Regiospecific Catalysis of Glycoconjugated Metalloporphyrins for Primary C-H Bond Mild Oxidation

Synthesis of Glycoconjugated Metalloporphyrins and Their Regiospecific Catalysis of Primary Carbon-Hydrogen Bonds Oxidation*

    Can-Cheng Guo**  Xiao-Bing Zhang   Jian-Xin Song   He-Ping Li  

College of Chemistry and Chemical Engineering, Hunan University, Changsha, 410082, China.

Two carbohydrate-porphines, tetra[2-acetylglucosyl-oxo-phenyl] porphins (T(o-glu)PPH₂) and tetra[3-acetylglycosy-oxo-phenyl]porphine (T(m-glu)PPH₂), were synthesized from the reaction of pyrrole with ortho- acetylglycosylate benzaldehyde and meta-acetylglycosylate benzaldehyde, respectively, by Lindsey’s method. Four acetylglycosylate metalloporphyrins, chloro[tetra(o-2,3,4,6-O-acetylglucose-1-O-phenyl)porphinato] iron (T(o-glu)PPFeCl), chloro[tetra(o-2,3,4,6-O-acetylglucose-1-O-phenyl)porphinato]manganese, (T(o-glu)PPMnCl), chloro[tetra(m-2,3,4,6-O-acetylglucose-1-O-phenyl)porphinato]iron (T(m-glu)PPFeCl) and chloro[tetra(m-2,3,4,6-O-acetylglucose-1-O-phenyl)porphinato]manganese (T(m-glu)PPMnCl) were prepared from these acetylglycosylate porphines.  The newly synthesized compounds were characterized by UV-Vis spectroscopy, ¹HNMR and elemental analysis. The selective catalytic oxidation of  2-methylbutane with PhIO as an oxidant at room temperature and under atmospheric pressure by four acetylglycosylate metalloporphyrins were studied. In contrast with metalloporphyrins without sugar groups, the selective catalysis of these acetylglycosylate metalloporphyrins for hydrocarbon oxidation was shown to be more close to cytochrome P-450 monooxygenase. Four acetylglycosylate metalloporphyrins catalyzed regiospecifically the hydroxylation of the end carbon-hydrogen bond for 2-methylbutane.

                              INTRODUCTION

Since the lately 70’s a great number of porphyrin compounds have been synthesized ^[1]. They were found application as catalysts for hydrocarbon oxidation ^[2]. 15 years ago, Suslick reported the first example of regioselectivity in alkane hydroxylation catalyzed by metalloporphyrins ^[3]. From then, the voluminous amount of research has been done in the field of regioselective oxidation with metalloporphyrins ^[4]. In the late years there has been increasing interest in carbohydrate-porphyrins ^[5-12] because both carbohydrates and porphyrins exist in bioorganism. Carbohydrate-porphyrins play important role in the research of asymmetric synthesis because of their chirality. It was reported that metallic complexes of these acetylglycosylate porphyrins were active catalysts for alkene epoxidation with asymmetric induction, due to the presence of charily sugar substituents in the vicinity of the metal center ^[13-16]. In contrast with metalloporphyrins without sugar groups, the epoxidation catalyzed by metalloporphyrins with sugar groups had higher yield and better stereoselectivity. It has not been reported up to now whether glycoconjugated metalloporphyrins has regioselectivity for alkane oxidation. In order to gain an insight into the catalytic effect of glycoconjugated metalloporphyrins on regioselectivity of alkane oxidation, we synthesized four acetylglycosylate metalloporphyrins according to the route shown in Fig 1, chloro[tetra(o-2,3,4,6-tetra-O-acetylgluose-1-O-phenyl)porphinato]iron (T(o-glu)PPFeCl, 6), chloro[tetra(o-2,3,4,6-tetra-O-acetylgluose-1-O-phenyl)porphinato]manganese (T(o-glu)PPMnCl, 7), chloro[tetra(m-2,3,4,6-tetra-O-acetylgluose-1-O-phenyl)porphinato]iron (T(m-glu)PPFeCl, 8), and chloro[tetra(m-2,3,4,6-tetra-O-acetylgluose-1-O-phenyl)porphinato]manganese (T(m-glu)PPMnCl, 9). We studied the selective catalysis of these acetylglycosylate metalloporphyrins for oxygenation of 2-methylbutane with PhIO as an oxidant at room temperature and under atmospheric pressure. The research showed a very exciting results that iron and manganese glycosylated porphyrin had the regiospecific catalysis for the oxidation of primary carbon-hydrogen bonds. The reaction product of the 2-methylbutane oxidation by PhIO was 3-methyl-1-butanol when carbohydrate- metalloporphyrins was used as catalysts, while products were 2-methyl-2-butanol and 3-methyl-2-butanone when metalloporphyrins without sugar groups were used as catalysts. This indicated that carbohydrate- metalloporphyrins had the regiospecific catalysis for the oxidation of the primary carbon-hydrogen bond of 2-methylbutane. With respect to the metalloporphyrins without sugar groups, the catalysis of glycoconjugated metalloporphyrins for hydrocarbon oxidation under very mild conditions is more close to cytochrome P-450 monooxygenase.

