Continuous-flow step-economical synthesis of thiuram disulfidesviavisible-light photocatalytic aerobic oxidation

Article abstract of DOI:10.1039/d0gc04270f

A continuous-flow photocatalytic synthesis of the industrially important thiuram disulfides has been developed, utilizing O₂as the oxidant and Eosin Y as the photoredox catalyst. This highly atom- and step-economical method features much reduced reaction time as well as excellent product yield and purity, making it a sustainable and potentially scalable process for industrial production.

Full text of DOI:10.1039/d0gc04270f

Green Chemistry
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Continuous-flow step-economical synthesis of
thiuram disulfides via visible-light photocatalytic
aerobic oxidation†
Cite this: Green Chem., 2021, 23,
1280
Hao-Xing Xu,a Ze-Run Zhao,a Yeersen Patehebieke,a Qian-Qian Chen,a
Shun-Guo Fu,b Shuai-Jun Chang,b Xu-Xu Zhang,b Zhi-Liang Zhangb and
a
Xiao Wang
*
Received 17th December 2020,
Accepted 8th January 2021
A continuous-flow photocatalytic synthesis of the industrially important thiuram disulfides has been
developed, utilizing O2 as the oxidant and Eosin Y as the photoredox catalyst. This highly atom- and step-
economical method features much reduced reaction time as well as excellent product yield and purity,
making it a sustainable and potentially scalable process for industrial production.
DOI: 10.1039/d0gc04270f
rsc.li/greenchem
The vulcanization accelerator is indispensable to the rubber and sulfuric acid in multiple steps. In addition, these steps are
industry and plays a critical role in rubber processing,1 as it strongly exothermic,10 which increases the safety risk and the
improves rubber performance and prolongs the service life. difficulty of accurate temperature control in large-scale pro-
Currently, the most popular classes of vulcanization accelera- duction. Moreover, the corrosive nature of sodium hydroxide
tors include thiazole, sulphonamide, thiuram, dithiocarba- and sulfuric acid increases the cost of equipment and waste
mate and ammonia. Thiuram has garnered much attention treatment.11 Although a variety of methods for synthesizing
due to its excellent vulcanization activity and high degree of thiuram disulfides have been reported, most of them have not
vulcanization,1,2 and has become a mainstream vulcanization been widely applied in industry due to safety and cost
accelerator. Tetraethylthiuram disulfide (TETD, Scheme 1) is issues12–14 and the requirement of metal reagent/catalysts.15,16
one of the most widely used thiuram-type accelerators. In With the pressing need for more sustainable and safer pro-
recent years, the total annual output of TETD has seen a cesses in industry, chemical processes under continuous-flow
steady increase worldwide. Interestingly, it has also been conditions have gained increasing attention in recent
reported to have diverse biological activities for treating alco- years.17–24 Industrially relevant reactions can be carried out in
holism, cancer, HIV and diseases in seeds3–6 (known as “disul- microchannels with diameters ranging from the µm to mm
firam” in medicinal chemistry). Thus, extensive research has levels. The small reactor scale allows for a much enhanced
been conducted on the preparation of TETD in both academia surface-to-volume ratio,25 which is particularly advantageous
and industry over the past two decades.
to heat and mass transfer thus offering much improved safety
In general, traditional synthesis of thiuram disulfide starts and reaction rate.26–28 In addition, microreactors can efficien-
with the treatment of a secondary amine with carbon disulfide tly minimize the gap between the laboratory and pilot scale
in aqueous sodium hydroxide solution to form dithiocarba- experiments, with a low scale-up effect than batch reactions.
mate, which is isolated and subsequently oxidized by hydrogen In particular, microflow technology reduces the cost by not
peroxide, and neutralized with sulfuric acid to give the corres- requiring airtight equipment for gas–liquid reactions.29
ponding thiuram disulfide. Then, the crude product under-
However, a small reactor diameter poses the problem of
goes filtration, washing and drying to afford thiuram disulfide handling solid formation from reagents, products or catalysts,
as a white powdery crystal.7–9 However, traditional methods which leads to clogging events. For example, Luo’s group
fall short in atom- and step-economies, as they require sequen-
tial addition of superstoichiometric amounts of H2O2, NaOH
aSchool of Chemistry and Chemical Engineering, Nanjing University, Nanjing,
210023 Jiangsu, China. E-mail: wangxiao@nju.edu.cn
bHebi Uhoo New Materials Co., Ltd, Hebi, 458000 Henan, China
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
d0gc04270f
Scheme 1 Structure and applications of TETD (disulfiram).
