Perfluoroalkylated poly(oxyethylene) thiols: Synthesis, adsorption dynamics and surface activity at the air/water interface, and bubble stabilization behaviour

Article abstract of DOI:10.1016/j.jfluchem.2014.10.020

We report the synthesis of four new perfluoroalkylated thiols, C_nF_2n+1(CH₂)₂(OCH₂CH₂)_ySH (FnH2(OE)_y with n = 4 and 6; y = 4 and 6, that have a hydrophilic poly(oxyethylene) (POE) segment inserted between the hydrophobic fluorinated chain and the thiol functional group. The dynamics of adsorption and surface activity of these compounds at the air/water interface were studied using bubble profile analysis tensiometry. The adsorption kinetics profiles show that all compounds diffuse rapidly to the air/water interface and decrease the interfacial tension of water to values ranging from 16.5 to 31.6 mN m^-1, which qualifies them as potential components of microbubble shells. Their ability to self-assemble and stabilize gaseous microbubbles in the presence or absence of a fluorocarbon gas (perfluorohexane) was investigated by optical microscopy. Three out of the four compounds (the two F6 derivatives and F4H2(OE)₆) were able to form and stabilize microbubbles. Microbubbles based on both F6 PEG thiols are more stable than those based on the F4 derivative. The number of oxyethylene (OE) groups substantially influences bubble stability; the higher the number of OEs, the more stable the microbubbles. Finally, the most important stabilising effect was obtained by introducing an internal fluorocarbon gas, whose presence in the bubble increases bubble stability from 6 h to 5 days for the most promising candidate, F6H2(OE)₆SH.

Full text of DOI:10.1016/j.jfluchem.2014.10.020

Journal of Fluorine Chemistry 171 (2015) 12–17
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Perfluoroalkylated poly(oxyethylene) thiols: Synthesis, adsorption
dynamics and surface activity at the air/water interface, and bubble
stabilization behaviour
*
Prasad Polavarapu, Marie Pierre Krafft
Institut Charles Sadron (CNRS UPR 22), Universite´ de Strasbourg, 23 rue du Loess, 67034 Strasbourg Cedex 2, France
A R T I C L E I N F O
A B S T R A C T
Article history:
We report the synthesis of four new perfluoroalkylated thiols, CnF2n+1(CH2)2(OCH2CH2)ySH (FnH2(OE)y
with n = 4 and 6; y = 4 and 6, that have a hydrophilic poly(oxyethylene) (POE) segment inserted between
the hydrophobic fluorinated chain and the thiol functional group. The dynamics of adsorption and
surface activity of these compounds at the air/water interface were studied using bubble profile analysis
tensiometry. The adsorption kinetics profiles show that all compounds diffuse rapidly to the air/water
Received 28 July 2014
Received in revised form 28 October 2014
Accepted 30 October 2014
Available online 6 November 2014
interface and decrease the interfacial tension of water to values ranging from 16.5 to 31.6 mN mÀ1
,
Keywords:
which qualifies them as potential components of microbubble shells. Their ability to self-assemble and
stabilize gaseous microbubbles in the presence or absence of a fluorocarbon gas (perfluorohexane) was
investigated by optical microscopy. Three out of the four compounds (the two F6 derivatives and
F4H2(OE)6) were able to form and stabilize microbubbles. Microbubbles based on both F6 PEG thiols are
more stable than those based on the F4 derivative. The number of oxyethylene (OE) groups substantially
influences bubble stability; the higher the number of OEs, the more stable the microbubbles. Finally, the
most important stabilising effect was obtained by introducing an internal fluorocarbon gas, whose
presence in the bubble increases bubble stability from 6 h to 5 days for the most promising candidate,
F6H2(OE)6SH.
Fluorosurfactant
Poly(ethylene glycol)
Thiol
Fluorous
Microbubble
Ultrasound
ß 2014 Elsevier B.V. All rights reserved.
