19-1

 Enolate anions are formed by treating an aldehyde, ketone, or ester, which has at least one a
-hydrogen, with base,
O
CH
3
-C- H + N aOH
O O
H C C-H
H
H C C-H
H
An enolate anion
Na
+
+ H
2
O
• Most of the negative charge in an enolate anion is on oxygen. oxygen
Reactive carbon
19-2

 Enolate anions are nucleophiles in S
N
2 reactions and carbonyl addition reactions ,
S
N
2
R
O
–
R
+ R' Br nucleophilic substitution
R
O
Br
R
An enolate anion
A 1° haloalkane or sulfonate
S
N
2
R R
R'
+
Carbonyl addition
O
–
R
R
An enolate anion
R +
R'
O
R'
A ketone nucleophilic
addition
R
O
R
O
R'
R'
R
A tetrahedral carbonyl
addition intermediate
19-3

 The most important reaction of enolate anions is nucleophilic addition to the carbonyl group of another molecule of the same or different compound.
• Catalysis: Base catalysis is most common although acid also works. Enolate anions only exist in base.
19-4

 The product of an aldol reaction is:
• a

-hydroxyaldehyde.
acid
O H O
CH
3
- C-H + CH
2
- C-H
Acetaldehyde Acetaldehyde
• or a

-hydroxyketone.
N aOH
CH
3

OH a
- CH- CH
2
O
-C- H
3-Hydroxybutanal
(a

-hydroxyaldehyde; racemic ) acid
H O
CH
2
-C-CH
3
OH a
O
Acetone Acetone 4-Hydroxy-4-meth yl-2-p entanone
(a

-hydroxyketone)
19-5

 Base-catalyzed aldol reaction (good nucleophile)
Step 1: Formation of a resonance-stabilized enolate anion.
H- O +
O
H- CH
2
- C-H H- O-H +
O
CH
2
- C-H
O
CH
2
= C- H p K a
20
(weaker acid) p K a
15.7
(stronger acid)
An enolate anion
Step 2: Carbonyl addition gives a TCAI.
O
CH
3
-C-H +
O
CH
2
-C-H
O
-
O
CH
3
-CH-CH
2
-C-H
A tetrahed al carbon yl addition intermediate
Step 3: Proton transfer to O completes the aldol reaction.
19-6

Mechanism : the Aldol Reaction: Acid catalysis
 Before showing the mechanism think about what is needed.
• On one molecule the beta carbon must have nucleophilic capabilities to supply an electron pair.
• On the second molecule the carbonyl group must function as an electrophile.
• One or the other molecules must be sufficiently reactive.
19-7

Mechanism : the Aldol Reaction: Acid catalysis
 Acid-catalyzed aldol reaction (good electrophile)
• Step 1: Acid-catalyzed equilibration of keto and enol forms.
O OH Nucleophilic
HA
CH
3
- C-H CH
2
= C- H carbon
• Step 2: Proton transfer from HA to the carbonyl group of a second molecule of aldehyde or ketone.
H
O O
CH
3
-C-H + H A CH
3
-C-H + A
Reactive carbonyl
19-8

Mechanism: the Aldol Reaction: Acid catalysis
• Step 3: Attack of the enol of one molecule on the protonated carbonyl group of the other molecule.
• Step 4: Proton transfer to A completes the reaction.
O
H
O
H
CH
3
-C-H + CH
2
=C-H + :A
-
OH O
CH
3
-CH-CH
2
-C-H
(racemic)
+ H-A
This may look a bit strange but compare to
19-9

The Aldol Products: Dehydration to alkene
• Aldol products are very easily dehydrated to a
,

unsaturated aldehydes or ketones.
OH O
CH
3
CHCH
2
CH warm in either acid or base
CH
3
 a
O
CH= CH CH + H
An a 
-unsaturated
2 aldehyde
O
• Aldol reactions are reversible and often little aldol is present at equilibrium.
• K eq for dehydration is generally large.
• If reaction conditions bring about dehydration, good yields of product can be obtained.
19-10

 In a crossed aldol reaction, one kind of molecule provides the enolate anion and another kind provides the carbonyl group.
O
CH
3
CCH
3 acid
+
O
HCH
NaOH
O
CH
3
CCH
2
CH
2
OH
4-Hyd roxy-2-b utanone
Nonacidic, no alpha hydrogens
19-11

