Optical Isomerism 

     Substances with the same elementary composition but different physical properties, isomers, were a problem for chemists until a theory of molecular structure was developed, from the 1860s on. A particular puzzle was the case of optical isomers, substances which appeared to be identical chemically and physically, except that one form rotated the plane of polarised light to the right and another to the left, while a third form seemed to be optically -inactive, with no effect on polarized light. The phenomenon of isomerism was discovered by the isolation of two almost identical substances fro, the tartars deposited by maturing wines. The major product (+)- tartaric acid, was found to be dextrorotatory to polarized light, whereas the minor product, racemic or paratartaric acid, proved to be optically inactive. Mitscherlich, whose law of isomorphism (1819) correlated a similarity of crystal shape with an analogy in chemical composition, reported in 1844 that the sodium ammonium salts of (+)-tartaric acid and of racemic acid are completely isomorphous and are identical in all respects otherwise, except optical activity. 

      Louis Pasteur, while still a student in Paris (1843-8), suspected that Mitscherlich's report on the tartrates was incomplete. The pioneer work on optical activity had been carried out on quartz crystals, which occur naturally in two morphological forms. The two types of quartz are distinguished by minor crystal faces, the hemihedral facets, which form a left-handed screw pattern in one set and a right - handed pattern in the other (Figure 1). At Cambridge, John Herschel had found in 1822 that sections cut perpendicular to the three-fold axis from any quartz crystal of the left-handed form are laevorotatory to polarized light whereas corresponding sections from crystals of the right-handed set are invariable dextrorotatory. In the light of Herschel's correlation, Pasteur set out to investigate the tartrate-racemate problem afresh. 

Molecular dissymmetry 

     On recrystallizing sodium-ammonium racemate, Pasteur (1848) observed the formation of two similar sets of crystals, characterised by the particular pattern of the hemihedral facets, as in the case of (+)- and (-)- quartz. One of the sets proved to be truly isomorphous with crystals of sodium-ammonium (+)-tartrate in facet pattern and gave the same positive specific optical rotation in solution. The other set had a nonsuperposable mirror-image crystal form and gave a specific rotation of polarized light with the same magnitude, but negative in sign. On acid treatment, the second crystal set liberated (-)- tartaric acid, the optical isomer of the major naturally-occurring form. Accordingly, racemic acid had to be regarded as a mixture of (+)- and (-)-tartaric acid and, thereafter, the term 'racemate' came to denote generally an optically-inactivc equimolar mixture of optical isomers. 

     From the view then generally current, due to Haüy (1809), that a crystal and its constituent molecules are 'images of each other' in overall shape, Pasteur concluded that the individuai molecules of (+)- and (-)- tartaric acid are strucurally 'dissymmetric', related as non-superposable mirror image forms, like the macroscopic hemihedral crystals of the corresponding sodium-ammonium salts. Later, Pasteur's terrn 'dissymetrie' for enantiomorphism (Gk. Enantios morphe, opposite shape), became generally supplanted by 'chirality' from the familiar analogy of the mirror-ímage relation between the left and the right hand. 
Subsequently Pasteur conjectured that chiral molecules and enantiomorphous crystals are the product of universal dissymmetric forces in nature. Following the discovery by Faraday (1846) of magnetically-induced optical rotation in an otherwise inactive medium, flint glass, Pasteur grew normallysymmetric crystals in a magnetic field with the object of inducing enantiomorphous crystal forms. The solar system is dissymmetric, Pasteur supposed, on account of the spin and orbital rotation of the planets. Regarding rotation as a dissymmetric force, he attempted to induce optical activity in synthetic products by running chemical reactions in a centrifuge, and to modify the optical activity of natural products by rotating the plants producing them with a clockwork mechanism. These experiments, and the negative results obtained, were reported by Pasteur only thirty years later, in a restatement of his belief in the universality of dissymmetric forces. 

