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INDEX

Serial No. Date Name of the experiment Page No.

01 Synthesis of Paracetamol. 2–5

02 Synthesis of acetanilide. 6–9

03 Synthesis of Esters. 10 – 12

04 Synthesis of Aspirin 13-16

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Experiment Number: 01 Date:18.09.2012
Name of The Experiment: Synthesis of Paracetamol

Principle:
Paracetamol or acetaminophen is an analgesic & antipyretic drug that may be conveniently prepared
in the laboratory from Para-Aminophenol. Para-Aminophenol is readily acetylated with acetic
anhydride to give paracetamol, or 4-Hydroxy acetanilide, or Parahydroxy acetanilide or para acetyl
aminophenol, or para aceaminidophenol, or para acetaminophenol, or N acetyl para aminophenol.

Reaction:

Mechanism of reaction:

The amino group (NH2) is more readily acetylated than the phenolic hydroxyl (OH) group.
The following steps are involved in the formation of paracetamol.

Step 1: First step involves the formation of Acetylium ion, the reaction is enhanced by proton
donation by concentrated acid.

Step 2: Amino group of Para-Aminophenol dissociates as follows:

Step 3: Acetylium ion attacks the anion at the nitrogen atom to form Para-acetyl Aminophenol or
Paracetamol.

Reagents:
1. Para-aminophenol 4. Concentrated H2SO4
2. Acetic anhydride 5. Distilled water
3. Alcohol

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Apparatus:
1. Beaker 5. Funnel
2. Filter paper 6. Stirrer
3. Water bath 7. Glass tube
4. Measuring cylinder 8. Vacuum pump

Procedure:

1. 5.5 gm of Para-Aminophenol and 15 ml of distilled water were taken in a 250 ml conical flask.

2. 7 ml of acetic anhydride and 2 drops of concentrated H2SO4 was added to it and was stirred .The
reaction mixture was stirred and then it was warmed on a were bath for about 10 minutes at the
temperature of 40-60°C. The volume of reaction mixture was decreased by heating it on the water
bath.

3. After 10 minutes when solid was dissolved, it was then cooled in refrigerator for about 10 minutes,
until the crystal’s ware appeared and vacuum filtered. The solid portion s was acetyl derivatives.

4. It was then recrystallized from 75 ml of hot water and 10 ml of alcohol. Warmed for 3 minutes and
cooled in the refrigerator for 10 minutes until crystal was appeared. Then the crystal was filtered by
vacuum pump and was dried.

Calculation:
Molecular weight of Para-Aminophenol =109 gm

Molecular weight of Paracetamol =151gm

109 gm of Para-Aminophenol yields= 151 gm of Paracetamol

151
So, 1 gm ,, ,, ,, ,, = gm of Paracetamol
109

151 5.5
Thus, 5.5 gm ,, ,, ,, ,, = gm of Paracetamol
109

=7. 61 gm of Paracetamol

Now upon the drying the weight of Paracetamol crystal was =

Obtained yield
Therefore percent (%) of Paracetamol yields =  100
Theoretical yield

= ×100
7.61

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Result:

The percent yield of Paracetamol from the experiment was =

Determination of melting point:

The synthesized Paracetamol showed the melting point at 169°C

Comment:

The percent yield of aspirin was less than the normal standard.

It may be due to the following reasons:

►A portion of the supplied sample may remain unreacted or biproduct may be formed by various side
reactions.

►A portion of the product may be lost during Washing, Drying, and Filtration.

►Weight variation may be occurred due to instrumental defect or variation.

►Amount of reagent and starting material taken may not be exact.

►Supplied reagent and starting material may not be pure.

►Cooling and heating may not be done properly.

►A portion of paracetamol crystal may be lost during transfer from vacuum filter paper.

►Filter paper may absorb a portion of crude aspirin.

►During drying some crystal may be lost.

Properties of Paracetamol:
The Paracetamol has the following Properties:
√ Physical form: Crystalline powder
√ Color : White (After purification)
√ Odor : Odorless
√ Melting point: 169-170 °C

√ Solubility : Soluble in 70 parts of water


Soluble in 7 parts of ethanol
Indications:
Paracetamol or acetaminophen is an analgesic & antipyretic drug.
1. As analgesic drug: As analgesic drug Paracetamol is used for the treatment of :
i.Headache ii. Arthralgia iii. Toothache
iv.Myalgia v. Threatened abortion vi. Dysmenorrhea,
vii. Backache, ix. Postoperative pain
2. As Antipyretic: As Antipyretic Paracetamol is used for the treatment of:
I. Influenza
II. In place of aspirin in to avoid stomach irritation & Allergy.
III. In childhood to avoid the possibility of Roy’s Syndrome.

