Synthesis, Surface Activity, and Antimicrobial Efficacy of Diaryliodonium Salt-Derived Amphiphiles

Article abstract of DOI:10.1002/jsde.12038

Two sets of 19 amphiphiles derived from diaryliodonium salt in the form of 4-methylbenzenesulfonate salts and trifluoromethanesulfonate salts were synthesized in good yields through the oxidation of 17 different aryl iodides using oxone (potassium peroxymonosulfate) as the oxidation agent in Route I and meta-chloroperoxybenzoic acid as the oxidation agent in Routes II and III, followed by Friedel–Crafts reaction with (2-(2-(2-methoxyethoxy)ethoxy)ethoxy)benzene to obtain the target compounds (1–19). Their structures were characterized by ¹H nuclear magnetic resonance (NMR), ¹³C NMR, and high-resolution mass spectrometry studies. Their surface activities were evaluated on the basis of surface tension and critical micelle concentration measurements by the Wilhelmy plate method at 25 °C. With their good water solubility, diaryliodonium salts (1–19) have excellent short-term bactericidal efficacy against Bacillus cereus in the concentration of 600 ppm at 20 °C. After compounding 1 or 18 with the broad-spectrum but skin-irritating antibacterial agent Kathon CG (methylchloroisothiazolinone in combination with methylisothiazolinone) in the ratio of 1:1 by mass, both formulations maintained lethality rate of >90% after 48 h.

Full text of DOI:10.1002/jsde.12038

J Surfact Deterg (2018)
DOI 10.1002/jsde.12038
ORIGINAL ARTICLE
Synthesis, Surface Activity, and Antimicrobial Efficacy of
Diaryliodonium Salt-Derived Amphiphiles
Mengen Huang1 · Shujia Xu1 · Xunshen Wu1 · Min Zhao2 · Limin Wang1,3
Received: 29 September 2017 / Revised: 25 December 2017 / Accepted: 11 February 2018
© 2018 AOCS
Abstract Two sets of 19 amphiphiles derived from diary-
liodonium salt in the form of 4-methylbenzenesulfonate
salts and trifluoromethanesulfonate salts were synthesized
in good yields through the oxidation of 17 different aryl
iodides using oxone (potassium peroxymonosulfate) as the
oxidation agent in Route I and meta-chloroperoxybenzoic
acid as the oxidation agent in Routes II and III, followed by
Friedel–Crafts reaction with (2-(2-(2-methoxyethoxy)eth-
oxy)ethoxy)benzene to obtain the target compounds (1–
19). Their structures were characterized by 1H nuclear mag-
netic resonance (NMR), 13C NMR, and high-resolution
mass spectrometry studies. Their surface activities were
evaluated on the basis of surface tension and critical
micelle concentration measurements by the Wilhelmy plate
broad-spectrum but skin-irritating antibacterial agent
Kathon CG (methylchloroisothiazolinone in combination
with methylisothiazolinone) in the ratio of 1:1 by mass,
both formulations maintained lethality rate of >90%
after 48 h.
Keywords Diaryliodonium salt ꢁ Amphiphile ꢁ
Antimicrobial agent ꢁ Kathon CG
J Surfact Deterg (2018).
Introduction
ꢀ
method at 25 C. With their good water solubility, diarylio-
Antimicrobial agents are widely used to prevent and tackle
microbial contamination in the fields of health care
(Rodrigues, Banat, Teixeira, & Oliveira, 2006), cosmetics
(Lundov, Johansen, Zachariae, & Moesby, 2011), textiles
(Simoncic & Tomsic, 2010), etc. Besides the commercially
available formulations triclosan (Mcdonnell & Russell,
1999), 2-methyl-4-isothiazolin-3-one (MIT), and 5-chloro-
2-methyl-4-isothiazolin-3-one (CMIT), quaternary ammo-
nium compounds (QAC) form an efficacious class of
antiseptics (Minbiole et al., 2016). It is well known that
lipopolysaccharides in Gram-negative and lipoteichoic acid
in Gram-positive bacteria contribute to the negatively
charged status of bacterial membranes (Pinazo et al., 2016).
Bearing hydrophobic motifs and hydrophilic regions
together in one molecule, QAC will interact with nega-
tively charged cell membrane of microorganisms via elec-
trostatic force, disrupt the integrity of cell envelope, and
consequently lead to the breakage of cell membrane, leak-
age of cytoplasm, and finally, death of the bacterial cell
(Tischer, Pradel, Ohlsen, & Holzgrabe, 2012). While
donium salts (1–19) have excellent short-term bactericidal
efficacy againstꢀ Bacillus cereus in the concentration of
600 ppm at 20 C. After compounding 1 or 18 with the
Electronic supplementary material The online version of this article
(doi:10.1002/jsde.12038) contains supplementary material, which is
available to authorized users.
* Liming Wang
wanglimin@ecust.edu.cn
1
Key Laboratory for Advanced Materials, Institute of Fine
Chemicals, School of Chemistry and Molecular Engineering, East
China University of Science and Technology, 130 Meilong Road,
Shanghai 200237, China
2
School of Chemistry and Molecular Engineering, East China
University of Science and Technology, 130 Meilong Road,
Shanghai 200237, China
3
Key Laboratory of Organofluorine Chemistry, Shanghai Institute
of Organic Chemistry, The Chinese Academy of Sciences, 345
Lingling Road, Shanghai 200032, China
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analyzing the mode of action, the roles played by a posi-
tively charged head group and a hydrophobic section must
be emphasized. Also, the subtle balance between hydrophi-
licity and lipophilicity plays an important role in determin-
ing the antibacterial ability of antiseptics (Tischer
et al., 2012).
In the field of antimicrobial agents, QAC with various
structures have been developed and thoroughly investigated
(Aiad, Tawfik, El-Shafie, & Rhman, 2017; Massi, Guittard,
Géribaldi, Levy, & Duccini, 2003; Massi, Guittard, Levy, &
Geribaldi, 2009; Negm, Aiad, & Tawfik, 2010; Tawfik,
Abd-Elaal, Shaban, & Roshdy, 2015). However, besides the
positively charged nitrogen atom, other cation-containing anti-
septics remain comparatively obscure. It was suggested that
hypervalent iodonium salts would exhibit a variety of inhibi-
tive actions on cells owing to their inhibition of pyrroloquino-
line quinone, a cofactor occurring in the redox cycle process
(Gallop et al., 1993). In 2004, Goldstein et al. (2004) evaluated
the antimicrobial ability of 11 hypervalent iodonium salts and
found that five of them possessed moderate to good antimicro-
bial efficacy against a set of anaerobic bacterial pathogens.
In this work, with the purpose of enhancing hydrophilic-
ity to significantly lower the amount of organic solvent
needed in the final formulation and better understanding
the structure–activity relationship of iodonium salts as anti-
microbial agents, we introduced a long hydrophilic ether
chain in the molecular design, synthesized 19 diaryliodo-
nium salts bearing different counterions and various substit-
uent groups (electron-donating as well as electron-
withdrawing groups) at different positions, determined their
surface-active properties, and evaluated their antimicrobial
ability under different concentrations when used alone and
when compounded with the efficacious but allergenic pre-
servative Kathon CG (a 3:1 mixture of CMIT and MIT). It
was found that all 19 diaryliodonium salts possess moder-
ate to good tensiometric properties, with 8 in particular
decreasing the surface tension of aqueous solution from
72.3 to 39.35 mN m−1. The critical micelle concentration
(CMC) values of the 19 diaryliodonium salts range from
0.69 to 1.31 mmol L . When applied at 20 C and at the
concentration of 600 ppm (μg mL−1), all diaryliodonium
salts maintained bactericidal rate of >85% within the first
4 h. When 1 and 18 were compounded with Kathon CG,
the mixture maintained excellent antimicrobial ability and
showed the prospect of decreasing the amount of Kathon
CG needed to keep the equivalent antibacterial efficacy.
Iodonium salts synthesized by Goldstein et al. (2004)
exhibited great antimicrobial efficacy with minimum inhibi-
tion concentration values between 128 and >512 μg mL−1
when applied to different bacterial strains. The diaryliodo-
nium salts synthesized in this work showed the same level
of antiseptic ability, keeping the lethality rate R above 50%
at the concentration of 400 μg mL−1 after 24 h of cultivation
(see Supporting Information). Massi et al. (2003) introduced
fluorine onto the QAC and synthesized seven fluorinated
bis-ammonium salts to be used as disinfectants. Fluorinated
diaryliodonium salts designed in this work showed equiva-
lent antiseptic efficacy. To sum up, the methodology of
adopting new cations instead of the positively charged
Diaryliodonium salts have received unprecedented atten-
tion in the field of organic synthesis in the last 30 years.
