Nucleophilic reactions involving

enolate anions

Aldehydes, Ketons and other carbonyl compounds having H on α-C

-> in equilibrium (in solution) -> Keto-Enol tautomerization

1
Nucleophilic reactions involving enolate anions

2
Nucleophilic reactions involving enolate anions

3
 Nucleophilic reactions involving enolate anions

Enolate anion
Conjugated base

4
 CARBANIONS
|
— C: –
|

The conjugate bases of weak acids,

strong bases, excellent
nucleophiles.
Carbanions are the conjugate bases of weak
acids and are therefore strong bases and
excellent nucleophiles that can react with
aldehydes/ketones (nucleophilic addition),
esters/acid chlorides (nucleophilic acyl
substitution), and alkyl halides (SN2), etc.
Reactions involving carbanions as nucleophiles:
1. Alpha-halogenation of ketones
2. Nucleophilic addition to aldehydes/ketones
a) aldol and crossed aldol
b) aldol related reactions
c) Grignard synthesis of alcohols
d) Wittig synthesis of alkenes
3. Nucleophilic acyl substitution with esters and acid
chlorides
a) Claisen and crossed Claisen
b) R2CuLi + RCOCl
4. SN2 with alkyl halides
a) Corey-House
b) metal acetylide
c) Malonate synthesis
d) Acetoacetate synthesis
5. Michael Addition to α,β-unsaturated carbonyl
compounds
1. Alpha-halogenation of ketones

O OH- or H+ O
C C + X2 C C + HX
H X

 -haloketone
X2 = Cl2, Br2, I2

O O
C + Br2, NaOH C + NaBr
H3C CH3 H3C CH2Br
acetone  -bromoacetone
 O O
Cl
+
+ Cl2, H + HCl

cyclohexanone 2-chlorocyclohexanone

O O
C CH3 + Br2, NaOH C CH2Br + NaBr

acetophenone  -bromoacetophenone
 Alpha-hydrogens: 1o > 2o > 3o

O O
CH3CH2CH2CCH3 + Br2, NaOH CH3CH2CH2CCH2Br + NaBr

2-pentanone 1-bromo-2-pentanone

Hydrogens that are alpha to a carbonyl group are weakly acidic:

O O
C + OH C + H2O
H3C CH3 H3C CH2
Hydrogens that are alpha to a carbonyl are weakly
acidic due to resonance stabilization of the carbanion.

O O
C C
R CH2 R CH2

"enolate" anion

The enolate anion is a strong base and a good nucleophile

Mechanism for base promoted alpha-bromination of acetone:

O O
RDS
1) C + OH C + H2O
H3C CH3 H3C CH2

O O
2) C + Br Br
H3C CH2 C + Br
H3C CH2Br

Rate = k [acetone] [base]

 Mechanism for acid catalyzed halogenation of ketones. Enolization.

O OH
1) C + H+ C
H3C CH3 H3C CH3
“enol”
OH OH
2) C + :B C + H:B
H3C CH3 H3C CH2

OH OH
3) C + Br Br C + :Br
H3C CH2 H3C CH2Br

OH O
4) C + H
C
H3C CH2Br H3C CH2Br
Oxidation of "methyl" ketones. Iodoform test.

O O
C + (xs) OI R C + CHI3
R CH3
O

NaOH + I2
O good
O leaving
R C CI3
C group
R CH2I OH

O O
C C + OH
R CHI2 R CI3
Carbanions.
The conjugate bases of weak acids; strong bases,
good nucleophiles.
1. enolate anions
2. organometallic compounds
3. ylides
4. cyanide
5. acetylides
Aldehydes and ketones: nucleophilic addition
O OY
C + YZ C
Z
Esters and acid chlorides: nucleophilic acyl
substitution
O O
C + Z C + W
W Z

Alkyl halides: SN2

R X + Z R Z + X

Carbanions as the nucleophiles in the above

reactions.
2. Carbanions as the nucleophiles in nucleophilic
addition to aldehydes and ketones:
a) aldol condensation
“crossed” aldol condensation
b) aldol related reactions
c) addition of Grignard reagents
d) Wittig reaction
a) Aldol condensation. The reaction of an aldehyde or
ketone with dilute base or acid to form a beta-
hydroxycarbonyl product.

OH
dil. NaOH
CH3CH=O CH3CHCH2CH O
acetaldehyde 3-hydroxybutanal

O OH O
dil. NaOH
CH3CCH3 CH3CCH2CCH3
acetone CH3
4-hydroxy-4-methyl-2-pentanone
 OH
dil. NaOH
CH3CH=O CH3CHCH2CH O
acetaldehyde 3-hydroxybutanal

OH + H2O
O
CH2CH=O + CH3CH O CH3CHCH2CH O

+ H2O

nucleophilic addition by enolate ion.

 O O OH
dil. NaOH CH3
C C C
H3C CH3 H3C C CH3
H2

OH + H2O

O O O O
CH3
C C C C
H3C CH2 H3C CH3 H3C C CH3
H2

+ H2O
 OH
CH3CH2CH=O + dil. NaOH CH3CH2CHCH2CH2CHO

CH3CHCH O
alpha!
OH
CH3CH2CH O CH3CH2CHCHCHO
CH3
O O
dil. OH-
OH

OH

O O

O + HOH
O
 O O
dil. H+
+ H2O

With dilute acid the final product is the α,β-unsaturated

carbonyl compound!
 dil NaOH OH
CH2CH O CH2 C CH CH=O
H
phenylacetaldehyde

dilute H+
CH2 C C CH=O + H2O
H

note: double bond is conjugated

with the carbonyl group!
 NB: An aldehyde without alpha-hydrogens
undergoes the Cannizzaro reaction with conc.
base.

