Created by Professor William Tam & Dr. Phillis Chang Ch. 19 Chapter 19 Chapter 19 Condensation and Condensation and Conjugate Addition Conjugate Addition Reactions of Carbonyl Reactions of Carbonyl Compounds Compounds More Chemistry of Enolates More Chemistry of Enolates
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Created by Professor William Tam & Dr. Phillis Chang Ch. 19 - 1 Chapter 19 Condensation and Conjugate Addition Reactions of Carbonyl Compounds More Chemistry.
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Created byProfessor William Tam & Dr. Phillis
Chang Ch. 19 - 1
Chapter 19Chapter 19
Condensation and Condensation and Conjugate Addition Conjugate Addition
Reactions of Carbonyl Reactions of Carbonyl CompoundsCompounds
More Chemistry of EnolatesMore Chemistry of Enolates
Ch. 19 - 2
1. Introduction Carbonyl condensation reactions.
● Claisen condensation:O
ORR'
O
ORR'
H
O
OR
O
R'
R'ROH +
+1. NaOR
2. H3O+
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An carbon anion(enolate) from oneester attacks the carbonyl of the other.
hydrogen do not undergo the usual Claisen condensation.
O
OMe
HThe carbon has only one hydrogen does not undergo the Claisen condensation using RO- (alkoxide). Use LDA, a stronger base, see slide 23. This is because an ester with only one
hydrogen will not have an acidic hydrogen when step 3 is reached, and step 3 promotes the favorable equilibrium that ensures the forward reaction.
Intramolecular (cyclic) Claisen condensation:● Dieckmann condensation.● Useful for the synthesis of five-
and six-membered rings.MeO
O O
OMe
O
OMe
O
1. NaOMe
2. H3O+
12
3
4
5
67
12
3
4
5
6 7
Ch. 19 - 16
O
OMe
O
Mechanism:
OMeMeO
O O
OMe123
4
5
67
H OMe
O
12
34
5
6
7
OMe
OO
OMe
O
OMe2
3
4
5
6 7 1
O
OMe
OH
OMe
O
OMe
O
O HH
H(This favorableequilibrium drives the reaction)
Ch. 19 - 17
Other examples:
EtO
O
OEt123456
O
1. NaOEt
2. H3O+ OEt
OO
(1)
12
34
56
Ch. 19 - 18
Other examples:
(2)MeO
O
OMe
O Me
1. NaOMe
2. H3O+
OMe
OO
MeOMe
OO
Me
not
Why?
Ch. 19 - 19
2B.2B. Crossed Claisen CondensationsCrossed Claisen Condensations Crossed Claisen condensations are
possible when one ester component has no hydrogens and, therefore, is unable to form an enolate ion and undergo self-condensation.
O
OMe
O
OMe
O
OMe
O1. NaOMe
2. H3O++
(no -hydrogen)
Ch. 19 - 20
Mechanism:
O
OMe
H
OMe+
O
OMe+ MeOH
O
OMe
O
OMe
O
OMe
O
OMe
O
H
Ch. 19 - 21
Mechanism:
O
OMe
O
H
(This favorable equilibriumdrives the reaction)
OMe
O
OMe
O
H O H
H
O
OMe
O
Ch. 19 - 22
Other examples:
O
OEtO
OEt
O
OEt
O
1. NaOEt
2. H3O+
+
(1)
(no hydrogen)
(2) O
MeO OMe
O
OMe+
1. NaOMe
2. H3O+
O
MeO OMe
O
(no carbon)
Ch. 19 - 23
Recall: esters that have only one hydrogen cannot undergo
Claisen Condensation by using sodium alkoxide.
However, they can be converted to the -keto esters by reactions that use very strong bases such as lithium diisopropyamide (LDA). LDA is strong enough to retain the anion.
Ch. 19 - 24
O
OMe
O
OMe
O
OMe
Cl
O
LDA
THF
O
Ch. 19 - 25
3. -Dicarbonyl Compounds by Acylation of Ketone Enolates
O
HH
O O
OO
NaNH2
Et2OO
Ph OMe
(kineticenolate)
slightly more acidic
Ch. 19 - 26
Intramolecular example:
Ha
O
Hb O
OMe
Hc
1234567
1. NaOMe
2. H3O+
O O
12
3 4
56
7
●The product was formed by deprotonation of Hb, the enolate formed at C5 and then adding to C1. A five membered ring is more stable than a seven membered ring.
Ch. 19 - 27
● Questions:i. Give the structure of the
product by deprotonation of Ha, and adding the resulting enolate (at C7) to C1. Explain why this product is not formed.
ii. Give the structure of the product by deprotonation of Hc, and adding the resulting enolate (at C2) to C6. Explain why this product is not formed.
Ch. 19 - 28
4. Aldol Reactions: Addition of Enolates and Enols to Aldehydes and Ketones
O
H
OH
H
O10% NaOH
H2O, 5 oC2
The product contains both an aldehyde and an alcohol functional group.
Therefore: aldol addition
Ch. 19 - 29
4A.4A. Aldol Addition ReactionsAldol Addition Reactions Mechanism of the aldol addition:
O
H
O
HH
HO
O
H
O
H+ H2O
O
H
OHO H
O
H
OH
+ HO
Shown on slide 3.
Ch. 19 - 30
4B.4B. The Retro-Aldol ReactionThe Retro-Aldol Reaction
Mechanism for reverse aldol:
OOH OHO
H2O2
OO
HO
HOO O
O
+
HO HO
+HO
Ch. 19 - 31
4C.4C. Aldol Condensation Reactions: Aldol Condensation Reactions: Dehydration of the Aldol Addition Dehydration of the Aldol Addition ProductProduct
Dehydration of the aldol product.●Base catalyzed aldol
condensation:O
H
OH
HOH
O
H+ H2O + OH
Aldol product.
This dehydration is easier than normal because the double bond is conjugated with the carbonyl.