SYNTHETIC REMEDIES.
Early Distinction between Inorganic and Organic Chemistry.
The development of organic chemistry in the course of the nineteenth century is a subject so vast that it is mentioned in this place with something approaching despair. The great chemists who, in the latter part of the eighteenth and in the early years of the nineteenth century, had rescued their science from the superstitious and fantastic theories and conceits which had encumbered it, Lavoisier, Priestley, Scheele, Cavendish, Dalton, Fourcroy, Berzelius, and many others who might be named, distinguished sharply between the products of the mineral kingdom and those which they called organic, that is, substances of vegetable or animal origin, combined, it was agreed, under the influence of what was described as vital force. This force, it was considered, inherent in living bodies, could never be imitated in the laboratory, and its achievements were beyond human skill. It was even doubted whether the elements composing organic substances were subject to the same laws of combination as were those of the mineral world.
Lavoisier, it is true, regarded organic bodies as consisting of radical compounds, hydrocarbon radicals, as he called them, instead of the metallic bases. His last scientific work was the investigation of the statics of organic chemistry, and on this subject his clear vision would probably have enabled him to anticipate many modern conclusions. He had already recognised some of the transformations of sugar, had analysed alcohol, and had declared that in animal and vegetable chemistry no less than in the inorganic kingdom nothing is ever destroyed, but that vegetation and animalisation are only inverse phenomena of combustion and putrefaction.
Synthetic Organic Compounds.
Some isolated results of the artificial productions of organic substances are recorded which do not seem to have been recognised as challenging the reign of vital force. Scheele, in 1786, formed oxalic acid by oxidising sugar by nitric acid; and in 1822 Döbereiner produced formic acid, previously known as a distillate of ants, by oxidising tartaric acid. In both these cases, however, the transformation was essentially one from a previous organic substance.
The inauguration of synthetic chemistry is understood to date from the year 1828 when Wöhler, then a professor of chemistry at Berlin, produced a supposed cyanate of ammonium by the action of ammonium chloride on silver cyanate. Wöhler was surprised to find the cyanate of ammonium which he had obtained did not correspond with other ammonium salts, but resembled, and as he afterwards proved, was identical with the organic substance, urea, a crystalline compound which constitutes about half of the solid matter dissolved in urine. Wöhler and Liebig next collaborated in a study of organic substances, and one of the early results of their investigations was the discovery of the compound radical, benzoyl, as they termed it, C7H5O, which they found could be combined with chlorine, bromine, iodine, sulphur, ammonium, and other substances, always retaining its own individuality. It was, in fact, a compound radical, and though it has never been isolated, its compounds prove its character. Berzelius was so struck by this discovery that he suggested the name of proine or orthrine, either meaning the dawn, in substitution for benzoyl.
Friedrich Wöhler.
(From the Royal Collection of Etchings at Munich.)
Born at Eschersheim, near Frankfort, 1800; died at Göttingen, 1882. Wöhler’s notable discovery of the artificial production of urea in 1828 is famous as the starting point of synthetic chemistry.
Henceforward discoveries and theories based on them, or propounded to explain them, so crowd the field that even in bulky volumes the story is only told in outline. But several of the famous theories or laws or expositions, on which modern chemistry relies, have been so fertile in consequences that they must be very briefly mentioned.
Substitution.
Before 1840 the famous French chemist J. B. A. Dumas developed the theory of substitution, or “metalepsy,” showing that the hydrogen atoms in organic substances can be removed one by one from their molecules, other atoms being substituted for them. A simple illustration of this process is manifest in the action of potassium on water, though this is not an example of organic substitution. The water, H2O takes up one atom of potassium, K, in place of one of its hydrogen atoms, becoming caustic potash, KOH. It is further possible by an indirect method to replace the remaining hydrogen atom by another of potassium, yielding potassium oxide, K2O. Changes of organic bodies are always proceeding on these lines, and Frankland said the recognition of the process had contributed more to the progress of the science than any other generalisation.
Homologues.
