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UBC Theses and Dissertations

Syntheses of strapped, capped and bent porphyrins Wijesekera, Tilak Panini 1980

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c / SYNTHESES OF STRAPPED, CAPPED AND BENT PORPHYRINS by TILAK PANINI WIJESEKERA B.Sc. (Honours), U n i v e r s i t y o f S r i Lanka, 1973 M.Sc, Simon F r a s e r U n i v e r s i t y , 1977 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY i n ; THE FACULTY OF GRADUATE STUDIES (Department of Chemistry) We accept t h i s t h e s i s as conforming t o the r e q u i r e d standard THE UNIVERSITY OF BRITISH COLUMBIA AUGUST 1980 (g) T i l a k P a n i n i Wijesekera I n p r e s e n t i n g t h i s t h e s i s i n p a r t i a l f u l f i l m e n t o f the r e q u i r e m e n t s f o r an a d v a n c e d degree a t t h e U n i v e r s i t y o f B r i t i s h C o l u m b i a , I a g r e e that t h e L i b r a r y 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 r e f e r e n c e and s t u d y . I f u r t h e r a g r e e t h a t p e r m i s s i o n f o r e x t e n s i v e c o p y i n g o f t h i s t h e s i s f o r s c h o l a r l y p u r p o s e s may be g r a n t e d by t h e Head o f my Department o r by h i s r e p r e s e n t a t i v e s . I t i s u n d e r s t o o d t h a t c o p y i n g o r p u b l i c a t i o n o f t h i s t h e s i s f o r f i n a n c i a l g a i n s h a l l n o t be a l l o w e d w i t h o u t my w r i t t e n p e r m i s s i o n . D e p a r t m e n t o f ' £ T £ y The U n i v e r s i t y o f B r i t i s h C o l u m b i a 2075 Wesbrook Place Vancouver, Canada V6T 1W5 Date S ' ^ ABSTRACT The doming of the p o r p h y r i n macrocycle,.and the accompanied movement of the c e n t r a l i r o n atom i n and out of the plane, have p r e v i o u s l y been suggested to be important i n the mechanism of r e v e r s i b l e oxygen b i n d i n g and c o o p e r a t i v i t y of heme p r o t e i n s . The o b j e c t i v e of t h i s work was to develop a s y n t h e t i c route f o r the c o n s t r u c t i o n of bent p o r p h y r i n s t h a t would serve as simple models f o r the b i o l o g i c a l systems. T h i s t h e s i s d e s c r i b e s the syntheses of the p o r p h y r i n s of the type 109 c o n t a i n i n g a d i a g o n a l l y a t t a c h e d carbon c h a i n , s h o r t enough to cause d i s t o r t i o n of the p o r p h y r i n . The i n t r o d u c t i o n of the s h o r t s t r a p p r i o r to c y c l i z a -t i o n was mandatory s i n c e the p o r p h y r i n i s extremely s t a b l e i n i t s p l a n a r c o n f i g u r a t i o n . T h e r e f o r e , i n the f i r s t step of the s y n t h e s i s , the s t r a p obtained as i t s t e r m i n a l d i c a r b o x y l i c a c i d , was l i n k e d t o two moles of the 3-unsubstituted p y r r o l e £6 by two simultaneous F r i e d e l - C r a f t s a c y l a t i o n r e a c t i o n s f o l l o w e d by the diborane r e d u c t i o n of the k e t o n i c groups. The c h a i n l i n k e d b i s p y r r o l e e t h y l e s t e r 89_ so obtained was converted to the s y n t h e t i c a l l y u s e f u l b i s f o r m y l p y r r o l e 93_ v i a the b i s p y r r o l e b e n z y l e s t e r 90_, the b i s c a r b o x y p y r r o l e 9_1 and the b i s a-unsub-s t i t u t e d p y r r o l e 9_2. The two formyl groups of 93_ were subse-quent l y p r o t e c t e d by c o n v e r t i n g t h i s t o the d i c y a n o v i n y l d e r i v a t i v e 9_4. Two m onochlorinations a t the a-methyl groups of 9_4 (using 2 e q u i v a l e n t s of s u l f u r y l c h l o r i d e ) f o l l o w e d by the condensation of the b i s a-chloromethyl d e r i v a t i v e w i t h two e q u i v a l e n t s of the a - u n s u b s t i t u t e d p y r r o l e 79 produced the dipyrromethane dimer 9_6. The s a p o n i f i c a t i o n of the two e s t e r groups and the d e p r o t e c t i o n of the formyl groups were e f f e c t e d i n a s i n g l e step by the use of s t r o n g aqueous a l k a l i . The a - f o r m y l - a ' - c a r b o x y d i p y r r o m e t h a n e dimer 107 so obtained was sub j e c t e d t o thermal d e c a r b o x y l a t i o n ( i n r e f l u x i n g d i m e t h y l -formamide) and the r e s u l t i n g c t-f o r m y l - a ' - u n s u b s t i t u t e d d i p y r r o -methane dimer 108 was c y c l i z e d under extremely h i g h d i l u t i o n u s i n g t o l u e n e - p - s u l f o n i c a c i d t o produce the p o r p h y r i n 109. Once the s y n t h e s i s of the p o r p h y r i n 109a (n=ll) was s u c c e s s f u l l y accomplished, the syntheses of the p o r p h y r i n s w i t h s h o r t e r carbon chains were attempted. I t was p o s s i b l e to s y n t h e s i z e the 10 and 9-carbon strapped p o r p h y r i n s (109b and 109c r e s p e c t i v e l y ) but the c y c l i z a t i o n of 108d (n=8) d i d not produce a p o r p h y r i n . An a l t e r n a t i v e s y n t h e t i c route t o strapped p o r p h y r i n s 109 i s a l s o d e s c r i b e d . The branch o f f p o i n t was the b i s fo r m y l -p y r r o l e 93^. T h i s was converted to the b i s c y a n o a c r y l a t e 115 and used t o produce the dipyrromethane dimer 117 i n a manner s i m i l a r to t h a t used t o prepare compound 96_ (the a - f r e e p y r r o l e used was 8_0) . Compound 117 was converted t o the p r o p h y r i n p r e c u r s o r 108 v i a 118 and 119 and sub j e c t e d t o a c i d - c a t a l y z e d c y c l i z a t i o n as p r e v i o u s l y d e s c r i b e d . The next phase of t h i s work d e a l t w i t h the c o n s t r u c -t i o n of the capped p o r p h y r i n 143. The key s y n t h e t i c i n t e r m e d i -ate was durene-bis-pentanoic a c i d 130 which was prepared from b i s ( c h l o r o m e t h y l ) durene v i a two malonate syntheses. The durene-b i s - p e n t a n o i c a c i d was c a r r i e d through the same r e a c t i o n sequence as p r e v i o u s l y d e s c r i b e d (the d i c y a n o v i n y l - e t h y l e s t e r route) f o r the simple d i c a r b o x y l i c a c i d s t o g i v e the capped p o r p h y r i n 143. The presence of a s h o r t s t r a p had a r h o d o f y i n g e f f e c t on the e l e c t r o n i c a b s o r p t i o n s p e c t r a of the p o r p h y r i n s . A d e f i n i t e t r e n d was observed i n going from the capped p o r p h y r i n 143 t o the p o r p h y r i n s of p r o g r e s s i v e l y s h o r t e r chains (109a -> 109b ->• 109c) . T h i s change was a t t r i b u t e d to d i s t o r t i o n of the macrocycle. "*"H NMR s p e c t r a e x h i b i t e d l a r g e u p f i e l d s h i f t s of the c h a i n methylene proton resonances and a l s o of the durene methyl proton resonance due to the i n f l u e n c e of the diamagnetic r i n g c u r r e n t of the p o r p h y r i n . i v V TABLE OF CONTENTS Page A b s t r a c t i i Table of Contents v i L i s t o f Tables i x L i s t of F i g u r e s x L i s t o f A b b r e v i a t i o n s x i i i Acknowledgements x i v 1. INTRODUCTION AND LITERATURE REVIEW 1 1.1 Porph y r i n s - A General Survey 2 1.2 S y n t h e t i c Aspects of Porph y r i n s 5 1.3 M e t a l l o p o r p h y r i n s as B i o l o g i c a l Oxygen C a r r i e r s 15 1.4 S y n t h e t i c Models f o r B i o l o g i c a l Oxygen C a r r i e r s 20 2. RESULTS AND DISCUSSION 35 2.1 S y n t h e t i c O b j e c t i v e . . . . . . 36 2.2 S y n t h e t i c P l a n . 39 2.3 S y n t h e s i s of Undecanedioic A c i d 46 2.4 Mo n o p y r r o l i c S t a r t i n g M a t e r i a l s and Intermediates 50 2.4.1 Syntheses of P y r r o l e s from A c y l i c P r e c u r s o r s 51 2.4.2 P r e p a r a t i o n of 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 Transformations of a - S u b s t i t u e n t s 55 2.5 Chain Linked B i s P y r r o l e s and t h e i r Chemical M o d i f i c a t i o n s 63 2.6 Dipyrromethanes and Porphyrins Therefrom . . 79 v i Page 2.7 Durene-Bis-Pentanoic A c i d and i t s Incorpor-a t i o n i n t o a P o r p h y r i n 124 2.7.1 S y n t h e s i s of Durene-Bis-Pentanoic A c i d 125 2.7.2 I n c o r p o r a t i o n of Durene-Bis-Pentanoic A c i d i n t o the P o r p h y r i n 140 3. EXPERIMENTAL 150 3.1 General Methods 151 3.2 Nomenclature of Porphyrins and t h e i r I n t e r -mediates . . . ; 153 3.3 Syntheses of A c y c l i c P r e c u r s o r s 155 3.4 Syntheses of Monopyrroles 161 3.5 S y n t h e s i s of the Model P o r p h y r i n and i t s Dipyrromethane P r e c u r s o r s 17 8 3.6 Syntheses of Chain Linked B i s P y r r o l e s . . . . 202 3.6.1 B i s P y r r o l e Diketones 202 3.6.2 B i s P y r r o l e E t h y l E s t e r s 210 3.6.3 B i s P y r r o l e Benzyl E s t e r s 216 3.6.4 B i s F o r m y l p y r r o l e s 221 3.6.5 B i s C y a n o v i n y l p y r r o l e s 2 31 3.7 Syntheses of Chain Linked Dipyrromethane Dimers 241 3.8 Syntheses of Strapped Porphyrins . 265 3.8.1 1,17-Diethyl-2,8,12,18-tetramethyl-3,13-undecamethyleneporphyrin 109a . . 265 3.8.2 7,17-Diethyl-2,8,12,18-tetramethyl-3,13-decamethyleneporphyrin 109b . . 271 3.8.3 7,17-Diethyl-2,8,12,18-tetramethyl-3,13-nonamethyleneporphyrin 109c . . 273 3.9 Syntheses of Durene-Bis-Pentanoic A c i d and i t s P r e c u r s o r s 275 3.10 Syntheses of Durene-Bis-Pentane Bridged Dimers and the P o r p h y r i n 143 . 289 v i i Page 4. SPECTRAL ASSIGNMENTS AND COMPARISON TABLES 307 4.1 "'"H NMR Spectra and Comparison Tables of Strapped P o r p h y r i n Intermediates 308 13 4.2 C NMR Spectra and Comparison Tables of Strapped P o r p h y r i n Intermediates 337 4.3 1H NMR Data of Strapped P o r p h y r i n s 358 13 4.4 C NMR Data of Strapped P o r p h y r i n s 383 4.5 E l e c t r o n i c A b s o r p t i o n Spectra of Po r p h y r i n s . . 392 REFERENCES 40 3 v i i i LIST OF TABLES Table T i t l e Page I 1H NMR Data of Chain Linked B i s P y r r o l e Diketones. . 314 II 1H NMR Data of Chain Linked B i s P y r r o l e a - E t h y l E s t e r s 316 I I I 1H NMR Data of Chain Linked B i s P y r r o l e a-Benzyl E s t e r s 319 IV 1H NMR Data of Chain Linked B i s - F o r m y l -p y r r o l e s 321 V 1H NMR Data of Chain Linked Bis-a-Dicyano-v i n y l p y r r o l e 32 3 VI 1H NMR Data of Chain Linked a - D i c y a n o v i n y l -a'-Ethoxycarbonyl Dipyrromethane Dimers 325 VII 1H NMR Data of Chain L i n k e d ct-Formyl-ct 1 -Carboxy Dipyrromethane Dimers . . . . . 328 V I I I 1 3 C NMR Data of Chain Linked B i s - P y r r o l e Diketones 341 13 IX C NMR Data of Chain Linked B i s P y r r o l e a - E t h y l E s t e r s 344 13 X C NMR Data of Chain Linked B i s P y r r o l e a-Benzyl E s t e r s 347 13 XI C NMR Data of Chain Linked B i s a-Formyl-p y r r o l e s 350 13 XII C NMR Data of Chain Linked B i s a-Dicyano-v i n y l p y r r o l e s 352 13 XIII C NMR Data of Chain Linked a - D i c y a n o v i n y l -a1-Ethoxycarbonyl Dipyrromethane Dimers 355 XIV Comparison of Chemical S h i f t s f o r S e l e c t e d Resonances of P o r p h y r i n s 366 13 XV Comparison of C Chemical S h i f t s of Porphyrins . . 390 XVI Comparison of E l e c t r o n i c A b s o r p t i o n S p e c t r a l Data of P o r p h y r i n s 399 XVII Comparison of E l e c t r o n i c A b s o r p t i o n S p e c t r a l Data of P o r p h y r i n s 401 i x LIST OF FIGURES F i g u r e T i t l e Page 1. F i s c h e r and IUPAC Numbering Systems f o r the P o r p h y r i n Nucleus . 2 2. L i n e a r T e t r a p y r r o l i c Intermediates i n P o r p h y r i n Syntheses 8 3. P o r p h y r i n Syntheses v i a the 2+2 Coupling of Dipyrromethane s 12 4. S y n t h e s i s of the Cyclophane P o r p h y r i n of T r a y l o r e t . a l . 23 5. S y n t h e s i s of the "Capped" P o r p h y r i n of Baldwin e t . a l . 25 6. S y n t h e s i s of the "Strapped" P o r p h y r i n of Baldwin e t . a l . 27 7. A R e t r o s y n t h e t i c A n a l y s i s of the Target Molecule. . 41 8. S y n t h e s i s of Undecanedioic A c i d 47 9. S y n t h e s i s of Knorr's P y r r o l e 52 10. Syntheses of Monopyrroles 6_6 and 6_7 by the V a r i a t i o n s of Knorr Reaction 54 11. P r e p a r a t i o n of S y n t h e t i c a l l y U s e f u l Monopyrroles v i a Transformations of a - S u b s t i t u e n t s 56 12. Syntheses of Chain Linked B i s P y r r o l i c I n t e r -mediates 64 13. S y n t h e s i s of the Dipyrromethane Dimer 9j[ 80 14. S y n t h e s i s of the Model P o r p h y r i n - E t i o p o r p h y r i n I I (106) 89 15. A c i d - C a t a l y z e d Rearrangements of D i p y r r o -methane s 92 16. Conversion of the Dipyrromethane Dimer 9_6 to the Strapped P o r p h y r i n 109 9 8 17. An A l t e r n a t i v e S y n t h e t i c Route to E t i o p o r p h y r i n I I (106) 106 18. An A l t e r n a t i v e S y n t h e t i c Route t o the Strapped P o r p h y r i n s 109 122; x F i g u r e T i t l e Page 19. S y n t h e s i s o f Durene-Bis-Pentanoic A c i d (130) . . . . 126 20. Syntheses of Durene-Bis-Pentane Linked B i s -P y r r o l i c Intermediates 141 21. Syntheses of Durene-Bis-Pentane Linked Dipyrromethane Dimers and of the Po r p h y r i n 143 . . . 148 22. 1H NMR Spectrum (100 MHz) of 88a i n 10% TFA-CDC1 3- . 313 23. 1H NMR Spectrum (100 MHz) of 89a i n CDC1 3 315 24. 1H NMR Spectrum (100 MHz) of 90a i n CDC1 3 317 25. 1H NMR Spectrum (100 MHz) of 134 i n CDC1 3 318 26. 1H NMR Spectrum o f 93a i n CDC1 3 320 27. 1H NMR Spectrum (100 MHz) of 94a i n CDC1 3 322 28. 1H NMR Spectrum (100 MHz) of 96a i n CDC1 3 324 29. 1H NMR Spectrum (100 MHz) of 107a i n DMSO-dg . . . . 327 30. 1H NMR Spectrum (100 MHz) of 115 i n CDC1 3 332 31. 1H NMR Spectrum (100 MHz) of 117 i n CDC1 3 333 32. 1H NMR Spectrum (100 MHz) of 118 i n DMSO-dg . . . . 334 33. XH NMR Spectrum (100 MHz) of 119 i n CDC1 3 335 34. 1H NMR Spectrum (100 MHz) of 108a i n CDC1 3 336 35. 1 3 C NMR Spectrum of 88a i n 10% TFA-CDC1 3 340 36. 1 3 C NMR Spectrum of 89a i n CDC1 3 343 37. 1 3 C NMR Spectrum o f 90a i n CDC1 3 346 38. 1 3 C NMR Spectrum of 93a i n CDC1 3 349 39. 1 3 C NMR Spectrum o f 94a i n CDC1 3 351 40. 1 3 C NMR Spectrum of 96a i n CDC1 3 354 41. 1H NMR Spectrum o f (270 MHz) of 143 i n CDC1 3 . . . . 359 42. 1H NMR Spectrum (400 MHz) of 109c i n CDC1 3 360 43. 1H NMR Spectrum (400 MHz) of 109b i n CDC1 3 361 44. 1H NMR Spectrum (400 MHz) of 109a i n CDC1 3 362 x i F i g u r e T i t l e Page 45. P a r t i a l 1 H N M R Spectra of 109b (400 M H z ) w i t h Simultaneous I r r a d i a t i o n s a t 6 3.67 and 6 3.46 . . . 372 46. P a r t i a l 1 H N M R S p e c t r a of 109b (400 M H z ) w i t h Simultaneous I r r a d i a t i o n s a t <5 1.51 and S 0.46 . . . 373 47. P a r t i a l 1 H N M R S p e c t r a of 109b (400 M H z ) w i t h Simultaneous I r r a d i a t i o n s a t 6 0.03 and 6-1.17 . . 375 48. P a r t i a l 1 H N M R Spectra of 109b (400 M H z ) w i t h Simultaneous I r r a d i a t i o n s a t 6 -1.79 and 6 -2.23 . . 376 49. P a r t i a l 1 H N M R Spectra of 109b (400 M H z ) w i t h Simultaneous I r r a d i a t i o n s a t 6 -5.13 and 6 -5.87 . . 377 50. 1 3 C N M R Spectrum of 143 384 51. 1 3 C N M R Spectrum of 109a 385 52. 1 3 C N M R Spectrum of 109b 386 53. 1 3 C N M R Spectrum of 109c 387 54. E l e c t r o n i c A b s o r p t i o n Spectra of 106 394 55. E l e c t r o n i c A b s o r p t i o n Spectra of 143 395 56. E l e c t r o n i c A b s o r p t i o n Spectra of 109a 396 57. E l e c t r o n i c A b s o r p t i o n Spectra of 109b 397 58. E l e c t r o n i c A b s o r p t i o n Spectra of 109c 39 8 x i i ABBREVIATIONS 13 C NMR = carbon-13 n u c l e a r magnetic resonance E t = e t h y l ''"H NMR = proton n u c l e a r magnetic resonance IR = i n f r a r e d Ph = phenyl TFA = t r i f l u o r o a c e t i c a c i d THF = t e t r a h y d r o f u r a n TLC = t h i n l a y e r chromatography 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 = doublet bs = broad s i n g l e t t = t r i p l e t br = broad r i s e q = q u a r t e t x i i i ACKNOWLEDGEMENTS I t has been a rewarding experience to work under the s u p e r v i s i o n o f P r o f e s s o r David Dolphin. His guidance and encouragement have pr o v i d e d i n v a l u a b l e support d u r i n g the course of t h i s work and f o r t h i s , I extend my s i n c e r e thanks to him. I a l s o wish to thank P r o f e s s o r B r i a n R. James f o r the v a l u a b l e d i s c u s s i o n s we have had d u r i n g the past three y e a r s . I am indebted t o Dr. John B. Paine I I I f o r the many .useful suggestions made d u r i n g the s y n t h e t i c work and a l s o f o r p r o v i d i n g access t o unpublished data. I a l s o wish to thank Dr. J.K.M. Sanders (Cambridge U n i v e r s i t y ) f o r h e l p f u l d i s c u s s i o n s on the analyses of NMR s p e c t r a o f strapped p o r p h y r i n s . I l i k e t o take t h i s o p p o r t u n i t y t o thank a l l the members of P r o f e s s o r Dolphin's r e s e a r c h group, pa s t and pres e n t , f o r making my stay a t U.B.C. a very p l e a s a n t one. S p e c i a l thanks are due to Mr. John Hiom and Dr. Quintus Perera f o r p r o o f r e a d i n g p a r t s o f the manuscript and to Mrs. Annette Hiom and Mrs. J o y c i e Miura f o r so competently t y p i n g t h i s t h e s i s . F i n a n c i a l support 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 of a U n i v e r s i t y Graduate F e l l o w s h i p (1979-80) and a t e a c h i n g a s s i s t a n t s h i p (1977-80) i s g r a t e f u l l y acknowledged. F i n a l l y , a deep sense o f g r a t i t u d e and lov e i s d i r e c t e d towards my w i f e , Kanthi, whose p a t i e n c e , t o l e r a n c e and constant encouragement made t h i s t h e s i s p o s s i b l e . x i v To my parents f o r t h e i r understanding and encouragement xv 1 CHAPTER 1 INTRODUCTION AND LITERATURE REVIEW 2 1.1 PORPHYRINS - A GENERAL SURVEY " T e t r a p y r r o l e " i s a t e r m u s e d w i d e l y t o r e f e r t o a member o f a c l a s s o f compounds whose m o l e c u l e s have f o u r r i n g s o f t h e p y r r o l e t y p e , u s u a l l y l i n k e d t o g e t h e r by s i n g l e atom b r i d g e s a t t h e i r a p p o s i t i o n s . The common a r r a n g e m e n t s o f t h e f o u r r i n g s f o r w h i c h t h i s name i s u s e d a r e , (a) m a c r o c y c l i c , as i n t h e p o r p h y r i n s and r e l a t e d compounds and (b) l i n e a r , as i n t h e b i l e p i g m e n t s . P o r p h y r i n s a r e f o r m a l l y d e r i v e d f r o m p o r p h i n ( F i g u r e 1) by t h e s u b s t i t u t i o n o f some o r a l l o f t h e p e r i p h e r a l h y d r o g e n s w i t h v a r i o u s g r o u p s . FIGURE 1 : F i s c h e r and IUPAC Numbering Systems f o r t h e P o r p h y r i n N u c l e u s B The nomenclature most g e n e r a l l y used has been t h a t of F i s c h e r , which i s based on a numeration scheme shown i n F i g u r e IA. The p e r i p h e r a l p o s i t i o n s are numbered from 1 to 8 and the " i n t e r p y r r o l i c " methine p o s i t i o n s , u s u a l l y termed "meso" are de s i g n a t e d ct , 3 , y and <5 . The F i s c h e r nomenclature a l s o i n v o l v e s a very l a r g e number of t r i v i a l names depending on the type of s u b s t i t u e n t s a t the p e r i p h e r y and an isomer numbering system based on t h e i r arrangements. E.g., the p o r p h y r i n with one methyl and one e t h y l group on each p y r r o l e p e r i p h e r y has been named " E t i o p o r p h y r i n " , w i t h f o u r "type-isomers" I to IV as shown below: Et Me Et Et Et Me Et Et / \ . / \ / \ / \ M e Et Me Me Me . Et Me Me Et Me Me Me Me Me Et Et \ / \ ' / \ / \ / M e Et Et Et Et Et Me Me TYPE I TYPE II TYPE III TYPE IV The compounds d e r i v e d from the common n a t u r a l l y o c c u r r i n g p o r p h y r i n s form a complex s e r i e s of s t r u c t u r e s and i n order to name them, F i s c h e r used f a r too many t r i v i a l names. Moreover the names do not convey c l e a r s t r u c t u r a l i n f o r m a t i o n and do not form an adequate b a s i s f o r naming new compounds. l In a r e c e n t review Bonnett has o u t l i n e d the.nomenclature of 4 b i o l o g i c a l l y i m p o r t a n t p o r p h y r i n s and r e l a t e d compounds. I t i s i n t e r e s t i n g t o note t h a t a l t h o u g h a more s y s t e m a t i c nomen-c l a t u r e i s now a v a i l a b l e ( v i d e i n f r a ) , most p o r p h y r i n c h e m i s t s s t i l l p r e f e r t o use F i s c h e r ' s , t r i v i a l n o m e n c l a t u r e . A complete numbering system f o r t h e p o r p h y r i n n u c l e u s ( F i g u r e IB) was f i r s t put f o r w a r d i n 1960. A c c o r d i n g t o t h i s , the c a r b o n atoms a r e numbered from 1 t o 20 w i t h the f o u r n i t r o g e n atoms b e i n g 21 t o 24. Based on t h i s numbering scheme a j o i n t commission on b i o c h e m i c a l - nomenclature (IUPAC-IUB) has proposed, a s y s t e m a t i c nomenclature f o r a l l p o r p h y r i n s and t h e i r d e r i v a t i v e s . The a p p l i c a t i o n o f t h e s e recommend-a t i o n s p e r m i t s t h e s e s u b s t a n c e s t o be named more s y s t e m a t i c a l l y -u s i n g fewer t r i v i a l names t h a n . a r e c u r r e n t l y used i n the l i t e r a t u r e . The p o r p h y r i n m a c r o c y c l e i s h i g h l y c o n j u g a t e d and a number of resonance forms can be w r i t t e n . There are 22 n - e l e c t r o n s on the c a r b o n s k e l e t o n b u t o n l y 18 o f t h e s e are i n c l u d e d i n any one d e l o c a l i z a t i o n pathway ( F i g u r e 1 ) . T h i s conforms w i t h H u c k e l ' s 4n+2 r u l e f o r a r o m a t i c i t y and a l s o e x p l a i n s why t h e s e compounds a r e e x t r e m e l y s t a b l e . The a r o m a t i c c h a r a c t e r i n p o r p h y r i n compounds has been c o n f i r m e d by measurements of t h e i r h e a t s o f combustion. F u r t h e r , X-ray i n v e s t i g a t i o n s o f b o t h m e t a l - f r e e p o r p h y r i n s and m e t a l l o -p o r p h y r i n s have shown th e p l a n a r i t y o f the n u c l e u s , which i s a b a s i c r e q u i r e m e n t f o r a r o m a t i c c h a r a c t e r . P o r p h y r i n s are h i g h l y c o l o r e d w i t h a v e r y i n t e n s e 5 a b s o r p t i o n band i n the r e g i o n o f 400nm. T h i s " S o r e t " band i s c h a r a c t e r i s t i c o f the m a c r o c y c l i c c o n j u g a t i o n and the r u p t u r e o f the m a c r o c y c l e r e s u l t s i n the d i s a p p e a r a n c e o f t h i s band. I n a d d i t i o n , t h e r e a r e f o u r bands i n the v i s i b l e r e g i o n , the r e l a t i v e i n t e n s i t i e s o f which v a r y depending on the p e r i p h e r a l s u b s t i t u e n t s o f the n u c l e u s . The i o n i z a t i o n o f the two i m i n e N-H p r o t o n s o f the p o r p h y r i n y i e l d s a d i a n i o n , which f u n c t i o n s as a v e r y s t a b l e t e t r a d e n t a t e l i g a n d towards a v a r i e t y o f m e t a l i o n s . The p o r p h i n a t o l i g a n d has t u r n e d o u t t o be v e r y v e r s a t i l e i n c o o r d i n a t i o n c h e m i s t r y but n a t u r e u t i l i z e s o n l y a few m e t a l s , Fe, Mg, Co, Cu and Zn b e i n g the most common ones. M e t a l l o -p o r p h y r i n s a r e c l a s s i f i e d a c c o r d i n g t o t h e i r s t o i c h i o m e t r y o r geometry o r b o t h . Four c o o r d i n a t e , s q u a r e - p l a n a r geometry i s r a t h e r r a r e and most c e n t r a l m e t a l i o n s t a k e up a d d i t i o n a l l i g a n d s t o complete t h e i r c o o r d i n a t i o n s p here. 1.2 SYNTHETIC ASPECTS OF PORPHYRINS In t h e l a b o r a t o r y , as w e l l as i n n a t u r e , p o r p h y r i n s a r e s y n t h e s i z e d from p y r r o l e s w h i c h i n t u r n a r e r e a d i l y o b t a i n e d from a c y c l i c p r e c u r s o r s . The meso car b o n atoms b r i d g e the a - p o s i t i o n s o f the s t a r t i n g p y r r o l e s , the 3-carbons becoming the 8 p e r i p h e r a l carbons i n the p o r p h y r i n m a c r o c y c l e . Thus t h e 6 s u b s t i t u t i o n p a t t e r n a t the p o r p h y r i n p e r i p h e r y depends p r i -m a r i l y on the 3 - s u b s t i t u t i o n of the s t a r t i n g p y r r o l e s . I t i s a l s o p o s s i b l e to i n t r o d u c e new groups or modify e x i s t i n g ones, a f t e r the p o r p h y r i n nucleus i s c o n s t r u c t e d . The p o r p h y r i n macrocycle c o u l d be c o n s t r u c t e d i n three fundamentally d i f f e r e n t ways. They ar e : (a) The s i n g l e step condensation of monopyrroles (b) The stepwise condensation of i n d i v i d u a l p y r r o l e s l e a d i n g to a l i n e a r t e t r a p y r r o l e and a f i n a l head-t o - t a i l c y c l i z a t i o n . (c) The c o u p l i n g of two d i p y r r o l i c i n t e r m e d i a t e s , commonly r e f e r r e d to as a "2+2 synthesis";; ' , The f i r s t method has very l i m i t e d s y n t h e t i c v a l u e . S i e d e l and W i n k l e r 4 obtained s e v e r a l 3 - s u b s t i t u t e d p o r p h y r i n s by h e a t i n g , e i t h e r dry or i n s o l u t i o n , compounds .having the g e n e r a l s t r u c t u r e shown below: HOOC When R = CH 3 , h e a t i n g a t 160O)-170o:iC gave 46.5% of octamethyl-p o r p h y r i n (OMP). T h i s r e a c t i o n i n v o l v i n g d e c a r b o x y l a t i o n and condensation was u n s u c c e s s f u l when one or both 3 - p o s i t i o n s 7 were u n s u b s t i t u t e d . T r e i b s and H a b e r l e 5 obtained 77% of OMP from the r e a c t i o n of 3,4-dimethylpyrrole w i t h formaldehyde , i n a c e t i c a c i d and p y r i d i n e . T h i s l a t t e r r e a c t i o n has been extended to prepare s e v e r a l meso-substituted p o r p h y r i n s , the most common one being meso-tetraphenylporphyrin 1 (TPP) 6 1 Porphyrins s u b s t i t u t e d i n both meso and 3 - p o s i t i o n s have been prepared by T r e i b s and H a b e r l e 5 and D o l p h i n 7 . The search f o r a l t e r n a t i v e s y n t h e t i c m ethods,[partic-u l a r l y f o r those p o r p h y r i n s with unsymmetrically arranged B - s u b s t i t u e n t s l e d to the development of syntheses i n v o l v i n g the c o u p l i n g of i n d i v i d u a l p y r r o l e s i n an unambiguous manner. Such methods u t i l i z e d s t a b l e i n t e r m e d i a t e s l e a d i n g to l i n e a r t e t r a p y r r o l e s which are c y c l i z e d i n the l a s t step. The four b a s i c types of l i n e a r t e t r a p y r r o l i c i n t e r m e d i a t e s are shown i n F i g u r e 2. 8 H H H H 1 , 1 9 - D i d e o x y b i l a n e H ° H b c H 1 , 1 9 - D i d e o x y b i l e n e - b H a b H 1 , 1 9 - D i d e o x y b i l a d i e n e - a c 1 , 1 9 - D i d e o x y b i l a t r i e n e - a b c FIGURE 2 : L i n e a r T e t r a p y r r o l i c Intermediates i n Po r p h y r i n Syntheses 9 The p r e p a r a t i o n of such i n t e r m e d i a t e s and t h e i r use i n p o r p h y r i n syntheses are d i s c u s s e d by Johnson 8. Syntheses of p o r p h y r i n s based on the c o u p l i n g of two d i p y r r o l i c i n t e r m e d i a t e s (2+2 syntheses) have been widely used i n p o r p h y r i n chemistry. Many ou t s t a n d i n g p o r p h y r i n syntheses have been accomplished u s i n g t h i s method. The three d i p y r r o l i c i n t e r m e d i a t e s encountered i n such syntheses are: (a) D i p y r r o m e t h a n e s (b) D i p y r r o m e t h e n e s ( c ) D i p y r r o k e t o n e s 1 0 D i p y r r o m e t h a n e s The u n s y m m e t r i c a l d i p y r r o m e t h a n e s 5 a r e p r e p a r e d b y t h e r e a c t i o n o f a p y r r y l c a r b i n y l c a t i o n 3_ w i t h an c t - U n s u b -s t i t u t e d p y r r o l e 4 as shown b e l o w . etc. The p y r r y l c a r b i n y l c a t i o n s c a n be f o r m e d r e a d i l y f r o m p r e c u r s o r s s u c h as 2 a n d a r e s t a b i l i z e d b y t h e d e r e a l i z a t i o n o f t h e 1 1 p o s i t i v e c h a r g e t h r o u g h o u t t h e e l e c t r o n r i c h p y r r o l e n u c l e u s . T h e s t a b i l i t y o f t h e d i p y r r o m e t h a n e s d e p e n d s o n t h e p r e s e n c e o f e l e c t r o n w i t h d r a w i n g s u b s t i t u e n t s s u c h a s e s t e r s , a l d e h y d e s e t c . ( a t l e a s t o n e p e r r i n g ) . T h e o n l y r e a c t i o n e f f e c t i v e l y e x p l o i t e d i n t h e 2 + 2 ' p o r p h y r i n ^ s y n t h e s e s ^ v i a d i p y r r o m e t h a n e s , h a s b e e n t h e a c i d c a t a l y s e d c o u p l i n g o f a n a - f o r m y l g r o u p w i t h a n a - f r e e p y r r o l e . T h e t w o t y p e s o f r e a c t a n t s c o m m o n l y u s e d a r e s h o w n i n F i g u r e 3 . I n e i t h e r c a s e , t h e r e a c t i o n p r o c e e d s v i a a b i l e n e - b t o a p o r p h o d i m e t h e n e w h i c h u n d e r g o e s a u t o x i d a t i o n n t o t h e p o r p h y r i n . D i p y r r o m e t h e n e s D i p y r r o m e t h e n e s a r e s t r o n g b a s e s a n d a r e b e s t h a n d l e d i n t h e i r m o r e s t a b l e p r o t o n a t e d f o r m , t h e d i p y r r o m e t h e n i u m s a l t s , o f w h i c h t h e b r o m i d e s h a v e b e e n b y f a r t h e m o s t p o p u l a r . T h e g e n e r a l s y n t h e s e s o f a d i p y r r o m e t h e n e i s t h e c o n d e n s a t i o n o f a n a - f o r m y l p y r r o l e 6_ w i t h a n c t - f r e e p y r r o l e 7 i n t h e p r e s e n c e o f a s t r o n g a c i d . 6 7 Por phodimethene Porphyr in FIGURE 3 : P o r p h y r i n S y n t h e s i s v i a the 2 + 2 Coupling of Dipyrromethanes 13 In a d d i t i o n , s e v e r a l s p e c i a l i z e d syntheses of dipyrromethenes have been d e v i s e d . S o l v o l y s i s of p y r r o l e s such as 8 i n a hot s o l u t i o n of hydrobromic and formic a c i d s l e a d to dipyrromethenes by head-to-head condensation. Br" _8 X = H. C02H. C02 t-Bu In the presence of bromine, a-methy1-a-free p y r r o l e s 9 condense i n a h e a d - t o - t a i l f a s h i o n , g i v i n g , a mixture of dipyrromethenes 10 and 11. 14 Porphy r i n s have been s y n t h e s i z e d from dipyrromethenes such as 10 by r e f l u x i n g i n formic a c i d . The s e l f - c o n d e n s a t i o n i s of the h e a d - t o - t a i l f a s h i o n and as such, the r e s u l t i n g p o r p h y r i n i s o f "type I" (Se c t i o n 1.1). The a-bromo a'-methyl d i p y r r o -methene perbromides 1_1 have a l s o been converted to p o r p h y r i n s by the use of anhydrous formic a c i d . The condensation of an a, a'-dibromodipyrromethene wi t h an a , a ' - d i m e t h y l d i p y r r o -methene under s i m i l a r c o n d i t i o n s i n the presence of 1 equiv-a l e n t of bromine producesca p o r p h y r i n o n l y upon e v a p o r a t i o n of the r e a c t i o n mixture i n a i r . T h i s suggests the involvement of a porphodimethene i n t e r m e d i a t e which o x i d i z e s to the p o r p h y r i n r a t h e r s l o w l y i n str o n g a c i d medium. Pipy r r o k e t o n e s Dipyrroketones have o n l y l i m i t e d use among the one step 2+2 . syntheses of p o r p h y r i n s . The meso ca r b o n y l f u n c t i o n a l i t y d e a c t i v a t e s the d i p y r r o k e t o n e , e s p e c i a l l y under a c i d i c c o n d i t i o n s , and prevents i t from being used as the n u c l e o p h i l e i n the u s u a l c o u p l i n g r e a c t i o n s . As the e l e c t r o -p h i l i c component, a., a' - d i f o r m y l d i p y r r o k e t o n e s c o u l d be condensed wi t h a , a ' - d i - u n s u b s t i t u t e d dipyrromethanes, to g i v e a f t e r o x i d a t i o n , an o x o p h l o r i n (oxyporphyrin) 12. 15 The o x o p h l o r i n s may be converted to por p h y r i n s by meso a c e t y l a t i o n f o l l o w e d by hydrogenative r e d u c t i o n and r e -O x i d a t i o n of the r e s u l t i n g porphyrinogen. Dipyrroketones have been f a r more u s e f u l i n the m u l t i s t e p s y n t h e s i s of por p h y r i n s v i a o x o b i l a n e s . In a r e c e n t review, P a i n e 9 d i s c u s s e s i n d e t a i l , the c o n s t r u c t i o n of the p o r p h y r i n macrocycle u s i n g d i p y r r o l i c i n t e r m e d i a t e s . 1.3 METALLOPORPHYRINS AS BIOLOGICAL OXYGEN CARRIERS Por p h y r i n s , p o r p h y r i n d e r i v a t i v e s and p o r p h y r i n -l i k e m a t e r i a l s p l a y a l a r g e number of w e l l d i v e r s i f i e d and w e l l e s t a b l i s h e d b i o l o g i c a l r o l e s . Of these, one of the most s i g n i f i c a n t i s i t s r o l e i n the transport,exchange and storage of oxygen. Hemoglobin and myoglobin combine r e v e r s i b l y w i t h dioxygen i n the blood and t i s s u e s of a l l v e r t e b r a t e s by v i r t u e of a "heme" [i i r o n (II) porphyrin] p r o s t h e t i c group 14_. For t h i s c l a s s o f r e s p i r a t o r y pigments, the Ee ( I I ) i o n i s c h e l a t e d to the four core n i t r o g e n atoms of the s p e c i f i c p o r p h y r i n , p r o t o p o r p h y r i n IX (Pp) 13. M = CH 3 V = CH=CH 2 P = CH2CH2COOH P r o t o p o r p h y r i n IX (Pp) 13 Heme = F e ( I I ) P p 14 In the heme p r o t e i n s of v e r t e b r a t e s the p o r p h y r i n i s embedded i n a s t r o n g l y non p o l a r hydrophobic environment p r o v i d e d by the amino a c i d s a l a n i n e , i s o l e u c i n e , l e u c i n e , p h e n y l a l a n i n e and v a l i n e of the p o l y p e p t i d e c h a i n s . The a c i d groups of the p o r p h y r i n extend out of t h i s pocket. Myoglobins are monomeric, being composed of onl y one p r o t e i n c h a i n while most v e r t e b r a t e hemoglobins are t e t r a m e r i c c o n t a i n i n g four such p o l y p e p t i d e s u b u n i t s , each having one heme group. The normal a d u l t human hemoglobin molecule c o n t a i n s two subunits known as the a-chains and two subunits c a l l e d the 3-chains. The s t r u c t u r e of the 3-subunit as deduced from x - r a y data i n d i c a t e s t h a t v t h e heme p r o s t h e t i c group l i e s i n a c r e v i c e , being h e l d i n pl a c e by non bonding i n t e r a c t i o n s with the p r o t e i n . The s i n g l e c o v a l e n t attachment of the heme to the p r o t e i n occurs by c o o r d i n a t i o n of the heme i r o n to the i m i d a z o l e n i t r o g e n of the s o - c a l l e d "proximal" h i s t i d i n e r e s i d u e . In the deoxygenated s t a t e the f e r r o u s i o n i s found to be f i v e - c o o r d i n a t e . Four of i t s c o o r d i n a t i o n s i t e s are s a t i s f i e d by the p o r p h y r i n moiety while the f i f t h a x i a l pos-i t i o n i s occupied by the im i d a z o l e group. In t h i s conformation the i r o n has been shown to be i n the hig h s p i n s t a t e with square pyramidal geometry. S t r u c t u r a l s t u d i e s on i r o n por-p h y r i n s have l e d to the g e n e r a l l y accepted p r o p o s a l t h a t the i r o n atom w i l l be a t l e a s t 0.5 A 0 out of the mean plane of the p o r p h y r i n , towards the c o o r d i n a t e d i m i d a z o l e . Oxygenation leads to a s i x - c o o r d i n a t e low s p i n system i n which the i r o n 11 i s e s s e n t i a l l y i n the porphyr-ini p^lane- and t h e motion, o f the i r o n atom upon oxygenation has been demonstrated by d i f f e r e n c e 1 2 F o u r i e r techniques . Although many d e t a i l s of the s t r u c t u r e s 18 of hemoglobin and myoglobin are known, the nature of the iro n - d i o x y g e n bond has been a c o n t r o v e r s i a l s u b j e c t f o r some time, p a r t i c u l a r l y as t o whether the geometry approximates to e i t h e r one of the s t r u c t u r e s shown below: 0 = 0 J — Fe — i i • — Fe — An a c c u r a t e d e t e r m i n a t i o n of oxyhemoglobin and oxymyoglobin s t r u c t u r e s has been delayed c o n s i d e r a b l y due to the problem of o x i d a t i o n o f the i r o n c e n t r e to Fe (III).' d u r i n g X-ray measurements. Recent advances i n low temperature techniques ha^ve made the s t r u c t u r e d e t e r m i n a t i o n p o s s i b l e f o r sperm whale 1 3 oxymyoglobin - , which has shown t h a t oxygen i s bonded i n the o end-on f a s h i o n w i t h an Fe-O-0 angle of 121 . The most i n t e r e s t i n g p r o p e r t y of hemoglobin i s i t s c o o p e r a t i v e b i n d i n g o f oxygen, which makes i t the unique oxygen c a r r i e r i n v e r t e b r a t e s . The e q u i l i b r i u m uptake of oxygen by t e t r a m e r i c hemoglobin t u r n s out to be more complex than f o r the case of the heme-protein monomers. The a f f i n i t y of a subuni t to add a s i n g l e molecule of oxygen i s ap p a r e n t l y dependent upon the number of other subunits oxygenated i n the tetramer. T h i s g i v e s hemoglobin the a b i l i t y to show high a f f i n i t y a t hig h p a r t i a l p r e s s u r e s (e.g., i n the lungs) and low a f f i n i t y a t low oxygen p r e s s u r e s (e.g., i n the t i s s u e s ) , which i s c r i t i c a l to e f f i c i e n t oxygen t r a n s p o r t . The co-o p e r a t i v i t y hinges f i r s t upon r e l a y i n g to the other hemes the i n f o r m a t i o n t h a t one heme has been l i g a t e d and second, upon u t i l i z i n g t h i s i n f o r m a t i o n to a l t e r the oxygen a f f i n i t y at thoseshemes. Of the many ways i n which the p r o t e i n might c o n t r o l the c o o p e r a t i v i t y of hemoglobin, the most widely accepted i s the t r i g g e r mechanism proposed by Perutz and co-workers 1 0' 1' 4 f o l l o w i n g the suggestions of W i l l i a m s 1 5 and H o a r d 1 6 . The b a s i s of t h i s model i s the e x i s t e n c e of two s t a t e s , a tense (T) s t a t e and a r e l a x e d (R) state,, f o r the hemoglobin tetramer. With no oxygen present, the T-state, c h a r a c t e r i z e d by a l a r g e i r o n - p o r p h y r i n d i s t a n c e i s s a i d to be more s t a b l e than the R-state. On oxygenation, the heme i r o n moves i n t o the mean plane of the por p h y r i n s which i s accompanied by the movement of the c o v a l e n t l y l i n k e d "proximal" h i s t i d i n e r e s i d u e . T h i s causes a change i n the s t r u c t u r e of the p r o t e i n t h a t r e s u l t s i n the decrease i n the s t a b i l i t y of the T - s t a t e r e l a t i v e t o the R-state and causes the observed c o o p e r a t i v i t y . Thus, t h i s model i s based e s s e n t i a l l y on the movement of the i r o n atom i n and out of the mean p o r p h y r i n plane. However, i t should be noted t h a t other i n v e s t i g a t o r s have concluded t h a t there are some shortcomings or unre s o l v e d d i f f i c u l t i e s i n t h i s t r i g g e r mechanism. 1 7 20 1.4 SYNTHETIC MODELS FOR BIOLOGICAL OXYGEN CARRIERS There have been many e f f o r t s to s y n t h e s i z e simpler Fe(II) complexes t h a t would r e v e r s i b l y bind oxygen i n the hope t h a t s t u d i e s on such systems would g i v e i n f o r m a t i o n about the nature of the metal-dioxygen bond and the a s s o c i a t e d k i n e t and thermodynamic f a c t o r s . A major problem i n d e s i g n i n g such a p r o t e i n - f r e e model f o r the heme p r o t e i n s has been the d i f f -i c u l t y of s y n t h e s i z i n g a s u i t a b l e h i g h - s p i n f i v e - c o o r d i n a t e F e ( I I ) ' , complex of the type F e I I ( P ) L (P = p o r p h y r i n ; L = nitrogeneous base such as i m i d a z o l e ) . Low-spin s i x - c o o r d i n a t e F e ^ y P j L u s u a l l y r e s u l t and i n c o n t r a s t to the r e v e r s i b l e . 2 oxygen b i n d i n g a b i l i t y of heme p r o t e i n s , such simple f e r r o u s p o r p h y r i n s are r a p i d l y and i r r e v e r s i b l y o x i d i z e d to Fe( I I I ) by molecular oxygen. The r e v e r s i b l e oxygen b i n d i n g p r o p e r t y of heme p r o t e i n s dependsCG'ri:treall>y-~o,n i^he^faettithat--the "iron c e n t r e i s not o x i d i z e d . I t i s now g e n e r a l l y b e l i e v e d t h a t t h i s a u t o x i d a t i o n proceeds v i a the formation o f the monomeric iron - d i o x y g e n adduct, which subsequently d i m e r i z e s to a M —peroxo dimer e v e n t u a l l y producing a y-oxocddmer. F e I 3 : ( P ) L 2 l FeIJ(P)L + L F e I 3 : ( P ) L + 0 2 J L ( P ) F e I 3 : 0 2 L ( P ) F e I 3 : 0 2 + F e i : [ ( P ) L + L ( P ) F e i : E I - 0 2 - F e i : C I ( P ) L L ( P ) F e I I I - 0 2 - F e I I I ( P ) L - 2 L ( P ) F e I V - 0 L ( P ) F e I V _ 0 + F e I 3 : ( P ) L + ( P ) F e I I I - 0 - F e I I I ( P ) + 2 L 21 Research on s y n t h e t i c models f o r the n a t u r a l l y o c c u r i n g heme p r o t e i n s has undergone s i g n i f i c a n t t h e o r e t i c a l and experimental developments w i t h i n the l a s t decade. Although carbon monoxide i s not a n a t u r a l s u b s t r a t e i n b i o l o g i c a l systems i t s i n t e r a c t i o n has a l s o been widely s t u d i e d . T h i s i n t e r e s t i n carbon monoxide d e r i v e s from i t s s t r o n g b i n d i n g to those m e t a l l o p r o t e i n s which bi n d or u t i l i z e oxygen and i t s consequent a b i l i t y to i n t e r f e r e with or i n h i b i t t h e i r f u n c t i o n . The s u b s t i t u t i o n o f i r o n by s e v e r a l d i v a l e n t metal ions has a l s o proved to be a u s e f u l technique i n these s t u d i e s . Since the work d e s c r i b e d i n t h i s t h e s i s i s concerned with the development of a new s y n t h e t i c route f o r model systems, on l y some s e l e c t e d models w i l l be d i s c u s s e d h e r e , " p r i m a r i l y . f r o m a 1 8 1 9 s y n t h e t i c p o i n t of view. Two e x c e l l e n t reviews" ' •'. have appeared r e c e n t l y t h a t d i s c u s s the k i n e t i c and thermodynamic o b s e r v a t i o n s i n t h i s area o f r e s e a r c h . The two most d e s i r a b l e f e a t u r e s of a model f o r the n a t u r a l heme o x y g e n - c a r r i e r s a r e : (a) the a b i l i t y t o form a s t a b l e f i v e - c o o r d i n a t e geometry of the type Fe**(P)L and-' (b) the suppression of the i r r e v e r s i b l e o x i d a t i o n by i n h i b i t -i n g d i m e r i z a t i o n . S e v e r a l o f the s y n t h e t i c models designed to prevent a u t o x i d a t i o n of the f e r r o u s heme have a l s o l e d to the formation of f i v e - c o o r d i n a t e d i r o n - p o r p h y r i n systems. The syntheses o f p o r p h y r i n s w i t h p r o t e c t i v e s t r u c t u r e s c o v e r i n g one face of the macrocycle appeared to be the best s o l u t i o n to the problem of d i m e r i z a t i o n . Foxr t h i s purpose two approaches 22 have been advanced. One route begins w i t h the non-porphyrin p a r t and the p o r p h y r i n p r e c u r s o r s are b u i l t onto the two ends. The p o r p h y r i n r i n g i s f i n a l l y c y c l i z e d by i n t r a m o l e c u l a r condensation. An a l t e r n a t i v e b r i d g e forming method s t a r t s w i t h the p o r p h y r i n nucleus i t s e l f . A p p r o p r i a t e f u n c t i o n a l groups are i n t r o d u c e d to the two d i a g o n a l l y s u b s t i t u t e d s i d e chains which are then condensed with another b i f u n c t i o n a l molecule to form the b r i d g e . 2 0 T r a y l o r and c o l l a b o r a t o r s were the f i r s t to r e p o r t the s y n t h e s i s of a p o r p h y r i n t h a t u t i l i z e d s t e r i c encumberance to i n h i b i t i r r e v e r s i b l e o x i d a t i o n . U n f o r t u n a t e l y , no b i n d i n g s t u d i e s have ever been r e p o r t e d with t h i s system. The two most s i g n i f i c a n t f e a t u r e s of t h i s s y n t h e s i s a r e , (a) the use of dipyrromethenes as i n t e r m e d i a t e s and (b) t a k i n g advantage of Cu(II). „. i o n c h e l a t i o n to f i x the dipyrromethene ends i n proper p o s i t i o n f o r an i n t r a m o l e c u l a r condensation. The cyclophane system 17_ (Figure 4) was s y n t h e s i z e d s t a r t i n g from b i p h e n y l 1(5 by two s u c c e s s i v e F r i e d e l - C r a f t s p a e y l a t i o n r e a c t i o n s (each f o l l o w e d by a W o l f f - K i s h n e r r e d u c t i o n ) , the f i r s t one u t i l i z i n g s u c c i n i c a c i d and the second u s i n g 3-carbomethoxypropionyl c h l o r i d e . The d i a c i d 1_7 was converted to the b i s a c i d c h l o r i d e 1_8_ and then l i n k e d to two molecules of the p y r r o l e 19 by F r i e d e l - C r a f t s aaey.Mvtion. The d i k e tone. 2 0 was subsequently reduced to 2_1 . T h i s was then c a r r i e d through standard p y r r o l e t r a n s f o r m a t i o n s to g i v e the a - f ormy 1 - a ''- cairboxy-py^rorlcel e dimer >-24 which was condensed with the a - u n s u b s t i t u t e d p y r r o l e 2_5 i n HBr i n a c e t i c a c i d to 1 5 R = (CH 2 )^CO^t 16 17 : x = OH 1 8 : x = ci 18 • «• 2 F l N C O ^ t 19 COjEt 2 0 -l2 'XX 21 C H 3 c o ^ t 2 2 C H 3 COjCHjPh 2 3 CHO C O ^ H j P h 2U CHO c o ^ 2 4 2 f l H N ' C H , .QHCH, „ , - , . 2 6 : R '=CO,H , R = (cH,),co-,Et 2 5 : R = ( C H ^ c o ^ t — 2 2 3 2 2 7 : R'= Br ; R ^ I C H ^ C O - E t 2 8 R'= I C H j I j C O ^ t FIGURE 4 : S y n t h e s i s of the Cyclophane P o r p h y r i n of T r a y l o r e t . a l . g i v e the dipyrromethene dimer 2_6. A f t e r c o n v e r t i n g the carboxy group o f 2_6 to bromo groups by r e a c t i n g w i t h Br^ i n a c e t i c a c i d , the r e s u l t i n g pyrromethene 2_7 was transformed i n t o i t s copper complex 28. Heating 2_8_ i n xylene with t r i e t h y l a m i n e gave the copper complex of the p o r p h y r i n 1_5 i n a low y i e l d of approx-ima t e l y 5%. The i n a b i l i t y of the authors to improve the y i e l d c o u l d be why more work has not been r e p o r t e d . Baldwin and co- w o r k e r s 2 1 s y n t h e s i z e d a more hindered "capped" p o r p h y r i n u t i l i z i n g the same s t r a t e g y , i . e . , b u i l d i n g up the p o r p h y r i n a t the ends of the "cap". The s y n t h e t i c approach was much simpler as they used the s i n g l e step c o u p l i n g o f an aromatic aldehyde w i t h p y r r o l e (Figure 5). The t e t r a a l d e h y d e s 29 (x = 2 or 3) were prepared from s a l i c y l a l d e h y d e and condensed s e p a r a t e l y with 4 e q u i v a l e n t s of p y r r o l e 30_ i n r e f l u x i n g prop-i o n i c a c i d to g i v e the "cap" (x — 2) and the "homologous cap" (x = 3) por p h y r i n s 3_1 i n approximately 2% y i e l d . R e v e r s i b l e oxygenation of the Fe(II) s u b s t i t u t e d capped p o r p h y r i n i n 2 2 p y r i d i n e s o l u t i o n had been f o l l o w e d s p e c t r o s c o p i c a l l y and at 25°C,, the l i f e time of the dioxygen adduct was found to be approximately 20 hours. In benzene s o l u t i o n s c o n t a i n i n g 5% 1-methylimidazole, the l i f e time had decreased to 5 hours. With the Fe(II) "homologous cap" system these workers r e c e n t l y r e p o r t e d 2 3 some s p e c t r o s c o p i c o b s e r v a t i o n s t h a t suggest the weak b i n d i n g of a second l-methylimidazol^e "- l i g a n d (under the cap) to y i e l d a 6-coordinate s p e c i e s . They b e l i e v e t h a t the complex so formed binds dioxygen r e v e r s i b l y , without d i s p l a c i n g 25 FIGURE 5 : S y n t h e s i s of the Capped P o r p h y r i n of Baldwin e t . a l . t h e w e a k l y bound l i g a n d . An a l t e r n a t i v e h i n d e r e d p o r p h y r i n known as a " s t r a p p e d " m o d e l was r e p o r t e d 2 4 by B a l d w i n ' s g r o u p , t h e s y n t h e s i s o f w h i c h a l s o u t i l i z e d t h e s t r a t e g y o f b u i l d i n g t h e p o r p h y r i n a t t h e e n d s o f t h e s t r a p ( F i g u r e 6 ) . The s y n t h e s i s f o l l o w e d t h e 2 5 d i p y r r o m e t h a n e r o u t e d e v e l o p e d by K e n n e r and c o l l a b o r a t o r s . The b i s a l d e h y d e s 32_ and 3_3 ( e a s i l y o b t a i n e d f r o m r e a d i l y a v a i l a b l e s t a r t i n g m a t e r i a l s ) w e r e e a c h c o n d e n s e d w i t h t h e a - u n s u b s t i t u t e d p y r r o l y l b e n z y l e s t e r 3_4 t o g i v e t h e b i s d i p y r r o m e t h a n e s 3_5 and 3_6. T h e s e were s u b s e q u e n t l y d e b e n z y l -a t e d ( c a t a l y t i c h y d r o g e n a t i o n ) and t r e a t e d w i t h t r i m e t h y l o r t h o f o r m a t e i n d i c h l o r o m e t h a n e w i t h t r i c h l o r o a c e t i c a c i d , t o p r o d u c e t h e p o r p h y r i n s 37_ and 3_8. A l t h o u g h t h e F e ( I I ) c o m p l e x e s o f b o t h p o r p h y r i n s w e re o x y g e n a t e d r e v e r s i b l y a t l o w t e m p e r a t u r e s (-55°C), a t 25°C t h e y w e r e c o n v e r t e d i r r e v e r s i b l y i n t o u-oxo d i m e r s . The more w i d e l y u s e d a p p r o a c h t o t h e s y n t h e s i s o f h i n d e r e d p o r p h y r i n s h a s b e e n t h e s e c o n d r o u t e m e n t i o n e d e a r l i e r , i . e . , t o c o n d e n s e a d i a g o n a l l y s u b s t i t u t e d p r e f o r m e d p o r p h y r i n w i t h a b i f u n c t i o n a l m o l e c u l e . B a t t e r s b y and c o - w o r k e r s 2 6 u s e d t h i s a p p r o a c h w i t h s e v e r a l s y n t h e t i c v a r i a t i o n s t o p r o d u c e a s e r i e s o f b r i d g e d p o r p h y r i n s y s t e m s . 27 FIGURE 6 : S y n t h e s i s of the Strapped P o r p h y r i n of Baldwin e t . a l . 28 The b i s a c i d c h l o r i d e of mesoporphyrin II 3_9 was used as the s t a r t i n g p o r p h y r i n and was r e a c t e d with h e x - 5 - y n - l - o l to g i v e the d i e s t e r 4_0. T h i s , when su b j e c t e d to an o x i d a t i v e c o u p l i n g a t h i g h d i l u t i o n with copper (II) a c e t a t e i n p y r i d i n e - e t h e r gave the copper complex of 4_1. The compound 41 was hydrogenated and d'emefca-Ma-bed'.d' to produce the s a t u r a t e d b r i d g e d system 42. These workers were a l s o able to s y n t h e s i z e the p o r p h y r i n 4_3_ with an amide l i n k e d b r i d g e system by r e a c t i n g 3_9 d i r e c t l y with 1 ,;i2Vdlfam1iinodo'd"ecan,ee under h i g h d i l u t i o n . The F e ( I I ) complexes of these systems were a l s o i r r e v e r s i b l y o x i d i z e d a t room temperature. 29 Using s i m i l a r s y n t h e t i c s t r a t e g y and s t a r t i n g m a t e r i a l s Ogoshi and c o - w o r k e r s 2 7 produced a s e r i e s of c y c l o -phane por p h y r i n s s i m i l a r to 43_ with d i f f e r e n t c h a i n l e n g t h s . A mixture of the p o r p h y r i n - b i s - p r o p i o n i c a c i d , i s o b u t y l c h loroformate and t r i e t h y l a m i n e i n dry t e t r a h y d r o f u r a n was t r e a t e d with bis-amines of the type H N-(CH ) -NH (n=6, 7, 2 2 n 2 8, 9, 10, 12), to o b t a i n the corresponding cyclophane p o r p h y r i n s . They observed t h a t with the -n=6 ^systemu-the-F e ( I I ) complex produced o n l y the 5-coordinate i n t e r m e d i a t e with p y r i d i n e , but was- r a p i d l y and i r r e v e r s i b l y o x i d i z e d i n the presence of oxygen. The s y n t h e s i s of the "crowned" p o r p h y r i n by Chang 2 8 was a l s o along the same l i n e s . He too used a p o r p h y r i n (d-ihexyldeuteroporphyrin II) which c a r r i e d two p r o p i o n i c a c i d s i d e c h a i n s . T h i s was condensed wi t h the bis-amine 44 c o n t a i n i n g a l a r g e crown ether group. 30 In the presence of 1-methylimidazole,' the F e ( I I ) complex of t h i s p o r p h y r i n e x h i b i t e d the r e g u l a r 6-coordinate spectrum i n d i c a t i n g t h a t the base had c r e p t under the s t r a p . F u r t h e r , i t s dioxygen complex was found to have a h a l f - l i f e of o n l y 3 minutes a t room temperature. Based on the same s y n t h e t i c approach T r a y l o r and c o - w o r k e r s 2 9 r e c e n t l y s y n t h e s i z e d the "anthracene-heme^ cyclophane" system by condensing a d i a g o n a l l y s u b s t i t u t e d porphyrin-bis-amine with the b i s a c i d c h l o r i d e 4_5 shown below. 46 47 In order to reduce the f l e x i b i l i t y of the cyclophane system, these workers performed a D i e l s - A l d e r a d d i t i o n of 4_6_ on the anthracene group and obtained the "pagoda p o r p h y r i n " , with the group 4_7 being l i n k e d to the d i a g o n a l 3 - p o s i t i o n s by -CH2-NH-CO-(CH2) -. P r e l i m i n a r y b i n d i n g s t u d i e s of the Fe ( I I ) system i n the presence of 1-methylimidazole have provided evidence f o r the e x i s t e n c e of a 5-coordinated s p e c i e s i n s o l u t i o n demonstrating the s t e r i c e f f e c t of the bulky group. Of a l l the s y n t h e t i c models t h a t have appeared to date, the one t h a t has had the g r e a t e s t success i n mimicking the r e v e r s i b l e oxygen b i n d i n g p r o p e r t y of heme p r o t e i n s i s the so c a l l e d " p i c k e t - f e n c e p o r p h y r i n " of Collman and co-workers. 3 0 Designing t h i s model was based on the f a c t t h a t i n meso-t e t r a p h e n y l - p o r p h y r i n (TPP) 1_, the phenyl r i n g s are perpen-d i c u l a r to the plane of the p o r p h y r i n . Thus^an^orthb-substituent on the phenyl r i n g , m o d i f i e d i n t o a bulky group c o u l d e f f e c t i v e l y b l ock one face of the p o r p h y r i n molecule. For t h i s purpose these workers prepared m e s o - t e t r a ( o - n i t r o p h e n y l ) p o r p h y r i n 4_8_ by r e a c t i n g o-nitrobenzaldehyde with p y r r o l e and by a g/tan'n~o<us5 c h l o r i d e r e d u c t i o n o f 48_, obtained meso-t e t r a (o-aminophenyl) p o r p h y r i n (H^TamPP) 49. 32 48 : R = N O 2  4 9 : R = N H 2  50 : R = N H C O C ( C H 3 ) 3 The a , a, a, a atropisomer was separated from the o t h e r s by chromatography and i t s c o n f i g u r a t i o n was f r o z e n by the form-a t i o n of the pivalamide 5_0. The four bulky pivalamide groups hinder the approach of a second such group so w e l l , t h a t these workers were ab l e to i s o l a t e a c r y s t a l l i n e dioxygen complex of F e ( I I ) and determine i t s c r y s t a l s t r u c t u r e . One of the b i g g e s t problems encountered i n attempting to mimic the b i o l o g i c a l system with most of the model compounds i s m a i n t a i n i n g a s i n g l e s p e c i e s i n solution',- i . e . , the 5-c o o r d i n a t e F e ( I I ) system. Unless a very bulky nitrogeneous base i s used a second l i g a n d molecule i s observed to c o o r d i n a t e 33 to the central i r o n atom on the side of the protective covering To overcome th i s problem Traylor and co-workers 3 1 constructed a porphyrin i n which a nitrogeneous base was covalently linked onto the periphery. These "tail-base" porphyrins produced 5-coordinate species as expected. Further, by using carbon monoxide to protect against oxidation and removing i t quickly by f l a s h photolysis these workers were able to use rapid spectroscopic and k i n e t i c methods i n mixtures of CO and 0^ to study the solution behaviour of the metalloporphyrins. By varying the length of the carbon chain that l i n k s the base to the porphyrin periphery i t has also been possible to obtain a working model for the R and T states of hemoglobin. 3 2 C O R 1 COR' 51 R 1 = R 2 = 0 H : R3= R 4 = C02CH2Ph 53 The l a t e s t addition to this long l i s t of synthetic models was the doubly b r i d g e d system of B a t t e r s b y and Hamilton. The s t a r t i n g p o i n t of t h i s s y n t h e s i s was the d i f f e r e n t i a l l y p r o t e c t e d p o r p h y r i n 5_1 which was l i n k e d to the p y r i d i n e con-t a i n i n g d i o l 52 by c o n v e r t i n g R1 and R2 (51) to c h l o r i d e s . The anthracene cap was subsequently i n t r o d u c e d by c o n v e r t i n g R 3 and R 4 to a c i d f u n c t i o n s (by h y d r o g e n o l y s i s ) , o b t a i n i n g the b i s a c i d c h l o r i d e and condensing t h i s w i t h the d i o l 53_ (The i n c o r p o r a t i o n of the metal i o n was found to be e a s i e r p r i o r to the i n t r o d u c t i o n of the anthracene c a p ) . P r e l i m -i n a r y s o l u t i o n s t u d i e s with t h i s system have shown t h a t i t binds dioxygen r e v e r s i b l y a t the F e ( I I ) c e n t r e but the l i f e time of the s p e c i e s has been s h o r t . 