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. 2020 Sep 10;5(37):23736–23742. doi: 10.1021/acsomega.0c02707

Reaction Pathway and Selectivity Control of Tetraethyl Thiuram Disulfide Synthesis with NaHCO3 as a pH Regulator

JiaYu Hu 1, Jiaxin Tian 1, Kai Wang 1, Jian Deng 1, Guangsheng Luo 1,*
PMCID: PMC7513355  PMID: 32984692

Abstract

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The selectivity of a chemical reaction is related to the effective utilization of raw materials as well as the cleanliness and economy of the process. Herein, it has been first proposed to synthesize tetraethyl thiuram disulfide (TETD) with sodium bicarbonate as the pH regulator with a reaction selectivity of ∼100%. The existence of a reaction intermediate, a sodium salt of diethyl dithiocarbamoylsulfenic acid (NaEt2DTCS), has been proved by experiments and theoretical calculations. The results indicate that TETD can not only be generated from NaEt2DTCS oxidized by H2O2 directly, but also from the conjugation of NaEt2DTC and NaEt2DTCS generated in the first stage of oxidation meanwhile. Accordingly, an oxidation reaction pathway has been proposed. The reaction selectivity with NaHCO3 or CO2 as the pH regulator has been compared, and the selectivity control mechanism is discussed. At relatively higher pH values with NaHCO3 as the pH regulator, peroxidation could be almost avoided.

Introduction

Tetraethyl thiuram disulfides (TETDs), one of the important rubber vulcanization accelerators,1 can also be applied to prevent fungal diseases2 and treat alcoholism.3 In some studies, it has been used to synthesize diethyldithiocarbamates based on the instability of the disulfide bond, phosphorothioate oligonucleotides, and tetraethyl thiuram monosulfides,4−7 and in recent years, it was found that TETD could act as an irreversible monoglyceride lipase (MGL) inhibitor to regulate the endocannabinoid system (ECS), which could hold therapeutic promise, for instance, in growth inhibition of prostate and breast cancer cells.8,9

The yield of TETD and the reaction selectivity must be well considered because these parameters are strongly related to the effective utilization of raw materials, emission of waste water, and economy of the process. The traditional TETD synthesis method, including adding a mixed solution of sulfuric acid and hydrogen peroxide to neutralize and oxidize NaEt2DTC, cannot avoid side reactions very well, like the peroxidation of raw materials.10 The high salinity and chemical oxygen demand (COD) value wastewater problem of its production remains very serious. Generally, the yield of TETD in the traditional synthesis process is around 90%,11,12 while the reaction selectivity was not taken into consideration. In order to further improve the yield to ∼100%, which means the reaction selectivity also reaches ∼100%, researchers have tried some methods. For example, changing the reaction condition from an aqueous solution to an organic solution, which requires solvent recovery rectification;13 using electrochemical synthesis method, which is hard to be put into production because of complex equipment, a slow reaction rate, and a complex subsequent product extraction process;10 and trying catalytic oxygen oxidation catalyzed by metallophthalocyanines or reduced graphene oxide, which takes more than 10 h of reaction time and has safety concerns because of the introduction of oxygen.2,14 Most of these methods give high yield and high reaction selectivity, meanwhile sacrificing efficiency. Improvement of the yield and selectivity in a more effective and economic way still requires more efforts.

The reaction pathway of this oxidation reaction could mainly determine the reaction selectivity, while only a few results about the side reactions of this oxidation process are reported until now. For example, TETD could be hydrolyzed in an alkaline environment,15 and its hydrolysis products have been detected before.16,17 The peroxidation of thiols and thiolates like NaEt2DTC is a common reaction in which they are oxidized into sulfenic, sulfinic, and sulfonic acids by oxidants.18−22 An intermediate, a sodium salt of diethyl dithiocarbamoylsulfenic acid (NaEt2DTCS), could be generated from the oxidation of NaEt2DTC and hydrolysis of TETD, and its subsequent reactions require to be further confirmed. Meanwhile, the instable sulfenic acid is very hard to obtain and detect directly,23 so a special substance was synthesized to stabilize it24 or some advanced detection methods were developed,21 and indirect investigation may be useful. In addition, the decomposition reaction of NaEt2DTCS to produce diethylcarbamothionic S-acid was proposed by A. Schmitt and H. Neibergall in 1988.16 The instability of diethyldithiocarbamate acid in water has also been reported before.25,26 It can decompose into carbon disulfide and diethylamine in water. The stronger the acidity of the solution is, the faster the decomposition rate of the substance will be.27 However, so far, few researchers have systematically summarized to give a reaction network.

