OPTICAL ACTIVITY OF MALAMIDE. 1859 CLXXX.- The InJEuerLcc of various Xubstituents on the Optical Activity o f Malarnide. By PERCY FARADAY FRANKLAND and EDWARD DONE, M.Sc. THE results recorded in this paper form part of a systematic investigation which is being made by one of us on the rotation of the amides of optically active acids, in connexion with which papers have already appeared on some substitution derivatives of glyceramide (P. Frankland, Wharton, and H. Aston, Trans., 1901, 79, 266), and of tartramide (P. Frankland and Slator, Trans., 1903,83,1349 ; Ormerod, Trans., 1903, 83, 1342 ; and Twiss, preceding paper). The present communication deals with the methylamide, ethylamide, normal- and bo-propylanaide, allylamide, normal- and iso-butylamide, and normal heptylamide of ordinary I-malic acid, as well as with the piperidide, and phenylhydrazide of the same acid, Of these derivatives, only the m-propylamide has been previously prepared (McCrae, Trans., 1903, 83, 1324), whilst the anilide and the three toluidides have been described by Guye and Babel (Arch.Xc". phya. nat., 1899 [iv], 7, 23), and by Walden (Zeit. physiknl. Chern., 1895, 17, 264). The alkylamides were all prepared by the interaction of the amine with diethylmalate, either alone or in alcoholic solution, and either in the cold or at a temperature not exceeding 100'. The yields were in most cases, and especially in the case of the higher amines in which no alcohol was used, very satisfactory. As in the corresponding1860 FRANKLAND AND DONE: THE INFLUENCE OF VARIOUS derivatives of tartramide, the poorest yield was obtained in the case of the isopropylamide.The piperidide was prepared by the prolonged heating of diethyl- malate with piperidine at 130", whilst the phenylhydrazide was prepared, on the one hand by Bulow's method, in which malic acid and phenylhydrazine are heated together at 120-1 40°, and, on the other, by Fischer and Passmore's method, in which an aqueous solution of malic acid is heated on the water-bath with a solution of phenylhydrazine in acetic acid. The products obtained by each of these methods had substantially the same rotation, showing that no racemisation occurs at the higher temperature to which the mixture is heated in the case of Biilow's method. The rotation was in all cases, excepting that of the phenylhydrazide, determined in pyridine, in methyl alcohol, and in glacial acetic acid solution.The rotation of the phenylhydrazide was determined in pyridine and in glacial acetic acid only, in consequence of its insolubility in methyl alcohol. The results of the polarimetric determinations are summarised in the following table :- Glacial Pyridine. Methyl alcohol. acetic acid. Melting * point." p. [MI?. p. Maldi-amide * . . . . . . . . . 157" c= 1.998 - 76.2" - ,, rnethylamide ... 99 4'634 89.6 6.250 10'080 90.0 9.982 ,, ethylamidc ...... 122 4.319 90.6 4.984 10.250 89.1 9.177 ,, n-propylamide . 126 4,530 90.5 5.020 7'896 88.8 11.340 ,, ivopropylamide. 150-151 2'548 69.1 3.803 3.986 69-0 6.039 ,, allylamide ...... 117.5 4.639 72.7 4.804 10-390 74'0 9.095 ,, n-butylamide ...125 3.776 87-1 5.633 10-850 86'3 10.540 ,, isobutylamide.. 121 5.394 86.9 5.316 7.984 89'4 9'128 ,, n-heptylamide.. 131 5.166 88.6 6'001 ,, benzylamide*.. 155.5 c=4*855 101.1 - ,, piperidide ...... 