阅读说明：本技术 聚乙二醇-b-聚（N-异丙基丙烯酰胺）表面活性剂及其合成与应用 (Polyethylene glycol-b- poly(N-isopropylacrylamide) surfactant and its synthesis and application ) 是由 侯庆锋 王源源 郑晓波 赵玉军 王哲 徐艳 倪晨 孙建锋 薛俊杰 刘强 于 2019-09-02 设计创作，主要内容包括：本发明公开了一种聚乙二醇-b-聚(N-异丙基丙烯酰胺)表面活性剂及其合成与应用。该方法包括以下步骤：S1、聚乙二醇大分子引发剂的合成；S2、聚乙二醇-b-聚(N-异丙基丙烯酰胺)的合成；将含有聚乙二醇大分子引发剂和N-异丙基丙烯酰胺单体的水溶液以及含有溴化铜、抗坏血酸和三(2-二甲氨基乙基)胺的水溶液分别进行除氧；在冰浴中将两者混合进行反应；反应结束后,反应液经后处理即得产物聚乙二醇-b-聚(N-异丙基丙烯酰胺)。该方法N-异丙基丙烯酰胺单体转化率可达100％,产品总收率超过30％,反应时间缩短到2小时以内,提高了合成效率；以溴化铜代替溴化亚铜进行反应,克服了原料在存储过程中容易氧化的缺点。(The invention discloses a kind of polyethylene glycol-b- poly(N-isopropylacrylamide) surfactant and its synthesis and application.Method includes the following steps: the synthesis of S1, polyethylene glycol macromole evocating agent；The synthesis of S2, polyethylene glycol-b- poly(N-isopropylacrylamide)；Aqueous solution containing polyethylene glycol macromole evocating agent and n-isopropyl acrylamide monomer and the aqueous solution containing copper bromide, ascorbic acid and three (2- dimethylaminoethyl) amine are subjected to deoxygenation respectively；The two is mixed in ice bath and is reacted；After reaction, reaction solution is post-treated up to product polyethylene glycol-b- poly(N-isopropylacrylamide).This method n-isopropyl acrylamide monomer conversion is up to 100%, and total yield of products is more than 30%, and the reaction time shortened within 2 hours, improved combined coefficient；It replaces cuprous bromide to be reacted with copper bromide, overcomes raw material disadvantage easy to oxidize in storing process.)

1. a kind of synthetic method of polyethylene glycol-b- poly(N-isopropylacrylamide) surfactant, which is characterized in that including Following steps:

The synthesis of S1, polyethylene glycol macromole evocating agent；

The synthesis of S2, polyethylene glycol-b- poly(N-isopropylacrylamide)；

By the aqueous solution containing polyethylene glycol macromole evocating agent and n-isopropyl acrylamide monomer and contain copper bromide, anti- The aqueous solution of bad hematic acid and three (2- dimethylaminoethyl) amine carries out deoxygenation respectively；

The two is mixed in ice bath and is reacted；After reaction, reaction solution is post-treated poly- up to product polyethylene glycol-b- (n-isopropyl acrylamide).

2. synthetic method according to claim 1, which is characterized in that poly- (the N- isopropyl acrylamide of polyethylene glycol-b- Amine) surfactant contains polyethylene glycol segment and poly(N-isopropylacrylamide) segment simultaneously；Wherein, polyethylene glycol segment The degree of polymerization be 45, the degree of polymerization of poly(N-isopropylacrylamide) segment is 20-200.

3. synthetic method according to claim 2, which is characterized in that the poly(N-isopropylacrylamide) segment gathers Right is 17-38 or 50-200.

4. synthetic method according to claim 2 or 3, which is characterized in that in poly(N-isopropylacrylamide) segment When the degree of polymerization is within the scope of 17-35, the LCST of the polyethylene glycol-b- poly(N-isopropylacrylamide) reaches 45 DEG C or more.

5. synthetic method according to claim 1, which is characterized in that the synthesis packet of polyethylene glycol macromole evocating agent in S1 It includes:

Polyethylene glycol and triethylamine are dissolved in tetrahydrofuran, ice-water bath stirring instills the tetrahydrofuran of 2- bromine isobutyl acylbromide Solution is reacted；

Liquid is filtered after reaction, filtrate revolving is taken to remove most of tetrahydrofuran, remaining liq sinks in low temperature ether It forms sediment；It filters and removes ether, precipitating is drying to obtain polyethylene glycol macromole evocating agent.

