THE ”PARENT ACEBEC DfiSSOCIAT’iON CONSTANT 5 OF SGME S-ARYLTETRAZOLES Thai: for flu Beam 9% M. S. WCHQGAN STA‘FE COLLEGE Konne?h R. Wilson 1955 :‘HESW ) \. f . x . . , 1 ‘ .I I " ’ r l. \ .4 . r vV/ v k ‘5 W s." k I. . . . .. 5 III. \ y‘Q o . (L .e u. H». , 1 . 3‘1. 2; I: .l!‘ V... U .- ismw.zmrav~ Juan” . ._ THE APPARM ACIDIC DISSOCIATION CONSI'ANTS OF SOME S-ARILTETRAZOLES By Kenneth R. Wilson 1 133315 Submitted to the School of Graduate Studies of Michigan State College of Agriculture and Applied Science in partial fulfillment of the requirements for the degree of HASTER OF $IENCE Depertment of Chemistry 1955 ~N~ V ACKNOWLEDCHBNT The author niche: to expreu hie eppmcietion to Doctor Robert H. Herb“ for hie helpful guidance end uliltance throughout the performance or thin work. W fiW W “H H * {agilfl 9 Q1‘ 11 "Efi‘lfl. fig; 1’ ABSTRACT The purpose of this study is to determine the apparent dissociation constants of a number of S—aryltetrazoles with systematic variation of the position and nature of a substituent in the phenyl group. The S-aryltetrasoles were prepared by heating the appropriately substituted bensonitrile with a solution of acetic acid and sodiun aside in n-butyl alcohol. The S-aryltetrasoles prepared in this work were the 5-0, s and pochlorOphenyl, Soc, 11: and pebronophenyl, 5-0 and ponethoq- phexvl and Scphenyl. Apparent dissociation constants were determined by potentionetric titration of the Soaryltetrasole in aqueous nethanolic solution with standard base. The S-phenyltetrasoles with 235.2 or as}: substituents were stronger acids than the correspondingly substituted bensoic acids, while the 93.22 substituted S-phenyltetrasoles were slightly weaker acids than the correspondingly substituted bensoic acids. For the S-aryltetra— soles with a substituent on the benzene ring the observed order of decreasing apparent dissociation constants is M ) pg: ) me, but in the substituted bensoic acids the order of decreasing apparent dissoci- ation constants is or_tho > E > page. Ultraviolet absorption spectra of the S-aryltetrazoles in 95% ethanol were determined and found to exhibit a single strong absorption band which appears in the range 210-250 my with the nets and 252 amb- stituted compounds and at somewhat shorter wave length with the orthg substituted compounds . iii T-LBLE 0? CONTENTS Page mmumTIwOOOOOOOOOOOIOOOOCOOOOOOOOOOOOOIOOOOIOOOOIIOOOOOGIO. 1 DIxDSSIOfl.‘0.0.0.0000000000000I...OOOOOOOOIIODOOOCCDO..0000... 3 Eva‘mwaOOOOOOOOOOIOOIOOOCOCOOOOIO0.......Q‘COCOCOOOOOQO... 28 Preparation of mbstituted Bensoyl Chlorides.............. 28 Preparation of Substituted Benzamides. . . . . . . . . . . . . . . . ... .. 28 Preparation of Substituted Bensonitriles . . . . . . . . . . . . . . . . . . 31 Preparation of tin S-iryltetruolaa............ ........ 31 Preparation of Silver Salts of the Soiryltetrasoles . . . .. . . 37 Preparation of tunim Salts of the S-Aryltetrasoles.. ...... 37 Determination of Apparent Dissociation Constants of the MluquIO.OIOOOOOOOOOOOII0.0.0.0...0.0.00.0...0 37 Ultraviolet Absorption Spectra of the Sotu'yltetraaoles.... 38 WICOCOOOOCOOCO0.0.0.010...IOOCUOOOOIGOOOIOIOOOOOOCOOOOOCCO ho anmag CITEOOIOIOOI...O.OOIOOOCCOOOIOIO...OCQOOOOOOOQGO... m Mann IO...OIOOICOOOIOOOODICIIIIOQOOOOOOIOQCIOOOOOIOIOOOOOOO h) mmn HOOD...DOOOOOOOOOOIICOOOIUOOOOOOOOCCOOIOOGOOOO.0.0... 58 iv TABLE II III IV LISI‘ OF TABLES smltatr“01a.00000000..00OOOQOOOOOOOIOOOOOOOO0....O... Apparent Dissociation Constants of S-Aryltetrasoles and the Corresponding Carboxylic Acids....................... darelemgths of Maxine and Extinction Coefficients of Tetrazole KM S‘Aryltatraz01e’seseeeeeeeeeeeeeeeeeeeeeeee Substituted Benzoyl Chlorides..................;......... Substituted Bemmides................................... substituted Bentonitrilel................................ Preparation of S-Aryltatmolea.......................... Sefiryitetrasolol......................................... “”1. of S‘Ary1t0tru018'.eeeeeeeeeeeeee‘eeeeeeeeeeeeee Page 6 16 29 32 3h 35 36 LIST OF FIGURES Figure Page 1. Ultraviolet absorption Spectrum of Tetrasole............. 18 2. Ultraviolet Absorption Spectrum of SoPhenyltetrazole..." l9 3. Ultraviolet Absorption Spectrum of S-p-Bromophenyl- t'et‘r‘ZOJ-eeeeeieseeeeeeeeeseeeeeeeeeeeeeeeeeeeeeeeeeeeeeee 20 h. Ultraviolet Absorption Spectrum of Sap-Chlorophenylo “traZOIBOOOOOOOOOOOODOOO0000.0OQOOOOOOOOQOOOOOOOOOOOIIso 21 5. Ultraviolet Absorption Spectm of 5-m-Bron0phenyle “trazOIGOOOOOCODOOCOIOOOOOOOOOOOOOO0.0....OOOOOOOCOQOOOI 22 6. Ultraviolet Absorption Spectrum of Son-C hlcrophenyl- “truOIOOODUOOOOOO.0....0.00.00.00.00OOOOOOOOOOOOOOOOO0. 