Diethyl malonate, also known as DEM, is the
diethyl ester
In chemistry, an ester is a compound derived from an acid (either organic or inorganic) in which the hydrogen atom (H) of at least one acidic hydroxyl group () of that acid is replaced by an organyl group (R). These compounds contain a distin ...
of
malonic acid. It occurs naturally in
grape
A grape is a fruit, botanically a berry, of the deciduous woody vines of the flowering plant genus ''Vitis''. Grapes are a non- climacteric type of fruit, generally occurring in clusters.
The cultivation of grapes began approximately 8,0 ...
s and
strawberries as a colourless
liquid
Liquid is a state of matter with a definite volume but no fixed shape. Liquids adapt to the shape of their container and are nearly incompressible, maintaining their volume even under pressure. The density of a liquid is usually close to th ...
with an
apple
An apple is a round, edible fruit produced by an apple tree (''Malus'' spp.). Fruit trees of the orchard or domestic apple (''Malus domestica''), the most widely grown in the genus, are agriculture, cultivated worldwide. The tree originated ...
-like
odour
An odor (American English) or odour (English in the Commonwealth of Nations, Commonwealth English; American and British English spelling differences#-our, -or, see spelling differences) is a smell or a scent caused by one or more volatilized ...
, and is used in
perfume
Perfume (, ) is a mixture of fragrance, fragrant essential oils or aroma compounds (fragrances), Fixative (perfumery), fixatives and solvents, usually in liquid form, used to give the human body, animals, food, objects, and living-spaces an agre ...
s. It is also used to
synthesize other
compounds such as
barbiturates,
artificial flavourings,
vitamin B1, and
vitamin B6.
Structure and properties
Malonic acid is a rather simple
dicarboxylic acid, with two
carboxyl groups close together. In forming diethyl malonate from malonic acid, the
hydroxyl group (−OH) on both of the carboxyl groups is replaced by an
ethoxy group (−OEt; −OCH
2CH
3). The methylene group (−CH
2−) in the middle of the malonic part of the diethyl malonate molecule is neighboured by two
carbonyl groups (−C(=O)−).
The hydrogen atoms on the carbon adjacent to the carbonyl group in a molecule are significantly more
acidic than hydrogen atoms on a carbon adjacent to
alkyl groups (up to 30 orders of magnitude). (This is known as the α position with respect to the carbonyl.) The hydrogen atoms on a carbon adjacent to two carbonyl groups are even more acidic because the carbonyl groups help stabilize the
carbanion resulting from the removal of a proton from the methylene group between them. The extent of resonance stabilization of this compound's conjugate base is suggested by the three resonance forms below:
:
Preparation
Diethyl malonate is produced from the reaction of the sodium salt of
chloroacetic acid
Chloroacetic acid, industrially known as monochloroacetic acid (MCA), is the organochlorine compound with the formula . This carboxylic acid is a useful building block in organic synthesis. It is a colorless solid. Related compounds are dichlo ...
with
sodium cyanide, which produces the
nitrile
In organic chemistry, a nitrile is any organic compound that has a functional group. The name of the compound is composed of a base, which includes the carbon of the , suffixed with "nitrile", so for example is called " propionitrile" (or pr ...
. This intermediate is then treated with ethanol in the presence of acid catalyst:
:
:
Alternatively,
sodium chloroacetate
Sodium chloroacetate is the organic compound with the formula CH2ClCO2Na. A white, water-soluble solid, it is the sodium Salt (chemistry), salt of chloroacetic acid. Many of its uses are similar to those of the parent acid. It is prepared by tre ...
undergoes
carboxyesterification by treatment with carbon monoxide and ethanol:
:
Dicobalt octacarbonyl is employed as the catalyst.
Reactions
Malonic ester synthesis
One of the principal uses of this compound is in the
malonic ester synthesis. The carbanion (2) formed by reacting diethyl malonate (1) with a suitable base can be alkylated with a suitable
electrophile
In chemistry, an electrophile is a chemical species that forms bonds with nucleophiles by accepting an electron pair. Because electrophiles accept electrons, they are Lewis acids. Most electrophiles are positively Electric charge, charged, have an ...
. This alkylated 1,3-dicarbonyl compound (3) readily undergoes
decarboxylation with loss of carbon dioxide, to give a substituted acetic acid (4):
:
In general, salts of the alkoxide anion whose alkyl part corresponds to the one used in the above alkylation are preferred as the base. The use of a conventional base may give
base hydrolysis
Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution, elimination, and solvation reactions in which water is the nucleophile.
Biological hydrolysi ...
products – for example, sodium hydroxide would simply produce sodium malonate and the alcohol, while other alkoxide salts will cause scrambling by
transesterification. Only the "same" alkoxide anion as the one that one used to alkylate the deprotonated active methylenic site will prevent both base hydrolysis and transesterification.
Other reactions
Like many other esters, this compound undergoes the
Claisen ester condensations. The advantage of using this compound is that unwanted self-condensation reactions are avoided. Like other esters, this compound undergoes
bromination at the alpha position.
Diethyl malonate can be
nitrosated with excess sodium nitrite in acetic acid to afford diethyl oximinomalonate, catalytic
hydrogenolysis of which in ethanol over Pd/C affords diethyl aminomalonate (DEAM). DEAM can be acetylated to produce
diethyl acetamidomalonate (useful in amino-acid synthesis), or can be added with 3-substituted 2,4-diketones to boiling acetic acid to afford in maximal yield variously substituted ethyl pyrrole-2-carboxylates of interest for porphyrin synthesis.
Applications
Diethyl malonate is used in the preparation of several medicinally useful compounds including
vigabatrin,
phenylbutazone
Phenylbutazone, often referred to as "bute", is a nonsteroidal anti-inflammatory drug (NSAID) for the short-term treatment of pain and fever in animals.
In the United States and United Kingdom, it is no longer approved for human use (except in t ...
,
nalidixic acid, and
rebamipide. Several pesticides are also produced from diethylmalonate, including
sethoxydim and the derivatives of 2-amino-4-chloro-6-methoxy
pyrimidine
Pyrimidine (; ) is an aromatic, heterocyclic, organic compound similar to pyridine (). One of the three diazines (six-membered heterocyclics with two nitrogen atoms in the ring), it has nitrogen atoms at positions 1 and 3 in the ring. The oth ...
.
[
]
References
{{reflist
Flavors
Malonate esters
Perfume ingredients
Ethyl esters