Van't Hoff, Le Bel, and the Development of Stereochemistry: A Reassessment Robert 6. Grossman Massachusetts Institute of Technology, Cambridge. MA 02139
Jacohus Henricus van't Hoff and Jules Achille Le Be1 are generally regarded as the founders of modern stereochemistry. In 1874 they each published papers that introduced the concept of the tetrahedrally coordinated carhon atom ( I , 2). The ideas presented in those papers have usually been treated hv historians as if thev. represented two different . aspects ofa single theory. In the present analysis, I show that the scientists' theories of 1874 were not different approaches to one theory (the theory of the "asymmetric carhon atom as chiral center"), but were really two very different theories, grounded in different assumptions and intended to explain different phenomena, which were conflated by later generations of siereochemists. Let me begin by defining some stereochemical terms. Two identical molecules are called homomers. If two molecules are not identical hut contain the same numbers of each kind of atom and the same interatomic linkaees and nonlinkaces. then they are called stereoisomers. If two stereoisomers-are mirror images of one another, then they are enantiomers; otherwise, they are diastereomers. A chiral molecule (from Greek xtlpos, "hand," in the sense of "right-handed" and "left-handed") is not identical to its mirror imane; an achiral molecule is.' A solution of chiral homomers will show optical actiuirj (will rotate the plane of polarized light); a solution of achiral molecules, or n solution containingequal concentrations of chiral molecules and their enantiomers, will not. Achiral molecules contain an element of. svmmetrv. " " . that is.. a .lane. center. or alternatineaxis of s y m m e t ~ yA . ~ carhon atom is stereogenic if a new isomer is created when two of the moups attached to the carbon switch positions; otherwise, the c&hon atom is nonstereoeenic (3). ~ h e s brief e definitions are obviously not intended to provide an education in stereochemistry to the uninitiated. For a more detailed exposition of stereochemical conventions and terminology, see any introductory organic chemistry textbook (4). Orlglnal Theorles In 1848 Louis Pasteur discovered that the crystals of the sodium ammonium salt of tartaric acid. a dextrorotatorv optically active substance, exhihited hemihedral facet;. These features, which had gone unnoticed for years, meant that the crystals were asym&etric, i.e., not identical to their mirror images. The crystals could he lined up so that the hemihedry always faced the left. Pasteur then found that the crystals of the sodium ammonium salt of racemic acid, an o~ticallvinactive isomer of tartaric acid. also exhihited hkmih&ral facets, hut that the hemihedry sometimes faced the right, and sometimes the left; that is, the racemate crystals were specimens of two asymmetric types, one the mirror imaee of the other. One of the tvoes of racemate cwstals was soon found to be identical to thetartrate crystals, and equallv concentrated solutions of the two types of racemate crystals were found to rotate plane-polarized light in equal and opposite directions (5). Pasteur quickly made the connect& between the chirality of the racemite and tartrate crys30
Journal of Chemical Education
talsand theiropticalactivity,andhe proceeded toextend his observations on the chiralitv of crvstals to the chiralitv of molecules: "The molecule of [dext;orotatory] tartaric icid, however else i t may he constituted, is asymmetric, and has that kind of asymmetry which is not superposable with its mirrored [sic] image. The molecule of the laevotartaric acid is formedhy exactly the opposite grouping of atoms" (6). Every asymmetric molecule or crystal would show optical activitv. he predicted. and everv svmmetric one would-not. ~ a s i e w ' s b o r kwasconducted Gefore the advent of Kekw 16's theory of the quadrivalency of carbon, so Pasteur was unable to investigate the molecular properties that gave rise to asymmetry.:' This task was instead undertaken hy Jules Achille in~ his ~ Le -~ - Rel ~ ~ 1874 ~ ~memoir 11). Le Be1 beean from Pasteur's hypothesisth*t a symmetricd molecule could not show optical activity (8): ~
If in our fundamental type [M&l we substitute but two radicals R'. H",it is possible t u have symmetry orasymmew according t o
the constitution of the original type M& . . . . If it happens not only that a single substitution furnishes but one derivative, but also that two and even three substitutions give only one and the same chemical isomer, we are obliged to admit that the four atoms A occupy the angles of a regular tetrahedron, whose planes of symmetry sre identical with those of the whole molecule MA4
....
