Optical Activity of Some Cinchona Alkaloids and Some of Their Salts In Mixtures of Water and Ethyl Alcohol JAMES C. ANDREWS, School of Medicine, University of North Carolina, Chapel Hill, N. C.
It has been found desirable to extend these investigations fo other cinchona alkaloids. The present paper records the results of investigations, previously reported for quinine, applied to quinidine, dihydroquipidine, cinchonine, and cinchonidine. This series, while very limited, provides examples of the effect on optical activity of stereochemical isomerism, of the removal of the ethoxy group from quinine, and of hydrogenation of the vinyl group. The procedure used was identical with that described by Andrews and Webb (2). I n the case of each compound the following data were determined :
Optical activity can be used as a criterion of the purity of cinchona alkaloids only if exact data are availabIe as to the relationship between this property and such conditions as composition of solvent and degree of neutralization of the cinchona base. Such data are presented for a representative series of the more common quinine derivatives. For each compound studied, data are recorded showing the variation in optical activity in progressively varied mixtures of water and ethyl alcohol of the free base, the sulfate, and the dihydrochloride, as well as the change in optical activity as the free base is progressively neutralized with sulfuric and hydrochloric acids. Studies were made on quinidine, dihydroquinidine, cinchonine, and cinchonidine.
1. The specific rotation of the free base, the sulfate, and the dihydrochloride in varying ,percentages of water and alcohol. 2. The effect on specific rotation of progressive neutralization of the free base with both sulfuric and hydrochloric acids.
The second of the above series was, in each case, carried
out at that percentage of ethyl alcohol which had given the maximum rotation when the water-alcohol curve for that particular salt was determined. All figures for [ a ]were ~ determined a t 25’ C. and refer to the free base, regardless of the salt used. These values are all rounded off to the nearest unit. I n the opinion of the writer the reporting of specific rotations in tenths of a unit is usually not justified by the accuracy of the reading, particularly when, as is often the case in the present paper, solubility limitations compel the use of comparatively dilute solutions.
I
N A recent paper (2)’ Andrews and Webb reported the results of a systematic investigation of the optical activity of quinine as the free base, the sulfate (Bz.H&304),and the hydrochloride (B .2HC1) in various mixtures of water and ethyl alcohol. At the same time there was reported the effect on optical activity of progressive neutralization of the free base with both sulfuric and hydrochloric acids. The purpose of this work was to establish optimum conditions for the use of optical activity as a criterion of purity of these alkaloids and to fill some of the many gaps in our knowledge of the stereochemistry of these compounds.
Quinidine Kahlbaum’s quinidine (base) was recrystallized four times by dissolving in 95 per cent alcohol and adding about five
TABLE I. SPECIFIC ROTATION OF CINCHONA ALKALOIDS Free Base Alcohol (by [a]% volume)
70
Sulfate Alcohol (by volume) LalY
70
(In varvine oercentaaes - _of water and ethyl alcohol) Dihydiochl&de Free Base Alcohol (by Alcohol (by volume) [a]’$ volume) [aIY
%
70
Quinidine Free Base, Quinidine Sulfate, and Quinidine Dihydrochloride 20.0 28.0 36.0 44.0 52.0 60.0 68.0 76.0 84.0 92.0 100.0
216 227 237 243 248 252 257 260 260 258 255
0.0 7.4 19.4 27.4 35.4 43.4 51.4 67.4 75.4 83.4 91.4 100.0
