Organic synthesis via enolates

Organic synthesis via enolates
Dr. Vimal Rarh
Dept. of Chemistry
S.G.T.B. Khalsa College
Acidity of Alpha Hydrogens
Acidity of β-dicarbonyl Compounds
Hydrogen-Deuterium Exchange
Alkylation of Enolate Anions
Alkylation Reactions of Enolate Anions
Regioselectivity in Enolate Anion Formation and Reaction
Keto-enol tautomerism of Ethyl Acetoacetate
Equilibrium of keto-enol Mixtures
Modern Theories of Tautomerism
Position of Equilibrium in keto-enol Tautomerism
Factors affecting the Enol Content
Synthesis of Ethyl Acetoacetate: the Claisen Condensation
Alkylation of Diethyl Malonate and Ethyl Acetoacetate
Alkylation of 1,3-Dithianes
Alkylation and Acylation of Enamines
Enamines, Enols and Enolate Ions
Acidity of Alpha Hydrogens
The α (alpha) - hydrogen is the hydrogen atom that is bound to the carbon (called as α -carbon
atom) adjacent to the carbonyl carbon. The next carbon is the β-carbon and the hydrogen atoms
Aldehydes and ketones are weak acids and have remarkably low pKa values (between 15 and
20). Hence, they may act as a Bronsted acid in an acid-base reaction with a strong base.
But, aldehydes and ketones are much stronger acids than alkanes. Due to the only minor
difference in electronegativity between hydrogen and carbon, C-H bonds in alkanes are hardly
polarized. Thus, hydrogens of alkanes are in fact not acidic. The pKa values of alkanes are
around 50.
The acidity of α-hydrogens of aldehydes and ketones is much less than carboxylic acids, which
have pKa values around 3 to 4.
Reason for acidity: The α - hydrogen of carbonyl compounds is acidic, as it is connected with
the α -carbon that is directly bound to the electron withdrawing carbonyl group.
The carbonyl compounds' relatively high acidity (as compared to alkanes) may be explained by
the resonance stabilization of the conjugate base by the carbonyl group, or, in other words,
through the stabilization of the anion formed by deprotonation. This anion is called an enolate
The negative charge is mainly distributed among the α -carbon and the carbonyl oxygen, by
resonance, which leads to the stabilization of the otherwise highly, energized carbanion. The
distribution of the negative charge and the nucleophilic qualities are at the carbon (in carbanion)
and at the oxygen (in enolate anion). As a result, the α- carbon and the carbonyl oxygen are the
nucleophilic positions of enolate anions.
Further, as the negative charge is more stable at more electronegative oxygen, than at
electropositive carbon, the negative charge is bound more strongly and closely to the oxygen
atom than is the case with the α− carbon. Thus, the α−carbon (as anion) is a soft base, while the
carbonyl oxygen (as anion) is a hard base. As a result, soft Lewis acids (electrophiles), such as
alkyl halides and the carbonyl carbon of carbonyl compounds, tend to be nucleophilically
attacked by the enolate's α− carbon.
In simple words, an enolate anion has two nucleophilic positions, namely the α- carbon and the
carbonyl oxygen. Enolate anions are hence ambident, that is, they possess two reactive
(nucleophilic) centres. Protonation of an enolate may yield two different products, the enol
(enolic form of a carbonyl compound), or the carbonyl compound (keto form).
Variation of acidity: The acidities of these α−hydrogen atoms is enhanced if an electron
withdrawing group is attached to the α−carbon atom.
On the other hand, the acidity of the α−hydrogen atoms decreases if an electron donating group
is attached to the α−carbon atom.
Keto-enol tautomerism
The keto form and enolic form are in equilibrium called as keto-enol tautomerism.
The establishment of equilibrium may be catalyzed by both acids and bases. Through suitable
means, such as by fractional crystallization or careful distillation in the absence of any acid and
any base, the keto and the enolic form may be separated from each other. The keto and enolic
form of a carbonyl compound are constitutional isomers.
The separation must be carried out in the absence of all acids and bases, as the equilibrium
reaction would otherwise proceed too rapidly. As a result, the separated, pure keto and enolic
form would immediately be "contaminated" at least to some degree by the other form again.
The various structural formulas of an enolate, in which the negative charge is located at various
positions, are actually merely resonance formulas of one and the same compound!
Equilibrium position in keto-enol tautomerism : The position of the keto-enol equilibrium is
influenced by the temperature and the solvent (if present). The keto form usually exceeds the
enolic form to a considerable degree.
For example, Acetone contains only 1.5 x 10-4 % of the enolic form.
Ketones are usually not enolized to such a degree as aldehydes are. However, β-dicarbonyl
compounds are significantly much more enolized, as the double bond of a monoenolized βdicarbonyl compound is additionally stabilized through resonance with the second carbonyl
group. As a result, the α- hydrogen between the two carbonyl groups of β-dicarbonyl
compounds is much more acidic.
On the other extreme, the classic example of a compound that is virtually completely enolized is
phenol. The equilibrium constant of keto-enol tautomerism equilibrium of phenol amounts to
roughly 1010. It follows that the enolic form of phenol predominates to over 99.99 %. Due to the
strikingly high resonance stabilization of the aromatic system, the enolic form of phenol is much
more stable than the non-aromatic keto form (cyclohexadienone).
Also, phenol's enolate is much more stable than non-aromatic enolates are, as its negative charge
is stabilized through resonance with the aromatic system. As a result, phenol is considerably
more acidic than other enols or alcohols. The pKa value of is 9.95.
Fig: keto and enol form of phenol
Acidity of β-dicarbonyl compounds
The acidity of β-dicarbonyl compounds is considerably higher than that of monocarbonyl
compounds and other dicarbonyl compounds. In keto-enol equilibrium of β-dicarbonyl
compounds, the (mono)enolic form usually exceeds the keto form. For example, 2,4-Pentadione
consists of about 76 % enolic form.