1. Introduction
contrast agents for 19F magnetic resonance imaging (MRI)
(Scheme 1b) [4]. The POE chains were intended to increase the
Partially fluorinated thiols have proved to be effective
components for the elaboration of 2D self-assembled monolayers
(SAMs) adsorbed at the surface of metals or metal oxides for
nanomaterials fabrication. Such SAMs provide nanoscale surface
coatings useful in various technologies such as corrosion
inhibition and microelectromechanical systems (MEM) and
biomaterials coatings [1,2]. Series of partially fluorinated thiols
CnF2n+1(CH2)mSH, with n = 6–10; m = 2–17 have been synthesized
and have produced nano-coatings with controlled wettability [2].
SAMs assembled on 2D flat surfaces have been shown to allow
selective immobilization of proteins [3]. In the latter case, the
SAMs were obtained from partially fluorinated disulfides with a
poly(oxyethylene) (POE) chain grafted in terminal position
(Scheme 1a) [3]. More recently, other POE fluorinated thiols
have been used as ligands to protect gold nanoparticles in
dispersibility of gold nanoparticles grafted with perfluoroalkyl
(F-alkyl) chains via the thiol function. However, to the best of our
knowledge, all the F-alkylated thiols reported so far carry the POE
moiety in terminal position, the fluorinated chain being inserted
between the latter and a hydrocarbon segment.
Here, we report the synthesis of four F-alkylated thiols,
CnF2n+1(CH2)2(OCH2CH2)ySH (FnH2(OE)y with n = 4 and 6; y = 4
and 6), in which a POE spacer is inserted between a terminal F-alkyl
chain and the thiol function (Scheme 1c). We expected that
changing the molecular topology of these compounds would
modify their behaviour in terms of adsorption at the air/water
interface and their molecular organization at this interface, as
compared to the previously reported compounds. Molecular
organization is known to depend strongly on the position of the
self-assembly-promoting F-alkyl chains [5,6]. More generally,
there is a critical need for new components specifically designed
for controlling interfacial film properties [7–9]. The mechanical
properties of thin surfactant films, such as stability and viscoelas-
ticity, are preeminent parameters that determine the practicability
*
Corresponding author. Tel.: +33 3 88 41 40 60; fax: +33 3 88 40 41 99.
E-mail address: krafft@unistra.fr (M.P. Krafft).
http://dx.doi.org/10.1016/j.jfluchem.2014.10.020
0022-1139/ß 2014 Elsevier B.V. All rights reserved.

P. Polavarapu, M.P. Krafft / Journal of Fluorine Chemistry 171 (2015) 12–17
13
2.2.3. 17,17,18,18,19,19,20,20,21,21,22,22,22-Tridecafluoro-1-
phenyl-2,5,8,11,14-pentaoxadocosane 3
A solution of compound 2 (3.28 g, 7.47 mmol, 1.20 eq) and F-
hexylethanol (C6F13C2H4OH) (1.35 mL, 2.27 g, 6.23 mmol) in dry
dioxane (30 mL) was stirred under argon. To this, powdered KOH
(1.40 g, 24.9 mmol, 4 eq) was added, and the resulting reaction
mixture was refluxed under argon for 48 h. The brown reaction
mixture was cooled down to room temperature and water added.
The mixture was extracted with diethyl ether (4 times) and the
combined ether phases were washed with water and dried over
Na2SO4. Solvent was evaporated to give a brown liquid, which was
purified by flash column chromatography on silica gel using a 1:1
mixture of ethyl acetate and pentane to afford compound 3
(963 mg, 25%) as a light orange coloured liquid. 1H NMR (CDCl3,
Scheme 1. Molecular formulae of F-alkylated disulfides (a) and thiols (b) bearing a
poly(oxyethylene) (POE) chain in terminal position; from [3] and [4], respectively.
