A facile synthesis of racemic 4-ethyl fatty acids

Article abstract of DOI:10.3184/174751912X13402672600994

The synthesis of racemic 4-ethyl fatty acids is reported. A Grignard reagent was first prepared by 3-chloroalkane reacting with magnesium and then 4-ethyl fatty acid methyl esters were synthesised by coupling the Grignard reagent with methyl 3-bromopropionate in the presence of the catalyst Li ₂CuCl₄. The 4-ethyl fatty acid methyl esters were saponified and then acidified to give the 4-ethyl fatty acids. The syntheses of 4-ethylhexanoic acid, 4-ethylheptanoic acid, 4-ethyloctanoic acid, 4-ethylnonaoic acid and 4-ethyl decanoic acid are described. The structures of the 4-ethyl fatty acid methyl esters and 4-ethyl fatty acids were confirmed by ¹H NMR, ¹³C NMR and HRMS.

Full text of DOI:10.3184/174751912X13402672600994

4
92 RESEARCH PAPER
AUGUST, 492–494
JOURNAL OF CHEMICAL RESEARCH 2012
A facile synthesis of racemic 4-ethyl fatty acids
Yu-ping Liu*, Wei Guan, De-Cai Yin, Hong-Yu Tian and Bao-guo Sun
School of Chemistry and Food, BeijingTechnology and Business University, Beijing 100048, P. R. China
The synthesis of racemic 4-ethyl fatty acids is reported. A Grignard reagent was first prepared by 3-chloroalkane
reacting with magnesium and then 4-ethyl fatty acid methyl esters were synthesised by coupling the Grignard reagent
with methyl 3-bromopropionate in the presence of the catalyst Li CuCl . The 4-ethyl fatty acid methyl esters were
2
4
saponified and then acidified to give the 4-ethyl fatty acids. The syntheses of 4-ethylhexanoic acid, 4-ethylheptanoic
acid, 4-ethyloctanoic acid, 4-ethylnonaoic acid and 4-ethyl decanoic acid are described. The structures of the 4-ethyl
1
13
fatty acid methyl esters and 4-ethyl fatty acids were confirmed by H NMR, C NMR and HRMS.
Keywords: synthesis, coupling reaction, 4-ethyl fatty acid methyl ester, 4-ethyl fatty acid
4
-Ethyl fatty acids are important branched fatty acids. They
in this work. The reason was to select a moderate coupling
reaction temperature (the greater the reactivity, the lower the
reaction temperature in the coupling reaction) and decrease
the production of by-products (the greater the reactivity, the
more the by-products). The coupling reaction temperature was
1
2
can be found in cheese, stewed beef/vegetable gravy, costus
root oil, flue-cured virginia tobacco and human axillary
secretions, and are responsible for the odours of these
substances. The special fatty and mutton-like flavour of the
goat milk cheeses and sheep milk cheeses is mainly due to
3
4
5,6
–
70 °C when the Grignard reagent prepared from a bromo-
11
1
alkane was used, while it became –10 °C when a 3-chloro-
alkane was used. However, when a 3-chloroalkane was used
for the preparation of the Grignard reagent, it was difficult to
form the Grignard reagent, so a small amount of 1, 2-dibromo-
ethane was added to initiate the reaction.
4
-ethylheptanoic acid and 4-ethyloctanoic acid, and the
characteristic axillary odours of human axillary secretions
come from the constituents including 4-ethylheptanoic acid,
4
-ethyloctanoic acid, 4-ethylnonanoic acid and 4-ethyldeca-
5
noic acid. Some 4-ethyl fatty acids have been used as flavour
and fragrance additives. For example, 4-ethyloctanoic acid
possesses a distinctive waxy, fatty, creamy, mouldy, sour
In the synthesis of 4-ethyl fatty acids, the 4-ethyl fatty acid
methyl ester was an important intermediate. The influences of
several controlling factors on the yield in the synthesis of
methyl 4-ethyloctanoate (3), such as the 3-chloroheptane to
methyl 3-bromopropanoate mole ratio, the reaction tempera-
ture and the Li CuCl quantity, were investigated. The yield
7
sweaty, cheesy odour with animal-like nuances and has been
recognised as a safe (GRAS) flavouring compound (FEMA
No. 3800). In addition, 4-ethylhexanoic acid has an animal
and slightly fatty odour and has been used in the perfume
2
4
of 3 increased as the mole ratio of 3-chloroheptane to methyl
-bromopropanoate increased from 1:1 to 2:1, then decreased
8
composition of the “aldehyde bouquet” type.
