CN106632925A - Preparation method for amphiphilic segmented copolymer with pH value and temperature sensitivities - Google Patents

Abstract

The invention relates to a preparation method of an amphiphilic multi-block copolymer with pH and temperature sensitivity. Using reversible addition-fragmentation chain transfer polymerization, a macromolecular chain transfer agent, poly(tert-butyl acrylate), was synthesized, and then RAFT was carried out again with dimethylaminoethyl methacrylate and ethylene glycol methyl ether methacrylate. The amphiphilic multi-block copolymer P(tBA) ‑b ‑P(DMAEMA‑ co ‑PEGMA) was synthesized by polymerization. In aqueous solution, the multi-block copolymer can self-assemble and form micelles with pH and temperature sensitivity. The critical pH value of the micelles is 7, and the critical temperature is 37.5 ℃. The present invention has the advantages of high yield, relatively wide range of applicable monomers, and low requirements on reaction conditions. The present invention is easy to operate and environmentally friendly. It is widely used in chemical production fields such as dye adsorption, environmental protection fields such as heavy metal pollution treatment, and biomedical fields such as controlled release of insoluble drugs.

Description

A kind of preparation method of amphiphilic multi-block copolymer with pH and temperature sensitivity

technical field

The invention belongs to the technical field of chemical engineering and new materials, and in particular relates to a preparation method of an amphiphilic multi-block copolymer P(tBA) -b -P(DMAEMA- co -PEGMA) with pH and temperature sensitivity.

Background technique

Environmentally responsive polymer materials refer to polymer materials that undergo some obvious physical or chemical property mutations in the case of minor external environment changes. Such materials usually undergo conformational adjustments in specific environments to respond to Responsive responses to environmental changes lead to phase structure transitions. Utilizing this characteristic of environmentally responsive polymer materials, smart materials with special responsiveness can be designed according to requirements. Amphiphilic multi-block copolymers can self-assemble in some selective solvents to form specific structures such as micelles and vesicles. Combining the advantages of the above two, the synthesized environmentally responsive amphiphilic multi-block copolymers can not only respond to stimuli that change the external environment such as pH and temperature, but also can form aggregates such as micelles and vesicles. Carries insoluble drugs or organic dyes, so this kind of material has application value in many fields such as biomedicine, chemical production and environmental protection.

Currently, most environmentally responsive polymer materials are synthesized in the same way as general block or graft copolymers and branched polymers. Commonly used methods include group transfer polymerization (GTP) and controlled living radical polymerization (CLRP), in which CLRP is further divided into reversible addition-fragmentation-transfer radical polymerization (RAFT), atom transfer radical polymerization (ATRP) and Nitroxide-mediated free radical polymerization (NMP).

GTP is currently widely used in the synthesis of polymethacrylate responsive polymers, but GTP is not based on a free radical mechanism, and its synthesis is limited to methyl methacrylate monomers, while the reaction rate of NMP polymerization in CLRP The range of suitable monomers is relatively low; the disadvantage of the ATRP polymerization method is that it cannot be applied to the direct polymerization of acidic, basic, amide or halogen-containing vinyl monomers, and metal elements are used in the reaction process. Although with the continuous improvement of ATRP technology, the amount of metal elements has been greatly reduced, but from the perspective of applicable environment and toxicology, the problem of using metal elements is inevitable, so the development of ATRP polymerization method is limited, especially in biological This problem is particularly prominent when applied in the medical field. The RAFT polymerization method overcomes the shortcomings of the above two methods, and can directly prepare the required functional polymer in the reaction medium. At the same time, we can further modify the dithioester or trithioester at the end of the obtained polymer, which is for the follow-up The reaction provides the desired functional group. Therefore, the present invention selects the method of RAFT living polymerization to prepare the amphiphilic multi-block copolymer P(tBA) -b -P(DMAEMA- co -PEGMA).

Contents of the invention

The purpose of the present invention is to overcome the deficiencies in the prior art and provide a method for preparing an amphiphilic multi-block copolymer P(tBA) -b -P(DMAEMA- co -PEGMA) with pH and temperature sensitivity.