(c) Molecular formula of F-alkylated thiols carrying a POE spacer inserted between
the thiol function and a terminal F-alkylated chain (this work).
of self-assembled colloids in a wide range of applications [9]. Gas
microbubbles are, for example, promising theranostic agents
susceptible to crossing physiological barriers with limited damage
under focalized application of ultrasound [10–12]. Shell film
viscosity and elasticity, and hence, shell composition, determine
the inertial cavitation threshold so as to either achieve or avoid
cavitation at a given operating pressure [13,14]. Control of
surfactant film elasticity is therefore highly desirable. The surface
activity of the new F-alkyl POE thiols was investigated by bubble
profile analysis tensiometry, and their kinetics of adsorption at the
air/water interface were determined. Their ability to stabilize
microbubbles of air or perfluorohexane-saturated air was also
investigated.
400 MHz)
d
(ppm): 7.27–7.38 (m, 5H), 4.56 (s, 2H), 3.55–3.8 (m,
(ppm): 128.3, 127.9,
18H), 2.42 (m, 2H). 13C NMR (CDCl3, 75 MHz)
d
127.7, 127.6, 107–122 (m), 73.2, 70.6, 70.6, 70.6, 70.5, 70.4, 70.2,
69.4, 69.2, 63.1 (t), 61.6, 31.5 (t), 21.6.
2.2.4. 15,15,16,16,17,17,18,18,19,19,20,20,20-Tridecafluoro-
3,6,9,12-tetraoxaicosan-1-ol 4
A solution of 3 (750 mg, 1.19 mmol) in methanol (25 mL) was
thoroughly degassed by using repeated cycles of vacuum and
argon. Pd/C (75 mg, 10% of the mass of the substrate) was added
and degassed repeatedly. Finally, the flask was filled with
hydrogen using a balloon and stirring was continued overnight
under hydrogen. The reaction flask was then flushed with argon
and the contents were filtered through celite and the celite was
thoroughly washed with methanol. The solvent was evaporated to
2. Experimental part
2.1. General
yield
a colourless oil that was purified by flash column
All starting materials were purchased from Sigma (See
Supporting Information) including F-hexane (purity > 99%) and
Pluronic F-68 (a polyoxyethylene-polyoxypropylene triblock
copolymer, MW ꢀ 8300, purity > 99%). Water was purified using
chromatography on silica gel; elution was achieved with a
gradient of pure ethyl acetate to 5% methanol in ethyl acetate to
get compound 4 (623 mg, 97%) as a colourless liquid. 1H NMR
(CDCl3, 400 MHz)
(CDCl3, 75 MHz)
d
: 3.5–3.8 (m, 18H), 2.43 (m, 2H). 13C NMR
(ppm): 107–122 (m), 72.5, 70.6, 70.5, 70.5, 70.4,
a
Millipore system (surface tension: 72.1 mN mÀ1 at 20 8C,
d
resistivity: 18.2 M
recorded in CDCl3 with a Bruker AM 400 spectrometer. Chemical
shifts are reported in parts per million ( in ppm) relative to Me4Si
(1H, 13C) and CFCl3 19F).
V
cm). 1H, 13C, and 19F NMR spectra were
70.3, 63.1 (t), 61.6, 31.5 (t).
d
2.2.5. 15,15,16,16,17,17,18,18,19,19,20,20,20-Tridecafluoro-
3,6,9,12-tetraoxaicosyl methanesulfonate 5
(
The detailed procedure for the synthesis of F6H2(OE)4SH is
described below.
To a solution of 4 (619 mg, 1.15 mmol) and triethylamine
(160
mL, 116 mg, 1.15 mmol) in dry THF (15 mL) under argon were
added dropwise methanesulfonyl chloride (131 mg, 1.15 mmol) in
THF (15 mL). The resulting turbid white reaction mixture was
stirred for 2 h and ether (25 mL) was added. The mixture was
washed with 2% HCl and water, dried over Na2SO4 and the solvent
was evaporated to give 5 (668 mg) as a white turbid liquid that was
used in the next reaction without further purification. 1H NMR
2.2. Synthesis of 15,15,16,16,17,17,18,18,19,19,20,20,20-
tridecafluoro-3,6,9,12-tetraoxaicosane-1-thiol 7 (F6H2(OE)4SH).