CHO COO- CH2OH

conc. NaOH
+

benzaldehyde
Crossed aldol condensation:
If you react two aldehydes or ketones together in
an aldol condensation, you will get four products.
However, if one of the reactants doesn’t have any alpha
hydrogens it can be condensed with another compound
that does have alpha hydrogens to give only one organic
product in a “crossed” aldol.

NaOH CH O
CH3CH2CH O + H2C O CH3CHCH2 OH
N.B. If the product of the aldol condensation under
basic conditions is a “benzyl” alcohol, then it will
spontaneously dehydrate to the α,β-unsaturated
carbonyl.
dil OH-
CH=O + CH3CH2CH2CH=O CH=CCH=O
CH2
CH3

OH -H2O
CHCHCH=O
CH2
CH3
A crossed aldol can also be done between an aldehyde
and a ketone to yield one product. The enolate
carbanion from the ketone adds to the more reactive
aldehyde.

O O OH
dil OH-
C CH3 + CH3CH=O C CH2 C CH3
H
acetaldehyde
acetophenone
b) Aldol related reactions: (see problem 21.18 page 811
of your textbook).

KOH
CH=O + CH3NO2 CH=CHNO2 + H2O

CH2NO2

NaOEt
CH=O + CH2C N CH=C CN + H2O

CHC N
 Perkin condensation

CH3COONa
CH=O + (CH3CO)2O CH=CHCOOH
+ CH3COOH

O
H2C C hydrolysis of
O anhydride
CH3 C
O

OH O H O
CHCH2 C C C C + H2O
O H O
CH3 C CH3 C
O O
Carbanions as the nucleophiles in nucleophilic addition
to aldehydes and ketones:
c) addition of Grignard reagents
Grignard reagents are examples of organo metallic
carbanions.

O OMgX
C + RMgX C
R
 d) Wittig reaction (synthesis of alkenes)
1975 Nobel Prize in Chemistry to Georg Wittig

R O R R
C O + Ph3P=C R' C C R' C C R' + Ph3PO
ylide PPh3

CH2CH=O + Ph3P=CH2 CH2CH=CH2 + Ph3PO

Ph = phenyl
 Ph R O
Ph P C R' C
Ph

ylide O R R
C C R' C C R' + Ph3PO
PPh3

nuclephilic addition by ylide carbanion, followed by loss of

Ph3PO (triphenylphosphine oxide)
O + Ph3PCHCH=CH2 CHCH CH2 + Ph3PO
3. Carbanions as the nucleophiles in nucleophilic
acyl substitution of esters and acid chlorides.
a) Claisen condensation
a reaction of esters that have alpha-hydrogens in
basic solution to condense into beta-keto esters

O
NaOEt
CH3COOEt CH3CCH2COOEt + EtOH
ethyl acetate ethyl acetoacetate
Mechanism for the Claisen condensation:

O
NaOEt
CH3COOEt CH3CCH2COOEt + EtOH

OEt

O O
CH2COOEt CH3 C CH3 C OEt
OEt CH2COOEt

nucleophilic acyl substitution by enolate anion

ethyl propionate ethyl 2-methyl-3-oxopentanoate

O
OEt
CH3CH2COOEt CH3CH2CCHCOOEt
CH3

OEt
O O
CH3CHCOOEt CH3CH2C CH3CH2C OEt
OEt
CHCOOEt
CH3
ethyl phenylacetate O
NaOEt
CH2C CHCOOEt
CH2COOEt

OEt

O O
CHCOOEt CH2C CH2C OEt
OEt CHCOOEt
Crossed Claisen condensation:

NaOEt O
COOEt + CH3COOEt C CH2COOEt

ethyl benzoate

OEt O
HCOOEt + CH3CH2COOEt H C CHCOOEt
ethyl formate CH3
 OC2H5 O CH3
COOEt
+ CH3CH2COOEt C CHCOOEt
COOEt
C OEt
ethyl oxalate
O

NaOC2H5 O CH3
COOEt
+ 2 CH3CH2COOEt C CHCOOEt
COOEt
C CHCOOEt
O CH3
 O COOEt
O COOEt
NaOEt
EtOCOEt + CH2 EtO C CH
ethyl carbonate COOEt COOEt
ethyl malonate

O
O O
NaOEt
CH3CH2COOEt + CH3CH2C
ethyl propionate
cyclohexanone

enolate from ketone in nucleophilic acyl substitution on ester

b) Coupling of lithium dialkyl cuprate with acid
chloride

O O
R C + R'2CuLi R C
Cl R'

nucleophile = R'
4. Carbanions as nucleophiles in SN2 reactions with
R’X:
a) Corey-House synthesis of alkanes
R2CuLi + R’X  R-R’
b) metal acetylide synthesis of alkynes
RCC-M+ + R’X  RCCR’
c) Malonate synthesis of carboxylic acids

d) Acetoacetate synthesis of ketones

5. Michael Addition to α,β-unsaturated carbonyl

compounds