Synthesis and odor evaluation of five new sulfur-containing ester flavor compounds from 4-ethyloctanoic acid

Article abstract of DOI:10.3390/molecules15085104

Five sulfur-containing flavor compounds were synthesized for the first time by the reaction of 4-ethyloctanoyl chloride with sulfur-containing alcohols or mercaptans. The synthesized compounds are 3-(methylthio)propyl 4-ethyloctanoate, 2-methyl-3-tetrahyd

Full text of DOI:10.3390/molecules15085104

Molecules 2010, 15, 5104-5111; doi:10.3390/molecules15085104
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Synthesis and Odor Evaluation of Five New Sulfur-Containing
Ester Flavor Compounds from 4-Ethyloctanoic Acid
Yuping Liu 1,2, Haitao Chen 2, Decai Yin 2 and Baoguo Sun 1,2,
*
1
College of Chemistry and Chemical Engineering, Shaanxi University of Science and Technology,
Xi’an 710021, China
2
School of Chemical and Environmental Engineering, Beijing Technology and Business University,
Beijing 100048, China
* Author to whom correspondence should be addressed; E-Mail: sunbg@btbu.edu.cn.
Received: 5 June 2010; in revised form: 16 July 2010 / Accepted: 27 July 2010 /
Published: 29 July 2010
Abstract: Five sulfur-containing flavor compounds were synthesized for the first time by
the reaction of 4-ethyloctanoyl chloride with sulfur-containing alcohols or mercaptans. The
synthesized compounds are 3-(methylthio)propyl 4-ethyloctanoate, 2-methyl-3-tetrahydro-
furanthiol 4-ethyloctanoate, 4-methyl-5-thiazoleethanol 4-ethyloctanoate, 2-furan-
methanethiol 4-ethyloctanoate and 2-methyl-3-furanthiol 4-ethyloctanoate. These five
synthetic sulfur-containing ester flavor compounds all have meaty odor and might be used
in foods if approved for this purpose in the future.
Keywords: sulfur-containing compounds; flavor; synthesis; odor characteristic
1. Introduction
Esters are important flavor compounds because of the large number of accessible ester compounds,
their occurrence in a wide range of natural sources, various odor characteristics and their wide range of
uses in flavourings. The odor of esters is related to the organic acid and alcohol from which they
derived. Moreover, the odor intensity of esters decreases with the increase of molecular weight;
however, the flavor industry needs esters with strong odors and high molecular weight to prolong the
duration of the odor of flavorings. Esters containing sulfur can be synthesized to yield flavor

