CHAPTER 17

Enolates and Carbanions: Building Blocks for Organic Synthesis

1

The Acidity of the Hydrogens of Carbonyl Compounds

Hydrogens on carbons to carbonyls are unusually acidic.

Why hydrogen is acidic

(enolate ion) Extremely strong bases are needed to form the enolate ion. Such as : NaNH2 CH3CH2CH2CH2Li [(CH ) CH] NLi 3 2 2 sodamide Sodium Butyllithium Lithium hydride diisopropylamide 3 (LDA) NaH

A hydrogen alpha to a single carbonyl is less acidic than a hydroxyl hydrogen

H CH3CH2 pKa 50 H O 20 H O CH2CCH3 CH2COCH2CH3 CH3CH2O H 16 25

Thus, alkoxide ion is not a good base to form the enolate ion from acetone or ethyl acetate.
O CH3COCH2CH3 + -OCH2CH3
-

CH2COCH2CH3 + CH3CH2OH
pKa=16

O CH3COCH2CH3
4

NH2

O
pKa=35

CH2COCH2CH3 +NH3
favored

The hydrogen of an ester is less acidic than that of a ketone

O CH3 C OCH2CH3 CH3 O
+

C OCH2CH3

Ethyl acetate

Major contributor

The ester carbonyl is less able to delocalize the negative charge of the enolate because the carbonyl oxygen already carries a partial negative charge.
5

Protons on the -carbon of -dicarbonyl compounds are acidic (pKa = 9-13)

O O
O H O

CH3CCHCCH3
acetylacetone pKa=9

CH3CCHCOCH2CH3
Ethyl acetoacetae pKa=11

O O CH3CCCOCH2CH3 HR
Acetoacetic ester pKa=13
6

O H

CH3CH2OCCHCOCH2CH3
diethyl malonate pKa=13

The acidity can be explained by resonance stabilization of the corresponding enolate by two carbonyl groups

pKa=16 Alkoxide is a good base to form the enolate- no need for a stronger base.

Nitro and cyanide groups enhance the acidity of hydrogen

CH2NO2 H
pKa=9

NCCHCN H
pKa= 13

O CH3CH2OCCHCN H
pKa=13
8

CHCN H

Alkylation of Malonic Ester

General: Synthesis of Substituted Acetic Acids

++ ) Na OC H H , H2O 2 5 CH2(CO2C2H5)2 1 RCH(CO2C2H5)2 heat RCH2CO2H 2) RX Diethyl malonate CO2

(malonic ester)

substituted acid

Example
++ ) Na OC2H5 H , H2O 1 CH2(CO2C2H5)2 CH3CH2CH(CO2C2H5)2 heat 2) CH3CH2Br CO2
9

From RX

CH3CH2CH2CO2H

Mechanism
Step1: formation of the enolate

10

11

 Step 3: Hydrolysis and Decarboxylation

12

Summary of alkylation of malonic ester CH (CO C H )

2 2 2 5 2

malonic ester
1) NaOC2H5 2) RX

H+, H2O CO2 RCH(CO2C2H5)2 RCH(CO H) RCH2CO2H 2 2 heat heat

1) NaOC2H5 2) R'X

a diacid

An acid

RC(CO2C2H5)2 R'
13

a diester

H+, H2O RC(CO2H)2 heat R'

a diacid

CO2 RCHCO2H heat R'

An acid

Examples

14

15

 By using two molar equivalents of malonate anion and a dihalide, the dicarboxylic acid is obtained

16

 C2 through C5 terminal dihalides can react to form rings by dialkylation of one molar equivalent of malonate

17

Alkylation of Acetoacetic ester

Synthesis of Methyl Ketones

18

 Hydrolysis of the ester and heating of the resultant -ketoacid causes decarboxylation
The product is a substituted acetone derivative

