1', “‘91:: ilk-f“, ,S (3‘ t d ‘3; Al‘KD 2‘11“! ‘fl‘i‘é 5X ‘3‘?“ EE: .{i‘g‘fufi ‘ cmwcw a, ”22355.:- J ‘ {5% 96¢?“ m1 Ugh L fuefl‘é'lGhflifi SW: Ffi’ 11‘;ng 5‘ s53: {Agata-h "‘ fiaiqa“ ,3 u. “If? M THEE»; This is to certify that the thesis entitled THE SYNTHESIS AND PROPERTIES OF POLYTHI OPHENFS presented by Arleigh Russell Dodson has been accepted towards fulfillment of the requirements for Pth g . degree in_Qhem:La_tI-y O-l69 LIBRARY Michigan State University ' ”LIBRARY Michigan State University PLACE IN RETURN BOX to remove this checkout from your record. TO AVOID FINES return on or before date due. MAY BE RECALLED with earlier due date if requested. DATE DUE DATE DUE DATE DUE JUN 1 6 2009 - L‘“ ' 7“- -J . .irilyl' 6/01 c:/ClRC/DateDuo.p65-p.15 ABSTRACT THE SYNTHESIS AND PROPERTIES OF POLYTHIOPHENES by Arleigh Russell Dodson Interest in the polythiophenes has received a real impetus recently because of their isolation from plants. They have also been shown to possess nematicidal activity. Further, polythiophenes should provide an opportunity to study thiophene as a substituent in substitution reactions of heterocyclic nuclei. The purpose of the investigation reported here is to develop good methods for the synthesis of polythiophenes. Three new methods for the synthesis of polythiophenes have been developed: (1) ring closure of 1,4-difunctional thienyls with sulfides, (2) ring closure of thienyl-4- mercapto-1,5-butadienes, (3) reaction of thenils with thio- diacetic acid esters. A fourth method, reaction of thienyl methyl ketones with sulfides, was investigated but could not be developed into a satisfactory method for the preparation of these compounds. The three successful synthetic methods have resulted in techniques which pemit a thienyl substituent to be substituted on any thiophene capable of acylation by succinic anhydride, to substitute a carboxythienyl substituent for an aromatic aldehyde functional group and to prepare isomers other than the OL -isomer of polythiophenes. THE SYNTHESIS AND PROPERTIES OF POLYTHIOPHENES By Arleigh Russell Dodson A THESIS Submitted to the School for Advanced Graduate Studies Michigan State University of Agriculture and Applied Science in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Department of Chemistry 1961 TABLE INTRODUCTION . . . . . . HISTORICAL O O O O O O 0 EXPERIMENTAL . . . . . . RESULTS AND DISCUSSION 0 SUMMARY 0 O O O O O O O BIBLIOGRAPHY . . . . . e OF CONTENTS 23 32 3h ACKNOWLEDGEMENTS The author wishes to express his sincere thanks to Professor Robert D. Schuetz for his interest and guidance throughout the course of this work and to the staff at Michigan State University for providing the funds that were necessary to complete this thesis. Grateful ac- knowledgement is also due Mrs. Clara Pederson and Mrs. Marion Dodson for their assistance in the preparation of the manuscript. INTRODUCTI CN INTRODUCTION Since the initial isolation of CK-terthienyl from Tagetes erecta L. (l), the first thiophene derivative iso- lated from a plant, a group of thiophene compounds have been isolated from various Composites (2,12,13,1h). Because of the natural occurrence of polythiOphenes and because of the possibility of studying thiophene as a substituent in sub- stitution reactions of heterocyclic nuclei (3), an investi- gation of the synthesis and chemistry of the polythiophenes has been initated in these laboratories. Since the synthetic methods which were available at the outset of this investi- gation (h) resulted in the preparation of only two of the fourteen possible isomers of trithiOphene, three new methods of synthesis have been developed to obtain the other isomers of these polythiophenes. A fairly recent review paper by Donald E. Wolf and Karl Folkers (5) lists four general methods and one in a miscella- neous category for the preparation of thiophenes, (1) reaction of l,h-difunctional compounds with sulfides (2) reaction of unsaturated compounds with sulfides (3) reaction of 1,2-difunctional compounds with thiodiacetic acid esters (A) reaction of aryl methyl ketones with sulfides (S) miscellaneous cyclization reactions w Three of these synthetic methods have been extended by the work described here to include the polythiOphenes. Further, a presentation of three new methods for the synthesis of polythiophenes and an evaluation of their utility is presented in this thesis. HIST ORI CAL HISTORICAL Polythiophenes are aromatic in character and consist of a chain of thiophene nuclei linked through either their 2- or 3-positions. All three isomeric bithiophenes have been char- acterized (A). Of the fourteen possible isomers of trithio- phene, only the 2,2',S',2"- and the 2,2‘.h',2"-trithiophenes have thus far been reported (h). Aside from the cx-isomers of the pclythiophenes, those from the tetra through the hepta compounds which have up to now been only available