JP6681619B2 - Method for producing phenolic compound - Google Patents

Description

  The present invention relates to a method for producing a phenolic compound from an aromatic compound. More specifically, the present invention relates to a method for producing a phenolic compound by directly oxidizing an aromatic compound using a specific copper complex.

  Phenol is produced using benzene as a raw material, but since benzene is an aromatic hydrocarbon having the simplest structure, it has very high stability and poor reactivity. For this reason, at present, phenol is produced by cumene oxidation via cumene (isopropylbenzene) instead of direct oxidation of benzene, but this cumene method is a multi-step method that requires high temperature and high pressure. Since its total yield is as low as about 5%, it is an inefficient method for producing phenol. Therefore, development of a method for directly converting (oxidizing) benzene into phenol is desired.

Recently, in Non-Patent Document 1, a method for directly producing phenol from benzene using a nickel complex of a tetradentate polypyridine ligand as a catalyst and using inexpensive hydrogen peroxide (H ₂ O ₂ ) as an oxidant has been reported. Has been done. However, the reported reaction requires more than 200 hours to obtain a catalyst turnover number of about 700 times.

  The present inventors also reported a method of directly producing phenol from benzene at a faster reaction rate than the method of Non-Patent Document 1 using a specific binuclear nickel complex as a catalyst (Non-Patent Document 2). However, a higher reaction rate is desired from the viewpoint of practical use.

J. Am. Chem. Soc., 2015, 137 (18), pp 5867-5870 Proceedings of the 65th Symposium of the Society for Complex Chemistry, pp354, 2PF-56

  In view of the above-mentioned problems, an object of the present invention is to provide a method capable of producing a phenolic compound by directly oxidizing an aromatic compound such as benzene more efficiently.

  As a result of repeated studies to solve the above-mentioned problems, the present inventors have used a specific copper complex as a catalyst, and have a much faster reaction rate than the case of using the nickel complex as a catalyst. , Succeeded in producing a phenolic compound from an aromatic compound, and completed the present invention.

The present invention produces a phenolic compound by oxidizing (hydroxylating) an aromatic compound with an oxidizing agent in the presence of a copper complex having a compound represented by the following formula (I) or (II) as a ligand. (In the formula below, R _{1 to} R ₉ each independently represents a methylene group or an ethylene group).

  The polypyridine ligand represented by the above formula (I) and the polypyridine ligand represented by the above formula (II) form a copper complex, and, even at a temperature of less than 100 ° C. and atmospheric pressure, respectively, The nickel complex having tepa as a ligand, which is reported to have the highest catalytic function in Non-Patent Document 1 and which can catalyze a monoatomic oxygenation reaction, and 6-hpea reported in Non-Patent Document 2, Since the catalyst turnover number (TON = turnover number) and the catalyst turnover frequency (TOF = turnover frequency) are much higher than those of the binuclear nickel complex as a ligand, the phenolic compound can be produced more quickly.

  In the present invention, the more preferred ligand of the copper complex is 1,2-bis (2- (bis (2-pyridylmethyl) aminomethyl) 6-pyridyl) ethane [6-hpa], tris (2-pyridylmethyl). Amine [tmpa], most preferred ligand is 6 hpa.

  According to the method of the present invention, benzene can be directly converted into phenol using hydrogen peroxide as an oxidant.

  Since the oxidation catalyst of the present invention can carry out monoatomic oxygenation of an aromatic compound at a high catalyst turnover number (TON) and catalyst turnover frequency (TOF), according to the production method of the present invention, the aromatic compound A phenolic compound can be rapidly produced from

FIG. 1 is a diagram showing preferred ligands and copper complexes thereof that can be used in the present invention. FIG. 2 is a diagram showing a preferred example of synthesizing 6-hpa. FIG. 3 is a diagram showing an electrospray ionization mass spectrometry (ESI-MS) spectrum of a 6-hpa copper complex. FIG. 4 is a diagram showing ORTEP of a copper complex of 6-hpa. FIG. 5 is a diagram showing an electrospray ionization mass spectrometry (ESI-MS) spectrum of the copper complex of tmpa. FIG. 6 is a diagram showing ORTEP of a copper complex of tmpa. FIG. 7 is a diagram showing the catalytic reaction and the catalyst turnover number by the copper complex of 6-hpa and the copper complex of tmpa. In the upper part of FIG. 7, when the substrate (benzene) is 30 mmol, the lower part of FIG. ) Is 60 mmol. FIG. 8: is a figure which shows the origin of the oxygen atom of a phenolic compound. FIG. 9 is a diagram showing the values of kinetic isotope effect (KIE) of 6-hpa copper complex and tmpa copper complex. The upper part of FIG. 10 is a diagram showing an absorption spectrum of a reaction intermediate formed by the copper complex of 6-hpa and hydrogen peroxide, and the lower part of FIG. 10 is formed by the copper complex of tmpa and hydrogen peroxide. It is a figure which shows the absorption spectrum of a reaction intermediate.

The ligand of the copper complex according to the present invention is a polypyridine ligand having 6 or 3 pyridine rings in its molecule and is represented by the following formula (I) or (II). _{1 to} R ₉ each independently represent a methylene group (—CH ₂ —) or an ethylene group (—CH ₂ CH ₂ —).

