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Gazz. Chim. It. 127,837 (1997)

THE DISCOVERY OF TETRAHEDRAL CARBON: CONTRIBUTIONS OF PATERNO' AND CANNIZZARO. *

Giorgio Montaudo, Dipartimento di Scienze Chimiche, Università di Catania. Viale A. Doria, 6 - 95125 Catania, Italy.

ABSTRACT Although the discovery of stereoisomerism is due to Van't Hoff and Le Bel (1875), the hypothesis of tetrahedral carbon, on which is actually based the stereoisomerism, is older. The latter is due to Kekulé (1862), who then built the tetrahedral carbon molecular models, and applied them to solve the problem of the structure of . The molecular models of Kekulé were used by the most talented pupils of his school (Dewar, Koerner, Van't Hoff), and were applied to diverse structural problems. Among these contributions, of great relevance is the work of Emanuele Paternò, who grew up in the laboratory of S.Cannizzaro in Palermo, and who came also in contact with the school of Kekulé. Paternò, using the molecular models of Kekulé, in 1869 applied for the first time the theory of the tetrahedral carbon to aliphatic organic compounds, and discussed the conformational isomerism of these compounds. Only a few years later, Van't Hoff and Le Bel succeeded in applying the hypothesis of Kekulé to the problem of optical antipodes, and discovered stereoisomerism...... * Plenary Lecture presented at the Meeting of the Italian Chemical Society, Sicilian Section, held in Catania 19-20 December 1996

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INTRODUCTION

The discovery of Van't Hoff and Le Bel (1865) is a landmark, one of those events that mark the beginning of a new era. The theory of stereoisomerism, that explicitly affirmed the tetrahedral structure of carbon, and the subsequent rationalization of the whole organic , ought to be numbered among the greatest scientific events of the XIX century. However, alike to nearly all the discoveries, also this one has an antefact, and the events connected to it are more complex than what the official storiography, always inclining to simplify, has handed down to us. In fact, the clamorous controversy provoqued by the proposal of Van't Hoff and Le Bel, appears to have covered the importance of previous contributions. Some salient points of the history preceeding the discovery of Van't Hoff and Le Bel have remained in the shadow, almost forgotten. However, the latters are important contributions, perhaps essential, bound to the name of the great Kekulé, and they include also first rate italian scholars such as Paternò and Cannizzaro. This fact makes even more interesting for us the attempt of reconstructing the variegated scientific scenery existing before the discovery.

INSTRUMENTALISM AND CHEMICAL THEORY The first atomic and structural hypotheses, those on which was based the "chemical theory" at the beginning of 1800, were accepted only at the "instrumental level" by the chemists of the XIX century, as well described in this fragment from Berzelius: "The theory is only a way to imagine the phenomena. Although in a certain historical of the scientific development it serves entirely as a true theory, with the accumulation of knowledge during the centuries, the way of imagining the phenomena of science shall change, perhaps without ever reaching the truth. Sometimes it happens that two different explanations are both possible: it is then necessary to study them both. If we change theory, the new one must explain better the facts." BERZELIUS 1819. In another example, the atomic theory appeared a valid hypothesis to explain the observed facts, but the real existence of was seriously doubted: "The principle that the atoms are indivisible is an hypothesis indifferent, and therefore only a convention. In fact, what difference it makes for the facts of chemistry if the elemental chemical masses would be susceptible of being cut indefinitely by means of forces independent from chemistry?" DUMAS 1836. The corpuscolar nature of the and of the remained in the shadow for all the XIX century, and it was necessary to wait (1898) to gather experimental evidence on the existence of the electron in order to start wondering about its actual function inside the . Without understanding the role of the electron it was'nt possible to understand the nature of the , and consequently the problem of remained for long time undefined, together with that of the existence of the atoms. This created big problems, especially in the field of , that started developing from 1828, when Wholer opened the way to organic syntheses. Within a short time this discipline became a crucial test for the further development of the chemical theory. In fact, the chemistry of soon showed enormous structural problems, such as the explanation of the widespread phenomenon of isomerism. The existence of isomerism in organic compounds might be accounted for by assuming a different order of the atoms inside these compounds, but serious doubts were risen in this respect: 3

