444 WREN AND STILL: CONFIQURATION OF THELIL- Configuration o j the Stereoisomeric Diphen yl-succinic Acids.By HENQY WREN and C~BCARLES JAMES STILL.IN spite of the large amount of research which has been devoted tothe symmetric diphenylsuccinic acids, the question of their con-figuration has not been definitely settled. Since these substancescontain two asymmetric carbon atoms, each united to the samegroups, it is obvious that one of them (i) must be resolvable intooptically active components, whilst the other (ii) must be of themeso type:QO,H yo,= p 2 HH-7-Ph Ph-7-H Ph-7-HPh-FII: H-7-Ph Ph-7-HCO,H C0,H CO,H(1.1 (11.)I n the present communication it is shown that 8-diphenylsuccinicacid is to be regarded as mesodiphenylsuccinic acid and a-diphenyl-succinic acid as r-diphenylsuccinic acid.The resolution of thelatter was accomplished by the use of brucine in aqueous solution,the brucine salt of the d-acid being the more sparingly soluble.d-Diphenylsuccinic acid melts to a pasty, non-transparent liquid a t1 79-180° after previous slight shrinkage, then re-solidifies, andagain melts at 212-214° to a yellow liquid, from which gas is notevolved. It has [u]” +397*9O when dissolved in amtone and1-Diphenylsuccinic acidmelts a t 176-177O, re-solidifies, and again melts a t 211’5-214O. I nethyl-alcoholic solution it has [a]E - 368.9O. d-Diphenylsuccinicacid has been isolated in an almost pure condition by McKenzie,Drew, and Martin (T., 1915, 107, 32) from thO products of theaction of magnesium phenyl bromide on Z-phenylchloroacetic acid.The specimen which they obtained had [u]: + 348O in ethyl-alcoholicsolution, and, after being dried a t looo, shrank sharply to a thincore a t 170-171°, which was unchanged until 211*5O, when itmelted sharply to a clear liquid, from which gas was not evolved.A consideration of the relative stability of the anhydrides ofa- and P-diphenylsuccinic acide has led Anschutz and Bendix(8niiaZen, lS90, 259, 81) to the coaclusion that the a-acid is theracemic variety.a-Diphenylsuccinic acid has a lower melting point than the &acid,and is the resolvable form. In the case of the isomeric dibrome+ 369.7O in ethyl-alcoholic solutionSTEREOISOMERIC DIPHENYLSUCCINIC ACIDS.445succinic acids, McKenzie (T., 1912, 101, 1196) has shown that itis the iso-form which melts a t a lower temperature than its inactiveisomeride, and can be resolved into optically active components,whilst Werner and Basyrin (Ber., 1913, 46, 3229) foand that thedimethylsuccinic acid of lower melting point is the resolvable form.The case of the aa’dimethyladipic acids, investigated by Noyes andKyriakides ( J . Amer.Chem. Soc., 1910, 32, 1057), presents similarfeatures. It appears remarkable that, in the inseances of thesymmetric di-substituted succinic acids which have been examinedfrom this point of view, the isomeride of lower melting pointshould be the racemic acid, whilst in the tartaric acid group thereverse is the cw0.EXPERIMENTAL.Interaction of Ethyl Phenylacetate and Iodine in Dry EtherealSolution in the Presence of SoZid Sodium Ethoxide.a-Diphenylsuccinic acid was prepared by Franchimmt (Ber.,1872, 5, 1050) by the action of an alcoholic solution of potassiumcyanide on ethyl phenylbromoacetate and treatment of the productwith potassium hydroxide.Subsequently, Reimer (Ber., 1881, 14,1802) found that this acid, and also the @-acid, are obtained byreducing the anhydride of stilbenedicarboxylic acid by means ofsodium amalgam in dilute alkaline solution, and that they can beconveniently separated by taking advantage of the widely differingsolubilities of the respective barium salts in water. According LQAnschiitz and Bendix (Zoc. cit.), the barium salt of the a-acid issoluble in 312 parts of water a t 17--18O, whilst the correspondingsalt of the fi-acid requires only 4.742 parts of water for solution.Reiiner also showed that the a-acid is completely converted intothe fi-isomeride by protracted treatment with aqueous hydrochloricacid