Alkaloids

ALKALOIDS. For reasons given below, it is not possible to give a precise definition of this term, although to (he chemist there is no ambiguity in its use. Man had from very early times drugs, but his knowledge of the alkaloids themselves began little more than a century ago. In 1803 Derosne observed that a syrupy extract of opium (q.v.),when diluted with water, deposited crystal line matter, which he separated and purified and so prepared the first alkaloid, probably impure narcotine (q.v.). He attempted to improve the yield by adding alkali to the diluted opium syrup and obtained a different substance, which undoubtedly contained the alkaloid morphine (q.v.). About the same time Seguin made simi lar observations and also had morphine in his hands. But the crowning achievement of first isolating a typical alkaloid in a pure state and describing its properties in unmistakable terms was re served for Serturner, who in 1816 was able to announce that he had found a new organic, alkaline, salt-forming base, apparently related to ammonia, of which he had prepared a number of salts and whose physiological action he had been able to demonstrate. Meanwhile, in 181o, B. A. Gomes, by treating an alcoholic extract of cinchona bark (q.v.) with alkali, obtained a precipitate, which he purified by crystallization from alcohol and called "cin chonino." Houtou-Labillardiere observed its basic properties and brought it to the notice of his friends Pelletier and Caventou, who, guided by Serturner's description of morphine as an "organic alkali," were able to show in 182o that "cinchonino" was a mixture of two substances, which they named quinine and cinchonine. Be tween 1817 and 184o practically all the more important alkaloids were isolated, including emetine, veratrine, strychnine, piperine, caffeine, quinine, berberine, confine, atropine, codeine, thebaine, (qq.v.), cinchonine (see CINCHONA), hyoscyamine (see HYOS CYAMINE), curarine, quinidine, aconitine and colchicine.

Definition.—Thetwo points Sertiirner stressed in his descrip tion of morphine—its basic, salt-forming, ammonia-like character and its physiological action—would be enough upon which to frame a definition of the term alkaloid, were it not for the fact that since then substances such as methylamine and amino-acids (q.v.), such as asparagine and betaine, have been found in plants. A growing knowledge of the intimate structure of some typical alka loids, led at one time to confining the term to naturally-occurring derivatives of pyridine (q.v.), which is a structural feature of the majority of known alkaloids; further knowledge, however, made it clear that pyridine formed no part of the 'structure of some alka loids and this narrow definition had to be abandoned. With our present knowledge, alkaloids may be defined as relatively complex, basic substances, occurring naturally and exhibiting physiological action. The simple substances already referred to, such as methylamine, asparagine and betaIne, together with those formerly known as "animal alkaloids," have been grouped together by Barger as "simple natural bases," though it is difficult to draw the dividing line.

General and Special Interest of Alkaloids.

Everyoneis familiar with the physiological action of alkaloids, e.g., quinine is naturally associated with malaria, morphine (q.v.) with the relief of pain, cocaine (q.v.) with minor surgical operations and atro pine (q.v.) with the skilled work of the oculist. The chemist on the other hand looks upon alkaloids as fascinating problems for the exercise of his technique and imagination. He has devoted much attention to devising methods for their detection, isolation and purification; and he has displayed considerable ingenuity in splitting them into recognizable fragments, and so acquiring such a knowledge of their intimate structure as will provide a basis for producing them at will in the laboratory. He has begun to take an interest also in the reason for the occurrence of these things in plants and the methods by which they are produced in nature; and one of his aims is to place the pharmacology (q.v.) of alka loids on a sound chemical basis; so that he may know, for exam ple, the nature of the chemical action which takes place when a neutral salt of cocaine is applied to a nerve-ending and local anaes thesia ensues, and is able to explain the remarkable specific tox icity of quinine and emetine to the protozoa which cause malaria and amoebic dysentery, respectively, in man.

