Mechanism of Preferential Enrichment, an Unusual Enantiomeric Resolution Phenomenon Caused by Polymorphic Transition during Crystallization of Mixed Crystals Composed of Two Enantiomers

The mechanism of Preferential Enrichment, an unusual enantiomeric resolution phenomenon
observed upon recrystallization of a series of racemic crystals which are classified as a racemic mixed
crystal with fairly ordered arrangement of the two enantiomers, has been studied. On the basis of the
existence of polymorphs and the occurrence of the resulting polymorphic transition during crystallization
from solution, the mechanism has been accounted for in terms of (1) a preferential homochiral molecular
association to form one-dimensional chain structures in the supersaturated solution of the racemate or
nonracemic sample with a low ee value, (2) a kinetic formation of a metastable crystalline phase retaining
the homochiral chain structures in a process of nucleation, (3) a polymorphic transition from the metastable
phase to a stable one followed by enantioselective liberation of the excess R (or S) enantiomers from the
transformed crystal into solution at the beginning of crystal growth to result in a slight enrichment (up to
10% ee) of the opposite S (or R) enantiomer in the deposited crystals, together with an enantiomeric
enrichment of the R (or S) enantiomer in the mother liquor, and (4) a chiral discrimination by the once
formed S (or R)-rich stable crystalline phase in a process of the subsequent crystal growth, leading to a
considerable enantiomeric enrichment of the R (or S) enantiomer up to 100% ee in the mother liquor. The
processes (3) and (4) are considered to be directly responsible for an enrichment of one enantiomer in the
mother liquor. The association mode of the two enantiomers in solution has been investigated by means
of (i) the solubility measurement and (ii) the number-averaged molecular weight measurement in solution
by vapor pressure osmometry, together with (iii) the molecular dynamics simulation of oligomer models.
The polymorphic transition during crystallization has been observed visually and by means of the in situ
FTIR technique and DSC measurement. Both metastable and stable crystals have been obtained, and
their crystal structures have been elucidated by X-ray crystallographic analysis of their single crystals.