Synthesis of 3-Carbethoxycoumarin
Timikeyi Egbuson
11/14/2013
Chemistry 213. 101
Michael Banales
Synthetic FFR 1
1|Egbuson
Introduction
Coumarins, a class of heterocyclic compounds, derived its name from “Coumarou”, the
vernacular name of the tonka bean (Dipteryx odorota Willd.,Fabacae), from which coumarin
itself was isolated in 1820. 1 Coumarins are found in fruits (e.g bilberry), cinnamon bark oil,
cassia leaf oil and consist primarily of four sub types: the simple coumarins, furanocoumarins,
pyranocoumarins and the pyrone-susbstitute coumarins.2 Coumarins are used in agrochemicals,
perfumes, food additives and also have widespread biological significance based on their
cytotoxic, anticoagulant, anxiolytic and antioxidant properties.3 Carbonyl condensation reactions
take place in various metabolic pathways and effectively synthesize various useful
macromolecules. The formation of carbon-carbon bonds in carbonyl condensation reactions
explains its use as a precursor for the formation of large compounds due to the ability of
carbonyl compounds to act as both the electrophile and nucleophile. Aldol condensation
reactions combine two carbonyl compounds by forming a bond between the α carbon of one of
the molecules and the carbonyl carbon of the other i.e a combination of nucleophilic addition and
α substitution. The dehydration of aldol products give rise to conjugated enones both in acidic
and basic conditions. In acidic conditions, the formation of enols occur and water acts as a good
leaving group based on elimination reactions. In basic conditions, the formation of an enolate ion
leads to the expulsion of the hydroxyl group based on the unimolecular elimination of the
conjugate base mechanism. 3-carbethoxycoumarin, a simple coumarin derivative, was
synthesized via base catalyzed trans esterification, followed by an aldol condensation reaction of
salicylaldehyde and diethylmalonate. The relatively easy accessibility of esters account for their
convenient use as starting materials in transesterification reactions. Not only is transesterification
vastly used in pure organic synthesis, it plays a role in polymerization and ring opening of cyclic
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compounds. A drying tube filled with Drierite was used to keep atmospheric moisture from the
reaction. Alternatively, 3-carbethoxycoumarin can be synthesized from the conjugated addition
of lithium and magnesium derivatives of o-carboranes.4 It is also used as a precursor in the
synthesis of more complex coumarin derivatives such as ethyl 4-phenyl-3,4-dihydro-3coumarincarboxylate.5
Scheme 1. Mechanism showing synthesis of 3-carbethoxycoumarin from salicyladehyde
and diethylmalonate via transesterification and aldol condensation.
,
Due to the relatively low pka (≃13) of the diethyl malonate in comparison to that of the aldehyde
(pka≃17), the acidic alpha hydrogen is easily deprotonated by the non-nucleophilic pyridine base
to form the nucleophilic enolate ion intermediate which attacks the electrophilic carbonyl of
salicylaldehyde. The resulting alkoxide picks up the acidic proton on the ethanol solvent and the
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hydroxide formed attacks an intermolecular hydride ion to form water (a good leaving group).
Dehydration occurs, thus, forming the stable conjugated enone while the phenol attacks the
carboxyl group in an intramolecular fashion eventually causing the ether group to leave. The
displaced ether group, which is the conjugate base of ethanol, is highly nucleophilic and attacks
the acidic proton on the carboxylic acid and upon tautomerization, 3 carbethoxycoumarin is
adequately formed.
Coumarins, and its derivatives, are widely utilized in agriculture and biology, explaining
the purpose of the synthesis of 3 carbethoxycoumarin via transesterification and aldol
condensation of diethyl malonate and salicyladehyde. The reaction progress was monitored using
thin layer chromatography based on spot intensities and retardation values while recrystallization
was employed for the purification of the crude product. Percent yield and recovery calculations
were determined while melting point analysis was taken to determine purity of product. Infrared
and nuclear magnetic resonance spectroscopy confirmed formation of desired product and
showed no starting materials or intermediates present.
Experimental
Salicylaldehyde (1.1 mL), diethyl malonate (1.7mL), ethanol (4mL), piperidine (20
drops) and glacial acetic acid (4 drops)were added to 25-mL round bottom flask and refluxed for
two hours, while stirring. The reaction was monitored by thin layer chromatography
(40%EtoAc/hexane). Upon cooling, crude crystals were isolated by vacuum filtration, using
Buchner funnel. Dry crude crystals were recrystallized using 95% ethanol and upon vacuum
filtration, white clear crystals evolved.
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Results and Discussion
The use of piperidine , rather than hydroxide, as base in the transesterification is due to
its relatively low nucleophilicity, but yet high solubulity in organic compounds. As a result, it
tends to interact with specific functional groups of interest in compounds with multiple
functional group based on its selective nature. Two thin layer chromatography plates were
spotted while the reaction was being refluxed. At about 60 min,
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