ARTHUR J. HILL AND ERWIN Be XELSGY* TABLE
Determination of the Ratio
--
, _ A -
5.038 5.039
5 .003 5.003 5.003 10.080 10.080 10. 006
for Fructosee.
Iff1 ;
Observed rotation.
Temperature Conc. in. g. /lo0 cc.
v.
t l a [ X = 546pp
D line.
A
-10.34 - 9.55 8.92 8.62 8.24
-
-20.89
546 p p .
1
-
0
546
7 t 546pp.
cp .a468
I . 1809
-11.27
0.8474
E * 1801
---x0.55
0.8455
I . 1828
-10.20
I. 1833
-20.51 -19.55
0.8451 0.8443 0.8482 0.8492 0.8458 0.8479 0.84.76
1. I799
1.1845 I . 1790
10.006
-19.32 -17 99 -17.39 ---*6.j7
15 .o
-27.09
-32.00
0 . 8466
I , 1812
20.0
-36.34
-42.87
0.8477
1.1797
10. 006
-21.27
Variation from mean.
[a]~"
-12.21
- 9.96 -24.63 -22 " 75
pp.
1.1775 I. 1823 *
1794
The ratios of the specific rotations using mercury and sodium lights respec~,iv~ly seem to vary with temperature at a concentration of 5 g. per roo cc. becoming slightly larger as the temperature increases, but in the case of IO g. per IOO cc. the ratio seems to be constant over the temperature range considered. If the values a t 25' for the different concentrations are considered a regular variation with concentration amounting to less than 3 parts per thousand is noticed. Hotvevvcr these variations are hardly larger than the experiniental errors and for most purposes the mean value of the ratio, namely 1.1809,or its reciprocal, 0.8q67, can be used. The average variation from the mean in the above figures i s about one part in a thousand while the extreme variation is 3 parts per NEW
YOWL,
N.
v. _-- -
_ I
[C0N*lRIBVTION S'RROM THE DEPARTMENT OF
CHEMISTRY, YALE UNWI3RSXTY. 1
VIII.' THE PREPARATION GETANILIDE. BY ARTHUR J, HILI, AND ERWIN B. KELSSP. Received M a y 24, 1920.
In order to develop certain phases of an extended research on thiocyanates and isothiocyanates, now in progress in the Sheffield Laboratory, it became necessary to obtain representatives of a series of amines of fhe general formula RNHCOCP-12NX-12, of which amino-acetanilide, ~ ~ ~ ~ ~ ~ ~ OisCtheX prototype. - I ~ N ~OurI atteulion ~ , was first turned to this latter compound, since it was evident that the principles underlying a successful method for its preparation would apply directly to the I Paper VTI, J . I d . Eng. Chcm., l a , 636 (IWO).
170.5
PREPAMTION OB AMMO-ACETANILIDES.
synthesis of its homologs or derivatives. A search revealed that, with one exception,1 the directions for its preparation were given in the patent iterature, Majert, in 1891,patented2 several processes for the preparation of amino-acetanilide and derivatives of the same. These compounds were stated by him to possess valuable therapeutic properties, since they were both antipyretic and analgesic in their action. Of these, amino~ h e n a c e t ~ nor, "phenocoll," 62R50.@6HaNX-ICOCZ-I2NNz,i t appears, has found application. Upon attempting to utilize these patents, the writers found it impossible to obtain amino-acetanilide without considerable modification of the directions. This observation also finds corroboration in the recent investigations of Dubksky and GranacherP8who experienced the same diEcukty, and were also compelled to utilize a modified procedure in order to obtain this base by the action of alcoholic ammonia upon chloroacetanilide, he methods of preparation, which are covered by Majert's patents, are indicated by the following equations. x n 4 C~H~NKCQCH2CI 2NH3 GJI5NHCOCH2NH2 NH&I In this process, alcoholic or aqueous ammonia is used and the operation caxried on a t ordinary temperature, or in an autoclave, either at 50-hoo or at 1x0'. 2.& 2CgMijNIP2 BC1.NH~CHzGOOC~Hs = CsHsNHzHCl C~H~NHCOCH&J"~ f C&I~O€I 3.' C&trjNH2 NH&H&QNR% == GeH6NHCOCH2NH2 NHa Our investigations have been confined, first, to a study of the action of alcoholic or aqueous ammonia upon chloro-acetanilide, and second, to the interaction of ethyl amino-acetate with aniline. The action of ammonia upon chloro-acetanilide was investigated as early as 1875 by as^,^ who states that in dil. alcohol ammonia functions as a metallic ~ i y ~ o x and ~ d ereacts with chloro-acetadde as follows, ~ ~ ~ ~ ~ H C QNHiOH G H ~ C ~ ~ ~ N H C -4- N&C1 Q ~ ~ ~ ~ H forming the phenylamide of glycollic acid. He assigned to this substance a melting point of 65". The anilide of glycollic acid has since been prepared by Bischoff and Walden,' and others, and neither the melting point
+
+ +
+
+
+
+
I
Dubksky and Granacher, Ber., $0, 1701
(1917).
