I222 INGOLD AND POWELL: EXPERIMENTS ON THE

CXXXV1.-Experiments on the Synthesis of the Polyncetic Acids of Methane. Part 11. Some Abnormal Condensations of Malonic and Cyano- acetic Esters with Halogenated Methlanes.

By CHRISTOPHER KELK INGOLD and WALTER JAMES POWELL.

FOR the proper development of the general inquiry now being conducted in these laboratories into the conditions governing the formation from open-chain substances of carbon rings, and par- ticularly of systems of associated rings, it has become necessary to undertake the preparation of a number of open-chain substances which either have never previously been prepared or have been obtained only in extremely small quantities. Amongst these are the higher polyacetic acids of methane, namely, methanetriacetic acid (I), the carboxytriacetic acid (11), the tetra-acetic acid (111), and the unsaturated triacetic acid (VI).

The necessity of devising methods for the preparation of such simply constituted substances is doubtless due to the fact that their synthesis is beset with experimental difficulties. The principal circumstances contributing to this result have been discussed in a recent paper (this vol., p. 341) by one of us, in which it is pointed out that the unsaturated acids IV, V, and VI, which have in their compositions one molecule of acetic acid less than the polyacetic acids I , 11, and I11 respectively, and which therefore might be expected to yield these acids by the cyanoacetic ester method, are all substances of the “ mobile ” glutaconic type; in fact, in their stable forms they are not unsaturated. Such substances condense with ethyl cyanoacetate, usually only with difficulty and in any case in an abnormal manner, giving rise to 1 : 3-additive products as the “ semi-aromatic ” mode of formulation (VII , VIII, and IX)

/CH,.CO,H CH CH,*CO,H

\CH,*CO,H (1.)

/CH,*CO,H CO,H*C--CH2*CO,H

\CH,*CO,H (11.1

CH,-CO,H CH<CH2*C02H CH*CO,H C02H*CGCH.C0,H

,CH*CO,H

\CH*CO,H CH2

(VII.)

(V.)

,eH*CO,H

\CH-CO2H (VIII.)

CO,H*CH

,/CH,.CO,H CO,H*C~I,*C’-CH,*CO,H

(HI.) \CH,*CO,H

CH,*CO,H Co2H*CH,*c<CH.C0,H (VI.1

CO,H *CH,*CH

(IX.)

,kH-CO,H

‘CH*CO,H

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SYNTHESIS OF POLYACETIC ACIDS OF METHANE. PART 11. 1223

requires. The difficulty of effecting the required condensation with the esters of the unsaturated acids IV, V, and VI, is therefore to be ascribed to the difficulty of obtaining these substances in a sufficiently stable condition owing to their tendency to pass into the “ normal ” isomerides VII, VIII, and IX.

In order, therefore, to obtain the required condensation product it is necessary to adopt some special means of ensuring that the glutaconic derivative shall react in its labile (unsaturated) form. One method of bringing about this result is to generate the appro- priate labile glutaconic ester in the presence of ethyl sodiocyano- acetate and thus effect combination of the latter with the unsaturated ester in its “ nascent ” condition. This method has successfully been applied (Zoc. cit .) to the preparation of methanetriacetic acid and there seems every reason to suppose that the tetra-acetic acid (111) would be produced in a similar way if the unsaturated acid VI could be obtained and employed in its nascent condition.

A means of effecting this appeared to be provided in Zelinsky and Doroschewsky’s allenetetracarboxylic ester (X), a substance which can easily be prepared in any desired quantity from carbon tetrachloride and malonic ester (Ber., 1894, 27, 3374). This ester should react with ethyl cyanoacetate to form a derivative (XI) of the unsaturated acid VI, and, whatever changes of structure might occur during isolation, i t must in the first place be produced in a form in which one of the two double bonds originally present in the allene derivative is preserved. If, therefore, the formation of this substance were to occur in the presence of ethyl sodiocyano- acetate, a further condensation with the nascent unsaturated ester should take place :

(CO,Et),C:C:C(COzEt)z + ( C o z E t ) 2 C : c < c H ( ~ ~ ~ . c ~ 2 ~ t CH(C0 Et) -4

(X. 1 (XI. )

(CO,Et),CH>C<CH(CO,Et), CO,Et*CH(CN) CH(CN)*CO,Et ’

The ultimate product (XII) should yield methanetetra-acetic acid on hydrolysis.

