Alkaloids

ALKALOIDS (from Arabic alkali—alkali and Greek eidos—form), the name for nitrogen-containing compounds isolated from plants that possess basic properties and, in most cases, a strong physiological effect. The first of such compounds, morphine, was obtained from opium by Sertürner and described in 1817 as an alkaline base capable of forming salts and similar in this respect to ammonia. Sertürner's discovery prompted similar research on other medicinal plants, which quickly led to the discovery of the most important alkaloids. The bases isolated from plants began to be called alkaloids at the suggestion of Meissner, who discovered veratrine in 1819. At present, more than 200 alkaloids are known. Relatively few alkaloids have been isolated from animal organisms. The concept of alkaloids has repeatedly changed in its scope: at times it encompassed all nitrogen-containing bases, at other times it narrowed to a specific group of pyridine derivatives, only to be soon extended again to other groups of nitrogen derivatives containing nitrogen only in the ring (Winterstein and Trier) or in the ring and in an open chain (Pictet, Tschirch, Gadamer). Classification. In view of the special properties of alkaloids, their study was of great interest, but also presented great difficulties. At present, the investigation of quite a few alkaloids has been crowned with the elucidation of their structure and even their synthesis. The elucidation of the structure of alkaloids determines their place in the general classification of organic compounds, but does not detach them from the group of alkaloids. Alkaloids are usually described together, as they all have much in common in their properties, genetic relationships, and biological significance. Alkaloids are classified according to the method of nitrogen bonding and the structure of the basic nucleus. According to Tschirch, they are divided into the following groups: 1. Aliphatic bases: methylamine, choline, muscarine, etc. 2. Aromatic amines and aliphatic bases with an aromatic nucleus: phenylethylamine, p-oxyphenylethylamine, adrenaline, ephedrine, etc. 3. Derivatives of pyrrolidine. 4. Derivatives of pyridine: nicotine, etc. 5. Derivatives of imidazole: imidazolyl-ethylamine (histamine), pilocarpine, allantoin, etc. 6. Derivatives of condensed pyrrolidine and piperidine rings: atropine, hyoscyamine, cocaine, alkaloids of pomegranate bark, etc. 7. Derivatives of pyrimidine. 8. Derivatives of purine: caffeine, theobromine, theophylline, piperine, coniine, arecoline, etc. 9. Derivatives of indole: strychnine, brucine, physostigmine. 10. Derivatives of quinoline.

Cinchona alkaloids—cinchonine, cupreine, quinine, etc., alkaloids of aconite, etc. 11. Derivatives of isoquinoline.

Opium alkaloids—papaverine, morphine, codeine, etc., alkaloids of ipecacuanha, Colombo, hydrastine, etc. 12. Alkaloids with oxygen and nitrogen in the ring: carpaine. 13. Alkaloids of unknown structure: veratrine, yohimbine, etc. Occurrence. Alkaloids are found only in certain specific plants and families. Cryptogamous plants contain alkaloids as exceptions (some fungi, ergot, fly agaric, and lycopods). Among gymnosperms, alkaloids have been isolated only from yew (Taxus) and ephedra. Among monocotyledons, alkaloids have been found in the families Palmae, Liliaceae, and Amaryllidaceae. However, the majority of alkaloids have been isolated from dicotyledonous plants, which are at a higher stage of development; the families richest in alkaloids are Apocynaceae, Berberidaceae, Leguminosae, Loganiaceae, Menispermaceae, Papaveraceae, Ranunculaceae, Rubiaceae, and Solanaceae. Each family of alkaloid-bearing plants has its own specific alkaloids, and only a few alkaloids, such as berberine and caffeine, are found in different families. In plants, it is rare to find only one alkaloid; for the most part, there are several; thus, more than 20 alkaloids have been isolated from opium and cinchona bark. In this case, a distinction is made between main alkaloids and secondary ones. In such cases, the alkaloids are close in structure and properties and are in genetic relationships with each other. Alkaloids are found in plants in very different quantities, usually in tenths of a percent or less (often only traces), but they also reach several percent (in cinchona bark more than 10%, in opium more than 20%). Soil, climate, weather, cultivation, and the age of the plant often have a great influence on the alkaloid content. In plants, alkaloids are in most cases bound to acids: mineral (sulfuric, phosphoric, and especially nitric), common plant acids (malic, citric, oxalic, succinic, etc.), or special acids characteristic of the plant (e.g., quinic, meconic, chelidonic, aconitic, etc.). Alkaloids are especially often bound to tannins in plants. Alkaloids are found in all parts of plants, but they are formed mainly in tissues that are in a state of high vegetative activity. On the formation of alkaloids in plants, several hypotheses have been put forward. In view of the nitrogen content in alkaloids, alkaloids were classified as reserve substances; due to the accumulation of alkaloids in the peripheral parts of plants and the toxicity of alkaloids, they were attributed the significance of protective substances against the consumption of plants by animals. Pictet viewed alkaloids as decomposition products of protein substances that had undergone further transformations for the purpose of detoxification. According to Gadamer, alkaloids are accidental products that arise during particularly high vegetative activity in parallel with protein synthesis. Baly, Heilborn, and Hudson established the initial stages of the photosynthesis of nitrogen compounds from potassium nitrate and activated formaldehyde and provided a general scheme: potassium nitrate, carbonic acid, potassium nitrite, activated formaldehyde.