The reason for this is the noticeably higher stabilization of the enol in comparison to other
carbonyl compounds. On the one hand, a β-dicarbonyl compound's enol is additionally stabilized
through resonance of the enol's carbon-carbon double bond with the second carbonyl group. On
the other hand, the enol's hydroxyl hydrogen is connected to the carbonyl oxygen by an
intramolecular hydrogen bond. The formation of this hydrogen bond is further facilitated by the
six membered planar structure of the enol-carbonyl resonance system.
Hydrogen-Deuterium Exchange
Due to the acidity of the α-hydrogens of enolizable carbonyl compounds, the α hydrogen may
easily be exchanged for deuterium (H/D exchange). H/D exchange may, for instance, occur
when the carbonyl compound is treated with heavy water (D2O).
Whenever a carbonyl compound is treated with a large excess of D2O, for instance, if it is
dissolved in D2O, virtually all α hydrogens of the carbonyl compound are exchanged. A large
excess of D2O is essential, since H/D exchange is an equilibrium reaction. The H/D exchange
happens faster in the presence of acids or bases.
Alkylation of enolate anions
Enolate anions are nulceophiles. Thus, they can participate in SN2 reactions. If reacted with alkyl
halides as electrophiles, alkylation of the enolate occurs. Due to the enolate's ambident character,
O-alkylation or C-alkylation may take place. The practicality of the reaction therefore depends
on the selectivity for one of the alkylation variations. The question is which position in the
enolate displays the highest nucleophilicity? Nucelophilicity also depends on the electrophile.
C-alkylation or O-alkylation? In alkylation with alkyl halides, the electrophile is a relatively
soft Lewis acid. For that reason, C-alkylation of the enolate is favored, as, due to carbon's lower
electronegativity, the enolate's carbon position is a much softer Lewis base than the oxygen
position. According to the HSAB concept, a soft Lewis base tends to react with a soft Lewis
acid, while a hard Lewis base tends to react with a hard Lewis acid.
On the other hand, if it is reacted with a harder base as an electrophile, O-alkylation is the
preferential route.
The complexity between reaction at C or at O in enolates is illustrated by the following
Important Factors
The negative charge density is greatest at the oxygen atom (greater
electronegativity), and coordination with the sodium cation is stronger there.
Because methyl iodide is only a modest electrophile, the SN2 transition state
resembles the products more than the reactants. Since the C-alkylation
product is thermodynamically more stable than the O-alkylated enol ether,
this is reflected in the transition state energies.
Trimethylsilyl chloride is a stronger electrophile than methyl iodide (note the
electronegativity difference between silicon and chlorine). Relative to the
methylation reaction, the SN2 transition state will resemble the reactants
(CH3)3Si–Cl more than the products. Consequently, reaction at the site of greatest
negative charge (oxygen) will be favored. Also, the high Si–O bond energy
(over 25 kcal/mole greater than Si–C) thermodynamically favors the silyl
enol ether product.
O-alkylation: Because of the substantial negative charge on the oxygen of ambident anions, it
might be expected that O-alkylation would be the rule rather than the exception. This, in fact, is
true when fully or extensively ionized enolate salts are reacted with strong electrophiles.
Ionization of enolates is facilitated by high dielectric solvents, such as DMSO and DMF
(dimethylformamide), especially for potassium and cesium cation salts. As shown in the lower
part of the second diagram, the negatively charged oxygens of DMSO cluster about a cation,
providing substantial solvation stabilization. No such solvation exists for the enolate anion,
leaving it open to reaction with an electrophile. Lithium enolates have significant covalent
character in the metal-oxygen bond, and this retards electrophile attack at oxygen.
Ether solvents such as THF and DME (dimethoxyethane or glyme) are commonly used for
alkylations because they are inert to strong base and dissolve enolate salts more effectively than
hydrocarbons. The difunctional ether DME (dimethoxyethane) is especially effective at solvating
cations; and this fact has led to the preparation of cyclic polyethers, known as crown ethers,
which are extraordinarily powerful solvating agents. Crown ethers may be added to enolate salt
solutions to enhance their ionization. Indeed, the size of the crown ether can be tailored to fit the
cation being used, providing additional control over the course of enolate reactions.
The nomenclature of crown ethers consists of two numbers. The first (larger) number designates
the overall ring size. The second number indicates the number of ether oxygens. A symmetrical
arrangement of the oxygens in the ring is assumed.
Another problem: Multiple alkylation : The possibility of a low selectivity between C- and Oalkylation is not the only problem of the alkylation of enolates. In addition, multiple Calkylation may also occur. As a result, a mixture of products is obtained.
For example,
In alkylation of carbonyl compounds, the enolate is actually the attacking nucleophile. Thus, if
enolization cannot occur, alkylation cannot take place. Therefore, carbonyl compounds that
contain only one α - hydrogen atom (i.e. CR3COCHR2) can only be monoalkylated. Multiple
alkylation is not an option. If the carbonyl compound possesses more than one α- hydrogen
atom, multiple alkylation can largely be prevented by applying a bulky, sterically demanding
base, such as the widely used lithium diisopropylamide (LDA). In this case, further
deprotonation and, thus, enolate formation of an existing monoalkylated carbonyl compound is
hampered by additional steric interactions between the alkyl group and the bulky isopropyl
substituents of LDA.
Alkylation Reactions of Enolate Anions
1. Use of a strong base LDA, leads to intermolecular alkylations of simple carbonyl compounds.
For example,
3. This shows the additive effect of carbonyl groups on alpha-hydrogen acidity.
Here the two hydrogen atoms activated by both carbonyl groups are over 1010 times more acidic
than the methyl hydrogens on the ends of the carbon chain.
