Studies of Halogen Bonding Induced by Pentafluorosulfanyl Aryl Iodides: A Potential Group of Halogen Bond Donors in a Rational Drug Design

The activation of halogen bonding by the substitution of the pentafluoro-λ6-sulfanyl (SF5) group was studied using a series of SF5-substituted iodobenzenes. The simulated electrostatic potential values of SF5-substituted iodobenzenes, the ab initio molecular orbital calculations of intermolecular interactions of SF5-substituted iodobenzenes with pyridine, and the 13C-NMR titration experiments of SF5-substituted iodobenzenes in the presence of pyridine or tetra (n-butyl) ammonium chloride (TBAC) indicated the obvious activation of halogen bonding, although this was highly dependent on the position of SF5-substitution on the benzene ring. It was found that 3,5-bis-SF5-iodobenzene was the most effective halogen bond donor, followed by o-SF5-substituted iodobenzene, while the m- and p-SF5 substitutions did not activate the halogen bonding of iodobenzenes. The similar ortho-effect was also confirmed by studies using a series of nitro (NO2)-substituted iodobenzenes. These observations are in good agreement with the corresponding Mulliken charge of iodine. The 2:1 halogen bonding complex of 3,5-bis-SF5-iodobenzene and 1,4-diazabicyclo[2.2.2]octane (DABCO) was also confirmed. Since SF5-containing compounds have emerged as promising novel pharmaceutical and agrochemical candidates, the 3,5-bis-SF5-iodobenzene unit may be an attractive fragment of rational drug design capable of halogen bonding with biomolecules.


