JP5231783B2 - Poly (metaphenylene) derivatives having hydrophilic substituents - Google Patents

Description

  The present invention relates to a novel compound having a helical structure that is stable in water. Specifically, the present invention relates to a novel poly (metaphenylene) derivative that is stable in an aqueous solution in which a hydrophilic substituent is introduced at the 5-position and a polymer thereof.

There are many substances in the natural world that have a helical structure, some of which play an important role as a source of life. On the other hand, in the world of synthetic chemistry, especially synthetic polymers, many helical structure compounds are produced and occupy an important position industrially. In addition, recently, various helical polymers have been synthesized from the viewpoint of mimicking natural products. However, many of these synthetic polymers are stable in an organic solvent or in a solid state, but are often unstable in an aqueous solvent. Oligomers and polymers consisting of metaphenylene skeleton, 5 ₁ in the solid - forms a helical structure in the solution are known to take a random conformation can not be maintained structure. The synthesis of water-based helical polymers has just started, and there are few reports on polyphenylacetylene (Non-patent document 1), polyisocyanide (Non-patent document 2), polysilane (Non-patent document 3), and the like.

K. Maeda et al. J. Am. Chem. Soc. 2004, 126, 16284-16285. M. Ishikawa. Et al. J. Am. Chem. Soc. 2004, 126, 732-733. K. Oka, et al. J. Organomet. Chem. 2000, 611, 45-51.

As already described, examples of the few helical structure compounds in water include polyphenylacetylene, polyisocyanide, polysilane, etc., all of which are decomposed by light, air (oxygen) or heat. Therefore, these have not reached industrial use.
An object of the present invention is to create and provide a helical structure compound that is stable in water.

The inventors of the present application have been diligently researching with the aim of overcoming these drawbacks and synthesizing, polymerizing and polymerizing compounds having a helical structure that is stable even in water. As a result, a poly (metaphenylene) derivative (hereinafter abbreviated as poly-1) introduced with a hydrophilic group at the 5-position, preferably an optically active substituent, has a helical structure that is stable in water contrary to expectations. The present invention has been completed.
That is, the present invention relates to a poly (metaphenylene) derivative having a hydrophilic substituent introduced at the 5-position of the phenyl ring. More specifically, the present invention provides the following formula (1),

(In the formula, R represents a hydrophilic substituent, and n represents the number of repetitions of the polymer.)
It is related with the poly (metaphenylene) derivative represented by these.
The present invention will be described in further detail as follows.
(1) Formula (1),
(In the formula, R represents a hydrophilic substituent, and n represents the number of repetitions of the polymer.)
A poly (metaphenylene) derivative represented by:
(2) The poly (metaphenylene) derivative according to (1), wherein the hydrophilic substituent is an oligoalkyleneoxy chain.
(3) The poly (metaphenylene) derivative according to the above (1) or (2), wherein the hydrophilic substituent is an oligoalkyleneoxy chain having 3 or more repeating units.
(4) The poly (metaphenylene) derivative according to any one of (1) to (3), which is an oligoalkyleneoxy chain in which the hydrophilic substituent is the repeating unit 4 or 5.
(5) The hydrophilic substituent is any group of an alkyl group, an ether group, an ester group, a ketone group, a nitrile group, a carboxyl group, an amino group, an amide group, a sulfide group, a thiol group, or a disulfide group. The poly (metaphenylene) derivative according to any one of (1) to (4), which is an optionally substituted oligoalkyleneoxy chain.
(6) The poly (metaphenylene) derivative according to any one of (1) to (5), wherein the hydrophilic substituent is an optically active oligoalkyleneoxy chain.
(7) The poly (metaphenylene) derivative according to any one of (1) to (6), which has a single chain helical structure in a solution.

