Tittle: Sythesis of aspirin

Abstract

Weighed out approximately 5.0gm(0.3625) of salicylic acid (recorded exact mass) and transferred it
to a clean, dry 100ml glass stoppered borosilicateconical flask Used the 10ml graduated pipette to
dispenser 7ml of acetic anhydride (7,5gm g/ml),0.073 mole) to the salicylic acid in step (1)
aboveCarefully added 4 drops of concentrated sulfuric acid to the reaction mixture (it acts as catalyst
and speeds up the reaction) and stopper the flask. Placed the flask on a water bath to about 70-80 0C,
in a hood and heat for 20 minutes after most of the solid has dissolved .Stirr the mixture with a glass
rod to break up any lumps Removed the sample from water bath, and measured and transfered
40ml of distilled water into the mixture in step 4 above .Swirled the flask for a few minutes to mix
the solutions and get rid any unreacted acetic anhydride.(The acetic anhydride reacts with water to
produce acetic acid)Placed the flask in an ice bath and watch for a while for a white solid to
crystallize out. Occasionally a reaction yielded an oily product that resisted crystallization. Scratched
the bottom and sides of the flask with a glass stir rod to help start crystal formation or warm the
mixture just until the oil dissolves, and then re-cool. Allow 10 minutes for crystallization to
occur.Pre-weighed the filter paper(18,5 cm diameter) and prepare a Buncher funnel filtration
systemEmpty quantitatively the matrix of the prepared aspirin on the filter paper attached to the
Buncher funnel flask and the aspirator. Washed the solid with a small amount of cold distilled water.
Discarded the liquid filtrate in the designated waste container. Dried the solid residue in a drying
oven at 350C for 8 hours

Introduction

Aspirin is the common name for the compound acetyl salicylic acid, widely used as a fever
reducer and as a painkiller. Aspirin is made primarily of willow bark and flowers of
meadowsweet plant having the active ingredient as salicin. Salicin is converted into salicylic
acid in the body. Although salicylic acid was effective at reducing pain and fever, it also had
some unpleasant side effects. It is irritating to the lining of the mouth, esophagus, and
stomach, and can cause hemorrhaging of the stomach lining. In 1899, the Bayer Company in
Germany patented a drug they called aspirin, which was a modification of salicylic acid.
Salicylic acid contains a phenol group, and phenols are known to be irritating. The Bayer
Company replaced the phenol group with an ester group. This esterified compound
(acetylsalicylic acid, also known as aspirin) was shown to be much less irritating than
salicylic acid. Unfortunately, it is still irritating to the stomach and can cause hemorrhaging
of the stomach walls.

An aspirin tablet contains a small amount of aspirin (usually 300-400 mg) in a starch
“binder” and sometimes contains other ingredients like caffeine and buffers. When aspirin is
ingested, it is broken down to salicylic acid by the basic conditions in the small intestine. It is
then absorbed into the bloodstream. Aspirin has a numerous benefits and it is commonly used
as an analgesic, antipyretic and anti-inflammatory. This pro drug was developed because it is
much less abrasive when delivered to the body and is much more easily absorbed.

Aspirin can be made by reacting salicylic acid with acetic acid in the presence of an acid
catalyst. The phenol group on the salicylic acid forms an ester with the carboxyl group on the
acetic acid. However, this reaction is slow and has a relatively low yield. If acetic anhydride
is used instead of acetic acid, the reaction is much faster and has a higher yield (since acetic
anhydride is much more reactive than acetic acid). (Davis, 2009).

The active ingredient of the drug aspirin can be synthesized through an esterification reaction
between salicylic acid and acetic anhydride. This type of reaction involves a reaction of
carboxylic acid with an alcohol in order to form a carboxylate ester. Salicylic is a weak acid
with an alcohol functional group attached to it. The products of the reaction between salicylic
acid and acetic anhydride are acetylsalicylic acid and acetic acid (Solomons, 2011).