More preferable ligands are as follows.
A compound of formula (I) "6-hpa" in which R _{1 to} R ₆ are all methylene groups: 1,2-bis (2- (bis (2-pyridylmethyl) aminomethyl) 6-pyridyl) ethane;
· R ₇ to R ₉ are all methylene compound of formula (II) "tmpa": tris (2-pyridylmethyl) amine.
The structures of 6-hpa and tmpa are shown below. Moreover, the structure of the copper complex which makes these into a ligand is shown in FIG.

The copper complex of the present invention can catalyze an oxidation reaction. Since the copper complex of the present invention has a very high oxidation catalytic activity, it introduces a phenolic hydroxyl group by oxidation (sp ² C—H bond sp ² C-OH bond). Further, when the copper complex of the present invention is used as a catalyst for the oxidation reaction of an aromatic compound, only one of the carbon atoms on the aromatic ring can be oxidized (selective monoatomic oxygenation), An aromatic compound having a plurality of hydroxyl groups and quinones (by-products) are scarcely produced, and a phenol compound having one hydroxyl group can be produced in a high yield. In addition, in this invention, a phenolic compound means the compound which has the hydroxyl group couple | bonded with the aromatic ring.

  The oxidation reaction of the present invention is preferably carried out in a polar organic solvent such as acetonitrile or acetone. When hydrogen peroxide is used as an oxidant, hydrogen peroxide is generally used in the form of an aqueous solution, and water is produced by the reaction, so water is mixed in the polar organic solvent. The oxidation reaction according to the present invention sufficiently proceeds even in a mixed liquid of the organic solvent and a polar organic solvent. The volume of water (volume at the start of the reaction) is preferably 3/4 or less, more preferably 2/3 or less, and preferably 1/2 or less with respect to 1 volume of the polar organic solvent. Particularly preferred.

The amount of the substrate (aromatic compound) with respect to the copper complex may be appropriately selected depending on the type of raw material used and the oxidation conditions. For example, when the copper complex having the formula (I) as a ligand is 1 mol, the substrate is about 10,000 to 200,000 mol (more preferably 20,000 to 150,000 mol, particularly preferably 30,000 to 100,000 mol). Mol), and when the copper complex having the ligand of formula (II) is 1 mol, the substrate is 5,000 to 100,000 mol (more preferably 10,000 to 75,000 mol, particularly preferably 15,000). Mol to 50,000 mol) is preferable.
Further, the amount of the oxidizing agent (preferably hydrogen peroxide) added may be appropriately adjusted depending on the kind of the substrate and the oxidizing conditions, but for example, 0.5 to 10 mol, more preferably 1 mol per 1 mol of the substrate. It can be added in a proportion of -8 mol, particularly preferably 2-5 mol.

Further, the oxidation reaction of the present invention may be carried out in the presence of a basic substance (for example, a tertiary amine such as triethylamine). In particular, when using a copper complex having the formula (II) as a ligand, it is preferable to carry out the oxidation reaction in the presence of a basic substance.
For example, when the copper complex having the formula (I) as a ligand is 1 mol, the basic substance is about 0 to 20 mol (more preferably 0 to 10 mol, particularly preferably 0 to 8 mol), and the formula ( When the copper complex having II as a ligand is 1 mol, the amount of the basic substance can be about 1 to 8 mol (more preferably 1.5 to 5 mol, particularly preferably 1 to 3 mol). . In the case of a copper complex having the formula (I) as a ligand, the reaction can be similarly progressed in the absence of a basic substance, although the initial rate is slightly decreased. Therefore, the presence or absence of addition of the basic substance can be properly used depending on the substrate.

The concentrations of the catalyst, substrate, oxidizing agent, basic substance and the like in the solvent in which the reaction is carried out can be appropriately selected according to the scale of the reaction, the reaction temperature, the substance used and the like. For example, the catalyst concentration can be about 10 μmol / L to 500 μmol / L.
The oxidation reaction of the present invention proceeds even at room temperature, and the final catalyst rotation number is similar to that under high temperature, but it is preferable to carry out the reaction under heating to increase the reaction rate. The preferred reaction temperature is 40 ° C to 80 ° C, particularly preferably 50 to 70 ° C. The oxidation reaction can be carried out under normal pressure.

  A preferred oxidizing agent for use in the present invention is hydrogen peroxide. Hydrogen peroxide is an oxidant that is easily available and inexpensive, and since it produces only water as a by-product of the reaction, it has the highest atom economy other than molecular oxygen and is the best oxidant.

An example of the method using the catalyst of the present invention is a method of directly converting (oxidizing) benzene into phenol as shown below. According to the catalyst of the present invention, unlike the cumene method, high temperature and high pressure are not required, and phenol can be produced from benzene under normal pressure and at a temperature of about 50 ° C.

  The aromatic compound that can be used in the present invention includes not only a homocyclic aromatic compound in which an aromatic ring is composed only of carbon, but also an aromatic ring is composed of carbon and another element (nitrogen, oxygen, or sulfur atom). Heterocyclic aromatic compounds are also included. Further, not only a compound having one aromatic ring but also a compound having a plurality of aromatic rings are included. Further, the aromatic compound of the present invention may have a substituent (various substituents including an alkyl group and a nitro group) other than the hydroxyl group, which is bonded to the aromatic ring.

  The ligand 6-hpa used in the present invention can be prepared, for example, by the synthetic route shown in FIG. 2, and tmpa is prepared by reacting 2-chloromethylpyridine with 2-picolylamine under basic conditions. Can be manufactured by. Further, since tmpa is commercially available, a commercially available product may be used.

