Synthesis of novel fluorous surfactants for microdroplet stabilisation in fluorous oil streams

Article abstract of DOI:10.1016/j.jfluchem.2009.12.010

The synthesis of a number of potential fluorous surfactants, prepared with a view to stabilising microdroplets in microfluidic systems is described. The surfactants comprised compounds with both perfluoropolyether (PFPE) and perfluoroalkyl (PFA) tails with three classes of hydrophilic head group, including crown ethers and hexaethylene glycol. Hydrophilic head groups and alkyl fluorous-based tails were coupled together via amide, ester and ether linkages to afford the fluorous surfactant candidates in good yields. The resulting molecules show promise in forming and stabilising both aqueous and non-aqueous microdroplets in fluorous oil streams within poly(dimethylsiloxane) (PDMS) devices to a greater degree than the pseudosurfactants commonly employed in microdroplet research. Crown Copyright

Full text of DOI:10.1016/j.jfluchem.2009.12.010

Journal of Fluorine Chemistry 131 (2010) 398–407
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Synthesis of novel fluorous surfactants for microdroplet stabilisation in
fluorous oil streams
1
*
Daniel J. Holt, Richard J. Payne , Chris Abell
University Chemical Laboratory, Lensfield Road, Cambridge CB2 1EW, UK
A R T I C L E I N F O
A B S T R A C T
Article history:
The synthesis of a number of potential fluorous surfactants, prepared with a view to stabilising
microdroplets in microfluidic systems is described. The surfactants comprised compounds with both
perfluoropolyether (PFPE) and perfluoroalkyl (PFA) tails with three classes of hydrophilic head group,
including crown ethers and hexaethylene glycol. Hydrophilic head groups and alkyl fluorous-based tails
were coupled together via amide, ester and ether linkages to afford the fluorous surfactant candidates in
good yields. The resulting molecules show promise in forming and stabilising both aqueous and non-
aqueous microdroplets in fluorous oil streams within poly(dimethylsiloxane) (PDMS) devices to a
greater degree than the pseudosurfactants commonly employed in microdroplet research.
Crown Copyright ß 2009 Published by Elsevier B.V. All rights reserved.
Received 27 August 2009
Received in revised form 9 December 2009
Accepted 12 December 2009
Available online 22 December 2009
Keywords:
Fluorosurfactant
Microdroplet
Synthesis
Perfluoropolyether
1. Introduction
require careful control of the various interfacial or surface tensions
within a microfluidic device to ensure successful droplet creation
Microdroplets within microfluidic environments are receiving
considerable attention as a route towards miniaturisation of many
biological and chemical systems, with concomitant benefits such
as a reduction in the amounts of sample required, increased
reaction efficiency in small volumes and increased throughput for
large screens [1,2].
Microdroplet formation requires a droplet phase flowing within
an immiscible carrier phase [3,4]. Fluorous oils [5] are increasingly
used as a carrier phase for aqueous droplets due to the high degree
of immiscibility between the two phases [6–9]. Aqueous droplets
are easy to form in such an environment at a wide variety of flow
rates. Further, fluorous oils permit the formation of non-aqueous
droplet environments due to the low fluorophilicity of common
organic solvents [11,12]. Any biologically or chemically active
contents of the droplets will also have lower partition coefficients
in fluorous oils relative to hydrocarbon oils. Therefore, fluorous oils
and stabilisation. While the surfaces within the device play an
important role in droplet formation [13], the interfacial tension
between organic or aqueous microdroplets within a stream of
fluorous oil (and thus their stability with respect to coalescence)
may only be altered by the addition of fluorous surfactants. It is
only relatively recently that surfactants to stabilise such a
microfluidic environment have received attention [11,10].
Synthesis of fluorosurfactants is a non-trivial exercise due to
the amphiphilic nature of the molecules produced, requiring
specialised fluorous phase purification [14]. This paper presents
the synthesis of 13 novel fluorosurfactant molecules as part of
investigations towards the use of microdroplets as reactors for
chemical and biological transformations, particularly regarding
the possibility of creating and stabilising microdroplets of common
organic solvents for use in chemical synthesis. The performance of
these surfactants for creation and stabilisation of both aqueous and
non-aqueous microdroplets is introduced.
represent
a more suitable carrier phase for such droplets,
permitting a wide degree of biological screening or synthetic
chemical reactions within droplets.
2. Surfactant molecule design
However, because such droplets are only metastable – that is,
they are prone to coalescence on contact with each other, they
A surfactant for a general oil–water emulsion comprises three
elements: a hydrophobic portion which will remain dissolved in
the oil phase, a hydrophilic portion, which will dissolve at least
partly into the aqueous phase, and a linker between the two [15].
For a fluorous oil–water emulsion, the hydrophobic portion of the
required surfactant will be a fluorocarbon. To maximise the use of
these surfactants in creating both aqueous and organic droplets, a
variety of head groups need to be created with variations in their
* Corresponding author at: University Chemical Laboratory, University of
Cambridge, Lensfield Road, Cambridge CB2 1EW, UK. Tel.: +44 1223 336405;
fax: +44 1223 336362.
E-mail address: ca26@cam.ac.uk (C. Abell).
1
Current address: School of Chemistry, The University of Sydney, NSW 2006,
Australia.
0022-1139/$ – see front matter. Crown Copyright ß 2009 Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2009.12.010

D.J. Holt et al. / Journal of Fluorine Chemistry 131 (2010) 398–407
399
Fig. 1. (a) The fluorous tails used in surfactant synthesis 1–3, and (b–d) the fluorosurfactant molecules 4–16.
ability to hydrogen bond, their van der Waals potential, and their
chemical similarity to common organic solvents (via assessment of
relative solubility parameters [16]). These surfactants need to be
simple enough to synthesise but robust enough such that they will
not degrade on use.
the greater free energy difference of transferring a –CF2– group
from the bulk state to a micellar environment relative to that of a –
CH2– group [19]. It is estimated that the gcmc of a fluorinated
surfactant is close to that of a hydrocarbon surfactant with 1.5
times the chain length.
The typical performance for a hydrocarbon surfactant is to
lower the interfacial tension to around 20–25 mN/m. A solution of
the common hydrocarbon surfactant Span 80 in dodecane was
There are a number of reports describing the synthesis of
fluorosurfactants [20–24]. These compounds are generally synthe-
sised by the conjugation of a perfluoroalkyl chain to a variety of
hydrophilic head groups via a variety of chemical linkers. Examples
of polar head groups include polyethers, [25,26], polyoxyethylenes
[27], amines [28,29] and carbonyl or sulfonyl groups [30,19].
However, to our knowledge, there are currently no commercially
available fluorosurfactants and, as such, synthesis of candidate
fluorosurfactants for more stable microdroplet creation is neces-
sary. For the purposes of this study, novel surfactants were
found to have a
g
cmc of 22.4 mN/m and a CMC of 1:9 ꢀ 10ꢁ5 M [17],
although gcmc will be strongly dependant on the nature of the oil
phase.
Fluorous surfactants have generally been found to be more
effective than hydrocarbon surfactants of comparable properties
(identical chain lengths and head groups), with lower gcmc values
and lower CMCs [18,19]. This has been rationalised as being due to

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D.J. Holt et al. / Journal of Fluorine Chemistry 131 (2010) 398–407
Fig. 2. Synthetic schemes for the formation of fluorosurfactants with carbohydrate head groups (4–6).
designed to tailor the affinity for stabilising both aqueous and non-
aqueous microdroplets.
be conjugated to the aforementioned fluorous tails. These include a
number of monosaccharides (Fig. 1b), crown ethers (Fig. 1c) and
hexaethylene glycol (Fig. 1d). It was anticipated that these would
display varied abilities to hydrogen bond with the aqueous phase
when combined with the various fluorous tails. Surfactants
2.1. Selection of fluorous tails for surfactant molecules
Fluorinert FC-77 (3 M), comprising several low molecular
weight fluorous ethers,2 is frequently used as the fluorous oil
phase in microdroplet devices [8]. As such, it was anticipated that
simple perfluoroalkyl (PFA) or perfluoroalkyl polyether (PFPE)-
based compounds would be a suitable starting point for the
compounds possessing surfactant properties due to their structur-
al similarity with the oil phase.
