Synthesis of highly fluorinated fatty acid esters of glycerol:glycerol tripalmitate-F39

Article abstract of DOI:10.1016/j.jfluchem.2006.04.016

Glycerol tripalmitate-F₃₉ has been prepared from glycerol and the acid chloride of R_F-palmitic acid-F₁₃ via a solid phase aluminum oxide catalyzed reaction. The product has been characterized by electrospray mass spectrometry and ¹H, ¹⁹F and ¹³C NMR methods. A second, less efficient synthesis is reported in which a chain elongation strategy is employed after reaction of glycerol with the acid chloride of 9-decenoic acid.

Full text of DOI:10.1016/j.jfluchem.2006.04.016

Journal of Fluorine Chemistry 127 (2006) 1042–1045
www.elsevier.com/locate/fluor
Synthesis of highly fluorinated fatty acid esters of glycerol:glycerol
tripalmitate-F39
*
Majid F. Rastegar, Gerald W. Buchanan , Melanie C. Bouffard
Ottawa-Carleton Chemistry Institute, Department of Chemistry, Carleton University, Ottawa, Canada K1S 5B6
Received 20 March 2006; received in revised form 27 April 2006; accepted 27 April 2006
Available online 13 May 2006
Abstract
Glycerol tripalmitate-F39 has been prepared from glycerol and the acid chloride of R
F
-palmitic acid-F13 via a solid phase aluminum oxide
13
1
19
catalyzed reaction. The product has been characterized by electrospray mass spectrometry and H, F and C NMR methods.
A second, less efficient synthesis is reported in which a chain elongation strategy is employed after reaction of glycerol with the acid chloride of
9
-decenoic acid.
2006 Elsevier B.V. All rights reserved.
#
Keyword: Highly fluorinated triglyceride
1
. Introduction
[6] of the use of 20% aqueous suspensions of non-fluorinated
lipid vesicles of particle size approximately 0.1 mm for the
1
29
Current initiatives in this laboratory have been directed
delivery of hyperpolarized Xe to human blood. The xenon
solubility is approximately four times greater than that in water
towards the synthesis of highly fluorinated fatty acids [1,2] and
their polyesters with sucrose [3] which are of potential
application in the preparation of novel biocompatible delivery
systems for dissolved hyperpolarized xenon to be used in
1
29
and the Xe spin lattice relaxation time is approximately three
times longer than that observed for a saline water/blood mixture.
Since it is expected that xenon solubility will be even higher in a
fluorinated lipid, the highly fluorinated fatty acid esters of
glycerol are of interest, provided that they are not metabolized.
Although no clear evidence to that effect is yet available, it has
been shown [7] that the incorporation of linear perfluoroalkanes
into liposomes induces a large decrease in pancreatic phospho-
lipase activity. No effect on enzyme activity was found when
nonfluorinated hydrocarbons were used indicating that the
fluorinated segment is required to hinder ester hydrolysis.
To date, no reports of the synthesis of any glycerol esters
containing fluorinated fatty acid chains have been published.
Herein we report two procedures for the synthesis of glycerol
tripalmitate-F39 (1) and its characterization by electrospray
mass spectrometry and NMR methods.
1
29
functional Xe magnetic resonance imaging (MRI) [4]. The
highly fluorinated sucrose polyesters have been chosen for
study since it is known [5] that the human lipase enzyme cannot
metabolize sucrose polyesters in which more than five of the
eight OH groups have been esterified with long chain fatty acids
and hence these materials pass unmetabolized through the
human gastrointestinal tract. Accordingly the application of
1
29
such compounds as part of a biocompatible Xe carrier for
functional imaging of Crohn’s disease and other gastrointest-
inal disorders can be envisaged. Our recent work [3] on sucrose
octaoleate-F104 demonstrated that this material, when present in
an aqueous emulsion with egg yolk phospholipid, is an efficient
1
29
carrier of dissolved hyperpolarized Xe gas.
The question then arises as to the possible use of highly
fluorinated fatty acid triesters of glycerol for the purposes of
delivery of hyperpolarized gases for imaging. There is one report
2. Results and discussion
2.1. Synthetic methodology
A number of attempts were made to prepare 1 via methods
which are successful for non-fluorinated palmitates, including
*
Corresponding author. Tel.: +1 613 520 3840.
E-mail address: gerald_buchanan@carleton.ca (G.W. Buchanan).
0022-1139/$ – see front matter # 2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2006.04.016

