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Synthetic Experiment 3: Synthesis of 3-Carbethoxycoumarin

Riddhi Patel
Madison Salvitti
Chemistry 213 W 001
June 30, 2016

Introduction:

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Coumarins are naturally occurring, versatile and multipurpose compounds found
in plants. They are fragrant organic chemicals found as a colorless crystalline substance used as
pesticides in plants, as flavorant food additive, and as aroma enhancers in perfumes, fabric
conditioners and certain alcoholic drinks. They are capable of incorporating many different
functional groups, resulting in over three hundred derivatives and applications such as warfarin,
a very effective anticoagulant. They have a wide variety of medicinal uses: vitamin K
antagonistic, blood thinning, antibacterial, anti-fungicidal, antitumor, anti-inflammatory and
analgesic properties. They are also used as diagnostic agents and pathologic probes.
3-Carbethoxycoumarin, is a compound that belongs to the family of coumarins which
can be synthesized in several ways. Pechmann condensation (esterification/transesterification
followed by Michael addition of phenols with -keto esters or carboxylic acids), Perkin reaction
(aldol condensation of aromatic aldehyde and acid anhydride catalyzed by an alkali salt) and
Kostanecki acylation (acylation of ketones with acid anhydrides followed by cyclization) are a
few examples. Perkin reaction between salicylaldehyde and acetic anhydride is one of the most
popular methods. Often times, the functional groups embedded in the coumarins play a role in
determining the reaction scheme and isolation method.
In this experiment, salicylaldehyde, 1, was reacted with diethyl malonate, 2, using
piperidine and ethanol as catalysts to synthesize ethyl 2-oxo-2H-chromene-3-carboxylate, 3, as
depicted in Scheme 1.

Scheme 1: Synthesis of 3-Carbethoxycoumarin from Salicylaldehyde and Diethyl malonate.

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As depicted in Scheme 2, the nucleophilic lone pair on piperidines nitrogen attacks the
hydrogen in salicylaldehydes phenol group, causing the extra pair of electrons to result in a
negative charge on the oxygen. The extra lone pair on the oxygen
reforms the double bond with the carbon

Scheme 2: Transesterification and aldol condensation to synthesize 3-Carbethoxycoumarin.

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The purpose of this experiment was to synthesize 3-Carbethoxycoumarin through

transesterification and aldol condensation of salicylaldehyde with diethyl malonate using
piperidine and ethanol as catalysts, and to purify it via recrystallization (95% ethanol). The product
was isolated and characterized by IR, 1HNMR (60 MHz and 400 MHz), and 13CNMR.
Experimental: 3-Carbethoxycoumarin: Salicylaldehyde (10.3 mmol, 1.26 g, 1.08 mL) and
diethyl malonate (11.3 mmol, 1.81 g, 1.72 mL) were mixed together with ethanol (4 mL),
piperidine (20 drops) and glacial acetic acid (4 drops). The mixture was refluxed for 2 hours while
being monitored by TLC (40% EtOAc/Hexane). Upon completion of the reaction, the mixture was
cooled to crystallize the crude crystals which were isolated using vacuum filtration.
Recrystallization (95% ethanol) afforded glossy, pure white crystals (1.12g, 50% yield) afforded
a pure white powder (0.04 g, 0.206 mmol, 44% yield). 1HNMR (400 MHz, CDCl3): (ppm) 1.42
(t, 3H), 4.43 (q, 2H), 7.33 (d, t, 2H), 7.65 (d, t, 2H), 8.54 (s, 1H); .13CNMR (400 MHz, CDCl3):
(ppm) 14.33, 62.05, 77.21, 116.83, 117.94, 118.32, 124.97, 134.46, 148.73, 155.21, 156.82,
163.09; IR (ATR) max (cm-1): 3395.8, 2917.7, 2846.3, 1761.6, 1555.3, 1445.9, 1420.4, 1242.2.
M.P.: 90.4 C 92.1 C.
Discussion and Conclusions:
In this experiment, a fused-ring heterocycle, 3-Carbethoxycoumarin, an example of a
class of heterocyclic compounds known as coumarins was synthesized. The synthesis involved a
transesterification followed by an aldol condensation reaction starting with salicylaldehyde and
diethyl malonate. The reactions were catalyzed by piperidine and ethanol, and monitored by TLC
(40% ethyl acetate/hexane). Upon completion, the mixture was cooled and the crude crystals

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were collected via vacuum filtration. Recrystallization, using 95% ethanol as the solvent, was
used to purify the crude product, and vacuum filtration was used to isolate and dry the purified
product.
Synthesis of 3-Carbethoxycoumarin involved a transesterification reaction followed by
aldol condensation. The first step involved the catalyst, piperidine, deprotonating the phenol group
in salicylaldehyde to facilitate its reactivity with diethyl malonate.
Aldol Condensation requiring ethanol Thin Layer Chromatography (TLC), an essential
technique in organic chemistry, was used to monitor the progress of the reaction to ensure it
reaches 100% completion before stopping, and to verify the products identity as 3Carbethoxycoumarin based on its molecular interactions with the polar stationary phase and the
use of a salicylaldehyde standard. The coumarin product with a Rf value of about 0.18 confirmed
to be more polar than salicylaldehyde whose Rf value was closer to 0.64 due to The mobile phase
for TLC was 40% ethyl acetate in hexanes,
Recrystallization is a very crucial purification method used to purify solids
contaminated with small amounts of impurities. It was the chosen purification technique because
the product, 3-Carbethoxycoumarin, is a solid compound capable of crystallization with very few
impurities. 95% ethanol was the chosen solvent for recrystallizing the 3-carbethoxycoumarin
because its polarity is similar to that of the product.
The experiment resulted in 1.30 g crude product and 1.12 g of purified 3carbethoxycoumarin. This meant the final product yield was 50% and percent recovery of pure 3carbethoxycoumarin from the crude was 86% which are consistent with experiments synthesizing
3-carbethoxycoumarin. Research and past experiments suggest that percent yield tend to be

