Optical Activity of Quinine and Some of Its Salts In Mixtures of Water and Ethyl Alcohol JAMES C. ANDREWS U D BAILEY D. WEBB, School of Iledicine, University of North Carolina, Chapel Hill, N. C.
I
N SPITE of the many years during which quinine has been a commonly used therapeutic agent, exact deter-
Rota tion of Quinine Free Base, Hydrochloride, and Sulfate i n Water-Alcohol Mixtures
minations of its physicochemical properties are frequently lacking in the literature. During the development of an improved microprocedure for the determination of quinine in blood and urine the authors found need for an independent method of determination which could be used on a macro or semimicro scale and used for this purpose the optical activity of quinine or its salts. The use of such a procedure on a semimicro scale has necessitated a search for those conditions under which the highest optical activity could be attained. The bibliographies provided by Allen (I), Schmidt and Grafe ( 8 ) , and other books on alkaloids include many references to the optical activity of quinine and its salts but with the partial exception of the work of Oudemans ( 7 ) , systematic studies of the effect of progressive neutralization of the free base, the effect of progressive change of solvent (ethyl alcohol, water), etc., under exact temperature control and with highly purified samples are largely lacking. Some data of this sort were reported by Hesse (3, 6)and, more recently, by Schoorl (9), Dietzel and Soellner ( 2 ) and Lapp (6). The data in the present paper are not in any essential way in contradiction with those of the above authors but constitute an amplification and a partial confirmation of their work. Oudemans' determinations, while the most complete in the literature, frequently fail to cover the range desired for present purposes.
A stock solution containing 2.5000 grams of the recrystallized free base made up to 100 ml. in freshly prepared absolute ethyl alcohol was used for the water-alcohol curve of the free base. Five-milliliter aliquots were measured into 50-ml. volumetric flasks, measured amounts of water were added from a buret, and the flasks were made up to volume with absolute alcohol. All concentrations of quinine were therefore 0.250 gram of free base per 100 ml. with the exception of the two solutions containing only 10 and 20 per cent of alcohol (by volume), respectively. These, because of the limited solubility of the free base, contained higher dilutions of the latter. Similar procedures were used with both the sulfate and the hydrochloride. In all cases the stock solution was made up in absolute ethyl alcohol.
Table I shows the results obtained with quinine free base, the dihydrochloride, and the sulfate. All figures for [crI2,5 refer to the free base regardless of the salt used. It is obvious that the same amount of quinine base produces a much higher rotation as the hydrochloride than as the sulfate or as the free base. Furthermore, for quinine hydrowith alcohol concentration reaches chloride the curve of [cr]'f a flat maximum at about 30 per cent alcohol by volume and gives, a t the maximum, a specific rotation of -280. Inaccuracies in the dilution of the alcohol-water mixture used as solvent would therefore have little effect on the final reading. With both quinine sulfate and the free base the maximum of the curve is reached a t about 60 per cent alcohol with lower specific rotation a t these points.
All determinations of optical activity were carried out at 25" =t0.5' C. using a Schmidt and Haensch half-shadow polarimeter reading to 10.01 , an electric sodium lamp providing practically monochromatic D light, and 4dm. tubes. Quinine as the free base was prepared by decomposition of either hydrochloride or sulfate with excess ammonia and crystallization at 0' C. from the water solution. Samplesbof the free base prepared from both salts gave identical optical activities. Quinine dihydrochloride was prepared by recrystallization from absolute alcohol. The resulting addition compound with alcohol was then decomposed by drying at room temperature in vacuo and then briefly at 110" C. This product gave rotation values practically identical with those of the U. S. P. product dried in vacuo over phosphorus pentoxide at room temperature. Q$nine sulfate was prepared by several successive recrystallizations of the U. S.P. product from hot water and the product was dried to constant weight in vacuo over phosphorus pentoxide. Constancy of optical activity was used as the criterion of comlete purification with both the free base and its salts. In all the following data, specific rotations are uniformly expressed in terms of the free base.
