Amide molecular cage as well as preparation method and application thereof

Abstract

The invention relates to the technical field of organic synthesis, and particularly discloses an amide molecular cage as well as a preparation method and application thereof. The amide molecular cage has the following structure: # imgabs0 #, wherein R is respectively and independently selected from-H and-XR1; x is O or-CH2-; when R1 appears every time, R1 is independently selected from straight-chain alkane with 1-10 C atoms, alkoxy, terminal alkenyl, terminal alkynyl, ester group, carboxylate substituent, ammonium salt substituent, sulfonate substituent, phosphate substituent, pyridine cation substituent or imidazole cation substituent. The amide molecular cage has a good cavity structure, can adapt to the shapes of anions through conformation adjustment, realizes efficient recognition of anions in various shapes, and realizes derivatization of molecular cages with tail chains with different functional groups through change of the functional groups of the tail chains.

Description

Technical Field

[0001] The present application relates to the technical field of organic synthesis, and in particular to an amide molecular cage and a preparation method and application thereof. Background Art

[0002] With the development of economy and science and technology, anions have an increasingly important impact on the research of medicine, life science, environmental protection, agricultural production and industrial catalysis. For example, negative ions have special physiological and biochemical functions for the body, and can effectively prevent dental caries and osteoporosis in the elderly; for people with alveolar fibrosis, the determination of chloride ion concentration in the body is particularly important; DNA that can carry genetic information is often a polyanion; many enzymes that play a key role in metabolism are also anions; phosphate anions play an important role in energy storage, information processing and transmission in organisms; in addition, polluting anions are closely related to the eutrophication of rivers (phosphate) and carcinogenicity (silicate). It can be seen that anion recognition technology and the design and synthesis of anion receptors are particularly important.

[0003] However, designing anion receptors faces more challenges than designing cation receptors. This is because anions usually have a larger radius and a smaller charge density than cations with the same number of electrons, resulting in weaker electrostatic interactions with receptors. At the same time, anions have diverse geometric shapes, and the receptor structure needs to be highly complementary to achieve efficient recognition of specific anions. In the development of anion recognition, a series of non-cyclic or monocyclic hosts have been reported at home and abroad to achieve recognition of anions, but overall the bonding strength is average. Compared with chain and macrocyclic host molecules, cage molecules with three-dimensional spatial structures can more completely encapsulate guests and embed more bonding sites, with better host-guest bonding properties, making them ideal anion receptors. At present, many amide molecular cages have been reported for anions (such as Cl - Br - 、CH3COO - However, their synthesis methods have complex steps, harsh reaction conditions, unstable intermediates, and are difficult to develop by derivatization. Therefore, the existing technology needs to be improved. Summary of the invention

[0004] In view of the above-mentioned deficiencies in the prior art, the purpose of the present application is to provide an amide molecular cage and a preparation method and application thereof, aiming to solve the problems of the existing amide molecular cage synthesis steps being complicated, the reaction conditions being harsh, the intermediates being unstable, and the derivatization development being difficult.

[0005] The technical solution of this application is as follows:

[0006] In a first aspect of the present application, an amide molecular cage is provided, wherein the amide molecular cage has a structure as shown below:

[0007]

[0008] Wherein, R is independently selected from -H, -XR 1 ; X is O or -CH2-; R 1 Each occurrence is independently selected from a straight chain alkane having 1 to 10 C atoms, an alkoxy group, a terminal alkenyl group, a terminal alkynyl group, an ester group, a carboxylate substituent, an ammonium salt substituent, a sulfonate substituent, a phosphate substituent, a pyridinium cation substituent or an imidazolium cation substituent.

[0009] Optionally, R is an alkoxy group having 1 to 10 C atoms or a triazole substituent having 20 to 30 C atoms.

[0010] Optionally, R is selected from one of the following structures:

[0011] -OC8H 17 、-OC8H 15 , Indicates the connection site.

[0012] In a second aspect of the present application, a method for preparing the above-mentioned amide molecular cage is provided, comprising the steps of:

[0013] 2,4,6-triethylbenzene-1,3,5-trimethylamine trihydrochloride, active carboxylic acid ester, reaction solvent and organic base are mixed, reacted under an inert atmosphere, and the system after the reaction is purified to obtain the amide molecular cage.

