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Synthesis of 2,2’,12,12’-bisdecamethylenedi- (7,17-diethyl-3,8,13,18-tetramethylphorrphine) Hiom, John 1981

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SYNTHESIS OF 2,2',12,12'-BISDECAMETHYLENEDI-(7,17-DIETHYL-3,8,13,18-TETRAMETHYLPORPHINE) by JOHN HIOM B.Sc. ( H o n o u r s ) , T r e n t P o l y t e c h n i c , 1975 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE i n THE FACULTY OF GRADUATE STUDIES (Department o f C h e m i s t r y ) We a c c e p t t h i s t h e s i s as c o n f o r m i n g t o t h e r e q u i r e d s t a n d a r d THE UNIVERSITY OF BRITISH COLUMBIA JUNE 1981 (c) J o h n Hiom In presenting t h i s thesis i n p a r t i a l f u l f i l m e n t of the requirements for an advanced degree at the University of B r i t i s h Columbia, I agree that the Library s h a l l make i t f r e e l y a v a i l a b l e f o r reference and study. I further agree that permission for extensive copying of t h i s thesis for scholarly purposes may be granted by the head of my department or by his or her representatives. I t i s understood that copying or pu b l i c a t i o n of t h i s thesis for f i n a n c i a l gain s h a l l not be allowed without my written permission. Department of Chemistry  The University of B r i t i s h Columbia 2075 Wesbrook Place Vancouver, Canada V6T 1W5 Date July 15, 1981 ABSTRACT The interactions between porphyrins and related t e t r a p y r r o l i c macrocycles play many varied and important b i o l o g i c a l functions. In many of these systems the te t r a p y r r o l i c macrocycles, whilst not covalently linked, are c l o s e l y associated and the proximity and r e l a t i v e orientations are of c r i t i c a l importance. This thesis describes the synthesis of a covalently b i s l i n k e d dimeric porphyrin. Our approach consists of constructing a single l i n k f i r s t , and building a porphyrin onto either end, simultaneously, i n symmetrical fashion v i a an a,c-biladiene. A variety of methenes were produced to enable the synthesis of porphyrins with reactive side-chains diagonally opposed to the f i r s t l i n k . Singly linked porphyrins with Cg,Cg and C ^ Q chains were produced. The porphyrin side chains were then modified to produce a terminal acetylene diagonally opposed to the f i r s t l i n k . The second l i n k was then achieved by an oxidative coupling 10 and c a t a l y t i c h y d r o g e n a t i o n t o y i e l d a b i s l i n k e d p o r p h y r i n dimer w i t h two h y drocarbon c h a i n s . A model r e a c t i o n i s a l s o d e s c r i b e d i n w h i c h a mono-m e r i c p o r p h y r i n was d i m e r i s e d t o a s s e s s the f e a s i b i l i t y o f the s i d e c h a i n m o d i f i c a t i o n and the f i n a l o x i d a t i v e c o u p l i n g r e a c t i o n t o produce the s i n g l y l i n k e d d i m e r . i i i TABLE OF CONTENTS Page A b s t r a c t i i Table o f C o n t e n t s i v L i s t o f F i g u r e s v i L i s t o f A b b r e v i a t i o n s i x Acknowledgements x 1. INTRODUCTION 1 1.1 G e n e r a l Review o f B i s p o r p h y r i n s 2 1.1.1 S y n t h e s i s 4 1.1.2 S p e c t r a l P r o p e r t i e s 23 1.1.3 A p p l i c a t i o n s 37 1.2 Nomenclature 42 1.2.1 P y r r o l e s 43 1.2.2 D i p y r r o l e s 44 1.2.3 T e t r a p y r r o l e s 44 2. RESULTS AND DISCUSSION 47' 2.1 S y n t h e t i c O b j e c t i v e s 48 2.2 P y r r o l e s 54 2.2.1 Monopyr r o l e s 56 2.2.2 S y n t h e t i c a l l y u s e f u l p y r r o l e s from 4- a c e t y l - 2 - b e n z y l o x y c a r b o n y l - 3 , . 5- d i m e t h y l p y r r o l e (91) 58 2.2.3 M o d i f i c a t i o n o f ^ - s u b s t i t u t e d p y r r o l e s 68 2.3 The F i r s t L i n k 7 0 2.4 2 - ( 2 H - P y r r o l - 2 - y l i d e n e m e t h y l / p y r r o l e s (Methenes) 73. 2.4.1 L i n k e d Methenes 7 5 i v Page 2.4.2 The R e a c t i v e S i d e C h a i n Methenes 77 2.4.3 B r o m i n a t i o n o f Methenes . . . 81 2.5 P o r p h y r i n S y n t h e s i s '83 2.5.1 The Johnson P o r p h y r i n S y n t h e s i s 84 2.5.2 S i n g l y L i n k e d P o r p h y r i n s . . . 87 2.5.3 The F i n a l L i n k 97 3. EXPERIMENTAL 101 3.1 G e n e r a l Methods 102 3.2 S y n t h e s i s o f A c y c l i c P r e c u r s e r s . . . 104 3.3 S y n t h e s i s o f M o n o p y r r o l e s 107^ 3.4 S y n t h e s i s o f C h a i n - l i n k e d P y r r o l e s . . 12? 3.5 S y n t h e s i s o f Methenes . . . . . . . . 139 3.6 S y n t h e s i s o f C h a i n - l i n k e d methenes . . 14 6 3.7 S y n t h e s i s of Model P o r p h y r i n 150 3.8 S y n t h e s i s o f S i n g l y L i n k e d P o r p h y r i n s 157 3.9 S y n t h e s i s o f Doubly L i n k e d P o r p h y r i n s 173 4. SPECTRAL DATA 178 4.1 1 H NMR S p e c t r a 179 4.2 1 3 C NMR S p e c t r a 194 4.3 E l e c t r o n i c A b s o p r t i o n S p e c t r a o f P o r p h y r i n s 203 REFERENCES • -217 v LIST OF FIGURES F i g u r e Page 1. Schematic o f U r o p o r p h y r i n s e r i e s 43 2. Proposed Route t o C g _ 6 Dimer 50 3. Proposed Route t o C g _ 8 Dimer 51 4. Proposed Route t o c-LQ-10 D-*- m e r ^ 2 5. Proposed Route t o Model C ^ Q Dimer -53 6. S y n t h e s i s o f K n o r r ' s P y r r o l e 55 7. S y n t h e s i s o f 3-free P y r r o l e (8'8) 56 8. S y n t h e s i s o f p y r r o l e (91) 57 9. S y n t h e s i s o f g-Side C h a i n P y r r o l e s 59 10. B o r o h y d r i d e r e d u c t i o n o f A c e t y l 61 11. O x i d a t i o n o f a-methyl t o aldehyde 62 12. P r e p a r a t i o n o f S y n t h e t i c a l l y U s e f u l P y r r o l e s v i a T r a n s f o r m a t i o n o f a - S u b s t i t u e n t s o f (100) 64 13. P r e p a r a t i o n o f P r o t e c t e d H y d r o x y e t h y l P y r r o l e s from (94) 6 9 14. S y n t h e s i s o f C h a i n L i n k e d B i s P y r r o l i c I n t e r m e d i a t e s 71 15. S y n t h e s i s o f Pyrromethene from a-Carboxy and a-Formyl P y r r o l e s .74 16. S y n t h e s i s o f C h a i n L i n k e d Bismethenes . . . 76 17. Proposed S y n t h e s i s o f S u b s t i t u t e d S i d e C h a i n Methenes 78 18. S y n t h e s i s o f C h l o r o e t h y l Methenes 78. 19. S y n t h e s i s of P r o t e c t e d H y d r o x y e t h y l Methenes 8 0. 20. B r o m i n a t i o n o f Methenes ;8 2 21. Mechanism of P o r p h y r i n C y c l i s a t i o n 85 22. S y n t h e s i s o f C h l o r o e t h y l p o r p h y r i n 87 v i Figure- Page 23.. S y n t h e s i s o f CQ B i s (bromoethyl p o r p h y r i n ) . . . 89 24. S y n t h e s i s o f Model Diyne B i s p o r p h y r i n 92 25. S y n t h e s i s o f C 1 Q B i s p o r p h y r i n 94 26. S y n t h e s i s o f C 1 Q B i s ( p e n t - 4 - y n e p o r p h y r i n ) . . 96 27. S y n t h e s i s o f C 1 Q - C 1 Q Doubly . l i n k e d Dimer . . . 98 69) 179 70) 18 0 71) 181 72) 182 73) 183 .75) 184 .76) 18 5 :77). 186 .78) 187 .79) 188 .80) . 189 .81) 190 .82) 191 .83) . 192 L85) 193 L68) 194 : (.171) 195 . L72) 196 46. 100.6 MHz 1 3 C NMR Spectrum o f (173) . . . . . . 197 47. 100.6 MHz 1 3 C NMR Spectrum o f (177) 198 28 . 270 MHz X H NMR Spectrum o f 29. 100 MHz 2 H NMR Spectrum of 30. 270 MHz ^H NMR Spectrum o f 31. 400 MHz XH NMR Spectrum o f 32. 400 MHz X H NMR Spectrum o f 33. 270 MHz NMR Spectrum o f 34. 270 MHz ^ NMR Spectrum o f 35. 400 MHz NMR Spectrum'. o f 36. 270 MHz X H NMR Spectrum o f 37 . 400 MHz XH NMR Spectrum of. 38. 270 MHz XH NMR Spectrum o f 39. 270 MHz 2 H NMR Spectrum of 40. 270 MHz ^ NMR Spectrum o f 41. 270 MHz 2 H NMR Spectrum o f 42. 400 MHz NMR Spectrum of 43. 20 ; MHz 13c NMR Spectrum o f 44 . 100 . 6 MHz 1 3 C NMR Spectrum 45. 20 : MHz 13c NMR Spectrum o f v i i Figure Page 48. 100.6 MHz l j C NMR Spectrum of (.178) 199 49. 100.6 MHz 1 3 C NMR Spectrum of (17 9) 200 50. 100.6 MHz 1 3 C NMR Spectrum of (.181) 201 51. 1 3 100.6 MHz C NMR Spectrum of (18 2) 202 52. Electronic Absorption Spectrum of (169) . . . 203 53. Electronic Absorption Spectrum of (170) . . . 204 54. Electronic" Absorption Spectrum of (171) . . . 205 55. Electronic Absorption Spectrum of (.172) . . . 206 56. Electronic Absorption Spectrum of (.175) . . . 207 57. Electronic Absorption Spectrum of (177) . . . 208 58 . Electronic Absorption Spectrum of (178) . . . 209 59. Electronic Absorption Spectrum of (179) . . . 210 60. Electronic Absorption Spectrum of (.181) . . . 211 61. Electronic Absorption Spectrum of (.182) . . . 212 62. Electronic Absorption Spectrum of (183) . . . 213 63. Electronic Absorption Spectrum of (183a) . . 214 64. Electronic Absorption Spectrum of (185) . . . 215 65. Electronic Absorption Spectrum of (185a) . . 216 v i i i ABBREVIATIONS """H NMR = p r o t o n n u c l e a r magnetic resonance 13 C NMR = carbon-13 n u c l e a r magnetic resonance Cg_g e t c = b i s l i n k a g e s of (CE^)g Bz = b e n z y l E t = e t h y l Me = m e t h y l EDA = e t h y l e n e d i a m i n e DMSO = d i m e t h y l s u l f o x i d e a-DCB = 1 , 2 - d i c h l o r o b e n z e n e Pyr = p y r i d i n e TMEDA = t e t r a m e t h y l e t h y l e n e d i a m i n e A b b r e v i a t i o n s i n NMR Assignments s = s i n g l e t m = m u l t i p l e t s d = d o u b l e t bs = broad s i n g l e t t = t r i p l e t bd = broad d o u b l e t q = q u a r t e t p yr = p y r r o l e ppm = p a r t s per m i l l i o n i x ACKNOWLEDGEMENTS I would l i k e t o thank P r o f e s s o r D a v i d D o l p h i n f o r h i s encouragement and guidance d u r i n g the c o u r s e o f t h i s work. I t has been an e n j o y a b l e and r e w a r d i n g e x p e r i e n c e . My thanks t o the members o f the D o l p h i n Group, p a s t and p r e s e n t , f o r t h e i r h e l p and f r i e n d s h i p . My thanks a l s o t o a l l the C h e m i s t r y Department s e r v i c e s , t he h e l p a f f o r d e d t o me by P e t e r Borda, the NMR and Mass S p e c t r o s c o p y departments i s g r a t e f u l l y acknowledged. A s p e c i a l thank you t o my w i f e A n n e t t e Hiom w i t h o u t whom none o f t h i s would have been p o s s i b l e . F i n a n c i a l s u p p o r t from the U n i v e r s i t y o f B r i t i s h Columbia i n the form o f a Teaching A s s i s t a n t s h i p (1976-81) i s g r a t e f u l l y acknowledged. x To P h i l l i p , Paul and Annette For Their Love and Understanding CHAPTER 1 INTRODUCTION 2 1 1. INTRODUCTION 1.1 G e n e r a l Review o f B i s p o r p h y r i n s N a t u r e h a v i n g once d i s c o v e r e d a u s e f u l system has no r e t i c e n c e i n e x p l o i t i n g i t t o t h e f u l l e s t . One such system i s t he p o r p h y r i n m a c r o c y c l e and i t s d i h y d r o and t e t r a h y d r o compounds, c h l o r i n and b a c t e r i o c h l o r i n . A d i v e r s e a r r a y o f hemes a r e employed i n n a t u r e , p r o b a b l y the b e s t known b e i n g hemoglobin, the t e t r a m e r i c heme p r o t e i n r e s p o n s i b l e f o r oxygen t r a n s p o r t i n mammals. M y o g l o b i n , i t s monomeric a n a l o g i s used f o r oxygen s t o r a g e i n mammal t i s s u e . 2 The cytochromes a r e a s e r i e s o f heme p r o t e i n s whose p r i n c i p a l b i o l o g i c a l f u n c t i o n i s e l e c t r o n and/or hydrogen t r a n s p o r t by v i r t u e o f a r e v e r s i b l e v a l e n c y change o f t h e i r heme i r o n . The cytochromes a r e c l a s s i f i e d i n t o f o u r groups depending upon t h e i r heme groups. Cytochrome a c o n t a i n s a f o r m y l s i d e c h a i n , cytochrome b has protoheme as the p r o s -t h e t i c group, cytochrome c has c o v a l e n t l y l i n k e d p r o t e i n s and cytochrome d has a c h l o r i n p r o s t h e t i c group. Cytochrome o x i d a s e i s r e s p o n s i b l e f o r the t e r m i n a l s t e p i n the f o u r e l e c t r o n r e d u c t i o n o f oxygen i n the r e s p i r a t o r y system, and c o n t a i n s two heme groups and two copper i o n s . The heme groups have been shown t o d i f f e r and 3 have been l a b e l l e d cytochromes a, a^', the copper i o n s have a l s o been shown by EPR t o be d i f f e r e n t , one as c u p r i c t h e 3 other of unknown valence. An o v e r a l l picture of the oxygen reduction i s the addition of one electron from each of the two iron and the two copper ions. The short half l i v e s of 5 intermediates postulated by Greenwood and Gibson suggest that the active s i t e must contain a l l four metal ions i n close proximity. The electrons for the oxidation are transported to cytochrome oxidase v i a a series of cyto-chromes. The electron transfer between heme groups would indicate the close proximity of these hemes during the transfer. Catalase and peroxidase,.heme proteins which bring about reductions of superoxide and peroxide, also exhibit electron transfer. Cytochrome P-450 a type b cytochrome exhibits oxygen binding and electron transfer i n a variety of b i o l o g i c a l hydroxylations. NADPH i s believed to enter the reduction twice, once as reductant of f e r r i c P-4 5 0 and again transforming the i n i t i a l oxygen adduct of ferrous P-4 50 into an active hydroperoxo-complex which then oxidises the bound substrate molecule aft e r transformation into a f e r r y l form. Chlorophyll, a dihydroporphyrin, and bacteriochlorophyll, a tetrahydroporphyrin, also have a variety of functions. In the photosynthetic process chlorophyll aggregates act as 6 antenna to absorb l i g h t energy. The electronic energy produced i s then transferred along the chlorophyll chains 4 7 to the so c a l l e d "special p a i r " . The "special p a i r " or P-700 (P870 i n bacteria), so l a b e l l e d because of t h e i r c h a r a c t e r i s t i c absorptions, i s believed to be two chlorophyll molecules i n close proximity which act as a primary electron donor. The r a d i c a l formed by the expulsion of an electron i s s t a b i l i z e d by the d e l o c a l i s a t i o n over the pair of macrocycles. The P-7 0 0 r a d i c a l has a c h a r a c t e r i s t i c Gaussian (ESR) signal with a g-value of 2.0025 and signal width 7 gauss which has been , 8 shown to be 1//2 that of the monomeric chlorophyll r a d i c a l . Theory predicts the signal should be 1 /V N when the r a d i c a l i s spread over N chlorophyll molecules. While i n none of the above systems are the t e t r a - " p y r r o l i c macrocycles covalently linked, t h e i r proximity and r e l a t i v e orientations are of c r i t i c a l importance. In nature t h i s spacing i s i n general achieved by orientation i n membranes. As-yet the bioorganic chemist i s not s u f f i c i e n t l y s k i l l e d to mimic these membranes. Instead the r e l a t i v e d i s p o s i t i o n of dimeric porphyrins have been controlled by l i n k i n g them covalently. We describe here the synthetic approaches towards such systems and some properties exhibited by dimeric porphyrins. 1.1.1 Synthesis The i n i t i a l approach was to take two porphyrins and covalently l i n k them with amide, ester or ether linkages. 5 Here follows a chronological review of these syntheses. 9 In 1972 Schwartz et a l . reported the synthesis of a covalently linked bisporphyrin (1). The authors reacted 2-carboxyl-7,12-diethyl-3,8,13,17,18 penta-methylporphyrin with oxalyl chloride to give the acid chloride; t h i s was treated with an excess of ethylene diamine or phenylene diamine to give 2-(p-amino-ethylaminocarboxyl) or 2-(p-amino-phenylaminocarboxyl) porphyrins. These were metallated with copper or cobalt and reacted with more of the acid chloride porphyrin to give a series of singly metallated bisporphyrins. Treatment with zinc acetate afforded the mixed metal bisporphyrins. While t h i s method of covalent linkage i s almost t r i v i a l l y easy, and despite the f a c t that others (vide infra) have followed the same path, the amide linkages (and esters or ethers also employed) present two major problems. Porphyrins and metalloporphyrins are inherently of low s o l u b i l i t y and dimeric porphyrins even more so; and the incorporation of an amide linkage a d d i t i o n a l l y decreases the s o l u b i l i t y . Secondly, the amide linkage i s a reasonably reactive functional group, and although amide linkages maintain t h e i r i n t e g r i t y 6 under physiological conditions t h i s i s not necessarily the case i n the laboratory. I t has been found that such covalently linked dimeric porphyrins r e a d i l y cleave to monomeric species. The only advantage other than convenience to such linkages i s that mixed-metal dimers are most r e a d i l y prepared by coupling of pre-metallated monomers. In 1976 Anton et al. 1°transesterified 5,10,15,20-tetraC4-carbomethoxyphenyllporphyrin C2) with an equimolar quantity of ethylene g l y c o l . The resultant six component mixture was separated by chromatography to give s t a r t i n g material monotransesterified, two d i t r a n s e s t e r i f i e d , t r i -t r a n s e s t e r i f i e d and the f u l l y t r a n s e s t e r i f i e d products. The mono and d i t r a n s e s t e r i f i e d products were metallated and reacted with the acid chloride of 5-carboxyphenyl-10,15,20-tri t o l y p o r p h y r i n (3) (prepared by a mixed-aldehyde synthesis) to give the bisporphyrin (4) and two trisporphyrins one of which i s shown (5). 7 CHo CO2CH3 CH3 ( 3 1 R =-C0 2CH 2CH 20 2C-Boxer and Closs, working on P-700 models, i n the hope of mimicking the chlorophyll "special p a i r " , t r a n s e s t e r i f i e d methyl pyropheophorbide a with ethylene gly c o l to afford the monoester. Treatment with pyropheophorbide a activated by 1,1 1-carbonyldiimidazole resulted i n the di-ester which 1 2 was metallated with magnesium by the Eschenmoser method to give (6). 8 (6) R = H (7) R =-C02CH3 1 3 Wasielewski et a l . " working i n the same f i e l d treated pheophorbide a at room temperature i n tetrahydrofuran/pyridine with methyl chloroformate and e s t e r i f i e d the anhydride with excess ethylene gly c o l to give the monoester of pheophorbide a. Coupling was carried out i n pyridine at 0° with a 2:1 molar r a t i o of the monoester to pheophorbide a using the mild acylating agent phosgene to give the dimer (7). While a single covalent l i n k ensures the two porphyrins are held within a spe c i f i e d distance of each other there i s no guarantee of metal-metal interactions; one would thus l i k e to have .better control over the r e l a t i v e d i s p o s i t i o n of the two macrocycles. In an attempt to meet this c r i t e r i o n the synthesis of doubly linked porphyrins was undertaken. 1 h In 1977 Ogoshi et a l . reacted 7,17-bis-(2-carboxyethyl)2, 3,12,13-tetraethyl-8,18-dimethylporphyrin with isobutyl chloro-formate i n tetrahydrofuran, t h i s was highly diluted and added dropwise to a tetrahydrofuran solution of 7,17-bis-(3-hydroxy-propyl)-2,3,12,13 tetraethyl-8,18-dimethylporphyrin to give the doubly linked bisporphyrin (8). 9 Collman et a l . condensed pyrrole (2 eq) with benzaldehyde (1 eq) and 2-nitrobenzaldehyde (1 eq) i n acetic acid to give a mixture of tetraphenylporphyrin and mono, d i , t r i and t e t r a n i t r o -phenylporphyrins. Chromatographic separation gave the diphenyl-dinitrophenylporphyrins. These were reduced with SnC^/HCl to give the a-trans (9) and <*f a - c i s diaminophenyl-diphenyl-porphyrins (10). The ct , a-trans diaminophenyl-diphenylporphyrin was treated with excess phosgene followed by a second equivalent of i t s e l f to give bisporphyrin (11). The same procedure using the a , a cis-diaminophenyl-diphenylporphyrin resulted i n the two bis porphyrins (12) and (13). Reaction ofa,a-cis diamino-phenylporphyrin with mesoporphyrin IX diacidchloride resulted i n the bisporphyrin (14). 10 a 3 i ti4) 1 6 A r n o l d e t a l , w h i l s t w o r k i n g on the r e a c t i o n s o f meso-h y d r o x y m e t h y l p o r p h y r i n ,found t h a t o c t a e t h y l - m e s o - h y d r o x y m e t h y l p o r p h i n a t o n i c k e l (15) r e f l u x e d i n di m e t h y l f o r m a m i d e i n the presence o f s u l f u r i c a c i d gave 50% y i e l d s o f meso, meso'-e t h y l e n e b i s o c t a e t h y l p o r p h i n a t o n i c k e l ( 1 6 ) . T h i s was the f i r s t r e p o r t e d dimer l i n k e d s o l e l y t h r o u g h c a r b o n . The s y n t h e s i s , o f c o u r s e , i s n o t amenable t o l i n k a g e s o t h e r than two-carbons l o n g . 11 (15) (16) 1 7 Wasielewski et a l . produced the bacteriochlorophyll dimer (17) by the e s t e r i f i c a t i o n of bacteriopheophorbide a with ethylene g l y c o l using benzotriazole N-methanesulfonate and triethylamine i n tetrahydrofuran to give the mono ester. (17) This was coupled with a second bacteriopheophorbide by the same method, except 4-dimethylaminopyridine was used as the base and methylene chloride as solvent. Whereas e a r l i e r work had used synthetic porphyrins i t was found to be convenient to use mixtures of monoesters available from the unselective mono-saponification of the diester (or mono-esterification of the diacid) of the read i l y available naturally derived porphyrins such as protoporphyrin. Owing t o the l a b i l i t y o f the v i n y l groups t o p h o t o - o x i d i s e , t hey are u s u a l l y hydrogenated t o e t h y l s (mesoporphyrin) o r c l e a v e d o f f ( d e u t e r o p o r p h y r i n ) b e f o r e b e i n g a p p l i e d t o dimer work. 1 8 I c h i m u r a p r e p a r e d a m i x t u r e o f s i n g l y - l i n k e d p o r p h y r i n s (one o f w h i c h i s shown as (18) by r e a c t i n g the a c i d c h l o r i d e o f the m i x t u r e o f monomethyl e s t e r s o f mesoporphyrin IX ( d e r i v e d from a p a r t i a l s a p o n i f i c a t i o n o f the d i e s t e r ) w i t h 2-(3-hydroxypropyl)-3,7,8,13,17,18-hexamethyl-12-p r o p y l p o r p h y r i n . R e a c t i o n o f the d i a c i d c h l o r i d e o f mesoporphyrin IX w i t h 3 , 7 - b i s ( 3 - h y d r o x y p r o p y l ) - 2 , 8 , 1 3 , 1 8 -t e t r a m e t h y l - 1 2 , 1 7 - d i e t h y l p o r p h y r i n gave the d o u b l y l i n k e d b i s p o r p h y r i n (19) as an i s o m e r i c m i x t u r e . R e a c t i o n o f the (19) same b i s ( 3 - h y d r o x y p r o p y l ) p o r p h y r i n w i t h 2 e q u i v a l e n t s of the a c i d c h l o r i d e o f the monomethyl e s t e r o f m e s o p o r p h y r i n IX gave a m i x t u r e o f t r i m e r s (such as 20). 13 CH 3 ^C-0CH2CH2CH2 xCH, C0-CH3 C H ^ C h ^ C ^ CH 3 CH3O2C (20) 1 9 Chang et a l . synthesised the porphyrin (21) R=COOH or R=CH2COOH, and manipulated the side chains to give R=CH2NR'H or R=CH2CH2NR1 H. High d i l u t i o n coupling of pairs of these porphyrins gave a series of c o f a c i a l dimers (22). R=(CH2) 2CONR(CH2) 2 R= (CH2) 2CONR(CH2) 3 R=CH2CONR(CH2)2 R=CH2CONR(CH2)3 (22) Various metal ions were incorporated at the monomer stage to give mixed metal systems. In order to r e l i e v e the low solu-b i l i t y discussed above, hexyl side chains were used to enhance the s o l u b i l i t y i n organic solvents. 20 Traylor et a l . coupled meso-1,2-di(3-pyridyl)-ethylene-diamine with mesoporphyrin IX monomethyl ester through the pi v a l o y l anhydride to give the bisporphyrin. Insertion of iron gave the bisporphyrin (23). 