CARBONYL CHEMISTRY 2:

Reactions at the -Position

 The carbon next to the carbonyl group is
designated as being in the  position.
• The  -hydrogens of a carbonyl compound exhibit
acidity i.e. in the presence of a base they can be
abstracted very easily to yield a carbanion.

1
Electrophilic substitution occurs at this position through
either an enol or enolate intermediate.

2
Enolization is catalysed by acids and bases

• Acid enolization leads to the formation of the

enol intermediate

3
• Base catalysed enolization leads to the enolate anion
intermediate

• Avoid using water or HO- bases when enolating esters, rather

use the alkoxide belonging to the ester (MeO- with methyl
esters and EtO- with ethyl esters)

4
• Carboxylic acids and Amides do not easily form
enolates because the base first remove the O-H or N-
H protons

5
-Hydrogens in carbonyl compounds are
weakly acidic:
Some pKa values
• Note - Acidities of
the alpha-hydrogen is
measured in pKa.
• Lower pKa value of
the hydrogen, more
acidic it is.

α-hydrogens from aldehydes are

more acidic than those from
ketones
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 Recap
• Carbonyl compounds acts as electrophiles

• And Enolates acts as nucleophiles

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Enolates are ambident nucleophiles: they can react on
carbon or oxygen, but this usually may be controlled to
give the desired carbon-alkylation.

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-Alkylation vs Oxygen alkylation

O
Favoured

R CH2 X
O
Less common

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Reaction through the Carbon

LDA suitable base:

 Stronger base (full
conversion to enolate)
 All SM and LDA
consumed, therefore, no
interference.
 LDA bulky base and
poor nucleophile. 10
Other modern variants of LDA:

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 Choice of electrophile for alkylation
(Constraints on enolate alkylation):

Enolate alkylations are

SN2 reactions. X
 Primary, allyl and X
benzylic alkyl halides
are best.
 Polar aprotic solvents,
good charged
nucleophiles.

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Alkylation of Ketones/Aldehydes

O
CH3
1. LDA

CH3 2.
Br

O
CH3

No mixture of products
because there is only CH3
one -hydrogen.

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 More on alkylation of ketones/aldehyde
O O O

1. base +
2. CH3I
9% 41%

O O

Mixture of products , +
there are more than
one -hydrogen. 6% 21%

This is usually observed with weak bases

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 Using specific enolates equivalents to alkylate aldehydes
and ketones (Special alkylation):

Therefore, use enolate

• Aldehydes enolates are equivalents:
not generally useful  Enamines

intermediates.  Silyl enol ethers

• WHY ?  Aza-enolates derived

from imines

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Alkylation using Enamine Intermediates
(Stork enamine reaction)

O NR2 NR2
HNR2 R I R
R Enamine R SN 2 R
formation
Alkylation

O Hydrolysis H2O
N N
H
N
H O
H
R + HNR2
R

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17
Special features of Stork Enamine
alkylation
O
Enamines are enolate equivalents.
They possess several attractive
features:
 No base is used, so no self-

1.
condensation occurs.
N H+  Monoalkylation is usually
H
2. CH3I
observed.
3. H3O+  Alkylation in unsymmetrical

ketones is regioselective:
O the major enamine is the less
substituted one.

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How it works

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Alkylation of carboxylic acids
O OLi

HO LiO
2 BuLi

OMe OMe
OMe OMe

+
H3O
I
O

HO

OMe
OMe

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 Alkylation of -Dicarbonyl
Compounds
The acidity of a H is greatly
enhanced when the C to
which it is bonded is  to O O
two carbonyl groups:
CH3CH2O CH2 OCH2CH3
Diethyl malonate
(Malonic ester)
pKa 13

O O

CH2 OCH3
Methyl acetoacetate pKa 10
(Acetoacetic ester)

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 The Malonic Ester Synthesis

 For preparing a carboxylic acid from an

alkyl halide while lengthening the carbon
chain by two carbon atoms.
OR the end product is
R X R CH2CO2H

alpha-substituted
ACETIC ACIDS 22
 The Acetoacetic Ester Synthesis

 Overall: converts an alkyl halide into a

methyl ketone.

 OR end product is
O
R X R CH2CCH3

alpha-substituted
ACETONE 23
24
25
With a dihaloalkane, rings can be formed
by two sequential alkylation reactions:

O
EtO2C CO2Et excess CO2Et
NaOEt EtO
+ H
Br Br Br
OEt

O
EtO2C CO2Et
CO2Et
EtO

Br
1. NaOH
2. HCl, heat

CO2H

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 Ketone Alkylation poses a problem in
regioselectivity

• We can control the reaction by

using an appropriate base:
Thermodynamic Vs Kinetic
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 Thermodynamic Vs Kinetic Bases

Thermodynamic Kinetic

Weak bases (e.g. NaOEt) Strong bases (LDA)

Reaction done at room temperature Reactions done at low

temperatures (-78 oC)

Deprotonate the most acidic proton Deprotonate the most accessible

leading to formation of the most proton, sometimes resulting in less
stable enolate stable enolate

Reactions are usually slow Reactions are generally fast

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Thermodynamically controlled

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Kinetically controlled

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 Class Exercise:
Consider the reaction sequence below to answer the following questions:

(a) Write the complete stepwise mechanism for the conversion of

Compound X into Compound Y. Show all electron flow with arrows
and draw all intermediate structures.

(b) Below are the structures and electron flow for the conversion of
Compound Y into Compound Z. Draw the structure of Compound
Z. (Hint: Compound Z is an alcohol.)

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