The poly (metaphenylene) derivative (poly-1) having a hydrophilic substituent introduced at the 5-position according to the present invention is a novel substance, and the present invention is stable in air, at high temperatures, or in an environment exposed to light. Provided is a compound having a water-soluble helical structure.
The present invention provides a water-soluble artificial helical compound that is stable in light, water, and air. As a result, it can be expected to make a great contribution in the fields of medicine and engineering. In addition, for example, HPLC chiral detection and preparative columns, chiral fluorescence sensors, and other features that enable mixing at the molecular level, biochemicals that could not be performed conventionally except for biological reactions such as enzymatic reactions. It is also possible to carry out a simple reaction in a low temperature range or a high temperature range, and it is possible to induce a spontaneous reaction similar to information transmission similar to gene information or proliferation. In addition, by making a water-soluble spiral that is stable in a normal environment, dramatic improvements in the elastic modulus, heat resistance, thermal properties, etc. of the film can be expected.
Furthermore, application to liquid crystal materials can also be expected.

The poly (metaphenylene) derivative of the present invention is characterized by having a hydrophilic substituent at the 5-position of the phenyl ring.
Examples of the “hydrophilic substituent” in the present invention include hydrophilic organic groups having a size of about 5 to 40 atoms, preferably about 9 to 20 atoms.
As preferred hydrophilic substituents, the following general formula (2),
—R ¹ — (O—R ² ) m—O—R ³ (2)
(In the formula, R ¹ and R ² each independently represent an alkylene group, R ³ represents an alkyl group, and m represents the number of repetitions.)
The oligoalkyleneoxy group represented by these is mentioned.
Examples of the alkylene group for R ¹ and R ² include a linear or branched divalent alkylene group having 1 to 6 carbon atoms, preferably 2 to 5 carbon atoms. Preferred alkylene groups include ethylene group, propylene group, butylene group, isobutylene group and the like.
Examples of the alkyl group for R ³ include linear or branched alkyl groups having 1 to 8 carbon atoms, preferably 1 to 5 carbon atoms, and more preferably 1 to ³ carbon atoms. Preferable alkyl groups include a methyl group and an ethyl group.
The number of repetitions of m is not particularly limited as long as it is 3 or more, but preferably 3 to 10, more preferably 3 to 6, and still more preferably 4 to 6. A preferable repeating number m is 3 to 5.

The hydrophilic substituent of the present invention or the above-described alkylene group or alkyl group may be further substituted with a substituent. Such a substituent is not particularly limited, but is preferably a hydrophilic substituent. Examples of such substituents include alkyl groups, hydroxyl groups, alkoxy groups, nitrile groups, carboxyl groups, amino groups, alkyl-substituted amino groups, thiol groups, and the like. Particularly preferred substituents include alkyl groups, hydroxyl groups, alkoxy groups, nitrile groups, carboxyl groups, amino groups and the like. Here, examples of the alkyl group include the alkyl group described above, and examples of the alkoxy group include an alkoxy group derived from the alkyl group described above.
In addition, one or more, preferably 1 to m, or 1 to 6 methylene groups or oxygen of the hydrophilic substituent of the present invention or the oligoalkyleneoxy group represented by the general formula (2). The atom is a divalent functional group such as an ether group (—O—), an ester group (—COO—), a ketone group (—CO—), an amide group (—CONH—), or a sulfide group (—S—). Or may be further substituted with a disulfide group (—S—S—) or the like. Particularly preferred substituents include ether groups, ester groups, ketone groups, sulfide groups and the like.

The hydrophilic substituent of the present invention or the oligoalkyleneoxy group represented by the general formula (2) is preferably an optically active substance containing an asymmetric carbon atom. In the case of the oligoalkyleneoxy group represented by the general formula (2), at least one of R ¹ , R ² , and R ³ , preferably an optically active substance in which R ¹ contains an asymmetric carbon atom is preferable. Such an asymmetric carbon atom may be formed by an alkylene group or an alkyl group itself, or may be formed by substitution of a functional group such as a hydroxyl group or an alkoxy group.
Moreover, it is preferable that at least one of these asymmetric carbon atoms is an optically active substance.
The poly (metaphenylene) derivative of the present invention has, for example, the following reaction formula:

(In the formula, R represents a hydrophilic substituent, and n represents the number of repetitions of the polymer.)
It can manufacture by the method represented by these. A desired poly (metaphenylene) derivative can be produced by introducing a hydrophilic substituent into 3,3-dibromophenol using R—OH and condensing it in the presence of a nickel catalyst.
R is the following formula:

