Organic preparations with molar amounts of volatile malodorous thiols

Article abstract of DOI:10.1080/00397911.2011.640968

Thiols are indispensable for the preparation of many organic sulfur compounds. Their strong smell and use for gas leakage perception render it almost impossible to work with them without arousing public attention. Molar amounts of the very odoriferous thiol 2-methyl-2-propanethiol (t-butylthiol) are needed, for example, for the large-scale synthesis of two useful synthetic building blocks, 1,2,4,5-tetrakis(t-butylthio)benzene and tetramethylbenzo-2,2, 6,6-[1,2-d;4,5-d']bis[1,3]dithiol. We investigated an array of alternatives to circumvent the problem: (1) alternative thiols (primary, long-chain, tertiary thiols of larger molar mass); (2) exhaust cleaning methods (adsorption, oxidation, conversion to a salt); and (3) thermal exhaust treatment. Only combustion of the fumehood exhaust with domestic gas at 900 °C in a regenerative thermal oxidation unit was able to completely prevent the thiol smell from escaping. Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications to view the free supplemental file.

Full text of DOI:10.1080/00397911.2011.640968

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Organic Preparations with Molar
Amounts of Volatile Malodorous Thiols
Diana Müller a , Klaus Adelsberger b & Peter Imming a
a Institut für Pharmazie, Martin-Luther-Universität, Halle, Germany
b Luft- und Thermotechnik Bayreuth GmbH & Co., Goldkronach,
Germany
Accepted author version posted online: 05 Jun 2012.Version of
record first published: 05 Mar 2013.
To cite this article: Diana Müller , Klaus Adelsberger & Peter Imming (2013): Organic Preparations
with Molar Amounts of Volatile Malodorous Thiols, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 43:10, 1447-1454
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Synthetic Communications1, 43: 1447–1454, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.640968
ORGANIC PREPARATIONS WITH MOLAR AMOUNTS
OF VOLATILE MALODOROUS THIOLS
Diana Mu¨ller,1 Klaus Adelsberger,2 and Peter Imming1
1Institut fu¨r Pharmazie, Martin-Luther-Universita¨t, Halle, Germany
2Luft- und Thermotechnik Bayreuth GmbH & Co., Goldkronach, Germany
GRAPHICAL ABSTRACT
Abstract Thiols are indispensable for the preparation of many organic sulfur compounds.
Their strong smell and use for gas leakage perception render it almost impossible to work
with them without arousing public attention. Molar amounts of the very odoriferous thiol
2-methyl-2-propanethiol (t-butylthiol) are needed, for example, for the large-scale
synthesis of two useful synthetic building blocks, 1,2,4,5-tetrakis(t-butylthio)benzene
and tetramethylbenzo-2,2,6,6-[1,2-d;4,5-d’]bis[1,3]dithiol. We investigated an array of
alternatives to circumvent the problem: (1) alternative thiols (primary, long-chain, tertiary
thiols of larger molar mass); (2) exhaust cleaning methods (adsorption, oxidation, conver-
sion to a salt); and (3) thermal exhaust treatment. Only combustion of the fumehood
exhaust with domestic gas at 900 ꢀC in a regenerative thermal oxidation unit was able to
completely prevent the thiol smell from escaping.
Supplemental materials are available for this article. Go to the publisher’s online edition
of Synthetic Communications1 to view the free supplemental file.
Keywords Exhaust air treatment; 2-methyl-2-propanethiol; odor of thiols; stench;
thermal exhaust treatment
INTRODUCTION
Sulfur compounds fulfill key functions in both organisms and technical
applications, including medicine. Of the drugs listed in the Merck index (drugs, pes-
ticides, and physiological substances), almost 13% contain one or more sulfur atoms,
40% of which are in sulfidic binding and almost 4% are thiols. Access to most organic
sulfur compounds requires a synthetic step with a strong-smelling bivalent sulfur
Received September 6, 2011.
Address correspondence to Peter Imming, Institut fur Pharmazie, Wolfgang-Langenbeck-Str. 4,
¨
Halle 06120, Germany. E-mail: peter.imming@pharmazie.uni-halle.de
1447

