THE SYNTHESIS OF ALKYLTRICARBALLYLIC ACIDS. 29 V.-The Synthesis of Al~~~ltricarballylic Acids. By WILLIAM A. BONE and CHARLES H. G. SPRANKLING. IN a previous communication (Trans., 1899, 75, 839), we described a method for the preparation of ethyl esters of cyanosuccinic acid and its alkyl derivatives ; for some time past, we have been investigating a general method for the synthesis of alkyltricarballylic acids, based30 BONE AND SPRANKLING: THE SYNTHESIS OF on the interaction of the sodium compounds of these othyl cyano- suucinates with the ethyl esters of a-bromo-fatty acids, as indicated by the general equation, CR,. C0,Et CN CR,Br*CO,Et + N E L C < ~ ~ ~ ~ ~ I = ~<~~,,, -I- NaBr, CR2 c02E CR, CO,E t where R indicates hydrogen or any alkyl radicle, A reference to the literature of the subject shows that tricarballylic aoid and its a-alkyl derivatives have been generally obtained by the condensation of the sodium compound of ethyl malonate, or one of its alkyl derivatives, with ethyl fumarate or maleate, and subsequent hydrolysis of the resulting ester, as follows : vNa( C0,E t), CRNa(C0,Et)2 +- CH*Co2Et I I = QH*CO,Et CH*Co2Et CHR*CO,Et Auwers and others (Ber., 1891, 24, 30'7, 288'7) prepared a number of a-alkyltricnrballylic acids from ethyl fumarate, but so far as we know no attempt has been made to see whether dialkyltricarballylic acids can be obtained by any similar method.In 1896, Zelinsky (Bey., 29, 333, 616) showed that three apparently stereoisomeric ay-dimethyltricarballylic acids are obtained when the highest fraction of the oil which results from the interaction of ethyl cyanoacetate (1 mol.), sodium ethoxide (2 mols.), and ethyl a-bromo- propionate (2 mols.) in alcoholic solution is hydrolysed with sulphuric acid.His investigation of the subject was incomplete and he has since abandoned it. Just as we were beginning our experiments, Haller and Blanu (Compt. rend., 1900, 131, 19) synthesised aa-dimethyltricarballylic acid from ethyl cyanosuccinate, but except in this one instance the practicability of preparing tricarballylic acids from ethyl alkylcgano- succinates has not so far been,studied.* As the result of a long and systematic investigation of the matter, we have shown that anyalkyltricarballylic acid in which the alkyl radicle or radicles occupy an a-position with respect to either of the two extreme carboxyl groups may readily be prepared by the method we have indicated.Besides the method just discussed, there is obviously another possible way of passing over from an acid of the succinic to one of the tricarballylic series, namely, by the interaction of an ethyl mono- * Since this paper was written, however, Dr. H. A. D. Jowett has published an account of the preparation of a-ethyltricarballylic acid from ethyl a-cyano-B-eth yl- succinate and ethyl bromoacetate (Trans. 1901, 79, 1346).ALKYLTRICARBALLYLIC ACIDS. 31 bromosuccinate with ethyl sodiocyanoacetate or malonate as represented by the general equation, C02Et*CR2*CRBr*C02Et i- NaCH<co,Et CN - - CO,Et*CR,*CR(CO,Et)*CH(CN)*CO,Et + NaBr, where R represents hydrogen or an alkyl radicle (or radicles).Hitherto, only tricarballylic acid itself has been prepared by this method (Emery, Bey. 1890,23,3759), and we therefore extended our experiments in this direction in order to ascertain whether this second method possesses any advantages over the first, or vioe versa. The results are very decisive on this point, for they indicate that whereas the first (" cyano- succinate ") method is a general one, the second can only be applied in certain cases (owing partly to the circumstance that the bromination of many substituted succinic acids does not proceed regularly, and partly also to the tendency which some ethyl bromosuccinates exhibit to lose hydrogen bromide and form unsaturated compounds). And, further, even when the second method can be applied, the yields of resulting tricarballylic acids are camparatively poor, Incidentally, however, we have accumulated valuable information as to the bromina- tion of alkylsuccinic acids, which will be briefly discussed later.During the course of the experiments, we have added to the know- ledge of the pr'operties of various alkyltricarballylic acids, their anhydro-acids and monomethyl salts, but have not been able con- jointly to finish the scheme of work originally drawn up; the results so far obtained are, however, sufficiently complete in themselves to justify their publication. The investigation of this interestiag and important series of acids will be continued. I. PREPARATION OF ETHYL CYANOTRICARBALLYLATES FROM ETHYL CYANOSUCCINATES.The method adopted may be briefly described as follows : To a solu- tion of 5.75 grams of sodium in alcohol is added one-fourth of a gram- mol. of the ethyl cyanosuccinate ; the sodium compound of the latter, which is at once formed, remains in solution. Rather more than the calculated quantity of the a-bromo-fatty ester is then cautiously added in small portions at a time. The interaction which follows is generally very vigorous, much heat is developed, and sodium bromide separates. The liquid usually becomes neutral after being heated for 30 to 60 minutes on the water-bath, after which it is poured into water and the ethyl cyanotricarballylate extracted with ether in the usual manner. On fractionating the crude oil under diminished pressure (20-35 mm.), a certain amount of it passes over at temperatures below 150"; the32 BONE AND SPRANKTJING: THE SYNTHESIS OF thermometer then rises rapidly to about ZOO', when the ethyl cyano- tricarballylate begins to distil.The following are the particulars concerning the yields, &c., obtained in the various preparations, and the properties of the refractionated ethyl cyanotricarballylates. Ethyl C~anotricarballylcte. The yield of refractionated oil obtained from ethyl cyanosuccinate and ethyl bromoacetate amounted to 75 per cent. of that theoretically possible; under 28 mm. pressure, it boiled a t 206-212'. On being rapidly cooled, the distillate solidified. By dissolving the solid in the minimum quantity of warm glacial acetic acid, then adding hot water until a faint turbidity appeared, and setting the liquid aside to cool slowly, the whole of the substance separated after some hours in prismatic and transparent crystals which melted sharply a t 40-41'.On analysis : 0,2213 gave 0.4421 CO, and 0.1376 H,O. 0.3116 ,, C = 54-48 ; H = 6.90. 