The copper complex according to the present invention can be produced by stirring a ligand and a copper (II) salt in an organic solvent or a mixed solution of an organic solvent and water.
In the case of the ligand of the formula (I), the molar ratio of the ligand and the copper (II) salt is about 1: 2 (particularly about 1: 2.05-2.3), and the ligand of the formula (II) is used. In the case of a ligand, it is preferable to measure and mix the ligand and the copper (II) salt so that the molar ratio is about 1: 1 (particularly about 1: 1.05 to 1.2).
The copper (II) salt used is not particularly limited. For example, various copper salts such as copper perchlorate and copper trifluoromethanesulfonate can be used. Further, as the organic solvent, methanol, ethanol, acetonitrile, acetone or the like can be used.

  Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to the examples.

The solvents used in the examples are described below. Unless otherwise specified, those manufactured by Wako Pure Chemical Industries, Ltd. were purchased and used as they were.
solvent
Acetonitrile (MeCN) was used for spectroscopic analysis manufactured by Wako Pure Chemical Industries, Ltd., which was heated under reflux in the presence of P ₂ O ₅ for 1 hour and then distilled. Acetone was used for spectroscopic analysis manufactured by Wako Pure Chemical Industries, which was stirred in the presence of anhydrous Ca (SO ₄ ) _{2 for} 48 hours, then decanted and distilled. CH ₂ Cl ₂ used for organic synthesis manufactured by Wako Pure Chemical Industries, was stirred overnight with anhydrous CaCl ₂ , decanted, heated under reflux in the presence of CaH ₂ , and then distilled. Methanol (MeOH) for organic synthesis was used after being heated and refluxed overnight in the presence of Mg (OMe) ₂ adjusted in the presence of Mg / I ₂ and then distilled.

[Production Example 1] Production of 6-hpa [1,2-bis (2- (bis (2-pyridylmethyl) aminomethyl) 6-pyridyl) ethane] 6-hpa was produced according to the synthetic route shown in FIG. The raw material (A) 2-amino-6-picoline and 2-chloromethylpyridine hydrochloride shown in FIG. 2 were obtained from Waken Yakuhin.

(B) Synthesis of 2-bromo-6-methylpyridine
A 1000 mL 4-neck round bottom flask was equipped with an alkali trap, an isobaric dropping funnel, a thermometer, and a mechanical stirrer. (A) 2-amino-6-picoline (27.0 g 0.25 mol) and 48% HBr (125 mL 2.31 mol) were put into this reaction container. The reaction vessel was immersed in an ice bath and cooled to 0 ° C. Br ₂ (37.5 mL 0.72 mol) was transferred to an isobaric dropping funnel, the temperature of the reaction solution was kept at 0 ° C., and the mixture was slowly added dropwise to the reaction container over 90 minutes while vigorously stirring with a mechanical stirrer. NaNO ₂ (42.5 g 0.62 mol) was weighed and dissolved in about 100 mL of distilled water. This was transferred to an isobaric dropping funnel and added dropwise over about 2 hours with vigorous stirring with a mechanical stirrer. At this time, care was taken so that the temperature of the reaction solution did not exceed 10 ° C. In order to complete the reaction, NaNO ₂ (2.50 g 0.036 mol) was further dissolved in about 10 mL of distilled water and added, and it was confirmed that nitrogen gas was not generated from the reaction vessel. NaOH (95.0 g 2.4 mol) was dissolved in about 300 mL of distilled water while cooling in an ice bath, and after sufficiently cooling, the solution was added little by little to neutralize. At this time, care was taken so that the temperature of the reaction solution did not exceed 20 ° C. The reaction mixture was extracted with Et ₂ O (200 mL × 4), and the organic layer was collected. Anhydrous Na ₂ SO ₄ was added, dried, and concentrated to give a brown oily substance. This oily substance was distilled under reduced pressure with a rectification tube, and fractional distillation at 55-60 ° C was performed at a reduced pressure of 7.00 mmHg to obtain a yellow oily substance. This material was stored at -40 ° C.
Yield: 72% (32.0g)

(C) Synthesis of 1,2-bis (2-bromo-6-pyridyl) ethane
A rotor was placed in a 500 mL three-neck reaction vessel, and a three-way cock, an isobaric dropping funnel (50 mL), a septum cap and a balloon were attached, and vacuum drying was performed. The reaction container was placed under a N ₂ atmosphere, and diisopropylamine (19.2 mL 0.137 mol) was added by a syringe. After adding dry THF (300 mL) to the reaction vessel with a syringe and replacing the inside of the reaction vessel with N ₂ , the mixture was cooled to −78 ° C. in an ethanol bath. After this time 1.6 M n-BuLi (85.6 mL 0.137 mol) was added via syringe. After reacting for 20 minutes, (B) 2-bromo-6-methylpyridine (23.4 g 0.136 mol) was added dropwise from a 50 mL isobaric dropping funnel over 20 minutes. After reacting at -78 ° C for 2 hours, 1,2-dibromoethane (11.8 mL 0.069 mol) was added by a syringe. The reaction vessel was removed from the ethanol bath, and the mixture was stirred overnight at room temperature. The reaction was stopped by adding distilled water. After concentrating THF, the mixture was separated with CHCl ₃ (100 mL × 3) using a separating funnel, and the organic layer was extracted. Anhydrous Na ₂ SO ₄ was added for dehydration, followed by concentration to obtain a reddish purple solid. The solid was washed with MeOH to give a pale red solid. The operation of concentrating the filtrate and washing with MeOH was repeated 4 times. The obtained pale red solid was dissolved in Hexane, heated to 70 ° C., filtered while hot, and the filtrate was allowed to stand to obtain a pale yellow solid.
Yield: 81% (18.9g)