at ZOOo, whilst the reverse transformation may be effectedby the use of an excess otf aqueous barium hydroxide a t the mmetemperature.It was further found that the hydrolysis of diphenyl-succinonitrile a t 200° by means of aqueous hydrochloric acid leadsto the formation of P-diphenylsuccinic acid, and this method gainsadditional value from the observation of Chalanay and Knoevena-gel (Ber., 1892, 25, 285) that the nitrile can be prepared inquantity by heating an equimolecular mixture of phenylacetonitrileand mandelonitrile in alcoholic solution in the presence of solidpotassium cyanide a t 50-60° during twelve to eighteen hours.I nthe course of the present investigation, considerable amounts ofthe @-acid have been prepared in this manner, but the inconveni-ence of obtaining the requisite quantity of acids by methodsinvolving the use of sealed tubes has led to the investigation ofG G 446 WREN AND STILL: CONFIGURATXON OF THEother processes. It has been found by Komnenos (Annulen, 1910,375, 254) that small yields of ethyl P-diphenylsuccinate areobtained when an ethereal soIution of iodine is added t o a moder-ately dilute alcoholic solution of ethyl phenylacetate and sodiumethoxide. By diminishing the quantity of alcohol employed, how-ever, the amount of ester obtained can be considerably increased,but a more decided improvement is effected by performing the con-densation in dry ethereal solution in the presence of solid sodiumethoxide ; in these circumstiances, ethyl 8-diphenylsuccinab isreadily isolated, whilst, in addition, notable amounts of ethyla-diphenylsuccinate are obtained.The following experiment istypical.A solution of iodine (27.3 grams) in absolute ether (140 c.c.)was gradually added to a well-cooled mixture of ethyl phenyl-acetate (35 grams), ether (70 c.c.), and finely powdered sodiumethoxide obtained from 5.7 grams of sodium. The colour of theiodine disappeared instantly, and a white precipitate was formed,which, when preserved, became yellow and ultimately yellowish-brown.The product of the reaction was treated with water andsodium thiosulphate solution, when an almost colourless aqueouslayer and a yellow ethereal solution were obtained, between which aconsiderable quantity of a yellowish precipitate ( A ) was suspended.The latter was separated, the aqueous layer was extracted withether, and the combined ethereal solutions were dehydrated overanhydrous sodium sulphate. After the removal of the ether, thermidue was heated under diminished pressure, whereby unchangedethyl phenylacetate (3-2 grams), strongly cdoured with iodine, wasrecovered. The residual ester solidified to a brownish-yellowcake ( B ) .The solution of the precipitate ( A ) in boiling alcohol deposited,on cooling, ethyl P-diphenylsuccinate (9.7 grams), m.p. 139-140'.The mother liquor was used for the crystallisation of the cake (B),whereby a mixture of the a- and &esters (8 grams), m. p. 74-130°,was isolated; the filtrate was evaporated to dryness, and the residuewas treated with sodium thiosulphate to remove further quantitiesof iodine which had gradually eeparated," and crystallised fromlight petroleum (b. p. 40-60°), when a quantity of approximatelypure a-ester, contaminated with a small amount of resinous matter,was obtained. The separation of the isomeric esters was accom-* In the course of these condensations, an unstable iodine compound, possiblyethyl phenyliodoacetate, is formed from which iodine is not completely eliminatedby the aid of sodium thiosulphite or by heating at about 140" under diminishedpressure. The separation of the halogen appears to be greatly facilitated byexposure to bright light.Somewhat analogous observations have been made byMcKenzie, Drew and Martin (Zoc. cit.)STEREOISOMERIC DIPHENYLSUCCINIC ACIDS. 