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Chemistry
Organic Chemistry Laboratory Experiments
2012-01-03
Fisher Esterification: Synthesis of
Volatile Esters
Mulcahy, Seann P.
http://hdl.handle.net/2144/2686
Boston University
Fisher Esterification
Introduction:
The flavor and fragrance industry relies heavily on small, volatile organic
compounds to create pleasant odors or tastes. Many of these compounds, which are often
found in mixtures of naturally-occurring substances called essential oils, bind to our
olfactory or taste receptors (for example, oil of wintergreen or oil of cloves, which are
single organic molecules). Some molecules in the flavor and fragrance industry, however,
are synthetic substitutes that fool our brain into thinking we have sampled by taste or
smell, the natural compounds. These artificial flavorings and odors, which also bind to
the olfactory and taste receptors, have been used because they are easier and cheaper to
obtain, and retain the same aromatic (not the chemical term, but the fragrance meaning)
characteristics that the natural compounds possess. Given this, entire industries have
developed with these compounds as their foundation: the artificial spice industry, soap
industry, and perfume industry are all significant employers of organic chemists.
Some of the best examples of natural and synthetic flavor and odor compounds
come from the class of organic compounds known as esters. Chemically, an ester is the
condensation product that results when a carboxylic acid is reacted with an alcohol.
Water is liberated in this reaction, which is why we call it a condensation reaction. Many
carboxylic acids are foul smelling (butyric acid = body odor/vomit, acetic acid = vinegar),
but when reacted with an alcohol, they can have wide-ranging flavors and fragrances,
such as pineapple, “Juicy Fruit,” or apple, some of which are below. Of course the
hydrolysis of the ester returns the original pungent properties of the carboxylic acid.
NH2 O
O
O
O
OMe
O
O
O
ethyl butyrate
isopentenyl acetate
methyl anthranilate
ethyl phenylacetate
pineapple
"Juicy fruit"
grape
honey
In this laboratory, you will be preparing esters which have pleasant odors by a
reaction called the Fisher esterification.
Fisher Esterification
A Fisher esterification is the condensation reaction between a carboxylic acid and
an alcohol that occurs in the presence of a mineral acid (normally, H2SO4 or HCl). The
mechanism for this reaction is shown below for the synthesis of the ester methyl butyrate,
which has an apple fragrance/flavor. First, protonation of the carbonyl oxygen lowers the
carbonyl LUMO (π*) sufficiently for addition of the weakly nucleophilic solvent,
methanol. Within the tetrahedral intermediate, proton transfer occurs to generate water as
a good leaving group. Reformation of the carbonyl π bond by elimination of water
generates the protonated ester. Loss of the proton then regenerates the acid catalyst and
provides the product ester in a reaction that is called a nucleophilic acyl substitution
reaction. This reaction occurs at high temperatures and can be pushed to completion by
removing water as it is formed. Performing the reaction in the alcohol solvent (methanol
in this example) also favors ester formation in this thermodynamically controlled
procedure.
O
OH
+
O
+
OH
- H+
MeOH
MeO
MeO
methyl butyrate
H2SO4
- H2O
+
OH
OH
OH
MeOH
Me
+ OH
OH
OH
- H+
Me
O
OH
+ H+
Me
OH
+
OH2
O
OH
+ OH
For your experiment, we will be using microwave irradiation as the heat source to
accelerate the reaction. Microwaves are a good source of energy for generating a
localized source of heat that is more efficient than an oil bath. In this way, reactions can
occur faster because the reaction flasks can be heated beyond the boiling point of the
reagents. This is an environmentally-friendly technique that has become very popular in
both industrial and academic settings, in what is commonly referred to as “green
chemistry.”
What should you learn by running this experiment? You will be introduced to an
important technique that is used by organic chemists to purify organic compounds:
distillation. Distillation is used to purify low-boiling liquids by heating the liquids into
the vapor state and then recondensing the vapors back into the liquid state. You will be
performing a simple distillation that allows you to collect different fractions of a
condensing liquid simply by heating a liquid to its boiling point. You will be assigned a
carboxylic acid and an alcohol and synthesize an ester via Fisher esterification. You will
purify your ester by distillation after liquid-liquid extraction.
Consider the following scenario for this experiment: You are employed as an organic
chemist at a local start-up company that is trying to develop new flavorings/fragrances
for soft drinks. You have been given a series of carboxylic acids and alcohols and have
been instructed to make combinations of these two substrates to create different esters
and look for compounds that have unique aromas (NOTE: at no point are you actually
going to taste these substances!).