Fig. 1

    EXPERIMENTAL

Instruments and Reagents   ¹HNMR spectra were recorded on a Bruker AG80 spectrometer in CDCl₃ as solvent. UV-Vis spectra were obtained with a Lambda 17 Perkin-Elmer spectrophotometer. IR spectra were recorded on a Perkin-Elmer model 783 IR spectrophotometer; GC analysis was performed on a Shimadzu GC-16A gas chromatograph with flame ionization detection (30 x 0.125 in. OV-101-5% CHP 100-125 mesh column). Perkin-Elmer 2400 elementary analyser and model 5012 constant temperature water-bath were used.

   Before used, benzene, dichloromethane and benzaldehyde were subjected to simple distillation from K₂CO₃; Pyrrole and 2-methylbutane were redistilled at atmospheric pressure from CaH₂. Other reagents were analytically pure or chemically pure as received.

   PhIO was synthetized according to documented procedures ^[17], the purity measured by iodimetry was 99％. Chloro[tetraphenylporphinatoiron] (TPPFe^ⅢCl) and Chloro[tetraphenylporphinatomanganese] (TPPMn^ⅢCl) were synthetized according to documented procedures^[18,19] and confirmed by elementary analysis, IR spectra and UV-Vis spectroscopy.

Synthesis of 1-α- Bromo-2,3,4,6-tetra-O-acetylglucose (1)

   Following a known procedure ^[20]: A sample of 66 g of glucose was dissolved in 280 mL of acetic anhydride with 3 drops of 98% sulfuric acid added. The reaction was allowed to proceed for 15 min at room temperature, then was refluxed for 2 h under steam both. The solvent was removed under reduced pressure affording the straw yellow pulpiness penta-O-acetylglucose. It was dissolved in 65 g of acetic anhydride and was cooled in ice-bath, and then dry hydrogen bromide was introduced until the weight increased 140-160 g. The reaction mixture was allowed to stand at 5℃ overnight affording a bright yellow solution. The solution was evaporated to dryness under reduced pressure and 60℃ with a water bath, affording 115 g of 1-α-bromo-2,3,4,6-tetra-O-acetylglucose (1) (85%). mp 87～88℃ after crystallization from 250 mL of absolute isopropyl ether.

Synthesis of ortho-2,3,4,6-Tetra-O-Acetylglycosylate Benzaldehyde (2)

   A solution of 2-hydroxybenzaldehyde (10.24 g) in methylene dichloride (100 mL) was vigorously stirred at room temperature with an aqueous solution of sodium hydroxide (5%, 140 mL) and tetrabutylammonium bromide (4.52 g) for 30 min. To this stirred (40 mL) mixture was added a solution of (1) (11.5 g) in methylene dichloride (40 mL) at room temperature. Stirring was continued for 3 days. After separation, the organic phase was washed with aqueous sodium hydroxide solution (5%, 80 mL) and sequentially with water and then dried over sodium sulfate and evaporated in vacuum. The crude yellow oil was chromatographed on a silica gel column using a mixture of ethyl acetate/hexane (4/1, V/V). The pure product (11.86 g, 51%) was obtained by twice chromatographic procedures. Anal. calc. for C₂₁H₂₄O₁₁: C，55.75； H， 5.35。Found：C，55.91；H, 5.32。¹HNMR(CDCl₃), : .0 (1H, aldehyde), 7.2~8.0 (4H, benzene), 3.4~5.0 (7H, glucose), 1.5~2.5 (12H, CH₃CO-).