 Crossed aldol reactions are most successful if
• one of the reactants has no a
-hydrogen and, therefore,
• cannot form an enolate anion ,
O
CHO
HCH
O
CHO
CHO
Formald ehyde Benzaldehyde Furfural 2,2-D imethylprop anal
• One reactant has a more acidic hydrogen than the other (next slide)
• One reactant is an aldehyde which has a more reactive carbonyl group.
19-12

Crossed Aldol Reactions, Nitro activation
 Nitro groups can be introduced by way of an aldol reaction using a nitroalkane.
HO +
O
H-CH
2
-N
O
N itromethane p K a
10.2
(stronger acid)
H-O-H +
Water p K a
15.7
(w eaker acid)
CH
2
-N
O
O
O
CH
2
=N
O
Resonance-stabilized an ion
• Nitro groups can be reduced to 1 ° amines.
O
Cyclohexan on e
+ CH
3
NO
2
N itrometh ane
NaOH
( aldol)
HO CH
2
NO
2
H
2
, Ni
HO CH
2
NH
2
1-(N itromethyl)cyclohexanol
1-(A min omethyl)-
cycloh exanol
19-13

• Intramolecular aldol reactions are most successful for formation of five- and six-membered rings.
• Consider 2,7-octadione, which has two a
-carbons .
a

O a

O O
KOH
-H
2
O a
O
2,7-Octanedione
O a


KOH
HO
O
O
(formed)
O
OH
-H
2
O
(n ot formed)
19-14

Synthesis : Retrosyntheic Analysis
Two Patterns to look for
19-15

Synthesis : Retrosyntheic Analysis
Recognition pattern
Analysis
19-16

Synthesis : Retrosyntheic Analysis
Example
Mixed aldol
Benzaldehyde
No alpha hydrogens
19-17

 Esters also form enolate anions which participate in nucleophilic acyl substitution .
O
2 CH
3
COEt
Ethyl ethan oate
(Ethyl acetate)
1 . EtO
-
Na
+
2 . H
2
O, HCl
O O
CH
3
CCH
2
COEt
Eth yl 3-oxobutanoate
(Ethyl acetoacetate)
+ EtOH
Ethanol
• The product of a Claisen condensation is a

ketoester.
C
O
C
 a
O
C C OR
Recognition
Element
A

-ketoest er
19-18

• Claisen condensation of ethyl propanoate
O
OEt
Ethyl propan oate
+
O
OEt
Ethyl propan oate
1 . Et O
-
Na
+
2 . H
2
O, HCl
O O
OEt
Eth yl 2-methyl-3oxopen tan oate
(racemic)
+ EtOH
Here the enolate part of one ester molecule has replaced the alkoxy group of the other ester molecule.
19-19

:
Step 1: Formation of an enolate anion.
Et O
-
+
O
H CH
2
-COEt p K a
= 22
(w eaker acid)
EtOH p K a
15.9
(stronger acid )
+
O
-
-
O
CH
2
-COEt CH
2
=COEt
Res on ance-s tab ilized enolate anion
Step 2: Attack of the enolate anion on a carbonyl carbon gives a TCAI.
O
CH
3
-C-OEt +
O
CH
2
-COEt
O
-
O
CH
3
-C-CH
2
OEt
-C-OEt
A tetrahedral carbonyl add ition in termediate
19-20

Step 3: Collapse of the TCAI gives a

-ketoester and an alkoxide ion.
O O
CH
3
-C-CH
2
-C-OEt
OEt
O O
CH
3
-C-CH
2
-C-OEt + Et O
Step 4: An acid-base reaction drives the reaction to completion. This consumption of base must be anticipated.
O O O O
Et O + CH
3
-C-CH-C-OEt + Et OH CH
3
-C-CH-C-OEt
H p K a
10.7
(stron ger acid) p K a
15.9
(w eaker acid)
19-21

Intramolecular Claisen condensation: Dieckman Condensation
O
Et O
O
Diethyl hexanedioate
(Diethyl adipate)
OEt
1 . Et O
-
Na
+
2 . H
2
O, HCl
O
O
OEt + Et OH
Acidic
Ethyl 2-oxocyclopentanecarboxylate
19-22