23 7. Ultraviolet Absorption Spectrum of S-o-BrcnOphenyl- “tfl'OIOCOOO.OOOOO-OOOOOOIOO.OOOOOOOQOOOOOOOCOOOOOOO.O... 21‘ 8. Ultraviolet Absorption Spectrum of Soc-Chlorophenyl- tatr‘zOIOOOOOOOOOOOOOOOOOQ...OOOOOOOOOOOOOOOOOOO.COCO.CO. 25 9. Ultraviolet Absorption Spectrum of 5-p-llethoryphenyl- htr“°1.........0.00...OOOOOOOOOOOOIOOOCOOCOOOCQOOOOOOI. 26 10. Ultraviolet Absorption Spectrum of S-o-Hethoxyphenylc “tr“OIOIOeseseeeeeeeeeaeeeeeeseOeeeseeeeoeeeeeeeeeeeese 2? INTRODUCTION Tetraaole derivatives in which the hydrogen atom attached to tie ring nitrogens has not been replaced generally behave as acidic sub- stances (1. 2. 3). The apparent acidic dissociation of the conpounds say be strongly influenced by the nature of the substituent on the carbon atom in the 5-position of the ring. A large variety of S-sub- stitutcd tetrasoles have been prepared and the effects of the substituent on the apparent acidic dissociation noted. In the S-alkyltetrasoles (R-CN‘H) the apparent acidic dissociation has been found to be about one-fifth to one-tenth as large as that of the corresponding aliphatic carboxylic acids (R-COOH). It has also been found that the variations in apparent acidic dissociation with the structure of the allql groups are generally parallel in the tetrasoles and carboxylic acids (1). In the S-aryltetrasoles the apparent acidic dissociation of only Swphem'ltetrasole and the S-tolyltetrasoles had been reported (1) . S-Phenyltetrazole was shown to be a stronger acid than bensoic acid and the S-tolyltetrasoles were stronger acids than the corresponding toluic acids. Furthersore, the apparent dissociation constants of the S-tolyl- tetrasolss increased in the order £1322 ,( page < is}; while the apparent dissociation constants of the toluic acids increased in the order 25.52. < at; ( 9319.9. . Ithese observations suggested that a study of the apparent acidity of other S-aryltetrasoles might help to explain this behavior. ll'he purpose of this study is to investigate improvements in the method of synthesizing S-aryltetrasoles, to prepare a number of Soaryl- tetrascles with systematic variation of the position and nature of a substituent in the phenyl group , and to deternine the apparent dissoci- ation constants of the new cospounds. S-Chlorophenyltetrasoles, S-broamphenyltetrasoles and S-Iethoxyphenyltetrasoles are described in this work. DI SCU SSION Tetrasoles with a substituent in the 5 position have been syn- thesized tron nitriles by two general procedures. Pinner (h) deve10ped a series of reactions that have been applied extensively to aryl cyanides which involved stepwise conversion of these compounds into the inino others, amidrazones, imide asides and tetrazoles as illustrated schematically below. c on Ho NINE irCN 3:; Arc/00' Nan. irc/ £331 [ammoa “new. ‘33 J's Arc\ ————->~ Ar-c—XH \H H l I \ / Recently it was shown that 5-substituted tetrssoles could be pre- pared in a single step by heating alkyl or aryl cyanides in sealed tubes with hydrazoic acid in benzene solution (1). It was also reported that a similar reaction took place when the nitrile was heated under similar conditions in isopropyl alcohol solution with equivalent. amounts of sodium aside and acetic acid. an 11-01! -—i-> 34 ———-—+ 3.0—“ Although the interaction of nitriles and hydrasoic acid had always been carried out in sealed tubes at 150° C (l) , it was of interest to attempt a simplification of this procedure. It was felt that the re- action night proceed successfully at a somewhat lower teleperature , in an Open system. Further simplification could be achieved if hydrasoic acid could be liberated from sodiun aside in the reaction mixture. The problem was essentially that of finding a solvent of sufficiently high boiling point in which sodium aside and a weak acid such as acetic acid would react with liberation of mdrasoic acid. Earlier work (1) had shown that alcohols might be suitable for this purpose. In order to determine the best conditions for the reaction a study was undertaken of the preparation of S-phenyltetrasole frou'bensonitrile, sodiu- aside and acetic acid in a series of alcohols of progressively higher boiling point. Using