Use of perfluoro groups in nucleophilic 18F-fluorination

Article abstract of DOI:10.1002/jlcr.1695

Substrates with leaving groups that contained perfluoro moieties were investigated in labelling chemistry in order to exploit their properties to improve reactivity and purification. [¹⁸F](Fluoromethyl)benzene was used as the model target compound. Precursors containing perfluoroalkyl and perfluoroaryl sulfonate moieties were subjected to nucleophilic ¹⁸F-fluorination, and the impact of perfluoro groups on the substitution reaction and product purification was investigated. [ ¹⁸F]Fluoride interacted with perfluoroalkyl chains, precluding nucleophilic substitution. When perfluoroaryl groups were used, the substitution proceeded, and the separation of product was explored. The radiolabelled product was obtained in 32% analytical yield and the radiochemical purity was increased to approximately 77% using fluorous solid phase extraction purification. Copyright

Full text of DOI:10.1002/jlcr.1695

Research Article
Received 8 July 2009,
Revised 13 November 2009,
Accepted 12 October 2009
Published online 25 November 2009 in Wiley Interscience
(www.interscience.wiley.com) DOI: 10.1002/jlcr.1695
Use of perfluoro groups in nucleophilic
18F-fluorination
Elisabeth Blom, Farhad Karimi, and Bengt Langstrom
Ã
˚
¨
Substrates with leaving groups that contained perfluoro moieties were investigated in labelling chemistry in order to
exploit their properties to improve reactivity and purification. [18F](Fluoromethyl)benzene was used as the model target
compound. Precursors containing perfluoroalkyl and perfluoroaryl sulfonate moieties were subjected to nucleophilic
18F-fluorination, and the impact of perfluoro groups on the substitution reaction and product purification was investigated.
[
18F]Fluoride interacted with perfluoroalkyl chains, precluding nucleophilic substitution. When perfluoroaryl groups were
used, the substitution proceeded, and the separation of product was explored. The radiolabelled product was obtained in
32% analytical yield and the radiochemical purity was increased to approximately 77% using fluorous solid phase
extraction purification.
Keywords: perfluoro; nucleophilic 18F-fluorination; F-SPE; chemical reactivity; purification
of a molecule, and include liquid–liquid extraction with organic
and fluorous solvents,10 F-SPE and fluorous HPLC.11,12 In the
Introduction
Owing to the short half-lives of the radionuclides used in
positron emission tomography (PET), the technique requires
tracers with high specific radioactivity that can be purified
quickly. A high specific radioactivity makes it possible to use a
very small amount of the tracer in the biological system, thereby
decreasing the risk of saturation or perturbation. 18F is a
radionuclide used in PET, and has interesting synthetic1,2 and
physical properties1. In this work, perfluorinated moieties have
been used as leaving groups in nucleophilic 18F-labelling. This
may both increase the reactivity of the leaving group and
simplify separation. The high electronegativity of the fluorine
atom means that a fluorous leaving group has significantly
different electronic properties, and consequently reactivity, from
a non-fluorinated group.3 Additionally, a fluorous starting
material can be removed using a fluorous separation technique4
like fluorous solid phase extraction (F-SPE), which allows faster
purification than the commonly used high-performance liquid
chromatography (HPLC) method. As time is an important
parameter in labelling chemistry, it would be advantageous to
improve the reactivity of the leaving group and/or the ease of
purification of a nucleophilic substitution reaction.5
current labelling strategy, we explored the use of F-SPE to
separate a non-perfluorinated 18F-labelled product from the
perfluorinated starting material. This technique uses fluorous
silica gel for the separation of fluorous from non-fluorous
compounds.13 Perfluoroalkyl and perfluoroaryl sulfonate groups
were used as leaving groups.
Results and discussion
Labelling
The effects of a perfluoro structure on chemical reactivity and
purification were explored in two model reactions, the syntheses
of [18F](fluoromethyl)benzene (8) and [18F](4-fluorobutyl)ben-
zene (10) by nucleophilic substitution (Schemes 1 and 2). As a
control, the tosyl compound 1 was used as a precursor for the
18F-labelling to give 8, which was obtained in 90% analytical
radiochemical yield. The radiolabelled products 8 and 10 were
identified using co-elution HPLC analysis (UV and radiodetec-
tors) with their unlabelled fluorinated counterparts, (fluoro-
methyl)benzene and (4-fluorobutyl)benzene, respectively. The
reference compounds were prepared from the corresponding
bromide compounds and tetrabutylammonium fluoride.
Fluorous-labelling strategies have previously been used in
radiolabelling with 18F, using perfluoro chains with two-carbon
spacers,6 as well as with other nuclides. A perfluoro leaving
group has been used in the synthesis of [18F]FDG,7 and an iodo-
demetalation 125I-labelling reaction was achieved using a
fluorine-rich tin support.8 F-SPE was used in combination with
fluorous scavengers in a 35S-labelling.9
A number of perfluoro-containing precursors were investi-
gated. All attempts to label 2 (Scheme 1), which bore a
perfluorooctyl chain on the sulfonate, with [18F]fluoride at 1501C
in acetonitrile failed. Neither additional heating to 1801C nor the
Fluorous separation techniques are methods for separating
fluorous or fluorous-labelled molecules from other types of
molecules, or from each other, based primarily on the structure
of their fluorous domain(s).4 These techniques are based on the
interaction between a fluorous medium and a fluorous portion
Department of Biochemistry and Organic Chemistry, Box 576, Husargatan 3,
BMC, S-751 23 Uppsala, Sweden
˚
*Correspondence to: Bengt Langstro¨m, Department of Biochemistry and Organic
Chemistry, Box 576, Husargatan 3, BMC, S-751 23 Uppsala, Sweden.