as by-pro- ducts from the Ullmann synthesis of 2,2'-bithiOphene (6), no other polythiophenes are known. Indeed, as late as 1952 Hartough (6) states that the " . . . (synthetic) methods are such that . . . the polythiophenes are no more than laboratory curiosities which occur in many cases as by-products in stand- ard reactions (for the preparation of thiophenes)." Hartough (6) employed a simplified system of nomenclature for the naming of polythiOphenes since only the O(-isomers were known at the time of his writings. Thus, he uses CK- terthieryl, O(-quaterthienyl, etc. for the following polythio- phones, Elisha nudism Oi-Terthienyl CK-Quaterthienyl Now that isomers other than the simple Oi-isomers are avail- able, a precise system of nomenclature suitable for naming the polythiophenes such as that used by Chemical Abstracts (7) or by Steinkopf (8) becomes absolutely essential. Since the Chemi- cal Abstracts system of nomenclature for the polythiophenes is unambigious and easily understood it will be used throughout this thesis. For example, Ok-quaterthienyl (Hartough's sys- tem of nomenclature) becomes 2,2',S',2",S",2”'-tetrathicphene in the Chemical Abstracts nomenclature. The isolation of 2,2',S',2"-trith10phene from Tagete erecta L. by Zechmeister and Sease (1) gave new impetus to polythiOphene chemistry since this raised the question of the role of thiophene and its derivatives in the biochemistry of plants. Their isolation of 2,2',S',2"—trithiophene was ex- tended by both chromatographic and spectral studies of the polythiOphenes available (9) at the time of their work. Uhlenbroek and Bijloo (10) reported that the root extracts of Tagetes have nematicidal activity and that the active prin- ciple is 2,2',S',2"-trithiophene. An informal international program of research on Tagetes and polythiOphenes has been de- veloped because of the importance of nematicides (11). A news- letter is published by this group. Birkinshaw and Chaplen (12) reported the isolating of an acetylenic thiophene, 6-( 1 EXPERIMENTAL 2,2'-bithiophene, 08H6323 M.“. 166.25 A 130 g. (0.630 mole) quantity of anhydrous sodium /3 - (2-thenoyl)-propionate was suspended in mineral oil and placed in a two liter flask fitted with a mechanical stirrer, a con- denser arranged for distillation, a dropping funnel and a thermometer. The reactants were heated to 300° and a mineral oil slurry of lhO g. (0.630 mole) of phosphorus pentasulfide was added to them at a rate sufficient to maintain a reaction temperature of 300°. Bithiophene was distilled directly from the reaction mixture. It was purified by distillation.yg 13222 to obtain 12.8 g. (0.077 mole), a 12% yield, of a pure product: mop. 33°; b.p. 260°. Literature (15) value 3h°3(8) m.p. 33°. bop. 260°. /3 -3-thieny1acraldehyde, 0736081 News 133.16 Acetaldehyde, 26 ml. (o.L6 mole): 3-thena1, 25 g. (0.22 mole); and 200 ml. of two percent aqueous sodium hydroxide were added to a 500 ml. flask fitted with a mechanical stirrer i All melting points and boiling points are uncorrected. s‘ne-r 10 and a reflux condenser. The reactants were stirred at room temperature for 17 hours. The product was removed by ex- traction of the reaction mixture with three, 100 ml. portions of ethyl ether. After drying the ether extract over anhy- drous sodium sulfate, the ether was removed in 13322 and the product was purified by fractional distillation to obtain a 7.0 g. (0.051 mole, 23%) yield of/B o3-thienylacra1dehyde, b.p. 90-1000 (1.75 m.m.) 11:0 : 1.71. Rhodanine derivative, m.p. 228-2290. Anal: Calc'd for CIOHYNOSB: C, u7.u1; H, 2.79; 3. 37.96 Foundtl 0. u7.53; H, 2.79; S, 38.20 fihsdanéne derivative of fi?~(2-thienyl)-acraldehyde, ClOH7N083: .-. 2 3.3u A solution containing 8.5 g. (0.063 mole) of rhodanine and 13.0 g. (0.159 mole) of anhydrous sodium acetate dissolved in ho ml. of glacial acetic acid was heated on a steam bath and 9.0 g. (0.063 mole) of IB-Z-thienylacraldehyde were added to it portion wise while shaking the reaction mixture. After heating the latter at its reflux temperature for ten minutes, it was poured into two liters of ice-cold water. The product precipitated as an orange-red colored solid. It weighed 12.0 g. (0.h7 mole), representing a 75.h% yield and melted at 180- All elemental analyses were preformed by Micro-Tech Laboratories, Skokie, Illinois. 11 o 185 . An analytical sample of the derivative after two re- crystallizations from toluene (Norite) melted at 187-188°. Anal: Calc'd for clOH7NOS3: C. h70h03 H: 2.783 N: 50533 3: 37.96 Found: C, “7.58; H, 2090; N, 5.69; S, 38009 5-(2-thienyll-2-merca to-2 - M.". 