Glycerol as a recyclable solvent in a microwave-assisted synthesis of disulfides

Abstract

We present here a clean and fast synthesis of organic disulfides starting from thiols using glycerol as solvent under microwave irradiation. This efficient method is general for aromatic, aliphatic, and functionalized thiols, affording the corresponding disulfides in good to excellent yields after easy work up. Glycerol can be easily recovered and utilized for further oxidation reactions.

Keywords:

• glycerol
• disulfides
• green chemistry
• microwave

1. Introduction

In organic synthesis, the choice of the solvent is a crucial step in a chemical reaction. The development of green solvents from renewable resources has gained much interest recently because of the extensive uses of solvents in almost all of the chemical industries and of the predicted disappearance of fossil oil 1–6. The wanted characteristics for a green solvent include no flammability, high availability, obtaining from renewable sources, and biodegradability 6. With the increase in biodiesel production worldwide, the market saturation of glycerol, a side product of biodiesel production, is inevitable 7. The peculiar physical and chemical properties, such as polarity, low toxicity, biodegradability, high boiling point, and ready availability from renewable feed stocks 8 prompted recently the use of glycerol 9–12 and their eutectics 13 as a green solvent in organic synthesis. Heck and Suzuki cross-couplings, ring closing metathesis of diolefins, multicomponent reactions, base- and acid-promoted condensations, catalytic hydrogenation, asymmetrical reduction, and cycloisomerization of (Z)-enynols into furans are some examples of the use of glycerol as a solvent in organic reactions 9–12.

On the other hand, thiols and disulfides are important in both biological 14–19 and chemical process 20–22 . Disulfides are useful reagents in organic synthesis 20–22 and essential moieties of biologically active compounds for peptide and protein stabilization 14–19. As disulfides are relatively more stable to organic reactions such as oxidation, alkylation, and acylation compared to the corresponding free thiols, the thiol group can conveniently be protected as a disulfide. Besides, there are a large number of commercially available thiols and the interconversion between thiols and disulfides is easy 23. These aspects are responsible for the continuous interest in development of new, selective and efficient protocols for the preparation of disulfides 20–22, 24–34. Recently reported procedures involve the use of stoichiometric amount of anhydrous potassium phosphate 24, potassium permanganate 25, molecular bromine supported on silica gel 26, N-phenyltriazolinedione 27, VO(acac)₂ 28, trichloroisocyanuric acid 29, nitric acid 30, 1,3-dibromo-5,5-dimethylhydantoin 31, basic alumina 32, CsF-Celite 33, and montmorillonite K10 34.

The development of environmentally benign and clean synthetic methods for the synthesis of disulfides, including those involving solvent-free or the use of alternative solvents, such as water and ionic liquids, has increased in recent years 27, 35–44. These methods involve the use of N-phenyltriazolinedione 27, pyridinium chlorochromate 35, 1,3-dibromo-5,5-dimethylhydantoin 36, SO₂Cl₂ 37, trichloronitromethane 38, KMnO₄/MnO₂ 39, KMnO₄ supported on montmorillonite K10 40, catalytic amount of iodine and CeCl₃·7H₂O in graphite 41, KF/Al₂O₃ 42, [bmim][SeO₂(OCH₃)] 43, and [bmim][BF₄] 44.

Despite several advantages, the solvent-free methods are restricted to systems where at least one of the reagents is liquid at room temperature, whereas the uses of ionic liquids, especially imidazolium systems with PF₆ and BF₄ anions, have some drawbacks, such as the high cost and liberation of hazardous HF during recycling 45–48. Thus, the use of alternative nonvolatile green solvents, such as glycerol, has been shown as an attractive way to cleaner synthesis of disulfides. According to our interest in the green protocols in organic chemistry (42, 43, 49–55, we describe here the use of glycerol as a green solvent in the oxidation of thiols to disulfides (Scheme 1).

Scheme 1.  General scheme of reaction.

2. Results and discussion

Firstly, we reacted benzenethiol 1a with K₂CO₃ as base, using glycerol as solvent at room temperature and under these conditions, no product was observed. When the reaction was performed at room temperature under microwave irradiation, product 2a was formed in 15% yield after 30 minutes. Encouraged for this result, we performed this oxidation reaction in microwave irradiation under different temperatures (Table 1). To our satisfaction, increasing the temperature to 120°C the reaction proceeds smoothly, furnishing the disulfide 2a in excellent yield (Table 1; entry 5) and the same result was obtained at 150°C (Table 1; entry 6).