6. synthetic method according to claim 5, which is characterized in that mole of the polyethylene glycol and 2- bromine isobutyl acylbromide Than for 1:2~1:4.

7. synthetic method according to claim 6, which is characterized in that the molar ratio of the 2- bromine isobutyl acylbromide and triethylamine For 1:1~1:2.

8. synthetic method according to claim 5, which is characterized in that the temperature of the ice-water bath is controlled at 0~15 DEG C, instead 24~48 hours between seasonable.

9. synthetic method according to claim 5, which is characterized in that the pressure of the revolving is 1~100KPa, and temperature is 30~100 DEG C.

10. synthetic method according to claim 5, which is characterized in that the low temperature ether temperature is -20~0 DEG C.

11. synthetic method according to claim 1, which is characterized in that in S2, the molar ratio of copper bromide and ascorbic acid is 1:0.8~1:1.2.

12. synthetic method according to claim 1, which is characterized in that in S2, copper bromide and three (2- dimethylaminoethyls) The molar ratio of amine is 1:0.5~1:3.

13. synthetic method according to claim 1, which is characterized in that in S2, polyethylene glycol macromole evocating agent and bromination The molar ratio of copper is 1:2~10:1.

14. synthetic method according to claim 1, which is characterized in that in S2, n-isopropyl acrylamide feeding quantity is it 0.8~1.2 times of target polymerization topology degree feeding quantity.

15. synthetic method according to claim 1, which is characterized in that the operation of protection gas is filled in the deoxygenation using pumping； Air suction process pressure is 20Pa~1KPa, time 5-30min, is evacuated-fills protection gas and operate number of repetition 1-5 times.

16. synthetic method according to claim 1, which is characterized in that the ice water bath temperature in S2 is 0~20 DEG C.

17. synthetic method according to claim 1, which is characterized in that described in S2 post-processing include distilled water dialysis and It is dry.

18. synthetic method according to claim 17, which is characterized in that the time of the dialysis of the dialysis is 2~14 days, Change water frequency every 2~24 hours once.

19. synthetic method according to claim 17, which is characterized in that dry select is freeze-dried, freeze-drying Pressure is 15Pa~1KPa, and temperature is -20~-50 DEG C, and the time is 6~48 hours.

20. poly- (the N- isopropyl acrylamide of the polyethylene glycol-b- that any one of the claim 1-19 synthetic method is prepared Amine) surfactant.

21. polyethylene glycol-b- poly(N-isopropylacrylamide) surfactant according to claim 20, feature exist In the surfactant contains polyethylene glycol segment and poly(N-isopropylacrylamide) segment simultaneously；Wherein, polyethylene glycol The degree of polymerization of segment is 45, and the degree of polymerization of poly(N-isopropylacrylamide) segment is 17-200.

22. polyethylene glycol-b- poly(N-isopropylacrylamide) surfactant according to claim 21, feature exist In the degree of polymerization of the poly(N-isopropylacrylamide) segment is 17-38 or 50-200.

23. polyethylene glycol-b- poly(N-isopropylacrylamide) the surfactant according to claim 21 or 22, special Sign is, when the degree of polymerization of poly(N-isopropylacrylamide) segment is within the scope of 17-35, the poly- (N- of polyethylene glycol-b- N-isopropylacrylamide) LCST reach 45 DEG C or more.

24. the described in any item polyethylene glycol-b- poly(N-isopropylacrylamide) surfactants of claim 20-23 are in stone Application in oil exploitation, drug delivery field.

Technical field

The invention belongs to technical field of organic synthesis, more particularly to a kind of poly- (the N- isopropyl third of polyethylene glycol-b- Acrylamide) surfactant and its synthesis and application.

Background technique

In recent years, temperature sensitive type polymer is above received more and more attention in the application such as nanosecond science and technology and life science, this Kind can show the water of lower critical solution temperature (lower critical solution temperature, LCST) in water Soluble polymer can be used for intelligent biological active surface, selectivity organism separation, immunoassays mutually separate and the drug of thermal induction The biomedical aspects such as delivering.So far, the LCST of poly(N-isopropylacrylamide) (PNIPAM) shows 32 in water DEG C or so, it is the temperature sensitive type polymer of most study in biologic applications.The LCST of this polymer close to body temperature, and its for Environmental condition relative insensitivity, the slight change of pH, concentration or chemical environment have little influence on the LCST (Jean- of PNIPAMLutz,Akdemir,Ann Hoth et al.Point by Point Comparison of Two Thermosensitive Polymers Exhibiting a Similar LCST:Is the Age of Poly(NIPAM) Over [J] .J.AM.CHEM.SOC., 2006,128:13046-13047.).