Ring closures to four, five, six and seven-membered rings are also possible by intramolecular
enolate alkylation. For example,
Regioselectivity in Enolate Anion Formation and Reaction
The importance of enolate anions as synthetic intermediates is well established. Nevertheless,
problems remain concerning their selective formation and reaction. The ambident nature of
enolate anions also enables electrophilic attack at both oxygen and carbon, but in most synthesis
applications bonding to carbon is desired. Finally, enolate anions may often be formed as E/Z
stereoisomers, and it has been shown that reaction stereoselectivity, when new chiral centers are
created, depends on the enolate configuration.
The following diagram illustrates how the conditions under which enolate anion formation is
accomplished can influence the regioselectivity of the reaction.
For example, the two ketone substrates, 2-heptanone and 2-methylcyclohexanone, each have
differently substituted alpha-carbons. In each case, enolate anion mixtures are generated by
reaction with a strong 2º-amide base (LDA is the usual choice).
- If the ketone is added to a cold THF solution of excess base, enolate anion formation is fast and
irreversible (procedure a).
- On the other hand, if a slight excess of ketone is allowed to remain in solution, an equilibrium
involving the ketone and the various enolate species is established (procedure b).
- At equilibrium the more stable enolate anion will predominate. The examples given in the
diagram also report results from an equilibrating preparation in which the lithium metal in LDA
is replaced by potassium (procedure c).
In both of the examples shown above (I and II), the conditions used in procedure (a) are typical
of kinetically favored enolate formation, whereas those used in procedure (b) favor
thermodynamic enolate formation. The comparative acidities provided by pKa values are
derived from measurements made under equilibrating conditions, and therefore reflect
thermodynamic acidity.
The second reaction (II) is an intramolecular alkylation that can occur in two different ways. If
the kinetically favored enolate (methyl proton removal) is formed at low temperature, it reacts
rapidly on warming to form a seven-membered ring. Alternatively, the weaker base, potassium
tert-butoxide (in the alcohol as solvent), generates an equilibrium mixture of enolates which
eventually react by intramolecular alkylation. The thermodynamically favored α'-enolate
predominates, and the resulting alkylation generates a five-membered ring.
Keto-enol tautomerism of ethyl acetoacetate
Acetic ester or ethyl acetoacetate is the ethyl ester of acetoacetic acid CH3 · CO · CH 2 · CO2 H , a
β-ketonic acid.
Acetoacetic ester was first discovered by Geuther (1863), who prepared it by the action of
sodium on ethyl acetate, and gave the formula as CH3 · C(OH) : CH · CO2C 2 H5 (β-hydroxycrotonic
In 1865, Frankland and Duppa, also prepared acetoacetic ester by the action of sodium on
ethyl acetate,but they proposed a different formula CH3 · CO · CH 2 · CO 2C 2 H 5 (β-ketobutyric
Which of these is correct?
Evidence in favour of the Geuther formula (reactions of an unsaturated alcohol),
(i) When acetoacetic ester is treated with sodium, hydrogen is evolved and the sodium
derivative is formed. This showed the presence of a hydroxyl group.
(ii) When acetoacetic ester is treated with an ethanolic solution of bromine, it readily
decolourises. This indicates the presence of an olefinic double bond.
(iii) When acetoacetic ester is treated with ferric chloride, a reddish-violet colour is produced.
This is characteristic of compounds containing the enolic group ( -C(OH)=C<) like phenols.
Evidence in favour of the Frandland-Duppa formula(reactions of a ketone).
(i) With sodium hydrogen sulphite, acetoacetic ester forms a bisulphate derivative.
(ii) With hydrogen cyanide, acetoacetic ester forms a cyanohydrin.
Thus, evidence for both the structure were there. The controversy continued until about 1910,
when chemists came to the conclusion that both formula were correct, and that the two
compounds existed together in equilibrium in solution (or in the liquid state):
CH3 · CO · CH2 · CO2C2H5
CH3 · C
CH · CO2C2H5
When a reagent which reacts with ketones
removed. This upsets the equilibrium, and
hydroxyl form of acetoacetic ester changes
reagent is added, acetoacetic ester
is added to acetoacetic ester, the ketone form is
in order to restore the equilibrium mixture, the
into the ketone form. Thus provided insufficient
reacts completely as the ketone form.
Similarly, when a reagent which reacts with olefins or with hydroxy-compounds is added in
sufficient quantity, acetoacetic ester reacts completely as the hydroxyl form.
Knorr (1911) succeeded in isolating both forms.
1. Ketone form: On cooling a solution of acetoacetic ester in light petrol to –78°, he obtained
crystals which melted at –39°. This substance gave no coloration with ferric chloride and did not
combine with bromine, and was therefore, the pure ketone form corresponding to the FranklandDuppa formula.
2. Hydroxyl form: By suspending the sodium derivative of acetoacetic ester in light petrol
cooled to –78°C, and treating this suspension with just enough HCl to decompose the sodium
salt, he obtained a glassy solid when cooled. This substance gave an intense coloration with
ferric chloride, and was therefore the pure hydroxyl form corresponding to the Geuther formula.
Thus acetoacetic ester is a substance that does the duty of two structural isomers, each isomer
being capable of changing rapidly into the other when the equilibrium is distributed, e.g., by
the addition of certain reagents.
This is a case of dynamic isomerism, and the name tautomersim (Greek: same parts) was given
to this phenomenon by Laar (1885).
The two forms are known as tautomers or tautomerides, the phenomenon being called the ketoenol tautomerism.
The word enol is a combination of -en for double bond and -ol for hydroxyl.
Stability of tautomers: When one tautomer is more stable than the other under ordinary
conditions, the former is known as the stable form, and the latter as the labile form.