(D) Synthesis of 1,2-bis (2-cyano-6-pyridyl) ethane
A 100 mL two-neck reaction vessel was equipped with a three-way cock, a balloon and a septum cap, and vacuum dried. (C) 1,2-bis (2-bromo-6-pyridyl) ethane (4.4g 12.8mmol), Pd / C (49.84% water, 1.1g), dppf (0.6g 1.01mmol), Zn (CN) ₂ (1.8 g 15.3 mmol) was placed in a two-neck reaction vessel, and the water contained in Pd / C was seen through the line. Then added dimethylacetamide a (DMA) (50mL) in a syringe, after deaerated and filled with nitrogen, Zn (HCO ₂₎ with nitrogen flow of _{2 · 2H 2 O (98.00%} ) (0.4g, 2.04mmol) was added to The mixture was stirred for 1 hour while heating at 110 ° C. Then, while lowering the temperature to 80 ° C., the mixture was stirred for 2 hours, after completion of stirring, the temperature was returned to room temperature, ethyl acetate (150 mL) was added to precipitate Pd / C, and the Pd / C was removed by filtration. Then, after liquid separation with water (200 mL × 2) and 5% aqueous ammonia (200 mL × 1), the organic layer was extracted. The extracted organic layer was concentrated with an evaporator. After dehydration with anhydrous Na ₂ SO ₄ , the mixture was concentrated with an evaporator to obtain a brown solid. This was recrystallized with CHCl ₃ : Hexane (50 mL: 300 mL) to obtain a skin-colored solid.
Yield: 88% (2.6g)

(E) Synthesis of 1,2-bis (2-aminomethyl-6-pyridyl) ethane ・ 4hydrochrolide
Put a rotor in a 300 mL three-neck reaction vessel, attach a three-way cock, a balloon, and a ball stopper, and add (D) 1,2-bis (2-cyano-6-pyridyl) ethane (1.0 g 4.27 mmol) and dry THF 200 mL. It was stirred. After the reaction vessel was put in an ice bath and sufficiently cooled, LiAlH ₄ (1.1 g 21.9 mmol) was added, and the mixture was stirred for 30 minutes in the ice bath and then at room temperature for 5 hours. The reaction vessel was again placed in an ice bath and 20% NaOHaq was added dropwise until the solution turned yellow. The precipitated salt was washed with THF and removed by Celite filtration, the filtrate was concentrated with an evaporator, appropriate amounts of H ₂ O and CHCl ₃ were added, and the mixture was extracted with CHCl ₃ (50 mL × 4) using a separating funnel. Anhydrous Na ₂ SO ₄ was added for dehydration, followed by concentration to obtain a yellow oily substance. The oily substance was dissolved in CHCl ₃ , 12M HCl was added until the pH was 1, the mixture was stirred for 10 minutes, and then extracted using a separating funnel. Water was concentrated with an evaporator in the presence of an alkali trap to obtain a yellow solid as a hydrochloride salt. The obtained solid was collected by filtration while being washed with Acetone and MeOH to obtain a yellow solid.
Yield: 98% (1.58g)

(F) Synthesis of 1,2-bis (2- (bis (2-pyridylmethyl) aminomethyl) 6-pyridyl) ethane (6-hpa)
Put a rotor in a 100mL reaction vessel, weigh (E) 1,2-bis (2-aminomethyl-6-pyridyl) ethane (1.0g 2.58mmol), 2-chloromethylpyridine ・ hydrochloride (1.86g 11.3mmol), and distill. It was dissolved in 10 ml of water. In an ice bath, a solution obtained by dissolving NaOH (1.56 g 38.6 mmol) in a minimum amount of distilled water was added, the inside of the reaction vessel was replaced with N ₂ , and the temperature was returned to room temperature and stirred for 48 hours. After 48 hours, it was extracted with CH ₂ Cl ₂ (50 mL × 3) using a separating funnel. Anhydrous Na ₂ SO ₄ was added for dehydration, followed by concentration and reduction of pressure by a vacuum line to deposit a brown solid. The solid was washed with a minimum amount of MeCN, collected by filtration, and vacuum dried to obtain a flesh-colored solid. When the complex was synthesized, it was recrystallized from CH ₂ Cl ₂ / n-hexane.
Yield: 52% (0.814g)

It was confirmed by a nuclear magnetic resonance spectrum ( ¹ H NMR spectrum) that the obtained product was 6-hpa.

[Production Example 2] Synthesis of 6-hpa binuclear copper (II) complex; [Cu ^II ₂ (μ-OH) (6-hpa)] (ClO ₄ ) ₃ .
6-hpa (0.1 g 0.165 mmol) was weighed into a 50 mL eggplant-shaped flask and dissolved in 30 mL of MeOH. To this solution, the addition of _{Cu (ClO 4) 2 · 6H} 2 O (0.134 g 0.363mmol), the solution became turbid moment, the solution turned homogeneous dark blue. A solution of Et ₃ N (0.167 g 1.65 mmol) dissolved in 5 mL of MeOH was added little by little, and the color was further darkened by stirring. A small amount of insoluble semi-oily oily substance was precipitated. A three-way cock and a balloon were attached, deaeration and nitrogen substitution were carried out in a vacuum line, and the mixture was stirred overnight. The insoluble semi-oil substance was removed by filtration with a Kiriyama funnel. A large excess of Et ₂ O was added to this residue to precipitate a complex. It was collected by filtration while washing with Et ₂ O and dried in vacuo. When recrystallized in air, a carbonate ion-crosslinked complex is formed. Therefore, dissolve it in a minimum amount of MeCN / CH ₂ Cl ₂ (v: v = 1: 1) under a nitrogen atmosphere, and Recrystallization from liquid-liquid diffusion of -CH ₂ Cl ₂ -Benzene gave a deep blue single crystal suitable for single crystal X-ray structural analysis. This complex was stable at room temperature in the air in the powder or crystalline state.