The invention proposes a preparation method of an amphiphilic multi-block copolymer P(tBA) -b -P(DMAEMA- co -PEGMA) with pH and temperature sensitivity. In this method, the macromolecular chain transfer agent poly(tert-butyl acrylate) (P(tBA)) was first synthesized by the RAFT polymerization method, and then the macromolecular chain transfer agent P(tBA), dimethylaminoethyl methacrylate (DMAEMA) and The amphiphilic multi-block copolymer P(tBA) -b -P(DMAEMA- co -PEGMA) was synthesized by RAFT polymerization of polyethylene glycol methyl ether methacrylate (PEGMA). In aqueous solution, the multi-block copolymer can self-assemble into micelles with dual sensitivity to pH and temperature, in which the hydrophilic P(DMAEMA- co -PEGMA) constitutes the shell of the micelles, and the PPEGMA comb-shaped segment structure The biocompatibility of the micelles can be enhanced, while the hydrophobic P(tBA) aggregates into the core of the micelles.

The present invention proposes a preparation method of an amphiphilic multi-block copolymer with pH and temperature sensitivity, and the amphiphilic multi-block copolymer is P(tBA) -b -P(DMAEMA- co -PEGMA ),Specific steps are as follows:

(1) Synthesis of polytert-butyl acrylate (P(tBA))

Weigh 1~5 g tert-butyl acrylate (tBA) into a 50 mL single-necked round bottom flask, take 5~50 mg 4-cyano-4-(thiobenzoyl)valeric acid and 1~10 mg Add 5-15 mL of dioxane to a 50-mL beaker to dissolve azadiisobutyronitrile. Then the two were mixed, and the one-necked flask was evacuated at 0 °C through the "T-shaped" tee, and nitrogen gas was introduced. Under the protection of nitrogen, put it in an oil bath at 60-90 °C for 6-24 h, and stir evenly with magnetic force. After the reaction was completed, the flask was cooled in an ice-water bath and ventilated to the atmosphere, and the cooled solution was added dropwise to 100-300 mL of methanol/water (v : v = 2 : 1) mixed solution, and allowed to stand for 1-6 h to remove The upper layer was liquid, and a pale pink precipitate was obtained at the bottom. The above precipitation step was repeated once, and finally the sample was vacuum-dried at 30-50 °C for 6-72 h to obtain poly(tert-butyl acrylate) (P(tBA)).

(2) Synthesis of amphiphilic multi-block copolymer P(tBA) -b -P(DMAEMA- co -PEGMA)

Put 0.5-2.5 g of dimethylaminoethyl methacrylate (DMAEMA) and 0.1-0.5 g of ethylene glycol methyl ether methacrylate (PEGMA) into a 50 mL single-necked round bottom flask. Weigh 0.5~1.5 g of the product of step (1) tert-butyl acrylate (P(tBA)) and 0.5~2.5 mg of azobisisobutyronitrile into a 50 mL beaker, add 5~15 mL of dioxane to dissolve . Then the two were mixed, and the one-necked flask was evacuated at 0 °C through the "T-shaped" tee, and nitrogen gas was introduced. Under the protection of nitrogen, put it in an oil bath at 60-90 °C for 6-36 h, and stir evenly with magnetic force. After the reaction was completed, the flask was cooled in an ice-water bath and ventilated to the atmosphere. The cooled solution was added dropwise to 100–300 mL ice petroleum ether, and left to stand for 4 h to remove the upper liquid to obtain a viscous sample at the bottom. The above precipitation step was repeated once, and finally the sample was vacuum-dried at 30-50 °C for 6-72 h to obtain the amphiphilic multi-block copolymer P(tBA) -b -P(DMAEMA- co -PEGMA).

(3) Preparation of P(tBA) -b -P(DMAEMA- co -PEGMA) micelles

Weigh 5~25 mg of the P(tBA) -b -P(DMAEMA- co -PEGMA) polymer in step (2), dissolve it in 1~10 mL N,N-dimethylformamide, stir until Dissolve, drop 5~15 mL deionized water into the solution, the solution can be observed to turn blue, continue to stir for half an hour after dropping, then put the solution into a dialysis bag with a molecular weight cut-off of 2000~5000 Da and dialyze with deionized water for 12~ After 72 h, N,N-dimethylformamide was removed to obtain P(tBA) -b -P(DMAEMA- co -PEGMA) micelles.

