CONJUGATE ADDITION

MICHAEL ADDITION
Addition of Nucleophiles to Enones
Conjugate Addition or Michael Addition
.. .. - .. -
:O :O: : O:
C C C
C C C C + C C
+

:Nu :Nu

1,2-addition 1,4-addition

OH O
C H C
C C C C
Nu
conjugate
Nu addition
 CONJUGATE ADDITION
.. .. -
O: : O:
H C H C
C C CH3 CH3
H C C
H H H
:N C
- H-OH
:N C
..
O:
H H C
In conjugate addition CH3
H C C
the nucleophile adds
H
and then picks up a :N C
hydrogen from the
solvent medium.
 CONJUGATE ADDITION
GENERALIZATION

stereochemistry
conjugated ketone O also matters

H C R
b a
C C
H H strong direct to C=O
bases 1,2-addition

weak
nucleophiles/bases

conjugate addition
1,4-addition
 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

 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:
 ADDITION TO CARBONYL
CH3MgI
O CuCl
O
HO CH3
CH3Li (CH3)2CuLi
or or
CH3MgI (CH3)2Cd CH3
strong bases add weaker bases add
by 1,2 addition _ by 1,4 addition
O _ O
:CH3
_
:CH3
+
C-Li and C-Mg bonds are R-Cu and R-Cd bonds are
more ionic (stronger bases) more covalent (weaker bases)
 STEREOCHEMISTRY ALSO MATTERS
LARGE GROUPS ON EITHER SIDE OF THE CARBONYL FAVOR CONJUGATE ADDITION

large groups here

STERIC HINDRANCE
promote 1,4 addition

O O
CH3 H CH3
H C CH3MgBr H C
C C CH CH3 CH CH3
H C C
H H
CH H
3

large groups here can major product

Oalso promote 1,4 addition OH
H C H H C H
CH3MgBr
C C C C
H H CH3
H H

major product
large groups here
small groups here
promote 1,2 addition
make 1,2 addition
more probable
FRONTIER MO THEORY

CONJUGATED KETONES
 FRONTIER MO THEORY
NUCLEOPHILE

HOMO
LUMO
FILLED MOs

HOMO
E+ :Nu-
FILLED MOs

ELECTROPHILE
LUMO MAPPED ONTO ELECTRON
DENSITY
BLUE REPRESENTS MAXIMUM DENSITY OF LUMO
A

A B

B
 ROBINSON ANNELATION

FORMING RINGS BY COMBINING

CONJUGATE ADDITION WITH AN ALDOL CONDENSATION

METHYL VINYL KETONE (MVK)

 Conjugate Addition of Cyclopentanone to MVK
MVK
enolate
weak base methyl vinyl ketone
.. .. .. -
.. : O:
:O O: :O
H C
- H C
CH3
CH3
: C
H H H H
H-OCH3
NaOCH3
CH3OH ..
.. O:
O :O
- .. C
: O-CH
.. 3
CH2 CH2 CH3

- ..
+ : O-CH
.. 3

can continue
 ROBINSON ANNELATION
USES MVK TO BUILD A RING
FROM PREVIOUS SLIDE

O O O O
H C NaOCH3 C
CH3 CH2 CH2 CH3
CH3OH
H H
Michael
addition
O O
-: CH
-O O 2
C
CH2 CH2 O
H3O+
(workup) Annelation
(ring formation)
internal aldol condensation
 ANOTHER EXAMPLE
MICHAEL ADDITION + ALDOL CONDENSATION

2 ALDOL

O H3C O
C O NaOEt
1
CH EtOH
O CH2 O

Most acidic set

of hydrogens MICHAEL
reacts first.