Synthesis and 19F NMR study of RF-oleic acid-F13

Article abstract of DOI:10.1016/S0022-1139(03)00162-3

A seven-step synthesis of Z-13,13,14,14,15,15,16,16,17,17,18,18, 18-tridecafluoro-octadec-9-enoic acid (oleic acid-F₁₃) is reported. The key step is a Wittig reaction to form the C9-C10 double bond with a Z:E isomeric ratio greater than 20:1. The ¹⁹F nuclear magnetic resonance (NMR) spectrum is included and unambiguous assignments have been made with the aid of ¹⁹F-¹⁹F correlation NMR spectroscopy (COSY spectra).

Full text of DOI:10.1016/S0022-1139(03)00162-3

Journal of Fluorine Chemistry 123 (2003) 255–259
19
Synthesis and F NMR study of RF-oleic acid-F13
Gerald W. Buchanan*, Rufus Smits, Elena Munteanu
Department of Chemistry, Ottawa–Carleton Chemistry Institute, Carleton University, Ottawa, Canada K1S 5B6
Received 27 May 2003; received in revised form 4 June 2003; accepted 6 June 2003
Abstract
A seven-step synthesis of Z-13,13,14,14,15,15,16,16,17,17,18,18,18-tridecafluoro-octadec-9-enoic acid (oleic acid-F13) is reported. The
key step is a Wittig reaction to form the C9–C10 double bond with a Z:E isomeric ratio greater than 20:1. The 19F nuclear magnetic resonance
(NMR) spectrum is included and unambiguous assignments have been made with the aid of 19F–19F correlation NMR spectroscopy (COSY
spectra).
# 2003 Elsevier B.V. All rights reserved.
Keywords: Terminally perfluorinated oleic acid; 19F NMR
1. Introduction
function is included in the phosphonium component. The
19F nuclear magnetic resonance (NMR) spectrum of oleic
acid-F13 has been recorded and unambiguous chemical shift
assignments have been made via 19F–19F correlation NMR
spectroscopy (COSY spectra).
Present initiatives in this laboratory are directed towards
the synthesis of highly fluorinated fatty acids with at least 10
fluorine atoms per chain for possible use in the preparation
of novel image enhancement agents in hyperpolarized xenon
magnetic resonance imaging (MRI). No reports of the
synthesis of highly fluorinated oleic acids have appeared
in the literature, although we recently published the synth-
esis of Z-heptadecafluoro-octadec-8-enoic acid via a proce-
dure that utilizes a Wittig reaction as its key step [1]. The
present report deals with the stereospecific synthesis of Z-
tridecafluoro-octadec-9-enoic acid (oleic acid-F13) via a
seven-step synthesis. Again a Wittig reaction is the key
chain-lengthening step, however the carbonyl component
and the phosphonium salt component are reversed from the
previously employed procedure and the carboxylic acid
2. Results and discussion
2.1. Synthesis of oleic acid-F13
The first step in our sequence involves radical addition [2]
of the commercially available perfluorohexyl iodide 1 to
ethylacrylate via the reaction described below. The known
iodoester 2 was obtained in 50% yield and reduced to
the known ester 3 in 93% yield via the published method
[3].
UV
CF3 - ( CF2)5 - I
CF3 - (CF2)5 - CH2 - CH - COO - CH2 - CH3
+
CH2 = CH - COO - CH2 - CH3
48 hrs
I
1
2
zinc
CF3 - (CF2)5 - CH2 - CH - COO - CH2 - CH3
I
CF3 - (CF2)5 - CH2 - CH2 - COO - CH2 - CH3
ethanol
3
* Corresponding author. Tel.: þ1-613-520-2600; fax: þ1-613-520-3749.
E-mail address: geraldbuchanan@pigeon.carleton.ca (G.W. Buchanan).