Synthesis of meta-2,3,4,6-Tetra-O-Acetylglycosylate Benzaldehyde (3)

   1-α-bromo-2,3,4,6-tetra-O-acetylglucose (1) (11.5g) reacted with 3-hydroxybenzaldehyde (10.24 g) following the general procedure described for compound 2. Column chromatography (silica-gel. hexane/ether acetate 1:4) afforded 10.2 g (44％) of meta- 2,3,4,6-tetra-O-acetylglycosylate benzaldehyde (3)。Anal. calc. for C₂₁H₂₄O₁₁：C，55.75； H, 5.35。Found：C，55.88; H, 5.33. ¹HNMR(CDCl₃), : 8.9 (1H, aldehyde), 7.2~8.0 (4H, benzene), 3.4~4.5 (7H, glucose), 1.5~2.4 (12H, CH₃CO-).

Synthesis of Tetra(o-2,3,4,6-tetra-O-acetylglucose-1-O-phenyl)porphine (T(o-glu)PPH₂, 4)

   4.5g of ortho-2,3,4,6-tetra-O-acetylglycosylate benzaldehyde (2)，0.668g of freshly distilled pyrrole and 0.4 mL of BF₃·Et₂O were dissolved in 800 mL of CH₂Cl₂ freshly distilled over P₂O₅. The reaction mixture under a nitrogen atmosphere was stirred at room temperature for 20 h. After addition of 1.0 g of 2,3-dichloro-5, 6-dicyano-1, 4-benzoquinone (DDQ), the reaction mixture was stirred for a further 2 h. Then 10 g of silica was added and the solvent evaporated. The residue supported on silica was purified by column chromatography (silica, CH₂Cl₂/acetone 7:1). After removing of the solvent, 1.3g (25.8％) of tetra(o-2,3,4,6-tetra-O-acetylglucose-1-O-phenyl)porphine (T(o-glu)PPH₂, 4) was obtained. Anal. calc. for C₁₀₀H₁₀₂N₄O₄₀：C, 60.1; H, 5.1; N 2.8. Found: C, 59.7; H, 5.2; N 3.0. UV-Vis(CH₂Cl₂)：λmax：418(ε,370000), 516(17000), 544.5(6000), 587.5(7000), 654(5500) nm. ¹HNMR(CDCl₃), :8.67 ～ 8.84 (8H, pyrrole), 7.51～7.90 (16H, benzene), 3.41～4.79 (28H, glucose)，-1.25～-0.25，0.5～1.3，1.51～2.19 (48H, CH₃CO-)，-2.81 (2H, NH)

Synthesis of Tetra (m-2, 3,4,6-tetra-O-acetylglucose-1-O-phenyl) porphine (T(m-glu)PPH₂, 5)

   4.5 g of meta-2,3,4,6-tetra-O-acetylglycosylate benzaldehyde (3) reacted with 0.668g of pyrrole following the general procedure described for compound 4. Column chromatography (silica-gel. CH₂Cl₂/acetone 7:1) afforded 1.1 g (22％) of T(m-glu)PPH₂ (5). Anal. calc. for C₁₀₀H₁₀₂N₄O₄₀：C, 60.1; H, 5.1; N, 2.8。Found：C, 59.85; H, 5.3; N, 3.2. UV-Vis(CH₂Cl₂)：λmax，415.5, 513.5, 546 588, 650 nm。¹HNMR(CDCl₃)   8.63 (8H pyrrole)；7.40～8.14 (10H, benzene), 5.33, 4.3～4.43, 4.07 (28H, glucose), 1.06～2.23 (48H, CH₃CO-), -2.97(2H, NH)。

Synthesis of Chloro[tetra(o-2, 3,4,6-tetra-O-acetylglucose-1-O-phenyl)porphinatoiron] (T(o-glu) PPFeCl, 6)

