MoS₂-Catalyzed Aerobic Synthesis of Tetraethylthiuram Disulfide in Batch and Continuous Flow

Abstract:

Tetraethylthiuram disulfide (TETD) is one of the most important thiuram-class rubber vulcanization accelerators and a ‘star molecule’ in other areas. The development of a mild, efficient, low-cost, safe, and sustainable approach to produce TETD is extremely desirable. Here, we developed a much-improved route to synthesize TETD using MoS₂ as the catalyst and ethanol as the solvent. A packed-bed microflow strategy was implemented to accelerate the catalytic process. TETD was obtained with an excellent yield and purity within a short residence time. Besides, this continuous process did not generate any waste salts, rendering it a sustainable method for producing thiuram-type compounds.

Tetraethylthiuram disulfide (TETD) is an important fine chemical in rubber industry.[1] As a highly efficient rubber vulcanization accelerator, it reduces both the amount of vulcanization agent and temperature. TETD is regarded as a ‘star molecule’ since it is also well-known for overcoming alcoholism and cocaine withdrawal treatment.[2] [3] [4] Recent medical studies showed that TETD also has promising antitumor activities.[5] In general, the traditional synthesis of TETD mainly involves the reaction between carbon disulfide and diethylamine with hydrogen peroxide as the oxidant along with superstoichiometric strong acids and bases.[6] The conventional process has been applied in industry for decades. However, the synthetic steps are strongly exothermic that causes safety risks, and the sewage treatment is cost-ineffective due to its richness in Na₂SO₄ and NaCl.[7] Synthesizing disulfide products with continuous-flow technology is regarded a potentially efficient, green, and safe strategy, with only a few reported examples.[8] [9] Some of these works can be utilized as excellent protocols in drug synthesis, e.g., the Noel lab demonstrated that oxytocin could be obtained in good yield via photocatalysis in continuous flow.[8] Luo and co-workers developed a green synthesis of thiuram disulfides using a microfluidic electrolysis reactor.[10] Our lab reported that TETD and other thiuram disulfides could be prepared in high yields by aerobic oxidation in flow, with eosin Y as an inexpensive, nontoxic photocatalyst.[11] Nevertheless, as the photocatalyst, most organic dyes tend to form a homogeneous solution, which resulted in the inconvenience in purification and low-quality, stained product. These problems urged us to seek an immobilized catalyst in the flow regime, to ensure catalytic efficiency while improve the above problems (Scheme [1]).

Transition-metal disulfide (TMD) has attracted increasing attention owing to its unique photoelectric and catalytic properties.[12] [13] [14] [15] Molybdenum disulfide (MoS₂) is often used as a prominent nanomaterial, as its inherent semiconductor character makes it a highly potent material in electronic devices, optoelectronics, sensing, and energy storage.[15] MoS₂ nanosheets have randomly distributed sulfur vacancies, which can serve as catalytic active sites,[16] [17] [18] e.g., hydrogen evolution reaction (HER), with several works focusing on the interface sites regulation of MoS₂ to improve its catalytic hydrogen evolution performance.[19] Furthermore, CO₂ can undergo a highly efficient low-temperature hydrogenation to yield CH₃OH at the sulfur vacancies on the MoS₂ nanosheets. Also, recent reports had demonstrated that thiol can functionalize MoS₂ and meanwhile be converted into disulfide.[20] [21] [22] [23] Inspired by these examples, we were intrigued to explore whether MoS₂ can be used to facilitate the synthesis of TETD, whose formation is essentially the construction of disulfide bond. Based on previous studies of the thiol/ MoS₂ interaction as well as the catalytic properties of MoS₂, we investigated the role of MoS₂ in TETD synthesis and demonstrated that MoS₂ can serve as a low-cost, recyclable and green catalyst to achieve efficient continuous-flow synthesis of TETD under mild conditions.

