Preparation method and application of polyiodo tetraphenylethylene derivative
By selectively introducing multiple iodine atoms onto the tetraphenylethylene derivative skeleton while retaining active functional groups, the synthesis challenges in existing technologies have been solved, resulting in highly efficient photosensitizers and CT contrast agents, thus expanding the application potential in biomedicine and materials science.
Patent Information
- Application Number
- CN202511714349.6
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-11-21
- Publication Date
- 2026-02-17
AI Technical Summary
Existing technologies make it difficult to simultaneously and precisely introduce multiple iodine atoms and retain a single active functional group in tetraphenylethylene derivatives, resulting in low yield, numerous byproducts, and limited functional expansion. Traditional radiosensitizers have significant toxic side effects, and the preparation of traditional inorganic scintillators is complex and costly.
A highly selective synthetic route was adopted to introduce heavy iodine atoms onto multiple benzene rings of a tetraphenylethylene skeleton. The heavy atom effect of iodine was used to enhance the photosensitizer potential, while retaining modifiable functional groups such as carboxyl or nitro groups to provide active sites for subsequent functional expansion of the molecule. The reaction was carried out in a specific solvent using iodination reagents and Lewis acid catalysts, combined with extraction and column chromatography purification.
This method achieves highly selective introduction of iodine atoms at multiple positions in the TPE backbone, maintaining molecular configuration stability, improving photosensitivity and CT imaging performance, expanding biocompatibility and targeting capabilities, and has broad application prospects. The synthetic route is clear, efficient, and yields high levels of yield.
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Figure CN121537283A_ABST
Abstract
Description
TECHNICAL FIELD
[0001] The application belongs to the technical field of organic synthesis, and particularly relates to a preparation method and application of a polyiodinated tetraphenylethene derivative. BACKGROUND
[0002] Tetraphenylethene (TPE) and its derivatives are a class of molecules with typical aggregation-induced emission (AIE) characteristics. They emit almost no light in dilute solution, but emit strong fluorescence in the aggregated state or solid state. This characteristic makes them highly concerned in the fields of biological imaging, chemical sensing and optoelectronic devices.
[0003] In order to expand the application of TPE, the existing technology usually carries out molecular design in two directions: one is to introduce one or more active functional groups (such as carboxyl-COOH, amino-NH2) on the TPE skeleton for subsequent connection, so as to realize biological coupling or targeting function; the other is to introduce specific groups (such as heavy atom iodine) to endow the molecule with new functions, such as AIE scintillator. However, when combining these two strategies, i.e. preparing TPE derivatives containing multiple iodine atoms and a single active functional group, the existing technology has obvious defects and challenges:
[0004] First, the contradiction and challenge in the synthesis strategy: the existing technology is difficult to realize the accurate preservation of multi-site iodination and functional groups in the same AIE molecule. Generally, when a TPE molecule with a functional group is subjected to strong iodination, the pre-designed functional group will affect the activity and regioselectivity of the iodination reaction, and at the same time, the reaction conditions may also destroy the functional group. On the other hand, if the iodine-containing TPE molecule or its precursor is first functionalized, the multiple iodine atoms introduced will interfere with the introduction or conversion of the subsequent functional group. This contradiction leads to low yield, many by-products, and it is difficult to obtain a target molecule with a clear structure.
[0005] Second, the limited functional expansion: the iodine-containing TPE derivatives reported so far usually do not contain active functional groups for biological coupling, which limits their application to the molecule itself and makes it difficult to be used in complex biological systems such as targeted therapy. Therefore, there is a lack of a TPE platform molecule that accurately iodinates while preserving a single active functional group in the art.
[0006] Third, the lack of high-efficiency organic radiotherapy sensitizers: traditional radiotherapy sensitizers have the problems of large toxic side effects and limited sensitization effect. Although the introduction of heavy atoms (such as iodine) can enhance the effect of radiotherapy, how to design and synthesize an organic small-molecule sensitizer with good biocompatibility and high iodine content is still a research hotspot at present.
[0007] Fourthly, the demand for the development of new organic AIE scintillator materials: traditional inorganic scintillators have problems such as complex preparation process, high cost, and serious self-absorption. Developing new organic AIE scintillators that are easy to process and have adjustable performance is an important development direction, and introducing heavy atoms into the AIE molecular skeleton is an effective way to improve the radiation detection efficiency, but the related molecular design and synthesis reports are still very rare.
