Synthesis of ethyl 5Z,9Z,12Z-octadecatrienoate (ethyl pinolenate) and methyl 12Z,15Z-octadecadienoate

Article abstract of DOI:10.1007/s11746-008-1226-x

Pinolenic acid (5Z,9Z,12Z-octadecatrienoic acid, 1a), one of the most abundant trienoic fatty acids in nature, is very difficult to obtain in quantity in a pure state from the highly complex mixture of unsaturated tall oil fatty acids. For this reason its chemistry has been little studied when compared to linolenic or linoleic acids. A simple synthesis of esters of 1a and of 12Z,15Z-octadecadienoic acid 3 using the one pot double Wittig procedure is described here. The products of double Wittig reactions were purified by argentation chromatography, and their structural purity was established by ¹H-, ¹³C-NMR and 2D-NMR spectroscopies.

Full text of DOI:10.1007/s11746-008-1226-x

J Am Oil Chem Soc (2008) 85:561–565
DOI 10.1007/s11746-008-1226-x
ORIGINAL PAPER
Synthesis of Ethyl 5Z,9Z,12Z-octadecatrienoate (ethyl pinolenate)
and Methyl 12Z,15Z-octadecadienoate
Seppo Kaltia Æ Jorma Matikainen Æ
Maija Ala-Peijari Æ Tapio Hase
Received: 9 November 2007 / Revised: 13 February 2008 / Accepted: 14 February 2008 / Published online: 11 March 2008
Ó AOCS 2008
Abstract Pinolenic acid (5Z,9Z,12Z-octadecatrienoic
acid, 1a), one of the most abundant trienoic fatty acids in
nature, is very difficult to obtain in quantity in a pure state
from the highly complex mixture of unsaturated tall oil
fatty acids. For this reason its chemistry has been little
studied when compared to linolenic or linoleic acids. A
simple synthesis of esters of 1a and of 12Z,15Z-octadeca-
dienoic acid 3 using the one pot double Wittig procedure is
described here. The products of double Wittig reactions
were purified by argentation chromatography, and their
structural purity was established by 1H-, 13C-NMR and 2D-
NMR spectroscopies.
synthesis of many of the isomers [2] and their intramolecular
Diels-Alder cyclization reactions [3, 4].
There are no reported syntheses of 1a in the literature,
nor in fact of any all-cis (n, n + 4, n + 7)-alkatriene sys-
tems as far as we know. The sensitive methylene/ethylene
interrupted triene functionality poses major problems for
synthesis, particularly if the double bonds are introduced
one at a time. This is because an initially created cis double
bond with allylic functionality must survive subsequent
operations required for the remaining C=C bond forming
chemistry.
The use of bisphosphonium salts in the one pot Wittig
syntheses of methylene skipped dienes was first reported
[5] by Wittig himself in 1958 for the preparation of
cycloalkapolyenes. Bestmann et al. [6] relied on this
strategy in syntheses of a number of 1,4-alkadienoic
pheromones and related compounds starting from C3–C8
bisphosphonium salts with simultaneous use of two dif-
ferent aldehydes. More recently Pohnert and Boland [7]
used a double alkenylation of bis-ylides from propylene-
1,3-bis(triphenylphosphonium) dibromide 2 or (Z)-hex-3-
enyl-l,6-bis-(triphenylphosphonium) diiodide to prepare
several methylene interrupted cis-trienoic hydrocarbons
and fatty acid esters. In all of these procedures strong
organic bases were used for bis-ylide generation, thus
requiring strictly anhydrous conditions and operation at
low temperatures.
Keywords Pinolenic acid (5Z,9Z,12Z-octadecatrienoic
acid) ꢀ 12Z,15Z-octadecadienoic acid ꢀ Wittig reaction ꢀ
Argentation chromatography
Introduction
Up to 10% of the fatty acids in northern European and
Siberian spruce and pine consist of pinolenic acid
(5Z,9Z,12Z-octadecatrienoic acid, 1a), which is one of the
most abundant1 trienoic fatty acids in nature, second only to
linolenic acid. Owing to the difficulties in obtaining pino-
lenic acid in quantity in a pure state, its chemistry has been
little studied when compared to linolenic or linoleic acids.
