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

Abstract

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.

Chiral Symmetry Breaking Phenomenon Caused by a Phase Transition

“…In 1998, this new phenomenon was referred to as preferential enrichment [20], which is completely opposed to preferential crystallization; in preferential enrichment it is in the mother liquor that substantial enantiomeric enrichment occurs by recrystallization, and at the same time slight enrichment of the opposite enantiomer always occurs in the deposited crystals ( Figure 3). In 2002, we proposed the mechanism of preferential enrichment in terms of a unique polymorphic transition during crystallization [21,22]. Later, on the basis of the proposed mechanism of this polymorphic transition, we have successfully induced and inhibited the occurrence of preferential enrichment by controlling the mode of the polymorphic transition with appropriate seed crystals [23,24].…”

“…Figure 4 exhibits a typical example of preferential enrichment for nearly racemic NNMe 3 ( Figure 5) which is a linear asymmetric secondary alcohol containing a glycerol moiety, an amide group, and a trimethylammonium p-nitrobenzenesulfonate structure [21]. This compound was synthesized from the racemic epichlorohydrin.…”

“…Thus far, we have found four types of solvent-assisted solid-to-solid transformations of a kinetically formed metastable γ-form crystalline phase into a thermodynamically more stable one (α-, α 1 -, δ-, or ε-form) [5,6,[20][21][22][23][24][25][33][34][35][36][37][38][39][40][41][42][43][44][45], which are relevant to the occurrence of preferential enrichment, in a process of crystal growth.…”

Principles, Concepts and Strategies of Stereoselective Synthesis

“…87 Employing this procedure, enantiopure or nearly enantiopure isomeric compounds can be often obtained from the conglomerate by sorting. In some cases, noncovalent interactions also can play a key role in the spontaneous resolution process.…”

“…90 Another form of a direct crystallization is a preferential crystallization, 91,92 which is also called resolution by entrainment of one enantiomer. [93][94][95] The process involves solution formation, e.g., under elevated temperature that will then be subcooled and seeded with crystals of the preferred species. Preferential crystallization is a potent method for the improvement of the product quality and at the same time achievement of a higher yield and productivity.…”