Synthesis of Aspirin - Semantic Scholar
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The Synthesis and Analysis of Aspirin
Department of Chemistry, American University, Washington, D.C. 20016 Date of Publication: February 26, 2014
ABSTRACT: Acetylsalicylic acid commonly known as aspirin is the most widely used drug in the world today. Its analgesic, antipyretic, and anti-inflammatory properties make it a powerful and effective drug to relive symptoms of pain, fever, and inflammation. The purpose of this experiment was to synthesize aspirin by reacting salicylic acid and acetic anhydride in the presence of phosphoric acid to form acetylsalicylic acid. After synthesis, the sample of acetylsalicylic acid was purified by recrystallization and TLC analysis was utilized to check the purity of the sample. The actual yield of aspirin synthesized was 0.546 grams and the theoretical yield was 2.628 grams, thus the percent yield was 20.77% resulting in a percent error of 79.22%. The Rf values of crude product, salicylic acid, and recrystallized product were 0.590 and 0.897, 0.818, and 0.606 and 0.879 respectively. Due to these Rf values, it was brought to the conclusion that the crude and recrystallized aspirin were composed of both salicylic acid and acetylsalicylic acid.
Aspirin, chemically known as acetylsalicylic acid, is the most commonly used anti-inflammatory drug. It is effective in relieving symptoms of pain (analgesic) due to headaches, injury, or arthritis, treating fever (antipyretic) and inflammation, and preventing blood clots (1). It was extracted by the Native Americans from willow and poplar tree bark about 2500 years ago. Native Americans used willow bark in teas to reduce fever. In 1763, Reverend Edward isolated and identified one of the compounds used to synthesize aspirin, which came to be known as salicylic acid. Large quantities of salicylic acid became available; however,
it caused severe stomach irritation. In 1893, German chemist Felix Hoffman synthesized an ester derivative of salicylic acid, acetylsalicylic acid ("aspirin"). The acetyl group cloaks the acidity when ingested. The drug then passes through the small intestine where it gets converted back to salicylic acid, and enters the bloodstream. Although, weaker than salicylic acid, aspirin had medicinal properties without the bitter taste and harsh stomach irritation. The company Bayer patented aspirin in 1899, which has made aspirin one of the most widely used and commercially available drugs today (2).
Aspirin is a nonsteroidal anti-inflammatory drug (NSAID) which works to reduce levels of prostaglandins, chemicals released due to inflammation, pain, and fever. Prostaglandins are located on receptors of different cells types, thus having multiple effects. Cyclooxygenase is the enzyme that makes prostaglandins. NSAIDs inhibit the enzyme reducing the levels of prostaglandins, in turn reducing inflammation, fever, and pain. Aspirin is not only anti-inflammatory, but also analgesic and antipyretic. Prostaglandins carry out fever and pain by activating the hypothalamus, the portion of the brain that controls autonomic and endocrinal functions. Inhibiting prostaglandins suppresses fever and pain by stopping nerve signals that are sent to the brain. Suppression of prostaglandins also desensitizes the function of platelets and the ability of blood clots, thus aspirin's antithrombotic effects have been approved to prevent heart attacks and strokes (2).
Despite the medicinal and wonderful properties of aspirin, negative effects have been associated with this drug. Symptoms associated with aspirin include nausea, vomiting, rashes, swelling, and
hives. Aspirin can still cause stomach irritation resulting in the risk of internal bleeding and ulcers. Aspirin has also been known to interfere with platelet functioning and may cause Reyes syndrome in children (1).
Thin Layer Chromatography (TLC) is a technique used in organic chemistry to separate a mixture of organic compounds. TLC is also used to identify and determine the purity of a compound. Through capillary action, compounds can separate due to their different affinities for the mobile and stationary phases. The stationary phase in TLC is the adsorbent, which is coated on a sheet of metal, plastic or glass. It is usually silica or alumina; however, in this experiment silica was used. The mobile phase is the solvent which slowly rises due to capillary action and polarity. In this experiment the mobile phase was the 18:2 solution of ethyl acetate: methylene chloride, which is slightly polar. Different compounds travel at different rates and distance in respect to the solvent front. Polar stationary phases absorb polar compounds, thus silica being a polar stationary phase will absorb polar compounds. Nonpolar compounds will remain free and move with respect to the solvent front. The polarity of a compound is determined by its functional groups and masses. Salicylic acid is more polar than aspirin. Acetylsalicylic acid has ester and acetyl functional groups and has a larger mass than salicylic acid. Salicylic acid has a hydroxyl functional group. Hydroxyl groups are more polar than acetyl groups, thus salicylic acid will absorb to the silica more willingly than the acetylsalicylic acid due to hydrogen bonding. Furthermore, the acetylsalicylic acid will be in a free state and travel further because the ester and acetyl functional groups no longer have hydrogen bonds that bond to the polar silica plate. If a sample is composed of a mixture of compounds, they will separate into a series of sports along the TLC plate. If a sample is pure, only one spot will be displayed. The crude aspirin might have two different spots because it is not entirely pure. UV light is used to visualize the compounds on the plate. TLC results are expressed in Rf values. Rf is the distance traveled by the sample over the distance traveled by the solvent front (3).