¨
D. MULLER, K. ADELSBERGER, AND P. IMMING
1448
species. The sulfur atoms often have to be introduced in the early stages of the
synthetic routes, entailing the need to handle large quantities. This severely limits
the accessibility of related starting materials and downstream products.
Typical thiols for the introduction of sulfur by nucleophilic substitution
are methanethiol, ethanethiol, 2-propanethiol, and 2-methyl-2-propanethiol
(t-butylthiol). They smell very unpleasantly and have a very low odor threshold. A
mixture of as little as 3.8 mg=m3 of three of them is added to domestic gas for the
perception of leaks. The concentration level results from the requirement that they
must be clearly perceived when the gas concentration in the air reaches 0.2 times
the lower flammable limit.[1] The smell will be interpreted as a gas leak even if it
stems from their synthetic use.
Alkylthiols like the ones mentioned are key reagents for the synthesis of quite a
few sulfur-substituted aromatic systems, for example, the tetraalkylthiobenzenes
9g, 9h, and 2a with methyl, isopropyl, and t-butyl substituents.[2–11] We needed to
prepare large amounts of 1,2,4,5-tetrakis(t-butylthio)benzene (2a) en route to
tetramethylbenzo-2,2,6,6-[1,2-d;4,5-d’]bis[1,3]dithiol (3). The latter is a basic build-
ing blocks for spin labels, that is, stable triarylmethyl (TAM) radicals[12] tailored
for modern pharmaceutical and medical imaging techniques,[13–15] particularly elec-
tron spin resonance (ESR) spectroscopy. TAMs (Scheme 1) are formally derivatives
of 1,2,4,5-benzenetetrathiols (10).[16–18] Their synthesis begins by reacting 1,2,4,5-
tetrachlorobenzene (1) with an appropriate thiol to yield the respective 1,2,4,5-
benzenetetrathioethers 2 or 9,[19,20] followed by conversion to 3 (Scheme 2). The
bivalent sulfur atoms are essential for the stability and ESR properties of the TAMs
that are at the end of a multistep synthesis. For the synthesis of the basic building
blocks 2 and 9 (which do not pose a particular problem for smell), molar amounts
of 2-methyl-2-propanethiol need to be handled, posing a major challenge especially
for academic research laboratories. We investigated the following techniques for
avoiding thiol odor release: Use of thiols that are less volatile or odoriferous exhaust
scrubbing, and exhaust combustion.
Scheme 1. Synthesis of TAM.[31] Reagents and conditions: (a) Na, DMF, 2-methyl-2-propanethiol; (b)
HBF4 (54% in Et2O), propane-2-one, toluene; (c) nBuLi (2.5 M in hexanes) 1 equiv. in Et2O; then 0.3
equiv. of methyl chloroformate; (d) nBuLi (2.5 M in hexanes) and TMEDA 10 equiv, followed by excess
DIBOC; and (e) CF3COOH.

