Structure-Odor Correlations in Homologous Series of Mercapto Furans and Mercapto Thiophenes Synthesized by Changing the Structural Motifs of the Key Coffee Odorant Furan-2-ylmethanethiol

Article abstract of DOI:10.1021/acs.jafc.8b00857

Furan-2-ylmethanethiol (2-furfurylthiol; 2-FFT, 1) is long-known as a key odorant in roast and ground coffee and was also previously identified in a wide range of thermally treated foods such as meat, bread, and roasted sesame seeds. Its unique coffee-like odor quality elicited at very low concentrations, and the fact that only a very few compounds showing a similar structure have previously been described in foods make 1 a suitable candidate for structure-odor activity studies. To gain insight into the structural features needed to evoke a coffee-like odor at low concentrations, 46 heterocyclic mercaptans and thio ethers were synthesized, 32 of them for the first time, and their odor qualities and odor thresholds were determined. A movement of the mercapto group to the 3-position kept the coffee-like aroma but led to an increase in odor threshold. A separation of the thiol group from the furan ring by an elongation of the carbon side chain caused a loss of the coffee-like odor and also led to an increase in odor thresholds, especially for ω-(furan-2-yl)alkane-1-thiols with six or seven carbon atoms in the side chain. A displacement of the furan ring by a thiophene ring had no significant influence on the odor properties of most of the compounds studied, but the newly synthesized longer-chain 1-(furan-2-yl)- and 1-(thiophene-2-yl)alkane-1-thiols elicited interesting passion fruit-like scents. In total, only 4 out of the 46 compounds also showed a coffee-like odor quality like 1, but none showed a lower odor threshold. Besides the odor attributes, also retention indices, mass spectra, and NMR data of the synthesized compounds were elaborated, which are helpful in possible future identification of these compounds in trace levels in foods or other materials.

Full text of DOI:10.1021/acs.jafc.8b00857

Subscriber access provided by the Henry Madden Library | California State University, Fresno
Chemistry and Biology of Aroma and Taste
Structure–Odor Correlations in Homologous Series of Mercapto
Furans and Mercapto Thiophenes Synthesized by Changing the
Structural Motifs of the Key Coffee Odorant Furan-2-ylmethanethiol
Sebastian Schoenauer, and Peter Schieberle
J. Agric. Food Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jafc.8b00857 • Publication Date (Web): 09 Apr 2018
Downloaded from http://pubs.acs.org on April 10, 2018
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 50
Journal of Agricultural and Food Chemistry
1 ꢀ
ꢀ
Structure–Odor Correlations in
Homologous Series of Mercapto Furans
and Mercapto Thiophenes Synthesized by
Changing the Structural Motifs of the Key
Coffee Odorant Furan-2-ylmethanethiol
Sebastian Schoenauer and Peter Schieberle*
Lehrstuhl für Lebensmittelchemie, Technische Universität München,
LiseꢀMeitnerꢀStraße 34, Dꢀ85354 Freising, Germany
*Corresponding Author
Phone: +49 871 976 981 60
Eꢀmail: peter.schieberle@ch.tum.de
1
ACS Paragon Plus Environment

Journal of Agricultural and Food Chemistry
2 ꢀ
Page 2 of 50
ꢀ
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
ABSTRACT.
Furanꢀ2ꢀylmethanethiol (2ꢀfurfurylthiol; 2ꢀFFT); 1, is longꢀknown as a key odorant in
roast and ground coffee, and was also previously identified in a wide range of
thermally treated foods, such as meat, bread, and roasted sesame seeds. Its unique
coffeeꢀlike odor quality elicited at very low concentrations, and the fact that only a
very few compounds showing a similar structure have previously been described in
foods make 1 a suitable candidate for structure–odor activity studies. To gain insight
into the structural features needed to evoke a coffeeꢀlike odor at low concentrations,
46 heterocyclic mercaptans and thio ethers were synthesized, 32 of them for the first
time, and their odor qualities and odor thresholds were determined. A movement of
the mercapto group to the 3ꢀposition kept the coffeeꢀlike aroma, but led to an
increase in odor threshold. A separation of the thiol group from the furan ring by an
elongation of the carbon side chain caused a loss of the coffeeꢀlike odor and also led
to an increase in odor thresholds, especially for ωꢀ(furanꢀ2ꢀyl)alkaneꢀ1ꢀthiols with six
or seven carbon atoms in the side chain. A displacement of the furan ring by a
thiophene ring had no significant influence on the odor properties of most of the
compounds studied, but the newly synthesized longerꢀchain 1ꢀ(furanꢀ2ꢀyl)ꢀ and 1ꢀ
(thiopheneꢀ2ꢀyl)alkaneꢀ1ꢀthiols elicited interesting passion fruitꢀlike scents. In total,
only four out of the 46 compounds also showed a coffeeꢀlike odor quality like 1, but
none showed a lower odor threshold. Besides the odor attributes, also retention
indices, mass spectra and NMR data of the synthesized compounds were
elaborated, which are helpful in possible future identification of these compounds in
trace levels in foods or other materials.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
ACS Paragon Plus Environment

Page 3 of 50
Journal of Agricultural and Food Chemistry
3 ꢀ
ꢀ
25
26
27
KEYWORDS. 2ꢀfurfurylthiol, coffee, odor quality, odor threshold, structure–odor
activity studies, mercaptan, furan, thiophene, thio ether, ωꢀ(furanꢀ2ꢀyl)alkaneꢀ1ꢀthiols,
1ꢀ(furanꢀ2ꢀyl)alkaneꢀ1ꢀthiols
ACS Paragon Plus Environment

Journal of Agricultural and Food Chemistry
4 ꢀ
Page 4 of 50
ꢀ
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
INTRODUCTION
Mercaptans or thiols, respectively, are a very interesting class of food
constituents, and up to now over 100 volatile compounds have been identified,
among them several very potent aroma compounds. Although usually occurring in
low concentrations, thiols can be key contributors to food aromas due to their often
extremely low odor thresholds, because the human odorant receptors are quite
sensitive for some sulfur compounds.
Among the most interesting thiols occurring in foods, furanꢀ2ꢀylmethanethiol (2ꢀ
furfurylthiol; 1) exhibiting a pleasant coffeeꢀlike odor quality at very low
concentrations, was first identified in roast and ground coffee by Reichstein and
1
Staudinger. Since then several studies have confirmed its importance in the overall
2ꢀ3
aroma of roasted coffee and coffee brew. 1 has also been found in a wide range of
4
5
6
other thermally treated foods like cooked beef, pork, and chicken as well as
7
8
9
10
roasted sesame seeds, popcorn, white bread, roasted hazelnuts, but also in
1
1
fermented products such as wine.
Interestingly, only a very few additional aromaꢀactive mercapto furans have been
reported in foods so far. In particular 2ꢀmethylfuranꢀ3ꢀthiol, with a meatꢀlike smell, is
another very wellꢀknown compound in this substance class, which was identified,
12
6
13
e.g., in cooked beef, chicken broth, and yeast extract. In addition, 5ꢀmethylꢀ2ꢀ
furfurylthiol and 2,5ꢀdimethylfuranꢀ3ꢀthiol were characterized as aroma compounds in
14
6
15
coffee and cooked beef, and 1ꢀ(furanꢀ2ꢀyl)ethaneꢀ1ꢀthiol and 2ꢀmethylfuranꢀ3ꢀ
16
ylmethanethiol were reported to occur in coffee and wine.
A smaller amount of structurally related mercapto thiophenes was also previously
described as food constituents, for example, 2ꢀthienylthiol was reported to contribute
1
7
18
to the aroma of roasted hazelnuts and roasted sesame seeds. In addition, also 2ꢀ
18
methylthiopheneꢀ3ꢀthiol was reported as constituent of roasted sesame seeds.
ACS Paragon Plus Environment