About 1850 C. F. Gerhardt, one of Liebig’s pupils who settled in France (and died in 1856 at the age of 40), gave the next great impetus to the development of organic chemistry, or the chemistry of carbon compounds, as it was coming to be termed, by showing how vast numbers of organic compounds could be classified and grouped into homologous series. Starting, for example, with marsh gas, CH4, which is chemically known as methane, he showed how from this type methyl alcohol, CH4O, and formic acid, CH2O2, are formed. Ethane, C2H6, comes next in the series and ethyl alcohol and acetic acid follow just as methyl alcohol and formic acid follow from methane. The addition of CH2 to ethane gives propane; propyl alcohol and propionic acid following; another addition of CH2 results in butane with butyl alcohol and butyric acid; and the next type is pentane, with amyl alcohol and valeric acid in its train. Thus it was perceived that all the multitude of complex bodies included in the organic kingdom were compounded in an orderly system.
Valency.
The English chemist Edward Frankland next put forward the doctrine of valency. According to this theory atoms possess one, two, three, four, or more links each, and require that number of other atoms of minimum combining capacity to “saturate” them in a molecule. Carbon, for example, is usually considered to be quadrivalent, and as shown in the instance of methane, requires four hydrogen atoms to saturate it. But how is it then that in the case of the next type, ethane, C2H6, the conditions are satisfied? The explanation is that the molecule is arranged in this manner:
each carbon atom having three hydrogen atoms attached to it, the fourth bond uniting it with the other carbon atom. This and other difficulties led to the theory of
Structural Formulas,
towards which Kekulé, of Heidelberg, was the principal contributor. “Rational formulæ” as distinguished from “empiric formulæ” were already recognised as shown by the homologous series of Gerhardt. Let this be illustrated by the instance of alcohol. The atomic composition of compound bodies was ascertained by many of the earlier chemists. Lavoisier analysed alcohol, and assigned to it almost the same composition as we know it to be. Its empirical formula is C2H6O; but that does not explain how it is built up. By deductive reasoning it is established that alcohol is ethane with one hydrogen atom in each molecule replaced by hydroxyl (OH). Ethane is C2H6; alcohol is thus formulated—C2H5OH. That is its “rational formula.” Alcohol is a comparatively simple substance; we shall deal with some formulas of much greater complexity presently.
August Kekulé.
Born at Darmstadt, 1829; died at Bonn, 1896.
But these explanations were by no means sufficient to meet all the cases which were coming before chemists, and now Kekulé’s brilliant “closed ring” theory was conceived, and on this most of the wonderful building up of the synthetic compounds has been planned. Kekulé was puzzling over the formula C6H6 which had been found to represent benzene, now so famous as the starting point of the aromatic series. He stated that the solution of the problem came to his mind on the top of a London omnibus in 1865, when he was an assistant in the chemical laboratory of St. Bartholomew’s Hospital Medical School. He conceived the idea of a hexagonal structure with an atom of carbon at each angle, each united to one atom of hydrogen, and on one side a double link or bond, and on the other a single one, connecting it with the next carbon atom, the quadrivalency of each atom being thereby satisfied.
The formula is depicted in the margin, and is generally accepted; but it ought to be stated that it has rivals, though all are founded on the necessity of providing for the saturation of the four links of the carbon atoms.
Aniline.
Among the events which gradually led to the production of artificial compounds for which physiological properties and action have been claimed, the discovery of aniline is prominent. The substance, now so well known by that name, was first separated from indigo in 1826 in the course of a dry distillation of that dye by a pharmacist of Erfurt, named Unverdorben. He named his product “crystalline,” from its character. In 1834 the same substance, as it was later known to be, was obtained from coal-tar by Runge, who, observing the violet colour which bleaching powder caused in its aqueous solution, designated the product “kyanol.” Ten years subsequently Hofmann continued the investigations which Runge had pioneered. Meanwhile Fritzsche had obtained anthranilic acid from indigo, and from that he had produced an oily base which he called “aniline.” This term was derived from the specific name of the indigofera anil, which was the Sanskrit designation of the famous blue dye. Hofmann’s researches ultimately proved that Unverdorben’s crystalline, Runge’s kyanol, and Fritzsche’s aniline were all chemically identical. Hofmann would have preferred to retain the first of these names, but the more definite aniline prevailed.