In a word, one can find that the reaction selectivity needs to be further improved and the reaction process has not been studied systematically enough, and also the reaction selectivity control method needs to be further developed. Hence, in this study, we report a new method with NaHCO3 as a pH regulator to synthesize TETD to improve the reaction selectivity. When the pH value of the reaction process ranges from 8 to 9.5, the selectivity could be around 100%, which is much higher than that using CO2 as an acidifier.28 By deeply investigating the reaction process, we propose a reaction network to discuss the possible mechanism of reaction selectivity control.

Results and Discussion

Results of the New Reaction Process with NaHCO3 as the pH Regulator

When sodium bicarbonate (the molar ratio of NaHCO3 to NaEt2DTC is 2:1) was added to the NaEt2DTC solution, the pH value of the solution immediately dropped from ∼10.3 to ∼8.2. Figure 1 shows the change in pH value during the reaction process. With the titration of H2O2, it increased gradually to ∼9.5. Meanwhile, a white solid product of TETD was generated in the reaction process. Without NaHCO3 addition, the pH value would only increase from ∼10.3 to more than 11.3 as shown in Figure S2 of Supporting Information.

Figure 1.

Figure 1

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pH Value change during H2O2 titration with NaHCO3 as the pH regulator

(H2O2: 0.58 mol/L, 1 mL/min, excess 10%; NaHCO3 dosage: 200%, 25 °C, 600 r/min).

Then the influences of different dosages of NaHCO3 and H2O2 on the reaction were investigated, and the results are shown in Table 1. When the dosage of NaHCO3 was increased, both the yield of TETD and the reaction selectivity were improved. Because when an enough amount of NaHCO3 was added, the stronger buffer capacity of the reaction system could accelerate the reaction rate compared with less NaHCO3 addition and reduce the decomposition of hydrogen peroxide and TETD. As for the H2O2 dosage, excess 10% can improve the yield and keep selectivity at ∼100%. However, increasing the dosage further would reduce the selectivity because of potential peroxidation. It is worth mentioning that the HPLC–MS detection result (Figure S1 and Table S2 in Supporting Information) of experiment entry 4 shows that there was no peroxidation during the oxidation process.

Table 1. Yield, pH Change, and Reaction Selectivity under Different Dosages of NaHCO3 and H2O2a.

entry molar ratio of NaHCO3 to NaEt2DTC molar ratio of H2O2 to NaEt2DTC yield pH change selectivity
1 1:1b 1:2 64.24% 8.21–10.28  
2 1.5:1c 1:2 74.60% 8.15–9.32 90.50%
3 2:1c 1:2 81.52% 8.33–9.42 ∼100%
4 2:1c 1.1:2 89.98% 8.11–9.45 ∼100%
5 2:1c 1.2:2 80.75% 8.12–9.47 89.73%
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a

Conditions: 0.58 mol/L of H2O2, titration speed:1 mL/min, 25 °C, 600 r/min.

b

0.60 mol/L of sodium diethyl dithiocarbamate, aging time: 1 h.

c

0.30 mol/L of sodium diethyl dithiocarbamate, aging time: 10 h.

Aging time after H2O2 titration is another important influencing factor in the reaction, and we investigated it by UV–vis detection every 30 min. As shown in Figure 2, except for the absorption peak at 257 and 282 nm, a new peak appeared at 326 nm. The absorbance value at 326 nm decreased with the increase in aging time. The ratio of the absorbance value at 257 nm to that at 282 nm decreased gradually to ∼1.03 (Table 2), which got closer to the ratio of the absorbance value at 257 nm to that at 282 nm of NaEt2DTC. As we mentioned the new absorbance peak and the ratio before,29 an intermediate appeared during oxidation which would transfer into other substance gradually as the reaction progressed, which will be discussed in more detail later. As the absorbance value at 326 nm became low and the ratio of the absorbance value at 257 nm to that at 282 nm became close to ∼1.03 after 2 h of aging, the reaction was thought to be completed. Hence, the aging time was set as 2 h.

Figure 2.

