Novel perfluoroalkylated oligo(oxyethylene) methyl ethers with high hemocompatibility and excellent co-emulsifying properties for potential biomedical uses

Article abstract of DOI:10.1016/j.jfluchem.2008.12.001

Two series of novel perfluoroalkylated amphiphilic compounds were synthesized from monomethyl ethers of mono-, di- and tri-(oxyethylene) glycols. The first series CH₃(OCH₂CH₂)_nOCH₂CH(OH)CH₂-CF₂(CF₂CF₂)_nCF₃ (n = 1-3) bearing the hydroxy group at the spacer between hydrophilic and hydrophobic parts was prepared by the reactions of the monomethyl ethers with 2-(perfluoroalkylmethyl)oxiranes in 76-97% yields. The second series CH₃(OCH₂CH₂)_nOCH₂CH₂CH₂-CF₂(CF₂CF₂)_nCF₃ (n = 1-3) possessing the non-hydroxylated spacer was synthesized from allyl methyl ethers of oligo(oxyethylene) glycols using radical additions of perfluoroalkyl iodides and subsequent selective reductions of the C-I bond in the adducts in overall yields of 23-69%. Some of the novel amphiphilic compounds displayed very low hemolytic activity to erythrocytes and excellent co-emulsifying properties on testing on perfluorodecalin/Pluronic F-68 microemulsions. 1-O-(2-Hydroxy-4,4,5,5,6,6,7,7,8,8,9,9,9-tridecafluorononyl)-d-xylitol was prepared by a novelized synthesis and employed as a standard compound in the testing.

Full text of DOI:10.1016/j.jfluchem.2008.12.001

Journal of Fluorine Chemistry 130 (2009) 308–316
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Novel perfluoroalkylated oligo(oxyethylene) methyl ethers with high
hemocompatibility and excellent co-emulsifying properties for potential
biomedical uses
a
a,
b
b
*
´
ˇ
´
´ˇ
Robert Kaplanek , Oldrich Paleta , Ivana Ferjentsikova , Milan Kodıcek
a
´
Department of Organic Chemistry, Prague Institute of Chemical Technology, Technicka 5, 16628 Prague 6, Czech Republic
b
´
Department of Biochemistry and Microbiology, Prague Institute of Chemical Technology, Technicka 5, 16628 Prague 6, Czech Republic
A R T I C L E I N F O
A B S T R A C T
Article history:
Two series of novel perfluoroalkylated amphiphilic compounds were synthesized from monomethyl
ethers of mono-, di- and tri-(oxyethylene) glycols. The first series CH3(OCH2CH2)nOCH2CH(OH)CH2–
CF2(CF2CF2)nCF3 (n = 1–3) bearing the hydroxy group at the spacer between hydrophilic and
hydrophobic parts was prepared by the reactions of the monomethyl ethers with 2-(perfluoroalk-
ylmethyl)oxiranes in 76–97% yields. The second series CH3(OCH2CH2)nOCH2CH2CH2–CF2(CF2CF2)nCF3
(n = 1–3) possessing the non-hydroxylated spacer was synthesized from allyl methyl ethers of
oligo(oxyethylene) glycols using radical additions of perfluoroalkyl iodides and subsequent selective
reductions of the C–I bond in the adducts in overall yields of 23–69%. Some of the novel amphiphilic
compounds displayed very low hemolytic activity to erythrocytes and excellent co-emulsifying
properties on testing on perfluorodecalin/Pluronic F-68 microemulsions. 1-O-(2-Hydroxy-
Received 7 October 2008
Received in revised form 28 November 2008
Accepted 1 December 2008
Available online 9 December 2008
Keywords:
Perfluoroalkylated oligo(oxyethylene)
ethers
Perfluoroalkylated oxiranes
Radical addition
4,4,5,5,6,6,7,7,8,8,9,9,9-tridecafluorononyl)-
D-xylitol was prepared by
a
novelized synthesis and
Reduction of C–I bond
1-O-Fluoroalkyl-D-xylitol
employed as a standard compound in the testing.
Hemocompatibility
ß 2008 Elsevier B.V. All rights reserved.
Microemulsion stability
1. Introduction
with dispersed PFC phase for skin and wound protection are main
areas of applied research for these colloidal systems [8–13]. As
perfluorocarbons are highly hydrophobic molecules, their water
emulsions can be prepared on using an appropriate biocompatible
amphiphilic surfactant [14].
Some classes of highly fluorinated or perfluorinated compounds
(PFCs), including perfluorocarbons, perfluorinated trialkylamines
or nitrogen heterocycles have ability to dissolve large amount of
gases, namely oxygen and carbon dioxide, even more than water or
blood [1,2]. Another outstanding property of these compounds is
their biological inertness. This property and ability to dissolve large
volumes of respiratory gases have made them attractive for
(potential) biomedical uses [3–7].
Water colloidal systems prepared from perfluorinated compo-
nents, as various types of emulsions, fluorinated vesicles (lipo-
somes), and other highly fluorinated self-assemblies, have
significant potential in the biomedical field. Emulsions for
injectable oxygen carriers (blood substitutes) useful in cardiopul-
monary bypass surgery, liquid ventilation, perfusion of isolated
organs or cell-cultivation, contrast agents for diagnosis by
ultrasound imaging, vesicles in drug delivery systems, and gels
Pluronic F-68 (the poly[oxyethylene]-poly[oxypropylene] block
copolymer) is one of the most biocompatible synthetic surfactants
known. It has found numerous applications in the biomedical field,
including the treatment of hemorrhagic shock or as a dispersant for
drugs. Lecithins are used as emulsifiers, especially in fat emulsions
for parenteral nutrition and for the preparation of liposomes for
drug targeting. However, neither Pluronic F-68 nor lecithins are
particularly fluorophilic, and the stability of the emulsions they
form with PFCs is usually poor. It has been shown that a strong
stabilization of PCFs emulsions can be achieved by combining
the properties of PF-68 with amphiphilic perfluoroalkylated
surfactants. A perfluoroalkylated tail improves the adhesion of a
co-surfactant to the fluorocarbon phase. Thus, fluorinated co-
surfactants play key role by allowing stabilization of such
emulsions. Some of them appeared to be low hemolytic [15–18].
Up to the present, a range of emulsifiers bearing perfluorinated
moiety have been studied. As the hydrophilic part, polyhydroxy-
* Corresponding author.
E-mail address: oldrich.paleta@vscht.cz (O. Paleta).
0022-1139/$ – see front matter ß 2008 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2008.12.001

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R. Kaplanek et al. / Journal of Fluorine Chemistry 130 (2009) 308–316
309
lated groups or saccharides [8,9,19–23], poly(oxyethylene) chain
or 2-hydroxyethyl groups [4,14,24–29], sulfinyl or sulfone group
[20,21,29–31], and organic salts [19,31–33] were employed.
Herein, we describe the synthesis of perfluoroalkylated
amphiphiles consisting of oligo(oxyethylene) hydrophilic part
and trimethylene spacer. Similar amphiphilic compounds bearing
polyethylene glycol moiety as hydrophilic part have been reported
[4,14,24,27,34,35].
Their ability to stabilize perfluorodecalin–water emulsions [4]
and hemolytic effect on a suspension of red blood cells were studied
[24,34]. In this paper we present results of testing of the novel
compounds for hemocompatibility, microemulsion stability and co-
emulsifying properties for two series of co-emulsifiers, which differ
in the corresponding pairs by hydroxy group attached to the
hydrocarbon spacer. In contrast to the former reports[8,16], we have
found that the properties tested are not simply dependent on the
chainlengthofthepoly(oxyethylene)and/orperfluoroalkylmoieties.
Scheme 1. Preparation of amphiphiles 7–12.
2. Chemistry
Both two series of the novel perfluoroalkylated amphiphilic
compounds 7–12 and 24–28 were synthesized by transformations
of the industrially available monomethyl ethers of mono-, di- and
tri-(oxyethylene) glycols 1–3.
were prepared by a three-step synthesis (Scheme 2). In the first
step, the starting monomethyl ethers 1–3 were converted into the
corresponding allyl methyl ethers 13–15. In the second step,
perfluorinated alkyls were introduced into the ethers 13–15 by the
radical addition of perfluoroalkyl iodides 16–18 initiated by N,N0-
azobis(isobutyronitrile) (AIBN) or sodium dithionite. In the third
step, the C–I bonds in the adducts 19–23 were reduced to obtain
the desired amphiphiles 24–28 (Scheme 2).
For the preparation of the allyl ethers 13–15, modified reaction
conditions of those published [39,40] were applied in that manner
that the monomethyl ethers 1–3 were metallated with sodium
hydride in diethyl ether and subsequently reacted with excess allyl
bromide (Scheme 2) to obtain 13–15 in 64–90% yields. Several
initiation systems have been reported for the radical additions of
perfluoroalkyl iodides 16–18, e.g. azo compounds, metals and their
salts, organic peroxides or sodium dithionite [41]. In our radical
additions, AIBN as the initiator without any solvent [41,42]
afforded generally higher yields of additions in comparison with
sodium dithionite in the acetonitrile–water system [42–46]. The
yields of the additions are summarized in Table 1. In the case of
perfluorooctyl iodide (18), the difference in yields is high probably
due to a low solubility of the iodide 18 in the acetonitrile–water
solvent.