There seemed every reason for anticipating that these reactions would proceed with ease, for in the first place Zelinsky and Doros- chewsky had shown that allenetetracarboxylic ester is a substance having strong additive properties, and in the second place the intermediate glutaconic derivative (XI) contains a number of a-substituents, a condition which always confers stability on the unsaturated modification. We were therefore considerably sur- prised to find in the product of the condensation no trace of the

(XII.)

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1224 INGOLD AND POWELL: EXPERIMENTS ON THE

esters XI or XI1 or of any product which might have been derived from them. Ultimately, the reason for the discrepancy was dis- covered in the fact that Zelinsky and Doroschewsky’s “ allenetetra- carboxylic ester ” was not an allene derivative, and, moreover, was not even a substance having the same empirical composition.

The initial product which Zelinsky and Doroschewsky obtained by the condensation of carbon tetrachloride and ethyl sodiomalonate was a yellow sodium compound, to which they gave the formula XIII. On treating this with dilute acids, the sodium was dis- placed by hydrogen, and there was produced an oily unsaturated ester (XIV), which on distillation eliminated alcohol and yielded the crystalline ester (X) :

(C02Et),C:C’Na*C(OEt)(CO2Et)2 -+ (C02Et)2C:CH’C(OEt)(C0,Et)2 -+ (X.) (XIII.) (XIV.)

On repeating the experiment under the exact conditions used by Zelinsky and Doroschewsky, we found no difficulty in confirming their results in every particular excepting as regards the compo- sitions and chemical characters of the substances isolated. Contrary to the conclusion of these investigators, however, the yellow sodium compound proved to be, not the ethoxy-derivative XIII, but the well-known substance first obtained by Conrad and Guthzeit by the condensation of chloroform with ethyl sodiomalonate (Ber., 1882,15, 284) ; this substance (XVI) on acidification gave the ester to which Zelinsky and Doroschewsky ascribed the f orrnula XIV, but which in reality is ethyl dicarboxyglutaconate (XVII) ; this, on distillation, passed into the solid ester which they regarded as an allene derivative, but which actually was the well-known ethoxy- lactone, XVIII :

(XVI.) (XVII.)

C02Et*F:CH-fi*C02Et CO*O*C*OEt . (XVIII.)

All these substances yielded glutaconic acid on hydrolysis and were further identified by analysis and by direct comparison with authentic specimens.

It must not be supposed that the production of these substances is due to the presence of chloroform aB an impurity in the carbon tetrachloride used. Even that used in our earliest experiments wits quite pure, distilling completely at an almost constant tem- perature. Moreover, the sample contained no trace of hydrogen

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SYNTHESIS OF POLYACETIC ACIDS OF METHANE. PART 11. 1225

and gave correct figures on complete analysis. Further, it did not reduce Fehling’s solution, whilst carbon tetrachloride containing 5 per cent. of chloroform readily attacked this reagent. Now, if the production of the yellow sodium compound is to be explained by assuming the presence of chloroform in the carbon tetrachloride, i t would be necessary to suppose that a t least 30 per cent. of chloroform was contained in the sample with which these tests and analyses were carried out, That clearly is impossible. In order to settle the matter beyond question, the effect was tried of using carbon tetrachloride which had been recovered from a previous condensation. If the production of the yellow sodium compound is due to the interaction of chloroform and ethyl sodiomalonate, the recovered carbon tetrachloride should be almost free from the reactive impurity and should yield little or no yellow sodium compound on condensing again in the same way. Actually, the quantity of the sodium compound produced was undiminished. The same yield was obtained from carbon tetra- chloride which had been treated with hot 6.5N-methyl-alcoholic potassium hydroxide, and even from carbon tetrachloride which had been subjected to prolonged boiling with Fehling’s solution. There can be no question, therefore, but that the carbon tetra- chloride itself is responsible for the formation of the yellow sodium compound XVI, and that it supplies the central carbon atom of that substance.

In order to obtain, if possible, some information as t o the mechanism of this remarkable change, the interaction of carbon tetrachloride and ethyl aodiocyanoacetate was next investigated. If carbon tetrachloride condensed normally with this sodio-ester, the product should be dicyanoallenedicarboxylic ester (XIX) ; if, on the other hand, the carbon tetrachloride behaved as though it were chloroform, the product should be ay -dicyanoglutaconic ester (XX), an easily isolated crystalline substance, which has been well characterised by Ruhemann and Browning (T., 1898, 73, 282) as well as by subsequent workers. Actually, the product of the

CO,Et*(CN)C:C:C( CN)*CO,Et C0,Et (CN)CH*CH:C(CN) *CO,Et (XIX.) (XX.)

condensation was dicyanoglutaconic ester, proving that here again carbon tetrachloride had reacted as though it were chloroform.