TABLE11. EFFECTON OPTICALACTIVITYOF PROGRESSIVE NEUTRALIZATION OF QUININEBASEWITH HYDROCHLORIC AND SULFURIC ACIDS Hydrpchloric Acid Molar ratio of HCI t o quinine - [aly 0 0.258 0.516 0.774 i.032 1.290 1.548 1.806 2.064 2 322 2 580 2 838
OF QUININE FREEBASE,QUININE TABLEI. SPECIFICROTATION DIHYDROCHLORIDE, AND QUININE SULFATE
(In varying percentages of water and aloohol) Alcohol Quinine Quinine Quinine (by Volume) Free Base Sulfate Dihydrochloride
9%
- [a]%
-[a]%
- [a]% 270 272
18.5 20.0 30.0 40.0 50.0 60.0 70.0 80.0 90.0 100.0
...
138 155
171 179 181 180 178 172 168
202
...
218 225 233 237 233 221 214 206
...
277 280 277 273 267 252 240 222 207
232
153 175 198 216 236 252 270 278 283 286 289 290
Sulfuric Acid Molar ratio of Hd304 to quinine 0 0.028 0.141 0.283 0.424 0,565 0.706 0.848 0,989 1.130
- [aly 177 184 200 217 234 246 252 256 257 258
Neutralization Curves of Quinine Base with Sulfuric and Hydrochloric Acids To determine the effect of progressive neutralization of the free base, fixed amounts were neutralized by addition of varying amounts of standard acid (hydrochloric or sulfuric). These solutions were so prepared as to contain that proportion of water and ethyl alcohol which was shown in Table I to give the maximum specific rotation of their respective salts (30 per cent alcohol for the hydrochloride and 60 per cent alcohol for the sulfate). The extent of neutralization is indicated by the molar ratio of acid to quinine. Tnis ratio is obviously 0.5 for the sulfate and 2.0 for the hydrochloride in the case of the purified salts used in the measurements of Table I. Table I1 shows the data obtained expressed as the specific rotation (as free base) for various molar ratios of acid to qui-
ANALYTICAL EDITION
April 15, 1941
nine. All solutions contained 0.250 gram of quinine per 100ml. of solution. All points of the hydrochloric acid curve were determined in 30 per cent alcohol and all of the sulfuric acid curve in 60 per cent alcohol. The data in Table I1 show for both acids only a smooth curve with no breaks at any stoichiometric ratios. They show, however, why somewhat higher rotations have been obtained when excess acid has beenadded to either the sulfate or the dihydrochloride. The report of Liquier (6) concerning plateaus in the curve of optical activity us. p H corresponding to the neutral and basic quinine sulfates has not been confirmed b y the authors.
SummarjData are presented to show the variation in optical activity of quinine as free base, dihydrochloride, and sulfate in mixtures of water and ethyl alcohol, and the variation as the free base is progressively neutralized with hydrochloric and SUI-
233
furic acids, each in t h a t water-alcohol solution which gives the maximum rotation for each salt.
Acknowledgment The authors wish to acknowledge the assistance of the Samuel S. Fels Fund in providing means for carrying out the work.
Literature Cited (1) (2) (3) i4j (5) (6)
18';
(9)
Allen, "Commercial Organic ilnalysis", 5th ed., Vol. VII, Philadelphia, P. Blakiston's Son & Co., 1929. Dietsel, R., and Soellner, K., Arch. Pharm., 268, 629 (1930). Hesse, O., Ann., 176, 205 (1875). Hesse, O., Ber., 4, 693 (1871). Lapp, C., Compt. rend, 201, 80 (1935). Liquier, J., Ibid., 183, 195 (1926). Oudemans, A. C., Ann., 182, 33 (1876). Schmidt, J., and Grafe, V., "Alkaloide", Berlin, Urban und Schwartzenberg, 1920. Schoorl, N., Pharm. Weekblud, 63, 469 (1926)
Effect of Temperature of Alcohol in Determination of Potash in Fertilizers C. W.HUGHES AND 0. W . FORD Purdue University Agricultural Experiment Station, Lafayette, Ind.
