Coumarin and carbazole dipyridine salt type water-soluble two-photon initiator, preparation method and application thereof

Abstract

The application provides a coumarin and carbazole dipyridine salt type water-soluble two-photon initiator, a preparation method and application thereof, and in particular, a use in the field of laser micro-nano processing technology. In the structural general formula of the two-photon initiator, R1 is selected from hydrogen, C 1‑12 alkyl, C 1‑12 hydroxyalkyl or an ethereal unit with a number of repetitions of 1-12; R2 is selected from methyl, ethyl or isopropyl; and Y is a corresponding anion. The two-photon initiator has a large conjugated structure, and the introduction of the dipyridine salt enables the two-photon initiator to be soluble in water. As an initiator, the two-photon initiator can initiate two-photon photopolymerization in an aqueous phase, and the two-photon absorption cross section is greater than 100 GM, so that the power threshold of two-photon photoinitiation during processing is low, i.e. 25 mW. Therefore, the high initiation activity and low two-photon polymerization threshold of the two-photon initiator enable the two-photon initiator to efficiently initiate two-photon polymerization in an aqueous phase, and the effect of processing three-dimensional hydrogels by using two-photon polymerization is outstanding.

Description

Technical Field

[0001] This invention belongs to the field of new materials and organic chemicals technology, specifically relating to the structure of a class of dipyridinium salt-type water-soluble two-photon initiators with coumarin and carbazole groups, their chemical preparation technology and their use as two-photon initiators, particularly in the field of laser micro-nano processing technology. Background Technology

[0002] Two-photon absorption refers to the simultaneous absorption of two photons of the same or different frequencies by a molecule or atom under intense laser excitation, transitioning from the ground state to an excited state via a "virtual state." Two-photon polymerization is a photopolymerization process initiated after two-photon absorption. Its reaction mechanism involves a photoinitiator absorbing two photons, generating reactive intermediates such as free radicals or cations, which then initiate the polymerization of monomer molecules. When the photoinitiator itself cannot directly generate reactive intermediates, energy can be transferred to a co-initiator or monomer through energy exchange, further initiating polymerization. Two-photon polymerization microfabrication has been extensively studied in recent decades, primarily for fabricating complex three-dimensional micro / nano devices. It has been proven to achieve high spatial resolution below 100 nm under high-energy focused beams and is considered a promising technology, paving the way for true 3D nanofabrication. State-of-the-art two-photon polymerization technology is currently being researched for the fabrication of precise 3D microstructures, such as three-dimensional micro / nano devices required in industrial applications, biocompatible microstructures for drug delivery and medical testing, and conductive micro / nanowires.

[0003] In recent years, the application of two-photon polymerization microfabrication in tissue engineering has attracted widespread attention because two-photon polymerization occurs only in a very small area at the laser focal point, resulting in structures with relatively high resolution. Photopolymerization using biocompatible polymer monomers in an aqueous phase to create three-dimensional microstructures for tissue engineering scaffolds is of great significance in the biomedical field. The initiator used in two-photon polymerization is a crucial factor affecting the success of the polymerization process; its initiation efficiency, initiation activity, and two-photon absorption cross-section all influence the polymerization speed and the accuracy of the three-dimensional structure. However, in two-photon polymerization microfabrication research, most photoinitiators are oil-soluble, and the polymerization process almost always takes place in organic solvents. This results in some organic solvent residues remaining in the microstructure after polymerization, limiting the application of these microstructures in biomedicine and tissue engineering. Current research on water-soluble photoinitiators faces challenges such as low solubility in aqueous phases, small two-photon absorption cross-sections, low initiation efficiency, high laser energy required for two-photon polymerization, and low resolution of the fabricated three-dimensional structures. Therefore, there is an urgent need to develop photoinitiators with high water solubility and low threshold values ​​to address these shortcomings.

[0004] To address the aforementioned technical challenges, it is essential to invent a two-photon photoinitiator that possesses strong two-photon absorption capability, good water solubility, and high photoinitiation activity. Coumarin-carbazole is known to have a large planar conjugated structure and a large two-photon absorption cross-section, resulting in excellent two-photon polymerization performance. Studies have shown that coumarin-carbazole derivatives can serve as two-photon initiators; however, due to their limited water solubility, they can only be used in organic solvents for three-dimensional structure processing (Chemical Communications, 2019, 55(44):6233-6236). Based on this, if a biscoumarin-carbazole structure is adopted to further expand the conjugated plane, thereby increasing the two-photon absorption cross-section, and water-soluble groups, such as pyridine salts (CN108299574 B), then it has great application potential in aqueous two-photon micro / nano construction. Summary of the Invention

[0005] To address the shortcomings of existing technologies, the first objective of this invention is to provide a class of coumarin-carbazole dipyridyl salt type water-soluble two-photon initiator compounds, overcoming the technical problems of poor water solubility, low initiation efficiency, and residual organic solvents in existing two-photon polymerization initiators in aqueous phases.