157.5 0'5981 55.2 4.975 ,, phenylhydrazide 214 5'119 54.1 - - - - 11'010 88.8 - - 8.845 - 7'175 55.0 - [bI]r. p. [M]zoo. - c=4'678 - 59.7" 107.9 8'185 117.2 110.3 4.170 116.0 111.8 7.995 117.2 114.3 4-278 115.4 114.7 5.040 114-8 - 9'048 112.8 92.0 3.710 92'1 90.3 6-284 92.5 1025 4.492 86.9 103.3 10.780 87.4 116'5 5.455 106.4 112.0 9.718 104.9 117.4 5.492 106.2 118.4 7.563 105.3 116.1 4'497 103.2 - 9.334 102.3 - e=4*654 63'0 73-7 3.575 +38'5 73.6 6.531 4-40-5 -109.6" 4'267 120.9 - 0.735 - 129'8 - - - * McCrae (Zoc. cit.). In the case of the n-propylamide prepared by McCrae, our results corroborate those obtained by this author with pyridine solution, but our values, given in this table, for the glacial acetic acid solution of thc n-propylamide are substantially higher than his, [M]igo - 101'3", c=4'798.The temperatures a t which McCrae's determinations were made were 20" for maldiamide in glacial acetic acid, 17" in yyridilie ; 22" for the dibenzylamide in glacial acetic acid, and 15" in pyridine solution.SUBSTITUENTS ON THE OPTICAL ACTIVITY OF MALAMIDE. 1861 From the above table it will be seen how greatly the rotation is influenced by the solvent, Thus the alkylamides have a lower lsvo- rotation in pyridine than in methyl alcohol or glacial acetic acid; on the other hand, the benzylamide and the aromatic amides have a higher lsvorotation in pyridine than in glacial acetic acid solution.Again, whilst in the normal series of alkylamides in pyridine solution the laevorotation is almost unaffected in passing from the methylamide to the n-heptylamide, in methyl alcohol there is a slight rise, and in glacial acetic acid solution a distinct decline in the molecular rotation. The derivatives of malamide in this respect exhibit much less regularity than those of tartramide (compare Frankland and Twiss), for in the latter series there is a continuous rise in the molecular rotation from the methyl to the heptyl term in the normal series in pyridine, and probably also in methyl alcohol and in water solution. In both the malic and the tartaric series the rotation of the normal- is greater than that of the iso-propylamide, whilst the relative magni- tudes of the rotation of the normal- and iso-butylamides in both series is dependent on the solvents, but in pyridine solution the isobutylamide, both malic and tartaric, has a higher rotation than the normal butyl- amide.I n both the malic and the tartaric series, the allylamide has a markedly lower molecular rotation, in all solvents, than the normal propylamide, thus showing that the presence of a double bond has not the invariable effect of increasing the optical activity as is often supposed. Malic benzylamide, in pyridine solution, has a higher molecular rotation than the n-heptylamide in the same solvent, whilst in glacial acetic acid the relations are reversed. On the other hand, in pyridine solution, the molecular rotation of tartaric benzylamide is slightly inferior to that of the n-heptylamide. The tartaric piperidide in pyridine solution is practically inactive, and therefore enormously less active than the n-heptylamide ; simi- larly, the malic piperidide, in pyridine and in the methyl alcohol, is much less active than the n-heptylamide, although still strongly lsvo- rotatory; in glacial acetic acid the difference is greatly further em- phasised inasmuch as the piperidide is strongly dextrorotatory.The phenylhjdrazide, again, in both malic and tartaric series, has in pyridine solution a much lower molecular rotation than the n-heptyl- amide, but