   A solution of 200 mg of tetra(o-2,3,4,6-tetra-O-acetylglucose-1-O-)phenylporphine (4) in 50 mL DMF was stirred under refluxing with FeCl₂ for 1 h. TLC (silica-gel, CH₂Cl₂ ) showed the complete disappearance of the starting material and UV-Vis spectroscopy showed the absence of non metallized porphyrin. After the mixture was cooled to room temperature and cautiously acidified with 50 mL 10% HCl, the product became crystalline. Recrystallization from hexane-benzene afforded 150 mg (75%) of T(o-glu)PPFeCl (6). Anal. calc. for C₁₀₀H₁₀₀N₄O₄₀FeCl：C, 57.49; H, 4.79; N, 2.68. Found：C, 57.11; H, 4.81; N, 2.65. UV-Vis(CH₂Cl₂): λmax：394, 424, 558, 594nm. ¹HNMR(CDCl₃), :8.5 ～ 8.8 (8H, pyrrole), 7.4～8.0 (16H, benzene), 3.2～4.5 (28H, glucose), 0.5~1.3, 1.7～2.3 (48H, CH₃CO-).

Synthesis of Chloro[tetra(o-2,3,4,6-tetra-O-acetylglucose-1-O-phenyl)porphinatomanganese] (T(o-glu)PPMnCl, 7)

    A solution of 200 mg of tetra(o-2,3,4,6-tetra-O-acetylglucose-1-O-phenyl)porphine (4) in 50 mL of DMF was stirred under refluxing with MnCl₂ H₂O for 6 h. TLC (silica gel, CH₂Cl₂) showed the complete disappearance of the starting material and UV-Vis spectroscopy showed the absence of non-metallized porphyrin ring. After evaporation of the solvent in vacuo, the residue was dissolved in CH₂Cl₂and washed with water. Column chromatography(silica-gel, CH₂Cl₂ ) afforded 170 mg (85%) of T(o-glu)PPMnCl (7)。 Anal. calc. for C₁₀₀H₁₀₀N₄O₄₀MnCl：C, 57.51; H, 47.9; N, 2.68.  Found：C, 57.31; H, 47.6; N, 2.69。UV-Vis(CH₂Cl₂)：λmax：399, 426, 510, 575, 654 nm. ¹HNMR(CDCl₃), :8.5 ～ 8.8 (8H, pyrrole), 7.5～7.9 (16H, benzene), 3.5～4.6 (28H, glucose)， 0.5～1.3，1.6～2.3 (48H, CH₃CO-).

Synthesis of Chloro[tetra(m-2,3,4,6-tetra-O-acetylglucose-1-O-phenyl)porphinatoiron] (T(m-glu)PPFeCl, 8)

   200 mg of T(m-glu)PPH₂ (5) was metallized with FeCl₂ following the general procedure described for compound (7). Column chromatography (silica-gel. hexane/ether acetate 1:4) afforded 170 mg (85％) of T(m-glu)PPFeCl (8). Anal. calc. for C₁₀H₁₀₀N₄O₄₀FeCl：C, 57.49; H,4.79; N,2.68. Found：C,57.69; H,4.81; N,2.64。UV-Vis(CH₂Cl₂): λ_max：398, 422, 557, 595 nm. ¹HNMR(CDCl₃), : 8.2～8.8 (8H pyrrole)；7.3～8.0 (10H, benzene), 4.3～5.3 (28H, glucose), 1.2～2.5 (48H, CH₃CO-).

Synthesis of Chloro[tetra(m-2,3,4,6-tetra-O-acetylglucose-1-O-phenyl)porphinatomanganese] (T(m-glu)PPMnCl, 9)

   200 mg of T(m-glu)PPH₂ (5) was metallized with MnCl₂ following the general procedure described for compound (8). Column chromatography (silica. hexane/ether acetate 1:4) afforded 160 mg (80％) of T(m-glu)PPMnCl (9). Anal. calc. for C₁₀₀H₁₀₀N₄O₄₀MnCl：C, 57.51; H, 4.79; N, 2.68. Found: C, 57.55; H, 4.73; N, 2.66。UV-Vis(CH₂Cl₂): λ_max：403, 425, 514, 575, 651 nm ¹HNMR(CDCl₃)   8.4～8.9 (8H pyrrole)；7.4～8.0 (10H, benzene), 4.2～5.3, (28H, glucose), 1.2～2.5 (48H, CH₃CO-)。

