¹Department of Pharmaceutical Chemistry and Drug Control, Charles University in Prague, Faculty of Pharmacy in Hradec Kralove, 500 05 Hradec Kralove, Czech Republic
tel.: +420-49-5067375, (272), fax: +420-49-5512423, e-mail: jamp@faf.cuni.cz, dolezalm@faf.cuni.cz

²Department of Organic Technology, Faculty of Chemical Technology, Institute of Chemical Technology, Prague, 166 28 Prague 6, Czech Republic
tel.: +420-2-24354216, fax: +420-2-24311968, e-mail: bohumir.dvorak@vscht.cz

* Author to whom correspondence should be addressed.

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Abstract: Disulfides rise very easily by oxidation from their thiols. Using thiols for the synthesis is often a great problem, because disulfides may be significant by-products. A lot of various methods of formation of bis(4-methoxyphenyl)disulfide from 4-methoxybenzenethiol (as the main product or as a by-product) have been described. This article deals with the formation of this disulfide as a by-product formed on copper heterogeneous catalysts — conductor, semiconductors and insulators; respectively it deals with the conditions of eliminating this unwanted product. A lot of various methods and conditions have been tried and at some reaction also various types of copper heterogeneous catalysts (metal, copper(I), copper(II)) were used.

Keywords: Heterogeneous catalysis; Copper; Conductor; Semiconductor; Insulator; Dimerization

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Introduction

Some problem arose at the alkylation of aromatic thiols substituted by substituent with positive mesomeric effect in the benzene ring and various copper heterogeneous catalysts at the same time. These compounds were oxidized respectively dehydrogenised to their disulfides. The reaction of thiols and thiolates with transition metals and their ions in higher oxidation groups are very quick reactions [1]. The reaction involves the intermediary of thiyl (RS·) radicals formed by one-electron oxidation of the thiolate anion. The autooxidation of thiol is catalysed by typical one-electron oxidants, e.g. Cu conductor and semiconductors [2]. These catalysts are usually employed to enhance the rate of oxidation. A number of studies of the interactions of metal compounds with thiols have been carried out [3—7]. In comparison to this effect of copper insulator catalysts is not only in generating thiyl radicals, but in generating cations too. Thiyl radical or cations react then with thiols or thiolates to their disulphides.

Most catalytic reactions belong to either of the two classes of reactions [8]. Oxidation—reduction (redox) reactions include hydrogenation, dehydrogenation, selective or complete oxidation. These reactions involve neutral radical-type intermediates bonded by homopolar bonds to the catalyst. They are catalyzed by metals, semiconductors. The solids among these catalysts represent redox systems and have common characteristics explainable by the presence of highly mobile electrons.

Acid—base reactions comprise various substitution, addition, elimination, and molecular rearrangement reactions exemplified by alkylation, isomerization. These reactions involve charged ionic intermediates and are catalyzed by acidic or basic solids as well as by soluble Broensted or Lewis acids and bases. Insulator catalysts have needed polar solvents or trace amount of water [9].

The metal copper (conductor) and its copper semiconductors (oxides, halides, sulphides) show high oxidative respectively dehydrogenative activity and their mechanism of effect is radical. The metallic character of the elements is closely connected with electronegativity. The catalytic activity of metals for redox-type reactions is a function of their chemisorption properties. The catalytic activity of certain metal oxides depends on their chemisorption capability, semiconductivity, and on the variable valence of their metal ions. Thus, semiconductive Cu catalysts show oxidation and hydrogenation—dehydrogenation activities. Especially copper semiconductors with copper(II) have been used in organic technology for oxidation, oxychloration and as mild dehydrogenative agents. They have been used e.g. for the production of methanol, butadiene, acrolein, methacrolein, acetic anhydride, vinyl acetate, dichloroethane, vinyl chloride [10].

Metal sulfides have semiconducting and acidic properties. Therefore, they have applications in both redox and acid-catalyzed reactions [11].

Cu(I),(II) halides have semiconducting properties too. Copper chlorides are the most utilization especially for oxychloration and for deacon reaction. The addition of chlorides of the rare-earth and alkaline-earth metals (potassium chloride) to the CuCl₂ catalyst reduces volatility of CuCl₂ and prevents formation of inactive polymeric CuCl₂ chains [12].