(H.CO.H) formhydroxamic acid, 4-N-1J-OH, N-OH, hexoses, nitrogenous bases, alpha-amino acids, alkaloids and xanthine derivatives, substituted alpha-amino acids (histidine, etc.), proteins. It must be kept in mind that the processes of building alkaloids, due to the diversity of their structure, cannot be uniform. The properties of alkaloids are very diverse. Alkaloids containing only C, H, and N are mostly liquid, volatile, and often possess a strong odor. Alkaloids containing also O are solid, in the majority crystallize well, and do not possess an odor. When heated at normal pressure, the majority of alkaloids decompose; only a few sublime in crystals (caffeine, atropine, etc.); in a vacuum at 10 mm pressure, the majority of them sublime. Usually, alkaloids are colorless; a few are colored, especially in the form of salts, yellow or yellow-red. In the ultraviolet region of the spectrum, alkaloids give characteristic absorption spectra. Some alkaloids possess fluorescence in solutions (quinine). The majority of alkaloids are optically active and rotate the polarized beam to the left or right. In relation to light and air, some alkaloids, especially oxygen-free ones, are quite sensitive, resinify, and turn brown. In water, free alkaloids, with few exceptions, are insoluble or difficult to dissolve; in alcohol, all dissolve without exception. Ether dissolves some alkaloids little or not at all (morphine). Alkaloids also dissolve in chloroform, amyl alcohol, ethyl acetate, benzene, less in petroleum ether and carbon disulfide. Solutions of alkaloids in water react alkaline to litmus, methyl red, and iodeosin and in the majority of cases possess a bitter taste. Chemically, alkaloids are organic derivatives of ammonia. They therefore possess basic properties and combine with acids into salts like ammonia and amine bases without the splitting off of water. The basic properties of alkaloids are weaker than those of ammonia and magnesium hydroxide, but often stronger than those of heavy metal hydroxides. The majority of alkaloids are tertiary bases, a few are secondary or quaternary ammonium bases. The nitrogen belongs either with all three valences to one or two rings, or two valences close a ring, and the third is connected to hydrogen or more often to CH₃ in the group =N-CH₃, named by Tschirch "alkaloidophoric." Salts of alkaloids, unlike free bases, in the majority of cases are easily soluble in water; in benzene, ether, chloroform, and amyl alcohol, on the contrary, they are difficult to dissolve or insoluble. Alcohol dissolves the majority of salts. These changes in the solubility of free bases and salts are very important for the extraction and purification of alkaloids. Some dibasic alkaloids give two series of salts (quinine). Many salts contain water of crystallization, which sometimes effloresces. The oxygen of alkaloids is found either in the form of an OH-group with the character of alcohols or phenols, or in the form of CO- or COOH-groups. In the hydroxyl and carboxyl, hydrogen is often substituted by CH₃, so that alkaloids are methyl esters. Some alkaloids have the character of esters, like atropine, cocaine, and are split upon prolonged heating of their salt solutions. This must be kept in mind when preparing sterilized solutions. Hydrochloric salts of alkaloids combine with chloroplatinic acid and chloroauric acid into difficultly soluble, mostly well-crystallizing, double salts. Also with chloride and iodide compounds of cadmium, mercury, and bismuth, they give very difficultly soluble double salts. With many other reagents: iodine in potassium iodide, tannin, phosphomolybdic, phospho- and silicotungstic, picric, picrolonic, and styphnic acids, alkaloids give precipitates of salts even in the most dilute solutions. Solutions of these substances are used for detecting the presence of alkaloids in general and are called general alkaloid reagents. Furthermore, alkaloids sometimes give very beautiful and characteristic-only-to-a-given-alkaloid phenomena of coloration and color transitions with strong mineral acids, with ferric chloride, with chlorine water, with molybdic, vanadic, and chromic acids in