Their structure includes two aryl moieties linked together by
an iodine atom and its associated counterion. Based on X-ray
findings, the iodine and two ligands share a hypervalent
bond, leading to a T-shaped structure of the molecule. Since
it is highly electron-deficient in the iodine region, diaryliodo-
nium salts attract nucleophiles and serve very well as arylat-
ing agents in a variety of synthetic reactions (Zhdankin &
Stang, 2008). The structure of diaryliodonium salts in solu-
tion is still being debated (Merritt & Olofsson, 2009), and
there is spectroscopic evidence contributed by Richter,
Cherry, Zook, and Koser (1997) that the widely adopted
Koser’s reagent hydroxyl(tosyloxy)iodobenzene (PhI(OH)
OT) would ionize completely into the hydroxy(phenyl)iodo-
nium ion (PhI+OH) and sulfonate ions in aqueous solution.
The synthesis of diaryliodonium salts requires, first, the
oxidation of aryl iodide under acidic conditions to the
aryliodine(III) compound and, subsequently, ligand
exchange with corresponding arenes under acidic or neutral
conditions (Merritt & Olofsson, 2009). Various synthetic
routes have been developed. Koser et al. first introduced
PhI(OH)OT, also called Koser’s reagent, as a versatile
aryliodine(III) intermediate and obtained a set of diarylio-
donium salts derived from it (Carman & Koser, 1983;
Koser, Wettach, & Smith, 1980). In 1992, Kitamura, Mat-
suyuki, Nagata, Furuki, and Taniguchi (1992) found a more
efficient acid, trifluoromethanesulfonic acid (TfOH), to
replace the conventional inorganic oxidizing agents. In
2010, Dohi, Yamaoka, and Kita (2010) found fluoroalco-
hols such as 2,2,2-trifluoroethanol and 1,1,1,3,3,3-
hexafluoroisopropanol to be more suitable solvents in the
ligand-exchange step. With the purpose of simplifying the
synthetic processes, direct one-pot syntheses have always
been of research interest. Recently, starting with aryl
iodides and arenes, Hossain Delwar and Kitamura (2006)
used potassium persulfate as oxidant plus trifluoroacetic
acid (TFA) as acidic agent in one pot and obtained diarylio-
donium triflates after a simple work-up. In 2007, Bielawski
et al. from Berit Olofsson’s research group introduced an
organic oxidant meta-chloroperoxybenzoic acid (mCPBA)
to replace the commonly adopted inorganic oxidant.
Together with 2–3 equiv. of TfOH in dichloromethane
(DCM), diaryliodonium triflates of various electronic prop-
erties could be synthesized directly from the corresponding
aryl iodides and arenes with easily applicable purification
procedures (Bielawski, Zhu, & Olofsson, 2007).
−1
ꢀ
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Scheme 1 Route A for the synthesis of (4-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)phenyl)(substituted phenyl)-λ3-iodane with the anion OT (1–7)
nitrogen atom may provide another train of thought when
designing the next generation of antiseptics.
Precision & Scientific Instrument Co. Ltd., Shanghai,
China). All data presented were uncorrected. The high-
resolution mass spectrometry (HRMS) spectra were mea-
sured on a Micromass GTC (Waters Technologies [Shang-
hai] Co., Ltd., Shanghai, China) spectrometer. Compounds
8–16 were purified via column chromatography on silica gel
(200–400 mesh) eluted with a mixture of DCM/methanol
(20:1, vol.).
Experimental
Materials and Characterization Methods
All reagents and solvents were of analytical grade and were
purchased commercially. All solvents were pretreated with
distillation and purification before use. The 1H NMR
(400 MHz, tetramethylsilane [TMS]) and 13C NMR
(100 MHz, TMS) spectra were obtained using a Bruker
AM-500 spectrometer with the J-values being listed in hertz.
Organic Synthesis
Route A for the Synthesis of (4-(2-(2-(2-Methoxyethoxy)
ethoxy)ethoxy)phenyl)(substituted phenyl)-λ3-iodane with
the Anion 4-Methylbenzenesulfonate (OT) (1–7)
Only the characteristic signals observed in 1H NMR and 13
C
NMR are reported. Melting point values were measured
using an SGW X-4 melting point apparatus (Shanghai
Route A involving three steps for the synthesis of unsym-
metrical diaryl-λ3-iodane was reported by Matsuzaki,
Fig. 1 Chemical structures of (4-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)phenyl)(substituted phenyl)-λ3-iodane with the anion OT (1–7)
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Okuyama, Tokunaga, Shiro, and Shibata (2014) in 2014
and adopted with minor modifications for this study. The
overall route is shown in Scheme 1 and the obtained
compounds are listed in Fig. 1. Briefly, in a 50-mL
round-bottomed flask was added 5 mL of DCM, substituted
iodobenzene (5 mmol), oxone 4.61 g (7.5 mmol), and TFA
15 mL (200 mmol). The mixture was stirred at room tem-
perature for 4 h. After the completion of the reaction, the
mixture was filtered and concentrated under reduced pres-
sure to remove the solvents and obtain the intermediate
compounds a1. Then, 20 mL of acetonitrile and 1.14 g
(6 mmol) of 4-methylbenzenesulfonic acid hydrate were
added to the 50-mL round-bottomed flask containing the
intermediate compounds a1. After 1 h of reaction at room
temperature, a white precipitate was observed, which was
filtered and dissolved in 20 mL of 2,2,2-trifluoroethan-1-ol
before adding (2-(2-(2-methoxyethoxy)ethoxy)ethoxy)ben-
zene 1.31 mL (6 mmol) into the mixture. This was fol-
lowed by stirring and reacting overnight at room
temperature. After the reaction was complete, the solvent
was removed via reduced-pressure distillation and the tar-
get product was purified by recrystallization from diethyl
ether.
(4-(2-(2-(2-Methoxyethoxy)ethoxy)ethoxy)phenyl)(1,2,3,4,5-
pentafluorophenyl)-λ3-iodane with the anion OT (1): Brown
solid, yield 85%, m.p. 167.6–167.8 ꢀC, 1H NMR (400 MHz,
DMSO [Dimethylsulfoxide]) δ 8.18 (d, J = 9.0 Hz, 2H),
7.46 (d, J = 8.1 Hz, 2H), 7.13–7.10 (m, 2H), 7.10–7.08 (m,
2H), 4.15 (t, J = 4.8 Hz, 2H), 3.76–3.71 (m, 3H), 3.58–3.54
(m, 3H), 3.53–3.50 (m, 2H), 3.50–3.47 (m, 2H), 3.42–3.38
(m, 3H), 2.29 (s, 3H); 13C NMR (100 MHz, DMSO) δ
161.5, 145.0, 138.0, 137.6, 128.1, 125.4, 118.2, 106.5, 71.2,
69.9, 69.7, 69.5, 68.6, 67.8, 58.0, 20.7; HRMS (Electrospray
Ionization-Time of Flight [ESI-TOF]) m/z: [M + K]+ Calcd
for C26H26F5IKO7S 743.0001; Found: 742.9992.
2H), 7.39–7.33 (m, 1H), 7.15–7.05 (m, 4H), 4.16–4.11 (m,
2H), 3.80 (s, 3H), 3.74–3.70 (m, 2H), 3.57–3.53 (m, 2H),
3.52–3.49 (m, 2H), 3.49–3.46 (m, 2H), 3.41–3.37 (m, 2H),
2.29 (s, 3H); 13C NMR (100 MHz, DMSO) δ 161.3, 157.8,
145.5, 137.7, 137.2, 136.9, 135.3, 128.0, 127.5, 125.5,
118.0, 116.9, 116.7, 105.7, 71.2, 69.9, 69.7, 69.5, 68.6,
67.7, 58.0, 20.8; HRMS (ESI-TOF) m/z: [M + H]+ Calcd
for C26H31FIO7S 633.0819; Found: 633.0817.
