Acetylsalicylic Acid (Organic Synthesis)

EXERCISE 11

Synthesis of Aspirin
(Acetylsalicylic Acid from Salicylic Acid)

RAQUID, Rency J
Group 5
18L

I. Introduction

Due to the demand of certain reagents in the laboratory in order to perform and conduct further experiments or produce essential compounds, chemists continuously develop organic synthesis. This process aims to prepare and synthesize desired organic compounds from commercially or readily available ones by providing the simplest route in synthesizing the compound.
One example of a compound being can be synthesized in the laboratory is acetylsalicylic acid, commonly known as aspirin. It is variedly used for different purposes: an analgesic to relieve minor body pains including headaches; an anti-inflammatory medication; and as an antipyretic to reduce fever.
The usage of this drug dates back in ancient times, roughly in the 2nd millennium, when Egyptians used willow tree (bark) and other salicylate rich plants as pharmacological specimens. In the 19th century, pharmacists conducted experimentations regarding the medicinal properties of salicylic acid.
It was not until 1853, that the German chemist Frederic Gerhardt produced acetylsalicylic acid (a more potent form) by using acetyl chloride and sodium salicylate. This breakthrough gave chemists an avenue for studying the chemical structure of the compound and more efficient methods of synthesis that are cheaper and shorter.
The physiological function of aspirin can be attributed in its ability to interfere with the production of prostaglandins, a naturally secreted chemical by the body which causes pain, headaches and blood clotting. The latter is actually a downside of the drug, because of possible extreme blood loss of patients who are frequently using the drug. But also, this property of aspirin helps in the prevention of blood clots in the blood vessels and in the brain which are fatal.
Acetylsalicylic acid is actually an ester derivative of salicylic acid. Esters are produced through reactions involving acid anhydrides and alcohols.In this experiment the starting material in synthesizing aspirin is salicylic acid. To prepare aspirin, salicylic acid is reacted with an excess of acetic anhydride. A small amount of a strong acid (phosphoric acid) is used as a catalyst which speeds up the reaction. The excess acetic acid will be hydrated by adding water.
The reaction of synthesis will proceed by nucleophilic acyl substitution. Thisis simply the replacement of one nucleophileattached to a carbonyl group with another. For the synthesis of aspirin from salicylic acid, acetic anhydride will be the acyl component beingnucleophilically substituted. The nucleophile attached to the acyl group that is being replaced is the acetate ion (CH3COO-). The newly formed nucleophile attacted to the acyl group is salicylic acid, the substrate that is being acylated.
Below is the synthesis reaction:

Since acetic acid is very soluble in water, it is easily separated from the aspirin product by the addition of water. This isolates the crude product, which can be purified by recrystallization, using ethanol as solvent and cold dH2O as the agent for recrystallization. To verify and test the purity of the synthesized aspirin, melting point (instrinsic property) is used. The melting point of acetylsalicylic acid ranges from 138 to 140 degree Celsius. If contaminants and impurities are present in the sample, there would be discrepancies in the value of the melting point of the compound.

II. Objectives This experiment aims to:
1. to explain the concept of organic synthesis
2. to synthesize acetylsalicylic acid from salicylic acid by nucleophilic acyl substitution; and
3. to describe and explain differences in the properties of acetylsalicylic acid and salicylic acid by simple chemical tests.

III. Materials and Methods A. Schematic Diagram

(+) 3mL acetic anhydride (+) 5 drops H3PO4 - swirl to mix - heat in steam bath (15 minutes) (+) 2mL dH2O (+) 20 mL cold dH2O - cool to room temperature - place in ice bath - subject to suction filtration (filter paper)

CONTINUED: - wash several times with cold dH2O - transfer to watch glass - air-dry and weigh - compute for percent yield

- separate a small quantity -determine melting poit - transfer to 125-mL Erlenmeyer flask (+) 95% ethanol dropwise until almost all are dissolved - swirl using stirring rod (+) cold dH2O dropwise until all crystals appear - cool flask in cold water bath -perform suction filtration

- calculate percent recovery

- transfer to vial, label -determine melting point - determine melting point - compare melting points
PROCEED TO CHARACTERIZATION
CHARACTERIZATION:

KMNO4 test: (+) pinch of sample in a test tube (+) 5 drops of slightly acidic KMnO4 - warm the test tube in water bath (5 min.)