Document (Polymer, 2005,46:2836-2840) reports a kind of poly- (N- isopropyl acrylamide of polyethylene glycol-b- Amine), which has higher LCST (38 DEG C).Not yet it is found to have higher poly- (the N- isopropyl third of LCST polyethylene glycol-b- Acrylamide) surfactant document report.Currently, the synthesis of the polyethylene glycol-b- poly(N-isopropylacrylamide) of open report Method mostly uses atom transfer radical polymerization and single electron transfer-active free radical polymerization:

(1) atom transfer radical polymerization (ATRP)

By polyethylene glycol (PEG) macromole evocating agent (0.1mmol) and NIPAM (n-isopropyl acrylamide, 5.0mmol) Vacuumize respectively-inflated with nitrogen three times, degasification distilled water (10mL) is separately added into form PEG macromole evocating agent and NIPAM solution. Degasification distilled water (20mL) and Me is added in cuprous bromide (0.1mmol) in nitrogen atmosphere₆TREN (three (2- dimethylaminoethyls) Amine, 0.1mmol).Initiator and monomer solution is added after stirring 5min at 25 DEG C, reaction is added a small amount of hydrochloric acid and stops after 24 hours Reaction.Reaction product dialyses 24 hours in the dialysis membrane that molecular cut off is 3500 to remove catalyst, ligand and unreacted Monomer.After removing water in dialysis solution, methanol lysate is added, then solution is added drop-wise in ether and is precipitated, filters Precipitated product and be dried in vacuo up to product (Keon Hyeong Kim, Jungahn Kim and Won Ho Jo, Preparation of hydrogel nanoparticles by atom transfer radical polymerization of N-isopropylacrylamide in aqueous media using PEG macro-initiator[J] .Polymer,2005,46:2836–2840)。

(2) single electron transfer-active free radical polymerization (SET-LRP)

By water (2mL) and Me₆TREN (three (2- dimethylaminoethyl) amine, 9 μ L, 0.035mmol) is in vacuum reaction pipe (1 Number) in another vacuum reaction pipe (No. 2) full of nitrogen that cuprous bromide (10mg, 0.07mmol) is housed is transferred to after degasification In, it is invaded in ice-water bath after stirring 30 minutes at room temperature.

It separately takes in a vacuum reaction pipe (No. 3) and water (3.5mL) is added, 2,3- dihydroxypropyl 2- bromine 2 Methylpropionic acid esters (2,3-dihydroxypropyl 2-bromo-2-methylpropanoate, 21mg, 0.087mmol) and NIPAM (0.79g, 7mmol).It is transferred the solution into after vacuum suction nitrogen charging in vacuum reaction pipe (No. 2), 30 minutes (Qiang is stirred to react at 0 DEG C Zhang,Paul Wilson,Zaidong Li et al,Aqueous Copper-Mediated Living Polymerization:Exploiting Rapid Disproportionation of CuBr with Me₆TREN[J] .J.Am.Chem.Soc.,2013,135:7355-7363)。

In the above method, atom transfer radical polymerization uses cuprous bromide for catalyst, and reaction speed is slow, product molecule Amount distribution is wide；And single electron transfer-active free radical polymerization is disproportionated in water using cuprous bromide, using copper powder as catalyst Cause, although solving, atom transition free radical polymerization reaction speed is slow, and molecular weight of product is distributed wide problem, it only makes Caused with small molecule initiator；If single electron transfer-the active free radical polymerization caused using small molecule initiator, can only close Synthesizing polyethylene glycol chain is unable at the n-isopropyl acrylamide segment in polyethylene glycol-b- (n-isopropyl acrylamide) Section；And remnant oxygen can also generate stable oxygen radical with radical reaction during the polymerization-filling, and reaction is hindered to carry out, The problems such as cuprous bromide catalyst is unstable in air totally makes the system for the poor resistance of oxygen.

To solve the above-mentioned problems, molecular weight distribution is relatively narrow, target molecular weight is relatively controllable to acquire by the present invention Polyethylene glycol-b- poly(N-isopropylacrylamide), the oxygen tolerance for improving reaction system are target, propose a kind of use The high-efficiency synthesis method of easily stored raw material.

Summary of the invention

Based on background above technology, it is living that the present invention provides a kind of polyethylene glycol-b- poly(N-isopropylacrylamide) surface Property agent and its synthesis and application, the shortcomings that the method overcome traditional SET-LRP oxygen poor resistances, be a kind of reaction speed Fastly, high conversion rate, the narrow method of product molecular weight distribution.

