Structural characterization and Hirshfeld surface analysis of 2-iodo-4-(pentafluoro-λ6-sulfanyl)benzonitrile

A novel trisubstituted arene compound bearing a pentafluorosulfanyl group (SF5) has been synthesized through a regioselective ortho lithiation, improved by the addition of a bidentate amine, followed by trapping with electrophilic I2. Incorporating the iodo group in 2-iodo-4-(pentafluoro-λ6-sulfanyl)benzonitrile strengthens the intermolecular interaction network with the cyano and pentafluoro substituents.


Chemical context
Organic compounds containing the trifluoromethyl (CF 3 ) or pentafluorothio (or pentafluoro-6 -sulfanyl, SF 5 ) groups play an important role in organofluorine chemistry because of their special properties including low surface energy, hydrophobicity, high chemical resistance, high thermal stability and high electronegativity (Kirsch et al., 1999(Kirsch et al., , 2014Iida et al., 2015;Beier et al., 2011). SF 5 , coined as the 'super-trifluoromethyl' group, is often preferred to CF 3 as it is more electronegative, lipophilic and chemically stable, and possesses a higher steric effect (Bowden et al., 2000). The current interest in the field of drug discovery of fluorinated substituents is based on the possibility of improving both the metabolic stability and bioavailability of receptor binders upon the incorporation of susbtituents with one or more fluorine atoms (Altomonte et al., 2014;Savoie & Welch, 2015;Sowaileh et al., 2017). In fact, several blockbuster drugs include such a group, demonstrating the prominent role of the trifluoromethyl group in the area of drug discovery (O'Hagan, 2010;Mü ller et al., 2007;Purser et al., 2008). New molecules incorporating the SF 5 group are thus potential alternatives to already existing biologically active molecules containing the CF 3 substitution.
Additionally, the chemical robustness of SF 5 has been explored in other areas such as polymer chemistry (Zhou et al., 2016). Despite the popularity of the title compound, an important precursor in organofluorine chemistry, its crystallographic characterization, which is an important milestone in the synthesis of next-generation materials containing this motif, has not been reported. Herein, we describe a variation to the synthetic approach and give details of its simple crystallization through slow evaporation methods, yielding X-ray diffraction-quality single crystals.
The title compound was obtained as part of our studies toward the synthesis of functionalized arenes containing the SF 5 moiety. Its synthesis involves a one-pot reaction in which the interaction of the cyano group in 4-(pentafluorosulfanyl)benzonitrile to the Lewis acidic lithium cation in lithium tetramethylpiperidide (LiTMP) allows deprotonation from the nearest ortho-H atom on the arene. The SF 5 -containing organolithium species is then quenched with iodine to yield the title compound. This reaction pathway was proposed by Iida et al. (2015) for the synthesis of SF 5 -substituted zinc phthalocyanines. We modified the synthesis by adding tetramethylethylenediamine (TMEDA), an amine additive that serves to break up the lithiated base aggregates, allowing for accelerated reactivity because of the increased basicity. This variation improves the total yield of the title compound by 8%. Fig. 1 shows the molecular structure of the title compound, which crystallizes in the space group Pnma. Its asymmetric unit comprises a single molecule lying on a mirror plane perpendicular to [010] with the iodo, cyano, and the sulfur and axial fluorine atoms of the pentafluorosulfanyl substituent in the plane of the molecule. The fluorine atoms of the pentafluorosulfanyl group in the equatorial positions lie above and below the plane in a staggered fashion relative to the two hydrogen atoms ortho to the substituent; of those, two of the four fluorine atoms are generated symmetrically by the mirror plane. The S1-F (eq) bond distances differ from each other depending on which side of the molecule the bond is located ( Table 1). The S1-F2 (eq) bond and its symmetry equivalent S1-F2 i (eq) [symmetry code: (i) x, Ày + 3 2 , z] are on the same side as the iodine atom and exhibit a longer bond distance of 1.572 (3) Å in comparison to S1-F1 (eq) and S1-F1 i (eq) , which are further away from the iodine and have a shorter bond length distance of 1.561 (4) Å . The S1-F3 (ax) bond length of 1.582 (5) Å is the longest and is consistent with those in similar structures [1.588 (2) and 1.573 (3) Å ; Du et al., 2016].

Figure 2
In plane contacts. A view along the b axis of crystal packing of the title compound, with short-contact interactions shown as dashed lines.

Hirshfeld surface analysis
The Hirshfeld surface (Spackman & Jayatilaka, 2009) for the title compound mapped over d norm is shown in Fig. 4 while

Database survey
A search of the Cambridge Structural Database (Version 5.39, updated May 2017; Groom et al., 2016) revealed no matching compounds with the title compound substructure and the three substituents. However, a search for SF 5 aryl compounds fragment revealed about 85 hits: 77 of these structures were reported in the last 10 years, which shows the increasing interest in the SF 5 group. Most of these compounds are used as reagents in the synthesis and modification of pharmaceuticals, such as the antimalarial agent mefloquine (Wipf et al., 2009) and the anti-obesity drug fenfluramine (Welch et al., 2007).
solution was cooled to 273 K and 700 mL of 2.5 M n-butyl lithium in hexane (1.75 mmol, 2 eq.) were added slowly. The reaction mixture was stirred at 273 K for 30 minutes and then cooled to 195 K. A solution containing 200 mg of 4-(pentafluorosulfanyl)benzonitrile (0.872 mmol, 1 eq.) in 4 mL THF was added dropwise: the solution changed from pale yellow to dark brown upon formation of the metalated intermediary.
After stirring for 1 h at 195 K, a solution of 244 mg I 2 (0.960 mmol, 1.2 eq.) in 4 mL THF was added dropwise and stirred for 2 h. The mixture was then warmed to room temperature and stirred for 1 h. The reaction was quenched with water and THF was removed under reduced pressure, followed by extraction with diethyl ether. The combined organic phase was washed with aqueous 0.1 M HCl, 0.1 M Na 2 S 2 O 3 and brine, then dried over MgSO 4 . The crude product was purified by column chromatography (9:1, hexane:ethyl acetate) to yield 71 mg (46%) of the pure arene product as a yellow solid (m.p. 367-369 K). Block-like yellow crystals suitable for X-ray diffraction were obtained by slow evaporation of a saturated CH 2 Cl 2 solution of the 2-iodo-4-(pentafluoro-6 -sulfanyl)benzonitrile at room temperature over a period of four days. NMR analyses were performed on a Bruker AV-500 spectrometer using chloroform-d as solvent (CDCl 3 ). The solvent signals at 7.26 and 77.00 ppm were used as internal standards for proton and carbon, respectively. 1 H NMR (500 MHz, Chloroform-d) 8.31 (d, J = 2.1 Hz, 1H), 7.89 (dd, J = 8.6, 2.1 Hz, 1H), 7.75 (d, J = 8.6 Hz, 1H). 13 C NMR (125 MHz, CDCl 3 ) , 98. 22, 117.83, 124.10, 126.16, 134.39, 136.82, 156.15.

Refinement
Data collection, crystal data and structure refinement parameters are summarized in Table 3. H atoms were included in geometrically calculated positions and refined as riding atoms with C-H = 0.93 Å and U iso (H) = 1.2U eq (C).

2-Iodo-4-(pentafluoro-λ 6 -sulfanyl)benzonitrile
Crystal data Special details 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.