ORGANIC PREPARATIONS WITH THIOLS
1449
Scheme 2. Synthesis of 2,2,6,6-tetramethylbenzo[1,2-d;4,5-d]bis[1,3]dithiole (3). Reagents and conditions:
(a) argon atmosphere, dry DMF, thiol, Na or NaH 60% (w=w) in mineral oil 0 ꢀC, 2–12 h reflux; (b) HBF4
(54% in Et2O), propan-2-one, toluene; and (c) Na in NH3.
RESULTS AND DISCUSSION
Less Volatile or Odoriferous Thiols
An alternative to 2-methyl-2-propanethiol would have to be less odoriferous,
be still strongly S-nucleophilic, and bear an alkyl rest removable as a carbenium
ion in the second step of the synthetic scheme depicted in Scheme 1. Table 1 lists
Table 1. Tertiary (7) and primary (8) thiols tested for the preparation of the sulfides 2 or 9 and the
bis(thioketal) 3
Tetrakis(thioalkyl)benzene,a
isolated yield (%)
Thiol
R1
CH3
R2
R3
3,b isolated yield
7a
7b
7c
7dc
7ec
7fd
8a
8b
8c
CH3
CH3
CH3
C2H5
CH3
CH3
—
—
—
—
—
—
—
2a, 60
2b, —e
2c, —e
2df
2ef
2fg
70
—
—
—
—
—
—
C9H19
C6H13
C2H5
C3H7
CH2COOH
—
—
—
—
—
—
—
—
C12H25
C8H17
C6H13
9a, —e
9b, 85h
9c, 80h
9d, —i
9e, —i
9f, —i
9gj
e
—
—
—
—
e
8d
8e
—
—
CH2COOH
CH2C6H5
CH2C6H4OCH3
CH3
—
—
—
—
—
8f
—
—
8g
8h
—
CH(CH3)2
9hj
aScheme 2, method a.
bScheme 2, method b.
cSynthesis according to Ref. 22.
dSynthesis according to Ref. 23.
eUn-identifiable product mixture.
fNot synthesized, thiol smell much too storng.
gNot synthesized, thiol insoluble in toluene.
hSynthesis according to Ref. 31.
iIncomplete substitution.
jNot synthesized.

¨
D. MULLER, K. ADELSBERGER, AND P. IMMING
1450
the thiols and alternative paths tested. In summary, (a) thiols with an alkyl chain of
less than six carbon atoms are too strong smelling because of their low volatility. (b)
Primary S-alkyl chains of whatever length were not transferable to toluene in the
next step (Scheme 2). (c) To circumvent this step, but still use a long-chain, primary
thiol, the preparation of 1,2,4,5-benzenetetrathiol (10) was attempted by reduction of
various alkylarylsulfides with sodium in liquid ammonia.[19] The alkylarylsulfides 2b,
2c, and 9a proved to be greasy materials that could not be extracted from the reac-
tion mixtures. The sulfides 9b and 9c were isolable; however, they failed to be con-
verted to 3 (Scheme 2, f) via 10. Judging from the physical properties of the reaction
mixtures, 10 polymerized faster than it did react with 2-propanone. (d) The tertiary
thiols 7d and 7e were prepared following published procedures.[21,22] Though their
smell did not suggest gas leakages, even their salts presented no improvement odor-
wise. Compound 7f[23] could not be used because it was insoluble in toluene. Thiols
8d–f gave only incomplete substitution.
All alternative thiols either were no improvement over 2-methyl-2-propanethiol
or yielded ill-defined reaction mixtures or products that were unsuitable for the next
steps on the way to TAM radicals.
Exhaust Cleaning
The synthetic pathway depicted in Scheme 1, especially step a, necessitated a
discontinued operational mode with strongly varying concentrations of substances
in the exhaust air over time. The exhaust cleaning could not be guided by infor-
mation on concentrations and changes over time. The total exhaust airstream to
be cleaned was unknown. As is often the case in academic laboratories, for technical
and financial considerations neither the temporary installation of an external pilot
plant nor an exhaust air-cleaning plant within the building were possible. The para-
meters known for exhaust air cleaning were the following: carrying gas, air from a
standard laboratory fumehood; standard air parameters (emission temperature
20–30 ꢀC; 45–60% relative humidity); and no superimposed foreign matter, only
components stemming from the process itself. The component to be separated pri-
marily was 2-methyl-2-propanethiol. Its residual concentration before release of
the exhaust air to the environment was defined as maximum of 0.01 mg=m3. In
[1]
Germany, the Technische Regel G 280–1 ‘‘Gas odoration’’ demands a minimum
concentration of gas odorant thiols of 0.03 mg=m3 so that even people with a weakly
developed olfactory sense are sure to notice the thiol smell in the air. Other exhaust
air components of considerable concentrations were N,N-dimethylformamide,
1,2,4,5-tetrachlorobenzene, and reaction intermediates. According to technical rules
on air pollution, they needed to be reduced to a maximum of 20 mg Cges=m3 in the
washed exhaust air. The following preliminary experiments were undertaken. They
did not lead to the basically required drop of the thiol concentration below the odor
threshold. Their short description highlights the limits set by the local conditions and
indicates what would have to be done to perhaps reach the goal by exhaust air clean-
ing. The main problem is that it would not be sufficient to absorb the odoriferous
exhausts from the reactor. Most of the 2-methyl-2-propanethiol (or related thiol
reagent) is set free during workup which includes long suction filtration of the reac-
tion mixture after pouring onto ice. This (typical) workup necessitates cleaning all