2.1.1. Preparation of amphiphiles 7–12
For the connection of the oligo(oxyethylene) moiety with the
hydroxylated spacer and perfluoroalkyls, we employed the
epoxide ring opening reaction of 2-(perfluoroalkyl)methyl oxi-
ranes 4–6 (Scheme 1) [23,36–38]. The reaction was catalyzed
efficiently by boron trifluoride diethyl etherate, a strong Lewis
acid, to activate the epoxide cycle to the O-nucleophile ring
opening in the perfluoroalkylated epoxides 4–6. The epoxide ring
opening proceeded with the complete regioselectivity at the less
substituted carbon atom [23,36–38].
The reactions were carried out without any solvent at 100 8C for
10 h (Scheme 1) to afford perfluoroalkylated amphiphiles 7–12 in
76–97% isolated yields. The preparation of the 7 and 12 we already
reported as intermediates in the synthesis of perfluoroalkylated
amphiphilic methacrylates [38].
2.1.2. Preparation of amphiphiles 24–28
Several methods have been reported for the reduction of C–I
bonds in addition products of perfluoroalkyl iodides. The
reagents include Bu3SnH/AIBN [47–51], H2/Pd/C [42,44,46],
Amphiphilic compounds with propane-1,3-diyl spacer between
a perfluoroalkyl chain and hydrophilic oligo(oxyethylene) moiety
Scheme 2. Preparation of amphiphiles 24–28.

´
310
R. Kaplanek et al. / Journal of Fluorine Chemistry 130 (2009) 308–316
Scheme 3. Preparation of xylitol derivative 31.
Table 1
with 2-(perfluorohexyl)methyl oxirane (5) without solvent in the
presence of BF3ꢀEt2O as a catalyst to afford the xylitol derivative 30
in the yield of 84% (Lit. 76% [37]). Deprotection of hydroxy groups
was carried out using hydrochloric acid in methanol in the yield of
95% of the end-product 31 (Lit. 82% [37]).
The results of the radical additions of perfluoroalkyl iodides onto allyl (oligo)ethers
13–15.
Alkene
Iodide
Initiator
Yielda (%)
CH3OCH2CH2OCH2CH CH2 (13)
CH3OCH2CH2OCH2CH CH2 (13)
CH3(OCH2CH2)2OCH2CH CH2 (14)
CH3(OCH2CH2)2OCH2CH CH2 (14)
CH3(OCH2CH2)3OCH2CH CH2 (15)
CH3(OCH2CH2)3OCH2CH CH2 (15)
CH3(OCH2CH2)3OCH2CH CH2 (15)
CH3(OCH2CH2)3OCH2CH CH2 (15)
CH3(OCH2CH2)3OCH2CH CH2 (15)
CH3(OCH2CH2)3OCH2CH CH2 (15)
C6F13I (17)
C6F13I (17)
C6F13I (17)
C6F13I (17)
C4F9I (16)
C4F9I (16)
C6F13I (17)
C6F13I (17)
C8F17I (18)
C8F17I (18)
AIBN
91
91
96
81
87
86
95
85
95
56
Na2S2O4
AIBN
3. Testing of co-emulsifying properties and hemocompatibility
Na2S2O4
AIBN
The novel amphiphiles 7–12 and 24–28 were tested as co-
surfactants for oxygen carriers and other biomedical uses as
specified in literature [7–13]. Perfluoroalkylated co-surfactants for
microemulsions are usually used in amounts up to 10% relatively to
the main emulsifier, e.g. Pluronic F-68, and can stabilize
microemulsions in positive cases [7,9,15–17]. For an assessment
of co-emulsion stability and hemolytic activity of the new
amphiphilic compounds, we applied methods that have been
used in our recent reports (the methods are briefly described in
Section 5) [22,23,37]. Microemulsions were prepared by sonica-
tion. In testing, a reference microemulsion of Pluronic F-68 with
perfluorodecalin was used, in which Pluronic was gradually
substituted with the amphiphile tested and the effect of this
substitution observed (Tables 2–5). The xylitol amphiphile 31 has
been included in testing as a standard compound to verify
reliability of testing results with respect to the quality of
hemoglobin used [37].
Na2S2O4
AIBN
Na2S2O4
AIBN
Na2S2O4
a
Isolated yield.
Zn/HCl(g) [52–54], Zn/AcOH [55–57], Zn/NiCl2 [58,59] or LiAlH4
[60,61]. Unfortunately, the reductions do not run with the
complete conversion of the starting iodo derivatives in particular
cases or the separation and purification of the products from a
reaction mixture can be problematic causing a decrease of yields.
The reduction of the iodo intermediates 19–23 using Zn/NiCl2 in
THF–water mixture at room temperature for 24 h was our
method of choice to afford the amphiphiles 24–28 in yields of
41–62% (Scheme 2).
2.1.3. Preparation of xylitol derivative 31
3.1. Co-emulsifying properties and microemulsion stability
Xylitol derivative 31 has been employed as a standard in testing
emulsion stability and hemocompatibility in recent papers [37].
Herein we report an improved method of the preparation of this
compound as follows (Scheme 3): protected xylitol 29 was reacted
The testing of co-emulsifying properties was based on visual
evaluation of the state of an emulsion (see Section 5). The first, a
very efficient test, was stability of emulsions during 5 min
centrifugation (Table 2). It was surprising that the amphiphiles
Table 2
Stabilitya,b of emulsions during centrifugation (400 ꢁ g for 5 min).
Emulsifier
Substitution of Pluronic F-68 by tested emulsifiers (% w/w PF-68)
20%
40%
60%
80%
100%
Emulsion stability
MeO(CH2CH2O)–CH2CH(OH)CH2–C6F13 (7)
MeO(CH2CH2O)2–CH2CH(OH)CH2–C4F9 (8)
MeO(CH2CH2O)2–CH2CH(OH)CH2–C6F13 (9)
MeO(CH2CH2O)2–CH2CH(OH)CH2–C8F17 (10)
MeO(CH2CH2O)3–CH2CH(OH)CH2–C6F13 (11)
MeO(CH2CH2O)3–CH2CH(OH)CH2–C8F17 (12)
MeO(CH2CH2O)–CH2CH2CH2–C6F13 (24)
MeO(CH2CH2O)2–CH2CH2CH2–C6F13 (25)
MeO(CH2CH2O)3–CH2CH2CH2–C4F9 (26)
MeO(CH2CH2O)3–CH2CH2CH2–C6F13 (27)
MeO(CH2CH2O)3–CH2CH2CH2–C8F17 (28)
[Xylitol-1-yl]-CH2CH(OH)CH2–C6F13 (31)c
+
+
+
+
+
ꢂ
+
ꢂ
+
ꢂ
+
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
Emulsions were not formeda
Emulsions were not formeda
+
+
ꢂ
+
+
+
+
+
+
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
+
+
+
ꢂ
+
ꢂ
+
ꢂ
ꢂ
ꢂ
+
ꢂ
+
ꢂ
+
a
For the compounds 11 and 12, the emulsions were not formed by initial sonication.
b
c
Plus (+) means no apparent change of the emulsion; minus (ꢂ) means colaps of the emulsion.
Ref. [37].

´
R. Kaplanek et al. / Journal of Fluorine Chemistry 130 (2009) 308–316
311
Table 3
Stability of emulsions during standing at r.t. for 8 weeksa,b
.
Emulsifier
Substitution of Pluronic F-68 by tested emulsifiers (% w/w PF-68)
20%
40%
60%
80%
100%
Emulsion stability
MeO(CH2CH2O)–CH2CH(OH)CH2–C6F13 (7)
MeO(CH2CH2O)2–CH2CH(OH)CH2–C4F9 (8)
MeO(CH2CH2O)2–CH2CH(OH)CH2–C6F13 (9)
MeO(CH2CH2O)2–CH2CH(OH)CH2–C8F17 (10)
MeO(CH2CH2O)–CH2CH2CH2–C6F13 (24)
MeO(CH2CH2O)2–CH2CH2CH2–C6F13 (25)
MeO(CH2CH2O)3–CH2CH2CH2–C4F9 (26)
MeO(CH2CH2O)3–CH2CH2CH2–C6F13 (27)
MeO(CH2CH2O)3–CH2CH2CH2–C8F17 (28)
[Xylitol-1-yl]-CH2CH(OH)CH2–C6F13 (31)c
+
+
+
+
+
ꢂ
+
ꢂ
+
ꢂ
+
ꢂ
ꢂ
ꢂ
+
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
+
ꢂ
+
ꢂ
+
+
+
+
+
ꢂ
+
ꢂ
+
ꢂ
+
ꢂ
+
ꢂ
+
ꢂ
+
ꢂ
ꢂ
ꢂ
ꢂ
a
For the compounds 11 and 12, the emulsions were not formed by initial sonication.
b
c
Plus (+) means no apparent change of the emulsion; minus (ꢂ) means colaps of the emulsion.