Table 1. Optimization of oxidation reaction.^a

Entry	Temperature (°C)	Base	Yield of 2a (%)^b
1	30	K2CO3	15
2	50	K2CO3	20
3	80	K2CO3	45
4	100	K2CO3	83
5	120	K2CO3	89
6	150	K2CO3	89
7	120	Na2CO3	92
8	120	Cs2CO3	92
9	120	Na3PO4	56
10	120	K3PO4	80
11	120	KOH	86
12	120	LiOAc	70
13	120	NaOAc	69
14	120	Et3N	82
15	120	–	–
16^c	120	Na2CO3	85
^aReactions are performed in the presence of 1a (1.0 mmol), base (1.1 mmol), glycerol (1 mL) in a microwave reactor (CEM Explorer).
^bYields are given for isolated product.
^cReaction performed using conventional heating for 12 h.

We observed that the nature of the base was critical for the success of the oxidation. When the reaction was carried out with different bases such as: Na₂CO₃, Cs₂CO₃, Na₃PO₄, K₃PO₄, KOH, LiOAc, NaOAc, and Et₃N, benzenethiol 1a was successfully oxidated (Table 1; entries 7–14), and the best results were obtained using Na₂CO₃ and Cs₂CO₃ as base. Gratifyingly, the use of Na₂CO₃, an inexpensive base, resulted in the oxidation of benzenethiol 1a in 92% isolated yield (Table 1; entry 7). It is also important to mention that when the reaction was performed without base no product was obtained (Table 1; entry 15). Reaction of benzenethiol 1a with Na₂CO₃ in glycerol was performed using a conventional heating and the product 2a was isolated in a good yield, however, in a longer reaction time comparing with microwave-assisted method (Table 1; entry 7 vs. 16).

To obtain an efficient methodology in terms of energy economy, we realized a study to establish the minimum time associated with a good reaction rate under the optimized conditions (Figure 1). Analyzing Figure 1, excellent conversion of benzenethiol in diphenyl disulfide 2a was observed after 15 minutes of reaction. A further decrease in the reaction time (less than 15 minutes) was followed by a considerable reduction in the conversion rate of benzenethiol.

Figure 1.  Plot of conversion vs. time for the oxidation of benzenethiol 1a.

In an optimized reaction, benzenethiol 1a (1.0 mmol) and Na₂CO₃ (1.1 mmol) were dissolved in glycerol (1.0 mL) and reacted under microwave irradiation at 120°C for 15 minutes, yielding 2a in 92% isolated yield.

After reaction optimization, a study regarding the recovering and reusing of glycerol was performed. After the total consumption of benzenethiol 1a, the reaction mixture was diluted and extracted with a mixture of hexane/ethyl acetate 95:5 (3×3 mL). The upper phase was dried and the solvent evaporated. The inferior, glycerol phase was dried under vacuum and directly reused. We observed that the glycerol phase reused furnishing diphenyl disulfide 2a in 89%. However, after second reuse, only traces of diphenyl disulfide 2a were obtained. In view of this result, we performed the reuse studies using NaCO₃ in all runs, as shown in Table 2. It was observed that a good level of efficiency was maintained even after being reused four times. Diphenyl disulfide 2a was obtained in 92%, 92%, 90%, 89%, and 88% yields after successive cycles, however, with an increase in the reaction time after the third run.

Table 2. Reuse of glycerol.^a

Run	Time (minutes)	Yield of 2a (%)^c
1	15	92
2^b	15	92
3^b	15	90
4^b	20	89
5^b	30	88
^aReaction was performed in the presence of benzenethiol 1a (1.0 mmol), Na2CO3 (1.1 mmol), glycerol (1 ml), at 120°C in a microwave reactor.
^bRecovered glycerol was used.
^cYields are given for isolated products.