The known symmetry properties of the molecules of the "marsh gas type", CHI, led tothe concluvionthat thegeometry of these molecules was tetrahedral. 1.e Hel's tetrahedron was a result of svmmetrv " areuments. not their startine point. and his thoughimade no use of the &ctural theory lbeyond the quadrivalency of carhon. If this sequence of thought seems improbable, it is only because chemistry today is so steeped in the structural theory that the modern reader has trouble thinking about mo1ec"les in any terms other than structural. Simultaneously with the publication of Le Bel's paper, there appeared the pamphlet by J. H. van't Hoff (2)in which the author took an entirely different (and entirely independent) path to the seemingly similar concept of the tetrahedral carbon atom. In his own words, van't Hoffs conception was a continuation of Kekule's law of the quadrivalence of carbon, with the added hypothesis that the four valences are directed towards the corners of a tetrahedron, at the centre of which is the carbon atom (9).
All bodles-not iust~molecules-are chiral or Chlralitv - ~ ~-~ , - ~-~ - - achiral. ,isa propeq of objects, of which molecLles are one kind. The plane and center of symmetry are actually two special cases of the alternating (or improper) axis of symmetry (such an axis exists when rotatlon of an object by a sub-multipleof a circiearound theaxis followed by reflection in a plane perpendicular to the axis gives an identical object), but they cover most chemical instances. Pasteur was convinced, though, that the asymmetry wasa consequence of vital forces (7). ~
~
~
~~
~
F i g w 1. The three cyciopropane-t,2di&oxyiic
acids
Figure 3. Two enantiomeric isomers of tetra-substituted aiiene.
Figwe 2. me~~Tmtaric acid. Note the ulnter of symmehy at the midpoint of the C-C band.
When the four affinities of the carbon atom are satisfied by four univalent groups differing among themselves, two and not more than two different tetrahedrons [sic] are obtained, one of which is the reflected image of the other .. . we have here to deal with two structural formulas isomeric in space (10). "Two formulas isomeric in space": to van't Hoff, enantiomerism was nothing more thananother case of the phenomenon of stereoisomerism, which was generally caused by the presence of a tetrahedral carbon atom. Enantiomerism could thus be explained in the same way as any other kind of stereoisomerism: i t needed no soecial theoretical treatment. For instance, in his book of 1898 van't Hoff explained that the isomerism possible in the ease of the lcyclopropane-l,2-carboxylicacids]may herepresented in the followingway: [see Fig I.] Thua we have three ~ossibilities.of which the second and third are nonsuperposahle;mages, and must therefore possess opposite [optical]activity (II). Van't Hoffs "asymmetric carbon atom" was therefore esaentiallv a stereoeenic one that was used to count isomers. enantiomeric or not. When one examines van't Hoffs hook of 1898 to see how cases in which optical activity did not correlate with the presence of an asymmetric carbon atom were handled, one sees that the asymmetric atom was not touted as the cause of molecular asymmetry and its experimental correlate, optical activity (more on the contrast between the 1874 and 1898
-
' A meso compound contains two or more stereogenic carbon atoms but has an element of symmetry. Thus it is achral, but at east some of ts diastereomers are chirai. The classic example is m e w tartaric acid (see Flg. 2). As Le Eel was independently wealthy, he could afford to decline any work that seemed distasteful to him, and for him "distasteful work" apparently meant supervisinggraduate students and procuring academic positions1 For many years after 1874 he continued to investigate stereochemical questions, but after some time his anention turned to botany and gardening, and he dropped his chemical work entirely.
