JP4507069B2 - Method for producing dialkylphenol dimer - Google Patents

Description

  The present invention relates to a method for producing a dialkylphenol dimer.

Dimers (phenols dimers) of phenol (phenols) having a substituent are widely used as resin materials and the like, and conventionally, methods for obtaining various phenol dimers have been proposed.
Patent Document 1 describes a dimerization method in which a substituted aromatic compound is reacted in an aqueous medium in the presence of a peroxidase enzyme, a peroxide, and a radical transfer agent.
In Patent Document 2, in response to a demand for a convenient and inexpensive synthesis method, 2,4- or 2,6- having an alkyl group having 1 to 6 carbon atoms in an aqueous medium containing a peroxide. Dialkylphenol is reacted with soybean peroxidase enzyme to produce tetraalkylbiphenol by oxidative coupling of 2,4- or 2,6-dialkylphenol, or tetraalkylquinone is produced, and this tetraalkylquinone is reduced. A process for producing tetraalkylbiphenols (corresponding to dialkylphenol dimers) is described.
Japanese National Patent Publication No. 11-503021 Japanese National Patent Publication No. 11-506903

  However, when a phenol dimer is synthesized by the methods described in Patent Documents 1 and 2, the yield of the resulting phenol dimer is not stable. In addition, temperature control such as heating is constantly required in the production process until the phenol dimer is obtained, which is a problem for efficient production. In addition, in the methods described in Patent Documents 1 and 2, a very long process such as more than 8 hours is required to obtain a phenol dimer having a sufficient concentration.

  The present invention has been made in view of the above circumstances, and an object thereof is to provide a production method for efficiently obtaining a dialkylphenol dimer in a short time at a low temperature and with a stable yield.

The method for producing a dialkylphenol dimer according to the present invention comprises reacting a dialkylphenol having an alkyl group having 1 to 4 carbon atoms, manganese peroxidase, hydrogen peroxide, and a divalent manganese ion in an aqueous medium. a first step of obtaining a first product Te, subsequent to the first step have a a second step of adding a reducing agent to said first product, the second step, 0 ° C. or higher 25 ° C. or less It is characterized by being performed by.

According to the production method of the present invention, a dialkylphenol dimer, which is a phenol dimer, can be stably produced using a dialkylphenol as a material, and the efficient conditions of low temperature and short time throughout the production process. Can be manufactured.
Furthermore, the dialkylphenol dimer can be provided with high yield by controlling the enzyme concentration and the substrate concentration.

The method for producing a dialkylphenol dimer according to the present invention includes a dialkylphenol having an alkyl group having 1 to 4 carbon atoms, manganese peroxidase, an oxidizing agent, and a divalent manganese ion (Mn ²⁺ ) in an aqueous medium. And a second step of adding a reducing agent to the first product subsequent to the first step.

In the present invention, first, a first step of obtaining a first product by reacting a dialkylphenol having an alkyl group having 1 to 4 carbon atoms, manganese peroxidase, an oxidizing agent, and Mn ^{2+ in} an aqueous medium. I do.
In the first step, for example, a reaction solution in which manganese peroxidase, dialkylphenol, and a manganese compound having an oxidation number of manganese of +2 are dissolved or dispersed in an aqueous medium is prepared, and an oxidizing agent is added to the reaction solution. It can be started by adding. A solution in which dialkylphenol is dissolved in an organic solvent may be dispersed in an aqueous medium. In this case, the organic solvent content in the aqueous medium described later may be 10% by volume or less.

As the aqueous medium, water, a pH buffer solution, or a mixed solution of water or a pH buffer solution and an organic solvent is used.
Examples of the pH buffer include malonate buffer, oxalate buffer, tartrate buffer, acetate buffer, succinate buffer, citrate buffer, phosphate buffer, and the like.
When the aqueous medium is a mixed solution of water and an organic solvent, the proportion of the organic solvent is 10% by volume or less, preferably 5% by volume or less. Here, representative examples of organic solvents that can be used include hexane, trichloromethane, methyl ethyl ketone, ethyl acetate, butanol, ethanol, methanol, dioxane, acetonitrile, tetrahydrofuran (THF), dimethylformamide methyl formate, acetone, n- Examples include propanol, isopropanol, t-butyl alcohol, and the like.

