Enantiopure (S)-butan-2-yl N-(4-x-phenyl)thiocarbamates, x = NO2, OCH3, F, and Cl

Enantiopure (S)-butan-2-yl-N-(4-x-phenyl)thiocarbamates, x = NO2, OCH3, F, and Cl were synthesized from reacting aryl isothiocyanate with (S)-2-butanol to form new chiral crystals as the basis for future research into their non-linear physical and potentially biological properties.


Structural commentary
Isothiocyanates were selected because of the ease with which the -N C S functional group can be reacted with amines or alcohols to form thioureas or thiocarbamates, which in turn are well suited for simple crystal-growth studies. The -R S linkage builds out selected hydrogen bonds, structuring the packing of the molecule and thereby enhancing crystal growth. In addition, the sulfur atom has sufficient anomalous scattering capability with Mo radiation, which permits absolute structure determinations via single crystal X-ray diffraction. Further, from comparing a series of crystals with small chemical variations, we hoped to gain insight into the functionality of those interchanged moieties, here NO 2 , OCH 3 , F, and Cl in the 4-x location on the structures of the phenylthiocarbamates. All four structures crystallize in the chiral space group P2 1 of the monoclinic system. Bond lengths and angles are in the expected ranges. We observed two pairings, where the 4-NO 2 and 4-Cl crystals exhibited a similarly short b-axis, whereas OCH 3 and F in the 4-x location had the longest axis dimensions along b. The chirality of the compounds was confirmed by the absolute structure parameters [(I)-(IV): À0.02 (3), À0.04 (4), 0.17 (13), and 0.022 (14), respectively].

Synthesis and crystallization
All chemicals were obtained from Sigma Aldrich. Compounds (I), (III), and (IV): 4 ml vials were charged with a stir bar, the aryl isothiocyanate [0.100 g, 0.555 mmol (I), 0.653 mmol (III), 0.590 mmol (IV)] and 2(S)-butanol (82.3 mg, 1.1 mmol). Using a hot oil bath, the reaction was run at 381 K for 24 h. Compound (II): A 4 mL vial was charged with a stir bar and 2(S)-butanol (0.054 g, 0.726 mmol). While stirring, triethylamine (0.011 g, 0.109 mmol) was added. After 5 minutes, the aryl isothiocyanate (0.100 g, 0.605 mmol) was added dropwise. The reaction was allowed to continue for 24 h at 358 K. Subsequently, for all four compounds, the vials, after allowing to cool, were covered with filter paper and left in a vacuum oven at 343 K. The crude product was purified by flash column chromatography, and eluted with 1:4 ethyl acetate/hexane.

Refinement
Crystal data, data collection, and structure refinement details are summarized in Table 5. Hydrogen atoms on carbon atoms were positioned geometrically, using a riding model, with C-H = 0.95-1.00Å . U iso (H) = 1.2 (1.5 for methyl groups) times U eq (C). The nitrogen protons were refined positionally, with U iso (H) = 1.2U eq (N). The two phenyl groups of the independent molecules of (III) were optimized to enhance the C-C bond precision with the C-C distance at 1.39 Å (AFIX 66). In (II), one of the two (S)-butan-2-yl moieties appeared threefold disordered, requiring restraint of the displacement parameters with a SIMU 0.01 command. One atom (C8) was constrained to the same displacement parameter for each fraction with EADP. The disordered geometries were linked through a SAME command to the geometry of the ordered moiety of the other molecule, and distances of O1 to C8, C8B and C8C were restrained to be similar (SADI), all with default esds. The occupancies of the three fractions were 0.444 (4), 0.354 (4), and 0.202 (4). For all structures, data collection: APEX2 (Bruker, 2012); cell refinement: SAINT (Bruker, 2012); data reduction: SORTAV (Blessing, 1995); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL2018/3 (Sheldrick, 2015); molecular graphics: ORTEP-3 for Windows (Farrugia, 2012); software used to prepare material for publication: WinGX publication routines (Farrugia, 2012).