To begin, a set of pilot reactions were carried out, motioned by HPLC. Based on our previous exploration on the synthetic conditions of TETD and the increasing need of eco-friendly solvents and oxidants, we selected ethanol as the solvent and molecular oxygen as the oxidant. Because MoS₂ has unique physical characteristics in photoluminescence and light absorption,[24] [25] we first tried to prepare TETD under white LED light. Carbon disulfide (1.2 equiv), diethylamine (1.0 equiv), triethylamine (1.0 equiv), and MoS₂ (0.125 equiv) were added to ethanol, and the mixture was stirred in the oxygen atmosphere (1 atm) under white LED light for 14 h at room temperature. The formation of TETD was confirmed by HPLC at a wavenumber of 254 nm, and the chromatographic yield was calibrated with styrene as an internal standard. To our delight, TETD was formed with a yield of 87% (Table [1], entry 1). In order to verify the necessity of photocatalysis, we set up a control experiment in dark with the rest of conditions same as above. Interestingly, the control experiment afforded an even higher chromatographic yield of 98% (Figure [1a] and entry 2). It seemed that the reaction was not facilitated in the present of a light source, thus MoS₂ was less likely to function as a photocatalyst in this process. The interaction between MoS₂ and thiol is known to be an anaerobic oxidation process, but the mechanism is still unclear.[22] Then, the oxidant reaction was attempted under Ar atmosphere, with a lower yield of 51% (Table [1], entry 4). Another control reaction was performed in the absence of MoS₂, however, no TETD was detected by HPLC (entry 3). Compared with the initial reaction under O₂ atmosphere in the present of MoS₂, we realized that MoS₂ was crucial to facilitate the reaction, and oxygen also played a key role in enhancing the degree of oxidation.

Next, our attention turned towards the investigation of other reaction parameters. We first explored the influences of solvent. Common organic solvents that could fully dissolve the reactants and product were screened at room temperature, including acetonitrile, acetone, dichloromethane, and ethyl acetate. Acetonitrile and EtOAc gave slightly lower yields of 65% and 56% (Table [2], entries 1 and 2), compared to EtOH. Dichloromethane afforded the lowest yield of TETD of 23%, accompanied by the detection of a major side peak (Figure [1b] and entry 4). The outcome with acetone (entry 3) was similar to that of dichloromethane. Therefore, ethanol seemed to be the most suitable solvent.

With the establishment of ethanol as the optimal solvent, the effect of reaction time on the yield was next examined. We tested a series of reactions run for 6, 10, 14 and 18 h (Table [2], entries 5–8). The yield increased steadily with the extension of the reaction time. After being run for 14 h, the conversion was almost quantitative and the yield of TETD reached the maximum. It was also worth mentioning the necessity of base, whose absence led to diminished yields. The base (trimethylamine in this reaction) could be responsible of deprotonating the reaction intermediate (diethylcarbamodithioic acid) and had a pronounced effect on the reaction rate, presumably via a proton-coupled electron-transfer (PCET) mechanism. In addition, we also examined the reaction under the air atmosphere, in which 34% yield of the target molecule was achieved (entry 9). This implied that the partial pressure of O₂ was also a decisive factor.

In order to enhance the reaction safety and the gas–liquid mass transfer, we next focused on implementing this reaction in a microflow system, with a packed-bed reactor that can facilely accommodate heterogeneous catalysts.[26] The use of a packed-bed reactor is an effective means to address the above-mentioned concerns, in which the reactants passed through the catalyst bed with a higher local catalyst-to-substrate ratio in comparison with the batch mode.[27] In this regard, several recent works have reported the advantages of packed-bed microreactors in enhancing oxidation reactions.[26] [28] For example, it was found that TiO₂ was excited by visible light with the assistance of triethylamine, which enabled the selective aerobic oxidation of sulfides to sulfoxides.[29]

In our work, MoS₂ was loaded into a stainless steel packed-bed reactor. Molecular oxygen was introduced into the reactor via a mass-flow controller (MFC) and mixed with the solution-phase reactants introduced by a plunger pump at a T-mixer. An intermittent flow with a gas–liquid volume ratio of 2:1 was formed and flowed into packed-bed microreactor (4.6 × 150 mm) filled with MoS₂ (Figure [2]). The reaction mixture resided in the microflow reactor for only 20–25 min and flowed to the collection tank through a backpressure regulator (40 psi). The upstream pressure of the reactor system was controlled at approximately 0.6 MPa. TETD was synthesized and isolated in multigram scale and purified by simple recrystallization with a yield of 88%. Above all, the packed-bed microreactor significantly accelerates the reaction, by shortening the reaction time from 14 h in batch to less than half an hour in flow. In comparison with the homogeneously catalyzed photosynthesis of TETD reported by our lab,[11] MoS₂ was much easier to be separated and recovered. The flow reaction was run for 13 h and with a steady output of TETD with >90% yield over the entire process.