As an example, the method for producing poly-1, which is a kind of the poly (metaphenylene) derivative of the present invention, will be described in more detail. First, an optically active or optically inactive hydrophilic substituent is introduced into 3,5-dibromophenol using the Mitsunobu reaction, thereby (S) -1,3-dibromo-5- (2- (2- (2- (2-Methoxyethoxy) ethoxy) ethoxy) propoxy) benzene ((S) -1,3-dibromo-5- (2- (2- (2-methoxyethoxy) ethoxy) ethoxy) propoxy) benzene) (hereinafter monomer (1) Abbreviated as)). Next, the monomer (1) is prepared using a nickel catalyst such as bis (1,5-cyclooctadiene) nickel (hereinafter abbreviated as Ni (cod) ₂ ). Polymerize. As a result, a mixture comprising a cyclic oligomer and a linear polymer is obtained, and these mixtures can be fractionated by HPLC to produce a high molecular weight component (abbreviated as poly-1).

  When the circular dichroic dispersion (hereinafter abbreviated as CD) and ultraviolet-visible near-infrared absorption spectrum (hereinafter abbreviated as UV-Vis) of poly-1 produced in this way were measured, it was clear in the chloroform solution. Although no cotton effect is shown, a strong cotton effect is observed in the absorption region of the main chain together with a light-colored effect with a clear absorption spectrum in methanol. These facts indicate that poly-1 has a helical structure biased in one-way winding through aromatic interaction. Poly-1 also has a monochromatic effect in the absorption spectrum and a strong cotton effect in the absorption region of the main chain at a water content of 50% by volume or less even in a water-methanol mixed solvent. You can see that Even if a dilution experiment is carried out in a chloroform-methanol solvent, no concentration dependence is observed, so it can be confirmed that poly-1 is not double-stranded but forms a single-stranded helical structure. These results are the first to show a single chain helical structure as a polymetaphenylene derivative.

  Examples will be shown in order to explain the present invention in an easy-to-understand manner, but the present invention is not limited to these examples.

(1) 3,5-dibromophenol (4.81 g, 19.0 mmol, Aldrich), (S) -2- (2- (2-) methoxyethoxy) ethoxy in argon atmosphere under water cooling (about 22 ° C.) ) Ethoxy) propanol ((S) -2- (2- (2-methoxyethoxy) ethoxy) ethoxy) propanol) (3.70 g, 16.6 mmol), triphenylphosphine (5.07 g, 19.1 mmol) in anhydrous tetrahydrofuran A solution of azodicarboxylic acid diisopropyl ester (3.87 g, 19.1 mmol) in THF (100 mL) was gradually added dropwise to the (THF, 200 mL) solution over 30 minutes, and the mixture was further stirred at that temperature for 22 hours.
After completion of the reaction, the reaction solution was concentrated, and ethyl acetate was added to obtain a suspension. The ethyl acetate insoluble part was removed by Celite filtration, and then the soluble part was concentrated to obtain a crude product. Further, this crude product was purified by a silica gel column (hexane / ethyl acetate = 1/1, v / v) to obtain a light yellow oily monomer (1). Yield 5.32 g (11.7 mmol, yield 70.1%).

(2) In argon atmosphere, to anhydrous N, N-dimethylformamide (DMF, 1.6 ml), bis (1,5-cyclooctadiene) nickel (0) (1.04 g, 3.78 mmol), 2, 2 '-Bipyridine (0.627 g, 4.01 mmol) and anhydrous 1,5-cyclooctadiene (0.49 ml) were added, and the mixture was stirred at 80 ° C. for 1 hour to prepare a zero-valent nickel complex. Compound 1 (1.00 g, 2.19 mmol) prepared in (1) above was added to the nickel complex solution, and the mixture was stirred at that temperature for 12 hours. The reaction solution was cooled at room temperature, concentrated hydrochloric acid was added to make a green transparent solution, and neutralized with triethylamine. After the solvent was completely distilled off, the dried solid was extracted with THF to recover the THF soluble part. Further, the soluble part was purified by an aminated silica gel column (methanol) to obtain a light brown oily crude product. Yield 611 mg (2.06 mmol), Yield 94.1%. Furthermore, it was fractionated by HPLC to obtain a light brown waxy high molecular weight polymer (poly-1). Yield 154 mg (0.520 mmol), yield 23.7%. The number average molecular weight (M _n ) of poly-1 was 1.09 × 10 ⁴ , the degree of polymerization (DP _n ) was 38, and the molecular weight dispersion M _w / M _n was 1.29.

