The document summarizes Molly Winterbottom's experiment to synthesize benzocaine through a three-step process from nitrotoluene. The first step was oxidizing nitrotoluene to form nitrobenzoic acid. The second step was a Fischer esterification of nitrobenzoic acid to form ethyl 4-nitrobenzoate. The third step reduced the nitro group to an amino group to form the final product, ethyl 4-aminobenzoate (benzocaine). TLC plates and IR spectroscopy confirmed the products of each step. Two analogs were also synthesized by modifying the second and third steps.

1. The Synthesis
and Analysis of
Benzocaine
By Molly Winterbottom

2. Introduction
The main purpose of this experiment was to
successfully synthesis Benzocaine from
Nitrotoluene using methods found whilst
researching how to get from Nitrotoluene to
Nitrobenzoic acid, then Nitrobenzoic acid to Ethyl-
4-nitrobenzoate, and finally Ethyl-4-nitrobenzoate
to Ethyl-4-aminobenzoate (Benzocaine).
Those methods were then adapted to use the
quantities preferred, smaller than those in the
methods.
By producing TLC plates throughout each step of
the synthesis of benzocaine, provides proof that
the reaction has taken place and the product
needed has been formed.
TLC
1
TLC 2 (compared with
another group (left))
TLC 3
TLC 4 TLC 5

3. First step was to oxidize the methyl group on the nitrotoluene using sodium dichromate,
concentrated sulphuric acid, sodium hydroxide, and water to form a carboxylic acid as the first
intermediate (Nitrobenzoic acid)
Materials and Methods
Scheme 1. Forward reaction of nitrotoluene forming
nitrobenzoic acid
Scheme 2. Retrosynthesis of step 1

4. The second step was a Fischer esterification
on the carboxylic acid group para to the nitro
group on the benzene using excess ethanol
and sulphuric acid as the catalyst, to form the
ester (Ethyl-4-nitrobenzoate) under reflux.
Scheme 3. Forward reaction of step 2, the synthesis of Ethyl-4-
nitrobenzoate from nitrobenzoic acid
Scheme 4. Retrosynthesis
of step 2

5. For the final step, forming
benzocaine from Ethyl-4-
nitrobenzoate, the nitro group on
the para position to the ester on the
benzene was reduced to an amino
group
Scheme 5. Reaction of Ethyl-4-nitrobenzoate forming the final product
Ethyl-4-aminobenzoate (Benzocaine)
Scheme 6. Retrosynthesis of the final step (step 3) in the retrosynthetic
route of Benzocaine

6. By using the same method as step 2 and
using some left over nitrobenzoic acid
the first analog was produced.
Instead of excess ethanol to form the
ethyl group on the ester, excess
methanol was used forming a methyl
group instead
Scheme 7. Reaction of nitrobenzoic acid forming Methyl-4-
nitrobenzoate as the first analog. The difference in product
from Ethyl-4-nitrobenzoate shown by the red circle.

7. Collecting the first analog product, the second
analog can be produced by using the same steps
from step 3.
Simply by reducing the nitro group to an amino
group keeping the methyl group on the ester, the
product formed is Methyl-4-aminobenzoate instead
of Ethyl-4-aminobenzoate
Scheme 8. Reaction of Methyl-4-nitrobenzoate forming the second
analog, Methyl-4-aminobenzoate, the similarity in the product
compared with Benzocaine and difference in the reactant shown by
the blue circle.

8. TLC 3 TLC 4
Discussion of TLC plates from steps 2 to 3:
Looking at TLC plate number 3 and 4 the
starting material (Ethyl-4-nitrobenzoate) spots
correlate with the pure sample in TLC 3 and
shows no spots in TLC 4 compared to the
sample product and pure product of Benzocaine,
therefore all sample material had successfully
reacted.

9. Excluding the fingerprint region, when looking at IR spectra of Ethyl-4-nitrobenzoate compared to
Ethyl-4-aminobenzoate (benzocaine) the main differences seen can be within the 2 red circles at
around a wavenumber of 3000-3500 cm -1 and 1200-1700 cm-1 due to changing the nitro group
for an amino group.
Spectra 1. IR of Ethyl-4-nitrobenzoate Spectra 2. IR of Ethyl-4-aminobenzoate (Benzocaine)
More discussion of the results from step 2 to step 3:

10. When comparing results on TLC 2
with another group of chemistry
students, the main spots that showed
on the TLC plate were in the same
place along with the sample used
before placing it on reflux for an hour
and a half, shown by the blue circles.
However, there are some more spots
present on the left TLC plate (the
other groups work), shown by the red
circle, most likely due to being left in
the TLC solvent for too long and
letting the solvent run up the plate for
too long, which can start to be seen in
our plate on the right by the little red
circle, but it was removed before any
more spots could develop.
TLC plate 2. Another groups result (Left) showing sample on the
left and product on the right, compared to our result (Right)
showing the sample on the right and product on the left before and
after reflux.
Comparison of results with another group on
step 2:

11. Results and discussion of Analog 1 and Analog 2:
Whilst excluding the fingerprint region, the main difference (shown by the red circles)
shown in the region with a wavenumber of around 2800-3400 cm-1 is due to the change
from the nitro group to an amino group on the benzene ring para to the ester.
Spectra 3. IR of Analog 1 (methyl-4-nitrobenzoate) Spectra 4. IR of Analog 2 (methyl-4-aminobenzoate)

12. Conclusions
A few things to take away from doing these experiments are mostly to
do with carrying out the methods found by adjusting them when
needed. For example, when putting samples on to reflux its best to
keep checking by spotting TLC plates, making sure all the sample has
reacted forming the product desired instead of just following the method
found online, but also making sure to not let the solvent run up the plate
too long. An example of this can be seen on TLC plate 2 on the left.
Another thing to keep in mind when trying to
purify crude products using rotary evaporators
to slowly turn the pressure down when enough
solvent is evaporating and condensing off due
to the possibility that all the sample will shoot
up the condenser if the pressure was too low.
TLC plate 2