Ref. [37].
Table 4
Stability of emulsions at 37 8C for 6 h after mixing with erythrocytesa,b
.
Emulsifier
Substitution of Pluronic F-68 by tested emulsifiers (% w/w PF-68)
20%
40%
60%
80%
100%
Emulsion stability
MeO(CH2CH2O)–CH2CH(OH)CH2–C6F13 (7)
MeO(CH2CH2O)2–CH2CH(OH)CH2–C4F9 (8)
MeO(CH2CH2O)2–CH2CH(OH)CH2–C6F13 (9)
MeO(CH2CH2O)2–CH2CH(OH)CH2–C8F17 (10)
MeO(CH2CH2O)–CH2CH2CH2–C6F13 (24)
MeO(CH2CH2O)2–CH2CH2CH2–C6F13 (25)
MeO(CH2CH2O)3–CH2CH2CH2–C4F9 (26)
MeO(CH2CH2O)3–CH2CH2CH2–C6F13 (27)
MeO(CH2CH2O)3–CH2CH2CH2–C8F17 (28)
[Xylitol-1-yl]-CH2CH(OH)CH2–C6F13 (31)c
+
+
+
+
+
ꢂ
+
ꢂ
+
ꢂ
+
ꢂ
ꢂ
ꢂ
+
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
+
ꢂ
+
ꢂ
+
+
+
+
+
+
ꢂ
+
ꢂ
+
ꢂ
+
ꢂ
ꢂ
ꢂ
+
ꢂ
+
ꢂ
+
ꢂ
+
a
For the compounds 11 and 12, the emulsions were not formed by initial sonication.
b
c
Plus (+) means no apparent change of the emulsion; minus (ꢂ) means colaps of the emulsion.
Ref. [37].
11 and 12, possessing tri(oxyethylene) hydrophilic part and
hydroxylated spacer, did not form microemulsions by initial
sonication even at only 20% substitution of Pluronic. In contrast,
their counterparts 27 and 28 possessing non-hydroxylated spacer
formed stable microemulsions at 20–60% and 20% substitution of
Pluronic, respectively (Table 2). In addition, also the amphiphile 25
with non-hydroxylated spacer formed more stable emulsions than
its counterpart 9. When comparing the effect of the perfluoroalkyl
length, it can be seen that perfluorobutyl causes instability of
emulsions at all concentrations (amphiphiles 8 and 26). Stable
emulsions at high concentrations of co-emulsifier are those
bearing perfluorohexyl: substitution of Pluronic up to 60% (9,
27), 80% (24, 25) or 100% (7) was found. On the other hand,
perfluorooctyl also caused almost complete instability of emul-
sions (compounds 10 and 28). The number of oxyethylene units in
the amphiphiles also influenced stability of emulsions. The effect is
Table 5
Range of hemolysisa,b
.
Emulsifier
Substitution of Pluronic F-68 by tested emulsifiers (% w/w PF-68)
20%
40%
60%
80%
100%
Range of hemolysisa,b
MeO(CH2CH2O)–CH2CH(OH)CH2–C6F13 (7)
MeO(CH2CH2O)2–CH2CH(OH)CH2–C4F9 (8)
MeO(CH2CH2O)2–CH2CH(OH)CH2–C6F13 (9)
MeO(CH2CH2O)2–CH2CH(OH)CH2–C8F17 (10)
MeO(CH2CH2O)–CH2CH2CH2–C6F13 (24)
MeO(CH2CH2O)2–CH2CH2CH2–C6F13 (25)
MeO(CH2CH2O)3–CH2CH2CH2–C4F9 (26)
MeO(CH2CH2O)3–CH2CH2CH2–C6F13 (27)
MeO(CH2CH2O)3–CH2CH2CH2–C8F17 (28)
[Xylitol-1-yl]-CH2CH(OH)CH2–C6F13 (31)
0c
1.4
0
0
0
3.0
0
0.5
5.3
1.0
0.3
1.1
23
0.5
5.6
0.8
0.5
NTd
98.6
63.6
79.7
0
1.5
0
0
0
0
0
0.5
5.2
2.7
2.5
0
0.8
10.6
7.5
9.0
0
3.1
1.7
1.3
0
10.9
52.5
0
0
0
0
0.6
0.8
a
For the compounds 11 and 12, the emulsions were not formed by initial sonication.
Hemolysis up to 1% is irrelevant.
b
c
Zero value means hemolysis below 0.5%.
Not tested.
d

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R. Kaplanek et al. / Journal of Fluorine Chemistry 130 (2009) 308–316
312
apparent in the series of amphiphiles having hydroxylated spacer:
compound 7 with one oxyethylene unit afforded emulsions stable
up to 100% substitution of Pluronic (Table 2); the emulsions
containing 9 bearing two oxyethylene units were stable up to 60%
substitution of Pluronic, while 11 with three oxyethylene units did
not form microemulsions at all.
and excellent co-emulsifying properties (7, 9, 24, 25, 27) on testing
on perfluorodecalin/Pluronic F-68 microemulsions. Thus, some of
the compounds synthesized are suitable for further biochemical
and pharmacological testing. These easily accessible surfactants
could find application in biomedical and also technical areas.
The second test of microemulsions was a long-term stability on
standing at room temperature for 8 weeks mimicking a long-term
storage. The results (Table 3) have revealed that the stabilities of
the emulsions were the same as those on centrifugation (Table 2)
with a slight divergence to a lower value for the amphiphile 28. The
third test was for stability of the microemulsions in the presence of
erythrocytes at 37 8C mimicking human blood. As shown in
Table 4, also this test revealed almost the same stabilities of the
microemulsions as those on centrifugation (Table 2) with a slight
divergence to a higher value (20% substitution of Pluronic) for the
amphiphile 10 and to a lower value for the amphiphile 28.
It can be summarized that very good co-emulsifying properties
enabling up to 60% of Pluronic substitution displayed amphiphiles
9 or 27 and excellent properties displayed amphiphiles 7, 24 and
25 (100, 80 and 80% substitution of Pluronic).
5. Experimental
5.1. General comments and chemicals
NMR spectra were recorded on a Varian Gemini 300 MHz (FT,
1H at 300 MHz, 13C at 75 MHz, 19F at 281 MHz) instrument using
TMS and CFCl3 as the internal standards. Chemical shifts are
quoted in ppm (d-scale; s: singlet; bs: broad singlet; d: doublet; t:
triplet; m: multiplet), coupling constants J in Hz, solvents: CDCl3,
CD3OD.
The chemicals used were as follows: perfluoroalkyl iodides
were obtained from Atofina S.A.; activated charcoal, AIBN, sodium
dithionite, sodium hydride (60% suspension in mineral oil; oil was
removed by washing with dry diethyl ether before use), 2-
(methoxy)ethanol, 3,6-dioxaheptan-1-ol, perfluorodecalin, tri-
fluoroacetic acid, 3,6,9-trioxadecan-1-ol, zinc (all Aldrich); allyl
bromide, nickel (II) chloride hexahydrate, BF3ꢀEt2O, sodium
hydrocarbonate (Lachema Brno, Czech Rep.); silica gel (60–
3.2. Hemocompatibility
Hemolytic activity of perfluoroalkylated amphiphiles 7–12 and
24–28 on human erythrocytes was tested using a reference
perfluorodecalin/Pluronic F-68 microemulsion mixed with ery-
throcytes (heterogeneous mixture). Pluronic F-68 was gradually
substituted with the amphiphile tested and the amount of
extracellular hemoglobin was determined spectrophotometrically
as per cent degree of hemolysis. The results of the testing are
summarized in Table 5 and reveal that the dominant effect on
hemolytic activity is the structure of the spacer: the set of
amphiphiles 7–10 bearing hydroxylated spacer displayed gen-
erally lower hemolytic activity (i.e. better hemocompatibility) than
the amphiphiles in the set 24–28. It has also been apparent that the
hemocompatibility increases with longer perfluoroalkyl-chain
length causing the complete hemocompatibility up to 100% of
Pluronic substitution for the amphiphiles 10 and 28.
100 mm, Merck). All solvents were purchased from Penta and
dried according to standard procedures. All reactions requiring
anhydrous conditions were performed using dried solvents and
under inert atmosphere.
2-(Perfluoroalkyl)methyl oxiranes were prepared according the
reported procedure [62]. 1,2:3,4-Di-O-isopropylidene-D-xylitol
was prepared according literature [63].