[0014] Optionally, the structure of the active carboxylate is as follows:

[0015]

[0016] Wherein, R is independently selected from -H, -XR 1 ; X is O or -CH2-; R 1 Each occurrence is independently selected from a straight chain alkane having 1 to 10 C atoms, an alkoxy group, a terminal alkenyl group, a terminal alkynyl group, an ester group, a carboxylate substituent, an ammonium salt substituent, a sulfonate substituent, a phosphate substituent, a pyridinium cation substituent or an imidazolium cation substituent.

[0017] Optionally, the R is selected from one of the following structures:

[0018] -OC8H 17 、-OC8H 15 , Indicates the connection site.

[0019] Optionally, the reaction temperature is 15-25°C, and the reaction time is 24-48h.

[0020] Optionally, the purification treatment includes rotary evaporation and column chromatography purification, the column chromatography purification method is thin layer chromatography, and the volume ratio of dichloromethane to tetrahydrofuran in the solvent of the thin layer chromatography is 4:1.

[0021] The third aspect of the present application provides an application of the above-mentioned amide molecular cage in anion recognition, wherein the anion includes at least one of chloride ion, bromide ion, nitrate ion, fluoroborate ion, hexafluorophosphate ion, and thiocyanate ion.

[0022] In a fourth aspect of the present application, there is provided an application of the above-mentioned amide molecular cage in the recognition of polar organic molecules, wherein the polar organic molecules include at least one of amino alcohol compounds, aspartic acid, and adenosine triphosphate.

[0023] Compared with the prior art, this application has the following advantages:

[0024] The amide molecular cage in this application has a good cavity structure, and the NH bonds in the amide bonds are highly pre-organized, all pointing to the inside of the cavity, which can serve as hydrogen bond donors, and the aromatic CH bonds adjacent to the carboxyl group point to the inside of the molecular cage, which can form CH-groups and anions with the guest, thereby enhancing the host-guest bonding strength. The amide molecular cage in this application has a larger hydrophobic cavity, which can adapt to the shape of the anion through conformational adjustment. In addition, the amide molecular cage in this application realizes the derivative expansion of molecular cages with different functional group tail chains through the change of the tail chain functional group, so as to be applied to different usage scenarios.

[0025] The amide molecular cage synthesis method in this application introduces active carboxylates with different side chain groups as side arms, uses 2,4,6-triethylbenzene-1,3,5-trimethylamine as a lid, and forms an amide molecular cage by one step through an amidation reaction at room temperature. The synthesis method has simple steps, mild reaction conditions, and realizes the derivatization of tail chain molecular cages with different functional groups, and uses molecular cages to achieve efficient recognition of anions of various shapes. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] In order to more clearly illustrate the technical solutions in the embodiments of the present application, the drawings required for describing the embodiments are briefly introduced below.

[0027] Figure 1 The hydrogen nuclear magnetic resonance spectrum of MC-1 provided in the examples of the present application;

[0028] Figure 2The hydrogen nuclear magnetic resonance spectrum of MC-2 provided in the examples of the present application;

[0029] Figure 3 The hydrogen nuclear magnetic resonance spectrum of MC-3 provided in the examples of the present application;

[0030] Figure 4 The hydrogen nuclear magnetic resonance spectrum of MC-4 provided in the examples of the present application;

[0031] Figure 5 MC-1 and Cl provided in the embodiments of the present application - ITC titration diagram in tetrahydrofuran;

[0032] Figure 6 MC-2 and Cl provided in the embodiments of the present application - ITC titration diagram in ethylene dichloride;

[0033] Figure 7 ITC titration diagram of MC-4 and G1 in water provided in the examples of this application. DETAILED DESCRIPTION

[0034] In order to make the purpose, technical solutions and advantages of the present application clearer, the technical solutions in the embodiments of the present application will be clearly and completely described below in combination with the drawings and embodiments of the present application. Obviously, the described embodiments are only part of the embodiments of the present application, not all of the embodiments. Based on the embodiments of the present application, all other embodiments obtained by ordinary technicians in this field without making creative work belong to the protection scope of the present application. In the absence of conflict, the following embodiments and features in the embodiments can be combined with each other.

