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Conjugate Addition Reactions

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Conjugate Addition vs Direct Addition
What is Conjugate Addition?
Conjugate addition refers to nucleophilic addition directed to
the electrophilic carbon of the C=C (double bond) in a,bunsaturated systems
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Direct Addition vs Conjugate Addition
The Nature of the Nucleophile
Attribute

Direct Addition

Conjugate Addition

Base strength of

Nucleophiles that are

Nucleophiles that are

nucleophile

stronger bases

weaker bases

Carbanion

Organolithium (RLi) and

Organocopper

nucleophiles

Grignard reagents

reagents (R2CuLi)

(RMgBr)

Cyanide (NaCN)
Enolates

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Hetero

Amines

Thiols

nucleophiles

(RNH2)

(RSH)

Hydride

Lithium aluminium

Copper hydride

Nucleophiles

hydride (LiAlH4)

(CuH)
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Conjugate Addition Reactions
The Process
Conjugate addition can be divided into four steps:

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Conjugate Addition Reactions
Factors that Favour the Process
Since the conjugate addition is performed under protic
conditions and the nucleophile is relatively nonbasic (usually
less basic than the product enolate), the product enolate is

rapidly protonated
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For reactions with enones, the 1,2-addition is highly reversible,
whereas the 1,4-addition is much less so
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They do not react with saturated aldehydes or ketones, but
undergo conjugate-addition with a,b-unsaturated enones to
provide saturated aldehydes or ketones, respectively
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Conjugate Addition Reactions
Reactions of Organocuprates
The mechanism of the conjugate addition to enones probably
involves an initial complexation between the cuprate and the
enone
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Conjugate Addition Reactions
Reactions of Enolates
Enolates, by virtue of being resonance stabilized, are weaker
nucleophiles; consequently they undergo conjugate addition
(1,4-addition or Michael addition) reactions to a,b-unsaturated
enones
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Thermodynamic control leads to conjugate addition, but kinetic
control leads to direct attack
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This enables the conjugate
addition to compete and, as its product is more stable

(thermodynamically stable), it eventually become the sole
product
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Conjugate Addition Reactions
Reactions with Enolates
Example

The 1,5-dicarbonyl compounds arising from the conjugate
addition reactions are important intermediates in the synthesis
of complex natural products
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Robinson annulation involves the following basic steps:
(1) Michael addition \ conjugate addition \ 1,4-addition
(2) Intramolecular Aldol addition
(3) Dehydration (base-catalysed)

Example

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Robinson Annulation
Preparation of the Wieland-Miescher Ketone
The Wieland Miescher ketone used in the total synthesis of
steroids such as progesterone and testosterone is synthesized
based on the Robinson annulation reaction

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