Preparation of the aldehyde 4 in 48% yield was accom-
plished by reductive oxidation using the recently reported
0022-1139/$ – see front matter # 2003 Elsevier B.V. All rights reserved.
doi:10.1016/S0022-1139(03)00162-3

256
G.W. Buchanan et al. / Journal of Fluorine Chemistry 123 (2003) 255–259
LiAlH4 and PCC method [4].
consistent with the structure containing six unique fluori-
nated carbons. Unambiguous assignment is possible using
19F–19F COSY spectroscopy [8]. The resonance for the CF3
group (C18) is clearly distinguishable from its integrated
intensity, characteristic chemical shift [9] (near À81 ppm
from CFCl3) and the fact that it has only one COSY con-
nection (to the peak at À123.9 ppm). The C13 position is also
expected to show only one COSY correlation since there is
just one CF2 group adjacent. Accordingly, the resonance at
À114.9 ppm can be assigned to this site. The À114.9 peak
shows a strong COSY connection to the peak at À122.3, thus
identifying the C14 site. The À122.3 peak shows a strong
COSY connection to the À126.5 ppm peak, thus C15 is
assigned. Similarly, the À126.5 ppm peak correlates to the
À123.2 peak, indicating that C16 must resonate at the latter
chemical shift. Finally, the À123.2 peak connects to À123.9,
which identifies C17. This is consistent with the observation
that the C18 resonance at À81.1 also exhibits a COSY
connection to the C17 peak at À123.9 ppm.
CF3ÀðCF2Þ5ÀCH2ÀCH2ÀCOOÀCH2ÀCH3
LiAlH4
! CF3ÀðCF2Þ5ÀCH2ÀCH2ÀCHO
PCC
4
The other nine carbon component was obtained starting
with 1,9-nonane diol 5 and carrying out selective mono-
bromination [5] to produce the bromoalcohol 6. The yield in
this reaction was 90% with optimal conditions involving
removal of the water as it is formed.
HOÀðCH2Þ ÀOHH!BrBrÀðCH2Þ ÀOH
9
9
5
6
Subsequent Jones oxidation [6] yielded 9-bromononanoic
acid 7 in 72% yield and the phosphonium salt 8 was
produced in 84% yield using xylene as solvent in an inert
atmosphere.
BrÀðCH2Þ ÀOHJones reagent
!
BrÀðCH2Þ8ÀCOOH
9
7
xylene
Argon
HOOC - (CH2)8 - P+
Br-
P
+
Br - (CH2)8 - COOH
8
For the key Wittig reaction between 4 and 8, conditions
were chosen [7] to optimize the proportion of the requisite
Z-isomer 9, namely a polar aprotic solvent (THF), low
reaction temperature (0 8C) and a non-lithiated base, potas-
sium t-butoxide. The Z:E isomer ratio was in excess of 20:1
as estimated from 1H NMR integration of the olefinic
proton signals, since no resonances arising from a possible
E-isomer were detected. The Z-stereochemistry of the
only isolated isomer was determined from a 1H NMR
NOESY experiment. The isolated yield of of Z-trideca-
fluoro-octadec-9-enoic acid 9 (oleic acid-F13) is 57.6%.
3. Experimental
3.1. General
Melting points are uncorrected. NMR spectra were
recorded using a Bruker AMX spectrometer in CDCl3 unless
otherwise noted with tetramethylsilane as internal standard
for both 1H (400 MHz) and 13C (100 MHz) spectra. For the
NOESYexperiment on 9, the mixing time was selected to be
consistent with the 1/T1 criterion [8] and in the present case
it was set to 1.5 s. An ASPECT 3000 process controller was
CF3(CF2)5-CH2-CH2
H
(CH2)7-COOH
H
K-t-butoxide
THF (0o)
HOOC - (CH2)8 - P+
Br-
C = C
+
CF3 - (CF2)5 - CH2 - CH2 - CHO
Oleic acid - F13
9
2.2. 19F NMR results
employed and the NOESY pulse sequence is contained in
the standard micro program present in the Bruker Software
Library. 19F NMR spectra were recorded with a Bruker AM
400 system operating at 376.4 MHz. 19F chemical shifts are
The 376.4 MHz 1H decoupled 19F NMR spectrum of 9 is
shown in Fig. 1. There are six clearly resolved resonances,

G.W. Buchanan et al. / Journal of Fluorine Chemistry 123 (2003) 255–259
257
Fig. 1. 19F NMR spectrum of oleic acid-F13 (9).
