Optically labile racemates

Another class of sulfoxidic substances, the aryl thiosulfinates ArS(0)SAr, which have recently been prepared in an optically active form, exhibit exceptionally high optical lability Racemization of thiolsulfinates may occur in an uncatalysed path involving pyramidal inversion at the sulfoxide sulfur. Reaction rate coeffi-... 

The classification rests on the recognition of the four broad categories (A) resolution of optically stable racemates, (B) optically selective inversion of configuration in optically labile racemates, (C) optically selective synthesis of new centers of dissymmetry, and (D) optically selective inactivation of existing centers of dissymmetry. 

S) Optically selective inversion of configuration in optically labile racemates. 

Second-order asymmetric transformation. Combination of an optically labile racemate with a stable, optically active substance in solution, crystallization under such conditions that the separation of the less soluble diastereoisomeride is more rapid than the interconversion of the labile antipodes of the original racemate, and subsequent removal of the added optically stable substance from the solid product. 

B, OPTICALLY SELECTIVE INVERSION OF CONFIGURATION IN OPTICALLY LABILE RACEMATES... 

The Pfeiffer effect is a term used to describe changes in the optical activity of solutions containing a chiral compound (the environmental substance ) on the addition of a racemic dissymmetric complex. The effect is generally attributed to a shift in the position of the equilibrium between d and l isomers for the racemic complex. The exact mechanism involved in mediating the chiral interaction is unknown. Perhaps surprisingly, both environmental substance and complex may simultaneously be cations. Studies of the Pfeiffer effect usually involve a moderately labile racemic complex [Cr(ox)3]3 is a popular choice for such studies, summarized in Table 82. Other studies of the optical activity of tris oxalates include work on photoinduced optical activity,898 photoracemization899 and the solid-state racemization of K3[Cr(ox)3]. 900 901... 

The same workers42 obtained an optically inactive racemate, 2,4 3,5-dimethylene-D,L-xylitol, by the direct methylenation of the pentitol in the presence of concentrated hydrochloric acid. Acetolysis of the racemate and treatment of the resulting diacetyl-acetoxymethyl-methylene-xylitol (XV) with sodium methoxide afforded 2,4-methylene-xylitol which was identified by its failure to react with periodate (see page 146).42 The labile methylene group may have occupied either the 1,3(3,5)- or the 1,5-position, but the latter possibility was eliminated on the grounds that the p-toluenesulfonate of the dimethylene-xylitol could be converted, by exchange with sodium iodide, into an iodo-desoxy-dimethylene-xylitol, and thence, by reduction, into a desoxy-dimethylene-xylitol, identical with that obtained when the known l-desoxy-2,3,4,5-diisopropylidene-D,L-xylitol was treated with formaldehyde and hydrochloric acid.42... 

The Pfeiffer Effect (1) is defined as the change in optical rotation of an optically active system (usually a solution of one enantiomer of an optically active compound, called the "environment substance", dissolved in an optically inactive solvent) upon the addition of a racemic mixture of a dissymmetric, optically labile coordination compound. Much work has been done on this Effect (2 - 8) and several mechanisms have been proposed to explain it, which are described in a review by Schipper (2). It is of interest to note that the Effect can occur with racemic mixtures of certain optically labile complex cations (e.g., D.L-[Zn(o-phen)3]2+) whether the environment substance is anionic (d- -bromo-camphor- -sulfonate), neutral (levo-nicotine), or cationic (d-cinchoninium), The most frequently used solvent for the Pfeiffer Effect is water (10), although the Effect is known to occur in other solvents as well (l.it.6). 

Dwyer and co-workers (2) and Kirschner and co-workers (3) have proposed that the enantiomers of racemic mixtures of optically labile, dissymmetric complexes are in equilibrium in solutions containing no environment substance, and that the equilibrium constant in such systems is equal to 1. However, in the presence of one enantiomer of an optically active environment substance, this equilibrium is shifted, with a consequent enrichment of one of the enantiomers of the complex, thereby changing the equilibrium constant to something greater or less than 1. An equation which represents a typical Pfeiffer Effect equilibrium is ... 

It can be seen from Table I that the same enantiomer (D-line) of the tris(bidentate) complex is enriched whenever the environment substance has the same absolute configuration, regardless of the sign of rotation of that environment substance. This indicates that whenever a racemic mixture of an optically labile complex "senses" an environment of a given absolute configuration, the equilibrium between the enantiomers... 

The same equilibria are attained if to a solution of racemate in an initially achiral medium (equal concentrations of d and I species) there is added another chiral species d or L. The equilibrium is then displaced in favour of one or other of the constituents of the racemic mixture. This process has recently been termed enantiomerization, although examples of optically labile systems in equilibria sensitive to the presence of other chiral molecules or ions have long been recognized. A typical example of what was earlier termed an asymmetric transformation of the first kind (no second-phase involved) is that of Read and McMath (1925) in which solutions in dry acetone of (—) or ( ) chlorobromomethanesulphonic acid d-l ) together with (—)-hydroxyhydrindamine (l+) showed a change of optical rotation interpreted in terms of an equilibrium... 

The Pfeiffer Effect (1) is the change in optical rotation of a racemic mixture of an optically labile complex when it is placed into a solution containing one enantiomer of an optically active compound (known as the "environment substance"). For example, if an aqueous solution of /evo-malic acid is added to a solution of a racemic mixture of an optically labile complex, such as D,L-[Ni(phen)3]Cl2 (phen = ortho-phenanthroline), a marked change in optical rotation of the system is observed (the "Pfeiffer Effect"), and this rotation continues to undergo change over a period of about 120 hours. It should also be noted here that if the same malic acid solution is added to a racemic mixture of an optically stable complex, e.g., [Co(en)3]Cl3 (en = ethylenediamine), no such change in optical rotation is observed. 