It is generally difficult to say which is the labile form, since very often a slight change in the
conditions, e.g., temperature, solvent, shifts the equilibrium from keto to enol or vice versa.
Tautomerism in the solid state is rare, and hence, in the solid state, one or other tautomer is
normally stable, but in the liquid or gaseous state, or in solution, the two forms usually exist as
an equilibrium mixture.
It has been found that the enol form is more volatile than the keto.
The change from enol to keto is extremely sensitive to catalysts like acid or bases.
Experiments using deuterium exchange reactions have also shown the presence of keto-enol
Equilibrium of keto-enol mixtures
Physical methods: Physical methods do not disturb the equilibrium as they do not depend on the
removal of one. Hence, they should be used wherever possible to determine the equilibrium
(i) The refractive index of the equilibrium mixture is determined experimentally. The
refractive indices of both the keto and enol forms are calculated (from the literature references of
atomic refractions). From these figures it is then possible to calculate the amount of each form
present in the equilibrium mixture.
(ii) If one form is an electrolyte, the electrical conductivity of the mixture is determined
experimentally, and the amount of this form present may be calculated from the results.
(iii) The composition of the equilibrium mixture may be determined by means of optical
rotation measurements, spectroscopy (I.R, N.M.R, etc).
Lately, physical methods, specially N.M.R are being extensively used to estimate the relative
percentage of keto and enol forms and to determine the equilibrium position.
Chemical methods: As these methods cause the removal of one form, it is necessary to use a
reagent that reacts with this form faster than the rate of interconversion of the tautomers.
Meyer (1911, 1912) found that in the case of keto-enol tautomerism, bromine reacts
instantaneously with the enol form. On the other hand, it reacts very slowly with the keto form.
He gave two methods:
a. Direct method: A weighed sample of the keto-enol mixture dissolved in ethanol is rapidly
titrated with a dilute ethanolic solution of bromine at 0º (to slow down the interconversion of the
tautomers). The first appearance of excess bromine indicates the end point.
The titration must be carried out rapidly; otherwise the keto form changes into the enol during
the time taken for the titration. This is practically impossible. So this method always results in
too high a value for the enol form.
b. Indirect method: An excess of dilute ethanolic solution of bromine is added rapidly to the
weighed sample dissolved in ethanol, and then an excess of 2-naphthol dissolved in ethanol is
added immediately.
By this means, the excess bromine is removed almost instantaneously, and so the keto-enol
equilibrium is not given time to be disturbed. Potassium iodide solution and hydrochloric acid
are now added, and the liberated iodine is titrated with standard thiosulphate.
The overall equation is :
CH 3 . CO . CHBr . CO 2 Et + 2I − + H + ⎯
⎯→ CH 3 . CO . CH 2 . CO 2 Et + I 2 + Br −
Mechanism of bromination:
C · CH3
Br– + CHBr · C · CH3
CH3 · CO · CHBr · CO2Et
More reliable results may be obtained by the indirect method.
Table showing % of enol content
% enol (in ethanol)
CH3 . CO . CH 2 . CO 2 CH3
CH3 . CO . CH 2 . CO 2C 2 H 5
CH3 . CO . CH 2 . CO . CH3
CH3 . CO . CH(CH3 ) . CO . CH3
C6 H 5 . CO . CH 2 . CO . C6 H 5
CH 2 (CO 2 C 2 H 5 ) 2
Aldehydes of type R . CH 2 . CHO
Ketones of type R . CH 2 . CO . CH 2 . R
The phenomenon of enolisation is exhibited by compounds containing either a methylene group,
·CH 2 · , or a methine group, ,adjacent to a carbonyl group. The actual amount of enol form present
depends on a number of factors; these are discussed later.
When the methylene or methine group is attached to two or three carbonyl groups, the hydrogen
atom may migrate equally well to one or other carbonyl group. However, practically, this is not
the case for unsymmetrical ketones and usually one enol form predominates. e.g., in
acetoacetic ester the hydrogen atom migrates exclusively to the acetyl carbonyl group.
When two or more enol forms are theoretically possible, ozonolysis may be used to ascertain the
structure of the form present; e.g., in hexane-2, 4-dione, CH3 . CO . CH 2 . CO . CH 2 . CH3 , the two
possible enols are :
Ozonolysis of (I) will give CH3 . CO 2 H and CH3 . CH 2 . CO . CHO; (II) will give CH3 . CO . CHO and
CH3 . CH 2 . CO 2 H. Identification of these compounds will decide whether the enol is (I) or (II), or
In ethyl acetoacetate, it is predominately the (I) form.
Enols resemble phenols in a number of ways; e.g., both form soluble sodium salts; both give
characteristic colorations with ferric chloride; and both couple with diazonium salts.
Modern theories of tautomerism
Ingold (1927) suggested the names
a. Cationotropy for all those cases of tautomerism which involve the separation of a cation
Lowry (1923) suggested the name prototropy for those cases in which a proton separates,
and called such systems prototropic systems. It can be seen that prototropy is a special case
of cationotropy.
b.Anionotropy for those cases which involve the separation of an anion.
Braude and Jones (1944) proposed the term oxotropy for aniontropic rearrangements
involving only the migration of hydroxyl group.
According to Hughes and Ingold, base-catalysed enolisation of a ketone proceeds through
the enolate anion, whose formation is controlled largely by the inductive effects of the alkyl
Acid catalysed enolisation involves the removal of a proton from the conjugate acid of the
ketone, and this process is dependent mainly on the hyperconjugation by the alkyl groups in the
transition state for the formation of the carbon-carbon double bond.
Termolecular mechanism:
In other cases, acid and base catalysis of enolisation take place by a concerted or push-pull
mechanism, i.e., the molecule undergoing change is attacked simultaneously at two places.