E-mail: Bengt.Langstrom@biorg.uu.se
J. Label Compd. Radiopharm 2010, 53 24–30
Copyright r 2009 John Wiley & Sons, Ltd.

E. Blom et al.
O
S
18F
O
R
O
i
1-7
2: R =
8
CH3
(CF2)7CF3
1: R =
(CF2)3CF3
(CF2)7CF3
3: R =
4: R =
F
F
F
(CF2)3CF3
5: R=
(CH2)2(CF2)7CF3
6: R =
F
7: R =
F
Scheme 1. General reaction of sulfonyl compounds 1–7 with [18F]fluoride to form [18F](fluoromethyl)benzene. (i): [K/K2.2.2.]118Fꢀ, acetonitrile/DMF, 15 min, 110–1801C,
0–32% yield.
O
was moderate compared with the control reaction with 1. This
18F
S
could be due to some incorporation of the [18F]fluoride into the
perfluoroaromatic ring structure,17 or to differences in reactivity.
Despite this lower radiochemical yield, using compound 6 as the
precursor not only makes the labelling reaction feasible, but also
makes the purification by F-SPE possible. The radiochemical
purity was increased to 77% after purification of the reaction
mixture by F-SPE using a silica gel modified with pentafluor-
ophenyl groups (Figure 1). The non-perfluoro product was
eluted in four fractions with a fluorophobic solvent system
(0.5 mL methanol/water (40:60)), with the purest product
obtained in the third fraction. The specific radioactivity was
120730 (n = 2) GBq/mmol after the purification. Using Fluoro-
Flashssilica, which features perfluorinated alkyl chains, increased
the radiochemical purity to approximately 40%. In this case the
product was eluted with 2 mL methanol/water (80:20). The
perfluoro molecules can be eluted using a fluorophilic solvent
like methanol, acetone, acetonitrile or tetrahydrofuran (THF).18
As a comparison, published labelling experiments that used a
chain containing a two-carbon spacer between the fluorous
chain and the sulfonyl group were repeated.6 Compound 7, was
labelled in 10% analytical radiochemical yield in acetonitrile at
1101C after 15 min. Compound 9,6 Scheme 2, was labelled in
50% yield, compared with the previously published 88%
radiochemical yield.6 This indicates that the reactivity of the
perfluoroalkyl chains and their possible interactions with
[18F]fluoride are clearly impacted by the hydrocarbon spacer.
O
(CH2)2(CF2)7CF3
i
O
9
10
Scheme 2. 18F-Labelling of compound 9. Reaction conditions (i): [K/K2.2.2.]118Fꢀ,
acetonitrile, 15 min, 1101C, 50% yield.
addition of water or methanol to influence solvation improved
the result. When tetrabutylammonium fluoride was added and
the reaction mixture was further heated for 1 h, a trace amount
of unlabelled (fluoromethyl)benzene was formed. The substitu-
tion that occurred at the sulfonyl group upon addition of excess
19Ffluoride could indicate that the perfluoroalkyl part of the
precursor interacts with the [18F]fluoride, preventing it from
taking part in the substitution reaction, since the addition of an
excess of fluoride ions seemed to release [18F]fluoride for
replacing the sulfonyl group. It has previously been observed
that perfluoro chains can leach fluoride ions, so the 19F-fluoride
likely comes from solvolysis, rather than 18/19F exchange.13 The
high reactivity of the perfluoroalkyl sulfonate group has been
reported to lead to the problematic formation of ammonium
sulfonate salts.14,15 To see whether this unwanted incorporation
of 19F could be reduced, a precursor with a four-carbon
perfluoroalkyl chain (3) was used. The outcome of this labelling
reaction was, however, the same as for the reaction of
compound 2. The next two precursors had modified tosyl
groups, with perfluoroalkyl chains of different lengths attached
Precursor synthesis
to benzene rings (4 and 5). A benzene ring has previously been Precursors 1–3 were prepared from the corresponding sulfonyl
used to insulate a perfluoroalkyl group from an active site.16 chloride and phenylmethanol by combining with sodium
Using these modified precursors in the labelling reaction gave hydride in THF19 (Scheme 3), in 9–50% yield.
the same result as for compounds 2 and 3, though trace
Compounds 4 and 5 were prepared by coupling the
amounts of products were also obtained in these cases when corresponding perfluoro iodides 11–12 to benzene rings using
fluoride ions were added. Acetonitrile, dimethyl sulfoxide the Grignard reaction20 (Scheme 4). Sulfonyl acid was attached
(DMSO) and dichloromethane were also used as solvents in and converted to sulfonyl chlorides 19–20 before coupling with
the labelling reaction, but did not improve the formation of phenylmethanol according to the procedure described above.
radiolabelled product. When the leaving group was perfluor- The precursors 4–5 were obtained in 5–6% overall yield.
ophenyl sulfonate (6), the labelled product 8 was obtained in
Precursor 6 was prepared starting from pentafluorobenzenesul-
32% analytical yield in a mixture of acetonitrile and N,N- fonyl chloride, which was heated in water to form the sulfonic acid
dimethylformamide (DMF). Apparently the [18F]fluoride does not 21, and subsequently combined with silver carbonate to give the
interact with the perfluorinated benzene ring as it does with the corresponding silver salt 2221 (Scheme 5). This, in turn, was coupled
perfluoroalkyl groups. The radiochemical yield of this reaction to (chloromethyl)benzene to give compound 6 in 10% yield.
