Esterification: The Synthesis of Aspirin (ASA)

Introduction

Most of us are familiar with esters, but are not aware of their presence in our everyday life.
Methyl salicylate, for example, is oil of wintergreen, isopentenyl acetate is oil of banana or pear,
butyl butanoate smells like pineapple, propyl-2-methylpropanoate smells like rum and p-
dimethylterephthalate and ethylene glycol (antifreeze) are used to make Dacron.

Medicinally, the most common ester is aspirin (ASA; acetyl salicylic acid). Other drugs such as
Worm Guard (anti-wormer), Maxicaine (local anesthetic), Malathion (organophosphate),
Mebendazole (antihelmenthic), Demerol (narcotic analgesic) and Equinil (sedative) are also
esters.

Theory

Esterification is simply
the reaction between a
carboxylic acid and an
alcohol which is
catalyzed, in this case, by
a mineral acid, e.g.,
sulfuric or phosphoric
acids. In general, the
mechanism for
esterification follows the
following scheme
(illustrated, above and
below, as well): The
proton from the acid attacks the carboxyl oxygen which in turn "pushes" the two electrons in one
of the bonds "down", i.e., it delocalizes the electrons and "spreads them out" between the two
oxygen atoms. The delocalized electrons then, in the presence of the alcohol, rearrange in such a
manner as to create a temporary bond between the two reactants. Note that the alcoholic oxygen
atom has a temporary
positive charge to it in the
intermediate in step #2.

The proton (Step #3)

from the alcohol attacks
the oxygen in the original
-OH portion of the acid
forming a positively
charged oxygen atom and
a sort of water molecule
still attached to the
intermediate. The
electrons "holding" the
"water" to the intermediate "flip down", releasing this water, leaving the delocalized intermediate
in the end of Step 3. In Step #4,
the proton added in Step 1 leaves
and the electrons left behind flip
down "closing" the double bond
on the oxygen atom and leaving
the ester product.

The starting reactants for this

experiment are salicylic acid and
acetic anhydride, image left.

1
Salicylic acid reacts better with
acetic anhydride (what is an
anhydride?) than acetic acid, so
acetic acid will provide the
acetyl group which will react
with the alcoholic -OH group
on the salicylic acid as follows,
image right:

Note that this mechanism follows the general reaction mechanism previously discussed.

Materials and Methods

Chemicals Equipment/Supplies

Salicylic acid 250 mL Erlenmeyer flask

Acetic anhydride Hot water bath

Concentrated sulfuric acid Ice bath

Electronic pan balance and weighing boat Buchner funnel and filter paper

Glass stirring rod

Put 3 grams of salicylic acid and 6 mL of acetic anhydride in a 250 mL Erlenmeyer flask. Add 4
drops of concentrated sulfuric acid to the mixture and stir. Although this reaction has been
micro-scaled, it is possible that you may feel the reaction vessel becoming warm. If you do not
feel it getting warm, add another 2 drops of the con sulfuric acid to the reaction mixture and
place the reaction vessel in the hot water bath (50° C) for 10 minutes. This step will allow the
reaction to run to completion.

Next, cool the flask in an ice bath and add 50 mL iced water slowly. Stir until precipitation is
complete, then filter over a Buchner funnel and rinse the crystals several times with ice water.
Place your samples in the incubator to dry.

Questions

Complete the Questions on separate paper and attach to this experiment for turn-in.

1. Would you feel comfortable taking the ASA you made in this lab? Why or why not?

2. What technique would you do to feel safe in taking the ASA you made in the lab?

3. What purpose does the acid in this experiment serve?

4. Library assignment: find the structures of acetaminophen, ibuprofen and ASA. Draw them out.
Do these compounds have similarities? Differences? What are they?

5. Write out the complete reaction mechanism (to include intermediates

and structures) for the reaction of trans-cinnamic acid with ethanol to form
ethyl cinnamate (one part of the sex pheromone of the male oriental fruit
moth).

6. Write out the complete reaction mechanism (to include intermediates

and structures) for the reaction of 1-methyl-4-phenyl-4-
piperidinecarboxylic acid with ethanol to form Demerol. The structure of
1-methyl-4-phenyl-4-piperidinecarboxylic acid is as follows, slight upper
right:

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