Synthesis of paracetamol via acetylation and analysis of product

Name: NN dccn2
Demonstrator: Experiment Date: 10-10-2022 Experiment Info:
Experiment A2 – Thursday Group - Bay 1 Report Date: 12/10/2022

Introduction & Theory

N-(4-hydroxyphenyl)ethanamide, more commonly known as paracetamol, is a non-opioid analgesic

used widely for pain relief. It is thought to work by limiting the chemical messengers for pain
signalling [1].

Structurally it is made up of phenol (OH group in the para position) bonded to an amide group via
nitrogen. Using 4-aminophenol [2] as the starting material, the experiment is based on the formation
of the amide bond from an amino group. This is done using an aqueous acid anhydride ((CH3CO)2O).
Crystallisation techniques were also used in this experiment to obtain the solid product crystals from
the reaction.

Reaction Scheme

Mechanism

The acetylation reaction is summarised above in the reaction scheme: 1 equivalent of 4-

aminophenol reacts with aqueous ethanoic anhydride (1 equivalent) and the heated mixture reacts
to form N-(4-hydroxyphenyl)ethanamide. The acetyl group is substituted for a hydrogen in the NH2
functional group.

The mechanism depicts the process of nucleophilic attack: NH2 is the nucleophile that attacks the
delta-positive carbon in C=O (nitrogen’s electronegativity allows easier nucleophile lone pair
donation compared to oxygen in the OH group). Frontier Molecular Orbital theory (FMO) explains
that the interaction occurs due to best interaction between C=O π* as the LUMO and N lone pair
orbital as the HOMO. The final stages of the mechanism depict the reformation of the carbonyl bond
due to the leaving group. Proton swap occurs and ethanoic acid leaves due to its much lower pKa
(approximate pKa of 4-5). 1:1 ratio of equivalents is used because side reactions are unlikely to occur
(the paracetamol is very bulky making nucleophilic attack unlikely, whilst the ethanoic acid would
react with 4-aminophenol to make paracetamol if still beneath its boiling point)

The experimental parameters involve initially heating the reaction mixture, and this is done to
dissolve the 4-aminophenol into the water so that the reaction with acetic anhydride takes place.
Once the reaction has had sufficient time to complete, cooling is then necessary for the precipitation
of the crude product. Filtering and then recrystallisation can be done to improve purity for later
analysis.

Experimental Method

To a solution of acetic anhydride (2.4 cm3, 0.025 mol), water and 4-aminophenol (2.4 g, 0.023 mol)
were added. The mixture was heated and stirred for 15 minutes. The mixture was then cooled on ice
and the crude product was collected in vacuo (3x 10 cm3 ice water used for washings). The product
was then recrystallised from 10% ethanol-water (dissolved, heated, cooled and filtrated with cold
ethanol-water washings) and dried in vacuo to give paracetamol as fine, white powdery solid (1.1g,
7.3 mmol, 33% yield).

Results and Data

Calculations

33% yield is low and this may likely be due to some of the paracetamol remaining dissolved in
solution, and so not fully obtained as crystals

Experiment observations

▪ The 4-aminophenol dissolved quickly upon heating to form an uncoloured solution

▪ The crude product obtained was a white needle-like powder
▪ During the recrystallisation crude product dissolved very slowly when added to the heated
ethanol-water (took 15 minutes to dissolve)

Thin layer chromatography

Product Rf = 0.19
Solvent system: 4:1 ethyl acetate : hexane
 The starting material and product were similar in polarity, the product is
slightly more polar due to paracetamol differing in being able to use the
oxygen on the amide group formed, as opposed to 4-aminophenol having the
amine group. It therefore reacted more with the silica of the plate and did
not travel as far at the starting material. Both the starting material and
product produced one spot each (and these matched with their respective
co-spots), so it is assumed that the samples used were free of UV-active
impurities. Since the two values are quite similar, a more polar solvent
system could have been used to separate the two even further if desired.

Melting point

Observed value: 169-170oC

Literature value [3]: 169.9oC to 172oC

A sharp melting was observed within the expected range.

Conclusion

The acetylation of 4-aminophenol to produce paracetamol was successful. This is supported by the
IR spectra, by the appearance of an RCONR2 amide stretch (~1650 cm-1) in the product spectra that
was not seen for the starting material. The 1H-NMR and 13C-NMR have the appropriate number of
environments to support the fact that synthesis of paracetamol has occurred (5 environments with
expected integrated peak values and 6 for 13C-NMR respectively), with a carbonyl environment seen
in the 13C-NMR aligning with the expected values of a C=O amide carbon (around 167 ppm). The TLC
also supports the idea of a successful reaction due to the difference in Rf values of the starting
material and product as expected (with no starting material found in the product TLC spot). Overall,
the data indicates that the desired reaction did take place.

In terms of purity, the sharp melting point suggests a high level of purity. Whilst the TLC suggests
that the starting material was not present, it is possible that there may be other compounds
remaining (e.g. ethanol, water or acetic anhydride) as these peaks would be difficult to distinguish
on the IR spectrum and NMR may be seen as low abundance impurity peaks on the NMR spectra.

It is important to note that the yield however was quite low (33%). This may have been due to losses
during filtration or some of the paracetamol may have remained in the solvent (this could be due to
the use of too much solvent or insufficient cooling time to allow complete precipitation). The yield
could be improved with by waiting longer during heating to limit the amount of solvent needed, and
by allowing more time for cooling.

References

[1] NHS, 2019. ‘Paracetamol for adults’ https://www.nhs.uk/medicines/paracetamol-for-

adults/#:~:text=Paracetamol%20seems%20to%20work%20by,brain%20that%20regulates%20body%
20temperature
[2] Grimshaw. J, 2000. ‘Electrochemical Reactions and Mechanisms in Organic Chemistry’
ScienceDirect, ch11 https://www.sciencedirect.com/topics/chemistry/4-
aminophenol#:~:text=The%20best%20yields%20of%204,65%25%20yield%20%5B70%5D.

[3] National Center for Biotechnology Information. "PubChem Compound Summary for CID 1983,
Acetaminophen" PubChem, https://pubchem.ncbi.nlm.nih.gov/compound/Acetaminophen.