Jacky Deng

CHEM 204 L01

Eric Dennis

PSL 1 Synthesis of Tylenol

Discussion:

In the initial reaction between p-aminophenol and acetic anhydride, the lone
pair of electrons on the primary amine of the p-aminophenol attacked the
delta positive carbon found on the acetic anhydride. Using this logic, paminophenol acted as the Lewis base (reducing agent) by donating electrons
to the Lewis acid (oxidizing agent), acetic anhydride. The mechanism
proceeds with the pi electrons on the acetic anhydride being pushed up onto
the oxygen, giving it a temporary negative charge. The lone pair on the
oxygen would then reform the pi bond, subsequently creating an acetate ion.
Along with the acetate anion, a positively-charged intermediate molecule
was formed with the bond between the p-aminophenol and the acetic
anhydride.

The next step of the mechanism involved the interaction between the
negative charge of the acetate anion and the positive charge on the amine
group of the intermediate molecule. The acetate anion, acting as a Lewis
base, would remove a hydrogen ion from the positively-charged amine group
of the intermediate. This allowed the electrons in the bond between the
1

Jacky Deng
CHEM 204 L01
Eric Dennis

target hydrogen and the nitrogen of the amine to fall back onto the nitrogen,
ultimately neutralizing the molecule and forming acetylaminophenol. The
acetate anion, with its new bond with the hydrogen ion, formed acetic acid.

Water was also present in the reaction to promote hydrolysis of the acetic
anhydride in order to form peptide bonds with the primary amine. In certain
instances, the water would protonate any remaining acetate anion to form
acetic acid. Water was also used as a solvent during recrystallization because
of its ability to dissolve the polar acetylaminophenol at higher temperatures.
This particular process required careful attention because excess water
would introduce new impurities to the crystals a redundancy if the goal of
recrystallization is to remove impurities.

The experimental synthesis of acetylaminophenol matched the expectations

of the experiment entirely. Based on experimental NMR data, an
acetylaminophenol product was procured without signs of significant
impurity. The only area of concern that arose during the experimental
procedure was the recrystallization step; an excess amount of water was
used that held the possibility of impurifying the desired product. Luckily, the
NMR data did not support the presence of any impurities via water.

The theoretical melting point of acetylaminophenol was found to be 169C.1

The experimental melting point range was found to be169.1C to 170.1C.
2

Jacky Deng
CHEM 204 L01
Eric Dennis

Because the theoretical melting point of 169C was 0.1C lower than the the
lower limit of the experimental melting point range, it was concluded that
the final acetylaminophenol product was very pure. The narrow range also
reinforces this, as the narrow range ends at 170.1C: a value still very close
to the theoretical melting point. Compounds that melt over a very narrow
range can usually be assumed to be relatively pure. The opposite of this,
compounds that melt over a wide range are assumed to be relatively impure.
Purity of the acetylaminophenol product was also confirmed upon
comparison of the literature and experimental NMR spectrum.2 The only
significant difference was that the experiental NMR spectrum possessed an
extra CH3 peak at approximately 3.0 ppm. This extra peak could have been
attributed to acetic acid impurities in the final product.

The theoretical yield of acetylaminophenol was calculated to be 1.80g, using

p-aminophenol as the limiting reagent in the reaction. The experimental yield
of acetylaminophenol was measured and found to be 0.91g, giving an overall
percent yield of 50.6%. Loss of nearly half the expected yield could be
attributed to several factors. The most prominent factor would be the loss of
acetylaminophenol during its transfer between containers during the
crystallization and recrystallization processes. A source of product loss
unique to this particular experiment may have been the over-addition of
water to the solution mixture during the dissolving stage of the
recrystallization process. In order to remove the excess water, the solution
was heated to the point at which water began to evaporate, possibly causing
significant losses in acetylaminophenol.

Conclusion:

Jacky Deng
CHEM 204 L01
Eric Dennis

Using knowledge of Lewis acid and base chemistry, p-aminophenol and

acetic anhydride were used to synthesize acetylaminophenol. Measurement
of the experimental melting point range and NMR spectral data found the
acetylaminophenol product to be very pure, whilst calculation of the percent
yield found a significant loss of yield in the final product. Nevertheless, the
process of acetylaminophenol synthesis turned out to be successful based on
the theoretical mechanisms provided.

References:
1) 4-acetoamidophenol, MSDS [Online]; Sigma-Aldrich; Oakville, ON,
August 16, 2014.
http://www.sigmaaldrich.com/catalog/product/aldrich/a7302?
lang=en&region=CA (accessed January 22, 2015)
2) 4'-hydroxyacetanilide, SDBS [Online]; Spectral Database for Organic
Compounds; Japan, May 15, 2013.
http://sdbs.db.aist.go.jp/sdbs/cgi-bin/direct_frame_disp.cgi?
sdbsno=3290 (accessed January 22, 2015)
3) "Melting Points." Journal of the Franklin Institute 159.6 (1905): 460.

Web. 22 Jan. 2015.

<http://www.chem.umass.edu/~samal/269/mp.pdf>.