35 CHAPTER 2 RESULTS AND DISCUSSION 36 2.1 SYNTHETIC OBJECTIVE One of the most s i g n i f i c a n t s t r u c t u r a l f e a t u r e s of m e t a l l o p o r p h y r i n s i s the l e n g t h of the metal-porphine n i t r o g e n (M-N) bond. The v a r y i n g s i z e s and the complexing powers of the metals c o o r d i n a t e d to the p o r p h y r i n diaruion l e a d to v a r y i n g M-N v a l u e s and as i s the case of a l l m a c r o c y c l i c l i g a n d s , c o n s t r a i n t s of the p o r p h y r i n r i n g l i m i t the range of a c h i e v a b l e M-N d i s t a n c e s . In c o n t r a s t to the r e s i s t a n c e of the porphinato core to undergo undue r a d i a l expansion or c o n t r a c t i o n i s the ease of i t s deformation normal to the mean plane. Such a doming of the pl a n a r system would a l l o w the i n c r e a s e of the M-N d i s t a n c e by p o s i t i o n i n g the metal out of the mean plane of the four n i t r o g e n atoms. Although such deformations are unfavourable to maximizing the d e l o c a l i z e d IE bonding, non-pla n a r conformations are known to e x i s t i n c r y s t a l l i n e m e t a l l o p o r p h y r i n s . The square pyramidal geometry (shown below) i s very common f o r 5-coordinate m e t a l l o p o r p h y r i n s e s p e c i a l l y f o r z i n c , magnesium, c o b a l t (II) and h i g h - s p i n i r o n systems. The displacement of the metal atom from the mean plane i s a p h y s i c a l l y r e a l p r o p e r t y of m e t a l l o p o r p h y r i n s of t h i s c l a s s and i t s magnitude v a r i e s from 0.1 to >0.5 A 0 . In Perutz's s t e r e o c h e m i c a l t r i g g e r mechanism f o r c o o p e r a t i v e 37 oxygenation o f hemoglobin ( S e c t i o n 1.3), the primary t r i g g e r i s the l a r g e change i n the s t e r e o c h e m i s t r y of the c o o r d i n a t i o n group of heme which i s concomitant with the t r a n s f o r m a t i o n from high s p i n 5 - c o o r d i n a t i o n to low s p i n 6 - c o o r d i n a t i o n . The domed p o r p h y r i n system w i t h the metal atom p o s i t i o n e d out of the plane o f the fo u r n i t r o g e n atoms i s thought to r e g a i n i t s p l a n a r i t y upon oxygenation w i t h the accompanying movement of the metal atom back i n t o plane. With such an emphasis l a i d on st e r e o c h e m i c a l changes of m e t a l l o p o r p h y r i n s i t was of i n t e r e s t to c o n s t r u c t a system i n which the p o r p h y r i n i s f o r c e d to be non-planar even i n i t s metal f r e e s t a t e . T h i s would a l l o w one to estimate a t l e a s t q u a l i t a t i v e l y , the importance of the phenomenon of 38 doming i n m e t a l l o p o r p h y r i n chemistry e s p e c i a l l y i n the context of oxygenation and c o o p e r a t i v i t y . Such a non-planar p o r p h y r i n c o u l d be s y n t h e s i z e d by c o v a l e n t l y l i n k i n g two d i a g o n a l 3 - p o s i t i o n s with a s h o r t carbon c h a i n t h a t would not al l o w the r i n g to a t t a i n p l a n a r i t y . With such a.porphyrin the metal i o n would have to be p o s i t i o n e d out of the mean plane of the n i t r o g e n atoms i n order to a t t a i n maximum o v e r l a p with the bonding o r b i t a l s of n i t r o g e n . An arrangement of t h i s type c o u l d be expected to favour a 5-coordinate system such as Fe l :?(P)L whereas the formation o f the 6-coordinate F e I I ( P ) L would be minimized. The p o r p h y r i n f i x e d i n t h i s domed c o n f i g u r a t i o n would not be able t o a t t a i n p l a n a r i t y w i t h the accompanying movement of the metal i o n to the c e n t r e of the cor>e to a l l o w a second l i g a n d molecule (base) to bin d . In a d d i t i o n , the s t e r i c encumberance of the s t r a p would not favour the approach of a l a r g e l i g a n d from t h a t s i d e . On the other hand, f o r smal l molecules such as 0 o and 'CO- the s t e r i c hindrance of the carbon s t r a p would not be s i g n i f i c a n t and i t would be i n t e r e s t i n g to see what e f f e c t the doming of the p o r p h y r i n has on t h e i r b i n d i n g p r o p e r t i e s . F u r t h e r , i t would be p o s s i b l e to vary the extent of deform-a t i o n by changing the l e n g t h of the carbon c h a i n . T h i s would p r o v i d e systems i n which the metal i o n i s p r o g r e s s i v e l y removed from the mean plane of the p o r p h y r i n n i t r o g e n atoms. 2.2. SYNTHETIC PLAN *x The requirement t h a t a p o r p h y r i n macrocycle maintains p l a n a r i t y i n order to a t t a i n maximum d e l o c a l i z a t i o n of the 18 T - e l e c t r o n system, imposes a s p e c i a l r e s t r i c t i o n on the s y n t h e t i c s t r a t e g y f o r the d e s i r e d product. Of the two b a s i c approaches t h a t have been u t i l i z e d f o r the s y n t h e s i s of cyclophane p o r p h y r i n s ( S e c t i o n 1.4) i t i s c l e a r t h a t the one t h a t i n v o l v e s the i n t r o d u c t i o n of the s t r a p to a preformed p o r p h y r i n cannot be made use of i n t h i s work. A p o r p h y r i n once formed, cannot be expected to condense with a carbon c h a i n i f i t would deform the molecule and thereby cause the r e d u c t i o n o f i t s . s t a b i l i t y . Thus i f a s h o r t s t r a p i s to be c o v a l e n t l y l i n k e d to a p o r p h y r i n i n order to f o r c e the molecule to be nonplanar i t has to be done before c y c l i z a t i o n and not a f t e r . T herefore the s y n t h e t i c s t r a t e g y should c o n s i s t of b u i l d i n g the p o r p h y r i n p r e c u r s o r s a t the ends of the ch a i n f o l l o w e d by an i n t r a m o l e c u l a r c y c l i z a t i o n . 40 As f o r any extended o r g a n i c s y n t h e s i s the b e s t approach f o r d e v e l o p i n g a s y n t h e t i c route was a r e t r o s y n t h e t i c a n a l y s i s of the t a r g e t molecule i t s e l f . The s y n t h e t i c p l a n t h a t was developed and d e s c r i b e d l a t e r i n t h i s t h e s i s was based on the a n a l y s i s g i v e n i n F i g u r e 7. The f i r s t d i s c o n n e c t i o n of the t a r g e t molecule 5_4_ l e d to the most c r u c i a l i n t e r m e d i a t e 5_5_ of the e n t i r e s y n t h e t i c scheme. With the p e r i p h e r a l sub-s t i t u e n t s chosen as R = R , R = R and R = R , the 1 4 2 5 3 6 double d i s c o n n e c t i o n 1 l e a d s to a symmetric d i p y r r o l i c i n t e r m e d i a t e a l r e a d y c a r r y i n g the c h a i n . The r e v e r s e of t h i s d i s c o n n e c t i o n i s a simple a c i d c a t a l y z e d r e a c t i o n of a-ho.a-unsubstituted p y r r o l e w i t h a f e a - f o r m y l p y r r o l e to produce a methene l i n k . In the case of compound 55_ one such con-d e n s a t i o n would h o l d the four p y r r o l e s i n p o s i t i o n f o r the second condensation to f o l l o w e v e n t u a l l y producing a t e t r a -p y r r o l i c macroeycle. Since the i n t e r m e d i a t e 5_5_ i s a t the dipyrromethane o x i d a t i o n l e v e l the t e t r a p y r r o l e formed would have two methane l i n k a g e s and two methene l i n k a g e s . Such a compound i s r e f e r r e d to as a porphodimethene. Porphodimethenes are u n s t a b l e i n the presence of a i r and are known to be r a p i d l y a u t o x i d i z e d to the more s t a b l e p o r p h y r i n . The c h o i c e of a dipyrromethane r a t h e r than a d i -pyrromethene i n t e r m e d i a t e f o r t h i s s i n g l e step 2+2- c o u p l i n g r e a c t i o n was c r u c i a l f o r the success of t h i s s y n t h e s i s . Of the three d i p y r r o l i c i n t e r m e d i a t e s g e n e r a l l y used f o r t h i s 3 type of syntheses only dipyrromethanes c o n t a i n s;p-< h y b r i d i z e d b r i d g i n g carbon atoms. The f i r s t t e t r a p y r r o l e t h a t would be FIGURE 7 : A R e t r o s y n t h e t i c A n a l y s i s of the Target Molecule formed from a h e a d - t o - t a i l c o u p l i n g a t any one of the two r e a c t i v e c e n t r e s of 55_ would be a b i l e n e - b ( s e c t i o n 1.2) which i s a l i n e a r t e t r a p y r r o l e with two methane b r i d g e s 3 2 (sjp- ) and one methene b r i d g e (sp-) . Such a system would be the most favoured to accommodate a d i a g o n a l l y p o s i t i o n e d s h o r t s t r a p . With dipyrromethenes as p r e c u r s o r s , the l i n e a r t e t r a -p y r r o l e most commonly encountered w i t h i s - the i b i l a d i e n e - a , c • 2 (S e c t i o n 1.2) with two sip h y b r i d i z e d b r i d g i n g carbon atoms which would f o r c e the two p y r r o l e s i n each h a l f to be i n one plane with the meso carbon. F u r t h e r , a b i l a d i e n e system with a s h o r t s t r a p would not be able to a t t a i n the c o r r e c t j u x t a p o s i t i o n f o r the second h e a d - t o - t a i l condensation necessary to form the c y c l i c system. On the other hand, a b i l e n e - b (the f i r s t product from dipyrromethanes) w i t h 3 two sjp h y b r i d i z e d carbon b r i d g e s should h o l d the other two r e a c t i n g groups i n the c o r r e c t o r i e n t a t i o n even i n the presence of a s h o r t s t r a p . Since the f i r s t c y c l i c product formed i s a porphod-imethene and not a p o r p h y r i n the s t r a i n imposed by a s h o r t c h a i n would be comparatively low and t h e r e f o r e i t s formation would be more f a c i l e . The r a p i d a u t o x i d a t i o n of porpho-dimethenes to the more s t a b l e p o r p h y r i n would be the d r i v i n g f o r c e f o r t h i s r e a c t i o n to go to completion. Although a t t a i n i n g p l a n a r i t y would not be favoured by the presence of a s h o r t carbon c h a i n i n the molecule the aromatic s t a b i l i t y t h a t would be gained by the o x i d a t i o n to a p o r p h y r i n should be more than s u f f i c i e n t to overcome i t . Of course a lower l i m i t 43 would be reached when the carbon c h a i n i s too s h o r t even f o r the formation of the porphodimethene. Another important f e a t u r e r e g a r d i n g t h i s 2+2 condensation should be noted. In order to o b t a i n the d e s i r e d product i n hig h y i e l d the i n t e r m e d i a t e 55_ should undergo two i n t r a m o l e c u l a r h e a d - t o - t a i l c o u p l i n g r e a c t i o n s . Although t h i s seems to be a reasonable p o s s i b i l i t y a c c o r d i n g to F i g u r e 7, i n r e a l i t y the c o n f i g u r a t i o n presented i s not the most favoured one f o r compound 55_ i n s o l u t i o n . The c t-formyl and/or the a- u n s u b s t i t u t e d p o s i t i o n of each h a l f would be f r e e to r e a c t with the a p p r o p r i a t e group of another molecule. Such i n t e r -molecular r e a c t i o n s would l e a d to d i m e r i z a t i o n and e v e n t u a l l y p o l y m e r i z a t i o n . The problem becomes more pronounced s i n c e a l l f o u r r e a c t i v e groups i n the molecule c o u l d r e a c t i n an i n t e r m o l e c u l a r f a s h i o n and i f any one does, the d e s i r e d product would not be obt a i n e d . The i n t e r m o l e c u l a r r e a c t i o n s c o u l d be minimized by c a r r y i n g out the c y c l i z a t i o n under extremely high d i l u t i o n . Proceeding f u r t h e r i n the r e t r o s y n t h e t i c a n a l y s i s (Figure 7 ) , i t c o u l d be seen t h a t a simple f u n c t i o n a l group i n t e r c o n v e r s i o n of 5_5 would l e a d to the i n t e r m e d i a t e 5_6 (step 2 ) wit h an c t-carboxy group. Compound 5_6 could be e a s i l y converted to 55_ by thermal d e c a r b o x y l a t i o n which i s a very common r e a c t i o n i n p y r r o l e chemistry. Step 3 i s another f u n c t i o n a l group i n t e r c o n v e r s i o n l e a d i n g to 5_7. The s y n t h e s i s of p y r r o l e s from a c y c l i c p r e c u r s o r s (Knorr and r e l a t e d syn-44 theses) g e n e r a l l y produce the a - e t h y l e s t e r d i r e c t l y and i s known to be a s y n t h e t i c a l l y u s e f u l s u b s t i t u e n t . A double d i s c o n n e c t i o n of i n t e r m e d i a t e 57_ would produce the p y r r o l i c systems represented by 58_. T h i s i s b a s i c a l l y the r e v e r s e of the s y n t h e s i s of dipyrromethanes. Dipyrromethanes are c o n v e n i e n t l y prepared by the n u c l e o -p h i l i c a t t a c k of an a - u n s u b s t i t u t e d p y r r o l e on a p y r r y l -c a r b i n y l c a t i o n generated by the l o s s of a good l e a v i n g group (Section 1.2). An a-methyl group i s the s y n t h e t i c s t a r t i n g p o i n t f o r such i n t e r m e d i a t e s . The f u n c t i o n a l group i n t e r c o n v e r s i o n of 5_8_ (step 5 ) g i v e s the key i n t e r m e d i a t e system 5_9_ which b a s i c a l l y c o n s i s t s of a c h a i n l i n k e d b i s -f o r m y l p y r r o l e 59a and an a - u n s u b s t i t u t e d p y r r o l e 59b. H H 5 9 a 5 9 b 45 The s e l e c t i o n o f t h e i d e a l c h a i n l e n g t h was a n o t h e r i m p o r t a n t s t e p i n t h e p l a n n i n g o f t h i s s y n t h e s i s . I f t h e c h a i n was t o o s h o r t a n d t h e f i n a l c y c l i z a t i o n r e a c t i o n f a i l e d , i t w o u l d n o t be p o s s i b l e t o d e t e r m i n e t h e c a u s e , i . e . , w h e t h e r i t was b e c a u s e t h e s t r a p was t o o s h o r t o r b e c a u s e o f t h e c h e m i s t r y i n v o l v e d . On t h e o t h e r h a n d , a l o n g s t r a p w i t h l i t t l e o r n o s t r a i n w o u l d n o t p r o v e t h e p o i n t t h a t a d i p y r r o l i c i n t e r m e d i a t e c o u l d be c y c l i z e d t o a p o r p h y r i n e v e n t h o u g h t h e p r o d u c t c a n n o t a t t a i n i t s u s u a l p l a n a r c o n f i g u r a t i o n . A c a r e f u l s t u d y o f s p a c e - f i l l i n g (CPK) m o d e l s o f t h e t a r g e t m o l e c u l e 5_4 i n d i c a t e d t h a t an e l e v e n c a r b o n c h a i n w o u l d be t h e i d e a l s t a r t i n g p o i n t . •.>Ther&-f&r.eA§-therIi r' sit5,§*f§eP' e d" p o r p h y r i n s y n t h e s i z e d was t h e u n d e c a n e p o r p h y r i n a n d t h e ' s y n t h e s e s o f t h e p o r p h y r i n s w i t h t h e d e c a n e , n o n a n e a n d o c t a n e s t r a p s w e r e u n d e r t a k e n t h e r e a f t e r . The e i g h t c a r b o n c h a i n was f o u n d t o b e t h e l o w e r l i m i t . The s t r a p t o be i n t r o d u c e d was r e q u i r e d as a t e r m i n a l d i c a r b o x y l i c a c i d . The e l e v e n c a r b o n d i a c i d u n d e c a n e d i o i c a c i d , a l t h o u g h c o m m e r c i a l l y a v a i l a b l e was e x p e n s i v e a n d t h e r e f o r e was s y n t h e s i z e d f r o m a d i p i c a c i d . The t e n , n i n e a n d e i g h t c a r b o n d i a c i d s w e r e r e l a t i v e l y c h e a p a n d w e r e p u r c h a s e d . The s y n t h e t i c r o u t e d e v e l o p e d h e r e was s u b s e q u e n t l y u s e d t o c o n s t r u c t a m o d e l t h a t w o u l d h e l p s u p p l e m e n t t h e r e s u l t s o b t a i n e d w i t h o t h e r s y n t h e t i c m o d e l s y s t e m s ( s e c t i o n 1.4), a n d p r o v i d e a b e t t e r u n d e r s t a n d i n g o f t h e n a t u r a l s y s t e m . 4 6 The b i g g e s t drawback of most s y n t h e t i c models was the i n -a b i l i t y to m a i n t a i n a 5 - c o o r d i n a t e i n t e r m e d i a t e i n s o l u t i o n . Even wi t h l a r g e p r o t e c t i v e s t r u c t u r e s c o v e r i n g one face .-of the p o r p h y r i n , a second l i g a n d had been observed to creep under i t to form a 6 - c o o r d i n a t e s p e c i e s . The advantage t h i s s y n t h e t i c route has over the others a l r e a d y r e p o r t e d , i s t h a t i t i s capable of i n t r o d u c i n g r e l a t i v e l y s h o r t e r s t r a p s . T h i s would a l l o w the space under the s t r a p to be minimized i n order to prevent l a r g e l i g a n d molecules from b i n d i n g under the s t r a p . 1", I, 2 # 4 / 5-Tetramethylbenzene (durene) was used as the bulky group f o r the p r o t e c t i v e s t r u c t u r e . CPK models i n d i c a t e d t h a t a five, carbon c h a i n on e i t h e r s i d e of the durene moiety would g i v e an u n s t r a i n e d p o r p h y r i n w i t h a reasonably small "hole" under the s t r a p . The commercially a v a i l a b l e 1 ; 4 - - fe j . .§ : (chloromethyl) - 2 , 3 .;• 5 , 6-teferamefehylbenzene •.. [(3S,y6;-b>is;(ch^ \«^ sj -is^ei asj ^ h i % . .sjtar-tingj. mat-e r i a l f o r the chemical m o d i f i c a t i o n of the para p o s i t i o n s i n order to o b t a i n the r e q u i r e d c h a i n l e n g t h . 2 . 3 SYNTHESIS OF UNDECANEDIOIC ACIB The o u t l i n e of t h i s s y n t h e s i s i s g i v e n i n F i g u r e - 8 . . 8 , . TMee key s t a r t i n g m a t e r i a l was the monoester of hexane-d i o i c a c i d ( a d i p i c acid) 6 _ 2 . The d i e t h y l e s t e r 6 1 was f i r s t FIGURE 8 : S y n t h e s i s of Undecanedioic A c i d 48 o b t a i n e d i n g r e a t e r than 7 5% y i e l d , by the e s t e r i f i c a t i o n o f a d i p i c a c i d 60_ with excess e t h a n o l , u s i n g c o n c e n t r a t e d s u l f u r i c a c i d as the c a t a l y s t . The d i e s t e r and the d i a c i d i n equimolar q u a n t i t i e s , were heated i n an i n e r t atmosphere i n the presence of tolLue-ne— p—su']!fondle; a c i d . A f t e r s e v e r a l hours, the r e a c t i o n mixture was f r a c t i o n a l l y d i s t i l l e d under reduced p r e s s u r e . A s u b s t a n t i a l amount of unreacted d i e s t e r d i s t i l l e d o f f f i r s t , f o l l o w e d by the monoester. In order to improve the o v e r a l l y i e l d , the d i e s t e r was recombined with the unreacted d i a c i d i n the r e a c t i o n v e s s e l and was reheated. T h i s process of h e a t i n g and d i s t i l l a t i o n was repeated twice. Since the r e a c t i o n mixture was observed to darken p r o g r e s s -i v e l y , the h e a t i n g was d i s c o n t i n u e d a t t h i s stage. The monoester f r a c t i o n s were combined and r e d i s t i l l e d under reduced p r e s s u r e to o b t a i n the pure monoester 62_ i n 56% y i e l d . In a n t i c i p a t i o n of low o v e r a l l y i e l d , the r e a c t i o n was c a r r i e d out on 1.5 mole s c a l e , so as to o b t a i n s u f f i c i e n t q u a n t i t i e s of 62. I t should be noted t h a t r e c e n t l y , Babler and Moy 3 4 have r e p o r t e d a s e l e c t i v e m o n o e s t e r i f i c a t i o n procedure f o r a d i a c i d (sebacic acid) u s i n g aqueous ethanol i n the presence of a s t r o n g a c i d c a t a l y s t . These workers have obtained y i e l d s g r e a t e r than 96%, by the continuous e x t r a c t i o n of the monoester as i t was formed (using cyclohexane), before i t c o u l d be converted to the d i e s t e r . They have observed t h a t the presence of a l a r g e amount of water permits the e x t r a c t i o n of the monoester to occur more r e a d i l y and a l s o reduce the 49 diester formation. The monoester 6_2 was next converted to the corres-ponding acid chloride 63_ by heating with thionyl chloride. The excess reagent was removed by evaporating (under reduced pressure) with carbon tetrachloride and the product was used for the next reaction without further p u r i f i c a t i o n . The conversion of the acid chloride 63_ to the keto d i a c i d 64_ was car r i e d out according to the method suggested '•35 by Durham, Mcleod and Cason-.,,. with certain modifications. The treatment of the acid chloride with triethylamine followed by saponification i n aqueous potassium hydroxide produced the desired product 64 i n y i e l d s comparable with those reported. The reaction proceeds v i a an i n i t i a l dehydro-halogenation of 63_ by triethylamine to produce a ketene, 50 which subsequently undergoes d i m e r i z a t i o n . I t i s e s s e n t i a l t h a t both t r i e t h y l a m i n e and the s o l v e n t (toluene) are a b s o l u t e l y dry i n order to prevent any h y d r o l y s i s of the ketene. Base h y d r o l y s i s of the ketene dimer leads to r i n g opening f o l l o w e d by the d e c a r b o x y l a t i o n o f the r e s u l t i n g 3-keto a c i d under the r e a c t i o n c o n d i t i o n s . The keto d i a c i d 6_4 was i s o l a t e d i n 60% o v e r a l l y i e l d ( c a l c u l a t e d on the b a s i s of the amount of monoester 6_2 used). W o l f f - K i s h n e r r e d u c t i o n 3 6 of the k e t o a c i d produced undecanedioic a c i d 6_5 i n 92% y i e l d . 2.4 MONOPYRROLTC STARTING MATERIALS AND INTERMEDIATES Only two p y r r o l e s were s y n t h e s i z e d from a c y c l i c precursors., the 3-unsubstituted p y r r o l e 6_6_ and the g - a c e t y l -p y r r o l e 67. The s e l e c t i o n of these two as the key p y r r o l i c s t a r t i n g m a t e r i a l s , was not a r b i t r a r y . Compound 66, with i t s s i n g l e u n s u b s t i t u t e d S - p o s i t i o n was used to l i n k two such molecules 66 6 7 to the two t e r m i n i of the carbon s t r a p . The p y r r o l e 67_, although not used d i r e c t l y , was the s t a r t i n g m a t e r i a l f o r a l l other monopyrrolic i n t e r m e d i a t e s d i s c u s s e d i n t h i s work. The a c e t y l group was not c h e m i c a l l y s i g n i f i c a n t but was the pr e c u r s o r to the e t h y l group. The e s t e r f u n c t i o n a l i t y present i n both 66 and 67 i s by f a r the most important b l o c k i n g and p r o t e c t i n g group i n p y r r o l e chemistry, by v i r t u e of the ease of removal and of the i n c r e a s e i n s t a b i l i t y t h a t such a s u b s t i t u e n t c o n f e r s on the p y r r o l e nucleus, w i t h r e s p e c t to o x i d a t i o n and p o l y -m e r i z a t i o n . The most common p y r r o l e s y n t h e s i s , the Knorr s y n t h e s i s and i t s v a r i a t i o n s , l e a d to such e s t e r s (vide i n f r a ) . 2.4.1 SYNTHESES OF PYRROLES FROM ACYCLIC PRECURSORS The p y r r o l e s 66_ and 6_7 were s y n t h e s i z e d by v a r i a t i o n s of the Knorr r e a c t i o n . In the c l a s s i c a l Knorr r e a c t i o n (Figure 9) , e t h y l oximinoacetoacetate 6J9 i s reduced to the a-amino ketone 7_0 wit h z i n c and a c e t i c a c i d which i s then r e a c t e d with another e q u i v a l e n t of e t h y l a c e t o a c e t a t e 68_. The r e a c t i o n i s thought to proceed v i a the S c h i f f s base 7_1. In the o r i g i n a l 3 7 Knorr r e a c t i o n , e t h y l a c e t o a c e t a t e was t r e a t e d with a h a l f e q u i v a l e n t of aqueous sodium n i t r i t e to g i v e an equimolar mixture of 68_ and 6_9, the l a t t e r being reduced i n s i t u , by z i n c and a c e t i c a c i d . U n f o r t u n a t e l y , the ct-amino ketone 0 0 CH-.CO Aq. NaN0 2 / 68 300^ 0 0 69 H3C 0 ^ / C H 3 Zn / CH3C02H H NH, 0 0 70 71 =0 72 FIGURE 9 : Sy n t h e s i s of Knorr's P y r r o l e so formed, self-condensed to produce a mixture of S c h i f f ' s bases, e v e n t u a l l y l e a d i n g to by-products. In order to minimize t h i s , the oxime i s now i s o l a t e d and added s l o w l y to a mixture of the r e d u c i n g agent and the keto e s t e r . T h i s e f f e c t i v e l y maintains the c o n c e n t r a t i o n of the amino ketone low, compared to t h a t of the 3-keto e s t e r . The v a r i a t i o n s p o s s i b l e f o r the Knorr r e a c t i o n are numerous s i n c e the oxime can be r e a c t e d with d i f f e r e n t -B-diketone systems. In the s y n t h e s i s of the p y r r o l e 67_, e t h y l oximinoacetoacetate was reduced to the corresponding amino ketone i n the presence of pentane-2,4-dione 7_3. The r e a c t i o n proceeds i n a manner s i m i l a r to the Knorr r e a c t i o n (Figure 10) The s y n t h e s i s of the 3-free p y r r o l e 6_6 was developed by K l e i n s p e h n 3 8 , who deduced t h a t the s u b s t i t u t i o n of d i e t h y l oximinomalonate 7_5 f o r e t h y l oximinoacetoacetate 69_ i n the s y n t h e s i s of 6_7_, would l e a d to the d e s i r e d product (Figure 10) The i n i t i a l n i t r o s a t i o n of d i e t h y l malonate 74_ was not as e f f i c i e n t as t h a t of the keto e s t e r e t h y l aeetoacetate.- . -Thus i n the s y n t h e s i s of the oximinomalonate, approximately 3 e q u i v a l e n t s of sodium n i t r i t e were used per e q u i v a l e n t of malonate. F u r t h e r , due to the e v o l u t i o n of the oxides of n i t r o g e n , the r e a c t i o n was c a r r i e d out i n the fumehood. 54 o o 68 OH 0 0 69 H 3 C \ | f ^ y/ C H 3 0 0 73 Zn / CH3C02H N / 1 N - ° H 0 0 75 Zn / CHgCOjH Aq. NaN02 CHgCOjH o o H 0 67 t t CH, H3C 0 .CH. H 3 c 7 ^ H \ / C H 3 H 3 L H 0 66 IU FIGURE 10 : Syntheses of Monopyrroles 66_ and 6_7 by the V a r i a t i o n s of the Knorr Reaction 55 2.4.2 PREPARATION OF SYNTHETICALLY- USEFUL PYRROLES VIA  TRANSFORMATIONS OF a-SUBSTITUENTS The c o n s t r u c t i o n of a p o r p h y r i n nucleus from mono-p y r r o l e s i n v o l v e s the m a n i p u l a t i o n of the a - s u b s t i t u e n t s of p y r r o l e s , whereas the 3 - s u b s t i t u e n t s are g e n e r a l l y c a r r i e d through unchanged. The g r e a t e r r e a c t i v i t y of the c t - s u b s t i t -uent over the 3, c h a r a c t e r i s t i c o f p y r r o l e s , was made use of i n s e l e c t i v e l y m o d i f y i n g the ct-methyl group i n both 6_6 and 67 without a f f e c t i n g the methyl group at the 3 - p o s i t i o n . Wifchiy.the e x c e p t i o n of the 3-free p y r r o l e 6_6 (which was s y n t h e s i z e d d i r e c t l y ) , a l l other monopyrroles r e q u i r e d i n t h i s work were prepared by the chemical m o d i f i c a t i o n of the p y r r o l e 67_. The d i f f e r e n t t r a n s f o r m a t i o n s are s c h e m a t i c a l l y r e p r e s e n t e d i n F i g u r e 11. The 3 - a c e t y l group of 67_, as mentioned e a r l i e r , was the p r e c u r s o r of an e t h y l s i d e c h a i n and t h i s c o n v e r s i o n had to be c a r r i e d out while the more r e a c t i v e c t - p o s i t i o n s were a l r e a d y blocked. The r e d u c t i o n of the c a r b o n y l to methylene cannot be performed under W o l f f - K i s h n e r c o n d i t i o n s (^ NNH-^ . and KOH) due to the s a p o n i f i c a t i o n of the e s t e r s i d e c h a i n . C a t a l y t i c hydrogenation had been used f o r t h i s t r a n s f o r m a t i o n u n t i l Whitlock and Hanauer 3 9 r e p o r t e d t h a t the use of diborane produced q u a n t i t a t i v e y i e l d s of the 3 , 4 - d i e t h y l analogue of 7_6_ from the corresponding 3 - a c e t y l p y r r o l e . In the present work, the diborane r e d u c t i o n of 67_ produced the compound 7_6 FIGURE 11 P r e p a r a t i o n of S y n t h e t i c a l l y U s e f u l Monopyrroles v i a Transformations of a - S u b s t i t u e n t s 57 i n over 8 0% y i e l d . The r e a c t i o n was c a r r i e d out by adding boron t r i f l u o r i d e e t h e r a t e , to a d i s p e r s i o n of 6_7 and sodium borohydride, i n tetrahy.drofuran, under an i n e r t atmosphere. The b o r o n t r i f l u o r i d e was added a t such a r a t e as to maintain the temperature of the r e a c t i o n mixture below 2 0°C. . In order to a v o i d the e t h y l e s t e r s i d e c h a i n of the p y r r o l e being a t t a c k e d by the excess reagent used, the r e a c t i o n was c a r r i e d out i n the presence of e t h y l a c e t a t e . The compound 7_6 i s commonly r e f e r r e d to as the c r y p t o p y r r o l e e t h y l e s t e r , 8JL being c r y p t o p y r r o l e i t s e l f . I t should be r e c a l l e d t h a t one of the two key i n t e r -mediates r e q u i r e d f o r the s y n t h e s i s of the p o r p h y r i n was the a - u n s u b s t i t u t e d p y r r o l e 59b (Se c t i o n 2.2). This i s e q u i v a l e n t 5 9 b to the p y r r o l e 79 (Figure 11) when R =R-» =C_H_ C M-.^R^CH ? - ' — 5 -2 5 •' 3 6 3. and R = C^Hi^ . The c o n v e r s i o n of the a -m e t h y l p y r r o l e 7_6_ to the s y n t h e t i c a l l y u s e f u l 'a - u n s u b s t i t u t e d p y r r o l e 79^  was c a r r i e d out v i a a.-carboxypyrrole 11_ and the a - i o d o p y r r o l e 78_. The f i r s t step was the t r i c h l o r i n a t i o n of the a.-methyl;jgr.oup..of 58 7 6 w i t h 3 e q u i v a l e n t s of s u l f u r y l c h l o r i d e , to be h y d r o l y s e d subsequently to the a c i d . The c h o i c e of the s o l v e n t was the major concern i n t h i s r e a c t i o n . ot-Methylpyrrole-c : ? _m6h6es"r.ers. *. have been t r i c h l o r i n a t e d i n ether s o l u t i o n w i t h h i g h l y v a r i a b l e r e s u l t s . Ether i s known to r e a c t w i t h s u l f u r y l c h l o r i d e , which i s c o n s i d e r e d to be the major cause f o r t h i s . C h l o r o -carbon s o l v e n t s have been used to av o i d t h i s problem but the t r i c h l o r i n a t i o n e i t h e r f a i l s to proceed to completion or the product i s damaged by the hydrogen c h l o r i d e evolved. By c o n t r a s t , ether seems to s o l v a t e the hydrogen c h l o r i d e formed, enhancing the product s t a b i l i t y under the r e a c t i o n c o n d i t i o n s . The t r i c h l o r i n a t i o n was c a r r i e d out a c c o r d i n g to the method r e p o r t e d by B a t t e r s b y and co-workers'* 0 , where the best use was made of both s o l v e n t s . The s t a r t i n g ct-methylpyrrole 76 was d i s s o l v e d i n methylene c h l o r i d e (a u n i f o r m l y good s o l v e n t f o r p y r r o l e s ) and anhydrous ether (approximately twice the volume) was addedy. j u s t p r i o r to the a d d i t i o n of the reagent. S u l f u r y l c h l o r i d e , d i l u t e d with methylene c h l o r i d e , was added r a p i d l y u s i n g a dropping f u n n e l ( u s u a l l y over a p e r i o d of 30-60 seconds) i n order to minimize i t s r e a c t i o n with e t h e r . With the slow a d d i t i o n procedures, the hindered and l e s s r e a c t i v e d - d i c h l o r o m e t h y l p y r r o l e i n t e r m e d i a t e might not be able to compete as w e l l as the s o l v e n t , f o r the o x i d a n t , r e s u l t i n g i n the formation of i n c r e a s e d amounts of aldehyde as thehby-product. The r e a c t i o n was performed i n a l a r g e f l a s k to make sure t h a t the v i g o r o u s e f f e r v e s c e n c e would not overflow the contents from the r e a c t i o n v e s s e l . Once the a d d i t i o n was c o m p l e t e , the s o l v e n t s were removed / i n vacuo, and the r e s u l t i n g r e d o i l was h y d r o l y s e d i n r e f l u x i n g aqueous ac e t o n e . The a - c a r b o x y p y r r o l e was o b t a i n e d i n g r e a t e r than 80% y i e l d a f t e r p u r i f i c a t i o n . H00C 77 76 79 The t r a n s f o r m a t i o n o f the a - c a r b o x y p y r r o l e 77_ t o the a - u n s u b s t i t u t e d p y r r o l e 7_9 b a s i c a l l y i n v o l v e s a d e carboxy-l a t i o n . A l t h o u g h t h i s c o u l d be a c h i e v e d t h e r m a l l y , i t has been o b s e r v e d 4 1 e a r l i e r t h a t an i n d i r e c t i o d i n a t i o n p r o c e d u r e ( v i a 78_) g i v e s h i g h y i e l d s and p u r e r p r o d u c t e s p e c i a l l y when the c a r b o x y p y r r o l e m o i e t y b e a r s e l e c t r o n w i t h d r a w i n g groups. The d e c a r b o x y l a t i v e i o d i n a t i o n [TT_^ 78_) was c a r r i e d o u t i n the two-phase system of 1 , 2 - d i c h l o r o e t h a n e and w a t e r , u s i n g sodium b i c a r b o n a t e t o s o l u b i l i z e the s t a r t i n g m a t e r i a l as i t s "anion. The d i c h l o r o e t h a n e e x t r a c t s the i o d o p y r r o l e 7_8_ as i t i s formed, p r e v e n t i n g the f o r m a t i o n o f s o l i d p y r r o l e -i o d i n e c h a rge t r a n s f e r complexes. T h i s a l s o r e d u c e s . t h e time a v a i l a b l e f o r the s a p o n i f i c a t i o n o f t h e e s t e r s i d e c h a i n by the b i c a r b o n a t e s o l u t i o n . S i n c e the m o l e c u l a r i o d i n e complexes cannot form, the i o d i n e t a k e n i n e x c e s s ( i n aqueous 60 potassium i o d i d e ) , was added r a p i d l y , to f u r t h e r reduce the time the e s t e r i s exposed to aqueous base. The product was i s o l a t e d from the o r g a n i c phase a f t e r d e s t r o y i n g the excess i o d i n e with sodium b i s u l f i t e . The y i e l d of the r e c r y s t a l l i z e d product was approximately 90%. h y d r o i o d i c a c i d i n s t e a d of c a t a l y t i c hydrogenation. A mixture of potassium i o d i d e and concentrated h y d r o c h l o r i c a c i d was used f o r t h i s purpose and the i o d i n e l i b e r a t e d was d e s t r o y e d with hypophosphorous a c i d . The a - u n s u b s t i t u t e d p y r r o l e 79, p u r i f i e d by chromatography, was obtained i n g r e a t e r than 94% y i e l d . The compound 8_0 was another a - u n s u b s t i t u t e d p y r r o l e used i n t h i s work. With the p y r r o l e 7_9, c e r t a i n problems were encountered i n attempting to remove the e t h y l e s t e r s i d e c h a i n d u r i n g the l a t t e r stages of the s y n t h e s i s (see S e c t i o n 2.6). To overcome t h i s , an a l t e r n a t i v e ..route was c o n s i d e r e d s u b s t i t u t i n g the p y r r o l e 7_9 w i t h the b e n z y l e s t e r analogue 8 0, s i n c e the benzyl e s t e r group can be removed e a s i l y by h y d r o g e n o l y s i s .followed by d e c a r b o x y l a t i o n . The p y r r o l e 80 The removal of i o d i n e was e f f e c t e d by the use of 79 80 was obtained from i t s e t h y l e s t e r analogue by a t r a n s e s t e r i f i c a t i o n i n b e n z y l a l c o h o l , u s i n g sodium be n z y l o x i d e as the c a t a l y s t . I t should be emphasized t h a t t r a n s b e n z y l a t i o n i s a very u s e f u l r e a c t i o n i n p y r r o l e chemistry due to i t s high y i e l d s and the ease of removal of the b e n z y l e s t e r when r ? r e q u i r e d . The compounds 8_6 and 8_7_ are two p y r r o l e s used as simple models f o r the c h a i n l i n k e d d i m e r i c systems. They were prepared by t r e a t i n g the corresponding a-methylpyrroles 84 and 8_5 w i t h one e q u i v a l e n t of s u l f u r y l c h l o r i d e . The compounds 8_4 and 8_5 were obtained from Dr. John B. Paine I I I They had been prepared by the t r a d i t i o n a l r o u t e s t a r t i n g from cryptopyrrole ethyl ester 7_6 (Figure 1 1 ) . The f i r s t step of th i s synthesis i s the conversion of 7_6_ to cryptopyrrole 8 1 . This i s effected by the saponification of the ethyl ester 83 82_ ~ with aqueous base, followed by the ne u t r a l i z a t i o n of the hot solution with a s l i g h t deficiency of acetic acid. These conditions r e s u l t i n decarboxylation and the v o l a t i l e a-free pyrrole 81_ i s steam d i s t i l l e d away from the tarry by-products. This i s then taken up i n dimethylformamide and treated with phosphorus's- oxychloride and the r e s u l t i n g iminium s a l t 8_2 i s hydrolysed i n aqueous sodium bicarbonate to give the a-formylpyrrole 8_3. The a-formylpyrrole when reacted with malononitrile i n the presence of an amine produces the a-dicyanoy rin.ylpyrrole 8_4. A l t e r n a t i v e l y , with methyl cyano-acetate the a-cyanoacrylate 8_5 i s formed. The formylation 63 of an o t - f r e e p y r r o l e and i t s subsequent p r o t e c t i o n as a c y a n o v i n y l d e r i v a t i v e are two r e a c t i o n s of immense s y n t h e t i c value i n p y r r o l e chemistry and would be d i s c u s s e d i n d e t a i l i n the f o l l o w i n g s e c t i o n . 2.5 CHAIN LINKED BIS PYRROLES AND THEIR CHEMICAL MODIFICATIONS With the important monopyrroles i n hand, i t now became necessary to c o n s i d e r the s y n t h e s i s of the c h a i n l i n k e d a -f o r m y l p y r r o l e dimer 59a. I t should be r e c a l l e d t h a t the r e t r o s y n t h e t i c a n a l y s i s presented i n s e c t i o n 2.2 suggested 59a t h i s compound to be a key s y n t h e t i c i n t e r m e d i a t e f o r the t a r g e t molecule. When both R-^  and R^  are methyl groups, 59a becomes e q u i v a l e n t to the b i s f o r m y l p y r r o l e 9_3, the s y n t h e s i s of which i s o u t l i n e d i n F i g u r e 12. The i n i t i a l s tep o f t h i s s y n t h e s i s was the l i n k i n g of the t e r m i n i of the r e q u i r e d carbon c h a i n to the 3 - p o s i t i o n s of two p y r r o l e s . T h i s was achieved by the simultaneous b i s a c y l a t i o n of two molecules of the 3-free p y r r o l e 6_6 with the b i s a c i d c h l o r i d e of the a p p r o p r i a t e d i a c i d . T h i s r e a c t i o n had H00C(CH 2) n_ 2C00H S O C I 2 ClOCICHjl^COCI FIGURE 12 : Syntheses of Chain Linked B i s P y r r o l i c Intermediates been developed as the f i r s t step i n a g e n e r a l route to the 4 2 s y n t h e s i s of c o v a l e n t l y l i n k e d d i m e r i c p o r p h y r i n s . The m i l d e r a c y l a t i o n c a t a l y s t , anhydrous s t a n n i c c h l o r i d e was used i n these r e a c t i o n s s i n c e p y r r o l e s are more r e a c t i v e towards e l e c t r o p h i l i c s u b s t i t u t i o n than benzenoid compounds. The b i s a c i d c h l o r i d e was prepared i n the u s u a l manner by h e a t i n g the d i a c i d with excess th i o n i y l c h l o r i d e . The a c y l a t i o n . i t s e l f was f i r s t c a r r i e d out a t 0°C under an i n e r t atmosphere, u s i n g s l i g h t l y more than two e q u i v a l e n t s of the 3-free p y r r o l e 6j5. A mixture of methylene c h l o r i d e and nitromethane was used as the s o l v e n t , the l a t t e r h e l p i n g to i n c r e a s e the s o l u b i l i t y of the product and thereby a v o i d -in g i t s premature c r y s t a l l i z a t i o n . The a c i d c h l o r i d e and the 3-free p y r r o l e , i n the .above s o l v e n t system, were t r e a t e d w i t h approximately four e q u i v a l e n t s of anhydrous s t a n n i c c h l o r i d e over a p e r i o d of 3-4 hours. The d i k e t o b i s p y r r o l e 88 c r y s t a l l i z e d out when the r e a c t i o n mixture was h y d r o l y s e d with d i l u t e aqueous a c i d . During the course of t h i s work d i a c i d s with h = 11, 10 and 9 were used, each producing g r e a t e r than 7 0% y i e l d s f o r the 1st crop. By c o n c e n t r a t i n g the o r g a n i c phase, i t was p o s s i b l e to i s o l a t e a f u r t h e r 10-15%. I t was subsequent-l y r e a l i z e d t h a t s l i g h t l y over two e q u i v a l e n t s of s t a n n i c c h l o r i d e was s u f f i c i e n t f o r t h i s a c y l a t i o n and i n a d d i t i o n , i t c o u l d be added reasonably f a s t (30 minutes as opposed to 3-4 h o u r s ) . F u r t h e r , c a r r y i n g out these r e a c t i o n s a t room temperature d i d not have any harmfu l e f f e c t s . I n f a c t , i n most i n s t a n c e s , these changes r e s u l t e d i n improved y i e l d s . The monoacylated d e r i v a t i v e i s a by product o f t h i s r e a c t i o n and prev ious work has shown , t h a t when n = 4 or 5, t h i s becomes the major or even the on ly p roduc t . I t has been suggested t h a t the i n te rmed ia te p y r r o l y l ke to ac id c h l o r i d e could c y c l i z e to an enol l a c t o n e , which upon work up would hydro lyse t o the p y r r o l y l keto ac id as shown below: I t would be n o t i c e d t h a t when h = 4 and 5, the lac tones are 5 and 6 membered r i n g systems r e s p e c t i v e l y , and the s t a b i l i t y of such systems would be the d r i v i n g fo rce f o r the predominant fo rmat ion o f the monopyr ro l ic by p roduc t . 67 The next step i n t h i s s y n t h e s i s was the r e d u c t i o n of the two k e t o n i c groups to methylenes. Once again, diborane was used f o r t h i s purpose and the progress of the r e a c t i o n was monitored by t'|>e a n a l y s i s . As expected, the diketone was the slowest moving spot and the f u l l y reduced product the f a s t e s t , w i t h the monoketo d e r i v a t i v e being i n t e r m e d i a t e . The s t a r t i n g m a t e r i a l d i d not d i s s o l v e f u l l y i n the s o l v e n t used ( t e t r a -hydrofuran) but the product d i d . The excess diborane was c a r e f u l l y d e s t r o y e d u s i n g a c e t i c a c i d and the product 8_9 was c r y s t a l l i z e d by the a d d i t i o n of water. The y i e l d s v a r i e d between 75 and 85%. I t should be noted t h a t t h i s r e a c t i o n i s best c a r r i e d out a t room temperature. When the r e a c t i o n f l a s k was.cooled i n i c e , v e r y l i t t l e product was formed even with the a d d i t i o n o o f excess reagent; most of the s t a r t i n g m a t e r i a l remained u n d i s s o l v e d . On a l l o w i n g the r e a c t i o n mixture to warm up to room temperature, the s o l i d was observed to go i n t o s o l u t i o n and the r e a c t i o n was complete i n a very s h o r t time. With the a p p r o p r i a t e carbon c h a i n s e c u r e l y i n p l a c e , the next task was to modify the e t h y l e s t e r f u n c t i o n a l i t i e s of 8_9^  to o b t a i n the s y n t h e t i c a l l y u s e f u l b i s f o r m y l p y r r o l e 93. As f o r the model system d i s c u s s e d i n s e c t i o n 2.4.2 (conversion of 7_6 to 83_) , t h i s had to i n v o l v e the complete removal of the e s t e r f o l l o w e d by the i n t r o d u c t i o n of the 68 formyl group. U n f o r t u n a t e l y , the r e a c t i o n s d e s c r i b e d f o r the simple t r i a l k y l p y r r o l e (Figure 11) were not a p p r o p r i a t e i n t h i s case. Although c r y p t o p y r r o l e 81 ,-£b,e'.Jbng yyjo.l-a t i le,, c o u l d be steam d i s t i l l e d out of the r e a c t i o n mixture, a c h a i n l i n k e d b i s - a - f r e e p y r r o l e of the type 92_ c o u l d not be expected to do the same. This meant t h a t the a - c a r b o x y p y r r o l e 91 had to be i s o l a t e d and then su b j e c t e d to thermal decarboxy-l a t i o n . T h i s would u s u a l l y i n v o l v e the s a p o n i f i c a t i o n of the e t h y l e s t e r 8_9 i n str o n g base f o l l o w e d by the p r e c i p i t a t i o n of the d e s i r e d product 91 by a c i d i f i c a t i o n a t room temperature or below. P y r r o l e c a r b o x y l i c a c i d s obtained i n t h i s manner are known to cause problems i n h a n d l i n g . They u s u a l l y p r e c i p -i t a t e out as g e l a t i n o u s s o l i d s which maiie the f i l t r a t i o n extremely t e d i o u s . F u r t h e r , they have to be d r i e d f o r s e v e r a l days over potassium hydroxide, under vacuum. C o n s i d e r i n g these f a c t o r s , the best approach to t h i s s y n t h e s i s was to convert the e t h y l e s t e r 8_9 to the corresponding b e n z y l e s t e r 90^  which c o u l d be removed c l e a n l y and c o n v e n i e n t l y by c a t a l y t i c hydrogenation. T h i s t r a n s e s t e r i f i c a t i o n was e f f e c t e d by a high temperature m o d i f i c a t i o n 4 ^5).-..43-'{ of the procedure developed by Kenner and c o - w o r k e r s 4 4 , u s i n g benzyl a l c o h o l and sodium b e n z y l o x i d e . The b e n z y l a l c o h o l was d i s -t i l l e d beforehand, from anhydrous potassium carbonate i n order to remove most of the water and any benzoic a c i d p r e s e n t . The e t h y l e s t e r 8_9 was heated to r e f l u x i n b e n z y l a l c o h o l and a s o l u t i o n of sodium i n b e n z y l a l c o h o l was added i n I S T I I L p o r t i o n s . A v i g o r o u s e v o l u t i o n of ethanol vapours was observed d u r i n g the r e a c t i o n , w i t h the concomitant lowering of the r e f l u x temperature. The product 9£ was i s o l a t e d by adding the hot r e a c t i o n mixture to methanol c o n t a i n i n g s u f f i c i e n t a c e t i c a c i d to quench the c a t a l y s t , f o l l o w e d by d i l u t i o n w i t h water. The e l e v e n , ten and nine carbon l i n k e d b i s p y r r o l e e t h y l e s t e r s 8 9a, 89b and 89c were t r a n s b e n z y l a t e d d u r i n g the course of t h i s work and i n g e n e r a l , y i e l d s g r e a t e r than 95% were obtained. The e i g h t carbon l i n k e d d i b e n z y l e s t e r 8 9d had p r e v i o u s l y been prepared by Dr. J.B.Paine I I I (also i n g r e a t e r than 95% y i e l d ) as an i n t e r m e d i a t e i n the s y n t h e s i s of c o v a l e n t l y l i n k e d d i m e r i c p o r p h y r i n s . S u f f i c i e n t q u a n t i t i e s of t h i s m a t e r i a l were obtained f o r f u r t h e r m o d i f i c a t i o n s . 70 I t should be emphasized a t t h i s stage t h a t subsequent t r a n s f o r m a t i o n s were c a r r i e d out i n a l l f o u r s e r i e s ; a n = 11, b n = 10, c n = 9 and d n = 8. (Figure 12). S e r i e s a was the f i r s t one to be s t u d i e d , the others were attempted o n l y a f t e r the c o n d i t i o n s o f a l l the r e a c t i o n s were o p t i m i z e d . Except f o r the f i n a l c y c l i z a t i o n s t ep, no major v a r i a t i o n s were observed i n experimental y i e l d s . The b i s benzyl e s t e r 90_ was next s u b j e c t e d to hydro-genation i n order to citeav/e the be n z y l e s t e r group. The r e a c t i o n was c a r r i e d out a t room temperature and 1 atmosphere pressure u s i n g approximately 10% by weight of 10% p a l l a d i z e d carbon as the c a t a l y s t . In each case, the uptake of hydrogen ceased when the c a l c u l a t e d amount of hydrogen was absorbed. F o l l o w i n g the removal of the c a t a l y s t , the s o l v e n t (tetrahydrofuran) was evaporated i n vacuo t o o b t a i n the b i s c a r b o x y p y r r o l e 9J_ as a p a l e y e l l o w s o l i d . The crude c a r b o x y p y r r o l e dimers were sub j e c t e d to thermal d e c a r b o x y l a t i o n without f u r t h e r p u r i f i c a t i o n . S e v e r a l h i g h b o i l i n g s o l v e n t s are g e n e r a l l y used f o r t h i s purpose of which dimethylformamide had a d i s t i n c t advantage over the o others f o r t h i s work. I t s r e f l u x temperature of 153 c was s u f f i c i e n t not onl y to de c a r b o x y l a t e the p y r r o l e but a l s o to remove any remaining toluene from the crude s t a r t i n g m a t e r i a l (toluene i s the other product of h y d r o g e n o l y s i s of the benzyl e s t e r ) . F u r t h e r , dimethylformamide was one of the reagents used i n the next r e a c t i o n , i . e . the V i l s m e i e r f o r m y l a t i o n and 71 t h e r e f o r e i t was-not necessary t o - i s o l a t e the decarboxylated product f ; The d e c a r b o x y l a t i o n of the a - c a r b o x y p y r r o l e dimer-;:91 i n dimethylformamide were f o l l o w e d by uv spectroscopy. The s t a r t i n g m a t e r i a l e x h i b i t e d a s i n g l e a b s o r p t i o n band a t approximately 285 nm. A f t e r 2 hours at r e f l u x , t h i s band was observed to be reduced to j u s t a shoulder but was never removed completely even a f t e r a f u r t h e r one hour of h e a t i n g . In order to reduce the time taken f o r t h i s r e a c t i o n , the higher b o i l i n g diethylformamide was t r i e d as the s o l v e n t but no a p p r e c i a b l e r e d u c t i o n was observed. On completion of the d e c a r b o x y l a t i o n , the f l a s k was c o o l e d and the product was used, i n dimethylformamide s o l u t i o n , f o r the f o r m y l a t i o n r e a c t i o n . The i n t r o d u c t i o n of the formyl group i s now e f f e c t e d i+ 5 by the V i l s m e i e r r e a c t i o n , whereby the a - u n s u b s t i t u t e d p y r r o l e i n dimethylformamide s o l u t i o n i s t r e a t e d w i t h phos-4 6 phorous o x y c h l o r i d e or benzoyl c h l o r i d e . T h i s i s known to proceed v i a an iminiium s a l t o f the type 8_2. The iminium 72 s a l t c o u l d be i s o l a t e d i n c r y s t a l l i n e form f o r simple t r i a l k y l -p y r r o l e s i f benzoyl c h l o r i d e i s used. This i s subsequently hydro l y s e d i n aqueous base to g i v e the a - f o r m y l p y r r o l e s . Since p y r r o l e aldehydes are somewhat s o l u b l e i n water, they o f t e n c r y s t a l l i z e w e l l from the h y d r o l y s i s s o l u t i o n . The f o r m y l a t i o n of the p y r r o l e dimer 9_2 was e f f e c t e d u s i n g phos-phorous o x y c h l o r i d e i n s t e a d of benzoyl c h l o r i d e , and the iminium s a l t was not i s o l a t e d but h y d r o l y s e d d i r e c t l y i n aqueous base. During the course of t h i s work, i t was observed t h a t the base used f o r the h y d r o l y s i s of the iminium s a l t was c r u c i a l , s i n c e the p u r i t y , y i e l d and the appearance of the product depended on i t . When aqueous ammonia was used, the product separated out as a r e d d i s h o i l which on h e a t i n g , turned i n t o dark brown lumps and e v e n t u a l l y coagulated i n t o one s t i c k y mass. Thin l a y e r chromatography of t h i s m a t e r i a l e x h i b i t e d s e v e r a l bands of v a r y i n g c o l o r s i n a d d i t i o n to the product. A l t e r n a t i v e l y , when a weakly b a s i c medium was p r o v i d e d f o r the h y d r o l y s i s by u s i n g sodium b i c a r b o n a t e , the product c r y s t a l l i z e d out as a p a l e grey powdery s o l i d which showed very few i m p u r i t i e s on t i c . Although aqueous ammonia i s the base g e n e r a l l y used f o r the h y d r o l y s i s of the iminium s a l t s , t h i s work i n d i c a t e d t h a t the use of sodium bi c a r b o n a t e r e s u l t s i n a purer product. 73 I t would be n o t i c e d t h a t s t a r t i n g from the b i s benzyl e s t e r 9_0, e s s e n t i a l l y 3 r e a c t i o n s had been c a r r i e d out without p u r i f i c a t i o n o f the two i n t e r m e d i a t e products. In f a c t , the a - f r e e p y r r o l e dimer 92_ was not even i s o l a t e d . Although a p u r i f i c a t i o n was necessary a t t h i s . s t a g e , the use of chroma-tography was not p o s s i b l e f o r t h i s purpose, a - F o r m y l p y r r o l e s are g e n e r a l l y adsorbed s t r o n g l y onto s i l i c a g e l and unl e s s the p o l a r i t y of the e l u t i n g s o l v e n t i s i n c r e a s e d c o n s i d e r a b l y they cannot be f o r c e d to move. T h i s of course r e s u l t s i n the movement of the i m p u r i t i e s as w e l l , r e n d e r i n g the chromatro-g r a p h i c s e p a r a t i o n almost i m p o s s i b l e . In order to overcome t h i s problem, the b i s - f o r m y l p y r r o l e 93_ was converted to a d e r i v a t i v e , which not only made i t s p u r i f i c a t i o n easy but a l s o served i n p r o t e c t i n g the s e n s i t i v e aldehyde f u n c t i o n -a l i t i e s ( v i d e v i n f r a ) . a - F o r m y l p y r r o l e s , although r e s i s t a n t to a u t o x i d a t i o n and ©annizzaro d i s p r o p o r t i o n a t i o n , are very s u s c e p t i b l e to decomposition under a c i d i c c o n d i t i o n s and i n the presence of the reagents commonly used i n p y r r o l e chemistry. In f a c t , the next stage of t h i s s y n t h e s i s was the o x i d a t i o n of the a-methyl groups of 93^  to p r o v i d e a source of p y r r y l c a r b i n y l c a t i o n s r e q u i r e d f o r the dipyrromethane formation and the formyl groups c o u l d not be expected to s u r v i v e the reagents used f o r t h i s purpose, i . e . , bromine ( f o r br o m i n a t i o n ) , s u l f u r y l c h l o r i d e ( f o r c h l o r i n a t i o n ) and l e a d t e t r a a c e t a t e -(f o r a c e t o x y l a t i o n ) . The p r o t e c t i o n o f the two formyl groups of compound 9^ w a s t h e r e f o r e mandatory. S e v e r a l p r o t e c t i n g groups are known f o r aldehydes but the most u s e f u l i n p y r r o l e chemistry are the c y a n o v i n y l groups: H. / / \^  N C C N D I C Y A N O V I N Y L C Y A N O A C R Y L A T E 7 5 • - - •- ' h i The c y a n o v i h y l p r o t e c t i n g groups -were•first used by F i s c h e r h 8 and l a t e r by Woodward i n h i s t o t a l s y n t h e s i s of c h l o r o p h y l l . Since then, the use of t h i s group f o r the p r o t e c t i o n o f a l d e -h 9 hydes has been expl o r e d f u r t h e r . Cyanovmyl d e r i v a t i v e s are prepared by the Knoevenagel r e a c t i o n of a - f o r m y l p y r r o l e s with m a l o n o n i t r i l e or e s t e r s of c y a n o a c e t i c a c i d , i n the presence of a b a s i c c a t a l y s t , u s u a l l y an amine. The r e a c t i o n c o n d i t i o n s r e q u i r e d to generate the p r o t e c t e d aldehyde are known to vary w i t h the s u b s t i t u t i o n p a t t e r n o f the p y r r o l e . Thus ,'a-^-formyl-a 1 - c a r b o x y l a t e e s t e r s tend to g i v e almost q u a n t i t a t i v e y i e l d s i n a few seconds while t r i a l k y l p y r r o l e s r e q u i r e prolonged treatment. In a d d i t i o n to being u s u a l l y w e l l c r y s t a l l i z e d , these d e r i v a t i v e s are l e s s s o l u b l e and-ITigy§. f a s t e r on s i l i c a g e l than the parent aldehydes. These f e a t u r e s make p o s s i b l e the use of the Knoevenagel reagent to scavenge the crude aldehyde and a l s o p u r i f y i t by chromatography. Due to the extended c o n j u g a t i o n , these compounds have a b s o r p t i o n maxima i n the range 390-410nm, r e s u l t i n g i n yel l o w to orange c o l o r s i n s o l u t i o n as w e l l as i n the s o l i d s t a t e . The main disadvantage of the use of c y a n o v i n y l pro-t e c t i n g groups i n p y r r o l e chemistry, i s the n e c e s s i t y to use strong aqueous a l k a l i f o r the r e g e n e r a t i o n of the aldehyde f u n c t i o n . T h i s o b v i o u s l y l i m i t s i t s u s e f u l n e s s t o p y r r o l e s b e a r i n g s u b s t i t u e n t s which are base i n e r t or e l s e r e p a r a b l e as e s t e r s . T h i s was not a matter of concern i n t h i s work 76 s i n c e the 3 - s u b s t i t u e n t s chosen were a l k y l groups. In f a c t t h i s s y n t h e s i s was designed to make best use of the r e q u i r e -ment of st r o n g base f o r t h i s d e p r o t e c t i o n . 