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阿司匹林的制备实验改进暨绿色合成方法探索  Experimental Improvement of Aspirin Preparation and Exploration of Green Synthesis Method

  Geng Yidi, Dong Yingying, Zhang Yurong, Gao Kefu, Jiang Xiaolei, Hu Fangdong
(School of Chemistry and Chemical Engineering, Linyi University, Linyi 276000, Shandong, China)

  abstract

摘 要：阿司匹林的制备是有机化学实验教学的经典内容之一。在大部分有机化学实验教材中，使用浓硫酸作为催化剂，而浓硫酸具有强氧化性和腐蚀性，不利于学生操作；同时反应原料乙酸酐作为溶剂使用，实验结束后通过水解法除去过量的乙酸酐，造成试剂浪费和环境污染。基于绿色环保理念，该实验选择无毒、绿色环保、可重复使用的 Amberlyst © 15 离子交换树脂作为催化剂，可以减少乙酸酐的用量，经条件优化在室温下以产率合成了阿司匹林，实现了阿司匹林制备实验的改进，探索了阿司匹林的绿色合成方法。该实验不仅可以提升学生的综合实验能力和环保意识，还能激发学生的创新思维和对科学研究的兴趣。
Abstract: The preparation of aspirin is one of the classic contents of organic chemistry laboratory teaching. In most organic chemistry laboratory textbooks, concentrated sulfuric acid is used as a catalyst, and concentrated sulfuric acid has strong oxidizing and corrosive properties, which is not conducive to students' operation. At the same time, acetic anhydride, the raw material of the reaction, is used as a solvent, and the excess acetic anhydride is removed by hydrolysis after the experiment, resulting in reagent waste and environmental pollution. Based on the concept of green environmental protection, the non-toxic, green and reusable Amberlyst © 15 ion exchange resin was selected as the catalyst, which could reduce the amount of acetic anhydride, and the 85 % 85 % 85%85 \% aspirin was synthesized at room temperature at room temperature with yield after optimization, which realized the improvement of aspirin preparation experiments and explored the green synthesis method of aspirin. The experiment can not only improve students' comprehensive experimental ability and environmental awareness, but also stimulate students' innovative thinking and interest in scientific research.

关键词：阿司匹林;Amberlyst © 15 离子交换树脂;实验改进;绿色合成方法 中图分类号：O62;G64 文献标识码：A doi：10.3969/j. issn.1672-4305.2024.01.009
CLC:O62; G64 Document ID: A doi:10.3969/j. issn. 1672-4305.2024.01.009

  Improvement of aspirin preparation experiments and exploration of green synthesis methods


Geng Yidi, Dong Yingying, Zhang Rongrong, Gao Kefu, Jiang Xiaolei, Hu Fangdong


( School of Chemistry and Chemical Engineering, Linyi University, Linyi 276000, China)

  abstract


The preparation of aspirin is one of the classic contents of organic chemistry laboratory teaching. In most organic chemistry laboratory textbooks, concentrated sulfuric acid is used as a catalyst. However, concentrated sulfuric acid is highly oxidizing and corrosive, which is not conducive to the operation of students. At the same time, the reaction raw material acetic anhydride is used as the solvent, and the excess acetic anhydride is removed by water after the experiment, resulting in reagent waste and environmental pollution. Based on the concept of green chemistry, the non-toxic, green and reusable Amberlyst © 15 ion exchange resin was selected as the catalyst for this experiment, which can reduce the amount of acetic anhydride. After optimizing the conditions, synthetic aspirin 85 % 85 % 85%85 \% yields at room temperature. Thus, the experiment realized the improvement of the aspirin preparation experiment, and at the same time explored the green synthesis method of aspirin. This experiment can not only enhance students' comprehensive experimental ability and environmental awareness, but also stimulate students' innovative thinking and interest in scientific research.


Key words: aspirin; Amberlyst © 15 ion exchange resin; experimental improvements; Green synthesis method

About author:Yidi Geng is an undergraduate student with research interests in organic synthetic chemistry. E-mail:3451603026@qq.com

Corresponding author: Fangdong Hu, Ph.D., associate professor, research direction of organic synthetic chemistry.邮箱：hufangdong@ lyu.edu.cn

Funds: Funded by the Curriculum Ideological and Political Research Center of Shandong Colleges and Universities (Project No.: SZ2023008); Linyi University Education Reform Project (Project No.: JG2021M09; T2021SZ004）。

