Richard E. Pincock and Keith R. Wilson University of British Columbia Vancouver
8,Canada
Spontaneous Generation of Optical Activity
An optically inactive substance may, without intervention of a chemical or physical resolving agent, spontaneously develop optical activity. This simple, matter of fact statement is usually not immediately accepted as valid by most scientists (I). Many students of organic chemistry seem to feel that the statement is false. There are few recognized examples of spontaneous generation of optically active material, hut scepticism developed on considering the phenomenon does not arise just because established examples are rare. Laboratory experience, the historical background concerning resolutions, and even thermodynamic principles have all contributed to the helief that spontaneous resolutions do not occur. Most chemists seem to feel that a t least some influence of an external polarizing agent is necessary to even partially resolve a racemic substance into its enantiomers. The purpose of this paper is to review the background that has led to these present attitudes concerning spontaneous resolutions, and to mention those published examples which illustrate the validity of the first sentence of this paper. Recent experimental examples of spontaneous resolution (i.e., production of measurable optical activity in the total absence of any external chiral influence) suggest that the role of chemical or physical resolving agents, as in various classical resolution methods, is overemphasized in principle if not in practice. Perhaps a change of emphasis in presenting methods of producing optically active samples from racemic material is necessary and may he prompted by this review.
Is Spontaneous Generation of Optical Activity Possible? Reviews of organic stereochemistry often present statements to the effect that reactions of optically inactive starting materials in a symmetrical environment will always produce optically inactive products. Such apparently general statements, taken dogmatically, suggest that there is some fundamental principle which prevents totally spontaneous development of an optically active sample from an inactive source. It is also often pointed out that racemization of an optically active compound in solution is driven thermodynamically by an increase in entropy due to greater disorder. An ideal solution of one enantiomer would gain 1.38 cal/mole deg (i.e., R In 2) on transforming into a mixture of enantiomers. The reverse process, spontaneous development of one enantiomer in an isolated racemic solution, would require a gain of free energy of 410 cal/mole at 25°C. Under these conditions the process of spontaneous resolution is therefore contrary to thermodynamic principles. The interconversion of enantiomers in solution cannot possibly lead to resolution hut will always he driven towards racemization. However, in going from a homogeneous system (as in a solution) to a heterogeneous system, resolution can hecome a possible, even probable, process (2). Resolution is compatible with the drive towards lower free energy hecause enthalpy and entropy changes accompanying phase transformations can more than compensate for any gam in free energy due to the formation of molecules of only one kind. Racemizations, as commonly observed in solutions, are certainly thermodynamically spontaneous processes.
However, resolutions in systems undergoing phase transformations may also occur by thermodynamically allowed spontaneous processes. Another factor concerning the acceptability of spontaneous generation of optically active material involves the familiar resolutions methods where some dissymmetric compound reacts with a racemic system to form diastereomers which are then used to generate individual enantiomers (3). Since these common resolutions require the use of a dissymmetric agent this tends to suggest that a resolving agent is always absolutely essential. However this is just a matter of practical experience, not a matter of principle. While spontaneous generation of noticeable optical activity may seem to he a rare event, i t is not unacceptable in theory. As discussed below, the phenomenon has been fairly rigorously demonstrated, and may he quite common even if i t is usually difficult to recognize experimentally. Induced Genesis of Optically Active Organic Substances The historical development of ideas concerning optical activity has also drawn attention to various chemical and physical resolving agents for optical activation (4) and these are still often emphasized. Spontaneous resolutions have been largely ignored and sometimes argued as impossible (5). This background seems to have contributed to the impression that optical activity cannot he produced directly in any sample without resolving agents. The first optically active compounds were isolated from organic materials and the genesis of optically active samples has therefore been considered to he closely related to the genesis of life-sustaining organic compounds (4-9). An interesting statement of this 19th century view is that "the absolute origin of compounds of one-sided