Surfactants were designed to include three different fluorous
tails. These include two different PFA chains; a (perfluoroocta-
noyl)-propan-1-ol 1 and a perfluorooctanoyl 2, and a PFPE chain of
defined molecular weight containing four repeating units 3
(Fig. 1a). These three fluorous chains terminate in alcohol, acid
chloride and acid fluoride functionalities, thus permitting conju-
gation to suitable polar head groups.
possessing carbohydrate head groups include: 4 containing
keto-L-gulonic acid, 5 and 6 containing D-glucose, 7 containing
D-galactose and 8 and 9 containing D-galactos-1-amine. Two
different crown ether head groups were proposed including
aminomethyl 15-crown-5 in 10 and 11 and aza-18-crown-6 in
12 and 13, while hexaethylene glycol was selected for 14–16.
These various polar head groups are linked via ester, amide and
ether functionalities to the PFA and PFPE chains described above.
3. Results and discussion
3.1. Fluorosurfactant synthesis
The synthesis of keto-L-gulonic acid-based ester 4 started from
the suitably protected precursor 2,3:4,6-di-O-isopropylidene-2-
keto-L-gulonic acid 17 (Fig. 2). This was coupled to 3-(perfluor-
ooctyl)propan-1-ol 1 using DCC to afford the desired ester 18 in
moderate yield. Deprotection of the acetonide groups was
achieved using 90% aqueous TFA to furnish the desired ester 4
in 91% yield.
2.2. Selection of hydrophilic head groups for surfactant molecules
The fluorosurfactants designed in this study are shown in
Fig. 1b–d. A variety of polar head groups were selected that could
2
The synthesis of D-glucose-based esters 5 and 6 began with
commercially available di-acetone-D-glucose 19 which allowed
FC-77 is a mixture of C7F16 and C8F16O in a batch-dependant ratio, with boiling
point 100 8C and density,
r
¼ 1:78 g/cm3.

D.J. Holt et al. / Journal of Fluorine Chemistry 131 (2010) 398–407
401
Fig. 3. Synthetic schemes for the formation of fluorosurfactants with carbohydrate head groups (7–9).
for selective acylation reactions on the C-3 alcohol (Fig. 2).
Preparation of 5 involved initial esterification of 19 by deprotona-
tion of the C-3 alcohol with n-butyllithium followed by the
addition of perfluorooctanoyl chloride 2 to give protected ester 20
in 74% yield. Acetonide deprotection was achieved by treatment
with 90% aqueous TFA followed by fluorous solid phase extraction
followed by purification by fluorous SPE furnished the D-galactose-
based ester 7 as a mixture of - and -anomers.
The synthesis of amides 8 and 9 bearing a D-galactopyransy-
lamine polar head group began from perpivaloylated derivative 24
(Fig. 3). Preparation of 8 involved deprotonation of 24 with
triethylamine followed by treatment with perfluorooctanoyl
a
b
(SPE) [14] to afford 5 as a mixture of
a
- and
b
-anomers in 86%
chloride 2 to afford protected amide 25 as solely the b-anomer
yield.
in 96% yield. Hydrolysis of the pivaloyl esters was achieved by
treatment with lithium hydroxide which, after purification by
fluorous SPE, gave 8 in 97% yield. In a similar manner, 9 was
prepared by initial deprotonation of 24 with triethylamine in a
mixture of THF and methoxynonafluorobutane (2:1, v/v). Addition
of the acid fluoride 3 and pyridine gave the desired amide 26 in 40%
yield. Hydrolysis of the pivaloyl esters followed by purification by
fluorous SPE gave amide 9 in 97% yield.
Preparation of
6 entailed deprotonation of 19 using n-
butyllithium in a mixture of THF and methoxynonafluorobutane
(1:2, v/v) followed by the addition of perfluoro-2,5,8,11-tetra-
methyl-3,6,9,12-tetraoxapentadecanoyl fluoride 3 and pyridine to
afford the desired ester 21 in 75% yield. The use of methoxynona-
fluorobutane as the solvent was necessary to solubilise the
branched fluorous chain of 3, while pyridine was used to neutralise
any excess hydrofluoric acid liberated upon formation of the ester.
Acetonide deprotection was achieved by treatment with 90%
aqueous TFA followed by purification by fluorous solid phase
extraction [14] to afford 6 in 95% yield.
Preparation of the D-galactose-based ester 7 began from
1,2:3,4-di-O-isopropylidene-D-galactopyranose 22 which allowed
for selective derivatisation of the C-6 hydroxyl group (Fig. 3).
Deprotonation of 22 with n-butyllithium followed by addition of
perfluorooctanoyl chloride 2 gave ester 23 in 79% yield. Treatment
with 90% aqueous TFA to remove the acetonide protecting groups
3.2. Synthesis of surfactants with crown ether head groups
Amides 10 and 12 bearing a perfluorooctanoyl chain were
synthesised in a similar manner to that described for carbohy-
drate-based analogue 8. Briefly, treatment of 15-crown-5 27 or 1-
aza-18-crown-6 28 with triethylamine and perfluorooctanoyl
chloride 2 followed by purification by fluorous SPE gave 10 and
12 in 96% and 77% yield respectively (Fig. 4). Amides 11 and 13
bearing a PFPE chain were synthesised in a similar manner to that

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D.J. Holt et al. / Journal of Fluorine Chemistry 131 (2010) 398–407
Fig. 4. The formation of fluorosurfactants with crown ether head groups (10–13).
described for 9. This involved deprotonation of 15-crown-5 27 or
1-aza-18-crown-6 28 with triethylamine in a mixture of THF and
methoxynonafluorobutane (2:1, v/v) followed by addition of acid
fluoride 3 and pyridine to afford, after silica gel chromatography,
the crown ether-based amides 11 and 13 in 27% and 49% yield
respectively (Fig. 4).
with tosylate 30 to afford the desired ether 16 in 32% yield after
fluorous SPE (Fig. 5).
Having completed the synthesis of molecules 4–16, their
surfactant properties were assessed with respect to the stabilisa-
tion of aqueous and non-aqueous microdroplets.
3.4. Creation of aqueous and non-aqueous microdroplets using
synthesised fluorosurfactants
3.3. Synthesis of surfactants with hexaethylene glycol head groups
In order to create molecules 14–16 possessing hexaethylene
glycol head groups it was first necessary to achieve either
monoprotection or monoactivation of a terminal hydroxyl group
on the hexaethylene chain therefore allowing for selective
modifications with fluorous derivatives 1, 2 and 3[31]. Activation
of hexaethyleneglycol 29 was achieved by mono-tosylation,
whereby the diol was reacted with silver (I) oxide and potassium
iodide in the presence of tosyl chloride to afford 30 in 67% yield
(Fig. 5). Mono-benzylation of 29 was achieved under similar
conditions using benzyl bromide in place of tosyl chloride to afford
31 in 68% yield.
Ester 14 bearing a perfluorooctanoyl chain was synthesised by
deprotonation of 31 with n-butyllithium followed by addition of
perfluorooctanoyl chloride 2 to afford benzyl protected ester 32 in
63% yield (Fig. 5). Hydrogenolysis of 32 furnished ester 14 in 76%
yield after fluorous SPE. In a similar manner, acid fluoride 3 and
pyridine were added to a deprotonated solution of 31 in a mixture
of THF and methoxynonafluorobutane (3:2, v/v) to afford 33 in 70%
yield which, upon hydrogenolysis and fluorous SPE, gave the
desired ester 15 in 89% yield.