3
A significant portion of the published literature about
slightly with the further increase in the mole ratio. This may be
ascribed to the presence of a side reaction, in which the excess
of 3-chloroheptane could give a by-product 5,6-diethyldecane
by coupling with the Grignard reagent. The results are shown
in Table 1. 5,6-Diethyldecane was deleted in the crude product
by GC-MS.
4
-ethyl fatty acids synthesis concerns the synthesis of 4-
ethyloctanoic acid. This is probably due to the ease of getting
the starting materials. Most 4-ethyl fatty acids can be synthe-
sised by two main routes. In the first, the 4-ethyl fatty acids
are prepared by the cleavage of butanolides using diethyl alu-
9
,10
minum chloride (Fig. 1). This method offers the advantages
of higher yields and a shorter reaction time, but the starting
material is not readily available and needs to be synthesised
by a multi-step reaction. The second route prepares the 4-ethyl
fatty acids by a coupling reaction (Fig. 2). This method
involves even more steps, and the operational conditions are
complex. In particular, this route is not suitable for preparing
1
1
4
-ethylhexanoic acid.
In this work, we report a new method for 4-ethyl fatty acids
12
synthesis, which essentially belongs to the second synthetic
route, i.e., by coupling reactions (Fig. 3). The advantages of
the new method include the cheap and readily available mate-
rials as well as the mild reaction conditions. The syntheses of
five 4-ethyl fatty acids are described here.
Fig. 2 Synthesis by a coupling reaction.
Results and discussion
Alkyl halides were used for preparing the Grignard reagent in
the synthesis of 4-ethyl fatty acid methyl esters. The reactivity
of bromoalkanes is greater than that of chloroalkanes.
However, the chloroalkane was chosen as the starting material
Fig. 1 The cleavage of butanolides.
*
Correspondent. E-mail: liuyp@th.btbu.edu.cn
Fig. 3 New synthesis method for 4-ethyl fatty acids.

JOURNAL OF CHEMICAL RESEARCH 2012 493
1
13
Table 1 Effects of 3-chloroheptane to methyl 3-bromopro-
panoate mole ratio on the yield
Peking University. H NMR and C NMR spectra were obtained on a
Bruker DRX-300 NMR spectrometer.
n
(3-chloroheptane):n(methyl 3-bromopropanoate)
1:1 1.5:1 2:1 2.5:1 3:1
28.3 47.2 55.3 54.4 54.6
Synthesis of 4-ethyl fatty acid methyl ester
Magnesium turnings (42 mmol, 1.0 g), anhydrous tetrahydrofuran
Yield of 3 (%)
(
10 mL) and a small crystal of iodine were taken in a dry 100 mL
Reaction conditions: methyl 3-bromopropanoate, 7.5 mmol;
Li
3
round-bottom flask equipped with a stirrer bar, an addition funnel and
a condenser with drying tube. A portion (1 mL) of a solution of the
2
4
CuCl , 0.45 mmol; reaction temperature, 0 °C; reaction time,
h.
3-chloroalkane (15 mmol) in anhydrous tetrahydrofuran (10 mL) as
well as a little 1,2-dibromoethane was put into the addition funnel and
added to the flask. The reaction mixture was heated under stirring.
The heating was stopped after the colour of iodine disappeared, and
then the remaining 3-chloroalkane solution was slowly added into the
flask. The flask was subsequently warmed for 30 min in an oil bath at
Table 2 Effects of reaction temperature on the yield
Reaction temperature (°C)
20
10
0
–10
–20
Yield of 3 (%)
28.3 32.3 49.2 58.0 56.1
7
0 °C to complete the preparation of the alkylmagnesium chloride.
The whole of the product mixture obtained was cooled and used for
the next step.
Reaction conditions: the mole ratio of 3-chloroheptane to
methyl 3-bromopropanoate, 2:1; methyl 3-bromopropanoate
7
.5mmol; Li
2
CuCl
4
, 0.45 mmol; reaction time, 3 h.
