Odorless substitutes for foul-smelling thiols: Syntheses and applications

Article abstract of DOI:10.1016/S0040-4039(01)02024-X

Several alkanethiols and p-alkylphenylmethanethiols were synthesized, and their odors were compared with those of ethanethiol and benzyl mercaptan by human and instrumental sensors. Among the various thiols analyzed, 1-dodecanethiol (1) and p-heptylphenylmethanethiol (3) were revealed to be odorless. 1-Dodecanethiol (1) has been used instead of ethanethiol for dealkylation of ethers, and p-heptylphenylmethanethiol (3) can replace benzyl mercaptan in the preparation of a 1,3-mercapto alcohol from an α,β-unsaturated ketone. These odorless thiols will greatly improve the physical environment of the researcher working with these foul-smelling compounds.

Full text of DOI:10.1016/S0040-4039(01)02024-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 9207–9210
Odorless substitutes for foul-smelling thiols: syntheses and
applications
Manabu Node,* Kamal Kumar, Kiyoharu Nishide, Shin-ichi Ohsugi and Tetsuo Miyamoto
Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto 607-8414, Japan
Received 5 October 2001; revised 25 October 2001; accepted 29 October 2001
Abstract—Several alkanethiols and p-alkylphenylmethanethiols were synthesized, and their odors were compared with those of
ethanethiol and benzyl mercaptan by human and instrumental sensors. Among the various thiols analyzed, 1-dodecanethiol (1)
and p-heptylphenylmethanethiol (3) were revealed to be odorless. 1-Dodecanethiol (1) has been used instead of ethanethiol for
dealkylation of ethers, and p-heptylphenylmethanethiol (3) can replace benzyl mercaptan in the preparation of a 1,3-mercapto
alcohol from an a,b-unsaturated ketone. These odorless thiols will greatly improve the physical environment of the researcher
working with these foul-smelling compounds. © 2001 Elsevier Science Ltd. All rights reserved.
Thiols are a fundamental and important functional
group in organic chemistry, and the literature contains
ample reports of organic and bioorganic chemistry on
this group.1 Commonly used thiols like ethanethiol and
benzyl mercaptan have a foul smell making them
difficult and unpleasant to use in the laboratory with-
out fume hoods. The problem becomes even worse in
industry where these malodorous reagents are used on a
large scale. Odorless substitutes are therefore always
required. While experimental assessment of human
olfactory thresholds has been reported for four alkan-
ethiols including 1-dodecanethiol,2 there have been no
serious attempts to pursue this research. We report
here, for the first time, the synthesis of new odorless
thiols to replace the usual foul-smelling ones, as well as
various applications in organic reactions.
reeked in spite of being a crystalline compound, a result
which seemed contradictory to the relationship between
volatility and odor. To understand this apparent con-
tradiction and to find other useful odorless thiol substi-
tutes, we planned to test the odor of a number of
alkanethiols. All of the alkanethiols were commercially
available except for 1-tetradecanethiol which was pre-
pared by reacting the tetradecyl Grignard reagent with
sulfur4 followed by lithium aluminum hydride
reduction.
The relative odor index of these thiols with the foul-
smelling ethanethiol perceived by the human nose of
two test subjects is listed in Table 1. The index of the
most malodorous thiol is 5; the index of the odorless
thiol, 0. The odor of a thiol depends virtually entirely
on its purity, i.e. 1-hexadecanethiol (2) purified by
HPLC on a GPC column was found to be almost
odorless,5 while the commercial 1-hexadecanethiol had
essentially the same odor as indicated in a chemical
catalog. Therefore, purification of all these thiols was
done on HPLC using a GPC column before analyzing
their respective odors. Among the alkanethiols, 1-dode-
canethiol (oil) was found to be odorless, while lower
carbon-chain thiols were found to be malodorous.
These facts suggest that the foul smell of thiol toward
the human olfactory cell is related to the length of its
carbon-chain.
Recently, we published an asymmetric Michael addition
to a,b-unsaturated carbonyl compounds using 10-mer-
captoisoborneol as the hydrogen sulfide equivalent.3
During the course of the study, we looked for an
odorless thiol substitute for the foul-smelling
ethanedithiol for the thiol exchange reaction of the
vinyl sulfide. Two commercially available thiols, 1-
dodecanethiol (1) and 1-hexadecanethiol (2), were
selected for odor testing because it was thought that the
smell of thiols was related to their volatility. Unexpect-
edly, 1 turned out to be an odorless liquid whereas 2
Furthermore, these alkanethiols were subjected to a
Fragrance and Flavor analyzer FF-1,6 as shown in Fig.
1.7 FF-1 consists of an odor concentration tube and 6
odor sensors (made by metal oxide semiconductors).
Keywords: odorless thiols; synthesis; odor scale; dealkylation;
Michael addition.
* Corresponding author. Tel.: +81-75-595-4639; fax: +81-75-595-4775;
e-mail: node@mb.kyoto-phu.ac.jp
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02024-X