"A popular prejudice is that it is possible to express by chemical formulas the molecular disposition of the compounds, that is, the real disposition of their atoms". "The chemical formulas are not meant to represent the disposition of the atoms, but have only the purpose to express in the most simple and precise way the ratios of the chemical bodies and their transformations". GERHARDT 1844. To face these objections, it became imperative to elaborate a new chemical formalism capable of explaining the complex differences among the varios compounds. The evolution of chemical symbols, that had been very slow starting from the ancient greek and alchemic symbols up to Lavoisier and , underwent a defined acceleration with Berzelius (1814), and from that point the symbolism used in the chemical formulas evolved up to the times of Kekulé. The 40 years from 1820 to about 1860, were marked by numerous and controversial attempts to establish a structural theory of organic chemistry, and culminated in the first KekulŠ formulation. Concluding a complex series of researches that brought him to the definition of the structural formulas of aliphatic homologous series, Kekulé (1858) affirmed that the carbon atom is always tetravalent, and also theoretized the existence of double bonds in unsaturated compounds. Of course, Kekulé was not alone in this enterprise, and a long series of great masters must also to be credited. Among many others, quite remarkable appears the contribution of Butlerov who, in the framework of the concepts emerging from the rationalization of the phenomena of isomery and homology, introduced the idea of chemical structure, defined as the way of reciprocal binding of the atoms inside to a compound: "I do not believe, at difference from Kolbe, that once ascertained the existence of the atoms, we shall not be capable of determining their position in the space." BUTLEROV 1863. "It is not impossible to represent in the plane the spatial position of atoms". "This is possible by means of mathematical formulas, and it is likely that the laws ruling the formation of the chemical shall find, in due time, their mathematical formulation". BUTLEROV 1863.

THE TETRAHEDRAL CARBON Already in 1858 Kekulé began to propose a cyclic strucure for benzene, but it was only in 1865 that he proposed the hexagonal formula with alternated double bonds. Actually, the benzene formula posed formidable structural problems at that time, and there were several plausible models. Kekulé started to think at the tetrahedral carbon already in 1862, when he formulated the hypothesis that "the valences of carbon are oriented in the direction of hesahedral axes terminating on the faces of a inscribed in a ". Due to the relevance and international prestige of Kekulé, whose laboratory was attended by the most promising european chemists, it is likely that the hypothesis of the tetrahedral carbon had wide circulation among the researchers in Europe in the '60 decade. Kekulé had immediate need to use this hypothesis in order to better define his benzene structural formula. Therefore, he built in his Gent laboratory molecular models based on tetrahedral carbon, of which we have notice starting from 1867. These models, later known as Kekulé-Baeyer models, were commonly used to represent the structure of organic compounds till about 1930, when they were substituted by the molecular models based on the X-ray diffraction data and on the orbital hybridization concepts proposed by Pauling (1931). 4