5.2. Chemistry
5.2.1. General procedure for preparation of 7–12
2-(Perfluoroalkyl)methyl oxirane 4–6, ethylene glycol mono-
methyl ether 1–3 (molar ratio 1:8–10) and BF3ꢀEt2O were heated
while stirring at 100 8C for 10 h. After cooling down, excess of
ethylene glycol monomethyl ether and BF3ꢀEt2O were removed
under reduced pressure. Crude product was purified by using
column chromatography on silica gel (eluent:petroleum ether/
acetone 4:1, v/v).
3.3. Effects of perfluoroalkyl chain length on amphiphiles properties
It can generally be concluded that the effects are more or less
combined with the hydrophilic moiety and a spacer in the
molecule of a perfluoroalkylated amphiphile. In addition, the
effects on emulsion stability and hemolytic activity are usually not
parallel as observed recently [23,37]. For example, in the case of
perfluoroalkylated aliphatic triols [23], hemocompatibility was
increasing with perfluoroalkyl chain length, while microemulsion
stability was better for perfluorohexyl than perfluorooctyl in
particular cases. Similar effects were observed for perfluoroalky-
5.2.1.1. 9,9,10,10,11,11,12,12,13,13,14,14,14-Tridecafluoro-2,5-diox-
atetradecan-7-ol
(7). l,2-Epoxy-4,4,5,5,6,6,7,7,8,8,9,9,9-trideca-
fluorononane (5; 1.505 g; 4 mmol), 2-methoxyethanol (1; 3.10 g;
40 mmol), BF3ꢀEt2O (0.20 mL). Product 7 was obtained as yellowish
liquid (1.330 g; 76%).
1H NMR (CDCl3):
d = 2.05–2.55 (m, 2H, CH2–RF), 3.35 (s, 3H,
CH3), 3.40–3.90 (m, 7H, 3ꢁ CH2–O and CH–O), 4.23 (s, 1H, OH). 13
C
NMR (CDCl3):
d = 34.5 (t, 1C, CH2–RF, J = 21 Hz), 58.8 (s, 1C, CH3),
lated
D
-galactopyranose and
D
,
L
-xylitol possessing 2-hydroxypro-
64.2 (s, 1C, CH); 70.6, 71.9 (2ꢁ s, 2ꢁ 1C, 2ꢁ CH2–O); 74.9 (s, 1C,
pane-1,3-diyl spacer [37]. In this paper, it can be observed that the
best emulsion stability revealed amphiphiles 7, 9, 24, 25, 27
bearing perfluorohexyl (Tables 2-4), while hemocompatibility was
the best for compounds 10 and 28 bearing perfluorooctyl (Table 5).
CH2–CH), 103.0–124.0 (m, 6C, 5ꢁ CF2 and CF3). 19F NMR (CDCl3):
d
= ꢂ81.4 (t, 3F, CF3, J = 10 Hz), ꢂ113.2 (m, 2F, CH2–CF2); ꢂ122.3,
ꢂ123.3, ꢂ124.1 (3ꢁ m, 3ꢁ 2F, 3ꢁ CF2); ꢂ126.6 (m, 2F, CF2–CF3).
Anal. Calcd. for C12H13F13O3: C, 31.87; H, 2.90. Found: C, 32.03;
H, 3.07%.
4. Conclusions
5.2.1.2. 12,12,13,13,14,14,15,15,15-Nonafluoro-2,5,8-trioxapentade-
can-10-ol (8). l,2-Epoxy-4,4,5,5,6,6,7,7,7-nonafluoroheptane (4;
0.579 g; 2.1 mmol), 3,6-dioxaheptan-1-ol (2; 2.40 g; 20 mmol),
BF3ꢀEt2O (0.20 mL). Product 8 was obtained as yellowish liquid
(0.772 g; 93%).
Two series of novel perfluoroalkylated amphiphilic compounds
consisting of oligo(oxyethylene) hydrophilic part and 2-hydro-
xypropane-1,3-diyl (7–12) or propane-1,3-diyl spacer (24–28)
were synthesized in overall yields of 73-97% and 23–69%,
respectively, for testing of co-emulsifier properties and hemo-
compatibility. Some of the amphiphilic compounds prepared (7, 9,
24, 28) displayed a zero level hemolytic activity to erythrocytes
1H NMR (CDCl3):
CH3), 3.40–4.00 (m, 11H, 5ꢁ CH2–O and CH–O), 4.25 (bs, 1H, OH).
13C NMR (CDCl3):
= 34.3 (t, 1C, CH2–RF, J = 21 Hz), 58.8 (s, 1C,
d = 2.05–2.45 (m, 2H, CH2–RF), 3.32 (s, 3H,
d

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313
CH3), 64.1 (s, 1C, CH), 70.4 (s, 2C, 2ꢁ CH2–O), 70.7 (s, 1C, CH2–O),
71.7 (s, 1C, CH2–O), 74.8 (s, 1C, CH2–CH), 105.0–120.0 (m, 4C, 3ꢁ
CH3), 64.0 (s, 1C, CH), 70:3 (s, 1C, CH2–O), 70.4 (s, 3C, 3ꢁ CH2–O);
70.6, 71.7 (2ꢁ s, 2ꢁ 1C, 2ꢁ CH2–O); 74.8 (s, 1C, CH2–CH), 105.0–
CF2 and CF3). 19F NMR (CDCl3):
d
= ꢂ81.7 (tt, 3F, CF3, J = 10.3/
124.0 (m, 8C, 7ꢁ CF2 and CF3). 19F NMR (CDCl3):
d
= ꢂ81.4 (t, 3F,
3.2 Hz), ꢂ113.0 (m, 2F, CH2–CF2), ꢂ124.7 (m, 2F, CF2), ꢂ126.5 (m,
CF3, J = 9.3 Hz), ꢂ112.8 (m, 2F, CH2–CF2); ꢂ122.2, ꢂ122.4, ꢂ122.4,
ꢂ123.2, ꢂ123.8 (5ꢁ m, 5ꢁ 2F, 5ꢁ CF2); ꢂ126.7 (m, 2F, CF2–CF3).
Anal. Calcd. for C18H21F17O5: C, 33.76; H, 3.31. Found: C, 33.68;
H, 3.32%.
2F, CF2–CF3).
Anal. Calcd. for C12H17F9O4: C, 36.37; H, 4.32. Found: C, 36.32; H,
4.37%.
5.2.1.3. 12,12,13,13,14,14,15,15,16,16,17,17,17-Tridecafluoro-2,5,8-
trioxaheptadecan-10-ol (9). l,2-Epoxy-4,4,5,5,6,6,7,7,8,8,9,9,9-tri-
decafluorononane (5; 1.880 g; 5 mmol), 3,6-dioxaheptan-1-ol (2;
6.00 g; 50 mmol), BF3ꢀEt2O (0.20 mL). Product 9 was obtained as
colourless liquid (2.280 g; 91%).
5.2.2. General procedure for preparation of ethylene glycol allyl
methyl ethers 13–15
The solution of ethylene glycol monomethyl ethers 1–3 in
diethyl ether were added dropwise to stirred suspension of NaH in
anhydrous diethyl ether. Mixture was refluxed for 2 h while
stirring. A solution of allyl bromide (2 molar equivalent per
alkanol) was then added dropwise and reaction mixture was
refluxed for 4 h. After cooling down, water was carefully added to
hydrolyze the excess of NaH. Volatile compounds were removed
under reduced pressure and crude product 13–15 was distilled.
1H NMR (CDCl3):
d = 2.07–2.40 (m, 2H, CH2–RF), 3.32 (s, 3H,
CH3), 3.38-3.70 (m, 11H, 5ꢁ CH2–O and CH–O), 4.21 (s, 1H, OH). 13
C
NMR (CDCl3):
d = 34.5 (t, 1C, CH2–RF, J = 21 Hz), 58.8 (s, 1C, CH3),
64.1 (s, 1C, CH); 70.4, 70.5, 70.7, 71.8 (4ꢁ s, 4ꢁ 1C, 4ꢁ CH2–O); 74.8
(s, 1C, CH2–CH), 104.0–124.0 (m, 6C, 5ꢁ CF2 and CF3). 19F NMR
(CDCl3):
d
= ꢂ81.4 (t, 3F, CF3, J = 10.1 Hz), ꢂ113.2 (m, 2F, CH2–CF2);
ꢂ122.3, ꢂ123.3, ꢂ124.1 (3ꢁ m, 3ꢁ 2F, 3ꢁ CF2); ꢂ126.6 (m, 2F, CF2–
5.2.2.1. 4,7-Dioxaoct-1-ene (13). Sodium hydride (60% suspension
in oil; 4.70 g; 117.5 mmol) in Et2O (100 mL), 2-methoxyethanol (1;
7.20 g; 95 mmol) in Et2O (20 mL), allyl bromide (24.20 g;
200 mmol). Product 13 was obtained as colourless liquid
(7.073 g; 64%; b.p. 127–128 8C).
CF3).
