Transcript Slide 1

Addition and Condensation reactions
of
Enol and Enolate Ions
•Properties of enol and enolate ions
•Tautomerization (acid/base)
•alpha substitution reactions
halogenation, alkylation, condensation
•Conjugate addition reactions
•Dieckman cyclization
•Robinson annulation
Properties of enols and enolates
The presence of a carbonyl dramatically increases the acidity
of the protons on the  carbon. The pKa of the  protons in
aldehydes and ketones is about 20. In the presence of
hydroxide or alkoxide only very small amount of the enolate is
formed. (what are the pka’s of water and alcohols)
O H
base
C C
O
O
C C
C C
enolate ion
alpha carbon
Properties of enols and enolates
Reportonation of the enolate ion can occur on the oxygen atom
to give the enol or on the -carbon to give the starting
carbonyl compound (keto).
O H
C
C
keto
+
H
O
C
+
H
O
C
C
enolate ion
C
OH
C
C
enol
There is an equilibium between the keto form and the enol form.
Keto-Enol Tautomerism
Carbonyl compounds with alpha hydrogen can exist in two different
forms. Conversion from one form to the other involves the shift of
a proton and a double bond. This type of isomerization is called
tautomerism. DO NOT confuse tautomerism with resonance
structures (resonance structures are different representations of
the same compound. The individual isomers are called tautomers.
Tautomers are different compounds.
OH
O
H
H
H
keto 99.99%
O
H CH3
?
enol 0.01%
Keto- enol Tautomerism

The interconversion between the keto-enol tautomers can be
either base or acid catalyzed.
Base-catalyzed tautomerism
O H
+
C C
OH-
O
O
OH
C C
C C
C C
Keto
enol
enolate
Acid-catalyzed tautomerism
H
O H
C
C
+
H3O
+
H
O H
O H
C
C
C
Keto
protonated carbonyl
C
H2O
OH
C
C
enol
Properties of enols and enolates
Though the concentration of the enolate is very small, it can
be used as a nucleophile. As the enolate reacts with an
electrophile the equilibrium for the formation of the enolate
shifts to the right. Ultimately, this results in the starting
carbonyl compound being consumed by the reaction.
enolate ion
O H
C C
base
O
O
C C
C C
Br
O
Br
Br
C C
+ Br -
Examples of alpha substitution on an enolate ion
O
O
C
C
C O
C
+
C O
RO
ester
C
C OH
addition product
O
O
enolate
C
ketone / aldehyde
enolate
C C
C
C O
+
O
ROH
O
C C C O
C
C C O
OR
addition product
+ RO-
Properties of enols and enolates
The equilibrium mixture of the enolate and base (hydroide and
alkoxide) are sometimes not useful because of side reactions
between the base and the electrophile. In these cases a stronger
base is used to completely convert the carbonyl compound to the
enolate.
OH- +
E+
E-OH
Properties of enols and enolates
One of the most effective bases for converting a carbonyl
compound to the enolate is lithium diisopropylamide (LDA). LDA
is prepared by treating diisopropylamine with n-butyllithium.
Note the LDA is a hindered molecule that would be a poor
nucleophile.
N H
+
CH3CH2CH2CH2Li
N
LDA
Li+
+ CH3CH2CH2CH3
Properties of enols and enolates
Treatment of cyclohexanone with LDA results in 100%
conversion to the enolate.
O
O
+ LDA
Li
+
(i-C3H7)2NH
pKa = 36
pKa = 19
Alpha halogenation reaction
The alpha halogenation of a carbonyl compound can be done under either
basic or acidic conditions.
Under basic conditions the reaction is called base promoted because an
equivalent of base is consumed during the reaction.
enolate ion
O H
C
C
OH -
O
O
C
C
C
X
X
O X
C
C
+ X-
C
Alpha halogenation reaction
Multiple halogenation is common with base promoted halogenation. As a
result it is not used to prepare monohalo ketones.
