Asymmetric carbon atom, van’t Hoff

From the chirality standpoint the next fundamental development occurred in 1874, when the tetrahedral carbon atom was proposed as a basis for molecular chirality by the Dutch and French chemists Jacobus Henricus van t Hoff (1852— 1911) [47, 48] and Joseph Achille LeBel (1847-1930) [49], respectively, independently and almost simultaneously. The discovery of the asymmetric carbon atom (van t Hoff s terminology) finally provided the explanation for the existence of optical isomers and for the chiral nature of the molecules of optically active substances, including many drugs. In his original 1874 pamphlet proposing the tetrahedron [47] van t Hoff listed camphor as a chiral molecule, but the structure he gave (19) was incorrect. 

Asymmetric carbon atom van t Hoffs definition for a carbon atom having four different ligands (i.e. Cabcd). See also stereo genic center, stereogenic element. 

Asymmetric Carbon.—Now van t Hoff and LeBel found that all optically active compounds contained at least one such carbon atom. They ascribed the existence of two optically active forms to the presence in the compound of this uns3anmetrically related or asymmetric carbon atom. The asymmetry of the compounds, in that one form is dextrorotatory the other levo-rotatory, is due to this asymmetric arrangement of the molecule in space. We emphasized the fact that our structural formulas as we have been using them are simply plane representations of relationships, and indicate nothing as to the arrangement in space of the atoms or groups in a molecule. The theory of van t Hoff and LeBel considers the molecule as it is arranged in space. The isomerism so explained is known as stereo-isomerism or space isomerism. 

The polarimeter is an instrument with which the essential oil chemist cannot possibly dispense. The hypothesis, first seriously enunciated by Le Bel and van t Hoff, that substances which contained an asymmetric carbon atom i.e. a carbon atom directly united to four different atoms or radicles) were capable of rotating the plane of polarisation of a beam of polarised light, has now become a fundamental theory of organic chemistry-. The majority of essential oils contain one or more components containing such a carbon atom, and so possess the power of effecting this rotation. In general, the extent to which a given oil can produce this effect is fairly constant, so that it can be used, within limits, as a criterion of the purity or otherwise of the oil. 

Isotopes were not available in van t Hoff s day. My student generation was taught that an asymmetric carbon atom was a carbon atom attached to 4 chemically different groups. When isotopes of carbon, UC and 13C, were first applied as tracers to study carbohydrate metabolism, the entire emphasis was on the chemical similarity of 11C and 13C to the more abundant isotope 12C. Thus, it was of pressing interest to determine whether CO 2 participated in the oxidation of carbohydrate in animal tissues, a conclusion strongly suggested by the demonstration in Krebs laboratory, that pyruvate and oxalacetate behaved alike in pigeon liver, and by Wood and Werkman s earlier demonstration that some he-... 

The dissection of a molecular model into those components that are deemed to be essential for the understanding of the stereochemistry of the whole may be termed factorization (9). The first and most important step toward this goal was taken by van t Hoff and Le Bel when they introduced the concept of the asymmetric carbon atom (10a, 1 la) and discussed the achiral stereoisomerism of the olefins (10b,lib). We need such factorization not only for the enumeration and description of possible stereoisomers, important as these objectives are, but also, as we have seen, for the understanding of stereoselective reactions. More subtle differences also giving rise to differences in reactivity with chiral reagents, but referable to products of a different factorization, will be taken up in Sect. IX. 

The essential role of our concept of ligand in the proper functioning of the Sequence Rule becomes apparent on examining an example taken from the paper by Cahn et al. (4). The authors state that C(3) of their anhydride 25 (15) is symmetric, as in the free acid, and hence receives no label. Both molecules lack symmetry beyond the trivial and ubiquitous one of C,. The center of C(3) of the anhydride is symmetric only in the sense that it is not linked to four different ligands and therefore is not an asymmetric carbon atom as defined by van t Hoff. However, this observation can be made only if the ring ligands are viewed as open-chain structures, as we are defining them, because only these... 

Pasteur s discovery, as noted above, connected chirality on the macroscopic scale to chirality on the molecular scale. Unlike the chiral morphology of quartz and tartrate crystals, dissymetrie moleculaire is not apparent to the eye, yet Pasteur3 provided the key insight on the essential requirement for molecular chirality well before the advent of structural theory and the asymmetric carbon atom of Jacobus Henricus van t Hoff ... 