In the course of this reaction a large quantity of cyanoacetamide (XXII) was invariably produced. This at first sight appears extraordinary, for in no stage of the reaction which results in the formation of dicyanoglutaconic ester can it be supposed that two G N or *&N: groups become attached to the same carbon atom.

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1226 INGOLD AND POWELL: EXPERIMENTS O N THE

The difficulty was, however, to a large extent removed when it was discovered that, along with the cyanoacetamide, there was present another crystalline by-product, namely, ethyl a-cyano- P-iminoglutarate (XXI), a substance originally prepared by Best and Thorpe (T., 1909, 95, 1518) by condensing ethyl cyanoacetate with its sodium derivative. Obviously, therefore, ethyl cyano- acetate must have been liberated during the condensation (probably by the action of the distinctly acidic dicyanoglutaconic ester), and niust then have combined with some of the unchanged sodio- derivative, forming ethyl a-sodio-a-cyano-p-iminoglutarate, from which the free cyanoimino-ester would doubtless be liberated by a similar mechanism :

CH,(CN) *CO,Et +CH(CN):C(ONa)*OEt + CO,Et*CH,*C(:NH)*C(CN):C(ONa)*OEt -+

CO,Et-CH,*C( :NH) *CH (CN) *CO,Et . (XXI.)

The imino-derivative, in its aminoglutaconic modification, must then have undergone fission a t the double bond, producing ethyl cyanomalonamate, which, in the presence of hot sodium ethoxide, would break down into cyanoacetamide and ethyl carbonate :

CO,Et*CH+ C(NH,) *CH( CN)*CO,Et -+CH( CN) (CO*NH,)CO,Et -+

(XXII.) CH,(CN)*CO*NH,+CO( OEt),.

In this reaction there must also have been formed a product derived from the residue CO,Et*CH: to the left of the dotted line. The nature of this product is unknown, but a t least it is certain that it was not ethyl butyrate, the substance to be expected had the fission reaction been of the nature of an alcoholysis. Since, however, the production of dicyanoglutaconic ester requires the oxidation of Some organic material in order to provide the necessary two atoms of hydrogen, we consider it probable that the CO,Et*CH: residue gave rise to an oxidation product such as glyoxylic ester or some polymeride of that substance, although no experimental evidence could be discovered to support this view.

The source of the two hydrogen atoms necessary for the pro- duction of Conrad and Guthzeit’s sodium compound from carbon tetrachloride and malonic ester is even more obscure, but there is indirect evidence pointing to the oxidation of alcohol as the probable source. For, whilst carbon tetrachloride, by treatment with benzene and aluminium chloride, yields the normal product, triphenylchloromethane (Gomberg, Ber., 1900, 33, 3144), on heat- ing with alcoholic potassium hydroxide gives rise to potassium

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SYNTHESIS OF POLPACETIC ACIDS OF METHANE. PART 11. 1227

formate (Nef, Annalen, 1899, 308, 330) and with sodium ethoxide to orthoformic ester, substances the production of which undoubtedly involves the oxidation of alcohol. Deeply coloured resinous by-products are always obtained in these reactions.

The apparent impossibility of obtaining a normal condensation product from carbon tetrachloride by the action of ethyl sodio- malonate or ethyl sodiocyanoacetate is of some significance in view of the fact that trichloroacetic ester yields no condensation product with either of these substances under the usual experimental conditions (Professor J. F. Thorpe, private communication) ; for i t would seem to follow that, no halogenated derivative of methane can react normally with such sodio-esters unless at least one hydrogen atom is attached to the carbon. If this is so, it is doubt- less no more than a phase of the general law that the production of a condition of unsaturation (which in these instances would involve bivalent carbon) is necessary to all organic reactions.

In order to test the matter as completely as possible, the behaviour towards ethyl sodiocyanoacetate and ethyl sodiomalonate of two other halogenated methanes was examined. The substances chosen were carbon tetrabromide and chloropicrin and the results obtained were in complete harmony with the general hypothesis ; for in neither case could a trace of the normal condensation product be isolated. The main products were ethyl dicyanosuccinate or ethyl ethanetetracarboxylate according to the sodio-ester employed.