The sulfates of copper act as unprotonated acids and cause double-bond isomerization [13] and alkylation. The applications of phosphates catalysts are in typical acid-catalyzed reactions and also in oxidation, aromatization, and dehydrogenation [14].

All these compounds are used for synthesis of unsymmetrical sulphides (Williamson synthesis); formed by the alkylation of metal salt of an aryl thiol with nonreactive aryl halides (without a substituent with negative mesomeric effect in the aromatical ring). 4-Methoxybenzenethiol was chosen as a model substance for easy oxidability resp. for its easy dehydrogenation. On this substrate the margin of ability of copper heterogeneous catalysts is tested to oxidate resp. dehydrogenate aromatic thiols with the substituent in position 4 of the aromatic core showing positive mesomeric effect on respective disulfides and thus to eliminate them from the main reaction.

In the below mentioned works besides disulfide different quantities of the other oxidation products appeared (sulfonic acids, sulfone). On the other hand the reactions carried out on copper heterogeneous catalysts always lead to disulfide as the only product of oxidation respectively dehydrogenation.

4-Methoxybenzenethiol (1) was oxidated to its bis(4-methoxyphenyl)disulfide (2) see Scheme 1. This product formed as many as 70 % of the yield by means of some methods.

Scheme 1: Bis(4-methoxyphenyl)disulfide (2) formation through copper heterogeneous catalysts.

Various conditions of generating its bis(4-methoxyphenyl)disulfide (2) using copper heterogeneous catalysts are described in this paper, but this could be prepared in various synthetic pathways with various yielding; bis(4-methoxyphenyl)disulfide could be generated as the main product by e.g. hydrogen peroxide [15] (98 %), sodium hypochlorite [16] (92 %), sodium iodate [17] (98 %), DMSO [18,19] (98 %), sodium iodide [20] (97 %), copper(II) nitrate [21] (99 %), aq. potassium hydroxide, potassium ferricyanide [22] (93 %), sodium perborate tetrahydrate [23,24] (78 %), chromium trioxide [25] (76 %), and as a by-product using e.g.: chlorotrimethylsilane [26] (80 %), 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2,2,2] octane bis(tetrafluoroborate) [27] (58 %), toluene-4-sulphonyl iodide [28] (37 %), meso-tetraphenylporphyrin [29] (13 %).


Results and Discussion

Our experiment was realized in different solvents with atmospheric oxygen, under the atmosphere of nitrogen or argon. Different types of copper heterogeneous catalysts with the copper component in different oxidizing state were tested. The catalysts were applied in powder form, the smooth dispersion of the effective component was prepared by means of coagulative or impregnating procedures.

In fact metal wire copper Cu^a and powder Cu^b were used and metal copper Cu^c (on inert support), which is the actived catalyst CHEROX 46-11. Then powder copper(I)oxide Cu₂O^d, powder copper(II)oxide CuO^e and CuO^f (CHEROX 46-00 oxide on inert support) were used. All the remaining copper heterogeneous catalysts are powders: Cu₂S^g, CuS^h, CuClⁱ, CuCl₂^j, CuI^k, CuOCl^l (according to IUPAC or GMELIN Cu(II)trihyroxichloride is CuCl₂ · 3Cu(OH)₂), CuSO₄^m, Cu(PO₄)₂ · 2H₂Oⁿ and CuCO₃ · Cu(OH)₂^o.

All the reactions are showed in four tables. Catalysts in tables are divided according to copper oxidizing state of the copper component (Table 1, 2, 3) and insulator catalysts are present in the Table 4.

Altogether 39 reactions were carried out on copper heterogeneous catalysts with the copper component in different oxidation state with different electronic parameters and various types of ligands.

On the basis of the experiments carried out it is evident that the activity of copper in the form of metal even in by relatively low temperatures (ethanol 78 °C). Cu(II) in accordance with all assumptions has not appeared to be the most efficient dehydrogenative catalyst, but Cu(0) is the most effective catalyst. Various types of ligands have great influence on oxidative respectively dehydrogenative properties of the catalysts. The most efficient dehydrogenative catalysts were halides, then oxides and the least activity have sulphides. Great disappointment was a proportionally high oxidizing respectively dehydrogenative activity of insulator catalysts, although these catalysts are used due to their properties for alkylation reactions mainly. Cu(PO₄)₂ · 2H₂O has the least oxidizing activity from the used insulator copper heterogeneous catalysts. Cu(I) has the least dehydrogenative activity. Using the same type of catalyst the yield of disulfide is higher in polar solvents and in the presence of water, which is important for insulator catalysts function. If the precursor is used in the form of salt (sodium or potassium) the yields of disulfide are higher. The reaction process is facilitated by atmospheric oxygen (parallel oxidation reaction).