[0008] Therefore, there is an urgent need in the art to develop a brand new synthetic method that can selectively introduce iodine atoms at multiple specific positions of the tetraphenyl ethene skeleton while accurately preserving at least one active functional group, thereby obtaining a new TPE derivative platform molecule with clear structure, multiple application potential (such as AIE scintillator, radiotherapy sensitization), and functional expansion (biological conjugation). SUMMARY
[0009] The present application provides a new type of polyiodinated tetraphenyl ethene derivative, and provides an efficient and controllable preparation method, aiming to:
[0010] 1. By introducing heavy atom iodine on multiple benzene rings of the TPE skeleton, the intersystem crossing efficiency of the molecule is enhanced by the "heavy atom effect", and the potential of the molecule as a photosensitizer is improved; at the same time, the iodine atom has good X-ray absorption ability, which endows the molecule with CT imaging and radiotherapy sensitization functions.
[0011] 2. One modifiable functional group (such as carboxyl or nitro) is preserved, which provides an active site for subsequent biological conjugation or functional expansion of the molecule.
[0012] 3. A synthetic route for selectively introducing iodine atoms at the para position of the TPE benzene ring is developed.
[0013] 4. Expand the application of this type of molecule, for example, by activating the carboxyl group and coupling with biological molecules such as amino acids to improve its biocompatibility and targeting.
[0014] To achieve the above purposes, the specific technical solutions adopted by the present application are as follows:
[0015] In a first aspect, the present application provides a polyiodinated tetraphenyl ethene derivative, the structure general formula of which is as follows:
[0016]
[0017] wherein R is a functional group, and at least one R group is iodine, and at least one R group is an active group or a derivative group; the active group is a carboxyl group (-COOH), a nitro group (-NO2), an aldehyde group (-CHO), a hydroxyl group (-OH), a sulfhydryl group (-SH), an amino group (-NH2), etc.; the derivative group is a group formed by amidation of the active group, which can be a group connected to a biomolecule or a small molecule through an amide bond, such as -CONH-CH2-COOCH3, or a group reacted with an aldehyde group to form a C=N bond, etc.
[0018] Preferably, in the structural formula of the polyiodinated tetraphenyl ethene derivative, three R groups are iodine, and one R group is an active group. Specifically, it can be compound 1 or compound 2.
[0019] The compound 1 is 4', 4'', 4'''-triiodo-tetraphenyl ethene-4-carboxylic acid, and the structural formula is as follows:
[0020]
[0021] The compound 2 is 4', 4'', 4'''-triiodo-tetraphenyl ethene-4-nitrobenzene, and the structural formula is as follows:
[0022]
[0023] Preferably, in the structural formula of the polyiodinated tetraphenyl ethene derivative, three R groups are iodine, and one R group is a derivative group. Specifically, it can be compound 3.
[0024] The compound 3 is a coupling product of compound 1 and glycine methyl ester, and the structural formula is as follows:
[0025]
[0026] In a second aspect, the present application provides a preparation method of the above-mentioned polyiodinated tetraphenyl ethene derivative. When three R groups in the structural formula are iodine, and one R group is an active group, method one is used; when three R groups in the structural formula are iodine, and one R group is a derivative group -CONH-CH2-COOCH3 (i.e. the polyiodinated tetraphenyl ethene derivative is compound 3), method two is used.
[0027] Specifically, the method one comprises the following steps:
[0028] S11. Taking TPE-R as a starting material, placing it in a reaction container, sequentially adding an iodination reagent, a solvent, and a Lewis acid catalyst, and reacting at room temperature or under heating for 4-12 hours; the TPE-R can be tetraphenyl ethene carboxylic acid (TPE-COOH), tetraphenyl ethene nitrobenzene (TPE-NO2), etc., and the structural formula is as follows (R is an active group):
[0029] ;
[0030] S12. After the reaction is completed, saturated sodium thiosulfate solution is added to quench the reaction, and the target product is obtained through extraction, washing, and column chromatography purification.