(+) pinch of sample in te test tube
FeCl3 test: (+) 3drops of aqueous FeCl3 (+) 1mL H2O

DIFFERENTIATION:

(+) 5 drops of dH2O (+) 5 drops of Iodine solution

B. Set-up

Figure 11.1.Suction Filtration Set-up.

Note: Rubber tubing was not used in the experiment, instead a rubber aspirator was used to create partial vacuum.

C. List of Necessary Chemicals.
Table 11.1.Table sheet for necessary chemicals/reagents.
NAME AND STRUCTURE OF COMPOUND
FUNCTION
PHYSICAL PROPERTIES
HAZARDS
PRECAUTIONS
Salicylic acid

Starting material
Solid granules
Odor: Odorless
MW: 138.12 g/mol
Color: white
BP: 211°C
MP: 159°C

Skin and eye irritant
-Apply with plenty and running water in case of contact

-Wear protective clothing

Acetic anhydride

Converts –OH group of salicylic acid to an acetyl group
Liquid
Odor: Strong
MW: 102.09 g/mol
Color: Light
BP: 139.9°C
MP: -73.1°C
Ρ= 1.082 g/mL
Corrosive and flammable
-Keep away from heat

-Store in cool dry area

-Wear protective clothing
Phosphoric acid

Catalyst
Liquid
Odor: Odorless
MW: 98.00 g/mol
Color: clear
BP: 158°C
MP: 21°C
Corrosive
-Avoid contact

-Wear protective clothing
95% Ethanol

Solvent
Colorless, liquid
MM: 46.07 g/mol
MP: -114 °C
BP: 78.37 °C
Skin and eye irritant
-Store in cool dry area

-Avoid heat contact

-Wear protective clothing

KMNO4

Differentiating reagent
Liquid
Odorless
MW: 158.034 g/mol
Color: purple
Density: 2.043 g/mL

Explosive
Skin and eye irritant
-Wash with running water in case of contact

FeCl3

Differentiating reagent
Liquid
Odorless
MW: 162.2 g/mol
Color: Yellow
Density: 2.898 g/ml
Corrosive
Toxic
Acidic
- Flush skin with plenty and running water in case of contact

IV. Data
Table 11.2.Description of Reagents. SAMPLE
DESCRIPTION
Salicylic acid fine, white powder
Acetic anhydride clear, colorless liquid
Phosphoric Acid clear, colorless liquid
95% ethanol clear, colorless liquid
KMnO4
brown liquid
FeCl3
intense, purple liquid
Iodine solution pale yellow liquid

Table 11.3.Preparation of Aspirin.
SAMPLE
OBSERVATION
Salicylic acid + acetic anhydride + phosphoric acid turbid mixture, clear mixture upon heating
Mixture at room temperature incomplete crystallization
After ice bath solid white crystals
Residue
white, slightly crystallized
Filtrate
clear, colorless liquid
Crude aspirin solid white crystals

Table 11.4.Recrystallization of Aspirin.
SAMPLE
OBSERVATION
Crude aspirin + ethanol partial dissolution
Mixture during cooling partial crystallization
Mixture after cooling recrystallized solids with residue
Residue
white crystals
Filtrate
clear, colorless liquid

Table 11.5.Recovery data of crude aspirin.
SAMPLE
OBSERVATION
Weight watch glass + filter paper (g)

Weight watch glass+ filter paper + product (g)

Weight product (g)
0.36 grams
Theoretical yield
1.30 grams
Percent recovery (%)
27.61%

Table 11.6.Recovery data of recrystallized aspirin.
SAMPLE
OBSERVATION
Weight watch glass +filter paper (g)
43.44 grams
Weight watch glass +filter paper +product (g)
43.80 grams
Weight product
0.34 grams
Theoretical yield
1.30 grams
Percent recovery (%)
26.15%

Table 11.7.Differentiation of starting material from product.
SAMPLE
KMnO4 test
FeCl3 test
Synthesized aspirin formation of black precipitate formation of purple complex
Salicylic acid
Formation of black precipitate formation of purple complex with precipitate

Table 11.8.Differentiation of synthesized aspirin to commercial aspirin.
SAMPLE
OBSERVATION
Synthesized aspirin + iodine solution clear, liquid solution
Commercial aspirin insoluble, clear liquid, clear precipitate

