Exercise 11

Synthesis of Aspirin

(Acetylsalicylic Acid from Salicylic Acid)

Ariel Joshua Juego Madrid

Group Number II

Section B - 21L

I. Introduction

Organic chemistry is not simply about understanding how

reactions occur. The use of those certain reactions to make

molecules is a very important part of chemistry. The process

of constructing desired organic compounds from smaller pieces

(or from commercially available compounds) is referred to as

organic synthesis.

Organic synthesis is also about preparing a desired organic

compound that is definitely chosen due to its scientific or

economic importance. The limitations imposed upon the process

of synthesis are the ones that challenges synthetic chemists.

In several ways, the process of organic synthesis is much like

finding a solution to a puzzle. The primary goal in synthesis

is to obtain a pure sample of the desired substance through

the most convenient and effective process. Obtaining a pure

sample is somehow difficult to achieve. That’s why it is a

must to use reactions that is expected to yield only a single

product and prevent reactions that will furnish a mixture of

products. One must also consider synthesis that requires only

few numbers of steps. This is so because every chemical and

physical step can reduce the overall efficiency of the

process. Choosing the most efficient method is also affected

by some other restrictions. There could be times that highly

reactive or toxic reagents are used just for the sake of

efficiency. This strategy may improve the efficiency, but it

may also increase the complexity of the synthesis due to the

necessity of applying some additional safety precautions.

Usually, a certain method is chosen because the reagents and

the starting materials that are needed are sufficient and

obtainable in inexpensive rate.

Aspirin, also known as acetylsalicylic acid, is often used

as analgesics to relieve pains and minor aches, an antipyretic

to reduce fever, and as an anti-inflammatory medication. It also

has an anti-platelet effect which binds platelet molecules

together in order to repair damaged blood vessels. That’s why

low doses of aspirin are used to prevent strokes, heart attack,

and blood clot formation in people who have high risk in

developing blood clots. The aspirin’s effect to hinder blood

clotting is actually a negative feature, but since that it can

also prevent strokes and heart attacks, it is then considered as

beneficial.

Below is the acid-catalyzed reaction for the formation of

aspirin:

II. Objectives

In this laboratory exercise, the students are expected:

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

1. Preparation of Acetylsalicylic Acid (Aspirin)

place in a 125mL Erlenmeyer

Flask

+ 3mL acetic anhydride

+ 5 drops 85% H3PO4

swirl and heat in a steam bath

(15 mins)

+ 2mL dH2O

+ 20mL ice-cold water

cool to room temp and place in

ice bath

1 g salicylic

suctionfiltration

wash with small

portions of cold dH2O

transfer to a pre-weighed

watch glass

air dry

weigh and calculate % yield

2. Recrystallization of Aspirin

transfer into a 125mL Erlenmeyer

flask

+ water dropwise while swirling

until all crude aspirin dissolves

warm in a hot water bath

if necessary, add more water

to dissolve the crystals

filtr

disca

resid

crudeaspirin

crudeaspirin

remainingcrude aspirin

small amountof crude

determinemelting

cool the flask to RT and then in a cool bath

wash several times with

cold dH2O

transfer to a pre-

weighed watch glass

air dry

weigh and compute %

recovery

transfer to a clean dry

vial

label properly

collectcrystals by

filtrate

discard

residue

recrystallized aspirin

determinemeltingpoint

3. Characterization of Aspirin

III.1 Proposed method for differentiating the product from

the starting materials. Perform this test on samples

of aspirin, acetic anhydride and salicylic acid.

Solubility in H2O

place in a test tube

+ 1mL dH2O

shake

Reaction with hot, acidic Potassium Permanganate

3 drops of liquidor spatula tip of

solid sample

observe

5 drops of dilute,hot, acidicaqueous KMnO4

place in a test tube

+ 3 drops of sample

warm in a hot water bath for 5 mins

Reaction with Ferric (III) Choride

place in a test tube

+ 5 drops of 2.5% aqueous FeCl3

III.2 Method for differentiating synthesized aspirin from

commercially available one

Test with Iodine Solution

examine

3 drops of liquidor spatula tip of

solid sample

examine

compare withblank usingwater as a

pinch ofaspirin

place in a test tube

dissolve in 2mL water

+ 1mL iodine solution

B. Set-ups

Figure 1. Set-up for Steam Bath/Hot Water Bath

observe

Figure 2. Suction Filtration Set-up

C. List of Necessary Chemicals

Name and

Structure of

the Compound

Function in

the

Exercise

Physical

Properties

Hazards Precaution

s

Salicylic

Acid

Starting

reagent for

the aspirin

synthesis

Powder-like

white solid,

138.121 g/mol,

(BP) 211°C,

(MP) 159° C,

1.44 g/cm3

eye and skin

irritant

avoid skin

contact

Acetyl

Salicylic

Acid

Substance

to be

synthesized

Colorless

solid, (BP)