To demonstrate that the molecules described above are
suitable surfactant candidates for the production and stabilisation
of microdroplets, a number of the synthesised surfactants were
added to the fluorous oil phase (FC-77) to create droplets of both
aqueous and organic solvents within channels in poly(dimethyl-
siloxane) (PDMS) microdevices (Fig. 6). Briefly, amide 11 was used
at 2.5 mM concentration to create droplets of methanol within
microdevices. Surfactant 15 was used at 1.6 mM concentration to
produce droplets of acetonitrile. Such droplets could not be
formed in the absence of surfactant, where the organic solvent
coflows with the fluorous oil phase, and may even in some cases
promote breakup of the oil phase to create fluorous droplets in an
organic solvent carrier phase (Fig. 6a). Lastly, surfactant 15 was
used at 13
mM concentration to stabilise water droplets within
microdevices. Such droplets were stable upon entering the exit
reservoir of the microdevice. This behaviour does not occur in the
absence of surfactant, where droplets coalesce upon entering the
reservoir.
The relative effectiveness and efficiency of these surfactant
molecules towards forming and stabilising both aqueous and non-
aqueous microdroplets remains to be investigated in more detail,
results of which will be reported in due course.
Preparation of ether-linked molecule 16 involved deprotona-
tion of 3-(perfluorooctyl)propan-1-ol 1 followed by treatment

D.J. Holt et al. / Journal of Fluorine Chemistry 131 (2010) 398–407
403
Fig. 6. Flows of water and organic solvents in fluorous-coated PDMS devices with
and without fluorous surfactants using FC-77 as the fluorous oil phase. (a) Without
surfactant, methanol with fluorous oil at total flow rates of 150
ml/h, produces a
coflowing stream before droplets of fluorous oil are created in a stream of methanol.
(b) With 2.5 mM of molecule 11 as surfactant in the oil phase, methanol droplets are
created in the channel within the fluorous oil stream. (c) Without surfactant,
acetonitrile coflows with fluorous oil at flow rates of 400
molecule 15 as surfactant in the oil phase, acetonitrile droplets are created in the
channel. (e) With 13 M of molecule 15 as surfactant in the oil phase, water
droplets exiting the microchannel into the larger reservoir are stabilised against
coalescence. The scale bar is 50 m. Fluids are flowing from left to right, being
ml/h. (d) With 1.6 mM of
m
m
created at flow junctions between oil and droplet phases to the left of the region
shown in the photographs.
for further study into the production of stable microdroplets in
such environments.
5. Experimental
5.1. Experimental procedures for surfactant synthesis
Chemicals used in surfactant synthesis were purchased from
Sigma–Aldrich Ltd. (Gillingham, UK) and Fluorochem Ltd (Derby-
shire, UK) and used as received. All non-aqueous reactions were
carried out in pre-dried glassware under an inert atmosphere (N2 or
Ar). Organic solvents were freshly distilled prior to use and milli-Q
deionised water was used for all synthetic and microfluidic work.
Analytical thin layer chromatography was carried out on commer-
cial silica gel 60 0.25 mm plates using either UV absorption or
potassium permanganate stain (3 g potassium permanganate, 20 g
potassium carbonate, 5 ml of 5% sodium hydroxide, 300 ml water)
for visualisation. Rf values are quoted with respect to the solvent
system used to develop the plate. Column chromatography was
carried out using 230–400 mesh silica gel 60. Fluorous solid phase
extraction (SPE) was performed using Fluoroflash columns pur-
chased from Fluorous Technologies, Inc. (Pittsburgh, USA). Unless
otherwise stated petroleum ether refers to the fraction collected
between 40 and 60 8C. 1H NMR spectra were recorded on a Bruker
AM-400 spectrometer in deuterated solvents, as indicated. 13C NMR
spectra were recorded on a Bruker Avance 500 spectrometer linked
to a Bruker 5 mm dual Cryoprobe operating at 125 MHz. 19F NMR
were recorded using a Bruker AVANCE 400 QNP spectrometer
operating at 376 MHz. All chemical shifts are quoted in parts per
Fig. 5. The formation of fluorosurfactants with hexaethylene glycol head groups
(14–16).
million (ppm) d
. Coupling constants for 1H and 19F NMR spectra are
4. Conclusions
assigned where possible and are given in Hz. 1H; 13C and 19F NMR
signals are assigned where possible. High resolution mass spec-
trometry was carried out using a Micromass Quadrapole-Time of
Flight (Q-TOF) spectrometer.
The synthesis of 13 potential fluorosurfactants containing a
number of hydrophilic head groups and fluoroalkane tails is
presented. The compounds were prepared using a variety of
coupling methods to bring together the fluorous tails and
hydrophilic head groups in good yields. A number of fluorosurfac-
tants demonstrated the ability to stabilise the interface between
fluorous oils and water, and also fluorous oils and organic solvents
to create both aqueous and non-aqueous microdroplets in
fluorous-coated PDMS devices. In the absence of surfactants such
microdroplets either cannot be formed or are prone to immediate
coalescence. As such, these molecules represent good candidates
5.1.1. Synthesis of (2R,3S,4R,5S)-4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,
11-heptadecafluoroundecyl 2,3,4-trihydroxy-5-
(hydroxymethyl)tetrahydrofuran-3-carboxylate (4)
DCC (1.08 g, 5.23 mmol) in anhydrous dichloromethane (4 ml)
was added dropwise to a mixture of 2,3:4,6-di-O-isopropylidene-
2-keto-L-gulonic acid monohydrate 17 (1.53 g, 5.23 mmol), 3-
(perfluorooctyl)propan-1-ol
1 (1 g, 2.09 mmol) and pyridine
(0.44 ml, 5.23 mmol) in dichloromethane (10 ml) at 0 8C. The

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D.J. Holt et al. / Journal of Fluorine Chemistry 131 (2010) 398–407
reaction was stirred at 22 8C for 24 h before filtering through a
small plug of celite and the solvent removed in vacuo. Purification
by column chromatography (eluent: 10:3, v/v petroleum ether/
ethyl acetate) gave the desired ester 18 as a pale yellow oil (0.53 g,
35%).
Ester 18 (90 mg, 0.12 mmol) was dissolved in 90 % TFA (1 ml)
and the reaction stirred at rt for 24 h. The solution was
concentrated in vacuo and resuspended in ethyl acetate (15 ml).
The organic fraction were washed with water, brine, dried
(Na2SO4) and the solvent removed in vacuo, giving the desired
tetraol 4 as a white solid (73 mg, 91%).
Ester 21 (200 mg, 0.19 mmol) was dissolved in 90% TFA (2 ml)
and the reaction stirred at 22 8C for 20 h. The solution was
evaporated and the resulting residue purified by fluorous SPE
(dissolved in MeOH and applied to a 2 ml cartridge) to give the
desired tetraol 6 as a cream oil as a mixture of diastereoisomers
(180 mg, 95%).