19

 A second alkylation can be performed

20

Summary of alkylation of acetoacetic ester

O CH3CCH2CO2C2H5 acetoacetic ester 1) NaOC2H5 2) RX O
+

CH3CCHCO2C2H5 H , H2O CH CCHCO H CO2 3 2 heat heat CH3CCH2 R R R 1) NaOC2H5 a keto acid a ketone 2) R'X O O O + CO2 CH3CCCO2C2H5 H , H2O CH3CCCO2H CH3CCHR' heat heat R R' R R' R a keto ester 21 a keto acid a ketone

example

22

Syntheses Using Alkylation Reactions

From CH3X

From malonic ester

CO2H CH3CH CO2H

From CH3X

From malonic ester

CH3 CHCO2H CH3CH2

From acetoacetic ester

From CH3CH2X

O CCH3 CH3CH2CH CO2C2H5

From CH3CH2X
23

From acetoacetic ester

O CH2CHCCH3 CH3

From C6H5CH2X

From CH3X

From C6H5CH2X

Example
O CH2CHCOH CH2CH3
1) -

From diethyl malonate From CH3CH2X

OC2H5

CH2(CO2C2H5)2

2)

CH3CH2I

CH3CH2CH(CO2C2H5)2
) 1 OC2H5 CH2Br 2)

O CH2CHCOH CH2CH3
24

H+, H2O heat - CO2

CH3CH2C(CO2C2H5)2 CH2C6H5

Alkylation of a Ketone
NON-CATALYTIC BASES REACT ONCE

O C CH3
LDA THF

one mole NaH

THF -hydrogens

one mole _ .. C CH2 + H

CH3-I one mole

O C CH2 CH3

.. C CH2

CH3-I

monoalkylation
_

: N : Li CH CH3 H3C CH
25

Sodium Hydride

CH3

CH3

LDA Lithium Diisopropyl Amide a strong base

NaH

EXAMPLE

26

Alkylation of esters

27

Alkylation and Acylation of Enamines

Aldehydes and ketones react with secondary amines to form enamines.

28

Enamines have a nucleophilic carbon and are the equivalent of ketone and aldehyde enolates

29

C-Acylation leads to -diketones

H2O

30

Enamine alkylation steps

O 1) Enamine formation R2CHCR
+

HN

H+

R R2C C N

2) Substitution

R R'X

R R2C C N R'
+

R2C C N

3) Hydrolysis
R'
31

R R2C C N
+

H+, H2O

R R2C C O R'

to C=O

 methyl ketone

O CHC CH3
a ketone
1)

Summary of enamine Reactions

O CHC CH2Ar
benzyl ketone

CH3I + 2) H2O,H
NR'2 CH C

O R'2NH

ArCH2X + 2) H2O,H O
1) RCCl + ) H , H 2O 2

1)

- diketone O
CHC CR

CH2C

O
1)

enamine

RCCH2X + ) H O,H O 2 2
CHC
32

O CHCH2X 1) CH2 + 2) H2O,H O CHC

allyl ketone

CH2CR O

- diketone

CH2CH CH2

How would you synthesis the following compound

O CCHCHO CH3

From propanal

HN CH3CH2CHO H
+

CH3CH CH N
1)

O CCHCHO CH3
33

Cl H2O,H+ O

2)

ALDOL CONDENSATION

34

The Aldol Condensation

O R CH2 C H + O R CH2 C H
H3O+ aldols easily lose water to form a double bond
35

ald + ol base

OH H R

R CH2 C CH C H
an aldol (-hydroxyaldehyde)

- H2O

R CH2 CH C C H R

,-unsaturated aldehyde

The Aldol Reaction: The Addition of Enolate Anions to Aldehydes and Ketones Acetaldehyde dimerizes in the presence of dilute sodium hydroxide at room temperature