Methyl 3-bromopropionate (7.5 mmol, 1.26 g) and anhydrous tetra-
hydrofuran (10 mL) with 0.1 M Li CuCl in THF (3 mL) were taken
2
4
in a dry 100 mL round-bottom flask equipped with a stirrer bar. The
mixture was cooled to –10 °C under stirring, then the above alkylmag-
nesium chloride was added. The reaction mixture was stirred for 3 h
at –10 °C. Then the reaction mixture was slowly added to 1 M HCl
solution (50 mL). The organic layer was separated, and the aqueous
layer was extracted with ethyl ether. The organic layer and the ethyl
ether extraction were then mixed together, washed with brine, dried
The temperature effects on the yield of 3 were also exam-
ined. The results are summarised in Table 2. Among the five
temperatures examined in this study, –10 °C gave the best
yield, while at the temperature –20 °C, the yield was slightly
decreased, which was very probably due to the decrease in the
solubility of the Grignard reagent in THF.
over anhydrous MgSO and filtered to remove the solids.After removal
4
The effects of the catalyst amounts were studied too, in
which the reactions were conducted under the same opera-
tional conditions except for the catalyst amounts. The results
are shown in Table 3. The yield of 3 reached its maximum
value as the ratio of Li CuCl to methyl 3-bromopropanoate
of the diethyl ether under reduced pressure, the residue was purified
by silica column chromatography (5% ethyl acetate/95% petroleum
ether). The fractions collected were monitored using TLC. The best
fractions were mixed together, and the petroleum ether and ethyl ace-
tate were removed under reduced pressure. The purified 4-ethyl fatty
acid methyl esters were obtained as colourless or slightly yellowish
liquids.
2
4
increased from 3% to 4%, then decreased with the further
increase in the mole ratio. This decrease may be ascribed to the
increase in the production of the by-product 5,6-diethyldec-
ane. This could be generated by the reaction of 3-chlorohep-
tane with the Grignard reagent, catalysed by excessive amounts
of catalyst.
The odour characteristics of the five 4-ethyl fatty acids were
evaluated. 4-Ethylhexanoic acid had an acidic, sweaty, mouldy
and slight fatty odour, while 4-ethylheptanoic acid had a sea-
food and mutton odour with a slight fatty nuance. 4-Ethylocta-
noic acid had a mutton and fatty odour. 4-Ethylnonaoic acid
had a fatty and slight garlic odour, and 4-ethyl decanoic acid
had a weak fatty odour.
12
1
Methyl 4-ethylhexanoate (1): Yield 70%; H NMR (CDCl , δ ppm)
3
3
.63 (3H, s), 2.25 (2H, t, J = 7.8 Hz), 1.51–1.59 (2H, m), 1.21–1.30
13
(
5H, m), 0.82 (6H, t, J = 7.1 Hz); C NMR (CDCl , δ ppm) 174.9
3
(
1
C=O), 51.7 (OCH ), 40.2 (CH), 31.9 (CH ), 28.1 (CH ), 25.3 (CH ),
3
2
2
2
+
+
1.0 (CH ); HRMS (ESI ) m/z 159.1382 [M + H] (Calcd for C H O ,
3
9
19
2
1
59.1380).
12
1
Methyl 4-ethylheptanoate (2): Yield 68%; H NMR (CDCl3,
δ ppm) 3.65 (3H, s), 2.27 (2H, t, J = 7.8 Hz), 1.49–1.59 (2H, m),
13
1.20–1.30 (7H, m), 0.86–0.89 (6H, m); C NMR (CDCl , δ ppm)
3
174.6 (C=O), 51.4 (OCH
), 38.1 (CH), 35.0 (CH ), 31.5 (CH ), 28.1
2 2
+
3
(
CH ), 25.4 (CH ), 19.6 (CH ), 14.3 (CH ), 11.0 (CH ); HRMS (ESI )
2
2
2
3
3
+
m/z 173.1537 [M + H] (Calcd for C H O , 173.1536).
