ACTIVE COMPOUNDS FROM INACTIVE SUBSTANCES. 1 305 CBXXVI’I.-Expe?.irnents on the Production of Optically Active Compounds from Inactive Substances. By J. B. COHEN and C. E. WHITELEY. THE withdrawal of one of us from this research has made i t desir- able to publish the results of our experiments as far as they have gone. In addition to the three well known methods devised by Pasteur For obtaining optically active compounds from inactive asymmetric1306 COHEN AND WHITELEY: PRODUCTIOX OF OPTICALLY materials, many new processes have in recent years been proposed. These methods may be said to consist in subjecting the material to an unsymmetrical action of either a physical or chemical nature. Among the physical processes may be mentioned the crystallisation of the inactive material in a magnetic field which Pasteur tried without success and which has since been repeated by Boyd (Landolt, Optische Drehungsvermogen, p.I1 I) and others with similar results. Kipping and Pope have employed the method of crystallisation of a racemic compound from a solvent containing an active substance in solution (Proc., 1898, 14, 113) and obtained evidence of its effect in promoting the deposition of a larger proportion of one of the enan- tiomorphs. Among the chemical processes are the following. The selective hydrolysis of glucosides was effected by E. Fischer, by means of enzymes (Zeit. physiol. Chem., 26, 60); the fractional esterification of an inactive acid in combination with an active alcohol, or the reverse process, namely, the partial hydrolysis of an ester composed of an inactive acid and an active alcohol, was successfully employed by Marckwald and McKenzie (Bey., 1899,32, 2130; 1901, 34, 469) and Walden (Ber., 1899, 32, 3617); the rate of hydrolysis of cane sugar effected by d- and Lcamphoric acid was investigated by E.Fischer with negative results (Ber., 1899, 32, 3617). The formation of a new asymmetric carbon atom under asymmetrical conditions has also been studied by E. Fischerin the synthesisof the sugars. It isthis process which has especially attracted our attention. E. Fischer (AnrzccZen, 1892, 270, 64) has shown that in the synthesis of one sugar from another by the addition of hydrogen cyanide to the lower member, a new asymmetric carbon atom is introduced which may give rise to two stereoisomeric compounds represented as follows : Although the two new groups are optical antipodes, the two iso- merides are not necessarily so as a whole, and are not always produced in equal quantities.Fischer has found, for example, thgt d-glucose forms two cyanohydrins in very unequal quantities (Zoc. cit.), whilst in the case of d-mannose only one of the two possible cyanohydrins is produced (Hartmann, Annalen, 1892, 2’72, 190). It is clear, there- fore, that the asymmetric molecule exerts its influence on the space configuration of the newly added asymmetric carbon group. I n these examples, it is impossible to determine exactly the influence of the active part of the original molecule on the activity of the new group, seeing that the latter cannot be detached from the molecule. As the formation of active substances in living organisms is probablyACTIVE COMPOUNDS FROM INACTIVE SUBSTANCES.130'7 closely connected with their production from other active substances from which they are afterwards removed, the idea occurred to us to attempt to produce a new asymmetric carbon atom in an already active compound from which the originally active group could be sub- sequently detached. A number of reactions readily presented themselves, such as the reduction, bromination, or hydroxylation of esters composed of an unsaturated acid and an active alcohol, or the reduction of a ketonic ester of an active alcohol, the alcohol being afterwards removed by hydrolysis. These reactions may be represented as follows : (X stands for an atom or group not being hydrogen, A indicates the active alkyl or aryl group, and C the new asymmetric carbon atom) : 1.