In the production method of the present invention, it is preferable to contain an organic acid in the aqueous medium in order to allow the enzymatic reaction with manganese peroxidase to proceed efficiently. As the organic acid, it is preferable to use malonic acid, oxalic acid, tartaric acid or the like. This is because these organic acids efficiently form complexes with trivalent manganese ions (Mn ³⁺ ) generated by oxidation of Mn ²⁺ accompanying the reduction of the oxidizing agent.
In particular, when an acetate buffer, succinate buffer, citrate buffer, phosphate buffer, or the like is used as the pH buffer, it is desirable to use the preferred organic acids described above.

  The dialkylphenol used in the present invention has an alkyl group having 1 to 4 carbon atoms. Dialkylphenols that can be used in the present invention include various substitutions such as 2,4-dialkylphenol, 2,6-dialkylphenol, 3,5-dialkylphenol, 2,3-dialkylphenol, and 2,5-dialkylphenol. Positional disubstituted phenols are mentioned. Among these, 2,4-isomer and 2,6-isomer are preferable, and in particular, 2,6-dialkylphenol represented by the following general formula (1) is used from the viewpoint of the yield of dialkylphenol dimer. preferable.

(In the formula, R ¹ and R ² independently represent an alkyl group having 1 to 4 carbon atoms.)
The alkyl group of the dialkylphenol may be linear or branched. Examples of the alkyl group having 1 to 4 carbon atoms include a methyl group, an ethyl group, a propyl group, an n-butyl group, and a tert-butyl group, and a methyl group is preferable. R ¹ and R ² in formula (1) may be the same or different.
Among 2,6-dialkylphenols, 2,6-dimethylphenol represented by the following formula (2) is particularly preferably used. This is because it is advantageous in terms of practicality.

  In the present invention, two or more different dialkylphenols may be used.

Manganese peroxidases include Phanerochaete chrysosporium, Phanerochaete sordida, Lentites betinus, Lentus betulinus, Lentus betuline, Pleur Is mentioned. These manganese peroxidases may be used alone or in combination of two or more.
Among manganese peroxidases, it is a basidiomycete described in “MATERIALS AND METHODS” in “The Journal of Biological Chemistry”, 1992, Vol. 267, No. 33. Manganese peroxidase isolated and purified from a culture cell bed of a certain Phanerochaete chrysosporium is preferable because of its high catalytic activity in the reaction of producing a dialkylphenol dimer described below from a dialkylphenol.

In the production method of the present invention, in the first step, the manganese peroxidase concentration (hereinafter referred to as “enzyme concentration”) in the aqueous medium when the reaction is started, that is, the manganese peroxidase concentration in the above reaction solution is 10 nmol / L. It is preferable to set it above, and it is more preferable to set it as 50 nmol / L or more.
In addition, the dialkylphenol concentration in the aqueous medium in the first step, that is, the dialkylphenol concentration in the reaction solution (hereinafter referred to as “substrate concentration”) is preferably 5 mmol / L or less, particularly preferably 2 mmol / L or less. .

Here, the dialkylphenol dimer can be obtained with a high yield by setting the substrate concentration to 2 mmol / L or less and the enzyme concentration to 50 nmol / L or more.
Furthermore, by setting the substrate concentration to 1 mmol / L or less and the enzyme concentration to 100 nmol / L or more, a dialkylphenol dimer can be obtained with a very high yield.

Examples of the oxidizing agent include peroxides such as hydrogen peroxide, methyl peroxide, and ethyl peroxide. Hydrogen peroxide is preferable from the viewpoint of reactivity and economy.
The compounding quantity of an oxidizing agent can be adjusted suitably. For example, when hydrogen peroxide is used as the oxidizing agent, the final concentration of hydrogen peroxide when added to the reaction solution is preferably 10 mmol / L or less, and in particular, considering the stability of manganese peroxidase, 0.1% It is particularly preferable to set it to ˜5 mmol / L.
In the first step, a manganese compound having an oxidation number of manganese of +2 can be used to supply divalent manganese ions to the reaction system. Examples of the manganese compound that can be used include manganese sulfate.