asymmetry found in the living world is a mystery as profound as the origin of life itself' (5). Pasteur's resolution of racemic sodium ammonium tartrates by carefully picking apart its dissymmetric crystals made the generation of optically active samples somewhat less mysterious (10). However, it apparently remained Pasteur's view that compounds exhibiting optical activity had basically never been obtained without the intervention of life (i.e., by action of previously resolved compounds) (11). As late as the turn of the century this vitalistic idea concerning the origin of optically active samples was emphasized and elaborated with statements like "the production of a single enantiomorph cannot conceivably occur through the chance play of symmetric forces" (5). That optical activity in a given sample could arise solely by actions within the sample alone was apparently not psychologically acceptable, nor more importantly, was it ohviously demonstrable. Therefore, various physical agents were suggested to account for genesis of optically active substances. Many agents were considered, electric or magnetic fields, heat, acceleration, cathode rays, etc., hut a t that time only circularly polarized light seemed likely to possess the chirality needed to generate optically active samples (9). After several failures, a few examples of successful generation or destruction of one enantiomer under the influence of circularly polarized Volume 50, Number 7, July 7973
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light have been well established (12). The essentially exclusive presence of one of two enantiomeric forms for compounds isolated from natural sources (e.g., L-amino acids, D-saccharides) could have resulted from some initial photochemical process involving polarized light, followed bv more selective dissvmmetric interactions of the initial1; generated substanc& Other types of naturally occurring polarizing agents which can be involved in the selection of one enantiomer from a racemic source have also been demonstrated. For example, selective destruction of one enantiomer by a dissymmetric surface (e.g., quartz) can also account in principle for an initial localized development of dissymmetric organic materials (13). Another very interesting possibility is that an innate chirality (as indicated by the nonconservation of parity) has somehow impressed itself upon this biochemical world in the form of dissymmetric compounds (14). Experiments to illustrate this have involved polarized 8-rays from radioactive decay, whose actions can lead to selective destruction of the D-isomer of tyrosine (15). However, the emphasis in all such experimental illustrations and reviews of the generation of optically active material from inactive sources is on the use of various external dissymmetric agents. Statements such as "single asymmetric forms cannot arise under chance conditions" and that "symmetry by itself cannot give rise to asymmetry" (5) have only rarely been exnerimentallv investieated bv attemots to eenerate onticaily active n&rial direct?\ f r k inaciive maierial alone. Spontaneous Genesis of Optically Active Samples Relative to the reported attempts to generate optically active substances through actions of various polarizing agents, the reported studies of totally spontaneous development of optically active samples have been largely neglected. Separation of enanatiomorphs can sometimes occur during conversion of a racemic system into crystalline products. The differences arising from enantiomeric shapes are maximized in the solid state and can result in high stereoselectivity. Thus as Pasteur first recognized with sodium ammonium tartrate, racemic substances may crystallize into separate enantiomeric crystals. This separation of enantiomers in the same sample has often been called "spontaneous resolution," hut unless the crystals are picked apart by some external agent no optical activity can be developed. However, as Pasteur discovered (16), if the racemic system is allowed to just partially crystallize and the initial crystals (or mother liquor) analyzed for optical activity, a permanent optical activity may be created. This is a type of crystal picking, but if the system is not artificially seeded the choice of which enantiomer (if any) predominates in the initially formed crystals is left to the system rather than to the chemist. External polarizing influences are absent (bowever, see below), so this type of resolution would seem to be a good test for truly spontaneous development of optical activity. There are quite a few examples where such partial crystallization of a racemic modification produces optically active products (17). Although hoth enantiomers have the same soluhilitv (but mav he deoosited to different extents because of kinetic effects of nuheation or crystal growth) the auestion arises as to the distribution of the enantiomers in a set of crystallizations. i t would be expected that with sufficient samples a symmetric distribution of right and left rotations would be observed. However, an early extensive study of the spontaneous crystallization of sodium ammonium tartrate reported a strong tendency to deposit dextrorotary crystals (18). A recent investigation of this same compound gave, after many control experiments, levorotatory material in ten out of ten runs (20). Crystallization of synthetic atropine sulfate showed a tendency to yield crystals of dextrorotary enantiomer, but hoth enantiomers could be obtained in high optical purity by simple recrystallizations (20). Spontaneous crystalliza456
