PURDIE & PITKEATELY: PRODUCTION OF ACTIVE ACIDS, ETC. 153 XVII1.-Production of Optically Active Mono- and Di-alkyloxysuccinic Acids j-onz Malic and Taj-taric A cids. By THONAS PURDIE, F.R.S., and WILLIAM PITBEATHLY, B.Sc., Berry Scholar in Science. IT has been shown in previous papers (Trans., 1898, 73, 287, 862) that the high optical activity of the ethereal malates and lactates, prepared from the respective silver salts, is due to the production of small quantities of the more active alkyloxy-derivatives, and Rodger and Brame (Trans., 1898, 73, 306) were consequently inclined to attribute the abnormally high rotation of the ethereal tartrates, which they prepared from silver tartrate, to a similar cause. On hydrolysing specimens of methylic tartrate, on the other hand, which had been prepared by this and by the commoner methods, they found that the products showed practically the same rotation, which sug-154 PURDIE AND PITKEATHLY : PRODUCTION OF OPTICALLY gested the possibility that the ethereal salts from the two different sources might be isomeric.The object of the present research was to obtain further evidence of the production of alkyloxy-derivatives in the interaction of the silver salts of hydroxy-acids with alkyl iodides, and t o find a modifi- cation of the reaction which might serve as tt practical method for their preparation. We have, accordingly, made further experiments on the production of alkyloxysuccinates from silver malate, and, Mr. Brame having kindly left us to continue his work, we have examined the product of the action of isopropylic iodide on silver tartrate for di-isopropoxysuccinic acid.We find that this compound is actually produced, and conclude, therefore, that a similar reaction occurs, although probably to a smaller extent, when other alkyl iodides are used. We find further that the ethereal malstes and tartrates can be readily alkylated by means of alkyl iodide in the presence of silver oxide, the reaction furnishing a convenient method of preparing the optically active mono- and di-alkyloxysuccinic acids from malic and tartaric acid respectively. The ethereal di-alkyloxysuccinates are highly active compounds, and their presence even in small quantity would account for the abnormally high rotation of the ethereal tartrates prepared from silver tartrate. Observations made on the metallic salts of diethoxysuccinic acid also explain the apparently anomalous results obtained by Rodger and Brame in the hydrolysis of methy lic tartrate.Action of AZkyZ Iodides on SiZvei* 3hZate. I n former experiments with ethylic iodide (Zoc. cit,), the crude distilled product of the reaction had always nearly the same rotation, - 14' ( I = 1). We now find that, by modifying the conditions, a somewhat more active liquid is obtained, although in no case is the proportion of ethoxysuccinate produced large enough to admit of its being separated from the malate. Thus, by adding the iodide (3 mols.) gradually to the silver malate (1 mol.), the treatment being otherwise the same as before, a product mas obtained which, without fractional distillation, gave the rotation -15.31O.Even when 2 mols. of iodide only were used and benzene added to moderate the action, con- ditions which should be unfavourable to the hydroxyl group being attacked, the ethovysuccinate was formed as before, the ethereal salt obtained showing a rotation almost identical with that just quoted. I n attempting to prepare isobutylic malate by the silver salt method (Trans,, 1896, 69, 824), the product was found t o consist mainly of free acid, which, however, mas not further examined at the time; as it seemed possible that this result might be due to theACTIVE MONO- AND DI-ALKYLOXYSUCCINIC ACIDS, ETC. 15.5 formation of isobutoxysuccinic acid, we have investigated the reaction more closely. The method employed was the same as bRfore, but the free organic acid was removed from the product before distillation by allowing it to stand over potassium carbonate.I n an experiment in which 92 grams of malate were added gradually to 167 grams of iodide, the yield of ethereal salt amounted to only 5 grams, and in another experiment, in which the order of mixture mas reversed, the yield was still less. The free organic acid, which was isolated as in a previous