[0031] Preferably, in step S11, the iodination reagent is iodine / potassium periodate (I2 / HIO3), iodine / potassium iodate (I2 / KIO3), or other iodination systems; the solvent is carbon tetrachloride, tetrahydrofuran, acetic acid, or other aprotic or protic solvents, which can be one or more; and the Lewis acid is sulfuric acid.
[0032] Preferably, in step S12, the organic solvent used for extraction is dichloromethane (DCM), the solution used for washing is saturated brine, and the eluent used for column chromatography is petroleum ether / ethyl acetate.
[0033] Specifically, the method two comprises the following steps:
[0034] S21. Compound 1 is prepared according to steps S11-S12 of the method one;
[0035] S22. Compound 1, glycine methyl ester hydrochloride, an organic base, and an initiator are dissolved in anhydrous acetonitrile, and the reaction is carried out at 80-85°C for 12-24 hours.
[0036] S23. After the reaction is completed, the product is obtained through extraction, washing, drying, rotary evaporation, and column chromatography purification.
[0037] Preferably, in step S22, the organic base is triethylamine or N,N-diisopropylethylamine (DIEA), and the initiator is 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC).
[0038] In a third aspect, the present application provides the use of the above-mentioned polyiodinated tetraphenyl ethene derivative. Due to its unique aggregation-induced emission (AIE) characteristics and novel photophysical, chemical, and biological properties brought by the introduction of iodine, the iodine-containing multifunctional tetraphenyl ethene derivative can be widely used in the following fields:
[0039] (a) Biomedical imaging field: as a fluorescent probe for cell or tissue imaging; as a contrast agent for X-ray computed tomography (CT), realizing fluorescent / CT dual-mode imaging;
[0040] (b) Medical field: as a photosensitizer for photodynamic therapy (PDT) or as a radiosensitizer for radiotherapy (RT); by coupling with targeting molecules (such as polypeptides, antibodies), realizing targeted imaging and treatment of specific lesions (such as tumors);
[0041] (c) Chemical and biological sensing: Designed as fluorescent sensors that specifically recognize certain ions, molecules, or biological macromolecules. Optoelectronic materials: Applied as luminescent materials in organic light-emitting diodes (OLEDs) and other devices;
[0042] (d) Organic synthesis: Iodine atoms in the molecule can serve as active sites, and as intermediates in organic synthesis, they can be further synthesized into more complex functional molecules through coupling reactions such as Suzuki and Sonogashira reactions;
[0043] (e) Radiation detection and scintillation materials: As a new type of AIE scintillator, it can be used to detect high-energy radiation such as X-rays and gamma rays, and has potential applications in radiation safety monitoring and high-energy physics.
[0044] The following combines the structural characteristics of the polyiodinated tetraphenylethene derivative of the present application to further illustrate its technical principles that can be applied to fluorescence imaging, optoelectronic materials, CT contrast, and treatment sensitization, etc.:
[0045] 1. AIE property source: The unique structure of the TPE mother nucleus makes it have a typical AIE effect. In the molecular state, the free rotation of multiple benzene rings will consume the excitation state energy through non-radiative transition, resulting in fluorescence quenching. In the aggregated state, the intramolecular rotation is restricted, which inhibits the non-radiative transition channel, so that the energy is released through radiative transition, thereby producing strong fluorescence.
[0046] 2. Heavy atom effect principle: The introduction of iodine atoms with high atomic number in the TPE molecule can significantly enhance the spin-orbital coupling of electrons. This promotes the intersystem crossing (ISC) process from the singlet excited state (S1) to the triplet excited state (T1) after the molecule is excited by light. Higher triplet state yield is beneficial to subsequent energy transfer processes, such as transferring energy to oxygen molecules to generate reactive oxygen species (ROS, such as singlet oxygen) for photodynamic therapy.
[0047] 3. CT contrast principle: Iodine has a high atomic number and electron density, which can effectively absorb and attenuate X-rays. The introduction of multiple iodine atoms into a molecule can significantly improve the X-ray attenuation ability of the molecule in a specific region, thereby producing stronger contrast on the CT image, acting as a contrast agent.