The obtained crystal was subjected to electrospray ionization mass spectrometry (ESI-MS) (see FIG. 3). As a result, the molecular ion peak {[Cu ₂ (OH) (6-hpa)] (ClO ₄ ) ₂ } ⁺ was observed at m / z 949 as the main peak.
The crystal structure of the complex was confirmed by X-ray structure analysis. FIG. 4 shows the results. The copper ion of the complex has a distorted trigonal and bipyramidal structure based on the calculated τ value, and one hydroxo oxygen, three pyridine nitrogen, and one tertiary amine nitrogen are coordinated to each copper ion. I know that Moreover, the Cu-O-Cu angle takes the value of a typical hydroxo bridge.

[Production Example 3] Production of tmpa [tris (2-pyridylmethyl) amine]
A rotor was placed in a 100 mL eggplant flask, a three-way cock and a balloon were attached, and vacuum drying was performed. Under a nitrogen atmosphere, 2-chloromethylpyridine · hydrochloride (2.0 g 12.2 mmol) was added and dissolved in 20 mL of distilled water. In an ice bath, NaOH (2.44 g 61.0 mmol) dissolved in a minimum amount of distilled water was slowly added, and 2-picolylamine (0.60 g 5.54 mmol) was added and stirred. At this time, if the solution was not uniform, a small amount of distilled water was added until it became uniform. The color of the solution was red. It was removed from the ice bath and stirred at room temperature for 48 hours. The color of the solution gradually became brown, and a brown oily substance insoluble in the aqueous solution was deposited. CH ₂ Cl ₂ 50 mL was added to the solution, the mixture was transferred to a separating funnel, CH ₂ Cl ₂ was used for liquid separation, and an organic layer was extracted (50 mL × 3). The extracted organic layer was dehydrated with Na ₂ SO ₄ and then concentrated with an evaporator to obtain a brown oily substance. The obtained oily substance was well dried in a vacuum line under vacuum to precipitate a brown semi-oiled solid. This was washed with a small amount of Et ₂ O to give a brown solid. The solid was recrystallized from Ligroin to obtain 0.68 g of pale yellow needle crystals.
Yield: 42%

It was confirmed by a nuclear magnetic resonance spectrum ( ¹ H NMR spectrum) that the obtained product was tmpa.

[Production Example 4] Copper complex of tmpa; Synthesis of [Cu ^II (MeCN) (tmpa)] (ClO ₄ ) ₂
In a 50 mL eggplant-shaped flask, tmpa (0.1 g 0.344 mmol) was weighed and dissolved in 20 mL of EtOH. Cu (ClO ₄ ) ₂ .6H ₂ O (0.140 g 0.379 mmol) was dissolved in 10 mL and added to this solution to precipitate a light blue solid. When this solid was left to stand, it became semi-oil and accumulated at the bottom. The supernatant was removed and repeated washing with EtOH gave a semi-oily blue solid. This was dried in a vacuum line well under vacuum to obtain a light blue solid. This solid was dissolved in MeCN / acetone (v: v = 1: 1) and recrystallized from liquid-liquid diffusion of MeCN-acetone-Et ₂ O to obtain a deep blue single crystal suitable for single crystal X-ray structural analysis. It was The crystals were efflorescent and, when taken out from the solution, efflorified to become light blue powder

Electrospray ionization mass spectrometry (ESI-MS) was performed on the obtained crystals. As a result, a mononuclear copper complex {[Cu (tmpa) (ClO ₄ )]} ⁺ was observed at m / z 452 as the main peak (see FIG. 5).
The crystal structure of the complex was confirmed by X-ray structure analysis. FIG. 6 shows the results.
This crystal structure was found to be in good agreement with the values reported in the past. From the calculated τ value, it was revealed that the copper ion of the complex had a distorted trigonal bipyramidal structure, MeCN was coordinated to the complex as a solvent molecule, and acetone was included as a crystal solvent.

[Example 1] Phenol formation reaction by oxidation (hydroxylation) of benzene (1)
Using 6-hpa binuclear copper (II) complex (hereinafter referred to as catalyst 1; referred to as cat.1 in the figure) as a catalyst and hydrogen peroxide as an oxidant, benzene was converted into phenol by the following procedure. Converted to:
A rotor was put in a 50 mL two-necked eggplant-shaped flask, a reflux tube and a three-way cock were attached to one side, and a ball plug was attached to the other side, and vacuum drying was performed. Catalyst 1 (1.0 μmol) and benzene (30 mmol) were added to the reaction vessel and dissolved in 20 mL of MeCN. To this, 0.1 M Et ₃ N / MeCN (50 μL 5.0 μmol) was added, followed by 12 MH ₂ O ₂ aqueous solution (10 mL 120 mmol), attached with a three-way cock and a balloon, and degassed and nitrogen in a vacuum line. It was replaced and immersed in an oil bath which had been heated to 50 ° C. in advance, and the mixture was heated and stirred. After a certain period of time, a small amount of the solution was taken out under a nitrogen flow, Nitrobenzene was added as an external standard, and the oxidation product (phenol) was quantified by GC using a calibration curve prepared in advance. In this reaction, independent experiments were conducted 5 times or more, and the number of catalyst revolutions (TON) at each time was determined from the amount of phenol produced at each time, and the average value and standard deviation were determined.