[0006] A second objective of this invention is to provide a method for preparing the above-mentioned coumarin-carbazole dipyridine salt type water-soluble two-photon initiator.

[0007] A third object of the present invention is to provide the use of the above-mentioned coumarin-carbazolium dipyridyl salt type water-soluble two-photon initiator in two-photon micro / nano constructions.

[0008] To achieve the above objectives, the solution of the present invention is:

[0009] The coumarin-carbazole dipyridinium salt type water-soluble two-photon initiator has a core structure of carbazole-coumarin with a large conjugated structure, which endows it with good light absorption ability. The dipyridinium salt gives it good water solubility and further improves light absorption ability. The structure is shown in general formula (I):

[0010]

[0011] in:

[0012] R1 is selected from hydrogen, C 1-12 Alkyl, C 1-12 Hydroxyalkyl or diethyl ether group with repeating units of 1-12;

[0013] R2 is selected from methyl, ethyl, or isopropyl;

[0014] Selected from anions.

[0015] Preferably, R1 is C1-12 In the case of alkyl chains, one or more of the -CH2- groups can be independently replaced by -O-, -S-, -CO-, -COO-, or -OCO-.

[0016] Anions are selected from the following structures:

[0017] .

[0018] A method for preparing the above-mentioned coumarin-carbazole dipyridyl salt type water-soluble two-photon initiator includes the following steps:

[0019] (1) Add phosphorus oxychloride (POCl3) dropwise to N,N An acylation reagent was prepared in dimethylformamide (DMF), and then 2,7-dihydroxycarbazole was added to the prepared acylation reagent to react and give intermediate (I)-a:

[0020] ;

[0021] (2) Intermediate (I)-a undergoes a cyclization reaction with ethyl isonicotinamide under alkaline catalysis to yield intermediate (I)-b:

[0022] ;

[0023] (3) Intermediate (I)-b reacts with chlorinated derivative R1-X in the presence of a basic catalyst to produce product (I)-c; where X represents a halogen:

[0024] ;

[0025] (4) Intermediate (I)-c reacts directly with R2-Y to produce product (I):

[0026] .

[0027] The overall preparation process is as follows:

[0028] .

[0029] The raw materials used in the preparation are known compounds in the prior art, which can be commercially available or easily prepared by known synthetic methods.

[0030] Preferably, in step (1), intermediate (I)-a is prepared by oxidizing the aldehyde group at the ortho position of the substituted dihydroxycarbazole with POCl3. The reaction is first carried out at 0°C for 1 h, and then the temperature is raised to 25°C and the reaction is continued for 1 h, with nitrogen as a protective condition.

[0031] Preferably, in step (2), the preparation of intermediate (I)-b is achieved by intermediate (I)-a undergoing a ring-closing reaction with ethyl isonicotinamide under the catalysis of a base, wherein the base is selected from piperidine, a mixture of piperidine and pyridine.

[0032] Preferably, in step (2), the solvent for the reaction is ethanol, the reaction temperature is 80°C, the reaction time is 2 hours, and nitrogen is used as a protective condition.

[0033] Preferably, in step (3), the preparation of intermediate (I)-c is achieved by intermediate (I)-b reacting with halide R1-X in the presence of an alkaline catalyst, wherein the alkaline catalyst is selected from one or more of 18-crown ether-6, sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, or potassium methoxide.

[0034] Preferably, in step (3), the halogen is selected from chlorine or bromine (Cl or Br).

[0035] Preferably, in step (3), the reaction is carried out in a solvent system. There are no particular limitations on the type of solvent used, as long as it can dissolve the raw materials and has no adverse effect on the reaction. Dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), or [other solvents are preferred]. N, N The reaction is carried out at one or more of the following: dimethylformamide (DMF), at room temperature (25°C), and the reaction time varies slightly depending on the type of raw material, usually 2-10 hours.

[0036] Preferably, in step (4), the solvent for the reaction is N,N -Dimethylformamide, the reaction temperature is 40℃, the reaction time is 12-24h. This process requires anhydrous and oxygen-free operation. The reaction solution is added to diethyl ether to obtain the precipitated product, which can be directly filtered without further purification.