J. Label Compd. Radiopharm 2010, 53 24–30
Copyright r 2009 John Wiley & Sons, Ltd.
www.jlcr.org

E. Blom et al.
(a)
[18F](fluoromethyl)benzene
(b)
Figure 1. Radiochromatogram of (a) crude reaction mixture from labelling of compound 6, (b) after purification by F-SPE.
biochemical compounds, Pre-conditioned Sep-PAKs, Light QMA
Cartridge with CO23ꢀ as counter ions, Radeberg). The QMA filter
was purged with helium for 3 min and thereafter the
[18F]fluoride was released with a 2 mL solution of 96:4 (by
volume, total volume 12 mL) acetonitrile–water mixture contain-
ing 55.9 mg of Kryptofix 2.2.2 (K2.2.2) and 12.7 mg K2CO3. After
the eluted 18F-Kryptofix/K2CO3 solution was dried under N2 (g)
at 1101C, it was further dried with 2 ꢁ 1 mL dry acetonitrile.
Synthia,22 an automated synthesis system, was used. Liquid
chromatographic analysis (LC) was performed with a VWR
Hitachi Pump L-2130 and a VWR Hitachi UV Detector L-2400 UV
detector in series with a b1-flow detector. A Discoverys C18,
Supelco, 25 cm ꢁ 4.6 mm, 5 mm HPLC column was used. The
following mobile phases were used: 25 mM KH2PO4 in water (A)
and acetonitrile/water 50:7 (B). Program: 60–90% (B) on 5 min,
then 90% for 10 min. In the analysis of the 18F-labelled
compounds, isotopically unmodified reference substances were
used for identification in all LC runs. Radioactivity was measured
in an ion chamber, Veenstra Instrumenten BV, VDC-202. F-SPE
columns FluoroFlashs containing Si(CH2)2C8F17 and Silica gel,
functionalized, pentafluorophenylpropyl silicate, 1 mmol/g, par-
ticle size: 40–3 mm, Acros Organics were used as bonded phases.
All chemicals were obtained from commercial suppliers and
used without further purification.
O
S
O
R
O
O
S
i
Cl
R
O
1-3
3: R = -(CF2)3CF3
1: R =
2: R = -(CF2)7CF3
CH3
Scheme 3. Synthesis of precursors 1-3. Reaction conditions (i): phenylmethanol,
NaH, THF, 16–94 h, room temperature (r.t.), 9–50% yield.
Compounds 7 and 9 (Scheme 6) were prepared using the
published procedure.6 1,1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8-Heptadeca-
fluoro-10-iododecane was converted to (diaminomethylene)
(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluorodecyl)sulfonium
iodide (23) by reaction with thiourea in ethanol. This was further
transformed into the sulfonyl chloride 24 and combined with
phenylmethanol or 4-phenylbutan-1-ol to give the respective
compound 7 or 9.
Only precursors 1 and 6 could be purified by column
chromatography on silica; the rest were purified by recrystalliza-
tion from CHCl3/petroleum ether.
General labelling procedure
The precursors 1-5, 7 and 9 (8–15 mmol) were dissolved in 200 mL
acetonitrile, DMSO, DMF or dichloromethane. Compound 6 was
dissolved in 200 mL DMF. The dissolved precursors were added
to a solution of the dried [K/K2.2.2.]118Fꢀ in 200 mL one of the
mentioned solvents. The reaction mixtures containing only
Experimental section
Radiosynthesis
General
No-carrier-added [18F]fluoride was produced from water 95% acetonitrile or dichloromethane were heated at 1101C for
enriched in 18O (Rotem Industries Ltd., Israel or Taiyo Nippon 15 min, whereas the one containing a mixture of acetonitrile
Sanso Corporation) by the nuclear reaction 18O(p,n)18F using a and DMF were heated at 1501C in a closed vessel. In some cases
Scanditronix MC-17 cyclotron at Uppsala Imanet. The produced (compounds 25) tetrabutylammonium fluoride (0.5 mL, 1 M in
[18F]fluoride in water was transferred from the cyclotron target THF) was also added and the reaction mixture heated at 1001C
by HPLC pump and trapped on a QMA filter (ABX, advanced for 1 h extra.
www.jlcr.org
Copyright r 2009 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2010, 53 24–30

E. Blom et al.
i
ii
iii
RMgBr
HO3S
R
RI
R
11-12
13-14
15-16
17-18
iv
O
S
O
R
v
O
4,11,13,15,17,19: R =
5,12,14,16,18,20: R =
(CF2)7CF3
(CF2)4CF3
ClO2S
R
19-20
4-5
Scheme 4. Synthesis of precursors 4-5. Reaction conditions: (i) Mg, EtBr, Et2O, 4 h, ꢀ40 to 351C, (ii) chlorobenzene, NiCl2(dppp), 20–48 h, 351C, (iii) ClSO3H,
1,2-dichloroethane, 20–22 h, r.t., (iv) thionyl chloride, DMF, 5–9 h, 801C, (v) phenylmethanol, NaH, THF, 5–18 h, r.t., 45–69% yield.
F
F
SO2Cl
SO2OH
SO3Ag
O
S
F
F
F
F
F
F
F
F
F
F
F
O
F
i
iii
ii
O
F
F
F
F
F
F
22
6
21
Scheme 5. Synthesis of precursor 6. Reaction conditions: (i) H2O, 22 h, 1001C, (ii) Ag2CO3, H2O, 25 h, r.t., (iii) (chloromethyl)benzene, CH3CN, 18 h, 851C, 10% yield.
NH2
NH2
i
I
ii
CF3(CF2)7(CH2)2I
CF3(CF2)7(CH2)2SO2Cl
F3C(CF2)7(CH2)2S
24
23
iii
O
O
S
(CH2)2(CF2)7CF3
(CH2)n
O
7 (n = 1)
9 (n = 4)
Scheme 6. Synthesis of precursors 7 and 9. Reaction conditions: (i) thiourea, ethanol, 20 h, 781C, (ii) KMnO4, HCl, acetic acid, H2O, 2 h, 0–101C, 50% yield,
(iii) phenylmethanol or 4-phenylbutan-1-ol, triethylamine, CH2Cl2, 20 h, r.t., 30–40% yield.
