Three great achievements characterise the pharmacy of the nineteenth century, namely, the discovery of alkaloids in its early years, of anæsthetics in the middle period, and of synthetic organic products in its later years.

ALKALOIDS.

The alkaloids extracted from vegetables are the ideal quintessences which the alchemical pharmacists of the sixteenth and seventeenth centuries sought so eagerly to obtain. Their characteristic property is that they are basic, that is, that definite salts can be formed from them by combination with acids. They all contain nitrogen, and have an alkaline reaction.

Of all the popular vegetable drugs opium was the one more than any other tortured to yield up its essence. The early laudanums and extracts of opium aimed at this result, and preparations, such as the Magisterium Opii of Ludovici of Weimar (born about 1625, and author of “Dissertations on Pharmacy”), were used in the belief that the quintessence had been in some degree secured. Robert Boyle experimented with opium with the object of extracting its essential principle. The process he adopted was first to treat the drug with calcined tartar (salt of tartar), and then extract with spirit of wine. By this means he obtained a solution which would be principally one of morphine.

In 1803 a French manufacturing chemist, working on an idea suggested by Vauquelin, produced a crystallisable salt which was at first supposed to be the active ingredient of opium. Experiments on animals seemed to confirm this opinion, and the salt of opium, or “sel narcotique de Derosne,” was believed to have solved the long-standing problem. The product was described in the “Annales de Chimie” of February, 1804. It was the substance now known as narcotine. Sertürner regarded it as meconate of morphium, a misapprehension which was corrected by Robiquet.

In December, 1804, Seguin, a chemist who had been a demonstrator under Fourcroy, and who subsequently got into trouble with Napoleon’s Government on charges of having enriched himself out of drug supplies to the Republican armies, read a paper to the Institute in which he described a process which would yield morphine. For some unexplained reason that paper was not published until 1814. Meanwhile Friedrich Wilhelm Adam Sertürner, a pharmacist of Eimbeck, in Hanover, had been working on Derosne’s salt, and had investigated more accurately than anyone before him the composition of opium. His first report was published in 1806, and in that he announced the discovery of “opium-säure” (opium acid), but in 1816 he named this product “meconic acid,” and explained how it was combined with an alkaline base which he called “Morphium.” He described this as analogous to ammonia, and prepared several salts from it. He came near to losing his life in the course of his experiments as, misled by the comparative harmlessness of Derosne’s salt, he had ventured on dangerous doses of his own product. Consequently he was able to determine very accurately the therapeutics of morphine at the same time that he announced its discovery.

“I flatter myself,” wrote Sertürner in 1816, “that chemists and physicians will find that my observations have explained to a considerable extent the constitution of opium, and that I have enriched chemistry with a new acid (meconic) and with a new alkaline base (morphium), a remarkable substance which shows much analogy with ammonia.”

Sertürner’s discovery excited much interest and emulation, and its importance was fully endorsed when, in 1831, the French Institute awarded to him a prize of 2,000 francs “for having opened the way to important medical discoveries by his isolation of morphine and his exposition of its character.”

Before Sertürner had definitely established the nature of alkaloids, Vauquelin had separated from tobacco a substance which he regarded as its active principle, and which was undoubtedly an impure nicotine. This was in 1809. The alkaloidal character of this extract was not, however, recognised until 1828, when Posselt and Reimann produced it in a pure form.

Vauquelin had in 1812 extracted daphnine from mezereon root, and in describing his experiments had alluded to its alkaline character. For this reason the credit of having been the first to have discovered an organic alkali has been attributed to him; and when in 1818 Pelletier and Caventou discovered an alkaloid in St. Ignatius’s beans, to which they gave the name of strychnine, they stated that it had been their original intention to designate the substance Vauqueline in honour of the celebrated chemist who had first established the existence of an organic alkali. It had, however, been pointed out to them by distinguished members of the Academy that it would have been a doubtful compliment to associate such an honoured name as that of Vauquelin with such an evil (malfaisant) substance as this new product.