The synthetic method that the present invention uses is the improvement carried out on the basis of SET-LRP method, uses copper bromide original position Reduction generates cuprous bromide and is reacted rather than be directly used in cuprous bromide catalyst unstable in air, improves reaction Stability；Simultaneously because the addition of reducing agent ascorbic acid, the remnant oxygen that can not eliminate in reduction system prevents oxygen Stable oxygen radical is formed during the reaction and then hinders free radical polymerization, so that reaction system has certain oxygen resistance to By property.The type of block copolymer can be also further expanded using the traditional small molecule initiator of macromole evocating agent replacement.

The LCST for the temperature response type surfactant polyethylene-b- poly(N-isopropylacrylamide) that the present invention synthesizes Highest can achieve 65 DEG C, therefore can meet the particular surroundings requirement that demulsification and emulsification are realized under higher temperature.

In order to achieve the goal above, the invention adopts the following technical scheme:

The present invention provides a kind of synthetic method of polyethylene glycol-b- poly(N-isopropylacrylamide) surfactant, packet Include following steps:

The synthesis of S1, polyethylene glycol macromole evocating agent；

The synthesis of S2, polyethylene glycol-b- poly(N-isopropylacrylamide)；

By the aqueous solution containing polyethylene glycol macromole evocating agent and n-isopropyl acrylamide monomer and contain bromination The aqueous solution of copper, ascorbic acid and three (2- dimethylaminoethyl) amine carries out deoxygenation respectively；

The two is mixed in ice bath and is reacted；After reaction, reaction solution is post-treated obtains product polyethylene glycol-b- Poly(N-isopropylacrylamide).

Preferably, the polyethylene glycol-b- poly(N-isopropylacrylamide) surfactant contains polyethylene glycol simultaneously Segment and poly(N-isopropylacrylamide) segment；Wherein, the degree of polymerization of polyethylene glycol segment is 45, poly- (N- isopropyl propylene Amide) segment the degree of polymerization be 20-200.

Preferably, the degree of polymerization of the poly(N-isopropylacrylamide) segment is 17-38 or 50-200.

Preferably, when the degree of polymerization of poly(N-isopropylacrylamide) segment is within the scope of 17-35, the poly- second two The LCST of alcohol-b- poly(N-isopropylacrylamide) reaches 45 DEG C or more, and highest can achieve 65 DEG C.

In synthetic method of the invention, the synthetic reaction equation of polyethylene glycol macromole evocating agent in S1 are as follows:

Polyethylene glycol and triethylamine (TEA) are dissolved in tetrahydrofuran (THF), ice-water bath stirring instills 2- bromine isobutyl The tetrahydrofuran solution of acylbromide is reacted；

Liquid is filtered after reaction, takes filtrate revolving to remove most of tetrahydrofuran, remaining liq is in low temperature ether Middle precipitating；It filters and removes ether, precipitating is drying to obtain polyethylene glycol macromole evocating agent.

Preferably, the molar ratio of the polyethylene glycol and 2- bromine isobutyl acylbromide is 1:2~1:4.

Preferably, the 2- bromine isobutyl acylbromide and the molar ratio of triethylamine are 1:1~1:2.

Polyethylene glycol is reacted with 2- bromine isobutyl acylbromide to carry out in ice-water bath, causes temperature to increase to prevent from reacting too fast, Side reaction aggravation.Preferably, the control of ice water bath temperature is at 0~15 DEG C, the reaction time 24~48 hours.

In the above polyethylene glycol macromole evocating agent purification process:

The pressure of revolving is preferably 1~100KPa, and temperature is 30~100 DEG C.When being precipitated in low temperature ether, low temperature ether temperature Preferably -20~0 DEG C of degree.

In synthetic method of the invention, the synthetic reaction side of polyethylene glycol-b- poly(N-isopropylacrylamide) in S2 Formula are as follows:

By the aqueous solution containing polyethylene glycol macromole evocating agent and n-isopropyl acrylamide monomer and contain bromination The aqueous solution of copper, ascorbic acid and three (2- dimethylaminoethyl) amine carries out deoxygenation respectively；The two is mixed in ice bath and is carried out Reaction；After reaction, reaction solution is dialysed, is drying to obtain product polyethylene glycol-b- poly(N-isopropylacrylamide).