Classical stereochemistry¹ 

     Pasteur established the overall shape-property of molecular handedness without a knowledge of molecular structure and, with a primary interest in microbiology after 1860, he was little concerned with the development of mainstream structural chemistry. Kekule extended his earlier (1858) one-dimensional theory of organic chain molecules, based upon the self-linkage of tetravalent carbon atoms, to the two-dimensional structural theory of aromatic substances, predicting from the assumed regular hexahonal ring structure for benzene (1866) the number and the type of structural isomers subsequently found in the mono- , di- and poly-substitution reactions. Aliphatic organic chemistry obtained little guidance from Kekule's structural theory. Even for simple cases, such as lactic acid, isolated in an optically-active form from muscle tissue and in an inactive form from sour milk, there appeared to be more isomers than could be acommodated by flatland molecular formulae. 

(c) Fundamental particle. The left – or right – handed chirality of an electron, or any other particle, derivesfrom the respective antiparalel or paralel relation between the linear momentum vector and the axial vector of the spin angular momentum 

Figure 1. Three domain of chirality; 
(a) macroscopic enantiomorphous crystals. 
(b) molecular enantiomeric structures, and 
(c) fundamental particles with spin ans translatory momentum. 

     The problem was taken up and solved independently in 1874 by Le Bel and van't Hoff. With the valencies of the carbon atom directed towards the vertices of a regular tetrahedron, the bonding of four different groups to the central atom gives two possible molecular structures, one being the non-superposable mirror-image of the other. The two structures correspond to the dextrorotatory (+)-form and the laevorotatory (-)-enantiomer of a pair of optical isomers containing a single chiral centre, the 'asymmetric' carbon atom (Figure 1). 
The introduction of a second chiral centre into a molecule, equivalent to the first, gives three possible structures, consisting of an enantiomeric pair of optical isomers and an internally-compensated. meso-form as in the case of the tartaric acids. Two inequivalent chiral centres result in four possible structures consisting of two enantiomeric nairs. A structure from one pair was defined as 'diastereometric' to a structure from the other pair. since the two structures lack the mirror-image relation of enantiomers, and the corresponding molecules differ in reactivity and physical properties. 

Asynetric synthesis and biomolecular homochirality 

     The generalisations of van't Hoff as to the number and types of stereoisomers resulting from multiple chiral centres were both tested and used as a guide by Emil Fischer in his investigation of the sugar series. An aldohexose sugar with four inequivalent chiral centres has sixteen stereoisomers, but the four asymmetric carbon atoms become two equivalent pairs in the corresponding dicarboxylic acid where the stereoisomerism is reduced to four pairs of enantiomers and two meso-forms. The change from inequivalent to equivalent chiral centres, the chemical elimination of the asymmetry at a chiral centre, and the ascent and descent of the sugar series, all served to support van't Hoff's guidelines while correlating the configurations of the sugars. 

     At each stage in the ascent of the sugar series, it was observed that the introduction of the additional chiral centre gave the two diastersomeric products in unequal yields. The elimination of the chiral centre distinguishing a pair of diastereomers was found to be similarly selective, particularly when mediated by chiral catalysts. Fischer (1894) showed that D-(-)-?-methylglucoside is hydrolysed by emulsin from bitter almonds, but not by maltase from yeast, whereas D-(+)-?-methylglucoside is cleaved by maltase, but not by emulsin. Moreover, neither of the corresponding L-glucosides are affected by either of the enzyme preparations. On the basis of such observations, Fischer (1894) proposed that the reactions of chiral substances are governed by a 'key and lock' principle, the particular product resulting from the best stereochemical fit being naturally selected. 

     Developments of Fischer's 'key and lock' principle go far to account for the general adoption of only one of the two enantiomeric series of the sugars and of the ?-amino acids in the biochemistry of living organisms. An economic and efficient turnover requires a homochiral biochemistry, just as efficient engineering depends upon the use of right-handed homochiral screws. Fischer's mechanism rests ultimately, on a dissymmetric force, however, or an equivalent source for the initial enantiomeric excess which subsequently becomes amplified by the internal chiral discrimination of biomolecular reactions. Moreover, the particular handedness of the initial excess, L or D, or the specific chiral bias of the dissymmetric forces acting continuously, is expected to correspond to the particular biomolecular homochirality sustained throughout the course of organic evolution, specifically the L-amino acids and the D-sugars^2-4. 

