STEREO-ISOMERISM: STEREO-CHEMISTRY

The first gropings in the search for light on the inner structure
of molecular groupings may be said to date from Biot’s work
on polarisation. In 1815 Biot, a pupil of Malus, made the
remarkable discovery that a number of naturally occurring organic
compounds—_e.g._, sugar, tartaric acid, oil of turpentine, camphor,
etc., are _optically active_—that is, rotate the plane of polarisation
in one direction or the other. The property had previously been
observed in quartz, and was assumed to be connected with the
crystalline character of that substance. Biot, however, pointed out
that the case of oil of turpentine which is a liquid, and the cases
of the other substances when in solution, showed that crystalline
character had no necessary connection with the phenomenon, but that it
must be dependent upon the internal or molecular arrangement of the
optically active substance.

In 1844 Mitscherlich, who first demonstrated the relation between
atomic constitution and crystalline form, drew attention to the
fact that the salts of the isomeric modifications of tartaric
acid, studied by Berzelius, although possessing the same chemical
composition, the same crystalline form, with the same angles, the
same double refraction, and therefore the same angles between their
optical axes, nevertheless behave quite differently as regards their
optical activity, solutions of the tartrates rotating the plane of
polarisation, whereas those of the racemates are inactive. In 1848
this remarkable circumstance engaged the attention of Louis Pasteur,
a young man who had just completed his course at the École Normale in
Paris, and was acting as assistant to Balard, the discoverer of the
element bromine. Pasteur, on examining the crystals of the two forms
of tartaric acid, and of some of their salts, detected the presence,
on some of them, of certain facets—so-called hemihedral faces—which
had hitherto been unrecognised, but were similar to facets which Haüy
had observed on quartz. Haüy had, in fact, divided quartz crystals
into two classes—right-handed and left-handed, depending upon the
side on which these facets occurred. The forms were, as it is termed,
enantiomorphous. Biot, moreover, found that some quartz crystals, cut
parallel to the axis, turned the plane of polarisation to the right,
whereas others turned it to the left; and Herschel suggested that the
phenomena were probably connected, and such was found to be the case.

Mindful of Herschel’s observation, Pasteur found that the crystals of
certain of the optically active tartrates showed hemihedral faces,
whereas those of the corresponding racemates showed no trace of them.
On recrystallising the racemates, however, it was noticed that two sets
of crystals were formed—enantiomorphic forms—the first set of crystals
having hemihedral forms on the right-hand side, and the second set
on the left-hand side. The forms, in fact, were so related that one
appeared, as if it were the image, as seen in a mirror, of the other.
When solutions of these crystals were examined, one set was found to
rotate to the right, the other to an equal degree to the left. The
dextro-rotatory salt yielded ordinary tartaric acid; the corresponding
lævo-rotatory acid was a hitherto unknown modification: the two
together, in equal proportions, constituted racemic acid.

In 1863 Wislicenus published a remarkable memoir on the synthesis of
lactic acid. The acid in sour milk was discovered by Scheele in 1780.
In 1807 Berzelius discovered a similar acid, called _sarcolactic acid_,
in muscle juice; this was erroneously pronounced by Liebig to be
identical with that of sour milk. Other forms of lactic acid were made
known, the structural character of which was not to be explained by
current hypotheses. Wislicenus concluded that their differences could
be due only to different arrangements of their atoms in space.

In 1874 the conception of atomic grouping received a remarkable
development by the publication of two memoirs—one by Van ’t Hoff, and
the other by Le Bel—which served to connect molecular structure with
optical activity. Confining their attention to carbon compounds, they
inferred that all optically active substances contained at least one
multivalent atom, united to other atoms or groups, so as to form in
space an unsymmetrical arrangement. Van ’t Hoff regarded the carbon
atom as occupying the centre of a tetrahedron, to the summits of which
its valencies were directed. If different groupings are attached to
these summits, the structure is _asymmetrical_, and is optically
active. The two forms of lactic acid, for example, may be represented
by the following space formulæ:

[Illustration]

It will be seen from an inspection of the figures that the one is the
image-form of the other, and, no matter how they are turned, they are
not superposable; they are right- and left-handed, or, as it is termed,
enantiomorphs.