Special details
Experimental. Crystals were mounted on a Cryoloop TM (0.2-0.3mm, Hampton Research) with Paratone (R) oil. Between 7 to 12 data sets were collected to cover full Ewald spheres to a resolution of better than 0.75 Å. Crystals were held at 100 K with a Cryostream cooler, mounted to a Bruker APEXII single crystal X-ray diffractometer, Mo radiation (Bruker 2012), equipped with a fine-focus X-ray tube, Miracol X-ray optical collimator, and CCD detector. Crystal-to-detector distance was 40 mm and the exposure times were between 20 to 120 seconds per frame for all sets, pending on sample size. The scan widths were 0.5°. Crystal data, data collection, and structure refinement details are summarized in Table 5. The data were integrated and scaled using SAINT, SADABS within the APEX2 software package by Bruker (2012). Data work-up was done with SAINT (Bruker, 2012). Structures were solved with SHELXS (Sheldrick, 2008), and refined with SHELXL (Sheldrick 2015). Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.

Special details
Experimental. Crystals were mounted on a Cryoloop TM (0.2-0.3mm, Hampton Research) with Paratone (R) oil. Between 7 to 12 data sets were collected to cover full Ewald spheres to a resolution of better than 0.75 Å. Crystals were held at 100 K with a Cryostream cooler, mounted to a Bruker APEXII single crystal X-ray diffractometer, Mo radiation (Bruker 2012), equipped with a fine-focus X-ray tube, Miracol X-ray optical collimator, and CCD detector. Crystal-to-detector distance was 40 mm and the exposure times were between 20 to 120 seconds per frame for all sets, pending on sample size. The scan widths were 0.5°. Crystal data, data collection, and structure refinement details are summarized in Table 5. The data were integrated and scaled using SAINT, SADABS within the APEX2 software package by Bruker (2012). Data work-up was done with SAINT (Bruker, 2012). Structures were solved with SHELXS (Sheldrick, 2008), and refined with SHELXL (Sheldrick 2015). Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å 2 )
x y z U iso */U eq Occ. (

(S)-2-Butyl N-(4-fluorophenyl)thiocarbamate (III)
Crystal data  (Parsons et al., 2013). Absolute structure parameter: 0.17 (13) Special details Experimental. Crystals were mounted on a Cryoloop TM (0.2-0.3mm, Hampton Research) with Paratone (R) oil. Between 7 to 12 data sets were collected to cover full Ewald spheres to a resolution of better than 0.75 Å. Crystals were held at 100 K with a Cryostream cooler, mounted to a Bruker APEXII single crystal X-ray diffractometer, Mo radiation (Bruker 2012), equipped with a fine-focus X-ray tube, Miracol X-ray optical collimator, and CCD detector. Crystal-to-detector distance was 40 mm and the exposure times were between 20 to 120 seconds per frame for all sets, pending on sample size. The scan widths were 0.5°. Crystal data, data collection, and structure refinement details are summarized in Table 5. The data were integrated and scaled using SAINT, SADABS within the APEX2 software package by Bruker (2012). Data work-up was done with SAINT (Bruker, 2012). Structures were solved with SHELXS (Sheldrick, 2008), and refined with SHELXL (Sheldrick 2015). Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.

Special details
Experimental. Crystals were mounted on a Cryoloop TM (0.2-0.3mm, Hampton Research) with Paratone (R) oil. Between 7 to 12 data sets were collected to cover full Ewald spheres to a resolution of better than 0.75 Å. Crystals were held at 100 K with a Cryostream cooler, mounted to a Bruker APEXII single crystal X-ray diffractometer, Mo radiation (Bruker 2012), equipped with a fine-focus X-ray tube, Miracol X-ray optical collimator, and CCD detector. Crystal-to-detector distance was 40 mm and the exposure times were between 20 to 120 seconds per frame for all sets, pending on sample size. The scan widths were 0.5°. Crystal data, data collection, and structure refinement details are summarized in Table 5. The data were integrated and scaled using SAINT, SADABS within the APEX2 software package by Bruker (2012). Data work-up was done with SAINT (Bruker, 2012). Structures were solved with SHELXS (Sheldrick, 2008), and refined with SHELXL (Sheldrick 2015). Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.
Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å 2 )