2.2.1. 1-Phenyl-2,5,8,11-tetraoxatridecan-13-ol 1
The benzyl protected compound 1 was synthesized following
an earlier report.[15] 1H NMR (CDCl3, 400 MHz)
d
(ppm): 7.27–
7.38 (m, 5H), 4.57 (s, 2H), 3.55–3.7 (m, 16H). 13C NMR (CDCl3,
75 MHz) (ppm): 137.8, 128.0, 127.5, 127.3, 72.9, 72.4, 70.2, 70.2,
(CDCl3, 400 MHz) d: 4.38 (m, 2H), 3.55–3.82 (m, 16H), 3.07 (s, 3H),
2.43 (m, 2H).
d
70.2, 69.9, 69.1, 61.2.
2.2.6. S-15,15,16,16,17,17,18,18,19,19,20,20,20-tridecafluoro-
3,6,9,12-tetraoxaicosyl ethanethioate 6
2.2.2. 1-Phenyl-2,5,8,11-tetraoxatridecan-13-yl 4-
methylbenzenesulfonate 2
A solution of mesylate 5 (650 mg, 1.05 mmol) and potassium
thioacetate (240 mg, 2.1 mmol, 2 eq) in dry DMF (5 mL) was heated
to 80 8C for 90 min under argon. The light orange coloured reaction
mixture was cooled down and water was added. It was extracted
with ethyl acetate (3 times) and the combined organic phase was
washed with water and dried over Na2SO4. Evaporation of the
solvent gave a yellow coloured liquid. This liquid was adsorbed
onto a silica gel column and eluted with gradients of 10 to 13%
ethyl acetate in dichloromethane to get 6 (460 mg, 73%) as a light
To a stirred solution of the benzyl-protected compound 1
(10.00 g, 35.17 mmol) and triethylamine (7 mL) under argon, was
added dropwise p-toluenesulfonyl chloride (6.91 g, 36.22 mmol,
1.03 eq) in dry CH2Cl2 (15 mL) over 5 min. The reaction mixture
was stirred for 16 h and diluted with diethyl ether (25 mL). The
organic phase was washed with a 1 N HCl solution, a 5% NaHCO3
solution, water and dried over Na2SO4, filtered and the solvent was
evaporated to give compound 2 (14.95 g, 97%) as a light brown
liquid. 1H NMR (CDCl3, 400 MHz)
7H), 4.56 (s, 2H), 4.15 (m, 2H), 3.5–3.7 (m, 14H), 2.44 (s, 3H). 13C
NMR (CDCl3, 75 MHz) (ppm): 144.7, 138.2, 133.0, 129.8, 128.3,
127.9, 127.7, 127.5, 73.2, 70.7, 70.6, 70.5, 69.4, 69.2, 68.6, 21.6.
d
(ppm): 7.8 (m, 2H), 7.27–7.4 (m,
yellow coloured liquid. 1H NMR (CDCl3, 400 MHz)
3.55–3.7 (m, 14H), 3.09 (t, 2H), 2.42 (m, 2H), 2.33 (s, 3H). 13C NMR
(CDCl3, 75 MHz) (ppm): 107–122 (m), 70.7, 70.6, 70.5, 70.3, 69.7,
63.1 (t), 31.5 (t), 30.5, 28.8.
d: 3.78 (t, 2H),
d
d

14
P. Polavarapu, M.P. Krafft / Journal of Fluorine Chemistry 171 (2015) 12–17
2.2.7. 15,15,16,16,17,17,18,18,19,19,20,20,20-Tridecafluoro-
3,6,9,12-tetraoxaicosane-1-thiol 7
equipped with a 3 mm titanium probe and operated at 20 kHz
with an output power of ꢀ600 W (duty cycle 40%). The
microbubbles were allowed to float for 1 min in order to eliminate
large bubbles prior to observation by optical microscopy.
