▷ Paracetamol synthesis | Chemistry Online (2024)

Written by J.A Dobado | Last Updated on May 2, 2024

Objective

In this experiment, the three-step synthesis ofparacetamol(p-acetamidophenol) from phenol is carried out.

3D structure

Background

paracetamol(p-acetaminophenol) is a crystalline solid with a melting point of 169-171 ºC that is used as an analgesic and antipyretic, although it has no significant anti-inflammatory action. Commercially it appears under different names: Commercially it appears under various names Acertol®, Actron®, Antidol®, Apiretal®, Bandol®, Calmanticold®, Cupanol®, Dafalgan®, Dolgesic®, Dolostop®, Duorol®, Efferalgan®, Febrectal®, Gelocatil®, Melabon infantil®, Panadol®, Pediapirin®, Perfalgan®, Resakal®, Sinmol®, Temperal®, Termalgin®, Tylenol®. For example, in 1955 it was put on sale in the USA under the nameTylenol, in 1956, in the UK under the namePanadol. It is a drug (non-opioid analgesic and non-steroidal anti-inflammatory drug) that is on theWHO list of essential medicines.

The synthesis ofparacetamolwas first performed byJ. von Meringin 1893 although it was not commercialized until 1953, being considered since then as a safer active ingredient thanaspirin,especially for children and patients with stomach ulcer.

Paracetamol can be synthesized in three steps fromphenol. In the first stage,phenolis nitrated and the isomers obtained are separated. In the second stage, the nitro group is reduced to the amino group, and in the third stage, the amino group is acetylated withacetic anhydrideselectively against the phenolic -OH group.

Experimental procedure

DANGER! “Carry out all experiments in fume cupboard”.

A) Nitration of phenol: synthesis ofp-nitrophenol

To a 250 ml flask, cooled with an ice bath, 15 g of sodium nitrate and 40 ml of water are added. The mixture is stirred until the solid is completely dissolved, and then 25 g (13.6 ml) of concentrated H2SO4is added little by little. Then, 9.4 g ofphenolare slowly added with the help of a spatula, so that the temperature of the mixture does not exceed 20 °C, which will take about 20 min.

After finishing of the addition, the reaction is stirred for 2 h at room temperature. Under these conditions a mixture of theo– andp-nitrophenolis produced.

With the aid of aPasteurpipette, the supernatant liquid is removed, 30 ml of water is added and a setup is made for asteam entrainment distillationwith internal steam source. The mixture is heated, adding water from the addition funnel at the same rate as the distillation of the vapors, until the product (2-nitrophenol) stops distilling.

When the mixture remaining in the flask is cooled, crystallization of the other isomer (4-nitrophenol) occurs, which can berecrystallizedusing an HCl solution of concentration 0.5 moles / 100 ml.

B) Reduction of the nitro group to amino: synthesis ofp-aminophenol

To an Erlenmeyer of 100 ml is added 4 g of NaOH, and 10 ml of deionized water. After the base has dissolved and the solution has cooled to room temperature, 0.56 g (14.7 mmol) of NaBH₄and 50 mg of 5 % Pd(C) are added.

The mixture is cooled in an ice/salt bath (-12 °C) and once cooled, 1 g (7. 2 mmol) ofp-nitrophenolwith magnetic stirring for 30 min, keeping the reaction temperature around 15 °C.

Check the temperature inside the Erlenmeyer flask with a thermometer without the stir bar hitting the bulb.

Once the addition is finished, the agitation is maintained at room temperature for another 15 min.

The reaction crude is then acidified with 6 M concentration HCl.
The catalyst isfilteredunder vacuum and the filtrate is pH adjusted to 8 by addition of NaHCO3in small portions. The precipitate is filteredunder vacuum, dried and weighed for use in the next step (estimated yield 75 %).

C) Synthesis of paracetamol: amide formation

In an Erlenmeyer containing 3.3 g ofp-aminophenoland 9 ml of water, 3.6 ml ofacetic anhydrideare added dropwise with caution, stirring the mixture constantly. It is then heated in a water bath at 60 °C until complete dissolution of the solid.

Stirring is maintained for an additional 10 min and then the solution is cooled in an ice bath until the appearance of a slightly pink crystalline product.The crystals appearing in the reaction crude arefilteredunder vacuum in a Büchner.

The final product can be analyzed using thin-layer chromatography (TLC). The R_f value of the product was found to be 0.50 and mesurement of melting point 169-171 ºC.

Physico-chemical properties

This table collects data for the molecular weight (M_w), melting point (M.p.) boiling point (B.p.) and density of the reactives and compounds used in this laboratory experiment.

GHS pictograms

Hazard pictograms form part of the international Globally Harmonized System of Classification and Labelling of Chemicals (GHS) and are collected in the followinf Table for the chemical compounds used in this experiment.

Name	GHS
Acetic anhydride
Benzoic acid
Phenol
o-Nitrophenol
p-Acetamidophenol
p-Nitrophenol
4-Aminophenol

International Chemical Identifier

The IUPAC InChI key identifiers for the main compounds used in this experiment are provided to facilitate the nomenclature and formulation of chemical compounds and the search for information on the Internet for these compounds.

References

• Isac-García, J.; Dobado, J. A.; Calvo-Flores, F. G.; and Martínez-García, H. (2015). Experimental Organic Chemistry Laboratory Manual. Elsevier Science & Technology. ISBN: 978-0-12-803893-2
• F. Ellis, C. Osborne, and M. J. Pack, Paracetamol: A Curriculum Resource, Royal Society of Chemistry, 2002.