Chapter 19 PDF

Organic Lecture Series
Enolate Anions
and Enamines
Chapter 19
1
The Aldol Reaction
• The most important reaction of enolate

anions is nucleophilic addition to the
carbonyl group of another molecule of the
same or different compound
– although these reactions may be catalyzed by
either acid or base, base catalysis is more
common
– The reaction results in a new C—C bond
2
The Aldol Reaction

The product of an aldol reaction is
– a β-hydroxyaldehyde or a β-hydroxyketone
C
H3O+
R H(R') OH O H O
+ H3O+
HC C C C
O R R
R H(R') OH- R H(R')
C OH- -hydroxycarbonyl -unsaturated carbonyl
R H(R')
Frequently, there is a second, dehydration step
The Aldol Reaction

• The product of an aldol reaction is
– a β-hydroxyaldehyde
O H O OH O
NaOH β α
CH3 -C-H + CH2 -C-H CH3 -CH-CH2 -C-H
A cetaldehyde A cetaldehyde 3-Hydroxyb utanal
(a β-hydroxyaldehyde;
racemic)
– or a β-hydroxyketone
O H O OH O
β α
Ba(OH) 2
CH3 -C-CH3 + CH2 -C-CH3 CH3 -C-CH2 -C-CH3
CH3
Acetone Acetone 4-Hydroxy-4-meth yl-2-p entanone
(a β-hydroxyketone) 4
The Aldol Reaction

• Base-catalyzed aldol reaction
Step 1: formation of a resonance-stabilized enolate anion
-
O O O
-
H-O + H-CH2 -C-H H-O-H + CH 2 -C-H CH2 =C-H
pK a 20 pK a 15.7 An enolate an ion
(w eak er acid) (s tronger acid)
Step 2: carbonyl addition gives a TCAI
-
O O O O
CH3 -C-H + CH2 -C-H CH3 -CH-CH2 -C-H
A tetrahed al carbon yl
addition intermediate
Step 3: proton transfer to O- completes the aldol reaction

5
The Aldol Reaction-Acidic

• Acid-catalyzed aldol reaction
– Step 1: acid-catalyzed equilibration of keto
and enol forms
O OH
HA
CH3 - C-H CH2 = C- H
– Step 2: proton transfer from HA to the
carbonyl group of a second molecule of
aldehyde or ketone
H
O O
CH3 -C-H + H A CH3 -C-H + A
6
The Aldol Reaction-acidic
– Step 3: attack of the enol of one molecule on

the protonated carbonyl group of another
molecule
– Step 4: proton transfer to A- completes the
reaction
H H
O O OH O
-
CH3 -C-H + CH2 =C-H + :A CH3 -CH-CH2 -C-H + H-A
(racemic)
(Steps 3 & 4 are combined here)
The Aldol Products-H2O

– aldol products are very easily dehydrated to
α,β-unsaturated aldehydes or ketones
OH O warm in either O
acid or base β α
CH3 CHCH 2 CH CH3 CH= CH CH + H2 O
An α,β-unsaturated
aldehyde
– aldol reactions are reversible and often little

aldol present at equilibrium
– Keq for dehydration is generally large
– if reaction conditions bring about dehydration,
good yields of product can be obtained
8
Crossed Aldol Reaction
In a crossed aldol reaction, one kind of

molecule provides the enolate anion and
another kind provides the carbonyl group
O O O
NaOH
CH3 CCH3 + HCH CH3 CCH2 CH2 OH
4-Hyd roxy-2-b utanone
Crossed Aldol Reaction
Crossed aldol reactions are successful if:

1. one of the reactants has no α-hydrogen and,
therefore, cannot form an enolate anion and
2. the other reactant has a more reactive
carbonyl group, namely an aldehyde
O
CHO CHO
HCH O CHO
Formald ehyde Benzaldehyde Furfural 2,2-D imethylprop anal
O O O
NaOH
CH3 CCH3 + HCH CH3 CCH2 CH2 OH
4-Hyd roxy-2-b utanone
10
Polyalkylation of Enolates:
11