works below). Instead, such cases were explained in terms of the symmetry ideas of Le Bel. Thus, "this [meso] configuration is also characterized by the fact that i t is symmetrical . There is accordingly no activity to be expected here; i t is, then, the 'inactive indivisible type' which results from the symmetry of t h e f ~ r m u l a " ~and, ; "The combination (R1R2)C=C=C(R3R4) [has] two isomers [which] are in this case enantiomorphous" (12) (see Fig. 3). In the second case, the fact that no asymmetric carbon atom was present was not mentioned by van't Hoff, but symmetry arguments were the only ones he could have used to predict the enantiomeric forms of this compound. Even van't Hoff realized that his "asymmetric carbon atom" system was usually best for counting stereoisomers, while Le Bel's "symmetry properties" system was often better for determining optical activity.
.. .
Later Developments
I discussed Le Be1 and Pasteur because their work shows the tremendous power of symmetry arguments in explaining some chemical phenomena, notably optical activity. Nonetheless, "the 1874ideas of van't Hoff rather than those of Le Be1 must [be] considered as the foundation of the stereochemistry of organic carbon compounds" (13). I t was van't Hoffs svstem that was adooted hv chemists: the svmmetrv conside;ations of Le Be1,'altho;gh often kited a s being amone the foundine ideas of stereochemistw, were usuallv pusheb into the badrground. They were hro~&htforth on& when the "asymmetric carbon atom" theory that descended from van't Hoff s thought failed to predict the phenomena correctly or completely. Why did this happen? First of all, van't Hoffs concepts were much easier to understand and assimilate than the abstract, mathematical concepts of Le Bel. Second, van't Hoff went on to an illustrious career in chemistry, continuine to make i m ~ o r t a n tcontributions to stereochemistrv. kinetics and physical chemistry, while Le Be1 quickly moved to the o e r i ~ h e wof the scientific c ~ m m u n i t vIf . ~Le Be1 had held tenured faculty position a t a major university in Germany, perhaps the idea of symmetry would have figured more prominently in the history of stereochemistry. Third, and most important, i t must be remembered that van't Hoffs structural ideas were much more compatible than Le Bel's ideas with the enterprise in which most organic chemists of the time were engaged, i.&, the synthesis and charac-
a
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dominance of van't Hoff's theory over Le Bel's is in the classification scheme for stereoisomers that is introduced to students of oreanic chemistrv" earlv" in their careers. The ~~~-fact - - ~ that enantiomks and diastereomers are more closely related by the traditional classification scheme than homomers and enantiomers, even though homomers and enantiomers are indistinguishable under achiral measuring conditions, and even though diastereomers and enantiomers behave no more similarly than nonisomeric bodies, shows that the basis of most stereochemical concepts continues to he van't Hoffs structural theory. A scheme of classification of stereoisomers based on their symmetry properties was introduced in 1977 by K. Mislow of Princeton University; although incorporated into several textbooks, however, i t has yet to see wide use ~
(2R,3r,4S); achiral
(2R,3s,4S); achiral
~
~
1171. ~-.,.
(2R,4R): chiral
(2S,4S); chiral
I do not mean to exonerate van't Hoff from all responsibility for the theoretical confusion. He himself sometimes made it seem as if the asymmetric carbon atom was to be viewed as the cause of optical activity. This was particularly ' ~ contrast, his 1898 book noticeable in his 1874 ~ a m v h l e t . In made the causal relatibnship hetween symmetry and optical activity clear, despite occasional statements such as, "In order to show now that the above-mentioned properties really accompany the asymmetric carbon atom wherever it occurs . ." (19). These i k o k t e n c i e s , though, do give rise to an important ouestion: what was van't Hoff reallv trvine t o sav about the reiationships among molecular symke&y, opticai activitv, and the asvmmetric carbon atom? The reason he gave such prominent play to the symmetry-activity relationship in 1898 after virtually ignoring the subject in 1874 isclear: in the meantime he had read Le Bel's paper. What is not so clear is why he continuedto use expressions thatemphasized the activity-asymmetric atom relationship, such as the one quoted above, even in 1898. I can only offer some possible explanations. Perhaps, in searching for ways to show chemists that they needed t o use the concept of the asymmetric carbon atom, he decided to ascribe as many phenomena to i t as possible-a choice of rhetoric, then, that had profound consequences. Perhaps he really did habitually think of optical activity in terms of asymmetric atoms, thinking about molecular symmetry only with conscious e f f o r t t h e same difficulty that continues to plague chemists a century later?' Or perhaps he simply used expressions such as the one above as a shorthand forconcepts t h a t would have been too wordy if expressed correctly. For whatever reasons they first appeared, though, inconsistencies that were present in van't Hoffs work have continued to crop up for more than a hundred years.