NMR: 1H (400 MHz, MeOD)
d (mixture of anomers) 3.47–3.58
(m, 2H), 3.64–3.85 (m, 2H), 4.10–4.15 (m, 1H), 4.45–4.70 (m, 2H),
5.13 (m, JCH ¼ 4:0, 9.5 Hz, 1H), 5.38 (t, JCH ¼ 9:5 Hz, 1H) ppm. 13
C
(125 MHz, MeOD)
d 60.7 (s, CH2), 66.3 (s, CH2), multiple peaks
between 67.8 and 82.3 (all s, CHOH & CH), 92.6 (s, CHOH), 96.8 (s,
CHOH), 99.5 (m, CF), 101.0 (m, CF), 103.5 (m, CF), 106.5 (m, CF),
108.5 (m, CF), 113.5 (m, CF2), 115.9 (m, CF2), 118.4 (m, CF2), 120.9
(m, CF2), 157.0 (m, CF3), 158.0 (m, –COO–) ppm. 19F (376 MHz,
NMR: 1H (400 MHz, MeOD)
d
1.95–2.10 (m, J ¼ 6:0 Hz, 2H,
CH2), 2.23–2.39 (m, J ¼ 8:0 Hz, 2H, CH2), 3.48–3.71 (m, J ¼ 2:0,
4.0, 6.0 Hz, 5H), 4.22–4.34 (m, J ¼ 6:0 Hz, 2H, CH2) ppm. 19F
(376 MHz, MeOD)
d
ꢁ78.7 (td, J ¼ 2:0, 10.0 Hz, CF3), ꢁ111.6 (m,
MeOD)
d
ꢁ77.1 (m, CF3), ꢁ82.6 (m, COCF2), ꢁ119.9 (m, CF2),
J ¼ 13:0 Hz, CH2CF2), ꢁ119.0 (m, CF2), - 112.0 (m, CF2), ꢁ120.0 (m,
CF2), ꢁ120.8 (m, CF2), ꢁ123.6 (m, J ¼ 6:0 Hz, CF2) ppm.
HRMS: for C17H15O7F17Na calcd 677.0439, found 677.0419.
ꢁ120.0 (s, CF2), ꢁ122.9 (s, CF2), ꢁ123.9 (m, CF2), ꢁ127.5 (m,
CF2) ppm.
HRMS: for C21H11O11F29Na calcd 1012.9731, found 1012.9774.
5.1.2. Synthesis of 2-(1,2-dihydroxyethyl)-4,5-
dihydroxytetrahydrofuran-3-yl 2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-
pentadecafluorooctanoate (5)
5.1.4. Synthesis of ((3R,4S,5R,6S)-3,4,5,6-tetrahydroxytetrahydro-
2H-pyran-2-yl)methyl 2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-
pentadecafluorooctanoate (7)
n-Butyllithium (1.26 ml of
a
1.6 M solution in hexanes,
n-Butyllithium (1.26 ml of a 1.6 M solution in hexanes,
2.02 mmol) was added dropwise over a period of 10 min to a
solution of di-acetone-D-glucose 19 (500 mg, 1.92 mmol) in THF
(10 ml) at ꢁ78 8C. The reaction was stirred at 22 8C for 1 h before
the dropwise addition of perfluorooctanoyl chloride 2 (2.08 g,
4.80 mmol). The reaction was stirred at 22 8C for 15 min before the
solvent was removed in vacuo at 30 8C. Purification by column
chromatography (eluent: 8:1, v/v petroleum ether/ethyl acetate)
gave the desired ester 20 as a colourless oil (930 mg, 74%).
Ester 20 (100 mg, 0.16 mmol) was dissolved in 90% TFA (1 ml)
and the reaction stirred at 22 8C for 24 h. The solution was
evaporated and the resulting residue purified by fluorous SPE
(dissolved in MeOH and applied to a 2 ml cartridge) to give the
2.02 mmol) was added dropwise over a period of 10 min to a
solution of 1,2:3,4-di-O-isopropylidene-D-galactopyranose 22
(500 mg, 1.92 mmol) in THF (10 ml) at ꢁ78 8C. The reaction was
stirred at 22 8C for 1 h before the dropwise addition of
perfluorooctanoyl chloride 2 (2.08 g, 4.80 mmol). The solution
was stirred at 22 8C for 20 min before the solvent was removed in
vacuo at 30 8C. Purification by column chromatography (eluent:
8:1, v/v petroleum ether/ethyl acetate) gave the desired ester 23 as
a white solid (1.00 g, 79%).
Ester 23 (240 mg, 0.37 mmol) was dissolved in 90% TFA (2.4 ml)
and the reaction stirred at 22 8C for 20 h. The solution was
evaporated and the resulting residue purified by fluorous solid
phase extraction (dissolved in MeOH and applied to a 2 ml
desired tetraol 5 as a cream oil as a mixture of
a
- and
b-anomers
(75 mg, 86%).
cartridge) to give the desired tetraol 7 as a mixture of a- and b-
anomers as a white solid (130 mg, 61%).
NMR: 1H (400 MHz, MeOD) (mixture of
a
- and -anomers)
b
d
3.40 (m, 2H), 3.58 (m, 3H), 3.67 (dd, J ¼ 6:0, 12.0 Hz, 1H), 3.72 (dd,
J ¼ 5:0, 12.0 Hz, 1H), 3.78 (dd, J ¼ 2:5, 12.0 Hz, 1H), 3.84 (dd,
J ¼ 2:0, 12.0 Hz, 2H), 4.56 (d, J ¼ 8:0 Hz, 1H), 5.09 (t, J ¼ 9:5 Hz,
1H), 5.14 (d, J ¼ 3:5 Hz, 1H), 5.38 (t, J ¼ 9:0 Hz, 1H) ppm. 13C
NMR: 1H (400 MHz, MeOD)
d
3.40–5.25 ppm multiple peaks
-anomers. 13C (125 MHz, MeOD)
between
59.0 and 104.0 multiple peaks arising from - and -anomers,
arising from
a
- and
b
d
b
a
105.7 (m, CF), 108.0 (m, CF), 110.5 (m, CF), 112.3 (m, CF), 113.3 (m,
CF), 115.8 (m, CF), 118.0 (m, CF), 157.3 (m, –OCO–) ppm. 19F
(125 MHz, MeOD) (mixture of
a- and b-anomers) d 62.1 (s, CH2),
62.2 (s, CH2), 69.2 (s, CH), 69.2 (s, CH), 71.6 (s, CH), 72.9 (s, CH), 74.0
(s, CH), 77.8 (s, CH), 82.3 (s, CH), 83.8 (s, CH), 94.0 (s, CHOH), 98.2 (s,
CHOH), 101.2, 109.5 (m, CF), 111.8 (m, CF), 114.2 (m, CF), 116.9 (m,
(376 MHz, MeOD)
CF2), ꢁ120.0 (s, CF2), ꢁ122.9 (s, CF2), ꢁ123.9 (m, CF2), ꢁ127.5 (m,
CF2) ppm.
d
ꢁ77.1 (m, CF3), ꢁ82.8 (m, COCF2), ꢁ120.0 (m,
CF), 118.8 (m, CF) 210.1 (s, –COO–) ppm. 19F (376 MHz, MeOD)
d
HRMS: for C14H11O11F15Na calcd 599.0147, found 599.0147.
ꢁ81.8 (m, CF3), ꢁ119.1 (m, C F2CO), ꢁ121.9 (m, CF), ꢁ122.1 (m, CF),
ꢁ122.6 (m, CF), ꢁ123.1 (m, CF), ꢁ126.7 (m, CF) ppm.
5.1.5. Synthesis of 2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-pentadecafluoro-N-
((2R,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-
2H-pyran-2-yl)octanamide (8)
HRMS: for C14H11O7F15Na calcd 599.0157, found 599.0158.
5.1.3. Synthesis of (2S,5S,8S,11S)-2-(1,2-dihydroxyethyl)-4,5-
dihydroxytetrahydrofuran-3-yl 2,4,4,5,7,7,8,10,10,11,13,13,14,14,14-
pentadecafluoro-2,5,8,11-tetrakis(trifluoromethyl)-3,6,9,12-
tetraoxatetradecan-1-oate (6)
Triethylamine (0.27 ml, 1.94 mmol) was added dropwise to a
solution of 2,3,4,6-tetra-O-pivaloyl-D-galactopyransylamine 24
(500 mg, 0.97 mmol) in THF (7 ml). The solution was cooled to
0 8C and perfluorooctanoyl chloride 2 (420 mg, 0.97 mmol) was
added dropwise over 15 min. The reaction was stirred at 0 8C for
1.5 h and at 22 8C for a further 18 h. The reaction was quenched
with saturated aqueous ammonium chloride solution (5 ml) before
the aqueous fraction was extracted with chloroform (3ꢀ 5 ml). The
combined organic fractions were washed with water, brine, dried
(Na2SO4) and the solvent removed in vacuo. Purification by column
chromatography (eluent: 8:1, v/v, petroleum ether/ethyl acetate)
gave the desired amide 25 as a white foam (0.85 g, 96%).
