Microwave-Assisted Aspirin Synthesis from Over-the-Counter Pain

Downloaded by PURDUE UNIV on November 25, 2016 | http://pubs.acs.org Publication Date (Web): November 16, 2016 | doi: 10.1021/bk-2016-1233.ch006

Chapter 6

Microwave-Assisted Aspirin Synthesis from Over-the-Counter Pain Creams Using Naturally Acidic Catalysts: A Green Undergraduate Organic Chemistry Laboratory Experiment J. T. Fahey,*,1 A. E. Dineen,1 and J. M. Henain1 1Division

of Natural Science, Mount Saint Mary College, 330 Powell Ave., Newburgh, New York 12550, United States *E-mail: [email protected]

The synthesis of aspirin using H2SO4 or H3PO4 is a common undergraduate organic laboratory experiment. Replacing these potentially harmful, strong acids with naturally acidic soft drinks or fruit juices demonstrates the use of green chemistry guidelines to undergraduate students. Isolation of methyl salicylate from over-the-counter pain creams, and subsequent conversion to aspirin was explored. Salicylic acid, obtained via hydrolysis of the methyl salicylate, was converted to aspirin using soft drinks or fruit juices as catalysts in a microwave synthesis. Average yields were 55%, but individual yields depended on the soft drink/juice used as a catalyst. The successful synthesis was tested with first-semester undergraduate organic chemistry students as a multi-week experiment. Results are discussed.

Introduction The traditional focus during the first-semester of organic chemistry is teaching various techniques used to synthesize organic molecules and performing simple synthesis reactions. In most organic chemistry laboratory manuals, synthesis reaction experiments are typically “cookbook” in nature, providing a specific list of instructions for the students to follow. Upon anecdotal observation, students do not show any personal interest/vestment in the experiments. The © 2016 American Chemical Society Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


hypothesis derived from this observation is that if the experiments could be made more memorable, applicable, and practical to students, their interest, and success would improve. One way of improving success is to have students synthesize a compound, i.e. aspirin, which many people use for pain relief, to reduce an elevated body temperature, or to reduce joint inflammation. The synthesis of aspirin is a common synthesis experiment performed in an undergraduate organic chemistry laboratory. Many organic chemistry laboratory manuals use conventional methods of aspirin synthesis from salicylic acid and acetic anhydride (Figure 1) utilizing acid catalysts (H2SO4 or H3PO4) under reflux to obtain high yields (1, 2).

Figure 1. The traditional synthesis of aspirin typical in undergraduate laboratory manuals. However, according to the Safety Data Sheets, sulfuric and phosphoric acids are highly corrosive and very hazardous in case of skin contact, and may produce burns (3, 4). After observing multiple students burn themselves using these acids, a safer, greener alternative was sought. In addition, a pathway for even higher yields was also sought. The initial idea was to replace the traditional reflux with microwave conditions, and to use naturally acidic sodas and juices as catalysts, replacing sulfuric or phosphoric acid. Microwave irradiation in organic synthesis has become common, offering benefits including improving product yields, decreasing reaction time, and improving efficiency while reducing cost (5). Microwave ovens used for irradiating chemical reactions can range from a standard household microwave oven to an industrial microwave specifically designed for chemical reactions in the organic chemistry laboratory. Microwave irradiation leads to new pathways to perform reactions, such as solvent free reactions (6) and the use of less hazardous materials (7). Green chemistry has increasingly become an area of interest both in industry and in academia. One of the primary goals of green chemistry is to eliminate or reduce the use of hazardous chemicals either by alteration of the experimental procedure or by substitution with less hazardous chemicals or water (8, 9). This proposed synthesis experiment is a greener approach to previous microwave synthesis experiments for aspirin as well as other analgesic drugs (10). The proven microwave syntheses of asprin used multiple catalysts, including H2SO4, H3PO4, MgBr2·OEt2, AlCl3, CaCO3, NaOAc, NEt3, and DMAP (11) 94 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


with yields of aspirin ranging from 55% to 97%. Initially, a greener synthesis of aspirin was investigated using an over-the-counter analgesic pain cream with methyl salicylate as an active ingredient (Figure 2) to provide salicylic acid for the reaction. Results showed that the extraction of methyl salicylate from Tylenol™ Precise pain cream (12) and the use of soda and juice catalysts allowed for a range of yields comparable to the traditional method, with applicability, practicality, memorability, and an increase in safety for the students.

