ON THE MYDRIATIC ALKALOIDS.

By ALBERT LADENBURG.

We translate the following important article, says the Chemists' Journal, from the Moniteur Scientifique of last month. It may be explained for the sake of our student readers that the word mydriatic is derived from the Greek mudriasis, which means paralysis of the pupil.

The synthetical researches which I have undertaken with a view to explain the constitution of atropine have shown me the necessity of studying the connection of atropine with the other alkaloids, which have an analogous physiological action. According to the early researches we could not discover any of these relationships which only become evident when we come to study the new discoveries which have been made in connection with the tropines, to which class belong both duboisine and hyoscyamine, which, although differing from atropine, are equally mydriatic in their action.

I.--ATROPINE.

Discovered by Mein in 1831 in the roots of belladonna. More thoroughly studied some time after by Geiger and Hesse, who confirmed Mein's results. Liebig next published an analysis of the alkaloid, which was afterward shown to be incorrect. He consequently modified his formula, and gave the following as the composition of atropine; C₁₇H₂₃NO₃. Liebig's amended analysis was afterward confirmed by Planta, who further showed that the alkaloid itself melted at 194° F., and its double gold salt at 275° F. It is worthy of remark that the first figure was considered correct until my researches proved the contrary. The physiological action of atropine, especially in relation to the eye, has been most carefully studied by several celebrated ophthalmologists, such as Graef, Donders, Bezold, and Bloebaum. Its chemical properties have also been the object of very extensive researches by Pfeiffer, Kraut, and Lassen. Pfeiffer first discovered that benzoic acid was one of the products of decomposition of atropine, and Kraut split atropine by means of baryta water into atropic acid, C₉H₆O₂, and tropine, C₈O₁₅NO. Lassen, who used hydrochloric acid, discovered the true products of the splitting up of atropine, viz., tropic acid, C₉H₈O₃, and tropine, C₈H₁₅N, and proved at the same time that atropic acid is easily formed by the action of boiling baryta water on tropic acid, while hydrochloric acid at all temperatures forms isatropic acid, an isomer of atropic acid. Kraut confirmed these results, and showed that atropic acid as well as cinnamic acid gives benzoic acid by oxidation, and hydratropic acid (the isomer of phenylpropionic acid) by reduction with sodium amalgam. These results are sufficient to show that tropic acid may have one of the following two formulae.

Fittig and Wurster, who discovered atrolactic acid, C₂H₁₀O₃, an isomer of tropic acid, gives tropic acid the second formula, while Burgheimar and myself have shown that it is the true formula of atrolactic acid. Lately we have succeeded in performing the complete synthesis of atropic acid, and the artificial preparation of atropine has been greatly facilitated since I have shown that we can easily reconstruct atropine by starting from its products of decomposition, tropic acid, and tropine.

Before my researches nothing was known of the constitution of tropine. New unpublished researches into this problem have shown that it closely resembles neurine,[1] a body which I hope will speedily lead us to the complete synthesis of atropine.

[Footnote 1: As we shall probably hear a great deal about this alkaloid, it may be as well to state that, although found in the brain and liver, it may be prepared synthetically by the action of ethylene oxide, (CH₂)₂O, water, H₂O, and trimethyiamine, N(CH₃)₃. Its constitution is that of trimethyl-ethylene-hydrate-ammonic-hydrate, and has the following constitutional formula:

or in other words, it is the hydrate of trimethyl-hydrethylene-ammonium.]

The fusing point of atropine is not 194° F., as stated by Planta, but 237° F. Crystallized from not too dilute alcohol it forms crystals which are aggregations of prisms. Toluene, alcohol, and chloroform all dissolve atropine readily. Its double gold salt is very characteristic. It is generally precipitated in the form of an oil which solidifies rapidly and may be crystallized from hot water after the addition of a little hydrochloric acid. This clouds in cooling, and after a certain time it separates in small crystals of indeterminate form which unite in warty concretions. After drying the salt forms a dull powder, melting between 275° F. and 280° F. It also melts in boiling water, and its aqueous solution exposed to the light is partially reduced, 100 grammes of water acidulated with 10 cubic centimeters of 1.190° solution of hydrochloric acid dissolves 0.137 gramme of the gold salt at 136° F. to 140° F.

I should fancy that the above particulars are sufficent to completely differentiate atropine from all the other mydriatic alkaloids.

II.--THE ATROPINE OF DATURA STRAMONIUM.

