Sumicad, CJ, Tavanlar, EMMT, Chem 40.1, Institute of Chemistry, University of the Philippines Los Ba±os
Organic synthesis is the process where a desired organic compound is constructed or prepared from commercially available materials. The objective of organic synthesis is to design the simplest synthetic routes to a molecule. Aspirin, also known as acetylsalicylic acid is as salicylate drug often used as analgesic to relieve minor aches and pains, as an antipyretic to reduce fever, and as an anti-inflammatory medication.
The history of aspirin and its medical use can be traced way back in the secong millenium BCE. Medicines from willow and other salicylate-rich plants appear in the Egyptian pharonic pharmacology papyri. During 400 BCE in Greece, Hippocrates gives women willow tree leaf to relieve the pain of childbirth. He also used salicylic tea to reduce fevers. Willow bark extract then became known for its effectiveness in reducing fever, pain and inflammation in the mid- eighteenth century. By nineteenth century,pharmacists were experimenting with and precribing a variety of chemicals related to salicylic acid, an active component of willow extract.
In 1853, chemist Charles Frdric Gerhardt treated acetyl chloride with sodium salicylate to produce acetylsalicylic acid for the first time; in the second half of the nineteenth century, other academic chemists established the compounds chemical structure and devised more efficient methods of synthesis. In 1897, scientists at the drug and dye firm Bayer began investigating acetylsalicylic acid as a less-irritating replacement for standard common salicylate medicines. Aspirin was first isolated by Felix Hoffmann, a chemist in the German company Bayer. By 1899, Bayer had dubbed this drug Aspirin and was selling it around the world.
The word Aspirin was Bayers brand name, rather than the generic name of the drug; however, Bayers rights to the trademark were lost or sold in many countries. Aspirins popularity grew over the first half of the twentieth century, spurred by its effectiveness In the wake of Spanish flu pandemic of 1918, and aspirins profitability led to fierce competition and the proliferation of aspirin brands and products. Some of the 1918 flu deaths were probably due to Aspirin poisoning.
Aspirins popularity declined after the development of acetaminophen/ paracetamol in 1956 and ibuprofen in 1962. In the 1960s and 1970s, John Vane and others discovered the basic mechanism of aspirins effects, while clinical trials and other studies from the 1960s to the 1980s established aspirins efficacy as an anti-clotting agent that reduces the risk of clotting diseases. Aspirin sales revived considerably in the last decades of the twentieth century, and remain strong in the twenty-first with widespread use as a preventive treatment for heart attacks and strokes.
In the preparation aspirin, salicylic acid is reacted with an excess of acetic anhydride. A small amount of a strong acid is used as a catalyst which speeds up the reaction. In this experiment, phosphoric acid will be used as the catalyst. The excess acetic acid will be quenched with the addition of water. The aspirin product is not very soluble in water so the aspirin product will precipitate when water is added. The synthesis reaction of aspirin is shown below:
This laboratory exercise aims to:
1. to synthesize acetylsalicylic acid from salicylic acid by nucleophilic acyl substitution; and 2. to describe and explain the differences in the properties of acetylsalicylic acid and salicylic acid by simple chemical tests.
A. Schematic Diagram
1 gram salicylic acid in 125-mL Erlenmeyer flask
+ 3-mL acetic anhydride + 1 drop 85% phosphoric acid
heat in steam bath for 15 mins
+ 2-mL dH2O
+ 20-mL ice cold H2O
-cool to RT
-place in an ice bath
-perform suction filtration
” wash several times ” transfer crystals to pre-weight watch glass air dry weight dry aspirin calculate % yield crude aspirin set aside small quantity for MP determination transfer the rest to 125-mL Eflask
+ 95% ethanol dropwise swirl until almost all dissolves
+ cold dH2O dropwise until almost all crystals appear cool flask in a cool bath suction filtration calculate % recovery
residue filtrate wash crystals with small portions of cold H2O transfer crystals to pre-weight watch glass air dry weight dry aspirin calculate % recovery transfer aspirin to vial label determine the MP of crude and recrystallized aspirin
Characterization of Aspirin:
Reaction with KMnO4 :
5 drops dilute, slightly acidic KMnO4 in test tube
+ pinch of the sample
warm the tube in water bath for 5 mins. examine mixture
Reaction with FeCl3 :
pinch of the sample in test tube
+ 3 drops 2.5% aqueous FeCl3
+ 1-mL dH2O
Differentiation of the synthesized acetylsalycylic acid from commercially available aspirin:
pinch of the sample test tube
+ 5 drops H2O
” repeat process but add 5 drops iodine solution
instead of H2O
Figure 11.1. Suction filtration set-up
C. Chemical Data Sheet
Table 11.1 Chemical data sheet for the synthesis of aspirin
Name and structure of the reagents
Functions in the exercise
Starting material a white powder-like substance with an MP of 159°C and a density of 1.44g/cm3 Skin and eyes irritants In case of contact, immediately flush skin with plenty of water acetic anhydride