*CH:CH*CO,A -+ *CHX*CHX*CO,A --+ *CHX*CHX*CO,H 2. *CH:CX.CO,A -+ *CH,*CHX*CO,A --+ *CH,*CHX*CO,H 3. *CO*CO,A -+ *CH(OH)*CO,A --+ *CH(OH)*CO,H Under 1, we have prepared the bromine derivatives of the amyl and menthyl cinnamates, and of dicinnamyltar taric acid and examined the action of various reagents on the dibromo-compounds. All these experiments, after a considerable loss of time, had to be abandoned. Although the dibromo-derivatives of amyl and menthyl cinnamates and of dicinnamyltmtaric acid could be readily obtained in a state of purity, they could not be directly hydrolysed without removing bromine, and all attempts to replace bromine by hydroxyl failed.Under 2, we have studied the reduction of the menthyl esters of mesaconic acid and a-methylcinnamic acid. Under 3, we have investigated the reduction of menthgl pyruvate. The results in all cases have been of a negative character, in spite of every care to avoid possible racemisation by conducting the critical steps in the reactions a t the ordinary temperature. EXPERIMENTAL. AmyZ Cinnamate. A few preliminary experiments were made with this compound with the object of introducing asymmetric carbon atoms into the acid portion of the ester in its combination with active amyl alcohol. The substance was prepared by heating together equal weights of cinnamio chloride find ordinary an yl alcohol u n t i l bydrogen chloride ceased to be evolved.The product was then wRshed with water, dried over1308 COHEN AND WHETELEY : PRODUCTION OF OPTICALLY calcium chloride, and distilled in a vacuum. It boiled at 186-1885 under 20 mm. pressure; d 2O0/2Oo=0*975. I n order to obtain the phenylglycerate, the amyl cinnamate was treated with dilute permanganate, but even in a freezing mixture it underwent oxidation to benzaldehyde and benzoic acid, and no trace of the dihydroxy-compound could be detected, It was then converted into the dibromo-derivative by adding one molecular equivalent of bromine dissolved in chloroform. The bromine was readily absorbed and the product, when purified, formed a colourless oil. All attempts to re- place bromine by hgdroxyl failed. It is a colourless oil with a faint odour of amyl alcohol.Menthyl Cinnamate. This ester was prepared with the same object as the amyl ester, and with equally fruitless results. It was obtained by heating together in the oil-bath at 140" equivalent quantities of cinnamyl chloride and menthol, and purified by adding sodium carbonate and distilling in steam. The residue was extracted with ether, dehydrated over calcium chloride, and the ether removed by evaporation. The ester formed a light yellow, viscid liquid which. did not crystallise. It was then converted into the dibromo-compound by the addition of the equivalent quantity of bromine in chloroform. The colour of the bromine slowly disappeared and after removal of the chloroform the dibromo-compound crystallised. After recrystallisation from glacial acetic acid, it formed colourless needles and melted at 84'. On analysis : 0.220 gave 0.1697 AgBr.Br = 36.1. C,,H2,0,Br, requires Br = 35.9 per cent. We were unsuccessful in all our attempts to replace bromine by hydroxyl, ethoxyl, or acyloxyl groups. ~~trr.abromodicinnam~~tartaric Acid. Dicinnamyltartaric anhydride is readily prepared by the method described by Freundler (Ann. Chirn. Phys., 1894, [vii], 3, 486). It was brominated in chloroform solution and the liquid product remain- ing, after removing chloroform, crystallised on the addition of a little water, forming colourless crystals of tetrabromodicinnamyltartaric acid. It was completely decomposed with alkalis, and with ammonia deposited crystals melting at 119O, which were identified as mono- br omocinnam ide, C6H,*CBr: CH* CO*NH,.ACTIVE COMPOUNDS FROM INACTIVE SUBSTANCES.1309 0.1316 gave 0.1073 AgBr. No hydroxy-derivative could be obtained from this substance. Br = 34-7. C,H,ONBr requires Br = 35.4 per cent. Mentlbyl Pyruvate. Thirty-one grams of pyruvic acid and 55 grams of menthol were heated under diminished pressure on the water-bath with a reflux condenser. The product was then distilled in a vacuum and the ester collected a t 136-140' under 22 mm. pressure. d 11.5°/40=0*9917 ; [ - 181 -7'. On analysis : 0.3153 gave 0.1249 CO, and 0.112 H,O. C=68.85; H=9*96. C,,H,,O, requires C = 69.03 ; H = 9.73 per cent. Mertthyl Lactate. After several trials with different reducing agents and under different conditions, the following process was found to give the most satisfactory result.Menthyl pyruvate (5- 10 grams) was reduced with constant stirring in the cold with four times the theoretical quantity of glacial acetic acid and zinc dust, the latter being added at intervals during 5-6 hours. The product was filtered and washed