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Volume 38, 1905
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Art. X.—The Detection and Estimation of the Alkaloids by means of their Double Sulphocyanides.

[Read before the Wellington Philosophical Society, 3rd May, 1905.]

The late Mr. Skey, who has enriched the Transactions of the New Zealand Institute by a large number of papers on chemical and physical subjects, has drawn attention to the fact that solutions containing certain alkaloids yield precipitates when treated with ammonium-sulphocyanide and a zinc or mercury salt. Neither the discoverer of the reaction nor any subsequent observer appears to have further investigated these insoluble precipitates. Consequently, at the suggestion of Professor Easterfield, the following investigation was made, with the twofold object of determining the nature of the reaction and of basing upon it a convenient method of volumetric analysis.

The more important alkaloids were examined, and it was found that in the presence of ammonium-sulphocyanide not only zinc and mercury but many other metals gave insoluble precipitates. In particular the cobalt compounds are characterized by the display of colour which occurs during the precipitation. This forms an excellent test for detecting small quantities of antipyrine. If a solution containing cobaltnitrate and ammonium-sulphocyanide is added to a liquid in which the drug is dissolved, there first appears a dark-blue precipitate, and the colour of the solution gradually changes through various shades of purple till it finally becomes red. Not only is this reaction as sensitive and characteristic as the ordinary tests for antipyrine, but in addition it possesses the advantage that it takes only a short time to perform.

Nickel also gives characteristic green precipitates with quinine and cocaine, but the reaction is not so sensitive as was found to be the case with cobalt. The other metals examined, with the exception of tin, give for the most part only faint precipitates.

The results are collected in Table I, and in the case of the more sensitive reactions the limit of dilution at which the precipitation occurs with excess of the reagents is also given.

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Table I.-Showing the Reactions of the More Important Alkaloids in the Presence of Ammonium-sulphocyanide and Different Metals.

[The section below cannot be correctly rendered as it contains complex formatting. See the image of the page for a more accurate rendering.]

Quinine. Cinchonine. Cinchonidine. Cocaine. Atropine. Brucine Strychnine. Morphine. Codeine Nicotine. Pilocarpin. Antipyrine.
Zinc. White pp. White pp. White pp. White pp. White pp. White pp. White pp. White pp. White pp. White pp. White pp. White pp.
1:50,00 1:25,000 1:15,000 1:10,000 1:4,000 (faint) (faint) (faint) (faint) 1:1,500
Cadmium Yellowish No reaction White pp. Yellowish No reaction White pp. No reaction No reaction No reaction No reaction No reaction Yellow
pp. (faint) pp. (faint) pp.
1:500 1:400
Cobalt. Blue pp. Blue pp. Blue pp. Dark-blue pp. Light- Blue pp. Ditto Ditto Ditto Ditto Ditto Blue pp.
1:1,000 pp, 1:500
Nickel. Dark- Faint pp. No reaction Green pp Faint pp. Brown " " " " " Green pp.
green pp. 1:300 pp.
Manganese White pp. No reaction Ditto White pp. No reaction White pp. " " " " " Brown pp.
Tin. " Yellow Yellow " Ditto White pp. White pp. " White pp. White pp. " White pp.
pp. pp. (faint)
Magnesium " No reaction No reaction " " No reaction No reaction " No reaction No reaction " No reaction
Thorium. No reaction Ditto Ditto No reaction " Ditto Ditto " Ditto Ditto " White pp.
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An examination of the above table will show that the cinchona alkaloids, and more especially quinine, give the most sensitive reactions. A solution of ammonium-sulphocyanide and zinc-sulphate compares favourably with the well-known alkaloidal reagents, as is seen from the following data:–

Reagent. Limit of Proportion of Quinine.
Zinc-ammonium-sulphocyanide 1 : 50,000
Phosphotungstic acid 1 : 100,000
Mercury-potassium-iodide 1 : 90,000
Potassium-periodide 1 : 80,000
Picric acid 1 : 40,000
Phosophomolybdic acid 1 : 30,000
Chlorine and ammonia (thalleioquin) 1 : 20,000

Further, it has the advantages–(1) the reagent is easy to prepare; (2) it is not extremely sensitive to other alkaloids, as is the case with reagents such as phosphotungstic acid, &c.