After adding an oxidizing agent to the reaction solution, the reaction for producing a dialkylquinone dimer and a dialkylphenol dimer proceeds from the dialkylphenol by maintaining at a desired reaction temperature, preferably at room temperature, and the dialkylphenol A first product comprising a dimer and a dialkylquinone dimer is obtained. This first product usually contains unreacted dialkylphenol depending on the reaction time.
For example, when 2,6-dialkylphenol is used as the dialkylphenol, the 2,6-dialkylphenol dimer is converted from 2,6-dialkylphenol (A) by the first step as shown in the following formula (I). (B) and 2,6-dialkylquinone dimer (2,2 ′, 6,6′-tetraalkylquinone) (C) are produced, and the 2,6-dialkylphenol dimer (B) And a first product comprising 2,6-dialkylquinone dimer (C).
This is because 2,6-dialkylquinone dimer (C) is produced from 2,6-dialkylphenol (A) through 2,6-dialkylphenol dimer (B) in an aqueous medium. Presumed.

(In the formula, R ¹ and R ² independently represent an alkyl group having 1 to 4 carbon atoms.)

In this invention, following the said 1st process, the 2nd process which adds a reducing agent to the 1st product obtained at the 1st process is performed.
By adding a reducing agent to the first product containing dialkylquinone dimer and dialkylphenol dimer, the reaction in which the dialkylquinone dimer contained is reduced to produce a dialkylphenol dimer is produced. Be started. For example, as shown in the following formula (II), 2,6-dialkylquinone dimer (C) is reduced to produce 2,6-dialkylphenol dimer (B).

  By performing this second step, a second product mainly containing a dialkylphenol dimer is obtained.

The reducing agent is not particularly limited, and examples thereof include sodium borohydride and sodium dithionite.
The amount of the reducing agent added is preferably equivalent to the dialkylquinone dimer concentration in the first product.

In the production method of the present invention, a first product mainly containing a dialkylphenol dimer and a dialkylquinone dimer can be stably obtained by using a substrate comprising dialkylphenol and manganese peroxidase.
By continuously adding a reducing agent to such a first product, a dialkylphenol dimer can be produced from a dialkylquinone dimer, and a dialkylphenol dimer already contained in the first product and In addition, a product containing a large amount of dialkylphenol dimer is obtained. Therefore, a dialkylphenol dimer can be produced at a high yield relative to the substrate concentration.
Here, since it is not necessary to cause a reduction reaction with respect to the total amount of the first product, a sufficient amount of dialkylphenol dimer can be obtained in a sufficiently short time even if the second step is performed under low temperature conditions.
Furthermore, by using manganese peroxidase and adding a reducing agent following the first step, the reaction time is shortened throughout the entire production process, and sufficient yield is achieved at low temperatures and while reducing the amount of enzyme used. Rate can be achieved.

The reaction temperature in the first step can be adjusted according to the type of manganese peroxidase, the enzyme concentration, etc., but can be set to a relatively low temperature, preferably 5 to 60 ° C., and preferably 10 to 40 ° C. More preferably. The reaction temperature may be room temperature.
Other reaction conditions such as pH can be appropriately adjusted according to the type of manganese peroxidase, etc., but preferably pH 2.5 to 6.5, particularly preferably pH 4.0 to 5.0.

In the present invention, the reaction time of the first step is reduced from the time when manganese peroxidase, dialkylphenol, oxidizing agent and divalent manganese ion coexist in an aqueous medium, for example, from the time when the oxidizing agent is added to the reaction solution. Up to the point when the agent is added. Here, the reaction time in the first step is preferably set to a time during which the dialkylphenol is sufficiently consumed. The consumption of dialkylphenol can be confirmed, for example, by fractionating the first product and subjecting it to high performance liquid chromatography, and measuring the residual amount of dialkylphenol with a detection wavelength of around 270 nm.
In the first step, after adding an oxidizing agent to the reaction solution, if the reaction is carried out for a long time, the polyphenylene alkoxide (D) is generated from the dialkylphenol (A) as shown in the following formula (III). May progress. Here, the mechanism by which polyphenylene alkoxide is produced is presumed that dialkylquinone dimer is once produced from dialkylphenol, and this dialkylquinone dimer is polymerized to produce polyphenylene alkoxide.