In this experiment, aspirin will be synthesized by reacting acetic anhydride with salicylic acid in the presence of phosphoric acid. The reaction equation is displayed below. After synthesis, the sample will be purified by recrystallization methods. The purity of the sample will then be analyzed using TLC. The results section will present all the numerical data necessary for this experiment (synthesis of aspirin masses, theoretical yield, percent yield and error, and TLC analysis). After synthesis and analysis, it will be determined if the crude and recrystallized samples were composed solely of either salicylic acid, acetylsalicylic acid, or a combination of both (3). Figure 1: Reaction of Aspirin (Snelling, 2013)
MATERIALS AND METHODS Goggles Gloves Lab coat Salicylic Acid 50 mL Erlenmeyer Flask Acetic Anhydride 85% Phosphoric Acid 250 mL hot water bath Stirring rod Distilled Water 250 mL ice bath Vacuum filter apparatus 1 110-mm Filter paper 2 pieces of round filter paper 2 Watch glasses
125 mL Erlenmeyer Flask
10 mL Ethanol
400 mL beaker
Silica gel coated TLC plate
18 mL Ethyl acetate
2 mL methylene chloride
Part 1: Synthesize Aspirin
Goggles, lab coats, and gloves were obtained for protection and used throughout the entire experiment. The reaction described below was conducted under a fume hood. 2.0 grams of salicylic acid was placed into a 50mL Erlenmeyer flask along with 5.0 mL of acetic anhydride and 5 drops of 85% phosphoric acid solution. The mixture was handled with care and then swirled to rinse off any pieces of solid. A 70-80?C hot water bath was prepared using a 250 mL beaker. The mixture previously prepared was kept in its flask and submerged in the water bath. Stirring occasionally, the mixture was heated for 15 minutes, until it started to release vapors. 2 mL of distilled water was added 10 minutes into the heating process. Once the reaction reached completion and no vapors appeared, it was removed from the hot plate and 20 mL of distilled water was added. The mixture was then cooled to room temperature and then transferred into an ice bath for five minutes. Crystals of aspirin started to form as the mixture cooled. Once the mixture cooled, a vacuum filtration was set up. Filter paper was massed and recorded to the nearest 0.001 g before the solid was filtered. The mixture was then filtered with vacuum suction. After most of the liquid was drawn through the funnel, suction was turned off, and the crystals were washed with 5mL of cold, distilled water. After about 15 seconds, suction was turned back on and the crystals were washed with cold, distilled water two more times in the same procedure. After filtration, the dried recrystallized product along with the filter paper
was massed to 0.001g and recorded in the data table. The mass of the dry aspirin sample was calculated and recorded in the data table (3).
Part 2: Purification of Aspirin
1 g of crude crystals was set aside for TLC analysis in Part 3. The mass of the remaining crude was measured. The remaining crude was added to a 125 mL Erlenmeyer flask. Approximately 10 mL of hot solvent (ethanol/water) was added to the crude aspirin, which was then placed into a warm water bath until all crystals dissolved. Once the crystals dissolved, the mixture was taken out, covered with a watch glass and cooled slowly. When the solution reached room temperature, it was placed into an ice bath to complete the crystallization process. After about ten minutes in the ice bath, vacuum filtration was used again to filter the crystals. The crystals were rinsed with two 3mL portions of ice cold deionized water and one 2 mL portion of ice cold ethanol. After rinsing, the crystals were placed onto a tared watch glass (3).