[Example 2] Phenol formation reaction by oxidation of benzene (2)
The tmpa copper (II) complex (hereinafter referred to as catalyst 2; referred to as cat.2 in the figure) as a catalyst was converted to benzene into phenol by the following procedure using hydrogen peroxide as an oxidizing agent:
A rotor was put in a 50 mL two-necked eggplant-shaped flask, a reflux tube and a three-way cock were attached to one side, and a ball plug was attached to the other side, and vacuum drying was performed. Catalyst 2 (2.0 μmol) and benzene (30 mmol) were added to the reaction vessel and dissolved in 20 mL of MeCN. To this, 0.1 M Et ₃ N / MeCN (50 μL 5.0 μmol) was added, followed by 12 MH ₂ O ₂ aqueous solution (10 mL 120 mmol), attached with a three-way cock and a balloon, and degassed and nitrogen in a vacuum line. It was replaced and immersed in an oil bath which had been heated to 50 ° C. in advance, and the mixture was heated and stirred. After a certain period of time, the solution was taken out under a nitrogen flow, and Nitrobenzene was added as an external standard to quantify the oxidation product (phenol) by GC using a calibration curve prepared in advance. In this reaction, independent experiments were conducted 5 times or more, and the number of catalyst revolutions (TON) at each time was determined from the amount of phenol produced at each time, and the average value and standard deviation were determined.

After the reaction according to Example 1 and Example 2, phenol production was confirmed, demonstrating that phenol can be produced from benzene in one step by the method according to the present invention.
Table 1 summarizes the TON results calculated from the amount of phenol produced according to Examples 1 and 2. It is considered that 6-hpa forms a binuclear copper complex and tmpa forms a mononuclear copper complex. Therefore, the number of moles of tmpa (2.0 μmol) in Example 2 is 6-hpa of Example 1. The number of catalyst revolutions in Table 1 is the number of revolutions per mol of the catalyst, although it was set to twice the number (1.0 μmol). The results are shown in Table 1 and the upper part of FIG. 7.

As shown in Table 1, the maximum TON of catalyst 1 was 6200 times, the maximum TON of catalyst 2 was 1188 times, the TOF of catalyst 1 was 527 (h ^-1 ), and the TOF of catalyst 2 was 216 (h ^-1 ). . The yields of the reactions of Example 1 and Example 2 were 21% in Example 1 (catalyst 1: 1.0 μmol) and 7.9% in Example 2 (catalyst 2: 2.0 μmol).
Non-Patent Document 1 reported that a benzene hydroxylation reaction using a nickel complex having tepa as a ligand (benzene: 5.0 mmol, H ₂ O ₂ : 25 mmol, catalyst: 0.50 μmol, triethylamine: 5.0 μmol; When the catalyst concentration in the reaction system is similar to that in Example 2), the yield of phenol after 216 hours at 60 ° C. is 7.5%, and the TON is 749 times. It was confirmed that TON and TOF were much higher than those of the catalyst of Non-Patent Document 1, and that phenol could be efficiently produced in a short time.
Moreover, the production of benzoquinone was confirmed as a by-product, but the amount thereof was very small (see FIG. 7), demonstrating the high selectivity of the catalyst according to the present invention. In particular, catalyst 1 showed high selectivity (the production ratio of phenol and benzoquinone was 93.2: 6.80 for catalyst 1 and 88.4: 11.6 for catalyst 2).

[Example 3] Change of substrate concentration The copper complex of 6-hpa and tmpa was used as a catalyst in the same manner as in Example 1 and Example 2 except that the addition amount of the substrate (benzene) was increased to 60 mmol. Then, an oxidation reaction from benzene to phenol was performed. The results are shown in Table 2 and the lower part of FIG. 7.

As is clear from Table 2, when the substrate concentration was increased from 30 mmol (Example 1) to 60 mmol, TON increased almost twice with both catalysts, and when catalyst 1 was used. The maximum TON was 12550, the TOF was 1006 (h ^-1 ), and the maximum TON when using catalyst 2 was 2481 and the TOF was 444 (h ^-1 ). The yield was almost the same as when the substrate concentration was 30 mmol, and was 21% when catalyst 1 was used and 8.3% when catalyst 2 was used. From this, it was found that when the phenolic compound is produced from the aromatic compound by using the catalyst of the present invention, the amount of the product can be increased by increasing the mass of the group. The ratio of phenol to by-product (benzoquinone) was 95.2: 4.80 for catalyst 1 and 91.3: 8.70 for catalyst 2, and it was confirmed that high selectivity was maintained regardless of the substrate concentration.
In the method of Non-Patent Document 1, the yield was 21% when the base mass was 10 times (5.0 μmol) the catalyst 0.5 μmol, but the base mass was 10,000 times the catalyst 0.5 μmol. When it was increased to (5.0 mmol), the yield decreased to 7.5%. On the other hand, the catalyst 1 of the present invention can maintain a high yield even when the mass of the base is 60,000 times the catalyst amount (on a molar basis), and thus it can be seen that the activity of the catalyst of the present invention is extremely high. .