D.K. P.,59,121;@hem. Zentr., 1892,(XI ~ $ 0wagmi. ; Tech., 37, 606
(1891); D.
R. B., 59374; W5gner Tech., 37, 608 (18gr). L O C . 6d.
27. K . Y.,59.ran. Ibid., 59,874. E&. sac. chim., 22, 3 (1874). Bischoff and Walden, Ann., 279, 49 (1894); Norton and %be*nidk, Bull. c/ti:i~., 30, 104 (1878).
SOL.
1706
ARTHUR J. HILL AND GRWIN 13. TG&SEY.
of their product (96-97°)1 nor its physical properties, agree with that of the compouiid prepared by Tommasi. Meyer l heated c'alora-acetanilide. as well as chloro-acetoiuide, under pressure with an excess of alcoholic ammonia at TOO'. The product in each ca5e was the secondary and not the primary base, i . e., zCsWbNHCoCH2GI JNP41 = ( ~ ~ ~ ~ N 4~ 2Nk1.4CI C ~ C W ~ ) ~ ~ ~ ~ ~ -t- JNM7 ~ = ( C ~ ~ ) ~ (q;)8H*(CI93)NHCOCH2)zNH4- 2NM*CI Theoretically, 3 products should be formed by the action OS a k o h o l i ~ or aqueous ammonia upon chloro-acetaidide, namely, ( I ) amino-aeetanilide, C&IsNHJCOCI42NJ&; (2) d ~ - ( ~ ~ ~ e ~ i yc d~ da ~ gi d~ ey )c o ~ -acid. ar~~d~~ ;NEICBCH2)2NII ; and (3) tri-(phenylamide) of triglycol-amidic acid, COCE-f&N. Majert states in %e German pata-iit No. 59 I i: I that r 2 may be formed in this reaction, the iormei by the action of a large excess of alcoholic ammonia upon e oro-acefa@&Iide,and the latter, when the theoretical amount of ainmorria is employed. The miters have investigated this reaction and have Seen able t o obtain exceltent yields of a ~ ~ ~ o - ~ cthrough e t ~ ~changes ~ ~ ~cfd conditions e and manipulative procedures. We have fotm d moreover, that even under the conditioxls productive oE the maximum yields of amin o-acetanilide, R c ~ ~ ~ p a r a large t ~ v amoui:i e ~ ~ ~f the secondary base i s formed, together w i t h a snraall amount of the tertiary bdse, a co~~ipound not hitherto described. Our method differs essentially from that- of Duhksky and Grmacher's in that the use of an autoclave is obviatd, since the reaction is carried out entirely a t room temperatures. 'The procedure for the isolation of the pure base also differs quite materially in detaill, and is imch simpler. Our yield, however, is but slighi!y beiter, namely ~ 4 7as~ compared ) to 68%. The various details of our process are described below in thc ex~ ~ r ~ ~park e noft the a ~paper.
+
~X~~~~~~~~~~
Part.
~ ~ ~ ~ large o 5-gallon ~ i stoppered ~ ~ - bottle - ~was used for this experiment. Five hundred and fifty 8. of cUoro-aeeianilide was added to I T kg. oi 95% alcohol, previously saturated with ammonia gas at 10' This solration was allowed to stand a i a temperature ai 20' for 5 clay.;. It was then evsporaled under diminished pressure to 4 of i t s original volume. At this concentration a sinall amount of material sepa~ated from the a!cohol. This concentrated so!ution was poured into 3500 cc. of waier, when a~ oil separated, which soon solidif'ed. This product, rhe secondary amine, was filtered, w~shedwith water and then purified a $ 1
Mevcr, Bet 8, 1 1 5 2 1875)
described belaw. %he aqueous filtrate was evaporated iiearly to dryness in order to decompose the amnionium chloride. The non-volatile amino -acetanilide is suficicierrtly basic to liberate ammonia from its salts. 'k'he residual material was then. dissolved in 2 parts of hot waters1 and the restdting s o l ~ t i o ndecolorized with the vegetable. carbon, "Norite. '' After the solution bad been cooled in an ice bath it was saturated with ammonia gas. Ira a short time amino-acetanilide crystaltllized either in long silky needles or in stout colorless transparat needles, depending on the rate of crystallization. This product was the hydrated base containing 2 molecules of water of ci-ystallizaeion. ajert states in his patent that the hydrated base contains K . s ilroieclrles water of crystahation. Our observation is confirmed by Z>ub&slrpand Gracacher . Water determination by drying at ion". Calc. Eor CGH"COCH? %.aFT#J:IP20, 1'),35. B'oe;~d: (1) 19.34, (XI) 1 9 . ~ 2 , Nitrogen determination (Kjelckahl methcd). Cdc. for CsHs~:RCOCMa~THe.zE-Iz0:P;, 15.05. Found: (I) 14.80; (11) 14.95.