Kinetic vs Thermodynamic Enolates
O-
CH3
Kinetic Enolate
1)"Less" Stable
B: 2) Form with LDA
O :B
H H
CH3
O-
CH3
Thermodynamic Enolate
1)"More" Stable
2) Form with OH- or OR-
3) Equilibrating conditions
12
Crossed Enolate Reactions using LDA
• With a strong enough base, enolate anion

formation can be driven to completion.
• The base most commonly used for this purpose
is lithium diisopropylamide, LDA.
• LDA is prepared by dissolving diisopropylamine
in THF and treating the solution with butyllithium.
[ ( CH3 ) 2 CH] 2 N H + CH3 ( CH2 ) 3 Li [ ( CH3 ) 2 CH] 2 N - Li + + CH3 ( CH2 ) 2 CH 3

Diisopropylamine Butyllithium Lithium diisopropylamde Butane
(pK a 40 (stronger base) (weaker base) pK a 50
(stronger acid) (weaker acid)
13
• Using a molar equivalent of LDA

converts an aldehyde, ketone, or ester
completely to its corresponding
enolate anion.
O O Li+
+
CH3 COC2 H5 + [ ( CH3 ) 2 CH] 2 N Li CH2 =COC2 H5 + [ ( CH3 ) 2 CH] 2 N H
Ethyl acetate Lithium Lithium enolate Diisopropylamine
pK a 23 diisopropylamide (weaker base) pK a 40
(stronger acid) (stronger base) (weaker acid)
14
• The crossed aldol reaction between

acetone and an aldehyde can be carried
out successfully by adding acetone to one
equivalent of LDA to preform its enolate
anion:
O
O O-Li+ 1.C H CH CH OH O
LDA 6 5 2
C6 H5
-78°C 2. H 2O 4-Hydroxy-5-phenyl-2-pentanone
Acetone Lithium
enolate (racemic)
• which is then treated with the aldehyde.

15
• For ketones with two sets of nonequivalent

α-hydrogens, is formation of the enolate
anion regioselective?
– The answer is that a high degree of
regioselectivity exists and that it depends on
experimental conditions.
16
– When 2-methylcyclohexanone is treated

with a slight excess of LDA, the enolate is
almost entirely the less substituted enolate
anion.
slight excess
of base
O O - Li + O - Li +
0°C + [ ( CH3 ) 2 CH] 2 N H
+ LDA +
(racemic)
99% 1%
17
• When 2-methylcyclohexanone is treated

with LDA under conditions in which the
ketone is in slight excess, the product is
richer in the more substituted enolate.
slight excess
of the ketone
O O - Li + O - Li +
0°C + [ ( CH3 ) 2 CH] 2 N H
+ LDA +
(racemic)
10% 90%
18
• The most important factor determining the

composition of the enolate anion mixture is
whether the reaction is under kinetic (rate) or
thermodynamic (equilibrium) control.
• Thermodynamic Control: Experimental
conditions that permit establishment of
equilibrium between two or more products of a
reaction.The composition of the mixture is
determined by the relative stabilities of the
products.
19

– Equilibrium among enolate anions is established
when the ketone is in slight excess, a condition under
which it is possible for proton-transfer reactions to
occur between an enolate anion and an α-hydrogen
of an unreacted ketone. Thus, equilibrium is
established between alternative enolate anions.
20
• Kinetic control: Experimental conditions under

which the composition of the product mixture is
determined by the relative rates of formation of each
product.
– In the case of enolate anion formation, kinetic control
refers to the relative rate of removal of alternative
α-hydrogens.
– With the use of a bulky base, the less hindered
hydrogen is removed more rapidly, and the major
product is the less substituted enolate anion.
– No equilibrium among alternative structures is set up.
21
Intramolecular Aldol Reactions

intramolecular aldol reactions are most
successful for formation of five- and six-
membered rings
consider 2,7-octadione, which has two α-carbons
O O O
α3 α1 -H2 O
KOH
O HO
(formed)
2,7-Octanedione
O O
O
α1 -H2 O
α3 KOH
OH
O (n ot formed) 22
Claisen Condensation
• Esters also form enolate anions which

participate in nucleophilic acyl substitution
the product of a Claisen condensation is a