Although this study is synthesis-oriented, plausible mechanisms of the reaction have been investigated. Because of the potential dual roles of MoS₂, two possible pathways were proposed. Path A is a plausible reaction pathway under anaerobic conditions, with a HER mechanism. Carbon disulfide and diethylamine undergo an addition reaction which forms diethylcarbamodithioic acid as the intermediate. The intermediate donates an H atom to the surface of MoS₂ to generate the corresponding thiyl radical and the hydrogenated H[MoS₂]. Two thiyl radicals subsequently dimerizes to yield TETD, and H[MoS₂] releases H₂ to regenerate MoS₂ (Scheme [2], path A). On the other hand, how does molecular oxygen accelerate the oxidation reaction in the absence of light? A general aerobic oxidation mechanism was proposed with MoS₂ being a single-electron transfer (SET) catalyst (Scheme [2], path B) with molecular oxygen as the stoichiometric oxidant. To our curiosity, we tried to verify whether the reaction produced reactive oxygen species (ROS) using 1,3-diphenylisobenzofuran (DPBF) as the fluorescent probe.[30] Upon capturing the ROS, DPBF was transformed into the corresponding endoxide intermediate (DPBF-EP) and subsequently converted into 1,2-dibenzoylbenzene (DBB). The optimal UV absorption wavenumber of DPBF is 410 nm in ethanol. The UV/Vis absorbance of DFBF decreased sharply from 0.40030 (before the reaction) to –0.1439 (after the reaction) at 410 nm. Nevertheless, DFBF is not a specific fluorescent probe, since it can capture multiple ROS such as ¹O₂, O₂ ^–•, ^•OH, etc. Wang and co-workers reported that simple aeration with MoS₂ can turn oxygen to superoxide anion radicals.[31] It is reasonable to believe that in path B the direct reduction product of O₂ is the superoxide anion radical, although more mechanistic details are being investigated in our lab.

In conclusion, we have demonstrated a highly sustainable and efficient aerobic oxidation for preparing tetraethylthiuram disulfide, utilizing MoS₂ as a recyclable catalyst and ethanol as a green solvent.[32] The use of a packed-bed microflow reactor further enhance the efficiency, with which the reaction time was shortened from 14 h to less than half an hour. In addition, this process produced much less organic and inorganic wastes than previous methods, which helped reduce the energy consumption and cost of wastewater treatment. In contrast to the traditional methods, this strategy has a promising potential for developing an economically and environmentally friendly route to prepare tetraethylthiuram disulfide. This work also breaks through the application limitation of MoS₂, which finds its extended usage as an efficient catalyst for aerobic oxidation.

Conflict of Interest

Nanjing University have filed a patent for the MoS2-Catalyzed Aerobic Synthesis of Tetraethylthiuram Disulfide (Application# CN 202211125886.3).