SPE conditions
Chemical synthesis
Silica gel, functionalized, pentafluorophenylpropyl silicate,
1 mmol/g, particle size: 40–63 mm, Acros Organics, 80 mg.
General
1H NMR, 13C NMR and 19F spectra were recorded on a Varian
Unity (1H at 400 MHz, 13C at 100 MHz, 19F at 376 MHz) or Varian
Mercury (1H at 300 MHz, 13C at 75 MHz, 19F at 282 MHz)
spectrometer using CDCl3 or CD3OD as deuterated solvent
(1) The cartridge was washed with 1 mL DMF.
(2) Preconditioning with 1 mL methanol/water (40:60).
(3) Reaction mixture loaded.
(4) Elution: 0.5 mL methanol/water (40:60) ꢁ 4.
F-SPE conditions23
1
(solvent peaks were used as the reference, CDCl3: H 7.26 ppm,
13C 77.0 ppm; CD3OD: 1H 3.31 ppm, 13C 49.00 ppm). In the
case of 19F NMR, CFCl3 was used as the reference. Chemical
shifts are reported in ppm. All NMR experiments were
conducted at 251C. Mass spectrometric analyses were per-
formed using a Finnigan MAT GCQ mass spectrometer in EI
mode. Thin-layer chromatography (TLC) was performed on
Merck silica gel F-254 aluminum plates using CH2Cl2 as eluent.
2 g SPE-column (FluoroFlashs, (Si(CH2)2C8F17))
(1) The cartridge was washed with 1 mL DMF.
(2) Preconditioning with 2 mL methanol/water (80:20).
(3) Reaction mixture loaded.
(4) Fluorophobic elution: 2 mL methanol/water (80:20) ꢁ 2.
J. Label Compd. Radiopharm 2010, 53 24–30
Copyright r 2009 John Wiley & Sons, Ltd.
www.jlcr.org

E. Blom et al.
ꢂ
ꢂ
Silica gel 60, particle size 0.040–0.063 mm, Merck, was used for ꢀ127.7 (m, 2F). EI–MS: m/z 590 [M] 1, 91 [C6H5CH2] 1, 77
column chromatography.
ꢂ
[C6H5] 1. Mp 79–801C. Rf = 0.78.
(Fluoromethyl)benzene (unlabelled reference for 8).24 Tetrabuty-
lammonium fluoride (1.5 mL, 1.5 mmol, 1 M in THF) was added
to (bromomethyl)benzene (0.144 g, 0.84 mmol). The reaction
mixture was heated at 901C for 45 min and then extracted with
pentane (3 ꢁ 50 mL) and water (100 mL). The organic phase was
evaporated by a flow of nitrogen to yield (fluoromethyl)benzene
Benzyl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (3). A solu-
tion of phenylmethanol (0.110 g, 1.02 mmol) in 2 mL dry THF was
added to sodium hydride (95%, 0.019 g, 0.76 mmol) in 5 mL dry
THF. A solution of 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl
chloride (0.163 g, 0.51 mmol) in 3 mL dry THF was added. The
reaction mixture was stirred at r.t. for 94 h and then extracted
with ethyl acetate (50 mL) and water (100 mL). The organic
phase was dried with MgSO4 and concentrated under reduced
pressure.19 The residue was recrystallized from CHCl3/petroleum
ether to yield 3 as white crystals (0.100 g, 50%). 1H NMR (CD3OD,
400 MHz) d 7.34–7.22 (m, 5H, ArH), 4.50 (s, 2H, –CH2–). 13C NMR
(CD3OD, 100 MHz) d 139.3 (ipso-C), 129.3 (m-C), 128.7 (o-C), 127.8
(p-C), 126.0-101.1 (m, –C4F11), 72.9 (–CH2–). 19F NMR (CD3OD,
1
as a colorless liquid (0.046 g, 50%) H NMR (CDCl3, 400 MHz) d
2
7.37–7.20 (m, 5H, ArH), 5.32 (d, JH,F = 48.9 Hz, 2H, –CH2F). 13C
2
NMR (CDCl3, 100 MHz) d 135.5 (d, JC,F = 16.5 Hz, ipso-C), 128.8
(d, JC,F = 4.1 Hz, m-C), 128.5 (p-C), 127.7 (d, JC,F = 5.0 Hz, o-C),
4
3
1
84.5 (d, JC,F = 165.0 Hz, –CH2F). 19F NMR (CDCl3, 376 MHz) d
ꢂ
ꢂ
ꢂ1
–204.1 (m). EI–MS: m/z 110 [M] 1, 91 [C6H5CH2] 1, 77 [C6H5]
Rf = 0.49.
.
3
376 MHz) d ꢀ82.5 (t, JF,F = 9.9 Hz, 3F), ꢀ115.9 (m, 2F), ꢀ122.7
(4-Fluorobutyl)benzene (unlabelled reference for 10). Tetrabuty-
lammonium fluoride (1.5 mL, 1.5 mmol, 1 M in THF) was added
to (4-bromobutyl)benzene (0.179 g, 0.84 mmol). The reaction
mixture was heated at 901C for 45 min and then extracted with
pentane (3 ꢁ 50 mL) and water (100 mL). The organic phase was
concentrated under reduced pressure to yield (4-fluorobutyl)-
benzene as a colorless liquid (0.079 g, 62%). 1H NMR (CDCl3,
400 MHz) d 7.16–7.07 (m, 3H, ArH), 6.97–6.92 (m, 2H, ArH),
4.32–4.17 (m, 2H, –CH2F), 2.72 (m, 2H, –CH2–C6H5), 1.80 (m, 4H,
–CH2CH2–). 13C NMR (CDCl3, 100 MHz) d 143.3 (ipso-C), 129.6
ꢂ
ꢂ1
(m, 2F), ꢀ127.3 (m, 2F). EI–MS: m/z 390 [M] 1, 91 [C6H5CH2]
,
ꢂ
77 [C6H5] 1. Mp 70–711C. Rf = 0.72.