isoprOpyl alcohol, secondary butyl alcohol and n—butyl alcohol and keeping other conditions the same, it was found that the yield of Sophenyltctrasole was 6M, 8141 and 911, respectively. Furthermore, it was noted that the crude product obtained when n-butyl alcohol was used as the “solvent was less colored and of higher melting point than when other alcohols were used as solvents. Apparently the main factor influencing the yield of S~phenyltetrasole was the boiling point of the reaction mixture when various solvents were used, as the best results were obtained at the higher temperatures. Since this method offered the advantage of eliminating the use of sealed tubes and thus made possible the use of larger quantities of reactants, it was adapted to the synthesis of all S-aryltetrasoles prepared in this study. Equivalent amounts of the aryl cyanide, sodiun aside and acetic acid in n-butyl alcohol were heated under re- flux for six days. To compensate for possible loss of hydrasoic acid small amounts of sodium aside and acetic acid were added after four days at reflux temperature. The S-aryltetrasoles prepared in this manner are listed in Iliable 1. Of this group S-phenyltetrasole, Soc-vchlorOphervltetrasols and S-p-methoxyphenyltetrasole have been previously described. The first had been prepared by several procedures (1, h, S, 6)) S-o-chlomphenyltetrazole had been prepared by the deanination of l-amino-S-o-chlorOphenyltetrasole (7)3 Sop-nethoxyphenyl- tetrasole had been prepared from p-methoxy’oensonitrile (8) by the series of reactions developed by Pinner. In addition to these Loosen had described a S-bronophervltetmole which resulted from treatment of S-phenyltetrasole with bromine water at elevated temperature (9) , but the position of bromine substitution had not been established. Lossen's coupound appears to be identical with the 5-p-bron0phenyltetrasole prepared from p-bromobensonitrile in this study. All of the tetrasoles listed in Table I are colorless, acidic substances. The melting points follow the same general elder found in substituted bensoic acids, where the 23.1.3 isomer melts considerably higher than the w isomer which in turn melts higher than the 223 issuer. ill the compounds in Table I are soluble in aqueous alkalies, alkali carbonates and bicarbonates and aqueous amonia. 5-Pherwltetra- A sole and the m and 9333 substituted compounds were insoluble in cold water, slightly soluble in hot water, ether and bensene and soluble TiBLE I 5~AHILTETRAZOLES Substituent n. P. °c Equivalent Wm (corr .) Cale . Found Phanyl 217-218 1h6.2 1&6.8 p-ChlorOphemrl 262-263 180.6 180.9 anhlorophenyl l39-139.S 180.6 181.2 o-ChlorOphenyl 179-180 180.6 181.3 p-aromophenyi 278-279 dec. 225.1 225.2 nnBrcmOphenyl 15h.S-155 225.1 225.6 o-Bmophenyl 183-1835 225.1 22h.8 p-Hethoxyphenyl 238-2385 176.2 176.8 o-Hethozqrphenyl 1585-1595 176.2 176.8 in alcohols, acetone and dioxane. The p113 isomers were generally less soluble than the other isomers; they were only moderately soluble in alcohols and acetone and practically insoluble in dioxane . The nitriles used as intermediates for the tetrasole syntheses which were not commercially available were prepared from tin acids by way of the acid chlorides and amides. Delvdration of the amides to the nitriles was accomplished smoothly and in very good yields by treatment with phosphorus ant-chloride in the presence of sodium meta- bisuli'ite (10). All of the S-aryltetrazoles form silver salts when silver nitrate in aqueous alcohol is added to a hot solution of the tetrazole in aqueous alcohol. The salts are not light sensitive but decompose with a flash when heated on a spatula. A method of analysis of the silver salts of S-alkylaminotetrasoles has been reported (11) in which the salts are dissolved by digesting in hot concentrated nitric acid, di- luted with water and the silver ion titrated by the Volhard method. An attempt was made to apply this method to Searyltetrazoles, however the silver salts could not be dissole by digesting in nitric acid. Attempts were made to prepare characteristic crystalline salts with benzylamine , ethylenediaminc , 2-minopyridine , piperidine and n-hexylamine. The salts were formed by addition of an alcoholic solu- tion of the amine to an ether-alcohol solution of the S-aryltetrasole. However, the salts did not lend themselves to characterization of the tetrasolss since well defined