Owing to the extreme insolubility of zinc-ammonium-quinine-sulphocyanide, it is evident that the proportion of sulphocyanide in the compound can be found indirectly by determining the excess of sulphocyanide in the filtrate after precipitation. Excess of zinc-sulphate and ammonium-sulphocyanide, however, should be present, as the precipitate is perceptibly soluble in pure water.

As the result of a large number of trials under different experimental conditions, the following method of experiment was finally adopted as being the most convenient for examining the nature of the reaction: Owing the fact that excess of the reagents are necessary to cause complete precipitation, a strong solution of ammonium-sulphocyanide must be added to the quinine. Then, as the excess of sulphocyanide left in solution after the precipitation is too great to be measured conveniently by the usual method of titration, this strong solution is diluted to a known volume, and then an aliquot portion is taken for analysis.

Ten c.c. of a decinormal solution of quinine dissolved in dilute nitric acid was treated with excess of zinc-sulphate and 10 c.c. of normal ammounium-sulphocyanide. The white flocculent precipitate, which forms immediately, became coherent on agitation, and was separated by filtration through a Gooch crucible. Such a crucible has a perforated bottom, which is covered to a depth of ⅛ in. with tightly packed threaded asbestos. The crucible is fitted into a thistle funnel with a piece of rubber tubing, and the funnel is fixed in a flask, as shown in Fig. 1. By the aid of a suction pump liquids can

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be filtered in such an arrangement in a remarkably short space of time.

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The precipitate, which remains in a, is washed with a small quantity of a solution containing zinc-sulphate and ammounium-nitrate, in which it is practically insoluble.

The liquid which collects in b is then transferred to a graduated flask of 100 c.c. capacity. It saves time, however, if the liquid is filtered directly into a measuring-flask to which a side tube is attached (Fig.2).

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After dilution 10 c.c. of the solution is treated with an equal volume of decinormal silver-nitrate, and N/10 sulphocyanide added until a red colour is developed with ferric sul-

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phate. Concordant results were obtained at different dilutions, and in the presence of varying amounts of nitric acid, zinc-sulphate, and ammonium-sulphocyanide, provided that excess was present.

The results obtained with a decinormal solution of quinine are given in Table II.

Table II.–Showing the Number of Equivalents of Zinc and Sulphocyanide added to One Equivalent of Quinine, the Number of Equivalents of Sulphocyanide removed by the Quinine, and the Total Volume of the Solution.

Quinine. Zinc. Sulphocvanide added. Total Volume. Sulphocyanide removed.
1 6 10 30 3·5*
1 12 10 30 3·5*
1 6 20 40 3·4
1 12 20 40 3·55
1 6 10 60 3·45
1 12 10 60 3·5

Similar results were obtained by working with normal potassium-sulphocyanide and washing the precipitate with a solution containing zinc and potassium ions.

From these experiments it appears that one equivalent of quinine combines with three and a half equivalents of sulphocyanide to form the double salt–i.e., 3·5 c.c. N sulphocyanide precipitates 0·324 gram quinine ∴ 1 c.c. N sulphocyanide precipitates 0·093 gram quinine. This method can thus be used for the quantitative estimation of quinine, and it has the great advantage that the whole determination can be performed in a few minutes.

Although cinchonine and cinchonidine do not form such insoluble precipitates as quinine, nevertheless these alkaloids can be satisfactorily determined in a similar manner.

Below is given the sensitiveness of the cinchona alkaloids in the presence of zinc-sulphate and (a) ammonium-sulphocyanide, (b) potassium-sulphocyanide, at ordinary temperatures.

Quinine. Cinchonine. Cinchonidine.
Ammonium 1:50,000 1:25,000 1:15,000
Potassium 1:40,000 1:20,000 1:12,000

The ammonium-salts are characterized by being slightly less soluble than the corresponding salts of potassium.