There is no fundamental distinction between the hypothesis of Van ’t
Hoff and Le Bel as to the effect of asymmetry on optical behaviour. Le
Bel regards the effect of asymmetry simply as a necessary consequence
of the presence of four dissimilar groupings, and as independent of
valency and the geometrical form of the molecule.

[Illustration: JACOBUS HENRICUS VAN ’T HOFF.]

It was surmised by Pasteur that every liquid or solid in solution
showing optical activity, if crystallisable, would be found to manifest
hemihedral faces; but this has not been generally established.
Further, it does not always happen that an optically active substance
in solution is so when solid. Lastly, optical activity may be latent
even in asymmetric carbon compounds if dextro- or lævo-modifications
are present in equal proportions, as in racemic acid. Such compounds
are, in fact, termed “racemic,” or _racemoids_; and they may be
separated occasionally by crystallisation, as in Pasteur’s method with
the tartrates; or as shown by him by the action of the racemoid upon
another optically active substance; or, lastly, by taking advantage
of the specific action (specific assimilation) of organisms—Pasteur’s
so-called biochemical method.

It is a physiological fact of great interest that the behaviour of
enantiomorphs towards the animal organism is frequently markedly
different. Lævo-tartaric acid administered to guinea-pigs is found to
be twice as poisonous as the dextro-acid; dextro-asparagine possesses
a sweet taste, but lævo-asparagine is tasteless; lævo-nicotine is more
poisonous than the dextro-alkaloid.

The ferments known as _enzymes_ are also found to possess the power
of selection, behaving differently towards the different optically
active modifications of the same substance. It is frequently observed
that an optically active substance may be rendered inactive by the
conversion of half the substance into its enantiomorph. This operation
was first performed by Pasteur, and may be brought about by heating
the substance, either alone or with water, under pressure. Indeed, it
is occasionally observed to take place at the ordinary temperature
(_autoracemisation_).

By the action of various reagents the derivatives of an optically
active substance are found not unfrequently to change the direction of
their optical activity. Indeed, by such means one enantiomorph may be
changed into another. Thus _lævo_-menthol may be converted into the
_dextro_-modification by treatment with sulphuric acid.

The rotatory power of a substance is frequently modified by the
character of its solvent, and varies with the temperature and
concentration of the solution. Landolt and Oudemans found that the
specific rotation of dilute solutions of tartrates and of salts of the
active alkaloids was independent of the nature of the base and acid
respectively present—a fact which finds its explanation in the theory
of electrolytic dissociation. It has been known for some years past
that the specific rotation of solutions of certain sugars changes with
time, being sometimes less and sometimes more than the initial amount.
This phenomenon is now known as _multirotation_, or _mutarotation_. It
seems to be connected with an alteration in the configuration of the
molecules.

There is a special case of stereo-isomerism, differing from that
of optical isomerism and of structural isomerism (with which we
have hitherto been alone concerned), which was predicted by Van ’t
Hoff in his remarkable work _La Chimie dans l’Espace_, published in
1877—noteworthy as being the first serious attempt to grapple with
the problem of spatial molecular grouping, foreshadowed by Wollaston,
Berzelius, and, indeed, all the early philosophic thinkers who accepted
the atomic theory. The special form of stereo-isomerism now referred
to, which has been more particularly investigated by Wislicenus, is
distinguished as _geometrical isomerism_; not, perhaps, a sufficiently
descriptive term, since, comprehensively, all forms of isomerism are
really cases of geometrical isomerism. Instances of it are to be
met with among the isomeric acids existing as glycerides in certain
fats, in cinnamic acid, in stilbene and its derivatives, etc. It was
first observed in _maleic_ and _fumaric acids_—isomeric acids of the
empirical formula C2H2 (COOH)2, obtained by the distillation of malic
acid, the characteristic acid met with in the apple and other fruits
and in certain other vegetal products. These acids may be represented
by the following space formulæ:

COOH——C——H COOH——C——H
║ ║
COOH——C——H H——C——COOH
Maleic acid. Fumaric acid.

which show no asymmetry, and hence no possibility of optical activity
or enantiomorphous modifications.

In the case of maleic acid it will be seen that the same groups (COOH
or H) are represented on the same side of the molecule—in other words,
they are placed symmetrically in a plane—whereas in fumaric acid they
are placed diagonally or are axially symmetrical. Isomers of the first
case are classified as _malenoid_ or _cis_-forms, while those of the
latter are termed _fumaroid_ or _trans_-forms.