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Side effects:
1. Early:
i. Nausea iii. Anorexia
ii. Vomiting iv. Abdominal pain

2. Delayed:
i. Hepatic necrosis v. Skin rash
ii. Renal tubular necrosis vi. Pancytopenia
iii. Hypoglycemic coma vii. Urticaria
iv. Leucopenia

Dose:
Single dose: 500 mg or 1 gm daily. Dose should not exceed 4 gm per day.
Dose for the children: About 30 mg /kg of the body weight
or 300 mg /day but, no longer than 5 days.

Precaution:
A doctor should consult before administration of paracetamol to a child age less than 3 years. In
children under 12 years, dose should not exceed 1-2 gm. Single dose should not be given at an
interval of less than 4 hours.

Dosage form:
 Tablet  Elixir
 Solution  Suspension
 Syrup  Capsule

Contraindication:
 Hypersensitivity to paracetamol  Liver disease
 Glucose-6-phosphate dehydrogeneous deficiency Kidneydisease
Severe hepatic dysfunction

Market preparation:
Trade name Manufacturer name
Napa Beximco
Apa Opsonin
Ace Square
Fast Acme
Reset Incepta
Aceta Biopharma
Zerin Jayson
Parapyrol GSK
ATP General
Remalgin Reman drug
Xpa Aristopharma

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Experiment Number:02 Date:18.09.2012
Name of The Experiment: Synthesis of Acetanilide

Principle:
Acetanilide can be synthesized from aniline by acetylation in the presence of acetic anhydride. Acetic
acid and zinc dust is used as a catalyst.

Mechanism of reaction:

The amino group (NH2) is more readily acetylated than the phenolic hydroxyl (OH) group.
The following steps are involved in the formation of Acetanilide.

Step 1: First step involves the formation of Acetylium ion, the reaction is enhanced by proton
donation by concentrated acid.

Step 2: Amino group of the aniline dissociates as follows:

Step 3: Acetylium ion attacks the anion at the nitrogen atom to form Acetanilide.

Reagents:

 Aniline
 Acetic anhydride
 Distilled water
 Glacial Acetic acid
 Zinc dust
 Ethanol

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Apparatus:
i. Round bottom flask vi. Pipette
ii. Reflux condenser vii. Suction pump
iii. Conical flask viii. Glass rod
iv. Water bath ix. Hot air oven
v. Beaker x. Filter paper
Purpose:
A. To synthesize acetanilide by reaction of aniline and acetic acid.

B. To purify acetanilide by crystallization method from water.

Procedure:

1. 2.5 ml of aniline was placed to a 250 ml round bottom flask.

2. 2.5 ml Acetic Anhydride was added gradually to the reaction mixture followed by 1.5 ml glacial
acetic acid and 1.65 gm Zinc dust.

3. The reaction mixture was heated at 50-60 °C for 5 minutes.

4. The reaction mixture was cooled by holding under tap water to bring it to the room temperature
and 25 ml of ice water was added to the reaction mixture.

5. The precipitation of crude acetanilide was collected by suction pump.

Recrystallization:

6. The crude acetanilide was dissolved in a 5 ml of hot ethanol. Then 100 ml of boiled water was
added gradually to it .The volume of solvent must be added till to the turbidity and further heated to
clear the solution.

7. The solution was cooled at the room temperature or in an ice water bath, the crystal was filtered at
the pump and dried in the hot air oven.

Calculation:

Molecular weight of aniline, M1=93


Taken amount of aniline, w1=2.33

Molecular weight of aniline, M2=135


Found amount of acetanilide,w2 = gm

w2  M 2
Therefore percent (%) yield of acetanilide = 100
w1  M1

 135
=  100
2.33  93

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Result:
The percent yield of Acetanilide from the experiment was =

Determination of melting point:


The synthesized Acetanilide showed the melting point at 114°C

Precaution:
Aniline and acetanilide are toxic chemicals. So care should be taken to avoid contact with the skin.

