THE VEGETABLE ALKALblDS. WITH PARTICULAR REFERENCE TO THEIR CHEMICAL CONSTITUTION. BY DR. AME PICTET, Pro/cssor in the Unimrsity of Geneva. FROM THE SECOND FRENCH EDITION. ■ RENDERED INTO ENGLISH, REVISED AND ENLARGED, WITH THE AUTHOR'S SANCTION, BY H. C. BIDDLE, Ph.D., Instructor in the University of California. 8vo, vii + 505 pages. Cloth, $5.00. Order through your bookseller, or copies will be forwarded postpaid by the ptiblishers on the receipt of the retail price. NEW YORK; JOHN WILEY & SONS. London; CHAPMAN & HALL, Limited. 1904. PREFACE. Since the appearance in 1897 of the second edition of Prof. Ame Pictet’s work, La Constitution Chimique des Alcaloides Vegetaux,” marked advances Lave been made in our knowledge of the alkaloids. ^ ^ The chemistry of xanthine, caffeine, theobromine, etc., has attained a certain completeness of development in the recognition of their common relation to purine and in the synthesis of the latter. The congtitudon of nicotine has been established by its synthesis and three new alkaloids have been isolated from the tobacco-plant (Pictet). Our conceptions regarding the jaborandi alkaloids have been completely revolutionized. The extensive in- vestigations of Ladenburg, Merling, and Willstatter have been brought to a brilliant conclusion in the complete synthesis of atropine, atropamine, belladonnine, inactive cocaine, and tropa- cocaine. Our knowledge regarding the constitution of morphine and codeine has been so far increased that probably within a short time the synthesis of these two alkaloids will be realized. These advances have precluded a simple translation of the French edition and have necessitated the complete rewriting of several chapters and the revision of the entire work. It is believed that the present English edition fairly sets forth the latest con- ceptions regarding the constitution of the more important veg- etable alkaloids. It may be noted that Prof. Pictet’s work on the alkaloids was rendered into German in 1900 by Wolffenstein and that a Russian edition is in process of preparation. H. C. Biddle. Berkeley, Calif., Dec. 22, 1903. iii r^-T.'S prs- |pcww\ t ’CONTENTS. • PAGE Introduction i FIRST PART. ARTIFICIAL BASES CLOSELY RELATED TO THE NATURAL ALKALOIDS. I. Pyridine . lo II. Homolooues oe Pyridine 32 A. The Picolinips 32 B. The Lutidines 37 C. The Collidines. ...*.• 40 Alcamines of the Pyridine Series 49 III. Carboxylic Acids OF Pyridine.^ 55 A. The Monocarboxylic Acids of Pyridine 55 B. The Dicarboxylic Acids of Pyridine 61 C. The Tricarboxylic Acids of Pyridine 66 D. The Tetracarboxylic Acids of Pyridine . 72 E. Pyridine Pentacarboxylic Acid 73 IV. Dipyridyls 76 V., Quinoline 79 VI. Methylquinolines. .'. 89 VII. Phenylquinolines 96 VIII. Monocarboxylic Acids of Quinoline 102 IX. Isoquinoline 107 SECOND PART. I THE NATURAL ALKALOIDS. X. Distribution and General Properties of the Natural Alkaloids .’ . . . 114 XL Alkaloids of the Hemlock 126 XII. PiPERINE 143 XIII. Trigonelline 149 XIV. Alkaloids OF THE Betel-nut Palm (Areca catechu) 152 XV. CiTRAZiNic Acid 157 • i p\ddi>i V VI CONTENTS. PAGE XVI. The Tobacco Aekaeoids 159 XVII. The Jaborandi AivKaloids 17 1 XVIII. Cytisine 179 XIX. Sparteine 182 XX. The Lupine Alkaeoids 184 XXI. The Solanum Aekaloids 188 XXII. The Coca Aekaeoids 232 XXIII. The Aekaloids of the Pomegranate-tree 258 XXIV. The Opium Alkaeoids 264 XXV. Alkaloids from Hydrastis canadensis 315 XXVI. Alkaloids from Corydalis cava 331 XXVII. The Cinchona Alkaloids 337 XXVIII. The Strychnos Alkaloids 382 XXIX. Alkaloids from Peganum harmala 395 XXX. Alkaloids of the Aconite Group 399 XXXI. The Veratrum Alkaloids 409 XXXII. Colchicine 417 XXXIII. The Xanthine Group 421 XXXIV. Allantoin 448 XXXV. The Asparagine Group 450 XXXVI. The Choline Group 470 XXXVII. The Alkaloids of Mustard- seed 479 XXXVIII. Trimethylamine 484 XXXIX. Alkaloids of Unknown Constitution 486 THE VEGETABLE