(4-(2-(2-(2-Methoxyethoxy)ethoxy)ethoxy)phenyl)(2,4-
difluorophenyl)-λ3-iodane with the anion OT (4): Brown
solid, yield 80%, m.p. 112.3–114.8 ꢀC, 1H NMR
(400 MHz, DMSO) δ 8.49–8.43 (m, 1H), 8.12 (d,
J = 8.8 Hz, 2H), 7.49–7.47 (m, 3H), 7.13–7.11 (m, 3H),
7.07 (d, J = 9.2 Hz, 2H), 4.15–4.12 (m, 2H), 3.72 (t,
J = 8.8 Hz, 2H), 3.57–3.54 (m, 2H), 3.51–3.50 (m, 2H),
3.49–3.48 (m, 2H), 3.41–3.39 (m, 2H), 3.21 (s, 3H), 2.29
(s, 3H); 13C NMR (100 MHz, DMSO) δ 166.2, 161.2,
159.0, 145.4, 138.4, 137.8, 137.1, 128.1, 125.5, 117.9,
115.1, 114.9, 106.2, 105.7, 71.2, 69.9, 69.7, 69.5, 68.6,
67.7, 58.0, 20.8; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd
for C26H29F2INaO7S 673.0544; Found: 673.0539.
(4-(2-(2-(2-Methoxyethoxy)ethoxy)ethoxy)phenyl)(3-fluor-
ophenyl)-λ3-iodane with the anion OT (5): Wine-red liquid,
yield 65%, 1H NMR (400 MHz, DMSO) δ 8.24 (dt,
J = 8.0 Hz, J = 2.0 Hz, 1H), 8.18 (d, J = 9.0 Hz, 2H), 8.04
(d, J = 7.9 Hz, 1H), 7.63–7.45 (m, 4H), 7.14–7.08 (m, 4H),
4.17–4.12 (m, 2H), 3.87 (s, 3H), 3.75–3.70 (m, 2H),
3.58–3.54 (m, 2H), 3.52–3.50 (m, 2H), 3.50–3.47 (m, 2H),
3.42–3.38 (m, 2H), 2.29 (s, 3H); 13C NMR (100 MHz,
DMSO) δ 161.9, 159.2, 141.3, 138.7, 134.2, 130.8, 130.3,
127.8, 122.0, 115.0, 114.4, 112.2, 71.2, 69.9, 69.7, 69.5,
68.6, 67.7, 58.0, 20.7; HRMS (ESI-TOF) m/z: [M + Na]+
Calcd for C26H30FINaO7S 655.0639; Found: 655.0635.
(4-(2-(2-(2-Methoxyethoxy)ethoxy)ethoxy)phenyl)(4-(tri-
fluoromethoxy)phenyl)-λ3-iodane with the anion OT (6):
1
ꢀ
(4-(2-(2-(2-Methoxyethoxy)ethoxy)ethoxy)phenyl)(4-(tri-
Brown solid, yield 76%, m.p. 190.1–194.3 C, H NMR
(400 MHz, DMSO) δ 8.32 (d, J = 9.2 Hz, 2H), 8.19 (d,
J = 9.0 Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H), 7.48 (d,
J = 8.0 Hz, 2H), 7.14–7.08 (m, 4H), 4.17–4.12 (m, 2H),
3.75–3.71 (m, 2H), 3.58–3.54 (m, 2H), 3.52–3.50 (m, 2H),
3.50–3.47 (m, 2H), 3.42–3.38 (m, 2H), 3.21 (s, 3H), 2.29
(s, 3H); 13C NMR (100 MHz, DMSO) δ 161.3, 150.4,
145.4, 137.7, 137.3, 137.2, 128.0, 125.5, 123.9, 121.1,
118.5, 117.9, 114.8, 105.8, 71.2, 69.9, 69.7, 69.5, 68.6,
67.7, 58.0, 20.7; HRMS (ESI-TOF) m/z: [M + H]+ Calcd
for C27H31F3IO8S 699.0736; Found: 699.0742.
fluoromethyl)phenyl)-λ3-iodane with the anion OT (2): A
1
wine-red liquid, yield, 60%, H NMR (400 MHz, DMSO)
δ 8.39 (d, J = 8.3 Hz, 2H), 8.21 (d, J = 9.0 Hz, 2H), 7.91
(d, J = 8.5 Hz, 2H), 7.47 (d, J = 8.0 Hz, 2H), 7.11 (d,
J = 8.9 Hz, 4H), 4.15 (t, J = 4.0 Hz, 2H), 3.75–3.71 (m,
2H), 3.58–3.54 (m, 2H), 3.52–3.49 (m, 2H), 3.49–3.47 (m,
2H), 3.42–3.38 (m, 2H), 3.21 (s, 3H), 2.29 (s, 3H); 13C
NMR (100 MHz, DMSO) δ 166.7, 151.2, 151.0, 142.8,
142.7, 140.8, 133.4, 133.2, 130.7, 127.6, 123.2, 110.8,
104.0, 76.5, 75.1, 75.0, 74.8, 73.8, 73.0, 63.2, 26.0; HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C27H31F3IO7S
683.0787; Found: 683.0790.
(4-(2-(2-(2-Methoxyethoxy)ethoxy)ethoxy)phenyl)(2-fluor-
ophenyl)-λ3-iodane with the anion OT (3): Brown solid,
yield 77%, m.p. 68.9–70.1 ꢀC, 1H NMR (400 MHz,
DMSO) δ 8.41–8.35 (m, 1H), 8.13 (d, J = 9.0 Hz, 2H),
7.74–7.68 (m, 1H), 7.59–7.53 (m, 1H), 7.47 (d, J = 8.0 Hz,
(4-(2-(2-(2-Methoxyethoxy)ethoxy)ethoxy)phenyl)(4-fluor-
ophenyl)-λ3-iodane with the anion OT (7): Yield of 64%, as
1
ꢀ
a brown solid, m.p. 120.3–122.4 C, H NMR (400 MHz,
DMSO) δ 8.30–8.25 (m, 2H), 8.16 (d, J = 9.2 Hz, 2H), 7.47
(d, J = 8.1 Hz, 2H), 7.40 (t, J = 8.8 Hz, 2H), 7.42–7.36 (m,
4H), 4.16–4.12 (m, 2H), 3.74–3.71 (m, 2H), 3.58–3.54 (m,
2H), 3.52–3.50 (m, 2H), 3.50–3.47 (m, 2H), 3.42–3.38 (m,
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Scheme 2 Route B for the synthesis of (4-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)phenyl)(substituted phenyl)-λ3-iodane with the anion OTf
(8–16)
3H), 2.29 (s, 3H); 13C NMR (100 MHz, DMSO) δ 162.5,
161.2, 145.7, 137.7, 137.6, 137.1, 128.0, 125.5, 119.1, 118.9,
117.8, 111.2, 71.2, 69.9, 69.7, 69.5, 68.6, 67.7, 58.0, 20.7;
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C26H31FIO7S
633.0819; Found: 633.0813.
trifluoromethanesulfonic acid 0.75 mL (8.5 mmol) was
added dropwise into the system. The resulting solution was
stirred at room temperature for 2 h. The crude product was
purified by column chromatography on silica gel eluted
with a mixture of DCM:methanol (20:1, vol.) to yield the
desired products.
(4-(2-(2-(2-Methoxyethoxy)ethoxy)ethoxy)phenyl)(1,2,3,4,5-
pentafluorophenyl)-λ3-iodane with the anion OTf (8): Wine-
red liquid, yield 60%, H NMR (400 MHz, DMSO) δ 8.18
Route B for the Synthesis of (4-(2-(2-(2-Methoxyethoxy)
ethoxy)ethoxy)phenyl)(substituted phenyl)-λ3-iodane with
the Anion Trifluoromethanesulfonate (OTf ) (8–16)
1
(d, J = 9.0 Hz, 2H), 7.11 (d, J = 9.1 Hz, 2H), 4.18–4.14 (m,
2H), 3.76–3.71 (m, 2H), 3.58–3.54 (m, 2H), 3.53–3.50 (m,
2H), 3.50–3.48 (m, 2H), 3.43–3.39 (m, 2H), 3.22 (s, 3H);
13C NMR (100 MHz, DMSO) δ 161.6, 137.6, 125.4, 122.2,
119.0, 118.2, 115.7, 106.4, 71.2, 69.8, 69.7, 69.5, 68.5,
67.8, 57.9, 48.5; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C20H20F8IO7S 682.9847; Found: 682.9843.
