Studies of halogen bonding induced by pentafluorosulfanyl aryl iodides: A potential group of halogen bond donors in a rational drug design

Article abstract of DOI:10.3390/molecules24193610

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.

Full text of DOI:10.3390/molecules24193610

molecules
Article
Studies of Halogen Bonding Induced by
Pentafluorosulfanyl Aryl Iodides: A Potential Group
of Halogen Bond Donors in a Rational Drug Design
Yuji Sumii 1 , Kenta Sasaki 1, Seiji Tsuzuki 2 and Norio Shibata 1,3,
*
1
Department of Nanopharmaceutical Sciences, and Department of Life Science and Applied Chemistry,
Nagoya Institute of Technology, Gokiso, Showa-ku, Nagoya 466-8555, Japan; sumii.yuji@nitech.ac.jp (Y.S.);
k.sasaki.699@stn.nitech.ac.jp (K.S.)
Research Center for Computational Design of Advanced Functional Materials, AIST, Tsukuba,
Ibaraki 305-8568, Japan; s.tsuzuki@aist.go.jp
2
3
Institute of Advanced Fluorine-Containing Materials, Zhejiang Normal University, 688 Yingbin Avenue,
Jinhua 321004, China
*
Correspondence: nozshiba@nitech.ac.jp; Tel./Fax: +81-52-735-7543
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
Academic Editor: Derek J. McPhee
Received: 24 August 2019; Accepted: 3 October 2019; Published: 7 October 2019
ꢀꢁꢂꢃꢄꢅꢆ
Abstract: The activation of halogen bonding by the substitution of the pentafluoro-
λ
6-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.
Keywords: halogen bonding; fluorine; iodine; pentafluorosulfanyl; titration; ab initio calculation;
NMR study; drug design
1. Introduction
Halogen bonding has attracted considerable attention in recent decades [
pioneering work on halogen bonding in supramolecular chemistry by Resnati et al. [
of halogen bonding has expanded to a wide variety of fields including crystal engineering, supramolecular
assemblies, liquid crystals, rational drug design, and organic reactions [ ]. Halogen bonding is a
noncovalent attraction between an electron-deficient region of a halogen atom ( -hole, a halogen bond
1–
4], particularly after the
5
]. The application
1–5
σ
donor) and an electron-rich center of molecules such as nitrogen, oxygen, and sulfur (Lewis base, a halogen
bond acceptor). The strength of the halogen bond increases with an increase of the positive electrostatic
potential of the
σ-hole, which can be activated by substitution of an electron-withdrawing group in
the neighborhood of the halogen atom. Thus, perfluoroalkyl iodides and perfluoro-iodobenzenes are
Molecules 2019, 24, 3610; doi:10.3390/molecules24193610
www.mdpi.com/journal/molecules

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well-studied halogen bond donors. In particular, aromatic iodides are of great interest due to the design
of halogen bond donors activated by substitution with several electron-withdrawing substituents [ ];
pentafluoro-iodobenzene [ ] and 3,5-bis-nitro(NO2)-iodobenzene [10] are representative examples
(Figure 1a). Besides, in these planar halogen bond donors, the intermolecular π−π charge-transfer [11],
anion– 12 13], cation– 14 15], and lone pair– 16 19] interactions are always competition for and/or
6,7
8,9
π
[
,
π
[
,
π
[
–
form a combination with halogen bonding in molecular assemblies. These aspects make the design of
halogen bond donors more elaborate, especially for applications in the rational design of drugs [20].
Statistical analysis of the protein structure database (PDB) showed that a noncovalent interaction
between halogenated ligands (halogen-containing drugs, halogen bond donors) and proteins (halogen
bond acceptors) frequently contributes to increasing selectivity and binding affinity [21,22]. This survey
revealed that a potential rational drug design is possible when the focus is on halogen bonding
interactions of halogenated drug candidates and nitrogen, oxygen, sulfur, and phosphate groups on
biomolecules such as peptides, protein, and DNA [1,23].
Figure 1.
) Examples of pentafluoro-
of SF5-containing biologically active molecules. (
containing SF5-group(s) and NO2-iodobenzenes (this work).
(
a
) The standard halogen bond donors pentafluoro-iodobenzene and 3,5-bis-NO2-iodobenzene.
6-sulfanyl (SF5)-containing analogs of marketed drugs. (
) Examples
) Potential halogen bond donors of aryl iodide
(
b
λ
c
d
In this context, we became interested in pentafluoro-
) as a new group of halogen bond donors. The SF5 group has attracted much attention in the field
of pharmaceuticals and agrochemicals [24 29]. Given the impressive physiochemical properties of
the SF5 unit, which include its high electronegativity ( = 0.61, = 0.68; nearly equivalent to the
λ
6-sulfanyl (SF5)-substituted iodobenzenes
(1
–
σ
σ
p
m
NO2 group:
group: = 0.88 and the NO2 group:
to that of the tert-butyl group) [34 35], the SF5-containing analogs of marketed drugs are attractive
σ
= 0.73,
σ
= 0.78) [30
–
32], high lipophilicity (π = 1.51; greater than that of the CF3
m
p
π
π
=
−
0.28) [32 34], and steric hindrance (nearly equivalent
–
,

