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Kristyn Murphy

Organic Chemistry I Laboratory


Synthesis of Acetaminophen
Introduction
The purpose of this experiment was to synthesize an amide (acetaminophen (p-acetamidophenol))
from an amine (p-aminophenol) and an acid anhydride (acetic anhydride). The general procedure used in
this experiment was to heat the mixture of p-aminophenol and acetic anhydride, isolate crude
acetaminophen by vacuum filtration on a Bchner funnel, purify the crude acetaminophen by
recrystallization, collect purified acetaminophen by vacuum filtration on a Bchner funnel, calculate the
percentage yield, and measure the melting point of the acetaminophen with a Mel-temp.
Experiment Scheme
Initially, 1.5g of p-aminophenol was weighed and placed in a 50mL Erlenmeyer flask. 4.5mL of
water were measured and added, followed by 1.7mL of acetic anhydride. Equation 1 shows the reaction
of p-aminophenol and acetic anhydride to form acetaminophen and acetic acid.
Equation 1. Formation of acetaminophen and acetic acid from p-aminophenol and acetic anhydride

+
p-aminophenol

acetic anhydride

+
acetaminophen

CH3COOH
acetic acid

A magnetic stir bar was added to the solution to prevent it from bumping. The flask was heated to 100C
on a hot plate. Once the solid was dissolved, it was heated for an additional 10 minutes at 100C. After
this period, it was removed from the hot plate and allowed to cool to room temperature. It was then
placed in an ice bath for 15 minutes. This mixture was poured into a Bchner funnel, and the crystals
were dried for 10 minutes using vacuum filtration. This apparatus can be seen in Figure 1.
Figure 1. Vacuum filtration and Bchner funnel apparatus

(At this point the system was accidentally tipped and much product was lost. The remainder of the
experiment was carried out with what product could be salvaged off the counter.) The dried crystals were
weighed and observed, and a small amount was set aside in order to determine the melting point.
After the crude acetaminophen was obtained, the process of purification via recrystallization
began. Approximately 20mL of a solvent mixture of 50% methanol and 50% water by volume was
obtained and heated to nearly boiling. The crude acetaminophen and 2.0g of sodium dithionite were
placed in a 50mL Erlenmeyer flask. The hot solution of methanol and water was slowly added to the
acetaminophen and sodium dithionite until most of the solid was dissolved. The flask was warmed to
attempt to dissolve the rest of the solid. After it seemed that no more of the solid would dissolve, the flask
was allowed to cool to room temperature. It was then cooled in an ice bath for 10 minutes. The solution
was again poured into a Bchner funnel and the crystals were dried for 5 minutes. An inappreciable
amount of material was collected, so although observations were made, nothing else could be done with
the substance. Normally, it would have been weighed to determine percent yield, and some of it would
have been used to determine the melting point.
Percent yield for the acetaminophen can be calculated by dividing the actual yield by the
theoretical yield (all in grams). The actual yield is simply the amount of pure acetaminophen that was
weighed. The theoretical yield was calculated by first using the amounts of p-aminophenol and acetic
anhydride and their respective molecular weights to determine which compound had fewer moles. The
compound with fewer moles was noted as the limiting reagent. It was then determined how many moles
and how many grams of acetaminophen could be created with that amount of limiting reagent.
The boiling point was determined using a Mel-temp (see Figure 2). A small amount of material
was placed in a melting-point tube and then the Mel-temp was used. This device contains a magnifying
lens so that the substance can be observed as it is gradually heated. The melting range begins as soon as
the substance begins to become soft and ends as soon as all of the material is liquid.
Figure 2. Mel-temp

Data
Table 1. Chemical Table1

Name

Formula

MW
(g/mol)

Amount
(g)

Moles

State
-2

Density
(g/mL)

M.P.

B.P.

Theo.
Yield

Hazards

(C)
185189

(C)
-

toxic; skin irritant

p-aminophenol

C6H7NO

109.13

1.5

1.37 * 10

acetic
anhydride

C4H6O3

102.09

1.9
(1.7mL)

1.79 * 10-2

1.1

-73

138140

avoid breathing/contacting

acetaminophe
n

C8H9NO2

151.16

168172

2.1

harmful if swallowed; eye,


respiratory, and skin
irritant

sodium
dithionite

Na2S2O4

174.11

2.0

1.15 * 10

2.5

300

harmful if swallowed; may


cause fire; emits toxic
gases with exposure to
water and acids

methanol

CH3OH

32.04

.79

-98

6465

highly flammable; toxic if


inhaled, contacted, or
swallowed

-2

The initial solution of p-aminophenol, water, and acetic anhydride was a dark purple-brown color.
This solution also gave off enough heat to make the flask very warm to the touch. The crystals that were
formed as a product of this reaction were a light-brown color. When the crystals were combined with the
sodium dithionite and the methanol-water solution for recrystallization, they slowly dissolved and the
solution gained a yellow tint. There were a few small clumps of white solid that remained in solid form
during the entire recrystallization process. These were assumed to be pure acetaminophen that would not
go into solution. During the cooling stage of recrystallization, there was a white, sugar-like substance
noted in the solution. This was also assumed to be pure acetaminophen. When this was poured into the
Bchner funnel, there was an initial filtration of the white material, but most of it seemed to eventually go
through the filter paper with the rest of the solution.
The melting range of the first portion of acetaminophen was seen to be 174C-180C. There was
not enough material gathered from the second portion to measure its melting point.
Equation 2 shows the calculation of the theoretical yield of acetaminophen, which comes out to be
2.1g. The amount of crude acetaminophen retrieved was 1.46g. There should also be an equation that
3