Part 3: TLC Analysis
A developing chamber was prepared using a 400 mL beaker and watch glass. A piece of 110-mm filter paper with the bottom trimmed straight across was placed into the chamber in order to saturate the chamber with solvent vapors. 18 mL of ethyl acetate and 2 mL of methylene chloride were measured out and placed in to the 400 mL beaker and covered with the watch glass. Before introducing the TLC plate, the solvent traveled all the way to the top of the filter paper. In three separate small beakers, about 3mg each of salicylic acid, crude product, and recrystallized product was dissolved by placing 5-6 drops of TLC solvent in each beaker. The TLC plate was prepared by marking ? inch from the bottom and marking 3 hashes evenly spaced for each of the spotted compounds. The TLC plate was spotted (no more than 1/8 in diameter) with the salicylic acid, crude product, and recrystallized product at each hash mark making sure a different spotting pipette was used for each compound. Once the TLC plate was prepared, it was placed into the developing chamber and the watch glass was replaced on top. When the solvent front stopped
moving (approximately ? inch from the top), the plate was removed and the solvent front was immediately marked. It then was dried and examined under a UV light. Spots that were seen were circled and measured using the Rf calculation. The TLC solvent was discarded in the appropriate container and all materials were washed and placed back in their appropriate location (3).
RESULTS Table 1: Synthesis of Aspirin
Mass of Salicylic Acid Used (g)
Volume of Acetic Anhydride used (mL)
Mass of Acetic Anhydride used
Mass of Aspirin and filter paper (g)
Mass of filter paper (g)
Mass of aspirin synthesized (g)
Theoretical yield of aspirin
Table 2: TLC Analysis
Compound Distance Distance Rf
2.3 cm & 3.5 cm
Salicylic Acid 3.3 cm
2.7 cm 0.818
Recrystallized 3.3 cm
2.0 cm & 0.606 &
2.9 cm 0.879
Equation 1: Mass of acetic anhydride used
Mass of acetic anhydride
Equation 2: Mass of aspirin synthesized
=(mass aspirin & filter paper)-(mass filter paper)
Equation 3: Limiting Reagent
1 mol salicylic acid 2.015g Salicylic Acid x
5.40 g Acetic Anhydride x ! !"# !"#$%" !"#$%&'%(
*Salicylic Acid is the limiting reagent*
Equation 4: Theoretical Yield
1 mol acetyl salicylic acid moles of Salicylic Acid x
1 mol salicylic acid 180.16 g 1 mol acetyl salicylic acid
1 mol acetyl salicylic acid = 0.01459 mol Salicylic Acid x
1 mol salicylic acid
=2.628 g acetyl salicyl-
! !"# !"#$%& !"#$%$% !"#$
Equation 5: Percent Yield
Percent Yield: !.!"#$ x 100 = 20.77%
Equation 6: Percent Error
Percent Error: |!"#$!% !"#$%!!"#$%#!&'() !"#$%| x 100
Percent Error: | !.!"# ! !!.!"# ! | x 100= 79.22%
Equation 7: Rf
!"#$%&'( !"#$%& !"#$%&%' (!") !"#$%&'( !" !"#$%&' !"#$% (!")
Rf (Crude product, spot 1)=
!.! !" =0.590 cm
Rf (Crude product, spot 2)=
!.! !" =0.897 cm
Rf (Salicylic Acid)=
!.! !" =0.818 cm
Rf (Recrystallized product, spot 1)= !.! !" =0.606 cm
Rf (Recrystallized product, spot 2)= !.! !" =0.879 cm
Table 1 displays all the raw and calculated data for the synthesis of aspirin. Salicylic acid was the limiting reagent and acetic anhydride was in excess. The actual yield of aspirin synthesized was 0.546 grams and the theoretical yield was 2.628 grams, thus the percent yield was 20.77% resulting in a percent error of 79.22%. Table 2 displays all data for TLC analysis. The Rf values of crude product, salicylic acid, and recrystallized product were 0.590 and 0.897, 0.818, and 0.606 and 0.879 respectively.
Esterification is the process of forming a carboxylate ester by reacting a carboxyl group with a hydroxyl group or phenol group. The formation of acetylsalicylic acid is an esterification reaction as well as an equilibrium process. Le Chatelier's principle is also known as the equilibrium law and allows one to determine the effects on equilibrium due to pressure, temperature, and concentration. As the reactants are used, the concentration of the reactions decreases and the concentration of the products increases. Le Chatelier's principle is used to favor products, because excess acetic anhydride forces the equilibrium to
shift towards the desired product, aspirin. Le Chatelier's principle also favors the reactants because aspirin can be converted back to salicylic acid and acetic anhydride and once the changes are adjusted, a new equilibrium will be established (3).
Salicylic acid contains two acidic functional groups; a phenol group and a carboxylic acid. The phenol group on the salicylic acid causes stomach irritation. An ester is formed from the phenol group and carboxylic acid on the acetic acid. It is desirable to do away with one of these groups because the acids on the molecules are what cause irritation. By replacing one of the acid groups, the acid strength is reduced making it easier to digest (4).
Figure 2: Synthesis of Aspirin Mechanism
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