212.27 p ,3 pentadienoic acid, 69380232: A solution prepared from 6.0 g. (0.02h mole) of the rhodanins derivative of /5'~(2-thienyl)-acraldehyde, 53 m1. (0.125 mole) of 10% sodium hydroxide and 100 m1. of water was heated on a steambath for 20 minutes. The solution was set in an ice-salt bath, and crushed ice was added directly to it, with efficient stirring, until the temperature of the reaction mixture fell to zero. When the temperature reached zero degrees under efficient stirring, 13 ml. of concentrated hydrochloric acid were added in one quantity. The pale yel- low colored precipitate was recovered by filtration, washed with cold water and dried, overnight, in a vacuum desicator. The crude product weighed h.7 g. (0.022 mole, 92%) and melted at 135-1360. S—carboxy-2,2'-bithiophene, cgaéozsz: M.W. 210.26 A solution containing 2.1 g. (0.010 mole) of crude K‘ 12 5-(2-thienyl)-2-mercapto-2,3¢pentadienoic acid, 5.0 g. (0.020 mole) of iodine, and 100 ml. of absolute ethanol was set aside at room temperature for 26 hours. After dilution of the re- action mixture with two liters of water, the excess iodine was destroyed by the addition of a bisulfite solution and the precipitated S-carboxy-Z,2'-bithiOphene was collected by fil- tration. The pale yellow colored solid weighed 1.9 3. (0.0091 mole, 91%) and melted at lSO-l60°. An analytical sample pre- pared by two recrystallizations from methanol (Norite) had a melting point of 183-l8ho. Literature (3) value, 183-18ho. Anal: CQIC'd for C9H602 2: C, Slohl‘ H, 2188; S, 30050 Found: C, 50.72; H, 2.8a; 3, 30.28 S-formyl-2,2'-bithiophene, C9H60323 M.W. 19h.25 To a well-stirred, precooled solution prepared from hl.6 g. (0.25 mole) of 2,2'-bithiophene and 2a ml. (23 g., 0.32 mole) of dimethylformamide, contained in a 500 ml. round bot- tom flask fitted with a condenser, dropping funnel, and mechan- ical stirrer, was added gradually 29 ml. (M8 g., 0.32 mole) of phosphorus oxychloride. When about half of the phosphorus oxy- chloride had been added, a strongly exothermic reaction set in, and despite cooling the reaction flask in an ice bath, the re- action mixture solidified to a red colored, solid mass. The remaining phosphorus oxychloride was rapidly added to the re- action mass followed by the addition of a 50 g. quantity of 13 crushed ice. The contents of the flask were poured into a h00 m1. beaker, neutralized (litmus paper) with sodium hydrOxide and extracted with ether. The ether extract was washed with water, dried over anhydrous sodium sulfate, and the ether was removed in_zgggg to obtain hh.1 g. (0.23 mole, 91%) of S- formy1-2,2'-bithiophene which had a melting point of 53-560. An analytical sample obtained by two recrystallizations from absolute methanol (Norite) melted at 57-58°~ Literature (15) value: m.p. 59°. The dark red colored, crystalline, 2,h- dinitrophenylhydrazone of this bithienyl aldehyde melted at 295° after recrystallization from dioxane. s l e C o 0 Anal. Gale (3 for ClngoNuOl-Iusz. , “.8012, H, 2.69, S, 17.13 Found: C, “.8012; H, 2.91; S, 1608? Following the development of this synthesis, Lescott, Buu-Hoi, and Xuong (15) reported the same synthesis. Their experimental procedure is more convenient, and is to be preferred despite its somewhat lower yield. 5-carboxy-2,2'-bithiophene, C9H60282: M.W. 210.26 Into a 200 ml. Erlenmeyer flask containing freshly pre- pared silver oxide, obtained by adding 30 m1. of a 0.333 N silver nitrate solution to an equal volume of a 0.666 N sodium hydroxide solution, was added 1.0 3. (0.0050 mole) of 5- formy1-2,2'-bithiophene. The reaction mixture was heated for "'1‘" ~7'.=‘.,'J".'i"'."'31'.- '~"C—_-'M!§¥T 5. wmwi. .' d _ :I" w" 1h an hour on a steam bath and immediately filtered while hot on a Buchner funnel. The free silver was washed with hot water directly on the filter combining the washings with the fil- trate. A pale yellow colored precipitate of S-carboxy-2,2'- bithiophene, 0.095 g. (0.00u5 mole, 90%) formed upon acidifi- cation of the filtrate. An analytical sample, melting at 183- 18h0, was obtained after two recrystallizations from absolute methanol (Norite). Anal: Calc'd for C9H60282: C, 51.h1; H, 2.88; S, 30.50 Found: C, 51.32; H, 2.98; S, 30053 2',S'-dicarboxy-3,3',h',3"-trithiophene, 01hH80u33: M.W. 336.38 To a solution containing 1.1 3. (0.0050 mole) of 3,3'- thenil and 0.77 3. (0.0050 mole) of dimethyl thiodigycollate dissolved in 10 m1. of anhydrous methanol was added 0.50 g. (0.022 mole) of sodium dissolved in 15 m1. of anhydrous metha- nol. The reaction mixture was set aside for six days at room temperature. Water (35. 