Figure 2

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UV absorbance change of solution with reaction aging time

Table 2. Change in the Ratio of the Absorbance Value at 257 nm to that at 282 nm with Aging.

aging time 30 min 60 min 90 min 120 min
ratio 1.094 1.061 1.043 1.034
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(2 wt % H2O2, 110% dosage; 200% NaHCO3 dosage; 5 wt % NaEt2DTC; 25 °C, 600 r/min).

The influence of the reaction temperature was also investigated. As shown in Table 3, when the temperature was 25 or 35 °C, the yield and the selectivity were about 89 and 100%, respectively. When it increased to 45 °C, the yield and selectivity decreased.

Table 3. Yield and Selectivity at Different Reaction temperaturesa.

temperature(°C) yield(%) selectivity(%)
25 88.26 99.84
35 89.82 100.00
45 83.57 97.62
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a

0.58 mol/L of H2O2, 110% dosage; 200% NaHCO3 dosage; 0.30 mol/L of NaEt2DTC; aging time: 2 h, 600 r/min.

Difference in Reaction Selectivity between the Two Methods

To compare with the NaHCO3 method, the CO2 method was also carried out with the same concentration of NaEt2DTC solution. The pH value of the solution was kept stable at ∼7. The yield was 93.06% and the selectivity was 96.82% with 10 minute of aging time. Compared with the NaHCO3 method, the reaction rate of the CO2 method is much faster and the yield is higher, while the selectivity is relatively lower. The organic side products of the CO2 method are sulfonates and sodium diethylcarbamothionic S-acid as detected by HPLC–MS, which are consistent with the side products of TMTD (tetramethyl thiuram disulfide) synthesis previously reported.28

Some HPLC detection results of mother liquor of the two methods are shown in Table 4 in which the content of sodium diethylcarbamothionic S-acid in the NaHCO3 method is higher than that in the CO2 method, but its actual content would be low because the mass fraction of NaEt2DTC in the mother liquor was close to the theoretical value based on the ∼90% yield and ∼ 100% reaction selectivity. Furthermore, the content of sodium diethylcarbamothionic S-acid in the CO2 method could be lower as its peak area is about one-tenth of that of the NaHCO3 method. Combining the types of detected substances in the mother liquor of these two methods, the organic byproduct, a sodium salt of sulfonic acid, is one of the main possible reasons that make the selectivity of the CO2 method lower than that of the NaHCO3 method.

Table 4. Some HPLC Detection Results of the Two Carbonization Methods.

acid reagent the product of dilution time and the peak area of sodium diethylcarbamothionic S-acid (RCOSNa) the mass fraction of NaEt2DTC in the mother liquor (wt %)
CO2a 3519.17 0.15
NaHCO3b 27629.42 ∼0.4
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a

2 wt % H2O2, 100% dosage; CO2: 60 mL/min; 5 wt % NaEt2DTC; aging time: 10 min, 600 r/min, 30 °C.

b

2 wt % H2O2, 110% dosage; 200% NaHCO3 dosage; 5 wt % NaEt2DTC; aging time: 2 h, 600 r/min, 30 °C.

Reaction Network

An Intermediate of Oxidation: NaEt2DTCS

As we found an intermediate, as seen from Figure 2 and Table 2, it is most likely NaEt2DTCS. Indirect methods were conducted to prove its existence including experiments and calculations. As the aforementioned description, the UV–vis absorption of that substance was detected, whose maximum absorption wavelengths are 261 and 326 nm (Figure 3), which is consistent with the absorption change shown in Figure 2 and a related report.30Figure S2 and Table S3 show that there are no peroxidation products, so there is no possibility of an absorption peak at 326 nm coming from the salts of sulfinic acid or sulfonic acid.

Figure 3.

Figure 3

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Calculated and experimental UV–vis absorption spectra of NaEt2DTCS.

To further determine whether the measured UV absorption graph is that of NaEt2DTCS, a related calculation was carried out.31 The main absorption peaks in the calculated results are 251 and 324 nm (Figure 3), whose difference is 10 and 3 nm from the experimental value determined separately. They are the results of transition from the ground state (S0) to different excited states (for S4, S5, S19, and S20 shown in Figure 3, refer to their structures in Figure S10). The differences may come from the different dilution solvents, water used for calculation, and NaOH solution used in the experiment (see part 8 in Supporting Information for more analysis details).