V. Sample Calculations Theoretical yield of Aspirin: (Given 1g salicylic acid; 3 mL acetic anhydride) (CH3CO)2O + C6H4(OH)COOH -> C9H8O4 + CH3COOH Mole ratio= 1:1:1 (salicylic acid: acetic anhydride: aspirin) MMsalicylic acid = 138.12 g/mol MMacetic anhydride = 102.09 g/mol ;ρ= 1.082 g/mL MMaspirin= 180.15 g/mol Moles salicylic acid = grams salicylic acid/MM salicylic acid = 1g salicylic acid/138.12g/mol = 0.00724 or 7.24 x 10-3 molessalicylic acid Massacetic anhydride = vol. acetic anhydridexρacetic anhydride = 3 mL x 1.082g/mol = 3.246 g acetic anhydride Molesacetic anhydride = gramsacetic anhydride/MMacetic anhydride = 3.426g/102.09g/mol = = 0.03356 or 3.34 x 10-2molesacetic anhydride 0.00724 moles salicylic acid x ( 1mole aspirin/1mole salicylic acid) x (180.15g/molaspirin) = 1.30 g aspirin (LR) 0.03356 molesacetic anhydride x ( 1mole aspirin/1mole acetic anhydride) x (180.15g/molaspirin­) = 6.04 g aspirin (ER) Since aspirin (from salicylic acid) < aspirin (from acetic anhydride), salicylic acid is the limiting reactant (LR), and acetic anhydride is the excess reactant (ER).
Theoretical yield=MMaspirin x molessalicylic acid =180.15g/mol x .00724 mol = 1.30 g aspirin
VI. Results and Discussion

Acetylsalicylic acidwas synthesized by a process called esterification. Esterification occurs when a carboxylic acid and an alcohol combine in a reaction to produce an ester, a carboxylic acid derivative (structure is similar/ derived from the original functional group) In the lab, the carboxylic acid alcohol mixture is heated in the presence of phosphoric acid (H2PO4), which acts as a catalyst. Awater molecule splits off and the remaining carboxylic acid and alcohol fragments become attached producing an ester. This will be later explained in the mechanism of formation of acetylsalicylic acid. In this experiment, the starting materials, salicylic acid and acetic anhydride were reacted. The anhydride reacts with water driving the reaction to the right and forming acetic acid. This leads to the elimination of water molecules of a water molecule.

Figure 11.2.Synthesis of aspirin chemical reaction. The reaction with only pure acetic anhydride is very slow, thus a strong acid is used as a catalyst to speed up the reaction. Following the Le Chatelier’s principle, excess acetic anhydride that was added to salicylic acid shifts the equilibrium to the right and thus forming the desired product, acetylsalicylic acid. Another reason why phosphoric acid (catalyst) was used, is to prevent the occurrence of side reactions that might lead to the formation of undesired products that might either decrease the yield of aspirin and also cause contamination that is unwanted and since aspirin will be purify by recrystallization in the latter part of the experiment. The synthesis was governed by the concept of nucleophilic acyl substitution, specifically esterification which is illustrated at Fig. 11.3:

Figure 11.3.Esterification mechanism in the formation of aspirin.