An efficacious one-pot synthesis method reported by Bie-
lawski et al. (2007) was adopted with minor modifications
in this section. The overall route is shown in Scheme 2, and
the obtained compounds listed in Fig. 2. Briefly, to a 50-
mL round-bottomed flask was added substituted iodoben-
zene (5 mmol), 20 mL of DCM, and mCPBA 1.22 g
(6 mmol, 85% purity), followed by the slow addition of
(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)benzene 1.31 mL
(4-(2-(2-(2-Methoxyethoxy)ethoxy)ethoxy)phenyl)(phenyl)-
λ3-iodane with the anion OTf (9): Wine-red liquid, yield
1
79%, H NMR (400 MHz, DMSO) δ 8.21–8.15 (m, 4H),
(6 mmol). After cooling the mixture to
0
ꢀC,
7.68–7.62 (m, 1H), 7.55–7.49 (m, 2H), 7.09 (d, J = 9.0 Hz,
Fig. 2 Chemical structures of (4-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)phenyl)(substituted phenyl)-λ3-iodane with the anion OTf (8–16)
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2H), 4.17–4.12 (m, 2H), 3.75–3.71 (m, 2H), 3.58–3.54 (m,
2H), 3.53–3.50 (m, 2H), 3.50–3.47 (m, 2H), 3.42–3.38 (m,
2H), 3.21 (s, 3H); 13C NMR (100 MHz, DMSO) δ 161.2,
137.1, 134.7, 131.8, 131.5, 122.1, 118.9, 117.8, 116.7, 71.1,
69.8, 69.6, 69.4, 68.5, 67.6, 57.8, 48.5; HRMS (ESI-TOF)
m/z: [M + H]+ Calcd for C20H25F3IO7S 593.0318; Found:
593.0314.
(ESI-TOF) m/z: [M + H]+ Calcd for C20H23Cl2F3IO7S
660.9538; Found: 660.9545.
(4-(2-(2-(2-Methoxyethoxy)ethoxy)ethoxy)phenyl)(3-nitro-
phenyl)-λ3-iodane with the anion of OTf (14): Wine-red liq-
1
uid, yield 73%, H NMR (400 MHz, DMSO) δ 9.12 (t,
J = 1.9 Hz, 1H), 8.58 (d, J = 8.0 Hz, 1H), 8.44 (dd, J = 8.0,
1.6 Hz, 1H), 8.24 (d, J = 8.8 Hz, 2H), 7.80 (t, J = 8.1 Hz,
1H), 7.12 (d, J = 8.8 Hz, 2H), 4.17–4.13 (m, 2H), 3.75–3.71
(m, 2H), 3.58–3.54 (m, 2H), 3.52–3.49 (m, 2H), 3.49–3.47
(m, 2H), 3.42–3.39 (m, 2H), 3.21 (s, 3H); 13C NMR
(100 MHz, DMSO) δ 161.4, 148.3, 140.7, 137.4, 132.6,
129.4, 126.5, 118.0, 117.0, 106.0, 71.2, 69.9, 69.7, 69.5,
68.6, 67.7, 58.0; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C20H24F3INO9S 638.0169; Found: 638.0165.
(4-(2-(2-(2-Methoxyethoxy)ethoxy)ethoxy)phenyl)(o-tolyl)-
λ3-iodane with the anion OTf (10): Wine-red liquid, yield
1
72%, H NMR (400 MHz, DMSO) δ 8.36 (d, J = 7.8 Hz,
1H), 8.13 (d, J = 9.0 Hz, 2H), 7.59–7.53 (m, 2H), 7.33–7.27
(m, 1H), 7.09–7.05 (m, 2H), 4.15–4.11 (m, 2H), 3.74–3.70
(m, 2H), 3.57–3.53 (m, 2H), 3.52–3.50 (m, 2H), 3.49–3.47
(m, 2H), 3.42–3.40 (m, 2H), 3.21 (s, 3H), 2.61 (s, 3H); 13C
NMR (100 MHz, DMSO) δ 161.1, 140.3, 137.0, 136.8,
132.6, 131.3, 129.2, 121.9, 119.0, 117.9, 104.8, 71.2, 69.9,
69.7, 69.5, 68.6, 67.7, 58.0, 24.9; HRMS (ESI-TOF) m/z:
[M + H]+ Calcd for C21H27F3IO7S 607.0474; Found:
607.0478.
(4-(2-(2-(2-Methoxyethoxy)ethoxy)ethoxy)phenyl)(2-meth-
oxyphenyl)-λ3-iodane with the anion OTf (15): Wine-red liq-
1
uid, yield 61%, H NMR (400 MHz, DMSO) δ 8.25 (dd,
J = 8.0, 1.2 Hz, 1H), 8.03 (d, J = 9.2 Hz, 2H), 7.67–7.61 (m,
1H), 7.29 (dd, J = 8.4, 0.9 Hz, 1H), 7.10–7.05 (m, 3H),
4.15–4.11 (m, 2H), 3.94 (s, 3H), 3.74–3.70 (m, 2H),
3.57–3.53 (m, 2H), 3.52–3.49 (m, 2H), 3.49–3.46 (m, 2H),
3.42–3.39 (m, 2H), 3.21 (s, 3H); 13C NMR (100 MHz,
DMSO) δ 161.0, 156.3, 137.1, 136.9, 134.7, 123.3, 117.7,
112.9, 107.0, 104.7, 71.2, 69.9, 69.7, 69.5, 68.6, 67.6, 58.0,
57.0; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C21H27F3IO8S 623.0423; Found: 623.0429.
(4-(2-(2-(2-Methoxyethoxy)ethoxy)ethoxy)phenyl)(p-tolyl)-
λ3-iodane with the anion OTf (11): Wine-red liquid, yield
1
75%, H NMR (400 MHz, DMSO) δ 8.13 (d, J = 9.0 Hz,
2H), 8.07 (d, J = 8.3 Hz, 2H), 7.32 (d, J = 8.3 Hz, 2H), 7.08
(d, J = 9.1 Hz, 2H), 4.26–4.22 (m, 2H), 3.74–3.71 (m, 2H),
3.58–3.54 (m, 2H), 3.53–3.50 (m, 2H), 3.50–3.47 (m, 2H),
3.42–3.39 (m, 2H), 3.21 (s, 3H), 2.34 (s, 3H); 13C NMR
(100 MHz, DMSO) δ 161.1, 142.3, 137.0, 134.8, 132.2,
122.2, 117.8, 113.3, 105.6, 71.2, 69.9, 69.7, 69.5, 68.6,
67.7, 58.0, 20.8; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C21H27F3IO7S 607.0474; Found: 607.0478.
(4-(2-(2-(2-Methoxyethoxy)ethoxy)ethoxy)phenyl)(4-meth-
oxyphenyl)-λ3-iodane with the anion OTf (16): Wine-red liq-
1
uid, yield 65%, H NMR (400 MHz, DMSO) δ 8.14–8.09
(m, 4H), 7.09–7.04 (m, 4H), 4.16–4.11 (m, 2H), 3.79 (s, 3H),
3.74–3.70 (m, 2H), 3.57–3.54 (m, 2H), 3.52–3.49 (m, 2H),
3.49–3.46 (m, 2H), 3.42–3.39 (m, 2H), 3.21 (s, 3H); 13C
NMR (100 MHz, DMSO) δ 161.8, 161.1, 136.8, 122.2,
119.0, 117.7, 117.2, 115.8, 71.2, 69.8, 69.7, 69.5, 68.5, 67.6,
57.9, 55.6; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C21H27F3IO8S 623.0423; Found: 623.0430.
(4-(2-(2-(2-Methoxyethoxy)ethoxy)ethoxy)phenyl)(m-tolyl)-
λ3-iodane with the anion OTf (12): Wine-red liquid, yield
1
64%, H NMR (400 MHz, DMSO) δ 8.14 (d, J = 9.0 Hz,
2H), 8.06 (s, 1H), 7.99 (d, J = 7.9 Hz, 1H), 7.47 (d,
J = 7.6 Hz, 1H), 7.40 (t, J = 7.8 Hz, 1H), 7.09 (d,
J = 9.1 Hz, 1H), 4.16–4.12 (m, 2H), 3.75–3.71 (m, 2H),
3.57–3.54 (m, 2H), 3.52–3.49 (m, 2H), 3.49–3.47 (m, 2H),
3.42–3.38 (m, 2H), 3.21 (s, 3H), 2.33 (s, 3H); 13C NMR
(100 MHz, DMSO) δ 161.2, 141.6, 137.1, 134.9, 133.4,
132.5, 131.8, 131.3, 117.8, 116.8, 105.3, 71.2, 69.9, 69.7,
69.5, 68.6, 67.7, 58.0, 20.7; HRMS (ESI-TOF) m/z:
[M + H]+ Calcd for C21H27F3IO7S 607.0474; Found:
607.0477.