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candidates in the future drug market (Figure 1b) [36
–
41]. More and more examples of biologically active
SF5-containing drug candidates have been reported in recent years (Figure 1c) [35
our research to the design and synthesis of SF5-containing biologically attractive molecules [45
and a halogen bonding research program [58 59], we are interested in aryl iodides 1a consisting of
,38
–44]. Extending
–
57]
,
–d
SF5-group(s) in the benzene ring as potential drug fragments capable of halogen bonding, in particular,
3,5-bis-SF5-iodobenzene (1d, Figure 1d). In this research, we have examined the halogen bonding
induced by SF5-aryl iodides 1a–d. The NO2-substituted iodobenzenes pentafluoro-iodobenzene and
iodobenzene were also examined for comparisons.
2. 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 NO2-iodobenzenes,
pentafluoro-iodobenzene, and iodobenzene for comparisons. Molecular electrostatic potential surfaces
of iodobenzenes were calculated with the density functional Becke, 3-parameter, Lee–Yang–Parr
(B3LYP) level of theory with a 6-311++G** basis set in a vacuum and water according to the reported
method [61] (Figure 2). The numbers indicate the molecular electrostatic potential (MEP, kJ/mol)
between the positive point probe and the surface of the molecule at that particular point, and Mulliken
charges at the iodine atom. The MEP value indicates a positive surface potential. The results disclose
that 1d shows a more positive electrostatic potential value and Mulliken charge (Figure 2d), almost as
same as that of the well-known halogen bond donors 3,5-bis-NO2-iodobenzene (Figure 2h) [10] and
pentafluoro-iodobenzene (Figure 2i), independent of calculation in a vacuum and water. It should be
noted that m- and p-substituted SF5-iodobenzenes (1b,1c, respectively) had a lower Mulliken charge of
the iodine atom compared to o-SF5-iodobenzene (1a), indicating a poor ability for halogen bonding
(Figure 2a vs. Figure 2b,c). The similar tendency of lower Mulliken charge was also observed for
m- and p-substituted NO2-iodobenzenes, while o-substituted NO2-iodobenzene has a more positive
Mulliken charge (Figure 2e vs. Figure 2f,g). Iodobenzene had the most negative value and was thus
most de-activated (Figure 2j).
Figure 2. The electrostatic potential surface of molecules with maximum values at iodine atoms in a
vacuum (black) and in water (blue). The numbers indicated interaction energy (in kJ/mol) and Mulliken
charge in parenthesis; (
1c), ( ) ,5-bis-SF5-iodobenzene (1d), (
iodobenzene, (h) 3,5-bis-NO2-iodobenzene, (i) pentafluoro-iodobenzene, and (j) iodobenzene.
a
) o-SF5-iodobenzene (1a), (
b
) m-SF5-iodobenzene (1b), (
c
) p-SF5-iodobenzene
(
d
e) o-NO2-iodobenzene, (
f
) m-NO2-iodobenzene, (g
) p-NO2-
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 ), the 3,5-bis-SF5-iodobenzene—pyridine complex
2d), the 3,5-bis-NO2-iodobenzene—pyridine complex ( ), and the pentafluoro-iodobenzene—pyridine
) were calculated by changing the intermolecular separation in a vacuum using the
,
,
–c
(
3
complex (
4