Over Boo alkaloids are known but of these only about 24 are in common use, chiefly in medicine, though some of them find other outlets, e.g., strychnine as a vermin killer, quinine and pilocarpine as cosmetics, while certain of the cinchona alkaloids are used for rendering woollen textiles moth-proof. They are comparatively restricted in their distribution among plants, occurring chiefly in the Rubiaceae, Papaveraceae, Fumariaceae, Solanaceae, Legumi nosae and Apocynaceae, and to a less extent in the _Rosaceae, Graminaceae, Labiatae and Compositae. Where alkaloids do occur they are to be found in all parts of the plants, but especially in the barks and fruit-rinds of perennial species, the leaves and seeds of annual plants and the roots of biennials. They tend to accu mulate in those parts of a plant which are thrown off at the end of the growing season, and this is one of the principal arguments for the view that alkaloids are of no use to plants, but are mere waste products of metabolism.

Detection and Preparation of Alkaloids.

The processes by which alkaloids are obtained from plants depend upon the complete extraction of the dry ground material (bark, roots, leaves or seeds) with a suitable solvent, usually alcohol or slightly acidified water. The solvent is then distilled off in vacuo and the resulting extract diluted with water, made distinctly acid, if nec essary, and left to stand to deposit impurities. It is next made alkaline, preferably with sodium carbonate or ammonia, when the bulk of the alkaloid is usually precipitated and can be filtered off. If the alkaloid is soluble in water, other devices involving the use of immiscible solvents (i.e., liquids which, when shaken with watery fluids, will remove soluble substances therefrom and then form a separate layer) and sometimes special precipitants or ab sorbents have to be adopted. These processes almost invariably yield a mixture of alkaloids, since the latter rarely occur singly in plants. The separation of these mixtures into their components can generally be achieved (a) by treating the mixture of bases with various solvents in turn, and (b) by converting the partially separated components into salts by exact neutralization with acids and fractional crystallization of the salts. These processes have to be repeated until there are no longer changes in the physical and chemical properties of the fractions. Each kind of alkaloidal plant requires different treatment and long experience has enabled the processes to be greatly simplified for most of the alkaloids which are produced on a large scale for use in medicine, though on the other hand the standard of purity required in these is con stantly rising. The balance between quality and expense of pro duction is settled periodically by the standards set up for medic inal alkaloids and their salts in the various national pharmaco poeias (q.v.) . The criteria of purity for alkaloids are the same as those for any other organic chemical, viz., determination of physi cal constants such as melting point, boiling point, optical rotation and the chemical composition as determined by ultimate analysis (see CHEMISTRY: Analytical). These, the methods of the research laboratory, are those which the works chemist and the analyst must always have in mind as the ultimate court of appeal in evolving their short routes to control of quality in alkaloids.

The analytical work of the toxicologist in connection with alka loids is important. The methods by which poisonous alkaloids are extracted from viscera and stomach contents do not differ in prin ciple from those for the extraction of alkaloids from plant mate rial, but in these cases the problem is greatly complicated by the risks of loss by decomposition of the small quantities of alkaloid to be recovered. The usual methods of purification and conversion into identifiable derivatives cannot be applied to these minute quantities; so use has to be made of crystalline form, colour tests which most of the alkaloids give with certain reagents, or in a few cases special pharmacological tests, methods which are perfectly satisfactory in the hands of experts.

Determination of the Intimate Structure of Alkaloids. —A few of the alkaloids are liquid and volatile and contain only three elements—carbon, hydrogen and nitrogen; but most of them contain oxygen in addition, and are colourless, crystalline solids. Most alkaloids are optically active (see STEREOCHEMISTRY) and in a few cases the salts show an optical activity opposite in kind to that of the base. Regarding the alkaloids as extensively substi tuted ammonias, those containing two atoms of nitrogen should be capable of forming salts containing two molecules of monobasic acids, and this is so with some alkaloids such as quinine, C2oH2402N2 (q.v.), but quite frequently, as in the case of strych nine (q.v.), also containing two atoms of nitrogen, the alkaloid combines with only one molecule of a monobasic acid, so that its hydrochloride is represented by the formula C21H2202N2, HCI, and this difference in the basicity of the two nitrogen atoms must be taken into account in assigning constitutional formulae (see CHEMISTRY : Organic) to such alkaloids.

In most cases the nitrogen atoms are tertiary, that is, each is united to three different carbon atoms, one of which in such cases is generally in a methyl group, so that the state of such nitrogen atoms can be graphically represented by (a).

