Racemic Triarylmethanol Derivative Crystallizes as a Chiral Crystal Structure with Enantiomeric Disorder, in the Sohncke Space Group P2₁

Abstract

The X-ray crystal structure of a racemic triarylcarbinol derivate ((±)-1) was determined. Compound (±)-1 crystallizes as a chiral structure in the noncentrosymmetric Sohncke space group P2 1 and the crystals show a special case of enantiomeric disorder with two molecules of opposite handedness sharing many of the atomic positions in the asymmetric unit. The corresponding (R)-and (S)-enantiomers of 1 were separated by chiral HPLC, and crystallized independently yielding single crystals of both of them. The X-ray diffraction analysis of the crystals allowed the determination of the absolute configuration of both enantiomers (R)-1 and (S)-1. Both enantiomers establish intermolecular hydrogen bonds in the solid state, which induce significant differences in their molecular arrangement when compared to racemic crystal (±)-1. ■ INTRODUCTIONRacemic mixtures of chiral molecules can crystallize as racemic compounds (the most common situation, a single crystalline phase with both enantiomers in a 1:1 ratio in the elementary cell), as conglomerates of chiral crystals (mechanical mixture of enantiomerically pure crystals; about 10% of the time), or as pseudoracemates (or racemic solid solutions). Racemic compounds can yield either chiral or achiral crystal structures, and can theoretically be arranged in any one of the 230 space groups, 1 although around 95% of the known racemic compounds crystallize as centrosymmetric achiral crystal structures. 2 In this paper, we report the structural study of (4-(dimethylamino)phenyl)(phenyl)(thiophen-2-yl)methanol (1, see Figure 1), a chiral molecule which was synthesized as a racemic mixture from achiral precursors in the course of ongoing research. This compound was designed by our group to be used as an OFF/ON optical chemodosimeter for nerve agent mimics, due to the changes in its optical properties in the presence of these toxic compounds. 3 We have found that (±)-1 crystallizes as an ordered racemic crystal structure in the noncentrosymmetric space group P2 1 . This space group is one of 65 Sohncke space groups, which are the groups allowed for chiral crystal structures, containing only symmetry operations of the first kind (rotations and translations). 4 Actually, around of 5.2% of the CSD structures (of a total of 682 999) belong to a P2 1 space group. 5 Racemic mixtures that happen to crystallize as chiral crystal structures in Sohncke space groups are a very unusual case, and few examples have been reported in the literature. 6−9 Furthermore, the corresponding R and S enantiomers of 1 were separated by chiral HPLC, and crystallized independently yielding single crystals of both of them suitable for X-ray diffraction.■ EXPERIMENTAL SECTION X-ray Diffraction Analysis. Appropriate colorless acicular crystals of compound (±)-1 3 were grown from heptane/2-propanol as solvent at 4°C by means of liquid−liquid diffusion and analyzed by X-ray diffraction technique. The crystallization of the enantiomers, (S)-1 (1a) and (R)-1 (1b), was carried out at 4°C by the slow evaporation method...

Observation of an infrequent enantiomer/conformer substitutional disorder in ethyl 13-ethyl-4-oxo-8,13-dihydro-4H-benzo[5,6]azepino[3,2,1-ij]quinoline-5-carboxylate heptane hemisolvate

“…Substitutional disorder between enantiomers of the same molecule have been reported before (Chulvi et al, 2015;Kaitner & Stilinović, 2007;Evain et al, 2003). The crystal structure of the racemic compound 5-(3-hydroxy-3-methylbut-1-ynyl)-3-(1-methylpyrrolidin-2-yl)pyridine (Evain et al, 2003) shows the two enantiomers in the asymmetric unit and substitutional disorder of the kind observed here, with one conformer of one enantiomer disordered at the site of the other enantiomer in a roughly 4:1 proportion, with parts of the two molecules showing exact overlap.…”

Chirality determination in crystals

“…It is interesting to note that, in the absence of identification or clear classification, some crystals that were described with generic terms such as "enantiomeric disorder" could be now be considered as representatives of solid solution classes. 76,77 Hereafter, we illustrate two cases of solid solutions from our work. The first example is again linked to the linear metallic clusters, and it can be classified as a type I solid solution.…”

“…Type II solid solution are more complicated to define than type I and they are presented as “crystalline phases where both enantiomers are largely recognized as different entities upon the formation of the crystal structure.” Thus, there is a preferred layout of enantiomers but the crystallographic molecular positions are not fully stereospecific but enantioselective (see 75 for more details and examples on both solid solution types). It is interesting to note that, in the absence of identification or clear classification, some crystals that were described with generic terms such as “enantiomeric disorder” could be now be considered as representatives of solid solution classes 76,77 …”