(4-(2-(2-(2-Methoxyethoxy)ethoxy)ethoxy)phenyl)(3,4-
dichlorophenyl)-λ3-iodane with the anion OTf (13): Wine-
red liquid, yield 78%, 1H NMR (400 MHz, DMSO) δ
8.61 (d, J = 2.0 Hz, 1H), 8.22–8.17 (m, 3H), 7.82 (d,
J = 8.6 Hz, 1H), 7.12 (d, J = 9.1 Hz, 2H), 4.18–4.13 (m,
2H), 3.75–3.72 (m, 2H), 3.58–3.55 (m, 2H), 3.53–3.50
(m, 2H), 3.50–3.47 (m, 2H), 3.42–3.38 (m, 2H), 3.21 (s,
3H); 13C NMR (100 MHz, DMSO) δ 161.4, 137.6, 137.3,
136.0, 135.4, 134.8, 133.3, 133.2, 118.0, 115.0, 105.9,
71.2, 69.9, 69.7, 69.5, 68.6, 67.7, 57.0, 54.9; HRMS
Route C for the Synthesis of (4-(2-(2-(2-Methoxyethoxy)
ethoxy)ethoxy)phenyl)(substituted phenyl)-λ3-iodane with
the Anion OT (17–19)
The overall synthetic route is shown in Scheme 3, and the
obtained compounds are shown in Fig. 3. In analogy to the
method of Petersen, Khan, and Olofsson (2011), to a solu-
tion of substituted iodobenzene (5 mmol) in 20 mL DCM
1.22 g (6 mmol, 85% purity) of mCPBA and 1.14 g
(6 mmol) 4-methylbenzenesulfonic acid hydrate were
ꢀ
added. The resulting solution was stirred at 60 C for 2 h
before removing the solvent under reduced pressure. After
adding 10 mL of diethyl ether, the resulting suspension was
cooled to 0 ꢀC, filtered, and washed with diethyl ether
thrice to obtain the intermediate product c1, which was then
dissolved in 20 mL of a solvent mixture composed of
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2H), 7.14–7.07 (m, 4H), 4.18–4.12 (m, 2H), 3.76–3.71 (m,
2H), 3.59–3.55 (m, 2H), 3.54–3.51 (m, 2H), 3.51–3.48 (m,
2H), 3.42–3.39 (m, 2H), 3.22 (s, 3H), 2.29 (s, 3H); 13C
NMR (100 MHz, DMSO) δ 161.4, 149.2, 145.6, 137.6,
135.9, 128.0, 126.0, 125.5, 123.2, 118.0, 105.7, 71.2, 69.9,
69.7, 69.5, 68.6, 67.7, 58.0, 20.7; HRMS (ESI-TOF) m/z:
[M + Na]+ Calcd for C26H30INaNO9S 682.0584; Found:
682.0581.
(4-(2-(2-(2-Methoxyethoxy)ethoxy)ethoxy)phenyl)(4-bro-
mophenyl)-λ3-iodane with the anion OT (19): White solid,
yield 80%, m.p. 53.1–56.4 ꢀC, 1H NMR (400 MHz,
DMSO) δ 8.20–8.12 (m, 4H), 7.69 (d, J = 8.6 Hz, 2H), 7.50
(d, J = 8.0 Hz, 2H), 7.12 (d, J = 7.9 Hz, 2H), 7.07 (d,
J = 9.1 Hz, 2H), 4.16–4.12 (m, 2H), 3.75–3.71 (m, 2H),
3.59–3.54 (m, 2H), 3.53–3.50 (m, 2H), 3.50–3.48 (m, 2H),
3.42–3.39 (m, 2H), 3.21 (s, 3H), 2.29 (s, 3H); 13C NMR
(100 MHz, DMSO) δ 161.2, 145.4, 137.8, 137.3, 136.8,
134.4, 128.1, 125.8, 125.5, 117.8, 115.6, 105.7, 71.2, 69.9,
69.7, 69.6, 68.6, 67.7, 58.0, 20.8; HRMS (ESI-TOF) m/z:
[M + H]+ Calcd for C26H31BrIO7S 693.0019; Found:
693.0015.
Scheme 3 Route C for the synthesis of (4-(2-(2-(2-methoxyethoxy)
ethoxy)ethoxy)phenyl)(substituted phenyl)-λ3-iodane with the anion
OT (17–19)
DCM and 2,2,2-trifluoroethan-1-ol (1:1, vol.) and added
into 1.31 mL (6 mmol) of (2-(2-(2-methoxyethoxy)ethoxy)
ethoxy)benzene. The resulting solution was stirred at room
temperature overnight. After the completion of the reaction,
the solvent was removed under reduced pressure. After
adding 10 mL of diethyl ether, the resulting suspension was
cooled to 0 ꢀC and subjected to rotary evaporation again to
remove the remaining solvent. The crude products were
washed with diethyl ether three times to obtain the target
compounds.
Surface Tension Measurements
(4-(2-(2-(2-Methoxyethoxy)ethoxy)ethoxy)phenyl)(3,4-
dichlorophenyl)-λ3-iodane with the anion OT (17): Yel-
low solid, yield 74%, m.p. 51.6–52.1 ꢀC, 1H NMR
(400 MHz, DMSO) δ 8.60 (d, J = 2.0 Hz, 1H), 8.21–8.16
(m, 3H), 7.81 (d, J = 8.6 Hz, 1H), 7.47 (d, J = 8.1 Hz,
2H), 7.11 (d, J = 8.8 Hz, 4H), 4.17–4.13 (m, 2H),
3.75–3.71 (m, 2H), 3.58–3.54 (m, 2H), 3.53–3.50 (m,
2H), 3.50–3.47 (m, 2H), 3.42–3.39 (m, 2H), 3.21 (s, 3H),
2.29 (s, 3H); 13C NMR (100 MHz, DMSO) δ 161.4,
137.6, 137.3, 136.0, 135.4, 134.8, 133.2, 133.1, 128.0,
125.4, 118.0, 115.1, 106.0, 71.2, 69.9, 69.7, 69.5, 68.6,
67.7, 58.0, 20.7; HRMS (ESI-TOF) m/z: [M + H]+ Calcd
for C26H30Cl2IO7S 683.0134; Found: 683.0125.
The surface tension values of the 19 diaryliodonium salt
solutions were measured on an automatic tensiometer
(JK99B; Shanghai Zhongchen Digiꢀtal Technic Apparatus
Co., Ltd., Shanghai, China) at 25 C based on the Wil-
helmy plate method. The surface tension values of each
concentration were measured at least three times, and the
average values as well as standard deviation data are
shown in Figs. 4–7. To obtain the CMC values of the 19
diaryliodonium salts, graphs of surface tension values ver-
sus the log c values (where c is the concentration of the
diaryliodonium salts in aqueous solutions) were con-
structed. The CMC value was located at the cross point of
the two simulated linear sections of each plot (Ahmad,
Patial, Kaur, & Kaur, 2014). The CMC values and the sur-
face tension at the CMC (γCMC) are summarized in
Table 1.
(4-(2-(2-(2-Methoxyethoxy)ethoxy)ethoxy)phenyl)(4-nitro-
phenyl)-λ3-iodane with the anion OT (18): Yellow solid,
1
ꢀ
yield 83%, m.p. 113–116 C, H NMR (400 MHz, DMSO)
δ 8.49–8.44 (m, 2H), 8.28–8.22 (m, 4H), 7.51 (d, J = 8.1 Hz,
Fig. 3 Chemical structures of (4-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)phenyl)(substituted phenyl)-λ3-iodane with the anion OT (17–19)
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Fig. 4 Surface tension isotherms for compounds 1–5 (diaryliodonium
Fig. 6 Surface tension isotherms for compounds 8–12 (diaryliodo-
salts with the OT anion) at 25 ꢀC
nium salts with the OTf anion) at 25 ꢀC
Antimicrobial Activity
of the mixture was determined by B. cereus test tablets
(Tianhe Lvzhou Biochemistry Research Center, Guang-
zhou, China), which was used as the control and defined as
c0. Twenty milliliters of the mixture was subpackaged into
50-mL blue-capped bottles, which were divided into four
groups and cuꢀltivated under the ꢀfollowing conditions:
In this study, Bacillus cereus ATCC 14579 was used for
antimicrobial tests and the lysogeny broth (LB) medium
containing tryptone (10 g L−1), yeast extract (5 g L−1), and
NaCl (10 g L−1) was used for the cultivation of the strain.