β-ketoester:
O O
β α
C C C C OR
A β -ketoest er 23
– Claisen condensation of ethyl propanoate

gives this β-ketoester
O O O O
- +
1 . Et O Na
OEt + OEt OEt + EtOH
2 . H2 O, HCl
Ethyl Ethyl Eth yl 2-methyl-3-
propan oate propan oate oxopen tan oate
(racemic)
Nota bene: the base should be the alkoxide of the ester group
(This will overcome trans-esterification.)
24
Step 1: formation of an enolate anion
O O O-
-
Et O - + H CH 2 -COEt EtOH + CH2 -COEt CH2 =COEt
pK a = 22 pK a 15.9 Res on ance-s tab ilized enolate anion
(w eaker acid) (stronger
acid )
Step 2: attack of the enolate anion on a

carbonyl carbon gives a TCAI
-
O O O O
CH3 -C-OEt + CH2 -COEt CH3 -C-CH2 -C-OEt
OEt
A tetrahedral carbonyl 25
add ition in termediate
Step 3: collapse of the TCAI gives a β-ketoester
and an alkoxide ion:
O O O O
CH3 -C-CH2 -C-OEt CH3 -C-CH2 -C-OEt + Et O
OEt
Step 4: an acid-base reaction drives the

reaction to completion:
O O O O
Et O + CH3 -C-CH-C-OEt CH3 -C-CH-C-OEt + Et OH
H
pK a 10.7 p Ka 15.9
(stron ger acid) (w eaker acid)26
Dieckman Condensation
• An intramolecular Claisen condensation

O - +
Et O 1 . Et O Na
OEt
2 . H2 O, HCl
O
Diethyl hexanedioate O O
(Diethyl adipate)
OEt + Et OH
Ethyl 2-oxocyclo-
pentanecarboxylate
27
Crossed Claisen Condensations

Crossed Claisen condensations between two
different esters, each with α-hydrogens, give
mixtures of products and are not useful
– crossed Claisen condensations are useful, if there is
an appreciable difference in reactivity between the
two esters; when one of them has no α-hydrogens
O O OO O
HCOEt EtOCOEt EtOC-COEt COEt
Eth yl D ieth yl D iethyl ethaned ioate Ethyl ben zoate

formate carbonate (D iethyl oxalate)
28
Crossed Claisen Condensations
– the ester with no α-hydrogens is

generally used in excess
O O - +
O O
+ 1 . CH3 O Na
Ph OCH3 OCH3 2 . H2 O, HCl Ph OCH3
Meth yl Meth yl Methyl 2-meth yl-3-oxo-

benzoate p ropan oate 3-ph enylprop anoate
(racemic)
Only this enolate can be formed
29
Carbonyl Condensations in Biochemistry

• Carbonyl condensations are among the most
widely used reactions in the biological world for
the formation of new carbon-carbon bonds in
such biomolecules as:
– fatty acids.
– cholesterol, bile acids, and steroid hormones.
– terpenes.
• One source of carbon atoms for the synthesis of
these biomolecules is acetyl coenzyme A
(acetyl-CoA). Coenzyme A is a carrier of the
two-carbon acetyl group, CH3-CO-
30
Cholesterol
H3 C
H3 C
H
H H
HO
More details in Chap. 26 31