shows the percent yield of the final portion of acetaminophen, but this was not possible because of the
small amount of substance retrieved.
Equation 2. Theoretical yield of acetaminophen
1.5g p-aminophenol * 1mol = .014mol p-aminophenol
109.13g
1.7mL acetic anhydride * 1.1g * 1mol = .018mol acetic anhydride
mL 102.09g
P-aminophenol has fewer moles and is therefore the limiting reagent.
P-aminophenol and acetaminophen are in a 1:1 ratio in this reaction so:
.014mol p-aminophenol = .014mol acetaminophen
.014mol acetaminophen * 151.16g = 2.1g acetaminophen
mol
Discussion
This experiment utilized a reaction where an amide (acetaminophen) was synthesized from an
amine (p-aminophenol) and an acid anhydride (acetic anhydride). This is an acetylation reaction, where
an acetyl group is substituted for an active hydrogen.2 Once this mixture was created, it was heated so
that it would go to completion. If this did not happen, some of the p-aminophenol may have remained in
its solid state rather than reacting with the acetic anhydride. After thorough heating, the solution was
cooled so that acetaminophen could crystallize. The crystals and the solution were in were put through a
Bchner funnel and then dried with vacuum filtration. This was done to remove any excess liquids from
the acetaminophen. After the crystals were dried, it was noted that they were light-brown. This was due
to oxidation of the p-aminophenol. The crystals were combined with sodium dithionite, which reduces
double bonds in the colored substance to create a colorless substance.3 A recrystallization process was
also conducted to attempt to purify the acetaminophen further. In this process, hot solvent was added to
the acetaminophen until it dissolved. The solution was then slowly cooled. As it cooled, selective
crystallization formed crystals of acetaminophen while the small amounts of impurities remained in
solution. This creates a mostly pure form of acetaminophen.4
4

When our vacuum filtration apparatus was tipped, a very large amount of product was lost. The
apparatus should have been clamped to something to stop this from happening. Further loss of product
may have occurred elsewhere as well. The initial reaction may not have carried through to completion, so
some product may have been lost there. It is also likely that some product was lost when it was filtered
through the Bchner funnel. If it had not crystallized yet, it may have been too small to have been
stopped by the filter. This was especially true in the second filtration, where a substance that appeared to
be product was seen slowly filtering down. Filters with smaller openings could have been used to reduce
this loss. Some product was also lost during the recrystallization process. The method of this process
dictates that not all of the dissolved product can be recovered because some of the pure product must be
lost along with the impure substances.5 It was also important to add just enough of the hot solvent to
dissolve the solid and no more, because too much would cause more product to remain in solution.
Determining the correct amount of solvent can be difficult thing to do, and it could very well be that too
much was added to the acetaminophen.
Another source of error in this experiment could have come in measuring the melting point of the
acetaminophen. The observed melting point range for crude acetaminophen was 174C-180C. The
melting-point range of crude substances is usually much more spread out. An error may have occurred in
determining when melting began. While it was easy to see that the all of the crystals became liquid at the
endpoint, it was more difficult to see when the crystals began to melt. It is more likely that they began to
melt closer to 160C, creating a 20 melting-point range.
The experiment was somewhat successful because it is likely that a small amount of pure
acetaminophen was synthesized and gathered. While the white color indicates this, it cannot be verified
because it was not possible to determine a melting point of the substance.
Questions
4. If 1.30 g of p-aminophenol is allowed to react with excess acetic anhydride, what is the theoretical
yield of acetaminophen in moles? In grams? Show your work!
1.30g p-aminophenol * 1mol = .0119mol p-aminophenol
109.13g
.0119mol p-aminophenol = .0119mol acetaminophen (theoretical yield in moles)
5

.0119mol acetaminophen * 151.16 g = 1.80 g acetaminophen (theoretical yield in grams)


mol
5. Give two reasons why the crude product in most reactions is not pure.
a) Both the reactants and products are allowed to interact with atmosphere, which will lead to impurities
being introduced into the system.
b) It could be that the reaction did not complete, so there may still be intermediate substances in the
product.
References
1. Sigma Aldrich. http://www.sigmaaldrich.com/safety-center.html. Date accessed: September 13,
2009.
2. The Free Dictionary. http://www.thefreedictionary.com/acetylation. Date accessed: September 20,
2009.
3. Pavia, Lampman, Kriz, Engel. Organic Chemistry Laboratory Manual. 2009. Pg 11.
4. Pavia, Lampman, Kriz, Engel. Techniques in the Organic Laboratory. 2002. Pg 139.
5. Pavia, Lampman, Kriz, Engel. Techniques in the Organic Laboratory. 2002. Pg 142.