The Synthesis of Phenacetin from Acetaminophen
Introduction
Acetaminophen, also known as paracetamol, and phenacetin (both shown in Figure 1) are non-
opioid analgesics. Acetaminophen was first synthesized in 1877, and first used in humans in 1887.
It is the most widely used, non-anti-inflammatory medication for mild to moderate pain relief and
fever reduction. Phenacetin is an analog of acetaminophen and was utilized for nearly 100 years
until the FDA banned its use in 1983 and all products it was contained in. Although it was effective
as a non-opioid analgesic, physicians and the FDA had concerns with its carcinogenic properties
as well as its negative effects on the kidneys.
Figure 1. The structures of acetaminophen and phenacetin
OH
N
H
O
acetaminophen
OCH
2
CH
3
N
H
O
phenacetin
The synthesis of phenacetin from acetaminophen will be accomplished via the Williamson-ether
synthesis. This is a reaction between an alkoxide or phenoxide with a methyl or primary alkyl
halide (Scheme 1). Scheme 1 depicts an ethoxide reacting with methyl iodide to yield the
compound ethyl methyl ether.
Scheme 1. The synthesis of an ether via the Williamson-ether reaction
O
CH3I, DMSO
O
ethoxide ethyl methyl ether
Scheme 2 shows the reaction that will be performed in this experiment. Acetaminophen is treated
Scheme 2. Phenacetin synthesized from acetaminophen using potassium carbonate
OH
N
H
O
K2CO3, CH3CH2I
O
, reflux, 1 h
acetaminophen
OCH2CH3
N
H
O
phenacetin
with anhydrous potassium carbonate and ethyl iodide, while 2-butanone is employed as the
solvent. The reaction is heated at reflux for 1 hour and then put through a series of workup steps.