in glacial acetic acid solution malic diphenylhydrazide has a higher rotation than the heptylamide.We have also found that the rotation of tartaric diphenylhydrazide is much greater in glacial acetic acid than in pyridine solution (see Frankland and Twiss). I n both malic and tartaric series, again, the aromatic amides have a much higher molecular rotation than the alkylamides.1862 FRANKLAND AND DONE: THE INFLUENCE OF VARIOUS EX P E R I M E N T A L. Ma ldirnethy Zamide. Twelve grams of diethyl malate and 21 grams of absolute alcohol were placed in a tall cylindrical bottle immersed in ice. Methylamine was liberated from Kahlbaum's 33 per cent. aqueous solution by heat, passed through a lime drying-tube, and then into the above mixture. When 6 grams of methylamine had been thus passed in, the bottle was stoppered and allowed to stand for three days.On evaporating the alcohol a yield of 50 per cent. was obtained. The methylamide is very soluble in hot or cold water, methyl alcohol, glacial acetic acid, methylated spirit, ethyl acetate, or pyridine, sparingly so in chloroform, benzene, or ether, and insoluble in carbon disulphide or light petroleum. From acetone it was obtained in acicular prisms and plates melting at 99'. 0.1047 gave 15.4 C.C. moist nitrogen at 11' and 762 mm. N = 17.60. C,H,,O,N, requires N = 17.50 per cent. Rotation of Maldimethylamide. P* cl 20"/4". I?. sip. [Wy- Pyridine 8ohthn. 4.634 0.987 1.9984 - 5'12" - 56.01" - 89.6" 10.080 1-001 1.9984 11 *35 56-27 90'0 Met]$ Alcohol XoZution. 6.250 0.8143 1.9984 - 6.97" - 68.50" - 109.6" 9 -982 0.8280 1'9984 11.14 67-42 107.9 Glacial Acetic Acid Solution.4.267 1.060 1.9984 - 6 . w - 75-54" - 120'9" 8.185 1.070 1.9984 12-83 73'26 117.2 Haldiethy Zamide. Seven grams of ethylamine (Kahlbaum) in the form of vapour were passed into a mixture of 11 grams of diethyl malate and 13 grams of absolute alcohol cooled with a freezing mixture. On standing for some days in a stoppered bottle, the whole set into a solid mass of fine white, silky needles. The ethylamide is very soluble in hot or cold water, methylated spirit, chloroform, pyridine, methyl alcohol, ethyl acetate, light petroleum, or Yield 90 per cent.SUBSTITUENTS ON THE OPTICAL ACTIVITY OF MALAMIDE. 1863 carbon disulphide. plates and needles melting at 122'. From benzene it was obtained as white, shining 0,1067 gave 14.0 C.C. moist nitrogen at 1 2 O and 735-1 mm.N = 15.05. C,H,,O,N, requires N = 14.89 per cent. Rotation of Ma Zdieth y lawaide. P. d 20"/4". 1. a20 D * [a]2,0'. Pyyidine Solutioia. 4.31 9 0.9854 1.9984 - 4.10" - 48.19" 10-250 0.9947 19984 9'66 47 *41 Methyl AZcoltol Solution. 4.984 0.8054 1-9984 - 4'71" - 58-69" 9.177 0-8185 1.9984 8-93 59.47 Glacial Acetic Acid Xolution. 4.170 1.056 1.9984 - 5.43" - 61.70" 7.995 1.060 1.9984 10.56 62-34 [MI?. - 90.6" 89'1 - 110'3' 111'8 - 116*0" 117-2 Maldi-n-propylarnide. Twelve grams of diethylmalate were added to 8 grams of n-propyl- amine (Kahlbaum), heat being evolved on mixing. On standing over- night the mixture had become almost solid. Yield 75 per cent. I n order to obtain a theoretical yield, it is necessary to allow the mixture t o stand for several days, or to heat on a warm water-bath for some hours.The propylamide (m. p. 126') is very soluble in water, benzene, alcohol, ethyl acetate, chloroform, pyridine, methyl alcohol, or glacial acetic acid, but insoluble in light petroleum or ether. It was purified by crystallisation from a mixture of benzene and light petroleum. Rotation of Baldi-n-propyhmide. 