Mode of Action:

Since acetanilide is in the same class of drugs as acetaminophen or Paracetamol, it shows analgesic
and antipyretic activity. It produces analgesic action by the elevation of the pain threshold and
antipyresis through the action on the hypothalamic heat-regulating centre.

Pharmacological uses:

1. Acetanilide has analgesic antipyretic properties. It is the same class of drug as paracetamol.
2. Acetanilide is used as an inhibitor in hydrogen peroxide and used to stabilize cellulose ester.
3. Acetanilide is used as a precursor in penicillin synthesis and other pharmaceuticals and it
intermediates.

Side effects:
1. It is well known to produce cyanosis in some humans when taken repeatedly, possibly due to
formation of sulfhemoglobin. Large doses in acute poisoning produce methemoglobin.

2. Acetanilide is depressants of CNS. Symptoms of nausea & vomiting, vertigo & ringing in ears
occur with large doses or in sensitive individuals with therapeutic doses. Sweating may be profuse.
Large doses lead to mental confusion, muscular in coordination & coma.

3. Circulatory collapse, with cold extremities, paleness...feeble rapid pulse & dyspnea, & coma, with
fixed, semi-dilated pupils, is characteristic finding in acute acetanilide poisoning.

4. Mild poisoning with acetanilide causes headache, weakness, hypotension, nausea & vomiting &
with more severe poisoning there is depression of cardiac & smooth muscle.

5. Chronic poisoning by acetanilide may lead to anemia & sulfhemoglobinemia, with discoloration
evident in conjunctival & retinal vessels.

Drug Warnings:

1. Acetanilide is especially dangerous in anemia, after hemorrhage and during menstruation.

2. Necrosis of renal papillae & terminal tubules has been associated with excessive doses of drug
mixtures containing acetophenetidin with acetanilide.

3. Acetanilide produces hemolytic anemia in individuals with genetic deficiency of erythrocytic


glucose-6-phosphate dehydrogenase.

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Interactions:

1.Thirty-molar excess of acetanilide reduced carcinogenicity of n-2-fluorenylacetamide on liver &


several other target organs in several species.

2. Acetanilide potentiates analgesic effects of opiates.

3. Enhancing effect of metapyrone upon the p-hydroxylation of acetanilide has been confirmed.

Reported Fatal Dose:

Death has followed taking of acetanilide as analgesic or antipyretic in doses of 0.66-2 g by children;
or by aged or sick patient. For healthy adult, the acutely fatal dose is probably above 30 g.
Between 4 & 5: 4= very toxic: probable oral lethal dose (human) 50-500 mg/kg, between 1
teaspoonful & 1 oz for a 70 kg person (150 lb). 5= extremely toxic: probable oral lethal dose (human)
5-50 mg/kg, between 7 drops & 1 teaspoonful for 70 kg person (150 lb).

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Experiment No. 03 Date: 15.10.11
Name of the experiment: Synthesis of Esters.

Introduction:
The esters are a group of organic compounds best known for their interesting odours.
Many perfumes and artificial flavorings are esters. Esters are formed when a carboxylic acid
reacts with an alcohol in the presence of a strong acid. A general equation for the formation
of esters is:

The R and R' represents alkyl groups such as methyl, ethyl, or propyl. The esters are
named after the compounds from which they are formed. The first part of the name comes
from the alcohol and the second part of the name comes from the carboxylic acid. Thus
when ethyl alcohol (ethanol) combines with acetic acid, the resulting ester is named ethyl
acetate.
The synthesis of an ester must be done in the presence of an acid in order to push the
reaction closer to completion. The reaction can be reversed by adding a strong base, such as
NaOH. The acid that you will be using as a catalyst in this experiment is sulfuric acid.
Many of the aromas of natural fruits and flowers are due to simple esters. Octyl ethanoate
has the odor of oranges, while apricots owe their characteristic aroma to pentyl butanoate.

Mechanism for reaction for acid catalyzed esterification:


Step 1: An acid/base reaction. Protonation of the carbonyl makes it more electrophilic.

Step 2: The alcohol O functions as the nucleophile attacking the electrophilic C in the
C=O, with the electrons moving towards the oxonium ion.

Step 3: Deprotonation of the alcoholic oxygen.

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Step 4: Protonation of –OH group of compound makes it good leaving group.