It was found in the case of cinchonine and cinchonidine that one equivalent of alkaloid requires three equivalents of sulphocyanide for precipitation–i.e., 3 c.c. N sulphocyanide

[Footnote] * These results are the mean of a number of closely concordant experiments in solutions with varying amounts of nitric acid.

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precipitates O 294 gram cinchonine or cinchonidine ∴ 1 c.c. N sulphocyanide precipitates 0·098 gram cinchonine or cinchonidine.

This volumetric method of analysis was then compared with the official B.P. methods for estimating quinine in the drug “ferri et quininæ citras,” and the total alkaloids in the crude cinchona-bark. Whilst losing nothing in accuracy, the new method effects a considerable reduction in the time and trouble which is expended in the performance of the analysis according to the British Pharmacopœia.

Ferri et Quininœ Citras.”–About 1·5 grams of the substance was dissolved in water, and the quinine was precipitated by ammonia, and extracted with chloroform. The quinine was removed from the chloroform by shaking with 5 per cent. nitric acid, and this solution was titrated as described above. The method of the British Pharmacopœia is to evaporate the chlorform-solution to dryness, and to heat to 100° till the weight is constant. The results obtained by the different methods are as follows:–

B.P. method (time, an hour and a quarter): 1·654 grams gave 0·246 gram quinine=14·8 per cent.

Titration method (time, half an hour): (a) 1·659 grams required 2·6 c.c. NH4CNS=14·6 per cent.; (b) 1·551 grams required 2·4 c.c. NH4CNS=14·4 per cent.

The Cinchona Bark (an epitome of the process is given in the adjoining table).–Fifteen grams of the finely powdered material were treated with lime and a small quantity of water. The alkaloids were then extracted with a boiling solution of bonzine, containing 20 per cent. of amy1 alcohol. This was shaken several times with dilute sulphuric acid, and the solution made up to 100 c.c. So far the method is identical with that of the B.P. Fifty c.c. were diluted to about 200 c.c., heated to boiling and neutralised with ammonia. On cooling the insoluble quinine-sulphate crystallizes out. The usual method of analysis is to collect this on a tared filter, and to heat to 100° till its weight is constant. This operation, however, takes a considerable time, and several weighings are necessary. Further, it often happens that the precipitate of quinine-sulphate separates in such a form that it cannot be conveniently placed on a filter.

In order to estimate the quinine by titration the solution is filtered without troubling to remove the precipitate which adheres to the beaker. After washing with a small quantity of ammonium-sulphate the precipitate on the filter and that left in the beaker is dissolved in a little dilute nitric acid. The amount of quinine in solution is then determined by adding sulph ocyanide and titrating as described above.

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[The section below cannot be correctly rendered as it contains complex formatting. See the image of the page for a more accurate rendering.]

Solution containing the sulphates of quinine, cinchonine, and cinconidine from the bark. Dilute to 100 c.c. Take 50 c.c., dilute, heat to boiling neutralise with ammonia, and cool.
Filtrate Add Rochelle Salt.
Precipitate, Quinine-sulphate, Precipitate, Cinchonidine-tartrate. Filtrate, containing Cinchonine.
Titration Method. Official Method. Titration Method. Official Method. Titration Method. Official Method.
Dissolve quinine-sulphate in a little dilute nitric acid and titrate. Collect the precipate on a tared filter and heat to 100°C till its weight is constant. Dissolve precipitate in a few drops of nitric acid and titrate. Collect the prticipitate on a tared filter, and heat to 100°C. till its weight is constant. Add nitric acid and titrate. Precipitate cinchonine with ammonia, extract with chloroform, heat to dryness, and weigh residu.
Quinine. Cinchonidine. Cinchonine.
Remanining 50 c.c., titrate directly with sulphocyanide.
Total alkaloid.
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To separate the cinchonidiue from the cinchonine the neutral solution from the quinne-sulphate is treated with excess of Rochelle salt and stirred vigorously. After an hour the precipitation is complete. It is usual to weigh the precipitate of cinchonidine-tartrate in the same manner as the quinine-sulphate. It is more rapid and convenient, however, to dissolve the precipitate in a little dilute nitric acid. and to titrate directly with sulphocyanide.