140oC, (MP)

eye and skin

irritant;

inhalation

avoid

inhalation

and direct

(Aspirin) from

salicylic

acid

135oC, 1.40g/cm3 may cause

irritation in

the

respiratory

tract

contact

Acetic

Anhydride

Starting

reagent for

the

synthesis

of aspirin;

solvent

clear colorless

homogenous

liquid, 102.09

g/mol, (BP)

139.8oC, (MP) -

73.1oC,

1.08g/cm3

corrosive,

flammable,

and toxic;

eye and

respiratory

tract

irritant

avoid skin

contact

and

inhalation

of fumes

85%

Phosphoric

Acid

Catalyst Clear colorless

viscous liquid,

98.00 g/mol,

(BP) 158oC,

(MP) 21oC, 1.88

g/cm3

extremely

corrosive and

toxic

Avoid skin

contact

and

inhalation

of fumes

Water Solvent clear

homogenous

liquid, 18.02

g/mol, (BP)

100oC, 1 g/cm3

not

considered

poisonous

not

considered

poisonous

Potassium

permanganate

Reagent for

characteriz

ation of

aspirin

Purple solid if exposed to

readily

oxidizable

substances,

explosion may

Put away

from

oxidizable

substances

occurFerric

Chloride

Reagent for

characteriz

ation of

aspirin

blood-like/dark

brown liquid,

162.2g/mol,

(BP) , 2.989

g/cm3

corrosive;

anhydrous

from is

irritant and

causes burn

to the area

of contact

avoid

direct

contact

with skin,

eyes, or

clothing

Iodine Reagent for

characteriz

ation of

crude and

commercial

aspirin

brown-reddish/

yellowish

brown, (BP)

185oC, (MP)

113oC, 4.93g/cm3

ingestion may

cause

vomiting ;

overexposure

may cause

irritation of

the eyes and

nose; causes

skin burn

Avoid

ingestion,

inhalation

and direct

contact

IV. Data

Table 11.1 Sample Description

SAMPLE DESCRIPTIONSSalicylic Acid

Acetic Anhydride85% Phosphoric AcidIodine SolutionTable 11.2 Observations on the Synthesis of Acetylsalicylic

Acid

SAMPLE CONDITIONS OBSERVATIONSSalicylic Acid after addition of

acetic anhydride

after addition of

phosphoric acid

Mixture of

Salicylic Acid,

Acetic Anhydride

and Phosphoric

Acid

before heating

during heating

after heating

upon addition of water

upon placing in ice

bath

Suction

Fltration

Filtrate

Residue

Air-dried crystals

Chemical equation for Synthesis of Aspirin

Table 11.3 Weight and Percentage Yield Of Crude and

Acetylsalicylic Acid

PARAMETERS MEASUREMENTSMass of filter paper + watch

glass, gMass of filter paper + watch

glass + aspirin, gMass of crude aspirin, gpercent yield, %

Table 11.4 Observations on the Recrystallization of Aspirin

SAMPLE OBSERVATIONS

Crude AspirinAddition of Water

Warming in a hot waterbath

Cooling in an ice bathSuctio Filtrate

nfiltration

Residue

Air-dried crystals

Table 11.5 Weight and Percent Recovery of Recrystallized Aspirin

PARAMETERS MEASUREMENTS

Mass of filter paper + watch glass, gMass of filter paper + watch glass+ aspirin, gMass of recovered aspirin, gPercent recovery, %

Table 11.6 Melting Point Determination of Crude and Recrystallized Aspirin

PARAMETERS CRUDE ASPIRIN RECRYSTALLIZEDASPIRIN

Melting point rangeLiterature value of MP of AspirinPercent purity, %

Table 11.7 Characterization of Starting Materials and Products

SAMPLE

TEST AND OBSERVATIONS

H2O (+,- FeCl3 (+,- Hot, (+,-

) ) acidic

KMnO4

)

