The story of barbituric acid - ACS Publications


Professor Kogel, a student of Willstatter, who in turn was a student and friend of Baeyer (16). It seems that when Baeyer prepared malonylurea he was...
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MARY KATHLEEN CARTER Tulane University, New Orleans, Louisiana

BAmmumc acid, prepared by Adolf van Baeyer in 1864, was only one of the many compounds which resulted from the work on the uric acid group. This compound probably is as important as any of the uric acid derivatives as a reault of its introduction into medicine in the form of the barbiturates, a group of the hypnotic drugs. The work in the field of the uric acid group began witb the well-known discovery of uric acid in 1776 by Scheele. Scheele noticed in his subsequent work on uric acid that when it dissolved in nitric acid a colorless solution formed which when applied to the skin gave a red color (1). The presence of the urea residue in uric acid was shown by Fourcroy' in 1802 when he obtained urea by treating uric acid with chlorine water (2). In 1818 Gasparo Brugnatelli found on repeating the experiment of Scheele that uric acid mixed with nitric acid reacted in the presence of chlorine water to form a substance which he isolated. He named this substance ergthric acid from the Greek word meaning to redden since it turned red when heated (3). This substance was later renamed alloxan by Liebig and Wohler since, according to them, it contained the constituent residues of allantoin and oxalic acid (4). Previous to the work of Liebig and Wohler, Prout had obtained erythric acid by the oxidation of murexide (ammonium purpurate) with nitric acid. He obtained the murexide by reacting a mixture of uric acid and nitric acid with ammonia (6, 6). Both of these compounds, urea and alloxan, were later used in the preparation and synthesis of barbituric acid. Liebig and Wohler published their classical work on uric acid in 1838 (4, 7). They found that oxidation of uric acid with dilute nitric acid gave another compound, known today as alloxantin, a condensation product of alloxan with dialuric acid. The reduction of alloxan to give alloxantin and the oxidation of alloxantin to give alloxan were clearly shown by these two men. Adolph Schlieper, a student of Liebig's, also worked on alloxan. In 1845 he published two papers on his work in which he had obtained hydurilic acid in attempting to prepare alloxan, and he also obtained dilituric acid by oxidizing alloxantin (8). These two last mentioned compounds were used specifically later on by Baeyer in preparing barbituric acid. In the winter of 1858-59, when Baeyer was going from Heidelberg to Ghent where he was to rejoin KekulB, he made Fourcroy assigned the name uric acid to the substance discovered by Scheele. It had previously been called beeaardic or lithic acid.

the acquaintance of Schlieper, who was then a manufacturer in Elberfeld where Baeyer's sister lived (9,10). Schlieper had saved the uric acid compounds on which he had worked and he now gave these to Baeyer for further investigation. Even though Baeyer remained a t Ghent only a year his investigations there led to the discovery of pseudo-uric acid which he published in collaboration with Schlieper (11). Later, Baeyer's famous student, Emil Fischer, worked out a synthesis for uric acid by the elimination of water from pseudouric acid (1s). Most of Baeyer's work on the uric acid group was done during the period from 1860 to 1872 while he was in Berlin. Baeyer found that the oxidation of hydurilic acid gave violuric acid, which on further oxidation gave dilituric acid. He worked out the relations among these various compounds and came to the conclusion that. they were all related, and that they originated from barbituric acid. Following is a list of the more important uric acid derivatives of the alloxan group as given by Baeyer (IS) : Related Compounds Between Barbituric Acid and Uric Acid

'

Barbituric acid Bmmobarbituric aoid Bibromobarbitwio acid Dialuric aoid Allaxan Violuric acid Dilituric acid Uramil Pseudo-uric acid Uric acid

Three of the allmantin "orouv. Alloxantin lHeO Z03Hb- H 2 0 Hydurilic acid :NOJH8 Violantin

In order to substantiate the hypothesis that barbituric acid was the beginning compound Baeyer prepared it. By the reaction of bromine on violuric acid, dilituric acid, or hydurilic acid he obtained alloxanbromide. The equation given by him for the reaction with the use of hydurilic acid is as follows (IS): N4CsOlH8 Hydurilic acid

+ HBO+ 3Br2

-

+

N,C,OaBr,H, N,C40,H2 Alloxanbromide Alloxan

+ 4HB1

Baeyer then worked out a better procedure for the preparation of alloxanbromide, or dibromobarbituric acid, which consisted in heating a mixture of hydurilic aoid and nitric acid saturated with bromine until the crystals formed dissolved witb the liberation of nitrous acid. On cooling, the alloxanbromide crystallized out (15). From dibromobarbituric acid Baeyer then pre-