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substances with strong odor and high molecular weight, as flavor compounds containing sulfur exhibit
very low odor threshold levels and very good odor characteristics.
The sulfur-containing esters can be divided into two classes; one in which the sulfur atom belongs
to the organic acid, such as CH3SCH2CH2COOCH3, and the other in which the sulfur atom is from an
alcohol or mercaptan (AOM), such as CH3COOCH2CH2SCH3 or CH3COSCH2CH2CH3. The first
sulfur-containing ester class can be synthesized by the thia-Michael addition reaction, which is facile
and efficient [1-3]. The second ester class can be synthesized by several methods. One method is the
preparation of the ester from AOM and an organic acid in the presence of a catalyst, which can be
basic, like triethylamine [4] or acidic [5,6] like solid superacids or p-toluenesulfonic acid. A second
method is treatment of AOM with an anhydride yielding the corresponding ester [6-9]; mercaptans can
be used directly as the starting reagent or can be obtained by reducing an alkyl disulfide with tributyl
phophine [9]. A third method is the preparation of the esters by reaction of an acyl chloride with AOM
[10-15]; however, the hydrogen chloride side product must sometimes be eliminated by pyridine
addition. The fourth method is the synthesis of esters by reaction of a haloalkane with the salt of a thio-
organic acid in THF [16]; these starting materials are not readily available, so this method is mainly
used in the synthesis of esters from thioacetic acid.
4-Ethyloctanoic acid has a low odor threshold of 1.8 ppb [17] and possesses an odor variously
described as waxy, fatty, creamy, moldy and cheesy, with animal-like nuances; it is used in flavoring
for goat meat with fatty, meaty nuances and savory notes [18]. 3-(Methylthio)propanol, 4-methyl-5-
thiazole ethanol, 2-methyl-3-furanthiol, 2-methyl-3-tetrahydrofuranthiol and 2-furanmethanethiol are
all very important sulfur-containing flavor compounds in formulating meaty flavorings [19-22] and are
also used to synthesize acetates. Their corresponding 4-ethyloctanoates would have desirable high
molecular weights but have never been synthesized. We have now synthesized and evaluated the odors
of the esters derived from 4-etyloctanoic acid with the above AOMs. The carbonyl in 4-ethyloctanoic
acid is a weak electrophile, so 4-ethyloctanoyl chloride is synthesized as an intermediate to increase
the electrophilic properties of the carbonyl group. 4-Ethyloctanoyl chloride (2) was synthesized by the
reaction of thionyl chloride with 4-ethyloctanoic acid (1), and then 2 reacted with either 3-
(methylthio)propanol, 2-methyl-3-tetrahydrofuranthiol, 4-methyl-5-thiazoleethanol, 2-furanmethane-
thiol and 2-methyl-3-furanthiol, respectively (Scheme 1), to give their corresponding esters 3a-3e
(Figure 1).
Scheme 1. Reaction route.
ROH (or R'SH)
SOCl2
OR (or SR')
OH
Cl
O
3
2
O
O
S
1
HO
HO
S
or
ROH=
N
HS
HS
HS
R'SH=
or
,
O
O
O

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Figure 1. Structures of compounds 3a-e.
S
O
S
O
O
O
3b
3a
O
S
O
N
O
S
O
3d
3c
S
O
O
3e
The esters underwent odor evaluation, which demonstrated that these five synthetic sulfur-
containing flavor compounds all have meaty odor and might be used in foods if approved for this
purpose in the future.
2. Results and Discussion
The effects of different mole ratios of materials on the yield were investigated using three different
ratios under the same experimental conditions, and the results are shown in Table 1. Because the 4-
ethyloctanoic acid used was a racemic compound, the five synthesized flavor compounds are
also racemic.
Table 1. Effect of different mole ratio of materials on the yield.
Yield (%)
Compound
n (alcohol or mercaptan) : n (4-ethyloctanoyl chloride)
1.2:1
1.6:1
90%
78%
89%
94%
84%
2.0: 1
85%
67%
93%
93%
79%
94%
94%
87%
95%
86%
3a
3b
3c
3d
3e
The yields of 3a, 3b, 3d and 3e increased as the ratio of mercaptan (or alcohol) to 4-ethyloctanoyl
chloride increased, while the yield of 3c decreased as the ratio of alcohol to 4-ethyloctanoyl chloride
increased. This phenomenon was related to the characteristics of the starting materials involved in each
reaction. In the reaction producing 3c, the 4-methyl-5-thiazoleethanol used as a starting material has
multiple nucleophilic centers (O, S and N), which may react with 4-ethyloctanoic chloride to give the
product or byproducts. Although the reaction temperature and steric-hindrance effect were not
appropriate to form byproducts, the yield increased as the ratio of 4-methyl-5-thiazoleethanol to 4-
ethyloctanoyl chloride increased. This may account for the low yield of 3c.