Thus the enolisation of e.g., acetone, proceeds by the simultaneous removal of a proton from an
α-carbon and the addition of a proton to the oxygen of the carbonyl group. This may be
represented as follows (B is a general base, and HA is a general acid):
B ..... H..... CH2
O ..... HA
BH + C
OH + A–
transition state
Position of equilibrium in keto-enol tautomerism
∆G° = ∆H° – T∆S° = –RTlnK
If the values of the enthalpy and entropy changes are known, ∆G° and thus K, the equilibrium
constant of the following reaction can be calculated
K = [enol]/[keto]
Consider the following equilibria:
ethyl acetoacetate Me
EtO · C
ethyl malonate
C · Me
C · OEt
Me · C
Me · C
C Me
EtO · C
C · OEt
Factors affecting the enol content
1. Ring strain: If the enol form is intra-molecularly hydrogen bonded, it is more stable and
would lead to a higher enol content. Cyclic monoketones contain more enol than the
corresponding acyclic 2-one. In the cyclic ketones, change from keto to enol involves a relatively
small change in strain in the ring due to the introduction of a double bond. For acyclic ketones,
the introduction of the double bond has a much greater effect on the freedom to take up different
2. Steric factor: The enol content of acetylacetone is higher than α-methylacetylacetone (in gas
phase). In the later compound, there is much greater steric repulsion due to the presence of the αmethyl group. Thus, the α-methyl enol form has greater internal strain than the enol form of
91 – 93%
43.5 – 44.5%
3. Nature of solvent: Any solvent that can form hydrogen bonds with the carbonyl group of the
keto form will stabilize this form (by solvation). The enol form, however, since it forms an
intramolecular bond, will be largely prevented from forming hydrogen bonds with the solvent
i.e., solvation will be less. Thus the keto form is stabilized with respect to the enol form e.g.,
solvents such as water, methanol, acetic acid, etc. tend to reduce the enol content.
On the other hand, in solvents such as hexane, benzene etc. the enol content will be larger, e.g.,
the enol content of acetylacetone in hexane is 92 per cent.
Synthesis of ethyl acetoacetate: the Claisen condensation
Ethyl acetoacetate is the ethyl ester of acetoacetic acid (CH3COOH) and is widely used as a
starting material for the synthesis of a variety of ketones and acids. It can be prepared by Claisen
condensation of ethyl acetate.
The condensation of two molecules of an ester (e.g. ethyl acetate), or of two molecules of
different esters, or of one molecule of an ester with one molecule of a ketone under the influence
of sodium or sodium ethoxide, is termed Claisen condensation (1887), and is one of the best
methods for preparing beta-ketonic esters like ethyl acetoacetate.
Two molecules of ethyl acetate condense in the presence of sodium ethoxide to produce ethyl
Claisen condensation may also be brought about by sodamide or tri-phenylmethylsodium etc.
Mechanism: It is similar to aldol condensation.
1.Formation of α−carbanion
H3 C
H2 C
+ EtOH
pKa ca. 16
pKa ca. 24
2. Addition step:
3. Elimination step:
Evidence to support this mechanism:
(i) Compounds containing an active methylene group undergo deuterium exchange with sodium
ethoxide in the presence of EtOD. This can be explained by the reversible formation of αcarbanion.
CH2 · CO
+ EtO–
EtOH +
+ EtO–
(ii) Optically active esters of the type RR ′CH ⋅ CO 2 Et are racemised by the ethoxide ion. The
planar delocalized carbanion intermediate is expected to lead to racemisation.
Alkylation of diethyl malonate and ethyl acetoacetate
Acetic ester or ethyl acetoacetate (E.A.A.) is the ethyl ester of acetoacetic acid
CH3 · CO · CH 2 · CO 2 H , a β-ketonic acid.
Malonic ester, CH 2 (CO 2 C 2 H 5 ) 2 , is the diethyl ester of malonic acid CH 2 (CO 2 H) 2 .
Both these compounds contain two α-hydrogen atoms each, which are more acidic than those of
simple aldehydes and ketones. These α -hydrogen atoms can be easily abstracted by the use of
an appropriate base like sodium alkoxide. This followed by the reaction with an alkyl halide
leads to alkylation of these compounds.
1. Alkylation of Ethyl acetoacetate : When treated with sodium ethoxide, acetoacetic ester forms
sodioacetoacetic ester
Sodioacetioacetic ester so formed, readily reacts with primary and secondary alkyl halides to
produce alkyl derivatives of acetoacetic ester in which the alkyl group is attached to carbon.
Vinyl and aryl halides do not react.
Mechanism: The negative ion (II) (like enolate ion) is formed, which is a resonance hybrid, i.e.,
this ion is ambident.
The C-alkylation occurs usually by SN2 mechanism as shown below :
HC ·· R
R + X–
The tendency for alkylation at the more electronegative atom (O-alkylation) of an ambident
anion usually increases with the S N 1 character of the reaction.
After one alkyl group has been introduced, the dialkyl derivative of acetoacetic ester may be
produced by repeating the whole process.
A recent method gives one step preparation of the disubstituted derivatives of acetoacetic ester.
For example, Sandberg (1957) prepared ethyl β-acetotricarballylate form acetoacetic ester, ethyl
bromoacetate and sodium hydride in benzene solution.
CH3·CO·CH2·CO2C2H5 + 2CH2Br · CO2C2H5
CH2 · CO2C2H5
CH3 · CO · C CO2C2H5
CH2 · CO2C2H5
Potassium t-butoxide is usually best for preparing the metallo-acetoacetic ester compounds
Amongst alkyl halides, generally alkyl iodides react faster than alkyl bromides.