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tion of racemic aspartic acid-copper solutions resulted in a solid rich in L-enantiomer (4). This enantiomer is the one that preferentially crystallized in all of three widely spaced laboratories using different sources of racemic material and with precautions to avoid contamination. Another especially interesting example concerns solutions of methylethylallylanilinium iodide where deposition of the dextrorotatory enantiomer occurred in twelve out of fourteen trials (2). In all these experiments the apparent inability to obtain an experimentally nearly equal distribution of enantiomorphs could have its origin in some innate dissymmetric influence. But there are too few individual trials in these examples and, a t least with the tartrate, the same enantiomer is not always preferentially deposited. It is more likely, as suggested by Wald ( 6 ) ,that the distribution of enantiomorphs is greatly affected by ubiquitous and almost unavoidable contaminants. These could perhaps be dust particles or very low concentrations of soluble dissymmetric impurities which promote preferential nucleation or growth of one enantiomer. Even though the extent of resolution they effect is low, such contaminants could be considered to be efficient resolving agents (considering their low concentrations). In this regard such "spontaneous resolutions" are not actually spontaneous at all. An outside agent is introducing the dissymmetric properties which finally result in a sample with measurable optical rotation. The examples given above do show that simple crystallization of a racemic system is a process which can lead to an optically active sample. In a few cases multiple recrystallizations of weakly active samples have led to near total resolution into enantiomers (17). In a practical sense however recrystallizations would usually be a very inefficient way to bring about a resolution. It should be noted however that samples of some "racemic" substances may have weak rotations arising from preferential crystallization in an enantiomeric crystal system. Because such rotations could be brought about by the actions of dissymmetric impurities in the crystallization process, it is to be emphasized that individual examples may be termed truly spontaneous only after it is shown that dissymmetric contaminants are not implicated. Most reported "spontaneous resolutions" by partial crystallization could have been caused by the action of dissymmetric impurities or by adventitious seeds. A truly spontaneous generation of optical activity has been demonstrated, however, in the crystallization of racemic 1,l'-binaphthyl from its melt. The melt consists of the two raoidlv enantiomers which mav so. . eauilibratine . lidify into an unequal mixture of the enantiomeric crystals of R- and S-binanhthvl (21). In two hundred c ~ s t a l l i z a tions an excess of R enantiomer was obtained inW52.5%of the trials (22). The sum of all the observed specific rotations was +0.14", while the maximum observed rotations were +206" and -218". Such a symmetrical distribution of optical activities proves that no external influence (such as impurities or seeds) was instrumental in effecting the crystallization of one or other form of binaphthyl. A high optical activity may be generated in any one sample and i t is purely a matter of chance, together with the properties of binaphthyl itself, which leads to this optical activity. Such an individual crystallization is then a truly spontaneous genesis of optical activity. The example of spontaneous resolution of 1,l'-binaphthyl most clearly illustrates the first sentence of this review. From a symmetrical, optically inactive material (ex.. l-bromonanhthalene) a samnle of racemic 1.1'-binaphihyl may be Gepared without the use of any dissymmetric agent. This binaphthyl, when melted and cooled, may develop optical activity in a completely spontaneous manner. Optical activity will have been created from inactive material.
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this may be increased by further crystallization or whether the slight excess may be noted by optical rotation measurements depends on the pecularities of the compound and on the care and persistence of the experimenter. It is clear that as a mechanism to account for the genesis of one sided optically active materials of nature, spontaneous resolutions seem very inefficient (1, 4, 6). Certainly as a means of practical laboratory resolutions the spontaneous crystallization method can apply only in rare cases. However, implications that dissymmetric material or forces must be present in order to generate other dissymmetric material are certainly invalid. Literature Cited
