384
NUCLEOPHILIC REACTIONS INVOLVING ENOLATE ANIONS
Box 10.13
Ester–ketone condensations: predicting the product
Let us use a systematic approach to consider what product is most likely to result when a mixture of an ester
and a ketone, both capable of forming enolate anions, is treated with base. For example, consider an ethyl
acetate–acetone mixture treated with sodium hydride in ether solution.
consider a mixed reaction between ester and ketone
e.g.
with four possible products
ketone as nucleophile
+ ketone as electrophile
ester as nucleophile
+ ester as electrophile
aldol reaction
ketone as nucleophile
+ ester as electrophile
ester as nucleophile
+ ketone as electrophile
Claisen reaction
aldol reaction
Claisen reaction
H 3 C
CH 3
OH O
H 3 C
H
H
H 3 C
OEt
O
O
H
H
H 3 C
OEt
OH O
H 3 C
H
H
H 3 C
CH 3
O
O
H
H
E
Nu
O
H 3 C
OEt
O
H 3 C
CH 3
NaH
Et 2 O
Four reactions and products can be considered, involving either ketone or ester as the nucleophile, with ketone
as the electrophile (aldol reactions) or ester as the electrophile (Claisen reactions).
Both aldol and Claisen reactions are equilibria, and product formation is a result of disturbing these equilibria.
This would be dehydration in aldol reactions and ionization in Claisen reactions. Ionization would be the more
immediate determinant. On that basis, it is obvious that the 1,3-dicarbonyl products from Claisen reactions are
going to be more acidic than the aldol products, which possess just one carbonyl group.
Now let us look at the ease of forming the enolate anion nucleophiles. Ketones are more acidic than esters
(see Section 10.7). Taken together, these factors mean the more favoured product is going to be the β-diketone
(acetylacetone), formed from a ketone nucleophile by a Claisen reaction with an ester. This is the reaction
observed.
product is β-diketone acetylacetone
electrophile
nucleophile
• ketone is more acidic than ester − ketone enolate favoured
• β-diketone is most acidic of four possible products
H 3 C
CH 3
O
O
H
H
O
H 3 C
OEt
O
H 3 C
CH 3
pK a 9
NaH
Et 2 O
H +
NUCLEOPHILIC REACTIONS INVOLVING ENOLATE ANIONS
Box 10.13
Ester–ketone condensations: predicting the product
Let us use a systematic approach to consider what product is most likely to result when a mixture of an ester
and a ketone, both capable of forming enolate anions, is treated with base. For example, consider an ethyl
acetate–acetone mixture treated with sodium hydride in ether solution.
consider a mixed reaction between ester and ketone
e.g.
with four possible products
ketone as nucleophile
+ ketone as electrophile
ester as nucleophile
+ ester as electrophile
aldol reaction
ketone as nucleophile
+ ester as electrophile
ester as nucleophile
+ ketone as electrophile
Claisen reaction
aldol reaction
Claisen reaction
H 3 C
CH 3
OH O
H 3 C
H
H
H 3 C
OEt
O
O
H
H
H 3 C
OEt
OH O
H 3 C
H
H
H 3 C
CH 3
O
O
H
H
E
Nu
O
H 3 C
OEt
O
H 3 C
CH 3
NaH
Et 2 O
Four reactions and products can be considered, involving either ketone or ester as the nucleophile, with ketone
as the electrophile (aldol reactions) or ester as the electrophile (Claisen reactions).
Both aldol and Claisen reactions are equilibria, and product formation is a result of disturbing these equilibria.
This would be dehydration in aldol reactions and ionization in Claisen reactions. Ionization would be the more
immediate determinant. On that basis, it is obvious that the 1,3-dicarbonyl products from Claisen reactions are
going to be more acidic than the aldol products, which possess just one carbonyl group.
Now let us look at the ease of forming the enolate anion nucleophiles. Ketones are more acidic than esters
(see Section 10.7). Taken together, these factors mean the more favoured product is going to be the β-diketone
(acetylacetone), formed from a ketone nucleophile by a Claisen reaction with an ester. This is the reaction
observed.
product is β-diketone acetylacetone
electrophile
nucleophile
• ketone is more acidic than ester − ketone enolate favoured
• β-diketone is most acidic of four possible products
H 3 C
CH 3
O
O
H
H
O
H 3 C
OEt
O
H 3 C
CH 3
pK a 9
NaH
Et 2 O
H +