A number of chemists narrowly missed the discovery of quinine. As early as 1746 Count Claude de la Garaye obtained from cinchona bark a crystalline salt which he termed sel essentiel de quinquina. Two other French chemists, Buquet and Cornette, subsequently introduced another sel essentiel de quinquina. Both these products were simply kinate of lime. A Swedish physician named Westerling announced in 1782 that he had discovered the active principle of cinchona, and he gave it the designation of vis coriaria. His product was in fact cinchotannic acid. Seguin perhaps made the worst mistake of all the investigators in coming to the conclusion that what was precipitated by tannin was the essence of cinchona from a medicinal point of view, and he actually recommended that gelatin should be substituted for cinchona in cases when price was an object. Fourcroy made several attempts to ascertain the true chemical constitution of the bark. In 1790 he separated a resinous principle, mixed with some colouring matter, since called cinchonic red. This he at first supposed was the essential medical constituent of the bark. Vauquelin later adopted this erroneous theory, and so missed his way. In 1792 Fourcroy got nearer to the truth when he observed incidentally that the water in which the bark had been macerated turned litmus paper green; and he also remarked that lime water caused a greenish precipitate in the infusion. He did not pursue the investigation, but his comment on what he had stated is noteworthy. “These researches,” he said, “will no doubt lead to the discovery one day of an anti-periodic febrifuge, which once known may be extracted from various vegetables.” Berthollet followed on Fourcroy’s lines, but came to the conclusion that the precipitate which lime water gave with decoctions of cinchona was magnesia, which he believed was a constituent of the bark in combination with hydrochloric acid.

In 1811 Gomez, of Lisbon, described a crystalline substance which Dr. Duncan, of Edinburgh, had obtained from certain species of cinchona, and gave to this product the name of cinchonine. Lambert later prepared it in a state of considerable purity. But neither of these chemists suspected its alkaline nature. In 1820 Pelletier and Caventou studied the whole chemistry of cinchona and succeeded in showing that the cinchonine of Gomez was a mixture of two alkaloids, to the second of which they gave the name of quinine. Quinidine was isolated by Henry and Delondre in 1833, and cinchonidine by Winckler in 1844, but the name of the latter was given by Pasteur in 1853. Pasteur also produced the alkaloidal derivatives cinchonicine and quinicine.

Robiquet had the idea that as the coffee plant belongs to the same family of plants as the cinchonas it might be possible to find quinine in coffee. In searching for it he isolated caffeine. This was in 1821. In 1827 Oudry found an alkaloid in tea and called it theine. Jobst and Mulder in 1838 proved that these alkaloids are identical. It is now recognised that the alkaloids of cocoa, of guarana, and of Paraguay tea are all the same substance, or closely related.

Pelletier and Caventou isolated strychnine from the St. Ignatius beans in 1818, and brucine from false angostura bark (Brucæa anti-dysenterica) in 1819; in the same years they obtained veratrine from cevadilla seeds and white hellebore root; but it would appear that in their investigation of cevadilla seeds, which was the first to yield the alkaloid, they were preceded by a very short time by Meissner. Pelletier and Magendie produced emetine from ipecacuanha in 1817, and Pelletier alone is credited with narceine in 1832. Codeine was discovered by Robiquet in 1821 when he was examining a new process for obtaining morphine which had been suggested by Dr. William Gregory, of Edinburgh. Belladonna had been studied by Vauquelin and many chemists after him, but it was not until 1833 that atropine in a state of purity was isolated from it. This was accomplished simultaneously by Geiger and Hess, two German chemists, and by Mein, a German pharmacist.

ANÆSTHETICS.

The greatest triumph achieved in any department of medicine, and worthy, perhaps, to be described as almost, if not quite, the most beneficent discovery in the world’s history, is that of the successful employment of anæsthetics. This great glory belongs to the nineteenth century. Indian hemp had been employed for centuries in the East, mandragora had a classical reputation, and from time to time the possibilities of hypnotism had been expounded by one or another of its professors. But it is only within the past sixty years that the terrible anxiety and suffering associated with surgical operations have been so far mitigated as largely to increase the prospects of success, and to annihilate the pain. To Sir Humphry Davy is due the credit of first suggesting the line of advance towards this precious goal by describing his experiences of the inhalation of nitrous oxide gas which he found had the effect of relieving toothache and other pains; “uneasiness swallowed up for a few minutes by pleasure,” were his own words; and he foresaw the possibility of this agent being employed as an inhalation “in such surgical operations as involved no great effusion of blood.” That was in the year 1800. About 1830 Faraday observed and noted the effect of ether on the nervous system, which he stated was similar to that of nitrous oxide gas.

