Ionic nitrogen heterocyclic carbene covalent organic frameworks, methods of making and using the same

Abstract

The present application relates to a kind of ionic nitrogen heterocyclic carbene covalent organic framework and its preparation method and application, the ionic nitrogen heterocyclic carbene covalent organic framework with amine monomer, aldehyde monomer and vinyl ionic liquid as raw material, by one-pot method, it is prepared by povalorov reaction.The ionic nitrogen heterocyclic carbene covalent organic framework prepared in the present application can be used for the deuterium reaction of a variety of aromatic aldehyde, heterocyclic aldehyde and multi-site substituted aldehyde substrate as catalyst, with high catalytic activity and recyclable performance.

Description

TECHNICAL FIELD

[0001] The application belongs to the field of porous material design and synthesis, and particularly relates to an ionic nitrogen heterocyclic carbene covalent organic framework and a preparation method and application thereof. BACKGROUND

[0002] C1 deuterated aldehyde refers to an aldehyde compound (R-CDO) in which the hydrogen on the aldehyde group carbon at the end of the molecular carbon skeleton (i.e., C1 position) is replaced by deuterium. C1 deuterated aldehydes have wide application value in the synthesis of deuterated drugs. C1 deuterated aldehydes can accurately transfer deuterium atoms to specific positions of target molecules through aldehyde-alcohol condensation, Wittig reaction, amination / amidation, etc., thereby avoiding exchange or dilution of deuterium during the multi-step synthesis process. The aldehyde group, as a "platform" functional group in organic synthesis, can be converted into alcohol, acid, ketone, alkene, alkyne, etc. Therefore, C1 deuterated aldehydes can be used as a universal deuterated building block to achieve efficient introduction of deuterium in complex molecule synthesis. The terminal aldehyde group in a drug molecule or the hydroxyl group and methylene group derived therefrom are often metabolically vulnerable sites. By introducing deuterium at the C1 position, the oxidation or dehydrogenation metabolism process can be effectively slowed down, thereby improving the in vivo stability of the compound. In the synthesis routes of various deuterated drugs, C1 deuterated aldehydes play a key role as intermediates. For example, deuterated propranolol and deuterated citarabine utilize C1 deuterated aldehydes to introduce deuterium in the early synthesis stage to ensure high site selectivity.

[0003] The currently reported synthesis method of C1 deuterated aldehyde is through direct deuterium exchange of the aldehyde group, most of which is obtained through Ru / Ir noble metal catalysts, which is costly and polluting. N-heterocyclic carbene (NHC) catalysis provides a mild and metal-free approach for the activation of the formyl C-H bond of aldehydes. The reaction mechanism is to form a Breslow intermediate with nucleophilicity, thereby realizing reversible hydrogen-deuterium exchange (HDE) in the presence of inexpensive and environmentally friendly deuterium source D2O. However, in the homogeneous catalytic system, NHC catalysts often face problems such as easy deactivation, frequent side reactions, low deuterium efficiency for aldehydes with large steric hindrance, and difficulty in achieving efficient recycling. SUMMARY

[0004] The purpose of the present application is to provide an ionic nitrogen heterocyclic carbene covalent organic framework and a preparation method and application thereof, so as to solve the problems of high cost and pollution, easy deactivation, frequent side reactions, low deuterium efficiency for aldehydes with large steric hindrance, and difficulty in achieving efficient recycling in the synthesis method of existing C1 deuterated aldehyde.

[0005] The present application provides an ionic nitrogen heterocyclic carbene covalent organic framework, which is prepared by one-pot Pavlov reaction with amine monomers, aldehyde monomers and vinyl ionic liquid as raw materials.

[0006] Preferably, the amine monomer includes but is not limited to one or more of 2,4,6-tris(4-aminophenyl)-1,3,5-triazine, 1,3,5-tris(4-aminophenyl)benzene, 1,3,5-tris(4-aminophenyl)amine, 1,3,5-triaminobenzene, chemical formula as shown in formula I-IV respectively:

[0007] .