Reducing agent ascorbic acid and copper bromide reaction raw materials are than depending on after deoxygenation in water depending on residual oxygen tolerance, three (2- of ligand Dimethylaminoethyl) amine and copper bromide feed molar ratio should be higher than that complexation reaction stoichiometric ratio, so that copper catalyst forms network completely Close object.

Preferably, the molar ratio of copper bromide and ascorbic acid is 1:0.8~1:1.2 in charging.

Preferably, the molar ratio of copper bromide and three (2- dimethylaminoethyl) amine is 1:0.5~1:3.

Preferably, the molar ratio of polyethylene glycol macromole evocating agent and copper bromide is 1:2~10:1.

N- isopropyl acrylamide needed for polyethylene glycol macromole evocating agent and n-isopropyl acrylamide monomer mole ratio regard Depending on the amine degree of polymerization, n-isopropyl acrylamide feeding quantity is 0.8~1.2 times of its target polymerization topology degree feeding quantity.

Reaction needs to carry out catalyst system and raw material deoxygenation operation respectively before carrying out；Skilled addressee readily understands that , the operation of protection gas is filled in the deoxygenation using common pumping.Preferably, air suction process pressure is 20Pa~1KPa, time 5-30min is evacuated-fills protection gas and operates number of repetition 1-5 times.The protection gas is nitrogen or inert gas, such as helium.

S2 reaction process needs to remove the heat generated in time, it is preferable that ice water bath temperature is 0~20 DEG C.

Preferably, post-processing described in S2 includes distilled water dialysis and drying.

In the purification process of polymer polyethylene glycol-b- poly(N-isopropylacrylamide):

In distilled water dialysis procedure, it is preferable that 2~14 days time of the dialysis changed water frequency every 2~24 hours one It is secondary.Skilled addressee readily understands that, the molecular cut off of dialysis simply needs to be less than molecular weight of product, and product is enabled not to be lost .

In product drying process, it is preferable that select freeze-drying, freeze-drying pressure is 15Pa~1KPa, and temperature is -20 ~-50 DEG C, the time is 6~48 hours.

In method of the invention, n-isopropyl acrylamide monomer conversion is more than up to 100%, total yield of products 30%, the reaction time shortened within 2 hours, improved combined coefficient；It replaces cuprous bromide to be reacted with copper bromide, overcomes Raw material disadvantage easy to oxidize in storing process.Poly- (the N- isopropyl acrylamide of polyethylene glycol-b- synthesized using the present invention Amine) it can be used for oil exploitation, the multiple fields such as drug delivery are a kind of novel temperature sensitive type surfactants.

Another aspect of the invention provides poly- (the N- isopropyl propylene of the polyethylene glycol-b- that the above synthetic method is prepared Amide) surfactant.

Preferably, the polyethylene glycol-b- poly(N-isopropylacrylamide) surfactant contains polyethylene glycol simultaneously Segment and poly(N-isopropylacrylamide) segment；Wherein, the degree of polymerization of polyethylene glycol segment is 45, poly- (N- isopropyl propylene Amide) segment the degree of polymerization be 17-200.

Preferably, the degree of polymerization of the poly(N-isopropylacrylamide) segment is 17-38 or 50-200.

The LCST of the surfactant is influenced by the poly(N-isopropylacrylamide) segment degree of polymerization, which gets over Small, LCST temperature is higher.

When the poly(N-isopropylacrylamide) segment degree of polymerization is within the scope of 17-35, LCST can achieve 45 DEG C or more, Highest can achieve 65 DEG C.In aqueous solution, which can (45 DEG C or more) realization hydrophilies and two at relatively high temperatures Switching between parent's property.

Another aspect of the present invention provides above-mentioned polyethylene glycol-b- poly(N-isopropylacrylamide) surfactant in stone Application in oil exploitation, drug delivery field.

Detailed description of the invention

Fig. 1 is the polyethylene glycol prepared in embodiment 1₄₅- b- poly(N-isopropylacrylamide)₁₀₀'s¹H NMR(D₂O, 500MHz) spectrogram.

Fig. 2 is the polyethylene glycol prepared in embodiment 1₄₅- b- poly(N-isopropylacrylamide)₁₀₀Infrared spectrum.

Fig. 3 is the polyethylene glycol of 5g/L in embodiment 4₄₅- b- poly(N-isopropylacrylamide)₃₅The LCST of solution schemes.

Specific embodiment

In order to illustrate more clearly of the present invention, below with reference to preferred embodiment, the present invention is described further.Ability Field technique personnel should be appreciated that following specifically described content is illustrative and be not restrictive, this should not be limited with this The protection scope of invention.