Next, the CD and absorption spectrum of poly-1 were measured in a mixed solvent of CDCl ₃ , CD ₃ OD, or CD ₃ OD / D ₂ O. The measurement conditions are 25 ° C. and the concentration is 1 mM / unit. The results are shown in FIG. The horizontal axis of FIG. 1 indicates the wavelength (nm), the left vertical axis indicates Δε (cm ⁻¹ · M ⁻¹ · unit− ¹ ), and the right vertical axis indicates ε (10 ⁴ × cm ⁻¹ · M). ^-1 unit- ¹ ). The broken line in FIG. 1 shows the case of CDCl ₃ , the thin solid line shows the case of CD ₃ OD, and the thick solid line shows the case of a mixed solvent of CD ₃ OD / D ₂ O (1: 1). Poly-1 did not show a clear cotton effect in the CDCl ₃ solution, but in CD ₃ OD, a strong cotton effect was observed in the absorption region of the main chain together with a light-colored effect with a clear absorption spectrum. These results indicate that poly-1 has a helical structure biased in one-way winding through aromatic interaction. Further, even in a mixed solvent of CD ₃ OD / D ₂ O, when the water content is 50% by volume or less, a monochromatic effect of the absorption spectrum and a strong cotton effect in the absorption region of the main chain are exhibited. It is thought that it is taking.

Next, dilution experiments were performed in CHCl ₃ / MeOH (20/80, v / v). The measurement conditions were 25 ° C. and the poly-1 concentration was changed from 0.02 mM to 5.19 mM. The results are shown in FIG. The horizontal axis of FIG. 2 indicates the molar concentration of the polymer ([P1 _H ] / M), the vertical axis on the left indicates Δε ₂₆₇ (cm ⁻¹ · M ⁻¹ · unit− ¹ ), and the vertical axis on the right indicates ε ₃₀₆ (10 ⁴ × cm ⁻¹ · M ⁻¹ · unit ⁻¹ ) is indicated. The white circle in FIG. 2 indicates the case of absorbance (molar extinction coefficient), and the black circle indicates the case of molar circular dichroism. As a result, since no concentration dependency was observed, it was confirmed that poly-1 was not double-stranded but formed a single-stranded helical structure. The above results are the first of the single helix structure of the polymetaphenylene derivative.

1,3-dibromo-5-((2- (2- (2-methoxyethoxy) ethoxy) ethoxy) ethoxy) -benzene (1,3-dibromo-5-((2- (2- (2-methoxyethoxy)) Production of ethoxy) ethoxy) ethoxy) benzene) (2):
The title polymer was prepared according to the reaction scheme shown below.

(1) 3,5-dibromophenol (5.49 g, 21.8 mmol), 2-((2- (2-methoxyethoxy) ethoxy) ethoxy) ethanol (2) under argon cooling in water (about 20 ° C.) -((2- (2-methoxyethoxy) ethoxy) ethoxy) ethanol) (5.00 g, 24.0 mmol), triphenylphosphine (6.25 g, 23.8 mmol) in anhydrous tetrahydrofuran (THF, 200 ml), azo A solution of dicarboxylic acid diisopropyl ester (4.81 g, 23.8 mmol) in THF (125 ml) was gradually added dropwise over 30 minutes, and the mixture was further stirred at that temperature for one day.
After completion of the reaction, the reaction solution was concentrated, and ethyl acetate was added to obtain a suspension. The ethyl acetate insoluble part was removed by Celite filtration, and then the soluble part was concentrated to obtain a crude product. Further, this crude product was purified by a silica gel column (hexane / ethyl acetate = 1/1, v / v) to obtain a light yellow oily monomer (2). Yield 6.83 g (15.4 mmol, yield 70.6%).

