Mechanism and Scope of Preferential Enrichment, a Symmetry-Breaking Enantiomeric Resolution Phenomenon

Abstract

The mechanism of "preferential enrichment", an unusually symmetry-breaking enantiomericresolution phenomenon that is observed upon simple recrystallization of a certain kind of organic racemiccrystal from the usual organic solvents without any external chiral element, has been rationalized in termsof a complexity system involving multistage processes that affect each other. These processes comprise:(1) preferential homochiral molecular association to give one-dimensional (1D) R andS chains in solution; (2) formation of γ-form prenucleationaggregates consisting of the same homochiral 1D chains; (3) nucleation and crystal growth of the metastableγ-form crystal composed of irregular alignment of the homochiral 1D R andS chains; (4) the solvent-assisted solid-to-solid type of polymorphictransition of the incipient γ-form crystal into the more stable polymorphic form, such as the α-,δ-, or ε-form; and (5) partial crystal disintegration in the transformed crystal to releaseexcess R or S moleculesinto solution. Based on this mechanism, both induction and inhibition of preferential enrichment have beenachieved by controlling the mode of polymorphic transition during crystallization with appropriate seedcrystals. We call this forced polymorphic transition on the surface of a seed crystal "epitaxialtransition".

Chiral Symmetry Breaking Phenomenon Caused by a Phase Transition

“…However, until our discovery of "preferential enrichment", an unusually symmetry-breaking enantiomeric resolution phenomenon observed upon recrystallization of organic racemic crystals [5][6][7][8], this fascinating subject was not realized.…”

“…These results strongly support our proposed mechanism of preferential enrichment. After a thorough investigation on the mechanism, preferential enrichment has been found to be initiated by the solvent-assisted solid-to-solid transformation of a metastable polymorphic form into a thermodynamically stable one during crystallization from the supersaturated solution of certain kinds of racemic mixed crystals (i.e., solid solutions or pseudoracemates) composed of two enantiomers without the aid of any external chiral element [5][6][7][8]. Most notably, this polymorphic transition process is followed by partial crystal disintegration inside the transformed crystal lattice to release the excess enantiomer into solution until the deposited crystals are slightly enriched with the opposite enantiomer (<10% ee), with full reproducibility [5][6][7][8].…”

“…After a thorough investigation on the mechanism, preferential enrichment has been found to be initiated by the solvent-assisted solid-to-solid transformation of a metastable polymorphic form into a thermodynamically stable one during crystallization from the supersaturated solution of certain kinds of racemic mixed crystals (i.e., solid solutions or pseudoracemates) composed of two enantiomers without the aid of any external chiral element [5][6][7][8]. Most notably, this polymorphic transition process is followed by partial crystal disintegration inside the transformed crystal lattice to release the excess enantiomer into solution until the deposited crystals are slightly enriched with the opposite enantiomer (<10% ee), with full reproducibility [5][6][7][8]. Thus, the interplay of i) such a solvent-assisted solid-tosolid polymorphic transition, ii) the subsequent selective redissolution process of the excess enantiomer, which arises from the increasing solubility of the sample with increasing ee value, and iii) the resulting deposition of mixed crystals, which can retain the resulting fairly-random alignment of two enantiomers inside the crystal lattice to memorize an event of chiral symmetry-breaking, has turned out to be responsible for this unique enantiomeric resolution phenomenon [5][6][7][8].…”

“…Most notably, this polymorphic transition process is followed by partial crystal disintegration inside the transformed crystal lattice to release the excess enantiomer into solution until the deposited crystals are slightly enriched with the opposite enantiomer (<10% ee), with full reproducibility [5][6][7][8]. Thus, the interplay of i) such a solvent-assisted solid-tosolid polymorphic transition, ii) the subsequent selective redissolution process of the excess enantiomer, which arises from the increasing solubility of the sample with increasing ee value, and iii) the resulting deposition of mixed crystals, which can retain the resulting fairly-random alignment of two enantiomers inside the crystal lattice to memorize an event of chiral symmetry-breaking, has turned out to be responsible for this unique enantiomeric resolution phenomenon [5][6][7][8].…”

“…Thus, by collecting the enantiomerically enriched mother liquors with the same handedness, very efficient separation of the two enantiomers (>96% ee) has been easily achieved. Accordingly, the technical and phenomenal features of preferential enrichment are summarized as follows [7,8]:…”