Molecules 2010, 15
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The hydrogen chloride generated in the reactions to produce 3d and 3e induces the breakage of
furan ring structure found in the starting material and the formation of resin-like byproducts. Pyridine
was used in these reactions to trap the hydrogen chloride [23]. Pyridine can also react with 4-ethyl-
octanoyl chloride to give pyridine 4-ethyloctanoate, which readily forms the desired ester product with
the mercaptan [24].
2-Methyl-3-furanthiol and 2-furanmethanethiol are isomers, where the latter one is more reactive
than the former. The mercapto group of 2-methyl-3-furanthiol is adjacent to the conjugated system,
which weakens its nucleophilicity. Consequently, the yield of 3e is lower than that of 3d.
The odor evaluation results are shown in Table 2. The results indicate that the five synthetic sulfur-
containing flavor compounds all have meaty odor, especially 3b, 3d and 3e. Amongst those five
compounds, the three derived from mercaptan and 4-ethyloctanyl chloride (3b, 3d and 3e) have
stronger odors than the two derived from a sulfur-containing alcohol and 4-ethyloctanyl chloride (3a
and 3c). All five flavor compounds have relatively high molecular weights (> 260) and are therefore
less volatile, which can prolong the flavoring lifetime to improve the flavoring quality.
Table 2. The results of odor evaluation.
Compound
Odor characteristics
meaty, sauce, savory odor with a slight potato, radish and sulfury nuance
meaty, onion, metallic, sulfury odor with a slight hot nuance
a slight meaty, roasted and, burnt odor with sesame oil and fatty nuance
meaty, roasted meat, onion, sulfury odor with a slight garlic nuance
meaty, brothy, sulfury roasted odor with a slight sweet note
3a
3b
3c
3d
3e
3. Experimental
3.1. General
The samples were analyzed by Varian CP3800 gas chromatography. Mass spectra were obtained
1
13
using a Waters Micromass Q-TOF mass spectrometer. H-NMR and C-NMR spectra were obtained
on a Bruker DRX-300 nuclear magnetic resonance spectrometer. IR spectra were acquired on a Nicolet
Avater 370 Fourier transform infrared spectrometer. Odor evaluation was carried out by gas
chromatography-olfactometry.
3.2. Synthesis of 4-ethyloctanoyl chloride (2)
To 4-ethyloctanoic acid (0.2 mol) was added thionyl chloride (0.28 mol) at 30 ºC. The resulting
solution was refluxed for 6 hours at 80 ºC, and the excess thionyl chloride was evaporated in vacuo to
1
collect the distillate at 74 ºC/0.4 kPa and give the 4-ethyloctanoyl chloride, yield 97%. H-NMR
(CDCl3, δ ppm) 2.75-2.80 (t, 2H), 1.58-1.60 (m, 2H), 1.16-1.22 (m, 9H), 0.77-0.83 (m, 6H); 13C-NMR
(CDCl3, δ ppm) 174.10 (C=O), 44.81 (CH2), 37.89 (CH), 32.31 (CH2), 28.67 (CH2), 28.25 (CH2),
25.41 (CH2), 22.98 (CH2), 14.06 (CH3), 10.60 (CH3); IR (KBr,cm-1) 2960, 2929, 2860, 1801, 1458,
1404, 1380, 956, 709, 686, 596.