Anal. Calcd. for C14H17F13O4: C, 33.88; H, 3.45. Found: C, 34.12;
H, 3.57%.
5.2.1.4. 12,12,13,13,14,14,15,15,16,16,17,17,18,18,19,19,19-Hepta-
1H NMR (CDCl3):
CH2–O), 3.97 (ddd, 2H, CH2-allyl, J = 5.5/2.7/1.1 Hz), 5.15 (dd, 1H,
CH2, J = 8.8/1.1 Hz), 5.26 (dd, 1H, = CH2, J = 17.0/1.1 Hz), 5.88
(ddt, 1H, CH–, J = 17.0/8.8/5.5 Hz). 13C NMR (CDCl3):
d
= 3.34 (s, 3H, CH3), 3.47–3.60 (m, 4H, 2ꢁ
decafluoro-2,5,8-trioxanonadecan-10-ol
(10). 1,2-Epoxy-4,4,5,5,
6,6,7,7,8,8,9,9,10,10,10-heptadecafluoroundecane (6; 0.710 g;
1.50 mmol), 3,6-dioxaheptan-1-ol (2; 1.80 g; 15 mmol), BF3ꢀEt2O
(0.20 mL). Product 10 was obtained as yellowish liquid (0.863 g;
97%).
d = 58.9 (s,
1C, CH3), 69.1 (s, 1C, CH2–OMe), 71.8 (s, 1C, CH2–CH2–OMe), 72.1
(s, 1C, CH2-allyl), 117.0 (s, 1C, CH2), 134.6 (s, 1C, –CH ).
Anal. Calcd. for C6H12O2: C, 62.04; H, 10.41. Found: C, 61.77; H,
10.56%.
1H NMR (CDCl3):
CH3), 3.40–4.00 (m, 11H, 5ꢁ CH2–O and CH–O), 4.28 (bs, 1H, OH).
13C NMR (CDCl3):
= 34.4 (t, 1C, CH2–RF, J = 21 Hz), 58.7 (s, 1C,
d = 2.10–2.45 (m, 2H, CH2–RF), 3.33 (s, 3H,
d
CH3), 64.1 (s, 1C, CH); 70.4, 70.4, 70.6, 71.7 (4ꢁ s, 4ꢁ 1C, 4ꢁ CH2–
5.2.2.2. 4,7,10-Trioxaundec-1-ene (14). Sodium hydride (60% sus-
pension in oil; 5.00 g; 150 mmol) in Et2O (120 mL), 3,6-dioxa-
heptan-1-ol (2; 12.02 g; 100 mmol) in Et2O (20 mL), allyl bromide
(24.20 g; 200 mmol). Product 14 was obtained as colourless liquid
(11.640 g; 73%; b.p. 86 8C/15 mm Hg.
O); 74.8 (s, 1C, CH2–CH), 102.0–124.0 (m, 8C, 7ꢁ CF2 and CF3). 19
F
NMR (CDCl3):
d
= ꢂ81.5 (t, 3F, CF3, J = 10.9 Hz), ꢂ112.8 (m, 2F, CH2–
CF2); ꢂ122.1, ꢂ122.3, ꢂ123.2, ꢂ123.7 (4ꢁ m, 4ꢁ 2F, 4ꢁ CF2);
ꢂ126.7 (m, 2F, CF2–CF3).
Anal. Calcd. for C16H17F17O4: C, 32.23; H, 2.87. Found: C, 32.15;
H, 2.89%.
1H NMR (CDCl3):
d
= 3.31 (s, 3H, CH3), 3.46–3.68 (m, 8H, 4ꢁ
CH2–O), 3.96 (dd, 2H, CH2-allyl, J = 5.5/1.1 Hz), 5.12 (dd, 1H, CH2,
J = 8.8/1.7 Hz), 5.23 (dd, 1H, CH2, J = 17.0/1.7 Hz), 5.83 (ddt,
5.2.1.5. 15,15,16,16,17,17,18,18,19,19,20,20,20-Tridecafluoro-
1H, = CH–, J = 17.0/8.8/5.5 Hz). 13C NMR (CDCl3):
d = 58.8 (s, 1C,
2,5,8,11-tetraoxaicosan-13-ol
(11). l,2-Epoxy-4,4,5,5,6,6,7,7,8,8,
CH3); 69.2, 70.3, 70.4, 71.7, 72.0 (5ꢁ s, 5ꢁ 1C, 5ꢁ CH2–O); 116.8 (s,
9,9,9-tridecafluorononane (5; 0.621 g; 1.66 mmol), 3,6,9-trioxa-
decan-1-ol (3; 1.65 g; 10 mmol), BF3ꢀEt2O (0.20 mL). Product 11
was obtained as yellowish liquid (0.785 g; 88%).
1C, CH2), 134.6 (s, 1C, –CH ).
Anal. Calcd. for C8H16O3: C, 59.98; H, 10.07. Found: C, 59.90; H,
10.02%.
1H NMR (CDCl3):
d
= 2.10–2.44 (m, 2H, CH2–RF), 3.33 (s, 3H,
CH3), 3.40–3.78 (m, 15H, 6ꢁ CH2–O and CH–O), 4.23 (bs, 1H, OH).
13C NMR (CDCl3):
= 34.4 (t, 1C, CH2–RF, J = 21 Hz), 58.8 (s, 1C,
5.2.2.3. 4,7,10,13-Tetraoxatetradec-1-ene (15). Sodium hydride
(60% suspension in oil; 2.40 g; 100 mmol) in Et2O (80 mL), 3,6,9-
trioxadecan-1-ol (3; 12.06 g; 73 mmol) in Et2O (20 mL), allyl
bromide (15.71 g; 130 mmol). Product 15 was obtained as
colourless liquid (13.497 g; 90%; b.p. 117–119 8C/5 mm Hg).
d
CH3), 64.1 (s, 1C, CH), 70.4 (s, 1C, CH2–O), 70.5 (s, 3C, 3ꢁ CH2–O);
70.7, 71.8 (2ꢁ s, 2ꢁ 1C, 2ꢁ CH2–O); 74.9 (s, 1C, CH2–CH), 105.0–
125.0 (m, 6C, 5ꢁ CF2 and CF3). 19F NMR (CDCl3):
d
= ꢂ81.3 (t, 3F,
CF3, J = 10.0 Hz), ꢂ113.2 (m, 2F, CH2–CF2); ꢂ122.3, ꢂ123.3, ꢂ124.1
(3ꢁ m, 3ꢁ 2F, 3ꢁ CF2); ꢂ126.6 (m, 2F, CF2–CF3).
Anal. Calcd. for C16H21F13O5: C, 35.57; H, 3.92. Found: C, 35.33;
H, 4.09%.
1H NMR (CDCl3):
CH2–O), 3.93 (d, 2H, CH2-allyl, J = 5.5 Hz), 5.09 (d, 1H, CH2,
J = 9.9 Hz), 5.20 (dd, 1H, CH2, J = 17.0/1.1 Hz), 5.82 (ddt, 1H, CH–
, J = 17.0/9.9/5.5 Hz). 13C NMR (CDCl3):
d
= 3.28 (s, 3H, CH3), 3.42–3.63 (m, 12H, 6ꢁ
d = 58.7 (s, 1C, CH3); 69.1,
70.2 (2ꢁ s, 2ꢁ 1C, 2ꢁ CH2–O); 70.3 (3ꢁ s, 3C, 3ꢁ CH2–O); 71.7, 71.9
(2ꢁ s, 2ꢁ 1C, 2ꢁ CH2–O); 116.7 (s, 1C, CH2), 134.5 (s, 1C, –CH ).
Anal. Calcd. for C10H20O4: C, 58.80; H, 9.87. Found: C, 58.79; H,
9.93%.
5.2.1.6. 15,15,16,16,17,17,18,18,19,19,20,20,21,21,22,22,22-Hepta-
decafluoro-2,5,8,11-tetraoxadocosan-13-ol (12). 1,2-Epoxy-4,4,5,5,
6,6,7,7,8,8,9,9,10,10,10-heptadecafluoroundecane (6; 0.619 g;
1.30 mmol), 3,6,9-trioxadecan-1-ol (3; 2.13 g; 13 mmol), BF3ꢀEt2O
Et2O (0.20 mL). Product 12 was obtained as yellowish liquid
(0.763 g; 91%).
5.2.3. General procedure for radical additions of perfluoroalkyl iodides
to allyl ethers 13–15
via AIBN: Allyl derivative 13–15, perfluoroalkyl iodide 16–18
(molar ratio 1:2) and AIBN (50 mg; two portions (2 mg ꢁ 50 mg)
were added in a hour interval) were heated under nitrogen
1H NMR (CDCl3):
CH3), 3.32–3.78 (m, 15H, 6ꢁ CH2–O and CH–O), 4.19 (bs, 1H, OH).