Page 5 of 50
Journal of Agricultural and Food Chemistry
5 ꢀ
ꢀ
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
Their importance in many food aromas make mercaptans suitable candidates for
structure–odor activity studies, i.e., to clarify the structural elements or odotopes,
respectively, needed to cause these interesting aroma attributes. Polster and
19,20
Schieberle
were among the first to perform a comprehensive study on such
relationships in alkane thiols, e.g. 3ꢀmercaptoꢀ2ꢀmethylalkanꢀ1ꢀols, of which 3ꢀ
mercaptoꢀ2ꢀmethylpentanꢀ1ꢀol is one of the most important odorants in processed
21
onions. For this purpose, several homologous series of alkane thiols and thio ethers
were synthesized and their odor qualities and thresholds were determined. In all
homologous series a minimum of thresholds was observed for compounds with five
to seven carbon atoms. However, longerꢀchain thiols showed an exponential
increase in thresholds and also lost the typical sulfury, onionꢀlike or passionꢀfruit like
odor attributes elicited by the shorter chain mercaptans. The authors also
demonstrated that a substitution of the thiol group either by a hydroxyl or a thiomethyl
group led to a significant increase in odor thresholds.
In a study on the influence of changes in the structural motifs of the potent
grapefruitꢀlike smelling 1ꢀpꢀmentheneꢀ8ꢀthiol, it was found that the double bond in the
pꢀmenthane structure and a tertiary thiol group in the side chain are crucial factors for
the grapefruitꢀlike odor and the very low threshold. In most cases, however, small
changes in the molecular structure of structurally related mercaptans led to a strong
increase in odor thresholds and a loss of the characteristic grapefruitꢀlike odor
quality. The natural aroma compound 1ꢀpꢀmentheneꢀ8ꢀthiol showed the lowest odor
22
threshold among the sulfur compounds synthesized. Based on this result, it was
speculated that odorant receptor structures must have been shaped by naturally
22
available aromaꢀactive volatiles. Recently it was shown that only one out of 390
human odorant receptors was activated by 3ꢀmercaptoꢀ2ꢀmethylpentanꢀ1ꢀol
23
corroborating the assumption that receptors for detection of thiols are specialists.
ACS Paragon Plus Environment

Journal of Agricultural and Food Chemistry
6 ꢀ
Page 6 of 50
ꢀ
80
81
82
83
84
85
86
87
88
89
90
91
92
Following the concept of our previous study on structureꢀactivity relationships in 1ꢀ
pꢀmentheneꢀ8ꢀthiol, the aim of this investigation was to find out which structural
features are responsible for the coffeeꢀlike odor quality as well as the very low odor
threshold of 1. To verify the assumption that the naturally occurring compounds
within one substance class are the most potent odorants among the structurally
related components, over 40 hetero aromatic sulfurꢀcontaining compounds were
synthesized with a structural relationship to 1. Their odor qualities and odor
thresholds were determined to check whether 1 also shows the lowest threshold
among a series of homologues and whether its coffeeꢀlike scent is also unique
among its homologues. Because potent mercaptans are often present in foods in
trace amounts, it was another purpose of the study to generate analytical data, such
as retention indices, mass spectra, and NMR data to facilitate their potential
identification in foods in future studies.
9
3
4
9
MATERIALS AND METHODS
9
9
9
9
9
5
6
7
8
9
Chemicals and Reference Odorants. Furanꢀ2ꢀylmethanethiol (2ꢀfurfurylthiol; 1)
and 2ꢀthenylthiol (8) were purchased from SigmaꢀAldrich (Steinheim, Germany) and
TCI Europe Laboratory Chemicals (Eschborn, Germany), respectively. Further
chemicals for syntheses were supplied by ABCR, AlfaꢀAesar (both Karlsruhe,
Germany), SigmaꢀAldrich (Steinheim, Germany), TCI Europe Laboratory Chemicals
(Eschborn, Germany), and VWR (Darmstadt, Germany). Solvents were obtained
from VWR and deuterated solvents were purchased from Eurisoꢀtop (Saarbruecken,
Germany). Diethyl ether and pentane were distilled prior to use.
1
1
1
1
1
00
01
02
03
04
Syntheses. In total 44 sulfur compounds were synthesized. The reactions were
carried out in dry glassware under an atmosphere of pure argon. Detailed synthetic
ACS Paragon Plus Environment

Page 7 of 50
Journal of Agricultural and Food Chemistry
7 ꢀ
ꢀ
1
05
06
07
08
09
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
procedures as well as mass spectra, NMR spectra and retention indices are given for
each compound in the Supporting Information.
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
Synthesis of ωꢀ(furanꢀ2ꢀyl)alkaneꢀ1ꢀthiols 2-7 (Figure 1). First, the corresponding
24
alcohols were prepared following the method by Baciocchi et al. starting from furan
and the appropriate ethyl iodo alkanoic acid as shown in Figure 2. As exemplified for
2ꢀ(furanꢀ2ꢀyl)ethaneꢀ1ꢀthiol in Figure 2, the target compounds were then synthesized
from the alcohols by substituting the hydroxyl by the mercapto group using a slightly
2
5
modified method consisting of tosylation, thio acetylation, and finally a reduction.
Synthesis of the ωꢀ(thiopheneꢀ2ꢀyl)alkaneꢀ1ꢀthiols 9-12 (Figure 1). The
compounds were synthesized as described above for the furan derivatives, but
substituting furan by thiophene in the reaction pathway shown in Figure 2.
Synthesis of 1ꢀ(furanꢀ2ꢀyl)alkaneꢀ1ꢀthiols 13-18 (Figure 3). These were
synthesized from the corresponding ketones and/or alcohols, respectively. After
26
reduction, the alcohols were transformed into the thiols as described previously and
as briefly shown for 1ꢀ(furanꢀ2ꢀyl)propaneꢀ1ꢀthiol in Figure 4.
Synthesis of 1ꢀ(thiopheneꢀ2ꢀyl)alkaneꢀ1ꢀthiols (19-24; Figure 3). The
corresponding thiophene derivatives were synthesized from the corresponding
alcohols whith a thiophene ring following closely the reaction pathway shown for the
respective furans in Figure 4. The longer chain alcohols 1ꢀ(thiopheneꢀ2ꢀyl)hexanꢀ1ꢀol
(intermediate for 23) and 1ꢀ(thiopheneꢀ2ꢀyl)heptanꢀ1ꢀol (intermediate for 24) were
27
synthesized as described by Fuller et al.
Synthesis of alkyl substituted 2ꢀfurfurylꢀ (25-28; Figure 5) and 2ꢀthenylthiols (29-
32; Figure 5). These compounds were synthesized from the corresponding ketones
and/or alcohols, respectively. After a reduction of the ketones, the alcohols were
transformed into the thiols following the same method as described for the 1ꢀ(furanꢀ2ꢀ
26
yl)alkaneꢀ1ꢀthiols in Figure 4.
ACS Paragon Plus Environment