The possibility of painless operations began to be imagined about this time, but not much serious experimental work seems to have been attempted. In 1842, Dr. Long, of Athens, Georgia, U.S.A., claimed to have removed a tumour from a patient under the influence of ether, and about the same time Dr. Jackson, of Boston, U.S.A., also professed to have carried out successfully a similar operation. These experiments have not been rigorously established, but there is no question about the authenticity of the next. Horace Wells, a dentist of Hartford, Connecticut, U.S.A., suffering from toothache, resolved to experiment on himself. He induced a colleague named Rigg to draw a molar while he was under the influence of nitrous oxide gas, and did not feel the pain of the extraction. This was in 1844. Wells then, in association with another dentist, named William Thomas Green Morton, started to demonstrate the discovery publicly. The first exhibition was an ignominious failure, and the two pioneers were derided as impostors. Wells suffered so severely from his disappointment on this occasion that he died insane a few years later. Morton, however, continued his investigations, and he and the Dr. Jackson already mentioned worked together on ether, and assured themselves of its anæsthetic powers by experiments on animals. Morton then inhaled it himself on September 30, 1846, and awoke from deep unconsciousness a few minutes later, convinced of the reality of his discovery. Just then a patient rang the bell. It was towards evening, but the visitor was shown into the surgery. He was in agony with the toothache, and begged the doctor to mesmerise him in the hope of getting some relief. The nerve was so sore, he said, that he could not summon up courage to have the tooth drawn. Morton, greatly excited, told his patient that he could do better for him than mesmerising him. He could take the tooth out without pain if he would consent. The sufferer agreed eagerly, and Morton, with two assistants, proceeded to operate. A handkerchief, saturated with ether, was applied to the mouth and nostrils, and unconsciousness was produced almost immediately. A tooth, a firmly-rooted bicuspid, was extracted without arousing the patient. Then followed a minute of intense fear. The man remained motionless, and Morton felt convinced he was dead. Seizing a glass of water he dashed it into the face of this first subject, who at once revived. “Are you ready to have your tooth drawn?” asked Morton. Rather hesitating assent was given, and then the extracted tooth was shown to the patient in the chair. His name, which ought to be recorded in the annals of surgery, was Eben Frost.

On October 16, 1846, a tumour was removed from a patient at the Massachusetts General Hospital, Boston. Morton administered the ether, and Dr. Collins Warren, the senior surgeon, operated. The patient made no sound, and after he recovered consciousness declared that he had experienced no pain. “Gentlemen, this is no humbug,” said Dr. Warren to the other surgeons who had witnessed the operation. Morton died in 1868.