14 (23) Porphyrin dimers linked four times have been prepared as well. If applied to g - o c t a a l k y l porphyrin dimers, four li n k s would remove the ambiguity of orientation inherent with dimers linked only twice (through diametrically opposite beta-positions), and r e s u l t i n a single, well defined substance. Such a synthesis has yet to be reported. In the context of meso-tetraaryl porphyrin chemistry, even two linkages (through opposite meso-positions) w i l l r e s u l t i n but a single isomer. The two additional linkages were added more to discourage slippage or t i l t i n g of the two porphyrin units with respect to each other, and to provide a more r i g i d l y defined geometry thereby. The only example reported so far i s by Kagan. The enormous problems of producing four covalent lin k s between two porphyrins was overcome by the synthesis of 15 the second p o r p h y r i n i n s i t u a t the ends of the fo u r l i n k s 2 1 i n a s i m i l a r manner to t h a t used by Almog e t a l . i n the 22 s y n t h e s i s of capped p o r p h y r i n s . Kagan e t a l , took p-2-hydroxyethoxybenzaldehyde and r e a c t e d i t wi t h p y r r o l e i n r e f l u x i n g a c i d i f i e d xylene, f o l l o w e d by e s t e r i f i c a t i o n with the a i d of p-carboxybenzaldehyde to g i v e (24). Reaction CHO I I C = 0 0 CH 2 CH2 0 i CH 2 CH2 0 C=0 ) CHO (24) of (24) w i t h p y r r o l e (4 eq) i n r e f l u x i n g p r o p i o n i c a c i d / ethylbenzene gave the t e t r a l i n k e d b i s p o r p h y r i n (25). 16 0 (25) C h l o r o p h y l l d e r i v a t i v e s have a l s o been d o u b l y l i n k e d 2 3 t o form the "sandwich" d i m e r s . I n 1978 W a s i e l e w s k i e t a l . c o n v e r t e d p h e o p h y t i n a t o m e t h y l p y r o p h e o p h o r b i d e a and e f f e c t e d an i n d i r e c t a n t i - M a r k o w n i k o f f h y d r a t i o n o f the v i n y l group by means of the t h a l l i u m ( I I I ) n i t r a t e o x i d a t i o n t o the aldehyde a c e t a l , f o l l o w e d by h y d r o l y s i s and c y a n o b o r o h y d r i d e r e d u c t i o n . The m e t h y l e s t e r was h y d r o l y s e d i n HC1 t o y i e l d the h y d r o x y - a c i d which was s e l f - c o u p l e d w i t h 2 - c h l o r o - N -m e t h y l p y r i d i n i u m i o d i d e i n the presence o f t r i e t h y l a m i n e and 4 - d i m e t h y l a m i n o p y r i d i n e i n r e f l u x i n g b u t y r o n i t r i l e . Magnesium was i n s e r t e d w i t h i o d o m a g n e s i u m - 2 , 6 - d i - t e r t - b u t y l -4-methylphenolate i n r e f l u x i n g d i c h l o r o m e t h a n e t o g i v e the c h l o r o p h y l l dimer (26). 17 (26) 2 4 L i t t l e , extending his work on oxygen binding models, employed a simple high y i e l d ether linkage for the synthesis of the bisporphyrin (27). 5-(2-Hydroxyphenyl)-10 ,15, 2 0 - t r i t o l y l -porphyrin was reacted with a greater than 10 f o l d excess of C271 1-, 3-dibromopropane i n refluxing dimethyl formamide i n the presence of potassium carbonate for 24 hours to y i e l d the w-bromoalkylporphyrin (28). This was reacted with two f o l d excess of 5-(4-hydroxyphenyl)-10,15,20-tritolylporphyrin to give, after gel permeation chromatography, the bisporphyrin C27).. 18 (28) 2 5 Landrum et a l . adopted the previously reported synthesis 2 6 of Collman et a l . to give a singly linked bisporphyrin (29). This was then treated with FeBr 2 or MnB^to give the metallo-bisporphyrin and subsequently treated with tetrabutyl ammonium imidazolate i n dry tetrahydrofuran to give the imidazolate bridged bisporphyrin (30) . In a singular departure from the more usual work i n the 2 7 f i e l d , Maltzan reacted meso-tetramethylporphyrin with N-bromosuccinimide to obtain the bromomethyl and the gTbromo 19 s u b s t i t u t e d p r o d u c t s w h i c h were t h e n r e a c t e d t o f o r m p o l y m e r s . The bromomethyl compound was c o n v e r t e d t o t h e m e t h o x y m e t h y l (31) w i t h s o d i u m m e t h o x i d e / m e t h a n o l . S u b s e q u e n t r e a c t i o n w i t h (31) (32) m e s o - t e t r a m e t h y l p o r p h y r i n i n c h l o r o f o r m and b u b b l i n g HC1 gas gave t h e b i s p o r p h y r i n (32) i n 70% y i e l d . The N i - N i and N i - P d d i m e r s were p r o d u c e d by a p p r o p r i a t e m e t a l l a t i o n o f t h e monomers w i t h s u b s e q u e n t c o u p l i n g . T h i s was t h e f i r s t r e p o r t e d example o f m e s o - b e t a ' d i m e r ( a l s o l i n k e d s o l e l y t h r o u g h c a r b o n ) b u t i s c l e a r l y n o t c a p a b l e o f much g e n e r a l i z a t i o n . The u s e o f amide o r e s t e r l i n k a g e s had c a u s e d a d e c r e a s e i n s o l u b i l i t y i n t h e s e s y s t e m s (which a l r e a d y had low s o l u -b i l i t y ) , t h u s i n o u r own l a b o r a t o r i e s we t o o k a d i f f e r e n t a p p r o a c h t o t h e l i n k i n g o f o c t a a l k y l p o r p h y r i n s . D o l p h i n 2 8 . and P a i n e c o v a l e n t l y l i n k e d b i s p o r p h y r i n s by an u n b r o k e n c h a i n o f c a r b o n atoms (of v a r i a b l e l e n g t h ) , a c c o m p l i s h e d by c o n s t r u c t i n g t h e l i n k f i r s t and s u b s e q u e n t l y b u i l d i n g a p o r p h y r i n a t e a c h end. T h i s has t h e a d v a n t a g e o f a l l o w i n g v e r y s h o r t c h a i n s , i . e . 3 , 3 ' - b i p o r p h y r i n ( 3 3 ) , and r e s u l t s i n a g r e a t e r s t a b i l i t y o f t h e l i n k , i . e . no h y d r o l y s i s as i n e s t e r s and a m i d e s . The p o r p h y r i n s were formed f r o m t h e 20 Johnson porphyrin s y n t h e s i s (stannic c h l o r i d e i n d i c h l o r o -methane followed by dimethyl s u l f o x i d e , p y r i d i n e ) to give the b i s p o r p h y r i n s (35). (35) This s y n t h e s i s i s amenable to branched ch a i n s , even f u n c t i o n a l i z e d ones, as w e l l as l i n e a r . The B , 3 1 - b i p o r p h y r i n was the f i r s t reported example of d i r e c t l y l i n k e d porphyrin 3 0 dimers; Paine has since managed to synthesize a m e s o - 3 ' -b i p o r p h y r i n i n low y i e l d from an a, g 1-dipyrrylmethane but 21 t o d a t e , s i m i l a r approaches t o a meso, meso 1 - b i p o r p h y r i n (from a 1 , 2 - b i s - 2 - p y r r o l y e t h a n e ) have proved f r u i t l e s s . (The l i n k a g e i s c l e a v e d d u r i n g t h e o x i d a t i o n p r o c e s s ) . To a v o i d the u s u a l d i f f i c u l t i e s w i t h l o n g - t e r m s t a b i l -i t y , D o l p h i n and P a i n e sought t o p r e p a r e s t r a t i - b i s - p o r p h y r i n s l i n k e d s o l e l y t h r o u g h c a r b o n - c a r b o n bonds, as t h e i r s i n g l y -l i n k e d d i m e r s had been. The o b v i o u s r o u t e e n t a i l e d a head-t o - t a i l c o u p l i n g o f the d i m e r i c pyrromethenes (34) used i n t h e i r e a r l i e r work. To m i n i m i z e p o l y m e r i z a t i o n , the r e a c t i o n had t o be e f f e c t e d under c o n d i t i o n s o f h i g h d i l u t i o n , and hence o n l y Johnson's s t e p w i s e p o r p h y r i n s y n t h e s i s would s e r v e . T e t r a b r o m i n a t i o n o f the d i m e r i c pyrromethenes (34), f o r wh i c h a new p r o c e d u r e had t o be d e v i s e d t o ensure maximal y i e l d and p u r i t y , a f f o r d e d d i m e r i c pyrromethene (36), which was r e a c t e d w i t h i t s a l p h a f r e e p r e c u r s o r (or analog) under h i g h d i l u t i o n (36) ( s t a n n i c c h l o r i d e - d i c h l o r o m e t h a n e ) t o g i v e a d o u b l y l i n k e d b i s - b i l a d i e n e , whose c y c l i z a t i o n under the u s u a l c o n d i t i o n s gave the b i s p o r p h y r i n (37) i n moderate y i e l d . As the s y n t h e s i s (37) 22 was stepwise, the two linkages needed not be of the same length, enabling a synthesis of unsymmetrical, " t i l t e d " s t rati-bis-porphyrins, as well as symmetrical ones. Work was also c a r r i e d out on tetraphenylporphine dimers. Zingoni treated 5-(p-hydroxyphenyl)-10,15,20-triphenylporphine with 1,6-ditosyloxyhexane and anhydrous potassium carbonate i n DMF for 24 hours at room temperature. P u r i f i c a t i o n by chroma-tography on an alumina column with dichloromethane solvent produced the TPP dimer (38) i n 77% y i e l d . This was then reduced with p-toluenesulfonylhydrazine i n pyridine i n the presence of anhydrous potassium carbonate at 105° to y i e l d the bacterio-c h l o r i n dimer (39). P a r t i a l oxidation of the bacteriochlorin dimer with equimolar DDQ i n benzene produced the c h l o r i n dimer 2 3 (4 0) as a m i x t u r e . In 1980 W a s i e l e w s k i and Svec"" p u b l i s h e d the f u l l d e t a i l s o f t h e i r e a r l i e r s y n t h e s e s o f d i m e r i c c h l o r o p h y l l a, P y r o c h l o r o p h y l l a, c h l o r o p h y l l b and B a c t e r i o c h l o r o p h y l l b, where the p h y t o l t a i l s had been r e p l a c e d by an e t h y l e n e g l y c o l l i n k a g e . 1.1.2 S p e c t r a l P r o p e r t i e s The p r e s e n c e o f two c l o s e and i n t e r a c t i n g c h l o r o p h y l l 3 3 m o l e c u l e s i n P-700 has been suggested by NMR and ESR. C h l o r o p h y l l a adducts w i t h e t h a n o l o r water have been p r e p a r e d which mxmic the o p t i c a l and ESR p r o p e r t i e s o f P-7 00. Sev-3 5 e r a l s t r u c t u r e s f o r P-7 00 have been put f o r w a r d , the major s t r u c t u r a l f a c e t b e i n g the hydrogen bonding o f a p o l a r m o l e c u l e between the magnesium of one c h l o r o p h y l l and the r i n g V k e t o c a r b o n y l o f the second c h l o r o p h y l l . The adduct f o r m a t i o n showed a h i g h l y u n f a v o r a b l e e n t r o p y f a c t o r i n d i c a t e d by h i g h 24 c h l o r o p h y l l c o n c e n t r a t i o n a t low te m p e r a t u r e s (77K). T h i s can be removed by the e x p e d i e n t o f c o v a l e n t l y bonding the two c h l o r o p h y l l s t o g e t h e r t o p r e v e n t d i f f u s i o n o f the r e a c t i v e s i t e s . Any P-7 00 models thus formed s h o u l d mimic c e r t a i n c h a r a c t e r -i s t i c s o f P-700. They s h o u l d have a r e d s h i f t e d a b s o r p t i o n compared t o the monomer from 677nm t o 700nm (780nm t o 870nm f o r b a c t e r i o c h l o r o p h y l l ) , s h o u l d e x h i b i t s i m i l a r ESR and NMR s p e c t r a and s h o u l d undergo p h o t o b l e a c h i n g r e a c t i o n s . The magnesium f r e e d i e s t e r (.41) o f Boxer and C l o s s ^ h a d v i s i b l e a b s o r p t i o n and f l u o r e s c e n c e s p e c t r a i n d i s t i n g u i s h a b l e from t h e monomer, showing no chromophore i n t e r a c t i o n . The b i s p y r o c h l o r o p h y l l i d e a (42) a l s o showed no d i f f e r e n c e s i n d r y benzene b u t i n wet benzene a r e d s h i f t was observed i n the a b s o r p t i o n s p e c t r a o f 666nm t o 696nm, and t o 717nm i n e m i s s i o n . (41) F r e e base R = H (42) R = H (.43) R = C0 2CH 3 25 The "'"H NMR resonances were broad i n d r y benzene b u t sharpened on the a d d i t i o n o f water . The a d d i t i o n o f p y r i d i n e - d , . caused f u r t h e r c h e m i c a l s h i f t d i f f e r e n c e s a t t r i b u t a b l e t o a s t r o n g c o o r d i n a t i o n t o the magnesium i o n thus p r e v e n t i n g c l o s e a s s o c i a t i o n o f the chromophores. "'"H NMR a l s o showed the max-imum o v e r l a p i n r i n g s I I I and V. i 3 The b i s c h l o r o p h y l l a (43) o f W a s i e l e w s k i a g a i n showed a dependence on the a d d i t i o n o f p o l a r m o l e c u l e s t o produce the r e d s h i f t from 677nm t o 697nm; w a t e r , e t h a n o l , methanol and p r i m a r y a l k a n e t h i o l s were a l l used. The a b i l i t y o f non-aqueous hydrogen bonding l i g a n d s t o in d u c e the r e d s h i f t opens up the p o s s i b i l i t y t h a t amino a c i d r e s i d u e s i n the p r o t e i n may be r e s p o n s i b l e f o r the P-7 00 f o r m a t i o n . S e v e r a l n o n p o l a r s o l v e n t s were a l s o used s u g g e s t i n g a h y d r o p h o b i c environment around the s p e c i a l p a i r as i n the hemoglobin system. The ''"H NMR c l o s e l y resembled the monomer w i t h broadened peaks, t h i s b e i n g due t o the e q u i l i b r i u m o f s t e r e o i s o m e r s a t C-10 e s t a b l i s h e d i n p o l a r s o l v e n t s g i v i n g a 3 : 1 m i x t u r e o f a-a and a-a' d i a s t e r e o m e r s . The system was shown t o undergo p h o t o b l e a c h i n g w i t h 1^, the 697nm a b s o r p t i o n b e i n g b l e a c h e d i n 10 minutes i n t h e d a r k and 30 seconds i n r e d l i g h t . The ESR s i g n a l from the b l e a c h e d system c o r r e s p o n d e d t o t h a t e x p e c t e d from an e l e c t r o n d e l o c a l i s e d o v e r b o t h c h l o r o p h y l l a m o l e c u l e s and compared w i t h t h a t o b s e r v e d w i t h P-700 i n c h l o r e l l a v u l g a r i s . I t was observed t h a t some a b s o r p t i o n remained a t 677nm even w i t h p o l a r s o l v e n t and a f t e r p h o t o b l e a c h i n g . T h i s was 26 a t t r i b u t e d t o the 25% a-a' dimer which would n o t f o l d t o g i v e the hydrogen bonded dimer due t o s t e r i c i n t e r a c t i o n s o f one carbomethoxy group between the m a c r o c y c l e s . 1 7 The b i s b a c t e r i o c h l o r o p h y l l a (44) was analogous t o the b i s c h l o r o p h y l l a, the a b s o r p t i o n b e i n g r e d s h i f t e d from 7 8 0nm t o 803nm b u t not s u f f i c i e n t l y t o acc o u n t f o r the 865nm o f b a c t e r i o c h l o r o p h y l l a s p e c i a l p a i r . The "^H NMR was c o n s i s t e n t (44) w i t h , t h e dimer s t r u c t u r e as i n t h e c h l o r o p h y l l a model. Thus the C-2 a c e t y l t a k e s no p a r t i n the hydrogen bonding o f the model system b u t c o u l d p o s s i b l y i n v i v o . The system d i d under-go p h o t o b l e a c h i n g and e x h i b i t e d an a b s o r p t i o n a t 1150nm as opposed t o the 1250nm a b s o r p t i o n o f the s p e c i a l p a i r c a t i o n r a d i c a l . 2 3 The b i s ( c h l o r o p h y l l ) c y c l o p h a n e (45) showed no s o l v e n t dependence i n i t s a b s o r p t i o n and "*"H NMR s p e c t r a , t h e s e b e i n g unchanged from the monomer. No 7 00nm a b s o r p t i o n c o u l d be produced and the photo o x i d a t i o n p r o d u c t showed a l i n e w i d t h i n t h e e s r i n d i c a t i v e o f the e l e c t r o n d e l o c a l i z e d over the 27 (45) two macrocycles. The H NMR indicated that the stacking i s central as opposed to the maximum overlap of rings III and V in the singly linked b i s c h l o r o p h y l l a. The chlorophyll special pair models could be judged to be successful i f they mimic the properties i n the i n vivo system. The bisporphyrins on the other hand have no obvious c r i t e r i a to meet. The bisporphyrins are thus synthesised and the i r proper-t i e s observed, the interactions between macrocycles and metal-metal interactions being a possible measure of the i r usefulness. To determine these interactions the absorption, emission, f l u o r -escence and phosphorescence spectra are often compared to the monomer. 9 Schwartz et a l . found no difference i n the absorption spectra of their singly linked bisporphyrin (46) but emission spectra at 77K showed t r i p l e t - t r i p l e t i n t e r a c t i o n for the et h y l -ene bridged system, manifested as a shortening of zinc porphyrin t r i p l e t state l i f e t i m e and quenching of the zinc porphyrin phos-phorescence. 28 R =-CH 2CH 2- or - C ^ - M = Cu, Zn 3 6 Anton e t a l . found no d i f f e r e n c e i n the a b s o r p t i o n s p e c t r a o f t h e i r dimer (47) o r t r i m e r s (48) w i t h r e s p e c t t o t h e i r mono-mers (49) and (50) . The "'"H NMR s p e c t r a were a l s o t h e sum o f the monomer s p e c t r a p l u s r e s o n a n c e s f o r the 8 p r o t o n s o f the e t h y l e n e l i n k s w h i c h appeared a t 4.93ppm. (148 L R =-C0 2CH 2CH 20 2C-29 (30) (49) 14 . Ogoshi et a l also notxced no s h i f t s i n the absorption spectra of the d i - z i n c complex of the i r bisporphyrin (51) but did observe incomplete incorporation of zinc on treatment with (.51) zinc acetate/methanol. The proton NMR spectra exhibited 9 signals for the 8 meso protons between 9-10ppm attributed by the author to an equal mixture of the syn and anti stereoisomers. In the zinc complex the meso protons are centered about lOppm 30 in a narrower band of 0.2ppm which the author saw as ind i c a t i v e of a more face to face configuration than with the free base, which had a p a r a l l e l displacement r e s u l t i n g in higher magnetic f i e l d s h i f t s , due to the r i n g currents of the porphyrins. A similar trend was observed with the methyl resonances as would be expected. Collman et a l . 1 5 found no spectral changes for their porphyrins which were not c o f a c i a l (52) and (53) but i n contrast to Ogoshi found that Soret bands of (54) and (55) had been blue shifted by approximately 15nm i n the free base porphyrins and 4-5nm for the cobalt and copper complexes. ESR spectra of the cobalt and copper complexes of (54) and (55) show hyperfine s p l i t t i n g consistent with metal-metal separation of approximately 6.5§. 31 Unlike the previous singly linked bisporphyrins whose 1 6 synthesis had been deliberate, Arnold et a l . had produced a nickel porphyrin whose broadened Soret band, red shifted by llnm and v i s i b l e bands 3nm red sh i f t e d , had led them to i d e n t i f y the product as a bisporphyrin (56), and whose i d e n t i -f i c a t i o n was confirmed by mass spectrometry. (56) 1 8 Ichimura observed a blue s h i f t of 8nm i n the Soret of (57) and greater than 10nm for the zinc and copper dimers with small red s h i f t s i n the v i s i b l e bands. The trimer (58) showed a s p l i t Soret, one band blue shifted with small red s h i f t s i n the v i s i b l e bands. The zinc complexes showed considerable (58) s e l f quenching of fluorescence, whereas the magnesium complexes exhibited only s l i g h t decrease i n fluorescence i n t e n s i t y . 37 Chang found blue s h i f t s of 14-16nm i n the Soret with red t a i l s for his bisporphyrins (59) with small red s h i f t s in the v i s i b l e region. In the copper, zinc and magnesium com-plexes the Sorets were blue s h i f t e d . These r e s u l t s were explained i n terms of exciton coupling between two p a r a l l e l t r a n s i t i o n dipoles. The s h i f t s would depend on two components a solvent parameter representing the difference i n the e f f e c t of solvation of the ground and excited states, and the nature of the exciton coupling which would depend on the geometry of the dimer. 33 (59) If the dimer geometry was of i d e a l symmetry, the r e s u l t would be a blue s h i f t to the Soret band, tempered by a red s h i f t due to the solvent parameter. However, t i l t i n g or s l i d i n g of the porphyrin planes would cause fl u c t u a t i o n of higher exciton l e v e l s and develop the lower exciton l e v e l s which was a possible explanationfor the red t a i l in the 45 0nm region. In the v i s i b l e region the solvent parameter and inhomogeneous solvent broadening were considered comparable in magnitude to the exciton coupling parameter r e s u l t i n g i n the small red s h i f t s . The model predicted fluorescence quenching but not to the magnitude shown by the dimers and t h i s was believed to be a manifestation of the red t a i l in the Soret enhancing self-quenching. 2 2 Kagan et a l . found absorption and emission spectra of t h e i r t e t r a linked bisporphyrin (60) to be broadened and red shifted i n the free base. The zinc complex had a broad-ened but unshifted Soret band while the v i s i b l e band and emission spectra were both red shifted and broadened. Quench-ing was also observed i n the emission spectrum. The proton 34 (60) NMR showed A 2 B 2 degeneracy °f the phenoxy and b e n z o y l r i n g p r o t o n s o f the monomer s p l i t i n t o AA'BB 1 q u a d r u p l e t s as the i n t e r i o r and e x t e r i o r f a c i n g p r o t o n s a r e not d i s t i n g u i s h a b l e . The a l k y l p r o t o n s appeared as AA'BB' m u l t i p l e t due t o t h e r e s t r i c t e d r o t a t i o n o f the O-C-C-0 bonds. 24 . . L i t t l e found no p o s i t i o n a l s h i f t i n the a b s o r p t i o n s p e c t r a o f (61) b u t found the i n t e n s i t y of the S o r e t was o n l y C H 3 C H 3 (61) 3 5 7 0% of that expected, apparently the r e s u l t of a s p l i t t i n g of the Soret observed as a d i s t i n c t shoulder to the red. Identical spectra were obtained i n d i f f e r e n t solvents r u l i n g out the p o s s i b l i t y of two species, folded and unfolded, being present. The ESR spectrum was the sum of the simple monomers and no-metal-metal i n t e r a c t i o n could be observed. 2 7 Maltzan observed a s p l i t Soret red shifted 7-15nm for his Ni-Ni (62) and Ni-Pd (63) dimers. The v i s i b l e band i n the Ni-Ni dimer was also s l i g h t l y red shifted which he attributed to meso substitution e f f e c t s . Variable temperature "*"H NMR was used to assign the configuration and confirm that rotation about the methylene linkage was r e s t r i c t e d . 2 8 Paine et a l . i n the series of porphyrins (64) m = 0-8 found no difference i n the spectra of m = 8 and the monomer, aetioporphyrin I, but when m = 1 and 0 the Soret was broadened (62) M (63) M Ni Pd CH (64) 36 and r e d s h i f t e d i n the f r e e base. The p r o t o n a t e d p o r p h y r i n gave a r e d s h i f t e d s p l i t S o r e t the v i s i b l e bands a l s o b e i n g r e d s h i f t e d . The w e l l r e s o l v e d d i c a t i o n d o u b l e t was e x p l a i n e d by c o n s i d e r i n g t h a t the S o r e t o f the d i c a t i o n monomers a r i s e from d o u b l y degenerate e x c i t e d s t a t e s . They can be c o n s i d e r e d t o i n t e r a c t i n p a i r s r e s u l t i n g i n f o u r dimer e x c i t e d s t a t e s . F o r m = 0 t h e t r a n s i t i o n d i p o l e s would be e x p e c t e d t o be p a r a l l e l t o the v e c t o r between c e n t e r s r e s u l t i n g i n a r e d s h i f t e d low energy s t a t e and p e r p e n d i c u l a r t o the v e c t o r between c e n t e r s r e s u l t i n g i n an u n s h i f t e d o r b l u e s h i f t e d 13 s t a t e . The C CMR f o r m = 3 showed the p o r p h y r i n n u c l e i t o be p s e u d o s y m m e t r i c a l , the meso carbons g i v i n g a s i n g l e broad band. F o r m = 0 o r 1, the meso carbons were r e s o l v e d i n t o f o u r w e l l d e f i n e d peaks. F o r m = 2 the meso carbons appeared a s a 6:2 d o u b l e t . 3 8 The d o u b l y l i n k e d dimers o f P a i n e showed s h i f t s i n the a b s o r p t i o n s p e c t r a a p p a r e n t l y dependent upon the l e n g t h o f the l i n k s and the o r i e n t a t i o n o f the two p o r p h y r i n l i n k s . The s h o r t e r t h e l i n k s t h e l a r g e r t h e s h i f t assuming b o t h l i n k s a r e s h o r t e n e d e q u a l l y . S h o r t e n i n g one l i n k appears t o reduce the i n t e r a c t i o n , presumably by t i l t i n g the macro-c y c l e s and the C„ , has l e s s s h i f t t han the C n „. 8—6 8-8 The dimer (65) m = n = 8 had a b l u e - s h i f t e d S o r e t o f 8nm i n the Zn-Zn complex, 3nm f o r the p r o t o n a t e d s p e c i e s and 9nm f o r the f r e e base compared t o OEP. 37 (65) Dimer (.651 m = 8, n = 6 had s m a l l e r s h i f t s t han the C D „, o — o the Zn-Zn complex had 3nm s h i f t e d S o r e t , the p r o t o n a t e d s p e c i e s 2nm and the f r e e base 7nm. The C 5 _ r - dimer (65) (m = n = 5) had the l a r g e s t S o r e t s h i f t s , t h e Zn-Zn complex 14nm, the p r o t o n a t e d s p e c i e s 14nm and the f r e e base 13nm. The v i s i b l e bands had s m a l l e r s h i f t s i n the C g _ g f r e e base. The p r o t o n a t e d s p e c i e s ' v i s i b l e bands were n o t changed. 