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.

Full characterization of the crystal structures of the racemate, nonracemate (20% ee), and pure enantiomer of [2-[4-(3-ethoxy-2-hydroxypropoxy)phenylcarbamoyl]ethyl]trimethylammonium p-bromobenzenesulfonate (NBMe3), which has successfully shown an unusual enantiomeric resolution phenomenon, "preferential enrichment," was achieved by means of X-ray crystallographic analysis and construction of the binary melting point phase diagram. The crystalline nature of the racemate is not a racemic compound but a fairly ordered mixed crystal composed of the two enantiomers. The crystal structure of the nonracemate (20% ee) is virtually identical with that of the racemate and similar to that of the pure enantiomer. The binary melting point phase diagram of NBMe3 is consistent with the nature of a mixed crystal composed of the two enantiomers.

A new mode of the solvent-assisted solid-to-solid transformation of the first-formed and least stable γ-polymorphic form into the most stable ε-polymorphic one occurring during crystallization from the supersaturated EtOH solution of (±)-[2-[4-(3-ethoxy-2-hydroxypropoxy)phenylcarbamoyl]ethyl]trimethylammonium benzenesulfonate [(±)-2], which shows an unusual enantiomeric resolution phenomenon called Preferential Enrichment, has been revealed. The crystal structure of the new ε-form, which was obtained as the monophasic powder sample by exhaustive polymorphic transitions via three other metastable polymorphic forms in contact with the solvent, has been solved from the powder X-ray diffraction data by the direct-space approach employing the Monte Carlo method with the subsequent Rietveld refinement. By comparison of the crystal structure of the least stable γ-form with that of the most stable ε-one, the mechanism of this polymorphic transition has been interpreted in terms of a new type of rearrangement of weak intermolecular interactions caused by a slight molecular movement inside the crystal lattice, in which intermolecular C(sp2)H···O interactions prominently control the crystal structure. This new finding complements our recent report on the mechamisn of Preferential Enrichment.