CHAPTER IX

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:

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.

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.