Substances of the character referred to are, as a rule, mutually
convertible with more or less ease; they are susceptible of what is
called _geometrical inversion_. Thus fumaric acid may be readily
converted into maleic acid by heating; maleic chloride is gradually
transformed into fumaric chloride at ordinary temperatures. Sunlight,
or a particular solvent, or the presence of some substance which acts
as a catalyst, may effect the inversion. _Cis_ and _trans_ isomerism is
also met with among cyclic compounds; it occurs among the terpenes; and
certain alkaloids, as, for example, cocaïne, exhibit it.

Although the doctrine of stereo-chemistry was first enunciated in
the case of carbon, and was, indeed, for a time solely confined to
compounds in which carbon was the nucleal element, there is no _a
priori_ reason why the phenomenon should be so restricted. Van ’t
Hoff, in fact, in 1878, discussed the question in relation to nitrogen
compounds. Stereo-isomeric nitrogen derivatives were first obtained
by Victor Meyer and his pupils, and the stereo-chemistry of nitrogen
has since proved to be a very fruitful field of investigation, notably
in the hands of Goldschmidt, Beckmann, Hantzsch and Werner, Le Bel,
Ladenburg, Bamberger, Kipping, H. O. Jones, Pope, and others. The
stereo-chemistry of nitrogen differs from that of carbon, inasmuch as
variation of valency plays a far more important part in the case of
nitrogen than it has hitherto been observed to do in that of carbon;
the spatial representation of the trivalent nitrogen atom differs from
that of the pentavalent atom. Le Bel, in 1891, succeeded in obtaining
an optically active nitrogen enantiomorph by the application of
Pasteur’s biochemical method. Optically active compounds have since
been prepared by Pope and Peachey and H. O. Jones. Pope and Peachey
have also prepared optically active compounds of sulphur, selenium, and
tin; and Kipping has obtained an asymmetric compound of silicon.

In 1863 Geuther, and, independently, Frankland and Duppa, made known
the existence of _aceto-acetic ester_. By Geuther this compound was
termed _ethyl-di-acetic acid_—

CH3.C(OH): CHCOOC2H5

by Frankland and Duppa it was considered to be _acetone-carboxylic
acid_—

CH3.CO.CH2.COOC2H5.

The essential difference in these formulæ, as the two names
respectively indicate, is that the first implies that the ester has an
acidic or hydroxylic character, proved by its forming characteristic
salts; the other that it contains the group CO, proved by its yielding
acetone and the usual reactions of the ketones. The attempt to settle
the constitution of this substance gave rise to much controversy,
and, as it was found to be very reactive, led to a great amount
of conflicting experimental work. The ultimate result was to show
that both formulæ are correct: at the time of reaction the ester
is sometimes hydroxylic, at other times ketonic, or, adopting the
terminology of Brühl, it sometimes shows the _enol_ form, at other
times the _keto_ form. Other substances were subsequently found to
behave in the same way. In 1885 the question was discussed by Laar,
who suggested the term _tautomerism_ (ταὐτό, the same; μέρος, a
part) to denote the fact that one and the same substance could have
structural formulæ varying with conditions of reaction and depending
upon the migrations of certain of its atoms within the molecule. During
the last twenty years a large number of examples of the kind have
been discovered. They are found to occur, not only among aliphatic
substances, but in cyclic and heterocyclic compounds. We now know that
such intermolecular changes may occur by the migration of any of the
elements or groups present in the molecule. Thus, to confine ourselves
to simple and well-known examples, the transformation of sodium phenyl
carbonate into sodium salicylate, discovered by Kolbe, is due to the
wandering of an atom of hydrogen from the benzene residue to oxygen,
thus:

OH
/
C6H5.O.COONa→C6H4
\
COONa.

The conversion of the nitriles into the cyanides by heating is due to
the transference of the alkyl radical from the nitrogen atom to the
carbon—

R.NC→NC.R.

Alkyl groups may also be transferred from oxygen to nitrogen; a radical
may detach itself from a carbon atom and wander to a nitrogen atom;
radicals in cyclic compounds may be transferred from the side chains to
the nucleus, etc.