30 ml.) was added and the mixture was heated at its reflux temperature on a steam bath for an hour. The methanol was removed ig_vacuo and the alkaline solution was filtered to remove unreacted 3,3'-thenil. Acidification of the filtrate precipitated a pale yellow colored solid pro- duct which weighed 1.1 3. (0.0033 mole, 66%) and melted with decomposition slightly above 300°. A sample was prepared for 742-7.,- .17. " V .. ‘ '3 O . t F 0 y C 'J 15 analysis by recrystallization from methanol (Norite). Anal: Calc'd for clhnathB: 0, h9o98; H, 2.h0; 3, 28.59 Found: c, 50.07; H, 2e57; 8, 28.511. Neutralization equivalent Calc'd; 168: Fbund; 171 3,3',h',3"-tr1th10pbena, CIZHBSB: Mow. 213.8036 A 1.0 g. (0.0030 mole) quantity of 2',S’-dicarboxy-3,3', h',3"-trithiophene was cautiously heated in a large test tube over a free flame until it melted and decomposed with the evo- lution of carbon dioxide, yielding the trithiophene. The pro- duct, on cooling, solidified. The contents of the test tube were extracted with chloroform, decolorized with Norite and the chloroform removed. The residue was recrystallized twice from ethanol to obtain 0.55 3. (0.0022 mole, 675) of a color- less, crystalline solid melting at fie-83°. Anal: Calc'd for ClZHBSB: C, 58.03; H, 3.25; S, 38.33 Found: C: 58e193 H: 30h73 89 38076 2',5'-dicarboxy-2,3',h',2"-trithiophene, CIHHBOhSB: M.“. 336.38 A solution containing dimethyl thicdiglycollate, 0.77 8. (0.0050 mole), and 1.1 8. (0.0050 mole) of 2,2'-then11 dis- solved in 10 ml. of anhydrous methanol was added to a solution of sodium methoxide freshly prepared from 0.5 g. (0.022 mole) p; _ I. . l- D I ‘. ’ a p I ' r \, b a ‘ a . ,.. C “ ‘ a. 't O U I. Q ._ I ‘ u a I O I ‘ '— E Z I ‘ a a O I 1 e ‘— — [I I. 16 of sodium and 15 ml. of anhydrous methanol. The reaction mixture immediately took on a dark green coloration which disappeared at the end of the first day. The reactants were set aside, at room temperature, for an additional five days. Water was added and the mixture was refluxed on a steam bath for a half hour. The methanol was removed in zaggg, the al- kaline solution was filtered, and the filtrate was acidified to precipitate a yellow colored product. It weighed 0.80 g. (0.002h mole, h8%) and melted with decomposition slightly above 300°. Anal: Calc'd for C1h3180h83: Ce (49e983 H) Zeno; S, 28e59 Found: C, 50e17; H, 2e68; S, 28e72 Neutralization equivalent Calc'd; 168$ Fbund; 171 2,3',h',2"-trithiophene, 612H883: M.H. 2h8.36 A 1.0 g. (0.0030 mole) quantity of 2',5'-dicarboxy-2,3', h',2"-trithiophene was carefully heated in a large test tube over a free flame until it melted and decomposed with the evolution of carbon dioxide, yielding the trithiophene. The product solidified when cooled. The contents of the test tube were extracted with chloroform, decolorized with Norite and the chloroform removed. The residue was recrystallized twice from ethanol to obtain 0.52 3. (0.0021 mole, 70%) of a light tan colored crystalline solid melting at 65.5-66.50. . I -‘ 17 Anal: Calc'd for C12H883: C, 58.03; H, 3.25; 3, 38.33 Found: Cs 570993 H: 3031; S: 38085 3-bromothiophene, ChH3BrS: M.W. 163.0h A 2h 3. (0.10 mole) quantity of 2,5-dibromoth10phene was placed in a 300 ml. flask fitted with a mechanical stirrer, reflux condenser and dropping funnel. Bromine, 18 g. (0.11 mole) was added dropwise to the well-stirred 2,5-dibr0mothio- phone while cooling the reaction flask in an ice bath. The reaction mixture was stirred for two hours after removing the ice bath and it was then set aside overnight at room tempera- ture. Approximately 100 m1. of water was added, and the aque- ous solution was extracted with ether. The ether was removed in gagug.and several potassium hydroxide pellets were cautious- ly added to the residue. The alkaline reaction mixture was refluxed an hour, then steam distilled until the distillate showed no turbidity (33. 800 ml.). After decantation of the water from the steam distillate, 16 ml. of glacial acetic acid, 50 m1. of water and 39 g. of zinc dust were added to the resi- dual oil and the mixture was heated at its reflux temperature for a day. Thiophene, 3-bromoth10phene and water were dis- tilled directly from the zinc reduction mixture until the tem- perature of the vapor in the distillation head reached 103°. The organic layer was separated, dried over anhydrous sodium I‘I 18 sulfate and fractionated. Following a very small forerun of thiophene, distilling at 117°, the product was distilled in the boiling range of lsu-157°. The yield was 5.0 g. (0.031 mole, 31%) of 3-bromothiophene, n :. 1.5915. Literature (16) values, b.p. 159-161°, n :0 : 1.5913. Thenoin of 5 formyl 2,2 bithiophene, 018312023h M.“. 388.52 An aqueous potassium cyanide solution containing 1.5 g. (0.023 mole) of salt dissolved in ten m1. of water and 12.5 g. (0.06h mole) of 5-formyl-2,2'-bithiophene was added to 25 ml. of 95% ethanol. After heating the reaction mixture at its reflux temperature for a half hour, it was cooled, acidified (litmus paper), filtered, and then rinsed initially with a small portion of 95% ethanol, followed by several larger a- mounts of water. The crude product, 12.5 g. (0.032 mole, 100%), which melted in the temperature range 125-130°, was used to prepare its thenil by oxidation. : I o e e S Anal Calc d for CIBHlZOZSh' C, 55.6h. H, 3.11, , 33.01 Fbund: 0, 55.80; H, 2.83; 5. 33.0h Thenil of 5-formy1-2,2'-bithiophene, c18HlOozsh: M.W. 386.50 Copper sulfate pentahydrate, 16 g. (0.06h mole), was dis- -m—n . a .