ALKALOIDS. INTRODUCTION. Taken in its etymological sense the word alkaloids may serve to designate all organic substances which possess basic properties; some authors, indeed, have thus used the term. In general, however, its application is limited to those organic bases which are formed in the organism of the plant. A distinction is in this way drawn between basic compounds which w'e find in nature and those which are prepared solely in the laboratory. The alkaloids, then, do not form a well-defined group in a rational classification of organic compounds, since such a classification would be based on chemical constitution and not upon the source from which they were derived. An attempt was made by Konigs in 1880 to develop a rational classification of the bases found in plants. Investigations on the constitution of these substances showed that, if not all, at least a large number of them yielded pyridine as the ultimate product of their decomposition. It was natural, then, to infer that they were derivatives of this base, just as the aromatic compounds are derivatives of benzol. Konigs suggested that the term alkaloids be reserved for those natural bases which are pyridine derivatives. The proposal at first met the hearty approval of chemists; it afforded a strictly scientific classification of an important group of organic substances, and this advantage appeared at the time 2 THE VEGETABLE ALKALOIDS. to afford compensation for the necessity of excluding from the group such bases as caffeine, choline, betaine, sinapine, musca- rine, etc., which do not contain the pyridine nucleus. Through later numerous and important investigations on the natural bases, however, the number of those which are not derivatives of pyridine has been greatly increase d ^lost im- portant among those to which the classification of Konigs would deny the name of alkaloid is morphine, the first substance, indeed, which received this name. Further investigation has shown, moreover, that of the basic derivatives of the same plant some may be derivatives of pyridine and others not. Finally, the natural bases of complicated structure, whose constitution is not yet fully known, appear to be only in part derivatives of pyridine. It seems necessar}', therefore, to return to the original signifi- cance of the word alkaloid and to apply it without distinction to all natural organic bases, whatever may be their constitution. We shall then consider that the expressions vegetable alka- loids and vegetable bases are identical in meaning and that they include all those substances which are directly obtained from the plant and which are able to unite vriih acids to form salts. The history' of alkaloidal chemistiy' begins ’^dth the early part of the last century'. In 1803 Derosne in Paris obtained from opium a cry'stalline substance which he called opium-salt, and which must have been a mixture of morphine and narcotine. The basic properties of this opium-salt he ascribed to an im- purity arising from the alkali used in the purification. The foUo’^A'ing year Seguin likewise examined morphine, but attached no significance to the obser\'ed alkaline reaction of his preparation. The honor of discovering the first vegetable base and of recognizing its basic character rests w'ith Sertiimer, an apothe- cary' of Hanover. Without kno^'ing of the work of Derosne and Seguin, he in 1806 announced that he had obtained from opium a cry'stalline body which was of basic character, united with acids to form salts, and in the. opium was in combination with a special acid. INTRODUCTION. 