Synthesis of 3-Carbethoxycoumarin
Claudia Hossain
November 3, 2011
Chem 213.102
TA: Kristin Beiswenger
Synthetic Report #1
Introduction
One of the most versatile and useful groups of compounds in organic chemistry is the
coumarin family. Coumarins are fused ring heterocyclic compounds that can be manipulated to
contain a wide variety of functional groups with different applications (1).
Figure 1: Coumarin and Coumarin Derivatives
Featured here: Coumarin (parent), Warfarin, Scoparone
Over three hundred derivatives have been discovered, notably in green plants. For their diversity,
coumarin and coumarin derivatives are highly explored in pharmacology and food science1. The
most notable coumarin derivative is warfarin (2), a recognized anticoagulant, or blood thinner.
Scoparone (3) also possesses medical benefits, namely as a cholesterol reducer. Other explored
utilities include explorations of coumarin as an antioxidant, enzyme inhibitor, and muscle
relaxant. Coumarins, in their parent and manipulated states, are also present in a wide variety of
foods and additives such as cinnamon, vanilla flavoring, and chamomile2.
Figure 2: Synthetic Route for Salicylaldehyde and diethyl malonate forming 3-carbethoxycoumarin
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Scheme 1: Reaction mechanism of the conversion of Salicylaldehyde to 3-carbethoxycoumarin
The reaction mechanism to convert salicylaldehyde to 3-carbethoxycoumarin is an aldol
condensation (Figure 2). Aldol condensations employ enolate chemistry to first form an aldol.
Dehydration then results in double bond formation and an ,  unsaturated compound. Aldol
condensations are highly useful reactions as they are an effective way of creating double bonds
and can be conducted on two identical aldehydes, two mixed aldehydes, or one molecule with
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multiple functionalities3. When one molecule is utilized, ,  unsaturated cyclic compounds can
be created3. In the first step of this mechanism, piperidine, a non-nucleophilic base, removes the
acidic hydrogen of salicylaldehyde, establishing a negative charge on the oxygen (Scheme 1).
The negative oxygen then attacks the electrophilic carbon of a diethyl malonate and subsequently
pushes out an ethyl group in a transesterification. The ethyl then abstracts the acidic hydrogen
between the two carbonyls, forming ethanol and an enolate. Through an aldol reaction, a
heterocyclic compound forms with the enolate attacking the aromatic aldehyde and a hydrogen
abstraction by the electronegative oxygen of the acidic hydrogen of ethanol. The alcohol is
further protonated and a condensation reaction occurs with the abstraction of the acidic hydrogen
by an ethyl to remove water and form an alkene. The cumulative aldol condensation results in 3carbethoxycoumarin4.
As coumarins are a family of compounds that have applications in a variety of areas
ranging from pharmacological drugs to food flavorings, they are essential compounds to be
familiar with synthesizing. The purpose of this lab was to create one coumarin derivative, 3carbethoxycoumarin. An initial transesterification and subsequent aldol condensation reaction
were employed to evolve this heterocyclic product. The reaction was monitored by TLC and
analyzed for melting point determination, IR, 1H NMR 400 MHz, and 13C NMR 400 MHz for
reaction success and purity.
Experimental
3-carbethoxycoumarin. Salicylaldehyde (1.1 mL, 10.3mmol), diethyl malonate (1.7 mL,
11.2mmol), ethanol (4 mL), piperidine (20 drops), and glacial acetic acid (4 drops) were added to
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25 mL round bottom flask and refluxed for two hours with continuous stirring. The reaction was
monitored by thin layer chromatography (40% EtOAc/hexane). Upon cooling in an ice bath,
yellow tinged crystals were isolated through vacuum filtration and washed with cold ethanol
(95%). The product was recrystallized in 95% ethanol and the solvent evaporated to yield white
crystals (.6076g, 27.03%); 1H NMR (400 MHz, CDCl3)  1.4358 (s, 3H), 4.4436 (q, 2H), 7.3364
(m, 2H), 7.6434 (m, 2H), 8.5501 (s, 1H); 13C NMR (400 MHz, CDCl3)  14.2291 (1C), 61.9111
(1C), 77.5623 (1C), 116.6594 (1C), 118.0921 (1C), 124.9153 (1C), 129.5998 (1C), 134.405
(1C), 148.6650 (1C), 155.0453 (1C), 156.7295 (1C), 162.9104 (1C); melting point 88-90C.