The intermediate of oxidation, NaEt2DTCS, is also one of the important substances in the whole reaction process. In addition to the related literature,18,19,22,24 its content change during oxidation (with or without pH regulator addition) was also detected using a UV–vis spectrum detector (Figure 4). The maximum concentration of NaEt2DTCS measured by the CO2 method was 0.82 wt %, which means that at least 18.63% of NaEt2DTC transferred into this substance. Similarly, at least about 27.17% of NaEt2DTC transferred into this substance in the NaHCO3 method. If part of the produced NaEt2DTCS do not transform into TETD, the yield of TETD in these methods could not reach 90% or above, which means that this substance not only transferred into a peroxidation product and sodium diethylcarbamothionic S-acid, but also transferred into TETD by reacting with NaEt2DTC with CO2 or NaHCO3 as the pH regulator (eq 1).

Figure 4.

Figure 4

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Concentration (wt %) change of NaEt2DTCS during oxidation.

graphic file with name ao0c02707_0002.jpg 1

Investigation of Reaction Mechanism

2,2,6,6-Tetramethylpiperidine-1-oxyl (TEMPO) was chosen to investigate the reaction mechanism as a radical scavenger as it can capture the sulfur radical (RS·)32,33 and often it is used to check if a reaction is a free radical reaction by excessive addition.4,34 As no white solid, TETD, appeared during oxidation and no TETD was detected by the HPLC–MS method, the oxidation to produce TETD was suggested to be a radical reaction. Meanwhile, sodium diethyldithiosulfonic acid was detected by HPLC–MS and NaEt2DTCS was detected by UV–vis (an absorption peak appeared at 326 nm) in both the CO2 and NaHCO3 methods, which means that this kind of oxidation could happen without sulfur radical generation (Figure 5).

Figure 5.

Figure 5

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Oxidation reaction diagram with 200% dosage TEMPO addition.

The related reaction mechanism has been discussed a lot while mainly in thiol chemistry for redox signaling.35,36 As NaEt2DTC has an additional apparent carbon–sulfur double bond than regular thiols, and most of them are in the form of thiolate in a neutral or weakly alkaline environment because of their low pKa value (∼ 3.6828), this substance has stronger nucleophilicity,37−39 which makes it is easier to react with H2O2.

According to the abovementioned experimental results, there could be two reaction paths to produce TETD. One is through disulfide formation by the conjugation of sulfenic acid generated in the first stage of oxidation with raw materials, and the other is from the dimerization of the sulfur radical (generated from hydroxyl radicals by taking the electrons of thiolate40).

Reaction Network

The final products of TETD hydrolysis, NaEt2DTC and sodium diethylcarbamothionic S-acid, have also been detected in our experiments (see part 9 of Supporting Information). Combining the aforementioned reactions, a relatively complete reaction pathway could be proposed (Figure 6).

Figure 6.

Figure 6

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Plausible reaction network.

Reaction Selectivity Analysis

According to the quantitative estimation based on HPLC detection, the side reaction has little effect on the loss of raw materials (see part 9 in Supporting Information). The side product, sodium diethylcarbamothionic S-acid, mainly comes from the decomposition of NaEt2DTCS produced during the oxidation process. Although raw materials could decompose, the pH value of the actual reaction environment is neutral or weakly basic, and the concentration of raw materials in thiol form (∼ 10–4 mol/L) and the decomposition rate constant27 (∼10–6 s–1) are very low that the loss of raw materials could be ignored. Thus, combined with all the quantitative analysis, the selectivity difference between the two methods is that peroxidation of NaEt2DTCS leads to lower selectivity compared to the CO2 method.

This selectivity difference can be explained by the different nucleophilicities of NaEt2DTC and NaEt2DTCS, of which the former is stronger than the latter, and different pH values of the reaction environment in the two methods. Because the existence of an oxygen-connecting sulfur atom in NaEt2DTCS drifts the electron cloud of C(S)S part of NaEt2DTC toward the CSO part of NaEt2DTCS, the nucleophilicity of the sulfur atoms are weakened. Thus, NaEt2DTC is easily oxidized. In the CO2 method, the reaction rate is comparatively fast, resulting from the lower pH value of the reaction environment, because a low pH value could accelerate the conjugation reaction between diethyldithiocarbamate acid and diethyl dithiocarbamoylsulfenic acid, which means that the content of NaEt2DTC is relatively low during oxidation and partly a larger heat release is favorable for the production of free radicals. H2O2 has a greater possibility of reacting with sulfenic acid to facilitate the peroxidation of raw materials. While the reaction rate is much slower in the NaHCO3 method compared with the CO2 method because of a relatively higher pH value of the solution environment, the content of NaEt2DTC is maintained at a relatively high level compared with the CO2 method and reaction heat is released more slowly. Hence, H2O2 is more likely to react with it than with NaEt2DTCS. Thus, peroxidation is more likely to happen in the CO2 method.