Acetoacetic ester and its alkyl derivatives can undergo two types of hydrolysis with potassium
(a) Ketonic hydrolysis: It is so called because a ketone is the chief product. It is carried out by
boiling with dilute aqueous or ethanolic potassium hydroxide solution, e.g.,
The ketone obtained is acetone or its derivatives, and the latter always contain the group
CH 3 . CO – .
Mechanism of decarboxylation:
(b) Acid hydrolysis: It is so called because an acid is the chief product, is carried out by
boiling with concentrated ethanolic potassium hydroxide solution, e.g.,
The acid obtained is acetic acid or its derivatives as the potassium salt. The free acid is readily
obtained from these salts by treatment with inorganic acids.
Mechanism of the cleavage:
CO2Et + EtO–
Me · CO2Et + –CHR · CO2Et
CH2R · CO2Et + EtO–
Applications: These alkylation reactions followed by ketonic hydrolysis or acidic hydrolysis are
used for the synthesis of various ketones and acids.
1.Synthesis of Ketones: The formula of the ketone is written down, and provided it contains
the group CH 3 . CO – , the ketone can be synthesized via acetoacetic ester as follows. The acetone
nucleus is picked out, and the alkyl groups attached to it are then introduced into acetoacetic
ester one at a time; this is followed by ketonic hydrolysis.
It is usually better to introduce the larger group before the smaller (steric effect).
Reaction type: Nucleophilic substitution, then ester hydrolysis & finally decarboxylation (!)
For example,
CH3 · CO · CH2 · CH3
3 →
CH 3 · CO · CH 2 · CO 2 C 2 H 5 ⎯⎯2 ⎯5 ⎯⎯→ [CH 3 · CO · CH · CO 2 C 2 H 5 ] – Na + ⎯⎯⎯
CH 3 · CO · CH (CH 3 ) · CO 2 C 2 H 5 ⎯ketonic
⎯→ CH 3 · CO · CH 2 · CH 3
CH3 · CO · CH · CH2 · CH3
[CH3·CO·CH·CO2C2H5]– Na+
[CH3·CO·C(C2H5)·CO2C2H5]– Na+
2. Synthesis of fatty acids: Here, the acetic acid nucleus is picked out, and the acetoacetic ester
derivatives are subjected to acid hydrolysis. The acetoacetic ester acid synthesis is usually
confined to the preparation of straight-chain acids or branched-chain acids where the branching
occurs on the α-carbon atom. For example,
n-Butyric acid.
CH3 · CH2 · CH2 · CO2H
ii.α-methyl-n-valeric acid:
3. Other synthesis: Sodioacetoacetic ester reacts with many other halogen compounds besides
alkyl halides, and so may be used to synthesise a variety of compounds.
(i) 1, 3-Diketones. Here, the halogen compound used is an acid chloride. As acid chlorides
react with ethanol, the reaction is not carried out in this solvent in the usual way. The reaction is
thus carried out by treating acetoacetic ester in benzene solution with magnesium and the acid
For example,
1. pentane-2, 4-dione
⎯→ (CH 3 · CO) 2 CH · CO 2 C 2 H 5 ⎯ketonic
CH 3 · CO · CH 2 · CO 2 C 2 H 5 + CH 3 · COCl ⎯⎯
CH 3 · CO · CH 2 · CO · CH 3
2. The O-acetyl derivative of acetoacetic ester, acetoxycrotonic ester, is obtained, if
sodioacetoacetic ester or acetoacetic ester itself is treated with acetyl chloride in pyridine as
The first reaction occurs by the S N 2 mechanism and the latter by S N 1 .
(ii) Dicarboxylic acids: These may be prepared by interaction of sodioacetoacetic ester and a
halogen derivative of an ester. e.g., preparation of succinic acid from ethyl chloroacetate:
[CH3 · CO · CH · CO2C2H5]– Na+ + ClCH2 · CO2C2H5
CH2 · CO2C2H5
CH3 · CO · CH · CO2C2H5
CH2 · CO2H
CH2 · CO2H
Long chain fatty acids. It involves a combination of methods (i) and (ii) given above.
(CH2)x · CO2C2H5
[CH3·CO·CH·CO2C2H5]– Na+
Br · (CH2)x · CO2C2H5
(i) C2HONa
(ii) CH3 · (CH3)y · COCl
(CH2)x · CO2C2H5
CH3 · CO · C · CO2C2H5
CO(CH2)y · CH3
These keto-acids are readily reduced to the corresponding fatty acid by means of the
Clemmensen reduction.
2. Alkylation of Diethyl Malonate
With sodium ethoxide, it forms a sodium derivative called as sodiomalonic ester. This reacts
with compounds containing a reactive halogen atom, e.g., alkyl halides, acid chlorides, halogensubstituted esters, etc.
OC2H5 Na+
OC2H5 Na+
OC2H5 + NaX
The process on repetition produces the disubstituted derivative of malonic ester.
⎯→ RR ′C(CO 2 C 2 H 5 ) 2
R · CH (CO 2 C 2 H 5 ) 2 ⎯⎯2 ⎯5 ⎯⎯→ [R · C(CO 2 C 2 H 5 ) 2 ] – Na + ⎯RX
These substituted derivatives of malonic ester can also be readily prepared in one step by treating
the ester with two equivalents of sodium ethoxide and then with two equivalents of alkyl halide.
This procedure is used only if two identical alkyl groups are to be introduced.
(i ) 2 EtONa
CH 2 (CO 2 C 2 H 5 ) 2 ⎯⎯ ⎯ ⎯⎯→ R 2 C (CO 2 C 2 H 5 ) 2 + 2 NaX
(ii ) 2 RX
Malonic acid and its derivatives eliminate a molecule of carbon dioxide when heated just above
the melting point of the acid (between 150° and 200°) to form acetic acid or its derivatives
CO 2 H · CH 2 · CO 2 H ⎯
⎯→ CH 3 · CO 2 H + CO 2
CO 2 H · CHR · CO 2 H ⎯
⎯→ R · CH 2 · CO 2 H + CO 2
Decarboxylation occurs faster if done by refluxing malonic acid or its derivatives in sulphuric
acid solution.