upfield relative to an external CFCl3 reference. All reagents
and solvents were commercial grade (Aldrich) and purified
according to established convention. Elemental analyses
were performed by Guelph Analytical Laboratories.
carried on for a further 2 h. The colorless solution was cooled,
filtered and poured into water (10 ml), and extracted with
diethyl ether (3 Â 10 ml). The collected organic extracts were
washed with water (2 Â 10 ml), then with brine (10 ml), dried
over magnesium sulfate and the solvent evaporated by rotary
evaporation. The product (3) obtained in a 94% yield (0.7 g)
was used in the next step without further purification.
1H NMR 4.19 (q, J ¼ 7:2, 2H), 2.63 (m, 2H), 2.18 (m, 2H),
1.28 (t, J ¼ 7:2, 3H). 13C NMR 171.3, 120.6 (m), 118.7
(m), 118.0 (m), 115.6 (m), 111.1 (m), 108.5 (m), 61.3, 26.7
(t, J ¼ 22:1), 25.6 (t, J ¼ 4:0), 14.2.
3.2. Ethyl-2-iodo-4,4,5,5,6,6,7,7,8,8,9,9,
9-tridecafluorononanoate (2)
To a 50 ml quartz tube were added perfluorohexyl iodide
(2.65 g, 5.9 mmol) and ethyl acrylate (1.78 g, 17.8 mmol).
The reactants were continuously mixed by running nitrogen
gas through the quartz tube. The mixture was irradiated in a
Rayonet photochemical reactor with 254 nm UV light at
room temperature for 48 h. The reaction mixture was pur-
ified by fractional distillation under vacuum and gave 1.62 g
(50% yield) of ethyl-2-iodo-4,4,5,5,6,6,7,7,8,8,9,9,9-tride-
cafluorononanoate (2), bp 60–62 8C (1 mmHg), reported [2]
bp 86–90 8C (2.3 mmHg).
3.4. 4,4,5,5,6,6,7,7,8,8,9,9,9-Tridecafluorononal (4)
To an oven dried 250 ml double-necked round bottom
flask equipped with a condenser, flashed with dry nitrogen
gas and maintained under static pressure of nitrogen, was
transferred a 1.0 M solution of lithium aluminum hydride
(20.2 ml, 0.0202 mol) in THF. To this stirred solution at
0 8C, ethyl-4,4,5,5,6,6,7,7,8,8,9,9,9-tridecafluorononanoate
(3) (11.3 g, 0.026 mol) was added dropwise and the reaction
mixture was stirred overnight at room temperature. Subse-
quently, this solution was added to a well-stirred suspension
of pyridinium chlorochromate (PCC) (12.8 g, 0.059 mol) in
methylene chloride (100 ml) dropwise using a syringe. The
mixture was stirred again overnight at room temperature.
The reaction mixture was diluted with diethyl ether (50 ml)
and the supernatant liquid was filtered through Florisil (60 g)
contained in a sintered glass funnel; the solid residue was
triturated with diethyl ether (3 Â 30 ml) and passed through
the same Florisil column. The solvent was removed by
3.3. Ethyl-4,4,5,5,6,6,7,7,8,8,9,9,
9-tridecafluorononanoate (3)
To a 100 ml double-necked round bottom flask equipped a
condenser and a dropping funnel, 2 (1 g, 0.0018 mol) was
added in absolute ethanol (1.2 ml). After heating the solution
to reflux temperature, zinc dust (10 to 20 mesh), (0.119 g,
0.0018 mol) was added, while stirring. Foaming and exother-
mic reaction were observed. To this reaction mixture hydro-
iodic acid (55%) was then added dropwise until the zinc was
dissolved. After 1 h at 65–70 8C another 0.119 g of zinc was
added,theslurrywasresaturatedwith55%HI,andthereaction

258
G.W. Buchanan et al. / Journal of Fluorine Chemistry 123 (2003) 255–259
rotary evaporation and the yellowish oil was further purified
by fractional distillation to give 4 (4.86 g, 48% yield) bp
40–43 8C (5 mmHg), reported [10] bp 40 8C (5 mmHg).
