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, H_{2}O 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, K_{2}O. 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, CH_{4}, which
is chemically known as methane, he showed how from this type methyl
alcohol, CH_{4}O, and formic acid, CH_{2}O_{2}, are formed. Ethane,
C_{2}H_{6}, 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 CH_{2} to ethane gives propane; propyl alcohol and
propionic acid following; another addition of CH_{2} 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, C_{2}H_{6},
the conditions are satisfied? The explanation is that the molecule is
arranged in this manner:
H H
| |
H--C--C--H
| |
H H
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 C_{2}H_{6}O;
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 C_{2}H_{6}; alcohol is
thus formulated--C_{2}H_{5}OH. That is its “rational formula.” Alcohol
is a comparatively simple substance; we shall deal with some formulas
of much greater complexity presently.
[Illustration: 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 C_{6}H_{6} 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.
H
C
/\\
HC CH
|| |
HC CH
\ //
C
||
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
[Illustration: 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 C_{6}H_{6}; aniline is a derivative of benzene in which one
atom of hydrogen has been replaced by the amino-group, NH_{2}. Its
formula is C_{6}H_{5}NH_{2}, and it is represented thus:
CH
// \\
HC CH
| |
HC CH
\\ //
CNH{2}
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 C_{5}H_{5}N. 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 (CH_{3}I), 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:--
CH CH CH CH
// \\ // \\ // \\ // \\
HC CH HC CH HC CH H{2}C CH{2}
| | | | | | | |
HC CH HC CCH{3} HC CC{3}H{5} H{2}C CHC{3}H{7}
\\ // \\ // \\ // \\ //
N N N NH
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
H H_{2}
H_{2}C----C----C CH_{2}OH
| / \ |
| N--CH_{3} CH--O--CO--CH
| \ / |
H_{2}C----C----C C_{6}H_{5}
H H_{2}
The molecule of quinoline contains a benzene and a pyridine nucleus
condensed thus:--
HC CH
\ C /
// \ / \\
HC || CH
HC || CH
\\ / \ //
\\/ C \//
HC N
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
CH
/ | \
/ | \
H_{2}C CH_{2} CH--CH==CH_{2}
| | |
H_{2}C HO·C CH_{2}
\ / | /
\/ | /
/\ | /
/ \ | /
CH_{2} N
/
HC C
// \ C / \\
CH_{3}OC| \ / |CH
HC| | | |CH
\\ C \ //
HC N
the formula being C_{20}H_{24}N_{2}O_{2}. 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.
HC CH
// \ C / \\
HC| \ / |CH
HC| | | |N
\\/ C \ //
HC CH
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.
(CH{3})N-----CO HN-----CO
| | | |
| | | |
CO C-N(CH{3}) CO C-N(CH{3})
| || \ | || \
| || /CH | || /CH
(CH{3})N-----C-N (CH{3})N-----C-N
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 (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.
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.