similar case (Trans., 1898, 73, 299), gave, on heating with a solution of barium hydroxide, n large quantity OC barium malate ; when dried at 160", it was found to contain 50.89 per cent. of barium, the calculated number being 50.93. The filtrate from this, on evaporation, left a less granular and more soluble salt, which analysis showed to be barium isobutoxysuccinate contaminated with some malate.Great difficulty was experienced in freeing the isobutoxy- succinic acid from malic acid. We found, finally, that although both barium salts are precipitated on boiling their aqueous solutions, the isobutoxysuccinate differs from the malate in redissolving readily when the solution cools, which enabled us to obtain the isobutoxy- succinate as a flocculent powder approximately free from malate. The results of the combustion of the substance, dried a t 160°, were as f ollowsl' I. C = 28-93. H = 4.08 ; Ba = 4 N 1 per cent. C8H,,05Ra requires C = 29.54 ; H = 3.69 ; Ba = 42.16 per cent. 11. C=29.03. H=4*05; Ba=43*36 ,, ,, In very dilute aqueous solutions (c=0.(1132) at 13', the salt showed the specific rotation -21.4'.The silver salt could not be obtained by precipitation. The sodium salt, prepared from the barium salt, gave in aqueous solution the specific rotation - 27.8" (c = 1.888), and, on analysis, was found to contain 19-46 per cent. of sodium, instead of the calculated number, 19.66. The rotations quoted are much higher than those of the corresponding malates, and are such as butoxysuccinates might be expected to exhibit. The 5 grams of ethereal salt, mentioned above, contained a small proportion of isobutylic isobutoxysuccinate. This mas evident from its high observed rotation, - 15.28' in a 100 mm. tube, that of the corresponding malate being only - 11.60' (Zeit. physikal. Chena., 1895), 17, 249), and was confirmed by the detection of barium isobutoxy- succinate in the product of hydrolysis. The quantity of substance was too small to admit of its being purified, but it showed a specific rotation nearly the same as that quoted above, namely, - 20.81' at 10' for c = 1.538.These observations show that the reaction between isobutylic iodide and silver malate does not follow the normal course,156 PURDIE AND PITKEATHLY: PRODUCTION OF OPTICALLY but that the main product is free malic acid, produced probably by the decomposition of the iodide into isobutylene and haloid acid, and that a considerable quantity of isobutoxysuccinic acid is also formed. Mr. J. C. Irvine mas good enough to examine for us the action of secondary butylic iodide on silver malate, in the hope that this iodide, like isopropylic iodide, would yield a larger proportion of the alkyloxy- acid.He obtained from the product only a small quantity of a very soluble barium salt of wax-like appearance which, although it could not be obtained quite pure, was evidently a barium butoxysuccinate. On combustion, it gave results approximating t o the calculated numbers, and its specific rotation in dilute aqueous solution, - 20*97", was practically the same as that of the isobutoxysuccinate. Action of Igoprop$ic Iodide on Silver Tartrate. Isopropylic iodide was used in this experiment, previous results having shown that it is more prone than other iodides to the reaction by which the alkyloxy-acid is produced. Sixty-seven grams of silver tartrate (1 mol.) were gradually added to 134 grams of the iodide (about 4 mols.) previously diluted with an equal volume of benzene, and the mixture was treated as in previous similar experiments. After distilling off the benz- ene and unaltered iodide, and shaking the residual liquid with a solution of sodium carbonate, a small quantity of an oily, ethereal salt remained, which, as it mas too dark coloured for polarimetric observation, was diluted with an equal bulk of alcohol and then examined in a 100 mm.tube, The observed rotation, about + 2 5 O , showed t h a t the substance was far more active than any of the ethereal tartrates. A crude, syrupy acid, obtained from this by hydrolysis with potassium hydroxide, acidifying with sulphnric acid, and extracting with ether, showed the specific rotation +%lo in about a 10 per cent.solution, an activity much exceeding that of tartaric acid. The barium and magnesium salts did not crystnllise ; the