The colour producing power of aniline had been observed (as has been already mentioned) by Runge in 1834, but it was not until 1856 that this property became of practical importance, when W. H. Perkin, at the time a pupil of Hofmann’s, commenced the investigation which resulted in such a complete revolution in the dyeing industry. Perkin’s patent for his “mauve” dye was obtained in 1858. It is an interesting circumstance that he made his discovery as a consequence of experiments he was conducting with the view of manufacturing an artificial quinine. Now we may turn to the
A. W. von Hofmann.
Born, 1818; died, 1892. Was Director of the Royal College of Chemistry, London, 1845–1864; subsequently Professor of Chemistry in Berlin University. Hofmann commenced the researches into coal-tar chemistry and established the chemical characteristics of aniline, and was thus one of the principal founders of modern organic chemistry.
Imitation of Natural Alkaloids
(showing how coniine, piperine, atropine, nicotine, caffeine, theobromine, and others, have been synthesised; and that quinine, strychnine, morphine, and codeine await conquest).
Liebig, Gerhardt, and other chemists had been progressing towards this attainment by studying the structural constitution of various alkaloids. In 1842 Gerhardt separated a base which he called quinoline from quinine, cinchonine, and strychnine. This base was subsequently identified by Hofmann with the leucol which Runge had obtained from coal-tar in 1834. In 1846 Runge also produced a substance which he called pyridine from bone oil. Hofmann showed that this was the base of certain other alkaloids, coniine, piperine, nicotine, and atropine among these. Now it will be necessary to illustrate progress by means of a few formulæ diagrams.
Benzene is C6H6; aniline is a derivative of benzene in which one atom of hydrogen has been replaced by the amino-group, NH2. Its formula is C6H5NH2, and it is represented thus:
Aniline is basic; that is, it combines with acids to form salts. Together with aniline in coal-tar there occur other basic nitrogenous substances; of these pyridine and quinoline have already been mentioned, and to them must be added isoquinoline, which is also the parent substance of a series of alkaloids.
In pyridine one of the CH groups of the benzene ring is replaced by a nitrogen atom, the formula of the substance being C5H5N. In 1886 Ladenburg succeeded in synthesising the alkaloid coniine, starting with pyridine. This was the first occasion on which the artificial preparation of an alkaloid was achieved. The steps of the process were as follows;—
By the action of methyl iodide (CH3I), pyridinium methyl iodide is formed, which is transformed on heating into α-methyl-pyridine hydriodide. The free base, when treated with acetaldehyde (p. 271), yielded a compound known as α-allyl-pyridine, which, in turn, was made to combine with nascent hydrogen. The resulting compound (isoconiine) becomes coniine on heating to 300° C. or boiling with solid potash. The chemical history is shown graphically below:—
Pyridine. α-Methyl-pyridine. α-Allyl-pyridine. Coniine.
Pyridine, it may be mentioned, can be built up from its elements.
This coniine triumph of synthetic chemistry has been followed by many others of a similar character, and now all the alkaloids mentioned above in connection with pyridine have been produced artificially. Piperine was synthesised by Ladenburg and Scholtz in 1894; atropine together with other solanaceous alkaloids, and cocaine[4] by Willstätter in 1901–2; and nicotine by Pictet in 1903. The structure of these alkaloids is considerably more complicated than that of coniine; atropine, for example, is represented by the formula
The molecule of quinoline contains a benzene and a pyridine nucleus condensed thus:—
Among the alkaloids of the quinoline group may be mentioned those of cinchona bark and nux vomica. The constitution of these alkaloids is very complex, and in most cases but little understood. As an example of the cinchona group quinine may be taken. Its structure is probably
the formula being C20H24N2O2. Quinine has not been completely synthesised, but it has been prepared from cupreine, another cinchona alkaloid. The strychnos alkaloids likewise have not yet been artificially prepared, and their structure still requires elucidation.
