From Configurational Notation of Stereoisomers to ... - ACS Publications

13 From Configurational Notation of Stereoisomers to the Conceptual Basis of Stereochemistry V. P R E L O G

Downloaded by UNIV OF ARIZONA on September 26, 2014 | http://pubs.acs.org Publication Date: June 1, 1975 | doi: 10.1021/bk-1975-0012.ch013

Laboratorium für Organische Chemie, Eidg. Technische Hochschule,

8006 Zürich,

Switzerland

This Symposium commemorates the appearance of two papers that were published a hundred years ago and constitute the foundation of "chemistry in space". In the fall of 1874 van't Hoff (1) published in Dutch his 14-page pamphlet dated Utrecht, September 5th,1874. The paper by Le Bel (2) appeared in the issue of the Bulletin de la Société chimique de France dated November 5th, 1874, i. e. virtually simultaneously with van't Hoff's publication. The two young scientists - van't Hoff was 22 and Le Bel 27 - were dealing with the problem of so called "excess isomers" (3). By considering which of these isomers are optically active and which not, they arrived at the conclusion that the ligand atoms on carbon form a stable tetrahedron - a conclusion which they bravely converted into a general postulate. On the basis of this postulate, and the ancillary assumption that there is, in essence, free rotation about single bonds, they were able to account for the number of the "excess isomers" - named later by Victor Meyer stereoisomers - and for their behaviour towards polarized light. These novel and far-reaching ideas played a great role in the thinking of chemists who were concerned with natural products such as sugars, terpenes and alkaloids ; and in this connection Emil Fischer's (4) utilization of the stereochemistry - as the "chemistry in space" was named by Victor Meyer (5) - was especially important. Fischer's unambiguous methods of determining the configuration of sugars by using symmetry arguments not only enabled him to rationalize the puzzling multiplicity of isomeric sugars but also substantially broadened the rather narrow experimental basis on which stereochemistry initially rested.

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In van't Hoff-Le Bel Centennial; Ramsay, O.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

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Apart f r o m the intrinsic m e r i t s of F i s c h e r ' s contributions the strong personality of this great experimentalist gave the stereochemistry a characteristic pragmatic stamp. It was v e r y important for the quick spread and success of stereochemistry that already i n his second paper L a chimie dans l'espace (6) published i n 1875, van't Hoff introduced the regular tetrahedron as a geometrical model for a carbon atom by means of which models isomorphous with molecules could be constructed. This enabled chemists to solve the problems which they encountered in their work by exhaustively inspecting the models. They did so for s e v e r a l decades without worrying about the geometrical basis of s t e r e o i s o m e r i s m or about the scope and l i m i t s of s ter eo chemis tr y. That i s nicely illustrated by the following paragraph f r o m Fischer's autobiography (7). He w r i t e s : I remember especially a stereochemical problem. During the winter 1890-91 I was busy with the elucidation of the configuration of sugars but I was not successful. Next spring i n Bordighera[where F i s c h e r was accompanied by Adolf von Baeyer] I had an idea that I might solve the problem by establishing the relation of pentoses to trihydroxyglutaric acids. However, I was not able to find out how many of these acids are possible; so I asked Baeyer. He attacked such problems with great z e a l and immediately con structed carbon atom models f r o m bread crumbs and toothpicks. After many t r i a l s he gave up because the problem was seeming l y too hard for him. Only later i n Wurzburg by long and careful inspection of good models did I succeed i n finding the final solution". E m i l F i s c h e r recognized that by using chemical transform ations it i s not only possible to correlate the relative configur ation of s e v e r a l asymmetric carbon atoms i n one molecule but that one can also often correlate the configurations of asym m e t r i c carbons i n different molecules. On the other hand, he was w e l l aware of the fact that it i s not possible to correlate by chemical methods the enantiomeric submicroscopic molecules with the macroscopic enantiomorphous geometrical models. To be able to use these models i n his work he attributed one of the two possible models a r b i t r a r i l y to one enantiomer of a compound which should act as reference compound and which he specified by the sign of its optical rotation with the calculated r i s k that this so-called F i s c h e r convention had 50 percent probability of being wrong. In the sugar s e r i e s he f i r s t chose dextrorotatory glucose as reference standard. On that basis he tried to c l a s s i f y a l l the


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11

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Conceptual Basis of Stereochemistry