To demonstrate the generality of this method, we prepared a series of organic disulfides 2a–t using aryl, heteroaryl or alkyl thiols, Na₂CO₃, and glycerol under microwave irradiation (Table 3). In most cases, the reactions proceeded fast and smoothly to give disulfides 2a–t in good to excellent yields. A structurally diverse range of aryl thiols were oxidated to corresponding diaryl disulfides in excellent yields (Table 3; entries 1–12). Diaryl disulfides containing electron donating (EDG) (Table 3; entries 2–6) and electron withdrawing groups (EWG) (Table 3; entries 7–10) could be obtained in high yields. Both aryl thiols containing EDG and EWG have no significant influence on the reactivity of the process, because the products were obtained in comparable yields. Satisfactory yields of oxidation were achieved using 2-amino-4-chlorobenzenethiol, 2-naphthalenethiol, and 2-mercaptobenzothiazole (Table 3; entries 11–13). Good results were obtained using benzylic or furfuryl thiols yielding the corresponding disufides 2n–p in 84–87%, but in 30 minutes reaction time (Table 3, entries 14–16). Finally, when we employed alkylic thiols, the corresponding dialkyl disulfides 2q–t were synthesized in good yields (Table 3; entries 17–20).

Table 3. Scope and generality of the synthesis of disulfides 2a–t using glycerol as solvent.^a

Entry	Product (Ref.)	Yield (%)^b	Entry	Product (Ref.)	Yield (%)^b
1		92	11		85
	2a 14			2k 23
2		87	12		88
	2b 15			2l 24
3^c		87	13
	2c 16			2m 25	89
4		91	14^c		87
	2d 17			2n 17
5		92	15^c		86
	2e 18			2o 26
6		88	16^c		84
	2f 19			2p 27
7		89	17^c
	2g 17			2q 28	86
8		93	18^c		82
	2h 20			2r 29
9		92	19^c		81
	2i 21			2s 21
10^c		92	20		81
	2j 22			2t 30
^aReactions are performed in the presence of thiol (1.0 mmol), Na2CO3 (1.1 mmol), glycerol (1 mL), at 120°C in a microwave reactor for 15 minutes.
^bYields are given for isolated product.
^cReactions are performed in 30 minutes.

3. Experimental section

3.1. General remarks

Proton nuclear magnetic resonance spectra (¹H NMR) were obtained at 200 MHz on a Bruker DPX-200 NMR spectrometer. Spectra were recorded in CDCl₃ solutions. Chemical shifts are reported in parts per million, referenced to the solvent peak of CDCl₃ or tetramethylsilane (TMS) as the external reference. Data are reported as follows: chemical shift (δ), multiplicity, coupling constant (J) in Hertz, and integrated intensity. Carbon-13 nuclear magnetic resonance spectra (¹³C NMR) were obtained at 50 MHz on a Bruker DPX-200 NMR spectrometer. Spectra were recorded in CDCl₃ solutions. Chemical shifts are reported in parts per million, referenced to the solvent peak of CDCl₃. Column chromatography was performed using Merck Silica Gel (230–400 mesh) following the standard methods. Thin layer chromatography (TLC) was performed using Merck Silica Gel GF₂₅₄, 0.25 mm thickness. For visualization, TLC plates were placed under ultraviolet light, stained with iodine vapor, or acidic vanillin. The reactions were monitored by TLC for disappearance of starting material. All microwave reactions were conducted using a CEM Discover, mode operating systems working at 2.45 GHz, with a power programmable from 1 to 300 W.

3.2. General procedure for the oxidation of thiols using glycerol

In a 10 mL glass vial equipped with a small magnetic stirring bar, containing Na₂CO₃ (0.116 g; 1.1 mmol) and glycerol (1 mL), thiol (1.0 mmol) was added. The vial was tightly sealed with an aluminum/Teflon crimp top. The mixture was then irradiated in a microwave reactor (CEM Explorer) for 15 minutes at 120°C (temperature was measured with an IR sensor on the outer surface of the reaction vial), using an irradiation power of 100 W and pressure of 100 psi (the ramp temperature rate was 45 sec). After the reaction was complete, the product was extracted by successive washings with a mixture of hexane/ethyl acetate (95:5) (3×3 mL) and concentrated under vacuum. The residue was purified by column chromatography on silica gel using hexane/ethyl acetate as the eluent.

1,2-diphenyl disulfide 2a 56. ¹H NMR (200 MHz, CDCl₃): δ (ppm) 7.41–7.39 (m, 4H); 7.22–7.07 (m, 6H). ¹³C NMR (50 MHz, CDCl₃): δ (ppm) 136.33, 129.10, 127.50, 127.30.

1,2-bis(2-tolyl) disulfide 2b 57. ¹H NMR (200 MHz, CDCl₃): δ (ppm) 7.52–7.49 (m, 2H); 7.15–7.10 (m, 6H); 2.42 (s, 6H). ¹³C NMR (50 MHz, CDCl₃): δ (ppm) 137.42, 135.40, 130.31, 127.78, 127.29, 126.75, 21.08.