We reported [1] earlier the isolation of 1a from tall oil by an
iodo-lactonization method, its alkali isomerization and the
We have for years successfully used the exceptionally
simple and robust K2CO3 mediated aqueous Wittig pro-
cedure [8] for the synthesis of various alkali isomerization
products of pinolenic [2] and linolenic [4] acid esters, as
S. Kaltia ꢀ J. Matikainen ꢀ M. Ala-Peijari ꢀ T. Hase (&)
Laboratory of Organic Chemistry, Department of Chemistry,
University of Helsinki, P.O. Box. 55, 00014 Helsinki, Finland
e-mail: tapio.hase@helsinki.fi
1
In Finland alone, several tens of thousands of tons of tall oil fatty
acids, containing ca. 10% of pinolenic acid, are annually distilled in
the tall oil industry.
123

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J Am Oil Chem Soc (2008) 85:561–565
well as other straight chain compounds [9, 10] capable of
producing hexahydroindenes via intramolecular Diels-
Alder reactions. We now report the results of using 2 as the
ylide generating precursor in the potassium carbonate
mediated one-pot aqueous double Wittig synthesis of
methylene skipped cis diene and triene structures, and
show that the obstacles just mentioned may be overcome to
an extent. Although moderate overall yields are obtained in
our synthesis, it is clear that the route makes macroscopic
amounts of pure pinolenic acid and related compounds
available for the first time in a fairly expedient manner.
To widen the scope of our synthetic procedure also
12Z,15Z-octadecadienoic acid 3 as methyl ester was syn-
thesized. This compound is one of the byproducts formed
on hydrogenation of linolenic acid containing vegetable
oils in the margarine industry.
the better a separation can be obtained, and it is important
that, when preparing a new batch, drying should be per-
formed as described above. If one attempts to oven dry a
new AgNO3–silica batch containing moisture, a vigorous
reaction usually ensues with evolution of NH3 gas (pre-
sumably originating from CH3CN), the surface of the
material becoming covered with a black layer of Ag(0).
This reaction does not occur when recovered material is
dried in the oven for reuse.
For ordinary thin layer chromatography, aluminum
sheets coated with silica gel 60 F, Merck, were used. For
thin layer argentation chromatography, the sheets were
immersed in a 10% solution of AgNO3 in acetonitrile and
dried at ambient temperature.
4-(Tetrahydropyran-2-yloxy)butanol (4)
Experimental Procedures
3,4-Dihydropyran (45 g, 0.53 mol) (Scheme 1) was added
slowly to a stirred mixture of 1,4-butanediol (60 g,
0.67 mol) and conc. H2SO4 (0.2 mL) in CH2Cl2 (70 mL) in
ice bath (exothermic !). Over a period of 10 min, the
temperature rose to ca. 35 °C. After stirring for 30 min at
room temperature the reaction mixture was neutralized
with 10% aq. NaHCO3 and CH2Cl2 was evaporated under
reduced pressure. One hundred and fifty milliliters of water
was added, the mixture was extracted with 70 mL of die-
thyl ether and the organic phase was separated and
extracted once with 100 mL of water. The combined water
phases were extracted with 30 mL of diethyl ether (dis-
carded), saturated with NaCl and extracted five times with
diethyl ether (5 9 20 mL). The combined ether phases
were dried on Na2SO4 and the solvent evaporated to give
4-(tetrahydropyran-2-yloxy)butanol 4 (23.5 g, 19%). 1H
NMR d 1.38 -1.54 (m, 4H, H-30b, H-40b, H-20b and H-
40a), 1.61–1.67 (m, 5H, H-2, H-3 and H-20a), 1.77 (m, 1H,
H-30a), 2.78 (br s, 1H, OH), 3.38 (dt, J = 9.8 Hz, 5.6 Hz,
1H, H-4b), 3.47 (m, 1H, H-50b), 3.60 (m, 2H, H-1), 3,74
(dt, J = 9.8 Hz, 5.8 Hz, 1H, H-4a ), 3.82 (m, 1H, H-50a),
The structure and purity of the products were established
by GC/MS and NMR (1H, 13C, 2D NMR) techniques.