Benzyl 4-(heptadecafluorooctyl)benzenesulfonate (4). Magnesium
(0.057 g, 2.33 mmol) was dried and 5 mL dry diethylether and
bromoethane (0.246 g, 2.26 mmol) were added. The reaction
mixture was heated at 351C for 4 h under a nitrogen atmo-
sphere. After cooling to ꢀ401C, 1,1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8-
heptadecafluoro-8-iodooctane 11 (1.000 g, 1.84 mmol) was
added. The temperature was raised to ꢀ201C and chloroben-
zene (0.209 g, 1.65 mmol) and NiCl2(dppp) (0.002 g, 3.7 mmol)
were added. The mixture was heated at 351C for 48 h under a
nitrogen atmosphere. After cooling to 01C, the mixture was
hydrolyzed by adding 2 M HCl (aq) and extracted with ether and
H2O. The organic phase was dried with MgSO4 and concentrated
under reduced pressure.20 The resulting (heptadecafluorooctyl)-
benzene 1525 was used in the next step without purification.
1H NMR (CDCl3, 400 MHz) d 7.37–7.32 (m, 2H, ArH), 7.31–7.24
(m, 3H, ArH). 13C NMR (CDCl3, 100 MHz) d 129.7 (m, (ipso-C)),
128.6 (m, m-C), 126.4 (m, o-C), 125.5 (p-C), 122.4–99.0
(m, –C8F17). 19F NMR (CDCl3, 282 MHz) d ꢀ81.3 (m, 3F), ꢀ117.4
(m, 2F), ꢀ118.6 (m, 2F), ꢀ120.2 (m, 2F), ꢀ122.7 (m, 2F), ꢀ123.2
1
(m-C), 125.8 (o-C), 125.6 (p-C), 83.5 (d, JC,F = 160.0 Hz, –CH2F),
2
33.4 (–CH2–C6H5), 31.5 (d, JC,F = 20.5 Hz, –CH2CH2F), 24.6
–CH2CH2CH2F. 19F NMR (CDCl3, 376 MHz) d ꢀ210.8 (m). EI–MS:
ꢂ
ꢂ
ꢂ
m/z 152 [M] 1, 91 [C6H5CH2] 1, 77 [C6H5] 1. Rf = 0.55.
Benzyl 4-methylbenzenesulfonate (1)19. A solution of phenyl-
methanol (0.082, 0.76 mmol) in 2 mL dry THF was added to
sodium hydride (95%, 0.019 g, 0.76 mmol) in 5 mL dry THF.
A
solution of 4-methylbenzenesulfonyl chloride (0.145 g,
0.76 mmol) in 3 mL dry THF was added. The reaction mixture
was stirred at room temperature (r.t.) for 16 h and then extracted
with ethyl acetate (50 mL) and water (100 mL). The organic
phase was dried with MgSO4 and concentrated under reduced
pressure. The residue was purified by column chromatography
(CH2Cl2) to yield 1 as a white solid (0.018 g, 9%). 1H NMR (CDCl3,
400 MHz) d 7.79 (AA0BB0, 2H, ArH), 7.34–7.30 (m, 5H, ArH),
7.25–7.23 (AA0BB0, 2H, ArH), 5.05 (s, 2H, –CH2–), 2.44 (s, 3H,
–CH3). 13C NMR (CDCl3, 100 MHz) d 144.8 (ArC–CH3), 133.3, 129.8,
129.0, 128.6, 128.5, 127.9, 71.9 (–CH2–), 21.6 (–CH3). EI–MS: m/z
ꢂ
(m, 2F), ꢀ124.3 (m, 2F), ꢀ126.6 (m, 2F). EI–MS: m/z 496 [M] 1, 77
ꢂ
[C6H5] 1. Rf = 0.84.
Compound 15 (0.100 g, 0.20 mmol) was dissolved in 2 mL 1,2-
dichloroethane and a solution of chlorosulfonic acid (0.023 g,
0.47 mmol) in 1 mL 1,2-dichloroethane was added dropwise.20
After stirring at r.t. for 22 h, the solvent was evaporated. The
resulting 4-(heptadecafluorooctyl)benzenesulfonic acid 17 was
ꢂ
ꢂ
ꢂ
262 [M] 1, 91 [C6H5CH2] 1, 77 [C6H5] 1. Mp 58–591C. Rf = 0.50.
Benzyl 1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-heptadecafluorooctane-1-sul- used in the next step without purification.1H NMR (CDCl3,
fonate (2).
A
solution of sodium hydride (95%, 0.058 g, 300 MHz) d 8.61 (AA0BB0, 2H, ArH), 7.87 (AA0BB0, 2H, ArH). 13C
2.31 mmol) in 6 mL dry THF was added to a solution of NMR (CDCl3, 75 MHz) d 133.9 (ArC-SO3H), 129.5 (m, o-C or m-C),
phenylmethanol (0.250 g, 2.31 mmol) in 1 mL dry THF. 128.0 (m, o-C or m-C), 125.8 (m, ArC-C8F17), 120.9-97.9 (m,
3
1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-Heptadecafluorooctane-1-sulfonyl
chloride (0.599 g, 1.16 mmol) was added.19 The reaction mixture ꢀ118.5 (m, 2F), ꢀ119.6 (m, 2F), ꢀ120.6 (m, 2F), ꢀ122.5 (m, 2F),
was stirred at r.t. for 24 h and then extracted with diethyl ether ꢀ123.1 (m, 2F), ꢀ124.1 (m, 2F), ꢀ126.5 (m, 2F). EI–MS: m/z 576
–C8F17). 19F NMR (CDCl3, 282 MHz) d ꢀ81.2 (t, JF,F = 8.8 Hz, 3F),
ꢂ
ꢂ
(50 mL) and water (100 mL). The organic phase was dried with [M] 1, 77 [C6H5] 1. Rf = 0.10.