However, Kekulé judged unwise to consider those models as real objects. Since the existence of atoms was not yet proven, one ought to be cautious. His position was instrumental, and he tended to stress the utility of the molecular models in suggesting possibilities of advancement od the chemical science, rather then insisting on their reality: "The question if the atoms exist or not belongs to the methaphysics. We need only to decide if the assumption of the atoms is a hypothesis able to explain the chemical phenomena, and if a further development of the atomic hypothesis promises an advancement of our knowledge about the mechanism of the chemical phenomena". KEKULE' 1867. and more: "I am inclined to think that some day we shall find, for what we now call atoms, a mechano- mathematical explanation which shall account for the atomic weight, atomicity, and for numerous other properties of the so-called atoms". KEKULE' 1867. Given the great importance of the molecular models that he had invented, one may wonder why Kekulé never published an official scientific report about his tetrahedral models. This fact, which at first may sound mysterios, is instead quite obvious. Due to his instrumental position (see above), it appears simply logic that Kekulé was not eager to write a paper on his molecular models. such a report would have involved the problem of discussing the concepts used in their construction, and Kekulé knew that he had no ground to defend his molecular models, based on the double assumption of atoms and of tetrahedral valences. The only result would have been to stir another controversy. And Kekulé suffered already of so many controversies in those years, in his attempt to sustain his theory of the constant valence against evidence for the contrary brought up by the inorganic chemists. Therefore, he kept his models as useful tools, together with the other instruments of his laboratory. However, the molecular models were available to the numerous talented researchers attending his laboratory, young people with alight fantasy, representing the best intelligence of their time.

THE WORKS OF DEWAR, KOERNER AND PATERNO' Already in 1867, Dewar published his seven structures of benzene, illustrated by based on molecular models of Kekulé type. It is known, however, that the young Dewar (25 years), had visited the laboratory of KekulŠ for a certain period during 1867. One of the formulas proposed was that of Kekulé, and among the others there was one that became later famous with the name of Dewar. Among the assistants of Kekulé in Gent there was also (1866-67) the young W.Koerner (27 years in 1866) who, having concluded the period with Kekulé, went to the laboratory of Cannizzaro in Palermo. It is likely that also Koerner brought with him some KekulŠ molecular models and, once in Palermo, he discussed them with Cannizzaro and with his new collegues in the laboratory. As matter of fact, in 1869 appear two papers, published on the "Giornale di Scienze Economiche" of Palermo (this Journal was actually the Bulletin of the local Academy of Sciences, chaired by Cannizzaro at that time). The first paper was signed by W.Koerner and the second by Paternò; both were based on the molecular models of Kekulé. The work of Koerner actually was a fairly comprehensive overview of the chemistry of benzene compounds and Cannizzaro, in the note of presentation that he used to write for the papers of his pupils, explains that Koerner comes from Gent, where he had studied with 5

Kekulé the chemistry of aromatic compounds, and that the paper seemed important to him also as a mean of introducing this new field, yet little known in Italy. It is not necessary to remark here the deep interest of Cannizzaro for organic chemistry. He had in fact started studying chemistry in Neaples just with the organic chemist Piria, and in 1857 he had discovered the reaction of dismutation of benzaldehyde, which is today known as the Cannizzaro reaction. In his paper, Koerner also proposed a formula of benzene, in alternative to that of his master Kekulé, quoting also the partial resemblance with that suggested by Claus. He conceived a non-planar structure ("where the 12 benzene atoms are placed in 4 different planes"), derived from the hypothesis of the tetrahedral carbon, and he gave also a graphic representation clearly based on the models of Kekulé. However, Koerner did not quote expicitly the models of KekulŠ in his paper, and we don't know if he omitted this quotation in order to avoid a direct involvment of Kekulé, or only to escape giving explanations on the use of molecular models, quite unorthodox for that time. It appears quite plausible that the young Koerner did not attribute outmost importance to the models and that, simlar to Kekulé, considered them only useful tools. At last, we have to remark that Koerner never proposed again his formula, that was almost totally forgotten in the subsequent literature. It appears that in this paper Koerner wished to lay down the basis for discussing later his well known studies on the determination of the position isomers in the benzene derivatives. E. Paternò (25 years in 1869), collaborated initially with Koerner in some researches, and most likely learned from him the use of the tetrahedral models of Kekulé, which he then used in the attempt of proving the supposed existence of three isomers in dibromoethane. The work of Paternò is concerned with the chemical synthesis of dibromoethane. At that time it was not yet ascertained if the isomers of dibromoethane were two or three, and the young Paternò correctly argued in favour of the equivalence of the four valences of carbon in this compound. The use of the molecular models was ingeniously introduced at the end of the paper, in order to account for the eventual existence of two isomers in 1,2-dibromoethane. Patern•, for the first time in the literature, drew two conformers of 1,2-dibromoethane and figured out a process that today we would define of "kinetically restricted" internal rotation. Furthermore, he formulated the hypothesis that this "frozen" situation would bring to the possiblility of having two distinct isomers (Figure 1). Today we know that the two conformers described by Paternò are eclipsed, and therefore they are not energetically stable. Instead, the energetically stable conformers of 1,2-dibromoethane are in the staggered form and interconvert rapidly, whereas the "kinetically restricted" internal rotation can be induced in this system only at extremely low temperatures, and it is detectable for instance by NMR techniques at variable temperature. The great innovation contained in the Patern• work lies in the fact that he, for the first time, applied the theory of the tetrahedral carbon to the study of saturated organic compounds. As matter of fact, Kekulé, Dewar and Koerner had studied only the structure of benzene, and had applied the tetrahedral models to it. Because of his pioneering work, some authors have advanced the idea that Paternò preceeded Van't Hoff and Le Bel (1874) in the discovery of the tetrahedral carbon and of the steroisomerism. But this is true only in part. Actually, it can be said that his paper is extremely brilliant and faces the isomerism problem on a new basis. But without taking anything from Paternò merits, the molecular models used by Paternò were those of Kekulé, and their application did not solve the problem of the isomers of dibromoethane, since it was later ascertained that they were two and not three. 6