Since acetic acid is very soluble in water, it is easily separated from the aspirin product. The
aspirin isolated in this step is the “crude product”. A “pure product” can be obtained through
recrystallization process of the crude (Davis, 2009). Below is the acid-catalyzed reaction for
the formation of aspirin:
The ester group is an important functional group that can be synthesized in a variety of ways.
Esters can be prepared by reacting a carboxylic acid with an alcohol in the presence of a
catalyst. This way of ester preparation is called Fischer esterification (Weldegirma, 2013).

Other methods are also available for synthesizing esters, most of which are expensive but
readily carried out in a lab on a small scale. Example: alcohols react with anhydrides and acid
chlorides (Weldegirma, 2013).

Safety Precautions

 Acetic anhydride is irritating to the nose and sinuses. Keep this compound under the
hood at all times, and avoid breathing the vapors.
 The aspirin that is made in this lab is NOT pure enough to be taken internally! Do not
ingest the aspirin!
 Avoid touching the chemicals.
 Wear your safety goggles. Waste Disposal:
  All waste must be placed in the organic waste containers (which have a pink label) in
one of the fume hoods.
 Objectives
1. To assemble the raw materials equipment required for the synthesis of aspirin
2. To describe the synthetic process of aspirin
3. Determine aspirin yield
4. To confirm the identity of the synthesized aspirin by determining the melting point

Methodology

1. Weighed out approximately 5.0gm(0.3625) of salicylic acid (recorded exact mass)

and transferred it to a clean, dry 100ml glass stoppered borosilicateconical flask
2. Used the 10ml graduated pipette to dispenser 7ml of acetic anhydride (7,5gm
g/ml),0.073 mole) to the salicylic acid in step (1) above
3. Carefully added 4 drops of concentrated sulfuric acid to the reaction mixture (it acts
as catalyst and speeds up the reaction) and stopper the flask
4. Placed the flask on a water bath to about 70-80 0C, in a hood and heat for 20 minutes
after most of the solid has dissolved .Stirr the mixture with a glass rod to break up any
lumps
5. Removed the sample from water bath, and measured and transfered 40ml of distilled
water into the mixture in step 4 above .Swirled the flask for a few minutes to mix the
solutions and get rid any unreacted acetic anhydride.(The acetic anhydride reacts with
water to produce acetic acid)
6. Placed the flask in an ice bath and watch for a while for a white solid to crystallize
out. Occasionally a reaction yielded an oily product that resisted crystallization.
Scratched the bottom and sides of the flask with a glass stir rod to help start crystal
formation or warm the mixture just until the oil dissolves, and then re-cool. Allow 10
minutes for crystallization to occur
7. Pre-weighed the filter paper(18,5 cm diameter) and prepare a Buncher funnel
filtration system
8. Empty quantitatively the matrix of the prepared aspirin on the filter paper attached to
the Buncher funnel flask and the aspirator. Washed the solid with a small amount of
cold distilled water. Discarded the liquid filtrate in the designated waste container
 9. Dried the solid residue in a drying oven at 350C for 8 hours

Results

Crystals of product had an appearance of white soft powder.

Figure 1: Crude product of aspirin

Table 1.1 Synthesis of Aspirin

Mass of salicylic acid used (g) 5.00

Volume of acetic anhydride used (mL) 7.00
Mass of filter paper (g) 1.50
Mass of crude aspirin and filter paper(g) 6.87
Mass of crude aspirin (g) 5.37

Table 1.2 Melting Point Determination

Melting point crude aspirin 129°C

Melting starts 128.6°C – 130.9°C
Calculations:

Equation 1: Determining the limiting reagent

Molecular Weight of Salicylic Acid

1 mol
5.00 g × =0.036 mol
138.12 g

Molecular Weight of Acetic Anhydride

1.08 g 1 mol
7.00 mL × × =0.074 mol
1 mL 102 g

Salicylic acid is the limiting reagent.