NMR spectra were acquired with Varian Inova or Varian
Unity spectrometers running at 300 MHz and at 500 MHz,
respectively. Solvent was CDCl3 in all cases and running
temperature 30 °C. Assignments are based on 2D-NMR
spectra (COSY 135, NOESY, HMBC, HSQC-TOCSY).
Especially the HSQC-TOCSY traces at appropriate 13C-
chemical shifts proved to be very effective in solving
ambiguous cases.
Full spectral details are given for new compounds only.
For argentation chromatography, silica gel (60 g; Kieselgel
60, E. Merck, Darmstadt, 230–400 mesh ASTM; kept
overnight in an oven at 120 °C) was treated with 100 mL
of a 10% solution of AgNO3 in acetonitrile, the latter
˚
predried over 3-A molecular sieves. After the removal of
acetonitrile under vacuum in a rotary evaporator at 70 °C,
the impregnated silica was ready for use. Details of
argentation chromatography are given for ethyl pinolenate
below. The drier the argentation chromatography system is,
13
4.56 (t, J = 3.5 Hz, 1H, H-10). C NMR d 19.39 (C-30),
Scheme 1 Synthesis of
pinolenic acid ethyl ester
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J Am Oil Chem Soc (2008) 85:561–565
563
13
25.25 (C-40), 26.31 (C-3), 29.79 (C-2), 30.48 (C-20), 62.15
(C-50), 62.33 (C-1), 67.35 (C-4), 98.70 (C-10).
J = 1.6 Hz, 1H, H-9). C NMR d 14.09 (C-20), 19.92
(C-3), 24.62 (C-4), 26.41 (C-7), 33.56 (C-2), 43.61 (C-8),
60.09 (C-10), 128.20 (C-6), 130.14 (C-5), 174.28 (C-1),
201.82 (C-9). Anal. calc. for C11H18O3, C 66.6, H 9.2;
found, C 66.9, H 9.1.
4-(Tetrahydropyran-2-yloxy)butanal (5)
4-(Tetrahydropyran-2-yloxy)butanol (4) (20 g, 0.12 mol)
was added to a suspension of NACAA [11] (nicotinic acid
chromic acid mixed anhydride betaine) (66 g, 280 mmol)
in CH2Cl2 (200 mL) and pyridine (45 mL). After vigor-
ous stirring at ambient temperature for 1 h, the reaction
mixture was run through a column of silica gel (70–230
mesh). The eluate was monitored by TLC (CH2Cl2/EtOAc
5:1) and the fractions containing the product collected to
Propylene-1,3-bis(triphenylphosphonium dibromide) (2)
1,3-Dibromopropane (16.0 g, 0.080 mol), triphenylphos-
phine (40.5 g, 0.15 mol) and 1.0 g of K2CO3 were refluxed
in acetonitrile (200 mL) for 2 days under Ar to give 31.5 g
(54%) of white crystals of 2.
1
give 10.2 g (50%) of 5 as an oil. H NMR d 1.45–1.58
Pinolenic Acid Ethyl Ester (1)
(m, 4H, H-30b, H-40b, H-20b and H-40a), 1.65 (m, 1H, H-
20a), 1.75 (m, 1H, H-30a), 1.96 (quintet, J = 6.6 Hz, 2H,
H-3), 2.50 (m, 2H, H-2), 3.38 (dt, J = 9.7 Hz, 6.1 Hz,
1H, H-4b), 3.46 (m, 1H, H-50b), 3.74 (dt, J = 9.7 Hz, 6.2
Hz,1H, H-4a), 3.78 (m, 1H, H-50a), 4.52 (dd, J = 4.4 Hz,
2,7 Hz, 1H, H-10), 9.75 (t, J = 1.7 Hz, 1H, H-1). 13C
NMR d 19.36 (C-30), 22.54 (C-3), 25.30 (C-40), 30.46 (C-
20), 40.97 (C-2), 62.14 (C-50), 66.27 (C-4), 98.72 (C-10),
202.19 (C-1).