The paper of Paternò was forgotten for about a century, although there are indications that Van't Hoff has read it, but only after having published his work on the stereoisomerism. In his paper, Paternò does not discuss the origin of these models, on the contrary, he assumes them as known. Furthermore, he does not claim any priority concerning the idea of the tetrahedral carbon. Instead, he deals with it as a well known hypothesis, and affirms that the latter derives from the "fundamental principles of the theory of the constitution of organic compounds". On the other side, if Paternò had intended to introduce for the first time the molecular models, he should have discussed thoroughly the theory that had brought him to propose them, and would have met with the recurrent difficulty of justifying the use of directional valences in objects (the atoms), whose existence was not yet demonstrated. Spatial structural formulas appeared at that time as an abstraction and were therefore highly speculative. It should also be mentioned here that Cannizzaro had an extreme interest towards the attempts of his pupil. In his introduction to the paper of Paternò he commented briefly the molecular models presented by Patern•, treating them as well known. On that occasion, Cannizzaro devoted to the subject a long and detailed introductory note, and stated clearly the theoretical problem that stands behind the determination of the number of isomers in the dibromoethane. The caution note regarding the proposal of Paternò, by which Cannizzaro concludes his introduction is really remarkable: "Mister Paternò shall pursue in his work and hopes to succeed in accumulating sufficient evidence to answer to his question: if the different relative position of the two equal () atoms joint to the two carbon atoms might cause the existence of isomeric compounds". "This point is of such fundamental importance for the theory of the carbon compounds, that it deserves the persevering study of perhaps several years". CANNIZZARO 1869. Actually, successive studies never appeared in the literature, and also that work was forgotten. The reason of this obsolescence lies in the fact that the bold hypothesis of Patern• did not solve the problem faced. Apparently, the tetrahedral carbon theory had been applied to account for the case of the dibromoethane isomers, and had failed. The isomers were two, not three as it had been predicted. Even if we today know the subtle why of that apparent failure (the low energy barrier to internal rotation), the theory was rejected on the basis of an erroneous prediction.

