Crystal structures of (S)-(+)-5-(3-bromo/chloro-4-isopropoxyphenyl)-5-methylimidazolidine-2,4-dione

The chiral title compounds are closely related hydantoin derivatives with bromo and chloro substituents at the 3-position of the benzene ring of the isopropoxyphenyl subtituent. In the both crystals, hydantoin groups are connected by N—H⋯O hydrogen bonds, forming two-dimensional sheets, made up from (20) rings.


Chemical context
In searching for a new synthetic -selective agonist toward liver X receptors (LXR), a series of compounds having the hydantoin tail, which may act as a linker, were synthesized and examined Koura et al., 2015). It has been revealed that the chirality of the hydantoin unit is crucial to the LXR activation and selectivity (Koura et al., 2016). In the present study, the absolute configuration of the (+)hydantoin unit, which leads to pharmacological activity, has been determined definitely from anomalous-dispersion effects in diffraction measurements on crystals of the title bromo and chloro derivatives.

Structural commentary
The conformations of the molecules (I) and (II) are similar to one another ( Figs. 1 and 2), although the inclination angles of ISSN 2056-9890 the C11-C16 benzene rings to the hydantoin group around the C7-C11 bond axes differ somewhat, the N5-C7-C11-C16 torsion angles being 12.9 (3) and À9.8 (2) for (I) and (II), respectively. The configuration around the asymmetric carbon atom C7 of the (+)-isomer has been determined to S for both (I) and (II). It is worthwhile to compare the Flack parameters calculated by classical refinement (Flack, 1983) and Parsons' quotient (Parsons et al., 2013) for these Br and Cl compounds which were measured with Mo K radiation. These values are 0.010 (7) and 0.018 (2) for (I), and 0.010 (50) and 0.009 (8) for (II), respectively. Flack parameters with much smaller s.u. values were obtained by Parsons' method.

Supramolecular features
The crystal structure of (I) projected along a is shown in Fig. 3. The hydantoin ring systems are linked by two sets of N-HÁ Á ÁO hydrogen bonds (Table 1) and are arranged in zigzag fashion along the twofold screw axes at z = 0 and z = 1 2 along a. Groups of four molecules are linked by these N-HÁ Á ÁO hydrogen bonds, generating R 4 4 (20) ring motifs, forming terraced sheets parallel to (001) as shown schematically in Fig. 4  The molecular structure of (I), showing displacement ellipsoids at the 50% probability level.

Figure 3
The crystal structure of (I), projected along a. Hydrogen bonds are shown as dashed lines.

Figure 4
A schematic drawing of the N-HÁ Á ÁO hydrogen-bonding network in (I).
The arrows indicate the twofold screw axes along a. modated between these sheets and linked by the C-HÁ Á ÁBr and C-HÁ Á ÁO hydrogen bonds, forming a three-dimensional architecture. Both (I) and (II) crystallize in space group P2 1 2 1 2 1 and the lattice constants are roughly similar for both. However, there are both similarities and significant differences in the packing modes between the two closely related molecules. The crystal structure of (II) projected along a is shown in Fig. 5. The hydantoin ring systems again lie approximately on planes at z = 0 or z = 1 2 , and are connected by N-HÁ Á ÁO hydrogen bonds (Table 2), forming a flat sheet parallel to (001). Between these sheets 3-chloro-4-isopropoxyphenyl groups are linked by C-HÁ Á ÁCl and C-HÁ Á ÁO hydrogen bonds, generating a three-dimensional structure of molecules stacked along a.
Comparison of the crystal structures reveals that (II) is more loosely packed than (I). There are significant differences in the van der Waals radii of the Br and Cl atoms (1.85 and 1.75 Å , respectively; Bondi, 1964) which is reflected in the C-X bond distances [C13-Br1 = 1.8945 (18) Å in (I); C13-Cl1 1.7396 (16) Å in (II)]. However, the effective volume of the molecule in (II) estimated by V/Z is larger by ca 4% than that for (I). This suggests that the nearly coplanar arrangement of the hydantoin groups in (II) is favorable for the formation of N-HÁ Á ÁO hydrogen bonds as seen from Table 2, but it also results in looser molecular packing.

Figure 5
The crystal structure of (II), projected along a. Hydrogen bonds are shown as dashed lines.
permethylated -cyclodextrin based on the known absolute configuration of the host. Martin et al. (2011) prepared the diastereomeric salt of (S)-(+)-5-phenyl-5-trifluoromethylhydantoin with (+)--methylbenzylamine to determine the configuration based on the known absolute configuration of the chiral amine. It is noted that the R and S notation remains unchanged when CH 3 at the 5-position of the hydantoin is replaced with CF 3 , although the priorities of the substituents in the sequence rule are altered. To our knowledge, the present paper is the first to report the absolute configuration of such compounds determined from anomalous-dispersion effects.

Synthesis and crystallization
Compounds (I) and (II) were prepared from the corresponding (+)-non-halogeno-derivatives, which were separated from a racemic mixture (Koura et al., 2016). Prismatic crystals of (I) were grown from ethylacetate solution. The specific rotation, [] D , of (I) at 293 K is +79.7 (c = 0.98, MeOH, where c is the concentration of units gram per 100 cm À3 ). Plate-like crystals of (II) were grown from ethylacetate solution. The specific rotation, [] D , of (II) at 293 K is +81.4 (c = 1.0, MeOH).