Enolate In organic synthesis

An enolate is chemical species consisting of a negatively charged oxygen atom bonded

to a carbon atom resulting from the deportation of a carbonyl compound (such as a
ketone or an aldehyde) at the alpha carbon position. Enolates are important inter
mediates in various organic reaction, especially in aldol condensations and Michael
additions.
The C=O group of carbonyl compounds is reactive to attack by both nucleophiles (N:)
and electrophiles (E+). The C=O group causes H’s attached to its α-C (H-Cα-C=O) to
be unusually acidic. As a result, these α-CH's are removed by bases giving enolate
ions {-:Cα-C=O)} that can react as nucleophiles with different electrophiles (E+) to
form compounds with the general structure E-Cα-C=O.

Halogenation, Alkylation, and Condensation Reactions

Enolate ions react with a variety of different substrates, but three types of reactions of
major importance are those with (a) molecular halogens (X2), (b) haloalkanes (R'X),
and (c) carbonyl compounds (R'C(=O) R").

Reaction (a) gives compounds in which a halogen atom replaces the H on an α-C-H so
it is referred to as α-halogenation. In reaction (b), an alkyl group R' in the reactant R'-
X replaces the H on an α-C-H and is referred to as α-alkylation. In reaction (c), the

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Nucleophilic α-C of an enolate ion adds to C of C=O groups in various carbonyl
compounds.
Reactions (c) are often referred to as condensation reactions. They are nucleophilic
addition reactions to C=O and give an intermediate tetrahedral addition product whose
subsequent reactions depend on the structure of the initial carbonyl compound reactant
(R’C (=O) R"). Because of the wide variety of enolate ions, and carbonyl compounds
that react with enolate ions, there are many types of condensation reactions.

Acidity of α -C-H's
Enolate ions are in equilibrium with carbonyl compounds as we show in figure for
reaction of ketones or aldehydes with the bases hydroxide ion (HO:-) or alkoxide ion
(R'O:-).

However, since hydroxide and alkoxide ions are much less basic than enolate ions,
enolate ions are present in only low concentrations in these equilibria.

Acetone and Ethoxide Ions.

We use the reaction of ethoxide ion and acetone to illustrate enolate ion-carbonyl
compound equilibria

Ethoxide ion (the base) removes a proton from acetone (the acid) to give the conjugate
acid ethanol and the enolate ion as the conjugate base.

The pKa value of the α-C-H of acetone (CH3(C=O) CH3) and other simple ketones is
about 20 (Ka = 10-20) while the pKa value of the O-H of ethanol (CH3CH2OH) and
other simple alcohols is about 16 (Ka = 10-16). Ethanol is a stronger acid by a factor
of 104 compared to acetone, so the basicity of ethoxide ion (from ethanol) is 104 less
than the basicity of the enolate ion (from acetone).

As a result, the equilibrium mixture resulting from treating acetone with ethoxide ion
has a much higher concentration of acetone relative to enolate ion.

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Resonance Stabilization.
The acidity of the α-C-H of a carbonyl compound such as acetone (pKa = 20) is
relatively low compared to a variety of other acids, but it is much greater than that of a
C-H in an alkane such as propane (pKa = 50).

This enormous difference in C-H acidity between acetone and propane arises because
the negative charge (electron pair) on the enolate ion is delocalized as we show with
the two resonance structures in Figure.

In contrast, the negative charge on C, formed by removing a proton from propane,

cannot delocalize. Neither the resultant CH3CH2CH2- nor (CH3)2CH- have resonance
structures.

The delocalization of charge in an enolate ion makes it sufficiently stable so that a

base such as hydroxide or alkoxide forms it in low concentration by removing an α-C-
H from the parent carbonyl compound. We will see later in this chapter that stronger
bases than -OH or –OR quantitatively convert the carbonyl compound to its enolate
ion.

Enol Form of the Carbonyl Compound

Enol forms of carbonyl compounds, as well as the carbonyl compound, are in
equilibria with enolate ions.

Protonation on C or O.
Protonation of the enolate ion on the α-C gives the original carbonyl compound. But
the enolate ion resonance structures also show that its negative charge is delocalized
on the O of the C=O group. As a result, protonation on O gives an Enol as we show in
Figure where we represent electron delocalization in the enolate ion using dotted
bonds and partial negative charges (δ-).
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The enol form and the carbonyl compound are always in equilibrium with each other.
In the presence of a base, the enolate ion is an intermediate in this equilibrium.

Acid Catalysed Enol Formation

Formation of enols from carbonyl compounds is also catalysed by acids.

Protonation of the C=O group of the carbonyl compound on O gives a carbocation that
is stabilized by the attached OH group. Subsequent loss of a proton from the OH group
gives the unprotonated carbonyl compound. However, loss of a proton from the α-C (as
shown in Figure) gives rise to an enol.