[0035] It should be noted that if there are descriptions involving "first", "second", etc. in the implementation of this application, the descriptions of "first", "second", etc. are only used for descriptive purposes and cannot be understood as indicating or suggesting their relative importance and implicitly indicating the number of technical features indicated. Therefore, the features defined as "first" and "second" may explicitly or implicitly include at least one of the features. In addition, the technical solutions between the various embodiments can be combined with each other, but they must be based on the fact that ordinary technicians in the field can implement them. When the combination of technical solutions is contradictory or cannot be implemented, it should be deemed that such combination of technical solutions does not exist and is not within the scope of protection required by this application.

[0036] Molecular cages are a class of three-dimensional organic or inorganic molecules with unique internal cavities, which are widely used in chemistry, materials science, and biomedical hospitals. Molecular cages can be synthesized through a variety of strategies, including self-assembly, chemical bonding, etc. They show significant confinement effects and stability in catalytic reactions, and can also be used as carriers for nanoscale drug delivery. They are a highly flexible and functional material system with broad application prospects. Molecular cages in the prior art have problems such as complex steps, harsh reaction conditions, unstable intermediates, and difficulty in derivatization development.

[0037] Based on this, the first aspect of the embodiment of the present application provides an amide molecular cage having the structure shown below:

[0038]

[0039] Wherein, R is independently selected from -H, -XR 1 ; X is O or -CH2-; R 1 Each occurrence is independently selected from a straight chain alkane having 1 to 10 C atoms, an alkoxy group, a terminal alkenyl group, a terminal alkynyl group, an ester group, a carboxylate substituent, an ammonium salt substituent, a sulfonate substituent, a phosphate substituent, a pyridinium cation substituent or an imidazolium cation substituent.

[0040] The amide molecular cage in the embodiment of the present application has a good cavity structure, the NH bonds in the amide bonds are highly pre-organized, all pointing to the inside of the cavity, and can serve as hydrogen bond donors, while the aromatic CH bonds adjacent to the carboxyl group point to the inside of the molecular cage, and can form CH-groups and anions with the guest to enhance the host-guest bonding strength. The amide molecular cage of the present application has a relatively large hydrophobic cavity, which can adapt to the shapes of different anions through conformational adjustment.

[0041] In some embodiments, R is selected from an alkoxy group having 1 to 10 C atoms or a triazole substituent having 20 to 30 C atoms.

[0042] Furthermore, R is selected from one of the following structures:

[0043] -OC8H 17 、-OC8H 15 , -OC8H 15 Can be: in, Indicates the connection site.

[0045] The amide molecular cage in the present application introduces different side arms (R groups) through active carboxylates with the same side chain groups to achieve the derivatization and expansion of molecular cages with different functional group tail chains, and utilizes the molecular cage to achieve efficient recognition of anions of various shapes for application in different usage scenarios.

[0046] According to a second aspect of the embodiment of the present application, a method for preparing an amide molecular cage in the embodiment of the present application is provided, comprising the steps of:

[0047] 2,4,6-triethylbenzene-1,3,5-trimethylamine trihydrochloride, active carboxylic acid ester, reaction solvent and organic base are mixed, reacted under an inert atmosphere, and the system after the reaction is purified to obtain the amide molecular cage. The gas of the inert atmosphere can be nitrogen, argon, helium, etc.

[0048] In some embodiments, the reaction solvent is selected from tetrahydrofuran (THF), N,N-dimethylformamide (DMF), 1,3-dimethyl-2-imidazolidinone (DMI), 1,4-dioxane, N-methylpyrrolidone (NMP), hexamethylphosphoric acid triamide (HMPA) or dimethyl sulfoxide (DMSO).

[0049] In some embodiments, the organic base is selected from N,N-diisopropylethylamine (DIPEA), triethylamine, tetramethylethylenediamine, pentamethyldiethylenetriamine or 4-dimethylaminopyridine (DMAP). The organic base activates 2,4,6-triethylbenzene-1,3,5-trimethylamine trihydrochloride during the reaction, removes the hydrochloric acid proton in 2,4,6-triethylbenzene-1,3,5-trimethylamine trihydrochloride, so that the amino group on it reacts with the active carboxylate, completing the cage process.