Aspirin, also known as acetylsalicylic acid, was first synthesized by Frederick Gérard in 1853 and used in the clinic by Dreiserr in 1899, and the drug has a history of more than 100 years. Aspirin, along with penicillin and diazepam, is still the most widely used antipyretic, analgesic and anti-inflammatory drug [ 1 − 2 ] [ 1 − 2 ] ^([1-2]){ }^{[1-2]} in the world, and it is also used as a standard preparation for comparing and evaluating other drugs. Aspirin not only has the above effects, but also has a positive effect on blood

Platelet aggregation has an inhibitory effect on preventing thrombosis, and is clinically used to prevent the formation of thrombosis after transient ischemic attack, myocardial infarction, prosthetic heart valve and venous fistula or other surgeries. Therefore, aspirin is a widely used drug, and its synthesis has important application value [ 3 ] [ 3 ] ^([3]){ }^{[3]} .

As a classic organic chemistry experiment, the synthesis of aspirin, i.e., acetylsalicylic acid, is an experimental project often done by chemistry and pharmacy majors, which plays an important role in promoting the training of students' basic experimental operation skills. [ 5 − 6 ] [ 5 − 6 ] ^([5-6]){ }^{[5-6]} [ 4 ] [ 4 ] ^([4]){ }^{[4]} At present, aspirin is synthesized by esterification of phenol and anhydride in domestic organic chemistry laboratory textbooks, using concentrated sulfuric acid as a catalyst, and using salicylic acid and acetic anhydride as raw materials. [ 7 − 8 ] [ 7 − 8 ] ^([7-8]){ }^{[7-8]} However, under the catalysis of concentrated sulfuric acid, the reactants need to be 80 ∼ 90 ∘ C 80 ∼ 90 ∘ C 80∼90^(@)C80 \sim 90^{\circ} \mathrm{C} heated 5 ∼ 10 min 5 ∼ 10 min 5∼10min5 \sim 10 \mathrm{~min} in a water bath, at which a certain amount of salicylic acid polymerization by-products will be generated, resulting in a low yield of the target product aspirin ( 60 % ∼ 70 % 60 % ∼ 70 % 60%∼70%60 \% \sim 70 \% ). [ 9 ] [ 9 ] ^([9]){ }^{[9]} 。 Although the amount of concentrated sulfuric acid used in this reaction is not much, due to the failure of concentrated sulfuric acid to be reused, it will still cause reagent waste and environmental pollution when conducting a large number of undergraduate basic experiments. In addition, concentrated sulfuric acid is highly oxidizing and corrosive, which will corrode equipment, and is not conducive to student operation, so it is less safe. In addition, the acetic anhydride added in the reaction is not only used as a substrate for the reaction, but also as a solvent for the reaction, it is greatly excessive, and the excess acetic anhydride needs to be removed by water in the post-treatment process, and a large amount of acetic acid will be generated in the process, and the smell is larger, causing certain harm to students. Therefore, it is important to find a green, reusable catalyst and synthesize aspirin under mild conditions. [ 10 − 11 ] [ 10 − 11 ] ^([10-11]){ }^{[10-11]} In this improvement experiment, we used green and pollution-free Amberlyst © 15 ion exchange resin instead of concentrated sulfuric acid as a catalyst to successfully prepare aspirin at room temperature with a high yield, which realized the improvement of aspirin preparation experiments in organic chemistry laboratory textbooks, and systematically explored the synthesis conditions of aspirin. Based on the concept of green chemistry, this improved method reduces reagent pollution and improves the safety of experiments, which is conducive to enhancing students' awareness of environmental protection and ecological civilization, and has important reference significance and application value for the industrial production of aspirin.

  1 Purpose of the experiment

  (1) Learn the principles and methods of aspirin preparation;
  (2) Master the operation technology of recrystallization using mixed solvents;

(3) Master the basic experimental operations such as vacuum filtration, washing, drying and melting point determination.

2 实验原理


With salicylic acid and acetic anhydride as reaction raw materials, salicylic acid is a bifunctional compound with phenolic hydroxyl and carboxyl groups, through which phenols are found in salicylic acid