MgSO4 and concentrated under reduced pressure. The residue
Compound 17 (0.100 g, 0.17 mmol) was dissolved in 3 mL dry
was recrystallized from CHCl3/petroleum ether to yield 2 as DMF and thionyl chloride (0.01 mL, 0.17 mmol) was added
white crystals (0.420 g, 31%). 1H NMR (CD3OD, 400 MHz) d dropwise. After heating the reaction mixture at 801C for 9 h, the
7.35–7.29 (m, 5H, ArH), 4.54 (s, 2H, –CH2–). 13C NMR (CD3OD, solvent was evaporated. The resulting 4-(heptadecafluorooctyl)-
100 MHz) d 139.5 (ipso-C), 129.4 (m-C), 128.9 (o-C), 128.6 (p-C), benzenesulfonyl chloride 19 was analyzed by TLC and used in
125.4–99.5 (m, –C8F17), 73.1 (–CH2–). 19F NMR (CD3OD, 376 MHz) the next step without purification. Rf = 0.80.
3
d –82.7 (t, JF,F = 10.1 Hz, 3F), ꢀ116.0 (m, 2F), ꢀ118.9 (m, 2F),
A solution of phenylmethanol (0.017 g, 0.16 mmol) in 3 mL dry
ꢀ122.0 (m, 2F), ꢀ123.0 (m, 2F), ꢀ123.3 (m, 4F), ꢀ124.1 (m, 2F), THF was added to a solution of sodium hydride (95%, 0.004 g,
www.jlcr.org
Copyright r 2009 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2010, 53 24–30

E. Blom et al.
0.16 mmol) in 3 mL dry THF. A solution of 19 (0.100 g, 0.16 mmol) 100 MHz) d 140.8, 135.4, 133.4, 130.2, 129.1, 128.5, 127.6, 127.0
in 5 mL dry THF was added.19 The reaction mixture was stirred at (m), 126.0–105.9 (m, –C4F11), 65.3 (–CH2–). 19F NMR (CDCl3,
r.t. for 5 h and then extracted with ethyl acetate (50 mL) and 282 MHz) d ꢀ83.8 (m, 3F), ꢀ111.5 (m, 2F), ꢀ120.0 (m, 2F), ꢀ125.1
ꢂ
ꢂ
ꢂ
water (100 mL). The organic phase was dried with MgSO4 and (m, 2F). EI–MS: m/z 466 [M] 1, 91 [C6H5CH2] 1, 77 [C6H5] 1. Mp
concentrated under reduced pressure. The residue was recrys- 70–711C. Rf = 0.75.
tallized from CHCl3/petroleum ether, to yield 4 as white crystals
(0.074 g, 69%). 1H NMR (CDCl3, 400 MHz) d 7.37–7.30 (m, 8H,
Benzyl pentafluorobenzenesulfonate (6). Pentafluorobenzenesul-
ArH), 7.25–7.23 (m, 1H, ArH), 3.01 (m, 2H, –CH2–). 13C NMR
fonyl chloride (3.030 g, 11.37 mmol) was added to 8 mL H2O. The
reaction mixture was heated at 1001C for 22 h and then
(CDCl3, 100 MHz) d 130.8, 128.8 (m), 128.6, 128.5, 128.3, 128.1,
127.6 (m), 127.0, 122.4–100.1 (m, –C8F17), 73.2 (–CH2–). 19F NMR
concentrated under reduced pressure. The resulting pentafluor-
obenzenesulfonic acid 2121 was redissolved in 10 mL H2O, and
silver carbonate (3.125 g, 11.33 mmol) was added. The reaction
(CDCl3, 282 MHz) d ꢀ81.1 (m, 3F), ꢀ118.0 (m, 2H), ꢀ119.2
(m, 2F), ꢀ120.3 (m, 2F), ꢀ122.3 (m, 2F), ꢀ123.4 (m, 2F), ꢀ124.3
ꢂ
ꢂ
(m, 2F), ꢀ126.0 (m, 2F). EI–MS: m/z 666 [M] 91 [C6H5CH2] 1, 77
mixture was stirred for 25 h at r.t. in darkness, and excess silver
carbonate was filtered off. The filtrate was concentrated under
reduced pressure. The resulting silver salt 2221 was dissolved in
ꢂ
[C6H5] 1. Mp 86–871C. Rf = 0.81.
Benzyl 4-(nonafluorobutyl)benzenesulfonate (5). Magnesium 9 mL dry acetonitrile and (chloromethyl)benzene (1.301 g,
(0.178 g, 7.32 mmol) was dried and 5 mL dry diethylether and 10.28 mmol) was added. The mixture was stirred at 851C in
bromoethane (0.774 g, 7.10 mmol) were added. The reaction darkness for 17 h and concentrated under reduced pressure. The
mixture was heated at 351C for 4 h under nitrogen atmosphere. residue was purified by column chromatography (CH2Cl2) to
After cooling to ꢀ401C, 1,1,1,2,2,3,3,4,4-nonafluoro-4-iodobu- yield 6 as yellow crystals (0.350 g, 10%). 1H NMR (DMSO-d6,
tane 12 (2.000 g, 5.78 mmol) was added. The temperature was 400 MHz) d 7.15–6.80 (m, 5H, ArH), 3.97–3.80 (m, 2H, –CH2–C6H5).
