Electron-deficient macrocyclic molecules, methods of making and using the same

Abstract

The application discloses a novel electron-deficient macrocycle molecule and a synthesis method and application thereof, wherein the structure of the novel electron-deficient macrocycle molecule is shown in any one of a, b or c; the synthesis method mainly realizes C-H activation / coupling of polyfluorinated arene by utilizing palladium catalytic coupling, and adopts a fragment synthesis strategy, so that polyfluorinated [14] m-resorcinols with different functional groups are synthesized; the synthesis method has strong universality and can be used for synthesizing a series of electron-deficient [14] MCPs with different structures. In addition, the novel electron-deficient macrocycle molecule with the structure shown in b or c can also form a dimer artificial capsule through hydrogen bond combination, expands the type of novel electron-deficient macrocycle molecules used for constructing artificial capsules, and has important significance in the field of supramolecular self-assembly.

Description

Technical Field

[0001] This invention relates to the field of supramolecular chemical synthesis, specifically to a novel electron-deficient macrocyclic molecule, its preparation method, and its applications. Background Technology

[0002] Artificial capsules formed through non-covalent interactions, with their large internal cavities, can be applied in supramolecular fields such as recognition, encapsulation, and separation, attracting great interest from scientists and making the construction of artificial capsules an important research direction in the field of supramolecular self-assembly.

[0003] Cyclosphene macrocyclic compounds with cavities possess unique advantages in material assembly due to their unique chemical structure and properties. For example, cyclosphene macrocyclic compounds can self-assemble into micro / nano structures (nanowires, nanotubes, vesicles, etc.) with different frameworks using various non-covalent bonding interactions such as π-π stacking, van der Waals forces, and hydrophobic effects. Among these, the conical conformation [1] n ]Inter-ring ([1 n MCPs have attracted much attention in the construction of artificial capsules, [1] n Meta-cyclic compounds mainly include macrocycles such as calix[n]arene, resorcinol[n]arene, and pyrogallol[n]arene. Currently, these macrocycles are basically electron-rich macrocyclic structures with electron-donating groups obtained through the Friedel-Crafts reaction. Regarding electron-deficient [1] n Currently, MCP is only obtained by post-modification based on the above and has not been used in the construction of artificial capsules.

[0004] Therefore, it is necessary to develop a method for directly synthesizing electron-deficient [1] n This study explores new pathways for [1n]MCPs and provides a series of novel electron-deficient [1n]MCPs, which are of great significance for the research of supramolecular self-assembly. Summary of the Invention

[0005] In view of the above, the purpose of this invention is to develop a method for directly synthesizing electron-deficient [1] n A new approach to MCP, while providing a series of novel electron-deficient pathways [1] n MCP is intended to lay the foundation for the development of artificial capsules with novel properties.

[0006] To achieve the above objectives, the present invention adopts the following technical solution:

[0007] In a first aspect, the present invention provides a novel electron-deficient macrocyclic molecule, the structure of which is shown in a:

[0008] a,

[0009] Among them, Q 1For NR1H, OR2 or R3; R1 or R2 is C. 1-10 Alkyl, C 1-10 Acyl group, C 6-20 Any of the aryl groups; R3 is H or C 1-10 Alkyl, C 1-10 Acyl group, C 6-20 Any of the aryl groups.

[0010] This invention also provides a novel electron-deficient macrocyclic molecule, the structure of which is shown in b or c:

[0011] b; c.

[0012] Secondly, the present invention provides a method for synthesizing the aforementioned novel electron-deficient macrocyclic molecule, wherein the method for synthesizing the novel electron-deficient macrocyclic molecule with structure α includes the following steps:

[0013] The cyclic precursor compound was coupled with 1,2,3,5-tetrafluorobenzene via a single palladium-catalyzed coupling reaction to yield a cyclic precursor compound with two fluorobenzene units.

[0014] The structure of the cyclic precursor compound is shown in d:

[0015] d;

[0016] A novel electron-deficient macrocyclic molecule is obtained by coupling the cyclic precursor compound having two fluorobenzene units with the cyclic precursor compound via a secondary palladium-catalyzed coupling reaction.

[0017] A method for synthesizing novel electron-deficient macrocyclic molecules with structure b includes the following steps:

[0018] The cyclic precursor compound was coupled with 1,2,3,5-tetrafluorobenzene via a single palladium-catalyzed coupling reaction to yield a cyclic precursor compound with two fluorobenzene units.