[0008] Preferably, the aldehyde monomer includes but is not limited to one or more of benzene-1,3,5-tricarbaldehyde, triformylphloroglucinol, tris(4-formylphenyl)amine, 1,3,5-tris(p-formylphenyl)benzene, 4,4',4''-(1,3,5-triazinyl-2,4,6-triyl)triphenylcarbaldehyde, benzo[1,2-b:3,4-b':5,6-b']trithiophene-2,5,8-tricarboxaldehyde, chemical formula as shown in formula V-X respectively:

[0009] .

[0010] Preferably, the vinyl ionic liquid includes but is not limited to one or more of 4-methyl-1-vinyl-1,2,4-triazolium salt, 4-methyl-1-vinyl-1,2,4-imidazolium salt, 4-methyl-1-vinylbenzyl-1,2,4-triazolium salt, 4-methyl-1-vinylbenzyl-1,2,4-imidazolium salt, chemical formula as shown in formula XI-XIV respectively:

[0011] .

[0012] The application provides a preparation method of ionic nitrogen heterocyclic carbene covalent organic framework, including the following steps: dissolving the amine monomer, the aldehyde monomer and the vinyl ionic liquid in a mixed solvent system, and performing a one-pot Povarov reaction, thereby obtaining the ionic nitrogen heterocyclic carbene covalent organic framework COF.

[0013] Preferably, the amount ratio of the amine monomer, the aldehyde monomer, the vinyl ionic liquid and the mixed solvent system is 0.1-0.2 mmol:0.1-0.2 mmol:0.4-0.6 mmol:2-4 mL.

[0014] Preferably, the mixed solvent system includes but is not limited to one or more of o-dichlorobenzene / ethanol, n-butanol / o-dichlorobenzene, N,N-dimethylacetamide (DMAc) / mesitylene, dioxane / mesitylene, dioxane.

[0015] Preferably, acetic acid is added in the one-pot Povarov reaction, and 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) is added as an oxidant, and boron trifluoride etherate (BF3·OEt2) is added as a dehydrating agent; the concentration of the acetic acid is 0.5-12 M; the amount ratio of the acetic acid, the oxidant, the dehydrating agent, and the vinyl ionic liquid is 0.1-2 mL:3-5 mg:8-10 uL:0.4-0.6 mmol.

[0016] Preferably, the reaction temperature is 60-240 ℃, and the reaction time is 3-7 days.

[0017] Preferably, a series of quinoline bond linked covalent organic framework (COF) materials can be prepared by selecting different monomers according to specific design requirements, and used for catalyzing the deuterium substitution reaction of various C1 aldehydes.

[0018] The application further provides a use of the above-mentioned ionic nitrogen heterocyclic carbene covalent organic framework in catalyzing the deuterium substitution reaction of C1 aldehyde, and the use comprises:

[0019] (1) dispersing the ionic nitrogen heterocyclic carbene covalent organic framework (COF) as a catalyst in a methanol / deuterium water mixed solution, and obtaining a uniform dispersion liquid by ultrasonic dispersion;

[0020] (2) adding a weak base and a C1 aldehyde to the dispersion liquid, and stirring at room temperature;

[0021] (3) after the dispersion liquid after stirring is filtered, extracted, and vacuum concentrated and dried, a C1 deuterated aldehyde product is obtained.

[0022] Preferably, in step (1), the mass-volume ratio of the COF to the methanol / deuterium water mixed solution is 10-100 mg:1-5 mL; the ultrasonic power is 100-1500 W, and the ultrasonic time is 5-30 min.

[0023] Preferably, in step (2), the weak base includes but is not limited to one of sodium carbonate, sodium bicarbonate, ammonia water, potassium carbonate, and cesium carbonate; the C1 aldehyde includes but is not limited to one of benzaldehyde, p-methoxybenzaldehyde, p-chlorobenzaldehyde, 3-nitrobenzaldehyde, thiofurfural, or pyridine aldehyde; and the amount ratio of the weak base, the C1 aldehyde, and the COF in step (1) is 0.15-0.5 mmol:0.5-1 mmol:10-100 mg.