13.8 C.C. nitrogen at 18' and 752 mm. N = 5.07. C,,H,,O,N requires C = 54.73 ; H = 6.66 ; N = 4.91 per cent, CH,*CH(CO,Et)*C*CH,*CO,Eb Ethyl a-ilfet h ylcyanotricarbally Zat 6, A CN C0,Et This substance may be prepared by the interaction of either the sodium derivative of ethyl 6-methylcyanosuccinate and et hy 1 bromo- acetate or of the sodium derivative of ethyl cyanosuccinate and ethyl a-bromopropionate. The first named method is much the better of the two, and the yield obtained by it amounted to 70 per cent.of the theoretical. The refractionated oil boiled at 202-204' under 23 mm. pressure, had a density d O o / 4 O = 1.1339, and a refractive index pNa = 1.4461. On analysis : 0.2002 gave 0.4137 CO, and 0,1316 H,O. 0.3102 ,, 12.75 C.C. nitrogen at 15' and 771 mm. N=4.87. C1,H210,N requires C = 56-18 ; H = 7-02 ; N = 4.68 per cent, C=55*86 ; H=7*31. Ethyl ay-Bimeth~ZcyanotricarbuZlylate, CH,* CH(C0,Et) C*CH( CH,) -CO,Et /\ CN C0,Et The yield of refractionated oil obtained from ethyl P-methylcyano- succinate and ethyl a-bromopropionate amounted to 65 per cent, of the theoretical. It boiled at 208-210' under 30 mm. pressure, had aALKYLTRICARBALLYLIC ACIDS. 33 density d Oo/4'=la1215, and a refractive index pNa=1*4484. analysis : On 0.1976 gave 0.4146 CO, and 0.1353 H,O.0,2863 ,, 11.3 C.C. nitrogen a t 16' and 758 mm. N = 4.59. C-57.21 ; H = 7.61. C,,H,,O,N requires C = 57-50 ; H = 7.34 ; N = 4.47 per cent. (CH3),C(C02Et)*C*CH,*C0,Et EthpZ aa-Dimethylcyanotl.iccco.baZZyZate, /\ CN C0,Et This may be prepared either by the method adopted by Haller and Blanc (Zoc. cit.) by the interaction of ethyl sodiocyanosuccinate and ethyl a-bromoisobutyrate, or by the interaction of ethyl PP-dimethylsodio- cyanosuccinate and ethyl bromoacetate. We have tried both methods and find that the second is by far the better one; the yield obtained by it amounts to 55 per cent. of the theoretical, and if after fraction- ating the crude product the portion of lower boiling point be again heated with a small quantity of sodium ethoxids in alcohol, a further quantity of the cyanotricarballylate is formed, bringing the total yield up t o nearly 70 per cent, of the theoretical. The refractionated oil boiled at 202-204' under 17 mm.pressure, had a density d 0°/4" = 1.1353, and a refractive index pNa = 1.4503. On analysis : 0.2006 gave 0,4206 CO, and 0,1341 H,O. C = 57.19 ; H = 7.43. U,,H2,0,N requires C = 57.50 ; H = 7.34 per cent. EthgZ ay-Diisopropg Zc?lanotricarbaZlgZate. This was prepared by the interaction of ethyl P-isopropylsodiocyano- succinate and ethyl a-bromoisovalerate ; the experiment cannot be properly carried out in an open vessel on the water-bath, as the reaction only proceeds very slowly under these conditions. The mixture was accordingly heated in soda-water bottles at 100' under pressure for 10-12 hours ; on fractionating the resulting crude oil under 15 mm.pressure, we obtained from 6 1 grams of ethyl /3-isopropylcyanosuccinate originally taken the following fractions : (a) Below 150 O... 33 grams. (y) 205-215 O... 10 grams. (p) 150-205" ... 37 grams. (6) Above 215O, a few drops only. The fraction (p) contained large quantities of nitrogen and bromine, and evidently consisted of :I mixture of unchanged cyanosuccinato and bromoisovalerate ; the fraction (a) contained no nitrogen to speak cf, but a large qiiantity of bromine, They were accordingly mixed, and after determining the amount of bromine in the mixture, the VOL. LXXXI. D34 BONE AND SYRANKLING: THE SYNTHESIS OF corresponding quantity of sodium ethoxide in alcoholic solution was added to it.The whole was then heated in a soda-water bottle a t 100" for 10 hours, as before, and on fractionating the resulting oil a further 10 grams passed over a t 205-215O under 15 mm. pressure. This was mixed with the fraction y obtained in the first part of the experiment, and the mixed oils were afterwards refractionated under 16 mm. pres- sure ; finally, 17 grams of a nearly colourless oil boiling a t 208-212' were obtained, which represent an 18 per cent. yield. On analysis : 0.2016 gave 0,4672 CO, and 0.1596 H20. 0.3259 C = 63.2 ; H = 8.8. ,, 11.1 C.C. nitrogen a t 5" and 762 mm. N=4.09. C,,H,lOoN requires C = 63.51 ; H = S.65 ; N= 3.90 per cent. The oil was very thick and viscous, it had a density d 0"/4" = 1.075 and refractive index pNa = 1.4595.Hydrolysis of the Oils.