Results and Discussion
The preparation of o-, m-, p-SF5-iodobenzenes (1a-c), and 3,5-bis-SF5-iodobenzene (1d) was achieved by the copper-catalyzed halogen exchange reaction of corresponding aryl-bromides according to our previous report [48,60]. We first simulated the electrostatic potential values for the iodine atoms of the targeted SF5-iodobenzenes, along with the corresponding values for NO2iodobenzenes, pentafluoro-iodobenzene, and iodobenzene for comparisons. Molecular electrostatic potential surfaces of iodobenzenes were calculated with the density functional Becke, 3-parameter, Lee  Next, the intermolecular interactions of iodobenzenes and pyridine were investigated by ab initio molecular orbital calculations. The intermolecular interaction energies [12,62,63] for the o-, m-, and p-SF5-iodobenzene---pyridine complexes (2a-c), the 3,5-bis-SF5-iodobenzene---pyridine complex Next, the intermolecular interactions of iodobenzenes and pyridine were investigated by ab initio molecular orbital calculations. The intermolecular interaction energies [12,62,63] for the o-, m-, and p-SF 5 -iodobenzene-pyridine complexes (2a-c), the 3,5-bis-SF 5 -iodobenzene-pyridine complex (2d), the 3,5-bis-NO 2 -iodobenzene-pyridine complex (3), and the pentafluoro-iodobenzene-pyridine complex (4) were calculated by changing the intermolecular separation in a vacuum using the second order Møller-Plesset perturbation method and the cc-pVTZ basis set (MP2/cc-pVTZ). The interaction energy potentials calculated for the complexes were compared with the interaction energy potential calculated for the iodobenzene-pyridine complex (5) (Figure 3a). The depths of interaction energy potentials of the SF 5 -iodobenzene-pyridine complex (2a-d) are deeper than those of the iodobenzene-pyridine complex (5). We note that the potential for o-SF 5 -substituted 2a is much deeper than for m-SF 5 -2b and p-SF 5 -2c, while the potential for 3,5-bis-SF 5 -2d is much deeper. The depths of interaction energy potentials of 3,5-bis-SF 5 -2d and 3,5-bis-NO 2 -3 are almost the same, and that of the pentafluoro-iodobenzene-pyridine complex (4) is the deepest. The interaction energies by the coupled-cluster calculations with single and double substitutions with non-iterative triple excitations [CCSD(T)] at the basis set limit (E CCSD(T)(limit) ) for the optimized geometries of 2a-d, 3, 4, and 5 were calculated. [64] The E CCSD(T)(limit) and the contribution of each intermolecular force are summarized in Table 1. The calculations show that the electrostatic (E es ) and dispersion (E corr ) interactions are the primary sources of the attraction, and the substituent dependence of the electrostatic interactions is mainly responsible for the substituent effects on the magnitude of the attraction of the halogen bonds. These calculated results strongly indicate that substitution of the SF 5 group induces halogen bonding, whose strength depends on the position of the substitution and numbers. The interaction energy potentials were also calculated by the density functional theory (DFT) method (B3LYP functionals with Grimme's D3 dispersion correction [65]) with and without polarizable continuum model (PCM) [66] to evaluate the effects of water as shown in Figure 3b,c. The depth of the potential calculated for each complex in water is 20-30% smaller than that calculated in a vacuum. As expected, 3,5-bis-SF 5 -iodobenzene (1d) is the most efficient template to induce halogen bonding in SF 5 -iodobenzenes (1), equivalent to the well-known halogen bond donor 3,5-bis-NO 2 -iodobenzene. The 3,5-bis-substitution is also attractive for improved biological activity, as evidenced in medicinal research [45,60]. (2d), the 3,5-bis-NO2-iodobenzene---pyridine complex (3), and the pentafluoro-iodobenzene--pyridine complex (4) were calculated by changing the intermolecular separation in a vacuum using the second order Møller-Plesset perturbation method and the cc-pVTZ basis set (MP2/cc-pVTZ). The interaction energy potentials calculated for the complexes were compared with the interaction energy potential calculated for the iodobenzene---pyridine complex (5) (Figure 3a). The depths of interaction energy potentials of the SF5-iodobenzene---pyridine complex (2a-d) are deeper than those of the iodobenzene---pyridine complex (5). We note that the potential for o-SF5-substituted 2a is much deeper than for m-SF5-2b and p-SF5-2c, while the potential for 3,5-bis-SF5-2d is much deeper. The depths of interaction energy potentials of 3,5-bis-SF5-2d and 3,5-bis-NO2-3 are almost the same, and that of the pentafluoro-iodobenzene---pyridine complex (4) is the deepest. The interaction energies by the coupled-cluster calculations with single and double substitutions with non-iterative triple excitations [CCSD(T)] at the basis set limit (ECCSD(T)(limit)) for the optimized geometries of 2a-d, 3, 4, and 5 were calculated. [64] The ECCSD(T)(limit) and the contribution of each intermolecular force are summarized in Table 1. The calculations show that the electrostatic (Ees) and dispersion (Ecorr) interactions are the primary sources of the attraction, and the substituent dependence of the electrostatic interactions is mainly responsible for the substituent effects on the magnitude of the attraction of the halogen bonds. These calculated results strongly indicate that substitution of the SF5 group induces halogen bonding, whose strength depends on the position of the substitution and numbers. The interaction energy potentials were also calculated by the density functional theory (DFT) method (B3LYP functionals with Grimme's D3 dispersion correction [65]) with and without polarizable continuum model (PCM) [66] to evaluate the effects of water as shown in Figure 3b,c. The depth of the potential calculated for each complex in water is 20-30% smaller than that calculated in a vacuum. As expected, 3,5-bis-SF5-iodobenzene (1d) is the most efficient template to induce halogen bonding in SF5-iodobenzenes (1), equivalent to the well-known halogen bond donor 3,5-bis-NO2iodobenzene. The 3,5-bis-substitution is also attractive for improved biological activity, as evidenced in medicinal research [45,60].   