n g e r w a v e l e n g t h s . 384' SCHEME 97 500 600 (nm) 5 0 0 60O (nm) ( i i i ) Oxorhodo^-type Spectra: Two "rhodofying" groups on diagonally opposite pyrrole rings enhance each other's e f f e c t r e s u l t i n g i n a pattern, III > II > IV > I. (iv) Phyllo-type Spectra: The presence of four or more unsubstituted positions on the porphyrin may r e s u l t i n an i n t e n s i t y pattern, IV > II > III > I. Since the strapped porphyrins have a l k y l substituents at the eight 3 8 5 g-positions, one would expect them to show the typical etio-type spectrum with IV > III > II > I. This i s indeed the case for those straps which incorporate a phenyl or quinone ring (Figs. 62-69). Even so, within each pair, comparison of the extinction coefficients (Table XI) shows a small decrease in intensity of band IV and increase in intensity of band III for the C over the C straps. As the strap length 5 6 decreases this change becomes more dramatic. For C^SC^ 87a and C -sulfoxide 88a the intensities of bands III and IV are approximately equal (Figs. 58, 60). Decreasing the strap length even further, O^SC^ 87b displays a typical rhodo-type spectrum with III > IV > II > I (Fig. 59). On oxidation to the C^-sulfoxide 88b the spectrum takes on oxorhodo-type features with III > IL' > IV > i (Fig. 61). These changes in intensities are accompanied by a shift to longer wavelength of the absorption maxima. Similar behaviour is displayed by the protonated porphyrins. For the longer straps the spectra are similar with the lower energy ot band about half as intense as the g-band. However as the strap becomes tighter there is an increase in intensity of the a relative to the g_ band; indeed for C,-sulfoxide 88b a > B, 4 The "rhodofying" effect of the strap is obviously due to distortion of the porphyrin macrocycle as the strap becomes tighter. However why this effect should manifest i t s e l f in the same way as an electron withdrawing group is unclear. TABLE XI: Comparison of Electronic Absorption Spectral Data of Porphyrins (Free base in CH Cl,,) X nm (los^e) max PORPHYRIN Soret Band IV Band III Band II Band I Etioporphyrin II' C6-(OMe)2 C5-(OMe)2 C--OH 6 C5-OH Cg-quinone C -sulfide 140a 140b C -0CH„ 117a 6 3 C5-0CH3 117b 118a 118b C,-quinone 143a b 143b 87a C -sulfoxide 88a C.-sulfide 87b 4 C -sulfoxide 88b 4 396.5 (5.23) 397.2 (5.19) 398.4 (5.19) 398. 2 (5.21) 397.2 (5.18) 398. 0 (5.24) 397.2 (5.25) 397.2 (5.21) 396.8 (5.21) 400.0 (5.22) 399.6 (5.20) 405.6 (5.16) 404.4 (5.24) 497.0 (4.16) 496.6 (4.14) 498.4 (4.10) 497.2 (4.13) 497.8 (4.07) 498.0 (4.12) 499.2 (4.10) 497.2 (4.08) 498.0 (4.07) 502.4 (4.03) 502.4 (4.01) 512.6 (3.84) 513.2 (3.89) 530.0 (4.02) 530.0 (3.99) 532.4 (4.01) 530.6 (3.99) 533.6 (3.98) 534.8 (4.00) 535.2 (4.01) 530.4 (3.94) 534.8 (3.98) 539.0 (4.03) 539.2 (4.03) 551.0 (4.01) 551.6 (4.09) 565.7 (3.84) 565.6 (3.80) 567.2 (3.80) 567.2 (3.82) 567.2 (3.78) 564.4 (3.84) 563.6 (3.84) 567.2 (3.79) 567.2 (3.82) 570.0 (3.79) 568.0 (3.82) 576.0 (3.79) 573.6 (3.89) 619.7 (3.72) 620.0 (3.72) 621.8 (3.68) 620.6 (3.70) 620.8 (3.63) 618.0 (3.69) 617.6 (3.59) 621.6 (3.63) 620.8 (3.58) 624.0 (3.52) 621.6 (3.49) 630.0 (3.32) 627.2 (3.35) * Ref. 117 387 TABLE XII: Comparison of Electronic (Dication in CH.C1 ) PORPHYRIN Soret Etioporphyrin I I * 399V5. (5. C 6-(0Me) 2 140a 403.6 (5. C 5-(0Me) 2 140b 401.2 (5. C -OCH 6 3 117a 400.0 (5. C5-0CH3 117b 400.0 (5. C^ -OH 6 118a 405.6 (5. C5-OH 118b 400.0 (5. C,-quinone 0 143a 401.2 (5. C^-quinone 143b 403.2 (5. C^-sulfide 87a 406.0 (5. C^-sulfoxide 88a 408.4 (5. C,-sulfide 4 87b 41010 (5. C.-sulfoxide 88b 416.8 (5. Absorption Spectra of Porphyrins nm (log e) max (3 a 58) 549. 1 (4. 25) 590. 7 (3.90) 50) 546. 6 (4. 16) 592. 4 (3.81) 65) 546. 6 (4. 18) 590. 8 (3.75) 54) 546. 0 (4. 15) 590. 0 (3.77) 47) 545. 4 (4. 15) 588. 4 (3.74) 55) 548. 4 (4. 18) 594. 0 (3.88) 58) 546. 8 (4. 21) 587. 2 (3.65) 57) 546. 0 (4. 20) 591. 2 (3.85) 60) 547. 2 (4. 21) 592. 4 (3.82) 49) 551. 0 (4. 13) 597. 2 (3.82) 52) 551. 6 (4. 14) 597. 2 (3.87) 32) 558. 4 (3. 97) 609. 2 (3.88) 43) 562. 0 (4. 02) 612. 0 (4.04) * Ref. 117 300 400 500 600 700 nm WAVELENGTH Fig. 58: Electronic Absorption Spectra of 87a 1.0-1 LU 0J6 -O z < CD or: O co 0.4-< 0.2-87b n = 4 0.0H 300 400 "i 1 r 500 600 WAVELENGTH free-base dication 700 n m Fig. 59: Electronic Absorption Spectra of 87b cc Fig. 60: Electronic Absorption Spectra of 88a 1.0 0 \ 1 I I 1 1 ' 1 300 400 500 600 700 nm WAVELENGTH Fig. 61: E l e c t r o n i c Absorption Spectra of 88b VO Fig. 62: Electronic Absorption Spectra of 117a Fig. 64: Electronic Absorption Spectra of 118a Co VO 1.0-1 300 400 500 600 700 n m WAVELENGTH Fig. 65: Electronic Absorption Spectra of 118b. 1.0-1 W A V E L E N G T H F i g . 66: Electronic Absorption Spectra of 140a u> VO a s 9 140b n=5 free - base dication 1 r 500 .600 W A V E L E N G T H F i g . 67: E l e c t r o n i c Absorption Spectra of 140b to 1.0-, 300 400 500 600 700 WAVELENGTH Fig. 68: Electronic Absorption Spectra of 143a Fig. 69: Electronic Absorption Spectra of 143b 400" REFERENCES Kao, O.H.W.; Wang, J.H. 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