[0037] The above-mentioned coumarin-carbazole dipyridyl salt type water-soluble two-photon initiator is used as a photoinitiator in an aqueous photocuring formulation system to prepare micro-nano structures.

[0038] Preferably, the photocurable formulation system includes:

[0039] (1) A compound containing at least one of the general formulas (I) is used as a two-photon active photoinitiator or a component of a photoinitiator;

[0040] (2) Contains water and at least one unsaturated water-soluble compound containing an alkene bond.

[0041] Preferably, unsaturated water-soluble compounds containing olefin bonds refer to compounds or mixtures in which olefin bonds are cross-linked through free radical polymerization.

[0042] Specifically, the unsaturated water-soluble compound containing olefin bonds can be in the form of polymers such as oligomers or prepolymers, or a copolymer formed from at least one of monomers, oligomers, and prepolymers.

[0043] The above-mentioned monomers, oligomers, prepolymers, or copolymers are all familiar to professionals in this field and are not particularly limited.

[0044] The final concentration of the coumarin-carbazole dipyridyl salt type water-soluble two-photon initiator after mixing with water is 1-5 mmol / L.

[0045] Furthermore, some representative molecular structures conforming to the present invention are as follows:

[0046] .

[0047] Due to the adoption of the above solution, the beneficial effects of the present invention are:

[0048] The water-soluble coumarin-carbazole two-photon initiator provided by this invention has a large conjugated structure, and the introduction of a bispyridine salt gives it the ability to dissolve in water. As an initiator, it can initiate two-photon photopolymerization in the aqueous phase, and its two-photon absorption cross-section is large (greater than 100 GM). Therefore, the power threshold of two-photon photoinitiation during processing is low (~25 mW). Thus, the high initiation activity and low two-photon polymerization threshold of this two-photon initiator enable it to efficiently initiate two-photon polymerization in the aqueous phase. In particular, it is outstanding in processing three-dimensional hydrogels using two-photon polymerization, thereby overcoming the problems of organic solvent residue in the prior art and showing great application potential. Attached Figure Description

[0049] Figure 1 This is a structural formula diagram of the coumarin-carbazole dipyridine salt type water-soluble two-photon initiator of the present invention.

[0050] Figure 2 This is a fabrication diagram of the (I)-1 two-photon lithography three-dimensional structure prepared in Example 1 of the present invention.

[0051] Figure 3 This is a fabrication diagram of the (I)-5 two-photon lithography three-dimensional structure prepared in Example 2 of the present invention. Detailed Implementation

[0052] The technical solution of the present invention will be further described in detail below with reference to several preferred embodiments and accompanying drawings. This embodiment is implemented on the premise of the technical solution of the invention, and provides detailed implementation methods and specific operation processes. However, the protection scope of the present invention is not limited to the following embodiments.

[0053] Unless otherwise specified, the experimental materials used in the examples below can be purchased from conventional biochemical reagent companies.

[0054] The technical solution of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0055] Example 1:

[0056] Preparation of water-soluble two-photon initiator (I)-1

[0057]

[0058] Step (1): POCl3 (9.8 mL, 104.00 mmol) was added dropwise to DMF (34 mL, 439.06 mmol) at 0 °C, and the mixture was stirred for 30 min while maintaining 0 °C. 2,7-Dihydroxycarbazole (10 g, 50.25 mmol) dissolved in 20 mL of DMF was added dropwise over 30 min, maintaining the temperature at 0 °C. Stirring was continued for another 30 min, and then the reaction mixture was raised to 25 °C and stirred for 1 h. The reaction was monitored by TLC to determine the completion of the reaction. The resulting reactants were poured into crushed ice, stirred thoroughly, and neutralized with sodium bicarbonate. The precipitate was filtered off and dried. Purification was then performed by silica gel column chromatography using toluene as the eluent to give (I)-1a in 48.6% yield.

[0059] Step (2): The (I)-1a (5.1 g, 20 mmol) prepared in the previous step and ethyl isonicotinamide (8.6 g, 45 mmol) were dissolved in 100 mL of ethanol. A catalyst amount of piperidine was added, and the mixture was refluxed for 2 h, precipitating a bright yellow crystalline compound. The completion of the reaction was monitored by TLC. The reactants were filtered, washed with ethanol, and (I)-1b was obtained in 84% yield.