Planta has already tried to show that atropine is identical with the daturine obtained by Geiger and Hesse, founding his opinion on facts which we nowadays look upon as doubtful. This identity was generally admitted by all chemists. The pharmacologists, headed by Soubeiran, Erhardt, Schroff, and Poehl, were much more reserved in their judgment. I thought it as well, therefore, to recommence the study of daturine, the more so as I had already determined the incorrectness of the long accepted point of fusion of atropine, and that my researches on hyoscyamine convinced me that this base is an isomer of atropine, although very analogous to it. I have also shown that Merck's daturine differs from atropine, and is merely pure hyoscyamine. A short time afterward there appeared a paper by Schmidt which again asserted the identity of daturine and atropine. I therefore requested Mr. Merck, of Darmstadt, to send me all the bases which he obtained from datura. This eminent manufacturer was good enough to comply with my request, and sent me two products, one of which was marked "light daturine," the other "heavy daturine," the separation of which was effected in the following manner: The solution of crude daturine in concentrated alcohol was mixed with a little hot water; this treatment caused the deposition of the "heavy daturine," while the "light daturine" remained in the mother liquor. The "heavy daturine," of which only a small quantity is obtainable, is far from being a body of definite composition, that is to say, it is a mixture of atropine and hyoscyamine. If we convert the base into a double gold salt we obtain by a single crystallization a dull looking salt, melting at from 275° F. to 280° F., the appearance of which is very different to that of atropine. I have succeeded in splitting up "heavy daturine" by two different methods. By recrystallizing the gold salt six times from boiling water, the salt of hyoscyamine, which melts at from 316° F. to 323° F., crystallizes our first, and by the successive evaporation of the mother liquor at last obtain the pure gold salt of atropine, which melts at 275° F. to 280° F. If we only want to isolate the atropine, it is better to crystallize the free base two or three times from alcohol at 50 per cent., always taking the earliest formed crystals.

These facts prove the presence of atropine in datura; but while Planta and Schmidt assert that only this alkaloid is found in the plant, I have proved that the proportion of atropine in it is but small, while its richness in hyoscyamine is great. I think, therefore, that both Planta and Schmidt must have worked with a mixture of atropine and hyoscyamine. It is true that Schmidt had received pure atropine under the name of daturine, for I have proved most conclusively that the so-called daturine supplied by Trommsdorff, of Erfurt, is pure atropine and nothing else. It has no action whatever on polarized light.

III.--HYOSCYAMINE FROM HYOSCYAMUS.

Discovered by Geiger and Hesse in 1833. It was first obtained in the form of needles, which were much more soluble than atropine. In the pure state it forms a viscous mass with a repulsive odor. These researches were repeated by Thibout, Kletinski, Ludwig, Lading, Bucheim, Wagymar, and Renard.

Hoehn and Reichardt have recently studied hyoscyamine in a very complete manner. They have obtained the body in the form of warty concretions as soft as wax, and melting at 194° F., having a formula according to them of C₁₅H₂₃NO₃. They have also studied the splitting up of the alkaloid by means of baryta water, and have obtained an acid which they have named hyoscinic acid, and which melts at about 219° F., and a basic body, hyoscine, C₆H₁₃N. They represent the reaction as follows:

C₁₅H₂₃NO₃ = C₉H₁₀O₃ + C₆H₁₃N.

According to this view hyoscyamine ought to be the hyoscinate of hyoscine, or at any rate an isomer of this body. It is to be remarked that they compare hyoscinic acid not with tropic acid, of which it possesses the composition, but with atropic acid, C₉H₈O₂. I have worked with the hyoscyamine of both Merck and Trommsdorff, as well as with a product which I obtained from hyoscyamus seeds myself. The best way of purifying the alkaloid is by recrystallizing its gold salt several times, so as to obtain it in brilliant yellow plates, melting at 320° F. By passing a stream of hydrosulphuric acid gas through the liquor the gold is precipitated in the form of sulphide. The liquid is filtered and evaporated, precipitated by an excess of a strong solution of potassium carbonate, and the alkaloid extracted by chloroform. The solution is dried over carbonate of potassium, and part of the chloroform is distilled off. By leaving the solution to evaporate spontaneously the alkaloid is obtained in silky crystals. The crystals are then dissolved in alcohol, which, on being poured into water, parts with them in the same form.

Hyoscyamine crystallizes in the acicular form, with greater difficulty even than atropine, it also forms less compact crystals. Its fusing point is 149.6° F. I have not yet succeeded in crystallizing any of its more simple salts. The double platinum salt melts at 392° F., with decomposition. The double gold salt, which has been described above, does not melt in boiling water, and its aqueous solution is reduced neither by boiling nor by long exposure to light. By leaving the hot saturated solution to cool it does not cloud, but the double salt separates pretty rapidly in the form of plates.

One liter of water containing 10 cubic centimeters of hydrochloric acid at 1.19° dissolves 65 centigrammes of the salt at 146° F.

These characteristics allow us to differentiate atropine and hyoscyamine, the reactions of which are almost identical, as will be seen from the following table, which shows the action of weak solutions of the acids named on the hydrochlorates of the bases:

(To be continued.)