ORGANIC PREPARATIONS WITH THIOLS
1451
the fumehood air. Researchers who did related reactions in laboratory gloveboxes
were not able to prevent the odor from escaping into the neighborhoods.[24]
Adsorption. As adsorbents, two different pelletized active charcoal brands
were used in a reactor tube of approximately 700 mm filling length and a diameter
of approximately 50 mm. The reactor tube received the exhaust volatile material
of the synthetic process. With an average bulk density of 300–400 kg=m3, it con-
tained approximately 500 g of active charcoal. If conditions for adsorption were
ideal, (flow rate; 4:1 ratio of height and length of the filling; transport mechanisms
of heat and materials; levels of temperature, humidity and partial pressures; no dis-
placement processes and co-adsorption of water; etc.), and with a maximum load
capacity of 20% by weight, up to 100 g of noxious substances could be adsorbed.
In reality, a laboratory fumehood setup, with a minimum amount of exhaust air
of 150 Nm3=h and a flow rate of at least 21 m=s resulted. In comparison with the
theoretical optimum of 1 m=s, the adsorber will be overrun massively, leading to
too short contact times.
An elaborate method for the determination of smell is described in technical
rules.[25] It was not carried out because the very strong and characteristic smell of
the thiol allowed for subjective assessment of the released air. Over the whole time,
the odor of the exhaust air was dominated by the typical thiol note. So even if the
adsorber held back most of the material, the necessary effect—no odor at all—
was not attained. It was therefore considered unnecessary to determine the exact
amount adsorbed.
Scrubbing. In addition to the active charcoal adsober (see previous para-
graph), two washing bottles were added before the adsorber, containing 500 ml of
washing solution each. The exhaust air was introduced, finely divided by way of a
glass sinter frit, using a standard method for the determination of gaseous harmful
substances.[26]
Oxidation. This aimed at destroying the thiol by oxidation with potassium
permanganate (4%) or hydrogen peroxide (3%). Again, two washing flasks were
arranged in series between the reaction flask and charcoal adsorber.
Salt formation. An aqueous sodium hydroxide solution (20%) was supposed
to absorb the thiol by conversion to its nonvolatile sodium salt.
In all cases, the concentration of the thiol remained above the odor threshold. Con-
cerning oxidation, this is partly connected with the well-known fact that tertiary
thiols are very resistant oxidation.[27] Since the experimental setup enforces a discon-
tinuous gas flow and accompanying release of the odor, optimal conditions for gas
washing could not be achieved, that is, very small flow rates with long contact times
in the washing media and very large surface for interaction due to an optimal
surface-to-volume ratio of the bubbles.
It was concluded that the relative chemical inertness of the thiol in connection
with its very low odor threshold and the large (molar) amounts render exhaust air
scrubbing and adsorption unsuitable under the (in terms of exhaust air purification)
inadequate local conditions.