A stirred solution of 6 (214 mg, 0.36 mmol) in of methanol
(10.6 mL, 0.32 mmol) and dichloromethane (20 mL) was cooled to
0 8C in an ice bath and acetyl chloride (8.9 mL, 9.82 g, 0.13 mol,
350 eq) was added dropwise over 5 min. The ice bath was removed
after 10 min and stirring was continued at room temperature for
36 h before water and dichloromethane were added. The phases
were separated and the aqueous phase was extracted with CH2Cl2
(4 times), and the combined organic phase was washed with water
(3 times), dried over Na2SO4 and the solvent was evaporated to
give a light brown, foul smelling liquid. This residue was adsorbed
on a silica gel column, eluted with 10 to 12% of ethyl acetate in
dichloromethane to give 7 (191 mg, 96%) as a very light orange
2.5. Optical microscopy
Three to four droplets of bubble dispersion were placed into a
concave glass slide, covered with a glass slide, and observed with a
Nikon Eclipse 90i microscope, one minute after preparation. The
average diameters of the microbubbles were determined by optical
microscopy (on 200 bubbles at least) by fitting the size distribution
with a Gaussian function.
coloured liquid. 1H NMR (CDCl3, 400 MHz)
d: 3.78 (t, 2H), 3.55–3.7
3. Results and discussion
(m, 14H), 2.7 (dt, 2H), 2.43 (m, 2H), 1.59 (t, 1H). 19F NMR (CDCl3):
À81.1 (CF3); À114.6 (CF2CH2); À122.5 (2F); À123.3 (2F); À124.0
3.1. Synthesis of F-alkyl POE thiols
(2F); À126.2 (CF3CF2). 13C NMR (CDCl3, 75 MHz)
d (ppm): 107–122
(m), 72.9, 70.7, 70.6, 70.5, 70.2, 63.1 (t), 31.5 (t), 24.3. C16F13H21O4S
(556.38): calcd. (%) C: 34.54, H: 3.80, S: 5.76; found (%) C: 34.26, H:
3.72, S: 5.62. MS (MALDI): m/z 579,8 [M + Ag]+ (Calc. 579,4)
The synthesis of the F-alkyl POE thiols CnF2n+1(CH2)2OCH2-
CH2)ySH involves 7 steps and followed the procedure reported in
Scheme 2 for n = 6, y = 4. The benzyl-protected tetraethylene glycol
1 was synthesized by selective protection of one of the alcohol
groups of ethylene glycol according to [15]. The alcohol group of 1
was tosylated [17]. Williamson condensation of the resulting
compound 2 with the F-alkyl alcoholate was then achieved
according to [15] yielding the protected F-alkyl POE compound 3.
This method allows in situ formation of the alcoholate using a
liquid–solid phase-transfer reaction (KOH is used as a powder). The
reaction takes place in dioxane and ethylene glycol serves as the
phase-transfer agent, allowing solubilisation of powered KOH. The
latter then becomes a substrate for the nucleophilic Williamson
reaction [15]. Hydrogenolysis [18] of the resulting benzyl-
protected compound 3 bearing the F-alkyl chain gave the F-alkyl
pegylated alcohol 4 in good yields (ꢀ95%). Subsequent methane-
sulfonylation gave compound 5 in the conditions described in [3].
Reaction of mesylate 5 with potassium thioacetate and removal of
the protecting group with HCl (generated in situ from AcCl and
MeOH in CH2Cl2) gave the target F-alkyl POE thiol 7 in quantitative
yields [19]. The overall yield of the seven step procedure was ꢀ10%.