Salicylic

Acid

Acetic

anhydrideAcetylsalicy

lic acid

Table 11.8 Differentiation of Synthesized Aspirin and

Commercially-available Aspirin

SAMPLE REACTION TO IODINE SOLUTIONSynthesized aspirin

Commercially available

aspirin

V. Sample Calculations

% yield = ___actual yield__ x 100

theoretical yield

*Calculation for theoretical yield

mass of aspirin =

1.0g salicylic acid x _1 mol salicylic acid_ x __1 mol

aspirin__ x 180.16g aspirin

138.12g salicylic acid 1 mol salicylic

acid 1 mol aspirin

=1.3 g aspirin

VI. Results and Discussion

Aspirin is produced from an acid-catalyzed reaction or

esterification between salicylic acid with acetic anhydride.

Esterification is a process wherein an organic compound, specifically

ester, is formed by reacting alcohol with an organic acid. In the

reaction, the alcohol group from the salicylic acid reacts with the

acetic anhydride which causes a chemical reaction that converts

salicylic acid’s hydroxyl group into an acetyl group. The by-products

of this reaction are aspirin and acetic acid. The reason for using

acetic anhydride is that it can be easily decomposed through addition

of water and it can be reused.

The reaction mechanism of the production of aspirin is as

follows:

The acid protonates the acetic anhydride. The proton from the

acid attacks the carboxyl oxygen which sequentially pushes the two

electrons from one of the double bond. The electrons then become

delocalized and are spread out to the two oxygen atoms. The

delocalized electrons then rearrange in such a way as to create a bond

between the two reactants, which is the salicylic acid and acetic

anhydride.

Since that there is a positively charged oxygen atom that has to

be neutralized, the electrons of the hydroxyl group delocalize to

establish neutralization. As the neutralization of the oxygen atom

was achieved, the bond between the carbon and the oxygen atom located

in the center of the anhydride gets broken. Lastly, the deprotonated

acid which is negatively charged, acts as a nucleophile and abstract

the hydrogen of protonated aspirin.

The main purpose of this experiment is to obtain aspirin from the

organic synthesis of salicylic acid by acetylation with acetic

anhydride and crystallization. After obtaining 1 gram of salicylic

acid in an Erlenmeyer flask, the group carefully added 3 mL of acetic

anhydride and 5 drops of 85% phosphoric acid to the obtained amount of

salicylic acid. H2SO4 (phosphoric acid), which is known to be a strong

acid, serves as a medium to the nucleophilic acetylation of the

salicylic acid.

After the addition of phosphoric acid, the mixture was swirled to

dissolve the solids, and then it was subjected to heat through a steam

bath for 15 minutes. The purpose of heating the mixture is to

completely dissolve the salicylic acid (white powdered solid).

Another purpose is to control the aspirin crystal formation and the

rate of reaction. However, the mixture was not heated for a very long

time for the reason that it will just allow for the hydrolysis of the

ester (acetic anhydride), which will just yield back to salicylic

acid.

After heating, 2 mL of distilled water was slowly added to the

mixture. Then, as the vigorous reaction ended, 20 mL of cold

distilled water was added to it. To separate aspirin from the rest of

the other products, cold water was added to the mixture. The reason

for using cold water rather than hot water for the recrystallization

of aspirin is that if hot water is used, it would cause an increase in

the temperature of the solution which in turn will convert the crude

product back to reactants. After addition of cold water, the mixture

was allowed to cool to room temperature and was placed in an ice bath

for the purpose of thorough recrystallization of aspirin. Since

aspirin is known to be insoluble in cold water, the crystals can be

still be obtained even after washing it several times. The crystals

were obtained through suction filtration. The obtained crystals were

then transferred to a pre-weighed watchglass. The product was weighed

and the mass obtained was 0.73 grams. The computed percentage yield

was 56.15%.