2). d 20"/4". 1. a","". [a]?. [ M]2,0". Pyridine Solution. 4.530 0.9833 1'9984 - 3.73" - 41.90" - 90.5" 7.896 0.9895 1.9984 6'42 41'11 88.8 Methyl AZcohol Solution. 11.340 093260 1.9984 9'94 53.10 114.7 5-020 0.8061 1'9984 - 4 '28" - 52-91" - 114.3" Gluciul Acetic Acid Solution. 5.040 1.052 1'9984 5.63 53'14 114.8 4.278 1.053 1.9984 - 4 . w - 53'430 - 115.4" 9.048 1.055 1.9984 9.96 52-20 112'81864 FRANKLAND AND DONE: THE INFLUENCE OF VARIOUS MccldiisopropyZamide.10.7 grams of diethylmalate were added to a solution of 5.8 grams of isopropylamine (Kahlbaum) in 8.4 grams of absolute alcohol, but the reaction takes place so slowly in the cold that even after five weeks only a small quantity of the amide bad crystallised out. The mixture was therefore heated in a stoppered bottle in a steam oven for six days. The yield was only 20 per cent. The substance is very soluble in hot water, alcohol, ether, acetic acid, pyridine, methyl alcohol, benzene, ethyl acetate, or acetone, but crystallises from each of these solutions on cooling. It is insoluble in light petroleum, and only very slightly soluble in carbon disulphide. It crystallises from acetone in long, slender needles melting a t 150-1 5 lo.0.1355 gave 15.7 C.C. moist nitrogen a t 15O and 738.4 mm. N= 13.17. CloH2008N2 requires N = 12.96 per cent. Rotation, of Ma ldiisopopykamide. P. d 20"/4". 1. UIp". [a]:O'. [ Pyridine Solution. 3'986 0.9828 0.999 1'25 31'93 69 '0 Aiethyl Alcohol Xolution. 6-039 0.8091 0'999 2-04 41'79 90.3 Glacial Acetic Acid Solution. 2.548 0.9813 1 *998P - 1'80" - 32.01" - 69.1" 3.803 0.8035 i w a 4 - 2-60" - 42.57" - 92.0" 3.710 1.050 0'999 - 1-66' - 42'65" - 92.1" 6-284 1 *056 0.999 2'84 42'83 92-5 Mu ldially lccmide. 11.1 grams of diethylmalate were mixed with 6.4 grams of allylamine (Kahlbaum) and 8.4 grams of absolute alcohol. Heat was developed on mixing, and, after standing for two days, a nucleus was obtained by placing a little of the mixture in a vacuum desiccator.On adding this nucleus t o the remainder, and allowing to stand for a few days longer, a crop of pure white needles separated out from which the alcohol was evaporated. The allylamide is very soluble in hot or cold water, methyl alcohol, methylated spirit, ethyl acetate, chloro- form, glacial acetic acid, or benzene. It is almost insoluble in light petroleum. From a mixture of benzene and light petroleum it was obtained in needles melting a t 11 7-54 Yield 90 per cent. 0.1438 gave 16.3 C.C. moist nitrogenat 12' and '752.8 mm. N = 13.32. C,,H,,03N, requires N = 13.21 per cent.SUBSTITUENTS ON THE OPTICAL ACTIVITY OF MALAMlDE. 1865 Rotation of Muldiallylamide. 2). d 20"/4". 1. a:p. [a]z,o'. [MI::. Pyridine Xolution.4.639 0.9837 1.9984 - 3.13" - 34.31" - 72 9" 10-390 0.9936 1.9984 7-20 34.89 74.0 MethpZ AZcohol Solution. 4.804 0.8056 1.9984 - 3'74" - 48-35" - 102.5" 9.095 o c m 4 1-9984 7'24 48.72 103-3 Glacial Acetic Acid Solution. 10.780 1.064 1'9984 9.45 41'22 87'4 4.492 1.060 1'9984 - 3.90" - 40.99" - 86.9" Maldi-n-but y lamide. 