Synthesis of Tylenol: Effects of Reaction Time and Temperature on Acetaminophen Product
Yield
By
Sondra Dean
A Research Paper
Submitted in Partial Fulfuillment of the
Requirements for the Bachelor of Science Degree
In
Chemistry, ACS Certified
_____________
Dr. David Oostendorp
Loras College
April, 2012
Department of Molecular and Life Sciences
Loras College
Dubuque, IA
Author:
Dean, Sondra F.
Title:
Synthesis of Tylenol: Effects of Reaction Time and Temperature on
Acetaminophen Product Yield
Degree/Major: BS Chemistry, ACS Certified
Research Advisor:
David Oostendorp, Ph.D.
Month/Year:
April, 2012
Number of Pages:
15
ABSTRACT
P-aminophenol and acetic anhydride were reacted under heat to synthesize crude acetaminophen.
The reaction conditions of reaction time and temperature were varied so as to determine their
effect on the product yield. Results showed that the greatest yield of acetaminophen was
obtained when the reaction temperature was 135°C and the reaction time was 10 minutes. A
yield of 66.5% was obtained under these conditions.
Chapter I: Introduction
Amongst the most common ingredients in nonprescription pharmaceuticals today is the chemical
acetaminophen. It may be found in such drugs as Alka-Seltzer, Bayer, Benadryl, Dayquil,
Excedrin, Midol, Nyquil, Robitussin, Sudafed, Theraflu, Triaminic, Tylenol, and Vicodin, to
name a few. It is utilized for both its analgesic and antipyretic properties to ease symptoms of the
common cold, headaches, toothaches, muscle aches, backaches, arthritis, menstrual cramps, and
to reduce fevers. As an analgesic, acetaminophen raises one’s threshold for pain thereby making
any pain or discomfort one may be experiencing easier to deal with. Although the processes by
which acetaminophen produces these effects have not yet been determined, it is believed that it
involves the inhibition of the nitric oxide pathway which is involved in regulating the flow of
blood through the vessels. As an antipyretic, acetaminophen hinders the action of pyrogens
which control the action of prostaglandins which signal to the anterior hypothalamus to increase
the temperature of the body. This drug may be preferred by some given that it more gentle on the
stomach than other nonprescription drugs and thus will not agitate the digestive tracts of those
suffering from such gastrointestinal ailments as acid reflux or ulcers. Additionally, physicians
suggest this drug as a safe option for both hemophiliacs and young children. However, despite
the many benefits that acetaminophen offers, its dangers are not to be overlooked. It is possible
to overdose on acetaminophen. If taken in excess, acetaminophen may severely damage the liver
or even cause death. Due to the importance of acetaminophen in pharmaceuticals today, it is
worthwhile to study its synthesis and how we may obtain the largest yields of this drug.
Statement of the Problem
It is well documented that acetaminophen may be easily synthesized in the laboratory from paminophenol and acetic anhydride using only heat to initiate the reaction. However, it has not yet
been studied how optimum product yields may be obtained from this reaction.
Purpose of the Study
The purpose of this study is to determine the optimal temperature and reaction time to synthesize
acetaminophen in order to obtain the greatest product yield.
Chapter II: Literature Review
Previous studies have been conducted on similar topics. Research has been performed seeking to
find which set of conditions in synthesis reactions of common pharmaceutical chemicals will
produce the greatest product yield. These studies vary widely in the drug and reaction variables
chosen to be investigated.
In general, undergraduate laboratories accept a reaction time of 10 minutes at a temperature of
115° C will give a sufficient yield of acetaminophen product. These conditions are satisfactory
when the synthesis is carried out utilizing only p-aminophenol and acetic anhydride reagents in
aqueous solution and supplying a heat source.
In 2010, Yandong Shao, Yonghong Li, Yinghua Yu, Qipeng Zhao, and Jia Wei performed
related research on the optimization of product yield in an acetaminophen synthesis. This
research team created their product by reacting p-aminophenol and acetic anhydride in a dilute
acetic acid solvent under microwave irradiation conditions. Additionally, zinc was utilized as an
antioxidant and activated carbon as a decolorizing agent. The greatest percent yield obtained was
82.1%. This was acquired when the reaction was run at a temperature of 105°C, the reaction was
permitted to run 17 minutes, the ratio of p-aminophenol to acetic anhydride was 1:1.3, the
concentration of the dilute acetic acid was 4%, and the power of the microwave radiation was
500W.