Turner and Harris have discussed the more general problem of rotational changes when a species, stable with respect to racemization, is added to a solution containing an optically labile species (not necessarily a metal complex). When new rotations evolve, the authors describe the changes as occurring through asymmetric transformations. Using an equilibrium equation, in which the resolved stable species (base) is B and the racemic species (acid) is A, the fraction distribution (x) could be represented as... 

The optical lability of the phenylchloroacetyl group, due to tautomeric change involving the dissymmetric carbon atom, is so marked in the presence of alkali that separation of the stable system from the labile by saponification (for we are dealing here with an ester, not a salt) results in the formation of the racemic acid. None the less, it is not inconceivable that refinements in technic might some day remove any formal objection to classifying this phenomenon as a second-order asymmetric transformation the same may apply to that recorded by Read and McMath (122). 

Similar arguments apply to the asymmetric catalytic racemization of amygdalin, recorded by Smith (133). Amygdalin is the gentiobioside of (-l-)-mandelonitrile. The extreme optical lability of the latter is reflected in the great precautions which have to be taken to avoid its racemization, for the pure crystalline (-b) nitrile is readily racemized by the presence of even a trace of water, probably by a mechanism of the type suggested by Fischer and Bergmann (40) ... 

Although somewhat more stable than its hexaammine relative, the air-sensitive [Co(en)3]2+ is still substitutionally labile and racemizes rapidly in solution. Chiral discrimination in its (racemic) solutions has been observed in outer sphere electron transfer reactions with optically active oxidants including [Coin(EDTA)], 209,210 [Cr(ox)3]3-,211,212 Co111 oxalate, malonate, and acetylacetonate (acac) complexes.213... 

In the kinetic resolution, the yield of desired optically active product cannot exceed 50% based on the racemic substrate, even if the chiral-discriminating ability of the chiral catalyst is extremely high. In order to obtain one diastereomer selectively, the conversion must be suppressed to less than 50%, while in order to obtain one enantiomer of the starting material selectively, a higher than 50% conversion is required. If the stereogenic center is labile in the racemic substrate, one can convert the substrate completely to gain almost 100% yield of the diastereomer formation by utilizing dynamic stereomutation. 

A number of Co(III) complexes, such as Co(edta) and Co(phen)3, can be resolved into optical isomers and are extremely stable towards racemization. The Co(II) analogs are configurationally labile and resolution has proved impossible. Suggest how with a double mixing apparatus it might be possible to measure half-lives in the 10 -1 s range for the first-order racemization of the Co(Il) complexes. 

Paul Pfeiffer discovered a very interesting stereochemical phenomenon, which now bears his name — the Pfeiffer effect this has received a good deal of attention.30 When an optically active substance which is stable in solution is added to a solution of a labile chiral substance, the optical rotation of the solution changes, reaching a new level in some hours. Several theories have been advanced to explain the phenomenon, the most satisfactory based on the supposition that the optically active ion or molecule forms an association with one isomer of the racemic pair of the labile substance and thus shifts the dextro—levo equilibrium. In general it is not possible to use this as a means of resolution, for when the added optically active substance is removed from the labile material, the latter immediately racemizes. 

To isolate the neat product, the more volatile ether/tri-methylamine combination was used in the reaction, because a higher recovery of product was obtained in trials conducted with the racemic material. However, the neat, distilled, optically active product proved to be stereochemically labile at ambient temperature, and was considerably racemized compared to that obtained directly in the benzene/triethylamine solution. Moreover, the latter was relatively stable when further diluted in benzene solution at ambient temperature, showing only a 14% decrease in optical rotation after 70 hours at 26. For stereochemical studies,... 

All of the optically active compounds prepared by diastereoisomer separation and/or conversion to enantiomers have proved to be configurationally stable at the metal center as long as they are in the solid state. Concerning their behavior in solution, however, the optically active or-gano-transition-metal compounds are divided into two groups (a) compounds configurationally stable at the metal center, which do not racem-ize or epimerize with respect to the metal atom prior to decomposition and (b) compounds configurationally labile at the metal center which racemize or epimerize with respect to the metal atom prior to decomposition. 

The racemization of optically active halides in the coupling process may, however, also be a result of the configurational lability of organoiron intermediates. 

Mutarotation at coordinated sulfenate S is slow, which is analogous to the situation with organic thiols. Introduction of the S=0 group imparts a high resistance to inversion. Racemization in p-(S )-[Co(cystO)(tren)]2+ occurs at the rate 9.92 x 10 5s l (30 °C pH independent) and the t-(S) isomer is some 80 times slower.1045 Other diastereoisomeric sulfenate systems have also been shown to be optically very stable. Protonation to form Co—S(OH)R (pATa 0) does not alter this, but addition of alkali does with mutarotation of A(S)-[Co (J )cysO (en)2]+ being rapid at both S and Co in 0.1 moldm 3OH (but not at C). This may occur via a labile Co11—SO(R) intermediate.1036... 

In such a process, one ligand (the optically active one) should be rigidly attached to a stationary phase, while the other (racemic) ligand should be able to move with the mobile phase. The metal atom forming the complex may be combined with either ligand. The important point is that the complex generated should be kineti-cally labile, i.e. readily decomposed and reformed. 

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