The Aldol Condensation

In the presence of a strong base, two molecules of aldehyde or ketone may combine to form a b-hydroxyaldehyde or a b-hydroxyketone. This reaction is called the aldol condensation.

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The Aldol Condensation

O R CH2 C + O R CH2 C H a bhydroxyaldehyde H
base

OH R CH2 C H

O CH C R H

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Example
O CH3 C H + O NaOH CH3 C H OH CH3 C H "Aldol" O CH2 C H

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Another Example
O CH3 CH2 C H + O NaOH CH3 CH2 C H OH CH3 CH2 C H CH CH3 O C H

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One More:
O CH3 C CH3 + O NaOH CH3 C CH3 OH CH3 C CH3 "Diacetone alcohol" O CH2 C CH3

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The Aldol Condensation Reaction: Mechanism

1) : O: CH3 C 2) : O: CH3 C _ .. CH2 3) .. : O: CH3 C H H : O: C H : O: fast CH2 C + H2O H CH3 C H CH2 C H _ .. + :OH .. donor H _ .. O + : .. fast H H .. O .. .. :O : slow CH3 C H :O : CH2 C .. :O H H + H .. CH2 _ : O: C H .. _ : O: CH2 C H

an enolate ion

acceptor

: O:

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The Aldol Condensation Reaction: Mechanism

The enolate ion (carbanion) is the actual nucleophilic reagent. The reaction breaks down to the following:
The a-carbon of the donor attaches itself to the carbonyl carbon of the acceptor
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The Heart of the Mechanism

H H3C + C .. CH2 C H O donor _ acceptor _ O H H3C C CH2 C H
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_ O

The Aldol Condensation

The carbonyl group plays two roles in this reaction:

1. It provides a site for nucleophilic attack by the enolate ion. 2. It makes the a-hydrogens sufficiently acidic to enable the formation of reasonable concentrations of enolate ion.

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The Aldol Condensation

NOTE: The must be a-hydrogens in order to have an aldol condensation.

Without a-hydrogens, the only possible reaction is the Cannizarro reaction (Chapter 17, Section 17.3 -- we skipped this)

NOTE ALSO: The aldol condensation is not an end-to-end condensation!

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Dehydration of Aldol Products

Aldol products are often very easily dehydrated, yielding a,b-unsaturated aldehydes or ketones. After dehydration, the a,b-unsaturated aldehydes and ketones are stabilized by resonance, thereby providing a driving force for the dehydration.
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Dehydration of Aldol Products

O OH CH3 C H C O C CH3 I2 warm CH3 H CH3 H Mesityl oxide + CH3 C C C CH3

Note here that iodine is a sufficiently strong Lewis acid to bring about dehydration.

H2O
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Dehydration of Aldol Products

The mechanism for the dehydration is E1. The dehydration happens because the product is conjugated (i.e., resonance-stabilized)

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The Crossed Aldol Condensation

What if we tried mixing two different aldehydes (or ketones) together?

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O CH3 C + O CH3 CH2 C H H NaOH

OH CH3 CH

O CH2 C + OH O CH CH3 + C H H

CH3 CH2 CH

OH CH3 CH CH CH3 + OH CH3 CH2 CH

O C H

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CH2 C

Crossed Aldol Condensation

If both carbonyl compounds have a-hydrogens, then we cant control which is the donor and which is the acceptor. But if we choose one carbonyl compound that does not have a-hydrogens, it can only act as an acceptor. Then, but adding the donor to a dilute solution of acceptor, we can control the reaction to give only one product.
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Crossed Aldol Condensations

O C H

acceptor
OH NaOH O CH2 C H

+ O CH3 C H

C H

donor

- H2O (spontaneously)

O CH CH C H

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Cannizzaro Reaction The disproportionation reaction of aldehydes without -hydrogens in presence of a strong base to furnish an alcohol and a carboxylic acid is called Cannizzaro reaction. One molecule of aldehyde is reduced to the corresponding alcohol, while a second one is oxidized to the carboxylic acid.

The applicability of Cannizzaro reaction in organic synthesis is limited as the yield is not more than 50% for either acid or alcohol formed. In case of aldehydes that do have -hydrogens, the aldol condensation reaction takes place preferentially. The ,,-Trihalo aldehydes undergo haloform reaction in strongly alkaline medium. E.g. Choral will give chloroform in presence of an alkali. WWU -- Chemistry

Cannizzaro Reaction mechanism

Crossed Cannizzaro Reaction

O H O OH-, H2O H OH O

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The Claisen Condensation

The Claisen Ester Condensation

Esters, like aldehydes and ketones, have acidic a-hydrogens. When an ester bearing an a-hydrogen is treated with a strong base, a condensation reaction takes place to yield a b-ketoester.

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The Claisen Ester Condensation

O R CH2 C + O R CH2 C O CH2 CH3 O CH2 CH3 O NaOCH2CH3 R CH2 C O CH C R a bketoester + CH3 CH2 O H O CH2 CH3

NOTE: The alkoxide should match the alkyl group of the ester in order to avoid a competing transesterification.
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Claisen Ester Condensation -- Mechanism (Part One)

1) O CH3 C + _ .. :O .. OC2H5 fast _ : CH2 O C OC2H5
enolate ion

.. _ :O : CH2 C OC2H5

HO

C2H5

C2H5

2)

O CH3 C _ : CH2

acceptor OC2H5 slow O C OC2H5

.. _ :O: CH3 C OC2H5 O OC2H5

CH2 C

donor

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Claisen Ester Condensation -- Mechanism (Part Two)

3) .. _ :O : CH3 C OC2H5 O CH2 C OC2H5 fast

: O: CH3 C O CH2 C + _ .. :O .. OC2H5

C2H5

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The Key to Claisen Ester Condensations

The a-carbon of the donor attaches itself to the carbonyl carbon of the acceptor. The alkoxy group of the acceptor leaves to form a C=O bond.

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Dieckman Condensation
An intramolecular Claisen condensation
O Et O OEt O Die thyl h exanedioate (Dieth yl adipate) 1 . Et O Na
+

2 . H2 O, HCl O O OEt Ethyl 2-oxocyclopentanecarboxylate

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+

Et OH

Perkin reaction The Perkin reaction is an organic reaction developed by William Henry Perkin that can be used to make cinnamic acids i.e. --unsaturated aromatic acid by the aldol condensation of aromatic aldehydes and acid anhydrides in the presence of an alkali salt of the acid.

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Perkin reaction mechanism

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MANNICH REACTION
ketone formaldehyde O O excess .. pH 6-8 Et NH + C + 2 C
R CH3 H H O C CH2 CH2 NEt2 R

O C .. CH2 R
A variety of R groups may be used

+ Et C N H Et

Cl

iminium salt
Mannich Base Schiffs Base

Aldehydes other than formaldehyde may be used. The reaction works best with methyl ketones. Et2NH - HCl is generally used in excess, hence the chloride counter ion. Other secondary amines sometimes work in place of diethylamine.

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MANNICH REACTION Mechanism

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Grignard Reagent / Reactions

+ + + + +

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Grignard Reagent / Reactions

Grignard & CO2 to produce Benzoic Acid

Grignard & Ketone to Produce Tertiary Alcohol

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Grignard Reagent / Reactions

Grignard & Aldehyde to Produce Secondary Alcohol

Grignard & Formaldehyde to Produce Primary Alcohol

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Darzens reaction The Darzens reaction (also known as the Darzens condensation or glycidic ester condensation) is the chemical reaction of a ketone or aldehyde with an -haloester in the presence of base to form an ,-epoxy ester, also called a "glycidic ester".

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Darzens reaction Mechanism

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