E X P E R I M E N T A L .

(A) PuriJication of Carbon Tetrachloride.

The carbon tetrachloride employed in the following experiments was prepared for use by four methods.

(a) Distillation.-The commercial material was found to boil almost constantly a t 77" and a middle fraction having a boiling point which appeared to be absolutely constant was therefore collected for use. Its purity was controlled by analysis (Found : C=7*6; C1=91*8. Calc., C=7*8; C1=92.2 per oent.), and by the absence of any reaction with Fehling's solution a t 60". This clearly proves that no considerable quantity of chloroform can be present, since the addition of 5 per cent. of chloroform to the carbon tetrachloride caused rapid reduction of the Fehling's solution to occur under the same experimental conditions.

( 6 ) Digestion with Pehling's Solution.-In order to remove any trace of chloroform present, the distilled carbon tetrachloride was digested with Fehling's solution for several hours at 60-70". The

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1228 INGOLD AND POWELL: EXPERIMENTS O N THE

flask was vigorously shaken from time to time, and, finally, the lower layer was removed, dried, and refractionated.

( c ) Treatment with Alcoholic Potassium Hydroxide.-The distilled carbon tetrachloride was treated with about 2 molecules of potassium hydroxide in 6.5N-methyl-alcoholic solution. When the addition was complete, the mixture was heated on a steam-bath for thirty minutes and then kept a t room temperature overnight. The unchanged carbon tetrachloride was then recovered by adding water and collecting in &her and was finally purified by fractional distillation.

(d) Treatment with Ethyl 8odiomaEomte.-Distilled carbon tetra- chloride was condensed with ethyl sodiomalonate in alcoholic solution under the conditions given below for the preparation of ethyl sodiodicarboxyglutaconate from carbon tetrachloride. The product was worked up in the usual way and, after the yellow sodium compound had been removed, the oily product was extracted with ether and divided into neutral and acid fractions by means of sodium carbonate. The unchanged carbon tetrachloride was then recovered from the neutral fraction by distillation.

(B) Action of Sodium E tholcide on Carbon Tetrachloride.

Carbon tetrachloride was boiled for forty-eight hours with an absolute alcoholic solution containing four molecular proportions of sodium ethoxide. The product, although still having a faintly alkaline reaction, was concentrated by evaporation and poured into water. The oil was extracted with ether and the extract washed several times with water, dried, and evaporated. The residue, on distillation, yielded three main fractions : (a) a small fraction, b. p. 70-go", ( b ) a large fraction, b. p. 135-150", (c) a small fraction, b. p. 150-168". Fraction (a) consisted essentially of unchanged carbon tetrachloride, fraction ( 6 ) of ethyl orthoformate, whilst fraction (c ) may have contained ethyl orthocarbonate, although this subsfance was not isolated owing to the smallness of the quantity.

Ethyl Orthoformate, CH( OC,H,),.

This ester was obtained (b. p. 143-145") by distilling fraction (b) until the distillate was free from chlorine (Found: C=57*1; H=10*8. Calc., C=56*8 ; H= 10.8 per cent.).

(C) Condensation of Carbon Tetrachloride with Ethyl Sod iomal onate.

This condensation was carried out by the method given by Zelinsky and Dorosehewsky (Eoc. c i t . ) for the preparation of the

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SYNTHESIS O F POLYACE'MC ACIDS OF METHANE. PART 11. 1228

additive product of ethyl allenetetracarboxylate and sodium ethoxide. The dark red product was filtered and the filtrate concentrated by distillation until the alcohol had been almost entirely removed. Water and ice were then added and the crystal- line solid thus precipitated was collected.

Ethyl Sodiodicarboxyglutuconute (XVI). The solid product was first purified by washing successively

with water, cold alcohol, and ether, and was finally crystallised from alcohol. It was thus obtained as bright yellow needles and was identified as ethyl sodiodicarboxyglutaconate by analysis (Found: Na=6-4. Calc., Na=6*5 per cent. A number of estimations were made, but we were unable to obtain a figure approaching that recorded by Zelinsky and Doroschewsky for this substance), by direct comparison with a specimen prepared from chloroform and ethyl sodioinalonate, by conversion into the two derivatives mentioned below, and by hydrolysis to glutaconic acid.

