[CONTRIBUTION FROM THE CHEMICAL LABORATORY OF THE UNIVERSITY OF ROCHESTER]
THE PREPARATION OF 8-QUIKOLINESULFONIC ACID’ G. E. McCASLAXD Received January SI, 1946
At the time this work vas started, 4-chloro-8-quinolinesulfonic acid was urgently needed as a synthetic intermediate for the preparation of a 4-dialkylaminoalkylamino-8-quinolinethiol,for test as an antimalarial. Two possible routes to the former (previously unreported) compound were the sulfonation of 4-chloroquinoline, and the chlorination of 8-quinolinesulfonic acid. Since there appeared to be no assurance that the sulfonic group would enter the 8-position of 4-chloroquinoline, we chose the second method, and planned to convert 8-quinolinesulfonic acid into the 4-chloro derivative via the N-oxide (1). The preparation of 8-quinolinesulfonic acid, at first expected to be a routine matter, was soon found to be a minor research project in itself, due to the confusing and contradictory state of the literature on quinolinesulfonic acids, most of which was published in the years 1881-1889. Some of the reasons for this confusion will now be described. When quinoline is heated with concentrated or fuming sulfuric acid, sulfonation occurs in the benzene ring in the 5- (“ana”), 6- (‘(par”’), 7- (“meta”), or 8(“ortho”) positions, depending on the conditions. The early literature was confused by a failure to distinguish between the 5- and 7-isomers, both of which were called “meta”. The prefixes ‘‘CY’’ and “b” were also used to refer to the 8and so-called “mets” isomers, respectively, while in current quinoline nomenclature they indicate the 2- and 3- positions. Since the isomeric sulfonic acids obtained melt unsharply above 30O0, they cannot be identified, or their purity established, by means of melting points. It is therefore particularly essential that the method of preparation be exactly specified, and that a convenient means of characterizing the product be offered. But it was found that in fact each reference was lacking in one or several of the essential details: time, temperature, quantities of reactants, method of isolating product, yield, and identity and homogeneity of the product. Lubavin (2), who first sulfonated quinoline, in 1870, said nothing about the possibility of isomerism. Bedall and Otto Fischer (3) attempted to identify Lubavin’s product by fusion with sodium hydroxide to a hydroxyquinoline. The results were uncertain because not all the hydroxyquinolines mere then known, because 7-hydroxyquinoline does not melt sharply, and because alkali fusion might cause rearrangement. They therefore tried conversion of the sulfonic acid to a nitrile by heating with potassium cyanide. A crystalline quinolinenitrile (now known to be the 5-isomer:i was isolated, and for identification was hydrolyzed to a quinolinecarboxylic ztcid, for comparison with the Skraup re1 The work described in this article was done under a contract recommended by the Committee on Medical Research, between the Office of Scientific Research and Development and the University of Rochester. 277
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action product from m-aminobenzoic acid. Unfortunately, this Skraup reaction could theoretically yield either the 5- or 7-quinolinecarboxylic acid (although it is now known to yield mainly the 5-). Actually Lubavin’s product probably consisted mainly of 8-quinolinesulfonic acid. I n a later paper (4), Fischer reported that presumably pure 8-sulfonic acid, due to a rearrangement, yielded mainly the crystalline so-called “meta” (actually 5-) nitrile, and only a small amount of the 8-nitrile (as an oil). Such rearrangements appear to have caused a mistaken belief that certain sulfonation products were a mixture of the 8- and so-called “meta” isomers, and that these isomers could not be separated by fractional crystallization from water. (Actually, the 8-isomer is so much less soluble than the 5- and 7- that it is probably easily separated from them by simple recrystallization.) Therefore a fractionation of the calcium salts (5) was used. Since these salts in turn have no useful melting points, identification was based on crystallographic examinations. Although it is probable that pure isomers were obtained in some cases, manipulative details are inadequately described, and the procedure is not attractive as a preparative method. La Coste and Valeur ( 6 ) stated that the calcium salt fractionation was impractical, and reported a separation of the 8- and so-called “meta-” isomers based on solubility of the :%mercury salt in cold water. The value of this method was questioned by Claus (7); and we now find that the 8-mercury salt is in fact quite insoluble in water. Further confusion was introduced by LeIlman (8), who postulated that two LI ana” quinolinesulfonic acids exist, due to some vague new form of isomerism. This brief description should suffice to indicate the difficulties which may confront anyone who attempts to extract a preparative method from the literature on quinolinesulfonic acids. Therefore we believe it will be useful a t this time to submit an exact description of a method which has been found convenient for the 8-sulfonic acid. The weight of evidence from the literature and our own observations indicates that 8-quinolinesulfonic acid is that insoluble isomer which is obtained by heating with about four parts by weight of 20-30y0 fuming sulfuric acid a t about 100”for about 40 hours (or probably up to 170”for shorter periods), and pouring the cooled reaction mixture into about four volumes of water and that it is 8quinolinesulfonic acid which with phosphorus pentachloride yields a sulfonchloride of map. 124-126’. The identity of our product, was established by conversion of a sample, in 58% yield, to this sulfonchloride. To establish the homogeneity of the product, it was desirable to find a sharp-melting derivative, which could be simply prepared in nearly quantitative yield, and from which the free sulfonic acid could readily be regenerated. [A more elegant method of establishing homogeneity might be use of the counter-current distribution technique of Craig (g).] The p-toluidine and n-butylamine derivatives were first prepared, but did not have sharp, reproducible melting points. Diazomethane failed t o give the methyl ester of this sulfonic acid, probably due to the acid’s dipolar character.
