PHENACETIN HYDROCHLORIDE* BY I R E S E H. S A S B O R S
-1lthough phenacetin itself is a well known antipyretic, its hydrochloride is rather an elusive substance. Apparently there was no reason to question its accessibility ; thus when its existence became a matter of interest in connection with the work on Phase Rule Studies on the Proteins by Wilder D. Bancroft and C. E. Barnett,’ the author proceeded with the usual methods for such an organic preparation. Phenacetin is para ethoxy phenyl acetanilide, C,HjOC6H4?ITHC2H30. From the behavior of the nitrogen atom in analogous compounds, Bancroft and Barnett stated in part that phenyl groups decrease the reactirity of the nitrogen; ethoxy groups increase it; adjacent carbonyl groups decrease it; and alkyl groups increase it. Acetanilide is a weak base but does combine with hydrogen chloride, while diacetanilide, with the diketo linkage, does not. X o statement was found in the literature regarding the hydrochloride of benzanilide, C6H5SHC0.CsHj;so Bancroft and Barnett tested it to find that it did form a definite hydrochloride. They concluded that “phenacetin should be at least as positive as acet,anilide and therefore must add on hydrogen chloride, although >leyer and Jacobson do not mention the fact.” Accordingly, three attempts were made to prepare the hydrochloride. Phenacetin is a stable, white, crystalline substance of m.p. 13 j°C, insoluble in cold water, slightly soluble in hot wat’er, and soluble in hot concentrated hydrochloric acid. -1sample was dissolved in hot absolute alcohol, and dry hydrogen chloride gas was passed into the solution. Although the solution was placed in an ice bath, no precipitate appeared. Either the phenacetin hydrochloride was not formed, or else it was dissolved in absolute alcohol. Another sample was dissolved in an alcohol-ether solution, containing just enough alcohol to keep the phenacetin in solution. The solution was kept cold, and dry hydrogen chloride passed into it as previously. A curdy white precipitate formed, apparently the hydrochloride. I n attempting to filter and wash this precipitate, decomposition was evidenced immediately, and phenacetin was recovered on the filter paper. One other method was tried. Phenacetin was melted, and to the melt concentrated hydrochloric acid was added. The mass was heated, and allowed t o stand in a desiccator over stick sodium hydroxide. A white powdery layer formed on the surface of the melt. Probably this was the hydrochloride, for upon exposure to the air it began to fume, and left a residue of phenacetin. ‘This work is a part of the programme now heing carried out at Cornell University under a grant to Professor Bancroft from the Heckscher Foundation for the Advancement of Research established by August Heckscher at Cornell University. 1 J. Phys. Chem., 34, jj3 (1930).
'346
I R E 3 E H. S A S B O R S
From these procedures it appeared rather evident that there is such a compound as phenacetin hydrochloride, and that it is exceedingly unstable. For this reason, other methods, whereby the hydrochloride would not be exposed to the air, were used. The apparatus used in Phase Rule Studies' was employed. Phenacetin was pulverized and dried over concentrated sulphuric acid in a desiccator for several days. A sample was placed in the reaction flask, the system was evacuated, and dry hydrogen chloride was introduced. Our dat'a show conclusively that phenacetin combines stoichiometrically with dry hydrogen chloride mol per mol. See data Fig. I and Table I.
FIG.I Phenacetin Hydrochloride
TABLE I Phenacetin and Hydrogen Chloride S.T.P. Sample 2 . j grams Dry Vol HCI added C.C.
Vol HC1 removed C.C.
5ij.z 17.1
21.8
1j2.4 I Y . 2
1120.4
11j.o 1
Set volume
Val HCI Vol HCI remaintaken ing UP
W t . HC1 taken
C.C.
Equilibrium pressure mm.
jjj.2
614
262
313.2
j12
5j8.1 j36.3 363.9 311.7
si6
246
312.1
526
224
312.3 315.9 312 I 191 j
508 j08,I
224
3
109.3
J. Phys. Chem., 34, 449 (1930).
25 I i I i
li
C.C.
48 32.6 32.6 32.6
C.C.
76
j
UP
mgm.
jI5 jo8 312 3 125
'317
PHES.\CETIS HYDROCHLORIDE
Theoretically one gram of phenacetin should take up 204 mgms. of hydrogen chloride for the formation of phenacetin hydrochloride. We find that it actually does take up that amount. The hydrochloride is a practically colorless fine powder with a dissociation pressure of 17 mm. It melts sharply at I j 4 O C at 7 4 1 mm. pressure, and decomposes immediately and completely in water into hydrogen chloride, and the flakey lustrous white phehacetin which gives a m.p. of 13 j"C. Some of t'he phenacetin hydrochloride was preserved in a closed tube and its properties tested about five months after its preparation. I t was found to be quite stable. Another part' was left in an open tube. During this same period this portion slowly decomposed. The surface layer gave a m.p. of 1 3 j ° C indicating ita decomposition into phenacetin and hydrogen chloride. I n order to obtain a separate proof of the existence of phenacetin hydrochloride, a method somewhat similar to the one used by T. W. Richards' to establish the identity of BaCl2.2H2Owas tried. For this experiment a special glass tube was used, so constructed that the sample and solvent could be introduced through A, and into which was sealed a long tube B with a flanged mouth which reached nearly to the bottom of the tube. See Fig. 2 . This arrangement made it possible to bring the entire sample in contact with the dry hydrogen chloride. The tube is of such a size that it rests unhampered FIG.2 upon the pan of the ordinary analytical Glass Drying Tube balance.