 Crossed Claisen condensations between two different esters, each with a
-hydrogens, give
 mixtures of products and are usually not useful .
But if one ester has no a
-hydrogens crossed
Claisen is useful.
O O
HCOEt EtOCOEt
Eth yl formate
D ieth yl carbonate
O O
EtOC-COEt
D iethyl ethaned ioate
(D iethyl oxalate)
No a
-hydrogens
O
COEt
Ethyl ben zoate
19-23

• The ester with no a
-hydrogens is generally used in excess.
O O
O O
Ph OCH
3
+
OCH
3
1 . CH
3
O
-
Na
+
2 . H
2
O, HCl
Ph OCH
3
Meth yl benzoate
Meth yl p ropan oate
Methyl 2-meth yl-3-oxo-
3-ph enylprop anoate
(racemic)
Used in excess
19-24

Synthesis:
 Claisen condensations are a route to ketones via decarboxylation
Reactions 1 & 2: Claisen condens ation followed by acidification.
O O O
1 . Et O
-
Na
+
OEt
2 . H
2
O, HCl
OEt + Et OH
Reactions 3 & 4: Saponification and acidification
O O
3 . Na OH, H
2
OEt
4 . H
2
O, HCl
O, he a t
O O
OH
+ Et OH
Reaction 5: Thermal decarboxylation.
O O
OH
5 . he at
O
+ CO
2
19-25

Synthesis:
The result of Claisen condensation, saponification, acidification, and decarboxylation is a ketone.
O
R-CH
2
-C
OR'
+
O
CH
2
-C-OR'
R from the ester furnish ing the carbonyl group s everal steps
O from the ester furnish ing the enolate anion
R-CH
2
-CCH
2
-R + 2 HOR' + CO
2
Note that in this Claisen (not crossed) the ketone is symmetric . Crossed Claisen can yield non symmetric ketones.
19-26

Synthesis:
Site of substitution, electrophile
Site of acidic hydrogen, nucleophile
New bond
19-27

Recall primary amines react with carbonyl compounds to give Schiff bases (imines), RN=CR
2
.
Primary amine
But secondary amines react to give enamines
Secondary
Amine
19-28

 Again, 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.
O
N
H
Pyrrolidine
N
H
Morpholine
19-29

• Examples:
O
+
H
+
N
H
N
OH
H
+
-H
2
O
N
An enamine
O
+
O
N
H
H
+
O
N
OH
H
+
-H
2
O
O
N
An en amin e
19-30

a
 The value of enamines is that the

-carbon is nucleophilic.
• Enamines undergo S
N
2 reactions with methyl and
1 ° haloalkanes, a
-haloketones, and a
-haloesters.
• Treatment of the enamine with one equivalent of an alkylating agent gives an iminium halide.
O O
••
N N Br
S
N
2
+ Br
The morph olin e en amin e of cyclohexan on e
3-Bromopropene
(Allyl bromide)
An iminiu m bromid e
(racemic)
19-31

Compare mechanisms of acid catalyzed aldol and enamine
O
H
O
••
N
O
H
CH
3
-C-H + CH
2
=C-H
+
+ :A
-
OH O
CH
3
-CH-CH
2
-C-H
(racemic)
+ H-A
O
N Br
Br
S
N
2
The morph olin e en amin e of cyclohexan on e
3-Bromopropene
(Allyl bromide)
An iminiu m bromid e
(racemic)
19-32

• Hydrolysis of the iminium halide gives an alkylated aldehyde or ketone.
O
O
O
+
N Br
-
HCl/ H
2
O
2-Allylcyclohexanone
+
+
N
H H
Cl
-
Morpholinium
chloride
Overall process is to render the alpha carbonss of ketone nucleophilic enough so that substitution reactions can occur.
19-33

a
• Enamines undergo acylation when treated with acid chlorides and acid anhydrides.
N
+
O
CH
3
CCl
Acetyl ch loride
Could this be made via a crossed Claisen followed by decarboxylation.
Cl
-
+
N
O
A n iminium chlorid e
(racemic)
HCl
H
2
O
O O
2-Acetylcyclohexan on e
(racemic)
+
+
N
H H
Cl
-
19-34

 The acetoacetic ester (AAE) synthesis is useful for the preparation of mono- and disubstituted acetones of the following types:
O
O O
RX
CH
3
CC H
2
R A mon os ubs tituted acetone
CH
3
CC H
2
COEt
O
Ethyl acetoacetate
(Acetoacetic ester)
CH
3
CC HR
A dis ubs tituted acetone
R'
Main points
1. Acidic hydrogen providing a nucleophilic center.
2. Carboxyl to be removed thermally
3. Derived from a halide
19-35