raised to ꢀ201C and chlorobenzene (0.519 g, 4.10 mmol) and 13C NMR (DMSO-d6, 100 MHz) d 144.9–133.8 (m, ArC-F), 138.8
NiCl2(dppp) (0.006 g, 11.6 mmol) were added. Thereafter, the (m, ipso-C), 130.5 (o-C or m-C), 128.9 (o-C or m-C), 126.5 (p-C),
mixture was heated at 351C for 20 h under a nitrogen 71.6 (–CH2–C6H5). 19F NMR (DMSO-d6, 376 MHz) d ꢀ140.5 (m, 2F,
atmosphere. After cooling to 01C, the mixture was hydrolyzed o-F), ꢀ148.2 (m, 2F, m-F), ꢀ158.7 (m, 1F, p-F). EI–MS: m/z 338
by adding 2 M HCl (aq) and extracted with ether (50 mL) and [M]21 ꢃ 1, 91 [C6H5CH2]ꢃ 1, 77 [C6H5]ꢃ 1. Mp 77–781C. Rf = 0.65.
H2O (10 mL). The combined organic phases were dried with
MgSO4 and concentrated under reduced pressure.21 The
Benzyl 3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluorodecane-1-
sulfonate (7). Thiourea (0.161 g, 2.11 mmol) was added to a
solution of 1,1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8-heptadecafluoro-10-io-
step without purification. H NMR (CDCl3, 300 MHz) d 7.42–7.28
dodecane (1.211 g, 2.11 mmol) in 20 mL ethanol. The reaction
resulting (nonafluorobutyl)benzene 1626 was used in the next
1
(m, 5H, ArH). 13C NMR (CDCl3, 75 MHz) d 134.3 (m, ipso-C), 129.7
(m, m-C), 128.6 (m, o-C), 126.4 (p-C), 125.5–104.3 (m, –C4F11). 19
F
mixture was heated at 781C for 20 h under an atmosphere of
nitrogen before the solvent was removed under reduced
pressure to yield (diaminomethylene)(3,3,4,4,5,5,6,6,7,7,8,8,9,9,
10,10,10-heptadecafluorodecyl)sulfonium iodide 23,6 as a white
solid. The product was used in the next step without
NMR (CDCl3, 282 MHz) d ꢀ85.9 (m, 3F), ꢀ111.2 (m, 2F), ꢀ120.3
ꢂ
ꢂ1
(m, 2F), ꢀ125.5 (m, 2F). EI–MS: m/z 296 [M] 77 [C6H5]
Rf = 0.73.
.
(Nonafluorobutyl)benzene 16 (0.140 g, 0.47 mmol) was dis-
solved in 4 mL 1,2-dichloroethane and chlorosulfonic acid
(0.03 mL, 0.47 mmol) was added dropwise.20 After stirring at
r.t. for 20 h, the solvent was evaporated. The resulting 4-
(nonafluorobutyl)benzenesulfonic acid 18 was used in the next
1
3
purification. H NMR (CD3OD, 400 MHz) d 3.47 (t, JH,H = 7.5 Hz,
2H, –CH2–S–), 2.70 (m, 2H, –CH2–C8F17). 13C NMR (CD3OD,
100 MHz) d 127.5 (m, = C–(NH2)2), 120.0–108.1 (m, –C8F17), 30.5
(m, –CH2–S–), 22.1 (m, –CH2–C8F17). 19F NMR (CD3OD, 376 MHz)
3
1
d ꢀ82.8 (t, JF,F = 10.0 Hz, 3F), ꢀ115.6 (m, 2F), ꢀ122.7 (m, 2F),
step without purification. H NMR (CDCl3, 300 MHz) d 7.43–7.28
(AA0BB0, 4H, ArH). 13C NMR (CDCl3, 75 MHz) d 134.3 (ArC-SO3H),
129.7 (m, o-C or m-C), 128.6 (m, o-C or m-C), 126.4 (m, ArC-
(CF2)7CF3), 126.0–105.0 (m, –C4F11). 19F NMR (CDCl3, 282 MHz) d
ꢀ85.1 (m, 3F), ꢀ110.0 (m, 2F), ꢀ120.9 (m, 2F), ꢀ126.0 (m, 2F).
ꢀ123.0 (m, 2F), ꢀ123.3 (m, 2F), ꢀ124.3 (m, 2F), ꢀ124.8 (m, 2F),
ꢀ127.7 (m, 2F). Rf = 0.73.
(Diaminomethylene)(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-hep-
tadecafluorodecyl)sulfonium iodide (1.184 g, 1.82 mmol) was
dissolved in a mixture of 10 mL acetic acid and 2 mL H2O, then
cooled to 101C. In another flask, which was cooled to 01C, HCl
(9.6 mL) was added dropwise to KMnO4 (3.635 g, 23.0 mmol) to
give Cl2 (g). The Cl2 gas was bubbled through water and into the
reaction mixture for 2 h at 101C. The mixture was stirred for one
additional hour, under a nitrogen flow, and then cooled to 01C.
This caused the product 3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-hep-
tadecafluorodecane-1-sulfonyl chloride 246 to fall out as white
crystals, which were removed by filtration and dried under
reduced pressure (0.497 g, 50%). The product was used in the
next step without purification. 1H NMR (CDCl3/CD3OD, 400 MHz)
d 3.43–3.40 (m, 2H, –CH2–SO2–), 2.58–2.36 (m, 2H, –CH2–C8F17).
13C NMR (CDCl3/CD3OD, 100 MHz) d 121.5–105.0 (m, –C8F17),
49.4 (m, –CH2–SO2–), 30.4 (m, –CH2–C8F17). 19F NMR (CDCl3/
ꢂ
ꢂ
EI–MS: m/z 376 [M] 1, 77 [C6H5] 1. Rf = 0.12.