Journal of Agricultural and Food Chemistry
8 ꢀ
Page 8 of 50
ꢀ
131
132
133
134
135
136
137
138
139
140
141
142
143
144
145
146
147
148
149
150
151
152
153
154
155
156
The synthesis of 3ꢀfurfurylthiol (33) and 3ꢀthienylthiol (34) followed a slightly
26
modified strategy published previously.
Synthesis of 35-46. Thio ethers of 1 and 8 were synthesized from the respective
thiols and iodo alkanes following a slightly modified method described by Nolan and
28
Cohen, as briefly shown in Figure 6.
Gas Chromatography–Flame Ionization Detection (GC-FID) and Gas
Chromatography–Olfactometry (GC-O). Analyses by GCꢀFID coupled with
olfactometry were carried out by means of a Trace GC Ultra gas chromatograph
(Thermo Scientific, Bremen, Germany) using helium as the carrier gas. A J&W
Scientific DBꢀ5 and a DBꢀFFAP capillary column (each 30 m × 0.32 mm i.d., 0.25 ꢁm
film thickness, 75 kPa head pressure) (ChromatographieꢀHandel Mueller, Fridolfing,
Germany) were used. Samples were injected by the coldꢀonꢀcolumn technique
(injection volume: 1 ꢀL) at 40 °C. After 2 min, the temperature of the oven was raised
at 8 °C/min to 230 °C (DBꢀFFAP) or 240 °C (DBꢀ5), respectively, and then held for
5 min. At the end of the capillary, the effluent was split 1:1 using a deactivated Yꢀ
shaped glass splitter into an FID (250 °C) and the sniffing port (200 °C) using two
deactivated fused silica capillaries (50 cm × 32 mm i.d.). The FID was operated with
hydrogen (20 mL/min) and air (200 mL/min); nitrogen (30 mL/min) was used as the
makeup gas. During a GCꢀO run, the panelist’s nose was placed above the sniffing
port and the odor was evaluated. If an odor quality was recognized, the retention time
was marked in the chromatogram, and the odor quality was annotated. Data obtained
by three panelists were averaged. Retention indices were calculated using a series of
nꢀalkanes.
Gas Chromatography–Mass Spectrometry (GC-MS). Mass spectra were
recorded by means of a 5890 series II gas chromatograph (HewlettꢀPackard,
Waldbronn, Germany) connected to an MAT 95 S sector field mass spectrometer
ACS Paragon Plus Environment

Page 9 of 50
Journal of Agricultural and Food Chemistry
9 ꢀ
ꢀ
1
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
(Finnigan, Bremen, Germany). Mass spectra in the electron ionization mode (MSꢀEI)
were recorded at 70 eV ionization energy and mass spectra in the chemical
ionization mode (MSꢀCI) at 115 eV with isobutane as the reactant gas.
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
Determination of Odor Thresholds in Air. Thresholds in air were determined by
aroma extract dilution analysis of a mixture containing known amounts of the
respective odorant and the internal standard (E)ꢀ2ꢀdecenal with an odor threshold in
2
9
air of 2.7 ng/L. Thresholds of the compounds were calculated from the flavor
19,20,22,30
dilution (FD) factors determined by using the method previously reported.
1
13
NMR-Spectroscopy. The H, C, and 2D NMR experiments (COSY, HMBC,
HSQC) were performed using a 400 MHz Avance III spectrometer (Bruker,
Rheinstetten, Germany) at 297 K with deuterated chloroform (+ 0.03%
tetramethylsilane) as the solvent.
RESULTS AND DISCUSSION
Previous results obtained in studies on structureꢀodor relationships of the natural
grapefruit aroma compound 1ꢀpꢀmentheneꢀ8ꢀthiol have shown that the thiol showed
the lowest odor threshold among the sulfur compounds synthesized. Based on this
result, it was speculated that human odorant receptors must have been shaped by
2
2
naturally available aromaꢀactive volatiles. To check whether the same is true for the
natural coffee aroma compound furanꢀ2ꢀylmethanethiol (2ꢀfurfurylthiol); 1, over 40
structurally related hetero aromatic sulfurꢀcontaining compounds were synthesized.
Their odor qualities and odor thresholds were determined to check whether 1 also
shows the lowest threshold among the structurally related sulfur compounds
considered, and whether its coffeeꢀlike scent is also unique among them.
ACS Paragon Plus Environment

Journal of Agricultural and Food Chemistry
10 ꢀ
Page 10 of 50
ꢀ
181
182
183
184
185
186
187
188
189
190
191
192
193
194
195
196
197
198
199
200
201
202
203
204
205
206
Elongation of the Side Chain in 1. To investigate the influence of the distance
between the furan ring and the thiol group, six further ωꢀ(furanꢀ2ꢀyl)alkaneꢀ1ꢀthiols (2-
7) were synthesized up to an alkyl chain length of seven carbon atoms (Figure 1).
The mass spectrum of 1 (Figure 7A) was compared to the spectrum of compound
5 (Figure 7B) bearing a seven carbon side chain. While 1 only revealed two distinct
+
signals, the molecular ion (M ) (m/z 114) and a strong signal m/z 81, caused by the
+
so called furanꢀ2ꢀylmethylium cation (C H O ), 5ꢀ(furanꢀ2ꢀyl)pentaneꢀ1ꢀthiol (5)
5
5
showed additional fragments generated by degradation of the side chain. The furanꢀ
2ꢀylmethylium cation (m/z 81) was the major ion in all longerꢀchain homologues.
Although the molecular ions were always detectable in 2-7, their intensities
decreased with increasing the length of the alkyl chain.
Among the ωꢀ(furanꢀ2ꢀyl)alkaneꢀ1ꢀthiols only 1 showed the characteristic burned,
roasty, and coffeeꢀlike odor quality, while the other homologues were described as
onionꢀlike, mushroomꢀlike, and/or rubberꢀlike (Table 1). The very low odor threshold
of 1 (0.0084 ng/L in air) was similar in the three homologues up to four carbon atoms
in the side chain (2-4), but then a strong increase in thresholds was observed with 7ꢀ
(furanꢀ2ꢀyl)heptaneꢀ1ꢀthiol (7) exhibiting an odor threshold of 350 ng/L, which was
higher by a factor of over 45 000 than that of 1 (Table 1).
Substitution of the Furan Ring by a Thiophene Ring. In a second series of
experiments, the furan ring in the ωꢀ(furanꢀ2ꢀyl)alkaneꢀ1ꢀthiols was replaced by a
thiophene ring. Besides the commercially available 2ꢀthenylthiol (8), four ωꢀ
(thiopheneꢀ2ꢀyl)alkaneꢀ1ꢀthiols (9-12; Figure 1) were synthesized.
Compound 8 showed a signal for the molecular ion (m/z 130) and for the
thiopheneꢀ2ꢀylmethylium cation (m/z 97) (Figure 8) generated by elimination of the
thiol group. In all homologues (9-12), the most intense signal was the thiopheneꢀ2ꢀ
+
ylmethylium cation (C
5
H
5
S ). 2ꢀ(Thiopheneꢀ2ꢀyl)ethanethiol (9) and 3ꢀ(thiopheneꢀ2ꢀ
ACS Paragon Plus Environment