[0048] 4. Functional group design principle: Retaining carboxyl, nitro and other functional groups provides a basis for the functionalization of the molecule. Carboxyl is one of the most commonly used functional groups in biological coupling, which can easily form stable amide bonds with amino groups on proteins, polypeptides, and amino acids. Nitro as a strong electron-withdrawing group can adjust the optoelectronic properties of the molecule, and can be reduced to amino for further chemical modification.
[0049] 5. Radiosensitization and AIE scintillation principle: Multiple heavy iodine atoms in the molecule can effectively absorb external high-energy rays (such as X-rays used in radiotherapy), generating a large number of photoelectrons and Auger electrons. These high-energy electrons can directly or indirectly cause DNA double-strand breaks, killing tumor cells, thereby achieving the effect of radiosensitization. Simultaneously, some energy in the aggregated state of the AIE molecule can be released through radiative transitions, producing visible light emission, i.e., the AIE scintillation phenomenon, which provides a possibility for radiation dose monitoring.
[0050] Compared with the prior art, the present invention has the following beneficial effects:
[0051] 1. Clear and efficient synthetic route: The method provided by this invention has clear steps and adopts mature organic chemical reactions. It has good regioselectivity (preferentially replacing the para position of the benzene ring, with the para position being far from the central double bond, resulting in minimal steric hindrance, which is conducive to the introduction of large-volume iodine atoms and maintaining molecular configuration stability; the para iodine is located on the outermost edge of the molecule, which can expose "heavy atoms" to the greatest extent, enhance spin-orbit coupling, and thus improve photosensitivity and CT imaging performance), high yield, and is easy to repeat and scale up for production.
[0052] 2. High structural tunability: By changing the functional groups of TPE (such as replacing -COOH with -NO2), or by further modifying the functional groups in different ways, the physicochemical properties (such as solubility, absorption and emission wavelengths) and biological functions of the derivatives can be easily controlled.
[0053] 3. Broad application prospects: These derivatives have shown great application potential in the fields of biomedicine and materials science, and are expected to solve the limitations of existing single-function materials.
[0054] 4. Expanding new application areas: This invention extends the concept of AIE materials to the field of radiation detection, and the proposed AIE scintillator concept opens up new avenues for developing low-cost, high-performance organic scintillator materials. Attached Figure Description
[0055] Figure 1 : The 1H NMR spectrum of compound 1 in Example 1.
[0056] Figure 2 : The 1H NMR spectrum of compound 2 in Example 2.
[0057] Figure 3 : The 1H NMR spectrum of compound 3 in Example 3. Detailed Implementation
[0058] The present invention will be further described below with reference to the accompanying drawings and specific embodiments.
[0059] Example 1: Preparation of 4',4",4"'-triiodotetraphenylstyrene-4-carboxylic acid (Compound 1)
[0060] The synthesis route of Compound 1 is as follows:
[0061]
[0062] The specific operation is as follows: tetraphenylstyrene-4-carboxylic acid (1.0 mmol) is placed in a reaction vessel, and iodine (1.8 mmol), potassium iodate (2.32 mmol), glacial acetic acid (15 mL), carbon tetrachloride (3.5 mL) and 50wt% sulfuric acid (2 mL) are added in turn. The reaction system is warmed to 80 ℃, and stirred for 4 hours. After the reaction is completed, it is cooled to room temperature, and saturated sodium thiosulfate solution is added to quench the reaction. Then it is extracted with dichloromethane (DCM) three times, and washed with saturated brine. The extract is purified by column chromatography (eluent is petroleum ether / ethyl acetate, gradient from 2:1 to 1:1, v / v), to obtain a light yellow solid product with a yield of 84%.
[0063] The structure of the product is confirmed by Figure 1 NMR spectrum (1H NMR) as shown in the spectrum data: 1 HNMR (400 MHz, CDCl3) δ 7.80, 7.78, 7.42, 7.42, 7.41, 7.40, 7.40, 7.39, 7.38,7.37, 7.36, 7.19, 7.02, 7.02, 7.00, 7.00, 6.67, 6.67, 6.66, 6.65, 6.64, 6.64,6.64, 6.63, 6.63, 6.62. The peak position and integral intensity ratio of the nuclear magnetic resonance correspond to the theory, indicating that the obtained product is the target compound 4',4",4"' -triiodotetraphenylstyrene-4-carboxylic acid. The spectrum has a flat baseline, and no obvious impurity peak or byproduct signal is observed except the solvent peak, indicating that the product has high purity.