The stock cell suspension was first inoculated into 4 mL
ꢀ
400 ppm at 30 C, 600 ppm at 10 C, 600 ppm at 20 C,
ꢀ
ꢀ
LB medium in test tubes, and was cultivated at 37 C and
and 400 ppm at 20 C. During the cultivation, 1 mL of the
220 rpm. After overnight cultivation, 1 mL of the cell cul-
ture was inoculated into 100 mL LB medium in 250-mL
Erlenmeyer flasks, which was then cultivated at 37 C and
220 rpm until optical density (OD)600 ≈ 3. The entire cul-
ture was then poured into 800 mL LB medium in 2-L flasks
and then cultivated until OD600 ≈ 5. Cell cultures from two
2-L flasks were then harvested and mixed uniformly for
antimicrobial tests. The colony forming unit (CFU) value
culture was sampled at different time intervals and their
CFU values were determined, which were defined as c1.
The lethality rate R was calculated based on Eq. (1) to eval-
uate the antimicrobial activity of the compounds:
ꢀ
C0 −C1
R =
× 100%
ð1Þ
C0
Fig. 7 Surface tension isotherms for compounds 13–16 (diaryliodo-
Fig. 5 Surface tension isotherms for compounds 6, 7, and 17–19 (dia-
nium salts with the OTf anion) at 25 ꢀC
ryliodonium salts with the OT anion) at 25 ꢀC
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deionized water, ethanol, methanol, and DCM, while they
were poor in low-polarity solvents including ethyl acetate,
acetone, and acetonitrile. To further evaluate the stability of
the aqueous solution at different temperatures, 19 translu-
cent aqueous solutions containing 5% (mass) diaryliodo-
ꢀ
nium salt were stored at 10, 20, and 30 C for 2 days. No
precipitates were observed, indicating excellent solubility
and stability in aqueous solutions.
The surface tension of aqueous solutions containing dif-
ferent diaryliodonium salts was measured by adopting the
Wilhelmy plate method. Based on the measured tensiomet-
ric data, it could be inferred that all 19 diaryliodonium salts
exhibited surface activity including surface tension lower-
ing and micelle formation. As illustrated in Figs. 4–7, the
surface tension of the tested media decreased almost line-
arly with the gradual increase of the concentration of the
compound before reaching a plateau where further increase
in concentration stopped to significantly lower the surface
tension. To obtain the CMC values, we simulated two
straight lines in the high- and low-concentration regions via
a linear least-squares analysis using Origin Pro 8 software
(OriginLab Corporation, Northampton, MA, US). The
crossing point of the two fitted lines gave the CMC and the
surface tension at CMC (γCMC); the results are shown in
Table 1.
Fig. 8 The lethality rate (R) of 0.2% (mass) Kathon, and 0.1% Kathon
compounded with 0.1% compound 1 or compound 18 at 20 ꢀC
The lethality rates (R) under the testing condition of
600 ppm at 20 ꢀC are given in Table 2.
Kathon CG, a 3:1 mixture of CMIT and MIT, is a widely
used broad-spectrum preservative in cosmetics and related
industries. Although it is an excellent antibacterial agent, it
may trigger allergic reactions on the skin and induce resis-
tance of the treated microorganism. Therefore, there is an
urgent need to develop other types of antimicrobial agents
that can be compounded with Kathon CG to reduce the
amount of use while maintaining decent antiseptic activity.
In order to evaluate the efficacy of a formulation composed
of 0.1% (mass) Kathon CG and 0.1% the corresponding
diaryliodonium salts, antimicrobial tests described above
were conducted, the results of which are listed in Fig. 8.
The chemical structure of diaryliodonium salts is differ-
ent from that of the traditional QAC whose central nitrogen
atom is substituted by one long alkyl chain (cetylpyridi-
nium chloride) or two long hydrophobic chains
Table 1 CMC and γCMC (surface tension value at CMC) of 19 diary-
liodonium salts
Compound
CMC (mmol L−1
)
γCMC (mN m−1
)
Results and Discussion
1
0.69
0.95
0.91
1.15
1.30
1.31
1.07
1.30
1.67
0.85
1.11
1.21
1.57
1.12
1.12
1.32
0.91
1.12
1.07
54.52
54.50
59.66
60.01
65.17
60.25
56.77
39.35
51.03
51.23
52.56
54.20
54.82
55.00
55.34
47.60
60.43
55.43
51.50
2
We have used three synthetic routes to obtain 19 diaryliodo-
nium salts, and all of them gave high yield, ideal purity, and
easy handling (Bielawski et al., 2007; Matsuzaki et al.,
2014; Petersen et al., 2011). To address the poor water solu-
bility issue of the fluorinated diaryliodonium salts (Goldstein
et al., 2004), a long ether chain containing three ethoxy
groups was added to one of the benzene rings of the scaf-
fold. The purity of the 19 diaryliodonium salts was roughly
determined by the experimental phenomenon that only one
spot was observed on thin layer chromatography (TLC)
measurements when using various developing solvents. This
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
1
was further verified by H NMR (400 MHz, TMS), 13C
NMR (100 MHz, TMS), and HRMS spectral results.
Tensiometric Properties
After the addition of a long ether chain, all 19 diaryliodo-
nium salts dissolved well in high-polarity solvents such as
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Table 2 Lethality rate (R) of 19 diaryliodonium salts at 600 ppm and
(didecyldimethylammonium chloride) (Forman, Jennings,
Wuest, & Minbiole, 2016; Mcdonnell & Russell, 1999;
Minbiole et al., 2016). The central iodine atom of diarylio-
donium salts could only be substituted with two benzene
rings (Merritt & Olofsson, 2009). As a result, structural
variations can only be achieved by changing corresponding
counterions or the substituent groups on two benzene rings.
Counterion effect plays a major role in modulating the
tensiometric property of diaryliodonium salts. It should be
noted from the CMC data listed in Table 1 that diaryliodo-
nium salts bearing OT as the counterion exhibit much
lower CMC values compared to their OTf-containing coun-
terparts. Comparing 1 and 8, both of which are substituted
with five fluorine atoms on the left benzene rings, we find
that the CMC value of 8 (with the OTf counterion,
1.30 mM) was almost double that of 1 (with the OT coun-
terion, 0.69 mM). Meanwhile, 13 (with the OTf counterion,
1.57 mM) and 17 (with the OT counterion, 0.91 mM), both
of which were substituted with two chlorine atoms at the
same site, exhibited the same CMC variation. Based on the
classification of the Hofmeister series, the two anions
adopted here are chaotropes, which are large ions posses-
sing low charge density (Collins & Washabaugh, 1985;
Nostro et al., 2004). As the OT anion is larger than OTf
(molecular weight 171.0121 for OT and 148.9526 for
OTf ), its interaction with water molecule is much weaker.
During the surfactant aggregation possess, in which the
originally hydrated cationic surfactant head and counterion
release a certain number of water molecules to form a neu-
tral pair, OT with a lower affinity to the water molecule is
more inclined to dehydrate, thus facilitating the construc-
tion of surfactant aggregate and leading to a lower CMC
value compared to that of OTf (Chauhan, Singh, & Bha-
dani, 2012; Feitosa et al., 2006; Sharma & Ilies, 2014).
The introduction of substituent groups into the left ben-
zene ring of diaryliodonium salts showed minor effects
regarding tensiometric property changes. Taking 8–16
(OTf salts) into consideration, we found in general that the
introduction of substituent groups led to the decrease of the
CMC values, as demonstrated by the fact that 9 with no
substituent group exhibited the highest CMC value. The
decrease of CMC values after introducing substituent
groups into the left benzene ring might be due to the
slightly elongated hydrophobic moiety, as amphiphiles with
a more hydrophobic head exhibit lower CMC values
(Rosen & Kunjappu, 2012). However, the type of substitu-
ent groups (electron-withdrawing ones like NO2 or
electron-donor ones like OCH3) and the substituent sites
(ortho-, meta-, or para-) led to little disparity on surface
activity. Among the OT salts, 1 substituted with five fluo-
rine atoms exhibited the lowest CMC value, in accordance
with the fact that fluorinated surfactants possess excellent
surface-active ability owing to their repellency toward not
20 ꢀC
Compound
Lethality rate R (%)
Duration of exposure (h)
24
4
48
1
95.38
89.66
86.90
85.34
85.30
91.00
91.50
92.57
95.25
98.43
98.43
97.57
95.29
88.86
95.00
96.75
90.00
95.15
96.65
82.48
58.62
55.17
56.90
51.72
95.24
96.25
93.16
92.56
94.86
92.29
92.43
95.14
84.29
90.06
96.24
95.34
97.23
84.50
60.45
36.21
48.28
37.93
41.38
37.51
50.00
30.00
17.52
42.86
45.71
41.43
40.00
40.05
20.13
45.07
39.95
71.60
35.76
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
only water but also oil and fat (Kissa, 2001; Kunieda &
Shinoda, 1976; Massi et al., 2009).