Molecules 2010, 15
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3.3. General Synthesis of Compounds 3a-c
To alcohol (or mercaptan) (0.1 mol) was added 4-ethyloctanoyl chloride (0.05 mol) at 30 ºC, and
the resulting solution was refluxed for 4 hours at 70 ºC. After cooling, ethyl ether (30 mL) was added.
The mixture was washed with 10% Na2CO3 aqueous solution and saturated NaCl aqueous solution to
pH 6-7, then the sample was dried with anhydrous NaSO4 and filtered. The ethyl ether was evaporated
in vacuo and the mixture was weighed. The composition of the product mixture was determined by
gas-chromatography, and the yield was calculated. The product was further purified using distillation
under the reduced pressure.
20
3-(Methylthio)propyl 4-ethyloctanoate (3a). Yield 94%; b.p. 142 ºC/0.4 kPa; refractive index (nD
)
1.4654; MS (EI), m/z, 260.1812 (M+), formula C14H28O2S, (calc. mass 260.1810). 1H-NMR (CDCl3, δ
ppm) 4.14-4.18 (t, 2H), 2.53-2.58 (t, 2H), 2.25-2.30 (t, 2H), 2.10 (s, 3H), 1.87-1.96 (m,2H), 1.55-1.60
(m, 2H), 1.23-1.30 (m, 9H), 0.84-0.90 (m, 6H); 13C-NMR (CDCl3, δ ppm) 173.82 (C=O), 62.65
(OCH2), 38.25 (CH), 32.33 (CH2), 31.60 (CH2), 30.50 (CH2), 28.66 (CH2), 28.15 (CH2), 28.12 (CH2),
25.42 (CH2), 22.91 (CH2), 15.30 (SCH3), 13.94 (CH3), 10.57 (CH3); IR (KBr,cm-1) 2958, 2925, 2864,
1737, 1460, 1383, 1349,1241, 1168, 1108, 1024, 960.
2-Methyl-3-tetrahydrofuranthiol 4-ethyloctanoate (3b). Yield 94%; b.p. 140 ºC/0.2 kPa; refractive
index (nD20) 1.4830; MS (EI), m/z, (M+) 272.1813, formula C15H28O2S, (calc. mass 272.1810).
1H- NMR (CDCl3, δ ppm) 4.09-4.13 (m, 0.5H), 3.95-4.03 (m, 0.5H), 3.89-3.93 (m, 1H), 3.70-3.82 (m,
1.5H), 3.48-3.53 (m, 0.5H), 2.41-2.53 (m,3H), 1.82-1.86 (m, 1H), 1.59-1.61(m, 2H), 1.16-1.26 (m,
12H), 0.80-0.88 (m, 6H); 13C-NMR (CDCl3, δ ppm) 199.48 (C=O), 80.19 (CH-O), 66.81 (CH2-O),
46.47 (CH-S), 41.68 (CH2), 38.33 (CH), 33.39 (CH2), 32.51 (CH2), 29.05 (CH2), 28.83 (CH2), 25.60
(CH2), 23.11(CH2), 17.00 (CH3), 14.19 (CH3),.10.77 (CH3); IR (KBr,cm-1) 2959, 2928, 2872, 1692,
1456, 1380, 1352, 1315, 1188, 1111, 1063, 1022, 990, 858.
4-Methyl-5-thiazoleethanol 4-ethyloctanoate (3c). Yield 93%; b.p. 175 ºC/0.4 kPa; refractive index
1
(nD20) 1.4920; MS (EI), m/z, 297.1766 (M+), formula C16H27O2SN, (calc. mass 297.1763); H-NMR
(CDCl3, δ ppm) 8.55 (s, 1H), 4.17-4.21 (t, 2H), 3.03-3.08 (t, 2H), 2.38 (s, 3H), 2.22-2.27 (m,2H),
13
1.53-1.55 (m, 2H), 1.19-1.24 (m, 9H), 0.78-0.87 (m, 6H); C-NMR (CDCl3, δ ppm) 173.90 (C=O),
149.86 (S-CH=N), 149.77 (N-C), 126.75 (S-C), 63.81 (O-CH2), 38.28 (CH), 32.36 (CH2), 31.65 (CH2),
28.72 (CH2), 28.07 (CH2), 25.77 (CH2), 25.45 (CH2), 23.03 (CH2), 14.90 (CH3), 14.10 (CH3), 10.68
(CH3); IR (KBr,cm-1) 2958, 2926, 2860, 1738, 1543, 1458, 1416, 1378, 1238, 1167, 1106, 1035, 915,
847, 786.
3.4. General Synthesis of Compound 3d-e
A mixture of 2-furanmethanethiol(or 2-methyl-3-furanthiol) (0.1 mol), pyridine (0.1 mol) and
dichloromethane (40 mL) was prepared and to this was added 4-ethyloctanoyl chloride (0.05 mol) at
30 ºC. The resulting solution was refluxed for 6 hours at 45 ºC. At the end of this period, the mixture
was filtered to remove solids, and the filtrate was washed with saturated NaCl aqueous solution. The
organic phase was dried with anhydrous NaSO4 and filtered. Dichloromethane and pyridine were