In fact, to allow the "change play of symmetric forces" in a melt of binaphthyl to crystallize into a sample with high optical activity is a more convenient way to resolve this compound than the classical chemical resolution via diastereomer formation. Related results have been obtained in deposition of enantiomorphic crystals of sodium chlorate. In solutions open to the air the product was mainly the left-handed enantiomer (from dust?), while sealed samples gave close to an equal distribution of enantiomorphic crystals (51.3% of 844 samples had an excess of right-handed crystals, 48.7% had left-handed crvstals in excess) (23). Other results record a weighted average of 50.08% dextrorotatory crystals from 46 independent crops (24). There seem to be no other examples of demonstrated spontaneous generation of enantiomorphic optically active material although, as noted above, optically active products have been produced by simple recrystallizations of racemic materials in anumber of cases. Summary
It seems that statements and ideas to the effect that optically inactive starting materials in a symmetrical environment will always produce optically inactive products must at least he modified to incorporate a probability factor. Unless it is desired to establish that the crystallization of an enantiomeric crystal mixture is not influenced by trace impurities, a large number of individual crystallizations of a racemic mixture would not he carried out. In a few trials, rather than an exact 50-50 distribution of enantiomers in the product, it is very probable that an excess of one or the other prevails. In terms of common laboratory practice involving a few crystallizations of a racemic material, chance conditions alone will give rise to at least slight excess of a single dissymmetric form. Whether
(1) For opinions expressing this view see references in: ( 0 ) Fox. S. W.. J. CHEM. EDUC., 34.472(1957). (blElias, W. E.. ibid.. 49.448(19l21. 121 . . Havinza. " . E... Bioehim. Bioohvs. . . Aclo.. 13.171 (19541. 13) For leview~of methods of resolution see, Eliel. E. L.. "Elemenu of Sfermchemistw." John Wiley and Sans. New York. 1969, p. 16; Miriow. K.. '"lntroduefion to s&mchemistry'. W. A. Benjamin. Inc. Neu York. 1965, p. 1 1 9 Eliel, E. L.. ',Sfereoehemistry of Csrhon Compounds." MeGrav-Hill Book Company, Ine.. 1 9 6 2 , ~47. . (4) For review on the origin of optically active materials see: Harada. K.. Nofurulis. smrchafton. 57. 114 (19101, and refereneea 11, 6-91 bdoe. Anexcellent recent review i~ by Bonner. W. A . in'~'Eiobiolw" (E.ditor Ponnamperums. C.1, "Fronticra 01 Bidow.". Vol. 23. North-Holland Publishing Company, Amsterdam, 1972. p. 170. (61 F.R.,Notur~,58. 452(18981. . ~ Japp. . W a l d , G . . ~ n nNYAcodemy N Y ~ c o d ~ mSeirnces, y (6) Wald,G..Ann 69.369(1957). (71 Ulbricht, T. L. V.. in "Comparative Biochemistry" (Editors Flmkin, M., and Mason H. S..) Aeademie Prcsl. New YoI~. Ymk. 1962. VOI.WE, p. 1. (8) Stryer. L.. in '"Biolapy and the Explozstion of Mars" (Editors: Pittendrigh. C. S.. virhniae. W.. ~~~~~~~~~~, T..I Nst. Academy of science-Nat. Rpspsrch vishniae, W.,, and pearman. J. P. T..) Council, Washington.D.C., 1966.p. 141. (91 Da~villier.A,. "The Photochemical Oriein of Life." Academic Preas. Ine., Now YO*. 1965.~.107. (10) See e.g. Fierer, L. F. and Fioser. M., "Advanced Organic Chemlatw'. Reinhold Publishing Company. New York. 1961, p. 69. (11) SeeRef.(9l.p. 108,andalaoHaldane.J.B.S..Nofure,185.87(19601. (121 Moradpour. A,. Nicoud. J. F.. Bslsvoine, G., Kagan. H.. and Tsoucaris. G..J Amer C h m . Soc, 93.2353 (1971lsndref~rences therein. (131 Klahunwski. E. I., in "The Oriein of Life on EartW (Editor Opsrin. A. I., e t d l . pergamon Preas, London. 1959, p, 158. See, howver. Amstiglio, A. snd H., in "Chemical Evolution and the Oriein of Life" (Editor: Buvct R.. and Ponnamperuma.C..lAmeiicanElsevierPub. Company.Ine.New York. 1971, p.63. (14) Ulbricht. T. L. V., Qvori. Re"., 13. 48 (1959). Ulhricht. T. L. V., and Vestor. F.. Tetrahedron, 18.629 (19621. (151 Gar8y.A. S.,Noture. 219.538~1968). (161 Pastour. L., Ann. Chem. Phys., 34. 30 (IffiZI; van't Hoff. J. H., and Dawson. H. M.. Be,., 31,528118981. (17) Greenruin. J. P..in "Adv in Pmtein Chemistry" (Editor: Anson. M. L.. Bailey, K.. and Edsall. J. T..) Academic Preu. Inr.. New Yark. 1954. O . 121. See also Duachimky, R., Chsm. and l n d . 53. 10 (1934); Dsrmoin. E.. Compf, rend.. 237. , 121 (19531: veuue, L.. ~ i n i a r d ,G.. and J&, R.,BUN SOC. chim. ~ m n c r 362, 903 119531; Vogler, K. and Kofler, M., Hdv. Chim. ocro, 39, 1387 (19561: Felreira, R. C.. Nature 171.39 11953). (181 Kin~in., F. S.. and Pope, W. J., Noturn, 59. 53 (18981; J. Chem. Soc., 95, 103
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(19) ~hiemann.w.. and wsgener. ~ . , ~ n g e them w. Inrermt ~ d i t . .9.740(1970l. (20) Andemon, L., and Hill, D. W.. J Chsm Sac. 993 (19281. (211 Pinewk,R. E.,and Wi1son.K.R.J Amm C h m . Soc. 93.1291 (19711. (22) Pincock, R. E., Perkins. R. R.. Ma. A. S.. and Wilson. K. R.. Science. 174. 1018
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