O H
OH -
C C
O
O
C C
C C
Br
Br
Br
the enolate ion is stabilized by the addition of the halogen
O
Br
C C
Br
Br
O
Br
C C
+
-
Br
Br
The second halogen addition is much faster than the first because of
the increased stability of the enolate formed from the alphahaloketone.
Alpha halogenation reaction
When there is an excess of halogen and base, the base promoted
halogenation generally continues until the alpha carbon is completely
halogenated. In the case of a methyl ketone, a trihalomethyl ketone is
obtained.
O
O
3 X2
R C CH3
3 OH
-
R C CX3
Trihalomethyl ketone
Alpha halogenation reaction (haloform reaction)
In the case of a methyl ketone, a trihalomethyl ketone is obtained.
Under basic conditions the trihalomethyl group serves a leaving group,
when the carbonyl carbon under goes nucleophlic attack . If the
nucleophile is hydroxide the product is a carboxlate ion.
O
R C
O
CX3
OH -
R C
O
CX3
+
R C O H
CX3-
OH
O
R C O
When iodine is use in the reaction it is referred
to as the iodoform test. Which gives a yellow
precipitate with methyl ketones.
-
carboxylate
+
HCX3
haloform
Alpha halogenation reaction
In contrast to the base promoted reaction the acid-catalyzed alpha
halogenation allows for replacement of a single alpha hydrogen. The enol
serve as the nucleophile.
O
H
C C
H
+
H3O
+
O
H
H O
C C
H
H2O
HO
C C
C C
Keto
enol
protonated carbonyl
H O
X X
C C
H
O
X
H O
C C
X
C C
X-
O
X
C C
enol
carbocation intermediate
The carbonium ion intermediate is not stabilized by the halogen.
Note that aldehydes can not be halogenated because they are easily
oxidized to carboxylic acids by the halogen.
+ HX
Alpha halogenation reaction
What would be the product from acid-catalyzed bromination of:
2-methylcyclohexanone
methylisopropyl ketone
Alpha bromination of carboxylic acids
Alpha bromination of a carboxylic acid is accomplished by the HellVolhard-Zelinsky (HVZ) reaction. The reaction involves treatment of the
acid with a combination of bromine and phosphorous tribromide, followed
hydrolysis of the intermediate acyl bromide.
• The initial step of the reaction is the formation of the acyl
bromide.
• The acyl bromide is then brominated in the alpha position via a
mechanism similar to the acid-catalyzed alpha halogenation of a
ketone.
• The intermediate alpha bromo acyl bromide can be isolated and
used to prepare other acid derivatives (ie esters) or hydrolyzed to
the alpha bromoacid.
Alpha bromination of carboxylic acids
H O
H O
Br2 / PBr3
R C C OH
R C C
H
C C
Br
O H
C C
H
Br Br
Br
enol
Br
H
Br
O H
+
R C C
Br
Br
H
H
acyl bromide
keto
R
OH
R
-
Br
O
+ HBr
R C C
Br
H
enol
H2O
Br
O
R C C
H
OH
Alpha alkylation of enolate ions
As we have seen the enolate ion is a nucleophile. The enolate ion
can be used as a nucleophile in many of the nucleophilic
substitution reactions that we have studied. The substrate
should be an unhindered halide or tosylate.
• enolate ions have two nucleophilic sites:
oxygen and the alpha carbon
Alpha alkylation of enolate ions
Alkylation reactions of enolate ions usually use very strong nonnucleophilic bases like LDA.
Bases such as hydroxide and alkoxide are not used because of
issues with competing side reactions.
If more than one type of alpha hydrogen is present multiply
products are possible.
Alpha alkylation of enolate ions
Predict the products / reactants from the following reactions.
O
1) LDA
2) CH3 Br
O
1) LDA
2)
O
Ph
C6H5CH2Br
O
CH3
CH3
CH3CH2CH2CH2
Ph
CH3
CH3
Alpha alkylation via the Stork Reaction
The Stork reaction allows for the alpha alkylation reaction to be done
under mild reaction conditions.