1.1.3 A p p l i c a t i o n s The c h l o r o p h y l l model systems have d e v e l o p e d our under-s t a n d i n g o f the p h o t o s y n t h e t i c p r o c e s s . The d e t e r m i n a t i o n o f the mechanism by which photo-energy i s c o n v e r t e d t o c h e m i c a l energy i s a major g o a l i n the e f f i c i e n t h a r n e s s i n g o f t h i s 11 energy r e s o u r c e . The c h l o r o p h y l l dimers o f Boxer and C l o s s 1 3 and W a s i e l e w s k i e t a l . proved t o be good models f o r the 1 7 P-7 00 p h o t o c e n t e r . The b a c t e r i o c h l o r o p h y l l dimer d i d n o t 38 however mimic the P-87 0 and other factors must be considered in t h i s case. (66) oxygen binding. The dimer was found to bind oxygen re v e r s i b l y , 3 9 a c h a r a c t e r i s t i c shown by other monoheme models, but unlike other models i t reacted with carbon monoxide with two d i f f e r e n t rate constants, displaying a cooperativity e f f e c t , an e f f e c t shown by hemoglobin. The double rate constant was explained by considering that the s t r a i n imposed by the short l i n k caused base elimination of one of the heme groups giving a p a r t i a l l y 4-coordinate form. This f a s t reacting form binds CO rapidly and closes to a 6-coordinate state, the second heme then proceeds to bind CO slowly without base elimination. Half oxidation of (66) resulted i n the disappearance of the fas t rate which would be expected as the faster reacting form would oxidise f i r s t . 39 (67) 2 5 Landrum's imidazolate bridged bisporphyrin (67), an attempted cytochrome oxidase model, showed s i g n i f i c a n t a n t i -ferromagnetic coupling, thus there i s heme-heme int e r a c t i o n , but the J values did not compare to those of cytochrome o x i -dase. The authors considered the metal-metal distances too large and other ligands might possibly bring them into closer proximity. 4 0 Chang ca r r i e d out p a r t i a l e l e c t r o l y t i c reduction of (70c) Mg-Mg and obtained a v i o l e t solution (A 670nm) which ^ ^ max was believed to be the monocation r a d i c a l . EPR measurements showed a single l i n e , g = 2.003, with a peak separation of CH 3 HEX c M = Cu 40 1.05 Gauss, less than half that of MgOEP rad i c a l s under the same conditions. The narrowing of l i n e width indicates extensive electron exchange between the macrocycles similar to that observed i n P-700 and P-870. 4 1 Chang also investigated the p o s s i b i l i t y of multi-electron reduction of oxygen by these dimers. Oxygenation of 5-coordinate imidazole complexes of (68b, 69b, 70b) showed two d i f f e r e n t behaviors. The large metal-metal separation dimers (68b, 69b) formed reversi b l e 1 : 1 Co-0 2 adducts with adsorption spectra showing 395nm Soret with only a small shoulder at 417nm. The shorter metal-metal separation of (70b) showed a 2:1 Co-0 2 adduct which was not reversi b l e on evacuation and showed an absorption spectrum with the major absorption at 417nm. Unfortunately Co(III)-X, oxygenated Co-0 2 and binuclear Co-02-Co a l l have near i d e n t i c a l absorption bands so only the rate and difference of reaction of (70b) can be observed. The oxygen adduct of (70b) was believed to be the y-peroxo dicobalt complex (Co-02~Co) which i s diamagnetic and shows no EPR sig n a l . However, treatment with I 2 should y i e l d a 15 l i n e EPR spectrum i f i t becomes oxidised to the y-superoxo dicobalt complex, thi s indeed was observed. The iron bisporphyrins showed similar behaviour, however, addition of oxygen to (7 0a) resulted i n spontaneous oxidation of the heme even at -45°C. The rate of reaction was rapid due to the favorable po s i t i o n of the two hemes for the formation of the ji-peroxo complex, the rate determining step i n monohemes. 41 Collman e t a l . c a r r i e d out a s e r i e s o f e x p e r i m e n t s w i t h a range o f p o r p h y r i n d i m e r s . As i n Chang's e a r l i e r work a s h o r t M-M d i s t a n c e dimer (.71) showed c o n s i d e r a b l e c a t a l y t i c a c t i v i t y t o the r e d u c t i o n o f oxygen w i t h o u t the p r o d u c t i o n o f s i g n i f i c a n t hydrogen p e r o x i d e . The b i s p o r p h y r i n was i n t r o d u c e d onto a p y r o l y t i c g r a p h i t e d i s k by a d s o r p t i o n from d i l u t e d i c h l o r o -methane s o l u t i o n . R o t a t i n g d i s k e x p e r i m e n t s were c a r r i e d o u t w i t h the g r a p h i t e d i s k and a p l a t i n u m r i n g i n 0.5M p e r c h l o r i c a c i d or 0.5M t r i f l u o r o a c e t i c a c i d w i t h oxygen a t a t m o s p h e r i c p r e s s u r e . For l o n g e r l i n k e d b i s p o r p h y r i n s and Co-Pd (71) c o n s i d e r a b l e hydrogen p e r o x i d e was formed. However no hydrogen p e r o x i d e was formed w i t h ( 7 1 ) , a hydrogen p e r o x i d e c o n t a i n i n g s o l u t i o n w i t h o u t oxygen was t e s t e d t o show t h a t i t d i d n o t reduce o r d i s p r o p o r t i o n a t e hydrogen p e r o x i d e . The a b i l i t y o f (71) t o reduce oxygen was found t o be dependent on the a v a i l a b i l i t y o f p r o t o n s ; u n b u f f e r e d s o l u t i o n s tend t o produce hydrogen p e r o x i d e when the s u p p l y o f p r o t o n s i s e x h a u s t e d . <+ 3 The x - r a y c r y s t a l s t r u c t u r e o f (71) shows a syn form as drawn w i t h a M-M s e p a r a t i o n o f 6.332 R . CH C H 3 (71) 42 1.2 Nomenclature 4 4 The w i d e s p r e a d use o f t r i v i a l names adopted by F i s c h e r and o t h e r s has l e d t o a haphazard nomenclature i n p o r p h y r i n c h e m i s t r y . The a d o p t i o n o f a s y s t e m a t i c nomenclature f o r p o r p h y r i n s w i l l r e q u i r e a system f l e x i b l e enough t o embrace the F i s c h e r system y e t i n f o r m a t i v e enough t o d i f f e r e n t i a t e a v a s t number o f n a t u r a l and s y n t h e t i c a n a l o g u e s . The F i s c h e r system i s based on the numbering system shown (7 2 ) . The p e r i p h e r a l p o s i t i o n s a r e numbered 1 t o 8 and the methine p o s i t i o n s , termed meso, are d e s i g n a t e d a , 3, y and 6. The system a l s o i n c l u d e s a l a r g e number of t r i v i a l 2 a 3 (72) names based on the type o f s u b s t i t u e n t s and an isomer numbering system based on t h e i r p e r i p h e r a l arrangements. Thus " U r o p o r p h y r i n I I I " has two d i f f e r e n t s u b s t i t u e n t s , a c e t i c (A) and p r o p i o n i c ( P ) , one o f each per r i n g , t h e s e a r e a r r a n g e d i n the sequence A, P, A, P, A, P, P, A. The f u l l s e r i e s of U r o p o r p h y r i n s i s shown i n F i g u r e 1. The s y s t e m a t i c name o f t h i s compound would be 2, 7, 12, 1 8 - t e t r a c a r b o x y m e t h y l - 3 , 8, 13, 1 7 - t e t r a c a r b o x y e t h y l -43 P A P P P A P R / \ / \ / \ / \ A P A A A P A P P A A A A A P P TYPE I TYPE n TYPE m TYPE IV FIGURE 1: Schematic of Uroporphyrin series porphyrin, a much too complex name for the conversational Uroporphyrin I I I . 4 5 Ln a recent review Bonnett outlined a semisystematic approach which retained the more important of the Fischer names but systemised and r a t i o n a l i s e d the less important t r i v i a l names. The nomenclature used i n the following work w i l l be consistent with the following guidelines, t r i v i a l names are given i n brackets. 1.2.1 Pyrroles The nitrogen i s numbered 1 and the substituents to give the lowest number to the f i r s t alphabetically as i n (73). o (.73) 2.,4-Diethyloxycarbonyl-3,5 dimethylpyrrole (Knorr's pyrrole) 44 1.2.2 D i p y r r o l e s Compounds c o n t a i n i n g two p y r r o l e r i n g s a r e numbered t o g i v e the s m a l l e s t numbers t o the d i p y r r o l i c l i n k as i n (74) . 5 H H 5' (74) 2 , 2 ' - B i p y r r o l e o r with, an i n t e r m e d i a t e c a r b o n atom (75) , (76) and (77) . (77) 2 - ( 2 H - P y r r o l - 2 - y l i d e n e m e t h y l ) p y r r o l e . (Dipyrromethene) 1.2.3 T e t r a p y r r o l e s The nomenclature o f the l i n e a r t e t r a p y r r o l e s i s based on B i l i n (7 8 ) . 45 21 a H b 23 c 24 22 (78) B i l i n : 22H Tautomer The number 2 0 i s o m i t t e d t o g i v e the c o r r e s p o n d i n g numbers i n t h e p o r p h y r i n ( a l s o used i n c o r r i n s y s t e m ) . The reduced systems a r e as i n ( 7 9 ) , (80) and (81). (79) 5 , 2 1 - D . i h y d r o b i l i n (b, c - B i l a d i e n e ) (80) 1 0 , 2 3 - D i h y d r o b i l i n ( a , c - B i l a d i e n e ) (81) 5 , 1 5 , 2 1 , 2 4 - T e t r a h y d r o b i l i n ( b - B i l e n e ) P o r p h y r i n nomenclature i s based on the p a r e n t p o r p h i n and i s numbered as i n (8 2) . 46 ^ C H (82) The r i n g s are l e t t e r e d A to D and s i d e - c h a i n s p o s i t i o n s can be numbered as shown when necessary. Where metal complexes are formed the macrocycle becomes porphinato metal complex. CHAPTER 2 RESULTS AND DISCUSSION 48 2 . 1 Synthetic Objective Once the singly linked bisporphyrin of Paine and 28 Dolphin had been prepared i t seemed l o g i c a l to continue and produce the doubly linked bisporphyrin with two unbroken carbon chains. Thus any d e s t a b i l i s i n g e f f e c t from the polar l i n k s of previous bisporphyrins upon the metalloporphyrin adducts would be removed. Two methods seemed to have synthetic p o s s i b i l i t i e s , the f i r s t a modification of Paine's single l i n k synthesis, whereby the linked methene was reacted with a linked tetrabrominated methene to give the doubly linked porphyrin. This reaction would have to be carried out at high d i l u t i o n to reduce the p o s s i b i l i t y of polymerisation. However, at this, time the methods for bromination of the a-methyl-a-unsubstituted methenes did not give pure products and due to the i n s t a b i l i t y of the bromomethyl group r e c r y s t a l l i s a t i o n i s out of the question. Thus u n t i l a better method for brominating these compounds was found the second p o s s i b i l i t y seemed favourable. This scheme was a continuation of the single l i n k synthesis, the f i r s t l i n k should be formed with side chains containing reactive s i t e s diagonally opposed to the l i n k . These could be modified and then joined to give the doubly linked bisporphyrin. 49 The i n i t i a l scheme ( F i g u r e 2) was the s y n t h e s i s o f a C g l i n k e d dimer w i t h h a l o e t h y l s i d e c h a i n s which were t o be l i n k e d w i t h a C 2 u n i t . T h i s was q u i c k l y d i s c a r d e d once the problems a s s o c i a t e d w i t h the h i g h d i l u t i o n r e a c t i o n i n the f i n a l s t e p had been e n v i s a g e d . The second scheme ( F i g u r e 3) seemed t o have a l l the p r e -r e q u i s i t e s o f a f e a s i b l y s y n t h e t i c r o u t e t o d o u b l y l i n k e d b i s p o r p h y r i n s . The f i n a l l i n k was u n i m o l e c u l a r and had been a c c o m p l i s h e d by many o t h e r r e s e a r c h e r s on comparably s i z e d systems,. I t was t h e r e f o r e d e c i d e d t o produce the Cg-Cg d o u b l y l i n k e d b i s p o r p h y r i n . A f t e r many at t e m p t s t o produce the C 0-C 0 d i m e r , the o o s y n t h e s i s o f t h e butyne s i d e c h a i n was found t o be u n a t t a i n -a b l e . T h i s i s due t o the i n s t a b i l i t y o f 2 - h a l o e t h y l sub-s t i t u e n t s towards e l i m i n a t i o n o f hydrogen h a l i d e under the c o n d i t i o n s r e q u i r e d f o r the f o r m a t i o n o f the a l k y n e . I t was thus d e c i d e d t h a t the C - ^ Q - C - ^ Q d-"- m e r w o u l d be s y n t h e s i s e d as i t was a v a i l a b l e from the more s t a b l e bromopropyl s i d e c h a i n . ( F i g u r e 4) The f e a s i b i l i t y o f the s e r e a c t i o n s was' t e s t e d by the s y n t h e s i s o f a s i n g l y l i n k e d b i s p o r p h y r i n ( F i g u r e 5). The p r o d u c t o f t h i s s y n t h e s i s was compared t o a sample produced by the method o f P a i n e and D o l p h i n and shown t o be i d e n t i c a l . The s y n t h e s i s o f the d o u b l y l i n k e d dimer was thus c o n s i d e r e d p r a c t i c a b l e by t h i s r o u t e and the s y n t h e s i s a ttempted. 50 51 FIGURE 4: Proposed Route t o C]_o_]_o Dimer 53 54 2.2 P y r r o l e s The s y n t h e s i s o f p o r p h y r i n s i n t h i s work i s based on f o u r p y r r o l e s which were s y n t h e s i s e d i n l a r g e q u a n t i t i e s k 6 by a m o d i f i e d K n o r r s y n t h e s i s . The K n o r r s y n t h e s i s i s a low y i e l d r e a c t i o n (30-50%) but uses i n e x p e n s i v e s t a r t i n g m a t e r i a l s and can be c a r r i e d out on l a r g e b a t c h e s (10-12 m o l e s ) . The l i m i t i n g ..factors a r e s e e m i n g l y the q u a n t i t y o f hoodspace and l a r g e volume g l a s s w a r e . In the c l a s s i c a l K n o r r r e a c t i o n , ( F i g u r e 6), e t h y l a c e t o a c e t a t e (83) i s r e a c t e d w i t h h mole aqueous sodium n i t r i t e t o g i v e an e q u i m o l a r m i x t u r e o f e t h y l a c e t o a c e t a t e and e t h y l o x i m i n o a c e t o a c e t a t e (84). The oxime (84) i s then reduced w i t h z i n c / a c e t i c a c i d t o g i v e the a-ami.no ketone (85); t h i s r e a c t s - w i t h (83) t o form .the S c h i f f ' s base (86) which c y c l i s e s f o r m i n g the p y r r o l e (87) on l o s s o f w a t e r . The a-aminoketone u n f o r t u n a t e l y s e l f condenses t o g i v e a m i x t u r e o f S c h i f f ' s bases and t h e s e l e a d to u n d e s i r a b l e s i d e p r o d u c t s . M o d i f i c a t i o n o f the K n o r r s y n t h e s i s i s p o s s i b l e by v a r i a t i o n b o t h o f the oxime and o f the g - d i k e t o n e . I s o l a t i o n o f the oxime and i t s d r o p w i s e a d d i t i o n t o a r e d u c i n g m i x t u r e c o n t a i n i n g e x c e s s 6 - d i k e t o n e a l s o r educes the p o s s i b i l i t y o f s e l f c o n d e n s a t i o n t o g i v e the wrong S c h i f f ' s base. C o n s i d e r -a t i o n o f t h e s e m o d i f i c a t i o n s and f u t u r e s y n t h e t i c r e q u i r e -ments d i c t a t e d the s t a r t i n g p y r r o l e s . Where p o s s i b l e one would p r e f e r t o use b e n z y l e s t e r s as opposed t o e t h y l e s t e r s , 5 5 Zn/AcOH (8 7) FIGURE 6: Synthesis of Knorr 1s Pyrrole 56 due to the ease of removal by c a t a l y t i c hydrogenolysis, thus benzyl acetoacetate was substituted for ethylacetoacetate wherever possible. Pyrroles with reactive 3-sidechains (the reactive sidechain required for the second l i n k i n the por-phyrin) were produced by using meso-substituted 3-diketones. 2.2.1 Monopyrroles The 3-free pyrrole (88) (Figure 7) was required i n the synthesis of the f i r s t l i n k and thus had to undergo F r i e d e l Crafts acylation with SnCl 4. Benzyl esters are cleaved under these conditions thus an ethyl ester was necessary. k 7 Kleinspehn deduced that ethyl oximinomalonate (89) with 2,4-pentanedione would lead to the 3-free pyrrole. The (88) FIGURE 7: Synthesis of 3-free Pyrrole (88). 57 n i t r o s a t i o n was found to be less e f f i c i e n t and thus 3 moles of aqueous sodium n i t r i t e are required to produce the oxime. The use of benzyl acetoacetate (90) (Figure 8) and 2,4-pentanedione led to the s y n t h e t i c a l l y useful 4-acetyl-2-benzyloxycarbonyl-3,5-dimethylpyrrole (91). After reduction of the acetyl group to ethyl t h i s pyrrole was manipulated to produce several other pyrroles. O FIGURE 8: Synthesis of pyrrole (91) The synthesis of pyrroles with reactive B-sidechains 2 9 was accomplished using the Johnson v a r i a t i o n of the Knorr synthesis where 3-alkyl-2,4-pentanedione was substituted for 2,4-pentanedione. Reaction of benzyl oximinoacetoacetate with methyl-3-acetyl-4-oxopenanoate (92) (R = CH 2C0 2CH 3) (Figure 9) under the usual conditions led to the substituted pyrrole (93) (R = CH 2C0 2CH 3). Reduction of the ester group with, diborane/tetrahydrofuran gave the hydroxyethyl pyrrole C94). which could l a t e r be manipulated to the desired function-a l i s e d ethyl side chain. The use of methyl-4-acetyl-5-oxohexanoate (95) (R = CH 2 CH2CC>2CH3) under the above conditions yielded pyrrole (96) CR = CH.2CH-2C02CH3) which was the star t i n g pyrrole for the propyl side chain porphyrins. 2.2.2 Synthetically useful pyrroles from 4-acetyl-2- benzyloxycarbonyl-3, 5-dimethylpyrrole (91) / CH H » 0 0 (91) (97) A l l porphyrin rings with ethyl and methyl groups are synthesised from th i s pyrrole. The i n i t i a l step i s the diborane reduction of the acetyl group, reported by Whitlock 59 H X f S Aq. NaN02 Ac OH R • C H 3 (.93). R=CH2CQ2CH3 (96) R=CH2CH2C02CH3 THF H X H R Zn/AcOH CH, (92) R=CH"2C02CH3 (95) R=CH2CH2C02CH3 c- R (94) R=CH2CH2OH FIGURE 9: Synthesis of g-Side Chain Pyrroles and Hanauer, t o produce the 2-benzyloxycarbony1-4-e t h y l - 3 , 5 - d i m e t h y l p y r r o l e (97). Throughout the f o l l o w i n g work d i b o r a n e r e d u c t i o n s a r e commonly used, they a r e r e a s o n a b l y e f f i c i e n t ( u s u a l l y g r e a t e r than 80% y i e l d s b e i n g o b t a i n e d ) , e a s i l y c a r r i e d o u t and the major s i d e p r o d u c t b o r i c a c i d i s e a s i l y removed. The method used v a r i e d o n l y s l i g h t l y f o r a l l the r e d u c t i o n s c a r r i e d o u t i . e . e t h y l a c e t a t e composed 25% of the s o l v e n t i n r e a c t i o n s where an e s t e r was p r e s e n t i n the m o l e c u l e t h a t was not r e q u i r e d t o be redu c e d . The d i b o r a n e was g e n e r a t e d i n s i t u by the d r o p w i s e a d d i t i o n o f boron t r i f l u o r i d e e t h e r a t e t o a c o o l e d s t i r r e d s u s p e n s i o n o f sodium b o r o h y d r i d e , and the m a t e r i a l t o be re d u c e d , i n t e t r a h y d r o f u r a n . 4BF_ + 3NaBH. ^2B„H C + 3NaBF . 3 4 2 6 4 The d i b o r a n e i s complexed by s o l u t i o n i n t e t r a h y d r o f u r a n t o g i v e the s t a b l e adduct BH^ * THF. The p r o g r e s s o f the r e a c t i o n s was observed by t i c and on c o m p l e t i o n they were quenched by the a d d i t i o n o f g l a c i a l a c e t i c a c i d f o l l o w e d by a d d i t i o n o f w a t e r . The a d d i t i o n o f a c e t i c a c i d t o quench the r e a c t i o n reduces the over v i g o r o u s r e a c t i o n on quenching found when water a l o n e i s used. The d i b o r a n e r e d u c t i o n s o f the " b e n z y l i c " k etones i t s h o u l d be n o t e d , do not s t o p a t the secondary a l c o h o l 61 b u t proceed f u r t h e r t o the methylene group. T h i s can be c o n s i d e r e d due t o the s t a b i l i s a t i o n o f the carbonium i o n produced ( F i g u r e 10) by C-0 bond c l e a v a g e f o l l o w e d by a b s t r a c -H FIGURE 10; B o r o h y d r i d e r e d u c t i o n o f a c e t y l . t i o n o f a h y d r i d e i o n t o g i v e the f u l l y reduced methylene. To produce s y n t h e t i c a l l y u s e f u l p y r r o l e s the a p o s i t i o n s o f C97) must be m o d i f i e d . The g r e a t e r r e a c t i v i t y o f the a - s u b -s t i t u e n t o v er the 3 - s u b s t i t u e n t o f p y r r o l e s i s employed t o m o d i f y the a-methyl w i t h o u t c h a n g i n g the B-methyl group. The f i r s t s t e p i n a c t i v a t i n g the m e t h y l group i s the d i c h l o r i n a t i o n by s u l f u r y l c h l o r i d e t o g i v e the d i c h l o r o -m e t h y l p y r r o l e (98) ( F i g u r e 11) f o l l o w e d by h y d r o l y s i s t o the 62 a - f o r m y l p y r r o l e (.99).. T h i s was c a r r i e d o u t i n i c e c o l d d i c h l o r o m e t h a n e t o reduce the p o s s i b i l i t y o f t r i c h l o r i n a t i o n w h ich would l e a d t o the c a r b o x y l p y r r o l e on h y d r o l y s i s . I t had a l s o been shown t h a t t r i c h l o r i n a t i o n was l e s s e f f e c t i v e k 9 m dxchloromethane a l o n e than o t h e r s o l v e n t s . H y d r o l y s i s was c a r r i e d o u t by s t i r r i n g the m i x t u r e w i t h water o v e r n i g h t , the o r g a n i c l a y e r was s e p a r a t e d and the s o l v e n t removed under vacuum. The r e s u l t i n g o i l was e x t r a c t e d w i t h h o t 1:1 w a t e r / e t h a n o l , the p r o d u c t c r y s t a l l -i s i n g when c o o l . The r e m a i n i n g mother l i q u o r was e x t r a c t e d by the e x p e d i e n t o f c o n v e r t i n g the f o r m y l group t o the me t h y l c y a n o a c r y l a t e group (100), by r e a c t i o n i n methanol w i t h m e t h y l c y a n o a c e t a t e and methylamine. T h i s r e a c t i o n 63 was also carried out on pure (99) i n the same manner, in 98% y i e l d . The bright yellow a n a l y t i c a l l y pure s o l i d c r y s t a l l i s e s out on cooling; t h i s i s an excellent p u r i f i -cation method for the formyl pyrrole as the impurities are l e f t i n the methanol solution. The 2-carboxyl-4-ethyl-5-formyl-3-methylpyrrole (101) was produced by hydrogenolysis of (99) i n triethylamine/ tetrahydrofuran with 10% palladium/charcoal. The solution was f i l t e r e d into acetic acid and the solvent removed under reduced pressure. The product c r y s t a l l i s e d with d i f f i c u l t y from methanol with water. (99) (101) The benzyl ester (.100) was cleaved by hydrogenolysis with, palladium/charcoal i n tetrahydrofuran to give the carboxypyrrole (.102) (Figure 12) which upon removal of t e t r a -hydrofuran, c r y s t a l l i s e d from methanol i n greater than 98% y i e l d . The carboxypyrrole (102) can then be decarboxylated to give the ct-free pyrrole (103) by an i n d i r e c t proceedure v i a the iodination product (104) which gives better y i e l d s than the bromination product (105). 