13C NMR (CDCl3):
= 34.3 (t, 1C, CH2–RF, J = 21 Hz), 58.6 (s, 1C,
d
= 2.05–2.40 (m, 2H, CH2–RF), 3.29 (s, 3H,
d

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314
atmosphere at 100 8C for 3 h. Volatile compounds were removed
under reduced pressure. The crude product 19–23 was purified by
column chromatography on silica gel (eluent:petroleum ether/
acetone 4:1, v/v).
1H NMR (CDCl3):
RF), 3.32 (s, 3H, CH3), 3.45–3.90 (m, 14H, 7ꢁ CH2–O), 4.21–4.38 (m,
1H, CH–I). 13C NMR (CDCl3):
= 14.2 (s, 1C, CH–I), 37.1 (t, 1C, CH2–
d
= 2.46–2.76 and 2.90–3.20 (2ꢁ m, 2H, CH2–
d
RF, J = 21 Hz), 58.8 (s, 1C, CH3); 70.3, 70.4, 70.4, 70.5, 70.5, 71.8 (6ꢁ
via sodium dithionite: Allyl derivative 13–15 and perfluoroalkyl
iodide 16–18 (molar ratio 1:2) were dissolved in acetonitrile.
Water was added followed by a mixture of Na2S2O4 and NaHCO3.
Reaction mixture was vigorously stirred at room temperature for
2 h. Water (150 mL) was then added and the mixture was
extracted with diethyl ether (5 mL ꢁ 50 mL). The organic fraction
was washed with brine (3 mL ꢁ 50 mL) and dried over MgSO4.
Diethyl ether and excess of perfluoroalkyl iodide were removed
under reduced pressure. The crude product 19–23 was purified by
column chromatography on silica gel (eluent:petroleum ether/
acetone 4:1, v/v).
s, 6ꢁ 1C, 6ꢁ CH2–O); 75.9 (s, 1C, CH2–CHI), 105.0–125.0 (m, 4C, 3ꢁ
CF2 and CF3). 19F NMR (CDCl3):
d
= ꢂ81.7 (tt, 3F, CF3, J = 3.0/
10.5 Hz), ꢂ113.0 (m, 2F, CH2–CF2), ꢂ124.6 (m, 2F, CF2), ꢂ126.4 (m,
2F, CF2–CF3).
Anal. Calcd. for C14H20F9IO4: C, 30.56; H, 3.66. Found: C, 30.56;
H, 3.76%.
5.2.3.4. 15,15,16,16,17,17,18,18,19,19,20,20,20-Tridecafluoro-13–
iodo-2,5,8,11-tetraoxaicosane (22). Via AIBN: 4,7,10,13-Tetraoxate-
tradec-1-ene (15; 2.040 g; 10 mmol), perfluorohexyl iodide (17;
8.910 g; 20 mmol), AIBN (150 mg). Product 22 was obtained as
yellowish liquid (6.177 g; 95%).
5.2.3.1. 9,9,10,10,11,11,12,12,13,13,14,14,14-Tridecafluoro-7-iodo-
2,5-dioxatetradecane (19). Via AIBN: 4,7-Dioxaoct-1-ene (13;
1.162 g; 10 mmol), perfluorohexyl iodide (17; 8.910 g; 20 mmol),
AIBN (150 mg). Product 19 was obtained as yellowish liquid
(5.112 g; 91%).
Via sodium dithionite: 4,7-Dioxaoct-1-ene (13; 0.750 g;
6.45 mmol), perfluorohexyl iodide (17; 5.354 g; 12.0 mmol),
acetonitrile (180 mL), water (45 mL), Na2S2O4 (85%, 6.750 g;
30.0 mmol), NaHCO3 (2.522 g; 30.0 mmol). Product 19 was
obtained as yellowish liquid (3.306 g; 91%).
Via sodium dithionite: 4,7,10,13-Tetraoxatetradec-1-ene (15;
0.530 g; 2.6 mmol), perfluorohexyl iodide (17; 1.800 g; 4.0 mmol),
acetonitrile (48 mL), water (12 mL), Na2S2O4 (85%, 2.250 g;
10.0 mmol), NaHCO3 (0.840 g; 10.0 mmol). Product 22 was
obtained as yellowish liquid (1.420 g; 85%).
1H NMR (CDCl3):
RF), 3.31 (s, 3H, CH3), 3.42–3.80 (m, 14H, 7ꢁ CH2-O), 4.27–4.35 (m,
1H, CH–I). 13C NMR (CDCl3):
= 14.2 (s, 1C, CH–I), 37.2 (t, 1C, CH2–
d
= 2.46–2.72 and 2.90–3.16 (2ꢁ m, 2H, CH2–
d
RF, J = 21 Hz), 58.7 (s, 1C, CH3); 70.3, 70.4, 70.4, 70.5, 71.7 (5ꢁ s, 5ꢁ
1C, 5ꢁ CH2–O); 75.9 (s, 1C, CH2–CHI), 104.0–126.0 (m, 6C, 5ꢁ CF2
1H NMR (CDCl3):
RF), 3.36 (s, 3H, CH3), 3.50–3.85 (m, 6H, 3ꢁ CH2–O), 4.29–4.41 (m,
1H, CH–I). 13C NMR (CDCl3):
= 14.2 (s, 1C, CH–I), 37.3 (t, 1C, CH2–
d
= 2.52–2.80 and 2.98–3.24 (2ꢁ m, 2H, CH2–
and CF3). 19F NMR (CDCl3):
d
= ꢂ81.3 (t, 3F, CF3, J = 9.9 Hz), ꢂ114.1
(m, 2F, CF2–CH2); ꢂ122.3, ꢂ123.3, ꢂ124.1, ꢂ126.6 (4ꢁ m, 4ꢁ 2F,
d
4ꢁ CF2).
RF, J = 21 Hz), 58.9 (s, 1C, CH3); 70.4, 71.8, 76.2 (3ꢁ s, 3ꢁ 1C, 3ꢁ
Anal. Calcd. for C16H20F13IO4: C, 29.56; H, 3.10. Found: C, 29.67;
H, 3.22%.
CH2–O); 104.0–127.0 (m, 6C, 5ꢁ CF2 and CF3). 19F NMR (CDCl3):
d
= ꢂ81.4 (t, 3F, CF3, J = 10 Hz), ꢂ114.1 (m, 2F, CF2–CH2); ꢂ122.2,
ꢂ123.3, ꢂ124.1, ꢂ126.6 (4ꢁ m, 4ꢁ 2F, 4ꢁ CF2).
Anal. Calcd. for C12H12F13IO2: C, 25.64; H, 2.15. Found: C, 25.55;
H, 2.20%.
5.2.3.5. 15,15,16,16,17,17,18,18,19,19,20,20,21,21,22,22,22-Hepta-
decafluoro-13–iodo-2,5,8,11-tetraoxadocosane
(23). Via
AIBN:
4,7,10,13-Tetraoxatetradec-1-ene (15; 1.630 g; 8 mmol), perfluor-
ooctyl iodide (18; 4.570 g; 15 mmol), AIBN (150 mg). Product 23
was obtained as yellowish liquid (5.670 g; 95%).
Via sodium dithionite: 4,7,10,13-Tetraoxatetradec-1-ene (15;
0.510 g; 2.5 mmol), perfluorooctyl iodide (18; 2.185 g; 4.0 mmol),
acetonitrile (50 mL), water (14 mL), Na2S2O4 (85%, 2.250 g;
10.0 mmol), NaHCO3 (0.840 g; 10.0 mmol). Product 23 was
obtained as yellowish liquid (1.050 g; 56%).
5.2.3.2. 12,12,13,13,14,14,15,15,16,16,17,17,17-Tridecafluoro-10–
iodo-2,5,8-trioxaheptadecane (20). Via AIBN: 4,7,10-Trioxaundec-
1-ene (14; 1.602 g; 10 mmol), perfluorohexyl iodide (17; 8.910 g;
20 mmol), AIBN (150 mg). Product 20 was obtained as yellowish
liquid (5.820 g; 96%).
Via sodium dithionite: 4,7,10-Trioxaundec-1-ene (14; 0.620 g;
3.78 mmol), perfluorohexyl iodide (17; 4.460 g; 10.0 mmol),
acetonitrile (100 mL), water (25 mL), Na2S2O4 (85%, 5.000 g;
25.0 mmol), NaHCO3 (2.131 g; 25.0 mmol). Product 20 was
obtained as yellowish liquid (1.907 g; 81%).