with dry ether, The filtrate was shaken in a separating funnel with water and excess of barium carbonate to remove the acetic acid, When all effervescence ceased, the product was filtered, and the ethereal layer removed from the filtrate and evapor- ated t o a syrupy consistency in a vacuum a t the ordinary temperature. The syrupy residue was mixed with the theoretical quantity of potassium hydroxide dissolved in methyl alcohol and left overnight in a vacuum a t the ordinary temperature, when complete hydrolysis was effected.Water was added to the dry product, which was extracted with ether to remove menthol, The aqueous solution of potassium lactate, which was free from pyruvate, was made strougly acid, evaporated to a gummy mass in a vacuum at the ordinary temperature, and the free lactic acid extracted several times with ether. On evaporation of the ether, the residue was boiled with water and zinc carbonate, and, from the filtrate, crystals of zinc lactate separated. Ten grams of menthyl pyruvate yielded about 3.6 grams of zinc lactate, or 50 per cent. of the calculated amount. The air-dried salt was analysed, with the following result : The stirring was continued for double that time, 1.4412, at 105O, lost 0,2612 H,O. 0.6032 gave 0.2017 ZnO. VOL. LXXIX. 4 x H20= 18.12.Zn = 22.00. (C3H,O,),Zn,3H,O requires H,O = 18-17 ; Zn = 21.98 per cent.1310 COEKEN AND WHITELEY : PRODUCTION OF OPTICALLY A saturated solution of zinc lactate in a 500 mm. tube gave a rota- Menthyl Mesueonate. The mesaconic acid was prepared by Fittig's method by the action of bromine on an ether-chloroform solution of citraconic acid. To prepare the mesaconyl chloride, 1O.S grams of the acid were mixed with 34.8 grams of phosphorus pentachloride, and heated on the water-bath until hydrogen chloride ceased to be evolved. The phosphorus oxy- chloride was then distilled off on the water-bath under diminished pressure, and the remainder (9.8 grams) consisted of the acid chloride. This was mixed with the theoretical quantity of menthol (18.3 grams) and heated to 130' on the oil-bath.The product was made alkaline with sodium carbonate solution and distilled in steam. The residue was extracted with ether and the ether evaporated. The product con- sisted of a thick liquid; d 17*6"/4O=0*9904; [u]E'~' -92.05". On analysis : tion of only 1'. 0.218 gave 0.5858 CO, and 0.2057 H,O. C = 73.28 ; H = 10.48. C,,H,,O, requires C = 73.89 ; H = 10.34 per cent. Menthyl Pyrotartvate. 23.6 grams of the mesaconic ester were dissolved in alcohol, and 50 grams of the aluminium-mercury couple added in small portions a t a time, a few drops of water being occasionally introduced. The operation lasted 6 weeks. The reduced product was then filtered, and further extracted from the excess of the couple and of aluminium hydr- oxide by means of hot alcohol.On evaporation of the alcohol, the liquid product,, which had d 1 1*S0/40= 0.978, and [u]:'~' - 71*6', was analysed, with the following results : 0.1830 gave 0.4910 CO, and 0.1769 H,O. C,,H,,O, requires C = 73.45 ; H = 10.88 per cent. The product was treated with the theoretical quantity of methyl alcoholic potash in the cold to effect hydrolysis, and then extracted with ether to remove the menthol. The solution of potassium pyro- tartrate was then acidified with hydrochloric acid and extracted with ether. On evaporating the ether, crystals of pyrotartaric acid separated, and had the correct melting point, namely, 112-1 13'. 7.1 grams of the menthyl pyrotartrate gave 2-37 grams of pure pyrotartaric acid. The acid was analysed, with the following results : C = 73.17 ; H = 10.82.0.1581 gave 0.263 GO, and 0.0855 H,O. 1.68 grams were dissolved in water and made up to 10 C.C. C =45*37 ; H = 6.04. C,H,O, requires C = 45.42 ; H = 6.06 per cent, TheACTIVE COMPOUNDS FROM INACTIVE SUBSTANCES. 1311 rotation in a 100 mm. tube was -5.5'. The substance was further purified by neutral ising with potash and extracting repeatedly with ether to remove any traces of menthol. 