In organic chemistry, kinetic resolution is a means of differentiating two enantiomers in a racemic mixture. In kinetic resolution, two enantiomers react with different reaction rates in a chemical reaction with a chiral catalyst or reagent, resulting in an enantioenriched sample of the less reactive enantiomer. As opposed to chiral resolution, kinetic resolution does not rely on different physical properties of diastereomeric products, but rather on the different chemical properties of the racemic starting materials. The enantiomeric excess (ee) of the unreacted starting material continually rises as more product is formed, reaching 100% just before full completion of the reaction. Kinetic resolution relies upon differences in reactivity between enantiomers or enantiomeric complexes. Kinetic resolution can be used for the preparation of chiral molecules in organic synthesis. Kinetic resolution reactions utilizing purely synthetic reagents and catalysts are much less common than the use of enzymatic kinetic resolution in application towards organic synthesis, although a number of useful synthetic techniques have been developed in the past 30 years.
History The first reported kinetic resolution was achieved by Louis Pasteur. After reacting aqueous racemic ammonium tartrate with a mold from Penicillium glaucum, he reisolated the remaining tartrate and found it was levorotatory. The chiral microorganisms present in the mold catalyzed the metabolization of (R,R)-tartrate selectively, leaving an excess of (S,S)-tartrate. Kinetic resolution by synthetic means was first reported by Marckwald and McKenzie in 1899 in the esterification of racemic mandelic acid with optically active (−)-menthol. With an excess of the racemic acid present, they observed the formation of the ester derived from (+)-mandelic acid to be quicker than the formation of the ester from (−)-mandelic acid. The unreacted acid was observed to have a slight excess of (−)-mandelic acid, and the ester was later shown to yield (+)-mandelic acid upon saponification. The importance of this observation was that, in theory, if a half equivalent of (−)-menthol had been used, a highly enantioenriched sample of (−)-mandelic acid could have been prepared. This observation led to the successful kinetic resolution of other chiral acids, the beginning of the use of kinetic resolution in organic chemistry.
Theory Kinetic resolution is a possible method for irreversibly differentiating a pair of enantiomers due to (potentially) different activation energies. While both enantiomers are at the same Gibbs free energy level by definition, and the products of the reaction with both enantiomers are also at equal levels, the Δ G ‡ {\displaystyle \Delta G^{\ddagger }} , or transition state energy, can differ. In the image below, the R enantiomer has a lower Δ G ‡ {\displaystyle \Delta G^{\ddagger }} and would thus react faster than the S enantiomer.
The ideal kinetic resolution is that in which only one enantiomer reacts, i.e. kR>>kS. The selectivity (s) of a kinetic resolution is related to the rate constants of the reaction of the R and S enantiomers, kR and kS respectively, by s=kR/kS, for kR>kS. This selectivity can also be referred to as the relative rates of reaction. This can be written in terms of the free energy difference between the high- and low-energy transitions states, Δ Δ G ‡ {\displaystyle \Delta \Delta G^{\ddagger }} .
s = k R k S = e Δ Δ G ‡ / R T {\displaystyle s={\frac {k_{R}}{k_{S}}}=e^{\Delta \Delta G^{\ddagger }/RT}}
The selectivity can also be expressed in terms of ee of the recovered starting material and conversion (c), if first-order kinetics (in substrate) are assumed. If it is assumed that the S enantiomer of the starting material racemate will be recovered in excess, it is possible to express the concentrations (mole fractions) of the S and R enantiomers as
[ S ] = ( 1 + e e ) ( 1 − c ) 2 {\displaystyle [S]={\frac {(1+ee)(1-c)}{2}}}
[ R ] = ( 1 − e e ) ( 1 − c ) 2 {\displaystyle [R]={\frac {(1-ee)(1-c)}{2}}}
where ee is the ee of the starting material. Note that for c=0, which signifies the beginning of the reaction, S 0 = R 0 = 1 2 {\displaystyle S_{0}=R_{0}={\frac {1}{2}}} , where these signify the initial concentrations of the enantiomers. Then, for stoichiometric chiral resolving agent B*,
… excerpt ends here. Continue reading the full article.
