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• Carbonyl compounds are generally Nucleophilic
group into two classes based on (Lewis basic) O
the reaction they undergo.
• Aldehydes and ketones Electrophilic C
• Carboxylic acids and their (Lewis acid)
derivatives
• The C=O in aldehydes and ketones O
Electrophilic attack O
are bonded to H and C which are
not electronegative enough to C
C
stabilize the negative charge. Thus
they are can’t act as leaving Nucleophilic attack
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 O E
and are therefore good leaving O
groups in Substitution reactions. C
C
Reactions of Carbonyl Compounds
• Carbonyl compounds undergo four major type of reaction via
the following mechanisms:
alkoxide intermediate is C Nu H C
formed Nu
3
• Two types of hybridization sp2 sp
transformation occurs H2 O
• If a neutral nucleophile (Nu-
H) is used, water is Nu
eliminated, and product is an C
sp2 hydridized compound.
sp2
Nucleophilic Acyl Substitution Reaction
• This reaction occurs only
with carboxylic acid and O
its derivatives. O O
or Nu H H2O
• Attacks occurs at the C Nu C C Y
carbonyl carbon. R Nu R Nu
R Y Y
• New carbonyl compound sp2 sp2
sp3
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.
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 C
B E
C
C H
C enolate ion O
a B- , H + E
OH C
C
C
C E
An enol
Carbonyl Condensation Reaction
• Occurs mostly in
aldehydes. O
O O O O
OH CH3 C H
CH2 C H CH2=C H H2O CH3 C CH2 C H
• Two carbonyl H
compound react
together to give an Enolate ion
hydroxyl aldehyde
OH O
product.
CH3 C CH2C H OH
H
• Enolate ion is formed.
• Commonly known as
aldol reaction.
• The base catalyzed carbon-carbon bond formation is
closely related to the carbon-carbon bond formation from
organometallic reagents.
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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
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• 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
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• The geometry (( Z )- or ( E )) of the enolate depends on
• The reaction conditions
• The nature of the substituents
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 chair-
shaped 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
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• 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
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• 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
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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
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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).
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The Perkin Reaction
• This process consists of the condensation of an acid
anhydride with an aromatic aldehyde using carboxylate
ion
• Mechanism
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The Stobbe Condensation
• The Stobbe condensation leads to attachment of three
carbon chain to a ketonic carbon atom
• Mechanism
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The Darzen Reaction
• The base-catalyzed condensation between an a -halo
ester and an aldehyde or ketone affords glycidic ester
• Mechanism
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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 O COC2H5
CHO (C2H5)2NH
CH3CCH2COC2H5 CH=C
C2H5OH CCH3
O
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• Mechanism
OH O O O
C2H5O COC2H5 OH
CH3CCHCOC2H5 CH CH COC2H5
CCH3 + CHCH
H CCH3
O
O
O
H2O COC2H5
CH=CH
CCH3
O
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Practise questions
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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 O O
aOC2H5
CH3COC2H5 CH3CCH2COC2H5
2) H
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• Mechanism
H O O
O OC2H5
CH2COC2H5 CH2=COC2H5
CH2COC2H5
O
O O
O O O
CH2COC2H5
CH3COC2H5 CH3-CCH2COC2H5
CH3-C -CH2COC2H5
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.
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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
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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.
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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.
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Alkylation of Monofunctional Compounds
• Depends on the reaction conditions (kinetic vs thermodynamic
control), enolate can be selectively alkylated
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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.
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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
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• 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
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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
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• Mechanism for Stephen Aldehyde Synthesis (Stephen
Reduction)
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Biological Carbonyl Condensation
Biological Aldol Reactions
• Aldol reactions are particularly important in
carbohydrate metabolism
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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
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Mixed Claisen condensations occur frequently in living
organisms
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