1. I. Introduction
Esters are important compounds in organic chemistry. They are used in numerous types of
synthetic reactions, to create different products for a vast array of purposes, including medicinal
and cosmetic. To produce an ester, one can utilize an esterification reaction. In particular, the
Fischer Esterification reaction was used in this lab to turn a carboxylic acid into an ester
benzocaine.
Esters are used in a wide range of fields, including the medical, cosmetology and fuels
industry. For instance, biodiesel fuel is an alternative fuel source that is composed mainly of
monoalkyl esters from vegetable oil or animal fats (1). Green, alternative energy sources are
highly sought after in the increasingly global economy, which brings high importance to
perfecting the synthesis of esters that can contribute to this. Other esters are used for their strong
fruity smells in cosmetology for perfumes, while still others are used as flavor additives in foods.
Benzocaine is an ester that has been used in the medical industry as a local anasethetic for
decades. Some contribute the use of benzocaine as an anesthetic to cause methemoglobinemia,
which is a negative disorder that is caused by high levels of methemglobin in the blood. A case
has been documented of an 83 year old man who was diagnosed with methemoglobinemia and
had symptoms of cyanosis and cardiovascular instability after benzocaine was used as the local
anesthetic for a surgery. This was considered an extreme case however, and benzocaine is still
used as a local anesthetic, and for commercial nasal and throat sprays for its numbing effect (2).
Benzocaine is also used to dilute or “cut” illegal cocaine due to its similar appearance, and
availability (3).
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2. The mechanism of the Fischer Esterification that was utilized to produce benzocaine is very
straightforward carbonyl chemistry. It begins with the carbonyl oxygen of a carboxylic acid
being protonated by the catalytic sulfuric acid. Once the double bond is broken, the lone pair of
the ethanol oxygen backside attacks the carbonyl carbon, forming the classic tetrahedral
intermediate. The oxygen of the new ethanol substituent has a positive charge; this causes the
lone pairs of the sulfuric acid to attack the hydrogen of the ethanol. Next, the lone pairs on the
hydroxyl group attack a hydrogen atom from sulfuric acid, forming water, a quality leaving
group. The lone pairs on the remaining hydroxyl group swing down to form a double bond with
carbon and displace the water. The sulfuric acid then relieves the double bonded oxygen of the
extra hydrogen and its unwanted positive charge. The final product is benzocaine, an ester.
Figure 1: Fischer Esterification Mechanism of the Formation of Benzocaine
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3. The purpose of this lab is to synthesize benzocaine, an ester, from p-aminobenzoic acid, a
carboxylic acid, by Fischer Esterification. This is a common mechanism in organic chemistry,
and its mastery is important in learning how carbonyl compounds behave. P-aminobenzoic acid
will be combined with ethanol and sulfuric acid in a reflux reaction to yield the desired product.
This product with then be analyzed by melting point, NMR, IR, and GC-MS to confirm its
identity as benzocaine. A percent yield will be calculated to determine how much benzocaine
was produced in lab, in comparison to how much was physically possible to synthesize.
II. Experimental
Benzocaine. P-aminobenzoic acid (119mg) and absolute ethanol (1.5mL) were added to a
microscale reaction tube and heated with a sandbath until dissolved. The mixture was then
cooled with ice and concentrated sulfuric acid (0.20mg) was added dropwise. An air condenser
was used to reflux the reaction for one hour. The reaction mixture was then cooled to room
temperature. The reaction mixture was transferred via Pasteur pipet to a 10-mL Erlenmeyer
flask. Distilled water (3mL) was added. 1M sodium bicarbonate (3mL) was added dropwise;
the reaction mixture was agitated after each addition. The pH was monitored until the reaction
was sufficiently neutral (pH 8). A Hirsch funnel was then used in vacuum filtration to isolate the
product. Crystals were washed with cold distilled water (3x 1mL). White, flaky crystals
(85.8%) were dried over night. Melting Point : 88-89⁰C.
Chemical Shift Splitting Pattern Integral Value
1.263 ppm Triplet 3
4.140 ppm Quartet 2
5.927 ppm Singlet 2
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4. 6.484 ppm Doublet 2
7.568 ppm Doublet 2
Figure 2: 1H NMR (60 MHz, CDCl3 ) for Benzocaine
Functional Group Absorption Frequency (cm-1)
N-H 3419.0
C-H for C6H6 3219.4
C=O for ester 1679.2
Figure 3: IR (ATR) for Benzocaine
Component RT M/Z Percent Composition
Benzocaine 18.94 165.0 100.00%
Figure 4: GC-MS for Benzocaine
III. Results and Discussions
Fischer Esterification was used to synthesize benzocaine from p-aminobenzoic acid, or
PABA. PABA was combined with excess absolute ethanol and catalytic sulfuric acid and was
allowed to reflux for over an hour. Sodium bicarbonate was then added to neutralize the excess
acid. The benzocaine crystals were then vacuum filtrated and washed with cold water to
maximize yield and were allowed to dry overnight. Once dry, the crystals were analyzed by
melting point, NMR, IR, GC-MS, and a percent yield was calculated.
