ACETANILIDE I N HEADACHE POWDERS
1091
TABLE 111. SOLCBILITY OF ACETAXILIDE, PHENACETINE, CAFFEINE A N D SALOL I N ORGANIC SOLVESTS. Solvent.
sp. gl.. of solvent. t')
Grains per
IOO
grams saturated solution :
_ A
Acelanilide.
Phenacetine.
Caffeine.
Salol.
0.56 0.11 2.14 insoluble 7.7 1.56 0.27 11.0 16.6 4.76 2.18 (0.E32) 90.99 31.75 (0.902) 10.68 1.22 ( 0 . S 7 j ) 8S.jj (1.145) 2.46 (0.S75) 0.65 (0.573) C' ? I.0jj 18.83 (1.06s) 5.44 (1.063) 11.62 (1.087) 0.S60 10.46 (o.SS2) 2.42 (0.865) 0.72 (0.862) S5.29 (1.136) 1.02 19.38 (1.034) 9.46 (r.025) 22.89 (1.080) very soluble 0 SI4 0.49 (0.810) 20.44 (0.569) 25 14.00 3.5r (0.519) 1.055 21. j 33.21 13.65 (1.064) 2.44 63.24 (1.143) 0.547 32.5 1.6j (0.847) 1.25 (0.847) 1.11 (0.S47) s7.14Toluene 0.S62 25.0 0.jo ( 0 . S 6 2 ) 0.30 (0.863) o 57 (0.861) 83.62 (1.12s) Figures i n parentheses are the specific gravities of the saturated solutions.
'Water 'Ether 'Chloroform Acetone Benzene Benzaldehyde Amylacetate Aniline Aniylalcohol Acetic acidY Xylene
0.997 25 0.716 '' 1.476 0.527 30-3I 0.S 7 2
Fairly good results have been obtained by t h e author in separating mixtures of different amounts of salol, caffeine, and acetanilide by digesting first in toluene for t h e removal of salol and then in amyl alcohol for t h e removal of the acetanilide. As is shown by t h e table, none of the four compounds are completely insoluble in any of the solvents, and consequently it cannot be expected t h a t a very sharp separation can be made. T h i s is especially true for mixtures containing relatively small amounts of either of the substances. I t is also to be mentioned that t h e influence of the presence of one substance upcn t h e solubility of the others in the mixture has not been investigated and therefore conclusions based upon t h e solubility of single substances in a given solvent may be considerably in error when applied to mixtures of two or more substances acted upon by t h e same solvent. T h e author regrets t h a t circumstances have prevented the extension of these determinations to a larger number of solvents and t h e application of t h e results to a more accurate method of separating and determining the constituents of headache powders. [CONTRIBUTION FROM THE DRUGLABORATORY, BVREAUOF CHEMISTRY, LISHED BY PERMISSION O F THE SECRETARY O F AGRICULTURE].
PUB-
A RAPID METHOD FOR THE QUANTITATIVE DETERMINATION OF ACETANILIDE IN HEADACHE POWDERS. BY ATHERTON S E I D E L L .
Received May
2. 1902.
\\.'bile continuing the investigations described in the previous paper a suggestion was obtained which has led to the following method for deterResults from U. 99.5 %
s. P., 8th Revision.
ATHERTON SEIDELL
1092
mining acetanilide in presence of man!. of tlie substaiiccs usuall!, associateil \\-it11 it in the headache and neuralgia rcniedies ioiind oii the iiiarkrt. In stutl!.ing the distribution of phenol am1 of aniline i)ct\veen \vatcar a11 1 x i e r a 1 iniiiiiscilile solvents T-aubel' :uid subsecluentl!- Kiede12 titrated the 1)lic1i~ilor aniline as tlie case might he \\.ith a staiidartl solution of potas+iiiiil hroiiiate antl found that very satisfactor!. dewrniiiiatioiis cotli(! i)c niacle. ?'lie method is based upon tile \vel1 1;iion.n property oi phenol awl of aniline to unite \vith Iiroiniiic iii a strongl!- acid acluvous solution t o for11i tlic iiisolulile tri-lm)tiiide in eacli case. \\.lien tlie precipitatioii is coniplcte tlie free bromine in solution is easi]!- tlctectetl 11:. the !eilo;v color ivliicli i t imparts to tlie liquid. A niethorl based upon this same reaction is given for carholic acid in the 1890 1;.S.l'harniacopteia, page I O . -ICcortling to this method, ho\vever, tlie excess of added bromate solution ( I first 1)oilctl se\.e:.al line 01minutes in a moderatel!, coilcentrated solutioi? of Ii!drochloric aci'l c ;iJ the hot solution titrated. T h e bromate solution is diluted so t h a t each cubic centimeter corresponds to 0.01grain of acetanilide ; this being a convenient strength t o use ; although a more dilute standard solution ma!- he used if desired. Experiments niade for the purpose of ascertaining the limits of strength of acid and time of heating necessary for complete sapoilification of acetanilide showed that the acid soluticn should contain not less than approsimately I part of concentrated hydrochloric acid to 4 parts of Ivater and the heating should he continued for at least an hour on the steam bath or the solution boiled energetically for fi\-e minutes. Tn these 2