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enantiomeric compounds that he was able to correlate by chem i c a l transformations with dextrorotatory glucose, independently of their optical rotations, as d- and their enantiomers as 1sugars. Because of their relationship with (+)-d- glucose, (-)-fructose and (-)-arabinose belong according to F i s c h e r to the d-series of sugars. Unfortunately the letters d and 1^ (as w e l l as D and L) had been widely used before to specify the sign of rotation and i t was often not clear what they r e a l l y mean i n a p a r t i c u l a r case. This inconvenience was finally eliminated by using s m a l l capital letters D and ^ for configurational notation, a convention that was endorsed by international nomenclature committees and soon found general acceptance. P a u l Walden's discovery (8) i n 1896-99 that a replacement reaction can take a stereochemically different course depending on the reaction conditions imposed severe l i m i t s on the use of chemical transformations for classification of enantiomers : these reactions can be used only i n cases i n which the bonds on the asymmetric atom i n question are not involved i n the reaction or i n which the steric course i s mechanistically w e l l substant iated. E m i l F i s c h e r was fully aware of this limitation but he overlooked i n his e a r l y work the fact that i f more than one ligand i s changed by chemical transformations i n the course of the correlation the assignment of an enantiomer into the d- or ^ - s e r i e s depends on the reaction path used. In a c l a s s i c a l and lucid paper M. A. Rosanoff (9) showed that division of enantiomers into two classes i s only possible by using some f o r m a l conventions. His diagram (Fig. 1) i n which he correlated sugars with (+)- and (-)-glyceraldehyde as standart compounds and showed that some of E m i l F i s c h e r ' s generic correlations were based on a faulty p r i n c i p l e i s an e a r l y important contribution by an A m e r i c a n scientist to general stereochemistry. To avoid confusion Rosanoff proposed that after his r e f o r m the misleading d e s c r i p t o r s d- and^should be replaced by Greek letters δ- and λ- but his proposal was not accepted by the chemical community. An example that even Rosanoff s paper did not remove a l l controversies was the case of the t a r t a r i c acids. It i s w e l l known that (+)-tartaric acid can be chemically c o r r e l a t e d either to (+)- or to (-)-glyceraldehyde depending on the reaction path used. According to the Rosanoff diagram it belongs to the λ- or 4*-series but this was never accepted by E m i l F i s c h e r and his school; i t i s interesting to see the confusion which this s c h i s m caused i n various widely used European and A m e r i c a n 1


V A N T H O F F - L E BEL CENTENNIAL


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Figure

1

textbooks. It is therefore not astonishing that K a r l Freudenberg wrote in his handbook of stereochemistry (1933) (10) The prefixes d and I have a systematic meaning only in narrow limited groups : outside these groups no systematic meaning should be ascribed to them. The significance of such notations is very often overestimated". In the period between 1930 and 1950 classifications of enantiomers analogous to those in sugar series have been proposed for several groups of compounds that could not be correlated to glyceraldehyde by chemical transformations. This made it necessary to choose several new standard compounds and conventions, and chemists working in the field often disagreed about them. A l l this stimulated C. Buchanan to send a note to Nature (11) in which he wrote: "Although the relative configurations of many optically active compounds could be established, it is impossible to allocate the compounds to D- and L - s e r i e s without ambiguity. This i s true even in carbohydrate chemff


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istry , Surely i t would be better to abandon the used of prefixes D- and L , except for those parts of the carbohydrate and a-amino-acids fields i n which they do serve a useful purpose . This note appeared almost at the same time as an article by R. S. Cahn and C. K. Ingold (12) i n which they l a i d down the principles of a configurational notation for tetrahedral asymm e t r i c atoms which avoids the ambiguity of previous systems. The most important part of the new system was the socalled sequence rule. The ligands around a tetrahedral atom were f i r s t ordered i n a sequence by using atomic numbers (or i n the case i f isotopes atomic weights) as criterion. The constitutional differences among the ligands were established with the help of a directed h i e r a r c h i c a l graph (Fig. 2) i n sets which


11

were equidistant f r o m the central atom. The tetrahedral model with ordered ligands i s then looked at f r o m the side remote f r o m the ligand of lowest p r i o r i t y (Fig. 3). A descriptor Ç was assigned to the enantiomer i f the ligands starting with that of highest precedence are ordered clockwise, a descriptor L i f they are ordered anticlockwise. In 1954 the A n n i v e r s a r y Meeting of the C h e m i c a l Society was held i n Manchester. It included a v e r y successful