the presence of sulfuric acid, with formalin and sulfuric acid, and many other reagents. The reason for the appearance of colors is mostly not clarified, but in many cases, the reactions can be considered as oxidative. Color reactions serve as special reactions for the recognition and determination of individual alkaloids. Methods of obtaining alkaloids from plants depend in each case on their physical and chemical properties. Volatile alkaloids are distilled with water vapor after alkalization with milk of lime. Mostly, the method of extraction is applied, whereby alkaloids are extracted in the form of salts or in the form of free bases. In those cases where alkaloids represent ammonium bases not decomposable by alkalis, alkaloids are precipitated from solutions by corresponding general alkaloid reagents, giving difficultly soluble precipitates. Then, to obtain the alkaloids, these precipitates are decomposed by one or another method, with barium hydroxide, hydrogen sulfide, etc. By applying the indicated methods, the isolation of alkaloids from plants and separation from accompanying substances is achieved. Since there is usually not one but several alkaloids in plants, a very difficult task of separating alkaloids from each other arises. Complete syntheses of alkaloids, already accomplished in a whole series of cases, have rather scientific interest. Practically, complete syntheses are already applied for the preparation of adrenaline, caffeine, theobromine, and theophylline. More often, partial syntheses of natural alkaloids and the obtaining of their derivatives are applied. An example of such a synthesis can be cocaine: from alkaloids accompanying cocaine, ecgonine is obtained, and it is then converted by benzoylation and methylation into cocaine. The obtaining of derivatives of natural alkaloids has as its goal to eliminate the harmful or unpleasant action of alkaloids or, by a deeper change in the composition and structure of alkaloids, to cause the manifestation of a new action and the suppression of the one that existed before. Thus, quinine, upon conversion into ethyl carbonate (Euquinine) or into diquinine carbonate (Aristochin), almost loses its bitter taste, etc. The study of the structure of alkaloids and the clarification of their physiologically active groups gives an indication of paths to the construction of similarly acting other substances. Thus, for example, the determination of the physiological significance of the benzoic acid radical in cocaine led to the synthesis of a large quantity of derivatives of benzoic acid, which turned out to be very valuable local anesthetic agents (novocaine, orthoform, and many others). The discovery of the quinoline nucleus in quinine long ago led to the syntheses of antifebrile agents, which led to the obtaining of a large number of valuable antipyretics (phenacetin, antipyrine, pyramidon, etc.), and recently the factory in Elberfeld (Bayer firm) offers an antimalarial agent—plasmochin, which is a derivative of quinoline and possesses an advantage over quinine in that it acts already in doses 10 times smaller and does not cause ringing in the ears; plasmochin in tropical malaria, although it acts slower than quinine, kills the crescent-shaped sexual forms in the blood. Despite the enormous importance of alkaloids as medicinal agents, in Russia before the imperialist war, alkaloids were not produced at all. The war gave an impetus to the establishment of the production of alkaloids, and at the present time, Gosmedtorgprom prepares atropine, morphine and its derivatives—codeine, dionin, heroin, and also stypticin. The need of the USSR for alkaloids for 1925/26 was calculated by the Special Conference on the Restoration of Fixed Capital of Industry under the Supreme Council of the National Economy for quinine and its salts at 88,000 kg, in the amount of 2,590 thousand rubles, for other alkaloids and their salts—10,811 kg, in the amount of 15,400 thousand rubles. In 1913, 64,000 kg of quinine and its salts were imported, and 22,600 kg of other alkaloids. The greater part of this import came from Germany: 43,700 kg of quinine and 13,000 kg of other alkaloids.