The cinchonine, which is left after the removal of the quinine and cinchonidine, is estimated by acidifying the solution and titrating in the usual manner. Care, however, must be taken to have excess of nitric acid when the silver-nitrate is added.

The remaining 50 c.c. of the original solution is now titrated, and in this manner the amount of total alkaloid can be determined. In the red bark, owing to the small amount of quinine present, 1 c.c. sulphocyanide = 0·097 total alkaloid; in the yellow bark, 1 c.c. sulphocyanide = 0·095 total alkaloid.

If the method is accurate the total alkaloid (b) should be equal to the sum (a) of the quinine, cinchonidine, and cinchonine. That this is the case is seen from the following determinations made with a specimen of red bark.

[The section below cannot be correctly rendered as it contains complex formatting. See the image of the page for a more accurate rendering.]

Per Cent.
Per Cent.
Quinine 1·2 1·2
Cinchonidine 2·6 2·8
Cinchonine 1·0 0·9
Total alkaloids (a)4·8 (a)4·9
(b)5·1 (b)5·0

The same bark was also analysed according to the B.P. method, in which the quinine and cinchonidine are precipitated together as tartrates and the mixture weighed on a tared filter. The cinchonine was estimated by treating the filtrate with ammonia, extracting with chloroform. and heating to dryness.

The results are given below, and compared with those obtained by the titration method.

[The section below cannot be correctly rendered as it contains complex formatting. See the image of the page for a more accurate rendering.]

P.B.Method. Titation Method.
Quinine (1.) (2.)
Cinchonidine 4·0 3·8 4·0
Cinchonine 1·2 10 0·9
Total alkaloids 5·2 4·8 4·9
5·1 5·0
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The Composition of the Double Sulphocyanides.

(a.) Zinc.

Ten c.c. of the solution of the alkaloid were precipitated in the usual manner with sulphocyanide in the presence of a known excess of zinc-sulphate. The liquid was filtered, and the zinc in the filtrate was estimated by precipitation with sodium-carbonate. From this the amount of zinc which combines with a known amount of alkaloid could be found by difference. The following are the results:—

(1.) Quinine-ammonium-zinc-sulphocyanide : 10 c.c. N/10 quinine required 0·0424 gram zinc. Calculated for 3B, 2Zn (CNS)2—0·0424 gram zinc.

(2.) Cinchonine-ammonium-zinc-sulphocyanide: 10 c.c.N/10 cinchonine required 0·0486 gram zinc. Calculated for 4B, 3Zn (CAS)2—0·0487 gram zinc.

(3.) Cinchonine-potassium-zinc-sulphocyanide: 10 c.c.N/10 cinchonine required (a) 0·0472 gram zinc, (b) 0·0494 gram zinc. Calculated for 4B, 3Zn (CNS)2—0·0487 gram zinc.

(4.) Cocaine-ammonium-zinc-sulphocyanide: 20 c.c.N/10 cocaine required (a) 0·0210 gram zinc, (b) 0·0232 gram zinc. Calculated for 3B, Zn (CNS)2—0·0217 gram zinc.

(b.) Ammonia.

Precipitation was caused by a definite volume of normal ammonium-sulphocyanide in the presence of excess of zinc-sulphate. After washing the precipitate with a small quantity of a dilute solution of zinc-sulphate, the ammonia in the filtrate was estimated by distillation with caustic soda. It was thus possible to determine the amount of ammonia in the double salt.

The method of operation will be illustrated by means of the detailed analytical results obtained in the case of quinine.

Preliminary Test Experiment.—10 c.c. N ammonium-sulphocyanide on distillation with caustic soda gave ammonia =10 0 c.c.N acid. The filtrate from 10 c.c.N/10 quinine and 10 c.c. N ammonium-sulphocyanide gave ammonia = (i) 9·5 c.c. N acid, (ii) 9·5 c.c. N acid. ∴ 1 c.c. N quinine combines with 0·5 c.c. N ammonia.