Equation 2: Theoretical Yield of Aspirin

1 mol Aspirin 180.16 g

0.036 mol × × =6.49 g Aspirin
1 mol SalicylicAcid 1 mol Aspirin

Equation 3: Percent Yield of Aspirin

5.37 g Actual yeild

× 100=82. 74 %
6.49 g T h eoretical yeild

Equation 4: Percent Recovery of Aspirin

2.82
× 100=52.51 %
5.37

Equation 6: Percent Error of Crude Aspirin Melting Point

129° C−128. 6 ° C
×100=0.31 %
129 ° C

Discussion

Esterification is a process in which two reactants, an alcohol and a carboxyl group in the
presence of an acidic catalyst forms a carboxylate ester. The particular esterification process
in this
experiment of forming acetylsalicylic acid from salicylic acid and acetyl anhydride is
reversible, thus it is an equilibrium process. One of the reactants in synthesizing aspirin is
salicylic acid. Salicylic acid contains two acidic functional groups, a carboxylic acid and a
phenol group. The hydroxyl group located in the benzene ring of the salicylic acid reacts with
the acetic anhydride, thus forming acetyl salicylic acid- the common name for aspirin.
Because the synthesis of aspirin is a slow reaction, a catalyst is needed. Sulfuric acid acts as a
catalyst to speed up the reaction between salicylic acid and acetic anhydride. It is a liquid
acid, thus it does not contain a large amount of water that would otherwise affect the yield of
the reaction. Shown above is the esterification reaction occurring between salicylic acid,
sulfuric acid and acetic anhydride.

The reaction of salicylic acid and acetic anhydride with the aid of sulfuric acid as a catalyst
gave a milky white liquid. The mixture-containing flask was submerged in a hot water bath
for 10 min. to speed up the reaction of the synthesis. The heating caused the salicylic acid to
dissolve more quickly as well as increase in solubility. This is an endothermic synthesis
reaction. Therefore the increase in temperature causes the reaction to move forward, favoring
the formation of products.

After heating the mixture, distilled water was added to the crude product to purify the crystals
and to decompose any remaining acetic anhydride because it strongly reacts with water.
There is remaining acetic anhydride because salicylic acid is the limiting reagent and acetic
anhydride is present in excess. Moreover, it is important to consider that acetylsalicylic acid
is not the only product that forms, another by product of the reaction is acetic acid. The
objective of this experiment is to isolate pure acetylsalicylic acid, thus the addition of
distilled water separates the crystals from the very water soluble acetic acid. The distilled
water was added after heating the mixture because the aspirin would not have formed if the
acetic anhydride had already reacted with water. Water also aided in nucleophilic substitution
at this point in the recrystallization process.

The errors committed in this experiment are as follows:

 low percent yield

  a wide range between the melting point of the crude aspirin and the recrystallized
aspirin from the literature value of melting point of aspirin

 low percent recovery of the recrystallized aspirin

By referring to Table 1.1, it can be observed that the experiment yielded 2.82g of purified
aspirin product. The theoretical yield for this experiment as shown in Equation 2 is 6.49 g.
The percent yield as shown in Equation 3 is 46.45%. Because the synthesis of aspirin is an
equilibrium process, it is difficult to obtain 100% yield because a large concentration of
products can cause the reaction to reverse and create the reactants.

The possible cause of the low percent recovery of the recrystallized aspirin is carrying out the
filtration even before the complete recrystallization. Some of the aspirin will be left in the
aqueous solution for this reason. If complete recrystallization was not achieved and filtration
was performed right after, some of the aspirin which may possibly crystallize after some time
will then be excluded from the amount of crystals obtained. So, if this happens, low amount
of the recovered aspirin will be acquired which will then result also to a lower percent
recovery since the possible amount that can be obtained is not maximized

In addition to this, a few errors could have contributed to the low percent yield of this
experiment. The percent yield is relatively low because of possible sources of errors.
Prolonged exposure to the environment and atmospheric air that may have caused air drying
could also be one of the errors. The product could have been lost while using vacuum
filtration. The product may have also slipped between the filter top and the filter paper. Low
percent yield may have been caused by the use of not so cold water. If the degree of coldness
of water that should be used for washing was not met, the crystals could have melted and thus
lowering the percent yield in the experiment. Lastly, inadequate heating time or high enough
temperature may have not allowed for a complete dissolution, resulting in a smaller product
yield.