447panied by considerable loss, and was best effected by repeatedextraction of the mixture with successive small quantities of boilinglight petroleum (b. p. 40-60°), in which the P-mter is sparinglysoluble. The final purification of the a-ester wm accomplishedby several crystallisations from methyl alcohol, and subsequentlyfrom light petroleum. I n this manner 3.2 grams of pure aesterwere obtained from the above mixture, in addition to a furtherquantity (2.1 grams) of B-ester.Ethyl 8-diphenylsuccinate separates from ethyl alcohol in almostcolourless needles, which melt a t 140-141O (corr.), whereas Reimer(Zoc.cit.) gives 136O, Anschutz and Bendix (Zoc. cit.) 140-141°,and Komnenos (Zoc. cit.) 140O. (Found, C=73*7; H=6.9. Calc.,C=73-6; H=6.8 per cent.)Ethyl a-diphenylsuccinate melts a t 82-83-5O (corr.). The valuesrecorded are 84-85O (Reimer) and 84O (Anschiitz and Bendix).(Found, C=73-9; H=6*9. Calc., C=73*6; €€=6*8 per cent.)Action of Acids and Alkalis o n the Isomeric EthylDiph.enylsuccinates.Ethyl Pdiphenylsuccinate is hydrolysed when heated in a sealedtube with concentrated aqueous hydrochloric acid a t ZOOo duringfive and a-half hours, P-diphenylsuccinic acid being produced ingood yield.Considerable discrepancies arc3 shown in the meltingpoints observed' for this substance, the following data beingrecorded : 229O, Reimer (Zoc. cit.) ; 229-230°, @halanay andKnsevenagel (Zoc. cit.) ; 245O, Anschutz and Bendix (Zoc. cit.) ;252O, with evolution of gas on rapid heating, Roser (AnnaZen, 1888,247, 152); 252O, Ruhemann and Naunton (T., 1912, 101, 50);228-230°, McKenzie, Drew, and Martin (Zoc. cat.). The acidobtained by the method described above, ils well as that preparedby the action of hydrochloric acid on diphenylsuccinonitrile, wasfound to melt a t 229-230°, and this value remained unchangedafter repeated crystallisation from ethyl or amyl alcohol or fromethyl benzoate.The fact that 8-diphenylsuccinic acid can be completely con-verted into the a-isomeride by protracted treatment with an excessof aqueous barium hydroxide a t a somewhat elevated tempera-ture, pointed t o the probability that a mixture of the potassiumsalts of the a- and 8-acids would be obtained by the hydrolysis ofethyl 8-diphenylsuccinate by potassium hydroxide.This hypo-thesis was confirmed by an experiment in which ethyl P-diphenyl-succinate (4 grams) was heated with a solution of potassium hydr-oxide (1.9 grams) in ethyl alcohol (30 c.c.) and water (10 c.c.).The resulting solution was exactly neutraliseed with hydrochlori448 WREN AND STILL: CONFIGURATION OF THEacid, evaporated to remove alcohol, and treated with a hot aqueoussolution of barium chloride. A crystalline precipitate of bariuma-diphenylauccinate was obtained, which weighed 4.3 grams, andfrom which a-diphenylsuccinic acid was isolated by the addition ofhydrochloric acid.The acid melted a t 18O-18lo, re-solidified, andagain melted a t 220°, whereas Reimer (Zoc. cit.) gives 183O and222O. The filtrate from the above barium salt yielded 8-diphenyl-succinic acid on the addition of mineral acid. I n a somewhatsimilar experiment, Komnenos (loc. cdt.) found that the acidobtained by the hydrolysis of ethyl P-diphenylsuccinate melted a t160°, and was led to the conclusion that it was probably a mixtureof the isomeric acids.The saponification of ethyl a-diphenylsuccinate with aqueous-alcoholic potassium hydroxide proceeds normally, a good yield ofa-diphenylsuccinic acid being obtained on the addition of mineralacid to the product.Preparation of a-Diphenylsuccinic Acid.When it is desired to prepare a-diphenylsuccinic acid from theproduct of the action of iodine and sodium ethoxicle on ethylphenylacetate, the separation of the isomeric diphenylsuccinicesters is unnecessary. The following experiment illustrates themethod adopted :Finely-powdered sodium ethoxide (obtained ffom 8 grams ofsodium) was suspended in a solution of ethyl phenylacetate (49.2grams) in anhydrous ether (100 c.c.).An ethereal solution ofiodine (35.1 grams in 200 c.c.) was slowly added to the mixture,which was cooled by immersion in ice and water. After remainingduring some hours a t the ordinary temperature, water