[0019] The structure of the precursor compound is shown in Figure e:

[0020] e;

[0021] The cyclic precursor compound having two fluorobenzene units is subjected to a secondary palladium-catalyzed coupling reaction with the cyclic precursor compound, followed by a deprotection reaction to remove the methyl protecting group, to obtain the product.

[0022] A method for synthesizing novel electron-deficient macrocyclic molecules with a c-structure includes the following steps:

[0023] The cyclic precursor compound was coupled with 1,2,3,5-tetrafluorobenzene via a single palladium-catalyzed coupling reaction to yield a cyclic precursor compound with two fluorobenzene units.

[0024] The structure of the precursor compound is shown in f:

[0025] f;

[0026] The cyclic precursor compound having two fluorobenzene units is subjected to a secondary palladium-catalyzed coupling reaction with the cyclic precursor compound, followed by a deprotection reaction to remove the acetyl protecting group, to obtain the product.

[0027] Furthermore, in the synthesis method of any of the novel electron-deficient macrocyclic molecules with structure ac, a step of adding pentovalinic acid is included before the primary or secondary palladium-catalyzed coupling reaction; the molar ratio of pentovalinic acid to the cyclization precursor compound is 2-3:1. In the above synthesis method, the addition of pentovalinic acid can further improve the yield of the reactants.

[0028] For example, in the synthesis method of any of the novel electron-deficient macrocyclic molecules with structure ac, the catalyst for the primary palladium-catalyzed coupling reaction or the secondary palladium-catalyzed coupling reaction can be selected from palladium trifluoroacetate, palladium chloride, bis(di-benzylacetone)palladium, palladium acetate, etc., preferably palladium acetate.

[0029] For example, in the synthesis method of any of the novel electron-deficient macrocyclic molecules with structure ac, the primary palladium-catalyzed coupling reaction is carried out at 100-150 °C. o Stirring at C for 10-15 hours; the secondary palladium-catalyzed coupling reaction is carried out at 100-150 °C. o Stir at temperature C for 20-30 hours.

[0030] Furthermore, in the method for synthesizing any of the novel electron-deficient macrocyclic molecules with structure ac, the molar ratio of the cyclization precursor compound to 1,2,3,5-tetrafluorobenzene is 1-3:1-10.

[0031] The molar ratio of the cyclic precursor compound having two fluorobenzene units to the cyclic precursor compound is 1-2:1.

[0032] Furthermore, in the method for synthesizing the novel electron-deficient macrocyclic molecule with the structure described in b, the preparation steps of the precursor compound include: using 5-methoxy-1,3-phenylenediic acid as the starting material, carrying out a reduction reaction to obtain 5-methoxy-1,3-phenylenediethanol, and then carrying out a bromination reaction to obtain the product;

[0033] .

[0034] The precursor compounds of this invention can be purchased directly or synthesized according to existing methods. In order to save costs, this invention uses inexpensive and readily available 5-methoxy-1,3-phthalic acid as the starting material and obtains 1,3-di(bromomethyl)benzene with various functional groups at the 5-position by using a reduction and rebromination strategy. It can be understood that the preparation steps of the precursor compounds are similar to those described above in the synthesis methods of novel electron-deficient macrocyclic molecules with structures as described in a or c.

[0035] Thirdly, the present invention provides a dimer artificial capsule, which is prepared by anionization from a novel electron-deficient macrocyclic molecule with the structure shown in b or c above.

[0036] Furthermore, the anion is F - Cl - ,Br - I - NO3 - OAc - BF4 - PF6 - Any one of them.

[0037] Furthermore, the present invention also provides an application of the above-mentioned dimer artificial capsule in the fields of adsorption, separation, catalysis, and fluorescence recognition.

[0038] Beneficial effects of the present invention

[0039] The synthesis method of the novel electron-deficient macrocyclic molecule of the present invention mainly utilizes palladium-catalyzed coupling conditions to achieve CH activation / coupling of polyfluorinated aromatic hydrocarbons, and adopts a fragment synthesis strategy to synthesize polyfluorinated

[14] mesocyclic cyclopeptides with different functional groups. This synthesis method has strong universality and can be used to synthesize a series of electron-deficient

[14] MCPs with different structures.

[0040] The polyfluorinated

[14] metacyclopanes containing hydroxyl or amino groups provided by this invention form dimer artificial capsules through hydrogen bonding under anion induction, further expanding the types of novel macrocyclic compounds that can be used to construct artificial capsules, and having significant research significance for the field of supramolecular self-assembly. Attached Figure Description

[0041] Figure 1 Compound 4 obtained in Example 1 is shown. 1 H NMR spectrum.