64 FIGURE 12: Preparation of Synthetically Useful Pyrroles v i a Transformations of a -Substituents of (100) 65 The a - i o d o p y r r o l e (104) was produced from (102) by the d r o p w i s e a d d i t i o n o f i o d i n e m o n o c h l o r i d e t o the p y r r o l e suspended i n g l a c i a l a c e t i c a c i d , a c e t i c a n h y d r i d e i n t h e p resence o f e x c e s s sodium a c e t a t e as b u f f e r . Excess i o d i n e was removed by h y p o p h o s p h o r o u s a c i d and c r y s t a l l i s a t i o n i n d u c e d by a d d i t i o n o f w a t e r . The p r o d u c t was r e c r y s t a l l i s e d from methanol/water t o g i v e b r i g h t y e l l o w n e e d l e s i n 82% y i e l d . The r e d u c t i o n o f the i o d o p y r r o l e (104) was attempted by h y d r o g e n o l y s i s u s i n g 10% p a l l a d i u m / c h a r c o a l i n t e t r a h y d r o f u r a n . The or- f r e e p r o d u c t (103) was found t o be orange due t o contam-i n a t i o n from the 2 , 2 ' - b i p y r r o l e (106) produced by c o n d e n s a t i o n o f (.1031 and (.104).. T h i s i s a p h o t o i n d u c e d r e a c t i o n and can be reduced g r e a t l y by the e x c l u s i o n o f l i g h t d u r i n g the h y d r o g e n o l y s i s . I t was found t h a t 99% y i e l d c o u l d be o b t a i n e d from t h i s r e a c t i o n u s i n g p l a t i n u m o x i d e as c a t a l y s t i n the d a r k over a t h r e e day p e r i o d . D u r i n g one r e a c t i o n a q u a n t i t y o f b a r r i e r s o l u t i o n (copper s u l p h a t e s o l u t i o n ) was sucked i n t o t h e r e a c t i o n v e s s e l . T h i s r e s u l t e d i n the p r e c i p i t a t i o n o f a l a r g e q u a n t i t y o f the 2 / 2 1 - b i p y r r o l e (106) i n an a n a l y t i c a l l y 5 0 pure form, a r e a c t i o n comparable t o t h e Ullmann c o u p l i n g . The c t-free p y r r o l e (103) was d e p r o t e c t e d by d i s s o l v i n g i n the minimum volume of methanol and a d d i n g 5-6N sodium h y d r o x i d e s o l u t i o n . The s o l u t i o n was b o i l e d t o remove the 66 m e t h a n o l and t h e n r e f l u x e d f o r 2-3 h o u r s u n d e r n i t r o g e n . The s o l u t i o n was a l l o w e d t o c o o l and t h e p a l e brown s o l i d (108) f i l t e r e d and washed. The compound was u s e d i n t h i s f o r m t o p r o d u c e a l l methenes. An a n a l y t i c a l sample was r e c r y s t a l l -i s e d f r o m w a t e r / m e t h a n o l t o g i v e w h i t e n e e d l e s . Y i e l d s v a r i e d s l i g h t l y between 8 0-8 5% due t o some l o s s by steam d i s t i l l a t i o n o f t h e p r o d u c t w h i c h c o u l d be d e t e c t e d by t h e p r e s e n c e o f w h i t e n e e d l e s i n t h e c o n d e n s e r . The c a r b o x y p y r r o l e (102) was a l s o c o n v e r t e d t o t h e a - b r o m o - p y r r o l e (105) by t h e r e a c t i o n o f b r o m i n e i n d i c h l o r o -methane added d r o p w i s e t o a s t i r r e d s u s p e n s i o n o f (102) and a n h y d r o u s p o t a s s i u m c a r b o n a t e i n t e t r a h y d r o f u r a n . The a d d i t i o n was c a r r i e d o u t i n t h e d a r k and f o l l o w e d by t i c , a t t h e f i r s t s i g n o f b i p y r r o l e t h e r e a c t i o n was quenched by p o u r i n g i n t o w a t e r . R e c r y s t a l l i s a t i o n o f t h e p r o d u c t f r o m m e t h a n o l / w a t e r gave an 8 0% y i e l d o f t h e p r o d u c t . I t had been f o u n d n e c e s s a r y d u r i n g t h e s y n t h e s i s o f some methenes t o p r o d u c e t h e b r o m o - f o r m y l p y r r o l e (107) i n q u a n t i t y . P r e v i o u s s y n t h e s i s had been: d i f f i c u l t and t h e p r o d u c t s u n r e l i a b l e , d e p r o t e c t i o n o f (105) by t h e u s u a l method (103) - (108) had p r o d u c e d i n t r a c t a b l e t a r s . N e c e s s i t y b e i n g t h e mother o f i n v e n t i o n i t was d e c i d e d t h a t a method f o r t h i s d e p r o t e c t i o n had t o be f o u n d . The d e p r o t e c t i o n was c a r r i e d o u t i n t h e n o r m a l manner and t h e r e a c t i o n o b s e r v e d by v i s i b l e s p e c t r o s c o p y . D u r i n g t h e i n i t i a l s t a g e s where t h e m e t h a n o l was b o i l e d o f f no ch a n g e s i n t h e s p e c t r u m was o b s e r v e d . D u r i n g t h e f o l l o w i n g 67 3-4 hours l o s s o f the 32 0 nm peak o c c u r r e d . On work up the y i e l d o f (107) was l e s s than 20%. As no change i n the v i s i b l e spectrum had o c c u r r e d b e f o r e the methanol was removed and t h e p y r r o l e remained i n s o l u t i o n a f t e r t h e methanol was removed i t was d e c i d e d t o use v e r y s m a l l q u a n t i t i e s of methanol i n the r e a c t i o n . The v i s i b l e s p e c t r a showed no changes e x c e p t t h a t the r e a c t i o n reached c o m p l e t i o n i n o n l y 2h h o u r s . Upon work up the y i e l d had u n e x p e c t e d l y r i s e n t o a p p r o x i m a t e l y 45%. I t was t h u s d e c i d e d t h a t t h e a b s o l u t e minimum o f methanol would be used. To d e t e r m i n e t h i s t h e p y r r o l e would be heated t o b o i l i n g i n aqueous sodium h y d r o x i d e and once b o i l i n g any r e m a i n i n g p y r r o l e would be d i s s o l v e d by the d r o p w i s e a d d i t i o n o f m ethanol. J u s t below the b o i l i n g p o i n t o f the s o l u t i o n a l l o f t h e p y r r o l e d i s s o l v e d . A t t h e same time a change i n the v i s i b l e spectrum g r e a t e r than any seen b e f o r e i n s i m i l a r t i m e s was o b s e r v e d . The r e a c t i o n went t o c o m p l e t i o n as d e t e r m i n e d by t h e l o s s o f the 320 nm band i n l e s s than 1% hours and on work up the p r o d u c t was i s o l a t e d i n 8 0% y i e l d as t a n n e e d l e s Mpt 104.5 - 105.5°. L a t e r e x p e r i m e n t s i n c r e a s e d the y i e l d t o 8 8%; r e c r y s t a l l i s a t i o n from m e t h a n o l / water gave p a l e t a n n e e d l e s which were a n a l y t i c a l l y pure a l t h o u g h t h i s compound was u s u a l l y used w i t h o u t r e c r y s t a l l -i s a t i o n as i s (108). T h i s d e p r o t e c t i o n method was attempted by o t h e r s on v a r i o u s p y r r o l e s w i t h r e s u l t s v a r y i n g from d i s a s t r o u s t o m o d e r a t e l y u n s u c c e s s f u l , a l t h o u g h t h i s work d i d p o i n t the way t o the subsequent use o f a h i g h e r b o i l i n g • 51 p o i n t a l c o h o l (n-propanol) f o r some d e p r o t e c t i o n s . 68 2.2.3 Modification of 8-substituted pyrroles The i n i t i a l synthesis schemes were based on the chloroethyl side chain, thus (94) (Figure 13) was converted to the 6-chloro-ethylpyrrole (109). This was car r i e d out by the dropwise addition of thionyl chloride to a reflux i n g mixture of (94) and anhydrous potassium carbonate i n dichloromethane. The product c r y s t a l l i s e d as white f l u f f y needles i n 92% y i e l d from methanol on removal of dichloro-methane by reduced pressure d i s t i l l a t i o n . I t was discovered in the c y c l i s a t i o n of the porphyrin that the chloroethyl sidechain was p a r t i a l l y converted to the bromoethyl.lt was therefore necessary to produce other side chains with protecting groups stable to the c y c l i s a t i o n conditions. The f i r s t of these was the bromoethylpyrrole (.110) which was synthesised s i m i l a r l y to the chloroethyl, thionyl bromide substituting for thionyl chloride. The other p o s s i b i l i t y was to protect the alcohol u n t i l after the c y c l i s a t i o n and then produce the halide a f t e r c y c l i s a t i o n . To try th i s route two esters were used, benzoate (111) and the acetate (112). The benzoate (111) was produced by the action of benzoyl chloride on (94) in pyrid i n e / t e t r a -hydrofuran and gave white needles i n 90% y i e l d r e c r y s t a l l i s e d from methanol. The acetate (112) was produced from (94) by treating with pyridine/acetic anhydride overnight i n the 69 FIGURE: 13: P r e p a r a t i o n o f P r o t e c t e d H y d r o x y e t h y l P y r r o l e s from (94) 70 dark. The mixture was then poured into ice water, f i l t e r e d , and the product r e c r y s t a l l i s e d from methanol as white needles in 92%. From the res u l t s obtained from these protected alcohols i t was found that the acetate protecting group was the most satis f a c t o r y for our purposes and thus only the acetate was subsequently used. O (96) (113) The acetoxypropylpyrrole (113) was produced from the methoxycarbonylethylpyrrole (96) d i r e c t l y without i s o l a t i o n of the hydroxypropylpyrrole. The product of the diborane reduction was dissolved i n pyridine/acetic anhydride and the above procedure followed. The acetoxypropylpyrrole was isolated in an o v e r a l l 96% y i e l d for the two reactions. 2.3 The F i r s t Link The f i r s t l i n k was carried out i n the manner described 2 8 by Paine. The d i a c i d chlorides (114, 115, 116) (Figure 14) were produced by heating the diacids (117, 118, 119) on a steambath with thionyl chloride for 1 hour; excess thionyl 71 HP n = 6 n = 8 0.19) n =10 SOCI 2 \ O } (CH 2 ) n -(114) n = 6 C - C . tH5) n = 8 I (116) n =10 S n C U / C H 2 C I 2 / C H 3 N 0 2 B 2 H 6 / T H F H3CV ( C H 2 ) n ^ ^ ^ C H 3 HaC> NaOCH 2 C 6 H 5 / CgK^CHsOH -<CH 2) n-(120) n = 6 (121) n = 8 (122) n =10 (123) n = 6 (124) n = 8 (125) n =10 (.126) n = 6 (127) n = 8 (128) n =10 FIGURE 14: S y n t h e s i s of Chain Linked B i s P y r r o l i c Intermediates chloride was then removed under reduced pressure. Any l a s t traces were removed by adding carbon tetrachloride and remov-ing under reduced pressure. The crude diacidchloride was added to an excess of 6-free pyrrole ( 8 8 ) i n 1 : 1 dichloro-methane-nitromethane and SnCl^ added dropwise. The conditions varied for the d i f f e r e n t chain lengths; during the period between synthesising the Cg l i n k and the C - ^ Q l i n k i t had been discovered that lower concentrations of SnCl^ could be used; the reaction could be run at room temperature as opposed to 0 ° C and the addition time could be reduced from 1 hour to ^ hour without loss of y i e l d or purity. The bis a c y l a t i o n products ( . 1 2 0 , 1 2 1 , 1 2 2 ) were obtained i n 8 0 - 8 5 % y i e l d , they were extremely insoluble, but r e c r y s t a l l -i s a t i o n from hot acetone produced a n a l y t i c a l l y pure compounds. The reduction of the two ketone f u n c t i o n a l i t i e s to methylenes was carried out with diborane i n tetrahydrofuran and monitored by t i c . The alkane linked bispyrroles ( 1 2 3 , 1 2 4 , 1 2 5 ) were obtained i n 8 3 , 8 2 , 8 9 % y i e l d s respectively. The higher y i e l d of ( . 1 2 5 ) was the r e s u l t of carrying out the reaction at room temperature as opposed to the 0 ° used in the previous experiments; this was again a modification which hadoccurred during the work on Cg and C ^ Q linked dimers. Due to the ease of removal of benzyl esters i t was decided to tr a n s e s t e r i f y the ethyl to the benzyl esters. The transbenzylation was affected by a 73 modification of Kenner's 5 2 procedure. The alkane bispyrroles (123, 124, 125) were dissolved under nitrogen in b o i l i n g benzyl alcohol (previously d i s t i l l e d from anhydrous potassium carbonate), and a solution of sodium benzyloxide c a t a l y s t (freshly prepared from sodium and benzyl alcohol) was added i n 1 mL portions. Vigorous evolution of ethanol was observed and the 1 mL portions repeated t i l l ethanol was no longer evolved. The solution was then allowed to cool s l i g h t l y and poured into methanol containing acetic acid to remove the catalyst. The solution was di l u t e d with water to induce c r y s t a l l i s a t i o n ; the yi e l d s of the benzyl esters (126, 127, 128) were greater than 90%. 2.4 2-C2H-Pyrrol-2-ylidenemethyl)pyrroles (Methenes) A l l the methenes produced i n th i s work were synthesised by reaction of a a-carboxypyrrole (129) (Figure 15) with a-formylpyrrole (130) . This i s a minor modification of the general aldehyde synthesis of methenes which makes use of the a-free pyrrole (131) reacting with the c t-formylpyrrole. The a-free i s formed i n s i t u by acidic decarboxylation on' the addition of hydrobromic acid. The protonated a-formyl-jpyrrole i s also formed', th i s i s i n e f f e c t a pyrrolhydroxy-carbinyl cation (132) which reacts with the a-free pyrrole to give the transient meso-hydroxydipyrromethane (133). Water i s l o s t i n s t a n t l y to give the methene (134). The free base methenes are not stable and are thus produced and used as the hydrobromide salts. (130) (.134) FIGURE 15: Synthesis of Pyrromethene from a-Carboxy and ct-Formyl Pyrroles 2.4.1 L i n k e d Methenes W i t h the s y n t h e s i s o f (126, 127, 128) :(Figure 16,) we have the f i r s t r i n g o f the p o r p h y r i n l i n k e d by an a l k y l c h a i n . The p o r p h y r i n can now be s i m u l t a n e o u s l y and symmetric-a l l y b u i l t a t the ends of the l i n k . The f i r s t s t e p i n the s y n t h e s i s o f the p o r p h y r i n r i n g i s the f o r m a t i o n o f the l i n k e d bismethenes. The b e n z y l e s t e r s , o f (126, 127 , 128) were c l e a v e d by c a t a l y t i c h y d r o g e n o l y s i s w i t h p a l l a d i u m / c h a r c o a l i n t e t r a -h y d r o f u r a n t o produce the a - c a r b o x y p y r r o l e s (135, 136, 137). To the s o l u t i o n o f a - c a r b o x y p y r r o l e was added 2.1 moles of ("108 >, the s o l u t i o n was then f i l t e r e d t o remove the h y d r o g e n a t i o n c a t a l y s t and hydrobromic a c i d was added; i n s t a n t l y t h e r e was a d a r k e n i n g i n the c o l o r o f the s o l u t i o n t o a d a r k y e l l o w . The s o l u t i o n was d i l u t e d w i t h methanol and t e t r a h y d r o f u r a n removed by reduced p r e s s u r e d i s t i l l a t i o n . The s o l v e n t was reduced i n volume u n t i l s o l i d (138, 139, 140) appeared i n the s o l u t i o n a t which p o i n t i t was c o o l e d i n i c e . The s o l i d was f i l t e r e d and washed w i t h e t h y l a c e t a t e . These s o l i d s c r y s t a l l i s e d a n a l y t i c a l l y pure i n a p p r o x i m a t e l y 90-95% y i e l d s . In one p r e p a r a t i o n o f (140) the a n a l y s i s was found t o be m a r g i n a l l y o u t s i d e the a c c e p t a b l e l i m i t s and r e - c r y s t a l l i s a t i o n from methanol/hydrobromic a c i d y i e l d e d the a n a l y t i c a l l y pure compound. 7 6 (1126) n = 6 (128) ~h£=10-Ha/Pd/C /THF FIGURE 16: Synthesis of Chain Linked Bismethenes 77 2.4.2 The Reactive Side Chain Methenes A l l the porphyrins were synthesised from two methenes, the f i r s t the linked bismethene and a second methene con-taining the reactive side chain which could be c y c l i s e d v i a the Johnson 2 9 synthesis. This second methene had two requirements, one the reactive side chain on the position diagonally opposite the f i r s t l i n k , secondly i t must be capable of only one c y c l i z a t i o n reaction with the linked methene. It thus required a reactive sidechain adjacent to an a-methyl and the other a-position to contain a group capable of conversion to the a-bromo. The simplest way to achieve these requirements was considered to be the methene (141) obtained from the g-chloroethyl-a-carboxypyrrole (142) (Figure 17), obtained from (109) by c a t a l y t i c hydrogenolysis, with the a-formyl-a'-carboxypyrrole (101). This did not y i e l d the required methene but gave i n t r a c t -i b l e tars when carr i e d out i n acetic acid, as i n the Fischer method, even a f t e r several modifications to the method. I t was thus decided that other g-substituted pyrroles should be t r i e d , the hydroxyethylpyrrole (14 3) gave the same res u l t s as did the benzyl ester (144). The a-carboxypyrrole was therefore abandoned and the more roundabout route to the a-free-a'formylpyrrole was followed. Reaction of (142) (Figure 18), with (108) also 78 (144) R = H CHI I R = Bz FIGURE 17: Proposed S y n t h e s i s o f S u b s t i t u t e d S i d e C h a i n Methenes d 0 7 ) (146) IGURE 18: S y n t h e s i s o f C h l o r o e t h y l Methenes 79 u n e x p e c t e d l y d i d not y i e l d the methene (145), t h i s was a g r e a t blow as i t had been e x p e c t e d t o be a f a c i l e r e a c t i o n . I t was a t t h i s p o i n t t h a t the d e c i s i o n t o produce the a-bromo-a - f o r m y l p y r r o l e (107) was made. When (107) was r e a c t e d w i t h (142) the r e q u i r e d methene (146) was o b t a i n e d i n over 90% y i e l d . On r e a c t i o n o f t h i s methene a f t e r b r o m i n a t i o n w i t h t h e l i n k e d methene i t was observed t h a t a p a r t i a l s u b s t i t u t i o n o f the c h l o r o e t h y l s i d e c h a i n o c c u r r e d - t h u s ^ r e n d e r i n g . t h e whole sequence i n o p e r a b l e ; a new r e a c t i v e s i d e c h a i n had t o be produced which would undergo the c y c l i s a t i o n r e a c t i o n . W i t h t h i s i n mind s e v e r a l o t h e r methenes were produced. I t was now c o n s i d e r e d u n n e c e s s a r y t o use (107) as o t h e r 6 4 workers had used (108) f o r s i m i l a r methenes. Thus (108) ( F i g u r e 19) was r e a c t e d w i t h (147,.148 and 14 9) t o g i v e the methenes (150, 151 and 152) i n a p p r o x i m a t e l y 90% y i e l d s w i t h o n l y one m o d i f i c a t i o n t o t h e u s u a l methene method. The methanol was added b e f o r e or w i t h the hydrobromic a c i d and the methanol volume never a l l o w e d t o reduce e x c e s s i v e l y d u r i n g the c o n c e n t r a t i o n because the e s t e r s c o u l d be c l e a v e d , g i v i n g o i l s r a t h e r than the c r y s t a l l i n e p r o d u c t s . F o r the C ^ Q l i n k e d dimer the p r o p y l group was s y n t h e s i s e d , by t h i s time i t was known t h a t the a c e t a t e was the most use-f u l p r o t e c t i n g group and so the a c e t o x y p r o p y l methene (153) was produced by r e a c t i n g (108) w i t h (154) i n the normal manner. FIGURE 19: Synthesis of Protected Hydroxyethyl Methenes 81 OAc AcO CH3 HBr EtOAc o H3o Br H O (.154) (108) (153) 2.4.3 Bromination of Methenes As mentioned e a r l i e r (Section 2.1) a good method for the conversion of methenes to bromo-bromomethylmethenes was not available i n the early work. The methene had to be refluxed with the r e q u i s i t e quantity of bromine i n small volumes of g l a c i a l acetic acid u n t i l bromine could no longer be observed i n the vapours. The reaction was then quenched by cooling ra p i d l y and f i l t e r i n g the c r y s t a l l i s e d s o l i d . The reaction could then be checked by NMR to determine the purity of the product. This often had to be repeated before the reaction went to completion; excess bromine could not be used, even though vapour was always l o s t , due to the tendency to form the dibromomethyl analogs. Fortunately a r e l i a b l e method for the bromination of methenes was developed which gave pure products i n good y i e l d (usually 90%) without the tendency to over brominate. 82 The bromination was carr i e d out i n 1:3 t r i f l u o r a c e t i c a c i d / 1,1-dichloroethane with excess bromine at room temperature over 4-5 days (some reacted i n 3 days but were not adversely affected i f l e f t even 7 days). The methenes (146, 150, 151, 153) (Figure 2 0 ) , were a l l treated with bromine i n t r i f l u o r a c e t i c a c i d / 1 ,1-dichloroethane; Br, TFA/(CH2CI)2 BrH2C (146) CH2CH2C1 (150) CH 2CH 20 2CCH 3 (151) CH 2C0 2CH 3 (153) CH2CH2CH202CCH, R' Br H H H R (155) CH2CH2C1 (156) CH 2CH 20 2CCH 3 (157) CH 2C0 2CH 3 (158) CH 2CH 2CH 20 2CCH 3 FIGURE 20: Bromination of Methenes the dibrominated methenes (155, 156, 157, 158) were obtained by evacuating excess bromine and evaporating to dryness. The s o l i d (in some cases o i l ) was redissolved i n 1 ,1-dichloroethane and c r y s t a l l i s e d by the addition of ethyl ether and petroleum 30-60° to the ice cold solution. Any perbromide could be des-troyed at the c r y s t a l l i s a t i o n stage by addition of cyclohexene or by dissol v i n g i n dichloromethene treating with cyclohexene and then evaporating to dryness before use. The c i o ~ C 1 0 bismethene (14) was tetrabrominated to give (159) by the above method to enable the c ^ o C 1 0 c ^ 1 l i n k e d 83 bisporphyrin to be synthesised by Paine's method to give a material for comparison purposes. B r 2 / T F A y t C H 2 C I ) 2 U 5 9 ) 2.5 Porphyrin Synthesis Synthesis of porphyrins based on the condensation of two d i p y r r o l i c intermediates ( 2 + 2 synthesis) have been widely used. In the early work of Fischer mixtures of products were frequently obtained, r e s u l t i n g i n tedious separations of isomeric porphyrins. The condensation of components i n a succinic acid melt often removed or altered 3 and meso substituents and minuscule yie l d s were common. 5 3 The dipyrromethane synthesis developed by MacDonald . was 84 thus a g r e a t improvement h a v i n g n o t a b l e s u c c e s s e s e.g. 6 5 Woodward's s y n t h e s i s o f c h l o r o p h y l l a. U n f o r t u n a t e l y t h e r e were l i m i t a t i o n s and s y m m e t r i c a l pyrromethenes a r e r e q u i r e d ; e l e c t r o n e g a t i v e s t a b i l i s i n g groups a r e r e q u i r e d t o p r e v e n t c l e a v a g e o f t h e d i p y r r o m e t h a n e b r i d g e w i t h subsequent r e -c o m b i n a t i o n and isomer f o r m a t i o n . The Johnson p o r p h y r i n s y n t h e s i s v i a a c - b i l a d i e n e s e l i m i n a t e d t h e s e problems and produced unambiguous p o r p h y r i n s . 2.5.1 The Johnson P o r p h y r i n S y n t h e s i s The i n i t i a l c o n d e n s a t i o n o f a c - b i l a d i e n e s w i t h copper a c e t a t e had s i m i l a r symmetry r e s t r i c t i o n s t o the p r e v i o u s methene s y n t h e s e s thus o t h e r c y c l i s a t i o n methods were sought. B r o m i n a t i o n o f 5 - u n s u b s t i t u t e d - 5 ' - m e t h y l d i p y r r o m e t h e n e hydrobromide (160) ( F i g u r e 21) t o g i v e 5-bromo-5'-bromomethyl-d i p y r r o m e t h e n e hydrobromide (161) e n a b l e d the s y n t h e s i s o f l - a l k y l - 1 9 - b r o m o - l , 1 9 - d i d e o x y b i l a d i e n e - a c (162) by conden-s a t i o n w i t h a 5 - u n s u b s t i t u t e d - 5 ' - a l k y d i p y r r o m e t h e n e (163) i n the p r e s ence o f S n C l ^ . The t i n complexes were n o t i s o l a t e d b u t c o n v e r t e d t o t h e d i h y d r o b r o m i d e i n good y i e l d . The s a l t s were then c y c l i s e d by r e f l u x i n g i n a-dichlorobenzene t o g i v e h i g h y i e l d s o f the r e q u i r e d p o r p h y r i n (164). The r e a c t i o n was m o d i f i e d by the use o f d i m e t h y l s u l f o x i d e and p y r i d i n e i n the d a r k a t room temperature w h i c h gave e x c e l l e n t y i e l d s o f o c t a a l k y l p o r p h y r i n s v i a the porphodimethene (165) . 8 5 86 Both c y c l i s a t i o n methods f o r the b i l a d i e n e s were used, a l t h o u g h the DMSO/pyridine method was p r e f e r r e d f o r the p r o t e c t e d h y d r o x y a l k y l p o r p h y r i n s , as t h i s gave b e t t e r y i e l d s and c l e a n e r p r o d u c t s . The method v a r i e d somewhat d u r i n g the p o r p h y r i n s y n t h e s e s i n the method o f i s o l a t i o n o r i n some cases t h e non i s o l a t i o n o f the b i l a d i e n e d i h y d r o b r o m i d e . E q u i v a l e n t q u a n t i t i e s o f 5-bromo-5-bromomethyldipyrromethene hydrobromide and 5 - u n s u b s t i t u t e d - 5 ' - m e t h y l d i p y r r o m e t h e n e hydro-bromide were d i s s o l v e d i n d r y d i c h l o r o m e t h a n e , and S n C l ^ added, the m i x t u r e was then l e f t f o r Th hours and quenched w i t h 48% hydrobromic a c i d / w a t e r . The .organic phase was s e p a r a t e d and washed w i t h water t o remove the t i n . Methanol (or e t h y l a c e t a t e ) and hydrobromic a c i d was added and the d i c h l o r o m e t h e n e removed under reduced p r e s s u r e a t 25°. The d i h y d r o b r o m i d e s a l t was f i l t e r e d , washed w i t h e t h y l e t h e r o r e t h y l a c e t a t e and d r i e d under vacuum. The c y c l i s a t i o n was then a c c o m p l i s h e d by r e f l u x i n g the s o l i d i n o - d i c h l o r o b e n z e n e f o r up t o 1 hour or d i s s o l v i n g i t i n d i m e t h y l s u l f o x i d e / p y r i d i n e and a l l o w i n g t o s t a n d i n the d a r k f o r s e v e r a l d a y s . The p o r p h y r i n formed as a scum on the s u r f a c e o f the s o l u t i o n , and was f i l t e r e d , washed w i t h methanol and d r i e d . 