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The synthesis of barbit,uric acid from malonic acid and urea was accomplished in 1879 by Edouard Grimaux (18). By heating on the water bath for two hours a mixture of equal parts of malonic acid and urea in the presence of phosphorous oxychloride and dissolving the resulting mixture in ten times as much boiling water he obtained on cooling a yellow flaky precipitate. The pure malonylurea was obtained by recrystallization of the precipitate from alcohol and water. Various other syntheses have been worked out hut they are only modifications of the one used by Grimaux in which different condensing agents are utilized. During the latter part of the nineteenth century much work was done On which were in nature' Joseph von Mering a t the Clinical Laboratories in Halle continued earlier work on this class of drugs. His work led eventually to t,he discovery of the hypnotic properties of diethylbarbituric acid. I t should be Max Conrad and Max Guthzeit prethat in pared this derivative of barbituric acid by heating the silver salt, of barbituric acid with ethvl iodide (19). . . When von Mering began anew his work on the hypnotic drugs he knew from his experience that ethyl groups in suif:ablecombination with urea had hypnotic properties (20). With this in mind he combined diethylmalonic acid and urea, using the mrt,hod of Grimaux, by condensing them with phosphorous oxychloride. He obtained a crystalline compound which he presumed to be diethylmalonylurea. Since von Mel.ing 17-as not an expert in determining the constitution of compounds he had the product analyzed by Emil Fischer in Berlin. Fischer and von Mering had known each other when Fischer was a st,udent a t Strassburg (21). Fischer's analysis confirmed von Mering's supposition. Fischer later published a method of preparing diethylbarbituric acid using sodium ethoxide as a condensing agent (33). This is the method most, commonly t,hought of when one considers the preparation of this and similar compounds. The name "Vnronal" given to t,his compound by von Mering was suggested to him as he approached Verona while on a trip through Italy (28). He seems to have had a fondnes~for inventing striking .* names such as hhis. Since the publication of Fischer and von Mering on t,he hypnot,ic properties of diethylbarbituric acid (34) literally thousands of barbituric acid derivatives have been prepared and their hypnotic value tested. I t has been found that, t,o l)e effective both hydrogen at,oms in > .

the fifth place of the molecule must be replaced by an alkyl or aryl group (25). By increasing the length of the alkyl chain, differences in potency of the compounds, usually an increase, are found. Other differences in action are found by varying the chains by branching or unsaturation. ACKNOWLEDGMENT

The author, a graduate student and assistant in pharmacology, wishes to thank Professor Clara deMilt for her suggest,ions and helpfulness in the preparation of this paper. LITERATURE CITED (1) S C ~ E E ~ ,KARlr E , WILHELM, OpuSCU]a11, 73-9, Cited by P. A. LEVENEAND L. W. BASS, "Nucleic Acids," The Chemical Catalogue Co., Inc., New York, 1931, p. 76. (2) F o u m o y , A. F. DE, Annales du Museum, 1, 98 (1802). Cited by EMIT,FIWHER,"Unter~uchunpenin der Puringruppe," Juliufi Springer, Berlin, 1907, p. 4. (3) HR~CNATELLI, GASPARO, Phil. Mag., 52,30-47 (1818). (4) W"HT.ER, F., A N D J. T,IBBIG, Ann., 26,241-340 (1838). (5) PROVT.W.. Trwns. ROW.Sac. (London). 1818.42&8. i6j PROI:T;w.; Ann. ~ h i l14, , 3 6 3 4 (18ik). ARTHUR,"The Spirit, of Organic Chemistry," (7) LACHMAN, The Macmillen Co., Ine., New York, 1904, p. 93. ADOLPH,Ann., 55, 251-97 (1845); 56, 1-29 (8) SCHI~IEPER, (1845). FERDINAND, J. CHEM.EDUC.,7, 123148 (1930). (9) HENRICH, W. H., "The Baeyer Memorial Lecture," in "Me(10) PERKIN, morial Imtures Delivered Before the Chemical Society, 1914-32," Burlington House, London, 1933, Val. 111, pp. 47-73. A,, AND A. HAEYER, Bull. a d . m y . mdd. Belg. (11) SCHLIEPER, 121, 9, No. 2. Cited by Auor,~RAEYER, Ann., 127, 1-27 (18631, p. 3. EIII., Ber., 30, 2226-54 (1897). (12) FISCHER, ADOLF,Ann., 127, 199-236 (1863). (13) BAEYER, ADOLF,ibid., 130, 129-75 (1864). (14) HAEYER, ADOLP,ibid., 131,291-302 (1864). (15) BAEYER, (16) COHEN- MEE ESTER, W. A. T., Chem. W'eekblad, 40, 176-9 (1043). E., Rer., 6,1233-7(1873). (17) MULDER, ~ ~ D O U ABull. R D , $ 0 chim. ~ Paris 121, 31, 146-9 (18) GRIMATEX, l l-R-7. .9. , i. (19) CONRAD, M., AND M. GUTHZEIT,'BW., 15,2844-50 (1882). (20) H o ~ s c nKURT, , "Emil Fincher, Sein Lebm und Sein Werk," Berlin, 1921, pp. 240-5. , "AUSMeinem Lehen," Julius Springer, Ber(21) F r s c n e ~EMU., lin, 1922, p. 55. EMIL,AND ALFREDDILTHEY,Ann., 335, 334-68 (22) FISCHER, (1904). (23) ZVNTZ,N., Miinch. med. Woehsehr., 55, 4 W 2 (1908). EMIL,A N D J. VON MERING, Thwap. Gegenwa~t,44, (24) FISCHER, 97-101 (1903). A. L., Phusiol. Rewa., 19, 472-502 (1939). (25) TAT~M,

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