(c.) Sulphocyanide.

The method has already been described and explained.

The following is a summary of the results obtained in the determination of ammonia and sulphocyanide:—

(1.) Quinine-ammonium-zinc-sulphocyanide: 10 c.c. N/10 quinine required (a) 0·5 c.c. N ammonia and 3·5 c.c.* sulpho-

[Footnote] * The mean of a large number of closely concordant determinations.

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cyanide, (b) 0·5 c.c. N ammonia. Calculated for 6B, 4Zn (CNS)2, 3 NH4CNS, 10 HCNS, 0·5—3·5 c.c. sulphocyanide.

(2.) Cinchonine-ammonium-zinc-sulphocyanide: 10 c.c.N/10 cinchonine required (a) 0·5 c.c. N ammonia and 3·0 c.c.* sulphocyanide, (b) 0·55 c.c. N ammonia. Calculated for 4B, 3Zn (CNS)2, 2 NH4CNS, 4 HCNS, 0·5—3·0 c.c. N sulphocyanide.

(3.) Cocaine-ammonium-zinc-sulphocyanide: 20 c.c. N/20 cocaine required (a) 0·5 c.c. N ammonia and 2·5 c.c. * N sulphocyanide, (b) 0·55 c.c. N ammonia. Calculated for 6B, 2Zn (CNS)2. 3 NH4CNS, 8 HCNS, 0·5—2·5 c.c. N sulphocyanide.

(d.) Alkaloid.

The precipitate from a known amount of alkaloid was collected on a Gooch crucible, and dried in a vacuum over sulphuric acid. Under these conditions the double salts still persistently retain a trace of water, which was removed by heating to 100°. The weights thus obtained should confirm those calculated from the formulæ, which were derived from the analytical results already given above.

(1.) Quinine-ammonium-zinc-sulphocyanide: Quinine = (a) 54·6 per cent., (b) 55·0 per cent. Calculated for 6B, 4Zn (CNS)2, 3NH4CNS, 10 HCNS—55·6 per cent.

(2.) Cinchonine-ammonium-zinc-sulphocyanide: Cinchonine = 54·9 per cent. Calculated for 4B, 3Zn (CNS)2, 2NH4CNS, 4 HCNS—55·7 per cent.

(3.) Cinchonine-potassium-zinc-sulphocyanide: Cinchonine = 55·4 per cent. Calculated for 4B, 3Zn (CNS2), 2 KCNS, 4 HCNS—55·6 per cent.

(4.) Cocaine-ammonium-zinc-sulphocyanide: This compound could not be dried without decomposition.

Summary and Conclusion.

1. Whereas many alkaloids give insoluble with ammonium- or potassium-sulphocyanide and zinc - sulphate, the double salts of quinine, cinchonine, cinchonidine, and cocaine are the most insoluble in the presence of excess of the reagents.

2. These double salts are exceedingly complex in their composition, a characteristic of many alkaloidal compounds. Thus, cinchonine-ammonium-zinc-sulphocyanide has the formula, 4 (C19H22N2O), 3 Zn (CNS)2, 2 NH4CNS, 4 HCNS. This corresponds closely with the formula of herepathite or sulphate of iodo-quinine, which may be written, 4 (C20H24N2O2), 3 H2SO4, 2 HI, 4 I2, + 3 aq.

[Footnote] * The mean of a large number of closely concordant determinations.

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3. Notwithstanding the complexity of these insoluble compounds, the determination of the amount of sulphocyanide required by the alkaloids for their formation serves as the basis of an accurate and speedy method of estimating quinine in the commercial drugs, and of assaying the crude cinchona-bark.

Experiments are now in progress to ascertain if this method may prove of value in estimating cocaine in the commercial preparations and in the assay of coca-leaves. With suitable modifications it may also serve as a means of separating different alkaloids, such as strychnine and brucine, or quinine and strychnine.

The above work was carried out in the Victoria College Laboratory, Wellington, under the conditions of the Jacob Joseph Scholarship.