Formation of C-C-bonds by
base catalysed condensation
• This reaction is a nucleophilic addition of enolates to a
carbonyl compounds
• These reactions are often called Aldo condensation or
Claisen condensation
• If the electrophile is a ketone or aldehyde then it is Aldol
condensation
• If the electrophile is an ester or a thioester then it is Claisen
condensation
• A quick review of nucleophilic reactions in carbonyl
compounds
2
• Carbonyl compounds are generally
group into two classes based on
the reaction they undergo.
• Aldehydes and ketones
• Carboxylic acids and their
derivatives
• The C=O in aldehydes and ketones
are bonded to H and C which are
not electronegative enough to
stabilize the negative charge. Thus
they are can’t act as leaving
groups in Nucleophilic substitution
reactions.
• The C=O in carboxylic acids and its
derivatives are bonded to O, Cl, N
etc can stabilize a negative charge
and are therefore good leaving
groups in Substitution reactions.
Nucleophilic
(Lewis basic)
Electrophilic
(Lewis acid)
O

O
C
Electrophilic attack O
C
C
Nucleophilic attack
O
C
E
O
C
Reactions of Carbonyl Compounds
• Carbonyl compounds undergo four major type of reaction via
the following mechanisms:
• Nucleophilic addition for aldehydes and ketones
only
• Nucleophilic acyl substitution for carboxylic acids
and its derivatives
• Alpha substitution in all carbonyl compounds
• Carbonyl condensation only mostly in aldehydes
and ketones
Nucleophilic Addition
• Only aldehyde and ketone
undergoes
nucleophilic
reaction.
• Attack occurs at the carbonyl
carbon.
• During the reaction an
alkoxide intermediate is
formed
• Two types of hybridization
transformation occurs
• If a neutral nucleophile (NuH) is used, water is
eliminated, and product is an
sp2 hydridized compound.
O
O
C
C
Nu
Nu
2
3
sp
sp
OH
O
C
Nu H
C
Nu
sp2
3
sp
H2 O
Nu
C
sp2
Nucleophilic Acyl Substitution Reaction
• This reaction occurs only
with carboxylic acid and
its derivatives.
O
• Attacks occurs at the C
carbonyl carbon.
R Y
• New carbonyl compound sp2
is formed.
• Aldehydes and ketones
cannot
undergo
substitution
because
they do not have a good
leaving group bonded to
the newly formed sp3
hybridized carbon.
O
Nu
or Nu H
H2O
C
R
Y
sp3
Nu
O
C
R Nu
sp2
Y
Alpha Substitution Reaction
• A base abstract an a-hydrogen i.e. reaction occurs at a-carbon to
the carbonyl carbon.
• All groups of carbonyl compounds can undergo this reaction.
• An enolate ion or an enol is formed.
O
O
B
H
C
C
a
B- , H +
C
C
enolate ion
E
O
C
OH
C
C
An enol
E
E
C
Carbonyl Condensation Reaction
• Occurs
mostly
aldehydes.
in
O
O
• Two
carbonyl
compound
react
together to give an
hydroxyl
aldehyde
product.
CH2 C H
OH
O
CH2=C H H2O
CH3 C H
O
O
CH3 C CH2 C H
H
Enolate ion
OH
O
CH3 C CH2C H
• Enolate ion is formed.
• Commonly known as
aldol reaction.
H
OH
• The base catalyzed carbon-carbon bond formation is
closely related to the carbon-carbon bond formation from
organometallic reagents.
• It involves the negatively polarized carbon reacting with
electrophilic carbon of carbonyl groups and related
compounds.
• Base-catalyzed reactions depends on three facts:
(i) A wide range of organic compounds that are able to form
carbanions
(ii) These carbanions undergo reaction with electrophilic carbon
in a variety of environments
(iii) The basicity of the reagent used to abstract the proton may
be widely varied
9
Reactions of Enolates with Carbonyl
Compounds
 Aldol Condensation
• It consists of the reaction between two molecules of
aldehydes or ketones that may be same or different.
