Sulfoxidation of Thioanisole and Epoxidation

Scientifica Acta 4, No. 1, Ch 3-10 (2010)

Chemistry

Sulfoxidation of Thioanisole and Epoxidation-Sulfoxidation of Allylsulfide Catalyzed by a Dinuclear Copper Complex Ilaria Gamba1,2 1 2

Laboratory of Bioinorganic Chemistry, University of Pavia, Pavia, Italy Current address: Department of Inorganic Chemistry, Universidad Autonoma de Madrid, Madrid, Spain

The catalytic activity of the complex [Cu2(L55)O2]2+ toward thioanisole and allylsulfide is reported. Thioanisole is selectively oxidized to the corresponding sulfoxide in presence of H2O2. Allylsulfide is oxidized to sulfone and surprisingly epoxidized on the double bond functions.

1

Introduction

The dinuclear copper complexes of the ligand α,α’-bis[[bis(1-methyl-2-benzimidazolyl) methyl]amino]m-xylene (L55) was first characterized and extensively studied by Casella et al. in the 1993.1 The ligand binds the copper ions with two adjacent five-member chelate rings, providing one amino tertiary nitrogen donor and two benzimidazole nitrogen donors for each metal center. The dinuclear copper complex of the ligand L55 likely binds molecular oxygen as a peroxo bridge between the metal centers. The copper(I) complex treated with molecular oxygen, at room temperature, is able to produce a stable bishydroxo or a bis-aquo complexes (as a function of the pH of the solution). In further studies the relevance of the dinuclear copper complexes of the ligand L55 relative to the catechol oxidase2 and tyrosinase3 enzymes activity was shown. The catalytic oxidation of orthodiphenols to quinones is the only known activity of the catechol oxidase enzyme and one of the activities of the tyrosinase enzyme. In these processes the oxidation of two molecules of catechol is coupled to the reduction of oxygen to water. The copper complex of the ligand catalyzes the oxidation of the 3,5-di-tert-butylcatechols (DTBC) in the presence of molecular oxygen.4 The catechol has a double role in the catalytic cycle, which occur in two different steps, the first being faster then the second. In the first step of the cycle one molecule of catechol is oxidized, reducing the dicopper(II) complex. During the second step a second molecule of catechols is oxidized by the dicopper(I)-oxygen formed upon oxygenation of the reduced complex. Several copper model complexes were studied as mimic of the catecholase activity,5-12 and among them the dinuclear copper complex of the ligand L55 exhibits the highest activity in the catalytic oxidation of catechols.10 An important feature of the reaction mediated by the complex [Cu(L55)]4+ is the possibility to separate the two steps of the catalytic cycle in which the two molecules of catechol are oxidized and allowed to studied mechanistic details of the reaction. Figure 1 shows the structure of the complex and a simplified version of the catalytic cycle for the catecholase activity.

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I. Gamba.: Sulfoxidation of Thioanisole and Epoxidation-Sulfoxidation of Allylsulfide Catalyzed

Figure 1. Molecular structure of the dinuclear copper(II) complex of the ligand L55 (left) and simplified mechanism of the catechol oxidase catalytic cycle (right). The oxygenated complex [Cu2(L55)O2]2+, obtained from the dinuclear copper(I) complex of the ligand exposed to oxygen, is extremely reactive and its timelife is very short, even at temperatures below -80 °C, and therefore it is not isolable.13 The high reactivity of the dioxygen complex [Cu2(L55)O2]2+ is due to the weak bond between the tertiary amine donors and the copper centers,13 which makes the bound dioxygen extremely electrophilic and suitable for application in catalytic processes. Recently a new aspect of the tyrosinase enzyme activity was observed.14 Mushroom tyrosinase was found to catalyze the oxidation of organic sulfides to sulfoxides in the presence of a catechol as cosubstrate, in a reaction that is unprecedented for this enzyme and resembles those performed by external monooxygenases. Figure 2 schematically describes the catalytic cycle performed by the enzyme.