• References and Notes

• 1 Gradwell MH. S, Grooff D. J. Appl. Polym. Sci. 2002; 83: 1119
  CrossrefSearch in Google Scholar
• 2 Brewer C. Alcohol and Alcoholism 1993; 28: 383
  PubMedSearch in Google Scholar
• 3 Grabar DG, McCrone WC. Anal. Chem. 2002; 22: 620
  CrossrefSearch in Google Scholar
• 4 Obholzer AM. Br. J. Addict. Alcohol Other Drugs 1974; 69: 19
  CrossrefPubMedSearch in Google Scholar
• 5 Chen D, Cui QC, Yang H, Dou QP. Cancer Res. 2006; 66: 10425
  CrossrefPubMedSearch in Google Scholar
• 6 Yao X, Zeng C, Wang C, Zhang L. Korean J. Chem. Eng. 2011; 28: 723
  CrossrefSearch in Google Scholar
• 7 Hu J, Wang K, Deng J, Luo G. Ind. Eng. Chem. Res. 2018; 57: 16572
  CrossrefSearch in Google Scholar
• 8 Bottecchia C, Erdmann N, Tijssen PM, Milroy LG, Brunsveld L, Hessel V, Noël T. ChemSusChem 2016; 9: 1781
  CrossrefPubMedSearch in Google Scholar
• 9 Talla A, Driessen B, Straathof NJ. W, Milroy L.-G, Brunsveld L, Hessel V, Noël T. Adv. Synth. Catal. 2015; 357: 2180
  CrossrefSearch in Google Scholar
• 10 Zheng S, Wang K, Luo G. Green Chem. 2021; 23: 582
  CrossrefSearch in Google Scholar
• 11 Xu H.-X, Zhao Z.-R, Patehebieke Y, Chen Q.-Q, Fu S.-G, Chang S.-J, Zhang X.-X, Zhang Z.-L, Wang X. Green Chem. 2021; 23: 1280
  CrossrefSearch in Google Scholar
• 12 Chen Y, Tan C, Zhang H, Wang L. Chem. Soc. Rev. 2015; 44: 2681
  CrossrefPubMedSearch in Google Scholar
• 13 Chhowalla M, Shin HS, Eda G, Li LJ, Loh KP, Zhang H. Nat. Chem. 2013; 5: 263
  CrossrefPubMedSearch in Google Scholar
• 14 Eda G, Yamaguchi H, Voiry D, Fujita T, Chen M, Chhowalla M. Nano Lett. 2011; 11: 5111
  CrossrefPubMedSearch in Google Scholar
• 15 Radisavljevic B, Radenovic A, Brivio J, Giacometti V, Kis A. Nat. Nanotechnol. 2011; 6: 147
  CrossrefPubMedSearch in Google Scholar
• 16 Benck JD, Hellstern TR, Kibsgaard J, Chakthranont P, Jaramillo TF. ACS Catal. 2014; 4: 3957
  CrossrefSearch in Google Scholar
• 17 Jaramillo TF, Jorgensen KP, Bonde J, Nielsen JH, Horch S, Chorkendorff I. Science 2007; 317: 100
  CrossrefPubMedSearch in Google Scholar
• 18 Li Y, Wang H, Xie L, Liang Y, Hong G, Dai H. J. Am. Chem. Soc. 2011; 133: 7296
  CrossrefPubMedSearch in Google Scholar
• 19 Zhu J, Wang ZC, Dai H, Wang Q, Yang R, Yu H, Liao M, Zhang J, Chen W, Wei Z, Li N, Du L, Shi D, Wang W, Zhang L, Jiang Y, Zhang G. Nat. Commun. 2019; 10: 1348
  CrossrefPubMedSearch in Google Scholar
• 20 Hu J, Yu L, Deng J, Wang Y, Cheng K, Ma C, Zhang Q, Wen W, Yu S, Pan Y, Yang J, Ma H, Qi F, Wang Y, Zheng Y, Chen M, Huang R, Zhang S, Zhao Z, Mao J, Meng X, Ji Q, Hou G, Han X, Bao X, Wang Y, Deng D. Nat. Catal. 2021; 4: 242
  CrossrefSearch in Google Scholar
• 21 Chen X, Berner NC, Backes C, Duesberg GS, McDonald AR. Angew. Chem. Int. Ed. 2016; 55: 5803
  CrossrefPubMedSearch in Google Scholar
• 22 Chen X, McGlynn C, McDonald AR. Chem. Mater. 2018; 30: 6978
  CrossrefSearch in Google Scholar
• 23 Li Q, Zhao Y, Ling C, Yuan S, Chen Q, Wang J. Angew. Chem. Int. Ed. 2017; 56: 10501
  CrossrefPubMedSearch in Google Scholar
