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David Belias, Chem 213


Synthetic #3 FFR
Experiment 9: Synthesis of a Coumarin Laser Dye
Introduction
Condensation reactions can be very useful in organic chemistry for the synthesis of
important molecules. One particular condensation reaction is the Knoevenagel condensation
reaction, which is used for the synthesis of , -unsaturated carbonyl compounds. Compounds
that can be produced by this reaction include therapeutic drugs, natural products, fine chemicals,
and compounds of biological importance.
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The Knoevenagel condensation can also be used in
domino reactions, in which two or more different bond forming reactions take place under
identical conditions to form complex molecules. One useful domino reaction is the
Knoevenagel-hetero-Diels-Alder reaction, which has been used to synthesize highly complex
natural products. The general steps of this reaction are Knoevenagel condensation of an
aldehyde with a 1,3-dicarbonyl compound, which then can undergo a hetero-Diels-Alder reaction
with an alkene. These domino reactions can synthesize complex molecules in a few steps, as
opposed to multi-step syntheses that can take up to twenty steps, saving time and money.
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An
important Knoevenagel reaction is the synthesis of coumarin laser dye, which is part of a useful
class of molecules.
Coumarin and its many derivatives are very useful to everyday life. These compounds
are used in many applications, including cosmetics, food preservatives, insecticides, and
fluorescent laser dyes. Many of the derivatives have been found to be useful in the medical
industry due to their antibiotic and antithrombic activity. A well-known derivative of coumarin,
warfarin, has been used as a blood thinner and rat poison.
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Some coumarin derivatives are used
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as laser dyes, optical brighteners, and fluorescence markers due to their properties. These
compounds have great optical properties, superior photostability, and an extended spectral range.
New studies have attempted to synthesize coumarin derivatives with carbon nitrogen double
bonds, which can undergo E-Z isomerism initiated by light, allowing it to be used as memory
media.
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In this experiment, a coumarin laser dye derivative was synthesized using a
Knoevenagel condensation reaction, which can be seen below in scheme 1.












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Scheme 1: Mechanism of Knoevenagel condensation of 4-(Diethylamino)salicylaldehyde and
ethyl acetoacetate to form a coumarin laser dye derivative.
In the first step, piperidine deprotonates ethyl acetoacetate to form an enolate. The
enolate then attacks the carbon of the aldehyde side group of 4-(Diethylamino)salicylaldehyde,
kicking electrons up to the oxygen. The oxygen then deprotonates the piperidine ion to form a
neutral piperidine. Another piperidine molecule then forms an enolate ion by deprotonating the
tertiary carbon between the two carbonyl groups. The electrons from the oxygen kick the double
bond to the next carbon, which kicks out a hydroxide ion. Piperidine then deprotonates the
hydroxyl group, which undergoes a self-attack on the carbonyl group, kicking electrons up to the
oxygen. The electrons then form a double bond between the carbon and oxygen, kicking out an
ethoxide ion to form the final product.
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Coumarin and its derivatives are a very important class of molecules in organic chemistry
that are used for a variety of purposes in industry. The purpose of the experiment was to
synthesize a coumarin laser dye via a Knoevenagel condensation reaction. The product was
purified by recrystallization to form pure coumarin. This coumarin was then analyzed by
1
H
NMR,
13
C NMR, UV/Vis, and melting point to confirm that the desired product was synthesized.

Experimental
Coumarin Laser Dye 4-(Diethylamino)salicylaldehyde (400 mg, 2.07 mmol) and ethyl
acetoacetate (0.53 mL, 4.19 mmol) were added to a 25-mL round-bottom flask and stirred with a
small stir bar. Piperidine (3 drops) was then introduced into the reaction mixture to form a dark
brown solution. The mixture was reacted for 30 minutes until a yellow/brown paste formed.
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Absolute ethanol (5 mL) was added to the mixture, forming a very fine precipitate. This mixture
was then refluxed until all of the precipitate dissolved back into the solution (8 minutes). After
cooling to room temperature, the flask was placed in a refrigerator to form bright yellow crystals.