10.2 grams of diethyl malate were mixed with 7.8 grams of normal butylamine (Kahlbaum). Heat was developed on mixing, and, after standing overnight the whole had set solid. The mixture was allowed to stand for a few days longer. The n-butylamide is very soluble in alcohol, ethyl acetate, benzene, or chloroform, insoluble in light petroleum or cold water, but soluble in hot water. It was obtained from dilute alcohol in shining, silver- white plates melting a t 125O.Yield 100 per cent. 0,2278 gave 22.8 C.C. moist nitrogen at 12' and 746.7 mm. N = 11-67. C,,H,,O,N, requires N = 11 *48 per cent. Rotation of Maldi-n-butylamide. P. d 20"/4". I?. aiW. bly. [M]2,0". Pyridina Solution. 10'850 0.9860 1'9984 7'56 35'35 86.3 3,776 o m 0 4 1-9984 - 2.64" - 35-68" - 87.1" Methyl Alcohol Solution. 5'633 0.8037 1.99811 - 4.32" - 47 '74" - 116.5" 10540 0.8160 1'9984 7%9 4 5' 90 112.0 Glacial Acetic Acid Solution. 9-718 1 '052 1'9984 8 -79 43'01 104.9 5 *455 1-052 1-9984 - 5.00" - 43-59" - 106.4"1866 FRANKT~AND ANT) DONE: THE INFLUENCE OF VARIOUS Alaldiisobzltylninide. Ten grams of ethyl malate were added to 10 grams of isobutylamine (Kahlbaum), a little heat being evolved on mixing. After standing for a day and then warming on a water-bath for two hours, the mixture became solid, and a theoretical yield was obtained.The pro- duct is very soluble in hot water, ethyl or methyl alcohols, acetone, ethyl acetate, benzene, chloroform, ether, glacial acetic acid, or pyridine. It was crystallised from R mixture of benzene and light petroleum. Melting point 121'. 0.1456 gave 14.5 C.C. moist nitrogen at 14-5' and 755.8 mm. N = 11.63. C1,H2,0,N, requires N = 11.48 per cent. Rotation of Maldiisobut y lumide. P. d 20"/4". 1. a',". [a]?. [M12,0". Pyridine Solution. 5'394 0.9813 1.9984 - 3.77" - 35.63' - 86.9" 7.9134 0-9a37 1 w a 4 5.75 36'64 89.4 Methyl Alcohol Solution. 5.316 o.ao39 1.9984 - 4.11" - 48.11" - 117'4" 9.128 0.8153 ~"XM 7.22 48-53 118.4 Glaciul Acetic Acid Solution.7 5 6 3 1.051 1 -9984 6-87 43-25 105.3 5'492 1'051 1.9984 - 5-02" - 43.51" - 106.2" MaJdi-n-hptylumide. Sixteen grams of It-heptylamine (Kahlbaum) were added to 10 grams of diethyl malate, the mixture being accompanied by heat evolution. On standing overnight the whole had set to a solid mass. Yield 100 per cent. The n-heptylamide is very soluble in hot alcohol, chloroform, pyridine, glacial acetic acid, or methyl alcohol, readily so in hot benzene or ethyl acetate. It is sparingly soluble in carbon disulphide, acetone, ether, or hot water. From methylated spirit it was obtained in beautiful white, shining plates melting at 1 30*5-131°. 0.2083 gave 15.6 C.C. moist nitrogen a t 12.5' and 746.5 mm. N = 8.71. CI8Hs6O,N2 requires N = 8.54 per cent.SUHSTITUEKTS ON THE OPTICAL ACTIVITY OF MALAMIDE 1867 Rotation of ~~alcli-n-heiutylamicle. P.c.? 20"/4". 1. aton. [a]ioo. [qO Yyridine Xolut ion. 11'010 0.9804 1.9984 5.84 27'08 88.8 Methyl AZcohoE 8olution. A 10 per cent. solution crystallised. Glacial Acetic Acid Solution. 9.334 1'053 1.9984 6-13 31 *20 102.3 5.166 0'9792 1'9984 - 2-73" - 27.01" - 88%" 6.001 0.8035 1-9984 - 3.41" - 35.38' - 116'1" 4'497 1.050 1.9984 - 2.97" - 31'47" - 103.2" Ma Zdipiperidide. Twelve grams of piperidine (Kahlbaum) were added to 10 grams of diethyl malate, and, although heat was evolved on mixing, only a 20 per cent. yield was obtained, even after keeping the mixture at 130° in an oil-bath for three days. A 50 per cent. yield was obtained by heating a similar mixture t o the same temperature for ten days.The progress of the reaction is indicated by the contents of the flask becoming more and more solid on cooling. An attempt to prepare the piperidide by heating piperidine and malic acid together for several days proved unsuccessful. The piperidide is very soluble in methylated spirit, but sparingly so in water, benzene, ethyl acetate, or pyridine. From a mixture of alcohol and acetone it was obtained in flat plate8 melting at 157.5O. 0.126 gave 11.2 C.C. moist nitrogen at 13' and 749.5 mm. N = 10.35. C,,H,,0,N2 requires N = 10.45 per cent, Rotation of illaldipiperidide. Y. i2 2Q0/4'. 