ALPHA CARBON COMPOUNDS

ALPHA CARBON COMPOUNDS – ENOL và

ENOLATE
Enolates are more
useful than enols
because :
(1) enolates possess a
full negative charge
and are therefore
more reactive than
enols and
(2) enolates can be
isolated and stored
for short periods of
time, unlike enols,
which cannot be
isolated or stored.
 ENOL FORMATION
In the presence of catalytic acid or base, a ketone will exist in
equilibrium with an enol.
 Enol
tautomer
The enol tautomer is generally present only in small amounts, but
it is very reactive. Specifically, the α position is very nucleophilic
due to resonance.
 ENOLATE FORMATION
When treated with a strong base, the α position of a ketone is
deprotonated to give a resonance- stabilized intermediate called an
enolate.

C-attack is nevertheless more

common than O-attack ambident
nucleophiles
Alpha Halogenation in Acidic
Conditions
Alpha Halogenation in Acidic
Conditions
 Alpha Halogenation in Acidic
Conditions
When an unsymmetrical ketone is used, bromination occurs
primarily at the more substituted side of the ketone.
Alpha Halogenation in Acidic
Conditions
Alpha Bromination of Carboxylic
Acids: The Hell-Volhard-Zelinski
Reaction
 Alpha Halogenation in Basic
Conditions: The Haloform Reaction

The base abstracts a proton to form the enolate, which then

functions as a nucleophile and undergoes alpha halogenation.
 Alpha Halogenation in Basic
Conditions: The Haloform Reaction
When a methyl ketone is treated with excess base and excess
halogen, a reaction occurs in which a carboxylic acid is produced
after acidic workup.

Also occurs with chlorine and iodine

 Alpha Halogenation in Basic
Conditions: The Haloform Reaction
The reaction must be followed by treatment with a proton source to
protonate the carboxylate ion and form the carboxylic acid. This
process is synthetically useful for converting methyl ketones into
carboxylic acids.

The haloform reaction is most efficient when the other side of the
ketone has no α protons.
 Aldol
Reactions
Aldol
When Additions
an aldehyde is treated with sodium hydroxide both the
aldehyde and the enolate will be present at equilibrium. Under such
conditions, a reaction can occur between these two species.

The reaction is called an aldol addition reaction (ald for

“aldehyde” and ol for “alcohol”).
The product of an aldol addition reaction is always a β-hydroxy
aldehyde or ketone
 Aldol
Reactions
Aldol
Additions
 Aldol
Additions
For most simple aldehydes, the position of equilibrium favors the
aldol product.

For most ketones, the aldol product is not favored, and poor yields
are common.

a retro-aldol
reaction
(1) deprotonation

(2) nucleophilic attack

(3)
protonation
Aldol
Reactions
 Aldol
Reactions
Aldol
Condensations
When heated in acidic or basic conditions, the product of an aldol
addition reaction will undergo elimination to produce unsaturation
between the α and β positions:

This two-step process (aldol addition plus dehydration) is called

an aldol condensation. The term condensation is used to
refer to any reaction in which two molecules undergo addition
accompanied by the loss of a small molecule such as water,
carbon dioxide, or nitrogen gas. In the case of aldol
condensations, water is the small molecule that is lost.
Aldol
Condensations
 Aldol
Condensations
In cases where two stereoisomeric π bonds can be formed, the
product with the least steric hindrance is generally the major product
(formation of the trans π bond is favored over formation of
the cis π bond).

Only the condensation product is obtained, because the condensation

reaction involves formation of a highly conjugated π system.
 Aldol
Condensations
Where the aldol addition product can be isolated (by
performing the reaction at a low temperature), the
yields for condensation reactions are often much
greater than the yields for addition reaction.
Crossed Aldol
Reactions
Crossed aldol, or
mixed aldol,
reactions, which are
aldol reactions that can
occur between different
partners.
 Crossed Aldol
Reactions
If one of the aldehydes lacks α protons and possesses an
unhindered carbonyl group, then a crossed aldol can be performed.
In this case, only one major aldol product is produced.
 Crossed Aldol
Reactions
Crossed aldol reactions can also be performed using LDA as a
base.

LDA causes irreversible enolate formation. If acetaldehyde is added

dropwise to a solution of LDA, the result is a solution of enolate ions.
Propionaldehyde can then be added dropwise to the mixture,
resulting in a crossed aldol addition that produces one major product.
This type of process is called a directed aldol addition, and its
success is limited by the rate at which enolate ions can equilibrate. In
other words, it is possible for an enolate ion to function as a base
(rather than a nucleophile) and deprotonate a molecule of
propionaldehyde. If this process occurs too rapidly, then a mixture of
products will result.
 Intramolecular Aldol
Reactions
Compounds that possess two carbonyl groups can undergo
intramolecular aldol reactions. In this case, a cyclic product is
formed. Intramolecular aldol reactions show a preference
for formation of five- and six-membered rings. Smaller
rings are possible but are generally not observed.
 Claisen
Condensations
The Claisen
Condensation
Like aldehydes and ketones, esters also exhibit reversible
condensation reactions.