Page 11 of 50
Journal of Agricultural and Food Chemistry
11 ꢀ
ꢀ
+
207
208
209
210
211
212
213
214
215
216
217
218
219
220
221
222
223
224
225
226
227
228
229
230
231
2
yl)propaneꢀ1ꢀthiol (10) exhibited also a signal for the fragment [M – H S] (m/z 112
and 126, respectively), while the longerꢀchain homologues showed signals for [M –
+
SH] .
A burned, roasty, and coffeeꢀlike odor was only elicited by 2ꢀthienylthiol (8), while
9 was described as onionꢀlike, burned, and rubberꢀlike (Table 2). Instead, the longerꢀ
chain homologues exhibited rubberꢀlike and mushroomꢀlike scents. While 8, 9, 10,
and 4ꢀ(thiopheneꢀ2ꢀyl)butaneꢀ1ꢀthiol (11) exhibited very similar odor thresholds
between 0.012 and 0.036 ng/L in air, for 5ꢀ(thiopheneꢀ2ꢀyl)pentaneꢀ1ꢀthiol (12) an
increase by two orders of magnitude was determined (1.2 ng/L)(Table 2).
Insertion of an Alkyl Chain into the Side Chain of 1. 1ꢀ(Furanꢀ2ꢀyl)ethaneꢀ1ꢀ
15
thiol (13) naturally occurs in coffee, and was also identified in model reactions of a
31
thermally treated mixture of glucose and cysteine and in further meat model
3
2
systems. Besides the elongation of the carbon chain between the furan ring and the
thiol group, also an insertion of an additional alkyl chain is possible, thus generating
1ꢀ(furanꢀ2ꢀyl)alkaneꢀ1ꢀthiols (13-18; Figure 3).
The mass spectra of 13 and 1ꢀ(furanꢀ2ꢀyl)propaneꢀ1ꢀthiol (14) with a short alkyl
chain showed the strongest signals at m/z 95 and m/z 109, respectively, for ([M –
+
SH] ). In Figure 9 the mass spectrum of 1ꢀ(furanꢀ2ꢀyl)butaneꢀ1ꢀthiol (15) is shown.
Interestingly, all longerꢀchain homologues (15-18) showed the highest signal at m/z
81 representing the furanꢀ2ꢀylmethylium cation. In addition, the furanꢀ2ꢀ
+
yl(mercapto)methylium cation (m/z 113), [M – SH] and the molecular ions were
always present.
While the shortꢀchain 1ꢀ(furanꢀ2ꢀyl)ethaneꢀ1ꢀthiol (13) showed a sulfury, meaty
odor quality, the scent of the longerꢀchain homologues changed to catty and passion
fruitꢀlike (Table 3). For compounds 13 to 16 the thresholds were quite similar, but for
ACS Paragon Plus Environment

Journal of Agricultural and Food Chemistry
12 ꢀ
Page 12 of 50
ꢀ
232
233
234
235
236
237
238
239
240
241
242
243
244
245
246
247
248
249
250
251
252
253
254
255
256
257
the longer chain 1ꢀ(furanꢀ2ꢀyl)hexaneꢀ1ꢀthiol (17) and 1ꢀ(furanꢀ2ꢀyl)heptaneꢀ1ꢀthiol
(18) an increase to 0.51 and 9.0 ng/L, respectively, was observed (Table 3).
Insertion of an Alkyl Chain into the Side Chain of 2-Thienylthiol (8)
1ꢀ(Thiopheneꢀ2ꢀyl)ethanethiol (19) was reported as constituent of a thermally
31
treated mixture of glucose and cysteine and thus, the homologous series of 20 to
24 (Figure 3) also represent very interesting structural modifications of 1. The
thiophene homologues showed a very similar mass spectrometric fragmentation
pattern compared to the furan derivatives except that, of course, all signals were
shifted by 16 mass units.
The odor qualities of the thiophene derivatives 19-24 were similar to those of the
furan derivatives. While 1ꢀ(thiopheneꢀ2ꢀyl)ethaneꢀ1ꢀthiol,19, and the corresponding
propaneꢀ1ꢀthiol homologue,20, smelled sulfury, meaty, in the longer chain
homologues a catty, passionꢀfruit like odor notes predominated (Table 4). Also the
threshold values of the thiophene derivatives were comparable to those of the furan
derivatives and showed a similar trend. While 19 revealed a threshold of 0.0075 ng/L,
the longer chain 1ꢀ(thiopheneꢀ2ꢀyl)heptaneꢀ1ꢀthiol (24) showed a threshold, which
was higher by a factor of 500 (Table 4).
Insertion of Additional Alkyl Chains into the Heteroaromatic Ring of 2-
Furfurylthiol and 2-Thienylthiol, respectively. 5ꢀMethylꢀ2ꢀfurfurylthiol (25; Figure
14
33
5) has been identified in coffee and yeast extract, and thus, it could be possible
that also other alkylated 2ꢀfurfurylthiols or 2ꢀthienylthiols, respectively may occur in
thermally processed foods. Therefore, either the side chain in the 5ꢀposition of 2ꢀ
furfurylthiol was extended as ethyl (26) or propyl group (27) or the methyl group was
shifted from the 5ꢀ to the 3ꢀposition in 28. Furthermore, the ring oxygen was
substituted by sulfur in the thiophene derivatives with a methyl group in the 5ꢀ, 29, as
ACS Paragon Plus Environment

Page 13 of 50
Journal of Agricultural and Food Chemistry
13 ꢀ
ꢀ
258
259
260
261
262
263
264
265
266
267
268
269
270
271
272
273
274
275
276
277
278
279
280
281
282
283
well as the 3ꢀ,31, and the 4ꢀposition in 4ꢀmethylꢀ2ꢀthenylthiol (32). In addition, the
methyl group in 5ꢀmethylꢀ2ꢀthenylthiol was replaced by an ethyl group (30; Figure 5).
As an example, the mass spectrum of the 5ꢀpropylꢀ2ꢀfurfurylthiol (27) is shown in
Figure 10. Without exception, all alkylꢀsubstituted 2ꢀfurfurylthiols showed a clear
signal of the molecular ion in their mass spectra, but the highest signal was always
+
the fragment generated by [M – SH] , e.g., m/z 95 for 25 or m/z 123 for 27. The mass
spectra of the respective thiophene derivatives showed the same fragmentation
pattern.
Compared to 1, an insertion of an alkyl chain at position 5 in the furan ring (25-27)
led to a clear change to an onionꢀlike and rubberꢀlike odor quality (Table 5). However,
the characteristic burned, roasty, and coffeeꢀlike odor quality of 1 was also elicited by
28 in which an additional methyl group was present in the 3 position. This compound
also showed a very low odor threshold.
The respective 2ꢀthienylthiols with the methyl or ethyl group in the 5 position
(29,30) showed rubberꢀlike and minty scents, while the 2ꢀthienylthiols with the methyl
group in either the 3ꢀ or the 4ꢀposition (31,32) exhibited burned, rubberꢀlike, and
garlicꢀlike odors, respectively.
3-Furfurylthiol and 3-Thienylthiol (Figure 11). Because of the structural
similarity to the parent compound 1, 3ꢀfurfurylthiol (33) and 3ꢀthienylthiol (34) were
also synthesized. The mass spectra were nearly identical with that of 2ꢀfurfurylthiol
(1) and 2ꢀthienylthiol (8), respectively. Both thiols showed a burned, roasty, and
coffeeꢀlike odor quality like 1 (Table 5). The odor thresholds of both, however, were
higher by factors of 10 or 20, respectively, compared to 1 and 8 (Table 5).
Loss of the Free Thiol Group of 2-Furfurylthiol and 2-Thienylthiol. In a last
series of experiments the influence of the free thiol group on the odor attributes of 1
and further homologues were evaluated. Thus, the respective alkyl thio ethers of 1
ACS Paragon Plus Environment