M.F. Rastegar et al. / Journal of Fluorine Chemistry 127 (2006) 1042–1045
1043
Scheme 1.
transesterification and base catalyzed (pyridine in DMF)
reaction between glycerol and palmitoyl chloride. However,
these proved not to be successful when using R -palmitic acid-
NMR spectrum, it is interesting to note that there are two ester
carbonyl resonances present at 173.2 and 172.8 ppm in the ratio
of 2:1. Hence the internal (more sterically congested) carbonyl
is slightly shielded relative to the carbonyls attached to C1 and
3. There is, however substantial overlap between resonances in
F
F13 and hence an alternative method was required. The recent
report [8] of efficient acylation of alcohols using reactions on an
Al O surface caught our attention and proved to be successful
1
9
the C1 and 3 versus C2 sidechains. The F NMR spectrum of 1
shows chemical shifts which are essentially identical to those
reported recently [9] for R -palmitic acid-F
2
3
in the present system.
In general, perfluorinated fatty acids tend to be lowly soluble
and hence the analogous reaction with perfluoropalmitic acid
has not been successful. In the present work, a two-step
synthesis of 1, as depicted in Scheme 1 (below) has been carried
out with an overall yield of 43%. An alternate method for the
preparation of 1 is depicted in Scheme 2. This involves free
radical addition of a six carbon perfluorohexyl moiety to each
chain of glycerol-tri-9-decenoate, followed by zinc reduction.
F
13.
3. Experimental
1
13
Melting points are uncorrected. Solution H and C NMR
spectra were recorded using a Bruker AMX-400 spectrometer
in CDCl unless other wise specified, with tetramethylsilane as
3
1
13
internal standard for both H (400 MHz) and C (100 MHz)
1
spectra. F NMR spectra were recorded on a Bruker Avance
300 NMR Spectrometer at 282.4 MHz. Chemical shifts are
referenced to external CFCl . Elemental analyses were
9
2
.2. NMR spectral data
3
1
The H NMR spectrum of 1 shows the expected complexity
performed by Guelph Analytical Laboratories. Electrospray
mass spectra were recorded using a Micromass Quattro–LC
in the regions near 5.2 and 4.2 ppm, respectively, for the protons
of the glycerol moiety due to the diastereotopic nature of the
+
Electrospray–Triple Quadrupole Mass Spectrometer with K
salts present in the sprayed solution.
1
3
geminal methylene protons on the C1 and 3 sites. In the
C
Scheme 2.