[0042] Figure 2 Compound 5 obtained in Example 1 is shown. 1 H NMR spectrum.

[0043] Figure 3 This illustrates the novel electron-deficient macrocyclic molecule prepared in Example 1.1 H NMR spectrum.

[0044] Figure 4 A schematic diagram of the preparation of dimer artificial capsules in Example 3 is shown. Detailed Implementation

[0045] Terminology Explanation and Description

[0046] Unless otherwise stated, the definitions of groups and terms recorded in this application specification and claims, including their definitions as examples, preferred definitions, and definitions of specific compounds in the embodiments, can be arbitrarily combined and combined with each other. Such combinations and combinations of group definitions and compound structures shall fall within the scope of this application.

[0047] Unless otherwise stated, superscripts for groups in this application are group designations, and subscripts generally indicate the number of groups.

[0048] The "C1-" used alone or as a suffix or prefix in this invention 10 "Alkyl" refers to branched and straight-chain saturated aliphatic hydrocarbon groups having 1 to 10 carbon atoms (or, if the specific number of carbon atoms is provided), such as "C". 1-6 Alkyl group. The "C" 1-4 "Alkyl" refers to an alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, and all isomers of the above groups.

[0049] Term "C" 6-20 "Aryl" should be understood as representing a monocyclic, bicyclic, or tricyclic hydrocarbon ring with 6 to 20 carbon atoms that is monovalent and partially aromatic, such as "C". 6-14 "Aromatic". The term "C" 6-14 "Aryl" should be understood as representing a monovalent aromatic or partially aromatic monocyclic, bicyclic, or tricyclic hydrocarbon ring ("C") having 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms. 6-14 Aryl groups, particularly rings with 6 carbon atoms (“C6 aryl”), such as phenyl; rings with 7 carbon atoms (“C7 aryl”), such as benzyl; or biphenyl; or rings with 9 carbon atoms (“C9 aryl”), such as indenyl or indenyl; or rings with 10 carbon atoms (“C…”). 10 Aryl groups, such as tetrahydronaphthyl, dihydronaphthyl, or naphthyl, or rings with 13 carbon atoms (“C…”). 13Aryl groups, such as fluorene groups, or rings with 14 carbon atoms (“C…”). 14 "Aryl", for example, anthracene.

[0050] The present invention will now be described in detail through embodiments. It should be noted that these embodiments are only used to further illustrate the present invention and should not be construed as limiting the scope of protection of the present invention. Those skilled in the art can make some non-essential improvements and adjustments based on the above description. Unless otherwise specified, the embodiments and features described in the present invention can be combined with each other.

[0051] Example 1: Providing a novel electron-deficient macrocyclic molecular compound

[0052] Synthetic precursor compounds:

[0053]

[0054] In air, add 1 (1.96 g, 10.0 mmol, 1.0 equiv) and 50 ml of anhydrous THF to a dry 250 ml round-bottom flask. A 1 mol / L LAH THF solution (65 ml, 65.0 mmol, 6.5 equiv) is added to a dry 250 ml round-bottom flask. o Slowly add it dropwise to the mixture at C, then transfer it to 25°C. o The reaction was carried out at C for 12 h. 3 mL of deionized water and 3 mL of 15 wt% NaOH aqueous solution were reacted at 0 °C. o Slowly add the solution dropwise to the reaction mixture at C, then transfer to a container at 25°C. o After adding 9 mL of deionized water, stir for 15 min. Add anhydrous sodium sulfate to the reaction solution, dry, filter through a Buchner funnel, remove solvent under reduced pressure, and the resulting colorless liquid is separated by column chromatography to obtain colorless liquid 2 (1.40 g, yield 82%). 1 H NMR (400 MHz, Chloroform- d ) δ 6.95 (s, 1H), 6.86 (s, 2H), 4.68 (d, J = 6.0 Hz, 4H), 3.83 (s, 3H), 1.67 (t, J = 6.0 Hz, 2H).