Example 4 Confirmation of Dependence on Substrate Concentration From Example 3, it was suggested that TON is increased by increasing the concentration of the substrate (benzene). Therefore, an experiment for investigating the relationship between the substrate concentration and the amount of phenol produced was further conducted. went. Specifically, an experiment was conducted in the same manner as in Example 1 and Example 2 except that the concentration of benzene was changed, and the amount of phenol produced 1 hour after the start of the reaction was calculated. The results are shown in Table 3.

  As is clear from Table 3, in both cases of using catalyst 1 and catalyst 2, the amount of phenol produced increased depending on the increase of the substrate concentration. From this, the catalytic activity of the copper complex according to the present invention is very high, and the generation of oxidizing active species occurs rapidly (that is, the generation stage of oxidizing active species does not become the rate-determining step), so that the substrate concentration is increased. It was shown that the production amount of the phenolic compound can be increased.

[Example 5] Confirmation of catalyst concentration dependency Furthermore, in order to investigate the effect of the catalyst concentration on the amount of phenol produced, an experiment was conducted in the same manner as in Example 1 except that the amount of catalyst 1 was changed, and the reaction was started. The catalyst concentration dependency was determined by calculating the amount of phenol produced in the subsequent 1 hour. Similarly, an experiment was conducted in the same manner as in Example 2 except that the amount of catalyst 2 was changed, and the catalyst concentration dependency was obtained. The results are shown in Table 4.

  As is clear from Table 4, the amount of phenol produced increased almost proportionally as the amount of catalyst increased, and showed a clear catalyst concentration dependency. From this, it was demonstrated that direct conversion of benzene to phenol occurs due to the action of the catalyst of the present invention, and that the amount of the phenolic compound is increased by increasing the amount of the catalyst.

[Example 6] Confirmation of influence of basic substance In order to investigate the influence of a basic substance (triethylamine) on the amount of phenol produced, the same method as in Example 1 and Example 2 was used except that the amount of triethylamine was changed. An experiment was conducted to investigate the influence of basic substances by calculating the amount of phenol produced one hour after the start of the reaction. The results are shown in Table 5.

  As shown in Table 5, when 3 to 10 mol of triethylamine was added to 1 mol of the catalyst 1, the amount of phenol produced 1 hour after the reaction was increased by about 1.5 to 2 times as compared with the case where triethylamine was not added. did. Especially when 5 to 7 mol of triethylamine was added, the yield of phenol increased. On the other hand, it was clarified that the catalyst 2 had an almost constant value of the amount of phenol produced 1 hour after the start of the reaction, regardless of the presence or absence of triethylamine.

Next, the time-dependent change of phenol production was measured when the oxidation reaction of benzene was carried out by the same method as in Example 1 (using catalyst 1) except that triethylamine was not added. The results are shown in Table 6.

  As shown in Table 6, when the change over time was observed in the case where the catalyst 1 was used and triethylamine was not added, the final catalyst rotation speed was changed as compared with Example 1 (see Table 1) in which 5 μmol of triethylamine was added. It became clear that there is no. From this, the addition of a basic substance promotes the deprotonation of hydrogen peroxide and increases the initial reaction rate, but when using catalyst 1, the basic substance affects the final catalyst rotation speed. It became clear that not give.

  On the other hand, in the case of catalyst 2, when the basic substance was not added, it was revealed that the final catalyst rotation speed was lower than that when the basic substance was added. These facts suggest that the product rotation by the produced phenol hinders the catalyst rotation of the catalyst 2. In other words, when phenol is accumulated by the catalytic reaction, it is considered that the phenol is coordinated with the active center of the complex to form a coordination-saturated complex, so that the complex is inactivated. Catalyst 2 has less steric crowding than Catalyst 1, so the phenoxide complex is relatively stable, and phenol accumulates and the amount of hydrogen peroxide becomes relatively small as at the end of the catalytic reaction. Under such conditions, the substitution reaction between the coordinated phenol and the hydrogen peroxide of the oxidizing agent becomes slow. Therefore, it is considered that if the basic substance does not coexist, the hydrogen peroxide is not deprotonated, and it becomes difficult for the hydrogen peroxide of the oxidant to coordinate with the copper ions, so that the catalyst 2 is inactivated.

[Example 7]
The following experiment was conducted in order to confirm the origin of the oxygen atom of the product (phenol) obtained by the method of the present invention.
[Hydroxylation of benzene with catalyst 1 using H ₂ ¹⁸ O ₂ ]
A rotor was placed in a 5 mL eggplant flask, a three-way cock and a balloon were attached, and vacuum drying was performed. Catalyst 1 (1.0 μmol) and benzene (30 mmol) were added to the reaction vessel and dissolved in 20 mL of MeCN. To this, 0.1 M Et ₃ N / MeCN (50 μL 5.0 μmol) was added, and then 0.5 MH ₂ ¹⁸ O ₂ aqueous solution (0.5 mL 0.25 mmol) was added, a three-way cock and a balloon were attached, and degassing was performed in a vacuum line. After substituting with nitrogen, it was placed in an oil bath which had been heated to 50 ° C. in advance, and heated under reflux for 12 hours. The solution was taken out by a nitrogen flow, and the ratio of the incorporated ¹⁸ O was calculated by calculating the peak intensity ratio of ¹⁶ O-Phenol and ¹⁸ O-Phenol from the isotope distribution of phenol produced by GC-MS. This measurement was performed 3 times, and the average value and standard deviation were calculated.