-With the exception of ethyl ay-diisopropyl- cyanotricarballylate, all the oils just described can be readily hydro- lysed by boiling them in a reflux apparatus for 10 to 20 hours with strong hydrochloric acid. This method we accordingly adopted. I n no case did any solid acid separate on cooling the liquid after all the oil had dissolved, nor did we find i t feasible to isolate the acids by means of their calcium salts, a plan which answers very well in the case of alkylsuccinic acids. We therefore resorted to the simple ex- pedient of saturating the liquid in each case with ammonium sulphate and then thoroughly extracting it with pure ether. After drying the ethereal solution over anhydrous sodium sulphate and distilling off the solvent, there remained an oily residue which usually solidified in the course of a few hours.This was then either recrystallised from a suitable solvent, or, in cases where it consisted of a mixture of isomeric acids, was submitted to a suitable process for their separation. I n one case, namely, that of act-dimethyltricarballylic acid, the oil which remained after distilling off the ether did not solidify even after stand- ing many days, and tthere was evidence that the hydrolysis had been incomplete; on heating the oil with dilute (10 per cent.) hydrochloric acid under pressure at 190"for a few hours, and afterwards evaporating the liquid in a vacuum over strong sulphuric acid, the pure acid was obtained . 11. TRICARBALLYLIC ACIDS, THEIR ANRYDRO-ACIDS AND MONOMETHYL SALTS. TrricarballyZic Acid.The acid, after being recrystallised from a mixture of glacial acetic acid and chloroform, melted at 157-159". On analysis :AI~KYLTKICARBALLYLIC ACIDS. 35 0.1806 gave 0*2703 CO, and 0.0762 H,O. 0.2164 silver salt gave 0.1407 Ag. C: = 40.81 ; H = 4.69. Ag = 65.02. CGH806 requires C = 40.90 ; H = 4.54 per cent. c,H,OGAg, ,, The dissociation constant of the acid is 0.022, a value practically identical with that given by Walker (0.0224) for tricarballylic acid (Trans., 1892, 61, 707). The calcium salts of this and the other acids of the tricarballylic series described in this paper are readily soluble in cold water, but are almost entirely precipitated when the solution is boiled. When a 25 per cent. solution of calcium chloride is added to a cold solution of the neutral ammonium salt of tricarballylic acid, no separation of the calcium salt occurs ; on boiling the solution, however, a dense, c r p t a l - line precipitate instantly appears which entirely redissolves when the liquid is cooled again.The process of alternately precipitating and then redissolving the calcium salt may be repeated several times, but the precipitate seems very gradually to become less soluble in cold water. The behaviour of these calcium salts may be contrasted with those of the succinic acids which, when once precipitated from a hot solution of the ammonium salts, 20 not redissolve when the liquid is cooled, Acids of the two series may be readily separated by means of their calcium salts. Anhyclro-acid.-The characteristic property which the tricarballylic acids possess of yielding anhydro-acids (generally crystalline) when they are boiled with acetyl chloride, or maintained a t a temperature of 200" or upwards, was first noticed by Emery (Ber., 1891, 24, 596) in the case of tricarballylic acid itself.These anhydro-acids combine the functions of a true anhydride and a monobasic acid, but it has not yet been shown whether in their formation from the tricarballylic acid, the elements of water are eliminated from the ap- or the ay-carboxyl groups, or, in other words, whether, say in the case of tricarballylic acid, the anhydro-acid has the formula I or 11. yH,* UO,H VH,--CO\ 1. $!H-CO CH,*CO Ag = 65-16 per cent. 11. FH*CO,H >O. >o CH,-CO' The best way of preparing these anhydro-acids is to dissolve the tricarballylic acid in warm acetyl chloride, and, after boiling the solu- tion for 2-3 hours in a reflux apparatus, to distil off the solvent and afterwards fractionate the residual liquid under diminished pressure.I n the case of tricarballylic acid, the anhydro-acid passed over between 215" and 225' under 45 mm. pressure; on cooling, it completely solidified, and after recrystallisation from a mixture of chloroform and glacial acetic acid, melted a t 130-131'. 0 236 BONE AND SPRANKLING: THE SYNTHESIS OF 0,1715 gave 0.2830 CO, and 0.0615 H,O. C,H,05 requires C = 45.57 ; H = 3.79 per cent. The following investigation of the monomethyl salts of tricarballylic acid shows that the anhydro-acid has probably the constitution ex- pressed by the formula I. Monomethyl Xdts.-There are two possible isomeric monomethyl salts of tricarballylic acid, and three methods by which they may be prepared, namely, ( d ) by the direct partial esterification of the acid ; ( b ) by the partial hydrolysis of the trimethyl ester, and (c) by the solution of the anhydro-acid in methyl alcohol.We have carefully investigated these methods as follows. (a) Direct EsteriJication of the Acid.-Five grams of the acid were heated for 10 minutes with methyl alcohol containing just sufficient dry hydrogen chloride to effect the esterification of one carboxyl group. The excess of alcohol was then distilled off under reduced pressure. A colourless oil * remained, which entirely dissolved in a cold solution of sodium carbonate, and on being titrated with a standard solution of barium hydroxide proved to have an acidity corresponding t o that of a methyl dihydrogen salt.The silver salt, prepared by adding silver nitrate t o a solution of the oil exactly neutralised with dilute ammonia, was analysed as follows : C = 45.10 ; H = 3.98. 0.1726, on ignition, gave 0.0920 h g . C,HsOGAg2 requires Ag = 53.47 per cent.? There can be no doubt, therefore, that the oil had the composi- tion of a methyl dihydrogen tricarballylate. The next question t o be decided was whether the oil was a single substance or a mixture of the two isomeric monomethyl salts. We according deter- mined its dissociation constant on the supposition that whereas a single monomethyl salt would give a value for the constant K which would remain practically the same for successive dilutions, a mixture of two isomeric monomethyl salts would be indicated by well-marked variations in the value of K on dilution.The results indicated that the oil was a single substance. * None of the methyl dihydrogen salts of tricarballylic acids investigated by 11s are solids, so that it was impossible to purify them by crystallisation ; nor did distillation under reduced pressure serve the purpose ; the evidence of their purity is derived from a study of their dissociation constants. -f Besides analysing the silver salts of the monomethyl dihydrogen tricarballylates described in the paper, we always ascertained the acidity of each by titration with a standard barium hydroxide solution.In each case, practically the calculated amount of the alkali was required. Ag = 53.30.ALKYLTR~CARBALr~Y LIC ACIDS. 