Control of polymorphic transition inducing preferential enrichment

Abstract

Preferential enrichment is an unusual symmetry-breaking enantiomeric resolution phenomenon that is 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 a certain kind of racemic crystals. On the basis of the proposed mechanism of preferential enrichment, both induction and inhibition of preferential enrichment were successfully achieved by controlling the mode of the polymorphic transition during crystallization either by minor molecular modification or with appropriate seed crystals. Furthermore, by inducing a desired polymorphic transition during crystallization of several -amino acids or their cocrystals with dicarboxylic acids, which were classified as a racemic compound, preferential enrichment could also be accomplished.

Preferential Enrichment of DL‐Leucine Using Cocrystal Formation With Oxalic Acid Under Nonequilibrium Crystallization Conditions

“…Meanwhile, semi‐oxalate molecules directly connect with each other by O‐H···O hydrogen bond (O3···O6: 2.63Å) forming a 1D chain structure along the a ‐axis [graph set: C 1 1 (5)] to contribute to the formation of DL ‐sheet pair structure. This crystal structure is quite different from those of racemic crystals that thus far showed PE; the latter consisted of heterochiral cyclic DL dimer chains as well as homochiral 1D d chains and L chains to form a heterochiral 2D sheet structure …”

“…Preferential enrichment (PE) is a unique enantiomeric resolution phenomenon that is caused by the polymorphic transition of an incipient metastable polymorphic form into a thermodynamically more stable form during crystallization from the supersaturated solution of a certain kind of racemic crystals (Fig. ) . We have proposed a mechanism for the occurrence of PE, based on extensive studies of the first‐generation chiral organic compounds of onium sulfonate salts that showed excellent PE (Fig.…”

“…We have proposed a mechanism for the occurrence of PE, based on extensive studies of the first‐generation chiral organic compounds of onium sulfonate salts that showed excellent PE (Fig. b), involves several successive key processes such as initial molecular association of homochiral 1D chains in solution followed by metastable mixed crystal formation, then solvent‐assisted solid‐to‐solid polymorphic transition, and partial redissolution of the excess enantiomer into solution due to irregular alignment of R and S chains inside the transformed crystal lattice until the deposited crystals were slightly enriched with the opposite enantiomers (Fig. ) .…”

“…b), involves several successive key processes such as initial molecular association of homochiral 1D chains in solution followed by metastable mixed crystal formation, then solvent‐assisted solid‐to‐solid polymorphic transition, and partial redissolution of the excess enantiomer into solution due to irregular alignment of R and S chains inside the transformed crystal lattice until the deposited crystals were slightly enriched with the opposite enantiomers (Fig. ) . Such an unusual enrichment of the opposite enantiomer in the deposited crystals is fully reproducible and is considered to be governed by nonlinear thermodynamics.…”

“…In accord with the above‐mentioned mechanism, there are five mandatory requirements for the occurrence of PE that have been proposed: 1) sufficient solubility difference (pure enantiomer >> racemate; more than two times); 2) occurrence of a polymorphic transition (phase transition); 3) formation of unique crystal structures involving heterochiral cyclic RS dimer chains as well as homochiral 1D R chains and S chains after the polymorphic transition (phase transition); 4) selective redissolution of the excess enantiomer from the transformed fragile crystals; and 5) eventual deposition of stable nonracemic mixed crystals capable of memorizing the event of chiral symmetry breaking …”