[0024] Preferably, in step (2), the stirring time at room temperature is 12-48 h.

[0025] Preferably, the filter membrane used in step (3) is a PAN membrane, and the reagent used for extraction is dichloromethane and water; the vacuum concentration temperature is 20-40 ℃, the time is 1-10 min, the drying temperature is 35-60 ℃, and the time is 5-18 h.

[0026] Preferably, the catalytic efficiency of the COF catalyst does not decrease obviously after 5 cycles, and still remains more than 95%.

[0027] Further, the solid product obtained by step (3) is washed with methanol and water for 1-3 times, vacuum dried at room temperature, and then treated with 0.1-1 M HCl for 5-12 h for catalyst activation; the activated COF catalyst is used to repeat steps (1)-(3) to realize cyclic catalysis.

[0028] Based on chemical structure design and diffusion channel optimization, the present application realizes uniform and efficient deuterium incorporation (>95% deuterium content) in a variety of aromatic aldehydes, heterocyclic aldehydes and multi-site substituted aldehyde substrates under mild conditions with D2O as the only deuterium source. The ionic nitrogen heterocyclic carbene covalent organic framework has a rich multi-level pore structure and ionic liquid site, and the synergistic effect of the NHC active site and the COF microporous confined environment not only significantly promotes the activation of the formyl C-H bond, but also effectively inhibits the benzoin condensation and other side reaction paths, ensuring high selectivity of the reaction, thereby meeting the market demand for efficient C1 aldehyde deuterium catalysts. Advantages

[0029] (1) The present application prepares a series of ionic nitrogen heterocyclic carbene covalent organic frameworks linked by quinoline bonds through reasonable chemical structure design, which has ionic liquid active sites and multi-level pore structures, and realizes efficient dispersion in solvents with excellent structural stability and rich charge characteristics.

[0030] (2) The ionic nitrogen heterocyclic carbene covalent organic framework prepared in the present application can be used as a catalyst for deuterium substitution reaction of a variety of aromatic aldehydes, heterocyclic aldehydes and multi-site substituted aldehyde substrates, and has high catalytic activity and recyclability.

[0031] (3) The preparation process of the present application is simple and convenient to operate, and can realize large-scale production. BRIEF DESCRIPTION OF DRAWINGS

[0032] Figure 1 X-ray diffraction patterns of the ionic nitrogen heterocyclic carbene covalent organic frameworks TZCOF1 (a) and TZCOF2 (b) prepared for Example 1 and Example 2.

[0033] Figure 2Infrared spectra of ionic N-heterocyclic carbene covalent organic frameworks TZCOF1 (a) and TZCOF2 (b) prepared in Example 1 and Example 2.

[0034] Figure 3 BET spectra of ionic N-heterocyclic carbene covalent organic frameworks TZCOF1 (a) and TZCOF2 (b) prepared in Example 1 and Example 2.

[0035] Figure 4 X-ray diffraction patterns of ionic N-heterocyclic carbene covalent organic frameworks TZCOF1 (a) and TZCOF2 (b) prepared in Example 1 and Example 2 soaked in different solvent conditions for 7 days.

[0036] Figure 5 Catalytic effect of ionic N-heterocyclic carbene covalent organic framework TZCOF1 prepared in Example 1 on various aromatic aldehydes, heterocyclic aldehydes and multi-site substituted aldehyde substrates.

[0037] Figure 6 Catalytic effect of ionic N-heterocyclic carbene covalent organic framework TZCOF1 prepared in Example 1 on benzaldehyde in 5 cycles. DETAILED DESCRIPTION

[0038] The application is further described in conjunction with the specific examples. It should be understood that these examples are used to explain the application and are not intended to limit the scope of the application. Furthermore, it should be understood that various modifications and changes can be made to the application by those skilled in the art which are within the scope of the application as taught by the present disclosure. Accordingly, the application is not limited to the examples described herein.