37 2.5.2 Singly Linked Porphyrins Although the C^-Cg (166) dimer was eliminated as a possible route to doubly linked dimers early i n i t s synthesis i t was decided to carry through the reactions to determine the i r f e a s i b i l i t y whilst concurrently synthesising the Cg linked bismethene (139). Thus the synthesis of a b i s -(chloroethylporphyrin) hexane (167) was attempted. The biladiene was synthesised i n the normal manner from (14 6) (Figure 22) and (138) and c y c l i s e d by both the DMSO/pyridine FIGURE' 22: Synthesis of Chloroethyl porphyrin 88 and o - d i c h l o r o b e n z e n e methods i n 45 and 39% y i e l d s . S y n t h e s i s o f t h e b i s - ( c h l o r o e t h y l p o r p h y r i n y l ) o c t a n e (168) was at t e m p t e d •i 2.3 by the o - d i c h l o r o b e n z e n e method, b u t H and C NMR showed (167) and (168) t o be m i x t u r e s o f c h l o r o e t h y l and b r o m o e t h y l p o r p h y r i n s . I t was t h u s n e c e s s a r y t o p r o t e c t t h e h a l o e t h y l f u n c t i o n a l i t y d u r i n g the p o r p h y r i n s y n t h e s i s . The use o f the a c e t a t e - p r o t e c t e d h y d r o x y e t h y l was d e c i d e d upon as t h i s had been p r e v i o u s l y used t o produce h a l o e t h y l 5 k s i d e c h a i n s by o t h e r w o r k e r s . The c y c l i s a t i o n o f (139) ( f i g u r e 23) w i t h two moles o f (156) y i e l d e d the p o r p h y r i n (169) i n 61.8% y i e l d . F o r t h e s y n t h e s i s o f t h e b i s p o r p h y r i n the n e x t s t e p was the b r o m i n a t i o n of the h y d r o x y e t h y l s i d e -c h a i n . The o b v i o u s methods f o r b r o m i n a t i o n o f the h y d r o x y l f u n c t i o n a l i t y , hydrobromic a c i d , t r i p h e n y l p h o s p h i n e / c a r b o n -t e t r a b r o m i d e e t c . d i d not produce the b r o m o e t h y l p o r p h y r i n and u s u a l l y l e d t o dark green s o l u t i o n s . B r o m i n a t i o n o f the h y d r o x y l group v i a t h e m e s y l a t e and t o s y l a t e were attem p t e d and t h e s e methods a g a i n gave green s o l u t i o n s . The green s o l u t i o n s were observed t o have a s t r o n g a b s o r p t i o n i n d i c a t i v e o f c h l o r i n s t h u s i t was p o s t u l a t e d t h a t t h e b r o m o e t h y l p o r p h y r i n s were e l i m i n a t i n g hydrogen bromide t o y i e l d v i n y l . p o r p h y r i n s , w h i c h were then a b l e t o undergo a p h o t o p r o t o type r e a c t i o n t o y i e l d a c h l o r i n . Thus a m i l d b r o m i n a t i n g agent was r e q u i r e d w h i c h was n o t s t r o n g l y a c i d i c o r b a s i c and d i d not a t t a c k the p o r p h y r i n r i n g . The method f i n a l l y a t t e m p t e d was t h e use o f t r i p h e n y l -p h o s p h i t e d i b r o m i d e i n d i c h l o r o m e t h a n e . T h i s was produced 89 H,C 1. SnCI 4 /CH 2 CI 2 2. DMSO/Pyr A c O AcO (CH,), 2 '8 (169) OAc 5XH 2 S0 4 /MeOH * 3 C H 3 FIGURE 23; Synthesis of C g Bis(bromoethyl porphyrin) 90 by a d d i n g bromine d i s s o l v e d i n d i c h l o r o m e t h a n e t o an i c e c o l d s o l u t i o n o f t r i p h e n y l p h o s p h i t e i n d i c h l o r o m e t h a n e . The h y d r o x y e t h y l p o r p h y r i n was added as a s o l i d w h i c h d i s s o l v e d i n a few minutes t o g i v e a p u r p l e s o l u t i o n . A t i c was t a k e n as a r e f e r e n c e f o r f u r t h e r samples and s u r p r i s i n g l y i t showed a l a r g e f a s t - r u n n i n g r e d band. The r e a c t i o n was o b s e r v e d over the n e x t two hours b u t showed l i t t l e change. The r e a c t i o n was quenched w i t h water and upon workup was found t o y i e l d the b r o m o e t h y l p o r p h y r i n (170) i n 65%. The mass spectrum o f (17 0) e x h i b i t e d a M +-2HBr r a t h e r than M + peak; l a r g e peaks a t m/e = 79,81 and 80,82 i n 1:1 r a t i o s showed e v i d e n c e f o r the l o s s o f HBr; a n a l y s i s and NMR were c o r r o b o r a t i v e o f the s t r u c t u r e a s s i g n e d t o (17 0 ) . The s y n t h e s i s o f the butyne s i d e c h a i n was attempted w i t h l i t h i u m a c e t y l i d e e t h y l e n e d i a m i n e complex i n DMSO but upon r e a c t i o n the s o l u t i o n t u r n e d green even i n the absence of s u n l i g h t and oxygen. V a r i o u s a t t e m p t s were made w i t h d i f f e r e n t s o l v e n t s , under v a r y i n g c o n d i t i o n s b u t t o no a v a i l as a l l a t t e m p t s t o r e a c t the b r o m o e t h y l p o r p h y r i n l e d t o e l i m i n a t i o n . I t was d e c i d e d a t t h i s time t o produce the ^^.O'^IO ^^ mer as t h i s would be produced from the b r o m o p r o p y l p o r p h y r i n (171) w h i c h s h o u l d n o t be s u b j e c t t o the e l i m i n a t i o n r e a c t i o n e n c o u n t e r e d w i t h the b r o m o e t h y l p o r p h y r i n , t h e r e b e i n g no c o n j u g a t i o n w i t h the r i n g as i n v i n y l p o r p h y r i n s . To ensure t h a t the butyne f u n c t i o n a l i t y was f e a s i b l e by 91 the proposed r o u t e , the model compound 2 , 1 2 , 1 7 - t r i e t h y l - 3 , 8 ,13 , 1 8 - t e t r a m e t h y l - 7 - ( p e n t y - 4 - y n e ) p o r p h i n e (171) ( F i g u r e 24)': was produced. S y n t h e s i s o f the a c e t o x y p r o p y l p o r p h i n e (17 2) from the methenes (173) and (153) was a c c o m p l i s h e d i n 56.6% y i e l d by t h e DMSO/pyridine method. B r o m i n a t i o n o f the h y d r o x y p r o p y l -p o r p h i n e (174) was c a r r i e d o u t i n 48% hydrobromic a c i d / s u l f u r i c a c i d and a l s o w i t h t r i p h e n y l p h o s p h i t e d i b r o m i d e i n 7 7 and 8 5% y i e l d s . Treatment o f the b r o m o p r o p y l p o r p h i n e (175) w i t h a l a r g e e x c e s s of l i t h i u m a c e t y l i d e e t h y l e n e d i a m i n e complex i n DMSO a t 45°C y i e l d e d a p o r p h y r i n w i t h mass s p e c t r a , and a n a l y s i s w h i c h agreed w i t h t h a t e x p e c t e d a l t h o u g h the 8 0MHz "*"H NMR was i n c o n c l u s i v e due t o o v e r l a p p i n g bands. Attempted d i m e r i s a t i o n o f the p o r p h y r i n f a i l e d t o y i e l d any d i m e r i c p o r p h y r i n . A 400MHz ''"H NMR s p e c t r a o b t a i n e d a t t h i s p o i n t i n d i c a t e d the p r e s ence o f a m e t h y l group <S = 1.77ppm w i t h a s m a l l c o u p l i n g J2Hz. T h i s i s i n d i c a t i v e o f an i n t e r n a l a c e t y l e n e and f u r t h e r i n t e r p r e t a t i o n o f t h e s p e c t r a e n a b l e d i t s s t r u c t u r e t o be a s s i g n e d as the b u t - 3 - y n e p o r p h i n e (176). T h i s seemed t o be a m o r t a l blow as t h i s p r o c e d u r e had been used s u c c e s s f u l l y t o produce t e r m i n a l a c e t y l e n e s by 5 5 many w o r k e r s . I t seemed p o s s i b l e t h a t the rearrangement o f the a c e t y l e n e was due t o the c o n d i t i o n s o f the r e a c t i o n ( s t r o n g bases a r e known t o r e a r r a n g e a c e t y l e n e s ) , thus t h e s y n t h e s i s was attempted u s i n g 1:1.2 m o lar r a t i o o f r e a g e n t s , u n f o r t u n a t e l y t h i s had no e f f e c t upon the p r o d u c t . I t was 92 CuCl /MeOH / P y r / T M E D A FIGURE 24: Synthesis of Model Diyne Bisporphyrin. 93 then decided to run the reaction at lower temperatures. Although i n DMSO i t i s not possible to use temperatures below 20°C i t was decided to remain with DMSO as solvent and try the reaction at ambient temperature and a shorter reaction time of 2 hours. The product from this reaction proved to be the required but-4-yneporphine (171), shown by the absence of a methyl signal i n the 400MHz NMR, the analysis and mass spectra remaining correct. Dimerisation of the zinc complex was accomplished by treatment of (171a) with cuprous chloride i n methanol/ pyridine/TMEDA under an oxygen atmosphere at 45°C. I t had already been ascertained that zinc would not be replaced by copper under these conditions. The reaction was monitored for 24 hours there apparently being no further change a f t e r 18 hours. The product (177) was obtained i n 56.5% y i e l d , r e a d i l y shown to be the dimer by high molecular weight fragments in the mass spectra. The mass spectrum showed an isotope d i s t r i b -ution at 1154 - 1164 i d e n t i c a l to that expected for (177a). C a t a l y t i c hydrogenation with palladium oxide/formic 56 acid reduced the bisdiyne to the bisporphinyldecane (178) (figure 25) which was shown to be i d e n t i c a l to an authentic sample produced by the method df Paine. With t h i s encouraging series of re s u l t s i t was con-cluded that the dimeric porphyrin should follow a similar pattern and produce a dimeric bislinked porphyrin. Unlike the monomeric porphyrins the dimers are extremely insoluble and thus reactions had to be carri e d out i n dichloromethane (177) H2/P60/ HC0 2tt 95 or with acid present to s o l u b i l i s e the porphyrins. The bis(acetoxypropylporphinyl)decane (179) was synthesised in a manner similar to that used for the C G analogue (169) (Figure 26). Deprotection of the acetate in 5% s u l f u r i c acid/methanol was t r i v i a l but r e c r y s t a l l i s a t i o n of the product proved extremely d i f f i c u l t due to i t s low s o l u b i l -i t y . Once the tetracation was neutralised the bis(hydroxy-propylporphinyl)decane (18 0) precipitated from solution as a dark brown s o l i d which could not be produced a n a l y t i c a l l y pure but i t s "*"H NMR showed loss of acetoxyprotons at 6 = 2.Oppm and was consistent with that of (180). As bromination of the hydroxypropylporphyrin (17 4) had been found to occur i n hydrobromic a c i d / s u l f u r i c acid i t was reasonable to assume that t h i s should be true for the dimer. Unfortunately the dimer (180) did not dissolve r e a d i l y even when the s u l f u r i c acid concentration was increased to a 1:1 r a t i o . Upon workup i t was found that a considerable portion of the dimer had been destroyed and the y i e l d of C - ^ Q bisbromopropylporphine (181) was minor. The triphenyl-phosphite dibromide method was attempted and although the dimer took considerably longer to dissolve i n the reagent (up to 2 hours i n some cases) i t did y i e l d (181) i n up to 65% y i e l d s ; some mono-bromination occurred and was variable i n quantity i n d i f f e r e n t runs. The workup was considerably aided by vi r t u e of converting (181) to i t s d i z i n c s a l t (181a) which was soluble i n THF. Thus the column chromatography of the dimers was found t o be c o n s i d e r a b l y e a s i e r . The compounds c o u l d be d i s s o l v e d i n the minimum o f THF d i l u t e d w i t h d i c h l o r o m e t h a n e / adsorbed onto the column and d i c h l o r o m e t h a n e then used t o e l u t e the bands. The d i z i n c p o r p h y r i n s r a n v e r y q u i c k l y (R f 0.95 by t i c ) w i t h d i c h l o r o -methane as e l u e n t and the monozinc dimers c o u l d be e l u t e d w i t h 2%. m e t h a n o l / d i c h l o r o m e t h a n e . The d i z i n c d i m e r s were a l s o n e c e s s a r y t o p r e v e n t form-a t i o n o f the copper s a l t s and t o i n c r e a s e the s o l u b i l i t y o f the dimers i n DMSO the f a v o u r e d s o l v e n t f o r r e a c t i o n s of l i t h i u m a c e t y l i d e EDA. The non m e t a l l a t e d dimer has o n l y m i n i m a l s o l u b i l i t y i n DMSO, whereas i t s d i z i n c complex i s v e r y s o l u b l e and r e a c t s r e a d i l y t o g i v e the C ^ Q b i s p e n t y n e p o r p h i n e (18 4) i n 7 0% y i e l d . The a n a l y s i s agreed w e l l w i t h the e x p e c t e d r e s u l t s and mass s p e c t r a gave the e x p e c t e d 13 i s o t o p e r a t i o . However the C NMR appeared t o g i v e a m i x t u r e o f a l k y n e s , i n d i c a t e d by the a l k y n e c a r b o n s i g n a l s a t '6 = 70.160 and 83.993 and 6 = 77.659 and 78 .654. T h i s c o u l d be due t o r u n n i n g the sample o v e r n i g h t i n 5% TFA/CDCl^ 1 13 s o l u t i o n (the H NMR a f t e r C NMR was c o n s i d e r a b l y more com p l e x ) . 2.5.3 The F i n a l L i n k C y c l i s a t i o n o f (182a) ( f i g u r e 27) was c a r r i e d o u t by a h i g h d i l u t i o n o x i d a t i v e c o u p l i n g r e a c t i o n . The dimer 98 C H , % (182a) M = Zn (183) M (183a) M H 2 / P d O / H C 0 2 H (185) M (185a) M = H 2 Zn 2ho (CH , ) „ CH. 1. S n C I 4 / C H 2 C I 2 2. DMSO/Pyr FIGURE 27: Synthesis of c 1 0 - C i o D o u b l Y Linked Dimer (182a) was d i s s o l v e d i n THF/dichloromethane and added, u s i n g a s y r i n g e pump, o v e r a seven hour p e r i o d t o a s o l u t i o n o f cuprous c h l o r i d e i n m e t h a n o l / p y r i d i n e i n t o which was bubbled oxygen. Workup c o n s i s t e d o f washing w i t h w a t e r , e v a c u a t i n g t o d r y n e s s under reduced p r e s s u r e and the u s u a l c h r o m a t o g r a p h i c system. A v e r y f a s t moving band was o b t a i n e d w h i c h proved t o be s i m i l a r t o s t a r t i n g m a t e r i a l , on e l u t i o n w i t h d i c h l o r o m e t h a n e / 2 % methanol a s l o w e r band was o b t a i n e d . Even w i t h such a m i l d workup i t was found t h a t the p r o d u c t c o u l d be o b t a i n e d w i t h o n l y one z i n c and t h a t r e m e t a l l a t i n g t o g i v e the d i z i n c dimer was e x t r e m e l y slow (observed by v i s i b l e s p e c t r u m ) ; t h i s i s a phenomenon n o t i c e d by o t h e r l k . . . . workers w i t h c o f a c i a l d i z i n c d i m e r s , and., had n o t been ob s e r v e d w i t h t h e s i n g l y l i n k e d d i y n e p o r p h i n e (177). The y i e l d o f dimer (183a) f o r t h i s r e a c t i o n was found t o be e x t r e m e l y low (o n l y 4 % ) , r e c o v e r y o f s t a r t i n g m a t e r i a l was 50%. The r e c o v e r e d (182a) was r e c y c l e d t h r o u g h the r e a c t i o n b u t a l t h o u g h some p r o d u c t was o b t a i n e d the y i e l d was even l e s s than t h a t p r e v i o u s l y o b t a i n e d . A l t h o u g h t h i s f a i l u r e c o u l d p o s s i b l y be a t t r i b u t e d t o a m i x t u r e o f (182a) and (184a) a t the s t a r t i n g m a t e r i a l s t a g e , rearrangement under the b a s i c c o n d i t i o n s o f the r e a c t i o n i s p o s s i b l e . The f a c t t h a t some c y c l i s e d p r o d u c t c o u l d be o b t a i n e d from the r e c y c l i s e d m a t e r i a l would tend t o su g g e s t t h a t the major problem might n o t l i e i n the rearrangement b u t i n t h a t the c o n f o r m a t i o n r e q u i r e d f o r c y c l i s a t i o n c o u l d be e x t r e m e l y u n f a v o u r a b l e . 100 C a t a l y t i c hydrogenation of the diyne was attempted with PdO/formic acid but d i f f i c u l t y was found i n maintaining the dimer (183a) i n solution. THF was added and this over-came the s o l u b i l i t y problems but reduced the a c t i v i t y of the c a t a l y s t as compared to the singly linked dimer (177). The c i o ~ C 1 0 dimer (185) produced was compared, using t i c , mass spectroscopy and AH NMR, and found to be i d e n t i c a l to a sample produced by the method of Paine. The y i e l d once again was extremely low (-5%) i t seemingly being easier to reduce the porphyrin than the diyne system. The normal method of regenerating the porphyrin aft e r reduction by bubbling a i r into the solution was found to regenerate porphyrin only once and then to only a minor degree. Thus we had produced the same compound v i a two d i s t i n c t routes. The stepwise synthesis discussed i n t h i s thesis whilst not viable for producing quantities of dil i n k e d bisporphyrins does prove the structure of the single step c y c l i s a t i o n product of Paine, which can of course be used to produce a variety of chain lengths and thus various metal-metal distances. CHAPTER 3 EXPERIMENTAL 102 3.1 GENERAL METHODS M e l t i n g P o i n t D e t e r m i n a t i o n s M e l t i n g p o i n t s were o b t a i n e d w i t h a Thomas-Hoover U n i m e l t , a c a p i l l a r y / o i l immersion a p p a r a t u s ; the r e s u l t s a r e p r e s e n t e d u n c o r r e c t e d . E l e m e n t a l A n a l y s i s E l e m e n t a l a n a l y s e s were performed by Mr. P. Borda of the M i c r o a n a l y t i c a l L a b o r a t o r y , U.B.C. N u c l e a r Magnetic Resonance S p e c t r o s c o p y U n l e s s o t h e r w i s e s t a t e d , p r o t o n NMR s p e c t r a were o b t a i n e d a t 100 MHz w i t h a V a r i a n XL-100 spe c t o m e t e r . 80 MHz s p e c t r a were r e c o r d e d on a B r u k e r WP-80 s p e c t r o m e t e r , 270 MHz s p e c t r a on a UBC NMR C e n t r e m o d i f i e d N i c o l e t - O x f o r d H-270 s p e c t r o -13 meter. 4 00 MHz and C NMR were r e c o r d e d w i t h a B r u k e r WH-4 00 13 . . s p e c t r o m e t e r . Some C NMR were a l s o r e c o r d e d w i t h a V a r i a n CFT-2 0. A l l s p e c t r a were r e c o r d e d w i t h TMS as i n t e r n a l s t a n d a r d & = 0. Che m i c a l s h i f t s a r e r e c o r d e d i n t h e 5(ppm) s c a l e . Mass S p e c t r o m e t r y Mass s p e c t r a were r e c o r d e d on a V a r i a n MAT CH 4-B s p e c t r o m e t e r o r a K r a t o s / A E I MS-902 s p e c t r o m e t e r . High m o l e c u l a r w e i g h t p o r p h y r i n s p e c t r a were o b t a i n e d on a K r a t o s / A E I MS-50 s p e c t r o m e t e r . 103 Electronic Spectroscopy A Cary recording spectrometer (Model 17) was used to obtain uv and v i s i b l e spectra. Chromatography Column chromatography was performed using s i l i c a gel obtained from ICN Pharmaceuticals (Woelm, 70-150 mesh, a c t i v i t y I ) . Thin Layer Chromatography (tic) was performed using precoated s i l i c a gel plates (Analtech-Uniplate, 250 ) and the compounds were detected by uv l i g h t (254 nm and 366nm). Starting Materials As none of the pyrroles required for t h i s work was commercially available at a reasonable p r i c e , a l l of the p y r r o l i c s t a r t i n g materials had to be synthesized. Although most of these compounds have appeared previously i n the l i t e r a t u r e , t h e i r syntheses have been included here for completeness, and the convenience of any who might wish to make use of the information contained herein. In some cases, useful modifications have been made. Reagents and Solvents A l l chemicals and solvents were reagent grade unless otherwise indicated. The dry dichloromethane used during th i s work was d i s t i l l e d from calcium hydride. 3.2 S y n t h e s i s o f A c y c l i c P r e c u r s e r s B e n z y l a c e t o a c e t a t e (90) E t h y l a c e t o a c e t a t e (1400 mL, 11 mole) and b e n z y l a l c o h o l (1042 mL, 10 mole) were mixed and l e f t o v e r n i g h t . The m i x t u r e was heated t o r e f l u x and e t h a n o l (560 mL, c a l c . 500) d i s t i l l e d o v e r . The r e s u l t i n g m i x t u r e was d i s t i l l e d under reduced p r e s s u r e and t h e p r o d u c t (1444.6g, 78%) had BP. 140-145°C/10 T o r r ( l i t . 152-157°C/11 To r r ) 20 n ^ u = 1.4734. A n a l : C a l c . f o r C 1 1 H 1 2 ° 3 : C ' 6 8 -73'" H,6.29; Found: C, 68.38; H,6.44%. 1 H NMR: (6, C C 1 4 ) ; a) k e t o form; 2.00 ( s , ~ C H 3 ) ; 3.24 ( s , -CO-CH2-CO) ; 4.98 ( s , 2H, -CH^CgH,.); 7.18 ( s , 5H, - C g H 5 ) ; b) e n o l form ( c a . 1 5 % ) ; 1.80 ( s , C H 3 ) . 105 Methyl-3-acetyl-4 oxopentanoate (92) Methyl chloracetate (.548 mL, 6 mole) was added dropwise to a s t i r r e d mixture of 2,4-pentanedione (616 mL, 6 mole) anhydrous potassium carbonate (830g, 6 mole)potassium iodide (180g, 1.08 mole). and 2-butanone (3000 mL) . When the mixture had ceased to re f l u x , i t was heated on a steam bath for a further 1 hour. The mixture was f i l t e r e d when cool, and the solvent removed under pressure. The residual o i l was d i s t i l l e d under reduced pressure, the product (610.7g) had 5 7 BP. 105-110°C/6 Torr ( l i t . 130-132°C/21 Torr) n^° = 1.4566 Q i t . 1.4555). Anal. Calc. for C 8 H 1 2 ° 4 : C,55.80; H,7.03: Found: C,55.50; H,7.07%. 1H NMR: (<5, CC1 4); a) keto form; 2.15 (s,-CH~3); 2.75 Cd, J7Hz,-CH2CO-) ; 3.56 (s, -OCH_3); 4.06 (t, -H) ; b) enol form (.ca.30%); 2.06 (s, -CHg); 3.20 (s, -CH -CO-) . 106 M e t h y 1 - 4 - a c e t y l - 5 - o x o h e x a n o a t e (95) M e t h y l a c r y l a t e (200 mL, 2.22 mole) was added dro p w i s e over 2 hours t o a s o l u t i o n o f 2,4-pentanedione (250 mL, 2.43 mole) and anhydrous p o t a s s i u m c a r b o n a t e ( l O g , 70 mmole) i n 2-butanone (175 mL). The m i x t u r e m a i n t a i n e d r e f l u x d u r i n g the a d d i t i o n , when complete the r e a c t i o n was heated f o r 2 0 min. and then f i l t e r e d t o remove the c a t a l y s t . The s o l v e n t was removed under reduced p r e s s u r e and the f r a c t i o n between 144-150°C/12 T o r r c o l l e c t e d (294g, 7 2 % ) . (lit 5 9148° 1 4 / T o r r ) . A n a l ; C a l c . f o r C 9 E 1 4 0 ^ - c / 58.05; H, 7.58: Found: C, 58.48; H, 7.80% NMR;(4 00 MHz): (<S , C D C l 3 ) ; a) k e t o ; 2.36 (m, J8Hz, 2H, -CH_2CH2CO) ; 2.44 ( s , 6H, CH^CO) ; 2.55 ( t , J8Hz, 2H, -CH 2CH 2CO) ; 3.90 ( s , 3H, -OCH 3); 3.98 ( t , J8Hz, IH, -CH-). b) e n o l •(ca,'22%); 1.39 ( s , 6H, CH^CO) ; 1.64 ( t , J l O H z , 2H, -CH^CH^O) ; I . 83 ( t , J l O H z , 2H, -CH 2CH 2CO); 1.91 ( s , 3H, OCH 3). 3.3 Synthesis of Mohopyrroles 2-Ethyloxycarbonyl-3,5-dimethylpyrrole (88) 107 A solution of sodium n i t r i t e (2070g, 30 mole) i n water (.3 000 mL) was slowly added to a s t i r r e d solution of, d i e t h y l malonate (1600g, 10 mole) i n g l a c i a l acetic acid (.1800 mL) . The oxime separated out as a yellow o i l which was added slowly to a solution of 2,4-pentanedione (lOOOg, 10 mole) i n g l a c i a l acetic acid (2,400 mL), zinc (1308g, 2 0 mole) was added in portions always maintaining an excess of zinc. The solution was maintained between 50-60°C during the addition of oxime then heated on a steambath for 1 hour. The mixture was poured into water when cool and f i l t e r e d , extracted with methylene chloride and the water separated. The solvent was replaced by methanol under reduced pressure, r e c r y s t a l l i s a t i o n gave product (661g, 39.5%) as small pale tan c r y s t a l s MP. 120-121 C ( l i t 116-11 Anal: Calc. for CgH13NC>2: C, 64.65; H, 7.84; N, 8.38: Found: C, 64.35; H, 7.90; N, 8.28%. ^H NMR: ($;, CDC1 3); 1.36 (t, J7.5Hz, 3H, -OCH2CH3); 2.26 (s, 3H, -CH 3); 2.32 (s, 3H, -CH3); 4.38 (q, J7.5Hz, 2H, -OCH2CH3); 5.82 (d, J3Hz, IH, pyr-H); 9.57 (bs, IH, NH). 108 2-Benzyloxycarbonyl -4-acetyl-3,5-dimethylpyrrole (91) A solution of sodium n i t r i t e (414g, 6 mole) i n water (800 mL) was slowly added to a s t i r r e d solution of benzyl acetoacetate (90) (1152g, 6 mole) i n g l a c i a l acetic acid (1250 mL) the temperature being maintained below 10°C. This was then added to a solution of 2,4-pentanedione (600g, 6 mole) in g l a c i a l acetic acid (2,200 mL), a mixture of zinc (780g, 12 mole) and anhydrous sodium acetate (985g, 12 mole) was added i n portions throughout the addition maintaining an excess of zinc at a l l times. When the addition was complete, the mixture was heated on a steam bath for one hour and then poured into water. The s o l i d was f i l t e r e d o f f , the product extracted with methylene chloride and the water removed. The solvent was replaced under reduced pressure by methanol, c r y s t a l l i s a t i o n from methanol gave product (738g, 45.4%) as white needles MP.133-134°C Anal: Calc. for C,,H,_NO-: C, 7 0.83; H, 6.32; N, 5.16; Found: C, 70.76; H, 6.44; N, 5.19%. ^H NMR: IS, CDC1 3); 2.44 (s, 3H, -CH_3) ; 2.51 (s, 3H, -CH3); 2.61 (s, 3H, -COCH_3) ; 5.35 (s, 2H, -CH^ CgH,.) ; 7.40 (bs, 5H, -C 6H 5); 9.65 (bs, lH, NH). 