'When the p r o t e c t i n g group i s c a r r i e d u n t i l the dipyrromethane dimer 57_ was formed the use of a l k a l i would not o n l y regenerate the aldehydes but a l s o s a p o n i f y the two e s t e r f u n c t i o n s and produce the i n t e r m e d i a t e 56. The c h o i c e of d i c y a n o v i n y l p r o t e c t i n g group as opposed to • c y a n o a c r y l a t e s f o r t h i s work, was i n p a r t d i c t a t e d by s o l u b i l i t y c o n s i d e r a t i o n s . M a l o n o n i t r i l e i s known to produce the l e s s s o l u b l e d e r i v a t i v e s and i s g e n e r a l l y avoided i n systems of i n h e r e n t l y low s o l u b i l i t y . In the b i s p y r r o l i c systems encountered here, the long methylene chains were expected to overcome t h i s problem a t l e a s t p a r t i a l l y . On the other hand, the lower s o l u b i l i t y of the d i c y a n o v i n y l d e r i v a t i v e was thought to help scavenge the crude aldehyde more e f f i c i e n t l y , thereby i n c r e a s i n g the y i e l d s . The c y a n o a c r y l a t e s e x i s t as c i s - t r a n s isomers although one isomer (with the bulky e s t e r group t r a n s to the p y r r o l e nucleus) i s known to predominate. Since two such groups would be prese n t i n a s i n g l e molecule, the number of p o s s i b l e isomers of the c h a i n l i n k e d b i s - p y r r o l i c systems would be i n c r e a s e d . T h i s was expected t o cause problems i n the c r y s t a l l i z a t i o n of the subsequent r e a c t i o n p r o d u c t s . The r e a c t i o n o f the crude b i s aldehyde 93. and malono-n i t r i l e was f i r s t attempted i n hot methanol u s i n g some methylene A a n = 11 93 CHO b n=10 c n= 9 94 C(H)=C(CNL d n= 8 c h l o r i d e to improve the s o l u b i l i t y of the s t a r t i n g m a t e r i a l . Thin l a y e r chromatography ( i n 2% CH 3 OH-CH^C^) was used to monitor the r e a c t i o n . The monoprotected d e r i v a t i v e moved f a s t e r than the dialdehyde s t a r t i n g m a t e r i a l , whereas the d i p r o t e c t e d d e r i v a t i v e moved w e l l ahead of both. The r e a c t i o n 78 appeared to take over two hours and even then some monoprotected compound c o u l d be observed on t i g . T r i e t h y l a m i n e , cyclohexylamine and p y r i d i n e were t r i e d as base c a t a l y s t s ; not much of a d i f f e r e n c e could be observed i n the r e a c t i o n times. The b i g g e s t problem encountered i n t h i s r e a c t i o n (i n the above mentioned s o l v e n t system), was the premature c r y s t a l l i z a t i o n of the monoprotected aldehyde. I t was d i f f -i c u l t to get i t back i n t o s o l u t i o n f o r f u r t h e r r e a c t i o n , even by the a d d i t i o n of more s o l v e n t ( e s p e c i a l l y f o r the c and d s e r i e s ) . The use of l a r g e r volumes of s o l v e n t appeared to help keep the monoaldehyde i n s o l u t i o n but the r e a c t i o n times c o u l d not be reduced. On the other hand, the use of the higher b o i l i n g s o l v e n t t o l u e n e , not onl y prevented the prem-ature c r y s t a l l i z a t i o n o f the monoaldehyde, but a l s o reduced the r e a c t i o n time to approximately 1 hour. In f a c t , c y c l o h e x y l -amine i n r e f l u x i n g toluene was found to be the best c a t a l y s t -s o l v e n t combination f o r t h i s r e a c t i o n . A z e o t r o p i n g o f f the water formed with toluene a l s o .helped d r i v e the r e a c t i o n to completion. E v a p o r a t i o n o f the toluene and the a d d i t i o n o f methanol r e s u l t e d i n the c r y s t a l l i z a t i o n of the b i s dicyano-v i n y l p y r r o l e 9_4 as a ye l l o w brown s o l i d . The b i s d i c y a n o v i n y l - d e r i v a t i v e was c o n v e n i e n t l y p u r i f i e d by chromatography on s i l i c a g e l ( a c t i v i t y I ) . Although approximately 4 00mL of methylene c h l o r i d e was r e q u i r e d to d i s s o l v e 15g of t h i s m a t e r i a l (the s o l u b i l i t y was lower f o r the c and d s e r i e s ) , the p u r i f i c a t i o n was e f f e c t e d on lOOg of s i l i c a g e l . T h i s was e s s e n t i a l l y a process of f i l t r a t i o n . 79 The dark c o l o r e d i m p u r i t i e s were adsorbed on the column and the only compound to move, i n methylene c h l o r i d e , was the product 94. T h i s too moved r a t h e r slowly but the a d d i t i o n of even 1% e t h y l a c e t a t e a t the i n i t i a l stages had r a t h e r adverse e f f e c t s ; the i m p u r i t i e s s t a r t e d moving and a good s e p a r a t i o n was not p o s s i b l e . In order to minimize waste, the s o l v e n t was r e c y c l e d d u r i n g chromatography. The b i s d i c y a n o v i n y l d e r i v a t i v e was r e c r y s t a l l i z e d from methanol, f o l l o w i n g chromatography. The o v e r a l l y i e l d of t h i s a n a l y t i c a l l y pure sample ( s t a r t i n g from the b i s -b e n z y l e s t e r 9_0_) was g r e a t e r than 60%. 2.6 DIPYRROMETHANES AND PORPHYRINS THEREFROM With the two p r o t e c t e d formyl groups i n t r o d u c e d a t the r e q u i r e d p o s i t i o n s , the next task was to tran s f o r m the two a-methyl groups of the p y r r o l e n u c l e i to p y r r y l c a r b i n y l c a t i o n s f o r the subsequent condensation with the a-unsub-s t i t u t e d p y r r o l e . Of the three ways g e n e r a l l y a v a i l a b l e f o r t h i s o x i d a t i o n , c h l o r i n a t i o n w i t h s u l f u r y l c h l o r i d e was s e l e c t e d f o r t h i s work. F i g u r e 13 s c h e m a t i c a l l y r e p r e s e n t s the t r a n s f o r m a t i o n of the b i s d i c y a n o v i n y l p y r r o l e 94_ to the dipyrromethane dimer 96. I t i s known t h a t the py r r o l e - a - m e t h y l groups are FIGURE 13 : S y n t h e s i s of the Dipyrromethane Dimer 9 6 81 s e l e c t i v e l y c h l o r i n a t e d o v er t h e 3-methyl groups by s u l f u r y l c h l o r i d e . I n a d d i t i o n , a s t e p w i s e c h l o r i n a t i o n c o u l d be e f f e c t e d by t h e use o f c a l c u l a t e d amounts o f t h e r e a g e n t . I t s h o u l d be n o t i c e d t h a t i n t h e c o n v e r s i o n o f 94_ t o 9_5, two m o n o c h l o r i n a t i o n s were r e q u i r e d , and a d i c h l o r i n a t i o n a t one m e t h y l group would r e n d e r t h a t p o s i t i o n u s e l e s s f o r the subsequent c o u p l i n g r e a c t i o n . I t s h o u l d a l s o be emphasized t h a t i f such a b y p r o d u c t was t o be produced i n s i g n i f i c a n t amounts, the s e p a r a t i o n and p u r i f i c a t i o n o f the d e s i r e d p r o d u c t 9_5 would be e x t r e m e l y d i f f i c u l t , s i n c e the c h l o r o -m e t h y l p y r r o l e s are n o t v e r y s o l u b l e i n the commonly used s o l v e n t s and a r e e a s i l y h y d r o l y s e d even on s i l i c a g e l used f o r chromatography. F o r t u n a t e l y , d i c h l o r i n a t i o n i s g e n e r a l l y s l o w e r than m o n o c h l o r i n a t i o n and i s known t o r e q u i r e more f o r c i n g c o n d i t i o n s . F u r t h e r , the l a r g e d e a c t i v a t i n g e f f e c t o f the c y a n o v i n y l group would a l s o reduce the p o s s i b i l i t y o f a second c h l o r i n a t i o n a t the same p y r r o l e r i n g . A t e s t r e a c t i o n was f i r s t c a r r i e d o u t w i t h lOOmg of compound 9_4. S u l f u r y l c h l o r i d e i n methylene c h l o r i d e was added d r o p w i s e , t o a s o l u t i o n o f 94_ i n methylene c h l o r i d e , a t room temperature and the s o l v e n t was b o i l e d o f f w h i l e c o n s t a n t l y r e p l e n i s h i n g w i t h d i e t h y l e t h e r . A y e l l o w powdery s o l i d p r e c i p i t a t e d o u t , w h i c h was c o l l e c t e d by f i l t r a t i o n and d r i e d . The p r o t o n nmr spectrum o f t h i s m a t e r i a l ( i n deuter'ochloroform) showed a s i n g l e t a t ^ 4.62(2 H) d o w n f i e l d from TMS, c h a r a c t e r i s t i c o f a-monochloromethyl p r o t o n s . There 82 was no indicat i o n of d i c h l o r i n a t i o n . As expected for compound 95, only a single methyl resonance was observed ( 6 = 2.16ppm). The s t a r t i n g material 94_ exhibited two methyl resonances at <5 2.26 and 2.12. Since the ch l o r i n a t i o n appeared to have taken place as expected, the next step was to condense the chloromethyl derivative with the a -free pyrrole 7_9 to produce the dipyrro-methane dimer 9_6. For the routine coupling of pyrrole mono-esters, a variety of conditions have been reported. Paine 4 3 has shown that chloromethylpyrrole monoesters react spon-taneously, at room temperature with certain a-free pyrroles in methylene chloride, r e s u l t i n g i n the evolution of hydrogen chloride. Although compound 9J3 was not very soluble i n methylene chloride, the coupling reaction was f i r s t attempted in t h i s solvent using approximately 2.2 equivalents of the pyrrole 79. Since no appreciable change could be observed at room temperature, the mixture was heated at reflux under nitrogen for 2 hours. A yellow s o l i d was iso l a t e d from the reaction mixture by replacing the methylene chloride with methanol. Unfortunately, the proton nmr spectrum of t h i s material did not exhibit a signal near 6„. 4.0 ppm, the the c h a r a c t e r i s t i c signal of the methylene bridge protons of dipyrromethanes. Further, the quartet and the t r i p l e t expected for the ethyl groups of 9_6 (originating from 7 9) were not observed. This c l e a r l y indicated that the reaction 83 had not worked. At t h i s stage, a c a t a l y t i c system was sought t h a t would help t h i s dipyrromethane s y n t h e s i s . Kenner and co-w o r k e r s 5 0 had r e p o r t e d t h a t a c e t o x y m e t h y l p y r r o l e s r e a c t e d w i t h a - f r e e p y r r o l e s a t 35°C i n methanol or a c e t i c a c i d i n the presence of a c a t a l y t i c amount of t o l u e n e - p - s u l f o n i c a c i d to g i v e unsymmetrical dipyrromethanes. In g e n e r a l , the y i e l d s had been hi g h (90+%) and the work-up, f a c i l e . On the other hand, working w i t h p y r r o l e s c o n t a i n i n g a c e t i c and p r o p i o n i c a c i d s i d e c h a i n s , B a t t e r s b y and c o - w o r k e r s 5 1 observed t h a t Kenner's procedure f r e q u e n t l y gave poor r e s u l t s . Instead, when the r e a c t i o n was c a r r i e d out i n dry methylene c h l o r i d e a t -15°C or below, with anhydrous s t a n n i c c h l o r i d e as c a t a l y s t , they obtained good y i e l d s of unsymmetrical dipyrromethanes. Paine ' had used t r i f l u o r o a c e t i c a c i d (TFA) as the c a t a l y s t to couple s i m i l a r r e a c t a n t s i n methylene c h l o r i d e and had observed t h a t the r e a c t i o n proceeds c l e a n l y and q u a n t i t a t i v e l y to dipyrromethane products a t room temperature. He a l s o noted t h a t no m onopyrrolic by-products were formed under these c o n d i t i o n s , whereas the s t a n n i c c h l o r i d e r e a c t i o n produced such by-products. The major drawback with t h i s system was the longer times r e q u i r e d f o r the completion of the r e a c t i o n . With the optimal TFA c o n c e n t r a t i o n of 0.5 to 2%, up to 6 days had been r e q u i r e d i n c e r t a i n i n s t a n c e s . 8 4 Of the d i f f e r e n t c a t a l y s t s r e p o r t e d f o r the d i p y r r o -methane c o u p l i n g r e a c t i o n s , anhydrous s t a n n i c c h l o r i d e was t r i e d f i r s t w ith t h i s system. A f r e s h sample of the b i s c h l o r o m e t h y l p y r r o l e 9jp_ was prepared and was taken up i n methylene c h l o r i d e with the ct - f r e e p y r r o l e 7_9. M a i n t a i n i n g o the temperature a t approximately 10 C, anhydrous s t a n n i c c h l o r i d e was added, when the r e a c t i o n mixture turned green almost immediately. When d i l u t e h y d r o c h l o r i c a c i d was added to quench the c a t a l y s t , the s o l u t i o n turned r e d . An attempt to i s o l a t e the product from the methylene c h l o r i d e s o l u t i o n r e s u l t e d i n an i n t r a c t a b l e t a r . The above r e s u l t suggested t h a t t h i s r e a c t i o n had to be c a r r i e d out under more c o n t r o l l e d c o n d i t i o n s . F u r t h e r , i t appeared a p p r o p r i a t e to s u b s t i t u t e the v a l u a b l e c h a i n l i n k e d b i s - p y r r o l i c system by a simple monopyrrolic model system i n the search f o r the i d e a l r e a c t i o n c o n d i t i o n s . For t h i s purpose, the c t - c h l o r o m e t h y l p y r r o l e 8j6 was s e l e c t e d and i t s condensation w i t h the same c t - f r e e p y r r o l e was s t u d i e d . (The s y n t h e s i s of 8_6 was d e s c r i b e d i n s e c t i o n 2 . 4 ) . Equimolar • q u a n t i t i e s of the two p y r r o l e s 8_6 and 7_9 were mixed i n methylene c h l o r i d e , under argon and allowed to s t i r f o r 2 hours a t room temperature. A t i c of the r e a c t i o n mixture e x h i b i t e d 2 y e l l o w s p o t s , the f a s t e r moving one being c o l o r e d red with bromine vapour (a t e s t f o r dipyrromethanes; the o x i d a t i o n of the methane b r i d g e to a methene i s respon-s i b l e f o r t h i s c o l o r change). Since t h i s was an i n d i c a t i o n t h a t the r e a c t i o n was t a k i n g p l a c e , although r a t h e r s l o w l y , the s o l u t i o n was heated to r e f l u x to d r i v e the r e a c t i o n t o completion. U n f o r t u n a t e l y , even a f t e r 2 hours very l i t t l e dipyrromethane c o u l d be observed. At t h i s stage, the r e a c t i o n mixture was c o o l e d to 0°C and approximately 0.5 e q u i v a l e n t s of anhydrous s t a n n i c c h l o r i d e was added. The s o l u t i o n immediately turned green and then red. F o l l o w i n g the work-up d e s c r i b e d e a r l i e r , the dipyrromethane product (the o n l y y e l l o w spot on t i c ) was i s o l a t e d by c a r e f u l chromatographic s e p a r a t i o n on s i l i c a g e l and c r y s t a l l i z e d from methanol. The proton nmr spectrum and the mass spectrum of the product were c o n s i s t e n t w i t h the s t r u c t u r e f o r the expected dipyrromethane 97_. U n f o r t u n a t e l y , the y i e l d was j u s t over 25%. I t appeared t h a t s t a n n i c c h l o r i d e was c a u s i n g the d e s t r u c t i o n of the r i n g system, suggesting t h a t t h i s reagent should be avoided. In an attempt to improve the y i e l d of t h i s r e a c t i o n , r e f l u x i n g toluene was used as the s o l v e n t with some anhydrous potassium carbonate being added to absorb the hydrogen c h l o r i d e l i b e r a t e d . The y i e l d was improved to almost 4 6% but once again 86 chromatography was r e q u i r e d f o r the p u r i f i c a t i o n of the product. 5 For the' c o u p l i n g ,o.f p y r r o l e monoes-ter-srMacDonald ' s group had d e v i s e d a procedure, whereby a bromomethylpyrrole or an acetoxymethylpyrrole was r e f l u x e d with an be-free component i n sodium a c e t a t e b u f f e r e d a c e t i c , a c i d . C o n s i d e r a b l e symmet-r i c a l by-product formation had been observed under these c o n d i t i o n s . E.g., with the s t a r t i n g m a t e r i a l s shown below, the d e s i r e d product 100 had been obtained i n approximately 70% y i e l d , contaminated by the symmetrical d i b e n z y l e s t e r 101 to the e x t e n t of 10%. The other symmetrical by-product 102 (the d i - t - b u t y l e s t e r ) had probably been l o s t i n the mother l i q u o r s . 87 A c e t i c a c i d had not been used before to couple c h l o r o m e t h y l p y r r o l e s b e a r i n g c y a n o v i n y l groups; the most common s o l v e n t used being methylene c h l o r i d e , with or without a c a t a l y s t . Since methylene c h l o r i d e had not produced apprec-i a b l y high y i e l d s even with the model system, t h i s condensation was attempted i n g l a c i a l a c e t i c a c i d . The a-chloromethylpyrrol 86 was suspended i n g l a c i a l a c e t i c a c i d together w i t h the a - f r e p y r r o l e 7_9 and the mixture was warmed on a water bath. In order to prevent any o x i d a t i o n of the a - f r e e p y r r o l e at high temperatures, a n i t r o g e n atmosphere was provided f o r the r e a c t i o n mixture. When the temperature reached 7 0°C , the chloro m e t h y l compound began to d i s s o l v e and w i t h i n 2 0 minutes, produced a c l e a r orange s o l u t i o n . ; A t i c e x h i b i t e d o n l y a s i n g l e y e l l o w spot and was c o l o r e d r e d d i s h v i o l e t by bromine vapour. T h i s i n d i c a t e d t h a t the r e a c t i o n had gone to completio and o n l y a s i n g l e : d i p y r r o m e t h a n e product had formed. The r e d d i s h i m p u r i t i e s remaining a t the o r i g i n of the t i c were minimal. C o n c e n t r a t i o n of the s o l u t i o n f o l l o w e d by the a d d i t i o n of methanol produced an orange-yellow c r y s t a l l i n e 88 s o l i d which was i d e n t i c a l to the dipyrromethane 97_ prepared e a r l i e r . A y i e l d of 87+% was obtained f o r the 1st crop and a f u r t h e r 8% was i s o l a t e d from the mother l i q u o r s f o r an o v e r a l l y i e l d of 95+%. T h i s h i g h y i e l d was not o n l y r e p r o d -u c i b l e w i t h the system c o n s i d e r e d above but a l s o f o r other s i m i l a r c o u p l i n g r e a c t i o n s between c h l o r o m e t h y l p y r r o l e s b e a r i n g c y a n o v i n y l groups and a - f r e e p y r r o l e s c a r r y i n g e s t e r f u n c t i o n s . F u r t h e r , u n l i k e MacDonald 1s work, the o n l y dipyrromethane formed was the d e s i r e d product; no rearranged products were observed. The s h o r t r e a c t i o n times as w e l l as the f a c i l e i s o l a t i o n of the uncontaminated product i n high y i e l d , rendered t h i s method extremely u s e f u l i n the 2+2 p o r p h y r i n syntheses, v i a dipyrromethanes. With s u f f i c i e n t q u a n t i t i e s of the dipyrromethane 9 7 i n hand, i t appeared reasonable to attempt i t s c o n v e r s i o n to the corresponding p o r p h y r i n 106, p r i o r to resuming work with the c h a i n - l i n k e d d i m e r i c system. F i g u r e 14 p r o v i d e s a schematic r e p r e s e n t a t i o n of the s y n t h e t i c p l a n . The f i r s t step was to t r e a t the dipyrromethane 97_ with aqueous base to d e p r o t e c t the aldehyde and a t the same time, s a p o n i f y the e t h y l e s t e r . T h i s was c a r r i e d out i n r e f l u x i n g aqueous e t h a n o l , under n i t r o g e n , u s i n g approximately 10 e q u i v a l e n t s of sodium hydroxide. When the ethanol was b o i l e d o f f a f t e r 3 hours, a p a l e tan s o l i d separated out of the s o l u t i o n , which was i s o l a t e d and c h a r a c t e r i z e d (by elemental a n a l y s i s , proton nmr, carbon nmr and mass spectrometry) as the d e p r o t e c t e d , ClHjC NC CN 86 H 6 79 CH3C02H 70° C V 89 o' \ _ Heat 0 105 a) Aq. KOH b) CH3C02H V o 106 FIGURE 14 : Synthesis of the Model Porphyrin - Etioporphyrin II 90 u n s a p o n i f i e d dipyrromethane 104. N e u t r a l i z a t i o n of the f i l t r a t e with a c e t i c a c i d gave a g e l a t i n o u s p r e c i p i t a t e of the d e s i r e d product 103. The f a c t t h a t the e t h y l e s t e r was not removed comp-l e t e l y under the c o n d i t i o n s which cleaved the d i c y a n o v i n y l group, was not s u r p r i s i n g . The g r e a t e r r e s i s t a n c e of the a - e s t e r group to h y d r o l y s i s c o u l d be due to i t s c a r b o n y l group being a weaker e l e c t r o p h i l e than a simple e t h y l e s t e r ; a r e s u l t o f i t s c o n j u g a t i o n w i t h the double bond system of the p y r r o l e nucleus. In f a c t , by u s i n g s h o r t e r r e a c t i o n times and somewhat higher base c o n c e n t r a t i o n s , i t was p o s s i b l e to i s o l a t e the a - f o r m y l - a 1 - e t h y l e s t e r 104 i n approximately 67% y i e l d . The a - f o r m y l - a 1 - c a r b o x y dipyrromethane 103 was obtained i n e s s e n t i a l l y q u a n t i t a t i v e y i e l d s by u s i n g approx-im a t e l y 50 e q u i v a l e n t s of sodium hydroxide. The r e a c t i o n was found to be complete i n 1% hours. In order to atyoid any d e c a r b o x y l a t i o n a t t h i s stage, the r e a c t i o n mixture was cooled i n i c e before n e u t r a l i z i n g with a c e t i c a c i d . The l a s t two steps of t h i s sequence are the de-c a r b o x y l a t i o n of compound 103 and the a c i d c a t a l y z e d 2+2 c o u p l i n g of the r e s u l t i n g a - f o r m y l - a ' - u n s u b s t i t u t e d d i p y r r o -methane 105. As encountered p r e v i o u s l y , the d e c a r b o x y l a t i o n c o u l d be e f f e c t e d t h e r m a l l y , under m i l d l y a c i d i c c o n d i t i o n s ( u s i n g . a c e t i c acid) or u n d e r - n e u t r a l or weakly b a s i c cond-i t i o n s (using dimethyl formamide), but the c h o i c e of the s o l v e n t here depends on the a c i d - c a t a l y s t system to be used i n the subsequent c y c l i z a t i o n r e a c t i o n . The decarboxylated product 105, w i t h the absence of an electron-withdrawing group on_the r i n g t h a t has an u n s u b s t i t u t e d a - p o s i t i o n , was not expected to be very s t a b l e and t h e r e f o r e i t s i s o l a t i o n was not c o n s i d e r e d . F u r t h e r , such compounds tend to be very s o l u b l e i n the h i g h b o i l i n g s o l v e n t s used f o r the d e c a r b o x y l a t i o n and hence t h e i r i s o l a t i o n would r e q u i r e the c o n c e n t r a t i o n o f the s o l u t i o n s to a very s m a l l volume. T h i s c o u l d r e s u l t i n the condensation o f the ° t-formyl and a - f r e e p o s i t i o n s , e s p e c i a l l y i f a c i d i c c o n d i t i o n s are used f o r d e c a r b o x y l a t i o n . Such a premature condensation would be h i g h l y u n d e s i r a b l e f o r the ch a i n l i n k e d d i m e r i c system, s i n c e i n concentrated s o l u t i o n , t h i s would l e a d to i n t e r m o l e c u l a r c o u p l i n g , which would not produce the d e s i r e d product (see S e c t i o n 2.2). The a c i d c a t a l y s t system to be used f o r the f i n a l c y c l i z a t i o n s t ep, had to be s e l e c t e d c a r e f u l l y . A c i d - c a t a l y z e d 5 3 rearrangement of dipyrromethanes i s a w e l l known phenomenon , e s p e c i a l l y when the p y r r o l e s l a c k e l e c t r o n - w i t h d r a w i n g sub-s t i t u e n t s . Such r e a c t i o n s are shown i n F i g u r e 15. These r e a c t i o n s s h u f f l e the p y r r o l e s around i n a t r u l y r e v e r s i b l e f a s h i o n , u n t i l o x i d a t i o n of the methane b r i d g e s produces s p e c i e s (dipyrromethenes) l e s s s u s c e p t i b l e to e l e c t r o p h i l i c a t t a c k . P y r r o l e s 'bearing e l e c t r o n - w i t h d r a w i n g s u b s t i t u e n t s , although more r e s i s t a n t to e l e c t r o p h i l i c a t t a c k , are not immune to these rearrangements. Since such rearrangements FIGURE 15 : A c i d - C a t a l y z e d Rearrangements of Dipyrromethanes l e a d to unexpected i s o m e r i c p roducts, the s e l e c t i o n of the proper a c i d c a t a l y s t was c r u c i a l . Of the s e v e r a l a c i d c a t a l y s t s t h a t have been used f o r the dipyrromethane c o u p l i n g r e a c t i o n s , two systems are of p a r t i c u l a r importance. The f i r s t i s by MacDonald and c o - w o r k e r s 5 k , who developed a procedure f o r the one step condensation of a dipyrromethane dialdehyde w i t h a b i s - a -u n s u b s t i t u t e d pyrromethane. The r e a c t i o n was performed a t f a i r l y h i g h d i l u t i o n i n g l a c i a l a c e t i c a c i d . A d i l u t e s o l u t i o n of h y d r o i o d i c a c i d , i n a c e t i c - a c i d , was added to a s o l u t i o n of the two r e a c t a n t s i n a c e t i c a c i d ( i n the dark) i n order to o b t a i n a f i n a l HI c o n c e n t r a t i o n of approximately 0.4%. The s o l u t i o n was observed to t u r n burgundy red as the i n t e r m e d i a t e porphodimethene was formed. T h i s was subsequently o x i d i z e d to t h e p o r p h y r i n a f t e r n e u t r a l i z i n g the a c i d with sodium a c e t a t e . These c o n d i t i o n s were shown to minimize the a c i d promoted rearrangements l e a d i n g to i s o m e r i c por-p h y r i n s . In the p a r t i c u l a r systems s t u d i e d , they obtained y i e l d s up to 65%. The second method was developed by Kenner and co-w o r k e r s 5 5 , who observed t h a t MacDonald's c o n d i t i o n s l e d to very low y i e l d s f o r s i m i l a r condensations with d i f f e r e n t dipyrromethane systems. However, i n the presence of to l u e n e -p - s u l f o n i c a c i d i n methanol-methylene c h l o r i d e s o l u t i o n , they obtained y i e l d s up to 40%. The p o r p h y r i n was i s o l a t e d as the 94 z i n c s a l t ( z inc a c e t a t e was added to n e u t r a l i z e the acid) which was p u r i f i e d by chromatography and d e m e t a l l a t e d i n 5% s u l f u r i c acid-methanol. 0 0 1 0 3 With -"the a-formyl-a'-carboxy-dipyrromethane 103 , i t was noted t h a t i f the d e c a r b o x y l a t i o n was c a r r i e d out i n a c e t i c a c i d , MacDonald's c y c l i z a t i o n procedure would be p r e f e r r e d s i n c e the same s o l v e n t i s used f o r both r e a c t i o n s . A l t e r n a t i v e l y , i f Kenner 1s method was to be used f o r the c y c l i z a t i o n , i t would be convenient to use dimethylformamide as the s o l v e n t f o r d e c a r b o x y l a t i o n . Another p o i n t c o n s i d e r e d a t t h i s stage was the poss-i b i l i t y of p a r t i a l condensation d u r i n g d e c a r b o x y l a t i o n , which would be important i f a c e t i c a c i d was to be used as the s o l v e n t . Such premature condensations, although not very s i g n i f i c a n t with the model systems, would l e a d to ex-c e s s i v e by-product formation i n the corresponding c h a i n -l i n k e d d i m e r i c system, due to i n t e r m o l e c u l a r condensations ( s e c t i o n 2.2). In order to minimize t h i s , the d e c a r b o x y l a t i o n 95 c o u l d be c a r r i e d out under high d i l u t i o n but t h i s would un-doubtedly l e a d to experimental d i f f i c u l t i e s . The c y c l i z a t i o n step i t s e l f may have caused problems i f h y d r o i o d i c a c i d was used as the c a t a l y s t . The high d i l u t i o n c y c l i z a t i o n has to be c a r r i e d out over s e v e r a l days (the r e a c t a n t has to be added sl o w l y t o the a c i d c a t a l y s t ) , which would leave the s t a r t i n g m a t e r i a l as w e l l as the in t e r m e d i a t e exposed to the a c i d c a t a l y s t f o r long p e r i o d s of time. T h i s would i n c r e a s e the p o s s i b i l i t y of rearrangements (of the type shown i n F i g u r e 15) t a k i n g p l a c e , e s p e c i a l l y when m i n e r a l a c i d i s used. I t should be emphasized t h a t MacDonald had employed r e a c t i o n times of o n l y 10 to 15 minutes, a f t e r which the a c i d was n e u t r a l i z e d w i t h sodium a c e t a t e . In a d d i t i o n , h y d r o i o d i c a c i d i s o x i d i z e d r a p i d l y i n a i r , which would make i t u n s u i t a b l e as an a c i d c a t a l y s t f o r r e a c t i o n s c a r r i e d out over long p e r i o d s of time. C o n s i d e r i n g a l l these f a c t o r s , the d e c a r b o x y l a t i o n of the-a^fqrmyl--.a '-carboxypyrrole 103 was c a r r i e d out i n r e f l u x i n g dimethylformamide, under n i t r o g e n . The r e a c t i o n was monitored by the disappearance of the uv a b s o r p t i o n band at 280nm. When the r e a c t i o n was complete, the s o l u t i o n was con c e n t r a t e d , i n vacuo, s u f f i c i e n t methylene c h l o r i d e added and most of the remaining dimethylformamide removed by e x t r a c t i o n with water. The r e a c t i o n product was not i s o l a t e d but was subj e c t e d to a c i d c a t a l y z e d c y c l i z a t i o n . The above s o l u t i o n was added, dropwise, to a s o l u t i o n of t o l u e n e - p - s u l f o n i c a c i d , i n methanol-methylene c h l o r i d e over a p e r i o d of 2 hours and . was allowed to s t i r f o r a f u r t h e r 15 hours. The work-up was somewhat d i f f e r e n t from t h a t used by Kenner and c o - w o r k e r s 5 5 ; the p o r p h y r i n was not i s o l a t e d as the z i n c s a l t but d i r e c t l y as the f r e e base. When the r e a c t i o n mixture was conc e n t r a t e d and the a c i d n e u t r a l i z e d with t r i e t h y l amine, the p o r p h y r i n 106 c r y s t a l l i z e d as shiny p u r p l e c r y s t a l s , i n an o v e r a l l y i e l d of almost 48% (from the p r e c u r s o r 103). For comparison, the d e c a r b o x y l a t i o n of 103 was a l s o attempted i n g l a c i a l a c e t i c a c i d , m o n i t o r i n g the r e a c t i o n once again by uv spectroscopy. On r e f l u x i n g i n a c e t i c a c i d , the a b s o r p t i o n band a t 28 0nm p r o g r e s s i v e l y d i m i n i s h e d i n i n t e n s i t y and i n 4 5 minutes, was reduced t o a shoulder of the band a t 320nm ( r e s u l t i n g from the f o r m y l p y r r o l e m o iety). A f u r t h e r 45 minute h e a t i n g d i d not remove the shoulder comp-l e t e l y but a new band s t a r t e d forming near 420nm. In a d d i t i o n , the s o l u t i o n e x h i b i t e d some f l u o r e s c e n c e under long wavelength uv l i g h t , both being i n d i c a t i o n s of extended c o n j u g a t i o n due to premature c y c l i z a t i o n . A t t h i s stage, the s o l u t i o n was cooled and t r e a t e d with a d i l u t e s o l u t i o n of h y d r o i o d i c a c i d i n a c e t i c a c i d . A f t e r a l l o w i n g the r e a c t i o n mixture to s t i r f o r 20 minutes, the a c i d was n e u t r a l i z e d w i t h sodium a c e t a t e ; the work up was as d e s c r i b e d by MacDonald e t a l . 5 4 The y i e l d of the p u r i f i e d p o r p h y r i n 106 was 42% ( o v e r a l l from 103). The above r e s u l t s f u r t h e r supported the arguments presented e a r l i e r on the disadvantages of u s i n g a c e t i c a c i d f o r d e c a r b o x y l a t i o n . The c y c l i z a t i o n i n d i c a t e d d u r i n g the de-c a r b o x y l a t i o n would not have a f f e c t e d the y i e l d of the model p o r p h y r i n , but would have had an adverse e f f e c t w i t h the strapped system. F u r t h e r , the y i e l d of the MacDonald c y c l i z a t i o n was lower (though not v e r y s i g n i f i c a n t ) than t h a t obtained by Kenner's method (both i n v o l v e d a d e c a r b o x y l a t i o n s t e p ) . A l l t h i s c o n s i d e r e d , the dimethylformamide d e c a r b o x y l a t i o n , coupled with the t o l u e n e - p - s u l f o n i c a c i d c y c l i z a t i o n was chosen f o r the c h a i n l i n k e d d i m e r i c systems. Returning to the d i m e r i c system, the f i r s t t ask was to prepare the dipyrromethane dimer 96_ i n h i g h y i e l d , by c o u p l i n g the b i s - a - c h l o r o m e t h y l p y r r o l e 9_5 with the .'a-unsub-s t i t u t e d p y r r o l e 7_9 (Figure 13) . The r e a c t i o n was c a r r i e d out i n warm g l a c i a l a c e t i c a c i d , as d e s c r i b e d f o r the model system. Once again , the d e s i r e d product was formed as the o n l y dipyrromethane product and no chromatographic p u r i f i c a t i o n was r e q u i r e d . Each time t h i s compound was prepared ( i n a l l f o u r s e r i e s , a to d) the f i r s t crop y i e l d was g r e a t e r than 85% ( s t a r t i n g from the b i s - a - m e t h y l p y r r o l e 94). I t was p o s s i b l e to i s o l a t e a second crop from the mother l i q u o r s , b r i n g i n g up the y i e l d to as h i g h as 95% i n c e r t a i n i n s t a n c e s . The c o n v e r s i o n of the dipyrromethane dimer 9_6 to the p o r p h y r i n 109 was attempted as o u t l i n e d i n F i g u r e 16, u s i n g the same r e a c t i o n s c a r r i e d out on the model dipyrromethane FIGURE 16 : Conversion of the Dipyrromethane Dimer 96 to the Strapped P o r p h y r i n 109 system. The f i r s t step here was the d e p r o t e c t i o n - s a p o n i f i c a t i o n , u s i n g s t r o n g aqueous base. In order to f o l l o w t h i s r e a c t i o n more c l o s e l y , the d e p r o t e c t i o n was monitored by u v - v i s i b l e s pectroscopy. The s t a r t i n g m a t e r i a l 9_6_ e x h i b i t e d a s t r o n g a b s o r p t i o n band a t 4 07nm (due to the d i c y a n o v i n y l group), a band o f medium i n t e n s i t y a t 27 5nm and a weak a b s o r p t i o n (a shoulder) a t 315nm. When t h i s was r e f l u x e d i n aqueous e t h a n o l i c potassium hydroxide (approximately 100 e q u i v a l e n t s ) , the a b s o r p t i o n a t 407nm decreased i n i n t e n s i t y (also moved to lower wavelengths) w i t h the simultaneous i n c r e a s e i n i n t e n s i t y of the band a t 315nm (due to p y r r o l e aldehyde). Since the r e a c t i o n appeared t o have gone to completion i n 3 hours, the ethanol was b o i l e d o f f . A t t h i s p o i n t , a brown powdery s o l i d separated out which d i d not r e d i s s o l v e on add-i t i o n of more water; i n f a c t more s o l i d separated out with the a d d i t i o n of water. Due to the s i m i l a r experience w i t h the model system, t h i s s o l i d was suspected to be the un-s a p o n i f i e d dipyrromethane e t h y l e s t e r . The s o l i d was r e -d i s s o l v e d by adding e t h a n o l and continued h e a t i n g f o r 3 more hours. When the e t h a n o l was b o i l e d o f f and the s o l u t i o n c o o l e d to room temperature, a brown o i l y product separated out, which r e d i s s o l v e d on the a d d i t i o n of more water. The s o l u t i o n was a c i d i f i e d with a c e t i c a c i d and the dark brown g e l a t i n o u s p r e c i p i t a t e was f i l t e r e d and d r i e d i n a vacuum d e s i c c a t o r over potassium hydroxide. 100 The proton nmr spectrum ( i n dimethyl s u l f o x i d e - d ^ ) 6 of t h i s s o l i d product e x h i b i t e d c e r t a i n f e a t u r e s t h a t were 0 0' 107 i n c o n s i s t e n t with the s t r u c t u r e of the expected product 107. The s i g n a l a t <5.; 3.82 ppm, c h a r a c t e r i s t i c of the methylene b r i d g e protons, contained a "hook" a t 6 ... 3.77, i n d i c a t i n g the presence of two types of dipyrromethanes. T h i s was f u r t h e r supported by the presence of four N-H proton s i g n a l s , i n s t e a d of the two expected f o r t h i s compound. Two of these (6, 11.00; 6,- 11.45) were of equal i n t e n s i t y and compared w a l l with the two N-H resonances of the corresponding simple model system 103 (6 - 11.00; 11.42). The other two, a t 6 9.87 and 6 11.24 were a l s o of equal i n t e n s i t y but l e s s i n t e n s e than the former p a i r . The two p y r r o l e r i n g methyl s i n g l e t s a t 6 2.15 and 6 2.17 were not of equal i n t e n s i t y and another s i n g l e t was 101 observed at 6 1.91. A l l the above f e a t u r e s were i n c o n s i s t e n t w i t h the s t r u c t u r e of compound. 107. A c l u e to what may have happened came from the broad s i n g l e t a t 6 6.33. A resonance here i s i n d i c a t i v e of an a-proton on a p y r r o l e nucleus. T h i s suggested t h a t the a-carboxy group of 107 would have undergone p a r t i a l d e c a r b o x y l a t i o n d u r i n g h y d r o l y s i s , which was not sur-p r i s i n g s i n c e the r e a c t i o n mixture had been r e f l u x e d f o r over 6 hours. I f d e c a r b o x y l a t i o n was the o n l y unexpected r e a c t i o n to have taken p l a c e , i t would not have been a matter of g r e a t concern s i n c e the next step i n the s y n t h e s i s was a thermal d e c a r b o x y l a t i o n (Figure 16). As such, the s y n t h e s i s of the p o r p h y r i n 109 was attempted wi t h t h i s m a t e r i a l as planned. Approximately 50 mg of the above s o l i d was taken up i n dimethylformamide and r e f l u x e d under n i t r o g e n . Once again, the d e c a r b o x y l a t i o n was f o l l o w e d by uv-spectroscopy. The a b s o r p t i o n band at 28 0 nm r a p i d l y decreased i n i n t e n s i t y although the one a t 32 0 nm (due to the formyl groups) remained unchanged. The r e a c t i o n appeared to be complete i n 2 hours. When most of the s o l v e n t was evaporated o f f and methylene c h l o r i d e was added, 108 102 some s o l i d separated out of s o l u t i o n . T h i s was s u r p r i s i n g , s i n c e the de c a r b o x y l a t e d product 108 was expected to be s o l u b l e i n methylene c h l o r i d e . N e v e r t h e l e s s , the c y c l i z a t i o n was attempted with t h i s m a t e r i a l . The above s o l u t i o n was d i l u t e d to approximately 600mL with methylene c h l o r i d e and was t r e a t e d with a s o l u t i o n of t o l u e n e - p - s u l f o n i c a c i d i n methanol. The r e a c t i o n mixture was allowed to s t i r o v e r n i g h t i n the dark. The s o l u t i o n was then c o n c e n t r a t e d , the a c i d removed by e x t r a c t i o n w i t h s a t -u r a t e d sodium b i c a r b o n a t e and the o n l y f l u o r e s c i n g m a t e r i a l (under 365nm l i g h t ) was i s o l a t e d by chromatography. The mass 109a n =11 spectrum of t h i s m a t e r i a l e x h i b i t e d the parent peak a t m/e = 574, as expected f o r the d e s i r e d p o r p h y r i n 109 and the h a l f mass peak 103 a t m/e = 287. Since there was the p o s s i b i l i t y of a doubly l i n k e d d i m e r i c p o r p h y r i n being formed, the mass range up to 1200 mass u n i t s was checked but there was no i n d i c a t i o n of such a compound. The o v e r a l l y i e l d of t h i s product s t a r t i n g from 107 was o n l y 7%. Since i t was not p o s s i b l e to r a t i o n -a l i z e the low y i e l d o b t ained (compared to almost 48% with the model system) as being due to the r e s t r i c t i o n s imposed on the c y c l i z a t i o n by the s h o r t s t r a p , a f r e s h sample of the s t a r t i n g m a t e r i a l 107 was prepared i n order t o . r e p e a t the c y c l i z a t i o n . The d e p r o t e c t i o n - s a p o n i f i c a t i o n r e a c t i o n of compound 96 was c a r r i e d out once agai n , as d e s c r i b e d e a r l i e r . Although the d e p r o t e c t i o n was complete i n j u s t 3 hours (as i n d i c a t e d by u v - v i s i b l e spectroscopy) i t was not p o s s i b l e to reduce the time taken f o r the o v e r a l l r e a c t i o n . When et h a n o l was b o i l e d o f f , a s o l i d separated out, i n d i c a t i n g incomplete s a p o n i f i c a t i o n . The product was e v e n t u a l l y i s o l a t e d as pr e -v i o u s l y d e s c r i b e d . T h i s m a t e r i a l e x h i b i t e d a proton nmr s i m i l a r to t h a t of the p r e v i o u s sample except t h a t the r e l a t i v e i n t e n s i t i e s o f the e x t r a peaks (not expected f o r 107) v a r i e d . T h i s was then s u b j e c t e d to d e c a r b o x y l a t i o n i n dimethylformamide and subsequently c y c l i z e d under more d i l u t e c o n d i t i o n s than those used e a r l i e r . The methylene c h l o r i d e s o l u t i o n of the deca r b o x y l a t e d m a t e r i a l was added dropwise to the a c i d c a t a l y s t s o l u t i o n over a p e r i o d of 6 hours and was allowed to s t i r over-n i g h t . The s o l u t i o n d i d not e x h i b i t any f l u o r e s c e n c e under 104 365nm l i g h t ( a l l p o r p h y r i n s f l u o r e s c e under these c o n d i t i o n s ) and no p o r p h y r i n product c o u l d be i s o l a t e d from i t . Both these r e a c t i o n s , 9_6 -> 107 and 107 -> 108 -> 109 were repeated s e v e r a l times, with the same d i s a p p o i n t i n g r e s u l t . I t was reasonable to assume t h a t the major cause f o r t h i s problem was not i n the co n v e r s i o n o f 107 -> 108 ->- 109, but i n the r e a c t i o n t h a t made 107 i t s e l f . Since the con-v e r s i o n of compound 108 to the p o r p h y r i n 109 i s i n t r a m o l e c u l a r , i t i s e s s e n t i a l t h a t a l l f o u r r e a c t i v e c e n t r e s of the same molecule be a v a i l a b l e f o r the 2+2 c o u p l i n g . Should any one be blocked, p o l y m e r i z a t i o n i s a l l t h a t c o u l d be expected. I t should be r e c a l l e d a t t h i s stage t h a t the long r e a c t i o n times r e q u i r e d f o r the co n v e r s i o n of 9_6 to 107 had been a matter of concern, s i n c e i t may have l e d to p a r t i a l decarboxy-l a t i o n . Such a premature d e c a r b o x y l a t i o n c o u l d be f o l l o w e d by an i n t e r m o l e c u l a r condensation o f the r e s u l t i n g a - f r e e p o s i t i o n with an a-formyl group, thereby b l o c k i n g one p o s i t i o n each of two molecules, towards i n t r a m o l e c u l a r c y c l i z a t i o n . T h i s would have l e d to e x t e n s i v e p o l y m e r i z a t i o n d u r i n g the f i n a l c y c l i z a t i o n step. Of the two r e a c t i o n s t h a t take p l a c e d u r i n g the treatment of the dipyrromethane 9_6 wit h base, the d e p r o t e c t i o n of the c y a n o v i n y l group appeared to proceed reasonably w e l l , as i n d i c a t e d by the changes i n the u v - v i s i b l e spectrum. On the other hand, the s a p o n i f i c a t i o n of the e s t e r c o u l d not be monitored. I t i s known t h a t p y r r o l e - a - e s t e r s are more r e s i s t a n t to base h y d r o l y s i s than a l i p h a t i c e s t e r s . One 105 s o l u t i o n to t h i s problem was to have an e s t e r f u n c t i o n t h a t c o u l d be removed by a r e a c t i o n , other than s a p o n i f i c a t i o n . The most obvious c h o i c e was the benzyl e s t e r , which can be removed e a s i l y by hydrogenation at room temperature. For t h i s purpose, the b e n z y l e s t e r analogue of 9j) was r e q u i r e d , which c o u l d be s y n t h e s i z e d by s u b s t i t u t i n g a - u n s u b s t i t u t e d - . a 1 - b e n z y l o x y c a r b o n y l p y r r o l e 8_0 f o r i t s ethoxycarbonyl analogue 7_9 i n the pyrromethane c o u p l i n g r e a c t i o n (Figure 13). Once again a c h a i n - f r e e monopyrrolic model system was used f i r s t , i n order to work out the optimum r e a c t i o n c o n d i t i o n s . F i g u r e 17 p r o v i d e s an o u t l i n e of the r e a c t i o n s t h a t were c a r r i e d out u s i n g model systems. The a - f r e e p y r r o l e -b e n z y l e s t e r 8_0 was condensed w i t h the a - c h l o r o m e t h y l p y r r o l e 86 under the c o n d i t i o n s developed d u r i n g the course of t h i s work. The r e a c t i o n proceeded as b e f o r e , to produce the dipyrromethane 110 i n 88% y i e l d . T h i s compound was then sub j e c t e d to c a t a l y t i c hydrogenation i n order to c l e a v e the benzyl e s t e r f u n c t i o n . The r e a c t i o n was c a r r i e d out i n t e t r a -hydrofuran under 1 atmosphere of hydrogen u s i n g 10% p a l l a d i z e d c h a r c o a l as the c a t a l y s t . The r a t e of uptake of hydrogen was moderate at f i r s t but stopped completely a f t e r absorbing one t h i r d of the t h e o r e t i c a l l y r e q u i r e d amount. A t i c a n a l y s i s of the r e a c t i o n mixture i n d i c a t e d the'".presence of a s u b s t a n t i a l amount of unreacted s t a r t i n g m a t e r i a l . The r e a c t i o n was continued with f r e s h c a t a l y s t , but once again i t stopped before t a k i n g up the r e q u i r e d amount. Another attempt to d r i v e the An A l t e r n a t i v e S y n t h e t i c Route to E t i o p o r p h y r i n I I 107 r e a c t i o n to completion u s i n g f r e s h c a t a l y s t , f a i l e d . In order to make sure t h a t the s t a r t i n g m a t e r i a l 110 was not contaminated with some m a t e r i a l t h a t poisoned the c a t a l y s t , a f r e s h sample was prepared and i t s hydrogenation was a t t -empted; the r e s u l t was the same. Th i s was a r a t h e r unexpected r e s u l t , e s p e c i a l l y s i n c e s u c c e s s f u l h y d r o g e n o l y s i s of simple monopyrroles c o n t a i n i n g both benzyl e s t e r and a c y a n o v i n y l p r o t e c t i n g group, 4 9 have been r e p o r t e d p r e v i o u s l y . T h e r e f o r e , r a t h e r than abandoning t h i s route a l t o g e t h e r , i t appeared to be reason-able to attempt the hydrogenation of the corresponding c y a n o a c r y l a t e d e r i v a t i v e 112, which was prepared i n a s i m i l a r manner u s i n g the a p p r o p r i a t e c h l o r o m e t h y l compound 87_ (Figure 17). I t was indeed a p l e a s a n t s u r p r i s e to obs e r v e . t h a t the. hydrogenation of 112 proceeded without any problems a t a l l . The r e a c t i o n was monitored c a r e f u l l y i n order to a v o i d any overhydrogenation which might r e s u l t from the a t t a c k of the c y a n o v i n y l p r o t e c t i n g group. The uptake of hydrogen was p l o t t e d as a f u n c t i o n of time and was found to be r a p i d and l i n e a r . F u r t h e r , i t stopped a f t e r o n l y one e q u i v a l e n t of hydrogen had been absorbed. The product 113 was c r y s t a l l i z e d from the s o l u t i o n by r e p l a c i n g t e t r a h y d r o f u r a n (the s o l v e n t f o r the hydrogenation) with methanol, a f t e r removing the c a t a l y s t . The y i e l d of t h i s a n a l y t i c a l l y pure m a t e r i a l was j u s t under 90%. I t i s not c l e a r why the d i c y a n o v i n y l -b e n z y l e s t e r 110 was not hydrogenated f u l l y when the cyano-a c r y l a t e ..analogue 112 was. 108 The d e c a r b o x y l a t i o n of 113 was performed i n neat t r i f l u o r o a c e t i c ' a c i d a t room temperature. The r e a c t i o n , which simply i n v o l v e d the s t i r r i n g of the s t a r t i n g m a t e r i a l i n a c i d , under n i t r o g e n , was monitored by t i c and was found to be complete i n j u s t 5 minutes. In order to a v o i d decomp-o s i t i o n of the product, i t was e s s e n t i a l t h a t the exposure of the r e a c t i o n mixture to atmospheric oxygen was minimal e s p e c i a l l y d u r i n g the work-up. The a c i d was removed f i r s t by e v a p o r a t i n g i n vacuo and then by e x t r a c t i n g the methylene c h l o r i d e s o l u t i o n of the r e s i d u e with a s a t u r a t e d sodium b i c a r b o n a t e s o l u t i o n . Since the product 114 was found to be reasonably s o l u b l e i n methanol, hexane was used to c r y s t a l l i z e i t . An o v e r a l l y i e l d of 92% was obtained i n two crops, f o r t h i s r e a c t i o n . The next step i n t h i s s y n t h e t i c route was the removal of the c y a n o a c r y l a t e p r o t e c t i n g group, which was c a r r i e d out i n aqueous potassium hydroxide u s i n g the minimum amount of methanol to get the s t a r t i n g m a t e r i a l i n t o s o l u t i o n . W i t h i n 15 minutes of r e f l u x i n g , the product, a - f o r m y l - a ' T u n s u b s t i t u t e d dipyrromethane 105 separated out of s o l u t i o n as a l i g h t tan c o l o r e d s o l i d i n an a n a l y t i c a l l y pure s t a t e ; the y i e l d was almost q u a n t i t a t i v e . The 2+2 c o u p l i n g of the dipyrromethane 105 was c a r r i e d out i n methylene c h l o r i d e - m e t h a n o l s o l u t i o n u s i n g t o l u e n e - p - s u l f o n i c a c i d as the c a t a l y s t . The experimental c o n d i t i o n s f o r t h i s c y c l i z a t i o n were the same as before and the model p o r p h y r i n , e t i o p o r p h y r i n II 106 was i s o l a t e d i n 109 68% y i e l d . I t should be noted t h a t i n both r o u t e s developed i n t h i s work (Figures 14 and 17), the immediate p r e c u r s o r to the p o r p h y r i n was the a-formyl-a 1 — u n s u b s t i t u t e d dipyrromethane 105. In the d i c y a n o v i n y l - e t h y l e s t e r route (Figure 14), t h i s compound was obtained i n s o l u t i o n , as the thermal decarboxy-l a t i o n product of the ct - f ormyl-ct ' -carboxydipyrromethane 103, but was not i s o l a t e d . On the other hand, i n the cyano-a c r y l a t e - b e n z y l e s t e r r o u t e , t h i s compound was i s o l a t e d and c h a r a c t e r i z e d , p r i o r to c y c l i z a t i o n . The most important f e a t u r e of t h i s l a t t e r route was t h a t o n l y one d e p r o t e c t i o n was c a r r i e d out with each reagent, thereby making i t easy f o r the r e a c t i o n s to be monitored; the d e b e n z y l a t i o n was f o l l o w e d by the uptake of hydrogen, d e c a r b o x y l a t i o n by t i c a n a l y s i s and 110 the removal of the c y a n o a c r y l a t e p r o t e c t i n g group by uv-v i s i b l e spectroscopy. Although t h i s i n t r o d u c e d more steps f o r the l a t t e r r o u t e , the high y i e l d s obtained throughout the 106 sequence were more than s u f f i c i e n t to o f f s e t the o v e r a l l lowering of the y i e l d . In f a c t , the p o r p h y r i n 106 was ob-t a i n e d i n an o v e r a l l y i e l d of 4 9% s t a r t i n g from the a - c h l o r o -m e t h y l p y r r o l e 87_ and the a - f r e e - p y r r o l e 8_0 (5 r e a c t i o n s ) while the y i e l d of the same p o r p h y r i n , s y n t h e s i z e d from the o t - c h l o r o m e t h y l p y r r o l e 8_6 and the a - u n s u b s t i t u t e d p y r r o l e 7j) was o n l y 43% (for 4 r e a c t i o n s ) .• I l l The c y a n o a c r y l a t e - b e n z y l e s t e r route t h e r e f o r e seemed to be a very promising a l t e r n a t i v e r o u t e f o r the strapped p o r p h y r i n 109. Since the removal of the benzyl e s t e r f u n c t i o n -a l i t y i s e f f e c t e d while the aldehyde i s s t i l l p r o t e c t e d , i t would not be p o s s i b l e f o r the a - u n s u b s t i t u t e d p o s i t i o n to undergo a premature condensation. F u r t h e r , s i n c e the penultimate step i n v o l v e s o n l y the removal of the p r o t e c t i n g group, the time t h a t the a - f o r m y l - a ' - u n s u b s t i t u t e d dipyrromethane i s exposed to s t r o n g base would be -greatly reduced. The ease of removal of the c y a n o a c r y l a t e p r o t e c t i n g group compared to the d i c y a n o v i n y l group should h e l p reduce t h i s time f u r t h e r . The major concern a t t h i s stage was the a v a i l a b i l i t y of s t a r t i n g m a t e r i a l . The branch o f f p o i n t i n t h i s r e a c t i o n sequence was the a - f o r m y l p y r r o l e dimer 93 which had to be 112 converted to i t s b i s c y a n o a c r y l a t e i n s t e a d of the b i s dicyano-v i n y l d e r i v a t i v e 94_. Since the f o r m y l p y r r o l e dimer was p u r i f i e d o n l y a f t e r c o n v e r t i n g i t to i t s d i c y a n o v i n y l d e r i v a t i v e , reasonably l a r g e q u a n t i t i e s of 94_ were i n hand a t t h i s stage but very l i t t l e of 9^3 i t s e l f was a v a i l a b l e . T h e r e f o r e , i n order to f o l l o w the new sequence i t was necessary to go back t o the b i s b e n z y l e s t e r 9J) and make more of the f o r m y l p y r r o l e i n t e r m e d i a t e 9_3. A l t e r n a t i v e l y , the b i s d i c y a n o v i n y l d e r i v a t i v e 94 had to be d e p r o t e c t e d w i t h base and the b i s aldehyde so obtained be r e - p r o t e c t e d as the b i s c y a n o a c r y l a t e . The a v a i l a b i l i t y of l a r g e q u a n t i t i e s of the b i s d i c y a n o v i n y l p y r r o l e 9j4 n e c e s s i t a t e d the r e i n v e s t i g a t i o n of the r e a c t i o n t h a t f o r c e d the d i c y a n o v i n y l - e t h y l e s t e r route to be abandoned; i . e . , the c o n v e r s i o n of 9_6 to 107. As mentioned 113 e a r l i e r , the main concern here was the long r e a c t i o n times and i t was reasonable to assume t h a t t h i s c o u l d be reduced by i n c r e a s i n g the r e a c t i o n temperature. For t h i s purpose, the s o l v e n t used i n t h i s r e a c t i o n (ethanol) had to be r e p l a c e d by a h i g h e r b o i l i n g s o l v e n t . Since the reagent used here was aqueous base and the s o l v e n t had to be m i s c i b l e with water, the next higher ;homologue, n - p r o p a n o l was the most obvious c h o i c e . The d e p r o t e c t i o n - s a p o n i f i c a t i o n r e a c t i o n of compound 9 6 was t h e r e f o r e reattempted i n n-propanol u s i n g potassium hydroxide as the base. Once again, the d e p r o t e c t i o n was monitored by uv spectroscopy. The strong a b s o r p t i o n a t 4 07nm, a t t r i b u t e d to the d i c y a n o v i n y l group, was completely removed i n 2.5 hours i n d i c a t i n g the completion of the d e p r o t e c t i o n . When propanol was b o i l e d o f f a brown o i l separated out which r e d i s s o l v e d r a t h e r e a s i l y when d i l u t e d with water. However, on c o o l i n g , the product separated out once again ( p a r t i a l l y ) as a brown s t i c k y mass. The s o l u t i o n was f i l t e r e d under s u c t i o n and the product d i s s o l v e d on the f i l t e r paper by the a d d i t i o n of the minimum amount of water. T h i s was found to be the most convenient way of d i s s o l v i n g t h i s m a t e r i a l . N e u t r a l i z a t i o n of the s o l u t i o n w i t h a c e t i c a c i d produced the a - f o r m y l - ; a V-carboxy-dipyrromethane dimer 107 i n g r e a t e r than 95% y i e l d . The product was p a l e brown i n c o l o r and i t s proton nmr spectrum was c o n s i s t e n t with i t s s t r u c t u r e ; u n l i k e the 114 previous batches, no extraneous s i g n a l s were observed. F u r t h e r , with the a (n = 11), b (n = 10) and d (n = 8) s e r i e s , the r e a c t i o n product was a n a l y t i c a l l y pure, without any r e c r y s t a l l i z a t i o n . On the other hand, compound 107c (n = 9 s e r i e s ) d i d not g i v e a good a n a l y s i s but no r e c r y s t a l l i z a t i o n was attempted due to the p o s s i b i l i t y of decomposition. The d e c a r b o x y l a t i o n of compound 107 was c a r r i e d out i n r e f l u x i n g dimethylformamide, under n i t r o g e n , the r e a c t i o n being monitored by uv spectroscopy. The a b s o r p t i o n band a t 280nm (due to the c a r b o x y p y r r o l e group) was reduced to a shoulder i n 2 hours while the band a t 3 2 0nm (due to the f o r m y l p y r r o l e group) remained unchanged. The product was taken up i n methylene c h l o r i d e as d e s c r i b e d before and was used i n the subsequent c y c l i z a t i o n r e a c t i o n without i s o l a t i o n . I t was i n t e r e s t i n g to note t h a t the r a t i o o f the i n t e n s i t i e s of the two a b s o r p t i o n bands, .A^ 'Q ^ / A ^ Q , of the s t a r t i n g mat-e r i a l was approximately 1.5 whereas the r a t i o f o r each of the p r e v i o u s batches was approximately 1. T h i s appeared to be r e l a t e d to the amount of the p o r p h y r i n produced i n the f i n a l c y c l i z a t i o n step. The maximum y i e l d f o r the decarboxy-l a t i o n - c y c l i z a t i o n r e a c t i o n was obtained when the A 2 8 d / A 3 2 0 r a t i o was l a r g e s t ( c l o s e r to 1.5), while lower y i e l d s were produced when t h i s r a t i o was s m a l l e r . In f a c t , with the prev i o u s batches of 107, t h i s r a t i o was 1 or l e s s and l i t t l e or no p o r p h y r i n was produced. The only l o g i c a l e x p l a n a t i o n f o r t h i s o b s e r v a t i o n i s t h a t a lower r a t i o c o u l d be an i n d i e -a t i o n of a p a r t i a l d e c a r b o x y l a t i o n d u r i n g the s a p o n i f i c a t i o n of 9^ 6. T h i s may have l e d to subsequent m o d i f i c a t i o n of t h i s very r e a c t i v e c e n t r e , thereby p r e v e n t i n g the molecule from undergoing an i n t r a m o l e c u l a r c y c l i z a t i o n . The c y c l i z a t i o n i t s e l f was e f f e c t e d a t high d i l u t i o n . The methylene c h l o r i d e s o l u t i o n o f 108 was added to the a c i d c a t a l y s t (toluene- p - s u l f o n i c a c i d i n methanol-methylene c h l o r i d e s o l u t i o n ) extremely s l o w l y , u s i n g a syringe-pump. T h i s i s a de v i c e t h a t i s used to add a s o l u t i o n a t a constant r a t e , through a hypodermic s y r i n g e . At the slowest speed of o p e r a t i o n , the pump emptied a 20mL s y r i n g e i n approximately 7 hours. I t was not p o s s i b l e to o b t a i n such a slow and c o n s t a n t a d d i t i o n r a t e w i t h a dropping f u n n e l . The d i l u t i o n of the p r e c u r s o r s o l u t i o n , as w e l l as the number of f l a s k s of c a t a l y s t s o l u t i o n used, were v a r i e d depending on the amount of s t a r t i n g m a t e r i a l used. In a t y p i c a l experiment s t a r t i n g w i t h approximately 1 mmol'of the ' a - f ormyl'-a ' - c a r b o x y - d i p y r r o -methane dimer (700mg of 107a), the d e c a r b o x y l a t i o n was c a r r i e d out i n 15 0mL of dimethylformamide and the f i n a l volume of the d e c a r b o x y l a t e d product, i n methylene c h l o r i d e , was a d j u s t e d to 500mL. Using two separate s y r i n g e s , t h i s s o l u t i o n was added i n t o two f l a s k s , each c o n t a i n i n g 4g t o l u e n e - p - s u l f o n i c a c i d i n methanol (25mL) and methylene c h l o r i d e (600mL). An excess of the l e s s p o l a r s o l v e n t , methylene c h l o r i d e was used here to h o l d the d i s s o c i a t i o n of the a c i d to a minimum. In f a c t , the amount of methanol used was j u s t s u f f i c i e n t to d i s s o l v e the a c i d . Under the d i l u t i o n c o n d i t i o n s s p e c i f i e d above, the o n l y p o r p h y r i n product obtained was the d e s i r e d s i n g l y b r i d g e d monoporphyrin 109 and t h e r e f o r e i t s chromato-gr a p h i c p u r i f i c a t i o n ( discussed l a t e r ) was convenient. I t was p o s s i b l e to s y n t h e s i z e the e l e v e n , ten and nine carbon strapped p o r p h y r i n s , 109a, 109b and 109c u s i n g the r e a c t i o n sequence d e s c r i b e d above. The h i g h e s t y i e l d s i n the c y c l i z a t i o n r e a c t i o n o b t a i n e d f o r the t h r e e p o r p h y r i n s were 39.6%, 37.3% and 26.8% r e s p e c t i v e l y . I t should be r e c a l l e d t h a t the y i e l d of the model p o r p h y r i n , e t i o p o r p h y r i n I I 106, s y n t h e s i z e d by the same method, was ca.48%. I f one c o n s i d e r s t h i s value as the maximum p o s s i b l e y i e l d f o r t h i s r o u t e , the reduced y i e l d s with the strapped systems should r e f l e c t the e f f e c t of the c h a i n l e n g t h on the c y c l i z a t i o n r e a c t i o n . There was an approximately 8% drop i n the y i e l d when an eleven carbon s t r a p was in t r o d u c e d but the r e d u c t i o n of the c h a i n l e n g t h by one carbon d i d not seem to a f f e c t the y i e l d s i g n i f i c a n t l y . On the other hand, the r e d u c t i o n of the c h a i n by one more carbon had a more pronounced e f f e c t ; the y i e l d dropped by almost 10%. This suggested t h a t with the nine carbon c h a i n , the lower l i m i t was being reached f o r t h i s i n t r a m o l e c u l a r ,<2+2 condensation. In the case of the e i g h t carbon s t r a p , no p o r p h y r i n product was obtained although every i n t e r m e d i a t e i n t h i s s y n t h e s i s ( s e r i e s d) compared w e l l i n s p e c t r a l p r o p e r t i e s with the corresponding ones i n the a, b and c s e r i e s . A n o n - f l u o r e s c e n t m a t e r i a l was i s o l a t e d i n extremely low y i e l d which e x h i b i t e d p e c u l i a r a b s o r p t i o n s p e c t r a (see Chapter 4 ) . I t should be emphasized t h a t although the f i r s t c y c l i c product formed (the porphodimethene) was expected to possess the necessary f l e x i b i l i t y to f a c i l i t a t e the i n i t i a l '2+2 c o u p l i n g , an e i g h t carbon c h a i n may have imposed e x c e s s i v e s t r a i n even to such a s p e c i e s . F u r t h e r , i f the i n i t i a l porphodimethene i n t e r m e d i a t e was formed, a l r e a d y s t r a i n e d , i t would not have been able to a t t a i n p l a n a r i t y (or near p l a n a r i t y ) i n order to g a i n the aromatic s t a b i l i t y . The chromatographic p u r i f i c a t i o n of the por p h y r i n s deserves a s p e c i a l mention. I t was observed t h a t the strapped 118 p o r p h y r i n s do not move on a c t i v i t y I s i l i c a g e l with pure methylene c h l o r i d e as the e l u t i n g s o l v e n t . T h e r e f o r e , most of the non-porphyrin by-products were f i r s t removed by pass-ing the conc e n t r a t e d r e a c t i o n mixture ( a f t e r removing the a c i d c a t a l y s t ) through a smal l q u a n t i t y of a c t i v i t y I s i l i c a g e l . When the e l u a t e was almost c o l o r l e s s , 2% methanol was added to methylene c h l o r i d e and the p o r p h y r i n was e l u t e d out. T h i s was e f f e c t i v e l y a f i l t r a t i o n p r o c e s s . The e l u a t e was concentrated and rechromatographed on a c t i v i t y IV s i l i c a g e l . A f t e r removing the l a s t t r a c e s of the f o r e r u n n i n g i m p u r i t i e s with methylene c h l o r i d e , the p o r p h y r i n was once a g a i n e l u t e d w i t h 2% methanol-methylene c h l o r i d e . The f i n a l p u r i f i c a t i o n was on b a s i c alumina. The only m a t e r i a l to move on the column was the p o r p h y r i n , the i m p u r i t i e s remaining a t the o r i g i n . I t was observed t h a t a l l three p o r p h y r i n s , e s p e c i a l l y the nine carbon strapped p o r p h y r i n 109c, were p a r t i a l l y protonated on s i l i c a g e l and c o u l d not be made to move un l e s s the s o l v e n t p o l a r i t y was i n c r e a s e d with methanol. In the case of 109c up to 5% of methanol was r e q u i r e d . T h i s always r e s u l t e d i n some i m p u r i t i e s contaminating the p o r p h y r i n and t h e r e f o r e the f i n a l p u r i f i c a t i o n on b a s i c alumina was e s s e n t i a l . I f the e l u a t e from the f i r s t column was rechromato-graphed d i r e c t l y on b a s i c alumina (without s u b j e c t i n g to a c t i v i t y IV s i l i c a p u r i f i c a t i o n ) , a dark y e l l o w band was observed to move ahead of and almost with the p o r p h y r i n product which made the s e p a r a t i o n almost i m p o s s i b l e . 