Figure 2. Conversion of methyl salicylate isolated from pain cream to aspirin using natural catalysts and microwave irradiation. During the course of the research and despite initial success with this procedure, the production of Tylenol™ Precise pain cream was discontinued. Additional pain creams such as IcyHot® and Bengay® were investigated; however, they failed to produce pure aspirin in a comparable percent yield. Therefore, the research focused on the use of naturally acidic sodas and juices as catalysts in the conversion of salicylic acid to aspirin using microwave irradiation. Various techniques, concepts, and reactions are introduced to students during this experiment (whether pain cream or pure salicylic acid is used as a starting material). Students practice techniques including extraction, reflux, and melting point determination. Additionally, students are introduced to the concept of microwave chemistry and its benefits over conventional heating. If using pain cream as a starting material, students will also learn about base-promoted ester cleavage (methyl salicylate to salicylic acid) and acid-catalyzed esterification (salicylic acid to aspirin) reactions. Analysis of product using infrared (IR) spectroscopy and melting point apparatus provides students with further hands-on experience. Lastly, they are familiarized with green chemistry and its future in the scientific community.

Experimental Procedure When starting with pain cream, the experiment can be completed over four laboratory periods (one lab per week). The first week of the procedure calls for a synthesis of salicylic acid from methyl salicylate using OTC pain cream (Tylenol™ Precise). Students weigh approximately 17 g of Tylenol™ Precise pain cream and mix it vigorously with methanol. The mixture is then vacuum filtered to separate the inactive ingredients, and the filtrate (methyl salicylate and methanol) is then placed on a hot plate to evaporate the methanol solvent. Students use 95 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


methyl tert-butyl ether (MTBE) as a solvent with a separatory funnel to separate the menthol and the methyl salicylate in the filtrate from each other. Once the extraction is complete, students let the methyl salicylate sit for one week (due to time constraints) and then weigh their product. During the second week, the methyl salicylate is refluxed in NaOH solution and then transferred, cooled, and acidified with HCl solution. A white precipitate (salicylic acid) should form, but scratching and letting the crystals sit over ice should further induce crystallization. The precipitate is then collected via vacuum filtration and left to dry until the following week. If pain cream is not available, the experiment can be started from this point using pure salicylic acid. Without the availability of the pain cream, the experiment can be shortened to two weeks. Approximately 1.4 g of salicylic acid is added to a microwave tube with 2.8 mL acetic anhydride and 5 drops of concentrated soda or juice catalyst (students carefully boil catalyst solution until half the original volume remains). For our experiment, each pair of students works with a different soda or juice (Table 1). The microwave used is a MARS CEM industrial chemical microwave. The aspirin synthesis is programmed to run at 400 Watts, 100% power. The microwave takes 5 minutes to ramp up to temperature and then is held at a constant temperature for 10 minutes (150 °C). After 10 minutes the microwave automatically cools the samples down for an additional 10 minutes; the reaction takes a total time of 25 minutes. Once out of the microwave, students’ mixtures are poured into beakers and allowed to cool. Water is added once the mixture is cool and crystallization is induced. The mixture is then allowed to sit until the following week.

Table 1. Soda and juice catalysts used by researcher and student groups Root Beer

Grapefruit Juice

Sierra Mist™

Coke™

Orange Juice

Mountain Dew™

Diet Coke™

Lemon Juice

Pineapple Juice

Orange Soda

Diet Pepsi™

Lime Juice

Sprite™

Red Bull™

Dr. Pepper™

Pepsi™

During the fourth week, students isolate aspirin crystals via vacuum filtration and rinse with cold water to ensure all crystals are collected. Aspirin crystals are allowed to sit under vacuum for 15-20 minutes to ensure dryness. Dry crystals are weighed and subjected to IR analysis (Perkin Elmer Spectrum 100 with Universal ATR Sampling Accessory) and melting point determination. Additionally, students perform a ferric chloride test for purity. To perform the ferric chloride test, students add a small amont of pure salicylic acid, synthesized salicylic acid, pure aspirin, synthesized aspirin, water, and sometimes commercial aspirin each to 6 separate test tubes. To each tube, 1 mL of 0.1% solution of ferric chloride is added. Students record the changes in color in the tubes, red/purple for phenols present (indicating salicylic acid) and yellow for no phenols (indicating aspirin). [Note: the prepared aspirin can give a purple color due to presence of unreacted salicylic acid.] 96 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

Students have the option of doing a recrystallization to remove the impurities introduced from the soda or juice catalyst, which often cause discoloration in the aspirin. Recrystallization can be done with or without charcoal.