Encouraged by the results of these calculations, 13 C-NMR titration experiments of SF 5 -iodobenzenes in the presence of pyridine or tetra(n-butyl)ammonium chloride (TBAC) in CDCl 3 to detect the existence of halogen bonding were carried out with comparisons using pentafluoro-iodobenzene and iodobenzene. 13 C-NMR is a well-studied technique to probe halogen bonding [67][68][69][70]. Namely, the increase of chemical shifts of the carbon atom bonded to iodine in Ar−I indicates stronger halogen bonding due to lengthening of the carbon−iodine bond by the donation of electrons from the halogen bond acceptor into iodine orbitals [12,71]. Our 13 C-NMR experiments are shown in Figures 4 and 5. First, the chemical shift of the carbon atom bonded to iodine in pentafluoro-iodobenzene increased with an increase in the addition of pyridine or TBAC. This phenomenon confirms the formation of halogen bonding interaction on the σ-hole of the iodine atom with a Lewis base (nitrogen atom of pyridine, or Cl anion). The observed up-field shift is a consequence of the donation of electron density from the halogen bond acceptor to the iodine group, and the more significant shifts donated by TBAC with respect to pyridine are consistent with the fact that anions function as better electron donors than pyridines, and form a stronger halogen bond than the nitrogen atom which possesses a neutral lone-pair.
On the other hand, the addition of pyridine or TBAC to iodobenzene leads to a decrease of the chemical shift of the carbon atom bonded to the iodine atom. This observation could be explained by the competitive interaction of the intermolecular π-π interaction [72] (with pyridine) or the cation-π interaction [73] (with tetra (n-butyl) ammonium cation), although this explanation needs further experimental support. Nevertheless, pentafluoro-iodobenzene is an activated halogen bond donor, but iodobenzene is not.
We next examined the titration experiments of a series of SF 5 -substituted iodobenzenes (1a-d) (Figures 4a and 5a). As mentioned above, the changes in chemical shift of pyridine titration are much smaller than those of TBAC titration, while the occurrence of halogen bonding is fundamentally the same. The chemical shifts of the carbon atom bonded to iodine in o-SF 5 -iodobenzene (1a) and 3,5-bis-SF 5 -iodobenzene (1d) increased after the addition of TBAC, which confirms the occurrence of halogen bonding. On the other hand, opposite phenomena were observed in the case of mand p-SF 5 -iodobenzene (1b, 1c, respectively) with TBAC, which confirms the absence of halogen bonding. These results of the occurrence/absence of halogen bonding depend on the o-, m-, or p-position of SF 5 -substitution, and are in good agreement with the Mulliken charges, as shown in Figure 2. This ortho-effect was also observed for the titration experiments of a series of NO 2 -substituted iodobenzenes (Figures 4b and 5b), which are in good agreement with the calculated Mulliken charges, as shown in Figure 2.    Finally, we examined the formation of halogen bonding interaction between 3,5-bis-SF5iodobenzene (1d) and 1,4-diazabicyclo[2.2.2]octane (DABCO). Since DABCO is a bifunctional halogen bond donor, the 2:1 halogen bonding complex of 1d and DABCO is expected. Indeed, X-ray Finally, we examined the formation of halogen bonding interaction between 3,5-bis-SF 5iodobenzene (1d) and 1,4-diazabicyclo[2.2.2]octane (DABCO). Since DABCO is a bifunctional halogen bond donor, the 2:1 halogen bonding complex of 1d and DABCO is expected. Indeed, X-ray crystallographic analysis of 3,5-bis-NO 2 -iodobenzene with DABCO revealed the formation of a 2:1 halogen bonding complex [10]. We thus examined the titration of 1d by the addition of DABCO ( Figure 6). With an increasing amount of DABCO, the chemical shift of carbon attached to iodine increased, providing proof of the formation of halogen bonding of I-N. More interestingly, one singlet peak at 92.442 ppm gradually changed to double singlets at 93.454 and 93.352 ppm, which provides evidence of two halogen bonds in the complex from 6 to 7. This phenomenon suggests that the 2:1-complex 7 is not entirely symmetrical, as in the case of 3,5-bis-NO 2 -iodobenzene [10]. crystallographic analysis of 3,5-bis-NO2-iodobenzene with DABCO revealed the formation of a 2:1 halogen bonding complex [10]. We thus examined the titration of 1d by the addition of DABCO ( Figure 6). With an increasing amount of DABCO, the chemical shift of carbon attached to iodine increased, providing proof of the formation of halogen bonding of I---N. More interestingly, one singlet peak at 92.442 ppm gradually changed to double singlets at 93.454 and 93.352 ppm, which provides evidence of two halogen bonds in the complex from 6 to 7. This phenomenon suggests that the 2:1-complex 7 is not entirely symmetrical, as in the case of 3,5-bis-NO2-iodobenzene [10].