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reported a continuous-flow synthesis of TETD under con- ditions determined, the synthesis of other thiuram disulfides
ditions that employed H2O2 as the oxidant.43 The yield of was then studied.
TETD reached 93% within 3 min of residence time. However,
First, a set of photocatalysts was screened in the batch reac-
the requirement of excess carbonic acid remains a problem, tion with ethanol as the solvent under irradiation by a 13 W
and the resulting sodium carbonate could clog the microchan- green LED. The results are shown in Table 1. Reactions using
nel. Thus, we aimed to develop a more economical and envir- bromocresol green, bromocresol purple (sodium salts) and
onmentally friendly continuous microflow approach to syn- methylene blue gave unsatisfactory results since the yields
thesize thiuram disulfides, in the hope of solving the above- were below 30%. To our delight, we found that the chromato-
mentioned challenges. Based on the reported solutions,30–32
a
graphic yield of TETD could reach 98% when the sodium salt
more attractive strategy would involve the introduction of a gas of Rose Bengal (RB) was employed as the photocatalyst. Eosin
phase for increasing the overall flow rate in microchannels. Y, a popular and versatile photocatalyst,39 does not work as
The gas–liquid segments at a high flow rate cause enhanced well as RB with which 72% chromatographic yield was
turbulence, which can help flush out solids stuck to the obtained. However, the limited solubility of RB in ethanol
channel wall. Molecular oxygen (O2) has received increasing renders it inappropriate for flow synthesis since clogging of
attention from both academia and industry as the most readily the microchannel was observed. Different light sources were
available green oxidant on the planet.33 Monbaliu and co- evaluated, in which the yields of TETD under blue and white
workers reported the photocatalytic aerobic oxidation of LED light were 60% and 48%. Therefore, the green LED was an
2-chloroethyl ethyl sulfide (CEES) with an O2-pressurized con- optimal light source for Eosin Y-catalysed reactions.
tinuous-flow setup,34 and the yield of the corresponding
Using Eosin Y as the optimal catalyst, we set out to explore
product, 2-chloroethyl ethyl sulfoxide (CEESO), reached 98% the most important operational conditions in microflow. A
in 4 min under the optimized conditions. Therefore, we envi- microreactor system was dedicatedly designed for the continu-
sioned a method without the use of toxic and stoichiometric ous synthesis of TETD, which is shown in Fig. 1 and 2. Herein,
oxidants by using O2 or compressed air as a green oxidant. The the reaction solution was introduced into one of the two inlets
rate of the biphasic reaction can be increased in the flow due of a T-micromixer using a plunger pump, which contained di-
to the improved mass transfer compared to the batch reaction. ethylamine and carbon disulfide premixed in a near-equimolar
Moreover, quantitative consumption of gaseous reactants can ratio of 1/1.1. The other inlet of the T-micromixer was con-
be realized by using a mass-flow controller.35
nected to a computer-controlled mass-flow controller (MFC)
The envisioned synthesis of TETD is shown in Scheme 2. A attached to the oxygen tank. The retention time was adjusted
photocatalyst was used to facilitate the oxidation.36 According by changing the flow rate of the MFC or pump. For the reactor
to the Beer–Lambert law, the small size of the microchannel section, the outlets of the T-micromixer were connected to the
can greatly increase light absorbance of the catalyst.37,38 The photoreaction microchannel (PTFE, diameter: 1/16′) sur-
proposed method employed a semi-equimolar ratio of diethyl- rounded by a 13 W green LED light strip. Segmented flow
amine (1.0 equiv.) and carbon disulfide (1.1 equiv.) that forms (Fig. 1b) gradually formed when oxygen gas and the solution
dithiocarbamate in situ. According to market reports, thiuram phase converged in the T-micromixer. The gas–liquid flow
accounts for a large proportion of vulcanization accelerators. pattern, often known as the Taylor flow,40 was expected to
However, safety and efficiency issues emerged as the scale provide a much higher reaction rate than that by the batch
went up in traditional production. In this work, the prepa- approach, due to the enhanced contact area and pressure drop
ration of TETD in batch and continuous-flow modes was first at the gas–liquid interface. A back-pressure regulator (BPR)
investigated as a proof of principle. With the optimal con- was installed downstream to control the overall pressure of the
system.