1044
M.F. Rastegar et al. / Journal of Fluorine Chemistry 127 (2006) 1042–1045
3
3
.1. Synthetic details
eluent. After solvent removal and high vacuum drying, 13.6 g
78%) of 9-decenoic acid was obtained as a colorless oil, whose
(
1
13
H and C spectral properties were identical to those reported
.1.1. Synthesis of R -palmitoyl-F chloride
F 13
R -palmitic acid-F was prepared as described previously
F
previously [12].
13
[
(
10]. To this acid (5.00 g, 10.19 mmol) dissolved in hexane
50 mL), under an argon atmosphere, was added dropwise with
3.2.2. Synthesis of 9-decenoyl chloride
stirring, 1.72 mL (20.39 mmol) of oxalyl chloride over a
0 min period. After the addition was complete, the tempera-
In a 100 mL round bottom flask, 10.8 g (63.5 mm) of 9-
decenoic acid was dissolved in 60 mL of hexane and placed
under argon atmosphere. With stirring at room temperature,
oxalyl chloride, 10.7 mL (126.9 mm) was added dropwise
over 10 min. The reaction temperature was then raised to 40–
45 8C and the reaction was continued overnight. The solvent
was removed by rotary evaporation and the crude product was
dried on a high vacuum pump to give 9-decenoyl chloride
[13] which was used without further purification in the next
step.
1
ture was raised to 40–45 8C and stirring was continued
overnight. The solvent was removed via rotary evaporation to
afford the crude acid chloride as judged by its IR spectrum,
ꢀ
1
C O stretch at 1803 cm . This crude acid chloride was used
without further purification in the next step.
3
.1.2. Synthesis of glycerol tripalmitate-F39
To the crude acid chloride from the previous step (under
argon) was added glycerol 156.5 mg, (1.70 mmol) and
79.8 mg (7.65 mmol) of oven dried neutral aluminum oxide
8]. The reaction mixture was stirred vigorously with heating at
0 8C overnight. After cooling, 50 mL of dichloromethane was
added and the crude mixture was filtered by suction. The
precipitates were washed with an additional 50 mL of
dichloromethane and the combined filtrates were stirred with
7
3.2.3. Synthesis of glycerol tri-9-decenoate
[
The crude product from the previous step was dissolved in
40 mL of anhydrous pyridine and to this was added 1.46 g
(15.86 mm) of glycerol. The reaction mixture was stirred under
argon atmosphere overnight.
4
After solvent removal under vacuum, the oily residue was
dissolved in 200 mL of dichloromethane and washed with brine
(2ꢁ 100 mL), distilled water (2ꢁ 100 mL) and dried over
sodium sulfate. After filtration and solvent removal under
vacuum a yellow oil was produced which was purified further
via column chromatography on silica gel using 9:1 hex-
ane:ethyl acetate as eluent. Yield of glycerol tri-9-decenoate
was 5.56 g (64%) as a colorless oil.
1
00 mL of distilled water. Following separation and drying of
the organic layer over anhydrous sodium sulfate, the solvent
was removed in vacuo to yield crude product as off-white solid.
This solid was then subjected to column chromatography on
silica gel using 9:1 hexane:ethyl acetate as eluent. The resulting
white solid was recrystallized from ethanol to yield glycerol
tripalmitate-F39 1, 1.1 g, m.p. 38–39 8C, in 43% overall yield.
Anal. Calcd. for C H F O :C 40.59, H 3.94, F 49.11, O 6.36.
1
H NMR: 5.70 (m, 3H), 5.21 (m, 1H), 4.90 (q, 6H), 4.18
(octet, J = 11.8, 6.0, 4.3 Hz, 4H), 2.22 (m, 6H), 1.97 (m, 6H),
5
1 59 39 6
Found C 40.75, H 4.02, F 48.62, O 6.61.
Mass spectrum Calcd. for C H F O : 1508.92, with K
+
1.25 (m, 30H).
1
5
1 59 39 6
3
1
4
548.02. Found 1547.3.
1
C NMR: 173.2, 172.8, 139.0, 138.9, 114.2, 68.9, 62.1,
34.0, 33.7, 29.1, 29.0, 28.9, 28.8, 24.9, 24.8.
H NMR: 5.28 (m,1H), 4.23 (octet, J = 11.90, 5.96, 4.30 Hz,
H), 2.32(m, 6H), 2.04 (m, 6H), 1.62 (m, 12H), 1.35 (m, 30H).
Anal. Calcd. for C H O : C 72.22, H 10.29, O 17.49.
3
3 56 6
1
3
C NMR: 173.2, 172.8, 120.6 (m), 118.4 (m), 115.9 (m),
14.0 (m), 111.0 (m), 108.3 (m), 68.9, 62.1, 34.1, 33.9, 30.9,
Found C 72.01, H 10.44, O 17.55.
1
3
0.8 (t, J = 22.3 Hz), 29.2, 29.1, 29.0, 28.9.
1
3.2.4. Synthesis of glycerol tri-(9-iodo) palmitate-F39
9
F NMR: ꢀ81.4, ꢀ114.6, ꢀ122.1, ꢀ123.1, ꢀ123.8, ꢀ126.4.
In a 25 mL oven dried round bottom flask, glycerol tri-9-
decenoate, 2.42 g (4.41 mmol) and perfluoro-n-hexyliodide
(Aldrich) 7.85 g (17.65 mmol) were mixed and stirred under an
argon atmosphere at 95–100 8C in an oil bath. To this mixture
3
3
.2. Synthesis via chain elongation
0
.2.1. Synthesis of 9-decenoic acid
In a 1.0 L round bottom flask, 9-decenol (Aldrich) 16.0 g
102.6 mm) was dissolved in 500 mL of acetone and cooled in
was added over 30 min 0.345 g (1.4 mmol) AHCN (1,1 -
azobis(cyclohexanecarbonitrile)) and the temperature was kept
below 100 8C. The reaction was continued overnight and the
reaction mixture was then cooled to room temperature, before
proceeding to the next step.
(
an ice bath. To this stirred mixture was added 60 mL of Jones
reagent [11] in a dropwise manner over 30 min. The reaction
mixture was stirred for 2 more hours at room temperature and
then quenched by the addition of isopropyl alcohol. The solid
precipitate was removed by filtration and the filtrate was
concentrated under reduced pressure. The resulting dark oil was
dissolved in ethyl acetate (300 mL) and washed with brine (3ꢁ
3.2.5. Synthesis of glycerol tripalmitate-F39
The crude product from the previous step was dissolved in
80 mL of THF, and to this was added NiCl ꢂ6H O, 0.63 g
2
2
(2.65 mmol) and zinc powder, 1.73 g (26.5 mm) and the
mixture was stirred overnight at room temperature. Following
solvent removal by rotary evaporation, the mixture was poured
into 100 mL of distilled water and extracted with dichloro-
methane (2ꢁ 100 mL). The combined organic extracts were
1
00 mL), distilled water (2ꢁ 100mL) and dried over sodium
sulfate. Subsequent solvent removal under reduced pressure
yielded a yellow oil which was further purified by column
chromatography on silica gel using 9:1 hexane:ethyl acetate as

M.F. Rastegar et al. / Journal of Fluorine Chemistry 127 (2006) 1042–1045
1045
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washed with saturated NaCl solution (2ꢁ 50 mL) and distilled
water (100 mL) before drying over anhydrous sodium sulfate.
Following filtration and solvent removal, the crude product was
purified by column chromatography on silica gel using 9:1
hexane:ethyl acetate as eluent, to yield 3.1 g of 1 (m.p. 38–
(
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[
[
[
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