(In the formula, R ¹ and R ² independently represent an alkyl group having 1 to 4 carbon atoms.)
A suitable reaction time in the first step may vary depending on the enzyme concentration, the substrate concentration, etc. For example, when the substrate concentration is 1 mmol / L and the enzyme concentration is 200 nmol / L, it is preferably 15 to 120 minutes, more preferably 30 to 60 minutes. It is.

  In the manufacturing method of this invention, the production | generation reaction of the dialkylphenol dimer can be stably advanced from the dialkylquinone dimer by performing the 2nd process which adds a reducing agent after said 1st process.

In the present invention, manganese peroxidase is used, but this does not inhibit the reduction reaction from the dialkylquinone dimer to the dialkylphenol dimer, and the reaction rate to the dialkylquinone dimer should be stably increased. Therefore, using a normal reducing agent, the reaction conditions can be set gently, and the production of the dialkylphenol dimer can proceed.
The reaction temperature in the second step is preferably 0 ° C. or higher in order to proceed the reduction reaction stably. In terms of production efficiency and suppression of by-product formation, the reaction temperature is preferably low, and is preferably 25 ° C. or less. In the present invention, it is possible to increase the yield while keeping the reaction temperature in the second step at room temperature. Therefore, the room temperature is preferable in terms of the balance between the yield and the production efficiency.
In the present invention, the reaction time of the second step starts from the time when the reducing agent is added.
The reaction time in the second step is preferably 30 seconds or less, more preferably 5 to 10 seconds.
In the second step, other reaction conditions such as pH can be appropriately adjusted according to the type of manganese peroxidase, etc., but it is preferably pH 2.5 to 6.5, particularly preferably pH 4.0 to 5.0. .

  In the present invention, when the manganese peroxidase is isolated and purified from the fungal bed of Funerocaete chrysosporium, 2,6-dimethylphenol is used as the dialkylphenol, hydrogen peroxide is used as the oxidizing agent, It is preferable to use sodium dithionite as an agent from the stability of the yield of dialkylphenol dimer.

The dialkylphenol dimers obtained by the method of the present invention are widely used in various fields, for example, the production of epoxy resins, flame retardants, antioxidants, polyesters, polycarbonates, etc., and other applications where aromatic diols are used. Can be used.
The dialkylphenol dimer obtained by the production method of the present invention is obtained in a form that is contained in a high content in the second product. Therefore, when the dialkylphenol dimer obtained by the method of the present invention is used for various purposes, the second product may be used as it is, or the dialkylphenol dimer may be purified and used by a known method. May be.

Hereinafter, the present invention will be described in more detail based on experimental examples. However, the present invention is not limited to the following experimental examples. Hereinafter, the unit “M” represents “mol / L”.
Hereinafter, in Examples and Comparative Examples, 2,6-dimethylphenol (“2,6-dimethylphenol” manufactured by Wako Pure Chemical Industries, Ltd.) is used as the dialkylphenol, and manganese sulfate (MnSO4) is used as the manganese compound having manganese having an oxidation number of +2. ₄ : “Manganese sulfate” manufactured by Wako Pure Chemical Industries, Ltd.) was used. Hereinafter, sodium dithionite (“Hydrosulfite Sodium” manufactured by Wako Pure Chemical Industries, Ltd.) was used as the reducing agent.

As the manganese peroxidase, a manganese peroxidase obtained from a cultured bacterial bed of Phanerochaete chrysosporium was used. The method for preparing this manganese peroxidase was as follows.
White rot fungus Phanerochaete chrysosporium ATCC 34541 was cultured at 37 ° C. in Kirk liquid medium (composition shown in Table 1). The culture was performed in 1 L of the above medium in a 2 L Erlenmeyer flask, cultured at 37 ° C. for 3 days, purged with 100% oxygen, and then purged with oxygen once a day. After culturing for a predetermined time, the culture solution was suction filtered to obtain a culture filtrate, and the obtained culture filtrate was used as a crude enzyme solution. After adjusting the pH of the crude enzyme solution to 7.2, it was charged with DEAE Sepharose (DEAE-Sepharose) packed in a column after swelling with a phosphate buffer solution of pH 7.2. Manganese peroxidase adsorbed on DEAE Sepharose packed in the column was discharged with a phosphate buffer at pH 6.0 and collected.

