Effect of Molecular Chirality on Racemate Stability: α-Amino Acids with Nonpolar R Groups

A racemate of two opposite and resolvable enantiomers is generally assumed to be more stable than the corresponding conglomerate. Demonstrating this structure-stability relation, however, has proved difficult owing to a sampling bias (data available only for systems whose racemates are stable enough to exist) and a possible kinetic bias (racemates may be easier to crystallize than conglomerates from racemic media). As a new approach to studying the relation, we determined how the relative stability of the conglomerate and the racemate changes with the molecule's degree of chirality in a series of alpha-amino acids with nonpolar R groups. We found that the excess energy of the conglomerate over the racemate, (E(C) - E(R)), increases with the size of the R group, a measure of the molecule's chirality. If valid in general, this relation demonstrates a tendency for chiral molecules to form racemates rather than conglomerates. Because of the entropy effect on crystal stability, however, the excess free energy of the conglomerate over the racemate, (G(C) - G(R)), shows no simple relation with the degree of chirality at the temperatures of study (-3 to 180 degrees C).