1,2-bis(3-tolyl) disulfide 2c 58. ¹H NMR (200 MHz, CDCl₃): δ (ppm) 7.34–7.21 (m, 8H); 2.13 (s, 6H). ¹³C NMR (50 MHz, CDCl₃): δ (ppm) 139.92, 137.19, 130.52, 129.89, 128.22, 127.75, 21.82.

1,2-bis(4-tolyl) disulfide 2d 59. ¹H NMR (200 MHz, CDCl₃): δ (ppm) 7.40 (d, J=8.3 Hz, 4H); 7.12 (d, J=8.3 Hz, 4H); 2.33 (s, 6H). ¹³C NMR (50 MHz, CDCl₃): δ (ppm) 139.02, 131.89, 130.78, 128.91, 21.01.

1,2-bis(4-methoxyphenyl) disulfide 2e 60. ¹H NMR (200 MHz, CDCl₃): δ (ppm) 7.40 (d, J=8.1 Hz, 4H); 6.84 (d, J=8.1 Hz, 4H); 3.80 (s, 6H). ¹³C NMR (50 MHz, CDCl₃): δ (ppm) 159.91, 132.67, 128.42, 114.61, 55.36.

bis(4-aminophenyl) disulfide 2f 61. ¹H NMR (200 MHz, CDCl₃): δ (ppm) 7.20 (d, J=8.5 Hz, 4H); 6.53 (d, J=8.5 Hz, 4H); 3.73 (bs, 4H). ¹³C NMR (50 MHz, CDCl₃): δ (ppm) 144.75, 130.55, 127.95, 118.60.

1,2-bis(2-chlorophenyl) disulfide 2g 59. ¹H NMR (200 MHz, CDCl₃): δ (ppm) 7.55 (dd, J ¹ =7.6 Hz, J ² =1.5 Hz, 2H); 7.35 (dd, J ¹ =7.6 Hz, J ² =1.5 Hz, 2H); 7.23–7.11 (m, 4H). ¹³C NMR (50 MHz, CDCl₃): δ (ppm) 134.33, 132.37, 131.32, 129.29, 128.98, 124.75.

1,2-bis(4-chlorophenyl) disulfide 2h 62. ¹H NMR (200 MHz, CDCl₃): δ (ppm) 7.40 (d, J=7.8 Hz, 4H); 7.13 (d, J=7.8 Hz, 4H). ¹³C NMR (50 MHz, CDCl₃): δ (ppm) 135.07, 132.19, 130.43, 128.74.

1,2-bis(4-bromophenyl) disulfide 2i 63.¹H NMR (200 MHz, CDCl₃): δ (ppm) 7.42 (d, J=8.2 Hz, 4H), 7.33 (d, J=7.8 Hz, 4H). ¹³C NMR (50 MHz, CDCl₃): δ (ppm) 133.03, 131.31, 130.24, 128.61.

1,2-bis(4-fluorophenyl) disulfide 2j 64. ¹H NMR (200 MHz, CDCl₃): δ (ppm) 7.40 (m, 4H); 6.95 (t, J=8.6 Hz, 4H). ¹³C NMR (50 MHz, CDCl₃): δ (ppm) 163.28 (d, J=246.5 Hz), 133.84 (d, J=2.9 Hz) 132.78 (d, J=8.6 Hz), 118.00 (d, J=21.1 Hz).

6,6′-disulfanediyl bis(3-chloroaniline) 2k 65. ¹H NMR (200 MHz, CDCl₃): δ (ppm) 7.15–6.76 (m, 6H); 5.60 (bs, 4H). ¹³C NMR (50 MHz, CDCl₃): δ (ppm) 144.98, 132.52, 128.06, 123.86, 123.36, 123.23.

2-Naphthyl disulfide 2l 66. ¹H NMR (200 MHz, CDCl₃): δ (ppm) 7.99 (d, J=0.9 Hz, 2H), 7.81–7.72 (m, 4H), 7.65–7.61 (m, 2H), 7.49–7.42 (m, 4H). ¹³C NMR (50 MHz, CDCl₃): δ (ppm) 134.03, 133.51, 132.55, 128.91, 127.84, 127.54, 126.73, 126.60, 126.21, 125.70.