.
Figure 4. me tour Z.3.4trihybroxygiutaric acMs
terization of new compounds. Van't Hoffs system was best for determining the numher of isomers that a particular reaction should nroduce or that a varticular comvound should have, a &estion of great imp&tance to most chemists. Optical activity was irrelevant to the work of most of them. In fact, according to Ramsay, "many chemists persisted in the belief that the observation of ovtical activitv had little chemical significance . . . even in thk 1860s" ( 1 4 ) : ~ Van't Hoffs theow, then, was more thoroughly assimilated hy chemists t h a n ~ eel's. Nevertheless, the importance of the idea of asymmetry in explaining optical activity could not be denied. Remember that van't Hoffs theory of the asymmetric tetrahedral carbon atom as the unit of stereoisomerism emphasized stereogenicity and isomer-counting, while Le Bel's theory of the asymmetric, tetrahedral molecule centered a t the carbon atom emnhasized svmmetrv and optical activity. A steady intellectual drift i n the deeades after 1874 succeeded in making the asymmetric carbon atom not only the unit of stereoisomers, but also the unit of chiralitv and ovtical activitv. "The theories of van't Hoff and Le el, as will as the branches of stereochemistry which they represent have become melded into one" (15). The instances in which this blending of the two theories has caused confusion are numerous indeed. In 1946, for example, the editors of Science thought that the issue of the origin of the optical inactivity of meso compounds was unsettled enough to warrant publication of a letter in which "[the author took] the position that a meso compound may be regarded as made up of two nonsuperimposable enantiomorphous halves, each rotating plane-polarized light in opposite directions t o the same extent . . . the symmetry property of the molecule as a whole . . . [was] apparently disregarded" (16a).7 In a more famous example, the central carbon atoms of (2R,3r,4S)- and (2R,3s,4S)-2,3,4-trihydroxyglutaric acid (see Fig. 4a) have been dubbed "pseudoasymmetric", because although the central carbons are "asymmetric" (i.e., stereogenic), the molecules are a ~ h i r a l . Until ~.~ recentlv..however. the reason for the noncorrelation between the symmetry (i.e., achira1ity)-of the molecules and the "asvmmetrv" (i.e.. stereoeenicitv) of the central carbon atoms in these acids remained obscure (3). Perhaps the most obtrusive example of the continuing
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T h u s , the inepressibie Charles Gerhardt in 1841: "We chemists require chemical [I] differences to distinguish oetween two bodies. and it therefore seems to me that those who attach such great importanceto rotatory power are deluding themselves strongly if they look to it for the future of chemistry" (15). 'Thus. Wright treated meso compounds as if they were racemic mixtures of two chiral half-molecules rotating light in opposite directions. The unfortunate but oft-repeated phrase "internal compensation of rotatory power" probably contributed to Wright's confusion. Chiral haif-molecules do not exist, however: molecules, not their parts, may be chiral or achiral (3). A pseudoasymmetric carbon atom arises in all molecules of the form C(A)(B)(R)(S), where C is carbon. A and Bare nonstereogenic groups, and R and S are stereogenic groups differingsolely in their configuration. 