The phenomenon, in fact, is now so general that grave doubts have
been thrown upon the uniform value of deducing the structural formula
of a substance from the study of its decomposition products, or from
the nature of its derivatives, owing to the readiness with which
tautomerism may occur. The change may be brought about by variation of
temperature, by the reagent itself, by the action of a solvent or the
presence of a catalyst—that is, of a substance which _apparently_ plays
no part in the metamorphosis. Hence the value of specific reagents as
clues to constitution is considerably weakened, since the results may
be equivocal. Fortunately, the great extension, within recent years,
of the application of physical methods has considerably strengthened
our means of gaining an insight into molecular structure; and the
investigations of Brühl on refraction and dispersion, of Perkin on
magnetic rotation, of Hantzsch on electrical conductivity, of Lowry on
solubility, of Lowry and E. F. Armstrong on optical activity, of Knorr
and Findlay on melting-points, and, lastly, of Hartley, Dobbie, Lauder,
Baly, and Desch on absorption spectra, have collectively afforded
valuable information on the mechanism of isomeric change based upon
dynamical considerations.

Space will not permit of a more extended treatment of the subject of
stereo-chemistry; and certain matters relating to it, as, for example,
the phenomena classed under the term _steric hindrance_, must be left
unnoticed. This term has reference to the hindrance which certain
groups, or the particular distribution in space of certain atoms, exert
on the progress or extent of a reaction, as, for example, of hydrolysis
or esterification, etc. The influence of special groupings in retarding
chemical change is apparently well established, but no comprehensive
theory of the subject is yet possible. Until such a theory is
forthcoming a dynamical theory of stereo-chemistry is incomplete.

In its widest sense, the term “synthesis,” as used in organic
chemistry, means the building-up of carbon compounds, either from
their constituent elements or from groups of differently constituted
molecules. At one period this term was confined to cases in which
the organic compound was prepared from inorganic materials, or from
combinations which themselves could be formed from their elements; but
latterly it has lost, in large measure, this restricted signification.
At the same time, the attempt has been made to indicate by special
terms certain classes of synthetical reactions. Thus the special
case of the formation of an organic compound by the union of two or,
it may be, more molecular groupings is now frequently spoken of as
_condensation_.

Organic chemistry has been largely developed by the discovery from time
to time of special reagents and special types of reactions which have
shown themselves to be capable of extensive application. Such, for
example, was Frankland’s discovery, in 1852, of zinc-ethyl—the first of
the organo-metallic compounds, and the type of a series of substances
of great theoretical importance, and of great practical value by reason
of their reactive powers. They led to the synthesis of the paraffins,
the secondary and tertiary alcohols, and ketones. A few years later
Wurtz introduced the use of metallic sodium as a condensing agent, and
showed thereby how the hydrocarbon _butane_ could be produced from
ethyl iodide:

2C2H5I + Na2 = C4H10 + 2NaI.

Use was made of the same agent by Fittig, in 1863, in effecting the
synthesis of the homologues of benzene by the action of an alkyl iodide
upon bromobenzene:

C6H5Br + CH3I + Na2 = C6H5.CH3 + NaI + NaBr.

In like manner Kekulé, in 1866, obtained benzoic acid by the action of
carbon dioxide upon bromobenzene:

C6H5Br + CO2 + Na2 = C6H5COONa + NaBr.

The readiness with which magnesium can now be obtained, mainly as the
result of Sonstadt’s efforts to develop its metallurgy, has led to its
application, at the suggestion of Barbier, in 1899, in place of zinc.
The particular form of magnesium compound now employed as a reagent was
prepared by Grignard in 1900, and is known by his name. It is obtained
by bringing an ethereal solution of an alkyl iodide or bromide into
contact with magnesium, when the metal is dissolved, forming, in the
case of methyl iodide,

MgCH3I.(C2H5)2O.

Grignard’s reagent has shown itself to be extraordinarily reactive, and
a great number of condensations—of hydrocarbons, alcohols, aldehydes,
acids, ketones, amides, and additive compounds—have been effected by
means of it.

Other condensing reagents of value are aceto-acetic ester, sodium
amalgam, sodamide, sodium ethoxide, dimethyl sulphate, zinc chloride,
aluminium chloride, fused caustic potash, hydrogen chloride,
phenyl-hydrazine, hydrogen peroxide in presence of a ferrous salt
(Fenton’s reagent), ammonia, and various amines. The application of
these reagents has led to the discovery of a variety of new compounds,
the mode of origin of which has served to elucidate their constitution.