230 240 260 267 272 275 277 275 272 267 262 258
n.n 10.8 18.8 26.8 34.8 42.8 50.8 58.8 66.8 74.8 82.8 90.8 98.8 100.0
190 203 215 219 225 231 235 234 228
0. 17.4 27.4 35.4 43.4 51.4 59.4 67.4 75.4 83.4 91.4 99.4
219 230 241 248 252 252 251 250 249 246 244 23s
0. 9.0 17.6 26.8 34.8 42.8 50.8 58.8 66.8 74.8 82.8 90.8 98.8
[=I’d
%
Dihydrochloride Alcohol (by volume) [a12
%
Cinchonine Free Base, Cinchonine Sulfate, and Cinchonine Dihydrochloride 32.0 0.8 195 0. 245 40.0 7.8 210 10.6 250 48.0 19.4 225 18.6 255 56.0 27.4 230 34.6 255 64.0 35.4 232 50.6 250 72.0 43.4 233 66.6 245 80.0 51.4 235 74.6 240 88.0 59.4 235 82.6 232 96.0 67.4 235 90.6 222 75.4 100.0 237 94.6 217 83.4 235 210 98.6 87.4 232 91.4 227 95.4 222 99.4 217
312 315 317 317 315 312 307 302 295 287 280 272 265 263
Dihydroquinidine Free Base, Dihydroquinidine Sulfate, and Dihydroquinidine Dihydrochloride 0. 20.0 40.0 50.0 60.0 70.0 80.0 90.0 100.0
Sulfate Alcohol (by volume)
Cinchonidine Free Base, Cinchonidine Sulfate, and Cinchonidine Dihydrochloride
277 281 285 287 287 285 277 270 262 25s 250 242 230
20.0 28.0 32.0 44.0 56.0 68.0 76.0 84.0 92.0 96.0
100.0
543
- [alY 44 88 100 115 127 125 122 120 117 115 108
- l a.] ? ._
-[a]”,”
0.1 5.9 18.7 38.7 58.7 70.7 78.7 82.7 86.7 90.7 94.7 98.7
140 150 165 1SO 185 190 195 190 185 180 170 155
0. 10.6 18.6 26.6 42.6 58.6 70.6 78.6 82.6 86.6 90.6 94.6 98.6
180 185 187 187 185 175 165 157 152 147 140 130 120
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Vol. 14, No. 7
INDUSTRIAL A N D ENGINEERING CHEMISTRY
volumes of water. The product was dried a t 110" C. A constant specific rotation [CY]': = +255.0 in absolute ethyl alcohol was obtained. This is somewhat higher than the usually accepted figure reported by Rabe (6),+243.5, but the ease of contamination of quinidine with dihydroquinidine and resulting lowering of its optical activity have already bcen commented on by Butler and Cretcher (3). On the other hand, the author has never succeeded in obtaining a figure for the anhydrous free base in absolute alcohol as high as that reported by Butler and Cretcher (+262), but they do not specify temperature and the author employed a concentration of 0.300 gram per 100 ml. as compared with 2.0 grams per 100 ml. used by them. The author has found only small concentration effects with the optical activity of these alkaloids and has not investigated the effect of temperature variations. His sample melted at 167.5" C. (corrected). Butler and Gretcher report 162" to 163" C. for U. S. P. quinidine and 170" to 171" C. for their product made by rearrangement of quinine. The sulfate and dihydrochloride were both made by adding the calculated amount of standard acid to the recrystallized free base, and diluting to volume with absolute ethyl alcohol to make the stock solution, The necessary correction was made for the amount of water introduced with the standard acid. Neutralization curves were run as described by Andrcws and Webb. In all cases, these curves were determined in that concentration of ethyl alcohol which had produced the highest specific rotation when the alcohol-water curve of that particular salt was run. Some deviations from this procedure were dictated by considerations of solubility of the salt. The actual percentage of alcohol used is recorded with each part of Table 11. Table I shows the variation in specific rotation of quinidine free base, quinidine sulfate (B*.H&Od), and quinidine dihydrochloride (B.2HCl). Table I1 shows the variation in specific rotation of quinidine (as free base) during progressive neutralization with sulfuric and hydrochloric acids a t the specified concentrations of ethyl alcohol.