Enol Content
Generally, the amount of enol form present in equilibrium with its isomeric carbonyl
compound is very small but there are exceptions. We show some examples of the
equilibrium percentages of enol forms in several different carbonyl compounds from.

The relatively large amounts of enol form present in the last two carbonyl compounds
result from conjugation of the C=C-OH double bond with the phenyl groups (Ph) in the
former, and with the second C=O group in the latter. We will see that both the enolate
ion and the enol form of carbonyl compounds are important in reactions of carbonyl
compounds.

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 Carbonyl Compound Enol Form

We will see that both the enolate ion and the enol form of carbonyl compounds are
important in reactions of carbonyl compounds.
Other Types of "Enolate" Ions
The term "enolate ion" originally referred specifically to the anion (-:C-C=O) formed
from removal of a C-H proton α to a C=O group. However, the terms "enolate ion" or
"enolate-type ion" are now frequently used to refer to a number of different anions with
a C: - centre attached to functional groups, other than the C=O group, that can stabilize
the (-) charge.

Active Hydrogen Compounds

Compounds that give "enolate ions" or "enolate-type ions" are said to have an "active"
hydrogen and we show general examples in Figure.
Active Hydrogen Compounds
R2CαH-Z and Z'-CαHR-Z (Z and/or Z' = C(=O) R, C(=O) Z, C≡N, NO2, S(=O) R, S(=O)2R)
The Z and/or Z' groups attached to the "Cα" stabilize its negative charge by electron
delocalization

The C(=O) R or C(=O) Z groups can be aldehyde (C(=O) H), ketone (C(=O) R'), ester
(C(=O) OR'), amide (C(=O) NR2'), or even carboxylate ion (C(=O) O-) groups.

Reactions of Active Hydrogen Compounds

The R2ZC: - and RZ2C: - "enolate-type" ions formed by removal of the proton from the
"α-C" can undergo reactions that are similar to those mentioned earlier for enolate ions
from aldehydes and ketones. We will specifically discuss examples of their alkylation
and condensation reactions.

Halogenation Reactions
Enolate ions, as well as enol forms of carbonyl compounds, react with the molecular
halogens Cl2, Br2 and I2 (X2) to form α-halocarbonyl compounds.

The General Halogenation Reaction

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We show general halogenation reactions for an aldehyde (R' = H) or a ketone (R' = alkyl
or aryl) as well as for a carboxylic acid (Z = OH) and or acid halide (Z = X) in Figure.

This regiospecific substitution of the α-CH by halogen (X) allows organic chemists to
increase the number of functional groups in a molecule by subsequently replacing the
α-C-X with another functional group. A specific example is this conversion of an α-
halocarboxylic acid into an α-amino acid.

α-Amino Acids
α-Amino acids are the building blocks of protein and peptide molecules. We do not
need this type of amino acid synthesis to make "naturally occurring" amino acids
because they are readily available from hydrolysis of naturally occurring peptide and
protein molecules. However, we use it to make "unnatural" amino acids that organic
chemists and biochemists sometimes find useful in the synthesis of "non-naturally
occurring" peptides and modified proteins.

Acid Catalysed Halogenation of Ketones and Aldehydes

The α-halogenation of ketones and aldehydes is catalysed by either acid or base. We
describe the acid catalysed reaction here.

Mechanism
During halogenation of a ketone or aldehyde catalysed by acid, molecular halogen
reacts with the enol form of the ketone or aldehyde.

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Formation of the carbocation intermediate (Step 2) and its subsequent deprotonation
(Step 3) are both rapid steps. The slow step of the reaction sequence in Figure is acid-
catalysed formation of the enol from the aldehyde or ketone (Step 1) that we showed
in Figure.
Consistent with this mechanism, the rate of formation of α-haloaldehyde or α-
haloketone depends only on the concentration of the aldehyde or ketone and not the
concentration of the molecular halogen. As a result, the rate of the halogenation
reaction is the same for chlorination, bromination, or iodination under the same
reaction conditions.
No Halonium Ions
Bromination and chlorination of alkenes occur via intermediate cyclic halonium ion
intermediates that subsequently react with nucleophiles such as bromide or chloride
ion.

In contrast, halonium ions are not considered to be intermediates in bromination or chlorination of enols because the
cation formed.
Polyhalogenation
When an aldehyde or ketone has two or more α-H's more than one may be replaced with
halogen. Multiple substitution of H by X occurs by mechanisms analogous to that for
monohalogenation starting with the α-haloaldehyde or α-haloketone. We can favour
monohalogenation by using an excess of carbonyl compound compared to the molecular
halogen because the relatively high concentration favors its reaction over that of the
monohalo product.

Regiospecificity
While there is only one type of α-C-H in an aldehyde, there are two different
types of α-CH's in unsymmetrical ketones.
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Since the reactivities of these two α-C-Hs may differ, one may be more likely to be
replaced than the other.
The reactivity order for acid catalysed halogenation of unsymmetrical ketones is
R2CH(C=O) R' > RCH2(C=O) R' > CH3(C=O) R'. This is because the rate of rate-
determining enol formation has the same reactivity order. In spite of these reactivity
differences, mixtures of α-halogenated products are often formed from unsymmetrical
ketones.