3 The discovery of Sertiirner remained at first almost unnoticed. It was at that time believed that plants were able to produce only acids, or bodies of neutral reaction. A second publication was required to attract the attention of chemists to this new subject. This publication appeared in 1817 and bore the title ‘‘ Ueber das Morphium, eine neue salzfahige Grundlage und die Mekonsaure als Hauptbestandtheile des Opiums.” In this article Sertiirner definitely characterizes morphium as a vegetable alkali and compares its behavior with that of ammonia. These exact results awakened interest; it was thought that other plants which possessed marked physiological activity might contain, as active principle, substances analogous to mor- phium. Many investigations were instituted, with the result that during the years 1817-1835 the most important alkaloids were isolated. The following is a chronological list of their discovery: 1817. Narcotine, by Robiquet (( Emetine, (( Pelletier and Magendie. 1818. Veratrine, Meissner. u Strychnine, u Pelletier and Caventou. 1819. Brucine, 11 (C il i' u Piperine, (( Oersted. 1820. Caffeine, C( Runge. (i Cinchonine (1 Pelletier and Caventou. u Quinine, i( u a (( (( Solanine, IC Desfosses. 1825. Sinapine, u Henry and Garot. 1826. Cor)^daline, u Wackenroder. u Berberine, u Chevallier and Pelletan 1828. Nicotine, ({ Posselt and Reimann. 1829. Aricine, u Pelletier and Corriol. (( Sanguinarine, u Dana. 1830. Curarine, u Roulin and Boussingault. 1831. Conine, (( Geiger. u Atropine, Geiger and Hesse. 4 THE VEGETABLE ALKALOIDS. 1832. (< 1833- u u {( 1835- Codeine, Narceine, Quinidine, Aconitine, Colchicine, Hyoscyamine, Thebai’ne, by Robiquet. “ Pelletier. “ Henr}^ and Delondre. “ Geiger and Hesse. (I u u u U U (( II “ Pelletier and Thiboumery. The composition of these substances was established by numerous analyses, the most of which we owe to Liebig, Ger- hardt, Regnault, and Laurent. Since 1835 the number of newly discovered alkaloids has increased year by year; to-day we have more than two hundred vegetable bases, which have been fully purified, carefully de- scribed and analyzed. In the case of a large number we have learned much regarding the structure of the molecule, and in many instances have succeeded, indeed, in effecting the com- plete synthesis of the base — the best test of the accuracy of our present conceptions regarding the constitution of the alkaloids. The complicated structure of the alkaloids first discovered rendered a study of their constitution very difficult. Berzehus explained their basic character by assuming that they held ammonia attached to an indifferent group — to a hydrocarbon or an organic oxide. Others, again, supposed that the nitro- gen was united with oxygen, or that it occurred in a form hke that of cyanogen. It remained for Liebig to afford the correct solution. He considered these bases as ammonia in which a hydrogen atom was replaced by an organic radical. The classical investigations of Wurtz and of Hofmann, which led (1848) to the discovery of the artificial organic bases, fully confirm this view. It was recognized that the artificial as well as the natural bases were partly or completely substituted ammonias. Apphcation to the alkaloids was now made of the reactions, through which Hofmann had learned to distinguish 8 THE VEGETABLE ALKALOIDS. their structure. Also in this direction considerable success has been attained. If we disregard the two bases, choline and betaine, which belong to the group of the fatty amines and whose synthesis was effected by Wurtz (1857) and Liebreich (1869), and con- sider only the alkaloids of cyclical structure, then the honor rests with Ladenburg of having first effected the complete synthesis of such an alkaloid; in 1886 he succeeded in building up from the elements conine, the chief alkaloid of the hemlock. The same year Hantzsch prepared the methyl-betaine of nicotinic acid, and this was shown by Jahns to be identical with trigonelline. Since then still other alkaloids have been synthe- sized: arecaidine and arecoline by Jahns (1891); piperine by Ladenburg and Scholtz (1894); the bases of the xanthine group, xanthine, caffeine, theobromine, and adenine by Fischer (1895- 