[0055]

[0056] In air, add 2 (1.40 g, 8.32 mmol, 1.00 equiv) and 40 mL of anhydrous diethyl ether to a dry 250 mL round-bottom flask. Phosphorus tribromide (2.40 mL, 25.5 mmol, 3.06 equiv) is added to a dry 250 mL round-bottom flask. oSlowly add it dropwise to the mixture at C, then transfer it to 25°C. o The reaction was carried out at C for 12 h. Deionized water was then used at 0°C. o The organic phase was slowly added dropwise to the reaction solution at C, and the aqueous phase was extracted three times with dichloromethane. The organic phases were combined and dried with anhydrous sodium sulfate. The solvent was removed by rotary evaporation, and the resulting transparent yellow oil was separated by column chromatography to give a pale yellow solid 3, which was the precursor compound (1.95 g, yield 80%). 1 H NMR (400 MHz, Chloroform- d ) δ7.00 (s, 1H), 6.86 (s, 2H), 4.44 (s, 4H), 3.82 (s, 3H).

[0057] Synthesis of novel electron-deficient macrocyclic molecules:

[0058]

[0059] In a nitrogen-filled glove box, Pd(OAc)₂ (135 mg, 0.60 mmol, 20 mol%), L (244 mg, 0.72 mmol, 24 mol%), anhydrous Cs₂CO₃ (4.70 g, 14.4 mmol, 4.80 equiv), and anhydrous toluene (180 ml) were added to a thick-walled, pressure-resistant bottle. The mixture was stirred in the glove box for 15 min. 1,2,3,5-Tetrafluorobenzene (2.30 g, 15.3 mmol, 5.10 equiv), β-tetrafluorobenzene (882 mg, 3.00 mmol, 1.00 equiv), and terpentine (735 mg, 7.20 mmol, 2.40 equiv) were added to the mixture sequentially. The container was capped, removed from the glove box, and heated to 120 °C. o The mixture was stirred at C for 12 hours. After cooling to room temperature, it was filtered through diatomaceous earth and ethyl acetate, and the solvent was removed under reduced pressure. Purification by silica gel column chromatography gave 4 (236 mg, 18% yield) of a white solid. 1 The H NMR spectrum is shown in [reference]. Figure 1 (As shown) 1 H NMR (400 MHz, Chloroform- d ) δ 6.76-6.73 (m, 3H), 6.60 (s, 2H), 3.90 (s, 4H), 3.74 (s, 3H).

[0060]

[0061] In a nitrogen-filled glove box, Pd(OAc)₂ (22.4 mg, 0.10 mmol, 20 mol%), PhJohnPhos (40.6 mg, 0.12 mmol, 24 mol%), anhydrous Cs₂CO₃ (780 mg, 2.4 mmol, 4.80 equiv), and anhydrous toluene (30 ml) were added to a thick-walled, pressure-resistant bottle. The mixture was stirred in the glove box for 15 min. Then, 3 (147 mg, 0.50 mmol, 1.00 equiv), 4 (216 mg, 0.50 mmol, 1.00 equiv), and pentylene acid (123 mg, 1.20 mmol, 2.40 equiv) were added to the mixture sequentially. The container was capped, removed from the glove box, and heated to 120°C. o The mixture was stirred at C for 24 hours. After cooling to room temperature, it was filtered through diatomaceous earth and ethyl acetate, and the solvent was removed under reduced pressure. Purification by silica gel column chromatography yielded a white solid of 5 (31 mg, 11% yield). 1 The H NMR spectrum is shown in [reference]. Figure 2 (As shown). 1 H NMR (400 MHz, Chloroform- d )δ 6.78 (s, 2H), 6.74 (s, 4H), 3.88 (s, 8H), 3.77 (s, 6H).

[0062]

[0063] In a nitrogen-filled glove box, 5 mg (40.0 mg, 0.071 mmol, 1.00 equiv) and 10 mL of anhydrous CH2Cl2 were added to a 40 mL glass bottle. The bottle was then sealed with a PTFE diaphragm cap and transferred from the glove box. At 0... o BBr3 (30 μL, 0.31 mmol, 4.37 equiv) was added to the mixture using a syringe at C. The reaction mixture was then heated at 0°C. o Stir at C for 20 minutes, then at 25°C. o Stirred at C for 12 hours. Quench the reaction with deionized water and dilute with ethyl acetate. Extract the aqueous phase three times with ethyl acetate. Wash the combined organic layers with brine and dry with anhydrous sodium sulfate, removing the solvent under reduced pressure. Separate by column chromatography and centrifugation to obtain white solid 6, which is the novel electron-deficient macrocyclic molecule (36 mg, yield 95%). 1 The H NMR spectrum is shown in [reference]. Figure 3 (As shown). 1 H NMR (400 MHz, Chloroform- d) δ 8.38 (s, 2H), 6.73 (s, 4H), 6.45 (s, 2H), 3.90 (s, 8H).