The bisphosphonium salt 2 (305 mg, 0.42 mmol), pow-
dered K2CO3 (120 mg, 0.87 mmol), the aldehyde 6
(83 mg, 0.42 mmol), hexanal (110 mg, 1.10 mmol), 1,4-
dioxane (1.5 mL) and H2O (25 lL) were heated and stirred
under Ar at 105 °C in an oil bath for 20 h. The solvent was
evaporated under reduced pressure, and the residue
extracted with hexane (15 mL) and filtered. Flash chro-
matography of the concentrate (silica gel, elution with
hexane/CH2Cl2 1:2) yielded 19.4 mg (15%) of crude 1,
containing a small amount of hexanal aldol condensation
product (Rf approximately the same as of ethyl pinolenate).
This by-product is easily removed by argentation chro-
matography on AgNO3 impregnated silica gel (CH2Cl2/
ethyl acetate 2:1). Elution was monitored by ordinary TLC
and, when all esters had eluted, a second analysis of frac-
tions was carried out on AgNO3 impregnated TLC plates.
The later fractions giving only one spot on an AgNO3 TLC
plate (Rf ca. 0.18) were combined, the solvent evaporated
under reduced pressure and the residue filtered through a
pad of silica gel (elution with hexane/CH2Cl2 1:1) to
remove silver residues from the preparate. The yield of
9-Oxo-5Z-nonenoic Acid Ethyl Ester (6)
The triphenylphosphonium salt from ethyl 5-bromopent-
anoate 7 (35.0 g, 74 mmol), K2CO3 (10.0 g, 72 mmol), the
aldehyde 5 (10.0 g, 58.0 mmol), 1,4-dioxane (60 mL) and
H2O (1.5 mL) were refluxed with stirring under Ar for
20 h. The solvent was evaporated under reduced pressure,
and the residue extracted with 5% ethyl acetate in CH2Cl2.
Flash chromatography of the concentrate in a silica gel
column (elution with 5% ethyl acetate in CH2Cl2) yielded
14.8 g of crude 9-(tetrahydropyran-2-yloxy)-5Z-nonenoic
acid ethyl ester 8 containing ca. 15% of the 5E-isomer (by
1H-integrals). This mixture was treated with 80 mL of
acetone and 30 mL of 3% H2SO4 in H2O at 50 °C for 3 h.
After neutralization with 10% NaHCO3 and evaporation of
acetone, the residue was extracted with ethyl acetate
(2 9 50 mL), dried on Na2SO4 and solvent evaporated to
yield 12.8 g of crude 9-hydroxy-5-nonenoic acid ethyl
ester. This was added to a suspension of NACAA (18 g) in
CH2Cl2 (60 mL) and pyridine (13 mL) to yield 7.4 g of
crude 6. Flash chromatography (silica gel, elution with 5%
ethyl acetate in CH2Cl2) yielded 1.88 g (overall 16.5%
from 5) of 6 containing ca 15% of the 5E-isomer. 1H NMR
d 1.26 (t, J = 7.1 Hz, 3H, H-20), 1.70 (quintet, J = 7.4 Hz,
2H, H-3), 2.10 (td, J = 7.4 Hz, 6.6 Hz, 2H, H-4), 2.36 (td,
J = 7.2 Hz, 6.7 Hz, 2H, H-7), 2.30 (t, J = 7.4 Hz, 2H,
H-2), 2.49 (td, J = 7.2 Hz, 1.6 Hz, 2H, H-8), 4.13 (q,
J = 7.1 Hz, 2H, H-10), 5.38 (dt, J = 10.7 Hz, 6.7 Hz, 1H,
H-6), 5.41 (dt, J = 10.7 Hz, 6.6 Hz, 1H, H-5), 9.77 (t,
1
pure 1b (99% by GC and H NMR) was 12.0 mg (9.3%).