1H NMR (CDCl3):
RF), 3.29 (s, 3H, CH3), 3.40–3.84 (m, 14H, 7ꢁ CH2–O), 4.20–4.40 (m,
1H, CH–I). 13C NMR (CDCl3):
= 14.2 (s, 1C, CH–I), 37.2 (t, 1C, CH2–
d
= 2.42–2.76 and 2.84–3.18 (2ꢁ m, 2H, CH2–
d
RF, J = 22 Hz), 58.7 (s, 1C, CH3), 70.3 (s, 1C, CH2–O), 70.4 (s, 3C, 3ꢁ
1H NMR (CDCl3):
RF), 3.34 (s, 3H, CH3), 3.46–3.81 (m, 10H, 5ꢁ CH2–O), 4.26–4.40 (m,
1H, CH–I). 13C NMR (CDCl3):
= 14.3 (s, 1C, CH–I), 37.4 (t, 1C, CH2–
d
= 2.50–2.76 and 2.94–3.18 (2ꢁ m, 2H, CH2–
CH2–O); 70.5, 71.7 (2ꢁ s, 2ꢁ 1C, 2ꢁ CH2–O); 76.0 (s, 1C, CH2–CHI),
105.0–125.0 (m, 8C, 7ꢁ CF2 and CF3). 19F NMR (CDCl3):
d
= ꢂ81.6 (t,
d
3F, CF3, J = 10.3 Hz), ꢂ112.8 (m, 2F, CH2–CF2); ꢂ122.1, ꢂ122.3 (2ꢁ
m, 2ꢁ 2F, 2ꢁ CF2); ꢂ123.2 (m, 4F, 2ꢁ CF2), ꢂ123.7 (m, 2F, CF2),
ꢂ126.7 (m, 2F, CF2–CF3).
RF, J = 21 Hz), 58.8 (s, 1C, CH3); 70.4, 70.5, 70.6, 71.9 (4ꢁ s, 4ꢁ 1C,
4ꢁ CH2–O); 76.2 (s, 1C, CH2–CHI), 102.0–125.0 (m, 6C, 5ꢁ CF2 and
CF3). 19F NMR (CDCl3):
2F, CF2–CH2); ꢂ122, ꢂ123.4, ꢂ124.2, ꢂ126.7 (4ꢁ m, 4ꢁ 2F, 4ꢁ CF2).
Anal. Calcd. for C14H16F13IO3: C, 27.74; H, 2.66. Found: C, 27.69;
H, 2.74%.
d
= ꢂ81.5 (t, 3F, CF3, J = 10.4 Hz), ꢂ114.2 (m,
Anal. Calcd. for C18H20F17IO4: C, 28.82; H, 2.69. Found: C, 28.67;
H, 2.77%.
5.2.4. General procedure for reduction of C–I bond in adducts 19–23
Zinc and NiCl2ꢀ6H2O (molar ratio 10:1) were suspended in THF
and one drop of water was added. Suspension was stirred under
nitrogen atmosphere at r.t. for 30 min, then a solution of iodo
derivative 19–23 (1 equivalent per NiCl2) in THF was added.
Reaction mixture was stirred for 24 h, then filtered and insoluble
material was washed with THF. Volatile compounds were removed
under reduced pressure. Crude product 24–28 was purified by
column chromatography on silica gel (eluent:diethyl ether).
5.2.3.3. 15,15,16,16,17,17,18,18,18-Nonafluoro-13–iodo-2,5,8,11-
tetraoxaoctadecane (21). Via AIBN: 4,7,10,13-Tetraoxatetradec-1-
ene (15; 2.249 g; 11 mmol), perfluorobutyl iodide (16; 5.193 g;
15 mmol), AIBN (150 mg). Product 21 was obtained as yellowish
liquid (5.282 g; 87%).
Via sodium dithionite: 4,7,10,13-Tetraoxatetradec-1-ene (15;
0.510 g; 2.5 mmol), perfluorobutyl iodide (16; 1.386 g; 4.0 mmol),
acetonitrile (50 mL), water (13 mL), Na2S2O4 (85%, 2.250 g;
10.0 mmol), NaHCO3 (0.840 g; 10.0 mmol). Product 21 was
obtained as yellowish liquid (1.182 g; 86%).
5.2.4.1. 9,9,10,10,11,11,12,12,13,13,14,14,14-Tridecafluoro-2,5-diox-
atetradecane (24). Zinc (1.300 g; 20 mmol), NiCl2ꢀ6H2O (0.483 g;

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315
2.0 mmol), THF (10 mL), water (one drop), 2,5-dioxa-
9,9,10,10,11,11,12,12,13,13,14,14,14-tridecafluoro-7-iodotetrade-
cane (19; 1.124 g; 2.0 mmol). Product 24 was obtained as
yellowish liquid (0.450 g; 52%).
15,15,16,16,17,17,18,18,19,19,20,20,21,21,22,22,22-hepta-
decafluoro-13-iodo-2,5,8,11-tetraoxadocosane (23; 0.750 g;
1.0 mmol). Product 28 was obtained as yellowish liquid (0.407 g;
64%).
1H NMR (CDCl3):
(m, 2H, CH2–RF), 3.35 (s, 3H, CH3), 3.44–3.74 (m, 6H, 3ꢁ CH2–O).
13C NMR (CDCl3):
= 20.7 (s, 1C, CH2–CH2–RF), 27.9 (t, 1C, CH2–RF,
d
= 1.77–2.00 (m, 2H, CH2–CH2–RF), 2.02–2.35
1H NMR (CDCl3):
d
= 1.75–1.90 (m, 2H, CH2–CH2–RF), 2.00–2.28
(m, 2H, CH2–RF), 3.31 (s, 3H, CH3), 3.40–3.80 (m, 14H, 7ꢁ CH2–O).
13C NMR (CDCl3):
= 20.6 (s, 1C, CH2–CH2–RF), 27.8 (t, 1C, CH2–RF,
d
d
J = 22.2 Hz), 58.9 (s, 1C, CH3); 69.7, 70.1, 71.9 (3ꢁ s, 3ꢁ 1C, 3ꢁ CH2);
J = 22.8 Hz), 58.7 (s, 1C, CH3); 69.5, 70.1, 70.4 (3ꢁ s, 3ꢁ 1C, 3ꢁ CH2);
105.0–125.0 (m, 6C, 5ꢁ CF2 and CF3). 19F NMR (CDCl3):
d
= ꢂ81.4
70.5 (s, 3C, 3ꢁ CH2), 71.8 (s, 1C, CH2), 102.0–125.0 (m, 8C, 7ꢁ CF2
(tt, 3F, CF3, J = 2.3/10.5 Hz), ꢂ113.2 (m, 2F, CF2–CH2); ꢂ122.3,
ꢂ123.3, ꢂ124.1, ꢂ126.6 (4ꢁ m, 4ꢁ 2F, 4ꢁ CF2).
Anal. Calcd. for C12H13F13O2: C, 33.04; H, 3.00. Found: C, 33.17;
H, 2.99%.
and CF3). 19F NMR (CDCl3):
d
= ꢂ81.6 (t, 3F, CF3, J = 10.3 Hz),
ꢂ112.9 (m, 2F, CH2–CF2), ꢂ122.1 (m, 2F, CF2), ꢂ122.3 (m, 4F, 2ꢁ
CF2); ꢂ123.2, ꢂ123.7 (2ꢁ m, 2ꢁ 2F, 2ꢁ CF2); ꢂ126.7 (m, 2F, CF2–
CF3).
Anal. Calcd. for C18H21F17O4: C, 34.63; H, 3.39. Found: C, 34.75;
H, 3.44%.
5.2.4.2. 12,12,13,13,14,14,15,15,16,16,17,17,17-Tridecafluoro-2,5,8-
trioxaheptadecane (25). Zinc (1.300 g; 20 mmol), NiCl2ꢀ6H2O
(0.483 g; 2.0 mmol), THF (10 mL), water (one drop),
12,12,13,13,14,14,15,15,16,16,17,17,17-tridecafluoro-10-iodo-
2,5,8-trioxaheptadecane (20; 1.204 g; 2.0 mmol). Product 25 was
obtained as yellowish liquid (0.390 g; 41%).
5.2.5. Preparation of standard for testing – xylitol derivative 31
5.2.5.1. 5-O-(4,4,5,5,6,6,7,7,8,8,9,9,9,-Tridecafluoro-2-hydroxynonyl)-
1,2;3,4-di-O-isopropylidene-DL-xylitol (30). 1,2:3,4-Di-O-isopropyli-
dene-DL-xylitol (29; 2.320 g; 10 mmol), 1,2-epoxy-4,4,5,5,6,6,7,7,
8,8,9,9,9-tridecafluorononane (5; 3.761 g; 10 mmol) and
BF3ꢀEt2O (0.20 mL) were heated at 80 8C for 8 h while stirring.
After cooling down, volatile compounds were removed under
reduced pressure. Crude product was purified by column
chromatography on silica gel (eluent:petroleum ether/acetone
4:1, v/v). Product 30 was obtained as yellowish viscous liquid
(5.122 g; 84%).
1H NMR (CDCl3):
(m, 2H, CH2–RF), 3.36 (s, 3H, CH3), 3.44–3.70 (m, 10H, 5ꢁ CH2–O).