'The (2R.4~7~ and (2S4.5) isomers (Fig. 4b) are chiral and their central carbon atoms are nonstereogenb, but no special name has been invented for these molecules or their centers. lo in conceiving that work, in fact, it is possible that van't Hoff missed the fundamental significanceof symmetry properties in determining optical activity: the work of Pasteur did not figure in the paper until the last two paragraphs (18). " If this is the case, one may be forced to ascribe no historical Significancewhatsoever to poor M. Le Bell
- ~
There is some irony in all of this theoretical confusion. In 1874, when van't Hoff first proposed his theory of the asymmetric carbon atom, a good deal was already known, both theoreticallv and ex~erimentallv.about ontical activitv. Molecular asymmetry was utterlycmtral scientists' inderstanding of the phenomenon. Van't HofPs theory was horn in the context of this knowledge, already two decades old by 1874, but it quickly s u ~ d a n t e dit, even thoueh the older theories were & v&d in-i900 as they were in 18j3. Such are the vagaries of scientific progress. Acknowledgment
Many thanks to G. L. Geison of Princeton University for his advice and comments throughout the preparation of this paper. Thanks also to K. Mislow for his comments and his help with some of the stereochemical concepts. Literature Cited 1.
L.Bel, J . A. "On the Relations which Exist htween the Atomic Formulksofolganic Comwunds and the Rotatory Power of their Solutionan (oria. oubl. 1874). In The
2. Van? Ho1f.J. H."ASuggestionLooking tothe Extension infospace of thestructural Parmvlaa at Plelent used inChemistry,andaNote"po" thenelations betwe." the optical Activity and the Chemical conatltution of Organl" Compaunds" (orig. publ. 18741. In T h ~ F o u n d a I i of o ~S f e r e ~ ~ h ~ m i s Rich.wdm. fry; G. M., Ed.; New Vmk, 1901: pp €4-73. See ref 1. 3. Mislow, K.; Slegel, J. J . Am. Chem. Soc. 1981,106,53193328. 4. Far example, Streitweiaer. A,. Jr.: Heathmek. C. H. lnfroducfion to Organic Charnirtry, 3rd ed.: MaeMillan: Nna Yark, 1985; esp. Chaptu7. 6. (4 Geisan, G. L.; Secord, J . A. Isis, in preaa. See also: (h) Ramany, 0. B. Sfelpmhe mlstry: Heyden: London. 1981: Chapter 4: and, (el Pastem, L. "On the Asymmetry of Naturslly oceuning 01ganic Campaunda" (orig. publ. 1860): in The F o u n d n f i o ~ of Sfereochemiatry;Richardmn, G. M., Ed.: New Y o l , 1901: p p 3 4 . 6. R e f h , p 19. 7. For examplo, ref 5e, pp 25 and 27. 8. Refl,p51. 9. Van? Hoff, J. H. The Arrangement of Atoms in Spoee; Eiloart, A.. trans.: London. 1895: pp 24. 10. Ref 2, p 38. R. -11-. . .s.f-9,n l.l.S-.
12. Ref 9,pp 75snd 103. 13. Sneldcls. H. A. M. In Von't Hoff-Le Eel Centennial: h a y , 0. 6.. Ed.; ACS Symposium Series, Vol. 12: ACS: Washington. DC, 1975: Chapfe.5: p72. 14. Ref 56. p 77. 15. Siegel, J . S. PhD Uloals,PtiocetonUnivemity, 1985: pp 5-4. 18. (a) Mia1rw.K. Science 1950,112,2621: inre (h) Wr1ght.G. F.Seienee 1946,104,lW 191 ~ -
17. (a) Mialow, K.Bull. Soe. Chim. &I#. 1977,86,595-598: also see (b) Ternay, A. L.. Jr. Contemporary Organic Chemistry. 2nd. d.:Saunders: Philadelphia. 1979;pp 1 4 146. 18. Compare, fmiastaoce, ref2, pp40and 44. 19. Ref 9,p 13.
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