1,2-bis(2-benzothiazolyl) disulfide 2m 67. ¹H NMR (200 MHz, CDCl₃): δ (ppm) 7.37 (dd, J ¹ =3.5 Hz, J ² =0.9 Hz, 2H); 7.32–7.25 (m, 4H); 7.25–7.21 (m, 2H). ¹³C NMR (50 MHz, CDCl₃): δ (ppm) 149.26, 145.86, 133.61, 127.24, 125.14, 120.86, 120.69.

1,2-dibenzyl disulfide 2n 59. ¹H NMR (200 MHz, CDCl₃): δ (ppm) 7.36–7.22 (m, 10H); 3.60 (s, 4H). ¹³C NMR (50 MHz, CDCl₃): δ (ppm) 137.20, 129.20, 128.20, 127.20, 43.32.

1,2-bis(4-chlorobenzyl) disulfide 2o 68. ¹H NMR (200 MHz, CDCl₃): δ (ppm) 7.29–7.27 (m, 4H); 7.15–7.13 (m, 4H); 3.57 (s, 4H). ¹³C NMR (50 MHz, CDCl₃): δ (ppm) 134.60, 133.02, 130.11, 127.96, 43.16.

1,2-difurfuryl disulfide 2p 69. ¹H NMR (200 MHz, CDCl₃): δ (ppm) 7.40–7.38 (m, 2H); 6.34–6.32 (m, 2H); 6.22 (d, J=3.2 Hz, 2H); 3.69 (s, 4H). ¹³C NMR (50 MHz, CDCl₃): δ (ppm) 149.46, 142.01, 111.85, 107.46, 35.99.

1,2-di(n-propyl) disulfide 2q 70. ¹H NMR (200 MHz, CDCl₃): δ (ppm) 2.41 (t, J=7.2 Hz, 4H); 1.46 (quint, J=7.2, 4H); 0.88 (t, J=7.2 Hz, 6H). ¹³C NMR (50 MHz, CDCl₃): δ (ppm) 41.26, 22.56, 13.12.

1,2-di(n-octyl) disulfide 2r 71. ¹H NMR (200 MHz, CDCl₃): δ (ppm)): 2.65 (t, J=8.0 Hz, 14H); 1.77–1.18 (m, 24H); 0.87 (t, J=7.2 Hz, 6H). ¹³C NMR (50 MHz, CDCl₃): δ (ppm) 39.84, 32.14, 29.72, 29.38, 28.63, 28.28, 22.72, 14.10.

1,2-di(t-butyl) disulfide 2s 63. ¹H NMR (200 MHz, CDCl₃): δ (ppm) 1.29 (s, 18H). ¹³C NMR (50 MHz, CDCl₃): δ (ppm) 45.71, 30.51.

1,2-bis-hydroxymethyl disulfide 2t 72. ¹H NMR (200 MHz, CDCl₃): δ (ppm) 4.64 (s, 2H), 4.32 (4H). ¹³C NMR (50 MHz, CDCl₃): δ (ppm) 64.81.

3.3. General procedure for the recycle of glycerol

In a 10 mL glass vial equipped with a small magnetic stirring bar, containing Na₂CO₃ (0.116 g; 1.1 mmol) and glycerol (1 mL), thiol (1.0 mmol) was added. The vial was tightly sealed with an aluminum/Teflon crimp top. The mixture was then irradiated in a microwave reactor (CEM Explorer, mode operating systems working at 2.45 GHz) for 15 minutes at 120°C (temperature was measured with an IR sensor on the outer surface of the reaction vial), using an irradiation power of 100 W and pressure of 100 psi. After the reaction was complete, the product was extracted by successive washings with a mixture of hexane/ethyl acetate (95:5) (3×3 mL) and concentrated under vacuum. The residue was purified by column chromatography on silica gel using hexane/ethyl acetate as the eluent.

4. Conclusion

In conclusion, glycerol has proved to be an efficient solvent for the oxidation of aromatic, aliphatic, and functionalized thiols under microwave irradiation. The reactions proceeds quickly, and the desired disulfides were obtained in good to excellent yields. In addition, glycerol can be easily recovered and utilized for further oxidation reactions and is particularly appropriate to the green chemistry concept.

Acknowledgements

The authors are grateful to FAPERGS (FAPERGS/PRONEX 10/0005-1 and 10/0027-4), CAPES, FINEP, and CNPq for the financial support.