• 24 Bahauddin SM, Robatjazi H, Thomann I. ACS Photonics 2016; 3: 853
  CrossrefSearch in Google Scholar
• 25 Li D, Li J, Han C, Zhao X, Chu H, Lei W, Liu X. Nano. 2016; 11: 1650114
  CrossrefSearch in Google Scholar
• 26 Thomson CG, Lee AL, Vilela F. Beilstein J. Org. Chem. 2020; 16: 1495
  CrossrefPubMedSearch in Google Scholar
• 27 Wang X. Nat. Catal. 2019; 2: 98
  Search in Google Scholar
• 28 Kong CJ, Fisher D, Desai BK, Yang Y, Ahmad S, Belecki K, Gupton BF. Bioorg. Med. Chem. 2017; 25: 6203
  CrossrefPubMedSearch in Google Scholar
• 29 Lang X, Hao W, Leow WR, Li S, Zhao J, Chen X. Chem. Sci. 2015; 6: 5000
  CrossrefPubMedSearch in Google Scholar
• 30 Zamojc K, Zdrowowicz M, Rudnicki-Velasquez PB, Krzyminski K, Zaborowski B, Niedzialkowski P, Jacewicz D, Chmurzynski L. Free Radic. Res. 2017; 51: 38
  CrossrefPubMedSearch in Google Scholar
• 31 Yu T, Wu W, Zhang J, Gao C, Yang T, Wang X. Res. Chem. Intermed. 2021; 47: 4763
  CrossrefSearch in Google Scholar
• 32 General Procedure for the Synthesis of Tetraethylthiuram Disulfide in Batch Carbon disulfide (144 μL, 2.4 mmol), dimethylamine (208 μL, 2.0 mmol), triethylamine (280 μL, 2 mmol, 1 equiv.), and MoS₂ (40 mg, 0.25 mmol) were stirred in ethanol (4 mL) under O₂ atmosphere at room temperature for 14 h. The resulting mixture was added styrene (internal standard, 1.0 mmol) and centrifuged at 10000 rpm. The supernatant (100 μL) was diluted with ethanol (1.50 mL) for HPLC analysis. HPLC analyses were performed on Wufeng LC 100 system with SHISEIDO CAPCELL PAK ADME S5 column (4.6 mm I.D. × 150 mm), at a detection wavelength of 254 nm and a flow rate of 0.8 mL/min, with water (pH 3, adjusted with formic acid, as phase A) and methanol (as phase B) as the eluents. The isocratic eluents conditions were A:B = 1:9. General Procedure for the Synthesis of Tetraethylthiuram Disulfide in Continuous Flow Carbon disulfide (1.8 mL, 30 mmol), dimethylamine (2.6 mL, 25 mmol), and triethylamine (3.5 mL, 25 mmol, 1 equiv.) were mixed in ethanol (50 mL). The packed bed (4.6 × 150 mm) was filled with MoS₂ (2.17g). Molecular oxygen was introduced in the reactor with a flow rate of 2.5 sccm via mass-flow controller (MFC) and mixed with solution-phase reactant introduced with a flow rate of 0.1 mL/min by a plunger pump at a T-mixer. An intermittent flow with a gas–liquid volume ratio of 2:1 was formed and flowed into packed-bed microreactor. The reaction mixture resided in the microflow reactor for 20–25 min and flowed to the collection tank through a backpressure regulator (40 psi). The pressure of the entire reactor system was controlled at approximately 0.6 MPa. TETD was isolated and purified by recrystallization, with an isolated yield of 88% in multigram scale (product: 3.92 g). The product was analyzed by NMR spectroscopy and HRMS. ¹H NMR (400 MHz, DMSO-d ₆): δ = 1.19 (t, 6 H, J = 8.0 Hz), 1.39 (t, 6 H, J = 8.0 Hz), 3.97 (quint, 8 H, J = 8.0 Hz) ppm. ¹³C NMR (110 MHz, DMSO-d ₆): δ = 190.84, 51.51, 47.24, 13.27, 11.16 ppm. HRMS: m/z calcd for C₁₀H₂₁N₂S₄ ⁺ [M + H]⁺: 297.0583; found: 297.0579.