Figure 2. Schematic representation of the catalytic cycle for the sulfoxidation catalyzed by tyrosinase in the presence of a catechol (i.e. L-dopa) as co-substrate. Only the oxy form of the enzyme is capable of oxidizing the sulfide in a two-electron process, while the resulting met form can only be recycled by reduction with catechol. The cosubstrate competes with the sulfide in the reaction with oxy-tyrosinase. The sulfoxidation of thioanisole was studied in the presence of L-dopa (L-3,4-dihydroxyphenylalanine) and was found to occur with moderate yields (20%) but with high enantioselectivity (85% e.e.), and favors (S)-methyl phenyl sulfoxide. The enantioselectivity can be further increased to >90% when excess ascorbic acid is added to the reaction to limit enzyme inactivation by the quinones produced by L-dopa oxidation. Experiments using 18O2 showed that 18-O incorporation into methyl phenyl sulfoxide was above 95%, verifying that the mechanism of the sulfoxidation involves oxygen transfer from oxy-tyrosinase to the sulfide. Since the copper complex of the ligand L55 has shown to be a good model for the enzyme, was employed to develop an efficient catalytic system for promoting thioanisole sulfoxidation.15 The mechanism proposed is depicted in Figure 3.

@2010 Università degli Studi di Pavia


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Figure 3. Catalytic cycle of the sulfoxidation reaction catalyzed by [Cu2(L55)]4+. Under the conditions of the experiments (methanolic aqueous buffer at pH 5.1), the copper complex is probably a mixture of dibridged bis(aqua) and monoaquamonohydroxo species. For simplicity it is represented here as a monohydroxo species. The dicopper(I) complex of the ligand L55, obtained by reduction in presence of a reductive co-catalyst (hydroxylamine, ascorbic acid or L-DOPA) is the form able to bind oxygen. The complex [Cu2(O2)L55]2+ is the active specie, which is able to transfer an oxygen atom to the aromatic sulfide, selectively producing the sulfoxide. The oxygen transfer occurs directly from the catalyst to the substrate, without formation of radical species, as highlighted by experiments using 18O2, which have shown the complete 18-O incorporation into methyl phenyl sulfoxide. The reductive agent could compete with the substrate in the reaction with the oxygenated complex. After oxidation of the sulfide (or reaction with co-substrate) the dicopper(II) form of the complex is restored.15 The catalytic activity of sulfide sulfoxidation mediated by copper complexes have been reported just in a few cases; however in the presence of hydrogen peroxide,16, 17 and the catalytic reaction occurs with high efficiency in only one case.18 Between the catalytic processes of oxidation of sulfides reported, just a very few cases concern the oxidation of sulfides by Cu(II) complexes and in the presence of hydrogen peroxide. The complex [Cu2(L55)O2]2+ has shown to be active in the hydroxylation of phenols19 and it is the best example of catalytic system for the oxidation of catechols;4, 20 as was discussed before. In the present work the oxygen transfer activity of the complex [Cu2(L55)O2]2+ toward thioanisole and allylsulfide is reported, in presence of H2O2 and O2 respectively.

2 2.1

Results and Discussion Sulfoxidation of Thioanisole from H2O2

In order to develop a new catalytic systems able to perform sulfoxidation without employing a cocatalytic agent (as NH2OH, necessary to restore the active form,15 see introduction), the activity of the dinuclear copper complex of the ligand L55 was investigated utilizing hydrogen peroxide for the production of the active catalytic specie (peroxo copper(II) complex of the ligand L55). In a typical experiment the complex, H2O2 and thioanisole were mixed in the ratio 1:3:72. The reaction was studied in methanol/aqueous phosphate buffer (pH 7, 50 mM) mixture. Blank experiments, in presence of H2O2 and Cu(ClO4)2, showed that in the first hours of reaction the production of sulfoxide was negligible. After more than 24 hours of reaction also the co-subtrate, H2O2, is able to oxidize the thioanisole. Since the oxidation promoted by H2O2 is important for long time incubation, the activity of the complex was studied after 1 hour of reaction, when the product formed by not catalytic reaction of hydrogen peroxide is negligible. @2010 Università degli Studi di Pavia