Results and Discussion
Synthesizing 3-carbethoxycoumarin from salicylaldehyde is an experiment in
transforming one ester group of a diethyl malonate and then executing an aldol condensation in
forming the heterocyclic product. Piperidine is used as a base because the starting materials are
highly susceptible to nucleophilic attack and if a nucleophilic base such as hydroxide was used, a
variety of other products would most likely evolve. Likewise, glacial acetic acid, or rather, acetic
acid devoid of water, is also used as a weak proton source sans the nucleophilic presence of
water. As condensation reactions inherently produce water, the affixed water condenser and
Drierite (a dehydrator), at the top of the flask effectually removed any water vapor, limiting the
scope of other possible byproduct creation. With all of these chemical considerations, the
reaction was geared towards successfully creating a fairly pure product.
By monitoring the reaction through TLC and using a standard salicylaldehyde against the
reaction mixture, the progress of the reaction was determined. During the two-hour duration, the
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salicylaldehyde starting material gradually diminished and completely disappeared from the
reaction mixture lane by TLC plate four. TLC plates four through seven all had reaction lanes
that contained a product spot below the salicylaldehyde spot. This is expected as 3
carbethoxycoumarin is more polar than the starting material and would thus have a much smaller
Rf. TLC plate seven also showed the evolution of a spot at the origin line as well. This
potentially indicates that a highly polar by-product developed. To examine the success of the
reaction and whether a pure sample of 3-carbethoxycoumarin was developed, the melting point
was determined and NMR and IR spectra were examined.
At a qualitative level, the obtained product aligns fairly closely to the expected result. 3
carbethoxycoumarin is a white, crystalline structure that melts at a temperature range between
92-94C. Accordingly, the product was also comprised of white crystals. Upon melting point
determination, the melting point range fell between 88-90C. Giving a five degree margin of
error to the literature melting point range, the obtained melting point fits fairly closely, indicating
a fairly pure product. Although the two melting point ranges do not align perfectly and the
obtained melting point is lower than the literature range, impurities are not believed to be the
primary causative agent in the discrepancy. If the product was inundated with impurities, even
excess solvent, the melting point would not only be much lower but also be broader. The melting
point range obtained is very tight, at an approximate two degree difference. A possible reason for
the discrepancy could be the Mel-Temp apparatus itself or the thermometer. Due to time
constraints, the thermometer used to obtain the melting point was not calibrated and a small
margin of error would be enough to provide the inconsistency.
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For further confirmation of product synthesis and purity, both 1H and 13C NMRs were
obtained. 60 MHz 1H NMR was first obtained to provide a general outlook on the nature of the
product and a subsequent 400 MHz 1H NMR was obtained for a more sensitive examination.
The 13C NMR reveals that the product contained twelve unique carbons (Figure 5,
Supplemental Information). While this does not rule out the possibility of other compounds
being present, since 3-carbethoxycoumarin contains twelve unique carbons and the starting
materials of salicylaldehyde and diethyl malonate contain seven and 4 unique carbons
respectively, this can be used as a positive indication of successful product development.
However, more definitive determinations of identity cannot be made from the 13C NMR alone
because many of the key peaks represent carbon bonds that mirror similar bonds in the starting
materials, such as aromatics, esters, and carbonyls.