Parity non-conservation 

     The  polar forces which Pasteur had taken to be intrinsically dissymmetric were shown by Pierre Curie (1894) to become chiral only in combination, as in the case of a parallel or an antiparallel electric and magnetic field, produced by a right-handed or a left-handed helical charge-displacement, respectively. The chiral combinations of the classical polar fields are even-handed, however, and they have no inherent discrimination between enantiomeric structures on a time and space average. The principle of parity-conservation, due to Wigner (1927), held that the forces of nature are symmetric to a space-inversion, or an equivalent mirror-reflection. 

     Developments from the Rutherford-Soddy (1904) theory of the spontaneous transmutation of the radioactive elements led to the discovery of two new natural forces, the strong and the weak nuclear interaction, mediating ?- and ?-decay, respectively. An accumulation of anomalies in elementary particle physics led Lee and Yang (1956) to conclude that mirror-image symmetry, is not a property of the weak nuclear interaction. A consequence of the proposed parity violation, the asymmetric ?-decay of radionucleides, was soon observed in the decay of ⁶⁰Co to ⁶⁰Ni with the emission of a ?-electron and in the corresponding antiparticle emission of a ?-positron from the transmutation of ⁵⁸Co to ⁵⁸Fe. The asymmetry found showed the electron to possess an intrinsic left-handedness and the positron an inherent righthandedness from the preferred relation, antiparallel and parallel, respectively, between the directions of the spin axis and the linear momentum (Figure 1). The preference is proportional to the ratio of the velocity of the particle, or antiparticle, to the speed of light. 

     The weak nuclear interactions initially studied involve charge changes, as in ??radioactivity. An additional and more significant weak neutral current interaction, involving the massive neutral boson Z° , detected at CERN in 1983, together with its charged counterparts, w?, emerged from the unification of the electromagnetic with the weak nuclear interaction during the 1960s. The unified electroweak interaction violates parity through the electromagnetic interaction, which primarily governs the binding of electrons to the nucleus in an atom and the bonding of the atoms in a molecule. Furthermore, the electroweak interaction does not vanish in the non-elativistic limit of small particle velocities, and parity violating effects are expected in the normal stationary states of an atom or molecule. 

     The main atomic and molecular expecuations from the electroweak interaction are, firstly, universal optical activity and, secondly, a difference between the electronic binding energy of two enantiomeric molecules in either a stationary or a transition state. The universal optical activity arising from the electroweak interaction is the more important for the heavier atoms, and high sensitivity polarization-rotation studies of thallium, lead and bismuth atoms in the gas phase give an optical rotation with the correce sign and order of magnitude⁵. 

     The electroweak interaction in chiral molecules gives rise to a parity-violating shift of the electronic binding energy, Epv , which is positive for one isomer and negative for its enantiomer. The energy shift, Epv , like ehe optical activity, is dependent, not only upon the overall stereochemical configuration, but also upon the detailed molecular conformation. Ab initio calculations for the two main regular conformations of the proteins, the ?-helix and the ?-sheet conformation, indicate that the polypeptides based upon the naturally occurring L-amino acids are stabilised relative to the corresponding D-enantiomers by some 10-14 J mol-1 per peptide unit. For the conformation preferred in aqueous solution, the L-isomer is similarly the more stable of the two alanine enantiomers (Figure 1). The parity violating energy difference between the enantiomers, ?Epv, is very small relative to the thermal energy, kT. The advantage factor, given by the ratio, (?Epv / kT), has the approximate value of 10–17, which is equivalent to an enantiomeric excess of some 106 molecules of the L-polypeptide, or the L-amino acid, per mole of the corresponding racemate in thermodynamic equilibrium at ambient temperatures⁶. 