¨
D. MULLER, K. ADELSBERGER, AND P. IMMING
1452
Thermal exhaust air treatment. With the high amount of sulfur com-
pounds and discontinued release of all components in the exhaust air, a process at
lower temperatures supported by catalysts was not considered.
We resorted to a thermal exhaust air treatment on site of LTB (Luft- und Ther-
motechnik Bayreuth GmbH & Co. KG), Germany. This proved to be the most econ-
omical, fastest, most functional, and safest solution. The complete exhaust air from the
fumehood the reaction was run under was transferred to a thermal after-burning unit.
This was almost unaffected by fast and pronounced fluctuations of the noxious compo-
nents, mode of operation (batch or continuous), and the composition of the exhaust
air. There were almost no negative influences on air combustion through interactions
of components, no displacement processes as in adsorption, etc. What needed to be
taken into account were rules to explosion prevention and emission limits (e.g., for
dioxines, furanes, aerosoles, total carbon).[28] The physical and chemical properties of
2-methyl-2-propanethiol and other exhaust air components further suggested thermal
after-burning to be the method of choice: all components had carbon skeletons; for
2-methyl-2-propanethiol the burning point was ꢁ24 ꢀC and ignition point, was 225 ꢀC.
In an on-site (LTB) standard fumehood, the synthesis, workup, isolation, and pre-
liminary purification of the target product were performed (2a, Scheme 2). The fume-
hood was connected to a regenerative thermal oxidation (RTO) unit so that the main
ventilator of the RTO constantly created a flow rate from the fumehood set to
900 Nm3=h. This high (in relation to the fumehood and process size) flow rate was
chosen to prevent any leakage of 2-methyl-2-propanethiol from the hood. Through
another suction port, the RTO could have been fed with fresh air to dilute the air
from the hood before combustion. This would have been necessary if the RTO
exhaust would have smelled for the thiol or if the immission limit had exceeded
25% of the lower explosion limit.[29] Both cases did not occur. The temperature in
the combustion chamber was optimized so that the combustion of the starting
material, 1,2,4,5-tetrachlorbenzene, would not lead to the formation of more dioxine
than allowed. The times for opening and closing the valves for the crude gas flow and
flushing had to be adjusted to the synthetic process. Because no thiol odor was
detected, further exhaust air analyses were not undertaken.
In conclusion, exhaust air after-burning proved to be a successful way of work-
ing with an extremely malodorous substance that otherwise could not have been used
in large quantities in the framework of academic research. The RTO unit used was
mobile and for lease and can be set up next to a lab building. Even smaller units,
suitable to be taken inside laboratories, could be manufactured.
EXPERIMENTAL
Full experimental details for the syntheses are provided in the Supplementary
Material, available online, including NMR spectra and characterization data.
A Roxitherm RTO units, manufactured by Luft- und Thermotechnik Bayreuth
GmbH & Co. KG, Goldkronach, Germany, was used.
Roxitherm from LTB is based on the thermal oxidation process with
regenerative heat recovery to transform organic materials to the oxides of the

ORGANIC PREPARATIONS WITH THIOLS
1453
respective elements. The energy required to preheat emission gasses is more than 90%
regeneratively recovered. The exhaust air is transported into one of three chambers.
After preheating by heat exchange to 800 ꢀC, it is led into the next chamber by way
of the burner compartment. On its way to the RTO exhaust, it preheats the heat
exchangers. With each cycle, the gas enters one of the three chambers and is led
out by the neighboring one, with a detention period of 2 min per chamber and a
purging time of approximatley 40 s for the third chamber. The purged gas is fed into
the main exhaust gas flow for oxidation. In a typical repeat cycle, the chambers con-
secutively hold contaminated gas, decontaminated gas, and gas for purging.
Scale was 1.5 (for maximum volume flow of 1500 Nm3=h). Volume flow during
synthesis and workup was 900 Nm3=h. Combustion medium was air oxygen with
domestic gas. Domestic gas flow was 9.0 m3=h. Temperature of combustion chamber
was 900 ꢀC. Connection power was 11 kW. Floor space (length ꢂ breadth ꢂ height)
was 7000 ꢂ 2500 ꢂ 3500 mm.
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