— —~ ‘ Q .— D i ‘ . 1 K o s .- 19 solved in a solution prepared from 25 m1. of pyridine and 10 m1. of water. After the cOpper sulfate solution had been heated to approximately 95° on a steam bath, 12.5 g. (0.032 mole) of crude 5-formyl-2,2'-bithiophene thenoin were added and the oxidation reaction was carried out at the steam bath temperature during two hours. The reaction mixture was then poured into 300 m1. of cold water, and filtered to yield 10.0 g. (0.026 mole, 80.h%) of fine maroon colored crystalline solid. An analytical sample recrystallized from a 1:1 di- methylformamide-water mixture melted at 187-191° and was shiny maroon colored in appearance. A : ' O 3 e e nal Calc d for 018310 ash c, 55.93, H, 2.61, 3. 33.18 Found: Cs 55.803 He 20833 S, 33.0h A second analytical sample recrystallized from a 131 dioxane- water mixture had a melting point of 189-1910 and was mustard yellow in color. Anal: Calc'd for CIBHIOOZSH: C: 55093; H, 2.613 S) 33018 Found: C, 55080; H, 2e83; S, 33e0u g”,g".gi§arb0fiy;2,2',5',3",h",2"',5"',2””-pentathiophene, 22 12 h S. O 0 500.62 A solution containing dimethyl thiodiglycollate, 1.78 g. _- '- 4- 1V 0 It 0 ' a C 9’ ’ t 1- a \, T T ‘ so 0 0 o \ ‘- \ n 20 (0.0100 mole), and 3.87 g. (0.0100 mole) of the thenil of s- formyl-2,2'-bithiophene dissolved in to ml. of absolute metha- nol were mixed with a freshly prepared solution of sodium meth- oxide made by dissolving 1.0 g. (0.0hh mole) of sodium in 30 m1. of absolute methanol. There was no visible evidence of reac- tion, but the reactants were set aside at room temperature for six days. Water was added to the reaction mixture and it was heated at its reflux temperature on a steam bath for thirty minutes. The methanol was removed ig_zgggg and the alkaline solution was filtered to recover 2.8 g. (0.0072 mole) of un- reacted material, m.p. 187-1910. The filtrate was acidified to Congo Red and filtered to obtain 1.2 g. (0.002h mole, 86%) of the crude dicarboxylic acid melting at 189-1920. This was recrystallized twice from methanol (Norite) and resulted in a golden colored product in the form of a crystalline solid which melted at 191-192°. A 1: C ' C H 0 S : C . ; H . o S , na alc d for 22 12 h 5 , 52 78 , 2 h2, , 32 02 Fomd: C, (4.8.1.19; H, 3e31; 8, 30.00 Neutralization equivalent Calc'd; 250: Found; 260 /3 -5-(2,2'-bithieny1) acrylaldehyde, C11H8032: M.W. 220.29 Thionyl chloride, 3.h5 g. (2.1 m1., 0.029 mole), was added to a slurry of /é§-5-(2,2'-bithienyl) acrylic acid, 6.15 g. ,‘ VI 21 (0.026 mole), and 25 m1. of chloroform. When the vigorous evolution of hydrogen chloride had subsided, the solvent and excess thianyl chloride were removed ig_zgggg. The crude re- action product was dissolved in 25 m1. of diglyme (dimethyl ether of diethyleneglycol) and cooled to the temperature of a dry ice-isopropanol bath. A 1.0 M solution of lithium tri- tertiarybutoxyaluminohydride in diglyme was added slowly to the reaction mixture. When 25 m1. had been added, a 5 m1. portion of the reactants was withdrawn and added to 50 ml. of 0.05 I 2,h-dinitrophenylhydrazine dissolved in 2‘M methanolic hydrogen chloride. The 2,h-dinitrophenylhydrazone obtained weighed O.h2 g. (1.0%) and melted at ass-290°. Attempted preparation of 2,2',h',2"-trithiophene, 0123833: . . 2h .36 Anhydrous hydrogen chloride and anhydrous hydrogen sul- fide were passed into a well-stirred mixture of 20.2 g. (0.160 mole) of 2-acetylth10phene and 250 m1. of 95% ethanol at the rates of 22.5 1./hr. and 12.7 1./hr. respectively. The reac- tion mixture was maintained between 10-150 for five hours during which time a grey precipitate formed. The reaction mixture was filtered and the filtrate was set aside in a refrigerator for 12-15 hours to allow further precipitation, during which the original grey precipitate (h.0 g.) became a black, tarry mass. 0 P . .- k I p . __ O _. . Q h“ ' - ,. - e ‘ 0 v I ‘2‘- .. . b ¢ as Q 9 .. .___.._..-————————————%...__.l 22 Additional black, tarry material (8.h g.) was obtained from the refrigerated filtrate, making a total quantity of 12.h g. of an unidentifiable material. Finely ground 00pper chromite (10 g.) was combined with 3.0 g. of this material and to m1. of xylene. The mixture was heated at its reflux temperature for 6 hours, vacuum filtered, and the residue washed on the filter with 30 ml. of hot xylene. The combined filtrate and washings were decolorized with Norite and evaporated 12.13222 to a thick syrup. The syrup was dissolved in 95% ethanol, but all attempts to obtain a crystalline product failed. An ethanol extract of the syrup had ultra-violet absorption maxima at 253 m/A and 282 m/M.e RESULTS AND DISCUSS ION I. RESULTS AND DISCUSSION One of the oldest and most frequently described syn- thetic methods for the preparation of thiophenes is the ring closure of 1,h-difunctional