1H NMR d 0.90 (t, J = 6.9 Hz, 3H, H-18), 1.26 (t,
J = 7.1 Hz, 3H, H-20), 1.30 (m, 2H, H-16), 1.31 (m, 2H,
H-17), 1.36 (quintet, J = 7.1 Hz, 2H H-15), 1.70 (quintet,
J = 7.4 Hz, 2H, H-3), 2.06 (q, J = 7.1 Hz, 2H, H-4), 2.09
(q, J = 7.0 Hz, 2H, H-14), 2.11 (m, 4H, H-7 and H-8),
2.31 (t, J = 7.5 Hz, 2H, H-2), 2.79 (br t, J = 6.2 Hz, 2H,
H-11), 4.13 (t, J = 7.1 Hz, 2H H-20), 5.33 (dtt, J = 10.7,
7.1, 1.5 Hz, 1H, H-12), 5.36 (m, 1H, H-5), 5.37 (m, 1H, H-
10), 5.38 (m, 2H, H-9 and H-13), 5.42 (dtt, J = 10.9, 6.8,
13
1.4 Hz, 1H, H-6). C NMR d 14.05 (C-18), 14.24 (C-20),
22.56 (C-17), 24.89 (C-3), 25.67 (C-11), 26.60 (C-14),
27.20 (C-4), 27.26 and 27.29 (C-7 and C-8), 29.32 (C-15),
31.51 (C-16), 33.75 (C-2), 60.19 (C-10), 127.78 (C-12),
128.57 (C-10), 128.99 (C-5), 129.25 (C-9), 130.21 (C-6),
130.30 (C-13), 173.67 (C-1). HRMS calc. for C20H34O2
306.2559, found 306.2572.
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J Am Oil Chem Soc (2008) 85:561–565
CH=CHR1, R1CH=CH- - -CH=CHR2 and R2CH=CH- - -
CH=CHR2 (ignoring geometric isomers) in a 1:2:1
ratio, respectively. Assuming equal reaction rates, the
maximal yield for the mixed product is just 50%, and
the entire concept may therefore appear somewhat waste-
ful. However, the aqueous potassium carbonate-based
procedure is very simple and may readily be scaled up.
Furthermore, if the two aldehydes are chosen so that one
is a simple alkanal, while the other carries an ester group at
the remote end of the chain, the three products (a hydro-
carbon, a monoester and a diester) possess widely differing
polarities, which may be readily exploited in a chromato-
graphic isolation of the individual products. Alternatively,
one may try to improve the yield of a desired product by
introducing one aldehyde first and then after a time the
second. In our experience this approach [5] affords only
rather modest improvements.
12-Oxododecanoic Acid Methyl Ester (9)
12-Hydroxydodecanoic acid was prepared by reduction
[12] of commercial (Fluka) dodecadienoic acid. 12-Hy-
droxydodecanoic acid was then oxidized with NACAA [(as
above for 4-(tetrahydropyran-2-yloxy)butanal 5)] to give
1
the aldehyde ester 9 in 38% yield. H NMR d 1.25 (m, 12
H, H-4, H-5, H-6, H-7, H-8 and H-9), 1.59 (sextet,
J = 7.1 Hz, 4 H, H-3 and H-10), 2.27 (t, J = 7.6 Hz, 2H,
H-2), 2.39 (td, J = 7.4 Hz, 1.8 Hz, 2H, H-11), 3.64 (s, 3H,
H-10), 9.74 (t, J = 1.8 Hz, 1H, H-12). 13C NMR d 21.98
(C-10), 24.85 (C-.3), 29.02, 29.05, 29.11, 29.22, 29.24 (2C)
(C-4–C-9), 34.00 (C-2), 43.81 (C-11), 51.32 (C-10), 174.19
(C-1), 202.75 (C-12).
12Z,15Z-Octadecadienoic Acid Methyl Ester (3)
The bisphosphonium salt 2 (7.0 g, 9.6 mmol), powdered
K2CO3 (5 g, 36 mmol), the aldehyde 9 (2 g, 8.77 mmol),
propanal (5 g, 8.6 mmol), 1,4-dioxane (60 mL) and H2O
(0.25 mL) were stirred in an autoclave under Ar at 100 °C.