Converts salicylic acids hydroxyl group into an acetyl group a colorless liquid with a density of 1.08 g/cm3 Corrosive and flammable Keep away from heat. Wear gloves, eye protection and face protection phosphoric acid
Serves as the catalyst a colorless viscous liquid with a density of 1.88 g/cm3 and a boiling point of 158°C Extremely corrosive
Avoid direct contact. Wear chemical protective clothing
Used for the recrystallization a colorless liquid with a melting point of 114°C and a density of 789.00kg/m3 Skin and eyes irritants. Long term use can result to serious liver damage Keep away from heat. Wear gloves, eye protection and face protection KMnO4
Differentiating agent a purple liquid
Highly explosive when reacted with concentrated sulfuric acid In case of contact, immediately flush skin with plenty of water for at least 15 minutes FeCl3
For the characterization of the synthesized aspirin and commercial aspirin Brown liquid with a molar mass of 162.20g/mol, a boiling point of 306 °C and a density of 2.9g/mL Corrosive, toxic and acidic
Flush skin with water in case of direct contact
Table 11.2. Description of reagents
DESCRIPTION salicylic acid white, powder-like substance acetic anhydride clear liquid with strong odor phosphoric acid clear, colorless liquid with strong odor 95% ethanol clear, colorless liquid with strong odor KMnO4 purple liquid FeCl3 brown liquid Iodine solution clear liquid
Table 11.3. Preparation of Aspirin
Salicylic acid + acetic anhydride + 85% phosphoric acid
salicylic acid was dissolved
Mixture at room temperature crystals were formed
Mixture after ice bath more crystals were formed
Suction Filtration: residue filtrate
fine, white crystals
clear liquid with small amounts of crystals at the bottom
fine white crystals
Table 11.4. Recrystallization of Aspirin
Crude aspirin + ethanol
dissolution of most crystals occurred
Mixture during cooling
crystals were formed
Mixture after cooling
more crystals were formed
fine, white crystals
Table 11.5. Recovery data of recrystallized aspirin
Weight of watch glass + filter paper (g)
Weight of watch glass + filter paper + product (g)
Weight of product (g)
Table 11. 6. Melting point determination
MELTING POINT RANGE (°C)
Table 11.7. Differentiation of starting material from the product TEST
disappearance of violet color and formation of brown precipitate the solution remained purple
the solution remained brown and not all of the sample dissolved the solution became darker shade of brown and not all of the sample dissolved
Table 11.8. Differentiation of synthesized acetylsalicylic acid from commercially-available aspirin by iodine test SAMPLE
Synthesized acetylsalicylic acid
all of the sample dissolved and the solution is turbid
Commercially- available aspirin
all of the sample dissolved and the solution is turbid
V. Sample Calculations
1.0g SA ( 1 mol SA/ 138.16 g) ( 1 mol ASA/1 mol SA) ( 180.21g/ 1 mol ASA) = 1.30g
3.00 mL AA ( 1.08g AA/ 1mL)( 1 mol AA/ 102.11g)(1 mol ASA/ 1 mol AA) (180. 21g/ 1 mol ASA) = 5.72g
% yield = Actual yield/ Theoretical yield X 100%
= 0.78g/ 1.30g X 100% = 60%
% recovery = Recovery yield / Actual yield X 100%
= 0.457g/ 0.78g X 100% = 59%
VI. Results and Discussion
In this exercise, the goal was to produce acetylsalicylic acid through the organic synthesis from the reaction of salicylic acid to acetic anhydride, the starting materials. Instead of using acetic acid, acetic anhydride was used as solvent since the anhydride reacting with water to form acetic acid tends to drive the reaction to the right. It results from the elimination of a molecule of water from two molecules of acetic acid (see Fig. 11.2). Figure 11.3 below shows the balanced chemical reaction of the synthesis of acetylsalicylic acid.
Figure 11.2. Structure of Acetic Anhydride
Figure 11.3. The balanced chemical reaction of the formation of aspirin.
Because the reaction is slow in pure acetic anhydride, the catalyst, commonly strong acids like phosphoric acid was used for the reaction. According to Le Chateliers principle, the presence of excess acetic anhydride forces the equilibrium towards the desired product, which in this case is the aspirin. In addition to this, the catalysts were also used to ensure that side reactions, which may cause the percentage yield to increase, will be avoided.
The reaction behind the synthesis is nucleophilic acyl substitution. According to McMurry (2000), nucleophilic acyl substitution happens when the initially formed intermediate expels one of the substitutes originally bonded to the carbonyl carbon leading to the formation of a new carbonyl compound. In this experiment, the specific nucleophilic acyl substitution is esterification. It occurs when a carboxylic acid in salicylic acid and an alcohol combine in a reaction to produce an ester.
Figure 11.4. Mechanisms on the formation of aspirin
Phosphoric acid protonates the carbonyl oxygen atom (C=O) of the anhydride to make it more prone to nucleophilic attacks. It gives the anhydride a positive charge thus, making it more susceptible to nucleophilic attacks. The nucleophilic hydroxyl group of salicylic acid attacks the electron deficient acetic anhydride resulting to a tetrahedral intermediate. The hydroxyl group (-OH) attached to the electrophilic carbon removed the hydrogen as proton thus donating the electron to form a double bond (C=O).The loss of the proton regenerates the phosphoric acid and thus, producing acetylsalicylic acid.
