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CONJUGATE ADDITION. MICHAEL ADDITION. Addition of Nucleophiles to Enones Conjugate Addition or Michael Addition. . . . -. -. :. :. :. :. :. +. +. :Nu. :Nu. 1,2-addition. 1,4-addition. Nu. conjugate addition. Nu. CONJUGATE ADDITION. . . -. :. :. :. -. H-OH. . :.

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CONJUGATE ADDITION

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CONJUGATE ADDITION

MICHAEL ADDITION


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Addition of Nucleophiles to Enones

Conjugate Addition or Michael Addition

..

..

..

-

-

:

:

:

:

:

+

+

:Nu

:Nu

1,2-addition

1,4-addition

Nu

conjugate

addition

Nu


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CONJUGATE ADDITION

..

..

-

:

:

:

-

H-OH

..

:

In conjugate addition

the nucleophile adds

and then picks up a

hydrogen from the

solvent medium.


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CONJUGATE ADDITION

GENERALIZATION

stereochemistry

also matters

conjugated ketone

b

a

strong

bases

direct to C=O

1,2-addition

weak

nucleophiles/bases

conjugate addition

1,4-addition


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Strong Bases : 1,2-Addition

  • Strong bases give direct addition to C=O (1,2-addition) unless

  • the C=O group is sterically hindered by large groups

Organolithium compounds RLi

Grignard reagents RMgX

Lithium Aluminum Hydride LiAlH4


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Weak Bases : 1,4-Addition

  • Good nucleophiles and weak bases give conjugate addition

  • (1,4-addition), also known as Michael Addition, especially if

  • the C=O group is hindered.

..

Amines R-NH2

Alcohols R-O-H Water H-O-H

Enolates

Organocopper and cadmium compounds

( RMgX + CuCl or CdCl2 )

Lithium dialkylcuprates

( RLi + CuCl )

Cyanide ion :C N:

..

..

..

..


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ADDITION TO CARBONYL

CH3MgI

CuCl

CH3Li

(CH3)2CuLi

or

or

CH3MgI

(CH3)2Cd

strong bases add

by 1,2 addition

weaker bases add

by 1,4 addition

C-Li and C-Mg bonds are

more ionic (stronger bases)

R-Cu and R-Cd bonds are

more covalent (weaker bases)


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STEREOCHEMISTRY ALSO MATTERS

LARGE GROUPS ON EITHER SIDE OF THE CARBONYL FAVOR CONJUGATE ADDITION

large groups here

promote 1,4 addition

STERIC HINDRANCE

major product

large groups here can

also promote 1,4 addition

major product

large groups here

promote 1,2 addition

small groups here

make 1,2 addition

more probable


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FRONTIER MO THEORY

CONJUGATED KETONES


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FRONTIER MO THEORY

NUCLEOPHILE

HOMO

LUMO

FILLED MOs

HOMO

:Nu-

E+

FILLED MOs

ELECTROPHILE


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LUMO MAPPED ONTO ELECTRON DENSITY

BLUE REPRESENTS MAXIMUM DENSITY OF LUMO

A

A

B

B


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ROBINSON ANNELATION

FORMING RINGS BY COMBINING

CONJUGATE ADDITION WITH AN ALDOL CONDENSATION

METHYL VINYL KETONE (MVK)


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-

:

O-CH3

..

Conjugate Addition of Cyclopentanone to MVK

MVK

enolate

weak base

methyl vinyl ketone

..

-

..

..

..

:

:

:

:

:

-

:

H-OCH3

NaOCH3

..

CH3OH

..

:

:

..

..

-

:

O-CH3

+

..

can continue


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ROBINSON ANNELATION

USES MVK TO BUILD A RING

FROM PREVIOUS SLIDE

NaOCH3

CH3OH

Michael

addition

-

:

-

H3O+

Annelation

(workup)

(ring formation)

internal aldol condensation


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ANOTHER EXAMPLE

MICHAEL ADDITION + ALDOL CONDENSATION

2

ALDOL

NaOEt

1

EtOH

Most acidic set

of hydrogens

reacts first.

MICHAEL


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