Compared with prior art, advantage of the present invention mainly contains following three points:

① The present invention is a method for synthesizing a pH- and temperature-sensitive amphiphilic multi-block copolymer based on the RAFT polymerization method. High, high polymerization rate, relatively wide range of applicable monomers, and low requirements for reaction conditions. ② The amphiphilic multi-block copolymer prepared by the present invention has dual sensitivity to pH and temperature. When the temperature rises to the lower critical solution temperature, the hydrophilicity of the polymer chain segment weakens, and the micelles reunite; when the temperature decreases, the already reunited micelles will separate again, realizing the reversibility of the environmental temperature change Sexual response; when the pH increases, the shell structure of the copolymer micelles shrinks to varying degrees, and the particle size decreases accordingly. ③ The preparation method of the present invention is easy to operate, green and environmentally friendly, and has broad application prospects. It can be applied to chemical production fields such as dye adsorption, environmental protection fields such as pollutant treatment, and biomedical fields such as controllable release of insoluble drugs. chemical polymer materials.

Description of drawings

Figure 1 is a schematic diagram of the synthesis of P(tBA) -b -P(DMAEMA- co -PEGMA) based on the RAFT polymerization method in Example 1.

Figure 2 is the critical micelle concentration of P(tBA) -b -P(DMAEMA- co -PEGMA) measured by the pyrene fluorescent probe method in Example 1.

Fig. 3 is the hydrodynamic diameter of P(tBA) -b -P(DMAEMA- co -PEGMA) micelles (1 mg/L) at different pH in Example 1.

Fig. 4 is the hydrodynamic diameter of P(tBA) -b -P(DMAEMA- co -PEGMA) micelles (1 mg/L) at different temperatures in Example 1.

detailed description

The present invention is further illustrated below by way of examples.

Example 1

Step 1: Weigh 2.75 g tert-butyl acrylate (tBA) into a 50 mL single-necked round bottom flask, take 20 mg 4-cyano-4-(thiobenzoyl)valeric acid and 3.52 mg azobis Dissolve isobutyronitrile in a 50 mL beaker by adding 10 mL of dioxane. Then the two were mixed, and the one-necked flask was evacuated at 0 °C through the "T-shaped" tee, and nitrogen gas was introduced. Under the protection of nitrogen, put it in an oil bath at 70°C for 12 h, and stir evenly with magnetic force. After the reaction was completed, the flask was cooled in an ice-water bath and ventilated to the atmosphere, and the cooled solution was added dropwise to 200 mL of methanol/water (v: v = 2: 1) mixed solution, allowed to stand for 4 h, and the upper liquid was removed to obtain Pale pink precipitate at the bottom. The above precipitation step was repeated once, and finally the sample was vacuum-dried at 40 °C for 48 h to obtain a pale pink sample, namely poly(tert-butyl acrylate) (P(tBA)).

The second step: 1.22 g of dimethylaminoethyl methacrylate (DMAEMA) and 0.24 g of ethylene glycol methyl ether methacrylate (PEGMA) were placed in a 50 mL single-necked round bottom flask. Weigh 1 g of the product of the first step, poly(tert-butyl acrylate) (P(tBA)), and 1.27 mg of azobisisobutyronitrile into a 50 mL beaker, and add 10 mL of dioxane to dissolve it. Then the two were mixed, and the one-necked flask was evacuated at 0 °C through the "T-shaped" tee, and nitrogen gas was introduced. Under the protection of nitrogen, put it in an oil bath at 70 °C for 24 h, and stir evenly with magnetic force. After the reaction was completed, the flask was cooled in an ice-water bath and ventilated to the atmosphere. The cooled solution was added dropwise to 200 mL of ice petroleum ether and allowed to stand for 4 h to remove the upper liquid to obtain a viscous sample at the bottom. The above precipitation step was repeated once, and finally the sample was vacuum-dried at 40 °C for 48 h. A pale yellow sample was obtained, that is, an amphiphilic multi-block copolymer P(tBA) -b -P(DMAEMA- co -PEGMA) was obtained.

Step 3: Weigh 15 mg P(tBA)- b -P(DMAEMA- co -PEGMA) polymer, dissolve it in 5 mL N,N-dimethylformamide, stir until dissolved, and remove 10 mL Ionized water is dropped into the solution, and the solution can be observed to turn blue. After the drop, continue to stir for half an hour, and then put the solution into a dialysis bag with a molecular weight cut-off of 3500 Da and dialyze it with deionized water for 48 hours to remove N,N-dimethylformamide , to obtain P(tBA) -b -P(DMAEMA- co -PEGMA) micelles.