To enhance the synthesis reaction, addition of heat and water after heating were done. The synthesis of reaction is favored by heating the mixture because it speeds up the dissolution process of salicylic acid and increases its solubility as well. Because this specific reaction is an endothermic process, addition of heat would favor a forward reaction resulting to the formation of products. Aside from that, nucleophile was completely facilitated by the addition of water after heating. Water was used in order to provide medium for further nucleophilic substitution.
The theoretical yield obtained is 1.30 grams after knowing that salicylic acid is the limiting reagent. The actual yield obtained is 0.78 grams thus, the % yield is 60% . This results are relatively low because of possible sources of error such as loss of product in the filter paper because of prolonged air dying, decomposition to acetic acid in solution so there wasnt a complete conversion of reagents and insufficient heating.
Upon obtaining the crude aspirin, recrytallization was done. This is performed to remove the traces of impurities. After cooling to room temperature and immersing on an ice cold water bath, suction filtration method was done to separate the filtrate from the residue which contains the recrystallized products. Suction filtration is the most practical technique to use when fast filtration of mixture is desired. It employs vacuum which can aid in the passage of filtrate through the filter paper (Basic Organic Chemistry: Laboratory Manual, 2012). In addition, since aspirin is an ester, it should not be recrystallized from hot water because it will allow the
crude sample to be hydrolyzed and yield undesirable products. The % recovery obtained is 59%.
After performing the synthesis of aspirin from salicylic acid, the verification of the identity and purity of the product through melting point determination was also performed.
In differentiating salicylic acid from the synthesized product, FeCl3 test and KMnO4 test were conducted. For the FeCl3 test, the positive will give a change from yellow-brown solution to a violet colored complex. For this test, the result is positive because of the presence of phenol in it. The oxygen atoms of the acid group COOH, and of the -OH group on the salicylic acid together can form a complex with Fe(H2O)6 +3. The test result on aspirin is negative because iron complex cannot be formed due to the absence of a hydroxyl group attached to benzene.
For the KMnO4 test, a positive result was obtained from the synthesized aspirin as seen by the disappearance of violet color and formation of the brown precipitate. Theoretically, salicylic acid would give a positive result because of the presence of hydroxyl group (-OH). Recalling the reactions in alcohols, KMnO4 was used to detect the presence of primary and secondary alcohols. Since the phenol group is absent in the synthesized aspirin, a negative result should be obtained.
Another test was conducted to differentiate the synthesized apirin from the commercially-available aspirin. Unfortunately, same results was obtained from both samples. Ideally, the commercially-available aspirin will give the positive result of the solution turning blue or violet because of the presence of strach to the commercially-available aspirin because pharmaceutical companies add starch to tablet medicines to give them its characteristic shapes. And the iodine test is use to detect the presence of starch in a sample.
Lastly, the melting point determination was conducted. One way of identifying a substance is through its melting point. The range of the melting point can give one an idea on the purity of the sample. The theoretical melting point range of aspirin is 128-137°C. In this experiment, the obtained melting point range of of the crude aspirin is 106- 112°C and for the recrystallized aspirin, it is 114-118°C. The results of melting point determination means that the samples have impurities in it. Narrow difference in the melting point range of the sample and the theoretical melting point range means that the substance is pure because of the uniform forces present in the molecules. When the range is wide, it means that the sample contains impurities. In this exercise, melting point determination is done. And the results show that it has a wide difference from the theoretical melting point range of aspirin. Thus it can be inferred from the results that the sample is not pure.
VII.Summary and Conclusion
Synthesis of organic compounds involves guidelines and steps that should be followed. The first one is the establishment of the starting materials which is in this are the salicylic acid and acetic anhydride together with the phosphoric acid that served as the catalyst for the reaction. The synthesis of aspirin involved the acid-catalyzed nuclephilic acyl substitution. The specific nucleophilic acyl substitution for this experiment is esterification. It happens when a carboxylic acid from the salicylic acid and an alcohol combine in a reaction therefore producing an ester. In this experiment, phosphoric acid was used as a catalyst to hasten the reaction between the salicylic acid and acetic anhydride.
Heat and addition of water was also done for effiecient production of the desired product. The percent yield obtained for this experiment is 69%. Low %yield can be caused by insufficient heating and that the product was lost in the filter paper because of prolonged air drying. The next step that was done was the recrystallization of the crude sample to obtain a more purified organic compound. Recrystallization was done by suction filtration. The last step for this experiment is the verification and differentiation of the samples. Through the KMnO4 test, it was verified that the synthesized product was indeed to be acetylsalicylic acid or most commonly known as aspirin. Other tests such as iodine test and FeCl3, unfortunately did not give the theoretical results.
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IX. Remarks and Recommendation
The synthesis of organic compounds is indeed very helpful in chemistry and through this process, one can have a glimpse on how chemical processes works in real life. The researcher recommends the use of other tests in order to obtain more accurate results in the differentiation of the synthesized aspirin from the commercially-available aspirin.