Racemization, and isotopic exchange

In our laboratory we have been investigating the mechanism of action of mandelic acid racemase from Pseudomonas putida (101), which catalyzes the racemization of either D or L-mandelic acid, 47. Evidence from kinetic and isotopic exchange studies indicates that the racemization proceeds via an... 

If it is assumed that ionization would result in complete randomization of the 0 label in the caihoxylate ion, is a measure of the rate of ionization with ion-pair return, and is a measure of the extent of racemization associated with ionization. The fact that the rate of isotope exchange exceeds that of racemization indicates that ion-pair collapse occurs with predominant retention of configuration. When a nucleophile is added to the system (0.14 Af NaN3), k y, is found to be imchanged, but no racemization of reactant is observed. Instead, the intermediate that would return with racemization is captured by azide ion and converted to substitution product with inversion of configuration. This must mean that the intimate ion pair returns to reactant more rapidly than it is captured by azide ion, whereas the solvent-separated ion pair is captured by azide ion faster than it returns to racemic reactant. 

Roitman and Cram (1971) have shown that the kinetic basicity of potassium alkoxide increases on complexation with dicyclohexyl-18-crown-6 ([20] + [21]). Both the rate of isotopic exchange and the rate of racemization of (—)-4-biphenylylmethoxydeuteriomethane [163] by t-BuOK in t-BuOH were found to increase by factors between 30 and 17 000. Isotopic exchange was... 

Attempts to achieve an asymmetric 1,3-proton shift reaction of (/ )-33, obtained from ethyl 3,3,3-trifhioro-2-oxopropanoate and (f )-l-phenylethanamine in 81 % yield, resulted in conversion into 34 in 89% yield, but without any reliably delectable enantiomeric excess.26 Even at 10% conversion, the Shiff base 34 formed is completely racemic. Imine 34 undergoes isotopic exchange in triethylamine/methanoI-r/4 at a rate 10 times slower than the isomerization of 33 to 34. The authors reason that if a 1.3-proton shift mechanism is operating, some enantiomeric excess would have to be observable in product 34 at low conversion. Since this is not the ease, a 1,5-proton shift to the carbonyl oxygen, via stabilized anion 37, to form achiral intermediate enol 38, was proposed.26... 

The various reactions undergone by coordinated amino acids have been the subject of several reviews28,31,32,438,446 and only a brief discussion will be given here. The reactions which occur can be roughly classified under three headings (a) aldol condensations, (b) reactions of complexes of amino acid Schiff bases, and (c) isotopic exchange and racemization at the a-carbon of the amino acid. 

Thermolysis of l,l-difluoro-2,3-diphenylcyclopropane in supercritical CO2 has allowed the rate of geometrical isomerization [i.e. cis-( 109) to /ra/M-(109)] and racemization [i.e. (/< )-( 109) to (S)-( 109)] to be determined from O2 dependence of the trapping rate of the postulated intermediate 1,3-biradical.246 Above 150 °C, the formation of 2,2-difluoroindane and its decomposition products is reported. A similar thermally induced equilibrating series of stereomutations has been observed with the analogous non-fluorinated cyclopropane in which rate constants and deuterium exchange isotope effects are reported.247 Theoretical studies of this isomerization have focused on classical248 and quasi-classical trajectories.249... 

Another application of isotope exchange has been developed mainly by Cram and his research group [33(a)], in which the rate of racemization (17) of an optically active carbon acid is compared with the rate of exchange of a hydrogen isotope (18) attached to the asymmetric carbon atom (L = H or D), viz. 

The first mechanism (a) occurs if fe t < k2 and the observed rate coefficient is given by feobs = k1. The second mechanism (b) applies if fe i > fe2 and then kohs = k2 x K where K = fe1 /fe j. The two mechanisms which correspond, respectively, to a rate-determining proton transfer and a pre-equilibrium followed by a subsequent step have been discussed in detail for isotope exchange reactions in Sect. 2.2.1. The second possibility (b) is apparently favoured by Cram [120] for racemization of 2-methyl-3-phenylpropionitrile whereas Melander [119] has interpreted his results in terms of the first (a). From the variation of the rate coefficient for racemization in different solvent mixtures of methanol/ dimethylsulphoxide a Bronsted exponent j8 = 1.1 was calculated [119] using an acidity function method which will be described fully in Sect. 4.6. 

Considerable interest in sulphonyl-activated carbon acids and their carbanions has arisen since the observation which was reached almost simultaneously in different laboratories that optically active 2-phenyl-sulphonyl octane undergoes base catalysed isotope exchange more rapidly than racemization [144], viz. 

Both antipodes racemize rapidly in solution, although less rapidly than the corresponding trioxalatochromates racemization is complete within 24 hours. Racemization is reported to occur even in the solid state. Isotopic exchange studies have shown only limited parallelism between the mechanisms of oxalate exchange and racemization. Optical rotatory dispersion measurements - have been used to determine the absolute configuration of the trioxalatocobaltate(III) ion. 

In the ionization mechanism exemplified by benzhydryl thiocyanate, the reaction is strictly first order over a wide concentration range. The rate of isomerization increases with increasing solvent polarity Tracer and stereochemical evidence indicates that this involves an internal ion-pair mechanism. Isomerization is faster than isotopic exchange and so it was concluded that the former process occurs via an intimate ion pair which was shown to collapse to thiocyanate and isothiocyanate in the ratio of 5 1. In the case of optically active 4-chlorobenzhydryl thiocyanate in acetonitrile, racemization occurs at a rate comparable with isomerization. With a given solvent the structural effect acts essentially on the energy term and for a given substrate, the solvent effect acts essentially on the entropy term. 

The isotopic exchange reaction between deuterium and (+)3-methyl-hexane on nickel and palladium catalysts at temperatures above 100° leads to racemization of the optically active hydrocarbon. In exchange between deuterium and cycloalkanes at temperatures between —50° and about 75°, a discontinuity separates the concentrations of C H D and. In cyclopentane at about 50°, for example, exchange... 

Similar intermediates seem to be involved in the net trans addition in hydrogenation, in racemization during exchange, and in transfer of the isotopic exchange process from one side of the cyclopentane ring to the other. 

---