To a solution of tetrapivolate 25 (150 mg, 0.17 mmol) in MeOH
(3.5 ml) was added lithium hydroxide monohydrate (17.3 mg,
0.41 mmol). The reaction was stirred at 22 8C for 48 h before
n-Butyllithium (1.26 ml of
a 1.6 M solution in hexanes,
2.02 mmol) was added dropwise over a period of 10 min to a
solution of di-acetone-D-glucose 19 (500 mg, 1.92 mmol) in THF
(6 ml) and methoxynonafluorobutane (4 ml) at ꢁ78 8C. The
reaction was stirred at 22 8C for 1 h before the dropwise addition
of pyridine (0.39 ml, 4.80 mmol) and perfluoro-2,5,8,11-tetra-
methyl-3,6,9,12-tetraoxapentadecanoyl fluoride
3
(3.98 g,
4.80 mmol). The reaction was stirred at 22 8C for 30 min before
the solvent was removed in vacuo at 30 8C. Purification by column
chromatography (eluent: 8:1, v/v petroleum ether/ethyl acetate)
gave the desired ester 21 as a colourless oil (1.54 g, 75%).

D.J. Holt et al. / Journal of Fluorine Chemistry 131 (2010) 398–407
405
Dowex 50W-X8(H+) (0.52 g) was added and stirring continued for
a further 10 min. After the resin was filtered off the filtrate was
evaporated to give a residue, which was purified by fluorous SPE
(dissolved in MeOH and applied to a 2 ml cartridge) to give the
desired tetraol 8 as a cream oil (90 mg, 95%).
chloride 2 (766 mg, 1.77 mmol) was added dropwise over 15 min.
The reaction was stirred at 0 8C for 1.5 h and at 22 8C for a further
18 h. The reaction was diluted with chloroform (20 ml), the organic
fraction washed with saturated aqueous ammonium chloride
solution (25 ml), water (25 ml), brine (25 ml), dried (Na2SO4) and
the solvent removed in vacuo. Purification by column chromatog-
raphy (eluent: 95:5, v/v chloroform/methanol) gave the desired
NMR: 1H (400 MHz, MeOD)
d
3.53 (dd, J ¼ 3:5, 9.5 Hz, 1H,
CHOH), 3.60–3.78 (m, CHOH, CH2, 4H), 3.90 (m, 3.5 Hz, CH
(CH2OH)OC, 1H), 4.95 (d, J ¼ 9:0 Hz, CHNH, 1H) ppm. 13C
amide 10 as a yellow oil (1.10 g, 96%).
3
(125 MHz, MeOD)
d
62.4 (s, CH2), 70.4 (s, CHOH), 70.8 (s, CHOH),
NMR: 1H (400 MHz, CDCl3)
d
3.30–3.38 (m, JHH ¼ 6:0 Hz,
3
75.7 (s, CHOH), 78.8 (s, CHOH), 82.0 (s, CHOH), 110.2 (m, CF), 112.0
4JHH ¼ 1:5 Hz, 1H, –NHCH2–), 3.46–3.73 (m, JHH ¼ 6:0 Hz, 20H,
1
3
4
(m, CF), 114.0 (m, CF), 117.4 (t, JCF ¼ 13:0 Hz, CF2), 119.6 (t,
CH2), 3.86 (m, JHH ¼ 6:0 Hz, JHH ¼ 1:5 Hz, 1H, –NHCH2–), 7.47
1
1JCF ¼ 13:0 Hz, CF2), 121.9 (t, JCF ¼ 13:0 Hz, CF2), 159.5 (t,
(br s, 1H, NH) ppm. 13C (125 MHz, CDCl3)
d 42.3 (s, –NHCH2–),
2JCF ¼ 10:5 Hz, C OCF2) ppm. 19F (376 MHz, MeOD)
d
ꢁ81.9 (tt,
multiple peaks between 69.5 and 72.0 (all s), CH2), 76.4 (s, –
NHCH2C H–), 77.2 (s, –NHCH2C H–), 105.7–107.1 (m, JCF ¼ 28:0,
129.0 Hz, CF2), 107.7–109.2 (m, JCF ¼ 127:0 Hz, CF2), 109.8–111.4
(m, JCF ¼ 127:5 Hz, CF2), 112.0–113.8 (m, JCF ¼ 38:0, 126.5,
133 Hz, CF2), 115.8 (t, 1JCF ¼ 131:5 Hz, CF2), 118.1 (t,
3JFF ¼ 10:0 Hz, JFF ¼ 2:5 Hz, CF3), ꢁ120.3 (m, J ¼ 10:5 Hz, CF2),
ꢁ121.9 (m, CF2), ꢁ122.5 (m, CF2), ꢁ122.9 (m, CF2), ꢁ123.2 (m, CF2),
ꢁ126.8 (m, CF2) ppm.
4
HRMS: for C14H12NO6F15Na calcd 598.0317, found 598.0389.
1J
1
CF
¼ 131:5 Hz, CF2), 120.4 (t, JCF ¼ 131:5 Hz, CF3), 157.1 (t,
5.1.6. Synthesis of (2R,5R,8R,11R)-
1JCF ¼ 102:5 Hz, –CONH2–) ppm. 19F (376 MHz, CDCl3)
d
ꢁ81.4 (m,
3
2,4,4,5,7,7,8,10,10,11,13,13,14,14,14-pentadecafluoro-2,5,8,11-
tetrakis(trifluoromethyl)-N-((2R,3R,4S,5R,6R)-3,4,5-trihydroxy-6-
(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-3,6,9,12-
CF3), ꢁ120.1 (t, JFF ¼ 14:0 Hz, CF2NH), ꢁ122.1 (m, CF2), ꢁ122.5
(m, CF2), ꢁ123.0 (m, CF2), ꢁ123.2 (m, CF2), ꢁ126.7 (m, CF2) ppm.
HRMS: for C19H23NO6F29 calcd 646.1284, found 646.1294.
tetraoxatetradecan-1-amide (9)
Triethylamine (0.27 ml, 1.94 mmol) was added dropwise to a
solution of 2,3,4,6-tetra-O-pivaloyl-D-galactopyransylamine 24
(500 mg, 0.97 mmol) in THF (5 ml) and methoxynonafluorobutane
(2.5 ml). The solution was cooled to 0 8C and pyridine (0.08 ml,
0.97 mmol) and perfluoro-2,5,8,11-tetramethyl-3,6,9,12-tetraox-
5.1.8. Synthesis of (2R,5R,8R,11R)-N-((1,4,7,10,13-
pentaoxacyclopentadecan-2-yl)methyl)-2,4,4,5,7,7,8,10,10,11,13,13,
14,14,14-pentadecafluoro-2,5,8,11-tetrakis(trifluoromethyl)-
3,6,9,12-tetraoxatetradecan-1-amide (11)
Triethylamine (0.41 ml, 2.90 mmol) was added dropwise to a
solution of aminomethyl 15-crown-5 27 (0.32 ml, 1.46 mmol) in
THF (5 ml) and methoxynonafluorobutane (2.5 ml). The solution
was cooled to 0 8C and pyridine (0.12 ml, 1.46 mmol) and
perfluoro-2,5,8,11-tetramethyl-3,6,9,12-tetraoxapentadecanoyl
fluoride 3 (1.21 g, 1.46 mmol) was added dropwise over 15 min.