119 I t was a l s o i n t e r e s t i n g to note t h a t a l l three p o r p h y r i n s were more s o l u b l e i n methylene c h l o r i d e than the model p o r p h y r i n , e t i o p o r p h y r i n I I . T h i s was not s u r p r i s i n g , s i n c e the molecules c o n t a i n long alkane chains which are known to i n c r e a s e the s o l u b i l i t y of molecules e x h i b i t i n g i n h e r e n t l y low s o l u b i l i t i e s . These alkane c h a i n s may a l s o have an i n d i r e c t e f f e c t on the s o l u b i l i t i e s of these p o r p h y r i n s . By c o v e r i n g one face of the p l a n a r p o r p h y r i n molecule, these carbon chains c o u l d g r e a t l y reduce the extent of molecular a g g r e g a t i o n , a w e l l known phenomenon i n p o r p h y r i n chemistry, t h a t r e s u l t i n lower s o l u b i l i t i e s . The i n c r e a s e d s o l u b i l i t i e s made i t d i f f i c u l t to c r y s t a l l i z e these compounds from methylene c h l o r i d e . For 109a and 10 9b, nitromethane was found to be the best s o l v e n t f o r r e c r y s t a l l i z a t i o n whereas f o r 109c, methanol proved to be b e t t e r . Although the syntheses of the strapped p o r p h y r i n s had been s u c c e s s f u l l y accomplished as o r i g i n a l l y planned, i t was of i n t e r e s t to study the f e a s i b i l i t y of the second s y n t h e t i c sequence ( v i a the benzyl e s t e r - c y a n o a c r y l a t e dipyrromethane) developed on the model system (Figure 17), i n the s y n t h e s i s of the p o r p h y r i n 10 9. Since approximately l g . of each of the three p o r p h y r i n s had been prepared f o r m e t a l l a t i o n and b i n d i n g s t u d i e s , the new sequence was attempted o n l y with the eleven carbon s e r i e s ( s e r i e s a ) . F u r t h e r , i n order to compare the y i e l d s of the two pathways, the s y n t h e s i s was s t a r t e d a t the c h a i n - l i n k e d b i s benzyl e s t e r 9_0 stage. 120 X 9 0 a C O 2 C H 2 C 6 H 5  93 a C H O 9 4 a C ( H ) = C ( C N ) 2 115 a C ( H ) = ^ C ( C N ) C O 2 C H 3 The compound 9 0a was f i r s t converted to the b i s formyl d e r i v a t i v e 93a as d e s c r i b e d e a r l i e r (Figure 12). The crude f o r m y l p y r r o l e dimer was subsequently p r o t e c t e d as the b i s c y a n o a c r y l a t e 115a by r e f l u x i n g i n toluene with two equiva-l e n t s of methylcyanoacetate and c a t a l y t i c amounts of c y c l o -hexylamine. A f t e r chromatographic p u r i f i c a t i o n , the product was i s o l a t e d i n approximately 76% o v e r a l l y i e l d , from the be n z y l e s t e r 90a. The h i g h e s t y i e l d recorded i n the c y a n o v i n y l sequence, f o r the corresponding s e r i e s of r e a c t i o n s (90 94) was 70.2% (for 94b) but i n g e n e r a l , the y i e l d s v a r i e d between 60-65%. 121 The r e a c t i o n sequence t h a t was used to convert the b i s c y a n o a c r y l a t e 115a to the p o r p h y r i n 109a i s s c h e m a t i c a l l y represented i n F i g u r e 18. The b i s a - m o n o c h l o r i n a t i o n of 115a was c a r r i e d out as b e f o r e , u s i n g s u l f u r y l c h l o r i d e and the product 116a was subsequently condensed with two e q u i v a l e n t s of the a - f r e e p y r r o l e ;a 1 -benzyl e s t e r 8_0 to produce the dipyrromethane dimer 117a. The product d i d not c r y s t a l l i z e when the r e a c t i o n mixture was conc e n t r a t e d and methanol was added. Instead, i t o i l e d out. The chromatographic p u r i f i c a t i o n of t h i s dipyrromethane d i d not a i d i t s c r y s t a l l i z a t i o n . When the s o l v e n t was removed on the vacuum-line, the compound g l a s s i f i e d . The m a t e r i a l so ob t a i n e d ( i n 81% y i e l d from the b i s - p y r r o l e 1X5a) was found to be a n a l y t i c a l l y pure and was used i n the subsequent r e a c t i o n s . The f a i l u r e of t h i s compound to c r y s t a l l i z e c o u l d w e l l be due to the presence of geometric isomers a t the c y a n o a c r y l a t e groups (see Chapter 4). The hydrogenation of compound 117a was c a r r i e d out as u s u a l i n t e t r a h y d r o f u r a n u s i n g 10% p a l l a d i z e d c h a r c o a l as the c a t a l y s t . The uptake of hydrogen was f a s t and uniform as f o r the corresponding model system 112 and once agai n , no overhydrogenation was e v i d e n t . The c a r b o x y p y r r o l e product 1X8a c r y s t a l l i z e d out i n an a n a l y t i c a l l y pure form when t e t r a -hydrof uran was r e p l a c e d by methanol. An o v e r a l l y i e l d of 84% was obtained i n two cro p s . The d e c a r b o x y l a t i o n of 118a was performed i n neat t r i f l u o r o a c e t i c a c i d and as i n the case of the model compound 122 FIGURE 18 : An A l t e r n a t i v e S y n t h e t i c Route to the Strapped P o r p h y r i n 10 9 123 113, the r e a c t i o n was complete i n j u s t 5 minutes. The u s u a l work up of the r e a c t i o n mixture produced the compound 119a i n g r e a t e r than 92% o v e r a l l y i e l d ( i n two c r o p s ) . T h i s m a t e r i a l was d e p r o t e c t e d u s i n g aqueous potassium hydroxide, with n-propanol being used once again to s o l u b i l i z e the s t a r t i n g m a t e r i a l . On removal of the a l c o h o l , the product separated out of the s o l u t i o n i n over 95% y i e l d . I t should be noted t h a t the product of the above r e a c t i o n , the a-formyl-a' -u n s u b s t i t u t e d dipyrromethane dimer 108a was the immediate p r e c u r s o r to the p o r p h y r i n 109a i n the d i c y a n o v i n y l - e t h y l e s t e r route as w e l l , although i t was never i s o l a t e d . The i n t r a m o l e c u l a r c y c l i z a t i o n of 108 was performed under p r e c i s e l y the same c o n d i t i o n s mentioned e a r l i e r . The y i e l d of the p u r i f i e d p o r p h y r i n 109a was 51.5%. The r e s u l t s presented above c l e a r l y i n d i c a t e t h a t the c y a n o a c r y l a t e - b e n z y l e s t e r route has g r e a t p o t e n t i a l as an a l t e r n a t i v e s y n t h e t i c pathway f o r p o r p h y r i n s , v i a the head-t o - t a i l c o u p l i n g of dipyrromethanes. The y i e l d s obtained were hig h and they more than compensated f o r the e x t r a steps i n v o l v e d i n t h i s sequence. S t a r t i n g from the b i s - c y a n o a c r y l a t e 115a, the p o r p h y r i n 109a was produced i n an o v e r a l l y i e l d of 31% whereas the same p o r p h y r i n was produced o n l y i n 28% y i e l d , v i a the d i c y a n o v i n y l - e t h y l e s t e r route ( s t a r t i n g from the corresponding d i c y a n o v i n y l - b i s - p y r r o l e 94_) . Although t h i s d i f f e r e n c e i s not very s i g n i f i c a n t , i t should be r e c a l l e d t h a t the s y n t h e s i s of 115a from the b i s benzyl e s t e r 9_0 was e f f e c t e d i n a higher o v e r a l l y i e l d of 76% compared to the 60-65% y i e l d s 124 g e n e r a l l y obtained f o r the c o n v e r s i o n of 9_0 to 94_. On the other hand, the s y n t h e s i s of the a - f r e e - p y r r o l e 8_0 used i n the c y a n o a c r y l a t e - b e n z y l e s t e r r o u t e i n v o l v e d an e x t r a step; i . e . , the t r a n s e s t e r i f i c a t i o n of the corresponding e t h y l e s t e r 79, which was e f f e c t e d i n 84% y i e l d . When one c o n s i d e r s the number of steps i n v o l v e d and the corresponding y i e l d s obtained,.both pathways d e s c r i b e d above seem to be e q u a l l y u s e f u l f o r the s y n t h e s i s of a strapped p o r p h y r i n . The c h o i c e of e i t h e r one f o r any p a r t i c u l a r syn-t h e s i s should be based on the p o s s i b l e e f f e c t s of the reagents used, on the r e q u i r e d B - s u b s t i t u e n t s of the i n t e r m e d i a t e s and t h e r e f o r e of the p o r p h y r i n . 2.7 DURENE-BIS-PENTANOIC ACID AND ITS INCORPORATION  INTO A PORPHYRIN The s y n t h e t i c route developed i n t h i s work was used to c o n s t r u c t y e t another model system f o r heme p r o t e i n s . U n l i k e the syntheses of the p o r p h y r i n s 109a, 109b and 109c where the aim was t o b u i l d a d i s t o r t e d p o r p h y r i n molecule, here the main concern was to i n t r o d u c e a bulky group above one f a c e of the p o r p h y r i n . Such a system was expected to favour the formation of a f i v e c o - o r d i n a t e s p e c i e s as opposed to s i x , i n the presence of a nitrogeneous base (due to s t e r i c r e a s o n s ) , thereby l e a v i n g a vacant s i t e a t the metal c e n t r e f o r the b i n d i n g of a small molecule. The s t r a p chosen f o r t h i s work was durene-bis-pentane ( S e c t i o n 2.2), which was r e q u i r e d as 125 the b i s pentanoic a c i d f o r the s y n t h e s i s . B i s ( c h l o r o m e t h y l ) durene , [1,4-bis(chloromethyl)-2,3,5,6-tetramethylbenzene] was commercially a v a i l a b l e ( A l d r i c h Chemical Co.) at a reason-able p r i c e and was s e l e c t e d as the s t a r t i n g m a t e r i a l . The s y n t h e s i s of the b i s pentanoic a c i d s t a r t i n g from the c h l o r o -methyl d e r i v a t i v e i s d i s c u s s e d i n s e c t i o n 2.7.1 whereas i t s i n c o r p o r a t i o n i n t o the p o r p h y r i n i s given i n s e c t i o n 2.7.2. The t r i v i a l name, durene, i s commonly used throughout the d i s c u s s i o n but these compounds have been named as d e r i v a t i v e s of 2,3,5,6-tetramethylbenzene. 2.7.1 SYNTHESIS OF DURENE-BIS-PENTANOIC ACID The s y n t h e t i c scheme, s t a r t i n g from b i s ( c h l o r o m e t h y l ) durene i s o u t l i n e d i n F i g u r e 19. I t was apparent t h a t the most convenient c h a i n e x t e n s i o n method would be two malonate syntheses, each condensation e l o n g a t i n g the c h a i n by two carbon atoms. The commercially a v a i l a b l e s t a r t i n g m a t e r i a l was most s u i t e d f o r the i n i t i a l malonate r e a c t i o n . Although c h l o r i d e s are the l e a s t r e a c t i v e o f the a l k y l h a l i d e s , towards nuc l e o -p h i l i c s u b s t i t u t i o n , the s t a b i l i t y of the be n z y l carbpnium i o n i s known to a i d i n the r e a c t i o n s i n v o l v i n g such groups. The e x t r a a c t i v a t i o n p rovided by the four methyl groups was B I S ( C H L O R O M E T H Y L ) D U R E N E C O J C ^ J 1 2 0 126 COjH 121 t Ouinoline heat COjH 1 2 2 E tOH / H 2 S O A V C02C2H5 123 FIGURE 19 : Synt h e s i s of Durene-Bis-Pentanoic A c i d 130 127 expected to favour the simultaneous b i s malonate s y n t h e s i s on the s t a r t i n g m a t e r i a l ; indeed t h i s was observed. The malonate r e a c t i o n was performed i n anhydrous ethanol u s i n g sodium ethoxide as the base, which was prepared by the d i s s o l u t i o n of m e t a l l i c sodium i n e t h a n o l . In order to prevent the formation of the d i a n i o n of malonate l e a d i n g to b i s a l k y l a l i o n , excess d i e t h y l malonate (4 e q u i v a l e n t s ) was used i n t h i s r e a c t i o n . In an analogous c o n v e r s i o n of b e n z y l c h l o r i d e to d i e t h y l b e n z y l malonate u s i n g equimolar q u a n t i t i e s of the malonate and the c h l o r i d e , M a r v e l 5 6 had o b t a i n e d o n l y 51-57% of the d e s i r e d product, with the r e -mainder being d i e t h y l d i b e n z y l malonate. When b i s ( c h l o r o -methyl)durene" was added to the monosodio d i e t h y l malonate generated i n s i t u , and the r e a c t i o n mixture brought to r e f l u x , no change c o u l d be observed; the white s o l i d s t a r t i n g m a t e r i a l appeared to remain u n d i s s o l v e d . N e v e r t h e l e s s , w i t h i n h a l f an hour, no s t a r t i n g m a t e r i a l c o u l d be observed on a t i c . The d i s s o l u t i o n of the s t a r t i n g m a t e r i a l and the p r e c i p i t a t i o n of sodium c h l o r i d e (the other product) had o c c u r r e d so f a s t and s i m u l t a n e o u s l y , t h a t the change i n the r e a c t i o n mixture was not o b s e r v a b l e . The product of t h i s r e a c t i o n , the t e t r a e t h y l e s t e r 12 0 was not i s o l a t e d but s a p o n i f i e d d i r e c t l y i n a s i n g l e - p o t r e a c t i o n , to the t e t r a a c i d 121. Once the a l k y l a t i o n was complete, approximately one t h i r d of the s o l v e n t (ethanol) was d i s t i l l e d o f f and the remainder was t r e a t e d with aqueous 128 potassium hydroxide s o l u t i o n . In order to ensure complete s a p o n i f i c a t i o n of a l l e s t e r groups, approximately 12 e q u i v a l e n t s of base were used. The mixture was r e f l u x e d f o r a s h o r t time and the remaining e t h a n o l was b o i l e d o f f u n t i l the r e f l u x temperature reached 100°C . A c i d i f i c a t i o n w i t h concentrated h y d r o c h l o r i c a c i d while m a i n t a i n i n g the s o l u t i o n a t r e f l u x , caused the d e c a r b o x y l a t i o n of malonic a c i d ( r e s u l t i n g from the excess d i e t h y l malonate used) as i t was formed, with the vi g o r o u s e v o l u t i o n of gas. Although the b i s malonic a c i d was expected to d e c a r b o x y l a t e under these c o n d i t i o n s , the white s o l i d product i s o l a t e d from the r e a c t i o n mixture i n d i c a t e d no d e c a r b o x y l a t i o n . The b i s malonic a c i d 121 obtained i n g r e a t e r than 95% o v e r a l l y i e l d from - b i s ( c h l o r o m e t h y l ) d u r e n e , -was found to be a n a l y t i c a l l y pure. The compound 121 was next subjected to thermal d e c a r b o x y l a t i o n . Q u i n o l i n e was s e l e c t e d as the s o l v e n t f o r t h i s purpose not o n l y due to i t s hi g h b o i l i n g p o i n t (237°C) , but a l s o due to i t s a b i l i t y to f a c i l i t a t e the process of d e c a r b o x y l a t i o n by the formation of the c a r b o x y l a t e anion. In r e f l u x i n g q u i n o l i n e , the d e c a r b o x y l a t i o n was almost i n s t a n t -aneous. The product 122 was c r y s t a l l i z e d by pouring the hot r e a c t i o n mixture 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 and c o l l e c t e d by f i l t r a t i o n . The q u i n o l i n e was recovered by n e u t r a l i z i n g the f i l t r a t e w i t h s o l i d sodium hydroxide and e x t r a c t i n g i n t o e t h e r . Although q u i n o l i n e was r e d i s t i l l e d p r i o r to use, i t darkened d u r i n g the r e a c t i o n (even under n i t r o g e n ) , c a using the product to be colored brown. Therefore, the crude product had to be p u r i f i e d by diss o l v i n g i n hot aqueous sodium b i -carbonate, f i l t e r i n g through a c e l i t e plug and r e p r e c i p i t a t i n g by a c i d i f i c a t i o n . The y i e l d of the p u r i f i e d product was greater than 96%. With the chain extended by two carbons, the next task was to convert the carboxylic acid f u n c t i o n a l i t i e s of 122 CO^ CH^H 122 to groups suitable for the second malonate synthesis. The f i r s t step was the reduction to hydroxymethyl groups, which was performed i n the usual manner using diborane. The st a r t i n g material 122'did not dissolve completely i n the solvent, t e t r a -hydrofuran, but appeared to dissolve during the reaction. Since a t i c of the reaction mixture indicated some streaking behind the fa s t moving product spot (no s t a r t i n g material l e f t ) , i t was allowed to s t i r for 10 minutes afte r the addition of boron t r i f l u o r i d e etherate. Unfortunately, the solution turned gelatinous and eventually hardened. This may have been due to the formation of insoluble borates of the product. 130 Since s t i r r i n g was v i r t u a l l y i m p o s s i b l e a t t h i s stage, the excess diborane was quenched wi t h a c e t i c a c i d and the s o l u t i o n was d i l u t e d with water which r e s u l t e d i n a c l e a r s o l u t i o n . The product 124 was i s o l a t e d by removing the t e t r a h y d r o f u r a n i n vacuo and was r e c r y s t a l l i z e d from aqueous e t h a n o l . Although t h i s m a t e r i a l e x h i b i t e d a very s t r o n g parent peak i n the mass spectrum a t m/e = 250 as expected f o r 124, i t s elemental a n a l y s i s was not a c c e p t a b l e . Carbon analysed approximately 2% below the expected v a l u e . The proton nmr was c o n s i s t e n t with the s t r u c t u r e 124 but the hydroxy proton resonance a t 6' 1*47 i n t e g r a t e d somewhat high e r than expected. Assuming t h a t t h i s was due to the product c r y s t a l l i z i n g out as a hydrate, a sample-was d r i e d on the vacuum-line a t 80°C f o r 24 hours. T h i s appeared to s o l v e the problem of the high i n t e g r a t i o n of the hydroxy protons i n the nmr but the carbon a n a l y s i s remained almost unchanged. N e v e r t h e l e s s , t h i s product was used f o r f u r t h e r m o d i f i c a t i o n . The next step i n the s y n t h e s i s was the c o n v e r s i o n of the two hydroxy groups to good l e a v i n g groups f o r the subsequent malonate s y n t h e s i s . Since the i n f l u e n c e of the tetramethylbenzene group was not a v a i l a b l e f o r the s t a b i l -i z a t i o n of the carbonium i o n , the use of a c h l o r o group was avoided. Two groups c o n s i d e r e d here were the methanesulfonyl group and the bromo group. Since m e s y l a t i o n (using methane-s u l f o h y l c h l o r i d e and p y r i d i n e ) should be c a r r i e d out under anhydrous c o n d i t i o n s and there were i n d i c a t i o n s t h a t the s t a r t i n g m a t e r i a l 124 was i n a p a r t i a l l y hydrated form, bromination was attempted f i r s t . A test reaction was carried out on a r e l a t i v e l y small scale (0.02 M) using the bis(hydroxypropyl)durene CH^H CH2Br m V27 124 sample prepared above. The st a r t i n g material was heated, under nitrogen, with a mixture of 48% aqueous hydrobromic acid and concentrated s u l f u r i c acid. The s o l i d s t a r t i n g material turned into an o i l and l a t e r produced an emulsion with the aqueous reagent. Within 30 minutes, the t i c of an aliquot extracted into methylene chloride exhibited a single spot, moving ahead of the st a r t i n g material (some decomposition products- were observed at the o r i g i n ) . This material was isolated i n approximately 90% y i e l d , the spectroscopic as well as a n a l y t i c a l data being consistent with the structure of bis(bromopropyl)durene 127. These re s u l t s were reproduced when the reaction was repeated on a larger scale using the same stock of bis(hydroxypropyl)durene 124 . 132 Before proceeding f u r t h e r , i t was necessary to go back and c a r r y out the l a s t two r e a c t i o n s on a l a r g e r s c a l e . As the f i r s t step, the diborane r e d u c t i o n of d u r e n e - b i s - p r o p i o n i c a c i d 122 was repeated on 0.2 M. s c a l e . Towards the end of the a d d i t -i o n of boron t r i f l u o r i d e e t h e r a t e , the r e a c t i o n mixture once again turned g e l a t i n o u s and hardened. Since s t i r r i n g was almost i m p o s s i b l e , t h i s was worked up and the product was i s o l a t e d as d e s c r i b e d b e f o r e . The s p e c t r o s c o p i c p r o p e r t i e s o f t h i s m a t e r i a l compared w e l l with those of the p r e v i o u s l y prepared sample. How-ever, i t s 1 3 C nmr spectrum e x h i b i t e d an anomalous peak a t 6 33.77, but the i n t e n s i t y of t h i s peak was low. The above product was subjected to bromination under the exact c o n d i t i o n s used e a r l i e r . The t i c taken a f t e r 30 min-utes e x h i b i t e d , i n a d d i t i o n to the spot corresponding to the expected product 127, another f a s t moving spot, almost behind i t . A s e r i e s of f a i n t bands were a l s o observed and the decomp-o s i t i o n product spot a t the o r i g i n appeared to be more i n t e n s e . Even a f t e r 3 hours of r e f l u x i n g the t i c d i d not show a s i g n i f -i c a n t change, the e x t r a spots remaining i n approximately the same r e l a t i v e i n t e n s i t i e s . Since the r e a c t i o n mixture had darkened c o n s i d e r a b l y by t h i s time i t was cooled and e x t r a c t e d w i t h methylene c h l o r i d e . A f t e r removing the a c i d with aqueous sodium b i c a r b o n a t e , the methylene c h l o r i d e s o l u t i o n was evap-o r a t e d i n the presence of methanol. Since the product o i l e d out under these c o n d i t i o n s , i t was r e d i s s o l v e d i n s u f f i c i e n t methylene c h l o r i d e and allowed to stand i n the r e f r i g e r a t o r 133 o v e r n i g h t , when c r y s t a l l i z a t i o n o c c u r r e d . T h i s m a t e r i a l c o n s i s t e d mainly of the ;bis (bromopropyl)durene .\ 127, with very l i t t l e of the i m p u r i t y . R e c r y s t a l l i z a t i o n from methy-lene c h l o r i d e - m e t h a n o l removed t h i s m a t e r i a l . I t was d i s a p p o i n t i n g to note t h a t the mother l i q u o r s contained a c o n s i d e r a b l e amount of 127 contaminated by the unknown i m p u r i t y . The mother l i q u o r s and washings were evaporated to dryness, the s o l i d s taken up i n methylene c h l o r i d e and a s e p a r a t i o n was attempted by repeated chromatography and c r y s t a l l i z a t i o n s . T h i s produced the pure bis(bromopropyl)durene 127 i n approx-i m a t e l y 65% y i e l d and a s u f f i c i e n t q u a n t i t y of the by-product f o r c h a r a c t e r i z a t i o n purposes. The lower y i e l d of 127 was not o n l y due to the formation of the above mentioned by-product, but a l s o due to the d i f f i c u l t y of p u r i f i c a t i o n . Both compounds appeared to have very s i m i l a r s o l u b i l i t y and adsorp-t i o n p r o p e r t i e s and as such, the s e p a r a t i o n was not very e f f i c i e n t . 13 The a n a l y s i s of the .: C-nmr spectrum of the by-product p r o v i d e d s u f f i c i e n t i n f o r m a t i o n i n order to.propose a s t r u c t u r e f o r t h i s compound. A resonance a t 6 173.09, c h a r a c t e r -i s t i c of a c a r b o n y l carbon and another a t 6 64.47 i n d i c a t i v e of 3. a carbon a t t a c h e d to an sp h y b r i d i z e d oxygen, suggested t h a t the molecule possessed an e s t e r l i n k a g e . There were two resonances a t 6 16.41 and 6 16.31, each corresponding to four carbons (four m e t h y l s ) , i n s t e a d of the s i n g l e resonance near 6 16 observed f o r a l l other symmetrical durene i n t e r m e d i a t e s , suggesting the e x i s t e n c e of two durene m o i e t i e s i n the molecule. In support of t h i s was the occurrence ;of seven resonances i n the aromatic r e g i o n . The symmetrical monomeric durene i n t e r -mediates e x h i b i t e d o n l y two resonances i n the aromatic r e g i o n , 13 i n a r a t i o o f 2:1. The three resonances observed i n the C-nmr spectrum of 127, a t <5 33 . 90, 6 32 .72 and <S 29.40, and assi g n e d to the three carbons o f . t h e bromopropyl s i d e c h a i n , were a l s o observed i n t h i s by-product ; a t 6 33.89, 6 32.71 and <$ 29.39. Each of these represented two carbon atoms as compared with the other four resonances observed i n the methyl-ene r e g i o n , which corresponded to one carbon each. Based on the a n a l y s i s presented above, the s t r u c t u r e 128 was proposed f o r the by-product i s o l a t e d i n the bromination r e a c t i o n . The carbon, hydrogen and bromine analyses as w e l l as the proton nmr s p e c t r a l data were c o n s i s t e n t with the 135 proposed s t r u c t u r e . The mass spectrum e x h i b i t i n g a parent mass combination of m/e = 620-622-624 was added support. With the i d e n t i t y of the r e a c t i o n by-product e s t a b l i s h e d , i t was necessary to r a t i o n a l i z e i t s o r i g i n i n order to work out how i t s formation c o u l d be avoided or m i n i -mized. I t was reasonable to assume t h a t the r e a c t i o n mixture c o n t a i n e d compound 125 which, i n the a c i d medium r e a c t e d with 124 to produce the e s t e r 126. T h i s on bromination would have pro duced the i s o l a t e d by-product 128. In order to e l i m i n a t e the p o s s i b i l i t y of 125 being formed by the p a r t i a l o x i d a t i o n of 124 i n conc e n t r a t e d s u l f u r i c a c i d , the bromination was repeated u s i n g 48% hydrobromic- a c i d alone. The r e s u l t was the same as b e f o r e ; i . e . , both 127 and 128 were formed. T h i s suggested t h a t the p a r t i c u l a r sample of bis(hydrox propyl) durene 124 used i n t h i s bromination r e a c t i o n may have been contaminated with the p a r t i a l l y reduced product 125. 136 Although a t f i r s t , t h i s was s u r p r i s i n g , s i n c e the diborane r e d u c t i o n of carboxy to hydroxymethyl i s known to be a f a c i l e r e a c t i o n , i t c o u l d not be r u l e d out, c o n s i d e r i n g the manner i n which the r e a c t i o n 122 124 proceeded. I t should be r e c a l l e d t h a t the d u r e n e - b i s - p r o p i o n i c a c i d 122 was not very s o l u b l e i n t e t r a h y d r o f u r a n and although i t was expected to go i n t o s o l u t i o n d u r i n g the r e a c t i o n (the product being more s o l u b l e ) , the premature c r y s t a l l i z a t i o n o f the p a r t i a l l y reduced product 125 may have prevented the r e a c t i o n from going to completion. The r e a c t i o n mixture turned g e l a t i n o u s and e v e n t u a l l y hardened even be f o r e the 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 was complete, and t h i s may have l e d to the e x i s t e n c e of the p a r t i a l l y reduced m a t e r i a l 125 i n the i s o l a t e d sample of 124. The anomalous peak observed 13 a t 6 33.77 i n the C-nmr spectrum o f t h i s m a t e r i a l c o u l d be a t t r i b u t e d to the presence of compound 125; methylene carbons a to a carboxy group are known to appear i n t h i s r e g i o n . In order to a v o i d the formation of t h i s by-product, the d u r e n e - b i s - p r o p i o n i c a c i d 122 was converted to i t s d i e t h y l e s t e r before s u b j e c t i n g to the diborane r e d u c t i o n . The d i e t h y l e s t e r 123 was obtained i n approximately 90% y i e l d by the r e a c t i o n of 122 w i t h e t h a n o l i n the presence of co n c e n t r a t e d s u l f u r i c a c i d . 137 Hf H3C CH3 123 122 The p r i o r e s t e r i f i c a t i o n g r e a t l y improved the s o l u b i l i t y of the s t a r t i n g m a t e r i a l i n t e t r a h y d r o f u r a n and the diborane r e d u c t i o n (123 V 124) proceeded without any problems. A r e l a t i v e l y l a r g e volume of s o l v e n t was used and no premature 124 i s o l a t e d i n g r e a t e r than 95% y i e l d gave an a c c e p t a b l e 13 carbon and hydrogen a n a l y s i s . F u r t h e r , the C nmr spectrum of t h i s m a t e r i a l d i d not e x h i b i t a peak at <5 33 .77 . T h i s was subsequently brominated u s i n g 48% aqueous hydrobomic a c i d . The r e a c t i o n was complete i n 3 0 minutes and the t i c of the r e a c t i o n mixture i n d i c a t e d no spot corresponding to the d i m e r i c i m p u r i t y 128. The bis(bromopropyl)durene'' 127 was i s o l a t e d i n approximately 90% y i e l d . i n t o the r e a c t i o n sequence, the new route proved to be s u p e r i o r to the o r i g i n a l one due to the e l i m i n a t i o n of the cumbersome s e p a r a t i o n of products a f t e r bromination. But i t should be c r y s t a l l i z a t i o n was observed. The b i s (hydroxypropyl)durene •" Although t h i s m o d i f i c a t i o n i n t r o d u c e d an e x t r a step 138 emphasized that i f problems were anticipated i n the diborane reduction of durene-bis-propionic acid 122, the diester 123 could have been obtained d i r e c t l y without passing through the d i a c i d . For t h i s purpose, the tetraethyl ester 120 CH 2Cl CH 2Cl BIS(CHLOROMETHYL) DURENE H^2°2' C U 2C 2H 5 120 C0 2C 2H 5 should have been isol a t e d following the malonate reaction of bis (chloromethyl) durene-:5 - without the hydrolysis of the esters. This i s e a s i l y achieved by the a c i d i f i c a t i o n of the reaction mixture (with g l a c i a l acetic acid) followed by d i l u t i o n with water. The decarbethoxylations of geminal diesters related to 12 0 have been effected i n dimethyl sulfoxide by water, with or without added s a l t s . This type of decarbalkoxylations of geminal diesters have been studied by Krapcho and co-workers 5 7 using a variety of substrates and diverse s a l t s . They have observed that substrates with electron withdrawing substituents such as d i e t h y l phenylmalonate and d i e t h y l benzylmalonate undergo decarbethoxylations f a i r l y r e a d i l y i n water-dimethyl 139 s u l f o x i d e whereas n - a l k y l s u b s t i t u t e d d i e t h y l malonates r e a c t s l o w l y under the above c o n d i t i o n s . The r e a c t i o n w i t h the l a t t e r group of geminal d i e s t e r s has been observed to be a c c e l e r a t e d by the a d d i t i o n of s a l t s such as KCN, NaCl- and L i C l . The bis(bromopropyl)durene 127 was then- su b j e c t e d to the malonate s y n t h e s i s under the c o n d i t i o n s d e s c r i b e d p r e v i o u s l y . The s t a r t i n g m a t e r i a l went i n t o s o l u t i o n a t the CH 3 130 onset of r e f l u x and w i t h i n 10 minutes sodium bromide c r y s t a l l i z e d out of s o l u t i o n . The b i s malonate e s t e r was s a p o n i f i e d without i s o l a t i o n and the t e t r a c a r b o x y l i c a c i d 129 was o b tained i n an o v e r a l l y i e l d of 95% (from 127). D e c a r b o x y l a t i o n of the . t e t r a a c i d i n r e f l u x i n g q u i n o l i n e produced the d e s i r e d product, durene-bis-pentanoic a c i d 130 i n 95% y i e l d and was c h a r a c t e r i z e d as i t s dimethyl e s t e r . 140 2.7.2 INCORPORATION OF DURENE-BIS-PENTANOIC ACID INTO  THE PORPHYRIN The durene-bis-pentanoic a c i d 130 was c a r r i e d through the r e a c t i o n sequence developed f o r the simple a l i p h a t i c c h a i n l i n k e d s e r i e s , to produce the c o r r e s p o n d i n g p o r p h y r i n . The main concern here was the lower s o l u b i l i t y of the i n t e r m e d i a t e s as compared with the a l i p h a t i c c h a i n l i n k e d analogues. The i n i t i a l stages of t h i s sequence are o u t l i n e d i n F i g u r e 20. Once again , the f i r s t step was the l i n k i n g of the s t r a p to g - p o s i t i o n s of two p y r r o l e s . T h i s was e f f e c t e d i n the u s u a l manner by c o n v e r t i n g the a c i d 130 to i t s b i s ; ' a c i d c h l o r i d e and u s i n g t h i s tov'aeylate two moles of the 3-unsubstituted p y r r o l e 6_6. The o v e r a l l y i e l d of the diketone 132 was r e l a t i v e l y low, 67%. The two k e t o n i c groups were subsequently reduced w i t h diborane i n t e t r a h y d r o f u r a n . When the usual volume of s o l v e n t was used, the r e a c t i o n d i d not go to completion even i n the presence of an excess of diborane and a c o n s i d e r a b l e amount of s t a r t i n g m a t e r i a l remained u n d i s s o l v e d . When more s o l v e n t (approximately 3 volumes) was added, a l l the s o l i d went i n t o s o l u t i o n and the r e a c t i o n was complete i n l e s s than 10 minutes. The product 133 was i s o l a t e d i n g r e a t e r than 87% y i e l d . The transb.enzylation of the b i s e t h y l e s t e r 133 produced the b i s b e n z y l •ester 134 i n over 98% yield-. -The 141 FIGURE 2 0 : S y n t h e s e s o f D u r e n e - B i s - P e n t a n e 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 higher y i e l d here could be due to the ease of c r y s t a l l i z a t i o n ; a consequence of i t s lower s o l u b i l i t y . The hydrogenolysis of the benzyl ester (134 -> 135) , the decarboxylation of the product (135 136) and the subsequent formylation under Vilsmeier conditions (136 -f 137) a l l proceeded without any complications. The bis formylpyrrole 137 was once again converted to i t s dicyanovinyl derivative 138 and p u r i f i e d . The o v e r a l l y i e l d of 138 from the bis benzyl ester 134 was over 6 0%. With the protected formyl groups i n place, i t was necessary to monochlorinate each of the two a-methyl groups of compound 138 i n order to condense with two moles of the a-unsubstituted pyrrole. Unlike the previous examples where the "strap" consisted of simple methylene groups, the presence of an activated benzene ring i n t h i s case, made t h i s c h l o r i n -ation the most c r u c i a l step i n the entire reaction sequence. Since side chain halogenations are known to occur with such systems s t r i c t control of reaction conditions appeared to be of importance i n d r i v i n g the reaction to the desired product. Side chain halogenations of polysubstituted ct-methyl-5 8 pyrroles have been known for a long time and have been recognized as intermediate steps i n the preparation of a number of pyrrole oligomers such as dipyrromethanes, dipyrro-methenes -and porphyrins. However, very l i t t l e attention has been paid to the mechanism of these reactions. In one instance, the side chain chlorination with s u l f u r y l chloride was assumed 143 5 9 to occur by a free r a d i c a l mechanism ; i n fact t h i s seems to be the general b e l i e f although the mechanism has not been est-ablished. Conversely, a considerable amount of work has been carried out on the halogenation of alkylbenzenes and there appears to be two d i s t i n c t mechanisms. One i s the well known 6 0 free r a d i c a l mechanism which i s most l i k e l y to occur i n the reaction of the lowest alkylated benzenes, with halogens, in non-polar, non-hydroxylic media. The other i s e l e c t r o -p h i l i c i n nature, and i s favoured i n the dark reaction of the higher alkylated benzenes i n non-polar and/or hydroxylic 6 1 6 2 media. In a closer examination of the l a t t e r mechanism ' the chlorination of hexasubstituted benzenes i n acetic acid solution proved to be quantitatively analogous to e l e c t r o -p h i l i c nuclear substitution by Cl^ i n the same solvent. The evidence involves the k i n e t i c form, the magnitude of the act i v a t i o n parameters, the reaction s e l e c t i v i t y , the influence of catalysts and the i n s e n s i t i v i t y to l i g h t . The "electro-p h i l i c side chain attack" was thus shown to proceed v i a an e l e c t r o p h i l i c nuclear attack of chlorine and have i d e n t i c a l k i n e t i c behaviour to aromatic nuclear ch l o r i n a t i o n . This i s attributed to the s i m i l a r i t y of the benzenonium ions (shown below) i n the rate determining step. R Cl 144 When R=H, the decomposition of the i o n r e s u l t s i n the e x p u l s i o n of the proton and the formation of the a r y l h a l i d e , but i n a p o l y a l k y l a t e d benzene, t h i s would i n v o l v e the r e -arrangement of the halogen from the nucleus to the s i d e c h a i n . Since t h i s m i g r a t i o n i s a subsequent f a s t s t ep, r e a c t i o n k i n e t i c s are of l i t t l e h e l p f o r the e l u c i d a t i o n of i t s mech-anism. I t i s c l e a r t h a t the o v e r a l l r e a c t i o n i n v o l v e s the l o s s of a prot o n , but whether t h i s takes p l a c e p r i o r to the a t t a c k by C l + or as a concerted process i s a matter of g r e a t i n t e r e s t . The s p e c i a l course taken by the c h l o r i n a t i o n r e a c t i o n of 2 , 4 , 6 - t r i m e t h y l - 3 , 5 - d i c h l o r o a n i s o l e and the c f a i l u r e of t h i s compound to y i e l d a 4-chloromethyl d e r i v a t i v e suggested the n e c e s s i t y f o r the presence of a methyl group a t a p o s i t i o n ortho to the p o i n t of e l e c t r o p h i l i c a t t a c k . 6 3 I f a proton i s l o s t a t the adjacent methyl group p r i o r to the rearrangement of c h l o r i n e , i t would l e a d to e q u i l i b r a t i o n of the benzenonium i o n with the corresponding methylene d e r i v a t i v e : 145 T h i s should r e s u l t i n e x t e n s i v e hydrogen i s o t o p e exchange. During the c h l o r i n a t i o n of hexamethylbenzen'e, no exchange with the medium c o u l d be d e t e c t e d and t h i s experimental 6 3 r e s u l t has been used by B a c i o c c h i and I l l u m i n a t i to suggest t h a t the proton l o s s i s probably engaged i n a concer t e d process i n v o l v i n g an i n t r a m o l e c u l a r m i g r a t i o n : The l i g h t induced c h l o r i n a t i o n of a l k y l benzenes by s u l f u r y l c h l o r i d e has been s t u d i e d i n d e t a i l by L e e 6 4 . The r e a c t i o n s had been c a r r i e d out i n carbon t e t r a c h l o r i d e s o l u t i o n a t 40°C u s i n g a 275 Watt sunlamp f o r i r r a d i a t i o n . Under these 146 c o n d i t i o n s , the r e a c t i o n proceeded v i a a r a d i c a l mechanism and the suggested course of the r e a c t i o n i s shown below: R-H + 'S0 2C1 -> R' + HC1 + S0 2 R* + S 0 2 C 1 2 -»• RC1 + *S0 2C1 *so2ci t so2 + C l " The evidence f o r the e x i s t e n c e of the c h l o r o s u l f i n y l r a d i c a l (*S02C1) had been provided by Kharasch and Z a v i s t 6 5 , i n 1951. Lee has concluded from h i s experimental o b s e r v a t i o n s t h a t i n non complexing s o l v e n t s , the hydrogen a b s t r a c t i o n i s mainly by the c h l o r o s u l f i n y l r a d i c a l . 6 6 Recently, I l l u m i n a t i and co-workers r e p o r t e d some very i n t e r e s t i n g o b s e r v a t i o n s on the h a l o g e n a t i o n of p o l y -s u b s t i t u t e d a - m e t h y l p y r r o l e s . They had i n v e s t i g a t e d the mechanism of the a-methyl c h l o r i n a t i o n with molecular c h l o r i n e i n dichloromethane and c h l o r o f o r m a t low temperatures and i n the dark, with f o u r c a r e f u l l y s e l e c t e d a - m e t h y l p y r r o l e s . The r e s u l t s suggest t h a t the o v e r a l l process c o n s i s t s of two s t e p s , s i m i l a r to the corresponding r e a c t i o n of c h l o r i n e with p o l y a l k y l a t e d benzenes; i . e . , the e l e c t r o p h i l i c n u c l e a r a t t a c k and the subsequent rearrangement of the halogen to the s i d e c h a i n . The halogen m i g r a t i o n from the nucleus to the s i d e c h a i n was found to be p o s s i b l e e i t h e r from the adjacent 3 - p o s i t i o n or from the v i n y l o g o u s a'.position. The f o r e g o i n g d i s c u s s i o n p o i n t s towards the f a c t t h a t a c o m p e t i t i o n between e l e c t r o p h i l i c and f r e e r a d i c a l mechanisms of s i d e c h a i n halogenations c o u l d r e s u l t from a combination of s e v e r a l f a c t o r s , i n c l u d i n g the s t r u c t u r e of the s u b s t r a t e , the s o l v e n t and r e a c t i o n c o n d i t i o n s . I t i s e v i d e n t t h a t s i n c e the f r e e r a d i c a l r e a c t i o n i s r a t h e r un-s e l e c t i v e and very slow i n the dark, the e l e c t r o p h i l i c a t t a c k e f f e c t i v e l y competes w i t h i t , e s p e c i a l l y i n s u b s t r a t e s t h a t are h i g h l y r e a c t i v e towards e l e c t r o p h i l i c reagents. In f a c t , w i t h hexamethyl benzene, the s i d e c h a i n h a l o g e n a t i o n v i a e l e c t r o p h i l i c a t t a c k had been observed to compete with the f r e e r a d i c a l mechanism i n carbon t e t r a c h l o r i d e even under i l l u m i n a t i o n 6 3 . I t appeared t h a t the r e a c t i o n c o n d i t i o n s f a v o u r a b l e f o r an e l e c t r o p h i l i c mechanism may l e a d to e x c l u s i v e halogen-a t i o n on the p y r r o l e methyl groups, i n the case of the s u b s t r a t e used i n the present work; i . e . , the b i s dicyano-v i n y l p y r r o l e 138 (Figure 21). Although t h i s molecule contained a p o l y a l k y l a t e d benzene moiety, the p y r r o l e nucleus i s known to be h i g h l y r e a c t i v e towards e l e c t r o p h i l i c a t t a c k which was expected to favour e x c l u s i v e c h l o r i n a t i o n a t the a-methyl group of the p y r r o l e s . Therefore the b i s - c h l o r i n a t i o n of 138 was c a r r i e d out i n the dark, i n methylene c h l o r i d e s o l u t -i o n , a t room temperature u s i n g two e q u i v a l e n t s of s u l f u r y l c h l o r i d e . The product 13 9 was i s o l a t e d , as b e f o r e , by r e p l a c i n g the s o l v e n t (methylene c h l o r i d e ) with d i e t h y l ether and condensed w i t h two e q u i v a l e n t s of the a - u n s u b s t i t u t e d p y r r o l e 79. The only dipyrromethane formed under these c o n d i t i o n s was the d e s i r e d product 140 and the u s u a l h i g h y i e l d of ca. 90% f o r the o v e r a l l r e a c t i o n (a-methyl+a-chloromethyl+dipyrromethane) confirmed the h i g h r e g i o s e l e c t i v i t y of the c h l o r i n a t i o n step. 148 149 When the r e a c t i o n was repeated under the c o n d i t i o n s of l a b o r a t o r y i l l u m i n a t i o n no change was observed i n the above r e s u l t s . Although t h i s does not c o n s t i t u t e c o n c l u s i v e proof, i t appears t h a t i n the absence of i n t e n s e i r r a d i a t i o n , . t h e s u l f u r y l c h l o r i d e c h l o r i n a t i o n of p y r r o l e - a - m e t h y l groups proceeds mainly v i a an e l e c t r o p h i l i c mechanism. The base h y d r o l y s i s o f the dipyrromethane dimer 140 was c a r r i e d out i n aqueous potassium hydroxide, u s i n g n-propanol to s o l u b i l i z e the s t a r t i n g m a t e r i a l . When the a l c o h o l was b o i l e d o f f a f t e r the completion of the r e a c t i o n , the product d i d not o i l out. Instead, i t remained d i s p e r s e d i n water as an emulsion. A c i d i f i c a t i o n of t h i s s o l u t i o n r e s u l t e d i n the p r e c i p i t a t i o n of a - f o r m y l - a 1 - c a r b o x y -dipyrromethane dimer 141 in. g r e a t e r than 9 0% y i e l d . The d e c a r b o x y l a t i o n of 141 and the subsequent c y c l i z a t i o n o f the decarboxylated product 142 were c a r r i e d out as d e s c r i b e d f o r the s t r a i g h t c h a i n analogues. The "durene-capped p o r p h y r i n " was found t o be more s o l u b l e i n nitromethane than i n methanol and as such,, was c r y s t a l l i z e d from the l a t t e r s o l v e n t . In s e v e r a l p r e p a r a t i o n s , the maximum y i e l d obtained f o r the d e c a r b o x y l a t i o n - c y c l i z a t i o n step was 31.4%. CHAPTER 3 EXPERIMENTAL 151 3.1 GENERAL METHODS M e l t i n g P o i n t Determinations M e l t i n g p o i n t s were obtained with a Thomas-Hoover Unimelt, a c a p i l l a r y / o i l immersion apparatus; the r e s u l t s are presented u n c o r r e c t e d . Elemental Ana1y s i s Elemental analyses were performed by Mr. P. Borda of the M i c r o a n a l y t i c a l Laboratory, U.B.C. Nuclear Magnetic Resonance Spectroscopy Unless otherwise s t a t e d , a l l proton nmr s p e c t r a were obtained a t 100 MHz with a V a r i a n HA-100 spectrometer f o r continuous wave s p e c t r a and V a r i a n XL-100 spectrometer f o r F o u r i e r - t r a n s f o r m s p e c t r a . In c e r t a i n i n s t a n c e s , s p e c t r a were recorded a t 270 MHz wit h a U.B.C. NMR Centre m o d i f i e d N i c o l e t - O x f o r d H-270 spectrometer. The chemical s h i f t s are recorded i n the <S (ppm) s c a l e with t e t r a m e t h y l s i l a n e (TMS) (6 = 0 ) as an i n t e r n a l standard. The proton nmr s p e c t r a of the strapped p o r p h y r i n s 109a, 109b and 109c were obtained i n d e u t e r o c h l o r o f o r m s o l u t i o n a t 4 00 MHz with a Bruker WH -400 spectrometer. T h i s instrument was c a l i b r a t e d w i t h TMS as an e x t e r n a l standard. The carbon-13 nmr s p e c t r a were obtained with a V a r i a n CFT - 2 0 spectrometer u s i n g TMS (6 = 0) as the i n t e r n a l standard. The chemical s h i f t s are recorded i n the 6(ppm) s c a l e . Mass Spectrometry Mass s p e c t r a were recorded on a V a r i a n MAT CH 4-B spectrometer or a Kratos/AEI MS-902 spectrometer. High r e s o l u t i o n measurements were obtained on a Kratos/AEI MS-50 spectrometer. I n f r a r e d Spectroscopy The i n f r a r e d s p e c t r a were ob t a i n e d from KBr d i s c s u s i n g a Perkin-Elmer Model 457 g r a t i n g spectrometer c o v e r i n g the frequency range 4000-250 cm The s p e c t r a were c a l i b -r a t e d w i t h p o l y s t y r e n e f i l m a t 1601.4 cm 'E l e c t r o n i c Spectroscopy A Cary r e c o r d i n g spectrometer (Model 17) was used to o b t a i n uv and v i s i b l e s p e c t r a . Chromatogr aphy Column chromatography was performed u s i n g s i l i c a g e l obtained from ICN Pharmaceuticals (Woelm, 70-150 mesh, a c t i v i t y I) and Camag aluminum oxide ( b a s i c , a c t i v i t y I ) . Thin Layer Chromatography ( t i c ) was performed u s i n g precoated s i l i c a g e l p l a t e s ( A n a l t e c h - U n i p l a t e , 250 V) and the compounds were de t e c t e d by uv l i g h t (254 nm). 153 S t a r t i n g M a t e r i a l s As none of the p y r r o l e s r e q u i r e d f o r t h i s work was commercially a v a i l a b l e a t 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 m a t e r i a l s had to be s y n t h e s i z e d . Although most of these compounds have appeared p r e v i o u s l y i n the l i t e r a t u r e , t h e i r syntheses have been i n c l u d e d here f o r completeness, and the convenience of any who might wish to make use of the i n f o r m a t i o n c o n t a i n e d h e r e i n . In some cases, u s e f u l m o d i f i c a t i o n s have been made. Reagents and So l v e n t s A l l chemicals and s o l v e n t s were reagent grade unl e s s otherwise i n d i c a t e d . 3.2 NOMENCLATURE OF PORPHYRINS AND THEIR INTERMEDIATES The nomenclature of a l l p o r p h y r i n s s y n t h e s i z e d d u r i n g t h i s work has been based on the IUPAC numbering scheme giv e n i n F i g u r e IB. The p y r r o l e n u c l e i of dipyrromethanes were numbered i n such a way as to a s s i g n 2 and 2' to the methane bri d g e d a p o s i t i o n s . The numbers 2', 3' e t c . have been used on one p y r r o l e r i n g ( i n the f i g u r e s ) only"- f o r the purpose of d i s t i n g u i s h i n g the .analogous p o s i t i o n s on the :.two r i n g s -i n s p e c t r a l assignments. 154 Following the Chemical Abstracts nomenclature, these compounds have been named as substituted (pyrrol - 2-yl)methyl-pyrroles.. For the chain-linked dimeric systems, the alkane was considered as the parent compound and they were named as term-i n a l l y bis-substituted alkanes. Further, the pyrrole nucleus has been numbered as shown below, so as to assign the chain linked 3-position the lower number possible. To avoid confusion, t h i s numeration scheme has been maintained for every bis-pyrrole and bis-dipyrromethane intermediate. 155 3.3 SYNTHESES QF ACYCLIC PRECURSORS D i e t h y l hexanediote ( D i e t h y l adipate) 6_1 Hexanedioic a c i d ( a d i p i c a c i d ) (295 g, 2.02 moi), 95% ethanol (650 mL), concentrated s u l f u r i c a c i d (20 mL) and toluene (360 mL) were p l a c e d i n a 2 - l i t e r round-bottomed f l a s k f i t t e d w i t h a Dean-Stark t r a p surmounted by a r e f l u x condenser. The r e a c t i o n mixture was heated under r e f l u x f o r 16 h. d u r i n g which time, approximately 350 mL of lower l a y e r were removed from the Dean-Stark apparatus. (The upper l a y e r was con-s t a n t l y r e i n t r o d u c e d to the r e a c t i o n f l a s k ) . The r e a c t i o n mixture was cooled to room temperature, e x t r a c t e d w i t h water (2x200 mL) to remove the s u l f u r i c a c i d and the o r g a n i c phase d i s t i l l e d under reduced p r e s s u r e . E t h a n o l , toluene and water d i s t i l l e d over below 30°C and the product was c o l l e c t e d between 139° and 145°C/20 T o r r , y i e l d , 308 g; 75.5%. 6 7 0 BP ( L i t . • ) : 136-137 C/19 T o r r 1H NMR (6, CDC1 3) : 1.23 ( t , 6H, J=7 Hz, -0-CH 2-CH_ 3), 1.42-1.81 (m, 4H, C-3, C-4, methylene protons) 2.05-2.50 (m, 4H, C-2, C-5, methylene p r o t o n s ) , 4.06 (q, 4H, J=7 Hz, -0-CH 2~CH 3) 156 Monoethyl hexanediote (Ethyl hydrogen adipate) 62_ Diethyl hexanedioate 6_1 (303.0 g, 1.5 moi), hex-anedioic acid (219.0 g, 1.5 moi) and toluene-p-sulfonic acid (2.0 g) were placed i n a 1 - l i t e r 3-neck flask f i t t e d with a thermometer, a nitrogen i n l e t tube and a condenser and heated at r e f l u x temperature for 15 h. Fra c t i o n a l d i s t i l l a t i o n of the reaction mixture under reduced pressure (13 torr) gave two frac t i o n s ; Ia, containing mainly the diester (bp 128-152°C) and I l a , the monoester (bp 152-170°C). The f r a c t i o n Ia was combined with the residue i n the flask (the diacid) and re-fluxed for a further 15 h period. Another reduced pressure (6 torr) d i s t i l l a t i o n gave the diester f r a c t i o n l b (bp 120-145°C) and the monoester f r a c t i o n l i b (bp 145-165°C). Ib was recombined with the residue and the processes of reflux i n g followed by f r a c t i o n a l d i s t i l l a t i o n were repeated once more. The monoester f r a c t i o n l i e was combined with the previous fractions I l a and l i b and r e d i s t i l l e d under reduced pressure to give 294.2 g (56.3%) of the pure hexanedioic acid, monoethyl ester. (BP : 150-153°C/6 Torr) o . 6 8 o MP : 27.5 - 28.5 C; L i t . : 28-29 C 69 0 BP : ( L i t : ' ) : 163 C(10 Torr) H NMR (6, CDC13) : 1.26(t, 3H, J=7 Hz-, -0-CH2~CH3) •; .'1. 