Biosynthesis of Steroids
The building block from which all carbon atoms

of steroids are derived is the two carbon acetyl
group of acetyl-CoA-
Stage 1: synthesis of isopentenyl pyrophosphate
from three molecules of acetyl-CoA
Stage 2: synthesis of cholesterol
Stage 3: conversion of cholesterol to other steroids
bile acids (e.g., cholic acid)

sex hormones (e.g., testosterone and estrone)
cholesterol
mineralocorticoid hormones (e.g., aldosterone)
glucocorticoid hormones (e.g., cortisone) 32
Acetyl-CoA in Biochemistry
– Claisen condensation of acetyl-CoA is
catalyzed by the enzyme thiolase.
O O
th iolas e
SCoA + SCoA
Clais en
Acetyl-CoA A cetyl-CoA cond ensation
O O
SCoA + CoASH
Acetoacetyl-CoA Coen zyme A
33
– This is followed by an aldol reaction with a second
molecule of acetyl-CoA. Note that this reaction is
stereoselective and gives only the S enantiomer.
O O O 3-hydroxy-3-methyl-
glutaryl-CoA synth etase
SCoA + SCoA
CoASH
cond ensation
at this carbonyl OH O
O
-
O SCoA
(S)-3-Hydroxy-3-
meth ylglutaryl-CoA
34
– Enzyme-catalyzed reduction by NADPH of the
thioester group.
4 1 4 1
O OH O 3-hydroxy-3-methyl- O OH
- glutaryl-CoA reductase -
O SCoA O OH
3 2 2 3
+
(S)-3-Hydroxy-3- 2 NADPH 2 NADP (R)-Mevalonate
meth ylglutaryl-CoA
Phosphorylation by ATP followed by β-elimination.

a phosp horic
ester a pyroph os phoric
ester
O OPO3 2 - β-elimin-
- ation 3- + CO2 + PO4
3-
O OP2 O6 3 - OP2 O6
(R)-3-Phosp ho-5-pyroph os pho- Isopen tenyl
mevalonate pyroph os phate 35

Biosynthesis of Cholesterol
O HO CH3
O
-
CH3 -C- S- Co A O OH
Acetyl Coenzyme A (R)-Mevalonate
OP2 O6 3 -
Isopentenyl pyrophosphate
C10 terpenes ( C1 0 ) Geranyl pyrophosphate
C15 and C20 terpenes ( C1 5 ) Farnesyl pyrophosphate
C30 terpenes ( C3 0 ) Squalene
Cholesterol 36
– Enzyme-catalyzed reduction by NADPH of the
thioester group.
4 1 4 1
O OH O 3-hydroxy-3-methyl- O OH
- glutaryl-CoA reductase -
O SCoA O OH
3 2 2 3
+
(S)-3-Hydroxy-3- 2 NADPH 2 NADP (R)-Mevalonate
meth ylglutaryl-CoA
The “Statin” drugs inhibit

HMGCoA Reductase and
exert their action in this step
37
Atorvastatin
Lipitor
Simvastatin
Zocor
Lovastatin
Mevacor
Pravastatin
Pravacol 38
Enamines
Enamines are formed by the reaction of a 2°
amine with the carbonyl group of an
aldehyde or ketone
the 2° amines most commonly used to prepare
enamines are pyrrolidine and morpholine:
N
N
H
H
Pyrrolidine M orpholine
39
Preparation of Enamines
O + +
H H
+ N N
N OH -H2 O
H
An enamine
O O
O O H
+ +
H
+ N N
OH -H2 O
N
H
An en amin e
Acid catalyst is usually TsOH; azeotropic removal of H2O.

40
See Chapter 16 for details
Enamines-Alkylation
The value of enamines is that the β-carbon
is nucleophilic (same C that was α to
carbonyl)
– enamines undergo SN2 reactions with methyl
and 1° haloalkanes, α-haloketones, and α-
haloesters
41
Enamines-Alkylation Organic Lecture Series
treatment of the enamine with 1 eq of an alkylating agent gives an iminium halide:
O O
••
N N Br
SN 2
+ Br
The morph olin e 3-Bromopropene An iminiu m

en amin e of (Allyl bromide) bromid e
cyclohexan on e (racemic)
hydrolysis of the iminium halide (salt) gives the alkylated aldehyde or ketone:
O
O O
+
N Br- + +
HCl/ H 2 O N Cl-
H H
2-Allylcyclo- Morpholinium
hexanone chloride
42
Enamines-Acylation
enamines undergo acylation when treated
with acid chlorides and acid anhydrides
N
O
+ CH3 CCl
Acetyl ch loride
+ O O
O
Cl N
-
HCl +
+ N Cl-
H2 O H H
A n iminium 2-Acetylcyclo-
chlorid e hexan on e
(racemic) (racemic)
43
Synthetic Advantages of
Enamines vs Enolates
1) Avoids proton transfer.