The derivatives of isoquinoline, which was discovered by Hoogewerff and van Dorp in 1885, include some of the opium alkaloids, papaverine and narcotine, for example. Morphine and codeine do not, strictly speaking, fall into either of the three groups mentioned; our knowledge of the chemical nature of these substances has been much advanced recently, and it is probable that their synthesis will be effected before long.
Isoquinoline.
One of the most beautiful pieces of work on the synthesis of vital products during recent years was the artificial preparation by Fischer (1895–98) of the bases caffeine and theobromine. The processes employed are too long and complicated to be described here, but the formulas may be given, since they demonstrate the close relationship which exists between the two substances.
Caffeine.
Theobromine.
Other Synthetic Products.
(Benzoic acid, camphor, adrenaline, salicylic acid.)
Certain chemical bodies which have been used in medicine for centuries have been analysed, their structural formulas ascertained, and then the atoms have been put together in the laboratory so perfectly that in many cases the artificial products cannot be distinguished from the natural original ones. Benzoic acid, obtained by subliming gum benzoin, has been in use since the latter part of the sixteenth century, when under the name of fleurs de benzoin, soon anglicised into flowers of benjamin, they were introduced by a French physician, named Blaise de Vigenère, who was secretary to Henri III. [The name benjamin was not a bad corruption after all, as the Arabic term from which the European designations were derived was Luban Jawa, the incense of Java. The Spaniards first dropped the first syllable under the mistaken impression that it was the Arabic article. Old etymologies traced the name to a supposed Ben-jui, or tree of the Jews.] The artificial benzoic acid is obtained by the oxidation of toluene, a hydrocarbon distilled from coal-tar.
Comparatively recent achievements of synthetic chemistry are the artificial production of camphor and of adrenaline, the active principle of the suprarenal gland. The synthetic products can be distinguished from the originals by their behaviour towards polarised light.
Salicylic acid, prepared by acting on carbolic acid by carbon dioxide in the presence of an alkali, became a practical commercial product in 1874, but its discoverer, Kolbe of Leipzig, had prepared it in his laboratory since 1859. The natural product, prepared from willow bark or oil of wintergreen, was worth twelve guineas a pound; the artificial salicylic acid in a few years came to be sold at not so many shillings per pound. Kolbe’s theory was that the compound he devised would decompose within the organism into phenol and carbon dioxide, and thus exercise an anti-putrefactive effect.
Physiological Speculations.
In many other cases the physiological effect of the compound was distinctly foreseen, and latterly the relation between chemical constitution and physiological action has become the objective of much research. It may be reasonably anticipated that before many years have passed it will be possible to predict the physiological powers of a substance from a knowledge of its structural formula, just as already many of its more noteworthy physical properties may be so foretold. Even at present certain trustworthy rules, affording guidance in this respect, have been formulated. Dujardin-Beaumetz and Bardel, dealing with compounds of the aromatic series, have laid down that (a) those containing hydroxyl (OH) are antiseptic; (b) those containing an amino-group (NH2) or an acid amide are hypnotic; and (c) those containing both an amino-group and an alkyl group (CH3, C2H5, etc.) are analgesic.
In order to show how synthetic remedies have been built up from simple products it will be convenient to take a few typical examples in the order of increasing chemical complexity, rather than with strict regard to chronological progression.
Alcohol, Ether, Aldehyde, Acetic Acid.
Ethyl (that is, ordinary) alcohol forms a convenient starting point. It has been already stated that the molecule of this substance is represented by the formula C2H5OH but for centuries before its constitution was unravelled it had been prepared in a more or less pure condition, as it still is, by a process of fermentation followed by distillation. Alcohol can be built up from its elements thus:—When an electric arc burns between carbon rods in an atmosphere of hydrogen, acetylene is formed; acetylene can be made to combine with hydrogen, forming ethane; ethane reacts with chlorine, yielding ethyl chloride; and this acted upon by an aqueous solution of potash gives alcohol as a result. The steps of the process are shown below:—
Acetylene. Ethane. Ethyl chloride. Ethyl alcohol.