Journal of Agricultural and Food Chemistry
14 ꢀ
Page 14 of 50
ꢀ
284
285
286
287
288
289
290
291
292
293
294
295
296
297
298
299
300
301
302
303
304
305
306
307
308
(35-40) as well as 8 (41-46) were synthesized (Figure 12) and their odor properties
were determined.
As exemplified for 2ꢀ((butylthio)methyl)furan, 38, (Figure 13), the mass spectra of
2ꢀ((alkylthio)methyl)furans (and also of 2ꢀ((alkylthio)methyl)thiophenes) only
contained very few signals. The most distinct signal was always the furanꢀ2ꢀ
ylmethylium cation (m/z 81) or the thiopheneꢀ2ꢀylmethylium cation (m/z 97),
+
respectively, together with a small signal at m/z 53, which is caused by C H , only
4
5
the molecular ion showed a considerable intensity.
Except for 35, the odors of the 2ꢀ((alkylthio)methyl)furans were characterized by
fatty and deep fried notes (Table 6) which was also true for the 2ꢀ
((alkylthio)methyl)thiophenes (Table 7). In both series of thio ethers, the odor
thresholds increased with increasing the molecular weight. For example, 2ꢀ((methylꢀ
thio)methyl)furan, 35 (Table 6), and 2ꢀ((methylthio)methyl)thiophene, 41 (Table 7),
showed thresholds of 1.4 and 0.42 ng/L, respectively, and constantly increased to 59
or 84 ng/L, respectively for 2ꢀ((hexylthio)methyl)furan, 40; (Table 6) and 2ꢀ
((hexylthiol)methyl)thiophene 46; (Table 7), respectively.
2ꢀFurfurylthiol (1) known as a key aroma compound in roast and ground coffee
exhibits a unique coffeeꢀlike flavor at the very low odor threshold of 0.0084 ng/L in
air, but none of the 45 mercaptans or the derived thio ethers investigated in this study
showed a significantly lower threshold. Only 3ꢀ(furanꢀ2ꢀyl)propaneꢀ1ꢀthiol, 3, and 1ꢀ
(thiopheneꢀ2ꢀyl)ethanethiol,19, also revealed low threshold values of 0.0080 and
0.0075 ng/L, respectively, which were in the same order of magnitude. Furthermore,
only four homologues, i.e., 2ꢀthienylthiol (8), 3ꢀmethylꢀ2ꢀfurfurylthiol (28), 3ꢀ
furfurylthiol (33), and 3ꢀthienylthiol (34) elicited a similar coffeeꢀlike aroma attribute as
1.
ACS Paragon Plus Environment

Page 15 of 50
Journal of Agricultural and Food Chemistry
15 ꢀ
ꢀ
309
310
311
312
313
314
315
316
317
318
319
320
321
322
323
324
325
326
327
328
329
330
331
332
333
Extending the distance between the furan ring and the thiol group resulted in a
strong increase in odor thresholds for mercaptans with longer “distances” (chain
length) (Table 1). Although the very low threshold value of 1 was kept for the smaller
homologues, the coffeeꢀlike scent was always lost. Thus, despite the similar low
thresholds, it can be assumed that 2ꢀ(furanꢀ2ꢀyl)ethanethiol (2) and 3 as well as 4ꢀ
(furanꢀ2ꢀyl)butaneꢀ1ꢀthiol (4) are not detected by the same odorant receptor as 1.
However, odor qualities and even odor thresholds of longerꢀchain ωꢀ(furanꢀ2ꢀ
yl)alkaneꢀ1ꢀthiols were comparable to those of the C9 and C10 alkane thiols
19,20
investigated by Polster and Schieberle
such longꢀchain thiols.
who also found mushroomꢀlike odors for
A displacement of the furan ring by a thiophene ring had almost no influence on
odor properties. As illustrated in Figures 14ꢀ16, the tendencies of thresholds with
respect to chain length were nearly identical for furan and thiophene derivatives, and
the odor qualities were often also the same.
The furans and thiophenes studied have a relatively high number of carbons, e.g.,
up to eleven in compounds 7, 18 and 24. However, alkane thiols with the same
19
number of carbons have shown significantly higher thresholds, e.g., compared to
the furan or thiophene derivatives. Obviously the hetero aromatic moiety leads to a
decrease in odor thresholds compared to alkanes with the same number of carbon
atoms. At a certain chain length, however, also in the hetero atomic mercaptans, the
thiol group loses its ability to generate low odor thresholds. Obviously from a certain
chain length onwards it is no longer relevant which functional group is located in the
19
molecule. This agrees with findings of Polster and Schieberle. As illustrated in
Figure 17, 2ꢀ((pentylthio)methyl)furan (39) and 2ꢀ((hexylthio)methyl)furan (40)
showed thresholds lower than 6ꢀ(furanꢀ2ꢀyl)hexaneꢀ1ꢀthiol (6) and 7ꢀ(furanꢀ2ꢀ
ACS Paragon Plus Environment

Journal of Agricultural and Food Chemistry
16 ꢀ
Page 16 of 50
ꢀ
334
335
336
337
338
339
340
341
342
343
344
345
346
347
348
349
350
351
352
353
354
355
356
357
358
yl)heptaneꢀ1ꢀthiol (7), while significant differences were observed for the shorterꢀ
chain homologues.
Very interesting passion fruitꢀlike odor qualities were found for longerꢀchain 1ꢀ
(furanꢀ2ꢀyl)alkaneꢀ1ꢀthiols and their respective thiophene homologues. These
compounds have not been synthesized before, and their odor properties are
described here for the first time. The fact that these different, but very similar ring
systems, with the same side chain generate the same odors and even very similar
thresholds (Figure 17), suggests that this is a structural motif activating one or more
specific odorant receptors. However, the longerꢀchain compounds have not yet been
reported as food constituents or naturally occurring aroma compounds.
1ꢀ(Furanꢀ2ꢀyl)alkaneꢀ1ꢀthiols showed only slightly higher odor thresholds than the
ωꢀ(furanꢀ2ꢀyl)alkaneꢀ1ꢀthiols for compounds with two to four carbon atoms in the side
chain, but a slower increase in thresholds with increasing molecular weight was
3
4
observed (Figure 15). Meilgaard found that tertiary thiols generally show lower
thresholds than primary and secondary ones, which was confirmed by Polster and
19
Schieberle. However, our results show that this is also possible for secondary
thiols.
As expected, the loss of the free thiol group led to a significant increase in odor
thresholds. In comparison to the corresponding thiols, 2ꢀ((methylthio)methyl)furan
(35) and 2ꢀ((methylthio)methyl)thiophene (41) showed thresholds which were higher
by factors of approximately 170 and 35, respectively. Within the homologous series
of thio ethers the thresholds then increased significantly (Figure 16). Thus, the thiol
group plays a very important role in the generation of low odor thresholds also for the
heterocycles examined in this study. However, as mentioned before, suddenly a
molecular weight is reached causing a significant increase in thresholds of the thiols.
ACS Paragon Plus Environment

Page 17 of 50
Journal of Agricultural and Food Chemistry
17 ꢀ
ꢀ
359
360
361
362
363
364
365
366
367
368
369
370
371
372
373
374
375
376
377
378
379
380
381
382
383
384
As mentioned above, only four out of 45 homologues showed the same coffeeꢀ
like odor quality as 1: these were 8, 28, 33, and 34, while in most cases structural
variations in the side chain, e.g., an elongation, led to a loss of the characteristic
coffeeꢀlike scent. The odor quality was only maintained when the furan ring was
replaced by a thiophene ring or if a methyl group was present at position 3 of the
furan ring, respectively. Also, moving the mercapto methylene group from position 2
to position 3 in either 2ꢀfurfurylꢀ or 2ꢀthenylthiol (33 and 34) gave a coffeeꢀlike scent.
Thus, the coffeeꢀlike scent was kept only by thiols with a very similar structural motif,
but the thresholds clearly increased with an increasing deviation from the structure.
Therefore, it can be concluded that the odorant receptor responsible for the
perception of 1 seems to be very specific.
In general, however, a relatively large number of thiols showed similar or only
slightly higher thresholds than 1. These include lowerꢀweight ωꢀ(furanꢀ2ꢀyl)alkaneꢀ1ꢀ
thiols, ωꢀ(thiopheneꢀ2ꢀyl)alkaneꢀ1ꢀthiols, 1ꢀ(furanꢀ2ꢀyl)alkaneꢀ1ꢀthiols, and 1ꢀ
(thiopheneꢀ2ꢀyl)alkaneꢀ1ꢀthiols as well as 28 and 3ꢀmethylꢀ2ꢀthenylthiol (31). The
basis structural motif of 1 thus seems to be a suitable one for the generation of low
3
5,36
odor thresholds. Besides the improved perception of thiols in general,
a possible
explanation for this could be the appearance of so called πꢀπ molecular interactions.
As also aromatic and hetero aromatic amino acids can occur within the respective
olfactory receptors, enhanced interactions and perception are possible.
None of the homologues showed a significantly lower odor threshold than 1, and
only a very few structurally related mercaptans elicited the same odor attribute. This
result is perfectly in line with data of our study on structural homologues of 1ꢀpꢀ
22
mentheneꢀ8ꢀthiol (1ꢀpMT). It can, therefore, be speculated that within evolutionary
development the odorant receptors that came in contact with naturally occurring
aroma compounds may have shaped them. Also compounds which are generated by
ACS Paragon Plus Environment