compounds by sulfides of phosphorus (17). A thiophene or polythiophene with an unsubstituted posi- tion should be capable of extension of an additional thiophene ring by acylation with succinic anhydride followed by phosphorus pentasulfide ring closure of the resulting 1,u-difunctional com- pound. Such a conjecture has been partially verified by the synthesis of 2,2'-bithiophene in a 12% yield by the ring clo- sure of f9-(2-thenoy1) propionate in the present study. Since this synthesis was accomplished in a single run, the 12% yield must be taken as a minimum value. Yields are usually increased by multiple runs (19). Since the course of acylation of 2,2'— bithiophene and 2,3'-bithiophene (18) has been elucidated, it seems that this method of ring closure could readily be exten- ded to the trithiophene series, albeit in the usual low yields. The commercial production of thiophene is based upon the ring closure of 1,3-butadiene or hydrocarbons convertable to 1,3-butadienes by dehydrogenation with sulfur (19). It has been suggested (19) that sulfur dehydrogenates butane to butane-2 with the production of hydrogen sulfide, and then dehydroge- nates butane-2 to 1,3-butadiene and hydrogen sulfide. The bu- 25 tadiene reacts with sulfur forming thiophene and hydrogen sulfide. This is not a convenient laboratory procedure, but may be converted to a laboratory procedure by using an analo- gous 1-mercapto-l,3-butadiene structure for the ring closure. Campaigns (20) has prepared substituted thiophenes using 1- mercapto-l,3-butadienes as starting materials. Thus a com- pound such as S-(2-thieny1)-2-mercapto-2,h-pentadienoic acid should yield S-carboxy—2,2'-bithiophene upon ring closure. Employing Campaigne's procedure, this conjecture has been veri- fied in this study by the synthesis of S-carboxy-2,2'—bithio- phone and 5- carboxy-2,3'-bithiophene. Since Julian (21) has shown that an aldehyde can be ex- tended by two carbon atoms to an (X -thiol acid through the use of its rhodanine derivative, any 0<,/6’-unsaturated al- dehyde may be used to obtain the intermediate l-mercapto-1,3- butadiene compound. (1)Rhodanine RCH=CHCHO -——————————+ RCH=CHCH :QCOOH (1) (2)dil. NaOH SH The synthesis of fg-(Z-thienyl) acraldehyde and /?-(3-thi- enyl) acraldehyde was accomplished by condensing acetaldehyde with 2-thenal and 3-thena1 respectively (22). Although /? - (B-thienyl) acraldehyde had not been prepared previously, it is prepared in exactly the same manner as/5’-(2-thienyl) acraldehyde (22). To evaluate the generality of this syn- thetic procedure it seemed desirable to start with S~f0rmyl- 2,2'-bithi0phene, and condense it with aceteldehyde to ob- tain/6’-5-(2,2'~bithienyl)-acra1dehyde, then, through its rhodanine derivative, to prepare the intermediate 5,-5-(2, 2'-bithienyl)-2-mercapto—2,h-pentadienoic acid. The starting material, S-formyl-2,2'-bithiOphene, was successfully pre- pared using a procedure in the literature (23), but as it had not previously been prepared it was necessary to establish the structure of this aldehyde. Since the acid, S-carboxy- 2,2'-bithiophene, corresponding to this aldehyde had been characterized (24), the aldehyde was oxidized to the acid. Due to solubility difficulties, silver oxide seems to be the only common oxidant which will oxidize this aldehyde to the acid in satisfactory yield. The synthesis of S—formyl-2,2'-bithiOphene from bithio- phene by the method of Buu-Hoi (15) is satisfactory, but the formyl compound would not condense with acetaldehyde using either two percent aqueous sodium hydroxide or two percent methanolic sodium hydroxide as the condensing agent. Since S-formyl-2,2'-bithiophene will condense with malonic acid in the presence of pyridine and piperidine (15), the resulting /3 -S-(2,2'~bithienyl)-acrylic acid can be reduced to the cor- responding acraldehyde by lithium tri-t—butoxyaluminohy- dride (25). TM l ”’8“? at M J- - i i s s v.H-olc00H s s cH-choso 2 (2)Li(tBu0)3A1a One of the practical values of this synthetic method is that the intermediate acid chloride does not have to be isolated. Thus, the acid chloride is prepared directly from the crude acid by an equivalent amount of thionyl chloride and is re- duced directly to the aldehyde by lithium tri-t-butoxyalumi- nohydride. The lithium tri-t-butoxyaluminohydride was pre- pared in ether employing Brown's procedure (25). The excess ether was decanted, and the lithium tri-t-butoxyaluminohy- dride was dissolved in sufficient diglyme (dimethyl ether of diethyleneglycol) to obtain a one molar solution of the re- ducing agent. The solution of the hydride in diglyme is stable for long periods without decomposition. Thus, it appears as though many thiOphene aldehydes may be extended to the corresponding acraldehyde by one or both of the above methods and these acraldehydes may be used to 27 substitute a thiOphene ring for the original formyl substituent. Hinsberg's procedure (26) for the preparation of thio- phenes has been shown to be entirely general. 