References:
1. Pavia, D. L.; Lampman, G. M.; Kritz, G. S.; Engel, R. G. Introduction to
Laboratory Techniques, 4th Ed. Thomson Brooks/Cole: Mason, OH, 2006; pp
106-108.
Fisher Esterification
H2SO4
O
+
OH
OH
H2SO4
O
OH
+
OH
+
µ-wave
O
O
H2SO4
O
OH
O
O
µ-wave
OH
Equipment:
Microscale glassware kit
25 and 50 mL beakers
10 mL graduated cylinder
5 mL syringes and needles
1 mL syringes and needles
Pasteur pipets
Capillary tubes
Cotton
Scintillation vials and caps
NMR tubes
HPLC vials
Thermowells
Stir bars
15 mL Falcon tubes
MARS microwave vessels
Chemicals:
Acetic acid
Propionic acid
n-Propanol
Isopentyl alcohol
2-Methyl-1-propanol
Sulfuric acid
Sodium bicarbonate (sat. aq.) (2 x 500 mL)
Sodium chloride (sat. aq.) (2 x 500 mL)
Deionized water
Anhydrous sodium sulfate
Methanol (2 x 500 mL)
CDCl3
µ-wave
O
O
Procedure: adapted from Pavia, D. L.; Lampman, G. M.; Kritz, G. S.; Engel, R. G.
Introduction to Laboratory Techniques, 4th Ed. Thomson Brooks/Cole: Mason, OH,
2006; pp 106-108.
Fisher Esterification: In a microwave reaction vessel containing a microwave stirrer,
combine your alcohol (20 mmol) and carboxylic acid (60 mmol). To this mixture, add 0.5
mL of concentrated sulfuric acid and immediately swirl the solution. (CAUTION: Do not
reverse the order of this addition. Always add sulfuric acid to the solvent mixture to avoid
splattering!) Secure the screw cap firmly over the top of the vessel (make sure your stirrer
is inside!) and place your sample in the microwave rack – be sure to note your position.
Your TF will then heat your reaction for 10 minutes under microwave irradiation. When
the reaction is complete, allow the mixture to cool to room temperature. It is actually a
good idea to either vent the vessel with a syringe needle or cool in an ice bath to make
sure there is no sudden pressure release upon opening the vessel.
Workup: Transfer your product mixture to a 15 mL Falcon tube and add 5 mL of water.
Gently shake the tube and separate the biphasic mixture (which layer will contain your
product?). Wash the organic layer with sodium bicarbonate solution (5 mL) and then with
sodium chloride solution (5 mL). Transfer the organic layer to an Erlenmeyer flask and
dry over sodium sulfate. Decant this solution into a 5 mL conical vial with a spin vane.
Prepare a distillation apparatus according to the diagram shown below. Using a
sand bath on a hot plate, distill your product ester by slowly heating the reaction. Use a
metal thermometer to record the increase in temperature. Heat the product mixture to
above 100 °C (note: many of these esters will boil much higher than this, so you may
need to insulate your apparatus with cotton and continue heating higher). Collect about 1
mL of distillate and then remove it from the Hickman head with a pipet and discard.
Continue collecting about 2 mL more distillate which you will save for characterization
in a tare scintillation vial. Note the temperature at which your distillation is occurring and
give this value in the analytical data section of your lab report (this should be a range, ie.
106-107 °C). After about 2 mL have been collected, cool your vial to room temperature
(do not let it run dry!) and discard the contents.
Analysis: Obtain a 1H and 13C NMR, IR, and GC/MS to fully characterize your data.
Gently waft the ester towards your nose and record any characteristic smell. Finally,
obtain a weight of your ester and record your yield.
Pre-Lab Exercise:
These questions do not need to be explicitly answered in writing, but you should be able
to answer them prior to your arrival in lab. Some of these questions will form the basis
for your lab report.
1. Why is microwave irradiation more favorable than conventional heating as a
synthetic technique?
2. What changes in the IR spectrum would you observe by converting starting
material to product?
3. During workup, what is the purpose of each of the following procedures: a)
washing with sodium bicarbonate; b) washing with sodium chloride solution; c)
adding sodium sulfate; and d) distillation?
4. How do you know when your product is distilling?
5. Why is it necessary to remove a small portion of the distillate first before
collecting the bulk of the distilled product?
6. If your product was much higher boiling (>250 °C), how might you be able to
distill the product quicker than conventional distillation?
Post-Lab Assignment: Ask your instructor.