Chiral symetry breaking 

     Although very small, the enantiomeric energy differences for the ?-amino acids and the polypeptides due to the electroweak interaction have a magnitude sufficient to break the chiral symmetry of open, non-equilibrium, racemic reaction systems. According to the mechanism of Frank⁷, an open system, in which each optical isomer autocatalyses its own production from an achiral substrate and competitively inhibits the propagation of its enantiomer, remains stable so long as the input of achiral substrate remains small, producing a racemic output. When the substrate input is increased, a critical point is reached where the racemic process becomes metastable and the system swityhes over to homochiral production, adopting either the L- or the D-channel, dependent upon chance fluctuations. The presence of even a small chiral perturbation at the critical point determines the particular homochiral production channel adopted, the parity violating energy differences between the enar.tiomers of the ? -amino acids being adequate⁸ (Figure 2). 

     The small chiral perturbation required for the transition to homochiral production by the Frank mechanism is not necessarily internal to the racemic reaction system. The universality of the electroweak interaction implies a minor enantiomeric discrimination in the geochemistry of the prebiotic period, providing optically-enriched chiral inorganic catalysts and templates. 
The terrestrial distribution of quartz crystals, for example, is not wholly racemic. Over a collection of samples, totalling 16,807 crystals, a 1% enantiomeric excess of (-)-quartz is recorded, the excess being common to all localities sampled, in the Americas, Europe and Asia⁹. 

 

d[L]/dt = (k₁-k₂[D] )[L]

For case (a) the enantiomer concentrations [L], and [D] are equal, and the paired rate constants, k₁ and k’₁, and k₂ and k’₂, are identical, leading to a metastable racemic production represented by the unique point, from which either branch of the homochiral production diverges, dependent upon chance perturbations. For case (b), with an inequality between the two rate constants of either pair, or between the enantiomer concentrations, the particular homochiral production branch with the advantage factor, (?E/kt) > 10^-17 , is selected. 

    It has been argued that bio-organic optical purity was achieved substantially by a mixed mineral-organic economy in a protobiotic period. Grounds for the proposal are that the formation of stereoregular chiral biopolymers, such as the poly-Dribonucleotides or the poly-L-peptide ?-helix, which proceed efficiently with the appropriate optically-pure monomer, are specifically and severely inhibited by the enantiomeric monomer in an optically-impure or racemic substrate¹⁰. Further, catalytic layered alumino-silicates related to the chiral kaolinites are found to self-replicate with fidelity over several generations, retaining their organic catalytic properties, from aqueous solutions which are not matched in chemical composition.^ll,l2. 

References and further reading 
 

1. The foundation of classical stereochemistry and the physical basis of optical activity and chiral differentiation are discussed in Mason, S.F. (1982) Molecular Optical Activity and the Chiral Discriminations, Cambridge University Press, Cambridge etc.
2. Bonner, W.A. (1972) in Exobiology (Ponnamperuma,C.,ed.) Ch.6, p 170 ff, North Holland, Amsterdam, London and New York.
3. Miller, S.L. and Orgel, L.E. (1974) The Origins of Life on the Earth, p.171, Prentice Hall, Englewood Cliffs.
4. Ulbricht, T.L.V. (1981) Origins of Life 11 , 55-70.
5. Emmons, T.P., Reevers, J.M. and Forston E.N. (1981) Phys.Rev.Lett. 51 , 2089-2092 and (1984) ibid 52, 86.
6. Mason,S.F. and Tranter, G.E. (1985) Proc.Roy.Soc. A397 ,45-65
7. Frank, F.C. (1953) Biochem. Biophys. Acta 11, 459-463.
8. Kondepudi,D.K. and Nelson, G.W. (1985) Nature, 314 ,438-441.
9. Palache,C., Berman,H. and Frondel,C. (1962-5). Dana's System of Mineralogy 7th edn., Vol. III, p.16, John Wiley, New York.
10. Joyce,G.J., Visser,G.M., van Boeckel, C.A.A., van Boom,J.H., Orgel,L.E. and Van Westrenen,J. (1984) Nature 310, 602-604.
11. Weiss,A. (1981) Angew.Chem.Int.Ed.Engl. 20, 850-860.
12. Cairns-Smith,A.G. (1985) Sci.Amer. 252 , N°6, 74-82.

STEPHEN MASON 
Professor of Chemistry University of London King's College 
Strand, London WC2R 
England.