Ethyl Dicarboxyglutaconate (XVII). This ester was prepared by shaking the sodium compound with

dilute hydrochloric acid and ether until the yellow colour had vanished and then drying and evaporating the ethereal solution (Found : C=54*2 ; H=6*7. Calc., C=54*55 ; H=6.7 per cent.). On hydrolysis if yielded glutaconic acid.

E thy1 6- Ethoxy-2 -pyrone -3 : 5 -dicarboxylate (X VIII) . The liquid ester, on distillation under diminished pressure,

quickly eliminated ethyl alcohol and yielded the pyrone, which passed over at 200°/10 mm. and separated from dry ether in needles melting at 94". It was identified by analysis * (Found : C=54.7; H=5% Calc., C=54.9; H=5*6 per cent.), by direct comparison and by a mixed melting point determination with an authentic specimen, and, finally, by hydrolysis fo glutaconic acid.

(D) Condensation of Carbon Tetrachloride w i t h E t h y l Sod ioc yanoacetate.

An alcoholic solution containing four molecules of ethyl sodio- cyanoacetate and one of carbon tetrachloride was heated at 100"

* The percentages calculated for ethyl allenetetracarboxylate (C =54-9 ; H=6*1) approximate r&hm closely to those for the true formula, a circum- ,stance which probrtbJy contributed to Zelinsky and Doroschewsky's mis- apprehension.

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1230 SYNTHESIS OF POLYACETIC ACIDS OF METHANE. PART 11.

for four hours. The mixture was then cooled and the solid material which had separated was collected with the aid of the pump. The filtrate was evaporated under reduced pressure, poured into water, and extracted with ether, the extracted material being separated by sodium carbonate in the usual manner into neutral and acid fractions.

Ethyl ay-Dicyanoglutuconate (XX). On drying and evaporating the acid extract there was obtained

a solid residue which, when crystallised from alcohol, melted a t 183-1 84". It was identified as ethyl ay-dicyanoglutaconate by direct comparison and by a mixed melting point determination with a specimen prepared from ethyl cyanoacetate and chloroform (Found : C=53*9 ; H=6-4. Calc., C=55-9 ; H=5*1 per cent.*).

Ethyl a-Cyano-p-iminoglutarate (XXI).

The neutral extract, on evaporation, yielded a crystalline residue which separated from ethyl bromide in needles melting a t 53" (compare Best and Thorpe, loc. cit.) (Found : C=52-8; H=6-45. Calc., C=53*1 ; H=6*2 per cent.).

Cyanoacetamide (XXII). The solid on the filter was washed with hot alcohol and the

residue obtained on evaporation of the washings crystallised from alcohol. The material thus obtained melted a t 120" and was identified as cyanoacetamide by analysis (Found : C=42*6 ; H=4-9. Calc., C=42-85; H=4-75 per cent.), and by direct comparison and a mixed melting-point determination with a known specimen.

(E) C o n d e n s a t i o n of C a r b o n Te t rabromide w i t h E t h y l Sod iomalona te a n d w i t h E t h y l Sodiocyanoaceta te .

These condensations were conducted similarly to the condensations with carbon tetrachloride and the substances formed were isolated in the same way. The principal product proved to be ethyl ethanetetracarboxylate or ethyl aa'-dicyanosuccinate, according to the sodio-ester employed. On hydrolysis with dilute sulphuric acid, succinic acid was obtained and in the case of the ethanetetra- carboxylic ester the .material was also identified by direct com-

* The poor results obtained on combustion are undoubtedly due to the difficulty of obtaining anhydrous specimens (compare Ruhemann and Brown- ing, Zoc. cit., and Errera, Guzzetta, 1879, 27, [ii], 393).

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DITHIOKETONES AND DITHIO-ETHERS. PART II. 1281

parison and by a mixed melting-point determination with a known specimen (Pound : C=52.9; H=7.0. Calc., C=52%; H=6*9 per cent .).

(F) Condensat ion of Chloropicrin w i t h E t h y l Sod io - malonate and w i t h E t h y l Sodiocyanoacetate.

With the exception that owing to the large amount of heat which is developed it is necessary to add the chloropicrin to the sodio-esters very slowly, these condensations were carried out like the condensations with carbon tetrabromide and gave the same results.

We desire to record our thanks to Professor J. F. Thorpe for his valuable suggestions and criticism and fo the Chemical Society for a grant which has defrayed a large part of the cost of this investigation.

IIYIPERIAL COLLEGE OF SCIENCE AND TECHNOLOGY, SOUTH KENSINGTON, S.W.7. [Received, May 25th, 1921.1

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