α-Halogenation of Ketones and Aldehydes Using Base

Halogenation of aldehydes and ketones using base to facilitate the reaction can occur by
reaction of X2 with either the enol form or the enolate ion.

Mechanisms.
In basic solution, reaction of X2 with the enol is the same as its reaction with the enol
in acidic solution. The only difference is that formation of the enol is catalysed by the
base rather than an added acid. Reaction of X2 with the enolate ion follows the
mechanism outlined in Figure.

The enolate ion is formed by removal of an α-CH in the slow Step 1, and rapidly reacts
with X2 in Step 2.
Polyhalogenation
If the α-halo carbonyl product formed in Step 2 has additional α-C H's, it reacts rapidly
with base to form a halo substituted enolate ion. This ion will also react with X2, so it
is difficult to stop the reaction after only one α-C-H has been replaced by X.. In fact, the
reactivity of an α-CH is increased by an X attached to the α-C since the halogen atom
stabilizes the negative charge by an inductive effect.

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 The negative charge stabilized by
Inductive effect

The Haloform Reaction

Base catalysed halogenation of the α-CH3 groups of methyl ketones (CH3C (=O) R)
and acetaldehyde (CH3C (=O) H) readily transforms them into CX3 groups. Since
halogen atoms stabilize negative charge on their attached C atoms, these CX3 groups
leave as -:CX3 anions (Figure 18.23) under the reaction conditions.
The last three steps in this reaction are analogous to nucleophilic substitution reactions
in Chapter 15 and 16 where a -: Z group leaves from the tetrahedral intermediate
formed by haloform reaction.

Some Historical Information. The haloform reaction was widely used to identify the
presence of the CH3C (=O) group in molecules. I2 was usually used as the molecular halogen
in this reaction because the product CHI3 (iodoform) is a bright orange solid with a
characteristic odor that readily precipitates from the aqueous reaction mixture. Since molecular
I2 can oxidize* alcohols of the structure CH3CH (OH) R to methyl ketones of the structure
CH3C (=O), these alcohols also lead to the formation of CHI3 when treated with aqueous base
in the presence of I2.

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Regiospecificity.
Like acid catalysed halogenation, two different enols and enolate ions can form when
unsymmetrical ketones react with base. Generally, the least substituted α-C is
halogenated more rapidly than the more substituted α-C. This is opposite what occurs in
acid catalysed α-halogenation where the most substituted C is preferentially
halogenated. The relative reactivity of α-C-H's toward base (their relative acidity) is CH
3(C=O)R' > RCH (C=O)R' and formation of the enolate ion is the rate-determining step.

Kinetic and Thermodynamic Enolates

When two different enolate ions can form from reaction of a carbonyl compound and
base, the less substituted enolate ion (A) forms more rapidly than the more
substituted enolate ion (B).

A B

As a result, when an unsymmetrical ketone is treated with base, the initial

concentration of (A) is higher then that of (B). However, the more substituted
enolate ion (B) is more thermodynamically stable than than the less substituted
enolate (A). So after the enolate ions equilibrate, the equilibrium concentration
of (B) is higher than that of (A).
Enolate (A) is called the "kinetic" enolate because its early predominant
formation depends on relative rate constants for enolate formation. Enolate (B)
is called the "thermodynamic" enolate because its ultimate predominance
depends on equilibrium constants. Products from the "kinetic" enolate are said to
arise from "kinetic control", while products arising from the "thermodynamic"
enolate are said to arise from "thermodynamic control". Kinetic versus
thermodynamic control of product distributions occurs in other reactions besides
those involving enolate ions.
-Halogenation of Carbonyl Compounds R-C (=O)-Z
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Carbonyl compounds other than aldehydes and ketones can also be -halogenated by
way of their enol forms or enolate ions.
Carboxylic Acids, Acid Halides, and Anhydrides.
Reaction of a carboxylic acid (R-C(=O)-Z where Z = OH) with Br2 and a catalytic
amount of PBr3, or with Cl2 and a catalytic amount of PCl3, leads to the formation of the
corresponding bromocarboxylic acid or -chlorocarboxylic acid in a process known as
the Hell-Volhard-Zelinskii reaction (H- V-Z reaction)

PBr3 or PCl3 convert carboxylic acids into acid halides and the enol forms of these acid
halides are halogenated by Br2 or Cl2.

The H-V-Z reaction takes advantage of the fact that acid halides have larger enol
concentrations than carboxylic acids or some other compounds of the structure
RC(=O)-Z such as esters or amides.

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Alkylation Reactions
Alkyl groups can be substituted for -C-Hs on carbonyl compounds by reaction of the
carbonyl compound with base followed by reaction with 1 or 2 haloalkanes.

