Mechanism of a New Type of Solvent-Assisted Solid-to-Solid Polymorphic Transition Causing Preferential Enrichment:  Prominent Influence of C(sp²)H···O Interaction on the Control of a Crystal Structure

Abstract

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.

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].…”

“…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.…”

“…As a result, the single crystal of racemic NPMe 3 ( Figure 5) was found to possess the desired γ-form crystal structure that is classified as a highly ordered racemic mixed crystal and is composed of alternating alignment of homochiral 1D R and S chains in an antiparallel direction with a space group P-1 (Z = 2) with the second lowest symmetry; each homochiral chain comprises an alternating alignment of the long-chain ammonium ion and the sulfonate ion by two hydrogen bonds (i) between one oxygen atom of the sulfonate ion and the hydroxy group and (ii) between the same sulfonate oxygen atom and the amide NH ( Figure 6) [21,22]. There is no interchain interaction.…”

“…This γ-form crystal structure is also seen in several other racemic samples such as NNMe 3 -OPr, NBMe 3 -OPr, NIMe 3 -OPr and NBMe 3 -OMe which failed to show preferential enrichment [21,23,44], indicating that the subsequent polymorphic transition into the more stable α-, α 1 -, δ-or ε-form is indispensable for preferential enrichment to occur. Actually, in the case of NPMe 3 , the successive polymorphic transition of the γ-form into the ε-form occurred slowly to induce preferential enrichment [21,22].…”

“…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.…”