Alcohol is the basis of a number of substances used in medicine. On treating it with a dehydrating agent such as strong sulphuric acid, the elements of water are removed, and two molecules of alcohol unite into one, the resulting product being ether (diethyl oxide). The reaction is rather more complicated than is explained here, but the net result is as stated. The process was described by the German physician, Valerius Cordus, and was incorporated in the “Dispensatory” published after his death by the Senate of Nuremberg, under the title of “Oleum vitriole dulce verum.” As explained in the article on Ether (Vol. I. p. 347), the chemical reaction was, until recent times, a favourite topic for investigation.
When alcohol (C2H5OH) is oxidised, a substance known as aldehyde (CH3CHO) is formed. This was first prepared and described by Fourcroy and Döbereiner, but its constitution was explained by Kolbe. On further oxidation acetic acid (CH3COOH) is formed. The relationship between the alcohol, aldehyde and acetic acid was traced by Liebig.
Chloral Hydrate and Chloroform.
The oxidation of alcohol may be effected by the agency of chlorine, and in that case an intermediate oily product is obtained, in which three of the hydrogen atoms of the aldehyde are replaced by three of chlorine. The compound resulting is chloral (CCl3CHO), and this readily combines with water and forms the familiar chloral hydrate crystals which were first prepared by Liebig in 1832, but only got into the “British Pharmacopœia” (Additions) in 1874. Chloral hydrate treated with caustic potash splits into chloroform and potassium formate. Chloroform was discovered in 1831 by Liebig and Soubeiran, and was admitted into the “London Pharmacopœia” of 1851, four years after Simpson had demonstrated its wonderful anæsthetic property.
Sulphonal.
Returning to acetic acid, it may be stated that by heating its calcium salt two substances, acetone, (CH3)2CO, and calcium carbonate are formed. Also that when alcohol is acted upon by phosphorus pentasulphide, mercaptan, C2H5SH, is obtained. By the reaction of acetone and mercaptan, mercaptol results, and this, when oxidised, becomes the well-known synthetic hypnotic, sulphonal. It is not necessary to give the full formulas of these reactions, as they may be found in the usual chemical manuals; but it may be stated that the full descriptive name of sulphonal is dimethyl-diethylsulphone-methane. The group of sulphones furnishes an illustration of the reasoning on which new synthetic compounds come to be constructed. The theory was that the physiological action of sulphonal was due to, or connected with, its ethyl group. It was supposed, therefore, that by increasing the number of such groups in a molecule the hypnotic effect would be proportionately developed. It was believed that experiments on dogs supported this deduction; but it was not maintained in clinical experience.
Acetanilide and Phenacetin.
Many of the popular synthetic remedies belong to the benzene series. Benzene is obtained from coal-tar, but, as shown by Berthelot, it is possible to prepare it by heating the gaseous hydrocarbon, acetylene, C2H2, in a closed vessel. By this means three molecules of acetylene are condensed into one, C6H6, which is benzene. Benzene acted upon by nitric acid yields nitrobenzene, and this by the action of nascent hydrogen is changed into aniline. Aniline may be regarded as ammonia, NH3, in which one hydrogen atom has been replaced by the phenyl group, C6H5, and, like ammonia, it combines with acids to form salts. Aniline acetate being formed, the elements of water being eliminated in the process, the product is acetanilide, or antifebrin. Acetanilide was first prepared by Gerhardt, in 1853, but its physiological action was only discovered by Cahn and Hepp in the ’eighties. By the substitution of an ethoxy-group for one of the hydrogen atoms of acetanilide, para-ethoxy-acetanilide, commonly called “phenacetin,” is produced.
Salol.
Phenol is another of the multitudes of substances obtainable from coal-tar; it can be prepared from aniline by the action of nitrous acid, and can be shown to be benzene with one hydrogen atom replaced by hydroxyl. If one of the adjacent hydrogen atoms of phenol is replaced by carboxyl, salicylic acid is produced; and in the presence of a suitable dehydrating agent salicylic acid reacts with phenol and phenyl salicylate, known as salol, is formed.
Antipyrin.