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H NMR is a more comprehensive and detailed examination of the product and is more
sensitive to illustrating atom location and impurities. As both the 60 MHz and the 400 MHz
spectra feature peaks in generally the same locations with fairly identical splitting patterns and
integrations, it can be reasonably assumed that the product was reasonably pure (Figures 3, 4,
Supplemental Information). 3-carbethoxycoumarin contains seven distinctive hydrogens, namely
four aromatic hydrogens, one vinylic, two off of an ester, and three methyl hydrogens (Figure
2). These peaks were all seen in both spectra. Four hydrogens were identified in the aromatic
region of 6-8 ppm, a multiplet within the 60 MHz and two doublets in the 400 MHz (Figures 3,
4, Supplemental Information). As the 400 MHz is more sensitive, it most likely was better able
to detect the downward shifting of the aromatic hydrogens closest to the cyclic oxygen, creating
the doublet splitting pattern (Figure 4, Supplemental Information). Both spectra also featured the
characteristic vinylic hydrogen at around 8.5 ppm, ester hydrogens around 4.5 ppm, and methyl
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hydrogens at 1.5 ppm (Figures 3, 4, Supplemental Information). All of these peaks would be
expected for 3 carbethoxycoumarin. No other hydrogen peaks were visible in either spectra and
the characteristic aldehyde and phenol hydrogens of the starting material, salicylaldehyde, were
also not apparent.
As a final piece of examination, the IR spectrum further confirms functional groups
indicative of 3 carbethoxycoumarin. A distinctive stretch is present in the carbonyl region at
approximately 1780 cm3 (Figure 6, Supplemental Information). No other majorly atypical
stretches are visible, especially the phenol stretch at 3500 cm3 or aldehyde stretch at 2720 or
2820 cm3 that would indicate presence of the starting material.
Taking into consideration the data from the melting point, various NMRs, and IR, it can
be reasonably concluded that a pure sample of 3 carbethoxycoumarin was synthesized from
salicylaldehyde. The melting point is fairly close to the literature value and all of the NMR and
IR spectra show expected peaks and no atypical peaks or stretches. Although the final TLC,
(TLC Plate 7), indicated the presence of another, highly polar product, this by-product was most
likely removed during the recrystallization process. More importantly, the removal of this
byproduct may be the primary reason for the approximately 27% yield. Understandably, a
substantial amount of materials and product were lost due to the nature of the laboratory set up
and through glassware transfers. Yet, since TLC plates 4 through 7 indicate that most, if not all,
of the starting material reacted, and TLC plate 7 indicated the evolution of a second product, it
can be concluded that the depression in the percent yield is most likely due to the formation of
by-products and other impurities. While aldol condensation reactions are effective, evidence
indicates that they inherently lend themselves to many variable by-products3. These by products
did not affect purity most likely because they were removed during recrystallization, but
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nonetheless, their evolution could have a major impact on the total product produced. To rectify
this in the future, it would be advisable to stop the reaction shortly after a TLC plate indicates the
absence of starting material. This would limit the potential for by-product development and
possibly increase the percent yield.
Conclusion
Within this experiment, the aim of executing a transesterification and aldol condensation
to create a coumarin derivative was successfully accomplished. Despite a mildly low percent
yield at 27%, the product obtained was a pure sample of 3-carbethoxycoumarin as confirmed
through various spectral analyses. In the future, this experiment may be repeated with certain
minor modifications to increase the amount of product obtained, but on the whole, the
experiment can be deemed as a success.
References:
(1) Hoult, J.R. and M. Paya. Gen. Pharmacol. 1996, 4, 713-722.
(2) Lachenmeier, Dirk W. Food Chemistry. 2008, 2, 462.
(3) Saito, Susumu. Chemistry : a European journal. 1999, 7, 1959-1962.
(4) Al-awar, Rima and George H. Wahl. Journal of Chemical Education. 1990, 3, 265.
(5) Rummel, Sheryl A. Ed. Lab Guide for Chem 213: Introductory Organic Chemistry Laboratory. Hayden
McNeil: Plymouth, MI 2011.
(6) Sigma-Aldrich Co., 2011 Product Database. Coumarin Derivative Synthesis from
Salicylaldehyde. Structural and chemical information. Online access. <www.sigmaaldrich.com/catalog> November
3, 2011.
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