The reaction was stirred at 0 8C for 1.5 h and at 22 8C for a further
18 h. The reaction was diluted with chloroform (20 ml), the organic
fraction washed with saturated aqueous ammonium chloride
solution (25 ml), water (25 ml), brine (25 ml), dried (Na2SO4) and
the solvent removed in vacuo. Purification by column chromatog-
raphy (eluent: 9:1, v/v chloroform/methanol) gave the desired
amide 11 as a mixture of diastereoisomers as a colourless oil
(0.40 g, 27%).
apentadecanoyl fluoride
3 (804 mg, 0.97 mmol) was added
dropwise over 15 min. The reaction was stirred at 0 8C for 1.5 h
and at 22 8C for a further 18 h. The reaction was diluted with
dichloromethane (20 ml), the organic fraction washed with
saturated aqueous ammonium chloride solution (25 ml), water
(25 ml), brine (25 ml), dried (Na2SO4) and the solvent removed in
vacuo. Purification by column chromatography (eluent: 8:1, v/v,
petroleum ether/ethyl acetate) gave the desired amide 26 as a
colourless oil (0.50 g, 40%).
To a solution of tetrapivolate 26 (210 mg, 0.17 mmol) in MeOH
(3.5 ml) was added lithium hydroxide monohydrate (17.3 mg,
0.41 mmol). The reaction was stirred at 22 8C for 48 h before
Dowex 50W-X8(H+) (0.52 g) was added and stirring continued for
a further 10 min. After the resin was filtered off the filtrate was
evaporated to give a residue, which was purified by fluorous SPE
(dissolved in MeOH and applied to a 2 ml cartridge) to give the
desired tetraol 9 as a mixture of diastereoisomers (150 mg, 97%).
NMR: 1H (400 MHz, CDCl3)
NHCH2), 3.52–3.55 (m, J = 6.0 Hz, 1H, NHCH2CH–), 3.56–3.63 (m,
d
3.36–3.46 (m, J ¼ 5:0, 7.0 Hz, 1H,
J = 4.0, 9.0 Hz, 14H, CH2), 3.69–3.74 (m, J = 4.0 Hz, 4H, CH2), 3.84 (s,
1H, NHCH2–), 7.40 (br s, 1H, NH) ppm. 13C (125 MHz, CDCl3)
d 42.3
NMR: 1H (400 MHz, MeOD) mixture of diastereoisomers
d
3.52
(m, NHCH2), multiple peaks between 69.6 and 71.9 (all s, CH2), 76.5
(s, NHCH2C H), 77.2 (s, NHCH2C H), 100.6–101.8 (m, JCF = 150.5 Hz,
CF), 102.4–104.4 (m, JCF = 145.0 Hz, CF), 105.8–107.1 (m,
JCF = 158.0 Hz, CF), 108.0–108.5 (m, JCF = 160.5 Hz, CF), 112.7–
114.6 (m, JCF = 31.5, 126.5 Hz, CF), 115.0–116.3 (m, JCF = 17.5,
127.0 Hz, CF), 117.0 (d, JCF = 121.0 Hz, CF), 117.6–118.6 (m,
JCF = 127.5, 131.0 Hz, CF), 119.3 (d, JCF = 123.5 Hz, CF), 120.0 (t,
JCF = 129.5 Hz, CF), 120.8 (d, JCF = 125.0 Hz, CF), 157.6 (m,
(ddd, J ¼ 1:5, 3.5, 9.5 Hz, CHOH, 1H), 3.58–3.75 (m, CHOH, CH2,
4H), 3.92 (ddd, J ¼ 0:5, 3.5, 8.0 Hz, CH (CH2OH)OC, 1H), 4.95 (dd,
J ¼ 4:0, 9.0 Hz, CHNH, 1H) ppm. 13C (125 MHz, MeOD) mixture of
diastereoisomers d 62.1 (s, CH2), 62.1 (s, CH2), 62.3 (s, CH2), 70.3 (s,
CHOH), 70.4 (s, CHOH), 70.8 (s, CHOH), 70.9 (s, CHOH), 70.9 (s,
CHOH), 75.8 (s, CHOH), 75.8 (s, CHOH), 78.6 (s, CHOH), 78.8 (s,
CHOH), 82.1 (s, CHOH), 82.2 (s, CHOH), 102.8 (m, CF), 105.1 (m, CF),
107.7 (m, CF), 114.7 (m, CF), 117.2 (m, CF), 119.3 (m, CF), 122.1 (m,
2JCF = 103.5 Hz, –CONH–) ppm. 19F (376 MHz, CDCl3)
d
ꢁ82.9 (d,
CF), 160.0 (m, CO) ppm. 19F (376 MHz, MeOD)
d
ꢁ80.9 (m, CF3),
JCF = 14.0 Hz), ꢁ82.8 (d, JCF = 14.5 Hz), ꢁ81.8 to ꢁ81.9 (m,
JCF = 6.0 Hz), ꢁ80.2 to ꢁ80.6 (m, JCF = 6.5, 10.5, 14.5 Hz), ꢁ130.0
(m, JCF = 9.5 Hz), ꢁ132.5 to ꢁ133.1 (m, JCF = 19.5, 27.0 Hz, CF2),
ꢁ144.8 to ꢁ145.7 (m, JCF = 22.0 Hz, CF) ppm.
ꢁ82.5 (s, CF), ꢁ83.4 (t, J ¼ 2:5 Hz, CF), ꢁ130.5 (s, CF), ꢁ133.5 to
ꢁ134.0 (m, CF), ꢁ145.0 to ꢁ146.0 (m, CF) ppm.
HRMS: for
1011.9863.
C21H12NO10F29Na calcd 1011.9890, found
HRMS: for
1082.0775.
C26H22NO10F29Na calcd 1082.0673, found
5.1.7. Synthesis of N-((1,4,7,10,13-pentaoxacyclopentadecan-2-
yl)methyl)-2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-pentadecafluorooctanamide
(10)
Triethylamine (0.49 ml, 3.54 mmol) was added dropwise to a
solution of aminomethyl 15-crown-5 27 (0.44 ml, 1.77 mmol) in
THF (7 ml). The solution was cooled to 0 8C and perfluorooctanoyl
5.1.9. Synthesis of 2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-pentadecafluoro-1-
(1,4,7,10,13-pentaoxa-16-azacyclooctadecan-16-yl)octan-1-one (12)
Triethylamine (0.53 ml, 3.80 mmol) was added dropwise to a
solution of 1-aza-18-crown-6 28 (500 mg, 1.90 mmol) in THF
(7 ml). The solution was cooled to 0 8C and perfluorooctanoyl

406
D.J. Holt et al. / Journal of Fluorine Chemistry 131 (2010) 398–407
chloride 2 (820 mg, 1.90 mmol) was added dropwise over 15 min.