Materials and Methods
All reactions were performed in oven-dried glassware under a positive pressure of nitrogen. Solvents were transferred via syringe and were introduced into the reaction vessels through a rubber septum. Chemicals were purchased and used without further purification unless otherwise noted. All of the reactions were monitored by thin-layer chromatography (TLC) carried out on a 0.25 mm Merck silica gel (60-F254) (Kenilworth, NJ, USA). TLC plates were visualized with UV light and 7% phosphomolybdic acid or KMnO4 in water/heat. Column chromatography was carried out on a column packed with silica gel (60N spherical neutral size 50-60 μm) supplied by Kanto Chemical Co., Inc. (Tokyo, Japan). The 1 H-NMR (300 MHz), 19

Materials and Methods
All reactions were performed in oven-dried glassware under a positive pressure of nitrogen. Solvents were transferred via syringe and were introduced into the reaction vessels through a rubber septum. Chemicals were purchased and used without further purification unless otherwise noted. All of the reactions were monitored by thin-layer chromatography (TLC) carried out on a 0.25 mm Merck silica gel (60-F 254 ) (Kenilworth, NJ, USA). TLC plates were visualized with UV light and 7% phosphomolybdic acid or KMnO 4 in water/heat. Column chromatography was carried out on a column packed with silica gel (60N spherical neutral size 50-60 µm) supplied by Kanto Chemical Co., Inc. (Tokyo, Japan). The 1 H-NMR (300 MHz), 19 F-NMR (282 MHz), and 13 C-NMR (126 MHz) spectra for each solution in CDCl 3 were recorded on Varian Mercury 300 (Agilent Technologies, Palo Alto, CA, USA) and Avance 500 (Bruker, Billerica, MA, USA) NMR spectrometers. Chemical shifts (δ) are expressed in ppm downfield from internal tetramethylsilane (δ = 0.0 ppm) for 1 H-NMR, C 6 F 6 (δ = −162.2 ppm) for 19 F-NMR, and CDCl 3 (δ = 77.00 ppm) for 13 C-NMR. Mass spectrometry was recorded on a SHIMADZU LCMS-2020 (ESI-MS) (Shimadzu Corporation, Kyoto, Japan). The 1 H, 13 C and 19 F-NMR spectra of compounds 1 are available in the Supplementary Material.

General Procedure of Pentafluoro-λ 6 -Sulfanyl Iodobenzene
o-, m-, p-SF5-iodobenzenes (1a-c), and 3,5-bis-SF5-iodobenzene (1d) were prepared from corresponding aryl bromides by a copper-catalyzed halogen exchange reaction. [74]. To a flame-dried Schlenk-tube, CuI (10 mol %), NaI (2.0 equiv), and aryl bromide (1.0 equiv) were added and evacuated and backfilled with argon. 1,4-Dioxane (1.0 mL/mmol for ArBr) and N,N′dimethylethylenediamine (20 mol %) were added; the mixture was stirred at room temperature for 3 min and then at 110 °C for 24-72 h. The resulting suspension was cooled to room temperature and filtered through a pad of SiO2. The filtrate was diluted in NaHCO3 aq and extracted with CH2Cl2 three times. The combined organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (nhexane) to give the desired product. The product was consistent with previously reported characterization data [48].

Calculations for Electrostatic Potential Values
Molecular electrostatic potential surfaces for SF5 or NO2-iodobenzenes were calculated with the density functional B3LYP level of theory with 6-311++G** basis set in a vacuum or in a water. The same level of theory was used to calculate the electrostatic potentials with the results presented in o-, m-, p-SF 5 -iodobenzenes (1a-c), and 3,5-bis-SF 5 -iodobenzene (1d) were prepared from corresponding aryl bromides by a copper-catalyzed halogen exchange reaction. [74]. To a flame-dried Schlenk-tube, CuI (10 mol %), NaI (2.0 equiv), and aryl bromide (1.0 equiv) were added and evacuated and backfilled with argon. 1,4-Dioxane (1.0 mL/mmol for ArBr) and N,N -dimethylethylenediamine (20 mol %) were added; the mixture was stirred at room temperature for 3 min and then at 110 • C for 24-72 h. The resulting suspension was cooled to room temperature and filtered through a pad of SiO 2 . The filtrate was diluted in NaHCO 3 aq and extracted with CH 2 Cl 2 three times. The combined organic layer was washed with brine, dried over Na 2 SO 4 , and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (n-hexane) to give the desired product. The product was consistent with previously reported characterization data [48].

Calculations for Electrostatic Potential Values
Molecular electrostatic potential surfaces for SF 5 or NO 2 -iodobenzenes were calculated with the density functional B3LYP level of theory with 6-311++G** basis set in a vacuum or in a water. The same level of theory was used to calculate the electrostatic potentials with the results presented in Figure 2. All calculations were carried out using Spartan 18 software (Wavefunction, Inc., Irvine, CA, USA). All molecules were geometry optimized with the maxima and minima in the electrostatic potential surface (0.002 e/au isosurface) determined using a positive point charge in the vacuum as a probe. The numbers indicate the interaction energy (kJ/mol) between the positive point probe and the surface of the molecule at that particular point. A positive value for the interaction energy indicates a positive surface potential.