1H NMR 9.83 (t, J ¼ 1:2, 1H), 2.84 (d, t, J ¼ 1:2, 7.2, 2H),
2.45(m,2H).13CNMR197.9,120.9(m),118.4(m),115.8(m),
113.3 (m), 111.1 (m), 108.3 (m), 34.8, 23.4 (t, J ¼ 22:3).
dry xylene (50 ml). The solution was heated at reflux over-
night under argon. After cooling to room temperature a
thick, glassy-like solid came out of solution. The solvent was
removed by rotary evaporation and the resulting crude
product was further purified by column chromatography
on silica gel with 5% methanol in chloroform to yield
9-bromo-triphenylphosphonononanoic acid 8 (20.5 g, 84%
yield) as a glassy solid.
3.5. 9-Bromononanol (6)
1H NMR 11.1 (bs, 1H), 7.82 (m, 9H), 7.73 (m, 6H), 3.61
(m, 2H), 2.31 (t, J ¼ 7:4, 2H), 1.56 (m, 6H), 1.24 (m, 6H).
13C NMR 177.0, 135.1 (d, J ¼ 2:8), 133.6 (d, J ¼ 10:0),
130.6 (d, J ¼ 12:6), 118.2 (d, J ¼ 85:9), 34.5, 30.1
(d, J ¼ 16:0), 28.5, 28.5, 28.4, 24.6, 22.7 (d, J ¼ 47:0),
22.4 (d, J ¼ 2:4).
1,9-Nonane diol (Aldrich) (20 g, 0.124 mol) was dis-
solved in toluene (250 ml) by heating the solution at about
60 8C, in a 500 ml round bottom flask. To this solution was
added hydrobromic acid (48%, 14.1 ml), dropwise with stir-
ring and the mixture was heated at reflux (178–180 8C) for
28 h. The water formed during the reaction was removed
using a Dean–Stark trap. After cooling to room tempera-
ture, the mixture was washed with 6N sodium hydroxide
solution (100 ml), 10% hydrochloric acid (100 ml), water
(2 Â 200 ml), and finally with brine (150 ml). The organic
layer was dried over anhydrous magnesium sulfate, filtered by
gravity and the solvent was removed by rotary evaporation.
The resulting yellowish oil was applied to a silica gel column
(grade 40, 6–12 mesh) and eluted with 4:1 hexane:ethylace-
tate. The second fraction contained 9-bromo-1-nonanol
(24.9 g, 90% yield) as a white solid with mp 33–35 8C.
1H NMR 3.63 (t, J ¼ 6:6, 2H), 3.41 (t, J ¼ 6:8, 2H), 1.85
(m,2H),1.74(s,1H),1.56(m,2H),1.42(m,2H),1.31(m,8H).
13C NMR 62.9, 34.0, 32.8, 32.7, 29.4, 29.3, 28.7, 28.1, 25.7.
3.8. Z-13,13,14,14,15,15,16,16,17,17,18,18,
18-Tridecafluoro-octadec-9-enoic acid (9)
To a double-necked round bottom flask was added 8
(3.0 g, 0.006 mol). The flask was equipped with a heating
mantle and connected to a high vacuum pump. The phos-
phonium salt was dried at 110 8C under high vacuum for
5 h. To this dried phosphonium salt, was added freshly
distilled THF (100 ml) and the resulting slurry was stirred
under argon atmosphere until the salt completely dissolved.