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CHO

J

H-

H

:HO ϊ—OH

Ε—α

^OH

:Η,·ΟΗ

CH OH 2


Figure

3

Symposium under the somewhat vague title "Dynamic Stereo chemistry". At the end of the meeting, on A p r i l 2nd, a Reception and Dance were organized by ICI i n its Hexagon House i n Blakley. Among the few non-dancing participants the Editor of the Society's Journal, R. S. Cahn, the President of the Society, C. K. Ingold, and I tried to k i l l time drinking beer and talking chemistry. Among other things we discussed Cahn and Ingold s proposal for configurational notation. As the result of this conversation they invited me to join them i n w r i t i n g a paper about the Specification of A s y m m e t r i c Configuration i n Organic C h e m i s t r y and I gratefully accepted their offer without the faintest notion of the consequences. We agreed easily by correspondence and during numerous meetings held i n England and i n Switzerland about the important principles which should guide us i n construction of the system. 1. The new system should be general and absolute. General, to cover (or to be adaptable to cover!) a l l types of stereoisomerism. Absolute, because Bijvoet, Peerdeman and van B o m m e l (13) had by then confirmed by X - r a y analysis that E m i l Fischer's correlation of the c h i r a l i t y of molecules and models was c o r r e c t ; the arbitrariness of the choice was there fore eliminated. 2. The new system, like Cahn and Ingold s o r i g i n a l system, should be based on a few exact rules which should be controlled only by the system itself and must not depend on nomenclature, numbering and/or other a r b i t r a r y factors beyond its control such as structural resemblance or genetic concepts. A one-to-one relation between a molecule and its stereochem i c a l descriptor, i . e. that i t must be impossible for the rules to lead to opposite descriptors for one enantiomer, i s essential and the validity of the descriptor can be guaranteed only if this condition i s fulfilled. The sequence r u l e of Cahn and Ingold was to r e m a i n the core of the new system but needed to be extended. 1

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3. The new system should not be based on projection formulae. Additional rules would be necessary to account for the neglected dimension. O r as Ingold aptly formulated i t : "Projection formulae are good slaves but bad masters". 4. To distinguish the new system f r o m the previous ones new descriptors should be chosen. After consideration of many others, descriptors JR and S (r andjs) were selected for many obvious reasons. A s the result of our endeavour a paper appeared i n 1956 i n the Swiss journal E x p e r i e n t i a (14) i n which our ambitious p r o g r a m and proposals for the solution of various problems i n connection with the specification of configuration were published. In addition to centers of asymmetry the concepts of axes and planes of asymmetry were introduced. These proposals have been c r i t i c i z e d f r o m different sides. I s h a l l not discuss here the c r i t i c i s m s of authors who did not accept the general principles, which we considered essential for the functioning of any such system. Of great value, however, were the comments of colleagues who accepted our proposals and used them i n their daily work. The most important of such users were the E d i t o r s of B e i l s t e i n s Handbuch, the late P r o f e s s o r F. R i c h t e r and his colleague Dr. O. Weissbach. The latter undertook the Herculean task of specifying many thousands of stereoisomers of a l l types by our system. In addition he invented many ad hoc cases to test it. This labour, which we later named " B e i l s t e i n test", and the subsequent positive and benevolent c r i t i c i s m by R i c h t e r and Weissbach as w e l l as by some other colleagues stimulated us not only to improve our system where necessary but also to extend it substantially. This was done rather slowly and with much deep thought and many fraternal arguments between 1961 and 1966. The resulting paper appeared i n Angewandte Chemie (15). The o r i g i n a l E n g l i s h text was translated into G e r m a n (16) b y Dr. H. H. Westen who, i n the last stages, also made some essential corrections and conceptual contributions. The " B e i l s t e i n test" persuaded us that we were on the right t r a c k ; no other system was ever applied on such a large scale. The corrections and improvements we had to make i n the third paper were substantial but the consequences were minor and the descriptors p r e v i o u s l y assigned to only a few compounds had to be changed. The most important extensions i n it included the treatment of conformational s t e r e o i s o m e r i s m and of the helicity i n general as w e l l as the specification of c h i r a l i t y of octahedral complexes. We recognized that we were specifying 1