The same procedure applied to the synthesis of the other F-alkyl
POE thiols gave the following overall yields: n = 4, y = 4: ꢀ15%;
n = 4, y = 6: ꢀ20%; n = 6, y = 6: ꢀ15%. All the final compounds were
characterized by 1H, 13C and 19F NMR and elemental analysis.
Precise mass spectra were obtained from a MALDI spectrometer,
excluding the formation of disulfides (n = 4, y = 4: m/z 479.9
[M + Ag]+ (Calc. 479.4); n = 4, y = 6: m/z 567.3 [M + Ag]+ (Calc.
567.5); n = 6, y = 4: m/z 579.8 [M + Ag]+ (Calc. 579.4); n = 6, y = 6:
m/z 667.1 [M + Ag]+ (Calc. 667.5).
2.3. Bubble profile analysis tensiometry
Axisymmetric bubble shape analysis was applied to a rising air
bubble formed in an aqueous solution of the F-alkyl POE thiol
investigated (0.9 and 0.09 mM in water). Time dependence of the
interfacial tension during surfactant adsorption at the gas/liquid
interface was measured using a Tracker1 tensiometer (Teclis,
Longessaigne, France).[16] A lid fitted on the measuring glass cell
(10 mL) prevented water evaporation during long equilibration
times. The bubble (typically 1–2
mL) was formed at the tip of a
stainless steel capillary with a tip diameter of 0.25 mm. In some
experiments, the surface area of the bubble was kept constant. In
other experiments, the bubble was submitted to compression of its
surface at a relative rate of 0.01–0.02 sÀ1. The experimental error
on the interfacial tension data was Æ0.5 mN mÀ1
.
2.4. Microbubble preparation
The F-alkyl POE thiols (1 mM) were first solubilized under
stirring in 10 mL of a solution of Pluronic F-68. Pluronic F68 was
added in order to facilitate dispersion of the surfactant and foam
formation (F-alkyl PEG thiol:F-68 molar ratio 10:1). Microbubbles
were prepared by sonication of the above solutions under an
atmosphere of air saturated with perfluorohexane (or not,
depending on the experiments) for 30 s (setting 2) at 25 8C. The
sonicator (Vibracell, Bioblock Scientific, Illkirch, France) was
Scheme 2. Synthesis of a perfluoroalkylated poly(oxyethylene) thiol amphiphile.

P. Polavarapu, M.P. Krafft / Journal of Fluorine Chemistry 171 (2015) 12–17
15
Table 1
3.2. Adsorption kinetics of F-alkyl POE thiols at the air/water interface
Equilibrium interfacial tension (
geq) of the F-alkylated POE thiols.
Æ0.5 mN mÀ1
) F4H2(OE)4SH F4H2(OE)6SH F6H2(OE)4SH F6H2(OE)6SH
In order to investigate the effect of the newly synthesized thiols on
bubble formation and stabilization, their kinetics of adsorption at the
air/water interface and their critical micelle concentration values
(CMCs) were determined using bubble profile analysis tensiometry.
The variations of interfacial tension at equilibrium as a function of
concentration are given in Fig. 1. The CMCs of the F-alkyl POE thiols
were found to be very close, ranging from 0.12 to 0.16 mM.
The study of the adsorption kinetics of the surfactants was
expected to provide information on how fast the surfactants
adsorb at the interface, and hence, is able to stabilize microbubbles
at the very first moments of their formation. Two concentrations
were investigated: 0.09 mM, that is, below the CMC, and 0.9 mM,
which is well above. The study also aimed at determining the
geq
(
c = 0.9 mM
24.6
28.4
26.9
31.6
16.5
20.5
18.0
23.2
c = 0.09 mM
the F6 derivatives are more surface active than the F4 derivatives
for both concentrations and whatever the number of OE units, as
shown by lower equilibrium tensions (Table 1). These results are in
line with increased amphiphilic character which generally also
promotes self-assembling properties [8,20,21].