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This ester had been prepared by another method by Claus and Steinitz (10); the yield was not stated, but was presumably too low to be useful in this case. A derivative meeting the above requirements was finally found in the previously unreported dipolar picrate-sodium salt. This compound is in itself of some interest in that both the basic and acidic groups of the quinolinesulfonic acid appear to be simultaneously involved in external salt formation, a type of compound which is apparently unusual. The compound is not obtained unless the solution is held within a certain pH range during preparation, by use of suitable praportions of sodium carbonate and acetic acid. The results obtained indicate that the crude sulfonic acid prepared in the manner described is sufficiently pure for ordinary purposes, but a product of presumably higher purity can be obtained by regeneration from the recrystallized picrate-sodium salt. All attempts to convert 8-quinolinesulfonic acid or its sulfonchloride to the Noxide by use of monoperphthalic or peracetic acids were unsuccessful. In an attempt to activate the halogen atom of 4-hydroxy-8-chloroquinolineby conversion to the N-oxide, as an alternate means of preparing the intermediate 4chlor0-8-quinolinethio1, the N-oxide likewise could not be prepared. Since in the meantime Riegel and co-workers (1l),working independently, had succeeded in sulfonating 4-chloroquinoline in the 8-position, no further attempts were made t o chlorinate the 8-sulfonic acid. EXPERIMENTAL
8-QuinoEinesuZfonic acid. To 123 ml. of fuming sulfuric acid (30% SOJ in an ice-cooled flask was added dropwise 59 ml. of dry, colorless quinoline (b.p. 105-107"/8 mm.) at such a, rate that the temperature did not exceed 90". The resulting dark solution was heated a t 90"for 40 hours with exclusion of moisture, and, after cooling, was poured cautiously into 500 ml. of water. The colorless prisms which crystallized out on cooling were filtered, washed with water, and dried; yield 67 g. (54%) of the practically pure 8-sulfonic acid. [The filtrate may presumably be used for the preparation of the more soluble 5- and 7-SUIfonic acids (12). The 6-sulfonic acid is prepared (13) with concentrated instead of fuming sulfuric acid. ] 8-Quinolinesulfonchloride. The method of Edinger (14) was followed, but i t was found better to extract the sulfonchloride with chloroform, and to recrystallize i t from benzenepetroleum ether. A sample of the sulfonic acid prepared as above described gave a 58% yield of sulfonchloride, m.p. 124-126'. Sodzum 8-quinolinesulfonate picrate. To 6.7 g. of the sulfonic acid prepared as above described was added in the order named 96 ml. of water, 8.2 g. of picric acid (10% HzO), 3.4 g. of anhydrous sodium carbonate, and 3.7 ml. of acetic acid, and the mixture heated until a clear solution resulted. On cooling, the picrate-sodium salt separated as golden leaflets in almost quantitative yield, m.p. 225-226", with decomposition. A sample recrystallized from water, for analysis, showed the maximum m.p. 226-227', with decomposition. Anal.* Calc'd for C16H9NlNa010S(460.3) : Na, 5.00; N, 12.17. Found: Na, 5.03; h-,12.23. Regeneration of the sulfonic acid. A 14.8-g. portion of the picrate-sodium salt was dissolved in 70 ml. of hot water, and 35 ml. of 6 N sulfuric acid was added. The hot solution
* Analysis by Dr. Carl Tiedcke.
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(containing suspended solid) was then extracted with 600 ml. of benzene (preheated to about 60') in four portions, each portion being decanted off. The colorless aqueous phase was fkally heated to boiling and allowed to cool. The sulfonic acid was collected, washed with water, and dried; colorless prisms, weight 6.0 g. (recovery 88%). SUMMARY
A synthetic method suitalde for the laboratory preparation of 8-quinolinesulfonic acid has been exactly described, and the product characterized by conversion to the sulfonchloride and a new picrate-sodium salt derivative of unusual type. ROCHESTER, S. Y. REFERENCES (1) MEISENHEIMER, Ber., 59, 1848 (1926); BACHYAN AND COOPER, J. Org. Chem., 9 , 302
(1944). (2) LUBAVIN,Ann., 155, 313 (1870). (3) BEDALL AND OTTOFISCHER, Rer., 14,442 (1881); 14,2570 (1881); 15,683 (1882). Ber., 15, 19'79 (1882). (4) OTTOFISCHER, (5) OTTOFISCHER,Ber., 15, 1979 (1882); CLAUS,J . prakt. Chem., (2) 37, 258 (1888). (6) LA COSTEAND VALEUR, Ber., 20, 95 (1887); cf. 0. FISCHER, Ber., 20, 731 (1887). (7) CLAUS,J.prakt. Chem., (2) 3'7,258 (1888). (8) LELLMAN, Ber., 20, 2172 (1887). (9) CRAIG,J. Biol. Chem., 155, 519 (1944). (10) CLAUSAND STEINITZ, Ann., 282, 130 (1894). (11) RIEGELAND CO-WORKERS, to be published. (12) BEILSTEIN, 4th Edition, X X T I , 390, 392. (13) BEILSTEIN,4th Edition, X X I I , 391-2. (14) EDINGER,Ber., 41, 937 (1908).
