Synthesis of Acetaminophen
Synthetic FFR 3
Chem 213 Section 2
TA: Michael Banales
By: Alexander Grego
4/16/13
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Introduction
Acetaminophen, or paracetamol, itself is one of the most resourceful and useful analgesic
in the world today. An analgesic is a chemical compound that helps relieve pain, reduce fevers
and help with inflammation.1 The way acetaminophen, and other analgesics, works is by
stopping the enzyme cyclooxygenase. Cyclooxygenase is known as a catalyst for converting
fatty acid into prostaglandins. Prostaglandins have many different functions but one of these
functions is producing pain and inflammation. Prostaglandins cause pain and inflammation at the
injury site in the central and peripheral nervous system. They also cause fevers because
prostaglandins raise body temperature through the heat regulation center in the brain.
Acetaminophen itself does not completely block the pain but reduces the primary pain that is
involved in the central nervous system by inhibiting a certain form of cyclooxygenase .1
Acetaminophen is made by a synthesis and a preparation of an amide. An amide can be
prepared by combing an amine and an acidic anhydride.2 Amides are very versatile with their
utility in organic synthesis because the carbonyl substituent allows amides to act as H-bond
acceptors. Coincidently the nitrogen to hydrogen dipoles allows the amide to act as an H-bond
donator as well. Due to these properties, amides can be widely used. The amide bond in general
can be used in polymers, peptides, natural products and a wide production of pharmaceuticals.3
The purpose of this lab was to run a reaction and create acetaminophen from paminphenol (the amine) and acetic anhydride (the acidic anhydride) .4 First the p-aminophenol
and acetic anhydride were refluxed. Next the crude acetaminophen was recrystallized and
isolated. Before purification, a decolorization technique using a sodium hydrosulfite and water
mixture as solvent was used to obtain colorless precipitate. Finally the now semi-colorless crude
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acetaminophen was recrystallized again to boil off the water, methanol and sodium
hydrosulfite/water combination. The mechanism for the combination of p-aminophenol and
acetic anhydride can be found below:
Scheme 1
The mechanism for synthesizing acetaminophen involves a preparation of an amide. The
reaction started off with a nucleophilic attack from the aromatic amine to the carbonyl carbon of
the acetic anhydride. The resulting adduct decomposed to produce the protonated acetaminophen
and leftover acetate. A proton was then transferred to the solvent acetate. This whole reaction
yielded the final product of acetaminophen.
Experimental
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1. P-aminophenol (0.750 g), water (2.25 mL), and acetic anhydride (0.850 mL) were
combined and refluxed for 15 minutes at 100 °C.
2. Scratched the bottom of the flask to start crystallization. Cooled mixture in ice bath
for 15 minutes. Vacuum filtrated crude product. Let crude acetaminophen dry in
locker.
3. Mixed sodium dithionite (1g) and water (7.5 mL) in flask. Added crude
acetaminophen. Heated for 15 minutes at 100°C. Cooled in ice bath and vacuum
filtrated the decolorized product.
4. Recrystallized the crude acetaminophen, in a 1:1 mixture of methanol/water (10mL
total). Cooled to room temperature and then cooled in ice bath for 15 minutes.
Vacuum filtrated and yielded crystals. The melting point was 168-171°C (lit value
168-172°C).Yield of acetaminophen: 49.1%. IR (ATS) v (𝑐𝑚−1 ) 3317.80, 3108.06,
1645.86, 1609.30, 1559.75, 1503.35, 1434.00; 1H NMR (60 MHz, CD𝐶𝐿3 ) δ (ppm)
9.62 (s, 1H), 9.11 (s, 1H), 7.27-7.42 (d, 2H), 6.59-6.74 (d, 2H), 1.98 (s, 3H); 1H NMR
(400 MHz, CD𝐶𝐿3 ) δ (ppm) 9.66 (s, 1H), 9.14 (s, 1H), 7.33-7.36 (d, 2H), 6.66-6.69
(d, 2H), 1.98 (s, 3H);
13
120.76, 114.94, 23.71.
C NMR (400 MHz, CD𝐶𝐿3 ) δ (ppm) 167.47, 153.08, 130.99,
Results and Discussion:
In this experiment, p-aminophenol was synthesized with acetic anhydride and water to
obtain a crude acetaminophen product. The synthesizing occurred when the starting materials
were refluxed. Crystallization, decolorization and recrystallization were then used to obtain and
purify a final product of acetaminophen with no solvents and colored properly.
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The main purpose of this lab was to synthesize acetaminophen from acetic anhydride and
p-aminophenol. The percent theoretical yield of the final product was 49.1% and This can
conclude that the whole synthesis was successfully completed and acetaminophen was formed.