109 2-Benzyloxycarbonyl-4-methoxycarbonylmethyl-3,5-dimethylpyrrole (93) H 3 C A solution of sodium n i t r i t e (lOOg, 1.45 mole) i n water (.350 mL) was slowly added to a s t i r r e d solution of benzyl acetoacetate (90) (260g, 1.35 mole) i n g l a c i a l acetic acid (450 mL) the temperature being maintained below 10°. After being l e f t i n the r e f r i g e r a t o r overnight the solution was slowly added to a solution of methyl-3-acetyl-4-oxopentanoate (92) (220g, 1.28 mole) i n g l a c i a l acetic acid (260 mL), a mixture of zinc dust (260g, 4 mole) and anhydrous sodium acetate (.260g, 3.17 mole) was added i n portions throughout the addition maintaining an excess of zinc at a l l times. When the addition was complete the reaction mixture was further heated on a steam bath for 1 hour and then poured into water. The s o l i d was f i l t e r e d o f f , and the product extracted with methylene chloride and the water removed. The solvent was then replaced by methanol under reduced pressure, c r y s t a l l i s a t i o n from methanol gave fine needles of the product (127g, 33%) MP. 104-105.5°C ( : l i t . 5 8 93-94°C) . Anal: Calc. for C 1 7H 1 9N0 4: C, 67.7 6; H, 6.36; N, 4.65; Found: C, 68.01; H',, 6.36; N, 4.73%. H N M R : CDC1 3); 2.21 (s, 3H, -CH_3); 2.31 (s, 3H, -CH 3); 3.40 (s, 2H, -CH2CO-); 3.67 (s, 3H, -OCH3); 5.32 (s, 2H, -CH 2C 6H 5); 7.39 (m, 5H, -C^) ; 9.18 (bs, IH, NH) . I l l 2 - B e n z y l o x y c a r b o n y l - 4 - ( 2 - h y d r o x y e t h y l - 3 , 5 - d i m e t h y l p y r r o l e (94) B o r o n t r i f l u o r i d e e t h e r a t e (38 mL, 0.30 mole) was added d r o p w i s e t o an i c e c o l d s t i r r e d m i x t u r e o f 2 - b e n z y l o x y c a r b o n y l -4 - m e t h o x y c a r b o n y l m e t h y l - 3 , 5 - d i m e t h y l p y r r o l e (93) (20g, 66 mmole), sodium b o r o h y d r i d e (8g, 0.22 mole) i n THF (150 mL) under n i t r o g e n . When the a d d i t i o n o f boron t r i f l u o r i d e was com-p l e t e the r e a c t i o n was checked f o r complete c o n v e r s i o n by t i c and then quenched by d r o p w i s e a d d i t i o n o f g l a c i a l a c e t i c a c i d (.5 0 mL) , f o l l o w e d by water (50 mL) . The p r o d u c t was e x t r a c t e d i n t o methylene c h l o r i d e (10 0 mL) and the s o l v e n t r e p l a c e d under reduced p r e s s u r e w i t h m e t h a n o l , r e c r y s t a l l i s e d from methanol/water t o g i v e the p r o d u c t (16.9g, 93.2%) as w h i t e n e e d l e s . MP. 117-118°C ( l i t 5 8 120-121.5°C) A n a l : C a l c . f o r C l 6 H i g N 0 3 : C, 70.13; H, 7.01; N, 5.13: Found: C, 70.41; H, 7.22; N, 5.21%. NMR: (<5, CDC1 3); 1.58 ( s , IH, -OH); 2.21 ( s , 3H, ~CH_ 3); 2.30 ( s , 3H, - C H 3 ) ; 2.65 ( t , J7Hz, 2H, -CH 2CH 2OH); 3.66 (-t, J7Hz, 2H, -CH 2CH 2OH) ; 5.30 ( s , 2H, -CH^CgH^ ; 7.38 (bs, 5H, - C 6 H 5 ) ; 8.84 (bs, I H , NH). 112 2-Benzyloxycarbonyl-4-(2-methoxycarbonylethyl)-3,5- dimethylpyrrole (96) To a s t i r r e d , ice cold solution of benzylacetoacetate (90) (280g, 1.5 mole) i n g l a c i a l acetic acid (300 mL), was added a solution of sodium n i t r i t e (145g, 2.1 mole) i n water (200 mL) over a 30 min. period. The mixture was s t i r r e d for a further 10 min. and the oxime separated from the aqueous layer. This was added dropwise over a period of 2 hours to a cooled suspension of methyl-4-acetyl-5-oxohexanoate (95) (275g, 1.49 mole), zinc (360g, 5.66 mole) i n g l a c i a l acetic acid (1500 mL). The solution was refluxed for 30 min. and then poured into water (4000 mL). The r e s u l t i n g s o l i d was f i l t e r e d , redissolved i n dichloromethane (535 mL) and c r y s t a l l i s e d from methanol by removal of the dichloromethane under reduced pressure to y i e l d product (190.5g, 40.3%) 59 MP. 98.5-99°C ( l i t 99-100°C). 113 Anal: Calc. for c 1 8 H 2 i N 0 4 : C ' 68.55; H, 6.71; N, 4.44: Found: C, 68.69; H, 6.56; N, 4.44%. 1H NMR: (£., CDC13) 2.28 (s, 3H, CH 3); 2.38 (s, 3H, CH_3); 2.52 (m, 2H, CH 2CH 2C0 2CH 3); 2.82 (m, 2H, CH 2CH 2C0 2CH 3); 3.75 (s, 3H, C0 2CH 3); 5.41 (s, 2H, CH^ CgH,.) ; 7.49 (bs, 5H, CH 2C 6H 5); 9.12 (bs, lH, NH). 114 2-Benzyloxycarbonyl-4-ethyl-3,5-dimethylpyrrole (97) Boron t r i f l u o r i d e etherate (336 mL, 2.67 mole) was., added dropwise to a s t i r r e d , ice cooled mixture of 2-benzyl-oxycarbonyl-4-acetyl-3,5-dimethylpyrrole (91) (308g, 1.14 mole)., sodium borohydride (76g, 2 mole) i n THF (1000 mL) and ethyl acetate (3 50 mL). When addition was complete the reaction mixture was checked for complete reaction by t i c and quenched by dropwise addition of g l a c i a l acetic acid (500 mL). The product was extracted with methylene chloride and the solvent replaced by ethanol under reduced pressure, c r y s t a l l i s a t i o n from 3:1 ethanol/water mixture gave product (234.3g, 80.2%) as white needles MP. 102-103°C ( l i t . 6 1 104-105°C). Anal: Calc. for C l 6H 1 9N0 2: C, 74.68: H, 7.44; N, 5.44: Found: C, 74.50; H, 7.51; N, 5.43%. "*"H NMR: (6, CDC1 3); 1.15 (t, J8Hz, 3H, -CH2CH_3); 2.24 (s, 3H, ~CH 3); 2.42 (s, 3H, -CH 3); 2.50 (q, J8Hz, 2H, -CH 2CH 3); 5.44 (s, 2H, -CH^CgH^); 7.52 (m, 5H, -CgH ); 9.36 (bs, IH, NH). 115 2 - B e n z y l o x y c a r b o n y l - 4 - e t h y l - 5 - f o r m y l - 3 - m e t h y l p y r r o l e (99) S u l f u r y l c h l o r i d e (66.2 mL, 0.81 mole) i n methylene c h l o r i d e (1000 mL) was added d r o p w i s e t o an i c e c o l d , s t i r r e d s o l u t i o n o f 2 - b e n z y l o x y c a r b o n y l - 4 - e t h y l - 3 , 5 - d i m e t h y l p y r r o l e (97) (102.8g, 0.4 mole) i n methylene c h l o r i d e (200 mL) under n i t r o g e n . When the a d d i t i o n was complete the m i x t u r e was heated on a steam b a t h f o r 1 hour. Water (5 00 mL) was added and the s o l u t i o n l e f t t o s t i r o v e r n i g h t . The o r g a n i c phase was s e p a r a t e d and t h e s o l v e n t removed under reduced p r e s s u r e . The o i l o b t a i n e d was e x t r a c t e d w i t h h o t w a t e r / e t h a n o l 1:1 and on c o o l i n g p r o d u c t (92g, 84.9%) c r y s t a l l i s e d as a w h i t e s o l i d 86-87°C ( l i t . 86-87°C). A n a l : C a l c . f o r C 1 6 H 1 7 N ° 3 : C ' 7 0- 8 3'" H ' 6.32; N, 5.16; Found: C, 70.81; H, 6.25; N, 5.16%. a H NMR: (5, CDC1 3); 1.20 ( t , J8Hz, 3H, -CH 2CH 3); 2.32 ( s , 3H, - C H 3 ) ; 2.76 (q, J8Hz, 2H, -CH^CH^; 5.37 ( s , 2H - C H 2 C 6 H 5 ) ; 7.42 ( s , 5H, -CgH^); 9.60 (bs, IH, NH); 9.79 ( s , IH, -CHO). 116 2-Benzyloxycarbonyl-5-(2-cyano-2-methoxycarbonylvinyl)-4-ethy1-3-methylpyrrole (100) 2-Benzyloxycarbonyl-4-ethyl-5-formyl-3-methylpyrrole (99) C35.8g, 0.13 mole) was dissolved i n b o i l i n g methanol (50 mL) to t h i s solution was added methyl cyanoacetate (25g, 0.17 mole) and methylamine (1 mL) the solution was allowed to b o i l for 5 minutes and then cooled. The product (45.7g, 98%) c r y s t a l l -ised out as yellow prisms MP. 122-123°C Anal: Calc. for C ^ H ^ N ^ : C, 68.17; H, 5.72; N, 7.94: Found: C, 6 8.13; H, 5.64; N, 7.94%. NMR: CDC1 3); 1.14 (t, J8Hz, 3H, -CH 2CH 3); 2.33 (s, 3H, -CH 3); 2.65 (q, J8Hz, 2H, -CH 2CH 3); 3.92 (s, 3H, OCH_3); 5.41 (s, 2H, -CH 9C 6H 5); 7.45 (m, 5H, -C^) ; 8.06 (s, IH, -H) ; 10.28 Cbs, IH, NH) . 117 2-Carboxyl-4-ethyl-5-formyl-3-methylpyrrole (101) 2-Benzyloxycarbonyl-4-ethyl-5-formyl-3-methylpyrrole (99) (5.42g, 20 ramole), 30% palladium on charcoal (0.35g) i n THF (150 mL) and triethylamine (3 mL) was hydrogenated u n t i l hydrogen uptake ceased (500 mL). The solution was f i l t e r e d into g l a c i a l acetic acid (10 mL) and the volume of solvent reduced; methanol (50 mL) and water (50 mL) was added and the solvent removed under reduced pressure, the product (3g, 82.9%) c r y s t a l l i s e d as metallic copper colored c r y s t a l s MP. 19 0°C(d) . Anal: Calc. for CgH-^NC^: C, 59.66; H, 6.12; N, 7.73; Found: C, 59.57; H, 6.16; N, 7.56%. H^ NMR: ( S T , CDC13/TFA) ; 1.26 (t, J7. 5Hz, 3H, -CH2CH_3); 2.37 (s, 3H, -CH 3); 2.84 (q, J7.5Hz, 2H, -CH 2CH 3); 9.78 (s, IH, CHO); 10.09 (bs, IH, NH). 118 5-(2-Cyano-2-methoxycarbonylvinyl)-4-ethyl-3-methylpyrrole  -2-carboxylic acid (102) A suspension of 2-benzyloxycarbonyl-5-(2-cyano-2-methoxycarbonylvinyl)-4-ethyl-3-nethylpyrrole (100) (23. 5g, 67 mmole), 10% palladium on charcoal (2g) i n THF (250 mL) and triethylamine (1 drop) was hydrogenated u n t i l uptake of hydrogen ceased (1700 mL). The solution was f i l t e r e d and the solvent replaced by methanol under reduced pressure, the product (17.25g, 98.6%) was obtained as a pale yellow powder MP. 200°C(d). Anal: Calc. for C 1 3 H 1 4 N 2 0 4 : C ' 5 9 - 5 3 ; H ' 5.38; N, 10.68: Found: C, 59.55; H, 5.52; N, 10.47%. NMR: (S , CDC13/TFA) ; 1.17 (t, J 7 . 5 H Z , 3H, -CH2CH_3); 2.36 (s, 3H, -CH 3); 2.70 (q, J7. 5Hz, 2H, -CH_2CH3); 3.01 (s, 3H, -OCH3); 8.19 (s, IH, -H); 10.16 (bs, lH, NH). o 119 2 - ( 2 - C y a n o - 2 - m e t h o x y c a r b o n y l 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 (103) o A s t i r r e d s u s p e n s i o n o f 5-(2-cyano-2-methoxycarbonyl-v i n y l ) - 4 - e t h y l - 2 - i o d o - 3 - m e t h y l p y r r o l e (104) (lOg, 30 mmole), p l a t i n u m o x i d e (0.2g) i n THF (150 mL) was hydrogenated i n the dar k over 3 days u n t i l uptake ceased (73 0 mL). The s u s p e n s i o n was f i l t e r e d and the s o l v e n t r e p l a c e d under reduced p r e s s u r e w i t h methanol. The p r o d u c t (6.3g, 99%) was o b t a i n e d as p a l e y e l l o w m i c r o c r y s t a l s MP. 141-142°C A n a l : C a l c . f o r • C 1 3 H 1 4 N 2 ° 2 : C ' 6 6 ' 0 3 ; H ' 6 - 4 7 ; N»- 12.84; Found: C, 65.98; H, 6.45; N, 12.74%. lE NMR: U , CDC1 3); 1.10 ( t , J8Hz, 3H, -CH 2CH 3); 2.02 (s , 3H, -CH. ) ; 2.58 (q, J8Hz, 2H, -CH 2CH 3); 3.81 ( s , 3H, -OCH 3); 6.98 (d, J4Hz, l H , p y r - H ) ; 7.95 ( s , IH, -CH=C-); 9.70 (bs, III, .NH) . 120 2-(2-Cyano-2-methyoxycarbonylvinyl)-3-ethyl-5-iodo-4- methylpyrrole. (104) O Iodine monochloride (9g, 55 mmole) in g l a c i a l acetic acid (50 mL) was added dropwise to a s t i r r e d suspension of 5-(2-cyano-2-methoxycarbonylvinyl)-4-ethyl-3-methylpyrrole -2-carboxylic acid (102) (13g, 50 mmole), anhydrous sodium acetate (15g, 0.18 mole), acetic anhydride (10 mL) and g l a c i a l acetic acid (200 mL) which had been gently heated to 8 0°C. When addition was complete the solution was cooled and water (3 00 mL) added, excess iodine removed with hypophosphorus acid, the s o l i d f i l t e r e d , washed with water and dried. R e c r y s t a l l i s a t i o n from methanol/water gave product (14g, 82%) as yellow needles MP. 163-164°C Anal: Calc. for C 1 2 H 1 3 N 2 ° 2 I : C ' 4 1 - 8 8 ' H ' 3- 8 1'' N / 8.14; I, 36.66: Found: C, 41.92; H, 3.75; N, 8.00; I, 36.66%. X B NMR: ( 6 , CDC13) ; 1.23 (t, J7. 5Hz, 3H, -CH2CH3) ; 2.02 (s, 3H, ~CH 3); 2.64 (q, J7.5Hz, 2H, -CH^CH^); 3.8 8 (s, 3H, -OCH3); 7.86 (s, IH, -H) , 9.65 (bs, IH, NH). 121 2-Bromo-5-(2-cyano-2-methoxycarbonylvinyl)-4-ethyl-3-methyl- pyrrole (105) Bromine (2.3g, 14.4 mmole) i n methylene chloride (30 mL) was added dropwise to a s t i r r e d solution of 2-(2-cyano-2-methoxycarbonylvinyl)-3-ethyl-4 methylpyrrol-2-carboxylic acid (102) (3g, 11.5 mmole), anhydrous potassium carbonate (2g, 2 0 mmole) i n THF (60 mL). The reaction was carried out in the absence of l i g h t and followed by t i c ; at the f i r s t signs of the orange bipyrrole, addition of bromine was ceased and the solution poured into water (100 mL). The product was extracted with methylene chloride and the solvent replaced by methanol under reduced pressure. C r y s t a l l i s a t i o n from methanbl/water gave bright yellow c r y s t a l s of product (2.7g, 80%) MP. 140-141°C Anal: Calc. for C 1 2H 1 3N 20 2Br: C, 48.50; H, 4.41; N, 9.43; Br, 26.89: Found: C, 48.52; H, 4.31; N, 9.32; Br, 26.66%. ^H NMR: ( 6 , CDC1 3); 1.15 (t, J8Hz, 3H, -CH2CH_3); 2.04 (s, 3H, "'CH ) ; 2.6 6 (q, J8Hz, 2H, -CH 2CH 3); 3.91 (s, 3H, -OCH3); 7.94 (s, IH, -H); 9.65 (bs, IH, NH). 122 2 - B r o m o - 4 - e t h y l - 5 - f o r m y l - 3 - m e t h y l p y r r o l e (107) A m i x t u r e o f 2-bromo-5-(2-cyano-2-methoxycarbonylvinyl) — 4 - e t h y l - 3 - m e t h y l p y r r o l e (105) (4g, 13.5 mmole), water (40 mL) and p o t a s s i u m h y d r o x i d e ( l O g , 0-.-1 mmole) was r e f l u x e d under n i t r o g e n f o r 1% hours and the r e a c t i o n o b s e r v e d by v i s i b l e s p e c t r o s c o p y . The s o l u t i o n was a l l o w e d t o c o o l and the p a l e brown s o l i d f i l t e r e d . C r y s t a l l i s a t i o n from m e t h a n o l / water gave the p r o d u c t (2.55g, 88%) as p a l e t a n n e e d l e s . MP. 104.5-105.5°C A n a l : C a l c . f o r CgH-^NOBr: C, 44.44; H, 4.63; N, 6.48; B r , 37.04: Found: C, 44.37; H, 4.53; N, 6.64; B r , 37.00%. ~^"H NMR: C6 , CDC1 3); 1.17 ( t , J7 . 5Hz , 3H, -CH 2CH_ 3); 1.94 ( s , 3H, - C H 3 ) ; 2.70 (q, J7.. 5Hz , 2H, -CH_ 2CH 3); 9.46 (s , l H , —CHO); 10.38 (bs, l H , NH). 123 3 - E t h y l - 2 - f o r m y l - 4 - m e t h y l p y r r o l e (108) A m i x t u r e o f 2 - ( 2 - c y a n o - 2 - m e t h o x y c a r b o n y l v i n y l ) - 3 -e t h y l - 4 - r a e t h y l p y r r o l e (103) (4.4g, 20 mmole), water (100 mL) and p o t a s s i u m h y d r o x i d e (8g, 0.14 mole) was r e f l u x e d under n i t r o g e n f o r 3 hours and the r e a c t i o n o b s e r v e d by v i s i b l e s p e c t r o s c o p y . The s o l u t i o n was then l e f t t o c o o l and the p r o d u c t f i l t e r e d as brown s o l i d i f i e d o i l (2.3g, 83%), r e a c t -i o n s were c a r r i e d o ut w i t h the compound i n t h i s crude form. R e c r y s t a l l i s a t i o n from water/methanol gave an a n a l y t i c a l sample. MP. 7 4-7 5°C A n a l : c a l c . f o r CgH-^NO: C, 70.04; H, 8.08; N, 10.21; Found: C, 70.13; H, 8.15; N, 10.17%. 1 H NMR: (<$;, CDC1 3/TFA); 1.22 ( t , J8Hz, 3H, -CH 2CH 3); 2.06 ( s , 3H, - C H 3 ) ; 2.75 (q, J8Hz, 2H, -CH 2CH 3); 6.87 Cd, J5Hz, IH, p y r - H ) ; 9.62 ( s , I H , -CHO). 124 2-Benzyloxycarbonyl-4-(2-chloroethyl)-3,5-dimethylpyrrole (109) CI H 3C Thionyl chloride (8 mL, 0.11 mole) was added dropwise to a s t i r r e d , r e f l u x i n g mixture of 2-benzyloxycarbonyl-4-(2-hydroxyethyl)-3,5-dimethylpyrrole (94) (lOg, 36.6 mmole), anhydrous potassium carbonate (20g, 0.14 mole) i n methylene chloride (500 mL). The mixture was s t i r r e d and refluxed for 2 hours then f i l t e r e d when cool. The solvent was replaced by methanol under reduced pressure, c r y s t a l l i s a t i o n from methanol gave product (9.8g, 91.8%), as f l u f f y white 6 3 needles MP. 118-118.5°C ( l i t . 121°C) Anal; Calc. for C l 6H 1 8NC10 2: C, 65.86; H, 6.22; N, 4.80; CI, 12.15: Found: C, 66.11; H, 6.00; N, 4.72; CI, 11.95%. lE NMR: (£, CDC1 3); 2.26 (s, 3H, -CH3) ; 2.34 (s, 3H, -CH_3) ; 2.88 (t, J8HZ, 2H, -CH 2CH 2C1); 3.56 (t, J8Hz, 2H, -CH2CH_2C1) ; 5.35 (s, 2H, -CH 2C 6H 5); 7.44 (bs, 5H, -CgH^); 8.76 (bs, IH, NH) . 125 2 - B e n z y l o x y c a r b o n y l - 4 - ( 2 - b r o m o e t h y l ) - 3 , 5 - d i m e t h y l p y r r o l e (110) T h i o n y l bromide (3g, 15 mmole) was added d r o p w i s e t o a s t i r r e d , r e f l u x i n g m i x t u r e o f 2 - b e n z y l o x y c a r b o n y l - 4 -( 2 - h y d r o x y e t h y l ) - 3 , 5 - d i m e t h y l p y r r o l e (94) (3.3g, 12 mmole), anhydrous p o t a s s i u m c a r b o n a t e ( l O g , 70 mmole) i n d i c h l o r o -methane ( 50 mL). The m i x t u r e was s t i r r e d and r e f l u x e d f o r 2 hours then f i l t e r e d when c o o l . The s o l v e n t was r e p l a c e d by methanol under reduced p r e s s u r e ; c r y s t a l l i s a t i o n from methanol gave p r o d u c t (2.58g, 6 5 . 5 % ) , as o f f w h i t e n e e d l e s MP. 124-125°C. A n a l : C a l c . f o r C 1 6 H 1 8 N B r 0 2 : C, 57.15; H, 5.40; N, 4.09; B r , 23.77. Found: C, 56.92; H, 5.38; N, 4.09; B r , 23.84%. 1 H NMR:( 6, CDC1 3) 2.22 ( s , 3H, CH 3) ; 2.30 ( s , 3H, CH_3) ; 2.94 ( t , J7Hz, 2H, CH_ 2CH 2Br) ; 3.77 ( t , J7Hz, 2H, CH 2CH_ 2Br); 5.32 ( s , 2H, C H 2 C 6 H 5 ) ; 7.39 ( s , 5H, CH^CgH^); 9.04 (bs, IH, NH). 126 2 - B e n z y l o x y c a r b o n y l - 4 - ( 2 - b e n z o x y e t h y l ) - 3 , 5 - d i m e t h y l p y r r o l e (111) H 3 C H B e n z o y l c h l o r i d e (20 mL, 0.17 mole) was added t o a s o l u t i o n o f 2 - b e n z y l o x y c a r b o n y l - 4 - ( 2 - h y d r o x y e t h y l ) - 3 , 5 - d i m e t h y l p y r r o l e (94) (25.5g, 93 mmole), p y r i d i n e (30 mL) i n THF (200 mL) the m i x t u r e was s t i r r e d f o r 4 0 m i n u t e s and t h e n poured i n t o water (200 mL). The aqueous phase was e x t r a c t e d w i t h e t h e r , the o r g a n i c phase was e v a p o r a t e d t o d r y n e s s and the s o l i d , suspended i n sodium b i c a r b o n a t e s o l u t i o n o v e r n i g h t . The s u s p e n s i o n was t h e n e x t r a c t e d w i t h methylene c h l o r i d e ; t h e o r g a n i c phase was s e p a r a t e d and the s o l v e n t r e p l a c e d by methanol under reduced p r e s s u r e , c r y s t a l l i s a t i o n from methanol gave w h i t e n e e d l e s (31.5g, 89.7%) MP. 109-110°C A n a l : C a l c . f o r C 2 3 H 2 3 N ° 4 : C ' 7 3 ' 1 9 ; H ' 6- 1 4'' N / 3.71; Found: C, 73.11; H, 6.15; N, 3.81%. NMR: ( 6 , CDC1 3);.2.19 ( s , 3H, "CH ) ; 2.30 ( s , 3H, - C H 3); 2.81 ( t , J7Hz, 2H, -CH 2CH 20-); 4.28 ( t , J7Hz, 2H, -CH 2CH 20-); 5.25 ( s , 2H, -CHjCgHg); 7.34 (m, 5H, -CH^gH^); H H H H  H  7.45 (m, 3H, -CO -jQ" ); 8.01 (dd, J6Hz, 2H, - Q « ) ; 8.85 (bs, IH, NH) H — H W  " H H 127 2-Benzyloxycarbonyl-4-(2-acetoxyethyl)-3,5-dimethylpyrrole (112) Acetic anhydride (20 mL, 0.21 mole) was added to a solution of 2-benzyloxycarbonyl-4-(2-hydroxyethyl)-3,5,-dimethylpyrrole (94) (lOg, 36.5 mmole) i n pyridine (30 mL, 0.37 mole) and the mixture s t i r r e d for 2 hours at room temperature. The solution was then poured slowly into ice water (2000 mL) and the precipitated s o l i d f i l t e r e d o f f . C r y s t a l l i s a t i o n from methanol gave the product (10.6g, 91.9%) as white needles MP. 73-74 C] ( l i t . 73.5-o Anal: Calc. fOr C^H^NC^: C, 68.55; H, 6.71; N, 4.44: Found: C, 68.35; H, 6.75; N, 4.50% 1H NMR: ( 6 , CDC1 3); 2.04 (s, 3H, -CH_3); 2.21 (s, 3H, -CH3) ; 2.32 (s, 3H, -COCH3); 2.71 (t, J7Hz, 2H, -CH2-CH20-); 4.08 (t, J7Hz, 2H, -CH 2CH 20-); 5.32 (s, 2H, -CH^CgH^ ; 7.39 (m, 5H, -C^) ; 9.18 (bs, IH, NH) . 128 2-Benzyloxycarbonyl-4-(3 acetoxypropyl)-3,5-dimethylpyrrole (113 Boron t r i f l u o r i d e etherate (100 mL, 0.79 mole) was added dropwise to a s t i r r e d ice cold suspension of 2-benzyl-oxycarbonyl-4-methoxycarbonylethyl)-3,5-dimethylpyrrole (96) (63g, 0.2 mole), sodium borohydride (20g, 0.53 mole) i n THF (.300 mL) under nitrogen. The reaction was followed by t i c and when complete was quenched by the addition of g l a c i a l acetic acid (.100 mL) followed by water (200 mL) *, the mixture was extracted into methylene chloride and evaporated to dry-ness. The s o l i d was dissolved i n pyridine (60 mL), and treated with acetic anhydride (90 mL); the solution was l e f t to s t i r overnight, poured into ice water (2L) and the pre c i p i t a t e f i l t e r e d . C r y s t a l l i s a t i o n from methanol/water gave product (63.3g, 96%) as fine white needles MP.76-77°C Anal : c a l c . for C i gH 2 3NC> 4: C, 69.28; H, 7.04; N, 4.25: Found: C, 68.99; H, 7.00; N, 4.36%. ^H NMR: ( .6 , CDC1 3); 1.75 (m, J7Hz, 2H, -CH2CH2CH20-) ; 2.03 (s, 3H, ~CH 3); 2.16 (s, 3H, ~CH 3); 2.29 (s, 3H, -OCH3); 2.46 (t, J7Hz, 2H, -CH2CH2CH20-) ; 4.05 (t, J7Hz, 2H, -CH2CH2CH_20 5.32 (s, 2H, -CH 2C 6H 5); 7.39 (m, 5H, -CgH ); 9.31 (bs, IH, NH) . 129 3.4 Synthesis of Chain Linked Pyrroles 1,6-Bis (5-ethyloxycarbonyl-4,2-dimethylpyrrol-3-yl)-1,  6-hexanedione (120) 0 o o H 0 A mixture of adipic acid (21.9g, 0.15 mole) and thionyl chloride (35 mL, 0.49 mole) was heated on a steam bath u n t i l dissolved. Carbon tetrachloride (25 mL) was added and the solvent removed under reduced pressure to remove the excess thionyl chloride. The r e s u l t i n g l i q u i d was added to a solu-tion of 2-ethoxycarbonyl-3,5-dimethylpyrrole (50.lg, 0.30 mole) i n methylene chloride (250 mL) and nitromethane (250 mL). The mixture was s t i r r e d under nitrogen and cooled i n i c e , stannic chloride (75 mL, 0.64 mole) was added dropwise over 1 hour and the solution s t i r r e d for a further hour. The solution was poured into d i l u t e hydrochloric acid (1000 mL), the organic layer separated and washed with water. The solvent was replaced with methanol under reduced pressure*, c r y s t a l l i -sation from methanol gave product (56g, 84.1%) as a white powder. An a n a l y t i c a l sample was r e c r y s t a l l i s e d from CDC1^/TFA/THF washed with dichloromethane MP. 254°C(d). 130 Anal: Calc. for C 2 4 H 3 2 N 2 ° 6 : °' 6 4 ' 8 4 ; H ' 7- 2 6'* N ' 6.30: Found: C, 64.19; H, 7.26; N, 6.08%. 1H NMR: (<5, CDC13/TFA) ; 1.45 (t, J7Hz, 6H, -CH2CH_3); 1.99 (bm, 4H, -COCH2CH_2); 2.65 (s, 12H, -CH 3); 3.07 (bt, 4H, COCH2); 4.49 (q, J7Hz, 4H, -CH 2CH 3); 10.43 (bs, 2H, NH). 131 1 , 8 - B i s ( 5 - e t h y l 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 ) - 1 , 8 -o c t a n e d i o n e . (121) A m i x t u r e o f o c t a n e d i o c a c i d (26. l g , 0.15 mole) and t h i o n y l c h l o r i d e (35 mL, 0.49 mole) was h e a t e d on a s t e a m b a t h u n t i l d i s s o l v e d . C a r b o n t e t r a c h l o r i d e (25 mL) was added and t h e s o l v e n t removed u n d e r r e d u c e d p r e s s u r e t o remove e x c e s s t h i o n y l c h l o r i d e . The r e s u l t i n g l i q u i d was added t o a s o l u t i o n o f 2-e t h y l o x y c a r b o n y l - 3 , 5 - d i m e t h y l p y r r o l ( 5 0 . l g , 0.30 mole) i n m e t h y l e n e c h l o r i d e (250 mL) and n i t r o m e t h a n e (250 mL). The m i x t u r e was s t i r r e d u n d e r n i t r o g e n and c o o l e d i n i c e , s t a n n i c c h l o r i d e (7 5 mL) added d r o p w i s e o v e r 1 hour and t h e s o l u t i o n s t i r r e d f o r a f u r t h e r h o u r . The s o l u t i o n was p o u r e d i n t o d i l u t e h y d r o c h l o r i c a c i d (1000 mL), t h e o r g a n i c l a y e r s e p a r a t e d and washed w i t h w a t e r . The s o l v e n t was r e p l a c e d w i t h m e t h a n o l u n d e r r e d u c e d p r e s s u r e ; c r y s t a l l i s a t i o n f r o m m e t h a n o l gave p r o d u c t (59.9g, 84.6%) as a w h i t e powder MP 178°C(d) A n a l : C a l c . f o r C_,H-,,N_0-: C, 66.08; H, 7.68; N, 5.93: Z D J O 2. D F o u n d : C, 66.35; H, 7.47; N, 5.64%. 1 H NMR: ( 6 , GDCl^/TFA) ; 1.42 ( t , J7Hz, 6H, - O C H 2 C H 3 ) ; 1.79 (bs, 8H, -COCH 2 (CH 2) 4CH 2CO-) ; 1.56 ( s , 6H, -CH_3) ; 1.58 ( s , 6H, ~ C H 3 ) ; 2.85 ( t , J8Hz, 4H, -COCH 2 (CH 2) 4CH_ 2CO-) ; 4.44 (q, J7HZ, 4H, - O C H 2 C H 3 ) . 132 1,10-jBis (5-ethyloxycarbonyl-4 , 2-dimethy 1-3-yl) -1,1:0-decanedione (122). A mixture of sebacic acid (30.3g, 0.15 mole) and th i o n y l -chloride (35 mL, 0.49 mole) was heated on a steam bath u n t i l dissolved. Carbon tetrachloride (25 mL) was added and solvent removed under reduced pressure to remove the excess t h i o n y l -chloride. The r e s u l t i n g l i q u i d was added to a solution of 2-athpxycarbonyl-3,5-dimethylpyrrole (50.lg, 0.30 mole) in methylene chloride (250 mL). The mixture was s t i r r e d under nitrogen and SnCl^ (75 mL, 0.64 mole) was added drop-wise i n J5 hour during which time the product c r y s t a l l i s e d out. The suspension was washed with d i l u t e hydrochloric acid, the pink s o l i d f i l t e r e d and r e c r y s t a l l i s e d from hot acetone to give product (64g, 8 5.1%) as a white powder. MP. 171-17 2 °C. Anal: Calc. for C 2 8 H 4 0 N 2 ° 6 : C ' 6 7 - 1 7 ; H ' 8 - 0 5 ; N<- 5.60: Found: C, 66.80; H, 8.04; N, 5.40%. lE NMR: (5, CDC13/TFA) ; 1.38 (bs, 4H, -COCH2CH2 (CH_2) ) ; 1.45 (t, J7Hz, 6H, -CH 2CH 3); 1.70 (bm, 4H, -COCH2CH_2); 2.61 (.s, 6H, -CH 3); 2.63 (s, 6H, -CH_3); 2.93 (t, J8Hz, 4H, COCH2); 4.47 (q, J7Hz, 4H, -CH 2CH 3); 11.30 (bs, 2H, NH). 