2) Regiochemistry of alkylation can be
controlled. (For un-symmetric ketones)
3) Avoids polyalkylation.
4) Avoids O-alkylation.
44
Claisen condensations as routes to ketones
Reactions 1 & 2: Claisen conden sation follow ed by acidification

O - + O O
1 . Et O Na
OEt 2 . H O, HCl OEt + Et OH
2
Reactions 3 & 4: Saponification and acidification

O O O O
3 . NaOH, H2 O, heat
OEt OH + Et OH
4 . H2 O, HCl
Reaction 5: th ermal decarboxylation

O O O
5 . heat
OH + CO2
This segment was added 45
Claisen condensations as routes to ketones
The result of Claisen condensation, saponification,

acidification, and decarboxylation is a ketone:
from the ester from the ester
furnish ing the furnish ing the
carbonyl group enolate anion
O O s everal O
steps
R-CH2 -C + CH2 -C-OR' R-CH2 -C-CH2 -R + 2 HOR' + CO2
OR' R
46
Acetoacetic Ester Synthesis
The acetoacetic ester (AAE) synthesis is

useful for the preparation of mono- and
disubstituted acetones of the following
types
O
CH3 CCH2 R A mon os ubs tituted
O O acetone
CH3 CCH2 COEt
O
Ethyl acetoacetate
(Acetoacetic ester) CH3 CCHR A dis ubs tituted
acetone
R'
47

– consider the AAE synthesis of this target
molecule, which is a monosubstituted acetone
these th ree carb on s the -R grou p of a
are from ethyl monosu bstitu ted
O acetone
acetoacetate
5-Hexen-2-one
48

– Step 1: formation of the enolate anion of AAE
O O
+
-
EtO Na
+ Na+ + EtOH
COOEt COOEt
Eth yl acetoacetate S od ium Sodiu m s alt Eth anol
p Ka 10.7 eth oxid e of ethyl pK a 15.9
(s tronger acid) acetoacetate (w eak er acid)
– Step 2: alkylation with allyl bromide

O + O
Na SN2
+ Br + NaBr
COOEt COOEt
3-Bromopropene (racemic)
(Allyl bromide) 49
– Steps 3 & 4 saponification followed by

acidification
O O
3 . NaOH, H2 O + Et OH
4 . HCl, H2 O
COOEt COOH
(racemic)
– Step 5: thermal decarboxylation

O O
heat
+ CO2
COOH 5-Hexen -2-on e
(a monosu bstitu ted aceton e)
50

– to prepare a disubstituted acetone, treat the
monoalkylated AAE with a second mole of base, etc
O O Na+
+ Et O- Na+ + Et OH
COOEt COOEt
(racemic)
O Na+ O
SN 2
+ CH3 I + Na+ I -
COOEt COOEt
(racemic)
O
O
3 . NaOH, H2 O
+ EtOH + CO2
COOEt 4 . HCl, H2 O
(racemic) 5 . heat 3-Methyl-5-hexen-2-one
51
(racemic)

The acetoacetic ester (AAE) synthesis is
useful for the preparation of mono- and
disubstituted acetones of the following types
O
CH3 CCH2 R A mon os ubs tituted
O O acetone
CH3 CCH2 COEt
O
Ethyl acetoacetate
(Acetoacetic ester) CH3 CCHR A dis ubs tituted
acetone
R'
O
These types of reactions involve CCH3
active (i.e. acidic) methylene units
as the nucleophilic component. H2C
CO2Et 52
Application: Synthesis of 4,4-Disubstituted Piperidines
HO
2
"O" 3
O 6
4 N CH3
N CH3 5
1
R
HO
"O"
N
53
Not exam material CH3