Subsequently, potassium t-butoxide (1.38 g, 0.0123 mol)
was added under argon. The resulting orange solution was
stirred for 30 min at room temperature after which time 4
(2.26 g, 0.006 mol) in 10ml of dry THF was added drop-
wise with stirring at 0 8C under argon. After all the
aldehyde was added the cooling bath was removed and
the slurry further stirred for 48 h. The reaction mixture
was then triturated with 50 ml of diethyl ether, acidified
with 2 M hydrochloric acid and extracted with diethyl
ether. The collected organic extracts were washed with
water, then with brine, dried over magnesium sulfate and
the solvent removed by rotary evaporation. The crude
product was purified by column chromatography on silica
gel with 3:1 hexane:ethyl acetate to yield Z-13,13,14,14,
15,15,16,16,17,17,18,18,18-tridecafluoro-octadec-9-enoic
acid (9) (1.78 g, 57.6%) as a white solid with mp 17.6–
18.1 8C.
3.6. 9-Bromononanoic acid (7)
To chromium trioxide (10.3 g, 0.102 mol) in water
(10 ml) at 0 8C was added dropwise concentrated sulfuric
acid (8.8 ml, 0.133 mol) followed by water (19 ml). The
resulting mixture was slowly added to a solution of 6 (15.2 g,
0.0682 mol) in acetone (50 ml) at À5 8C. After stirring for
2 h at 0 8C, the solution was left overnight at room tem-
perature. The mixture was extracted with diethyl ether
(3 Â 60 ml) and the combined organic extracts were washed
with water (2 Â 60 ml), brine (70 ml), then dried over
anhydrous magnesium sulfate, and filtrated through Florisil
(200 mesh). The solvent was removed by rotary evaporation.
Column chromatography on silica gel with dichloromethane
was carried out on the resulting yellowish oil and the fraction
having the Rf value of 0.48 in DCM on TLC was collected,
yielding 9-bromo-nonanoic acid (7) (11.6 g, 72%) as a white
solid, mp 31.5–33.5 8C, reported [6], colorless oil.
1H NMR 10.8 (bs 1H), 5.48 (m, 1H), 5.34 (m, 1H), 2.36
(m, 4H), 2.05 (m, 4H), 1.64 (m, 2H), 1.32 (m, 8H). 13C NMR
180.6, 132.4, 126.3, 121.2 (m), 119.2 (m), 116.4 (m), 113.9
(m), 111.3 (m), 108.6 (m), 34.2, 31.2 (t, J ¼ 22:1), 29.5,
29.3, 29.1, 29.0, 27.2, 24.8, 18.4 (t, J ¼ 4:2). Anal. Calcd.
for C18H21F13O2: C 41.86, H 4.10, F 47.84, O 6.20. Found C
41.62, H 4.32, F 47.98.
1H NMR 11.1 (bs, 1H), 3.40 (t, J ¼ 6:8, 2H), 2.35 (t,
J ¼ 7:5, 2H), 1.85 (m, 2H), 1.63 (m, 2H), 1.42 (m, 2H), 1.32
(m, 6H). 13C NMR 180.1, 34.0, 33.9, 32.8, 29.0, 28.9, 28.5,
28.1, 24.6.
Acknowledgements
3.7. 9-Bromotriphenylphosphonononanoic acid (8)
G.W. Buchanan thanks the Natural Sciences and
Engineering Research Council of Canada (NSERC) for
support of this work via a Discovery Grant. We thank Brian
In a 250 ml round bottom flask were added 7 (11.6 g,
0.048 mol) and triphenylphosphine (12.8 g, 0.048 mol) in

G.W. Buchanan et al. / Journal of Fluorine Chemistry 123 (2003) 255–259
259
Dawson and Derek Hodgson of Health Canada for the 19F
NMR spectra.
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Tetrahedron 45 (1989) 2057–2065.
[7] B.E. Maryanoff, A.B. Reitz, B.A. Duhl-Emswiler, J. Am. Chem. Soc.
107 (1985) 217–226.
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