37 Dissociation Constcmt. K= 0'0075. (Temp. 25O.) V. P U S 112. K. 7.62 8.2 7 0.0236 0,00748 15.24 11.65 0.0333 0,00753 30.48 16.42 0,0469 0.00756 60.96 23.03 0,0658 0*00761 (b) Purtial Hydrolysis of Trinzethyl Tricarba2Eylate.-It was first of all necessary t o prepare the trimethyl ester from the acid by snturat- ing a solution of it in methyl alcohol with dry hydrogen chloride in the usual manner. The resulting oil was washed with a dilute sodium carbonate solution, and distilled under 48 mm. pressure, when it passed over at 205--208'. It was then quit,e colourless, having a density d Oo/4O= 1.1381, and a refractive index pNa= 1.4398.On analysis : 0.2110 gave 0.3823 CO, and 0.1246 H20. C,H,,O, requires C = 49.50 ; H = 6.42 per cent. Six grams of the oil were added to a quantity of potassium hydr- oxide, dissolved in methyl alcohol, just sufficient to effect the hydrolysis of two methoxy-groups. A drop of a methyl alcoholic solution of phenolphthalein was added, and the liquid allowed to stand at the ordinary temperature in an atmosphere free from carbon dioxide until only the faintest pink tinge remained. Two drops of a methyl alcoholic solution of met.hy1-orange were then added, and dry hydrogen chloride passed into the well-cooled liquid until a pink colour first appeared. The liquid was at once filtered from the potassium chloride which had separated, and the filtrate evaporated in an exhausted desiccator over sulphuric acid.The residual oil was dissolved in a slight excess of sodium carbonate solution, and the liquid extracted with pure ether in order t o remove any trace of unchanged trimethyl ester. Finally, the solution was acidified with hydrochloric acid, and again extracted with pure ether, About 4.6 grams of a colourless oil were thus obtained; the silver salt was prepared and analysed as follows : C -- 49.41 ; H= 6-56. 0.2610 gave on ignition 0,1389 Ag. Its dissociation constant was then determined as follows : Ag = 53.32. CTH,0,Ag2 requires Ag = 53.47 per cent. Dissociution constant. K= 0.00925. (Temp. 2 5 O . ) 2'. P U. 172. K. 11 a47 9.15 0.0320 0.00922 22.94 15.78 0.0457 0.00926 45.88 22.1 2 0.0632 0.00929 91.76 30.94 0.0884 0.0093338 BONE AND SPRANRLING: THE SYNTHESIS OF These numbers show that the oil WBS a single monomethyl di- hydrogen tricarballylate and isomeric with that obtained by the direct esterification of tricarballylic acid.Now it has been shown by V. Meyer, Sudborough, and other workers on the subject of esterifi- cation that a carboxyl attached to a primary carbon atom is much more easily esterified than one attached to a secondary carbon atom; consequently we must regard the monomethyl dihydrogen tricarballylate obtained by the direct esterification of the acid as hhe a-compound, C0,Me*CH,*CH(C0,H)*CH2*C0,H, and therefore the isomeric ester obtained by the partial hydrolysis of $rimethyl tricarballylate must be the P-compound, CO,H*CH,*CH(CO,Me)*CH,*CO,H. ( c ) By Solution of the Anhydro-mid in Methyl Alcohol.-The anhydro- acid was boiled for 45 minutes in a reflux apparatus on a sand-bath with a quantity of pure dry methyl alcohol slightly in excess of that required to effect its conversion into the monomethyl dihydrogen salt.The liquid wits then placed in a vacuum over sulphuric acid in order to get rid of the slight excess of alcohol, and, after some days, the residue was subjected to a further purification by means of sodium carbonate as described under ( b ) . The silver salt of the purified oil mas analysed as follows : 0.1167 gave on ignition 0.0611 Ag. The dissociation constant of the monomethyl salt wnq determined as Ag=52*35. C7H,06Ag2 requires Ag = 52.47 per cent. follows : Dissociation constccnt. K = 0.00945.(Temp. 25O.) u. PV* 112. K. 12.82 9.74 0.0342 0.00945 25.64 16.80 0.0480 0.00944 51.28 23.55 0.0673 0,00946 102.56 32.87 0.0939 0-00949 This shows, therefore, that the monomethyl dihydrogen tricarballyl- ate obiained by dissolving the anhydro-acid in methyl alcohol is the &compound, CO,H*CH,*CB(CO,Me) *CH,°C02H, and such as can only result from an anhydro-acid of the constitution represented by formula I (p. 35). a-Metl~yltricccrbaZZyylic Acids, CH,*CH(C0,H)*CH(C02H)*CH2~~02H. Since this acid contains two asymmetric carbon atoms, it exists in two inactive forms, meso- and racemic. Auwers, von Meyenberg, and Kobner (Ber., 1891, 24, 307, 2887) succeeded in isolating these from the hydrolysed product of the condensation of ethyl fumarateALKYLTRICARBALLYLIC ACIDS.39 (1 mol.) with ethyl sodiomethylmalonate (2 mols). Their acids melted at 134O and 184' respectively, and it was shown that the isomeride of lower melting point is partially converted into the other on being boiled with strong hydrochloric acid. Our experiments showed that when 26 grams of ethyl a-methyl- cyanotricarballylate were hydrolysed with strong hydrochloric acid in the manner described, 16.5 grams of a mixture of isomeric acids were obtained ; this only solidified aEter being kept for some days in ice. The substance, however, still contained a little nitrogen, and it was therefore heated with dilute (10 per cent.) hydrochloric acid in sealed tubes a t 180-200' for 24 hours. The solid which finally remained after evaporating the liquid to dryness melted between 160' and 170".On rapidly extracting this residue with small quantities of cold water, one of the stereoisomeric acids dissolved, and the melting point of the residue gradually rose to 179O and afterwards remained constant. The washings, on evaporation, yielded a residue melting between 136' and 145O, and when this was once again subjected to fractional extrac- tion with cold water, an acid melting a t 134-135' was obtained from the first washings. The acids were analysed and their dissociation constants determined as follows : trans-Acid, m. p. 179". 