Calculations for Interaction Energies
The Gaussian 09 program [78] was used for the ab initio molecular orbital calculations. The basis sets implemented in the program were used. Electron correlation was accounted for by the second-order Møller-Plesset perturbation (MP2) method [79,80], Becke, 3-parameter, Lee-Yang-Parr (B3LYP) [81][82][83], and by coupled-cluster calculations with single and double substitutions with non-iterative triple excitations (CCSD(T)) [64]. The basis-set superposition error (BSSE) [84] was corrected for all calculations by using the counterpoise method unless otherwise noted [85]. The geometries of the complexes were optimized at the counterpoise-corrected MP2/6-311G* level. The DGDZVP basis set [86] was used for iodide. The MP2 interaction energies of the complexes at the basis set limit (E MP2(limit) ) were estimated by the method of Helgaker et al. [87] from the calculated MP2 interaction energies (E MP2 ) by using the aug-cc-pVDZ and aug-cc-pVTZ basis sets. The E MP2(limit) for the 3,5-bis-NO 2 -iodobenzene-pyridine complex (3) was estimated using the cc-pVDZ and cc-pVTZ basis set. The CCSD(T) interaction energies at the basis set limit (E CCSD(T)(limit) ) were calculated as the sum of E MP2(limit) and the estimated CCSD(T) correction term at the basis set limit (∆CCSD(T)(limit)), which was estimated from the difference between the interaction energies calculated at the CCSD(T) and MP2 levels (∆CCSD(T) = E CCSD(T) − E MP2 ) by using the 6-31G* basis set [88,89]. Electrostatic energies were calculated as the interactions between distributed multipoles [90,91] of interacting molecules by using the ORIENT program [92]. Distributed multipoles up to hexadecapole were obtained on all atoms from the MP2/6-311G** level wave functions of isolated molecules by using the GDMA program [93]. Induction energies were calculated as the interactions of polarizable sites with the electric field produced by the distributed multipoles of the monomers [94]. The atomic polarizabilities of carbon (α = 10 a.u.), nitrogen (α = 8 a.u.), oxygen (α = 6 a.u.), fluorine (α = 3 a.u.), sulfur (α = 20 a.u.), and iodine (α = 34 a.u.) were used for the calculations [95]. The distributed multipoles were used only to estimate the electrostatic and induction energies. The MP2/6-311G** level optimized geometries of isolated molecules were used to calculate the intermolecular interaction energy potentials. The B3LYP calculations with Grimme's D3 dispersion correction using the cc-pVTZ basis set (B3LYP-D3/cc-pVTZ) level interaction energy potentials [65]) were calculated with and without polarizable continuum model (PCM) [66] to evaluate the effects of the solvent. The B3LYP-D3 level interaction energies were calculated without BSSE correction.

Conclusions
In conclusion, we have studied the potential of SF 5 -substituted iodobenzenes as halogen bond donors. The simulated electrostatic potential values of SF 5 -substituted iodobenzenes, the ab initio molecular orbital calculations of intermolecular interactions with pyridine, and the 13 C-NMR titration experiments of SF 5 -substituted iodobenzenes in the presence of halogen bond acceptors were investigated to assess the existence of halogen bonding. It should be noted that halogen bonding of iodobenzenes induced by the SF 5 -substituted group is strictly dependent on the position of SF 5 -substitution on the benzene ring, i.e., o-SF 5 -iodobenzene acts as halogen bond donor, while mand p-SF 5 -iodobenzenes do not. The ortho-effect was also observed for a series of NO 2 -iodobenzenes. 3,5-Bis-SF 5 -iodobenzene is the most effective halogen bond donor in the series, and it is almost an equivalent to the well-known 3,5-bis-NO 2 -iodobenzene, as supported by our calculations and 13 C-NMR titration experiments. These observations are in good agreement with the Mulliken charge of corresponding iodine. Since SF 5 -containing compounds are promising drug candidates, the present results should provide useful information for the rational design of drugs capable of halogen bonding with biomolecules. The X-ray crystallographic analyses of 3,5-bis-SF 5 -iodobenzene with halogen bond acceptors are now being considered