Applications: These alkylation reactions followed by decarboxylation are used for the synthesis
of various higher acids called as fatty acids.
Reaction type: Nucleophilic substitution, then ester hydrolysis & finally decarboxylation (!)
1. Synthesis of fatty acids: Malonic ester is preferable to acetoacetic ester in synthesizing
The structural formula of the acid required is written down, the acetic acid nucleus picked out,
and the required alkyl groups introduced into sodiomalonic ester. The substituted ester is then
refluxed with potassium hydroxide solution, acidified with hydrochloric acid, and the
precipitated acid dried and then heated just above its melting point. Alternatively, the potassium
salt may be refluxed with sulphuric acid.
n – Valeric acid
CH3 · CH2 · CH2 · CH2 · CO2H
[CH(CO2C2H5)2]– Na+
C3H7 · CH(CO2K)2
C3H7 · CH(CO2H)2
C3H7 · (CO2C2H5)2
150 – 200°
CH3 · CH2 · CH2 · CH · CO2H
Dimethylacetic acid.
CH3 · CH · CO2H
2C H ONa
KOH, etc.
CH 2 (CO 2C 2 H 5 ) 2 ⎯⎯5⎯5⎯⎯→ (CH 3 ) 2 C(CO 2C 2 H 5 ) 2 ⎯⎯ ⎯ ⎯
⎯→ (CH 3 ) 2 CH · CO 2 H
2CH 3 I
Aryl-substituted derivatives are prepared indirectly. Claisen condensation is followed by
decarboxylation. e.g., ethyl phenylmalonate.
Synthesis of dicarboxylic acids: Dicarboxylic acids of the type RR ′C(CO 2 H) 2 are readily
prepared from malonic ester. For example,
Adipic acid
CO2H · CH2 · CH2 · CH2 · CH 2 · CO2H
(C 2 H 5O 2 C) 2 CH ] – Na + + BrCH 2 · CH 2 Br + Na + [CH (CO 2 C 2 H 5 ) 2 ] – ⎯
(i ) KOH
(C 2 H 5O 2 C) 2 CH · CH 2 · CH 2 · CH (CO 2 C 2 H 5 ) 2 ⎯⎯ ⎯⎯→
(ii ) HCl
150 – 200°
(HO 2 C) 2 CH · CH 2 · CH 2 · CH (CO 2 H ) 2 ⎯⎯ ⎯ ⎯⎯→ CO 2 H· CH 2 · CH 2 · CH 2 · CH 2 · CO 2 H
Succinic acid.
CO2H · CH2 · CH2 · CO2H
(i ) KOH
[CH (CO 2 C 2 H 5 ) 2 ] – Na + + ClCH 2 · CO 2 C 2 H 5 ⎯
⎯→ (C 2 H 2 O 2 C) 2 CH · CH 2 · CO 2 C 2 H 5 ⎯⎯ ⎯⎯→
(ii ) HCl
150° – 200°
(HO 2 C) 2 CH · CH 2 · CO 2 H ⎯⎯ ⎯ ⎯⎯→ CO 2 H · CH 2 · CH 2 · CO 2 H
[(C 2 H 5O 2 C) 2 CH ] – Na + + I 2 + Na + [CH (CO 2 C 2 H 5 ) 2 ] – ⎯
(i ) KOH
(C 2 H 5O 2 C) 2 CH · CH (CO 2 C 2 H 5 ) 2 ⎯⎯ ⎯⎯→ (HO 2 C) 2 CH· CH (CO 2 H ) 2
(ii ) HCl
150° – 200°
⎯⎯ ⎯ ⎯⎯→ CO 2 H · CH 2 · CH 2 · CO 2 H
Synthesis of ketones
Synthesis of higher ketonic acids: Sodiomalonic ester is treated with the acid chloride-ester
derivative of a dibasic acid, e.g., ε-ketoheptanoic acid:
[(C 2 H 5O 2 C) 2 CH ] – Na + + COCl · (CH 2 ) 4 · CO 2 C 2 H 5 ⎯
° − 200°
(C 2 H 5O 2 C) 2 CH · CO(CH 2 ) 4 · CO 2 C 2 H 5 ⎯⎯ ⎯⎯→ (HO 2 C) 2 · CO(CH 2 ) 4 · CO 2 H ⎯150
(i ) KOH
(ii ) HCl
[CO 2 H · CH 2 · CO · (CH 2 ) 4 · CO 2 H] ⎯
⎯→ CH 3 · CO · (CH 2 ) 4 · CO 2 H
4. Synthesis of polybasic acids:
CHBr(CO2C2H5)2 + [CH(CO2C2H5)2]– Na+
2[CH(CO2C2H5)2]– Na+
NaBr + (C2H5O2C)2CH·CH(CO2C2H5)2
Alkylation of 1,3-dithianes
Alcohols add to aldehydes and ketones via nucleophilic addition, producing cyclic acetals and
cyclic ketals.
For example,
Similarly, treatment of an aldehyde with a dithiol generates a cyclic thioacetal. The reaction
here also is done in the presence of acids. Lewis acids are preffered.
This reaction is of synthetic interest because of the change in acidity of the aldehydic hydrogen
that occurs when the aldehyde is converted to the corresponding cyclic thioacetal. While the pKa
of an aldehydic proton is approximately 45, it drops to approximately 32 in the cyclic thioacetal.
Hence, deprotonation of the cyclic thioacetal with LDA is essentially complete; Keq being
approximately 106. This is due to the resonance stabilization which leads to the greater acidity of
cyclic thioacetals.