36

Mechanism

37

Examples
O O OH
-

OH

CH3CH2CH2CH + CH3CH2CH2CH

CH3CH2CH2CHCHCH CH2CH3

O
O CH
+

O CH

OH-

OH CH

CH

38

Dehydration of the Aldol Product

The aldol product easily undergo dehydration to an ,unsaturated aldehyde Dehydration is favorable because the product is stabilized by conjugation of the alkene with the carbonyl group

-hydroxy aldehyde
39

Dehydration is Spontaneous if the double bond is in conjugation with aromatic ring

O OH O spontaneous CH CHCH CH CH2CH

3-hydroxy-3phenylpropanal

3-phenylprpenal

40

Ketones Also Give Aldol Condensations

O C CH 3

OH C CH3
C CH3

.. - CH 2
C O

NaOH

CH2 C O

CH C O

-H2O

aldol

41

CROSSED ALDOL CONDENSATIONS

42

 Crossed Aldol Reactions

Crossed aldol reactions (aldol reactions involving two different aldehydes) are of little use when they lead to a mixture of products

43

Practical Crossed Aldol Reactions

Crossed aldol reactions give one predictable product when one of the reaction partners has no hydrogens

44

Crossed-aldol reactions in which one partner is a ketone

45

Formation of Rings
1
O

2
O

H3C C CH2CH2CH2 C CH3

NaOH

CH3
O

CH3

OH

CH3

: CH2
O

46

Why dont 2 hydrogens react ?

Syntheses Pattern
HO
R CH2 C

O
CH C R

-hydroxy to C=O
(H) 3-hydroxyaldehyde or 3-hydroxyketone

ALDOL

(H)

R
-H2O

O
R CH2 C

,-unsaturated C=O
2-propen-1-al or 2-propen-1-one

C R

ALDOL
(with loss of H2O)

47

Syntheses Using Aldol Condensation

O C6H5C CHCC6H5 CH3
From acetophenone
OH O

CH3CH2CHCHCH CH3

From prpanal

48

Knoevenagel Condensation
Reaction of an aldehyde or a ketone with a compound hat has a hydrogen to two activating groups (C=O or CN). Amine is a catalyst.
O CH3(CH2)3CH
+

piperidine CH2(CO2C2H5)2 heat

CH3(CH2)3CH C(CO2C2H5)2
49

+ H2O

More examples
O
+

CN NH4+-O2CCH3 CH2 CO2C2H5

CN C H2O CO2C2H5
+

O CH
+

CH2(CO2H)2

NH3 heat

CH CHCO2H
+

H2O

+CO2

50

CLAISEN CONDENSATIONS

51

The Claisen Ester Condensation

General:

The overall reaction involves loss of an a hydrogen from one ester and loss of ethoxide from another
Notice that the base, the solvent and the leaving group CH3CH2O- Na+, CH3CH2OH, CH3CH2Oall match (this is required in most cases).
52

The Claisen Condensation: Synthesis of -Keto Esters

53

Mechanism of Claisen Condensation

54

-Keto ester
55

Crossed Claisen Condensations

Crossed Claisen condensations can lead to one major product when one of the two esters has no hydrogen

56

Crossed Claisen Condensation Between Ketones and Esters

O COC2H5
+

O CH2CCH3

O CH3CCH3

1) OC2H5 + ) H 2

O O CCH3 ) 1 OC2H5 + C2H5OC(CH2)3CH3 + ) H 2

O CCH2

O C(CH2)3CH3

57

-diketone

Dieckmann Condensation
A CYCLIC CLAISEN CONDENSATION

58

Syntheses Using Ester Condensation

Claisen Pattern

2 RCH2CO2C2H5

base

O RCH2CCHCO2C2H5 R
a -keto ester
H+, H2O heat

O RCH2CCHCO2H heat
-

O
CO2

RCH2CCH2R
a Ketone

a -keto acid
59

Syntheses problems
O CH3CH2CH2CCHCO2C2H5 CH2CH3
From ethyl benzoate

O CCHCO2H CH2CH3
From ethyl butanoate

From ethyl butanoate

O
From ethyl benzoate
60

CCH2CH2CH3

From ethyl butanoate

Dieckmann Condensation Pattern

O O base H+, H2O heat CO2C2H5 CO2H

O
heat CO2

CO2C2H5 (CH2)3 or 4 CH2CO2C2H5 base O CO2C2H5 H+, H2O heat O CO2H

O heat CO2

61

Michael Additions
A Michael addition involves conjugate addition of the anion derived from an active hydrogen compound (e.g., an enolate) to an ,unsaturated carbonyl compound