The first operation under ether in Great Britain was performed by Liston at University College Hospital in December, 1846. In January, 1847, James Young Simpson commenced to employ it in midwifery cases in Edinburgh. Simpson had already acquired a high reputation as a gynecologist, and was an enthusiast in his profession. Delighted though he was with the results of his trials of ether, he felt sure that an anæsthetic with more lasting effect could be found or made, and with characteristic courage and pertinacity he and his two assistants, Drs. Keith and Duncan, carried on personal experiments at Simpson’s private house on such evenings as they could spare. At the same time the scientific world was appealed to for suggestions. About this time David Waldie, a Scotch pharmacist then settled in Liverpool, where he was manager of the Liverpool Apothecaries Company, was visiting Edinburgh and had a conversation with Simpson on his absorbing topic. Waldie had had some special experience with chloric ether at Liverpool, and had made experiments on its chemical character, which had led him to the conclusion that the chloric ether then used was chemically only a mixture of chloroform with some undecomposed spirit. Chloroform, it must be remembered, was then but little known. Dr. Samuel Guthrie, formerly an army surgeon, but later practising at Jewelsville, Jefferson County, N.Y., published an account of a chloric ether he had made from alcohol and chloride of lime in May, 1831. In October of the same year Soubeiran in France, and a month later Liebig in Germany, announced the discovery of a similar compound. None of these products was an absolute chloroform, but all were heavy substances. Dr. Guthrie called his chloric ether, and familiarly sweet whisky, Soubeiran’s was a bichloric ether, and Liebig described his as a trichloride of carbon, but Dumas showed in 1834 that the essential substance was a trichloride of formyl, HCCl₃ and a substitution product of marsh gas. He invented the name chloroform. It appears too that another French chemist, Flourens, in March, 1847, reported to the Academy of Sciences of Paris some experiments he had made with chloroform on animals, which indicated its anæsthetic properties; but probably neither Simpson nor Waldie was aware of this paper. This was the chemical which Waldie recommended to Simpson in the summer of 1847, and the chemist promised to send some to Simpson on his return to Liverpool. A fire in the laboratory of his establishment prevented the fulfilment of this promise, and also, Waldie said, prevented him from experimenting on himself with chloroform, as he had intended to do. Simpson got chloroform from Duncan and Flockhart in Edinburgh, but did not expect it would answer on account of its density. The sample was set aside for some time, but on November 4, 1847, he and Duncan and Keith resolved to test it. They all inhaled some from a tumbler, and almost immediately became loquacious and hilarious. Then unconsciousness came on, and Simpson, who was the first to recover, found Duncan under the table, eyes staring, and snoring vigorously, while Keith was kicking at the supper table. The experiment was repeated a few evenings later, and this time a niece of Simpson was induced to take a turn. After inhaling the vapour she fell asleep, murmuring “I’m an angel; I’m an angel.” Simpson at once began the use of chloroform in his practice, and his great reputation and powerful advocacy soon caused its general adoption.

A Mysterious Anæsthetic.

A strange and little known story is told by Professor Franck. Van Swieten was a Dutch physician, a pupil of Boerhaave. He did not succeed in his native land so well as he ought to have done, for he was a devout Catholic. He went to Vienna, where he attained the highest medical position and the utmost esteem from his patroness, the Empress Maria Theresa. On May 1, 1771, three young gentlemen called on Van Swieten and were shown into his study. The professor was then an old man, 71 years of age.

“What do you desire, my children?” he asked, as he fingered his beads.

“We come to teach Van Swieten what he knows not,” answered one of the young men.

“That is not difficult,” replied the veteran. Then they told him they wished to show him a medicine new to the world, and as the doctor smiled incredulously, one of his visitors added:

“Like the philosopher of old, we will say to Pain:—Thou art but an idle word.”

Van Swieten was doubtful, but after further explanation he invited them to come to his hospital the next morning and demonstrate their secret. When they were gone he went to Maria Theresa and told her of the interview. The Empress declared her intention of being present at the experiment.

The next day when the three young men appeared at the hospital they found Van Swieten and a veiled lady awaiting them. Certain chemicals had previously been placed in retorts by them, and a mastiff was made to inhale the product. The animal exhibited symptoms of inebriation, and soon fell on the floor unconscious. One of the strangers made a deep incision into the dog’s chest and covered the wound with a surgical dressing. The animal showed no sign of pain, and shortly afterwards recovered consciousness, got on his feet, and walked about as if nothing had happened.

“This is indeed a miracle,” said the Empress.

“Would you dare to operate thus on a patient?” asked Van Swieten.

“Willingly, Master,” was the reply.

“Then operate on me,” said the Professor.

To this proposal, however, they demurred, and the Empress supported their objection. An appointment for further experiment a few days later was made, but when the day arrived Van Swieten was ill. He died on May 18, and Maria Theresa was at the time immersed in political troubles. The sequel to that strange history has never been told, but some of the old books tell of the “Holland Oil,” which is believed to have been the mysterious medicament employed. Professor Franck thinks one of the strangers was Gautier Van Decoren, a physician of Flemish Holland.

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.

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.

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

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, 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.

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.

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:—

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.