42-192 157 (m, 4H, C-3, C-4, methylene p r o t o n s ) , 1.92-2.14 (m, 4H, C-2, C-5, methylene p r o t o n s ) , 4.14 (q, 2H, J=7 Hz, -0-CH_2CH3) 6-0xoundecanedioic a c i d 64 Monoethyl hexanedioate 6_2_ (184.0 mL, 1.06 moi) and t h i o n y l c h l o r i d e (140 mL, 1.95 moi) were p l a c e d i n a 1 - l i t e r round-bottomed f l a s k f i t t e d with a r e f l u x condenser and a c a l c i u m c h l o r i d e d r y i n g tube. The f l a s k was heated on a steam bath u n t i l the e v o l u t i o n of gases ceased (approximately 1.5 h) .' The excess t h i o n y l c h l o r i d e was removed wi t h carbon t e t r a c h l o r i d e (5x50 mL) by e v a p o r a t i n g under reduced p r e s s u r e . The monoacid c h l o r i d e thus obtained was used i n the next r e a c t i o n without f u r t h e r p u r i f i c a t i o n . T r i e t h y l a m i n e [NOTE 1] (210 mL, 1.5 moi) and dry toluene [NOTE 2] (900 mL) were c o o l e d to 3-5°C i n a 2 - l i t e r three-necked f l a s k f i t t e d with a mechanical s t i r r e r , a therm-ometer, (extending i n t o the l i q u i d ) and a dropping f u n n e l (with a d r y i n g tube f i l l e d w ith c a l c i u m c h l o r i d e ) . The a c i d c h l o r i d e prepared above was added r a p i d l y to the w e l l s t i r r e d l i q u i d , m a i n t a i n i n g the temperature of the r e a c t i o n mixture below 25°C. When t h e ^ m i l d l y exothermic r e a c t i o n had subsided, the i c e - b a t h was r e p l a c e d by a warm water bath to r a i s e the temp-e r a t u r e of the r e a c t i o n mixture to 35°C and allowed to s t i r f o r 30 minutes. A t h i c k white p r e c i p i t a t e of t r i e t h y l a m i n e hydro-c h l o r i d e separated out. The s o l i d was d i s s o l v e d i n water (3 00 mL), 158 the organic phase separated and the solvent (toluene) removed by evaporating under reduced pressure. A solution of potassium hydroxide (120g) i n water (450mL) and ethanol (lOOmL) was added to the residue and heated under reflux for 2 h to give a completely homogeneous solution. Ethanol and the excess toluene were evaporated off under reduced pressure and the aqueous solution was a c i d i f i e d with concentrated hydrochloric acid (approximately 200mL) when the product c r y s t a l l i z e d out as a thick white p r e c i p i t a t e . The solution was cooled i n ice overnight and the s o l i d was col l e c t e d by suction f i l t r a t i o n , washed with ice-water and dried i n a i r . The y i e l d of 6-oxoundecanedioic acid was 72.9g (60.0%, s t a r t i n g from monoethyl hexanedioate). MP : 107.5-109.0°C, NMR (6, DMSO-d ), 1.28-1.52 (m, 8H, C-3, C-4, C-8, C-9 j methylene protons), 1.98-2.32(m, 4H, C-2, C-10 methylene protons), 2.32-2.68 (m, 4H, C-5, C-7 methylene protons), 10.93 (br, 2H, -COOH) NOTE 1 Triethylamine was p u r i f i e d i n the following manner. Fisher reagent grade triethylamine was f r a c t i o n a l l y d i s t i l l e d through a 2 0cm. Vigreux column and the fra c t i o n c o l l e c t e d over the range 88.5-90°C was then L i t . : 108-109°C , 111°C 1 159 refluxed with p h t h a l l i c anhydride and r e d i s t i l l e d . This was d i s t i l l e d once more from 1-naphthyliso-cyanate, before use. NOTE 2 A quantity of reagent grade toluene was dried by d i s t i l l i n g about one-fourth of i t and then cool-ing the residue with protection from moisture by the use of a calcium chloride tube. Undecanedioic acid i 6_5 Diethylene g l y c o l (340mL) and potassium hydroxide (60g, 0.91 moi) were placed i n a 1 - l i t e r erlenmeyer flask f i t t e d with a Claisen head (side-arm stoppered) and a reflux condenser. The mixture was magnetically s t i r r e d and care-f u l l y heated on a hot plate u n t i l the potassium hydroxide was completely dissolved. The solution was cooled to 8 0°C, 6-oxoundecanedioic acid 64_ (70.0g, 0.30 moi) and 95% hydra-zine (32g, 0.95 moi) added and heated under reflux for 1 h. The reflux condenser was removed, a thermometer suspended i n the heated l i q u i d and the mixture was d i s t i l l e d through the side arm of the Claisen head. When the l i q u i d temperature reached 205-210°C (approximately 52mL of d i s -t i l l a t e was c o l l e c t e d ) , the thermometer was removed, the side arm stoppered and heated under reflux for 3 h. The r e a c t i o n mixture was c o o l e d to 110 UC and poured i n t o water (300 mL), an a d d i t i o n a l 200 mL of water was used to r i n s e the r e a c t i o n f l a s k . T h i s s o l u t i o n was a c i d i f i e d with 6M hydro-c h l o r i c a c i d (250 mL) and allowed to stand o v e r n i g h t . The product was f i l t e r e d , washed with water and remelted i n water (550 mL) to remove occluded i m p u r i t i e s . Undecanedioic a c i d was r e s o l i d i f i e d on c o o l i n g , c o l l e c t e d by f i l t r a t i o n and r e c r y s t a l l i z e d from hot toluene to g i v e 60.7 g (92.3%). MP : 110-111.5°C •" L i t . 3 5 : 110 .-5-112°C 1H NMR (6, DMSO-d6) : 1.06 (br, 10H, C-4 to C-8 methylene protons) 1.34-1.70 (m, 4H, C-3, C-9 methylene p r o t o n s ) , 2.19 ( t , 4H, J=7.5 Hz, C-2, C-10 methylene p r o t o n s ) , 11.94 (br, 2H, -COOH) 161 3.4 SYNTHESES OF MONOPYRROLES 2-Ethoxycarbonyl-3,5-dimethylpyrrole 66 66 Diethyl malonate (128 0 g, 8.0 moi)and g l a c i a l acetic acid (1440 g, 24.0 moi), s t i r r e d magnetically i n a 1 2 - l i t e r f l a s k , were treated dropwise with a saturated solution of sodium n i t r i t e (1656 g, 24.0 moi) i n water, over a period of 12 h. (NOTE 1). The solution turned blue, then green and f i n a l l y yellow and the inter n a l temperature reached 45°C. The reaction mixture was allowed to s t i r overnight. Diethyl oximinomalonate separated out as a dark yellow viscous o i l and was used i n the next stage without p u r i f i c a t i o n . Pentane-2,4-dione (900 g, 9.0 moi) and acetic acid (4020 g, 67.0 moi), were mechanically s t i r r e d i n a 1 2 - l i t e r 3-neck flask as the oxime prepared above was added, rapidly dropwise, along with f i n e l y ground zinc dust (1246 g, 19.0 moi) (NOTE 2). The exothermicity of the reaction brought the solution to near reflux but was not cooled (NOTE 3). The hot 162 solution was decanted from the unreacted zinc into several flasks and slowly diluted with two or three times of water. 2-Ethoxycarbonyl-3,5-dimethylpyrrole c r y s t a l l i z e d as a yellow s o l i d , was collected by f i l t r a t i o n and washed with hot water. The s o l i d was redissolved i n dichloromethane, the dis s o l u t i o n being f a c i l i t a t e d by heating on a steam bath. When the pyrrole went into solution, a considerable amount of water trapped within the s o l i d , separated o f f as a layer. The organic phase was gravity f i l t e r e d and the product c r y s t a l l i z e d out from methanol. The s o l i d was suction f i l t e r e d , washed with methanol and a i r dried to give 373.1 g (27.9%). The mother liquors were concentrated to give a second crop of 130.1 g (9.7%) (NOTE 4). MP : 121.0-122.5°C ; L i t 3 8 124.0 - 124.5°C .Anal.Calcd. for C 9H 1 30 2N : C, 64.65; H, 7.84 ; N, 8.38. Found : C, 64.35; H, 7.90; N, 8.28 1H NMR (6, CDC13) : 1.36 (t, 3H, J=7 Hz, -0-CH2-CH_3), 2.26 3H, 5-CH3), 2.32 (s, 3H, 3-CH 3), 4.34 (q, 2H, 3=1 Hz, 0-CH2-CH3) 5.82 (d, IH, J=2.6 Hz, 4-H), 9.40 (bs, IH, N-H) 1 3 C NMR (6, CDC13) : 162.34 (C=0), 133.00 (pyrrole 5-C), 128.97 (pyrrole 3-C), 117.93 (pyrrole 2-C), 111.34 (pyrrole 4-C), 59.68 (0-CH 2-CH 3), 14.57 (0-CH 2-CH 3), 12.90 (3-CH3, 5-CH3) 163 Notes 1. Since nitrogen oxides are evolved during the n i t r o s a t i o n , the reaction was carried out i n the fume-hood. 2. The zinc dust i s best added as a thick s l u r r y i n water. 3. Cooling tends to set i n premature c r y s t a l l i z a t i o n . 4. Refluxing the solution for 90 minutes after the addition of the reagents has been shown to improve the y i e l d . 4-Acetyl-2-ethoxycarbonyl-3,5-dimethylpyrrole 67 acid (1080 g, 18.0 moi) were ice cooled and magnetically s t i r r e d 7 0 .CH 67 Ethyl acetoacetate (1040 g, 8.0 moi) and acetic 164 i n a 5 - l i t e r f l a s k . A saturated solution of sodium n i t r i t e (560 g, 8.1 moi) i n water was added, rapidly dropwise and the viscous product was suitable for immediate use. Anhydrous sodium carbonate (900 g,), acetic acid (4 l i t e r s ) and pentane-2,4-dione (850 g, 8.5 moi) were s t i r r e d vigorously i n a 1 2 - l i t e r 3-neck flask as the above solution of ethyl oximinoacetoacetate was added dropwise along with zinc dust (1046 g, 16.0 moi). The temperature of the reaction mixture was maintained between 75 - 80°C. S t i r r i n g was cont-inued for 3 0 minutes after the addition was complete, the mixture poured into water arid'-the c r y s t a l l i z e d product coll e c t e d by f i l t r a t i o n . The s o l i d was dissolved i n chloroform (by warming on a steam bath) to separate the trapped water. The organic phase was suction f i l t e r e d and evaporated under reduced pressure after adding methanol. 4-Acetyl-2-ethoxycarbonyl-3, 5-dimethylpyrrole c r y s t a l l i z e d as white needles and was c o l l e c t -ed by f i l t r a t i o n to give 910.2 g. (54.-4%). The mother liquors were concentrated for the second and t h i r d crops of 324.4 g (19.4%). MP : 142.5°-143.5°C; Lit'. 7 1 143-144°C 1H NMR (6, CDC13) : 1.37 (t, 3H, J=7 Hz, -O-CH^CH^), 2.42 (s, 3H, COCH_3), 2.52 (s,, 3H, 3-CHg), 2.57 (s., 3H, 5-CH_3), 1 6 5 4.33 (q, 2H, J=7 Hz, 0-CH_2-CH3), 9.62 (bs, IH, N-H). 1 3 C NMR (6, 10% TFA-CDC1-) : 201.62 (COCH-)/ 164.30 (CO-CnH.-), J — 3 — Z Z D 144.42 (pyrrole 5-C) , 133.48 (pyrrole 3-C) , 122.76 (pyrrole 4-C) , 119.31 (pyrrole 2-C), 62.89 (-0-CH2-) , 29.53 (COCH3), 15.84 (5-CH 3), 14.27 (0-CH 2-CH 3), 13.28 (3-CH 3). Mass spectrum : m/e, 209 (M +,), 194 (M-CH 3) +, 164 (M-C 2H 50) + 163 (M-CH3CH2OH)+, 162 [M-(CH3CH2OH+H)]+, 148 [M-(CH3CH2OH + C H 3 ) ] + 2-Ethoxycarbonyl-4-ethyl-3,5-dimethylpyrrole 76 76 4-Acetyl-2-ethoxycarbonyl-3 ,5-dimethylpyrrole 67_ (836.7 g, 4.0 moi), sodium borohydride (160.1 g, 4.2 moi) and ethyl acetate (14 00 mL) i n tetrahydrofuran (4 l i t e r s ) under nitrogen, were treated dropwise with boron t r i f l u o r i d e etherate (700 mL). Throughout the addition, the solution was vigorously s t i r r e d and the temperature was maintained between 15-20°C. When the addition was complete, an aliquot of the 166 r e a c t i o n m i x t u r e was removed, quenched w i t h water and checked by t i c f o r any u n r e a c t e d s t a r t i n g m a t e r i a l . The e x c e s s d i b o r a n e was d e s t r o y e d by the c a u t i o u s a d d i t i o n o f a c e t i c a c i d (300 mL) and water ( 2 - l i t e r s ) . Sodium c h l o r i d e (250 g) was s t i r r e d i n t o the s o l u t i o n f o l l o w e d by e t h y l a c e t a t e (1 l i t e r ) and water (1 l i t e r ) c a u s i n g the r e a c t i o n m i x t u r e t p s e p a r a t e i n t o an upper o i l y s o l u t i o n o f the p r o d u c t i n t e t r a h y d r o f u r a n and a l o wer aqueous s o l u t i o n o f sodium f l u o r o b o r a t e and some b o r i c a c i d . The o r g a n i c phase was i s o l a t e d , combined w i t h the e t h y l a c e t a t e e x t r a c t s of the aqueous phase and 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 crude p r o d u c t was d i s s o l v e d i n h o t 95% e t h a n o l and the s o l u t i o n was t r e a t e d w i t h water u n t i l c r y s t a l l i z a t i o n ensued. The s o l u t i o n was c o o l e d and the p r o d u c t c o l l e c t e d by f i l t r a t i o n , y i e l d 438.8 g. ( 5 6 . 2 % ) . The mother l i q u o r was c o n c e n t r a t e d t o o b t a i n t h e second c r o p of 108.7 g. (13.9%). MP : 90-91.5°C; L i t . . 90-91°C38/', 95-96°C 7 2 '''H NMR ( 6 , CDC1 3) : 1.02 ( t , 3H, J=7.5 Hz, 4 - e t h y l C H 2 - C H 3 ) , 1.30 ( t , 3H, J=7 Hz, - 0 - C H 2 - C H 3 ) , 2.16 ( s , 3H, 5-CH_3), 2.24 (S, 3H, 3 - C H 3 ) , 2.36 (q, 2 H , J=7.5 Hz, 4 - e t h y l CH_ 2-CH 3), 4.26 (q, 2H, J=7 Hz, -0-CH_ 2-CH 3) , 8.83 (bs, I H , N-H) 1 3 C NMR (<5;CDC13) : 162.71 (C=0) , 130.23 ( p y r r o l e 5-C) , 126.69 ( p y r r o l e 3-C), 123.83 ( p y r r o l e 4-C), 116.94 ( p y r r o l e 2-C), 59.74 (-0-CH 2-), 17.41 ( 3 - e t h y l CH 2-CH 3), 15.45 ( 4 - e t h y l CH 2-CH 3), 167 14.66 (-6-CH2-CH3), 11.12 (5-CH 3), 10.72 (3-CH 3). Mass spectrum : m/e, 195 (M +), 180 (M-CH 3) +, 166 (M-C 2H 5) +, 150 (M-C2H50) + , 149 (M-CH3CH2OH)+, 148 [M-(CH3CH2OH+H) ] + , 134 [M-(CH3CH2OH+CH3)]+ 5-Ethoxycarbonyl-3-ethyl-4-methylpyrrole-2-carboxylic acid' 77 HOOC 77 2-Ethoxycarbonyl-4-ethyl-3,5-dimethylpyrrole 7_6 (58.5 q, 0.30 moi) was dissolved i n methylene chloride (300 mL) in a 5 - l i t e r round-bottomed fl a s k . The solution was magnetically s t i r r e d and ether (500 mL) was added, immediately followed by the rapid dropwise addition of a solution of s u l f u r y l chloride (128.36 g, 0.95 moi) i n methylene chloride (200 mL). The solution was allowed to s t i r for a further 10 minutes and evaporated o f f the solvents under reduced pressure. The residual red o i l was added into hot 20% water-acetone and the re s u l t i n g dark yellow solution was heated under reflux for 5 minutes causingcthe product-to c r y s t a l l i z e out as a pale yellow s o l i d . The s o l i d was collected. .' 168 by f i l t r a t i o n , washed with a .1:1 water-acetone mixture and then with water. The crude a-carboxypyrrole was r e d i s s o l v e d i n methanol and s a t u r a t e d aqueous sodium b i c a r b o n a t e by warming on a steam bath. The u n d i s s o l v e d s o l i d was e x t r a c t e d i n t o ether and the aqueous phase was c a u t i o u s l y a c i d i f i e d with concentrated h y d r o c h l o r i c a c i d . The product r e p r e c i p i t a t e d as a white s o l i d and was f i l t e r e d , washed with water and d r i e d i n a i r to g i v e 54.1 g (80.2%). MP : 210-211°C; L i t 7 3 : 211°C 1H NMR (6, DMSO-d6) : 1.06 ( t , 3H, J=7 .5 Hz, 3-CH2-CH_3), I. 33 ( t , 3H, J=7 Hz, OCH 2-CH_ 3) , 2.24 (s , 3H, 4-CH_3), 2.72 (q, 2H, 3=1.5 Hz, 3-CH 2-CH 3), 4.2 9 (q, 2H, 3=1 Hz, -O-CHj-CILy) > I I . 18 (bs, IH, N-H), 12.62 (bs, IH, -COOH) Mass spectrum : m/e, 225 (M +), 210 (M-CH 3) +, 196 (M-C 2H 5) +, 180 (M-C 2H 50) + , 178 [M-(CH 3CH 2OH+H)] +, 164 [M-(CH 3CH 2OH+CH 3) ] + • 169 2-Ethoxycarbonyl-4-ethyl-5-iodo-3-methylpyrrole 7 8 78 5-Ethoxycarbonyl-3-ethyl-4-methylpyrrole-2-carboxylic acid 77_ (22.5 g, 0.10 moi), sodium bicarbonate (33.0 g, 0.39 moi), water (250 mL) and !dichloroethane (15 0 mL) were placed i n a 1 - l i t e r erlenmeyer flask and heated on a steam bath. The s t a r t i n g material dissolved with effervescence. The f l a s k was removed from the steam bath and with the aid of a dropping funnel, a solution of iodine (29.0 g, 0.11 moi) and potassium iodide (45.1 g, 0.27 moi) i n water (150 mL) was added within 2 minutes (the reaction mixture was magnetically s t i r r e d throughout the addition). The solution was refluxed for 3 0 minutes and the excess iodine was destroyed with sodium b i -s u l f i t e (a pale yellow color remained i n the organic layer while the aqueous layer turned c o l o r l e s s ) . The flask was cooled, methylene chloride (200 mL) added, the organic phase separated and gravity f i l t e r e d . The clear yellow solution was evaporated to dryness and the crude product redissolved i n hot absolute ethanol (200 mL). The s o l i d was reprecipitated by adding water, col l e c t e d by f i l t r a t i o n and washed with 50% ethanol-water f o l l o w e d by water to g i v e 21.5 g (7 0.0%). The mother l i q u o r s were concentrated f o r a second crop of 5.9 g (19.2%) MP : 114.0-115.5°C; L i t . 7 4 : 114-115°C 1H NMR (<5, CDC1 3) : 1.03 ( t , 3H, J=7 .5 Hz, 4-CH2CH_3), 1.33 ( t , 3H, J=7 Hz,-0-CH 2-CH 3) , 2.27 (s , 3H, 3-CH_3), 2.37 (q, 2H, J=7.5 Hz, 4-CH_2CH3), 4.31 (q, 2H, J=7 Hz ,-0-CH_2CH3) , 9.02 (bs, IH, N-H), 1 3 C NMR (6, CDC1 3) : 161.38 (C=0), 131.88 ( p y r r o l e 4-C), 126.05 ( p y r r o l e 3-C), 123.96 ( p y r r o l e 2-C), 73.42 ( p y r r o l e 5-C), 60.42 (0-CH 2CH 3), 20.00 (4-CH 2-CH 3), 14.81 (4-CH 2-CH 3), 14.60 (6-CH 2-CH 3), 10.98 (3-CH 3) Mass spectrum: m/e, 307 (M +), 292 (M-CH 3) +, 278 (M-C 2H 5) +, 262 (M-C 2H 50) +, 261 (M-CH 3CH 2OH) +, 260 [M-(CH 3CH 2OH+H)] +/ 246 [M-(CH 3CH 2OH+CH 3)] + 2-Efchoxycarbonyl-4-ethyl-3-methylpyrrole 7 9 1 7 1 79 2-Ethoxycarbonyl-4-ethyl-5-iodo-4-methylpyrrole 7_8 (30.7 g, 0.10 moi) was d i s s o l v e d i n 95% et h a n o l (250 mL) by warming on a steam bath. When a b s o l u t i o n of. potassium ' i o d i d e ;.(26 .5 .g, 0.16 moi) i n water (20; mL);. and con c e n t r a t e d h y d r o c h l o r i c a c i d (40 mL) was added, i o d i n e was liberated-. 50% Aqueous hypophosphorus. a c i d (25 mL) was added to d i s c h a r g e the i o d i n e c o l o r . A f u r t h e r 25 mL of hyppphosphoru-S; a c i d was added and the r e a c t i o n mixture was heated on the steam bath f o r 15 minutes. The s o l u t i o n was c o o l e d , methylene c h l o r i d e (250 mL) and water (150 mL) added, the o r g a n i c phase i s o l a t e d and d r i e d with anhydrous sodium s u l f a t e . The s o l v e n t s were evaporated ----- under reduced p r e s s u r e , the r e s i d u a l dark red o i l d i s s o l v e d i n methylene c h l o r i d e (25 mL) and chromatographed on s i l i c a g e l (85 g, a c t i v i t y I) u s i n g methylene c h l o r i d e as the e l u t i n g s o l v e n t . A l l of the c o l o r e d i m p u r i t i e s remained a t the o r i g i n and the a - f r e e p y r r o l e e l u t e d out c l e a n as a p a l e y e l l o w l i q u i d . The s o l v e n t was evaporated, .-the product t r a n s f e r r e d i n t o a weighed f l a s k and the l a s t t r a c e s of s o l v e n t removed on the vacuum l i n e a t room temperature. The y i e l d of the a - f r e e p y r r o l e was 17.2 g (94.9%). 172 MP : 22.0-23.0°C ; L i t . 7 5 25°C '''H NMR (6 , CDC13) : 1.14 (t, 3H, J=7 .5 Hz, 4-CH 2CH 3), 1.32 (t, 3H, J=7.2 Hz, -0-CH 2CH 3), 2.24 ( s , 3H, 3-CH 3), 2.40 (q, 2H, J=7.5, 4-CH 2CH 3), 4.27 (q, 2H, J=7 . 2 Hz, -0-CH 2CH 3), 6.61 (d, IH, J=2.8 Hz, 5-H), 8.88 (b s , IH, N-H). 1 3 C NMR (6, CDC13) : 162.44 (C=0), 127.39 (pyrrole 4-C), 125.92 (pyrrole 3-C), 119.82 (pyrrole 5-C), 119.52 (pyrrole 2-C), 59.94 (-o-CH2CH3), 18.41 (4-CH 2CH 3), 14.58 (-0-CH2CH3), 14.58 (4-CH 2CH 3), 10.34 (3-CH3) Mass Spectrum m/e : 181 ( M + ) , 166 (M-CH 3) +, 152 (M-C 2H 5) +, 136 (M-C 2H 50) +, 135 (M-CH 3CH 2OH) +, 134 [M-(CH 3CH 2OH+H)] +, 120 [M-(CH 3CH 2OH+CH 3)] + 2 - Be n z y 1 oxy c ar bony 1 - 4- ethyl-3 -me thylpyrrole ';8 0 80 2-Ethoxycarbonyl-4-ethyl-3-methylpyrrole 7_9 (5.0 g, 0.028 moi) was heated, under nitrogen, i n r e d i s t i l l e d benzyl 173 a l c o h o l (30 mL, 31.2 g, 0.29 mols), to r e f l u x a t 209°C to ensure the complete removal of water. A t t h i s temperature, a con-c e n t r a t e d s o l u t i o n of sodium i n benzyl a l c o h o l was added i n 1 mL p o r t i o n s , r e s u l t i n g i n the v i g o r o u s e v o l u t i o n of e t h a n o l vapours and the lowering of the r e f l u x temperature. With the a d d i t i o n of 3 mL, the r e a c t i o n appeared t o be complete and the r e a c t i o n mixture continued to r e f l u x a t 209°'C. The hot s o l u t i o n was poured i n t o a m a g n e t i c a l l y s t i r r e d mixture of a c e t i c a c i d (10 mL) and methanol (200 mL). Water (250 mL) was added when the s o l u t i o n turned t u r b i d and an orange-brown o i l separated out. The o i l was e x t r a c t e d i n t o methylene c h l o r i d e (250 mL) and the s o l v e n t was evaporated o f f under reduced p r e s s u r e (an o i l pump had to be connected to the r o t a r y evaporator to remove the excess benzyl a l c o h o l ) . The r e s i d u a l dark brown o i l was d i s s o l v e d i n methylene c h l o r i d e (5 mL) and chromatographed on s i l i c a g e l (4 0 g, a c t i v i t y I) u s i n g methylene c h l o r i d e as the e l u t i n g s o l v e n t . Most of the dark brown i m p u r i t i e s remained a t the o r i g i n but a dark yellow band e l u t e d out s l i g h t l y ahead of the c o l o r l e s s product and c o u l d not be separated. The s o l v e n t was removed and the a - f r e e b e n z y l e s t e r was s t o r e d i n the f r e e z e r f o r 10 days when the pa l e y e l l o w s o l i d turned dark brown. When the s o l i d was rechromatographed on s i l i c a gel (30 g, a c t i v i t y I ) , a l l the c o l o r e d i m p u r i t i e s remained a t the o r i g i n . The s o l v e n t was removed and the be n z y l e s t e r was obtained as a pal e y e l l o w o i l , y i e l d 5.6 g, (83.6%). 174 MP : 26.5-28.0°C Mol.Wt. : 243.31 A n a l . C a i c d . f o r C 1 5 H 1 7 N 0 2 : C ' 7 4 - 0 5/" H, 7.04; N, 5.76; Found : C, 74.06; H, 7.16; N, 5.63. 1H NMR (6, CDC1 3) : 1.16 ( t , 3H, J=7 . 5 Hz, 4-CH 2CH 3), 2.30 (s, 3H, 3-CH_3) , 2.43 (q, 2H, J=7 .5 Hz, 4-CH_2CH3), 5.31 (s, 2H, -0-CH„), 6.64 (d, IH, J=2.8 Hz, 5-H), 7.38 (m, 5H, C,H C), 9.00 (bs, IH, N-H) 1 3 C NMR (6, CDC1 3) : 161.91 (C=0), 136.80 (benzene 1-C), 128.54/128.04 (benzene r i n g ) , 127.46 ( p y r r o l e 4-C), 126.35 ( p y r r o l e 3-C.) , 120.02 ( p y r r o l e 5-C) , 119.09 ( p y r r o l e 2-C) , 65.63 (-0-CH 2~), 18.29 (4-CH 2CH 3), 14.62 (4-CH 2CH 3), 10.41 (3-CH 3) Mass spectrum : m/e 243 (M +) , 228 (M-CH_.) + , 152 (M»C,H cCH n) + , j o b 2. 136 (M-C 6H 5CH 20) +, 108 (C 6H 5CH 2OH) +, 107 ( C 6 H 5 C H 2 0 ) + , 92 ( C 6 H 5 C H 3 ) + , 91 ( C 7 H y + ) 175 5 - C h l o r o m e t h y l - 2 - ( 2 , 2 - d i c y a n o v i n y l ) - 4 - e t h y l - 3 - m e t h y l p y r r o l e - 86 86 2- (2 , 2-Dicyanovinyl) -4-ethyl-3 , 5 - d i m e t h y l p y r r o l e 8_4 (3.98 g, 0.02 moi) i n dry methylene c h l o r i d e (75 mL) was t r e a t e d with a s o l u t i o n of s u l f u r y l c h l o r i d e (2.75 g, 2.70 g : 0.02 moi) i n methylene c h l o r i d e (50 mL) a t room temperature ( s u l f u r y l c h l o r i d e was added r a p i d l y and dropwise t o a m a g n e t i c a l l y s t i r r e d s o l u t i o n ) . The s t i r r e d s o l u t i o n was allowed t o b o i l down c a r e f u l l y w h i l e anhydrous d i e t h y l ether was added, ca u s i n g the c r y s t a l l i z a t i o n of the product as f l u f f y y e l l o w needles, y i e l d 4.1 g (87.8%). An a n a l y t i c a l sample was r e c r y s t a l l i z e d from methylene c h l o r i d e - m e t h a n o l . MP : 176.0-178.0°C (dec) Mol.Wt : 233.70 Anal. C a l c d . f o r c 1 2 H i 2 C l N 3 : C ' 6 1 - 6 7 ' " H / 5.18; N, 17.98; C l , 15.17; Found : C, 61.38; H, 5.30; N, 17.73; C l , 15.00 1H NMR : (6, CDC1 3): 1.11 ( t , 3H, J=7.5 Hz, 4-CH 2CH 3), 2.17 (s, 3H, 3-CH 3), 2.48 (q, 2H, J=7.5 Hz, 4-CH_2CH3), 4.61 (s, 2H, CH 2C1), 7.46 (s, IH, CH=C(CN) 2), 9.52 (bs, IH, N-H) 176 Mass spectrum, m/e : 233 (M +, very weak), 199 (M-C1+H)+, 184 (M-C1-CH 3+H) + IR ( v ^ v , KBr) : 3340 (N-H), 2220 (C=N) , 1595 (C=C) cm" T h i s compound had p r e v i o u s l y been prepared by R.B. Woodward 7 5 as an i n t e r m e d i a t e i n the s y n t h e s i s of c h l o r o p h y l l but n e i t h e r the experimental d e t a i l s nor i t s s p e c t r a l p r o p e r t i e s have been reported.. 5-Chloromethyl-2-(2-cyano-2-methoxycarbonylvinyl)-2-(2-Cyano-2-methoxycarbonylvinyl)-4-ethyl-3,5-dimethylpyrrole 8_5 (5.0 g, 21.6 mmol) i n dry methylene c h l o r i d e (7 0 mL) was cooled i n i c e and m a g n e t i c a l l y s t i r r e d w h i l e being t r e a t e d , dropwise, wi t h a s o l u t i o n of s u l f u r y l 177 c h l o r i d e (3.05 g, 2.92 g = 21.6 mmol) i n dry methylene c h l o r i d e (20 mL) over a p e r i o d of 30 minutes. The r e a c t i o n mixture was allowed to s t i r f o r a f u r t h e r 3 0 minutes at room temperature. Methylene c h l o r i d e was evaporated o f f under reduced p r e s s u r e , r e p l a c e d w i t h anhydrous d i e t h y l ether and the product i s o l a t e d from hexane, to g i v e a f i r s t crop of 2.42 g. (42.2%). The mother l i q u o r s were concentrated to o b t a i n a second crop of 2.41 g. (42.0%). MP : 157.0 - 159.0°C (dec.) Mol.Wt = 266.73 Anal C a l c d . f o r C ^ H ^ C I N ^ : C, 58.54; H, 5.67; N, 10.50; C l , 13.29; Found : C, 58.64; H, 5.66; N, 10.42; C l , 13.19 1H NMR , ( 6 CDC1 3) : 1.09 ( t , 3H, J=7.5 Hz, 4-CH 2CH 3), 2.18 (s, 3H, 3-CH 3), 2.46 (q, 2H, J=7.5 Hz, 4-CH_2CH3), 3.86 (s, 3H, 0-CH 3), 4.60 (s, 2H, CH_2C1), 8.00 [ s , 1H, CH=C (CN) CC^CH^ , 9. 64- (bs, IH,- N-H) . Mass Spectrum, m/e : 266 (M +), 232 (M-C1+H)+, 231 (M-C1) +, 217 (M-C1-CH 3+H) +, 199 (M-C1-CH 30H) + 185 [M-(Cl+CH 3OH+CH 3)+H] + IR v KPr') . = 3300 (N-H) , 2220 (C=N) , 1725 (C=0) , 1595 (C=C) c m - 1 178 3.5 SYNTHESIS OF THE MODEL PORPHYRIN AND ITS DIPYRROMETHANE  PRECURSORS 5- ( 2 , 2 - D i c y a n o v i n y l ) - 2 - [ ( 5 - e t h o x y c a r b o n y l - 3 - e t h y l - 4 - m e t h y l p y r r o l - 2-yl)methyl] - 3 - e t h y l - ^ - m e t h y l p y r r o l e 97 5-Chloromethyl-2- (2 ,2-dicyanovinyl) -4-ethyl-3-"' m e t h y l p y r r o l e 8_6_ (3.57 g, 15.3 mmol) and 2-ethoxycarbonyl-4-e t h y l - 3 - m e t h y l p y r r o l e 7_9 (2.87 g, 15.8 mmol) were suspended i n g l a c i a l a c e t i c a c i d (150 mL) under n i t r o g e n and warmed i n a water bath a t 7 0°C. Within 0.5 h the s t a r t i n g m a t e r i a l s d i s s o l v e d g i v i n g a c l e a r orange s o l u t i o n . A drop removed i n t o methylene c h l o r i d e , washed with water, showed a s i n g l e y e l l o w spot on t i c (2% CH 30H-CH 2C1 2), c o l o r e d v i o l e t with bromine vapor. The s o l u t i o n was c o o l e d to room temperature, evap-o r a t e d down to approximately 2 0 mL, t r e a t e d with methanol 179 (80 mL) and allowed to stand o v e r n i g h t . The ye l l o w f i n e l y c r y s t a l l i n e s o l i d was c o l l e c t e d by f i l t r a t i o n , r i n s e d with methanol and d r i e d i n a i r to g i v e a f i r s t crop of 5.05 g (87.4%). The mother l i q u o r s were evaporated to dryness, the s o l i d s taken up i n methylene, c h l o r i d e (8 0 mL), and washed w i t h s a t u r a t e d sodium b i c a r b o n a t e (2x20 mL) and water (20 mL). A second crop was obtained by eva p o r a t i n g the methylene c h l o r i d e s o l u t i o n a f t e r the a d d i t i o n of methanol, y i e l d 482 mg (8.3%). An a n a l y t i c a l sample was r e c r y s t a l l i z e d from methylene c h l o r i d e - m e t h a n o l . MP : 186.0-187.0°C; Mol.Wt. : 378.48 A n a l . C a l c d . f o r C 2 2 H 2 6 N 4 ° 2 C / 6 9 , 8 4 ; H ' 6- 8 8'* N> 14.81; Found : C, 69.66; H, 6.84; N, 14.80. 1 H NMR (6, CDC1 3) : 1.05 ( t , 3H, J=7.5 Hz, 3 ,-CH 2CH 3), 1.08 ( t , 3H, J=7.5 Hz, 3-CH2CH_3), 1.35 ( t , 3H, J=7 Hz, -0-CH 2CH 3), 2.17 (s, 3H, 4-CH 3), 2.30 (s, 3H, 4'-CH ), 2.44 (q, 2H, J=7.5 Hz, 3'-CH 2CH 3), 2.46 (q, 2H, J=7 .5 Hz, 3-CH_2CH3), 3.98 (s, 2H, br i d g e CH_2), 4.30 (q, 2H, J=7 Hz, -0-CH 2CH 3), 7.34 (s, IH, CH=C(CN) 2), 8.7 6 (br, IH, l'-NH), 9.2 0 (br, IH, 1-NH). 1 3 C NMR (6,CDC1 3) : 162.15 (C=0) , 140.78 [ CH=C (CN) 2] , 140.44 ( p y r r o l e C-2), 136.06 ( p y r r o l e C-4), 127.11, 126.41, 126.21, 180 125.15 ( p y r r o l e C-3, C-2', C-3', C-4'), 124.16 ( p y r r o l e C-5), 118.93 ( p y r r o l e C-5'), 116.78 (C=N), 115.99 (C=N) , 64.11 [CH=C(CN) 2] , 59.96 ( 0 - C H 2 C H 3 ) , 23.75 (bridge C H 2 ) , 17.34 (3'.CH 2CH 3) , 17.12 (3-CH 2CH 3), 15.36 (3 "-^CI^CI^) , 14.67 (3-CH„CH_), 14.48 O-CH CH ), 10.52 (4 1-CH-), 9.38 (4-CH_) Mass Spectrum R e l a t i v e m/e I n t e n s i t y Assignment 37 9 27 M+' + H 378 99 M + 363 13 .". (M-CH3) + 333 34 (M-C 2H 50) + 332 100 (M -C 2H 5OH) + 317 42 (M- C 2H 5OH- C H 3 ) + 197 44 IR ( v ; ^ KBr) : 3400 (N-H), 3280 (N-H), 2220 (C=N) , —~— I u c l X 1665 (C=0), 1585 (C=C) cm" 1. 181 2-[(5-Carboxy-3-ethyl-4-methylpyrrol-2-yl)methyl]-3-ethyl 5-formyl-4-methylpyrrole 103 5-(2,2-Dicyanovinyl)-2-[(5-ethoxycarbonyl-3-ethyl-4-methylpyrrol-2yl)methyl]-3-ethyl-4-methylpyrrole 9_7 (500 mg , 1.32 mmol) dissolved i n re f l u x i n g ethanol (25 mL) was treated with sodium hydroxide (2.5 g) i n water (10 mL). The mixture was refluxed under nitrogen for 0.5 h, water (50 mL) was added and continued refl u x i n g for 1 h. Ethanol was boiled o f f (reflux temperature reached 100°C), more water (50 mL) was added and cooled to room temperature. Acetic acid was added dropwise u n t i l the solution was a c i d i c (pH~5) and the grey gelatinous p r e c i p i t a t e was f i l t e r e d , washed with water and dried over potassium hydroxide i n a vacuum dessicator, y i e l d 380.7 mg (95.3%). Further drying on the vacuum l i n e (0.2 torr) at room temperature for 18 h-_, gave an a n a l y t i c a l l y pure sample. The reaction was repeated with 2.5 g of star t i n g material to give the product i n e s s e n t i a l l y quantitative y i e l d . 182 MP : 188.0 -190.0°C (dec.) Mol.Wt. : 302.37 An a l . C a l c d . f o r C 1 7 H 2 2 N 2 0 3 C ' 6 7 ' 5 3 ; H ' 7 - 3 3 " N, 9.26 Found : C, 67.26; H, 7.32; N, 9.35. 'H NMR (6, DMS0-d6) : 0.83, 0.85 (two t r i p l e t s , 6H, J=7.5 Hz, 3- and 3'- CH 2-CH 3), 2.11 (s, 3H, 4-CH3>, 2.15 (s, 3H, 4'-CH 3), 2.29, 2.31 (two q u a r t e t s masked by DMSO-d^ s i g n a l , 3- and 3'-CH 2CH 3), 3.77 (s, 2H, br i d g e C H 2 ) f 9.46 (s;, IH, .CHO)',, 11.00 (br, IH, 1-NH), 11.42 (br, IH, l'-NH) Mass spectrum : R e l a t i v e m/e I n t e n s i t y Assignment 3 02 18 M + 258 74 (M- C 0 2 ) + 1 4 9 1 0 0 i U X A 122 32 121 25 HX N N ' X " H 0 \ / C H 3 HX 1 0 9 1 4 , . i X 3 108 35. H" N ^ H H H 183 I R ( v m a- v K B r ) : 3 2 6 5 (broad, N-H), 1670 (broad, C=0) cm -1. 2- [(5-Ethoxycarbonyl-3-ethyl-4-methylpyrrol-2-yl)methyl]-3- ethyl-5-formyl-4-methylpyrrole 104 5-(2,2-Dicyanovinyl)-2-[(5-ethoxycarbonyl-3-ethyl -4-methylpyrrol-2-yl)methyl ] -3-ethyl-4-methylpyrrol 97_ (502 mg, 1.33 mmol) i n ethanol (10 mL) and potassium hydroxide (2 g) i n water (2 0 mL) were heated on a steam bath. Within 1 h the f l u f f y yellow s t a r t i n g material changed into a l i g h t tan, powdery s o l i d . More water (50 mL) was added, cooled, f i l t e r e d , washed with water and dried to give 275 mg (62.7%). A r e p i t i t i o n of the synthesis gave a y i e l d of 305 mg (69.7%). MP : 167.5 - 168.0°C Moi. Wt. : 330.43 Anal. Calcd. for C 1 9 H 2 6 N 2 0 3 : ' c > 6 9 •06'" H ' 7-93, N, 8.48, Found C, 68.75; H, 8.01; N, 8.42. 1H NMR (6, CDC1 3) : 1.04, 1.05 (two t r i p l e t s , 6H, J=7.5 , 3-, 3'-CH 2CH 3), 1.25(t, 3H, J=7 Hz,-0~CH 2CH 3), 2.25 6H,4-, 4'-CH 3), 2.44 (q, 4H, 3-, 3'-CH 2CH 3), 3.89 (s , 2H, bri d g e CH 2) 4.19 (q, 2H, J=7 Hz, -OCH_2CH3) , 9.45 (s, IH, CHO), 9.97 (br, 1, l'-NH), 10.68 (br, IH, 1-NH). Mass spectrum : R e l a t i v e m/e I n t e n s i t y Assignment 330 97 M + 315 17 (M-CH 3) + 301 17 ( M - C „ H C ) + 193 31 -149 100, J^..\ ~ H 0 IR (v m^ x.. KBr) : 3265 (broad, N-H), 1680 (C=0) , 1625 (C=0) cm 185 2 - [ ( 5 - B e n z y l o x y c a r b o n y l - 3 - e t h y l - 4 - m e t h y l p y r r o l - 2 - y l ) m e t h y l ] -5- ( 2 , 2 - d i c y a n o v i n y l ) - 3 - e t h y l - 4 - m e t h y l p y r r o l e . 110 5-C h l o r o m e t h y l - 2 - ( 2 , 2 - d i c y a n o v i n y l ) - 4 - e t h y l - 3 -m e t h y l p y r r o l e 8_6 (1.02 g, 4.37 mmol) and 2-benzyloxycarbonyl-4 - e t h y l - 3 - m e t h y l p y r r o l e 80_ (1.103 g, 4.54 mmol) i n g l a c i a l a c e t i c a c i d (7 0 mL) were warmed i n a water bath a t 7 0°C f o r 0.5h.. The c l e a r orange c o l o r e d s o l u t i o n was co o l e d to room temperature and s u c t i o n f i l t e r e d to remove any i n s o l u b l e p a r t i c l e s when the product c r y s t a l l i z e d out i n the f i l t e r f l a s k i t s e l f . The f l u f f y y e l l o w s o l i d was c o l l e c t e d by f i l t r a t i o n and washed with methanol to g i v e 1.5 g (78.0%). The mother l i q u o r s were evaporated under reduced p r e s s u r e to approximately 10 mL, added methanol (3 0 mL) and allowed to stand o v e r n i g h t , from which a second crop of 197 mg (10.3%) was i s o l a t e d . An a n a l y t i c a l sample was r e c r y s t a l l i z e d from methylene c h l o r i d e - m e t h a n o l . 1 8 6 MP 192.0-193.0 C Moi. Wt. : 44 0.55 Anal. Calcd. for C 2 7 H 2 8 N 4 ° 2 : C ' 7 3 ' 6 1 ; H ' 6.41; N, 12.72; Found : C, 73.70; H, 6.37; N, 12.66. 1H NMR : (6, CDC13) : 1.02, 1.04 (t, 6H, J=7.5 Hz, 3- and 3'-CH 2CH 3), 2.12 (s, 3H, 4-CH.j), 2.28 (s, 3H, 4'-CH_3), 2.40 (q, 4H, J=7.5 Hz, 3- and 3'- CH_2CH3), 3.93 (s, 2H, bridge CH2) , 5.21 (s, 2H, -0-CH 2C 6H 5), 7.21 (s, IH,-CH=C(CN)2), 7.22-7.37 (m, 5H, C r E c ) , 9.00 (br, IH, 1V-NH), 9.17 (br, IH, 1-NH) b—b ' — — 1 3 C NMR (6, CDC13) : 162.64 (C=0), 140.87[CH=C(CN)2], 139.79 (pyrrole C-2), 136.44 (benzene C - l ) , 135.91 (pyrrole C-4), 128.56/128.01 (benzene r i n g ) , 127.81, (hook), 126.32, 125.41 (pyrrole C-3, C-2', C-3', C-4'), 124.24 (pyrrole C-5), 118.62 (pyrrole C-5'), 116.76 (C=N), 115.79 (C=N), 65.75 (-0-CH2C6H5), 64.68 [CH=C (CN) 2) ] , 23.82 (bridge CH 2), 17.32 P'-CH^H^, 17.13 (3-CH 2CH 3), 15.33 P'-CH^H^, 14.68 (3-CH 2CH 3), 10.60 (4'-CH 3), 9.41(4-CH3). Mass Spectrum : Relative ion m/e Intensity Assignment 1 440 27 M + 2 349 18 (M-C,H[.CH,J + 3 199 21 (ion 4 + H) 187 R e l a t i v e i o n m/e I n t e n s i t y Assignment NC CN 6 9 1 100 C H T U 7 H 7 — : ( vmax K B r ) : 3 3 8 0 (N-H), 3320 (N-H), 2220 (C=N), 1660 (0=0), 1595 (C=C) cm" 1. 2 - [ ( 5 - B e n z y l o x y c a r b o n y l - 3 - e t h y l - 4 - m e t h y l p y r r o l - 2 - y l ) m e t h y l ] - 5-(2-cyano-2-methoxycarbonylvinyl)-3-ethyl-4-methylpyrrole 112 188 5-Chloromethyl-2-(2-cyano-2-methoxycarbonylvinyl) - 4 - e t h y l - 3 - m e t h y l p y r r o l e 87_ '(1.19 g, 4.46 mmol) was suspended i n g l a c i a l a c e t i c a c i d (60 mL) and 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-methylpyrrole 8_0 (1.15 g, 4.73 mmol) i n a c e t i c a c i d (20 mL) s t i r r e d i n . The mixture was warmed i n a water bath under n i t r o g e n a t 70°C f o r 0.5 h and the c l e a r orange s o l u t i o n was co o l e d to room temperature and f i l t e r e d under s u c t i o n . The f i l t r a t e was evaporated under reduced p r e s s u r e to 10 mL, methanol (4 0 mL) added and then water (10 mL). The product c r y s t a l l i z e d out as a y e l l o w f i n e l y c r y s t a l l i n e s o l i d and was c o l l e c t e d by f i l t r a t i o n , washed w i t h methanol and a i r -d r i e d to g i v e 1.86 g (88.1%). An a n a l y t i c a l sample was r e c r y s t a l l i z e d from methylene c h l o r i d e - m e t h a n o l . MP : 168.0-169.0°C Mol.Wt. 473.57 A n a l . C a l c d . f o r c 2 8 H 3 l N 3 ° 4 : C ' 7 1 - 0 2 ' " H> 6.60; N, 8.87; Found : C, 71.09; H, 6.58; N, 8.87. X E NMR (6, CDC1 3) : 1.00, 1.02 (two t r i p l e t s , 6H, J=7.5 Hz, 3- and 3 '-CH^CHLj) , 2.08 (s , 3H, 4-CH.j), 2.27 (s , 3H, 4'-CH_3), 2.35, 2.39 (two q u a r t e t s , 4H, J=7.5 Hz, 3- and 3'-CH 2CH 3), 3.77 (s, 3H, -0-CH 3), 3.87 (s , 2H, b r i d g e CH 2) , 5.20 (s , 2H, 0-CH 2C 6H 5), 7.12-7.40 (m, 5H, , 7.77 ['s , IH, CH=C (CN) ^  , 8.82 (br, IH, l'-NH), 9.28 (br, IH, 1-NH). 189 1 3 C NMR, : (6, CDC1 3) : 165.19 (C0 2CH 3), 161.64 (CC> 2CH 2C 6H 5) , 138.32 [CH=C(CN)C0 2CH 3], 137.70 ( p y r r o l e C-2), 136.54 (benzene C - l ) , 135.38 ( p y r r o l e C-4)> 128.45 (benzene ring-two carbons), 127.98 ( p y r r o l e C-2', benzene r i n g - t h r e e .carbons), 127.09 ( p y r r o l e C-4'), 125.71 ( p y r r o l e C-3), 125.23 ( p y r r o l e C-3'), 123.65 ( p y r r o l e C-5), 119.42 (C=N), 118.43 ( p y r r o l e C-5'), 86.14 [C (H)=C (CN) C0 2CH 3] , 65.57 (-O-CH^-CgB^) , 52.38 (O-CH^), 23.62 (bridge CH 2), 17.32 (3'-CH 2CH 3), 17.13 (3-CH 2CH 3), 15.35 (3'-CH 2CH 3), 14.72 (3-CH 2CH 3), 10.57 (4'-CH 3), 9.16 (4-CH 3). Mass spectrum : R e l a t i v e m/e I n t e n s i t y Assignment 474 33 (M+H)+-473 100 M + 382 20 (M-C 6H 5CH 2) + 365 49 (M-CrHcCH-.sOH)+ [ 364 40 (M-C 6H 5CH 2OH-H) + 231 18 230 19 91 65 190 IR ( v - KBr) : 3380 (N-H), 3310 (broad, N-H), 2205 (C=N), 1685 (broad, C=0), 1590 (C=C) cm" 1. 2-[ (5-Carboxy-3-ethyl-4-methypyrrol-2-yl)methyl] -5-(2-cyano- 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 113 113 2 - [ ( 5 - B e n z y l o x y c a r b o n y l - 3 - e t h y l - 4 - m e t h y l p y r r o l - 2 - y l ) methyl]-5-(2-cyano-2-methoxycarbonylvinyl)-3-ethyl-4-methylpyrrole 112 (1 g, 2.12 mmol) i n t e t r a h y d r o f u r a n (35 mL) w i t h 10% p a l l a d i z e d c h a r c o a l (101 mg) was s t i r r e d a t room temperature under 1 atm of hydrogen. The uptake of hydrogen was r a p i d and l i n e a r with time and reached a p l a t e a u i n 25 min. A f t e r a f u r t h e r 10 min of s t i r r i n g (during which p e r i o d no more hydrogen was taken up), the c a t a l y s t was f i l t e r e d o f f and a t i c a n a l y s i s of the s o l u t i o n showed no s t a r t i n g m a t e r i a l . The s o l v e n t was evaporated o f f under reduced pressure and methanol added when the product c r y s t a l l i z e d out as a lemon ye l l o w f i n e l y c r y s t a l l i n e s o l i d . The s o l i d was c o l l e c t e d by f i l t r a t i o n , washed with methanol and e t h e r , to g i v e 681 mg (84.1%). T h i s r e a c t i o n was repeated w i t h 3.01 g (6.36 mmol) of the dipyrromethane 112 and 3 00 mg of c a t a l y s t i n t e t r a h y d r o f u r a n (80 mL). The f i r s t crop weighed 1.55 g (63.6%) and the second, 0.64 g (26.3%) f o r a t o t a l y i e l d of 89.9%. The sample darkened p r o g r e s s i v e l y above 205.0°C and melted a t 216.0°C. (dec.) An a n a l y t i c a l sample was r e c r y s t a l l i z e d from tetrahydrofuran-methanol. Moi. Wt. : 383.45 An a l . C a l c d . f o r c 2 i H 2 5 N 3 ° 4 : C ' 6 5 - 7 8 " H ' 6.57; N, 10.96 Found : C, 65.73; H, 6.46; N, 10.89. -"H NMR : (6, DMSO-dg) : 0.8 9 ( t , 6H, J=7 .5 Hz, 3- and 3'-CH 2CH 3), 2.14 (s, 3H, 4-CH 3), 2.20 (s, 3H, 4 1-CH 3), 2.39 (two q u a r t e t s masked by the DMSO-d^ s i g n a l , 3- and 3'-CH 2CH 3), 3.80 (s, 3H,-0-CH 3), 4.04 (s , 2H, bridge CH_2), 7.87 [ s , l H , CH=C(CN)C0 2CH 3], 10.39 (br, IH, 1-NH), 11.05 (br, IH, l'-NH), 11.84 (bs, IH, C0 2H). Mass spectrum R e l a t i v e m/e I n t e n s i t y Assignment 384 25 (M+H)+ 383 100 M + m/e 365 339 231 R e l a t i v e I n t e n s i t y 24 28 28 Assignment (M-OH-H)+ (M-C0 2) + •OCH, 230 26 OCH, I R ( v™ = „ KBr) : 3380 (N-H), 3265 (broad, N-H), 2200 (C I l l c i X 1690 (C=0), 1640 (C=0), 1580 (C=C) cm" 1. 5-(2-Cyano-2-methoxycarbonylvinyl)-3-ethyl-2-[ (3-ethyl-4 - m e t h y l p y r r o l - 2 - y l ) m e t h y l ] - 4 - m e t h y l p y r r o l e 114 114 193 2-[ (5-Carboxy-3-ethyl-4-methylpyrrol-2-yl)methyl] -5-(2-eyano-2-methoxycarbonylvinyl)-3-ethyl-4-methylpyrrole 113 (1.01 g, 2.64 mmol) and t r i f l u o r o a c e t i c a c i d ( 8 mL) were s t i r r e d under n i t r o g e n f o r 5 min. Removal of an a l i q u o t i n t o methylene c h l o r i d e and checking on t i c ( i n methylene c h l o r i d e ) r e v e a l e d a s i n g l e y ellow spot, c o l o r e d r e d by bromine vapour. No spot remained a t the o r i g i n , i n d i c a t i n g the complete disappearance of the s t a r t i n g m a t e r i a l . Most of the t r i -f l u o r o a c e t i c a c i d was removed by e v a p o r a t i n g under reduced p r e s s u r e , the r e s i d u e taken up i n methylene c h l o r i d e (50 mL) washed with s a t u r a t e d sodium b i c a r b o n a t e s o l u t i o n (2x2 0 mL) and water (20 mL) and d r i e d w i t h anhydrous sodium s u l f a t e . The s o l u t i o n was concentrated a f t e r the a d d i t i o n of hexane and the orange m i c r o c r y s t a l l i n e s o l i d was f i l t e r e d , washed with hexane and a i r d r i e d to g i v e 701 mg (78.4%). The mother l i q u o r s were con c e n t r a t e d and c o o l e d i n i c e , to o b t a i n an a d d i t i o n a l 122 mg (13.6%), f o r an o v e r a l l y i e l d of 92%. MP : 156.0 - 157.0°C Mol.Wt. : 339.44 A n a l . C a l c d . f o r c 2 o H 2 5 N 3 ° 2 : C ' 7 0 - 7 7 ; H ' 7 - 4 2 ; N, 12.38; Found : C, 70.79; H, 7.54; N, 12.36. 1H NMR (6, CDC1 3) : 1.05 ( t , 6H, J-7.5 Hz, 3- and 3'-CH 2CH 3), 2.02 (s, 3H, 4'-CH 3), 2.12 (s, 3H, 4-CH 3), 2.40 (q, 4H, J=7.5, 3- and 3' -CH'2CH3) , 3.77 (s, 3H, 0~CH 3), 3.87 (s', 2H b r i d g e CH 2), 6.41 (d, IH, J=2 Hz, 5'-H), 7.63 (br, IH, l'-NH), 7.78 [ s , IH, CH=C(CN)C0 2CH 3], 9.31 (br, IH, 1-NH). "^C NMR (6, CDC1 3) : 165.29 (CC>2CH3), 140.47 ( p y r r o l e C-2), 137.63 [CH=C(CN)C0 2CH 3], 135.56 ( p y r r o l e C-4), 125.52 ( p y r r o l e C-3), 123.54 ( p y r r o l e C-5), 122.47 . ( p y r r o l e C-2'), 120.71 ( p y r r o l e C-3'), 119.61 (0=N), 118.43 ( p y r r o l e C-4'), 115.19 ( p y r r o l e C-5'), 85.55 (-CH=C(CN)C0 2CH 3), 52.37 (0-CH 3), 23.68 (bridge C H 2 ) f 17.62 p'-CI^CB^), 17.12 (3-CH 2CH 3), 15.63 (3'-CH 2CH 3), 14.78 (3-CH 2CH 3), 10.33 (4'-CH 3), 9.30 (4-CH 3). Mass spectrum m/e 340 339 307 231 R e l a t i v e I n t e n s i t y 23 100 16 41 Assignment (M + H) + M (M-CH3OH) + C H , 230 57 NC • 0CH3 122 59 \ _ / C H 3 f t H X ^ N ^ H m/e R e l a t i v e I n t e n s i t y Assignment IR ( v m a x KBr) : 3410 (N-H), 3400 (v.weak), 3360 (N-H) 2200 (C=N), 1690 (C=0), 1590 (C=C) cm" 1. 196 3- E t h y l - 2 - [ ( 3 - e t h y l - 4 - m e t h y l p y r r o l - 2 - y l ) m e t h y l ] - 5 - f o r m y l -4- m e t h y l p y r r o l e 105 5-(2-Cyano-2-methoxycarbonylvinyl)-3-ethyl-2-[(3-e t h y l - 4 - m e t h y l p y r r o l - 2 - y l ) m e t h y l ] - 4 - m e t h y l p y r r o l e 114 (503 mg, 1.48 mmol) and potassium hydroxide (2 g) i n water (20 mL) were heated under n i t r o g e n . Methanol (15 mL) was added causing the y e l l o w s t a r t i n g m a t e r i a l to d i s s o l v e completely and w i t h i n 15 min.' of h e a t i n g , l i g h t tan f l u f f y needles separated out of the s o l u t i o n . Heating was continued f o r 3 0 min,, more water (30 mL) added, c o o l e d and f i l t e r e d . The s o l i d was washed with Water and d r i e d i n a vacuum d e s s i c a t o r over c a l c i u m s u l f a t e to g i v e 380 mg (99.2%). The sample, d r i e d on the vacuum-line f o r 2h a t room temperature, was found to be a n a l y t i c a l l y pure. The r e a c t i o n was repeated with 1.43 g s t a r t i n g m a t e r i a l to g i v e 1.05 g (97.1%) of the product. MP : 137.0 - 137.5°C (dec.) Moi. Wt : 258.37 A n a l . C a l c d : f o r C 1 6 H 2 2 N 2 0 : C, 74.38 ; H, 8.58; N, 10.84,' Found C, 74.30; H, 8.33; N, 10.7 2 197 1H NMR : (6, C D C l 3 ) , 1.06, 1.07 (two t r i p l e t s , 6H, J=7.5 Hz, 3- and 3'- CH2CH_3) , 2.02 (s, 3H, 4'-CH 3), 2.23 (s, 3H, 4-CH.j) , 2.43 (q, 4H, J=7.5 Hz, 3- and 3'- CH_ 2CH 3), 3.83 (s, 2H, brid g e C H 2 ) , 6.36' (d, IH, J=2 Hz, 5'-H), 8.4 6 (s , IH CHO), 9.38 (br, IH, l'-NH), 9.99 (br, IH, 1-NH). 1 3 C NMR (6, CDC1 3) : 175.91 (CHO), 138.81 ( p y r r o l e C-2) , 133.58 ( p y r r o l e C-4), 128.43 ( p y r r o l e C-5), 124.85 ( p y r r o l e C-3), 122.75 ( p y r r o l e C-2'), 120.98 ( p y r r o l e C-3'), 117.53 ( p y r r o l e C-4'), 114.78 ( p y r r o l e C-5'), 22.74 (bridge C H 2), 17.70 (3'-CH 2CH 3), 17.03 (3-CH 2CH 3), 15.83 (3'CH 2CH 3), 15.21 (3-CH 2CH 3), 10.36 (4'-CH 3), 8.76 (4-CH 3). Mass spectrum m/e 258 243 229 149 122 R e l a t i v e I n t e n s i t y Assignment 8 6 M + 13 (M-CH 3) + 22 ( M - C „ H C ) + 100 33 0CH3 ~ H N0 f t 198 R e l a t i v e m/e I n t e n s i t y Assignment \ _ v C H 3 121 28 J = \ IR (v-V- . KBr) : 3330 (N-H), 3270 (N-H), 1610 (C=0) cm 1, I T l c i X 3,7,13,17-Tetraethyl-2,8,12,18-tetramethylporphyrin ( E t i o p o r p h y r i n II) 106 199 Method A 2 - [ ( 5 - C a r b o x y - 3 - e t h y l - 4 - m e t h y l p y r r o l - 2 - y l ) m e t h y l ] - 3 - e t h y l - 5 -f o r m y I - 4 - r m e t h y l p y r r o l e 103 (1.013 g, 3.35 mmol) was d i s s o l v e d i n N,N-dimethylformamide (100 mL) and heated t o r e f l u x under n i t r o -gen. The d i s a p p e a r a n c e o f the uv a b s o r p t i o n band a t 28 0 nm was t a k e n as an i n d i c a t i o n o f d e c a r b o x y l a t i o n . A f t e r 3 h, the s o l u t i o n was e v a p o r a t e d under reduced p r e s s u r e t o a p p r o x i m a t e l y 25 mL, added t o methylene c h l o r i d e (150 mL) and e x t r a c t e d w i t h water (2x50 mL) t o remove most of the r e m a i n i n g d i m e t h y l f o r m a m i d e . The methylene c h l o r i d e s o l u t i o n o f the d e c a r b o x y l a t e d p r o d u c t 105 was d r i e d w i t h anhydrous sodium s u l f a t e , f i l t e r e d and added dropwise t o a s o l u t i o n o f t o l u e n e - p - s u l f o n i c a c i d 200 (4.0 g) i n methanol (25 mL) - methylene c h l o r i d e (450 mL) over a p e r i o d of 2 h. The s o l u t i o n was allowed t o s t i r i n the dark f o r a f u r t h e r 16 h and then evaporated under vacuum to approximately 25 mL. Methanol(75 mL) was added, the a c i d was n e u t r a l i z e d with t r i e t h y l a m i n e and the mixture was allowed to stand i n the r e f r i g e r a t o r f o r 0.5 h. The p u r p l e s o l i d was f i l t e r e d o f f from the g r e e n i s h brown s o l u t i o n and washed wi t h methanol to g i v e 382 mg (47.7%). 7- 7 MP : > 280°C .-Lit. . : 360-366°C Moi. Wt.Calcd. f o r C 3 2 H 3 g N 4 : 478.3097 Found, by h i g h r e s o l u t i o n mass spectrometry : 478.3093 A n a l . C a l c d . f o r C 3 2 H 3 g N 4 : C, 80.29; H, 8.00; N, 11.70; Found : C, 80.00; H, 7.93; N, 11.56. 1H NMR : (6, CDCl 3) : 1.89 ) t , 12H, J=7.5 Hz, CH 2CH 3), 3.66 (s, 12H, 2-, 8-, 12-, 18-CH 3), 4.12 (q, 8H, J=7.5 Hz, CH 2CH 3), 10.12 (s, 4H, methine CH). 1 3 C NMR : (6, 10% TFA-CDC1 3) : 143.54 (3-,7-, 13-, 17-C) , 142.29 (1-, 9-, 11-, 18-C), 141 .53 (4-, 6-, 14-, 16-C), 98.39, 97.95 (5-, 10-, 15-, 20-C) , 20.11 (CH 2CH 3), 16.42 (CH 2CH 3), 11.67 (CH 3). 2 0 1 Method B 3-Ethyl-2-[ (3-ethyl-4-methylpyrrol-2-?yl)methyl] -5-formyl -4-methylpyrrole 105 (706 mg, 2.74 mmol) was d i s s o l v e d i n methylene c h l o r i d e (200 mL) and added dropwise to a s o l u t i o n of t o l u e n e - p - s u l f o n i c a c i d (4.3 g) i n methanol (25 mL)-methylene c h l o r i d e (475 mL) over a p e r i o d of 2 h. The s o l u t i o n was allowed to s t i r f o r a f u r t h e r 16 h, evaporated under reduced pressure to 50 mL. , methanol (7 5 mL) added and the a c i d n e u t r a l i z e d with t r i e t h y l a m i n e . The p u r p l e s o l i d was f i l t e r e d and washed w i t h methanol, y i e l d 447 mg (68.4%). MP : > 280°C A n a l . C a l c d . f o r C 3 2 H 3 8 N 4 : C ' 80-29; H, 8.00; N, 11.70; Found : C, 80.04; H, 7.91; N, 11.76. 1E NMR (<S, CDC1 3), 1.89 ( t , 12H, J=7 .5 Hz, CH 2CH_ 3), 3.65 (S1, 12H, 2-, 8-, 12-, 18-CH 3), 4.12 (q, 8H, J=7.5 Hz, CH 2CH 3), 10.13 (s., 4H, methine CH) . 1 3 C NMR : (6, 10% TFA-CDC1 3) : 143.46 (3-, 7-, 13-, 17-C) , 142.29 (1-, 9-, 11-, 18-C), 141.52 (4-, 6-, 14-, 16-C), 98.35, 97.91 (5-, 10-, 15-, 20-C), 20.10 (CH 2CH 3), 16.45 (CH 2CH 3), 11.67 (CH 3). 202 3.6 SYNTHESES OF CHAIN LINKED BIS PYRROLES 3.6.1 BIS PYRROLE DIKETONES 88 1,ll-Bis(5-ethoxycarboriyI-2> 4 - d i m e t h y l p y r r o l - 3 - y l ) - 1,11-d i oxoundec ane (n=ll) 88a Undecanedioic a c i d (21.4 g, 0.10 moi) and t h i o n y l c h l o r i d e (46.3 g, 0.39 moi) were p l a c e d i n a round bottomed f l a s k f i t t e d with a r e f l u x condenser and a c a l c i u m c h l o r i d e d r y i n g tube. The mixture was heated on a steam bath f o r 3 0 min. u n t i l the vig o r o u s e v o l u t i o n of gas subsided. The excess t h i o n y l c h l o r i d e was d r i v e n o f f by eva p o r a t i o n under reduced p r e s s u r e with carbon t e t r a c h l o r i d e (4x3 0 mL) and the b i s a c i d c h l o r i d e was used i n the next stage of the s y n t h e s i s without f u r t h e r p u r i f i c a t i o n . In an i c e - c o o l e d 1 - l i t e r erlenmeyer f l a s k f i t t e d with 203 a C l a i s e n head, a n i t r o g e n i n l e t tube, a dropping f u n n e l ( p r e s s u r e - e q u a l i z i n g type) and a d r y i n g tube, were p l a c e d , -2-ethoxycarbonyl-3 , 5-dimethylpyrr.ole (35 g, 0.21 moi), methylene c h l o r i d e (250 mL) and nitromethane (200 mL). The system was f l u s h e d with n i t r o g e n and the a c i d c h l o r i d e prepared above was i n t r o d u c e d to the f l a s k with the a i d of methylene c h l o r i d e (50 mL). Anhydrous s t a n n i c c h l o r i d e (104.2 g, 0.40 moi) was added dropwise over a p e r i o d of 3 h and the r e a c t i o n mixture was allowed to s t i r f o r a f u r t h e r 4 h p e r i o d . The s o l u t i o n was poured 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 (10 mL concentrated a c i d i n 350 mL water) and was allowed to s t i r f o r 15 min causing ..the product ..to . separate but and form an emulsion w i t h the org a n i c s o l v e n t s and water. The s o l i d was f i l t e r e d , washed wi t h water and methylene c h l o r i d e a.nd the f i l t r a t e (which had now separated i n t o two layers)was s e t a s i d e to i s o l a t e a second crop. The s o l i d was washed wit h methanol (under s u c t i o n ) a n d . a i r d r i e d t© g i v e 37.8 g (73.5% from the d i a c i d ) . The organic phase of the mother l i q u o r s was separated and evaporated down under reduced pressure to i s o l a t e a second crop of 6.3 g (12.3%). T h i s s y n t h e s i s was repeated twice on the same s c a l e under i d e n t i c a l r e a c t i o n c o n d i t i o n s . F i r s t crop y i e l d s of 71.6% and 75.1% were obtained; a second crop was not i s o l a t e d . An a n a l y t i c a l sample was c r y s t a l l i z e d from t e t r a -hydrof uran-methanol . 204 MP : 173.5 - 175.0°C Moi. Wt.Calcd. f o r ^ 2 9 H 4 2 N 2 ° 6 : 5 1 4 - 3 0 4 3 ' Found, by high r e s o l u t i o n mass spectrometry : 514.3060. A n a l . Calcd.. f o r C o„H.„N„0v : C, 67.7 0; H, 8.17; N, 5.48; 2a 42 2 6 Found : C, 67.71; H, 8.12; N, 5.68. 1H NMR (6, 10% TFA-CDC1 3) : 1.33 (br, 10H, ch a i n methylene protons 4'-, 5'-, 6'-,. 7'-, 8'-CH 2), 1.43 ( t , 6H, J=7 Hz, -Q-CH 2CH 3), 1.6 9 (m, 4H, c h a i n methylene protons 3'-, 9'-CH 2), 2.57 (s, 6H, 4-CH3) , 2.59 ,(s , 6H, 2-CH_3), 2.86 ( t , 4H, J=7 . 5 Hz, c h a i n methylene protons 2'- and 10'-CH 2), 4.46 (q, 4H, J=7 Hz, -0-CH 2-CH 3), 10.15 (bs, 2H, NH). 1 3 C NMR (6, 1C% ;TFA-CDC1 3) : 204.07 (chain C=0, C - l ' and C - l l 1 ) , 164 (ester C=0) , 142.31 ( p y r r o l e C-2), 132.26, ( p y r r o l e C-4), 122.80 ( p y r r o l e C-3), 118.49 ( p y r r o l e C-5), 62.34 ( e s t e r - 6 - C H 2 ) , 42.27 (chain CO-CH 2 C-2' and C-10'), 29.37 (chain methylenes, C-4 1, C-5', C-6', C-7 1 , C-8 1) , 25.74 (chain methylenes C-3' and C-9'), 15.43 (2-CH 3), 14.23 (ester-0-CH 2CH 3), 12.94 (4-CH 3). 205 Mass spectrum m/e 514 R e l a t i v e I n t e n s i t y (%) 23 Assignment M + 209 72 O H H J L H 0 194 100 0C\ ^ C H 3 148 87 oc CH-> I R K B r ) : 3290 (N-H), 1650 (C=0) cm 1 . 1,10-Bis (5-e thoxy car bony 1 - 2 ,4-d ime thy l p y r r o 1- 3-y 1)'  1,10-dioxodecane (n=10) 88b Decanedioic a c i d (sebacic acid) was obtained from Eastman Kodak Chemical Company and was found to be s u i t a b l e 206 f o r use without f u r t h e r p u r i f i c a t i o n . The b i s a c i d c h l o r i d e and the b i s p y r r o l y l diketone were s y n t h e s i z e d a c c o r d i n g to the procedure g i v e n f o r the analogous undecane d e r i v a t i v e 88a. Four e q u i v a l e n t s of s t a n n i c c h l o r i d e were used f o r the a c y l a t i o n r e a c t i o n and the y i e l d of the f i r s t crop was 79.2% (from the d i a c i d ) . A second crop was not i s o l a t e d . An a n a l y t i c a l sample was c r y s t a l l i z e d from t e t r a -hydrofuran-methanol. MP : 158.5 - 159.5°C A n a l . C a l c d . f o r C 2 8 H 4 0 N 2 ° 6 : C, 67.18; H, 8.05; N, 5.59 Found : C, 67.07; H, 7.88; N, 5.55. 1H NMR .. (6, 10% TFA-CDC1 3) : 1.33 (br, 8H, c h a i n methylene protons 4.'-, 5'-, 6'-, 7'-CH 2), 1.43 ( t , 6H, J=7 Hz,-0-CH 2CH 3), 1.66 (m, 4H, c h a i n methylene protons 3 1-,8 1-CH 2), 2.57 (s, 6H, 4-CH 3), 2.59 (s, 6H, 2-CH3>, 2.86 ( t , 4H, J=7.5 Hz, ch a i n methylene protons 2'- and 9'-CH 2), 4.45 (q, 4H, J=7 Hz, 0-CH 2-CH 3), 10.15 (bs, 2H, NH). 1 3 C NMR (6, 10% TFA-CDC1 3) : 203.68 (chain C=0) , C - l ' and C-10'), 163.76 (ester C=0), 141.94 ( p y r r o l e C-2), 131.96 ( p y r r o l e C-4), 122.79 ( p y r r o l e C-3), 118.42 ( p y r r o l e C-5), 62.16 (ester 0-CH 0), 42.27 (chain C0CH o C-2' and C - 9 1 ) , 207 29.41 (chain C-4' and C-7 ' ) , 29.24 (chain C-5', C-6'), 25.58 (chain C-3 1, C-8 1) , 15.39 (2-CH 3), 14.23 (ester -0-CH 2-CH 3), 12.89 (4-CH 3). Mass spectrum : R e l a t i v e m/e I n t e n s i t y (%) Assignment 500 26 M + O H ® 20 9 71 H 2 C - C X / c h 3 A Y -194 148 1, g-Sl-s'T'S-'-'e't-hd'xyc-'arrKDny 1-2,4 -dime thy l p y r r o 1 -3 -y 1) -1,9- dioxononane (n=9) 88c T e c h n i c a l grade nonanedioic a c i d ( a z e l a i c a c i d , mp 93-96°C) was obtained from Eastman Kodak Chemical Company 208 and r e c r y s t a l l i z e d twice from hot formic a c i d . The m e l t i n g p o i n t of the r e c r y s t a l l i z e d sample was 101°C, 5° below the l i t e r a t u r e v alue of 106°C. The b i s a c i d c h l o r i d e and the b i s p y r r o l y l diketone were s y n t h e s i z e d as d e s c r i b e d f o r the undecane analogue, u s i n g four e q u i v a l e n t s of s t a n n i c c h l o r i d e f o r the a c y l a t i o n s t e p . The y i e l d of the f i r s t crop was 69.1%, s t a r t i n g from the d i a c i d . The s y n t h e s i s was repeated u s i n g o n l y two e q u i v a l e n t s of s t a n n i c c h l o r i d e f o r the a c y l a t i o n step (1 moi of s t a n n i c c h l o r i d e / a t o m c h l o r i n e of the a c i d c h l o r i d e ) r e s u l t i n g i n the f i r s t crop y i e l d of 7 9.6%. The two samples were i d e n t i c a l , each showing a s i n g l e spot on t i c . In both i n s t a n c e s , second crops were not i s o l a t e d . An a n a l y t i c a l sample was c r y s t a l l i z e d from hot dimethylformamide. M P : 173.0 -173.5°C " - _ A n a l . Calcd.. f o r C 2 7 H 3 8 N 2 ° 6 : C ' 6 6 ' 6 4 ; H, 7.87; N , 5.76. Found : C, 66.34; H, 7.82; N , 5.69. N M R (6, 10% TFA-CDC1 3) : 1.36 (br, 6H, c h a i n methylene protons 1 4'-,5'-, 6'-CH 2), 1.43 ( t , 6H, J=7 Hz, 0-CH 2CH 3), 1.69 (m, 4H, c h a i n methylene protons - 3'- and 7'-CH 2), 2.57 (s, 6H, 4-CH 3), 2.59 (s, 6H, 2-CH 3) # 2.87 ( t , 4H, J=7.5 Hz, c h a i n methylene protons 2'- and 8'-CH 0), 4.46 (q, 4H, J=7 Hz -0-CH 2CH 3), 10.15 (bs, 2H, NH). 1 3 C NMR (<5, 10% TFA-CDC1 3) : 203.79 (chain C=0, C - l ' and C-9*) 163.95 (ester C=0) , 142.25 ( p y r r o l e C-2), 132.19 ( p y r r o l e C-4) 122.78 ( p y r r o l e C-3), 118.49 ( p y r r o l e C-5), 62.32 (ester 0-CH 2), 42.23 (chain C0CH 2. C-2' and C-8 ' ) , 29.32 (chain C-4', C-5', C-6'), 25.57 ( c h a i n - C-3' and C-7') , 15.44 (2-CH 3), 14.23 (ester -0-CH 2-CH 3), 12.94 (4-CH 3). Mass spectrum : R e l a t i v e m/e I n t e n s i t y (%) Assignment 486 24 M + 209 77 0 H ® H 2 C ^ C \ ^ C H 3 H 0 148 87 210 3.6.2 BIS PYRROLE ETHYL ESTERS 6 9 1,11-Bis (5-ethoxycarbonyl-2 / 4 - d i m e t h y l p y r r o l - ; 3 - y l ) undecane (n=ll) 89a 1,11-Bis( 5 - e t h o x y c a r b o n y l - 2 , 4 - d i m e t h y l p y r f o l - 3 - y l ) 1,11-dioxoundecane 8_8 (32.0 g, 62.3 mmol) and d r y t e t r a d hydrofuran (300 mL) were p l a c e d i n a 1 - l i t e r erlenmeyer f i t t e d with a C l a i s e n adapter, a n i t r o g e n i n l e t (connected to the s i d e arm of the C l a i s e n a d a p t e r ) , a dropping f u n n e l (pressure e q u a l i z i n g type) and a c a l c i u m c h l o r i d e d r y i n g tube. The f l a s k was i c e - c o o l e d and the mixture was m a g n e t i c a l l y s t i r r e d under n i t r o g e n . (The s t a r t i n g m a t e r i a l d i d not d i s s o l v e f u l l y ) . Sodium borohydride (5.0 g, 132.3 mmol) was added, fo l l o w e d by the c a r e f u l dropwise a d d i t i o n of boron tri-? f l u o r i d e e t h e r a t e (30 mL, 238.1 mmol). The r e a c t i o n mixture appeared as a b u f f c o l o r e d emulsion and was checked by t i c f o r any unreacted s t a r t i n g m a t e r i a l . 211 A c e t i c a c i d (100 mL) was added to d e s t r o y the excess diborane ( c a r e f u l l y , w h ile p a s s i n g nitrogen) f o l l o w e d by water (200 mL). As water was added, the s o l u t i o n f i r s t went c l e a r (pale brown c o l o r ) and w i t h more water, the crude product c r y s t a l l i z e d out as a white s o l i d . The s o l i d was d i s s o l v e d i n methylene c h l o r i d e , the or g a n i c phase i s o l a t e d , g r a v i t y f i l t e r e d and concentrated a f t e r adding methanol. The b i s ( p y r r o l y l ) undecane was c o l l e c t e d by f i l t r a t i o n , washed wi t h methanol and d r i e d i n a i r to g i v e 25.1 g, (82.9%). The mother l i q u o r s were concentrated to gi v e a f u r t h e r 1.2 g, (4.0%). T h i s r e a c t i o n was repeated on the same s c a l e and an o v e r a l l y i e l d of 83.5% was obtained. An a n a l y t i c a l sample was r e c r y s t a l l i z e d from methylene c h l o r i d e - m e t h a n o l . MP : 11.5.0 -116. 