Such a group is called a methylimino-group, and a method of estimating these in alkaloids has been devised. Sometimes a sec ondary nitrogen group is present, e.g., ammonia, in which only two of the hydrogen atoms have been replaced by carbon linkages (b). The hydrogen of a secondary nitrogen group can in most cases be replaced in an alkaloid by a methyl group, and the secondary nitrogen (b) is thereby converted into a methylimino group (a) which can be estimated.

By similar means it is possible to discover how the oxygen atoms in an alkaloid are built into the molecule. Most frequently they are present as hydroxyl (•OH) groups or derivatives of such groups, such as methoxy acetoxy or ben zoxy Occasionally a carboxyl group (.COOH) is present, either as such or linked up with the nitrogen to form a betaine (q.v.) or with its hydrogen atom replaced by methyl forming a methyl ester. There are now well-established methods of ascertaining the presence or absence of all these various types of groups, and after a preliminary investigation of a new alkaloid in this fashion the chemist arrives at a point at which he can write the empirical formula of the alkaloid in some such extended form as (c), that is, he has still to ascertain how the alkaloidal nucleus, consisting of x carbon atoms and y hydrogen atoms is built up, and how the groups shown in brackets are built into it. This further information is generally obtained by breaking up the alkaloid chemically into small fragments, examining each of the pieces in the same way as the parent alkaloid was examined, and going on with this process until a recognizable fragment, which may be any one of the thousands of known organic compounds, is found. With that first clue to guide him, and within the limits rigidly prescribed by all he knows as to the composition and reactions of the alkaloid, the chemist can then proceed to visualize a constitutional formula. This breaking-down process is generally accomplished by carefully regulated oxidation of the . alkaloid, with such agents as potassium permanganate, chromic acid or nitric acid, substances which burn off a few carbon atoms at a time leaving products which generally become simpler in char acter ; or a more complicated process called "exhaustive methyla tion" may be used, in which the nitrogen atom of a carbon nitrogen ring is loaded with substituents until it breaks from its cyclic carbon attachments leaving fragments either recognizable or convertible into recognizable substances.

The Opium Alkaloids.

Opium(q.v.) contains at least 25 alkaloids of which morphine (q.v.) is by far the most important, followed by codeine (morphine methyl ether), thebaine, narcotine, papaverine, and protopine (qq.v.). Much progress has been made in the determination of the intimate structure of the alkaloids of opium and they can all be regarded in a broad sense as derivatives of isoquinoline. Thus the five minor alkaloids, papaverine, laudanosine, codamine, laudanine and laudanidine, form a group of substituted /-benzylisoquinolines; narcotine and narceine (q.v.) are /-meconylisoquinolines, and as the meconyl residue .CH-C6H2(0Me)2-00.0 itself can be regarded as derived from benzyl, C61-15-CH2, all seven alkaloids are derivatives of /-benzyl isoquinoline.

The next group of opium alkaloids, morphine, codeine and the baine are more condensed and more complex in structure. The simplest member of the group to which they belong is glaucine, found in the yellow-horned poppy, Glaucium luteum, but not in the opium poppy. Glaucine has been synthesized from laudanosine by a simple reaction, which gives rise to a phenanthrene (q.v.) complex by internal condensation within the benzylisoquinoline structure and so this whole group of alkaloids is conveniently spoken of as the phenanthrene group. Synthesis of the simpler members of this group is in progress, but their representatives in opium, the three alkaloids just mentioned, constitute an interesting variation on the typical structure of the phenanthrene group and for them possible formulae—of which those of Pschorr 0905), Knorr and Horlein (1906), and Gulland and Robinson (1923) may be mentioned—are still being discussed.

A third group is represented in opium by two members, proto pine and cryptopine. The former is almost the typical alkaloid of the poppy order (Papaveraceae) since it has been found in most species of this order, the alkaloids of which have been systematically examined. This group can be regarded as developed from berberine (q.v.), though curiously enough no alkaloids of the berberine type have been found in any member of the poppy order. Their intimate structure has been determined by W. H. Perkin, in whose laboratory both protopine and cryptopine have been synthesized (1926).

(See also EPHEDRINE, HYDRASTINE, LAEVO-HYOSCINE, NICO TINE, PHYSOSTIGMINE, PILOCARPINE, PURINE, SPARTEINE CHEM