Journal of Agricultural and Food Chemistry
18 ꢀ
Page 18 of 50
ꢀ
385
386
387
388
389
390
391
392
393
394
395
396
397
398
399
400
401
402
403
404
405
406
407
408
409
410
thermal treatment of raw foods may be seen as “natural”, because fire was used by
humans since about 1 million years. Therefore, synthetically generated analogues
are probably not perceived with the same low detection limit, because the odorant
receptors are not tailorꢀmade for them. In contrast to the results for 1ꢀpMT showing
that no homologue reached its low odor threshold by far, a relatively large number of
the structurally related mercaptans of 1 showed similar or slightly higher thresholds.
The fact that, in comparison to 1ꢀpMT, furane and thiophene thiols often showed
thresholds in the range of 1, can be explained by the natural occurrence of several
6, 12ꢀ18
further hetero aromatic thiols in foods.
probably more broadly tuned.
Therefore, these odorant receptors are
Acknowledgment. The authors thank Dr. Johannes Polster and especially Dr.
Johanna Kreissl for recording the NMR spectra as well as SamiꢀKaviani Nejad and
Ines Otte for recording the MS spectra.
Notes. The authors declare no competing financial interest.
ASSOCIATED CONTENT
Supporting Information. Experimental procedures and spectral data (NMR, MS) of
the 46 synthesized compounds and intermediates. In Figures S1, S22, and S67 the
synthetic routes are illustrated. Figures S2ꢀS21, S23ꢀS66, and S68ꢀS95 show the
NMR spectra of the synthesized sulfur compounds.
This material is available free of charge via the Internet at http://pubs.acs.org.
ACS Paragon Plus Environment

Page 19 of 50
Journal of Agricultural and Food Chemistry
19 ꢀ
ꢀ
411
412
413
Notes. The authors declare no competing financial interest.
ABBREVIATIONS USED. FD, flavor dilution; FFAP, free fatty acid phase; FFT, 2ꢀ
414
furfurylthiol; M
r
, relative molecular mass; 1ꢀpMT, 1ꢀpꢀmentheneꢀ8ꢀthiol;
ACS Paragon Plus Environment

Journal of Agricultural and Food Chemistry
20 ꢀ
Page 20 of 50
ꢀ
4
15
16
REFERENCES
4
4
17
18
(1) Reichstein, T.; Staudinger, H. The aroma of coffee. Perfum. Essent. Oil Rec.
1955, 46, 86ꢀ88.
4
4
19
20
(2) Blank, I.; Sen, A.; Grosch, W. Potent odorants of the roasted powder and brew of
4
Arabica coffee. Z. Lebensm.ꢁUnters. Forsch. 1992, 195, 239ꢀ245.
4
21
22
(3) Semmelroch, P.; Grosch, W. Studies on character impact odorants of coffee
4
brews. J. Agric. Food Chem. 1996, 44, 537ꢀ543.
423
424
425
(4) Garbusov, V.; Rehfeld, G.; Wolm, G.; Golovnja, R. V.; Rothe, M. Volatile sulfur
compounds contributing to meat flavour. Part. I. Components identified in boiled
meat. Nahrung 1976, 20, 235ꢀ241.
4
26
27
(5) Mottram, D. S. The effect of cooking conditions on the formation of volatile
4
heterocyclic compounds in pork. J. Sci. Food Agric. 1985, 36, 377ꢀ382.
4
28
29
(6) Gasser, U.; Grosch, W. Primary odorants of chicken broth. A comparative study
4
with meat broths from cow and ox. Z. Lebensm.ꢁUnters. Forsch. 1990, 190, 3ꢀ8.
430
431
432
(7) Nakamura, S.; Nishimura, O.; Masuda, H.; Mihara, S. Identification of volatile
flavor components of the oil from roasted sesame seeds. Agric. Biol. Chem. 1989,
53, 1891ꢀ1899.
4
33
34
(8) Schieberle, P. Primary odorants in popcorn. J. Agric. Food Chem. 1991, 39, 1141ꢀ
4
1144.
4
35
36
(9) Rychlik, M.; Grosch, W. Aroma from toasted white bread. Veroeff. Arbeitsgem.
Getreideforsch. 1996, 266, 42ꢀ49.
4
437
438
439
440
(10) Matsui, T.; Guth, H.; Grosch, W. A comparative study of potent odorants in
peanut, hazelnut, and pumpkin seed oils on the basis of aroma extract dilution
analysis (AEDA) and gas chromatographyꢀolfactometry of headspace samples
(GCOH). Fett/Lipid 1998, 100, 51ꢀ56.
441
442
443
(11) Tominaga, T.; Blanchard, L.; Darriet, P.; Dubourdieu, D. A powerful aromatic
volatile thiol, 2ꢀfuranmethanethiol, exhibiting roast coffee aroma in wines made from
several Vitis vinifera grape varieties. J. Agric. Food Chem. 2000, 48, 1799ꢀ1802.
ACS Paragon Plus Environment

Page 21 of 50
Journal of Agricultural and Food Chemistry
21 ꢀ
ꢀ
4
44
45
(12) Gasser, U.; Grosch, W. Identification of volatile flavor compounds with high
4
aroma values from cooked beef. Z. Lebensm.ꢁUnters. Forsch. 1988, 186, 489ꢀ494.
4
46
47
(13) Ames, J. M.; Mac Leod, G. Volatile components of a yeast extract composition.
4
J. Food Sci. 1985, 50, 125ꢀ131.
4
48
49
(14) Tressl, R.; Silwar, R. Investigation of sulfurꢀcontaining components in roasted
4
coffee. J. Agric. Food Chem. 1981, 29, 1078ꢀ1082.
450
451
452
453
(15) Mayer, F. Untersuchungen über das Aroma von Arabica Kaffee: Einfluß von
Provenienz und Röstgrad auf Phenolꢀ und Schwefelverbindungen und (E)ꢀβꢀ
Damascenon ꢀ Bestimmung der Abdampfraten von Aromastoffen.PhD thesis,
Technical University Munich, 2000.
454
455
456
457
(16) Campo, E.; Cacho, J.; Ferreira, V. The chemical characterization of the aroma of
dessert and sparkling white wines (Pedro Ximenez, Fino, Sauternes, and Cava) by
gas chromatographyꢀolfactometry and chemical quantitative analysis. J. Agric. Food
Chem. 2008, 56, 2477ꢀ2484.
458
459
460
(17) BurdackꢀFreitag, A.; Schieberle, P. Changes in the key odorants of Italian
hazelnuts (Coryllus avellana L. Var. Tonda Romana) induced by roasting. J. Agric.
Food Chem. 2010, 58 , 6351ꢀ6359.
461
462
463
(18) Tamura, H.; Fujita, A.; Steinhaus, M.; Takahisa, E.; Watanabe, H.; Schieberle, P.
Identification of novel aromaꢀactive thiols in panꢀroasted white sesame seeds. J.
Agric. Food Chem. 2010, 58, 7368ꢀ7375.
464
465
466
(19) Polster, J.; Schieberle, P. Structureꢀodor correlations in homologous series of
alkanethiols and attempts to predict odor thresholds by 3DꢀQSAR studies. J. Agric.
Food Chem. 2015, 63, 1419ꢀ1432.
4
67
68
(20) Polster, J.; Schieberle, P. Structureꢀodor correlations in homologous series of
4
mercaptalkanols. J. Agric. Food Chem. 2017, 65, 4329ꢀ4340.
469
470
471
472
(21) Granvogl, M.; Christlbauer, M.; Schieberle, P. Quantitation of the intense aroma
compound 3ꢀmercaptoꢀ3ꢀmethylpentanꢀ1ꢀol in raw and processed onions (Allium
cepa) of different origins and in other Allium varieties using a stable isotope dilution
assay. J. Agric. Food Chem. 2004, 52, 2797ꢀ2802.
ACS Paragon Plus Environment