5°C 'MoT. Wt.Calcd. f o r C 2 9 H 4 6 N 2 ° 4 : 4 8 6 - 3 4 5 8 " Found, by high r e s o l u t i o n mass spectrometry : 486.3452 A n a l . C a l c d . f o r C „ n H N O. : C, 71.60; H, 9.47; N, 5.76; zy 46 2 4 Found : C, 71.60; H, 9.54; N, 5.85. 1H NMR (6, CDC1 3) : 1.08-1.58 (m, 18H, c h a i n 2'-, 3'-, 4'-, 5'-, 6'-, 7'-, 8'-, 9'-, 10'-CH 2), 1.31 ( t , 6H, J=7 Hz, -0~ CH 2-CH 3), 2.14 (s, 6H, 2-CH 3), 2.22 (s, 6H, 4-CH 3), 2.18 -212 2.44 (m, 4H, c h a i n 1 1-CH 2 and l l ' - C F ^ ) , 4.25 (q, 4H, J=7 Hz, -6CH 2CH 3), 8.7 3 (bs, NH). 1 3 C NMR (6, CDC1 3) : 162.24 (C=0), 130.04 ( p y r r o l e 2-C), 126.99 ( p y r r o l e 4-C), 122.36 ( p y r r o l e 3-C), 116.76 ( p y r r o l e 5-C), 59.56 (-OCH 2CH 3), 30.95 (chain 2 1-C and lO'- C ) , 29.69 (chain 3'-C, 4'-C, 5*-C, 6'-C, 7'-C, 8 '-C, 9'-C), 24.10 (chain 1 1-C and l l ' - C ) , 14.64 ( - o-CH 2-CH 3), 11.41 (2-CH 3), 10.73 (4-CH 3). Mass spectrum R e l a t i v e m/e I n t e n s i t y (%) Assignment 486 65 M + 440 86 (M-CH 3CH 2OH) + 180 100 0 134 IR K B r ) : 3330 (N-H), 1675 (C=0) cm 213 1,10-Bis (5-ethoxycarbony!-2">4.-d^ (n=10) 89b The diketone 88b (38.0 g, 7 6 mmol) was reduced with diborane, generated by sodium borohydride (7.5 g, 198 mmol) and boron t r i f l u o r i d e e t h e r a t e (40 mL, 317 mmol), a c c o r d i n g to the procedure given f o r the undecane analogue 88a. A f i r s t crop of 3 0.1 g and a second crop of 0.7 g were obtained f o r an o v e r a l l y i e l d of 85.9%. MP : 143.0 - 144.0°C . Anal.Ca l c d . f o r C 2 8 H 4 4 N 2 ° 4 : C, 71.15; H, 9.138; N, 5.92 Found : C, 70.89; H, 9.41; N, 5.70. '''H NMR : (6, CDC1 3) : 1.12-1.60 (m, 16H, c h a i n 2" 1, 3'-, 4'-5'-, 6'-, 7'-, 8'-, 9'-CH 2), 1.30 ( t , 6H, -0-CH 2-CH 3), 2.14 (s, 6H, 2-CH 3), 2.20 (s , 6H, 4-CH 3), 2.20-2.48 (m, 4H, c h a i n l ' - C H 2 and 10'-CH 2), 4.26 (q, 4H, J=7 Hz, -0-CH_ 2-CH 3), 8.81 (bs, NH). 1 3 C NMR : (6, CDC1 3) : 161.84 (C=0), 129.49 ( p y r r o l e 2-C), 127.05 ( p y r r o l e 4-C), 122.42 ( p y r r o l e 3-C), 116.79 ( p y r r o l e 5-C), 59.52 (-OCH 2CH 3), 30.88 (chain 2'-C and 9'-C), 29.62 (chain 3'-C, 4'-C, 5 *-C , 6 '-C, 7 *-C, 8'-C), 24.06 (chain l ' - C and l O ' - C ) , 14.62 (-0-CH 2CH 3), 11.47 (2-CH 3), 10.62 (4-CH 3). 214 Mass Spectrum R e l a t i v e m/e I n t e n s i t y (%) Assignment 472 62 M + 426 88 (M-CH 3CH 2OH) + 180 100 H 2 C \ _ - ^ C H 3 134 1, 9-Bis (5-ethoxycarbonyl-2 , 4-"dimethylpyrroT-3-yI) nonane-(n=9) 89c The diketone 88c (30.3 g, 62.3 mmol) was reduced as d e s c r i b e d f o r the undecane analogue 88a, u s i n g sodium borohydride (5.0 g, 132.3 mmol) and boron t r i f l u o r i d e e t h e r a t e (30 mL, 238.1 mmol). The crude product was i s o l a t e d and r e -c r y s t a l l i z e d from methylene chlori d e - m e t h a n o l to g i v e 19.8 g. (69.3%). The r e a c t i o n was repeated with 77.0 g (158.4 mmol) of the diketone 88c and an o v e r a l l y i e l d of 55.1 g (75.9%) were ob t a i n e d . 215 MP : 132.0 - 133.0°C Anal : C a l c d . f o r C 2 7 H 4 2 N 2 ° 4 : C ' 7 0 - 7 0 ' * H ' 9 - 2 3 " N ' 6.11. Found : C, 7 0.4 0; H, 9.22; N, 6.04. 1H NMR : ( 6 , CDC1 3) : 1.12 - 1.60 (m, 14H, c h a i n 2'-, 3'-, 4'-, 5'-, 6'-, 7'-, 8'-CH 2), 1.29 ( t , 6H,-0-CH 2CH 3), 2.14 (s, 6H, 2-CH 3), 2.22 (a, 6H, 4-CH 3), 2.18-2.48 (m, 4H, c h a i n l ' - C H 2 and 9'CH 2), 4.26 (q, 4H, J=7 Hz, O-CH 2-CH 3), 8.77 (bs, NH). 1 3 C NMR : ( 6 , CDC1 3) : 162.04 (C=0), 129.75 ( p y r r o l e 2-C), 127.00 ( p y r r o l e 4-C), 122.37 ( p y r r o l e 3-C), 116.78 ( p y r r o l e 5-C), 59.55 (-OCH_2CH3), 30.90 (chain 2 '-C and 8'-C), 29.61 (chain 3'-C, 4"-C, 5'-C, 6'-C, 7'-C), 24.06 (chain 1 1-C and 9'-C), 14.59 (-0-CH 2-CH 3), 11.43 (2-CH 3>, 10.66 (4-CH 3). Mass spectrum : R e l a t i v e m/e I n t e n s i t y (%) Assignment 458 61 M + 412 87 (M-CH 3CH 2OH) + 134 86 216 3.6.3 B I S PYRROLE BENZYL ESTERS 90 1 , l l - B i s ( 5 - b e n z 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 ) -u n d e c a n e ( n = l l ) 90a 1 , l l - B i s ( 5 - e t h o x y c a r b o n y l - 2 , 4 - d i m e t h y l p y r r o l - 3 - y l ) -u n d e c a n e 89a (24 g , 4 9.4 mmol) and r e d i s t i l l e d b e n z y l a l c o h o l (125 mL) were h e a t e d u n d e r n i t r o g e n , w i t h m a g n e t i c s t i r r i n g , i n a 500 mL e r l e n m e y e r f l a s k . When t h e b e n z y l a l c o h o l r e a c h e d r e f l u x t e m p e r a t u r e , a c o n c e n t r a t e d s o l u t i o n o f s o d i u m i n b e n z y l a l c o h o l was a d d e d , i n 1 mL p o r t i o n s w h i l e m a i n t a i n i n g a s t e a d y f l o w o f n i t r o g e n . E t h a n o l v a p o u r s w ere l i b e r a t e d w i t h a s i m u l t a n e o u s d r o p i n t h e r e f l u x t e m p e r a t u r e . A f t e r t h e a d d i t -i o n o f 3 mL o f c a t a l y s t , no e f f e r v e s c e n c e c o u l d be o b s e r v e d and t h e r e a c t i o n was c o m p l e t e . The h o t s o l u t i o n was p o u r e d i n t o a c e t i c a c i d (20 mL) i n m e t h a n o l (500 mL) t o q u e n c h t h e c a t a l y s t and t h e r e a c t i o n f l a s k was washed w i t h b e n z y l a l c o h o l . W a t e r was a d d e d s l o w l y , u n t i l t h e i n i t i a l s o l i d was o b s e r v e d and t h e n a l l o w e d t o s t i r f o r " 5 m i n c a u s i n g t h e p r e c i p i t a t e t o t h i c k e n . - - M o r e w a t e r 217 was added, s t i r r e d f o r 5 minutes and the product was c o l l e c t e d by f i l t r a t i o n (the s o l i d was pa l e pink i n c o l o r and was observed to darken with time, p r i o r to f i l t r a t i o n ) . The d i b e n z y l e s t e r , washed with 50% methanol-water and a i r d r i e d , weighed, 28.4 g. (94.3%) . T h i s r e a c t i o n was repeated with 23 g. of the e t h y l e s t e r 89a to y i e l d 89.3% of the d i b e n z y l e s t e r . An a n a l y t i c a l sample was r e c r y s t a l l i z e d from tetrahydrofuran-methanol. MP : 108.5 - 110.5°C Moi .Wt.- C a l c d . 'for C 3 9 H 5 0 N 2 O 4 : 6 1 0 .37-71; .Found"-by h i g h r r -r e s o l u t i o n mass spectrometry : 610.3790 Anal .-Calcd.. f o r . C 3 9 H 5 Q N 2 0 4 : C, 76.69; H, 8.25; N, 4.59, Found : C, 76.61; H, 8.29; N, 4.69. 1H NMR (6, CDC1 3) : 1.27 (br, 18H, c h a i n 2'-, 3'-, 4'-, 5'-, 6'-, 7'-, 8'-, 9'-, 10'-CH 2), 2.18 (s, 6H, 2-CH 3), 2.29 (s, 6H, 4-CH 3), 2.20-2.52 (m, 4H, c h a i n 1 1-CH 2 and l l ' - C B ^ ) , 5.31 (s, 4H, O-CH -C,H ), 7.22-7.56 (m, 10H, C,H C), 8.67 (bs, NH). —z b 5 D—~> -• 1 3 C NMR (6, CDC1 3) : 161.68 (C=0), 136.77 (benzene C - l ) , 130.37 ( p y r r o l e 2-C), 128.46, 127.91 (benzene r i n g ) , 127.52 ( p y r r o l e 4-C), 122.50 ( p y r r o l e 3-C), 116.37 ( p y r r o l e 5-C), 65.30 (-OCH_C,Hc) , 30.85 (chain 2 1-C and l O ' - C ) , 29.61 (chain — Z o o 3'-C, 4'-C, 5'-C, 6'-C, 7'-C, 8'-C, 9'-C), 24.02 (chain 1'-C and l l ' - C ) , 11.37 (2-CH 3), 10.84 (4-CH 3). 218 Mass s p e c t r u m : R e l a t i v e m/e I n t e n s i t y (%) A s s i g n m e n t 610 37 M + 502 22 ( M - C 6 H 5 C H 2 O H ) + 242 19 H 0 108 22 ( C 6 H 5 C H 2 O H ) + 91 100 C 7 H 7 + — (v'max K B r ) : 3 3 2 0 ( N - H ) ' 1 6 7 0 ( C = 0 ) c m 1 1 , 1 0 - B i s ( 5 - b e n z 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 ) - D e c a n e (n=10) 90b The e t h y l e s t e r 8 9b ( 2 4 . 0 g , 50.8 mmol) was t r a n s -b e n z y l a t e d i n r e d i s t i l l e d b e n z y l a l c o h o l (125ml) i n t h e manner d e s c r i b e d p r e v i o u s l y . The y i e l d o f t h e b i s b e n z y l e s t e r 90b was 28.9 g ( 9 5 . 4 % ) . An a n a l y t i c a l s a m p l e was r e c r y s t a l l i z e d f r o m t e t r a h y d r o f u r a n - m e t h a n o l . 219 MP 142.5-144.0 C An a l . Calc.d.- f o r C 3 8 H 4 8 N 2 0 4 : C ' 76.48; H, 8.11; N, 4.69; Found :C,76.59;H, 8.30;N,'4.60. 1H NMR-, (6, CDC1 3) : 1.27 (br, 16H, c h a i n 2'-, 3'-, 4'-, 5'-, 6'-, 7'-, 8'-, 9'-CH ), 2.17 (s , 6H, 2-CH ), 2.29 (s , 6H, ^ 3 4-CH 3), 2.18-2.55 (m, 4H, c h a i n 1'-CH 2 and 10'-CH 2), 5.31 (S, 4H, ) , 7 .25-7.55 (m, 10H, CrHc.) , 8.63 (bs,-NH). —Z O D D—D 1 3 C NMR (6, CDC1-J : 161.53 (C=0), 136.83 (benzene 1-C), 130.05 ( p y r r o l e 2 - c ) , 128.49, 128 .01 (benzene r i n g ) , 127.64 ( p y r r o l e 4-C) , 122.57 ( p y r r o l e 3 - c ), 116.41 ( p y r r o l e 5-C), 65.37 (-OCH„C,H c), — Z O 3 30.88 (chain 2 ' - c and 9'-C), 29.61 (chain 3'-C, 4'-C, 5'-C, 6'-C, 7'-C, 8'-C), 24.04 (chain 1'-C and lO'- C ) , 11.48 (2-CH 3), 10.78 (4-CH 3). Mass spectrum R e l a t i v e m/e I n t e n s i t y (%) Assignment 596 43 M + 488 29 (M-C 6H 5CH 2OH) + 24 2 21 i ^CH3 H 0 108 27 (C cH cCH o0H) + D D Z 91 100 C 7 H 7 + 220 1-9-Bis(5-benzyloxycarbonyl-2,4-dimethylpyrrol-3-yl)-nonane (n=9) 90c The b i s e t h y l e s t e r 8 9c (16.0 g, 34.9 mmol) was t r a n s e s t e r i f i e d i n benzyl a l c o h o l (120 mL) as d e s c r i b e d f o r the undecane analogue. The y i e l d of the b i s b e n z y l e s t e r was 18.0 g, (88.7%). T h i s r e a c t i o n was repeated with 55.0 g of the s t a r t i n g m a t e r i a l and 2 50 mL be n z y l a l c o h o l to g i v e 65.7 g (94.0%) of the t r a n s e s t e r i f i e d product. MP : 120-121. 5°C y _ • .. A n a l . C a l c d . f o r C 3 7 H 4 6 N 2 0 4 : c> 7 6 - 2 6 ; H, 7.96; N, 4.81. Found : C, 7 6.18; H, 7.99; N, 4.79. XE NMR (<5, CDC1 3) : 1.28 (br, 14H, c h a i n 2'-, 3'-, 4'-, 5'-, 6'-, 7'-, 8 :-CH 2), 2.18 (s, 6H, 2-CH 3), 2.29 (s, 6H, 4-CH 3), 2.24-2.50 (m, 4H, c h a i n l ' ~ C H 2 and 9'-CH 2), 5.31 (s, 4H, 0-CH--C.HJ , 7.28-7.52 (m, 10H, C e H c ) f 8.62 (bs, NH). 1 3 C NMR (6, CDC1 3) : 161.57 (C=0), 136.85 (benzene 1-C), 130.16 ( p y r r o l e 2-C), 128.49, 127.93 (benzene r i n g ) , 127.61 ( p y r r o l e 4-C), 122.52 ( p y r r o l e 3-C), 116.39 ( p y r r o l e 5-C), 65.33 (0-CH 2C 6H 5), 30.84 (chain 2'-C and 8'-C), 29.53 (chain 3'-C, 4 1-C, 5'-C, 6'-C, 7'-C), 24.03 (chain 1 1-C and 9'-C), 11.44 (2-CH 3), 10.77 (4-CH 3). Mass spectrum R e l a t i v e m/e I n t e n s i t y Assignment 582 39 M + 474 27 (M-C 6H 5CH 2OH) 24 2 22 H j t x / C H 3 H 0 108 26 (C 6H 5CH 2OH) + 91 100 C 7 H 7 + 222 1 , l l - B i s ( 5 - f o r m y l - 2 , 4 - d i m e t h y l p y r r o l - 3 - y l ) u n d e c a n e (n=ll) 93a The p r e p a r a t i o n of t h i s compound, s t a r t i n g from the b i s benzyl e s t e r 90a i n v o l v e d , ( i ) t h e h y d r o g e n o l y s i s of the benzyl e s t e r to produce the b i s - c a r b o x y p y r r o l e 9 1 a , ( i i ) t h e thermal d e c a r b o x y l a t i o n of the above product a n d ( i i i ) t h e V i l s m e i e r f o r m y l a t i o n of the r e s u l t i n g b i s - a - f r e e p y r r o l e 92a. The i n t e r m e d i a t e compounds 91a and 92a were not i s o l a t e d . The i d e a l experimental c o n d i t i o n s f o r these r e a c t i o n s are des-c r i b e d i n the p r e p a r a t i o n of the nonane analogue 93c. The crude dialdehyde i s not r e a d i l y p u r i f i e d by chromatographic techniques whereas i t s d i c y a n o v i n y l d e r i v a t i v e , with a much higher r ^ value i s e a s i l y p u r i f i e d . There- ••• f o r e the e n t i r e sample of 93a was converted to the b i s d i c y a n o v i n y l p y r r o l e 94a. For c h a r a c t e r i z a t i o n purposes, a sample of pure 94a was deprotected i n aqueous potassium hydroxide u s i n g a n-propanol to s o l u b i l i z e the s t a r t i n g m a t e r i a l , y i e l d 98%. The b i s f o r m y l p y r r o l e 93a prepared i n t h i s manner was a n a l y t i c a l l y pure. MP : 133.5 - 135.0°C M o l . W t . C a l c d . f o r C 2 5 H 3 8 N 2 ° 2 : 3 9 8 - 2 9 3 3 ; Found, by high r e s o l u t i o n mass spectrometry : 398.2934 An a l . C a l c d . f o r C ^ H ^ N ^ : C, 75.33; H, 9.61; N, 7.03; Found : C, 75.27; H, 9.88; N, 7.20. 223 1H NMR. , (6, CDC1 3) : 1.26 (br, 18H, ch a i n 2'-, 3'-, 4'-, 5'-, 6'-, 7'-, 8'-, 9'-, 10'-CH 2), 2.27 (a, 12H, 2-CH 3 and 4-CH 3), 2.27 - 2.49 (m, 4H, c h a i n 1'-CH2 and l l ' - C B ^ ) , 9.50 (s, 2H, HCO), 9.84 (bs, 2H, NH). 1 3 C NMR - (6, CDC1 3) : 175.52 (C=0), 136.74 ( p y r r o l e 2-C), 132.71 ( p y r r o l e 4-C), 127.87 ( p y r r o l e 5-C), 123.44 ( p y r r o l e 3-C), 30.61 (chain. 2 1-C and l O ' - C ) , 29.59 (chain 3'-C, 4'-C, 5'-C, 6'-C, 7'-C, 8'-C, 9'-C), 23.76 (chain 1'-C and l l ' - C ) , 11,61 (2-CH 3), 8.87 (4-CH 3). Mass spectrum R e l a t i v e m/e I n t e n s i t y (%) Assignment 398 22 M + 370 23 (M-CO) + 108 IR (v• , KBr) : 3240 (N-H), 1640 (C=0) cm 2 2 4 1,10-Bis(5-formyT-2,4-dimethylpyrrol-3-yl)decane (n=10) 93b 1,10-Bis(5-benzyloxycarbonyl-2,4-dimethylpyrrol-3-y l ) decane 9Ob was converted to the dialdehyde 93b i n the manner d e s c r i b e d f o r the nonane analogue. An a n a l y t i c a l sample was prepared by the d e p r o t e c t i o n of the pure b i s d i c y -a n o v i n y l p y r r o l e 94b i n aqueous potassium hydroxide. MP ' : 170.0 - 170. 5°C Moi. Wt. C a l c d i , f o r C 2 4 H 3 6 N 2 ° 2 : 3 8 4 • 2 7 7 7 " Found, by high r e s o l u t i o n mass spectrometry : 384.2773 •Anal. •. Caleck- ' f o r C 2 4 H 3 6 N 2 ° 2 : C , 74.96; H, 9.44; N, 7.28; Found : C, 74.66; H, 9.57; N, 7.15. 1H NMR ; (6, CDC1 3) : 1.27 (br, 16H, c h a i n 2'-, 3'-, 4'-, 5'-, 6'-, 7'-, 8'-, 9'-CH 2), 2.20 (s, 12H, 2-CH 3 and 4-CH 3), 2.26 - 2.48 (m, 4H, cha i n 1'-CH2 and 10'-CH 2), 9.44 (s, 2H, HC=0), 9.98 (bs, 2H, NH). 1 3 C NMR ••• (<5, CDC1 3) : 175.53 (C=0) , 136.51 ( p y r r o l e 2-C), 132.63 ( p y r r o l e 4-C), 127.88 ( p y r r o l e 5-C), 123.46 ( p y r r o l e 3-C), 30.60 (chain 2'-C and 9'-C), 29.58 (chain 3'-C , 4'-C , 5 ' -C , 6'-C, 7'-C, 8'-C), 23.77 (chain 1'-C and lO ' - C ) , 11.63 (2-CH 3), 8 . 87 (4-CH-,) . 225 Mass s p e c t r u m R e l a t i v e m/e I n t e n s i t y (%) A s s i g n m e n t 384 29 M + 356 31 (M-CO) + 136 100 V x / " 3 3 H Q 108 70 H j C 1,9-Bis(5-£ormyl-2,4-dimethylpyrrol-3-yl)nonane (n=9) 93c ( i ) D e b e n z y l a t i o n 1 , 9 - B i s ( 5 - b e n z 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 ) nonane 90c (20.0 g, 34.4 mmol) and 10% p a l l a d i u m on c h a r c o a l (1.5 g) were s t i r r e d o v e r n i g h t u n d e r h y d r o g e n (1 a t m o s p h e r e ) i n t e t r a h y d r o f u r a n (150 mL) c o n t a i n i n g 5 d r o p s o f t r i e t h y l a m i n e . When t h e u p t a k e o f h y d r o g e n c e a s e d , t h e c a t a l y s t was f i l t e r e d t h r o u g h a c e l i t e p l u g and t h e s o l u t i o n c h e c k e d by t i c f o r a n y u n c o n v e r t e d s t a r t i n g m a t e r i a l . The s o l v e n t was e v a p o r a t e d o f f , i n v a c u o , l e a v i n g t h e b i s c a r b o x y -226 p y r r o l e 91c as a p a l e yellow s o l i d . The crude product was used, as i s , i n the next r e a c t i o n . ( i i ) D e c a r b o x y l a t i o n . The crude b i s - c a r b o x y p y r r o l e prepared above was d i s s o l v e d i n dimethylformamide (15 0 mL) and p l a c e d i n a 5 00 mL erlenmeyer f l a s k f i t t e d with a C l a i s e n adapter and a n i t r o g e n i n l e t . A drop of t h i s s o l u t i o n was d i l u t e d with methylene c h l o r i d e and a uv a b s o r p t i o n spectrum was recorded, showing a s i n g l e a b s o r p t i o n band a t A 286 nm. The d i m e t h y l -formamide s o l u t i o n was heated a t i t s r e f l u x temperature (153°C) (the s o l u t i o n turned dark brown) and every 0.5 h, a drop was removed i n t o methylene c h l o r i d e and the uv spectrum recorded. The a b s o r p t i o n band a t A-28 6 nm. was reduced to j u s t a shoulder i n two hours but a f u r t h e r h a l f hour of h e a t i n g d i d not remove t h i s completely. The s o l u t i o n was c o o l e d i n i c e and used i n the next r e a c t i o n . ( i i i ) V i l s m e i e r f o r m y l a t i o n . To an i c e - c o o l e d s o l u t i o n of dimethylformamide (40 mL) i n dry methylene c h l o r i d e (150 mL), phosphorous o x y c h l o r i d e (35 mL) was added and m a g n e t i c a l l y s t i r r e d . The V i l s m e i e r reagent prepared thus, was t r e a t e d , r a p i d l y and dropwise, w i t h the c h i l l e d dimethylformamide s o l u t i o n of the b i s a - f r e e p y r r o l e 92c prepared above. Once the a d d i t i o n was complete, the s o l u t i o n was s t i r r e d f o r a f u r t h e r h a l f 227 hour to ensure the completion of the r e a c t i o n . The methylene c h l o r i d e was removed by e v a p o r a t i o n under reduced pressure and the s o l u t i o n was poured onto crushed i c e (500 g . ) . S o l i d sodium b i c a r b o n a t e was added, c a r e f u l l y , w i t h s t i r r i n g , u n t i l the s o l u t i o n was weakly b a s i c to pH-paper and then heated on the steam bath (the s o l u t i o n became a c i d i c again and more b i c a r b o n a t e had to be added). A dark brown phase separated out a t the bottom, c o n t a i n i n g the product, i n dimethylformamide and unremoved methylene c h l o r i d e . Heating was continued on the steam bath and as the methylene c h l o r i d e evaporated o f f , a c l e a r brown s o l u t i o n (one "phase) was" obtained . The hot s o l u t i o n was f i l t e r e d to remove a few brown p a r t i c l e s , the volume a d j u s t e d to 14 00 mL with water and r e -heated on the steam bath. When the temperature reached 7 5°C, the s o l u t i o n turned t u r b i d and a grey c o l o r e d s o l i d separated out. The h e a t i n g was continued f o r a f u r t h e r 3 0 min, the s o l i d was f i l t e r e d and washed with water. The crude product 93c was d r i e d i n a i r over s e v e r a l days to g i v e 11.8 g. (93%) . In s e v e r a l p r e p a r a t i o n s , the y i e l d s of the crude product were between 90-100%. The e n t i r e sample of the crude s o l i d was used f o r the next r e a c t i o n , the p r o t e c t i o n of the aldehyde as the d i c y a n o v i n y l d e r i v a t i v e . An a n a l y t i c a l sample was prepared by the d e p r o t e c t i o n of the pure b i s -d i c y a n o v i n y l p y r r o l e 94c i n aqueous potassium hydroxide. 228 MP : 165.0 - 165.5°C Moi. Wt. C a l c d . f o r C 2 3 H 3 4 N 2 0 2 : 370.2620; Found, by high r e s o l u t i o n mass spectrometry : 37 0.2625 A n a l . •-. C a l c d ; f o r C ^ H ^ N ^ : C, 74.56; H, 9.25; N, 7.56; Found : C, 74.57; H, 9.21; N, 7.64. 1E NMR (6, CDC1 3) : 1.26 (br, 14H, c h a i n 2'-, 3'-, 4'-, 5'-, 6'-, 7'-, 8'-CH ), 2.21 (s, 12H, 2-CH 3 and 4-CH 3), 2.22 -2.42 (m, 4H, c h a i n 1'-CH 2 and 9'-CH 2), 9.38 (s, 2H, HC=0), 9.96 (bs, 2H, NH). 1 3 C NMR (5, CDC1 3) : 175.52 (C=0), 136.61 ( p y r r o l e 2-C), 132.60 ( p y r r o l e 4-C), 127.89 ( p y r r o l e 5-C), 123.43 • ( p y r r o l e 3-C), 3 0.58 (chain 2'-C and 8'-C), 29.51 (chain 3'-, 4'-, 5'-, 6'-, 7'-C), 23.74 (chain 1'-C and 9'-C), 11.60 (2-CH 3), 8.86 (4-CH 3). Mass spectrum : R e l a t i v e m/e I n t e n s i t y (%) 370 26 342 25 Assignment M + (M-CO) + m/e R e l a t i v e I n t e n s i t y (%) Assignment 229 108 73 T i 1 , 8 - B i s ( 5 - f o r m y l - 2 , 4 - d i m e t h y l p y r r o l - 3 - y l ) o c t a n e (n=8) 93d 1, 8 - B i s ( 5 - b e n z 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 ) octane.90d used as the s t a r t i n g m a t e r i a l was k i n d l y p r o v i d e d by Dr. J.B. Paine I I I . The r e a c t i o n s were c a r r i e d out as d e s c r i b e d f o r the nonane analogue. MP : 185.5 - 187.0°C Moi. Wt. ••Calcd. - f o r C 2 2 H 3 2 N 2 ° 2 : 3 5 6 * 2 4 6 4 '* F o u n d '  hY high r e s o l u t i o n mass spectrometry : 356.2463. Anal. -.-Calcd.;. f o r C 2 2 H 3 2 N 2 0 2 : C, 74.12; H, 9.05; N, 7.86; Found : C, 74 . 22 ; H, 9.23; N, 7.90. 230 "'"H NMR (6, CDC1 3) : 1.30 (br, 12H, c h a i n 2'-, 3'-, 4'-, 5'-, 6'-, 7'-CH 2), 2.22, 2.24 (s, s, 12H, 2-CH 3 and 4-CH 3), 2.22-2.42 (m, 4H, c h a i n 1'-CH9 and 8'-CH^), 9.48 (s, 2H, HC=0), 9.90 (bs, 2H, NH). 13C NMR ; (6, CDC1 3) : 175.56 (C=0), 136.55 ( p y r r o l e 2-C), 132.58 ( p y r r o l e 4-C), 127.96 ( p y r r o l e 5-C), 123.38 ( p y r r o l e 3-C) 30.57 (chain 2'-C and 7'-C), 29.51, 29.35 (chain 3'-C, 4'-C, 5'-6'-C), 23.76 (chain 1'-C and 8'-C), 11.61 (2-CH 3), 8.89 (4-CH 3>. Mass spectrum : R e l a t i v e m/e I n t e n s i t y (%) Assignment 356 43 M + 328 32 (M-CO) + 136 100 H 2 C N _ ^ C H 3 108 57 HX CH3 Il \ H 2 3 1 3.6.5. BIS CYANOVINYLPYRROLES l , l l - B i s [ 5 - ( 2 , 2 - d i c y a n o v i n y l ) - 2 , 4 - d i m e t h y l p y r r o l - 3 - y l ] undecane (n=ll) 94a The crude b i s f o r m y l p y r r o l e 93a was converted to i t s b i s d i c y a n o v i n y l d e r i v a t i v e by h e a t i n g w i t h m a l o n o n i t r i l e and * t r i e t h y l a m i n e i n methanol-methylene c h l o r i d e . " In s e v e r a l p r e p a r a t i o n s , the o v e r a l l y i e l d s (from the b i s b e n z y l e s t e r 90a) of the p u r i f i e d product v a r i e d between 4 0% and 67%. The y i e l d was found t o be dependent p r i m a r i l y on the p u r i t y of the b i s formypyrrole 93a. The optimum r e a c t i o n c o n d i t i o n s are d e s c r i b e d f o r the s y n t h e s i s of the decane analogue. * Toluene was subsequently found-to be a b e t t e r s o l v e n t f o r t h i s r e a c t i o n . At the r e f l u x temperature, toluene d i d no't cause the premature c r y s t a l l i z a t i o n o f the monoprotected d e r i v a t i v e . MP : 153.0 - 154.5°C 232 MoT.Wt. -caicd... for C^H^Ng : 494.3158 : Found, by high resolution mass spectrometry : 494.3167. Anal. .Calcd: for C 3 1 H 3 8 N 6 : c> 75.27; H, 7.74; N, 16.98; Found : C, 75.28; H, 7.46; N, 16.80. 1H NMR ; (6, CDC13) : 1.24 (br, 18H, chain 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-CH2);f 2.10 (s , 6H, 4-CH ), 2.27 (s , 6H, 2-CH 3), 2.27-2.47 (m, 4H, chain, 1-CH2 and 11-CH 2), 7.27 [s, 2H, C(H)=C(CN) 2], 9.35 (bs, 2H, NH). 1 3 C NMR ;: (6, CDC13) : 141.37 (pyrrole 2-C) , 140.48 •[ C(H)=C (CN) '] , 136.44 (pyrrole 4-C) , 125.82 (pyrrole 3-C) , 124.14 (pyrrole 5-C), 117.64 (C=N), 116.26 (C=N), 62.51 [CH=C(CN) 2], 30.25 (chain 2-C and 10-C), 29.59 (chain 3-C, 4-C , v5-C, 6-C, 7-C, 8-C, 9-C) , 23.92 (chain 1-C and 11-C) , 12.56 (2-CH 3), 9.64 (4-CH3>. Mass spectrum: Relative m/e Intensity (%) Assignment 495 24 (M+H)+ 494 68 M + 184 100 233 — : (vmax K B r ) : 3200-3600. (broad, N-H), 2205 (C=N), 1595 (C=C) CM - 1. 1,10-Bisr 5-(2,2-dicyanovinyl)-2,4-dimethylpyrrol-3-yl]decane (n=10) '94b The crude 1,10-bis(5-formyl-2,4-dimethylpyrrol-3-yl) decane (5.01 g, 13.0 mmol) was dissolved i n methylene chloride (100 mL) and methanol (20 mL), by heating on a steam bath;cand the volume was reduced to approximately 50 mL. The solution was cooled, malononitrile (2.0 g, 3 0.3 mmol), triethylamine (1 mL) and more methanol (250 mL) were added and reheated on the steam bath with occasional swirling. I t was possible to monitor the reaction by t i c , since the mono and bis-dicyanovinyl derivatives were e a s i l y distinguished from each other as well as from the s t a r t i n g material. In 2% methanol-methylene chloride, the bis-protected derivative had an r f of 0.65-0.70, the mono-protected, an r ^ of 0.4 0-0.45 and the s t a r t i n g material, an r f of 0.10-0.20. The solution was boiled down to approximately 100 mL and cooled to room temperature when a yellow-brown s o l i d c r y s t a l l i z e d out. This was c o l l e c t e d by f i l t r a t i o n and washed with methanol, y i e l d 5.05 g. The mother liquors were concentrated on the steam bath and cooled to give an 234 additional 0.45 g. The combined crude product (5.5 g) was dissolved i n methylene chloride (150 mL) and chromatographed on s i l i c a gel (45 g, a c t i v i t y I) using methylene chloride as the eluting solvent. The dark colored impurities remained at the o r i g i n and the pure bis dicyanovinyl derivative eluted out as a yellow solution. The product was c r y s t a l l i z e d by evaporating the methylene chloride, i n vacuo, aft e r the addition of methanol. The lemon yellow s o l i d thus obtained, was a n a l y t i c a l l y pure, y i e l d , 4.59 g •: (73.3% from the crude bis aldehyde; 70.2% from the bis';:benzyl e s t e r ) . MP : 186.0 - 186.5°C Anal. Calcd.. for C 3 0 H 3 6 N 6 : C, 74.97; H, 7.56; N, 17.48. Found : C, 74.76; H, 7.57; N, 17.46. 1H NMR : (6, CDC13) : 1.28 (br, 16H, chain 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-CH2), 2.15 (s , 6H, 4-CH3), 2.33 (a, 6H, 2-CH 3), 2.26-2.50 (m, 4H, chain 1-CH2 and 10-CH 2), 7.34 [a, 2H, C(H)=C(CN) 2], 9.56 (bs, 2H, NH). 1 3 C NMR ( (6, CDC13) : 141.25 (pyrrole 2-C), 140.48 C(H)=C(CN) 2 , 136.38 (pyrrole 4-C), 125.79 (pyrrole 3-C), 124.11 (pyrrole 5-C), 117.61 (G=N), 116.18 (C=N) , 62.62 [C(H)=C(CN) 2] / 30.27 (chain 2-C and 9-C) , 29.61, .29.49 (chain 3-C, 4-C, 5-C, 6-C, 7-C, 8-C), 23.93 (chain 1-C and 10-C), 12.56 (2-CH 3), 9.64 (4-CH 3). 235 Mass spectrum : R e l a t i v e m/e I n t e n s i t y Assignment 481 22 (M+H) + 480 65 M + 184 100 H # . // W NC' "CN 1 , 9 - B i s [ 5 - ( 2 , 2 - d i c y a n o v i n y l ) - 2 , 4 - d i m e t h y l p y r r o l - 3 - y l ] n o n a n e (n=9) 94c The crude dialdehyde 93c was converted to the corresponding b i s d i c y a n o v i n y l d e r i v a t i v e 94c i n the manner d e s c r i b e d f o r the decane analogue. In three attempts, o v e r a l l y i e l d s of 55.8%, 67.1% and 68.6% (from the b i s benzyl e s t e r ) of the p u r i f i e d product were obtained. MP : 182.0-182.5°C : ( c r y s t a l l i n e form changed at 169°C) Anal. C a l c d . .- f o r C ^ H ^ N g : C, 74.65; H, 7.34; N, 18.01; Found : C, 74.87; H, 7.33; N, 18.05. 236 1H NMR (6, CDC13) : 1.29 (br, 14H, chain 2-, 3-, 4-, 5-, 6-, 7-, 8-CH2), 2.15 (s, 6H, 4-CH3), 2.33 (s, 6H, 2-CH 3), 2.26-2.52 (m, 4H, chain, 1-CH2 and 9-CH2), 7.35 [s, 2H, C(H)=C(CN) 2], 9.36 (bs, 2H, NH). 1 3 C NMR (6, CDC13) : I'41.31 (pyrrole 2-C), 140.49 [C(H)=C(CN) 2], 136.36 (pyrrole 4-C), 125.82 (pyrrole 3-C), 124.14 (pyrrole 5-C), 117.54 (C=N), 116.18 (G=N), 62.55 [C(H)=C(CN) 2] , 30.24 (chain, 2-C and 8-C), 29.47 (chain, 3-C, 4-C, 5-C, 6-C, 7-C), 23.93 (chain, 1-C and 9-C), 12.51 (2-CH 3), 9.64 (4-CH 3). Mass spectrum : m/e 467 466 Intensity (%) 27 71 Assignment (M+H) + M + 184 100 CH, NC CN 1,8-Bis[ 5- (2 , 2-dicyanovinyl) -2 ,4-dimethylpyrrol-3-yl] octane (n=8) 94d The crude dialdehyde 93d (6.03 g. 16.9 mmol) was 237 r e a c t e d with m a l o n o n i t r i l e (2.57 g, 38.9 mmol) i n the presence of t r i e t h y l a m i n e a c c o r d i n g to 'the procedure given f o r the decane analogue. The crude b i s - d i c y a n o v i n y l d e r i v a t i v e o b tained (7.0 g. i n two crops) was d i s s o l v e d i n methylene c h l o r i d e (250 mL) and chromatographed on s i l i c a g e l (80 g . a c t i v i t y I) to g i v e 5.38 g (65.7% o v e r a l l y i e l d from the b i s benzyl e s t e r ) of the a n a l y t i c a l l y pure product. MP : 216.5 - 217.5°C An a l . C a l c d ; f o r C^gH^Ng : C, 74.31; H, 7.13; N, 18.57. Found : C, 74.41; H, 7.00; N, 18.65. NMR ' (6, CDC1 3) : 1.30 (br, 12H, c h a i n 2-, 3-, 4-, 5-, 6-, 7-CH 2), 2.15 (s, 6H, 4-CH 3), 2.33 (s, 6H, 2-CH 3), 2.30-2.50 (m, 4H, c h a i n 1-CH 2 and 8-CH 2), 7.36[s , 2H, C(H)=C(CN) 2] , 9.36 (bs, 2H, NH) . 13 C NMR (6,.10% TFA-CDC1 3) : 145.85 ( p y r r o l e 2-C), 140.49 [C(H)=C(CN) ] , 139.19 ( p y r r o l e 4-C), 127.29 ( p y r r o l e 3-C), 125.22 ( p y r r o l e 5-C) , 117.12 (C^N) , 116.21 (C*=N) , 57.97 [C(H)=C(CN) ] , 30.26 (chain 2-C and 7-C), 29.61 (chain 3-C, 4-C, 5-C, 6-C), 24.03 (chain 1-C and 8-C), 12.57 (2-CH 3), 9.80 (4-CH 3). 238 Mass spectrum : R e l a t i v e m/e I n t e n s i t y (%) Assignment 453 21 (M+H)+ 452 66 M + 1 ,T1-Bis[5 - (2-cyano-2-methoxycarbonylvinyl)-2,4-dimethylpyrrol-3-yl] undecane 115 1,1 1 - B i s ( 5 - b e n z 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-yl) undecane 90a (9.5 g. 15.6 mmol) was i n i t i a l l y converted to the b i s f o r m y l p y r r o l e 93a i n the manner d e s c r i b e d p r e v i o u s l y . The e n t i r e sample of t h i s crude s o l i d was taken up i n toluene (260 mL) with methyl cyanoacetate (3.2 g. 36.8 mmol) and cyclohexylamine (3 mL) and heated a t r e f l u x on a s t i r r e r - h o t p l a t e . The r e a c t i o n was monitored by t i c and was found to be complete i n approximately 2 h. The s o l v e n t was evaporated, i n vacuo, the r e s i d u e taken up i n methylene c h l o r i d e and the s o l u t i o n allowed to stand o v e r n i g h t a f t e r adding methanol. The product was i s o l a t e d by f i l t r a t i o n and a second crop obtained by c o n c e n t r a t i n g the mother l i q u o r s . The t o t a l crude product (7.6 g) was d i s s o l v e d i n methylene c h l o r i d e (100 mL) and chromatographed on s i l i c a g e l (100 g, a c t i v i t y . I ) . The i m p u r i t i e s were adsorbed on the column and the product e l u t e d out, c l e a n , w i t h methylene c h l o r i d e as the s o l v e n t . The s o l v e n t p o l a r i t y was g r a d u a l l y i n c r e a s e d , f i r s t with 0.5% and then with 1% e t h y l a c e t a t e to f a c i l i t a t e e l u t i o n without c a u s i n g the i m p u r i t i e s t o move. The product was c r y s t a l l i z e d from the chromatographed s o l u t i o n by c o n c e n t r a t i n g i n the presence of methanol, y i e l d 6.6 g (75.9% o v e r a l l from the b i s be n z y l e s t e r 90a). The b r i g h t y e l l o w powdery s o l i d o b t a i n e d was a n a l y t i c a l l y pure. MP : 158.0 - 159.5°C " -A n a l . Calcd-. f o r C H ^ N ^ : C, 7 0 . 6 9 ; H, 7 . 9 1 ; N , 9 . 9 9 . Found : C, 7 0 . 4 4 ; H, 8 . 0 6 ; N , 9 . 8 0 . NMR '• (6, CDC1 3) : 1.28 (br, 18H, c h a i n 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-CH 2) , 2.19 (s , 6H, 4-CH3) , 2.32 (s , 6H, 2-CH3) , 2.26-2.50 (m, 4H, c h a i n 1-CR"2 and 11-CH 2), 3.88 (s, 6H, -QCH3) , 7.95 [5, 2H, C (H) =C (CN) 2] , 9.51 (bs, 2H, NH) . 1 3 C NMR (6,, CDCL 3) : 165.15 (C=0) , 139.16 ( p y r r o l e 2-C) 135.62 ( p y r r o l e 4-C), 125.01 ( p y r r o l e 3-C), 123.46 ( p y r r o l e 5-C) 120.29 (C=?N) , 84.85 (CH=C (CN) C0 2CH 3) , 52.38 (0-CH 3), 30.41 (chain 2-C and 10-C) , 29.54 (chain 3-C, 4-C, 5-C, 6-C, 7-C, 8-C, 9-C), 24.01 (chain 1-C and 11-C), 12.38 (2-CH 3), 9.66 (4-CH 3). Mass spectrum m/e 560 528 496 R e l a t i v e I n t e n s i t y (%) 39 11 16 Assignment M + (M-CH 3OH) + (M-2 CH 3OH) H 217 89 OCH , 185 100 CN 241 3.7 SYNTHESES OF CHAIN LINKED DIPYRROMETHANE DIMERS 1, T 1 - B i s { 5 - ( 2 , 2 - d i c y a n o v i n y l ) - 2 - [ ( 5 - e t h o x y c a r b o n y l - 3 - e t h y l -4 - m e t h y l p y r r o l - 2 - y l ) m e t h y l ] - 4 - m e t h y l p y r r o l - 3 - y l > undecane (n=ll) 96a (i) M o n o c h l o r i n a t i o n of the a-methyl groups. 1,11-Bis [ 5 - ( 2 , 2 - d i c y a n o v i n y l ) - 2 , 4 - d i m e t h y l p y r r o l - 3 -yl]undecane 94a (2.05 g, 4.15 mmol), d i s s o l v e d i n dry methylene c h l o r i d e (80 mL), was s t i r r e d on a magnetic s t i r r e r / h o t p l a t e i n an erlenmeyer f l a s k , and t r e a t e d dropwise with a s o l u t i o n of s u l f u r y l c h l o r i d e (1.13 q> 8.37 mmol) i n methylene c h l o r i d e (50 mL), a t room temperature. The pa l e y e l l o w s o l u t i o n turned orange d u r i n g the a d d i t i o n . The s o l v e n t was c a r e f u l l y b o i l e d away and r e p l a c e d with anhydrous d i e t h y l ether causing the product to c r y s t a l l i z e . The a-chloromethyl d e r i v a t i v e 95a was c o l l e c t e d by f i l t r a t i o n , washed with 10% methylene c h l o r i d e - e t h e r f o l l o w e d by e t h e r , and d r i e d i n a i r . The lemon y e l l o w powdery s o l i d was used i n the next r e a c t i o n without f u r t h e r p u r i f i c a t i o n . ( i i ) P r e p a r a t i o n of the dipyrromethane dimer The compound 95a prepared above was suspended i n g l a c i a l a c e t i c a c i d (120 mL) and s t i r r e d i n , 2-ethoxycarbonyl-4 e t h y l - 3 - m e t h y l p y r r o l e 7_9 (1.8 0 g, 9.94 mmol) i n g l a c i a l a c e t i c a c i d (30 mL). The mixture was warmed, under n i t r o g e n , on a water bath a t 7 0°C f o r 1 h. when the s t a r t i n g m a t e r i a l r e a c t e d and went i n t o s o l u t i o n . (The s o l u t i o n turned orange-red i n c o l o r ) . A t i c a n a l y s i s of the r e a c t i o n mixture ( i n 2% methanol-methylene c h l o r i d e ) i n d i c a t e d the product as a s i n g l e y e l l o w spot, c o l o r e d v i o l e t by bromine vapour. The s o l u t i o n was c o o l e d to room temperature, evaporated down to approximately 2 5 mL under reduced p r e s s u r e , methanol (100 mL) added and allowed to stand o v e r n i g h t i n the r e f r i g e r a t o r . The dipyrromethane dimer 96a c r y s t a l l i z e d out as a dark y e l l o w s o l i d and was c o l l e c t e d by f i l t r a t i o n and washed with methanol. The y i e l d of the a n a l y t i c a l l y pure sample was 3.04 g (85.9% o v e r a l l y i e l d from 94a). A second 243 crop was not isola t e d . In four separate syntheses, y i e l d s of 83.3%, 85.0%, 85.2% and 92.6% were obtained. MP : 168.0 - 170.0°C (dec) Moi. Wt. .Calcd- for C 5 1 H 6 4 N 8 0 4 : 852.5051 : Found, by high resolution mass spectrometry: 852.5045 Anal. Calcd. for C 5 1 H 6 4 N 8 0 4 : C, 71.80; H, 7.56; N, 13.13. Found : C, 72.04; H, 7.55; N, 13.35. "H NMR (6, CDC13) : 1.03 (t, 6H, J=7.5 Hz, 3'-CH2CH3), 1.18-1.54, 1.34 (br, t, 24H, chain- 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-CH ,-.-Q-CH2CH3) , 2.15 (s, 6H, 4-CH_3), 2.30 (s, 6H, 4'-CH3), 2.21-2.58, 2.43 (m, q, 8H, chain 1-CH2 and 11-CH2, 3 ,-CH 2CH 3), 3.98 (s, 4H, bridge CH 2), 4.29 (q, 4H, J=7 Hz, 0-CH2-CH3), 7.34 [s, 2H, C(H)=C(CN)2] , 8.90 (br, 2H, l'-NH), 9.24 (br, 2H, 1NH). 1 3 C NMR (6, CDC13) : 162.13 (C=0), 140.78 [C(H)=C(CN) ], 140.57 (pyrrole 2-C), 136.25 (pyrrole 4-C), 127.09, 126.02, 125.16 (pyrrole 3-C, 2'-C, 3'-C, 4'-C), 124.15 (pyrrole 5-C), 118.91 (pyrrole 5'-C), 116.84 (G=N), 115.96 (C=iJ) , 64 . 27 [CH=C(CN)2~, 59.96 (0-CH 2CH 3), 30.30 (chain 2-C and 10-C) , 29.59 (chain 3-C, 4-C, 5-C, 6-C, 7-C, 8-C, 9-C), 23.95 (bridge CH 2, chain 1-C and 244 11-0,17.39 (3'-CH 2CH 3), 15.38 P'-C^CH^, 14.46 (OCH2CH3), 10.52 (4'-CH 3), 9.62 (4-CH 3). Mass spectrum : m/e, 852 (M +), 806 (M-C H c0H) +, 760 (M-2.CnH_OH) 2 -> 2 o IR : (v KBr) : 3100-3600 (broad, N-H), 2210 (C=N), — max ' ' 1585 (C=C) cm"1. 1,T0-Bis{5-(2,2-dicyanovinyl)-2-[(5-ethoxycarbonyl-3-ethyl-4-methylpyrrol-2-yl)methyl]-4-methylpyrrol-3-yl>decane (n=10) 96b Compound 94b (1.82 g. 3.79 mmol), i n methylene chloride (100 mL) was chlorinated using a solution of s u l f u r y l chloride (1.03 g. 7.62 mmol) i n methylene chloride (50 mL) as described for the undecane analogue 94a. The bis a-chloromethyl derivative was then reacted with 2-ethoxycarbonyl-4-ethyl-3-methylpyrrole 7 9 (1.50 g. 8.29 mmol) i n acetic acid (200 mL) to give the decane linked dipyrromethane dimer 96b i n 88.9% ove r a l l y i e l d . The product, c r y s t a l l i z e d out of the reaction mixture, was found to be a n a l y t i c a l l y pure. The r e p e t i t i o n of t h i s synthesis resulted i n f i r s t crop y i e l d s of 86.7% and 87.4%. 245 MP : 198.0 - 200.5°C (dec) Moi. Wt. C a l c d . C 5 0 H 6 2 N 8 ° 4 : 8 3 8 • 4 8 9 4 Found, by high r e s o l u t i o n mass spectrometry : 838.4884 A n a l . C a l c d . f o r c 5 o H 6 2 N 8 ° 4 : C ' 7 1 - 5 7 ; H ' 7 - 4 5 ' ' N> 13.35. Found : C, 71.51; H, 7.42; N, 13.47. 1H NMR (6, CDC1 3) : 1.03 ( t , 6H, J=7 . 5 Hz, 3'-CH2CH_3), 1.16-1.53, 1.36 (br, t , 22H, c h a i n .- 2-, 3-, 4-, 5-, 6-, 7-, 8- , 9-CH2, Q-CH 2CH_ 3), 2.15 (a, 6H, 4-CH_3), 2.29 (s , 6H, 4 ,-CH 3), 2.22-2.59, 2.41 (m, q, 8H, c h a i n 1~CH 2 and 10-CH 2, 3'-CH 2CH 3), 3.98 (a, 4H, b r i d g e CH_2), 4.29 (q, 4H, J=7 Hz, 0-CH 2-CH 3), 7.34 [ s , 2H, C(H)=C(CN) 2], 8.87 (br, 2H, 1'-NH), 9.22 (br, 2H, 1-NH). 1 3 C NMR (6, 10% TFA-CDC1 3) : 164.75 (C=0), 142.75 [C(H)=C(CN) 2], 141.78 ( p y r r o l e 2-C), 138.58 ( p y r r o l e 4 - C ) , 129.81, 128.96, 126.57, 126.12 ( p y r r o l e 3-C, 2'-C, 3'-C, 4'-C), 125.12 ( p y r r o l e 5-C), 118.11 ( p y r r o l e 5'-C), 116.88 (C^I) , 116.11 ( C s N ) , 61.92 (0-CH 2-CH 3), 61.26 [CH=C(CN) 2], 30.31 (chain 2-C and 9- C) , 29.80 (chain 3-C, 4-C, 5-C, 6-C, 7-C, 8-C), 24.18 (bridge CH 2, c h a i n 1-C and 10-C), 17.43 (3'-CH 2CH 3), 15.29 (3'-CH 2CH 3), 14.29 (OCH2CH-3), 10.86 (4'-CH 3) / 9.71 (4-CH 3>. Mass spectrum : m/e, 838 (M+) , 792 (M-C0H,-OH)+, 746 (M-2 C^H^OH) 246 1.9-Bis{5-(2,2-dicyanovinyl)-2-[ (5-ethoxycarbonyl-3-ethyl- 4-methylpyrrol-2-yl)methyl]-4-methylpyrrol-3-yl}nonane (n=9) 96c Thi s compound was prepared by the same procedure as th a t employed i n the p r e p a r a t i o n o f compound 96a. With 2.01 g (4.31 mmol) of s t a r t i n g m a t e r i a l 94c, an o v e r a l l y i e l d o f 88.0% o f the a n a l y t i c a l l y pure m a t e r i a l was obtained. In three other attempts, the product was i s o l a t e d i n 8 6.4%, 88.1% and 88.6% y i e l d . A second crop was not i s o l a t e d . MP : 205-210 C (dec) Mo 1.Wt -Calcd. f o r C 4 g H N Q0 4 : 824.4737 ; Found, by high r e s o l u t i o n mass spectrometry : 824.4727 A n a l . -Calcd. f o r c 4 9 H 6 0 N 8 o 4 C, 71.33; H, 7.33; N, 13.58; Found : C, 71.12; H, 7.21; N, 13.38 X H NMR (6, CDC1 3) : 1.00 ( t , 6H, J=7.5 Hz, 3'-CH 2CH 3), 1.14-1.48, 1.35 (br, t , 20H, c h a i n 2-, 3-, 4-, 5-, 6-, 7-, 8-CH 2, 0-CH2-CH_3) , 2.15 (s , 6H, 4-CH_3), 2.29 (s , 6H, 4'-CH 3), 2.22 7 2.56, 2.40 (m,q, 8H, c h a i n 1"CH 2 and 9-CH2, 3'-CH 2CH 3), 3.99 (s , 4H, b r i d g e C H 2 ) , 4.31 (q, 4H, J=7 Hz, 0-CH 2CH 3), 7.34 [ s , 2H, C(H)=C(CN) 2J , 9.03 (br, 2H, l'-NH), 9.23 (br, 2H, 1-NH) 247 1 3 C NMR ( 6 , 10%TFA-CDC1 3): 1 6 4 . 8 0 (C=0), 142.97[C(H)=C(CN) 2], 141.85 ( p y r r o l e 2-C), 1.38 .78 ( p y r r o l e 4-C), 129.85, 128.93, 126.64, 126.14 ( p y r r o l e 3-C, 2'-C, 3'-C, 4'-C), 125.17 ( p y r r o l e 5-C), 118.09 ( p y r r o l e 5'-C), 116.79 (CsN), 115.84 ( O s M ) , 62.00 (0-CH 2CH 3) , 60.90 [C (H) =C (CN) ] , 30.32 (chain 2-C and 8-CX, 29.77 (chain 3-C, 4-C, 5-C, 6-C, 7-C), 24.19 (bridge CH 2, c h a i n 1-C and 9-C), 17.43 (3'-CH 2CH 3), 15.27 (3'-CH 2CH 3), 14.27 (0-CH 2CH 3), 10.84 (4'-CH ), 9.70 (4-CH 3). Mass spectrum : m/e, 824 (M+-), 778 (M-C2H5OH) + , 732 (M-2.C2H5OH) 1, 8 - B i s { 5 - ( 2 , 2 - d i c y a n o v i n y l ) - 2 - [ ( 5 - e t h o x y c a r b o n y l - 3 - e t h y l - 4 - m e t h y l p y r r o l - 2 - y l ) m e t h y l ] - 4 - m e t h y l p y r r o l - 3 - y l } o c t a n e ( n= 8 ) 96d The c h l o r i n a t i o n o f compound 94d (2.01 g, 4.4 6 mmol) and the subsequent c o n v e r s i o n to the dipyrromethane dimer 96d were c a r r i e d out a c c o r d i n g to the procedure g i v e n f o r the undecane analogue. Due to the lower s o l u b i l i t y of the com-pounds i n t h i s s e r i e s (8-carbon c h a i n ) , more s o l v e n t had to be used to get the s t a r t i n g m a t e r i a l s and products i n t o s o l u t i o n . For the c h l o r i n a t i o n step, the b i s a-methyl compound 94d was d i s s o l v e d i n 180 mL methylene c h l o r i d e 248 ( c f . 80 mL used to d i s s o l v e approximately the same amount of the undecane analogue 94a) and f o r the c o u p l i n g step, 250 mL of a c e t i c a c i d was used to get the product i n s o l u t i o n . ( c f . 150 mL of a c e t i c a c i d with the undecane analogue). F u r t h e r , the dipyrromethane dimer 96d, c r y s t a l l i z e d out when the a c e t i c a c i d s o l u t i o n was cooled to room temperature, p r i o r to c o n c e n t r a t i o n and the a d d i t i o n of methanol. The s o l i d was removed and a second crop was i s o l a t e d by con-c e n t r a t i n g the mother l i q u o r s and adding methanol. The o v e r a l l y i e l d f o r t h i s c o v e r s i o n was 90.9%. MP : 202.5 - 206.5 (dec.) Ana l . Calcdv f o r C 4 8 H 5 8 N 8 0 4 : C, 71.08; H, 7.21; N. 13.82; Found : C, 7 0.75; H, 7.09; N, 13.57. "H NMR (6, CDC1 3) : 1.01 ( t , 6H, J=7.5 Hz, 3'-CH 2CH 3), 1.14-1.46, 1.36 (br, t , 18H, c h a i n 2-, 3-, 4-, 5-, 6-, 6-CH2, 0-CH 2CH_ 3), 2.15 (s, 6H, 4-CH 3), 2.30 (s, 6H, 4'-CH 3), 2.22-2.54, 2.40 (m, q, 8H, c h a i n 1-CH 2 and 8-CH 2, 3'-CH_2CH3), 3.99 (s":, 4H, br i d g e CH 2), 4.29 (q, 4H, J=7 Hz, 0CH 2CH 3), 7.34 [ s , 2H, (H)=C(CN ) 2 1 , 8.93 (br, 2H, l'-NH), 9.23 (br, 2H, 1-NH). 1 3 C NMR (6, 10% TFA-CDC1 3) : 164.73 (C=0) , 142.71 [ C (H) =C (CN) 2] , 141.76 ( p y r r o l e 2-C), 138.51 ( p y r r o l e 4-C), 129.78, 128.87, 126.48, 126.08 ( p y r r o l e 3-C, 2'-C, 3'-C, 4'-C), 125.06 ( p y r r o l e 5-C), 118.09 ( p y r r o l e 5'-C), 116.87 (G=N), 115.89 (G=N), 61.93 (0-CH 2-CH 3), 61.29 [ C(H)=C(CN)J , 30.28 (chain 2-C and 249 7-C), "29.69 (chain, 3-C, 4-C, 5-C, 6-C) , 24.12 (bridge CH 2 , c h a i n 1-C and 8-C), 17.40 O'-CI^CB^), 15.27 O'-CI^CH^, 14.28 (OCH 2-CH 3), 10.85 (4'-CH 3), 9.67 (4-CH 3>. l , l l - B i s { 2 - [ ( 5 - c a r b o x y - 3 - e t h y l - 4 - m e t h y l p y r r o l - 2 - y l ) m e t h y l ] -5-formyl-4-methylpyrrol-3-yl}undecane (n=ll) 107a 250 In a 1 l i t e r erlenmeyer f l a s k f i t t e d with a C l a i s e n adapter, a n i t r o g e n i n l e t and a r e f l u x condenser, p l a c e d 1,11-b i s { 5 - ( 2 , 2 - d i c y a n o v i n y l ) - 2 - [ ( 5 - e t h o x y c a r b o n y l - 3 - e t h y l - 4 -m e t h y l p y r r o l - 2 - y l ) m e t h y l ] - 4 - m e t h y l p y r r o l - 3 - y l } u n d e c a n e 96a (1.88 g. 2.21 mmol) and a s o l u t i o n of potassium hydroxide (23 g) i n water (200 mL). The m a g n e t i c a l l y s t i r r e d suspension was heated to r e f l u x temperature and n-propanol (7 0 mL) was added. The yellow s o l i d s t a r t i n g m a t e r i a l immediately went i n t o s o l u t i o n r e s u l t i n g i n a p a l e brown s o l u t i o n . The r e f l u x i n g was continued and every h a l f an hour an a l i q u o t was removed, d i l u t e d w i t h water and i t s u v - v i s i b l e spectrum recorded;. T h i s spectrum was compared with t h a t of the s t a r t i n g m a t e r i a l i n methylene c h l o r i d e , d i l u t e d with e t h a n o l . The s t a r t i n g m a t e r i a l showed a strong a b s o r p t i o n a t 4 07 nm, a moderately i n t e n s e a b s o r p t i o n a t 27 5 nmand a shoulder around 315 nm. During the r e a c t i o n , the peak a t 407 nm, d i m i n i s h e d with the simultaneous i n c r e a s e i n the i n t e n s i t y of peaks a t lower wavelengths. In 1.5 h, the peak at 4 07 nm had d i s -appeared completely, i n d i c a t i n g the complete removal of the d i c y a n o v i n y l p r o t e c t i n g groups. The lower wavelength bands (now a t 269 nm and 320 nm) were very i n t e n s e . The condenser was removed, added more water (3 00 mL) and the s o l v e n t was allowed to b o i l o f f u n t i l the r e f l u x temperature reached 100°C. The s o l u t i o n was allowed to c o o l to room temperature, while under n i t r o g e n , when the product p a r t i a l l y separated out as a brown slimy m a t e r i a l - The s o l u t i o n was f i l t e r e d under s u c t i o n (Whatman 541 f i l t e r paper was used to f a c i l i t a t e f i l t r a t i o n ) , and the brown m a t e r i a l d i s s o l v e d , w h ile on the f i l t e r paper by adding more water. The f i n a l c l e a r s o l u t i o n ( 14 00 mL) was cooled i n i c e and a c i d i f i e d with g l a c i a l a c e t i c a c i d . The s o l i d was c o l l e c t e d by f i l t r a t i o n , washed with water and d r i e d i n a vacuum d e s s i c a t o r over potassium hydroxide f o r s e v e r a l days. The pale brown f l u f f y s o l i d was a n a l y t i c a l l y pure. The y i e l d was q u a n t i t a t i v e . In every attempt, the y i e l d was g r e a t e r than 95%. MP : 139.0 - 142.5°C (dec) Anal . ,Calcd. . f o r C 4 1 H 5 6 N 4 0 6 : c / 70.26; H, 8.05; N, 7.99; Found : C, 70.45; H, 8.16; N, 8.20. "H NMR (6, DMSO-d6) : 0.84 ( t , 6H, J=7 Hz, 3'-CH 2CH 3), 1.21 (br, 18H, c h a i n 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-CH 2), 2.15, 2.18, 2.16-2.46 (s, s, m, 20H, 4-CH_3, 4 1-CH 3 , 3'-CH 2.CH 3 chain. 1-CH_2 and 11-CH 2), 3.82 (s, 4H, bri d g e CH^), 9.49 (s, 2H, HC=0), 11.00 (br, 2H, 1-NH), 11.45 (br, 2H, l'-NH). Mass Spectrum : m/e, 700 (M +, weak), 699 (M-H) +, 698 (M-2H) 612 (M-2 =C02) . 252 I, 1 0 - B i s { 2 - [ ( 5 - c a r b o x y - 3 - e t h y l - 4 - m e t h y l p y r r o l - 2 - y l ) m e t h y l 1 - 5-formyl-4-methylpyrroi-3-y1)decane (n=10) 107b The dipyrromethane dimer 96b (1.51 g, 1 .8 0 mmol) was de p r o t e c t e d and s a p o n i f i e d with aqueous potassium hydroxide (21 g i n 200 mL water) as d e s c r i b e d f o r the undecane analogue 96a. The s p e c t r a l changes observed, as w e l l as the time taken f o r the r e a c t i o n to be complete, were s i m i l a r . The product, a p a l e brown s o l i d , was a n a l y t i c a l l y pure and was obtained i n 96.3% y i e l d . MP : 159.0 - 162.0°C (darkened p r o g r e s s i v e l y above 14 8°C and decomposed a t mp). A n a l . . C a l c d : f o r C 4 Q H 5 4 N 4 0 6 : C, 69.94; H, 7.92; N, 8.16; Found : C, 69.84; H, 7.81; N, 8.29. 1H NMR (6, DMSO-d6) : 0.84 ( t , 6H, J=7 Hz, 3'-CH 2CH 3), 1.22 (br, 16H, c h a i n - 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-CH 2), 2.18, 2.20, 2.18-2.44 (s, s, m, 20H, 4-CH 3 4'-CH 3, 3'-CH CH , c h a i n -1-CH 2 and 10-CH 2), 3.85 (s, 4H, b r i d g e CH 2) , 9.54 (s, 2H, HC=0), I I . 05 (br, 2H, 1-NH), 11.49 (br, 2H, l'-NH). Mass spectrum : m/e, 686 (M +, weak), 685 (M-H) +, 684 (M-2H) +, 598 (M-2.C0 2) +. 253 1,9-Bis{2-f (5-carboxy-3-ethyl-4-methylpyrrol-2-yl)methyl] -5-formyl-4-methylpyrrol-3-yl}nonane (n=9) 107c T h i s compound was prepared by the same procedure as t h a t employed i n the p r e p a r a t i o n of the undecane analogue 107a. In one attempt, 2.51 g (3.05 mmol) of s t a r t i n g m a t e r i a l 96c were r e a c t e d with aqueous potassium hydroxide (26.5 g i n 250 mL) to g i v e 2.04 g (96.7%) of the product 107c. Only 14 00 mL of water were r e q u i r e d to d i s s o l v e the potassium s a l t of 107c, before a c i d i f i c a t i o n . T h i s was l e s s than t h a t r e q u i r e d f o r the undecane analogue. MP : 152.0 - 153.5°C (dec) A n a l . C a l e d . f o r C 3 9 H 5 2 N 4 0 6 : C ' 6 9 - 6 2 ' * H ' 7.79; N, 8.33; Found, C, 68.94; H, 7.82; N, 8.51. 1H NMR (6, DMSO-dg) : 0.86 ( t , 6H, J=7 Hz, 3'-CH2CH_3), I. 22 (br, 14H, c h a i n 2-, 3-, 4-, 5-, 6-, 7-, 8-CH 2), 2.18, 2.20, 2.16-2.46 ,(s, s, m, 20H, 4-CH 3, 4'-CH 3, 3'-CH 2CH 3, c h a i n 1-CH 2 and 9-CH 2), 3.84 (s, 4H, b r i d g e CH 2), 9.52 (s, 2H, HC=0), I I . 02 (br, 2H, 1NH), 11.47 (br, 2H, l'-NH). Mass spectrum: m/e, 67 2 (M +, weak), 67 0 (M-2H) +, 58 4 (M-2.C0 o) + 254 1 , 8 - B i s { 2 - [ ( 5 - c a r b o x y - 3 - e t h y l - 4 - m e t h y l p y r r o l - 2 - y l ) m e t h y l ] - 5-formyl-4-methylpyrrol-3-yl}octane (n=8) 10 7 d The dipyrromethane dimer 96d (1.03 g, 1.27 mmol) was re a c t e d w i t h potassium hydroxide (12.5 g) i n water (150 mL) and n-propanol (50 mL) as d e s c r i b e d f o r the syntheses of the unde-cane analogue 107a. The y i e l d o f the pa l e brown a n a l y t i c a l l y pure product 107d was 764 mg (91.4%). MP : 232.5°C (darkened p r o g r e s s i v e l y above 187°C and decomposed a t mp). An a l . C a l c d . f o r c 3 8 H 5 0 N 4 O 6 : C ' 6 9 - 2 8 f H ' 7.65; N, 8.50. Found : C, 69.27; H, 7.67; N, 8.59. 1H NMR (6, DMSO-d6) : 0.86 ( t , 6H, J=7 Hz, 3'-CH2CH_3), 1.23 (br, 12H, c h a i n 2-, 3-, 4-, 5-, 6-, 7-CH 2), 2.18, 2.21, 2.16-2.48 (s, s, m, 20H, 4-CH 3, 4'-CH 3, 3'-CH_2CH3, c h a i n 1-CH 2 and 9-CH 2), 3.85 (s, 4H, br i d g e CH 2), 9.54 (s, 2H, HC=0), 11.03 (br, 2H, 1-NH), 11.48 (br, 2H, l'-NH). Mass spectrum : m/e, 658 (M +, weak), 656 (M-2H) +, 570 (M-2.C0 o) + 255 1 , l l - B i s {2-[ ( 5 - b e n z y l o x y c a r b o n y l - 3 - e t h y l - 4 - m e t h y l p y r r o l - 2 - y l )  methyl] -5-(2-cyano-2-methoxycarbonylvinyl)-4-methylpyrrol-3-yl} undecane 117 Q 117 l , l l - B i s [ 5-(2-cyano-2-methoxycarbonylvinyl)-2,4-dimethylpyrrol-3-yl]undecane 115 (2.80 g, 5 mmol) i n methylene c h l o r i d e (80 mL) was t r e a t e d , dropwise, with a s o l u t i o n : o f ' s u l f u r y l c h l o r i d e (1.45 g f 10.7 mmol) i n methylene c h l o r i d e (40 mL) over a p e r i o d of 30 min. The r e a c t i o n mixture was allowed to s t i r f o r a f u r t h e r 10 min and evap-ora t e d under reduced p r e s s u r e . The b i s a-chloromethyl d e r i v a t i v e 116 c r y s t a l l i z e d out of the s o l u t i o n on the a d d i t i o n of hexane and was f i l t e r e d , washed wi t h hexane and used i n the next r e a c t i o n without f u r t h e r p u r i f i c a t i o n . 256 The b i s g - c h l o r o m e t h y l p y r r o l e • 1 1 6 was s u s p e n d e d i n g l a c i a l a c e t i c a c i d (150 mL) t o g e t h e r w i t h 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 - m e t h y l p y r r o l e 8_0 (2.7 g , 11.1 mmol) and h e a t e d u n d e r n i t r o g e n , on a w a t e r b a t h . When t h e t e m p e r a t u r e r e a c h e d 70° t h e s t a r t i n g m a t e r i a l w e n t i n t o s o l u t i o n , p r o d u c i n g a c l e a r d a r k r e d s o l u t i o n . T i c a n a l y s i s o f t h e r e a c t i o n m i x t u r e i n d i c a t e d a s i n g l e d i p y r r o m e t h a n e p r o d u c t . The s o l u t i o n was e v a p o r a t e d down t o a p p r o x i m a t e l y 50 mL and c r y s t a l l i z a t i o n was a t t e m p t e d , a s b e f o r e , u s i n g m e t h a n o l . T h i s c a u s e d t h e p r o d u c t t o o i l o u t . 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 , t h e r e s i d u e t a k e n up i n m e t h y l e n e c h l o r i d e (100 mL) and t h e r e m a i n i n g a c i d r e m o v e d by e x t r a c t i o n w i t h s a t u r a t e d a q u e o u s s o d i u m b i c a r b o n a t e (2x40 mL) and w a t e r (40 mL). The d r i e d m e t h y l e n e c h l o r i d e s o l u t i o n was t h e n c h r o m a t o g r a p h e d on s i l i c a g e l (90 g, a c t i v i t y I ) . The e x c e s s a - f r e e p y r r o l e s t a r t i n g m a t e r i a l 8_0„ e l u t e d o u t w i t h m e t h y l e n e c h l o r i d e a n d t h e p r o d u c t was remo v e d u s i n g 5% e t h y l a c e t a t e - m e t h y l e n e c h l o r i d e . The c r y s t a l l i z a t i o n o f t h e p r o d u c t was a t t e m p t e d u s i n g d i f f e r e n t s o l v e n t s y s t e m s ; m e t h y l e n e c h l o r i d e - e t h y l a c e t a t e , m e t h y l e n e c h l o r i d e - m e t h a n o l , m e t h y l e n e c h l o r i d e - d i e t h y l e t h e r , b u t i n e v e r y i n s t a n c e , i t o i l e d o u t . The p r o d u c t was e v e n t u a l l y i s o l a t e d a s a n o n - c r y s t a l l i z a b l e g l a s s , b y e v a p o r a t i n g t h e s o l v e n t , y i e l d 5 .22 g ( 8 1 . 6 % ) . MP : 91.0 - 93.0°C Anal,. .Calcd.. f o r C^H^NgOg : C, 72.53; H, 7.15; N, 8.06; Found : C, 72.53; H, 7.05; N, 7.99. 1H NMR (6, CDC1 3)' : 1.03 ( t , 6H, J= 7.5, 3 '-CH2CH_3 ) , 1.25 (br, 18H, c h a i n , 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-CH 2), 2.14 (s , 6H, 4-CH3) , 2.31 (s , 6H, 4'-CH 3), 2.28-2.60 (m, 8H, 3,-CH_2CH3'/ c h a i n , 1-CH 2 and 11-CH 2), 3.76, 3.8 5 (s , s, 6H, 0-CH 3 i s o m e r s ) , 3.94 (s , 4H, b r i d g e CH^) , 5.29 (s;, 4H, 0-CH 2C 6H 5), 7.90 [s, 2H, C (H)=C(CN)C0 2CH 3, hook a t 7.25-isomer] , 7.37 (m, 10H, CgH^), 8.84 (br, 2H, l'-NH), 9.40 (br, 2H, 1-NH). 1 3 C NMR (6, CDC1 3) : 165.16 (C0 2CH 3, hook a t 166.78-isomer), 161.54 (CO-CH^C^H,.) , 138.45 [ C (H) =C (CN) C0„CH o , hook a t 138.94 — Z Z o o — Z 6 i s o m e r ] , 137.71 ( p y r r o l e 2-C), 136.44 (benzene 1-C), 135.65 ( p y r r o l e 4-C), 128.42 (benzene ring-two c a r b o n s ) , 127.94 (benzene r i n g - t h r e e c a r b o n s ) , 127.71 ( p y r r o l e 2'-C), 126.98 ( p y r r o l e 4'-C), 125.23 ( p y r r o l e 3'-C), 124.39 ( p y r r o l e 3-C), 123.60 ( p y r r o l e 5-C), 119.48 (C=N), 118.31 ( p y r r o l e 5 V-C), 86.00 [C(H)=C(CN)CO„CH_] , 65.56 (-0-CH„-C cH c) , . 52.45 (-Q-CH-) — Z 5 — Z b o : i- . > \ i 30.37 (chain 2-C and 10-C), 29.59 (chain, 3-C, 4-C, 5-C, 6 7C, 7^C, 8-C, 9-C), 23.84 (bridge CH 2, c h a i n 1-C and 8-C), 17.33 (3'-CH 2CH 3), 15.39 P'-CH^CH^), 10.60 (4 ' -CH 3) , 9 . 36 (4-CH 3). Mass spectrum : m/e, 1043 (M +, v. weak), 952 (M-C 6H 5CH 2) +, 934 (M-C 6H 5CH 2OH) +, 108 (CgH^Ct^OH) +, 91 (C ?H 7 + ) . 258 1 , l l - B i s { 2 - [ ( 5 - c a r b o x y - 3 - e t h y l - 4 - m e t h y l p y r r o l - 2 - y l ) m e t h y l ] - 5-(2-cyano-2-methoxycarbonylvinyl)-4-methylpyrrol-3-yl} undecane 118 118 l , l l - B i s { 2 - [ ( 5 - b e n z y l o x y c a r b o n y l - 3 - e t h y l - 4 - m e t h y l p y r r o l - 2-yl)methyl]-5-(2-cyano-2-methoxycarbonylvinyl)-4-methylpyrrol -3-yl}undecane 117 (2.11 g, 2.02 mmol) and 10% p a l l a d i z e d c h a r c o a l (182 mg), i n t e t r a h y d r o f u r a n (50 mL), were s t i r r e d at room temperature under 1 atm of hydrogen. The uptake of hydrogen was r a p i d and l i n e a r with time and reached the expected volume i n approximately 1 h. The c a t a l y s t was f i l t e r e d and the s o l u t i o n was concentrated a f t e r the a d d i t i o n of methanol. The product c r y s t a l l i z e d out as a ye l l o w powder and the s o l u t i o n was allowed to stand o v e r n i g h t i n the f r e e z e r f o r complete p r e c i p i t a t i o n . The s o l i d was f i l t e r e d and washed with methanol to g i v e 1.14 (65.5%) of a n a l y t i c a l l y pure m a t e r i a l . The mother l i q u o r s were concentrated f o r a second crop of 0.34 g (19.5%). MP : 180.0 - 181.0°C A n a l . Calcd;. f o r C 4 9 H 6 2 N 6 0 8 : C ' 6 8 - 1 9 ' ' H ' "7.24; N, 9.74. Found : C, 68.18; H, 7.44; N, 9.66. 1H NMR • (6, DMSO-dg) : 0.87 ( t , 6H, J=7 Hz, S'-CH^H^), 1.23 (br, 18H, c h a i n , 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-CH 2) 2.16 (s, 6H, 4-CH 3), 2.21 (s, 6H, 4'-CH 3) / 2.26-2.49 (m, 8H, 3'-CH 2CH 3, c h a i n 1-CH 2 and 11-CH 2>, 3.83 (s, 6H, 0-CH 3), 4.07 (s, 4H, b r i d g e CH_2), 7.91 [ s , 2H, C (H) =C (CN) C0 2CH 3] , 10.55 (br, 2H, 1-NH), 11.12 (br, l'-NH). Mass spectrum : m/e, 774 (M-2 C 0 2 ) , 742 [M-(2 C0 2 + CH 3OH)], 665[M-(2 C0 2 + C 7 H i ; L N ) ] . 1,11-Bis{ 5- (2-cyano-2-methoxycarbonylvinyl) -2-[- ( 3 - e t h y l -4-methyloyrrol-2-yl)methyl] -4-methylpyrrol-3-yl}undecane 119 119 l , l l - B i s { 2-[ (5-carboxy-3-ethyl-4-methylpyrrol-2-yl)methyl] -5-(2-cyano-2-methoxycarbonylvinyl)-4-methylpyrrol-3-yl}undecane 118 (1.39 g 1.61 mmol) and r e d i s t i l l e d t r i -f l u o r b a c e t i c a c i d (15 mL) were s t i r r e d under n i t r o g e n f o r 5 min. Removal of an a l i q u o t i n t o methylene c h l o r i d e and checking by t i c ( i n 2% methanol-methylene c h l o r i d e ) r e v e a l e d a s i n g l e y e l l o w spot, c o l o r e d red by bromine vapour. No y e l l o w spot remained a t the o r i g i n , i n d i c a t i n g the complete disappearance of the s t a r t i n g m a t e r i a l . Most of the a c i d was removed by e v a p o r a t i n g under reduced p r e s s u r e , the 261 r e s i d u e taken up i n methylene c h l o r i d e (75 mL), washed with s a t u r a t e d aqueous sodium b i c a r b o n a t e (2x30 mL) and water (30 mL) and d r i e d w i t h anhydrous magnesium s u l f a t e . The product was c r y s t a l l i z e d by c o n c e n t r a t i n g t h i s s o l u t i o n i n the presence o f methanol. The y i e l d of the orange, micro-c r y s t a l l i n e s o l i d was 1.02 g (81.8%). The mother l i q u o r s were concentrated and co o l e d i n i c e , to o b t a i n an a d d i t i o n a l 0.13 g (10.4%)' . MP : 132.0 - 134.0°C A n a l . C a l c d . f o r C 4 7 H 6 2 N 6 0 4 : C ' 7 2 - 8 4 " H ' 8.06; N, 10.84. Found : C, 73.00; H, 7.90; N, 10.73. "''H NMR (6, CDC1 3); 1.07 ( t , 6H, J=7 .5 Hz, 3'-CH2CH_3), 1.28 (br, 18H, c h a i n , 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-CH 2) 2.06 ( s, 6H, 4'-CH 3), 2.17 (s, 6H, 4-CH 3), 2.24-2.62 (m, 8H, 3'-CH 2CH 3, c h a i n 1-CH 2 and 11-CH 2) , 3.84 (s, 6H, G-CH_3), 3.94 (s, 4H, b r i d g e CH 2), 6.51 (d, 2H, J=2 Hz, 5"-H), 7.56 (br, 2H, l'-NH), 7.91 [s, 2H, C(H)=C(CN)C0 2CH 3], 9.41 (br, 2H, 1-NH) . •:) 1 3 C NMR (<5, CDC1 3) : 165.22 (C=0), 140.43 ( p y r r o l e 2-C), 137.80 [C(H)=C(CN) 2], 135.68 ( p y r r o l e 4-C), 124.15 ( p y r r o l e 3-C), 123.45 ( p y r r o l e 5-C), 122.44 ( p y r r o l e 2'-C), 120.70 ( p y r r o l e 3'-C), 119.71 (C^N), 118.49 ( p y r r o l e 4'-C), 115.11 ( p y r r o l e 5'-C), 88.62 [C(H)=C(CN) 2], 52.44 (0-CH 3), 30.44 (chain, 2-C and 10-C), 29.59 (chain, 3-C, 4-C, 5-C, 6-C, 1-C, 8-C, 9-C), 23.84 (bridge CH 2, c h a i n 1-C and 11-C) , 17.59 P'-CB^CR^), 15.65 (3'-CH 2CH 3), 10.33 (4'-CH 3), 9.56 (4-CH 3). Mass spectrum : m/e, 774(M +), 742 (M-CH" OH) + , 665 (M-C_7H1 n N ) + . l , l l - B i s { 2 - [ ( 3 - e t h y l - 4 - m e t h y l p y r r o l - 2 - y l ) m e t h y l ] - 5 - f o r m y l - 4-methylpyrrol-3-yl}undecane 108a l , l l - B i s { 5 - ( 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 ) - 2 -[ ( 3 - e t h y l - 4 - m e t h y l p y r r o l - 2 - y l ) m e t h y l ] - 4 - m e t h y l p y r r o l - 3 - y l } undecane 119 (903 mg, 1.17 mmol) and potassium hydroxide (4 g) i n water (75 mL) were heated under n i t r o g e n . At the onset of r e f l u x , n-propanol (35 mL) was added to s o l u b i l i z e the s t a r t i n g m a t e r i a l and the r e a c t i o n was f o l l o w e d by u v - v i s i b l e spectroscopy. The a b s o r p t i o n band a t 4 07 nm, c h a r a c t e r i s t i c of the c y a n o a c r y l a t e group f s h i f t e d to lower wavelength and decreased i n i n t e n s i t y . A new band appeared a t A=320 nm i n d i c a t i n g the d e p r o t e c t i o n of the formyl group. The r e a c t i o n was complete i n approximately 2.5 h. When the a l c o h o l was b o i l e d o f f , the product separated out, p a r t l y as brown lumps and p a r t l y as a f i n e c r y s t a l l i n e s o l i d . T h i s was i s o l a t e d by f i l t r a t i o n , washed with water and d r i e d i n a vacuum-d e s s i c a t o r over potassium hydroxide, y i e l d 682 mg (95.6%). MP : 157.0 - 158.5°C A n a l . C a l c d . f o r C 3 9 H 5 6 N 4 0 2 : C, 76.43; H, 9.21; N, 9.14; Found : C, 75.61; H, 9.06; N, 9.35. 