[0050] Specifically, the preparation method of the amide molecular cage includes the steps of:

[0051] S1. Mix 2,4,6-triethylbenzene-1,3,5-trimethylamine trihydrochloride, active carboxylic acid ester, reaction solvent and organic base, and react under argon atmosphere to obtain a reaction product.

[0052] In some embodiments, the molar ratio of 2,4,6-triethylbenzene-1,3,5-trimethylamine trihydrochloride to active carboxylic acid ester is 1:1.5. Under this ratio, while ensuring the synthesis of amide molecular cage, there is no excess raw material, which reduces the generation of impurities after the reaction and avoids cost problems caused by waste.

[0053] In some embodiments, the reaction temperature is 15-25°C, for example, the reaction temperature is 15°C, 16°C, 17°C, 18°C, 19°C, 20°C, 21°C, 22°C, 23°C, 24°C or 25°C, etc. The reaction time is 24-48h, for example, the reaction time is 24h, 28h, 32h, 36h, 40h, 44h or 48h, etc.

[0054] In some embodiments, the structure of the active carboxylic acid ester is as follows:

[0055]

[0056] Wherein, R is independently selected from -H, -XR 1 ; X is O or -CH2-; R 1 Each occurrence is independently selected from a straight chain alkane having 1 to 10 C atoms, an alkoxy group, a terminal alkenyl group, a terminal alkynyl group, an ester group, a carboxylate substituent, an ammonium salt substituent, a sulfonate substituent, a phosphate substituent, a pyridinium cation substituent or an imidazolium cation substituent.

[0057] Furthermore, R is selected from one of the following structures:

[0058] -OC8H 17 、-OC8H 15 , -OC8H 15 Can be: in, Indicates the connection site.

[0060] In some embodiments, the step of S1 can be: under argon, 2,4,6-triethylbenzene-1,3,5-trimethylamine trihydrochloride (1.00 g, 2.80 mmol, 2 equiv.), active carboxylate (4.20 mmol, 3 equiv.), deionized water (70 mL) and tetrahydrofuran (THF, 300 mL) are added to a 500 mL two-necked flask, and a THF solution (60 mL) of N,N-diisopropylethylamine (DIPEA, 1.45 g, 11.2 mmol, 8 equiv.) is slowly added to the two-necked flask through a syringe pump, and the reaction is carried out at room temperature for 36 hours.

[0061] In dilute solution and mild reaction conditions, an amide molecular cage with multiple hydrogen bond recognition sites was synthesized in one step by amidation reaction using active esters and 2,4,6-triethylbenzene-1,3,5-trimethylamine trihydrochloride. Compared with previously reported methods, this method is relatively novel, with mild reaction conditions, simple steps and high yield. In addition, by regulating the type of active carboxylate side chains, the derivatization of molecular cages with different functional group tail chains was achieved.

[0062] S2. The reaction product is subjected to rotary evaporation treatment and extracted with dichloromethane to obtain a combined organic phase.

[0063] The rotary evaporation treatment can be carried out using a rotary evaporator or a self-assembled device including but not limited to a rotary evaporator. Those skilled in the art can make a selection according to the actual situation. The rotary evaporation treatment can increase the evaporation area with the help of a rotary flask under reduced pressure, improve the efficiency of distillation, and achieve the purpose of separation and purification. By rotary evaporating the reaction product, THF in the reaction product is removed. The number of times of dichloromethane extraction can be 1 time, 2 times or 3 times, and the purpose is to fully dissolve the target component in the reaction product in dichloromethane.

[0064] S3. Purify the combined organic phases using column chromatography to obtain the amide molecular cage.

[0065] In some embodiments, the column chromatography purification is a thin layer chromatography method, wherein the volume ratio of dichloromethane to tetrahydrofuran (CH2Cl2:THF) in the solvent of the thin layer chromatography is 4:1.

[0066] The amide molecular cage prepared by the preparation method has good host-guest chemical properties, and the prepared amide molecular cage has a relatively large hydrophobic cavity, which can adapt to the shape of the anion through conformational regulation.

[0067] In a third aspect of the embodiments of the present application, there is provided an application of the amide molecular cage in the embodiments of the present application in anion recognition, wherein the anion comprises at least one of chloride ion, bromide ion, nitrate ion, fluoroborate ion, hexafluorophosphate ion, and thiocyanate ion.