9208
M. Node et al. / Tetrahedron Letters 42 (2001) 9207–9210
Table 1. The odour scale for alkanethiols
Entry
Thiols
Marker in Fig. 1
Carbon length
Bp (°C)a
Odor scaleb
A
B
1
2
3
4
5
6
7
8
CH3CH2SH
ꢀ
2
ꢁ
ꢂ
ꢃ
ꢄ
+
×
ꢅ
ꢆ
"
ꢇ
ꢈ
ꢉ
2
3
4
5
6
7
8
9
10
11
12
14
15
16
35
67–68
98
126
150–154
173–176
197–200
220
5
5
5
4
3
4
2
2
1
1
0
0
0
0
5
5
4
3
3
3
1
1
1
0
0
1
0
0
CH3(CH2)2SH
CH3(CH2)3SH
CH3(CH2)4SH
CH3(CH2)5SH
CH3(CH2)6SH
CH3(CH2)7SH
CH3(CH2)8SH
CH3(CH2)9SH
CH3(CH2)10SH
CH3(CH2)11SH (1)
CH3(CH2)13SH
CH3(CH2)14SH
CH3(CH2)15SH (2)
9
114/13 mmHg
103–104/3 mmHgc
266–283
10
11
12
13
14
298–320 (mp 7)c
125–128/0.1 mmHgd
184–191/7 mmHg (mp 18–20)
a Cited from the Aldrich chemical catalog unless otherwise noted.
b Odor scale: foul-smelling 5 to odorless 0 by the human nose of two test subjects A and B.
c Cited from Dictionary of Organic Compounds; 2nd ed.; Koudansya: Tokyo, 1989.
d Experimental data.
Figure 1. Results of a principal-component analysis of the response of the six odor semiconductor sensors to samples using the
FF-1.
The first principal component was depicted as PC1.
PC1 would be indicative of the odor intensity in the
experiment because each sample has a minute odor
quality difference. Although the odor index using the
FF-1 instrument depends on the thiol’s sensitivity to
the detectors in the instrument and on the vapor pres-
sure of each thiol, no appreciable linear correlation
between odor index and the length of the carbon-chain
of the thiols was observed in the FF-1 instrument.
However, 1-dodecanethiol (1) was found to have the
lowest value among the alkanethiols tested, which coin-
cided with its odorlessness for the human nose.
alkyl Grignard reagent in the presence of the cuprous
bromide dimethyl sulfide complex8 gave the p-alkylben-
zylic bromides in moderate yields along with the radical
coupling product, 1,2-(4,4%-dialkyl)diphenylethane. Sub-
stitution of the bromide with thiourea afforded the
thiouronium salt, which was hydrolyzed to give the
p-alkylphenylmethanethiols in high yields.9 The whole
process for the synthesis of thiols involves no foul-
smelling reagents or intermediates and thus can be
scaled up to an industrial level.
Results of the odor testing of various thiols are shown
in Table 2. p-Heptylphenylmethanethiol (3) was chosen
as the odorless substitute for benzyl mercaptan.
Some p-alkylphenylmethanethiols were prepared hav-
ing an alkyl chain length similar to 1-dodecanethiol.
The syntheses of the new p-alkylphenylmethanethiols
are described in Scheme 1. In order to prepare the
p-alkylphenylmethanethiols, we chose p-xylylene dibro-
mide as the starting material. Mono-alkylation with
Some applications using odorless 1-dodecanethiol (1)
and p-heptylphenylmethanethiol (3) are shown in
Scheme 2. Previously, we developed useful reagent sys-
tems (hard Lewis acid and thiol) for demethylation of

