Stability difference between diastereomers

This is not the actual order, however, because enthalpy differences between diastereomers are rather small (2-3 kJ mol-1), and an entropy factor must also be considered. Entropy favors the SSX and <5AA species because they are three times as probable as the ddd and AAA ones. Hence the best estimate of relative stabilities, which in fact agrees with all experimental data, becomes... 

Additionally, it was found that the energy difference between the two transition states (3 and 4) is determined mainly by the difference in the conformational energy of the a-chloro aldehyde in the two transition states i.e., the energetic preference of transition state 3 over 4 is due to a more favorable conformation of the aldehyde rather than a more favorable interaction with the attacking nucleophile. In fact, interaction between lithium hydride and 2-chloropropanal stabilizes transition state 4, which yields the minor diastereomer. 

If the substrate contains two identical substituents at one terminus of the allylic position such as shown in Scheme 8E.26, the it-allyl intermediate can undergo enantioface exchange via the formation of a a-palladium species at that terminus. This process should occur faster than the nucleophilic addition, which is the enantio-determining step (fc, > 2[Nu ] and 2[Nu ]). Thus, enantioselection can be derived from the relative rate of the nucleophilic addition to each diastereomer the relative stabilities of the two diastereomeric complexes need not have a direct effect on the enantioselectivity (Curtin-Hammett conditions). Although the achiral allylic isomer 120 is expected to follow the same kinetic pathway as the racemic substrate 119, the difference between the results from the two systems often gives an indication as to the origin of enantioselection—complexation or ionization versus nucleophilic addition. 

A kinetic resolution is a chemical reaction in which one enantiomer of a racemate reacts faster than the other. Most kinetic resolutions of pharmaceutical compounds are catalyzed processes. Catalysts used in a kinetic resolution must be chiral. Binding of a chiral catalyst with a racemic material can form two different diastereomeric complexes. Since the complexes are diastereomers, they have different properties different rates of formation, stabilities, and rates of reaction. The products form from the diastereomeric substrate-catalyst complexes at different rates. Therefore, a chiral catalyst is theoretically able to separate enantiomers by reacting with one enantiomer faster than the other. The catalysts used in kinetic resolutions are often enzymes. Enzymes are constructed from chiral amino acids and often differentiate between enantiomeric substrates. 

When a diastereomeric mixture is an eutectic mixture, the difference in solubility between the diastereomers can be roughly correlated to the difference in thermodynamic stability between them if the conditions for crystallization, such as temperature and solvent, are unchanged. Then it becomes meaningful to estimate the stabilities of a pair of diastereomeric crystals and to observe the correlation between the difference of the stability of the pair of diastereomeric crystals and the efficiency of the chiral discrimination. 

The relative stabilities of the four diastereomers have been extensively investigated. First, it can easily be shown that the diastereomers must, in principle, differ in stability because there are different nonbonded (repulsive) interactions between the rings in each case. Figure 1-20 shows these differences for any two rings in the complex. When any reasonable potential function is used to estimate the magnitudes of the repulsive energies, it is concluded that the order of decreasing stability is... 

Since enantiomers have identical physical and chemical properties, their separation requires a mechanism that recognizes the difference in their shape. A suitable mechanism for chromatography is provided by the formation of reversible transient diastereomer association complexes with a suitable chiral selector. To achieve a useful separation the association complexes must differ in stability resulting from a sterically controlled preference for the fit of one enantiomer over the other with the chiral selector. In addition, the kinetic properties of the formation/dissociation of the complex must be fast on the chromatographic time scale to minimize band broadening and achieve useful resolution. Enantioselectivity based on the formation of transient diastereomer complexes is commonly rationalized assuming a three-point interaction model [1-4,17,18]. Accordingly, enantioselectivity requires a minimum of three simultaneous interactions between the chiral selector and at least one of the enantiomers, where at least one of these interactions is stereochemically dependent. The points of interactions... 

---