2-Methylbutane Hydroxylation with PhIO

   2-Methylbutane hydroxylation in this paper was carried out under a nitrogen atmosphere in the following procedures unless otherwise specified. A solution of PhIO (100 mg, 4.5x10^-4 mol), T(m-glu)PPFeCl (10 mg, 3.0x10^-6 mol), 5mL of chlorobenzene and 0.5 mL of 2-methylbutane was warmed to 303 ± 0.5 K by circulating water and stirred 2 h with an eletromagnetic stirrer. Products were analysed by gas chromatography.

                        RESULTS AND DISCUSSION

Synthesis and Spectral Characteristic of Acetylglycosylate Metalloporphyrins

  Maillard et al ^[21] synthesized ortho-2,3,4,6-tetra-O-acetylglycosylate benzaldehyde by per-acetylation of Helicine. Halazy et al ^[22] synthesized ortho-2,3,4,6-tetra-O-acetylglycosylate benzaldehyde by the reaction of 1-α- bromo-2,3,4,6-tetra-β-O-acetylglucose with 2-hydroxybenzaldehyde. We prepared ortho-2,3,4,6-tetra-O-acetylglycosylate benzaldehyde by Halazy’s method, and synthesized tetra (o-2,3,4,6-tetra-O-acetylglucose-oxo-phenyl)porphine by Lindsay’s method ^[23]. Our studies showed that Halazy’s synthetic method of tetra(ortho-acetylglucose-oxo-phenyl)porphine could be used to the synthesis of tetra(m-2,3,4,6-tetra-O-acetylglucose-oxo-phenyl)porphine.

   We tried to synthesize 5-acetylglycosylate-oxo-phenyl-10, 15,20-triphenyl)porphine from the reaction of 5-para-hydroxylphenyl-10,15,20-triphenylporphine with 1-bromo-2,3,4,6-tetra-O-acetylglucose, but, unfortunately, failed.

   The reaction of tetra-acetylglycosylate porphine T(o-glu)PPH₂ (4) and T(m-glu)PPH₂ (5) with FeCl₂ and MnCl₂ provided chloro[tetra(o-2, 3,4,6-tetra-acetylglucose-oxo-phenyl)porphinatoiron] (6), chloro[tetra(m-2,3,4,6-tetra-acetylglucose-oxo-phenyl)porphinatoiron] (7), chloro[tetra(o-2,3,4,6-tetra-acetylglucose-oxo-phenyl)porphinatomanganese] (8) and  chloro[tetra(o-2,3,4,6-tetra-acetylglucose-oxo-phenyl)porphinato-manganese] (9) respectively. In order to avoid forming μ-oxo-dimer of acetylglycosylate metalloporphyrins during the course of the reaction, we used the modified Adler’s method ^[19] by slowly adding 6  mol/l of hydrochloric acid into the hot reactants until acetylglycosylate metalloporphyrins precipitated. The reaction completed within 1 h.

The electronic spectra of tetraacetylglycosylphenylporphines T(o-glu)PPH₂ (4) and T(m-glu)PPH₂ (5) were the same as that of tetraphenylporphine TPPH₂. The electronic spectra of their metal complexes T(o-glu)PPFeCl (6), T(m-glu)PPFeCl (7), T(o-glu)PPMnCl (8) and T(m-glu)PPMnCl (9) were essentially same as  that of the metal complexes of tetraphenylporphine, TPPFeCl and TPPMnCl, too. This showed that there was no evidence of the effect of acetylglucose group linking onto porphine benzene ring on electronic absorption of porphine. In contrast with ¹HNMR of tetraphenylporphine TPPH₂, acetylglycosylate tetraphenylporphine T(o-glu)PPH₂ (4) and T(m-glu)PPH₂ (5) had ¹HNMR peaks of acetyl group at 1.06-2.23 ppm and glucose group at 4.07-5.33 ppm, and ¹HNMR of tetraphenylporphine ring split into complicated multiple peaks after acetylglucose group being introduced on porphine benzene ring. Above phenomenon showed that it was possible that there existed some interaction among the protons of acetylglucose group and porphine ring. Moreover, ¹HNMR of T(o-glu)PPH₂ (4) showed an absorption peak at -1.2 ppm, which is not the case with T(m-glu)PPH₂ (5). This proposed rather different stereochemistry of acetylglycosylate porphine when acetylglucose group was introduced on ortho- and meta- position of the porphine benzene ring.