A small quantity of the crude aspirin was obtained and its

melting point was determined using the Fischer-Johns melting point

apparatus. The melting point range obtained was 102oC-104oC. The

remaining crude aspirin was placed in a 125 mL Erlenmeyer flask. It

was added with water dropwise with swirling until almost all of the

crude aspirin were dissolved. After that, the mixture was warmed in a

hot water bath. The flask was then cooled to room temperature and

then placed in a cool bath in order to allow for recrystallization.

The crystals formed were then collected through suction filtration.

Small portions of cold distilled water were used to wash the crystals.

The obtained crystals were transferred to a pre-weighed watchglass.

The recovered aspirin was weighed, and the resulting mass is 0.38

grams. The percent recovery was calculated, and the obtained value is

52%. The melting point of the recovered aspirin was determined using

the Fischer-Johns melting point apparatus and the obtained melting

point range was 112oC-139oC. This range is close to the literature

value of melting point of aspirin, which is 136oC, though such long

range of values means that impurities are still on the recovered

product.

For the characterization of aspirin, the tests performed were (1)

solubility in water, (2) reaction with hot, acidic, potassium

permanganate, and (3) reaction with ferric (III) chloride. For the

solubility in water, 3 drops of liquid (or spatula tip of solid

sample) was placed in a test tube and added with 1 mL of distilled

water. The mixture was shaken, and was then observed. The acetic

anhydride appeared to be soluble in water while both the

acetylsalicylic acid (aspirin) and salicylic acid appeared to be

insoluble (or immiscible). For the reaction with hot, acidic,

potassium permanganate, 5 drops of it was placed in a test tube and

then 3 drops of sample was added to it. The mixture was warmed in a

hot water bath for 5 minutes and then it was observed. The salicylic

acid showed a positive result, which is the loss of purple solution

and formation of brown precipitate, together with the acetylsalicylic

acid which also exhibited the same result. And for the last

characterization which is the reaction with ferric (III) chloride, 3

drops of liquid (or spatula tip of solid sample) was placed in a test

tube and was added with 5 drops of 2.5% aqueous FeCl3. After that, the

mixture was examined. Again, both the salicylic acid and

acetylsalicylic acid showed a positive result among the three samples.

A purple complex was formed for the salicylic acid and acetylsalicylic

acid while for the acetic anhydride, an orange complex was formed.

In the experiment, the aspirin that was produced appeared to be

insoluble in water which is the expected result. For the reaction

with ferric chloride, the aspirin exhibited color change. The

expected result is that it should have not undergone color change

because ferric chloride only reacts when there is a presence of a

phenolic hydroxyl group, which is only found to be present in a

salicylic acid. For the reaction with hot, acidic, potassium

permanganate, the aspirin is expected to resist to oxidation knowing

that it as a benzene ring, a carboxylic acid group and an ester group

which are all known to be unreactive with potassium permanganate.

From the experiment, the result did not agree with what was expected.

So, from the results of the chemical tests, I could say that aspirin

was synthesized in this experiment, though some a impurities may have

been incorporated in the aspirin crystals lattice.

To differentiate the synthesized aspirin from commercially

available aspirin, the reaction of both with iodine solution was

considered. The synthesized aspirin, upon reaction with iodine

solution, showed formation of yellow liquid and white precipitate.

These observations imply negative result. In the case of the

commercially available aspirin, formation of white precipitate in dark

blue solution was observed and this entails a positive result. The

result shows that the commercially available aspirin contains starch.

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

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. Another cause may be due to loss

of some products during transfer from a container to another.

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 136oC. 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.

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.

VII. Summary and Conclusion

Crystallization is a process wherein atoms (or molecules) are

arranged from a liquid state into a solid state. 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. A way

to differentiate commercially available aspirin and the synthesized

aspirin is to observe the reaction of each with an iodine solution.

There are three tests to differentiate the starting material of

synthesis of aspirin from the product. These tests are solubility in

water, wherein acetic anhydride shows positive result, and reaction

with FeCl3 and reaction with hot, acidic, potassium permanganate,

wherein salicylic acid should be the only one to have a positive

result in both tests.

VIII. References

http://www.drcarman.info/kem220lb/01lab220.pdf

http://www.scribd.com/doc/31805594/Aspirin-Sythesis

J Clayden, Organic chemistry, pp. 599

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

(3rd edition). Boston: Houghton Mifflin

http://www.scribd.com/doc/13771512/Aspirin-Synthesis-Sample-

Prelaboratory

IX. 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.