[0064] Example 2: Preparation of 4',4",4"' -triiodotetraphenylstyrene-4-nitrobenzene (Compound 2)
[0065] The synthesis route of Compound 2 is as follows:
[0066]
[0067] The specific procedure was as follows: Tetraphenyl-4-nitrobenzene (1.0 mmol) was placed in a reaction vessel, and iodine (1.8 mmol), potassium iodate (2.32 mmol), glacial acetic acid (15 mL), carbon tetrachloride (3.5 mL), and 50 wt% sulfuric acid (2 mL) were added sequentially. The reaction system was heated to 80 °C and stirred for 4 hours. After the reaction was completed, it was cooled to room temperature, and the reaction was quenched by adding saturated sodium thiosulfate solution. Subsequently, it was extracted with dichloromethane (DCM) and washed with saturated brine. The extract was purified by column chromatography (eluent: petroleum ether / ethyl acetate, in a gradient from 10:1 to 4:1, v / v) to give a yellow-green solid product in 54% yield.
[0068] Product structure through Figure 2 The ¹H NMR spectrum shown confirms this, and the data in the spectrum are as follows: 1 ¹H NMR (500 MHz, CDCl₃) δ 7.99 (d, J = 8.8 Hz, 1H), 7.53–7.45 (m, 2H), 7.14 (d, J = 8.8 Hz, 1H), 6.71 (dd, J = 13.0, 8.3 Hz, 2H). The peak positions and integrated intensity ratios of the NMR correspond to the theoretical values, indicating that the obtained product is the target compound 4',4'',4'''-triiodotetraphenyl-4-nitrobenzene. Furthermore, the spectrum has a flat baseline, and apart from the solvent peak, no obvious impurity peaks or byproduct signals were observed, indicating that the product has high purity.
[0069] The synthetic methods for compounds 1 and 2 have the following advantages:
[0070] (1) Precise control of chemoselectivity: Highly selective asymmetric iodination was achieved by using electron-withdrawing groups (carboxyl / nitro groups) to passivate the benzene ring. Conventional methods are difficult to precisely introduce iodine atoms only on a few other benzene rings while retaining the active functional groups.
[0071] (2) Enhanced effect of biphase mixed solvent: The use of CCl4 / HOAc mixed solvent solved the solubility contradiction between the TPE skeleton (lipophilic) and the iodide reagent (hydrophilic). The microenvironment formed by this specific system significantly improved the reaction rate and yield, and produced very few by-products, thus optimizing the synthesis process.
[0072] Example 3: Preparation of the coupling product of compound 1 and glycine methyl ester (compound 3)
[0073] This embodiment aims to demonstrate the ability of the compounds of the present invention to be bioconjugated through functional groups to expand their applications. The conjugated product is compound 3, and the synthetic route is as follows:
[0074]
[0075] The specific operation is as follows: compound 1 (0.5 mmol), glycine methyl ester hydrochloride (0.6 mmol), DIEA (1.5 mmol) and EDC-HCl (0.06 mmol) are dissolved in 20 mL of anhydrous acetonitrile, and the reaction is stirred and refluxed at 85°C for 12 hours. After the reaction is completed, the mixture is cooled to room temperature, extracted with dichloromethane three times. The organic phase is combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent is removed by rotary evaporation, and the obtained crude product is purified by silica gel column chromatography (elution system: ethyl acetate / petroleum ether = 3:1, v / v) to obtain a white solid product with a yield of 97%.
[0076] The structure of the product is confirmed by Figure 3 The nuclear magnetic resonance hydrogen spectrum (1H NMR) shown in the spectrum data shows: 1 H NMR (400 MHz, CDCl3) δ 7.58 (d, J = 8.3 Hz, 2H), 7.53-7.38 (m, 6H), 7.05 (d, J = 8.3 Hz, 2H), 6.71 (dd, J = 10.0, 8.4 Hz, 6H), 4.23 (d, J = 5.0 Hz, 2H), 3.80 (s, 3H). The peak position and integral intensity ratio of the nuclear magnetic resonance correspond to the theory, indicating that the obtained product is compound 3. The spectrum has a flat baseline, and no obvious impurity peaks or byproduct signals are observed except for the solvent peak, indicating that the product has high purity.