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by descriptors the "handedness" of molecules o r of the parts thereof. It was v e r y convenient to use for "handedness" the t e r m " c h i r a l i t y " coined by L o r d K e l v i n (17) many years ago and rediscovered by theoretical physicists (18). We therefore gave our paper the title "Specification of Molecular C h i r a l i t y " . During the last stages of writing we were aware that this would be our last common paper on the subject and we mentioned it sometimes i n the course of our discussions. S i r Christopher managed to write the final v e r s i o n of the text i n spite of his preoccupation with the manuscript of the 2nd edition of his monumental "Structure and Mechanism i n Organic C h e m i s t r y " (19). He insisted that publication should not be delayed although during the reading of galley proofs we encount ered some conceptual difficulties. P o s s i b l y he had a pre sentiment that he would have to leave us i n not too distant future. I would like to confess here that the cooperation and contacts with this great man are among the most important events of my scientific life. Through cooperation on the papers about conformational notation and the specification of molecular c h i r a l i t y I became aware, as already mentioned at the beginning of my talk, that stereochemistry developed as a pragmatic science and that its concepts were neither w e l l defined nor appropriately taught. The geometrical fundamentals had not been separated f r o m the physical consequences, as i s i n many instances evident f r o m the terminology. In every textbook of organic chemistry old misnomers such as "geometrical isomers", "optical antipodes", "optical i s o m e r i s m " etc. are s t i l l used for fundamental concepts. In fact a l l stereoisomers are geometrical isomers, and enantiomers are not "antipodes" (i. e. rotated by 180° Ï). Enantiomers are optically active but the enantiomerism itself i s a geometrical feature; the optical activity i s only a consequence of the symmetry, as are dipole moments of compounds without a center of symmetry. It i s indeed possible to imagine a perfect stereochemistry without a knowledge of the phenomenon of optical activity. To determine the scope and l i m i t s of stereochemistry it i s necessary to trace it to its geometrical source and that i s chirality. C h i r a l i t y i n three-dimensional space i s w e l l known, but the less f a m i l i a r two-dimensional c h i r a l i t y plays an equally important role (20),(21). B y combining equal and different two- and three-dimensionally a c h i r a l and c h i r a l building blocks a catalogue of geometrical figures can be constructed which are isomorphous models for a l l types of stereoisomers. The items of such a


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catalogue are examples of c l a s s i c a l and new stereochemical concepts such as elements of chirality, pseudoasymmetry, prochirality, heterotopy etc. It i s beyond the scope of my lecture even to sketch how, i n my opinion, that can be achieved. I have here wished only to illustrate how efforts to solve a seemingly simple problem, such as to fix conventions for configurational notation, can become a starting point for thoughts about the framework and structure of stereochemistry as a whole.


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Literature Cited 1.


2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19.

20.

21.

van't Hoff, J. Η . , Voorstel tot nitbreiding der tegenword in de scheikunde gebruikte structur- formules in de ruimte, Greven, Utrecht 1874. Le Bel, J. A., Bull. Soc. Chim. [2] 22, 337 (1874). Wislicenus, J., Ber. deutsch. chem. Ges. 2, 620 (1869). Fischer, Ε., Ber. deutsch. chem. Ges. 23, 2114 (1890); 27, 3189 (1894). Meyer, V., Ber. deutsch. chem. Ges. 23, 567 (1890). van't Hoff, J. H., La chimie dans l'espace, Bazendijk, Rotterdam 1875. Fischer, Ε., Aus meinem Leben, Springer, Berlin 1922, p. 134. Walden, P., Ber. deutsch. chem. Ges. 29, 133 (1896); 30, 2795, 3146 (1897); 32, 1833, 1855 (1899). Rosanoff, M. A., J. Amer. chem. Soc. 28, 114 (1906). Freudenberg, Κ . , Stereochemie, Deuticke, Leipzig und Wien 1932, p. 671. Buchanan, C., Nature 167, 689 (1951). Cahn, R. S., and Ingold, C. K., J. chem. Soc. (London) 1951, 612. Bijvoet, J. M., Peerdeman, A. F., and van Bommel, A. F., Nature (London) 168, 271 (1951). Cahn, R. S., Ingold, C. Κ . , and Prelog, V., Experientia 12, 81 (1956). Cahn, R. S., Ingold, Sir Christopher, and Prelog, V., Angew. Chemie, Intern. Edit. 5, 385 (1966). Cahn, R. S., Ingold, Sir Christopher, and Prelog, V., Angew. Chemie 78, 413 (1966). Lord Kelvin, Baltimore Lectures, C. J. Clay and Sons, London 1904, pp. 436, 619. Whyte, L . L., Nature (London) 180, 513 (1957); 182, 198 (1958). Ingold, Sir Christopher, Structure and Mechanism in Organic Chemistry, 2nd Ed., Cornell University Press, Ithaca, New York 1969. Prelog, V., Robert Robinson Lecture, Dublin, 3. April 1968. Summary by R. S. Cahn, Chem. in Britain 4, 382 (1968). Prelog, V., Paul Karrer Lecture, Zürich, 26. Juni 1974, Angew. Chemie (in preparation).


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