The melting point of the product was 168-171°C and was almost exact to the literature value of
168-172°C which can conclude accuracy. The IR spectrum showed the appropriate and
distinguishing peaks of the product. The significant peaks of the acetaminophen product were
3317.80 cm, 3108.06 cm, 1645.86 cm, 1609.30 cm, 1559.75 cm, 1503.35 cm, and 1434.00 cm.
The significant distinguishing peak at 3317.80 cm showed the amine nitrogen to hydrogen
stretch. This peak was significant because the starting material amine peak would have shown
two distinct peaks for each hydrogen attached to the nitrogen. Since there was only one peak the
amide group of the product was shown. The peak at 3108.06 cm showed the oxygen to hydrogen
stretch found in both starting material and product. The other significant distinguishing peak at
1645.86 cm showed the entire amide group. This peak was shown lower and more distinct
towards the amide than the original carbonyl peak that would appear if the starting material was
present. The peaks from 1503.35 – 1609.30 cm showed the carbon to carbon double bonds. The
methyl group present off of the carbonyl was shown by the peak at 1434.00 cm.
Other distinguishing factors were the 1H NMR (60 MHz and 400 MHz) and the 13C
NMR (400 MHz) data. From the 400 MHz (Figure 3), the significant peaks were shown at 9.66
ppm, 9.14 ppm, 7.33-7.36 ppm, 6.66-6.69 ppm and 1.98 ppm. The peak at 9.66 ppm showed the
amine group. It was important to notice that this peak had an integration value of ~1 instead of
the starting materials predicted integration value of ~2. This means that the product was formed
rather than amine on the acetic acid in the starting material. The peak at 9.14 ppm showed the
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aromatic alcohol group found in the starting material and product. The peak from 7.33 to 7.36
ppm and 6.66 to 6.69 ppm showed the C-H aromatic groups. The 7.33 to 7.36 ppm was more
deshielded because of the amine and carbonyl groups closer to it. The peak at 1.98 ppm showed
the methyl group from the carbonyl. The impurity peak at 3.41 ppm showed leftover water and
the peak at 2.50 to 2.51 ppm showed leftover dimethyl sulfoxide. In order to be more accurate, a
13
C NMR (Figure 4) was performed and more distinct peaks appeared. For the original p-
aminophenol group, peaks at 153.08 ppm, 120.76 ppm, 114.94 ppm and 130.99 ppm were
shown. For the carbonyl group from the acetic acid, peaks at 23.71 ppm for the methyl and
167.47 ppm for the carbonyl double bond were shown. The 167.47 ppm bond was deshielded
though, due to the fact of the new attachment of the amine.
The main goal of this experiment was to synthesize acetaminophen from its main
components p-aminophenol (amine) and acetic anhydride (acidic anhydride). First both
components were synthesized and refluxed with water. The crude acetaminophen was then
decolorized and recrystallized in order to remove solvents and obtain pure acetaminophen.
Percent yield, melting points, IR, 1H NMR (60 MHz, 400 MHz) and a 13C NMR (400 MHz)
were used to analyze and confirm the success and accuracy of creating acetaminophen. Each test
analysis showed the creation of acetaminophen and even the small, yet informative, detail of the
new formation of the amide proving that the synthesis was accomplished. The percent yield
overall also showed that acetaminophen was properly synthesized, yet overall this experiment
would need to be done on a large scale in order to obtain enough product. In conclusion, the
preceding data has shown and proved that a successful synthesis of acetaminophen had been
conducted.
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References
1. Regina M. Botting, Mechanism of Action of Acetaminophen: Is There a Cyclooxygenase 3?
Clinical Infectious Diseases , Vol. 31, Supplement 5. A Symposium Marking 4
Millenia of Antipyretic Pharmacotherapy (Oct., 2000), pp. S202-S210, Published
by: Oxford University Press, Article Stable URL: http://www.jstor.org/stable/4461386
2. ChemGuide, n.d. , "Acid Anhydrides with Ammonia or Primary Amines." Acid Anhydrides
with Ammonia or Primary Amines. Web. 18 Apr. 2013.
3. Conference; Meeting Abstract ,Abstracts of Papers, 245th ACS National Meeting &
Exposition, New Orleans, LA, United States, April 7-11, 2001, PagesORGN-556;
Computer Optical Disk, 2013
4. Pavia, D.L.; Lampman, G.M.; Kriz, G.S.; Engel, R.G. Introduction to Organic Laboratory
Techniques, A Small Scale Approach, 2nd Edition. 2005, Thompson, Brooks, Cole
Publisher, pages 68 – 71.
5. Acetaminophen. Sigma-Aldrich.
http://www.sigmaaldrich.com/catalog/product/sial/A3035?lang=en&region=US (accessed:
April 17, 2013)
6. Rummel, Sheryl A. Lab Guide for Chemistry 213: Introductory Organic Chemistry
Laboratory; Hayden-McNeil Publishing, 2001
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