10
21
2
12
1
Methyl 4-ethyloctanoate (3): Yield 67%; H NMR (CDCl , δ ppm)
3
3
.63 (3H, s), 2.25 (2H, t, J = 7.8 Hz), 1.47–1.62 (2H, m), 1.21–1.28
Experimental
13
(
9H, m), 0.79–0.88 (6H, m); C NMR (CDCl , δ ppm) 175.0 (C=O),
3
Magnesium turnings, potassium hydroxide, hydrochloric acid
51.8 (OCH
(CH ), 25.9 (CH
m/z 187.1693 [M + H] (Calcd for C11
3
), 38.7 (CH), 32.8 (CH
2
), 31.9 (CH
2
), 29.1 (CH
3
2
), 28.6
+
(36.5%), sodium sulfate (anhydrous), 1,2-dibromoethane, ethyl bro-
2
2
), 23.4 (CH ), 14.5 (CH
2
3
), 11.1 (CH ); HRMS (ESI )
+
mide, methanol, ethyl ether, n-propanal, n-butanal and tetrahydrofu-
ran were purchased from the Sinopharm Chemical Reagent Beijing
Co., Ltd; methyl 3-bromopropionate was obtained from the Jiangsu
WDL Chemical Co., Ltd; n-hexanal and n-heptanal were obtained
from the Beijing Peking University Zoteq Co. Ltd; n-pentanal and
Li CuCl (0.1 M in THF) were purchased from the Aldrich Chemical
H
23
O
2
, 187.1693).
12
1
Methyl 4-ethylnonanoate (4): Yield 72%; H NMR (CDCl
, δ
3
ppm) 3.63 (3H, s), 2.25 (2H, t, J = 7.8 Hz), 1.52–1.81 (2H, m), 1.21–
13
1.25 (11H, m), 0.79–0.92 (6H, m); C NMR (CDCl
, δ ppm) 175.0
3
(
C=O), 51.8 (OCH ), 38.7 (CH), 33.0 (CH ), 32.6 (CH ), 31.9 (CH ),
3
2
2
2
2
8.5 (CH ), 26.5 (CH ), 25.8 (CH ), 23.0 (CH ), 14.4 (CH ), 11.0
2
2
2
2
3
2
4
+
+
(
CH ); HRMS (ESI ) m/z 201.1849 [M + H] (Calcd for C H O ,
Co.
3
12 25
2
2
01.1849).
Methyl 4-ethyldecanoate (5):
3
-Alcohols were obtained by the nucleophilic addition reaction of
11,12
1
Yield 77%; H NMR (CDCl , δ
3
ethylmagnesium bromide with the aldehyde according to the litera-
13
ppm) 3.63 (3H, s), 2.25 (2H, t, J = 7.8 Hz), 1.52–1.85 (2H, m), 1.11–
ture. 3-Chloroalkanes were prepared from the 3-alcohol and thionyl
13
14
1.39 (13H, m), 0.79–0.92 (6H, m); C NMR (CDCl , δ ppm) 175.1
3
chloride according to the literature.
(
C=O), 51.9 (OCH ), 38.8 (CH), 33.1 (CH ), 32.3 (CH ), 32.0 (CH ),
The samples were analysed using Varian CP3800 gas chromatogra-
phy. High-resolution mass spectra were obtained using a Bruker Apex
IV Fourier-Transform Ion Cyclotron Resonance Mass Spectrometer at
3
2
2
2
3
0.1 (CH ), 28.6 (CH ), 26.9 (CH ), 25.9 (CH ), 23.1 (CH ), 14.5
2 2 2 2 2
+ +
(
CH ), 11.1 (CH ); HRMS (ESI ) m/z 215.2006 [M + H] (Calcd for
3
3
C H O , 215.2005).
13
27
2
Synthesis of 4-ethyl fatty acid; general procedure
2 4
Table 3 Effects of the mole ratio of Li CuCl to methyl 3-bromo-
Potassium hydroxide (70.0 mmol, 3.93 g) was dissolved in a mixture
of methanol (20 mL) and deionised water (5 mL) in a 100 mL round-
bottom flask equipped with a stirrer bar. Then 4-ethyl fatty acid methyl
esters (25 mmol) and methanol (15 mL) were added. The reaction
mixture was refluxed for 3 hours, then most of the methanol was
removed by distillation and deionised water (50 mL) was added. The
mixture was washed with ethyl ether (20 mL×3). The remaining water
phase was acidified with HCl (conc.) and the organic layer was
separated. The water phase was extracted with ethyl ether. The organic
propanoate on the yield
n(Li2CuCl4):n(methyl 3-bromopropanoate) 3:100 4:100 5:100 6:100 7:100
Yield of 3 (%)
51.5 65.3 63.2 58.4 58.5
Reaction conditions: the mole ratio of 3-chloroheptane to
methyl 3-bromopropanoate, 2:1; the mole of methyl 3-bromo-
propanoate 7.5mmol; reaction time, 3h; reaction temperature,
–
10 °C.