Step 5: The electrons of adjacent oxygen helps to leaving the group as a water molecule.
Step 6: Deprotonation of the oxonium ion reveals the carbonyl in the ester product.

Apparatus:
i. Beaker (250 ml) vii. Full face shield
ii. 2 test tubes viii. Centigram balance
iii. Thermometer ix. Glazed paper
iv. Test tube rack x. Plastic gloves
v. Safety goggles xi. Graduated cylinder (10ml)
vi. Dropper pipette xii. Hotplate

Reagents:
i. Methanol iv. Salicylic acid
ii. Ethanol v. Concentrated sulfuric acid
iii. Glacial acetic acid

Procedure:
1. Two test tubes were taken and labeled them as A and B.
2. Following reagent in the following ratio:
A. 1 ml acetic acid 1 ml ethanol
B. 1 g salicylic acid 1 ml methanol
3. 4 drops of conc. sulfuric acid was carefully added to each test tube.
4. About 150 ml of water was putted in a 250 ml beaker. The test tubes were placed into
the water and heated the water on a hot plate to a temperature of 60°C. The test tubes were
heated in the hot water bath for 15 minutes. It was ensured that, the water bath remained at
approximately 60°C for that period of time.
5. The test tubes were cooled for a few minutes and then immersed in an ice bath. This
step was added to prevent any test tubes from cracking.
6. 5 ml of distilled water was added to each of the test tubes. This step was included to
dilute the ester and soften its odour.

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7. The odour of the contents of each of the test tubes was carefully noted. It was done by
wafting the odours of the test tubes toward the nose. The observations were documented in the
table.

Required Combinations:
i. Methyl alcohol + acetic acid, benzole acid, salicylic acid
ii. Ethyl alcohol + acetic acid, benzoic acid, salicylic acid

Result:
Test Alcohol Carboxylic Ester Odor of Ester
tube1 Ethyl alcohol acid
Acetic acid Produced
Ethylacetate Fingernail Polish Remover
2 Ethyl alcohol Benzoic Acid Ethylbenzoate Fruity
3 Methyl alcohol Salicylic acid Methyl Salicylate Wintergreen

Safety Precautions:
1. Concentrated sulfuric acid is a strong oxidizing agent. It will start a fire if mixed
incorrectly with any of the alcohol or other acids used in this experiment. Use exactly as
directed.
2. All of the liquid acids used in this experiment are corrosive to skin, eyes and clothing.
While working on this experiment, ware safety goggles, full face shield, gloves and lab
apron. Wash spills and splashes off the skin and clothing immediately, using plenty of water.
3. The alcohol and the organic acids used in this experiment are all flammable. Be sure
all burners and other flames in the laboratory are extinguished before starting the experiment.
4. The detection of odours should be done cautiously. Breathing the vapors of some of
these esters can cause sore throat, dizziness, headache and drowsiness. The test tube should
be held about 30 cm away and 15 cm below the nose. Waft the odor toward the nose, sniffing
cautiously, once or twice. Should not breathe deeply while sniffing.

Page 12 of 16
Experiment Number: 04 Date:17.09.2012
Name of The Experiment: Synthesis of Aspirin

Principle:
Phenols, unlike amine cannot be acetylated satisfactorily in aqueous solution. Acetylation proceeds
readily with acetic anhydride in the presence of dilute H2SO4.Salicylic acid upon acetylation yields
acetyl salicylic acid or aspirin.

Reaction:

Mechanism:
The following steps are involved in the mechanism of reaction of Aspirin.

1. First step involves in the formation of Acetylium ion, the reaction is enhanced by proton donation
by concentrated acid.

2. Due to the presence of phenolic group, salicylic acid is acidic in nature , so it is dissociated as
follows:

3. Acetylium ion attacks the anion of oxygen to form acetyl salicylic acid or aspirin.

Reagent: Apparatus:
1. Concentrated H2SO4. 1. Conical Flask
2. Acetic anhydride. 2. Water bath.
3. Distilled water. 3. Stirrer
4. Alcohol. 4. Thermometer
5. Funnel
6. Filter paper

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Procedure:

1. 5gm of dried salicylic acid and 7 ml of acetic anhydride was taken in a conical flask.

2. 2 drops of concentrated H2SO4 was added to it .Then flask was rotated in order to confirm through
mixing.

