Synthesis of Acetaminophen and Phenacetin
Since their synthesis in the late 1800s paracetamol (acetaminophen) and
phenacetin have followed divergent pathways with regard to their popularity
as mild analgesic/antipyretic drugs. Initially, paracetamol was discarded in
favor of phenacetin because the latter drug was supposedly less toxic. Today
the opposite is true, and paracetamol, along with aspirin, has become one of
the two most popular 'over-the-counter' non-narcotic analgesic agents. This
marked increase in the wide approval attained by paracetamol has been
accompanied by the virtual commercial demise of phenacetin because of its
role, albeit somewhat circumstantial, in causing analgesic nephropathy. Both
paracetamol and phenacetin are effective mild analgesics, suitable for
treating mild to moderate pain, and their actions are broadly comparable with
those of aspirin and related salicylates, although they do not appear to
possess significant anti-inflammatory activity. Since a major portion of a
dose of phenacetin is rapidly metabolized to paracetamol, it seems possible
that phenacetin owes some of its therapeutic activity to its main metabolite,
paracetamol, whereas its most troublesome side effect (methaemoglobinaemia)
is due to another metabolite, p-phenetidine. The mechanism of action of
paracetamol is poorly defined, although it has been speculated that it may
selectively inhibit prostaglandin production in the central nervous system,
which would account for its analgesic/antipyretic properties. The lack of any
significant influence on peripheral cyclooxygenase would explain the absence
of anti-inflammatory activity. At therapeutic doses paracetamol is well
tolerated and produces fewer side effects than aspirin. The most frequently
reported adverse effect associated with paracetamol is hepatotoxicity, which
occurs after acute overdosage (usually doses greater than 10 to 15g are
needed) and, very rarely, during long term treatment with doses at the higher
levels of the therapeutic range. Paracetamol damages the liver through the
formation of a highly reactive metabolite which is normally inactivated by
conjugation with glutathione.
OH
O
HO
NH 2
O
O
+
N
H
O
acetic anhydride
p-aminophenol
Acetaminophen
H
N
OH
O
CH3ONa
+
N
H
Acetaminophen
O
I
ethyl iodide
O
Phenacetin
Experimental Procedure
Safety Notes!
Para-aminophenol can cause sensitization and dermatitis upon skin contact.
Inhalation can cause asthma and methemoglobin formation. Avoid inhalation,
ingestion and skin contact. In case of skin contact, flush with copious
amounts of water.
Ethyl iodide is an alkylating agent and therefore a likely human carcinogen.
Avoid inhalation, ingestion and contact with skin. In case of accidental skin
contact, flush with copious amounts of water and seek medical advice.
Sodium methoxide is corrosive to skin and can spontaneously combust when
exposed to moisture. Carefully prevent exposure to all sources of moisture,
including air. In case of accidental skin contact, flush with copious amounts
of water.
Ethanol is toxic and flammable. Avoid inhalation and ingestion and keep away
from flames and sparks, such as those that may be generated when
plugging/unplugging electrical equipment. IN case of accidental skin contact,
flush with copious amounts of water.
Synthesis of Acetaminophen
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Put a magnetic stir bar and 0.01 mol of p-aminophenol and 3 mL of H2O in
a 25-mL round-bottom flask. Then add 1.2 mL of acetic anhydride.
Stir and heat the reaction mixture in an 80ºC water bath until the
solid dissolves, then heat an additional 15 minutes.
Remove the heat for 5 minutes, and then cool the reaction mixture using
an ice-water bath until crystals have finished forming. Add 5 mL of
ice water, swirl the entire mixture, and collect the crystals by vacuum
filtration using a Buechner funnel. Wash the crystals twice with 1 mL
of ice water, each time turning off the vacuum to rinse the crystals
before using the vacuum to remove the rinse water. Then use the vacuum
to pull air through the crystals until they are dry. Dry in the oven.
Weigh the crystals and determine the number of moles of product you
have obtained. Retain a small amount of this product to determine its
melting point and IR spectrum.
Synthesis of Phenacetin
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Use the acetaminophen you just made to prepare phenacitin. The
procedure below is written for starting with 0.010 mol of
acetaminophen. If you have significantly less, adjust the relative
amounts of ethanol, NaOCH3, and EtI.
Dissolve 0.01 mol of acetaminophen in 6 mL of absolute ethanol in a 25mL round-bottom flask.
Add 0.55 g of NaOCH3. Important notes: (1) The container of NaOCH3
must be kept tightly closed to protect it from the atmosphere. (2)
NaOCH3 is a fine powder and can be spread around inadvertently. Handle
with great care!
Add 1.20 mL of EtI.
Place a condenser fitted with a drying tube on the reaction flask, heat
the mixture until it’s refluxing, and then continue refluxing for 45
minutes.
Remove the heat, and let the reaction mixture stand 5 minutes.
Remove the condenser and add 15 mL of H2O.
Using a clamp to hold the round-bottom flask, pour the mixture into a
50-mL Erlenmeyer flask. Allow the solution to cool until crystals
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form, and then cool the mixture in an ice-water bath to complete the
crystallization of your product.
Collect the crystalline product by vacuum filtration. Turn off the
vacuum and wash the crystals using 2 mL of ice-cold water, removing the
rinse water by vacuum. Wash the crystals a second time. Then continue
using the vacuum to pull air through the crystals to dry them.
Recrystallize your product by dissolving it in a minimum amount of hot
ethanol: Heat several mL of 95% EtOH, and then add small amounts of it
slowly to dissolve your product in a 50-mL Erlenmeyer flask, keeping it
warm while you dissolve the solid. Then, using hot water, add just
enough to cause the solution to begin to become cloudy. Heat the
solution to boiling (it should be near boiling already), and then allow
the mixture to cool slowly. You may need to scratch the side of the
flask with a glass rod to induce crystallization. Once crystals have
formed at room temperature, cool the solution in an ice-water bath to
complete crystallization.
Collect the crystals by vacuum filtration. Pull air through the
crystals to dry them (about 8-10 minutes) and determine their weight.
Determine the melting points of your acetaminophen and phenacitin.
Obtain an IR of each if time permits – if not, you will be given an IR
spectrum of each. The 1H NMR and 13C NMR spectra of phenacetin are
included below, for your analysis as part of your report. As with all
spectra, assign all peaks to peaks in your compound.
Clean up
Discard all wastes in the appropriately-labeled containers. No organic
materials from this experiment go down the drain in the sink! After you have
poured all you can into the waste containers, wash glassware containing only
residual amounts (clinging to the sides of the glassware) in the sink.
Proton nmr of phenacetin
Carbon nmr of phenacetin