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between 45-65%.2, 3 Variations in results are inherent due to the variation in the synthesis method
chosen.
Melting point of the final product was determined to be about 90.4-92.1C whereas the
actual melting point range of 3-Carbethoxycoumarin is 92-94 C. The melting point determined
matches very closely to the actual melting point of the desired product suggesting that the product
was indeed synthesized. However, the slight depression in the MP indicates a slight contamination
of the product, possibly starting reactants or the solvent. The IR spectra shows peaks at: 3395.8
cm-1, 2917.7 cm-1, 2846.3 cm-1, 1761.6 cm-1, 1555.3 cm-1, 1445.9 cm-1, 1420.4 cm-1, and 1242.2
cm-1, indicating the presence of a phenol (-OH) group, 2 amino group, aromatic hydrogens,
aliphatic C-H bonds, a C=O bond in an amide group, C=C bond in aromatic ring, methyl group
stretch, C-N bond in amide, and a C-O bond in phenol respectively (Figure 1, Supplemental
Information). 1HNMR (60 and 400 MHz) shows a triplet peak at 1.42 or 1.418 ppm integrating
to 3 hydrogens, characteristic of a methyl group; a quartet peak at 4.484 or 4.43 ppm integrating
to 2 hydrogens, characteristic of the two hydrogens on the carbon adjacent to the methyl group; a
doublet and a triplet peak at 7.29 or 7.33 ppm and 7.56 or 7.65 ppm, each integrating to 2 hydrogens
each, characteristic of the four aromatic hydrogens; and a singlet peak at 8.53 or 8.54 ppm
integrating to about 1 hydrogen, characteristic of the vinyl hydrogen. The peak observed at 2.3
ppm is characteristic of salicylaldehyde suggesting the presence of some starting material residue.
Some of the peaks didnt completely integrate to a whole number suggesting some possible
compromise in the purification of the product. But the absence of any additional hydrogens on the
1

H NMR suggests no other major contamination (Figures 2 and 3, Supplemental Information).

.13CNMR (400 MHz) showed peaks at 14.33, 62.05, 77.21, 116.83, 117.94, 118.32, 124.97,
134.46, 148.73, 155.21, 156.82, 163.09, each integrating to one carbon per peak. Hence, there are
12 unique and total carbons in 3-carbethoxycoumarin. The only contaminated peaks observed

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around 76.8-77.5 ppm were characteristic of CDCl3 solvent used in the preparation of sample for
NMR analysis (Figure 4, Supplemental Information).
In conclusion, the process of synthesizing 3-Carbethoxycoumarin from Salicylaldehyde
and Diethyl malonate proved to be relatively effective as evident by the 50% yield of pure
product. The spectral data including 1HNMR, 13CNMR and IR analysis (Supplemental
Information) along with melting point determination all indicate substantial purification as the
sample integrates to the expected number of atoms more or less and isnt particularly lacking or
showing any major peaks besides the CDCl3 solvent. This proves that the product is not
contaminated with the starting material or any other known by-products. Moreover, the percent
recovery of 86% further indicates that the crude product was purified of the contaminants while
still yielding a substantial amount of the desired product. Sources of error could include failing to
maintain a constant temperature while heating the solution, stopping the reaction before
completion, isolating the product along with some impurities due to fast cooling among others.
Research studies show that excellent percent yields are achieved via the cascade transformation
of Knoevenagel condensation and amide esterification and that concentrated ethanol proves to be
a successful solvent for the recrystallization of coumarins and its derivatives.4 Future studies
could experiment with the different methods (Perkin reaction vs. Pechmann condensation) of
making coumarins by varying the reactants class of compounds (ex. carboxylic acids vs. esters),
trying different combination of solvents and reagents (AlCl3 often used as the catalyst)3,
manipulating the mobile phases of TLC to better see the spots on the plate, in order to determine
which combination yields a higher percent yield of 3-Carbethoxycoumarin with the least amount
of impurity.
References:

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Coumarin-3-carboxylic acid (531-81-7)1HNMR. Coumarin-3-carboxylic acid (531-817)1HNMR. Chemical Book.

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Mitra, Alok Kumar, Aparna De, Nilay Karchaudhuri, Swapan Kumar Misra, and Apurba
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Prabhakar, Maddela, J. S. Reddy, Ravi N. Kumar, Ganesh S. Viswanadha, and Solomon K.

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Rummel, S.; Beiswenger, MK. Chemistry 213 Introductory Organic Chemistry

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