M. Node et al. / Tetrahedron Letters 42 (2001) 9207–9210
9209
Br
Br
R
R
R
1) 6% NaOH
reflux, 3 h
thiourea
(1 equiv.)
RMgX
CuBr Me2S
ether, 0oC
ethanol
reflux, 14 h
2) 1N-HCl
NH
HBr
NH2
SH
Br
S
4
6
5
RMgX
(equiv.)
CuBr Me2S
(equiv.)
Yield of 4
(%)
Yield of 5
(%)
Yield of 6
(%)
Time (h)
R
X
propyl
butyl
42
37
37
41
28
41
75
100
99
99
91
79
87
90
78
1.5
1.5
1.5
1.5
1.0
1.5
0.6
0.6
0.75
0.6
0.1
0.6
6
18
6
Br
Cl
Br
Br
Br
Br
pentyl
hexyl
heptyl
octyl
6
81
18
6
74
90
Scheme 1. Synthesis of p-alkyl substituted benzylic mercaptans.
Table 2. The odor scale for benzylic mercaptans
a phenolic methyl ether in the presence of methyl ester
was observed using the new reagent system. We have
also demonstrated that the odorless benzyl mercaptan 3
can be used instead of benzyl mercaptan in the Michael
addition of a thiol to an a,b-unsaturated ketone.
Reductive cleavage of the benzylic carbonꢀsulfur bond
with sodium metal in liquid ammonia gave the 1,3-mer-
capto alcohol in good yield.
Odor Scalea
Thiols
CH2SH
Entry
A
5
1
2
B
5
1
1
1
2
CH2SH
CH2SH
CH2SH
CH2SH
CH2SH (3)
CH3(CH2)3
CH3(CH2)4
CH3(CH2)5
CH3(CH2)6
3
4
5
In conclusion, we have found that 1-dodecanethiol (1)
and p-heptylphenylmethanethiol (3) are odorless thiols
compared to the commonly used malodorous thiols.
Although biological studies must be carried out to
ultimately prove the relationship between the carbon
length of the thiol and the biological mechanism in
human olfactory cells, it is obvious that the twelve-car-
bon length of the thiol is crucial for the diminished
odor of thiols. We have demonstrated that the foul-
smelling ethanethiol and benzyl mercaptan can be
replaced by 1-dodecanethiol and p-heptylbenzyl mer-
captan in dealkylation and Michael addition, respec-
tively. We believe that eliminating the stench of thiols is
an important part of sulfur chemistry and that the use
of these odorless thiols will greatly improve the physical
environment of the researcher working with these foul-
smelling compounds.
2
0
1
1
0
0
6
CH3(CH2)7
CH3(CH2)8
CH2SH
CH2SH
1
1
0
1
7
8
a) Odor scale: foul-smelling 5 to odorless 0 by the human nose
of two test subjects A and B
aliphatic and aromatic methyl ethers.10 The yields of
the parent alcohols and phenols from methyl, benzyl,
and MOM ethers using aluminum chloride and 1-dode-
canethiol (1) were very high, similar to those using the
previous reagent system. The selective demethylation of
OH
OR
AlCl3 in 1
RO
CO2Me
AlCl3 in 1
r.t. 1 h
HO
RO
R = Me
R = H
95 % (94 %; AlBr3-EtSH, r.t. 1 h)#
R = Me
R = Bn
R = MOM 96 %
r.t. 4.5 h
77 %
97 %
# cited from ref. 10e,f.
3
OH
SH
O
SR
O
1) LAH, THF
NaOH (10%)
THF
r. t.
2) Na, liq. NH3
nC7H15
β-OH: 59% (2 steps)
α-OH: 10% (2 steps)
95%
(+)-pulegone
CH2
R =
Scheme 2. Synthetic applications of odorless thiols 1 and 3.

9210
M. Node et al. / Tetrahedron Letters 42 (2001) 9207–9210
into the sampling bag made of polyethylene terephtha-
Acknowledgements
late. A sample gas was generated until a saturated condi-
tion was achieved in the sample bag headspace at a room
temperature of 25°C. The sample gas was analyzed by a
Fragrance and Flavor analyzer FF-1 (made by Shimadzu
Corporation) the ‘electronic nose.’
We are grateful for a Grant-in-Aid (No. 13470474)
from the Ministry of Education, Science, Sports and
Culture of Japan, for partial financial support of this
research. We thank Dr. Jun-ichi Kita for instrumental
odor analyses of thiols using a Shimadzu Fragrance
and Flavor analyzer FF-1. We also thank the Wako
Pure Chemical Industries, Ltd., Kawagoe, Saitama,
Japan, for its kind gift of several alkanethiols.
7. A colony of the spots on a principal-component analysis
shows an odor character of the samples. Each scale of
coordinates indicates the intensity of the odor.
8. (a) Marfat, A.; McGuirk, P. R.; Kramer, R.; Helquist, P.
J. Am. Chem. Soc. 1977, 99, 253–255; (b) Marfat, A.;
McGuirk, P. R.; Helquist, P. Tetrahedron Lett. 1978,
1363.
9. Grogan, C. H.; Rice, L. M.; Sullivan, M. X. J. Org.
Chem. 1953, 18, 728–735 and references cited therein.
10. (a) Node, M.; Hori, H.; Fujita, E. J. Chem. Soc., Chem.
Commun. 1975, 898–899; (b) Node, M.; Hori, H.; Fujita,
E. J. Chem. Soc., Perkin Trans. 1 1976, 2237–2240; (c)
Fujita, E.; Node, M.; Hori, H. J. Chem. Soc., Perkin
Trans. 1 1977, 611–621; (d) Fuji, K.; Ichikawa, K.; Node,
M.; Fujita, E. J. Org. Chem. 1979, 44, 1661–1664; (e)
Node, M.; Nishide, K.; Sai, M.; Ichikawa, K.; Fuji, K.;
Fujita, E. Chem. Lett. 1979, 97–98; (f) Node, M.;
Nishide, K.; Fuji, K.; Fujita, E. J. Org. Chem. 1980, 45,
4275–4277; (g) Also, see a review: Node, M. Yakugaku
Zasshi 1986, 106, 1–16.
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5. Compounds were purified by a recycle HPLC (LC-908,
Japan Analytical Industry Co., Ltd.) on GPC columns
(JAIGEL 1H and 2H) after purification on silica gel.
6. Each sample (15 mg) and 2 L of nitrogen gas were placed