The amphiphilic multi-block copolymer P(tBA) -b -P(DMAEMA- co -PEGMA) micellar size variation with pH (pH = 2~11) was tested by dynamic light scattering (DLS). The results are shown in Figure 3. It can be seen from Figure 3 that the micelles have obvious pH response properties, and when the pH is 6.5, the particle size changes abruptly.

DLS was used again to test the change of micelle particle size with temperature (T = 30~45°C). When the temperature is 37.5℃, the particle size changes abruptly.

Example 2

Compared with Example 1, the amount of tert-butyl acrylate (P(tBA)) in the first step is changed to 2.29 g, and other conditions remain unchanged, then the monomer tert-butyl acrylate, chain transfer agent 4-cyano The molar ratio of base-4-(thiobenzoyl)valeric acid and initiator azobisisobutyronitrile becomes 250: 1: 0.3.

Example 3

Compared with Example 1, the amount of tert-butyl acrylate (P(tBA)) in the first step is changed to 1.84 g, and other conditions remain unchanged, then the monomer tert-butyl acrylate and chain transfer agent 4-cyanide in the system The molar ratio of base-4-(thiobenzoyl)valeric acid and initiator azobisisobutyronitrile becomes 200: 1: 0.3.

Example 4

Compared with Example 1, the amount of tert-butyl acrylate (P(tBA)) in the first step is changed to 1.38 g, and other conditions remain unchanged, then the monomer tert-butyl acrylate and chain transfer agent 4-cyanide in the system The molar ratio of base-4-(thiobenzoyl)valeric acid and initiator azobisisobutyronitrile becomes 150: 1: 0.3.

Example 5

Compared with Example 1, the amount of dimethylaminoethyl methacrylate (DMAEMA) in the second step is changed to 1.01 g, and other conditions remain unchanged, then the monomer dimethylaminoethyl methacrylate, chain The molar ratio of transfer agent 4-cyano-4-(thiobenzoyl)valeric acid and initiator (azobisisobutyronitrile) was changed to 250: 1: 0.3.

Example 6

Compared with Example 1, the amount of dimethylaminoethyl methacrylate (DMAEMA) in the second step is changed to 0.81 g, and other conditions remain unchanged, then the monomer dimethylaminoethyl methacrylate in the system, the chain The molar ratio of transfer agent 4-cyano-4-(thiobenzoyl)valeric acid and initiator azobisisobutyronitrile becomes 200: 1: 0.3.

Example 7

Compared with Example 1, the amount of dimethylaminoethyl methacrylate (DMAEMA) in the second step is changed to 0.61 g, and other conditions remain unchanged, then the monomer dimethylaminoethyl methacrylate in the system, the chain The molar ratio of transfer agent 4-cyano-4-(thiobenzoyl)valeric acid and initiator azobisisobutyronitrile becomes 150: 1: 0.3.

Example 8

Compared with Example 1, the amount of ethylene glycol methyl ether methacrylate (PEGMA) in the second step is changed to 0.36 g, and other conditions remain unchanged, then the monomer ethylene glycol methyl ether methacrylate in the system , The molar ratio of the chain transfer agent 4-cyano-4-(thiobenzoyl)valeric acid and the initiator azobisisobutyronitrile becomes 15: 1: 0.3.

Example 9

Compared with Example 1, the amount of ethylene glycol methyl ether methacrylate (PEGMA) in the second step is changed to 0.48 g, and other conditions remain unchanged, then the monomer ethylene glycol methyl ether methacrylate in the system , The molar ratio of the chain transfer agent 4-cyano-4-(thiobenzoyl)valeric acid and the initiator azobisisobutyronitrile becomes 20: 1: 0.3.

The amphiphilic multi-block polymer P(tBA) -b -P(DMAEMA- co -PEGMA) obtained in Examples 2-9 with dual sensitivity to pH and temperature has similar properties to the product in Example 1.