Molecules 2010, 15
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evaporated in vacuo and the mixture weighed. The composition of the product was determined by gas-
chromatography and the yield calculated. The product was further purified via distillation under
reduced pressure.
20
2-Furanmethanethiol 4-ethyloctanoate (3d). Yield 95%; b.p. 142 ºC/0.3 kPa; refractive index (nD
)
1.5005; MS (EI), m/z, 268.1500 (M+), formula C15H24O2S, (calc. mass 268.1497); 1H-NMR (CDCl3, δ
ppm) 7.31 (m, 1H), 6.27 (m, 1H), 6.19-6.20 (m, 1H), 3.03-3.08 (t, 2H), 4.13 (s, 2H), 2.51-2.56 (m,
13
2H), 1.63 (m, 2H), 1.23-1.28 (m, 9H), 0.81-0.90 (m, 6H); C-NMR (CDCl3, δ ppm) 198.54 (C=O),
150.61 (=C-O), 142.13 (=CH-O), 110.53 (CH=), 107.82 (CH=), 41.41 (CH2), 38.24 (CH), 32.42
(CH2), 28.73 (CH2), 25.63 (CH2), 25.55 (CH2), 25.51 (CH2), 23.03 (CH2), 14.10 (CH3), 10.68 (CH3);
IR (KBr, cm-1) 2958, 2927, 2859, 1694, 1596, 1502, 1460, 1380, 1246, 1151, 1071, 1010, 935, 885,
807, 735, 597.
20
2-Methyl-3-furanthiol 4-ethyloctanoate (3e). Yield 86%; b.p. 134 ºC/0.2 kPa; Refractive index (nD
)
1.4960; MS (EI), m/z, 268.1499 (M+), formula C15H24O2S, (calc. mass 268.1497); 1H-NMR (CDCl3, δ
ppm) 7.35-7.36 (d, 1H), 6.31-6.32 (d, 1H), 2.59-2.62 (t, 2H), 2.26 (s,3H), 1.63-1.70 (m, 2H), 1.26-1.32
(m, 9H), 0.84-0.92 (m, 6H); 13C-NMR (CDCl3, δ ppm) 197.49 (C=O), 155.92 (=C-O), 140.88
(=CH-O), 114.78 (CH=), 104.30 (S-C), 40.70 (CH2), 38.25 (CH), 32.41 (CH2), 28.71 (CH2), 28.68
(CH2), 25.50 (CH2), 22.95 (CH2), 13.99 (CH3), 11.78 (CH3), 10.62 (CH3); IR (KBr, cm-1) 2959, 2926,
2859, 1715, 1588, 1514, 1387, 1228, 1129, 1090, 1020, 940, 889, 728, 648, 603, 525.
3.5. Odor evaluation
These compounds were purified by column chromatography. Odor assessments were carried out by
using a Agilent 6890 GC coupled with a Sniffer 9000 system. Separations were achieved with a HP-5
capillary column, 30 m × 0.250 mm; with a programmed temperature ramp, (200 ºC, holding for 2 min,
then programmed to 300 ºC at 10 ºC/min and held at 300 ºC for 2 min; injection temperature, 280 ºC)
detector (FID) temperature at 300 ºC. By one ‘Y’ shape glass splitter, the column effluent was divided
(1:1) between the flame ionization detector (FID) and the olfactometer (Sniffer 9000). The effluent to
the odor port was enclosed with a stream of humidified air of 6 mL/min and transferred to the glass
detection cone by one long capillary at the temperature of 280 ºC. Five trained assessors were selected
for smelling and recording the odor characteristics [25,26].
4. Conclusions
We report the synthesis and odor evaluation of sulfur-containing esters derived from 4-ethyl-
octanoic acid. The structures of five new flavor compounds were characterized by MS, 1H-NMR, 13C-
NMR and IR, and odor evaluation indicated they all have meaty odors. This research will be helpful to
develop new flavor compounds based on organic acid and sulfur-containing alcohols (or mercaptans).
Acknowledgements
The project was supported by Beijing Municipal Party Committee Organization Department (No:
20081D0500300127)

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Sample Availability: Samples of the compounds 3a-3e are available from the authors.
© 2010 by the authors; licensee MDPI, Basel, Switzerland. This article is an Open Access article
distributed under the terms and conditions of the Creative Commons Attribution license
(http://creativecommons.org/licenses/by/3.0/).