If one or more R group is H, the -alkylated product can be further alkylated.

 -Alkylation Mechanism (18.3A)

We illustrate a general mechanism for -alkylation of ketones or aldehydes in Figure.

A base removes an -H in Step 1 giving an enolate ion. In Step 2 the -C of the enolate
ion reacts in an SN2 reaction with the haloalkane to give the -alkylated ketone or
aldehyde.

C versus O Alkylation
The O atom of the enolate ion can also serve as the nucleophilic center in the S N2 reaction
leading to the formation of the O-alkylated product (enol ether). C is the more
nucleophilic atom, the products are primarily C-alkylated ketones or aldehydes.

Bases and Solvents

All of the carbonyl reactant must be converted to its enolate ion to prevent its reaction
with enolate ion to give condensation products as we describe in the next section of this
chapter.
Bases. Hydroxide ions (HO-) and alkoxide ions such as ethoxide (CH3CH2O-) or t-
butoxide ((CH3)3CO-) ions, and hydroxide ion (HO-), are much less basic than the
enolate ion. As a result, they convert only a small fraction of a ketone, aldehyde, or
other carbonyl compound RC (=O)-Z, to their corresponding enolate ions. In contrast
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stronger bases such as those in Table quantitatively convert carbonyl compounds to
enolates.

Solvents. Solvents for these reactions must not have acidic protons. They must be
aprotic since protic solvents like alcohols or water act as acids and protonate enolate
ions. Some aprotic solvents are 1, 2-dimethoxyethane, tetrahydrofuran, N, N-
dimethylformamide, and liquid NH3.

Choice of electrophile for alkylation

Enolate alkylations are SN2 reactions (polar solvents, good charged nucleophile) so the
electrophile needs to be SN2-reactive if the alkylation is to succeed: primary and benzylic
alkyl halides are among the best alkylating agents. More branched halides tend to prefer to
undergo unwanted E2 elimination reactions, because the anions themselves are rather
basic. As a result, tertiary halides are useless for enolate alkylation.

Lithium enolates of carbonyl compounds

The problem of self-condensation of carbonyl compounds (that is, enolate reacting with
unenolized carbonyl) under basic conditions does not exist if there is absolutely no
unenolized carbonyl compound present. One way to achieve this is to use a base
sufficiently strong (pKa at least 3 or 4 units higher than pKa of the carbonyl compound) to
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ensure that all of the starting carbonyl is converted into the corresponding enolate. This
will work only if the resulting enolate is sufficiently stable to survive until the alkylation
is complete. Lithium enolates are stable, and are among the best enolate equivalents for use
in alkylation reactions.
The best base for making lithium enolates is usually LDA, made from diisopropylamine
(i-Pr2NH) and BuLi. LDA will deprotonate virtually all ketones and esters that have an
acidic proton to form the corresponding lithium enolates rapidly, completely, and
irreversibly even at the low temperatures (about –78°C) required for some of these reactive
species to survive.
Deprotonation occurs through a cyclic mechanism illustrated below for ketones and esters.
The basic nitrogen anion removes the proton as the lithium is delivered to the forming
oxyanion.

Alkylations of lithium enolates

The reaction of these lithium enolates with alkyl halides is one of the most important C–C
bond forming reactions in chemistry. Alkylation of lithium enolates works with both
acyclic and cyclic ketones as well as with acyclic and cyclic esters (lactones). The general
mechanism is shown below.

Typical experimental conditions for reactions of kinetic enolates involve formation of the
enolate at very low temperature (–78°C) in THF. Remember, the strong base LDA is used
to avoid self-condensation of the carbonyl compound but, while the enolate is forming,
there is always a chance that self-condensation will occur. The lower the temperature, the
slower the self-condensation reaction, and the fewer by-products there are. Once enolate
formation is complete, the electrophile is added (still at –78°C: the lithium enolates may
not be stable at higher temperatures). The reaction mixture is then usually allowed to warm
up to room temperature to speed up the rate of the SN2 alkylation

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Alkylation of Ketones and Aldehydes
-Alkylation of ketones is usually more successful than alkylation of aldehydes. With
aldehydes, it is difficult to avoid condensation reactions because we see later they are
readily attacked by enolate ions. We describe indirect reactions that -alkylate aldehydes
later in this section.
Ketones.
We can alkylate ketones using the bases and solvents above Figure.

The haloalkane reactants can be 1 or 2 as well as allylic or benzylic, as we see in this
example. The SN2 displacement mechanism makes 3 haloalkanes unsuitable since they
primarily undergo E2 elimination with enolate ion serving as the base

Some elimination can occur even with 1 and 2 haloalkanes. In place of

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haloalkanes, other substrates (R-L) can be used where L is a good living group.
Aldehydes. Since direct alkylation of aldehydes leads to unwanted side reactions, we
can use the indirect sequence in Figure to obtain the desired -alkylated products.