3' '. 9_e~:*.rv-;m ma; .1... .. - .__ __. __._ 28 ,ca.,coea NaOR ' I X3r + s ‘- ——> acoc CCOR S (3) x and y may be -H, -OH, oalkyl, -ary13 R is either methyl or ethyl. Selenodigylcollate and oxydiglycollate may be used in place of the thiodiglycollate resulting in the correspon— ding selenOphenes and furans (2?). By the proper selection of the 1,2-dicarbonyl compound, many tri- and higher polythio- phenes should be readily available. It should be emphasized here that other heterocyclic dicarbonyls (0, N, Si, Se, etc.) or mixed heterocyclic dicarbonyls could be employed as the starting material in this general synthesis. Thus the Hins- berg procedure is seen to be an extremely versatile synthetic method limited only by the availability of the necessary di- carbonyl compounds. The benzoin condensation (28,29) of various thiophene aldehydes followed by oxidation of the thenoins to the cor- responding thenils provides a direct synthetic route to the necessary dicarbonyl compounds in the thiophene series. The thenoins of 2-thenal, 3-thenal and S-formyl-2,2'-bithiophene were prepared. It was found that copper sulfate in pyridine (28) is the best oxidizing agent for the thenoin of S-formyl- 29 2,2‘-bithi0phene and 3,3'-thenoin while iodine in methanolic sodium methoxide (30) is the best oxidizing agent for 2,2'- thenoin. Both 2,2'-thenil and 3,3'-thenil had been previously prepared (28,29), but the thenoin and the thenil of S-formyl- 2,2'-bithiophene had not been prepared previously. An ele- mental analysis was obtained for these two compounds, but the results were nearly identical as would have been predicted. The thenoin has an absorption masimum at 2A9 m/u , the thenil absorbs at 300 m/A, and 2",S"-dicarboxy-2,2',5),3",h",2"',S"', 2""-pentath10phene absorbs at 262 m/A. Neither the thenoin nor the thenil of S—formy1-2,2'-bithiophene gave a positive iodide-iodate test for acids (32), while the 2",S"-dicarboxy- 2,2',S',3",h",2"',S"',2""-pentath10phene prepared from the thenil did give a positive iodide-iodate test. If the di- carboxylic acid may be considered as a derivative, then its elemental analysis and neutralization equivalent may be con- sidered as proof of structure for the thenil. Another attractive feature of the Hinsberg reaction is the facile decarboxylation of the intermediate polythiophene dicarboxylic acids to the free polythiophenes. For example, 2,3',h',2"-trithiophene and 3,3',h',3"-trithiophene are easily and unequivocaly prepared by simply heating the corresponding 2',S'-dicarboxylic acid to its melting point, at which tem- perature it smoothly decarboxylates by loss of carbon dioxide. Since indene, cyclOpentadiene and fluorene will undergo jar ."§?’9”- .t raw? main! :‘ my) t. up '5’... 2.19%: 42*?- .5.:. . ‘ . . 30 the aldol condensation (36), it seemed that various thenyl sulfides should undergo the Hinsberg reaction. Y NaOR I I l ' - I) H u h u--—+l' Eh [J l (R) Y + S CHZSC“ S S S S This would be an important extension of Hinsberg's procedure X'Q c O 0 because mixed sulfides of 2-thenyl and 3-thenyl compounds could be prepared easier than mixed thenils of 2-thenoyl and 3-thenoyl compounds. As the x and y substituents of the di- carbonyl compound are also capable of wide variation, this modification would indeed be a most desirable addition to the Hinsberg procedure. Using the method of Kipnis and Ornfeld (31), 2-thenyl sulfide1 was prepared. Unfortunately the 2-thenyl sulfide failed to condense with diacetyl, glyoxal or benzil to give the corresponding substituted thiophenes. Sodium methoxide was used as the condensing agent, but no trithiophenes were obtained despite numerous attempts under widely varying re- action conditions. Since 2-thenyl sulfide is not soluble in sodium methoxide solutions, it is assumed that there was no carbanion formation. 1 A three m1., highly purified sample of 2- -thenyl chloride exploded with great violence while being stored in the dark in an air tight, glass stoppered bottle. -- L-warv -- ' --‘I|.r . 31 Campaigne (33,3u) treated acetophenone (I) with hydrogen sulfide and decomposed the intermediate "anhydrotriacetOphenone disulfide" (II) with cepper chromite to form 2,u-diphenyl-thio- phene (III). C6HS \\ C H 9 H28 S H Copper ' I 6 5 3 CCH ——9 CH3|\ Chg -———-> CéHc; s (5) 3 H01 06HS 3 c6 5 Chromite ’ It seemed that 2-acetylthiophene and 3-acetylth10phene could be used to prepare 2,2',h',2"-trithiophene and 3,2',h',3"- trithiophene respectively. Although the reaction of 2-acetyl- thiophene appeared to proceed similarily to the reaction of acetophenone as reported by Campaigns (3M), no 2,2',u',2"-tri- thiophene could be isolated. An ethanol extract of the cepper ‘ chromite treated residue had a >\max 253 m/A and 283 m/A with the 253 m/A peak having