and sodiumthiosulphate solution were added.The flocculent precipitate ofethyl P-diphenylsuccinate was removed, and the aqueous solutionextracted with ether. The combined ebhereal extracts were dried,and, after the removal of the ether, heated under diminished pres-sure, whereby unchanged ethyl phenylacetate (7 grams) wasrecovered. The residue in the distilling flask was united with theprecipitated ester and hydrolysed by an excess of aqueous-alcoholicpotassium hydroxide. The resulting solution was heated in anopen dish until the alcohol was completely removed, filtered froma small amount of brown, resinous matter, heated to boiling, andtreated with an excess of a boiling concentrated solution of bariumchloride in water, when a heavy, white precipitate of bariuma-diphenylsuccinate was obtained.This was filtered and washedwith water. The filtrate was transferred to an autoclave, andheated for five hours a t 1 9 5 O , when a further quantity of bariuSTEREOISOMERIC DIPHENYLSUCCINIC ACIDS. 449a-diphenylsuccinate was precipitated, which was removed afterexwt neutralisation of the excess of alkali by means of hydrochloricacid. The united crops were suspended in water, and decomposedby hydrochloric acid. The precipitated a-diphenylsuccinic acid wascrystallised from boiling water, when 18.8 grams of acid wereobtained, which melted a t 183O, and, after resolidification, a t220-221O. The yield obtained, calculated on the amount of ethylphenylaoetate which entered into action, was 50.4 per cent.of thattheoretically possible.Resolution of a-Diphenylsuccinic Acid.A mixture of a-diphenylsuccinic acid (30 grams) and brucine(97.1 grams) was heated on the boiling-water bath with water(6,820 c.c.), until almost complete solution was obtained. Afterfiltration, the solution was allowed to cool, and seeded with a smallquantity of brucine a-diphenylsuccinate obtained from a previousresolution. (In this instance, the use of a pure seeding materialwas found to be without influence on the purity of the crop, butadvantageous in that it caused the latter t o separate fairly rapidlyand in a much more distinctly crystalline condition than wasotherwise the case.) After remaining for some days in an ice-chesta t about 5O, the crop was separated and dried on porous earthen-ware, when 87 grams of crystals were obtained, which were purifiedby repeated crystallisation from hot water, 70 C.C.of the solventbeing used for each gram of product. The course of the resolutionwas followed by determining the specific rotation of the acidrecovered from the successive filtrates. The following values f o r[a], were thus obtained, the observations being made in acebn0solution : - 195'2O, - 109*6O, + 10-lo, + 76*6O, + 206'7O, + 252.9O.The crop from which the last filtrate had been obtained, whichconsisted of long, well-formed prisms weighing 20.8 grams, wasdecomposed by treatment with dilute hydrochloric acid, and ex-tracted with ether, whereby 4.5 grams of d-diphenylsuccinic acid,having [a], +344*9O in acetone solution, were isolated.After twocrystallisations of this acid from considerable quantities of water,this value had risen to +397-3O, and khen remained unchangedaftler a further recrystallisation.d-Diphenylsuccinic acid separates from water in felted masses ofminute needles. It is sparingly soluble in the hot solvent, verysparingly so in the cold. Ik dissolves sparingly in boiling benzene,readily in cold ether, methyl and ethyl alcohols, and in ethylacetate. When heated in a capillary tube, it melk to a pastyliquid a t 179-180°, then solidifies, and melts a t 212-214O to ayellow liquid, from which gas is not evolved. ThO temperatures are450 WREN AND STILL: CONFIGURATION OF THEhowever, somewhat dependent on the mode of heating, and thediameter osf the tribe employed.The acid is hygroscopic. Analysesand determinations of specific rotation were made with samplawhich had been dried a t 100-105° until constant in weight:0.1412 gave 0.3688 CO, and 0.0666 