Synthesis method and application of a carbon borane skeleton aggregation-induced emission molecule

Abstract

This invention discloses a method for synthesizing aggregation-induced emission (AIE) molecules with a carborane skeleton, belonging to the field of organic synthesis. Using 1-iodo-2-methyl-o-carborane as a starting material, alkenyl iodocarborane is obtained in one step via photocatalysis with copper. Subsequently, two Suzuki cross-coupling reactions yield an AIE molecule with a carborane skeleton. The target molecule was then characterized by optical properties, verifying its AIE ability, cell activity, and cell imaging capabilities. This method utilizes readily available raw materials, offers high operational safety, uses inexpensive catalysts, and employs a mild reaction system, providing a practical new route for the large-scale preparation of AIE molecules with a carborane skeleton.

Description

Technical Field

[0001] This invention relates to a method for synthesizing aggregation-induced luminescent molecules with a carborane skeleton, belonging to the field of organic synthesis. Background Technology

[0002] Carboranes are three-dimensional spherical structures with σ-aromaticity. They are three-dimensional analogs of benzene rings, exhibiting an electron-deficient effect at the carbon end and an electron-donating effect at the boron end. Introducing them into target molecules can significantly alter the luminescence properties and structural characteristics of the material. Currently, they have found significant applications in circularly polarized luminescence, fluorescent molecule construction, and organic catalyst design.

[0003] Traditional carbon-terminal functionalization of carboranes relies on deprotonation with strong bases, such as butyllithium or sodium amino, followed by nucleophilic substitution or cross-coupling reactions. The entire reaction system requires strong bases and expensive transition metals (palladium, iridium).

[0004] Therefore, developing efficient, inexpensive and readily available reaction systems to achieve carbon-terminal functionalization is of great significance and has a significant promoting effect on the construction of high-value fluorescent molecules. Summary of the Invention

[0005] The present invention aims to provide a novel method for carbon-terminal functionalization that is mild, simple, and low-cost, and to further prepare aggregation-induced luminescent molecules with a carborane backbone, and to study their imaging ability in distinguishing between living and dead cells.

[0006] To achieve the above objectives, the present invention adopts the following technical solution: using 1-iodo-2-methyl-o-carborane as a raw material, alkenyl iodocarborane is obtained in one step through photocatalysis with copper; subsequently, after two Suzuki cross-coupling reactions, an aggregation-induced emission molecule with a carborane skeleton is obtained; the optical properties of the target molecule are then characterized to verify its aggregation-induced emission ability, cell activity, and cell imaging ability.

[0007] This invention first provides an aggregation-induced emission molecule with a carborane backbone, the chemical structure of which is as follows: .

[0008] The method for synthesizing aggregation-induced luminescent molecules with a carborane skeleton according to the present invention includes the following steps: In step A, compound 1 and phenylacetylene 2 undergo an atom transfer radical addition reaction under light in the presence of copper salt, phenanthroline ligand and organic solvent to give compound 3; , In step B, compound 3 and compound 4 undergo a Suzuki cross-coupling reaction in the presence of a palladium catalyst, a phosphine ligand, an inorganic base, and an organic solvent to give compound 5. , In step C, compound 5 and compound 6 undergo a Suzuki cross-coupling reaction in the presence of a palladium catalyst, a phosphine ligand, an inorganic base, and an organic solvent to obtain an aggregation-induced luminescent molecule with a carborane skeleton. .

[0009] Furthermore, in step A of the above technical solution, the reaction temperature is 0-30℃, and the organic solvent is dichloromethane.

[0010] Furthermore, in step A of the above technical solution, the illumination adopts a wavelength of 450-460nm.

[0011] Furthermore, in step A of the above technical solution, the molar ratio of compound 1, phenylacetylene 2, copper salt and ligand is 1: 2: 0.1: 0.2.

[0012] Furthermore, in step B of the above technical solution, the molar ratio of compound 3, compound 4, palladium catalyst and ligand is 1:1.5:0.01:0.015.

[0013] Furthermore, in step B of the above technical solution, the reaction temperature is 0-30℃, and the organic solvent is a mixture of tetrahydrofuran and methanol.

[0014] Furthermore, in step C of the above technical solution, the molar ratio of compound 5, compound 6, palladium catalyst and ligand is 1:1.5:0.01:0.015.

[0015] Furthermore, in step C of the above technical solution, the reaction temperature is 0-30℃, and the organic solvent is a mixture of tetrahydrofuran and methanol.

[0016] This invention also provides the application of the above-mentioned carborane skeleton aggregation-induced luminescent molecules in distinguishing between living and dead cells. Beneficial effects of the invention

[0017] The method of this invention uses readily available raw materials, is highly safe to operate, uses inexpensive catalysts, and has a mild reaction system, providing a practical new approach for the large-scale preparation of aggregation-induced luminescent molecules with a carborane skeleton. Attached Figure Description

[0018] Figure 1 For compound 7 (1x10 -5 M) Emission wavelength diagrams in different acetonitrile-water mixtures; Figure 2 For compound 7 (1x10 -5 M) Fluorescence spectra of different acetonitrile-water mixtures; Figure 3 This is a graph showing the cell viability of compound 7. Figure 4 Imaging experiment diagram to distinguish between live and dead cells after adding compound 7. Detailed Implementation Example 1

[0019] , , a Unless otherwise specified, the reaction proceeds as follows: 1 (0.2 mmol), 2 (0.4 mmol), copper salt (10 mol%), ligand (20 mol%) react in (2.0 mL) solvent for 24 hours. b Separation yield c No light.

