SYNTEESCS OF afl&TRIMETHY LGLUTARIC ACID, 61 VIL-Synthesis of apB- Trimethylglutan'c Acid. COOH- CH(CH8)*C(CH,),* CH,. COOH. By W. H. PERHIN, jun., and JOCELYNF. THORPE. OF the four theoretically possible trimethylglutaric acids, two only, up to the present, have been prepared synthetically, namely, the U ~ U ~ - acid, COOH. C(CH,),* CH,* CH(CH,)*COOH, by Auwers and Victor Meyer (Ber., 1890,23,293) from ethylic u-bromisobutyrate and 6' mole- cular '' silver, and the +acid, COOH. C(CH,),* CH(CH,)*CH,m COOH,62 PPRKIN AND THORPE: SYNTHESIS OF which was prepared by us (Trans., 1897, 71, 1187), by the reduction of the corresponding trimet hylglutaconic acid, COOH- C(CH,),* C(CH,):CH* COOH. The remaining two acids are app ...... COOH*CH(CH,)*C(CH,),*CH,*COOH, and apa COOH.CH(CH,)*CH(CH,)*CH(CR,)*COOH. Of these, the first has a special interest, for the following reason. By the oxidation of camphoric acid with permanganate at the ordi- nary temperature, Balbiano (Bey., 1894, 27, 2133 ; 189'7, 30, 1908), obtained an acid of the formula C,H,,05, to which he assigned the constitution COOH. C(CH,)* C(CH,),* CH. COOH. 1-0- I This acid, on reduction, yielded a lactonic acid of the probable formula CH(CH,)*C(CH,),* He COOH, and this, by further reduction with hydriodic acid, was converted into an acid, C,H1,O,, which Balbiano considered to be upp-trimethyl- glutaric acid, because, on oxidation, it yielded aa-dimethylsuccinic acid. Assuming that this acid is app-trimethylglutaric acid, its formation from camphoric acid is important, as affording evidence that the latter contains the group C*C(CH,).C(CH,),* C-C, a conclusion which, to- gether with results obtained from the great amount of work which has been done on camphoronic acid, throws much light on the constitution of camphoric acid (compare Trans., 1898, 73, '797).It thus became an important matter to be certain that the formula Balbiano assigned to his acid is correct, and for this resson we have, ever since the publication of his paper, been endeavouring to synthesise upp-trimethylglutaric acid, and it is only quite lately that we have been able to accomplish this. I n the first place, we found, as the result of a great many experi- ments, that it seems to be impossible to introduce a methyl group into etb ylic dimethylpropanetricarboxylate, 60--- 8 (COOC,H,),C&* C(CH,),* OH,.COOC,H,, at the point marked *, by the action of sodium ethoxide and methylic iodide. Arguing from analogy to other mono-substitution products of ethylic malonate, this experiment should have yielded an ethereal salt which would have given a&3-trimethylglutaric acid on hydrolysis@&TRIMETHY LGLUTARIC ACID. 63 and elimination of carbon dioxide, but, although tried under very varied conditions, no trace of this acid was obtained. It was then thought possible that the ethylic trimethylpropanetri- carboxylate, (COOC2H5),C(CH3)*C(CH3),* CH,* COOC,H,, which should have resulted from the above experiment, might be formed by the condensation of ethylic dimethylacrylate with the sodium derivative of ethylic methylmalonate, but the experiments made in this direction did not yield a trace of the de,sired compound, and many other syn- theses, which need not be mentioned here, also gave negative results.Ultimately, we discovered the following synthesis, which is so easily carried out that large quantities of c@p-trimethylglutaric acid can now be obtained in a short space of time. The method consists in heating together ethylic dimethylacrylate and the sodium derivative of ethylic cyanacetate in alcoholic solution until the condensation to the sodium derivative of ethylic cyanodi- methyZyZutarate, which probably has the formula, COOC,H,* C(CN)Na* C(CH,),* OH2* COOC2H5, is complete (see p. 52). The crude product is then directly treated with methylic iodide, when an almost quantitative yield of ethylic cyanotrimethylglutarate, COOC,H,* C(UH3)(CN)* C(CH,),* CH,* COOC,H,, is obtained.This, on hydrolysis with methyl alcoholic potash or hydrochloric acid, yields the beautiful, crystalline imide of a&3-trimethylglutaric acid, which, when heated with hydrochloric acid, at 200°, is converted quantitatively into aPP-trimethylglufaric acid. A direct comparison of the acid thus synthesised with that obtained from camphoric acid was rendered possible by the kindness of Professor Balbiano, who sent us a sample of the acid which he was the first to prepare. Both acids melted a t S7", and on treatment with acetyl chloride yielded the same anhydride melting a t 82", and from this by the action of aniline an anilic acid was prepared which in both cases melted a t 150-151", so that there can be no doubt as to the identity of the synthetical acid and Balbiano's acid.I n experimenting with a/3P-trimethylglutaric anhydride, it was found that, not only does it crystallise from water unchanged, but that it actually crystallises with water of crystallisation, in prisms melting at 61°, and without being converted into the acid. This is certainly a very unusual property of an anhydride, and the only somewhat similar case which we have been able to find is that of the p-lactone of dimethylmalic acid, (CH,)2?