THE DISCOVERY OF STEROISOMERISM From the foregoing discussion it can be deduced that Kekulé hypothesis on the tetrahedral carbon was circulating in Europe during all the years '60, and that it was used explicitly at least three times (Dewar, Koerner, Paternò) in scientific publications. Dewar and Koerner, very young but not unexperienced, both attempted to find better solutions to the structure of benzene, with respect to that proposed by Kekulé. Of course, the old master (Kekulé) had well evaluated all the other structural possibilities before proposing his formula. The attempts of Dewar, Koerner and also that of Paternò, who first applied the theory to the study of the isomery in saturated compounds, should be seen as the first independent attempts of the Kekulé pupils to apply the new theory of the tetrahedral carbon to account for the experimental facts. Despite of the frequent lack of success, we are in presence of a vanguard of first order, originating directly from Kekulé thoughts. It is his school that undertakes the task of testing the theory in new fields. 7

A few years later, in 1872, we find Van't Hoff (20 years) in the laboratory of Kekulé, who has moved in the meantime to Bonn. It is more than likely that also Van't Hoff has seen in Bonn the famous molecular models, and that has heard about the tetrahedral carbon. However, he does not aknowledge this debit when (1874) he publishes an article, followed shortly after by the famed "La Chimie dans l'Espace", where he attributes the optical activity to the existence of spatial isomers (stereoisomerism), and admits that the hypothesis of the tetrahedral carbon lies at the basis of his theory. Van't Hoff did not use directly the models of Kekulé, but he chose to build some solid to represent the carbon atoms, stating that they could be combined through their vertex, sides and faces. This representation had two advantages: i) it lended itself splendidly to describe the molecular asymmetry and its consequences on the rotatory power of organic compounds; ii) it was an attempt to escape to the critics about the tetrahedral hypothesis of carbon, by picturing the carbon atom as a solid tetrahedron that reminded the asymmetric crystalline structures, already well known at that time (Pasteur). However, the optical activity is mantained when the are dissolved in a , it is therefore not a property of the crystals, and has instead a molecular character. In fact, the attempt of Van't Hoff to escape criticism did not succeed at all. J.A. Le Bel (27 years) in 1874 sustained too that it exists a relationship between the atomic formulas of organic compounds and the rotatory power of their solutions. He hypothesized too the tetrahedral carbon in order to explain the phenomenon. Van't Hoff and Le Bel had worked together in 1874 in the laboratory of Wurtz in Paris, but both swore to have never talked about the tetrahedral carbon. The hypothesis of the tetrahedral carbon was circulating from at least twelve years, and Kekulé and his pupils had applied it several times when in 1874 Van't Hoff and Le Bel proposed it again. One might therefore argue: there was not much new in the work of Van't Hoff and Le Bel. But is this true indeed? The historical perspective helps us in clarifying this question. Van't Hoff got immediately busy to publicize his ideas, and sent his articles to the most eminent chemists of his time. He was able to defende his work against the critics, both practical and theoretical, that were soon moved against it. In retrospective, recollecting the facts and looking at the identity of the groups who originated the controversy, it can be easily seen that the criticism came mainly from the rival laboratories of Kekulé, and also from those who had not come to know before about the tetrahedral carbon hypothesis, and now toiled to digest it. Famous is the invective of the old Kolbe against Van't Hoff : "A certain mister Van't Hoff, who occupies a position at the Veterinarian School of Utrecht, for sure does not like the exact researches. He considered more pleasant riding Pegasus (most likely borrowed from the Veterinarian School) and to discover in his "Chimie dans l'Espace", how are looking the atoms in the ". KOLBE 1877. However, the idea that the chemists of his time did not want absolutely to accept the tetrahedral hypothesis appears exaggerated. In fact, after only ten years, in 1884, the theory of Van't Hoff and Le Bel was firmly established, and the ferocious critics moved by Kolbe in 1877 stirred only hilarity. The main reason for the success of Van't Hoff and Le Bel lies in the fact that they applied their theory to solve a fundamental problem in organic chemistry, that is, the existence of optical isomers. Examples of optical activity had been accumulating since the times of Pasteur, and they constituted a typical anomaly. 8