We convert the aldehyde to an imine and then react the imine with a strong base to give an
"enolate-type" ion. Reaction of this ion with haloalkanes gives an -alkylated imine that
we can hydrolyze to give the desired -alkylated aldehyde.

Alkylation of Esters and Carboxylic Acids

Both esters and carboxylic acids can be directly alkylated.

Esters. -Alkylation of esters (RC (=O)-OR) is analogous to -alkylation of ketones.

Generation Of Necleophile

They can be directly alkylated since they give just one enolate ion on reaction with base,
and are even less reactive than aldehydes in condensation reactions.
Carboxylic Acids. When a carboxylic acid is reacted with a base, it is quantitatively
converted into its carboxylate ion.

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In spite of this, strong bases such as those in Table will go on to remove an -H
from that carboxylate ion to give an enolate dianion.

This dianion will react with haloalkanes to give the -alkylated carboxylate ion shown
above that can be protonated to give the -alkylcarboxylic acid.

Condensation Reactions
Although reaction between an enolate ion and its parent aldehyde during -alkylation
is an unwanted side reaction, this condensation reaction is a very useful way to
convert smaller organic molecules into larger organic molecules with multiple
functional groups.
The Aldol Reaction
If you treat acetaldehyde with a base such as hydroxide or alkoxide in the absence of
other reactants, the product is a 4-carbon compound with an OH and C=O group .
The common name of this hydroxy aldehyde product is aldol and the reaction is the
simplest example of a large group of condensation reactions called aldol reactions.
In aldol reactions, two aldehydes, two ketones, or an aldehyde and a ketone react
together to form a new C-C bond.

The Base. A base frequently employed for the aldol reaction is aqueous sodium (or
potassium) hydroxide (-OH/H2O). Hydroxide ion converts only a small fraction of the
carbonyl compound to the enolate ion, but that is all that is necessary. The enolate ion
reacts with unreacted carbonyl compound and more enolate ion forms as it is used in the
reaction.

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Hemiacetal Formation. Independent of all the other reactions we have been
describing in this chapter, aldehydes always react with aqueous hydroxide ion to
form hydrates.

This reaction does not interfere with the aldol reaction since it is an equilibrium and
regenerates the aldehyde reactant as needed.
The New C-C Bond. It's important to carefully examine what happens in the aldol
reaction. The new C-C bond forms between the C (=O) carbon of a ketone or aldehyde
molecule and the R"2C carbon (the alpha-C) of another ketone or aldehyde molecule. These
C's have been underlined in the reactants and in the products for the purpose of
identification.
Because of this new C-C bond, the C (=O) group of the first ketone or aldehyde has been
transformed into a C (-OH) group and the two original carbonyl compounds join together
into a single molecule
Aldol Reaction Mechanism.
We show the mechanism of the aldol reaction for acetaldehyde.
Base forms an enolate ion from acetaldehyde in Step 1. The nucleophilic enolate then adds to
the C=O group of a second acetaldehyde molecule in Step 2. In Step 3, the resultant tetrahedral
intermediate from Step 2 is protonated to give the aldol product.

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Steps 2 and 3 are completely analogous to the many examples of nucleophilic addition
to C=O groups.
The C in the atomic grouping HO-C-C-C=O in the product corresponds to the -C of
the enolate ion. The HO-C group forms from the O=C group of the carbonyl compound
attacked by the enolate ion. The C=O group of the carbonyl compound giving the enolate
ion is the C=O in the final aldol product.

Dehydration of the Aldol Product.

Aldol products readily lose water if there is an H on the -C

The dehydration product contains a C=C-C=O conjugated system where the  and 
labels show the origin of the term , -unsaturated carbonyl compound. The favorable
stability resulting from conjugation in the ,-unsaturated carbonyl product often causes
it to form spontaneously from the aldol product during the aldol reaction.

If dehydration does not occur under basic conditions, it can be accomplished with acid
catalysis. We show the mechanism for base catalyzed dehydration of aldols and acid
catalyzed dehydration.

Aldol Condensation.
The aldol reaction is often called the aldol condensation reaction, and the term
condensation is commonly applied to all reactions in which enolate ions add to C=O
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groups. But in fact, the term condensation is correctly used only when the product
isolated from the reaction mixture is the ,-unsaturated compound.

Aldol Reactions are Equilibria.

Each step of the aldol reaction is an equilibrium process. The reaction can go in the
"forward" direction beginning with aldehydes and/or ketones, or it can go in the "reverse"
direction starting with the aldol addition product (or ,-unsaturated dehydration
product)

The equilibrium favors the aldol addition product from two aldehydes, but this is not the
case when the starting carbonyl compounds are both ketones. The aldol product formed
from two ketones has steric strain not present in the aldol product from two aldehydes.

This steric strain in the product from two ketones arises because the C-C bond is fully
substituted (has no C-H bonds). In contrast, the R' group is H in the aldol product from
two aldehydes so there is significantly less steric strain across the new C-C bond

Acid Catalysed Aldol Reactions.