The great majority of organic syntheses, especially when they start
by the use of inorganic materials, consist in passing from simple to
complex molecular groupings by condensation processes. An interesting
example of the reverse process is seen in the production of _carbon
suboxide_, or _carbon carbonyl_, C3O2, obtained from various malonyl
compounds, but most conveniently prepared by the action of phosphoric
oxide on malonic acid under diminished pressure, or by treating an
ethereal solution of dibromomalonyl chloride with zinc:

COOH CO
/ //
(1) CH2 = 2H2O + C
\ \\
COOH CO

CO
//
(2) CBr2(COCl.)2 + Zn2 = ZnCl2 + ZnBr2 C
\\
CO

Carbon suboxide is a colourless, extremely mobile, refractive,
poisonous liquid, of sp. gr. 1.11, with a strong and peculiar
smell. It boils at 7°, and freezes at -107°. It is stable only at
low temperatures; at ordinary temperatures it polymerises to a red
solid, which dissolves in water, forming a solution of the colour of
eosin. The change is almost instantaneous at 100°. Carbon suboxide is
inflammable, burning with a blue but smoky flame: C3O2 + 2O2 = 3CO2.
Its low boiling-point and the high value of its molecular refraction
and dispersion, its general resemblance to the metallic carbonyls and
ketones, etc., indicate that this remarkable oxide of carbon is, in
all probability, the anhydride of malonic acid. Indeed, by the action
of water upon it, it is reconverted into malonic acid.

In point of principle, and viewed as chemical operations, the synthesis
of vital products is in nowise different from the synthesis of any
other group of organic compounds; and the special interest, and even
astonishment, at one time created by the artificial preparation of such
products has largely died away. The synthetical production of some of
the substances formerly known only to be formed by vital action, either
in the animal or the plant, has already been incidentally referred
to. But it may be convenient to treat the subject of the artificial
production of this group of bodies rather more comprehensively and as a
sub-section of this chapter on organic synthesis, since their formation
by such means constitutes a phase in the development of chemistry, and
has undoubtedly exercised a profound influence on scientific thought
and on philosophical and even theological doctrine. During the past
fifty or sixty years the chemist has been enabled to form the active
principles or characteristic products of many plants and animals.
He has built up substances which were formerly regarded as capable
of being made only by the very process of living. He has prepared
compounds which were at one time considered as only producible by
changes in organised matter after death.

Since the date of Wöhler’s epoch-making discovery, already referred
to[4] _urea_ has been synthetically prepared by many reactions,
notably by Regnault and Natanson by the action of ammonia on carbonyl
chloride, and by Basarow and Dexter from ammonium carbamate. Both these
substances can be formed directly or indirectly from their elements. It
may also be obtained by the hydrolysis of lead cyanate:

Pb(CNO)2 + 2H2O = PbCO3 + CO(NH2)2.

[4] Vol. I., p. 163.

The successive steps in its production from inorganic materials by this
method are:

K + C + N → KCN → KCNO
→ Pb(CNO)2 → CO(NH2)2.

Associated with urea as products of metabolism are _uric acid_,
_xanthine_, and _sarcine_. Urea was first artificially transformed into
uric acid by Horbaczewski, and its synthesis was effected by Behrend
and Roosen. Closely related in chemical composition to these substances
are _theobromine_ and _caffeine_, the characteristic principles
respectively of cocoa (the fruit of _theobroma cacao_); and of coffee,
tea, maté (the leaves of _ilex paraguayensis_); “guarana,” obtained
from the seeds of the South American plant _paullinia sorbilis_,
and the kola-nut of Central Africa. Strecker, in 1860, showed how
theobromine may be converted into caffeine; and Emil Fischer, by
similar means, transformed xanthine into theobromine. Since that time
xanthine itself has been prepared artificially. Caffeine can now be
built up from its elements by a series of transformations effected by a
succession of chemists, as follows:

1. Carbon and oxygen give carbonic oxide.—_Priestley_, _Cruickshank_.

2. Carbonic oxide and chlorine give carbonyl chloride.—_J. Davy._

3. Carbonyl chloride and ammonia give urea.—_Natanson._

4. Urea gives uric acid.—_Horbaczewski_; _Behrend and Roosen_.

5. Uric acid gives xanthine.—_E. Fischer._

6. Xanthine gives theobromine.—_Strecker._

7. Theobromine gives caffeine.—_E. Fischer._

Synthetic theobromine is now made on the large scale, and introduced as
a soda compound, in combination with sodium acetate, into medicine as a
diuretic under the name of agurin. Synthetic caffeine is also prepared
on a manufacturing scale from uric acid through the medium of the
methylxanthines. The close relationship of xanthine to uric acid is of
great physiological significance, since there is little doubt that the
xanthine bases are the most important sources of uric acid within the
organism.

In this connection reference may be made to the large number of
synthetic organic products which have been introduced into medicine
during the past few years. The investigation of the constitution of
the alkaloids has served to show in many cases to what particular
molecular grouping the physiological action of the drug is mainly due,
and this has led to the production of substances containing these
groups, but not necessarily existing as natural products. Among these
may be mentioned _antipyrin_, a derivative of the pyrazol group,
discovered by Knorr in 1883, and of which upwards of 17,000 kilos, of
the approximate value of £35,000, were produced in 1899. This substance
is a _phenyl-dimethyl-pyrazolone_.

_Acetanilide_ C6H5NH.COCH3, an aniline derivative, was discovered by
Gerhardt in 1853. _Phenacetin_ is a derivative of _para_-aminophenol:

OC2H5
/
C6H4
\
NH.COCH3.

An extraordinary number of synthetical soporifics have been introduced
at various times during recent years—_e.g._, _chloral hydrate_,
_veronal_, _sulphonal_, _trional_ and _tetronal_, etc. The three
last-named substances are closely related, as the following formulæ
indicate:

CH3 CH3
\ \
C(SO2C2H5)2 C(SO2C2H5)2
/ /
CH3 C2H5
Sulphonal. Trional.

C2H5
\
C(SO2C2H5)2
/
C2H5
Tetronal.

Sulphonal is prepared by the oxidation of a substance obtained by
the combination of acetone and ethylmercaptan. _Veronal_ is an ethyl
compound of barbituric acid, obtained by the condensation of urea and
diethyl malonyl chloride:

NH.CO
/ \
CO C(C2H5)2
\ /
NH.CO
Veronal.

Attempts have been made to connect the physiological working of local
anæsthetics with particular constitutional groupings, as, for example,
in cocaïne; and these have led to the introduction of such substances
as the _orthoforms_, _nirvanine_, _stovaïne_, _alyhine_, _novocaïne_,
and _adrenaline_ into medicine. Adrenaline, used in conjunction with
cocaïne, has proved itself a most valuable agent in producing what is
called _lumbal anæsthesia_, whereby large sections of the lower half
of the body may be rendered completely insensitive to pain.

The study of the putrefactive changes of albuminous substances of
animal origin, induced by the activity of micro-organisms, has revealed
the existence of a number of basic nitrogenous compounds, some of
which are highly poisonous. These were classed by Selmi under the
generic name of _ptomaines_ (πτῶμα, a corpse). Brieger found that the
typhoid bacillus yielded a poisonous substance—_typhotoxine_, and that
the bacillus of tetanus forms a highly toxic basic body, _tetanine_.
All the ptomaines, however, are not poisonous. Some of them, like
_choline_ (χυλὴ, bile)—originally discovered by Strecker in bile, in
the brain, in yolk of egg, and now found to be among the products of
the putrefaction of meat and fish—have been known for some time past.
Choline was first synthetically prepared by Wurtz. _Neurine_ (νεὺρον,
nerve), a derivative of brain substance, is related to choline, and
is readily transformed into it, but differs from it in being very
poisonous. It has been synthesised by Hofmann and by Baeyer. Another
of the so-called corpse-alkaloids—_cadaverine_—has been synthetically
formed by Ladenburg. Schmiedeberg and Kopp isolated the poisonous
principle of the fungus _agaricus muscarius_, which they named
_muscarine_. It occurs with choline, from which it can be readily
obtained, among the products of the putrefaction of flesh, as well as
in many fungi.