Because sulfur has low lying empty 3d orbitals, the negative charge that initially resides on the
carbon atom may be delocalized onto both adjacent sulfur atoms. This stabilizes the conjugate
base, making deptotonation of the cyclic thioacetal feasible.
A comparable acid-base reaction is not possible in cyclic acetals because the conjugate base is
not stabilized by resonance; the oxygen atoms do not have d orbitals available to accomodate
electron density.
The electronic nature of the carbon atom has changed from being electrophilic in the aldehyde
to being nucleophilic in the conjugate base of the cyclic thioacetal.
This is called as Umpolung or polarity inversion. This refers to the chemical modification of a
functional group with the aim of the reversal of polarity of that group.
This is noteworthy because the direct alkylation of aldehydes by the following reaction is not
However, the above conversion may be accomplished indirectly by the 3-step sequence as
The last step of this sequence, the work-up, involves hydrolysis of the thioacetal, a process that is
facilitated by the Lewis acid mercuric chloride.
Alkylation and acylation of enamines
Primary amines react with aldehydes and ketones to produce imines. For example, the reaction of
acetophenone with methyl amine.
In this reaction the initially formed tetrahedral intermediate, A, undergoes dehydration. The loss
of the OH group in A could be accompanied by loss of a proton from either the NH group or the
CH3 group. The former alternative is preferred because the C-N double bond is more stable than
the C-C double bond that would be produced via the latter route, i.e. the more stable product is
preferred. Also the hydrogen attached to nitrogen is more acidic as compared to carbon and in
acid catalysed dehydration, the hydrogen attached to nitrogen gets lost.
Note that the amine has to be primary, i.e. have two hydrogen atoms attached to the nitrogen, for
the imine to form.
On the other hand, reaction of a secondary amine initially follows the same course as that of a
primary amine, but now the tetrahedral intermediate, B, cannot form an imine because the
nitrogen does not have a second hydrogen atom to lose:
Consequently, intermediate B undergoes dehydration to form an alkene. (Note that the starting
material must have at least one hydrogen attached to the α-carbon in order for this reaction to
occur.) But this type of alkene is special.
It is called an enamine.
Imines and enamines may be converted into aldehydes and ketones by acid catalysed hydrolysis,
i.e. by reaction with a large excess of water.
Enamines, Enols and Enolate Ions
Ketones exist in solution in equilibrium with their enol tautomers. Enolate ions exist as a
resonance hybrid in which the negative charge resides primarily on the carbonyl oxygen and
the α−carbon.
Similar charge delocalization occurs in enamines as well. The following diagram presents a
comparison of the structural and chemical similarities between enols, enolates, and enamines.
In all of these compounds a lone pair of electrons is conjugated to the pi system of the C-C
double bond. This interaction lends nucleophilic character to the α-carbon atom as indicated by
the resonance structures e1, e2, and e3, in which the α-carbons bear a formal negative charge.
Note the structural similarity between e2 and e3; enamines may be regarded as synthetic
equivalents of enolate ions.
However, as we shall see, there are significant differences between these two types of
nucleophilic reagents.
The 3 Es
The synthetic utility of enamines
In the case of unsymmetrical ketones, two enamines may be formed.
For example, the reaction of cyclic secondary amine pyrrolidine with 2-methylcyclohexanone
produces isomeric enamines.
The reaction produces a mixture of enamines in which the less substituted isomer
Presumably a steric interaction between the methyl group of the cyclohexyl ring and the
methylene group of the pyrollidine ring, reduces the extent of conjugation between the lone pair
of electrons on the nitrogen atom and the π- system of the double bond in the more substituted
Keeping in mind the limitations implied by the above reactions, let's take a look at the reactions
of enamines with electrophilic reagents.
Alkylation of Enamines
Enamines may be converted into aldehydes and ketones by acid catalysed hydrolysis, i.e. by
reaction with a large excess of water.
The following is a specific example of the 3-step process involved in the alkylation of aldehydes
and ketones via enamines.
First step involves the formation of the enamine. In this case benzene is used as a solvent and
the water that is formed is removed by azeotropic distillation.
Steps 2 and 3 proceed without isolation of any intermediates. Compare step 3 to the reverse of
the reaction outlined in Equation 2.
Since enamines are inherently less reactive than their enolate ion analogs, it is necessary to treat
them with highly reactive alkylating agents in order to effect a reaction.
For example,
The α-bromoketone is extremely reactive towards nucleophiles because of the orbital overlap
between the π− system of the carbonyl group and the p orbital that develops as the hybridization
of the reaction center changes from sp3 to sp2 in order to accomodate the incoming nucleophile in
the pentavalent transition state.
Although enamines are not as nucleophilic as their enolate ion equivalents, their relatively low
reactivity makes them excellent partners for Michael additions.
Thus, the enamine derived from 2-methylcyclohexanone reacts with acrylonitrile as shown
By contrast, direct alkylation of 2-methylcyclohexanone with acrylonitrile yields the regiosiomer
as shown below.
Michael addition of enamines to α,β−unsaturated ketones may be coupled with intra
molecular aldol condensations to produce cyclic ketones. This sequence of reactions is an
alternative approach to traditional Robinson annulations.
For example,
Acylation of Enamines
Similar to alkylation, acylation can be done using acetyl chloride.
For example,
Advantages and Disadvantages of using the enamine route:
The main advantage of using the enamine route for reaction of ketones and aldehydes with
electrophiles is that substitution occurs on the least substituted α-carbon and polysubstitution is
also avoided which may not be the case when enolate ions are used.
The main disadvantage is that only reactive halides, like allylic or benzylic halides and α-halo
carbonyl compounds can be used. Simple alkyl halides like methyl iodide react with enamines to
give quaternary nitrogen compounds, hydrolysis of which gives back the starting carbonyl