calcium salt was very soluble i n cold water, but was precipitated as a crystalline powder on boiling its aqueous solution. Estimations of calcium in the salt, dried at 130°, gave the results 14.77 and 14-89 per cent., the calculated percentage for calcium di-isopropoxysuccinate being 14.70. The production of the alkyloxy-compound in the reactions, which have been described in this and previous papers, appears t o be due t o some of the ethereal salt of the hydroxy-acid, which is-formed in the first instance, reacting further with alkylic iodide and unaltered silver salt with the formation of silver iodide, ethereal salt of the alkyloxy- acid, and free hydroxy-acid, which is always present in the product.The free alkyloxy-acid or its acid alkyl salt, which also frequently results from the reaction, may be produced from the normal alkylACTIVE MONO- AND DI-ALKYLOXYSUCCINIC ACIDS, ETC. 157 salt by water accidentally present, or by a reaction suoh as the following, in the case, for example, of silver malate and ethylic iodide, Consideration of the reaction in question suggested that the alkyla- tion would probably be much more complete if the ethereal salt of the hydroxy-acid was first prepared and then treated with alkyl iodide in the presence of silver oxide, or other metallic oxide of a similar nature. Ethylic malate, ethylic iodide, and lead oxide gave a negative result, but the product obtained by heating the malate and iodide with mercuric oxide yielded, on distillation in a vacuum, an ethereal salt much more active than the original malate, the rotation having risen from - 1 1 .8 O to - 3 0 * 7 O ( I = 1). A mixture of ethylic malate and ivopropylic iodide reacted very vigorously with silver oxide, and gave an ethereal salt showing the rotation - 30.5'. As these results indi- cated that the expected reaction had occurred, the action of ethylic iodide on ethylic malate and on ethylic tartrate in presence of silver oxide was examined in detail. OH* C,H3(COOAg)2 + 2EtI = OEt* C,H,(COOEt)*COOH + 2AgI. Pyepc6mtion of Etkgh'c Ethom~succinnte from EtJqliC Afcdute. The materials used were 52 grams of ethylic malate, the rotation of which was a= - 1 1 * 8 3 O (I= 1, t = 6O), 86 grams of ethylic iodide, and 64 grams of dry silver oxide, these proportions being chosen on the assumption that the reaction occurs in accordance with the equation OH*C,H,(COOEt), + 2EtI + Ag,O = OEt*C,H,(COOEt), + EtOH + 2AgI.The mixture, which underwent an energetic reaction on being gently warmed, mas afterwards heated for some time on a water-bath, then diluted with benzene, filtered," and distilled under reduced pressure, when it yielded 43 grams of a liquid having a nearly constant boiling point, and showing the rotation - 4 1 . 2 1 O in a 100 mm. tube at 6'. Assuming that the liquid consisted of only ethylic ethoxysuccinate and malate, the rotation indicated the presence of about 60 per cent. of the former compound. To remove the malate, the mixture was shaken repeatedly with a cold 10 per cent.aqueous solution of potassium hydroxide until the residual oil was reduced to about one-half its original weight. The oil, after being washed with mnt,er and dried with calcium chloride, mas found on distillation to boil at the same temperature as ethylic cl-ethoxysuc- cinate formerly prepared (Trans., 1895, 67, 972), namely, at 124O under a pressure of 10 mm., and its analysis gave the following results agreeing with the composition of that substance. * The silver rcsi(1iies froin these and the sncceeding espcriments were. black aild their composition reinairis to be esamiued. VOL. LXXV. 31158 PURDIE AND PITKEATHLY : PRODUCTION OF OPTICALLY Found : I. C-54-63 ; H =8*68 per cent. 11. C=54*79 ; H-8.44 ,, ,, Calculated : C-55.05; H=8*26 per cent.A determination of the specific rotation of the liquid at 6' gave the following result : a= - 58.85', E = 1, d 6'/4'= 1*0501, hence [.ID = - 5 4 ~ 1 4 ~ . The specific rotation of ethylic cl-ethoxysuccinate from the active acid, which was obtained by resolution of the racemoid com- pound (loc. cit., p. 979), was + 55.48'. The somewhat lower rotation now found is accounted for by the substance being contaminated with some ethylic fumarate, produced probably in the preparation of the ethylic malate. The specific rotation of an