18 (0.100 g, 0.27 mmol) was dissolved in 4 mL dry DMF and
thionyl chloride (0.02 mL, 0.27 mmol) was added dropwise. The
reaction mixture was heated at 801C for 5 h and then the solvent
was evaporated. The resulting 4-(nonafluorobutyl)benzenesul-
fonyl chloride 20 was analyzed by TLC and used in the next step
without purification. Rf = 0.70.
A solution of sodium hydride (95%, 0.003 g, 0.12 mmol) in
3 mL dry THF was added to a solution of phenylmethanol
(0.013 g, 0.12 mmol) in 2 mL dry THF A solution of 20 (0.050 g,
0.12 mmol) in 4 mL dry THF was added next.19 The reaction
mixture was stirred at r.t. for 18 h and then extracted with ethyl
acetate (50 mL) and water (100 mL). The organic phase was dried
with MgSO4 and concentrated under reduced pressure. The
residue was recrystallized from CHCl3/petroleum ether to yield 5
as white crystals (0.025 g, 45%). 1H NMR (CDCl3, 400 MHz) d
7.36–7.27 (m, 9H, ArH), 4.69 (s, 2H, –CH2–). 13C NMR (CDCl3,
3
CD3OD, 376 MHz) d ꢀ81.2 (t, JF,F = 9.6 Hz, 3F), ꢀ114.6 (m, 2F),
ꢀ122.3 (m, 2F), ꢀ122.6 (m, 2F), ꢀ122.9 (m, 2F), ꢀ123.3 (m, 2F),
ꢀ123.7 (m, 2F), ꢀ126.6 (m, 2F). Rf = 0.63.
J. Label Compd. Radiopharm 2010, 53 24–30
Copyright r 2009 John Wiley & Sons, Ltd.
www.jlcr.org

E. Blom et al.
Triethylamine (0.312 mL, 0.24 mmol) and 24 (0.612 g,
1.12mmol) were added to a solution of phenylmethanol
(0.242 g, 2.24 mmol) in 5 mL dry CH2Cl2. The reaction mixture
was stirred at r.t. for 20 h. H2O (10 mL) was added and the
mixture was extracted with CH2Cl2 (3 ꢁ 20 mL). The combined
organic phases were dried with MgSO4 and concentrated under
reduced pressure. The residue was recrystallized from CHCl3/
Acknowledgement
Financial support from The Swedish Science Research Council
and the Juvenile Diabetes Research Foundation (JDRF) (B. L.) is
gratefully acknowledged. This work was conducted in collabora-
tion with Uppsala Imanet, GE Healthcare.
1
petroleum ether to yield 7 as white crystals (0.296 g, 40%). H
NMR (CDCl3, 400 MHz) d 7.43–7.30 (m, 5H, ArH), 5.20 (s, 2H,
–CH2–C6H5), 2.93–2.89 (m, 2H, –CH2–SO2–), 2.63–2.50 (m, 2H,
–CH2–C8F17). 13C NMR (CDCl3, 100 MHz) d 138.2 (ipso-C), 128.7
(o-C or m-C), 126.7 (o-C or m-C), 125.6 (p-C), 124.1–100.5
(m, –C8F17), 70.7 (m, –CH2–O–), 48.0 (–CH2–SO2–), 25.0 (m,
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3
–CH2–C8F17). 19F NMR (CDCl3, 376 MHz) d ꢀ80.1 (t, JF,F = 9.8 Hz,
3F), ꢀ113.5 (m, 2F), ꢀ121.1 (m, 2F), ꢀ121.9 (m, 2F), ꢀ122.0 (m,
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660 [M] 1, 91 [C6H5CH2] 1, 77 [C6H5] 1. Mp 51–521C. Rf = 0.75.
´
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concentrated under reduced pressure. The residue was recrys-
tallized from CHCl3/petroleum ether to yield 9 as white crystals
(0.027 g, 30%). 1H NMR (CDCl3, 400 MHz) d 7.40–7.25 (m, 5H,
¨
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ArH), 4.17 (t, JH,H = 6.5 Hz, 2H, –CH2–O–), 3.44 (tt, JH,H = 7.1,
4JH,F = 1.0 Hz, 2H, –CH2SO2–), 2.62 (m, 2H, –CH2–C6H5), 1.86–1.77
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´
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3
19F NMR (CDCl3, 376 MHz) d ꢀ81.3 (t, JF,F = 9.9 Hz, 3F), ꢀ114.4
(m, 2F), ꢀ122.3 (m, 2F), ꢀ122.7 (m, 2F), ꢀ123.1 (m, 2F), ꢀ123.4
ꢂ
1
(m, 2F), ꢀ123.9 (m, 2F), ꢀ126.1 (m, 2F). EI–MS: m/z 560 [M]
ꢂ
ꢂ
133 [C6H5(CH2)4] 1, 91 [C6H5CH2] 1. Mp 55–561C. Rf = 0.82.
˚
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Conclusion
The model target compound [18F](fluoromethyl)benzene was
obtained from the perfluorinated precursor benzyl pentafluor-
obenzenesulfonate in 32% analytical radiochemical yield, but
was not obtained from the perfluoroalkyl containing precursors.
The radiochemical purity was increased to 77% after application
to an F-SPE column with a perfluorinated benzene stationary
phase. Even though the radiochemical yield is moderate, the
results suggest that further exploration of perfluoro compounds
in labelling is worthwhile, especially as it may enable the use of
an automatic system for labelling and fast separation.
˚
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B. Langstrom, Presented at Proceedings of the VIth Workshop
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Copyright r 2009 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2010, 53 24–30