[Hydroxylation of benzene with catalyst 2 using H ₂ ¹⁸ O ₂ ]
A rotor was placed in a 5 mL eggplant flask, a three-way cock and a balloon were attached, and vacuum drying was performed. Catalyst 2 (2.0 μmol) and benzene (30 mmol) were added to the reaction vessel and dissolved in 20 mL of MeCN. To this, 0.1 M Et ₃ N / MeCN (50 μL 5.0 μmol) was added, and then 0.5 MH ₂ ¹⁸ O ₂ aqueous solution (0.5 mL 0.25 mmol) was added, a three-way cock and a balloon were attached, and degassing was performed in a vacuum line. After substituting with nitrogen, it was placed in an oil bath which had been heated to 50 ° C. in advance, and heated under reflux for 12 hours. The solution was taken out by a nitrogen flow, and the ratio of the incorporated ¹⁸ O was calculated by calculating the peak intensity ratio of ¹⁶ O-Phenol and ¹⁸ O-Phenol from the isotope distribution of phenol produced by GC-MS. This measurement was performed 3 times, and the average value and standard deviation were calculated.

The results of Example 6 are summarized in FIG. As shown in FIG. 8, the incorporation rate of ¹⁸ O in phenol exceeded 90% in both catalyst 1 and catalyst 2. From this result, it was confirmed that H ₂ O ₂ was the oxygen source of the phenolic hydroxyl group.

[Example 8] Value of kinetic isotope effect (KIE) Example 1 and Example 2 except that the substrate was changed to benzene (15 mmol) and d ₆ -benzene (15 mmol) in total of 30 mmol. Oxidation of benzene was carried out by the same method, and the value of kinetic isotope effect (KIE) in the catalytic reaction was calculated. The value of KIE was calculated from Phenol and d ₅ -Phenol peak intensity ratio of the GC-MS (KIE = Phenol / d 5 -Phenol).
The results are shown in Fig. 9. As is apparent from FIG. 9, the KIE value was almost 1 (that is, the production amount of phenol and d ₅ -phenol was about 1: 1) both with the catalyst 1 and with the catalyst 2. . This indicates that in the reaction of the present invention, C—H bond cleavage is not the rate-determining step.

Example 9 Detection of Reaction Intermediate (1) Detection of Reaction Intermediate Generated by Reaction of Catalyst 1 with H ₂ O ₂ Catalyst 1 (0.05 mM in yeast / MeCN (v: v = 20: 1)), Solutions of Et ₃ N (50 mM in acetone / MeCN (v: v = 20: 1)) and H ₂ O ₂ (10 mM in yeast / MeCN (v: v = 20: 1)) were prepared. 2 mL (0.1 μmol) of 1 solution was added to a UV cell, a three-way cock and a balloon were attached, degassing and nitrogen substitution were performed, and left for about 10 minutes until the temperature (−60 ° C.) became stable. Immediately after starting the measurement, 10 μL (0.5 μmol) of the above Et ₃ N solution was added with a microsyringe, and there was no particular change in the color or spectrum of the solution, then 10 μL of H ₂ O ₂ solution (0.1 μL) was added. μmol) was added, and the color changed to dark purple.The spectrum change is shown in the upper part of FIG.

(2) Detection of reaction intermediate generated by reaction of catalyst 2 with H ₂ O _{2 of} catalyst 2 (0.5 mM in MeCN), Et ₃ N (0.1 M in MeCN), H ₂ O ₂ (0.1 M in MeCN) Each solution was prepared. A 2 mL (1 μmol) MeCN solution of catalyst 2 was added to the UV cell, and a three-way cock and a balloon were attached to degas and replace with nitrogen. It was left for about 10 minutes until the temperature (-40 ° C) became stable. The measurement was started after the temperature became stable. Immediately after the start of the measurement, 10 μL (0.5 μmol) of the above Et ₃ N MeCN solution was added with a microsyringe. The solution color changed from blue to yellow. Then, 20 μL (2.0 μmol) of a MeCN solution of H ₂ O ₂ was added. The color changed to yellow-green. This spectrum change is shown in the lower part of FIG.

From the results of this example, it is found that the reaction of catalyst 1 with hydrogen peroxide produces a trans-μ-1,2-peroxo complex (Cu ^II —O—O—Cu ^II : peak at 525 nm) as a reaction intermediate. Conceivable. In addition, since this absorption peak disappears rapidly after that, it is considered that after the peroxo complex is formed, its O—O bond is immediately cleaved to generate an active species. It is considered to contribute to the hydroxylation reaction.
On the other hand, it is considered that the reaction of catalyst 2 with hydrogen peroxide produces a hydroperoxo complex (Cu ^II —O—OH: peak at 375 nm) as a reaction intermediate, and the O—O bond of this reaction intermediate is It is considered that when cleaved, active species are generated, and these active species contribute to the hydroxylation reaction of the aromatic compound.

Claims (3)

A method for producing a phenolic compound by oxidizing an aromatic compound with an oxidizing agent in the presence of a copper complex having a compound represented by the following formula (I ) as a ligand (in the following formula, R _{1 to} R ₆ Are each independently a methylene group or an ethylene group).
The ligand is 1,2-bis (2- (bis (2-pyridylmethyl) aminomethyl) 6- pyridyl) ethane [6-hpa], The method of claim 1. The method according to claim 1 or 2, wherein the oxidizing agent is hydrogen peroxide and the aromatic compound is benzene .