133 1,6-Bis(5-ethyloxycarbonyl-2,4-dimethylpyrrole-3-yl)-hexane. (123) Borontrifluoride etherate (70 mL, 0.56 mole) was added dropwise to an ice cold s t i r r e d suspension of l,6-bis(5-ethyloxycarbonyl-2,4-dimethylpyrrol-3-yl)-1,6-hexanedione (.120) (.55g, 0.11 mmole), sodium borohydride (16g, 0.42 mole) in THF (.5 00 mL) under nitrogen. The reaction was checked by t i c for completion and quenched by the dropwise addition of g l a c i a l acetic acid (200 mL). On the addition of water (.150 mL) the product precipitated out, this was f i l t e r e d / redissolved i n hot THF and r e c r y s t a l l i s e d to give product (42.8g, 83.1%) as a white powder MP. 181-183°C. Anal: Calc. for C 2 4 H 3 6 N 2 ° 4 : C ' 69-20"> H / 8.71: N, 6.73: Found: C, 68.92; H, 8.70; N, 6.70%. '''H NMR: (.6, CDCl^TFA) ; 1.35 (bs , 8H, -CH2 (CH2) 4CH 2") ; 1.38 (t, J 7 . 5 H Z , 6H, -CH 2CH 3); 2.24 (s, 6H, CH 3); 2.28 (s, 6H, CH 3); 3.36 (bs, 4H, -CH 2(CH 2) 4CH 2-); 4.36 (q, J7.5Hz, 4H, CH 2CH 3); 9.35 (bs, 2H, NH). 1,8-Bis(5-ethyloxycarbonyl-2,4-dimethylpyrrole-3-yl)-octane (124) Borontrifluoride etherate (70 mL, 0.56 mole) was added dropwise to an ice cold s t i r r e d suspension of l,8-bis(5-ethyloxycarbonyl-2,4-dimethylpyrrol-3-yl)-1,8-octanedione (121) (40g, 85 mmole),sodium borohydride (16g, 0.42 mole) in THF (5 00 mL) under nitrogen. The reaction was quenched by the dropwise addition of g l a c i a l acetic acid (100 mL) and water (500 mL) and extracted with methylene chloride (500 mL). The solution was evacuated to dryness and the s o l i d r e c r y s t a l l -ised from THF to give product (29.9g, 7 9.5%) as white powder MP. 155-157°C. Anal ; Calc. for C 2 6H 4 QN 20 4: C, 70.23; H, 9.07; N, 6.30: Found: C, 70.09; H, 9.15; N, 6.28%. 1H NMR: (6, CDC1_,/TFA) ; 1.28 (bm, 12H, -CH„(CH„),CH„-); 1.33 It, J7Hz, 6H, -OCH2CH3); 2.16 (s , 6H, -CH_3); 2.21 (s, 6H, -CH 3); 2.32 (t, J6Hz, -CH 2(-CH 2) 6CH 2); 4.29 (q, J7Hz, 4H, -OCH2CH3); 9.25 (bs, 2H, NH). 135 1 , 1 0 - B i s ( 5 - e t h y l 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 ) - de-cane (125) Boron t r i f l u o r i d e e t h e r a t e (7 0 mL, 0.56 mole) was added d r o p w i s e t o a room t e m p e r a t u r e , s t i r r e d s u s p e n s i o n o f 1,10-b i s ( 5 - e t h y l 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 ) - 1 , 10-decanedione (122) (35g, 70 mmole), sodium b o r o h y d r i d e (16g, 0.42 mole),, i n THF (500 mL) under n i t r o g e n . The r e a c t i o n was checked f o r c o m p l e t i o n by t i c and quenched by the dr o p -w i s e a d d i t i o n o f g l a c i a l a c e t i c a c i d (100 mL) and water (200 mL). 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 , washed w i t h water and d r i e d . The s o l i d was d i s s o l v e d i n d i c h l o r o m e t h e n e and the s o l v e n t . r e p l a c e d by methanol under reduced p r e s s u r e t o g i v e p r o d u c t (29.5g, 89%) as w h i t e powder MP.143-144°C A n a l : C a l c . f o r C ^ H ^ N . ^ : C, 71.15; H, 9.38; N, 5.93: Found:.C, 70.89; H, 9.41; N, 5.70% 1 H NMR: ( 6 , CDC1 0/TFA) ; 1.28 (bm, 16H, -CH_(CH,J 0CH 0-) ; j z —z o z 1.30 ( t , J7Hz, 4H, OCH 2CH 3); 2.14 ( s , 12H,-CH 3); 2.34 ( t , 4H, -CH 2 (CH 2) 8CH 2~) ; 4.26 (q, J7Hz, 4H, -CH 2CH 3); 8.81 (bs, 2H, NH) . 1,6-Bis(5-benzyloxycarbonyl-2,4-dimethylpyrrol-3-yl)-hexane. (126) 1, 6-Bis („2-ethyloxycarbonyl-3 , 5-dimethylpyrrol-4-yl) -hexane (123) (18.7g, 45 mmole) was dissolved in dry benzyl alcohol (30 mL, 0.29 mole) and heated to reflux under nitrogen. To thi s solution was added 1 mL portions of freshly prepared sodium benzyloxide i n benzyl alcohol u n t i l ethanol evolution ceased. The hot solution was then poured into a s t i r r e d solution of methanol (400 mL), water (.250 mL) and g l a c i a l acetic acid (10 mL) . The precipitated s o l i d was f i l t e r e d , washed and r e c r y s t a l l i s e d from methanol to give product (.22.lg, 91%) as a pink powder MP. 174-176.5°C. Anal: Calc. for c 3 4 H 4 o N 2 ° 4 : C ' 7 5 - 5 2 ' ' H ' 7.46; N, 5.18: Found: C, 75.77; H, 7.51; N, 5.20% 1H NMR: ( 6 , CDCl 3/TFA) ; 1.33 (bs, 8H, -CH2 (CH_2) 4CH 2~) ; 2.20 (s, 6H, -CH 3); 2.25 (s, 6H, -CH 3); 2.35 (t, overlap, 4H, -CH 2(CH 2) 4CH 2-); 5.34 (s, 4H, -CH^CgH^; 7.40 (bs, 10H, "CgH^) 9.4 0 (bs, 2H, NH). 137 1,8-Bis(5-benzyloxycarbonyl-2,4-dimethylpyrrol-3-yl)- octane (127) 1,8-Bis (5-ethyloxycarbonyl-2,4-dimethylpyrrol-3-yl)-octane (124) (17g, 38 mmole) was dissolved i n dry benzyl alcohol (50 mL, 0.5 mole) and heated to ref l u x under nitrogen. To t h i s solution was added 1 mL portions of freshly prepared sodium benzyloxide i n benzyl alcohol u n t i l ethanol evolution ceased. The hot solution was then poured into a s t i r r e d solution of methanol (300 mL), water (100 mL) and acetic acid (20 mL). The precipitated s o l i d was f i l t e r e d washed and r e c r y s t a l l i s e d from methylene chloride/methanol to give product (19.5g, 89.7%) as of f white powder MP. 133.5-135°C. Anal: Calc. f or C 3 5 H 4 4 N 2 0 4 : C / 7 6- 0 2'" H ' 7-80; N, 4.93: Found: C, 7 5.96; H, 7.70; N, 4.90%. 1 H NMR: ( 5, CDCl.,) 1.25 (bs, 12H, -CH -(CH~),-CH„); 2.08 3 2 — z 6 Z (s, 6H, -CH 3); 2.2 0 (s, 6H, -CH 3); 2.30 (t, overlap, 4H, -CH2 (CH2) 6CH 2-) ; 5.22 (s, 4H, -CH^CgH^; 7.30 (m, 10H, CgH^) ; 8.99 (bs, 2H, NH) . 138 1,10-Bis(5-benzyoxycarbonyl-2,4-dimethylpyrrol-3-yl)-decane (128) 1,10-Bis(5-ethyloxycarbonyl-2,4-dimethylpyrrol-3-yl)-decane (125) (18g, 38 mmole) i n dry benzyl alcohol (75 mL, 0.75 mole) and heated to reflux under nitrogen. To th i s solution was added 1 mL portions of freshly prepared sodium benzyloxide i n benzyl alcohol u n t i l ethanol evolution ceased. The hot solution was poured into s t i r r e d methanol (500 mL) containing acetic acid (25 mL) and when cool,water (200 mL) was added. The s o l i d was f i l t e r e d , dried and r e c r y s t a l l i s e d from methanol to give product (21.8g, 95.9%) as white powder MP. 142.5-144°C. Anal: Calc. for C 3 8 H 4 8 N 2 0 4 : C, 76.47; H, 8.11; N, 4.69: Found: C, 76.59; H, 8.30; N, 4.60%. NMR: (6, CDC13/TFA) ; 1.29 (bs, 16H, -CH2" (CH_2) g-CH^-) 2.23 (s, 6H, -CH 3); 2.27 (s, 6H, -CH_3) ; 2.36 (t, overlap, 4H, -CH2 (CH2) gCH -) ; 5.36 (s, 4H, -CH^CgHg); 7.41 (s, 10H, C gH 5); 9.47 (bs, 2H, NH). 13 3.5 Synthesis of Methenes 5'-Bromo-4-(2-chloroethyl)-3'-ethyl-3,4',5-trimethyl-2-(2H-pyrrol-2 ''-ylidenemethyl) pyrrole hydrobromide (146) 2-Benzyloxycarbonyl-4-(2-chloroethyl)-3,5-dimethylpyrrole (.109) (3g, 10.3 mmole), 10% palladium on charcoal (1 . 3g.) was hydrogenated i n tetrahydrofuran u n t i l uptake of hydrogen ceased (24 0 mL). 2-Bromo-4-ethyl-5-formyl-3-methylpyrrole (107) (2.3g, 10.6 mmole) was added, the solution f i l t e r e d and 48% hydrobromic acid (10 mL) was added followed by methanol (50 mL). The solution was concentrated under reduced pressure and the product (3.3g, 7 3.5%) obtained as orange/red c r y s t a l s MP. 200°C(d). The remaining solution was placed i n the r e f r i g e r a t o r overnight and product (lg, 22.3%) obtained as deep purple c r y s t a l s . The two were shown to be i d e n t i c a l by analysis and nmr. Anal ; Calc. for C 1 6H 2 1N 2Br 2C1: C,44.01; H, 4.85; N, 6.42; Br, 36.61; CI, 8.12: Found: C, 44.57; 44.62; H, 4.93, 4.95; N, 6.38, 6.40; Br, 36.16; CI. 8.26%. NMR:(ft, CDC1 3); 1.22 (t, J8Hz, 3H, -CH^CH^); 2.06 (s, 3H, -CH 3); 2.38 (s, 3H, -CH 3); 2.69 (s, overlap, -CH3); 2.70 (q, overlap, -CH_2CH3) ; 2.93 (t, J7Hz, 2H, -CH 2CH 2C1); 3.64 (t, J7H 2H, -CH 2CH 2C1); 7.19 (s, IH, -CH=); 12.29 (bd, 2H, NH). 140 4-(2-Acetoxyethyl)-3'-ethyl-3 /4',5-trimethyl-2-(2H-pyrrol-2'-ylidenemethyl) pyrrole hydrobromide (150) A suspension of 2-benzyloxycarbonyl-4-(2-acetoxyethyl)-3, 5-dimethylpyrrole (112) (4.5g, 14.3 mmole), 10% palladium on charcoal (0.4g), triethylamine (2 drops) i n THF (200 mL) was hydrogenated u n t i l uptake of hydrogen ceased (360 mL). To th i s mixture was added 4-ethyl-5-formyl-3-methylpyrrole (108) (2.74g, 20 mmole) and the solution f i l t e r e d under vacuum* the r e s u l t i n g solution was treated with 48% hydrobromic acid (5 mL), the solution turned a dark yellow almost immed-i a t e l y . The solvent was then replaced with methanol under reduced pressure, c r y s t a l l i s a t i o n gave product (4.4g, 80.9%) as red orange c r y s t a l s MP. 148-149Cd)°C. Anal: Calc. for C 1 8H 2 5N 20 2Br: C, 56.69; H, 6.61; N, 7.35; Br, 20.96: Found: C, 56.76; H, 6.57; N, 7.10; Br, 21.00%. 1H NMR: ( 5 , CDC13/TFA); 1.17 (t, J7.5Hz, 3H, -CH 2CH 3); 1.98 (s, 3H, -CH_3) ; 2.03 (s, 3H, -CH_3); 2.36 (s, 3H, 0OCH_3); 2.63 (s, 3H, ~CH_3) ; 2.75 (m, overlap, 4H, -CH2CH3 and -CH_2CH20-) ; 4.10 (t, J 6 . 5 H Z , 2H, -CH2CH_20-) ;. 6.81 (s, lH, -CH=) ; 7.44 (d, J3Hz, pyr-H); 12.83 (bs, IH, NH); 13.00 (bs, IH, NH). 141 4-(3-Acetoxypropyl)-3'-ethyl-3,4',5-trimethyl-2-(2H-pyrrol-2'-ylidenemethyl)pyrrole hydrobromide (153) 2-Benzyloxycarbonyl-4-(3-acetoxypropyl)-3,5-dimethyl-2-(2H-pyrrol-2'-ylidenemethyl)pyrrole hydrobromide (113) (3.29g, 10 mmole), 10% palladium on charcoal (0.33g) i n THF (200 mL) was hydrogenated u n t i l hydrogen uptake ceased (500 mL). 4-Ethyl-5-formyl-3-methylpyrrole (108) (1.4g, 10.2 mmole) was added, the solution f i l t e r e d and 48% hydrobromic acid (2 mL) added. Ethyl acetate (3 0 mL) was added and the solution concentrated under reduced pressure; the product (3.48g, 88%) c r y s t a l l i s e d as bright orange c r y s t a l s MP.148°C(d) Anal; Calc. for C 1 9H 2 7N 2B r 0 2: C, 57.22; H, 6.88; N, 7.09; Br, 20.21: Found: C, 57.68; H, 6.85; N, 7.05; Br, 20.11%. ^H NMR; (<$, CDC1 3); 1.16 (t, J8Hz, 3H, -CH2CH_3); 1.76 (m, J7.5HZ, 2H, -CH2CH2CH20) ; 2.04 (s, 6H, -CH_3 and -C0CH_3) ; 2.28 (s, 3H, -CH 3); 2.50 (t, J7.5HZ, 2H, -CH_2CH2CH20) ; 2.67 (q, J8Hz, 2H, -CH 2CH 3); 2.68 (s, 3H, -CH3); 4.05 (t, J7.5HZ, 2H, -CH 2CH 2CH 20); 7.15 (s, IH, -CH=); 7.54 (d, J4Hz, IH, pyr-H); 13.02 (bs, IH, NH); 13.2 0 (bs, IH, NH). 14 2 5'-Bromo-5-bromomethyl-3'-(2-chloroethyl)-3,4'-dimethyl-2- (2H-pyrrol-2'-ylidenemethyl)pyrrole hydrobromide (155) 2-Benzyloxycarbonyl-4-(2-chloroethyl)-3,5-dimethylpyrrole (109) (2.63g, 9 mmole), 10% palladium on charcoal (0.25g) were hydrogenated in THF (2 00 mL) u n t i l hydrogen uptake ceased (460 mL). 2-Bromo-4-ethyl-5-formyl-3-methylpyrrole (107) (2g, 9.2 mmole) was added, the solution f i l t e r e d and 48% hydrobromic acid (10 mL) added. Methanol (50 mL) was added and the solution concentrated under reduced pressure; the product (3.85g, 83.2%) c r y s t a l l i s e d as deep red c r y s t a l s MP 150°C(d) Anal: (calc. for C, CH„ „N„Br 0Cl • *sHBr: C, 34.56; H, 3.63; l b zu z J N, 5.04; Br, 50.31; CI, 6.38: Found: C, 34.35; • r H, 3.56; N, 4.81; Br, 50.09; CI, 6.44%. -''H NMR: (6, CDC1 3); 1.20 (t, J7 . 5Hz, 3H, -CH2CH_3); 2.04 (s , 3H, -CH 3); 2.36 (s, 3H, -CH_3) ; 2.75 (q, J7. 5Hz, 2H, -CH2CH3) ; 2.99 (t, J7Hz, 2H, CH 2CH 2C1); 3.67 (t, J7Hz, 2H, CH2CH_2C1) ; 4.90 (s, 2H, CH 2Br); 7.18 (s, IH, -CH=); 7.48 (bs, IH, NH). 143 4-(2-Acetoxyethyl)-5'-bromO-5-brOmOmethyl-3'-ethyl-3,4'-dimethy1-2- :(2H-pyrrol-2'-ylidehemethy1)pyrrole hydrobromide (156) 4-(2-Acetoxyethyl)-3 1-ethyl-3,4 1,5-trimethyl-2-(2H-pyrrol-2 1-ylidenemethyl)pyrrole hydrobromide (150) (1.5g, 4 mmole) was dissolved i n 1,2 dichloroethane (12mL) and t r i f l u o r a c e t i c acid (4 mL) , bromine (.2g, 11 mmole) was added and the mixture l e f t protected from moisture for 5 days. The solvent and excess bromine was removed under vacuum, and the r e s u l t i n g s o l i d dissolved i n dichloroethane (20 mL). This solution was cooled i n ice and ethyl.ether. (10 mL) added slowly with swirling; petroleum ether (10 mL) was then added slowly u n t i l c r y s t a l l i s a t i o n of the product (2.05g, 97%) as dark red/purple c r y s t a l s occurred. The product was washed with ether and dried. MP. 177(d)°C. Anal: Calc. for C 1 8H" 2 3N 2Br £> 2 : C, 40.10; H, 4.30; N, 5.20; Br, 44.47. Found: C, 39.20; H, 4.10; N, 4.92; Br, 44.80%. '''H NMR: (6, CDC13/TFA) ; 1.24 (t, J 7 . 5 H Z , 3H, CH2CH3) 2.10 (s, 3H, CH3) ; 2.17 (s, 3H, COCH_3); 2.39 (s, 3H, CH_3); 144 2.82 (q, J7.5H.Z, 2H, CH 2CH 3); 2.95 (t, J7Hz, 2H, CH2CH2~0) ; 4.33 (t,.J7Hz, 2H, CH2CH_20) ; 4.86 (s, 2H, CH_2Br) ; 7.32 (s, IH, =CH-); 12.99 (bd, 2H, NH). 14 5 4-(3-Acetoxypropyl)-5'-bromo-5-bromomethyl-3,4~dimethyl-2- (2H-pyrrol-2'-ylidenemethyl)pyrrole hydrobromide (158) 4-(.3-Acetoxypropyl)-3 '-ethyl-3 ,4 ' , 5-trimethyl-2- (2H -pyrrol-2'-ylidenemethyl)pyrrole hydrobromide (153) (2g, 5.1 mmole) was dissolved i n 1,2-dichloroethane (14 mL) and t r i f l u o r a c e t i c acid (7 mL) bromine (4g, 25 mmole) was added and the mixture l e f t protected from moisture for 5 days. The solvent and excess bromine were removed under-vacuum, and the r e s u l t i n g s o l i d dissolved i n 1,2-dichloro-ethane (15 mL); cyclohexene (5 mL) was added followed by ethyl ether (10 mL) and the solution cooled i n i c e . Petroleum ether (30 mL) was then added slowly with s t i r r i n g , the product (2.49g, 89%) bing obtained as dark red c r y s t a l s MP. 172(d)°C. Anal: Calc. for C, „H O I-N oBr^0 o : C, 41.25; H, 4.56; N, 5.06; ± y Z D Z j Z Br, 43.34: Found: C, 40.95; K, 4.41; N, 5.00; Br, 43.11%. ^ NMR: ( 6, CDC13/TFA) ; 1.16 (t, J8Hz,, 3H, -CH2CH_3); 1.92 (m, 2H, CH2CH_2CH20) ; 2.04 (s, 3H, -COCH_3); 2.08 (s, 3H, -CH 3); 2.30 (s, 3H, -CH 3); 2.60 (t, overlap, -CH 2CH 2 C H2 0) ; 2.75 (q, J8Hz, -CH_2CH3); 4.12 (t, J6Hz, -CH2CH2CH20) ; 4.85 (s, 2H, -CH 2Br); 7.19 (s, IH, -CH=); 13.42 (bs, 2H, NH). 14 6 3.6 Synthesis of Chain Linked Methenes 1,6-Bis{3'-ethyl-3,4',5-trimethyl-2-(2H-pyrrol-2'-ylidenemethyl) pyrrol-4-yl}-hexane dihydrobromide (138) H , C 1,6-Bis(2-benzyloxycarbonyl-3,5-dimethylpyrrol-4-yl)-hexane (126) (2.7g, 5 mmole), 30% palladium on charcoal (O.lg) were hydrogenated i n THF (250 mL) u n t i l hydrogen uptake ceased (250 mL). 4-Ethyl-5-formyl-3-methylpyrrole (108) (1.5g, 11 mmole) was added, the solution f i l t e r e d and the solvent removed under reduced pressure. The s o l i d was dissolved i n methanol (50 mL) and 48% hydrobromic acid (4 mL) added. The solution was concentrated under reduced pressure; the p r e c i p i t a t e formed was f i l t e r e d and washed with 20% methanol/ethyl ether to y i e l d (2.85g, 84.8%) red brown c r y s t a l s MP. 189°C(d). Anal; Calc. for C ^ H ^ ^ B r ^ C, 60.71; H, 7.19; N, 8.33; Br, 23.76: Found: C, 60.66; H, 7.16; N, 8.14; Br, 23.87%. '''H NMR: (&, CDC13/TFA) ; 1.20 (t, J8Hz, 6H, -CH2CK_3); 1.36 (bs, 8H, -CH,2 (CH2) 4CH2_^; 2.0 9 (s, 6H, ~CH 3); 2.31 (s, 6H, -CH 3) ; 2.44 (t, J7Hz, 4H, -CH_2 (CH2) 4CH 2 ) ; 2.67 (s, 6H, -CH 3); 2.71 (q, J8Hz, 4H,-CH2CH3); 7.20 (s, 2H, -CH=); 7.56 (d, J3.5HZ, 2H, pyr-H), 12.62 (bs, 2H, NH); 12.78 (bs, 2H, NH) 147 1,8-Bis{ 3'-ethyl-3,4',5-trimethyl-2-(2H-2'-ylidenemethyl) pyrrol-4-yl}-octane dihydrobromide (139) 1,8—Bis(2-benzyloxycarbonyl-3,5-dimethylpyrrol-4-yl)-octane (127) (.2g, 3.5 mmole), 10% palladium on charcoal (0.2g) was hydrogenated i n THF (200 mL) u n t i l hydrogen uptake ceased (200 mL). 4-Ethyl-5-formyl-3-methylpyrrole (1.3g, 9.5 mmole) was added, the solution f i l t e r e d , and 48% hydrobromic acid (5 mL) was added followed by methanol (50 mL).. ,'The 'solution was concentrated under reduced pressure and the product (2.4g, 95.3%)/obtained as red brown c r y s t a l s , was washed with 20% methanol/ethyl ether. MP. 200°C(d). Anal: Calc. for C 3 6 H 5 2 N 4 B r 2 : C, 61.71: H, 7.48; N, 8.00; Br, 27.81: Found: C, 61.54; H, 7.47; N, 7.81; Br, 22.99%. NMR: (6, CDC1 3): 1.2 0 (t, J8Hz, 6H, -CH2CH_3); 1.32 (bs, 12H, -CH2 (CH_2) 6CH 2~) ; 2.09 (s, 6H, -CH3) ; 2.31 (s, 6H, OCH3); 2.44 (t, J7Hz,4HrPH2(CH2) 6CH 2-) ; 2.71 (s, 6H, -CH3) ; 2.72 (q, J8Hz, 4H, -CH 2CH 3); 7.18 (s,2H>-CH=); 7.54 (d, J3.5Hz, IH, pyr-H); 12.97 (bs, 2H, NH); 13.17 (bs, IH, NH). 148 l,10-Bis{ 3'-ethyl-3,4',5-trimethyl-2-(2H-pyrrol-2'-ylidenemethyl) pyrrol-4-yl }-decane dihydrobromide. (140) 1,10-Bis (2-benzyloxycarbonyl-3,5-dimethylpyrrol-4-yl)-decane (128) (5.96g, 10 mmole), 10% palladium on charcoal (0.5g) was hydrogenated in THF (200 mL) u n t i l hydrogen uptake ceased (500 mL). 4-Ethyl-5-formyl-3-methylpyrrole (108) (2.9g, 21 mmole) was added and the solution f i l t e r e d ; 48% hydrobromic acid (5 mL) was added i n methanol (5 mL) followed by ethylacetate (50 mL). The solution was concent-rated under reduced pressure and the product (7g, 96%) obtained as a dark brown powder, washed with ethyl acetate MP. 17 9°C(d). Anal: Calc. for C 3gH 5 &N 4Br 2: C, 62.63; H, 7.75; N, 7.53; Br, 21.93; Found: C, 62.53; H, 7.65; N, 7.69; Br, 21.85%. ,:LH. NMR: (6, CDC1 3); 1.20 (t, J8Hz, 6H, -CH 2CH 3); 1.29 (bs, 16H, -CH (CH 2) gCH 2-); 2.09 ( s, 6H, -CHg); 2.31 (s, 6H, -CH3); 2.43 (t, J7Hz, 4H, -CH2 (CH2)gCH^-) ; 2.70 (s, 6H, -CH_3); 2.71 (q, J8Hz, 4H, -CH_2CH3); 7.18 (s, 2H, -CH=) ; 7.54 (d, J2Hz, pyr-H); 13.00 (bs, 2H, NH); 13.20 (bs, 2H, NH). C H 3 C H 3 H 3 C 14 9 1,10-Bis{ 5 ' -bromo-5-bromome-thyl-3 ' -ethyl-3., 4 ' -dimethyl-2-(2H-pyrrol-2'-ylidenemethyl)pyrrol-4-yl}decane dihydrobromide (159) Bromine (l.Og, 6.3 mmole) was added to a solution of 1,10-bis(3 1-ethyl-3,4 1,5-trimethyldipyrromethen-4-yl)-decane dihydrobromide (14 0) (l.Og, 1.4 mmole) i n 30% TFA/ 1, 2Tr,dichloroethane (25 mL) and l e f t for 4 days. To t h i s solution was added, slowly with swirling, a mixture of cyclohexene (5 mL) and ethylether (15 mL). Dark red/purple c r y s t a l s formed without cooling; pet. ether (10 mL) was added to ensure complete c r y s t a l l i s a t i o n . The product (1.41g, 98.4%) was f i l t e r e d , washed with pet. ether and dried. MP. 190°C(d). Anal: Calc. for C 3 g H 5 2 N 4 B r 6 : C, 43.70; H, 5.02; N, 5.37; Br, 45.91; Found: C, 43.59; H, 5.16; N, 5.30; Br, 46.13%. 1H NMR: (400 MHz) (6, CDC13/TFA) 1.21 (t, J8Hz, 6H, CH2CH_3); 1.28, 1.32 (bd, 12H, CH 2CH 2(CH 2) 6CH 2CH 2); 1.52 (bs, 4H, CH 2CH 2(CH 2) gCH 2CH 2); 2.07 (s, 6H, CH 3); 2.29 (s, 6H, CH 3); 2.49 (t, J.7Hz, 4H, CH_2 (CH2) gCH 2) ; 2.74 (q, J8Hz, 4H, CH 2CH 3); 4.79 (s, 4H, CH 2Br); 7.15 (s, 2H, =CH-); 12.91,-. 12.96 (s, 4H, NH). 3.7, Synthesis of Model Porphyrin 2,12,17-Triethyl-3,8,13rlS-tetramethyl-^- Cpent^-yne) porphine (171) 3-Bromopropylporphine (175) (90mg, 0.16 mmole) was dissolved in DMSO (25 mL) and treated with excess lithium acetylide ethylenediamine under an i n e r t atmosphere and s t i r r e d for 2 hours protected from moisture. The reaction was quenched by pouring into water and extracting with dichloromethane. The solution was evaporated to dryness, the s o l i d redissolved i n dichloromethane and column chromatographed on a c t i v i t y IV s i l i c a g e l , using . -. . " dichloromethane, as eluent. The product (55mg, 67.6%) was c r y s t a l l i s e d from dichloromethane/methanol. Anal: Calc. for C 3 5H 4 0N 4: C f 81.35; H, 7.80; N, 10.84: Found: C, 81.56; H, 7.74; N, 10.84%. 1H NMR: (400 MHz) ( <5, CDC13/TFA) ; 1.70 (t, J7.5HZ, 9H, -CH 2CH 3); 2.38, 2.41 and 2.47 (overlap, 5H, CH2CH2CH2C3CH) 3.80 and 3.81 (2s, 12H, CH 3); 4.27 (q, J7.5Hz, 6H, -CH2CH3) 4.43 (t, J7Hz, 2H, CH_2 (CH2) 2C=CH) ; 10.69 (s, 3H, meso H) ; 10.83 (s, IH, meso H). V i s i b l e Spectrum (CH 2C1 2) : A (nm) 397 497 530 566 620 max peak r a t i o 36.43 2.86 2.04 1.36 1.00 152 2-(3-Acetoxypropyl)-7,12,17-triethyl-3,8,13,18-tetra- methylporphine (17 2) CH 3 Cyclohexene (2 mL) was added to a solution of.' 5'-bromo-5-bromomethyl-4,3'-diethyl-3,4 1-dimethyldipyrromethene hydrobromide (173) (2.90g, 6.0 mmole) i n dry dichloromethane (100 mL) and the solution evaporated to dryness under reduced pressure. The r e s u l t i n g s o l i d and 4-(3-acetoxypropyl)-3 1-ethyl-3,4',5-trimethyldipyrromethene hydrobromide (153) (1.97g, 5.0 mmole)were dissolved i n dry dichloromethane (100 mL) and treated with stannic chloride ( 3 mL). After standing for 1% hours the bright orange/red solution was quenched with 48% hydrobromic acid (10 mL) i n methanol (5 mL). The solution was washed with water (100 mL x 3) and treated with 48% hydrobromic acid (5 mL), ethyl acetate (50 mL) and methanol (50 mL). The dichloromethane was removed under reduced pressure and the dark red/brown pr e c i p i t a t e (3.2g) formed, f i l t e r e d , washed with ether/ pet. ether and dried. The biladiene was dissolved i n pyridine (25 mL) and DMSO (100 mL) and l e f t in the dark open to the atmosphere 153 for 5 days. The porphyrin (1.553g, 56.6%) was f i l t e r e d , washed with methanol and drie d . An a n a l y t i c a l sample was prepared by column chromatography on a c t i v i t y IV s i l i c a gel using dichloromethane as solvent due to some deprotection of hydroxypropyl f u n c t i o n a l i t y . Anal: Calc. for C 3 5 H 4 2 N 4 0 2 : C ' 7 6 - 3 3 ' H ' 7-69; N, 10.17: Found: C, 76.55; H, 7.69; N, 10.16%. 1H NMR: (400MHz) (5, CDC13/TFA) : 1.68 (t, J8Hz, 9H,-CH2CH_3); 2.15 (s, 3H, -COCH3); 2.41 (m, J7Hz, 2H, -CH2CH2CH2-0-); 3.58 (s, 12H, -CH 3); 4.04 (q, J8Hz, 6H, -CH 2CH 3); 4.12 (t, J7Hz, 2H, -CH 2CH 2CH 2-0-); 4.30 (t, J7Hz, 2H, -CH 2CH 2CH 2-0); 10.53, 10.54 (2s, 4H, -H). 1 3 C NMR: (<5, 5% TFA/CDC13): 171.34 (IC, -COO-); 143.62, 142,47, 142.03, 141.53, 140.42, 137.45, 136.91 (16C, - and - p y r r o l i c carbons); 98.21 (4C, meso-carbons 5T,.10-, 15-and 20-C); 63.66 (IC, -CH 2CH 2CH 2-0-); 30.93 (IC, -CH2CH2-CH2-0-); 23.07 (IC, -CH2CH2CH2-0-) ; 20.94 (IC, CH_3 CO); 20.08 (3C, -CH 2CH 3); 16.42 (3C, -CH 2CH 3); 11.74 (4C, B- CH 3). V i s i b l e Spectrum (CH 2C1 2) : > (nm) 397 497 530 516 619 max peak r a t i o 31.2 2.66 1.93 1.3 1 154 2-(3-Bromopropyl)-7,12,17-triethyl-3,8,13,18- t e t r a m e t h y l p o r p h i n e . (17 5) CH 3 Method A 3 - A c e t o x y p r o p y l p o r p h i n e (172) (250mg, 0.45 mmole) was r e f l u x e d i n 48% hydrobromic a c i d (15' mL) and s u l f u r i c a c i d (2 mL) f o r 3 h o u r s . The r e a c t i o n was checked by t i c and found t o be i n c o m p l e t e ; f u r t h e r r e f l u x d i d n o t appear t o improve the y i e l d and the r e a c t i o n was thus quenched by washing w i t h water (30 mL) and e x t r a c t i n g w i t h d i c h l o r o -methane (30 mL). The e x t r a c t was washed w i t h water u n t i l n e u t r a l and the s o l v e n t removed under reduced p r e s s u r e . The p r o d u c t (200mg, 77%) was chromatographed on a c t i v i t y IV s i l i c a g e l w i t h 2% m e t h a n o l / d i c h l o r o m e t h a n e as e l u e n t . I n c r e a s i n g methanol c o n t e n t e n a b l e d the r e c o v e r y o f 3-hydroxy-p r o p y l p o r p h i n e (50mg, 21.6%). Method B The p r o d u c t was produced by t h e t r i p h e n y l p h o s p h i t e d i b r o m i d e method used f o r compound (181) u s i n g 3-hydroxy-p r o p y l p o r p h i n e (174) (50rng, 98 mmole) and t r i p h e n y l p h o s p h i t e 155 dibromide (150mg, 300 mmole), y i e l d i n g 3-bromopropyl-porphinato zinc (175a) (53mg, 85%). Anal: Calc. for C 3 3H 3 9N 4Br-H 20: C, 67.22; H, 7.01; N, 9.50; Br, 13.55. Found: C, 67.19; H, 6.79; N, 9.47; Br, 13.44%. 1H NMR: (400 MHz) (6, CDC1 3/TFA). 1.75 (t, J7.5Hz, 9H,-CH2CH3); 2.48 (m, J7.5HZ, 2H, -CH 2CH 2CH 2Br); 3.66 and 3.68 (2s, 12H, ~CH 3); 4.15 (q, J7.5HZ, 6H, -CH 2CH 3); 4.21 (t, J7.5Hz, 2H, -CH 2CH 2CH 2Br); 4.38 (t, J7.5Hz, 2H, -CH_2CH2CH2Br) ; 10.62 and 10.63 (2s, 4H, meso -H). 1 3 C NMR: (<5, 5% TFA/CDC13): 144.531, 144.482, 144.434, 142.698, 142.650, 142.516, 142.104, 141.922, 141.788, 141.606, 140.830, 138.415, 138.136, 137.736, 137.699 (16C, a- and 3- carbons); 98.882, 98.518 (4C, meso carbons 5-, 10-, 15- and -20C); 34.461, 33.102 (2C, -CH 2-CH 2CH 2CH 2Br); 24.608 (IC, -CH 2CH 2CH 2Br); 20.191 (3C, -CH 2CH 3); 16.284 (3C, -CH 2-CH 3); 11.989, 11.819, 11.746 (4C, 3-CH3). V i s i b l e Spectrum (CH 2C1 2): A (nm) 397 497 531 566 620 max peak r a t i o 35.60 2.92 2.05 1.40 1.00 156 2,12,17-Triethyl-3,8,13,18-tetramethyl  7-(pent-3-yne)porphine (176) The r e a c t i o n was c a r r i e d o u t on (175) (50mg, 0.087 mmole) as f o r (171) b u t the r e a c t i o n was heated t o 50°C o v e r n i g h t . The p r o d u c t (42.5mg, 94.1%) was found t o have i d e n t i c a l a n a l y s i s , v i s i b l e s p e c t r a , and p a r e n t mass t o the pent-4-yne p o r p h i n e (171) . Assignment was by "*"H NMR. 1 H NMR: (<5, CDC1 3) -3.81 ( s , 2H, NH) , 1.77 ( t , J2Hz, 3H, C CCH 3) ; 1.85 ( t , J7 . 