Product yield optimization studies have been conducted on many other pharmaceutical
chemicals, as well. One such study was conducted on acetylsalicylic acid (aspirin) by Jin Wang
and Wei Sun in 2009. The reaction conditions of interest to them included the reaction
temperature, the reaction time, the identity of the catalyst, and the catalyst concentration. They
found that the ideal conditions for their synthesis that produced the greatest product yield was a
reaction temperature of 55°C, a reaction time of 50 minutes, and a sodium acetate catalyst at a
concentration of 3%. These conditions produced a yield of 81.9%.
Chapter III: Methods and Materials
This research study sought to determine how the greatest percent yield of acetaminophen could
be obtained from a synthesis reaction utilizing p-aminophenol and acetic anhydride as reagents.
The reaction conditions varied were the reaction time and temperature. An aqueous solution of
micro-amounts of p-aminophenol and acetic anhydride reagents was prepared in a reaction flask.
Approximately 0.100 g of p-aminophenol was reacted. The acetic anhydride was added to the
solution using a micropipette. Therefore, the volume of acetic anhydride was a constant 0.110
mL. This solution was then heated until the p-aminophenol solid dissolved. The temperatures at
which the reactions were carried out were 105°C, 115°C, 125°C, or 135°C. After no more solid
was visible in the solution, the mixture was heated for a timed period. Either the solution was
heated for 5, 10, or 15 minutes. This was the case for all trials except for that which the reaction
was carried out at 115°C. At this temperature, only a trial of a 10 minute reaction time was
conducted so as to analyze the amount of acetaminophen product obtained when the reaction was
carried out exactly as many undergraduate laboratory procedures suggest, at 115°C for a period
of 10 minutes. After the reaction occurred, the product was removed from the heat and permitted
to cool to room temperature. Once ambient temperature was achieved, it was placed in an ice
bath for approximately 15 minutes. The crystals were then collected on a Hirsch funnel using
vacuum filtration and washed with two 1 mL portions of ice water. Finally, to dry the crystals,
air was drawn through them for 10 minutes on a Hirsch funnel and they were left to air dry on a
watch glass overnight before the mass was taken.
Data Analysis
The expected acetaminophen yield was calculated from the amount of p-aminophenol reagent
utilized. The percent yield of each trial was then calculated using this value and the experimental
yield. An average percent yield was then calculated for each reaction time and temperature set.
These average percent yields were utilized to determine which reaction temperature and time set
produced the greatest acetaminophen product yield.
Chapter IV: Results
Acetaminophen was synthesized from p-aminophenol and acetic anhydride at different reaction
time and temperature combinations. For each temperature trial of 105°C, 115°C, 125°C, and
135°C three reaction time trials were run for 5, 10, and 15 minutes. Furthermore, for each
temperature and reaction time trial, three reactions were conducted so as to obtain an average
percent yield of acetaminophen product for that set of reaction conditions.
The tables below provide the data obtained from this research. The mass of p-aminophenol
reagent is given as is the theoretical yield, experimental yield, and percent yield of
acetaminophen. All these values are given in terms of grams.
Figure 1: Results of 105°C Trial
Reaction Time
5 min.
10 min.
15 min.