The synthesis of the alkaloids _conine_, _atropine_, _cocaïne_,
_piperine_, and _nicotine_ has been already referred to[5] as also that
of _vanillin_, the aromatic principle of the dried fermented pods of
certain orchids; _coumarin_, the odoriferous principle of woodruff and
of the tonka bean; of _salicylic acid_, _oil of wintergreen_, _oil of
mustard_, _bitter-almond oil_, and _camphor_. _Acetic_, _succinic_,
_tartaric_, and _citric acids_ have also been artificially obtained,
and may, indeed, be built up from their elements.

[5] P. 133.

No synthesis of recent years created more widespread interest than that
of _alizarin_, first effected by Graebe and Liebermann in 1868. Its
successful commercial manufacture by Sir William Perkin in this country
and by Caro in Germany created nothing less than a revolution in one
of our leading industries, and completely destroyed a staple trade of
France, Holland, Italy, and Turkey. To procure alizarin, anthraquinone
is treated with sulphuric acid, and the product is fused with alkali
and potassium chlorate.

The remarkable industrial results attending the synthetical formation
of this madder-product naturally led to attempts to procure other
important vegetable dye-stuffs artificially, notably _indigo_.
The synthetical production of indigo has been accomplished by
the joint labours of many chemists, notably Baeyer, Heumann, and
Heymann, and the substance is now prepared on an industrial scale.
The starting-point is _naphthalene_, obtained from coal-tar. This
is converted into _phthalic acid_, which is then transformed into
_phthalimide_. The last-named substance is converted into _anthranilic
acid_, which, on treatment with monochloracetic acid, is changed into
_phenylglycin_-ortho-_carbonic acid_. On melting this with caustic
potash it yields _indoxyl acid_, which is transformed into _indoxyl_,
and thence into _indigo_.

Another method is to treat the sodium salt of phenylglycin with
sodamide, whereby _indoxyl_ is at once obtained, and this by
condensation yields _indigo blue_:

C6H5.NH.CH2.COONa + Na.NH2
Sodium salt of Sodamide.
phenylglycin.

CO
/ \
→C6H4 CH2
\ /
NH
Indoxyl.

CO CO
/ \ / \
→C6H4 C:C C6H4
\ / \ /
NH NH
Indigo blue.

Phenylglycin is obtained by the action of monochloracetic acid
on aniline, which in its turn is obtained through nitrobenzene
from benzene. Since benzene can be synthetically prepared by the
condensation of acetylene, which can be obtained by the direct union of
carbon and hydrogen at a high temperature, it is theoretically possible
to build up indigo blue from inorganic materials.

Synthetical indigo blue was placed on the market in 1897 with an
almost immediate effect on the production and price of the natural
variety, and to-day the output of Bengal indigo has fallen by more
than fifty per cent. In 1902 the amount of the natural product was
probably not greater than three million kilos, whereas in the same
year the production of synthetic indigo was upwards of five million
kilos. Before the introduction of the artificial variety the price of
pure indigo blue ranged from sixteen to twenty shillings per kilo; by
the end of 1905 it had fallen to seven or eight shillings. Mention
should be made also of _thio-indigo red_ and the _thionaphthene_
derivatives, some of which promise to be important colouring matters.
In recent years the so-called _sulphur colouring matters_ have acquired
considerable importance. Space will not permit of any fuller treatment
of the development of the manufacture of the artificial organic
colouring matters. This industry had its beginnings in England, but it
is now mainly carried on in Germany. Its importance may be gleaned
from the fact that the value of the production at the present time
amounts to not less than £12,500,000 per annum, two thirds of the
output being exported. It demands the services of battalions of skilled
chemists, and gives employment to many thousands of artisans.

Some of the most notable achievements of modern synthetical chemistry
are to be found in the work of Emil Fischer on the _sugars_ and the
_proteins_. Although the sugars have from the earliest times been
reckoned among the most characteristic products of plant life, and have
long been used as food and as sources of alcohol, comparatively little
was known until lately of their real nature and mutual relations,
in spite of numerous attempts to elucidate their constitution. Much
of the mystery surrounding their chemical history has now been
dispelled. Not only has the molecular structure of the more important
naturally occurring sugars been unravelled, but a large number of
hitherto unknown members of the various groups of the great family
to which they belong have been prepared. The first insight into the
constitution of these bodies may be said to date from the researches
of Kiliani, made about a quarter of a century ago. In 1887 Fischer
effected the synthesis of a form of fructose (fruit sugar), and
immediately afterwards of ordinary dextro-glucose (grape sugar) and
its enantiomorph lævo-glucose, and the two optically active forms
of natural fruit sugar. Since that time such sugars as arabinose,
xylose, fucose, mannose, sorbose, cane-sugar, maltose, lactose, etc.,
and the sugars existing as glucosides, have been examined, their
stereo-chemical relations defined, and synthetic methods of production
devised. Incidentally, their behaviour towards enzymes has been
studied, and the remarkable selective action of these ferments on the
various groups, due apparently to differences of configuration, has
been established, with the result that much light has been thrown
on the mechanism of enzyme action and on the general theory of
fermentation.

