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CH421 Experiment 4
Synthesis of Benzocaine via Fischer Esterification of para-Aminobenzoic Acid
Reading: Organic Chemistry by John McMurry, 8e, Chapter Sections 21.3 and 21.6
Techniques: IR, NMR
Introduction
Carboxylic acid esters (or just esters) have the general formula RCO2R', where R and R' may be an alkyl or an aryl group.
Some esters are flavoring or odor concentrates, while others have medicinal uses. Esters may be formed by the direct
reaction of a carboxylic acid with an alcohol. This reaction is called Fischer esterification, which is both acid-catalyzed
and reversible.
The acid catalyst, generally a mineral acid, protonates the carbonyl group of the carboxylic acid making it more readily
attacked by the nucleophilic oxygen of the alcohol. After proton transfer, a molecule of water is then eliminated to form
the ester.
At reflux temperatures and in the presence of an acid catalyst, both the forward and reverse esterification reactions are
rapid, and the system reaches equilibrium rather quickly. In order to obtain a high yield of ester, however, the
equilibrium must be shifted toward the products (Le Chatelier’s Principle). One technique for accomplishing this is to use
a large excess of one of the reactants (usually the alcohol). Another method is to remove one (or more) of the products
as they are formed. This can be accomplished by physical (e.g., azeotropic distillation of water) or chemical means. The
position of equilibrium is determined by the equilibrium constant (K), as defined by the following mass-action
expression:
K =
The equilibrium constants for the formation of a couple different esters of acetic acid from the corresponding alcohols in
the presence of an acid catalyst are given in the table below. The K values were determined experimentally from
systems at equilibrium and may be taken as a measure of the efficiencies of the esterification processes. For example,
the values indicate that ethyl acetate (K = 3.96) is prepared much more efficiently than is t-butyl acetate (K = 0.0049). In
general, primary alcohols are comparatively easy to esterify, while secondary alcohols are esterified with some difficulty,
and tertiary alcohols hardly react.
K values for the formation of esters of acetic acid
Alcohol
ethanol
t-butanol
Ester
Equilibrium Constant (K)
ethyl acetate
3.96
t-butyl acetate
0.0049
Experiment 4: Synthesis of Benzocaine
In this laboratory, the local anesthetic benzocaine is synthesized by Fischer esterification of para-aminobenzoic acid
(PABA) (see scheme below with the reaction table). The Fischer esterification is normally catalytic in acid, since the acid
is regenerated in the mechanism. However, if there is/are basic group(s) present in the substrate, stoichiometric acid is
required since the basic group will consume the acid catalyst, as is the case in the esterification of PABA. In the workup
of this reaction, aqueous Na2CO3 affords benzocaine in its free base form (the pKa of protonated benzocaine is 2.8). The
water-insoluble product is thus readily isolated by filtration.
Safety Precautions
Ethanol is flammable. Sulfuric acid is extremely caustic. Safety glasses and gloves are mandatory. If any acid gets onto
your skin, wash with excessive water.
Pre-Lab Notebook (to be completed prior to the start of lab)
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•
Enter date, experiment number and title on notebook page and in TOC with corresponding page number.
Copy the reaction and the reaction table below (in your own writing) into your notebook and complete all empty
cells in the table. Make sure to check your calculations with your instructor before starting the experiment.
d (g/mL)
vol
(mL)
_____
___
46.07
0.789
12.0
____
98.08
1.84
1.0
____
_____
___
Lit. mp
=
Name
MW (g/mol)
mass (g)
p-aminobenzoic acid
137.17
1.2
ethanol
sulfuric acid
ethyl-4-aminobenzoate
(benzocaine)
165.19
Theor. mass
=
mmol
Theor. mmol
=
equiv
____
mp (°C)
bp (°C)
____
___
Experiment 4: Synthesis of Benzocaine
Procedure
Fischer Esterification
To a 100 mL round-bottom flask equipped with a magnetic stir bar, add 1.2 g of p-aminobenzoic acid and 12.0 mL
absolute ethanol. Stir the mixture until the solid dissolves. Slowly add 1.0 mL of concentrated H2SO4 using a glass
pipette to transfer the acid. A precipitate is expected to form. Attach a reflux condenser to the flask, secure the
apparatus with clamps, and heat the mixture at a gentle reflux for 60-75 minutes using a heating mantle and Variac
power controller. The solid should dissolve as it undergoes reaction.
Reaction Workup
After completion of the reflux, allow the reaction mixture to cool to room temperature. Pour the reaction mixture
(along with the stir bar) into a 200 mL beaker containing 30 mL of ice water. While stirring this mixture, slowly add
approximately 10 mL of a 10% Na2CO3 solution. Gas evolution will be observed as the acid is neutralized; the final pH
should be approximately 8. Vacuum filter the resulting precipitate, and wash the product with three 10 mL portions of
water. Empty the filtrate into the aqueous waste container #1, then replace the empty Erlenmeyer flask and continue
pulling a vacuum on the product to allow it to dry for ca. 15 mins.
Obtain the mass of product and calculate the percent yield. Record the IR spectrum, and obtain the 1H NMR spectrum
of the product in CDCl3 (approximately 15 mg dissolved in ~ 0.75 mL CDCl3).
Waste
Aqueous Waste #1: the aqueous filtrate.
Organic Waste #2: NMR solution and all acetone rinses (glassware, sidearm flask with crude product, NMR tube, etc.)
Solid Chemical Waste #4: filter paper
Data (collect and record in your notebook during the lab)
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Describe product, give mass of product isolated, and calculate % yield (show calculation).
Obtain IR (solid is best), staple in notebook, and assign major functional group peaks.
Obtain 1H NMR spectrum (CDCl3), label as “Name and Name Expt 4 prod in CDCl3,” and staple into notebook.
Draw the structure of the product on the NMR spectrum, and label all peaks.
Conclusion (record in your notebook)
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State outcome, yield, proof of success and purity, possible sources of error, and any other information
deemed necessary and relevant.
Experiment 4: Synthesis of Benzocaine
The IR and 1H NMR spectra for the PABA starting material are given below for your reference.
IR of p-aminobenzoic acid (nujol mull)
1
H NMR of p-aminobenzoic acid (90 MHz, DMSO-d6)
d, 2H
d, 2H
br s, 2H
br s, 1H