While aldol reactions are usually carried out using a base to form the enolate ion, it is
possible to catalyse the reaction with acid.

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A protonated C=O group reacts with the enol form of another carbonyl compound.
Formation of both the enol form (A) and protonated carbonyl compound is catalysed by
acid and they react in Step 2 via an electrophilic addition reaction on the C=C. Subsequent
deprotonation gives the aldol addition product. If it contains an α-CH, rapid dehydration
occurs to give the α,β unsaturated carbonyl compound.

Variations on the Aldol Reaction

Only one product can form when the aldol reaction involves a single aldehyde. However,
there are a number of possible variations that include reactions between two different
aldehydes and/or ketones, as well as "aldol-like" reactions where an aldehyde or ketone
reacts with an enolate ion or "enolate-type" ion that does not arise from a ketone or an
aldehyde.
Also, if a molecule contains two C=O groups, intermolecular aldol reactions leading to
cyclic products are possible.

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Cross-condensations
So far we have considered only ‘self-condensations’—dimerization reactions of a single
carbonyl compound. These form only a tiny fraction of known aldol reactions. Those
that occur between two different carbonyl compounds, one acting as a nucleophile in its
enol or enolate form, and the other as an electrophile, are called cross-condensations.
They are more interesting than self-condensations, but working out what happens needs
more thought. We shall start with an example that works well. The ketone PhCOMe
reacts with 4-nitrobenzaldehyde in aqueous ethanol under NaOH catalysis to give a
quantitative yield of an enone.

The first step must be the formation of an enolate anion using NaOH as a base. Though
both carbonyl compounds are unsymmetrical, there is only one site for enolization as
there is only one set of α protons, on the methyl group of the ketone. The aldehyde has
no α protons at all.

To get the observed product, the enolate obviously attacks the aldehyde to give an
aldol, which then dehydrates by the E1cB mechanism.

Steric Strain and Cross Aldol Reactions.

The steric strain that causes aldol reactions between two ketones to be unfavorable
similarly affects aldol reactions between an aldehyde enolate and a ketone. However,
this is not the case for the reaction between a ketone enolate and an aldehyde. This
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latter mixed reaction is particularly good when the aldehyde has no -CH and cannot
condense with itself since the aldol reaction (which is an equilibrium) is very
unfavorable for the two ketone molecules.

Intermolecular Aldol.
We can use the aldol reaction to make five- and six-membered rings and show an example
of the formation of a five-membered ring in Figure.

The enolate ion formed in Step 1 reacts with the other C=O group to give a five-
membered ring intermediate in Step 2. Subsequent protonation in Step 3 gives the cyclic
aldol product.
The Enolate Ion is not from a Ketone or Aldehyde.
There are several types of condensation reactions where aldehydes or ketones react
with enolate ions formed from carbonyl compounds other than aldehydes or ketones,
or with "enolate-type ions" from compounds that are not carbonyl compounds.

These are not formally "aldol reactions", but they are frequently called that (or called
"aldol- type reactions") if the nucleophilic carbon species (R2ZC:-)) attacks an aldehyde or
a ketone (R-C(=O)-R'). We show some examples in Figure
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The Claisen Condensation
An aldol-type reaction between two ester molecules is called a Claisen Condensation.

This example is the base catalyzed reaction between two molecules of ethyl acetate that
forms the new C-C* bond shown in the -ketoester product.

Claisen Condensation Mechanism

We show the reaction mechanism in Figure

The enolate ion formed in Step 1 adds to the C=O group of a second alkyl acetate molecule
in Step 2. The resulting tetrahedral intermediate then loses alkoxide ion in Step 3 to give
the - ketoester product.

Steps 1 and 2 are analogous to aldol reaction mechanisms, but Step 3 is different. The
loss of alkoxide ion in Step 3 is analogous to what occurs when a variety of nucleophiles
add to esters.

General Examples.
We show a general representation of the Claisen condensation between two esters in Figure.

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Ester (B) is the source of the enolate ion and the new C-C bond forms between the
underlined C's. Reactions where enolate ions from molecules other than esters react with
the C=O group of esters are also referred to as Claisen condensations and we illustrate
some of those later in this section.

A Cautionary Note about the Names of these Reactions.

The reaction in which an ester enolate reacts with an aldehyde or ketone (first
example in Figure) is sometimes referred to as a "Claisen reaction". This
nomenclature is confusing since in addition the reaction of a ketone enolate with
an aldehyde, is called a "Claisen-Schmidt" reaction.
To minimize confusion in this text we will refer to reactions of all enolates with (a)
ketones and aldehydes as "aldol" or "aldol-type" condensations or reactions, and (b)
with esters as "Claisen" condensations or reactions.

The Choice of -OEt as the Base.

