JP5130514B2 - Two-photon absorption compound - Google Patents

Description

  The present invention relates to a novel compound, and particularly to a compound having a large two-photon absorption cross section.

  In recent years, organic compounds having a large two-photon absorption cross section (hereinafter referred to as “two-photon absorption compounds”) have been attracting interest among third-order nonlinear optical materials, and various applications are expected in optical devices and biotechnology. Yes.

  Many nonlinear optical materials using organic compounds are known. For example, carbazole derivatives (Patent Document 1), compounds having an iodonium salt structure (Patent Document 2), tetrabenzoporphyrin derivatives (Patent Document 3), metal porphyrins ( Patent Document 4), phthalocyanine compounds (Patent Document 5), tetraazaporphine compounds (Patent Document 6), and the like. Among them, the following compound has been proposed as an organic material that efficiently absorbs two photons, that is, an organic material having a large two-photon absorption cross section (Patent Document 7).

（Ｘ^１，Ｘ^２は置換もしくは無置換のアリール基、または置換もしくは無置換のヘテロ環基を表し、同一でも異なってもよく、Ｒ^１、Ｒ^２、Ｒ^３およびＲ^４は、それぞれ独立に水素原子、または置換基を表しＲ^１、Ｒ^２、Ｒ^３およびＲ^４のうちのいくつかが互いに結合して環を形成してもよく、ｎおよびｍは２以上の場合、複数個のＲ^１、Ｒ^２，Ｒ^３およびＲ^４は同一でも、それぞれ異なってもよく、ｎおよびｍは、それぞれ独立に１〜４の整数を表す。）
一般に非線形光学材料は、印加する光電場の２乗、３乗等に比較する非線形の光学応答を示す物質で、２光子吸収をする、第二高調波や第三高調波等を発生する、２光子励起発光を生ずるなどの特性を示す。

(X ¹ and X ² represent a substituted or unsubstituted aryl group or a substituted or unsubstituted heterocyclic group, which may be the same or different, and R ¹ , R ² , R ³ and R ⁴ are each independently A hydrogen atom or a substituent, and some of R ¹ , R ² , R ³ and R ⁴ may be bonded to each other to form a ring, and when n and m are 2 or more, a plurality of R ¹ , R ² , R ³ and R ⁴ may be the same or different, and n and m each independently represent an integer of 1 to 4.)
In general, a nonlinear optical material is a substance that exhibits a nonlinear optical response compared to the square of a photoelectric field to be applied, etc., and generates a second harmonic, a third harmonic, or the like that absorbs two photons. It shows characteristics such as photon excitation light emission.

  Two-photon absorption is a phenomenon in which a compound is excited by simultaneously absorbing two photons. That is, a phenomenon in which two photons are simultaneously absorbed and electrons are transitioned to an excited state in an energy region where no compound absorption band exists is called two-photon absorption.

  Even when the compound is excited by two-photon absorption, energy is released in various forms at the stage of releasing energy, as in the case of one-photon absorption excitation. For example, there are those that release energy as fluorescence, phosphorescence or heat in the deactivation process, and those that digest energy by changing the molecular structure of the compound.

  Since the efficiency of two-photon absorption is proportional to the square of the applied photoelectric field, when a two-dimensional plane is irradiated with a laser, two-photon absorption occurs only at a position where the electric field strength is high at the center of the laser spot, It is possible to create a situation in which absorption of two photons does not occur in the peripheral portion where the electric field strength is weak. On the other hand, in a three-dimensional space, laser light is collected by a lens and excited by increasing the electric field strength at the focal point, causing two-photon absorption at one point in the space, causing two-photon emission only at the focal point, or high heat. High spatial resolution can be given to photoexcitation such as causing chemical change. For this reason, it is possible to process the inside of an object, particularly a translucent object, or to cause special light emission inside the object. In particular, application to imaging of biological tissue (bioimaging), photodynamic therapy, up-conversion lasing, etc. has many advantages over conventional one-photon excitation in terms of phototoxicity and three-dimensional spatial resolution.

  However, when used in a living body or the like, irradiating a living body with excessively strong light may cause excessive damage due to light damage to living tissue or deterioration of the two-photon absorption compound itself. Cannot use strong light. Therefore, it is desired that the two-photon absorption efficiency of the compound is high and the efficiency of light emission and heat generation is high due to the excited state by two-photon absorption. In addition, the compound to be used must satisfy conditions such as being harmless to the living body and having affinity for living tissue.

However, two-photon absorption compounds that satisfy such conditions are hardly proposed at present.
JP 2001-264828 A JP-A-10-325968 JP-A-9-179153 JP-A-7-218939 JP-A-7-218939 JP-A-5-5916 JP 2003-183213 A

  The present invention has been made in view of the above situation, and an object of the present invention is to provide a novel two-photon absorption compound having good affinity for a living body, good two-photon absorption efficiency, and high efficiency such as two-photon emission in an excited state. And

  In order to achieve the above object, a first aspect of the present invention is a two-photon absorption compound represented by the following general formula (1).