Thc kydrate was crystallized from gsy& alcohol. A yield of 424 g. was obt:tined, CGrreS~QndiiIgto 70%. This hydrate may be crystallized fmm .;l;ater. I-t is a colorless campcund, soPdde in water and alcohol, a d i ~ s ~ l u bin l e benzene or in ethereP-.It melts at 62'. The anhydrorzs base may 5e prepa.rid by allowing the hydrated base to stand over sulfuric acid i: a vacwmn desiccator for several days. It is a ong!y basic compourad wliich colors litmus and will absorb carbon dioxide from t i l e air. Hot. acpeotrs solutions displace ammonia from its salts. i t is col~i-kss.~.;.heii freshly prepared, but becomes yellow on long standizg. It has 1-20well defined nie1"cn.g point. The hydrochloride of the base is a colorless compound, soluble in water and in alcohol, but insoluiile in eti;zr and in benzene. It crystallizes from water or a?eol:ol in thick &ransparent. plates, which melt between rgo-.~gg'. The melting point is not well de611ed. Nitrogen determination (MjeldahZ method). 1: N , 15.02. PQl.Ind: 14.
~(~~~~~~~~~~~~ caf ID (CsH~NHGOGE%2)2NH.-'~~e solid which was obkained when the partially evaporated alcoholic liquor was poured into water, was easily purified by crystallizatiop, from 95$< alcohol. Seventy-eight g. of the di-pbenyianid;, of diglycof-am.idk acid was obtained. This secondary base is in-, soluble in water, but erystdlizes from alcohol in colorless needles melting 1-4slight rnodiiication of this procedure was also used successfully. The residue The hydrochloride of the hsse crystal-
was dissolved in warm alcohol instead of water.
lized koni the former npon coo!ir,g. The free base mas obtained by dissolving the . hydxochloride in 2 volumes of water arid then saturating the sol~tionwith waseous a ninionia . -?
J.06. G i l .
ARTHTJR J. €III,I, AND ERWIN Ei. KELSEY.
at 141'. If a concentrated alcoholic solution is saturated with hydrogen chloride the hydrochloride is precipitated in white plates. It may be purified by crystallization from warm water or alcohol. It crystallizes from the latter solvent in thin colorless plates melting a t 235237 with effervescence. Nitrogen determination (Kjeldahl method). Calc. for GI&~O~N~.HCI: N, 13-14. Pound:
13.10,
13.28.
ertiary Base. The Tri- (phenylamide) of Triglycol-amidic Acid, (GsNaNHCOCH~)3N.-This base is formed in small quantities only. In fact, oftentimes it is not possible to identify it in a run. It appears a9 an insoluble body when the crude secondary base is dissolved in alcohol. It is insoluble in the common solvents, alcohol, ether, benzene and water, but crystallizes readily from glacial acetic acid in small plates melting a.t 238-239 ', with slight decomposition. A molecular weight det,ermination by the ebullioscopic method, with glacial acetic acid as the solvent, gave a value of 395. The calculated value is 416. Nitrogen determination (Kjeldahl method). Calc. for G4HZ(OSN~: N,13.46. Found: 13.48, 13.40.
The results of 2 of our larger scale experiments are summarized in Table I. An innovation was introduced in E:xpt. 2 in that the reaction mixture was saturated every other day with ammonia, in order to maintain the concentration of the base. Moreover, the initial amount of the alcoholic solution was reduced to 13 parts by weight instead of 20. In this experiment the yield was slightly better than the first, but, on the other hand, the ratio of primary to secondary amine was not as good. Subsequent observations have lead us to believe that this occasional saturalion with ammonia is of doubtful advantage and that, in general, the conditions set forth in the first experiment are to be preferred. So far we have been unable to obtain a yield better than 74y0of the theoretical. T~em Z.--]Cmas SCALEEXPERIMENTS. Chloroacetanilide. G.
Expt.
E............ 550 2
..... . .. . O
.
,
700
Alcoho!ic ammonia. Kg. I1
9.
Time. Days.
5 IO
Anhyd. primary amine. G.
340 463
Secondary amine.
G. 78
1: 15
Ratio primary to secondary amine.
4.4:1 4.o:x
The procedure described above for the preparation of amino-acetanilide and the isolation of the secondary and tertiary bases, was the result of a series of experiments carried out with 25 g. units of chloro-acetanilide. It is hardly necessary to describe all of these in detail. Suffice it to say that the major difficulty was in evolving an efficient procedure for the isolation of the products of this reaction in a state of purity. When this had been accomplished, the factors of time, concentration, etc., were easily esbdblished. Some of the more important experiments will be discussed.
Table I1 records the experiments which were made in order to fix a suitable time period of reaction, as well as the optimum concentration of ammonia. TABLE II.--Trha& 25
PERIODS. Each Experiment.
g. of Chloro-acetanilide Used in Aleoholjc
Expt.
.................... ................. s . . . . . ................
3.