[0068] The amide molecular cage in the embodiment of the present application achieves derivatization and expansion of the molecular cage with different functional group tail chains through changes in the side chain groups, so as to be applied to anion recognition.

[0069] According to a fourth aspect of the embodiments of the present application, there is provided an application of the amide molecular cage in the embodiments of the present application in the recognition of polar organic molecules, wherein the polar organic molecules include at least one of amino alcohol compounds, aspartic acid, and adenosine triphosphate.

[0070] The amide molecular cage in the embodiment of the present application realizes the derivatization and expansion of the molecular cage with different functional group tail chains through the change of the side chain groups, so as to be applied to the recognition of polar organic molecules.

[0071] The following is further described by specific examples. Unless otherwise specified, the materials used in the following examples can be purchased.

[0072] Example 1

[0073] Under argon, 2,4,6-triethylbenzene-1,3,5-trimethylamine trihydrochloride (1.00 g, 2.80 mmol, 2 equiv.), active carboxylate (4.20 mmol, 3 equiv.), deionized water (70 mL) and THF (300 mL) were added to a 500 mL two-necked flask, and a THF solution (60 mL) of DIPEA (1.45 g, 11.2 mmol, 8 equiv.) was slowly added to the two-necked flask through a syringe pump, and the reaction was carried out at room temperature for 36 h. After the reaction was completed, THF in the reaction solution was removed by rotary evaporation, and dichloromethane was added for extraction 3 times to obtain a combined organic phase. The combined organic phase was purified by column chromatography (CH2Cl2:THF=4:1) to obtain the target product MC-1. Its synthetic route is:

[0074]

[0075] MC-1: (white solid, yield 28%). Its nuclear magnetic resonance detection results are as follows Figure 1 As shown. Among them, 1 H NMR(500MHz,THF-d8)δ8.16(dd,J=8.0,1.5Hz,6H),7.89(s,3H),7.59(t,J=8.0Hz,3H) ,7.15(br,6H),4.66(d,J=5.0Hz,12H),2.80(q,J=7.5Hz,12H),1.25(t,J=7.5Hz,18H).

[0076] Example 2

[0077] Under argon, 2,4,6-triethylbenzene-1,3,5-trimethylamine trihydrochloride (1.00 g, 2.80 mmol, 2 equiv.), active carboxylate (4.20 mmol, 3 equiv.), deionized water (70 mL) and THF (300 mL) were added to a 500 mL two-necked flask, and a THF solution (60 mL) of DIPEA (1.45 g, 11.2 mmol, 8 equiv.) was slowly added to the two-necked flask through a syringe pump, and the reaction was carried out at room temperature for 36 h. After the reaction was completed, THF in the reaction solution was removed by rotary evaporation, and dichloromethane was added to extract 3 times to obtain a combined organic phase. The combined organic phase was purified by column chromatography (CH2Cl2:THF=4:1) to obtain the target product MC-2. Its synthetic route is:

[0078]

[0079] MC-2: (white solid, yield 36%). Its nuclear magnetic resonance detection results are as follows Figure 2 As shown. Among them, 1H NMR (500MHz, CDCl3) δ7.81(d,J=1.5Hz,6H),6.97(t,J=1.5Hz,3H),5.92(t,J=4.5Hz,6H),4.69(d,J=4.5Hz,12H),4.10(t,J=6.5Hz,6 H), 2.69 (q, J = 7.0Hz, 12H), 1.87-1.80 (m, 6H), 1.52-1.45 (m, 6H), 1.32 (t, J = 7.5Hz, 18H), 1.38-1.26 (m, 24H), 0.91 (t, J = 7.0Hz, 9H).