 The strategy of a malonic ester (ME) synthesis is identical to that of an acetoacetic ester synthesis, except that the starting material is a

diester rather than a

-ketoester.
O
R CH
2
COH A mon os ubs tituted acetic acid
O O
EtOC CH
2
COEt
D iethyl malonate
(Malonic ester)
RX
R O
R CHCOH A dis ubs tituted acetic acid
Main points
1. Acidic hydrogen providing a nucleophilic center
2. Carboxyl group removed by decarboxylation
3. Introduced from alkyl halide
19-36

 Consider the synthesis of this target molecule:
O
These tw o carbons are from diethyl malon ate
MeO OH
5-Methoxyp entanoic acid
Recognize as substituted acetic acid.
Malonic Ester Synthesis
19-37

1. Treat malonic ester with an alkali metal alkoxide.
Na
+
COOEt COOEt
+ EtO
-
Na
+ +
COOEt COOEt
EtOH
D ieth yl malon ate p K a
13.3
(s tronger acid)
Sodiu m ethoxide
Sodiu m s alt of dieth yl malonate
Eth anol p K a
15.9
(w eaker acid)
MeO
2. Alkylate with an alkyl halide.
Br +
Na
+
COOEt S
N
2
MeO
COOEt
COOEt
+ Na
+
Br
-
COOEt
19-38

3. Saponify and acidify.
MeO
COOEt
COOEt
3 . NaOH, H
2
O
4 . HCl, H
2
O
MeO
4. Decarboxylation.
MeO
COOH
+ 2 EtOH
COOH
COOH
COOH heat
COOH
MeO
5-Methoxypentan oic acid
+ CO
2
19-39

Michael Reaction, addition to a
,

-unsaturated carbonyl
 Michael reaction: the nucleophilic addition of an enolate anion to an a
,

-unsaturated carbonyl compound.
• Example:
O O
EtOOC
COOEt
Dieth yl prop anedioate
(D iethyl malonate)
+
3-Buten-2-one
(Methyl vinyl k eton e)
Et O
-
Na
+
EtOH
EtOOC
COOEt
Recognition Pattern:
Nucleophile – C – C – CO (nitrile or nitro)
19-40

These Types of a
-Unsaturated
Compounds are Nucleophile
Acceptors in Michael Reactions
O
CH
2
= CHCH
O
CH
2
= CHCCH
3
O
CH
2
= CHCOEt
O
CH
2
= CHCNR
2
CH
2
= CHC N
CH
2
= CHN O
2
Aldehyde
Ketone
Ester
Amide
Nitrile
Nitro compound
These Types of Compounds
Provide Effective Nucleophiles for Michael Reactions
O O
CH
3
CCH
2
CCH
3
O O
CH
3
CCH
2
COEt
O
CH
3
CCH
2
CN
O O
Et OCCH
2
COEt




-Diketone
-Ketoester
-Ketonitrile
-Diester
Enamine
N
CH
3
C= CH
2
N H
3
, RNH
2
, R
2
NH Amine
19-41

Example:
O
COOEt
Eth yl 3-oxobutanoate
(Ethyl acetoacetate)
+
O
EtO
-
Na
+
EtOH
2-Cyclohexen on e
O
O
COOEt
• The double bond of an a
,

-unsaturated carbonyl compound is activated for attack by nucleophile.
O O
+
+
O
More positive carbon
19-42

 Mechanism
1: Set up of nucleophile; Proton transfer to the base.
N u-H + :B
-
Base
N u:
-
+ H- B
2: Addition of Nu: to the
 carbon of the a
,

-unsaturated carbonyl compound.
Nu +
O
C C C Nu C C
O
C Nu C C
O
C
Resonance-stabilized enolate anion
19-43

Step 3: Proton transfer to HB gives an enol.
Nu C C
O
C + H-B Nu
1
4 3 2
C C
O-H
C +
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
19-44

• Resonance-stabilized enolate anions and enamines are weak bases, react slowly with a
,