Results and Discussion This experiment was designed to provide students with a more efficient, greener pathway to synthesize aspirin. Initially, the experiment was designed to start with an over-the-counter pain cream as the source of methyl salicylate. The methyl salicylate would then be converted to salicylic acid, the traditional starting material for the synthesis of aspirin. Various brands of pain creams were initially investigated for their potential use in the experiment. Since each brand of pain cream has varying percentages of methyl salicylate, it was thought those creams with higher percentages of the active ingredient would provide higher yields of salicylic acid. Bengay® was used and shown to work previously in an experiment in Experimental Organic Chemistry (1). (Note: the original procedure used Original Strength Bengay® which only contains methyl salicylate and menthol as active ingredients. Currently, only Extra Strength Bengay® is commercially available, which contains a third active ingredient, camphor.) Six common pain creams, all containing methyl salicylate as an active ingredient, were investigated: Bengay® Extra Strength, IcyHot®, Tylenol Precise™, Mentholatum®, Thera-gesic®, and Nature Plex®. Analysis of results (Table 2) shows that only Bengay®, IcyHot®, and Tylenol Precise™ produced salicylic acid that could be converted to aspirin. Mentholatum® produced a low yield of salicylic acid, not enough to continue the conversion to aspirin. Thera-gesic® and Nature Plex® both appeared to produce salicylic acid, however, upon further analysis with melting point and IR spectroscopy it was determined that both had large amounts of sodium acetate present but not salicylic acid as expected.

Table 2. Percent yields and melting point data for aspirin obtained from various over-the-counter pain creams

97 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Only salicylic acid derived from Bengay®, IcyHot®, and Tylenol Precise™ was used in the subsequent conversion to aspirin. All three were successful in conversion to aspirin as confirmed with IR spectroscopy. However, upon analysis of the melting points, only Tylenol Precise™ provided results close to the actual melting point of aspirin. The extremely low melting point obtained for aspirin obtained from Bengay® and IcyHot® confirmed that the conversion to pure aspirin was unsuccessful. It was hypothesized that the presence of camphor as a third active ingredient could have interfered with the conversion of methyl salicylate to salicylic acid, and the reported percent yield of salicylic acid included unreacted camphor. It may be possible that the camphor further interfered with the conversion of any produced salicylic acid to aspirin. Further research must be done to determine the exact effect of the camphor in the reactions as well as possible ways to remove the camphor at the start. Until this research can be conducted, Bengay® and IcyHot® were omitted from use. It was therefore determined that Tylenol Precise™ pain cream was the only choice that would allow for successful conversion to salicylic acid with subsequent conversion to aspirin in high yield and higher purity as confirmed by IR spectroscopy, melting point, and nuclear magnetic resonance (NMR) analysis. To make the experiment greener, various soda and fruit juices were used in place of concentrated phosphoric or sulfuric acids during the conversion of salicylic acid to aspirin. A student researcher performed the reaction using both pure salicylic acid and pain cream derived salicylic acid for comparison. The results with three of the soda/juices are presented in Table 3.

Table 3. Yields of aspirin made from pure salicylic acid and from salicylic acid extracted from Tylenol Precise™ pain cream using various sodas and juices as a catalyst Aspirin Yield (%): from Pure Salicylic Acid

Aspirin Yield (%): using Salicylic Acid prepared from Pain Cream

Orange Juice

81.40

73.62

Diet Pepsi™

78.86

69.43

Coke™

83.16

75.30

Catalyst

Although pure salicylic acid consistently produced significantly higher yields of aspirin (p

Microwave-Assisted Aspirin Synthesis from Over-the-Counter Pain

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