Catalysis of Acetyglycosylate Metalloporphyins for the Regiospefic Oxidation Toward Primary Carbon-hydrogen Bonds of 2-Methylbutane

   Lyons et al ^[24] reported halogenated metalloporphyrin complexe as catalysts for selective reaction of alkane with molecular oxygen. These work showed that metallic complexes of halogenated porphyrinato ligand systems were active catalysts for the oxidation of unactivated alkanes have either econdary or tertiary carbon-hydrogen bonds, but primary carbon-hydrogen bonds were quite rresistant to oxidative attack in the presence of these catalysts. In order to study the regioselective oxidation of alkane catalyzed by acetyglycosylate metalloporphyins, we built the model of PhIO-acetylglycosylate metalloporphyrin-2-methylbutane. We chose 2-methylbutane as the substrate which has primary, secondary and tertiary carbon-hydrogen bonds. The oxidation of 2-methylbutane catalyzed by metalloporphyrins had five competition products that are shown in flollowing:

3-Methyl-2-butanone (1) and 3-methyl-2-butanol (3) come from the oxidation of the secondary carbon-hydrogen bonds, 2-methyl-2-butanol (2) comes from the oxidation of the tertiary carbon-hydrogen bonds, and 2-methyl-1-butanol (4) and 3-methyl-1-butanol (5), from the primary bonds.

Table 1 listed the comparing results of the reaction catalyzed by different metalloporphyrins.

Table 1 Regioselectivity in 2-Methylbutane oxidation catalyzed by acetylglycosylate metalloporphyrins

One could see from Table 1 that oxidation of 2-methylbutane catalyzed by acetylglycosylate metalloporphyrins occurred on the end carbon and the product was 3-methyl-1-butanol while oxidation catalyzed by tetraphenylmetalloporphrin had two products which were 3-methlyl-2-butanone and 2-methyl-2-butanol. The results showed that acetylglycosylated metalloporphyrins regiospecfically catalyzed the oxidation of the primary carbon-hydrogen bonds even though the reaction run at low turnover unmber compared with uasual metalloporphyrrins. The acetylglycosylated metalloporphyrins’ better catalytic selectivity to oxidation of 2-methylbutane could better imitate the cytochrome P-450’s catalytic reaction in organism than others.

Porphyrins and glucose are both activated species existing in organism. Glucose had the influence of the selectivity of catalytic oxidation of alkane when it was introduced on the pophyrin ring. Acetylglycosylate metalloporphyrins could better imitate the organism’s chemical conditions than metalloporphyrins without sugar, the reasons will be studied further.

Relative Reactiveity of Secondary and Tertiary Carbon-hydrogen Bonds Oxidation by Metalloporphyrins Without Sugar Groups

One could see from Table 1 that there existed differences in oxidation yields between secondary carbon-hydrogen bonds and tertiary carbon-hydrogen bonds when isopentane oxidation was catalyzed by TPPFeCl and TPPMnCl, which showed that reactivity of the secondary carbon-hydrogen bones was different from that of tertiary carbon-hydrogen bones. Moreover, the ratios of yields of oxidation of secondary carbon-hydrogen bones to those of tertiary carbon-hydrogen bones were relation to metallic atoms of metalloporphyrins. According to numbers of secondary and tertiary hydrogen atoms and their oxidation yields, the quantitation analysis for relative reactiveity between secondary and tertiary carbon-hydrogen bonds by TPPFeCl and TPPMnCl can be expressed mathematically as the following.

Relative reactivity = reativity of secondary C-H : reativity of tertiary C-H

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* The chinese edition of this paper was  publiced in ACAT CHIMICA SINICA, 2000, 58, 332.