Transcript Enols and Enolates a Substitutions and Condensations of Ketones and Aldehydes O a e nol ate base O acid O H a e nol.

Enols and Enolates
a Substitutions and Condensations of
Ketones and Aldehydes
O
a
e nol ate
base
O
acid
O
H
a
e nol
Tautomerization Accelerated in Acid
a-Halogenation
O
O
Cl2, HOAc
Cl
+ HCl
Reaction Occurs via Enol
+
H
O
O
Cl2, HOAc
Cl
+ HCl
Cl
H
OH2
O
H
O
H
+
-H
O
Cl
e n ol
Cl
H
Cl
Tautomerization Acceleration in Base
Alkylation in Base
Reaction with 1o RX
fu n cti on al grou p
carboxylic acid
-diket one
-ket oest er
e xam pl e
CH3CO2H
O
O
CH3CCH2CCH3
O
O
CH3CCH2COCH2CH3
O
-diest er
pKa
5
9
11
O
CH3OCCH2COCH3
13
alcohol
CH3CH2OH
16
aldehyde
O
C
H3CH
O
17
CH3CCH3
19
ket one
Using LDA as Base to form
Enolate
O Li
O
Li N
H
in T HF
+
Lit hium diisopropylamide
"LDA"
+
HN
Alkylation a to C=O
C-alkylation preferred
O
O
H
1) LDA in T HF
2) (CH3)2CHCH2Br
O Li
Br
CH2CH(CH3)2
Alkylation Occurs on Less
Hindered Side of C=O
O
O
1) LDA, T HF
2) CH3CH2I
Malonic Ester Synthesis of
Carboxylic Acids
O
O
R-X
O
O
H
H
diet hyl malonat e
RCH2CO2H
H’s are unusually acidic
O
O
1) NaOEt, EtOH
O
O
H
H
diethyl malonate
CH3CH2CO2H + 2 EtOH
2) CH3I
+
3) H3O (to hydrolyze esters)
(loss of CO2)
+ CO2
O
O
1) NaOEt, Et OH
O
O
H
2) CH3I
+
3) H3O (t o hydrolyze esters)
H
+ CO2
(loss of CO2)
OEt
O
CH3CH2CO2H + 2 Et OH
+
O
O
H 3O
(-CO2)
O
H
Na
CH3
O
I
O
O
H 3O
O
O
H
CH3
O
+
heat
HO
OH
H
CH3
Decarboxylation (loss of CO2)
O
O
HO
O
OH
H
CH3
H
O
O
OH
H
CH3
-CO2
H
O
CH3
tautomerize
O
H
OH
OH
CH3
+ CO2
2 Acidic a H’s, 2 Alkylations;
Determine the Product of the
Synthesis
O
1) NaOEt, EtOH
2) CH3CH2Br
O
EtO
OEt
H
H
3) NaOEt, EtOH
4)
CH2Br
+
5) H3O , heat
All -keto acids are unstable and
Decarboxylate
O
O
COCH3
O
+
H3O , heat
+ CH3OH + CO2
Enamines can be Alkylated
Alkylation of an Enamine
a Position is Activated
Complements LDA Reaction
O
O
1) LDA, T HF
2) CH3CH2I
N H
O
+
H3O , pH = 4
N
H3O
CH3CH2I
I
N
+
LDA vs. Enamine Reaction
1) LDA/T HF
2) CH3Br
CH3
O
O
+
1) HNR2, H3O pH 4
2) CH3Br 3) H3O
+
O CH3
a-Selenation: Formation of
a,-Unsaturated Ketones
O
O
OH
1) LDA, T HF
2)
SeBr
3) H2O2
+
SeBr
Mechanism
O
O
1) LDA, T HF
+
SeOH
2)
SeBr
3) H2O2
Se Br
O
O
O
Se
C6H5 H2O2
C6H5
Se
O
H
Synthesis
O
O
CH3N
H
O
O
1) LDA, T HF
2) C6H5SeBr
3) H2O2
4) CH3NH2, H2O
CH3N
H
Aldol Condensation
Enolate Undergoes
Nucleophilic Addition
Aldol Condensation
Dimerization of 3-Pentanone
O
NaOCH3, CH3OH
O
0.5 mol equiv. base
H
OH
OCH3
CH3OH
O
O
O
O
Crossed Aldol Between 2
Different C=O Compounds
1) NaOEt
CH3CH2CHO + CH3CHO
+
2) H3O
4 Products
Four Possible Condensation
Products
Crossed Aldol Condensation
O
O
H
1) NaOCH3 in CH3OH
OH
CHCH3
2) CH3CHO
+
3) H3O
use full molar equivalent of base t o minimize side-products
O
+
H
O
O HCCH3
O
CHCH3
Dehydration of Aldol Products
O
O
OH
CHCH3
1) NaOCH3 in CH3OH
H
2) CH3CHO
+
3) H3O
H2SO 4
heat
O
CHCH3
H2O +
Predicting Aldol Dehydration
Products
Intramolecular Aldol
O
O
B
O
A
NaOCH3
methanol
O
H3O
A
B
OH

+
+ H2O
Predict the Product
O
O
O
+
O
CH
NaOCH3
in CH3OH
O
O
O
O
+
O
CH
HO
NaOCH3
in CH3OH
O
O
O
O
Na
O
O
O
O
CH3OH
Conjugate Addition
1,2 - vs. 1,4 - Addition
Michael Addition
Conjugate Addition of Enolate to a,Unsaturated Ketone
O
O
1) LDA, T HF
O
2)
3) H3O
+
O
Robinson Annulation:
Michael Addition followed by Aldol
Consensation
O
O
CH3
CH3
1) NaOH, CH3OH
2)
O
O
3) NaOH (-H2O)
O
O
O
CH3
H
O
CH3
NaOH
-H2O
1) NaOCH3, CH3OH
2)
O
O
3) NaOH (-H2O)
O
CH3
O
O
O
CH3
O
O
HOCH3
O
CH3
O
O
H