In addition, for a given F-chain length and at all concentrations,
eq is slightly lower for the shortest OE unit. This is likely due to the
fact that compounds with 4 OEs are more efficiently packed at the
air/water interface than those with 6 OEs.
g
equilibrium interfacial tension geq. The kinetics of adsorption of
the four thiols F6H2(OE)4SH, F6H2(OE)6SH, F4H2(OE)4SH and
F4H2(OE)6SH are plotted on Fig. 2. The first important point is that
Where the adsorption dynamics is considered, the kinetics of
the compounds with 4 OEs is generally faster than for 6 OEs, which
reflects higher hydrophobic character. Moreover, it is noteworthy
that, for the lowest concentration (c = 0.09 mM), the time required
by the two F4 derivatives to organize at the interface is quite slow
(>600 s), meaning that this concentration is probably too low to
allow formation and stabilization of microbubbles.
The results show that for the highest concentration (0.9 mM) all
compounds present favourable adsorption characteristics, that is,
they diffuse rapidly to the air/water interface and, once there, are
able to decrease the interfacial tension down to very low values.
These properties qualify them as shell components for micro-
bubbles.
3.3. Ability of the F-alkylated POE thiols to form and stabilize gaseous
microbubbles
Microbubbles have raised interest in the last decades owing to
their potential as contrast agents for ultrasound diagnosis, as drug/
gene delivery systems and as mechanical intravascular tools
[22–27]. In consequence, the physical chemistry of such bubbles,
and in particular the properties of their shells with regards to
microbubbles’ basic attributes such as size and stability control
[28–31], viscosity [9,32], resonance intensity and frequency [33],
capacity to generate sound harmonics [34–36], to enable gene
transfer [27,37] and to undergo ultrasound-triggered disruption
[38], have been investigated. Various types of shells, made of
Fig. 1. Variation of the interfacial tension as a function of concentration of aqueous
solutions of F4H2(OE)4SH (blue down triangles), F4H2(OE)6SH (green up triangles),
F6H2(OE)4SH (black squares) and F6H2(OE)6SH (red circles). The CMCs are
indicated by arrows. (For interpretation of the references to color in this figure
legend, the reader is referred to the web version of this article.)
biodegradable block copolymers, such as poly(D,L-lactide-co-
glycolide) [39], polyelectrolyte multilayers [40], proteins [41],
phospholipids [24,42], as well as neutral [43] and charged
surfactants [44], have been investigated. To the best of our
knowledge, no amphiphilic thiols were ever reported to be used as
microbubble shell components.
We prepared and studied microbubbles in which the four
synthesized thiols were used as shell components at a concentra-
tion of 1 mM. The lowest concentration of 0.1 mM was found
insufficient to generate enough microbubbles to perform mean-
ingful statistical size analysis by optical microscopy. Pluronic F-68
is necessary as a foaming agent that plays a crucial role during the
very first steps of the microbubble formation. F-68 does not
perturb the film formed by the fluorinated surfactants at the
microbubble surface because it is desorbed from the air/water
interface for very low lateral pressures [45].
The influence of perfluorohexane (F-hexane) gas as an osmotic
stabilizer was also investigated [10,22,28]. The results are
summarized in Table 2. Fig. 3 shows optical micrographs of the
microbubbles, as well as their size distributions, when measured
just after preparation. Under our conditions, the microbubbles
Fig. 2. Adsorption kinetics at 25 8C of aqueous solutions of F4H2(OE)4SH (blue),
F4H2(OE)6SH (green), F6H2(OE)4SH (black) and F6H2(OE)6SH (red), at two
concentrations, 0.9 mM (solid lines) and 0.09 mM (dashed lines). (For interpretation
of the references to color in this figure legend, the reader is referred to the web version
of this article.)
have average diameters ranging from 5.2 to 9.2
mm (Table 2). The
presence of the fluorocarbon gas decreases significantly the

16
P. Polavarapu, M.P. Krafft / Journal of Fluorine Chemistry 171 (2015) 12–17
Fig. 3. Typical optical micrographs of microbubbles with a shell made from (a) F4H2(OE)6SH, (b) F6H2(OE)4SH and (c) F6H2(OE)6SH (c = 1 mM). In the right panels the
microbubbles are stabilized by F-hexane, whilst in the left panels, only air is present in the bubbles’ gas phase. Scale bar: 20
mm.
