Chapter 22

Carbonyl α-Substitution Reactions

Intended learning outcomes:

1. To understand the acidity of the α position of carbonyl compounds
(compare acidity of difference poisitons)
2. To understand the structure and reactivity of enol and enolate ion,
as well as the conditions for enolate ion formation.
3. To understand the conditions α halogentation of aldehydes,
ketones, and carboxylic acids.
4. To understand the α alkylation of different carbonyl compounds
and the application of the alkylation reactions for more complex
compound synthesis (Malonic ester synthesis, Acetoacetic ester
synthesis)
The α-Position

The anion is stabilized

by resonance.

The α-hydrogen is acidic.

Keto–Enol Tautomerism
A carbonyl compound with an α hydrogen rapidly equilibrates with its
corresponding enol.

Tautomerism

https://www.youtube.com/watch?v=uvcdXDF6REM
• Tautomers are structural isomers, not resonance structures.
• Tautomers interconvert rapidly while ordinary isomers do not.
Ordinary isomers
Enol Stability

Normally, the keto form is much more stable:

Formed rapidly can serve as a reaction intermediate.

Stability of the enol tautomer proportional to the α-H acidity.

Some stable enols

aromaticity
https://www.youtube.com/watch?v=Es6FE6NCj2k
Catalyzed Enolization (Tautomerism)
normally slow at room temperature, but can be catalyzed by both acid and base.
Some Consequences: Enolization/Tautomerization

1. Racemization of α chiral center:

2. H-D Exchange:

What are the electrophiles in the above reactions?

Enols: Better Nucleophiles than Alkenes

EDG increase the carbon nucleophilicity:

Reactivity of Enols: The Mechanism of Alpha-Substitution Reactions

Carbonyl compounds that form enols undergo

substitution reactions at the a-carbon:
α Halogenation of Aldehydes and Ketones

Aldehydes and ketones can be halogenated at their  positions by reaction

with Cl2, Br2, or I2 in acidic solution
Other reactions based on bromination
Utility of α-Bromination: further eliminate to ,β-unsaturated ketones

poll

α-Deuteration
α-Bromination of Carboxylic Acids

Unlike aldehydes and ketones:

Reason: Acids, as well as esters and

amides, do not enolize easily.

Solution: Hell–Volhard–Zelinskii Reaction:

Hell–Volhard–Zelinskii Reaction

Mechanism: Convert to acid bromides, which can enolize:

Utility of α-Bromination of Carboxylic Acids

Acidity of α-Hydrogen Atoms

• α-H of carbonyl groups:

acidic

• Stabilized anion

• More stable anion, higher

acidity (lower pKa)

d- d+ d+
d-

EWG increases acidity.

EDG decreases acidity.

https://www.youtube.com/watch?v=jOH39jZ4HHg
Acidity of Dicarbonyl Compounds
pKa: H2O (15.7) CH3CH2OH (16.0) , H-N(i-Pr)2 (40)
Considerations of Enol or Enolate Formation
1. Acid catalysis does not change the keto-enol equilibrium constant. (catalytic)
2. Base (one equivalent) can change the equilibrium.
3. A weak base can completely deprotonate a 1,3-dicarbonyl compound and
strong base LDA can deprotonate all carbonyl compounds.
Choice of a Base for Enolate Ion Formation
LDA: Strong Base for Enolate Ion Formation

LDA

 a very strong base (conjugate acid is very weak: pKa ~40).

 soluble in organic solvents such as THF.
 hindered weak nucleophile (no nucleophilic addition to carbonyl compounds).
 effective even at –78 oC.

Sodium hydride (NaH) is another commonly used base for enolate ion formation.
Reactivity of Enolate Ions: Ambident Nucleophile

• Ambident: can react at two positions.

• The α-C and O both reactive

• Depends on E+ and conditions

• Reaction on C: more common

• E+ = H+ : Protonation, occurs
preferentially on O.
α-Halogenation

Recall: Acidic Conditions

Only one α-hydrogen is substituted by α-bromine.

Base-Promoted

All α-hydrogens are substituted by bromine:

How about ?
Haloform Reaction

Conversion of a methyl ketone to a carboxylic acid

CI3- is a stable anion: a good leaving group.

CH3- << CF3- < CCl3- < CBr3-, CI3-

https://www.youtube.com/watch?v=Ce4BGV1DVVg
α-Halogenation : Summary

Ketone
Acidic condition

Methyl ketone
Basic condition

Acid
(Hell–Volhard–Zelinskii Reaction)

Utility
a-Substitution Reactions

1. a-Halogenation
aldehyde and ketone with acid or
base catalysis (enol or enolate ion)

2. Aldol reaction
aldehyde and ketone with acid or
base catalysis (enol or enolate ion)

3. Michael addition
enolate ion (more reactive) required

4. a-alkylation
enolate ion (more reactive) required

Electrophile reactivity:
Alkylation of Enolate Ions

Constraints on the electrophile R－X:

• SN2 reaction: X can be chloride, bromide, iodide, or tosylate (OTs)

• R－X: should be preferably methyl, primary, allylic or benzylic halides.
(2o and 3o halides: bad reagents due to competing elimination)

Constraints on the reaction conditions:

Must have complete enolate ion

formation without any ketone
present because:
Direct Alkylation of Ketones

Complete enolate ion formation

Note: only molecules with one type of a-H should be used.

Direct Alkylation of Esters and Nitriles

Nitrile
Alkylation of Malonic Esters

1st Alkylation

2nd Alkylation

pKa of malonic ester: 13

pKa of EtOH: 16 complete enolate ion formation with EtONa
Malonic Ester Hydrolysis and Decarboxylation

Conditions: acidic and heating

Decarboxylation:

 Not general for

carboxylic acids

 Requires a β-carbonyl
group
The Malonic Ester Synthesis

Melonic ester alkylation + decarboxylation:

Overall: Alkyl halide → Carboxylic acid (+ two C atoms)

Preparation of
Cycloalkane
Carboxylic Acids
Start from Acetoacetic Ester (Ethyl Acetoacetate)

1st Alkylation

2nd Alkylation

Why not start from this?

Overall Conversion: Acetoacetic Ester Synthesis

Alkyl halide → Methyl ketone

Applicable to other β-keto esters:

Alkylation of 1,3-Diketones:
Some Useful Thoughts on Synthesis

Strategies for adding one-carbon unit:

Strategies for adding two-carbon unit:

α-Alkylation: Overview

Malonic ester
synthesis

Acetoacetic ester
synthesis

Diketone
synthesis

Aldehydes, ketones, esters,

amides, nitriles
Practice Problems

7th Ed.
22.20, 22.21, 22.23, 22.26, 22.27, 22.30
22.31, 22.34, 22.35, 22.36, 22.37, 22.38
22.42, 22.44, 22.46, 22.47, 22.49, 22.50
22.51, 22.53, 22.56, 22.58

8th Ed.
22.21, 22.24, 22.28, 22.30, 22.26, 22.20
22.22, 22.35, 22.40, 22.37, 22.38, 22.41
22.42, 22.43, 22.49, 22.47, 22.51, 22.53
22.50, 22.52, 22.54, 22.59