（但し、Ｒは水素又はメチレン基で、該メチレン基は互いに結合し、環を形成している。Ｘ、Ｙは、水素原子、アルキル基、アルコキシ基及びアミノ基から選ばれる基、ｎは０から２の整数を表す。）
更に本発明において好ましい態様は、上記第１の態様において、２つのＲがメチレン基であり、且つ該メチレン基は互いに結合し、シクロペンタノン環を形成した化合物である。

(However, R is hydrogen or a methylene group, and the methylene groups are bonded to each other to form a ring. X and Y are groups selected from a hydrogen atom, an alkyl group, an alkoxy group and an amino group, and n is 0. Represents an integer from 2 to 2.)
Further, a preferred embodiment of the present invention is a compound in which two Rs are methylene groups in the first embodiment, and the methylene groups are bonded to each other to form a cyclopentanone ring.

  Another embodiment is a two-photon absorption compound in which two Rs are hydrogen in the general formula (1).

  The greatest feature of the present invention is that it has an azulene ring at both ends of the compound.

  Azulene itself can be a pharmaceutical, and the compound of the present invention is generally considered to have a high affinity for a living body.

  Further, as will be apparent from the examples described later, the compound having an azulene ring of the present invention has a much larger two-photon absorption cross section than the substance of the following chemical formula (2) which is a normal aromatic compound having the same molecular weight. Has characteristics.

本発明において、前記一般式（１）のＸ及びＹは、水素原子又は置換基であって、特に電子供与性置換基である。一般にアミノ基、水酸基、アルキル基、アルコキシ基などである。なかでも、メチルアミノ基、エチルアミノ基、プロピルアミノ基、ブチルアミノ基などのモノアルキルアミノ基、ジメチルアミノ基、ジエチルアミノ基、ジプロピルアミノ基、ジブチルアミノ基などのジアルキルアミノ基、メトキシ基、エトキシ基、プロポキシ基、ブトキシ基等のアルコキシ基、メチル基、エチル基、プロピル基、ブチル基などのアルキル基が好ましく、特にジアルキルアミノ基、アルコキシ基及びアルキル基が高い吸収断面積を与える。勿論、各Ｘ及びＹは同一の基であってもよいし、また任意に異なる基又は原子であってもよい。

In the present invention, X and Y in the general formula (1) are a hydrogen atom or a substituent, particularly an electron donating substituent. Generally, an amino group, a hydroxyl group, an alkyl group, an alkoxy group and the like. Among them, monoalkylamino groups such as methylamino group, ethylamino group, propylamino group, and butylamino group, dialkylamino groups such as dimethylamino group, diethylamino group, dipropylamino group, and dibutylamino group, methoxy group, and ethoxy group Alkoxy groups such as a group, propoxy group and butoxy group, and alkyl groups such as a methyl group, an ethyl group, a propyl group and a butyl group are preferred, and particularly a dialkylamino group, an alkoxy group and an alkyl group give a high absorption cross section. Of course, each X and Y may be the same group or arbitrarily different groups or atoms.

  It is important that the compound of the present invention has a carbonyl group at the center and the azulene groups at both ends are connected by conjugated double bonds. In general, it is preferable that n represented by the general formula (1) is selected from 0, 1 and 2 (represented as 0 to 2).

  The present invention is a novel two-photon absorption compound in which an azulene ring is bonded to both ends thereof, and has a large two-photon absorption cross section.

  In addition, since it generally has a high affinity for a living body, it is expected to expand into a treatment method utilizing in-vivo, for example, intracellular situation search and extreme heat generation.

  This invention is a compound represented by the said General formula (1), The means to synthesize | combine these compounds is not specifically limited. What is necessary is just to synthesize | combine according to the synthetic | combination means which a normal chemist will perform when seeing this compound. For example, a commercially available azulene may be formylated with or without introducing the electron-donating substituent by a conventional method, and this is converted to cyclopentanone, 2.5 di (ethylidene) cyclopentanone, acetone, diallyl ketone, and the like. By reacting, for example, compounds represented by the following chemical formulas (3), (4), (5) and (6) are obtained.

以下に実施例を示すが、本発明はこれらに限定されるものではないし、また化合物の合成方法もこれらに限定されるものではない。

Examples are shown below, but the present invention is not limited to these examples, and the method for synthesizing the compounds is not limited thereto.