Table 1 Comparison of TETD yields (%) with different visible-light
photocatalysts (the colors of bars represent the exact colors of catalysts)
Scheme 2 Reaction diagram of the step- and reagent-economical syn-
thesis of TETD.
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Fig. 1 Microreactor system for the continuous photocatalytic synthesis
of TETD with O2 as the oxidant.
Fig. 3 (a) Effect of pressure on the yield of TETD with EtOH as the
solvent; (b) effect of residence time on the yield of TETD with EtOH as
the solvent; (c) effect of residence time on the yield of TETD with MeOH
as the solvent.
Fig. 2 Microreactor system for the continuous synthesis of thiuram
disulfides.
With the flow system established, we first probed the
pressure effect on the yield using ethanol as a green solvent.
Fig. 3a shows that higher pressure led to improved TETD yield.
A complete conversion could be achieved when the pressure
was set to 0.5 MPa. Notably, solid precipitation was observed if
the solution resided for a prolonged period of time in the
microchannel at higher pressure. Therefore, 0.5 MPa was
selected as the optimal pressure to avoid clogging.
The influence of residence time (tR) was investigated next and
was adjusted by changing the flow rates of the liquid and gas
phases (Fig. 3b). A varying degree of pulse was observed at low
flow rates due to the relatively large cavity volume of the adjusta-
ble, stainless steel BPR (approximately 3 mL, Fig. 4a), which
increased the difficulty of precisely controlling the residence
time of the gas–liquid segments. Thus, a BPR (manufactured by
IDEX, Fig. 4b) with a small cavity volume (approximately 0.1 mL)
was adopted. We monitored the time required for the pulsed
gas–liquid segmented flow to reach the steady state, and found
that the pulse effect diminished with an increasing flow rate.
Fig. 3b shows the HPLC yields of TETD with ethanol as the
solvent under different residence times. The yield increased with
the residence time, which was prolonged not by reducing the
flow rate, but by increasing the length of the microchannel
Fig. 4 Schematics of the experimental setup for the continuous pro-
duction of TETD: (a) adjustable back-pressure regulator (BRP); (b) micro
BPR with fixed-pressure (75 psi); (c) gas–liquid segmented flow under
visible-light irradiation.
pattern (Fig. 4c). The reaction could be completed with a tR of
25 min, which was significantly shortened compared to that of
the batch reaction (3.5 h). The chromatographic yield reached
100%, and the TETD product was isolated in 94% yield. Next, we
evaluated the potential for scale-up and obtained 11.24 g of
Fig. 5 TETD crystals produced by flow synthesis (left) and powders pro-
under a constant flow rate to maintain a workable Taylor flow duced by conventional batch synthesis (right).
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TETD with an isolated yield of 96%. Gratifyingly, crystalline
Next, we turned our attention to another commonly-used
TETD could be readily isolated by simply evaporating the solvent in industry, methanol. The advantages of using metha-
solvent, probably due to the absence of the unreacted starting nol include lower cost and energy-efficient post-production re-
material and superstoichiometric amount of the oxidant. In con- cycling due to its low boiling point. The applicability of metha-
trast, most commercial TETD products manufactured by conven- nol was explored under the same conditions as ethanol. Fig. 3c
tional processes are in powder form (Fig. 5).
shows the HPLC yields of TETD with methanol as the solvent
Table 2 The scope of the photocatalytic synthesis of thiuram disulfides
Entry
1
Substrate
Product
Isolated yield (%)
94a, 90b
1a
2a
2
3
1b
1c
2b
2c
53c, 43d
64a, 69b
4
5
1d
1e
2d
2e
60a, 72b
39a, 46b
6
7
8
1f
2f
66b, 76e
64e, 34f
61e, 52f
1g
1h
2g
2h
9
1i
1j
2i
2j
12a, 15b
9a, 21b
10
a Unless otherwise indicated, the reaction conditions were as follows: photo-flow microreactor, molar ratio of 1 : CS2 : Eosin Y = 1 : 1.1 : 0.002,
pressure = 0.5 MPa, residence time = 25 min, 13 W green LED light, oxygen, EtOH (as the default solvent). b Residence time = 20 min, MeOH as
solvent. c Residence time = 5 min. d Residence time = 6.5 min, MeOH as solvent. e Batch, pressure = 0.1 MPa, reaction time = 3.5 h. f Batch,
pressure = 0.1 MPa, reaction time = 3.5 h, MeOH as solvent.