J. pr. Clieni., ( 2 ) 67, 476, (1903). 2 . physik. Chetri., 5 6 , 233, (1906).
ACETANILIDE I N HE.IDACHE POWDERS
1093
exflerinients half grani samples of acetanilide and approximately Go cc. of tlie acid solution were used, and the mixtures heated in 200 cc. Erleiinieyer flasks. In regard to the accuracy which may be attained it was found that lvith half grani samples of acetanilide, the amounts recovered as calculated from the cc. of standard bromate used agree in practically all cases to within one per cent. of the weight of acetanilide taken. T h e n e s t point investigated \\-as the effect upon the reaction of other substances in solution. ,Among the first of these considered was caffeine I t \vas found that i\-ith half grain samples of acetanilide amounts of caffeine yarying between one-half and two grams did not interfere at all with the accuracy of the titration. I t is veri- probable that the presence of caffeine in even larger relative aniouiits would not seriously affect the accuracy of the determinations although it was noticed that with the larger ainounts of caffeine there is some tendency for the yellow color of the free bromine in the solution at the end of the titration to fade on standing. -4s is of co:irse to be expected, sodiuni bicarbonate and other unoxidizable inorganic salts which niay possibly be used in headache powders do not interfere with the accurate titration of the acetanilide. Il-ith sugar, which is a frequent constituent of this class of medicines it is found that heating to the temperature of the steam bath o r boiling with h! drochloric acid of the concentration required for the saponification of the acetanilide, causes the sugar to carbonize with a resulting darkening of the solution. T h e dark color prevents the detection of the end point of the rezction, but it is found that in such cases on cooling the solution and adding a little aiiinial charcoal and filtering, the dark color may be satisfactorily removed and an accurate titration of the clear solution made. -A more satisfactory plan, ho\vever, is to remove the acetanilide from the sample by means of chloroform or some other solvent, antl after evaporating the latter, determine the acetanilide as above outlined. In some cases, on the other hand, it may be desirable to dissolve out the SLIg a r antl other water soluble constituents with the least possible amount of cold water and then saponify the undissolved acetanilide with hpdrochloric acid as described. Esperiments made with mixtures of salol and acetanilide showed that tlie accuracy of the determination is in no wise influenced by tlie presence of the salol. T h e above named substances are the ones which are usually found in the ordinary headache and neuralgia preparations which are sold by druggists and therefore the very simple and rapid method here described is applicable in the large majority of cases. In order to test the method, a iiiiiiiber of headache powders containing various amounts of acetanilide
1094
ilTHERTOS S E I D E L L
iiiisctl ivitli sugar, sotliuin l)icarbonati.. caffeiiie. salol. ctc., ivcre l i r i . p ~ r e ~ l ant1 the acetanilicle cletermiiiecl b!. tlie titration as al)o\.e clcscrilietl. l i i ail tlie aiiioumts found agreed ivitliin a ic\\.teiitlis of a per cuit. \ \ . i t i i tiic aniount \viiicli tlie sauiple \vas I;iio\vn to contain. I n atltlitioii to acetanilide. the only otlicr sitlxtances \vhicli have found cstcnsivc application in the relief of lieatlaclies are plienacetine a d antip!-riiic hut the m e of tlicsc as coiiipare(1 \\.it11 acetanilide lias until recently been largely restrictcd oii accoiiiit of their higher price. T h e action of these sulistaiices iipoii tlie nerve centers is very siiiiilar to that of acetanilitle and for this reason it is not to be expected that they \vi11 gencrally he used together ivitli acctaiiilitle i n headache remedies, iievertlieles~ it \vas thought desirable tu examine their iiitluetice iipoii tlie titration niethod clescribetl above. Ai few tests imnieiliately indicated the impossibilit!. of titrating the saponified acetanilide soliitioii with potassium Iironiate \vlieii evcn the siiiallest amount of either phenacetine or antip).riiie is present in the original sample. In tlie case of phenacetine the first feiv drops of the I)romate solution turns tlie liquid pink to purple color and this becomes darker, even to deep black \\it11 coiitiiiuetl atltlitioii of the liromate solution.’ \\-it11 the presence of aiitip!.rine the end point of the titration is also obscuretl. A t the present time apparently tlie only satisfactory metliotls available for the quantitative deterinination of phenacetine antl of antipyrine are the Zeisel ’ ethos!, antl methoxy distillation method for the iormer and L h gault‘s iodine titration method for the latter. :i nuniber of tleteriiiiiiatioiis made b y tlie author ivitli tlie %cisel mcthotl indicated that tlie procctlure caii be carried out only I]!. a skillctl \vorker! ant1 this fact together \\.it11 the amount of time required for each tletermiiiatioii will uiicloul~teelly impair the usefulness of tlie method for ortliiiar!. practice in control lahoratoric>. I n regartl to the method for aiitip!.riiie, it is evident that the tleterminatioii can not be made upon saiii1)les containing caffeine or other sulistances which unite reatlil!- \\-it11 free iodine. 111 vi?\\: of these colisiderations it appearetl especially tlesirahle t o niotlif!, the titration methotl for acetanilide proposed in the first part of this paper, i n such a nianiier that at least quantitative determinations of this substance in presence of phciiacctine could be satisfactoril!, niatle. \\.it11 this itlea i n mind a very large nmilm- of experiinents have been made antl so far only partial success has been attained. T h e cause o f the tlificulty lics iii tlie presence of ~
1 This observation suggests a simple test for detecting the presence of phenacctine in acetanilide. Dissolve the sample in moderately strong hydrochloric aci(1, boil and add a few drops of potassium brornate solution, a purple color indicates tile presence of phenacetine. 2 See Tingle’s translation of Hans Meyers’ little book up011 the ‘cDetemminatiun of Radicals in Carbon Compounds,” p. 3s. J . pliarni. cliim., ( 6 ) 7, 161, 11, 97.
G R O W T H OF SEEDLINGS
1095
the ethoxy group in the plienacetine. T h e bromine acting upon this portion of the molecule converts the compound into an intensely colored quinone derivative which makes it impossible to observe the end point of the reaction. h n i o n g the plans for getting around this difficulty which have so f a r been tried without success may be mentioned, the attempts to remove or render the ethoxy group inactive either by oxidation o r reduction methods; titration with the use of spotting plates or test papers upon removed portions of the solution ; and the use of mild saponifying agents for liberating aniline from the acetanilide without acting upon t 11 e p hen acet ine . I t was found that although acetanilide alone, and with less success phenacetine, could be titrated directly (without previous saponification) in the cold, acidified, aqueous solution with standard potassium bromate, the reaction is slow since time must be allowed for the dissolving of the phenacetine o r acetanilide during the titration, and in addition the presence of caffeine seriously interferes with the determination of the end point. T h e only process which has appeared to be worthy of further study is based upon the statements found in hleyer and Jacobsen, vol. 2, p. 4j5, that chloride of lime acting upon p-aniinophenols produces quinone chloramide and this product is very easily reduced back to the p-phenol by means of reducing agents. Quantitative experiments made with stannous chloride as the reducing agent showed that if an excess of the bromate solution be added to the acid sqponified solution of a mixture of acetanilide and plienacetine, this excess could be titrated back with stannous chloride and the difference corresponds fairly closely to the amount required 11)- the acetanilide alone in the mixtcre. Further work will be reqi tired Iionever to demonstrate the practical applicability of this proced u r e ; and in the mean time it is hoped that the method as described for acetanilide alone will prove useful particularly to the chemists having charge of the enforcement of the new Pure Food and D r u g Law.
A STUDY OF THE INFLUENCE OF MAGNESIUM SULPHATE ON THE GROW'TH OF SEEDLINGS. BY GERTRUDES. B U R L I S G H A M .
Received M a r c h 29. 1907.
Introduction T h i s investigation is a n outgrowth of a more comprehensive problem in nutrition,the aim of which was to learn t h e effects of t h e different minerai nutrients upon t h e growth of a test plant, from these data to compound a perfect nutrient solution, and then to note t h e variations in structure and form which might be produced by modifying t h e composition of this nutrient solution. Abufilon abufiioz was chosen as t h e test plant,