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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 (
interaction energy potentials of the SF5-iodobenzene—pyridine complex (2a–d) are deeper than those
of the iodobenzene—pyridine complex ( ). 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- are almost the same, and that
of the pentafluoro-iodobenzene—pyridine complex ( ) is the deepest. The interaction energies
by the coupled-cluster calculations with single and double substitutions with non-iterative triple
5) (Figure 3a). The depths of
5
3
4
excitations [CCSD(T)] at the basis set limit (ECCSD(T)(limit)) for the optimized geometries of 2a–d
, and
are summarized in Table 1. The calculations show that the electrostatic (Ees) and dispersion (Ecorr
,
3
,
4
5 were calculated. [64] The ECCSD(T)(limit) and the contribution of each intermolecular force
)
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-NO2-iodobenzene.
The 3,5-bis-substitution is also attractive for improved biological activity, as evidenced in medicinal
research [45,60].
(SF5)n
O2N
O2N
F
F
F
F
2a
2b
: o-SF5-iodobenzene –pyridine
: m-SF5-iodobenzene –pyridine
I
N
F
I
N
I
N
I
N
2c: p-SF5-iodobenzene –pyridine
2d
: 3,5-bis-SF 5-iodobenzene –pyridine
n = 1, 2
3
5
4
Figure 3. Interaction energy curves (energies versus I—N distance (R)) calculated for the
iodobenzene—pyridine complexes ( ). ( ) second order Møller–Plesset perturbation calculations
(MP2; vacuum), ( ) Becke, 3-parameter, Lee–Yang–Parr calculation with Grimme’s D3 dispersion
correction (B3LYP-D3, vacuum), and (c) B3LYP-D3 (water).
2–
5
a
b

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Table 1. Electrostatic, induction, and dispersion energies of halogen-bonded complexes a.
E (kcal mol−1
)
Complex
a
c
e
b
d
Eint
Eind
Ecorr
Ees
Eshort
o-SF5-iodobenzene—pyridine (2a)
m-SF5-iodobenzene—pyridine (2b)
p-SF5-iodobenzene—pyridine (2c)
3,5-bis-SF5-iodobenzene—pyridine (2d)
3,5-bis-NO2-iodobenzene—pyridine (3)
pentafluoro-iodobenzene—pyridine (4)
iodobenzene—pyridine (5)
−4.88
−4.27
−4.28
−5.21
−4.83
−5.71
−3.25
−4.48
−4.20
−4.02
−5.60
−5.23
−5.83
−2.73
−1.32
−1.20
−1.15
−1.65
−1.52
−1.68
−0.82
4.43
4.40
4.02
5.54
4.46
5.11
3.30
−3.52
−3.27
−3.13
−3.49
−2.53
−3.31
−2.99
a Estimated interaction energy by coupled-cluster calculations with single and double substitutions with non-iterative
b
c
triple excitations (CCSD(T)) at the basis set limit (ECCSD(T)(limit)).
Electrostatic energy.
Induction energy.
d
Contribution of short-range (orbital–orbital) interactions (= EHF
−
Ees ind). The interaction energy by
−
E
Hartree-Fock calculations with aug-cc-pVTZ basis set (HF/aug-cc-pVTZ) was used as EHF. Eshort is mainly the
contribution of exchange–repulsion interactions. e Contribution of electron correlation (= Eint
−
EHF). Ecorr is mainly
dispersion energy.
Encouraged by the results of these calculations, 13C-NMR titration experiments of SF5-iodobenzenes
in the presence of pyridine or tetra(n-butyl)ammonium chloride (TBAC) in CDCl3 to detect the existence of
halogen bonding were carried out with comparisons using pentafluoro-iodobenzene and iodobenzene.
13C-NMR is a well-studied technique to probe halogen bonding [67
chemical shifts of the carbon atom bonded to iodine in Ar
lengthening of the carbon iodine bond by the donation of electrons from the halogen bond acceptor
into iodine orbitals [12
71]. Our 13C-NMR experiments are shown in Figures 4 and 5. First, the chemical
–
70]. Namely, the increase of
−
I indicates stronger halogen bonding due to
−
,
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 SF5-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-SF5-iodobenzene (1a) and
3,5-bis-SF5-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 m- and
p-SF5-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 SF5-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 NO2-substituted
iodobenzenes (Figures 4b and 5b), which are in good agreement with the calculated Mulliken charges,
as shown in Figure 2.