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with different residence times. When tR was set to 20 min, the
chromatographic yield was the maximal (100%), greater than
that with ethanol. In other words, methanol ensures a shorter
reaction time than ethanol with the same level of yield.
However, the yield started to decrease with longer residence
times, which was probably attributed to the observed clogging
of the microchannel by the product at low flow rates.
With the success of the flow synthesis of TETD, we
attempted to test the scope of this method (Table 2). The same
experimental conditions as that for TETD were employed to
prepare other thiuram disulfides in flow. It is worth mention-
ing that the low solubility of tetramethylthiuram disulfide (2b)
in both methanol and ethanol resulted in a gradual deposition
of the solid product inside the microchannel which eventually
led to a total blockage. Therefore, we had to increase the flow
rate to flush out the deposited solid, at the cost of lower yield
due to reduced residence time. When methanol was used as
the solvent, the isolated yield reached up to 43% with a *tR of
6.5 min (see the ESI†). When ethanol was used, a slightly
higher yield of 53% could be achieved with a tR of 5 min. The
corresponding products were obtained in good yields as
n-propyl and n-butyl analogs (2c and 2d). Diisobutylamine was
treated with CS2 to give 2e in moderate yields both in ethanol
and methanol. For 2f–2h, it is noteworthy that they are much
less soluble than other thiuram disulfides, and exhibit high
viscosity in the crude form, which made them unsuitable for
the flow reactor. A microreactor with a larger diameter might
be helpful, but is unlikely to completely solve the clogging
problem due to the extra low solubility of 2f–2h in most
organic solvents. Instead, we carried out the photocatalytic
synthesis in batch mode. To our delight, the isolated yields
were satisfactory with a reaction time of 3.5 h (entries 6–8). It
was later found that dipentamethylenethiuram disulfide (2f)
has higher solubility in methanol, and therefore the flow reac-
tion was also performed with an isolated yield of 66%. In con-
trast, 2i and 2j were obtained in poor isolated yields as aro-
matic secondary amines are less reactive. The melting ranges
of the isolated TETD, TMTD and TBzTD were 66–68 °C,
142–144 °C and 98–100 °C, respectively, which were identical
to those of commercial samples manufactured by the conven-
tional process in the rubber industry. NMR, FT-IR and MS ana-
lyses also indicated that they were identical to the commercial
products (see the ESI†).
Scheme 3 A plausible mechanism for the aerobic photocatalytic syn-
thesis of thiuram disulfide.
Diphenylisobenzofuran (DPBF), a singlet oxygen trapping
1
agent, can react with O2 to form the corresponding endoper-
oxide (DPBF-EP) and eventually o-benzoylbenzophenone
(Scheme 4). The UV-Vis spectra of a mixture of Eosin Y and
DPBF under irradiation by a green LED light displayed a sharp
decrease in the absorption intensity at around 409 nm (Fig. 6).
These results suggested that 1O2 was involved as the reactive
oxidative species in the reaction.
Scheme 4 The singlet oxygen trapping reaction of DPBF.
A plausible mechanism of this photocatalytic transform-
ation is proposed in Scheme 3. Firstly, diethylamine and
carbon disulfide undergo an addition reaction to form diethyl-
dithiocarbamic acid in situ. Exposure of Eosin Y (EY) to visible-
light promotes EY to its excited state (EY*). Subsequently, di-
ethyldithiocarbamic acid loses an electron to generate a thiyl
radical via proton-coupled electron-transfer (PCET). Then,
single-electron oxidation of [Eosin Y]− by O2 forms the super-
oxide radical (O2)− and closes the photoredox cycle. Finally,
the thiyl radical reacts with the diethyldithiocarbamate anion
to give the desired thiuram disulfide product.
Fig. 6 UV-Vis spectra of the reaction mixture with
between readings (the characteristic absorption of DPBF is at 409 nm).
Reaction conditions: Batch, molar ratio of DPBF : Eosin Y = 1 : 1, O2
1 h intervals
Additional experiments were carried out to verify the possi-
bility of singlet oxygen in this photochemical process.41,42 1,3- pressure = 0.1 MPa, green LED light, and EtOH as solvent.
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The authors received research funding from Hebi Uhoo New
Materials Co., Ltd for this study. Hebi Uhoo New Materials
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