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Chapter 7

The document discusses various reactions of carbonyl groups including addition-elimination, cyanohydrin, acetal and ketal, halogenation and alkylation, aldol condensation, Claisen-Schmidt condensation, Mannich condensation, Claisen and Dieckmann condensation, and Perkin condensation reactions.

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86 views26 pages

Chapter 7

The document discusses various reactions of carbonyl groups including addition-elimination, cyanohydrin, acetal and ketal, halogenation and alkylation, aldol condensation, Claisen-Schmidt condensation, Mannich condensation, Claisen and Dieckmann condensation, and Perkin condensation reactions.

Uploaded by

yigermalamanuel32
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© © All Rights Reserved
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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

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