[0080] Example 3

[0081] Under argon, 2,4,6-triethylbenzene-1,3,5-trimethylamine trihydrochloride (1.00 g, 2.80 mmol, 2 equiv.), active carboxylate (4.20 mmol, 3 equiv.), deionized water (70 mL) and THF (300 mL) were added to a 500 mL two-necked flask, and a THF solution (60 mL) of DIPEA (1.45 g, 11.2 mmol, 8 equiv.) was slowly added to the two-necked flask through a syringe pump, and the reaction was carried out at room temperature for 36 h. After the reaction was completed, THF in the reaction solution was removed by rotary evaporation, and dichloromethane was added for extraction 3 times to obtain a combined organic phase. The combined organic phase was purified by column chromatography (CH2Cl2:THF=4:1) to obtain the target product MC-3. Its synthetic route is:

[0082]

[0083] MC-3: (white solid, yield 35%). Its nuclear magnetic resonance detection results are as follows Figure 3 As shown. Among them, 1 H NMR (500MHz, CDCl3) δ7.79(d,J=1.5Hz,6H),6.95(t,J=1.5Hz,3H),5.89(t,J=4.5Hz,6H),5.86-5.76(m,3H),5.08-4.88(m,6H),4.67(d,J=4 .5Hz,12H),4.08(t,J=6.5Hz,6H),2.67(q,J=7.5Hz,12H),2.09-2.04(m,6H),1.88-1.74(m,6H),1.51-1.36(m,18H),1.29(t,J=7.5Hz,18H).

[0084] Example 4

[0085] Under argon, 2,4,6-triethylbenzene-1,3,5-trimethylamine trihydrochloride (1.00 g, 2.80 mmol, 2 equiv.), active carboxylate (4.20 mmol, 3 equiv.), deionized water (70 mL) and THF (300 mL) were added to a 500 mL two-necked flask, and a THF solution (60 mL) of DIPEA (1.45 g, 11.2 mmol, 8 equiv.) was slowly added to the two-necked flask through a syringe pump, and the reaction was carried out at room temperature for 36 h. After the reaction was completed, THF in the reaction solution was removed by rotary evaporation, and dichloromethane was added for extraction 3 times to obtain a combined organic phase. The combined organic phase was purified by column chromatography (CH2Cl2:THF=4:1) to obtain the intermediate product MC-click. The intermediate product MC-click (80 mg, 30 μmol) and dichloromethane (30 mL) were added to a 100 mL eggplant-shaped bottle, and 5 mL of trifluoroacetic acid was added under ice bath conditions, followed by reaction at room temperature for 8 h. After the reaction, the organic solvent was removed, the product was precipitated by adding water, and a white solid was obtained by suction filtration. The dried solid (61 mg, 28.4 μmol) was dissolved in 1 mL of sodium hydroxide solution (1.14 mg, 28.4 μmol) and dried with a freeze dryer to obtain the target product MC-4, the synthesis route of which is:

[0086]

[0087] MC-4: (white solid, yield 20%). Its nuclear magnetic resonance detection results are as follows Figure 4 As shown. Among them, 1 H NMR(500MHz,D2O)δ8.25(s,3H),7.73(d,J=1.5Hz,3H),7.72(d,J=1.5Hz,6H),5.43(s,6H),4.59(s,12H), 3.90 (s, 18H), 3.54 (t, J = 7.0Hz, 18H), 2.65-2.57 (m, 12H), 2.26 (t, J = 7.0Hz, 18H), 1.14 (t, J = 7.5Hz, 18H).

[0088] Test Example 1

[0089] The amide molecular cage MC-1 prepared in Example 1 was used to recognize anions. An isothermal titration calorimeter was used to measure the reaction of the amide molecular cage MC-1 prepared in Example 1 with Cl in tetrahydrofuran. - Br - 、NO3 - and BF4 - The bonding constant (Ka) of MC-1 and Cl was measured by isothermal titration calorimeter model: TANano ITC LV; solvent: tetrahydrofuran; temperature: 25°C.- The results of ITC titration in tetrahydrofuran are as follows Figure 5 As shown, MC-1 reacts with Cl in tetrahydrofuran. - Br - 、NO3 - and BF4 - The test results of the bonding constants are shown in Table 1:

[0090] Table 1. Bonding constants of MC-1 with anions in tetrahydrofuran

[0091]

[0092]

[0093] From the data in Table 1, we can see that MC-1 shows obvious size selectivity in the recognition of anions. For smaller anions, such as Cl - Br - 、NO3 - , showing extremely strong bonding ability, the bonding constant can reach 10 7 M -1 , while for larger anions, such as BF4 - , the bonding constant dropped significantly by 3 orders of magnitude.