1.8 grams in 10 C.C. now gave a rotation of 4-4'. This small rotation can scarcely be regarded as undoubted proof of the formation of an optically active compound. Menthyl a-il~eth?lZcinnccn~cLte, G6H5* CH: C( CH,). CO,*C1,H, g. The a-methylcinnamic acid was prepared by the method described by Edoleano (Bey., 1887, 20, 61s). It was converted into the chloride by heating with an equal weight of phosphorus trichloride on the water-bath for an hour.The liquid was decanted from solid phos- phorus compounds and the residue rinsed out with ether, which was added t o the clear liquid; On distilling off the ether, the acid chloride solidified, and after recrystallisation from ether melted a t 48-50'. Ten grams of acid yielded 8 grams of acid chloride. An equal weight of menthol (8 grams) was added to the acid chloride and the mixture heated in the oil-bath at 120-130" for an hour. The product was made alkaline with sodium carbonate solution and distilled in steam until free menthol ceased to distil over. The residue was extracted with ether and dehydrated over calcium chloride. On removing the ether, the residue (12 grams) solidified. It WRS purified by dissolving in methyl alcohol, from which i t crystallised in large tablets melting at 50'.On analysis : 0.1568 gave 0.4567 CO, and 0,1314 H,O. C = 79.43; H= 9.38. C,,H,80, requires C = 79.92 ; H = 9.42 per cent. The rotation in a 30.48 mm. tube a t 58' was -20'44'. After various reducing reagents had been tried unsuccessfully, the aluminium- mercury couple was finally adopted, although its action is very slow. Five grams of the ester were reduced by a large excess:of the couple (40 grams) during 3 months, and 4 grams of pure crystallised menthyl a-methylhydrocinnamate melting at 37' were obtained. The purity of the product was determined by comparison with some of the pure menthyl ester prepared directly from a-methylhydrocinnamic acid, Four grams of the acid were warmed on the water-bath with 6 grams of phosphorus pentachloride, and the phosphorus oxychloride was then removed by distilling under reduced pressure from the water-bath.The residue distilled a t 160' under 30 mm. pressure. The distillate consisted of a pale yellow liquid which did not solidify. It was heated in the oil-bath at 140" with an equal weight of menthol and distilled in steam with the addition of sodium carbonate solution to remove menthol. The residue was extracted with ether and dehydrated over calcium chloride. On removing the ether, the menthyl ester solidified, 4 x 213 12 ACTlVE COMPOUNDS FROM INACTIVE SUBSTANCES. and after recrystallisation from methyl alcohol melted a t 36-38', in agreement with the above result.The menthyl ester obtained by reduction with the couple was hydrolysed with alcoholic potash in the cold as described in the other cases, and 0.75 gram of pure acid (m. p. 36-38O) dissolved in chloro- form and the rotation determined in a 200 mm. tube. The rotation was +4', which is of the same order as that observed in the other cases, and too small to be looked upon as positive evidence of optical activity. Our thanks are due to Dr. T. S. Patterson for kindlyplacing his polarimeter at our disposal. Reduction of the a-Methylcinnamic Esters. The great difference shown in the rate at which methyl and menthyl cinnamate undergo reduction on the one hand, and menthyl a-methyl- cinnamate on the other, suggested the possibility that the additional methyl group in the side-chain of the acid radicle retarded the action of the couple. In order to obtain further evidence, the methyl, ethyl, propyl, and isopropyl esters of a-methylcinnamic acid were prepared. The first three were obtained by Fischer and Speier's method, and the last by the action of isopropyl iodide on the silver salt of the acid. The specific gravitiea and melting and boiling points of them esters are as follows : Ester. d 15'/15O. M. p. B. p. - Methyl ...., .... - 3 9 O Ethyl ........... 1.049 - 155-160° (30 mm.). Propyl ......... 1.027 - 162-165 (25 mm.). isoPropyl ...... 1-026 - 155-160 (20 mm.). The method for determining the rate of reduction was to reduce 1 gram of the methyl ester and a proportionate quantity of the others in ethyl alcoholic solution with excess of the couple (1 gram) during the same period of time, to remove the alcohol, hydrolyse the product, and titrate the alkaline solution with standard permanganate, which rapidly oxidises the unsaturated acid but not the reduced compound. No difference could, however, be detected between the esters. They were all readily and completely reduced. Our thanks are due t o Mr. C. P. Finn for his help in carrying out some of these experiments on the reduction of the esters. THE YOHKSHIRE COLLEGE, LPEDS.