1. a',"". [a]?. [ M y . Pyridine Solution. 0-5981 o w 9 4 3.899 - 0.47" - 20.58" - 65'2' Methyl Alcohol Solution. 8.845 o m o o 0-999 1.99 27'47 73'6 Glacial Acetic Acid Solution.3 a575 1.061 1.9984 + 1 *09" + 14-37" + 38'50 6.531 1.067 0.999 1 -05 16 -08 40 -5 4*975 0.8078 1.9984 - 2'21" - 27.41" - 7367" VOL. LXXXIX. 6~1868 OPTICAL ACTIVITY OF MA1,AhlI DE. This compound was prepared, firstly, by Bulow’s method (Annalen, 1886, 236, 194), which involves the use of a high temperature ( 120-140°), and secondly, by Fischer and Passmore’s method (Ber., 1889, 22, 2734), in which the reaction is carried out on the water-bath. As mill be seen below, however, the products obtained by both methods were of substantially the same rotatory power, thus showing that the higher temperature does not lead to any racemisation. Bulow’s Method.-T wenty-eight grams of phenyl hydrazine (Kahlbaum) were added to 20 grams of finely powdered malic acid ; the mixture which solidified with evolution of much heat mas further heated to 120-140O for eight hours until no more steam was evolved.The heating must be begun with caution as there is a sudden evolution of a large amount of steam. The resulting mass, which was of a light brown colour, was first well washed with dilute acetic acid, and then with a solution of ammonium carbonate. The yield was 55 per cent. The substance is almost insoluble in water, methyl alcohol, or light petroleum, sparingly soluble in methylated spirit, and only slightly so in acetone, chloroform, carbon disulphide, ethyl acetate, ether, glacial acetic acid, or pyridine. It was obtained from alcohol in white shining plates melting at 214O with slight decomposition. 0.1232 gave 18.4 C.C. moist nitrogen at ll’and 764.2 mm. N = 17.91. C,,H,,O,N, requires N = 17.83 per cent. Fischer and Passmore’s Method.-Twenty grams of dried malic acid were dissolved in 180 grams of water, and to this were added a solution of 22 grams of glacial acetic acid in 22 grams of water with 40 grams of phenylhydrazine, the whole being then heated on the water-bath in a flask provided with an air-condenser. The reaction took place suddenly after heating for 4 hours, much of the liquid being violently projected into the condenser. The light brown produd was washed successively with water, dilute acetic acid, and ammonium carbonate solution. The product had to be crystallised three times from glacial acetic acid before being obtained in a state of chemical and optical purity. Melting point 214’. The yield was only 20 per cent.THE ACTION OF POTASSIUM CPANIDE ON PULEGONE. 1869 Rotation of ,~~ldip~en~~l~ycE./.azide. p . ti 20"/4". 1. D . [a]r. [MI:, Pyridine Solution. Prepration by 0,9929 1-9984 - 1-75' - 17-22" - 54.1" Ifiilow's method. { !:;:! 0.9987 1.9984 2.51 17.53 55.0 6-390 0.9960 1.9984 2.17 17'06 53-6 Preparation by 4'809 0'9914 1.9984 - 1-65" - 17-28" -54.3" Glacial Acetic Acid Solution. P. d 20°/4". 1. a~o'. [ a l y . [ M]zoo. CHEMICAL DEPARTMENT, 0.7350 1.054 0.999 - 0.32" - 41 '35" - 129'8" UNIVERSITY OF BIRMINGHAM.