Many of the synthetic chemicals are much more complex than those so far described. They are built up on similar lines, but the processes involve a greater number of stages. Antipyrin (phenazone, or phenyl-dimethylisopyrazolone) may be added to the examples selected for this notice. Antipyrin is represented by the annexed formula, which is said to be heterocyclic, because its molecules, like those of pyridine, consist of rings not made up exclusively of carbon atoms.
It must be understood that in this sketch only a very few notable instances of modern chemical research have been given, these being some of the more familiar products which have been introduced into medicine. Favourite colours, odours, and flavours have likewise been synthesised, and the manufacture of some of these artificial products has developed into vast businesses. The object of this chapter has been to make it clear that the marvellous activity which has been displayed in these directions during the past half-century, has been guided by the most profound and skilful research, one step leading to another, and that the new products have not been hit upon by mere chance.
XXIV
NAMES AND SYMBOLS
“Every trade and handicraft, every art, every science, is constantly changing its materials, its processes, and its products; and its technical dialect is modified accordingly, while so much of the results of this change as affects or interests the general public finds its way into the familiar speech of everybody.”
(W. Dwight Whitney:—“Language and its Study.” 1876.)
The technological vocabulary of pharmacy is very voluminous, and has been recruited from all languages. Many of the names of vegetable drugs literally household words in English, have been transferred direct from savage tongues. Guaiacum, ipecacuanha, and jalap may be cited as examples. Other names of drugs cover histories which well repay investigation.
Take, for example, the word hyoscyamus and its English equivalent henbane (which I select because it does not happen to be alluded to elsewhere in this work). The obvious and usual explanation of these names is that hyoscyamus is the Greek genitive hyos, of a hog, and kyamos, a bean, and in fact the name of hog’s bean is applied to it in several languages. Henbane, too, is supposed to be self-explanatory. But there is good reason to believe that neither of these interpretations is correct. Dioscorides, who calls the plant hyoscyamos, also mentions that its almost obsolete name was dioskyamos; and henbane is well known to be a corruption of henne-bell. The obsolete name is obviously more likely to convey the original meaning than its corruption, and therefore hyoscyamos is more likely to have meant the bean of the gods than the bean of the pigs. Possibly its name was traceable to the idea that the delirium which the drug produced was the condition induced in human beings when the gods communicated with them, or that some priests used it to produce that condition in which messages presumably from the higher powers could be transmitted. Henbane, again, is not satisfactorily accounted for by its surface meaning. There is no evidence that hens ever eat the herb or the seeds. But the Saxon name henne-bell suggests some sort of a musical instrument, and it is a curious fact that in mediæval Latin henbane was sometimes known as Symphoniaca Herba; the Symphoniaca being a rod with a number of little bells on it. This description might be appropriately applied to the plant, and we have only to suppose a Saxon term “hengebelle” to clear up the mystery.
I am indebted for the foregoing notes to three very suggestive articles in The Chemist and Druggist of October and November, 1877, and February, 1878, by Mr. W. G. Piper.
Next we come to the fanciful and poetic names of metals and their salts, and of all sorts of chemical compounds, invented by the alchemists. They gave the names of aquila alba, mercurius dulcis, panchymagogum minerale, manna metallorum, draco mitigatus, and others to calomel; regulus, or the little king, to antimony (gold being king); lunar caustic, ethiops martial, and salts of Saturn; vitriol, tartar, pompholix, and scores of others, not selected without judgment, but intended rather to mystify the public than to instruct them.
Chemical nomenclature of the present day has gone to the opposite extreme. The ingenious laboratory devisers of synthetic products have developed a nomenclature which it is impossible to use. It explains itself to the initiated, but even for intercommunication between chemists, pharmacists, and physicians words like tetrahydroparamethyloxyquinoline or calcium betanaphthol-alphamonosulphonate insist on being simplified if the substances they describe come into medicinal use; and to do them justice it must be admitted that the inventors of the products are always ready to meet this requirement with a more or less expressive title which can be protected as a trade mark. This forces other manufacturers to devise other distinct names for the same article, so that among the new chemicals which have become popular within the past thirty years there are sometimes a dozen designations for the same substance.