3. The reaction mixture was warmed on a water bath for about 50ºC-60 °C with stirring for about 10
minutes.

4. The mixture was allowed to cool with no stirring.

5. 75 ml of hot water was added and stirred well and then it was kept in the refrigerator for 10 minutes
for crystallization & then filtered by vacuum filter pump .This was crude aspirin, which required
further processing for the purification.

6. Purification was done by adding 15 ml of alcohol and 75 ml of water to the crude aspirin and
heated in hot water bath for 2-3 minutes.

7. As solid separation takes place at this step, the previous mixture was not essential if no solid is
separated.

8. The solution was cooled in a refrigerator for about 7-8 minutes.

9. Niddle like crystal were appeared and separated with the help of filter vacuum pump and was
collected on a white paper for drying in an oven at the temperature of 50-60°C.

Calculation:

Molecular weight of Salicylic acid (C7H6O3) =138

Molecular weight of Aspirin (C9H8O4) =180

138 gm of Salicylic acid yields = 180 gm of Aspirin

180
So, 1 gm,, ,, ,, ,, = gm of Aspirin
138

180  5
Thus, 5 gm,, ,, ,, ,, = gm of Aspirin
138

=6.5 gm of Aspirin

Practical yield weight of aspirin was =

Obtained yield
Therefore percent (%) yield of Aspirin =  100
Theoretical yield

= ×100
6.5

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Result:

The percent yield of aspirin from the experiment was =

Determination of melting point:

Aspirin was decomposed when heated and did not possess a true clearly defined melting point.

The decomposition point ranging from 128-135°C.

The synthesized aspirin has the melting point at = °C.

Comment:

The percent yield of aspirin was less than the normal standard.

It may be due to the following reasons:

i. A portion of the supplied sample may remain unreacted or biproduct may be formed by
various side reactions.

ii. A portion of the product may be lost during Washing, Drying, and Filtration.

iii. Weight variation may be occurred due to instrumental defect.

iv. Amount of reagent and starting material taken may not be exact.

v. Supplied reagent and starting material may not be pure.

vi. Cooling and heating may not be done properly.

vii. A portion of aspirin crystal may be lost during transfer from vacuum filter paper.

viii. Filter paper may absorb a portion of crude aspirin.

ix. During drying, some crystals may be lost.

Properties of aspirin:

Aspirin has the following Properties:

√ Physical form: Needle like Crystal


√ Color : White
√ Odor : Odorless
√ Melting point : 128-135 °C
√ Solubility : 1 gm in 300 ml water
1 gm in 5 ml alcohol
1 gm in 17 ml CHCl3
√ Stability : Stable in dry air but in the presence of moisture it slowly hydrolyze into
acidic acid and salicylic acid.

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Indications:

i. Headache ix. Arthritis


ii. Rheumatic fever x. Cholera
iii. Acute diarrhea xi. Infertility
iv. Toothache xii. Feverish illness
v. Myalgia xiii. Threatened abortion
vi. Dysmenorrhoea, xiv. Backache,
vii. Bony metastases, xv. Postoperative pain
viii.Rheumatoid arthritis and related connective tissue disorders, xv. Gout and soft tissue disorders

Adverse effects:
i. Urticaria vi. Angioneuratic edema
ii. GIT disturbance (Nausea, Vomitting, Diarrhoea) vii. Rashes
iii. Shock viii. Bleeding tendency
iv. Asthma ix. Renal irritation
v. Fever x. Iron deficiency anemia
Dose:
Normal dose : 300 mg thrice daily.
In rheumatoid arthritis: 4-6 gm/day.
Adult : 2-3 tablets four (4) hourly or as required.
1
Children: 2-5 years: to 1 tablets 4 hourly.
2
6- 12 years: 1-2 tablets 4 hourly.

Aspirin must be dissolved in half glass of water before intake not more than 5 does should be given in
24 hours.
Contraindication:
i. Hypersensitivity of aspirin
ii. Patient with severe peptic ulcer
iii. Severe hepatic dysfunction
iv. Patient with anti-coagulant therapy
v. Patient with clotting disorder
vi. Patient with vitamin-K deficiency
vii. During pregnancy

Dosage form:

√Soluble tablet √Elixir


√Capsule √Suppositories.
√Enteric-coated tablet

Market preparation:
Preparation Company
Acipin CV ACI
Solrin Opsonin
Ecospirin Acme
Carva Square
G-Aspirin Gonoishasthaya

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