Corresponding Author

Publication History

Received: 25 October 2022

Accepted after revision: 16 December 2022

Accepted Manuscript online:
16 December 2022

Article published online:
13 January 2023

© 2022. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

• References and Notes

• 1 Gradwell MH. S, Grooff D. J. Appl. Polym. Sci. 2002; 83: 1119
  CrossrefSearch in Google Scholar
• 2 Brewer C. Alcohol and Alcoholism 1993; 28: 383
  PubMedSearch in Google Scholar
• 3 Grabar DG, McCrone WC. Anal. Chem. 2002; 22: 620
  CrossrefSearch in Google Scholar
• 4 Obholzer AM. Br. J. Addict. Alcohol Other Drugs 1974; 69: 19
  CrossrefPubMedSearch in Google Scholar
• 5 Chen D, Cui QC, Yang H, Dou QP. Cancer Res. 2006; 66: 10425
  CrossrefPubMedSearch in Google Scholar
• 6 Yao X, Zeng C, Wang C, Zhang L. Korean J. Chem. Eng. 2011; 28: 723
  CrossrefSearch in Google Scholar
• 7 Hu J, Wang K, Deng J, Luo G. Ind. Eng. Chem. Res. 2018; 57: 16572
  CrossrefSearch in Google Scholar
• 8 Bottecchia C, Erdmann N, Tijssen PM, Milroy LG, Brunsveld L, Hessel V, Noël T. ChemSusChem 2016; 9: 1781
  CrossrefPubMedSearch in Google Scholar
• 9 Talla A, Driessen B, Straathof NJ. W, Milroy L.-G, Brunsveld L, Hessel V, Noël T. Adv. Synth. Catal. 2015; 357: 2180
  CrossrefSearch in Google Scholar
• 10 Zheng S, Wang K, Luo G. Green Chem. 2021; 23: 582
  CrossrefSearch in Google Scholar
• 11 Xu H.-X, Zhao Z.-R, Patehebieke Y, Chen Q.-Q, Fu S.-G, Chang S.-J, Zhang X.-X, Zhang Z.-L, Wang X. Green Chem. 2021; 23: 1280
  CrossrefSearch in Google Scholar
• 12 Chen Y, Tan C, Zhang H, Wang L. Chem. Soc. Rev. 2015; 44: 2681
  CrossrefPubMedSearch in Google Scholar
• 13 Chhowalla M, Shin HS, Eda G, Li LJ, Loh KP, Zhang H. Nat. Chem. 2013; 5: 263
  CrossrefPubMedSearch in Google Scholar
• 14 Eda G, Yamaguchi H, Voiry D, Fujita T, Chen M, Chhowalla M. Nano Lett. 2011; 11: 5111
  CrossrefPubMedSearch in Google Scholar
• 15 Radisavljevic B, Radenovic A, Brivio J, Giacometti V, Kis A. Nat. Nanotechnol. 2011; 6: 147
  CrossrefPubMedSearch in Google Scholar
• 16 Benck JD, Hellstern TR, Kibsgaard J, Chakthranont P, Jaramillo TF. ACS Catal. 2014; 4: 3957
  CrossrefSearch in Google Scholar
• 17 Jaramillo TF, Jorgensen KP, Bonde J, Nielsen JH, Horch S, Chorkendorff I. Science 2007; 317: 100
  CrossrefPubMedSearch in Google Scholar
• 18 Li Y, Wang H, Xie L, Liang Y, Hong G, Dai H. J. Am. Chem. Soc. 2011; 133: 7296
  CrossrefPubMedSearch in Google Scholar
• 19 Zhu J, Wang ZC, Dai H, Wang Q, Yang R, Yu H, Liao M, Zhang J, Chen W, Wei Z, Li N, Du L, Shi D, Wang W, Zhang L, Jiang Y, Zhang G. Nat. Commun. 2019; 10: 1348
  CrossrefPubMedSearch in Google Scholar
• 20 Hu J, Yu L, Deng J, Wang Y, Cheng K, Ma C, Zhang Q, Wen W, Yu S, Pan Y, Yang J, Ma H, Qi F, Wang Y, Zheng Y, Chen M, Huang R, Zhang S, Zhao Z, Mao J, Meng X, Ji Q, Hou G, Han X, Bao X, Wang Y, Deng D. Nat. Catal. 2021; 4: 242
  CrossrefSearch in Google Scholar
• 21 Chen X, Berner NC, Backes C, Duesberg GS, McDonald AR. Angew. Chem. Int. Ed. 2016; 55: 5803
  CrossrefPubMedSearch in Google Scholar
• 22 Chen X, McGlynn C, McDonald AR. Chem. Mater. 2018; 30: 6978
  CrossrefSearch in Google Scholar