Claims (3)

1. a kind of preparation method with pH and the amphipathic multi-block copolymer of temperature sensitivity, it is characterised in that the amphiphilic Property segmented copolymer be P (tBA)-b-P(DMAEMA-co- PEGMA), comprise the following steps that：

(1) synthesis of the polyacrylic acid tert-butyl ester (P (tBA))

Weigh 1 ~ 5 g tert-butyl acrylates (tBA) to be placed in 50 mL single necked round bottom flask, take 5 ~ 50 mg 4- cyano group -4- (sulphur For benzoyl) valeric acid and 1 ~ 10 mg azodiisobutyronitriles in 50 mL beakers, add the dissolving of 5 ~ 15 mL dioxane；Then Both are mixed, by " T-shaped " threeway, single-necked flask is vacuumized at 0 DEG C, and be passed through nitrogen；It is placed under nitrogen protection 6 ~ 24 h, uniform magnetic agitation are reacted under 60 ~ 90 DEG C of oil baths；Reaction leads to air after after terminating flask is cooled down in ice-water bath, Solution after cooling is added drop-wise to into 100 ~ 300 mL methanol/water (v: v = 2 :1) in mixed solution, 1 ~ 6 h is stood, is removed Supernatant liquid, obtains bottom pale pink precipitation；Repeat above settling step once, finally vacuum is done at 30 ~ 50 DEG C by sample Dry 6 ~ 72 h, obtains the polyacrylic acid tert-butyl ester (P (tBA))；

(2) amphipathic multi-block copolymer p (tBA)-b-P(DMAEMA-co- PEGMA) synthesis

By 0.5 ~ 2.5 g dimethylaminoethyl acrylate methyls ammonia ethyl ester (DMAEMA) and 0.1 ~ 0.5 g EGME methacrylates (PEGMA) in being placed in 50 mL single necked round bottom flask；Weigh 0.5 ~ 1.5 g steps（1）Product polypropylene tert-butyl acrylate (P ) and 0.5 ~ 2.5 mg azodiisobutyronitriles are in 50 mL beakers, (tBA) dissolving of 5 ~ 15 mL dioxane is added；Then will Both mixing, by " T-shaped " threeway, vacuumize to single-necked flask at 0 DEG C, and are passed through nitrogen；60 are placed under nitrogen protection 6 ~ 36 h, uniform magnetic agitation are reacted under ~ 90 DEG C of oil baths；Reaction leads to air after after terminating flask is cooled down in ice-water bath, will Solution after cooling is added drop-wise in 100 ~ 300 mL ice petroleum ethers, stands 4 h, removes supernatant liquid, obtains bottom viscous samples； Repeat above settling step once, finally sample is vacuum dried into 6 ~ 72 h at 30 ~ 50 DEG C, obtain amphipathic multi-block copolymerization Thing P (tBA)-b-P(DMAEMA-co-PEGMA)；

(3) P(tBA)-b-P(DMAEMA-co- PEGMA) micella preparation

Weigh 5 ~ 25 mg steps（2）In P (tBA)-b-P(DMAEMA-co- PEGMA) polymer, 1 ~ 10 mL N are dissolved in, In dinethylformamide, electromagnetic agitation is until dissolving, by 5 ~ 15 mL deionized waters instillation solution, can be observed solution general Indigo plant, continues to stir half an hour after dripping off, and then solution loaded the bag filter deionization of the Da of molecular cut off 2000 ~ 5000 Water dialyse 12 ~ 72 h remove DMF, obtain P (tBA)-b-P(DMAEMA-co- PEGMA) micella.

2. a kind of preparation side with pH and the amphipathic multi-block copolymer of temperature sensitivity according to claim 1 Method, it is characterised in that described many blocks are respectively polyacrylic acid tert-butyl ester block (P (tBA)) and the poly- (methyl of random copolymer Acrylic acid diformazan ammonia ethyl ester-co- methoxypolyethylene glycol methacrylate) block (P (DMAEMA-co-PEGMA))。

3. a kind of preparation side with pH and the amphipathic multi-block copolymer of temperature sensitivity according to claim 1 Method, it is characterised in that the described polyacrylic acid tert-butyl ester (P (tBA)) and the polyacrylic acid tert-butyl ester-b- poly- (dimethylaminoethyl acrylate methyl Ammonia ethyl ester-co- methoxypolyethylene glycol methacrylate) (P (tBA)-b-P(DMAEMA-co- PEGMA)) chemical structural formula Difference is as follows：

Here, m=80 ~ 2000

(a) polyacrylic acid tert-butyl ester (P (tBA))

Here, m=80 ~ 2000, n=80 ~ 2000

(b) amphipathic multi-block copolymer p tBA-b-P(DMAEMA-co-PEGMA)。