1H NMR (6,CDC1 3) : 1.08 ( t , 6H, J=7.5 Hz, 3'-CH 2CH 3), 1.29 (br, 18H, c h a i n 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-CH 2) , 2.05 (s, 6H, 4'-CH 3), 2.27 (s, 6H, 4-CH 3), 2.27-2.63 (m, 8H, 3'-CH 2CH 3, 1-CH 2 and 11-CH 2), 3.87 ( s, 4H, bri d g e CH 2), 6.44 (d, 2H, J=2 Hz, 5'-H), 8.07 (br, 2H, l'-NH), 9.41 (br, 2H, 1-NH), 9.47 Cs, 2H, HC=0). 264 1 3 C NMR (6, CDC1 3) : 175.93 (C=0), 138.10 ( p y r r o l e 2-C), 133.20 ( p y r r o l e 4-C), 128.27 ( p y r r o l e 5-C), 123.34 ( p y r r o l e 3-C), 123.35 ( p y r r o l e 2'-C), 121.39 ( p y r r o l e 3'-C), 117.76 ( p y r r o l e 4'-C), 114.78 ( p y r r o l e 5'-C), 30.77 (chain, 2-C and 10-C), 29.63 (chain, 3-C, 4-C, 5-C, 6-C, 7-C, 8-C, 9-C, 10-C), 23.81 (chain, 1-C and 11-C), 22.97 (bridge C H 2), 17.68 (3'-CH 2CH 3), 15.82 P ' - C I ^ C H ^ , 10.35 (4'-CH 3), 8.92 (4-CH 3>. Mass spectrum : m/e, 612 (M +), 583 (M-C 2H 5) +, 122 (CgH^N)"1" 121 (C 8H 1 ; LN) + , 94 (C 6H gN) + . 265 3.8 SYNTHESES OF STRAPPED PORPHYRINS 3.8.1 7 /17-Diethyl-2,8,12,18-tetramethyl-3,13-undecamethyleneporphyrin 109a 109a n =11 Method A (i) D e c a r b o x y l a t i o n : l , l l - B i s { 2- [ (5-carboxy-3-ethyl-4-methylpyrrol-2-yl)methyl]-5-formyl-4-methylpyrrol-3-yl}undecane 107a (715 mg, 1.02 mmol) was d i s s o l v e d i n dimethylformamide (160 mL) i n a 500 mL erlenmeyer f l a s k , f i t t e d w ith a C l a i s e n adapter and a n i t r o g e n i n l e t . The uv spectrum of a drop of 2 6 6 t h i s s o l u t i o n , d i l u t e d w i t h methylene c h l o r i d e , showed two bands, one a t 280 nm, and the oth e r a t 320 nm. The m a g n e t i c a l l y s t i r r e d dimethylformamide s o l u t i o n was heated a t i t s r e f l u x temperature (153°C) f o r 2 h. At r e g u l a r i n t e r v a l s , an a l i q u o t was removed i n t o methylene c h l o r i d e and i t s uv spectrum recorded. The i n t e n s i t y of the 28 0 nm band was observed to decrease r e l a t i v e to t h a t o f the 320 nm band, which was taken as an i n d i c a t i o n of the extent of d e c a r b o x y l a t i o n . In 2 h, the 28 0 nm band was reduced to a shoulder. The s o l u t i o n was coo l e d to room temperature under n i t r o g e n , evaporated under reduced pressure to approximately 50 mL and added to methylene c h l o r i d e (200 mL). T h i s was then e x t r a c t e d with water (3x6 0 mL) to remove most of the remaining dimethylformamide, d r i e d with anhydrous sodium-su l p h a t e , f i l t e r e d , d i l u t e d to 500 mL with methylene c h l o r i d e and used i n the c y c l i z a t i o n s t e p . ( i i ) I n t r a m o l e c u l a r 2+2 c o u p l i n g : The c y c l i z a t i o n was c a r r i e d out i n two 2 - l i t e r erlenmeyer f l a s k s , covered with aluminum f o i l , each c o n t a i n i n g t o l u e n e - p - s u l f o n i c a c i d (4.0 g ) , d i s s o l v e d i n methanol (25 mL) and d i l u t e d with methylene c h l o r i d e (6 00 mL). The d i p y r r o -methane dimer 108a prepared above ( i n methylene c h l o r i d e ) was added very s l o w l y to the m a g n e t i c a l l y s t i r r e d a c i d c a t a l y s t s o l u t i o n by means of a s y r i n g e pump. The sy r i n g e pump, operat-267 i n g a t i t s slowest speed, took approximately 7 h. to empty one 20 mL s y r i n g e . The e n t i r e a d d i t i o n was completed i n 6 days. The r e d d i s h v i o l e t s o l u t i o n was con c e n t r a t e d down to approximately 150 mL and e x t r a c t e d w i t h s a t u r a t e d sodium b i c a r b o n a t e s o l u t i o n (3x50 mL) to remove the a c i d c a t a l y s t . With the removal of the a c i d the s o l u t i o n turned dark brown but was f l u o r e s c e n t under 365 nm l i g h t . T h i s was then taken to dryness i n vacuo (an o i l pump had to be connected to the r o t a r y evaporator to remove the l a s t t r a c e s of d i m e t h y l -formamide), the r e s i d u e taken up i n minimum methylene c h l o r i d e and chromatographed as d e s c r i b e d below. ( i i i ) Chromatographic p u r i f i c a t i o n of the p o r p h y r i n . The crude p o r p h y r i n was f i r s t chromatographed u s i n g a methylene c h l o r i d e s l u r r y of a c t i v i t y I s i l i c a g el (8 0 g •.) . The column was overloaded and the dark brown non-porphyrin i m p u r i t i e s were adsorbed throughout the e n t i r e column; the excess e l u t e d out. The p o r p h y r i n was adsorbed on the column, although no s p e c i f i c band c o u l d be observed (due to the masking by the brown i m p u r i t i e s ) . The s o l u t i o n e l u t i n g out d i d not show any f l u o r e s c e n c e under 365 nm l i g h t . The e l u t i o n was continued with pure methylene c h l o r i d e u n t i l the e l u a t e was almost c o l o r l e s s . The s o l v e n t was changed to 2% methanol-methylene c h l o r i d e and the p o r p h y r i n e l u t e d out as a dark 268 p u r p l e s o l u t i o n , together w i t h some brown i m p u r i t i e s (observed on t i c ) . The p a r t i a l l y p u r i f i e d p o r p h y r i n was rechromatographed on a c t i v i t y IV s i l i c a gel (40 g ) u s i n g methylene c h l o r i d e as the s o l v e n t . The p o r p h y r i n and some of the i m p u r i t i e s were adsorbed a t the o r i g i n . The f i r s t band e l u t i n g out was brown and n o n - f l u o r e s c e n t . T h i s was f o l l o w e d by a f l u o r e s c e n t band (very d i l u t e and e x h i b i t i n g an e t i o type spectrum) which was a l s o d i s c a r d e d . The s o l v e n t was then changed to 1% methanol-methylene c h l o r i d e to get the product moving on the column. A t r a c e of brown im p u r i t y moved almost behind the p o r p h y r i n and was c o l l e c t e d s i n c e i t c o u l d not be separated without s a c r i f i c i n g a c o n s i d e r a b l e amount of the p o r p h y r i n . The f i n a l p u r i f i c a t i o n was c a r r i e d out u s i n g 20 g. b a s i c alumina (3% water added) with methylene c h l o r i d e as the e l u t i n g s o l v e n t . A l l the i m p u r i t i e s were adsorbed a t the o r i g i n and o n l y the p o r p h y r i n product moved. The c l e a n r e d d i s h v i o l e t s o l u t i o n e l u t i n g out was c o n c e n t r a t e d and the p o r p h y r i n was c r y s t a l l i z e d from nitromethane, d r i e d on the vacuum-line, to g i v e 232 mg.. (39.6%) of the p o r p h y r i n 109a. The o v e r a l l y i e l d s of t h i s d e c a r b o x y l a t i o n -c y c l i z a t i o n r e a c t i o n v a r i e d between 22.0% and 39.6% and appeared to depend, to a l a r g e e x t e n t , on the p a r t i c u l a r sample of the s t a r t i n g m a t e r i a l (108a). A l l the y i e l d s recorded were f o r the f i r s t crops o n l y ; the mother l i q u o r s of a l l p r e p a r a t i o n s were combined and s t o r e d i n the r e f r i g e r a t o r . T h i s was l a t e r rechromatographed (some decomposition had s e t in) and a combined second crop obtained. 269 MP : 297.0 - 298.0°C Mol.Wt. C a l c d . f o r C 3 Q H 5 ( ) N 4 : .574.4036; Found, by high r e s o l u t i o n mass spectrometry : 574.4040 A n a l . C a l c d . f o r C ^ H ^ N j : C, 81.49; H, 8.77; N, 9.75. Found: C, 81.22; H, 8.73; N, 9.77. 1H NMR (400 MHz,6, CDC1 3) : 9.97 (s, 2H, methine protons 10-H and 20-H), 9.80 (s, 2H, methine protons 5-H and 15-H), 3.72 (m, 6H, CH_2CH3 and one pr o t o n each a t c h a i n t e r m i n i ) , 3.65, 3.64 (m, s, 8H, one proton each a t c h a i n t e r m i n i , two CH_3) , 3.37 (s, 6H, two CH_3) , 1.84 ( t , 6H, CH 2CH 3), 1.43 (m, 4H, c h a i n p r o t o n s ) , 0.12 (m, 2H, c h a i n p r o t o n s ) , -0.12 (m, 2H, c h a i n protons, -2.58 (m, 4H, c h a i n p r o t o n s ) , -2.82 (m, 4H, c h a i n p r o t o n s ) , -3.46 (br, 2H, NH), -4.03 (m, 2H, c h a i n p r o t o n s ) . 1 3 C NMR (6, 10% TFA-CDC1 3) : 146.73, 145.12, 143.67, 141.41, 140.56, 140.24, 140.05, 139.20 (16C, a-and p - p y r r o l i c carbons), 100.89, 99.94 (4C, meso carbons 5-, 10-, 15-, 20-C), 28.86, 28.67, 27.00, 25.98, 25.38 (11C, c h a i n c a r b o n s ) , 20.21 (2C, CH 2CH 3), 16.61 (2C,CH 2CH 3), 12.21, 11.75 (4C, CH 3). V i s i b l e spectrum (CH 2C1 2) : - (nm) , 400.7 503.1 539.8 571.9 625.8 l o g e, 5.24 4.05 4.05 3.80 3.59 270 Method B : The s t a r t i n g m a t e r i a l f o r t h i s s y n t h e s i s was the a- f o r m y l - a ' - u n s u b s t i t u t e d dipyrromethane dimer 108a prepared v i a the c y a n o a c r y l a t e - b e n z y l e s t e r r o u t e . Compound 108a (317 mg, 0.52 mmol) i n methylene c h l o r i d e (200 mL): was c y c l i z e d u s i n g a s o l u t i o n o f t o l u e n e - p - s u l f o n i c a c i d (4 g) i n methanol (25 mL) and methylene c h l o r i d e (600 mL). The experimental d e t a i l s f o r the c y c l i z a t i o n r e a c t i o n , work-up and chromatographic p u r i f i c a t i o n were the same as those d e s c r i b e d i n Method A above. The y i e l d of the p u r i f i e d p o r p h y r i n 109a was 153 mg (51.5%). The s p e c t r a l p r o p e r t i e s of t h i s m a t e r i a l were i d e n t i c a l to those observed i n the samples of 10 9a prepared by Method A. F u r t h e r , the mixed m e l t i n g p o i n t d i d not show any d e p r e s s i o n . 271 3.8.2 7,17-Diethyl-2 , 8,12,18-tetramethyl-3,13-decamethylene  p o r p h y r i n 109b 109 b n=10 This compound was prepared by the Method A d e s c r i b e d f o r the s y n t h e s i s of the undecamethylene p o r p h y r i n 109a. In f i v e p r e p a r a t i o n s , o v e r a l l y i e l d s (from 107b) of 29.1%, 31.3%,33.2%, 34.7% and 37.3% of the p o r p h y r i n 109b were obtained. The product was c r y s t a l l i z e d from the chromatographed methylene c h l o r i d e s o l u t i o n s u s i n g nitromethane. MP : 269.0 - 270.5°C MoT.Wt. C a l c d . f o r C^H^IS^ : 560.3879 ; Found, by high r e s o l u t i o n mass spectrometry : 560.3873. Anal. Calcd. for C 3 gH 4gN 4 : C , 81.38; H, 8.63; N, 9.99; Found: C, 81.04; H, 8.62; N, 9.93. '''H NMR (400 MHz, 6, CDC13) : 9.89 (s, 2H, methine protons 10-H and 20-H), 9.67 (s, 2H, methine protons 5-H and 15-H), 4.06 (m, 4H, CH 2CH 3), 3.67 (m, 2H, chain l'-H, lO'-H), 3.60 (s, 6H, CH 3), 3.46 (m, 2H, chain l'-H, lO'-H), 3.27 (s, 6H, CH 3), 1.81 (t, 6H, CH 2CH 3), 1.51 (m, 2H, chain 2'-H, t 9'-H) , "fd . 4 6 (m, 2H, chain 2'-H, 9'-H), 0.03 (m, 2H, chain 3'-H, 8'-H), -1.17 (m, 2H, chain 3'-H, 8'-H), -1.79 (m, 2H, chain 4'-H, 7'-H), -2.23 (m, 2H, chain 5'-H, 6'-H), -3.27 (br, 2H, NH), -5.13 (m, 2H, chain 4'-H, 7'-H), -5.87 (m, 2H, chain 5'-H, 6'-H). I 3 C NMR ( 6 : , 10% TFA- CDC13) \ 146 . 87/, 145 . 61 > 143.'61, • 141.22, 140.44, 140.29, 138.95, 138.23 (16C, a - and 6-p y r r o l i c carbons), 100.24, 100.05 (4C, meso carbons 5-, 10-, 15--, 20-C) , 28.47, 27.94, 26.96, 26.46, 25. 96 (10C, chain carbons), 20.20 (2C, CH 2CH 3), 16.62 (2C, CH 2CH 3), 11.77 (4C, CH 3). V i s i b l e spectrum (CH„C1 ) : 2 2 Amax ( n m ) ' 4 0 2 -0 log e , 5.21 507.5 544.4 572.7 626.2 3.96 4.03 3.78 3.37 273 3.8.3 7,17-DiethyT-2,8,12,18-tetramethyl-3,13-nonamethylene  p o r p h y r i n 109c 109 C n= 9 The procedure used i n the p r e p a r a t i o n of t h i s p o r p h y r i n was the same as t h a t employed i n the p r e p a r a t i o n of the undecamethyleneporphyrin 109a (Method A ) . Th i s p o r p h y r i n was found to be adsorbed onto s i l i c a g e l , more than the undecamethylene and the decamethylene analogues. On a c t i v i t y I s i l i c a g e l , 5% methanol-methylene c h l o r i d e was necessary t o make the product t o move, but i t e l u t e d out with some i m p u r i t i e s . On a c t i v i t y IV s i l i c a g e l , 2% methanol-methylene c h l o r i d e e l u t e d out the p o r p h y r i n but once agai n , was contaminated with i m p u r i t i e s . U n l i k e the undecamethylene and decamethylene analogues, t h i s d i d not move wit h methylene c h l o r i d e alone, on b a s i c alumina (3% water). In 10% e t h y l acetate-methylene c h l o r i d e , the 274 p o r p h y r i n e l u t e d out pure, l e a v i n g a l l the i m p u r i t i e s a t the o r i g i n . The maximum y i e l d obtained f o r the p u r i f i e d p o r p h y r i n was 26.8%. In f o u r other syntheses, y i e l d s of 20.0%, 21.8%, 25.1% and 25.0% were obt a i n e d . In a l l i n s t a n c e s the p o r p h y r i n was c r y s t a l l i z e d out from nitromethane. I t was observed, l a t e r , t h a t t h i s p o r p h y r i n (109c), was l e s s s o l u b l e i n methanol than i n nitromethane; the r e v e r s e was true f o r the decamethylene and undecamethylene analogues. MP-: > 330°C MoT. Wt. C a l c d . f o r C 3 ? H 4 6 N 4 : 54 6.37 23 ; Found by high r e s o l u t i o n mass spectrometry : 546.3737. A n a l . C a l c d . f o r C ^ H ^ N j : C, 81.27; H, 8.48; N, 10.25. Found : C, 81.33; H, 8.57; N, 10.24. NMR (400 MHz, 6, CDC1 3) : 9.71 (s, 2H, methine protons 10-H, 20-H) , 9.36 (s., 2H, methine protons 5-H, 15-H) , 3.97 (m, 4H, CH 2CH 3), 3.57 (s , 6H, CH_3) , 3.29 (m, 2H, c h a i n l'-H,.9'-H), 3.03, 3.00 (m, s , 8H, c h a i n 1*-H, 9'-H and r i n g C H _ 3 ) , 1.79 ( t , 6H, CH2CH_3) , 0.56 (m, 4H, c h a i n 2'-CH 2, 8'-CH 2), -1.14 (m, 2H, c h a i n 3'-H, 7'-H), -1.56 (m, 2H, c h a i n 3'-H, 7'-H), -3.06 (br, 2H, NH) , --3.33 (m, 2H, c h a i n 5'-CH ), -4.15 (m, 2H, c h a i n 4 1-H, 6'-H), -4.35 (m, 2H, c h a i n 4'-H, 6'-H). NMR ( 6 , 10% TFA-CDCT 3) : 146.60, 144.65, 141.21, 140.42, 139.59, 139.07, 134.27 (16C, a-and g - p y r r o l i c c a r b o n s ) , 101.48, 99.72 (4C, meso carbons 5-, 10-, 15-, 20-C), 28.72, 28.22, 25.84, 24.97 (9C, c h a i n c a r b o n s ) , 20.12 (2C, CH 2CH 3), 16.47 (2C, CH 2CH 3), 11.66 (4C, CH 3). V i s i b l e Spectrum (CH 2C1 2) : A (nm), 405.3 513.5 551.7 579.1 633.0 max l o g - e , 5.23 3.91 4.08 3.82 3.43 3.9 i SYNTHESES OF DURENE-BIS-PENTANOIC ACID AND ITS PRECURSORS 1,4-Bis C2,2-dicarboxyethyl)-2,3,5,6-tetramethylbenzene 121 121 F r e s h l y cut m e t a l l i c sodium (12.85 g, 0.56 moi) was d i s s o l v e d i n anhydrous ethanol (600 mL) i n a 2 - l i t e r 276 erlenmeyer f l a s k , under n i t r o g e n . D i e t h y l malonate (152 mL, 160.4 g 1.0 moi) was s t i r r e d i n , f o l l o w e d by 1 , 4-bis(chloromethyl) - 2 , 3 , 5 , 6 - t e t r a m e t h y l b e n z e n e [ b i s ( c h l o r o m e t h y l ) d u r e n e ] (57.8 g 0.25 moi) which was washed down with another 5 0 mL of anhydrous e t h a n o l . The s t a r t i n g m a t e r i a l d i d not d i s s o l v e . The mixture was r e f l u x e d on a s t i r r e r - h o t plate> f o r 0.5 h; a white s o l i d remained throughout t h i s p e r i o d . A t i c a n a l y s i s of the r e a c t i o n mixture d i d not show any s t a r t i n g m a t e r i a l but a s i n g l e f a s t moving spot. Ethanol (approximately 200 mL) was d i s t i l l e d o f f from the r e a c t i o n mixture, c o o l e d to room temperature and a s o l u t i o n of potassium hydroxide (200 g, 3.04 moi) i n water (4 00 mL) was added. The d i s t i l l a t i o n of ethanol was continued u n t i l the temperature reached 100°C. Water was added u n t i l a l l of the s o l i d d i s s o l v e d (approximately 1 - l i t e r o f water), t r a n s f e r r e d the s o l u t i o n i n t o a 3 - l i t e r erlenmeyer f l a s k and reheated to b o i l i n g . The b o i l i n g aqueous s o l u t i o n was next t r e a t e d , dropwise,'with concentrated h y d r o c h l o r i c a c i d (250 mL). A white s o l i d p r e c i p i t a t e d out when the s o l u t i o n became a c i d i c . A f u r t h e r 150 mL of a c i d were added and the s o l u t i o n was c o o l e d . The s o l i d was c o l l e c t e d by f i l t r a t i o n , washed w e l l with water and d r i e d i n a i r f o r s e v e r a l days to g i v e 86.8 g, (94.9%). The product was found to be a n a l y t i c a l l y pure without r e c r y s t a l l i z a t i o n . In another p r e p a r a t i o n s t a r t i n g with 64.7 g b i s 277 (chloromethyl)durene, the product 121 was i s o l a t e d i n 98.2% y i e l d . MP : 278.0 - 280.0°C (dec) A n a l . C a l c d . f o r C 1 8 H 2 2 ° 8 : C ' 5 9 - 0 1 ; H ' 6.05. Found : C , 58.95; H, 5.92. XH NMR (270 MHz, 6, DMSO-d,) : 2.13 (s, 12H, durene-CHj , b j 3.13-3.22 (m, 4H, s i d e c h a i n 1-CH 2), 3.22-3.33 (m, 2H,-CH ( C 0 2 H ) 2 ) . Mass spectrum : m/e 278 (M-2.C02) + , 219 [ M- (2 . CG"2+CH2C02H) ] + , 205 [M-(2.C0 2+CH 2CH 2C0 2H)] +, 44 (CC>2) + . 1 , 4-Bis(2-carboxyethyl)-2,3,5,6-tetramethylbenzene 122 COjH 122 Q u i n o l i n e (140 mL) was pl a c e d i n a 2 - l i t e r erlenmeyer f l a s k f i t t e d w i t h a C l a i s e n adapter and a n i t r o g e n i n l e t and 278 heated a t the maximum s e t t i n g of a s t i r r e r - h o t p l a t e . At the onset of r e f l u x , the b i s malonic a c i d 121 was added i n small p o r t i o n s . Vigorous e v o l u t i o n of carbon d i o x i d e was observed throughout the a d d i t i o n . The e n t i r e g l a s s apparatus was wrapped i n aluminum f o i l and continued h e a t i n g ; q u i n o l i n e r e f l u x e d a t the top of the C l a i s e n adapter, washing down a l l the s o l i d adhering to the g l a s s . The s o l u t i o n was heated f o r a f u r t h e r 10 min. to ensure complete d e c a r b o x y l a t i o n and poured i n t o 6M h y d r o c h l o r i c a c i d (400 mL). The product c r y s t a l l i z e d out was c o l l e c t e d by f i l t r a t i o n and the f i l t r a t e saved to re c o v e r the q u i n o l i n e . The s o l i d was washed w e l l with water under s u c t i o n . The crude s o l i d was heated with a s a t u r a t e d s o l u t i o n of sodium b i c a r b o n a t e i n water (500 mL) on a steam bath. More s o l i d sodium b i c a r b o n a t e and water ( t o t a l volume of 1500 mL) were added to d i s s o l v e the product. The s o l u t i o n was f i l t e r e d w h i le hot, u s i n g a steam-heated Buchner f u n n e l c a r r y i n g a c e l i t e p l u g . The f i l t r a t i o n was extremely slow. The b i s ( c a r b o x y e t h y l ) d u r e n e was r e p r e c i p i t a t e d by a c i d i f y i n g the f i l t r a t e w ith c o n c e n t r a t e d h y d r o c h l o r i c a c i d and was c o l l e c t e d by f i l t r a t i o n , washed with water and d r i e d i n a i r to gi v e 62.15 g (96.3%). MP : 284.0 - 286.0°C A n a l . C a l c d . f o r C, .-H__0. : C, 69.04; H, 7.97; Found : l b zz 4 C, 68.48; H, 7.93. 1H NMR (<5 , DMSO-d,) : 2.13 (S, 12H, durene CH_), 2.06-2.39 (m, 4H, side chain 2-CH 2), 2.72-3.02 (m, 4H, side chain 1-CH2). A 1 g- sample of 122 was converted to i t s dimethyl ester for the purpose of characterization. The s o l i d was refluxed with four equivalents of thionyl chloride u n t i l the evolution of gases ceased. The excess reagent was driven o f f by evaporating, i n vacuo, with carbon tetrachloride and the bis acid chloride was refluxed- with methanol for 1 h. Methanol was evaporated o f f , the residue taken up i n methylene chloride and the a c i d i c impurities removed by extraction with saturated sodium bicarbonate and water. The diester was c r y s t a l l i z e d out by replacing methylene chloride with aqueous methanol and p u r i f i e d by chromatography ( s i l i c a g e l , a c t i v i t y I ) . C02CH3 MP : 108.5 - 110.0°C Anal. Calcd. for C 1 8 H 2 6 0 4 : c / 70.56; H, 8.55; Found : C, 7 0.35; H, 8.53. 280 LH NMR (6, CDC1 3) ; 2.19 (s, 12H, durene CH 3) , 2.30 - 2.54 (m, 4H, s i d e c h a i n 2-CH 2), 2.90 - 3.14 (m, 4H, s i d e c h a i n 1-CH 2), 3.66 (s, 6H, -Q-CE^).' 1 3 C NMR (6,CDC1 3) : 173.46 (C=0), 135.19 (durene 1-C and 4-C), 132.42 (durene 2-C, 3-C, 5-C, 6-C), 51.59 (0-CH 3), 33.93 (side c h a i n 2-CH 2), 26.13 (side c h a i n 1-CH 2), 16.28 (durene-CH 3) • Mass spectrum : .m/e 306 (M +), 275 (M-OCH 3) +, 233 (M-CH 2C0 2CH 3) +, 219 (M-CH 2CH 2C0 2CH 3) +. 1,4-Bis(2-ethoxycarbonylethyl)-2,3,5,6-tetramethylbenzene 123 C 02 C2 HS 123 1,4-Bis (2-carboxyethyl) - 2 ,3 ,'5 , 6-tetramethylbenzene 12 2 (158.94 g,- 0.57 moi) . ethanol (400 mL) , toluene (200 mL) and concentrated s u l f u r i c a c i d (27 mL) were p l a c e d i n a 2 - l i t e r erlenmeyer f l a s k f i t t e d with a Dean-Stark t r a p ( f i l l e d with toluene) surmounted by a r e f l u x condenser. The s o l u t i o n was r e f l u x e d on a s t i r r e r - h o t p l a t e f o r approximately 4 h. During t h i s p e r i o d , no water was observed to separate out i n the t r a p . The contents i n the t r a p were i n t r o d u c e d i n t o the r e a c t i o n f l a s k , together with more ethanol (100 mL) and the azeotrope was allowed to c o l l e c t i n the t r a p (approx-i m a t e l y 3 00 mL) . When the r e a c t i o n mixture was c o o l e d , the product c r y s t a l l i z e d out but the s o l u t i o n separated i n t o two phases. More toluene (4 00 mL) was added and the s o l u t i o n was reheated on a steam bath to d i s s o l v e the s o l i d . Water (500 mL) was added and the cloudy water phase was removed. The or g a n i c phase was washed s e v e r a l times with water and allowed to c o o l over i c e . The s o l i d was c o l l e c t e d by f i l t r a t i o n , washed wit h petroleum ether ( b o i l i n g range 30-60°C) and d r i e d to g i v e 151.80 g, (79.6%). The f i l t r a t e s were con c e n t r a t e d to g i v e a second crop of 18.66 g (9.8%), f o r an o v e r a l l y i e l d of 89.4%. MP : 118.5 - 120.0°C A n a l . C a l c d . f o r C 2 0 H 3 Q O 4 : C, 71.82; H, 9.04; Found : C, 72.10; H, 9.11. -"-H NMR (6, CDC1 3) : 1.25 ( t , 6H, J=7 Hz, -OCH2CH_3), 2.18 (s, 12H, durene CH 3), 2.28 - 2.50 (m, 4H, s i d e c h a i n 2-CH 2), 2.90 - 3.12 (m, 4H, s i d e c h a i n 1-CH 2), 4.14 (q, 4H, J=7 Hz, -0-CH 2-CH 3) . 282 1 3 C NMR ( , .CDC13) : 173.10 (C=0) , 135.25 (durene 1-C and 4-C), 132.39 (durene 2-C, 3-C, 5-C, 6-C), 60.41 (-0-CH2CH3), 34.21 (side chain 2-C) 26.15 (side chain 1-C), 16.30 (durene CHg), 14.28 (0-CH 2-CH 3). Mass spectrum : m/e 334 (M +), 289 (M-OC„H c) +, 247 (M-CH„ C 0 2 C 2 H 5 ) + ' 2 3 3 ( M " C H 2 C H 2 C 0 2 C 2 H 5 ) + ' 1, 4-Bis (3-hydroxypropyl) -2,3,5, 6-tetramethylbenzene •- 124 CHjOH 124 1,4-Bis(2-ethoxycarbonylethyl)-2,3,5,6-tetramethylbenzene (16.7 g, 0.05 moi) was dissolved i n dry tetrahydrofuran (200 mL) in a 1 - l i t e r erlenmeyer flask f i t t e d with a Claisen adapter, nitrogen i n l e t , a dropping funnel (pressure equalizing type) surmounted by a calcium chloride drying tube. To the magnetically s t i r r e d solution, sodium borohydride (8.5 g> 0.22 moi) was added, followed by the rapid dropwise addition of boron t r i f l u o r i d e etherate (45 mL, 0.36 moi). Tic analysis of the reaction mixture (in CH 2Cl 2) showed a single spot, with a lower r ^ value than that of the s t a r t i n g material. 283 The excess diborane was destroyed with a c e t i c a c i d (50 mL) and water (100 mL) and the s o l v e n t was evaporated under reduced pressure causing the product to separate out as a white s o l i d . More water (3 00 mL) was added and the s o l i d was c o l l e c t e d by f i l t r a t i o n . The crude product was r e c r y s t a l l i z e d by d i s s o l v i n g i n warm ethanol (350 mL) and r e p r e c i p i t a t i n g with water. Two crops of the r e c r y s t a l l i z e d b i s ( h y d r o x y p r o p y l ) d u r e n e amounted to 11.2 g , an o v e r a l l y i e l d of 89.6%. MP : 158.0 - 159.5°C A n a l . C a l c d . f o r C 1 6 H 2 6 ° 2 : C / 7 6 - 7 5 ; H ' 1 ° - 4 7 ; Found : C, 77.02; H, 10.64. 1H NMR (6, CDC1 3) : 1.50 (s, 2H, -OH), 1.58-1.94 (m, 4H, s i d e c h a i n 2-CH 2), 2.26 (s, 12H, durene CH 3), 2.66-2.90 (m, 4H, s i d e c h a i n l - C H ^ , 3.78 ( t , 4H, -CH_2OH) . 1 3 C NMR (<S, CDC1 3) : 136.16 (durene 1-C and 4-C), 132.23 (durene 2-C, 3-C, 5-C, 6-C), 63.14 (CH 2OH), 32.82 (side c h a i n 1-C), 26.96 (side c h a i n 2-C), 16.38 (durene CH 3). Mass spectrum : m/e, 250 (M +), 205 (M-CH 2CH 2OH) +, 191 (M-CH 2CH 2CH 2OH) +, 147 [ C . ^ (CH 3 ) ^ \ + . 284 1,4-Bis(3-bromopropyl)-2,3,5,6-tetramethylbenzene 127 CH2Br 127 1,4-Bis (3-hydroxypropyl)-2,3,5,6-tetramethylbenzene 12 6 (7.5 g , 0.03 moi) and 48% aqueous hydrobromic-. a c i d (24 mL) were heated a t r e f l u x under n i t r o g e n . The s t a r t i n g m a t e r i a l d i d not d i s s o l v e , but turned i n t o a p a l e yellow o i l , r e s u l t i n g i n an o v e r a l l emulsion. A t i c a n a l y s i s of the r e a c t i o n mixture a f t e r 30 min showed a s i n g l e spot, moving f a s t e r than the s t a r t i n g m a t e r i a l . The s o l u t i o n was c o o l e d to room temperature, methylene c h l o r i d e (100 mL) added and the a c i d e x t r a c t e d out with water (20 mL) and s a t u r a t e d sodium b i c a r b o n a t e s o l u t i o n (2x30 mL). The methylene c h l o r i d e s o l u t i o n was d r i e d with anhydrous sodium s u l f a t e and evaporated under reduced p r e s s u r e a f t e r adding methanol. The product c r y s t a l l i z e d out as s i l v e r y white needles, y i e l d 9.4 g (83.3%). The mother l i q u o r s were concentrated to g i v e a second crop of 0.90 g r (7 . 9 % ) . In another p r e p a r a t i o n , an o v e r a l l y i e l d of 90.9% was o b t a i n e d . MP : 113.0 - 114.0°C A n a l . C a l c d . f o r C 1 6 H 2 4 B r 2 : C, 51.09; H, 6.43; Br, 42.48: Found : C, 50.95; H, 6.49; Br, 4 2.28. 1H NMR (6,CDC1 3) : 1.84-2.10 (m, 4H, s i d e c h a i n 2-CH"2) , 2.17 (s, 12H, durene C H 3), 2.68-2.92 (m, 4H, s i d e c h a i n 1-CH2) , 3.45 ( t , 4H, J=6.5, CH_2Br) . 1 3 C NMR ( 6 , CDC1 3) : 135.39 (durene 1-C and 4-C), 132.33. (durene 2-C, 3-C, 5-C, 6-C) , 33.92 (CH 2Br), 32.69 :(side c h a i n 1-CH"2) , 29.37 (side c h a i n 2-CH"2), 16.44 (durene-CH"3) . Mass spectrum : m/e, 374-376-378 (M +), 267-269 (M-CH.,CH0Br) + 1,4-Bis (4 ,4-dicarboxy'butyl) -2 ,3 , 5 , 6-tetramethylbenzene 12 9 129 To a s t i r r e d s o l u t i o n of sodium (2.4 g , 104 mmol) i n anhydrous e t h a n o l (200 mL), d i e t h y l malonate (25 mL, 26.4 165 mmol) and the bis(bromopropyl)durene 127 (15g . , 40 mmol) were added and the resulting'mixture.was heated on a hot p l a t e under n i t r o g e n . As the s o l u t i o n reached r e f l u x , the s t a r t i n g m a t e r i a l d i s s o l v e d , g i v i n g a p a l e y e l l o w s o l u t i o n . W i t h i n 10 min. of he a t i n g a white s o l i d (sodium bromide) separated out. The s o l u t i o n was r e f l u x e d f o r 3 0 min and a t i c a n a l y s i s i n d i c a t e d the complete c o n v e r s i o n of the s t a r t i n g m a t e r i a l to a s i n g l e product. The s o l v e n t was d i s t i l l e d o f f (approx-ima t e l y 120 mL) and the r e a c t i o n mixture was t r e a t e d with a s o l u t i o n of potassium hydroxide (45 g ) i n water (200 mL). The h e a t i n g was continued u n t i l the r e f l u x temperature reached 100°C and the hot s o l u t i o n was a c i d i f i e d with concentrated h y d r o c h l o r i c a c i d . The product c r y s t a l l i z e d out as a white s o l i d , y i e l d 15.9 g (94.9%). MP : 193.5 - 195°C (dec) Ana l . C a l c d . f o r C 2 2 H 3 0 ° 8 : C / 6 2 > 5 5 ; H ' 7- 1 6'" Found : C, 62.32; H, 7.20. 1H NMR (6, DMSO-d,,) : 1.14-1.98 (m, 8H, s i d e c h a i n 2-CH 2 3-CH 2), 2.07 (s, 12H, benzene CH 3), 2.38-2.74 (m, 4H, si d e c h a i n 1-CH 2), 3.25 ( t , 2H, J=7 Hz, C H(CC> 2H) 2). Mass spectrum : m/e, 334 (M-2.C0 2) + , 247 [M-(2.C0 2+CH 2CH 2CH 2C0 2H) 1 147 [ C y H 3 ( C H 3 ) 4 ] + , 44 (CC>2) + . 287 1,4-Bis(4-carboxybutyl)-2,3,5,6-tetramethylbenzene (Durene - b i s - p e n t a n o i c acid) HOjC^ 130 1,4-Bis(4,4-dicarboxybutyl)-2,3,5,6 tetramethylbenzene 12 9 (15.5 g , 36.7 mmol) was decarboxylated i n r e f l u x i n g q u i n o l i n e (50 mL) i n the manner d e s c r i b e d f o r 1,4-bis (2 , 2-dicair boxy e t h y l ) -2 ,3 ,5 , 6-tetramethylbenzene 121. The crude product was r e d i s s o l v e d i n hot aqueous sodium carbonate, f i l t e r e d through a c e l i t e p l u g and r e p r e c i p i t a t e d with concentrated h y d r o c h l o r i c a c i d to g i v e 11.6 g (94.6%). MP : 210.0 -211.0°C •1H NMR (6, DMSO-d^) : 1.10-1.82 (m, 8H, s i d e c h a i n 2-CH n and 3-CH 2), 2.13, 2.06-2.38 (s, m, 16H, durene CH 3, s i d e c h a i n 4-CH 2), 2.42-2.76 (m, 4H, s i d e c h a i n 1-CH 2). One gram of t h i s m a t e r i a l was converted to i t s dimethyl e s t e r , f o r c h a r a c t e r i z a t i o n , i n the manner d e s c r i b e d f o r compound 122. 130 CO^ 288 C H 3 MP : 74.5 - 75.0UC Anal. Calcd. for C 22 H34°4 : C, 72.89; H, 9.45; Found : C, 72.70; H, 9.34. 1H NMR (6, CDC13) : 1.24-1.98 (m, 8H, side chain 2-CH2, 3- CH 2), 2.21 (s, 12H, durene CH 3), 2.24-2.50 (m, 4H, side chain 4-CH2), 2.54-2.80 (m, 4H, side chain 1-CH2) , 3.66 (s'', 6H, 0-CH 3). 1 3 € NMR (S , CDC13) : 174.01 (C=0), 136.45 (durene 1-C and 4- C), 131.99 (durene 2-C, 3-C, 5-C, 6-C), 51.41 (0-CH 3), 33.95 (CH 2C0 2CH 3), 30.38, 29.40 (side chain 1-C, 2-C), 25.50 (side chain 3-CH 2), 16.35 '(durene CH 3). Mass Spectrum : m/e, 362 (M +), 261 (M-CH 2CH 2CH 2C0 2CH 3) +, 247 (M-CH2CH2CH2CH2C02CH3) + , 147 [ C ?H 3 (CH3) ] + , 115 [ ( C H 2 ) 4 . C0 2CH 3] +. 3.10 SYNTHESES OF DURENE-BIS-PENTANE BRIDGED DIMERS AND THE PORPHYRIN 1, 4 - B i s [ 5 - ( 5 - e t h o x y c a r b o n y l - 2 , 4 - d i m e t h y l p y r r o l - 3 - y l ) - 5 -oxopentyl]-2,3,5,6-tetramethylbenzene 132 132 Durene-bis-pentanoic a c i d 130 (16.7 g , 0.05 moi) was converted to i t s b i s a c i d c h l o r i d e and t h i s i n tu r n was used t o a c y l a t e two e q u i v a l e n t s of the B-free p y r r o l e 6_6 . The experimental d e t a i l s f o r t h i s a c y l a t i o n r e a c t i o n were as given f o r the s y n t h e s i s of the undecane analogue 88a. The b i s a c i d c h l o r i d e was a s o l i d u n l i k e the s t r a i g h t c h a i n analogues. Only one mole of s t a n n i c c h l o r i d e was used per atom of c h l o r i n e i n the a c y l a t i o n r e a c t i o n , and was added w i t h i n 15 min to the r e a c t i o n mixture main-t a i n e d a t room temperature. The product was i s o l a t e d i n three c r o p s , to g i v e an o v e r a l l y i e l d of 21.2 g (67.1%). An a n a l y t i c a l sample was r e c r y s t a l l i z e d by adding ethanol to a concentrated s o l u t i o n of 132 i n methylene c h l o r i d e and minimum t r i f l u o r o a c e t i c a c i d . MP : 207.5 - 209.0°C A n a l . C a l c d . f o r C 3 8 H 5 2 N 2 ° 6 : C ' 7 2 * 1 2 ; H ' 8- 2 8'" N / 4.43. Found : C, 72.10; H, 8.08; N, 4.63-1H NMR (fi, 10% TFA-CDC1 3) : 1.46, 1.38-2.10 ( t , br, 14H, 0-CH 2CH 3, c h a i n 2-, 2'-, 3-, 3*-CH 2), 2.24 (s, 12H, durene CH 3 2.39 (s , 6H, p y r r o l e 4-CH 3), 2.42 (s., 6H, p y r r o l e 2-CH 3), 2.58-2.85 (m, 4H, c h a i n 1-, l'-CH^), 2.96 ( t , 4H, J=7.5 Hz, c h a i n 4-, 4'-,CH 2), 4.47 (q, 4H, J=7 Hz, 0-CH_2-CH3), 10.20 (bs, 2H, NH). 1 3 C NMR (6, 10% TFA-CDC1 3) : 204.11 (chain C=0, 5-C and 5'-C), 164.25 (ester C=0), 142.50 ( p y r r o l e 2-C), 136.59 (durene 1-C and 4-C), 132.37 ( p y r r o l e 4-C, durene 2-C, 3-C, 5-C, 6-C), 123.03 ( p y r r o l e 3-C), 118.61 ( p y r r o l e 5-C), 62.57 (-0-CH 2CH 3), 42.27 (chain CO-CH 2"), 30.62, 29.88 (chain, 1-, 1'-, 2-, 2'-C), 26.12 (chain, 3-, 3'-C), 16.41 (durene CH 3), 15.44 ( p y r r o l e 2-CH 3), 14.26 (-0-CH 2-CH 3), 13.03 ( p y r r o l e 4-CH,). Mass s p e c t r u m : R e l a t i v e m/e I n t e n s i t y (%) A s s i g n m e n t 632 19 M + 209 100 OH ® AV-H3C N 194 148 IR (v K B r ) : — max 3280 (NH), 1645-1665 (C=0) cm 292 1,4-Bis[5-(5-ethoxycarbonyl-2,4-dimethylpyrrol-3-yl)pentyl] -2/3,5,6-tetramethylbenzene 133 133 The diketone 132 (17 g , 26.9 mmol) was suspended i n tetrahydrofuran (150 mL) and treated with sodium borohydride (3 g , 79.4 mmol) and boron t r i f l u o r i d e etherate (14 mL , 111 mmol) i n the usual manner. Unlike the straight chain analogues, the s o l i d did not appear to dissolve and a t i c analysis of the reaction mixture showed more than 8 0% of unreacted s t a r t i n g material. More sodium borohydride (1 g) and boron t r i f l u o r i d e etherate (5 mL) were added and allowed to s t i r for 30 min. but no change was observed on t i c . More tetrahydrofuran (300 mL) was added to the reaction mixture and with 5 min. of s t i r r i n g , a l l the s o l i d went into solution and no st a r t i n g material could be detected on t i c . The excess diborane was destroyed and the reaction mixture worked up i n the usual manner. The crude s o l i d was dissolved i n hot tetrahydrofuran (300 mL), f i l t e r e d to remove brown i m p u r i t i e s and r e c r y s t a l l i z e d from methanol to g i v e 14.3 g of white powdery s o l i d , i n two crops; an o v e r a l l y i e l d of 88.3%. MP :: 198.0 - 199.0 °C A n a l . C a l c d . f o r C 3 8 H 5 6 N 2 0 4 : C, 75.46; H, 9.33; N, 4.63: Found : C, 75.18; H, 9.32; N, 4.72. 1H NMR ( S, CDC1 3) : 1.35, 1.32-1.62 ( t , br, 18H, 0-CH 2~CH 3 c h a i n , 2-, 2'-, 3-, 3'-, 4-, 4'-CH 2), 2.20, 2.22, 2.28, 2.24-2.50 ( s , s , s , m , 28H, p y r r o l e 2-CH 3, durene CH 3, p y r r o l e 4-CH 3, c h a i n 5-, 5'-CH 2), 2.50-2.80 (m, 4H, c h a i n 1-, 1'-CH2 4.32 (q, 4H, J=7 Hz, 0-CH 2~CH 3), 8.73 (bs, 2H, NH). Mass spectrum : m/e R e l a t i v e I n t e n s i t y (%) 604 62 558 29 180 100 134 90 294 I R ( v™. v K B r ) : . 3310 (N-H), 1670 (C=0) cm 1. 1 , 4 - B i s \ 5 - ( 5 - b e n z 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 ) p e n t y l ] -2/3/5,6-tetramethylbenzene 134 134 The d i e t h y l e s t e r 133 (13.1 g , 21.5 mmol) was t r a n s e s t e r i f i e d i n 125 mL of r e d i s t i l l e d b e nzyl a l c o h o l as d e s c r i b e d f o r the undecane analogue 89a. The y i e l d of the d i b e n z y l e s t e r 134 was 15.5 g (98.1%). An a n a l y t i c a l sample was r e c r y s t a l l i z e d from tetrahydrofuran-methanol. MP : 171.0 - 172. 0° C Ana l . C a l c d . f o r C 4 g H 6 ( ) N 2 0 4 : C, 79.08; H, 8.30; N, 3.84. Found : C, 78.91; H, 8.47; N, 3.83. 1H NMR (<5 , CDC1 3) : 1.46 (br, 12H, c h a i n 2-, 2'-, 3-, 3'-, 4-, 4'-CH 2), 2.19, 2.22, 2.30, 2.22-2.50 ( s , s , s , m, 28H, p y r r o l e 2-CH 3, durene CH"3, p y r r o l e 4-CH 3, c h a i n , 5-, 5'-CH 2), 2.50-2.78 (m, 4H, c h a i n 1-, 1'-CH 2), 5.31 (s, 4H, 0-CH_ 2C 6H 5), 7.30-7.52 (m, 10H, C g H 5 ) , 8.60 (bs, 2H, NH). 1 3 C NMR (<5, 10% TFA-CDC1 3) : 164.53 (C=0) , 137.17 (durene 1-C and 4-C), 135.81 (benzene 1-C), 134.25 ( p y r r o l e 2-C), 132.35 (durene 2-C, 3-C, 5-C, 6-C), 131.03 ( p y r r o l e 4-C), 128.91, 128.69, 128.39 (benzene 2-C, 3-C, 4-C, 5-C, 6-C), 123.96 ( p y r r o l e 3-C), 115.57 ( p y r r o l e 5-C), 67.37 (-0-CH 2C 6H 5), 30.96, 30.82, 30.24, 30.07 (chain 1-, 1'-, 2-, 2'-, 3-, 3'-, 4-, 4 , - C ) , 24.20 (chain, p y r r o l e t e r m i n i , 5-C, 5'-C), 16.49 (durene CH^), 11.69, 11.34 ( p y r r o l e 2-CH^, 4-CH-,). Mass—spectrum R e l a t i v e m/e I n t e n s i t y (%) Assignment 728 88 M + :6 L5~"2' 620 36 (M-C cH cCH.OH)+ 24 2 3? H^N—i^ 0" 3 ^ Hf H 0 108 100 (C 6H 5CH 2OH) + 91 68 C 7 H 7 + 296 IR (v K B r ) : : 3330 (NH), 1670 (C=0) cm — max 1 , 4 - B i s [ 5 - ( 5 - f o r m y l - 2 , 4 - d i m e t h y l p y r r o l - 3 - y l ) p e n t y l ] - 2 , 3 , 5 , 6 - tetramethylbenzene 137 T h i s compound was prepared by the same procedure as t h a t employed i n the p r e p a r a t i o n of the dialdehyde 93c. The c r u d e - b i s f o r m y l p y r r o l e was-obtained i n q u a n t i t a t i v e y i e l d and was converted to the d i c y a n o v i n y l d e r i v a t i v e 138, befo r e p u r i f i c a t i o n . , An a n a l y t i c a l sample was prepared by d e p r o t e c t i n g the p u r i f i e d d i c y a n o v i n y l d e r i v a t i v e 138 with aqueous potassium hydroxide i n n-propanol. MP : 233.0 - 234. 0° C A n a l . C a l c d . f o r C 3 4 H 4 8 N 2 ° 2 : C ' 7 9 - 0 2 ' " H ' 9.36; N, 5.42; Found : C, 78.87; H, 9.47; N, 5.43. 1H NMR (6, 270 MHz, CDC1 3) : 1.46 (br, 12H, c h a i n 2-, 2'-, 3-, 3'-, 4-, 4'-CH ), 2.20 (s, 12H, durene CH 3), 2.22, 2.26 (s, s, 12H, p y r r o l e 2-CH 3, 4-CH 3), 2.30-2.43 (m, 4H, c h a i n 5-, 5'-CH 2), 2.56-2.69 (m, 4H, c h a i n 1-, l ' - C H ^ , 8.99 (bs, 2H, NH), 9.44 (s, 2H, HCO) . Mass spectrum : m/e, 516 (M+) , 488 (M-CO) +, 473 [M-(CO+CH 3)] +. IR (v KBr).: 3260 (NH) , 1640 (C=0) cm" 1. 1 , 4 - B i s { 5 - [ 5 - ( 2 , 2 - d i c y a n o v i n y l ) - 2 , 4 - d i m e t h y l p y r r o l - 3 - y l ] p e n t y l l -2,3,5,6-tetramethylbenzene 138 The crude dialdehyde 137_ (6.51 g :) and m a l o n o n i t r i l e (2.0 g , 30.3 mmol) were r e f l u x e d i n toluene (300 mL) i n the presence of cyclohexylamine (2 mL). As u s u a l , t i c of the r e a c t i o n mixture showed two yellow spots i n a d d i t i o n to the slow moving s t a r t i n g m a t e r i a l . In 1.5 h no s t a r t i n g m a t e r i a l c o u l d be seen on t i c and the slower moving y e l l o w spot (corresponding to the mono p r o t e c t e d d e r i v a t i v e ) was very f a i n t . No change i n t i c c o u l d be observed even a f t e r another 3 0 min. Toluene was evaporated i n vacuo and methanol added. The s o l i d was c o l l e c t e d by f i l t r a t i o n and washed with methanol. The mother l i q u o r s were evaporated to dryness, the r e s i d u e taken up i n methylene c h l o r i d e , methanol added and con-c e n t r a t e d to gi v e a second crop. The f i r s t and second crops were combined and chromatographed on s i l i c a g e l ( a c t i v i t y I, 120 g , ) . Methylene c h l o r i d e was used as the s o l v e n t i n i t i a l l y , but was changed to 0.2% e t h y l acetate-methylene c h l o r i d e l a t e r . The product e l u t e d out c l e a n l y but very s l o w l y . The amount of e t h y l a c e t a t e i n the s o l v e n t was i n c r e a s e d g r a d u a l l y to 0.3%, 0.5%, 0.7% and f i n a l l y t o 0.8%, a t which stage the i m p u r i t i e s s t a r t e d e l u t i n g out. The s o l v e n t was evaporated, i n vacuo, methanol added and the b i s d i c y a n o v i n y l d e r i v a t i v e 138 was c r y s t a l l i z e d out as a lemon y e l l o w powder, y i e l d 4.82 g (62.6% o v e r a l l from the b i s . b e n z y l e s t e r 134). The s o l i d thus obtained was a n a l y t i c a l l y pure. 299 MP : 228.5 - 229.5°C Anal. Calcd. for C 4 QH 4gN 6 : C, 78.39; H, 7.89; N, 13.71 Found : C, 7 8.49; H, 7.77; N, 13.63. 1H NMR (6, 270 MHz, CDC13) : 1.44 (br, 12H, chain 2-, 2'-, 3- , 3'-, 4-, 4'-CH ), 2.13 (s, 6H, pyrrole 4-CH-), 2.20 ( s, 2 J 12H, durene CH 3), 2.31 (s, 6H, pyrrole 2-CH 3), 2.34-2.45 (m, 4H, chain 5-, 5'-CH2), 2.56-2.69 (m, 4H, chain 1-, l'-CH 2), 7.28 [s, 2H, C(H)=C(CN) 21, 9.29 (bs, 2H, NH). 1 3 C NMR (6, 10% TFA-CDC13) : 145.09 (pyrrole 2-C), 140.97 [C (H)=C(CN) 2], 138.80 (pyrrole 4-C), 136.85 (durene 1-C and 4- C), 132.19 (durene 2-C, 3-C, 5-C, 6-C), 126.94 (pyrrole 3-C), 125.04 (pyrrole 5-C)., 117.24 (C=N) , 116.29 (C=N) , 58.77 [C(H)=C(CN) 2], 30.83 (chain, durene terminii 1-C, 1*-C), 30.11 (chain, 2-, 2'-, 3-, 3'-, 4-, 4'-C), 24.04 (chain, pyrrole terminii 5-, 5'-C), 16.45 (durene CH 3), 12.59 (pyrrole 2-CH 3), 9.81 (pyrrole 4-CH 3). Mass spectrum : m/e, 612 (M +), 597 (M-CH 3) +, 184 ( C 1 1 H 1 0 N 3 + ) • I R ( v m a v KBr;) :. 3300-3460 (broad, NH) , 2200 (C=N) , 1590 (C=C) cm"1. 300 l,4-Bis{5-[ 2-1 ( 5 - e t h o x y c a r b o n y l - 3 - e t h y l - 4 - m e t h y l p y r r o l - 2 y l )  methyl] -5-(2 , 2 - d i c y a n o v i n y l ) - 4 - m e t h y l p y r r o l - 3 - y l ] pentyl} -2,3,5,6-tetramethylbenzene 14 0 NC 140 T h i s compound was prepared by the same procedure as t h a t employed i n the p r e p a r a t i o n of the undecane analogue 96a. S t a r t i n g from 1.23 g (2.01 mmol) of the b i s dicyano-v i n y l p y r r o l e 138, 1.74 g (89.2%) of the dipyrromethane 14 0 were obtained as a dark y e l l o w powder. I t should be emphasized t h a t u n l i k e with the s t r a i g h t c h a i n analogues, the lower s o l u b i l i t y of the product r e q u i r e d the a d d i t i o n of more a c e t i c a c i d to d r i v e the r e a c t i o n to completion (In t h i s case, 600 mL of s o l v e n t 301 were r e q u i r e d as compared with approximately 8 0 mL of the undecane analogue). An a n a l y t i c a l sample was r e c r y s t a l l i z e d from methylene c h l o r i d e - m e t h a n o l . MP : 186.0 - 190.0°C A n a l . C a l c d . f o r C „ H ^ , N o 0 , : C, 74.20; H, 7.68; N, 11.54 bu /4 o 4 Found : C, 73.99; H, 7.51; N, 11.60. 1H NMR (6, 270 MHz, CDC1 3): 1.02 ( t , 6H, J=7.5 Hz, 3'-CH 2 CH 3) , 1.32 ( t , 6H, J=7 Hz, -OCH2CH_3) , 1.44 (br, 12H, c h a i n 2-, 2'-, 3-, 3'-, 4-, 4'-CH 2), 2.13 (s, 6H, p y r r o l e 4-CH 3), 2.20 (s, 12H, durene CH 3), 2.26 (s , 6H, p y r r o l e 4'-CH 3), 2.33-2.48 (m, 8H, 4 '-CH_2CH3 , c h a i n 5-, 5'-CH 2), 2.56-2.69 (m, 4H, c h a i n 1-, 1'-CH ) , 3.94 (s, 4H, brid g e CH 2) , 4.23 (q, 4H, J=7 H, 0-CH 2CH 3), 7.28 [C(H)=C(CN) ] , 8.75 (br, 2H, l'-NH), 9.17 (br, 2H, 1-NH). I 3 C NMR (6, 10% TFA-CDC1 3) : 164.74 (C=0), 142.93 [C(H)= C ( C N ) 2 1 , 141.89 ( p y r r o l e 2-C), 138.78 ( p y r r o l e 4-C), 136.89 (durene 1-C, 4-C), 132.21 (durene 2-C, 3-C, 5-C, 6-C), 129.82, 128 .98, 126.51, 126.11 ( p y r r o l e 3-C, 2'-C, 3'-C , 4'-C), 125.19 ( p y r r o l e 5-C), 118.09 ( p y r r o l e 5'-C), 116.75 (C=N), 115.67 (CsN), 61.97 (-0-CH 2-CH 3), 60.99 [C(H)=C(CN) 2], 30.82 (chain, durene t e r m i n i 1-C, l ' - C ) , 30.19 (4C), 29.97 (chain, 2-, 2'-, 302 3-, 3'-, 4-, 4'-C), 24.20 ( cha in , p y r r o l e t e rm i n i 5-, 5'-C), 17.44 (py r ro le 3'-CH 2CH 3), 16.42 (durene CH 3), 15.29 (pyr ro le 3'-CH 2CH 3), 14.24 (-0-CH 2CH 3), 10.85 (py r ro le 4'-CH 3) f 9.76 (py r ro l e 4-CH 3). — ( V a x K B r ) : 3 4 1 0 ( N H ) ' 3 3 2 0 ( N H ) ' 2 2 1 0 ( C - N ) ' 1 7 1 0 (C=0), 1580 (C=C). 1,4-Bis(5-[2-[(5 - c a rboxy-3 - e t hy l-4 -me thy l py r r o l-2 - y l )me thy l ] -5-formy l-4 -methy lpyr ro l-3 -y l ]penty l}-2,3,5,6 - te t ramethy lbenzene 141 The procedure used f o r the s y n t h e s i s of t h i s compound was the same as t h a t employed i n the p r e p a r a t i o n of the dipyrromethane dimer 107. The q u a n t i t i e s of reagent and s o l v e n t s used f o r 1.21 g (1.25 mmol) of the s t a r t i n g m a t e r i a l 140 were, 7.5 g potassium hydroxide, 100 mL of water and 6 0 mL of n-propanol. When propanol was d r i v e n o f f a f t e r the completion of the r e a c t i o n and water added to b r i n g the t o t a l volume to 300 mL. the product d i d not o i l out but remained as an emulsion (with the s t r a i g h t carbon c h a i n analogues, more than double t h i s volume of water was r e q u i r e d to get the gummy product i n t o s o l u t i o n ) . The s o l u t i o n was a c i d i f i e d w ith a c e t i c a c i d and the product i s o l a t e d and d r i e d to g i v e 1.01 g, (99.0%). In s e v e r a l other p r e p a r a t i o n s , the y i e l d v a r i e d between 9 0% to q u a n t i t a t i v e . The pa l e brown powdery s o l i d i s o l a t e d from the r e a c t i o n mixture was a n a l y t i c a l l y pure. MP ; 158.0 - 160.0°C (dec) Ana l . C a l c d . f o r C 5 Q H 6 6 N 4 0 6 : C, 73.32; H, 8.12; N, 6.84; Found : C, 73.28; H, 8.22; N, 6.80. 1 H NMR (6 , DMSO-dJ : 0.84 ( t , 6H, 3'-CH 0CH_), 1.32 o z — j (br, 12H c h a i n 2-, 2'-, 3-, 3'-, 4-, 4 ,-CH 2), 1.96 - 2.44 (m, br, 36H, durene CH"3 , p y r r o l e 2-, 4-CH"3', c h a i n 1-, 1'-, 5-, 5'-CH 2, 3'-CH 2CH 3), 3.78 (br, 4H, bridge CH_2), 9.48 304 (s, 2H, HCO) , 10.94 (bs, 2H, 1-NH), 11.48 (bs, 2H, l'-NH). Mass spectrum : . 818 (M +, very weak), 816 (M-2H) +, 730 (M-2C0 2) +. 7 ,17-Di-ethyl-2 , 8 ,12 ,18-tetramethyl-3 ,13—[-2 ,3 ,5 , 6-tet-ramet-hyl—-phenyl erie-1, 4-bis (pen tame thy lene)"] p o r p h y r i n 143 U 3 The s y n t h e s i s of t h i s p o r p h y r i n and i t s chromato-gra p h i c p u r i f i c a t i o n were c a r r i e d out i n the manner d e s c r i b e d f o r the undecamethyleneporphyrin 109a. The o v e r a l l y i e l d , s t a r t i n g from the dipyrromethane 141 v a r i e d between 22% and 31%. The porphyrin was c r y s t a l l i z e d from the methylene chloride solution using methanol rather than nitromethane since i t was more soluble i n the l a t t e r solvent. MP : 273.0 - 274.5°C Moi. Wt. Calcd. for C.0H,nN. : 692.4818 ; Found, by high resolution mass spectrometry : 692.4866. Anal. Calcd. for C 4 8 H 6 0 N 4 : C ' 8 3- 1 9'" H ' 8.7 3; N, 8.08; Found : C, 81.50; H, 8.90; N, 7.72; Anal. Calcd. for C48 H60 N4* C H 3 0 H : C ' 8 1 - 2 2 ; H ' 8.84; N, 7.73. NMR (270 MHz, 6, CDCl 3) : 9.94 (s, 2H, methine protons 10-H and 20-H), 9.86 (s, 2H, methine protons 5-H and 15-H), 4.09 (m, 6H, CH_2CH3 and one proton each at chain termini), 3.84 (m, 2H, one proton each at chain termini), 3.64 (s, 6H, two CH 3), 3.48 (s, 6H, two CH 3), 1.90, 1.87 (t, m, 10H, CH2CH_3 and four chain protons), 1.40 (t, 4H, chain-durene termini), 0.91 (m, 2H, chain protons), 0.69 (m, 2H, chain protons), -1.06 (m, 4H, chain protons), 3.81 (bs, 2H, N-H) 1 3 C NMR (6, 10% TFA-CDC13) : 146.07, 143.08, 142.90, 142.71, 141.25, 140.31, 139.17 (16C, a - and 3-pyrrolic carbons), 134.79 (2C, durene 1-C, 4-C), 130.25 (4C, durene 2-, 3-, 5-, 6-C), 99.87 , 98.91 (4C,meso carbons 5-, 10-, 15-, 20-C)., 30.80, 29. 27.20 (10C, cha i n c a r b o n s ) , 20.16 (2C, CH 2CH 3), 16.67 (2C, CH 2CH 3), 14.65 (4C, durene CH 3), 12.28, 11.68 (4C, 2-, 8-, 12-, 18-CH 3). V i s i b l e spectrum (CH 2C1 2) : max (nm), 400.7 500.8 537.0 569.8 623.9 l o g e, 5.16 4.04 3.98 3.76 3.64 CHAPTER 4 SPECTRAL ASSIGNMENTS AND COMPARISON TABLES 308 4.1 1H-NMR SPECTRA AND COMPARISON TABLES QF STRAPPED  PORPHYRIN INTERMEDIATES The t a b l e s I to VII l i s t the proton nmr chemical s h i f t s o f c h a i n l i n k e d b i s p y r r o l e s and dipyrromethane dimers s y n t h e s i z e d d u r i n g the course of t h i s work. Each t a b l e i s accompanied by the spectrum of the undecane l i n k e d d e r i v a t i v e which has been s e l e c t e d as the r e p r e s e n t a t i v e compound. These t a b l e s and the i l l u s t r a t e d s p e c t r a both demonstrate why proton nmr was one of the most important a n a l y t i c a l t o o l s i n t h i s work. The magnitude of the chemical s h i f t s f o r analogous f u n c t i o n s i n s i m i l a r compounds tend to be very s i m i l a r as can be r e a d i l y seen by i n s p e c t i n g these t a b l e s . The nmr s p e c t r a were u s e f u l not on l y i n v e r i f y i n g the homogeneity of samples but a l s o i n i d e n t i f y i n g major i m p u r i t i e s p r e s e n t by reason of s i d e - r e a c t i o n s , e t c . Some f e a t u r e s of the proton nmr s p e c t r a o f these i n t e r m e d i a t e s should be noted here. In every b i s - p y r r o l e and dipyrromethane dimer with a simple alkane c h a i n (except the d i k e t o n e s 88a - 88c)the c h a i n methylene resonances were observed i n two d i s t i n c t groups; the four protons a t the p y r r o l e t e r m i n i , as a m u l t i p l e t (6 2.18 - 2.50) and the r e s t as a broad r i s e near 6 1.3. As expected, the c h a i n methylene protons of the d i k e t o n e s , 88a - 88c, (Figure 22; Table I) appear i n three groups; a t r i p l e t around 6 2.8 f o r the protons next to the c a r b o n y l group, a m u l t i p l e t f o r the next adjacent CH^ groups, and a broad r i s e f o r the r e s t . In the durene-bis-pentane s e r i e s , the resonances of the c h a i n methylene protons e x h i b i t a s i m i l a r p a t t e r n except f o r two d i f f e r e n c e s . F i r s t , the CH"2 protons a t the durene t e r m i n i produce a separate m u l t i p l e t a t 6 2.5 - 2.8, and second, the broad r i s e due to the i n t e r m e d i a t e methylene protons i s s h i f t e d d o wnfield by approximately 0.2 ppm (Figure 25; c f F i g u r e 24). I t should be emphasized here t h a t i n order to f a c i l i t a t e the comparison, the c h a i n carbon atoms of durene bis-pentane have been numbered i n a manner s i m i l a r to t h a t used f o r the simple alkane c h a i n s . Therefore the p y r r o l e t e r m i n i , remain 1-C and n-C (n=10) whereas the durene t e r m i n i are 5-C and 6-C. T h i s numbering system has been maintained throughout the nmr data t a b l e s . The chemical s h i f t s of the 2- and 4- methyl protons of the p y r r o l e nucleus e x h i b i t an i n t e r e s t i n g p a t t e r n . For the 5-ethoxycarbonyl system (Figure 23; Table I I ) , the resonance a t 6 2.14 i s due to the 2-CH^ group whereas the 4-CH^ group occurs a t 6 2.20. Comparisons of v a r i o u s 310 m e t h y l / e t h y l s u b s t i t u t e d p y r r o l e s h a v e a l l o w e d 4 3 t h e a s s i g n - -ment o f s p e c i f i c c h e m i c a l s h i f t s f o r a s i m p l e t r i m e t h y l p y r r o l e shown b e l o w . S i m i l a r c h e m i c a l s h i f t p a t t e r n s a r e a l s o o b s e r v e d f o r t h e c o r r e s p o n d i n g b e n z y l e s t e r s ( F i g u r e 24, 25; T a b l e I I I ) . I n t e r e s t i n g l y e n o u g h , when t h e e l e c t r o n w i t h d r a w i n g g r o u p was c h a n g e d t o an a l d e h y d e (HC=0), t h e two m e t h y l r e s o n a n c e s a p p e a r e d t o move c l o s e r t o g e t h e r . A s shown i n F i g u r e 26 and T a b l e I V , t h e u n d e c a n e d e c a n e and nonane l i n k e d b i s f o r m y l p y r r o l e s e x h i b i t o n l y a s i n g l e m e t h y l r e s o n a n c e w h i l e i n t h e o c t a n e a n a l o g u e , t h e two s i g n a l s a r e o n l y 2 Hz a p a r t . When t h e e l e c t r o n - w i t h d r a w i n g g r o u p i s o n e . o f t h e c y a n o v i n y l t y p e , two w e l l s e p a r a t e d s i n g l e t s a p p e a r o n c e more ( F i g u r e 27; T a b l e V ) , b u t i t c a n be shown c o n c l u s i v e l y t h a t t h e o r d e r i s r e v e r s e d ; t h e u p f i e l d s i g n a l i s now due t o t h e 4 - m e t h y l , w h i l e t h e one d o w n f i e l d i s due t o t h e 2 - m e t h y l g r o u p . When compound 94a was r e a c t e d w i t h 2 e q u i v a l e n t s o f s u l f u r y l c h l o r i d e (known t o s u b s t i t u t e one p r o t o n e a c h o f t h e two 311 a-methyl groups), the product 95a d i d not e x h i b i t the down-f i e l d s i g n a l of the above p a i r , and the one u p f i e l d was s h i f t e d s l i g h t l y . 94a n=11 S i m i l a r r e s u l t s have been obtained with d i m e r i c c y a n o a c r y l a t e s (115 116) as w e l l as wit h simple monopyrrolic d e r i v a t i v e s . I t i s p o s s i b l e t h a t a t h e o r e t i c a l e x p l a n a t i o n c o u l d be d e v e l -oped f o r the r e v e r s a l of the order o f methyl resonances, but no attempt i s made here to do so. Another i n t e r e s t i n g f e a t u r e , o b s e r v e d i n the proton nmr s p e c t r a of d i m e r i c p y r r o l e s p o s s e s s i n g an a - f o r m y l group or an a - d i c y a n o v i n y l group, was the e x i s t e n c e of a resonance near 1.7 d e l t a . The i n t e n s i t y of t h i s peak was found to vary 312 from l e s s than 1 proton up to 2 or 3 protons and was not constant even f o r d i f f e r e n t samples of the same compound. For the simple alkane l i n k e d d i m e r i c systems, t h i s peak was w e l l separated from the b r o a d - r i s e of the c h a i n methylene protons (6 ; ^ 1 . 3 ) , but i n the compounds of the durene s e r i e s (137, 138 and 14 0) t h i s e x t r a peak i n t e r f e r e d with the c h a i n methylene resonance. T h i s was as expected, s i n c e i n the l a t t e r s e r i e s , the c h a i n methylene protons appear d o w n f i e l d (6 ~-1.5) of the corresponding protons of the alkane analogues (6 -—1.3). When the s p e c t r a were recorded a t 27 0 MHz, the two resonances were r e s o l v e d as two broad s i n g l e t s and the one a t higher f i e l d (6 = 1.44 ppm) accounted f o r the expected number of protons of the c h a i n . T h i s e x t r a peak near 1.7 d e l t a was a t t r i b u t e d to protons of water molecules, hydrogen bonded to the compound. As expected, t h i s peak was removed when the spectrum was recorded i n the presence of D o0. FIGURE 22 : H NMR Spectrum(100 MHz) of 88a i n 10% TFA-CDC1 i—1 LO TABLE I : H NMR DATA OF CHAIN LINKED B I S PYRROLE DIKETONES ( i n 10% TFA-CDC1,) 88 X = GROUP - < C H 2 ) 3 - " < C H 2 ) 4 - - ( C H 2 ) 5 - - C H 2 . C H 2 . C 6 ( C H 3 ) 4 . C H 2 88c (n=9) 88b ( n = l l ) 88a ( n = l l ) 132 (n= 1 0 ) C h a i n 4 1 t o ( n - 3 ) 1 CH 3-CH 2-0 C h a i n 3' and ( n - 2 ) ' D u r e n e - C H 3 P y r r o l e 4-CH 3 P y r r o l e 2-CH 3 C h a i n , d u r e n e t e r m i n i 5 1 , 6' C h a i n , 2' and ( n - l ) ' C H 3-CH 2-0 N-H 1.36 1.43 1.69 2.57 2.59 2.87 4.46 10.15 1.33 1.43 1. 66 2.57 2.59 2.86 4.45 10.15 1.33 1.43 1.69 2.57 2.59 2.86 4.46 10.15 1.38-2.10 ( 3 ' , 4 ' , 7 ' , 8 ' ) 1.46 2 ,24 2.39 2.42 2.58-2.85 2.96 4.47 10.20 TABLE I I : H-NMR DATA OF CHAIN LINKED B I S PYRROLE a-ETHYL ESTERS ( i n CDC1 3) 89 X = GROUP - ( C H 2 ) 7 - - ( C H 2 ) g - - ( C H 2 ) g - - ( C H 2 ) 4 . C g ( C H 3 ) 4 . ( C H 2 ) 4 -89c (n=9) 89b (n=10) 89a ( n = l l ) 133 (n=10) C h a i n 2' t o ( n - 1 ) ' C H 3~CH 2-0 D u r e n e CH, P y r r o l e 2-CH 3 P y r r o l e 4-CH 3 C h a i n , p y r r o l e t e r m i n i l 1 and n 1 C h a i n , d u r e n e t e r m i n i 5',6 1 CH 3-CH_ 2-0 N-H 1.12-1.60 1.12-1.60 1.08-1.58 1.29 2 .14 2.22 4.25 8 .77 1.30 2.14 2.20 4.26 8.81 1.31 2.14 2.22 2.18-2.48 2.20-2.48 2.18-2.44 4.26 8.73 1.32-1.62 ( 2 ' , 3 ' , 4 ' , 7 ' , 8 ' , 9 ' ) 1.35 2. 22 2.20 2.28 2.24-2.50 2.50-2.80 4.32 8.73 i—1 TABLE I I I : 1 H NMR DATA OF CHAIN LINKED BIS-PYRROLE g-BENZYL ESTERS ( i n CDC1 ) X = GROUP 90 -<CH 2) 6- " ( C H 2 ) 7 - - ( C H 2 ) 8 - - ( C H 2 ) 9 - - ( C H 2 ) , 4 . C 6 ( C H 3 ) 4 . ( C H 2 ) 4 -90d (n=8) 90c (n=9) 90b (n=10) 90a ( n = l l ) 134 (n=10) C h a i n 2 1 t o ( n - l ) 1 P y r r o l e 2-CH 3 D u r e n e C H 3 P y r r o l e 4-CH 3 C h a i n , p y r r o l e t e r m i n i , 1 ',n 1, C h a i n , d u r e n e t e r m i n i , 5 ' , 6 1, C 6 H 5 - C H 2 - 0 C6*5 N-H 1.29 2.15 2.29 5.20 8 .83 1.28 2.18 2.29 1.27 2 .17 2.29 5.31 5.31 8 .62 8.63 1. 27 2 .18 2.26 2.22-2.44 2.24-2.50 2.18-2.55 2.20-2.52 5.31 7.30-7.52 7.28-7.52 7.25-7.55 7.22-7.56 8.67 1.46 ( 2 ' ,3' ,4' ,7' ,8' ,9') 2.19 2.22 2.30 2.22-2.50 2.50-2.78 5.31 7.30-7.52 8 .60 VD TABLE I V "H NMR DATA OF CHAIN LINKED BIS-FORMYLPYRROLES ( i n CDC1 3) 9 3 X = GROUP -<CH 2)g- " ( C H 2 ) 7 "(CH ) " ( C H 2 ) 93d (n=8) 93c (n=9) 93b (n=10) 93a ( n = l l ) ( C H 2 ) 4 . C 6 ( C H 3 ) 4 . ( C H 2 ) 4 -137 (n=10) C h a i n , 2 ' t o ( n - l ) • D u r e n e C H 3 P y r r o l e C H 3 C h a i n , p y r r o l e t e r m i n i , 1', n 1 C h a i n , d u r e n e t e r m i n i , 5 1 , 6' H-C=0 N-H 1.30 1.26 2.22,2,24 9.48 9. 