Example 1
First, in a test tube, 50 mM, pH 4.5 malonate buffer (malonate buffer), manganese peroxidase to 200 nM, 2,6-dimethylphenol to each substrate concentration shown in Table 2 In addition, manganese sulfate was further added to a final concentration of 0.5 mM to prepare a reaction solution.
Furthermore, hydrogen peroxide as an oxidizing agent was added so as to have a final concentration of 0.75 mM, and the temperature was maintained at 30 ° C.
One hour after the addition of hydrogen peroxide, the reducing agent was added. The product was measured after 30 seconds with the temperature controlled at 25 ° C.

(Evaluation methods)
The product was measured by HPLC (high performance liquid chromatography) under the following conditions.
Detector: HPLC
Column: STR ODS-II (Shimadzu GLC)
Elution conditions: 0.59 g / L phosphoric acid aqueous solution (20% acetonitrile) / 100% acetonitrile 0-5 minutes: 20% (acetonitrile%)
5-21 minutes: 20-100% Gradient 21-31 minutes: 100%
Liquid feeding speed: 1.0 mL / min
Detection wavelength: 270 nm

Yield of dialkylphenol dimer: From the intensity of the absorption peak detected in the HPLC measurement under the above conditions, the molar concentration C of the dialkylphenol dimer contained in the product was determined.
The yield (“yield”) of 2,6-dimethylphenol dimer relative to 2,6-dimethylphenol was calculated according to the following equation. The yield is shown in Table 2.
(Yield) [%] = C / [(1/2) × (2,6-dimethylphenol molar concentration when the reaction starts)] × 100

(Example 2)
The same procedure as in Example 1 was conducted except that the concentration of 2,6-dimethylphenol was fixed to 5 mM and hydrogen peroxide was added so that the final concentration was as shown in Table 3. The yield of 2,6-dimethylphenol dimer is shown in Table 3.

(Comparative Example 1)
As the enzyme, soybean peroxidase was used instead of manganese peroxidase, and the same procedure as in Example 1 was performed except that the enzyme concentration was 200 nM and the substrate (2,6-dimethylphenol) concentration was 1 mM. The yield of 2,6-dimethylphenol dimer was 47.4%.

As is clear from the above results, in Examples 1 and 2 using manganese peroxidase, it was shown that dialkylphenol dimers can be obtained efficiently with respect to the amount of enzyme used.
On the other hand, the reaction temperature and the reaction time were the same as those in the example, and in Comparative Example 1 using soybean peroxidase, the yield was much smaller than in the example in which the substrate concentration, enzyme concentration, and oxidizing agent concentration were the same. . Therefore, in the comparative example, it was shown that the dialkylphenol dimer cannot be obtained efficiently and stably under mild reaction conditions.

Claims (5)

A first step of obtaining a first product by reacting a dialkylphenol having an alkyl group having 1 to 4 carbon atoms, manganese peroxidase, hydrogen peroxide, and divalent manganese ions in an aqueous medium;
Possess a second step of adding a reducing agent to said first product subsequent to the first step,
The said 2nd process is performed at 0 degreeC or more and 25 degrees C or less, The manufacturing method of the dialkylphenol dimer characterized by the above-mentioned .   The method for producing a dialkylphenol dimer according to claim 1, wherein an organic acid is contained in the aqueous medium in the first step.   The dialkylphenol dimer according to claim 1 or 2, wherein in the first step, the manganese peroxidase concentration in the aqueous medium when the reaction starts is 50 nmol / L or more and the dialkylphenol concentration is 2 mmol / L or less. Manufacturing method.   The method for producing a dialkylphenol dimer according to any one of claims 1 to 3, wherein the dialkylphenol is 2,6-dialkylphenol.   The method for producing a dialkylphenol dimer according to any one of claims 1 to 4, wherein the alkyl group is a methyl group.