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

Abstract

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.

Synthesis and biological evaluation of benzodiazepines containing a pentafluorosulfanyl group

“…[17][22] However, the attempt was unsuccessful and one speculation for the failure was the poor nucleophilicity of the aniline. To validate this hypothesis, we attempted the same reaction with 2-amino-5nitrobenzophenone as the nitro group has an electronic effect fairly close to that of the SF5 group (p = 0.68 [5] for SF5 and p = 0.78 [23] for NO2). The result was as postulated, unsuccessful.…”

Recent Advances in the Synthesis and Medicinal Chemistry of SF5 and SF4Cl Compounds

“…Scheme 68 Synthesis of (S)-meta-SF5 ostarine analogues 61 Scheme 69 Synthesis of (S)-para-SF5 ostarine analogues 61 Shibata et al investigated the effect of SF5-substitution in iodobenzenes on halogen bonding activation, using a combination of 13 C NMR experiments and ab initio molecular orbital calculations, using pyridine as halogen bonding acceptor. 62 The results indicated the following halogen bonding donor effectiveness: 3,5-bis-SF5-iodobenzene > o-SF5-substituted >> m-and p-SF5 substitutions, which did not activate the halogen bonding. Similar ortho-effect was confirmed -for comparison -on a series of NO2-substituted iodobenzenes.…”

“…Figure 8 The 2:1 halogen bonded complex between 3,5-bis-SF 5 -iodobenzene and DABCO 62 Togni et al reported the analysis of crystal structures of SF 5 -or SF 4 Cl containing molecules (such as those shown in Figure 9), which revealed that these groups are often surrounded by H or other F-atoms. 63 It was also shown that these compounds form a number of repeating structural motifs through contacts involving SF 5 groups, including different supramolecular dimers and infinite chains.…”

(Hetero)aryl‐SVI Fluorides: Synthetic Development and Opportunities

“…As a result of such unique properties, aryl‐SF 5 compounds have attracted attention, and synthetic efforts towards their preparation have been the focus of intensive research [11] . Investigations on Ar−SF 5 span from applications as t Bu and CF 3 isosteres in medicinal chemistry, [10, 58] optoelectronic materials, [59] or agrochemicals, [60] to their ability to function as push‐pull fluoro‐ [61] and choromophores [62] . Before discussing Ar−SF 5 compounds, it is important to mention that the first syntheses of C−SF 5 compounds were reported in the 1950s by Cady and co‐workers (Scheme 25).…”