Flash and argentation chromatography gave 76 mg (10%)
4-(Tetrahydropyran-2-yloxy)butanal 5, Scheme 1, pre-
pared from the corresponding diol by mono-THP ether
formation, followed by oxidation using the NACAA reagent
[11], was reacted with the phosphonium salt from ethyl 5-
bromo-pentanoate under the K2CO3–aqueous dioxane con-
ditions to give 9-oxo-5Z-nonenoic acid ethyl ester 6 with a
Z:E selectivity ratio of 4:1 (16.5 % from 5). This mixture was
used as such for the subsequent step, the minor impurities of
E-isomers being removed by argentation chromatography in
the final purification. Better Z-selectivity was observed in the
one pot double Wittig reaction with the bisphosphonium salt
2, propanal and the aldehyde ester 5, there being less than
10% of E-isomers (by 1H-integrals) formed. Ethyl pinolenate
1b was obtained from the aldo ester 6 in 15% yield (as
explained above, the maximal theoretical yield of 1b is
50%). Ethyl pinolenate was purified by argentation chro-
matography, and its structural purity was established by 1H-,
13C-NMR and 2D-NMR spectroscopy.
1
of 3. H NMR d 0.97 (t, J = 7.6 Hz, 3H, H-18), 1.27 (m,
12H, H-4, H-5, H-6, H-7, H-8 and H-9), 1.33 (m, 2H, H-
10), 1.52 (quintet, J = 7.3 Hz, 2H, H-3), 2.05 (q,
J = 7.2 Hz, 2H, H-11), 2.07 (quintet, J = 7.6 Hz, 2H,
H-17), 2.30 (t, J = 7.6 Hz, 2H, H-2), 2.77 (t, J = 6.8 Hz,
2H, H-14), 3.66 (s, 3H, H-10), 5.33 (m, 1H, H-15), 5.36 (m,
1H, H-13), 5.38 (m, 1H, H-12), 5.39 (m, 1H, H-16). 13C
NMR d 14.23 (C-18), 20.49 (C-17), 24.92 (C-3), 25.49
(C-14), 27.17 (C-11), 29.12, 29.22, 29.25, 29.40, 29.45,
29.51 (C-4, C-5, C-6, C-7, C-8 and C-9), 29.62 (C-10),
34.07 (C-2), 51.35 (C-10), 127.39 (C-15), 127.92 (C-13),
130.13 (C-12), 131.69 (C-16), 174.25 (C-1). HRMS calc.
for C19H34O2 294.2559, found 294.2570.
For comparison, an authentic reference sample of 1a
was also separated from tall oil fatty acids [13] using urea
crystallization. Although the concentrate, 60% in pinolenic
acid, contains about 5% of 5Z,11Z,14Z-eicosatrienoic acid
(sciadonic acid), repeated argentation chromatography of
esterified material gave pure (99.7% by GC) 1b, with
spectral data and other properties identical with synthetic
ethyl pinolenate.
Results and Discussion
A symmetric bisphosphonium ylide, undergoing a double
Wittig reaction between two different aldehydes (R1CHO
and R2CHO), all used in equimolar quantities, may in
principle form three different dienes R1CH=CH- - -
Scheme 2 Synthesis of methyl
12Z,15Z-octadecadienoate
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J Am Oil Chem Soc (2008) 85:561–565
565
5. Wittig G, Eggers H, Diffner P (1958) New syntheses of cyclo-
polyenes. Ann 619:10–18
The double Wittig technique was also applied to
the synthesis of methyl 12Z,15Z-octadecadienoate 3
(Scheme 2). The aldehyde ester 9 was obtained from the
corresponding x-hydroxy ester by NACAA oxidation. The
K2CO3–H2O phase transfer double Wittig reaction fur-
nished 3 in 10% yield, containing less than 10% of E
6. Bestmann HJ, Zeibig T, Vostrowsky O (1990) Pheromones 69.
Stereoselective syntheses of nonconjugated bisolefinic Lepidop-
tera pheromones and structural analogs. Synthesis 1039–1047
7. Pohnert G, Boland W (2000) Highly efficient one-pot double-
Wittig approach to unsymmetrical (1Z,4Z,7Z)-homoconjugated
trienes. Eur J Org Chem 1821–1826
8. Le Bigot Y, Delmas M, Gaset A (1983) Direct synthesis of
dipteran sex pheromones by the Wittig reaction in a heterogenous
medium. J Agric Food Chem 31:1096–1098
1
isomers (by H-integrals).
¨
9. Matikainen J, Kaltia S, Hase T, Kilpelainen I, Drakenberg T,
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