Through essentially group theoretical reasoning van t Hoff and Le Bel were led to postulate the asymmetric carbon atom [5], This was the beginning of stereochemistry. Other spectacular applications of group theory are the enumeration of isomers by Polya [6], De Bruijn [7], Ruch et al. [8a], and the group theoretical approaches to chirality [8 b]. 

The first of these was van t Hoff s principle of optical superposition, namely, that, in a compound having two or more asymmetric carbon atoms, the optical activities of the individual atoms can be added algebraically. This principle was applied with considerable success to carbohydrates by Hudson, in the form of his well known isorotation, lactone, and amide rules. These rules have been reviewed elsewhere, " and will not be discussed here. 

However, the designation of arrangement in space as 4- or —, which was introduced by Van t Hoff and retained unchanged by me, can lead easily in case of such complicated molecules to an erroneous interpretation. In order to avoid this I regard it as necessary that a more detailed interpretation of the formula be stated, and for this purpose I begin by designating the four asymmetric carbon atoms through the use of the numbers 1 to 4. 

This then, is the van t Hoff-LeBel Theory of Stereo-isomerism known also as the Theory of the Asymmetric Carbon Atom or as the Tetrahedral Theory. The theory is supported by a large number of facts and has been fruitful in leading to new discoveries. We shall find cases of stereo-isomerism in several of the classes of compounds which we shall study and some of our most common substances, such as lactic acid,... 

It is this fourth unresolvable inactive tartaric acid which gives to tartaric acid its especial interest and importance in connection with the theory of stereo-isomerism. This acid, like the other three, has been fully explained in accordance with the tetra-hedral theory of van t Hoff and LeBel. The explanation rests upon the fact that there is a second asymmetric carbon atom in tartaric acid. We may construct, by models, or, by drawings, space-formulas for tartaric acid. According to the tetra-hedral theory, the dextro, levo and racemic inactive forms will be as follows, analogous to the corresponding formulas for the three lactic acids. The meso-tartaric acid is represented by the third drawing. 

The other example of note is the optically active tartaric acids (Fig. 11). Tartaric add contains two asymmetric carbon atoms. The dextro- and levo-tartaric adds are enantiomers. However, a third isomer is possible in which the two rotations due to the two asymmetric carbon atoms compensate and the molecule is optically inactive as a whole. That is, the molecule contains a plane of symmetry. This form, meso-tartaric acid, was also discovered by Pasteur, differs from the two optically active tartaric adds in being internally compensated, and is not resolvable. Thus, the tetrahedral model for carbon and the asymmetric carbon atom proposed by van t Hoff were able to completely explain the observations of Pasteur relating to the three isomers of tartaric add. 

Le Bel published his stereochemical ideas two months later, in November 1874, under the title, The relations that exist between the atomic formulas of organic compounds and the rotatory power of their solutions" (14). An English translation is presented in Le Bel (15). Le Bel approached the problem from a different direction from van t Hoff. His hypothesis was based on neither the tetrahedral model of the carbon atom nor the concept of fixed valences between the atoms. He proceeded purely from symmetry arguments he spoke of the asymmetry, not of individual atoms, but of the entire molecule, so that his views would nowadays be classed under the heading of molecular asymmetry. Only once does he mention the tetrahedral carbon atom, which he regarded as not a general principle but a special case. Today, substituted allenes, spiranes, and biphenyls are but a few examples of asymmetric molecules that do not contain any asymmetric carbons, thus confirming Le Bel s views on molecular asymmetry. The reason for the different approaches by van t Hoff and le Bel is easy to understand, van t Hoff came from the camp of structural chemists, and he... 

We can now end this historical journey. We have walked through the early days of stereochemistry in the company of giants. In 1949, almost exactly 100 years after the first resolution of d,Martaric add by Pasteur, the Dutchman Bijvoet (16), using x-ray diffraction, determined the actual arrangement in space of the atoms of the sodium rubidium salt of (+)-tartaric add, and thus made the first determination of the absolute configuration about an asymmetric carbon. To further complete the link with the past, Bijvoet did this work while the Director-of the van t Hoff Laboratory at the University of Utrecht. 

This paragraph, coupled with the next but one before it, clearly implies a r ular tetrahedral structure for methane, a fact that has been denied by some. (Gf. A. Findlay, A Hundred Tears of Chemistiyf New York Macmillan, 1938, p. 73. The author suggests that in van t Hoff s mind arose the idea of the tetrahedral carbon atom, in le Bel s the idea of the asymmetric carbon atom. In fact, each paper contains both ideas. Cf. also A. Sementsov, American Scientist 43, 97 (1955).)—O.T.B.]... 

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