• 23 Li Q, Zhao Y, Ling C, Yuan S, Chen Q, Wang J. Angew. Chem. Int. Ed. 2017; 56: 10501
  CrossrefPubMedSearch in Google Scholar
• 24 Bahauddin SM, Robatjazi H, Thomann I. ACS Photonics 2016; 3: 853
  CrossrefSearch in Google Scholar
• 25 Li D, Li J, Han C, Zhao X, Chu H, Lei W, Liu X. Nano. 2016; 11: 1650114
  CrossrefSearch in Google Scholar
• 26 Thomson CG, Lee AL, Vilela F. Beilstein J. Org. Chem. 2020; 16: 1495
  CrossrefPubMedSearch in Google Scholar
• 27 Wang X. Nat. Catal. 2019; 2: 98
  Search in Google Scholar
• 28 Kong CJ, Fisher D, Desai BK, Yang Y, Ahmad S, Belecki K, Gupton BF. Bioorg. Med. Chem. 2017; 25: 6203
  CrossrefPubMedSearch in Google Scholar
• 29 Lang X, Hao W, Leow WR, Li S, Zhao J, Chen X. Chem. Sci. 2015; 6: 5000
  CrossrefPubMedSearch in Google Scholar
• 30 Zamojc K, Zdrowowicz M, Rudnicki-Velasquez PB, Krzyminski K, Zaborowski B, Niedzialkowski P, Jacewicz D, Chmurzynski L. Free Radic. Res. 2017; 51: 38
  CrossrefPubMedSearch in Google Scholar
• 31 Yu T, Wu W, Zhang J, Gao C, Yang T, Wang X. Res. Chem. Intermed. 2021; 47: 4763
  CrossrefSearch in Google Scholar
• 32 General Procedure for the Synthesis of Tetraethylthiuram Disulfide in Batch Carbon disulfide (144 μL, 2.4 mmol), dimethylamine (208 μL, 2.0 mmol), triethylamine (280 μL, 2 mmol, 1 equiv.), and MoS₂ (40 mg, 0.25 mmol) were stirred in ethanol (4 mL) under O₂ atmosphere at room temperature for 14 h. The resulting mixture was added styrene (internal standard, 1.0 mmol) and centrifuged at 10000 rpm. The supernatant (100 μL) was diluted with ethanol (1.50 mL) for HPLC analysis. HPLC analyses were performed on Wufeng LC 100 system with SHISEIDO CAPCELL PAK ADME S5 column (4.6 mm I.D. × 150 mm), at a detection wavelength of 254 nm and a flow rate of 0.8 mL/min, with water (pH 3, adjusted with formic acid, as phase A) and methanol (as phase B) as the eluents. The isocratic eluents conditions were A:B = 1:9. General Procedure for the Synthesis of Tetraethylthiuram Disulfide in Continuous Flow Carbon disulfide (1.8 mL, 30 mmol), dimethylamine (2.6 mL, 25 mmol), and triethylamine (3.5 mL, 25 mmol, 1 equiv.) were mixed in ethanol (50 mL). The packed bed (4.6 × 150 mm) was filled with MoS₂ (2.17g). Molecular oxygen was introduced in the reactor with a flow rate of 2.5 sccm via mass-flow controller (MFC) and mixed with solution-phase reactant introduced with a flow rate of 0.1 mL/min by a plunger pump at a T-mixer. An intermittent flow with a gas–liquid volume ratio of 2:1 was formed and flowed into packed-bed microreactor. The reaction mixture resided in the microflow reactor for 20–25 min and flowed to the collection tank through a backpressure regulator (40 psi). The pressure of the entire reactor system was controlled at approximately 0.6 MPa. TETD was isolated and purified by recrystallization, with an isolated yield of 88% in multigram scale (product: 3.92 g). The product was analyzed by NMR spectroscopy and HRMS. ¹H NMR (400 MHz, DMSO-d ₆): δ = 1.19 (t, 6 H, J = 8.0 Hz), 1.39 (t, 6 H, J = 8.0 Hz), 3.97 (quint, 8 H, J = 8.0 Hz) ppm. ¹³C NMR (110 MHz, DMSO-d ₆): δ = 190.84, 51.51, 47.24, 13.27, 11.16 ppm. HRMS: m/z calcd for C₁₀H₂₁N₂S₄ ⁺ [M + H]⁺: 297.0583; found: 297.0579.

• Supplementary Material