The reaction was hastened by the application of heat and mechanical action (swirling) in order to allow more interaction between the reagent molecules. Addition of water was done to provide a medium for nucleophilic attacks. In isolating the compound, cold distilled water and ice bath was used to crystallize acetylsalicylic acid, and to induce partial elimination of unwanted compounds. There was a 0.94 gram difference between the theoretical and the actual yield, causing a very low percent yield of 27.61%. This was caused by the accidental spilling of most of the mixture during crystallization. The recrystallization yielded 0.34 grams, thus having a percent recovery of 26.15%. In recrystallizing the compound, suction filtration was used. An effective set-up that takes advantage of a partial vacuum to filter and separate the residue (desired) of the solution and its filtrate (unwanted/contaminant). After the isolation of acetylsalicylic acid, it was subjected into different test including melting point determination to verify the purity of the product compound and also, to compare it to the starting material: The 1st and 2ndtests, were conducted to compare the synthesized aspirin to its starting material, salicylic acid. In the KMnO4 test, the synthesized aspirin has shown a false positive result, the loss of the purple color and formation of a black precipitate which detects the presence of primary and secondary alcohols. There should be a negative result since the phenol group is absent in aspirin. On the other hand, salicylic acid exhibited the positive indication of oxidation, which was caused by the –OH group attached to secondary carbon. It is suspected that the presence of the salicylic acid in the recrystallized sample might have caused the exhibition of the positive result. The presence of salicylic acid can be attributed to the insufficient air-drying or rapid cooling during recrystallization. Another test used to differentiate the aspirin from salicylic acid was the FeCl3 test. Again both of the samples have shown a positive result, wherein acetylsalicylic acid should be otherwise since the –OH attached on a benzene ring is absent. This functional group is where the complex Fe(H2O)6+3 will interact, enabling salicylic acid to form a purple complex. This again is due to the inadequate conversion of aspirin from its starting material. To test the viability of the synthesized product, it was compared to a commercially available aspirin using the iodine test which theoretically should give a blue or violet result because of the starch but instead an insoluble clear precipitate (commercial) and clear solution (synthesized) resulted from the test, which again is attributed to the contamination and improper recrystallization of the compound. The last test that was conducted was the melting point determination. The literature value of acetylsalicylic acid ranges from 138-140 degrees Celsius while the melting point of salicylic acid ranges from 158-161 degree Celsius. The measured melting of the crude sample 148-153 while the recrystallized sample has a melting point of 156-157. It can be seen that the measured melting point of the recrystallized sample is very far from the literature value of the pure acetylsalicylic acid and even closer to the melting point of its starting material, salicylic acid. Thus, it can be inferred that most of the salicylic acid was not converted to acetylsalicylic acid and a lot of undesired products or contaminants were present in the sample.

VII. Summary and Conclusion Organic synthesis is a process used by chemists to produced desired substances from readily available compound in the laboratory. This aims to provide the shortest synthetic route to the formation of the substance. During organic synthesis there must be intricate performance of steps which includes all the necessary and even the secondary precautions in order to come up with a pure and desirable compound. In this experiment, aspirin (acetylsalicylic acid) was attempted to be synthesized and isolated, by using different methods which includes: the addition of acetic anhydride to react with the starting material, salicylic acid via nucleophile acyl substitution (esterification) and addition of a catalyst, phosphoric acid to speed up the chemical reaction and; the crystallization of the compound by using suction filtration. The synthesized aspirin was also subjected into different tests in order to first, determine the difference of acetylsalicylic acid from salicylic acid, and to test the viability of the synthesized compound by comparing it to a commercially available aspirin. In the KMnO4 test and FeCl3 test, the recrystallized sample gave a false positive result by exhibiting results which should be exhibited only by salicylic acid because of the presence of the functional group, phenol (-OH group attached to a benzene ring). The synthesized compound was also proven to be non-viable because of its negative response to the iodine solution. Furthermore, the melting point range of the crude and recrystallized sample were found to be closer in the literature value of the salicylic acid than in the desired compound, giving an impression that most likely, most of the salicylic acid were not converted to acetylsalicylic acid.

VIII. References
Brown, Lemay and Bursten(2009). Chemistry: The Central Science 11th ed. Prentice Hall, 534-537.

Division of Organic Chemistry and Natural Products (2004).Basic Organic Chemistry Laboratory Manual.10th ed. Institute of Chemistry, College of Arts and Sciences, University of the Philippines Los Baños.

History of Aspirin (2013). Retrieved on October 5, 2013 from http://en.wikipedia.org/wiki/History_of_aspirin
McMurry, R.S. (2008). 7TH Ed. Organic Chemistry.USA: Prentice Hall, 332-345.
Rodriguez, E.B. (1997). Basic Principles of Organic Chemistry. UP Open University: Diliman Quezon City . 295 – 336.
Telow, A.J.V. et al. Retrieved on November 24, 2014 from https://www.academia.edu/

IX. Remarks and Recommendation Organic synthesis is indeed important to the society now more than ever, especially that we are now entering an era of information of technology. Chemists and scientists need to develop more ways on how to synthesize unobtainable or rarely occurring substances, for this will enable us to understand more about how chemical processes and interactions helps us in our everyday lives. It is recommended to other researchers that would work on the synthesis of aspirin to develop more ways and method in synthesizing and isolating the said compound which are less error prone, efficient, cheaper and time saving.