--?H0 ''OH, which, GO-064 PERKIN AND THORPE: SYNTHESIS OF as Baeyer and Villiger (Ber., 1897,30, 1955) have shown, crystallises with lH,O. We are at present engaged in investigating other condensations between unsaturated ethereal salts and a-cyano-ethereal salts, and also on the action of halogen compounds on the sodium derivative of ethylic cyanodimethylglutarate, and we are especially interested in the ethereal salt which this sodium derivative yields on treatment with ethylic bromacetate, because, if Baeyer's formula for isocam- phoronic acid be correct, this should lead to a synthesis of this very important acid, Ethylic a-Cyano-al-pp-trimethylglutarate, COOC,H,* CH(CN)*C( CH,),.CH( CH,)*COOC,H,. I n order to prepare this substance, ethylic dimethylacrylate is digested in alcoholic solution with the sodium derivative of ethylic cyanacetate, as explained on page 52, and after heating for 15 hours excess of methylic iodide is added and the boiling continued until the liquid has a neutral reaction ; water is then added, and the oily product extracted with ether.The ethereal solution, after washing well with water, drying over calcium chloride, and evaporating, deposits a thick oil which, after twice fractionating, boils constantly a t 181' (25 mm.), and consists of pure ethylic cyanotrimethylglutarate. 0.22 gave 11.8 C.C. nitrogen at 23' and 750 mm. C13H21N04 requires N = 5.50 per cent. The yield of this pure ethereal salt obtained in this condensation is about 68 per cent. of the theoretical, and it is remarkable that, in this case, only traces of an acid ether'eal salt are formed, whereas, as explained on p. 52, if the condensation is worked up before the treat- ment with methylic iodide the principal product is the acid ethereal salt.N= 5-94, This substance is formed when ethylic cyanotrimethylglutarate is hydrolysed either with methyl alcoholic potash or with concentrated hydrochloric acid j in the former case, the product often consists of the acid amide, a white, deliquescent solid which, however, can readily be converted into the imide by boiling for a short time with concen- trated hydrochloric acid. apb-Trimethylglutarimide is sparingly soluble in cold, but readily in hot water, and crystallises in long needles closely resembling PP-dimethylglutarimide (p. 5 3) in appear- ance. It melts a t 126'.~z~~~~-TRIMETHYLGLUTARIC ACID, 65 0.1163 gave 9.4 C.C. nitrogen at 32' and 765 mm. N = 9-20. C,H,,NO, requires N -c 9.03 per cent. is obtained as a beautiful, crystalline precipitate when dilute ammonia is carefully added to a, warm solution of the imide and silver nitrate, Ag = 41.53.C,HI,O,NAg requires Ag = 41 *22 per cent. 0.0874 gave 0.0363 Ag. a&3-TrirnethyZgZzctaric acid, COOH. CH(CH,)*C(CH,),* CH,* COOH. This acid is best prepared from the imide just described by heating it with three times its weight of concentrated hydrochloric acid in a sealed tube for 5 hours a t 200'. The product is evaporated to dryness on the water bath, and the residue extracted with ether j after drying over calcium chloride, the ethereal solution deposits the acid in an almost pure condition on evaporation. For the analysis, the acid was crystallised from water, from which it separates in glistening plates melting at 88'. 0.1316 gave 0.2675 CO, and 0.0960 H,O.C = 55.43 j H = 8.23. C8H,,0, requires C = 55.17 j H = 8005 per cent. which is the most characteristic derivative of aPP-trimethylglutaric acid, is readily prepared by digesting the pure acid for a short time with excess of acetyl chloride, and then evaporating to dryness on the water bath. The crystalline residue, which consists of the almost pure anhydride, crystallises from a mixture of ethylic acetate and light petroleum in prisms which melt a t 82'. 0.1445 gave 00.3248 GO, and 0.0991 HzO. C,H,,03 requires C = 61-54 ; H = '7.67 per cent, This anhydride is quite insoluble in cold dilute sodium carbonate solution, and is only very slowly converted into the acid even on boiling. If this anhydride is boiled with a large quantity of water, and the clear solution, rapidly poured off from the oily drops, is allowed to cool, a small quantity of the anhydride crystallises out in needles (I) ; the same substance is produced on melting the anhydride under hot water and stirring vigorously until it becomes solid (11).The pro- duct in both cases melts a t 61", and consists of the anhydride with half a molecule of water of crystallisation. The following are the results of the analyses of specimens of I and 11. C = 61.34; H = 7.62. VOL, LXXV. F66 DUNSTAN AND HENRY: OCCURRENCE OF ORTHOHYDROXY- I. 0.2322 gram, after drying on a porous plate for 3 hours, lost 11. 0.4712, heated at 50° until constant, lost 0.0242. C,H1,O3 + 4H20 requires H,O = 5.4 per cent. The water of crystallisation is given off rapidly on gently warming, and slowly over sulphuric acid in a vacuum desiccator ; the residue then melts at 82', the melting point of the dry anhydride, 0.01 34 gram at 50'. H,O = 5.8 per cent. H,O = 5.15. app- Trimeth y l g h t armilic Acid, C,H,*NH*CO*CH(CH,)*C(CH,)2*CH,*COOH(?). On the addition of aniline to a solution of the anhydride in benzene, this compound separates after some time as a white, crystalline precipitate, After being purified by recrystallisation from dilute methylic alcohol, from which i t separates in long needles, it melted a t 150-151', and, on analysis, gave the following result. 0.2515 gave 12.2 c,c. nitrogen a t 21' and 752 mm. N = 5.47. C,,H,,NO, requires N = 5.60 per cent. Our thanks are due to Messrs. F. Howles and F. H. Lees, for much valuable help in connection with this and the preceding research, and we wish also to state that the very considerable expense which these experiments have entailed has been largely met by grants from the Royal Society Research Fund. MANCHESTER. OWENS COLLEGE,