5Hz, 9H, CH 2CH_ 3); 3.05 (m, J2Hz, J7Hz, 2H, CH 2CH 2C=CCH 3); 3.61 and 3.63 (2s, 12H, C H 3 ) ; 4.07 (q, J7.5Hz, 6H, -CH_ 2CH 3); 4.24 ( t , J7Hz, 2H, CH 2CH 2C=C-) ; 10.07 ( s , 4H, meso H). 3.8 Synthesis of Singly Linked Porphyrins l b 1 Bis. 1,10 - (17 ,12 ,17 - t r l e thy 1 - 3 ,8 ,13 ,18 - te trame thy lporphin- 2 -y 1) deca-4,6-diyne (17 7) To a solution of (171) (15mg, 0.03 mmole) i n dichloro-methane (10 mL) was added saturated solution of zinc acetate i n methanol. The solution was washed with water (2 x 2 0 mL) and the solvent removed under reduced pressure. The s o l i d was dissolved i n pyridine (10 mL) and methanol (5 mL), cuprous chloride (20mg) and TMEDA (1 mL) were added and resultant solution bubbled with oxygen while s t i r r i n g , the solution was heated to 4 5°C and l e f t overnight. Tic showed a fas t running band of s t a r t i n g material with a slower running band which also fluoresced a f t e r 6 hours. After 18 hours the slower running band was stronger than the f i r s t but af t e r 24 hours no further change seemed obvious thus the reaction was quenched with water (50 mL) and extracted with dichloromethane (50 mL). The organic phase was washed with water (2 x 30 mL) and sat. sodium chloride 158 solution (30 mL). The solvent was removed under reduced pressure and the product chromatographed on a c t i v i t y IV s i l i c a gel eluted with dichloromethane. The product (9.5mg, 56.5%) was c r y s t a l l i s e d from dichloromethane/pet. ether. V i s i b l e Spectrum (CH 2C1 2) : A (nm) max . peak r a t i o 397 498 531 31.07 2.80 2.04 567 620 1.39 1.00 Mass Spectrum: (177a) ISOTOPE COMBINATION PATTERN FOB THE MOLECUUi / ION (17 7a) C70 H74 N 8 ZN 2 A c t u a l s p e c t r u m * * * Computer s i m u l a t i o n PEAK MASS NOMINAL MASS OF MOST ABUNDANT PEAK -115B 159 Bis 1, 8{ 12 - ("2-ace foxy ethyl)-7,17-diethy1-3,8,13,18- tetramethylpOrphin-2-yl} octane (16 9) C H 3 AcO OAc C H 3 C H 3 Cyclohexene (3 mL) was added to a solution of 4-(2-acetoxyethyl)-5'-bromo-5-bromomethyl-3 1-ethyl-3,4'-dimethyldipyrromethene hydrobromide (156) (1.45g, 2.7 mmole) in dry dichloromethane (50 mL). The solution was evaporated to dryness under reduced pressure. The resultant s o l i d and 1,8-bis(3 1-ethyl-3,4 1-5-trimethyldipyrromethene-4-yl)octane dihydrobromide (139) (0.9g, 1.3 mmole)were dissolved i n dry dichloromethane (100 mL), treated with stannic chloride (3 mL) and l e f t to stand, protected from moisture for 1% hours. The reaction was quenched by the addition of 48% hydro-bromic acid (10 mL) and water (50 mL). The organic phase was separated and washed with water (2 x 100 mL). To the organic phase was added 48% hydrobromic acid (5 mL) and methanol (50 mL), the dichloromethane was removed under reduced pressure and the precipitated biladiene was f i l t e r e d 160 and washed with ethyl acetate. The biladiene was dissolved i n DMSO (65 mL) and pyridine (5 mL), the solution was allowed to stand i n the dark open to the a i r for 5 days. The product (0.88g, 61.8%) was f i l t e r e d , washed with methanol and dried. Anal: Calc. for C^HggNgC^: C, 76.67; H, 7.69; N, 9.94. Found: C, 7 6.50; H, 7.77; N, 9.74%. 1H NMR: (270 MHz) ( fi, CDC13/TFA), 1.35 (bs, 4H, -(CH 2) 3 (CH2) 2 (CH 2) 3-) ; 1.55 (bs, 4H, - (CH2) 2CH_2 (CH2) 2GH 2 (CH^ 2~) ; 1.70 (m, 10H, overlap CH 2CH 3 & -CH 2CH 2(CH 2) 4CH 2CH 2-); 2.04 (s, 6H, COCH3); 3.59 (s, 12H/CH_3); 3.66 (s, 6H, CH_3); 3.69 (s, 6H, CH_3) ; 4.10 (m, 12H, overlap -CH_2 (CH2) 6CH 2~ & CH 2CH 3); 4.59 (t, J6.5Hz, 4H, CH 2CH 20-); 4.96 (t, J6.5Hz, 4H, CH 2CH 20-); 10.59, 10.61, 10.66, 10.72 (s, 4H, meso H). V i s i b l e Spectrum (CH 2C1 2) X (nm) 397 497 533 567 620 max peak r a t i o 42.66 3.22 2.38 1-61 1.00 161 B i s l,8-{ 1 2 - ( 2 - b r o m o e t h y l ) - 7 , 1 2 - d i e t h y l - 3 , 8 , 1 3 , 1 8 - t e t r ame t h y 1 p o r p h i n - 2 - y 1 } - o c fane (170) B i s 1,8- 1 2 - ( 2 - a c e t o x y e t h y l ) - 7 , 1 7 - d i e t h y l - 3 , 8 , 1 3 , 1 8 -t e t r a m e t h y l p o r p h i n - 2 - y l o c t a n e (169) (20mg, 0.02 mmole) was d e p r o t e c t e d w i t h 5% s u l f u r i c a c i d / m e t h a n o l . The h y d r o x y e t h y l -p o r p h i n e formed was d i s s o l v e d i n a s o l u t i o n o f t r i p h e n y l -p h o s p h i t e d i b r o m i d e (150mg, 0.3 mmole) i n d r y d i c h l o r o m e t h a n e (15 mL). A f t e r 2 hours t h e r e a c t i o n was quenched by p o u r i n g i n t o water (30 mL). The o r g a n i c l a y e r was s e p a r a t e d , washed w i t h water (30 mL x 3 ) , e v a p o r a t e d under reduced p r e s s u r e and chromatographed on a c t i v i t y IV s i l i c a w i t h d i c h l o r o m e t h a n e as e l u e n t . The p r o d u c t (13.5g, 65%) was c r y s t a l l i s e d from d i c h l o r o m e t h a n e / m e t h a n o l . A n a l : C a l c . f o r C^ 0H 0 nN 0Br„.H„0: C, 68.78; H, 6.96; N, 9.44. 6 o o U o 2 2 Found: C, 68.25; H, 6.96; N, 8.82%. 1 H NMR: (6, CDCl.,); 1.41 & 2.03 (bs, 12H, -CH„ (CH„) rCH„-) ; j 2 —2 b 2 1.72 ( t , J7.5HZ, 12H, C H 2CH 3); 3.60 ( s , 12H, CH_ 3); 3.67 162 (s, 6H, CH_3); 3.70 (s, 6H, CH 3); 4.08 (m, H, overlap, CH 2CH 3, CH 2(CH 2) 6CH 2 and CH 2CH 2Br); 4.7 0 (t, J7.5Hz, 4H, CH2CH_2Br) ; 9.60, 9.62, and 9.67 (3s, 8H, meso H). V i s i b l e Spectrum (CH 2C1 2) : A (nm) 398 497 535 568 621 max peak r a t i o 38.57 3.00 2.18 1.57 1.00 163 B i s 1,10-(7,12,17-triethyl-3,8,13,18-tetramethylporphin-2-yl) decane (178) C H 3 C H 3 CH 3 C H 3 C H 3 Method A. Cyclohexene (2 mL) was added to a solution of 51-bromo-5-bromomethyl-3',4-diethyl-3,4 *-dimethyl dipyrromethene hydrobromide (173) (0.5g, 1.04 mmole) in dry dichloromethane (50 mL) and the solution was evaporated to dryness under reduced pressure. The r e s u l t i n g s o l i d and 1,10-bis(3'-ethyl-3,4',5-trimethyl-dipyrromethene-4-yl) decane dihydrobromide (140) (0.36g, 0.5 mmole)were dissolved i n dry dichloromethane (50 mL) treated with stannic chloride (2 mL) and l e f t for 2 hours. The bright orange/red solution was quenched with 48% hydrobromic acid (10 mL) and methanol (5 mL). The organic phase was washed with water (3 x 100 mL). Ethyl acetate (50 mL), 48% hydrobromic acid (5 mL) and methanol (5 mL) were added and the dichloromethane removed under reduced pressure. The 164 biladiene c r y s t a l l i s e d as a red/brown s o l i d , was f i l t e r e d , washed with ethyl acetate and dried. The biladiene was dissolved i n DMSO (100 mL) and pyridine (20 mL) then l e f t i n the dark, open to the atmosphere for 5 days. The product (0.3 03g, 42.6%) formed as a purple scum, was f i l t e r e d , washed with methanol and dried. Method B Compound (177a) (lOmg, 0.008 mmole) was dissolved i n formic acid (20 mL) and hydrogenated over PdO'.('lmg) u n t i l 10% of the absorbance had been l o s t i n the v i s i b l e spectrum. The solution was then f i l t e r e d and evaporated to dryness under reduced pressure. The s o l i d was chromatographed on a c t i v i t y IV s i l i c a gel eluted with dichloromethane. The fast running band was shown to be i d e n t i c a l to the product above by t i c , mass spectra, and NMR. Anal: Calc. for C^HggNg: C, 80.88; H, 8.34; N, 10.78; Found: C, 81.38; H, 8.20; N, 10.56%. 1H NMR: (6, CDC1 3/TFA): -3.10 (bs, 4H, NH); 1.29, 1.41 and 1.61 (3bs, 12H, - (CH2) 2 (CH2) g (CH2) 2-) ; 1.73 (m, 12H, CH2CH_3); 2.07 (m, 4H, CH 2CH 2 (CH2) 6CH 2CH 2) ; 3.60 (s, 12H, CH_3); 3.64 (s, 12H, CH 3); 4.10 (bm, 16H, overlap, CH_2(CH2)gCH2 and CH 2CH 3); 9.47, 9.48, 9.49 and 9.50 (4s, 8H, meso H). 1 3 C NMR: (6, CDC13/5%TFA): 144.567, 143.439, 142.322, 141.825, 141.497, 138.221, 137.893 (32C, a- and g-carbons); 98.481 165 (8C, meso-carbons 5-, 10-, 15-, 20-C), 32.253 (2C, chain 2', 9'C); 30.008 (2C, chain 3',8'C); 29.523 (2C, chain 4',7'C); 29.438 (2C, chain 5', 6'C); 26.877 (2C, chain 1', 10'C); 20.167 (4C, -CH 2CH 3); 16.284 (4C, -CH 2CH 3); 11.904, [ll.770 (8C, g-CH 3). V i s i b l e Spectrum (CH 2C1 2) : A (nm) max peak r a t i o Mass Spectrum 400 70.43 497 2.87 532 2.63 566 2.22 620 1.00 ISOTOPE COMBINATION PATTERN POR THE MOLECULE / iUN (178a) C70 H82 N 8 ZN 2 A c t u a l s p e c t r u m * * * Computer s i m u l a t i o n PEAK MASS NOMINAL MASS OF MOST ABUNDANT PEAK =1167 166 B i s - l , 1 0 f 1 2 - ( 3 - a c e t o x y p r o p y l ) - 7 , 1 7 - d i e t h y l - 3 , 8 , 1 3 , 1 8 -t e t r a m e t h y l p o r p h y r i n - 2 - y l J d e c a n e . (179) C H 3 OAc AcO C H 3 C H 3 Cyclohexene (3 mL) was added t o a s o l u t i o n o f 4-(3-a c e t o x y p r o p y l ) - 5 1 - b r o m o - 5 - b r o m o m e t h y l - 3 , 4 1 - d i m e t h y l d i p y r r o -methene hydrobromide (158) (2.8g, 5.06 mmole) i n d r y d i c h l o r o -methane (100 mL); the s o l u t i o n was e v a p o r a t e d t o d r y n e s s under reduced p r e s s u r e . The r e s u l t i n g s o l i d and 1,10-bis ( 3 ' - e t h y l -3 , 4 , 5 1 t r i m e t h y l d i p y r r o m e t h e n e - 4 - y l ) decane d i h y d r o b r o m i d e (140) (1.8g, 2.47 mmole) were d i s s o l v e d i n d r y d i c h l o r o m e t h a n e (500 mL) and t r e a t e d w i t h s t a n n i c c h l o r i d e (5 mL). A f t e r s t a n d i n g f o r 1% hours the b r i g h t o r a n ge/red s o l u t i o n was quenched w i t h 48% hydrobromic a c i d (10 mL) i n methanol (50 mL). The s o l u t i o n was then washed w i t h water (5 00 mL x 3) and a m i x t u r e of hydrobromic a c i d (5 mL), methanol (5 mL) and e t h y l a c e t a t e (50 mL) was added. The d i c h l o r o m e t h a n e was removed under reduced p r e s s u r e u n t i l a deep r e d brown b i l a d i e n e p r e c i p i t a t e d . T h i s was f i l t e r e d , washed w i t h e t h y l a c e t a t e and d r i e d . 1-67. The biladiene was dissolved i n DMSO (100 mL), pyridine (25 mL) and l e f t open to the atmosphere i n the dark for 5 days. The porphyrin formed as a purple scum and was f i l t e r e d and washed with methanol. The product (1.95g, 66.7%) was r e c r y s t a l l i s e d from dichloromethane/methanol. An a n a l y t i c a l sample was produced by metallating the porphyrin with zinc and drying at 120°C/.01 Torr for 4 days. Deprotection of the alcohol was carried out i n 5% s u l f u r i c acid/methanol, extracted with dichloromethane, washed with water and c r y s t a l l i s e d from methanol i n 95% y i e l d . Anal: Calc. for C^H^NgO^: C, 77.12; H, 8.01; N, 9.47. Found: C, 7 6.50; H, 8.02; N, 9.29%. Calc. for C 7 6H 9 0NgO 4Zn 2-H 2O: C, 68.77; H, 6.98; N, 8.44: Found: C, 68.62; H, 7.10; N, 8.20%. 1H NMR (400 MHz): (6, CDC13/TFA) ; 1.24 (bs, 4H, -(CH 2) 4-CH_ 2-CH 2(CH 2) 4); 1.37 (bs , 4H, - (CH2) 3-CH 2r (GH2;) 2 _ C I 2 ~ ( C H 2 } 3 _ ) ; 1.56 (m, 4H, -(CH 2) 2-CH 2-(CH 2) 4-CH 2-(CH 2) 2-); 1.69 & 1.71 (2t, 12H, -CH 2CH 3); 2.14 (m, 4H, -CH^CH^- (CH2) 6-CH2"CH2) ; 2.26 (s, 3H, -OCOCH3) ; 2.54 (m, 4H, -CH2CH_2CH2C02CH3) ; 3.60 (s, 6H, -CH3) ; 3.64 (s, 6H, -CH_3); 4.15 (q, overlap, 8H, -CH_2CH3); 4.20 (t, overlap, 4H, -CH_2-(CH2) g-CH2~) ; 4.28 (t, J6Hz, 4H, -CH 2CH 2CH 2C0 2CH 3); 4.47 (t, J6Hz, 4H, -CH 2CH 2CH 2C0 2CH 3); 10.60, 10.63, 10.65 (4s, 8H, meso H). 1 3 C NMR: (6, 5% TFA/CDC13): 174.148 (2C, -COO); 144.590, 143.446, 142.508, 142.384, 142.026, 141.791, 141.529, 141.433, -168 140.950, 138.344, 138.220, 137.889, 137.792 ( 3 2 C , a - and g- c a r b o n s ) ; 98.632, 98.329 (4C, meso-carbons 5-, 10-, 15-, and -20C); 64.835 (2C, -CH 2CH 2CH 2-0-); 32.238 (2C, c h a i n 2', 9'C); 30.694 (2C, -CH 2CH 2CH 2-0-); 29.991 (2C, c h a i n 3', 8'C); 29.508 (2C, c h a i n 4', 7'C); 29.439 (2C, c h a i n 5', 6'C); 26.888 (2C, c h a i n 1', 10'C); 23.124 (2C, -CH 2CH 2CH 2-0-); 20.987 (2C, CH 2CO); 20.159 (4C, -CH 2CH 3); 16.243 (4C,-CH 2CH 3); 11.927, .111.872, 11.721 (8C, £_-CH 3). V i s i b l e Spectrum (CH.2.C1.2) : A (nm) 399 496 532 567 619 peak r a t i o 48.75 3.0 3.0 2.57 1.00 -169 1,10-Bis{12-(3-bromOpropyl)-7,17-diethy1-3,8,13,18- tetramethylporphinato zinc }-decane (181a) C H 3 Br Br C H 3 C H 3 Bromine (lOOmg, 0.63 mmole) i n dichloromethane (10 mL) was added slowly with swirling to an ice cold solution of triphenylphosphite (200mg, 0.64 mmole) i n dichloromethane (10 mL). 1,10-Bis{ 7 ,17-diethyl-12- (3-hydroxypropyl) -3 ,8 ,13, 18-tetramethylporphin-2-yl Idecane (180) (150mg, 0.14 mmole) was dissolved i n the triphenylphosphite dibromide solution and s t i r r e d for 3 0 mins. The solution was washed with water (2 x 30 mL), sat. zinc acetate i n methanol solution was added (1 mL), and the solution washed once again with water (30 mL) and with sat. spdium chloride solution (30 mL). The solvent was removed under reduced pressure and the s o l i d dissolved i n the minimum THF dil u t e d with dichloromethane (2 mL) and chromatographed on a c t i v i t y IV s i l i c a gel with dichloromethane solvent. When allowed to stand the product (120mg, 65.1%).crystallised from the dichloromethane solution; the bright orange s o l i d was f i l t e r e d , washed with dichloro-methane and dried. .170 Anal: Calc. -for C_ 0H 0,N oBr„Zn„2H o0. C, 62.21; H, 6.53; IZ ob o Z Z Z N, 8.06: Found: C, 61.80; H, 6.35; N, 8.00%. 1H NMR: (<5, CDC13/TFA) 1.30 (bs, 4H, - (CH2) 4-CH_2CH_2 (CH2) 4~) ; 1.41 (bs, 4H, -(CH 2) 3-CH 2-(CH 2) 2-CH 2(CH 2) 3~); 1.62 (bs, 4H, - (CH2) 2-CH2-;(CH2) 4-CH 2-(CH 2) 2) ; 1.72 and 1.74 (2t, J7 . 5Hz , 12H, -CH 2CH 3); 2.09 (m, 4H, -CH2-CH2~ (CH2) 6-CH_2-CH2) ; 2.71 (m, 4H, -CH 2CH 2CH 2Br); 3.65 (s, 12H, -CH 3); 3.67 (t, J7Hz,4H, -CH 2CH 2CH 2Br); 3.71 (s, 12H, ~CH 3); 4.11 (q, J7.5Hz, 8H, -CH_2CH3); 4.16 (t, J7.5Hz, 4H, -CH2~ (CH2) g-CH_2-) ; 4.38 (t, J7.5HZ, 4H, -CH 2CH 2CH 2Br); 10.66, 10.67, 10.68 and 10.87 (4s, 8H, meso H). 1 3 C NMR (&, 5% TFA/CDC13): 145.332, 145.271, 144.167, 142.492, 142.383, 141.958, 141.776, 141.679, 141.606, 141.449, 139.240, 138.985, 138 .913, 138 .524 (32C, a and g. -carbons); 99.064 , 98.858, 98.736 (4C, meso-carbons 5-, 10-, 15-, 20-C); 34.401, 33.126 (4C, -CH 2CH 2CH 2Br); 32.313 (2C, Chain 2', 9'C); 30.093 (2C, Chain 3', 8'C); 29.571 (2C, Chain 4', 7'C); 29.450 (2C, Chain 5", 6'); 26.914 (2C, Chain 1', 10'C); 24.596 (2C, -CH 2CH 2CH 2Br); 20.191 (4C, -CH 2CH 3); 16.284, 16.248 (4C, -CH 2CH 3); 12.013, 11.904, 11.673 (8C, £-CH 3). V i s i b l e Spectrum (CH 2C1 2) : '^ max ( n m ) 399 497 532 566 620 peak r a t i o 33.33 2.90 2.07 1.41 1.00 171 1,10-Bis{ 12- (pent-4-yne) -7 ,17-diethyl-3,8,13,18-tetramethylporphinato-zinc}-decane (18 2 a) C H 3 C H 3 H H The C - ^ Q bis-bromopropylporphinato zinc (181a) (49mg, 0.036 mmole) was dissolved in DMSO (15 mL) and treated with excess lithium acetylide ethylenediamine. The solution was l e f t to s t i r at room temperature protected from moisture for 3 hours. The mixture was then poured into water (50 mL) and extracted with dichloromethane (50 mL) and THF (10 mL). The solution was washed with water (2 x 30 mL) and f i n a l l y with sat. sodium chloride solution (30 mL). The solvent was removed under reduced pressure and the s o l i d dissolved i n the minimum volume of THF d i l u t e d with dichloromethane (2 mL) and chromatographed on a c t i v i t y IV s i l i c a gel with dichloro-methane eluent. The fa s t running band was col l e c t e d and c r y s t a l l i s e d from dichloromethane/pet. ether to y i e l d product (31.5mg, 70.0%) . 172 Anal: Calc. for C ? gH 8 gNgZn 2.2H 20: C, 71.41; H, 7.10; N, 8.77. Found: C, 71.18; H, 6.93; N, 8.14%. 1H NMR: (<5, CDC13, TFA) 1.3 2 (bs, 4H, - (CH2) 4CH2CH_2 (CH2) 4~) ; 1.42 (bs, 4H, -(CH 2) 3CH 2(CH 2) 2CH 2(CH 2) 3~); 1.63 (bs, 4H, -(CH 2) 2 CH_2 (CH2) 4CH 2 (CH2) 2~) ; 1.78 (t, J7.5Hz, 12H, -CH2CH_3) ; 2.12 (m, 4H, - C H _ C H „ ( C H _ ) , C H „ C H N - ) ; 2.72 (m, 4H, - C H „ C H _ C H „ C E C H ) ; 2 —2 2 o —2 2 2 —2 2 3.65 (s, 12H, -CH_3) ; 3.71 (t, J7Hz, C H 2 C H 2 C H 2 C H C H ) ; 3.72 (s, 12H, -CH 3); 4.09 (q, J7 . 5Hz, 8H, -CH_2CH3); 4.15 (t, J7. 5Hz, 4H, -CH2 (CH2) gCH2-) ; 4.45 (t, J7.5Hz, 4H, -CH_2CH2CH2C = CH) ; 10.59, 10.64, 10.65 and 10.72 (4s, 8H, meso H). V i s i b l e Spectrum (CH 2C1 2); X nm 398 495 533 565 620 max peak r a t i o 31.43 2.70 1.95 1.30 1.00 Mass Spectrum ISOTOPE COMBINATION PATTERN FOR THE MOLECULE / ION (182a) C76 H84 N B ZN 2 5 H 40-A c t u a l s p e c t r u m * * * Computer s i m u l a t i o n PEAK MASS NOMINAL MASS OF MOST ABUNDANT PEAK =1241 173 3.9 Synthesis of Doubly Linked Porphyrins 2,2'-Decamethylene-12,12'-deca'4,6-diynedi(7,17-diethyl-3,8,13,18-tetramethylporphinato zinc) (183a) III C (CHj). '10 To a s t i r r e d solution of cuprous chloride (O.lg, 1.0 mmole) i n methanol (80 mL) and pyridine (80 mL) was added a solution of bis-1,10{7,17-diethyl-3,8,13,18-tetramethyl-12(pent-4-yne) porphinatozinc-2-yl} decane (182a) (25mg, 0.02 mmole) i n THF (50 mL) over a seven hour period using a syringe pump. The solution was washed with water (3 x 100 mL) and sat. sodium chloride solution (100 mL). The organic phase was evaporated under reduced pressure, and the s o l i d dissolved i n dichloromethane and chromatographed on a c t i v i t y IV s i l i c a gel with dichloromethane as eluent. The f i r s t f a s t moving band was st a r t i n g material (12mg); the second slower band was eluted with 2% methanol/dichloromethane. The solvent was removed under reduced pressure and product (lmg, 4%) obtained as a dark red s o l i d . 174 H NMR: (270 MHz): (6, CDC13/TFA) 1.05, 1.14 and 1.30 (3bs, 12H, ( C H 2 ) 2 ( C H 2 ) 6 ( C H 2 ) 2 ) ; 1.38 (2t, 12H, CH 2CH 3); 1.68 (m, 4H, CH 2CH 2 (CH2) 6CH 2CH 2) ; 1.94 (2m, 8H, CH^CH^C CCH^CH^); 2.91 (s, 12H, CH 3); 2.95 (2s, 12H, CH 3); 3.30 (m, 12H, CH 3); 3.44 (m, 4H, CH 2(CH 2) 2C C (CH2) 2CH_2) ; 8.52 (4s, 8H, meso H) . V i s i b l e Spectrum (CH 2C1 2) : Amax ( n m ) 399 (378) ? 500 535 594 622 peak r a t i o 31.42 shoulder 3.16 2.25 1.69 1.00 Mass Spectrum ISOTOPt; COMBINATION I'ATTEKN KOH THtl HOLa 'ULE / I ON (183a) C76 HH6 N 6 ZN 2 A c t u a l spectrum * * * Computer s i m u l a t i o n PEAK MASS 1 NOMINAL MASS OF MOST ABUNDANT PEAK ° U 4 5 175 2,2',12,12'-Bisdecamethyleriedi-(7,17-diethyl-3,13,18- tetramethylporphin) (185) Method A. Cyclohexene (2 mL) was added to a solution of 1,10-bis (.5 '-bromo-5-bromomethyl-3 1 -ethyl-3 , 4 ' -dimethyldipyrro-methene-4-yl) decane dihydrobromide (159) (0.53g, 0.5 mmole) in dry dichloromethene (100 mL) and the solution evaporated to dryness under reduced pressure. The resultant s o l i d and 1,10-bis-(3 1ethyl-3,4 1,5-trimethyldipyrromethene-4-yl)decane dihydrobromide (140) (0.364g, 0.5 mmole) were dissolved i n dry dichloromethane (1,4 00 mL) and added dropwise to a s t i r r i n g solution of stannic chloride (25 mL) i n dry dichloro-methane (500 mL) over a period of 6 hours. When the addition was complete the solution was l e f t for a further 1 hour before being quenched with 48% hydrobromic acid (25 mL) and washed with water (3 x 50 0 mL). To ensure complete removal of the t i n , the solution was further treated with TFA (10 mL) and washed with water (500 mL). The solution was reduced i n volume (approximately 150 mL), DMSO (200 mL) and pyridine (20 mL) were added and the solution l e f t to stand open to the a i r for 5 days. 17 6 The p o r p h y r i n was f i l t e r e d , washed w i t h methanol and d r i e d . The p o r p h y r i n was then d i s s o l v e d i n d i c h l o r o m e t h a n e , f i l t e r e d t o remove p o l y m e r i c m a t e r i a l and chromatographed on a c t i v i t y IV s i l i c a g e l w i t h 5% e t h y l a c e t a t e / d i c h l o r o -mehtane as e l u e n t . The p r o d u c t (31mg, 5.5%) was r e c r y s t a l l -i s e d from d i c h l o r o m e t h a n e / p e t / e t h e r . Method B. A s o l u t i o n o f 2 ,2'-decamethylene-12,12 1-deca-4,6-diynedi ( 7 , 1 7 - d i e t h y l - 3 , 8 , 1 3 , 1 8 - t e t r a m e t h y l p o r p h i n a t o z i n c ) (183a) (lOmg, 0.008 mmole) i n f o r m i c a c i d (5mL) and THF (2 mL) was hydrogenated over p a l l a d i u m o x i d e f o r 6 h o u r s . The s o l u t i o n was e x t r a c t e d w i t h d i c h l o r o m e t h a n e (3 0 mL), washed w i t h water (30 mL), t r e a t e d w i t h z i n c a c e t a t e . m e t h a n o l s o l u t i o n and washed a g a i n w i t h water (30 mL x 2) and w i t h s a t . sodium c h l o r i d e s o l u t i o n . The s o l v e n t was removed under reduced p r e s s u r e and t h e s o l i d chromatographed on a c t i v i t y IV s i l i c a g e l w i t h d i c h l o r o m e t h a n e e l u e n t . The p r o d u c t (~0.5mg, 5% ) , o b t a i n e d by removing the s o l v e n t on a vacuum pump o v e r n i g h t , was shown t o be i d e n t i c a l t o the p r o d u c t from method A by t i c , h a v i n g a much l a r g e r than the s t a r t i n g m a t e r i a l , mass s p e c t r a , v i s i b l e s p e c t r a and "'"H NMR. A n a l : C a l c . f o r C 7 g H g 2 N g Z n 2 : C, 73.12; H, 7.43; N, 8.98; Found: C, 72.85; H, 7.40; N, 8.69%. 177 'H NMR: (400 MHz) (6,CDC13/TFA) -4.93 (bs, 2H, NH); -4.45 (bs, 2H, NH); 0.59, 0.69 and 8.95 (3bs, 24H, (CH 2) 2(CH 2) (CH2) 1.47 (bs, 8H, CH 2CH 2(CH 2) 6CH 2CH 2); 1.63 (t, J8Hz, 12H, CH2CH3) 3.49 (s, 12H, CH 3); 3.55 (s, 12H, CH 3); 4.03 (m, 16H, overlap CH 2CH 3 and CH_2 (CH2) gCH2) ; 10.47 (s, 4H, meso H) ; 10.51 (s, 4H, meso H). V i s i b l e Spectrum (CH 2C1 2) : A v (nm) 390 (382) 500 532 568 621 peak r a t i o 31.86 shoulder 3.02 2.05 1.49 1.00 Mass Spectrum ISOTOPE COMBINATION PATTERN FOB THE MOLECULE / ION ( ] 8 5a} C76 H92 N 6 ZN 2 1 ' a <0— A c t u a l s p e c t r u m * * * C o m p u t e r s i m u l a t i o n PEAK MASS NOMINAL MASS OF MOST ABUNDANT PEAK =1249 CHAPTER 4 SPECTRAL DATA 4i. FIGURE 36: 270 MHz 1H NMR Spectrum of (178) h-1 00 00 FIGURE 40: 270 MHz H NMR Spectrum of (18 2) 4 1 l 1 l 1 I 1 l 1 l 1 i 1 I 1 i 1 i 1 l  FIGURE 43: 2 0 MHz C NMR Spectrum of "(168) FIGURE 44: 100.6 MHz 1 3 C NMR Spectrum' of (171) i i i i i i i ' i i i 1 i - 1 " FIGURE 4 5 T 20 MHz 1 3 C NMR Spectrum o f (172); FIGURE 46: 100.6 C NMR Spectrum of .(17 3) i — 1 FIGURE 47: 100.6 MHz C NMR Spectrum of (177) FIGURE 48: 100.6 MHz C NMR Spectrum.of (178) - FIGURE 49: 100.6 MHz C NMR Spectrum of (17 9) to o o L»|»M»JI|H FIGURE 50: 100.6 MHz 1 3 C NMR Spectrum of (181) FIGURE 51: 100.6 MHz 1 3 C NMR Spectrum of (18 2) O « NJ W A V E L E N G T H FIGURE 52: Electronic Absorption Spectrum of (169) f r e e base d i c a t i o n - I 1 1 1 1 1 1 ~» 350 400 450 500 550 600 650 700 W A V E L E N G T H FIGURE 53: E l e c t r o n i c A b s o r p t i o n Spectrum o f (170) WAVELENGTH FIGURE 54: Electronic Absorption Spectrum of (171) 3 5 0 4 0 0 4 5 0 5 0 0 5 5 0 6 0 0 6 5 0 7 0 0 n m . to o WAVELENGTH FIGURE 55; Electronic Absorption Spectrum of (172) 1-0 Zn s a l t d i c a t i o n free base 350 400 450 500 550 600 650 700 nm. W A V E L E N G T H FIGURE 56: Electronic Absorption Spectrum of (175) o W A V E L E N G T H FIGURE 57: E l e c t r o n i c A b s o r p t i o n Spectrum of (177) -~r 1 1 1 1 1 r J r 350 400 450 500 550 6 0 0 650 700 nm. WAVELENGTH FIGURE 58: Electronic Absorption. Spectrum of (178-) ~~i 1 r 6 1 1 1 r"~ T 350 400 450 500 550 600 650 700 WAVELENGTH FIGURE 59: Electronic Absorption Spectrum, of (179)! WAVELENGTH FIGURE 60; Electronic Absorption Spectrum of (181) ~i 1 1 1 1 1 — r * " i 350 400 450 500 550 600 650 700 WAVELENGTH FIGURE 61: Electronic Absorption Spectrum of (182) FIGURE 62: Electronic Absorption. Spectrum of (183) W A V E L E N G T H FIGURE 63: Electronic Absorption Spectrum of (183a) WAVELENGTH FIGURE 65: Electronic Absorption Spectrum of (185a) 2.17 REFERENCES 1. Published i n rewritten form. D. Dolphin, J . Hiom and J. B. Paine I I I , Heterocycles, 16, 417 (1981). 2. R. Lemberg and J. Barrett, Cytochromes, Acad. Press, (1973); D. F. Wilson and M. 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