Melting point is the temperature at which the solid and liquid forms of a pure substance can
exist in equilibrium. The melting temperature of crystalline solids is a characteristic figure
and is used to identify pure compounds and elements. The melting point range is very narrow
for pure solids, and it is an intensive physical property. The presence of even a small amount
of impurity will lower the compound’s melting point by a few degrees and broaden the
melting point range. Therefore melting point can be used to determine the purity of
compounds.

The obtained melting point range of the crude sample and the recrystallized aspirin has wide
range compared to the literature value of the melting point of aspirin, which is 140 oC.
Impurities in the reactants or in the aspirin cannot be controlled during the process of
recrystallization. The laboratory wherein the experiment was done and the glasswares that
were used are unlikely to be sterilized. Because of these, impurities probably have
participated in the reaction at any time. Even though the laboratory apparatuses that were
used in the experiment were washed, it is still possible that chemical residue or contaminants
are present during the performance of the synthesis experiment.

Aspirin has a reference standard temperature of 135°C, it follows that if the temperature will
vary with the reference temp more than ±1°C or ±3-4°C for others, the substance recovered is
not pure. Impure salicylic acid may contribute as interference in the product we want to
obtain. Crude aspirin has a melting point of 128.4°C-130.9°C and it has a difference of 6 °C
thus it is not pure. The pure aspirin was also tested to know its purity and it shows that it has
a difference of 2.5°C so it can be inferred that the product obtained was a pure aspirin.
However, the purity of aspirin can further be enhanced by eliminating systematic errors.

CONCLUSION

Aspirin can be synthesized by performing the esterification of salicylic acid with acetic
anhydride in the presence of phosphoric acid. A method to check the purity of the sample is
to determine its melting point and compare the obtained value to the literature melting point
of the substance. A more pure substance has a narrow melting point range due to the less
presence of impurities that may vary the melting point range. A less pure substance has a
wider range of melting point since that it contains a larger presence of impurities that widens
the range. With a minimum difference with respect to the reference standard temperature, it
can be inferred that the aspirin product obtained in this experiment was pure. A total of 2.87 g
of pure aspirin was synthesize out of a possible yield of 6.49 g. The percent yield of the
product was 43.45%.As noted by the small percent yield, much of the product was lost or not
successfully synthesized to aspirin. However to prevent further errors, the recrystallized
product needs to be better purified

Remarks and Recommendations

To further improve this experiment, proper execution of the procedure must be achieved. To
lessen or avoid the possible impurities adsorbed to the obtained crystals, one must assure that
the glasswares to be used are free from contaminants or any chemical substance that are left
from previous experiments. Proper washing of the crystals must also be considered in order
to remove completely all the adsorbed impurities. To obtain a mass of the crude sample that
is close to the expected amount, proper air-drying must be done. In order to maximize the
amount of crystals that can be obtained, complete recrystallization must be observed.

On the laboratory equipments, it is recommended to use a Büchner funnel and filter paper
that are not faulty or damaged for it may results in loses of yields. New and more
sophisticated equipments are also recommended to maximize every work and time.

Reffrences

Davis, Aaron. Lab Synthesis of acetylsalicylic acid, and analysis. Norco State
College,California, 2009.

Solomons, Graham, Craige and Snyder. Organic Chemistry, 11th edition. New Jersey: Wiley
&Sons, 2011.

J Clayden, Organic chemistry, pp. 599

Williamson, k.I (1999). Macroscale and microscale organic experiments (3 rd edition).

Boston: Houghton Mifflin

Weldegirma, Solomon. Experimental Organic Chemistry. University of South Florida, 2013.