The initial step of the reaction is the conversion of the carbonyl
compound to the enamine.
The enamine will then serve as the nucleophile in the alkylation or
acylation reaction.
N
N
C
C
major
C
C
minor
Alpha alkylation via the Stork Reaction
Enamines are formed by the acid catalyzed condensation reaction
between a secondary amine and either an aldehyde or a ketone. (Do not
confuse enamines with imines, which are form from primary amines.)
.
Alpha alkylation via the Stork Reaction
Draw the enamines formed the following reactions
O
O
+
N
H
H
O
N
+
acetaldehyde
+
N
H
Alpha alkylation via the Stork Reaction
Mechanistically the alkylation and acylation reaction of an enamine are
the same, with the enamine serving as the nucleophile. The stock
reaction works best with very reactive halides and acid chlorides. Note
that the stork reaction gives mono substitution products.
Alpha alkylation via the Stork Reaction
Predict the products from the following reactions.
O
+
1) pyrrolidine / H
2) C6H5CH2Br
+
3) H / H2O
O
O
O
O
O
OH
O
O
O
O
O
Aldol condensation reactions
of aldehydes and ketones
The aldol condensation involves the nucleophilic attack of an enolate ion
on a second carbonyl group. The initial product of this reaction is a βhydroxy ketone or aldehyde. The initially formed β-hydroxy carbonyl
compound can then undergoes dehydration to give the α, β -unsaturated
carbonyl compound.
Draw the mechanism for the base catalyzed formation of the aldol
product of acetaldehyde. Page 1058
Aldol condensation reactions
of aldehydes and ketones
The first step of the aldol condensation is an equilibrium process.
Aldehydes generally produce more of the aldol product at equilibrium
than ketones.
ie. Acetaldehyde produces ~50% aldol product at equilibrium,
while acetone produces only about 1% of the aldol product.
Good conversion of ketones to
the aldol product can be
accomplished using unique
experimental techniques.
Page 1058
Aldol condensation reactions
of aldehydes and ketones
The aldol condensation will also occur under acidic conditions. Under acidic
conditions the nucleophile is the enol and the electrophile is a protonated
carbonyl.
Draw the acid catalyzed mechanism for the condensation of acetaldehyde.
Page 1059
Aldol condensation reactions
of aldehydes and ketones
The dehydration of the aldol product can be carried out under either acid or
basic conditions. Mechanistically the acid dehydration is the same as the
acid dehydration of any other alcohol. The base catalyzed dehydration
involves removal of the second alpha hydrogen followed by loss of hydroxide
as a leaving group.
OH
H H C H
C C H
O
H
aldol
OH
-
OH
H H C H
C C
O
H
H
H
C
H
C
O
C
H
α, β -unsaturated carbonyl
enolate
Crossed Aldol Condensation
The crossed aldol reaction generally involves reacting an aldehyde or ketone
that can form an enolate ion with a second carbonyl compound that can not
form an enolate.
For example consider what would result from the reaction of acetaldehyde
with propanal.
Draw the aldol condensation product for acetaldehyde and benzaldehyde.
Internal aldol condensations
(cyclization)
When there are two carbonyl groups present in a molecule the aldol
condensation can be used to form 5 and 6 member ring structures. The
starting materials for these reactions are generally 1,4-dicarbonyl
compounds or 1,5-dicarbonyl compounds.
Internal aldol condensations
(cyclization)
Examples:
OH O
O
O
OH -
O
Internal aldol condensations
(cyclization)
How were these materials formed via aldol condensation?
O
OH
O
O
Claisen condensation: synthesis
of beta keto esters
The first step of the Claisen condensation is similar to the aldol condensation.
A strong base, usually an alkoxide abstracts an alpha hydrogen generating an
enolate ion. The resulting enolate ion will then serve as a nucleophile, attacking
a second ester molecule.