[Illustration: EMIL FISCHER.]

The study of the proteins by Fischer constitutes a new chapter in
bio-chemistry. Although long recognised as among the most important
of vital products, from the circumstance that they enter into the
composition of animal tissues and secretions and are essential
constituents of protoplasm, the proteins are among the worst defined
substances known to the chemist. They are difficult to separate, as
they closely resemble one another, and afford no certain indications of
individuality. Very few of them have been obtained in a form in which
their identity could be established. _Oxyhæmoglobin_ was isolated some
years ago, but the proteins of serum albumin and of egg albumin have
only recently been obtained in definite crystalline shape. All the
proteins—even the simplest of them—are of great complexity, and possess
apparently very high molecular weights. _Hæmoglobin_, for example,
appears to have approximately the formula C158H123N195O218FeS3, with
a minimum molecular weight of 16,600. Indeed, there is experimental
evidence to show that it is even considerably higher than this.

The main clues to the nature of these substances have been gained by
the systematic study of their hydrolysis, induced by reagents, or
by the action of enzymes, whereby they are found to break down into
proteoses, peptones, and a great variety of amino acids, some of which
have been synthesised. Among the proteins of simplest constitution are
the _protamines_, found in the spermatozoa of fish. They are basic
substances, especially rich in nitrogen, forming salts with platinum
chloride and certain metallic oxides. The best investigated member of
the group is _salmine_, obtained from the testicle of the salmon. The
products of its hydrolysis have been fairly well ascertained, and their
quantitative relation is such that the substance must have at least a
molecular weight of 2045, corresponding to the formula C81H155N45O18.
Many of the albumins and globulins—coagulable proteins contained in the
animal tissues—have been isolated in a more or less definite form, and
some of them have been found to yield substances akin to carbohydrates.
_Thyreoglobulin_, the globulin of the thyroid gland, has been found to
contain iodine, apparently as a normal constituent of a body which can
be isolated as a definite proximate principle. The presence of this
element is possibly connected with the curative value of the globulin
in crétinism. A considerable amount of work on the vegetable albumins
has also been done of late years; and some of them, as _edestin_ from
hemp seed and _zein_ from maize, have been obtained in definite form.

The limits of this work preclude a more detailed account of one of
the most interesting but at the same time one of the most obscure
departments of chemistry. The field has hitherto been tilled in a
somewhat intermittent and partial manner. Now that it has been entered
by chemists of experience and resourcefulness, armed with modern
methods of cultivation, it will doubtless soon yield a rich harvest of
facts, valuable alike to the physiologist and the physician.

There can be no reasonable doubt that the chemical processes of organic
life are essentially similar to those of the laboratory. The doctrine
that a special “vital force” is concerned in the production of vital
products receives no support from the teaching of modern science,
and is, indeed, contradicted by it. At the same time, it must be
admitted that we know very little as yet of the real agencies at work
in the elaboration and mutations of chemical products in the living
organism. Because we have effected the putting together of such a
product by purely laboratory processes—it may be, indeed, by a variety
of different and dissimilar processes—it by no means follows that
any one of them is identical with that actually occurring in nature.
The building up of materials in the plant by the agency of light,
for example, has not yet been imitated in the laboratory. Many plant
products are produced by the action of unorganised ferments—so-called
enzymes—none of which the chemist has succeeded in creating.

Processes akin to condensation undoubtedly occur in the living
organism; but the means by which they are effected are, in all
probability, very different from anything known to the chemist at
present. Many laboratory condensations are only accomplished at
relatively high temperatures or under considerable pressure—or, in
other words, under totally different conditions from those which obtain
in the organism.

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