-unsaturated carbonyl compounds, and give 1,4-addition products.
• Organolithium and Grignard reagents, on the other hand, are strong bases, add rapidly to carbonyl groups, and given primarily 1,2addition.
O Ph O
-
Li
+
PhLi
Phenyllithiu m
+
4-Methyl-3pen ten-2-one
Ph OH
H
2
O
HCl
4-Methyl-2-phen yl-
3-penten -2-ol
19-45

fast
-
Nu: +
O
C C C
C C
O
-
C
Nu
OH
ROH
C C C
Nu
+
1,2-Add ition
(les s stab le prod uct)
RO
s low
Nu C C
O
-
C
ROH
Nu C
H
C
O
C + RO
-
1,4-Add ition
(more stable p rodu ct)
Addition of the nucleophile is irrevesible for strongly basic carbon nucleophiles (kinetic product)
19-46

a  unsaturated
Carbanion site
O
COOEt
Ethyl 2-oxocyclohex-
anecarboxylate
+
O
3-Buten-2-one
(Methyl vinyl ketone)
1 . Na OEt , Et OH
(Michael reaction)
O
COOEt
O
2 . Na OEt , Et OH
(Aldol reaction)
Dieckman
COOEt
O
19-47

thes e three carbons from acetoacetic ester
O O this carb on los t by this b on d formed in a Mich ael reaction
O O
O
O
COOEt
Eth yl acetoacetate
+
Meth yl vinyl
k eton e decarboxylation
COOH
Recognize as substituted acetone, aae synthesis
Recognize as Nucleophile – C – C – CO
Michael
19-48

• Enamines also participate in Michael reactions.
N 1 . CH
2
=CHCN
2 . H
2
O, HCl
Pyrrolidin e enamine of cycloh exanone
O
(racemic)
CN
+ +
N
H H
Cl
-
19-49

 Gilman reagents undergo conjugate addition to a
,

-unsaturated aldehydes and ketones in a reaction closely related to the Michael reaction.
O
O
CH
3
3-Methyl-2cyclohexenone
1 . ( CH
3
)
2
CuLi, eth er, -78°C
2 . H
2
O, HCl
CH
3
CH
3
3,3-D imethylcyclohexanone
• Gilman reagents are unique among organometallic compounds in that they give almost exclusively 1,4addition.
• Other organometallic compounds, including Grignard reagents, add to the carbonyl carbon by 1,2-addition.
19-50

 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 butyl lithium.
[ ( CH
3
)
2
CH]
2
N
-
Li
+
[ ( CH
3
)
2
CH]
2
N H + CH
3
( CH
2
)
3
Li
Diisopropylamine
(pK a
40
(stronger acid)
Butyllithium
(stronger base)
Lithium diisopropylamde
(weaker bas e)
+ CH
3
( CH
2
)
2
CH
3
Butane pK a
50
(weaker acid)
LDA
19-51

 The crossed aldol reaction between acetone and an aldehyde can be carried out successfully by adding acetone to one equivalent of LDA to completely preform its enolate anion, which is then treated with the aldehyde.
O
LDA
O
-
Li
+
O
1.
C
6
H
5
CH
2
CH
C
6
H
5
Acetone
-78°C
Lithium enolate
2. H
2
O
OH O
4-Hydroxy-5-phenyl-2-pentanone
(racemic)
19-52

Crossed aldol
Michael
Alkylation
Acylation
19-53

Question: For ketones with nonequivalent a
hydrogens , can we selectively utilize the nonequivalent sites?
Answer: A high degree of regioselectivity exists and it depends on experimental conditions.
19-54

• 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 [ ( CH
3
)
2
CH]
2
N H
+ LDA +
+
(racemic)
99% 1%
• When 2-methylcyclohexanone is treated with LDA where the ketone is in slight excess, the product is richer in the more substituted enolate.
O slight excess of the ketone
+ LDA
0°C
O
-
Li
+
+
O
-
Li
+
+ [ ( CH
3
)
2
CH]
2
N H
(racemic)
10%
19-55
90%

 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.
19-56

• 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 and an a
-hydrogen of an unreacted ketone. Thus, equilibrium is established between alternative enolate anions.
O
-
Li
+
O O O Li
+
H
CH
3
+
(racemic) Less stable enolate anion
(racemic)
More stable enolate anion
+
(racemic)
19-57

 Kinetic control : Experimental conditions under which the composition of the product mixture is determined by the relative rates of formation of each product. First formed dominates.
• In the case of enolate anion formation, kinetic control refers to the relative rate of removal of alternative a
-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.
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1. 1.01 mol LDA, kinetic control
1. 0.99 mol LDA, thermodynamic control
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