Part 33

(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 (NH{2}) or an acid amide are hypnotic; and (c) those containing both an amino-group and an alkyl group (CH{3}, C{2}H{5}, 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 C{2}H{5}OH 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:--

CH CH{3} CH{2}Cl CH{2}OH | --> | --> | --> | CH CH{3} CH{3} CH{3}

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 (C{2}H{5}OH) is oxidised, a substance known as aldehyde (CH{3}CHO) is formed. This was first prepared and described by Fourcroy and Döbereiner, but its constitution was explained by Kolbe. On further oxidation acetic acid (CH{3}COOH) 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 (CCl_{3}CHO), 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, (CH{3}){2}CO, and calcium carbonate are formed. Also that when alcohol is acted upon by phosphorus pentasulphide, mercaptan, C{2}H{5}SH, 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, C{2}H{2}, in a closed vessel. By this means three molecules of acetylene are condensed into one, C{6}H{6}, 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, NH{3}, in which one hydrogen atom has been replaced by the phenyl group, C{6}H_{5}, 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,

H{3}CC-----CH | | H{3}CN CO \ / \ / N | C{6}H{5}

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.

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