[0039] The monomers and reagents used in the synthesis of the covalent organic frameworks in the following examples were obtained from Shanghai Bide Reagent Co., Ltd. without further treatment, and the ionic liquids were synthesized independently by the laboratory.

[0040] Example 1

[0041] This example provides an ionic N-heterocyclic carbene covalent organic framework, and a preparation method thereof comprises:

[0042] A mixture of 0.056 g of 2,4,6-tris(4-aminophenyl)-1,3,5-triazine, 0.06 g of 4,4',4''-(1,3,5-triazin-2,4,6-triyl)triphenylaldehyde and 0.1365 g of 4-methyl-1-vinylbenzyl-1,2,4-triazolium salt was dissolved in 3 mL of a mixed solvent of o-dichlorobenzene / n-butanol (V / V, 1:1) and ultrasonicated for 20 min, and then placed in a 10 mL schlenk tube. 0.1 mL of 6 M acetic acid solution, 5 mg of oxidant DDQ (2,3-dichloro-5,6-dicyano-p-benzoquinone) and 10 uL of dehydrating agent BF3·OEt2(trifluoroboron ethyl ether complex) were added. It was placed in a 120 °C oven for 7 days. After cooling to room temperature, it was washed with tetrahydrofuran, methanol and acetone respectively for three times, and then vacuum dried at 60 °C for 12 h. Finally, the ionic heterocyclic carbene covalent organic framework TZCOF1 which can be used for catalyzing deuterium substitution reaction was obtained, and its structure is as follows: .

[0043] Example 2

[0044] The present example provides an ionic heterocyclic carbene covalent organic framework, and a preparation method thereof comprises:

[0045] A mixture of 0.056 g of 2,4,6-tris(4-aminophenyl)-1,3,5-triazine, 0.06 g of 4,4',4''-(1,3,5-triazin-2,4,6-triyl)triphenylaldehyde and 0.1185 g of 4-methyl-1-vinyl-1,2,4-triazolium salt was dissolved in 3 mL of a mixed solvent of o-dichlorobenzene / n-butanol (V / V, 1:1) and ultrasonicated for 20 min, and then placed in a 10 mL schlenk tube. 0.1 mL of 6 M acetic acid solution, 5 mg of DDQ and 10 uL of BF3·OEt2 were added. It was placed in a 120 °C oven for 168 h. After cooling to room temperature, it was washed with tetrahydrofuran, methanol and acetone respectively for three times, and then vacuum dried at 60 °C for 12 h. Finally, the ionic heterocyclic carbene covalent organic framework TZCOF2 which can be used for catalyzing deuterium substitution reaction was obtained, and its structure is as follows:

[0046] .

[0047] The X-ray diffraction patterns of the ionic heterocyclic carbene covalent organic frameworks TZCOF1 and TZCOF2 were tested, and the results are as follows Figure 1As shown in a-b, it can be seen from the XRD spectrum that TZCOF1 and TZCOF2 exhibit strong reflection peaks at about 2theta = 4.3°, for its (100) crystal face, indicating that it has good crystallinity and long-range ordered structure, which also provides a guarantee for the rapid mass transfer in the catalytic process.

[0048] The infrared spectrum of the ionic nitrogen heterocyclic carbene covalent organic framework TZCOF1 and TZCOF2 is as shown in Figure 2 a-b, in the infrared spectrum, it can be clearly seen that new peaks appear at 1605 cm -1 and 1580 cm -1 , corresponding to the absorption vibration peak of the quinoline ring in the skeleton structure, further confirming that the quinoline ring is formed through the multi-component one-pot Povarov reaction, indicating that the prepared material has excellent structural stability, which provides favorable support for subsequent cycle catalysis.

[0049] The BET spectrum of the ionic nitrogen heterocyclic carbene covalent organic framework TZCOF1 and TZCOF2 is as shown in Figure 3 a-b, the spectrum results show that the specific surface area of TZCOF1 and TZCOF2 is 110 m 2 g -1 and 444 m 2 g -1 , respectively, indicating that the prepared COF material has a porous structure, rich pore structure and large specific surface area, which provides favorable support for subsequent cycle catalysis.