TABLE I1 Phenacetin Hydrochloride (Curve A) Sample of phenacetin 0.480 grams. Wt. HC1 taken u p mgms
Time
Hours
Days
Equivalence in HCI mol per mol.
3.6
.8 '7 ' I
'7 Sote:
I
equiva1ent:for this sample is 97 mgms.
Z. anorg. Chem., 17, 1 6 j (1898).
1.3
48
IRENE
n. SANBORN
The sample of finely divided dry phenacetin was placed in the special tube. 2 5 cc. of freshly distilled dry chloroform was added to the sample. The tube was gently heated to dissolve the phenacetin; after which dry hydrogen chloride was passed through B into the solution. During this process the tube was retained in a bath of warm water until the chloroform had been completely evaporated. The tube was then placed in a desiccator containing concentrated sulphuric acid and stick sodium hydroxide, being removed periodically for the purpose of weighing. The data for two samples are found in Fig. 3 and Tables I1 and 111.
0
2
/
3
J
I
7
6
6
/ O / /
9
Fro. .i Dissappearance of HCI from Phenacetin Hydrochloride
TABLE 111 Phenacetin Hydrochloride (Curve B) Sample of phenacetin 0.26j grams. Wt. HC1 taken up mgms
147 99
57 50 44
Time Hours
Days
Equivalence in HCI mol per mol.
24
I
36 96
1.5
2 . 7 1.8
4
I.0j
I20
5
.92
6
.80
I44 44 264 S o t e : I equivalent for this sample is j 4 mgms.
I1
.80
The intersection of the line “a” with the curve A represents the point a t which the sample contains one equivalent of hydrogen chloride. There should be a break in curve A a t this point. As shown, there is none; but there are no points between one and two days and between two days and four days. Consequently the curve as drawn may not be right. To check this a second
PHENACETIN HYDROCHLORIDE
‘349
experiment was done. The intersection of the line “b” with the curve B represents the point at which the sample contains one equivalent of hydrogen chloride. In this case the break comes pretty fairly well at the right place, the loss being about 17 mg. per day from 1.5 to 4 days and 7 mg. per day from 4 to 5 dags. Neither curve A nor curve B becomes theoretically horizontal at any point; but the rate of diffusion happens to be very low. The method is not especially accurate in its present form; but it does show conclusively the existence of a definite chemical compound with a composition pretty close to the monohydrochloride. Another experiment was devised of a similar nature. d weighed sample of the finely divided dry phenacetin was spread upon a weighed watch-glass, thoroughly moistened with concentrated hydrochloric acid, and placed in a vacuum desiccator containing concentrated sulphuric acid. The desiccator was evacuated, and then filled with dry hydrogen chloride. After allowing the sample to remain in the desiccator long enough to insure the complete removal of any trace of water, the sample was removed and weighed. The amount of hydrogen chloride with which it had combined was calculated. The experiment was done twice, using first a small sample of phenacetin, 0.361 g.; and second a larger sample, 2 . 9 5 4 g. The same watch glass was used in each case. After standing in desiccator for a week, a t which time all the water had been removed, sample I had combined with 0.062 gms. of hydrogen chloride, an amount equivalent mol per mol to 0.84 mol of hydrogen chloride. Sample 2 remained in desiccator for over a month. Upon removal and subsequent weighing it had combined with 0 .j55 gms. of hydrogen chloride, an amount equivalent to 0 . 9 ~ 4mol of hydrogen chloride. See Table IF’.
TABLE IV I
Phenacetin samples
0.361 grams.
Amount HC1 combined after one week.
0.062
Amount HCl combined after one month. Equivalence to HC1 mol per mol.
2
2.954 grams.
,555 0.84
0.924
The results are conclusive as to the existence of a definite chemical compound; but the results are not such as to lead one to prefer this method to the one in which the pressure is studied. The last two methods have the advantage that there are no stop-cocks to leak and spoil the experiment near the end of a run.
Conclusions Phenacetin combines stoichiometrically with hydrogen chloride mol per mol to form phenacetin hydrochloride. z . Phenacetin hydrochloride exists as a stable compound in the presence of hydrogen chloride gas. I t is a very pale yellow powder wlth a m.p. of I j4OC. I.
3'
50
IRENE E.SANBORN
3 . At room conditions, phenacetin hydrochloride is unstable because of the dissociation pressure of about I j mm. It decomposes gradually to give hydrogen chloride and phenacetin. 4. I n aqueous solution its decomposition is immediate into phenacetin and hydrogen chloride. j. TT.hile it is possible to show the existence of a compound between phenacetin and hydrogen chloride by passing hydrogen chloride into a solution of phenacetin and ether, the compound cannot be obtained both pure and dry in the ordinary way. 6. The phenacetin hydrochloride has been analyzed indirectly in three different ways, just to show how the problem can be solved. 7 . The existence of phenacetin hydrochloride is in accordance with the criteria laid down by Bancroft and Barnett. Cortitll L'nii,erxiLjy.