62

63

64

Examples
O CH2 CHCH
+

O
CH2(CO2C2H5)2
1) 2)

NaOC2H5 H+, H2O

NaOC2H5

CH2

CH2CH
O

CH(CO2C2H5)2
CH3CH CH2COC2H5 CH(CO2C2H5)2

O CH3CH CHCOC2H5
+

CH2(CO2C2H5)2

1)

+ 2) H , H2O

H+,H2O heat

CH3CHCH2CO2H CH2CO2H
65

CO2 heat

CH3CHCH2CO2H CH(CO2H)2

Michael addition products of malonic ester and ,,-unsaturated ester

O

RCH CHCOC2H5 + R'CH(CO2C2H5)2 NaOC2H5 RCH CH2COC2H5 R'C(CO2C2H5)2

a triester

H+,H2O heat

RCHCH2CO2H R'CHCO2H
66

CO2 heat

RCHCH2CO2H R'C(CO2H)2
a triacid

a diacid

ROBINSON ANNULATION
FORMING RINGS BY COMBINING CONJUGATE ADDITION WITH AN ALDOL CONDENSATION METHYL VINYL KETONE (MVK)

67

Michael Addition of Cyclopentanone to MVK

enolate weak base

:O

.. :

MVK methyl vinyl ketone

O:

..

:O
CH3

..
H C H

.. : O:
C H CH3

H H

C H

NaOCH3 CH3OH

H-OCH3

- .. : O-CH 3 ..

:O

..

O: C CH2 CH2 CH3

..

- .. + : O-CH 3 ..
68

can continue

ROBINSON ANNULATION
USES MVK TO BUILD A RING
FROM PREVIOUS SLIDE

O H H O

O C H O CH3

O C CH2 CH2 CH3

NaOCH3

NaOCH3 CH3OH Michael addition

O

-O
H3O+ (workup)
69

-: CH

C CH2 CH2 O
(ring formation)
internal aldol condensation

Annelation

ANOTHER EXAMPLE MICHAEL ADDITION + ALDOL CONDENSATION

2 ALDOL

O
1

H3 C

C O

NaOEt EtOH

CH CH2

70

Most acidic set of hydrogens MICHAEL reacts first.

Another Example of Robinson Annulation

71

Summary of Synthesis of Dicarbonyl Compouds

1. 1,3- dicarbonyl compounds () a. From enamine + acid chloride
O H+, HN 2) RCCl
1)

O R O
O R'' O

O + 3) H , H2O

b. From Claisen Condensation.

O RCOR'
72

1) base R''CH2COR' + ) H 2

RCCHCOR'

2. 1,4- Dicarbonyl compounds. a. From enamine + -haloketone

+ HN ) H , 1 R''CCH2R' 2) RCCH2Cl

O R'

R''CCHCH2CR

O + ) H , H2O 3

b. From acetoacetic ester + -haloketone

O
1)

O R' base RCCH X OR' R C2H5O O O

2)

O R' H+, H2O heat O R

C2H5O

73

3. 1,5-Dicarbonyl compounds from Michael Addition O

RCCH CHR'
+

CH2(CO2C2H5)2
O

1)

base

+ ) H 2

RCCH2 CHCH(CO2C2H5)2 R'

4. 1,6-Dicarbonyl componds By Oxidation of cycolhexene

KMnO4
74

CO2H CO2H