Table 2
Size and stability characteristics of microbubbles with a shell of F-alkylated POE thiol in the presence, or absence, of F-hexane in the gas phase (c = 1 mM).
F4H2(OE)4SH
F4H2(OE)6SH
F6H2(OE)4SH
F6H2(OE)6SH
Air
No bubbles
No bubbles
Av. size: 5.4
Av. size: 5.2
m
m
m unstable
ꢀ 2 h
Av. size: 6.0
Av. size: 5.4
m
m
m
s
s
ꢀ 2 h
Av. size: 9.2
Av. size: 7.2
m
m
s
s
ꢀ 6 h
F-hexane-saturated air
m
s
m
ꢀ 24 h
mm
> 5 days
bubbles’ diameter. The microbubbles were monitored over time
and considered stable over a certain period of time as long as the
Third, when the inner gaseous phase was saturated with F-hexane, it
led to dramatic stabilization of the microbubbles. For example,
F4H2(OE)6 produces only few unstable bubbles in the absence of the
fluorocarbon, but is able to stabilize microbubbles for ꢀ2 h when
F-hexane is present. The effect is even more pronounced for the F6
derivatives. The fluorocarbon gas strongly increases microbubble
stability, from 2 h to 24 h for F6H2(OE)4SH and from 6 h to 5 days for
F6H2(OE)4SH. F-hexane is expected to act as an osmotic stabilizer by
reducing the solubility and diffusibility of the internal microbubble gas
phase into the surrounding aqueous phase [22,47]. F-hexane has also
been shown to act as a co-surfactant with other surfactants,
phospholipids in particular, and reduce interfacial tension, and hence,
Laplace pressure [10,28,48].
s
variation of their mean diameter, as determined by optical
microscopy, was lower than 10% over this period. First, it can be
seen that the length of the F-alkyl chain determines both the ability
of the F-alkyl POE thiols for forming and for stabilizing micro-
bubbles. The F6 derivatives were more effective than the F4 ones
(Table 2). This result is supported by the adsorption profiles that
evidence much lower geq values for the F6 compounds. The
interfacial tension that determines Laplace pressure according to
PL = 2 g/r (r being the microbubble’s radius) is indeed a key element
of microbubble stability [46].
Second, for a given F-chain length, the compound with the highest
number of OEs was the most effective. The shortest compound
F4H2(OE)4 did not produce bubbles at all in the conditions applied,
whilst F4H2(OE)6 did produce bubbles, although unstable. For the F6
series, the effect is clear-cut, as increasing the number of OEs from 4 to
6 resulted in an increase of the microbubbles’ stability from 2 to 6 h.
4. Conclusions
Four new amphiphiles with a poly(oxyethylene) spacer inserted
between a thiol function and a F-alkylated chain have been

P. Polavarapu, M.P. Krafft / Journal of Fluorine Chemistry 171 (2015) 12–17
17
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group, these F-alkylated POE thiols adsorb rapidly at the air/water
interface and decrease strongly the interfacial tension of water to
values as low as ꢀ16 mN mÀ1. All the compounds, but the shortest
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Acknowledgements
The authors thank the European Commission (FP7 2007–2013;
grant no. NMP3-SL-2008-214032), the French National Research
Agency (ANR, grant no. 2010-BLAN-0816-01), and the GIS Fluor for
Financial Support. P.P. thanks the EC for a post-doctoral research
fellowship. Teclis (Longessaigne, France) is acknowledged for
technical help.
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