1898); atropine, atropamine, belladonine, and inactive cocaine by Willstatter (1901, 1902); and nicotine by Pictet (1903). This work is divided into two parts. The first part gives a rapid review of the artificial derivatives oj pyridine. The chief data which we have in regard to the constitution of a large number of alkaloids rest upon investigations concerning the constitution of simple pyridine derivatives, into which these alkaloids are converted by their decomposition. Consequently it seems to us best to discuss first the structure of these derivatives and to indicate the methods which have been employed in deter- mining their constitution. In this first part, however, we shall not lose sight of our chief object, the study of the constitution of the vegetable alkaloids, and we shall therefore consider only those artificial derivatives which in their mode of formation, in their molecular structure, or in any other important way are closely related to the natural bases. In the second part we shall seek to gather together system- atically the experimental results which have ‘ -thus far been derived from the study of the chemical constitution of the natural INTRODUCTION. 9 alkaloids, and to discuss the theoretical conclusions which have been drawn from these results. No attempt will be made to present a complete monograph of the vegetable alkaloids; we shall not consider in detail either their physiological or physical properties, nor shall we present the specific tests employed in detecting the natural bases. Attention will be fixed rather on the purely chemi- cal behavior of the alkaloids and the bearing of this on their chemical constitution. CHAPTER XVI. THE TOBACCO ALKALOIDS. For many years it was supposed that the leaves of the tobacco- plant {Nicotiana tabaccum L., family of the Solanaceae) con- tained but one alkaloid, nicotine. In 1901, however, Pictet and Rotschy ^ showed that there are present in tobacco,' as in most alkaloid-bearing plants, several organic bases. Thus far the following four alkaloids have been isolated: These alkaloids are found in the aqueous extract from tobacco ; in their separation advantage may be taken of the fact that the first two are volatile with steam. The last three have been separated in very small quantities as compared with nicotine; of the entire alkaloidal content of the aqueous extract, nicoteine forms possibly 2%, nicotimine J%, and nicotelline tV%- In the plant these alkaloids are in combination chiefly with malic and citric acids, to a less extent with oxalic, tartaric, and succinic acids. Nicotine was isolated from the leaves of the tobacco-plant by Posselt and Reimann ^ in 1828. The quantity found in the Nicotine . . . Nicotimine Nicoteine. Nicotelline I. Nicotine. ^ Pictet and Rotschy, B. 34, 696. ^ Posselt and Reimann, Magazin fur Pharmacie, 24, 138. 159 i6o THE VEGETABLE ALKALOIDS. plant varies considerably (0.6-8%) ; in general the better grades of tobacco contain the smaller amounts of the alkaloid. The empirical formula of nicotine, H14N2, was established by Melsens ^ in 1843. Nicotine is a colorless liquid which boils without decomposi- tion at 245°, but does not solidify at- —30°; its specific gravity is 1. 01 at 20°. In the pure condition it is almost odorless and acquires the odor peculiar to tobacco only after standing for some time in contact with the air. Its taste is sharp and burning. It is very hygroscopic and dissolves readily in water and the ordinary organic solvents. The free alkaloid is strongly laevo- rotatory; its salts, on the contrary, are dextrorotatory. Nicotine is one of the most active poisons with which we have to deal; the inhalation of its vapor even in small quantities occasions difficulty in breathing. It is a diacid base and forms salts with one or two equivalents of acid. It unites with two molecules of an alkyl iodide.