CHAPTER-7
Reactions of Carbonyl Groups
Chapter Contents
Carbonyl addition-elimination reaction
Cyanohydrin reaction
Acetal and ketal reaction
Halogenation and alkylation reactions
Aldol condensation reaction
Claisen-Schmidts condensation reaction
Mannich condensation reaction
Claisen and Dieckmann condensation reaction
Perkin condensation reaction
Witting reaction
Reactivity of carbonyl compounds toward addition
• In addition reactions at carbonyl groups, the key step is the addition of a
nucleophile, which generates a tetracoordinate carbon atom
• The overall reaction is then determined by the fate of this tetrahedral intermediate.
• Addition occurs when the tetrahedral intermediate goes directly on to product.
• Condensation occurs if the carbonyl oxygen is eliminated and a double bond
is formed
• Substitution results when one of the groups is eliminated from the tetrahedral
intermediate to re-form a carbonyl group
There are three possible mechanisms for addition of a nucleophile
and a proton to give a tetrahedral intermediate in a carbonyl addition
reaction.
1) Protonation followed by nucleophilic attack on the protonated carbonyl group
2) Nucleophilic addition at the carbonyl group followed by protonation
3) Concerted proton transfer and nucleophilic attack
Hydration and addition of alcohols to aldehydes and ketones
Under acidic condition
Under basic condition
• The product of addition of one molecule of alcohol to an aldehyde or ketone is
referred to as a hemiacetal/hemiketal. Dehydration followed by addition of a
second molecule of alcohol gives an acetal
-Hemiacetal if alldehyde
-Hemiketal if ketone
Addition of hydrogen cyanide to ketone or aldehyde to form cyanohydrin
Addition-elimination reactions of aldehydes and Ketones with
nitrogen nucleophiles
• The mechanistic pattern of hydration and alcohol addition reactions of ketones
and aldehydes also works for reactions of carbonyl compounds with amines
and related nitrogen nucleophiles
Alkylation of enolates and other carbon nucleophiles
• Carbon-carbon bond formation is the basis for the construction of the
molecular
framework of organic molecules.
• Carbon-carbon bond formation is a reaction between a nucleophilic and an
electrophilic carbons.
• Carbon nucleophiles such as enolates, imine anions, and enamines, can react with
the carbon electrophiles like Carbon
alkylating agents via SN2 mechanism
electrophile
Carbon nucleophile
Imine anions analogues
Generation of enolates by deprotonation
A primary consideration in the generation of an enolate or other stabilized
carbanion by deprotonation is the choice of base
The base is hydroxide ion or primary alkoxide ions
The base is amide
Alkylation of highly stabilized enolates
Alkylation/halogenation of ketone enolates
These reactions also work
similarly for halogenation
using X2 (Cl2, Br2, I2) as
electrophiles
Alkylation of aldehyde enolate
Alkylation of aldehyde enolates is not very common. One reason is that
aldehydes are rapidly converted to aldol addition products by base
Alkylation of ester, carboxylic acid, amides and nitriles enolates
• Ester enolates are somewhat less stable than ketone enolates because of the
potential for elimination of alkoxide
• Carboxylic acids can be directly alkylated by conversion to dianions with two
equivalents of LDA. The dianions are alkylated at the σ-carbon, because the
enolate carbon is a more strongly nucleophilic than the carboxylate anion
• Nitriles can also be converted to anions and alkylated
Ester
carboxylic acid
Nitrile
Reactions of carbon nucleophiles with carbonyl compounds
• The reaction begins with the addition of a stabilized carbon nucleophile to a
carbonyl group. The aldol reaction, the Robinson annulation, the Claisen
condensation and other carbon acylation methods and the Wittig reaction and
other olefination methods are some of such reactions
• Conjugate addition is also another reaction which involves addition of
nucleophiles to α ,β -unsaturated carbonyl compounds and other electrophilic
double or triple bonds in the presence of electron-withdrawing group (EWG)
Aldol addition and condensation reactions
• This is addition of enolates and enols to acid- or base-catalyzed carbonyl
groups of ketone or aldehyde. The reaction product may undergo dehydration
leading to an α ,β -unsaturated aldehyde or ketone
General reaction
Steps Under basic condition
Under acidic condition
Examples of aldol addition and condensation reactions
2 Under basic condition
2 Under acidic condition
Claisen-Schmidt condensation
It is example of mixed aldol condensation which involves two different carbonyl