The crystals were collected by washing with chilled pure ethanol (1 x 10 mL) and recrystallized
in ethanol (95 %). The crystals were vacuum filtered and the remaining solvent was evaporated
to yield coumarin laser dye, as bright yellow crystals (0.321 g, 59.8%); mp 152-154C;
1
H NMR
(400 MHz, CDCl
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) (ppm) 8.43 (s, 1H), 7.41-7.38 (d, 1H), 6.64-6.61 (d, 1H), 6.46 (s, 1H), 3.49-
3.44 (q, 4H), 2.68 (s, 3H), 1.27-1.23 (t, 6H);
13
C NMR (400 MHz, CDCl
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) (ppm) 195.8, 160.9,
158.8, 153.1, 147.9, 132.0, 116.1, 109.9, 108.2, 96.61, 45.25, 30.72, 12.53; UV/Vis
max
434 nm.
Results and Discussion
This experiment involved the synthesis of a coumarin laser dye from 4-
(Diethylamino)salicylaldehyde and ethyl acetoacetate. The identity of the product was
confirmed by
1
H NMR,
13
C NMR, UV/Vis, and melting point determination. This analysis
confirmed that the identity of the product was the coumarin laser dye, and it contained minimal
impurities. Overall, this experiment was successful, producing a pure product with a yield that
was expected.
After running the reaction and purifying the product by recrystallization, the mass of the
pure coumarin crystals was determined to be 0.321 g. The theoretical yield of coumarin using
the limiting reagent was 0.537 g, giving percent yield of 59.8%. This percent yield was close to
what was expected from previous trials of this experiment. Typical yields for this experiment in
the past have been anywhere between 45-60%.
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There could be several reasons that account for the losses of product. One reason could
be that the reaction did not run for long enough, which would decrease the amount of product in
the reaction mixture. During the workup and purification steps, most of the impurities would be
removed, leaving behind less of the desired product. To prevent this, the reaction could be
monitored by TLC to determine when most of the starting material has reacted. Another reason
could be that some of the product was lost during the purification by recrystallization. If too
much solvent was used, there was a chance that the entire product would not crystallize. Using
too much solvent allows more product to be held in solution. This would decrease the amount of
product that crystallized, decreasing the percent yield. A third reason could be due to a lack of
agitation as the reaction continued. After twenty minutes of reaction, the mixture turned into
paste and was difficult to mix evenly. If all of the components of the reaction did not mix evenly
towards the end, the reaction would not proceed effectively to completion. To prevent this in the
future, a larger stir bar could be used to ensure that all of the components of the mixture were
evenly mixed until completion of the reaction.
After completing a melting point determination of the purified coumarin laser dye, it was
concluded that the product was pure. The melting point range was 152-154C, compared to the
literature value of 151-153C.
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The observed range was within the literature value, suggesting
that the synthesized compound was the desired coumarin laser dye. The tight range means that
the product was uniform throughout, so all of the material melted at around the same temperature
due to minimal impurities.
After analyzing the
1
H NMR, it was concluded that coumarin laser dye was the
compound synthesized. First, 60 MHz
1
H NMR (Figure 1) was run on the product to confirm
that coumarin was produced. The singlet peak at 8.43 ppm with an integral value of 0.86
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corresponds to the hydrogen on the double bond of the lactone. The doublet peak from 7.33-7.29
ppm with integral value of 0.89 corresponds to the aromatic hydrogen furthest from the amino
group. The two peaks between 6.71-6.48 ppm with an integral value of 1.51 represent the two
aromatic hyrdogens closest to the amino group. At a shift of 3.64-3.29 ppm, the quartet peak
with an integral value of 3.70 corresponds to the hydrogens on the secondary carbon of the
amino group. The hydrogens on the carbon of the ketone group correspond to the singlet peak at
2.68 ppm with an integral value of 2.92. The triplet peak between 1.36-1.13 ppm with an
integral value of 6.00 represents the hydrogens on the primary carbon of the amino group. The
total integral value adds up to 15.88, which is close to the expected value of 17. There is also a
peak at 2.17 ppm, corresponding to an acetone impurity that came from cleaning the NMR tube.
Other than acetone, there were no other impurities detected by NMR.