aqueous solution of I-ethoxysuccinic acid, which was obtained by hydrolysing the ethylic salt, acidifying the product and extracting it with ether, was found to be - 31.14' ( c = 8.0588, t = 7'), a number about 3' lower than that previously found, the discrepancy here being greater than in the Case of the ethylic salts owing to the fumaric acid being chiefly con- tained in the crystallised portion of the acid which was used in the determination. For further comparison of the acids from the two sources, observations were made on the acid ammonium salt which could be free'd by crystallisation from fumarate. A determination of the specific rotation of the hydrated salt in aqueous solution at 8" gave the following result : a = - 6*00', I= 2, c = 10.0288, hence [a]= = - 29.91'.The value formerly found for similar concentration at 17' was 28.46'. To obtain evidence of the purity of the compound, a silver salt was made from it, and analysed with the following result.Found : C = lS.90 ; H = 2.37 ; Ag = 57.76 and 57-69 per cent. C,H,O,Ag, requires C = 19.15 ; H = 2.1 3 ; Ag = 57.45 per cent. The yield of alkyloxysuccinic acid by the process which has been described would probably be increased by employing a larger propor- tion of alkyl iodide and silver oxide, in order to allow €or the loss which is doubtless entailed by their partial direct interaction. Pyepurcction of Etlhylic d-D,iet?boxysuccinate fvom EtAylic Tartrate. Attempts have been frequently made to alkylate the alcoholic hydroxyl groups of tartaric acid, but without success. Perkin (Trans., 1867, 20, 155), by the action of ethylic iodide on ethylic monosodio- tartrate, obtained an oil which he thought was probably ethylic mon- ethyltartrate, but the later researches of Lassar Cohn (Bes.., 1887,20, 2003), Mulder (Rec.T?w. Clhim., 1889, 8, 361) and Freundler (Bull. Xoc. (%xh2., 1894, 11, 308) have shown that neithei- the sodium nor potassium derivatives of ethylic tartrate react in the usual way with alkyl iodides. The ethylic diethoxysuccinate which Michael andACTIVE MONO- AND DI-UKYLOXYSUCCINIC ACIDS, ETC. 159 Bucher (Bey., 1896,20, 1792) found to be one of the products of the action of sodium ethoxide on ethylic dibromosuccinate and on ethylic acetylenedicarboxylate, was shown by these authors to be the unsym- metrical compound. The proportions of ethylic iodide and silver oxide employed in our experiments were 6 mols. of the iodide and 3 mols. of the oxide to 1 mol. of the tartrate, that is to say, an excess of one-half over the calculated quantity, assuming the reaction to proceed in the sense indicated in the case of ethylic malate.On adding the oxide to the mixture of iodide with tartrate, the reaction set in spontaneously, and became so violent that it had to be moderated by cooling. The liquid. product, obtained as described under et hylic ethoxysuccinate, was about equal in quantity to the tartrate employed, its boiling point was nearly constant, and its observed rotation varied in different preparations from +83*5O to +92*5O in a 100 mm. tube. As the percentage numbers found, on analysis, were somewhat lower than those calculated for ethylic diethoxysuccinate, and as it proved impossible to purify the substance either by fractional distillation or by shaking with water, which we expected would remove unaltered ethylic tartrate, if present, we had to resort to the method of partial hydrolysis by shaking with a 10 per cent.aqueous solution of potassium hydroxide. The p~ocess entailed a considerable loss of material, but the residual oil, on redistillation (b. p. 149-151' at 15 mm.), had increased in rotation to +97*5', and on analysis gave results in agreement with the calculated numbers. Found : I. C = 54.99 ; H = 8.71 per cent. 11. C=54*87 ; H=8*67 ,, ,, Calculated for C12H,,06 : C = 54.96 ; H = 5.40 per cent. The specific rotation of the liquid a t 18' was as follows : a = + 97-52", I = 1, d 1So!4O = 1.0460, hence [a], = + 93.23'. The ethereal salt of lower activity, which was removed by the partial hydrolysis, gave an uncrystallisable acid, which me intend to examine further.d-Diethoxysuccinic acid, which was obtained from the ethylic salt in the same manner as the monethoxy-acid, is sparingly soluble in benzene, readily soluble in ether, alcohol, chloroform, and