0.1624 gave 0.2633 CO, and 0.0769 H,O. 0.3007 silver salt gave 0.1897 Ag. C = 44.11 ; H = 5.35. Ag= 63.10. C7H,,0, requires C = 44.21 ; H = 5.26 per cent. C7H70,Ag, ,, Ag = 63.39 per cent. Dissociation Constant.K= 0.0322. (Temp. as0.) V. P V . I?&. K. 20.0 27.46 0.0767 0.0319 40.0 37.42 0.1069 0.0320 80.0 52.14 0.1489 0.0326 160.0 71-10 0.2032 0.0324 cis-Acid, m. p. 134-135'. C7HI0O6 requires C = 44-21 ; H = 5.26 per cent. 0.21 13 gave 0.3425 GO, and 0.1023 H,O. C = 44.09 ; H = 5.38. Dissocichtion Cbmtant. K= 0*0480. (Temp. 25O.) V. Pw 112. K. 20.64 32.83 0.0938 0.0470 41.28 45*89 0.1311 0.0475 82.56 66.52 0.1 900 0.0481 165.12 90.00 0.2583 0,048640 BONE AND SPRANKLING: THE SYNTHESIS OF Anhydvo-acid.*--We have found that each acid on being dissolved in acetyl chloride yields its own liquid anhydro-acid, and that even after being distilled under reduced pressure neither of the anhydro-acids solidifies. Each anhydro-acid, however, with water yielded the acid from which it was originally derived, and on heating the trans-anhydro- acid with acetyl chloride, or acetic anhydride, for several hours, it was completely transformed into the cis-isomeride.Conversion of cis- into trans-Acid.-We are able to confirm Auwers' observation that the cis-acid is partially converted into the trans-iso- meride on being treated with hydrochloric acid under ,pressure at 190-200° and find that equilibrium is established when 80 per cent. is so transformed. The behaviour of the anhydro-acids leaves no doubt as to the con- stitution of the two isomeric acids from which they are derived; the cis-anhydride is the more easily formed from its acid, and is more stable than the trans-isomeride. The two acids, therefore, have the following constitutions : H* C CO,H CO,H*(PH H*?* CO,H H*F*H H*$?*H C0,H CO,H Monomethyl SaZts.-So far we have only studied the monomethyl salts of the &-acid ; on determining the dissociation constants of those prepared by the three methods described in the case of tri- carballylic acid (pp. 36-38), we obtained practically identical numbers as follows : trans-Acid, m. p.179". cis-Acid, m. p. 134-135". Mean values of K at 25". .Direct esterification of acid ........................... 0.00893 Partial hydrolysis of trimethyl ester.. ................ 0.00857 Solution of anhydro-acid in methyl alcohol ......... 0*00888 At this stage of the inquiry we do not feel able to express any decided opinion as to the interpretation of these results, and the matter is receiving further investigation.Monomethyl salt prepared by ay- DimethyZtricabaZZ~Zic Acids, CH,*CH( C0,H) CH( CO,H)*CH(CH,) *CO,H. By the hydrolysis of the oil of higher boiling obtained by the inter- actiou of sodium ethoxide (2 mols.) ethyl cyanoacetate, (1 mol.), and * Auwers did not study these substances.ALRYLTRICARBALLYLIC ACIDS. 41 ethyl a-bromopropionate (2 mols.), Zelinsky (Zoc. cit.) obtained three isomeric acids, C,H,,06, as follows : K for M. p. M. p. acid. acid. anhydro-acid. 203 -204' 0.042 11 1-1 13' 175-1 76 0-054 129-130 (1) (2) (3) 148-149 0.051 117-119 and although his experiments were not quite conclusive, he brought forward evidence in favour of the view that the three acids are stereo- isomeric ay-dimethyltricarbnllylic acids, If this be so, it is the only instance of the synthetical formation of three inactive stereoisomeric forms of a compound, C(abc)*C(ab)*C(abc), corresponding to the three trihydroxyglutaric acids (the one Izevorotatory, to which there is, of course, a corresponding racemic ' acid, and the other two ' meso '- inactive) obtained by Fischer (Ber., 1891, 24, 1842, 2686, 4222) by the oxidation of I-arabinose, xylose, and ribose respectively.The point seemed t o us sufficiently important to warrant further and independent investigation. When ethyl ay-dimethylcyanotricarballylate was hydrolysed by boiling it with excess of strong hydrochloric acid for 12 hours, and the resulting liquid extracted with ether, a solid mass was obtained which melted gradually between 140' and 160O. By boiling it for some time with successive small quantities of hydrochloric acid, part dissolved, leaving finally an insoluble constituent which melted at 206-207O, and was not altered by further treatment with hydrochloric acid.On concentrating the hydrochloric acid solution in a vacuum over sulphuric acid, two sucessive crops of crystals were obtained which melted at 170-188' and 171 -1 73' respectively. This second fraction was twice recrystallised from strong hydrochloric acid and then melted sharply at 174". We were unable to isolate any third acid either from the first crop of crystals melting at 170--188O, or from the hydrochloric acid mother liquors. The two acids melting at 206-207' and 174" were analysed, and their dissociation constants determined, as follows : Briefly stated, our results are as follows.Acid, m. p. 206-207'. 