[0064] Example 2 provides a dimer artificial capsule

[0065]

[0066] The synthesis steps include: in air, mixing 6 and... n -BuN4Cl was prepared into 20 mM stock solutions. Then, 250 μL of each solution was taken and mixed together to form equimolar ratios (10 mM) of 6 and n A mixed solution of -BuN4Cl, followed by sonication, yields dimer artificial capsules ([6]2[Cl). – 2) Solution.

[0067] Mass spectrometry was used to detect the dimer artificial capsules. The results showed that: HRMS (ESI): [6]2[Cl – ]2[ n -Bu4N + C 72 H 68 F 16 Cl2NO4, theoretical value 1384.4275, measured value 1384.4339.

[0068] Two-dimensional NMR spectroscopy was used to detect the dimer artificial capsules. The results showed that DOSY (600 MHz, Chloroform- d The diffusion coefficient D before mixing is 1.77 × 10⁶. -9 The diffusion coefficient D of the mixed substance is 1.32 × 10⁶. -9 That is, the hydrodynamic diameter increases from 0.8 nm to 1.1 nm.

[0069] Example 3 provides a dimer artificial capsule

[0070]

[0071] The synthesis steps included: at 25 °C, diffusing diethyl ether into a solution of acetone / acetonitrile (1:1) and excess Et4NCl from Example 1 to obtain chloride ion-induced dimer artificial capsule single crystals (see schematic diagram). Figure 4 ).

[0072] The size of the artificial dimer capsules in the crystal matches the diameter values ​​based on DOSY data measured in Example 2. The crystalline artificial dimer capsules have a width of 11.5 Å (distance between chlorides), a depth of 10.4 Å (distance between fluorine atoms at the upper edge of the same macroring), and a height of 12.2 Å (distance between the top and bottom fluorine atoms). The capsules are orthogonally oriented in the crystal structure and are stacked together through π-π interactions.

[0073] Obviously, the above embodiments of the present invention are merely examples for clearly illustrating the present invention, and are not intended to limit the implementation of the present invention. For those skilled in the art, other variations or modifications can be made based on the above description. It is impossible to exhaustively list all the implementation methods here. All obvious variations or modifications derived from the technical solutions of the present invention are still within the protection scope of the present invention.

Claims

1. An electron-deficient macrocyclic molecule, characterized in that, Its structure is shown in b: b。 2. A method for synthesizing an electron-deficient macrocyclic molecule as described in claim 1, characterized in that, A method for synthesizing electron-deficient macrocyclic molecules with structure b includes the following steps: The cyclic precursor compound was coupled with 1,2,3,5-tetrafluorobenzene via a single palladium-catalyzed coupling reaction to yield a cyclic precursor compound having two fluorobenzene units. The structure of the precursor compound is shown in Figure e: e； The cyclic precursor compound having two fluorobenzene units is subjected to a secondary palladium-catalyzed coupling reaction with the cyclic precursor compound, followed by a deprotection reaction to remove the methyl protecting group, to obtain the product.

3. A synthesis method as described in claim 2, characterized in that, The process includes adding tervaline before performing a single or double palladium-catalyzed coupling reaction; wherein the molar ratio of tervaline to the cyclization precursor compound is 2-3:

1.

4. The synthesis method according to claim 2, characterized in that, The molar ratio of the cyclic precursor compound to 1,2,3,5-tetrafluorobenzene is 1-3:1-10; The molar ratio of the cyclic precursor compound having two fluorobenzene units to the cyclic precursor compound is 1-2:

1.

5. The synthesis method according to claim 2, characterized in that, The preparation steps of the precursor compound with structure e include: using 5-methoxy-1,3-phenylenediic acid as the starting material, carrying out a reduction reaction to obtain 5-methoxy-1,3-phenylenediethanol, and then carrying out a bromination reaction to obtain the product; 。 6. A dimer artificial capsule, characterized in that, It is prepared from the electron-deficient macrocyclic molecule of claim 1 under the action of anion.

7. The dimer artificial capsule according to claim 6, characterized in that, The anion is F. - Cl - ,Br - I - NO3 - OAc - BF4 - PF6 - Any one of them.

8. The application of a dimer artificial capsule as described in any one of claims 6-7 in the fields of adsorption, separation, catalysis, and fluorescence recognition.

Images