[0060] Step (3): Dissolve (I)-1b (5.1 g, 10 mmol), bromoethane (1.6 g, 15 mmol), and anhydrous potassium carbonate (2.76 g, 20 mmol) prepared in the previous step in 40 mL of DMF, and then add a small amount of 18-crown ether-6 as a catalyst. The reaction solution is stirred at 25 °C for 10 h under a nitrogen atmosphere. Then, after cooling the reaction solution to room temperature, it is poured into 400 mL of water to precipitate the crude product, which is purified by column chromatography to obtain (I)-1c in 72% yield.

[0061] Step (4): The (I)-1c (3.2 g, 6 mmol) prepared in the previous step and iodomethane (7.0 g, 30 mmol) were dissolved in 20 mL of DMF and reacted overnight in a 40 °C oil bath under N2 protection. The reaction was monitored by TLC. After cooling to room temperature, the reaction solution was added to 80 mL of diethyl ether solution and stirred. A precipitate appeared. The precipitate was filtered off, and the product was a yellow solid. No further purification was required to obtain (I)-1, with a yield of 72%. MS (C 34 H 25 N3O6 2+ m / z: 285.58; Experimental result: 285.58.

[0062] Example 2:

[0063] Preparation of water-soluble two-photon initiator (I)-5

[0064]

[0065] Steps (1), (2) and (3) are the same as the preparation process of (I)-1.

[0066] Step (4): The (I)-5c (3.1 g, 6 mmol) prepared in the previous step and methyl p-toluenesulfonate (1.8 g, 10 mmol) were dissolved in 20 mL of DMF solution and reacted overnight in a 40 °C oil bath under N2 protection. The reaction was monitored by TLC. After cooling to room temperature, the reaction solution was added to 80 mL of diethyl ether solution and stirred. A precipitate appeared. The precipitate was filtered off, and the product was a yellow solid. No further purification was required to obtain (I)-5, with a yield of 88%. MS (C 34 H 25 N3O6 2+ m / z: 285.58; Experimental result: 285.58.

[0067] Example 3: <Testing of Two-Photon Absorption Cross Section>

[0068] The two-photon absorption cross-sections of the molecular structures prepared in the two examples were tested using two-photon induced fluorescence. The specific testing method was as follows: using 10... -4 Using a mol / L fluorescein NaOH aqueous solution (pH = 11) as a reference, the prepared molecules were prepared into 10... -4 For a mol / L DMSO solution, the two-photon absorption cross section of the two molecules at 780 nm was calculated by measuring the fluorescence intensity of the two-photon induced fluorescence. The calculation formula is as follows:

[0069]

[0070] In the formula, σ s , σr The two-photon absorption cross sections of the sample and reference are respectively, F s F r The two-photon induced fluorescence integral intensities of the sample and the reference under the same experimental conditions are Φ. s 、 r The fluorescence quantum yields of the sample and reference are respectively, c s c r The concentrations of the sample and the reference, respectively, n s n r The values ​​represent the solvent refractive indices of the sample and the reference, respectively. Tests revealed that the two-photon absorption cross sections of (I)-1 and (I)-5 are 105 GM and 115 GM, respectively.

[0071] Example 4: <Applications of Two-Photon Polymer Micro / Nano Fabrics>

[0072] Using the water-soluble two-photon initiator (I)-1 from Example 1, two-photon polymerization in the aqueous phase was initiated to fabricate three-dimensional microstructures:

[0073] 10 mg of water-soluble two-photon initiator (I)-1 was dissolved in 100 μL of ultrapure water. 30 mg of N-methyldiethanolamine was weighed as an amine auxiliary agent. Then, 0.5 g of polyethylene glycol diacrylate (PEGDA, MW=400) monomer was added and stirred thoroughly. The mixture was then wrapped in aluminum foil and stored in the dark. The prepared photoresist was dropped onto the center of a clean glass plate. A Ti:sapphire femtosecond laser was used as the light source, with a center wavelength of 780 nm, a pulse width of 120 fs, a pulse repetition frequency of 80 MHz, and a laser energy of 25 mW. The laser was exposed to the focal point of the femtosecond laser, which was focused by an objective lens (63 × 1.4 NA oil immersion objectives). The three-dimensional structure was fabricated using two-photon polymerization on a computer-controlled three-dimensional moving platform. After fabrication, the sample was soaked in ethanol for 8 min to remove unpolymerized monomers, and then repeatedly rinsed with flowing deionized water to obtain a finely processed structure. The microstructure morphology of the dried sample was observed using a scanning electron microscope. Figure 2 As shown in the figure, this structure is a ball-and-stick model of diamond carbon. As can be seen from SEM, the fabricated hydrogel microstructure has a clear outline and a good surface morphology.