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Figure 4. Change in the 13C-NMR chemical shift of the carbon atom bonded to iodine in Ar
with equivalents of pyridine in CDCl3. ) pentafluoro-iodobenzene; o-SF5-iodobenzene (1a);
m-SF5-iodobenzene (1b); p-SF5-iodobenzene (1c); 3,5-bis-SF5-iodobenzene (1d). ( ) iodobenzene;
o-NO2-iodobenzene; m-NO2-iodobenzene; p-NO2-iodobenzene; 3,5-bis-NO2-iodobenzene.
−I
(
a
b

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Figure 5. Change in the 13C-NMR chemical shift of the carbon atom bonded to iodine in Ar
equivalents of tetra (n-butyl) ammonium chloride (TBAC) in CDCl3. ( ) pentafluoro-iodobenzene;
o-SF5-iodobenzene (1a); m-SF5-iodobenzene (1b); p-SF5-iodobenzene (1c); 3,5-bis-SF5-iodobenzene (1d).
) iodobenzene; o-NO2-iodobenzene; m-NO2-iodobenzene; p-NO2-iodobenzene; 3,5-bis-NO2-iodobenzene.
−
I with
a
(b

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Finally, we examined the formation of halogen bonding interaction between 3,5-bis-SF5-
iodobenzene (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-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].
Figure 6. Change in the 13C-NMR chemical shift of the carbon atom bonded to iodine in 1d with
equivalents of 1,4-diazabicyclo[2.2.2]octane (DABCO) in CDCl3.
3. 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
µ
m) supplied by Kanto Chemical Co., Inc.
(Tokyo, Japan). The H-NMR (300 MHz), 19F-NMR (282 MHz), and 13C-NMR (126 MHz) spectra
1
for each solution in CDCl3 were recorded on Varian Mercury 300 (Agilent Technologies, Palo Alto,
CA, USA) and Avance 500 (Bruker, Billerica, MA, USA) NMR spectrometers. Chemical shifts (
are expressed in ppm downfield from internal tetramethylsilane (
= 0.0 ppm) for 1H-NMR, C6F6
162.2 ppm) for 19F-NMR, and CDCl3 ( = 77.00 ppm) for 13C-NMR. Mass spectrometry was
δ)
δ
(δ
=
−
δ

Molecules 2019, 24, 3610
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recorded on a SHIMADZU LCMS-2020 (ESI-MS) (Shimadzu Corporation, Kyoto, Japan). The 1H, 13
and 19F-NMR spectra of compounds 1 are available in the Supplementary Material.
C
3.1. General Procedure of Pentafluoro-λ6-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,N0-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 (n-hexane) to give the desired product.
3.1.1. Pentafluoro(2-iodophenyl)-λ6-sulfane (1a)
1
92% yield. H-NMR (300 MHz, CDCl3)
δ
8.14 (d, J = 7.6 Hz, 1H), 7.81 (d, J = 8.5 Hz, 1H), 7.45 (t-like,
: 83.5 (quintet, J = 152.6 Hz,
J = 7.5 Hz, 1H), 7.12 (t-like, J = 7.4 Hz, 1H). 19F-NMR (282 MHz, CDCl3)
δ
1F), 63.5 (d, J = 151.7 Hz, 4F) ppm. 13C-NMR (126 MHz, CDCl3)
δ 158.4 (quintet, J = 16.3 Hz), 143.9,
132.2, 130.1 (t-like, J = 5.4 Hz), 127.9, 88.2 ppm. MS (ESI) m/z: 353 [(M + Na)+]. The product was
consistent with previously reported characterization data [60].
3.1.2. Pentafluoro(3-iodophenyl)-λ6-sulfane (1b)
1
91% yield. H-NMR (300 MHz, CDCl3)
δ
8.08 (s, 1H), 7.86 (d, J = 7.6 Hz, 1H), 7.74 (d, J = 7.4 Hz, 1H),
82.5 (quintet, J = 150.9 Hz, 1F), 62.3 (d,
7.22 (t-like, J = 8.4 Hz, 1H) ppm. 19F-NMR (282 MHz, CDCl3)
δ
J = 151.7 Hz, 4F) ppm. 13C-NMR (126 MHz, CDCl3)
δ 154.4 (quintet, J = 17.7 Hz), 140.6, 134.7 (t-like,
J = 4.5 Hz), 130.3, 125.2, 93.1 ppm. MS (ESI) m/z: 353 [(M + Na)+]. The product was consistent with
previously reported characterization data [48,75–77].
3.1.3. Pentafluoro(4-iodophenyl)-λ6-sulfane (1c)
1
91% yield. H-NMR (300 MHz, CDCl3)
δ
7.82 (d, J = 8.2 Hz, 2H), 7.48 (d, J = 8.5 Hz, 2H) ppm. 19F-NMR
δ
83.0 (quintet, J = 150.0 Hz, 1F), 62.3 (d, J = 150.0 Hz, 4F) ppm. 13C-NMR (126 MHz,
(282 MHz, CDCl3)
CDCl3)
δ
153.5 (quintet, J = 18.2 Hz), 137.9, 127.5 (t-like, J = 4.5 Hz), 98.2 ppm. MS (ESI) m/z: 353
[(M + Na)+]. The product was consistent with previously reported characterization data [48,76,77].
3.1.4. (5-Iodo-1,3-phenylene)bis(pentafluoro-λ6-sulfane) (1d)
1
95% yield. H-NMR (300 MHz, CDCl3)
δ
8.23 (s, 1H), 8.12–8.07 (m, 2H) ppm. 19F-NMR (282 MHz,
CDCl3)
154.0 (quintet, J = 20.0 Hz), 137.8, 123.5 (t, J = 4.5 Hz), 92.4 ppm. MS (ESI) m/z: 479 [(M + Na)+].
The product was consistent with previously reported characterization data [48].
δ
80.1 (quintet, J = 151.7 Hz, 1F), 62.7 (d, J = 151.7 Hz, 4F) ppm. 13C-NMR (126 MHz, CDCl3)
δ