0.1706 gave 0.2951 CO, and 0.0922 H,O. 0,1064 silver salt gave 0.0654 Ag. C,H,,O, requires C = 47.58 ; H = 5.88 per cent. C,H,O,Ag, ,, C = 47.1 9 ; H = 6.01. Ag = 61.49. Ag = 61.70 per cent,.42 BONE AND SPRANKLING: THE SYNTHESIS OF Dissociation constant. K = 0.0445. (Temp. 25O.) 21. F U * m. K. 33.71 40.18 0.1 148 0.0441 67.42 55.81 0.1594 0.0448 134.84 75.93 0.2169 0,0446 269.68 101.70 0.29 1 1 0,0443 Acid, m. p. 174". 0,1926 gave 0.3302 CO, and 0.1038 H,O. 0.1099 silver salt gave 0.0676 Ag. C,H,,O, requires C = 47.58 ; H = 5.88 per cent. C8H,06Ag, ,, C-47-49 ; H=5*99. Ag=61*56. Ag = 61-70 per cent. Dissociatiolz colzstant. K= 0.0545. (Temp. 25O.) V. Pv. m. K. 20.7 35-03 0.1 002 0,0559 41.4 48.67 0.1 38'7 0.0540 82.8 66.72 0.1 906 0.0542 165.6 90.60 0.2588 0,0546 Anhydro-aids.-Each acid dissolved in acetyl chloride, yielding its own solid anhydro-acid ; that obtained from the acid of higher melting point (206-207O) fused at 110-112°, and that from the acid of lower melting point (174') fused a t 130".Mutual Conversion.-(l) The acid melting at 206-207' was heated for 4 hours a t 180° under pressure with acetic anhydride, and from the dark-coloured liquid the acid melting at 174" was recovered by means of its potassium salt. It is clear, therefore, that the nnhydro- acid of the former is a t high temperatures converted into that of the latter. (2) The acid melting at 174" was partially converted into that melt- ing at 206-207" by heating it with strong hydrochloric acid at 210" for several hours.There can be no doubt, therefore, that these two acids are identical with two of the acids obtained by Zelinsky, and, further, that they are stereoisomeric. Zelinsky hydrolysed the oil from which he obtained his three acids with sulphuric acid ; we therefore hydrolysed another portion of the ethyl uy-dimethylcyanotricarballylate by boiling it with 50 per cent. sulphuric acid. The operation was rather a slow one, and was only complete after 2 or 3 days. On cooling the liquid a crop of crystals, A, separated, melting at 190' or thereabouts; on furtherALKYLTRICARBAT~LYLIC ACIDS. 43 concentrating the mother liquor, two more crops of crystals were obtained, namely, R, melting at 170-180°, and C, at temperatures be- low 139'.From fractions A and B, by furtherpurification, were obtained two acids melting a t 204-206' and 174-176', identical in all respects with those obtained in the earlier experiments. Fraction C was sub- mitted to two or three recrystallisations fro= water ; its melting point gradually rose to 143" and then remained constant ; analysis showed that it had the empirical formula C8H,,06. On being treated with acetyl chloride, it yielded an anhydro-acid, C8Hlo05, melting quite sharply a t 116-117", which with water regenerated the original acid. Dissociation constant. K= 0.0572. (Temp. 25'.) 2). P U * m. K. 21.78 36.97 0.1056 0.0573 43.56 57.1 1 0.1 460 0.0573 87.1 2 69.80 0.1994 0.0570 174.24 94.29 0,2693 0.0569 The most curious point about this acid is that on being warmed with strong hydrochloric acid it is very quickly and quantitatively transformed into the acid melting a t 174"; for example, on recrystal- lising a portion of i t from warm hydrochloric acid its melting point rose to 160-164', after a second recrystallisation to 171-173', and after a third to 174'.The question therefore arises : Is this acid melting at 143" a third inactive stereoisomeric form of ay-dimethyltricarballylic acid, or is it merely a molecular mixture of the other two forms? Three facts are in favour of the first view, namely (1) that it yields its o w n anhydro- acid with acetyl chloride ; (2) that its dissociation constant varies very little with successive dilutions, and is higher than the correspond- ing values for the other two acids ; and (3) that treatment with strong hydrochloric acid converts it into the second (174") acid, whereas the acid melting at 206" remains absolutely unchanged when heated with hydrochloric acid under the ordinary pressure.One of the three acids must be the racemic (tvans-) form, the other two must be meso-modifications of uy-dimethyltricarballylic acid which we may distinguish as the cis,- and cis,-acids. Since the an- hydro-acid of the acid melting at 174" is the most stable of the three anhydro-acids at high temperatures, it is probably one of the cis- (meso-) forms ; the other cis-form is, therefore, the acid melting at 143". The someride having the highest melting point must therefore be the trams- or racemic form, as under :44 BONE AND SPRANKLING: THE SYNTHESIS OF p 3 p 3 p 3 H-Q* C0,H H* ?*CO,H H* Q* C0,H H* C*CO,H H*y*CO,H CO,H*y*H CO,H*$'*H H*F*CO,H H 7 C0,H Trans- or iacemic, m.p. 206-207'. cEr, CH3 CH3 cis,- and cis,-Acids (meso). At present we are unable to decide which of the two acids, melting a t 174' and 143' respectively, is the cis,- and which the cis,-form. The further investigation of the subject is in hand, however. au-Dimet~yZtricarbaZZ~Zic Acid, (CH3),C(C02H)*CH(C0,H)*CH,*C0,H. This acid is a very interesting member of the series, inasmuch as it is an oxidation product of pinonic acid (Tiemann and Semmler, Ber., 1895, 28, 1349), also of fenchone (Gardner and Cockburn, Trans., 1898, 63, 710) and camphoceenic acid (Jagelki, Bey., 1899, 32, 1498). The acid we obtained by hydrolysing ethyl aa-dimethylcyanotricarb- allylate melted at 143'.On analysis : 0.21 36 gave 0.3722 CO, and 0.1145 H,O. C = 4751 ; H = 5.96. C,H,,O, requires C = 47.58 ; H = 5.88 per cent. Dissociation constant. K= 0.0318. (Temp. 25O.) V . Pu* 712. h-. 23.67 29-16 0-0833 0.0320 47.34 40.39 0.1 154 0.0318 94.68 54.67 0.1562 0,0315 189.36 75-12 0,2146 0.0309 The anhydro-acid, recrystallised from chloroform, melted at 0,2022 gave 0.1900 CO, and 0.1003 H20. C,H,,O, requires C = 51.61 ; H = 5.3'7 per cent. The trimethyl ester was a thick oil boiling at 170-174' under 33 mm. pressure; it had a density d Oo/4O= 101403 and a refractive index pNa = 1 -441 7. 