105°C Reaction Temperature
p-aminophenol
theoretical yield experimental yield percent yield
0.100
0.139
0.003
2.166
0.109
0.151
0.006
3.974
0.126
0.175
0.009
5.157
p-aminophenol
theoretical yield experimental yield percent yield
0.110
0.152
0.005
3.282
0.101
0.140
0.006
4.289
0.116
0.161
0.004
2.489
p-aminophenol
theoretical yield experimental yield percent yield
0.090
0.125
0.005
4.011
0.105
0.145
0.096
66.007
0.102
0.141
0.078
55.208
Figure 2: Results of 115°C Trial
Reaction Time
10 min
115°C Reaction Temperature
p-aminophenol
theoretical yield experimental yield percent yield
0.101
0.140
0.007
5.004
0.108
0.150
0.019
12.701
0.101
0.140
0.036
25.733
Figure 3: Results of 125°C Trial
Reaction
Time
5 min
10 min
15 min
125°C Reaction Temperature
p-aminophenol
theoretical yield experimental yield percent yield
0.113
0.157
0.035
22.361
0.098
0.136
0.014
10.314
0.100
0.139
0.047
33.932
p-aminophenol
theoretical yield experimental yield percent yield
0.098
0.136
0.077
56.725
0.112
0.155
0.066
42.543
0.114
0.158
0.043
27.231
p-aminophenol
theoretical yield experimental yield percent yield
0.095
0.132
0.045
34.198
0.107
0.148
0.053
35.760
0.108
0.150
0.046
30.750
Figure 4: Results of 135° C Trial
Reaction
Time
5 min
10 min
15 min
135 °C Reaction Temperature
p-aminophenol
theoretical yield experimental yield percent yield
0.104
0.144
0.081
56.229
0.098
0.136
0.092
67.775
0.104
0.144
0.054
37.486
p-aminophenol
theoretical yield experimental yield percent yield
0.110
0.152
0.098
64.319
0.103
0.143
0.083
58.177
0.103
0.143
0.110
77.101
p-aminophenol
theoretical yield experimental yield percent yield
0.110
0.152
0.063
41.348
0.102
0.141
0.073
51.669
0.104
0.144
0.064
44.428
Figure 5: Average Percent Yield of Acetaminophen Product Obtained from Each Trial
Reaction Time and Temperature
vs. Average Percent Yield
100.000
90.000
Percent Yield
80.000
70.000
60.000
115 C
50.000
135 C
40.000
125 C
30.000
105 C
20.000
10.000
0.000
5 min
10 min
15 min
To ensure that my product was in fact acetaminophen, an IR spectra was obtained. Three
characteristic peaks of this chemical were expected if I was successful in my synthesis. A peak at
3100-3500 cm-1 characteristic of an N-H bond, a peak at 3200-3650 cm-1 characteristic of an
alcohol group, and a peak at 1690-1760 characteristic of a carbonyl group were all expected.
These peaks were found to be present on the IR spectra. Therefore, it may be concluded that the
procedures utilized in this study were successful in synthesizing the desired acetaminophen
product.
Figure 6: IR Spectrum of Acetaminophen Product
Chapter V: Discussion
Acetaminophen is a widely used nonprescription pharmaceutical favored for its analgesic and
antipyretic properties. It may be easily synthesized in the lab by reacting a solution of paminophenol and acetic anhydride and adding heat. Common undergraduate laboratory
procedures suggest a reaction temperature of 115°C and a reaction time of 10 minutes and states
that sufficient yields may be acquired under these reaction conditions. However, it has not been
studied which reaction time and temperature combination yields the greatest amount of
acetaminophen product from the starting materials. That is the information that this research
study sought to determine.
Conclusions
In general, it was discovered that larger product yields were obtained at greater reaction
temperatures where the most product was obtained at a temperature of 135°C the least was
obtained at a temperature of 105°C. Additionally, in general, it was found that the greatest
product yields were obtained after a 10 minute reaction time. More product was acquired after a
reaction time of 10 minutes than after 5 minutes, but the percent yield decreased for times longer
than this.
The greatest average percent yield obtained using this method of synthesizing acetaminophen
was 66.532%. This yield was obtained at a reaction temperature of 135°C for a reaction time of
10 minutes. The temperature I found to give the greatest yield was 30°C greater than the 105°C
temperature at which Shao, Li, Yu, Zhao, and Wei discovered the most acetaminophen product
could be obtained. In fact, the least amount of product was obtained at this temperature using my
experimental set up. Additionally, the reaction time of 10 minutes I found to give the greatest
yield was 7 minutes less than their 17 minute reaction time. These discrepancies in our findings
are likely attributable to their use of microwave irradiation, diluted acetic acid solvent, and zinc
antioxidant to assist the reaction.
Comparing my results to the set of reaction conditions suggested in undergraduate laboratory
procedures for the synthesis of acetaminophen, I found that greater yields could be obtained if
the temperature at which the reaction was carried out was increased by 20°C. Although it is
commonly recommended the reaction be carried out at 115°C, my results show more product
could be obtained if it were carried out at 135°C. The recommended reaction time of 10 minutes
was in agreement with my results, giving the greatest amount of product.
Recommendations
Further research into this topic could be conducted evaluating the yield of acetaminophen
obtained at even greater temperatures than those studied in this project. Additionally, longer
reaction times could be studied to see if these produce considerably greater yields of product, as
the Shao lab discovered.
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