Application: Synthesis of 4,4-Disubstituted Piperidines
Cl
Ph
NaH
CH2 N CH3 NCH3
NC
CN
Cl
1) NaOH
2) HCl
Ph EtOH Ph
NCH3 NCH3
cat H+
EtO2C HOOC
Meperidine
Demerol ® 54
Not exam material
Malonic Ester Synthesis
– treat malonic ester with an alkali metal alkoxide

+
Na
COOEt COOEt
+ EtO- Na+ + EtOH
COOEt COOEt
D ieth yl malon ate Sodiu m Sodiu m s alt of Eth anol
pK a 13.3 ethoxide dieth yl malonate p Ka 15.9
(s tronger acid) (w eaker acid)
– alkylate with 1-bromo-3-methoxy propane
+
Na
COOEt SN2 COOEt +
MeO Br + MeO Na+ Br-
COOEt COOEt
55
Malonic Ester Synthesis

– saponify and acidify
COOEt 3 . NaOH, H2 O COOH
MeO MeO + 2 EtOH
4 . HCl, H2 O
COOEt COOH
– decarboxylation
COOH heat COOH + CO
MeO MeO 2
COOH 5-Methoxypentan oic acid
56
Addition to α,β-unsaturated Carbonyls

When the carbonyl group is conjugated with an
alkene, the two groups can act in tandem to
expand synthetic utility.
α,β-unsaturated carbonyl compounds can exhibit
properties of both the carbonyl and alkene group:
1 3 1 3 1
3 O
O O
4 4 4
2 2 2
CH3 CH3 CH3
57
1 ,2 A d d itio n O OH
:N u Nu Nu
CH3 CH3
3 1
δ+ O
4
δ+ 2
CH3
:N u O OH
Nu CH3 Nu CH3
1 ,4 A d d itio n
C o n ju g a te A d d itio n
M ic h a e l A d d itio n Nu O
58
CH3
Michael Reaction
• Michael reaction: the nucleophilic addition

of an enolate anion to an α,β-unsaturated
carbonyl compound (1,4 addition)
– Example:
O - + O
EtOOC Et O Na EtOOC
+
COOEt EtOH
COOEt
Dieth yl 3-Buten-2-one
prop anedioate (Methyl vinyl
(D iethyl malonate) k eton e)
59
Michael Acceptors & Nucleophiles

Th ese Types of α,β-Un saturated Th ese Types of Compound s
Comp ou nds are N u cleophile Provide Effective N ucleoph iles
A ccep tors in Michael Reactions for Michael Reactions
O O O
CH2 =CHCH A ldehyde CH3 CCH2 CCH3 β-D iketone
O O O
CH2 =CHCCH3 Keton e CH3 CCH2 COEt β-Ketoester
O O
CH2 =CHCOEt Ester CH3 CCH2 CN β-Ketonitrile
O O O
CH2 =CHCNH2 Amide EtOCCH2 COEt β-D iester
CH2 =CHC N N itrile
En amin e
CH2 =CHNO2 N itro compoun d N
CH3 C=CH2
NH3 , RNH2 , R2 NH Amine
60
Michael Reaction
Example:
O
O O
- +
EtO Na
+ O
COOEt EtOH
Eth yl 3-oxobutanoate 2-Cyclohexen on e
COOEt
(Ethyl acetoacetate)
– the double bond of an α,β-unsaturated

carbonyl compound is activated for
nucleophilic attack:
O O O
+
+
61
Michael Reaction
• Mechanism
Step 1: proton transfer to the base
N u-H + :B- N u:- + H- B

Base
Step 2: addition of Nu:- to the β carbon of the

α,β-unsaturated carbonyl compound
O O O
Nu + C C C Nu C C C Nu C C C
Resonance-stabilized enolate anion