135-136'. On analysis : C = 51.25 ; H = 5.50. 0.1829 gave 0,3588 CO, and 0,1236 H,O. Monomethyll XaZts.-There are three possibleisomeric monomethyl salts of this acid, namely, (a) (CH,),C(C0,H)*CH(C0,H)*CH2*C0,Me, (6) (CH3),C(C0,H)*CH(C0,Mc)*CH,*C02H, and C=53.5 ; H= 7.51.CllH1806 requires C = 53.7 ; H = 7.32 per cent. (c) (CH,),C(CO,Me)*CH(CO,H)*CH,*CO,H.ALRYLTRICARBALLYLIC ACIDS. 45 We prepared monomethyl salts from the acid, the trimethyl ester, and the anhydro-acid, by the methods already described (pp. 36-38), with the following results : (i) By Direct Esterijication of the Acid.-A colourless oil. 0,1526 of its silver salt gave 0.076 Ag. Ag = 49.79. C1,H1,O,Ag, requires Ag = 50.00 per cent. Dissociation constant. K = 0.01 80. (Temp. as0.) V. PV. 721. K. 31.2 25.34 0.0724 0-0181 62.4 35.10 0.1003 0.0179 124.8 48.52 0.1386 0.0179 249.6 65.92 0.1883 0.01 75 There can be no doubt, therefore, that the oil was a single sub- stance, and from the fact that it was formed by the direct esterification of the acid (which contains only one primary CO,H group), we may conclude that it has the formula (a).(ii) By Partial Hydyolysis of the Trimethyl Ester.-A colourless oil. 0*2038 of i t s silver salt gave 0.1022 Ag. Ag=50*12. Dissociation constant. K = 0,00865, (Temp. 2 5 O . ) V. P V . 71%. K. 8.95 9.63 0.0275 0*00870 17.90 13.51 0.0386 0.00866 3590 18.94 0.0541 0.00863 71.60 26-28 0.0751 0.00859 There can be no doubt that the oil was a single substance and quite different from that obtained by direct esterification of the acid, but we have no means of judging at present which of the two formulae, ( b ) and (c), represents its constitution. (iii) Pbonz the Anhydro-acid.-A colourless oil.0.1286 of its silver salt gave 0.0642 Ag. Ag=4991 per cent. Dissociution constant. K= 0.01 86. (Temp. 2 5 O . ) 2'. PV* 71%. K. 12.52 15.89 0.0454 0.01 89 25.04 23.14 0.0661 0.0186 50.08 31.96 0.0913 0.0183 This monomethyl salt, therefore, is probably the same as that Comparing now the obtained by the direct esterification of the acid.46 BONE AND SPRANKLING: THE SYNTHESIS OF values for K, determined for tricarballylic and aa-dimethyltricarballylic acids and their monomethyl salts, Nonomethyl salt from Acid. Acid. Trimethyl ester. Anhydro-acid. 0.00925 Tricarballylic.. . .. . . . . . .. . . . 0.022 0 *O 09 4 5 aa-Dimethyltricarballylic 0.032 0.0180 0.00865 0.01860 we see that in both cases the monomethyl salt obtained by the direct esterification of the acid is quite different from that obtained by the par- tial hydrolysis of the trimethyl ester ; but that the salt obtained from the anhydro-acid is in the one case identical with that obtained from the trimethyl ester, and, in the other case, with that yielded by direct esterification of the acid.0.0075 a y - Dii so pro py lt riccw b d l y lic Acids. These acids were prepared with the view of determining whether the substitution of two isopropyl groups in ay-positions has an influence upon the dissociation constant of tricarballylic acid at all com- parable with that exerted upon the constant of succinic acid by the symmetrical substitution of two hydrogen atoms by isopropyl groups (compare Trans., 1900, 77, 667). Ethyl ay-diisoi?rol3ylc~c~no~r~c~~,balZyZate is a difficult oil to hydrolyse ; we found it best to perform the operation in two stages, namely, (l), with alcoholic potassium hydroxide, and (2), with 50 per cent.sulphuric acid. Finally, on extracting the acid liquid with ether we obtained from 17 grams of oil 9.8 grams of a solid mixture of stereoisomeric acids. These were difficult to separate, but on dissolving the mixture in water, saturating the solution with hydrogen chloride, and allowing it to stand for some time, we were able to resolve it into fractions of higher and lower melting point, by reason of the greater solubility of the latter. Two pure stereoisomeric acids were finally obtained, melting a t 173' and 156" respectively. Each yielded its own liquid anhydro-acid, but we had not sufficient material to investigate these properly, and it is possible tbat, had we been able to purify them further they would have solidified.The acid of higher melting point was transformed into the anhydro- acid of its isomeride on being boiled for many hours with acetyl chloride. Each acid was analysed, and its dissociation constant determined as follows : Acid, m. p. 173'. 0.2326 gave 0.4707 CO, and 0.1653 H,O. 0.1687 silver salt gave 0.0943 Ag. C,,H,oO, requires C = 55.38 , H = 7.69 per cent, C,,H,70,Ag, ,, C = 55.18 ; H = 7.90. Ag =5640. Ag = 55-90 per cent.ALKYLTRICARBAl~LYLIC ACIDS. 47 Dissociation constant. K = 0,193. (Temp. 25'.) I). m . K. 171.5 151.6 0.4332 0.1 93 343.0 191.5 0,5469 0.192 686.0 233.1 0.6660 0.1 94 1372.0 270.7 0.7731 0.192 Acid, m.p. 156'. 0,1971 gave 0,3982 CO, and 0,1397 H,O. C = 55.09 ; H = 7.8s. 0.2018 silver salt gave 0.1130 Ag. C,,H,,O, requires C = 55-38 ; H= 7.69 per cent. C,,HI7O,Ag, ,, Ag=55*99. Ag = 55.90 per cent. Dissociation constant. K= 0.1625. (Temp. 25O.) V. PV. m. K. 95.9 113.7 0.3241 0.1621 191.8 148.8 0.4250 0.1628 383.6 188.3 0.5380 0.1633 767.2 230.0 0,6570 0.1 640 If we compare these values with those for tricarballylic acid (0.022) and a-isopropyltricarballylic acid (0*0434--Auwers, Zoc. cit.), we see a t once that, in both cases, the introduction of the two isopropyl radicles has had a very marked ' raising ' effect on the dissociation constant, but there is no such enormous difference between the constants of the two isomerides as there is between those of cis- and tmns-s-diisopropyl- succinic acids.The subject of the variation of dissociation constants with molecular constitution in this series of acids presents many interesting features, and will be discussed more fully in a future communication. 