[0050] The X-ray diffraction patterns of the ionic nitrogen heterocyclic carbene covalent organic framework TZCOF1 and TZCOF2 soaked in different solvent conditions for 7 days were tested, and the results are as shown in Figure 4 a-b, TZCOF1 and TZCOF2 both maintain good crystallinity under extreme conditions of H2O and D2O and 6 M HCl, indicating that the synthesized quinoline-linked ionic nitrogen heterocyclic carbene covalent organic framework can be used for the deuteration reaction of C1 aldehyde in D2O.

[0051] Example 3

[0052] The present embodiment provides an ionic nitrogen heterocyclic carbene covalent organic framework, and the preparation method specifically refers to Example 2, except that the 4-methyl-1-vinyl-1,2,4-triazolium salt is replaced by 4-methyl-1-vinyl-1,2,4-imidazolium salt; the oven reaction time is changed to 3 days, and the ionic nitrogen heterocyclic carbene covalent organic framework IMCOF2 is prepared, and its structural formula is as shown below:

[0053] .

[0054] Example 4

[0055] The deuterium substitution reaction of C1 aldehyde was catalyzed by TZCOF1 prepared in Example 1, TZCOF2 prepared in Example 2 and IMCOF2 prepared in Example 3, which specifically included the following steps:

[0056] (1) 10 mg or 20 mg of ionic nitrogen heterocyclic carbene covalent organic framework powder was added to a mixed solvent of 2 mL of methanol and deuterium water, and ultrasonic dispersion was performed at an ultrasonic power of 1000 W for 10 min, to obtain a uniformly dispersed turbid dispersion liquid;

[0057] (2) 21.7 mg (0.15 mmol), 41.5 mg (0.3 mmol) or 69.1 mg (0.5 mmol) of potassium carbonate and 51 uL (0.5 mmol) or 102 uL (1 mmol) of benzaldehyde were added to the dispersion liquid, and stirring was performed at room temperature for 2 d;

[0058] (3) The stirred dispersion liquid was suction filtered with a PAN filter membrane, washed with dichloromethane and methanol, extracted with water and dichloromethane, and the organic phase was collected and combined, dehydrated with excess anhydrous magnesium sulfate, and then vacuum concentrated to remove the solvent, to obtain the deuterium substitution product of benzaldehyde, which was tested by nuclear magnetic resonance hydrogen spectrum, and the deuterium substitution rate was calculated, and the results are shown in Table 1.

[0059] Table 1 Catalytic effect of ionic nitrogen heterocyclic carbene covalent organic framework

[0060]

[0061] Example 5

[0062] The catalytic effect of TZCOF1 prepared in Example 1 on various aromatic aldehydes, heterocyclic aldehydes and multi-site substituted aldehyde substrates RCHO (such as benzaldehyde, p-methoxybenzaldehyde, p-chlorobenzaldehyde, thiophene aldehyde, p-phenylenediamine and m-phenylenediamine) was tested. The results are shown in Table 1. Figure 5 The ionic nitrogen heterocyclic carbene covalent organic framework TZCOF1 in this example exhibited excellent catalytic performance and substrate applicability, and has good application prospect.

[0063] The recycling performance of the TZCOF1 catalyst in S1 group in Example 4 was evaluated: the powder solid obtained by suction filtration in step (3) was washed with water and methanol for 3 times respectively, dried at 60 ℃ for 12 h, and then taken out and soaked in 5 mL of 0.5 M HCl for 2 h to activate and regenerate the catalyst, and then steps (2) and (3) were repeated to test the catalytic effect of TZCOF1 on benzaldehyde in 5 cycles. The results are shown in Table 2. Figure 6As shown, the ion-type N-heterocyclic carbene covalent organic framework TZCOF1 exhibited excellent cycle stability, and the catalytic efficiency did not decrease significantly during 5 cycles of catalysis.