The theoretical yield of benzocaine was 144.5mg of product. The actual yield was
124.0mg, giving a percent yield of 85.8%. This is a high percent yield, indicating a successful
synthesis. The melting point recorded in lab was 88-89⁰C; this is very close to the literature
value of 88-90⁰C. This accuracy in melting point indicates a pure product. Impurities in the
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5. benzocaine product would depress the melting point, and cause a wider melting point range. The
short range and accuracy implies a successful synthesis.
NMR was also used to analyze the product synthesized in lab. Five different peaks
appeared in the NMR spectra of benzocaine (Figure 2, Supplemental Data), correlating to five
different sets of chemically different protons. The first peak at 1.146ppm with an integral value
of three displayed the protons at the end of the ethyl group bonded to the non-carbonyl oxygen of
the ester as a triplet. Because these hydrogen atoms are the farthest from the electron
withdrawing oxygen atoms, it makes sense that they would have the lowest chemical shift, and
suffer the most shielding of all the protons of the molecule. The next peak, a quartet, at
4.140ppm corresponds to the hydrogen atoms on the carbon bonded to the non-carbonyl oxygen
atom of the ester. This CH2 group has less shielding than the aforementioned CH3 group, and
thus a higher chemical shift because it is closer to the oxygen atoms of the compound. The third
peak at 5.927ppm displays the two hydrogen atoms bonded to the amine substituent on the
benzyl functional group. These protons are deshielded by the nitrogen atom, but are not as
shifted as far as the next two peaks because they are so far from the oxygen atoms of the ester.
The next peak, a doublet with a chemical shift of 6.48ppm shows the symmetrical hydrogen
atoms on the benzene ring closest to the ester substituent. These two protons are shifted so far
down due to the deshielding caused by the ester and the amine substituents. The final peak at
7.568ppm is a doublet that shows the two symmetrical protons on the benzene ring closest to the
amine group. These protons are close enough to the carbonyl ester and the amine to be
deshielded the most and to have the highest chemical shift. This NMR spectrum accounted to
for all the protons benzocaine should have, with peaks that had chemical shifts that made sense,
indicating that it indeed was representing benzocaine.
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6. IR was also a useful mode of analysis for the final results of the reaction. Several
important peaks in the IR spectrum of benzocaine (Figure 3, Supplemental Data) were used to
identify the product as benzocaine. A short sharp spike at 3419.0cm-1 indicates the presence of a
nitrogen-hydrogen bond on the molecule, which corresponds to the structure of benzocaine. A
peak at 1679.2cm-1 shows the ester group of benzocaine. An alcohol spike did not appear at
3500cm-1, which indicates the starting material, p-aminobenzoic acid, which has the OH group
on the carboxylic acid, was not present in the IR sample. This shows that the reaction
successfully went to completion.
GC-MS was also used to analyze the crystals produced in lab. Only one peak was
present in the GC-MS chromatogram (Figure 4, Supplemental Data). A peak appeared at 18.94
minutes; this corresponded to the peak on mass spectrum that had a value of 165.0m/z. This is
exactly the molecular weight of benzocaine, which indicates that this is what was in the crystals
produced in lab. Other ions of benzocaine were present in the mass spectrum, including a peak
at 150.12m/z, which displays the ion of benzocaine that is missing the nitrogen group off of the
benzene ring. Another peak in the mass spectrum was at 91.95m/z, which displays the ion that is
lacking the ester group on the benzene ring. All of these molecular weight values line up with
what the weight of the ion would be if it was missing said functional groups. This indicates that
the GC-MS does indeed depict benzocaine, the desired product of the Fischer Esterification
reaction.
IV. Conclusion
Fischer Esterification was used as a means to synthesize benzocaine, an ester, from p-
aminobenzoic acid, a carboxylic acid. This is done by adding excess alcohol, in this case
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7. ethanol, and catalytic sulfuric acid. The reaction takes place as a reflux, and yields large, white
and flaky crystals. These crystals are the benzocaine product, and their identity was confirmed
by melting point, NMR, IR, and GC-MS analysis. These techniques all gave confirming results
that the crystals produced in lab were the desired benzocaine product.
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8. V. References
(1) Wang, P.S.; Tat, M.E.; Gerpen J.V. The Production of Fatty Acid Isopropyl Esters and their
Use as a Diesel Engine Fuel. Journal of the American Oil Chemist’s Society. Springer, 2011.
Volume 82, Number 11, 845-849.
(2) Rodriguez, L.F.; Smolik, L.M.; Zbehlik, A.J. Benzocaine-induced Methemoglobinemia. The
Annals of Pharmacotherapy. Harvey Whitney Books Company, 2012. Volume 28, Number 5,
643-649.
(3) Freye, E.; Levy, J.V. Pharmacology, and Abuse of Cocaine, Amphetamines, Ecstasy, and
Related Designer Drugs. Springer, 2009. 36.
(4) Rummel, S.A. Lab Guide for Chemistry 213: Introductory Organic Chemistry Lab.
Hayden, McNeil, 2011, pgs 65-82, 295-308.
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