The esterification of hydroxyl groups with acetic anhydride is synthesized into acetylsalicylic acid, i.e., aspirin (see Figure 1). Since the carboxyl and hydroxyl groups in the salicylic acid molecule form intramolecular hydrogen bonds, the reactivity of the phenolic hydroxyl group is reduced. Amberlyst © 15 ion exchange resin can break the hydrogen bonds within the salicylate molecule and improve the reactivity of phenolic hydroxyl groups, so that salicylic acid and acetic anhydride can be esterified smoothly to synthesize acetylsalicylic acid. During the reaction, the salicylic acid molecule itself can undergo an esterification reaction to form dimeric and multimeric by-products (see Figure 1); In addition, salicylic acid and acetylsalicylic acid can also undergo esterification reactions to give acetylsalicylate salicylate, and these by-products can be removed during the recrystallization step. At the end of the reaction, a small amount of salicylic acid may remain in the target product, which may be due to incomplete reaction or hydrolysis of acetylsalicylic acid during separation and purification. In order to detect whether the final target product contains salicylic acid, the phenolic hydroxyl group in the salicylic acid can be used to test the color-developing properties of the ferric chloride solution.
  Fig.1 Synthesis of aspirin and its side effects

3 实验部分

3.1 试剂


Salicylic Acid ( 99 % 99 % 99%99 \% , Sarn Chemical Technology Co., Ltd.), Amberlyst © 15 Ion Exchange Resin (Dry Type, Sarn Chemical Technology Co., Ltd.), Acetic Anhydride (AR, Sinopharm Chemical Reagent Co., Ltd.), Petroleum Ether (AR, Tianjin Yongda Chemical Reagent Co., Ltd.), Ethyl Acetate (AR, Tianjin Yongda Chemical Reagent Co., Ltd.), Ethanol (AR, Tianjin Yongda Chemical Reagent Co., Ltd.).

3.2 仪器

圆底烧瓶，茄形瓶，砂芯漏斗，锥形瓶，量筒，展开缸，天平，磁子，磁力搅拌器，旋转蒸发仪，干燥箱，熔点仪（SGW X-4，上海仪电物理光学仪器有限公司），气相色谱-质谱联用仪（TSQ 8000EV，美国 Thermo Fisher Scientific 公司），核磁共振波谱仪（德国 Bruker AVANCE400 型核磁共振波谱仪）。

3.3 实验步骤


1.38 g of salicylic acid, a certain amount of Amberlyst © 15 ion exchange resin were placed in a dry 50 mL round-bottom flask, 5 mL of solvent, 1.43 mL of acetic anhydride and a magnet were added, the 50 mL round-bottom flask was placed on a magnetic stirrer, the reaction temperature was set, the stirring was started, the rotation speed was adjusted, and the reaction was passed by thin layer chromatography (the developing agent is petroleum ether:ethyl acetate = 2 : 1 = 2 : 1 =2:1=2: 1 ) after 2 hours The reaction progress was detected, at which point the salicylic acid basically disappeared, and a large number of white solids appeared in the round-bottom flask, and the reaction was stopped.

Add an appropriate amount of absolute ethanol to the round-bottom flask to completely dissolve the white solids, use a sand core funnel for decompression filtration, wash the round-bottom flask and Amberlyst © 15 ion exchange resin three times with a small amount of absolute ethanol, collect the filtrate, and recover the Amberlyst © 15 ion exchange resin. The ethanol solvent in the filtrate is removed by a rotary evaporator to obtain a white solid, which is a crude product. The crude product was transferred to a 50 mL Erlenmeyer flask, 8 mL of ethanol was added, the pheasant flask was 70 ∘ C 70 ∘ C 70^(@)C70^{\circ} \mathrm{C} heated in a water bath, and when all the white solids disappeared, 30 mL of distilled water was added to the round-bottom flask, shaked evenly, and cooled in an ice bath for 30 min, a large number of white crystals appeared in the Erlenmeyer flask, and the sand core funnel was used for decompression filtration, washed twice with cold water, and the water was drained as much as possible, and the solids were transferred to the round-bottom flask. Place it on a rotary evaporator to remove a small amount of residual water, dry it in an oven to obtain a white solid, weigh it, and calculate the yield. A small amount of the product was taken and its melting point was determined, and its purity and structure were characterized by gas chromatography-mass spectrometry and nuclear magnetic resonance spectrometer. In addition, a small amount of product was taken to detect whether salicylic acid was left in the product through the color reaction with ferric chloride solution.