^ With methyl iodide it forms two isomeric methiodides: the first is obtained by directly mixing equimolecular quantities of the two substances ; the second by treating the monohydriodide of nicotine with an excess of methyl iodide and afterwards eliminating the hydriodic acid by means of sodium carbonate.® These results indicate that nicotine is a bitertiary base. In apparent contradiction to them, however, is an observation of Etard ® that the alkaloid with acetyl and benzoyl chloride yields an acetyl and a benzoyl derivative. But, as Pinner ^ has shown, this contradiction is only apparent. If the acetyl- or benzoyl-nicotine of Etard is saponified, nicotine is not again obtained, but an isomeric base, which has received the name metanicotine. This is an oily liquid which is optically inactive and boils at 275-278°. It forms a secondary base;. ^Melsens, A. ch. [3] 9, 465. ^ Kekule and von Planta, A. 87, 2. Stahlschmidt, A. 90, 222. ® Pictet and Genequand, Chemiker-Zeitung, 21, 246. « Etard, C. r. 97, 1218; 117, 170, 278; Bl. [2] 42, 297; [3] 14, 342. ’Pinner, B. 27, 1053, 2861; 28, 456. THE TOBACCO ALKALOIDS. i6i treated with acetic anhydride or benzoyl chloride, it yields the acetyl or benzoyl derivative from which it was obtained. From this Pinner concludes that these are not derivatives of nicotine itself, but of metanicotine, and that in the reaction in which they are formed tertiary nicotine is probably transformed to secondary metanicotine. We shall return to this reaction later on. Nicotine is an unsaturated body. When heated to 260° with hydriodic acid and red phosphorus it is reduced to dihy- drofiicotine, C10H16N2, a laevorotatory liquid boiling at 263-264°. On treatment with sodium and alcohol it adds six or eight atoms of hydrogen and yields hexahydronicotine and octohydronicotine. Hexahydronicotine, C10H20N2, first obtained by Liebrecht,® has been studied chiefly by Blau.® It is a solid which melts near 30° and boils at 245^.5. It dissolves readily in water, alcohol, and ether, and closely resembles piperidine in odor. It is a diacid base of secondar}^-tertiar\' character (mononitroso-derivative). Octohydronicotme, C10H22N2, is a liquid which boils at 259- 260°. It yields with nitrous acid a dinitroso-derivative and it is consequently a bi-secondary base. On passing the vapor of nicotine through a tube heated to redness, Cahours and Etard obtained hydrogen, ammonia, hydrocyanic acid, methane, ethane, ethylene, propylene, and pyridine bases. Among these last they isolated /?-propylpyridine, a lutidine, a picoline, and pyridine. The presence of these bases has also been determined in tobacco-smoke.^^ Oxidation of Nicotine. — Nicotine is readily oxidized; on exposure to the air it absorbs oxygen, turning brown in color. Under the action of oxidizing agents it yields different products whose study has thrown much light on the constitution of the alkaloid. ® Liebrecht, B. i8, 2969; 19, 2587. ® Blau, B. 24, 326; 26, 628, 1029; 27, 2535; M. 13, 330. Cahours and Etard, C. r. 88, 999; 90, 275; 92, 1079; Bl. [2] 33, 951; 34, 449. “ Vohl and Eulenberg, A. Pharm. 147, 130. Kissling, Dingier' s polytech- nisches Journal, 244, 64, 234. Le Bon and Noel, C. r. 90, 1538. i 62 THE VEGETABLE ALKALOIDS. By the action of chromic acid on nicotine, Huber in 1867 obtained an acid of the formula CeHgNOj, which he named nicotinic acid. Later the same result was attained by Weidel and Laiblin by using nitric acid or potassium permanganate. Now nicotinic acid we found to be /?