Abdelrahman Elshamsy

April 30th 2014

The Fischer Esterification of Benzocaine
Benzocaine is a local anesthetic used in medical applications to reduce
pain and increase comfort of painful drugs. Such applications are
administered with the leprosy drug, chaulmoogra oil and even reducing
the pain from needle injections 4 7. Benzocaine is also used in aerosol
spray lotions to relieve the discomfort of sunburns 3 6. Benzocaine is
synthesized with p-aminobenzoic acid, ethanol, and sulfuric acid as a
catalyst.

Figure 1: The Fischer Esterification Reaction of Benzocaine

The mechanism of benzocaine starts off by the attack of one of the

hydrogens of the sulfuric acid by the carbonyl of PABA. The oxygen
then becomes protonated causing the break of the double bond. The
oxygen of the ethanol then attacks the carbon previously associated
with the carbonyl group. The lone pairs of the sulfur then deprotonate
the ethanols oxygen leading to the formation of an ester group. One
of the hydroxyl groups binds to a hydrogen of the sulfuric acid leading
to its removal from the central molecule. The negative charge of the
carbon (previously known as the carbonyl carbon) results in the
formation of a double bond to the hydroxyl group. Due to the newly
found positive charge of the hydroxyl group, the lone pairs of the sulfur
group deprotonate it. The final product is the ester, benzocaine, and
water. View Figure 2 for a visual reference.

Figure 2: The mechanism walkthrough of the esterification of benzocaine.

Experimental:
Benzocaine from PABA, ethanol, and sulfuric acid.
Benzocaine. 4-aminobenzoic acid (250mg) and ethanol (3mL, 100%)
were added to a round bottom flask (25mL) and stirred under a heated
sand bath until dissolved. Mixture is cooled in ice and sulfuric acid
(0.40 mL) is added dropwise. Mixture is then refluxed for 70 minutes.
After cooling to room temperature, distilled water is added to the
reaction mixture in a beaker (50mL). Sodium bicarbonate (8mL) is then
added dropwise to the reaction mixture until the pH of the solution is
more than 8. Crude white crystals of benzocaine are collected by
vacuum filtration and recrystallized (100% ethanol, hot water) after
drying the next lab period. Final purified product was vacuum filtered
and dried as a white crystalline solid (192mg; 76.8%); pH (8.0-9.0); MP
(86-88C); IR (cm-1) 1115.72, 1679.56, 2983.68, 3221.11, 3340.71,
3419.59; GC (benzocaine, 40C to 250C at 10C per min) RT 14.20;
GC-MS (phenyl methylpolysiloxane, 40C to 250C at 10C per min) RT
18.95, 165m/z. 1HNMR (60 MHz, DMSO) (ppm), 1.268 (t, 3H), 4.140 (q,
2H), 5.935 (s, 2H), 6.605 (d, 2H), 7.573 (d, 2H).

Discussion and Conclusion:

Benzocaine, an ester, was synthesized from p-aminobenzoic acid,
absolute ethanol, and sulfuric acid. The synthesis of benzocaine is an
important procedure because it is a common anesthetic with many
uses in the medical and is also a learning experience of Fischer
esterification processes. In this reaction, sulfuric acid plays a huge role
as a catalyst and is necessary for this reaction to undergo. The
nucleophilic substitution of the reaction results in the change between
the OH group of the carboxylic acid to an OCH2CH3 group. The yielded
amount was 192 mg or 76.8% yield that fell short of the European
Polymer Journal article which was at 90% yield2. An explanation to the
slightly lower yield is from lost product through transfers (from beaker
to watch glass, etc) as well as product adhered to the filter papers from
the vacuum filtration processes done twice. Purification by
recrystallization was a successful process as there were no starting
materials or intermediates in the mixture shown by 1HNMR, IR, GC, MP
and GC-MS data. However, there was evidence of an impurity along
with the product. The melting point data had a slightly lower range
than the observed range on sigmaaldrich.com, but however, the
acquired range matched the minimum temp from the observed range
on sigmaaldrich.com (88-90C)8. The impurity is believed to be water
and is seen on the 1HNMR data. Its presence may have possibly
occurred from a product that was not fully dried.
1

HNMR data showed the presence of benzocaine without starting

materials. There are peaks in the data that are solely present in
benzocaine and is as follows. At the triplet peak 1.268 with integral
value of approximately 3 is the peak for the CH3 group (Ha) in its
proper position. Quartet peak at 4.140 with the integral value of 2 is for
the CH2 group that is attached to the oxygen and methyl group. In the
1
HNMR results, the hydroxyl hydrogen for the carboxylic acid is not
present. This peak would have a singlet splitting patter and would be
found at the 11.0-12.0 range. The hydroxyl hydrogen of the ethanol
also does not show up on the 1HNMR data, which would be a doublet
peak at 0.5-5.0 and an integral value of 1. 1HNMR spectra of
benzocaine on sigmaaldrich.com confirm the correctness of the 1HNMR
spectra acquired8.
The IR data is not very much different of that of the starting materials
besides for one peak. The IR data is a good reference however for the

presence of the product, benzocaine. All of the significant peaks are

present at 3419.59 for the NH stretch, 3340.71 and 3221.11 for the
benzyllic CH stretch, 2983.68 for the CH stretch, 1679 for the C=O
stretch, and 1115.72 for the C-O stretch. The only difference in this IR
data from the IR data of the starting materials is the presence of the
ester at 1115.72, which is clearly not present in starting materials as it
was the highlight of this reaction. IR spectra of Fluorescein on
sigmaaldrich.com confirm the correctness of the IR spectra acquired8.
GC data showed one significant peak at 14.20 (retention time) with
area percentage at 100%. GC-MS data also showed one peak at 18.95
(retention time) with area percentage of 100% and 165 m/z. The GC
and GC-MS data both showed that the single peak at 14.20 & 18.95 is
in fact for benzocaine from the library database.
Overall, the product was successfully acquired. The drying time
couldve been increased to remove the water and acetone as seen in
the 1HNMR and the depressed melting point but due to time constraints
this wasnt an option during this attempt. The IR, melting point, GC,
GC-MS and 1HNMR all correlated to one another and showed that the
product was successfully present with little impurities.

References:
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Toluene: An Organic Multistep Synthesis in a Project-Oriented
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2. European Polymer Journal 2013, 49 , 2247
3. Gilpin, R. K., Pachla, L.A., & Ranweller, J.S.. Pharmaceuticals and
Related Drugs. Anal. Chem., 2002, 55 (5), pp 70R87R
4. Nusstein, J. M. & Beck, M. Effectiveness of 20% benzocaine as a
topical anesthetic for intraoral injections. Anesth Prog. 2003; 50(4): 159163.
5. Rummel, A. S., Ed. Lab Guide for Chemistry 213; Hayden Mcneil; University Park, PA,
2013.
6. Rummel, A. S. Experiment 16: The Fischer Esterification of Benzocaine 2013. The
Pennsylvania State University ANGEL Course Spring 2014 Chem 213 Web site.

7.Science Service. Leprosy Drug Now Administered Painlessly. J. Chem.

Educ., 1928, 5 (4), p 444
8. Sigma Aldrich. Chemical database. www.sigmaaldrich.com. Mar 23rd
2014.