Antimicrobial Efficacy
The bactericidal ability of all the 19 diaryliodonium salts
was measured against Gram-positive B. cereus under the
ꢀ
following test conditions: 400 ppm at 30 C, 600 ppm at
ꢀ
ꢀ
10 ꢀC, 600 ppm at 20 C, and 400 ppm at 20 C. The
lethality rates R under the test conditions of 600 ppm at
ꢀ
20 C (calculated by the method introduced in the experi-
mental section) are listed in Table 2 (for lethality rate
R measured under the other three conditions, see Support-
ing Information).
From Table 2, it can be concluded that all the 19 diarylio-
dinium salts exhibit potent antibacterial ability within the
first 4 h, with the R values of all the compounds surpassing
85%. After 24 h of cultivation, the lethality rates remained
above 50% for all the 19 diaryliodonium salts. The great
antimicrobial efficacy of the synthesized diaryliodonium
salts can be attributed to their chemical structure: a posi-
tively charged iodine center, two substituted benzene rings,
and a long hydrophilic ether chain. Bearing a positively
charged iodine center, the diaryliodonium salts would
adsorb onto the negatively charged cell membrane of the
tested microorganism via electrostatic interaction in the
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same way as QAC (Pinazo et al., 2016). It was suggested
that after absorption onto the outer cell membrane, the
hydrophobic end of long-chain QAC would interact with
the hydrophobic section of the membrane bilayer, further
resulting in cell leakage and death (Mcdonnell & Russell,
1999). Bearing two benzene rings as the hydrophobic moi-
ety, the synthesized hypervalent iodine salts would disrupt
bacterial cell membrane in the same manner, causing the
disintegration of the cell membrane, leakage of cytoplasmic
components, and subsequent death. The introduction of a
long ether chain has not only enhanced the hydrophilicity of
the diaryliodonium salts resulting in a better hydrophilic–
lipophilic balance (Goldstein et al., 2004) but also facilitated
the interaction between the amphiphilic molecule and bacte-
rial cell membrane via the formation of hydrogen bonds. As
suggested by the structural descriptors predicting antiseptic
efficacy summarized in Cronin et al.’s (2002) work, hydro-
gen bonds help to strengthen the interaction between antibac-
terial compounds and the outer cell membrane, further
contributing to enhanced antibacterial efficacy. QAC with
polyethylene glycol chains synthesized by Abd-Elaal and
colleagues exhibited improved antibacterial efficacy owing
to the presence of strong hydrogen-bond interaction (Tawfik
et al., 2015), in accordance with the finding of our work.
Based on the results listed in Table 2, it was found that
compounds 1 and 18 were the most potent antimicrobial
agents within the group of OT salts. When the testing period
was prolonged to 48 h, compounds 1 and 18 maintained the
lethality rate above 60%, while the rest of the salts exhibited
insufficient efficacy. The left benzene ring of compounds
1 and 18 were substituted with five fluorine atoms and a
nitro group, respectively. These two sets of substituent
groups exhibited very strong electron-withdrawing effects
onto the linked benzene ring, further contributing to the
positively charged status of the central iodine atom and
tighter interaction between the agent and bacterial cell
membrane. The advanced antimicrobial efficacy of com-
pound 1 could also be attributed to the enhanced surface-
active ability caused by introduction of five fluorine atoms,
a result in accordance with the improved antiseptic ability
of fluorinated QAC mentioned by Massi et al. (2009).
maintained the lethality rate above 90% after 48 h of culti-
vation, suggesting potential application for industrial use.
Conclusion
Two sets of 19 diaryliodonium salts were synthesized, and
their tensiometric property as well as antimicrobial ability
against Gram-positive B. cereus was tested. All 19 salts dis-
solve well in water without the addition of any organic sol-
vent. Diaryliodonium salt bearing OT as the counterion
exhibited lower CMC values than its OTf counterpart. The
surface-active properties of diaryliodonium salt could be
enhanced considerably by introducing fluorine onto its
molecular structure. Antibacterial measurement results sug-
gested that all 19 diaryliodonium salts exhibited high bacte-
ricidal efficacy within the first 4 h, indicating great short-
term antimicrobial efficacy and implying possible antiseptic
mechanism through oxidation. By further compounding
compounds 1 and 18 with Kathon CG, it was found that
the formulation of 0.1% (mass) Kathon CG and 0.1% dia-
ryliodonium salts in a water solution could maintain excel-
lent antimicrobial efficacy, offering a feasible strategy to
reduce the amount of allergenic Kathon CG and apply
water instead of organic solvents as the dispersing agent in
the formulation.
Acknowledgements This research was financially supported by the
National Natural Science Foundation of China (21772039 and
21272069) and the Fundamental Research Funds for the Central Uni-
versities and Key Laboratory of Organofluorine Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences.
References
Ahmad, I., Patial, P., Kaur, C., & Kaur, S. (2014) Cationic imidazo-
lium monomeric surfactants: Their synthesis and surface active
properties. Journal of Surfactants and Detergents, 17:269–277.
https://doi.org/10.1007/s11743-013-1527-4
Aiad, I. A., Tawfik, S. M., El-Shafie, M., & Rhman, A. L. A. (2017)
4-Aminoantipyrine derived cationic surfactants: Synthesis, charac-
terization, surface activity and screening for potential antimicrobial
activities. Egyptian Journal of Petroleum. https://doi.org/10.1016/j.
ejpe.2017.05.006
Bielawski, M., Zhu, M., & Olofsson, B. (2007) Efficient and general
one-pot synthesis of diaryliodonium triflates: Optimization, scope
and limitations. Advanced Synthesis & Catalysis, 349:2610–2618.
https://doi.org/10.1002/adsc.200700373
Carman, C. S., & Koser, G. F. (1983) Regiospecific synthesis of aryl
(2-furyl)iodonium tosylates, a new class of iodonium salts, from
[hydroxy(tosyloxy)iodo]arenes and 2-(trimethylsilyl)furans in
organic solvents. The Journal of Organic Chemistry, 48:
2534–2539. https://doi.org/10.1021/jo00163a022
With the purpose of better combining the short-term anti-
microbial efficacy of diaryliodonium salts and the long-term
antimicrobial efficacy of selected antiseptics, we designed a
formulation of Kathon CG, a commercially prevalent but
dermatologically allergenic preservative (Nicoletti, Boghos-
sian, Gurevitch, Borland, & Morgenroth, 1993), with com-
pounds 1 or 18. During the antimicrobial tests, two aqueous
solutions containing 0.1% (mass percent) compounds 1 or
18 and 0.1% Kathon CG were used as experimental sets,
while 0.2% Kathon CG was used as the positive control.
Based on the results shown in Fig. 8, it is clear that the
replacement of half the amount of Kathon CG with 1 or 18
Chauhan, V., Singh, S., & Bhadani, A. (2012) Synthesis, characteriza-
tion
and
surface
properties
of
long
chain
β-hydroxy-γ-alkyloxy-N-methylimidazolium surfactants. Colloids
J Surfact Deterg (2018)

J Surfact Deterg
and Surfaces A: Physicochemical and Engineering Aspects, 395:
1–9. https://doi.org/10.1016/j.colsurfa.2011.11.022.
α-pentafluorophenyl carbonyl compounds with an all-carbon
stereocenter. ChemistryOpen, 3:233–237. https://doi.org/10.1002/
open.201402045
Mcdonnell, G., & Russell, A. D. (1999) Antiseptics and disinfectants:
Activity, action, and resistance. Clinical Microbiology Reviews, 12:
147–179.
Merritt, E. A., & Olofsson, B. (2009) Diaryliodonium salts: A journey
from obscurity to fame. Angewandte Chemie International Edition,
48:9052–9070. https://doi.org/10.1002/anie.200904689
Minbiole, K. P. C., Jennings, M. C., Ator, L. E., Black, J. W.,
Grenier, M. C., LaDow, J. E., … Wuest, W. M. (2016) From anti-
microbial activity to mechanism of resistance: The multifaceted role
of simple quaternary ammonium compounds in bacterial eradica-
tion. Tetrahedron, 72:3559–3566. https://doi.org/10.1016/j.tet.