The 400 MHz
1
H NMR (Figure 2) also suggests that coumarin laser dye was produced,
without contamination from starting material. The singlet peak at 8.43 ppm with an integral
value of 0.969 corresponds to the hydrogen on the double bond of the lactone. The doublet peak
between 7.41-7.38 ppm with an integral value of 0.987 corresponds to the aromatic hydrogen
furthest from the amino group. The doublet peak between 6.64-6.61 ppm with an integral value
of 1.001 corresponds to the aromatic hydrogen furthest from the lactone. At a shift of 6.46 ppm
with an integral value of 0.985 is the singlet peak corresponding to the aromatic hydrogen
nearest to the oxygen of the lactone. Hydrogens on the secondary carbon of the amino group are
represented by the quartet peak between 3.49-3.44 ppm with an integral value of 3.998. The
singlet peak at 2.68 ppm with an integral value of 2.961 corresponds to the hydrogens on the
ketone side chain. At a shift between 1.27-1.23 ppm, the triplet peak with an integral value of
6.123 represents the hydrogens on the primary carbons of the amino group. The total integral
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value for this spectrum adds up to 17.024 which is the same as the expected value of 17. The
only impurity appearing on the spectrum is a weak singlet peak at 7.27 ppm that most likely
corresponds to a residual solvent peak from deuterated chloroform.
The critical peaks suggesting that coumarin was the product were the singlet at 2.68 ppm
corresponding to the hyrdogens of the ketone and four peaks in the aromatic region. These peaks
were expected for coumarin, but not for the starting material. The starting material has only
three aromatic hydrogens, but the product has an extra one in the aromatic region from the
hydrogen on the double bond of the , unsaturated ketone. Also, there was not a singlet peak
with a shift between 9.0-10 ppm, which corresponds to the hydrogen of the aldehyde from the
starting material. Another peak not present was the singlet peak between 10-12 ppm,
corresponding to the hydrogen of the hydroxyl group. These two peaks correspond to peaks
expected from the starting material, but they do not appear in the spectrum, also suggesting that
coumarin was produced. On both the 60 and 400 MHz
1
H NMR, these details were observed,
suggesting that coumarin was synthesized.
The 400 MHz
13
C NMR (Figure 3) also suggests that coumarin laser dye was synthesized
in this experiment. The spectrum of the synthesized compound displayed thirteen carbon peaks,
which was expected for coumarin. There are fifteen carbons in the molecule, but the two
primary carbons of the amino group are equivalent, as well as the secondary carbons. The
starting material was only expected to have nine peaks, so this is one reason for the synthesis of
coumarin. One of the critical peaks is at 30.72 ppm, which corresponds to the methyl group on
the ketone and is not expected in the spectrum of the starting material. Another critical peak is
the peak at 160.9 ppm, corresponding to the carbonyl carbon of the lactone. There is a peak in
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the ester carbonyl region, signifying the formation of the lactone. These two critical peaks were
useful in determining that the synthesis was successful.
UV/Vis analysis (Figure 4) was useful in confirming the success of this experiment. The
color of the product was yellow, which was an instant identifier that coumarin laser dye was
synthesized. Since the color of the compound was yellow, it was expected to absorb in the
violet/blue region, which is between 400-430 nm. The observed
max
value from the UV/Vis was
434 nm, falling close to the expected range. Based on the color and absorbance of the
compound, the data suggests the synthesis of coumarin.
After analysis with
1
H NMR,
13
C NMR, UV/Vis, and melting point, it was confirmed that
the product of the synthesis was coumarin laser dye. The product was pure based on a melting
point very similar to the literature value, as well as a lack of impurities appearing on the spectral
data. The percent yield was in the expected range based on previous trials of the same
experiment in other labs. In the future, steps can be taken to improve the yield, such as
monitoring the reaction by TLC or adding less solvent during recrystallization. Overall, this was
a very successful experiment that produced the desired coumarin laser dye.
References
(1) Yu, Y.; Wang, Z. A Simple, Efficient and Green Procedure for Knoevenagel
Condensation in Water or Under Solvent-Free Conditions. Journal of the Chinese
Chemical Society. 2013, 60, 288-292.
(2) Tietze, L.F.; Rackelmann, N. Domino Reactions in the Synthesis of Heterocyclic Natural
Products and Analogs. Pure and Applied Chemistry. 2004, 76, 1967-1983.
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(3) Aktoudianakis, E.; Dicks, A. Convenient Microscale Synthesis of a Coumarin Laser Dye
Analog. Journal of Chemical Education. 2006, 83, 287-289.
(4) Flak, R.; Stankoviov, H.; Gplovsk, A.; Donovalov, J. Synthesis and Study of
Novel Coumarin Derivatives Potentially Utilizable as Memory Media. Molecules. 2009,
14, 4838-4848.
(5) McMurry, J. Organic Chemistry, 8
th
Edition; Brooks/Cole: Belmont, California, 2012,
905-907.