111. TRICARBALLYLIC ACIDS FROM ETHYL BROMOSUCCINATES. As already stated, we have studied the preparation of ethyl cyano- tricarballylates by the interaction of ethyl bromosuccinates with the sodium compound of ethyl cyanoacetate, and have been able to carry it out in the following instances. Yricarbullylic Acid, The best method for preparing tolerably pure ethyl bromosuccinate, is to act on succinic anhydride with the calculated quantity of dry amorphous phosphorus and bromine, to form the dibromide of mono- bromosuccinic acid, and afterwards to pour the product into excess of48 BONE AND SPRANKLING: THE SYNTHESIS OF alcohol.I n this way we obtained an 80 per cent. yield of ethyl bromosuccinate boiling a t 140-143' under 29 mm. pressure, On condensing this with the calculated quantity of ethyl sodiocyanoacetate suspended in alcohol, a 70 per cent. yield of ethyl cyanotricarballylate resulted ; when hydrolysed, this yielded tricarballylic acid, melting at 157-159'. On analysis : 0.2023 gave 0.3028 CO, and 0.0854 H,O. C = 40.81 ; H = 4.69. C6H806 requires C = 40.90 ; H = 4.54 per cent. a-MethyZtricarbaZZylic Acid. On brominating 26 grams of monomethylsuccinic acid by the Hell- Volhard-Zelinsky method, pouring the product into alcohol, and extracting the resulting bromo-ester with ether, we obtained 38 grams of an oil which distilled over a t 151-153' under 44 mm.pressure. On analysis : 0.4166 gave 0.2798 AgBr. Br = 29-07. There are two possible isomeric ethyl monobromomethylsuccinates, C,H1,O4Br requires Br = 29.96 per cent. namely, (a) CH,*CBr(C0,Et)*CH2*C0,E t, and If the oil obtained by the method first indicated had the formula (a), then on condensing it with ethyl sodiocyanoacetate we should obtain the cyano-ester of P-methyltricarballylic acid ; on the other hand, if i t had the constitution (p), it would under similar treatment yield the cyano-esters of the a-methyltricarballylic acids, On trying the experiment we obtained a 50 per cent. yield of an ethyl methylcyanotricarballylate (b. p. 235-245' under 30 mm.pressure) which, on hydrolysis with strong hydrochloric acid, yielded the two a-methyltricarballylic acids, melting a t 177-180' and 134' respec- tively, but not a trace of any /3-methyltricarballylic acid. Hence the ethyl monobromomethylsuccinate obtained when methylsuccinic acid is brominated in the manner described has the constitution CH,*CH(CO,Et)* CHBr C0,Et. (p) CH,*CH( COzEtj*CHBr.CO,Et. The two a-methyltricarballylic acids obtained were analysed as Acid, m. p. 177--180'. 0.1921 gave 0.3174 CO, and 0.0953 H,O. 0.3011 silver salt gave 0.1900 Ag. Acid, m. p. 134". 09614 gave 0.4228 GO, and 0.1280 H,O. 0.1991 silver salt gave Oe1255 Ag. C7Hlo06 requires C=44.21 ; H=5-26 per cent. C7H70,Ag, ,, follows : C = 44.0 ;. H = 5.51. A g = 63.10. C=44*11 ; H=5*44.Ag = 63.06. Ag = 63.39 per cent.ALKY LTRICARBALLYLIC ACIDS. 49 aa-Dirnetk?lltricar6aZZyZ~c Acid. Twelve grams of as-dimethylsuccinic acid, on bromination by the Hell-Volhard-Zelinsky method, yielded 20 grams of monobromo-ester boiling at 159-164' under 70 mm. pressure. On analysis : 0,2442 gave 0.1589 AgBr. Br = 27-69. CloHI7O,Br requires Br = 28.47 per cent. On condensing this with the calculated quantity of ethyl sodiocyano- acetate, we obtained a 50 per cent. yield of ethyl aa-dimethylcyanotri- carballylate boiling at 210-220° under 35 mm. pressure. When hydrolysed with strong hydrochloric acid, this yielded aa-dimethyltri- carballylic acid melting at 140-142'. On analysis : 0.2611 gave 0.4554 CO, and 0.1408 H,O. 0.2122 silver salt gave 0.1308 Ag. C,Hl,O, requires C = 47.58 ; H = 5 *88 per cent. C,H,O,Ag, ,, We have also studied the bromination of cis-s-dimethylsuccinic acid by methods similar to those already described. Many workers have investigated the bromination of this and the isomeric trawls-acid under varying conditions and with widely different results. Hell and Roth- berg (Ber., 1889, 22, 66) state that both acids behave normally on bromination, yielding cis-monobromodimethy lsuccinic acid ; Zelinsky and Krnpivin (Ber., 1889, 22, 390), Bischoff and Voit (Bey., 1890, 23, 390), and Auwers and Imhauser (Ber., 1891,24, 2233), on the contrary, assert that neither acid can be brominated under any conditions, and that the substance which results is always the anhydride of pyre cinchonic acid (m. p. 95O), so that if any monobromo-anhydride (or acid) is momentarily produced it must a t once lose hydrogen bromide as follows : C = 47.59 ; H = 5.99. Ag=61%1. Ag = 61.71 per cent, Our own experience shows that when a mixture of cis-s-dimethylsuccinic acid and amorphous phosphorus is treated with the quantity of dry bromine required to form the dibromide of the monobromo-acid, bromina- tion certainly takes place, for on pouring the product into alcohol, and extracting and fractionating the resulting ester, we obtained a very fair yield of a bromo-ester containing 26.86 per cent. of bromine (C10H1,04Br requires Br = 28.47 per cent.). On condensing this bromo-ester with ethyl sodiocyanoacetate, sodium bromide was at once eliminated, but the product obtained was not a cyanotricarballylic ester, and up to the present we have not been VOL. Lxxxr. E50 BONE AND SFRANKLING : able to ascertain what really happened. investigation. The subject is still under I n conclusion, we wish to state that one of us is investigating the preparation and properties of tri- and tetra-methyltricarballylic acids. The cost of the materials required for this investigation has been largely defrayed out of grants from the Research Fund of the Society. THE OWENS COLLEGE, MANCHESTER.