Claisen condensations are frequently carried out in the solvent ethanol (EtOH)
specifically using ethoxide ion (EtO-) as the base. Since the ethyl esters used in these
reactions can react by nucleophilic substitution with any RO - base, when this reaction
occurs with EtO- there is no change in the ester functional group.

The Claisen Condensation Product is "Acidic" . The Claisen condensation reaction is an

equilibrium process like the aldol reaction. However, the -ketoester product usually
cannot revert to the starting esters by cleavage of the newly formed C-C bond. This is
because - ketoesters with -CHs rapidly react with base in the reaction mixture to form
an anion that is  to two C=O groups.

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This anion is particularly stable because of electron delocalization into both C=O groups.

This resonance stabilized anion is unreactive toward further reaction by the EtO - ion. Since
attack by EtO- at the keto C=O group is necessary to reverse the last step of the Claisen
condensation, this reaction is effectively irreversible in most cases.

The Dieckmann Condensation.

When two ester functional groups are present in the same molecule and separated by 4 to
6 C's, an intramolecular Claisen condensation can occur to give a cyclic system. We show
six-membered ring formation.

This intramolecular condensation is called a Dieckmann condensation and it can give 5,

6, or 7-membered rings.

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Ring-Forming Reactions. Reactions that make rings by forming C-C bonds, such as
the Dieckmann condensation or an intramolecular aldol reaction, are very important in
synthetic organic chemistry.

Variations of the Claisen Condensation. As we saw with the aldol reaction, mixed or
crossed Claisen condensations where two different esters react with each other are best
carried out when only one of the esters has -Hs.

Esters also can react with enolate ions or "enolate-type" ions from sources other than esters.

Enolate Ions from -Dicarbonyl Compounds

In our discussion of Claisen condensations we saw that -CHs flanked by two C=O
groups are particularly acidic.

As a result, it is easy to make enolate ions of such compounds and they are particularly
useful in organic synthesis.
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Acidity of  -H's in  -Dicarbonyl Compounds
We compare the relative acidities of several types of both C-H and O-H protons in Table.
You can see that the acidities (or pKa values) for -CHs between two C=O groups
(numbers 2-4) fall between those of carboxylic acids (number 1) and simple alcohols
(number 5). As a result, alkoxide ions RO- react quantitatively with the -dicarbonyl
compounds (numbers 2-4) to form enolate ions as we described for the Claisen
condensation in the previous section.

In contrast, the acidity of alcohols (number 5) is greater than that of the -H's of simple
ketones or esters (numbers 6 and 7). As a result, alkoxide ions (RCH2-O-) convert only
a small fraction of a ketone or ester to its enolate ion. Although -ketoesters (number
3) (and -diesters (number 4)) are more acidic than alcohols, they are still much less
acidic than carboxylic acids (number 1).
Other Reactions of Enolate Ions and Enols
In addition to the wide variety of reactions we have seen in this chapter there are many
analogous reactions involving structurally similar reactants. We show some of these in this
section.
Michael Addition Reactions
We have seen many reactions where enolate or "enolate-type" ions {represented as N:-
(neuclophile)} add to C=O groups to give tetrahedral intermediates.

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When the C=O group is conjugated with a C=C, the enolate ion (N:- ) can also add to the C=C.This conjugate
addition reaction is called a Michael addition reaction

Mechanism. We show the mechanism of a Michael addition reaction in Figure using a

general example.

Addition of the nucleophilic enolate ion (N:-) to the C=C-C=O group (Step 1) gives an
anion that is also an enolate ion. Subsequent protonation on oxygen gives the enol form
(Step 2a), while protonation on carbon gives the keto form (Step 2b). The keto form is the
final reaction product, but initial protonation of the intermediate anion occurs mainly on O
(Step 2a). The resulting enol rapidly isomerizes to the keto form (Step 3). As a result, the
Michael Addition reaction is a 1,4-addition reaction like those described for other
conjugated systems.

1, 2-versus 1, 4-Addition. When a nucleophilic species N: - adds to a C=O group

to form N-C-O-H, we refer to this 1, 2-addition on C=O as "direct" addition. In
contrast, when N: - adds to the -C of the C=C-C=O group to ultimately give N-
C-C (H)-C=O, we say the addition is a "Michael" addition or "1,4" addition.
Although it appears from the final product that N and H have simply added in a 1,2-
fashion across the C=C bond, the reaction is actually a 1,4-addition. The first formed
product is the enol N-C-C=C-O-H that subsequently isomerizes to the final product.

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C=C bonds are much more reactive toward electrophiles (E+) than nucleophiles (N:-
) such as enolate ions. In this case the reason that the C=C is reactive to N:- is because
the conjugated C=O group stabilizes the (-) charge on the intermediate anion as shown
by the resonance structures above.

Examples
We show an example of a Michael addition reaction where the enolate ion from malonic
ester reacts with an ,-unsaturated ketone in Figure.