Table 1. Conditions and yields of performed reactions with metal copper Cu(0).

Method	Conditions	Atmosphere	Yields %
1a	Na, ethanol, Cua	oxygen	51
1b	Na, ethanol, Cua	nitrogen	43
2a	KOH(aq), Cua	oxygen	69
2b	KOH(aq), Cua	nitrogen	63
3a	K2CO3, Et-Me ketone, Cub	oxygen	56
3b	K2CO3, Et-Me ketone, Cub	nitrogen	49
3c	K2CO3, Bu-Me ketone, Cub	oxygen	72
3d	K2CO3, Bu-Me ketone, Cub	nitrogen	65
4a	Bu-Me ketone, Cub	nitrogen	49
3e	K2CO3, Bu-Me ketone, Cuc	argon	50
4b	Bu-Me ketone, Cuc	nitrogen	32
4c	Bu-Me ketone, Cuc	argon	23

^[a] is wire, ^[b] is powder 97% purity, ^[c] metal on "silicate" support


Table 2. Conditions and yields of performed reactions with Cu(I) semiconductors.

Method	Conditions	Atmosphere	Yields %
3f	K2CO3, Bu-Me ketone, Cu2Od	argon	15
4d	Bu-Me ketone, Cu2Od	argon	9
5a	K2CO3, DMF, Cu2Od	argon	5
6a	NaH, DMF, Cu2Od	argon	3
7a	xylene, Cu2Od	argon	1
6b	NaH, DMF, Cu2Sg	argon	2
7b	xylene, Cu2Sg	argon	0.5
6c	NaH, DMF, KCl, CuCli	argon	23
7c	xylene, KCl, CuCli	argon	19
6d	NaH, DMF, CuIk	argon	12
7d	xylene, CuIk	argon	7

^{[d, g, i, k]} catalysts are powder 99 % purity


Table 3. Conditions and yields of performed reactions with Cu(II) semiconductors.

Method	Conditions	Atmosphere	Yields %
3g	K2CO3, Bu-Me ketone, CuOe	argon	32
4e	Bu-Me ketone, CuOe	argon	27
5b	K2CO3, DMF, CuOe	argon	25
7e	xylene, CuOe	argon	22
6e	NaH, DMF, CuOf	argon	31
7f	xylene, CuOf	argon	28
6f	NaH, DMF, CuSh	argon	23
7g	xylene, CuSh	argon	19
6g	NaH, DMF, CuOCll	argon	34
7h	xylene, CuOCll	argon	30
6h	NaH, DMF, KCl, CuCl2j	argon	43
7i	xylene, KCl, CuCl2j	argon	39

^{[e, h, j]} catalysts are powder 97% purity, ^[f] is on "silicate" support and ^[l] is powder 50 % purity


Table 4. Conditions and yields of performed reactions with Cu(II) insulators.

Method	Conditions	Atmosphere	Yields %
5c	K2CO3, DMF, CuSO4m	argon	41
6i	NaH, DMF, CuSO4m	argon	36
5d	K2CO3, DMF, Cu(PO4)2 · 2H2On	argon	27
5e	K2CO3, DMF, CuCO3 · Cu(OH)2o	argon	42

^[m] is powder 99 % purity, ^[n] is powder 97 % purity, ^[o] is not mentioned

Conclusions

The carried out experiments proved that the lowest percentage of the formation of disulfide from thiophenols with the substituent in position 4 of the aromatic ring is achieved when using copper(I)sulphide, oxide and iodide as heterogeneous catalysts. Inert atmosphere and using anhydrous dipolar aprotic solvents (DMF) or nonpolar solvents (xylene) help the reduction the yield of the disulphide.