Conclusions

In this study, NaHCO3 was first proposed to synthesize TETD as a pH regulator, which achieved ∼100% reaction selectivity by adjusting the pH value of the reaction environment in the range of 8 to 9.5 and almost avoided the peroxidation of raw materials. By experiments and calculation investigation of the oxidation process, a possible reaction pathway was proposed. In particular, TETD can not only be generated from NaEt2DTC oxidized by H2O2 directly, but also from the conjugation of sulfenic acid generated in the first stage of oxidation with raw materials. The selectivity difference between the NaHCO3 method and the CO2 method was that peroxidation causes lower selectivity in the CO2 method, which was analyzed further based on the differences in nucleophilicity between NaEt2DTC and NaEt2DTCS and the pH value of the reaction environment. To achieve cleanliness of the whole TETD synthesis process further, the byproduct of oxidation, sodium carbonate, could be replaced by sodium hydroxide to synthesize NaEt2DTC, which is under research in our lab.

Experimental Section

Synthesis of TETD with NaHCO3 or CO2 as the pH Regulator

NaHCO3 was added to the NaEt2DTC aqueous solution (0.3 mol/L, 30 g) in molar ratios of 1:1, 1.5:1, and 2:1, which changed the pH value of the reaction system from ∼10.3 to ∼8.2. (The quantities of raw materials are based on the solubility of NaHCO3 in different concentrations of NaEt2DTC solution, see Table S1 in Supporting Information). Next, half equivalent of H2O2 solution (0.58 mol/L, 7.46 g) was titrated into the reaction solution at a flow rate of 1 mL/min, and a pH meter recorded the change in the pH value at the same time. After a period (1 to 10 h) of aging, the solid produced in the reaction was filtered, washed three times with 50 mL of ultrapure water, and dried at 50 °C for 4 h. The whole process was conducted at 600 r/min stirring speed. The solid product was weighed for calculating the yield. The mother liquor was collected for HPLC–MS detection. Furthermore, experiments with CO2 as the acid reagent were conducted as described in our previous work.28

Synthesis and Calculation of NaEt2DTCS

During oxidation, an intermediate, NaEt2DTCS, appeared (see 3.3.1 in the Discussion section). We prepared this substance by titrating H2O2 (0.58 mol/L, 1% molar excess, 1 mL/min) into the NaEt2DTC aqueous solution (0.3 mol/L, 30 g) and it was aged based on pre-experiments (see part 6 in Supporting Information). Then, we used it as the standard solution, whose concentration can be determined by chemical stoichiometric ratio and mass conservation, to obtain the UV–vis detection result. Its concentration–absorbance standard curve was obtained at 257 and 326 nm, which could help to determine its concentration in the mixture solution.

Theoretical calculations for UV–vis absorption of NaEt2DTC and NaEt2DTCS were performed using Gaussian 09 software package.41 The calculation details are provided in the Supporting Information.

The oxidation reaction mechanism was also studied using TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) as the sulfur radical scavenger to investigate whether the related reactions are radical reactions or not. After an almost saturated aqueous solution of TEMPO (∼ 0.05 mol/L) was obtained, its half molar amount of NaEt2DTC was added and the solution was still clear and transparent, and then CO2 was introduced or NaHCO3 (double molar amount of NaEt2DTC, with N2 introduction) was added to conduct the oxidation reaction with H2O2 as the oxidant. The reaction phenomenon was observed and the solution was detected by the HPLC–MS method.

Acknowledgments

The authors gratefully acknowledge the support from the National Natural Science Foundation of China (Nos.21991100 and 21991104).

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.0c02707.

  • Experimental materials, selectivity calculation, supplementary experiments, analytical method, standard concentration curve of NaEt2DTCS, solubility of NaHCO3 in different concentrations of NaEt2DTC solution, UV–vis absorption spectra calculation, electron–hole graphs of excited states of NaEt2DTC and NaEt2DTCS, and HPLC detection results of TETD hydrolysis (PDF)

The authors declare no competing financial interest.

Supplementary Material

ao0c02707_si_001.pdf (659.5KB, pdf)

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