(2) Synthesis of poly-2 by polymerization of monomer (2):
In an argon atmosphere, to anhydrous N, N-dimethylformamide (DMF, 2.4 ml), bis (1,5-cyclooctadiene) nickel (0) (1.20 g, 4.36 mmol), 2,2′-bipyridine (0.680 g, 4.35 mmol) and anhydrous 1,5-cyclooctadiene (0.51 ml) were added, and the mixture was stirred at 80 ° C. for 1 hour to prepare a zero-valent nickel complex. The monomer (2) produced in the above (1) (0.53 g, 1.20 mmol) was added to the nickel complex solution, and the mixture was stirred at that temperature for 12 hours. The reaction solution was cooled at room temperature, concentrated hydrochloric acid was added to make a green transparent solution, and neutralized with triethylamine. After the solvent was completely distilled off, the dried solid was extracted with THF to recover the THF soluble part. Further, the soluble part was purified by an aminated silica gel column (methanol) to obtain a light brown oily crude product. Yield 340 mg (1.20 mmol), yield 100%. Furthermore, it was fractionated by HPLC to obtain a light brown waxy high molecular weight polymer (poly-2). Yield 76.0 mg (0.268 mmol), Yield 22.3%. The number average molecular weight (M _n ) of poly-2 was 1.39 × 10 ⁴ , the degree of polymerization (DP _n ) was 49, and the molecular weight dispersion M _w / M _n was 1.32.

Next, the absorption spectrum of poly-2 was measured in a CHCl ₃ , MeOH, or MeOH / H ₂ O mixed solvent. The measurement conditions are 25 ° C. and the concentration is 1 mM / unit. The results are shown in FIG. The horizontal axis in FIG. 3 indicates the wavelength (nm), and the vertical axis indicates the absorbance ε (10 ⁴ × cm ⁻¹ · M ⁻¹ · unit ⁻¹ ). As a result, a clear light color effect was observed in poly-2 in MeOH and in a MeOH / H ₂ O mixed solvent as compared with the case in CHCl ₃ . This result shows that poly-2 forms a single-stranded helical structure like poly-1.

  The present invention provides a water-soluble artificial helical compound that is stable in light, water, and air. For example, HPLC chiral detection / preparative column, chiral fluorescent sensor, etc., and mixing at the molecular level. It is possible to conduct biochemical reactions that could not be performed other than biological reactions such as enzymatic reactions in the low temperature range or high temperature range, and transfer information similar to genetic information. Spontaneous reactions similar to proliferation can be induced. In addition, by making it a water-soluble spiral that is stable under normal circumstances, it can be expected to dramatically improve the elastic modulus, heat resistance, thermophysical properties, etc. of the film. Has industrial applicability.

FIG. 1 shows poly-1 CD and absorption spectra in various solvents (deuterated chloroform, deuterated methanol, deuterated methanol / heavy water (1/1)). FIG. 2 shows the results of the concentration dependence of poly-1 Δε ₂₆₇ and ε ₃₀₆ in deuterated chloroform / deuterated methanol (2/8) mixed solvent. FIG. 3 shows the absorption spectrum of poly-2.

Claims (4)

The following formula (1)
(Wherein R represents the general formula (2),
—R ¹ — (O—R ² ) m—O—R ³ (2)
(In the formula, R ¹ and R ² each independently represent an alkylene group having 1 to 6 carbon atoms, R ³ represents an alkyl group having 1 to 5 carbon atoms, and R ¹ , R ² and R ³ are further represented by may be substituted by a alkyl group, m represents an oligoalkyleneoxy group represented by represents.) the number of repetitions is 3 to 10, n represents the number of repeating is polymer and 38 to 49. )
A poly (metaphenylene) derivative represented by:   The poly (metaphenylene) derivative according to claim 1, wherein m is 4 or 5.   The poly (metaphenylene) derivative according to claim 1, wherein the oligoalkyleneoxy group is an optically active oligoalkyleneoxy group.   The poly (metaphenylene) derivative according to any one of claims 1 to 3, wherein the poly (metaphenylene) derivative has a single chain helical structure in the solution.