62
Michael Reaction
Step 3: proton transfer to HB gives an enol
1
O O-H
4 3 2
Nu C C C + H-B Nu C C C + B
A n enol
(a p rodu ct of 1,4-ad dition)
Step 4: tautomerism of the less stable enol form

to the more stable keto form
O-H H O
Nu C C C Nu C C C
Less stable en ol form More stab le keto form 63
Michael Reaction
A final note about nucleophilic addition to

α,β-unsaturated carbonyl compounds:
resonance-stabilized enolate anions
and enamines are weak nucleophiles,
react slowly with α,β-unsaturated
carbonyl compounds
give 1,4-addition products
64
Retrosynthesis of 2,6-Heptadione
thes e three
carbons from this b on d formed
acetoacetic ester in a Mich ael reaction
O O
O O O O
+
COOEt
this carb on COOH
Eth yl Meth yl vinyl
los t by acetoacetate k eton e
decarboxylation
O MVK is the reagent to add a 2-oxobutyl side chain
H3C C
C CH3
H2
65
Michael-Aldol in Combination:
The Robinson Ring Annulation
O O 1 . NaOEt , Et OH
H +
COOEt (Michael reaction)
3-Buten-2-one
Ethyl 2-oxocyclohex- (Methyl vinyl
anecarboxylate ketone)
O O O
2 . NaOEt , Et OH
(Aldol reaction)
COOEt COOEt
66

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Organic Lecture Series

Organic Lecture Series

The Aldol Reaction

• The most important reaction of enolate

The Aldol Reaction

Frequently, there is a second, dehydration step

Organic Lecture Series

The Aldol Reaction

The Aldol Reaction

Step 3: proton transfer to O- completes the aldol reaction

Organic Lecture Series

The Aldol Reaction-Acidic

The Aldol Reaction-acidic

– Step 3: attack of the enol of one molecule on

Organic Lecture Series

The Aldol Products-H2O

– aldol reactions are reversible and often little

Crossed Aldol Reaction

In a crossed aldol reaction, one kind of

Organic Lecture Series

Crossed Aldol Reaction

Crossed aldol reactions are successful if:

Organic Lecture Series

Crossed Enolate Reactions using LDA

• With a strong enough base, enolate anion

[ ( CH3 ) 2 CH] 2 N H + CH3 ( CH2 ) 3 Li [ ( CH3 ) 2 CH] 2 N - Li + + CH3 ( CH2 ) 2 CH 3

Organic Lecture Series

Crossed Enolate Reactions using LDA

• Using a molar equivalent of LDA

Crossed Enolate Reactions using LDA

• The crossed aldol reaction between

• which is then treated with the aldehyde.

Organic Lecture Series

Crossed Enolate Reactions using LDA

• For ketones with two sets of nonequivalent

Crossed Enolate Reactions using LDA

– When 2-methylcyclohexanone is treated

Organic Lecture Series

Crossed Enolate Reactions using LDA

• When 2-methylcyclohexanone is treated

Crossed Enolate Reactions using LDA

• The most important factor determining the

Organic Lecture Series

Crossed Enolate Reactions using LDA

Crossed Enolate Reactions using LDA

• Kinetic control: Experimental conditions under

Organic Lecture Series

Intramolecular Aldol Reactions

• Esters also form enolate anions which

the product of a Claisen condensation is a

Organic Lecture Series

– Claisen condensation of ethyl propanoate

Step 2: attack of the enolate anion on a

Organic Lecture Series

Step 4: an acid-base reaction drives the

• An intramolecular Claisen condensation

Organic Lecture Series

Crossed Claisen Condensations

Eth yl D ieth yl D iethyl ethaned ioate Ethyl ben zoate

Crossed Claisen Condensations

– the ester with no α-hydrogens is

Meth yl Meth yl Methyl 2-meth yl-3-oxo-

Only this enolate can be formed