Journal of Agricultural and Food Chemistry
22 ꢀ
Page 22 of 50
ꢀ
473
474
475
(22) Schoenauer, S.; Schieberle, P. Structureꢀodor activity studies on monoterpenoid
mercaptans synthesized by changing the structural motifs of the key food odorant 1ꢀ
pꢀmentheneꢀ8ꢀthiol. J. Agric. Food Chem. 2016, 64, 3849ꢀ3861.
476
477
478
479
(23) Noe, F.; Polster, J.; Geithe, C.; Kotthoff, M.; Schieberle, P.; Krautwurst, D.
OR2M3: A highly specific and narrowly tuned human odorant receptor for the
sensitive detection of onion key food odorant 3ꢀmercaptoꢀ2ꢀmethylpentanꢀ1ꢀol.
Chem. Senses 2017, 42, 195ꢀ210.
480
481
482
(24) Baciocchi, E.; Muraglia, E.; Sleiter, G. Homolytic substitution reactions of
electronꢀrich pentatomic heteroaromatics by electrophilic carbonꢀcentered radicals.
Synthesis of αꢀheteroarylacetic acids. J. Org. Chem. 1992, 57, 6817ꢀ6820.
4
83
84
(25) Simian, H.; Robert, F.; Blank, I. Identification and synthesis of 2ꢀheptanethiol, a
4
new flavor compound found in bell peppers. J. Agric. Food Chem. 2004, 52, 306ꢀ310.
485
486
487
(26) Hofmann, T.; Schieberle, P. Evaluation of the key odorants in a thermally treated
solution of ribose and cysteine by aroma extract dilution techniques. J. Agric. Food
Chem. 1995, 43, 2187ꢀ2194.
488
489
490
(27) Fuller, L.; Iddon, B.; Smith, K. Thienothiophenes. Part 2.1 Synthesis, metalation
and bromineꢀlithium exchange reactions of thieno[3,2ꢀb]thiophene and its
polybromo derivatives. J. Chem. Soc., Perkin Trans. 1 1997, 3465ꢀ3470.
4
91
92
(28) Nolan, S.; Cohen, T. A general approach to 4ꢀsubstitution of 2ꢀalkylfurans. J.
Org. Chem. 1981, 46, 2473ꢀ2476.
4
4
93
94
(29) Teranishi, R.; Buttery, R.; Guadagni, D. Odor quality and chemical structure in
4
fruit and vegetable flavors. Ann. NY Acad. Sci. 1974, 237, 209ꢀ216.
495
496
497
(30) Ullrich, F.; Grosch, W. Identification of the most intense volatile flavor
compounds formed during autoxidation of linoleic acid. Z. Lebensm. Unters. Fosch.
1987, 184, 277ꢀ282.
498
499
500
(31) Hofmann, T.; Schieberle, P. Identification of potent aroma compounds in
thermally treated mixtures of glucose/cysteine and rhamnose/cysteine using aroma
extract dilution techniques. J. Agric. Food Chem. 1997, 45, 898ꢀ906.
5
01
02
(32) Guentert, M.; Bruening, J.; Emberger, R.; Koepsel, M.; Kuhn, W.; Thielmann, T.;
Werkhoff, P. Identification and formation of some selected sulfurꢀcontaining flavor
5
ACS Paragon Plus Environment

Page 23 of 50
Journal of Agricultural and Food Chemistry
23 ꢀ
ꢀ
5
03
04
compounds in various meat model systems. J. Agric. Food Chem. 1990, 38, 2027ꢀ
5
2041.
505
506
507
(33) Werkhoff, P.; Bretschneider, W.; Emberger, R.; Guentert, M.; Hopp, R.; Köpsel,
M. Recent developments in the sulfur flavor chemistry of yeast extracts. Chem.
Mikrobiol. Technol. Lebensm. 1991, 13, 30ꢀ57.
5
08
09
(34) Meilgaard, M.; Flavor chemistry of beer. II. Flavor and threshold of 239 aroma
5
volatiles. Tech. Q. Master Brew. Assoc. Am. 1975, 12, 151ꢀ168.
5
10
11
(35) Wang, J.; LutheyꢀSchulten, Z.; Suslick, K. Is the olfactory receptor a
5
metalloprotein? Proc. Natl. Acad. Sci. U.S.A. 2003, 100, 3035ꢀ3039.
512
513
514
515
(36) Duan, X.; Block, E.; Li, Z.; Connelly, T.; Zhang, J.; Huang, Z.; Su, X.; Pan, Y.;
Wu, L.; Chi, Q.; Thomas, S.; Zhang, S.; Ma, M.; Matsunami, H.; Chen, G.; Zhuang, H.
Crucial role of copper in detection of metalꢀcoordinating odorants. Proc. Natl. Acad.
Sci. U.S.A. 2012, 109, 3492ꢀ3497.
ACS Paragon Plus Environment

Journal of Agricultural and Food Chemistry
24 ꢀ
Page 24 of 50
ꢀ
5
16
17
FIGURE CAPTIONS
5
518
519
520
521
522
523
524
525
526
527
528
529
530
531
532
533
534
535
536
537
538
539
540
Figure 1. Structures of 2ꢀfurfurylthiol (1), further ωꢀ(furanꢀ2ꢀyl)alkaneꢀ1ꢀthiols (2-7)
and ωꢀ(thiopheneꢀ2ꢀyl)alkaneꢀ1ꢀthiols (8-12).
Figure 2. Synthetic route used for the preparation of ωꢀ(furanꢀ2ꢀyl)alkaneꢀ1ꢀthiols
shown for 2ꢀ(furanꢀ2ꢀyl)ethanethiol.
Figure 3. Structures of 1ꢀ(furanꢀ2ꢀyl)alkaneꢀ1ꢀthiols (13-18) and 1ꢀ(thiopheneꢀ2ꢀ
yl)alkaneꢀ1ꢀthiols (19-24).
Figure 4. Synthetic route used for the preparation of 1ꢀ(furanꢀ2ꢀyl)alkaneꢀ1ꢀthiols
shown for 1ꢀ(furanꢀ2ꢀyl)propaneꢀ1ꢀthiol.
Figure 5. Structures of alkylated 2ꢀfurfurylthiols (25-28) and 2ꢀthenylthiols (29-32).
Figure 6. Synthetic route used for the preparation of 2ꢀ((alkylthio)methyl)furans
shown for 2ꢀ((methylthio)methyl)furan.
Figure 7. Mass spectrum (MSꢀEI) of (A) 2ꢀfurfurylthiol (1) and (B) 5ꢀ(furanꢀ2ꢀ
yl)pentaneꢀ1ꢀthiol (5).
Figure 8. Mass spectrum of 2ꢀthenylthiol (8).
Figure 9. Mass spectrum (MSꢀEI) of 1ꢀ(furanꢀ2ꢀyl)butaneꢀ1ꢀthiol (15).
Figure 10. Mass spectrum (MSꢀEI) 5ꢀpropylꢀ2ꢀfurfurylthiol (27).
Figure 11. Structural formulas of 3ꢀfurfurylthiol (33) and 3ꢀthenylthiol (34).
Figure 12. Structures of 2ꢀ((alkylthio)methyl)furans (35-40) and ꢀthiophenes (41-46).
Figure 13. Mass spectrum (MSꢀEI) 2ꢀ((butylthio)methyl)furan (38).
Figure 14. Influence of different heterocyclic ring systems on the odor thresholds of
homologous series of ωꢀsubstituted alkaneꢀ1ꢀthiols.
Figure 15. Influence of different heterocyclic ring systems at position C1 on the odor
thresholds of homologous series of alkaneꢀ1ꢀthiols.
ACS Paragon Plus Environment