4 实验结果与讨论

4.1 反应条件优化


1.38 g of salicylic acid, 100 mg of Amberlyst © 15 ion exchange resin, 5 mL of solvent, 1.43 mL of acetic anhydride and one magneton were added to a 50 mL round-bottom flask, stirred at room temperature for 2 hours, and the effect of solvent on aspirin yield was screened, and the experimental results are shown in Table 1. When ethyl acetate is used as the reaction solvent, the target product can be obtained in 78 % 78 % 78%78 \% the yield of . When the reaction solvent was changed to dichloromethane and acetonitrile, the yield decreased slightly. When acetone is used as the reaction solvent, the reaction effect is poor, and the target product can only be obtained at 29 % 29 % 29%29 \% the yield of . When chloroform is used as a reaction solvent, the target product can be obtained in 47 % 47 % 47%47 \% the yield of . When ether, tetrahydrofuran and dioxane were used as reaction solvents, the target products were obtained in 52 % 52 % 52%52 \% 41 % 41 % 41%41 \% yields of , and 59 % 59 % 59%59 \% , respectively . From the above experimental results, it can be concluded that ethyl acetate is the best solvent for this reaction.
  Table 1 Effect of solvent on yield
  serial number   solvent   Yield/%
1   ethyl acetate 78
2   dichloromethane 75
3   Acetonitrile 76
4   acetone 29
5   chloroform 47
6   ethyl ether 41
7   Tetrahydrofuran 52
8   Dioxane 59
序号 溶剂 产率/% 1 乙酸乙酯 78 2 二氯甲烷 75 3 乙腈 76 4 丙酮 29 5 氯仿 47 6 乙醚 41 7 四氢呋喃 52 8 二氧六环 59| 序号 | 溶剂 | 产率/% | | :---: | :---: | :---: | | 1 | 乙酸乙酯 | 78 | | 2 | 二氯甲烷 | 75 | | 3 | 乙腈 | 76 | | 4 | 丙酮 | 29 | | 5 | 氯仿 | 47 | | 6 | 乙醚 | 41 | | 7 | 四氢呋喃 | 52 | | 8 | 二氧六环 | 59 |

The effect of basket reaction temperature on aspirin yield was shown in Table 2 when 1.38 g of salicylic acid, 100 mg of Amberlyst © 15 ion exchange resin, 5 mL of ethyl acetate, 1.43 mL of acetic anhydride, and a magneton were added to a 50 mL round-bottom flask. When the reaction is at room temperature and 40 ∘ C 40 ∘ C 40^(@)C40{ }^{\circ} \mathrm{C} reaction, the target product can be obtained in 78 % 78 % 78%78 \% the yield of . When the reaction temperature is increased to 50 ∘ C 50 ∘ C 50^(@)C50{ }^{\circ} \mathrm{C} and 60 ∘ C 60 ∘ C 60^(@)C60^{\circ} \mathrm{C} , the yield of the target product is and 75 % 75 % 75%75 \% , respectively 74 % 74 % 74%74 \% ; When the reaction temperature 70 ∘ C 70 ∘ C 70^(@)C70{ }^{\circ} \mathrm{C} is further increased , the yield is reduced to 61 % 61 % 61%61 \% . From the above reaction results, it can be seen that when the temperature is lower than 60 ∘ C 60 ∘ C 60^(@)C60{ }^{\circ} \mathrm{C} , the reaction temperature has little effect on the yield, and when the reaction reaches 70 ∘ C 70 ∘ C 70^(@)C70{ }^{\circ} \mathrm{C} , the yield decreases significantly. In general, the increase in reaction temperature leads to a decrease in yield, which may be due to an increase in side reactions due to an increase in reaction temperature.
  Table 2 Effect of reaction temperature on yield
  serial number   Reaction temperature / ∘ C / ∘ C //^(@)C/{ }^{\circ} \mathrm{C}   Yield / % / % //%/ \%
1 R. T. 78
2 40 78
3 50 74
4 60 75
5 70 61
序号 反应温度 //^(@)C 产率 //% 1 r. t. 78 2 40 78 3 50 74 4 60 75 5 70 61| 序号 | 反应温度 $/{ }^{\circ} \mathrm{C}$ | 产率 $/ \%$ | | :---: | :---: | :---: | | 1 | r. t. | 78 | | 2 | 40 | 78 | | 3 | 50 | 74 | | 4 | 60 | 75 | | 5 | 70 | 61 |

The effect of basket catalyst dosage on aspirin yield is shown in Table 3 by adding 1.38 g of salicylic acid, a certain amount of Amberlyst © 15 ion exchange resin, 5 mL ethyl acetate, 1.43 mL of acetic anhydride, stirring for 2 hours at room temperature, and the effect of basket selection catalyst dosage on aspirin yield. When using 100 mg of catalyst, the yield of aspirin was 78 % 78 % 78%78 \% ; On this basis, the amount of catalyst was reduced to 50 mg, and the yield of the target product was reduced to 44 % 44 % 44%44 \% ; The yield of the target product was increased to 150 mg and the yield of the target product was increased to 85 % 85 % 85%85 \% 200 mg. In summary, under the condition of 150 mg catalyst, good solidification can be obtained