While the major product of this reaction at room temperature is the Michael addition
product, a small amount of aldol addition product forms from 1,2-addition of the
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enolate ion on the C=O group. Generally speaking, Michael addition reactions (1,4-
addition) predominate over 1,2-addition.

Robinson Annulation
The Robinson Annulation begins with a Michael addition reaction, followed by an
aldol condensation reaction. The term annulene means ring so an annulation reaction
is one in which a ring is formed.

Mechanism. The reaction proceed in conjugate addition of an enolate to an enone

followed by aldol condensation forming a six member ring with unsaturated
ketone.

Stork Enamine Reaction.

Enamines are used to facilitate -alkylation of ketones via the Stork enamine
reaction as we show for the -alkylation of cyclohexanone.
Reaction of the cyclic 2 amine pyrrolidine (azacyclopentane) with cyclohexanone in
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Step 1 of this sequence gives the enamine. It reacts with a haloalkane to form an
intermediate aminium ion (Step 2) that is hydrolyzed to form the -substituted
cyclohexanone (Step 3).

Dialkylation. The intermediate aminium ion is in equilibrium with a tautomeric

enamine. This enamine can add another alkyl group by a second alkylation reaction with
the haloalkane. Dialkylation occurs if two equivalents of haloalkane are present in the
reaction mixture, but is not a significant reaction if only one equivalent of haloalkane is
used. Although two different enamines can form from the monosubstituted aminium ion,
the less substituted enamine is formed most rapidly because the C-H on the less
substituted C is more acidic.

Reformatsky Reaction
Organozinc compounds arising from reaction of -haloesters and zinc metal react like
enolate ions.

The C-Zn bond is polarized (-) C-Zn (+) by the attached electropositive Zn for other
Organozinc and organometallic compounds in general.

Products and Mechanism.

Reactions of these Organozinc enolates with carbonyl compounds are called
Reformatsky reactions. We show an example using the reactants ethyl -bromoacetate
and acetophenone.

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Reaction of the -bromoester with activated Zn metal gives the organozinc compound
(Step 1) that then reacts with the ketone (Step 2). The resulting product is protonated to
give a - hydroxy ester.

Unlike most other organometallic reactions, the haloester, Zn metal, and carbonyl
compound can be mixed together in the same reaction vessel. Otherwise the overall
mechanism is analogous for nucleophilic addition reactions of organometallic
compounds to carbonyl compounds.
The Mannich Reaction

The reaction of an enol or enolate ion with an iminium ion as shown below is the last
step of the Mannich reaction.
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The iminium ion forms from the reaction between an amine (R = H or alkyl) and an
aldehyde which is often formaldehyde.

The reaction occurs and involves a nucleophilic addition of the free amine to the
aldehyde, followed by loss of water to give the iminium ion. It is catalyzed by both
dilute acid and dilute base. While it has been proposed that under basic conditions the
enolate ion directly attacks the intermediate R2N-CH2-OH displacing hydroxide ion
(-OH), this seems unlikely under the typically mild reaction conditions because -OH
is a very poor leaving group.

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Conclusion
Enolates play a crucial role in organic synthesis, particularly in the context of carbonyl
chemistry. Enolates are derived from the deprotonation of enols, which are tautomeric
forms of carbonyl compounds. The process involves removing a proton adjacent to the
carbonyl group, resulting in a resonance-stabilized anion known as the enolate.

Key points about enolates in organic synthesis include:

1. **Nucleophilic Reactivity:** Enolates are powerful nucleophiles due to the presence

of a lone pair of electrons on the oxygen atom and the negative charge on the α-carbon.
They can react with electrophiles in various reactions.

2. **Aldol Reaction:** Enolates are commonly involved in the aldol reaction, where
they add to another carbonyl compound, typically an aldehyde or ketone. This leads to
the formation of β-hydroxy carbonyl compounds.

3. **Claisen Condensation:** Enolates also participate in the Claisen condensation,

where they react with esters or other carbonyl compounds to form β-keto esters or β-
diketones, respectively.

4. **Michael Addition:** Enolates act as nucleophiles in Michael additions, reacting

with α,β-unsaturated carbonyl compounds to form a new carbon-carbon bond.

5. **Crossed Aldol Reactions:** Enolates allow for crossed aldol reactions, where the
enolate from one carbonyl compound reacts with a different carbonyl compound,
enabling the synthesis of complex molecules.

6. **Synthesis of β-Dicarbonyl Compounds:** Enolates are key intermediates in the

synthesis of β-dicarbonyl compounds, which are versatile building blocks in organic
chemistry.

7. **Control of Selectivity:** Enolate formation and reactivity can be influenced by

factors such as the choice of base, solvent, and reaction conditions, allowing chemists
to control regioselectivity and stereoselectivity in synthesis.

Overall, enolates serve as versatile intermediates in organic synthesis, enabling the

construction of diverse and complex molecular structures through various reactions with
carbonyl compounds. Understanding and manipulating enolate chemistry are essential
skills for synthetic chemists.

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