crystals could not be obtained and the compounds did not possess sharp melting points. Apparent acidic dissociation constants (Table II) and neutral- ization equivalents (Table I) of all the S-aryltetrasoles were deter- mined potentiometrically in 50% or 75% aqueous methanol. All the titration curves were typical of a weak acid titrated with a strong base. The phenyl group causes an increase in the acid strength of Sophenyltetrazole as compared with tetrazole, while with bensoic acid a decrease as compared with formic acid is observed. The S-phenyltetra- soles with 2.353 and 5353 substituents were stronger acids than the correspondingly substituted bensoic acids while the 2:32 substituted S-aryltetrasoles were slightly weaker acids than the correspondingly substituted benzoic acids. The acidity of tetrasole itself may be explained on the basis of resonance stabilisation of the anion by virtue of the increased symmetry and number or the forms contributing to the resonance hybrid of the anion as compared with the unionized molecule. 1 ¢ (1) It has been suggested that tetrasole and its S-substituted de- rivatives R-CI‘H may be considered comparable to the carbonylic acids 3—0001! (1). In such derivatives the tetrasole anion offers a greater TABLE II APPARENT DISSOCIATION congrats or s-mnwrmzoms AND we CORRESPONDING cmoxmc ACIDS?l R 2-533. 2-333- Cefis 29 13(1 8.0 o-cacw. 15.2" 9.331D ”among 20.0b 1;.27b p-Cflacwi 1.5.2" 3.55b o-ClC.H.. 57 25Cl 70.8° ”010.11, 87 1h.5° p-ClCJI‘ 32d ' 10 .0° o-BrCJI‘ 60 70 .30 n-BrCGH‘ 92 hzd 135° p-BrCJI. 30d 9.133" o.cs,oc,m 1.2 6.5 Minoan, 1h 2 .8 a) Determined in 50% (701.) methanol at 25°C unless otherwise noted. b) Reference 13. e) Determined at 18-22%), Reference 114. d) Determined in 75% (VOL) methanol. 10 number of resonance forms than the carboxylate ion. If resonance alone is considered this might cause one to predict a greater stability for the tetrazols anion as compared with the carbonylate anion, which would suggest that the tetrasoles should be stronger acids than the carboxylic acids. However, since tetrazole and its 54.1w}. derivatives .are generally weaker acids than the carbonylic acids some factor other than resonance considerations must exert a determining influence. It is likely that the greater electronegativity of oxygen as compared with» nitrOgen is the controlling factor in determining the relative acidity of the two types of acids. Similar substituents attached to the tetrasole group or the carbonyl group should have similar effects on the acidic dissociation of these groups. Anw'group that increases the proton affinity of the tetrasole group or the carbonyl group should cause a similar decrease in the acidity of both types of compounds as compared with the parent substances, tetrasole and formic acid. Conversely, groups that decrease the proton affinity should cause an increase in acid strength.of the tetrasole or carboxylic acid. It has been observed in the case of S-alkyltetrasoles that the apparent acidic dissociation constant is smaller than that of the unsubu stituted ring system {1). The decrease in acidity is generally parallel to the decrease in.acidity of the alkyi carboxylic acids as compared to formic acid. In these cases the alkyl groups, through the Operation of an inductive effect which causes an increase in the proton affinity of the tetrazole ring or carboxyl group, cause a significant decrease in the apparent acidity as compared with the unsubstituted compounds. In the case of the S-aryltetrasoles the resonance of the tetra- sole anion may be supplemented by ‘the resonance contribution of the bensene ring. In addition to the forms indicated before (I) for the parent substance, resonance forms of the following types may also contribute to the hybrid of the Sdphexwltetrazole anion. “IV—H N—H O“ 'u «0/ I r~ \J—N \R: N q <34 1, ”sag; «m <34: The increase in the number of resonance foms contributing to the hybrid and tin resulting lessening of the proton affinity of the tetra- sole nucleus would be reflected in a higher degree of acidity. For bensoic acid no resonance forms such as (II) can be drawn. Resonance forms of the bsnsoate ion involving interaction of the bensene ring and the carboxylate group require'a charge separation (III) . Similar resonance forms with charge separation may also be written for the 5-phsnyltetrazols anion. (n =1: -—s >4 12 o" + " H 0‘ Deg - C - +I