The reaction was stirred at 0 8C for 1.5 h and at 22 8C for a further
18 h. The reaction was diluted with chloroform (20 ml), the organic
fraction washed with saturated aqueous ammonium chloride
solution (25 ml), water (25 ml), brine (25 ml), dried (Na2SO4) and
the solvent removed in vacuo. Purification by column chromatog-
raphy (eluent: 9:1, v/v chloroform/methanol) gave the desired
amide 12 as a yellow oil (960 mg, 77%).
chloride (3.77 g, 0.020 mol). After stirring the reaction for
20 min the precipitated silver salts were removed by filtration
through a pad of celite which was washed thoroughly with ethyl
acetate. The combined filtrate was concentrated in vacuo and the
residue purified by column chromatography (eluent: 3:2, v/v
dichloromethane/acetone) to give the desired tosylate 30 as a pale
yellow oil (5.24 g, 67%).
d 2.34 (s, CH3Ar, 3H), 3.05 (s, CH2,
2H), 3.45–3.61 (m, CH2, 20H), 4.07 (m, J = 5.0 Hz, CH2, 2H), 7.25 (d,
J = 8.0 Hz, ArH, 2H), 7.67 (d, J = 8.0 Hz, ArH, 2H) ppm. 13C (125 MHz,
NMR: 1H (400 MHz, CDCl3)
NMR: 1H (400 MHz, CDCl3)
d
3.55–3.62 (m, J = 6.0 Hz, J = 5.5 Hz,
3
20H, CH2) ppm, 3.73 (t, JHH = 6.0 Hz, 2H, –NCH2 CH2O–), 3.77 (t,
3JHH = 5.5 Hz, 2H, –NCH2CH2 O–). 13C (125 MHz, CDCl3)
d
48.3 (br s,
CDCl3), d 22.3 (s, CH3), 62.2 (s, CH2), 69.3 (s, CH2), 70.0 (s, CH2),
–NCH2–), 48.8 (s, –NCH2–), 68.1 (s, –NCH2C H2–), 68.2 (s, –NCH2C
H2–), 68.3 (s, –NCH2C H2–), 68.5 (s, –NCH2C H2–), multiple peaks
between 70.0 and 70.7 (all s, CH2), 106.3 (dq, JCF = 130.5 Hz,
71.1–71.3 (several s, CH2), 73.2 (s, CH2), 128.6 (s, Ar), 130.5 (s, Ar),
133.7 (s, Ar), 145.5 (s, Ar) ppm.
1
2JCF = 24.0 Hz, CF3C F2–), 109.2–107.6 (m, CF2), 111.5–109.7 (m,
CF2), 113.9–112.1 (m, CF2), 115.9 (t, 1JCF = 131.0 Hz, CF2), 118.2 (t,
5.1.12. Synthesis of 2-(2-(2-(2-(2-(2-benzyloxy-ethoxy)-ethoxy)-
ethoxy)-ethoxy)-ethoxy)-ethanol (31) [31].
1
1JCF = 132.0 Hz, CF2), 120.5 (t, JCF = 130.5 Hz, CF3), 157.9 (t,
Hexaethylene glycol 29 (0.89 ml, 3.54 mmol) was added
dropwise to a solution of silver (I) oxide (1.23 g, 5.31 mmol) and
potassium iodide (0.24 g, 1.42 mmol) in dichloromethane (30 ml).
Benzyl bromide (0.46 ml, 3.89 mmol) was added dropwise over
5 min and the reaction stirred at 22 8C for 2 h. The suspension was
filtered through celite which was thoroughly washed with
dichloromethane. The combined filtrate was concentrated in vacuo
and the residue purified by column chromatography (eluent: 95:5,
v/v, ethyl acetate/methanol) to give benzyl ether 31 as a colourless
oil (900 mg, 68%).
2JCF = 100.0 Hz, –CON–) ppm. 19F (376 MHz, CDCl3)
d
ꢁ81.2 (tt,
3JFF = 11.0 Hz, JFF = 2.5 Hz, CF3), ꢁ111.2 (tt, JFF = 14.5 Hz,
4JFF = 3.0 Hz, –CF2CON–), ꢁ120.6 (m, CF2), ꢁ121.0 (m, J = 4.0 Hz,
CF2), ꢁ122.3 (m, CF2), ꢁ122.9 (m, CF2), ꢁ126.5 (m, J = 7.6 Hz,
J = 3.5 Hz, CF2) ppm.
4
3
HRMS: for C20H24NO6F15Na calcd 682.1256, found 682.1286;
for C20H25NO6F15 calcd 660.1437, found 660.1448.
5.1.10. Synthesis of (2R,5R,8R,11R)-
2,4,4,5,7,7,8,10,10,11,13,13,14,14,14-pentadecafluoro-2,5,8,11-
tetrakis(trifluoromethyl)-3,6,9,12-tetraoxatetradecan-1-al
compound with 16-methyl-1,4,7,10,13-pentaoxa-16-
NMR: 1H (400 MHz, CDCl3)
d 3.55–3.70 (m, CH2, 24H), 4.53 (s,
ArCH2, 2H), 7.31 (m, ArH, 5H) ppm.
HRMS: for C19H33O7 calc. 373.2220, found 373.2217, for
azacyclooctadecane (1:1) (13)
C19H32O7Na calc. 395.2040, found 395.2039.
Triethylamine (0.53 ml, 3.80 mmol) was added dropwise to a
solution of 1-aza-18-crown-6 28 (500 mg, 1.90 mmol) in THF
(5 ml) and methoxynonafluorobutane (2.5 ml). The solution was
cooled to 0 8C and pyridine (0.15 ml, 1.90 mmol) and perfluoro-
2,5,8,11-tetramethyl-3,6,9,12-tetraoxapentadecanoyl fluoride 3
(1.58 g, 1.90 mmol) was added dropwise over 15 min. The
reaction was stirred at 0 8C for 1.5 h and at 22 8C for a further
18 h. The reaction was diluted with chloroform (20 ml), the
organic fraction washed with saturated aqueous ammonium
chloride solution (25 ml), water (25 ml), brine (25 ml), dried
(Na2SO4) and the solvent removed in vacuo. Purification by
column chromatography (eluent: 9:1, v/v chloroform/methanol)
gave the desired amide 13 as a mixture of diastereoisomers as a
pale yellow oil (0.95 g, 49%).
5.1.13. Synthesis of 2-(2-(2-hydroxyethoxy)ethoxy)ethyl
2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-pentadecafluorooctanoate (14)
n-Butyllithium (0.53 ml of
a 1.6 M solution in hexanes,
0.85 mmol) was added dropwise over a period of 10 min to a
solution of 31 (300 mg, 0.81 mmol) in THF (6 ml) at ꢁ78 8C. The
reaction was stirred at 22 8C for 1 h before the dropwise addition of
perfluorooctanoyl chloride 2 (0.87 g, 2.01 mmol). The solution was
stirred at 22 8C for 30 min before the solvent was removed in vacuo
at 30 8C. Purification by column chromatography (eluent: 97.5:2.5,
v/v, ethyl acetate/methanol) gave the desired ester 32 as a
colourless oil (390 mg, 63%).
Benzyl ether deprotection was accomplished via addition of
10% palladium on carbon (30 mg) to a solution of 32 (270 mg,
0.35 mmol) dissolved in methanol (7 ml) and the flask
flushed with H2. The reaction was stirred under an H2
atmosphere for 18 h at which point the suspension was filtered
through celite, and the celite washed thoroughly with methanol.
The filtrate was concentrated in vacuo and the residue purified
by fluorous SPE (dissolved in DMF and applied to a 2 ml
cartridge) to give the desired alcohol 14 as a white solid
(180 mg, 76%).