FOR
a number of years the referee on potash in fertilizers of the Association of Official Agricultural Chemists has recommended investigation of the solubility of potassium chloroplatinate in alcohol and acid-alcohol. Pierrat gives the solubility of potassium chloroplatinate in alcohol at 14" C. (3) b u t makes no reference to the solubility at the higher temperatures a t which most laboratory work is done. Allen reports on the greater solubility of potassium chloroplatinate in 80 per cent alcohol than in 95 per cent alcohol (1) b u t makes no reference to the temperature of the alcohol used. Archibald, JTilcox, and Buckley give the solubility of potassium chloroplatinate in alcohol-water mixtures of various alcohols at 20" C. (2) b u t do not mention the solubility in acid-alcohol. This work, while important in itself, has not been inclusive enough t o encompass the conditions existing in the determination of potash b y the official method, as, for example, the effect of temperature on the solubility of potassium chloroplatinate in alcohol and acid-alcohol. During the summer of 1939 a large number of lorn-analysis potash fertilizers analyzed in the authors' laboratory were found to be running below guarantee. The daily temperatures during this period were unusually high but after cooling the alcohol to about 18" C. the results were from 0.1 to 0.3 per cent higher. Since a rise of about 8" C. was noted upon addition of concentrated hydrochloric acid t o alcohol (when added at the rate of 0.6 ml. of hydrochloric acid t o 6 ml. of alcohol) and the temperature remained above room temperature for the 15-minute extraction period, it was found advisable to mix the acid and alcohol and cool before adding it to the po~~
TABLEI.
~
LOSS O F POTASSIUM CHLOROPLATIS4TE BY TION WTH ACID-ALCOHOL
EXTRAC-
(0 I-gram portions of K2PtC16 used) K20 LOBt
Treatment
Mixed acid-alcohol Acid and alcohol separate
18' C
380 c .
MQ
MQ.
.WQ
5 1 7 6
8 2 9 7
10 8 11 6
48'
C
tassium chloroplatinate. Subsequently the effect of temperature on the solubility of potassium chloroplatinate in acid alcohol was studied. Known concentrations of pure potassium chloride mere used for samples in place of commercial fertilizers in order to avoid other sources of error in the potash determination.
Procedure The study is divided into two steps. 1. Extraction of weighed amounts of pure potassium chloroplatinate with definite volumes of acid and alcohol under controlled temperature conditions. Tenth-gram portions of pure potassium chloroplatinate were transferred to 250-ml. beakers. To these were added 137.5 ml. of acid alcohol at a definite temperature for the mixed acid-alcohol determinations and 125 ml. of alcohol and 12.5 ml. of concentrated hydrochloric acid for the determinations in which the acid and alcohol were added separately. The mixtures were stirred for 15 minutes a t controlled temperatures. Finally the determinations were filtered into sintered-glass crucibles and washed with 137.5 ml. more of alcohol at corresponding temperatures. Table I gives the amounts of potassium chloroplatinate lost by extraction. 2. Determination of the effect of the temperature of acidalcohol on the solubility of potassium chloroplatinate precipitated from two concentrations of pure potassium chloride. Two concentrations of potassium chloride were used. The first contained 6.25 grams of potassium chloride per liter, made to volume at 4" C. and kept at that temperature till used. The theoretical value of t.his solution is 0.3948 per cent KzO. The second solution contained 12.5 grams of potassium chloride per liter and the theoretical X 2 0value for this solution is 0.7896 per cent. Aliquots of the above concentrations (25 ml.) were measured into platinum dishes, measured amounts of chloroplatinic acid were added, and the solutions were evaporated to a thick paste on the steam bath. The dishes were then removed and to each dish were added 6 ml. of 83 per cent alcohol and 0.6 ml. of concentrated hydrochloric acid for the determinations in which the acid and alcohol were added separately or a mixture of 6 ml. of alcohol and 0.6 ml. of acid for the mixed acid-alcohol determinations. The samples were extracted for 15 minutes at 18' or at 38" C. The temperatures in each case were controlled by a constant-temperature bath. At the end of the &minute extraction, the s m les were washed with 125 ml. more of 83 per cent alcohol adjustef to the corresponding tem erature. It was estimated that 125 ml. of alcohol mere norrnafiy used in the potash deter-