One of the most mysterious facts of organic chemistry was the separation of tartaric in its optical antipodes, which had been performed by Pasteur in 1848. Examples of optical isomery were mushrooming in the literature, and were becoming too many to be ignored. In 1873 it appeared the paper of Wislicenus on the lactic isomers, and the young Van't Hoff offered the explanation that Wislicenus was seeking. In fact, Wislicenus (influent german professor and successor of Kolbe in 1884 to the prestigeous chair of Leipzig), became immediately the main defender of the theory of stereoisomery. The theory of Van't Hoff and Le Bel introduced the concept of asymmetric carbon atom at the basis of the modern stereochemistry, and provided an "a priori" criterion to establish the structures that might present optical activity. Under this respect, it is worth recalling the contoversy about the styrene extracted from natural products. Berthelot in 1875 mantained that this material was optically active, but Van't Hoff could easily demonstrate that the optically activity was due only to impurities. When the whole community of the organic chemists understood that the hypothesis of tetrahedral carbon allowed to account accurately the structure of organic compounds, including that of the optical isomers, overcoming therefore a test extremely fine and exaustive, the theory was accepted as the basis of organic chemistry. Baeyer (a pupil a Kekulé), in 1884 perfected the tetrahedral models and used them to sustain his theory of ring tension in alicyclic compounds. Bishoff (1890) established the criteria for the internal rotation around single bonds, posing the basis for the development of the concept of rotational isomery, conformers, and energy minima. E.Fischer (a pupil of Baeyer) in 1890 showed, by synthetic methods, the existence of all the stereoisomers predicted (2n) from the theory of Van't Hoff for the saccharides containing n asymmetric carbon atoms adjacent to each other. In 1893, the theory was extended by Werner to account for the coordination structure of complex salts. Van't Hoff finally recognized (1894) his debt towards Kekulé, and in a commment related to his discovery, he said: "Le Bel has advanced the ideas of Pasteur, whereas I have advanced the ideas of Kekulé". To him, alone, it was awarded the first in history (1901).

Acknowledgement. Partial financial support from the Italian Ministry of University and Technological Research (MURST) and from National Council of Research (Rome), is gratefully acknowledged.

REFERENCES

1. Partington, J.R. (1970) "A Histoty of Chemistry"; McMillan, London 2. Anshutz, R., (1929) "Augustus KekulŠ"; Verlag Chemie, Berlin 3. Kekulé, A., (1861-82) "Lehrbuch der Organishen Chemie", Erlangen, Stuttgart. 4. Natta, G., Farina, M., (1968) "Stereochimica Molecole in 3D", Mondadori, Milan, p. 231 5. Butlerov, A.M., (1953) Socinenija (Opere), Moscow 6. Le Bel, J.A., (1874) Bull. Soc. Chim. 22 (2), 337 9

7. Vant'Hoff, J.H., (1875) "La Chimie dans l'Espace", P.M. Bazendijk; Rotterdam 8. Vant'Hoff, J.H., (1876) Ber. 9, 1888 9. Berzelius, J.J., (1819) Jaresberichte, XVII 9-10, 21 10. Wislicenus, J., (1873) Ann. Chem. Pharm. CLXVII, 334 11. Cannizzaro, S., (1869) Giorn. Sci. Nat. Econom., V, 115-116 12. Paternò, E., (1869) Giorn. Sci. Nat. Econom., V, 117-122 13. Cannizzaro, S., (1869) Giorn. Sci. Nat. Econom., V, 208-211 14. Koerner, W., (1869) Giorn. Sci. Nat. Econom., V, 212-256 15. Kolbe, H., (1877) J. Pract. Chemie, XV, 473 16. Baeyer, A., (1885) Ber. XVIII, 2269

FIGURE 1. Molecular models built according to the hypothesis of tetrahedral carbon, used by E. Patern• in order to justify the existence of three isomers in 1,2-dibromoethane.