Mechanistic Flexibility of Solvent-Assisted Solid-to-Solid Polymorphic Transition Causing Preferential Enrichment: Significant Contribution of π/π and CH/π Interactions as Well as Hydrogen Bonds

Abstract

A new mode of solvent-assisted solid-to-solid polymorphic transformation of the first-formed and metastable γ-form into a stable, new α1-form, which occurs during crystallization from individual supersaturated EtOH solutions of a series of (±)-[2-[4-(2-hydroxy-3-phenoxypropoxy)phenylcarbamoyl]ethyl]trimethylammonium p-halobenzenesulfonates [(±)-1], has been found to cause an unusual symmetry-breaking enantiomeric resolution phenomenon called preferential enrichment. This polymorphic transition has been followed by the in situ attenuated total reflectance Fourier-transform infrared spectroscopy (ATR-FTIR) (ReactIR) measurement of the crystallization mixture and differential scanning calorimetry (DSC) analysis of the deposited crystals. The crystal structures with the α1-form have been solved either by X-ray crystallographic analysis of the single crystal or by the direct-space approach employing the Monte Carlo method with the subsequent Rietveld refinement from powder X-ray diffraction data of the powder sample. By comparison of the supramolecular structure characteristic of the metastable γ-form with that of the stable α1-form, the mechanism of this polymorphic transition has been interpreted in terms of a new type of rearrangement of weak intermolecular interactions caused by slight molecular movement inside the crystal lattice, in which intermolecular π/π and CH/π interactions as well as hydrogen bonds prominently control the crystal structure. This finding shows the flexibility in the mode of polymorphic transition inducing preferential enrichment.