Dihydroquinidine A sample of dihydroquinidine base (kindly furnished by the laboratories of Merck & Co., Inc.) was dried at 110" C. to constant weight and gave in absolute alcohol a value of [a]y = +228.0 (concentration of base = 1.852 grams per 100 ml. of solution). Since a recrystallized sample produced no measurable difference in optical activity, the original dried sample of the base was used. The value given by Rabe (6) is +237.5 a t 15" C. and by Henry (4) is +230. In neither case is the concentration of alcohol specified. Using the author's sample of the base, the same determinations were made as described above for quinidine. The results for the alcohol-water curves of the free base, the sulfate (B2.H2S04),and the dihydrochloride (B. 2HC1) are shown in Table I and the data concerning neutralization of the free base with sulfuric and hydrochloric acids in Table 11. Cinchonine The fact that commercial samples of cinchonine, as usually obtainable, are highly contaminated with quinine makes necessary special precautions for obtaining a pure product. The sample used aa a starting point for purification showed, in absolute ethyl alcohol, a specific rotation of 177 as compared with the figure of +224.4 reported by Rabe and +229 (at 17" C.) by Henry. I n substantial agreement with Rabe's figure, the author's highest rotation in absolute ethyl alcohol, reached after successive purification, is +224.0. The procedure used is based on the fact that the chief
+
TABLE11. EFFECTON OPTICAL ~ ~ V I OF T Y PROQRESSIVE NEUTRALIZATION WITH SULFURIC AND HYDROCHLORIC ACIDS Sulfuric Acid Molar ratio of HrSOd to base
Hydrochloric Acid Molar ratio of HCl to baas Quinidine Base.
0. 0.235 0.470 0.706 0.941 1.177 1.412 1.647 1.882 2.352 3.293
216 220 235 257 280 294 316 33s 339 346 345
Dihydroquinidine Bases 0. 0.177 0.355 0.532 0.710 0.888 1.065 1.242 1.420 1.775
208 225 248 269 283 292 295 296
Cinchonine Base' 0.
150 230 251 260 265 267 268 267
0.205 0.410 0.615 0.820 1.025 1.435 2.05 3.28
...
Cinchonidine Based
-Ids 0. 0.160 0.320 0.480 0.640 0,800 1.120 1.600 2.400 3.200
-b l Y 110 142 166 182 187 189 187 186 184
...
Sulfuric acid neutralization run in 50% ethyl alcohol by volume; hydrochloric acid in 20% ethyl alcohol by volume. b Sulfuric acid 'neutrslization run in 50% ethyl alcohol by volume; hydrochloric acid in 30% ethy! alcphol by volume. c Sulfuric acid neutralization run in 75% ethyl alcohol by volume; hydrochloric acid in 30% ethyl alcohol by volume. d Sulfuric acid neutralization run in 80% ethyl alcohol by volume; hydrochloric acid, in 40% ethyl alcohol by volume.
contaminant, quinine, is much more soluble in ether than is cinchonine and can therefore be removed by successive extractions. These were repeated until the ether extracts showed a constant optical activity and a constant amount of solid residue on evaporation. As the quinine content of the sample approaches zero, the amount of alkaloid dissolved by the ether and the optical activity shown by the solution gradually approach that produced by the very limited solubility of cinchonine base in ether. This is listed by Allen (I) as 0.27 gram of cinchonine per 100 ml. of ether. The specific rotation of +177 for this sample indicates, by interpolation, the presence of about 12 per cent of quinine, assuming no other alkaloids to be present. A 25-gram sample was shaken mechanically for some hours with 100 ml. of ether. The filtered ether solution was read in a 4-dm. polariscope tube and 25-ml. ortions were evaporated to dryness and the residues weighed. %wenty-six such extractions were made before constancy of rotation and of solubility was obtained. During this series the observed rotation changed roressively from -2.90 to +1.20 as the quinine was removed. $he fmt three extractions gave satisfactorily constant values averaging 0.170-gram residue per 100 ml. of ether solution.
Assuming cinchonine to be the only solid phase present, this indicates an ether solubility of this alkaloid a t 25" C.
July 15, 1 W
A N A L Y T I C A L EDITION
of 0.170 gram per 100 ml. of solution, a figure much lower than that of Allen (1). This also gave a specific rotation in ether of [ala: = +176. The residual cinchonine when dried gave a specific rotation of +224.0. This sample of the base was used for all optical activity determinations as described above under quinidine. The results for the alcohol-water curves of the free base, the sulfate (Bt. H2S0,), and the dihydrochloride (B.2HCl) are shown in Table I, and data concerning neutralization with sulfuric and hydrochloric acids in Table 11. Because of the more limited solubility of cinchonine base in water, the data for the former in Table I could not be extended to alcohol concentrations below 32 per cent. Even at this point only 0.02 gram of base per 100 ml. was possible. The error of the determination is therefore correspondingly large.