O
CH3CH2O
H
C C H
H
OCH2CH3
O
CH3CH2O
C C H
H
The alpha hydrogens pka of an ester are not as acidic as those of
aldehydes and ketones, but the ion is resonance stabilized in a similar
way.
Claisen condensation: synthesis
of beta keto esters
The second step of the reaction is the nucleophilic attack of the enolate on a
second ester molecule. Followed by loss of an alkoxide ion. This reaction is
considered to be a base promoted reaction because the base is consumed in
the reaction. The base is actually consumed in a reaction to form the keto
ester enolate.
Claisen condensation: synthesis
of beta keto esters
Predict the products from the following reactions.
O
CH3
O
1) OCH3
2) H+
OCH2CH3
1) NaOC2H5
2) H+
O
O
1) NaOC2H5
OCH2CH3
2) H+
Dieckman condensation
The Dieckman condensation is simply an internal Claisen condensation that
occurs in molecules that contain two ester functional groups.
Heating the beta keto ester in acidic condition results in hydrolysis of the
ester followed by decarboxylation.
Dieckman condensation
Predict the products:
O
OCH3
1) OCH3
+
2) H
O
OCH3
O
O
CH3O
OCH3
O
1) OCH3
2) H+
Crossed Claisen condensation
The crossed Claisen involves reacting the enolate (nucleophile) formed from
an ester that has alpha hydrogens with an ester that does not have alpha
hydrogens (the electrophile). Crossed Claisen condensations can also be
carried out with ketones and esters.
Some useful ester that do not have alpha hydrogens are benzoates,
formates, carbonates and oxalates. Page 1071
Crossed Claisen condensation
Examples:
Crossed Claisen condensation
Predict the products:
O
1) NaOCH2CH3
CH2C OCH2CH3
+
diethylcarbonate
+
2) H
O
Ester + ketone/aldehyde
O
CH3
C CH3
O
+
CH3
C OCH3
O
H
1) OCH3
+
2) H
O
O
H C CH C OCH3
Beta-dicarbonyl compounds
The alpha hydrogens in beta-dicarbonyl compounds are much more acidic then
the alpha hydrogens in aldehydes, ketones and esters.
Malonic ester and acetoacetic ester synthesis
Reactions involving beta-dicarbonyl compounds fall into one of two
categories. The first is the Malonic ester synthesis and the second is the
acetoacetic ester synthesis.
Malonic ester and acetoacetic ester synthesis
The malonic ester synthesis is used to prepare substituted acetic acid
derivatives as shown below.
Malonic ester and acetoacetic ester synthesis
The reaction of acetoacetic esters is very similar to the malonic ester
synthesis, however the product that is obtained after decarboxylation is a
methyl ketone.
See page 1081 for example problems.
Michael addition reaction (conjugate addition).
The beta carbon of an alpha beta-unsaturation carbonyl compound has a
partial positive charge and is subject to attack by a nucleophile.
The addition reaction can occur either to two way. The first is
called 1,2-addition and the second is called 1,4 addition.
Michael addition reaction (conjugate addition).
H
C C
H
C
OH
O
O
Nuc:
+
C Nuc
C C
CH3
H
H
CH3
H
H
H
H
C C
H
C Nuc
CH3
H
1,2-addition
O
H
C C
H
C
H
Nuc:
CH3
O
H
Nuc
C C
H
H
C
H
CH3
OH
H
+
Nuc
C C
C
H
H
Nuc
CH3
C C
H
enol
1,4-addition
O
H
tautomers
H
keto
C
H
CH3
Michael addition reaction (conjugate addition).
Michael addition reaction (conjugate addition).
Propose a synthesis for the following materials.
NC CH2 CH2 CH2 CO2H
O
CH3
O
CH2CH2 C
O
O
Ph
Robinson annulation
The Robinson annulation involves two steps the initial step is a Michael
addition of an enolate. This initial addition is followed by a rapid
intramolecular aldol type reaction to give a ring. The aldol reaction
normally occurs with dehydration.