The Claisen condensation is simply a

nucleophilic acyl substitution reaction in which
the nucleophile is an ester enolate and the
electrophile is an ester. The product of this
reaction is a β-keto ester.
 Claisen
Condensations
The Claisen
Condensation

After the reaction is complete, it is necessary to use a mild acid in

order to protonate the doubly stabilized enolate.
 Claisen
Condensations
The Claisen
HydroxideCondensation
cannot be used as the base for a Claisen condensation
because it can cause hydrolysis of the starting ester.

Specifically, the alkoxide used must be the same OR group that is

present in the starting ester in order to avoid transesterification.
 Claisen
Condensations
Crossed Claisen
1. Condensations
If one ester has no α protons and cannot form an
enolate

2. A directed Claisen condensation can be performed

in which LDA is used as a base to irreversibly form an
ester enolate, which is then treated with a different
ester.
 Claisen
Condensations
Intramolecular Claisen Condensations: The Dieckmann
Cyclization

Dieckmann cyclization: the product is a cyclic, β-keto ester.

Intramolecular Claisen
condensations show a preference
for formation of five- and six-
membered rings
 Alkylation of the Alpha
Position
Alkylation via Enolate
Ions of a ketone can be
The α position
alkylated via a two-step process:
(1) formation of an enolate followed by

(2) treating the enolate with an alkyl

halide.
The enolate ion functions as a
nucleophile and attacks the alkyl halide
in an S 2 reaction.
N

It is possible to choose
conditions that will favor
formation of either enolate.
Alkylation of the Alpha
Position
Alkylation via Enolate
Ions
 Alkylation of the Alpha
Transformation of a halide into
Position a carboxylic acid with two new
The Malonic Ester
carbon atoms.
Synthesis

Mechanis
m
 Alkylation of the Alpha
Position
The Malonic Ester
Diethyl malonate,
Synthesis the starting material, is first
deprotonated, then treated with an alkyl halide, and then
treated with aqueous acid at elevated temperature.

Diethyl malonate can also be dialkylated (with different alkyl

groups) to produce carboxylic acids.
 Alkylation of the Alpha
Position
The Acetoacetic Ester
convertsSynthesis
an alkyl halide into a methyl ketone with three new carbon
atoms.
 Alkylation of the Alpha
Position
The Acetoacetic Ester
Synthesis
 Conjugate Addition
Reactions
Michael
Reactions

Grignard reagents tend

to attack the carbonyl
group rather than the β
position.

Lithium dialkyl cuprate

(R2CuLi) is less reactive
than a Grignard reagent,
and the R group is
ultimately positioned at
the β position
 Michael
Reactions
Conjugate addition, or a
1,4-addition

1,4- 1,2-
addition addition
In general, enolates are less reactive than Grignard reagents but
more reactive than lithium dialkyl cuprates. As such, both 1,2-
addition and 1,4-addition are observed, and a mixture of products
is obtained. In contrast, doubly stabilized enolates are sufficiently
stabilized to produce 1,4 conjugate addition exclusively.
Conjugate Addition
Reactions
Michael
Reactions
 Conjugate Addition
Reactions
Michael
Reactions
This process is called a Michael reaction. The doubly
stabilized enolate is called a Michael donor, while the
α,β-unsaturated aldehyde is called a Michael acceptor.

Any one of the Michael donors in this table will react with any one
of the Michael acceptors to give a 1,4-conjugate addition
reaction.
Conjugate Addition
Reactions
The Stork Enamine
Synthesis
The Stork Enamine
Synthesis

Stork enamine
synthesis has three steps:
(1) formation of an enamine,

(2) a Michael addition, and

(3) hydrolysis.
 Conjugate Addition
Reactions
The Robinson Annulation
Reaction
A Robinson annulation, a two-step method for forming a
ring, in which a Michael addition is followed by an
intramolecular aldol condensation, often used for the
synthesis of polycyclic compounds.
 Synthesis
Strategies
Reactions That Yield difunctionalized
Compounds
The Stork enamine synthesis produces 1,5-difunctionalized
compounds.

Aldol addition reactions and Claisen condensation reactions both

produce 1,3-difunctionalized compounds.
 Synthesis
Strategies
Alkylation of the Alpha and Beta Positions
A method for alkylating both the
α and β positions in one reaction
flask
The two alkyl groups need not be
same
First, a carbon nucleophile is used to install
an alkyl group at the β position, and then a
carbon electrophile is used to install an alkyl
group at the α position.