water, from which it crystallises in long prisms melting a t 126-128O. The results of the analysis of the substance, dried at loo', were as follows, Found : I. C = 46.86 ; H = 7.04 per cent. 11. C=46*81 ; H=6.90 ,, ,, Calculated for C,H,,06 : c' = 46.60 ; H = 6.80 per cent. The acid showed the following specific rotations in aqueous soh- M 2160 PURDIE AND PITKEATHLY : PRODUCTION OF ACIDS, ETC. tions at 20' : U = + 6.73, c = 10.1488, l= 1, hence [ + 66.31' ; a= +2*70', c-4.0595, I= 1, hence [a]== + 66.51'.The silver salt is soluble in water, and does not decompose much on evaporating the solution. An estimation of silver in the salt gave the result; 51-01 per-cent., the calculated number being 51.43. The acid potassiunz and acid anzmoniunz salts are crystalline. The normal sodium salt, in aqueous solution at 17', showed the specific rotation + 41.11' (c= 3.138) ; the residue left on evaporating the solution, dried at 120°, was found to contain 18.35 per cent. of sodium instead of the calculated number, 18.40. The ccclciuwz salt is very soluble, and was not obtained in the crystalline state. The bnviunz salt, which is characteristic, is sparingly soluble in cold water, a,nd crystallises readily in large, glassy prisms, contniuiiig apparently 4H,O, which is lost at 120-139O.Analysis of the anhydrous salt gave the following resul ta. Pwnd : C = 27.78 ; H = 3.77 ; Ba = 39.94 and 40.12 per cent. An aqueous solution of the salt at 16' had the specific rotation Ethglic d-diethoxysuccinate is also obtained by the direct action of ethylic iodide and silver oxide on tartaric acid, but the yield is smaller than when the alkyl t,artrate is used as the starting point. From 17 grams of tartaric acid me obtained in this way 12 grams of an ethereal oil having the same boiling point, and the same observed rotation, + 85', as the crude ethylic diethoxysuccinate prepared from e t h y lic tartrate. The optical effect of t'he replacement of the alcoholic hydrogen of tartaric acid by alkyl mdicles is of the same nature as that which attends a similar substitution in lactic and malic acids ; the sign of rotation, defined in the case of lactic acid as that of its salts, remains unchanged ; a st,riking rise of activity, observable more particularly in the free acids and the ethereal salts, is produced, and the specific rotation of the acids in aqueous solutions of varying concentration becomes mare constant.Thus, in passing from tartaric t o diethoxy- succinic acid the molecular rotation of the ethylic salt is raised from + 15.8' to + 244*3', and that of the free acid at similar concentration from + 20.6' to + 136.6". The ionic rotation, however, does not ex- perience a proportional rise, the result being that, whilst in the case of the three hydroxy-acids mentioned the molecdar rotations of the alkali salts in dilute solution greatly exceed those of the free acids, these rotations become nearly equal in the citw of the dkyloxypro- pionic compounds, and the order of their value is reversed in the case of the mono- aud di-alkyloxysuccinic compounds. Calculated : C = 28.15 ; H = 3.52 ; Bn = 40.15 ,, ,, + 26 25' (C == 1.8092).CROSSLEY AND LE SUEUR : CONSTITUTION OF FATTY ACIDS. 161 Our observations furnish a satisfactory explanation of the apparently anomalous results obtained by Rodger and Brame, which have been already referred to, An admixture of 6 per cent. of ethylic d-di ethoxysuccinate would suffice to account for the high rotation of the ethylic tartrate which they prepared by the silver salt method, but the difference between the rotations of the products of hydrolysis of such a mixture and of pure ethylic tartrate respectively would not, under the conditions of the experiment described by them, amount to more than O*1-0*2ro.* The action of alkyl iodides and silver oxide on the alkyl salts of optically active hgdroxy-acids furnishes a general method of obtaining the active alkyloxy-acids. We have used the method with success for the preparation of alkyloxypropionic and alkyloxyphenylacetic acids from active lactic and mandelic acids, and we are a t present studying the application of the alkylating agent to the a-lkyl tartrates in general and to other compounds. UKITI%D c'OLtICGE OF ST. SALVATOR AND ST. LRONAItD, C'SIVERSITP O F ST. ANl>ItEWS.