(Synthesis of formylazulene)

アルゴン雰囲気下、室温でアズレン（０．２６ｇ，２ｍｍｏｌ）をベンゼン（８ｍｌ）に溶かしてＤＭＦ（０．３１ｍｌ，４．０ｍｍｏｌ）を加え、氷冷したでＰＯＣｌ_３（０．３７ｍｌ，４．０ｍｍｏｌ）を徐々に滴下した。発熱が収まったら、溶液を８５℃で２時間加熱還流した。反応溶液に飽和重曹水に加えてアルカリ性にし、ＣＨＣｌ_３で抽出、無水硫酸ナトリウムで乾燥、濃縮してカラムクロマトグラフィー（シリカゲル、ヘキサン／酢酸エチル＝５／１）により分離精製した。紫色液体、収量０．３１ｇ、収率９７．６％であった。
（α，α’−ジ（１−アズレニリデン）シクロペンタノンの合成）

Under argon atmosphere, azulene (0.26 g, 2 mmol) was dissolved in benzene (8 ml) at room temperature, DMF (0.31 ml, 4.0 mmol) was added, and the mixture was cooled with ice and POCl ₃ (0.37 ml, 4.0 mmol) was added. Was gradually added dropwise. When the exotherm subsided, the solution was heated to reflux at 85 ° C. for 2 hours. The reaction solution was made alkaline by adding saturated aqueous sodium bicarbonate, extracted with CHCl ₃ , dried over anhydrous sodium sulfate, concentrated, and separated and purified by column chromatography (silica gel, hexane / ethyl acetate = 5/1). Purple liquid, yield 0.31 g, yield 97.6%.
(Synthesis of α, α'-di (1-azulenylidene) cyclopentanone)

窒素雰囲気下、室温で１−ホルミルアズレン（０．３３ｇ，２ｍｍｏｌ）とシクロペンタノン（０．０８ｇ，１ｍｍｏｌ）をエタノール３００ｍｌに溶かして、飽和水酸化ナトリウム水溶液を１ｍｌ加え、室温で１０時間攪拌した。−１０℃で１２時間放置し、得られた粗生成物をクロロホルムで再結晶した。深紫色針状晶、収量０．０５ｇ、収率１３．９％であった。このものはＮＭＲにより次のピークが得られたことから、α，α’−ジ（１−アズレニリデン）シクロペンタノンであることが確認された。

In a nitrogen atmosphere, 1-formylazulene (0.33 g, 2 mmol) and cyclopentanone (0.08 g, 1 mmol) were dissolved in 300 ml of ethanol at room temperature, 1 ml of a saturated aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 10 hours. . The resulting crude product was recrystallized from chloroform by standing at -10 ° C for 12 hours. Deep purple needles, yield 0.05 g, yield 13.9%. This was confirmed to be α, α′-di (1-azulenylidene) cyclopentanone since the following peak was obtained by NMR.

¹ HNMR spectrum (solvent: CDCl ₃ ): 3.28 (4H, s), 7.30 (2H, t, J = 9.7 Hz), 7.39 (2H, t, J = 9.9 Hz), 7 .52 (2H, d, J = 4.2 Hz), 7.72 (2H, t, J = 9.8 Hz), 8.28 (2H, d, J = 4.2 Hz), 8.35 (2H, s), 8.36 (2H, d, J = 8.8 Hz), 8.87 (2H, d, J = 9.8 Hz)
[Method for evaluating two-photon absorption cross section]
The evaluation of the two-photon absorption cross section of the compound of the present invention is described in M.M. Sheik-Bahae et. al. , IEEE J. Quantum Electronics 1990, 26, 760. The description was made with reference to the method described. As a light source for measuring the two-photon absorption cross section, Ti: sapphire pulse laser light (pulse width: 120 fs, repetition rate: 1 kHz, average output: 0.4 mW, peak power: 3.3 GW) passed through a regenerative amplifier is used. The two-photon absorption cross section of each compound was obtained by measuring the two-photon absorption cross section in the wavelength range of 700 nm to 1000 nm. As a sample for two-photon absorption measurement, a solution in which a compound was dissolved in chloroform at a concentration of 1 × 10 ⁻³ was used.

The two-photon absorption cross section of the compound of the present invention was measured by the above method, and the obtained results are shown in Table 1 in GM units (1 GM = 1 × 10 ⁻⁵⁰ cm ⁴ s / photon). The value shown in the table is the maximum value of the absorption cross section in the two-photon absorption band observed in the wavelength region where resonance with one-photon absorption does not occur on the longer wave side than the absorption edge wavelength of one-photon absorption.

  Note that α, α′-di (1-naphthylidene) cyclopentanone is used as a comparative example to show that the two-photon absorption compound of the present invention has a much larger two-photon absorption cross-section than other similar compounds. Also, the two-photon absorption cross section was measured and shown in Table 1.

Claims (3)

A two-photon absorption compound represented by the following general formula (1).

(However, R is hydrogen or a methylene group, and the methylene groups are bonded to each other to form a ring. X and Y are groups selected from a hydrogen atom, an alkyl group, an alkoxy group and an amino group, and n is 0. Represents an integer from 2 to 2.)   2. The two-photon absorption compound according to claim 1, wherein R is a methylene group and is bonded to each other to form a cyclopentanone ring.   The two-photon absorption compound according to claim 1, wherein R is hydrogen.