NMR: 1H (400 MHz, CDCl3)
CONCH2 CH2O–), 3.56–3.70 (m, JHH = 6.0 Hz, 20H, CH2) ppm. 13C
(125 MHz, CDCl3) 49.2 (s, –NCH2), 49.3 (s, –NCH2), 50.3 (s, CH2),
d
3.74-3.89 (m, 3JHH = 6.0 Hz, 4H, –
3
d
50.3 (s, CH2), 68.2 (s, CH2), 68.4 (s, CH2), multiple signals between
70.0 and 70.7 (all s, CH2), 100.9–101.6 (m, CF), 102.3–104.0 (m,
JCF = 156.5 Hz, CF), 104.9 (m, CF), 106.2 (m, CF), 113.0–113.8 (m,
JCF = 163.5 Hz, CF), 115.2–116.3 (m, JCF = 83.0 Hz, CF), 117.1–118.6
(m, JCF = 112.5 Hz, 129.5 Hz, CF), 119.5 (d, JCF = 131.0 Hz, CF), 120.8
(d, JCF- 128.0 Hz, CF), 121.9 (d, JCF = 120.5 Hz, CF), 157.7 (d,
NMR: 1H (400 MHz, MeOD)
CH2), 3.63 (m, 20H, CH2), 3.78 (m, 2H, CH2) ppm. 13C (125 MHz,
MeOD) 62.2 (s, CH2), 68.9 (s, CH2), 69.3 (s, CH2), 71.4 (s, CH2), 71.4
d 3.28 (m, 1H, OH), 3.54 (m, 2H,
2JCF = 96.0 Hz, –CON–) ppm. 19F (376 MHz, CDCl3)
d
ꢁ80.0 (t,
J = 9.5 Hz, CF3), ꢁ80.2–7 (m, J = 10.0 Hz, CF3), ꢁ81.8 (m, J = 5.0 Hz,
CF3), ꢁ81.9 (m, CF3), ꢁ82.0 (m, CF3), ꢁ125.6 (m, CF2), ꢁ130.1 (m,
CF2), ꢁ144.7 to ꢁ145.7 (m, J = 18 Hz, CF) ppm.
d
(s, CH2), 71.4 (s, CH2), 71.5 (s, CH2), 71.5 (s, CH2), 71.5 (s, CH2), 71.5
1
(s, CH2), 71.6 (s, CH2), 73.7 (s, CH2), 107.3 (t, JCF = 130.0 Hz, CF3),
HRMS: for
1096.0788.
C
27H24NO10F29Na calcd 1096.0829, found
109.2–110.1 (m, CF2), 111.3–112.5 (m, CF2), 113.5–114.6 (m, CF2),
1
1
117.3 (t, JCF = 130.0 Hz, CF2), 119.6 (t, JCF = 130.0 Hz, CF2), 121.9
(m, CF2), 159.1 (t, JCF = 116.0 Hz, –COO–) ppm. 19F (376 MHz,
2
5.1.11. Synthesis of toluene-4-sulfonic acid 2-(2-(2-(2-(2-(2-
hydroxy-ethoxy)-ethoxy)-ethoxy)-ethoxy)-ethoxy)-ethyl ester (30)
[31].
MeOD)
d
ꢁ78.7 (m, J = 2.5 Hz, J = 10.5 Hz, J = 22.5 Hz, CF3), ꢁ116.1
(m, 2JFF = 37.0 Hz, 3JFF = 13.5 Hz, 4JFF = 3.0 Hz, –CF2 COO–), ꢁ118.8
to ꢁ119.0 (m, CF2), ꢁ119.2 to ꢁ119.5 (m, CF2), ꢁ119.9 to ꢁ120.1
(m, CF2), ꢁ120.2 to ꢁ120.3 (m, CF2), ꢁ123.5 to ꢁ123.7 (m,
CF2) ppm.
To a 0 8C solution of hexaethylene glycol 29 (4.45 ml, 0.018 mol)
in dichloromethane (50 ml) were added silver (I) oxide (6.26 g,
0.027 mol), potassium iodide (0.60 g, 3.60 mmol) and tosyl
HRMS: for C20H25F15O8Na calcd 701.1202, found 701.1300.

D.J. Holt et al. / Journal of Fluorine Chemistry 131 (2010) 398–407
407
5.1.14. Synthesis of (2S,5S,8S,11S)-2-(2-(2-
HRMS: for C23H31O7F17Na calcd 765.1673, found 765.1673.
hydroxyethoxy)ethoxy)ethyl 1,1,1,2,4,4,5,7,7,8,10,10,11,13,13,14,14,
14-octadecafluoro-5,8,11-tris(trifluoromethyl)-3,6,9,12-
tetraoxatetradecane-2-carboxylate (15)
5.2. Creation and observation of droplets in microfluidic devices
n-Butyllithium (0.53 ml of
a
1.6 M solution in hexanes,
Microfluidic devices were created in PDMS (Slygard 184, Dow
Corning, Coventry, UK) from CAD designs using standard
photolithographic techniques [32,33]. Fluorous coating was
applied to the channels using the method of Roach et al. [34].
0.85 mmol) was added dropwise over a period of 10 min to a
solution of 31 (300 mg, 0.81 mmol) in THF (6 ml) and methox-
ynonafluorobutane (4 ml) at ꢁ78 8C. The reaction was stirred at
22 8C for 1 h before the dropwise addition of pyridine (0.16 ml,
2.01 mmol) and perfluoro-2,5,8,11-tetramethyl-3,6,9,12-tetraox-
apentadecanoyl fluoride 3 (1.67 g, 2.01 mmol). The solution was
stirred at 22 8C for 30 min before the solvent was removed in vacuo
at 30 8C. Purification by column chromatography (eluent: 97.5:2.5,
v/v, ethyl acetate/methanol) gave the desired ester 33 as a
colourless oil (662 mg, 70%).
All channels were 50
mm wide and 25 mm deep. Fluids were
introduced into device using PE20 tubing (Becton Dickinson, ID
0.38 mm) attached to 1 ml plastic syringes. Fluid flow was
controlled using PHD 2000 syringe pumps (Harvard Apparatus,
UK). Device performance was observed using a Phantom v7.1 fast
camera attached to an Olympus IX70 microscope with 10ꢀ and
40ꢀ lenses.
Benzyl ether deprotection was accomplished via addition of
10% palladium on carbon (30 mg) to a solution of benzyl ether 33
(256 mg, 0.22 mmol) dissolved in methanol (7 ml) and the flask
flushed with H2. The reaction was stirred under an H2 atmosphere
for 18 h at which point the suspension was filtered through celite,
and the celite washed thoroughly with methanol. The filtrate was
concentrated in vacuo and the residue purified by fluorous SPE
(dissolved in DMF and applied to a 2 ml cartridge) to give the
desired alcohol 15 as a colourless oil (200 mg, 89%). Rf (95:5, v/v,
chloroform/methanol) = 0.26.
Acknowledgements
The authors acknowledge the RCUK and EPSRC for funding via
the Basic Technology and Platform Grants, respectively. DJH
gratefully acknowledges the Ralph Raphael & Todd Funds and
Christ’s College, Cambridge for financial support.
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3
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NMR: 1H (400 MHz, MeOD)
d 1.85 (m, CH2, 2H), 2.10–2.25 (tt,
3
3JHH = 8.5 Hz, JHF = 19.5 Hz, CH2, 2H), 2.47 (s, OH, 1H), 3.53 (t,
3JHH = 6.0 Hz, 2H, CH2), 3.59 (m, CH2, 4H), 3.64 (m, CH2, 17H), 3.71
(m, J = 4.0 Hz, CH2, 3H) ppm. 13C (125 MHz, MeOD)
d 20.7 (s, CH2),
2
28.9 (t, JCF = 114.7 Hz, CH2), 61.7 (s, CH2), 69.6 (s, CH2), 70.2 (s,
CH2), 70.2 (s, CH2), 70.5 (s, CH2), 70.5 (s, CH2), 70.5 (s, CH2), 70.5 (s,
CH2), 70.6 (s, CH2), 106.6 (m, CF2), 107.8–109.2 (m, CF2), 109.9–
111.6 (m, CF2), 112.1–113.7 (m, CF2), 116.2 (m, CF2), 118.3 (q,
2JCF = 140.0 Hz, CF3, 120.5 (t, 2JCF = 140.0 Hz, CF2) ppm. 19F
3
(376 MHz, MeOD)
d
ꢁ81.1 (t, JFF = 10.5 Hz, CF3), ꢁ114.6 (t,
3JFF = 15.0 Hz, CF2 CH2), ꢁ122.0 (m, CF2), ꢁ122.2 (m, CF2), ꢁ123.0
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(m, CF2), ꢁ123.7 (m, CF2), ꢁ126.3 (m, CF2), ꢁ126.3 (m, CF2) ppm.