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After few hours of reaction, in the presence of the catalyst, was possible to obtain the 40 % conversion of sulfide to the correspondent sulfoxide of thioanisole selectively (after 1 hour of reaction 30 catalytic cycle were realized, when the direct transfer of oxygen from H2O2 to the thioanisole did not occur). The reaction could occur through two different mechanisms. The first mechanism provides a direct transfer of oxygen from the active peroxo specie to thioanisole, which can be described by equation (1): (1) [Cu2(L55)(O2)]2+ + S + H+ → [Cu2(L55)(OH)]3+ + SO In this case H2O2 could have a double role: it is necessary for the production of the active specie and it is the source of oxygen for the process. The second possible mechanism considers a radical pathway in which the catalyst activates the formation of radical cationic sulfides by mono-electronic oxidation. The radical species produced are then reactive with the water present in the solvent. The process could be summarized by equations (2) and (3): (2) [Cu2(L55)(O2)]4+ + S + 3H+ → [Cu2(L55)(OH)]3+ + S+. + H2O (3) 2S+ + H2O → S + SO + 2H+ The sulfoxide is produced through radical mechanism by dismutation in the presence of water or methanol. The two mechanisms differ for the source of oxygen and, in order to discriminate which one occurred an experiment in presence of 18O2H2 was performed. The % of incorporation found was 14 % (Figure 4 shows the MS spectrum of the products). The % of incorporation of 18O in the sulfoxide product was calculated by the equation (4): (4) A(140) = 0.03*[A(140) + A(142)] + 0.97*[A(140) + A(142)]*(1 – e) In which A(140) is the intensity ratio of the GC-MS molecular peak at 140 amu, A(142) is the intensity ratio of the GC-MS molecular peak at 142 amu and e is the yield of 18O incorporated in the product. .

Figure 4. MS spectrum obtained for the sulfoxidation of thioanisole, catalyzed by the peroxo complex synthesized in presence of 18O2H2, showing the 18O sulfoxide peak at 142 amu, the 16O sulfoxide peak at 140 amu and peaks derived from the fragmentation. 2.2

Epoxidation and Sulfur Oxidation of Allylsulfide from O2

The reactivity of the complex was tested toward the diallyl sulfide. Hydroxylamine was used to restore the copper(I)-copper(I) species able to bind dioxygen, producing the active catalytic species, as reported in case of aromatic sulfides.15 In a standard reaction, allyl sulfide (0.1 M) and [Cu2(L55)](ClO4)4 (10 µM) were stirred at RT in 1 mL of a 3 :1 (v/v) mixture of methanol and either aqueous phosphate or acetate buffer (50 mM, pH 5.1). The reaction was started by addition of hydroxylamine hydrochloride (10 mM). After the given reaction time



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(usually 24 h), the reaction mixture was quenched with dilute aqueous perchloric acid (0.4 mM). The residues obtained were analyzed by 1HNMR (using benzophenone as internal standard) and by GC-MS. Blank experiment was carried out in absence of the ligand L55: by 1H-NMR analyses the formation of the sulfoxide and no modification of the double bond zone were observed. In the case of the diallyl sulfide, the modifications of the double bond region was observed by 1HNMR (Figure 5).

Figure 5. Enlargement of the 1HNMR spectra between 2 and 7 ppm: 1HNMR spectrum of the substrate diallyl sulfide () overlaid to 1HNR of the product obtained after work-up of the reaction (). The spectrum recorded is consistent with the presence of a single symmetric product. The structure of the possible product obtained is shown in the inset (), together with the structure of the starting sulfide (). Analyses of the solution mixture by GC-MS showed presence of a single reaction product. The molecular peak, of the MS spectrum, is detected at 182.02 amu, which can correspond to the bishydroxylated product, obtained from the opening of the epoxide rings during MS analyses. Figure 6 shows the chromatogram obtained from GC analysis and the MS spectra corresponding to the peak of the product.


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Figure 6. GC-MS analysis of the solution after work-up: a) whole chromatogram obtained, showing the peak of the reagent at 9.4 min and the peak of the product at 15.88 min; b) enlargement of the peak of the product and related MS spectra.

3 Conclusions The peroxo copper complex of the ligand L55 has shown to be able to perform the catalytic oxidation of aromatic sulfides. The active catalytic specie could be obtained from the copper(II) complex of the ligand in the presence of hydrogen peroxide. Also the co-subtrate was found to perform substrate oxidation for long reaction time. The low incorporation of 18O into the sulfoxide indicates that the process is occurring through a radical mechanism, which typically occurs in the sulfoxidation catalyzed by peroxidases in the presence of H2O2,21-24 even if in some cases a direct oxygen transfer occurs even with these enzymes.25, 26 The peroxo copper complex of the ligand L55 has shown also to be able to perform the catalytic oxidation of alifatic sulfides, as the allylsulfide, achieving the attach to the double bond function as well as the sulfur centre, promoting both epoxidation and sulfoxidation of the substrate. Four oxygen atoms are included into the substrate: one to each double bond and two at the sulfide site. The oxygen atoms could be transferred from the oxygenated catalyst directly or from the solvent (trough production of radical species) and experiments in presence of 18O2 can be crucial to discriminate the two behaviors. Further studies are required in order to elucidate the reaction mechanism of the systems described.