N. Valyashko.

Detection of Alkaloids in forensic cases. The objects of investigation (viscera, food residues, or others) are ground up and infused with alcohol acidified with tartaric acid; from time to time, the alcohol is drained and replaced with new portions. Infusion is continued for 3-4 days. Then the alcoholic extracts, combined and filtered, are evaporated (in a vacuum or on a water bath at a temperature not higher than 40°) to the consistency of syrup. The residue is treated with absolute alcohol, adding it dropwise; the liquid is allowed to settle and is filtered, the filtrate is evaporated again, and the operation is repeated until the alcohol ceases to precipitate anything. Then the syrupy residue, after evaporation of the alcoholic filtrate, is dissolved in a small amount of water (25-50 cc) and repeatedly extracted in a separatory funnel with chloroform until the chloroform ceases to leave anything upon evaporation. After this, the aqueous liquid is alkalized with aqueous ammonia and again repeatedly extracted with chloroform until the chloroform ceases to extract anything (which is determined by evaporating a drop of the extract on a watch glass). The chloroform extract from the alkaline solution is evaporated at room temperature. For purification, the residue is dissolved in a small amount of water with the addition of a small amount of hydrochloric acid until a weakly acidic reaction is achieved, and filtered. The filtrate is repeatedly extracted with chloroform, then the aqueous liquid is again alkalized with ammonia and extracted with chloroform. The chloroform extract from the alkaline solution is evaporated. If necessary, the purification is repeated. Having dissolved the residue in chloroform, it is distributed onto several watch glasses. -General reagents for Alkaloids. A small part of the residue is dissolved in a few drops of water with the help of 1% HCl, distributed onto 3-4 watch glasses, evaporated, and the residues are dissolved in 1-2 drops of water. Alkaloids, as bases, form simple and complex salts with acids; many of these salts are sparingly soluble in water. To precipitate Alkaloids, one drop of one of the reagents that form insoluble salts is added to a drop of the obtained solution. Of their large number, the following solutions are most often used: 1) tannin, 2) picric acid, 3) iodine in the presence of potassium iodide, 4) bismuth iodide in the presence of potassium iodide, 5) phosphomolybdic acid, 6) chloroplatinic acid. Besides alkaloids, all these reagents precipitate proteins and their decomposition products (peptones, ptomaines, etc.). Therefore, in the absence of precipitates, the absence of Alkaloids is proven by general reagents. Almost always, traces of protein decomposition products, which are precipitated by general reagents for Alkaloids, are extracted from proteinaceous objects by chloroform. -Color reactions. Many Alkaloids give colored products with certain reagents. Sometimes similar color reactions are also given by protein decomposition products, which forces one to treat color reactions with greater caution and to draw conclusions from them only when they coincide with the results of physiological testing for Alkaloids: 1) concentrated sulfuric acid gives a yellow coloration, then orange, turning into violet-red with veratrine; 2) concentrated sulfuric acid with traces of nitric acid: blood-red with brucine, similar to pure sulfuric acid with veratrine, yellow-red with papaverine, red, turning into violet-red upon heating, with narcotine; 3) concentrated sulfuric acid with formaldehyde (Marquis reagent): violet with morphine, codeine, heroin, narcotine, and papaverine; violet, quickly turning into black-green, with apomorphine; 4) concentrated sulfuric acid with molybdic acid (Fröhde reagent): violet with morphine, red with brucine, yellow, turning into violet-red with veratrine; 5) concentrated sulfuric acid with a crystal of potassium dichromate: blue (colored streaks), turning into violet, red, then disappearing, with strychnine. There are other color reactions; only the most characteristic ones are indicated here. -Quantitative determination of Alkaloids is usually performed volumetrically. The Alkaloid residue is dissolved in a specific volume of ⁿ/₁₀₀ HCl solution, and the excess acid is titrated with an ⁿ/₁₀₀ sodium hydroxide solution using iodeosine as an indicator in an ethereal solution. It is verified beforehand that the flask in which the titration is performed does not release alkali into the distilled water, which is evident from the absence of a change in the color of the iodeosine.