Experimetal

All organic solvents used for the synthesis were of analytical grade. The solvents were dried and freshly distilled under argon atmosphere. Flash chromatography was realized on Silica gel Kieselgel 60 by Merck. TLC was performed on Silufol UV 254 plates (Kavalier, Votice). Silica gel plates, besides detection under UV 254, were visualized in addition to the solution of bromothymol blue in NAOH (proof of thiol, sulphide, disulphide). Melting points were measured on Kofler block BOËTIUS PHMK 05 (VEB KOMBINAT NAGEMA, VEB Wagetechnik RAPIDO, Radebeul, Germany). Elementary analysis was carried out on Automatic Microanalysers EA1110CE (Fisons Instruments S.p.A., Milano). Infrared spectra were measured in KBr pellets on IR-Spectrometer Nicolet Impact 400. ¹H and ¹³C NMR Spectra were recorded on Varian Mercury — Vx BB 300 (299.95 MHz - ¹H and 75.43 MHz - ¹³C) Bruker Comp. (Karlsruhe, Germany). Chemical shifts reported are given relative to internal Si(CH₃)₄.

Copper catalyst Cu^a — wire copper (ThermoQuest Italia S.p.A., cod 338 35310) and Cu^b — powder 99% purity (Sigma-Aldrich, cod 29,258-3) were used and metal copper Cu^c is an activated catalyst CHEROX 46-11, the precursor of this catalyst is a product of CHEMOPETROL a. s. Litvínov. Suspension activated powder catalyst in an organic solvent was prepared. The catalyst is formed, metallic copper being finely dispersed on silicate support. CHEROX 46-11 was activated in organic solvent in autoclave under hydrogen atmosphere under the temperature of 180 °C and pressure 5 MPa. Cu₂O^d — powder 97% purity (Sigma-Aldrich, cod 20,882-5) and CuO^e 98% purity (Sigma-Aldrich, cod 20,884-1) were used. CuO^f is the product of CHEMOPETROL a. s. Litvínov CHEROX 46-00 (catalyst contents 40 % CuO on "silicate" support: SiO₂, MgO, CaCO₃). CuOCl^l (CuCl₂ · 3Cu(OH)₂) powder 50% purity is the product of SPOLANA a. s. Neratovice KUPRIKOL 50. Cu(PO₄)₂ · 2H₂Oⁿ powder 97 % purity is the product of Riedel-deHaën, cod 04252. The mixture of CuCO₃ · Cu(OH)₂^o is the product of Sigma-Aldrich, cod 20,789-6. Purity is not mentioned. All the rest copper heterogeneous catalysts are powder 99% purity from Sigma-Aldrich: Cu₂S^g (cod 51,065-3), CuS^h (cod 34,246-7), Cu₂Cl₂ⁱ (cod 22,433-2), CuCl₂^j (cod 45,166-5), Cu₂I₂^k (cod 21,555-4), anhydrous CuSO₄^m (cod 45,167-7).


Bis(4-methoxyphenyl)disulfide (2)