Page 25 of 50
Journal of Agricultural and Food Chemistry
25 ꢀ
ꢀ
541
542
543
544
Figure 16. Influence of different ring systems on the odor thresholds of homologous
series of heterocyclic thio ethers.
Figure 17. Influence of different structural modifications on the odor thresholds
homologous series of 2ꢀfurfurylthiol derivatives.
ACS Paragon Plus Environment

Journal of Agricultural and Food Chemistry
26 ꢀ
Page 26 of 50
ꢀ
Table 1.
Retention Indices and Sensory Properties of ωꢀ(Furanꢀ2ꢀyl)alkaneꢀ1ꢀ
thiols
RI
odor threshold
a
b
no.
compound
odor quality
(ng/L in air)
0.0084
FFAP DBꢀ5
1
2
3
4
5
2ꢀfurfurylthiol
1417
914
burned, roasty,
coffeeꢀlike
2ꢀ(furanꢀ2ꢀyl)ethanethiol
1470
996
onionꢀlike, burned,
rubberꢀlike
0.013
0.0080
0.0088
0.85
3ꢀ(furanꢀ2ꢀyl)propaneꢀ1ꢀthiol
4ꢀ(furanꢀ2ꢀyl)butaneꢀ1ꢀthiol
5ꢀ(furanꢀ2ꢀyl)pentaneꢀ1ꢀthiol
1590 1108
1712 1220
1825 1326
burned, roasty,
mushroomꢀlike
burned,
mushroomꢀlike
rubberꢀlike, onionꢀ
like, mushroomꢀlike
6
7
6ꢀ(furanꢀ2ꢀyl)hexaneꢀ1ꢀthiol
7ꢀ(furanꢀ2ꢀyl)heptaneꢀ1ꢀthiol
1925 1423 rubberꢀlike, burned
86
2034 1527 rubberꢀlike, burned
350
a
b
Compound numbers correspond to the numbers in the text. Odor quality as perceived at
the sniffing port during GCꢀO at threshold level.
ACS Paragon Plus Environment

Page 27 of 50
Journal of Agricultural and Food Chemistry
27 ꢀ
ꢀ
Table 2.
Retention Indices and Sensory Properties of ωꢀ(Thiopheneꢀ2ꢀyl)alkaneꢀ
ꢀthiols
1
RI
odor threshold
(ng/L in air)
a
b
no.
compound
2ꢀthenylthiol
odor quality
FFAP DBꢀ5
1663 1086
8
burned, roasty,
coffeeꢀlike
0.012
0.030
0.036
0.025
1.2
9
2ꢀ(thiopheneꢀ2ꢀyl)ethanethiol
1723 1172
onionꢀlike, burned,
rubberꢀlike
1
0
1
2
3ꢀ(thiopheneꢀ2ꢀyl)propaneꢀ1ꢀthiol 1845 1288
rubberꢀlike,
mushroomꢀlike
rubberꢀlike,
1
1
4ꢀ(thiopheneꢀ2ꢀyl)butaneꢀ1ꢀthiol
5ꢀ(thiopheneꢀ2ꢀyl)pentaneꢀ1ꢀthiol
1975 1404
2077 1516
mushroomꢀlike
rubberꢀlike,
mushroomꢀlike
a
b
Compound numbers correspond to the numbers in the text. Odor quality as perceived at
the sniffing port during GCꢀO at threshold level.
ACS Paragon Plus Environment

Journal of Agricultural and Food Chemistry
28 ꢀ
Page 28 of 50
ꢀ
Table 3.
Retention Indices and Sensory Properties of 1ꢀ(Furanꢀ2ꢀyl)alkaneꢀ1ꢀ
thiols
RI
odor threshold
a
b
no.
compound
1ꢀ(furanꢀ2ꢀyl)ethanethiol
FFAP DBꢀ5
odor quality
(ng/L in air)
1
3
4
1394
961
meaty, onionꢀlike
0.030
0.012
1
1ꢀ(furanꢀ2ꢀyl)propaneꢀ1ꢀthiol 1457 1039 onionꢀlike, passion fruitꢀ
like
15
16
17
18
1ꢀ(furanꢀ2ꢀyl)butaneꢀ1ꢀthiol
1541 1128
catty, passion fruitꢀlike
catty, passion fruitꢀlike
catty, passion fruitꢀlike
0.022
0.082
0.51
9.0
1ꢀ(furanꢀ2ꢀyl)pentaneꢀ1ꢀthiol 1633 1223
1ꢀ(furanꢀ2ꢀyl)hexaneꢀ1ꢀthiol 1717 1329
1ꢀ(furanꢀ2ꢀyl)heptaneꢀ1ꢀthiol 1832 1426
catty, passion fruitꢀlike
a
b
Compound numbers correspond to the numbers in the text. Odor quality as perceived at
the sniffing port during GCꢀO at threshold level.
ACS Paragon Plus Environment

Page 29 of 50
Journal of Agricultural and Food Chemistry
29 ꢀ
ꢀ
Table 4.
Retention Indices and Sensory Properties of 1ꢀ(Thiopheneꢀ2ꢀyl)alkaneꢀ
ꢀthiols
1
RI
odor threshold
(ng/L in air)
a
b
no.
compound
1ꢀ(thiopheneꢀ2ꢀyl)ethanethiol
odor quality
FFAP DBꢀ5
1643 1125
19
sulfury, meaty,
onionꢀlike
0.0075
2
0
1
1ꢀ(thiopheneꢀ2ꢀyl)propaneꢀ1ꢀthiol 1700 1207
sulfury, meaty
catty, passion
fruitꢀlike
0.057
0.039
2
1ꢀ(thiopheneꢀ2ꢀyl)butaneꢀ1ꢀthiol
1ꢀ(thiopheneꢀ2ꢀyl)pentaneꢀ1ꢀthiol
1ꢀ(thiopheneꢀ2ꢀyl)hexaneꢀ1ꢀthiol
1ꢀ(thiopheneꢀ2ꢀyl)heptaneꢀ1ꢀthiol
1782 1299
1878 1399
1977 1503
2085 1608
22
23
24
catty, passion
fruitꢀlike
0.088
0.11
3.3
catty, passion
fruitꢀlike
passion fruitꢀlike
a
b
Compound numbers correspond to the numbers in the text. Odor quality as perceived at
the sniffing port during GCꢀO at threshold level.
ACS Paragon Plus Environment