H,O. C=715?; H=5-3.The following determinations of the specific rotation wereIn acetone solution:C,,H,,O, requires C= 71.1 ; H =5.2 per cent.made :I = 2, C = 1.4525, ag + 11-54', [a]" + 397.3'I = 2, c = 2 3015, a$ + 18*32', [a]: + 3'37.9'.I n ethyl-alcoholic solution :I = 2 , ~=1*4955, a: +.11*05', [a]; +369*5'I = 2, C= 2,3450, a$'5 + 17.34', +369.7'.I n methyl-alcoholic solution :I = = 2, C = 1.8075, a: + 12-61', + 369.2'.I n ethyl acetate solution :I = 2, C = 1.4665, a: + 1 1.SZo, [a?: + 403.0'.I n another experiment an attempt was made t o effect the finalpurification of the d-acid by crystallisation from benzene, butthis solvent was found to be less suitable for the purpose thanwater.Preprn.tion of I-Diphenylsuccinic Acid.The isolation of I-diphenylsuccinic acid was accomplished by thefractional crystallisation from water of the crude, Izvorotatorymixture of acids obtained from the filtrate from the first crop ofbrucine salt (see above).I n one case, crude Ediphenylsuccinicacid (11 grams, [a], - 135'2O in ethyl-alcoholic solution) was dis-solved in boiling water, 160 c . ~ . of the latter being used for eachgram of acid. A somewhat felted crop separated on cooling, which,after being dried, weighed 5.6 grams, and had [a], -259O(c = 2.6255) in ethyl-alcoholic solution.On continuing the process,using the same relative quantities of acid and water, the succes-sive crops had [a], - 347*6O, - 361*8O, - 366.0°, - 368*0°, and-368-9O, the latter value agreeing satisfactorily with the value,+369*7O, found f o r the d-acid in the same solvent.I-Biphenylsuccinic acid closely resembles its d-isomeride in itsproperties. It melts a t 176-177O t o a pasty liquid, which thenresolidifies and again melts a t 211'5-214O to a yellow liquid, fromwhich gas is not evolved. As in the case of the d-acid, these ternSTEREOISOMERIC DIPHENY LSUCCINIC ACIDS. 451peratures depend somewhat on the rate of heating and the diameterof the capillary tube.For the analysis and for the determination of the specific rotationthe acid was dried a t 100-105° until constant in weight:0.1339 gave 0.3473 CO, and 0.0632 H,O.C=70.7; H=5*3.C,GH,,O, requires C = 71-1 ; H = 5.2 per cent.The specific rotatioil was determined in ethyl-alcoholic solution :The unexpectedly great purification caused by the first crystal-lisation of the crude Z-acid, considered in conjunction with tl>eweighb of material involved, rendered an examination of the aci 1contained in the filtrate a matter of interest. It was therefoi Iextracted with ether, and, on examination in ethyl-alcoholic solu-tion, was found to be slightly dextrorotatory (Z=2, c=4.167,a, +0*34O, [a], +4*l0). This result was a t first attributed to thepresence of an optically active impurity in the materials employed,but the initial udiphenylsuccinic acid was optically inactive, whilst,also, a series of blank experimenla gave completely negative results.I n a second experiment an acid having [a],, -152O was crystallisedunder similar conditions; the acids obtained from the crop andfiltrate respectively had [aID - 295'5O and + 3'05O in ethF1-alcoholicsolution. I n like manner, a crude &acid which had [a], + 135*6O,was separated into two portions, having [alD +255*2O and - 3 iorespectively.Attempts were also made to employ other alkaloids for theresolution of u-diphenylsuccink acid. With quinine, cinchonine,strychnine, or morphine in aqueous solution, and with morphine inethyl-alcoholic solution, no evidence of resolution could be obtained.I = 3, c = 2.3325, a:' - 17*21°, [~t]: - 368.9".Attempts to Resolve 6-Diphenylsuccinic Acid.I n the preliminary part of this investigation attempts were madeto resolve Bdiphenylsuccinic acid by means of morphine and brucinerespectively in aqueous solution. In each case, crystalline saltswere readily prepared, from which, however, an optically activeacid was not obtained; these salts were not further investigated.MUNICIPAL TECHNICAL INRTITUTE,B E LFABT. [Received March 3 4 19151