Alkylation of Enolate Ions

1
Alkylation of Enolate Ions

1. The malonic ester synthesis
2. The acetoacetic ester synthesis
3. Direct alkylation of ketones, esters and nitriles

2
Relative acidity of selected organics

• Structure pKa
• 5
• 9
• 11
• 13
• These compounds are MORE ACIDIC than CH3CH2OH
  (pKa 16) NaOCH2CH3 can
  deprotonate them.

3
Relative acidity of selected organics

• Structure pKa
• 16
• 17
• 19
• These compounds are SLIGHTLY LESS ACIDIC than
  CH3CH2OH
• NaOCH2CH3 would result in only a small amount
  of deprotonation.

4
Relative acidity of selected organics

• Structure pKa
• 25
• 25
• 35
• 40
• These compounds are MUCH LESS ACIDIC than
  CH3CH2OH
• to deprotonate the top two, a base such as the
  R2N anion must be used.

5
Acidity of b-dicarbonyl compounds
A base removes a proton a to both carbonyl groups
Resonance stabilizes the resulting anion
6
General mechanism for alkylation
The anion attacks the carbon bearing a leaving
group
A second equivalent of base can remove the second
proton
7
Introduction of a second alkyl group
This anion can be alkylated by a second alkyl
halide
8
Hydrolysis and Decarboxylation
a substituted malonic ester
a substituted acetic acid
9
Hydrolysis and Decarboxylation
a substituted acetoacetic ester
a substituted acetone
10
Overall Process, single substitution,
using abbreviations
11
Overall Process, double substitution,
using abbreviations
12
Forming a ring that includes the a-carbon
Substituted acetic acids having a ring that
includes the a-carbon can be synthesized
similarly using diethyl malonate
5- or 6-membered rings can be made using a 4- or
5-carbon alkyl dihalide
13
Direct alkylation of ketones, esters, and
nitriles (but NOT aldehydes)