Alkylation of Enolate Ions

1. 2.

3.

The malonic ester synthesis The acetoacetic ester synthesis Direct alkylation of ketones, esters and nitriles

Relative acidity of selected organics

Structure
O CH3C OH O O

pKa
5 9 11

CH3CCH2CCH3
O O

CH3CCH2COCH3
O O

CH3OCCH2COCH3

13

These compounds are MORE ACIDIC than CH3CH2OH (pKa = 16); NaOCH2CH3 can deprotonate them.

Relative acidity of selected organics

Structure
O CH3CCl

pKa
16 17 19

O CH3CH
O CH3CCH3

These compounds are SLIGHTLY LESS ACIDIC than CH3CH2OH; NaOCH2CH3 would result in only a small amount of deprotonation.

Relative acidity of selected organics

Structure
O CH3COCH3

pKa
25 25 35

CH3C N

N H3

R2NH

40

These compounds are MUCH LESS ACIDIC than CH3CH2OH; to deprotonate the top two, a base such as the R2N anion must be used.

Acidity of b-dicarbonyl compounds

A base removes a proton a to both carbonyl groups:
O C H C O C H OCH2CH3 O C C O C H + C H3CH2OH

Resonance stabilizes the resulting anion:

O C C O C H O C C H O C O C C H O C

General mechanism for alkylation

The anion attacks the carbon bearing a leaving group:
O C C O C H R X RX O C R C O C H + X

A second equivalent of base can remove the second proton :

O C R C O C H OCH2CH3 O C R C O C + C H3CH2OH

Introduction of a second alkyl group:

This anion can be alkylated by a second alkyl halide
O C R R' X C O C R'X O C R C O C R' + X

Hydrolysis and Decarboxylation

O CH3CH2O C R C O C H OCH2CH3 OH, heat followed by H3O or, H3O, heat O HO C R C O C H OH

a substituted malonic ester

O HO C R C O C H H C R H HO OH HO O C R H C O C H H3O, heat O HO H + C R O C H C R H H O C O

O C

O HO C

a substituted acetic acid

Hydrolysis and Decarboxylation

O CH3 C R C O C H OCH2CH3 OH, heat followed by H3O or, H3O, heat O CH3 C R C O C H OH

a substituted acetoacetic ester

O CH3 C R C O C H H C R H CH3 OH CH3 O C R H C O C H H3O, heat O CH3 H + C R O C H C R H H O C O

O C

O CH3 C

a substituted acetone

Overall Process, single substitution, using abbreviations

O O 1. Na OEt 2. RBr 3. H3O, 1. Na OEt 2. RBr 3. H3O,
+ +

O RCH2COH

EtOCCH2COEt

O R CH2CCH3

CH3CCH2COEt

Overall Process, double substitution, using abbreviations

O O 1. Na OEt 2. RBr 3. Na OEt 4. R'Br 5. H3O,
+

O RCHCOH R'

EtOCCH2COEt

1. Na OEt 2. RBr 3. Na OEt 4. R'Br 5. H3O,

+

O RCHCCH3 R'

CH3CCH2COEt

Forming a ring that includes the a-carbon

O O 1. Na OEt 2. BrCH2CH2CH2CH2Br 3. Na OEt 4. H3O,
+

CH3CCH2COEt

CH2

CH2

CHCCH3

CH2 CH 2

Substituted acetic acids having a ring that includes the a-carbon can be synthesized similarly using diethyl malonate:
O O 1. Na OEt 2. BrCH2CH2CH2CH2CH2Br 3. Na OEt 4. H3O,
+

CH2 CH2 CH2

O CHCOH CH2

EtOCCH2COEt

CH2

5- or 6-membered rings can be made using a 4- or 5-carbon alkyl dihalide

Direct alkylation of ketones, esters, and nitriles (but NOT aldehydes)

O C CH3 1. Li N(CH(CH3)2)2 (lithium diisopropylamide, LDA) 2. CH3I 1. Li N(CH(CH3)2)2 (lithium diisopropylamide, LDA) 2. CH3CH2I 1. Li N(CH(CH3)2)2 (lithium diisopropylamide, LDA) CH3CH2CH2C N 2. CH3I O C CH2CH3

O CH3CH2COCH3

O CH3CHCOCH3 CH2CH3

CH3 CH3CH2CHC N