[0074] Example 5: <Applications of Two-Photon Polymer Micro / Nano Fabrics>

[0075] Using the water-soluble two-photon initiator (I)-5 from Example 2, two-photon polymerization was initiated in the aqueous phase to fabricate three-dimensional microstructures:

[0076] 10 mg of water-soluble two-photon initiator (I)-5 was dissolved in 100 μL of ultrapure water. 30 mg of N-methyldiethanolamine was weighed as an amine auxiliary agent. Then, 0.5 g of polyethylene glycol diacrylate (PEGDA) monomer was added and stirred until homogeneous. The mixture was then wrapped in aluminum foil and stored in the dark. The remaining process was identical to that in Example 3. The resulting three-dimensional structure is shown below. Figure 3 As shown, the structure is a cube, and SEM images show that the processed hydrogel microstructure does not exhibit significant deformation.

[0077] The above description of the embodiments is intended to enable those skilled in the art to understand and use the present invention. Obviously, the described embodiments are only some, not all, of the embodiments of the present invention. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without inventive effort are within the scope of protection of the present invention.

Claims

1. A coumarin-carbazole dipyridyl salt type water-soluble two-photon initiator, characterized in that, Its general structural formula is shown in (I): in: R1 is selected from hydrogen, C1- 12 Alkyl, C1- 12 Hydroxyalkyl or diethyl ether group with repeating units of 1-12; R2 is selected from methyl, ethyl, or isopropyl; R1 is C1- 12 In the case of alkyl chains, one or more -CH2- are independently replaced by -O-, -S-, -CO-, -COO-, or -OCO-; Selected from the following structure: 、 。 2. A method for preparing the coumarin-carbazole dipyridyl salt type water-soluble two-photon initiator as described in claim 1, characterized in that, It includes the following steps: (1) Add phosphorus oxychloride dropwise to N,N In dimethylformamide, an acylation reagent is prepared, and then 2,7-dihydroxycarbazole is added to the prepared acylation reagent to react and give intermediate (I)-a: ； (2) The intermediate (I)-a undergoes a cyclization reaction with ethyl isonicotinamide under alkaline catalysis to obtain intermediate (I)-b: ； (3) The intermediate (I)-b reacts with the chlorinated derivative R1-X under 18-crown-6 catalysis to generate product (I)-c; wherein X represents a chlorine atom: ； (4) The intermediate (I)-c reacts directly with R2-Y to form a salt, generating product (I): ； R 1、 The definitions of the substituents for R2 and Y are the same as in claim 1.

3. The preparation method according to claim 2, characterized in that, In step (1), the reaction is first carried out at 0°C for 1 hour, and then the temperature is raised to 25°C and the reaction continues for 1 hour, with nitrogen as a protective condition.

4. The preparation method according to claim 2, characterized in that, In step (2), the base is selected from piperidine, a mixture of piperidine and pyridine.

5. The preparation method according to claim 2, characterized in that, In step (2), the solvent for the reaction is ethanol, the reaction temperature is 80°C, the reaction time is 2 hours, and nitrogen is used as a protective condition.

6. The preparation method according to claim 2, characterized in that, In step (3), the solvent for the reaction is selected from dimethyl sulfoxide, tetrahydrofuran, or... N,N The reaction is carried out at a temperature of 25°C and a time of 2-10 hours, and is carried out at one or more of dimethylformamides.

7. The preparation method according to claim 2, characterized in that, In step (4), the solvent for the reaction is N,N -Dimethylformamide, the reaction temperature is 40℃, and the reaction time is 12-24h.

8. The use of the coumarin-carbazole dipyridyl salt type water-soluble two-photon initiator as described in claim 1 as a photoinitiator in an aqueous photocuring formulation system for the preparation of micro / nano structures.

9. The use according to claim 8, characterized in that, The photocurable formulation system includes: (1) Contains at least one compound of general formula (I) as a photoinitiator or a component of a photoinitiator; (2) Contains water and at least one unsaturated water-soluble compound containing an alkene bond.

10. The use according to claim 9, characterized in that, The unsaturated water-soluble compounds containing olefin bonds refer to compounds or mixtures in which olefin bonds are cross-linked through free radical polymerization.

11. The use according to claim 9, characterized in that, The unsaturated water-soluble compound containing olefin bonds is selected from monomers, oligomers, or prepolymers, or mixtures or copolymers of the three.

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