Method 1: Sodium (0.23 g, 10.0 mmol) was dissolved in dry ethanol (20 mL) then 4-methoxybenzenethiol (1.0 g, 8.0 mmol) was dissolved there and Cu^a (3.0 g) was added and the reaction mixture was stirred and refluxed for 3 h according to the open air (1a) method or under nitrogen (1b). Then the reaction mixture was filtered while hot and the filtrate evaporated in vacuo.
Method 2: Potassium hydroxide (1.4 g, 25 mmol) was dissolved in H₂O (12 mL), 4-methoxybenzenethiol (1.0 g, 8.0 mmol) and Cu^a (3.0 g) were added and the reaction mixture was stirred and refluxed for 3 h according to the open air (2a) method or under nitrogen (2b). Then the reaction mixture was extracted with EtOEt and the combined extracts were dried over MgSO₄ and evaporated in vacuo.
Method 3: K₂CO₃ (0.7 g, 5.0 mmol) was suspended in freshly distilled Et-Me ketone, respectively in Bu-Me ketone (20 mL) and 4-methoxybenzenethiol (1.0 g, 8.0 mmol) and Cu^b (1.0 g) for 3a-d; Cu^c (0.2 g) for 3e; Cu₂O^d (1.0 g) for 3f; CuO^e (1.0 g) for 3g were added. The reaction mixture was stirred and refluxed for 1 h according to the open air (3a, 3c) method or under nitrogen (3b, 3d) or under argon (3e, 3f, 3g). Then the reaction mixture was filtered while hot and the filtrate evaporated in vacuo.
Method 4: 4-Methoxybenzenethiol (1.0 g, 8.0 mmol) was dissolved in freshly distilled dry Bu-Me ketone (20 mL) and copper catalyst was added; method 4a: Cu^b (1.0 g); method 4b, 4c: Cu^c (0.2 g); method 4d Cu₂O^d (1.0 g); method 4e CuO^e (1.0 g) were added. The reaction mixture was stirred and refluxed for 1 h under nitrogen (4a,b) or argon (4c-e). Then the reaction mixture was filtered while hot and the filtrate evaporated in vacuo.
Method 5: K₂CO₃ (0.7 g, 5.0 mmol) was suspended in freshly distilled DMF (20 mL), 4-methoxybenzenethiol (1.0 g, 8.0 mmol) was dissolved there and Cu₂O^d (1.0 g) for 5a; CuO^e (1.0 g) for 5b; CuSO₄^m (2.5 g) for 5c; Cu(PO₄)₂ · 2H₂Oⁿ (3.0 g) for 5d; CuCO₃ · Cu(OH)₂^o (2.5 g) for 5e was added. The reaction mixture was stirred and refluxed for 1 h under argon. Then the reaction mixture was filtered while hot and the filtrate evaporated in vacuo.
Method 6: NaH 60% suspension in paraffin oil (0.2 g, 9.0 mmol) was suspended in freshly distilled dry DMF (20 mL), 4-methoxybenzenethiol (1.0 g, 8.0 mmol) was dissolved there and Cu₂O^d (1.0 g) for 6a; Cu₂S^g (1.0 g) for 6b; CuClⁱ (1.0 g) and KCl (0.1 g) for 6c; CuI^k (1.0 g) for 6d; CuO^f (0.2 g) for 6e; CuS^h (1.0 g) for 6f; CuOCl^l (2.5 g) for 6g; CuCl₂^j (1.0 g) and KCl (0.1 g) for 6h; CuSO₄^m (2.5 g) for 6i was added. The reaction mixture was stirred and refluxed for 1 h under argon. Then the reaction mixture was filtered while hot and the filtrate evaporated in vacuo.
Method 7: 4-Methoxybenzenethiol (1.0 g, 8.0 mmol) was dissolved in freshly distilled dry xylene (20 mL) and Cu₂O^d (1.0 g) for 7a; Cu₂S^g (1.0 g) for 7b; CuClⁱ (1.0 g) and KCl (0.1 g) for 7c; CuI^k (1.0 g) for 7d; CuO^e (1.0 g) for 7e; CuO^f (0.2 g) for 7f; CuS^h (1.0 g) for 7g; CuOCl^l (2.5 g) for 7h; CuCl₂^j (1.0 g) and KCl (0.1 g) for 7i was added. The reaction mixture was stirred and refluxed for 1 h under argon. Then the reaction mixture was filtered while hot and the filtrate evaporated in vacuo.

Flash chromatography on silica gel provided bis(4-methoxyphenyl)disulfide as lightly yellow solid compound. Yields are described in Tables 1—4, m. p. = 39.0—39.5 °C, petroleum ether-diethylether (φ_r = 3 : 1), R_f = 0.49 (disulphide), 0.88 (thiol). For C₁₄H₁₄S₂O₂ (M_r = 278.22) w_i (calc.): 60.40 % C, 5.07 % H, 23.03 % S; w_i (found): 60.46 % C, 5.09 % H, 22.93 % S. IR spectrum (KBr), /cm: 1249 (C-O), 1590 (Ph), 2835 (O-CH₃), 2956 (CH₃). ¹H NMR (300 MHz, DMSO), δ: 7.42-7.38 (m AA'BB', 4H CH_arom.), 6.96-6.94 (m AA'BB', 4H CH_arom.), 3.76 (s, 3H CH₃). ¹³C NMR (75 MHz, DMSO), δ: 159.92, 132.31, 127.14, 115.23, 55.53.


Acknowledgements. This work was supported by the Research project LN00B125 of the Czech Ministry of Education. We thank Mrs. D. Karlickova for elementary analysis, Mrs. J. Zizkova for IR spectrum, Mr. T. Vojtisek for his skillful technical assistance and Doc. PharmDr. J. Kunes, CSc. for the service of NMR spectrometer.


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