13C NMR (CDCl3):
= 28.5 (s, 1C, CH2–CH2–RF), 29.7 (t, 1C, CH2–RF,
d = 1.77–1.94 (m, 2H, CH2–CH2–RF), 2.05–2.30
d
J = 22 Hz), 58.9 (s, 1C, CH3); 70.5, 70.7, 71.8, 74.9 (4ꢁ s, 4ꢁ 1C, 4ꢁ
CH2); 105.0–125.0 (m, 6C, 5ꢁ CF2 and CF3). 19F NMR (CDCl3):
d
= ꢂ81.4 (t, 3F, CF3, J = 9.9 Hz), ꢂ113.3 (m, 2F, CF2–CH2); ꢂ122.3,
ꢂ123.3, ꢂ124.1, ꢂ126.6 (4ꢁ m, 4ꢁ 2F, 4ꢁ CF2).
Anal. Calcd. for C14H17F13O3: C, 35.01; H, 3.57. Found: C, 35.24;
H, 3.68%.
1H NMR (CDCl3):
d
= 1.16, 1.18, 1.37 and 1.43 (4ꢁ s, 12H, 4ꢁ
CH3), 1.95–2.48 (m, 2H, CH2–RF), 2.72 (s, 1H, OH), 3.30–4.60 (m,
0
10H, 7ꢁ xylitol protons, CH–OH, CH21 –O). 13C NMR (CDCl3): 21.7
5.2.4.3. 15,15,16,16,17,17,18,18,18-Nonafluoro-2,5,8,11-tetraoxaoc-
tadecane (26). Zinc (0.790 g; 12 mmol), NiCl2ꢀ6H2O (0.281 g;
1.2 mmol), THF (10 mL), water (one drop), 15,15,16,16,
17,17,18,18,18-nonafluoro-13-iodo-2,5,8,11-tetraoxaoctadecane
(21; 0.833 g; 1.5 mmol). Product 26 was obtained as yellowish
liquid (0.390 g; 61%).
and 21.8 (2ꢁ s, 4C, 4ꢁ CH3), 34.7 (t, 1C, C-30, J = 21 Hz), 64.4 (s, 1C,
C-20), 66.7 and 68.2 (2ꢁ s, 1C, C-1), 69.0 (s, 1C, C-2), 69.2 (s, 1C, C-5),
71.4 (s, 1C, C-10), 72.4 (s, 2C, C-3, C-4), 109.4 (s, 2C, 2ꢁ quart. C),
105.0–125.0 (m, 6C, 5ꢁ CF2 and CF3). 19F NMR (CDCl3):
d
= ꢂ81.4 (t,
3F, CF3, J = 8.7 Hz), ꢂ114.1 (m, 2F, CF2–CH2); ꢂ122.2, ꢂ123.3,
1H NMR (CDCl3):
(m, 2H, CH2–RF), 3.30 (s, 3H, CH3), 3.40–3.80 (m, 14H, 7ꢁ CH2–O).
13C NMR (CDCl3):
= 20.5 (s, 1C, CH2–CH2–RF), 27.6 (t, 1C, CH2–RF,
d = 1.70–1.90 (m, 2H, CH2–CH2–RF), 2.00–2.30
ꢂ124.1, ꢂ126.6 (4ꢁ m, 4ꢁ 2F, 4ꢁ CF2).
Anal. Calcd. for C20H25F13O6: C, 39.48; H, 4.14. Found: C, 39.40;
H, 4.34%.
d
J = 22.7 Hz), 58.7 (s, 1C, CH3); 69.4, 70.0, 70.3 (3ꢁ s, 3ꢁ 1C, 3ꢁ CH2);
5.2.5.2. 5-O-(4,4,5,5,6,6,7,7,8,8,9,9,9-Tridecafluoro-2-hydroxyno-
nyl)-DL-xylitol (31). 5-O-(2-Hydroxy-4,4,5,5,6,6,7,7,8,8,9,9,9,-tride-
cafluorononyl)-1,2:3,4-di-O-isopropylidene-DL-xylitol (30;
5.120 g; 8.42 mmol) was dissolved in methanol (40 mL) and
hydrochloric acid (36%; 2 mL) was added. Reaction mixture was
stirred at room temperature for 1 h. Volatile compounds were then
removed under reduced pressure. Crude product 31 was purified
using activated charcoal. Product 31 was obtained as yellowish
semi-solid mass (4.223 g; 95%).
70.4 (s, 3C, 3ꢁ CH2), 71.7 (s, 1C, CH2), 105.0–125.0 (m, 4C, 3ꢁ CF2
and CF3). 19F NMR (CDCl3):
d
= ꢂ81.7 (tt, 3F, CF3, J = 3.0/9.4 Hz),
ꢂ113.0 (m, 2F, CH2–CF2), ꢂ124.7 (m, 2F, CF2), ꢂ126.4 (m, 2F, CF2–
CF3).
Anal. Calcd. for C14H21F9O4: C, 39.63; H, 4.99. Found: C, 39.67; H,
5.10%.
5.2.4.4. 15,15,16,16,17,17,18,18,19,19,20,20,20-Tridecafluoro-
2,5,8,11-tetraoxaicosane (27). Zinc (1.300 g; 20 mmol), NiCl2ꢀ6H2O
(0.483 g; 2.0 mmol), THF (10 mL), water (one drop), 15,15,16,
16,17,17,18,18,19,19,20,20,20-tridecafluoro-13-iodo-2,5,8,11-tet-
raoxaicosane (22; 1.133 g; 2.0 mmol). Product 27 was obtained as
yellowish liquid (0.650 g; 62%).
1H NMR (CD3OD):
d = 2.10–2.60 (m, 2H, CH2CF2), 3.40–4.35 (m,
10H, 4ꢁ CH–OH, CH2OH, 2ꢁ CH2–O), 4.86 (m, 5H, 5ꢁ OH). 13C NMR
(CD3OD):
d = 35.6 (t, 1C, CH2CF2, J = 20 Hz), 64.3 (s, 1C, C-1), 65.1 (s,
1C, C-20), 72.0 (s, 1C, C-2), 72.2 and 72.3 (2ꢁ s, 1C, C-3), 73 and 73.9
(2ꢁ s, 1C, C-4), 74.0 (s, 1C, C-5), 76.2 (s, 1C, C-10), 105.0–125.0 (m,
1H NMR (CDCl3):
(m, 2H, CH2–RF), 3.34 (s, 3H, CH3), 3.45–3.80 (m, 14H, 7ꢁ CH2–O).
13C NMR (CDCl3):
= 22.5 (s, 1C, CH2–CH2–RF), 27.4 (t, 1C, CH2–RF,
d = 1.74–1.94 (m, 2H, CH2–CH2–RF), 1.98–2.30
6C, 5ꢁ CF2 and CF3). 19F NMR (CD3OD):
d
= ꢂ81.0 (t, 3F, CF3,
J = 9.8 Hz), ꢂ112.4 (m, 2F, CF2–CH2); ꢂ121.5, ꢂ122.6, ꢂ123.3,
d
ꢂ126.0 (4ꢁ m, 4ꢁ 2F, 4ꢁ CF2).
J = 19.4 Hz), 58.9 (s, 1C, CH3); 60.1, 62.0, 69.3, 69.7, 69.8, 70.0, 70.2
(7ꢁ s, 7ꢁ 1C, 7ꢁ CH2); 102.0–125.0 (m, 6C, 5ꢁ CF2 and CF3). 19F
Anal. Calcd. for C14H17F13O6: C, 31.83; H, 3.24. Found: C, 31.55;
H, 3.33%.
NMR (CDCl3):
d
= ꢂ81.3 (tt, 3F, CF3 J = 2.4/10.8 Hz), ꢂ113.2 (m, 2F,
CF2–CH2); ꢂ122.3, ꢂ123.3, ꢂ124.1, ꢂ126.6 (4ꢁ m, 4ꢁ 2F, 4ꢁ CF2).
Anal. Calcd. for C16H21F13O4: C, 36.65; H, 4.04. Found: C, 36.89;
H, 3.92%.
5.3. Co-emulsifying properties of the novel amphiphiles
5.3.1. Preparation of the emulsions
Perfluorodecalin (0.125 mL) was mixed with isotonic Tris–HCl
buffer of pH 7.4 and Pluronic F-68 (block co-polymer of
polyoxypropylene and polyoxyethylene, 5%, w/v) as a standard
5.2.4.5. 15,15,16,16,17,17,18,18,19,19,20,20,21,21,22,22,22-Hepta-
decafluoro-2,5,8,11-tetraoxadocosane (28). Zinc (0.520 g; 8 mmol),
NiCl2ꢀ6H2O (0.190 g; 0.8 mmol), THF (8 mL), water (one drop),

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316
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of an emulsion.
5.3.2. Testing of co-emulsifying properties
In the preparation of an emulsion (see above), Pluronic F-68 was
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any apparent phase separation of water and perfluorodecalin
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iodides. The research was supported by the Grant Agency of the
Czech Republic (Project 203/01/1131) and of the Ministry of
Education of the Czech Republic (Project MSM 6046137301).
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