4
94 JOURNAL OF CHEMICAL RESEARCH 2012
phase and extracts were combined, washed with water and brine,
dried over anhydrous Na SO and filtered to remove the solids. After
Financial support from Beijing Municipal Party Committee
Organisation Department (No: 20081D 0500300127) is
gratefully acknowledged.
2
4
the removal of ethyl ether by evaporation, 4-ethyl fatty acids were
obtained. The composition of the product mixture was analysed by
gas-chromatography, and the yields were calculated. The products
were further purified using distillation under the reduced pressure.
Received 29 March 2012; accepted 7 June 2012
Paper 1201236 doi: 10.3184/174751912X13402672600994
Published online: 8 August 2012
1
5
4
-Ethylhexanoic acid (6): Yield 95%, b.p. 94 ºC/1.1 kPa [lit. 120–
1
1
1
21 ºC/1.6 kPa]; H NMR (CDCl , δ ppm) 2.30–2.36 (2H, m), 1.51–
3
13
.60 (2H, m), 1.22–1.30 (5H, m), 0.83 (6H, t, J = 7.0 Hz); C NMR
(
2
CDCl , δ ppm) 180.7 (COOH), 39.8 (CH), 31.6 (CH ), 27.5 (CH ),
3
2
2
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5.0 (CH ), 10.7 (CH ); HRMS(ESI ) m/z 143.1070 [M - H] (Calcd
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3
1
2
3
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8
15
2
16
1
4
-Ethylheptanoic acid (7): Yield 97%, b.p. 116 ºC/1.1 kPa; H
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3
13
1
.29 (7H, m), 0.82–0.90 (6H, m); C NMR (CDCl , δ ppm) 180.8
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2
2
2
2
+
1
9.6 (CH ), 14.4 (CH ), 10.7 (CH ); HRMS(ESI ) m/z 157.1226
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[
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9 17 2
6
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17
4
-Ethyloctanoic acid (8):Yield 98%, b.p. 140 ºC/1.5 kPa [lit. 142–
1
2
006, 3, 1.
1
1
43 ºC/1.3 kPa]; H NMR (CDCl , δ ppm) 2.26–2.39 (2H, m), 1.52–
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8
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13
.62 (2H, m), 1.07–1.44 (9H, m), 0.61–0.90 (6H, m); C NMR
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3
2
2
2
(
1
9.3 (CH ), 28.5 (CH ), 26.0 (CH ), 23.6 (CH ), 14.6 (CH ), 11.2
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2
2
2
3
+
+
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3
10 19
2
11
12
13
14
15
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71.1380).
18
1
4
-Ethylnonanoic acid (9): Yield 96%, b.p. 155 ºC/1.4 kPa; H
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3
13
1
.40 (11H, m), 0.82–0.89 (6H, m); C NMR (CDCl , δ ppm) 180.7
3
(
COOH), 38.4 (CH), 32.8 (CH ), 32.3 (CH ), 31.6 (CH ), 28.0 (CH ),
2 2 2 2
2
6.3 (CH ), 25.6 (CH ), 22.8 (CH ), 14.2 (CH ), 10.8 (CH );
2 2 2 3 3
+ +
HRMS(ESI ) m/z 185.1536 [M - H] (Calcd for C H O 185.1536).
1
1
21
2
19
4
-Ethyldecanoic acid (10): Yield 92%, b.p. 178 ºC/1.1 kPa [lit.
1
1
1
73–175 ºC/1.8 kPa]; H NMR (CDCl , δ ppm) 2.29–2.34 (2H, m),
3
13
16 L. Katz, J.L. Fortman, J.D. Keasling, WO 2009134899, 2009-11-05.
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.51–1.61 (2H, m), 0.82–1.40 (13H, m), 0.60–0.75 (6H, m); C NMR
1
7
(
CDCl , δ ppm) 181.0 (COOH), 38.7 (CH), 33.1 (CH ), 32.3 (CH ),
3
2
2
18 U. Weerasooriya, J. Boorem, B. Hodle, A. Boorem, P. Radford,
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3
2.0 (CH ), 30.1 (CH ), 28.3 (CH ), 26.9 (CH ), 25.9 (CH ), 23.1
2 2 2 2 2
+ +
(
(
CH ), 14.5 (CH ), 11.1 (CH ); HRMS(ESI ) m/z 199.1691 [M - H]
2 3 3
Calcd for C H O 199.1692).
12
23
2

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