Cinchonidine A commercial sample of the free base was recrystallized from solution in 95 per cent ethyl alcohol by addition of sufficient water to reduce the alcohol percentage to 25 per cent. The resulting precipitate was filtered, washed with 25 per cent ethyl alcohol, and dried. Three such treatments gave a product showing, in absolute ethyl alcohol, a constant optical activity of [ala: = - 107.3. A value of - 111.0 was reported by Rabe. Since further recrystallization did not alter the author’s figure (-107.3), it was taken as representing the pure base under the conditions specified. Using this sample, the determinations were made as described above for quinidine. The results for the alcohol-water curves of the free base, the sulfate (Be.HzSOd), and the dihydrochloride (B.2HC1) are shown in Table I, and data concerning neutralization of the free base with sulfuric and hydrochloric acids in Table IT.
545
It is obvious that the curves of all of these alkaloids follow the same pattern. As in the case of quinine, the water-alcohol curves of optical activity of free base, sulfate, and dihydrochloride all rise to flat maxima a t intermediate percentages of water and alcohol, giving lower values of specific rotation in both pure water and pure ethyl alcohol. The position of these maxima varies with the different cinchona derivatives examined, but it may be said that for the free bases, the maxima lie between 60 and 95 per cent alcohol by volume, for the sulfates between 50 and 75 per cent, and for the dihydrochlorides between 20 and 30 per cent. Using, in each case, the percentage of alcohol giving maximum rotation for that salt, the neutralization curves shown in Table I1 were run. These follow the course previously reported for quinine: a smooth curve with no breaks corresponding to any stoichiometric ratios. I n some cases, particularly with the hydrochlorides, addition of excess acid causes a slight drop in the maximum rotation attained. Some examples of this will be noted in the table. Acknowledgment The author wishes to acknowledge the assistance of the Samuel S. Fels Fund in providing means for carrying out this work. Literature Cited (1) Allen, “Commercial Organic Analysis”, 6th ed., Vol. VII, Philadelphia, P. Blakiston’s Son & Co., 1929. (2) Andrews, J. C.,and Webb, B. D., IND. ENQ.CHEM.,AahL. ED., 13, 232 (1941).
(3) Butler, C.L., and Cretcher, L. H., 3. Am. Pharm. Aseoe., 22,414 (1933). (4) Henry, T. A,, “The Plant Alkaloids”, 3rd ed., Philadelphia, P. Blakiston’s Son & Co., 1939. ( 5 ) Rabe, P., Ann., 492, 242 (1932).
Oil Absorption of Pigments M.A. AZAM’, Industrial Research Laboratory, Calcutta, India At a certain point in oil absorption of pigments the paste in oil is very easily taken off on the palette knife. This marks the point of saturation and the indication is sharp within 1 drop of oil (0.05 cc.) from an ordinary standard buret. When pastes, f u l l y or partly saturated
T
HE term “oil absorption” has been vaguely defined and
the method of determining its value has not been truly standardized. I n view of the circumstances, a rigorous study of oil absorption with strictly accurate and reproducible results has not yet been possible. Oil absorption has been defined in various ways: as nothing but the iilling of a void (6) or the filling of interspaces of the pigment particles with oil, the wetting power of the liquid (S),or the maximum quantity of oil required with any pigment for an intimate mixture in liquid state with minimum tendency to flow. A point which does not appear to be appreciated and whish adds to the difficulty of attaching Present address, Plastics Industries Technical Institute. Los Angeles. Calif.
with oil according to the above standard, are immersed in a bath of oil stock used for absorption, saturated pastes absorb no more oil, while unsaturated pastes absorb oil almost equal to the calculated deficiency for saturation in one to two days (24 to 48 hours), significance to oil-absorption measurement is the problem of defining experimentally the condition of complete wetting of the pigment. The criterion usually adopted by specifications depends on a rather vague visual judgment of consistency at the end point, which although it may afford a fairly accurate basis for comparing samples of the same pigment, does not necessarily serve well for comparison between different pigments. Apart from such interpretations, there is in general neither a fixed method nor a sharp finishing point in the determination of oil absorption. The current methods of locating the end point have more or less the common flow of a rulesfthumb experiment and, as such, the end point determined by these methods is scarcely reproducible with exact precision.