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3.2. Computational Method
3.2.1. 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 Figure 2.
All calculations were carried out using Spartan018 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.
3.2.2. 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) [81–83],
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
(EMP2(limit)) were estimated by the method of Helgaker et al. [87] from the calculated MP2 interaction
energies (EMP2) by using the aug-cc-pVDZ and aug-cc-pVTZ basis sets. The EMP2(limit) for the
3,5-bis-NO2-iodobenzene—pyridine complex (
set. The CCSD(T) interaction energies at the basis set limit (ECCSD(T)(limit)) were calculated as the sum
of EMP2(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) = ECCSD(T) 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
3) was estimated using the cc-pVDZ and cc-pVTZ basis
∆
∆
−
E
,
,
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.
4. Conclusions
In conclusion, we have studied the potential of SF5-substituted iodobenzenes as halogen
bond donors. The simulated electrostatic potential values of SF5-substituted iodobenzenes, the ab
initio molecular orbital calculations of intermolecular interactions with pyridine, and the 13C-NMR
titration experiments of SF5-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 SF5-substituted group is strictly dependent on the position of

Molecules 2019, 24, 3610
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SF5-substitution on the benzene ring, i.e., o-SF5-iodobenzene acts as halogen bond donor, while m-
and p- SF5-iodobenzenes do not. The ortho-effect was also observed for a series of NO2-iodobenzenes.
3,5-Bis-SF5-iodobenzene is the most effective halogen bond donor in the series, and it is almost
an equivalent to the well-known 3,5-bis-NO2-iodobenzene, as supported by our calculations and
13C-NMR titration experiments. These observations are in good agreement with the Mulliken charge
of corresponding iodine. Since SF5-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-SF5-iodobenzene with halogen bond
acceptors are now being considered
Supplementary Materials: The following are available online. 1H, 13C, and 19F-NMR spectra of compounds 1.
Author Contributions: N.S. conceived and designed the experiments and directed the project; K.S. and Y.S.
performed the experiments and analyzed the data; S.T. performed the ab initio calculation; Y.S. and N.S. wrote
the paper.
Funding: This work was partially supported by the JSPS KAKENHI Grant-in-Aid for Scientific Research (B) Grant
Number 18H02553 and the Central Glass Co., Ltd. Award in Synthetic Organic Chemistry, Japan (Y.S.).
Acknowledgments: We thank Ube Industries, Ltd. for the gift of SF5-aryl bromides.
Conflicts of Interest: The authors declare no conflicts of interest.
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Sample Availability: Samples of the compounds 1a–d are available from the authors.
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