the greater absorbence. Andrisano (35) reports A¥ma 260 m/x and 282 m/A for 2-acetylthiophene while (x Wynberg (h) reports >‘max283 m/A for 2,2',h',2"-trithicphene. Th‘s, the preparation of 2,2',u',2"-trithiophene appears to have failed. It has been demonstrated that three general synthetic methods for thiophenes may be extended to the synthesis of polythiophenes. The author hopes that the chemistry of poly- thiophenes will be expanded beyond its "laboratory curiosity" stage now that some of the parent polythiOphenes are available. mg?! H. UP-‘MA RY SUMMARY Three new methods for the synthesis of polythiOphenes have been developed: (1) ring closure of l,h~difunctional thienyls with sulfides, (2) ring closure of thienyl-h-mer- capto-l,3-butadienes, (3) reaction of thenils with thio- diacetic acid esters. A fourth method, reaction of thionyl methyl ketones with sulfides, was attempted but apparently failed. Synthetic method (1) is used to add a thienyl substitu- ent to any thiophene capable of acylation by succinic anhy- dride. Method (2) has resulted in the facile, unequivocal synthesis of the heretofore difficultly accessible S-car- boxy-2,3'-bithiophene as well as in a general method to substitute a carboxythienyl substituent for an aromatic aldehyde functional group. The application of synthetic method (3) has doubled the number of known isomers of trithiOphene and has led to the first synthesis of a pentathicphene that is not an al- isomer. Method (3) is the only simple, versatile, synthetic method for preparing isomers other than the 0(-isomer of trithiophene. BIBLIOGRAPHY 1. 2. 3. h. 5. 6. 7. 8. 10. 11. 12. 13. 1h. BIBLIOGRAPHY L. Zechmeister and J. W. Sease, J. Am. Chem. Soc. 62, 273 (19u7)e J. S. Sorensen and N. A. Sorensen, Acta Chem. Scand. is. 771 (1958). H. Wynberg and A. Bantjes, J. Am. Chem. Soc. fig, 1AA? (1960)e H. Wynberg, A. Logothetis and D. Verploeg, J. Am. Chem. Soc.,12, 1972 (19 7). D. E. Wolf and K. Folkers, Organic Reactions Volume III., John Wiley and Sons, New York, (1951), pp h11-h68. H. D. Hartau h Ihiophene and its Derivatives, Inter- science, (1952), p.137. (Chemistry of Heterocyclic Compounds, Volume III. . c. A. 32, 5878 (19h5). W. Steinkopf, Die Chemie des Thicphens Theodor Stein- kopf, Dresden and Leipzig, (lehl), p if . J. W. b'ease and L. Zechmeister, J. Am. Chem. Soc. $2. 270 (19t7). J. H. Uhlenbrock and J. D. 813100, Rec. trav. chim. ll. lOOh (1958). Lawrence D. Hills, Henry Doubleday Research Association, 20 Convent Lane, Booking, Braintree, Essex, England, Private Communication, 1960). J. H. Birkinshaw and P. Chaplen, Biochem. J. 69, 255 (1955). F. Challenger and J. L. Holmes, J. Chem. Soc. 1837 (1953). E. Guddal and N. A. Sorensen, Acta Chem. Scand. l}, 1185 (1959). F. Lescot, jun. Ng. Pb. Bun-H01, and N. D. Xuong, J. Chem. Soc. 323h.(1959)e .....::-Wgee- _~ .;~'3' '.; 4. . " ~... ..'.' r ~~‘ ’.‘~' _- ‘1... 1.- Z O y- . 9 ' R Q . ' D D c Q C O Q 0 9 P " t t i I R“ ‘Q “ ‘ ' . to ~ . i ' . 1 ’ ~ . O! 3 O :: Y'I ’1 n o g ¢ e .. s ‘ <' \ \ ~. .. g l O t D ' ' D Q C a q I: Q 9 0 ‘" w ( ‘ V it Q t; ’1 1* O i W ' 9 ' 1 D 1. 9.. , -. fi . a: q n O 1 4 Q i: ' ' 1' I I v A ' . 5 a 5 . ‘7 ' O I n C a e » a n e ' " o . 0 ’ ' ., . o O b a O ‘ e '3 P .2 . T T ' t . i 19. 20. 21. 22. 23. 2h. 25. 26. 27. 36 S. Gronowitz, Acta Chem. Scand. ‘llg 10u5 (1959)e R. C. Elderfield, Heterocyclic Compounds Volume 1., John Wiley and Sons, Inc., New York, (1950), p 213. H. Wynberg and A. Bantjes, J. Am. Chem. Soc. 8g, lhh? (1960). H. E. Rasmussen, H. C. Hansford and A. N. Sachanen, Ind. Eng. Chem. gfi, 376 (19nd). E. E. Campaigne and R. E. Cline, J. Org. Chem.|g;. 39 (1956). P. L. Julian and B. M. Sturgis, J. Am. Chem. Soc. 51, 1126 (1935). E. A. Braude, J. S. Fawcett and D. D. E. Newman, J. Chem. SOC. DIES (1952)e E. E. Campaigne and W. L. Archer, J. Am. Chem. Soc. 15, 989 (1953). W. Steinkopf, Die Chemie des Thiophens, Theodor Stein- kopf, Dresden and Leipzig (19h1) p 1M7. H. C. Brown and B. C. Subba Rae, J. Am. Chem. Soc. 89, 5377 (1958). O. Hinsberg, Ber. 33. 901 (1910). H. J. Backer and w. Stevens, Rec. trav. chim.I§2, A23 (l9uo). S. Zo Garden and P. Lankelma, J. Am. Chem. Soce‘lg, h2h8 (19MB). E. E. Camgaigne and W. M. Le Suer, J. Am. Chem. Soc. 12, 1555 (19h ). I. Deachamps, w. J. King and F. F. Nord, J. Org. Chem. F. Kipnis and J. Ornfeld, J. Am. Chem. Soc. 1;. 3571 (19h9 e F. F6131, Spot Tests in Organic Analysis, Elsevier, New York, (1956), p 116. E. E. Campaigne, J. Am. Chem. Soc. 66, 68h (19hh). fl /' 34. 35. 36. 37 E. E. Campaigne, W. B. Reid, Jr., and J. D. Pera, J. Org. Chem. gs, 1229 (1959). R. Andrisano and G. Pappalardo, Boll, sci. fac. chim. ind. Bologna, 11’ 100 (1956); C. A. 52, 19446 (1958). E. E. Royals, Advanced Organic Chemistry, Prentice Hall, Inc., New York, (1954), p 787. OIEMISTEY LIBRARY IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII *uI(HI(1M)(willingly(I