Claims

1. An ionic nitrogen-heterocyclic carbene covalent organic framework, characterized in that, The ionic nitrogen-heterocyclic carbene covalent organic framework is prepared by a one-pot Povarov reaction using amine monomers, aldehyde monomers, and vinyl ionic liquids as raw materials. The amine monomer is 2,4,6-tris(4-aminophenyl)-1,3,5-triazine; the aldehyde monomer is 4,4',4''-(1,3,5-triazinecyclo-2,4,6-triyl)tribenzaldehyde; and the vinyl ionic liquid includes one or both of 4-methyl-1-vinyl-1,2,4-triazolium salt and 4-methyl-1-vinylbenzyl-1,2,4-triazolium salt.

2. A method for preparing an ionic nitrogen heterocyclic carbene covalent organic framework as described in claim 1, characterized in that, The method includes the following steps: dissolving amine monomers, aldehyde monomers, and vinyl ionic liquids in a mixed solvent system and performing a one-pot Fapovarov reaction to obtain an ionic nitrogen-heterocyclic carbene covalent framework (COF); the ratio of the amount of amine monomers, aldehyde monomers, vinyl ionic liquids, and the mixed solvent system is 0.1-0.2 mmol: 0.1-0.2 mmol: 0.4-0.6 mmol: 2-4 mL; the mixed solvent system includes one or more of o-dichlorobenzene / ethanol, n-butanol / o-dichlorobenzene, N,N-dimethylacetamide / trimethylbenzene, and dioxane / trimethylbenzene.

3. The preparation method according to claim 2, characterized in that, Acetic acid was added to the one-pot Fabovarov reaction, along with 2,3-dichloro-5,6-dicyanobenzoquinone as an oxidant and boron trifluoride diethyl ether complex as a dehydrating agent. The ratio of acetic acid, oxidant, dehydrating agent, and vinyl ionic liquid was 0.1-2 mL: 3-5 mg: 8-10 uL: 0.4-0.6 mmol. The reaction temperature was 60-240 °C, and the reaction time was 3-7 days.

4. The application of the ionic nitrogen heterocyclic carbene covalent organic framework as described in claim 1 in the catalytic deuteration reaction of C1 aldehydes, characterized in that, The applications include: (1) Ionic nitrogen heterocyclic carbene covalent organic framework (COF) was dispersed as a catalyst in a methanol / deuterium water mixed solution and ultrasonically dispersed to obtain a uniform dispersion. (2) Add the weak base and C1 aldehyde to the dispersion and stir at room temperature; (3) After stirring, the dispersion was filtered, extracted, concentrated and dried under vacuum to obtain the C1 deuterated aldehyde product.

5. The application according to claim 4, characterized in that, In step (1), the mass-to-volume ratio of COF to methanol / deuterium water mixed solution is 10-100 mg: 1-5 mL; the ultrasonic power is 100-1500 W, and the ultrasonic duration is 5-30 min.

6. The application according to claim 4, characterized in that, The weak base in step (2) includes one of sodium carbonate, sodium bicarbonate, ammonia, potassium carbonate, and cesium carbonate; the C1 aldehyde includes one of benzaldehyde, p-methoxybenzaldehyde, p-chlorobenzaldehyde, 3-nitrobenzaldehyde, thiophene formaldehyde, or pyridine formaldehyde; the ratio of the weak base, C1 aldehyde, and COF in step (1) is 0.15-0.5 mmol: 0.5-1 mmol: 10-100 mg.

7. The application according to claim 4, characterized in that, The filter membrane used for step (3) is a PAN membrane, and the reagents used for extraction are dichloromethane and water; the vacuum concentration temperature is 20-40 ℃, the time is 1-10 min, the drying temperature is 35-60 ℃, and the time is 5-18 h.

8. The application according to claim 4, characterized in that, The solid product obtained by filtration in step (3) is washed with methanol and water 1-3 times, dried under vacuum at room temperature, and then activated by treatment with 0.1-1 M HCl for 5-12 h. Steps (1)-(3) are repeated using the activated COF catalyst to achieve cyclic catalysis.

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