- pyridine carboxylic acid (page 57); nicotine is accordingly a pyridine derivative having in the /^-position the group — CgHjoN : COOH 1 \/ 1 1 \/ N N Nicotinic acid Nicotine The oxidation of the quaternary derivatives of nicotine leads- to a like result. We have seen that nicotine yields two mono- methiodides. One of these is formed by treating the monohy- driodide of the alkaloid with methyl iodide. In this derivative,, then, the methyl iodide is attached to that nitrogen atom which ;is less strongly basic. On changing this methiodide to the hydroxide and oxidizing it with potassium permanganate, Pictet and Genequand obtained trigonelline (the methyl betaine of nicotinic acid): / ^-C^HioN 0 \/ \/ 1 N— OH 1 N 0 1 CH3 I CH3 Nicotine monomethyl hydroxide Trigonelline This result seems to indicate that the nitrogen atom of the pyridine nucleus is less basic than the other, and that in the Huber, A. 141, 271; B. 3, 849. 13 Weidel, A. 165, 328. 11 Laiblin, A. 196, 129; B. 10, 2136; 13, 1212, 1996. 13 Pictet and Genequand, B. 30, 2117. THE TOBACCO ALKALOIDS. 163 monacid salts of the alkaloid the acid is attached to the nitrogen of the group CgHi^N. With weaker oxidizing agents nicotine yields other oxidation- products. Heating it with mercuric oxide to 240° gives rise to oxy trinicotine ^ C35H27N6O2. Hydrogen peroxide oxidizes nico- tine to a base, oxynicotine {nicotine oxide) ^ CioHi4N20.^® Under the action of potassium ferricyanide in alkaline solu- tion, of silver oxide, or of silver acetate, nicotine loses four atoms of hydrogen and is converted into a base, nicotyrine^ C10H10N2. Cahours and Etard, who first obtained this substance, gave it the name is odi pyridine. When, however, it was shown that nicotine is not a dipyridyl derivative, as it had been supposed to be, Blau proposed that the name be changed to nicotyrine. Nicotyrine is a colorless, oily liquid which boils at 280-281°. It is little soluble in water; its odor is characteristic. Unlike nicotine, nicotyrine is optically inactive. Action of Bromine on Nicotine. — This action has been studied by Pinner. When a solution of nicotine in acetic acid is treated at the ordinary temperature with bromine there is formed a perbromide, CioHnBr5N20. Boiling water, ammonia, or sul- phurous acid serve to convert the latter into dihromcotininej C5H4N — C5HeBr2NO (prisms melting at 125°). On oxidation dibromcotinine yields nicotinic acid — a reaction which indi- cates that the pyridine nucleus of the molecule has not been affected by the bromine. On reduction with zinc-dust and dilute hydrochloric acid, it is converted into cotinine, C10H12N2O. Cotinine forms a mass of radiating crystals which melt at 50°; it boils at 336°. Both dibromcotinine and cotinine are monacid bases. If nicotine is heated to 100° with bromine in a solution of hydrobromic acid, it yields the hydrobromide of dihromticoniney C5H4N — C5H4Br2N02-HBr. The free dibromticonine forms granular cr}^stals which melt at 196°. It is likewise a monacid Pinner and Wolffenstein, B. 24, 61, 1378; 25, 1428. Auerbach and Wolffen- stein, B. 34, 2411. Pinner, B. 25, 2807; 26, 292, 765; 27, 2861; 28, 18, 1932. 3 0112 072534065 164 THE VEGETABLE ALKALOIDS. base, and on oxidation yields nicotinic acid. Reduction with zinc-dust in alkaline solution gives rise to monobromticonme, C5H4N— CsH^BrNO,. ... When heated with baryta-water to 100°, dibromticonine is decomposed into nicotinic acid, malonic acid, and methylamine. This decomposition indicates that nicotine contains the atomic groups -c— C— C— C— — NCHg N Inactive Nicotine— Nicotine possesses a high specific rotatory power -i66°.33). The conversion of the active alkaloid into the inactive form is effected by heating an aqueous solution of the monochloride or sulphate for some time at about 200 . Pictet *’ thus reduced the specific rotation to - 3 °.g 5 , which repre- sents a conversion into inactive nicotine to the extent of 97.7%- In nearly all its properties, save optical activity, t-mcotme appears to be identical with the active form. From this Pictet concludes that the former does not constitute a distinct racemic derivative, but is simply a mixture of d- and f-mcotine. The separation of f-nicotine into its active constituents has been partly effected recently by Pictet and Rotschy.^* By re- peatedly recrystallizing the salt formed with