[0020] Optimization of reaction conditions revealed that the ligand skeleton structure has a crucial impact on the reaction outcome, with the o-phenanthroline skeleton showing better compatibility than the bipyridine and terpyridine ligands. Substituent effect studies showed that the 2,9-dimethyl o-phenanthroline ligand yielded the optimal yield. Solvent optimization indicated that dichloromethane was the optimal reaction solvent, while solvents containing active CH bonds (such as tetrahydrofuran and toluene) yielded almost no target product. Copper salt screening showed that... It is the optimal copper catalyst. Other types of copper salts are difficult to form a sufficient amount of key catalytic active species due to differences in solubility, thus affecting the reaction effect.

[0021] The optimal conditions for this reaction were ultimately determined to be: 10 mol% The reaction was carried out at 25 °C for 24 hours using copper salt, 20 mol% of 2,9-dimethyl-1,4-phenanthroline as ligand, and dichloromethane as solvent.

[0022] General reaction conditions: Under an argon atmosphere, Cu(CH3CN)4PF6 (10 mol%, 0.36 mmol, 134 mg), ligand L (20 mol%, 0.72 mmol, 150 mg), compound 1 (3.6 mmol, 1022 mg), DCM (2.0 mL), and phenylacetylene 2 (7.2 mmol, 735 mg) were sequentially added to a 10 mL reaction tube. The tube was then placed in a 457 nm blue LED photochemical reaction apparatus and stirred overnight at 25°C. After the reaction was complete, the reaction mixture was transferred to a 50 mL round-bottom flask; 20–50 mg of silica gel was added, the solvent was removed under reduced pressure, and the mixture was purified by rapid column chromatography, eluting with pure petroleum ether to obtain product 3. 1H NMR (400MHz, CDCl3) δ: 7.39-7.33 (m, 3H), 7.23-7.21 (m, 2H), 6.68 (s, 1H), 2.05 (s, 3H). 11 B NMR (128 MHz, CDCl3) δ: -2.5 (1B), -5.7 (1B), -9.4 - -12.7 (8B). 13 CNMR (100 MHz, CDCl3) δ: 140.8, 132.3, 129.4, 128.5, 127.2, 109.8, 76.4, 76.3,23.8. HR MS (ESI-TOF) m / z: [M+H] + cal C 11 H 20 11 B 10 127 I 389.1535, find 389.1533. Example 2

[0023] , Under an argon atmosphere, compound 3 (0.3 mmol, 115 mg), 5-bromothiophene-2-boronic acid 4 (0.36 mmol, 74 mg), Pd(OAc)2 (0.03 mmol, 7 mg), PPh3 (0.045 mmol, 12 mg), K2CO3 (0.6 mmol, 83 mg), THF (2.5 mL), and CH3OH (2.5 mL) were sequentially added to a 10 mL glass tube. The reaction mixture was then stirred overnight at 25°C. After the reaction was complete, the reaction mixture was transferred to a 50 mL round-bottom flask, 50 mg of silica gel was added, the solvent was removed under reduced pressure, and the mixture was purified by rapid column chromatography, eluting with pure petroleum ether, to give 56.8 mg of product 5, in 45% yield. Example 3

[0024] , Under an argon atmosphere, compound 5 (0.12 mmol, 51 mg), 4-(diphenylamine)phenylboronic acid 6 (0.144 mmol, 42 mg), Pd(OAc)2 (0.012 mmol, 3 mg), PPh3 (0.018 mmol, 5 mg), K2CO3 (0.24 mmol, 33 mg), THF (1.5 mL), and CH3OH (1.5 mL) were added sequentially to a 10 mL glass tube. The reaction mixture was then stirred overnight at 25°C. After the reaction was complete, the reaction mixture was transferred to a 50 mL round-bottom flask, 50 mg of silica gel was added, the solvent was removed under reduced pressure, and the mixture was purified by rapid column chromatography, eluting with pure petroleum ether, to give 47 mg of aggregation-induced luminescent molecule 7 with a carborane skeleton, yield 67%. 1 H NMR (400 MHz, CDCl3) δ: 7.45-7.36 (m, 6H), 7.25-7.19 (m, 6H), 7.10-7.08 (m, 5H), 7.05-7.00 (m, 4H), 6.98-6.97 (d, J = 3.1 Hz, 1H), 6.48-6.47 (d, J = 3.1 Hz, 1H), 6.22 (s, 1H), 2.03 (s, 3H). 11 B NMR (128 MHz, CDCl3)δ: -3.2 (1B), -5.9 (1B), -10.1 (8B). 13 C NMR (100 MHz, CDCl3) δ: 148.0, 147.3,146.0, 145.6, 143.3, 135.3, 130.2, 129.7, 129.4, 128.8, 128.3, 126.7, 124.8,123.5, 123.1, 122.6, 116.5, 23.7. HRMS (ESI-TOF) m / z: [M+H] + cal C 32 13 CH 36 11 B 10 N 32 S 589.3527, find 589.3522. Example 4