• One of the reactants is converted into a nucleophile by
forming its enolate in the presence of base and the second
acts as an electrophile
• If the base removes another an acid hydrogen as shown
above, two different reactions can occur
• Addition of another aldehyde or ketone
• Elimination of water to for a,b-unsaturated aldehyde
10
• If the reactants are not the same (Mixed aldol
condensation) the reaction can lead to the formation of
diastereoisomers and their distribution depends on the
reaction conditions and the nature of the substituents
11
• The geometry (( Z )- or ( E )) of the enolate depends on
• The reaction conditions
• The nature of the substituents
• Strong base (e.g. LDA), low temperature and short
reaction time lead to kinetic enolate , while weak base
(e.g. hydroxide ion), high temperature and longer reaction
time favour the formation of thermodynamic enolate
12
• For the thermodynamic control, the ( Z )- and ( E )-forms of the
enolates are in rapid equilibrium, and the product distribution is
determined by the relative stabilities of the six-membered chairshaped cyclic of the transition states that includes the metal
counter-ion (as shown below)
• The transition state that leads to the syn product has R in the less
stable axial position, whereas in that leading to anti product both R
and R' are in the more stable equatorial position. The latter is
therefore of lower energy, leading to a major anti product
13
• Under kinetic control, the ( Z ) and ( E ) enolates are
formed rapidly and irreversibly, and their relative amounts
determine the product distribution. For examples, for
ketone CH3CH3COt-Bu, the ( Z )-enolate is normally formed
to afford the syn diasteroisomer as a major product
• If R is reduced by isopropyl the selectivity fall to 4:1
(syn:anti). This is due to the difference in steric repulsion
of the methyl group with t-butyl and isopropyl groups
14
• To increase the degree of diastereoselectivity, the general
technique is to convert the enolate into silyl enol ethers
that can be separated by distillation.
• The separated silyl enol ethers can then be converted
into pure ( Z )- or ( E )-enoate by treatment with fluoride
ion
15
The Reformatsky Reaction
• The enolate generated from an a-bromo ester with zinc
reacts with an aldehyde or ketone to give an aldol-type
product in b-hydroxyl ether
16
 Mechanism
Zinc metal react at the carbon-halogen bond of the α-haloester by
oxidative addition (1). This compound dimerizes and rearranges to
form two zinc enolates (2). The oxygen on an aldehyde or ketone
coordinates to the zinc to form the six-member chair like transition
state (3). A rearrangement occurs in which zinc switches to the
aldehyde or ketone oxygen and a carbon-carbon bond is formed
(4). Acid workup (5), removal of zinc to yield zinc(II) salts (6)and a
β-hydroxy-ester (7).
17
The Perkin Reaction
• This process consists of the condensation of an acid
anhydride with an aromatic aldehyde using carboxylate
ion
• Mechanism
18
The Stobbe Condensation
• The Stobbe condensation leads to attachment of three
carbon chain to a ketonic carbon atom
• Mechanism
19
The Darzen Reaction
• The base-catalyzed condensation between an a -halo
ester and an aldehyde or ketone affords glycidic ester
• Mechanism
20
The Knoevenagel Reaction
• This is the condensation of methylene group bonded with
two electron withdrawing groups with aldehydes or
ketones using weak base
• The reaction is more useful with aromatic than with
aliphatic aldehydes
O
O
CHO
O
CH3CCH2COC2H5
(C2H5)2NH
C2H5OH
COC2H5
CH=C
CCH3
O
21
• Mechanism
OH
CH3CCHCOC2H5
C2H5O
CH
O
O
COC2H5
CH
CCH3
O
H
+
OH
O
COC2H5
CHCH
CCH3
O
O
H2O
COC2H5
CH=CH
CCH3
O
22
Practise questions
23
Reactions with Esters and Analogues
The Claisen Condensation
• This condensation is between esters.
• It is important to note that an equivalent amount of base
must be employed for this reaction.
O
CH3COC2H5
aOC2H5
2)
H
O
O
CH3CCH2COC2H5
24
• Mechanism
H
O
OC2H5
O
O
CH2=COC2H5
CH2COC2H5
CH2COC2H5
O
O
CH3COC2H5
CH2COC2H5
O
O
CH3-C -CH2COC2H5
O
O
CH3-CCH2COC2H5
OC2H5
Altnough the desired product is the ketone ester above, the presence of the alpha hydrogens makes the
ketoester subsecptive to further reaction in which abstraction of an alpha hydrogen can initate further
reaction to give varying product(s) depending on the amount of nuclophile present.