4 Experimental section 4.1 Syntheses of the ligand α ,α '-Bis[[bis( l-methyl-2-benzimidazolyl)methyl]amino]-m-xylene (L55) The synthesis of the ligand was performed as reported before.13 A mixture of α,α'-diamino-m-xylene dihydrochloride (0.38 g, 1.8 mmol), 2-(chloromethyl)-1methylbenzimidazole (1.35 g. 7.4 mmol), anhydrous sodium carbonate (1.5 g, 14.2 mmol), and dry DMF @2010 Università degli Studi di Pavia


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(100mL) was refluxed for about 8 h. After evaporation to dryness under vacuum, the solid residue was treated with chloroform and the inorganic salts were filtered off. The filtrate was concentrated to a small volume, and diethyl ether was added to precipitate the product (yield 70%). Anal.Calcd. for C44H44N10: C, 74.13; H, 6.22; N, 19.65. Found: C, 74.00; H, 6.20; N, 19.55. 1H NMR (CDCl3) δ, ppm: 3.25 (s, 12H, NCH3), 3.76 (s, 4H, CH2-phenyl), 3.94 (s, 8H, CH2-benzimidazolyl), 7.27.4 and 7.6-7.8 (m, 16H, Ph-H + benzimidazolyl-H). UV (MeOH), λmax, nm (ε, M-1cm-1): 258 (29400), 271 (23 600), 278 (25 900), 286 (22 900), 336 (1340), 350 sh, 376 sh, 400 sh. 4.2. Syntheses of the complex [Cu2(L55)](ClO4)4 The ligand L55 (0.52 g, 0.73 mmol) was dissolved in hot methanol (30 mL), and a solution of copper(II) perchlorate hexahydrate (0.57 g, 1.53 mmol) in a few milliliters of methanol was added. The resulting green solution was stirred for several minutes and concentrated to a small volume. The green precipitate formed was collected by filtration and dried. Anal. Calcd for C44H56N10Cl14Cu2O22: C, 39.26; H, 4.19; N, 10.41. Found: C, 39.29; H, 4.04; N, 10.28. UVvis(MeCN), λmax, nm (ε, M-1cm-1): 247 (33 800), 274 (37 000), 280 (33 500), 300 sh (3800), 390 sh (500), 650 (350). IR (Nujol mull), cm-1: 3480 [ν (OH)]; 1618, 1539, 1506, 1487 [ν (ring)]; 1110, 623 [ν (Cl04)]; 940, 748 [δ(CH)]. 4.3. Sulfoxidation of Thioanisole from H2O2 In a typical experiment, the complex (0.45 mM), H2O2 (1.5 mM) and thioanisole (32.5 mM) were mixed. The reaction was performed in methanol/aqueous (3:1 v/v) phosphate buffer (pH 7, 50 mM) mixture. After the given reaction time (usually 24 h), the reaction mixture was quenched with dilute aqueous perchloric acid (0.4 mM). The methanol phase was removed under reduced pressure and the aqueous solution extracted with CH2Cl2. The organic residues obtained were collected and analyzed by 1HNMR (using benzophenone as internal standard) and by GC-MS. Blank experiments, in presence of H2O2 and Cu(ClO4)2 were performed under comparable conditions. 4.4. Epoxidation and Sulfur Oxidation of Allylsulfide from O2 In a standard reaction, allyl sulfide (0.1 M) and [Cu2(L55)](ClO4)4 (10 µM) were stirred at RT in 1 mL of a 3 :1 (v/v) mixture of methanol and either aqueous phosphate or acetate buffer ( 50 mM, pH 5.1). The reaction was started by addition of hydroxylamine hydrochloride (10 mM). After the given reaction time (usually 24 h), the reaction mixture was quenched with dilute aqueous perchloric acid (0.4 mM). The methanol phase was removed under reduced pressure and the aqueous solution extracted with CH2Cl2. The organic fractions obtained were collected and analyzed by 1HNMR (using benzophenone as internal standard) and by GC-MS.

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