Preferential enrichment: Full crystallographic analysis of the unusual phenomenon in the mixed crystals' version

Abstract

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.

Chiral Symmetry Breaking Phenomenon Caused by a Phase Transition

“…Furthermore, the crystal structure of the S-rich (20% ee) NBMe 3 was virtually isostructural with that of the racemate and very similar to that of the pure S enantiomer (Figure 7) [40]. [24,25].…”

“…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.…”

“…Among them, the δ-form and α 1 -form crystals are most commonly found for the compounds showing preferential enrichment [20][21][22][23][24][25][33][34][35][36][37][38][39][40][41][42][43][44][45], while only one case is observed for each of the α-and ε-forms [5,6,21,22,39]. In this section, the crystal structures of the δ-and α 1 -forms are described in detail, because this crystal structure provides a crucial information on the mechanism of the polymorphic transition causing preferential enrichment.…”

“…(a) δ-form In the δ-form crystals of racemic and S-rich (20% ee) NBMe 3 [40], the orientational disorder was observed at the position of the hydroxy group on an asymmetric carbon atom (Figure 7). The degree of disorder per asymmetric unit (one salt) for the racemic or S-rich sample was estimated to be 67:33 or 75:25 (R vs. S, or S vs. R), respectively, by calculating the constrained occupancy factors of the hydroxy group, corresponding to a fairly ordered racemic mixed crystal.…”

Principles, Concepts and Strategies of Stereoselective Synthesis

“…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.…”