25
Dieckmann Condensation
• Condensation of the diesters of having C6 and C7 can
be accomplished to afford five and six membered
cyclic β -ketoesters.
• The diesters of short-chain do not show cyclization,
while diesters with C8 and C9 provide the cyclized
products in fewer yields .
• Mechanism
26
Enamines
• The reaction of secondary amine with aldehyde or ketone
that contains an a -hydrogen atom affords enamine.
• The process is driven to right by removing the water as it
is formed, either by azotropic distillation or with
molecular sieves.
• Similar to the enolates derived from ketones, enamines
react with acid chlorides to give imine derivative that
could be hydrolyzed to β -diketones
27
The Alkylation of Enolates
• Enolates, like other nucleophiles, also undergo reaction
with alkyl halides and sulfonates with the formation of
carbon-carbon bonds.
• Depending on the reaction conditions and nature of the
substrates, the reaction can occur either at oxygen atom
or carbon atom of enolate.
28
Alkylation of Monofunctional Compounds
• Depends on the reaction conditions (kinetic vs thermodynamic
control), enolate can be selectively alkylated
• Kinetic control with LDA : Proton abstraction takes place at less
hindered a -CH position and the reaction is faster and essentially
irreversible.
• Thermodynamic control with t-BuOK : equilibration takes place
between the two enolates and the methyl-substituted one, being
the more stable, is present in high concentration.
• However, when the highly substituted position is strongly sterically
hindered, alkylation with t-BuOK occurs at the less sterically
substituted carbon.
29
Alkylation of Bifunctional Compounds
• A C-H bond adjacent to two electron withdrawing
groups is more acidic than that adjacent to one electron
withdrawing group and the alkylation could be carried
out in milder conditions.
30
Addition of Enolates to Activated Alkenes
• Enolates undergo addition to alkenes that are activated by
conjugation to carbonyl, ester, nitro and nitril groups.
• These reactions are usually referred to as Michael addition
31
• Reactions Involving Alkynes
• Acetylene and its monosubstituted derivatives are more
acidic than alkenes and alkanes and take part in reactions
with both carbonyl-containing compounds and alkyl
halides in the presence of bas
32
Reactions of Cyanides with Alkyl Halides and Sulfonates
• HCN, like acetylene, is a weak acid whose anion may be generated by
base and is reactive towards primary and secondary alkyl halides and
sulfonates to give the corresponding nitriles.
• It is more convenient to introduce the cyanide as cyanide ion (e.g.
NaCN, TMSCN) rather than as HCN.
• These reactions provide a way of extending aliphatic carbon chains
by one carbon atom. It is often known as Stephen Aldehyde
synthesis or Stephen reduction
33
• Mechanism for Stephen Aldehyde Synthesis (Stephen
Reduction)
34
Biological Carbonyl Condensation
Biological Aldol Reactions
• Aldol reactions are particularly important in
carbohydrate metabolism
 Enzymes called aldolases catalyze addition of a
ketone enolate ion to an aldehyde
 Type I aldolases occur primarily in animals and
higher plants
 Operate through an enolate ion
 Type II aldolases occur primarily in fungi and
bacteria
35
Mechanism of Type I aldolase in glucose biosynthesis
• Dihydroxyacetone phosphate is first converted into an
enamine by reaction with the –NH2 group on a lysine
amino acid in the enzyme
• Enamine adds to glyceraldehyde 3-phosphate
• Resultant iminium ion is hydrolyzed
36
Mechanism of Type II aldolase in glucose biosynthesis
 Aldol reaction occurs directly
 Ketone carbonyl group of glyceraldehyde 3-phosphate
complexed to a Zn2+ ion to make it a better acceptor
37
Biological Claisen Condensations
• Claisen condensations occur in a large number of
biological pathways
 In fatty acid biosynthesis an enolate ion generated by
decarboxylation of malonyl ACP adds to the carbonyl group
of another acyl group bonded through a thioester linkage to
a synthase enzyme
 The tetrahedral intermediate expels the synthase, giving
acetoacetyl ACP
38
Mixed Claisen condensations occur frequently in living
organisms
 Butyryl synthase, in the fatty-acid biosynthesis pathway,
reacts with malonyl ACP in a mixed Claisen condensation
to give 3-ketohexanoyl ACP
39