compounds. One of the most general mixed aldol condensations involves the use of
aromatic aldehydes (electrophiles) with alkyl ketones or aldehydes (nucleophiles)
Examples
Intramolecular cyclization of phthalaldehyde
Acid-catalyzed condensation at
the more substituted positon
The Mukaiyama aldol reaction
Refers to Lewis acid–catalyzed aldol addition reactions of silyl enol ethers,
silyl ketene acetals, and similar enolate equivalents. Silyl enol ethers are not
sufficiently nucleophilic to react directly with aldehydes or ketones. However,
Lewis acids (TiCl4 and SnCl4) cause reaction to occur by coordination at
the carbonyl oxygen, activating the carbonyl group to nucleophilic attack
LA- TiCl4 or SnCl4
Silyl enol ether
Intramolecular aldol reactions
The Robinson Annulation
It is important example of the intramolecular aldol reaction and conjugate
addition of the enolate to methyl vinyl ketone or a similar enone. This is
followed by cyclization by an intramolecular aldol addition. Dehydration usually
occurs to give a cyclohexenone derivative
Examples
DABCO = 1,4-
diazabicyclo [2.2.2]octane
or triethylenediamine
(TEDA)
Addition reactions of imines and iminium ions
Imines and iminium ions are nitrogen analogs of carbonyl compounds
and they undergo nucleophilic additions like those involved in aldol
reactions
Imine
Iminium ion
Addition of enols, enolates, or enolate equivalents to imines or iminium
ions provides an important route to β-amino ketones
imine
enol/enolate β-amino ketones
The Mannich reaction
• The Mannich reaction is the condensation of an enolizable carbonyl
compound with an iminium ion
• It is usually done using formaldehyde and introduces an α-dialkylaminomethyl
substituent
carbonyl group formaldehyde
as sources of
nucleophile
• The electrophile is often generated in situ from the amine and formaldehyde
Example
Acylation of carbonyl carbon nucleophiles
• It involves addition of carbon nucleophiles to carbonyl centers
having a potential leaving group. The tetrahedral intermediate
formed in the addition step reacts by expulsion of the leaving group
• The overall transformation results in the acylation of the carbon
nucleophile
Claisen and Dieckmann condensation reactions
An important group of acylation reaction which involves esters, in which the leaving
group is alkoxy or aryloxy. The self-condensation of esters is known as the Claisen
condensation
Ethyl acetoacetate, for example, is prepared by Claisen condensation of ethyl acetate
All of the steps in the mechanism are reversible, and a full equivalent of base is needed to
bring the reaction to completion
Ethyl acetoacetate is more acidic than any of the other species present and is converted to
its conjugate base in the final step. The β-ketoester product is obtained after neutralization
Ethyl acetoacetate
The intramolecular version of ester condensation is called the
Dieckmann condensation
It is an important method for the formation of five- and six-
membered rings and has occasionally been used for formation of
larger rings
Perkin aldol condensation reaction
• It is used to synthesis α,β-unsaturated aromatic acid like cinnamic
acids and thier cyclic coumarins by the aldol condensation of an
aromatic aldehyde/alkali salts of salicylaldehyde and an acid
anhydride, in the presence of an alkali salt of the acid. The alkali
salt acts as a base catalyst, and other bases can be used.
O O O O
H
H CH3COONa
H + O OH
H H -CH3COOH
Cinnamic acid
Benzaldehyde Acetic anhydride
O
O O
H CH3COONa
H + H
O -CH3COOH
O O
O Na H H
Coumarin
Sodium salt of
salicylaldhyde
Olefination reactions of stabilized carbon nucleophiles
• These rections can be used to convert a carbonyl group to an alkene by reaction with
a carbon nucleophile. In each case, the addition step is followed by an elimination leads
to formation of alkenes
The Wittig and related reactions of phosphorus-
stabilized carbon nucleophiles
The Wittig reaction involves phosphonium ylides as the nucleophilic carbon
species
An ylide is a molecule that has a contributing resonance structure with opposite
charges on adjacent atoms
Phosphonium ylides are stable, but quite reactive, compounds. They can be
represented by two limiting resonance structures, which are referred to as the
ylide and ylene forms
Preparation of phosphonium ylides
Phosphonium ylides are usually prepared by deprotonation of phosphonium
salts. The phosphonium salts are often alkyltriphenylphosphonium halides, which
can be prepared by the reaction of triphenylphosphine and an alkyl halide. The
alkyl halide must be reactive toward SN 2 displacement
General olefination reaction mechanism
Examples of Wittig reaction