[0025] AIE effect spectroscopy test: First, acetonitrile and water were mixed to obtain acetonitrile-water mixtures with water volume percentages (v / v%) of 0%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, and 90%. Then, compound 7 (1x10⁻⁶) was added to the above mixtures. -5 After thorough mixing (M), the mixture was tested using a fluorescence spectrophotometer. According to... Figure 1 and 2 The fluorescence emission spectrum of compound 7 shown reveals that the emission intensity of the compound gradually increases as the water content of the acetonitrile-water mixture increases from 0% to 90%, indicating that the compound exhibits an AIE effect. Example 5

[0026] Cytotoxicity: The cytotoxicity of compound 7 was investigated in HeLa cells using the standard Methylthiazolyl tetrazolidinium (MTT) colorimetric assay. Figure 3 As shown, at a compound concentration of 1x10 -5 With both M and a culture time of 24 hours, cell viability reached over 85%. This indicates that compound 7 exhibits negligible cytotoxicity and can be applied to bioimaging. Example 6

[0027] Imaging experiment to distinguish between living and dead cells: This experiment was divided into two groups.

[0028] Live cell group: adherent HeLa cells were mixed with compound 7 (1*10) -5 M) After incubation at 37°C for 30 minutes, the sample was washed three times with PBS. Then, 1 mL of DMEM was added for fluorescence imaging experiments.

[0029] Dead cell group: Adherent HeLa cells were treated with 4% paraformaldehyde fixative (1 mL) for 30 minutes, followed by washing three times with PBS. Then, compound 7 (1*10) was added. -5 M) Incubate at 37°C for 30 minutes. After incubation, wash cells three times with PBS. Finally, add 1 mL of DMEM for fluorescence imaging experiments.

[0030] The results are as follows Figure 4 As shown, the fluorescence intensity of live cells is significantly higher than that of dead cells.

[0031] The above description is merely a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the scope of the technology disclosed in the present invention, based on the technical solution and inventive concept of the present invention, should be covered within the scope of protection of the present invention.

Claims

1. An aggregation-induced luminescent molecule with a carborane backbone, characterized in that, The chemical structure is as follows: 。 2. The method for synthesizing aggregation-induced luminescent molecules with a carborane skeleton as described in claim 1, characterized in that, Includes the following steps: In step A, compound 1 and phenylacetylene 2 undergo an atom transfer radical addition reaction under light in the presence of copper salt, phenanthroline ligand and organic solvent to give compound 3; ， In step B, compound 3 and compound 4 undergo a Suzuki cross-coupling reaction in the presence of a palladium catalyst, a phosphine ligand, an inorganic base, and an organic solvent to give compound 5. ， In step C, compound 5 and compound 6 undergo a Suzuki cross-coupling reaction in the presence of a palladium catalyst, a phosphine ligand, an inorganic base, and an organic solvent to obtain an aggregation-induced luminescent molecule with a carborane skeleton. 。 3. The method for synthesizing aggregation-induced luminescent molecules with a carborane skeleton according to claim 2, characterized in that: In step A, the reaction temperature is 0-30℃, and the organic solvent is dichloromethane.

4. The method for synthesizing aggregation-induced luminescent molecules with a carborane skeleton according to claim 2, characterized in that: In step A, the illumination uses a wavelength of 450-460nm.

5. The method for synthesizing aggregation-induced luminescent molecules with a carborane framework according to claim 2, characterized in that: In step A, the molar ratio of compound 1, phenylacetylene 2, copper salt and ligand is 1: 2: 0.1: 0.

2.

6. The method for synthesizing aggregation-induced luminescent molecules with a carborane skeleton according to claim 2, characterized in that: In step B, the molar ratio of compound 3, compound 4, palladium catalyst and ligand is 1:1.5:0.01:0.

015.

7. The method for synthesizing aggregation-induced luminescent molecules with a carborane skeleton according to claim 2, characterized in that: In step B, the reaction temperature is 0-30℃, and the organic solvent is a mixture of tetrahydrofuran and methanol.

8. The method for synthesizing aggregation-induced luminescent molecules with a carborane skeleton according to claim 2, characterized in that: In step C, the molar ratio of compound 5, compound 6, palladium catalyst, and ligand is 1:1.5:0.01:0.

015.

9. The method for synthesizing aggregation-induced luminescent molecules with a carborane skeleton according to claim 2, characterized in that: In step C, the reaction temperature is 0-30℃, and the organic solvent is a mixture of tetrahydrofuran and methanol.

10. The application of the aggregation-induced luminescent molecule with the carborane skeleton as described in claim 1 in distinguishing between living and dead cells.

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