90 2.21 9.38 9.96 1. 27 2.20 2.22-2.44 2.22-2.42 2.26-2.48 9.44 9.98 1.26 2.27 2.27-2.49 9.50 9.84 1.46 ( 2 ' , 3 ' ,4' ,7' ,8',9') 2.20 2.22,2.26 2.3 0-2.43 2.56-2.69 9.44 8.99 D a t a f r o m 27 0 MHz s p e c t r u m U) TABLE V : H-NMR DATA OF CHAIN LINKED BIS-ct-DICYANOVINYLPYRROLE ( i n CDC1-) NC CN N C CN 94 X = GROUP " ( C H 2 ) 6 - - ( C H 2 ) 7 - " ( C H 2 ) 8 " ( C H 2 ) 9 94d (n=8) 94c (n=9) 94b (n=10) 94a (n=ll) ( C H 2 ) 4 . C 6 ( C H 3 ) 4 . (CH 2) 4-138 (n=10) Chain, 2' t o ( n - 1 ) ' P y r r o l e 4-CH 3 Durene CH^ P y r r o l e 2-CH 3 Chain, p y r r o l e t e r m i n i 1',n 1 Chain, durene t e r m i n i , 5',6' C(H)=C(CN) n N-H * 1.30 2.15 2.33 2.30-2.50 7.36 9.36 Data from 27 0 MHz spectrum 1.29 2.15 2.33 2.26-2.52 7.35 9.36 1. 28 2.15 2.33 7.34 9.56 1.24 2.12 2 . 27 2.26-2.50 2.27-2.47 7 .28 9.35 1.44 (2',3',4',7',8' ,9') 2.13 2.20 2 .31 2.34-2.45 2.56-2.69 7.28 9.29 CO LO TABLE VI "H NMR DATA OF CHAIN LINKED ct-DICYANOVINYL-a ' -ETHOXYCARBONYL DIPYRROMETHANE DIMERS ( i n CDC1 3) NC / CN 96 X = GROUP -<CH 2) g- -<CH 2> 7- " ( C H 2 ) 8 - - ( C H 2 ) q -96d (n=8) 96c (n=9) 96b (n=10) 96a (n=ll) ( C H 2 ) 4 . C 6 ( C H 3 ) 4 . (CH 2) 4-*140 (n=10) 3'-CH 2CH 3 -0-CH 2-CH 3 Chain, 2"to(n-l) 1.01 1.00 1.03 1.03 1.36 1.35 1.36 1.34 1.14-1.46 1.14-1.48 1.16-1.53 1.18-1.54 1.02 1.32 1.44 (2",3",4",7",8",9") LO K> TABLE VI - Continued GROUP 96d 96c P y r r o l e 4-CH 3 2.15 2.15 Durene CH^ P y r r o l e 4'-CH3 2.30 2.29 C h a i n , p y r r o l e 2.22-2.54 2.22-2.56 t e r m i n i : 1 ,n 3'-CH 2CH 3 2.4 0 2.4 0 Chain, durene ter m i n i , 5 " , 6 " Methane bri d g e q q CH„ J ' y y 3 .99 0- CH 2-CH 3 4.29 4.31 C(H)=C(CN) 2 7.34 7.34 l'-NH 8.93 9.03 1- NH 9.23 9.23 * Data from 27 0 MHz spectrum 96b 96a 140 2.15 2.29 .22-2.59 2.41 3 .98 4.29 7.34 8.87 9.22 2.15 2.30 2.21-2.58 2.43 3.98 4.29 7.31 8.90 9.24 2.13 2.20 2.26 2.33-2.48 2.33-2.48 2.56-2.69 3.94 4.23 7.28 8.75 9.17 T A B L E - V I I . : H-NMR DATA OF CHAIN LINKED a-FORMYL-a'-CARBOXY DIPYRROMETHANE DIMERS ( i n DMSO-d X = - ( C H 2 ) g - - ( C H 2 ) 7 - -(CH ) 8 - - ( C H 2 ) 9 - - ( C H 2 ) 4 . C 6 ( C H 3 ) 4 . ( C H 2 ) 4 -GROUP 107d (n=8) 107c (n=9) 107b (n=10) 107a ( n = l l ) 141 (n=10) 3'-CH 2CH 3 0.86 0.86 0.84 0.84 0.84 C h a i n , 2 " t o ( n - 1 ) " 1.23 1.22 1.22 1.21 1.32 P y r r o l e 4-CH 3 2.18 2.18 2.18 2.15 D u r e n e C H 3 - - - - 2.13 P y r r o l e 4 1-CH., 2.21 2.20 2.20 2.18 TABLE VII - Continued GROUP 107d 107c C h a i n , p y r r o l e t e r m i n i , l " , n " 2.16-2.48 2.16-2.46 3'-CH 2CH 3 Chain, durene _ t e r m i n i , 5",6" Methane brid g e oc o o A CH 2 H-C=0 9.54 9.52 1-N-H 11.03 11.02 l'-N-H 11.48 11.47 107b 107a 141 2.18-2.44 2.16-2.46 1.94-2.44 3.85 9. 54 11.05 11.49 3.82 9.49 11. 00 11.45 3.78 9.48 10. 94 11.48 330 F i g u r e s 30-34 i l l u s t r a t e the proton nmr s p e c t r a of the i n t e r m e d i a t e s s y n t h e s i z e d i n the c y a n o a c r y l a t e - b e n z y l e s t e r route to the undecane strapped p o r p h y r i n . T h i s route made p o s s i b l e the i s o l a t i o n of compound 108 which was the immediate p r e c u r s o r to the p o r p h y r i n i n both r o u t e s , and thereby o b t a i n i t s s p e c t r a l p r o p e r t i e s . I t should be r e c a l l e d a t t h i s stage t h a t the f i r s t dipyrromethane s y n t h e s i z e d i n t h i s r o u t e , the a - c y a n o a c r y l a t e -ct' -benzyl e s t e r 117 c o u l d not be c r y s t a l l i z e d from the chromato-graphed s o l u t i o n and t h e r e f o r e had to be i s o l a t e d as a non-c r y s t a l l i z a b l e g l a s s . T h i s was suggested to be due to the e x i s t e n c e of geometric isomers a t the c y a n o a c r y l a t e groups. The s t e r e o c h e m i s t r y of the c y a n o a c r y l a t e s i s not known f o r c e r t a i n , and h a r d l y matters here, c o n s i d e r i n g the uses these compounds are intended f o r . They are g e n e r a l l y assumed to e x i s t w i t h the c a r b o n y l group t r a n s to the p y r r o l e nucleus i n order to minimize s t e r i c crowding. T h i s s t e r e o c h e m i s t r y has been confirmed i n one simple monopyrrolic c y a n o a c r y l a t e , 70 by X-ray c r y s t a l l o g r a p h y The proton nmr spectrum of compound 117 (Figure 31) e x h i b i t e d some s t r i k i n g f e a t u r e s t h a t suggested the e x i s t e n c e of c i s - t r a n s isomerism a t the c y a n o a c r y l a t e group. In a d d i t i o n to the methoxy peak at <5 3.85, an anomalous hook, approximately one f i f t h the i n t e n s i t y of the former, was observed a t 6 3.76. Together, they i n t e g r a t e d p e r f e c t l y f o r the expected s i x protons (2 methoxy groups). I t i s c l e a r 331 t h a t these two resonances are the r e s u l t of c i s - t r a n s isomerism s i n c e the environment of the methoxy protons would be d i f f e r e n t , depending on whether i t i s c i s or t r a n s to the p y r r o l e r i n g . Another i n t e r e s t i n g o b s e r v a t i o n r e l a t e d to the above, was the e x i s t e n c e of a minor v i n y l peak a t 6 7.25, c o n s i d e r a b l y u p f i e l d of the major peak at 6 7.90. The l a t t e r , which appeared a t the u s u a l p o s i t i o n f o r the cyano-a c r y l a t e v i n y l p roton, i n t e g r a t e d to l e s s than the expected two protons; the i n t e g r a t i o n of the minor peak c o u l d not be determined due to the presence of the m u l t i p l e t f o r the a r y l protons and the s o l v e n t resonance i n the same r e g i o n . Both the above o b s e r v a t i o n s may w e l l be due to the e x i s t e n c e of two isomers. The proton nmr s p e c t r a of the b i s - p y r r o l e 115 (Figure 30) and the dipyrromethane 119 (Figure 33) a l s o e x h i b i t e d very minor v i n y l peaks a t 6 7.25, but the i s o m e r i c methoxy s i g n a l a t 6 3.76 c o u l d not be observed. Thus i t seems reasonable to assume t h a t i n the case of the compound 117, the minor isomer e x i s t e d i n r e l a t i v e l y l a r g e q u a n t i t i e s , thereby making the process of c r y s t a l l i z a t i o n extremely d i f f i c u l t . 4 .2 •"''C-NMR SPECTRA AND COMPARISON TABLES OF STRAPPED  PORPHYRIN INTERMEDIATES 13 . . . . C nmr spectroscopy was used i n t h i s work p r i m a r i l y f o r the purpose of supplementing proton nmr data i n the c h a r a c t e r i z a t i o n of i n t e r m e d i a t e s . However, i n c e r t a i n 13 i n s t a n c e s C nmr alone was s u c c e s s f u l l y used to p r e d i c t the s t r u c t u r e s of unexpected by-products. F u r t h e r , i t was p o s s i b l e to p o s t u l a t e the presence and the s t r u c t u r e of minor i m p u r i t i e s i n c e r t a i n i n t e r m e d i a t e s which caused problems i n subsequent r e a c t i o n s . The t a b l e s g i v e n i n t h i s s e c t i o n p r o v i d e a comparison of the chemical s h i f t s of the b i s p y r r o l e s and the dipyrromethane dimers of d i f f e r e n t c h a i n l e n g t h s . As i n the pr e v i o u s s e c t i o n , each t a b l e i s accompanied by the spectrum of the undecane analogue which has been s e l e c t e d as the r e p r e s e n t a t i v e compound. 13 The C nmr data have been obtained from proton n o i s e decoupled s p e c t r a . The s o l v e n t used throughout t h i s work was deuterochloroform. T h i s was mainly because the assignments, e s p e c i a l l y those of the p y r r o l e carbon atoms, were based on the a l r e a d y a v a i l a b l e data on simple monopyrroles and dipyrromethanes, which had been o b t a i n e d i n t h i s s o l v e n t . Whenever s u f f i c i e n t q u a n t i t i e s o f a compound co u l d not be d i s s o l v e d i n de u t e r o c h l o r o f o r m alone, 10% t r i f l u o r o a c e t i c a c i d i n deuterochloroform (w/w) 338 was used, provided t h a t the compound was s t a b l e i n a c i d . The changes i n chemical s h i f t v a l u e s a n t i c i p a t e d due to the presence of a c i d were taken i n t o account d u r i n g the assignments. I t should be emphasized t h a t although t h i s s o l v e n t was prepared a c c u r a t e l y , no attempt was made to m a i n t a i n the molar c o n c e n t r a t i o n of the compounds constant throughout these d e t e r m i n a t i o n s . T h e r e f o r e , the v a r i a t i o n s i n chemical s h i f t v a l u e s f o r a p a r t i c u l a r carbon of analogous compounds co u l d be p a r t l y due to c o n c e n t r a t i o n e f f e c t s . The assignments of the peaks, p a r t i c u l a r l y those of the p y r r o l e r i n g carbons and the s u b s t i t u e n t s a t t a c h e d , were based on e l e c t r o s t a t i c c o n s i d e r a t i o n s and comparison with a l r e a d y a v a i l a b l e data. A number of monopyrroles and dipyrromethanes with d i f f e r e n t e l e c t r o n - w i t h d r a w i n g groups have been s t u d i e d p r e v i o u s l y by Paine and i n most i n s t a n c e s , the chemical s h i f t v a l u e s compared w e l l . The unambiguous assignment of the peaks corresponding to the p y r r o l e r i n g carbons of dipyrromethanes (shown below) was not p o s s i b l e due to anomalous valu e s of the observed 78 CHAIN / CN NC chemical s h i f t s . When compared with the s h i f t s of i n d i v i d u a l monopyrrolic systems c a r r y i n g the same e l e c t r o n withdrawing group, the carbons 2-,4-,5- and 5'- d i d not show any s i g n i f -i c a n t v a r i a t i o n . On the other hand, the peak due to 2 1-C had moved u p f i e l d and t h a t due to 3'-C to l o w f i e l d r e s u l t i n g i n four peaks between 6 126 and 6 130 (Table X I I I ) . I t would be n o t i c e d t h a t each of these resonances occurs a t a comparable value i n the d i f f e r e n t s e r i e s except i n the case of the undecane d e r i v a t i v e (the o n l y sample whose spectrum was recorded i n deuterochloform a l o n e ) . No attempt has been made to a s s i g n these resonances to i n d i v i d u a l carbon atoms or to r a t i o n a l i z e the anomalous chemical s h i f t s observed. • I • I • I I I . 40pOHz 20 10 I . I . I J — i — i — I i i i i ' i i X / 1 88 a n = 11 H r fit** /W»vnf fr» 1 I 1 I 1 I E I 1 I T — l — i — I— r — i— i 250 200 150 100 50 5 FIGURE 35 : C NMR Spectrum of 88a i n 10% TFA-CDC1 1 I 1 I 1 EjZ 0 CO o TABLE V I I I : 13C-NMR DATA OF CHAIN LINKED BIS-PYRROLE DIKETONES [ i n 10% TFA-CDCl^ (w/w)] 8 8 x GROUP ~ ( C H 2 ) 7 - - ( C H 2 ) 8 - - ( C H 2 ) Q -88c (n=9) 88b (n=10) 88a (n=ll) ( C H 2 ) 4 . C 6 ( C H 3 ) 4 . ( C H 2 ) 4 132 (n=10) Chain l ' - C , n'-C(C=0) E s t e r C=0 P y r r o l e 2-C Durene 1-C, 4-C Durene 2-C,3-C,5-C,6-C P y r r o l e 4-C P y r r o l e 3-C P y r r o l e 5-C E s t e r -0-CH 2~CH 3 203.79 163.95 142.25 132.19 122.78 118 .49 62.32 203.68 163 .76 141.94 131.96 122.79 118.42 62 .16 204.07 164.00 142.31 132.26 122 .80 118.49 62.34 204.11 164.25 142.50 136.56 132.37 123.03 118.61 62.57 u> TABLE VIII - Continued GROUP Chain 2'-C, (n-1)'-C (-CH2-CO-) 88c 42.23 Chain, 4'-C to (n-3)'-C 29.32 Chain, 3'-C, (n-2)'-C 25.57 Durene CEU Pyrrole 2-CH"3 15.44 Ester-Q-CH 2-CH 3 14.23 Pyrrole 4-CH3 12.94 8 8b 42.27 29.41 29.24 25.58 15.39 14 .23 12.89 88a 42.27 29.37 25.74 15.43 14.23 12.94 132 42.27 30.62 29.88 26.12 16.41 15.44 14.26 13.03 FIGURE 3 6 : C NMR Spectrum of 89a i n CDC1 13 TABLE IX : C-NMR DATA OF CHAIN LINKED BIS PYRROLE g-ETHYL ESTERS (in CDC1. 89 X GROUP Ester C=0 Pyrrole 2-C Pyrrole 4-C Pyrrole 3-C Pyrrole 5-C Ester -0-CH2-CH3 Chain [2'-C, (n-l)'-C] Chain [3 '-C to (n-2) »C ] "(CH 2) 7-89c (n=9) 162.04 129.75 127.00 122.37 116.78 59.55 30.90 29. 61 -<CH 2) 8-89b (n=10) 161.84 129.49 127.05 122.42 116.79 59.52 30.88 29.62 -(CH 2) 9-89a (n=ll) 162.24 130.04 126.99 122.36 116.76 59.56 30.95 29.69 TABLE IX - Continued GROUP 8 9c Chain, p y r r o l e t e r m i n i „. n (. ( l ' - C , n'-C) ^4.Ub E s t e r -0-CH2-CR"3 14.59 P y r r o l e 2-CH 3 11.4 3 P y r r o l e 4-CH 3 10.66 8 9b 24.06 14.62 11.47 10.62 8 9a 24.10 14; 6 4 11.41 10.73 • I I I I I • I I I I I I l l l l l l l l . i l 4*0 Hi HMO 10DO 90Q n=11 LXJL i • i • i ' i i i i i i i i i i i i i i 1 — i — i — i — i — i — i — r ~ r 200 150 100 50 0 FIGURE 37 : C NMR Spectrum of 90a i n CDC1 TABLE X : 13C-NMR DATA OF CHAIN LINKED BIS PYRROLE a-BENZYL ESTERS (90a,90b 90c: i n CDC13; 90d, 134 i n 10% TFA-CDC13) 9 0 X = GROUP -(CH 2) g- -(CH 2) 7- -(CH 2)g- -(CH 2) q- - (CH 2) 4.C 6 (CH 3) 4. (CH 2) 4 90d (n=8) 90c (n=9) 90b (n=10) 90a (n-11) 134 (n=10) Ester C=o 163.21 Durene 1 -C , 4-C Benzene 1-C 136.25 161.57 136.85 161.53 136.83 161.68 136.77 164.53 137.17 135.81 Durene 2-C, 3-C, 5-C, 6-C Pyrrole 2-C 132.30 130.16 130.05 130.37 132.35 134.25 TABLE X - Continued GROUP 90d 90c Benzene 2-C, 3-C, 128.66 128.49 4-C, 5-C, 6-C. 128.18 127.93 P y r r o l e 4-C 129.25 127.61 P y r r o l e 3-C 123.24 122.52 P y r r o l e 5-C 115.96 116.39 Ester-0-CH„-C,H c 66.34 65.33 — 2 6 5 Ch a i n [ 2 1 - C , (n-1) ' ±C ] 30.90 30.84 Chain[3'-C to (n-2) «-C] 29.53 29.53 Chain, p y r r o l e 24.03 24.03 t e r m i n i (l'-C,n'-C) Durene CH"3 P y r r o l e 2-CH 3 11.44 P y r r o l e 4-CH 3 11.11 10.77 90b 128.49 128.01 127.64 122.57 116.41 65. 37 30.88 29.61 24.04 11.48 10.78 90a 128.46 127.91 127.52 122.50 116.37 65.30 30.85 29.61 24 . 02 11.37 10.84 134 128.91 128.69 128.39 131.03 123.96 115.57 67 .37 30.96 30.82 30.24 30. 07 24 .20 16.49 11.69 11. 34 • I • I • I . I . I . I • I i I • i • i • [ • i i i i I • I i I i I i I i " T ~ T ^ -ICH2>n H C H 3 V N„ 9 3 a n = !1 I I I I I I I I I I I I I I I I ' I I I ' I • I. ' I I I I I ' I ' I • I 1 I R 200 150 100 50 0 FIGURE 38 : C NMR Spectrum of 93a i n CDC1 TABLE XI 13 C-NMR DATA OF CHAIN LINKED BIS g-FORMYLPYRROLES (in CDC13) 93 GROUP -(CH 2) 6-93d (n=8) -(CH 2) 7-93c (n=9) -(CH 2) 8-93b (n=10) "(CH 2) 9-93a (n=ll) Aldehyde C=0 Pyrrole 2-C Pyrrole 4-C Pyrrole 5-C Pyrrole 3-C Chain[ 2 '-C, (n-l) '-C] Chain[3'C to (n-2)'-C] Chain, pyrrole termini (l'-C, n'-C) Pyrrole 2-CH^ Pyrrole 4-CH 175.56 136.55 132.58 127.96 123.38 30.57 29.51 29.35 23.76 11.61 8.89 175.52 136.61 132.60 127.89 123.43 30.58 29.51 23.74 11. 60 8.86 175.53 136.51 132.63 127.88 123.46 30.60 29.58 23.77 11. 63 8.87 175.52 136.74 132.71 127.87 123.44 30.61 29.59 23.76 11. 61 8 .87 . I . I . I . I . I , i i i i i i i i i i i i i i i ~ r 40\N Hi 10DO 1000 •io Wain H 3 H NC' "CN NC CN 9 * Q n»11 1 I 1 I 1 I 1 I 1 I 1 I I 1 I '~1 r 200 150 100 50 13 FIGURE 3 9 : C NMR Spectrum of 94a i n CDC1. 0 TABLE X i i ' : 13C^NMR DATA OF CHAIN LINKED BISa-DICYANOVTNYLPYRROLES (94a, 94b, 94c i n CDC13 94d, 138 i n 10% TFA-CDC13)' NC CN 94 NC CN X = GROUP -<CH 2 )g - (CH 2) 7- -(CH 2) 8 "(CH 2) 9 94d (n=8) 94c (n=9) 94b (n=10) 94a (n=ll) - ( C H 2 ) 4 . C 6 ( C H 3 ) 4 . (CH 2) 4-138 ,(n=10) Pyrrole 2-C 145.85 C(H)=C'(CN)2 140.49 Pyrrole 4-C 139.19 Durene 1-C,4-C Durene 2-C,3-C, 5-C, 6-C Pyrrole 3-C 127.29 141.31 140.49 136.36 141.25 140.48 136.38 141.37 140.48 136.44 125.82 125.79 125.82 145.09 140.97 138.80 136.85 132.19 126.94 TABLE XII - Continued GROUP P y r r o l e 5-C C =N C ;=.N C (H)=C(CN) 2 C h a i n [ 2 1 - C , (n-1)'-C] Chain [3'-C to (n-2)'-C] C h a i n , p y r r o l e t e r m i n i ( 1 1 - C , n'-C) Durene CH 3 P y r r o l e 2-CH"3 P y r r o l e 4-CH 94d 125.22 117 .12 116.21 57 .97 30.26 29.61 24.03 12.57 9.80 94c 124.14 117.54 116.18 62.55 30.24 29.47 23.93 12.51 9.64 94b 94a 138 124.11 117.61 116.18 62.62 30.27 29.61 29.49 23.93 12.56 9.64 124.14 117.64 116.26 62.51 30.25 29.59 23.92 12.56 9.64 125.04 117.24 116.29 58.77 30.83 30.11 24.04 16.45 12.59 9.81 I I I I I I I I I I I I I I ' I I I I I I I ' I ' I I I I I ' I ' I 1 I 1 I 1 " 200 150 100 50 0 8 13 FIGURE 4 0 : C NMR Spectrum of 96a i n CDC1 3 13 TABLE XIII : C-NMR DATA OF CHAIN LINKED a-DICYANOVINYL-a'-ETHOXYCARBONYL DIPYRROMETHANE DIMERS (96a i n CDCl^ ; gjjb, 96d and 140in 10% TFA-CDC1 3 ) X= GROUP " ( C H 2 ) 6 -96 - ( C H 2 ) 7 - " ( C H 2 ) 8 - " ( C H 2 ) 9 -96d (n=8) 9_6c (n=9) 96b (n=10) 96a (n=ll) - ( C H 2 ) 4 . C 6 ( C H 3 ) 4 . (CH 2) 4-140 (n=10) E s t e r C=0 C(H)=C(CN) 2 P y r r o l e 2-C P y r r o l e 4-C Durene 1-C, 4-C 164.73 142.71 141.76 138.51 164.80 142.97 141.85 138 .78 164.75 142.75 141.78 138.58 162.13 140.78 140.57 136.25 164.74 142.93 141.89 138 .78 136.89 t n TABLE XIII - Continued GROUP 96d 96c Durene 2-C,3-C, 5-C,6-C P y r r o l e 3-C P y r r o l e 2 1-C P y r r o l e 3'-C P y r r o l e 4'-C J P y r r o l e 5-C P y r r o l e 5'-C C=N ' ' cm C(H)=C(CN) n E s t e r 0-CH 2-CH 3 Chain[2"-C, ( n - l ) " - C ] Chain[3"-C to (n-2) M-C] 129.78 128.87 126.48 126.08 125.06 118.09 116.87 115.8:9 61.29 61. 93 30.28 29.69 129.85 128.93 126.64 126.14 125.17 11.8 . 09 116.79 115.84 60.90 62.00 30.32 29.77 96b 96a 140 129.81 128.96 126.57 126.12 125.12 118.11 116.88 116.11 61.26 61. 92 30.31 29.80 127.09 126.02 125.16 (125.16) 124.15 118.91 116.84 115.96 64. 27 59.96 30.30 29.59 132.21 129.82 128.98 126.51 126.11 125.19 118.09 116.75 115.67 60.99 61. 97 30.82 30.19 29. 97 TABLE X I I I - Continued GROUP 96d 9 6c C h a i n , p y r r o l e t e r m i n i (1-C,n"-C) and methane bridge CH„ 24.12 24.19 P y r r o l e 3'-CH 2-CH 3 17.40 17.43 Durene CH^ P y r r o l e 3'-CH 2-CH 3 15.27 15.27 E s t e r 0-CH 2~CH 3 14.28 14.27 P y r r o l e 4'-CH3 10.85 10.84 P y r r o l e 4-CH 3 9.67 9.70 96b 24 .18 17.43 15.29 14 .29 10.86 9.71 9 6a 23.95 17 .39 15.38 14 .46 10.52 9.62 14 0 24.20 17.44 16.42 15.29 14 . 24 10.85 9.76 358 4.3 NMR DATA OF STRAPPED PORPHYRINS Figures 41 - 44 i l l u s t r a t e the proton nmr spectra of the four strapped porphyrins synthesized during the course of t h i s work. In order to conserve space, the following abbreviations w i l l be used for the free base porphyrins, throughout the discussion: Compound Number T r i v i a l Name Abbreviation 106 Etioporphyrin II H 2 P E 109a Undecamethyleneporphyrin H2 P11 109b Decamethyleneporphyrin H2 P10 109c Nonamethyleneporphyrin H2 P,9 143 Dureneporphyrin H2 PD The nmr spectrum of each porphyrin was recorded i n deutero-chlorof orm solution using tetramethylsilane (TMS) as the reference standard. Except i n the case of etioporphyrin II, where s o l u b i l i t y was a l i m i t i n g factor, i n every other instance the concentration of the sample solution was maintained approximately at 005 M. This was important i n order to minimize the v a r i a t i o n of chemical s h i f t s due to the concentration e f f e c t s and thereby afford a d i r e c t comparison of peak positions. Concentration dependence of free base porpyrin spectra has 7 9 8 0 been investigated by Abraham et a l . and Janson and Katz Not only did i t become apparent that concentration could r e s u l t in considerable changes i n chemical s h i f t s , but protons could become nonequivalent. These concentration e f f e c t s have 109C n= 9 i 1 1 . 1 -1 -2 -3 -U ' -5 10 8 6 5 2 FIGURE 4 2 : •1H NMR Spectrum (400; MHz) of 109c i n CDC1 3 co (Ti O 109b j j A A A A_J\ i l r 0 1 -1 -2 AJ J U - j /V_j\ A A_A 10 9 ~T~ 8 7 i 6 T r - r 2 1 r 0 -1 FIGURE 43 : H NMR Spectrum (400 MHz) of 109b i n CDC1. FIGURE 44 : 1H NMR Spectrum (400 MHz) of 109a i n CDC1-j u> 363 been a t t r i b u t e d by Abraham to the s e l f - a g g r e g a t i o n of p o r p h y r i n 79 molecules i n s o l u t i o n '. The s p e c t r a of the s t r a i g h t c h a i n strapped p o r p h y r i n s (H„P n, H_P,A and H„P,' ) were recorded a t 400 MHz whereas z y z i u z i i those of H nP^ and H^P^, a t 270 MHz and 100 MHz,-respectively. 2 D 2 E ' The three p o r p h y r i n s H2Pg, **2P10 a n c ^ H 2 P 1 1 ^ a <^ P r e v i ° u s l y been recorded a t 270 MHz and no improvement i n r e s o l u t i o n was observed a t 4 00 MHz. T h i s c o u l d be due to the computer l i m i t a t i o n s , of the Bruker WH-4 00 machine a t the time of use. The chemical s h i f t s of e t i o p o r p h y r i n II compared w e l l 81 with the data p u b l i s h e d p r e v i o u s l y . The four methine (meso) protons (5,10,15,20) were observed as a s i n g l e t a t 6 10.12, the four r i n g methyl protons (2, 8,12,18) as a s i n g l e t a t 6 3.64 and the methyl and methylene protons of e t h y l groups as a t r i p l e t and a q u a r t e t a t 6 1.89 364 and 4.12 r e s p e c t i v e l y . The i n n e r N-H protons expected a t approximately 6 -4 were not observed, probably due to exchange broadening. S e v e r a l i n t e r e s t i n g changes were observed i n the nmr s p e c t r a of the strapped p o r p h y r i n s when compared with t h a t of e t i o p o r p h y r i n I I . The s t r u c t u r a l change i n going from e t i o p o r p h y r i n I I to the strapped p o r p h y r i n s c o u l d be envisaged as l i n k i n g the 3, 13-ethyl groups i n the form of a c h a i n , over one face of the macrocycle. The asymmetry i n t r o d u c e d i n t o the molecule by t h i s s t r u c t u r a l change was c l e a r l y i l l u s t r a t e d by the s p l i t t i n g of c e r t a i n resonances. Of s p e c i a l s i g n i f i c a n c e were the changes observed i n the methine proton resonances and the r i n g methyl proton resonances. I t was i n t e r e s t i n g to note t h a t although the changes i n chemical s h i f t s were not l a r g e , a d e f i n i t e trend c o u l d be e s t a b l i s h e d i n the case of the resonances of common groups, based on the v a r i a t i o n of the c h a i n l e n g t h . For t h i s purpose i t was necessary to c o n s i d e r the s t r a p of the durene-capped p o r p h y r i n H 2 P D a S c o n s i s ' t i n < ? °f a simple 12 carbon c h a i n ; i . e . , the durene cap was c o n s i d e r e d as being approximately equiv-a l e n t to two methylene groups i n l e n g t h . Table XIV shows 365 U 3 some i n t e r e s t i n g v a r i a t i o n s i n chemical s h i f t s . The i n t r o -d u c t i o n of the s t r a p caused the s p l i t t i n g of the s i n g l e methine proton resonance of e t i o p o r p h y r i n I I i n t o two s i n g l e t s , each i n t e g r a t i n g to two protons. As the ch a i n l e n g t h was decreased, i n going from H 2 P D to H 2P g, the s e p a r a t i o n o f the two s i g n a l s was observed to i n c r e a s e . More s i g n i f i c a n t -l y , t here was an u p f i e l d s h i f t of both peaks on lowering the cha i n l e n g t h , the change of the u p f i e l d one of the p a i r being g r e a t e r than t h a t of the oth e r . T h i s u p f i e l d resonance was shown to be due to the methine protons a t 5- and 15-r i n g p o s i t i o n s (discussed l a t e r ) , and i t was reasonable to suggest t h a t the d i s t o r t i o n s caused by redu c i n g the c h a i n l e n g t h should a f f e c t these two p o s i t i o n s more than the other two (10-, 20-) . S i m i l a r changes were observed f o r the resonances due to the r i n g methyl protons. The i n t r o d u c t i o n of the s t r a p TABLE XIV : COMPARISON OF CHEMICAL SHIFTS FOR SELECTED RESONANCES OF PORPHYRINS H 2 P E H 2 P D H 2 P 1 1 H 2 P 1 0 H 2P 9 METHINE C - H RING CH 3 N-H 10.12 3.64 -3.78 9.94 9.86 3.64 3.48 •3.81 9.97 9.80 3.64 3.37 •3.46 9.89 9. 67 3.60 3.27 •3.27 9.71 9.36 3.57 3.00 -3. 06 Reference 81 (Tl 367 caused a s p l i t t i n g of the s i n g l e peak a t 6 3.64 and as the c h a i n l e n g t h was reduced, the s e p a r a t i o n of the two peaks i n c r e a s e d and both peaks moved u p f i e l d . Once again, the e f f e c t o f the v a r i a t i o n of c h a i n l e n g t h seems to be g r e a t e r on one peak (the u p f i e l d one) than the other. I t should be noted t h a t compared with the c o r r e s -ponding v a l u e s of e t i o p o r p h y r i n I I (H„P ), a maximum u p f i e l d s h i f t of 0.76 ppm was observed f o r the methine protons of ^2^9 a n d a c n a n g e of 0.64 ppm i n the same d i r e c t i o n f o r the methyl protons. The most obvious i n t e r p r e t a t i o n i s t h a t t h i s change was due to a lowering of the r i n g c u r r e n t of the p o r p h y r i n macrocycle. A s m a l l e r r i n g c u r r e n t could a r i s e from a reduced resonance s t a b i l i z a t i o n r e s u l t i n g from the d i s t o r t i o n of the p o r p h y r i n from i t s most s t a b l e p l a n a r c o n f i g u r a t i o n . As noted e a r l i e r , t h i s u p f i e l d movement was p r o g r e s s i v e l y i n c r e a s e d as the c h a i n l e n g t h was decreased, a change t h a t would l e a d to g r e a t e r d i s t o r t i o n . The above . i n t e r p r e t a t i o n was c o n s i s t e n t with the change i n chemical s h i f t observed f o r the N-H protons. I f a reduced r i n g c u r r e n t a r i s i n g from the d i s t o r t i o n o f the p o r p h y r i n was the reason f o r the u p f i e l d s h i f t of methine and methyl protons, i n going from H 2 P E to H 2Pg, one would have expected the N-H resonance to move downfield f o r the same reason. T h i s was e s s e n t i a l l y what was observed. Of the strapped porphyrins, H 2 P ^ e x h i b i t s the N-H resonance at 6 -3.46 which moves down to 6 -3.27 f o r H^P n n and 6 -3.06 f o r H^Pg (the N-H peak of e t i o p o r p h y r i n I I i s a t 6 -3.78). The p o s i t i o n of the N-H resonance of the dureneporphyrin H2P D appeared to be anomalous a t 6 -3.81 but i t should be noted t h a t these two protons would be e x p e r i e n c i n g the diamagnetic r i n g c u r r e n t of the durene moiety. T h i s should r e s u l t i n an u p f i e l d s h i f t of the N-H peak. The most i n t e r e s t i n g f e a t u r e of the proton nmr s p e c t r a of strapped p o r p h y r i n s was the l a r g e u p f i e l d s h i f t s e x h i b i t e d by the c h a i n methylene protons. Being above the plane of the p o r p h y r i n r i n g , these protons experience a s h i e l d i n g e f f e c t due to the r i n g c u r r e n t which l e a d to the observed s h i f t s . As i l l u s t r a t e d i n F i g u r e s 41-44, the resonances of the c h a i n methylene protons are d i s p e r s e d over a wide range of chemical s h i f t s ; from approximately +4 ppm up to -6 ppm. U p f i e l d s h i f t s o f protons a r i s i n g from diamagnetic r i c u r r e n t e f f e c t s have p r e v i o u s l y been observed by other workers s t u d y i n g s i m i l a r systems. B a t t e r s b y and H a m i l t o n 3 3 had observed t h a t i n t h e i r doubly b r i d g e d "anthracene capped" p o r p h y r i n (discussed i n s e c t i o n 1.4), the anthracene protons moved 1.6 and 2.7 ppm u p f i e l d r e l a t i v e to those of the f r e e s t r a p 53_ and the aromatic s i g n a l s from the p y r i d i n e r e s i d u e s h i f t e d 1.2 and 5.5 ppm u p f i e l d r e l a t i v e to the f r e e d i o l 52. The m u l t i p l e t s due to the c h a i n methylenes have been observed 3 1 up to 6 -1. T r a y l o r and co-workers have a l s o r e p o r t e d l a r g e u p f i e l d s h i f t s f o r the c h a i n protons and i m i d a z o l e protons of 369 the i r "tail-base" porphyrins (section 1.4), upon coordination of the base to a metal centre. In t h i s system, two resonances at 6 2.34 and 6 -0.17 have been assigned to two protons of the same methylene group. This i l l u s t r a t e s the v a r i a t i o n of the ring current e f f e c t experienced by protons depending on the d i r e c t i o n i n which they are pointing. Further, the 2 and 4 positions of the imidazole ligand were strongly shifted u p f i e l d by the ring current of the macrocycle; an e f f e c t which i s known to increase i n strength both approaching the porphyrin plane 8 2 and the ligand axis through the metal. The unambiguous assignment of the peaks was complicated by several factors. The rotation about the in d i v i d u a l carbon-carbon bonds produce d i f f e r e n t r o t a t i o n a l conformations i n which the chemical environment of a proton would be d i f f e r e n t . This i s p a r t i c u l a r l y important since the ring current experienced at the d i f f e r e n t conformations would not be the same. In a r i g i d strap as encountered here, one can expect the rotation at the carbon-carbon bonds to be r e l a t i v e l y slow (at le a s t at room temperature) and therefore the protons on the same carbon would not produce a time-averaged resonance. The analysis of the spectra of these porphyrins was further complicated by the fact that i n cert a i n instances, more than one nucleus i s buried in a complex absorption multiplet, where several of the coupling constants are of similar size. In addition to v i c i n a l and geminal couplings, long-range coupling through more than three saturated bonds could e x i s t here. Since the v i c i n a l coupling 370 constant v a r i e s as a f u n c t i o n of the d i h e d r a l angle, the i n d i v i d u a l J value would depend on the e q u i l i b r i u m conformation a t each carbon i n these presumably s t r a i n e d s t r a p s , which would be d i f f i c u l t to determine a c c u r a t e l y . Keeping the above f a c t o r s i n mind, a s e r i e s of double resonance experiments were c a r r i e d out on the decamethylene-p o r p h y r i n H 2 P 1 0 """n o r d e r t o o b t a i n a f i r s t - o r d e r assignment of the peaks a r i s i n g from the c h a i n methylene protons. The s e l e c t i o n of H P, n f o r t h i s study was based on s e v e r a l f e a t u r e s 2 10 1 observed i n i t s spectrum (Figure 43). I t would be n o t i c e d t h a t the 20 c h a i n methylene protons appear as 10 d i s t i n c t m u l t i p l e t s , each c o n s i s t i n g of two protons, a f e a t u r e t h a t made the a n a l y s i s simpler ( c f . F i g u r e s 41,42,44). In a d d i t i o n , each m u l t i p l e t i s separated from i t s n e a r e s t neighbour by a t l e a s t 50 Hz, which made i t p o s s i b l e to i r r a d i a t e a peak without having a s i g n i f i c a n t i n f l u e n c e on the one next to i t . F i g u r e s 45-49 i l l u s t r a t e the s p e c t r a obtained by a s e r i e s of double resonance experiments c a r r i e d out on the c h a i n methylene protons. In order to a f f o r d a d i r e c t comp-a r i s o n with the undecoupled spectrum, these s p e c t r a were recorded i n the same range and on the same expansion. The ten resonances due to the c h a i n methylene protons have been l a b e l l e d A to J , s t a r t i n g from the one at the lowest f i e l d . The two lowest f i e l d resonances A and B, each of two protons can e a s i l y by assigned to the f o u r protons a t the ch a i n t e r m i n i ( C - l and C-10). Being attached to the p e r i p h e r y 371 of the p o r p h y r i n r i n g , these protons experience the l a r g e s t d e s h i e l d i n g e f f e c t due to the d e l o c a l i z e d n - e l e c t r o n system of the macrocycle. That both A and B c o n t a i n 1 proton each from C - l and C-10 of the c h a i n , and not two protons of the same carbon, was r e a d i l y demonstrated by the i r r a d i a t i o n of the resonance A (Figure 45b); t h i s r e s u l t e d i n a s i g n i f i c a n t change i n the f i n e s t r u c t u r e of the resonance B. In a d d i t i o n , t h i s i r r a d i a t i o n caused a change a t resonance C and a l s o a sharpening of the l i n e s a t resonance D, i n d i c a t i n g t h a t the protons at C and D are coupled to those a t A. I t can a l s o be seen t h a t the resonances E to J are u n a f f e c t e d by t h i s i r r a d i a t i o n . T h e r e f o r e , both C and D should c o n s i s t of one proton each from C-2 and C-9 of the c h a i n . T h i s assignment was f u r t h e r confirmed by the i r r a d i a t i o n a t resonance B (Figure 45c) which a f f e c t e d o n l y A, C and D. F i g u r e 46b i l l u s t r a t e s the r e s u l t of d e c o u p l i n g of the protons a t resonance C. As expected, changes were observed at A, B and D but i n a d d i t i o n , the resonance at E e x h i b i t e d the l o s s of a c o u p l i n g . T h i s suggested t h a t E was due to one proton each from the next adjacent carbon atoms C-3 and C-8. Although F d i d not show any s i g n i f i c a n t change, t h i s was t e n t a t i v e l y assigned to the other two protons of C-3 and C-8. The i r r a d i a t i o n at D (assigned to the other two protons of C-2 and C-9) p r o v i d e d the c o n f i r m a t i o n f o r the e a r l i e r a s s i g n -ment t h a t F was due to protons from C-3 and C-8. As i l l u s t r a t e d 372 T 1 1 1 :—r 1 0 - 1 - 2 -3 X=grease 8 FIGURE 4 5 : P a r t i a l 1H NMR S p e c t r a of 109b; Ca) Normal Spectrum Cb). Simultaneous I r r a d i a t i o n a t 6 3.67 (c) Simultaneous I r r a d i a t i o n a t 6 3.4 6 I i 1 I — 1 1 1 1 1 r 3 . 2 1 0 -1 - 2 - 3 - 4 -5 -6 X=grease 0 FIGURE 46 : P a r t i a l H NMR Spectra of 109b; (a) Normal Spectrum (b) Simultaneous I r r a d i a t i o n a t 6 1.51 (c) Simultaneous I r r a d i a t i o n a t 6 0.46 374 i n F i g u r e 4 6c, the f i n e s t r u c t u r e of resonance F changed together with those of A, B and C. Once again, i t was i n t e r e s t i n g to note t h a t t h i s i r r a d i a t i o n d i d not a f f e c t the peak due to the other two protons a t C-3 and C-8 (E). Decoupling of the protons a t . E ( a s s i g n e d to C-3 and C-8 protons) produced some very i n t e r e s t i n g r e s u l t s (Figure 47b). As expected, t h i s r e s u l t e d i n changes at C and D (both due to C-2 and C-9 protons) and a t F (assigned to the other two C-3 and C-8 p r o t o n s ) . In a d d i t i o n , a l a r g e c o u p l i n g was l o s t a t G i n d i c a t i n g t h a t t h i s resonance c o n t a i n s protons from C-4 and C-7. However, the peak H was u n a f f e c t e d but f u r t h e r u p f i e l d , resonance I was observed to l o s e p a r t of i t s c o u p l i n g , s t r o n g l y suggesting t h a t I and not H contained the other two protons from C-4 and C-7. T h i s l e f t peaks H and J to be a s s i g n e d to one proton each from C-5 and C-6. The r e s u l t s of the subsequent decouplings proved t h i s assignment to be c o r r e c t . I r r a d i a t i o n a t F (protons of C-3,and C-8), i n a d d i t i o n to causing changes at C, D and E, r e s u l t e d i n d e c o u p l i n g protons a t G and I but not at H and J (Figure 47c), a s i t u a t i o n expected on the above assignment. That H and J were due to protons a t C-5 and C-6 were f u r t h e r s u b s t a n t i a t e d by the i r r a d i a t i o n s a t these two peaks; n e i t h e r caused a s i g n i f i c a n t change at E and F which had p r e v i o u s l y been assigned to protons of C-3 and C-8 (Figures 48c and 49c). Thus, the f i r s t order, assignment .of the protons a t 375 FIGURE 47 : P a r t i a l H NMR Spectra of 109b; (a) Normal Spectrum (b) Simultaneous I r r a d i a t i o n a t 6 +0.03 > (c) Simultaneous I r r a d i a t i o n a t <S -1.17 376 FIGURE 4 8 : P a r t i a l . H NMR Spectra of 109b; (a) Normal Spectrum (b) Simultaneous I r r a d i a t i o n a t 6 -1.7 9 (c) Simultaneous I r r a d i a t i o n at 6 -2.23 D E ® F G H I J -1 -6 X = g r e a s e FIGURE 4 9 : P a r t i a l H NMR Spectra of 109b; (a) Normal Spectrum Cb) Simultaneous I r r a d i a t i o n a t 6 -5.13 (c) Simultaneous I r r a d i a t i o n at <5 -5.87 378 the d i f f e r e n t c h a i n carbon atoms co u l d be made as shown below: 1 1 1 1 1 1 1 1 1 1 r 4 3 2 1 0 - 1 - 2 - 3 - 4 - 5 -6 5 .. I t would be n o t i c e d t h a t , as one gets towards the centr e of the c h a i n , the protons experience a hi g h e r r i n g c u r r e n t e f f e c t , a f e a t u r e observed by ot h e r workers s t u d y i n g s i m i l a r systems. But i s was s u r p r i s i n g to note t h a t two protons on the same carbon atom c o u l d be separated as much as t h a t observed i n peaks G/I and H/J. The two protons on carbon 5 (as w e l l as carbon 6) resonate 3.64 ppm a p a r t which i s the h i g h e s t sep-a r a t i o n observed f o r any n e u t r a l molecule. The two protons on carbon 4 (and carbon 7) appear 3.34 ppm a p a r t . These r e s u l t s c l e a r l y i l l u s t r a t e the s i g n i f i c a n c e of the conformation a t each carbon e s p e c i a l l y w i t h r e s p e c t to the diamagnetic r i n g c u r r e n t of the p o r p h y r i n macrocycle. 'CThe two protons on the same carbon could experience s u b s t a n t i a l l y , d i f f e r e n t r i n g c u r r e n t s depending on whether they p o i n t towards or away from the macrocycle. A s i m i l a r s e r i e s of d e c o u p l i n g experiments were 379 c a r r i e d out w i t h nonamethyleneporphyrin H^Pg and the assignments based on the a n a l y s i s of the s p e c t r a are shown below. The two protons on the c e n t r a l carbon (C-5) appeared i n one i i 1 1 1 1 1 1 1 r 4 3 2 1 0 - 1 - 2 - 3 - 4 - 5 S m u l t i p l e t a t 5 -3.33 while the protons a t C-4 and C-6 appeared i n two m u l t i p l e t s a t 6 -4.15 and -4.35. The f a c t t h a t both protons on C-5 resonate as one m u l t i p l e t i s not s u r p r i s i n g s i n c e the c h a i n c o n s i s t s of an odd number of carbon atoms and the e q u i l i b r i u m conformation of the c h a i n protons may r e s u l t i n both the protons of the c e n t r e carbon p o i n t i n g i n one d i r e c t i o n . The i n f o r m a t i o n a v a i l a b l e i s not s u f f i c i e n t to suggest whether the two protons are p o i n t i n g towards the p o r p h y r i n or away from i t . The f a c t t h a t none o f the c h a i n methylene proton resonances o v e r l a p s with any other resonance a l s o made p o s s i b l e the o b s e r v a t i o n of o t h e r i n t e r e s t i n g f e a t u r e s d u r i n g the double resonance experiments of H 2 P i o * I r r a d i a t i o n of the m u l t i p l e t a t 6 4.06 (the methylene protons of e t h y l groups) r e s u l t e d i n an approximately 12% i n c r e a s e i n i n t e n s i t y of 380 the methine resonance at 6 9.67, r e l a t i v e to t h a t a t 6 9.89. T h i s change, a t t r i b u t e d to the n u c l e a r Overhauser e f f e c t , enabled the assignment of the u p f i e l d resonance (6 9.67) to the 5- and 15- methine protons. A s i m i l a r r e s u l t was ob-t a i n e d with the nonamethyleneporphyrin H „ P n . z y Another i n t e r e s t i n g f e a t u r e observed i n the spectrum of H 2 P i o w a s t * i e e x l s t e n c e °f the methylene protons of the e t h y l groups as a complex m u l t i p l e t r a t h e r than a simple Undecoupled (expanded) Simultaneous I r r a d i a t i o n a t 6 1.81 q u a r t e t expected f o r the CH 2 protons of an e t h y l group. Decoupling of the methyl protons ( t r i p l e t a t 6 1.81) gave a t y p i c a l AB q u a r t e t f o r the methylene protons such t h a t the s p i n system can be d e s c r i b e d as ABR^ f o r the e t h y l s i d e ,9 3 c h a i n s . Abraham and Smith 7' were the f i r s t to demonstrate the non-equivalence of the a-methylene protons u s i n g aquo-3 381 o c t a e t h y l p o r p h i n a t o t h a l l i u m (III) hydroxide shown below. Two i n t e r p r e t a t i o n s f o r the phenomenon wer,e suggested; e i t h e r the i n v e r s i o n of the methyl groups ( i . e . , r o t a t i o n about the C ^ - C g ' , s i n g l e bond i s slow, which would r e s u l t i n an i n t r i n s i c asymmetry of the p o r p h y r i n molecule or the asymmetry i n t r o d u c e d i n t o the p o r p h y r i n r i n g by the metal atom and i t s l i g a n d s may be s u f f i c i e n t to account f o r the observed s p e c t r a , even with r a p i d i n v e r s i o n of the methyl groups. Such asymmetry could a r i s e both from asymmetrically c o o r d i n a t e d l i g a n d s ( f i v e c o o r d i n a t e geometry around the metal, or two d i f f e r e n t a x i a l l i g a n d s ) and from an asymmet-r i c a l l y c o o r d i n a t e d (out-of-plane) metal. The former i n t e r p r e t a t i o n of "hindered r o t a t i o n " was favoured by these authors who c a l c u l a t e d an a c t i v a t i o n energy of ca. 20 k c a l mole ^ f o r t h i s r o t a t i o n . I t was concluded t h a t an a c t i v a t i o n energy of t h i s magnitude would produce a slow enough r o t a t i o n to g i v e the observed anisochronous behaviour of the methylene pro t o n s . 382 84 Dolphin and Busby argued t h a t the a c t i v a t i o n energy f o r r o t a t i o n c o u l d not be as high as 20 k c a l mole f o r the above system and t h a t i n s i m i l a r cases where the b a r r i e r to r o t a t i o n should be even h i g h e r , no hindered r o t a t i o n has been observed. With the y-oxo dimer of scandium (III) o c t a e t h y l p o r p h y r i n (shown below) i n which the " i n s i d e " and " o u t s i d e " of the sandwich pres e n t two d i f f e r e n t environments, these workers observed the same complex p a t t e r n f o r the methylene prot o n s . F u r t h e r , t h i s complex p a t t e r n was observed to c o l l a p s e to a P a s c a l q u a r t e t o n l y a t 180°G. Although these o b s e r v a t i o n s can be e x p l a i n e d e i t h e r by the r e l i e f o f hindered r o t a t i o n of the e t h y l s i d e chains or by the r e v e r s i b l e breakdown of the dimer, the authors argued t h a t the former e x p l a n a t i o n r e q u i r e s t h a t the b a r r i e r to r o t a t i o n be e x c e e d i n g l y , i f not i m p o s s i b l y , high. They 383 conclude t h a t the observed a n i s o c h r o n i c i t y of the methylene protons r e s u l t s from the i n h e r e n t asymmetry of the molecule. 8 5 '8 6 Other workers ' have a l s o observed the non-equivalence of these protons i n m e t a l l o p o r p h y r i n systems. 4 .4 X'JC NMR DATA OF STRAPPED PORPHYRINS 13 F i g u r e s 50-53 i l l u s t r a t e the C nmr s p e c t r a o f the strapped p o r p h y r i n s s y n t h e s i z e d d u r i n g the course of t h i s work. The most s t r i k i n g f e a t u r e of these s p e c t r a i s the e x i s t e n c e of o n l y two resonances (of approximately the same i n t e n s i t y ) f o r the four meso carbons (5-,10-,15- and 2 O 7 ) i n the molecules (6--V-100). The meso carbon atoms are p a r t i c u l a r l y s e n s i t i v e to the nature of the s u b s t i t u e n t s a t the p o r p h y r i n p e r i p h e r y and t h e r e f o r e the number of resonances i n t h i s r e g i o n as w e l l as t h e i r r e l a t i v e i n t e n s i t i e s can be used as evidence f o r any rearrangements t a k i n g p l a c e d u r i n g the a c i d - c a t a l y z e d c y c l i z a t i o n . The s u b s t i t u t i o n o f a methyl group by an e t h y l group i s s u f f i c i e n t to cause an observable change i n the chemical s h i f t s of the meso carbons and t h e r e f o r e r e s u l t i n a change i n the peak p a t t e r n i n t h i s r e g i o n . T h i s has 7 ° 13 been c l e a r l y i l l u s t r a t e d i n the C nmr s p e c t r a o f the four "type isomers" of e t i o p o r p h y r i n . E t i o p o r p h y r i n I FIGURE 51 : 1 3 C NMR Spectrum of 109a i n 10% TFA-CDC1 FIGURE 52 : C NMR Spectrum of T09b i n 10% TFA-CDC1 FIGURE 53 : C NMR Spectrum of 109c i n 10% TFA-CDC1 388 Et Me Et Et Et Me Et Et / \ / \ / \ / \ Me Et Me Me Me Et Me Me Et Me Me Me Me Me Et Et \ y \ y \ y \ / Me Et Et Et Et Et Me Me TYPE I TYPE II TYPE III TYPE IV e x h i b i t s a s i n g l e r e s o n a n c e a t <5 98 . 16 as e x p e c t e d , whereas e t i o p o r p h y r i n I I e x h i b i t s two (6 98.94, 98 .54 ) . Type I I I and t y p e IV i s o m e r s show t h r e e r e s o n a n c e s e a c h , i n t h e r a t i o o f 1:1:2. The two samples o f e t i o p o r p h y r i n I I s y n t h e s i z e d by two d i f f e r e n t r o u t e s ( b o t h c y c l i z e d u n d e r i d e n t i c a l c o n d i t i o n s ) e x h i b i t e d two r e s o n a n c e s e a c h , i n d i c a t i n g t h a t l i t t l e o r no r e a r r a n g e m e n t has t a k e n p l a c e d u r i n g t h e t i m e t h e p o r p h y r i n and i t s d i p y r r o l i c p r e s u r s o r were e x p o s e d t o t h e a c i d c a t a l y s t s y s t e m . I t c a n be s e e n ( F i g u r e s 50-53) t h a t t h i s i s t r u e f o r t h e f o u r s t r a p p e d p o r p h y r i n s s y n t h e s i z e d d u r i n g t h e c o u r s e o f t h i s work. As d i s c u s s e d e a r l i e r ( s e c t i o n 2 . 6 ) , t h e a c i d c a t a l y s e d r e a r r a n g e m e n t l e a d i n g t o i s o m e r i c p o r p h y r i n s i s a s i g n i f i c a n t drawback o f most c a t a l y s t s y s t e m s u s e d f o r c y c l i z a t i o n . T h i s was p a r t i c u l a r l y c r u c i a l i n t h e s y n t h e s i s o f t h e s t r a p p e d p o r p h y r i n s s i n c e t h e c y c l i z a t i o n was c a r r i e d 389 out over a p e r i o d of approximately one week. 13 The C resonances of the p o r p h y r i n s c o u l d be d i v i d e d i n t o four major groups; (i) the a- and g - p y r r o l i c carbons, ( i i ) the meso carbons, ( i i i ) the a l i p h a t i c carbons of the s u b s t i t u e n t s and (iv) the c h a i n methylene carbons. E t i o p o r p h y r i n II e x h i b i t s only 4 resonances i n the aromatic r e g i o n (Table XV), two due to the two types of 3-carbons and the other two being due to the corresponding a-carbons. For the 16 p y r r o l i c carbons of the strapped p o r p h y r i n s , one would expect 8 resonances; t h i s was indeed what was observed. In the "durene capped" p o r p h y r i n H^Prj a n < ^ nonamethylene p o r p h y r i n H^Pg, o n l y seven peaks were observed but one was of approximately twice the i n t e n s i t y as the r e s t . The two resonances at 6 -20 ppm and 6-16 ppm can be assigned to the CH^ and CH^ carbons r e s p e c t i v e l y of the e t h y l s i d e c h a i n s . The carbons of the r i n g methyl groups are observed between 11 and 12 ppm. The methyl groups of H^P-^ and H_P_ produced two s i g n a l s whereas those of H „ P n and zu z y H 2 P 1 0 9 a v e r i s e t o o n l y one. Although g r e a t care was taken to m a i ntain a constant molar c o n c e n t r a t i o n of the p o r p h y r i n i n s o l u t i o n , i t i s d i f f i c u l t to a s c r i b e t h i s d i f f e r e n c e to any s t r u c t u r a l changes i n the molecules. I t should be mentioned here t h a t the s p e c t r a were recorded i n 10% TFA-CDCT^ and t h e r e f o r e , are of the p o r p h y r i n d i c a t i o n s . The c h a i n methylene carbons appear i n the r e g i o n TABLE XV : COMPARISON OF C CHEMICAL SHIFTS OF PORPHYRINS Assignment H 2 P E H 2 P D H 2 P 1 1 a- and B - p y r r o l i c carbons 143 . 54 142.29 141.53 136.92 146.07 143.08 142.90 142.71 141.25 140.31 (140.31) 139.17 146.73 145.12 143.67 141.41 140.56 140.24 140.05 139.20 Durene r i n g carbons 134.79 130.25 Meso carbons 98.39 97.95 99.87 98.91 100.89 99. 94 Chain methylene carbons 30.80 29.46 (29.46) (29.46) 27 .20 28.86 28.67 (28.67) 27.00 25. 98 25.38 CH -CH CH^-CH^ Durene CH^ Po r p h y r i n CH^ 20.11 16.42 11.67 20.16 16.67 14 .65 12.28 11.68 20.21 16.61 12 . 21 11.75 n 10% TFA-CDC1 3) H 2 P 1 0 H 2 P 9 146.87 146.60 145.61 (146.60) 143.61 144.65 141.22 141.21 140.44 140.42 140.22 139.59 138.95 139.07 138.23 134.27 101.24 101.48 100.05 99.72 28.47 28.72 27.94 (28.72) 26.96 28.22 26.46 25.84 25.96 24.97 20.20 20.12 16.62 16.47 11.77 11.66 391 13 between 25 ppm and 3 0 ppm of the C nmr spectrum. For H 2 P 1 0 ' w;"-tn- a c h a i n of an even number of carbon atoms, f i v e s i g n a l s were observed i n one group (Figure 52). For E^l?^, o n l y three s i g n a l s were observed, a t <$ 30.80, 29.46 and 27.20. The peak a t 6 29.46 was broader and c o u l d be a t t r i b u t e d to 6 carbons, the other two being due to 2 carbons each. The spectrum of ^2P±i (Figure 51) e x h i b i t e d 5 resonances, of which two ( 6 28.86 and 28.67) appeared as one broad peak. The s i n g l e c e n t r e carbon of the c h a i n may a l s o resonate a t t h i s f i e l d and the broad resonance here would be due to 5 carbons, the other three r e s u l t i n g from two carbons each. The spectrum of H „ P n (Figure 53) e x h i b i t e d a s i m i l a r p a t t e r n -The peaks a t 6 25.84 and 24.97 would be due to 2 carbons each while the one a t <5 28 .72 would be due to 4 carbons. The "hook" a t 6 28.22 should be due to the odd carbon atom of the c h a i n . I t can be seen t h a t the resonances of the carbon atoms of the c h a i n do not undergo as l a r g e an u p f i e l d s h i f t as the proton resonances do, by the e f f e c t of r i n g c u r r e n t . Since some c o m p l i c a t i n g f a c t o r s such as the p o s s i b l e v a r i a t i o n of the s o l v e n t a c i d c o n c e n t r a t i o n c o u l d e x i s t , no attempt i s made here to a s s i g n the resonances to i n d i v i d u a l carbon atoms. 392 4.5 ELECTRONIC ABSORPTION SPECTRA OF PORPHYRINS Porphyrins e x h i b i t a c h a r a c t e r i s t i c e l e c t r o n i c a b s o r p t i o n spectrum c o n s i s t i n g o f one very i n t e n s e band • 5 (e -^10 ) around 400 nm, known as the "Soret" band and four l e s s i n t e n s e bands i n the r e g i o n from 500 to 7 00 nm. The Soret band i s observed i n a l l t e t r a p y r r o l e s i n which the nucleus i s f u l l y conjugated and i s g e n e r a l l y regarded as a c h a r a c t e r i s t i c of the m a c r o c y c l i c c o n j u g a t i o n . The r e l a t i v e i n t e n s i t i e s of the four v i s i b l e bands are s e n s i t i v e to the nature of the p e r i p h e r a l s u b s t i t u e n t s , g i v i n g r i s e to four main s p e c t r a l c l a s s i f i c a t i o n s . - I — 1 1 • 1 • 1 500 600 500 600 nm v a r y i n g a's I V > I I I > I I > I . One s t r o n g l y e l e c t r o n - w i t h d r a w i n g g r o u p ( f o r m y l , c a r b o x y l i c a c i d , e s t e r e t c . ) a t a 3 p o s i t i o n c a u s e s b and I I I t o become more i n t e n s e t h a n band I V r e s u l t -i n g i n a r h o d o - t y p e s p e c t r u m . T h e s e g r o u p s a l s o c a u s e s h i f t s o f a b s o r p t i o n b a n d s t o l o n g e r w a v e l e n g t h s . Two e l e c t r o n -w i t h d r a w i n g g r o u p s on a d j a c e n t " p y r r o l e " m o i e t i e s c a n c e l o u t e a c h o t h e r s e f f e c t p r o d u c i n g an e t i o - t y p e s p e c t r u m w h e r e a s two s u c h g r o u p s , d i a g o n a l l y p l a c e d , r e s u l t i n t h e o x o - r h o d o s p e c t r u m . The p h y l l o - t y p e s p e c t r u m i s p a r t i c u l a r l y r e p -r e s e n t a t i v e o f mono meso a l k y l s u b s t i t u t e d p o r p h y r i n s a l t h o u g h p o r p h y r i n s w i t h f o u r o r more u n s u b s t i t u t e d p e r i p h e r a l p o s -i t i o n s a l s o e x h i b i t s i m i l a r s p e c t r a . The s t r a p p e d / c a p p e d , p o r p h y r i n s s y n t h e s i z e d d u r i n g t h e c o u r s e o f t h i s w o r k e x h i b i t e d v e r y i n t e r e s t i n g e l e c t r o n i c a b s o r p t i o n s p e c t r a a s i l l u s t r a t e d i n F i g u r e s 55-58. The m o s t s t r i k i n g f e a t u r e o f t h e f r e e b a s e s p e c t r u m was t h e i n c r e a s e i n t h e i n t e n s i t y o f band I I I r e l a t i v e t o I V , a c h a n g e t h a t became more p r o n o u n c e d a s t h e c h a i n l e n g t h was d e c r e a s e d . F u r t h e r m o r e , a s h i f t o f a b s o r p t i o n b a n d s t o l o n g e r w a v e l e n g t h s was a l s o n o t e d ( T a b l e X V I ) , t h i s t o o b e i n g p r o g r e s s i v e l y i n c r e a s e d i n g o i n g f r o m t h e l o n g e s t t o t h e s h o r t e s t s t r a p . I n f a c t , t h e n o n a m e t h y l e n e p o r p h y r i n H „ P n e x h i b i t e d a t y p i c a l 2. y r h o d o - t y p e s p e c t r u m ( F i g u r e 58) a l t h o u g h t h e m o l e c u l e d o e s n o t c o n t a i n an e l e c t r o n - w i t h d r a w i n g g r o u p . The o n l y l o g i c -a l e x p l a n a t i o n t o t h i s i s t h a t a d i s t o r t i o n i n t h e p o r p h y r i n m o i e t y , r e s u l t i n g f r o m t h e s h o r t s t r a p , c a u s e s e f f e c t i v e l y 1-0-1 1 I I I 1 — " ^ " T 30 0 350 400 450 500 550 600 650 700 n m . WAVELENGTH FIGURE 54 E l e c t r o n i c A bsorption Spectra of 106 LO WAVELENGTH FIGURE 55 : E l e c t r o n i c A bsorption Spectra of 143 CO Cn FIGURE 56 E l e c t r o n i c A bsorption Spectra of 109a O J 0> WAVELENGTH FIGURE 57 E l e c t r o n i c A bsorption Spectra of 109b U) —3 FIGURE 58 : E l e c t r o n i c A bsorption Spectra of 109c CO CO TABLE XVI : COMPARISON OF ELECTRONIC ABSORPTION SPECTRAL DATA OF PORPHYRINS (Free base i n CH 2C1 2) Por p h y r i n H 2 P E H 2 P D H 2 P 1 1 H 2 P 1 0 H 2 P 9 Soret 396.5 (5.23) 400.7 (5.16) 400.7 (5.24) 402.0 (5.21) 405.3 (5.23) A. Band IV 497.0 (4.16) 500.8 (4.04) 503.1 (4.05) 507.5 (3.96) 513.5 (3.92) nm (log e ) Band I I I 530.0 (4.02) 537 .0 (3.98) 539 .8 (4.05) 544 .4 (4.03) 551.7 (4.08) Band II 565.7 (3.84) 569.8 (3.76) 571. 9 (3.80) 572.7 (3.78) 579.1 (3.82) Band I 619.7 (3.72) 623 .9 (3.64) 625.8 (3.59) 626.2 (3.37) 633 . 0 (3.43) LO VO VO 400 the same changes i n the e n e r g i e s of the molecular o r b i t a l s as does a s i n g l e e l e c t r o n - w i t h d r a w i n g group a t the p e r i p h e r y . I t should be p o s s i b l e to p r o v i d e a t h e o r e t i c a l b a s i s f o r the observed changes i n the e l e c t r o n i c a b s o r p t i o n s p e c t r a , but no attempt would be made here to do so. The v i s i b l e r e g i o n of p o r p h y r i n d i c a t i o n a b s o r p t i o n s p e c t r a e x h i b i t two major bands, with weaker bands appearing as shoulders to the main peaks. T h i s s p e c t r a l s i m p l i f -i c a t i o n i s thought to be a r e s u l t of the approach towards square ( D^ n) symmetry i n the d i c a t i o n . Although the strapped p o r p h y r i n s a l s o e x h i b i t e d t h i s two band spectrum i n a c i d medium, the r e l a t i v e i n t e n s i t i e s of the two bands appeared to be changed p r o g r e s s i v e l y i n going from a p o r p h y r i n with a long s t r a p to one with a s h o r t e r s t r a p . In a d d i t i o n , the f i n e s t r u c t u r e of the two bands a l s o showed s i g n i f i c a n t change. An i n t e r e s t i n g f e a t u r e observed d u r i n g the h a n d l i n g of the strapped p o r p h y r i n s i n s o l u t i o n was the ease of decomposition e s p e c i a l l y under the i n f l u e n c e of l i g h t . A new band developed i n the a b s o r p t i o n spectrum around 650 n m which c o u l d be a t t r i b u t e d to the p r o d u c t i o n of a c h l o r i n . C h l o r i n s are p o r p h y r i n - l i k e m a t e r i a l s with one of the p e r i p h e r a l double bonds reduced. The change from a p o r p h y r i n to a c h l o r i n c o u l d t h e r e f o r e be a way by which the s t r a i n i n the m a c r o c y c l i c system i s reduced. T h i s decomposition appeared to be r a p i d i n the case of the nonamethylene-p o r p h y r i n H_P Q, and i f exposed to l i g h t f o r long p e r i o d s of TABLE XVII : COMPARISON OF ELECTRONIC ABSORPTION SPECTRAL DATA OF PORPHYRINS (D i c a t i o n i n CH 2C1 2) Porphyr i n X nm (log e ) max ^ Soret Band A Band B H„P^ 399.5 549.1 590.7 2 E (5.58) (4.25) (3.90) H 2 P D 405.0 549.2 594.4 (5.57) (4.16) (3.76) H2Pii 402.7 550.9 597.3 (5.58) (4.12) (3.79) H 2 P 1 Q 405.5 553.4 601.5 (5.55) (4.08) (3.75) H 2P g 409.2 559.3 609.5 (5.53) (4.03) (3.95) 402 time, the "four band" spectrum was observed to disappear completely. The b l u e - b l a c k m a t e r i a l i s o l a t e d from the c y c l i z a t i o n r e a c t i o n of the 8-carbon s e r i e s e x h i b i t e d an a b s o r p t i o n spectrum q u i t e d i f f e r e n t from t h a t of a p o r p h y r i n . In a d d i t i o n to e x h i b i t i n g only two broad bands i n the v i s i b l e r e g i o n , the band around 385 nm was o n l y 1.5 times as i n t e n s e as the more i n t e n s e v i s i b l e band. Since the extended con-j u g a t i o n i n the p o r p h y r i n macrocycle causes the band around 400 nm to be a t l e a s t 10 times as i n t e n s e as the most i n t e n s e v i s i b l e band, i t c o u l d be concluded t h a t t h i s m a t e r i a l i s not a p o r p h y r i n . 403 REFERENCES 1. R. Bonnett i n "The P o r p h y r i n s " , (D. Dolphin, ed.), V o l . 1, p. 1, Academic P r e s s , New York, (1978). 2. A r e p o r t by the Commission on the Nomenclature of B i o l o g i c a l Chemistry, J . Am. Chem. 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