[0094] Test Example 2

[0095] The amide molecular cage MC-2 prepared in Example 2 was used to identify anions. The bonding constants (Ka) of the amide molecular cage MC-2 prepared in Example 2 with anions of various shapes in dichloroethane were measured using an isothermal titration calorimeter. The isothermal titration calorimeter model was: TA Nano ITC LV; solvent: dichloroethane; temperature: 25°C. - The results of ITC titration in dichloroethane are as follows Figure 6 As shown, the test results of the bonding constants of MC-2 with anions of various shapes in dichloroethane are shown in Table 2:

[0096] Table 2. Bonding constants of MC-2 with anions in dichloroethane

[0097] object <![CDATA[Binding constant (K a / M -1 )]]> <![CDATA[Cl - ]]> <![CDATA[(1.2±0.3)×10 7 ]]> <![CDATA[Br - ]]> <![CDATA[(3.0±0.3)×10 6 ]]> <![CDATA[SCN - ]]> <![CDATA[(5.4±1.3)×10 6 ]]> <![CDATA[NO3 - ]]> <![CDATA[(4.0±0.4)×10 7 ]]> <![CDATA[BF4 - ]]> <![CDATA[(2.1±0.1)×10 5 ]]> <![CDATA[PF6 - ]]> <![CDATA[(6.9±0.9)×10 3 ]]>

[0098] From the data in Table 2, we can see that the bonding anions of MC-2 are similar to those of MC-1. The recognition of anions shows obvious size selectivity. For small anions, such as spherical, planar triangular and linear anions, it shows extremely strong bonding ability, and the bonding constant can reach 10 7 M -1 For larger tetrahedral anions, such as BF4- , the bonding constant drops by 3 orders of magnitude, while for larger octahedral anions, such as PF6 - , the bonding constant dropped by 4 orders of magnitude.

[0099] Test Example 3

[0100] The amide molecular cage MC-4 prepared in Example 4 was used to identify hydrophilic polar organic molecules in the water phase. The bonding constants (Ka) of MC-4 with various organic small molecules in water were determined by isothermal titration calorimetry. The isothermal titration calorimeter model was: MalvernMicroCal PEAQ-ITC Automated instrument; solvent: ultrapure water; temperature: 25°C. Among them, the organic small molecules are shown in Table 3 below:

[0101] Table 3. Hydrophilic polar organic molecules

[0102]

[0103] The test data is shown in Table 4:

[0104] Table 4. Bonding constants of MC-4 with hydrophilic polar organic molecules in water

[0105]

[0106]

[0107] The data in Table 4 show that MC-4 has a high affinity for a variety of hydrophilic polar organic molecules in water, and the bonding constants for amino alcohol compounds G1 and G2 are as high as 10 5 M -1 The bonding constants for the pesticide trichlorophenol G4 and phosphate G5 also reached 10 5 M -1 In addition, MC-4 also has a binding capacity of 10 4 M -1 .

[0108] In combination with Examples 1-4 and Test Examples 1 and 2, it can be seen that the method for preparing amide molecular cages in the embodiments of the present application uses active esters and 2,4,6-triethylbenzene-1,3,5-trimethylamine trihydrochloride in a dilute solution and mild reaction conditions to synthesize an internally modified molecular cage with multiple hydrogen bond recognition sites in one step through an amidation reaction. Compared with previously reported methods, this method is relatively novel, with mild reaction conditions, simple steps, and high yield. By regulating the types of active carboxylate side chains, the derivatization of molecular cages with different functional group tail chains is achieved.

[0109] At the same time, the amide molecular cages in the examples of the present application have good host-guest chemical properties. MC-1 prepared in Example 1 and MC-2 prepared in Example 2 show high affinity and obvious size selectivity for anions in organic solvents, and the bonding constant for size-matched anions reaches 10 7 M -1 , can be used in biomedicine (such as anion transmembrane transport), supramolecular catalysis, polymer materials, etc., and has broad application prospects. The water-soluble derivatized amide molecular cage MC-4 prepared in Example 4 exhibits good affinity for hydrophilic polar organic molecules, and the bonding constant for amino alcohol compounds can reach 10 5 M -1 The bonding constant for aspartic acid and ATP is also 10 4 M -1 , can selectively identify neutral molecules, polar molecules and organic pollutants in water, and also has broad application prospects.