[0077] The successful synthesis of compound 3 proves that after the introduction of multiple heavy atom iodine, the remaining active functional group (carboxyl) of compound 1 does not lose activity and still has excellent biological coupling activity. Glycine methyl ester as a model molecule of amino acid derivatives, its successful coupling directly proves that the platform molecule can be further extended to the modification of polypeptides, proteins or amino-containing polymers.
[0078] This specific embodiment is only an explanation of the present application and is not a limitation of the present application. Any changes made by those skilled in the art after reading the specification of the present application will be protected by the patent law as long as they are within the scope of the claims of the present application.
Claims
1. A polyiodotetraphenylene derivative, characterized in that, Its general structural formula is as follows: ； Wherein, R is a functional group, and at least one R group is iodine, and at least one R group is an active group or a derived group; the active group includes carboxyl, nitro, aldehyde, hydroxyl, mercapto, and amino groups; the derived group is a group formed by the amidation reaction of the active group.
2. The polyiodotetraphenylene derivative according to claim 1, characterized in that, In its structural formula, three R groups are iodine and one R group is an active group.
3. The polyiodotetraphenylene derivative according to claim 2, characterized in that, It is either compound 1 or compound 2; Compound 1 is 4',4'',4'''-triiodotetraphenyl-4-carboxylic acid, with the following structural formula: ； Compound 2 is 4',4'',4'''-triiodotetraphenyl-4-nitrobenzene, with the following structural formula: 。 4. The polyiodotetraphenylene derivative according to claim 1, characterized in that, In its structural formula, three R groups are iodine groups, and one R group is a derivatizing group, specifically compound 3; compound 3 is the coupling product of compound 1 and glycine methyl ester, with the following structural formula: 。 5. The method for preparing the polyiodotetraphenylene derivative according to claim 2 or 3, characterized in that, Includes the following steps: S11. Using TPE-R as the starting material, place it in a reaction vessel, add iodine reagent, solvent and Lewis acid catalyst in sequence, and react at room temperature or under heating conditions for 4-12 hours; S12. After the reaction is complete, a saturated sodium thiosulfate solution is added to quench the reaction. The product is then purified by extraction, washing, and column chromatography to obtain the target product.
6. The method for preparing the polyiodotetraphenylene derivative according to claim 5, characterized in that, In step S11, the iodizing reagent is an iodine / periodic acid or iodine / potassium iodate iodization system, the solvent is one or more of carbon tetrachloride, tetrahydrofuran, and acetic acid, and the Lewis acid is sulfuric acid.
7. The method for preparing the polyiodotetraphenylene derivative according to claim 5, characterized in that, In step S12, the organic solvent used for extraction is dichloromethane, the washing solution is saturated saline, and the eluent used for column chromatography is petroleum ether / ethyl acetate.
8. The method for preparing the polyiodotetraphenylene derivative according to claim 4, characterized in that, Includes the following steps: S21. Prepare compound 1 according to steps S11-S12 as described in any one of claims 5-7; S22. Dissolve compound 1, glycine methyl ester hydrochloride, organic base, and initiator in anhydrous acetonitrile and react at 80-85℃ for 12-24 hours; S23. After the reaction is complete, the product is obtained by extraction, washing, drying, rotary evaporation and column chromatography purification.
9. The method for preparing the polyiodotetraphenylene derivative according to claim 8, characterized in that, In step S22, the organic base is triethylamine or DIEA, and the initiator is EDC.
10. The application of the polyiodotetraphenylene derivative according to any one of claims 1-4, characterized in that, include: (a) Biomedical imaging field: Applications as fluorescent probes or CT contrast agents; (b) Pharmaceutical field: Applications in the preparation of drugs for photodynamic therapy, radiosensitizing drugs for radiotherapy, or tumor-targeting diagnostic reagents; (c) Chemical and biological sensing: Applications as fluorescent sensors or luminescent materials; (d) In the field of organic synthesis: its application as an intermediate in organic synthesis; (e) Radiation detection and scintillation materials: Application as AIE luminescent material.