2016.01.014
Negm, N. A., Aiad, I. A., & Tawfik, S. M. (2010) Screening for poten-
tial antimicrobial activities of some cationic uracil biocides against
wide-spreading bacterial strains. Journal of Surfactants and Deter-
gents, 13:503–511. https://doi.org/10.1007/s11743-010-1229-0
Collins, K. D., & Washabaugh, M. W. (1985) The Hofmeister effect
and the behaviour of water at interfaces. Quarterly Reviews of Bio-
physics, 18:323–422. https://doi.org/10.1017/s0033583500005369
Cronin, M. T. D., Aptula, A. O., Dearden, J. C., Duffy, J. C.,
Netzeva, T. I., Patel, H., … Schüürmann, G. (2002) Structure-based
classification of antibacterial activity. Journal of Chemical Informa-
tion and Computer Sciences, 42:869–878. https://doi.org/10.1021/
ci025501d
Dohi, T., Yamaoka, N., & Kita, Y. (2010) Fluoroalcohols: Versatile
solvents in hypervalent iodine chemistry and syntheses of
diaryliodonium(III) salts. Tetrahedron, 66:5775–5785. https://doi.
org/10.1016/j.tet.2010.04.116
Feitosa, E., Brazolin, M. R., Naal, R. M., Del Lama, M. P.,
Lopes, J. R., Loh, W., & Vasilescu, M. (2006) Structural organiza-
tion of cetyltrimethylammonium sulfate in aqueous solution: The
effect of Na2SO4. Journal of Colloid and Interface Science, 299:
883–889. https://doi.org/10.1016/j.jcis.2006.02.051
Forman, M. E., Jennings, M. C., Wuest, W. M., & Minbiole, K. P. C.
(2016) Building a better quaternary ammonium compound (QAC):
Branched tetracationic antiseptic amphiphiles. ChemMedChem, 11:
1401–1405. https://doi.org/10.1002/cmdc.201600176
Gallop, P. M., Paz, M. A., Flückiger, R., Stang, P. J.,
Zhdankin, V. V., & Tykwinski, R. R. (1993) Highly effective PQQ
inhibition by alkynyl and aryl mono- and diiodonium salts. Journal
of the American Chemical Society, 115:11702–11704. https://doi.
org/10.1021/ja00078a007
Goldstein, E. J. C., Citron, D. M., Warren, Y., Merriam, C. V.,
Tyrrell, K., Fernandez, H., … Conrads, G. (2004) In vitro activities
of iodonium salts against oral and dental anaerobes. Antimicrobial
Agents and Chemotherapy, 48:2766–2770. https://doi.org/10.1128/
AAC.48.7.2766-2770.2004
Hossain Delwar, M., & Kitamura, T. (2006) Reaction of iodoarenes
with potassium peroxodisulfate/trifluoroacetic acid in the presence
of aromatics. Direct preparation of diaryliodonium triflates from
iodoarenes. Tetrahedron, 62:6955–6960. https://doi.org/10.1016/j.
tet.2006.04.073.
Nicoletti, G., Boghossian, V., Gurevitch, F., Borland, R.,
&
Morgenroth, P. (1993) The antimicrobial activity in vitro of chlor-
hexidine, a mixture of isothiazolinones (“Kathon” CG) and cetyl
trimethyl ammonium bromide (CTAB). Journal of Hospital Infec-
tion, 23:87–111. https://doi.org/10.1016/0195-6701(93)90014-Q
Nostro, P. L., Nostro, A. L., Ninham, B. W., Pesavento, G.,
Fratoni, L., & Baglioni, P. (2004) Hofmeister specific ion effects in
two biological systems. Current Opinion in Colloid & Interface
Science, 9:97–101. https://doi.org/10.1016/j.cocis.2004.05.011
Petersen, T. B., Khan, R., & Olofsson, B. (2011) Metal-free synthesis
of aryl esters from carboxylic acids and diaryliodonium salts.
Organic Letters, 13:3462–3465. https://doi.org/10.1021/ol2012082
Pinazo, A., Manresa, M. A., Marques, A. M., Bustelo, M.,
Espuny, M. J., & Pérez, L. (2016) Amino acid-based surfactants:
New antimicrobial agents. Advances in Colloid and Interface Sci-
ence, 228:17–39. https://doi.org/10.1016/j.cis.2015.11.007
Richter, H. W., Cherry, B. R., Zook, T. D., & Koser, G. F. (1997)
Characterization of species present in aqueous solutions of
[hydroxy(mesyloxy)iodo]benzene and [hydroxy(tosyloxy)iodo]ben-
zene. Journal of the American Chemical Society, 119:9614–9623.
https://doi.org/10.1021/ja971751c
Rodrigues, L., Banat, I. M., Teixeira, J., & Oliveira, R. (2006) Biosur-
factants: Potential applications in medicine. Journal of Antimicro-
bial Chemotherapy, 57:609–618. https://doi.org/10.1093/jac/dkl024
Rosen, M. J., & Kunjappu, J. T. (2012) Surfactants and interfacial
phenomena (4th ed.). Hoboken, NJ: John Wiley & Sons, Inc.
Sharma, V. D., & Ilies, M. A. (2014) Heterocyclic cationic gemini
Kissa, E. (2001) Fluorinated surfactants and repellents (2nd ed.).
New York, NY: Marcel Dekker.
Kitamura, T., Matsuyuki, J.-I., Nagata, K., Furuki, R.,
&
Taniguchi, H. (1992) A convenient preparation of diaryliodonium
triflates. Synthesis, 1992:945–946.
Koser, G. F., Wettach, R. H., & Smith, C. S. (1980) New methodol-
ogy in iodonium salt synthesis. Reactions of [hydroxy(tosyloxy)
iodo]arenes with aryltrimethylsilanes. The Journal of Organic
Chemistry, 45:1543–1544. https://doi.org/10.1021/jo01296a050
Kunieda, H., & Shinoda, K. (1976) Krafft points, critical micelle con-
centrations, surface tension, and solubilizing power of aqueous
solutions of fluorinated surfactants. Journal of Physical Chemistry,
80:2468–2470.
surfactants:
A
comparative overview of their synthesis,
self-assembling, physicochemical, and biological properties. Medic-
inal Research Reviews, 34:1–44. https://doi.org/10.1002/med.
21272
Simoncic, B., & Tomsic, B. (2010) Structures of novel antimicrobial
agents for textiles—A review. Textile Research Journal, 80:
1721–1737. https://doi.org/10.1177/0040517510363193
Tawfik, S. M., Abd-Elaal, A. A., Shaban, S. M., & Roshdy, A. A.
(2015) Surface, thermodynamic and biological activities of some
synthesized Gemini quaternary ammonium salts based on polyeth-
ylene glycol. Journal of Industrial and Engineering Chemistry, 30:
112–119. https://doi.org/10.1016/j.jiec.2015.05.011
Lundov, M. D., Johansen, J. D., Zachariae, C., & Moesby, L. (2011)
Low-level efficacy of cosmetic preservatives. International Journal
of Cosmetic Science, 33:190–196. https://doi.org/10.1111/j.
1468-2494.2010.00619.x
Massi, L., Guittard, F., Géribaldi, S., Levy, R., & Duccini, Y. (2003)
Antimicrobial properties of highly fluorinated bis-ammonium salts.
International Journal of Antimicrobial Agents, 21:20–26. https://
doi.org/10.1016/S0924-8579(02)00271-6
Tischer, M., Pradel, G., Ohlsen, K., & Holzgrabe, U. (2012) Quater-
nary ammonium salts and their antimicrobial potential: Targets or
nonspecific interactions? ChemMedChem, 7:22–31. https://doi.
org/10.1002/cmdc.201100404
Zhdankin, V. V., & Stang, P. J. (2008) Chemistry of polyvalent
iodine. Chemical Reviews, 108:5299–5358. https://doi.org/10.1021/
cr800332c
Massi, L., Guittard, F., Levy, R., & Geribaldi, S. (2009) Enhanced
activity of fluorinated quaternary ammonium surfactants against
Pseudomonas aeruginosa. European Journal of Medicinal Chemis-
try, 44:1615–1622. https://doi.org/10.1016/j.ejmech.2008.07.032
Matsuzaki, K., Okuyama, K., Tokunaga, E., Shiro, M., & Shibata, N.
(2014) Sterically demanding unsymmetrical diaryl-λ3-iodanes for
electrophilic pentafluorophenylation and an approach to
J Surfact Deterg (2018)