[0110] In summary, the amide molecular cage in the present application has a good cavity structure, and the NH bonds in the amide bonds are highly pre-organized, all pointing to the inside of the cavity, which can serve as hydrogen bond donors, while the aromatic CH bonds ortho to the carboxyl group point to the inside of the molecular cage, which can form CH-anion interactions with the guest, and enhance the host-guest bonding strength. The amide molecular cage of the present application has a large hydrophobic cavity, which can be adapted to the shape of the anion by conformational regulation. In addition, the amide molecular cage in the present application realizes the derivatization and expansion of molecular cages with different functional group tail chains through the change of the tail chain functional group, so as to be applied to different usage scenarios. The amide molecular cage synthesis method in the present application, by introducing active carboxylates with different side chain groups as side arms, using 2,4,6-triethylbenzene-1,3,5-trimethylamine as a lid, and through an amidation reaction at room temperature, the cage is closed in one step to form an amide molecular cage. The synthesis method is simple in steps, mild in reaction conditions, and realizes the derivatization of molecular cages with tail chains of different functional groups, and uses molecular cages to realize efficient recognition of anions of various shapes.

[0111] It should be understood that the application of the present application is not limited to the above examples. For ordinary technicians in this field, improvements or changes can be made based on the above description. All these improvements and changes should fall within the scope of protection of the claims attached to this application.

Claims

1. An amide molecular cage, characterized in that: The amide molecular cage has the structure shown below: Wherein, R is independently selected from -H, -XR 1 ; X is O or -CH2-; R 1 Each occurrence is independently selected from a straight chain alkane having 1 to 10 C atoms, an alkoxy group, a terminal alkenyl group, a terminal alkynyl group, an ester group, a carboxylate substituent, an ammonium salt substituent, a sulfonate substituent, a phosphate substituent, a pyridinium cation substituent or an imidazolium cation substituent.

2. The amide molecular cage according to claim 1, characterized in that: R is preferably an alkoxy group having 1 to 10 C atoms or a triazole substituent having 20 to 30 C atoms.

3. The amide molecular cage according to claim 2, characterized in that: R is selected from one of the following structures: -OC8H 17 、-OC8H 15 、 Indicates the connection site.

4. A method for preparing an amide molecular cage according to any one of claims 1 to 3, characterized in that: Includes steps: 2,4,6-triethylbenzene-1,3,5-trimethylamine trihydrochloride, active carboxylic acid ester, reaction solvent and organic base are mixed, reacted under an inert atmosphere, and the system after the reaction is purified to obtain the amide molecular cage.

5. The preparation method according to claim 4, characterized in that: The structure of the active carboxylate is as follows: Wherein, R is independently selected from -H, -XR 1 ; X is O or -CH2-; R 1 Each occurrence is independently selected from a straight chain alkane having 1 to 10 C atoms, an alkoxy group, a terminal alkenyl group, a terminal alkynyl group, an ester group, a carboxylate substituent, an ammonium salt substituent, a sulfonate substituent, a phosphate substituent, a pyridinium cation substituent or an imidazolium cation substituent.

6. The preparation method according to claim 5, characterized in that: The R is selected from one of the following structures: -OC8H 17 、-OC8H 15 、 Indicates the connection site.

7. The preparation method according to claim 4, characterized in that: The reaction temperature is 15-25°C, and the reaction time is 24-48h.

8. The preparation method according to claim 4, characterized in that: The purification treatment includes rotary evaporation and column chromatography purification; The column chromatography purification method is a thin layer chromatography method, and the volume ratio of dichloromethane to tetrahydrofuran in the solvent of the thin layer chromatography is 4:

1.

9. Use of the amide molecular cage according to any one of claims 1 to 3 in anion recognition; The anion includes at least one of chloride ion, bromide ion, nitrate ion, fluoroborate ion, hexafluorophosphate ion, and thiocyanate ion.

10. Use of the amide molecular cage according to any one of claims 1 to 3 in the recognition of polar organic molecules; The polar organic molecules include at least one of amino alcohol compounds, aspartic acid, and adenosine triphosphate.

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